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    • 专利摘要:
    The present invention relates to substituted cyclohexane-1,4-diamine derivatives, methods for their preparation, medicaments comprising these compounds and the use of substituted cyclohexane-1,4-diamine derivatives for the manufacture of medicaments.
    公开号:KR20040017214A
    申请号:KR10-2003-7014568
    申请日:2002-05-08
    公开日:2004-02-26
    发明作者:준더만베른트；헨니스하겐-하인리히；엥글베르거베르너；쾨겔바벳테-이폰네
    申请人:그뤼넨탈 게엠베하；
    IPC主号:
    专利说明:

    Substituted cyclohexane-1,4-diamine derivatives
    [1] The present invention relates to substituted cyclohexane-1,4-diamine derivatives, methods for their preparation, medicaments comprising these compounds and the use of substituted cyclohexane-1,4-diamine derivatives for the manufacture of medicaments.
    [2] Heptadecapeptide nociceptin is an endogenous ligand of the ORL1 (opioid receptor-like) receptor belonging to the opioid receptor class [Meunier et al., Nature 377, 1995, p. 532-535] and is found in a number of 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]. Such peptides have a high affinity for ORL1 receptors (K d values of about 56 pM) [Ardati et al., Mol. Pharmacol. 51, p. 816-824 and high selectivity. The ORL1 receptor is homologous to the μ, κ and δ opioid receptors, and the amino acid sequence of the nociceptin peptide has a strong similarity to that of known opioid peptides. Nociceptin-induced activation of these receptors inhibits adenylate cyclase through coupling with G i / o proteins. See Meunier et al., Nature 377, 1995, p. 532-535]. Functional similarity of the μ, κ, and δ receptors with the ORL1 receptor is also found in the activation of potassium channels [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 calcium channels [Conner et al., Br. J. Pharmacol. 118, 1996, p. 205-207; Knoflach et al., J. Neuroscience 16, 1996. p. 6657-6664, at the cellular level.
    [3] After cerebral ventricular administration, the nociceptin peptide shows hypergonal and hyperalgesia activity in various animal models. Reinscheid et al., Science 270, 1995, p. 792-794; Hara et al., Br. J. Pharmacol. 121, 1997, p. 401-408]. This finding can be explained as inhibition of stress-induced analgesia. Mogil et al., Neurosci. Letters. Letters 214, 1996, p 131-134; and Neuroscience 75, 1996, p. 333-337]. In addition, anti-anxiety activity of nociceptin can be detected in this regard. Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858.
    [4] On the other hand, it has been possible to demonstrate the nociceptive effect of nociceptin in various animal models, especially after intramedullary administration. Nociceptin may be activated by cyanate or glutamate stimulated posterior ganglion neurons [Shu et al., Neuropeptides, 32, 1998, 567-571] or by activity of glutamate stimulated spinal cord neurons [Faber et al., Br . J. Pharmacol., 119, 1996, p. 189-190] and the tail flick test of mice (King et al., Neurosci. Lett., 223, 1997, 113-116], bent reflex models in rats (Xu et al., NeuroReport, 7, 1996, 2092-2094) and formalin tests in rats [Yamamoto et al., Neuroscience, 81, 1997, p. 249-254] has a nociceptive action. In addition, it has been possible to demonstrate nociceptin's nociceptive action in neuropathic pain models (Yamamoto and Nozaki-Taguchi, Anesthesiology, 87, 1997), especially as the activity of nociceptin increases after incision of the spinal cord nerves. Interesting. This is in contrast to conventional opioids whose activity is reduced under these conditions. Abdulla and Smith, J. Neurosci. 18, 1998, p. 9685-9694].
    [5] In addition, ORL1 receptors are involved in the regulation of further physiological and pathophysiological processes. These, in particular, are learning and memory formation [Sinin et al., Eur. J. Neurosci., 9, 1997, p. 194-197; Manabe et al., Nature, 394, 1997, p. 577-581], hearing [Nishi et al., EMBO J., 16, 1997, p. 1858-1864], feeding [Pomonis et al., NeuroReports, 8, 1996, p. 369-371], regulation of blood pressure [Gumusel et al., Life Sci., 60, 1997, p. 141-145; Campion and Kadowitz, Biochem. Biophys. Res. Comm., 234, 1997, p. 309-312, Epilepsy [Gutierrez et al., Abstract 536.18, Society for Neuroscience, vol 24, 28th Ann. Meeting, Los Angeles, November 7th-12th, 1998] and diuresis (Kapista et al., Life Sciences, 60, 1997, PL 15-21). Summary paper by Carlo et al., Br. J. Pharmacol., 129, 2000, 1261-1283, provides a general indication or biological process for which ORL1 receptors are or are likely to act. Mentions include, among others, analgesic, stimulation and control of eating, effects on μ-agonists (eg morphine), withdrawal symptoms, reduced likelihood of abuse of morphine, anti-anxiety, control of motor activity, memory diseases, epilepsy; Regulation of neurotransmitter secretion, in particular glutamate, serotonin and dopamine, and thus neurodegenerative diseases; Cardiovascular effects, erection initiation, diuresis, antisodium urinary excretion, electrolyte equilibrium, arterial blood pressure, stagnant disease, gastrointestinal movement (diarrhea), relaxation effects on the respiratory system, urinary incontinence (urinary incontinence). The use of agonists and antagonists as anorexia, analgesic (also coadministered with opioids) or brain supplements has been further discussed.
    [6] The possible uses of the compounds that bind to and activate or inhibit the ORL1 receptor vary accordingly.
    [7] It is an object of the present invention to provide a medicament that acts on the nociceptin / ORL1 receptor system and is therefore suitable for use in the various diseases or indications mentioned in connection with such a system, especially according to the prior art.
    [8] Thus, the present invention relates to substituted cyclohexane-1,4-diamine derivatives of the general formula (hereinafter referred to as compound group (A)), optionally racemates thereof, pure stereoisomeric forms, in particular enantiomers or diastereomers In the form or in a specific mixing ratio of stereoisomeric mixtures, in particular enantiomeric or diastereomeric mixtures; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or solvates thereof, especially hydrate forms.
    [9]
    [10] In Formula I above,
    [11] R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    [12] R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    [13] R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    [14] R 4 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; And C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , wherein X is O or S and R 7 Is H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated straight or branched mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    [15] R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H; Saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And each unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl; or
    [16] R 4 and R 5 together form a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms, wherein the heterocyclic radical may optionally be fused with an additional ring. Forming,
    [17] Provided that when R 3 is substituted or unsubstituted phenyl and at least one of R 1 and R 2 is H or C 1 -C 8 -alkyl, R 4 is not alkyl and R 4 and R 5 together are heterocyclic radicals Does not form
    [18] When R 3 is unsubstituted phenyl and R 1 and R 2 together form a ring of formula (CH 2 ) 5 and R 4 is selected from H and C 1 -C 8 -alkyl, Y is not O or S; R 5 is not C 1 -C 6 -alkyl.
    [19] A further object of the invention is a substituted cyclohexane-1,4-diamine derivative of the formula (hereinafter referred to as compound group (B)), optionally its racemic form, pure stereoisomeric form, especially enantiomers or Diastereomeric forms or stereoisomeric mixtures, in particular enantiomers or diastereomeric mixtures, in particular mixing ratios; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or by providing their solvates, in particular hydrate forms.
    [20] Formula I
    [21]
    [22] In Formula I above,
    [23] R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    [24] R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    [25] R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    [26] R 4 is H, C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 where X is O or S And R 7 is H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated straight or branched mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    [27] R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H; Saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is unsubstituted or mono- or polysubstituted C 3 -C, respectively. 8 -cycloalkyl, aryl and heteroaryl.
    [28] A further object of the present invention is a substituted cyclohexane-1,4-diamine derivative of formula (hereinafter referred to as compound group (C)), optionally its racemic form, pure stereoisomeric form, in particular enantiomer or Diastereomeric forms or stereoisomeric mixtures, in particular enantiomers or diastereomeric mixtures, in particular mixing ratios; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or by providing their solvates, in particular hydrate forms.
    [29] Formula I
    [30]
    [31] In Formula I above,
    [32] R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    [33] R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    [34] R 4 is H, C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 where X is O or S R 7 is H, saturated or unsaturated, branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated straight or branched mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    [35] R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively.
    [36] A further object of the invention is a substituted cyclohexane-1,4-diamine derivative of the formula (hereinafter referred to as compound group (D)), optionally in its racemic form, pure stereoisomers, in particular enantiomers or moieties Stereoisomeric forms or mixtures of stereoisomers in a particular mixing ratio, in particular enantiomers or diastereomeric mixtures; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or by providing their solvates, in particular hydrate forms.
    [37] Formula I
    [38]
    [39] In Formula I above,
    [40] R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    [41] R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono- or poly-substituted monocyclic or unsaturated branched or linearly substituted or Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    [42] R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted, mono- or polysubstituted heteroaryl; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    [43] R 4 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; And C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , wherein X is O or S and R 7 Is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated straight or branched mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    [44] R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And each unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl; or
    [45] R 4 and R 5 together form a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms, wherein the heterocyclic radical may optionally be fused with an additional ring. Form.
    [46] A further object of the invention is a substituted cyclohexane-1,4-diamine derivative of formula (hereinafter referred to as compound group (E)), optionally in its racemic form, pure stereoisomers, in particular enantiomers or moieties Stereoisomeric forms or mixtures of stereoisomers in a particular mixing ratio, in particular enantiomers or diastereomeric mixtures; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or by providing their solvates, in particular hydrate forms.
    [47] Formula I
    [48]
    [49] In Formula I above,
    [50] R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    [51] R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    [52] R 4 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; And C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , wherein X is O or S and R 7 Is H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated straight or branched mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    [53] R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is unsubstituted or mono- or polysubstituted C 3 -C, respectively. 8 -cycloalkyl, aryl and heteroaryl; or
    [54] R 4 and R 5 together form a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms, wherein the heterocyclic radical may optionally be fused with an additional ring. Form.
    [55] These compounds and compound groups according to the invention exhibit marked binding to the ORL1 receptor.
    [56] Compounds exhibiting specific relationships with the compounds proposed herein are known in the following documents.
    [57] Related US Pat. No. 4,460,604, US Pat. No. 4,447,454 and US Pat. No. 4,113,866 (Lednicer et al.). In these patents, the mentioned compounds are described as having analgesic action, but no mention is made of the ORL1 receptor.
    [58] US Patent No. 5,304,479 (Lin et al.). The compounds described in this patent are for use in analytical test systems for measuring pencyclidine (PCP), especially in body fluids, but no reference is made to the ORL1 receptor.
    [59] See De Costa et al., J. Chem. Soc., Perkin Trans. 1 (1992), 1671-80. The compounds mentioned are mentioned in connection with the synthesis of irreversible ligands at the dopamine reuptake site, but not with respect to the ORL1 receptor.
    [60] In the context of the present invention, alkyl and cycloalkyl radicals are understood to mean saturated and unsaturated (but not aromatic) branched, straight and cyclic hydrocarbons which may be unsubstituted, mono- or polysubstituted. C 1 -C 2 -alkyl means C 1 -or C 2 -alkyl, C 1 -C 3 -alkyl means C 1- , C 2 -and C 3 -alkyl, and C 1 -C 4- Alkyl means C 1- , C 2- , C 3 -or C 4 -alkyl, and C 1 -C 5 -alkyl means C 1- , C 2- , C 3- , C 4 -or C 5 -alkyl C 1 -C 6 -alkyl means C 1- , C 2- , C 3- , C 4- , C 5 -or C 6 -alkyl, and C 1 -C 7 -alkyl is C 1 -, C 2- , C 3- , C 4- , C 5- , C 6 -or C 7 -alkyl, C 1 -C 8 -alkyl means C 1- , C 2- , C 3- , C 4- , C 5- , C 6- , C 7 -or C 8 -alkyl, C 1 -C 10 -alkyl means C 1- , C 2- , C 3- , C 4- , C 5 -, C 6- , C 7- , C 8- , C 9 -or C 10 -alkyl, wherein C 1 -C 18 -alkyl is C 1- , C 2- , C 3- , C 4- , C 5- , C 6- , C 7- , C 8- , C 9- , C 10- , C 11- , C 12- , C 13- , C 14- , C 15- , C 16- , C 17 -Or C 18 -alkyl. In addition, C 3 -C 4 -cycloalkyl means C 3 -or C- 4 cycloalkyl, C 3 -C 5 -cycloalkyl means C 3- , C 4 -or C 5 -cycloalkyl and , C 3 -C 6 -cycloalkyl means C 3- , C 4- , C 5 -or C 6 -cycloalkyl, and C 3 -C 7 -cycloalkyl means C 3- , C 4- , C 5 -, C 6 -or C 7 -cycloalkyl, wherein C 3 -C 8 -cycloalkyl means C 3- , C 4- , C 5- , C 6- , C 7 -or C 8 -cycloalkyl C 4 -C 5 -cycloalkyl means C 4 -or C 5 -cycloalkyl, C 4 -C 6 -cycloalkyl means C 4- , C 5 -or C 6 -cycloalkyl and , C 4 -C 7 -cycloalkyl means C 4- , C 5- , C 6 -or C 7 -cycloalkyl, and C 5 -C 6 -cycloalkyl means C 5 -or C 6 -cycloalkyl C 5 -C 7 -cycloalkyl means C 5- , C 6 -or C 7 -cycloalkyl. In the context of cycloalkyls, the term also encompasses saturated cycloalkyls in which one or two carbon atoms are substituted by heteroatoms S, N or O. However, the term cycloalkyl also includes monocyclic or polysubstituted, preferably monosubstituted cycloalkyl which does not contain heteroatoms in the ring, provided that cycloalkyl is not an aromatic system. Alkyl and cycloalkyl radicals are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propynyl, methylethyl, glued, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, Cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl and adamantyl, CHF 2 , CF 2 or CH 2 OH, and pyrazolone, oxopyrazolinone, [1,4] dioxane Or dioxolane.
    [61] With respect to alkyl and cycloalkyl (unless explicitly stated otherwise), the term substituted herein refers to at least one (optionally one or more) hydrogen radicals in the context of the present invention F, Cl, Br, I, NH 2 , SH Or OH, and in the case of polysubstitution, “polysubstituted” or “substituted” means that the substitution occurs several times with the same or different substituents at different or the same positions, eg CF Three times on the same C atom as in the case of 3 or at different positions as in the case of -CH (OH) -CH = CH-CHCl 2 . Particularly preferred substituents here are F, Cl and OH. In the context of cycloalkyls, hydrogen radicals are also OC 1 -C 3 -alkyl or C 1 -C 3 -alkyl (monosubstituted or polysubstituted or unsubstituted, respectively), in particular methyl, ethyl, n-propyl, isopropyl, May be substituted by CF 3 , methoxy or ethoxy.
