HK1065305B

HK1065305B - Substituted 4-aminocyclohexanol derivatives

Info

Publication number: HK1065305B
Application number: HK04107861.7A
Authority: HK
Inventors: Bernd Sundermann; Hagen-Heinrich Hennies; Babette-Yvonne Kögel; Stephan Wnendt
Original assignee: Grunenthal Gmbh
Priority date: 2001-07-17
Filing date: 2002-07-15
Publication date: 2008-07-18

Description

The present invention relates to substituted 4-aminocyclohexanol derivatives, methods of their manufacture, medicinal products containing these compounds and the use of substituted 4-aminocyclohexanol derivatives for the manufacture of medicinal products for the treatment of various indications, in particular pain.

The heptadecapeptide nociceptin is an endogenous ligand of the opioid receptor receptor ORL1 (Meunier et al., Nature 377, 1995, p. 532-535), which belongs to the family of opioid receptors and is found in many regions of the brain and spinal cord (Mollereau et al., FEBS Letters, 341, 1994, p. 33-38, Darland et al., Trends in Neurosciences, 21, 1998, p. 215-221). The peptide is characterised by high affinity, with a Kd value of approximately 56 pM (Ardati et al., Mol. Pharmacol. 51, p. 816-824), and by high selectivity for the ORL1 receptor. The ORL1 receptor μ is homologous to the opioid receptor and is known to have a strong similarity to the ORL1 receptor and a similarity to the ORP1 receptor κ.The nociceptin-induced activation of the receptor leads to inhibition of the adenylate cyclase via coupling with Gi/o proteins (Meunier et al., Nature 377, 1995, p. 532-535). functional similarities of the μ, κ and δ opioid receptors to the ORL1 receptor are also present at the cellular level with respect to potassium channel activation (Matthes et al., Mol. Pharmacol. 50, 1996, p. 447-450; Vaughan et al., Br. J. Pharmacol. 117, 1996, p. 1609-1611) and inhibition of L, N and P/Q-type calcium channels (Con et al., Br. J. Pharmacol. 11-208, 1996, s. 205-207; Knoflach et al., J. Neuroscience, 1996, p. 665-674).

The nociceptin peptide has been shown to exhibit pronociceptive and hyperalgesic activity after intercerebroventicular application in various animal models (Reinscheid et al., Science 270, 1995, p. 792-794; Hara et al., Br. J. Pharmacol. 121, 1997, p. 401-408). These findings can be explained by the inhibition of stressed analgesia induction (Mogil et al., Neurosci. Letters 214, 1996, s131-134; and Neuroscience 75, 1996, p. 333-337). An anxiolytic activity of nociceptin has also been demonstrated in this context (Jenck et al., Proc.

On the other hand, an antinociceptive effect of nociceptin has been shown in various animal models, particularly after intrathecal application, in the Tail Flick test in the mouse (King et al., Neurosci. 223, 1997, 113-116), in the Flexor reflex model in the rat (Shu et al., Neuropeptides, 1998, 32, 567-571) or in the glutamate-stimulated spinal cord neurons (Faber et al., Br. J. Pharmacol., 119, 1996, p. 189-190); it has antinociceptive effects in the Tail Flick test in the mouse (King et al., Neurosci. 223, 1997, 113-116), in the Flexor reflex model in the rat (Xu et al., Neuroport, 1996, No 7, 2092-2094) and in the Spinal nerve neuron (Y. S. S., No 85, 969, No 87, Oct. 85, 1997-94). This effect has also been shown to be of particular interest in the Neuroimaging and Neuroimaging test (Neuroimaging and Neuroimaging), and in the Flexor reflex test in the rat (Neuroimaging and Neuroimaging, No 8, No. 969, No. 85, 1997-94).

The ORL1 receptor is also involved in the regulation of other physiological and pathophysiological processes, including learning and memory formation (Sandin et al., Eur. J. Neurosci., 9, 1997, pp. 194-197; Manabe et al., Nature, 394, 1997, pp. 577-581), hearing (Nishi et al., EMBO J., 16, 1997, pp. 1858-1864), food intake (Pomonis et al., NeuroReport, 8, 1996, pp. 369-371), regulation of blood pressure (Gumusel et al., Life Sci., 60, 1997, pp. 141-145; Campion and Kadowitz, Biochem. Biophysics. Resm., 239-34, 1997, pp. 3012), Epilepsy (Gutirez et al., 5316, Vol. 24, Nov. 28, 1998) and Abstract from the Annals of Neuroscience and Neurology (November 28, 1998) (Meeting, 28-12, and 28).Life Sciences, 60, 1997, PL 15-21). A review article by Calo et al. (Br.J. Pharmacol., 129, 2000, 1261 -1283) gives an overview of the indications or biological processes in which the ORL1 receptor plays a role or might play a role with high probability. These include: analgesia, stimulation and regulation of food intake, influence on μ-agonists such as morphine, treatment of withdrawal symptoms, reduction of the addictive potential of morphine, anxiolytic, modulation of physical activity, memory disorders, epilepsy; modulation of neurotransmitter release, particularly of glutamate, dopamine and serotonin, and thus impairment of neurotransmission; effects on the cardiovascular system, electrolyte excretion (high blood pressure, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atThe use of agonists and antagonists as anorectic, analgesic (also in co-administration with opioids) or nootropic, but also as antitussives, is discussed.

Accordingly, the potential uses of compounds that bind to and activate or inhibit the ORL1 receptor are diverse.

The purpose of the present invention was to make available active substances acting on the nociceptin/ORL1 receptor system, which would make them suitable for use in medicinal products, particularly for the treatment of the various diseases associated with this system according to the state of the art or for use in the indications mentioned therein.

The invention is therefore concerned with substituted 4-aminocyclohexanol derivatives according to the general formula I, Other , in which R1 and R2 are independently selected from H; C1-8 alkyl or C3-8 cycloalkyl, either saturated or unsaturated, branched or unbranched, simply or multiple substituted or unsubstituted; aryl or heteroaryl, either simply or multiple substituted or unsubstituted; or aryl, C3-8 cycloalkyl or heteroaryl, either simply or multiple substituted or unsubstituted, bound to C1-3 alkyl, where R1 and R2 are not both H, or the residues R1 and R2 together form a ring and mean CH2CH2OCH2CH2, CH2CH2NR5CH2CH2 or (CH2) 3-6, with R5 selected from H; C1-8 alkyl or C3-8 cycloalkyl, whether or not saturated or unsaturated, branched or unbranched,Aryl or heteroaryl, either simply or repeatedly substituted or unsubstituted; or aryl, C3-8, cycloalkyl or heteroaryl, either simply or repeatedly substituted or unsubstituted, bound by C1-3 alkyl groups; R3 is selected from C3-8 cycloalkyl, unsubstituted or simply or repeatedly substituted; or via a saturated or unsaturated, unbranched, substituted or unsubstituted C1-4 alkyl group bound to aryl, C3-8 cycloalkyl or heteroaryl, either unsubstituted or simply or repeatedly substituted; R4 is selected from C3-8 cycloalkyl, aryl or heteroaryl, either unsubstituted or simply or multiple substituted; -CHR6R7, -CHR6-CH2R7, -CHR6-CH2-CH2R7, -CHR6-CH2-CH2R7, -C(Y) R7, -C(Y) -CH2R7, -C(Y) -CH2R7 or -CY) -CH2-CH2R7; or -R8-L-R9 with Y = O, S or H2, with R6 selected from H, C1-7-alkyl,Saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted; or C ((O) O) C1-6-alkyl, saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted; and selected from R7 H; C3-8-cycloalkyl, aryl or heteroaryl, whether or not substituted, or simply or in multiple substitutions, with R8 selected from Aryl or heteroaryl, whether or not substituted, or simply or in multiple substitutions, with L selected from Other -C (O) -NH, -NH-C (O) -C (O) -O-O, -O-C (O) -O, -O, -S or -S (O) -O) 2 Other with R9 selected from Aryl or heteroaryl, whether or not substituted, or simply or in multiple substitutions, where appropriate, in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular enantiomers or diastereomers, in any mixing ratio; in the form of pictograms or in the form of acids or bases or salts thereof,in particular physiologically compatible salts, or in the form of their solvates, in particular hydrates.

All of these compounds or groups of compounds of the invention show excellent binding to the ORL1 receptor.

Err1:Expecting ',' delimiter: line 1 column 819 (char 818)

For the purposes of this invention, alkyl or cycloalkyl residues are saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which may be unsubstituted or single or multiple substitutions, C1-2-alkyl for C1 or C2 alkyl, C1-3-alkyl for C1, C2 or C3 alkyl, C1-4-alkyl for C1, C2, C3, or C4 alkyl, C1-5-alkyl for C1, C2, C3, C4, C4, or C5 alkyl, C1-6-alkyl for C1, C2, C3, C4, C5, or C6 alkyl, C1-7-alkyl for C2, C1, C5, C5, C5, C5, C5, C6, C6, C6, C6, C8, C8, C8, C8, C8, C8, C8, C8, C8, C8, C8, C8, C8, C8, C8, C8, C8, C8, C8, C8, C8, C8, C8, C8, C8, C8, C8, C9, C8, C8, C9, C9, C9, C9, C9, C9, C1-8 and C1-10 alkyl.C2-, C3--, C4--, C5--, C6--, C7--, C8--, C9--, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17- or C18-alkyl. C3-4-cycloalkyl for C3- or C4-cycloalkyl, C3- or C5-cycloalkyl for C3- or C4- or C5-cycloalkyl, C3- or C6-cycloalkyl for C3-, C4-, C5- or C6-cycloalkyl, C3- or C7-cycloalkyl for C3-, C4-, C5-, C6- or C7-cycloalkyl, C3- or C8-cycloalkyl for C3- or C4-, C5-, C6- or C7-cycloalkyl, C3- or C5-cycloalkyl, C4- or C5- or C5-cycloalkyl, C5- or C5- or C5-cycloalkyl, C5- or C5- or C5-cycloalkyl, C5- or C5- or C5-cycloalkyl, C5- or C5- or C5-cycloalkyl, C5- or C5- or C5- or C5-cycloalkyl, C5- or C5- or C5- or C5-cycloalkyl, C5- or C5- or C5- or C5-cycloalkyl, C5- or C5- or C5- or C5- or C5-cycloalkyl, C5- or C5- or C5- or C5- or C5-cycloalkyl, C5- or C5- or C5- or C5- or C5- or C5-cycloalkyl, C5- or C5- or C5- or C5- or C5- or C5-cycloalkyl, C5- or C5- or C5- or C5- or C5- or C5-cycloalkyl, C5- or C5- or C5- or C5- or C5- or C5-cycloalkyl, C5- or C5- or C5- or C5- or C5- or C5- or C5-cycloalkyl, C5- or C5- or C5- or C5- or C5- or C5- or C5- or C5-cycloalkyl, C5- or C5- or C5- or C5- or C5- or C5- or C5- or C5- or C5-C5-The term cycloalkyl includes in particular mono- or mono-unsaturated cycloalkyl with no heteroatom in the ring, preferably simple, as long as the cycloalkyl does not constitute an aromatic system. The alkyl or cycloalkyl residues are preferably methyl, ethyl, vinyl (ethylene), propyl, allyl (2-propenyl), 1-propinyl, methyl, butyl, 1-methyl, 2-methyl, CF-methyl, 1,1-dimethyl, 1,1-dimethyl, pentopy, 1,1-dimethyl, 1,2-dimethyl, 2,2-dimethyl, 2,2-dimethyl, 1,2-methyl, 1,2-methyl, 1,2-methyl, 1-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-methyl, 2-meth

Err1:Expecting ',' delimiter: line 1 column 351 (char 350)

The term (CH2) 3-6 means -CH2-CH2-CH2, -CH2-CH2-CH2, -CH2-CH2-CH2-CH2-CH2- and CH2-CH2-CH2-CH2-CH2-CH2-; the term (CH2) 1-4 means -CH2, -CH2-CH2, -CH2-CH2-CH2- and -CH2-CH2-CH2-; the term (CH2) 4-5 means -CH2-CH2-CH2- and -CH2-CH2-CH2-CH2-CH2-, etc.

