Substituted derivatives of 4-aminocyclohexane

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of general formula (1), which possess affinity for µ-opioid receptor and ORL1-receptor, to medications, containing said compounds, and to application of said compounds for obtaining medications, suitable for treating pain, fear, stress and other diseases or conditions. In general formula (1) Y1, Y1', Y2, Y2', Y3, Y3', Y4 and Y4' stand for -H; R1 and R2 independently on each other stand for -H or -CH3; on condition that R1 and R2 both simultaneously do not stand for -H; Q stands for: -C6-16-aryl, non-substituted or mono- or poly-substituted with -F, -Cl, -Br or -I; or heteroaryl; R3 stands for: -C1-8-alkyl, non-substituted or mono- or poly-substituted -OR0, where R0 stands for non-substituted -C1-3-alkyl; non-substituted -C3-6-cycloalkyl-C1-4-alkyl; non-substituted -C1-4-alkyl-C3-6-cycloalkyl; -C6-16-aryl, non-substituted or mono- or poly-substituted with -F, -Cl, -Br, -I, -CN, -R0 or -OR0, where R0 stands for non-substituted -C1-8-alkyl; or heteroaryl; n stands for 0; X stands for -NRA-; RA stands for -H or -R0; where R0 stands for non-substituted -C1-4-alkyl; and RB stands for -C(=O)R0; where R0 stands for non-substituted -C2-8-alkenyl-C6-16-aryl or non-substituted -C1-8-alkyl-(C6-16-aryl)1-2.

EFFECT: obtaining compounds for obtaining medications, suitable for treatment of pain, fear, stress and other diseases or conditions.

10 cl, 14 tbl, 164 ex

 

The present invention relates to substituted derivatives of cyclohexane, which have affinity to the µ-opioid receptor and the receptor ORL1, to the way they are received, medicines containing these compounds and to the use of these compounds to obtain drugs.

Derivatives of cyclohexane, which have affinity to the µ-opioid receptor and receptor ORL1, known from the prior art. In this regard, in full you can make reference, for example, in 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 006/108565, WO 2007/079927, WO 007/079928, WO 007/079930, WO 007/079931, WO 007/124903, WO 008/009415 and WO 008/009416.

However, the known compounds in some respects are not satisfactory, and there is a need for other compounds with comparable or improved properties.

Thus, the known compounds in suitable assays binding sometimes show some affinity to the hERG ion channel, calcium ion channel L-type (sites linking phenylalkylamine, benzodiazepine, dihydropyridines), respectively, for sodium channel in VTH analysis (batrachotoxin), which in each case can be explained as symptoms of cardiovascular adverse action is th. Further, many known compounds have negligible solubility in aqueous media, in particular, can have a negative impact on bioavailability. In addition, the chemical stability of the known compounds is often insufficient. Thus, sometimes the connection doesn't show enough of pH stability, resistance to UV, respectively, resistance to oxidation, which in particular may adversely affect the stability during storage, and oral bioavailability. Further known compounds 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 the known compounds. Improved metabolic stability may be reflected in increased bioavailability. Weak or absent interaction with molecules-carriers, which are involved in the receipt and allocation of drugs, should be regarded as an indication of improved bioavailability and, in any case, minor drug interactions. Next as well as possible minor must be interaction with enzymes involved in the breakdown and excretion of drugs, such as Raza is taty tests likewise show that, in any case, you should expect a slight or even absent drug interactions.

Further known compounds sometimes show very little selectivity in respect of the Kappa-opioid receptor, which is responsible for side effects, especially dysphoria, sedation, diuresis. In addition, the known connection sometimes show a very high affinity for µ-opioid receptor, which is associated with other adverse effects, particularly such as respiratory depression, constipation and drug dependency.

WO 01/87838 reveals antagonists of NK-1-receptor.

J. Med. Chem. 1996, 9, 911-920; J. Am. Chem. Soc. 1950, 72, 2411-2417; and Tetrahedron 2006, 62, 5536-5548 in each case, in particular reveal gemenele substituted cyclohexyl-1,4-diamines, however, in which the amino group is always replaced by hydrogen atoms.

DE 28 39 891 A1 in particular, discloses 4-(dimethylamino)-1-methyl-4-µ-tollcollect acetate.

The basis of the invention lies task is to provide compounds which are suitable for pharmaceutical purposes and have advantages in comparison with the compounds of the prior art.

This problem is solved by the object presented in the claims.

It has been unexpectedly discovered that can be obtained substituted derivatives of cyclohexane, which have sredstv the m to µ-opioid receptor and the receptor ORL1.

The invention relates to compounds of General formula (1),

where

Y1, Y1', Y2, Y2', Y3, Y3', Y4and Y4' in each case independently of one another selected from the group consisting of-H, -F, -Cl, -Br, -I, -CN, -NO2, -Cho, -R0, -C(=O)R0, -C(=O)H, -C(=O)-OH, -C(=O)OR0, -C(=O)NH2, -C(=O)other0, -C(=O)N(R0)2, -OH, -OR0, -OC(=O)H, -OC(=O)R0, -OC(=O)OR0, -OC(=O)other0, -OC(=O)N(R0)2, -SH, -SR0, -SO3H, -S(=O)1-2-R0, -S(=O)1-2NH2, -NH2-The other0, -N(R0)2, -N+(R0)3, -N+(R0)2O-, -NHC(=O)R0, -NHC(=O)OR0, -NHC(=O)NH2, -NHC(=O)other0, -NHC(=O)N(R0)2; mainly in each case independently of one another selected from the group consisting of-H, -F, -Cl, -CN and-C1-8-alipac; or Y1and Y1'or Y2and Y2'or Y3and Y3'or Y4and Y4' together denote=0;

Q means-R0, -C(=O)-R0, -C(=O)OR0, -C(=O)other0, -C(=O)N(R0)2or-C(=NH)-R0;

R0in each case, independently means-From1-8-lifat, -C3-12-cycloaliphatic, -aryl, -heteroaryl, -C1-8-alipac-C3-12-cycloaliphatic, -C1-8-alipac-aryl, -C1-8-alipac-heteroaryl, -C3-8-cycloolefin-C1-8-lifat, -C3.8-qi is lolitat-aryl or-C 3.8-cycloolefin-heteroaryl;

R1and R2independently from each other denote H or-R0; or R1and R2together form a ring and denote-CH2CH2Och2CH2-, -CH2CH2NR4CH2CH2- or -(CH2)3-6-; indicating that R2mostly both at the same time does not mean ' N;

R3means R0;

R4in each case independently denotes-H, -R0or-C(=O)R0;

n means an integer from 0 to 12; mainly means 0;

X represents-O-, -S - or-NRA-; mostly means-NRA-;

RAmeans-N, -R0, -S(=O)0-2R0, -C(=O)R0, -C(=O)OR0, -C(=O)NH2, -C(=O)other0or-C(=O)N(R0)2;

RBmeans-H, -R0, -C(=O)H, -C(=O)R0, -C(=O)OH, -C(=O)OR0, -C(=O)NH2, -C(=O)other0, -C(=O)N(R0)2l-S(=O)1-2-R0l-S(=O)1-2-OR0, -S(=O)1-2-NH2, -S(=O)1-2-Other0or-S(=O)1-2-N(R0)2; or RAand Rb together form a ring and denote -(CH2)2-5-, -CH2CH2Och2CH2- or-CH2CH2NR4CH2CH2-; indicating that if X is-O - and at the same time n is 0, then Rb is not means-N;

and

"Halifat" in each case represents a branched or nerazvit the military, saturated or mono - or multiply unsaturated, unsubstituted or mono - or multiply substituted, aliphatic hydrocarbon residue;

"cycloaliphatic" in each case saturated or mono - or multiply unsaturated, unsubstituted or mono - or multiply substituted, epicycle, mono - or multicyclone hydrocarbon residue, the number of cyclic carbon atoms which is mostly in the specified range (i.e. "C3-8"Cycloolefin mainly has 3, 4, 5, 6, 7 or 8 cyclic carbon atoms);

and regarding "Halifat and cycloolefin" under the "mono - or multiply substituted" refers to single or multiple substitution of one or more hydrogen atoms, for example, single, double, triple or complete substitution, the substituents independently of one another selected from the group consisting of-F, -Cl, -Br, -I, -CN, -N02, -CHO,=O, -R0, -C(=O)R0, -C(=O)H, -C(=O)OH, -C(=O)OR0, -C(=O)NH2, -C(=O)other0, -C(=O)N(R0)2)-OH, -OR0, -OC(=O)H, -OC(=O)R0, -OC(=O)OR0, -OC(=O)other0, -OC(=O)N(R0)2, -SH, -SR0, -SO3H, -S(=O)1-2-R0, -S(=O)1-2NH2, -NH2-The other0, -N(R0)2, -N+(R0)3, -N+(R0)2O-, -NHC(=O)R0, -NHC(=O)OR0, -NHC(=O)NH2, -NHC(=O)-other0, -NH-C(=O)N(R0)20)3, -PO(OR0)2;

"aryl" in each case independently denotes carbocyclic ring system with at least one aromatic ring, but without heteroatoms in this ring, and aryl residues optionally may be condensed with other saturated, (partially) unsaturated or aromatic ring systems, and each aryl residue can be unsubstituted or mono - or multiply substituted, and aryl substituents may be the same or different and in any and possible position of the aryl;

"heteroaryl" means a 5-, 6 - or 7-membered cyclic aromatic residue, which contains 1, 2, 3, 4 or 5 heteroatoms, where the heteroatoms are identical or different nitrogen, oxygen or sulfur, and the heterocycle may be unsubstituted or mono - or multiply substituted; and in the case of substitution of the heterocycle, the substituents may be the same or different and in any and possible position of heteroaryl; and the heterocycle can also be part of a bicyclic or polycyclic system;

with respect to "aryl" and "heteroaryl" under the "mono - or multiply substituted" refers to single or multiple substitution of one or more hydrogen atoms of the ring system substituents, selected from the group Castiadas-F, -Cl, -Br, -I, -CN, -NO2, -CHO,=O, -R0, -C(=O)R0, -C(=O)H, -C(=O)OH, -C(=O)OR0, -C(=O)NH2, -C(=O)other0, -C(=O)-N(R0)2, -OH, -0(CH2)i.20-, -OR0, -OC(=O)H, -OC(=O)R0, -OC(=O)OR0, -OC(=O)other0, -OC(=O)N(R0)2, -SH, -SR0, -SO3H, -S(=O)1-2-R0, -S(=O)1-2NH2, -NH2-The other0, -N(R0)2l-N+(R0)3, -N+(R0)2O-, -NHC(=O)R0, -NHC(=O)OR0, -NH-C(=O)NH2, -NHC(=O)other0, -NHC(=O)N(R0)2, -Si(R0)3, -PO(OR0)2and if necessary, the existing N-ring atoms in each case may be oxidized (N-oxide);

in the form of a single stereoisomer or mixtures thereof, the free compounds and/or their physiologically compatible salts and/or solvate, preferably excluded 4-(dimethylamino)-1-methyl-4-µ-tollcollect acetate and its salts.

When the compilation of the various residues, for example, Y1, Y1', Y2, Y2', Y3, Y3', Y4and Y4'a generalization of residues in their substituents, such as, for example, -OR0, -OC(=O)R0, -OC(=O)other0one Deputy, for example, R0for two or more residues, e.g.,- OR0, -OC(=O)R0, -OC(=O)other0within one substance can take different values.

Compounds according to the invention shows the indicate good binding to the ORL1 receptor and µ-opioid receptor.

In one preferred form of implementation of the compounds according to the invention have a ratio of ORL1/μ-affinity of at least 0.1. The ratio of ORL1/(defined as 1/[Ki(ORL1)/Ki(µ)]. Particularly preferably, the ratio of ORL1/(is at least 0.2 or at least 0.5, and preferably at least 1.0 or, at least, to 2.0, more preferably at least 3.0, or at least about 4.0, most preferably at least 5.0 or at least 7.5 and in particular at least 10 or at least 15. In one preferred form of implementation, the ratio of ORL1/(is in the range from 0.1 to 30, preferably from 0.1 to 25.

In one preferred form of implementation of the compounds according to the invention have a ratio of ORL1/μ-affinity of more than 30, preferably at least 50, more preferably at least 100, most preferably at least 200, and in particular at least 300.

Compounds according to the invention preferably have Kivalue (- opioid receptors at most 500 nm, preferably at most 100 nm, more preferably 50 nm, most preferably at most 10 nm and in particular at most 1.0 nm.

Methods for the determination of Kivalues in µ-opioid receptors known special is STU in the art. Preferably, the identification is performed, as described in connection with examples.

Compounds according to the invention preferably have Kivalue ORL1-receptor at most 500 nm, is preferable to the more than 100 nm, more preferably 50 nm, most preferably at most 10 nm and in particular at most 1.0 nm.

Methods for the determination of Kivalues for the ORL1-receptor well-known specialist in this field of technology. Preferably, the identification is performed, as described in connection with examples.

It was unexpectedly found that compounds with affinity for ORL1 - and µ-opioide receptor, which is defined by 1/[Ki(ORL1)/Ki(µ)] the ratio of the ORL1 (ranges from 0.1 to 30, mainly from 0.1 to 25, have a pharmacological profile that is compared to another ligand of the opioid receptor has clear advantages:

1. Compounds according to the invention demonstrate efficacy in models of acute pain, which is sometimes comparable with commonly used stage-3 opioids. But at the same time they differ clearly improved! compatibility in terms of classical µ-opioids.

2. In contrast to commonly used stage-3 opioid compounds according to the invention show a clearly higher efficient models mononeuropathies pain and polyneuropathies bol is, because of the synergism ORL1 - and µ-opioid component.

3. In contrast to commonly used stage-3 opioid compounds according to the invention in neuropathic animals show a significant, preferably full, split intelligencesm respectively antihyperalgesic actions and antinociceptive effect.

4. In contrast to commonly used stage-3 opioid compounds according to the invention in animal models for chronic inflammatory pain (in particular, the carrageenan-induced or CFA-induced hyperalgesia, visceral inflammatory pain) show a clear enhanced activity against acute pain.

5. In contrast to commonly used stage-3 opioids typical µ-opioid side effects (in particular, the respiratory depression caused by opioid hyperalgesia, physical dependence/withdrawal, psychological dependence/mania) in the compounds according to the invention in a therapeutically effective dose interval is clearly reduced, respectively, mostly not observed.

On the basis of reduced µ-opioid side effects on the one hand and increased efficiency in chronic, preferably neuropathic pain, on the other hand mixed ORL1/μ-agonists thus differ clearly age is sponding intervals of safety in comparison with pure μ-opioids. From this it follows clearly increased "therapeutic window" in the treatment of painful conditions, preferably chronic pain, more preferably neuropathic pain.

Preferred Y1, Y1', Y2, Y2', Y3, Y3', Y4and Y4' in each case independently of one another selected from the group consisting of-H, -F, -Cl, -Br, -I, -CN, -NH2, -NH-C1-6-lifat, -NH-C3-8-cycloaliphatic, -NH-C1-6-alipac-OH, -N(C1-6-alipac)2, -N(C3-8-cycloolefin)2, -N(C1-6-alipac-OH)2, -NO2, -NH-C1-6-alipac-C3-8-cycloaliphatic, -NH-C1-6-alipac-aryl, -NH-C1-6-alipac-heteroaryl, -NH-aryl, -NH-heteroaryl, -SH, -S-C1-6-lifat, -S-C3-8-Cycloaliphatic, -S-C1-6-alipac-C3-8cycloolefin, -S-C1-6-alipac-aryl, -S-C1-6-alipac-heteroaryl, -S-aryl, -S-heteroaryl, -OH, -O-C1-6-lifat, -O-C3-8-Cycloaliphatic, -O-C1-6-alipac-OH, -O-C1-6-alipac-C3-8-cycloaliphatic, -O-C1-6-alipac-aryl, -O-C1-6-alipac-heteroaryl, -O-aryl, -O-heteroaryl, -O-C(=O)1-6-lifat, -O-C(=O)3-8-cycloaliphatic, -O-C(=O)1-6-alipac-OH, -O-C(=O)1-6-alipac-C3-8-cycloaliphatic, -O-C(=O)C1-6-alipac-aryl, -O-C(=O)C1-6-alipac-heteroaryl, -O-C(=O)aryl, -O-C(=O)heteroaryl, -C1-6-lifat, -C3-8-cycloaliphatic, -C1-6-alipac-C3-8cycloolefin, -C1-6-alipac-aryl, -C1-6-alipac-heteroaryl, -aryl, -heteroaryl, -C(=O)1-6-lifat, -C(=O)3-8-cycloaliphatic, -C(=O)1-6-alipac-C3-8-cycloaliphatic, -C(=O)1-6-alipac-aryl, -C(=O)1-6-alipac-heteroaryl, -C(=O)aryl, -C(=O)heteroaryl, -CO2H, -CO2-C1-6-lifat, -CO2-C3-8-cycloaliphatic, -CO2-C1-6-alipac-C3-8-cycloaliphatic, -CO2-C1-6-alipac-aryl, -CO2-C1-6-alipac-heteroaryl, -CO2-aryl, -CO2-heteroaryl; or Y1and Y1'or Y2and Y2'or Y3and Y3'or Y4and Y4' together denote=0. Preferred Yi, Y1', Y2, Y2', Y3, Y3', Y4and Y4' in each case independently of one another selected from the group consisting of-H, -F, -Cl, -Br, -I, -CN, -NH2and-HE.

In one preferred form of implementation of one of the remnants of Yi, Yi', Y2, Y2', Y3, Y3', Y4and Y4' not equal to H and the remaining remnants of the mean-N.

Particularly preferably, Y1, Y1', Y2, Y2', Y3, Y3', Y4and Y4' in each case denote-N.

Preferably Q implies R0, -C(=O)R0or-C(=NH)R0. Particularly preferably Q means-C1-8-lifat, -aryl, -heteroaryl, -C1-8-alipac-aryl, -C1-8-alipac-heteroaryl, -C(=O)-C1-8-lifat, -C(=O)-aryl, -C(=O)-heteroaryl, -C(=O)-C1-8-alipac-aryl, -C(=O)-C1-8-alipac-heteroaryl, -C(=NH)-C1-8-lifat, -C(=NH)-apnn-C(=NH)-heteroaryl, -C(=NH)-C1-8-alipac-aryl, or-C(=NH)-C1-8-alipac-heteroaryl.

Particularly preferably Q means-From1-8-lifat, -aryl, -heteroaryl, -C1-8-alipac-aryl, -C(=O)-heteroaryl or-C(=NH)-heteroaryl.

At the same time-aryl and-heteroaryl in each case may be unsubstituted or mono - or multiply substituted, mainly substituents, which independently of each other selected from the group consisting of-C1-8-lifat, -OH, -OC1-8-lifat, -C1-8-alipac-O-C1-8-alipac (for example, -CH2-O-CH3), -CF3, -F, -DM, -Br, -NO2, -CN, -heteroaryl, -C1-8-alipac-aryl and-C1-8-alipac-heteroaryl.

In one preferred form of implementation of the Q selected from the group consisting of-C1-8-alkyl, -phenyl, -benzyl, -pyrrolyl, -furyl, -thienyl, pyridyl, -indolyl, -benzofuran and-benzothiazyl, and in each case may be unsubstituted or mono - or multiply substituted, mainly substituents, which independently of each other selected from the group consisting of-C1-8-lifat, -OH, -OC1-8-lifat, -C1-8-alipac-O-C1-8-lifat, -CF3, -F, -Cl, -Br, -NO2, -CN, -heteroaryl, -C1-8-alipac-aryl and-C1-8-alipac-heteroaryl (for example, -ethyl-4-pyridyl). Particularly preferably Q is selected from the group consisting of:

R0preferably in each case independently denotes-C1-8-lifat, -C3-12-cycloaliphatic, -aryl, -heteroaryl, -C1-8-alipac-C3-12-cycloaliphatic, -C1-8-alipac-aryl or-C1-8-alipac-heteroaryl. This means-From1-8-alipac-C3-12cycloolefin, -C1-8-alipac-aryl or-C1-8-alipac-heteroaryl that remains-From3-12-cycloaliphatic, -aryl or-heteroaryl in each case linked through a divalent bridge-C1-8-alipac-. Preferred examples of-C1-3-alipac-aryl are-CH2-C6H5, -CH2CH2-C6H5and-CH=CH-C6H5.

Preferably R1and R2independently from one another denote H; -C1-6-alipac; -C3-8-cycloaliphatic, -C1-6-alipac-aryl, -C1-6-alipac-C3-8-cyclea is IFAT or-C 1-6-alipac-heteroaryl; or residues R1and R2together form a ring and denote-CH2CH2Och2CH2-, -CH2CH2NR4CH2CH2- or -(CH2)3-6-, indicating that R1and R2mostly both at the same time mean-N. Preferably R1and R2independently of one another denote H; -C1-5-alipac; or residues R1and R2together form a ring and denote-CH2CH2Och2CH2-, -CH2CH2NR4-CH2CH2-or -(CH2)3-6-, and R4preferably means is N or-C1.5-lifat, indicating that R1and R2mostly both at the same time mean-N. Especially preferred compounds, where R1and R2independently of one another denote-CH3or N, and R1and R2not both-H mean; or R1and R2form a ring and denote -(CH2)3-4. Highly preferred compounds, where R1and R2mean-CH3or where R1means N and R2means-CH3.

Particularly preferably R1and R2together with the nitrogen atom to which they are attached, form one of the following functional groups:

Preferably R3OZNA the AET-C 1-8-lifat, -C3-8-cycloaliphatic, -aryl, -heteroaryl; or in each case means a-C1-3-alipac group associated-aryl, -heteroaryl or-C3-8-cycloolefin.

Particularly preferably R3means-ethyl, -propyl, -butyl, -pentyl, -hexyl, -heptyl, -cyclopentyl, -cyclohexyl, -phenyl, -benzyl, -naphthyl, -anthracene-thiophenyl-benzothiophenes, -furyl, -benzofuranyl, -benzodioxolyl, -indolyl, -indanyl, -benzodioxane, -pyrrolyl, -pyridyl, pirimidil or pyrazinyl, in each case unsubstituted or mono - or multiply substituted; saturated, unbranched-C1-3-alipac group associated With5-6-cycloaliphatic, -phenyl, -naphthyl, -anthracene-thiophenyl-benzothiophenes, -pyridyl, -furyl, -benzofuranyl, -benzodioxolyl, -indolyl, -indanyl, -benzodioxane, -pyrrolyl, pirimidil, -triazolyl or pyrazinyl, in each case unsubstituted or mono - or multiply substituted.

More preferably R3means-propyl, -butyl, -pentyl, -hexyl, -phenyl, -furyl, -thiophenyl, -naphthyl, -benzyl, -benzofuranyl, -indolyl, -indanyl, -benzodioxane, -benzodioxolyl, -pyridyl, pirimidil-pyrazinyl, -triazolyl or benzothiophene, in each case unsubstituted or mono - or multiply substituted; saturated, unbranched-C1-3-alipac group associated-phenyl, -furyl or-thiophenyl, who each case unsubstituted or mono - or multiply substituted.

More preferably R3means-propyl, -butyl, -pentyl, -hexyl, -phenyl, -phenethyl-thiophenyl, -pyridyl, -triazolyl-benzothiophene or benzyl, in each case substituted or unsubstituted, particularly preferably means-propyl, -3-methoxypropyl, -butyl, -pentyl, -hexyl, -phenyl, -3-were, -3-forfinal, -benzo[1,3]-dioxolan-thienyl-benzothiophenes, -4-chlorbenzyl, -benzyl, -3-Chlorobenzyl-4-methylbenzyl, -2-Chlorobenzyl-4-tormentil, -3-methylbenzyl, -2-methylbenzyl, -3-tormentil, -2-tormentil, -1-methyl-1,2,4-triazolyl or phenethyl.

Highly preferably, R3means-butyl, -ethyl, -3-methoxypropyl-benzothiophenes, -phenyl, -3-were, -3-forfinal, -benzo[1,3]-dioxole, -benzyl, -1-methyl-1,2,4-triazolyl-thienyl or phenethyl.

Most preferably R3means-phenyl, -benzyl or-phenethyl, in each case unsubstituted or ring mono - or multiply substituted; -C1-5-lifat, -C4-6-cycloaliphatic, -pyridyl, -thienyl, -thiazolyl-imidazolyl, -1,2,4 triazolyl or benzimidazolyl, unsubstituted or mono-or multiply substituted.

Particularly preferably R3means-phenyl, -benzyl, -phenethyl-thienyl, -pyridyl, -thiazolyl-imidazolyl, -1,2,4 triazolyl, -benzimidazolyl or É, unsubstituted or mono - or multiply substituted by-F, -Cl, -Br, -CN, -CH3- 2H , -NH2, -NO2, -SH, -CF3, -OH, -och3, -OS2H5or-N(CH3)2; -ethyl, n-propyl, -2-propyl, allyl, n-butyl, -ISO-butyl, sec-butyl, tert-butyl, -n-pentyl-one-of pentyl, -neo-pentyl, -n-hexyl-cyclopentyl or cyclohexyl, in each case unsubstituted or mono - or multiply substituted by-OH, -och3or-OC2H5and mostly-thienyl, -pyridyl, -thiazolyl-imidazolyl, -1, 2, 4 triazolyl and-benzimidazolyl are unsubstituted.

Particularly preferably, R3 is phenyl, unsubstituted or mono substituted by-F, -Cl, -CN, -CH3; -thienyl; -ethyl, n-propyl or n-butyl, unsubstituted or mono - or multiply substituted by-co3HE or-OC2H5especially through-och3.

Preferably R4means-H, -C1-5-lifat, -C3-8-cycloaliphatic, -aryl, -heteroaryl, -C1-6-alipac-aryl, -C1-6-alipac-C3-8-cycloaliphatic, -C1-6-alipac-heteroaryl, -C(=O)aryl, -C(=O)heteroaryl, or-C(=O)1-6-lifat, preferably denotes-H or-C1-5-alipac.

Preferably n means an integer from 0 to 6, preferably means 0,1, 2 or 3, more preferably denotes 0 or 1, particularly preferably n=0.

Preferably RBmeans-H, -C1-6-lifat, -C3-8-cycloalkyl is t, -C1-6-alipac-C3-8-cycloaliphatic, -C1-6-alipac-aryl, -C1-6-alipac-heteroaryl, -aryl, -heteroaryl, -C(=O)H, -C(=O)1-6-lifat, -C(=O)3-8-cycloaliphatic, -C(=O)C1-6-alipac-C3-8-cycloaliphatic, -C(=O)1-6-alipac-aryl, -C(=O)C1-6-alipac-heteroaryl, -C(=O)-C3-8-cycloaliphatic-aryl, -C(=O)-C3-8-cycloolefin-heteroaryl, -C(=O)aryl, -C(=O)heteroaryl, -C(=O)HE, -CO2-C1-6-lifat, -CO2- C3-8-Cycloaliphatic, -CO2-C1-6-alipac-C3-8-cycloaliphatic, -CO2-C1-6-alipac-aryl, -CO2-C1-6-alipac-heteroaryl, -CO2-aryl, -CO2-heteroaryl, -C(=O)NH2-C(=O)N1-6-lifat, -C(=O)N3-8-cycloaliphatic, -C(=O)NHC1-6-alipac-C3-8-cycloaliphatic, -C(=O)N1-6-alipac-aryl, -C(=O)N1-6-alipac-heteroaryl, -C(=O)N, -C(=O)N, -C(=O)N(C1-6-alipac)2, -C(=O)N(C3-8-cycloolefin)2-C(=O)N(C1-6-alipac-C3-8-cycloolefin)2-C(=O)N(C1-6-alipac-aryl)2-C(=O)N(C1-6-alipac-heteroaryl)2-C(=O)N(aryl)2, -C(=O)N(heteroaryl)2, -S(=O)1-2-C1-6-lifat, -S(=O)1-2-C3-8-Cycloaliphatic, -S(=O)1-2-C1-6-alipac-C3-8-cycloaliphatic, -S(=O)1-2-C1-6-alipac-aryl, -S(=O)1-2-C1-6-alipac-heteroaryl, -S(=O)1-2-C3-8-cycloaliphatic-aryl, -S(=O)1-2-C3-8-the CEC is kalifat-heteroaryl-S(=O) 1-2-aryl, -S(=O)1-2-heteroaryl, -S(=O)1-2-OC1-6-lifat, -S(=O)1-2-OS3-8-cycloaliphatic, -S(=O)1-2-OS1-6-alipac-C3-8-Cycloaliphatic, -S(=O)1-2-OS1-6-alipac-aryl, -S(=O)1-2-OS1-6-alipac-heteroaryl, -S(=O)1-2-Oeil, -S(=O)1-2-Heteroaryl, -S(=O)1-2-NH2l-S(=O)1-2-NHC1-6-lifat, -S(=O)1-2-N3-8-cycloaliphatic, -S(=O)1-2-NH1-6-alipac-C3-8-cycloaliphatic, -S(=O)1-2-NHC1-6-alipac-aryl, -S(=O)1-2-NC1-6-alipac-heteroaryl, -S(=O)1-2-NHap, -S(=O)1-2-NH-heteroaryl, -S(=O)1-2-N(C1-6-alipac)2, -S(=O)1-2-N(C3-8-cycloolefin)2, -S(=O)1-2(C1-6-alipac-C3-8-cycloolefin)2, -S(=O)1-2-N(C1-6-alipac-aryl)2, -S(=O)1-2-N(C1-6-alipac-heteroaryl)2, -S(=O)1-2-N(aryl)2or-S(=O)1-2-N(heteroaryl)2.

Particularly preferably RInmeans-H, -C1-8-lifat, -C1-8-alipac-aryl, -C1-8-alipac-heteroaryl, -C(=O)-C1-8-lifat, -C(=O)-C1-8-alipac-aryl, -C(=O)-C1-8-alipac-heteroaryl, -C(=O)-C3-8-cycloaliphatic-aryl, -C(=O)-C3-8-cycloolefin-heteroaryl, -C(=O)NH-C1-8-lifat, -S(=O)1-2-C1-8-lifat, -S(=O)1-2-aryl, -S(=O)1-2-heteroaryl, -S(=O)1-2-C1-8-alipac-aryl, -S(=O)1-2-C1-8-alipac-heteroaryl, -(=O) 1-2-C3-8-cycloaliphatic-aryl or-S(=O)1-2-C3-8-cycloolefin-heteroaryl.

Preferably X is-O - or-NRA-, particularly preferably means-NRA-.

If X represents-O-, RBpreferably not means-N. If RBmeans-N, n preferably is 1, 2, 3 or 4. If X represents-O-, n preferably denotes 0 or 1 and RBpreferably means-C1-8-alipac or-C1-8-alipac-aryl.

If X is-NRA-, RAmeans-N, -R0, -S(=O)0-2R0, -C(=O)R0, -C(=O)OR0, -C(=O)NH2, -C(=O)other0or-C(=O)N(R0)2; means preferably-H or-R0(in particular, C1-8-alipac); particularly preferably denotes-H or-CH3; or RAtogether with RBforms a ring and means -(CH2)3-4-.

Preferably the group RB-X-(CH2)n-means

Preferred representatives of the groups -(CH2)n-NH-C(=O)-C1-8-alipac-aryl are presented below:

In one preferred form of implementation of the compounds according to the invention is RA=RB. In another preferred form of the westline compounds according to the invention is R A≠RB.

In one particularly preferred form of implementation of the compounds according to the invention is n=0 and X is-NRA-. Then we are talking about gemenele disubstituted 1,4-diamines of General formula (1.1),

moreover, at least one of the two amino groups, mainly the two amino groups, may not simultaneously, respectively, can be replaced by two hydrogen remains.

In order to describe the hydrocarbon residues are divided into aliphatic hydrocarbon residues with one hand and aromatic hydrocarbon residues from the other side.

Aliphatic hydrocarbon residues with their side is divided into acyclic aliphatic hydrocarbon residues with one hand (="Halifat") and cyclic aliphatic hydrocarbon residues, i.e. alicyclic hydrocarbon residues, on the other hand (="cycloaliphatic"). Cycloaliphatic can be monocyclic or multicyclone. Alicyclic hydrocarbon residues (cycloolefin") include both pure aliphatic carbocycle and aliphatic heterocycles, i.e - if not specified - covers "cycloaliphatic" pure aliphatic carbocycle (e.g., cyclohexyl), pure aliphatic heterocycles (for example, piperidyl or piperazin), as well as non-aromatic, multicyclone,if necessary, mixed systems (e.g., declines, decahydroquinoline).

Aromatic hydrocarbons with his hand subdivided into carbocyclic aromatic hydrocarbons with one hand (="aryl") and heterocyclic aromatic hydrocarbons on the other hand (="heteroaryl").

Ordering multicyclonic, at least partially aromatic systems mainly depends on whether at least one aromatic ring multicyclonic system, at least one heteroatom (typically N, O or S) in the ring. If this ring has at least one heteroatom, preferably it is about "heteroaryl" (even if necessary, as additional existing cycle multicyclonic system has more carbocyclic aromatic or non-aromatic ring with or without heteroatoms); if one of, if necessary, multiple aromatic rings multicyclonic system such heteroatom is absent, it is preferably about the "aryl" (even if one optionally available, non-aromatic cycle multicyclonic system there is a ring heteroatom).

Within the cyclic substituents accordingly is preferably operates the following priority order: heteroaryl>aryl>cycloolefin.

For the purposes of the description of the conceptual dif is t monovalent and polyvalent, for example, divalent hydrocarbon residues, i.e. covers "With1-3-alipac", depending on the semantic relationships, such as With1-3-alkyl, -C1-3alkenyl and-C1-3-quinil, and, for example, -C1-3-alkylene-, -C1-3-albaniles - and C1-3-akinyan-.

Preferably alift in each case is a branched or unbranched, saturated or mono - or multiply unsaturated, unsubstituted or mono - or multiply substituted, aliphatic hydrocarbon residue. Because alipac is mono - or multiply substituted, the substituents independently of one another selected from the group consisting of-F, -Cl, -Br, -I, -CN, -NO2, -CHO,=O, -R0, -C(=O)R0, -C(=O)-OH, -C(=O)OR0, -C(=O)NH2, -C(=O)other0, -C(=O)N(R0)2, -OH, -OR0, -OC(=O)H, -OC(=O)R0)-OC(=O)OR0, -OC(=O)-other0, -OC(=O)N(R0)2, -SH, -SR0, -SO3H, -S(=O)1-2-R0, -S(=O)1-2NH2, -NH2-The other0, -N(R0)2. -N+(R0)3, -N+(R0)2O-, -NHC(=O)R0, -NHC(=O)OR0, -NHC(=O)NH2, -NHC(=O)other0, -NH-C(=O)N(R0)2, -Si(R0)3, -PO(OR0)2. Thus "Halifat" includes acyclic saturated or unsaturated hydrocarbon residues, which may be branched or straight chain, i.e. alcalali, alkenyl and alkinyl. This and kenely have at least one carbon-carbon double bond and alkinyl at least one carbon-carbon triple bond. Preferred unsubstituted monovalent aliphati include-CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)2- (CH3)3, -CH2CH2CH2-CH2CH3and-CH2CH2-CH2CH2CH2CH3; and-CH=CH2, -C=CH, -CH2CH=CH2, -CH=CH-CH3, -CH2C=CH, -C=CLO3and-CH=CHCH=CH2. Preferred unsubstituted divalent aliphati include-CH2-, -CH2CH2-, -CH2CH(CH3)-, -CH(CH3)-CH2-, -CH2CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH(CH3)-CH2-, -CH2CH2CH(CH3)-, -CH-(CH2CH3)CH2- and-CH2CH2-CH2CH2-; and-CH=CH-, -C=C-, -CH2CH=CH-, -CH=SNSN2-, -CH2C=C - and-C=C-CH2-. Preferred substituted monovalent aliphati include-CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, -CH2OH, -CH2CH2OH, -CH2CHOHCH3, -CH2OCH3and CH2CH2OCH3. Preferred substituted divalent Alif what you include-CF 2-, -CF2CF2-, -CH2SNON-, -SNONCE2- and-CH2SNONCE2-. Especially preferred methyl, ethyl, n-propyl and n-butyl.

Preferably cycloolefin in each case is a saturated or mono - or multiply unsaturated, unsubstituted or mono - or multiply substituted, aliphatic (i.e. non-aromatic), mono - or multicylinder hydrocarbon residue. The number of cyclic carbon atoms, is mostly in the specified range (i.e. "C3-8"cycloolefin has mainly 3, 4, 5, 6, 7 or 8 cyclic carbon atoms). For the purposes of the description "3-8-cycloolefin" is preferably a cyclic hydrocarbon with 3, 4, 5, 6, 7 or 8 cyclic carbon atoms, saturated or unsaturated but non-aromatic, and optionally one or two carbon atoms independently from each other substituted with one heteroatom S, N or O. Since cycloalkyl is mono - or multiply substituted, the substituents independently of one another selected from the group consisting of-F, -Cl, -Br, -I, -CN, -NO2, -Cho,=0, -R0, -C(=O)R0-C(=O)HE, -C(=O)OR0, -C(=O)NH2, -C(=O)other0, -C(=O)N(R0)2>-OH, -OR0, -OC(=O)H, -OC(=O)R0, -OC(=O)OR0, -OC(=O)other0, -OC(=O)-N(R0)2, -SH, -SR0, -SO3H, -S(=O)1-2-R0, -S(=O)1-2NH2, -NH2-The other0, -N(R0 )2, -N+(R0)3, -N+(R0)2O-, -NHC(=O)R0, -NHC(=O)OR0, -NHC(=O)NH2, -NHC(=O)other0, -NH-C(=O)N(R0)2, -Si(R0)3, -PO(OR0)2. Preferably3.8-cycloolefin selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctanol and tetrahydropyranyl, dioxane, dioxolane, morpholine, piperidine, piperazinil, pyrazolinone and pyrrolidinyl.

Preferably in connection with the "alfacom" respectively "cycloaliphatic" under the "mono - or multiply substituted" understand mono - or multiple substitution, e.g. single, double, triple or quadruple substitution, one or more hydrogen atoms by F, -Cl, -Br, -I, -OH, -OC1-6-alkyl, -OC(=O)1-6-alkyl, -SH, -NH2, -NHC1-6-alkyl, -N(C1-6-alkyl)2-C(=O)OC1-6-alkyl or-C(=O)IT. The preferred connection, where "Halifat substituted or cycloolefin substituted" means alipac or cycloolefin substituted by-F, -Cl, -Br, -I, -CN, -CH3- 2H5, -NH2,-NO2, -SH, -CF3, -OH, -och3, -OS2H5or-N(CH3)2. Particularly preferred substituents are F, -Cl, -OH, -SH, -NH2and-C(=O)HE.