    [62] The term (CH 3 ) 3-6 is -CH 2 -CH 2 -CH 2- , -CH 2 -CH 2 -CH 2 -CH 2- , -CH 2 -CH 2 -CH 2 -CH 2 -CH 2- And -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2- , (CH 2 ) 1-4 is -CH 2- , -CH 2 -CH 2- , -CH It is understood to mean 2 -CH 2 -CH 2 -and -CH 2 -CH 2 -CH 2 -CH 2- , (CH 2 ) 4-5 is -CH 2 -CH 2 -CH 2 -CH 2- And —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 — and the like.
    [63] Aryl radicals are understood to mean ring systems comprising at least one aromatic ring and no heteroatoms in any of the rings. Examples thereof mean phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which may be unsubstituted or mono- or polysubstituted.
    [64] Heteroaryl radicals are understood to mean heterocyclic ring systems comprising at least one saturated ring, wherein the saturated ring may contain one or more heteroatoms selected from the group consisting of nitrogen, oxygen and / or sulfur and It may be monosubstituted or polysubstituted. Examples that may be mentioned as heteroaryl groups are furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo [1,2,5] -thiadia Sol, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole, indole and quinazoline.
    [65] With respect to aryl and heteroaryl, substituted aryl or heteroaryl is R 22 , OR 22 , halogen, preferably F and / or Cl, CF 3 , CN, NO 2 , NR 23 R 24 , C 1- Meaning substituted with C 6 -alkyl (saturated), C 1 -C 6 -alkoxy, C 3 -C 8 -cycloalkoxy, C 3 -C 8 -cycloalkyl or C 2 -C 6 -alkylene I understand.
    [66] Wherein the radical R 22 is bonded via H, C 1 -C 10 -alkyl, preferably C 1 -C 6 -alkyl, aryl or heteroaralkyl, or C 1 -C 3 -alkyl and is saturated or unsaturated Aryl or heteroaryl radicals bonded through an aryl or heteroaryl or C 1 -C 3 -alkylene group, wherein these aryl and heteroaryl radicals can be unsubstituted or substituted with aryl or heteroaryl radicals ,
    [67] The same or different radicals R 23 and R 24 are bonded via H, C 1 -C 10 -alkyl, preferably C 1 -C 6 -alkyl, aryl, heteroaryl, or C 1 -C 3 -alkyl and are saturated Aryl or heteroaryl radicals which are bonded via a monovalent or unsaturated aryl or heteroaryl radical or a C 1 -C 3 -alkylene group, wherein these aryl and heteroaryl radicals may be unsubstituted or substituted with aryl or heteroaryl radicals. Or
    [68] The radicals R 23 and R 24 together represent CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 25 CH 2 CH 2 or (CH 2 ) 3-6 ,
    [69] The radical R 25 is H, C 1 -C 10 -alkyl, preferably C 1 -C 6 -alkyl, aryl or heteroaryl radical, or aryl which is bonded or saturated or bonded via C 1 -C 3 -alkyl or Aryl or heteroaryl radicals which are bonded via a heteroaryl radical or a C 1 -C 3 -alkylene group, wherein these aryl and heteroaryl radicals may be unsubstituted or substituted with aryl or heteroaryl radicals.
    [70] The term salt is understood to mean any form of the active compound according to the invention in which the active compound is in ionic form or charged, coupled with a counter-ion (cation or anion) or present in solution. The term is also understood to mean complexes of the active compounds with other molecules and ions, in particular complexes complexed through ionic interactions. In particular, the term refers to physiologically acceptable salts, in particular physiologically acceptable salts with cations or bases and physiologically acceptable salts with anions or acids or also physiologically acceptable acids or physiologically acceptable cations It is understood that it means a salt formed by (and this is also a preferred embodiment of the present invention).
    [71] The term physiologically acceptable salt with an anion or an acid refers to one or more according to the present invention as a cation with one or more anion which is physiologically acceptable (particularly when used in humans and / or animals) in connection with the present invention. It is understood to mean salts of the active compounds (in most cases protonated, for example, in nitrogen). In particular, the term refers to salts formed with physiologically acceptable acids in connection with the present invention, ie salts of physiologically acceptable inorganic or organic acids with certain active compounds (when used in humans and / or mammals). It is understood that. Examples of physiologically acceptable salts with acids in particular are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1- Dioxo-1,2-dihydroλ 6 -benzo [d] isothiazol-3-one (saccharic acid), monomethyl sebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2 Salts of 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid, a-riphonic acid, acetylglycine, acetylsalicylic acid, hypouric acid and / or aspartic acid. Hydrochloride salts are particularly preferred.
    [72] The term salts formed with physiologically acceptable acids is understood in the context of the present invention to mean salts of certain active compounds with inorganic or organic acids that are physiologically acceptable (when used in humans and / or mammals). . Hydrochloride is particularly preferred. Examples of physiologically acceptable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1 , 2-dihydroλ 6 -benzo [d] isothiazol-3-one (saccharic acid), monomethyl sebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid, α-riphonic acid, acetylglycine, acetylsalicylic acid, hypouric acid and / or aspartic acid.
    [73] The term physiologically acceptable salt with a cation refers to one or more compounds according to the invention as an anion with one or more physiologically acceptable cations in connection with the invention, in particular when used in humans and / or animals. Is understood to mean a salt of [in most cases, an (deprotonated) acid]. Alkali and alkaline earth metals and also salts of NH 4 + are particularly preferred, in particular (mono-) or (di-) sodium, (mono-) or (di-) potassium, magnesium or calcium salts.
    [74] The term salts formed with physiologically acceptable cations refers to salts of one or more specific compounds as anions with one or more inorganic cations that are physiologically acceptable (particularly when used in humans and / or animals) in connection with the present invention. It is understood to mean. Particular preference is given to salts of alkali and alkaline earth metals and also NH 4 + , with particular preference to (mono-) or (di-) sodium, (mono-) or (di-) potassium, magnesium or calcium salts.
    [75] In a preferred embodiment of compound group (A), (B) or (D),
    [76] R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl, except when R 1 and R 2 are hydrogen at the same time, or
    [77] R 1 and R 2 together represent the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 , wherein R 6 is H; and a saturated or unsaturated branched or straight chain mono- or polysubstituted Is unsubstituted C 1 -C 8 -alkyl) or (CH 2 ) 3-6 to form a ring,
    [78] Preferably, R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl, except when R 1 and R 2 are hydrogen at the same time, or R 1 and R 2 are Together form a ring of formula (CH 2 ) 4-5 ,
    [79] In particular, substituted cyclohexane-1,4- in accordance with formula (I), wherein R 1 and R 2 are independently selected from methyl and ethyl, or R 1 and R 2 together form a ring of formula (CH 2 ) 5 Diamine derivatives are constructed.
    [80] In a preferred embodiment of compound group (E),
    [81] R 1 and R 2 together represent the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 , wherein R 6 is H; and a saturated or unsaturated branched or straight chain mono- or polysubstituted Is unsubstituted C 1 -C 8 -alkyl) or (CH 2 ) 3-6 to form a ring,
    [82] Preferably, R 1 and R 2 together form a ring of formula (CH 2 ) 4-5 ,
    [83] In particular, substituted cyclohexane-1,4-diamine derivatives according to formula (I) are constructed in which R 1 and R 2 together form a ring of formula (CH 2 ) 5 .
    [84] In a preferred embodiment of the compound group (C),
    [85] R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl, except when R 1 and R 2 are hydrogen at the same time,
    [86] Preferably, R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl, except when R 1 and R 2 are hydrogen at the same time,
    [87] In particular, substituted cyclohexane-1,4-diamine derivatives of the formula (I) are constructed, wherein R 1 and R 2 are independently selected from methyl and ethyl.
    [88] In a preferred embodiment of the compound group (A), (B) or (C),
    [89] Each R 3 is bonded via an unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, and a saturated or unsaturated branched or straight-chain substituted or unsubstituted C 1 -C 2 -alkyl group, respectively Unsubstituted or mono- or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl,
    [90] Preferably, R 3 is unsubstituted or mono- or polysubstituted C 5 -C 6 -cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxola Nil, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl; And unsubstituted or monosubstituted or monosubstituted C 5 -C 6 -cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothio, each bonded via a saturated straight chain C 1 -C 2 -alkyl group Phenyl, pyridyl, furyl, benzofuranyl, benzodioxolanil, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl,
    [91] In particular, R 3 is unsubstituted or mono- or polysubstituted phenyl, furyl, thiophenyl, cyclohexanyl, naphthyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pi Rollyl, pyrimidyl, pyrazinyl or benzothiophenyl; And substituted cyclohexane-1,4- of formula I, selected from unsubstituted or monosubstituted or monosubstituted phenyl, furyl or thiophenyl, each bonded via a saturated straight chain C 1 -C 2 -alkyl group Diamine derivatives are constructed.
    [92] In a preferred embodiment of the compound group (D),
    [93] Each R 3 is bonded via an unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl or heteroaryl, and a saturated or unsaturated straight-chain substituted or unsubstituted C 1 -C 4 -alkyl group Each selected from unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl or heteroaryl,
    [94] Preferably, R 3 is unsubstituted or mono- or polysubstituted C 5 -C 6 -cycloalkyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolalanyl, indolyl, indanyl, Benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl; And unsubstituted or monosubstituted or monosubstituted C 5 -C 6 -cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothio, each bonded via a saturated straight chain C 1 -C 2 -alkyl group Phenyl, pyridyl, furyl, benzofuranyl, benzodioxolanil, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl,
    [95] In particular, R 3 is unsubstituted or mono- or polysubstituted furyl, thiophenyl, cyclohexanyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pyrrolyl, pyrimidyl, Pyrazinyl or benzothiophenyl; And substituted cyclohexane-1,4- of formula I, selected from unsubstituted or monosubstituted or monosubstituted phenyl, furyl or thiophenyl, each bonded via a saturated straight chain C 1 -C 2 -alkyl group Diamine derivatives are constructed.
    [96] In a preferred embodiment of all of the above compounds and compound groups according to the invention, substituted cyclohexane-1,4-diamine derivatives of the formula (I) in which R 4 is H are constructed.
    [97] In a preferred embodiment of all the above compounds and compound groups according to the invention,
    [98] R 4 is H, C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , where X is O or S Is selected from
    [99] Preferably, R 4 is selected from H, C (X) R 7 , C (X) NR 7 R 8 and C (X) OR 9 , wherein X is O,
    [100] In particular, R 4 is selected from H and C (O) R 7 wherein R 7 is H; and saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; Preferably, selected from H; and saturated branched or straight chain unsubstituted C 1 -C 3 -alkyl; in particular CH 3 ) substituted cyclohexane-1, 4-diamine derivatives of formula (I) Is composed.
    [101] In a preferred embodiment of compound group (A), (D) or (E),
    [102] R 4 and R 5 together may be a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms; Preferably, in addition to the essential atom N, having 5 to 7 ring atoms, 0 or 1 heteroatom further selected from N, S and O is further present in the ring and is monocyclic or polysubstituted or unsubstituted heterocyclic radical [Herein, the heterocyclic radicals formed by R 4 and R 5 may optionally be fused together with additional rings, preferably aromatic and / or heteroaromatic rings, wherein these rings can again be fused with further aromatic and / or heteroaromatic rings. Can be fused together, in particular the heterocyclic radicals formed by R 4 and R 5 together with one or two further rings, preferably heterocyclic formed by R 4 and R 5 The radical is fused with two further rings such that R 4 and R 5 together form Substituted cyclohexane-1,4-diamine derivative of Formula (I).
    [103] In a preferred embodiment of compound group (A), (D) or (E),
    [104] R 4 is H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl,
    [105] Preferably, H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 6 -alkyl,
    [106] In particular, H; And substituted cyclohexane-1,4-diamine derivatives of formula (I) selected from saturated straight chain unsubstituted C 1 -C 3 -alkyl.
    [107] In a preferred embodiment of all the above compounds and compound groups according to the invention,
    [108] R 5 is each selected from unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl and heteroaryl,
    [109] Preferably, R 5 is unsubstituted or monosubstituted or monosubstituted cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothio Phenyl, indanyl, benzodioxanyl, benzodioxolanil, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthenyl, benzo Thiazolyl, benzotriazolyl, benzo [1,2,5] thiazolyl, 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolononyl, oxopyrazolinonyl, dioxolanyl , Adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl and quinazolinyl,
    [110] In particular, R 5 is unsubstituted or mono- or polysubstituted cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxa Substituted cyclohexane-1,4-diamine derivatives of formula (I) selected from nil, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl and pyrimidyl Is composed.
    [111] In a particularly preferred further embodiment of all the above compounds and compound groups according to the invention,
    [112] R 5 is -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O , S or H 2 ),
    [113] Preferably, R 5 is -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 and —C (Y) —CH 2 —CH 2 R 12 , wherein Y is O or S,
    [114] In particular, R 5 is -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -C (Y) R 12 and -C (Y) -CH 2 R 12 A substituted cyclohexane-1,4-diamine derivative of Formula (I) is selected, wherein Y is O.
    [115] With respect to this embodiment, R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 4 -alkyl,
    [116] Preferably, H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl; And saturated straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 2 -alkyl,
    [117] In particular, substituted cyclohexane-1,4-diamine derivatives selected from H, CH 3 , C 2 H 5 and C (O) O-CH 3 are particularly preferred,
    [118] R 12 is each selected from unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl and heteroaryl,
    [119] Preferably, R 12 is unsubstituted or mono- or polysubstituted cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothio Phenyl, indanyl, benzodioxanyl, benzodioxolanil, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthenyl, benzo Thiazolyl, benzotriazolyl, benzo [1,2,5] thiazolyl, 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolononyl, oxopyrazolinonyl, dioxolanyl , Adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl and quinazolinyl,
    [120] In particular, R 12 is unsubstituted or mono- or polysubstituted cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxa Particular preference is given to substituted cyclohexane-1,4-diamine derivatives selected from nil, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl and pyrimidyl Do.