An aryl residue is a ring system with at least one aromatic ring but no heteroatoms in any of the rings, such as phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, especially 9H-fluorenyl or anthracenyl residues, which may be unsubstituted or simply or repeatedly substituted.

A heteroaryl residue is a heterocyclic ring system with at least one unsaturated ring containing one or more heteroatoms from the nitrogen, oxygen and/or sulphur group, which may be simply or repeatedly substituted. Examples of the heteroaryl group are furan, benzofuran, thiophen, benzothiophen, pyrrol, pyrimidine, pyrimidine, pyrrazine, quinoline, pyraquinoline, isokinoline, phthalazine, benzo[1,2,5]thiadiazole, benzothiazole, indolenz, benzotriazole, bodioxolan, benzodioxan, carbazole, indolenz and chinazolin.

In the context of aryl and heteroaryl, the substitution of the aryl or heteroaryl with R82, OR82 by a halogen, preferably F and/or Cl, a CF3, a CN, a NO2, a NR83R84, a C1-6 alkyl (saturated), a C1-6 alkoxy, a C3-8 cycloalkyl, a C3-8 cycloalkyl or a C2-6 alkyl is understood.

where the residue R82 is H, a C1-10 alkyl, preferably a C1-6 alkyl, an aryl or heteroaryl or an aryl or heteroaryl residue bound to a C1-3 alkyl, saturated or unsaturated, or a C1-3 alkyl group, and these aryl and heteroaryl residues must not be replaced by aryl or heteroaryl residues themselves, the residues R83 and R84, whether or not different, mean for H, a C1-10 alkyl, preferably a C1-6 alkyl, an aryl, a heteroaryl or a C1-3 alkyl, saturated or unsaturated, or an aryl or heteroaryl residue bound to a C1-3 alkyl group, whereby these aryl and heteroaryl residues may not be themselves substituted by aryl or heteroaryl residues, or the residues R83 and R84 together mean CH2CH2OCH2CH2, CH2CH2NR85CH2CH2 or (CH2) 3-6, and the residue R85 for H, a C1-10 alkyl, preferably a C1-6 alkyl, an aryl or heteroaryl residue or for a C1-3 alkyl, saturated or unsaturated, or an aryl or heteroaryl residue bound to a C1-3 alkyl group, whereby these aryl and heteroaryl residues must not themselves be replaced by aryl or heteroaryl residues.

The term salt means any form of the active substance of the invention in which it takes or is charged in an ionic form and is coupled with or in solution with a antigene (a cation or anion). It also includes complexes of the active substance with other molecules and ions, in particular complexes complexed by ionic interactions. In particular, it includes (and this is also a preferred embodiment of the invention) physiologically compatible salts, in particular salts that are physiologically compatible with cations or bases and physiologically similar to anions or acids or also with a physiologically compatible acid or a physiologically compatible salt formed by a chemical reaction.

Physiologically compatible means that the substance, especially the salt as such, is tolerable when used in humans or mammals, i.e. does not have an unphysiological (e.g. toxic) effect.

For the purposes of this invention, the term physiologically compatible salt with anions or acids means salts with at least one of the compounds of the invention - usually protonated, for example, to nitrogen - as a cation with at least one anion that is physiologically stable, particularly when used in humans and/or mammals. In particular, for the purposes of this invention, it means the salt formed with a physiologically compatible acid, namely salts of the respective active substance with inorganic or organic acids that are physiologically stable, especially when used in humans and/or mammals. Examples of physiologically compatible salts of certain acids are: Hypophosphoric acid, L-amino acid, sulfuric acid, 1-Hydroxy-3-aminobenzene, 1-Hydroxy-3-aminobenzene, 1-Hydroxy-3-aminobenzene, 2-Hydroxy-1, 1-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, 2-Hydroxy-1, and 2-Hydroxy-1, and 2-Hydroxy-1,Hydroxy-1,Hydroxy-1,Hydroxy-1,Hydroxy-1,Hydroxy-1,Hydroxy-1, and 2-Hydroxy-1,Hydroxy-1,Hydroxy-1,Hydroxy-1,Hydroxy-1,Hydroxy-1, and 2-Hydroxy-1,Hydroxy-1,Hydroxy-1,Hydroxy-1,Hydro

For the purposes of this invention, the term salt formed with a physiologically compatible acid means salts of the active substance with inorganic or organic acids that are physiologically compatible, especially when used in humans and/or mammals. Hydrochloride is particularly preferred. Examples of physiologically compatible acids are: hydrochloric acid, hydrobromic acid, sulfuric acid, methanosulfonic acid, formic acid, acetic acid, oxalic acid, amber acid, acetone, ammonium, ammonium, ammonium, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury, mercury,

The term physiologically compatible salt with cations or bases is understood to mean, for the purposes of this invention, salts of at least one of the compounds of the invention - usually a (deprotonated) acid - as an anion with at least one, preferably inorganic, cation that is physiologically compatible, especially when used in humans and/or mammals.

For the purposes of this invention, the term salt formed with a physiologically compatible cation means salts containing at least one of the respective compounds as an anion with at least one inorganic cation which is physiologically viable, particularly when used in humans and/or mammals.

For the 4-aminocyclohexanol derivatives substituted in accordance with the invention described above, it is preferable to use: R1 and R2 are independently selected from H; C1-8 alkyl, saturated or unsaturated, branched or unbranched, simply or multiplely substituted or unsubstituted; where R1 and R2 may not be both H, or the residues R1 and R2 together form a ring and mean CH2CH2OCH2CH2, CH2CH2NR5CH2CH2 or (CH2) 3-6, with R5 selected from H; C1-8 alkyl, saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted, preferably R1 and R2 are independently selected from H; C1-4 alkyl, saturated or unsaturated, branched or unbranched, simply or multiplely substituted or unsubstituted; where R1 and R2 may not be both H, or the residues R1 and R2 together form a ring and mean (CH2) 4-5 In particular: R1 and R2 are independently selected from methyl or ethyl or the residues R1 and R2 together form a ring and mean (CH2) 5.

For the 4-aminocyclohexanol derivatives substituted in accordance with the invention described above, it is preferable to use: R3 is selected from C5-6 cycloalkyl, unsubstituted or simply or repeatedly substituted; or via a saturated, unbranched C1-2 alkyl group bound to C5-6 cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, pyridyl, furyl, benzofuranyl, benzodioxolanyl, indoyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl, either unsubstituted or simply or repeatedly substituted; In particular: R3 is selected from a phenyl, pyridyl, furyl or thiophenyl bound via a saturated, unbranched C1-2 alkyl group, either unsubstituted or simply or repeatedly substituted.

For the 4-aminocyclohexanol derivatives substituted in accordance with the invention described above, it is preferable to use: R4 is selected from C3-8 cycloalkyl, aryl or heteroaryl, either unsubstituted or simply or repeatedly substituted; or -R8-L-R9 preferably R4 is selected from cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indoyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl or benzo[1,2,5] or 1,2-dihydroacetylinyl, pyridyl, furanyl, benzofuranyl, pyrazoline, oxandrolone, dioxanyl, pyridyl, pyrophenyl or phenylenyl, or simply substituted with or without R9 or R9 or more, or In particular: R4 is selected from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indoyl, naphthyl, benzothiazolyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, whether or not substituted or simply or in combination; or -R8-L-R9.

In relation to the immediate preferred embodiment for R4, further preference is given to: R8 is selected from In the form of a liquid, the value of all the materials of Chapter 9 used does not exceed 20% of the ex-works price of the product L selected from Other -C (O) -NH, -NH-C (O) -C (O) -O-O, -O-C (O) -O, -O, -S or -S (O) 2-, Other and/or R9 is selected from The following substances are to be classified in the same heading as the active substance:Oxopyrazolinonyl, pyrimidinyl, quinolinyl, isokinolinyl, phthalazinyl or chinazolinyl, whether or not substituted or simply or in combination, preferably R8 is selected from Indolyl, benzothiophenyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, whether or not substituted or simply or in combination with another substance, L selected from Other -C ((O) -NH-, -NH-C ((O) -C ((O) -O), -O-C ((O) -O or -S ((O) 2-, Other and/or R9 is selected from Indolyl, benzothiophenyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, whether or not substituted or simply substituted or mixed In particular: R8 is selected from Indolyl, unsubstituted L selected from Other -S (O) 2 - Other and R9 is selected from Phenyl unsubstituted. In a whiter embodiment, it is preferable to use, with respect to the 4-aminocyclohexanol derivatives substituted according to the invention described, R4 is selected from -CHR6R7, -CHR6-CH2R7, -CHR6-CH2-CH2R7, -CHR6-CH2-CH2-CH2R7, -C(Y)R7, -C(Y) -CH2R7, -C(Y) -CH2-CH2R7 or -C(Y) -CH2-CH2-CH2R7 with Y = O,S or H2, preferably The test chemical is used to determine the concentration of the active substance in the test chemical. with Y = O or S, In particular: R4 is selected from -CHR6R7, -CHR6-CH2R7, -C(Y)R7 or -C(Y) -CH2R7 with Y=O.

In relation to the immediate preferred embodiment for R4, further preference is given to: R6 is selected from H, C1-4 alkyl, saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted; or C(O) O-C1-4 alkyl, saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted; preferably H, C1-4 alkyl, saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted; In particular: H, CH3 and C2H5.

In relation to the immediate preferred embodiment for R4, it is furthermore also preferred if: R7 is selected from C3-8 cycloalkyl, aryl or heteroaryl, either unsubstituted or single or multiple substituted; preferably R7 is selected from cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indoyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl or benzo[1,2,5] or 1,2-dihydroacetinyl, pyridyl, furanyl, benzofuranyl, pyrazoline, oxandrolone, dioxanyl, dioxanyl, pyrimidyl, pyrimidyl or phenylenediol, or simply substituted or substituted with one or more of the following: In particular: R7 is selected from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indoyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, whether or not substituted or simply or multiple substituted.

