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HK1062911B - Substituted 2-pyridine-cyclohexane-1,4-diamine derivatives - Google Patents

Substituted 2-pyridine-cyclohexane-1,4-diamine derivatives Download PDF

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Publication number
HK1062911B
HK1062911B HK04105744.4A HK04105744A HK1062911B HK 1062911 B HK1062911 B HK 1062911B HK 04105744 A HK04105744 A HK 04105744A HK 1062911 B HK1062911 B HK 1062911B
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HK
Hong Kong
Prior art keywords
unsubstituted
polysubstituted
mono
saturated
unsaturated
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HK04105744.4A
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German (de)
French (fr)
Chinese (zh)
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HK1062911A1 (en
Inventor
Bernd Sundermann
Corinna Maul
Helmut Buschmann
Barbara Heller
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Grunenthal Gmbh
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Priority claimed from DE10123163A external-priority patent/DE10123163A1/en
Application filed by Grunenthal Gmbh filed Critical Grunenthal Gmbh
Publication of HK1062911A1 publication Critical patent/HK1062911A1/en
Publication of HK1062911B publication Critical patent/HK1062911B/en

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Description

The present invention relates to substituted 2-pyridine cyclohexane-1,4-diamind derivatives, methods for their manufacture, medicinal products containing these compounds and the use of substituted 2-pyridine cyclohexane-1,4-diamind derivatives for the manufacture of medicinal products.
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.Mod., 223, 1997, 113-116), in the Flexor reflex model in the rat (Shu et al., Neuropeptides, 32, 1998, 567-571) or in the glutamate-stimulated spinal cord neurons (Faber et al., Br. J. Pharmacol., 119, 1996, p. 189-190); it has an antinociceptive effect in the Tail Flick test in the mouse (King et al., Neurosci.Mod., 223, 1997, 113-116), in the Flexor reflex model in the rat (ReuXu et al., Neuroport., 1996, 7, 2092-2094) and in the Spinal nerve neuron (Y.S.S.S., Spinal nerve Neurosci.Mod., No. 865, No. 867, Oct. 88, 1997, No. 89, and No. 964, which has been shown to be particularly effective in neurotoxic conditions, and in the Neuroimaging and Neuroscience test (Smits), No. No. 88, No. 88, No. 88, No. 88, No. 98, No. 88, No. 98, No. 98, No. 98, No. 98, No. 98, No. 98, No. 98, No. 98, No. 98, No. 98, No. 98, No. 98, No. 98, No. 98, No. 98, No. 98, No. 98, No. 98, No. 98, No. 98, No. 98, No. 98, No. 98, No. 108, No. 108, No. 108, No. 108, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 109, No. 10
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 morphine addiction potential, anxiolytic, modulation of movement activity, memory disorders, epilepsy; modulation of neurotransmitter release, particularly of glutamate, dopamine and serotonin, thereby affecting neurological function; effects on the cardiovascular system, blood pressure, elevated blood pressure, electrolyte levels, electrolyte levels, the circulatory system, the circulatory system, the circulatory system, the circulatory system, the circulatory system, the circulatory system, the circulatory system, the circulatory system, the circulatory system, the circulatory system, the circulatory system, the circulatory system, the circulatory system, the circulatory system, the circulatory system, the circulatory system, the circulatory system, the circulatory system, the circulatory system, the circulatory system, the circulatory system, the circulatory system, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatory, the circulatoryThe use of agonists and antagonists as anorectic, analgesic (also co-administered with opioids) or nootropic is further 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 medicinal products which act on the nociceptin/ORL1 receptor system and are therefore suitable for use in medicinal products, in particular 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 2-pyridine cyclohexane-1,4-diamind derivatives of the general formula I, Other whereinR1 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, or the residues R1 and R2 together form a ring and mean CH2CH2OCH2CH2, CH2CH2NR6CH2CH2 or (CH2) 63; with R6 selected from H; C1-8 alkyl or C3-8 cycloalkyl, whether or not saturated, branched or unbranched, simply or repeatedly substituted or unsubstituted; aryl or heteroaryl, either simply or repeatedly substituted or unsubstituted; or aryl bound over C1-3 alkyl,C3-8-cycloalkyl or heteroaryl, whether or not simply substituted or repeatedly substituted;R3 is selected from H;C1-8-alkyl, whether or not saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or repeatedly unsaturated;C3-8-cycloalkyl, whether or not simply or repeatedly substituted or repeatedly substituted;Aryl or heteroaryl, whether or not simply or repeatedly substituted or repeatedly substituted;or C1-3-linked aryl, C3-8-cycloalkyl or heteroaryl, whether or not simply or repeatedly substituted or repeatedly substituted;SH, F, OH, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, NO, R26 selected from C1-6 alkyl, saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted; C3-8 cycloalkyl, saturated or unsaturated, simply or repeatedly substituted or unsubstituted; aryl or heteroaryl,unsubstituted or simply or repeatedly substituted with F, Cl, Br, l, NH2, NO2, CF3, CHF2, CH2F, CH3, C2H5, C3H7, C4H9, OCF3, OCHF2, OCH2F, OCH3, OC2H5, OC3H7, OC4H9, SH and/or OH; via a C1-3 alkyl, saturated or unsaturated, bound aryl, C3-8-cycloalkyl or heteroaryl, each unsubstituted or once or repeatedly substituted with F, Cl, CF, 1, NH2, NO2, NO3, CHF2, CH2F, CH3, C2H5, C3H7, C4H9, OH3, OCF2, OCH2F, OCH3, OCCH2H5, OCH37, OCH4 or OH9, and/or with R27 and R28 independently selected from H, C1-6-alkyl, saturated or unsaturated, branched or unbranched, simply or multiplely substituted or unsubstituted; C3-8-cycloalkyl, saturated or unsaturated, simply or multiplely substituted or unsubstituted; aryl or heteroaryl,unsubstituted or simply or repeatedly substituted with F, Cl, Br, I, NH2, NO2, CF3, CHF2, CH2F, CH3, C2H5, C3H7, C4H9, OCF3, OCHF2, OCH2F, OCH3, OC2H5, OC3H7, OC4Hg, SH and/or OH; over C1-3 alkyl, saturated or unsaturated, bound aryl, C3-8 cycloalkyl or heteroaryl, each unsubstituted or once or repeatedly substituted with F, Cl, Br, 1, NH2, NO2, CF3, CHF2, CH2F, CH3, C2H5, C3H7, C4H9, OH3, OCHF2, OCH2F3, OCH2F3, OCCH2H5, OCH37, OCH3H9, and/or SH4H; and or the residues R27 and R28 together mean CH2CH2OCH2CH2, CH2CH2NR29CH2CH2 or (CH2) 3-6, with R29 selected from H, C1-6-alkyl, saturated or unsaturated, branched or unbranched, simply or multiplely substituted or unsubstituted; C3-8-cycloalkyl,Aryl or heteroaryl, whether or not substituted with F, Cl, Br, I, NH2, NO2, CF3, CHF2, CH2F, CH3, C2H5, C3H7, C4H9, OCF3, OCHF2, OCHF2, OCH2F, OCH3, OC2H5, OC3H7, OC4H9, SH and/or OH; via C1-3 alkyl, whether or not saturated, bound to aryl, C3-8 cycloalkyl or heteroaryl, whether or not substituted with F, Cl, Br, I, NO2, NH3, CHF2, CHF2, CHF2, CHF3, CHF2, CHF2, CHF3, CHF2, CHF3, CHF2, CHF3, CHF2, CHF2, CHF3, CHF2, CHF2, CHF2, CHF3, CHF2, CHF2, CHF3, CHF2, CHF2, CHF3, CHF2, CHF2, CHF3, CHF2, CHF3, CHF2, CHF2, CHF3, CHF2, CHF2, CHF3, CHF2, CHF3, CHF2, CHF2, CHF3, CHF2, CHF3, CHF2, CHF3, CHF2, CHF3, CHF2, CHF3, CHF2, CHF3, CHF2, CHF3, CHF2, CHF2, CHF3, CHF2, CHF3, CHF2, CHF3, CHF2, CHF3, CHF2, CHF3, CHF2, CHF3, CHF2, CHF3, CHF2, CHF3, CHF3, CHF2, CHF3, CHF3, CHF3, CHF3, CHF3, CHF2, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3, CHF3,The following is the list of the substances which are to be classified as 'metals' in Annex I to Regulation (EC) No 1907/2006 of the European Parliament and of the Council: with X = O or S, R7 selected from H, C1-8 alkyl or C3-8 cycloalkyl, whether or not saturated, branched or unbranched, simply or with multiple substitutions or unsubstituted; aryl, heteroaryl, whether or not unsubstituted or simply or with multiple substitutions; bound by a saturated or unsubstituted, branched or unbranched, substituted or unsubstituted C1-4 alkyl group to aryl, C3-8 cycloalkyl or heteroaryl, either simply or with multiple substitutions or unsubstituted; with R8 selected from H, C1-4 alkyl, saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted; or The residues R7 and R8 together form a ring and mean CH2CH2OCH2CH2, CH2CH2NR10 CH2CH2 or (CH2) 3-6. with R10 selected from H; C1-8 alkyl or C3-8 cycloalkyl,whether or not saturated, branched or unbranched, simply or in multiple substitutions or unsubstituted; aryl or heteroaryl, either simply or in multiple substitutions or unsubstituted; or aryl, C3-8-cycloalkyl or heteroaryl, whether or not simply or in multiple substitutions or unsubstituted, bound by C1-3 alkyl groups; R9 selected from C1-8 alkyl or C3-8 cycloalkyl, whether or not saturated or unsaturated, branched or unbranched, simply or with multiple substitutions or unsubstituted; aryl, heteroaryl, either unsubstituted or simply or with multiple substitutions; aryl, C3-8 cycloalkyl or heteroaryl, whether or not substituted or with single substitution or with multiple substitutions, bound by a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C1-4 alkyl group;R5 selected is C3-8 cycloalkyl, aryl or heteroaryl, either unsubstituted or with multiple substitutions or with simple substitutions or unsubstituted;CH11R12,The following substances are to be classified as "chemical" in the Annex to this Regulation: with Y = O, S or H2, with R11 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 with R12 H; C3-8-cycloalkyl, aryl or heteroaryl, whether or not substituted, or simply or in multiple substitutions, or R4 and R5 together form a heterocycle with between 3 and 8 atoms in the ring, saturated or unsaturated; simply or repeatedly substituted or unsubstituted, which may be condensed with further rings, if necessary, 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 the 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 salts of physiologically compatible acids or cations; or in the form of their solvates, in particular the hydrates.