    [121] In addition, in particular
    [122] N'-benzyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine hydrochloride, nonpolar diastereomers,
    [123] N'-benzyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine hydrochloride, polar diastereomers,
    [124] 1, N'-dibenzyl-N, N-dimethyl-cyclohexane-1,4-diamine hydrochloride, nonpolar diastereomers,
    [125] 1, N'-dibenzyl-N, N-dimethyl-cyclohexane-1,4-diamine hydrochloride, polar diastereomers,
    [126] N- (4-benzyl-4-dimethylamino-cyclohexyl) -N-propyl-benzamide hydrochloride,
    [127] N, N-dimethyl-1-phenyl-N'-propyl-cyclohexane-1,4-diamine hydrochloride, nonpolar diastereomers,
    [128] N- (4-dimethylamino-4-phenyl-cyclohexyl) -N-propyl-benzamide hydrochloride, nonpolar diastereomers,
    [129] N- (4-dimethylamino-4-phenyl-cyclohexyl) -N-propyl-benzamide hydrochloride, polar diastereomers,
    [130] 1, N'-dibenzyl-N, N, N'-trimethyl-cyclohexane-1,4-diamine hydrochloride, nonpolar diastereomers,
    [131] 1, N'-dibenzyl-N, N, N'-trimethyl-cyclohexane-1,4-diamine hydrochloride, polar diastereomers,
    [132] N- (4-benzyl-4-dimethylamino-cyclohexyl) -N-methyl-benzamide hydrochloride, polar diastereomers,
    [133] N- (4-benzyl-4-dimethylamino-cyclohexyl) -N-ethyl-benzamide hydrochloride, polar diastereomers,
    [134] 1-benzyl-N '-(1H-indol-3-ylmethyl) -N, N-dimethyl-cyclohexane-1,4-diamine dihydrochloride,
    [135] 1-benzyl-N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-cyclohexane-1,4-diamine, cis / trans mixture,
    [136] 1-benzyl-N'-indan-5-yl-N, N-dimethyl-cyclohexane-1,4-diamine hydrochloride,
    [137] 1-benzyl-N'-indan-1-yl-N, N-dimethyl-cyclohexane-1,4-diamine dihydrochloride, cis / trans mixture,
    [138] N'-indan-1-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine,
    [139] N '-(1H-indol-5-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine,
    [140] N '-(1H-indol-3-ylmethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, cis / trans mixture,
    [141] N '-(1H-indol-3-ylmethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, nonpolar diastereomer,
    [142] N '-[2- (1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, nonpolar diastereomer,
    [143] N '-[2- (1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, cis / trans mixture,
    [144] N'-indan-5-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, nonpolar diastereomer,
    [145] N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, nonpolar diastereomer,
    [146] N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, cis / trans mixture,
    [147] N '-[2- (5-benzyloxy-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, cis / trans mixture,
    [148] N '-(9H-fluoren-1-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride,
    [149] N'-indan-2-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, cis / trans mixture,
    [150] N '-(9H-fluoren-9-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, cis / trans mixture,
    [151] 1-benzyl-N '-(9-fluoren-9-yl) -N, N-dimethyl-cyclohexane-1,4-diamine,
    [152] 1-benzyl-N '-(1H-indol-3-ylmethyl) -N, N-dimethyl-cyclohexane-1,4-diamine, cis / trans mixture,
    [153] N, N-dimethyl-N '-(1-methyl-1H-indol-3-ylmethyl) -1-phenyl-cyclohexane-1,4-diamine, cis / trans mixture,
    [154] N, N-dimethyl-N '-(1-methyl-1H-indol-3-ylmethyl) -1-phenyl-cyclohexane-1,4-diamine, polar diastereomer,
    [155] N '-(2-benzo [b] thiophen-3-yl-ethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, cis / trans mixture,
    [156] N '-(2-benzo [b] thiophen-3-yl-ethyl) -1-benzyl-N, N-dimethylcyclohexane-1,4-diamine dihydrochloride, cis / trans mixture,
    [157] N'-acenaphthen-1-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomers,
    [158] N'-acenaphthen-1-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomers,
    [159] N'-benzo [b] thiophen-5-yl-1-benzyl-N, N-dimethyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomers,
    [160] N'-benzo [b] thiophen-5-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine hydrochloride, nonpolar diastereomers,
    [161] N'-benzothiazol-6-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomers,
    [162] N'-benzo [1,2,5] thiadiazol-4-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomers,
    [163] N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    [164] N'-adamantan-2-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride,
    [165] N '-(9-ethyl-9H-carbazol-3-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    [166] N '-(3H-benzotriazol-5-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine hydrochloride, nonpolar diastereomers,
    [167] N '-(3H-benzotriazol-5-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine hydrochloride, polar diastereomers,
    [168] N '-(9H-fluoren-9-yl) -N, N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, cis / trans mixture,
    [169] N'-cyclooctyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride,
    [170] N '-(1H-indol-3-ylmethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    [171] N '-(1H-indol-3-ylmethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomers,
    [172] N'-benzo [b] thiophen-3-ylmethyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    [173] N'-benzo [b] thiophen-3-ylmethyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomers,
    [174] N'-anthracen-2-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine hydrochloride, nonpolar diastereomers,
    [175] N'-benzo [b] thiophen-3-ylmethyl-1-benzyl-N, N-dimethyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomers,
    [176] N'-benzo [b] thiophen-3-ylmethyl-1-benzyl-N, N-dimethyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomers,
    [177] N '-[2- (1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-naphthalen-2-yl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    [178] N-[2- (1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    [179] N '-[2- (1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomer,
    [180] N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomer,
    [181] Methyl 2- (4-dimethylamino-4-phenyl-cyclohexylamino) -3- (1H-indol-3-yl) -propionate dihydrochloride, nonpolar diastereomers,
    [182] Methyl 2- (4-dimethylamino-4-phenyl-cyclohexylamino) -3- (1H-indol-3-yl) -propionate dihydrochloride, polar diastereomers,
    [183] N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-naphthalen-2-yl-cyclohexane-1,4-diamine dihydrochloride, nonpolar Diastereomer,
    [184] N'-benzo [1,3] dioxol-5-ylmethyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diaminedihydrochloride, cis / trans mixture,
    [185] N '-[2- (6-Fluoro-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer ,
    [186] N '-[2- (6-Fluoro-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomer ,
    [187] N '-[2- (1H-indol-3-yl) -ethyl] -N, N, N'-trimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    [188] N '-[2- (1H-indol-3-yl) -ethyl] -N, N, N'-trimethyl-1-phenyl-cyclohexane-1, 4-diamine dihydrochloride, polar diastereomer,
    [189] N, N-dimethyl-N '-[2- (7-methyl-1H-indol-3-yl) -ethyl] -1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    [190] N, N-dimethyl-N '-[2- (7-methyl-1H-indol-3-yl) -ethyl] -1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomer,
    [191] N '-[2- (5-Fluoro-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer ,
    [192] N '-[2- (5-Fluoro-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1, 4-diamine dihydrochloride, polar diastereomer ,
    [193] N'-acenaphthene-5-ylmethyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    [194] N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, Nonpolar diastereomers,
    [195] N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, Cis / trans mixture,
    [196] N '-[2- (7-benzyloxy-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer ,
    [197] N'-cyclooctyl-N, N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomers,
    [198] N'-adamantan-2-yl-N, N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    [199] 3- [2- (4-dimethylamino-4-phenyl-cyclohexylamino) -ethyl] -1 H-indol-5-ol dihydrochloride, nonpolar diastereomer,
    [200] 3- [2- (4-dimethylamino-4-phenyl-cyclohexylamino) -ethyl] -1 H-indol-5-ol dihydrochloride, polar diastereomer,
    [201] N '-[2- (5-methoxy-1 H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1, 4-diamine dihydrochloride, nonpolar diastereomer ,
    [202] N '-[2- (5-methoxy-1 H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomer ,
    [203] N, N-dimethyl-N '-[2- (5-methyl-1H-indol-3-yl) -ethyl] -1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    [204] N, N-dimethyl-N '-[2- (5-methyl-1H-indol-3-yl) -ethyl] -1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomer,
    [205] Dimethyl- [1-phenyl-4- (1,3,4,9-tetrahydro-b-carboline-2-yl) -cyclohexyl] -amine dihydrochloride,
    [206] N- (4-dimethylamino-4-phenyl-cyclohexyl) -N- [2- (4-fluoro-phenyl) -ethyl] -acetamide hydrochloride, nonpolar diastereomers,
    [207] 2- (4-dimethylamino-4-phenyl-cyclohexylamino) -3- (5-fluoro-1 H-indol-3-yl) -propionic acid methyl ester dihydrochloride, nonpolar diastereomers,
    [208] N- (4-dimethylamino-4-phenyl-cyclohexyl) -N- (3-phenyl-propyl) -acetamide hydrochloride, nonpolar diastereomers,
    [209] 2- (4-dimethylamino-4-phenyl-cyclohexylamino) -3- (6-fluoro-1 H-indol-3-yl) -propionic acid methyl ester dihydrochloride, nonpolar diastereomers,
    [210] N- (4-dimethylamino-4-phenyl-cyclohexyl) -2- (1H-indol-3-yl) -acetamide hydrochloride, polar diastereomers,
    [211] 2- (4-dimethylamino-4-thiophen-2-yl-cyclohexylamino) -3- (1H-indol-3-yl) -propionic acid methyl ester dihydrochloride, nonpolar diastereomers and
    [212] N- (4-dimethylamino-4-phenyl-cyclohexyl) -2- (5-methoxy-1H-indol-3-yl) -acetamide hydrochloride, nonpolar diastereomers Substituted cyclohexane-1,4-diamine derivatives, or optionally their racemates, pure stereoisomeric forms, in particular enantiomeric or diastereomeric forms, or stereoisomers, in particular enantiomers or diastereomers, in particular mixing ratios Mixture form; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or solvates thereof, especially hydrate forms.
    [213] The substances according to the invention are toxicologically acceptable to be suitable as pharmaceutically active compounds in medicine.
    [214] The invention therefore also relates to at least one substituted cyclohexane-1,4-diamine derivative of the formula (hereinafter referred to as compound group (F)), optionally in its racemic form, pure stereoisomers, in particular enantiomers Or diastereomeric forms or stereoisomeric mixtures, in particular enantiomers or diastereomeric mixtures, in particular mixing ratios; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or a solvate, especially a hydrate form thereof, and optionally a medicament comprising a suitable additive and / or adjuvant material and / or optionally further active compounds.
    [215] Formula I
    [216]
    [217] In Formula I above,
    [218] R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    [219] R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    [220] R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    [221] R 4 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; And C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , wherein X is O or S and R 7 Is H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated straight or branched mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    [222] R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And each unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl; or
    [223] R 4 and R 5 together form a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms, wherein the heterocyclic radical may optionally be fused with an additional ring. Forming,
    [224] Provided that when R 3 is substituted or unsubstituted phenyl and at least one of R 1 and R 2 is H or C 1 -C 8 -alkyl, R 4 is not alkyl and R 4 and R 5 together are heterocyclic radicals Does not form.
    [225] The invention also relates to one or more substituted cyclohexane-1,4-diamine derivatives (hereinafter referred to as compound group (G)), optionally racemate forms thereof, pure stereoisomers, in particular enantiomers or moieties. Stereoisomeric forms or mixtures of stereoisomers in a particular mixing ratio, in particular enantiomers or diastereomeric mixtures; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or a solvate, especially a hydrate form thereof, and optionally a medicament comprising a suitable additive and / or adjuvant material and / or optionally further active compounds.
    [226] Formula I
    [227]
    [228] In Formula I above,
    [229] R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    [230] R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    [231] R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl, or heteroaryl, which are bonded via a saturated or unsaturated branched or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    [232] R 4 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; And C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , wherein X is O or S and R 7 Is H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated straight or branched mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    [233] R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And each unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl; or
    [234] R 4 and R 5 together form a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms, wherein the heterocyclic radical may optionally be fused with an additional ring. Form.
    [235] The invention also relates to one or more substituted cyclohexane-1,4-diamine derivatives (hereinafter referred to as compound group (H)), optionally racemate forms thereof, pure stereoisomers, in particular enantiomers or moieties. Stereoisomeric forms or mixtures of stereoisomers in a particular mixing ratio, in particular enantiomers or diastereomeric mixtures; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or a solvate, especially a hydrate form thereof, and optionally a medicament comprising a suitable additive and / or adjuvant material and / or optionally further active compounds.
    [236] Formula I
    [237]
    [238] In Formula I above,
    [239] R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    [240] R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    [241] R 4 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; And C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , wherein X is O or S and R 7 Is H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated straight or branched mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    [242] R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And each unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl; or
    [243] R 4 and R 5 together form a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms, wherein the heterocyclic radical may optionally be fused with an additional ring. Form.
    [244] The invention also relates to one or more substituted cyclohexane-1,4-diamine derivatives of the formula (hereinafter referred to as compound group (J)), optionally racemate forms thereof, pure stereoisomers, in particular enantiomers or moieties. Stereoisomeric forms or mixtures of stereoisomers in a particular mixing ratio, in particular enantiomers or diastereomeric mixtures; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or a solvate, especially a hydrate form thereof, and optionally a medicament comprising a suitable additive and / or adjuvant material and / or optionally further active compounds.
    [245] Formula I
    [246]
    [247] In Formula I above,
    [248] R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    [249] R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    [250] R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    [251] R 4 is H, C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 where X is O or S And R 7 is H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated straight or branched mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    [252] R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively.
    [253] Preferred agents according to the invention are those wherein R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl, except when R 1 and R 2 are hydrogen at the same time, or
    [254] R 1 and R 2 together represent the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 , wherein R 6 is H; and a saturated or unsaturated branched or straight chain mono- or polysubstituted Is unsubstituted C 1 -C 8 -alkyl) or (CH 2 ) 3-6 to form a ring,
    [255] Preferably, R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl, except when R 1 and R 2 are hydrogen at the same time, or R 1 and R 2 are Together form a ring of formula (CH 2 ) 4-5 ,
    [256] In particular, R 1 and R 2 are independently selected from methyl and ethyl, or R 1 and R 2 together are selected from one of compound groups (F) and (G), which together form a ring of formula (CH 2 ) 5 At least one substituted cyclohexane-1,4-diamine derivative of formula (I).
    [257] Preferred agents according to the invention are those in which R 1 and R 2 taken together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 , wherein R 6 is H; and a saturated or unsaturated side chain or Linear mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl) or (CH 2 ) 3-6 to form a ring,
    [258] Preferably, R 1 and R 2 together form a ring of formula (CH 2 ) 4-5 ,
    [259] In particular, include R 1 and R 2 with the formula (CH 2) to form a ring of 5, the group of compounds at least one substituted cyclohexane-1,4-diamine derivatives of formula (I) is selected from (H).
    [260] Preferred agents according to the invention are those wherein R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl, except when R 1 and R 2 are hydrogen at the same time,
    [261] Preferably, R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl, except when R 1 and R 2 are hydrogen at the same time,
    [262] In particular, R 1 and R 2 are each independently selected from methyl and ethyl,
    [263] R 1 and R 2 together represent the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 , wherein R 6 is H; and a saturated or unsaturated branched or straight chain mono- or polysubstituted Is unsubstituted C 1 -C 8 -alkyl) or (CH 2 ) 3-6 to form a ring,
    [264] Preferably, R 1 and R 2 together form a ring of formula (CH 2 ) 4-5 ,
    [265] In particular, at least one substituted cyclohexane-1,4-diamine derivative of formula I selected from compound group (J), wherein R 1 and R 2 together form a ring of formula (CH 2 ) 5 .