For the 4-aminocyclohexanol derivatives substituted in accordance with the invention described, it is preferable to select from the following group: 4-Benzyl-4-dimethylamino-1-phenethylcyclohexanol and the corresponding hydrochloride,4-Dimethylamino-1,4-diphenethylcyclohexanol and the corresponding hydrochloride,4-Benzyl-4-dimethylamino-1-[2-diphenethyl-fluorphenyl]ethyl]cyclohexanol and the corresponding hydrochloride,4-Benzyl-4-dimethylamino-1-[2-diphenethyl-fluorphenyl]phenethyl and the corresponding hydrochloride,4-Dimethylamino-4-cyclocyclolamide,4-Benzyl-4-fluorphenethyl-cyclolamide,4-Benzyl-4-diphenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl-phenethyl where appropriate, in the form of their racemates, pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular enantiomers or diastereomers, in any mixing ratio; in the form shown or in the form of their acids or bases or in the form of their salts, in particular the physiologically compatible salts, or in the form of their solvates, in particular the hydrates.

The substances of the invention are toxicologically harmless and therefore suitable as pharmaceutical active substances in medicinal products.

Therefore, the invention also covers medicinal products containing at least one substituted 4-aminocyclohexanol derivative of the invention, as appropriate, in the form of its racemate, pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of stereoisomers, in particular enantiomers or diastereomers, in any mixing ratio; in the form shown or in the form of acids or bases or in the form of salts, in particular physiologically compatible salts, or in the form of solvents, in particular hydrates; and, as appropriate, suitable additives and/or auxiliaries and/or other active substances, as appropriate.

The medicinal products of the invention contain, in addition to at least one 4-aminocyclohexanol derivative substituted in accordance with the invention, suitable additives and/or excipients, as appropriate, as well as carrier materials, fillers, solvents, diluents, dyes and/or binders, and may be administered as liquid forms in the form of solutions for injection, drops or juices, as semi-solid forms in the form of granules, tablets, pellets, patches, capsules, plastics or aerosols. The selection of the excipients and the amount of the plastics to be recycled depend on whether the product is intended to be administered orally, as a powder, as a solvent, as a parenteral or intravenous drug, as a solution for injection, as a solution for oral administration, as a solution for injection, as a semi-solid drug in the form of granules, tablets, pellets, patches, capsules, or other specialised preparations, or as a substitute for oral or intramuscular application. The preparations may be administered in the form of tablets, syring, syring, or other preparations, or in the form of tablets, or in a solution, such as a syringe, or in the form of a syringe, or other preparation, or in the form of a solution, such as a solution, or in the case of use.

The dose to be administered to the patient varies according to the patient's weight, type of application, indication and severity of the disease, usually 0.005 to 1000 mg/kg, preferably 0.05 to 5 mg/kg, of at least one 4-aminocyclohexanol derivative substituted according to the invention.

For all the above forms of medicinal products of the invention, it is particularly preferable that the medicinal product contains, in addition to at least one substituted 4-aminocyclohexanol derivative, an opioid, preferably a strong opioid, in particular morphine, or an anaesthetic, preferably hexobarbital or halothane.

A 4-aminocyclohexanol substitute of the invention is present in a preferred form of the medicinal product as a pure diastereomer and/or enantiomer, as a racemate or as a non-equimolar or an equimolar mixture of the diastereomers and/or enantiomers.

As indicated in the state of the art introduction, the ORL1 receptor has been identified in pain in particular, and therefore substituted 4-aminocyclohexanol derivatives of the invention can be used to manufacture a medicinal product for the treatment of pain, in particular acute, visceral, neuropathic or chronic pain.

Therefore, the invention also relates to the use of a 4-aminocyclohexanol derivative substituted in accordance with the invention, where appropriate in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular enantiomers or diastereomers, in any mixing ratio; in the form shown or in the form of its acids or bases or in the form of its salts, in particular the physiologically acceptable salts, or in the form of its solvates, in particular the hydrates, to produce a medicinal product for the treatment of pain, in particular acute, chronic, visceral, neuropathic or neuropathic pain.

As already mentioned in the introduction, the ORL1 receptor plays a role in a wide range of other physiological processes, including those of medical importance, in addition to its function in pain.

Therefore, another subject matter of the invention is the use of a 4-aminocyclohexanol derivative substituted in accordance with the invention, as appropriate, in the form of its racemate, its pure stereoisomers, in particular, enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular, the enantiomers or diastereomers, in any mixing ratio;in the form shown or in the form of its acids or its bases or in the form of its salts, in particular, the physiologically representative salts, or in the form of its solvates, in particular, the hydrates, to manufacture a drug for the treatment of anxiety, anxiety and stress-related hypersensitivity, depression, epilepsy, seizures, seizures, general cognitive disorders, anxiety, depression, depression, depression, depression, depression, and/or depression, and/or for the treatment of narcotic drugs, including antipsychotics, anti-psychotics, anti-alcotic drugs, anti-diarrhea, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants, anti-oxidants

In one of the above uses, it may be preferable to use a substituted 4-aminocyclohexanol derivative used as a pure diastereomer and/or enantiomer, as a racemate or as a non-equimolar or equimolar mixture of the diastereomers and/or enantiomers and/or to use an opioid, preferably a strong opioid, in particular morphine, or an anaesthetic, preferably hexobarbital or halothane, in addition to the substituted 4-aminocyclohexanol derivative.

The invention also relates to a procedure for the treatment, in particular in one of the above indications, of a non-human mammal or human being requiring the treatment of pain, in particular chronic pain, by the administration of a therapeutically flexible dose of a cyclohexane-1,4-diamond derivative substituted according to the invention or a medicinal product according to the invention.

A further subject matter of the invention is a process for the production of the substituted 4-aminocyclohexanol derivatives of the invention as described and illustrated below.

In particular, a procedure with the following steps is appropriate: a. A cyclohexane-1,4-dione protected by groups S1 and S2 according to formula II is converted into a protected N-substituted 1-amino-4-oxo-cyclohexanecarbonitrylde derivative according to formula III in the presence of a compound of formula HNR01R02 with a cyanide, preferably potassium cyanide; Other where applicable, then in any order and where applicable repeatedly acylated, alkylated or sulphonated and/or, in the case of compounds with R01 and/or R02 and/or R06 = with a protected group H, at least once a protective group is cleaved and, where applicable, acylated, alkylated or sulphonated and/or, in the case of compounds with R01 and/or R02 and/or R06 = H, at least once a protective group is introduced and, where applicable, acyled;alkylated or sulphonated,b. the aminonitrile according to formula III is converted to a compound according to formula IVa by metal-organic reagents, preferably Grignard or organolithium reagents, formula Metal-R3; Other where applicable, then in any sequence and where applicable repeatedly acylated, alkylated or sulphonated and/or, in the case of compounds with R01 and/or R02 and/or R06= with a protected group H, at least one protective group is cleaved and, where applicable, acylated, alkylated or sulphonated and/or, in the case of compounds with R01 and/or R02 and/or R06= H, at least one protective group is introduced and, where applicable, acylated, alkylated or sulphonated,c. at the compound according to formula IVa according to formula III, the protective groups S1 and S2 are cleaved,to give a 4-substituted 4-aminocyclohexane derivative according to formula IV; Other then, in any order and where appropriate, repeatedly acylated, alkylated or sulphonated and/or, in the case of compounds with R01 and/or R02 and/or R06 = with a protective group H, at least once a protective group is cleaved and, where appropriate, acyled, alkylated or sulphonated and/or, in the case of compounds with R01 and/or R02 and/or R06 = H, at least once a protective group is introduced and, where appropriate, acyled, alkylated or sulphonated, i.e. the 4-substituted 4-aminocyclohexandrude derivative according to formula IV with metal-organic reagents, preferably Grignard or organo-metal reagents, which are transformed into a compound according to formula V; Other where appropriate, then acylated in any order and repeated if necessary,alkylated or sulphonated and/or in the case of compounds with R01 and/or R02 and/or R04 and/or R05 and/or R06 = with a protected group H, at least once a protective group has been cleaved and, if applicable, acylated, alkylated or sulphonated and/or in the case of compounds with R01 and/or R02 and/or R04 and/or R05 and/or R06 = H, at least once a protective group has been introduced and, if applicable, acylated, alkylated or sulphonated until a compound in accordance with formula I is formed, where R1, R2, R3 R4 and R5 have the meanings given in claim 1. and R01 and R02 are independently selected from H; H with a protective group; C1-8 alkyl or C3-8 cycloalkyl, either saturated or unsaturated,Branched or unbranched, simply or repeatedly substituted or unsubstituted; aryl or heteroaryl, either simply or repeatedly substituted or unsubstituted; or aryl, C3-8-cycloalkyl or heteroaryl, whether or not simply or repeatedly substituted or unsubstituted, bound by C1-3 alkyl groups; or the residues R01 and R02 together form a ring and mean CH2CH2OCH2CH2, CH2CH2NR05CH2CH2 or (CH2) 3-6, R05 selected from H; H with a protective group; C1-8 alkyl or C3-8 cycloalkyl, whether or not saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted; aryl or heteroaryl, whether or not simply or repeatedly substituted or unsubstituted; or aryl, C3-8 cycloalkyl or heteroaryl, whether or not simply or repeatedly substituted or unsubstituted, bound by C1-3 alkyl groups; R04 is selected from H,H; C3-8-cycloalkyl, aryl or heteroaryl, whether or not substituted, or simply or multiple substituted; -CHR6R7, -CHR6-CH2-CH2R7, -CHR6-CH2-CH2-CH2R7, -C(Y) R7, -C(Y) -CH2R7, -C(Y) -CH2-CH2R7 or -C(Y) -CH2-CH2-CH2R7; or -R8-L-R9 with Y = O, S or H2, with R6 selected from H, C1-7, alkyl, saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted; or C(O) O) C1-6, alkyl, saturated or unsaturated, branched or unsaturated, simply or repeatedly substituted or unsubstituted; and selected from R7 H; C3-8-cycloalkyl, aryl or heteroaryl, whether or not substituted, or simply or in multiple substitutions, with R8 selected from Aryl or heteroaryl, whether or not substituted, or simply or in multiple substitutions, with L selected from Other The following shall be added to the list of substances which are to be classified in the additive:-S- or -S(O) 2- Other with R9 selected from Aryl or heteroaryl, whether or not substituted, or simply or in multiple substitutions, and S1 and S2 are selected independently from each other from protective groups or together represent a protective group, preferably monoacetals.

With regard to the particularly suitable method described, it is particularly preferable to select the H protection groups for R01, R02, R04 and/or R05 from alkyl, benzyl or carbamate, e.g. FMOC, Z or Boc.

The following illustrations of the invention are given, but are not limited to them.

Examples

The following examples illustrate compounds of the invention, their presentation and the efficacy studies performed with them.

The following information is generally applicable:

The chemicals and solvents used were either commercially sourced from conventional suppliers (Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI etc.) or synthesised.