On the multiply substituted residues understand these residues, either in different or the same atoms are substituted several times, for example twice or three times, for example, three times in the same C-atom, as in the case of CF3or-CH2CF3or in different places, as in the case of-CH(OH)-CH=CH-CHCl2. Multiple substitution can occur are the same or different substituent. If necessary, one Deputy on its part can also be replaced; so-Olivet in particular, covers-och2CH2O-CH2CH2-HE. Preferably, if alipac or cycloolefin substituted by-F, -Cl, -Br, -I, -CN, -CH3- 2H5, -NH2, -NO2, -SH, -CF3, -OH, -OCH3, -OS2H5or-N(CH3)2. Highly preferably, if alipac or cycloolefin substituted by-OH, -och3or-OS2H5.

Preferably the aryl in each case independently denotes carbocyclic ring system with at least one aromatic ring, but without heteroatoms in this ring, and aryl residues optionally may be condensed with other saturated, (partially) unsaturated or aromatic ring systems, and each aryl residue can be unsubstituted or mono - or multiply substituted, and aryl substituents can be the same and different and in any and possible position of the aryl. The preferred Allami are phenyl, naphthyl, anthracene, Phenanthrenyl, Fiorentini, feranil, indanyl and tetralinyl. Particularly preferred phenyl and naphthyl. As the aryl is mono - or multiply substituted, the aryl substituents can be the same or different and in any and possible position of the aryl, and independently from each other selected from the group consisting of-F, -Cl, -Br, -I, -CN, -NO2, -SNO,=O, -R0, -C(=O)R0, -C(=O)OH, -C(=O)OR0, -C(=O)-NH2, -C(=O)other0, -C(=O)N(R0)2, -OH, -0(CH2)1-20-, -OR0, -OC(=O)H, -OC(=O)R0, -OC(=O)OR0, -OC(=O)-other0, -OC(=O)N(R0)2, -SH, -SR0, -SO3H, -S(=O)1-2-R0, -S(=O)1-2NH2, -NH2-The other0, -N(R0)2, -N+(R0)3, -N+(R0)2O-, -NHC(=O)R0, -NHC(=O)OR0, -NHC(=O)NH2, -NHC(=O)other0, -NH-C(=O)N(R0)2, -Si(R0)3, -PO(OR0)2. Preferred substituted 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-chlorophenyl, 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.

Suppose the equipment heteroaryl means a 5-, 6 - or 7-membered cyclic aromatic residue, which contains 1, 2, 3, 4 or 5 heteroatoms, where the heteroatoms identically or differently represent a nitrogen, oxygen or sulfur, and the heterocycle may be unsubstituted or mono - or multiply substituted; and in the case of substitution of the heterocycle, the substituents may be the same or different and in any and possible position of heteroaryl; and the heterocycle can also be part of a bicyclic or polycyclic system. Preferably heteroaryl selected from the group consisting of pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothiazyl, benzothiadiazoles, benzoxadiazole, benzothiazolyl, benzoxazolyl, benzotriazolyl, benzodioxolyl, benzodioxane, phthalazine, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazoles,purinol, indolizinyl,chinoline,ethenolysis,hintline, carbazolyl, phenazines, phenothiazines or oxadiazolyl, and communication can occur via any possible ring member of the heteroaryl residue. Because heteroaryl is mono - or multiply substituted, the heteroaryl, the substituents may be the same or different and in any and possible position of heteroaryl, and independently from each other selected from groups who, consisting of-F, -Cl, -Br, -I, -CN, -NO2, -SNO,=O, -R0, -C(=O)R0-C(=O)HE, -C(=O)OR0, -C(=O)-NH2, -C(=O)other0, -C(=O)N(R0)2, -OH, -O(CH2)1-2O-, -OR0, -OC(=O)H, -OC(=O)R0, -OC(=O)OR0, -OC(=O)other0, -OC(=O)-N(R0)2, -SH, -SR0, -SO3H, -S(=O)1-2-R0, -S(=O)1-2NH2, -NH2-The other0, -N(R0)2, -N+(R0)3, -N+(R0)2O-, -NH-C(=O)R0, -NHC(=O)OR0, -NHC(=O)NH2, -NHC(=O)other0, -NH-C(=O)N(R0)2, -Si(R0)3, -PO(OR0)2.

As for the "aryl" or "heteroaryl", "mono - or multiply substituted" understand single or multiple, for example double, triple, quadruple or quintuple the substitution of one or more hydrogen atoms of the ring system.

Especially preferred are the substituents of the aryl and heteroaryl in each case independently from each other selected from-F, -Cl, -Br, -I, -CN, -Cho, -CO2H, -NH2, -NO2-The other0, -N(R0)2, -N+(R0)3, -N+(R0)2O-, -SH, -SR0, -OH, -OR0, -C(=O)R0, -CO2R0, -C(=O)NH2, -C(=O)other0, -C(=O)N(R0)2, -S(=O)1-2R0, -S(=O)2NH2l-SO3H=O or-R0. Preferred substituents are F, -Cl, -Br, -I, -OH, -OC1-6-alkyl, -O-C(=O)-C1-6-Alki is, -SH, -NH2, -NHC1-6-alkyl, -N(C1-6-alkyl)2-C(=O)OS1-6-alkyl or-C(=O)OH. The preferred connection, where "aryl substituted" or "heteroaryl substituted" means aryl or heteroaryl substituted by-F, -Cl, -Br, -I, -CN, -CH3- 2H5, -NH2,-NO2, -SH, -CF3, -OH, -och3, -OS2H5or-N(CH3)2. Particularly preferred substituents are F, -CL, -OH, -SH, -NH2and-C(=O)HE.

Compounds according to the invention can be in the form of a single stereoisomer or mixtures thereof, the free compounds and/or their physiologically compatible salts and/or solvate.

Compounds according to the invention, depending on the sample substituent can be chiral or achiral.

Compounds according to the invention, depending on the substitution relative to the cyclohexane ring can represent isomers, in which a sample of the substituent in the 1,4-position 1-position:>C(NR1R)R3; 4-position:>CQ((CH2)nXRB) can also be denoted by SYN/anti. "SYN/anti isomers" are a subgroup of stereoisomers (configuration isomers).

In one preferred form of implementation, the excess of diastereoisomers SYN-isomer is at least 50%de, preferably at least 75%de, more preferably, by at least 90%de, most preferably at least 95%de and in particular at least 99%de. In one preferred form of implementation is the excess of diastereomers anti-isomer, at least 50%de, preferably at least 75%de, more preferably at least 90%de, most preferably at least 95%de and in particular at least 99%de.

Suitable methods of separation of isomers (diastereomers) is known to the person skilled in the art. As examples may be given: column chromatography, preparative HPLC and the methods of crystallization.

If the compounds according to the invention are chiral, mostly they are in the form of a racemate or in enriched form enantiomer. In one preferred form of implementation is the excess of the enantiomers (S)-enantiomer, at least 50%, preferably at least 75%, more preferably at least 90%, most preferably at least 95%and especially at least 99%EE. In one preferred form of implementation, the excess of the enantiomers (R-enantiomer is at least 50%, preferably at least 75%, more preferably at least 90%, most preferably at least 95%and in particular less the th least 99%of it.

Suitable methods for the separation of enantiomers is known to the person skilled in the art. As examples can be named by preparative HPLC on chiral stationary phases and transferred in diastereomeric intermediate products. Moving in diastereomeric intermediate products can occur, for example, as salt formation with a chiral, enantiomerically pure kilole separation educated so diastereomers salt then can be converted to a free base or another salt.

If not definitely specified, each reference to the compounds according to the invention includes all isomers (e.g., stereoisomers, diastereomers, enantiomers in any ratio of components of the mixture.

If not definitely specified, each reference to the compounds according to the invention of the available connections (i.e. forms that are not in the form of a salt) and all physiologically compatible salts.

For the purposes of describing physiologically compatible salts of the compounds according to the invention are in the form of salts with anions or acids of the corresponding compounds with inorganic respectively organic acids which are physiologically compatible, especially when used in humans and/or mammals.

Examples of physiologically compatible is Olga specific acids are salts of: 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, monomethylaniline acid, 5-oxo-Proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3 - or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid, a-lipanova acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid. Especially preferred hydrochloride, citrate, and polycitra.

Physiologically compatible salts with cations or bases are salts of the respective compounds as anion with at least one, mainly inorganic, cation, which are physiologically compatible, especially when used in humans and/or mammals. Especially preferred salts are alkali and alkaline earth metals, and ammonium salts, but in particular salts (mono-) or (di-) sodium, (mono) or (di-) potassium, magnesium or calcium.

Further illustrated is preferred in each case form the implementation of the compounds according to the invention. If not definitely specified, then the all in each case explained earlier about the determining of the substituents (i.e. for example, R0to R4from Yi to Y4', etc. Q), respectively, and their respective preferred forms of implementation and are therefore not repeated.

A preferred form of implementation of the compounds according to the invention of General formula (1) have the General formula (2):

and

(hetero-)aryl means heteroaryl or aryl; preferably phenyl; in each case unsubstituted or mono - or multiply substituted with substituents mostly independently from each other selected from the group consisting of-F, -Cl, -Br, -I, -CN, -N02, -Cho, -R0, -C(=O)R0-C(=O)H, -C(=O)HE, -C(=O)OR0, -C(=O)NH2, -C(=O)NH-R0, -C(=O)-N(R0)2, -OH, -0(CH2)i.20-, -OR0, -OC(=O)H, -OC(=O)R0, -OC(=O)OR0, -OC(=O)other0, -OC(=O)N(R0)2, -SH, -SR0, -SO3H, -S(=O)1-2-R0, -S(=O)1-2NH2, -NH2-The other0, -N(R0)2, -N+(R0)3, -N+(R0)2O-, -NHC(=O)R0, -NHC(=O)-OR0, -NH-C(=O)NH2, -NHC(=O)other0and-NHC(=O)N(R0)2; preferably-F, -Cl, -Br, -I, -CF3, -CN and-N02.

Particularly preferred form of implementation of the compounds according to the invention of General formula (2) have the General formula (2.1), (2.2), (2.3), (2.4), (2.5), (2.6), (2.7), (2.8), (2.9), (2.10), (2.11), (2.12), (2.13) or (2.14):

and

Rcmeans-H, -F, -Cl, -Br, -I, -CN, -NO2, -CF3HE or-OCH3; and, if available, (hetero-)aryl means heteroaryl or aryl; preferably means phenyl, -benzyl or-2-indolyl; in each case unsubstituted or mono - or multiply substituted with substituents mostly independently from each other selected from the group consisting of-F, -Cl, -Br, -I, -CN, -NO2, -Cho, -R0, -C(=O)R0, -C(=O)H, -C(=O)HE, -C(=O)OR0, -C(=O)NH2, -C(=O)-NH-R0-C(=O)-N(R0)2, -OH, -O(CH2)1-2O-, -OR0, -OC(=O)H, -OC(=O)R0, -OC(=O)OR0, -OC(=O)other0, -OC(=O)N(R0)2, -SH, -SR0l-SO3H, -S(=O)1-2-R0, -S(=O)1-2NH2, -NH2-The other0, -N(R0)2, -N+(R0)3, -N+(R0)2O-, -NHC(=O)R0, -NHC(=O)-OR0, -NH-C(=O)NH2, -NHC(=O)other0and-NHC(=O)N(R0)2; preferably-F, -Cl, -Br, -I, -CF3, -CN and-NO2; and

m means 0,1, 2, 3, 4, 5 or 6.

The preferred representation is the prevalence of the compounds of General formula (2.14) are for example, the connection from E-1 to E-12:

Other preferred forms of implementation of the compounds according to the invention of General formula (1) have the General formula (3):

and

Q' means -(CH2)0-4-, -C(=O)- or-C(=NH)-; and

(hetero-)aryl means heteroaryl or aryl; preferably phenyl; in each case unsubstituted or mono - or multiply substituted with substituents mostly independently from each other selected from the group consisting of-F, -Cl, -Br, -I, -CN, -N02, -CHO, -R0, -C(=O)R0, -C(=O)H, -C(=O)OH, -C(=O)OR0, -C(=O)NH2, -C(=O)NH-R0, -C(=O)-N(R0)2, -OH, -0(CH2)1-2O-, -OR0, -OC(=O)H, -OC(=O)R0, -OC(=O)OR0, -OC(=O)other0, -OC(=O)N(R0)2, -SH, -SR0, -SO3H, -S(=O)1-2-R0, -S(=O)1-2NH2, -NH2-The other0, -N(R0)2, -N+(R0)3, -N+(R0)2O-, -NHC(=O)R0l-NHC(=O)-OR0, -NH-C(=O)NH2, -NHC(=O)other0and-NHC(=O)N(R0 )2; preferably-F, -Cl, -Br, -I, -CF3, -CN and-N02.

Particularly preferred form of implementation of the compounds according to the invention of General formula (3) have the General formula (3.1), (3.2), (3.3), (3.4), (3.5), (3.6), (3.7) or (3.8):

moreover, if there is,

D is =O or =NH;

W denotes-O-, -S-, -NR11-, -CR12=CR13-, -CR12=N - or-N=CR13means; means preferably-O-, -S-, or-NRn-; especially preferably means-NR11-;

R5, R6, R6', R11, R12and R13in each case, independently of one another denote-H, -F, -Cl, -Br, -I, -CN, -NO2, -CHO, -R0, -C(=O)R0, -C(=O)H, -C(=O)OH, -C(=O)OR0, -C(=O)NH2, -C(=O)other0, -C(=O)-N(R0)2, -OH, -O(CH2)1-2O-, -OR0, -OC(=O)H, -OC(=O)R0, -OC(=O)OR0, -OC(=O)other0, -OC(=O)N(R0)2, -SH, -SR0, -SO3H, -S(=O)1-2-R0, -S(=O)1-2NH2, -NH2-The other0, -N(R0)2, -N+(R0)3, -N+(R0)2O-, -NHC(=O)R0, -NHC(=O)OR0, -NH-C(=O)NH2, -NHC(=O)other0, -NHC(=O)N(R0 )2; or R5and R6or R6and R6' or R6'and R12together form a five-membered or six-membered, saturated, partially unsaturated, aromatic, unsubstituted or mono - or multiply substituted ring which optionally includes one or two heterocyclic atom, independently from each other selected from N, S and O;

A1means-N=or-CR7=,

And2means-N=or-CR8=,

And3means-N=or-CR9=,

And4means-N=or-CR10=;

indicating that at most two of the residues of A1And2And3and a4mainly mean 0,1 or 2 residues of A1And2And3and a4mean-N=;

R7, R6, R9and R10in each case, independently of one another denote-H, -F, -Cl, -Br, -I, -NO2, -CF3, -OR14, -SR14, -SO2R14, -CN, -COOR14, -CONR14, -NR15R16,=O or-R0; mostly means-F, -Cl, -Br, -I, -CF3l-CN or-NO2;

R14in each case independently denotes H or-R0;

R15and R16independently of one another denote H or-R0; or R15and R16together denote-CH2CH2Och2CH2-, -CH2CH2NR4CH2CH2- or -(CH2)3-6-.

If W means, voltage is emer, -CR12=CR13-, -CR12=N - or-N=CR13-we get mainly the following functional groups:

If R6and R6' together form, for example, six-membered aromatic ring which has no heterocyclic atoms in each case are the following functional groups:

Educated together, if necessary, by R5and R6or R6and R6'or R6' and R12five-membered or six-membered, saturated, partially unsaturated or aromatic ring can include one or two heterocyclic atom, which independently from each other selected from N, S and O. the formed ring can be unsubstituted or mono - or multiply substituted with substituents mostly independently from each other selected from the group consisting of-F, -Cl, -Br, -I, -CN, -NO2, -Cho, -R0, -C(=O)R0-C(=O)H, -C(=O)HE, -C(=O)OR0, -C(=O)NH2, -C(=O)other0-C(=O)-N(R0)2, -OH, -O(CH2)1-2O-, -OR0, -OC(=O)H, -OC(=O)R0, -OC(=O)OR0, -OC(=O)other0, -OC(=O)N(R0)2, -SH, -SR0, -SO3H, -S(=O)1-2-R0, -S(=O)1-2NH2, -NH2-The other0 , -N(R0)2, -N+(R0)3, -N+(R0)2O-, -NHC(=O)R0, -NHC(=O)OR0, -NH-C(=O)NH2, -NHC(=O)other0and-NHC(=O)N(R0)2; preferably-F, -Cl, -Br, -I, -CF3, -CN and-NO2.

Preferably R5means-H, -F, -Cl or-R0; preferably denotes-H, -F, -C1-8-lifat, -C1-8-alipac-aryl, -C1-8-alipac-heteroaryl or-C1-8-alipac-O-CL-in-alipac (for example, -CH2Och3).

Preferably, Re and R6 together form a six-membered, saturated, partially unsaturated or aromatic ring, which may optionally include one or two heterocyclic atom, which independently from each other selected from N, S and O. This formed ring can be unsubstituted or mono - or multiply substituted with substituents mostly independently from each other selected from the group consisting of-F, -Cl, -Br, -I, -CN, -N02, -CHO, -R0, -C(=O)R0l-C(=O)H, -C(=O)OH, -C(=O)OR0, -C(=O)NH2, -C(=O)other0, -C(=O)-N(R0)2, -OH, -0(CH2)1-2O-, -OR0, -OC(=O)H, -OC(=O)R0, -OC(=O)OR0, -OC(=O)other0l-OC(=O)-N(R0)2, -SH, -SR0, -SO3H, -S(=O)1-2-R0, -S(=O)1-2NH2, -NH2-The other0, -N(R0)2, -N+(R0)3, -N+(R0)2O-, -NHC(=O)R0l-NHC(=O)OR0, -NH-C(=O)NH2, NHC(=O)other 0and-NHC(=O)N(R0)2; preferably-F, -Cl, -Br, -I, -CF3, -CN and-NO2.

R11, R12and R13mostly independently from each other selected from the group consisting of-H, -F, -Cl, -CN, -OH, -R0and-OR0. Particularly preferred R11, R12and R13 - if there is - in each case.

Other preferred forms of implementation of the compounds according to the invention of General formula (1) have the General formula (4):

and

(hetero-)aryl means heteroaryl or aryl; preferably phenyl; in each case unsubstituted or mono - or multiply substituted with substituents mostly independently from each other selected from the group consisting of-F, -Cl, -Br, -I, -CN, -N02, -CHO, -R0, -C(=O)R0, -C(=O)H, -C(=O)OH, -C(=O)OR0, -C(=O)NH2, -C(=O)NH-R0, -C(=O)-N(R0)2, -OH, -0(CH2)1-20-, -OR0, -OC(=O)H, -OC(=O)R0, -OC(=O)OR0l-OC(=O)other0, -OC(=O)N(R0)2, -SH, -SR0, -SO3H, -S(=O)1-2-R0, -S(=O)1-2NH2, -NH2-The other0, -N(R0)2, -N+(R0)3, -N+(R0)2O-, -NHC(=O)R0, -NHC(=O)-OR0, -NH-C(=O)NH2, -NHC(=O)other0and-NHC(=O)N(R0)2; preferably-F, -Cl, -Br, -I, -CF3, -CN and-NO2.

Compounds according to the invention are defined by substituents, for example, through R1,R 2and R3(Deputy of the 1st generation), which on its part optionally substituted (the substituents of the 2nd generation). Depending on the definition of these substituents of substituents on its part can be substituted (the substituents of the 3rd generation). If, for example, Y1=-R0and R0=-C1-8-alipac (Deputy of the 1st generation),- C1-8-alipac its part may be substituted by, for example, through-OR0and R0=-aryl (Deputy 2nd generation). From this we obtain the functional group-C1-8-alipac-Oail. Then-aryl its part can be substituted, for example, through-Cl (Deputy 3rd generation). Then the whole thing is a functional group-C1-8-alipac-Oeil-Cl.

However, in one preferred form of implementation of the deputies of the 3rd generation may not be re-substituted, i.e. then there are no substituents at the 4-th generation.

In one preferred form of implementation of the deputies of the 2nd generation may not be re-substituted, i.e. then there are no substituents at the 3-th generation. In other words, in this form of implementation of functional groups for R0to YV in each case optionally can be substituted, but then respective deputies never can be again replaced by the output.

In one preferred form of implementation of already deputies of the 1st generation cannot be again substituted, i.e. then there is no Vice-2nd or Vice-3rd generation. In other words, in this form of implementation of functional groups for R0to Y4' in each case may not be replaced.

According to the invention a particularly preferred form of implementation of the compounds of General formula (1) are compounds of General formula (2.2)

and

Q means-C1-8-alipac (mostly C1-8-alkyl), -aryl (mostly-phenyl), -C1-8-alipac-aryl (mostly C1-8-alkyl-phenyl)- heteroaryl (mostly-indolyl), -C(=O)-heteroaryl (mainly-C(=O)-indolyl) - or-C(=NH)-heteroaryl (mainly-C(=NH)-indolyl);

R1means-CH3;

R2means-N or-CH3; or

R1and R2together form a ring and denote -(CH2)3-4-;

X represents-O - or-NRA-;

RAmeans-N or-C1-8-alipac (mostly1-8-alkyl);

RBmeans-H, -C1-8-alipac (mostly C1-8-alkyl), -C1-8-alipac-aryl (mostly C1-8-alkyl-phenyl), -C1-8-alipac-heteroaryl (mostly C1-8-alkyl-indolyl), -C(=O)-C1-8-is left (mainly-C(=O)-C 1-8-alkyl), -C(=O)-C1-8-alipac-aryl (mainly-C(=O)-benzyl), -C(=O)-C1-8-alipac-heteroaryl (mainly-C(=O)-C1-8-alkyl-indolyl), -C(=O)-C3-8-cycloaliphatic-aryl (mainly-C(=O)-cyclopropyl-aryl), -C(=O)-C3-8-Cycloolefin-heteroaryl (mainly-C(=O)-cyclopropyl-heteroaryl), -C(=O)NH-C1-8-alipac (mainly-C(=O)NH-C1-8-alkyl), -S(=O)1-2-C1-8-alipac(mostly-S(=O)2-C1-8-alkyl), -S(=O)1-2aryl (mostly-S(=O)2-phenyl), -S(=O)1-2-heteroaryl, -S(=O)1-2-C1-8-alipac-aryl, -S(=O)1-2-C1-8-alipac-heteroaryl, -S(=O)1-2-C3.8-cycloaliphatic-aryl (mostly-S(=O)2-cyclopropyl-aryl) or-S(=O)1-2-C3-8-cycloolefin-heteroaryl (mostly-S(=O)2-cyclopropyl-heteroaryl); or RAand Rb together form a ring and denote -(CH2)3-4-; indicating that if X is-O - and at the same time n means O, RBdoes not mean ' N;

Rc denotes-H, -F, -Cl, -Br, -I, -CN, -NO2, -CF3HE or-och3; and

n means 0,1, 2, 3 or 4;

alipac, aryl and heteroaryl in each case are unsubstituted or mono - or multiply substituted.

Highly preferred compounds from the group:

-1-(imino(1-methyl-1H-indol-2-yl)methyl)-N1,N1,N4,N4-tetramethyl-4-phenylcyclohexane-1,4-diamine is IP(2-hydroxypropan-1,2,3-tricarboxylate);

-4-(dimethylamino)-4-phenyl-1-(pyrrolidin-1-yl)cyclohexyl)(1-methyl-1H-indol-2-yl)methanon;

-1-(imino(1-methyl-1H-indol-2-yl)methyl)-N1,N1,N4,N4-tetramethyl-4-phenylcyclohexane-1,4-diamine bis(2-hydroxypropan-1,2,3-tricarboxylate);

-1,4-bis(dimethylamino)-4-phenylcyclohexyl)(1-methyl-1H-indol-2-yl)methanon;

-4-(imino(1-methyl-1H-indol-2-yl)methyl)-N,N-dimethyl-1-phenyl-4-(pyrrolidin-1-yl)cyclohexanamine;

-4-(dimethylamino)-4-phenyl-1-(pyrrolidin-1-yl)cyclohexyl)(1-methyl-1H-indol-2-yl)methanon;

-N1,N1,N4-trimethyl-1,4-diphenylsiloxane-1,4-diamine;

-N1,N1,N4,N4-tetramethyl-1,4-diphenylsiloxane-1,4-diamine;

-1-benzyl-N1,N1,N4,N4-tetramethyl-4-phenylcyclohexane-1,4-diamine;

-4-methoxy-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexane 2-hydroxypropan-1,2,3-tricarboxylate;

-4-(benzyloxy)-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexane;

-4-ethoxy-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexane 2-hydroxypropan-1,2,3-tricarboxylate;

-N-((-4-(dimethylamino)-1-methyl-4-phenyl cyclohexyl)methyl)ndimethylacetamide 2-hydroxypropan-1,2,3-tricarboxylate;

-4-chloro-N-((-4-(dimethylamino)-1-methyl-4-phenylcyclohexyl)methyl)benzosulfimide 2-hydroxypropan-1,2,3-tricarboxylate;

-N-((1-butyl-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-4-chlorobenzenesulfonamide 2-hydroxypropan-1,2,3-tricarboxylate;

-N-((-4-(dimethylamino)-4-phenyl-1-(4-shall Tilbury)cyclohexyl)methanol;

-N(4-((dimethylamino)methyl)-N,N-dimethyl-1,4-diphenylsiloxane;

-4-benzyl-4-((dimethylamino)methyl)-N,N-dimethyl-1-phenylcyclohexane;

-4-(((1H-indol-2-yl)methylamino)methyl)-N,N,4-trimethyl-1-phenylcyclohexylamine;

-N1,N1,N4,N4-tetramethyl-1-(3-methyl-1H-indol-2-yl)-4-phenylcyclohexane-1,4-diamine;

-N-(4-(dimethylamino)-1-(3-methyl-1H-indol-2-yl)-4-phenylcyclohexyl)-N-medicority amide;

-N-(4-(dimethylamino)-1-(3-methyl-1H-indol-2-yl)-4-phenyl cyclohexyl)-N-methylacetamide;

-[4-benzyl-4-(dimethylaminomethyl)-1-phenyl-cyclohexyl]-dimethyl-amine

-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-dimethyl-amine (non-polar diastereoisomer)

-(E)-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-phenyl-acrylamide (non-polar diastereoisomer)

-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-ndimethylacetamide (non-polar diastereoisomer)

-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-methanesulfonic acid amide (polar diastereoisomer)

-(E)-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-phenyl-acrylamide (polar diastereoisomer)

-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-ndimethylacetamide (polar diastereoisomer)

-3-benzyl-1-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-1-methyl-urea (non-polar diastereoisomer)

-3-benzyl-1-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-1-methyl-urea (polar diastereoisomer)

-1-(4-dimethylamino-1,4-diphenyl-cyclohex the l)-3-ethyl-1-methyl-urea (non-polar diastereoisomer)

-1-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-3-ethyl-1-methyl-urea (polar diastereoisomer)

-(4-benzyl-4-((dimethylamino)methyl)-N-methyl-1-phenylcyclohexylamine (polar diastereoisomer)

-(1-benzyl-4-dimethylamino-4-phenyl-cyclohexyl)-methyl-dimethyl-amine (polar diastereoisomer)

-[4-(dimethyl-amino)-4-(3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-[4-dimethylamino-4-(3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-[4-(dimethylaminomethyl)-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-dimethyl-(4-methylamino-4-phenyl-1-thiophene-2-yl-cyclohexyl)-amine (non-polar diastereoisomer)

-dimethyl-(4-methylamino-4-phenyl-1-thiophene-2-yl-cyclohexyl)-amine (polar diastereoisomer)

-[4-(dimethyl-amino)-4-phenyl-1-thiophene-2-yl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-(4-dimethylamino-4-phenyl-1-thiophene-2-yl-cyclohexyl)-dimethyl-amine (non-polar diastereoisomer)

-(E)-N-[[4-dimethylamino-4-(3-forfinal)-1-methyl-cyclohexyl]-methyl]-3-phenyl-acrylamide (polar diastereoisomer)

-(E)-N-[[4-dimethylamino-4-(3-forfinal)-1-methyl-cyclohexyl]-methyl]-3-phenyl-acrylamide (non-polar diastereoisomer)

-(E)-N-[[4-dimethylamino-4-(3-forfinal)-1-methyl-cyclohexyl]-methyl]-2-phenyl-atenololbuy acid amide (non-polar diastereoisomer)

-(E)-N-[[4-dimethylamino-4-(3-forfinal)-1-methyl-C is clohessy]-methyl]-2-phenyl-atenololbuy acid amide (polar diastereoisomer)

-(1-butyl-4-methylamino-4-phenyl-cyclohexyl)-dimethyl-amine (non-polar diastereoisomer)

-(1-butyl-4-methylamino-4-phenyl-cyclohexyl)-dimethyl-amine (polar diastereoisomer)

-[4-(butyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-[4-(butyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-[4-(benzyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-[4-(benzyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-N-[4-(dimethyl-amino)-1,4-diphenyl-cyclohexyl]-N-methyl-2,2-diphenyl-ndimethylacetamide (polar diastereoisomer)

-dimethyl-[4-(3-methyl-1H-indol-2-yl)-1-phenyl-4-pyrrolidin-1-yl-cyclohexyl]-unindividualized (polar diastereoisomer)

-dimethyl-[4-(3-methyl-1H-indol-2-yl)-1-phenyl-4-pyrrolidin-1-yl-cyclohexyl]-amine

-[4-(azetidin-1-yl)-4-(3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-methanesulfonic acid amide (non-polar diastereoisomer)

-(4-butyl-4-dimethylamino-1-phenyl-cyclohexyl)-dimethyl-amine (non-polar diastereoisomer)

-(4-butyl-4-dimethylamino-1-phenyl-cyclohexyl)-dimethyl-amine (polar diastereoisomer)

-[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-methyl-amine (non-polar diastereoisomer)

-[4-(cyclopentyl-mate is)-4-dimethylamino-1-phenyl-cyclohexyl]-methyl-amine (polar diastereoisomer)

-[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-(E)-N-[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-N-methyl-3-phenyl-acrylamide (non-polar diastereoisomer)

-(E)-N-[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-N-methyl-3-phenyl-acrylamide (polar diastereoisomer)

-2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-acetic acid (polar diastereoisomer)

-2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-acetic acid (non-polar diastereoisomer)

-[1-(4-methoxyphenyl)-4-methylamino-4-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-[1-(4-methoxyphenyl)-4-methylamino-4-phenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-dimethyl-[4-methylamino-4-phenyl-1-[4-(trifluoromethyl)-phenyl]-cyclohexyl]-amine (non-polar diastereoisomer)

-dimethyl-[4-methylamino-4-phenyl-1-[4-(trifluoromethyl)-phenyl]-cyclohexyl]-amine (polar diastereoisomer)

-[4-(dimethyl-amino)-4-phenyl-1-[4-(trifluoromethyl)-phenyl]-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-[4-dimethylamino-4-phenyl-1-[4-(trifluoromethyl)-phenyl]-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-[4-(dimethyl-amino)-1-(4-methoxyphenyl)-4-phenyl-cyclohexyl]-dimethyl-amine (polar dieste Eomer)

-[4-dimethylamino-1-(4-methoxyphenyl)-4-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-[4-[(1H-indol-3-yl-methylamino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-[4-[(1H-indol-3-yl-methylamino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-[4-[(1H-indol-3-yl-methyl-methyl-amino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-[4-[(1H-indol-3-yl-methyl-methyl-amino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-[3-[[[4-(dimethyl-amino)-1-methyl-4-phenyl-cyclohexyl]-methyl-methyl-amino] methyl]-1H-indol-1-yl]-methanol (polar diastereoisomer)

-(E)-N-[4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-phenyl-cyclohexyl]-N-methyl-3-phenyl-acrylamide (polar diastereoisomer)

-[4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-phenyl-cyclohexyl]-methyl-amine (polar diastereoisomer)

-[4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-phenyl-cyclohexyl]-methyl-amine (non-polar diastereoisomer)

-benzyl-[4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-phenyl-cyclohexyl]-amine; 2-hydroxy-propane-1,2,3-tricarboxylic acid

-dimethyl-[4-[methyl-(pyridine-3-yl-methyl)-amino]-1,4-diphenyl-cyclohexyl]-amine (polar diastereoisomer)

-[4-[[4,6-bis(methylamino)-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-[4-[[4-(4-methoxy-Fe is hydroxy)-6-methylamino-[1,3,5]triazine-2-yl]-methyl-amino]1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-N-[4-(dimethyl-amino)-1,4-diphenyl-cyclohexyl]-N-methyl-pyridine-3-carboxylic acid amide (non-polar diastereoisomer)

-dimethyl-[4-[methyl-(pyridine-3-yl-methyl)-amino]-1,4-diphenyl-cyclohexyl]-amine (non-polar diastereoisomer)

-[4-[[4,6-bis(methylamino)-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-[4-[[4-(4-methoxy-phenoxy)-6-methylamino-[1,3,5]triazine-2-yl]-methyl-amino] 1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-N-[4-(dimethyl-amino)-1,4-diphenyl-cyclohexyl]-N,1-dimethyl-1H-pyrazole-3-carboxylic acid amide (polar diastereoisomer)

-N-[4-(dimethyl-amino)-1,4-diphenyl-cyclohexyl]-N,1-dimethyl-1H-pyrazole-3-carboxylic acid amide (non-polar diastereoisomer)

-[4-(dimethyl-amino)-1-(3-forfinal)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-4-(azetidin-1-yl)-1-(3-forefeel)-N,N-dimethyl-4-(3-methyl-1H-indol-2-yl)cyclohexanamine (non-polar diastereoisomer)

-4-(azetidin-1-yl)-1-(3-forefeel)-N,N-dimethyl-4-(3-methyl-1H-indol-2-yl)cyclohexanamine (polar diastereoisomer)

-[4-dimethylamino-1-(3-forfinal)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-(trifluoromethyl)-benzamide (non-polar diastereoisomer)

-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-(trifluoromethyl)-benzamide (field is hydrated diastereoisomer)

-[4-[[4,6-bis(4-methoxy-phenoxy)-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-[(1-methyl-1H-pyrazole-3-yl)-methyl]-amine (polar diastereoisomer)

-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-[(1-methyl-1H-pyrazole-3-yl)-methyl]-amine (non-polar diastereoisomer)

-[4-[[4,6-bis(4-methoxy-phenoxy)-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-4-methoxy-N-methyl-benzamide (non-polar diastereoisomer)

-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-4-methoxy-N-methyl-benzamide (polar diastereoisomer)

-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-[(4-methoxyphenyl)-methyl]-methyl-amine (polar diastereoisomer)

-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-[(4-methoxyphenyl)-methyl]-methyl-amine (non-polar diastereoisomer)

-[1-(3-forfinal)-4-(3-methyl-1H-indol-2-yl)-4-pyrrolidin-1-yl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-[1-(3-forfinal)-4-(3-methyl-1H-indol-2-yl)-4-pyrrolidin-1-yl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-[1-(3-forfinal)-4-methylamino-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethyl-amine

-dimethyl-[4-(3-methyl-1H-indol-2-yl)-1-phenyl-4-piperidine-1-yl-cyclohexyl]-amine (non-polar diastereoisomer)

-[1-(3-forfinal)-4-(3-methyl-1H-indol-2-yl)-4-piperidine-1-yl-illogical]-dimethyl-amine (polar diastereoisomer)

-[4-(dimethyl-amino)-4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-[[3-(trifluoromethyl)phenyl]-methyl]-amine (polar diastereoisomer)

-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-[[3-(trifluoromethyl)phenyl]-methyl]-amine (non-polar diastereoisomer)

-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-3-fluoro-N-methyl-benzamide (non-polar diastereoisomer)

-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-3-fluoro-N-methyl-benzamide (polar diastereoisomer)

-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-[(3-forfinal)-methyl]-methyl-amine (non-polar diastereoisomer)

-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-[(3-forfinal)-methyl]-methyl-amine (polar diastereoisomer)

-2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-ethanol (polar diastereoisomer)

-2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-N,N-dimethyl ndimethylacetamide (polar diastereoisomer)

-2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-N,N-methyl-ndimethylacetamide (polar diastereoisomer)

-2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-N,N-dimethyl ndimethylacetamide (non-polar diastereoisomer)

-2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-N-methyl-ndimethylacetamide (non-polar diastereoisomer)

-[4-dimethylamino-4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

<> -[4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-phenyl-4-pyrrolidin-1-yl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-2-[[4-(dimethyl-amino)-1,4-diphenyl-cyclohexyl]-methyl-amino]-ethanol (non-polar diastereoisomer)

-[4-[[4,6-bis(dimethylamino)-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-dimethyl-[4-[methyl-(4-methylamino-6-piperidine-1-yl-[1,3,5]triazine-2-yl)-amino]-1,4-diphenyl-cyclohexyl]-amine (polar diastereoisomer)

-4-[[4-(dimethyl-amino)-1,4-diphenyl-cyclohexyl]-methyl-amino]-butane-1-ol (polar diastereoisomer)

-3-[[4-(dimethyl-amino)-1,4-diphenyl-cyclohexyl]-methyl-carbarnoyl]-propionic acid (polar diastereoisomer)

-[4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-phenyl-4-pyrrolidin-1-yl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-[1-(3-forfinal)-4-(3-methyl-1H-indol-2-yl)-4-piperidine-1-yl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-[4-(azetidin-1-yl)-4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-(3-forfinal)-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-[4-(azetidin-1-yl)-4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-(3-forfinal)-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-[4-(5-fluoro-3-methyl-1H-indol-2-yl)-4-morpholine-4-yl-1-phenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-[4-(5-fluoro-3-methyl-1H-indol-2-yl)-4-methylamino-1-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-[4-(5-fluoro-3-IU the Il-1H-indol-2-yl)-4-methylamino-1-phenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-dimethyl-[4-methylamino-4-(3-methyl-1H-indol-2-yl)-1-thiophene-2-yl-cyclohexyl]-amine (polar diastereoisomer)

-[4-(5-fluoro-3-methyl-1H-indol-2-yl)-4-morpholine-4-yl-1-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-[4-[(4-aniline-6-methylamino-[1,3,5]triazine-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-[4-[[4-(isopropyl-methyl-amino)-6-methylamino-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-[4-[(4-aniline-6-methylamino-[1,3,5]triazine-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-[4-[[4-(benzylamino)-6-methylamino-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-[4-[(4-butylamino-6-methylamino-[1,3,5]triazine-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-[4-[[4-(4-methoxy-phenoxy)-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-(1,4-diphenyl-4-pyrrolidin-1-yl-cyclohexyl)-methyl-amine (polar diastereoisomer)

-(1,4-diphenyl-4-pyrrolidin-1-yl-cyclohexyl)-methyl-amine (non-polar diastereoisomer)

-[4-[(benzyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethyl-amine

-[4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-thiophene-2-yl-cyclohexyl]-methyl-amine (non-polar diastereoisomer)

-(1,4-diphenyl-4-pyrrolidin-yl-cyclohexyl)-dimethyl-amine (polar diastereoisomer)

-(1,4-diphenyl-4-pyrrolidin-1-yl-cyclohexyl)-dimethyl-amine (non-polar diastereoisomer)

-[4-[[4-(benzylamino)-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-dimethyl-[4-[methyl-(4-piperidine-1-yl-[1,3,5]triazine-2-yl)-amino]-1,4-diphenyl-cyclohexyl]-amine (polar diastereoisomer)

-[4-[(4-butylamino-[1,3,5]triazine-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-[4-[(4-aniline-[1,3,5]triazine-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-[4-[[4-(isopropyl-methyl-amino)-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-[4-[[4-(tert-butylamino)-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

-[4-(cyclohexyl-methylamino)-1-(3-forfinal)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-[4-(cyclopentylamine)-1-(3-forfinal)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-[4-aniline-1-(3-forfinal)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethyl-amine

-[1-(3-forfinal)-4-(3-methyl-1H-indol-2-yl)-4-(pyridine-4-ylamino)-cyclohexyl]-dimethyl-amine

-[4-[(butyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

-[4-[(butyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dim the Teal-amine (polar diastereoisomer)

-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-cyclohexanecarboxylic acid amide (polar diastereoisomer)

-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-tetrahydro-Piran-4-carboxylic acid amide (polar diastereoisomer)

-cyclohexyl-methyl-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amine (polar diastereoisomer)

-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-(tetrahydro-Piran-4-yl-methyl)-amine (polar diastereoisomer)

-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-M,1-dimethyl-piperidine-4-carboxylic acid amide (polar diastereoisomer)

-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-[(1-methyl-piperidine-4-yl)-methyl]-amine (polar diastereoisomer)

and their physiologically compatible salts and/or solvate.