    [266] Preferred agents according to the invention are C 3 -C 8 -cycloalkyl, aryl or heteroaryl, wherein R 3 is unsubstituted or mono- or polysubstituted, respectively, and saturated or unsaturated straight-chain unsubstituted or unsubstituted C 1- Unsubstituted or monosubstituted or monosubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, each bonded via a C 2 -alkyl group,
    [267] Preferably, R 3 is unsubstituted or mono- or polysubstituted C 5 -C 6 -cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxola Nil, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl; And unsubstituted or monosubstituted or monosubstituted C 5 -C 6 -cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothio, each bonded via a saturated straight chain C 1 -C 2 -alkyl group Phenyl, pyridyl, furyl, benzofuranyl, benzodioxolanil, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl,
    [268] In particular, R 3 is unsubstituted or mono- or polysubstituted phenyl, furyl, thiophenyl, cyclohexanyl, naphthyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pi Rollyl, pyrimidyl, pyrazinyl or benzothiophenyl; And compound groups (F), (H) and (J), each selected from unsubstituted or monosubstituted or monosubstituted phenyl, furyl or thiophenyl which are bonded via a saturated straight chain C 1 -C 2 -alkyl group At least one substituted cyclohexane-1,4-diamine derivative of formula (I) selected from one of
    [269] Preferred agents according to the invention are C 3 -C 8 -cycloalkyl or heteroaryl, wherein R 3 is unsubstituted or mono- or polysubstituted, respectively, and saturated or unsaturated straight-chain unsubstituted or unsubstituted C 1 -C 4 Is selected from unsubstituted or monosubstituted or monosubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, each bonded via an -alkyl group,
    [270] Preferably, R 3 is unsubstituted or mono- or polysubstituted C 5 -C 6 -cycloalkyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolalanyl, indolyl, indanyl, Benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl; And unsubstituted or monosubstituted or monosubstituted C 5 -C 6 -cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothio, each bonded via a saturated straight chain C 1 -C 2 -alkyl group Phenyl, pyridyl, furyl, benzofuranyl, benzodioxolanil, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl,
    [271] In particular, R 3 is unsubstituted or mono- or polysubstituted furyl, thiophenyl, cyclohexanyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pyrrolyl, pyrimidyl, Pyrazinyl or benzothiophenyl; And substituted through a saturated straight-chain C 1 -C 2 -alkyl group, each selected from compound group (G) selected from unsubstituted or monosubstituted or polysubstituted phenyl, furyl or thiophenyl At least one cyclohexane-1,4-diamine derivative.
    [272] Preferred medicaments according to the invention comprise at least one substituted cyclohexane-1,4-diamine derivative of formula (I) selected from compound groups (F), (G), (H) and (J), wherein R 4 is H Include.
    [273] Preferred agents according to the invention are those in which R 4 is H, C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 Wherein X is O or S, and
    [274] Preferably, R 4 is selected from H, C (X) R 7 , C (X) NR 7 R 8 and C (X) OR 9 , wherein X is O,
    [275] In particular, R 4 is selected from H and C (O) R 7 wherein R 7 is H; and saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; Preferably selected from H; and saturated branched or straight chain unsubstituted C 1 -C 3 -alkyl; in particular CH 3 ), and the compound groups (F), (G), (H) and At least one substituted cyclohexane-1,4-diamine derivative of formula (I) selected from (J).
    [276] Further preferred agents according to the invention are, R 4 and R 5 together, saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radicals having 3 to 8 ring atoms; Preferably, in addition to the essential atom N, having 5 to 7 ring atoms, 0 or 1 heteroatom further selected from N, S and O is further present in the ring and is monocyclic or polysubstituted or unsubstituted heterocyclic radical [Here, the heterocyclic radicals formed by R 4 and R 5 together may optionally be fused with further rings, preferably aromatic and / or heteroaromatic rings, wherein these rings can in turn be fused with further aromatic and / or heteroaromatic rings. Can be fused together, in particular the heterocyclic radicals formed by R 4 and R 5 together with one or two further rings, preferably heterocyclic formed by R 4 and R 5 The radical is fused with two further rings such that R 4 and R 5 together form At least one substituted cyclohexane-1,4-diamine derivative of formula (I) selected from compound groups (F), (G) and (H).
    [277] Preferred agents of the present invention are those wherein R 4 is H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl,
    [278] Preferably, H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 6 -alkyl,
    [279] In particular, H; And at least one substituted cyclohexane-1,4-diamine derivative of formula I selected from compound groups (F), (G) and (H), selected from saturated straight chain unsubstituted C 1 -C 3 -alkyl. It includes.
    [280] Preferred agents of the invention are selected from C 3 -C 8 -cycloalkyl, aryl and heteroaryl, wherein each R 5 is unsubstituted or mono- or polysubstituted,
    [281] Preferably, R 5 is unsubstituted or monosubstituted or monosubstituted cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothio Phenyl, indanyl, benzodioxanyl, benzodioxolanil, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthenyl, benzo Thiazolyl, benzotriazolyl, benzo [1,2,5] thiazolyl, 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolononyl, oxopyrazolinonyl, dioxolanyl , Adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl and quinazolinyl,
    [282] In particular, R 5 is unsubstituted or mono- or polysubstituted cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxa Compound groups (F), (G), (H) and selected from nil, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl and pyrimidyl At least one substituted cyclohexane-1,4-diamine derivative of formula (I) selected from (J).
    [283] In addition, the medicament of the present invention preferably, R 5 is -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 ,
    [284] Preferably, R 5 is -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 and —C (Y) —CH 2 —CH 2 R 12 , wherein Y is O or S,
    [285] In particular, R 5 is -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -C (Y) R 12 and -C (Y) -CH 2 R 12 At least one substituted cyclohexane-1,4-diamine derivative of formula I selected from compound groups (F), (G), (H), and (J), wherein Y is O .
    [286] With regard to the last group of preferred drugs,
    [287] R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 4 -alkyl,
    [288] Preferably, H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl; And saturated straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 2 -alkyl,
    [289] In particular substituted cyclohexane-1,4-diamine derivatives of formula I and / or selected from H, CH 3 , C 2 H 5 and C (O) O-CH 3
    [290] R 12 is H; And unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively,
    [291] Preferably, R 12 is unsubstituted or mono- or polysubstituted cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothio Phenyl, indanyl, benzodioxanyl, benzodioxolanil, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthenyl, benzo Thiazolyl, benzotriazolyl, benzo [1,2,5] thiazolyl, 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolononyl, oxopyrazolinonyl, dioxolanyl , Adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl and quinazolinyl,
    [292] In particular, R 12 is unsubstituted or mono- or polysubstituted cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxa Substituted cyclohexane-1,4-diamine derivatives of formula (I) selected from nil, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl and pyrimidyl Particularly preferred is a drug containing.
    [293] In addition to one or more substituted cyclohexane-1,4-diamine derivatives according to the invention, the medicaments according to the invention may optionally contain suitable additive and / or adjuvant materials, ie carrier materials, fillers, solvents, diluents, pigments and / or binders. And in the form of liquid pharmaceuticals in the form of injectable solutions, drops or juices, which may be administered in the form of semisolid pharmaceuticals in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols. The choice of adjuvant material and the like and the amount thereof used may be such that the agent is oral, oral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, oral, rectal or topical, for example, It depends on whether it is administered to the skin, mucous membranes or eyes. Formulations in the form of tablets, coated tablets, capsules, granules, drops, juices and syrups are suitable for oral administration and liquids, suspensions, easy to reconstitute anhydrous formulations and sprays are suitable for parenteral, topical and inhalation administration. . The substituted cyclohexane-1,4-diamine derivatives according to the invention in depot, dissolved or plaster form with an agent added to facilitate permeation through the skin are suitable formulations for transdermal administration. Formulations that can be used orally or transdermally release the substituted cyclohexane-1,4-diamine derivatives according to the invention in a delayed manner. Other further active compounds known to those skilled in the art can in principle be added to the medicaments according to the invention.
    [294] The amount of active compound administered to a patient depends on the patient's weight, mode of administration, signs and severity of the disease. It is convenient to administer from 0.005 to 1,000 mg / kg, preferably from 0.05 to 5 mg / kg of one or more substituted cyclohexane-1,4-diamine derivatives according to the invention.
    [295] In all of the above pharmaceutical forms according to the invention, in addition to at least one substituted cyclohexane-1,4-diamine derivative, the medicament is also an opioid, preferably an effective opioid, in particular morphine, or an anesthetic, preferably hexobarbital Or halotan.
    [296] In a preferred pharmaceutical form, the substituted cyclohexane-1,4-diamine derivatives according to the invention contained are pure diastereomers and / or enantiomers, racemates, or diastereomers and / or enanties. It is present as a mixture of boiling or equimolar amounts of thiomers.
    [297] As can be seen from the introduction of the prior art, the ORL1 receptor has been specifically identified in the pain state. Thus, the substituted cyclohexane-1,4-diamine derivatives according to the invention can be used for the preparation of a medicament for the treatment of pain, in particular acute, neuropathic or chronic pain.
    [298] The invention also relates to substituted cyclohexane-1,4-diamine derivatives of the formula (I) (hereinafter referred to as compound group (K)) for the preparation of a medicament for the treatment of pain, in particular acute, neuropathic or chronic pain, optionally Racemic forms, pure stereoisomers, in particular enantiomeric or diastereomeric forms, or stereoisomeric mixtures, in particular enantiomeric or diastereomeric mixtures, in certain mixing ratios; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or their solvates, in particular in the form of hydrates.
    [299] Formula I
    [300]
    [301] In Formula I above,
    [302] R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    [303] R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    [304] R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    [305] R 4 is H; Saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 8 -alkyl; And C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , wherein X is O or S and R 7 Is H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated, branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    [306] R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And each unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl; or
    [307] R 4 and R 5 together form a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms, wherein the heterocyclic radical may optionally be fused with an additional ring. Forming,
    [308] Provided that when R 3 is substituted or unsubstituted phenyl and at least one of R 1 and R 2 is H or C 1 -C 8 -alkyl, R 4 is not alkyl and R 4 and R 5 together are heterocyclic radicals Does not form.
    [309] The invention also relates to substituted cyclohexane-1,4-diamine derivatives of the formula (I) (hereinafter referred to as compound group (L)) for the purpose of enhancing drugs for the treatment of pain, in particular acute, neuropathy or chronic pain, optionally Racemic forms, pure stereoisomers, in particular enantiomeric or diastereomeric forms, or stereoisomeric mixtures, in particular enantiomeric or diastereomeric mixtures, in certain mixing ratios; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or their solvates, in particular in the form of hydrates.
    [310] Formula I
    [311]
    [312] In Formula I above,
    [313] R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    [314] R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene and each Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    [315] R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    [316] R 4 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; And C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , wherein X is O or S and R 7 Is H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated straight or branched mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    [317] R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And each unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl; or
    [318] R 4 and R 5 together form a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms, wherein the heterocyclic radical may optionally be fused with an additional ring. Form.
    [319] The invention also relates to substituted cyclohexane-1,4-diamine derivatives of the formula (I), hereinafter referred to as compound group (M), for the preparation of a medicament for the treatment of pain, in particular acute, neuropathic or chronic pain. Racemic forms, pure stereoisomers, in particular enantiomeric or diastereomeric forms, or stereoisomeric mixtures, in particular enantiomeric or diastereomeric mixtures, in certain mixing ratios; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or their solvates, in particular in the form of hydrates.
    [320] Formula I
    [321]
    [322] In Formula I above,
    [323] R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    [324] R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    [325] R 4 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; And C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , wherein X is O or S and R 7 Is H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl which is bonded via C 1 -C 3 -alkylene, respectively, C 3 -C 8 -cycloalkyl or hetero Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated, branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    [326] R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H and unsubstituted or mono- or polysubstituted C 3, respectively. -C 8 -cycloalkyl, aryl or heteroaryl; or
    [327] R 4 and R 5 together form a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms, wherein the heterocyclic radical may optionally be fused with an additional ring. Form.
    [328] The invention also relates to substituted cyclohexane-1,4-diamine derivatives of the formula I (hereinafter referred to as compound group (N)) for the preparation of a medicament for the treatment of pain, in particular acute, neuropathic or chronic pain, optionally Racemic forms, pure stereoisomers, in particular enantiomeric or diastereomeric forms, or stereoisomeric mixtures, in particular enantiomeric or diastereomeric mixtures, in certain mixing ratios; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or their solvates, in particular in the form of hydrates.
    [329] Formula I
    [330]
    [331] In Formula I above,
    [332] R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    [333] R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    [334] R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    [335] R 4 is H, C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 where X is O or S R 7 is H, saturated or unsaturated, branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated, branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    [336] R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively.
    [337] As already mentioned in the introduction, in addition to its function in pain, ORL1 receptors also play an important role in many other physiological processes, especially important medically relevant processes, and thus the present invention also provides anxiety, stress and stress Related syndromes, depression, epilepsy, Alzheimer's disease, elderly dementia, general cognitive dysfunction, learning and memory disorders (as brain supplements), withdrawal symptoms, alcohol and / or drug and / or drug abuse and / or dependence, sexual dysfunction, Cardiovascular disease, hypotension, hypertension, tinnitus, itching, migraine, hearing impairment, intestinal motility, eating insufficiency, anorexia, sinus, exercise disorders, diarrhea, cachexia and incontinence medications, or medications as muscle relaxants, anticonvulsants or anesthetics , Or agents used in combination with opioid analgesics or anesthetics, diuretic or antisodium urinary excretion and / or antianxiety agents Substituted cyclohexane-1,4-diamine derivatives of formula I (hereinafter referred to as compound group (O)), optionally racemate forms thereof, pure stereoisomers, in particular enantiomers or diastereomers, for the preparation of In the form or in a specific mixing ratio of stereoisomeric mixtures, in particular enantiomer or diastereomeric mixtures; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or their solvates, in particular in the form of hydrates.
    [338] Formula I
    [339]
    [340] In Formula I above,
    [341] R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    [342] R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    [343] R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    [344] R 4 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; And C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , wherein X is O or S and R 7 Is H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl which is bonded via C 1 -C 3 -alkylene, respectively, C 3 -C 8 -cycloalkyl or hetero Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated, branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    [345] R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; And -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S Or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; or
    [346] R 4 and R 5 together form a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms, wherein the heterocyclic radical may optionally be fused with an additional ring. Form.
    [347] In one of the above uses, the substituted cyclohexane-1,4-diamine derivative is in pure diastereomeric and / or enantiomeric form, as a racemate or in boiling molar amounts of diastereomers and / or enantiomers, or It is preferable to use it as equimolar amount mixture.
    [348] In one of the above uses of a substituted cyclohexane-1, 4-diamine derivative selected from one of compound groups (K), (L) and (O), R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl, except when R 1 and R 2 are hydrogen at the same time, or
    [349] R 1 and R 2 together represent the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 , wherein R 6 is H; and a saturated or unsaturated branched or straight chain mono- or polysubstituted Is unsubstituted C 1 -C 8 -alkyl) or (CH 2 ) 3-6 to form a ring,
    [350] Preferably, R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl, except when R 1 and R 2 are hydrogen at the same time, or R 1 and R 2 are Together form a ring of formula (CH 2 ) 4-5 ,
    [351] In particular, substituted cyclohexane-1,4-, wherein R 1 and R 2 are independently selected from methyl and ethyl, or the radicals R 1 and R 2 together form a ring of formula (CH 2 ) 5 Preference is given to the use of diamine derivatives.