All of these compounds or groups of compounds of the invention show excellent binding to the ORL1 receptor.
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-, 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-, C4-, C5-, C6- or C7-cycloalkyl, C3- or C5-cycloalkyl, C5- or C5-cycloalkyl, C5- or C5-cycloalkyl, C5- or C5-cycloalkyl, 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-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-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-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-alkyl, C5- or C5- or C5- or C5- or C5- or C5- or 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' means a substance that is a mixture of two or more substances, one of which is a substance of a particular nature, and the other a substance of which is a mixture of two or more substances.
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 R22, OR22 by a halogen, preferably F and/or CI, a CF3, a CN, a NO2, an NR23R24, 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 R22 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 R23 and R24, 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 R23 and R24 together mean CH2CH2OCH2CH2, CH2CH2NR25CH2CH2 or (CH2) 3-6, and the residue R25 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.
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.
In a preferred embodiment, the substituted 2-pyridine cyclohexane-1,4-diamind derivatives are constructed in such a way that, according to formula I, R1 and R2 are independently selected from H; C1-8 alkyl, saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted; or the residues R1 and R2 together form a ring and mean CH2CH2OCH2CH2, CH2CH2NR6CH2CH2 or (CH2) 3-6, with R6 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 repeatedly substituted or unsubstituted; 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.
In a preferred embodiment, the substituted 2-pyridine cyclohexane-1,4-diamond derivatives are constructed as follows: R3 is selected from H; C1-8 alkyl, whether or not saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted; C3-8 cycloalkyl, saturated or unsaturated, 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 to C1-3 alkyl; SH, OH, F, Cl, 1, Br, CN, NO2, OR2, NH26; R26 selected from C1-6 alkyl, saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted; preferably R3 is selected from H; C1-6 alkyl, whether saturated or unsaturated, branched or unbranched, simply or multiple substitution or unsubstitution; SH, OH, F, Cl, I, Br, CN, NO2, NH2, OR26; R26 selected from C1-6 alkyl, saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted; In particular: R3 is selected from H.
In a preferred embodiment, the substituted 2-pyridine cyclohexane-1,4-diamond derivatives are constructed in such a way that, according to formula 1 R4 is selected from H, C(X) R7, C(X) NR7R8, C(X) OR9, C(X) SR9 or S(O2) R9 with X = O or S, preferably R4 is selected from H, C(X) R7, C(X) NR7R8 or C(X) OR9 with X = O, In particular: R4 is selected from H or C (O) R7; preferably with R7 selected from H; or C1-8 alkyl, saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted; preferably H; or C1-3 alkyl saturated, unsubstituted, branched or unbranched; in particular CH3.
In a preferred embodiment, the substituted 2-pyridine cyclohexane-1,4-diamind derivatives are constructed in such a way that, according to formula I, R4 and R5 together form a heterocycle with between 3 and 8 atoms in the ring, saturated or unsaturated; simply or repeatedly substituted or unsubstituted, preferably with between 5 and 7 atoms in the ring, of which, in addition to the mandatory N, between 0 and 1 additional heterocycle selected from N, S or O is in the ring; where the heterocycle formed by R4 and R5 together may be condensed with additional rings, if necessary, preferably with aromatic and/or heteroaromatic rings, which may be condensed with other aromatic and/or heteroaromatic rings, in which the heterocycle formed by R4 and R5 together is condensed with one or two additional rings, preferably the heterocycle formed by R4 and R5 together is condensed with two more rings so that R4 and R5 together Other I mean.
In a preferred embodiment, the substituted 2-pyridine cyclohexane-1,4-diamind derivatives are constructed in such a way that, according to formula I, R4 is selected from H or C1-8 alkyl, saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted, preferably H or C1-6 alkyl, saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted, In particular: H or C1-3 alkyl, saturated, unbranched and unsubstituted.
In a preferred embodiment, the substituted 2-pyridine cyclohexane-1,4-diamind derivatives are constructed in such a way that, according to formula I, R5 is selected from C3-8 cycloalkyl, aryl or heteroaryl, either unsubstituted or single or multiple substituted; preferably R5 is selected from cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indoyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, bertsodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, fluorine isophenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl or benzo[1,2,5] or 1,2-dihydroacetinyl, pyridyl, furanyl, benzofuranyl, pyrrazine, oxandrolone, dioxanyl, pyrophenyl, pyrophenyl or phenylenol, or simply substituted or substituted in the manufacture of any of the following: R5 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.
In another particularly preferred embodiment, the substituted 2-pyridine cyclohexane-1,4-diaminderivatives are constructed in such a way that, according to formula I, The test chemical is used to determine the concentration of the test chemical in the test chemical. with Y = O, S or H2, preferably The test chemical is used to determine the concentration of the test chemical in the test chemical. with Y = O or S, In particular: The test chemical is used to determine the concentration of the test chemical in the test medium. with Y=O.
In this case, it is particularly preferable to use: R11 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; or C(O) O-C1-2 alkyl, saturated, unbranched, simply or repeatedly substituted or unsubstituted; In particular: H, CH3, C2H5 and C ((O) O-CH3. and/or it is also particularly preferred if: R12 is selected from C3-8 cycloalkyl, aryl or heteroaryl, either unsubstituted or single or multiple substituted; preferably R12 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-dihydroacenyl, pyridyl, furanyl, benzofuranyl, pyrrazine, oxandrolone, dioxanyl, pyridyl, pyrimidyl or phenylenedioxyl, or simply substituted or substituted with, or in addition to, quinone; In particular: R12 is selected from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indoyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyi, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, whether or not substituted or simply or multiple substituted.
Furthermore, the 2-pyridine cyclohexane-1,4-diamond derivatives substituted according to the invention are particularly preferred, in particular from the following group: The use of the active substance in the active substance shall be authorised only if the substance is classified in the active substance as a non-polar dihydrochloride. where appropriate, also in the form of their racemates, the abovementioned or other 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; where appropriate, also in the form of acids or bases or in the form of other salts, in particular physiologically compatible salts or salts of physiologically compatible acids or cations; or in the form of their solvates, in particular 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 2-pyridine cyclohexane-1,4-diaminder derivative of the invention, where appropriate in the form of its racemate, 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 salts or salts compatible or cations; or in the form of its solvates, in particular the hydrate, and where appropriate other suitable additives/auxiliary substances/additives and, where appropriate, weights.
The medicinal products of the invention contain, in addition to at least one substitution of 2-pyridine cyclohexane-1,4-diamind derivative of 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, substitution pills or aerosols. The balance of the substitution agents, as well as the set of excipients to be used, depend on whether the product is a granular spray, or a solution containing a solution for oral administration, a solution for intravenous administration, a solution for oral administration, a solution for oral administration, a solution for oral administration, a solution for oral administration, a solution for oral administration, a solution for intra-cutaneous administration, a solution for oral administration, a solution for intra-cutaneous administration, a solution for oral administration, a solution for intra-cutaneous administration, a solution for oral administration, a solution for intra-cutaneous administration, a solution for oral administration, a solution for intra-ocular administration, a solution for intra-ocular administration, a solution for oral administration, a solution for intra-ocular administration, a solution for intra-ocular administration, a solution for intra-ocular administration, a solution for intra-ocular administration, or intra-ocular administration, a solution for the intra-ocular application, a solution for the intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-ocular, or intra-
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 2-pyridine cyclohexane-1,4-diamond derivative substituted according to the invention.