Compounds according to the invention affect, for example, relevant in connection with various diseases ORL1-receptor, so they are suitable as a pharmaceutical active substance in the medicinal product.

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

Compounds according to the invention have comparable affinity for ORL1-receptor, as the compounds according to WO 03/008370. However, compared to these compounds, they exhibit higher selectivity in respect of the Kappa-opioid receptor, which is responsible for side effects, such as dysphoria, sedation, and diuresis. In addition, the compounds according to the invention with a favorable ratio ORU/p-affinity are balanced affinity for µ-opioid receptor, which is not strong. This is an advantage, since the µ-opioid receptor establishes communication with the side effects, especially such as respiratory depression, constipation and drug dependence. And therefore, compounds according to the invention are particularly suitable for drug development.

Medicinal product according to the invention together with at least one compound according to the invention optionally contain suitable additives and/or auxiliary substances and carriers, fillers, solvents, diluents, dyes and/or binders, and can be used as liquid dosage forms in the form of injection solutions, drops or juices, as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules,

plasters/spray plasters or aerosols. The choice of auxiliary substances etc. and they used the number depends on how to apply the drug: oral, orally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccal, rectally or topically, for example, on the skin, mucous membranes or eyes. For oral administration suitable preparations in the form of tablets, pills, capsules, granules, drops, juices and syrups, for parenteral, local, and inhalation use suitable solutions, suspensions, easily recoverable dry preparations and sprays. Compounds according to the invention are suitable percutaneous preparations for use in the form of delayed release, in dissolved form or in a plaster, optionally with the addition of tools to facilitate skin penetration. Preparative forms used orally or transdermally, and can slowly release the compounds according to the invention. Compounds according to the invention can also be used in parenteral forms of prolonged action, such as, for example, the implant or implant pumps. In principle, to medicines according to the invention may be added other ingredients known to the person skilled in the technical field.

The number of entered patients of the active substance varies depending on the patient's weight, the type of application, indications and severity of the disease. Usually when enaut from 0,00005 to 50 mg/kg, preferably from 0.001 to 0.5 mg/kg, of at least one compound according to the invention.

For all the above forms of medicines according to the invention is particularly preferred, if the medicinal product, together with at least one compound according to the invention contains one other active substance, in particular opioid, mainly a strong opioid, in particular morphine, or an anaesthetic, preferably hexobarbital or halothane.

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

In particular ORL1-receptor has been identified in causing pain. Accordingly, the compounds according to the invention can be applied to obtain drugs for the treatment of pain, in particular acute, neuropathic or chronic pain.

Therefore, another object of the invention concerns the use of compounds according to the invention for obtaining a medicinal product for the treatment of pain, in particular acute, visceral, neuropathic or chronic pain.

Another object of the invention concerns the use of compounds according to the invention for obtaining a medicinal product for the treatment of States of fear, stress and related astraslim syndromes depression, epilepsy, Alzheimer's disease, senile dementia, General cognitive dysfunctions, disorders of learning and memory (as nootrop), withdrawal symptoms, alcohol and/or drugs and/or abuse of drugs and/or alcohol, drug, drug dependency, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinnitus, pruritus, migraine, hearing loss, lack of motility of the intestine, eating disorders, anorexia, obesity, locomotor disorders, diarrhoea, cachexia, urinary incontinence, respectively, as a muscle relaxant, anticonvulsive or anaesthetic respectively for joint administration in the treatment with an opioid analgesic or with an anaesthetic, for diuresis or antinatriuretic, anxiolysis, for modulation of motor activity, for modulation of the distribution of neurotransmitters and treatment related neurodegenerative diseases, for the treatment of withdrawal symptoms and/or to reduce the narcotic potential of opioids.

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

Another volume of the CT invention relates to a method of treatment, in particular, when one of the above indications, nonhuman mammal or human, to whom or which it is necessary to treat pain, in particular chronic pain, by introducing a therapeutically effective dose of the compounds according to the invention, or of a medicinal product according to the invention.

Another object of the invention relates to a method for producing compounds according to the invention, as indicated in the following description and examples.

a) synthesis of cyclohexane-1,4-diamines

Method 1:

The structure of the formula a-2 can be obtained by reaction of ketones And-1 with amines and acidic reagents Z-H. Suitable reagents Z-H are, for example, hydrogen cyanide, 1,2,3-triazole, benzotriazole or pyrazole.

Especially preferred route for producing compounds of structure a-2 is the interaction of ketones with cyanides metals and the appropriate amine in the presence of acid, mainly in alcohol, at temperatures from - 40 to 60°C., preferentially at room temperature with cyanides of alkali metals in methanol.

Others, especially the preferred route for producing compounds of structure a-2 is the interaction of ketones with 1,2,3-triazole and the appropriate amine in the presence of dehydrating conditions, mainly when using vodoohda the El at elevated temperature in an inert solvent or by use of molecular sieve or other desiccant. Similarly can be similar to the a-2 structure with benzotryazolyl or pyrazol groups instead of triazole groups.

In General, cyclohexane-1,4-diamines And-3 can also be obtained by substitution of suitable leaving groups Z in the structures of formula a-2. Suitable leaving groups are preferably ceanography; 1,2,3-triazole-1-yl group. Other suitable leaving groups are 1H-benzo[Nam.][1,2,3]triazole-1-yl group and the pyrazole-1-yl group (Katritzky et al., Synthesis 1989, 66-69).

Especially preferred route for producing compounds of structure a-3 is the interaction of aminonitriles a-2 with the corresponding ORGANOMETALLIC compounds, mainly Grignard compounds, mainly in ethers, mostly in CT. ORGANOMETALLIC compound or available commercially, or can be obtained according to known methods.

Others, especially the preferred route for producing compounds of structure a-3 is the interaction of aminotriazole a-2 with the corresponding ORGANOMETALLIC compounds, mainly Grignard compounds, mainly in ethers, mostly in CT.

ORGANOMETALLIC compound or available commercially, or can be obtained according to methods known from the literature.

Method 2:

The Minister of the tours of the formula a-4 can be obtained by reaction of ketones And-1 with primary amines and acidic reagents Z-H. Suitable reagents Z-H are, for example, hydrogen cyanide, 1,2,3-triazole, benzotriazole or pyrazole.

Especially preferred route for producing compounds of structure a-4 is the interaction of ketones with cyanides metals and the appropriate amine in the presence of acid, mainly in alcohol, at temperatures from - 40 to 60°C., preferentially at room temperature with cyanides of alkali metals in methanol.

Others, especially the preferred route for producing compounds of structure a-4 is the interaction of ketones with 1,2,3-triazole and the appropriate amine in the presence of dehydrating conditions, mainly in the application of the separator at high temperatures in an inert solvent or by use of molecular sieve or other desiccant. Can be similarly introduced a similar a-4 patterns with benzotryazolyl or pyrazol groups instead of triazole groups.

In General, cyclohexane-1,4-diamines And-5, can also be obtained by substitution of suitable leaving groups Z in the structures of formula a-4. Suitable leaving groups are preferably ceanography; 1,2,3-triazole-1-yl group. Other suitable leaving groups are 1H-benzo[Nam.][1,2,3]triazole-1-yl group and the pyrazole-1-yl group (Katritzky et al., Synthesis 1989, 66-69).

Especially preferred way is to obtain compounds of the structure A-5 is the interaction of aminonitriles a-4 with the corresponding ORGANOMETALLIC compounds, mainly Grignard compounds, mainly in ethers, mostly in CT. ORGANOMETALLIC compound or available commercially, or can be obtained according to known methods.

Others, especially the preferred route for producing compounds of structure A-5 is the interaction of aminotriazole a-4 with the corresponding ORGANOMETALLIC compounds, mainly Grignard compounds, mainly in ethers, mostly in CT.

ORGANOMETALLIC compound or available commercially, or can be obtained according to methods known from the literature.

Cyclohexane-1,4-diamines of type a-3 can be synthesized by methods known to the person skilled in the art from A-5. Introduction (alkyl)substituents can then be carried out under conditions of reductive amination via the aldehyde component. Such well-known specialist in the art a method that can represent the interaction with the aldehyde with the addition of a reducing agent, e.g. sodium borohydride.

b) synthesis of (1,4-diaminocyclohexane)(heteroaryl)methanone

Substituted (1,4-diaminocyclohexane)(heteroaryl)methanone type a-7, X=O can be synthesized by well-known specialist in this field of technology is modami of the above original product a-2, Z=CN. Through interaction metallizovannyh heterocycles of type a-6 with a triple bond a-2,Z=CN receive the intermediate product a-7, X=NH. Then at acidic conditions is obtained by hydrolysis of the splitting of the imine And-7, X=O.

C) synthesis of 4-alkylcyclohexane-1-amines

Substituted 4-alkylcyclohexane-1-amines of type a-10 can be synthesized by well-known specialist in the art methods from the original product a-1. The alcoholate obtained by reaction metallizovannyh alkynes with a-1, is subjected to the interaction with the corresponding electrophiles, for example, R0X (with X=for example, Br, I, OTos, OTf etc) to obtain a-8. The interaction of carbinols A-9 to obtain according to the invention substituted 4-alkylcyclohexane-1-amines of type a-10 can take place in organic solvents such as tetrahydrofuran, dimethylformamide, benzene, toluene, xylenes, dimethoxyethane or dimethyl ether of diethylene glycol, in the presence of inorganic bases, for example sodium carbonate, potassium carbonate or cesium carbonate or potassium phosphate, in the presence of PdCl2Pd(OAc)2, PdCl2(MeCN)2, PdCl2(PPh3)2or chloride [1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ilidene]-(3-chloropyridin)palladium(II) (PEPPSI®), optionally in the presence of additional ligands, voltage is emer, triphenyl-, tri-o-tolyl-, tricyclohexyl or tri-n-butylphosphine, optionally in the presence of phase transfer catalysts, for example, chloride, Tetra-n-butylamine, hydrochloride Tetra-n-butylamine or iodide, Tetra-n-butylamine and at temperatures between 60°C and 180°C, also when exposed to microwaves.

) synthesis of 4-aminomethyl-cyclohexyl-1-amine

Substituted 4-aminomethyl-cyclohexyl-1-amine type a-14 can be synthesized by well-known specialist in the art by methods known from the original products a-1. Based on ketones, such as a-1 through referirovanija Wittig with phosphorilation receive intermediate alkenes And-11. Then the compounds of formula A-12 can be obtained from the corresponding precursors A-11 in the presence of a complex of cobalt-(II)-Salins by hydrocyanide (CarreiRa et al. Angew. Chem. Int. Ed., 46, 2006, 4519.). The interaction of nitrile groups in the a-12 with a reducing agent, for example, a hydride such as sodium borohydride or lithium borohydride, cyanoborohydride sodium, acetoxyvalerenic sodium hydride diisobutylaluminum, three(Deut.-butyl)lithium borohydride (L-Selectride®) or hydride layalina, optionally in the presence of Lewis acids, for example, ZnCl2, Ni(OAc)2or CdCl2gives amines A-13.

Method 1:

Amines of type a-13 a well-known specialist is in the art can be etilirovany, sulfonylureas or carbamylcholine to obtain the compounds A-14. Such known to the person skilled in the technical field method can be an interaction with the anhydride or acid chloride of the acid with the addition of one base, such as triethylamine.

Method: 2

Amines of type a-13 a method known to a person skilled in the art can be restorative aminating to produce compounds of type a-14. Such known to the person skilled in the technical field method can be an interaction with the aldehyde with the addition of a reducing agent, e.g. sodium borohydride.

d) synthesis of (4-aminocyclohexane)methanol

Substituted (4-aminocyclohexane)methanol type a-18 can be synthesized by well-known specialist in the art by methods known from the original products a-15. In the literature described the deprotonation of esters And-15 with a base, for example, diisopropylamide lithium (LDA) and the interaction with the corresponding electrophiles, for example, R0-X (with X=, for example, Br, I, OTos, OTf etc) to obtain A-16 (Williams et al. J. Org. Chem. 1980, 45, 5082; Shiner et al. J. Am. Chem. Soc. 1981,103,436; Xia et al. Org. Lett. 2005, 7,1315.). The interaction of A - 16 can occur with a reducing agent, for example, a hydride such as sodium borohydride or borohydride l is ment, cyanoborohydride sodium, acetoxyvalerenic sodium hydride diisobutylaluminum, three(Deut.-butyl)lithium borohydride (L-Selectride®) or hydride layalina, optionally in the presence of Lewis acids, for example, ZnCl2, Ni(OAc)2or CoCl2and cleavage Catala well-known specialist in this field

engineering methods by removing protection with acids. Thus X is selected from the group of alkyl, alkyl/ alkyliden/ with aryl or alkyl (saturated/unsaturated) replaced by alkylidenes. Protection of the hydroxyl group of well-known specialist in the art methods, for example, by interacting with a simple alkylvinyl esters, results in the corresponding simple α-alkyloxyalkyl esters And-17.

The structure of the formula A-18 can be obtained by reaction of ketones And-17 with amines and acidic reagents Z-H. Suitable reagents Z-H are, for example, hydrogen cyanide, 1,2,3-triazole, benzotriazole or pyrazole.

Especially preferred way to obtain such aminonitriles is the interaction of ketones with cyanides metals and the appropriate amine in the presence of acid, mainly in alcohol, at temperatures from -40 to 60°C, preferentially at room temperature with cyanides of alkali metals in methanol.

Others, especially the preferred way to obtain such menonite the s is the interaction of ketones with 1,2,3-triazole and the appropriate amine in the presence of dehydrating conditions, mainly when using the water separator at elevated temperature in an inert solvent or by use of molecular sieve or other desiccant. Can be similarly introduced similar patterns with benzotryazolyl or pyrazol groups instead of triazole groups.

The introduction of the residue R3 can be performed by substitution of suitable leaving groups Z, such as, for example, already described for the interaction of a-2 to a-3.

The compounds of formula A-18 can be selected from the corresponding acetals, or their salts known to the person skilled in the technical field of methods by removing protection with acids. While PG is selected from a group known to a person skilled in the technical field acetylenic protective groups for hydroxyl groups, for example, protective groups simple α-alkyloxyaryl ether.

e) synthesis of 4-indolylacetic-1,4-diamines

Method 1:

Stage 1:

Keto group according to methods known from the literature, especially when applying relevant for the synthesis of a-1 excerpts of literary sources, can be translated in monomethylamine.

Stage 2:

Aminonitriles And-19 with the corresponding ORGANOMETALLIC compounds, mainly organolithium compound and compounds Greene is Yara, mainly in ethers, mostly in CT can be converted to alkyne derivatives of the a-20. ORGANOMETALLIC compound or available commercially, or can be obtained according to known methods.

Stage 3:

Derived alkyne And 20 according to F. Messina et al. / Tetrahedron: Asymmetry 11 (2000) 1681-1685 can be transferred in a protected derivative of indole And-21.

Stage 4:

Derivatives of indole And-21 according to methods known from the literature, (see Protective Groups in Organic Synthesis by Peter G. M. Wuts, TheodoRA W. Greene, WileyBlackwell; 4th ed.) may be subject to interaction to obtain derivatives of indole And-22.

Stage 5:

Derivatives of indole And 22 by means of methods known to the person skilled in the technical field can be converted into amides of a-23. Such well-known specialist in the art, the method may be, for example, interaction with A-22 carboxylic acid with the addition of reagent combinations, for example, carbonyl diimidazol.

Derivatives of indole And 22 by means of methods known to the person skilled in the art can be converted to sulfonamides And-23. Such well-known specialist in the art, the method may be, for example, interaction with a-22 with sulphonylchloride with the addition of one base, such as triethylamine.

Derivatives of indole And 22 by means of the methods, swetnam skilled in the art, can be converted to amines a-23. Such well-known specialist in the art, the method may be, for example, interaction with a-22 with the aldehyde with the addition of a reducing agent, e.g. sodium borohydride.

Method 2:

Substituted cyclohexanamine type a-25 can be synthesized from the original product a-1 by reaction with metallizovannyj alkynes. The interaction of carbinols And 8' and 9 to obtain the substituted 4-alkylcyclohexane-1-amine type a, 10' may be carried out in organic solvents such as tetrahydrofuran, dimethylformamide, benzene, toluene, xylenes, dimethoxyethane or dimethyl ether of diethylene glycol, in the presence of inorganic bases, for example sodium carbonate, potassium carbonate or cesium carbonate, or potassium phosphate, in the presence of PdCl2Pd(OAc)2, PdCl2(MeCN)2, PdCl2(PPh3)2or chloride [1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ilidene]-(3-chloropyridin)palladium(II) (PEPPSI®), optionally in the presence of additional ligands, for example, triphenyl-, tri-o-tolyl-, tricyclohexyl or three t-butylphosphine, optionally in the presence of phase transfer catalysts, for example, chloride, Tetra-n-butylamine, hydrochloride Tetra-n-butylamine or iodide, Tetra-n-butylamine and at temperatures between 60°C and 180°S, t is the train exposed to microwaves. An alternative to this interaction metallizovannyh heterocycles And 9' with the original product a-1 in organic solvents at temperatures between 25°C and -100°C may result in carbinols type a, 10'. Subsequent cyclization of A-10' to obtain ammonium salts And 24 can occur in organic solvents in the presence of fluorinating agents at temperatures between 25°C and -100°C. Disclosure of salt A-24 to receive according to the invention replaced cyclohexanamine type a-25 can be carried out with suitable nucleophiles without or in the presence of organic solvents at temperatures between 0°C and 180 "C, also when exposed to microwaves.

f)synthesis of N-heteroaryl-1,4-diamines

Substituted cyclohexanamine type a-26 and a-27 can be synthesized from the original product A-5. By reactions of heterocycles (method 1) or tiantou (method 2) with suitable leaving groups (for example, LG=Cl or 4-OMe-C6H4) get the intermediate product a-3'. The remaining leaving group may be substituted consistently suitable nucleophiles (Nu) and get a connection according to the invention replaced cyclohexanamine type a-26 and a-27.

d) preliminary stage

Compounds of General formula a-1 and a-15 or available commercially, or receive them aware of the level of t is the transport or obvious to a person skilled in the art by a method derived from the prior art. In particular this is relevant cited the following sources: Jirkovsky et al., J. Heterocycl. Chem., 12, 1975, 937-940; Beck et al., J. Chem. Soc. Perkin 1,1992, 813-822; Shinada et al., Tetrahedron Lett., 39, 1996, 7099-7102; Garden et al., Tetrahedron, 58, 2002, 8399-8412; Lednicer et al., J. Med. Chem., 23, 1980, 424-430; Bandini et al. J. Org. Chem. 67, 15; 2002, 5386 - 5389; Davis et al., J.Med.Chem. 35, 1, 1992,177-184; Yamagishi et al., J.Med.Chem. 35,11,1992, 2085-2094; Gleave et al.; Bioorg.Med.Chem.Lett. 8, 10, 1998, 1231-1236; Sandmeyer, Helv.Chim.Acta; 2; 1919; 239; Katz et al.; J. Med. Chem. 31, 6,1988; 1244-1250; You et al. Tetrahedron Lett. 1988, 29, 2819; Ma et al. J. Org. Chem. 2001, 66, 4525; Kato et al. J. cpTopine Chem. 99, 1, 1999, 5-8.

Regarding other details of the synthesis of compounds according to the invention can in full may be made by reference to WO 002/090317, WO 002/90330, WO 003/008370, WO 003/008731, WO 003/080557, WO 004/043899, WO 004/043900, WO 004/043902, WO 004/043909, WO 004/043949, WO 004/043967, WO 005/063769, WO 005/066183, WO 005/110970, WO 005/110971, WO 005/110973, WO 005/110974, WO 005/110975, WO 005/110976, WO 005/110977, WO 006/018184, WO 006/108565, WO 007/079927, WO 007/079928, WO 007/079930, WO 007/079931, WO 007/124903, WO 008/009415 and WO 008/009416.

Examples

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

The outputs of the obtained compounds is not optimized. All temperatures are not amenable to correction. Specifying "plain air" means diethyl ether, the ethyl acetate and DHM" dichloromethane. The indication of "equivalent" means the equivalent number of substances, "MP" melting point, respectively, the temperature range p is Alenia, "Decomp." decomposition, "CT" room temperature, "abs." absolute (anhydrous), "rat." racemic, "conc." concentrated, "min" minutes, "h" hours, "DN" days, "vol.%" volumetric percentage, "wt.%" mass percentage and "M" is an indication of the concentration in mol/L.

As a stationary phase for column chromatography was used silica gel 60 (0.040-0.063 mm) of the firm E. Merck, Darmstadt. Studies using thin-layer chromatography was performed using ready-to-HPTLC plates, silica gel 60 F 254, company E. Merck, Darmstadt. The mixing ratio of the solvents for chromatographic studies is constantly shown in vol./vol.

Example 1:

1-(imino(1-methyl-1H-indol-2-yl)methyl)-M1,M1,M4,M4-tetramethyl-4-phenylcyclohexane-1,4-diamine bis(2-hydroxypropan-1,2,3-tricarboxylate)

a) 1,4-bis-dimethylamino-4-phenylcyclohexanecarboxylic

A mixture of methanol (50 ml) and water (50 ml) was acidified with hydrochloric acid (37%, 0.2 ml) and under ice cooling, and stirring was mixed with aqueous solution of dimethylamine (40%, 11.5 ml, 91 mmol). Then to the solution was added 4-dimethylamino-4-phenylcyclohexanone (2.17 g, 10 mmol) and KCN (1.6 g, 24.6 mmol). After 15 minutes formed a bright solution. The ice cooling was removed, and the composition was stirred for 2.5 h at RT, and after approx. 1 o'clock in the sediment began to fall white solid. To complement deposition is left with cooling with ice for 1 h again brought up to approx. 0°Statem precipitate was separated using a Frit and dried in a vacuum at a bath temperature 40°Sprucely mixture of diastereoisomers title compounds with access to 1.83 g (67%) and with a melting point in 82-92°C.

13C NMR (101 MHz, CDCl3) 5 frequently million: 29.3*. 30.2, 31.2, 37.7, 38.2, 39.9, 58.4*. 60.2, 62.4*, 118.7, 119.0, 126.8, 127.4, 127.7, 128.0, 136.2*. 137.7* *extended signals (b) 1-[imino-(1-methyl-1H-indol-2-yl)methyl]-m,M|M,M,-tetramethyl-4-phenyl-cyclohexane-1,4-diamine [non-polar diastereoisomer and polar diastereoisomer]

When removing moisture at 0°C. to a solution of n-utility (2.5N n-hexane, 4 ml, 10 mmol) in dry THF (10 ml) was added N-methylindol [1.31 g, 10 mmol, dissolved in dry THF (10 ml)]. Composition 60 minutes was stirred, maintaining the cooling, and after approx. 10 minutes a precipitate began to fall solid. Then were added and the mixture diastereoisomers from the previous stage [of 1.33 g, 5 mmol, dissolved in dry THF(10 ml)] within 10 minutes After the final addition, the cooling was removed, and the part after reaching the CT was stirred further for 18 hours For processing the composition was carefully mixed with a mixture of THF (5 ml) and water (1 ml). Then to the mixture was added a saturated solution of NaCl (30 ml). The organic phase was separated, the aqueous phase was extracted with ethyl acetate (4×20 ml). The combined organic extracts were dried over MgSO4

c) 1-(imino(1-methyl-1H-indol-2-yl)methyl)-N1,N1,N4,N4-tetramethyl-4-phenylcyclohexane-1,4-diamine bis(2-hydroxypropan-1,2,3-tricarboxylate)

Non-polar diastereoisomer (230 mg, 0.61 mmol) was dissolved in propan-2-OLE (5 ml) at boiling point and mixed with a hot solution of citric acid [382 mg, 2 mmol, propane-2-OLE (4 ml)]. Upon cooling of the solution to CT fell sediment. Composition to complement deposition 20 hours kept at 5°C. then the solid was separated by using a Frit and dried. Biscarrat, thus, was obtained as a glassy solid with a yield 310 mg (64%).

13C NMR (101 MHz, DMSO-D6) δ frequent, million: 25.5 (propane-2-ol), 26.9, 27.4, 30.9, 37.5, 38.1, 43.3, 62.0 (propane-2-ol?), 62.7, G, 71.9, 101.3*, 110.1, 119.7, 120.7, 122.1, 126.3, 128.6, 128.8, 132.1*. 137.0, 137.3, 171.2, 173.5, 175.5

*highly advanced signals

Example 2:

(4-dimethylamino-4-phenyl-1-(pyrrolidin-1-yl)cyclohexyl)-(1-methyl-1H-indol-2-yl)methanon (non-polar diastereoisomer)

During the synthesis of the exemplary compound 6, step a) was also quite similar non-polar compound in the form of a mixture, which (680 mg) was mixed with 2N HCl (20 ml) and 18 hours premesis what does CT. In the sludge precipitated solid. For processing the reaction mixture at room temperature was podslushivaet by 2N NaOH (30 ml). The aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were dried over MgSO4and then concentrated. Attempts at recrystallization of the resulting crude product from ethyl acetate and DMSO) did not lead to the separation of impurities. One part of the obtained crude product was purified chromatography [silica gel 60 G (10 g); cyclohexane/ethyl acetate 2: 8 (100 ml)]. The title compound was isolated, thus, with a melting point in 212-218°C in the amount of 59 mg

13C NMR (101 MHz, CDCl3) δ frequent, million: 24.6, 26.4*, 29.9, 32.3, 37.9, 45.6, 59.9* 67.6, 110.1, 110.6, 120.3, 122.7, 124.9, 125.8, 126.5, 127.3, 127.6, 134.4, 138.2*. 138.9, 198.2 *advanced signals

Example 3:

1-(imino(1-methyl-1H-indol-2-yl)methyl)-N1,N1,N4,N4-tetramethyl-4-phenylcyclohexane-1,4-diamine bis(2-hydroxypropan-1,2,3-tricarboxylate)(polar diastereoisomer)

Polar diastereoisomer from example 1, stage (b) (248 mg, 0.66 mmol) was dissolved in propan-2-OLE (5 ml) at boiling point and mixed with a hot solution of citric acid [382 mg, 2 mmol, in hot propan-2-OLE (4 ml)]. Upon cooling of the solution to CT fell sediment. Composition to complement deposition was kept for 20 hours at 5°C. then the solid was separated by using a Frit and dried. Citrate, in affect, is, was obtained with the yield 380 mg (73%, melting point 80°C) in the form of Bistaratu. 13C NMR (101 MHz, DMSO-D6) 6 frequently million: 24.0, 25.4 (propane-2-ol), 28.1, 31.4, 37.4, 37.5, 43.4, 62.0, 64.4 (propane-2-ol), 67.8, 71.8, 103.4, 110.2, 119.7,

121.0, 122.4, 126.2, 128.8, 129.2, 129.3, 130.2, 136.2, 137.8, 170.9, 171.2, 175.6

Example 4:

(1,4-bis-dimethylamino-4-phenyl cyclohexyl)-(1-methyl-1H-indol-2-yl)methanon (non-polar diastereoisomer)

Exemplary compound 1 (250 mg, of 0.62 mmol) was mixed with 2N HCl (10 ml) and was stirred 3 hours at RT and 1 h at 50°C (bath temperature). During the reaction fell sediment. For processing the reaction mixture at room temperature is first neutralized with CSOS and then sharply podslushivaet with 2N NaOH (1 ml). The aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were dried over MgSO4and then concentrated. The obtained residue (240 mg) was purified chromatography [silica gel 60 G (10 g); cyclohexane/ethyl acetate 1:1, (100 ml)]. Thus, the title compound was still separated from the source of the product and was obtained with the yield 120 mg (48%) with a melting point in the 165 to 169°C. (after recrystallization from ethanol).

13C NMR (101 MHz, CDCl3) δ frequent, million: 24.2, 30.2, 32.3, 37.9, 38.8, 59.0, 69.6, 110.1, 111.5, 120.3, 122.9, 125.0, 125.8, 126.3, 126.8, 127.4, 134.8, 139.0, 139.3, 198.9

Example 5:

(1,4-bis-dimethylamino-4-phenyl cyclohexyl)-(1-methyl-1H-indol-2-yl)methanon (polar diastereoisomer)

2CO3and sharply podslushivaet with 2N NaOH (1 ml). The aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were dried over MgSO4and then concentrated. The obtained residue (240 mg) was purified chromatography [silica gel 60 G (10 g); cyclohexane/ethyl acetate 1:1, (150 ml), ethyl acetate (50 ml)]. The title compound was isolated, thus, with the release of 234 mg (65%) with a melting point in 109-111°C (after recrystallization from propan-2-ol).

13C NMR (101 MHz, CDCl3) δ frequent, million: 25.2, 29.8, 32.5, 38.3, 38.5, 61.8, 69.7, 110.2, 111.7, 120.3, 122.9, 125.1, 125.8, 126.5, 127.8, 127.9, 133.7, 136.8, 139.2, 198.4

Example 6:

4-(imino(1-methyl-1H-indol-2-yl)methyl)-N,N-dimethyl-1-phenyl-4-(pyrrolidin-1-yl)cyclohexanamine (polar diastereoisomer)

a) 4-dimethylamino-4-phenyl-1-(pyrrolidin-1-yl)cyclohexanecarbonitrile

A mixture of methanol (50 ml) and water (50 ml) was acidified with hydrochloric acid (37%, 0.2 ml) and under ice cooling, and stirring was mixed with pyrrolidine (7.5 ml, 91 mmol). Then to the solution was added 4-dimethylamino-4-phenylcyclohexanone (2.17 g, 10 mmol). In order to achieve complete dissolution of ketones, the composition was stirred 10 minutes Then was carried out by adding KCN 1.6 g, 24.6 mmol). The ice cooling was removed and part of 2 days. was stirred at RT, and the precipitate precipitated white solid. To complement deposition composition 1 hour with cooling with ice again and drove approx. To 0°C. Then the precipitate by Frits was separated and dried in a vacuum at a bath temperature 40°C. was Obtained a mixture of diastereoisomeric the title compound with a yield of 2.7 g (90%) and with a melting point in 136-142°C.

AS 09460:13C NMR (101 MHz, CDCl3) 5 frequently million: 23.4, 23.5, 29.1*, 31.4, 32.3*. 37.7, 38.2, 48.0, 48.1, 58.8*. 60.3*. 61.8*. 62.2*. 119.7, 120.0, 126.7, 126.8, 127.4, 127.7, 127.9, 136.4*. 137.5*

* advanced signals

b) 4-(imino(1-methyl-1H-indol-2-yl)methyl)-N,N-dimethyl-1-phenyl-4-(pyrrolidin-1-yl)cyclohexanamine(polar diastereoisomer)

When removing moisture at About°C to a solution of n-utility (2.5N in n-hexane, 4 ml, 10 mmol) in dry THF (10 ml) was added N-methylindol [1.31 g, 10 mmol, dissolved in dry THF (10 ml)]. The composition was stirred for 60 minutes, while maintaining the cooling, and after approx. 10 minutes a precipitate began to fall solid. Then were added and the mixture diastereoisomers from the previous stage [1,49 g, 5 mmol, was dissolved in dry THF (20 ml)] within 20 minutes After the final addition, the cooling was removed, and the part after reaching the CT was stirred further for 18 hours For processing the composition was carefully mixed with a mixture of THF (5 ml) and water (1 ml). Then to the mixture after the Lyali saturated NaCl (30 ml). The organic phase was separated, the aqueous phase was extracted with ethyl acetate (4×20 ml). The combined organic extracts were dried over MgSO4and then concentrated. The obtained residue (2,78 g) was purified chromatography [silica gel 60 G (10 g); ethyl acetate (200 ml), ethyl acetate/ethanol 1:1 (50 ml)]. Thus, the polar diastereoisomer can be highlighted with the release of 6% (140 mg) as a viscous mass, non-polar diastereoisomer was obtained in the form of a mixture.

13C NMR (101 MHz, CDCl3) δ frequent, million: 24.2, 26.0, 29.8, 31.7, 38.2, 44.9, 61.3, 64.2, 104.9, 109.8, 119.9, 121.4, 122.7, 126.5, 127.0, 127.6, 127.7, 137.0, 137.3, 138.3, 175.2

Example 7:

(4-dimethylamino-4-phenyl-1-(pyrrol one-1-yl)cyclohexyl)-(1-methyl-1H-indol-2-yl)methanon (polar diastereoisomer)

Exemplary compound 6, step B) (99 mg, 0.23 mmol) was mixed with 2N HCl (3 ml) and stirred 18 h at RT. Immediately after adding the acid began staining solution in orange.- For processing the reaction mixture at room temperature was podslushivaet by 2N NaOH (5 ml). The aqueous phase was extracted with dichloromethane (3×10 ml). The combined organic extracts were dried over MgSO4and then concentrated.

The obtained residue (84 mg) was purified chromatography [silica gel 60 G (10 g); ethyl acetate (120 ml)]. The title compound was isolated, thus, with the release of 68 mg (68%) with a melting point of 134°C.

13C NMR (101 MHz, CDCl3/sub> ) δ frequent, million: 24.1, 26.3*. 29.9, 32.4, 38.3, 45.3, 61.6*, 67.9, 110.2, 111.1, 120.3, 122.9, 125.0, 125.9, 126.5, 127.8, 127.9, 134.1, 136.9*. 139.1, 198.1

* advanced signals

Example 8:

N,N,N'-trimethyl-1,4-diphenyl-cyclohexane-1,4-diamine (non-polar diastereoisomer)

a) 4-dimethylamino-1-methylamino-4-phenyl-cyclohexanecarbonitrile

To a cooled to 0°C. a solution of 4N hydrochloric acid (3.75 ml) and methanol (2.25 ml) was added 40%aqueous solution of methylamine (8.7 ml, 69 mmol) and 4-dimethylamino-4-phenylcyclohexanone (3.13 g, 14.4 mmol)dissolved in methanol (15 ml). Then the reaction mixture was mixed with potassium cyanide (2.25 g, 34 mmol) and 5 days. was stirred at RT. For processing the mixture was mixed with water (60 ml) and was extracted with simple ether (3×50 ml). The combined organic phases were dried with sodium sulfate and concentrated in VAC. Output: 3.48 g (94%), mixture of diastereomers

1H-NMR (DMSO-d6): 1.31 (1 H, m); 1.64 (1 H, m); 1.79 (2H, m); 1.93 (6 H, d); 2.03 (2H, m); 2.22 and 2.34 (3H, dd); 2.77 (1 H, m); 2.63 and 2.77 (1 H, m); 7.33 (5 H, m).

o) N,N,N'-trimethyl-1,4-diphenyl-cyclohexane-1,4-diamine (non-polar diastereoisomer)

Finality (8.4 ml, 15 mmol, 1.8 M solution in debutalbum ether) were placed under argon and at RT dropwise mixed with a solution of a mixture of diastereoisomers from the previous stage (1.29 g, 5 mmol) in diethyl ether (15 ml). When this reaction solution was heated to 35°C., and the precipitate was becoming solid. The reaction mixture 30 minutes boiled the flask under reflux (bath 50°C), then hydrolyzed in an ice bath (0-10°C) with 20%solution of NH4Cl (10 ml) and the organic phase was separated. The aqueous phase was extracted with simple ether (2×30 ml). The combined organic solutions were dried over Na2SO4and concentrated in the WAC. The residue was separated by flash chromatography (50 g silica gel) with chloroform/methanol(20:1→9:1→1:1+1% TEA).

Output: 283 mg (18%) non-polar diastereoisomer, oil

1H-NMR (DMSO-d6): 1.64 (2H, m); 1.86 (3H, s); 1.92 (6 H, s); 2.09 (6 H, m); 7.25 (2H, m); 7.35 (6 H, m); 7.49 (2H, m).

Example 9:

N,N,N'-trimethyl-1,4-diphenyl-cyclohexane-1,4-diamine (polar diastereoisomer)

When cleaning the approximate connection 8 stage B) can be allocated in a similar polar diastereoisomer.

Output: 306 mg (20%) of the polar diastereoisomer.

1H-NMR (DMSO-d6): 1.47 (2H, m); 1.87 (5 H, m); 1.95 (6 H, s); 2.13 (4 H, m); 7.10 (1 H, m); 7.23 (5 H, m); 7.34 (4 H, m).