    [352] In one of the above uses of a substituted cyclohexane-1,4-diamine derivative selected from compound group (M), R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 , wherein R 6 is selected from H; and a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl ring, or a ring of (CH 2 ) 3-6 Form the
    [353] Preferably, R 1 and R 2 together form a ring of formula (CH 2 ) 4-5 ,
    [354] In particular, the use of substituted cyclohexane-1,4-diamine derivatives of the formula (I) in which R 1 and R 2 together form a ring of formula (CH 2 ) 5 is preferred.
    [355] In one of the above uses of a substituted cyclohexane-1,4-diamine derivative selected from compound group (N), R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl, except when R 1 and R 2 are hydrogen at the same time,
    [356] Preferably, R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl, except when R 1 and R 2 are hydrogen at the same time,
    [357] In particular, R 1 and R 2 are each independently selected from methyl and ethyl,
    [358] R 1 and R 2 together represent the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 , wherein R 6 is H; and a saturated or unsaturated branched or straight chain mono- or polysubstituted Is unsubstituted C 1 -C 8 -alkyl) or (CH 2 ) 3-6 to form a ring,
    [359] Preferably, R 1 and R 2 together form a ring of formula (CH 2 ) 4-5 ,
    [360] In particular, the use of substituted cyclohexane-1,4-diamine derivatives of the formula (I) in which R 1 and R 2 together form a ring of formula (CH 2 ) 5 is preferred.
    [361] In one of the above uses of a substituted cyclohexane-1, 4-diamine derivative selected from one of compound groups (K), (M), (N) and (O), R 3 is each unsubstituted or mono-substituted or Unsubstituted or monosubstituted, each bonded via a polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, and a saturated or unsaturated straight or branched, substituted or unsubstituted C 1 -C 2 -alkyl group Or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl,
    [362] Preferably, R 3 is unsubstituted or mono- or polysubstituted C 5 -C 6 -cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxola Nil, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl; And unsubstituted or monosubstituted or monosubstituted C 5 -C 6 -cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothio, each bonded via a saturated straight chain C 1 -C 2 -alkyl group Phenyl, pyridyl, furyl, benzofuranyl, benzodioxolanil, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl,
    [363] In particular, R 3 is unsubstituted or mono- or polysubstituted phenyl, furyl, thiophenyl, cyclohexanyl, naphthyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pi Rollyl, pyrimidyl, pyrazinyl or benzothiophenyl; And substituted cyclohexane-1,4- of formula I, selected from unsubstituted or monosubstituted or monosubstituted phenyl, furyl or thiophenyl, each bonded via a saturated straight chain C 1 -C 2 -alkyl group Preference is given to the use of diamine derivatives.
    [364] In one of the above uses of a substituted cyclohexane-1, 4-diamine derivative selected from compound group (L), R 3 is unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl or heteroaryl, respectively And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from aryl,
    [365] Preferably, R 3 is unsubstituted or mono- or polysubstituted C 5 -C 6 -cycloalkyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolalanyl, indolyl, indanyl, Benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl; And unsubstituted or monosubstituted or monosubstituted C 5 -C 6 -cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothio, each bonded via a saturated straight chain C 1 -C 2 -alkyl group Phenyl, pyridyl, furyl, benzofuranyl, benzodioxolanil, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl,
    [366] In particular, R 3 is unsubstituted or mono- or polysubstituted furyl, thiophenyl, cyclohexanyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pyrrolyl, pyrimidyl, Pyrazinyl or benzothiophenyl; And substituted cyclohexane-1,4- of formula I, selected from unsubstituted or monosubstituted or monosubstituted phenyl, furyl or thiophenyl, each bonded via a saturated straight chain C 1 -C 2 -alkyl group Preference is given to the use of diamine derivatives.
    [367] In one of the above uses of a substituted cyclohexane-1, 4-diamine derivative selected from one of compound groups (K), (L), (M), (N) and (O), wherein R 4 is H, Preference is given to the use of substituted cyclohexane-1,4-diamine derivatives of the formula (I).
    [368] Also in one of the above uses of a substituted cyclohexane-1,4-diamine derivative selected from one of compound groups (K), (L), (M), (N) and (O), R 4 is H , C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , where X is O or S Become,
    [369] Preferably, R 4 is selected from H, C (X) R 7 , C (X) NR 7 R 8 and C (X) OR 9 , wherein X is O,
    [370] In particular, R 4 is selected from H and C (O) R 7 wherein R 7 is H; and saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; Preferably, selected from H; and saturated branched or straight chain unsubstituted C 1 -C 3 -alkyl; in particular CH 3 ) substituted cyclohexane-1, 4-diamine derivatives of formula (I) The use of is preferred.
    [371] In one of the above uses of a substituted cyclohexane-1,4-diamine derivative selected from one of compound groups (K), (L), (M) and (O), R 4 and R 5 together are a ring atom Saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radicals having 3 to 8 numbers; Preferably, in addition to the essential atom N, having 5 to 7 ring atoms, 0 or 1 heteroatom further selected from N, S and O is further present in the ring and is monocyclic or polysubstituted or unsubstituted heterocyclic radical [Here, the heterocyclic radicals formed by R 4 and R 5 together may optionally be fused with further rings, preferably aromatic and / or heteroaromatic rings, wherein these rings can in turn be fused with further aromatic and / or heteroaromatic rings. Can be fused together, in particular the heterocyclic radicals formed by R 4 and R 5 together with one or two further rings, preferably heterocyclic formed by R 4 and R 5 The radical is fused with two further rings such that R 4 and R 5 together form Preference is given to the use of the substituted cyclohexane-1,4-diamine derivatives of formula (I).
    [372] In one of the above uses of a substituted cyclohexane-1, 4-diamine derivative selected from one of compound groups (K), (L), (M) and (O), R 4 is H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl,
    [373] Preferably, H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 6 -alkyl,
    [374] In particular, H; And the use of substituted cyclohexane-1,4-diamine derivatives of formula I, selected from saturated straight chain unsubstituted C 1 -C 3 -alkyl.
    [375] In one of the above uses of a substituted cyclohexane-1,4-diamine derivative selected from one of compound groups (K), (L), (M), (N) and (O), R 5 is each unsubstituted Or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl and heteroaryl;
    [376] Preferably, R 5 is unsubstituted or monosubstituted or monosubstituted cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothio Phenyl, indanyl, benzodioxanyl, benzodioxolanil, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthenyl, benzo Thiazolyl, benzotriazolyl, benzo [1,2,5] thiazolyl, 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolononyl, oxopyrazolinonyl, dioxolanyl , Adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl and quinazolinyl,
    [377] In particular, R 5 is unsubstituted or mono- or polysubstituted cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxa Substituted cyclohexane-1,4-diamine derivatives of formula (I) selected from nil, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl and pyrimidyl The use of is preferred.
    [378] Furthermore, in one of the above uses of a substituted cyclohexane-1,4-diamine derivative selected from one of compound groups (K), (L), (M), (N) and (O), R 5 is- CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 ,- C (Y) —CH 2 R 12 , —C (Y) —CH 2 —CH 2 R 12 and —C (Y) —CH 2 —CH 2 —CH 2 R 12 , wherein Y is O, S or H 2 ), and
    [379] Preferably, R 5 is -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 and —C (Y) —CH 2 —CH 2 R 12 , wherein Y is O or S,
    [380] In particular, R 5 is -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -C (Y) R 12 and -C (Y) -CH 2 R 12 Preference is given to the use of the substituted cyclohexane-1,4-diamine derivatives of the formula (I), wherein Y is O.
    [381] In connection with the above embodiments, in the substituted cyclohexane-1,4-diamine derivatives of formula (I) used, R 11 is H, a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 4 -alkyl,
    [382] Preferably, H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl; And saturated straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 2 -alkyl,
    [383] In particular those selected from H, CH 3 , C 2 H 5 and C (O) O—CH 3 and / or
    [384] In the substituted cyclohexane-1,4-diamine derivatives of formula (I) used, R 12 is each selected from unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl and heteroaryl,
    [385] Preferably, R 12 is unsubstituted or mono- or polysubstituted cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothio Phenyl, indanyl, benzodioxanyl, benzodioxolanil, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthenyl, benzo Thiazolyl, benzotriazolyl, benzo [1,2,5] thiazolyl, 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolinonyl, oxopyrazolinonyl, dioxolanyl , Adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl and quinazolinyl,
    [386] In particular, R 12 is unsubstituted or mono- or polysubstituted cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxa Particular preference is given to those selected from nil, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl and pyrimidyl.
    [387] In general, under certain circumstances, in both the substituted cyclohexane-1,4-diamine derivatives, medicaments or methods described above, R 4 and R 5 do not together form a heterocyclic radical. It may be desirable.
    [388] In addition, the present invention is directed to a non-human person in need of treatment of a pain, in particular chronic pain, by administering a substituted cyclohexane-1,4-diamine derivative according to the invention or a pharmaceutically therapeutically active dose according to the invention. Provided are methods of treating the aforementioned diseases of a mammal or a human.
    [389] The present invention also provides a process for preparing substituted cyclohexane-1,4-diamine derivatives according to the invention as described in the following detailed description and examples.
    [390] Herein, the cyclohexane-1,4-dione of formula (II) protected by groups S 1 and S 2 is reacted with a cyanide, preferably potassium cyanide, in the presence of a compound of formula HNR 01 R 02 to Obtain an N-substituted 1-amino-4-oxo-cyclohexane-carbonitrile derivative and optionally, subsequently, in any desired order and optionally, repeatedly, acylation, alkylation or sulfonation And / or for compounds wherein R 01 and / or R 02 and / or R 06 are H protected with a protecting group, one or more protecting groups are separated off and optionally acylated, alkylated or sulfonated For compounds wherein R 01 and / or R 02 and / or R 06 are H, introducing one or more protecting groups and optionally performing acylation, alkylation or sulfonation, (a),
    [391] The aminonitrile of formula III is reacted with an organometallic reagent of formula metal-R 3 , preferably a Grignard reagent or an organolithium reagent, to form a compound of formula IVa, optionally, subsequently, in any desired order and , Optionally, repeatedly, acylation, alkylation or sulfonation, and / or in the case of compounds wherein R 01 and / or R 02 and / or R 06 are protected with a protecting group, isolating at least one protecting group And optionally perform acylation, alkylation or sulfonation, and / or for compounds wherein R 01 and / or R 02 and / or R 06 are H, introduce one or more protecting groups, and acylate, alkylate or sulfonate (B) arbitrarily performing
    [392] In the compound of formula IVa, protecting groups S 1 and S 2 are separated off to form a 4-substituted 4-aminocyclohexanone derivative of formula IV, optionally, subsequently, in any desired order and optionally , Repeatedly performing acylation, alkylation or sulfonation, and / or for compounds wherein R 01 and / or R 02 and / or R 06 are protected with a protecting group, isolating one or more protecting groups, Optionally perform acylation, alkylation or sulfonation, and / or for compounds wherein R 01 and / or R 02 and / or R 06 are H, introduce one or more protecting groups and optionally acylation, alkylation or sulfonation. Performing step (c) and
    [393] Reductively amination of the 4-substituted 4-aminocyclohexanone derivative of Formula IVa with a compound of Formula HNR 04 R 05 to form a cyclohexane-1,4-diamine derivative of Formula V; Particularly suitable are the processes for the preparation of the substituted cyclohexane-1, 4-diamine derivatives according to the invention (hereinafter referred to as main processes).
    [394]
    [395] II III
    [396]
    [397] III IVa
    [398]
    [399] IVa IV
    [400]
    [401] IV V
    [402] In Schemes 1-4 above,
    [403] R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 1,
    [404] R 01 and R 02 are each independently of the other H; H protected with a protecting group; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively,
    [405] R 01 and R 02 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 06 CH 2 CH 2 (wherein R 06 is H; protected with a protecting group; each saturated or unsaturated side chain or straight chain) Mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl of mono- or polysubstituted or unsubstituted aryl or heteroaryl, and C 1 -C 3 -alkyl, respectively And are monocyclic or polysubstituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or heteroaryl, each of which is bonded through a ene) or forms a ring of (CH 2 ) 3-6 ,
    [406] R 04 is H protected by a protecting group; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl,
    [407] R 05 is H protected by a protecting group; Unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; And -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is H 2 , R 11 is H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl, R 12 is H; And each unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl; or
    [408] R 04 and R 05 together form a saturated or unsaturated, mono or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms,
    [409] S 1 and S 2 are independently selected from a protecting group or together represent a protecting group, preferably monoacetal.
    [410] Here, alkylation is also understood to mean reductive amination, since it leads to the same result.
    [411] The present invention also preferably provides a 4-aminocyclo of formula VI by reductive amination of cyclohexane-1,4-dione of formula II protected with groups S 1 and S 2 with a compound of formula HNR 04 R 05 To form a hexanone derivative, optionally, subsequently, in any desired order and optionally, repeatedly, to acylation, alkylation or sulfonation, and / or R 04 and / or R 05 to a protecting group For compounds with protected H, one or more protecting groups are separated off, optionally acylated, alkylated or sulfonated, and / or for compounds with R 04 and / or R 05 H, Introducing and optionally performing acylation, alkylation or sulfonation (a),
    [412] Reacting the 4-aminocyclohexanone derivative of formula VI with a cyanide, preferably potassium cyanide, in the presence of a compound of formula HNR 01 R 02 to give a cyclohexanone-nitrile derivative of formula VII, optionally, subsequently , Acylation, alkylation or sulfonation in any desired order and optionally, repeatedly, and / or R 01 and / or R 02 and / or R 04 and / or R 05 and / or R 06 For compounds that are H protected with a protecting group, one or more of the protecting groups are separated off and optionally subjected to acylation, alkylation or sulfonation, and / or R 01 and / or R 02 and / or R 04 and / or R For compounds wherein 05 and / or R 06 is H, introducing one or more protecting groups and optionally performing acylation, alkylation or sulfonation, (b),
    [413] The cyclohexanone-nitrile derivative of formula VII is reacted with an organometallic reagent of formula metal-R 3 , preferably a Grignard reagent or an organolithium reagent, and finally, the protective groups S 1 and S 2 are separated off to form To form a cyclohexane-1,4-diamine derivative of and optionally undergo subsequent acylation, alkylation or sulfonation in any desired order and, optionally, repeatedly, and / or R 01 and / Or in the case of compounds in which R 02 and / or R 04 and / or R 05 and / or R 06 are H protected with a protecting group, one or more protecting groups are separated off and optionally acylated, alkylated or sulfonated And / or for compounds wherein R 01 and / or R 02 and / or R 04 and / or R 05 and / or R 06 are H, introduce one or more protecting groups and optionally perform acylation, alkylation or sulfonation To form a compound of formula (I) Provides a process for the preparation of a cyclohexane-1,4-diamine derivative substituted, according to the invention comprises the step (c) to (hereinafter referred to as the alternative method).