For all the above forms of the medicinal products of the invention, it is particularly preferable if the medicinal product contains, in addition to at least one substituted 2-pyridine cyclohexane-1,4-diamond derivative, an opioid, preferably a strong opioid, in particular morphine, or an anaesthetic, preferably hexobarbital or halothane.
A preferred form of the medicinal product contains a 2-pyridine cyclohexane-1,4-diamond substitute derivative of the invention, as a pure diastereomer and/or enantiomer, as a racemate or as a non-equimolar or equimolar mixture of the diastereomers and/or enantiomers.
As can be seen in the introduction to the state of the art, the ORL1 receptor has been identified in particular in pain, and therefore substituted 2-pyridine cyclohexane-1,4-diamind derivatives of the invention can be used to manufacture a medicinal product for the treatment of pain, in particular acute, neuropathic or chronic pain.
Therefore, another subject matter of the invention is the use of substituted 2-pyridine cyclohexane-1,4-diamind derivatives of the invention, 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 tolerable salts or salts of physiologically tolerable acids or cations; or in the form of their solvates, in particular the hydrate, for the manufacture of a medicinal product for the treatment of pain, in particular acute, neuropathic or chronic pain.
As already indicated in the introduction, the ORL1 receptor plays a role in a variety of physiological processes, in addition to its function in pain, and is of particular medical importance, so that the invention also covers the use of substituted 2-pyridine cyclohexane-1,4-diamond derivatives of the invention, 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 the enantiomers or diastereomers, in any proportion; in the form of analogues or in the form of their stress hormones or their base hormones or in their analogues, in particular the anti-inflammatory or anti-tumor hormones; in the form of analgesics or analgesics, in the form of drugs, especially for the treatment of muscle and blood disorders, especially in the treatment of depression, anxiety, depression, and/or other symptoms of stress or of depression; in the form of drugs, especially anti-hypertensive or anti-inflammatory drugs, for the treatment of muscle and/or anti-inflammatory disorders; in the form of drugs, in particular, for the treatment of general, mental disorders, depression, anxiety, depression, depression, and/diarrheaval, and/or depression, and/or for the treatment of mental disorders, especially those with a narcotic drugs, such as medicinal drugs, drugs, drugs, drugs, drugs, drugs, drugs, drugs, drugs, drugs, drugs, drugs, drugs, drugs, drugs, drugs, drugs, drugs, drugs, drugs, drugs, drugs, or drugs, and/other substances, especially for the treatment of narcotic, and/or for the treatment of mental disorders, or mental disorders, and/or mental disorders, especially for the treatment of the patient, for the patient, for the patient, for the patient, for the patient, for the patient, for the patient, for the patient, for the patient, for the patient, for the patient, for the patient, for the patient, for the patient, for the patient, for the patient, for the patient, for the patient, for the patient
It may be preferred in one of the above uses if a substituted 2-pyridine cyclohexane-1,4-diamind derivative is 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.
Another subject of the invention is a process for the production of the substituted 2-pyridine cyclohexane-1,4-diamond derivatives as described and illustrated below.
A method, described in the following main method A, is particularly suitable for the production of a 2-pyridine cyclohexane-1,4-diamond derivative substituted according to the invention according to formula I with R3 = H using the following steps: 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 of formula III is combined with cyclopentadienyl-cycloocta-1,5-diene-cobalt ((I) [cpCo(cod) ] and irradiated under acetylene to form a compound of formula IVa; 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, acyled, alkylated or sulphonated and/or at least one protective group is introduced and, where applicable, acyled, alkylated or sulphonated in a compound with R01 and/or R02 and/or R06 = H, c. at the compound according to formula IVa, the protective groups Sui1 and Sui2 are cleaved to form a 4-substituted 4-aminocyclohexane derivative according to formula IV; 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 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 R06 = H, at least once a protective group has been introduced and, if applicable, acylated, alkylated or sulphonated, i.e. the 4-substituted 4-aminocyclohexane derivative according to formula IVa is reduced amined with a compound according to formula HNR04R05 to give a 2-pidin cyclohexane-1,4-diamond derivative according to formula Vyr; Other then, if applicable, in any order and repeatedly 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 = protected group H,at least once a protective group has been cleaved and, where 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, where applicable, acylated, alkylated or sulphonated until a compound conforming to formula I has been formed, where R1, R2, R4 and R5 have the meanings given for compounds of the invention according to formula I 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 multiplely substituted or unsubstituted; aryl or heteroaryl, either simply or multiplely substituted or unsubstituted; or aryl bound via C1-3 alkyl,C3-8-cycloalkyl or heteroaryl, whether or not single or multiple substitution; or the residues R01 and R02 together form a ring and mean CH2CH2OCH2CH2, CH2CH2NR06CH2CH2 or (CH2) 3-6, R06 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, with a protective group H; C1-8 alkyl, saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted; R05 is selected from H,H; C3-8-cycloalkyl, aryl or heteroaryl, whether or not substituted, or simply or in multiple substitutions; -CHR11R12, -CHR11-CH2-CH2R12, -CHR11-CH2-CH2CH2R12, -C(Y) R12, -C(Y) -CH2R12, -C(Y) -CH2-CH2R12 or -C(Y) -CH2-CH2-CH2R12 where Y = H2, with R11 selected from H, C1-7, alkyl, saturated or unsaturated, branched or unbranched, simply or in multiple substitutions or unsubstituted; and selected from with R12 H; C3-8-cycloalkyl, aryl or heteroaryl, whether or not substituted, or simply or in multiple substitutions, or R04 and R05 together form a heterocycle with between 3 and 8 atoms in the ring, whether or not saturated; simply or repeatedly substituted or unsubstituted, and S1 and S2 are selected independently from each other from protective groups or together represent a protective group, preferably monoacetals.
A method, described in the following alternative method A, is particularly suitable for the production of a 2-pyridine cyclohexane-1,4-diamond derivative substituted according to the invention according to formula I with R3 = H using the following steps: a. A cyclohexane-1,4-dione protected by groups S1 and S2 according to formula 11 is reduced by an amine with a compound of formula HNR04R05 to a 4-aminocyclohexane derivative according to formula VI; Other where appropriate, then acylated, alkylated or sulphonated in any order and where appropriate repeatedly and/or in the case of compounds with R04 and/or R05 = with a protected group H, at least once a protective group is cleaved and, where appropriate, acylated, alkylated or sulphonated and/or in the case of compounds with R04 and/or R05 = H, at least once a protective group is introduced and, where appropriate, acyled;alkylated or sulphonated,b. the 4-aminocyclohexane anhydride derivative of formula VI is converted to a cyclohexane n-tri-dihydrate derivative of formula VII in the presence of a compound of formula HNR01R02 with cyanide, preferably potassium cyanide, Other where appropriate, 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 R04 and/or R05 and/or R06 = with a protected group H, at least once a protective group is cleaved and, where appropriate, acylated, alkylated or sulphonated and/or at least once a protective group is introduced and, where appropriate, acylated, alkylated or sulphonated in the case of compounds with R01 and/or R02 and/or R04 and/or R05 and/or R06 = H,c. the cyclohexane nitrate derivative of formula VII is replaced by cyclopentadienylcycloocta-1,5-diene-cobalt (I) [cpCo (cod) ] and irradiated under acetylene to give a 2-pyridine cyclohexane-1,4-diamond derivative according to formula V, 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 R04 and/or R05 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 R04 and/or R05 and/or R06 = H, at least once a protective group is introduced and, where applicable, acylated, alkylated or sulphonated until a compound in accordance with formula I is formed, where R1, R2, R4 and R5 have the meanings given for compounds of the invention according to formula I and R01 and R02 are independently selected from H; H with a protective group; C1-8 alkyl or C3-8 cycloalkyl,whether or not saturated, branched or unbranched, simply or in multiple substitutions or unsubstituted; aryl or heteroaryl, either simply or in multiple substitutions or unsubstituted; or aryl, C3-8-cycloalkyl or heteroaryl, whether or not simply or in multiple substitutions or unsubstituted, bound by C1-3 alkyl groups; or the residues R01 and R12 together form a ring and mean CH2CH2OCH2CH2, CH2CH2NR06CH2CH2 or (CH2) 3-6, R06 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; C1-8 alkyl, with a protective group, saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted; R05 is selected from H with a protective group; C3-8-cycloalkyl, aryl or heteroaryl, either unsubstituted or simply or multiple substituted; -CHR11R12, -CHR11-CH2R12, -CHR11-CH2-CH2R12, -CHR11-CH2-CH2-CH2R12, -C(Y) R12, -C(Y) -CH2R12, -C(Y) -CH2-CH2R12 or -C(Y) -CH2-CH2-CH2R12 where Y = H2, with R11 selected from H, C1-7, alkyl, saturated or unsaturated, branched or unbranched, simply or in multiple substitutions or unsubstituted; and selected from with R12 H; C3-8-cycloalkyl, aryl or heteroaryl, whether or not substituted, or simply or in multiple substitutions, or R04 and R05 together form a heterocycle with between 3 and 8 atoms in the ring, whether or not saturated; simply or repeatedly substituted or unsubstituted,Other and S1 and S2 are selected independently from each other from protective groups or together represent a protective group, preferably monoacetals.