Example 10:

N,N,N',N'-tetramethyl-1,4-diphenyl-cyclohexane-1,4-diamine (non-polar diastereoisomer)

The approximate solution of compound 8 (242 mg, 0.78 mmol) and formalin (1.1 ml, 37%aqueous solution) in acetonitrile (10 ml) portions was mixed with cyanoborohydride sodium (200 mg, 3.2 mmol) and was stirred 45 minutes at RT.

Then was added conc. acetic acid until neutral and 45 minutes was stirred at RT.

For recycling the solvent was removed in VAC., the remainder resuspendable in 2N NaOH (10 ml) and then was extracted question is th ether (3×10 ml). The organic solution was dried over Na2SO4and concentrated in the WAC. The remaining residue was purified by flash chromatography with l3/Meon (1:1). Yield: 230 mg (92%) melting Point: 117-118°C

1H-NMR (DMSO-d6): 1.76 (4 H, W); 1.96 (12 H, s); 2.28 (4 H, W); 7.15 (2H, m); 7.27 (8H, m).

Example 11:

N,N,N',N'-tetramethyl-1,4-diphenyl-cyclohexane-1,4-diamine (polar diastereoisomer)

The approximate solution of the compound (9), stage (b) (223 mg, 0.72 mmol) and formaldehyde (1.0 ml, 37%aqueous solution) in acetonitrile (10 ml) portions was mixed with cyanoborohydride sodium (182 mg, 2.9 mmol) and 45 minutes at RT was stirred. Then was added conc. acetic acid until neutral and 45 minutes was stirred at RT.

For recycling the solvent was removed in VAC., the remainder resuspendable in 2N NaOH (10 ml) and then was extracted with simple ether (3×10 ml). The organic solution was dried over Na2SO4and concentrated in the WAC. The remaining residue was purified by flash chromatography with l3/Meon (9:1). Yield: 160 mg (69%) melting Point: 197-198°C

1H-NMR (CD30D): 1.47 (4 H, d); 1.91 (12 H, s); 2.75 (4 H, d); 7.32 (2H, m); 7.46 (8H, m).

Example 12:

1-benzyl-N,N,N',N'-tetramethyl-4-phenyl-cyclohexane-1,4-diamines (non-polar diastereoisomer)

a) 1,4-bis-dimethylamino-4-phenyl-cyclohexanecarbonitrile

To a mixture of 4N hydrochloric acid (14 ml) and methanol (5 ml) under ice cooling was added a 40% aqueous solution is of imacillin (14 ml, 110.5 mmol), 4-dimethylamino-4-phenylcyclohexanone (5.00 g, 23.04 mmol) and potassium cyanide (3.60 g, 55.3 mmol). A mixture of 2 days. was stirred at room temperature and then after adding water (200 ml) was extracted with simple ether (4×150 ml). After concentrating the solution, the residue resuspendable in dichloromethane (200 ml) and during the night was dried with magnesium sulfate, was filtered and the solvent was removed in HAC. The nitrile was obtained in the form of oil, which crystallized. Output: 5.87 g (90%)

1H-NMR (DMSO-d6): 1.36 (1H, m); 1.61 (1 H, m); 1.61 (2H, m); 1.92 (8H, m); 2.16 (4H, m); 2.28 (3H, s); 2.44 (1 H, m); 2.59 (1 H, m); 7.35 (5 H, m).

b) 1-benzyl-M,m,M',M'-tetramethyl-4-phenyl-cyclohexane-1,4-diamines (non-polar diastereoisomer)

For the title compound of the previous step (5.84 g, 20.5 mmol) was dissolved in THF (115 ml) and under ice cooling is added dropwise mixed with chloride benzylamine 2M (36 ml, 71.57 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was mixed with 20%solution of ammonium chloride (15 ml) and water (10 ml) and was extracted with diethyl ether (3×50 ml). The combined organic phases were washed with water (50 ml) and us. NaCl (50 ml), dried over Na2SO4, was filtered and was concentrated in the WAC.

The residue was purified by flash chromatography with cyclohexane/ethyl acetate (1:1).

Output: 770 mg (11%) non-polar diastereoisomer

1H-NMR (DMSO-d): 1.57 (4 H, m); 1.72 (2H, m); 1.79 (6 H, s); 2.19 (6 H, s); 2.23 (2H, m); 2.63 (2H, s); 7.26 (10H, m).

Example 13:

1-benzyl-N,N,N',N'-tetramethyl-4-phenyl-cyclohexane-1,4-diamines (polar diastereoisomer)

When cleaning the approximate connection 12 stage b) can be allocated in a similar polar diastereoisomer.

The residue was purified by flash chromatography with cyclohexane/ethyl acetate (1:1). Non-polar diastereoisomer was obtained pure. Polar diastereoisomer was isolated contaminated and again purified on a flash chromatography with acetonitrile/ methanol/1 N NH4Cl(9:1:1).

Yield: 600 mg (9%) polar diastereoisomer

1H-NMR (DMSO-d6): 0.88 (2H, t); 1.70 (2H, m); 1.85 (6N, s); 1.90 (2H, m); 2.14 (2H, m); 2.26 (6N, s); 2.48 (2H, s); 7.00 (6 H, m); 7.18 (4H, m). 13C-NMR (DMSO-d6): 27.1; 28.6; 36.3; 36.8; 37.8; 57.0; 60.5; 125.2; 125.8; 127.1; 127.2; 130.2; 136.9; 138.7.

Example 14:

4-methoxy-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexane 2-hydroxypropan-1,2,3-tricarboxylate

a) [4-methoxy-4-(3-methoxy-prop-1-inyl)-1-phenyl-cyclohexyl]-dimethyl-amine

To 2.5 M solution of utility in hexane (8.4 ml, 21.0 mmol) at -30°C under argon was injected dropwise methylpropyloxy ester (1.47 g, 21.0 mmol), dissolved in absdf (15 ml). Then at -30°C was added a solution of 4-dimethylamino-4-phenylcyclohexanone (4.34 g, 20.0 mmol) in absdf (20 ml) and lithium bromide (0.87 g, 10 mmol), dissolved in absdf (2.5 ml). The reaction mixture was heated to -5°C., dropwise mixed with a solution of methyliodide 4.25 g, 30 mmol) in absda (25 ml) and was stirred 2 hours at 50°C. For processing the reaction mixture while cooling in an ice bath was added water (30 ml) and was extracted with cyclohexane (4 x 50 ml). The organic phase is washed with 20%solution of ammonium chloride, dried over Na2SO4and concentrated in the WAC. The remaining residue was purified by flash chromatography with SNS/Meon (20:1). Output: 2.34 g (39%)

1H-NMR (DMSO-d6): 1.57 (2H, m); 1.96 (10 H, m); 2.25 (2H, m); 3.18 (3H, s); 3.27 (3H, m); 4.05 (2H, s); 7.37 (5 H, m).

b) [4-methoxy-4-(3-methoxy-prop-1-inyl)-1-phenyl-cyclohexyl]-dimethyl-amine

2-stanlin (328 mg, 1.5 mmol), the title compound of the previous step (452 mg, 1.5 mmol) and sodium carbonate (795 mg, 7.5 mmol) under argon was dissolved in absdf (10 ml). Then was added the catalyst (PEPPSI®, 204 mg, 0.3 mmol) and the solution at 100°C. was stirred for 24 hours For processing black reaction solution was concentrated in HAC. To dryness, the residue was dissolved in SNS and washed with water. The organic phase was dried over Na2SO4and concentrated in the WAC. The remaining residue was purified by flash chromatography Snss/Meon(20:1→9:1). Yield: 71 mg(12%)

1H-NMR (DMSO-d6): 1.62 (2H, m); 2.22 (10 H, m); 2.63 (2H, m); 3.00 (3H, s); 3.10 (3H, m); 4.46 (2H, s);6.95 (2H, m); 7.28 (1 H, d); 7.46 (6 N; t); 10.72 (1 H, s).

c) 4-methoxy-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexane 2-hydroxypropan-1,2,3-tricarboxylate

The title compound pre is striding the stage (217 mg, 0.55 mmol) was dissolved in hot ethanol (4 ml) and mixed with a solution of citric acid (106 mg, 0.55 mmol) in hot ethanol (2 ml). After 2-hour incubation in the refrigerator and add a simple ester formed solid substance was pumped out and dried in the WAC.

Yield: 165 mg(51%)

melting point: 184-186°C

1H-NMR (DMSO-d6): 1.61 (2 H, m); 2.22 (4 H, m); 2.37 (6 H, s); 2.52 (4 H, m); 3.01 (3H, s); 3.08 (3H, m); 4.45 (2H, s); 6.99 (2H, m); 7.25 (1 H, d); 7.50 (4 H, m); 7.65 (2H, m); 10.73 (1 H, s).

Example 15:

4-(benzyloxy)-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexane

a) [4-benzyloxy-4-(3-methoxy-prop-1-inyl)-1-phenyl-cyclohexyl]-dimethyl-amine

To 2.5 M solution of utility in hexane (2.1 ml, 5.2 mmol) at -30°C under argon was injected dropwise methylpropyloxy ester (0.36 g, 5.2 mmol), dissolved in absdf (5 ml). Then added at -30°C. a solution of 4-dimethylamino-4-phenylcyclohexanone (1.08 g, 5.0 mmol) in absdf (5 ml) and lithium bromide (0.22 g, 2.5 mmol)dissolved in absdf (2.0 ml). The reaction mixture was heated to -5°C., dropwise mixed with a solution of benzylbromide (1.28 g, 7.5 mmol) in absda (10 ml) and was stirred 2 hours at 50°SDS processing of the reaction mixture while cooling in an ice bath was added water (10 ml) and was extracted with cyclohexane (4 x 20 ml). The organic phase is washed with 20%solution of ammonium chloride, dried over Na2SO4and concentrated in the WAC. OST is wsysa the residue was purified by flash chromatography with l 3/Meon (40:1). Output: 541 mg (29%), non-polar connection

1H-NMR (DMSO-d6): 1.67 (2H, m); 1.94 (6 H, s); 2.04 (4 H, m); 2.30 (2H, m); 3.19 (3H, s); 4.09 (2H, s); 4.60 (2H, s); 7.31 (10 H, m).

b) 4-(benzyloxy)-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexane

2-acetylamino-stanlin (359 mg, 1.37 mmol), the title compound of the previous step (519 mg, 1.37 mmol) and sodium carbonate (726 mg, 6.85 mmol) was dissolved in absdf (10 ml) under argon. Then was added the catalyst (PEPPSI, 190 mg, 0.28 mmol) and the solution at 1000mixed With 24 hours For processing black reaction solution was concentrated in HAC. to dryness, the residue was dissolved in l3and washed with water. The organic phase was dried Na2SO4and concentrated in the WAC. The remaining residue was purified by flash chromatography with CHCl3/ Meon (50:1). Yield: 210 mg(33%)

1H-NMR (DMSO-d6): 1.67 (2H, m); 1.61 (2H, m); 2.10 (6 H, bs); 2.38 (2H, m); 2.70 (2H, m); 3.11 (3H, s); 4.13 (2H, s); 4.57 (2H, s); 7.02 (2H, m); 7.30 (12 H, m); 10.78 (1 H, s).

Example 16:

4 ethoxy-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexane 2-hydroxypropan-1,2,3-tricarboxylate

a) [4 ethoxy-4-(3-methoxy-prop-1-inyl)-1-phenyl-cyclohexyl]-dimethyl-amine

To 2.5 M solution of utility in hexane (8.4 ml, 21.0 mmol) at -30°C under argon was injected dropwise methylpropyloxy ester (1.47 g, 21.0 mmol), dissolved in absdf (15 ml). Then at -30°C was added a solution of 4-dimethylamino-4-dryers is cyclohexanone (4.34 g, 20.0 mmol) in absdf (20 ml) and lithium bromide (0.87 g, 10 mmol), dissolved in absdf (2.5 ml). The reaction mixture was heated to -5°C., dropwise mixed with a solution of ethyliodide (4.68 g, 30 mmol) in absda (30 ml) and stirred 2 hours at 50°SDS processing of the reaction mixture while cooling in an ice bath was added water (30 ml) and was extracted with cyclohexane (4 x 50 ml). The organic phase is washed with 20%solution of ammonium chloride, dried over PA2SO4and concentrated in the WAC. The remaining residue by flash chromatography with Snss/Meon (20:1) was purified. Output: 3.92 g (62%)

1H-NMR (DMSO-school): 1.12 (3H, t); 1.58 (2H, m); 1.96 (10 H, m); 2.25 (2H, m); 3.17 (3H, s); 3.51 (2H, q); 4.04 (2H, s); 7.37 (5 H, m).

b) [4 ethoxy-4-(3-methoxymethyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethyl-amine

N-(2-iodine-phenyl)-ndimethylacetamide (522 mg, 2.0 mmol), the title compound of the previous step (631 mg, 2.0 mmol) and sodium carbonate (1.06 g, 10.0 mmol) was dissolved in absdf (10 ml) under argon. Then was added the catalyst (PEPPSI, 272 mg, 0.4 mmol) and the solution at 100°C. was stirred for 24 hours For processing black reaction solution was concentrated in HAC. to dryness, the residue was dissolved in Snss and washed with water. The organic phase was dried over Na2SO4and concentrated in the WAC. The remaining residue by flash-chromatography purified l3/Meon (50:1).

Output: 249 mg (31%)

1H-NMR (DMSO-d6): 1.11 (3H, t); 1.61 (2H, m); 1.99 (8H, m); 2.19 (2 is, m); 2.48 (2H, m); 3.12 (5 H, m); 4.53 (2H, s); 6.99 (2H, m); 7.27 (2H, d); 7.47 (5 H, m); 10.61 (1 H, s).

C) 4-ethoxy-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexane 2-hydroxypropan-1,2,3-tricarboxylate

The title compound of the previous step (188 mg, 0.462 mmol) was dissolved in hot ethanol (4 ml) and mixed with a solution of citric acid (89 mg, 0.462 mmol) in hot ethanol (2 ml). After 2-hour incubation in the refrigerator and add a simple ester formed solid substance was pumped out and dried in the WAC.

Output: 152 mg(55%)

melting point: 166-167°C

1H-NMR (DMSO-d6): 1.12 (3H, t); 1.57 (2H, m); 2.17-2.35 (10 H, m); 2.58 (4 H, m); 2.70 (2H, m); 3.11 (3H, m); 4.51 (2H, s); 6.98 (2H, m); 7.24 (2H, d); 7.43 (4 H, m); 7.62 (2H, m); 10.67 (1H, s).

Example 17:

N-((-4-(dimethylamino)-1-methyl-4-phenylcyclohexyl)methyl)ndimethylacetamide 2-hydroxypropan-1,2,3-tricarboxylate

a) dimethyl-(4-matila-1-phenyl-cyclohexyl)-amine

Under argon was placed tert-GFCF (0.550 g, 4.74 mmol) in absprache ether (10 ml) was added methyl bromide-triphenylphosphine (1.89 g, 4.74 mmol). Then, they were heated to 40°C for 30 minutes After this time the reaction was carefully let dropwise 4-dimethylamino-4-phenylcyclohexanone (1.00 g, 4.60 mmol), dissolved in absdf (10 ml), and the reaction solution was heated to 50°C for 5 hours, the Reaction composition was stirred over night at room temperature and concentrated in the WAC. to dryness. The remainder R is suspended in dioxane (50 ml) and was mixed with HCl/dioxane (5 ml). Precipitated precipitated solid was aspirated and washed simple ether. Selected hydrochloride was podslushivaet using 2N NaOH and was extracted with dichloromethane (2 x 80 ml). The organic phase was dried over Na2SO4, was filtered and was concentrated in the WAC. Yield: 0.86 g (61%)

1H-NMR (DMSO-d6): 1.82 (2H, m); 1.99 (2H, m); 2.30 (2H, m); 2.43 (6 H, d); 3.01 (2H, m); 4.67 (2H, s); 7.55 (3H, m); 7.72 (2H, m).

b) 4-dimethylamino-1-methyl-4-phenyl-cyclohexanecarbonitrile

The complex RH-RF-cobalt-(And)-Salins (Jacobsens Ligand, 26.0 mg, 0.04 mmol) was dissolved in dichloromethane (5 ml)was mixed with acetic acid (29 RL, 0.08 mmol, 2 EQ.) and 30 minutes was stirred in an open flask. Then the composition was concentrated in the WAC. and with a toluene azeotrope was removed excess acetic acid. The catalyst cobalt-(III) under argon was placed in Absattar (5 ml). After 2 minutes was carried out by adding the title compounds of the preceding stage (0.860 g, 3.99 mmol) was dissolved in ethanol (8 ml), µ-toluensulfonate (714 mg, 5.58 mmol) followed by phenylsilane (0.49 ml, 3.99 mmol). Then again, was added ethanol (5 ml) and the reaction solution 3 days. was stirred at room temperature. Composition to dryness concentrated in the WAC. and the residue was purified flash chromatography (2 x on normal silica gel and 1 x on ultramega silica gel) with ethyl acetate. Other studies have shown that once was enough to clean the key column chromatography on ultramega silica gel with chloroform/methanol (20:1).

Output: 0.130 g (13%)

1H-NMR (DMSO-d6): 1.09 (2 H, m); 1.16 (3H, s); 1.78 (2H, m); 1.87 (2H, m); 1.92 (6 H, s); 2.56 (2H, m); 7.32 (5 H, m).

13C-NMR (DMSO-d6): 25.4; 29.8; 33.1; 33.7; 37.8; 60.3; 124.5; 126.5; 127.5; 127.7; 135.4.

c) (4-aminomethyl-4-methyl-1-phenyl-cyclohexyl)-dimethyl-amine

LiAlH4(38.0 mg, 0.81 mmol) were placed under argon in absdf (5 ml)was slowly mixed with the compound indicated in the heading of the preceding stage (0.130 g, 0.54 mmol)dissolved in absdf (5 ml)and the reaction mixture was stirred 3 hours in a flask with reflux condenser. Then, with ice cooling THF (10 ml) was added water (4 ml) and stirred 30 minutes the Precipitate was filtered through celite, and washed with dichloromethane (50 ml). The filtrate was concentrated in HAC. to dryness. Yield: 0.12 g (90%)

1H-NMR (DMSO-d6): 0.72 (3H, s); 0.99 (2H, m); 1.13 (2H, t, NH2); 1.50 (2H, m); 1.84 (2H, m); 1.90 (6 H, s); 2.04 (2H, m); 2.39 (2H, t); 7.24 (5 H, m).

d) N-(4-dimethylamino-1-methyl-4-phenyl-cyclohexylmethyl)-ndimethylacetamide

The title compound of the previous step (0.120 g, 0.48 mmol) was dissolved in absdf (2.5 ml) was mixed with triethylamine (72.0 RL, 0.53 mmol) and acetylchloride (42.0 mg, 38.0 RL, 0.53 mmol). The reaction mixture was stirred 16 hours at room temperature. The composition was concentrated to dryness in HAC., the remainder resuspendable in ethyl ether acetic acid (10 ml) and washed with saturated solution of NaHC3(2×10 ml) and saturated NaCl solution. The organic phase was dried over Na2 SO4, was filtered and was concentrated in the WAC. Yield: 109 mg (77%)

1H-NMR (DMSO-d6): 0.71 (3H, s); 0.96 (2H, m); 1.17 (2H, m); 1.47 (2H, m); 1.84 (3H, s); 1.91 (6 H, s); 2.11 (2H, m); 3.02 (2H, d), 7.30 (5 H, m); 7.69 (1H, t).

e) N-((-4-(dimethylamino)-1-methyl-4-phenylcyclohexyl)methyl)ndimethylacetamide 2-hydroxypropan-1,2,3-tricarboxylate

The title compound of the previous step (102 mg, 0.35 mmol) was dissolved in hot ethanol (4 ml). Citric acid (67.0 mg, 0.35 mmol) was dissolved in hot ethanol (1.0 ml) was added. The composition was stirred 2 hours at room temperature. So as not fell the precipitate, the solution was concentrated in HAC. The residue was stirred with simple ether, again concentrated in the WAC. and then dried in the WAC. The desired citrate was obtained in the form of porous solids. Yield: 167 mg(98%)

1H-NMR (DMSO-d6): 0.62 (3H, s); 0.92 (2H, m); 1.45 (2H, m); 1.83 (3H, s); 2.07-2.60 (14 H, m); 3.07 (2H, d), 7.46 (5 H, m); 7.72 (1 H, t).

Example 18:

4-chloro-N-((-4-(dimethylamino)-1-methyl-4-

phenylcyclohexyl)methyl)benzosulfimide 2-hydroxypropan-1,2,3-tricarboxylate

a) 4-chloro-N-(4-dimethylamino-1-methyl-4-phenyl-cyclohexylmethyl)-benzosulfimide

The title compound from example 17, step C) (0.160 g, 0.65 mmol) was dissolved in absdf (3.4 ml)was mixed with triethylamine (97 RL, 0.714 mmol) and chloride of 4-chlorobenzenesulfonic acid (151 mg, 0.71 mmol) and 1-ordinator. was stirred at room temperature. The composition was concentrated in the WAC. D. the dryness and the residue was purified flash chromatography: 1st column with ethyl ether acetic acid/ethanol (9:1) and 2nd column with ethyl ether acetic acid. Yield: 70 mg (26%)

1H-NMR (DMSO-d6): very poorly soluble range.

b) 4-chloro-N-((-4-(dimethylamino)-1-methyl-4-

phenylcyclohexyl)methyl)benzosulfimide 2-hydroxypropan-1,2,3-tricarboxylate

The title compound of the previous step (0.070 g, 0.17 mmol) was dissolved in hot isopropanol (4 ml). Citric acid (32.0 mg, 0.17 mmol) was dissolved in hot isopropanol (1.0 ml) was added. The composition was stirred 2 hours at room temperature. So as not fell the precipitate, the solution was concentrated in HAC. The residue was stirred with simple ether, again concentrated in the WAC. and then dried in the WAC. The desired citrate was obtained in the form of porous solids. Yield: 58 mg (57%)

1H-NMR (DMSO-d6): 0.64 (3H, m); 0.90-1.04 (6 H, m); 1.54 (2H, m); 1.92 (2H, m); 2.31 (6 H, s); 2.73 (4 H, m); 7.47-7.84 (5 H, m); 10.8 (2N, W).

Example 19:

N-((1-butyl-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-4-chlorobenzenesulfonamide 2-hydroxypropan-1,2,3-tricarboxylate

a) (4 butylidene-1-phenyl-cyclohexyl)-dimethyl-amine

Tert-butyl potassium (2.75 g, 23.7 mmol) under argon was placed in absprache ether (50 ml) and was mixed with butyl bromide-triphenylphosphane (9.45 g, 23.7 mmol). Composition of 30 minutes was heated to 40°Statem gently let dropwise 4-dimethylamino-4-phenylcyclohexanone (5.00 g, 23.0 mmol), dissolved in absdf (50 ml) (exothermic reaction). The composition was heated for 6.5 hours at 50°C and stirred during the course the e night at room temperature. Then the composition was concentrated to dryness in HAC., resuspendable in dioxane (20 ml) and was mixed with HCl/ dioxane (5 ml). Thus fell the sediment. Which was filtered off, washed with simple ether (10 ml), then was podslushivaet using 2N NaOH and was extracted with dichloromethane (2 x 40 ml). The organic phase was dried over Na2SO4that was filtered and HAC. concentrated to dryness.

Output: 4.60 g (77%)

1H-NMR (DMSO-d6): 0.83 (3H, t); 1.27 (2H, m); 1.94 (9 H, m); 2.09 (5 H, m); 2.29 (2H, m); 5.04 (1 H, t); 7.23 (1 H, m); 7.36 (4 H, m).

b) 1-butyl-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile

The catalyst of the cobalt-III (297 mg, 0.456 mmol) were placed in Absattar (100 ml) under argon. Then was added the title compound of the previous step (11.6 g, 45.3 mmol)dissolved in ethanol (40 ml), and then added a µ-toluensulfonate (13.0 g, 68.0 mmol), phenylsilane (5.6 ml, 45.3 mmol) and ethanol (10 ml). The temperature rose to 35°C, and cooled with ice water. The composition was stirred 72 h at room temperature and then in the WAC. concentrated to dryness. The residue was purified by flash chromatography with chloroform/methanol (20:1). Cleared the matter again was purified by MPLC column chromatography with chloroform/methanol(50:1, 20:1). Output: 0.233 g (1.8%)

1H-NMR (DMSO-d6): 0.83 (3H, t); 1.08 (2H, m); 1.27 (6 H, m); 1.75 (2H, m); 1.93 (8H, m); 2.63 (2H, m); 7.36 (5 H, m).

c) (4-aminomethyl-4-butyl-1-phenyl-cyclo is exil)-dimethyl-amine

The title compound of the previous step (247 mg, 0.856 mmol) was dissolved in abs. THF (5 ml). Then added under argon LiAlH4(64 mg, 1.71 mmol) and the composition of 5.5 hours was heated to boiling. For processing to the composition when cooled with ice was added THF (12 ml) and NGOs (5 ml) and was stirred 30 minutes. The composition was filtered through a Frit with diatomaceous earth (2 cm)were subjected to further washing with dichloromethane (50 ml) and chloroform (50 ml) and concentrated in HAC. The residue was purified by flash chromatography chloroform/methanol (20:1, 9:1, methanol). Yield: 70 mg (28%)

1H-NMR (DMSO-d6): 0.80 (3H, t); 1.08 (9 H, m); 1.45 (2H, m); 1.93 (10 H, m); 2.45 (2H, m); 7.31 (5 H, m).

d) N-(1-butyl-4-dimethylamino-4-phenyl-cyclohexylmethyl)-4-chloro-benzosulfimide

The title compound of the previous step (65.0 mg, 0.225 mmol) was dissolved under argon in absdf (5 ml) and was mixed with triethylamine (33.5 RL, 0.247 mmol). Then the composition was added chloride 4-chlorobenzenesulfonic acid (52.0 mg, 0.247 mmol). The composition was stirred over night at room temperature. Then in the WAC. concentrated to dryness. The remainder resuspendable in ethyl acetate (10 ml) and washed with saturated solution of Panso3(2×10 ml) and saturated NaCl (2×10 ml). The organic phase was dried over Na2SO4, was filtered and was concentrated in the WAC. to dryness.

Yield: 103 mg (98%)

1H-NMR (DMSO-d6): 0.76 (3H, t); 0.97 (8H, m); 1.44 (2 is, m); 1.87 (10 H, m); 2.63 (2H, m); 7.35 (5H, m); 7.52 (1 H, t); 7.68 (2H, m); 7.85 (2H, m).

e) N-((1-butyl-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-4-chlorobenzenesulfonamide 2-hydroxypropan-1,2,3-tricarboxylate

The title compound of the previous step (103 mg, 0.22 mmol) was dissolved in hot ethanol (3 ml). Citric acid (42 mg, 0.22 mmol) was dissolved in hot ethanol (1 ml) was added. The composition was cooled to room temperature and then in the WAC. concentrated to dryness. Yield: 128 mg (88%)

Melting point: porous solid

1H-NMR (DMSO-d6): 0.86 (3H, t); 0.94 (6 H, m); 1.10 (2H, m); 1.50 (2H, m); 1.86 (2H, m); 2.28 (6 H, s); 2.51-2.64 (6 H, m); 7.52 (6 H, m); 7.72 (2H, t); 7.87 (2H, m).

Example 20:

(-4-(dimethylamino)-4-phenyl-1-(4-phenylbutyl)cyclohexyl)methanol(non-polar diastereoisomer)

a) 1,4-dioxaspiro[4,5]decane-8-ethyl ester of carboxylic acids

A solution of ethyl-4-oxocyclohexanecarboxylate (28.9 g, 169 mmol), ethylene glycol (36.7 g, 33.0 ml, 592 mmol) and µ-toluenesulfonic acid (380 mg, 2.0 mmol) in toluene (90 ml) was stirred overnight at room temperature. The reaction solution was poured into a simple ether (150 ml) and washed with water and 5% sodium hydrogen carbonate solution (150 ml). The organic phase was dried with sodium sulfate and concentrated in VAC. As the crude product (26.8 g) was obtained pure, it can be used directly next. Output: 26.8 g (74%), colorless oil

b) -(4-phenylbutyl)-1,4-dioxaspiro[4,5]decane-8-ethyl ester of carboxylic acids

2.5 M solution of n-utility (2.5 g, 15.7 ml, 39.2 mmol) at -78°C under argon was slowly let dropwise to a solution of Diisopropylamine (3.96 g, 5.50 ml, 39.2 mmol) in absolute tetrahydrofuran (50 ml). To him let dropwise in turn 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidone (DMPU, 10.0 g, 9.42 ml, 78.2 mmol) and a solution of the title compound, of the preceding stage (8.40 g, 39.2 mmol) in absolute tetrahydrofuran (30 ml). The reaction solution for 2 hours then stirred at this temperature before the solution was injected dropwise 1-bromo-4-phenylbutane (10.0 g, 47.0 mmol) in absolute tetrahydrofuran (50 ml). The resulting solution was stirred overnight at room temperature. Then was added a saturated solution of ammonium chloride (50 ml) and was extracted with simple ether (2 x 50 ml). The combined organic phases were washed with a saturated solution of sodium chloride (50 ml), dried with sodium sulfate and concentrated in VAC. The crude product (17.7 g) was purified using flash chromatography (400 g, 20×7.5 cm) with cyclohexane / ethyl acetate (9:1). Yield: 10.3 g (76%), colorless oil

1H-NMR (DMSO-d6): 1.12 (t, 3H, J=7.1 Hz); 1.39-1.62 (m, N); 1.91-2.03 (m, 2H); 2.54 (t, 2H, J=7.4 Hz); 3.82 (s, 4H); 4.05 (q, 2H, J=7.1 Hz); 7.12-7.17 (m, 3H); 7.22-7.28 (m, 2H).

c) [8-(4-phenylbutyl)-1,4-dioxaspiro[4.5]dem-8-yl]methanol

To the suspension of hydride layalina (2.50 g, 67.0 mmol) in absolute tetrahydrofuran (100 ml) was injected dropwise under argon at 65°C To dissolve the title compound, the previous stage (10.2 g, 33.5 mmol) in absolute tetrahydrofuran (50 ml) and was stirred 3 hours at this temperature, after which the interaction was complete. The reaction mixture after cooling was mixed with water (4.5 ml) and 4 N sodium lye (1.1 ml) and was filtered from the resulting precipitate. The residue was washed with tetrahydrofuran (2 x 60 ml) and the filtrate concentrated in VAC. Because the crude product was obtained pure, it can be used directly next. Output: 9.44 g (93%), light yellow oil

1H-NMR (DMSO-d6): 1.14-1.32 (m, 6N); 1.34-1.39 (m, 2H); 1.40-1.57 (t, 6N); 2.57 (t, 2H, J=7.4 Hz); 3.17 (DD., 2H, J=5.2 Hz); 3.82 (s, 4H); 4.36 (t, 1H, J=5.2 Hz); 7.13-7.19 (m, 3H); 7.24-7.29 (m, 2H).

d) 4-hydroxymethyl-4-(4-phenylbutyl)cyclohexanone

A solution of the title compound, of the preceding stage (9.40 g, 30.9 mmol) in acetone (150 ml) was mixed with 1 N hydrochloric acid (32 ml) and was stirred over night at room temperature. The reaction solution with 1 N sodium liquor was adjusted to pH 8 and concentrated in the WAC. The residue was mixed with water (50 ml) and then was extracted with dichloromethane (3×50 ml). The combined organic phases were washed with a saturated solution of sodium chloride (30 ml), dried with sodium sulfate and concentrated in VAC. Because the crude product was obtained pure, it can be used directly next. Output: 7.96 g (99%), light yellow oil

1H-NMR (DIR-d6): 1.19-1.67 (m, 10H); 2.22 (t, 4H, J=6.8 Hz); 2.59 (t, 2H, J=7.5 Hz); 3.30 (DN., 2H, J=5.2 Hz); 4.54 (t, 1H, J=5.1 Hz); 7.13-7.21 (m, 3H); 7.24-7.29 (m, 2H).

e) 4-(1-ethoxy-ethoxymethyl)-4-(4-phenylbutyl)cyclohexanone

A solution of the title compound, of the preceding stage (7.95 g, 30.5 mmol) in absolute dichloromethane (100 ml) was mixed with tosylates pyridinium (100 mg) and simple ethylvanillin ester (2.64 g, 3.51 ml, 36.6 mmol) and was stirred over night at room temperature. The reaction solution is then washed with 5% sodium hydrogen carbonate solution, water (2×50 ml) and saturated sodium chloride solution (50 ml), dried with sodium sulfate and concentrated in vacuum. The crude product (8.87 g) was purified using flash chromatography (400 g, 20×7.5 cm) with cyclohexane / ethyl acetate (9:1). Output: 6.97 g (69%), colorless oil

1H-NMR (DMSO-d6): 1.09 (t, 3H, J=7.0 Hz); 1.17 (DN., MN, J=5.3 Hz); 1.21-1.32 (m, 2H); 1.43-1.50 (m, 2H); 1.52-1.70 (m, 6N); 2.20-2.26 (m, 4H); 2.59 (t, 2H, J=7.5 Hz); 3.24 (DD., 1H, J=9.4 Hz); 3.34-3.42 (m, 2H); 3.49-3.59 (m, 1H); 4.62 (q, 1H, J=5.3 Hz); 7.14-7.29 (m, 5H).

f) 1-dimethylamino-4-(1-toxicokinetic)-4-(4-phenylbutyl)cyclohexanecarbonitrile

To ice a mixture of 4 N hydrochloric acid (1.52 ml, 6.1 mmol) and methanol (1.7 ml) was added first 40% solution of dimethylamine (3.74 ml, 24.2 mmol), then the title compound of the previous step (2.04 g, 6.1 mmol) and potassium cyanide (953 mg, 14.6 mmol). Formed suspension was stirred 4 h at room temperature. The suspension was mixed with water (100 is l) and then was extracted with diethyl ether (SX 100 ml). The combined organic phases were dried with sodium sulfate and concentrated in VAC. Yield: 2.30 g (97%), light yellow oil

1H-NMR (DMSO-d6): 1.08 (dt, 3H, J=2.5, 7.0 Hz, 1.075 (t, 1.5 H, J=7.0 Hz); 1.085 (t, 1.5H, J=7.0Hz); 1.14-1.18 (m, 3H); 1.19-1.39 (m, 6H); 1.41-1.68 (m, 6H); 1.89-2.00 (m, 2H); 2.22 (s, 2.6H); 2.23 (s, 3.4H); 2.53-2.62 (m, 2H); 3.10 (DD., 0.5H, J=9.3 Hz); 3.13 (DD., 0.5H, J=9.2 Hz); 3.22-3.29 (m, 1H); 3.33-3.39 (m, 1H); 3.47-3.59 (m, 1H); 4.56-4.63 (m, 1H); 7.13-7.29 (m, 5H).

d) [4-(1-toxicokinetic)-1-phenyl-4-(4-phenylbutyl)cyclohexyl]dimethylamine

To ice a 2 M solution of chloride vinylmania (2.03 g, 7.4 ml, 14.8 mmol) in tetrahydrofuran under argon was slowly let dropwise a solution of the title compound, of the preceding stage (a mixture of diastereoisomers, 2.30 g, 5.9 mmol) in absolute tetrahydrofuran (30 ml) and then during the night was stirred at room temperature. The reaction solution was mixed with a saturated solution of ammonium chloride and water (20 ml), the phases were separated and the aqueous phase was extracted with diethyl ether (3 * 30 ml). The combined organic phases were washed with a saturated solution of sodium chloride (30 ml), dried with sodium sulfate and concentrated in VAC. Was 2.73 g of crude product as a mixture of diastereoisomers, which is completely separated by using MPLC (LiChroprep Si60 15-25 µm, 230 g, 3.6×46 cm) with ethyl acetate / methanol (9:1).

Non-polar diastereoisomer:

Output: 918 mg (36%), light yellow oil

1H-NMR (DMSO-d6): 1.00 (t, ZN, J=7.1Hz); 1.06 (DN., MN, J=5.3 Hz); 1.10-1.20 (m, 2H); 1.21-1.29 (m, 2H); 1.32-1.48 (m, 2H); 1.51-1.62 (m, 2H); 1.90 (s, 6N); 1.92-1.99 (m, 4H); 2.59 (t, 2H, J=7.6 Hz); 2.98 (DD., 1H, J=9.3 Hz); 3.11 (DD., 1H, J=9.3 Hz); 3.21-3.29 (m, 2H); 3.39-3.50 (m, 2H); 4.48 (q, 1H, J=5.3 Hz); 7.13-7.37 (m, 10H).

h) (-4-(dimethylamino)-4-phenyl-1-(4-

phenylbutyl)cyclohexyl)methanol(non-polar diastereoisomer)

A solution of the title compounds (non-polar diastereoisomer) of the preceding stage (469 mg, 1.1 mmol) in acetone (50 ml) was mixed with 2 N hydrochloric acid (2 ml) and 18 hours was stirred at room temperature. The reaction solution with 1 N sodium liquor was adjusted to pH 8, was concentrated in VAC., the remainder resuspendable in water (50 ml) and was extracted with dichloromethane (3×30 ml). The combined organic phases were washed with a saturated solution of sodium chloride (30 ml), dried with sodium sulfate and concentrated in VAC. The crude product (381 mg) was purified using flash chromatography (18 g, 20×2.0 cm) with ethyl acetate / methanol (4:1).

Output: 325 mg (81%), white solid melting Point: 105-106°C

1H-NMR (DMSO-d6): 1.00-1.14 (m, 2H); 1.18-1.28 (t, 2H); 1.29-1.41 (m, 4H); 1.49-1.60 (t, 2H); 1.81-1.85 (t, 1H); 1.90 (s, 6N); 1.94-2.06 (t, ZN); 2.59 (t, 2H, J=7.7 Hz); 3.02 (DD., 2H, J=5.2 Hz); 4.21 (t, 1H, J=5.2 Hz); 7.13-7.37 (m, 10H). 13C-NMR (DMSO-d6): 22.4; 28.1; 28.2; 32.2; 34.1; 34.3; 35.9; 36.7; 37.9; 60.1; 66.2; 125.5; 125.7; 126.0; 127.2; 127.3; 128.1; 128.2; 137.4; 142.4. LC-MS (method: ASCA-7MIN-80GRAD.M): m/z: [M+1]+=366.6, Rt2.38 minutes

Example 21:

(-4-(dimethylamino)-4-phenyl-1-(4-phenylbutyl)cyclohexyl)methanol (polar the initial diastereoisomer)

a) [4-(1-toxicokinetic)-1-phenyl-4-(4-phenylbutyl)cyclohexyl]dimethylamine

In the stage of synthesis of for example 20, step d) when the chromatographic separation

also turned out to be pure polar diastereoisomer.