The analysis was performed by NMR spectroscopy, where appropriate in combination with other analytical methods such as thin film chromatography, mass spectrometry or HPLC.

Example 1 General possibility of manufacturing compounds of the invention

The preparation of these compounds is based on a suitable cyclohexane-1,4-dione II protected as a monoacetal, for example. Reaction with potassium cyanide in the presence of a secondary amine gives a protected N-substituted 1-amino-4-oxo-cyclohexane tricarbonyl derivative III. Other

The implementation of aminonitryl III with metal-organic reagents, preferably Grignard or organolithium reagents, results in a substitution of the nitrile function, so that after subsequent cleavage of the carbonyl protective group, a 4-substituted 4-aminocyclohexane derivative IV is obtained. Other

Finally, intermediates of type IV can be converted into 4-aminocyclohexanol derivatives I according to the invention by addition of metal-organic reagents, preferably Grignard or organolithium reagents. Other

Example 2 Measurement of ORL1 binding

The 4-aminocyclohexanol derivatives of generic formula I were studied in a receptor binding assay with 3H-nociceptin/orphanine FQ on membranes of recombinant CHO-ORL1 cells, using the test system presented by Ardati et al. (Mol. Pharmacol., 51, 1997, p. 816-824), where the concentration of 3H-nociceptin/orphanine FQ was 0.5 nM. The binding acid was obtained with 20 μg of membrane protein per 200 μl of ED in 50 mM of hepsin, pH 7.4, 10 mM MgCl2 and 1 mMTA. The binding to the ORL1 receptor was determined using 1 mg of WPA-S Sham Sham (Pharmacy-Kiiburg, formerly known as Antinitide) in the presence of a freeze-drying agent (Affluent) at room temperature and in the presence of a liquid. Other


Nr.		(in µmol)
4	0,02
5
6	0,03
7	0,04
8	0,05
9	0,03
10	0,20
11	0,02
12
13	0,06
14	0,90
15	0,40
16	0,89
17	0,04
18	0,13
19	0,045
20	0,15
21	0,15

Example 3 Analgesia test in the tail-flick test in the mouse

The analgesic effect of the compounds of the invention was investigated in the tail-flick test on mice according to the method of D'Amour and Smith (J. Pharm. Exp. Ther. 72, 74 79 (1941) using NMRI mice weighing between 20 and 24 g. The animals were placed individually in special test cages and the tail base exposed to a focused thermal beam from an electric lamp (tail-flick type 55/12/10.fl, Labtec, Dr. Hess). The lamp intensity was set so that the time from the light switching on to the sudden disappearance of the tail (painful) in untreated animals was increased by 3 to 5 seconds.

((T_{1} - T_{0}) / (T_{2} - T_{0})) \times 100

T0 is the latency time before and T1 is the latency time after application of the substance, T2 is the maximum exposure time (12 sec).

To determine dose dependence, the respective compound of the invention was applied at 3-5 logarithmically increasing doses, each including the threshold and maximum dose, and the ED50 values were determined by regression analysis at the maximum dose 20 minutes after intravenous administration.

The compounds tested showed a marked analgesic effect, the results of which are summarised in the following table. Other


Nr.		(Dosierung in mg/kg intravenös)	mg/kg intravenös
4	100 (1)	0,015
5	100 (1)	0,040
6	98 (1)	0,055
7	93 (1)	0,10
8	97 (1)	0,093
9	100 (1)	0,089
10	97 (1)	0,16
11	99 (1)	0,059
12	90 (1)
13	97 (10)
14	78 (1)
15	92 (1)
16	100 (1)	0,028
17	100 (1)	0,15
18	63 (10)
19	100(1)	0,04

Example 4 4-Benzyl-4-dimethylamino-1-phenethylcyclohexanol hydrochloride

The resulting white suspension was extracted four times with 800 ml of diethyl ether, the combined extracts were first concentrated and incorporated with 500 ml of dichloromethane, the organic phase was separated, the sodium sulfate was dried, filtered, eaten and largely solvent-treated in a vacuum. 265 g of 8-diethyl ether-1,4-dimethyl ether-84-methyl-aspirate was obtained as a white solid.

50 g 8-dimethylamino-1,4-dioxaspiro[4.5]decan-8-carbonitrile were dissolved in 400 ml of tetrahydrofuran p.a., added to 214 ml of 2.0 molar benzyl magnesium chloride solution in THF at nitrogen atmosphere and stirred overnight at room temperature. 200 ml of saturated ammonium chloride solution was added for processing under ice-cooling, the phases were separated, the aqueous phase was extracted twice with 250 ml of diethyl ether, the combined organic phases were dried using sodium sulphate, filtered, solidified and largely soluble in a vacuum. The advanced raw solution (84-dimethylamino-1,4-dimethylamino-1,4-dimethylamino-84.4) was concentrated in a vacuum for 24 hours (32 ml) and then further concentrated in a solid solution of 120 ml of diethyl ether, initially mixed with diethyl ether and dissolved in water, and then extracted from the solution at room temperature by means of an alkaline solution, which was then dissolved in water for a further 120 ml (32 ml) of diethyl ether, and then mixed with diethyl ether for a further three hours, and then dissolved in water, and dissolved in a vacuum.

25.0 g 4-benzyl-dimethylaminocyclohexane were dissolved in 150 ml of tetrahydrofuran p.a., 151 ml of 1.0 molar phenethylmagnesium chloride solution were added to THF when refrigerated in an ice bath under a nitrogen atmosphere and stirred overnight at room temperature. 150 ml of ammonium chloride solution (20% by weight) were added for reconstitution under ice cooling, the phases were separated, the aqueous phase was extracted three times with 80 ml each, the combined organic phases were extracted three times with 70 ml of dilute hydrochloric acid (5 ml by weight), the combined aqueous extracts were extracted with 50 ml of diethylmagnesium chloride solution with water solution (25 ml by weight) and three times with water solution (25 μg/ m2) The product was extracted from 4-benzyl-dimethylmethylmethylmethylmethyl-4-4-methylmethylmethylmethyl-4-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-meth

Example 5 4-Dimethylamino-1,4-Diphenethylcyclohexanol hydrochloride

45 g 8-dimethylamino-1,4-dioxaspiro[4.5]decan-8-carbonitrile were dissolved in 250 ml of tetrahydrofuran p.a., added 238 ml of 1.0 molar phenethylmagnesium chloride solution in THF at nitrogen atmosphere and stirred overnight at room temperature. 100 ml of ammonium chloride solution (20% by mass) was added for processing under ice-cooling, the phases were separated, the aqueous phase was extracted twice with 200 ml of diethyl ether each, the combined organic p-residue was washed successively with 100 ml of water and 100 ml of saturated sodium chloride solution, the sodium sulphate was mixed, the filtrate was filtered, the e-rock was filtered and the solution was concentrated in water. The solution was then obtained as a vacuum-concentrated solution of 120 ml (34-4,2-4,2-g/ml) of dimethyl ether (34-4,4-g/ml) and was initially extracted from the raw diethyl ether, at room temperature, and then further processed by an alkaline filtration process, which took about 35 to 70 ml of water.

For preparation, 43 ml of ammonium chloride solution (20% by weight) were added under ice chill and extracted three times with 80 ml each of diethyl ether, the combined organic phase was extracted with 70 ml of dilute hydrochloric acid (5 ml each), the combined aqueous extracts were washed with 50 ml of diethyl ether, the combined aqueous extracts were washed with 50 ml of diethyl ether (25 ml each of diethyl ether) 9 times with 9 ml of diethyl ether, followed by 80 ml of diethyl ether (1-1,38 μg/ night), the combined organic phase was extracted with 70 ml of dilute hydrochloric acid (5 ml each of diethyl ether), the combined aqueous extracts were washed with 50 ml of diethyl ether, the combined aqueous solution (25 ml/ night) 9 times with ammonium ether (25 ml/ day), the combined aqueous solution was 80 μg/ day, followed by 4 ml of diethyl ether (1-1,38 μg/ day), the extract was obtained from diethyl ether (diethyl ether) 37 mg/ night, and the product was obtained by filtering the diethyl ether with diethyl ether at room temperature (temperature of the vacuum) and extracting it with 26 ml of diethyl ether (1,54-dimethyl ether).

Example 6 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

11,4 g of lithium aluminium hydride were presented in 100 ml of tetrahydrofuran p.a., heated to return to flow under nitrogen atmosphere, 50 g of 2-fluorophenyl acetic acid, dissolved in 400 ml of tetrahydrofuran p.a., added, and the reaction mixture heated for a further two hours. 72 ml of water were added for preparation, followed by 250 ml of semi-concentrated hydrochloric acid (16%) in an ice bath, and then stirred for cooling. 250 ml of diethyl ether were extracted twice, the combined extracts were washed twice with 100 ml of sodium hydrocarbonate solution (5%) and dried, filtered, pressed and largely de-iced in vacuum.

In a stainless steel autoclave, 50 g 2- (β-fluorphenyle) ethanol, 19 ml of concentrated sulphuric acid and 58 ml of hydrobromic acid (47 g/l) were heated overnight to 100 °C. After cooling, the compound was diluted with 500 ml of water, extracted twice with 250 ml of dichloromethane, dried with potassium carbonate, filtered, compressed and largely removed from solvent residues in a vacuum. 61.8 g 1- (β-bromethyl) 2-fluorbenzole was obtained.

The remaining solution was rapidly dripped after the start of the grinding, stirred for one hour after the final addition, then 2.97 g of 4-benzyl-4-dimethylaminocyclohexanone, dissolved in 13 ml of tetrahydrofuran p.a., added to the solution and stirred overnight. The remaining solution was added to 26 ml of tetrahydrofuran p.a. (1,5 g/ ml) of 2-bromethyl) 2-fluorobenzol solution after the start of the grinding process, and the remaining solution was rapidly dripped after the start of the grinding process, stirred for one hour after the final addition, then 2.97 g of 4-benzyl-4-dimethylaminocyclohexanone, dissolved in 13 ml of tetrahydrofuran p.a., added to the solution and stirred overnight.

Example 7 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C4.]

1- (β-bromethyl) -4-fluorobenzene was produced from 4-fluorophenyl acetic acid as described above for 1- (β-bromethyl) -2-fluorobenzene.

The remaining solution was rapidly dripped after the start of the grinding, stirred for one hour after the final addition, then 4,00 g of 4-benzyl-4-dimethylaminocyclohexanone, dissolved in 17 ml of tetrahydrofuran p.a., was added to the solution and stirred overnight. The remaining solution was added to 35 ml of 1- ((2-bromethyl) 2-fluorobenzol in 17 ml of tetrahydrofuran p.a. After the start of the grinding, stirred for one hour, then 4,00 g of 4-benzyl-4-dimethylaminocyclohexanone, dissolved in 17 ml of tetrahydrofuran p.a., was added to the solution and stirred overnight. The remaining solution was added to 35 ml of 1- ((2-bromethyl) 2-fluorobenzol in 17 ml of tetrahydrofuran p.a. After the start of the grinding, stirred for one hour, then stirred for 4,00 g of 4-benzyl-4-dimethylaminocyclohexanone, dissolved in 17 ml of tetrahydrofuran p.a., stirred and stirred for about one third of the solution and stirred overnight.