For both methods A, it is particularly advantageous to select the H protection groups at R01, R02, R04, R05 and/or R06 from alkyl, benzyl or carbamate, e.g. FMOC, Z or Boc.
For main method A, it is particularly advantageous if the reductive amination takes place in step d in the presence of ammonium formate, ammonium acetate or NaCNBH3.
For main method A, it is particularly advantageous to react the compound IV with hydroxylamine in step d instead of reductive amination with HNR04R05 and to reduce it after oxymerization.
For main method A, it is particularly advantageous if the irradiation in step b lasts between 5 and 7 h and/or takes place at room temperature and/or saturated acetylene atmosphere and/or under protective gas.
For alternative method A, it is particularly advantageous if the irradiation in step c lasts between 5 and 7 h and/or takes place at room temperature and/or saturated acetylene atmosphere and/or under protective gas.
A further suitable method, referred to in the following main method B, is to produce a 2-pyridine cyclohexane-1,4-diamond derivative substituted according to the invention with the following steps: a. A cyclohexane-1,4-dione protected by groups S1 and S2 according to formula 11 is converted into a protected N-substituted 1-amino-4-oxo-cyclohexanecarbonitryldependent 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, the formula Metal-2-pyridine-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, 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 protected 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-aminocyclohexandriate according to ForVaxan I is reduced by an amine with a compound of formula HNRR0405 to a 2-pyridine-cyclohexan-1,4-diamethylamine inhibitor 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 1 has been formed, where R1, R2, R3, R4 and R5 have the meanings given for compounds of the invention according to formula 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, CH2CH2NR06CH2CH2 or (CH2) 3-6, R06 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; C1-8 alkyl, with a protective group, saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted; R05 is selected from H with a protective group; C3-8 cycloalkyl, aryl or heteroaryl, either unsubstituted or simply or repeatedly substituted; -CHR11R12, -CHR11-CH2-CH2R12, -CHR11-CH2CH2-CH2R12, -C(Y) R12, -C(Y) -CH2R12, -C(Y) -CH2-CH2R12 or -C(Y) -CH2-CH2CH2R12 where Y = H2, with R11 selected from H, C1-7, alkyl, saturated or unsaturated, branched or unbranched, simply or in multiple substitutions or unsubstituted; and selected from with R12 H; C3-8-cycloalkyl, aryl or heteroaryl, either unsubstituted or simply or repeatedly substituted, or R04 and R05 together forming a heterocycle with between 3 and 8 atoms in the ring, saturated or unsaturated; simply or repeatedly substituted or unsubstituted,Other and S1 and S2 are selected independently from each other from protective groups or together represent a protective group, preferably monoacetals.
Alkylation is also understood as reductive amination, as it leads to the same result.
A further preferred subject matter of the invention is a process, referred to as alternative method B, for the production of a substituted 2-pyridine cyclohexane-1,4-diamond derivative of the invention, using the following steps: a. A cyclohexane-1,4-dione protected by groups S1 and S2 according to formula II is reduced by an amine with a compound of formula HNR04R05 to a 4-aminocyclohexane derivative according to formula VI; Other where appropriate, then acylated, alkylated or sulphonated in any order and where appropriate repeatedly and/or in the case of compounds with R04 and/or R05 = with a protected group H, at least once a protective group is cleaved and, where appropriate, acylated, alkylated or sulphonated and/or in the case of compounds with R04 and/or R05 = H, at least once a protective group is introduced and, where appropriate, acyled;alkylated or sulphonated,b. the 4-aminocyclohexane anhydride derivative of formula VI is converted to a cyclohexane n-tri-dihydrate derivative of formula VII in the presence of a compound of formula HNR01R02 with cyanide, preferably potassium cyanide, where appropriate, 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 R04 and/or R05 and/or R06= with a protected group H, at least once a protective group is cleaved and, where appropriate, 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 is introduced and, where appropriate, acylated, alkylated or sulphonated,c. the cyclohexane nitrate derivative of formula Formulation VII is treated with metal-organic reagents,prefers Grignard or organolithium reagents, the formula metal-2-pyridine-R3 is implemented and finally the protective groups S1 and S2 are cleaved to form a 2-pyridine cyclohexane-1,4-diamind derivative according to formula V, 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 R04 and/or R05 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 R04 and/or R05 and/or R06 = H, at least once a protective group is introduced and, where applicable, acylated, alkylated or sulphonated until a compound in accordance with formula I is formed,Other where R1, R2, R3, R4 and R5 have the meanings given for the compounds of the invention in accordance with Formula I 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 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 groups; or the residues R01 and R02 together form a ring and mean CH2CH2OCH2CH2, CH2CH2NR06CH2CH2 or (CH2) 3-6, with R06 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; R04 is selected from H, with a protective group H; C1-8 alkyl, saturated or unsaturated, branched or unbranched, simply or repeatedly substituted or unsubstituted; R05 is selected from H with a protective group; C3-8-cycloalkyl, aryl or heteroaryl, either unsubstituted or simply or multiple substituted; -CHR11R12, -CHR11-CH2R12, -CHR11-CH2-CH2R12, -CHR11-CH2-CH2-CH2R12, -C(Y) R12, -C(Y) -CH2R12, -C(Y) -CH2-CH2R12 or -C(Y) -CH2-CH2-CH2R12 where Y = H2, with R11 selected from H, C1-7, alkyl, saturated or unsaturated, branched or unbranched, simply or in multiple substitutions or unsubstituted; and selected from with R12 H; C3-8-cycloalkyl,Aryl or heteroaryl, whether or not substituted, or simply or in multiple substitutions, or R04 and R05 together form a heterocycle with between 3 and 8 atoms in the ring, whether or not saturated; simply or repeatedly substituted or unsubstituted, and S1 and S2 are selected independently from each other from protective groups or together represent a protective group, preferably monoacetals.
For both methods B, it is preferable that the H protection groups at R01, R02, R04, R05 and/or R06 are selected from alkyl, benzyl or carbamate, e.g. FMOC, Z or Boc.
Furthermore, it is preferable for main method B if the reductive amination in step d takes place in the presence of ammonium formate, ammonium acetate or NaCNBH3.
For the main method B, a particularly advantageous embodiment is also the reaction of the compound IV with hydroxylamine in step d instead of reductive amination with HNR04R05 and reduction after oxygenesis.
Equally advantageous for alternative method B is that in step b of formula HNR01R02 the residue R01 = H, the conversion with the cyanide with TMSCN and, if necessary, the subsequent introduction of a protective group at R01.
The following illustrations of the invention are given.
Examples
The following examples are intended to illustrate the invention.
The yields of the compounds produced are not optimized.
All temperatures are uncorrected.
Err1:Expecting ',' delimiter: line 1 column 54 (char 53)
The stationary phase for column chromatography was silica gel 60 (0.040 - 0.063 mm) from E. Merck, Darmstadt.
The thin-film chromatographic studies were carried out with HPTLC-prepared plates, silica gel 60 F 254, by E. Merck, Darmstadt.
The mixing ratios of the reagents used for chromatographic examinations are always given in terms of volume.
The following is the list of active substances in the active substance:
The resulting white suspension was extracted four times with 800 ml of ether, the combined extracts were compressed, the residue was absorbed in about 500 ml of dichloromethane and the phases were separated. The organic phase was dried, filtered and compressed using sodium sulphate. 265 g of 8-dimethylamino-1,4-dioxa-spiro[4.5]decan-8-carbonitrile was obtained as a white solid.
A solution of 4.5 g 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile, 50 mg cyclopentadienyl-cycloocta-1,5-diene-cobalt (cpCo) (cod) and 100 ml toluene was transferred to the reaction vessel in the protective gas/acetyl counterstroke. After saturation with acetylene, the reaction solution was irradiated under strong agitation at 25°C for 6 hours. The reaction was interrupted by turning off the lamps and air supply and the reaction solution was concentrated. The resulting raw product (5,47 g) was concentrated in a mixture of water (8,7 g) and concentrated saline (15 ml) and absorbed overnight. The reaction was treated with 100 ml (32 ml) RT-X diethyl methacrylate (32,3 ml) of nitric acid (32,3 ml) separated with 32 x diethyl methacrylate (NaOH) and ethyl chloride (32,3 ml) of exchlorothiazine, which were obtained by extracting 32 ml of diethyl methacrylate (32,3 ml) and exchlorotriol ethyl nitrate (32,3 ml) separated with exchlorothiazine.