Polar diastereoisomer: 700 mg (27%), light yellow oil

1H-NMR (DMSO-d6): 0.96-1.23 (m, 14N); 1.36-1.57 (m, 4H); 1.90 (s, 6N); 1.92-2.00 (m, 4H); 2.45-2.47 (t, 1H); 3.16-3.21 (t, 1H); 3.35-3.43 (t, 1H); 3.51-3.61 (t, 1H); 4.61 (q, 1H, J=5.2 Hz); 7.09-7.38 (m, 10H).

b) (-4-(dimethylamino)-4-phenyl-1-(4-phenylbutyl)cyclohexyl)methanol(polar diastereoisomer)

A solution of the title compound, of the previous step (622 mg, 1.42 mmol) in tetrahydrofuran (5 ml) was mixed with glacial acetic acid (3.0 ml) and water (1.5 ml), and the first 8 hours was stirred while boiling in a flask with reflux condenser. Since the reaction was still not complete, then overnight at 50°C and then again 8 hours was stirred while boiling in a flask with reflux condenser. Although then the interaction was still not complete, the reaction solution was concentrated in HAC. and the residue repeatedly resuspendable in toluene (3×10 ml) and in each case, again concentrated in the WAC. The remainder resuspendable in 5% sodium hydrogen carbonate solution (30 ml) and was extracted with ethyl acetate (3×20 ml). The combined organic phases were washed with a saturated solution of sodium chloride (30 ml), dried with sodium sulfate and concentrated in VAC. That is how the crude product still contained starting material, then it was separated using flash chromatography (400 g, 20×7.5 cm) with ethyl acetate / methanol (4:1) (77 mg). First received only 245 mg very polar target compounds. By washing the column with methanol (500 ml) was allocated to another product (220 mg).

Output: 465 mg (86%), white solid melting Point: 123°C

1H-NMR (DMSO-d6): 0.90-1.03 (m, 2H); 1.11 (brs, 4H); 1.35-1.53 (m, 4H); 1.92 (br s, 10H); 2.47 (DD., 2H, J=8.2 Hz); 3.25 (DD., 2H, J=4.9 Hz); 4.35 (t, 1H, J=4.7 Hz); 7.09-7.15 (m, MN); 7.18-7.24 (m, MN); 7.28-7.39 (m, 4H). 13C-NMR (DMSO-d6): 22.3; 28.1; 28.2; 35.2; 35.7; 37.6; 38.9; 59.9; 65.3; 125.4;. 126.1; 127.4; 128.0; 128.1; 142.3.

Example 22:

[4-benzyl-4-(dimethylaminomethyl)-1-phenyl-cyclohexyl]-dimethyl-amine step 1:

4-benzyl-1-(dimethylamino)-4-((dimethylamino)methyl)cyclohexanecarbonitrile

To a mixture of 4N hydrochloric acid (3 ml) and methanol (1.05 ml) under ice cooling was added a 40%aqueous solution of dimethylamine (2.8 ml, 22.1 mmol), 4-benzyl-4-((dimethylamino)methyl)cyclohexanone (1.13 g, 4.60 mmol) and potassium cyanide (0.70 g, 11.0 mmol). A mixture of 2 days. was stirred at room temperature and then after adding water (200 ml) was extracted with simple ether (4 x 150 ml). After concentrating the solution, the residue resuspendable in dichloromethane (200 ml) and during the night was dried with magnesium sulfate, filtered, and the solvent in the WAC. removed. The nitrile was obtained in the form of an oil which crystallized. Yield: 1.06 g (77%)

1H-NMR (DMSO-d6): 1.23 (2H, m); 1.74 (2H, m); 2.16 (6 H, s); 2.24 (6 H, s); 2.32 (2H, m); 2.68 (2H, s); 7.16 (5 H, m).

Stage 2:

[4-benzyl-4-(dimethylaminomethyl)-1-phenyl-cyclohexyl]-dimethyl-amine

The title compound of stage 1 (0.88 g, 2.94 mmol) was dissolved in THF (35 ml) and under ice cooling is added dropwise was mixed with 2M solution of phenyl magnesium (5.1 ml, 10.2 mmol). The reaction solution was heated for 8 hours to boil. For the processing solution while cooling with ice was mixed with 20%solution of NH4Cl (0.6 ml) and water (0.4 ml), was extracted with simple ether (3×25 ml), the ether solution washed with water, dried (No. 2804) and concentrated in HAC. The residue was purified column chromatography with tO/HER (1:20). Received 2 faction, and the polar fraction (300 mg) according IHMS in particular contain the desired substance. Yield: 90 mg (9%)

1H-NMR (DMSO-d6): 1.23 (4 H, m); 1.39 (2H, m); 1.82 (2H, s); 1.89 (6 H, s); 2.09 (6 H, s); 2.10 (2H, m); 2.73 (2H, s); 7.25 (10 H, m).

Example 23:

(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-dimethyl-amine

Stage 1:

Ethyl ester of 5-cyano-2-oxo-5-phenyl-cyclohexanecarboxylic acid

To a solution of benzylcyanide (35.6 g, 304 mmol) and ethyl ester bromopropionic acid (126 g, 694 mmol) in dry toluene (1070 ml) at 0 to 5°C. was added in portions with stirring for 3 h NaNH2(100 g, 2560 mmol). Then 6 hours was heated to boiling (first reaction was exothermic, so temporarily it was necessary to withdraw the th of the heating bath). Then the mixture was cooled to 0°C and rapidly cooled with a mixture of acetic acid (240 ml) and water (120 ml). Toluene phase was separated, the aqueous phase was extracted with toluene (2×200 ml) and the combined organic phase was washed with a solution Panso3(2×200 ml) and water (2×200 ml) and dried with Na2SO4.

Then the solvent was removed in HAC.

Output: 70,8 g (86%), brown solid

1H-NMR (DMSO-d6): 1.25 (3H, t); 2.24 - 2.88 (6 H, m); 4.19 (2H, q); 7.50 (5 H, m).

Stage 2:

4-oxo-1-phenyl-cyclohexanecarbonitrile

The title compound of stage 1 (70.8 g, 261 mmol) was heated to boiling in a mixture of acetic acid (810 ml) and concentrated hydrochloric acid (354 ml) 3.5 hours TX under control. Then the mixture was cooled to 0 to 5°C., was diluted with water (1 l)was extracted with saturated NaCl and cold ethyl ester acetic acid (3×300 ml). The ethyl acetate phase was washed with water and concentrated in the WAC. The solid residue again dissolved in ethyl acetate, washed with a solution of N and concentrated to dryness. The output of 43.3 g (83%), yellow solid

The residue without further purification was used to interact with the ethylene glycol.

1H-NMR (DMSO-d6): 2.41 (6 H, m); 2.71 (2H, m); 7.40 (3H, m); 7.60 (2H, m).13C-NMR (DMSO-de): 35.3; 38.1; 42.3; 121.7; was 125.6; 128.2; 129.0; 139.2; 206.7.

Stage 3:

8-phenyl-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile

The title compounds is their stage 2 (43.3 g, 217 mmol) and ethylene glycol (27.4 g, 435 mmol) in toluene (430 ml) adding µ-toluenesulfonic acid (1.87 g, 10.9 mmol) in water separator 3 o'clock boiled under reflux. After the reaction was cooled, washed with a solution of NaHCO3and naration NaCl, dried PA2SO4and concentrated in the WAC. Output: 48.8 g (96%), solid

1H-NMR (DMSO-d6): 1.85 (4H, m); 2.13 (4H, m); 3.92 (4H, s); 7.44 (5 H, m).13C-NMR (DMSO-d6): 32.1; 34.0; 42.5; 63.8; 106.1; 122.1; 125.5; 128.0; 128.9; 139.9.

Stage 4:

With-(8-phenyl-1,4-dioxa-Spiro[4.5]Dec-8-yl)-methylamine

To a mixture of LiAlH4(1-87 g, 49.3 mmol) in dry THF (25 ml) under a protective gas slowly let dropwise a solution of the title compound, stage 3 (10.0 g, 41.1 mmol) in dry THF (70 ml). Then 3 hours was stirred while boiling in a flask with reflux condenser. After cooling, the reaction mixture while cooling with ice let dropwise a solution of water (1.87 ml, 104 mmol), diluted with a small amount of THF and was stirred 10 minutes. Then 15%aqueous NaOH (1.87 ml, 8.17 mmol), diluted with a small amount of THF, let dropwise and then added water (5.6 ml). The precipitate was filtered through kieselguhr and the solvent was removed in HAC. As residue remained Amin. Output: 7.96 g (78%), yellow oil

13C-NMR (DMSO-d6): 29.9; 31.0; 42.7; 53.9; 63.5; 108.3; 125.5; 126.8; 128.2; 143.8.

With the adiya 5:

Dimethyl-(8-phenyl-1,4-dioxa-Spiro[4.5]Dec-8-ylmethyl)-Amin

The title compound of stage 4 (5.40 g, 21.8 mmol) was dissolved in acetonitrile (150 ml), and formed a cloudy solution. Was added water, and 37%formalin solution (30.6 ml, 407 mmol). The composition was stirred 20 minutes at RT and then was mixed with cyanoborohydride sodium (5.76 g, 91.7 mmol). The reaction was monitored by m / V in chloroform/methanol (9:1). After 4 hours the solution was installed with acetic acid to pH 7 and concentrated in the WAC. The remainder resuspendable in chloroform, washed with a solution of Mancos and the aqueous phase was extracted with simple ether. The combined organic phase was dried over Na2SO4and concentrated in the WAC. The crude product was purified by flash chromatography chloroform/methanol(50:1→20:1→9:1).

Output: 5.40 g (67%)

1H-NMR (DMSO-de): 1.32 (2H, m); 1.56 (2H, m); 1.77 (2H, m); 1.91 (6 H, s); 2.14 (2H, m); 2.28 (2H, s); 3.80 (4 H, m); 7.16-7.39 (5 H, m).

Step 6:

4-dimethylaminomethyl-4-phenyl-cyclohexanone

The title compound stage 5 (5.40 g, 19.6 mmol) was dissolved in 5%H2SO4(300 ml) and 1 days. was stirred at RT. Then the solution is washed three times with simple ether and the ether phase is averted. The aqueous phase while cooling with ice podslushivaet using 5N NaOH and was extracted three times with dichloromethane. The organic phase is washed with a small amount of water, dried over Na2SO4and conc who was narrowly in the WAC. Output: 4.89 g (100%)

1H-NMR (DMSO-d6): 1.92 (6 H, s); 1.94-2.00 (2H, m); 2.07-2.25 (4 H, m); 2.39-2.46 (4H, m); 7.23 (1 H, m); 7.37 (2H, m); 7.48 (2H, m).

Step 7:

1-dimethylamino-4-dimethylaminomethyl-4-phenyl-cyclohexanecarbonitrile

To a mixture of 4N hydrochloric acid (5 ml) and methanol (3 ml) under cooling with ice let dropwise 40%, aqueous solution of dimethylamine (12.8 ml, 21.1 mmol). Then was added the title compound of stage 6 (4.89 g, 21.1 mmol) and KCN (3.30 g, 50.7 mmol). A mixture of 3 days. was stirred at RT. For processing the composition was mixed with water (10 ml) and was extracted with diethyl ether (3×20 ml). The ether phase was concentrated in VAC., the balance in CH2Cl2(20 ml) resuspendable, dried over Na2SO4and concentrated in the WAC. Output: 5.16 g (86%)

1H-NMR (DMSO-d6): 1.28 (2H, m); 1.69 (2H, m); 1.94 (6 H, s); 2.05 (2H, m); 2.15 (6 H, s); 2.26 (2H, m); 2.37 (2H, s); 7.19 (1 H, m); 7.35 (4 H, m).

Step 8:

(4-dimethylaminomethyl-1,4-diphenyl-cyclohexyl)-dimethyl-amine

To a solution of the title compound, stage 7 (1.00 g, 3.5 mmol) in absdf (10 ml) under nitrogen atmosphere and cooling with ice at 10°C was slowly let dropwise 2M solution of chloride vinylmania in THF (3.5 ml, 7.0 mmol). The solution was stirred 20 hours at RT. Then added a 20%solution of NH4Cl (5 ml) and water (2 ml) and the solution was extracted with simple ether (3×5 ml). The combined organic phases were washed with water (2 ml) and saturated RA is tworoom NaCl (2 ml), dried over Na2SO4and concentrated in the WAC. By flash chromatography of the residue with chloroform/methanol (20:1) was obtained salt of the product which was isolated by 1N NaOH, extracted with chloroform, dried over Na2SO4and in the WAC. freed from the solvent.

Output: 336 mg (28%) non-polar diastereoisomer, porous solid1H-NMR (CDCl3): 1.39 (2H, m); 1.65-1.78 (2H, m); 1.82 (6N, s); 1.96 (6N, s); 2.20 (2H, s); 2.28-2.41 (4H, m); 7.15-7.44 (10 H, m).

Example 24:

(E)-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-phenyl-acrylamide (non-polar diastereoisomer)

The title compound from example 8 (202 mg, 0.656 mmol) were placed in the dry. THF (20 ml) and mixed with TEA (97 RL, 0.702 mmol). Then add the cinnamic acid chloride (116 mg, 0.702 mmol). The composition was stirred 20 hours at room temperature. After this time the reaction composition was concentrated in the WAC. to dryness. The remainder resuspendable in ethyl acetate (20 ml) and washed with saturated solution of NaHCO3(2×20 ml) and saturated NaCl solution (2×20 ml). The organic phase was dried over Na2SO4and concentrated in the WAC. The residue was purified by flash chromatography with chloroform/methanol (20:1). Yield: 95 mg (33%)

1H-NMR (DMSO-d6): 1.61 (2H, bs); 1.97 (5 H, bs); 2.45 (1 H, m); 2.49 (4 H, m); 2.94 (3H, bs); 3.23 (1 H, s); 3.35 (1 H, s); 3.35 (2H, m); 7.02 (1H, m); 7.25 (2H, m); 7.34 (9 H, m); 7.46 (2H, m); 7.57 (2H, m).

Example 33:

4-benzyl-4-((dimethylamino)methyl)-N-methyl-1-phenylcyclohexylamine (polar diastereoisomer)

Stage 1:

4-benzyl-4-dimethylaminomethyl-1-methylamino-cyclohexanecarbonitrile To a cooled to 0°C. a solution of 4N hydrochloric acid (6.6 ml) and methanol (4.00 ml) was added 40%aqueous solution of methylamine (15.3 ml, 121 mmol) and 4-benzyl-4-((dimethylamino)methyl)cyclohexanone (6.20 g, 25.3 mmol)dissolved in methanol (25 ml). Then the reaction mixture was mixed with potassium cyanide (4.00 g, 60 mmol) and 5 days. was stirred at room temperature. For processing the mixture was diluted with water (180 ml) and was extracted with simple ether (3×100 ml). The combined organic phase was dried over Na2SO4that was filtered and HAC. concentrated to dryness.

Output: 5.80 g (81%)

1H-NMR (DMSO-d6): 1.35 (5 H, m); 1.58 (8H, m); 2.25 (6 H, m); 2.65 (4 H, m); 4.35 (1 H, m); 7.14 (3H, m); 7.28 (2H, m).

Stage 2:

(4-benzyl-4-((dimethylamino)methyl)-N-methyl-1-phenylcyclohexylamine (polar diastereoisomer)

Finality (33 ml, 60 mmol, 1.8 M solution in debutalbum ether) under argon and at room temperature dropwise mixed with a solution of the title compound from stage 1 (5.70 g, 20 mmol) in diethyl ether (60 ml). When this reaction solution was heated to 35°C., and the precipitate was becoming solid. The reaction mixture was stirred 30 minutes at the boiling flask with a reflux condenser, and then hydrolyzed in an ice bath with a 20%solution of NH4Cl (40 ml) and the organic phase CTD is ranged. The aqueous phase was extracted with simple ether (3×100 ml). The combined organic phase was dried over Na2SO4and concentrated in the WAC. The residue was purified by flash chromatography with chloroform/methanol(20:1→9:1→1:1→1 % TEA).

Polar diastereoisomer was obtained pure. Non-polar diastereoisomer was isolated untreated. Yield: 1.40 g (21%), polar diastereoisomer1H-NMR (DMSO-d6): 1.13 (2H, m); 1.74 (4 H, m); 1.89 (3H, m); 1.96 (4 H, m); 2.23 (6 H, s); 2.68 (2H, s); 7.15 (4 H, m); 7.26 (2H, m); 7.33 (2H, m); 7.48 (2H, m).

Example 34:

(1-benzyl-4-dimethylamino-4-phenyl-cyclohexyl)-methyl-dimethyl-amine (polar diastereoisomer)

A solution of the title compound of example 33 (1.40 g, 4.16 mmol) and formalin (5.8 ml, 37%aqueous solution) in acetonitrile (40 ml) portions was mixed with cyanoborohydride sodium (1.03 g, 16.6 mmol) and was stirred 45 minutes at room temperature. Then was added conc. acetic acid until neutral and was stirred 45 minutes at room temperature. For recycling the solvent was removed in VAC., the remainder resuspendable in 2N NaOH (40 ml) and then was extracted with simple ether (3×40 ml). The organic phase was dried over Na2SO4and concentrated in the WAC. The remaining residue was purified by flash chromatography with ethyl acetate (methanol→methanol+2% TEA). Yield: 200 mg (14%)

1H-NMR (DMSO-d6): 1.10 (2H, m); 1.56 (2H, m); 1.89 (6 H, s); 2.00 (2H, m); 2.04 (2H, s); 2.11 (2H, m);2.25 (6 H, s); 2.58 (2H, m); 7.19 (10 H, m).

Example 37:

[4-(dimethylaminomethyl)-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

To a solution of the title compound, example 23, step 7 (1.00 g, 3.5 mmol) in absdf (10 ml) under nitrogen atmosphere and cooling with ice at 0-10°C was slowly let dropwise 2M solution of chloride vinylmania in THF (3.5 ml, 7.0 mmol). The solution was stirred 20 hours at RT. Then added a 20%solution of NH4Cl (5 ml) and water (2 ml) and the solution was extracted with simple ether (3x5 ml). The combined organic phases were washed with water (2 ml) and a saturated solution of NaC (2 ml), dried over Na2SO4and concentrated in the WAC. Flash chromatography of the residue with chloroform/methanol(20:1→9:1→4:1→1:1→1:1+1% NH3→MeOH+1% NH3gave 20:1 hydrochloride, non-polar diastereoisomer, which was allocated by 1N NaOH, extracted with chloroform, dried over Na2SO4and concentrated in the WAC. Using the Meon+1% NH3got polar diastereoisomer. Because here first range of equally pointed to salt, it also identified the polar diastereoisomer by 1N NaOH, extracted with chloroform, dried over Na2SO4and concentrated in the WAC. Yield: 81 mg (7%), polar diastereoisomer, porous solid1H-NMR (DMSO-d6): 1.59 (2H, W); 1.77-1.86 (2H, m); 1.89 (6 H, s); 1.95 (6 H, s); 1.97-2.05 (2H, m); 2.25 (2H, m); 2.39 (2H, s; 7.07-7.37 (10H, m).

Example 42:

(E)-N-[[4-dimethylamino-4-(3-forfinal)-1-methyl-cyclohexyl]-methyl]-3-phenyl-acrylamide (polar diastereoisomer)

Stage 1:

4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexanecarboxaldehyde

To a solution of the chloride (methoxymethyl)triphenylphosphine (6.58 g, 19.2 mmol) in absdf (25 ml) at 0°C under argon was injected dropwise KOtBu (2.15 g, 19.2 mmol), dissolved in absdf (25 ml). The resulting red solution over 30 minutes at 0°C was mixed with a solution of 4-dimethyl-amino-4-(3-fluoro-phenyl)-cyclohexanone (3.0 g, 12.76 mmol) in absdf (25 ml) and during the night was stirred at RT. The solvent was removed in VAC., the residue was mixed with 1M sulfuric acid (50 ml) and was stirred 2 hours. Dropped when this precipitate was separated and the filtrate (pH 1) was washed by a simple ether (6x 30 ml). The aqueous solution was determined by means of 5N NaOH to pH 11 and extracted with ethyl ether acetic acid (3×50 ml). The combined organic phase was dried over Na2SO4and concentrated in the WAC. Yield: 3.20 g (100%), brown oil, a Mixture of diastereomers 1:1

1H-NMR (DMSO-d6): 1.20 (1H, m); 1.62 (2H, m); 1.75 (3H, m); 1.93 (6 H, s); 2.37 (3H, m); 7.12 (3H, m); 7.40 (1H, m); 9.50 (0.5 H, s); 9.62 (0.5 H, s).

Stage 2:

4-dimethylamino-4-(3-fluoro-phenyl)-1-methyl-cyclohexanecarboxaldehyde

A solution of the title compound, phase 1 (2.73 g, 10.95 mmol) in abstimmen (50 ml) at 0°C under argon was mixed with tert-GFCF (1.47 is, 13.14 mmol) and methyliodide (747 RL, 12 mmol). After 30 minutes the composition was heated to CT and then stirred over night (in the sludge precipitated solid substance). The reaction mixture was mixed with saturated NaCl solution (50 ml) and was extracted with dichloromethane (3×30 ml). The combined organic phase was dried over Na2SO4concentrated in the WAC. and the remaining residue was purified flash chromatography with ethyl ether acetic acid/Meon 20:1.

Yield: 1.39 g (51%)

1H-NMR (DMSO-d6): 0.85 (1.5 H, s); 1.00 (1.5 H, s); 1.50 (1 H, m); 1.54-1.77 (4 H, m); 1.89-1.95 (7 H, m); 2.11-2.31 (2H, m); 7.11 (3H, m); 7.38 (1 H, m); 9.36 (0.5 H, s); 9.44 (0.5 H, s).

Stage 3:

4-dimethylamino-4-(3-fluoro-phenyl)-1-methyl-cyclohexanecarboxaldehyde

A solution of the title compound, stage 2 (1.38 g, 5.53 mmol) and hydroxylamine hydrochloride (576 mg, 8.3 mmol) in alternale (20 ml) was mixed with amberlyst And 21 (3.9 g) and 16 hours was stirred at RT. The ion exchanger was filtered, the solution was concentrated and the residue was podslushivaet with 1N NaOH. The aqueous phase was extracted with ethyl ether, acetic acid, dried over Na2SO4and concentrated in the WAC. Yield: 1.54 g (100%)

Stage 4:

[4-aminomethyl-1-(3-fluoro-phenyl)-4-methyl-cyclohexyl]-dimethyl-amine

Hydride layalina (440 mg, 11.6 mmol) suspended under argon in abs. THF (50 ml), dropwise mixed with a solution of the title compound, stage 3 (1.54 g, 5.53 shall mol) in absdf (20 ml) and 4 o'clock boiled in a flask with reflux condenser. Then the composition at 10°C and hydrolyzed with water (10 ml) and was filtered through diatomaceous earth. THF was removed in VAC., the residue was established by means of 1 N NaOH to pH 11 and extracted with ethyl ether acetic acid. The combined organic phase was dried over Na2SO4concentrated in the WAC. and the remaining residue was separated by flash chromatography with Meon+2% NH3. Output: 435 mg (30%, non-polar diastereoisomer)

1H-NMR (DMSO-d6): 0.85 (3H, s); 1.03 (2H, m); 1.29 (2H, m); 1.83 (2H, m); 1.91 (6 H, s); 2.08 (2H, m); 2.17 (2H, s); 7.09 (3H, m); 7.38 (1 H, m). Yield: 510 mg (35%, polar diastereoisomer)1H-NMR (DMSO-d6): 0.72 (3H, s); 1.00 (2H, m); 1.49 (2H, m); 1.78 (2H, m); 1.91 (6N, s); 2.07 (2H, m); 2.38 (2H, s); 7.09 (3H, m); 7.39 (1H, m).

Stage 5:

(E)-N-[[4-dimethylamino-4-(3-forfinal)-1-methyl-cyclohexyl]-methyl]-3-phenyl-acrylamide (polar diastereoisomer)

A solution of the title compound, stage 4 (polar diastereoisomer) (250 mg, 0.94 mmol) and the base Hunya (169 RL, 1.0 mmol) in abstimmen (10 ml) was mixed with cinnamic acid chloride (166 mg, 1.0 mmol) and was stirred 24 h at RT. The organic solution was washed with saturated solution of NaHCO3and a saturated solution of NaCl, dried over Na2SO4concentrated in the WAC. and the remaining residue was purified flash chromatography with ethyl ether acetic acid/Meon 4:1. Output: 295 mg (80%), porous solid

<> 1H-NMR (DMSO-d6): 0.77 (3H, s); 1.03 (2H, m); 1.53 (2H, m);1.87 (2H, m); 1.93 (6N, s); 2.12 (2H, m); 3.17 (2H, d); 6.76 (1H, d); 7.07 (3H, m); 7.37 (5 H, m); 7.56 (2H, m); 7.96 (1H, t).

Example 48:

[4-(butyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

Stage 1:

N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-butyramide

The title compound from example 8 (308 mg, 1.0 mmol) were placed in absdf (15 ml) and mixed with TEA (165 RL, 1.2 mmol) and botrylloides (103 mg, 1.2 mmol, V=124 RL). The composition was stirred 20 hours at room temperature and then concentrated in HAC. to dryness. The remainder resuspendable in ethyl acetate (20 ml) and washed with saturated solution of Panso3(2×20 ml) and saturated NaCl solution (2×20 ml). The organic phase was dried over Na2SO4and concentrated in the WAC. The residue was purified using flash chromatography with chloroform/methanol (50:1). Yield: 206 mg (53%)

1H-NMR (DMSO-ds): 0.76 (3H, t); 1.41 (2H, q); 1.60 (2H, m); 1.95 (6N, s); 2.22 (4 H, t); 2.33 (2H, m); 2.82 (3H, s); 7.20-7.39 (10 H, m).

Stage 2:

[4-(butyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

The title compound from stage 1 (200 mg, 0.528 mmol) was dissolved in absdf (15 ml). LiAlH4(39 mg, 1.06 mmol) was added under argon. Part 7 including boiled in a flask with reflux condenser. Then the composition was cooled to room temperature, while cooling with ice was mixed with THF (12 ml) and N 20 (5 ml) and was stirred 30 minutes. The composition was filtered through a Frit with diatomaceous earth and subjected to further washing with dichloromethane (50 ml). The combined filtrates were concentrated in the WAC. Yield: 194 mg (100%), oil

1H-NMR (DMSO-d6): 0.74 (3H, t); 1.12 (4 H, m); 1.73 (4 H, W); 1.83 (6N, s); 1.90 (3H, s); 1.92 (1H, s); 1.96 (2H, W); 2.25 (4H, width); 7.25 (2H, m); 7.38 (8H, m).

Example 49

[4-(butyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

The title compound from example 9 (308 mg, 1.0 mmol) and Butyraldehyde (72 mg, 1.0 mmol, V=89 RL) were placed in absaloutly (30 ml) and mixed with cyanoborohydride sodium (250 mg, 4.0 mmol). The composition was stirred 45 minutes at room temperature, then mixed with conc. acetic acid (approx. 500 RL) and was stirred 45 minutes at room temperature. For processing the composition was concentrated in the WAC. to dryness.

The residue was mixed with 2N NaOH and was extracted with simple ether (3×20 ml). The combined organic phase was dried over Na2SO4and concentrated in the WAC. The residue was purified using flash chromatography with chloroform/methanol (9:1). Yield: 111 mg (30%), oil

1H-NMR (DMSO-d6): 0.86 (3H, t); 1.30 (6N, m); 2.05 (12 H, m); 2.35 (5H, m); 7.29 (10H, m).

Example 50:

[4-(benzyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

Stage 1:

N-(4-dimethylamino-1,4-diphenyl-cyclohex the l)-N-methyl-benzamide the Title compound from example 8 (308 mg, 1.0 mmol) were placed in absdf (15 ml) and mixed with TEA (165 RL, 1.2 mmol) and benzoyl chloride (168 mg, 1.2 mmol, V=RL 147). The composition of 16 hours was stirred at room temperature and then concentrated in HAC. to dryness. The remainder resuspendable in ethyl acetate (20 ml), washed with saturated solution of NaHCO3(2×20 ml) and saturated NaCl solution (2×20 ml). The organic phase was dried over Na2SO4and concentrated in the WAC. The residue was purified using flash chromatography with chloroform/methanol (20:1). Output: 169 mg(41%)

1H-NMR (DMSO-d6): 1.75 (2H, m); 1.98 (6N, s); 2.38 (3H, m); 2.55 (2H, m); 2.69 (4 H, s); 7.24-7.41 (13 H, m); 7.54 (2H, d).

Stage 2:

[4-(benzyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

The title compound from stage 1 (160 mg, 0.387 mmol) was dissolved in absdf (15 ml) and mixed with LiAlH4(29 mg, 0.775 mmol) under argon. Part 7 including boiled in a flask with reflux and then cooled to room temperature. To the composition when cooled with ice was added THF (5 ml) and N2O (5 ml) and was stirred 30 minutes. The composition was filtered through a Frit with diatomaceous earth and subjected to further washing with dichloromethane (50 ml). The combined filtrates were concentrated in the WAC. Output: 149 mg (97%)

1H-NMR (DMSO-d6): 1.78 (3H, s); 1.85 (10 H, s); 2.33 (4 H, m); 3.14 (2H, bs); 7.04-7.20 (4 H, m); 7.31 (2H, m); 7.40 (9 H, m).

Example 51:

[4-(benzyl-methyl-AMI is about)-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

Stage 1:

M-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-g>1-methyl-benzamide the Title compound from example 9 (308 mg, 1.0 mmol) were placed in absdf (15 ml) and mixed with TEA (165 RL, 1.2 mmol) and benzoyl chloride (168 mg, 1.2 mmol, V=RL 147). The composition of 16 hours was stirred at room temperature and then concentrated in HAC. to dryness. The remainder resuspendable in ethyl acetate (20 ml), washed with saturated solution of Panso3(2×20 ml) and a saturated solution of NaC (2×20 ml). The organic phase was dried over Na2SO4and concentrated in the WAC. The residue was purified using flash chromatography with chloroform/methanol (20:1). Output: 304 mg (74%)

1H-NMR (DMSO-d6): 1.63 (2H, m); 1.92-2.00 (10 H, m); 2.52 (1H, m); 2.76 (3H, s); 7.16 (1H, m); 7.28 (4 H, m); 7.39-7.49 (10 H, m).

Stage 2:

[4-(benzyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

The title compound from stage 1 (290 mg, 0.702 mmol) was dissolved in absdf (15 ml) under argon was mixed with LiAlH4(52 mg, 1.40 mmol). Part 7 including boiled in a flask with reflux and then cooled to room temperature. The composition was filtered through a Frit with diatomaceous earth and subjected to further washing with dichloromethane (50 ml). The combined filtrates were concentrated in the WAC. Yield: 250 mg (89%)

1H-NMR (DMSO-d6): 1.43 (1H, m); 1.72-1.76 (1H, m); 1.89 (3H, s); 1.99 (6N, s); 2.42 (3H, width); 3.25 (2H, bs); 7.16-7.39 (15 H, m).

the example 66:

2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-acetic acid (polar diastereoisomer)

Stage 1:

Tert-butyl ether [(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-acetic acid

A solution of the title compound from example 9 (246 mg, 0.8 mmol) and tert-butyl methyl ether bromoxynil acid (132 RL, 0.9 mmol) in absdf (10 ml) was mixed with potassium carbonate (124 mg, 0.9 mmol) and was stirred 20 hours at RT. Then the solvent was removed in VAC., the residue was dissolved in dichloromethane (20 ml), washed with water (2×10 ml) and saturated NaCl (2×10 ml) and dried over Na2SO4. The organic solution was concentrated in HAC. and the remaining residue was purified flash chromatography with ethyl ether acetic acid/Meon 20:1. Output: 133 mg(39%)

1H-NMR (CDCl3): 1.44 (9 H, s); 1.78 (2H, bs); 1.95 (2H, bs); 2.09 (6N, s); 2.21 (3H, s); 2.43 (4 H, m); 2.92 (2H, s); 7.16 - 7.31 (10 H, m).

2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-acetic acid (polar diastereoisomer)

The title compound from stage 1 (130 mg, 0.3 mmol) was dissolved in anisole

(0.5 ml) and triperoxonane acid (2.5 ml) and was stirred 20 hours at RT.

Then was concentrated in the WAC. to dryness, the solid residue was stirred with 1N

NaOH, the solid was filtered, washed with water and HAC.

dried up.

Yield: 69 mg (63%)

Melting point: 270-273°C

1H-NMR (DMSO-d6): 170 (3H, br); 1.96 (6N, s); 2.00 (3H, s); 2.25 (2H, m); 2.45 (4 H, m); 3.32 (2H, s); 7.14 (2H, m); 7.25 (8 H, m).

Follow the instructions as described in example 66 except that there were used the original products, are given in table 1-1, received the following connection.

Table 1-1:
Approx. No.Ex. productProductSu (%) / MS (m/z)
67Approx. 82-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-acetic acid (non-polar diastereoisomer)63 (367)

Example 68

[1-(4-methoxyphenyl)-4-methylamino-4-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

Stage 1:

[8-(4-methoxy-phenyl)-1,4-dioxa-Spiro[4.5]Dec-8-yl]-dimethyl-amine

Magnesium (3.65 g, 150 mmol) and a crystal of iodine were placed under nitrogen atmosphere and was heated. Then added absplastic ether (10 ml) and let dropwise a solution of 4-bromoanisole (18.8 ml, 150 mmol) in absprache ether (150 ml) so that a simple air of gently boiling. The resulting solution was stirred 1 h at RT and then dropwise at RT was mixed with a solution of 8-dimethylamino-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile (10.5 g, 50.0 mmol who) in absdf (100 ml), the solution while adding to boiling was heated up to 37-40°SIS solution precipitated sludge and composition during the night was stirred at RT. The solution under cooling with ice mixed with NH4Cl-solution (150 ml), the phases were separated, the aqueous phase was extracted three times with simple ether, the combined organic phases were washed with saturated NaCl solution and water, dried over Na2SO4and concentrated in the WAC. Flash chromatography of the residue with ethyl acetate/methanol(20:1→9:1→4:1→1:4→Meon) gave the desired product. Output: 6.80 g (47%)

Stage 2:

4-dimethylamino-4-(4-methoxy-phenyl)-cyclohexanone

The title compound from stage 1 (6.80 g, 23 mmol) was dissolved in a simple ether (100 ml)was mixed with 5%H2SO4(100 ml) and a solution of 2 days. much was stirred at RT. The phases were separated and the ether phase is averted. The aqueous phase while cooling with ice podslushivaet with 5 N NaOH and was extracted three times with simple ether, then the combined organic phases were washed with water, dried over Na2SO4and concentrated in the WAC. Output: 4.20 g (73%)

1H-NMR (DMSO-d6): 2.00 (6N, s); 2.01-2.14 (4 H, m); 2.42-2.48 (2H, m); 2.53-2.63 (2H, m); 3.76 (3H, s); 6.93 (2H, d); 7.34 (2H, d).

Stage 3:

4-dimethylamino-4-(4-methoxy-phenyl)-1-methylamino-cyclohexanecarbonitrile

To a mixture of 4N hydrochloric acid (1.98 ml) and methanol (2.3 ml) under cooling with ice let dropwise 40%aqueous methylamine-R is the target (3.50 ml, 40.1 mmol). Then the solution was added the title compound from step 2 (2.00 mg, 8.09 mmol) in methanol (30 ml) and potassium cyanide (1.32 g, 20.3 mmol). A mixture of 3 days. was stirred at RT and then after adding water (10 ml) was extracted with simple ether 4. The combined organic phase was dried over Na2SO4and concentrated in the WAC.

Yield: 2.23 g (96%)of crude product, the crude was subjected to further cooperation

1H-NMR (DMSO-d6): 1.29 (1H, m); 1.61 (1H, m); 1.69-1.86 (4 H, m); 1.90 (6N, d); 1.93-2.04 (2H, m); 2.28 (3H, dd); 2.75 (1H, dq); 3.75 (3H, d); 6.90 (2H, d); 7.23 (2H, dd).

Stage 4:

[1-(4-methoxyphenyl)-4-methylamino-4-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

Finality (12.9 ml, 23.3 mmol, 1.8 M solution in debutalbum ether) were placed under argon and at RT dropwise mixed with a solution of the title compound, stage 3 (2.23 g, 7.76 mmol) in abstination ether (30 ml). When this reaction solution was heated to 35°C., and the precipitate was becoming solid. The reaction mixture was stirred 1 h at boiling in a flask under reflux (bath 50°C), then hydrolyzed in an ice bath (0-10°C) with 20%solution of NH4Cl (20 ml) and the organic phase was separated. The aqueous phase was extracted with simple ether (3×50 ml). The combined organic solutions were dried over Na2SO4and concentrated in the WAC. By flash chromatography (100 g silica gel) with ethyl is the first ether acetic acid/methanol (20:1-+9:1→Meon→Meon+2% NH 3) received non-polar diastereoisomer in a mixed fraction with the original substance and the ketone and finally the polar diastereoisomer. Mixed fraction with nonpolar diastereoisomer was purified by repeated flash chromatography with dichloromethane/methanol(50:1→20:1→9:1→4:1). Output: 232 mg (9%), non-polar diastereoisomer

1H-NMR (CDCl3): 1.71 (2H, m); 1.98 (4 H, m); 1.99 (6N, s); 2.11 (1H, m); 2.19-2.41 (5 H, m); 3.81 (3H, s); 6.91 (2H, m); 7.27 (3H, m); 7.37 (2H, m); 7.48 (2H, m).

Example 69

[1-(4-methoxyphenyl)-4-methylamino-4-phenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

During the synthesis of the title compounds of example 68 within stage 4, you could also select polar diastereoisomer.

Yield: 177 mg (7%), polar diastereoisomer

1H-NMR (CDCl3): 1.58-1.92 (4 H, m); 2.03 (4 H, m); 2.07 (6N, s); 2.10-2.18 (2H, m); 2.29 (2H, m); 3.80 (3H, s); 6.87 (2H, d); 7.14 (1H, m); 7.20-7.33 (6N, m).