Example 8 4-Dimethylamino-4- ((2-fluorobenzyl)-1-phenethylcyclohexanol hydrochloride

The remaining solution was rapidly dripped after the start of the grinding, stirred for one hour after the final addition, then a solution of 5.00 g 8-dimethylamino-1,4-dioxaspiro[4.5]decan-8-carbonitrile was dripped into 25 ml diethyl ether p.a. and stirred overnight. The reaction mixture was added under ice cooling to 36 ml ammonium chloride solution (20% by mass) separating the phases, each phase being rapidly combined with 50 ml diethyl ether p.a. and 20 ml of organic water.The resulting raw [8- ((2-fluorobenzyl) --1,4-dioxaspiro[4.5]dec-8-yl]dimethylamine (7,34 g) was stirred for 24 hours without further purification with a mixture of 18 ml of concentrated hydrochloric acid (32% by weight) and 10 ml of water at room temperature, then washed three times with 50 ml of diethyl ether, then cooled to 9 by the addition of aqueous ammonia (25%) by ice, extracted three times with 50 ml of dichloromethane, the combined dichloromethane extracts were dried with sodium tetrofluoric acid, filtered, ecycled and heated in a vacuum with a high-temperature solution. 5,80 g of dimethylamine (42-dimethyl fluoride) were obtained in a solid form at 5,42 ml of nitrogen tetrocyclofluoride, obtained by heating the solution in a vacuum.The molar phenylethylmagnesium chloride solution was added to THF and stirred overnight at room temperature. 42 ml of ammonium chloride solution (20% by weight) was added to the treatment under ice-cooling, the phases separated, the aqueous phase was extracted three times with 50 ml of diethyl ether each, the combined organic phases were washed with 30 ml of water, the combined aqueous extracts were washed with 50 ml of dilute hydrochloric acid (5% by weight each), the combined aqueous extracts were washed with 50 ml of diethyl ether each, the ammonium solution (25%) was adjusted to ph of 9%, the combined aqueous extracts were extracted three times with 50 ml of diethyl ether each, the combined extracts were diethyl ether trifurcated, filtered, and largely filled with vacuum. The product was obtained in a crude solution (V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V/V1,33 g of the nonpolar diastereoisomer of 4-dimethylamino-4- ((2-fluorobenzyl) -fenethylcyclohexanol was obtained to produce 536 mg of the corresponding hydrochloride as described in example 4.

Example 9 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The remaining solution was rapidly dripped after the start of the grinding, stirred for one hour after the final addition, then a solution of 4.00 g 8-dimethylamino-1,4-dioxaspiro[4.5]decan-8-carbonitrile was added to 25 mi diethyl ether p.a. and stirred overnight. The remaining solution was dripped under ice for 29 ml of diethyl ether solution (20 g/m3) separated by a wide-spread liquid filter (20 g/m3) which was then separated into two separate phases, each containing 50 ml of diethyl ether. The solution was then mixed with 20 ml of diethyl ether (expressed as ammonium nitrate) at a temperature of 40 °C. The resulting solution was obtained by mixing it with ammonium nitrate (expressed as ammonium nitrate) and obtained by extracting 40 ml of diethyl ether at a temperature of 40 °C.

4,67 g 4-dimethylamino-4- (((3-fluorobenzyl) cyclohexanone were dissolved in 28 ml of tetrahydrofuran p.a., added 34 ml of 1.0 molar phenethylmagnesium chloride solution in THF when refrigerated in a nitrogen atmosphere in an ice bath and stirred overnight at room temperature. 34 ml of ammonium chloride solution (20% by weight) were added for processing under ice cooling, the phases were separated, the aqueous phase was extracted three times with 40 ml of diethyl ether each, the combined organic phases were washed with 25 ml of water, the combined organic phases were added three times with 40 ml of dilute cornthrous acid (5% by weight) extracted, the combined diethyl phenol extracts were diluted with 25 ml of diethyl ether water, the combined diethyl ether was filtered with a glossophenol solution (25%) by mass. The product was obtained from a vacuum-exhaustant product of 4-dimethyl ether (HDPE) (HDPE) obtained from 4-dimethyl ether, the product was obtained by extracting the diethyl ether from the raw material (e.g.g. 4-dimethyl ether) and dissolving it with 1,28 g/methyl ether (HDPE) in a solution of 1,12 g/methyl ether (e.g.g.g. 4-dimethyl ether) and obtained by dissolving it with 4-dimethyl ether (HDPE) of 4-dimethyl ether (HDPE) and the product was obtained by dissolving it with 1,12 glossophenol ether (e.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g.g

Example 10 4-Dimethylamino-4- ((4-fluorobenzyl)-1-phenethylcyclohexanol hydrochloride

The remaining solution was rapidly dripped after the start of the grinding, stirred for one hour after the final addition, then a solution of 4.00 g 8-dimethylamino-1,4-dioxaspiro[4.5]decan-8-carbonitrile was dripped into 25 ml diethyl ether p.a. and stirred overnight. The reaction mixture was added under ice cooling to 29 ml ammonium chloride solution (20 per cent by mass) separating the two phases, each phase being mixed with 50 ml diethyl ether p.a. and 20 ml of organic water.The resulting raw [8- ((4-fluorobenzyl) --1,4-dioxa-spiro[4.5]dec-8-yl]dimethylamine (5,76 g yellow solid) was stirred for 24 hours without further purification with a mixture of 14 ml of concentrated hydrochloric acid (32% by weight) and 8 ml of water at room temperature, then washed three times with 30 ml of diethyl ether, then chilled to pH 9 by addition of aqueous ammonia (25% by weight), extracted three times with 40 ml of dichloromethane, the combined dichloromethane extracts were dried, filtered, e-liquidised and heavily nitrified with sodium tetracyclamide. The resulting solution of 4-dimethylamine (dimethylamine) was obtained in a vacuum solution of 4,70 g (4.4-dimethylaminofluorophenol) in 28 ml of 4-dimethyl phthalate, at 4,69 g (4.4-dimethylaminofluorophenol) and obtained in a solution of 34 ml of 4-dimethylaminofluorphthalate.0 molar phenylethylmagnesium chloride solution in THF and stirred overnight at room temperature. 34 ml of ammonium chloride solution (20% by weight) were added for processing under ice-cooling, the phases separated, the aqueous phase was extracted three times with 40 ml of diethyl ether each, the combined organic phases were washed with 25 ml of water each, the combined aqueous extracts were washed with 40 ml of dilute hydrochloric acid (5% by weight each), the combined aqueous extracts were washed with 25 ml of diethyl ether each, the ammonium solution (25%) was adjusted to ph = 9, the combined aqueous extracts were extracted three times with 40 ml of diethyl ether each, the combined diethyl ether extracts were further diluted with nitric acid, filtered, and the product was obtained by applying a vacuum gel (V/H40/H) to the solution (V/H40/H1H1) in the raw material.1,45 g of the nonpolar diastereoisomer of 4-dimethylamino-4- ((4-fluorobenzyl) -fenethylcyclohexanol was obtained to produce 1,44 g of the corresponding hydrochloride as described in example 4.

Example 11 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C4.]

1- (β-bromethyl) 3-fluorobenzene was produced from 3-fluorophenyl acetic acid as described above for 1- (β-bromethyl) 2-fluorobenzene.

The remaining solution was rapidly dripped after the start of the grinding, stirred for one hour after the final addition, then 3.60 g of 4-benzyl-4-dimethylaminocyclohexanone, dissolved in 16 ml of tetrahydrofuran p.a., dripped and stirred overnight. The remaining solution was then dripped under ice to 31 ml of 1- ((2-bromethyl) -fluorobenzol in 16 ml of tetrahydrofuran p.a. The remaining solution was dripped separately after the start of the grinding process, stirred for one hour after the final addition, then dripped to 3.60 g of 4-benzyl-4-dimethylaminocyclohexanone, dissolved in 16 ml of tetrahydrofuran p.a., and stirred overnight.

Example 12 4-Benzyl-4-dimethylamino-1- ((2-fluorbenzyl) cyclohexanol hydrochloride

The remaining solution was rapidly dripped after the start of the grinding, stirred for one hour after the final addition, then dripped 3.60 g of 4-benzyl-4-dimethylaminohexanone, dissolved in 40 ml diethyl ether p.a., and stirred overnight. The remaining solution was rapidly dripped after the start of the grinding, stirred for one hour, then dripped 3.60 g of 4-benzyl-4-dimethylaminohexanone, dissolved in 40 ml diethyl ether p.a., and stirred overnight. The remaining solution was then dripped under evaporation with 31 ml of 2-fluorobenzyl chloride in 15 ml diethyl ether p.a. The three phases were separated into two phases, each with 40 g of diethyl ether per phase. The extraction of the extract was obtained by mixing 30 g of diethyl ether p.a. (expressed as 4-dimethyl ether) with a solution of water (expressed as 2-diethyl ether) of the extract, which was obtained by mixing 30 ml of water (expressed as 2-diethyl ether) of the extract with 30 g of diethyl ether (expressed as 2-diethyl ether) and 30 ml of water (expressed as 2-diethyl ether) of the extract, which was obtained by mixing with 30 g of the extract of diethyl ether (expressed as 2-diethyl ether) of the extract) of the extract with water (expressed as 2-diethyl ether) and 30 g of the extract of the extract was obtained by mixing with 30 ml of water (expressed with diethyl ether) of the extract of the extract of the extract of diethyl ether (expressed as 2-diethyl ether) of the extract of the extract of the extract of the extract of the extract of the extract of the diethyl ether.

Example 13 4-Allylmethylamino) benzyl-1-phenethylcyclohexanol hydrochloride

A mixture of 9 ml of water, 5.3 ml of hydrochloric acid (32% by weight), 8 ml of methanol, 17.5 g of allylmethylamine, 8.00 g of 1,4-dioxaspiro[4.5]decan-8-on and 8.0 g of potassium cyanide was stirred at room temperature for 65 hours. The resulting yellowish-white suspension was extracted four times with 25 ml of diethyl ether each, the combined extracts were dried using sodium sulphate, filtered, compressed and largely de-solvented in a vacuum. 11.3 g of 8- (allylmethylamino)-1,4-dioxaspiro[4.5]decan-8-carbonitrile was obtained as a light-brown liquid.

A solution of 3.50 g 8- ((Allylmethylamino) - 1,4-dioxaspirone[4.5]decan-8-carbonitrile was added to 14.8 ml of 2.0 molar benzyl magnesium chloride solution in THF, dripped into 35 ml of tetrahydrofuran p.a. in a nitrogen atmosphere and stirred overnight at room temperature. 25 ml of saturated ammonium chloride solution was added to the solution for preparation, refrigerated, the phases separated, the aqueous phase was extracted with 25 ml of diethyl ether each, the organic compounds were combined via sodium sulphate solution, filtered, dried and largely concentrated in a vacuum by the solvent. The concentration of allyl-hydroxylamino-1,4-dioxaspirone[4.4-dioxaspirone] was further concentrated in a vacuum (32.41 ml of diethyl ether) at a temperature of 30 °C. The solution was then combined with 13 ml of sodium sulphate, initially concentrated in a vacuum, and concentrated in water for a further 24 hours, and then concentrated in a vacuum by the solvent, and concentrated in water for a further 30 ml of diethyl ether.