After adding sodium triacetoxyborohydride (1,2 g), the reaction mixture was stirred for three days under argon at room temperature. For preparation, the solvent was removed in the oven, the residue was incorporated in 1 N of sodium tetrahydrofuran (40 ml) and diethyl ether (40 ml), the pyroxene was separated, the aqueous phase was extracted with diethyl ether (2 x 30 ml), the organic compounds were concentrated, the solid product was obtained by dissolving methanol (150-1-1-12-dimethyl ether) at 150 °C. The product was obtained by dissolving methanol (1-1-12-dimethyl ether) in a vacuum (150-12-dimethyl ether) at a temperature of 150 °C. The product was obtained by dissolving methanol (1-1-52 mg/Nm3) in a vacuum and dissolving it in a white powder.
The residue was absorbed and stirred in 1 M sodium chloride solution (20 ml) and ethyl acetate (20 ml), leaving a white solid that could be absorbed (86 mg). The white phase of the filtrate was extracted with ethyl dihydrate (2 x 20 ml). The combined organic extracts were then dried and heated for 22 hours. The residue was obtained at a slightly identical temperature to the residue. The residue was absorbed and stirred at 20 °C. The white phase of the filtrate was extracted with ethyl dihydrate (2 x 20 ml). The combined organic extracts were then heated to a temperature of 24 °C. The residue was obtained at a temperature of 20 °C. The residue was absorbed and stirred at 20 °C. The residue was left with a white solid that could be absorbed (86 mg). The white phase of the filtrate was extracted with ethyl dihydrate (2 x 20 ml). The combined organic extracts were then heated after drying.
Example 2: N'-[2-(1H-lndol-3-yl) -ethyl]-N,N-dimethyl-1-pyridine-2-yl-cyclohexane-1,4-diamine trihydrochloride, nonpolar diastereomer
The N'-[2- ((1H-Indol-3-yl) -ethyl]-N,N-dimethyl-1-pyridine-2-yl-cyclohexane-1,4-diamine (342 mg) obtained from example 1 was dissolved in 2-butanone (20 ml) and transferred to the corresponding trihydrochloride (beige solid; 408 mg) with chlortrimethylsilan (0,59 ml).
The following is added to the list of active substances:
As described in example 1, 171 mg of the polar diastereoisomers of N'-[2-(1 H-Indol-3-yl) -ethyl]-N,N-dimethyl-1-pyridine-2-yl-cyclohexane-1,4-diamine were obtained, dissolved in 2-butanone (20 ml) and transferred to the corresponding trihydrochloride with chlortrimethylsilan (0,297 ml) (171 mg beige solid, temperature 225-230 °C).
The test chemical is a poly (ethylene) polymer with a high specificity for the preparation of poly (ethylene) polymers.
The hydrochloride of L-tryptophan methyl ester (1,01 g) was stirred vigorously with 1,2-dichlorethane (20 ml) and saturated NaHCO3 solution (20 g) for 15 min. After drying with Na2SO4, the organic phase was reduced to 40 ml and mixed with 4-dimethylamino-4-pyridine-2-methyl cyclohexanone (873 mg) under argon. To make a clear solution, ice acid (0.448 ml) and Na2SO4 (2 g) were added. After a reaction time of 15 min, the aqueous phase was extracted with NaBH3O (1,2 g) and transferred to room temperature for four days. The organic phase was reduced to 40 ml and mixed with 4-dimethylamino-4-pyridine-2-methyl cyclohexanone (873 mg) under argon. The product was mixed with hydrochlorothanol (1,3 mg/L) and mixed with a white solution of methanol (420 mg/L) and extracted with a white solution of ethyl methanol (220 mg/L) and obtained by pressing the mixture into a white solution of ethyl methanol (1,3 mg/L) and hydrochlorothron (1,3 mg/L) for 15 minutes. The product was then mixed with white solution of methanol (220 mg/L) and mixed with a white solution of ethyl methanol (220 mg/L) and extracted with water.
Example 5: (S)-2- ((4-dimethylamino-4-pyridine-2-yl-cyclohexylamino) 3- ((1-H-indol-3-yl) -propionic acid methyl ester trihydrochloride , more polar diastereomers
As described in example 4, 284 mg of the polar diastereoisomers of S)-2- ((4-dimethylamino-4-pyridine-2-yl-cyclohexylamino) -3- ((1H-indol-3-yl) propionic acid methyl ester were also obtained and transferred to the corresponding trihydrochloride (171 mg white solid; Smp. 170-175 °C; [α]D20 = 17,61 (MeOH, c = 1,45)) with chlortrimethyl silane (0.43 ml) dissolved in 2-butane (15 ml).
The following is added to the list of active substances:
After 70 hours, compress, dissolve the remaining yellow oil in water (10 ml), wash the aqueous phase with ethyl acetate (3 x 20 ml) and dilute with 5,5N HCl (9,0 ml). The aqueous phase was e-dihydrated and the residue digested with ethanol (2 x 20 ml). The recycled KCl was separated and the filter was etherised and etherised. The aqueous phase was washed with ethyl acetate (3 x 20 ml) and dilute with 5,5N HCl (9,0 ml). The aqueous phase was e-dihydrated and the residue digested with ethanol (2 x 20 ml). The recycled KCI was separated and the etherised ether was etherised. The aqueous phase was obtained from dihydrated dihydramine (Dihydroxylamino-3-dihydrochloride) (Dihydroxylamino-3-dihydrochloride) (Dihydroxylamino-3-dihydrochloride) (Dihydroxylamino-3-dihydrochloride) (Dihydroxylamino-3-dihydrochloride) (Dihydroxylamino-3-dihydrochloride) = 20,0-3,Dihydroxylamino-3,Dihydroxylamino-3,Dihyd-dihydrochloride = 1,69-3,Dihydroxylamino-3,Dihydroxylamino-3,Dihyd-dihydrochloride = 20,0 (Dihydroxylamino-3,Dihyd) = 1,2-dihydrochloride) (Dihydroxylamino-3,Dihyd) = 1,2-dihydrochloride) (Dihydroxylamino-3,Dihyd,Dihydroxylamino-3,Dihyd) = 1,2-dihydrochloride) (Dihyd,Dihydroxylamino-3,Dihyd,Dihyd,Dihydroxylamino-3,Dihyd,Dihyd,Dihydroxy,Dihydroxy,Dihydroxy,Dihyd,Dihydroxy,Dihydroxy,Dihydroxy,Dih
Example 8: Measurement of ORL1 binding
Cyclohexane-1,4-diamind 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 assays were performed with 20 μg of membrane protein per 200 μl of ED in 50 mM of hepsin, pH 7.4, 10 mMCl2 and 1 mMTA. The binding to the ORL1 receptor was performed using 1 mg of WPA-Ssham (Pharmacy-Piburg, Kiwi, and Mecantia), measured by means of a freeze-drying method (TGA) at room temperature and at ambient temperature.
Beispiel ORL1 Ki/µM
1 0,18
2 0,013
3 0,34
4 0,093
5 0,47
6 0,28
Example 9: Analgesia test in the tail-flick test in the mouse
The mice were individually placed in a test cage and the tail base exposed to the focused heat beam of an electric lamp (tail-flick type 50/08/1.bc, Labtec, Dr. Hess). The lamp intensity was adjusted so that the time from the lighting of the lamp to the sudden flickering of the tail (pain latency) in untreated mice was 3 to 5 seconds. Before the solutions containing the compound of the invention or the respective comparison solutions were applied, the mice were pre-tested twice within five minutes and the mean of these measurements was calculated as the mean of the previous test.
The solutions of the compound of the invention of the general formula I and the comparator solutions were then administered intravenously. Pain measurements were carried out 10, 20, 40 and 60 minutes after each intravenous application. The analgesic effect was determined as an increase in pain latency (% of the maximum possible antinociceptive effect) according to the following formula: % MPE = T 1 - T 0 ) / ( T 2 - T 0 × 100
The time T0 is the latency time before application, the time T1 is the latency time after application of the combination of active substances and the time T2 is the maximum exposure time (12 seconds).
The compounds tested showed analgesic effects, and the results of selected studies are summarised in the following table. Other
1 71 (10)
4 91 (10)
: In each column, the dose is given in mg/ kg for intravenous administration.