Follow the instructions as described in examples 68 and 69 except that the applied bromide or the corresponding Grignard reagents, as well as carbonitrile, such as is shown in table 1-2 were obtained the following compounds.

Table 1-2:

Carbonitrile:

8-dimethylamino-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile (CN-A) 8-(pyrrolidin-1-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (CN-B)

Approx. No.R-B/MgX CarbonitrilProductSu (%)/MS (m/z)
38(CN-A)dimethyl-(4-methylamino-4-phenyl-1-thiophene-2-yl-cyclohexyl)-amine (non-polar diastereoisomer)20 (315)
39(CN-A)dimethyl-(4-methylamino-4-phenyl-1-thiophene-2-yl-cyclohexyl)-amine (polar diastereoisomer)33 (315)
46(CN-A)(1-butyl-4-methylamino-4-phenyl-cyclohexyl)-dimethyl-amine (non-polar diastereoisomer)2 (289)
47(CN-A)(1-butyl-4-methylamino-4-phenyl-cyclohexyl)-dimethyl-amine (polar diastereoisomer)28(289)
60(CN-A)[4-(cyclopentyl-methyl) - dimethylamine-1-phenyl-cyclohexyl]-methyl-amine (non-polar diastereoisomer) 8(315)
61(CN-A)[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-methyl-amine(polar diastereoisomer)36(315)
70(CN-A)dimethyl-[4-methylamino-4-phenyl-1-[4-(trifluoromethyl)-phenyl]-cyclohexyl]-amine (non-polar diastereoisomer)8 (377)
71(CN-A)dimethyl-[4-methylamino-4-phenyl-1-[4-(trifluoromethyl)-phenyl]-cyclohexyl]-amine(polar diastereoisomer)7 (377)
147(CN-B)(1,4-diphenyl-4-pyrrol one-1-yl-cyclohexyl)-methyl-amine (polar diastereoisomer)8 (335)
148(CN-B)(1,4-diphenyl-4-pyrrol one-1-yl-cyclohexyl)-methyl-amine (nonpolar dia is dereamer) 3 (335)

Example 74:

[4-dimethylamino-1-(4-methoxyphenyl)-4-phenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

A solution of the title compound of example 69 (111 mg, 0.33 mmol) and formalin (0.45 ml, 37%aqueous solution) in acetonitrile (3 ml) was mixed with cyanoborohydride sodium (83 mg, 1.32 mmol) and was stirred 45 minutes at RT. Then was added conc. acetic acid until neutral and 45 minutes was stirred at RT. For recycling the solvent was removed in VAC., the remainder resuspendable in 2N NaOH (5 ml) and then was extracted with simple ether (3×10 ml). The organic solution was dried over Na2SO4and concentrated in the WAC. The remaining residue was purified by flash chromatography with ethyl acetate/methanol (1:2→Meon).

Yield: 82 mg (71%)

1H-NMR (CDCl3): 1.62-2.05 (4 H, m); 2.07 (12 H, s); 2.37 (4 H, m); 3.79 (3H, s); (6.77 (3H, s); 6.83 (2H, d); 7.20 (3H, m); 7.28 (4 H, m).

Example 75:

[4-dimethylamino-1-(4-methoxyphenyl)-4-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

A solution of the title compound of example 68 (96 mg, 0.28 mmol) and formalin (0.39 ml, 37%aqueous solution) in acetonitrile (3 ml) was mixed with cyanoborohydride sodium (72 mg, 1.15 mmol) and was stirred 45 minutes at RT. Then was added conc. acetic acid until neutral and 45 minutes was stirred at RT. For recycling the solvent was removed in in the K., the remainder resuspendable in 2N NaOH (5 ml) and then was extracted with simple ether (3×10 ml). The organic solution was dried over Na2SO4and concentrated in the WAC. The remaining residue was purified by flash chromatography with ethyl acetate/methanol(2:1→1:1→1:1+2% NH3). Yield: 62 mg (62%)

1H-NMR (CDCl3): 1.59 (4H, m); 1.92 (6N, s); 1.93 (6N, s); 2.48 (4 H, m); 3.81 (3H, s); 6.90 (2H, m); 7.20-7.41 (7H, m).

Follow the instructions as described in examples 74 and 75, except that was used is shown in table 1-3 source products, received the following connections.

152
Table 1-3:
Approx. No.Ex. the product (Approx. No.)ProductSu (%) / MS (m/z)
4039[4-(dimethyl-amino)-4-phenyl-1-thiophene-2-yl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)73 (329)
4138(4-dimethylamino-4-phenyl-1-thiophene-2-yl-cyclohexyl)-dimethyl-amine (non-polar diastereoisomer)69 (329)
5846(4-butyl-4-dimethylamine is-1-phenyl-cyclohexyl)-dimethyl-amine (non-polar diastereoisomer) 27(303)
5947(4-butyl-4-dimethylamino-1-phenyl-cyclohexyl)-dimethyl-amine (polar diastereoisomer)79 (303)
6260[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)51 (329)
6361[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)86 (329)
7271[4-(dimethyl-amino)-4-phenyl-1-[4-(trifluoromethyl)-phenyl]-cyclohexyl]-dimethyl-amine (polar diastereoisomer)36 (391)
7370[4-dimethylamino-4-phenyl-1-[4-(trifluoromethyl)-phenyl]-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)68 (391)
151147(1,4-diphenyl-4-pyrrolidin-1-yl-cyclohexyl)-dimethyl-amine (polar diastereoisomer)34 (349)
148(1,4-diphenyl-4-pyrrol one-1-yl-cyclohexyl)-dimethyl-amine (non-polar diastereoisomer)45 (349)

Example 76:

[4-[(1H-indol-3-yl-methylamino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

Stage 1:

4-dimethylamino-4-phenyl-cyclohexanecarboxaldehyde

To a solution of the chloride (methoxymethyl)triphenylphosphine (25.7 g, 75.0 mmol) in absdf (100 ml) at 0 "C under argon was injected dropwise tert-GFCF (8.41 g, 75 mmol), dissolved in absdf (100 ml). The resulting red solution over 30 minutes at 0°Smesiteli with a solution of 4-dimethylamino-4-phenyl)-cyclohexanone (10.9 g, 50.0 mmol) in absdf (100 ml) and during the night was stirred at RT. The solvent was removed in VAC., the residue was mixed with 1N sulfuric acid (150 ml) and was stirred 2 hours. Dropped when this precipitate was separated and the filtrate (pH 1) was simple washed with ether (6×100 ml). The aqueous solution was determined by means of 5N NaOH to pH 11 and extracted with ethyl ether acetic acid (3×100 ml). The combined organic phase was dried over Na2SO4and concentrated in the WAC. Yield: 11.6 g (100%), brown oil, a Mixture of diastereomers 1:1

1H-NMR (flMCO-d6): 1.18 (1H, m); 1.59-1.91 (5 H, m); 1.92 (6N, s); 2.36 (3H, m); 7.23-7.38 (5 H, m); 9.48 (0.5 H, s); 9.62 (0.5 H, s).

Stage 2:

4-dimethylamino-1-methyl-4-phenyl-cycle is exacerbated

A solution of the title compound from stage 1 (11.6 g, 50.0 mmol) in abstimmen (200 ml) at 0°C under argon was mixed with tert-GFCF (6.50 g, 58.0 mmol) and methyliodide (3.42 ml, 55.0 mmol). After 30 minutes the composition was heated to CT and then during the night mixed (in the sludge precipitated solid substance). The reaction mixture was washed with water and saturated NaCl solution (50 ml), dried over Na2SO4concentrated in the WAC. and the remaining residue was purified flash chromatography with ethyl ether acetic acid/Meon 20:1. Output: 5.90 g (48%)1H-NMR (DMSO-d6): 0.83 (1.5 H, s); 1.00 (1.5 H, s); 1.08 (1H, m); 1.55-1.82 (5 H, m); 1.88 (3H, s); 1.92 (3H, s); 2.14-2.32 (2H, m); 7.27 (5 H, m); 9.36 (0.5 H, s); 9.45 (0.5 H,s).

Stage 3:

4-dimethylamino-1-methyl-4-phenyl-cyclohexanecarboxaldehyde

A solution of the title compound from stage 2 (5.90 g, 24.0 mmol) and hydroxylamine hydrochloride (2.50 g, 36.0 mmol) in Absattar (100 ml) was mixed with amberlyst And 21 (17.0 g) and was stirred 20 hours at RT. The ion exchanger was filtered, the solution was concentrated, and the residue was podslushivaet by 1N NaOH. The aqueous phase was extracted with ethyl ether, acetic acid, dried over Na2SO4and concentrated in the WAC. Output: 6.25 g (100%)

Stage 4

[4-aminomethyl-4-methyl-1-phenylcyclohexyl]-dimethyl-amine

Hydride layalina (1.82 g, 48.0 mmol) under argon suspended in absdf (200 ml), dropwise mixed to dissolve the ohms of the title compound, from stage 3 (6.25 g, 24.0 mmol) in absdf (20 ml) and 4 h was boiled in a flask with reflux condenser. Then the composition at 10°was Gidrolizuacy water (20 ml) and was filtered through diatomaceous earth. THF was removed in VAC., the residue was established by means of 1 N NaOH to pH 11 and extracted with ethyl ether acetic acid. The combined organic phase was dried over Na2SO4concentrated in the WAC. and the remaining residue was separated by flash chromatography with Meon+1% NH3. Yield: 1.44 g (24%, non-polar diastereoisomer)

1H-NMR (DMSO-d6): 0.86 (3H, s); 1.03 (2H, m); 1.29 (2H, m); 1.84 (2H, m); 1.91 (6N, s); 2.10 (2H, m); 2.16 (2H, s); 7.24 (1H, m); 7.32 (4 H, m). Yield: 1.53 g (26%, polar diastereoisomer)1H-NMR (DMSO-d6): 0.72 (3H, s); 1.00 (2H, m); 1.49 (2H, m); 1.83 (2H, m); 1.90 (6N, s); 2.05 (2H, m); 2.39 (2H, s); 7.23 (1H, m); 7.34 (4 H, m).

Stage 5:

[4-[(1H-indol-3-yl-methylamino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

Indole-3-aldehyde (203 mg, 1.4 mmol) and non-polar diastereoisomer of stage 4 (345 mg, 1.4 mmol) was dissolved in absdf (10 ml), was mixed with Na2SO4(2.0 g) and was stirred 24 h at RT. Then was added dichloroethane (10 ml) and acetoxyvalerenic sodium (423 mg, 2.0 mmol) and then was stirred 24 h at RT. For recycling the solvent was removed in VAC., the residue was mixed with IT (20 ml), water (20 ml) and 10%sulfuric acid (to pH 1) and the phases were separated. The aqueous phase was determined by means of 5N NaOH is about pH 11 and was extracted three times with ethyl ether, acetic acid. The combined organic phase was dried over Na2SO4concentrated in the WAC. and the remaining residue was purified flash chromatography with ethyl ether acetic acid/Meon 1:1+1% NH3. Output: 397 mg (76%), porous solid

1H-NMR (DMSO-d6): 0.92 (3H, s); 1.14 (2H, m); 1.32 (2H, m); 1.89 (8 H, bs); 2.05 (2H, m); 2.22 (2H, s); 3.75 (2H, s); 6.9-7.54 (10 H, m); 10.75 (1H, s).

Example 77:

[4-[(1H-indol-3-yl-methylamino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

Indole-3-aldehyde (203 mg, 1.4 mmol) and the polar diastereoisomer of example 76, step 4 (345 mg, 1.4 mmol) was dissolved in absdf (10 ml), was mixed with Na2SO4(2.0 g) and was stirred 24 h at RT. Then was added dichloroethane (10 ml) and acetoxyvalerenic sodium (423 mg, 2.0 mmol) and stirred 24 h at RT. For recycling the solvent was removed in VAC., the residue was mixed with ethyl ether acetic acid (20 ml), water (20 ml) and 10%sulfuric acid (to pH 1) and the phases were separated. The aqueous phase was determined by means of 5N NaOH to pH 11 and was extracted three times with ethyl ether, acetic acid. The combined organic phase was dried over Na2SO4concentrated in the WAC. and the remaining residue was purified flash chromatography with ethyl ether acetic acid/Meon (1:1+1%NH3). Yield: 370 mg (70%) melting Point: 55-56 °C

1H-NMR (DMSO-d6): 0.78 (3H, s); 1.02 (2H, m); 1.57 (3H, m); 1.79 (2H, m), 1.86 (6N, s); 2.02 (2H, m); 2.44 (2H, s); 3.89 (2H, s); 6.97 (1H, t); 7.06 (1H, t); 7.22-7.32 (7H, m); 7.64 (1H, d); at 10.82 (1H, s).

Example 78:

[4-[(1H-indol-3-yl-methyl-methyl-amino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

A solution of the title compound of example 76 (300 mg, 0.8 mmol) and formalin (1.2 ml, 37%aqueous solution) in acetonitrile (10 ml) portions was mixed with cyanoborohydride sodium (201 mg, 3.2 mmol) and was stirred 2 hours at RT. Then was added conc. acetic acid until neutral and 45 minutes was stirred at RT.

For recycling the solvent was removed in VAC., the remainder resuspendable in 2N NaOH (10 ml) and then was extracted with simple ether (3×20 ml). The organic solution was dried over Na2SO4and concentrated in the WAC. The remaining residue was purified by flash chromatography with ethyl ether acetic acid/Meon (1:1). Output: 189 mg(56%)

According to NMR and IHMS it is about the connection of hydroxymethyl, which was dissolved in 1N NaOH (2 ml) and THF (2 ml) and 2 hours was boiled in a flask with reflux condenser. Then was extracted with simple ether (2×20 ml). The organic solution was dried over Na2SO4and concentrated in the WAC.

The remaining residue was purified by flash chromatography with HER/Meon (1:1+1% NH3).

Yield: 119 mg(38%)

1H-NMR (CDCl3): 1.04 (3H, s); 1.32 (4 H, m); 1.87 (2H, m); 2.05 (6N, s), 2.14 (2H, s); 2.15 (3H,s); 2.34 (2H, m); 3.63 (2H, s); 6.78 (1H, s); 7.08 (1H, t); 7.17 (1H, t); 7.30-7.41 (6N, m); 7.62 (1H, d); 7.99 (1H, s).

Example 79:

[4-[(1H-indol-3-yl-methyl-methyl-amino)-methyl]-4-methyl-1-phenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

A solution of the title compound of example 77 (300 mg, 0.8 mmol) and formalin (1.2 ml, 37%aqueous solution) in acetonitrile (10 ml) portions was mixed with cyanoborohydride sodium (201 mg, 3.2 mmol) and was stirred 2 hours at RT. Then was added conc. acetic acid until neutral and 45 minutes was stirred at RT. For recycling the solvent was removed in VAC., the remainder resuspendable in 2N NaOH (10 ml) and then was extracted with simple ether (3×20 ml). The organic solution was dried over Na2SO4and concentrated in the WAC. The remaining residue was mixed with HER/Meon (1:1, 5 ml), the precipitate precipitated colorless solid, which was separated. According to NMR and IHMS it was about the connection hydroxymethyl.

The mother liquor was concentrated (240 mg), they also talked about the connection of hydroxymethyl.

Output: 299 mg (89%)

Connection hydroxymethyl (240 mg, 0.57 mmol)) was dissolved in 1N NaOH (2 ml) and THF (2 ml) and 2 hours was boiled in a flask with reflux condenser. Then was extracted with simple ether (2×20 ml). The organic solution was dried over Na2SO4and concentrated in the WAC. The remaining residue was purified by flash-chromatography is HER/Meon (1:1+1% NH 3).

Output: 181 mg(82%)

1H-NMR (CDCl3): 0.88 (3H, s); 1.13 (2H, m); 1.74 (2H, m); 1.80 (4 H, m), 2.10 (6N, s); 2.29 (3H, s); 2.44 (2H, s); 3.78 (2H, s); 7.10-7.40 (9 H, m); 7.85 (1H, d); 8.24 (1

N).

Example 80:

[3-[[[4-(dimethyl-amino)-1-methyl-4-phenyl-cyclohexyl]-methyl-methyl-amino]-methyl]-1H-indol-1-yl]-methanol (polar diastereoisomer)

In the framework of the synthesis of example 79 was the connection hydroxymethyl in the form of an intermediate product. Output: 299 mg (89%)

1H-NMR (CDCl3): 0.41 (2H, m); 0.62 (2H, m); 0.65 (3H, s); 1.27 (2H, m), 1.61 (2H, m); 1.75 (6N, s); 2.28 (2H, s); 2.47 (3H, s); 3.64 (2H, s); 5.63 (2H, s); 7.01 (2H, m); 7.14-7.40 (7 H, m); 7.76 (1H, d)

Example 86:

[4-[[4,6-bis(methylamino)-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

The title compound of example 103 (200 mg, 0.31 mmol) was dissolved in 33%th solution of methylamine in ethanol (2 ml) and stirred in the microwave for 30 minutes at 100°C. and 60 minutes at 120°C. the precipitation was aspirated and dried in the WAC.

Yield: 89 mg (64%)

Melting point: 250-252 °C

1H-NMR (DMSO): 1.65 (2H, m); 1.96 (6N, s); 2.41 (4 H, m); 2.60 (6N, s); 3.06 (5 H, m); 6.21 (2H, m); 7.16-7.43 (10 H, m).

Example 87:

[4-[[4-(4-methoxy-phenoxy)-6-methylamino-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

In the framework of the synthesis of the title compounds of example 86 the mother liquor was concentrated in the WAC. and the remaining residue was purified on a flash XP is matography with ethyl ether acetic acid.

Yield: 25 mg(15%)

Melting point: 181-182°C

1H-NMR (DMSO), Temp: 100°C: 1.70 (2H, m); 1.99 (6N, s); 2.24 (2H, m); 2.38 (2H, m); 2.56 (2H, m); 2.67 (3H, d); 2.96 (3H, s); 3.76 (3H, s); 6.71 (1H, m); 6.98 (3H, m); 7.15-7.38 (10H, m).

Follow the instructions as described in examples 86 and 87, except that there were used the original products, such as listed in table 1-4 were obtained the following compounds.

Table 1-4:
Approx. No.Ex. productThe method according toProductSu (%) / MS(m/z)
90Approx. 100Approx. 86[4-[[4,6-bis(methylamino)-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine(polar diastereoisomer)13 (446)
91Approx. 100Approx. 87[4-[[4-(4-methoxy-phenoxy)-6-methylamino-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)59 (539)

Example 94:

[4-(dimethyl-amino)-1-(3-forfinal)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethyl-amine (olamy the diastereoisomer)

Stage 1

4-(dimethylamino)-4-(3-forefeel)-1-(3-methyl-1 H-indol-2-yl)cyclohexanol (nonpolar and polar diastereoisomer)

In an argon atmosphere to a solution of skatole (1,00 g, 7.62 mmol) in absolute tetrahydrofuran (25 ml) at -78°C was slowly added n-utility (8,39 mmol, 3,35 ml, 2.5m in hexane). Formed colorless precipitate. After 10 minutes the solution was heated to room temperature. Then the reaction mixture for approx. 3 minutes was injected carbon dioxide. Formed colourless solution. After 5 minutes of volatile components were completely removed in vacuum at room temperature (the temperature of the water bath, ≤ 30°C). The colorless solid residue was again dissolved in absolute tetrahydrofuran (20 ml). The light yellow reaction mixture was cooled to -78°C and let dropwise tert-utility (8,39 mmol, 5,59 ml, 1.5M in pentane). Formed orange solution. Which was stirred 1 h at -20°C and then cooled to -78°Statem let dropwise 4-(dimethylamino)-4-(3-forefeel)cyclohexanone [1,97 g, 8,39 mmol) in absolute tetrahydrofuran (20 ml)] and the formed solution was stirred 2 hours. Then to the reaction mixture was injected dropwise a saturated aqueous solution of ammonium chloride (50 ml)was stirred 10 minutes, the mixture was heated to 0°C and was stirred 20 minutes. After this was added 2N aqueous solution of hcl (50 ml) and was stirred 10 minutes (light gases the division). Then the pH value of dairy slurry was podslushivaet a saturated solution of sodium bicarbonate (50 ml) and a 5N solution of sodium hydroxide (20 ml). After 10 minutes, the phases were separated. The organic phase contained a colourless solid. The phases were separated. The aqueous phase was extracted with dichloromethane/methanol 20:1 (3×50 ml). The organic solutions were combined. Volatile components were completely removed in vacuum. The remaining light brown powder was extracted with methanol (5×75 ml). The remainder consisted entirely of nonpolar diastereoisomer 6b/7b (450 mg (1,23 mmol, 16%). The extracts were concentrated in vacuo to dryness. The remainder resuspendable in methanol (approx. 30 ml). Bright solid did not dissolve. Which was separated using a Frit and then dried under vacuum. Received 980 mg (or 2.67 mmol, 35%) as a colorless powder. Which consisted of both diastereoisomers.

The mother liquor was separated by chromatography [silica gel 60 (150 g); trichlormethane/ethanol 50:1 (500 ml), 19:1 (500 ml), 9:1 (300 ml), 5: 1 (300 ml), 1:1 (300 ml), in each case 0.5% triethylamine, it is better to start with trichloromethane/ethanol 100:1]. The fractions obtained both diastereoisomers had to be precrystallization from methanol. Received 93 mg (0.25 mmol, 3%) nonpolar diastereoisomer (MP. 197-202°C) and 146 mg (0.40 mmol, 5%) of the polar diastereoisomer (179-188°C). 13C{1H}-NMR (101 MHz, DMSO-d6, (frequent, mn, non-polar diastereoisomer): 9.5 (1C), 28.4 (2), 32.5 (2), 37.8 (2), 58.2 (1C, br), 69.4 (1C), 102.7 (1C), 111.0 (1C), 113.0 (1C, DN., J=21 Hz), 113.4 (1C, DN., J=21 Hz), 117.3 (1C), 117.8 (1C) 119.9 (1C), 122.6 (1C, DN., J=2 Hz), 128.9 (1C, J=8 Hz), 129.8 (1C), 133.9 (1C), 142.1 (1C, br), 142.7 (1C, DN., J=5 Hz), 161.9 (1C, DN., J=242 Hz)

13C{1H}-NMR (101 MHz, flMCO-D6, 8 frequent, million, polar diastereoisomer): 9.0 (1C), 26.9 (2, br), 33.5 (2C), 37.6 (2C), 55.9 (1C, br), 68.5 (1C), 102.3 (1C), 110.9 (1C), 113.5 (1C, sbr), 115.8 (1C, sbr), 117.2 (1C), 117.8 (1C) 120.0 (1C), 125.0 (1C, sbr), 126.6 (1C), 130.0 (1C, br), 133.7 (1C), 141.1 (1C, br), 162.4 (1C, d, J=244 Hz), n.b. (1C)

Stage 2:

1-(3-forefeel)-4-(1H-indol-2-yl)-7,7-dimethyl-7-azoniabicyclo[2.2.1]gatefold

Alcohol from stage 1 (both diastereoisomer, 2.20 g, 6,00 mmol) at -78°C, suspended in absolute dichloromethane (50 ml). Were added triethylamine (3,65 g, 36,02 mmol, 4,99 ml, 0.73 g/ml), DMAP (16 mg, 0.12 mmol) and DAST (2,90 g to 18.01 mmol, of 2.36 ml of 1.23 g/ml). The solution was stirred 1 h at -78°C. Then the reaction mixture for 10 hours (during the night) was heated to room temperature. Then was added a saturated solution of sodium bicarbonate (50 ml) and was stirred 15 minutes (until the end of gassing). Then the solution was added sodium hydroxide (5N, 20 ml) and was stirred 10 minutes. The phases were separated.

Red-brown organic phase was concentrated in vacuo to dryness. Then, the resulting brown solid was dissolved in methanol (50 ml).

The aqueous phase was concentrated in in the cosmology vacuum to dryness. Light residue was extracted with methanol (5×75 ml).

The combined solution of methanol was concentrated in vacuo to dryness. The remainder of the first was extracted with dichloromethane (2×30 ml) and then methanol (5×75 ml). Remained bright and solid.

The methanol extracts were concentrated in vacuo to dryness. Remained 1.20 g (3,26 mmol, 54%) of product as a light solid. The dichloromethane extracts were concentrated in vacuo to dryness. The remainder resuspendable in methanol (5 ml) and defended. In the sludge precipitated white solid. Thus, the received other of 0.43 g (1,16 mmol, 19%) of product (MP. 175 °C).

13With{1H}-NMR (101 MHz, DMSO-D6, (frequent, million): 11.2 (1C), 29.8 (2), 30.3 (2), 40.6 (2), 81.2 (1C, DN., J=2 Hz), 83.2 (1C), 111.5 (1C), 114.4 (1C), 116.7 (1C, DN., J=23 Hz), 117.6 (1C, DN., J=21 Hz), 119.11 (1C), 119.13 (1C) 121.7 (1C), 123.4 (1C), was 125.6 (1C, J=3 Hz), 128.8 (1C), 131.0 (1C, DN., J=8 Hz), 132.2 (1C, DN., J=7 Hz), 135.8 (1C), 162.3 (1C, DN., J=244 Hz)

Stage 3:

[4-(dimethyl-amino)-1-(3-forfinal)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

The title compound from step 2 (500 mg, of 1.36 mmol) suspended in acetonitrile/methanol (1:1, 20 ml). Then was added dimethylamine (2M in tetrahydrofuran (THF, 14 ml, 27,15 mmol) and 2 days. was stirred at room temperature. The solution was stirred 6 hours at 80°C.(oil bath temperature), then put on a large silica gel and separated f the Yesh-chromatography [silica gel 60 (150 g); trichlormethane/ethanol 50:1 (1000 ml), 19:1 (500 ml), 9:1 (1000 ml), in each case 0.5% triethylamine]. First allocated non-polar diastereoisomer. In addition, allocated 250 mg of a mixture of solids. The mixture of solids was dissolved in methanol (10 ml), was added 50 mg of potassium hydroxide and 10 minutes was stirred. Volatile components were completely removed in vacuum. Light residue was extracted with ethyl ether acetic acid (3 x 20 ml). The extracts were freed in vacuo from volatile components. Allocated 135 mg (0.34 mmol, 25%) of the polar diastereoisomer (MP. 65-73 °C).

13With{1H}-NMR (101 MHz, DMSO-D6, (frequent, million, polar diastereoisomer): 10.7 (1C), 28.8 (2, br), 29.3 (2, br), 37.7 (2), 38.7 (2), 58.7 (1C, br), 60.5 (1C, br), 107.0 (1C, br), 110.5 (1C), 112.9 (1C, DN., J=21 Hz), 113.7 (1C, DN., J=21 Hz), 117.5 (1C), 117.7 (1C), 120.4 (1C), 122.9 (1C, br), 128.9 (1C, DN., J=8 Hz), 129.0 (1C), 132.5 (1C, sbr), 134.5 (1C), 141.4 (1C, br), 161.9 (1C, DN., J=243 Hz)

Example 97:

[4-(dimethyl-amino)-1-(3-forfinal)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

During the synthesis of the title compounds of example 94 stage 3 was also obtained non-polar diastereoisomer. Allocated 152 mg (0,39 mmol, 29%) (MP. 126-132 °C).

13With{1H}-NMR (101 MHz, DMSO-De, 8 frequent, million, non-polar diastereoisomer): 10.7 (1C), 29.6 (2, br), 29.7 (2, br), 37.8 (2), 38.7 (2), 60.0 (1C, br), 60.6 (1C, br), 107.0 (1C, br), 110.5 (1C), 113.0 (1C, DN., J=21 Hz), 114.2 (STN., J=21 Hz), 117.5 (1C), 117.8 (1C), 120.4 (1C), 123.5(1 is, br), 129.1 (1C), 129.1 (1C, DN., J=6 Hz), 132.2 (1C, br), 134.6 (1C), 140.4 (1C, br),

162.2 (STN., J=242 Hz)

Follow the instructions as described examples 94 and 97, except that the applied source products, such as listed in table 1-5, received the following connections.

Table 1-5:
Indoles:
skatole
5-fluorescent-3-methyl-1H-indole (IN-A)
Ketones:
4-dimethylamino-4-phenylcyclohexanone (BB-A)
4-(dimethylamino)-4-(3-forefeel)cyclohexanone (IV)
4-(dimethylamino)-4-(thiophene-2-yl)cyclohexanone (IV)
Approx. No.IndoleKetoneAminProductSu*(%) / MS(m/z)
35skatoleBB-dimethylamine[4-(dimethyl-amino)-4-(3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethyl-amine(polar is the diastereoisomer) 27(376)
36skatoleBB-dimethylamine[4-(dimethyl-amino)-4-(3-methyl-1 H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)25(376)
53skatoleBB-pyrrolidindimethyl-[4-(3-methyl-1H-indol-2-yl)-1-phenyl-4-pyrrolidin-1-yl-cyclohexyl]-unindividualized (polar diastereoisomer)17(402)
54skatoleBB-pyrrolidindimethyl-[4-(3-methyl-1H-indol-2-yl)-1-phenyl-4-pyrrol one-1-yl-cyclohexyl]-amine (non-polar diastereoisomer)48(402)

Approx. No.IndoleKetoneAminProductSu* (%) /MS(m/z)
56skatoleBB-azetidin [4-(azetidin-1-yl)-4-(3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)19(388)
82skatoleBB-methylamine[4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-phenyl-cyclohexyl]-methyl-amine (polar diastereoisomer)26(362)
83skatoleBB-methylamine[4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-phenyl-cyclohexyl]-methyl-amine (depolarisation)22(362)
84skatoleBB-benzylaminebenzyl-[4-dimethylamino-1 -(3-methyl-1 H-indol-2-yl)-4-phenyl-cyclohexyl]-amine; 2-hydroxy-propane-1,2,3-tricarboxylic acid12(438)
95skatoleBB-INazetidin4-(azetidin-1-yl)-1-(3-forefeel)-N,N-dimethyl-4-(3-methyl-1H-indol-2-yl)cyclohexanamine (non-polar diastereoisomer) 33(406)
96skatoleBB-INazetidin4-(azetidin-1-yl)-1-(3-forefeel)-N,N-dimethyl-4-(3-methyl-1H-indol-2-yl)cyclohexanamine (polar diastereoisomer)-4(406)

Approx. No.IndoleKetoneAminProductSu* (%) / MS(m/z)
108skatoleBB-inpyrrolidin[1-(3-forfinal)-4-(3-methyl-1H-indol-2-yl)-4-pyrrolidin-1-yl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)36(420)
109skatoleBB-inpyrrolidin[1-(3-forfinal)-4-(3-methyl-1H-indol-2-yl)-4-pyrrolidin-1-yl-cyclohexyl]-dimethyl-amine(polar diastereoisomer)29(420)
110skatoleBB-inmethylamine [1-(3-forfinal)-4-methylamino-4-(3-methyl-1 H-indol-2-yl)-cyclohexyl]-dimethyl-amine10(380)
111skatoleBB-piperidinedimethyl-[4-(3-methyl-1H-indol-2-yl)-1-phenyl-4-piperidine-1-yl-cyclohexyl]-amine (non-polar diastereoisomer)23(416)
112skatoleBB-INpiperidine[1-(3-forfinal)-4-(3-methyl-1H-indol-2-yl)-4-piperidine-1-yl-cyclohexyl]-dimethyl-amine(polar diastereoisomer)4(434)
133skatoleBB-inpiperidine[1-(3-forfinal)-4-(3-methyl-1H-indol-2-yl)-4-piperidine-1-yl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)35 (434)
113IN-ABB-dimethylamine[4-(dimethyl-amino)-4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethyl-amine(polar diastereoisomer)41(394)

Approx. No.IndoleKetoneAminProductSu* (%) /MS(m/z)
125IN-ABB-dimethylamine[4-(dimethyl-amino)-4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)27(394)
126IN-ABB-pyrrolidin[4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-phenyl-4-pyrrolidin-1-yl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)42 (420)
132IN-ABB-pyrrolidin[4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-phenyl-4-pyrrolidin-1-yl-cyclohexyl]-dimethyl-amine(polar diastereoisomer)38 (420)
134IN-ABB-INazetidin[4-(azetidin-1-yl)-4-(5-fluoro-3-methyl-1 H-indol-2-yl)-1-(3-forfinal)-cycle is hexyl]-dimethyl-amine(polar diastereoisomer) 55 (406)
135IN-ABB-INazetidin[4-(azetidin-1-yl)-4-(5-fluoro-3-methyl-1H-indol-2-yl)-1-(3-forfinal)-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)28 (406)
136IN-ABB-morpholine[4-(5-fluoro-3-methyl-1H-indol-2-yl)-4-morpholine-4-yl-1-phenyl-cyclohexyl]-dimethyl-amine(polar diastereoisomer)30 (436)

Approx. No.IndoleKetoneAminProductSu*(%) / MS(m/z)
140IN-ABB-morpholine[4-(5-fluoro-3-methyl-1 H-indol-2-yl)-4-morpholine-4-yl-1-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)15 (436)
137IN-ABB-methylamine [4-(5-fluoro-3-methyl-1H-indol-2-yl)-4-methylamino-1-phenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)11 (380)
138IN-ABB-methylamine[4-(5-fluoro-3-methyl-1H-indol-2-yl)-4-methylamino-1-phenyl-cyclohexyl]-dimethyl-amine(polar diastereoisomer)11(380)
139IN-ABB-methylaminedimethyl-[4-methylamino-4-(3-methyl-1H-indol-2-yl)-1-thiophene-2-yl-cyclohexyl]-amine (polar diastereoisomer)21 (368)
150IN-ABB-methylaminedimethyl-[4-methylamino-4-(3-methyl-1H-indol-2-yl)-1-thiophene-2-yl-cyclohexyl]-amine (non-polar diastereoisomer)46(368)
159IN-ABB-INcyclohexylethylamine[4-(cyclohexyl-methylamino)-1-(3-forfinal)-4-(3-methyl-1 H-indol-2-yl)-cyclohexyl]-dimethyl-amine(depolarisation)43(42)

Approx. No.IndoleKetoneAminProductSu* (%) /MS(m/z)
160IN-ABB-INcyclopentylamine[4-(cyclopentylamine)-1 -(3-forfinal)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethyl-amine(depolarisation)36(434)
161IN-ABB-INaniline[4-aniline-1-(3-forfinal)-4-(3-methyl-1H-indol-2-yl)-cyclohexyl]-dimethyl-amine28(381; M+1-NMe2-IU)
162IN-ABB-IN4-aminopyridine[1-(3-forfinal)-4-(3-methyl-1H-indol-2-yl)-4-(pyridine-4-ylamino)-cyclohexyl]-dimethyl-amine5 (443)

* for the last stage.

Follow the instructions as described in example 86 except that the amines used and original products, as shown in table 1-6 and in the case of highly ipasa amines were also processed without solvent, received the following connections.

Table 1-6:
Approx. No.Ex. productAminProductSu (%) / MS (m/z)
129Approx. 91piperidinedimethyl-[4-[methyl-(4-methylamino-6-piperidine-1-yl-[1,3,5]triazine-2-yl)-amino]-1,4-diphenyl-cyclohexyl]-amine (polar diastereoisomer)89 (500)

Approx. No.Ex. productAminProductSu (%) / MS (m/z)
141Primaniline[4-[(4-aniline-6-methylamino-[1,3,5]triazine-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)38 (508)
142PrimN-isopropylbenzylamine[4-[[4-(isopropyl-methyl-amino)-6-methylamino-[1,3,5]triazine-2-yl]-ethyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer) 44 (488)
143Primaniline[4-[(4-aniline-6-methylamino-[1,3,5]triazine-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)84 (508)
144Primbenzylamine[4-[[4-(benzylamino)-6-methylamino-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)90 (522)
145Primbutylamine[4-[(4-butylamino-6-methylamino-[1,3,5]triazine-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)86(488)

Example 100:

[4-[[4,6-bis(4-methoxy-phenoxy)-[113,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer) Solution of the title compounds of example 9 (616 mg, 2.0 mmol) and 4-methoxyphenylalanine (895 mg, 6.0 mmol) in Absalon (20 ml) for 3 days. was stirred at RT. Then the solvent was removed in HAC. and the remaining residue was purified flash chromatography with ethyl ether acetic acid/Meon (20:1). Yield: 1.16 g (92%)

1H-NMR (CDCl3): 1.77 (4H, m); 1.89 (6N, s); 2.50 (4H, m); 3.07 (3H, s); 3.76 (6N, s); 6.84-7.36 (M,t).

Example 103:

[4-[[4,6-bis(4-methoxy-phenoxy)-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

A solution of the title compounds of example 8 (154 mg, 0.5 mmol) and 4-methoxyphenylalanine (224 mg, 1.5 mmol) in Absalon (10 ml) for 3 days. was stirred at RT. Then the solvent was removed in HAC. and the remaining residue was purified flash chromatography with ethyl acetate/cyclohexane (1:1). Output: 226 mg (72%)

1H-NMR (CDCl3): 1.80 (4 H, m); 1.96 (6N, s); 2.28 (2H, m); 2.43 (2H, m); 3.04 (3H, s); 3.80 (6N, s); 6.89 - 7.40 (18 H, m).

Follow the instructions as described in example 24 except that the used reagents acylation or sulfonylurea and amines, such as is shown in table 1-7, received the following connections.