A solution of 3.50 g 4- ((Allylmethylamino) - benzylcyclohexanone in 21 ml tetrahydrofuran p.a. was added to 14.8 ml 1.0 molar phenylemagnesium chloride solution in THF, dripped in a nitrogen atmosphere, stirred overnight at room temperature, and 19 ml ammonium chloride solution (20% by weight) was added for reconstitution under ice-cooling, the phases separated, the aqueous phase extracted three times with 20 ml each of diethyl ether, the combined organic pollutants with 20 ml of water, the combined organic pollutants with 20 ml of water, the combined organic pollutants with 20 ml each of dilute hydrochloric acid (5% by weight) extracted, the combined aqueous extracts with 20 ml of diethyl ether filtered with 80 ml of diethyl ether, the combined aqueous extracts with 20 ml of diethyl ether extracted with diethyl ether solution (25%) The product was obtained from a vacuum containing 9 mg/ml of diethyl ether (Hydroxanthanone) (Hydroxanthoxylamine) (Hydroxanthoxylamine) - 4- 4- (Allyl-methylamine) ether) - 4- (Hydroxanthoxylamine) 4- (Hydroxanthoxylamine) 4-) 4- (Hydroxanthoxyethyl ether) 4- (Hydroxanthoxylamine) 4- (Hydroxanthoxylamine) 4-) 4- (Hydroxanthoxylamine) 4- (Hydroxanthoxylamine) 4-) 4- (Hydroxanthoxylamine) 4- (Hydroxanthoxylamine) 4- (Hydroxanthoxy) 4-) 4- (Hydroxanthoxylamine) 4- (Hydroxanthoxylamine) 4- (Hydroxanthoxy) 4-) 4- (Hydroxanthoxylamine) 4- (Hydroxanthoxy-4) 4-) 4- (Hydroxanthoxylamine) 4- (Hydroxanthoxy

Example 14 4-Benzyl-4-dimethylamino-1- ((3-fluorbenzyl) cyclohexanol hydrochloride

The remaining solution was rapidly dripped after the start of the grinding, stirred for one hour after the final addition, then dripped 3.60 g of 4-benzyl-4-dimethylaminohexanone, dissolved in 30 ml diethyl ether p.a., and stirred overnight. The remaining solution was rapidly dripped after the start of the grinding, stirred for one hour, then dripped 3.60 g of 4-benzyl-4-dimethylaminohexanone, dissolved in 30 ml diethyl ether p.a., and stirred overnight. For processing, 31 ml of ammonium diethyl chloride (20% by mass) were added, separating the three phases into two phases, each with 40 g of diethyl ether. The ammonium diethyl ether was extracted from the ammonium diethyl ether, concentrated on a solid solution of water (expressed as ammonium diethyl ether) of 40 ml (2,93% by mass) and mixed with a solution of ammonium diethyl ether (expressed as ammonium diethyl ether) (expressed as ammonium diethyl ether) and obtained from the extracted water (expressed as ammonium diethyl ether) by means of a solution of water (expressed as ammonium diethyl ether) of 40 ml (494-dimethyl ether) and ammonium diethyl ether) of 40 g/methyl ether.

Example 15 4-Benzyl-4-dimethylamino-1- ((4-fluorbenzyl) cyclohexanol hydrochloride

The remaining solution was rapidly dripped after the start of the grinding, stirred for one hour after the final addition, then dripped 3.60 g of 4-benzyl-4-dimethylaminohexanone, dissolved in 30 ml diethyl ether p.a., and stirred overnight. For processing, 31 ml of ammonium diethyl chloride (20% by mass) were added to the solution, separating the three phases into two phases, each with 40 g of diethyl ether. The ammonium diethyl ether was obtained from a solution of 4-benzyl-4-dimethylaminohexanone (HDPH) concentrated on a white solution of 40 ml (2,5 g/mol) of water (expressed as ammonium diethyl ether) and mixed with a solution of ammonium diethyl ether (HDPH) containing 40 g of diethyl ether (expressed as ammonium diethyl ether) and obtained in the form of a liquid containing 40 ml of diethyl ether.

Example 16 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The remaining solution was rapidly dripped after the start of the grinding, stirred for one hour after the final addition, then a solution of 4.00 g 8-dimethylamino-1,4-dioxaspiro[4.5]decan-8-carbonitrile was dripped into 25 ml diethyl ether p.a. and stirred overnight. The reaction mixture was added under ice cooling to 29 ml ammonium chloride solution (20% by mass) separating the phases, each phase being mixed with 50 ml diethyl ether, 20 ml of organic water and 20 ml of sodium chloride.The resulting raw [8- ((3-fluorobenzyl) --1,4-dioxa-spiro[4.5]dec-8-yl]dimethylamine (5,75 g yellow solid) was stirred for 24 hours without further purification with a mixture of 14 ml of concentrated hydrochloric acid (32% by weight) and 8 ml of water at room temperature, then washed three times with 30 ml of diethyl ether, then chilled to 9 by addition of aqueous ammonia (25% by weight), extracted three times with 40 ml of dichloromethane, the combined dichloromethane extracts were dried, filtered, e-liquidated and mixed with a high-level of glamethyl trifluoride. The resulting 4-dimethylamine was obtained in vacuum as 4-dimethyl-4-4-diethylamino-4-fluoro-4-fenyl-4-methyl-4-fluoro-4-fenyl in the form of a 1,4-dimethyl-4-fluoro-4-methyl-4-fluoro-4-methyl-fluoro-4-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-The resulting nonpolar diastereoisomer of 1-benzyl-4-dimethylamino-4- ((3-fluorbenzyl) cyclohexanol as described in example 4 was transferred to 261 mg of the corresponding hydrochloride after chromatography on silica gel.

Example 17 It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

A mixture of 55 ml of water, 33 ml of hydrochloric acid (32% by weight), 50 ml of methanol, 127 ml of pyrrolidine, 50.0 g of 1,4-dioxaspiro[4.5]decan-8-on and 50.0 g of potassium cyanide was stirred at room temperature for 65 hours. The resulting light brown suspension was extracted four times with 50 ml of diethyl ether each, the combined extracts were dried using sodium sulphate, filtered, swallowed and largely dissolved in a vacuum. 76.7 g of 8-pyrrolidine-1,4-dioxaspiro[4.5]decan-8-carbonitrile was obtained as a light brown liquid. 127 ml of 2,0 molar benzyl magnesium chloride was added to the solution in nitrogen nitrogen under pressure of 40,0 ml of ammonium sulphate, and 50 ml of ammonium chloride was added to the solution at room temperature.[4.4]The resulting raw 1- ((8-benzyl-1,4-dioxaspiro[4.5]dec-8-yl) pyrrolidine (54.0 g of yellow substance) was stirred for 24 hours without further purification with a mixture of 128 ml of hydrochloric acid (32 g/l) and 74 ml of water at room temperature. The reaction mixture was then washed twice with 50 ml of diethyl sulphate, then cooled by ice-cooling by adding three extracts of sodium chloride (32 g/l) and concentrated in 100 ml of concentrated sodium chloride, concentrated in a vacuum filter, and dried in a solution of sodium chloride.40.3 g of 4-benzyl-4-pyrrolidine-1-yl-cyclohexanone was obtained.

A solution of 4.00 g 4-benzyl-4-pyrrolidine-1-yl-cyclohexanone in 40 ml of tetrahydrofuran p.a. was added to 23.3 ml of 1.0 molar phenethylmagnesium chloride solution in THF under nitrogen atmosphere and ice bath cooling and stirred overnight at room temperature. 25 ml of ammonium chloride solution (20% by mass) was added for preparation under ice cooling, the phases were separated, the aqueous phase was extracted three times with 50 ml of diethyl ether each, the combined organic phases were drained over sodium sulphate, filtered, ejected and passed through a vacuum largely contaminated with solvent residues. The resulting crude oil (6,26 g) was obtained from 4-benzyl-methyl 1-methyl ethyl ether containing 1,48 g of methanol/Ethyl ether (Vithyl ether) (Vithyl ether) (Vithyl ether) 1,48 g of the untreated methyl ether, for example, 1,48 g of methanol.

Example 18 4-Benzyl-4-dimethylamino-1- ((1-methyl-1H-indol-2-yl) cyclohexanol)

After completion of the addition, the reaction mixture was stirred for a further two hours at 0 °C. A solution of 4-benzyl-4-methylamino flashhexanone (3.88 mg, 3.81 mm) was then added to a dry argon stream at - 5 °C. The tert-butyllithium (4.19 mmol, 2.47 ml of a 1.7 molar pentane solution) was dripped to a temperature of 0 °C and then heated for four hours at room temperature. The reaction mixture was then heated with 4-benzyl-4-methylamino flashhexanone (20 mg/mol) in a 4-benzyl-4-methylamino flashhexanone (3.88 mg, 3.81 mmol) phase at - 0 °C. The mixture was stirred at 0 °C for 15 minutes and then at room temperature for four hours. The reaction was heated with 4-benzyl-methylamino cycloride (20 mg/mol/mol) in a vacuum with a 4-benzyl-methylamino phenol (E-41-E-1) and dissolved in water. The mixture was then dissolved in an organic solution of 4-benzyl-methylamino phenol (20 mg/mol/mol/mol) and dissolved in water.

Example 19 The following substances are to be classified in the same heading as the active substance:

A solution of benzo[b]thiophen (1.50 mg, 3.73 mmol) in 20 ml of dry THF was cooled to -5 °C under an argon stream. Then tert-butyllithium (4.47 mmol, 2.63 ml of a 1.7 molar pentanol solution) was dripped to a temperature of 0 °C. After completion of the addition, the reaction mixture was stirred for two hours at 0 °C. Then a solution of 4-benzyl-4-dimethylaminocyclohexanone (3.86 mg, 3.73 mmol) was added to a dry THF (8) at 0 °C. The mixture was stirred at 0 °C for 15 minutes and then at room temperature for five hours. The reaction was carried out by means of a cyclohexanol-methylmethylmethyl ammonium solution (30 mg/Ethylmethylmethyl methyl phthalate) with a vacuum dissolved in water. The mixture was obtained by mixing the organic solvent with 1-methyl phthalate (1-12-128 mg/Ethylmethylmethylmethyl phthalate) and dissolved in water.