Example 10: Parenteral solution of a substituted 2-pyridine cyclohexane-1,4-diamond derivative of the invention
38 g of one of the 2-pyridine cyclohexane-1,4-diamind derivatives substituted according to the invention, here according to example 1, is dissolved in 1 I water for injection at room temperature and then adjusted to isotonic conditions by addition of anhydrous glucose for injection.

Claims (22)

  1. Substituted 2-pyridine cyclohexane-1,4-diamine derivatives having the general formula I, wherein
    R1 and R2 are mutually independently selected from H; C1-8 alkyl or C3-8 cycloalkyl, each being saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl or heteroaryl, each being mono- or polysubstituted or unsubstituted; or aryl, C3-8 cycloalkyl or heteroaryl bonded via C1-3 alkylene, each being mono- or polysubstituted or unsubstituted;
    or the radicals R1 and R2 together form a ring and denote CH2CH2OCH2CH2, CH2CH2NR6CH2CH2 or (CH2)3-6, where R6 is selected from H; C1-8 alkyl or C3-8 cycloalkyl, each being saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl or heteroaryl, each being mono- or polysubstituted or unsubstituted; or aryl, C3-8 cycloalkyl or heteroaryl bonded via C1-3 alkylene, each being mono- or polysubstituted or unsubstituted;
    R3 is selected from H; C1-8 alkyl, each being saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; C3-8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted; aryl or heteroaryl, each being mono- or polysubstituted or unsubstituted; or aryl, C3-8 cycloalkyl or heteroaryl bonded via C1-3 alkylene, each being mono- or polysubstituted or unsubstituted; SH, OH, F, Cl, I, Br, CN, NO2, OR26, NR27R28; where R26 is selected from C1-6 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; C3-8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted; aryl or heteroaryl, each being unsubstituted or mono- or polysubstituted with F, Cl, Br, I, NH2, NO2, CF3, CHF2, CH2F, CH3, C2H5, C3H7, C4H9, OCF3, OCHF2, OCH2F, OCH3, OC2H5, OC3H7, OC4H9, SH and/or OH; aryl, C3-8 cycloalkyl or heteroaryl bonded via C1-3 alkyl, saturated or unsaturated, each being unsubstituted or mono- or polysubstituted with F, Cl, Br, I, NH2, NO2, CF3, CHF2, CH2F, CH3, C2H5, C3H7, C4H9, OCF3, OCHF2, OCH2F, OCH3, OC2H5, OC3H7, OC4H9, SH and/or OH; where R27 and R28 are mutually independently selected from H, C1-6 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; C3-8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted; aryl or heteroaryl, each being unsubstituted or mono- or polysubstituted with F, Cl, Br, I, NH2, NO2, CF3, CHF2, CH2F, CH3, C2H5, C3H7, C4H9, OCF3, OCHF2, OCH2F, OCH3, OC2H5, OC3H7, OC4H9, SH and/or OH; aryl, C3-8 cycloalkyl or heteroaryl bonded via C1-3 alkyl, saturated or unsaturated, each being unsubstituted or mono- or polysubstituted with F, Cl, Br, I, NH2, NO2, CF3, CHF2, CH2F, CH3, C2H5, C3H7, C4H9, OCF3, OCHF2, OCH2F, OCH3, OC2H5, OC3H7, OC4H9, SH and/or OH; or the radicals R27 and R28 together denote CH2CH2OCH2CH2, CH2CH2NR29CH2CH2 or (CH2)3-6, where R29 is selected from H, C1-6 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; C3-8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted; aryl or heteroaryl, each being unsubstituted or mono- or polysubstituted with F, Cl, Br, I, NH2, NO2, CF3, CHF2, CH2F, CH3, C2H5, C3H7, C4H9, OCF3, OCHF2, OCH2F, OCH3, OC2H5, OC3H7, OC4H9, SH and/or OH; aryl, C3-8 cycloalkyl or heteroaryl bonded via C1-3 alkyl, saturated or unsaturated, each being unsubstituted or mono- or polysubstituted with F, Cl, Br, I, NH2, NO2, CF3, CHF2, CH2F, CH3, C2H5, C3H7, C4H9, OCF3, OCHF2, OCH2F, OCH3, OC2H5, OC3H7, OC4H9, SH and/or OH;
    R4 is selected from H, C1-8 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C(X)R7, C(X)NR7R8, C (X) OR9, C(X) SR9, S(O2)R9 where X = O or S, where R7 is selected from H, C1-8 alkyl or C3-8 cycloalkyl, each being saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl, heteroaryl, each being unsubstituted or mono- or polysubstituted; aryl, C3-8 cycloalkyl or heteroaryl bonded via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C1-4 alkyl group, each being unsubstituted or mono- or polysubstituted; where R8 is selected from H, C1-4 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted or the radicals R7 and R8 together form a ring and denote CH2CH2OCH2CH2, CH2CH2NR10CH2CH2 or (CH2)3-6, where R10 is selected from H; C1-8 alkyl or C3-8 cycloalkyl, each being saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl or heteroaryl, each being mono- or polysubstituted or unsubstituted; or aryl, C3-8 cycloalkyl or heteroaryl bonded via C1-3 alkylene, each being mono- or polysubstituted or unsubstituted; where R9 is selected from C1-8 alkyl or C3-8 cycloalkyl, each being saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl, heteroaryl, each being unsubstituted or mono-or polysubstituted; aryl, C3-8 cycloalkyl or heteroaryl bonded via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C1-4 alkyl group, each being unsubstituted or mono- or polysubstituted;
    R5 is selected from C3-8 cycloalkyl, aryl or heteroaryl, each being unsubstituted or mono- or polysubstituted; -CHR11R12, -CHR11-CH2R12, -CHR11-CH2-CH2R12, -CHR11-CH2-CH2-CH2R12, -C(Y)R12, -C(Y)-CH2R12, - C (Y) -CH2-CH2R12 or -C(Y)-CH2-CH2-CH2R12 where Y = O, S or H2, where R11 is selected from H, C1-7 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C(O)O-C1-6 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; and where R12 is selected from H; C3-8 cycloalkyl, aryl or heteroaryl, each being unsubstituted or mono- or polysubstituted,
    or R4 and R5 together form a heterocyclic compound with between 3 and 8 atoms in the ring, saturated or unsaturated; mono- or polysubstituted or unsubstituted, which can optionally be condensed with other rings,
    optionally in the form of their racemates, their 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 described or in the form of their acids or their bases or in the form of their physiologically compatible salts or salts of physiologically compatible acids or cations; or in the form of their solvates, in particular hydrates.
  2. Substituted 2-pyridine cyclohexane-1,4-diamine derivatives according to claim 1, characterised in that R1 and R2 are mutually independently selected from H; C1-8 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or the radicals R1 and R2 together form a ring and denote CH2CH2OCH2CH2, CH2CH2NR6CH2CH2 or (CH2)3-6, where R6 is selected from H; C1-8 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, preferably R1 and R2 are mutually independently selected from H; C1-4 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or the radicals R1 and R2 together form a ring and denote (CH2) 4-5, in particular R1 and R2 are mutually independently selected from methyl or ethyl or the radicals R1 and R2 together form a ring and denote (CH2)5.
  3. Substituted 2-pyridine cyclohexane-1,4-diamine derivatives according to claim 1, characterised in thatR3 is selected from H; C1-8 alkyl, each being saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; C3-8 cycloalkyl, saturated or unsaturated, mono-or polysubstituted or unsubstituted; aryl or heteroaryl, each being mono- or polysubstituted or unsubstituted; or aryl, C3-8 cycloalkyl or heteroaryl bonded via C1-3 alkylene, each being mono- or polysubstituted or unsubstituted; SH, OH, F, Cl, I, Br, CN, NO2, NH2, OR26; where R26 is selected from C1-6 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; preferably R3 is selected from H; C1-6 alkyl, each being saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; SH, OH, F, Cl, I, Br, CN, NO2, NH2, OR26; where R26 is selected from C1-6 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; in particular R3 is selected from H.
  4. Substituted 2-pyridine cyclohexane-1,4-diamine derivatives according to one of claims 1 to 3, characterised in that R4 is selected from H, C (X) R7, C(X)NR7R8, C(X)OR9, C(X) SR9 or S(O2)R9 where X = O or S, preferably R4 is selected from H, C(X)R7, C(X)NR7R8 or C(X)OR9 where X = O, in particular R4 is selected from H or C(O)R7; preferably with R7 selected from H; or C1-8 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; preferably H; or C1-3 alkyl, saturated, unsubstituted, branched or unbranched; in particular CH3.