Table 1-7:
Approx. No.AminReagentProductSu (%) /MS(m/z)
25Approx. 8acetylchlorideN-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-ndimethylacetamide (non-polar diastereoisomer)68(351)

Approx. No.AminReagentProductsu(%) /MS(m/z)
26Approx. 9methanesulfonyl chlorideN-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-methanesulfonic acid amide(polar diastereoisomer)36 (387)
27Approx. 9the cinnamic acid chloride(E)-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-phenyl-acrylamide (polar diastereoisomer)90 (439)
28Approx. 9acetylchloride(N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-ndimethylacetamide (polar diastereoisomer)65 (351)
29Approx. 8benzylsuccinic3-benzyl-1-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-1-methyl-urea (non-polar diastereoisomer)79 (442)
30Approx. 9benzylsuccinic3-benzyl-1-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-1-methyl-urea (polar diastereoisomer)88 (442)
31Approx. 8utilitzant1-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-3-ethyl-1-methyl-urea (depolarisation)60 (380)
32Approx. 9utilitzant1-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-3-ethyl-1-methyl-urea (polar diastereoisomer)100 (380)

Approx. No.AminReagentProductsu(%) /MS(m/z)
43Approx. 42, stage 4 (Napoleon.)the cinnamic acid chloride(E)-N-[[4-dimethylamino-4-(3-forfinal)-1-methyl-cyclohexyl]-methyl]-3-phenyl-acrylamide (non-polar diastereoisomer)96 (395)
44 Approx. 42, stage 4 (Napoleon.)(E)-2-phenylacetonitrile chlorides(E)-N-[[4-dimethylamino-4-(3-forfinal)-1-methyl-cyclohexyl]-methyl]-2-phenyl-atenololbuy acid amide (non-polar diastereoisomer)68 (431)
45Approx. 42, stage 4 (polar)(E)-2-phenylacetonitrile chlorides(E)-N-[[4-dimethylamino-4-(3-forfinal)-1-methyl-cyclohexyl]-methyl]-2-phenyl-atenololbuy acid amide(polar diastereoisomer)66 (431)
52Approx. 9diphenylacetyleneN-[4-(dimethyl-amino)-1,4-diphenyl-cyclohexyl]-N-methyl-2,2-diphenyl-ndimethylacetamide (polar diastereoisomer)23 (337)
57Approx. 8methanesulfonanilideN-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-methanesulfonic acid amide (non-polar diastereoisomer)15 (387)
64Approx. 60the cinnamic acid chloride(E)-N-[4-(cyclopentyl-methyl)-4-is metilamino-1-phenyl-cyclohexyl]-N-methyl-3-phenyl-acrylamide(depolarisation) 75 (445)

Approx. No.AminReagentProductSu (%) /MS(m/z)
65Approx. 61the cinnamic acid chloride(E)-N-[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-N-methyl-3-phenyl-acrylamide (polar diastereoisomer)63 (445)
81Approx. 82the cinnamic acid chloride(E)-N-[4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-phenyl-cyclohexyl]-N-methyl-3-phenyl-acrylamide (polar diastereoisomer)17 (492)
88Approx. 8the nicotinic acid chloride hydrochlorideN-[4-(dimethyl-amino)-1,4-diphenyl-cyclohexyl]-N-methyl-pyridine-3-carboxylic acid amide (non-polar diastereoisomer)58 (414)
92Approx. 91-methyl-1 H-pyrazole-3-carboxylic acid chlorideN-[4-(dim the Teal-amino)-1,4-diphenyl-cyclohexyl]-N,1-dimethyl-1H-pyrazole-3-carboxylic acid amide (polar diastereoisomer) 93 (417)
98Approx. 83-trifluoromethyl-benzoyl chlorideN-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-(trifluoromethyl)-benzamide (non-polar diastereoisomer)43 (481)
99Approx. 93-(trifluoromethyl)benzoyl chlorideN-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-(trifluoromethyl)-benzamide (polar diastereoisomer)67 (481)
104Approx. 84-methoxy-phenyl-carboxylic acid chlorideN-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-4-methoxy-N-methyl-benzamide (non-polar diastereoisomer)59 (443)

Approx. No.AminReagentProductsu(%) /MS(m/z)
105Approx. 94-methoxy-phenyl-carboxylic acid chlorideN-(4-dimethylamino-1,4-diphenyl-cyclohexyl)--methoxy-N-methyl-benzamide (polar diastereoisomer) 90 (443)
116Approx. 83-perbenzoateN-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-3-fluoro-N-methyl-benzamide (non-polar diastereoisomer)49 (431)
117Approx. 93-perbenzoateN-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-3-fluoro-N-methyl-benzamide(polar diastereoisomer)84 (431)
165Approx. 9cyclohexanecarbonyl acid chlorideN-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-cyclohexanecarboxylic acid amide(polar diastereoisomer)50(419)
166Approx. 9tetrahydro-Piran-4-carboxylic acid chlorideN-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-Tetra-hydro-Piran-4-carboxylic acid amide (polar diastereoisomer)30(421)
169Approx. 91-methyl-piperidine-4-carboxylic acid chloride N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N,1-dimethyl-piperidine-4-carboxylic acid amide (polar diastereoisomer)79(434)

Follow the instructions as described in example 48, step 2, except that the applied amides, such as is shown in table 1-8, received the following connections.

Table 1-8: BB-1:

N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-nicotinamide

A solution of the title compound from example 9 (308 mg, 1.0 mmol) and triethylamine (334 RL, 2.4 mmol) in absdf (15 ml) was mixed with nicotinic acid chloride hydrochloride (214 mg, 1.2 mmol) and 3 days. was stirred at RT. Then the solvent was removed in VAC., the remaining residue was dissolved in ethyl acetate, washed naration NaHCO3and naration NaCl, dried over Na2SO4and purified flash chromatography with ethyl ether acetic acid/Meon 1:1.

Yield: 300 mg (73%), porous solid

1H-NMR (DMSO): 1.67 (2H, m); 1.92 (2H, m); 1.98 (8 H, s); 2.48 (2H, m); 2.80 (3H, s); 7.15-7.41 (10 H, m); 7.52 (1H, m); 7.92 (1H, m); 8.69 (2H, m).

Approx. No.AmideProductSu (%) / MS (m/z)
85BB-1dimethyl-[4-[methyl-(pyridine-3-yl-methyl)-the Mino]-1,4-diphenyl-cyclohexyl]-amine (polar diastereoisomer) 37 (400)
89Approx. 89dimethyl-[4-[methyl-(pyridine-3-yl-methyl)-amino]-1,4-diphenyl-cyclohexyl]-amine (non-polar diastereoisomer)73 (400)
101Approx. 92(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-[(1-methyl-1H-pyrazole-3-yl)-methyl]-amine (polar diastereoisomer)71 (403)
102Approx. 93(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-[(1-methyl-1H-pyrazole-3-yl)-methyl]-amine (non-polar diastereoisomer)67 (403)
106Approx. 105(4-dimethylamino-1,4-diphenyl-cyclohexyl)-[(4-methoxyphenyl)-methyl]-methyl-amine (polar diastereoisomer)85 (429)
107Approx. 104(4-dimethylamino-1,4-diphenyl-cyclohexyl)-[(4-methoxyphenyl)-methyl]-methyl-amine (non-polar diastereoisomer)77 (429)
114Approx. 99(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-[[3-(reformer)phenyl]-methyl]-amine (polar diastereoisomer) 81 (467)

Approx. No.AmideProductSu (%) / MS (m/z)
115Approx. 98(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-[[3-(trifluoromethyl)phenyl]-methyl]-amine (non-polar diastereoisomer)42 (467)
118Approx. 116(4-dimethylamino-1,4-diphenyl-cyclohexyl)-[(3-forfinal)-methyl]-methyl-amine (non-polar diastereoisomer)98 (417)
119Approx. 117(4-dimethylamino-1,4-diphenyl-cyclohexyl)-[(3-forfinal)-methyl]-methyl-amine (polar diastereoisomer)99 (417)
167Approx. 165cyclohexyl-methyl-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amine (polar diastereoisomer)84 (405)
168Approx. 166(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-(tetrahydro-Piran-4-yl-methyl)-amine (polar di is streamer) 44 (407)
170Approx. 169(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-[(1-methyl-piperidine~4-yl)-methyl]-amine (polar diastereoisomer)93 (420)

Example 120:

2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-ethanol (polar diastereoisomer)

Stage 1:

methyl ester [(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-acetic acid

The title compound from example 9(463 mg, 1.50 mmol) were placed in absdf (10 ml) and was mixed with potassium carbonate (347 mg, 1.65 mmol) and methyl ether bromoxynil acid (157 RL, 1.65 mmol). Composition 3 days. was stirred at room temperature and then concentrated in HAC. to dryness. The remainder resuspendable in dichloromethane (50 ml) and washed with water (2×50 ml) and saturated NaCl solution (50 ml), the organic phase is then dried over Na2SO4and concentrated in the WAC. The residue was purified using flash chromatography with ethyl ether acetic acid/methanol (9:1).

Output: 338 mg (59%)

1H-NMR (DMSO-d6): 1.73 (4 H, m); 1.96 (6N, s); 2.04 (3H, s); 2.31 (4 H, m); 2.96 (2H, m); 3.58 (3H, s); 7.17 (2H, m); 7.28 (8 H, m).

Stage 2:

2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-ethanol (polar diastereoisomer)

The title compound from stage 1 (322 mg, 0.85 mmol) p who was storyli in absdf (15 ml), mixed with LiAlH4(64 mg, 1.69 mmol) under argon and 3 o'clock boiled in a flask with reflux condenser. Then the composition was cooled to room temperature, while cooling with ice was mixed with THF (10 ml) and N2O (5 ml) and was stirred 30 minutes. The composition was filtered through a Frit with diatomaceous earth and the diatomaceous earth was further washed with dichloromethane (50 ml). The combined filtrates were concentrated in the WAC. The crude product was mixed with water (10 ml) and was extracted with dichloromethane (3×20 ml). The organic phase was dried over Na2SO4and concentrated in the WAC. The residue was purified using flash chromatography with ethyl ether acetic acid/methanol (1:1). Output: 213 mg(71%)

1H-NMR (DMSO-d6): 1.72 (4 H, m); 1.95 (6N, s); 2.06 (3H, s); 2.19 (2H, m); 2.29 (4 H, m); 3.39 (2H, m); 4.25 (1H, m); 7.17 (2H, m); 7.27 (8 H, m).

Example 122:

2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-N-methyl-ndimethylacetamide (polar diastereoisomer)

The title compound from example 66 (293 mg, 0.8 mmol) was dissolved in abs. DMF (10 ml) and was mixed with N-hydroxybenzotriazole hydrate (135 mg, 0.88 mmol) and TEA (1.11 ml, 8.0 mmol). After 30 minutes was added N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (460 mg, 2.4 mmol) and methylamine (440 RL, 0.88 mmol, 2M solution in THF) and during the night was stirred at RT. The solution was filtered and concentrated in HAC.

Table 1-9:
Approx. No.Ex. productAminProductSu (%)/MS(m/z)
121Primdimethylamine2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-N,N-dimethyl-ndimethylacetamide (polar diastereoisomer)17(394)
123Primdimethylamine2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-N,N-dimethyl-ndimethylacetamide (non-polar diastereoisomer)55(380)
124Primmethylamine2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-N-methyl-ndimethylacetamide (non-polar diastereoisomer)55(394)

Example 127:

2-[[4-(dimethyl-amino)-1,4-diphenyl-cyclohexyl]-methyl-amino]-ethanol (non-polar diastereoisomer)

Stage 1:

methyl ester of 4[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-amino]-acetic acid

By flash chromatography of the residue with ethyl ether acetic acid/Meon (4:1→1:1) was obtained salt is the product, which was allocated by 1N NaOH, extracted with CH2Cl2, dried over Na2SO4and in the WAC. freed from the solvent. Output: 182 mg(60%)

1H-NMR (DMSO): 1.47 (2H, m); 1.96 (7 H, s); 1.99 (3H, s); 2.24 (3H, m); 2.42 (2H, m); 2.64 (6N, m); 7.24 (9 H, m); 7.60 (1H, m).

Follow the instructions as described in example 122 except that was used is shown in table 1-9 acids and amines were obtained the following compounds.

The title compound from example 8 (463 mg, 1.50 mmol) were placed in the abs. DMF (10 ml) and was mixed with potassium carbonate (347 mg, 1.65 mmol) and methyl ether bromoxynil acid (157 RL, 1.65 mmol). Composition 3 days. was stirred at room temperature and then concentrated in HAC. to dryness. The remainder resuspendable in dichloromethane (50 ml) and washed with water (2×50 ml) and saturated NaCl solution (50 ml)then the organic phase was dried over Na2SO4and concentrated in the WAC. The residue was purified using flash chromatography with ethyl ether acetic acid/methanol (9:1). Output: 234 mg (41%)

1H-NMR (DMSO-d6): 1.72 (4 H, m); 1.84 (6N, s); 1.93 (3H, s); 2.27 (4 H, m); 2.87 (2H, m); 3.48 (3H, s); 7.26 (2H, m); 7.38 (8 H, m).

Stage 2:

2-[[4-(dimethyl-amino)-1,4-diphenyl-cyclohexyl]-methyl-amino]-ethanol (non-polar diastereoisomer)

The title compound from stage 1(228 mg, 0.60 mmol) was dissolved in abs. THF (10 ml)under argon was mixed with LiAlH4(45 mg, 1.20 mmol)and 3 hours boiled in a flask with reflux condenser. Then the composition was cooled to room temperature, while cooling with ice was mixed with THF (10 ml) and N20 (5 ml) and was stirred 30 minutes. The composition was filtered through a Frit with diatomaceous earth and the diatomaceous earth was re-washed with dichloromethane (50 ml). The combined filtrates were concentrated in the WAC. The crude product was mixed with water (10 ml) and was extracted with dichloromethane (3×20 ml)then the organic phase was dried over Na2SO4and concentrated in the WAC. The residue was purified using flash chromatography with ethyl ether acetic acid/methanol(9:1→4:1). Output: 174 mg(82%) melting Point: 144-149 °C

1H-NMR (DMSO-d6): 1.73 (4 H, m); 1.84 (6N, s); 1.96 (3H, s); 2.09 (2H, m); 2.27 (4 H, m); 3.23 (2H, m); 4.14 (1H, m); 7.25 (2H, m); 7.38 (8 H, m).

Example 128:

[4-[[4,6-bis(dimethylamino)-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

Stage 1:

N-(4,6-dichloro-[1,3,5]triazine-2-yl)-N,N',N'-trimethyl-1,4-diphenyl-cyclohexane-1,4-diamine

Cyanuric chloride (86 mg, 0.49 mmol) were placed in the abs. THF (3 ml), was mixed with a solution of the title compound from example 8 (150 mg, 0.49 mmol) in abs. THF (6 ml) and L/-ethyldiethanolamine (80 RL, 0.49 mmol) and 16 hours was stirred at RT. The solution was concentrated in VAC., the remainder resuspendable in ethyl acetate (20 ml) and washed with saturated solution of NaHCO3(2×10 ml) and saturated the NaCl solution (10 ml). The organic phase was dried over Na2SO4and concentrated in the WAC. The crude product was purified by flash chromatography with ethyl ether acetic acid/Meon (20:1). Yield: 67 mg (30%)

13C-NMR (CDCl3): 30.4, 31.4, 33.6, 38.0, 59.3, 66.4, 126.4, 126.7, 127.0, 127.1, 127.7, 128.2, 137.6, 143.1, 165.4, 168.0, 169.1

Stage 2:

[4-[[4,6-bis(dimethylamino)-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

The title compound from stage 1 (57 mg, 0.12 mmol) was dissolved in a 2M solution of dimethylamine in THF (2.0 ml, 4 mmol), and when the microwave was stirred 2 hours at 120°Creazioni the solution was concentrated in VAC., the remaining balance resuspendable in ethyl acetate (10 ml) and washed with saturated solution of NaHCO3(2×5 ml) and saturated NaCl (5 ml). The organic phase was dried over Na2SO4and concentrated in the WAC. The crude product was purified by flash chromatography with ethyl ether acetic acid/Meon (20:1).

Melting point: 195-197°Exit: 45 mg (76%)

1H-NMR (DMSO-d6): 1.62 (2H, m); 1.98 (6N, s); 2.39 (2H, m); 2.46 (2H, m); 2.91 (12 H, s); 3.13 (3H, s); 7.15 (1H, m); 7.22 - 7.38 (9 H, m).

Example 130:

4-[[4-(dimethyl-amino)-1,4-diphenyl-cyclohexyl]-methyl-amino]-butane-1-ol (polar diastereoisomer)

Stage 1:

Tert-butyl ester 1H-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-1-methyl-succinic acid

The title compound from the example of the 131 (100 mg, 0.244 mmol) were placed in abstimmen (5 ml), was mixed with the anhydride triperoxonane acid (135 RL, 0.976 mmol) and was stirred 10 minutes. To the composition was added tert-butanol (2 ml) and was stirred 30 minutes. Then the composition was mixed with 10%NaOH and the phases were separated. The organic phase was washed with H20 (1×10 ml), dried over Na2SO4and concentrated in the WAC. Yield: 80 mg (70%)

1H-NMR (DMSO-d6): 1.38 (9 H, s); 1.53 (2H, m); 1.78 (2H, m); 1.92 (6N, s); 2.37 (3H, m); 2.62 (2H, m); 2.93 (3H, s), 7.11-7.27 (6N, m); 7.36 (4 H, m).

Stage 2:

4-[[4-(dimethyl-amino)-1,4-diphenyl-cyclohexyl]-methyl-amino]-butane-1-ol (polar diastereoisomer)

The title compound from stage 1 (836 mg, 1.8 mmol) was dissolved in abs. THF (15 ml). Under argon was added LiAlH4(136 mg, 3.6 mmol), 2 hours boiled in a flask with reflux condenser, cooled to room temperature and was stirred overnight. Under ice cooling to the composition was added THF (2 ml) and N2About (2 ml) and stirred 30 minutes, the Composition was filtered through a Frit with diatomaceous earth, diatomaceous earth was washed with dichloromethane (50 ml), the organic phases were combined and concentrated in VAC. The residue was purified by flash chromatography with chloroform/methanol (9:1). Output: 405 mg (59%)

1H-NMR (DMSO-d6): 1.39 (4 H, m); 1.74 (3H, m); 1.96 (6N, s); 2.01 (3H, s); 2.11 (2H, m); 2.30 (3H, m); 3.36 (2H, m); 4.41 (1H, m); 7.18 (2H, m); 7.28 (8 H, m).

Example 131:

3-[[4-(dimethyl-amino)-1,4-given the l-cyclohexyl]-methyl-carbarnoyl]-propionic acid (polar diastereoisomer)

The anhydride of succinic acid (0.97 g, 9.27 mmol) was heated to 130°C. and melted. Then was added the title compound from example 9 (1.00 g,. 3.24 mmol) and 7 hours then heated at this temperature. The composition was purified by flash chromatography with chloroform/methanol(9:1→4:1→1:1→1:2→methanol). Yield: 1.08 g (81%)

1H-NMR (DMSO-d6): 1.55 (2H, m); 1.81 (2H, m); 1.94 (6N, s); 2.37 (4 H, m); 2.62 (2H, m); 2.76 (1H, m); 2.94 (3H, s); 7.14 (3H, m); 7.17 (2H, m); 7.26 (1H, m); 7.38 (4 H, m).

Example 146:

[4-[[4-(4-methoxy-phenoxy)-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

Stage 1:

N-(4-chloro-[1,3,5]triazine-2-yl)-N,N',N'-trimethyl-1,4-diphenyl-cyclohexane-1,4-diamine

A solution of the title compound from example 9 (462 mg, 1.5 mmol), 2,4-dichloro-1,3,5-triazine (225 mg, 1.5 mmol) and diisopropylethylamine (248 RL, 1.5 mmol) in abs. THF (10 ml) was stirred overnight at RT. Then the solvent was removed in VAC., the remaining residue was dissolved in ethyl acetate, washed naration of Na and naration NaCl, dried over Na2SO4and purified flash chromatography with ethyl ether acetic acid/Meon (9:1). Yield: 166 mg (26%)

1H-NMR (CDCl3): 1.97 (4 H, m); 2.06 (6N, s); 2.47 (4 H, bs); 3.01 (2H, W); 3.34 (3H, s); 7.14-7.40 (10 H, m); 8.29 (1H, s).

Stage 2:

[4-[[4-(4-methoxy-phenoxy)-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

The title is Obedinenie stage 1 (166 mg, 0.39 mmol), 4-methoxyphenol (56 mg, 0.45 mmol) and sodium hydride (18 mg, 0.45 mmol, 60%dispersion in mineral oil) in abscissae (10 ml) was stirred 4 h at RT. Then the solvent was removed in VAC., the remaining residue was dissolved in ethyl acetate, washed naration NaHC3and us. NaCl, dried over Na2SO4and purified flash chromatography with ethyl ether acetic acid/Meon (4:1).

Yield: 126 mg (63%), porous solid

1H-NMR (CDCl3): 1.84 (4H, s); 2.03 (6N, s); 2.60 (4H, width); 3.23 (3H, s); 3.80 (3H, s); 6.87 - 7.38 (14 N, W); 8.37 (1H, s).

Example 149:

[4-[(benzyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethyl-amine step 1:

Dimethyl 4-cyano-4-phenyl-heptadecanoic acid

Phenylacetonitrile (11.7 g, 100 mmol) and methyl acrylate (47 ml, 500 mmol) were placed in tert-butanol (60 ml) and heated to boiling. Then deleted the heat source. Dissolved in tert-butanol (23 ml) and Triton b (hydroxide designed, 40%in methanol, 15.2 ml) was injected dropwise slowly at first, then immediately. After addition of the composition to 4 h was heated to boiling. Over night the reaction mixture was cooled to room temperature. For processing the composition was mixed with toluene (100 ml) and water (70 ml), the organic phase was separated and washed with water (70 ml) and saturated NaCl solution (50 ml). After drying with Na 2SO4the solvent drove away. Purification was performed by distillation in vacuo (Kugelrohr) at a temperature of approx. 235 "Sproduct may be allocated in the form of a colorless, viscous flow of the substance. Output: 22. 5 g (75%)

1H-NMR (DMSO-d6): 2.32 (8 N, PL); 3.51 (6N; s); 7.40 (5 H, m).

13C-NMR (DMSO-d6): At 22.47; 27.16; at 39.28; 44.11; 113.82; 118.55; 120.83; 121.78; 129.10; 164.44.

Stage 2:

Methyl ester of 5-cyano-2-oxo-5-phenyl-cyclohexanecarboxylic acid

Dimethyl 4-cyano-4-phenylheptanoic acid (19.8 g, 68 mmol) was dissolved in dry Tetra hydrofera not (480 ml). Then portions were added mpem.-butyl potassium (13.2 g, 120 mmol). With this addition the reaction mixture turned orange. After that 5 o'clock boiled in a flask with reflux condenser. During boiling was formed brown solution. Over night the reaction mixture was cooled to room temperature. Under ice cooling to the reaction mixture was slowly allowed dropwise 2.5N acetic acid (230 ml). Then the composition was mixed with toluene (100 ml), the organic phase was separated and washed with saturated solution of NaHCO3(3×100 ml), N2O (3×50 ml) and NaCl solution (1 x 100 ml). After drying with Na2SO4the solvent drove in the WAC. Remained yellowish solid. Yield: 16.1 g (92%) melting point: 75-77°C

1H-NMR (DMSO-d sub> 6): 2.23-2.74 (6N, m); 3.74 (3 H, s); 7.35-7.60 (5 H, m); 12.08 (1H, bs).

13C-NMR (DMSO-d6): 26.95; 30.18; 34.04; 51.90; 94.79; 121.90; 125.46; 128.05; at 128.85; 138.92; 169.95; 171.09.

Stage 3:

4-oxo-1-phenyl-cyclohexanecarbonitrile

Methyl ester of 5-cyano-2-oxo-5-phenylcyclohexanecarboxylic acid (16.1 g, 63 mmol) was dissolved in 10%sulfuric acid (218 ml) and conc. acetic acid (502 ml) and 21 o'clock was stirred at 100 °C.

For processing the composition when cooled with ice was carefully diluted with water (400 ml), extracted with ethyl acetate (3×100 ml), the organic phase is thoroughly washed with water (6×100 ml), saturated solution of N3(10×100 ml) and saturated NaCl (1×100 ml). After drying with Na2SO4the solvent drove in the WAC.

Output: 8.91 g (72%)

Melting point: 106-107°C

1H-NMR (DMSO-d6): 2.38-2.48 (6N, m); 2.70 (2H; m); 7.36 (1H, m); 7.44 (2H, m); 7.62 (2H, m).

13C-NMR (DMSO-d6): At 35.31; 38.10; 42.33; 121.73; 125.65; 128.19; 129.02; 139.17; 208.79.

Stage 4:

8-phenyl-1,4-dioxa-Spiro[4.5]decane-8-carbonitrile

The title compound of stage 3 (8.91 g, 44.73 mmol) resuspendable in toluene (300 ml) and was mixed with ethylene glycol (6 ml, 106.8 mmol). After adding p-toluenesulfonic acid (0.128 g, 0.745 mmol) composition 3.5 hours was heated in a water separator to a boil. The reaction was observed by TX.

After cooling the reaction mixture in toluene solution extragere is whether water (5×60 ml) and saturated NaCl solution (3×40 ml) and dried over Na 2SO4. After removal of the solvent in the WAC. Received ketal in the form of a yellow solid.

Yield: 11.6 g (100%)

Melting point: 108-110°C

1H-NMR (DMSO-d6): 1.86 (4H, m); 2.01-2.30 (4H, m); 3.92 (4H, s); 7.38-7.53 (5H, m).13C-NMR (DMSO-d6): 32.10; at 34.07; 42.49; 63.86: 106.11; 122.14; 125.51; 128.16; 129.02; 139.90.

Stage 5:

8-phenyl-1,4-dioxa-Spiro[4.5]decane-8-carboxylic acid

The title compound from stage 4 (10.9 g, 46.9 mmol) was dissolved in ethylene glycol (92 ml)was mixed with NaOH (4.00 g, 100 mmol) and then heated in a flask under reflux to boiling. After 20 hours was not found nitrile. For processing the composition was mixed with ice (approx. 250 g), covered by a simple ether (90 ml) and acidified by slow addition of polutants. HCl (118 ml). The aqueous phase was extracted with simple ether (3×70 ml), the combined organic extracts were washed with saturated solution of NH4Cl (2×70 ml), dried over Na2SO4and concentrated to dryness in HAC. By recrystallization of the remaining sediment from the toluene was allocated the desired carboxylic acid in the form of a crystalline solid. Output: 7.42 g (59%) melting Point: 134-139°C

1H-NMR (DMSO-d6): 1.64 (4 H, m); 1.91 (2H; m); 2.41 (2H, m); 3.86 (4 H, s); 7.36 (5 H, m); 12.52 (1H, bs).13C-NMR (DMSO-d6): 31.51; 32.05; 49.19; 63.65: 107.23; 125.70; 126.94; 128.39; 142.82; 175.53.

8-phenyl-1,4-dioxa-Spiro[4.5]decane-8-karbonvansty benzyl-methyl-amide

The title compound from stage 5 (8.00 g, 30.48 mmol) was dissolved in dichloromethane (240 ml) and at 0°C was mixed with 1,3-diisopropylcarbodiimide (4.44 g, 5.44 ml, 35.52 mmol) and 1-hydroxy-1H-benzotriazole hydrate (5.44 g, 35.5 mmol). The reaction composition was stirred 5 minutes while cooling with ice and then added N-benzylmethylamine (3.87 g, 4.12 ml, 32.0 mmol). The reaction mixture is 3 days. was stirred at room temperature. For processing the composition was concentrated in the WAC. to dryness. The residue was purified by flash chromatography with cyclohexane/ethyl acetate (1:1). Output: 7.31 g (66%)

1H-NMR (DMSO-d6): 1.61 (4H, m); 1.68 (4H, m); 2.35 (3H, m); 3.85 (6N, s); 7.28 (10H, br m).

Step 7:

Benzyl-methyl-(8-phenyl-1,4-dioxa-Spiro[4.5]Dec-8-ylmethyl)-Amin

The title compound of stage 6 (1.20 g, 3.28 mmol) was dissolved in obstetrician (160 ml), LiAlH4(0.25 g, 6.59 mmol) under argon was added and was stirred 5 hours at the boiling flask with reflux condenser. Then the composition was cooled to room temperature and was stirred overnight. Under ice cooling, the composition of the hydrolyzed with THF (20 ml) and N2O (20 ml) and was stirred 30 minutes. The composition was filtered through a Frit with diatomaceous earth, repeatedly washed with THF and dichloromethane (50 ml) and concentrated in HAC. The residue was purified using flash chromatography and cyclohexane/ethyl acetate (1:1). Yield: 0.50 g (43%)

1H-NMR (DMSO-d6

4-[(benzyl-methyl-amino)-methyl]-4-phenyl-cyclohexanone

The title compound from stage 7 (3.40 g, 9.67 mmol) was mixed with 5%sulfuric acid (300 ml) and 48 hours at room temperature and was stirred. For processing the reaction composition was mixed with simple ether (100 ml), the phases were separated and the aqueous phase was extracted with simple ether (2×100 ml). Then the aqueous phase was podslushivaet by 5N NaOH and was extracted with dichloromethane (3×100 ml). The organic phase was dried over Na2SO4that was filtered and HAC. concentrated to dryness. Output: 2.74 g (92%)

1H-NMR (DMSO-d6): 1.79 (3H, s); 2.07 (2H, m); 2.16 (5 H, m); 2.22 (1H, m); 3.26 (2H, s); 7.22 (6N, m); 7.37 (2H, t), 7.55 (2H, d).

Step 9:

4-[(benzyl-methyl-amino)-methyl]-1-methylamino-4-phenyl-cyclohexanecarbonitrile

To a cooled to 0°C. a solution of 4N hydrochloric acid (2.33 ml) and methanol (1.40 ml) was added 40%aqueous solution of methylamine (5.40 ml, 42.7 mmol) and the title compound from stage 8 (2.74 g, 8.91 mmol)dissolved in methanol (10 ml). Then the reaction mixture was mixed with potassium cyanide (1.40 g, 21.1 mmol) and 1-ordinator. at room temperature was stirred. For processing the mixture was mixed with water (30 ml) and simple ether (3×50 ml) were extracted. The combined organic phases were dried with Na2SO4that was filtered and conc is listed in the WAC. Output: 2.69 g (90%)

1H-NMR (DMSO-d6): 1.11 (2H, m); 1.68 (1H, m); 1.72 (2H, m); 1.78 (1H, m); 1.86 (2H, s); 1.92 (2H, m); 2.22 (2H, d). 2.28 (1H, m); 2.38 (2H, m); 2.67 (1H, m); 3.17 (1H, m); 3.29 (2H, m); 7.25 (10 H, m).

Step 10:

{4-[(benzyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl}-methyl-amine Finality (12.9 ml, 23.2 mmol, 1.8 M in debutalbum ether) were placed under argon, is added dropwise was mixed with the title compound from stage 9 (2.69 g, 7.74 mmol) in THF (15 ml) and the reaction solution was stirred 1 h at boiling flask with reflux condenser. While cooling in an ice bath, the reaction composition is hydrolyzed with saturated solution of NH4Cl (27 ml) and the phases were separated. The aqueous phase was extracted with simple ether (3×50 ml). The combined organic phase was dried over Na2SO4, was filtered and was concentrated in the WAC. to dryness. The residue was separated using chromatotron and dichloromethane → dichloromethane/methanol (9:1)→ methanol. Allocated 1.20 g of the ketone. The target product was obtained as a mixture of diastereoisomer and as such were subject to further interaction. Output: 0.360 g (12%)

1H-NMR (DMSO-d6): 1.75 (1H, m); 1.79 (3H, s); 1.92 (1H, m); 2.02 (3H, m); 2.17 (6N, m); 2.46 (1H, m); 2.61 (2H, m); 7.25 (13 H, m); 7.54 (2H, m).

Stage 11:

[4-[(benzyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethyl-amine

A solution of the title compound from stage 10 (mixture of diastereomers) (0.350 g, 0.878 mmol) and formalin (1.23 ml, 37%wagnerstr) in acetonitrile (15 ml) portions was mixed with cyanoborohydride sodium (0.250 g, 3.86 mmol) and was stirred 45 minutes at room temperature. Then was added conc. acetic acid until neutral and was stirred 45 minutes at room temperature. For recycling the solvent was removed in VAC., the remainder resuspendable in 2N NaOH (40 ml) and then was extracted with simple ether (3×40 ml). The organic solution was dried over Na2SO4, was filtered and was concentrated in the WAC. The remaining residue was purified using chromatotron and with cyclohexane/ethyl acetate 1:1. It was impossible to achieve separation of the diastereomers. Yield: 70 mg(19%)

1H-NMR (DMSO-d6): 1.60 (4H, m); 1.72 (3H, s); 1.82 (6N, s); 2.14 (2H, m); 2.49 (4 H, s); 3.19 (2H, s); 6.93 (2H, m); 7.21 (5H, m); 7.40 (8 H, m).

Example 153:

[4-[[4-(benzylamino)-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

The title compound of example 146, step 1 (100 mg, 0.236 mmol), benzylamine (55 RL, 0.5 mmol) and diisopropylethylamine (50 RL, 0.3 mmol), dissolved in abs. THF (2.0 ml)at 70°C was stirred in a closed vessel for 5 hours Then the solvent was removed in VAC., the remaining residue was dissolved in dichloromethane, washed naration NaHCO3, dried over Na2SO4and purified flash chromatography with ethyl ether acetic acid/Meon(4:1→1:1). The product still contained benzylamine, which was removed in the WAC. at 90 °C.

Yield: 82 mg (70%), oil

H-NMR (CDCl3): 1.77 (4 H, m); 2.02 (6N, s); 2.37 (2H, m); 2.97 (2H, W); 3.28 (3H, s); 4.38 (2H, s); 6.01 (1H, s); 7.12-7.40 (15 H, m); 8.00 (1H, s).

Follow the instructions as described in example 153, except that was used is shown in table 1-10 amines, received the following connections.

Table 1-10
Approx. No.AminProductSu (%) /MS (m/z)
154cyclohexylamindimethyl-[4-[methyl-(4-piperidine-1-yl-[1,3,5]triazine-2-yl)-amino]-1,4-diphenyl-cyclohexyl]-amine (polar diastereoisomer)71(471)
155n-butylamine[4-[(4-butylamino-[1,3,5]triazine-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)68(459)
156aniline[4-[(4-aniline-[1,3,5]triazine-2-yl)-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)59(479)

Approx. No.ProductSu (%)/MS(t/2)
157isopropyl methylamine[4-[[4-(isopropyl-methyl-amino)-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)75(459)
158t-butylamine[4-[[4-(tert-butylamino)-[1,3,5]triazine-2-yl]-methyl-amino]-1,4-diphenyl-cyclohexyl]-dimethyl-amine(polar diastereoisomer)64(459)

Example 163:

[4-[(butyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

Stage 1:

8-phenyl-1,4-dioxa-Spiro[4.5]decane-8-carboxylic acid-butyl-methylamide

The title compound from example 149, step 5 (6.50 g, 24.8 mmol) was dissolved in dichloromethane (200 ml) and at 0°C was mixed with diisopropylcarbodiimide (3.60 g, 4.41 ml, 28.8 mmol) and 1-hydroxy-1H-benzotriazole hydrate (4.41 g, 28.8 mmol). The reaction composition was stirred 5 minutes while cooling with ice and then added L/-methylbutylamine (2.34 g, 3.08 ml, 26.0 mmol). The reaction mixture was 2 days. was stirred at room temperature. For processing the composition was concentrated in the WAC. to dryness. The residue was purified by flash chromatography with cyclohexane/ethylacetate the (2:1). Output: 3.50 g (43%)

1H-NMR (DMSO-d6): 0.95 (6N, m); 1.39 (2H, s); 1.80 (2H, m); 1.85 (6N, m); 2.24 (2H, m); 2.51 (1H, m); 3.10 (1H, LG m).); 3.84 (4 H, s); 7.23 (3H, m); 7.34 (2H, m).

Stage 2:

Butyl-methyl-(8-phenyl-1,4-dioxa-Spiro[4.5]Dec-8-ylmethyl)-Amin

The title compound from stage 1 (3.50 g, 10.6 mmol) was dissolved in obstetrician (400 ml), under argon was added LiAlH4(0.66 g, 17.5 mmol) and was stirred 5 hours at the boiling flask with reflux condenser. Then the composition was cooled to room temperature and was stirred overnight. Under ice cooling, the composition of the hydrolyzed with THF (20 ml) and N2O (20 ml) and was stirred 30 minutes. The composition was filtered through a Frit with diatomaceous earth, repeatedly washed with THF and dichloromethane (50 ml) and concentrated in HAC. The residue was purified using flash chromatography and cyclohexane/ethyl acetate(9:1→1:1).

Yield: 2.50 g (76%)

1H-NMR (DMSO-d6): 0.77 (3H, t); 1.19 (6N, m); 1.52 (2H, m); 1.77 (2H, m); 1.83 (3H, s); 2.05 (2H, m); 2.18 (2H, m); 2.31 (2H, s); 3.84 (4 H, br m); 7.19 (1H, m); 7.33 (4 H, m).

Stage 3:

4-[(butyl-methyl-amino)-methyl]-4-phenyl-cyclohexanone Title compound from stage 2 (2.50 g, 7.8 mmol) was mixed with 5%sulfuric acid (300 ml) and was stirred 48 hours at room temperature. For processing the reaction composition was mixed with simple ether (100 ml), the phases were separated and the aqueous phase was extracted with simple ether (2×100 ml). Then the aqueous phase was podslushivaet through the om 5N NaOH and was extracted with dichloromethane (3×100 ml). The organic phase was dried over Na2SO4that was filtered and HAC. concentrated to dryness. Yield: 1.53 g (73%)

1H-NMR (DMSO-d6): 0.78 (3H, t); 1.15 (4 H, br, m); 1.87 (3H, s); 1.93 (2H, m); 2.13 (6N, LG m); 2.45 (4 H, m); 7.25 (1H, t); 7.37 (2H, t); 7.49 (2H, d).

Stage 4:

4-[(butyl-methyl-amino)-methyl]-1-methylamino-4-phenyl-cyclohexanecarbonitrile

To a cooled to 0°C. a solution of 4N hydrochloric acid (1.50 ml) and methanol (0.89 ml) was added 40%aqueous solution of methylamine (3.42 ml, 27 mmol) and the title compound of stage 3 (1.54 g, 5.60 mmol)dissolved in methanol (5 ml). Then the reaction mixture was mixed with potassium cyanide (0.901 g, 13.4 mmol) and 3 days. was stirred at room temperature. For processing the mixture was mixed with water (50 ml) and was extracted with simple ether (3 x 100 ml). The combined organic phase was dried by Na2SO4, was filtered and was concentrated in the WAC.

Output: 1.76 g (100%)

1H-NMR (DMSO-d6): 0.77 (3H, m); 1.07 (5 H, m); 1.68 (3H, m); 1.77 (1H, s); 1.84 (1 H, m); 1.92 (2H, m); 2.03 (1H, m); 2.12 (2H, m); 2.21 (2H, m); 2.31 (3H, m); 2.43 (1H, m); 2.63 (1H, m); 7.19 (1H, m); 7.37 (4 H, m).