Example 20 The following substances are to be classified in the same heading as the active substance:

After completion of the addition, the reaction mixture was stirred for two hours at -78 °C. A solution of 4-benzyl-4-dimethylaminocyclohexanone (977 mg, 4.22 mmol) was then cooled in an argon stream at -78 °C. Then n-butyllithium (5.07 mmol, 3.17 ml of a 15 per cent hexane solution by mass) was carefully dripped so that a reaction temperature of -75 °C was not exceeded. After completion of the addition, the reaction mixture was stirred for two hours at -78 °C. A solution of 4-benzyl-4-dimethylaminocyclohexanone (977 mg, 4.22 mmol) was then stirred in a dry diethylhexanone (10 per cent) at -78 °C. The mixture was stirred at -78 °C (25 per cent by mass) for four hours and then stirred at 160 °C (30 per cent) and then stirred in a vacuum. The mixture was dissolved in a liquid containing 3-dimethylaminocyclohexanone (3-3 mg/ml) and dissolved in water. The mixture was then obtained by dissolving the mixture in an organic solution of 1-dimethylaminocyclohexanone (3-3 mg/ml) and 3-dimethylaminohexanone (34 ml/ml/ml/ml/ml/ml).

Example 21 The following substances are to be classified in the same heading as the active substance:

A solution of benzo[b]furan (612 mg, 5.12 mmol) in dry THF (40 ml) was cooled to -8 °C under an argon stream. Then tert-butyllithium (6.22 mmol, 4.14 ml of a 1.5 molar pentane solution) was dripped to a temperature of -5 °C. After completion of the addition, the reaction mixture was stirred for two hours at -5 °C. A solution of 4-benzyl-4-dimethylaminohexanone (1,20 g, 5.18 mmol) was then added to a dry THF (10) at 0 °C. The mixture was stirred at 0 °C for one hour and then at room temperature for four days. The reaction was obtained by heating the reaction site with a solution of cyclohexanone (Vithyl-methyl-methyl-methyl-methyl-methyl) in a vacuum with a pH of 380 °C (20 mg/L) and dissolving the mixture with a mixture of 2-hydroxy-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-

Beispiel
Nr.
4	4-Benzyl-4-dimethylamino-1-phenethylcyclohexanol Hydrochlorid
5	4-Dimethylamino-1,4-diphenethylcyclohexanol Hydrochlorid
6	4-Benzyl-4-dimethylamino-1-[2-(2-fluorphenyl)ethyl]cyclohexanol Hydrochlorid
7	4-Benzyl-4-dimethylamino-1-[2-(4-fluorphenyl)ethyl]cyclohexanol Hydrochlorid
8	4-Dimethylamino-4-(2-fluorbenzyl)-1-phenethylcyclohexanol Hydrochlorid
9	4-Dimethylamino-4-(3-fluorbenzyl)-1-phenethylcyclohexanol Hydrochlorid
10	4-Dimethylamino-4-(4-fluorbenzyl)-1-phenethylcyclohexanol Hydrochlorid
11	4-Benzyl-4-dimethylamino-1-[2-(3-fluorphenyl)ethyl]cyclohexanol Hydrochlorid
12	4-Benzyl-4-dimethylamino-1-(2-fluorbenzyl)cyclohexanol Hydrochlorid
13	4-(Allylmethylamino)-4-benzyl-1-phenethylcyclohexanol Hydrochlorid
14	4-Benzyl-4-dimethylamino-1-(3-fluorbenzyl)cyclohexanol Hydrochlorid
15	4-Benzyl-4-dimethylamino-1-(4-fluorbenzyl)cyclohexanol; Hydrochlorid
16	1-Benzyl-4-dimethylamino-4-(3-fluorbenzyl)cyclohexanol Hydrochlorid
17	4-Benzyl-1-phenethyl-4-pyrrolidin-1-ylcyclohexanol Hydrochlorid
18	4-Benzyl-4-dimethylamino-1-(1-methyl-1 H-indol-2-yl)cyclohexanol
19	1-Benzo[b]thiophen-2-yl-4-benzyl-4-dimethylaminocyclohexanol
20	1-Benzo[b]thiophen-3-yl-4-benzyl-4-dimethylaminocyclohexanol
21	1-Benzofuran-2-yl-4-benzyl-4-dimethylaminocyclohexanol

Claims

Substituted 4-aminocyclohexanol derivatives of the general formula I wherein R¹ and R² independently of one another are chosen from H; C_1-8-alkyl or C_3-8-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl-, or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or aryl, C_3-8-cycloalkyl or heteroaryl bonded via C_1-3-alkylene and in each case mono- or polysubstituted or unsubstituted; wherein R¹ and R² may not both be H, or the radicals R¹ and R² together form a ring and denote CH₂CH₂OCH₂CH₂, CH₂CH₂NR⁵CH₂CH₂ or (CH₂)_3-6, where R⁵ is chosen from H; C_1-8-alkyl or C_3-8-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or aryl, C_3-8-cycloalkyl or heteroaryl bonded via C_1-3- alkylene and in each case mono- or polysubstituted or unsubstituted; R³ is chosen from C_3-8-cycloalkyl, unsubstituted or mono- or polysubstituted; or aryl, C_3-8-cycloalkyl or heteroaryl bonded via a saturated or unsaturated, unbranched, substituted or unsubstituted C_1-4-alkyl group and in each case unsubstituted or mono- or polysubstituted; R⁴ is chosen from C_3-8-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; -CHR⁶R⁷, -CHR⁶-CH₂R⁷, -CHR⁶-CH₂-CH₂R⁷, -CHR⁶-CH₂-CH₂-CH₂R⁷, -C(Y)R⁷, -C(Y)-CH₂R⁷, -C(Y)-CH₂-CH₂R⁷ or -C(Y)-CH₂-CH₂-CH₂R⁷; or - R⁸-L-R⁹ where Y = O, S or H₂, where R⁶ is chosen from H, C_1-7-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C(O)O-C_1-6-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; and where R⁷ is chosen from H; C_3-8-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted, where R⁸ is chosen from aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted, where L is chosen from -C(O)-NH-, -NH-C(O)-, -C(O)-O-, -O- C(O)-, -O- , -S- or -S(O)₂- where R⁹ is chosen from aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted, wherein "substituted" in connection with alkyl and cycloalkyl denotes that at least one (optionally also several) hydrogen radical(s) is/are replaced by F, Cl, Br, I, NH₂, SH or OH, and "substituted" in connection with aryl and heteroaryl denotes that one or more hydrogen radical is/are replaced by R⁸², OR⁸², a halogen, a CF₃, a CN, an NO₂, an NR⁸³R⁸⁴, a C₁-₆-alkyl (saturated), a C_1-6-alkoxy, a C_3-8-cycloalkoxy, a C_3-8-cycloalkyl or a C_2-6-alkylene, wherein the radical R⁸² denotes H, a C_1-10-alkyl, preferably a C_1-6-alkyl, an aryl or heteroaryl, or an aryl or heteroaryl radical bonded via C_1-3-alkyl, saturated or unsaturated, or a C_1-3-alkylene group, wherein these aryl and heteroaryl radicals may not themselves be substituted by aryl or heteroaryl radicals, the radicals R⁸³ and R⁸⁴, which are identical or different, denote H, a C_1-10-alkyl, preferably a C_1-6-alkyl, an aryl, a heteroaryl, or an aryl or heteroaryl radical bonded via C_1-3-alkyl, saturated or unsaturated, or a C_1-3-alkylene group, wherein these aryl and heteroaryl radicals may not themselves be substituted by aryl or heteroaryl radicals, or the radicals R⁸³ and R⁸⁴ together denote CH₂CH₂OCH₂CH₂, CH₂CH₂NR⁸⁵CH₂CH₂ or (CH₂)_3-6, and the radical R⁸⁵ denotes H, a C_1-10-alkyl, preferably a C_1-6-alkyl, an aryl or heteroaryl radical, or an aryl or heteroaryl radical bonded via C_1-3-alkyl, saturated or unsaturated, or a C_1-3-alkylene group, wherein these aryl and heteroaryl radicals may not themselves be substituted by aryl or heteroaryl radicals, optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; in the form shown or in the form of their acids or their bases or in the form of their salts, in particular the physiologically acceptable salts, or in the form of their solvates, in particular the hydrates.
Substituted 4-aminocyclohexanol derivatives according to claim 1, characterized in that R¹ and R² independently of one another are chosen from H; C_1-8-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; where R¹ and R² may not both be H, or the radicals R¹ and R² together form a ring and denote CH₂CH₂OCH₂CH₂, CH₂CH₂NR⁵CH₂CH₂ or (CH₂)_3-6, where R⁵ is chosen from H; C_1-8-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, preferably R¹ and R² independently of one another are chosen from H; C_1-4-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; where R¹ and R² may not both be H, or the radicals R¹ and R² together form a ring and denote (CH₂)_4-5, in particular R¹ and R² independently of one another are chosen from methyl or ethyl or the radicals R¹ and R² together form a ring and denote (CH₂)₅.
Substituted 4-aminocyclohexanol derivatives according to one of claims 1 and 2, characterized in that R³ is chosen from C_5-6-cycloalkyl, unsubstituted or mono- or polysubstituted; or C_5-6-cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, pyridyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl bonded via a saturated, unbranched C_1-2-alkyl group and in each case unsubstituted or mono- or polysubstituted; in particular R³ is chosen from phenyl, pyridyl, furyl or thiophenyl bonded via a saturated, unbranched C_1-2-alkyl group and in each case unsubstituted or mono- or polysubstituted.
Substituted 4-aminocyclohexanol derivatives according to one of claims 1 to 3, characterized in that R⁴ is chosen from C₃-₈-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; or -R⁸-L-R⁹ preferably R⁴ is chosen from cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl or benzo[1,2,5]thiazolyl or 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolinonyl, oxopyrazolinonyl, dioxolanyl, adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl or quinazolinyl, in each case unsubstituted or mono- or polysubstituted; or -R⁸-L-R⁹ in particular R⁴ is chosen from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzothiazolyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, in each case unsubstituted or mono- or polysubstituted; or -R⁸-L-R⁹.
Substituted 4-aminocyclohexanol derivatives according to claim 4, characterized in that R⁸ is chosen from indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl or benzo[1,2,5]thiazolyl or 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolinonyl, oxopyrazolinonyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl or quinazolinyl, in each case unsubstituted or mono- or polysubstituted, L is chosen from -C (O) -NH-, -NH-C(O)-, -C (O) -O-, -O- C(O)-, -O-, -S- OR -S(O)₂-, and/or R⁹ is chosen from indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl or benzo[1,2,5]thiazolyl or 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolinonyl, oxopyrazolinonyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl or quinazolinyl, in each case unsubstituted or mono- or polysubstituted, preferably R⁸ is chosen from indolyl, benzothiophenyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, in each case unsubstituted or mono- or polysubstituted, L is chosen from -C(O)-NH-, -NH-C(O)-, -C(O)-O-, -O-C(O)- or- S(O)₂-, and/or R⁹ is chosen from indolyl, benzothiophenyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, in each case unsubstituted or mono- or polysubstituted, in particular R⁸ is chosen from indolyl, unubstituted, L is chosen from -S(O)₂- and R⁹ is chosen from phenyl, unsubstituted.
Substituted 4-aminocyclohexanol derivatives according to one of claims 1 to 3, characterized in that R⁴ is chosen from -CHR⁶R⁷, -CHR⁶-CH₂R⁷, -CHR⁶-CH₂-CH₂R⁷, -CHR⁶-CH₂-CH₂-CH₂R⁷, -C(Y)R⁷, -C(Y)-CH₂R⁷, -C(Y)-CH₂-CH₂R⁷ or -C(Y)-CH₂-CH₂-CH₂R⁷ where Y = O, S or H₂, preferably R⁴ is chosen from -CHR⁶R⁷, -CHR⁶-CH₂R⁷, -CHR⁶-CH₂-CH₂R⁷, -C(Y)R⁷, -C(Y)-CH₂R⁷ or -C(Y)-CH₂-CH₂R⁷where Y = O or S, in particular R⁴ is chosen from -CHR⁶R⁷, -CHR⁶-CH₂R⁷, -C(Y)R⁷ or -C(Y)-CH₂R⁷ where Y = O.
Substituted 4-aminocyclohexanol derivatives according to claim 6, characterized in that R⁶ is chosen from H, C_1-4-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or-unsubstituted; or C(O)O-C_1-4-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; preferably H, C_1-4-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; in particular H, CH₃ and C₂H₅.
Substituted 4-aminocyclohexanol derivatives according to claim 6, characterized in that R⁷ is chosen from C_3-8-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; preferably R⁷ is chosen from cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl or benzo[1,2,5]thiazolyl or 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolinonyl, oxopyrazolinonyl, dioxolanyl, adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl or quinazolinyl, in each case unsubstituted or mono- or polysubstituted; in particular R⁷ is chosen from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, in each case unsubstituted or mono- or polysubstituted.
Substituted 4-aminocyclohexanol derivatives according to one of claims 1 to 8, characterized in that they are chosen from the following group:
• 4-benzyl-4-dimethylamino-1-phenethylcyclohexanol and the corresponding hydrochloride,