  5. Substituted 2-pyridine cyclohexane-1,4-diamine derivatives according to one of claims 1 to 3, characterised in that R4 and R5 together form a heterocyclic compound with between 3 and 8 atoms in the ring, saturated or unsaturated; mono- or polysubstituted or unsubstituted, preferably with between 5 and 7 atoms in the ring, of which in addition to the obligatory N, 0 to 1 other heteroatoms, selected from N, S or O, are in the ring; wherein the heterocyclic compound formed by R4 and R5 together can optionally be condensed with other rings, preferably with aromatic and/or heteroaromatic rings, wherein these can be condensed with other aromatic and/or heteroaromatic rings, in particular the heterocyclic compound formed by R4 and R5 together is condensed with one or two other rings, the heterocyclic compound formed by R4 and R5 together is preferably condensed with two other rings in such a way that R4 and R5 together denote
  6. Substituted 2-pyridine cyclohexane-1,4-diamine derivatives according to one of claims 1 to 3, characterised in that R4 is selected from H or C1-8 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, preferably H or C1-6 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, in particular H or C1-3 alkyl, saturated, unbranched and unsubstituted.
  7. Substituted 2-pyridine cyclohexane-1,4-diamine derivatives according to one of claims 1 to 6, characterised in that R5 is selected from C3-8 cycloalkyl, aryl or heteroaryl, each being unsubstituted or mono- or polysubstituted; preferably R5 is selected 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, each being unsubstituted or mono- or polysubstituted; in particular R5 is selected from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, each being unsubstituted or mono- or polysubstituted.
  8. Substituted 2-pyridine cyclohexane-1,4-diamine derivatives according to one of claims 1 to 6, characterised in that R5 is selected from -CHR11R12, -CHR11-CH2R12, -CHR11-CH2-CH2R12, -CHR11-CH2-CH2-CH2R12, -C(Y)R12, -C(Y)-CH2R12, -C(Y)-CH2-CH2R12 or -C(Y) -CH2-CH2-CH2R12 where Y = O, S or H2, preferably R5 is selected from -CHR11R12, -CHR11-CH2R12, -CHR11-CH2-CH2R12, -C(Y)R12, -C(Y)-CH2R12 or -C(Y) -CH2-CH2R12 where Y = O or S, in particular R5 is selected from -CHR11R12, -CHR11-CH2R12, -CHR11-CH2-CH2R12, -C(Y)R12 or -C(Y)-CH2R12 where Y = O.
  9. Substituted 2-pyridine cyclohexane-1,4-diamine derivatives according to claim 8, characterised in that R11 is selected from H, C1-4 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C(O)O-C1-4 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; preferably H, C1-4 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C(O)O-C1-2 alkyl, saturated, unbranched, mono- or polysubstituted or unsubstituted; in particular H, CH3, C2H5 and C(O)O-CH3
  10. Substituted 2-pyridine cyclohexane-1,4-diamine derivatives according to claim 8, characterised in that R12 is selected from C3-8 cycloalkyl, aryl or heteroaryl, each being unsubstituted or mono- or polysubstituted; preferably R12 is selected 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, each being unsubstituted or mono- or polysubstituted; in particular R12 is selected from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, each being unsubstituted or mono- or polysubstituted.
  11. Substituted 2-pyridine cyclohexane-1,4-diamine derivatives according to one of claims 1 to 10, characterised in that they are selected from the following group:
    • N-(4-dimethylamino-4-pyridin-2-yl cyclohexyl)-N-[2-(1H-indol-3-yl)ethyl] acetamide dihydrochloride, non-polar diastereoisomer
    • N'-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-yl cyclohexane-1,4-diamine trihydrochloride, non-polar diastereoisomer
    • N'-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-yl cyclohexane-1,4-diamine trihydrochloride, polar diastereoisomer
    • (S)-2-(4-dimethylamino-4-pyridin-2-yl cyclohexylamino)-3-(1H-indol-3-yl) methyl propionate trihydrochloride, non-polar diastereoisomer
    • (S)-2-(4-dimethylamino-4-pyridin-2-yl cyclohexylamino)-3-(1H-indol-3-yl) methyl propionate trihydrochloride, polar diastereoisomer
    • (S)-2-(4-dimethylamino-4-pyridin-2-yl cyclohexylamino)-3-(1H-indol-3-yl) propionic acid dihydrochloride, non-polar diastereoisomer,
    optionally also in the form of their racemates, the cited or other pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of stereoisomers, in particular enantiomers or diastereomers, in any mixing ratio; optionally also in the form of acids or bases or in the form of other salts, particularly physiologically compatible salts or salts of physiologically compatible acids or cations; or in the form of their solvates, in particular hydrates.
  12. Medicament containing at least one substituted 2-pyridine cyclohexane-1,4-diamine derivative according to one of claims 1 to 11, optionally 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 described or in the form of its acids or its bases or in the form of its physiologically compatible salts or salts of physiologically compatible acids or cations; or in the form of its solvates, in particular hydrates, and optionally containing suitable additives and/or auxiliary substances and/or optionally other active ingredients.
  13. Medicament according to claim 12, characterised in that in addition to at least one substituted 2-pyridine cyclohexane-1,4-diamine derivative the medicament also contains an opioid, preferably a strong opioid, in particular morphine, or an anaesthetic, preferably hexobarbital or halothane.
  14. Use of a substituted 2-pyridine cyclohexane-1,4-diamine derivative according to one of claims 1 to 11, optionally 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 described or in the form of its acids or its bases or in the form of its physiologically compatible salts or salts of physiologically compatible acids or cations; or in the form of its solvates, in particular hydrates; for the production of a medicament for the treatment of pain, in particular of acute, neuropathic or chronic pain.
  15. Use of a substituted 2-pyridine cyclohexane-1,4-diamine derivative according to one of claims 1 to 11, optionally 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 described or in the form of its acids or its bases or in the form of its physiologically compatible salts or salts of physiologically compatible acids or cations; or in the form of its solvates, in particular hydrates; for the production of a medicament for the treatment of anxiety conditions, stress and stress-related syndromes, depression, epilepsy, Alzheimer's disease, senile dementia, general cognitive disfunctions, learning and memory difficulties (as a nootropic), withdrawal symptoms, alcohol and/or drug and/or medication abuse and/or dependency, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinnitus, pruritus, migraines, hearing difficulties, deficient intestinal motility, eating disorders, anorexia, obesity, locomotive disorders, diarrhoea, cachexia, urinary incontinence or as a muscle relaxant, anticonvulsive agent or anaesthetic or for coadministration in treatment with an opioid analgesic or with an anaesthetic, for diuresis or antinatriuresis and/or anxiolysis.
  16. Process for the production of a substituted 2-pyridine cyclohexane-1,4-diamine derivative according to one of claims 1 to 11 where R3 = H, comprising the following steps:
    a. a cyclohexane-1,4-dione protected with groups S1 and S2 according to formula II is reacted in the presence of a compound having the formula HNR01R02 with a cyanide, preferably potassium cyanide, to give a protected N-substituted 1-amino-4-oxocyclohexane carbonitrile derivative according to formula III; acylation, alkylation or sulfonation is then optionally performed in any sequence and optionally more than once and/or in the case of compounds where R01 and/or R02 and/or R06 = H protected by a protective group, a protective group is eliminated at least once and acylation, alkylation or sulfonation optionally performed and/or in the case of compounds where R01 and/or R02 and/or R06 = H, a protective group is introduced at least once and acylation, alkylation or sulfonation optionally performed,
    b. the aminonitrile according to formula III is brought into contact with cyclopentadienyl cycloocta-1,5-diene cobalt(I) [cpCo(cod)] and irradiated under acetylene, such that a compound according to formula IVa is produced; acylation, alkylation or sulfonation is then optionally performed in any sequence and optionally more than once and/or in the case of compounds where R01 and/or R02 and/or R06 = H protected by a protective group, a protective group is eliminated at least once and acylation, alkylation or sulfonation optionally performed and/or in the case of compounds where R01 and/or R02 and/or R06 = H, a protective group is introduced at least once and acylation, alkylation or sulfonation optionally performed,
    c. the protective groups S1 and S2 are eliminated at the compound according to formula IVa such that a tetrasubstituted 4-aminocyclohexanone derivative according to formula IV is produced; acylation, alkylation or sulfonation is then optionally performed in any sequence and optionally more than once and/or in the case of compounds where R01 and/or R02 and/or R06 = H protected by a protective group, a protective group is eliminated at least once and acylation, alkylation or sulfonation optionally performed and/or in the case of compounds where R01 and/or R02 and/or R16 = H, a protective group is introduced at least once and acylation, alkylation or sulfonation optionally performed,
    d. the tetrasubstituted 4-aminocyclohexanone derivative according to formula IVa is reductively aminated with a compound having the formula HNR04R05 such that a 2-pyridine cyclohexane-1,4-diamine derivative according to formula V is produced; acylation, alkylation or sulfonation is then optionally performed in any sequence and optionally more than once and/or in the case of compounds
    where R01 and/or R02 and/or R04 and/or R05 and/or R06 = H protected by a protective group, a protective group is eliminated at least once and acylation, alkylation or sulfonation optionally performed and/or in the case of compounds where R01 and/or R02 and/or R04 and/or R05 and/or R06 =H, a protective group is introduced at least once and acylation, alkylation or sulfonation optionally performed, until a compound according to formula I is produced, wherein R1, R2, R4 and R5 have the meaning given in claim 1 and R01 and R02 are mutually independently selected from H; H provided with a protective group; C1-8 alkyl or C3-8 cycloalkyl, each being saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl or heteroaryl, each being mono- or polysubstituted or unsubstituted; or aryl, C3-8 cycloalkyl or heteroaryl bonded via C1-3 alkylene, each being mono- or polysubstituted or unsubstituted; or the radicals R01 and R02 together form a ring and denote CH2CH2OCH2CH2, CH2CH2NR06CH2CH2 or (CH2)3-6, where R06 is selected from H; H provided with a protective group; C1-8 alkyl or C3-8 cycloalkyl, each being saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl or heteroaryl, each being mono- or polysubstituted or unsubstituted; or aryl, C3-8 cycloalkyl or heteroaryl bonded via C1-3 alkylene, each being mono- or polysubstituted or unsubstituted; R04 is selected from H, H provided with a protective group; C1-8 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; R05 is selected from H, H provided with a protective group; C3-8 cycloalkyl, aryl or heteroaryl, each being unsubstituted or mono- or polysubstituted; - CHR11R12, -CHR11-CH2R12, -CHR11-CH2-CH2R12, -CHR11-CH2-CH2-CH2R12, -C (Y) R12, -C (Y) -CH2R12 , C (Y) - CH2-CH2R12 or -C (Y) CH2- CH2-CH2R12 where Y = H2, where R11 is selected from H, C1-7 alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; and where R12 is selected from H; C3-8 cycloalkyl, aryl or heteroaryl, each being unsubstituted or mono- or polysubstituted, or R04 and R05 together form a heterocyclic compound with between 3 and 8 atoms in the ring, saturated or unsaturated; mono- or polysubstituted or unsubstituted, and S1 and S2 are mutually independently selected from protective groups or together denote a protective group, preferably monoacetal.