Stage 5:

{4-[(butyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl}-methyl-amine

Finality (9.33 ml, 16.8 mmol, 1.8 M in debutalbum ether) were placed under argon, is added dropwise was mixed with the title compound from stage 4 (1.76 g, 5.61 mmol) in a simple ether (15 ml) and the reaction solution was stirred 1 h the ri 50°C. While cooling in an ice bath, the reaction composition is hydrolyzed with a saturated solution of NH4Cl (100 ml) and the phases were separated. The aqueous phase was extracted with simple ether (3×50 ml). The combined organic phase was dried over Na2SO4that was filtered and HAC. concentrated to dryness. The residue was separated using chromatotron and dichloromethane. Output: 0.400 g (20%), non-polar diastereoisomer

1H-NMR (DMSO-d6): 0.71 (3H, t); 1.05 (5 H, m); 1.59 (3H, m); 1.76 (6N, s); 2.01 (6N, m); 2.40 (2H, br s); 7.19 (2H, m); 7.34 (6N, m); 7.47 (2H, d). Output: 0.170 g (9%), polar diastereoisomer

1H-NMR (DMSO-d6): 0.76 (3H, t); 1.13 (4 H, m); 1.37 (2H, m); 1.75 (4 H, s); 1.86 (3H, m); 2.06 (6N, m); 2.41 (2H, s); 3.17 (1H, s); 7.13 (2H, m); 7.26 (6N, m); 7.38 (2H, m).

Step 6:

[4-[(butyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (non-polar diastereoisomer)

A solution of the title compound of stage 6 (non-polar diastereoisomer) (0.400 g, 1.1 mmol) and formalin (1.54 ml, 37%aqueous solution) in acetonitrile (20 ml) portions was mixed with cyanoborohydride sodium (0.313 g, 4.84 mmol) and was stirred 45 minutes at room temperature. Then was added conc. acetic acid until neutral and was stirred 45 minutes at room temperature. For recycling the solvent was removed in VAC., the remainder resuspendable in 2N NaOH (40 ml) and then was extracted with simple ether (3×40 ml). The organic phase was dried over Na2S 4, was filtered and was concentrated in the WAC.

The residue was purified using chromatotron and dichloromethane-methanol. Yield: 220 mg (53%)

1H-NMR (DMSO-d6): 0.70 (3H, t); 0.99 (4 H, m); 1.42 (2H, m); 1.58 (2H, m); 1.75 (3H, s); 1.86 (6N, s); 1.95 (2H, m); 2.16 (4 H, m); 2.32 (2H, m); 7.18 (1H, m); 7.38 (9 H, m).

Example 164:

[4-[(butyl-methyl-amino)-methyl]-1,4-diphenyl-cyclohexyl]-dimethyl-amine (polar diastereoisomer)

A solution of the title compound of example 163, step 6 (polar diastereoisomer) (0.170 g, 0.47 mmol) and formalin (0.66 ml, 37%aqueous solution) in acetonitrile (8.2 ml) in portions was mixed with cyanoborohydride sodium (0.134 g, 2.07 mmol) and was stirred 45 minutes at room temperature. Then was added conc. acetic acid until neutral and was stirred 45 minutes at room temperature. For recycling the solvent was removed in VAC., the remainder resuspendable in 2N NaOH (40 ml) and then was extracted with simple ether (3×40 ml). The organic phase was dried over Na2SO4)was filtered and concentrated in HAC.

The residue was purified using chromatotron and dichloromethane → methanol. Yield: 75 mg (41%)

1H-NMR (DMSO-d6): 0.77 (3H, t); 1.18 (5 H, m); 1.51 (2H, m); 1.76 (5 H, m); 1.94 (6N, s); 2.04 (3H, m); 2.27 (2H, m); 2.40 (2H, s); 7.23 (10 H, m).

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

This method examines the solubility of a substance when it is installed is oncentration (1 RM, 3 PM, 10 PM, 30 PM and 100 PM) in 10 mm phosphate buffer solution at pH 7.4.

Initially required a 10 mm solution of the compounds in DMSO, from which the 100-multiples of the basic solutions of the above concentration levels again in DMSO, final DMSO concentration in the test composition is 1% (v/v). The experiment is carried out with a multiple definition. After adding DMSO to the main solutions to the buffer, the composition is incubated for 2 hours at 37°C before is the determination of absorbance at 620 nm. Absorbance rises above pure solution buffer/DMSO, it is an indicator of sediment. Lower limit of solubility ("lower bound") is a concentration that precedes the first precipitate (for example, 3 RM, if the sediment was detected at 10 PM).

Research on the effectiveness of the compounds according to the invention

Measurement ORL1-link

Compounds were investigated in the analysis of the binding of the receptor with3N-nociceptin/orphanin FQ with membranes of recombinant CHO-ORL1 cells. This test system was carried out according to the method presented in Ardati et al. (Mol. Pharmacol., 51,1997, cc. 816-824). Concentration3H-nociceptin/orphanin FQ in this study was 0.5 nm. Analyses of binding were carried out using 20 WG membrane protein 200 RL of composition 50 mm HEPES, R is 7,4,10 mm MgCfe and 1 mm EDTA. Binding to the ORL1 receptor was determined using 1 mg of WGA-SPA beads (Beads (Amersham-Pharmacia, Freiburg), by one-hour incubation of the composition at room temperature and subsequent measurement in a Trilux scintillation counter (Wallac, Finland). Affinity are listed in table 1 as nanomolar Kivalue or % inhibition at C=1 µm.

Measurement of the µ-link

The affinity of the receptor for the human μ-opiate receptor was determined in a homogeneous composition in microtiter plates. To do this for 90 minutes at room temperature, incubated with the diluted series in each case, check the connection with a receptor membrane preparation (15-40 µg of protein per 250 l incubation composition) Cho-K1 cells, which Express the human μ-opiate receptor (RB-HOM receptor membrane preparation firm NEN, Zaventem, Belgium) in the presence of 1 nmol/l of the radioactive ligand [3H]-naloxone (NET719, firm NEN, Zaventem, Belgium)and 1 mg of WGA-SPA Beads (Wheat germ agglutinin SPA Beads company Amersham/Pharmacia, Freiburg, Germany) in a total volume of 250 RL.

As the incubation buffer used 50 mmol/l Tris-HCl supplemented to 0.05 wt.-% sodium azide and 0.06 wt.-% albumin serum of cattle. To determine nonspecific binding was further added 25 mol/l of naloxone. After ninety-minutes long, Inc. is belonoha period microtiter tablets for 20 minutes at 1000 g was separated by centrifugation and measured the radioactivity in a β-counter (Microbeta-Trilux, the company PerkinElmer Wallac, Freiburg, Germany). Determined the percentage displacement of the radioactive ligand from its binding to the human μ-opiate receptor at a concentration of reference substance in 1 mol/l and indicated as the percentage inhibition (% inhibition) of the specific binding. On the basis of the percentage displacement, due to the different concentrations of the control compounds of General formula IIC50partly expected inhibiting concentration, which contributed to a 50% displacement of the radioactive ligand. By recalculation using the proportion of Chen-Prusoff (Cheng-Prusoff) received Ki values for test compounds. In some cases, refused to determine Ki values determined only inhibition at a test concentration of 1 μm.

The definition of Kappa-binding

Definition occurred in a homogeneous composition in microtiter plates. To do this for 90 minutes at room temperature, incubated with the diluted series in each case, check the connections with a receptor membrane preparation (7 µg of protein per 250 RL incubation composition) Cho-K1 cells, which Express the human K-opiate receptor in the presence of 1 nmol/l of the radioactive ligand [3H]-Cl-977 and 1 mg of WGA-SPA Beads (Wheat germ agglutinin SPA Beads company Amersham/Pharmacia, Freiburg, Germany) in a total volume of 250 µ is.

As the incubation buffer used 50 mmol/l Tris-HCl supplemented to 0.05 wt.-% sodium azide and 0.06 wt.-% albumin serum of cattle. To determine nonspecific binding was further added 100 nmol/l of naloxone. After ninety-minutes long incubation period of the microtiter plates for 20 minutes at 500 revolutions/minute was separated by centrifugation and measured the radioactivity In the counter (Microbeta-Trilux 1450, the company PerkinElmer Wallac, Freiburg, Germany). Determined the percentage displacement of the radioactive ligand from its binding to the human K-opiate receptor at a concentration of reference substance in 1 nmol/l and indicated as the percentage inhibition (% inhibition) of the specific binding. On the basis of the percentage displacement, due to the different concentrations of the control compounds could be calculated Yu5about inhibiting concentration, which contributed to a 50% displacement of the radioactive ligand. By recalculation using the proportion of Chen-Prusoff (Cheng-Prusoff) received Kj-values for controlling emissions. The results are shown in the table below:

9
Approx.% inhibition (ORL1) [1 µm]Ki (ORL1) environments. [µm] % inhibition (µ) [1 µm]Ki(µ) environments. [µm]
126not ODA.46not ODA.
29not ODA.22not ODA.
381not ODA.0not ODA.
4330,9438not ODA.
5370,635820,0705
6510,18830,049
7340,9948.1,16
814not ODA.30not ODA.
800,01775490,64
1018not ODA.34not ODA.
11870,006590,6
12530,365860,0805
13361,31660,155
1417not ODA.67not ODA.
1583not ODA.98not ODA.
1618not ODA.65not ODA.
17171,17 610,14
18950,00271000,00125
19940,017960,0475
20920,0111010,0011
21430,49570,78333
2243not ODA.92not ODA.
2313not ODA.15not ODA.
24820,063970,01425
25600,19910,0154
26 76not ODA.69not ODA.
27950,0049980,00805
28301,01360,895
29700,09980,0015
30930,001699,50,0022
31600,0955900,022
32650,051810,052
3393,955421,11
34271,89810,215
35290,99333not ODA.0,41
3630not ODA.not ODA.not ODA.

42 60
Approx.% inhibition (ORL1)[1 µm]Ki (ORL1) environments. [µm]% inhibition (µ)[1 µm]Ki (µ) environments. [µm]
37660,1025not ODA.2,455
3835not ODA.29not ODA.
39730,0535930,555
40840,0255460,445
4119not ODA.4,11
42281,3951010,0018
43350,755580,1305
44680,0775960,01335
45720,0485990,00124
46490,72840,188
47391,605650,755
48221,25480,9
49970,00155930,0615
5058 0,1045690,12
51910,00128900,044
52870,01930,018
5361not ODA.18not ODA.
5436not ODA.61not ODA.
5622not ODA.56not ODA.
5743not ODA.80not ODA.
58520,425710,115
59690,175800,034
470,53770,107
61560,37584to 0.032
62490,0895850,0475
63600,087910,0066
64830,0345960,0053
65490,435740,0925
66354,011810,23
6731not ODA.385,205
6815not ODA.43 not ODA.
69500,20667400,65
7028not ODA.77not ODA.
71380,36551,19

Approx.% inhibition (ORL1) [1 µm]Ki (ORL1) environments. [µm]% inhibition (µ) [1 µm]Ki (µ) environments. [µm]
72580,115401,695
73450,165840,027
74670,057520,66
75242,955 340,67
76550,295830,18
77980,000711000,0004
78390,73670,385
7996not ODA.95not ODA.
8091not ODA.99not ODA.
8182not ODA.91not ODA.
8253not ODA.78not ODA.
8347not ODA.82not ODA.
8472not ODA.97not ODA.
85990,00081not ODA.0,115
8635not ODA.not ODA.not ODA.
8753not ODA.not ODA.not ODA.
8854not ODA.not ODA.not ODA.
89241,075not ODA.0,325
90440,525not ODA.1,055
91980,00535not ODA.0,74
9297 0,015not ODA.0,00635
93840,235not ODA.0,045
9468not ODA.83not ODA.
9532not ODA.49not ODA.
9664to 0.108620,235
9718not ODA.32not ODA.
9891not ODA.101not ODA.
9997,50,000541000,0012
100850,217 2,4
101930,00245790,063
10218not ODA.37to 3.73
10325not ODA.64not ODA.
104670,033930,01
105930,000651010,0012

Approx.% inhibition (ORL1) [1 µm]Ki (ORL1) environments. [µm]% inhibition (µ) [1 µm]Ki (µ) environments. [µm]
106870,02980,435
10719 of 1.485381,995
10853not ODA.89not ODA.
10960not ODA.43not ODA.
110380,62780,155
111271,055600,42
11247not ODA.not ODA.not ODA.
11348not ODA.not ODA.not ODA.
114910,01385not ODA.0,13
115241,165not ODA. 1,66667
116850,021not ODA.0,014
117760,00013not ODA.0,00035
11852not ODA.not ODA.not ODA.
119890,00143not ODA.0,039
120360,465not ODA.2,9
121700,23not ODA.1,425
122830,0074not ODA.0,17667
12365not ODA.not ODA.2,595
14 23not ODA.not ODA.0,735
125352,05not ODA.0,255
12623not ODA.not ODA.not ODA.
12718not ODA.28not ODA.
128150,93460,255
12967not ODA.33not ODA.
130880,018620,415
13137not ODA.229,02
13252 0,19211,58
13334not ODA.37

not ODA.- not defined

The study of the pharmacological properties of the model compounds

The model of Chang (Chung): pain when mononeuropathy after spinal nerve ligatures

Animals: male rats Sprague Dawley (140-160 g), from commercial farmer (Janvier, Genest St. Isle, France)were kept under a 12:12 h rhythm of light-darkness. Optionally, the animals were supplied with food and tap water. Between the delivery of the animals and the operation has stood the interval of one week. After surgery, animals were subjected to the repeated testing over a period of time in 4-5 weeks and was sustained time of leaching, at least in one week.

Model description: under General anesthesia of pentobarbital (Narcoren ®, 60 mg/kg I.P. Pavlova., Merial GmbH, Hallbergmoos, Germany), exhibited the left L5 and L6 spinal nerves, while the removed piece of paravertebral muscles and part of the left spinal process of the L5 body of the lumbar vertebrae. Spinal nerves L5 and L6 were carefully isolated and tied a strong ligature (NC-silk black.USP 5/0, metric 1, Braun Melsungen AG, Melsungen, Germany) (Kim and Chung 1992). After ligature of the muscle and surrounding tissue was sutured and the wound behind the dug with metal clasps.

After a rest period of one week the animals were placed in cages with wire bottoms in order to measure mechanical allodynia. On the ipsilateral and/or contralateral hind paw each time was determined threshold otdergivanija using electronic Frey filament (Somedic AB, Malmo, Sweden). The median value of five stimulations were given data point. Animals were exposed to the test for 30 minutes and at different periods of time after application of a solution of the test substance or solution dosage basis. Data was defined as % maximum possible effect (%MPE) of the preliminary tests of individual animals (=0%MPE) and test values simulated (sham) control group (=100%MPE). Alternative were presented thresholds otdergivanija in grams.

Statistical estimation:ED50 values and 95% confidence limits were determined by semi-log regression analysis at the time of maximum activity. Data were analyzed variance analysis with repeated measurements, as well as using secondary analysis (post hoc) according to Bonferroni (Bonferroni). Group size typically was n=10.

Reference:Kim, S.H. and Chung.J.M., An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat, Pain, 50 (1992) 355-363.

The results are shown in the table below (Chung model):

Approx. No.MPE (%) (dose in µg/kg, rat, i.v.)
1125 (100)
5129 (100)
3016(100)

Compounds according to the invention of type E with W=-NHMe or NMe2 (Approx. 9,11 and 13) were compared with the corresponding compounds of type E with W=-IT (V-1 and V-2):

Etc.WQR3Ki (µ)/ Ki (ORL1)Ki (Kappa)/ Ki (ORL1)Ki (ORL1) environments. [µM]Ki (p) environments. [µm]Ki (Kappa) environments. [µm]
936650,0180,6401,170
111001930,0060,6001,160

Etc.WQR3Ki (µ)/ Ki (ORL1)Ki (Kappa)/ Ki (ORL1)Ki (ORL1) environments. [µM]Ki (µ) environments. [µM]Ki (Kappa) environments. [µm]
V-1:0,70,82,921,892,24
130,12,91,3100,1553,745
V-2:0,0031,461,0000,0031,460

As I confirm the above data comparison, the compounds according to the invention (W=-NHMe, or-NMe2compared to structurally similar substances (W=HE) have a higher selectivity in respect of the Kappa-opioid receptor (defined as 1/[KI(ORL1)/Ki(Kappa)]),. In addition, the substances according to the invention with a favorable ratio of ORL1/μ-affinity also have a high selectivity in respect of the µ-opioid receptor (defined as 1/[Ki(ORL1)/Ki(µ)]).

Compounds according to the invention of type 1 with n=0, X=-NMe and Q=phenyl (Approx. 27, 30, 31, 32, 49, 85 and 92) were compared with the compounds of the type F (V-3 to V-5) with Z=NMe or NCOR, R5,R6=N, W=NH, And1-4=CH and R1to R3from Y1to Y4and Y1' to Y4'(1):

Approx.RBThe diastereoisomerNephelometry (lower bound) µm
1Mefallspolar100
49fallspolar100
85fallspolar100
V-3:fallsNMepolar3
92fallspolar100
27fallspolar100
V-4:fallsfield is NYY 12
30fallspolar100

Approx.RBzThe diastereoisomerNephelometry (lower bound) µm
V-5:fallsnonpolar12
31fallsnonpolar100
32fallspolar100

As confirmed by the above comparison, the compounds according to the invention from examples 27, 30, 31, 32, 49, 85 and 92 compared to structurally similar compounds (V-3 to V-5) exhibit better solubility in aqueous medium, which in particular must provide pre is the property, taking into account the properties of absorption and/or bioavailability.

1. The compound of General formula (1)

where Y1, Y1', Y2, Y2', Y3, Y3', Y4and Y4' mean-H;
R1and R2independently of one another are H or-CH3; provided that R1and R2both do not mean-H;
Q means:
-C6-16aryl, unsubstituted or mono - or multiply substituted by-F, -Cl, -Br or-I; or
-heteroaryl;
R3means:
-C1-8-alkyl, unsubstituted or mono - or multiply substituted OR0where R0means unsubstituted-C1-3-alkyl;
unsubstituted-C3-6-cycloalkyl-C1-4-alkyl;
unsubstituted-C1-4-alkyl-C3-6-cycloalkyl;
-C6-16aryl, unsubstituted or mono - or multiply substituted by-F, -Cl, -Br, -I, -CN, -R0or0where R0means unsubstituted-C1-8-alkyl; or
-heteroaryl;
n means 0;
X is-NRA-;
RAmeans-H or-R0; where R0means unsubstituted-C1-4-alkyl; and
RBmeans-C(=O)R0; where R0means unsubstituted-C2-8alkenyl-C6-16aryl or unsubstituted-C1-8-alkyl-(C6-16-aryl)1-2;
and "alkyl" in each case represents a branched or unbranched, saturated with the first aliphatic hydrocarbon residue;
"alkenyl" in each case represents a branched or unbranched, mono - or multiply unsaturated aliphatic hydrocarbon residue;
"cycloalkyl" in each case represents a saturated alicyclic, mono - or multicyclone hydrocarbon residue, the number of cyclic carbon atoms which is mostly in the specified range (i.e. "C3-8"cycloolefin mainly has 3, 4, 5, 6, 7 or 8 cyclic carbon atoms);
"aryl" in each case independently denotes carbocyclic ring system with at least one aromatic ring, but without heteroatoms in this ring, and aryl residues optionally may be condensed with other saturated, (partially) unsaturated or aromatic ring systems, and aryl substituents may be the same or different and any possible position of the aryl;
"heteroaryl" means a 5-, 6 - or 7-membered cyclic aromatic residue, which contains 1, 2, 3, 4 or 5 heteroatoms, where the heteroatoms identically or differently represent a nitrogen, oxygen or sulfur, and the heterocycle may be unsubstituted or mono - or multiply substituted; and in the case of substitution of the heterocycle, the substituents may be the same or different and any possible position is heteroaryl; and the heterocycle can also be part of a bicyclic or polycyclic system;
and regarding the "heteroaryl" under the "mono - or multiply substituted" refers to mono - or multiple substitution of one or more hydrogen atoms of the ring system unsubstituted-C1-8-alkyl;
in the form of an individual stereoisomer or a mixture thereof, the free compounds and/or their physiologically compatible salts.

2. The compound according to claim 1, in which R3means-C6-16aryl, unsubstituted or mono - or multiply substituted by-F, -Cl, -Br, -I, -CN, -R0or0where R0means unsubstituted-C1-8-alkyl; or-heteroaryl.

3. The compound according to claim 2, which has the General formula (2.2)

where RCmeans-H, -F, -Cl, -Br, -I, -CN, or-OCH3.

4. The compound according to claim 3, in which
Q means-C6-16aryl, unsubstituted or mono - or multiply substituted by-F, -Cl, -Br or-I; or heteroaryl;
R1means-CH3;
R2means-N or-CH3;
X is-NRA-;
RAmeans-H or-C1-4-alkyl;
RBmeans unsubstituted-C(=O)-C2-8alkenyl-C6-16aryl or unsubstituted-C(=O)-C1-8-alkyl-(C6-16-aryl)1-2;
RCmeans-H, -F, -Cl, -Br, -I, -CN, or-OCH3;
n means 0.

5. The compound according to claim 4, in which
Q means-phenyl, not alseny or mono - or multiply substituted by-F, -Cl, -Br or-I; or indolyl;
R1means-CH3;
R2means-N or-CH3;
X is-NRA-;
RAmeans-H or-C1-4-alkyl;
RBmeans unsubstituted-C=O-C1-8-alkyl-(C6-16-aryl)1-2;
RCmeans-H, -F, -Cl, -Br, -I, -CN, or-OCH3;
n means 0.

6. The compound according to claim 1, selected from the group consisting of

and its physiologically compatible salts.

7. The compound according to claim 1, selected from the group consisting of:
-(E)-N-(4-dimethylamino-1,4-diphenylacetyl)-N-methyl-3-phenyl-acrylamide (non-polar diastereoisomer);
-(E)-N-(4-dimethylamino-1,4-diphenylacetyl)-N-methyl-3-phenyl-acrylamide (polar diastereoisomer);
-N-[4-(dimethylamino)-1,4-diphenylsiloxane]-N-methyl-2,2-diphenyl-ndimethylacetamide (polar diastereoisomer);
-(E)-N-[4-(cyclopentylmethyl)-4-dimethylamino-1-phenylcyclohexyl]-N-methyl-3-phenylacrylate (non-polar diastereoisomer);
-(E)-N-[4-(cyclopentylmethyl)-4-dimethylamino-1-phenylcyclohexyl]-N-methyl-3-phenylacrylate (polar diastereoisomer);
-(E)-N-[4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-phenylcyclohexyl]-N-methyl-3-phenylacrylate (polar diastereoisomer);
and its physiologically compatible salts.

8. A drug that has affinity for ORL1-receptor and µ-opioid receptor containing a therapeutically effective amount of at m is d one compound according to one of claims 1 to 7 in the form of an individual stereoisomer or a mixture thereof, the free compounds and/or their physiologically compatible salts, and suitable additives and/or auxiliary substances.

9. The use of compounds according to one of claims 1 to 7 in the form of an individual stereoisomer or a mixture thereof, the free compounds and/or their physiologically compatible salts to obtain drugs for the treatment of pain.

10. The use of compounds according to one of claims 1 to 7 in the form of an individual stereoisomer or a mixture thereof, the free compounds and/or their physiologically compatible salts to obtain drugs for the treatment of States of fear, stress and stress-related syndromes, depression, epilepsy, Alzheimer's disease, senile dementia, General cognitive dysfunctions, disorders of learning and memory (as nootrop), withdrawal symptoms, alcohol and/or drugs and/or abuse of drugs and/or alcohol, drug, drug dependency, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinnitus, pruritus, migraine, hearing loss, lack of motility of the intestine, eating disorders, anorexia, bulimia, locomotor disorders, diarrhoea, cachexia, urinary incontinence or as a muscle relaxant, anticonvulsive or anaesthetic or for co-admission for treatment with opioid analgesic for the treatment of diuresis or antinatriuretic, anxiolysis, for modulation of motor activity, for modulation of the distribution of neurotransmitters and treatment related neurodegenerative diseases, for the treatment of withdrawal symptoms and/or to reduce the narcotic potential of opioids.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compound for formula (1) , antioxidant, containing formula (1) compound or its salt as active ingredient, and to application of formula (1) compound or its salt for oxidant manufacturing. Invention also relates to formula (2) compound, which is intermediate for obtaining formula (1) compound.

EFFECT: formula compound, demonstrating antioxidant properties.

4 cl, 1 tbl, 13 ex

FIELD: chemistry.

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

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

22 cl, 1 tbl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5-membered heterocyclic compounds of general formula (I), their prodrugs or pharmaceutically acceptable salts, which possess xanthine oxidase inhibiting activity. In formula (I) T represents nitro, cyano or trifluoromethyl; J represents phenyl or heteroaryl ring, where heteroaryl represents 6-membered aromatic heterocyclic group, which has one heteroatom, selected from nitrogen, or 5-membered aromatic heterocyclic group, which has one heteroatom, selected from oxygen; Q represents carboxy, lower alkoxycarbonyl, carbomoyl or 5-tetrasolyl; X1 and X2 independently represent CR2 or N, on condition that both of X1 and X2 do not simultaneously represent N and, when two R2 are present, these R2 are not obligatorily similar or different from each other; R2 represents hydrogen atom or lower alkyl; Y represents hydrogen atom, hydroxy, amino, halogen atom, perfluoro(lower alkyl), lower alkyl, lower alkoxy, optionally substituted with lower alkoxy; nitro, (lower alkyl)carbonylamino or (lower alkyl) sulfonylamino; R1 represents perfluoro(lower alkyl), -AA, -A-D-L-M or -A-D-E-G-L-M (values AA, A, D, E, G, L, M are given in i.1 of the invention formula).

EFFECT: invention relates to xanthine oxidase inhibitor and pharmaceutical composition, which contain formula (I) compound.

27 cl, 94 tbl, 553 ex

FIELD: chemistry.

SUBSTANCE: invention relates to phenyl alkyl piperazines of formula (I) , in which: R1 represents independently on each other hydrogen atom, halogen atom, (C1-C5)alkyl group, (C1-C5)halogenalkyl group, (C1-C2)perfluoroalkyl group, (C1-C5)alkoxyl group or (C1-C2)perfluoroalkoxyl group; R2 stands for (C1-C5)alkyl group or (C1-C5)alkoxyl group, R3 represents (C1-C5)alkyl group; A represents =CH- and =N-; in form of base or additive salt with acid. Invention also relates to pharmaceutical composition for modulation of activity of TNF-alpha, which contains claimed compounds, and to method of their obtaining.

EFFECT: obtained are novel compounds which can be applied in medicine as medications for treating or preventing pain and/or diseases, associated with inflammatory of immune disorders.

24 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds, particularly novel pyridinone derivatives of formula (I) or stereochemically isomeric forms thereof, where R1 is C1-6alkyl or C1-3alkyl, substituted with C3-7cycloalkyl; R2 is a halogen, trifluoromethyl, C1-3alkyl or cyclopropyl; X is a covalent bond, O or O-CH2; Ar is an unsubstituted phenyl or phenyl substituted with n radicals R4, where n equals 1, 2 or 3; where each R4 is a halogen; or pharmaceutically acceptable addition salts or solvates thereof. The invention also relates to a pharmaceutical composition, having the activity of positive allosteric modulators of the metabotropic glutamate receptor subtype 2, based on compounds of formula I and use of compounds of formula I to prepare a medicinal agent for treating or preventing neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved.

EFFECT: novel compounds which can be useful in treating and preventing neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved are obtained and described.

15 cl, 4 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to N-[2,4-dioxo-6-(tetrahydrofuran-2-yl)-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]methanesulphonamide and N-[6-(1-isopropoxyethyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H- quinazolin-3-yl] methanesulphonamide, having antagonistic activity on the AMPA receptor. The invention also relates to a pharmaceutical composition.

EFFECT: use of said compounds to produce drugs for treating AMPA mediated conditions and primarily for treating epilepsy or schizophrenia.

6 cl, 81 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyranyl aryl methylbenzoquinazolinone compounds of formula (I), which are positive allosteric modulators of the M1 receptor and which can be used to treat diseases associated with the M1 receptor, such as Alzheimer's disease, schizophrenia, pain disorders or sleep disturbance. In formula (I) X-Y are selected from a group comprising (1) -O-CRARB-, (2) -CRARB-O-, (3) -CRARB-SRC-, (4) -CRARB-NRC- and (5) -NRC-CRARB-, where each RA and RB is a hydrogen atom, and RC is selected from a group comprising (a) hydrogen, (b) -C(=O)-C1-6alkyl, (c) -C1-6alkyl, (d) -C(=O)-CH2-C6H5, (e) -S(=O)2-C1-6 alkyl, R1 is a hydroxy group, R2 is selected from a group comprising (1) -phenyl, (2) - heteroaryl, where the phenyl or heteroaryl group R2 is optionally substituted; the rest of the values of the radicals are given in the claim.

EFFECT: obtaining novel pyranyl aryl methylbenzoquinazolinone compounds.

28 cl, 12 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of 2-nitroheterylthiocyanates, particularly 4-rhodano-5-nitropyrimidine and 2-rhodano-3-nitripyridine derivatives of general formula (I), optionally in crystalline form or in form of pharmaceutically acceptable addition salts thereof with acids or bases, having activity on fungal strains, fungal infection agents, for producing pharmaceutical compositions that are suitable for local application. The compounds are also active on strains that are resistant to existing drugs. In general formula (I) X=N or C-R3, R1 denotes a proton, a saturated or unsaturated linear alkoxy radical having 1-5 carbon atoms; a cycloalkyloxy radical having up to 6 carbon atoms; a saturated linear alkylmercapto radical having 1-3 carbon atoms; an amino radical having 1-10 carbon atoms, selected from a saturated or unsaturated linear mono- or dialkylamino radical or a cycloalkylamino radical, cyclic amino radical. Each of the cyclic groups can be substituted with 1-2 methyl groups, or a benzylamino group; R2 denotes a proton, a saturated or unsaturated linear alkyl radical having 1-5 carbon atoms, or a cyclic aliphatic radical having up to 6 carbon atoms, trifluoromethyl, styryl or methylmercapto group; R3 denotes a trifluoromethyl, formyl, acetyl, nitro, benzoyl, cyano group or an alkoxycarbonyl substitute having 1-3 carbon atoms in the alkoxy group.

EFFECT: improved properties of compounds.

5 cl, 3 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention relates to triazole compounds which are represented by specific chemical formulae and which can be used for preventing or treating diseases in which 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) participates, particularly dementia. It was found that the triazole derivative, in which one of 3rd and 5th positions of the triazole ring accommodates a (di)alkyl methyl or cycloalkyl, each substituted, -O-aryl or heterocyclic group, each of which can be substituted, or (lower alkylene)cycloalkyl, and the other position accommodates an aryl, heterocyclic or cycloalkyl group, each of which can be substituted, or a pharmaceutically acceptable salt thereof, has powerful inhibiting action on 11β-HSD1.

EFFECT: improved properties of the derivatives.

8 cl, 141 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyran derivatives of general formula (I), wherein Y represents a 5-, 6- or 7-member ring, preferentially a 5- member ring, methyl- or ethyl- mono- or polysubstituted and optionally unsaturated; R1, R2, R3, R4 represent (each independently) a hydrogen atom or a linear or branched C1-5-alkyl group; X is present or absent when X is present, all R5, R6, R7, R8, R9 are present, while X is a hydrogen atom or the group OZ wherein Z is a hydrogen atom or the group R10 or the group C(O)R10; when X is absent, there is a double bond at a carbon atom in the 4th position, and R7, R8 and R9, and one of R5 or R6 are present (if R6 is present, then R5 is absent, and conversely), or one of R5, R6 and R7, and one of R8 or R9 are present (if R8 is present, then R9 is absent, and conversely), or R7 represent a group =C(R11)(R12), and R5, R6, R8, R9 are present; each of the groups R5-R12, when present, independently represent a hydrogen atom or a linear or branched C1-5-alkyl or C2-5-alkenyl group. The invention also relates to method for making these compounds, a pharmaceutical composition and using at least one pyran of formula (I) as a perfuming agent.

EFFECT: preparing new pyran derivatives.

14 dwg, 1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the new naphtylene derivative having general formula (I-A) and to their pharmaceutically acceptable salts having the property of inhibition of the cytochrome ferment P450RAI (Cyp26) activity, to the pharmaceutic composition thereof and to the method of inhibition of cytochrome ferment P450RAI (Cyp26). , wherein X is selected from imidasolyl or triasolyl; R2 and R3, independently represent H, C1-10-alkyl; G1 is -NR72R82 or G1 and R3 taken together with attached carbon atom form 3-10-membered saturated ring or heterocyclic saturated ring containing N as heteroatom which is optionally substituted with substituting group R72, Z, R4b, R5b, Q1, R72, n2, n3 and n4 values are indicated in the formula of the invention.

EFFECT: present invention refers to the intermediates for compounds with general formula (I-A) and to their pharmaceutic salts thereof.

37 cl, 30 dwg, 7 tbl

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention describes compound of the general formula (3): wherein R15 represents a heterocyclic group chosen from 3-7-membered saturated or 4,7-membered unsaturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom, or 7-14-membered polycyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R16 represents a cycloalkyl group comprising 3-7 carbon atoms, monocyclic aromatic hydrocarbon group comprising 6-14 carbon atoms, or heterocyclic group chosen from 3-7-membered saturated or 4-7-membered unsaturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R17 represents a monocyclic aromatic hydrocarbon group comprising 6-14 carbon atoms or heterocyclic group chosen from 4-7-membered saturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R18 represents hydrogen atom or (C1-C)-alkyl group; X represents -S-, -SO- or -SO2; or N-oxide or S-oxide of this compound; their salt; or solvate of above described compound. Proposed compounds possess the inhibitory activity against producing/secretion of β-amyloid protein and can be used in treatment of such diseases as Alzheimer's disease, Down's disease and other diseases associated with amyloid deposition.

EFFECT: valuable medicinal properties of inhibitors.

7 cl, 1 tbl, 410 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

The invention relates to a new method of producing compounds of the formula I

< / BR>
where a represents a C1-C6is alkyl, aryl, mono - or Disaese F, Cl, Br, och3C1-C3-alkyl or benzyl, - inhibitors of 5-lipoxygenase, are useful for the treatment or relief of inflammatory diseases, Allergy and cardiovascular diseases

FIELD: chemistry.

SUBSTANCE: invention includes (a) at least one optical bleaching agent of formula (1) , wherein R1 denotes hydrogen or SO3M, R2 denotes hydrogen or SO3M, R3 denotes hydrogen or CH2CO2M, R4 denotes CH2CO2M, CH(CO2M)CH2CO2M or CH(CO2M)CH2CH2CO2M, where M denotes hydrogen, a cation of an alkali metal, ammonia, mono-methyl-di-C2-C3-hydroxyalkylammonium, dimethyl-mono-C2-C3- hydroxyalkylammonium, ammonium, which is mono-, di- or trisubstituted with a C2-C3 hydroxyalkyl radical, or a mixture of said compounds, (b) a magnesium salt or (c) binder, which is selected from a group consisting of natural starch, enzyme-modified starch, and chemically modified starch, wherein there are 0.1-15 parts of component (b) for one part of component (a). The invention also relates to a method of bleaching paper using said composition.

EFFECT: composition is a more efficient means of achieving high paper whiteness.

9 cl, 4 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) where R1 denotes hydrogen or SO3, R2 denotes hydrogen or SO3, R3 denotes hydrogen or CH2CO2, R4 denotes CH2CO2, CH(CO2)CH2CO2 or CH(CO2)CH2CH2CO2, and where M denotes a stoichiometric cation equivalent required to balance the anionic charge in formula (1) and is a combination of Mg2+ with at least 1 additional cation. The additional cations are selected from a group consisting of H+, a cation of an alkali metal, a cation of an alkali-earth metal other than Mg2+, ammonium, mono-C1-C4 alkyl-di-C2-C3-hydroxyalkylammonium, di-C1-C4-alkyl-mono-C2-C3-hydroxyalkylammonium, ammonium, which is mono-, di- or trisubstituted with a C2-C3 hydroxyalkyl radical, and mixtures thereof. The invention also relates to versions of the method of producing said compound and use of said compound in binding compositions for bleaching paper.

EFFECT: compound is a more efficient paper bleaching agent.

8 cl, 4 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: described is an improved method of producing melamine cyanurate which is used in different compositions as a flame retardant. The method involves reaction of cyanuric acid and melamine in molar ratio of 1:1 in the presence of 2-30% water of the weight of dry reactants at temperature ranging from 10 to 100°C in countercurrent air streams at pressure of 2-10 kgf/cm2. The method can be realised continuously.

EFFECT: end product is obtained with high output with low power consumption.

1 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: described is an improved method for synthesis of 2,5,8-triazido-sim-heptazine of formula (I) by reacting 2,5,8-trichloro-sim-heptazine with an azidation agent in form of sodium azide in the medium of aqueous acetone at room temperature, followed by extraction of the end product via deposition from water. The invention can be used in organic synthesis.

EFFECT: high-tech and cheap method for synthesis of 2,5,8-triazido-sim-heptazine of formula (I) from commercially available 2,5,8-trichloro-sim-heptazine and a cheap azidation agent in simpler conditions for synthesis and extraction of the end product with high output and purity.

FIELD: synthesis of phosphorus-containing derivatives of organic compounds.

SUBSTANCE: invention relates to method of preparing polyphosphates of organic compounds, to mixture of polyphosphates of organic nitrogenous bases, and to use of polyphosphates and mixture of polyphosphates as fire retardants for plastics, preferably thermoplastics and, more particularly, polyamides and polyesters. Polyphosphates of organic compounds are prepared via exchangeable decomposition of mixture of phosphorus pentoxide and at least one organic nitrogenous base with a compound releasing water when decomposed under reaction conditions, the latter compound being used in such molar proportion that water would release in amount corresponding to essentially two moles of water per one mole of phosphorus pentoxide. Water-releasing compound can be compound forming, along with water, only volatile decomposition products and this compound can be selected from group including anhydrous oxalic acid, oxalic acid dehydrate, and formic acid. Exchangeable decomposition reaction is conducted at 100 to 250°C. Mixture of polyphosphates of organic nitrogenous bases is characterized by following properties: when heated to 320°C it looses less than 2% of its mass; pH value of its 10% water suspension exceeds 5 at 25°C, preferably from 5.2 to 7.7 and, more preferably, from 5.8 to 7; its solubility in water is less than 0.1 g and preferably less than 0.01 g per 100 mL water.

EFFECT: expanded synthetic possibilities.

6 cl, 5 ex

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