• 4-dimethylamino-1,4-diphenethylcyclohexanol and the corresponding hydrochloride,

• 4-benzyl-4-dimethylamino-1-[2-(2-fluorophenyl)ethyl]cyclohexanol and the corresponding hydrochloride,

• 4-benzyl-4-dimethylamino-1-[2-(4-fluorophenyl)ethyl]cyclohexanol and the corresponding hydrochloride,

• 4-dimethylamino-4-(2-fluorobenzyl)-1-phenethylcyclohexanol and the corresponding hydrochloride,

• 4-dimethylamino-4-(3-fluorobenzyl)-1-phenethylcyclohexanol and the corresponding hydrochloride,

• 4-dimethylamino-4-(4-fluorobenzyl)-1-phenethylcyclohexanol and the corresponding hydrochloride,

• 4-benzyl-4-dimethylamino-1-[2-(3-fluorophenyl)ethyl]cyclohexanol and the corresponding hydrochloride

• 4-benzyl-4-dimethylamino-1-(2-fluorobenzyl)cyclohexanol and the corresponding hydrochloride,

• 4-(allylmethylamino)-4-benzyl-1-phenethylcyclohexanol and the corresponding hydrochloride,

• 4-benzyl-4-dimethylamino-1-(3-fluorobenzyl)cyclohexanol and the corresponding hydrochloride,

• 4-benzyl-4-dimethylamino-1-(4-fluorobenzyl)cyclohexanol and the corresponding hydrochloride,

• 1-benzyl-4-dimethylamino-4-(3-fluorobenzyl)cyclohexanol and the corresponding hydrochloride or

• 4-benzyl-1-phenethyl-4-pyrrolidin-1-ylcyclohexanol and the corresponding hydrochloride

• 4-benzyl-4-dimethylamino-1-(1-methyl-1H-indol-2-yl)cyclohexanol

• 1-benzo[b]thiophen-2-yl-4-benzyl-4-dimethylaminocyclohexanol

• 1-benzo[b]thiophen-3-yl-4-benzyl-4-dimethylaminocyclohexanol

• 1-benzofuran-2-yl-4-benzyl-4-dimethylaminocyclohexanol
optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; in the form shown or in the form of their acids or their bases or in the form of their salts, in particular the physiologically acceptable salts, or in the form of their solvates, in particular the hydrates.
Medicament comprising at least one substituted 4-aminocyclohexanol derivative according to one of claims 1 to 9, optionally in the form of its racemate, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; in the form shown or in the form of the acids or the bases or in the form of the salts, in particular the physiologically acceptable salts, or in the form of the solvates, in particular the hydrates; and optionally suitable additives and/or auxiliary substances and/or optionally further active compounds.
Medicament according to claim 10, characterized in that in addition to at least one substituted 4-aminocyclohexanol derivative, the medicament also contains an opioid, preferably a potent opioid, in particular morphine, or an anaesthetic, preferably hexobarbital or halothane.
Use of a substituted 4-aminocyclohexanol derivative according to one of claims 1 to 9, optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; in the form shown or in the form of its acids or its bases or in the form of its salts, in particular the physiologically acceptable salts, or in the form of its solvates, in particular the hydrates; for the preparation of a medicament for treatment of pain, in particular acute, visceral, neuropathic or chronic pain.
Use of a substituted 4-aminocyclohexanol derivative according to one of claims 1 to 9, optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; in the form shown or in the form of its acids or its bases or in the form of its salts, in particular the physiologically acceptable salts, or in the form of its solvates, in particular the hydrates; for the preparation of a medicament for treatment of anxiety states, of stress and stress-associated syndromes, depressions, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunctions, learning and memory difficulties (as a nootropic), withdrawal symptoms, alcohol and/or drug and/or medicament abuse and/or dependency, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinnitus, pruritus, migraine, impaired hearing, deficient intestinal motility, impaired food intake, anorexia, obesity, locomotor disorders, diarrhoea, cachexia, urinary incontinence or as a muscle relaxant, anticonvulsive, antitussive or anaesthetic or for co-administration in treatment with an opioid analgesic or with an anaesthetic, for diuresis or antinatriuresis and/or anxiolysis.
Process for the preparation of a substituted 4-aminocyclohexanol derivative according to one of claims 1 to 9 with the following steps:
a. a cyclohexane-1,4-dione, protected with the groups S¹ and S², according to formula II is reacted with a cyanide, preferably potassium cyanide, in the presence of a compound of the formula HNR⁰¹R⁰² to give a protected N-substituted 1-amino-4-oxo-cyclohexanecarbonitrile derivative according to formula III; optionally acylation, alkylation or sulfonation is then carried out in any desired sequence and optionally repeatedly, and/or in the case of compounds where R⁰¹ and/or R⁰² and/or R⁰⁶ = H protected with a protective group, at least once a protective group is split off and optionally acylation, alkylation or sulfonation is carried out, and/or in the case of compounds where R⁰¹ and/or R⁰² and/or R⁰⁶ = H, at least once a protective group is introduced and optionally acylation, alkylation or sulfonation is carried out,

b. the aminonitrile according to formula III is reacted with organometallic reagents, preferably Grignard or organolithium reagents, of the formula metal-R³, so that a compound according to formula IVa is formed; optionally acylation, alkylation or sulfonation is then carried out in any desired sequence and optionally repeatedly, and/or in the case of compounds where R⁰¹ and/or R⁰² and/or R⁰⁶ = H protected with a protective group, at least once a protective group is split off and optionally acylation, alkylation or sulfonation is carried out, and/or in the case of compounds where R⁰¹ and/or R⁰² and/or R⁰⁶ = H, at least once a protective group is introduced and optionally acylation, alkylation or sulfonation is carried out,

c. on the compound according to formula IVa according to formula III, the protective groups S¹ and S² are split off so that a 4-substituted 4-aminocyclohexanone derivative according to formula IV is formed; optionally acylation, alkylation or sulfonation is then carried out in any desired sequence and optionally repeatedly, and/or in the case of compounds where R⁰¹ and/or R⁰² and/or R⁰⁶ = H protected with a protective group, at least once a protective group is split off and optionally acylation, alkylation or sulfonation is carried out, and/or in the case of compounds where R⁰¹ and/or R¹² and/or R⁰⁶ = H, at least once a protective group is introduced and optionally acylation, alkylation or sulfonation is carried out,

d. the 4-substituted 4-aminocyclohexanone derivative according to formula IV is reacted with organometallic reagents, preferably Grignard or organolithium reagents, of the formula metal-R³ so that a compound according to formula V is formed; optionally acylation, alkylation or sulfonation is then carried out in any desired sequence and optionally repeatedly, and/or in the case of compounds where R⁰¹ and/or R⁰² and/or R⁰⁴ and/or R⁰⁵ and/or R⁰⁶ = H protected with a protective group, at least once a protective group is split off and optionally acylation, alkylation or sulfonation is carried out, and/or in the case of compounds where R⁰¹ and/or R⁰² and/or R⁰⁴ and/or R⁰⁵ and/or R⁰⁶ = H, at least once a protective group is introduced and optionally acylation, alkylation or sulfonation is carried out, until a compound according to formula I is formed,
wherein R¹, R², R³, R⁴ and R⁵ have the meaning given in claim 1 and R⁰¹ and R⁰² independently of one another are chosen from H; H provided with a protective group; C_1-8-alkyl or C_3-8-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or aryl, C_3-8-cycloalkyl or heteroaryl bonded via C_1-3-alkylene and in each case mono- or polysubstituted or unsubstituted; or the radicals R⁰¹ and R⁰² together form a ring and denote CH₂CH₂OCH₂ CH₂CH₂NR⁰⁵CH₂CH₂ or (CH₂)_3-6, where R⁰⁵ is chosen from H; H provided with a protective group; C_1-8-alkyl or C_3-8-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or aryl, C_3-8-cycloalkyl or heteroaryl bonded via C_1-3-alkylene and in each case mono- or polysubstituted or unsubstituted; R⁰⁴ is chosen from H, H provided with a protective group; C_3-8-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; -CHR⁶R⁷, -CHR⁶-CH₂R⁷, -CHR⁶-CH₂-CH₂R⁷, -CHR⁶-CH₂-CH₂-CH₂R⁷, -C(Y)R⁷, -C (Y) - CH₂R⁷, -C (Y) -CH₂-CH₂R⁷ or -C (Y) -CH₂-CH₂-CH₂R⁷; or-R⁸-L-R⁹ where Y = O, S or H₂, where R⁶ is chosen from H, C_1-7-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C(O)O-C_1-6-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; and where R⁷ is chosen from H; C_3-8-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted, where R⁸ is chosen from aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted, where L is chosen from -C(O)-NH-, -NH-C(O)-, -C(O)-O-, -O- C(O)-, -O-, -S- or -S(O)₂- where R⁹ is chosen from aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted, and S¹ and S² independently of one another are chosen from protective groups or together denote a protective group, preferably monoacetal.
Process for the preparation of a substituted 4-aminocyclohexanol derivative according to claim 14, characterized in that the protective groups on H in R⁰¹, R⁰², R⁰⁴ and/or R⁰⁵ are chosen from alkyl, benzyl or carbamates, for example FMOC, Z or Boc.