  17. Process for the production of a substituted 2-pyridine cyclohexane-1,4-diamine derivative according to one of claims 1 to 11 where R3 = H, comprising the following steps:
    a. a cyclohexane-1,4-dione protected with groups S1 and S2 according to formula II is reductively aminated with a compound having the formula HNR04R05 such that a 4-aminocyclohexanone derivative according to formula VI is produced; acylation, alkylation or sulfonation is then optionally performed in any sequence and optionally more than once and/or in the case of compounds where R04 and/or R05 = H protected by a protective group, a protective group is eliminated at least once and acylation, alkylation or sulfonation optionally performed and/or in the case of compounds where R04 and/or R05 = H, a protective group is introduced at least once and acylation, alkylation or sulfonation optionally performed,
    b. the 4-aminocyclohexanone derivative according to formula VI is reacted in the presence of a compound having the formula HNR01R02 with cyanide, preferably potassium cyanide, to give a cyclohexanone nitrile derivative having formula VII, acylation, alkylation or sulfonation is then optionally performed in any sequence and optionally more than once and/or in the case of compounds where R01 and/or R02 and/or R04 and/or R05 and/or R06 = H protected by a protective group, a protective group is eliminated at least once and acylation, alkylation or sulfonation optionally performed and/or in the case of compounds where R01 and/or R02 and/or R04 and/or R05 and/or R06 = H, a protective group is introduced at least once and acylation, alkylation or sulfonation optionally performed,
    c. the cyclohexanone nitrile derivative having formula VII is brought into contact with cyclopentadienyl cycloocta-1,5-diene cobalt(I) [cpCo(cod)] and irradiated under acetylene, such that a 2-pyridine cyclohexane-1,4-diamine derivative according to formula V is produced, acylation, alkylation or sulfonation is then optionally performed in any sequence and optionally more than once and/or in the case of compounds where R01 and/or R02 and/or R04 and/or R05 and/or R06 = H protected by a protective group, a protective group is eliminated at least once and acylation, alkylation or sulfonation optionally performed and/or in the case of compounds where R01 and/or R02 and/or R04 and/or R05 and/or R06 = H, a protective group is introduced at least once and acylation, alkylation or sulfonation optionally performed, until a compound according to formula I is produced, wherein R1, R2, R4 and R5 have the meaning given in claim 1 and the radicals R01, R02, R06, R04, R05, R11, R12, S1 and S2 have the meaning given in claim 16.
  18. Process for the production of a substituted 2-pyridine cyclohexane-1,4-diamine derivative according to one of claims 16 or 17, characterised in that the protective groups at H in R01, R02, R04 , R05 and/or R06 are selected from alkyl, benzyl or carbamates, for example FMOC, Z or Boc.
  19. Process for the production of a substituted 2-pyridine cyclohexane-1,4-diamine derivative according to claim 16, characterised in that the reductive amination in step d takes place in the presence of ammonium formate, ammonium acetate or NaCNBH3.
  20. Process for the production of a substituted 2-pyridine cyclohexane-1,4-diamine derivative according to one of claims 1 to 11 where R3 = H, comprising the following steps:
    a. a cyclohexane-1,4-dione protected with groups S1 and S2 according to formula II is reacted in the presence of a compound having the formula HNR01R02 with a cyanide, preferably potassium cyanide, to give a protected N-substituted 1-amino-4-oxocyclohexane carbonitrile derivative according to formula III; acylation, alkylation or sulfonation is then optionally performed in any sequence and optionally more than once and/or in the case of compounds where R01 and/or R02 and/or R06 = H protected by a protective group, a protective group is eliminated at least once and acylation, alkylation or sulfonation optionally performed and/or in the case of compounds where R01 and/or R02 and/or R06 = H, a protective group is introduced at least once and acylation, alkylation or sulfonation optionally performed,
    b. the aminonitrile according to formula III is brought into contact with cyclopentadienyl cycloocta-1,5-diene cobalt(I) [cpCo(cod)] and irradiated under acetylene, such that a compound according to formula IVa is produced; acylation, alkylation or sulfonation is then optionally performed in any sequence and optionally more than once and/or in the case of compounds where R01 and/or R02 and/or R06 = H protected by a protective group, a protective group is eliminated at least once and acylation, alkylation or sulfonation optionally performed and/or in the case of compounds where R01 and/or R02 and/or R06 = H, a protective group is introduced at least once and acylation, alkylation or sulfonation optionally performed,
    c. the protective groups S1 and S2 are eliminated at the compound according to formula IVa such that a tetrasubstituted 4-aminocyclohexanone derivative according to formula IV is produced; acylation, alkylation or sulfonation is then optionally performed in any sequence and optionally more than once and/or in the case of compounds where R01 and/or R02 and/or R06 = H protected by a protective group, a protective group is eliminated at least once and acylation, alkylation or sulfonation optionally performed and/or in the case of compounds where R01 and/or R02 and/or R06 = H, a protective group is introduced at least once and acylation, alkylation or sulfonation optionally performed,
    d. compound IV is reacted with hydroxylamine and reduced after oxime formation acylation, alkylation or sulfonation is then optionally performed in any sequence and optionally more than once and/or in the case of compounds where R01 and/or R02 and/or R04 and/or R05 and/or R06 = H protected by a protective group, a protective group is eliminated at least once and acylation, alkylation or sulfonation optionally performed and/or in the case of compounds where R01 and/or R02 and/or R04 and/or R05 and/or R06 = H, a protective group is introduced at least once and acylation, alkylation or sulfonation optionally performed, until a compound according to formula I is produced, wherein R1, R2, R4 and R5 have the meaning given in claim 1 and the radicals R01, R02, R06, R04, R05, R11, R12, S1 and S2 have the meaning given in claim 16.
  21. Process for the production of a substituted 2-pyridine cyclohexane-1,4-diamine derivative according to claim 16, characterised in that the irradiation in step b lasts between 5 and 7 h and/or takes place at room temperature and/or in a saturated acetylene atmosphere and/or under protective gas.
  22. Process for the production of a substituted 2-pyridine cyclohexane-1,4-diamine derivative according to claim 17, characterised in that the irradiation in step c lasts between 5 and 7 h and/or takes place at room temperature and/or in a saturated acetylene atmosphere and/or under protective gas.
HK04105744.4A 2001-05-09 2002-05-08 Substituted 2-pyridine-cyclohexane-1,4-diamine derivatives HK1062911B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10123163A DE10123163A1 (en) 2001-05-09 2001-05-09 Substituted cyclohexane-1,4-diamine derivatives
DE10123163.6 2001-05-09
PCT/EP2002/005078 WO2002090330A1 (en) 2001-05-09 2002-05-08 Substituted 2-pyridine-cyclohexane-1,4-diamine derivatives

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HK1062911B true HK1062911B (en) 2007-12-21

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