    [414]
    [415] II VI
    [416]
    [417] VI VII
    [418]
    [419] VII V
    [420] In Scheme 5-7 above,
    [421] R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 1,
    [422] R 01 and R 02 are each independently of the other H; H protected with a protecting group; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or heteroaryl, which is bonded through C 1 -C 3 -alkylene, respectively,
    [423] R 01 and R 02 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 06 CH 2 CH 2 (wherein R 06 is H; protected with a protecting group; each saturated or unsaturated side chain or straight chain) Mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl of mono- or polysubstituted or unsubstituted aryl or heteroaryl, and C 1 -C 3 -alkyl, respectively And are monocyclic or polysubstituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or heteroaryl, each of which is bonded through a ene) or forms a ring of (CH 2 ) 3-6 ,
    [424] R 04 is H protected by a protecting group; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl,
    [425] R 05 is H protected by a protecting group; Unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; And -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is H 2 , R 11 is H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl, R 12 is H; And each unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl; or
    [426] R 04 and R 05 together form a saturated or unsaturated, mono or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms,
    [427] S 1 and S 2 are independently selected from a protecting group or together represent a protecting group, preferably monoacetal.
    [428] In both methods above, the protecting group on H in R 01 , R 02 , R 04 , R 05 and / or R 06 is selected from alkyl, benzyl and carbamate, for example FMOC, Z and Boc. desirable.
    [429] In addition, reductive amination in step (d) is preferably carried out in the presence of ammonium formate, ammonium acetate or NaCNBH 3 .
    [430] Also in the main method, instead of reductive amination with HNR 04 R 05 in step (d), it is particularly preferred that the compound of formula IV is reacted with hydroxylamine and the reduction is carried out after oxime formation.
    [431] Also in an alternative method, in step (b) the radicals R 01 in formula HNR 01 R 02 are H and the reaction with cyanide is carried out using TMSCN, optionally, subsequently, a protecting group is introduced onto R 01 . It is desirable to be.
    [432] The invention is further illustrated by the following examples, but the invention is not limited thereto.
    [433] Example
    [434] The following examples are used to illustrate the invention in more detail, but do not limit the scope of the invention.
    [435] The yield of the compound produced is an unoptimized yield.
    [436] All temperatures are uncorrected.
    [437] The term "ether" is diethyl ether, "EE" is ethyl acetate and "MC" is methylene chloride. The term "equivalent" is equivalent to a quantity of substance, "mp" is melting point or melting range, "RT" means room temperature, the term "vol%" means volume%, and the term "wt%" By weight percent, the term "M" is the concentration in mol / L.
    [438] Silica gel 60 (0.040 to 0.063 mm) (manufacturer: E. Nerk from Darmstadt) was used as the stationary phase for column chromatography.
    [439] Thin layer chromatography analysis was performed using HPTLC precoated plates, silica gel 60 F 254 (manufactured by Emerk from Darmstadt).
    [440] The mixing ratio of the mobile phase for chromatographic analysis is always expressed in volume / volume.
    [441] Example 1: N'-benzyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine hydrochloride, nonpolar diastereomer
    [442] 200 mL methanol, 1680 mL (40%) aqueous dimethylamine, 303 g dimethylamine hydrochloride and 200 g calcium cyanide are added to 1,4-dioxa-spiro [4.5] decane-8-one and stirred for about 65 hours. The white suspension obtained is extracted four times with 800 mL of ether each time, the combined extracts are concentrated, then the residue is dissolved in about 500 mL of methylene chloride and the phases are separated. The methylene chloride phase is dried over sodium sulfate, filtered and then concentrated. 265 g of 8-dimethylamino-1,4-dioxa-spiro [4.5] decane-8-carbonitrile was obtained as a white solid.
    [443] 50.0 g of 8-dimethylamino-1,4-dioxa-spiro [4.5] decane-8-carbonitrile is dissolved in 400 mL of analytical grade tetrahydrofuran and 216 mL of a commercially available 2M phenylmagnesium chloride solution in tetrahydrofuran. Was added dropwise under nitrogen atmosphere while cooling in an ice bath, then the mixture was stirred overnight while warming to room temperature. During workup, 200 mL (20% by weight) of ammonium chloride ice cold solution is added with stirring and cooling in an ice bath, and after 30 minutes, the phases are separated. The aqueous phase is extracted with 250 mL of ether each time, the extract is combined with the organic phase and the mixture is washed with 200 mL of water, washed with 200 mL of saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate is concentrated. 60.0 g of dimethyl- (8-phenyl-1,4-dioxa-spiro [4.5] dec-8-yl) -amine are obtained.
    [444] Dilute 165 mL (32% by weight) of hydrochloric acid with 100 mL of water, add 60.0 g of dimethyl- (8-phenyl-1,4-dioxa-spiro [4.5] dec-8-yl) amine to about 6M hydrochloric acid, and then mix Stir for 24 hours. The reaction mixture is washed three times with 50 mL diethyl ether each time, made up of alkali (pH > 10) with 100 mL (32% by weight) of sodium chloride solution, and then extracted three times with 100 mL of methylene chloride each time. The extracts are combined, dried over sodium sulfate, filtered and the filtrate is concentrated. 36.1 g of 4-dimethylamino-4-phenyl-cyclohexanone are obtained.
    [445] 2.00 g of 4-dimethylamino-4-phenyl-cyclohexanone are dissolved in 30 mL of analytical grade tetrahydrofuran, 986 mg of benzylamine is added with stirring in an ice bath, and then 794 μl of glacial acetic acid is added. Then, 2.72 g of sodium triacetoxyborohydride is added in part over 15 minutes, and then the mixture is stirred for about 65 hours. During workup, 15 mL of 2M sodium hydroxide solution is added dropwise (pH> 10) and the mixture is extracted three times with 25 mL of diethyl ether each time. The combined organic phases are then washed twice with 20 mL of water each time, dried over sodium sulfate, filtered and the filtrate is concentrated. The obtained crude product is chromatographed on silica gel using diethyl ether with 1% by volume (25% by weight) of ammonia solution. Obtain 844 mg of N'-benzyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine as a nonpolar diastereomer, dissolved in 6.8 mL of 2-butanone, and 27.1 μL of water were added, 381 μl of chlorotrimethylsilane are added and converted to 843 mg of the corresponding hydrochloride by stirring overnight.
    [446] Example 2: N'-benzyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine hydrochloride, polar diastereomers
    [447] As described in Example 1, 1.01 g of the polar diastereomer of N'-benzyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine was also obtained, and 8.1 mL of 2-butanone Is dissolved in, and 32.5 [mu] l of water are added, then 457 [mu] l of chlorotrimethylsilane is added and converted to 781 mg of the corresponding hydrochloride by stirring overnight.
    [448] Example 3: 1, N'-dibenzyl-N, N-dimethyl-cyclohexane-1,4-diamine hydrochloride, nonpolar diastereomer
    [449] 50.0 g of 8-dimethylamino-1,4-dioxa-spiro [4.5] decane-8-carbonitrile [Example 1] is dissolved in 400 mL of analytical grade tetrahydrofuran and is commercially available in tetrahydrofuran. 214 mL of 2M benzyl magnesium chloride solution is added dropwise under nitrogen atmosphere while cooling in an ice bath, and then the mixture is stirred overnight while warming to room temperature. During workup, 200 mL (20% by weight) of ammonium chloride ice cold solution is added with stirring and cooling in an ice bath, and after 30 minutes, the phases are separated. The aqueous phase is extracted with 250 mL of ether each time, the extract is combined with the organic phase and the mixture is washed with 200 mL of water, washed with 200 mL of saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate is concentrated.
    [450] Dilute 200 mL (32% by weight) of hydrochloric acid with 120 mL of water, add 78.4 g of crude (8-benzyl-1,4-dioxa-spiro [4.5] dec-8-yl) -dimethyl-amine to about 6 M hydrochloric acid, The mixture is stirred for 24 hours. The reaction mixture is washed three times with 100 mL diethyl ether each time, made alkaline (pH> 10) with 100 mL (32% by weight) of sodium chloride solution while cooling in an ice bath and then extracted three times with 100 mL of methylene chloride each time. The extracts are combined, dried over sodium sulfate, filtered and the filtrate is concentrated. 50.4 g of 4-benzyl-4-dimethylamino-cyclohexanone are obtained.
    [451] 2.00 g of 4-benzyl-4-dimethylamino-cyclohexanone are dissolved in 30 mL of analytical grade tetrahydrofuran, 926 mg of benzylamine is added with stirring in an ice bath, and then 794 μl of glacial acetic acid is added. Then, 2.56 g of sodium triacetoxyborohydride is added in part over 15 minutes, and then the mixture is stirred for about 65 hours. During workup, 15 mL of 2M sodium hydroxide solution is added dropwise (pH> 10) and the mixture is extracted three times with 25 mL of diethyl ether each time. The combined organic phases are then washed twice with 20 mL of water each time, dried over sodium sulfate, filtered and the filtrate is concentrated. The obtained crude product is chromatographed on silica gel using diethyl ether with 1% by volume (25% by weight) of ammonia solution. Obtain 774 mg of 1, N'-dibenzyl-N, N-dimethylcyclohexane-1,4-diamine as a nonpolar diastereomer, dissolve in 6.2 mL of 2-butanone, add 23.8 μL of water, and then add chloro 334 [mu] l of trimethylsilane is added and converted to 731 mg of the corresponding hydrochloride by stirring overnight.
    [452] Example 4: 1, N'-dibenzyl-N, N-dimethyl-cyclohexane-1,4-diamine hydrochloride, polar diastereomer
    [453] As described in Example 3, 820 mg of 1, N'-dibenzyl-N, N-dimethylcyclohexane-1,4-diamine as a polar diastereomer was also obtained, dissolved in 6.6 mL 2-butanone and 25.2 μl of water are added followed by 354 μl of chlorotrimethylsilane and converted to 793 mg of the corresponding hydrochloride by stirring overnight.
    [454] Example 5: N- (4-benzyl-4-dimethylamino-cyclohexyl) -N-propyl-benzamide hydrochloride
    [455] 6.00 g of 4-benzyl-4-dimethylamino-cyclohexane [Example 3] were dissolved in 90 mL of analytical grade tetrahydrofuran, 1.53 g of n-propylamine was added while cooling in an ice bath, followed by 3.36 mL of glacial acetic acid. Add. Subsequently, 7.68 g of sodium triacetoxyborohydride is added in portions over 15 minutes, and then the mixture is stirred for about 65 hours. During workup, 45 mL of 2 M sodium hydroxide solution is added dropwise (pH> 10) and the mixture is extracted three times with 50 mL of diethyl ether each time. The combined organic phases are then washed twice with 50 mL of water each time, dried over sodium sulfate, filtered and the filtrate is concentrated. The resulting crude product (6.43 g) is chromatographed on silica gel using diethyl ether with 1% by volume (25% by weight) of ammonia solution. 707 mg of 1-benzyl-N, N-dimethyl-N'-propyl-cyclohexane-1,4-diamine as a nonpolar diastereomer is obtained.
    [456] 700 mg of non-polar diastereomer 1-benzyl-N, N-dimethyl-N'-propyl-cyclohexane-1,4-diamine was dissolved in 10 mL of methylene chloride, 370 μl of triethylamine and DMAP (4-dimethylaminopyridine ) About 10 mg. 311 μl of benzyl chloride was added dropwise while cooling in an ice / methanol bath, then the reaction mixture was stirred overnight while warming to room temperature. During workup, 10 mL of 5M KOH solution and 10 mL of water are added dropwise, the mixture is stirred for 10 minutes, then extracted three times with 20 mL of methylene chloride each time, the combined extracts are dried over magnesium sulfate, and then the filtrate is filtered. Concentrate. From the obtained crude product (834 mg), 909 mg of N- (4-benzyl-4-dimethylamino-cyclohexyl) -N-propyl-benzamide hydrochloride was prepared using an example of water in 2-butanone and chlorotrimethylsilane. Prepared as described in 1.
    [457] Example 6: N, N-dimethyl-1-phenyl-N'-propyl-cyclohexane-1,4-diamine hydrochloride, nonpolar diastereomer
    [458] 10.0 g of 4-dimethylamino-4-phenyl-cyclohexanone are dissolved in 160 mL of analytical grade tetrahydrofuran, 2.72 g of n-propylamine is added while cooling in an ice bath, followed by 5.97 mL of glacial acetic acid. Subsequently, 13.6 g of sodium triacetoxyborohydride is added in portions over 15 minutes, and then the mixture is stirred for about 65 hours. During workup, 85 mL of 2M sodium hydroxide solution is added dropwise (pH> 10) and the mixture is extracted three times with 100 mL of diethyl ether each time. The combined organic phases are then washed twice with 100 mL of water each time, dried over sodium sulfate, filtered and the filtrate is concentrated. 5.00 g of the obtained (9.79 g) crude product is chromatographed on silica gel using diethyl ether with 1% by volume (25% by weight) of ammonia and increasing the methanol addition from 1% by volume to 40% by volume. 2.79 g of nonpolar diastereomer N, N-dimethyl-1-phenyl-N'-propyl-cyclohexane-1,4-diamine and N, N-dimethyl-1-phenyl-N'-propyl polar diastereomer 1.33 g of cyclohexane-1,4-diamine are obtained. From a sample of 356 mg of the nonpolar diastereomer, 253 mg of the corresponding hydrochloride is obtained as described in Example 1 using water in 2-butanone and chlorotrimethylsilane.
    [459] Example 7: N- (4-Dimethylamino-4-phenyl-cyclohexyl) -N-propyl-benzamide hydrochloride, nonpolar diastereomers
    [460] 1.00 g of the nonpolar diastereomer N, N-dimethyl-1-phenyl-N'-propyl-cyclohexane-1,4-diamine (Example 6) was dissolved in 15 mL of methylene chloride and 560 μl triethylamine. And about 10 mg of DMAP. 468 μl of benzyl chloride was added dropwise while cooling in an ice / methanol bath, then the reaction mixture was stirred overnight while warming to room temperature. During workup, 12 mL of 5M KOH solution and 12 mL of water were added dropwise, the mixture was stirred for 10 minutes, then extracted three times with 25 mL of methylene chloride each time, the combined extracts were dried over magnesium sulfate, filtered and the filtrate was filtered. Concentrate. From the obtained crude product (1.31 g), 1.01 mg of N- (4-benzyl-4-dimethylamino-cyclohexyl) -N-propyl-benzamide hydrochloride as a non-polar diastereomer was converted to water and chloro in 2-butanone. Prepared as described in Example 1 using trimethylsilane.
    [461] Example 8: N- (4-Dimethylamino-4-phenyl-cyclohexyl) -N-propyl-benzamide hydrochloride, polar diastereomers
    [462] 1.00 g of the polar diastereomer N, N-dimethyl-1-phenyl-N'-propyl-cyclohexane-1,4-diamine (Example 6) was dissolved in 15 mL of methylene chloride and 560 μl triethylamine. And about 10 mg of DMAP. 468 μl of benzyl chloride was added dropwise while cooling in an ice / methanol bath, then the reaction mixture was stirred overnight while warming to room temperature. During workup, 12 mL of 5M KOH solution and 12 mL of water were added, the mixture was stirred for 10 minutes, then extracted three times with 25 mL of methylene chloride each time, the combined extracts were dried over magnesium sulfate, filtered and the filtrate was concentrated Let's do it. From the obtained product (1.29 g), 752 mg of N- (4-benzyl-4-dimethylamino-cyclohexyl) -N-propyl-benzamide hydrochloride as a polar diastereomer was converted to water and chlorotrimethylsilane in 2-butanone. It is prepared as described in Example 1 using.
    [463] Example 9: 1, N'-dibenzyl-N, N, N'-trimethyl-cyclohexane-1,4-diamine hydrochloride, nonpolar diastereomer
    [464] Dissolve 10.0 g of 4-benzyl-4-dimethylamino-cyclohexanone [Example 3] in 150 mL of analytical grade tetrahydrofuran, add 5.24 g of benzyl-methyl-amine while cooling in an ice bath, and then glacial acetic acid. Add 5.60 mL. Subsequently, 12.8 g of sodium triacetoxyborohydride is added in portions over 15 minutes, and then the mixture is stirred overnight. During workup, 75 mL of 2 M sodium hydroxide solution is added dropwise (pH> 10) and the mixture is extracted three times with 100 mL of diethyl ether each time. The combined organic phases are then washed twice with 100 mL of water each time, dried over sodium sulfate, filtered and the filtrate is concentrated. The obtained crude product (13.1 g) is added with ethyl acetate, with increasing methanol addition to 0 to 100% by weight, and chromatography on silica gel. In addition to the 5.23 g mixed fraction, 5.37 g of the nonpolar diastereomer N, N-dimethyl-1-phenyl-N'-propyl-cyclohexane-1,4-diamine and the N, N-dimethyl-1 polar diastereomer 1.20 g of -phenyl-N'-propyl-cyclohexane-1,4-diamine are obtained. From the nonpolar diastereomers, 5.44 g of the corresponding hydrochloride is obtained as described in Example 1 using water in 2-butanone and chlorotrimethylsilane.
    [465] Example 10 1, N'-dibenzyl-N, N, N'-trimethyl-cyclohexane-1,4-diamine hydrochloride, polar diastereomer
    [466] As described in Example 9, 1.24 g of the corresponding hydrochloride is obtained from 1.20 g of 1, N'-dibenzyl-N, N, N'-trimethyl-cyclohexane-1,4-diamine as a polar diastereomer. .
    [467] Example 11: N- (4-benzyl-4-dimethylamino-cyclohexyl) -N-methyl-benzamide hydrochloride, polar diastereomers
    [468] 15.0 g of 4-benzyl-4-dimethylamino-cyclohexanone [see Example 3] were dissolved in 225 mL of analytical grade tetrahydrofuran, 4.38 g of methylamine hydrochloride, 8.9 mL of triethylamine while cooling in an ice bath. And 8.40 mL glacial acetic acid are added. Subsequently, 19.2 g of sodium triacetoxyborohydride are added in portions over 15 minutes, and then the mixture is stirred overnight. During workup, 110 mL of 2 M sodium hydroxide solution is added dropwise (pH> 10) and the mixture is extracted three times with 200 mL of diethyl ether each time. The combined organic phases are washed twice with 200 mL of water each time, dried over sodium sulfate, filtered and the filtrate is concentrated. The obtained crude product (15.0 g) was chromatographed on silica gel using methanol to which 1 volume% of aqueous ammonia solution (25% by weight) was added. 11.6 g of still highly contaminated product are obtained and chromatographed on silica gel using ethylacetate with increasing methanol from 25% to 50% by volume. 6.67 g of 1-benzyl-N, N, N'-trimethyl-cyclohexane-1,4-diamine are obtained as a cis / trans mixture.
    [469] 3.00 g of 1-benzyl-N, N, N'-trimethyl-cyclohexane-1,4-diamine is dissolved in 50 mL of methylene chloride, and 1.78 mL of triethylamine and about 10 mg of DMAP are added. 1.41 mL of benzoyl chloride is added dropwise while cooling in an ice / methanol bath, then the reaction mixture is stirred overnight while warming to room temperature. During workup, 50 mL of 5M KOH solution and 50 mL of water are added, the mixture is stirred for 10 minutes, then extracted three times with 50 mL of methylene chloride each time, the combined extracts are dried over magnesium sulfate, filtered and the filtrate is concentrated Let's do it. The resulting crude product (3.61 g) is chromatographed on silica gel using methanol / ethanol (1: 1). Obtain 231 mg of the polar diastereomer N- (4-benzyl-4-dimethylamino-cyclohexyl) -N-methyl-benzamide, from which 188 mg of the corresponding hydrochloride is water and chlorotrimethylsilane in 2-butanone It is prepared as described in Example 1 using.
    [470] Example 12 N- (4-benzyl-4-dimethylamino-cyclohexyl) -N-ethyl-benzamide hydrochloride, polar diastereomers
    [471] Dissolve 15.0 g of 4-benzyl-4-dimethylamino-cyclohexanone [Example 3] in 225 mL of analytical grade tetrahydrofuran, add 2.89 g of ethylamine while cooling in an ice bath, and then add 8.40 mL of glacial acetic acid. Add. Subsequently, 19.2 g of sodium triacetoxyborohydride are added in portions over 15 minutes, and then the mixture is stirred overnight. During workup, 110 mL of 2 M sodium hydroxide solution is added dropwise (pH> 10) and the mixture is extracted three times with 200 mL of diethyl ether each time. The combined organic phases are washed twice with 200 mL of water each time, dried over sodium sulfate, filtered and the filtrate is concentrated. The obtained crude product (15.7 g) was chromatographed on silica gel using methanol to which 1 volume% of aqueous ammonia solution (25% by weight) was added. 14.1 g of still contaminated product is obtained and chromatographed on silica gel using methanol to which 1% by volume of aqueous ammonia solution (25% by weight) is added. 12.1 g of 1-benzyl-N'-ethyl-N, N-dimethylcyclohexane-1,4-diamine are obtained as a cis / trans mixture.
    [472] 3.00 g of 1-benzyl-N'-ethyl-N, N-dimethylcyclohexane-1,4-diamine is dissolved in 50 mL of methylene chloride, and 1.68 mL of triethylamine and about 10 mg of DMAP are added. 1.41 mL of benzoyl chloride is added dropwise while cooling in an ice / methanol bath, then the reaction mixture is stirred overnight while warming to room temperature. During workup, 50 mL of 5M KOH solution and 50 mL of water are added, the mixture is stirred for 10 minutes, then extracted three times with 50 mL of methylene chloride each time, the combined extracts are dried over magnesium sulfate, filtered and the filtrate is concentrated Let's do it. The resulting crude product (4.05 g) is chromatographed on silica gel using methanol / ether (1: 1). 1.09 g of N- (4-benzyl-4-dimethylamino-cyclohexyl) -N-ethyl-benzamide, which is a polar diastereomer, is obtained from which 1.01 mg of the corresponding hydrochloride is water and chloro in 2-butanone. Prepared as described in Example 1 using trimethylsilane.
    [473] Example 13: 1-benzyl-N '-(1H-indol-3-ylmethyl) -N, N-dimethylcyclohexane-1,4-diamine dihydrochloride
    [474] 14.5 g of 3-formylindole and 13.9 g of hydroxyamine hydrochloride are heated at a boiling point for 2 hours in a mixture of anhydrous pyridine (80 mL) and anhydrous ethanol (80 mL). Initially the yellow reaction mixture becomes deep red during this time. Thereafter, the solvent mixture is distilled off under vacuum. To remove pyridine, the residue is evaporated to dryness three more times with ethanol (30 mL each time). Then water (100 mL) is added to the residue and the mixture is vigorously stirred for 30 minutes using a magnetic stirrer. The reaction solution with the pink solid formed is cooled in the freezer for 2 hours. The resulting oxyl was filtered off with suction, washed with water (3 x 25 mL) and dried in a drier. 15.6 g of 1H-indole-3-carbaldehyde (Z) -oxime having a melting point of 190 to 193 ° C is obtained.
    [475] 4.8 g of 1H-indole-3-carbaldehyde (Z) -oxy is suspended in methanol (100 mL) (poor solubility) and the suspension is diluted with 5 M sodium hydroxide solution (100 mL). The reactor is always flushed with a gentle stream of argon. Some Devarda alloy (20 g) is added to the mixture. The addition depends on the intensity of the reaction. The mixture is sometimes cooled using ice water. After 2 hours, the addition is terminated, then the mixture is stirred at room temperature for 30 minutes and diluted with water (100 mL). Methanol is removed under vacuum and the aqueous solution is extracted with ether (4 x 50 mL). After drying and distilling off the ether, the residue is purified by recrystallization from toluene (20 mL). 2.2 g of C- (1H-indol-3-yl) -methylamine are obtained as a beige solid (melting point: 90-94 ° C.), which changes color easily in daylight and room temperature. Dark bottles and freezers can be stored for several days.
    [476] 292 mg of C- (1H-indol-3-yl) -methylamine are partially dissolved in anhydrous 1,2-dichloroethane (10 mL) under argon. After addition of 463 mg of 4-benzyl-4-dimethylamino-cyclohexanone [Example 3], glacial acetic acid (4 mmol) and sodium triacetoxyborohydride (550 mg), the suspension is stirred at room temperature for 72 hours. . After workup, water (10 mL) is added to the reaction mixture. The organic phase is separated off and the aqueous phase is extracted twice with ether and then made strongly alkaline using sodium hydroxide solution. The mixture is extracted again with ethyl acetate (4 x 10 mL). Even during processing, a light precipitate precipitates from the combined ethyl acetate phases. After cooling, the precipitate is suction filtered off, washed twice with cold ethyl acetate and then dried. The product obtained in this manner (235 mg) is a white solid (melting point: 194-198 ° C.). 217 mg is dissolved in 2-butanone / ethanol (30 + 10 mL) at high temperature and saturated ethanol hydrochloric acid (1.5 mL; 1.85 M) is added at room temperature with stirring. After 2 hours, no precipitate precipitates. Even after reducing the amount of solvent and cooling, no hydrochloride precipitates. Thus, the mixture is evaporated to dryness at 40 ° C. under vacuum and excess HCl is removed. 260 mg of 1-benzyl-N '-(1H-indol-3-ylmethyl) -N, N-dimethylcyclohexane-1,4-diamine dihydrochloride as a residue a pale pink solid (melting point: 170 to 174 ° C) To obtain.
    [477] Example 14 1-benzyl-N '-[2- (1H-indol-3-yl) -1-methylethyl] -N, N-dimethylcyclohexane-1,4-diamine, cis / trans mixture
    [478] 348 mg of DL-α-methyltryptamine was dissolved in anhydrous 1,2-dichloroethane (10 mL) under argon (clear solution), 463 mg of 4-benzyl-4-dimethylamino-cyclohexane [Example 3], and Glacial acetic acid (229 μl) is added and the mixture is stirred at room temperature for 1 hour. Then 550 mg sodium triacetoxyborohydride are added and the suspension is stirred for an additional 72 hours at room temperature. During workup, water (20 mL) is added to the reaction mixture, the organic phase is separated off and the aqueous phase is extracted once with ether and made strongly alkaline (pH> 10) using sodium hydroxide solution. The gelatinous precipitate is precipitated by dissolving ethyl acetate. The aqueous phase is extracted with ethyl acetate (4 x 10 mL). All ethyl acetate phases are combined, dried over sodium sulphate and then concentrated to dryness. 766 mg of cis and trans-1-benzyl-N '-[2- (1H-indol-3-yl) -1-methylethyl] -N, N-dimethylcyclohexane-1,4-diamine were dissolved in a glassy solid (melting point: 48 to 53 ° C).
    [479] Example 15 1-benzyl-N'-indan-5-yl-N, N-dimethyl-cyclohexane-1,4-diamine dihydrochloride
    [480] 266 mg of 5-aminoindane and 462 mg of 4-benzyl-4-dimethylamino-cyclohexanone (see Example 3) were dissolved in anhydrous 1,2-dichloroethane under argon and used for 2 hours at room temperature using 2 g of sodium sulfate. Stirring 600 mg sodium triacetoxyborohydride is added to the mixture and the mixture is stirred at room temperature for 2 hours. During workup, the reaction mixture is concentrated and the residue is adjusted to pH 11 with 5M sodium hydroxide solution. The alkaline phase is diluted with water (10 mL) and extracted with ethyl acetate (4 x 20 mL). The combined extracts are dried over anhydrous sodium sulfate, filtered and the filtrate is concentrated. The crude product is chromatographed on silica gel using ethyl acetate. 440 mg of 1-benzyl-N'-indan-5-yl-N, N-dimethylcyclohexane-1,4-diamine are obtained as a colorless oil. To precipitate the hydrochloride, the base is dissolved in 2-butanone (8 mL) and 1.85 M ethanol hydrochloric acid (1.75 mL) is added. The precipitated solid is filtered off with suction and dried. 280 mg of 1-benzyl-N'-indan-5-yl-N, N-dimethylcyclohexane-1,4-diamine-hydrochloride are obtained as a white solid (melting point: 200 to 203 ° C).
    [481] Example 16: 1-benzyl-N'-indan-1-yl-N, N-dimethyl-cyclohexane-1,4-diamine dihydrochloride, cis / trans mixture
    [482] 266 mg of 1-aminoindane and 462 mg of 4-benzyl-4-dimethylamino-cyclohexanone (see Example 3) are dissolved in anhydrous 1,2-dichloroethane under argon, and the solution is dissolved at room temperature using 2 g of sodium sulfate. Stir for 24 hours 600 mg sodium triacetoxyborohydride is added to the mixture and the mixture is stirred at room temperature for 2 hours. During workup, the reaction mixture is concentrated and the residue is adjusted to pH 11 with 5M sodium hydroxide solution. The alkaline phase is diluted with water (10 mL) and extracted with ethyl acetate (4 x 20 mL). The combined extracts are dried over anhydrous sodium sulfate, filtered and the filtrate is concentrated. The crude product is chromatographed on silica gel using ethyl acetate. 696 mg of 1-benzyl-N'-indan-1-yl-N, N-dimethylcyclohexane-1,4-diamine are obtained as a colorless oil. To precipitate the hydrochloride, the base is dissolved in 2-butanone (10 mL) and 1.85 M ethanol hydrochloric acid (2.80 mL) is added. The precipitated solid is filtered off with suction and dried. Cis-1-benzyl-N'-indan-1-yl-N, N-dimethyl-cyclohexane-1,4-diamine dihydrochloride and trans-1-benzyl-N'-indan-1-yl-N, 540 mg of a mixture of N-dimethyl-cyclohexane-1,4-diamine dihydrochloride is obtained as a white solid (melting point: 170 to 172 ° C).
    [483] Example 17 N'-indan-1-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine
    [484] 266 mg of 1-aminoindane and 434 mg of 4-dimethylamino-4-phenyl-cyclohexanone are dissolved in anhydrous 1,2-dichloroethane (10 mL) and THF (10 mL) under argon. Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) are added to the mixture and the mixture is stirred at room temperature for 24 hours. During workup, the reaction mixture is concentrated and the residue is adjusted to pH 11 with 5M sodium hydroxide solution. The alkaline phase is diluted with water (10 mL) and extracted with ethyl acetate (5 x 20 mL). The combined extracts are dried over anhydrous sodium sulfate, filtered and the filtrate is concentrated. The crude product is chromatographed on silica gel using ethyl acetate / ethanol (1: 1). 200 mg of N'-indan-1-yl-N, N-dimethyl-1-cyclohexane-1,4-diamine are obtained as a white solid (melting point: 99-101 ° C.).
    [485] Example 18 N '-(1H-indol-5-yl) -N, N-dimethyl-1-phenylcyclohexane-1,4-diamine
    [486] 264 mg of 5-aminoindane and 434 mg of 4-dimethylamino-4-phenyl-cyclohexanone are dissolved in anhydrous 1,2-dichloroethane under argon. Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) are added to the mixture and the mixture is stirred at room temperature for 24 hours. During workup, the mixture is concentrated and the residue is adjusted to pH 11 with 5M sodium hydroxide solution. The alkaline phase is diluted with water (10 mL) and extracted with ethyl acetate (4 x 20 mL). The combined extracts are dried over anhydrous sodium sulfate, filtered and the filtrate is concentrated. The crude product is chromatographed on silica gel using ethyl acetate / ethanol (1: 1). 315 mg of N '-(1H-indol-5-yl) -N, N-dimethyl-1-phenylcyclohexane-1,4-diamine are obtained as a white solid (melting point: 191 to 192 ° C).
    [487] Example 19 N '-(1H-indol-3-ylmethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, cis / trans mixture
    [488] 292 mg of C- (1H-indol-3-yl) methylamine are dissolved in anhydrous 1,2-dichloroethane (15 mL) and THF (5 mL) under argon to give an almost clear solution. After addition of 4-dimethylamino-4-phenylcyclohexane (435 mg), glacial acetic acid (4 mmol) and sodium triacetoxyborohydride (550 mg), a suspension is present and stirred for 72 hours at room temperature. During workup, water (20 mL) is added to the reaction mixture and the mixture is stirred vigorously for 1 hour. The organic phase is separated off and the aqueous phase is extracted twice with ether (10 mL) and then made strongly alkaline using 5 M sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate (4 x 10 mL). The solid is dissolved in ethyl acetate (50 mL) at elevated temperature, which precipitates out. The combined extracts are dried over sodium sulfate, filtered and the filtrate is concentrated. The crude product obtained (382 mg) is recrystallized from a mixture of ethanol (1 mL) and ethyl acetate (5 mL). The precipitate is suction filtered off and washed with some cold ethyl acetate. 156 mg of N '-(1H-indol-3-ylmethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine are obtained as a cis / trans mixture.
    [489] Example 20 N '-(1H-indol-3-ylmethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, nonpolar diastereomer
    [490] The mother liquor obtained in Example 19 is concentrated. 173 mg (melting point: 170-178 ° C.) of N ′-(1H-indol-3-ylmethyl) -N, N′-dimethyl-1-phenyl-cyclohexane-1,4-diamine as non-polar diastereomers are obtained .
    [491] Example 21 N '-[2- (1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, nonpolar diastereomer
    [492] Tryptamine (320 mg) is dissolved in anhydrous 1,2-dichloroethane (10 mL) under argon. After addition of 4-dimethylamino-4-phenylcyclohexane (435 mg), glacial acetic acid (229 μl) and sodium triacetoxyborohydride (550 mg), the suspension is stirred at room temperature for 3 hours. During workup, water (20 mL) is added to the reaction mixture. The organic phase is separated off and the aqueous phase is extracted once with ether and then made strongly alkaline with sodium hydroxide solution. The aqueous phase was whitish at pH 10. The aqueous phase is extracted with ethyl acetate (4 x 10 mL), the extracts are combined, dried over sodium sulfate, dried and concentrated to dryness. The obtained crude product (674 mg) is recrystallized twice from ethyl acetate (5 mL). 22 mg of N '-[2- (1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine as a nonpolar diastereomer (melting point: 134-138 ° C.) ).
    [493] Example 22 N '-[2- (1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, cis / trans mixture
    [494] As described in Example 21, 320 mg of N '-[2- (1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine (melting point) : 149-153 ° C.) are obtained as a mixture of cis / trans isomers.
    [495] Example 23 N'-indan-5-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, nonpolar diastereomer
    [496] 5-aminoindane (266 mg) and 4-dimethylamino-4-phenylcyclohexanone (434 mg) are dissolved in anhydrous 1,2-dichloroethane (10 mL) under argon. Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) are added and the mixture is stirred at room temperature for 24 hours. During workup, the reaction mixture is concentrated and the residue is adjusted to pH 11 with 5M sodium hydroxide solution. The alkaline phase is diluted with water (10 mL) and extracted with ethyl acetate (4 x 20 mL). The combined extracts are dried over sodium sulfate, filtered and the filtrate is concentrated. The obtained crude product is chromatographed on silica gel using ethyl acetate / ethanol (1: 1). 270 mg of the nonpolar diastereomer N'-indan-5-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine is obtained as a white solid (melting point: 162 to 164 ° C).
    [497] Example 24 N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, nonpolar diastereomer
    [498] DL-α-methyltryptamine (348 mg, 2 mmol) is dissolved in anhydrous 1,2-dichloroethane (10 mL) under argon. 4-Dimethylamino-4-phenylcyclohexanone (435 mg) and glacial acetic acid (229 μl) are added, and then the mixture is stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (550 mg) is then added and the suspension is stirred for 4 days at room temperature. During workup, water (15 mL) is added to the reaction mixture. The clear phase is separated and the aqueous phase is washed with ether (10 mL) and then made strongly alkaline using sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate (4 x 10 mL) and the combined extracts are dried over sodium sulphate and then filtered and the filtrate is concentrated. The resulting crude product (723 mg) is recrystallized twice with an ethyl acetate / cyclohexane (2 mL / 6 mL) mixture. Non-polar diastereomer N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine fraction (128 mg, Melting point: 155 to 162 ° C.).
    [499] Example 25 N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, cis / trans mixture
    [500] 375 mg N '-[2- (1H-indol-3-yl) -methyl-ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine as described in Example 24 Is obtained as a mixture of cis / trans isomers (dark yellow oil).
    [501] Example 26 N '-[2- (5-benzyloxy-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, cis / trans mixture
    [502] 5-benzyloxytryptamine (440 mg, 1.65 mmol) is dissolved in 1,2-dichloroethane (14 mL) under argon (slight cloudy solution). After adding 4-dimethylamino-4-phenylcyclohexanone (359 mg, 1.65 mmol) and glacial acetic acid (189 μl, 3.3 mmol), the mixture is stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (462 mg) is then added and the suspension is stirred for 4 days at room temperature. During workup, water (15 mL) is added to the reaction mixture. The phases are separated and the aqueous phase is washed with ether (20 mL) and then made strongly alkaline with sodium hydroxide solution. The aqueous phase is extracted with ether (2 × 10 mL) and ethyl acetate (4 × 10 mL), the combined extracts are dried over sodium sulphate and then filtered and the filtrate is concentrated. The resulting crude product (686m) is recrystallized from a mixture of ethyl acetate / cyclohexane (35 mL / 5 mL). 396 mg of N '-[2- (5-benzyloxy-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine was dissolved in a cis / trans mixture (melting point : 130 to 134 ° C).
    [503] Example 27 N '-(9H-Fluoren-1-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride
    [504] 1-aminofluorene (181 mg, 1 mmol) and 4-dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmol) are dissolved in anhydrous 1,2-dichloroethane (10 mL) under argon. Glacial acetic acid (1 mmol) and sodium triacetoxyborohydride (300 mg) are added to the mixture and the mixture is stirred at room temperature for 24 hours. During workup, the mixture is concentrated and the residue is adjusted to pH 11 with 5M sodium hydroxide solution. The alkaline phase is diluted with water (10 mL) and extracted with ethyl acetate (4 x 20 mL). The combined extracts are dried over sodium sulfate, filtered and the filtrate is concentrated. The crude product is chromatographed on silica gel using ethyl acetate / ethanol (1: 1). 200 mg of N '-(9-fluoren-1-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a colorless oil, and 2-butanone ( 5 mL), then 1.85 M ethanol HCl (0.7 mL) is added. The resulting N '-(9H-fluoren-1-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride was suction filtered off and dried (220 mg, melting point: 223 to 225 ° C).
    [505] Example 28 N'-indan-2-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, cis / trans mixture
    [506] 2-aminoindane (266 mg, 2 mmol) and 4-dimethylamino-4-phenylcyclohexanone (434 mg, 2 mmol) are dissolved in anhydrous 1,2-dichloroethane (10 mL) under argon. Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) are added to the mixture and the mixture is stirred at room temperature for 24 hours. During workup, the mixture is concentrated and the residue is adjusted to pH 11 with 5M sodium hydroxide solution. The alkaline phase is diluted with water (10 mL) and extracted with ethyl acetate (4 x 20 mL). The combined extracts are dried over sodium sulfate, filtered and the filtrate is concentrated. The crude product is chromatographed on silica gel using ethyl acetate / ethanol (1: 1). 490 mg of N'-indan-2-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine was obtained as a white solid and dissolved in 2-butanone (10 mL) to prepare hydrochloride. Next, 1.85 M ethanol HCl (2 mL) is added. Cis-N'-indan-2-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride and trans-N'-indan-2-yl-N, N-dimethyl- The mixture with 1-phenyl-cyclohexane-1,4-diamine dihydrochloride is suction filtered off and dried (540 mg, melting point: 224-226 ° C.).
    [507] Example 29 N '-(9H-Fluoren-9-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, cis / trans mixture
    [508] 9-aminofluorene (362 mg, 2 mmol) and 4-dimethylamino-4-phenylcyclohexanone (434 mg, 2 mmol) are dissolved in anhydrous 1,2-dichloroethane (10 mL) under argon. Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) are added to the mixture and the mixture is stirred at room temperature for 24 hours. During workup, the mixture is concentrated and the residue is adjusted to pH 11 with 5M sodium hydroxide solution. The alkaline phase is diluted with water (10 mL) and extracted with ethyl acetate (5 x 20 mL). The combined extracts are dried over sodium sulfate, filtered and the filtrate is concentrated. The crude product is chromatographed on silica gel using ethyl acetate / ethanol (1: 1). 440 mg of N '-(9H-fluoren-9-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine was obtained as a white oil, and 2-butanone ( 10 mL), then 1.85 M ethanol HCl (1.55 mL) is added. The mixture of N '-(9H-fluoren-9-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride is filtered off with suction and dried (460 mg, melting point: 202 to 205 ° C).
    [509] Example 30 1-benzyl-N '-(9H-fluoren-9-yl) -N, N-dimethyl-cyclohexane-1,4-diamine
    [510] 1-aminofluorene (181 mg, 1 mmol) and 4-dimethylamino-cyclohexanone (231 mg, 1 mmol) are dissolved in anhydrous 1,2-dichloroethane (10 mL) under argon. Glacial acetic acid (1 mmol) and sodium triacetoxyborohydride (300 mg) are added to the mixture and the mixture is stirred at room temperature for 24 hours. During workup, the mixture is concentrated and the residue is adjusted to pH 11 with 5M sodium hydroxide solution. The alkaline phase is diluted with water (10 mL) and extracted with ethyl acetate (4 x 20 mL). The combined extracts are dried over sodium sulfate, filtered and the filtrate is concentrated. The crude product is chromatographed on silica gel using ethyl acetate / ethanol (1: 1). 150 mg of 1-benzyl-N '-(9H-fluoren-9-yl) -N, N-dimethyl-cyclohexane-1,4-diamine are obtained as a white solid (melting point: 123 to 125 ° C).
    [511] Example 31 1-benzyl-N '-(1H-indol-3-ylmethyl) -N, N-dimethyl-cyclohexane-1,4-diamine, cis / trans mixture
    [512] 292 mg of C- (1H-indol-3-yl) -methylamine are dissolved in anhydrous 1,2-dichloroethane (10 mL) under argon. After addition of 463 mg of 4-benzyl-4-dimethylamino-cyclohexane (Example 3), glacial acetic acid (4 mmol) and sodium triacetoxyborohydride (550 mg), the suspension is stirred at room temperature for 72 hours. During workup, water (10 mL) is added to the reaction mixture. The organic phase is separated off and the aqueous phase is extracted twice with ether and then made strongly alkaline using sodium hydroxide solution. Extract again with ethyl acetate (4 x 10 mL). The pale colored precipitate is precipitated from the combined ethyl acetate phases even during production. After cooling, the precipitate is suction filtered off, washed twice with cold ethyl acetate and then dried. 235 mg (melting point: 194-198 ° C.) of 1-benzyl-N ′-(1H-indol-3-ylmethyl) -N, N-dimethyl-cyclohexane-1,4-diamine are obtained as a cis / trans mixture.
    [513] Example 32: N, N-dimethyl-N '-(1-methyl-1H-indol-3-ylmethyl) -1-phenyl-cyclohexane-1,4-diamine, cis / trans mixture
    [514] 450 mg of C- (1H-indol-3-yl) -methylamine are dissolved in anhydrous 1,2-dichloroethane (10 mL) under argon. After adding 609 mg of 4-dimethylamino-4-phenylcyclohexane, glacial acetic acid (5.6 mmol), sodium sulfate (2 g) and sodium triacetoxyborohydride (770 mg), the suspension is stirred at room temperature for 5 days. During workup, water (20 mL) is added to the reaction mixture. The organic phase is separated off and the aqueous phase is washed twice with ether (5 mL) and then made strongly alkaline with sodium hydroxide solution. Extract with ether (2 x 5 mL) and ethyl acetate (4 x 10 mL), combine the combined extracts with sodium sulfate, filter and concentrate the filtrate. The crude product obtained is chromatographed on silica gel using methanol / triethylamine (100: 1). 52 mg of N, N-dimethyl-N '-(1-methyl-1H-indol-3-ylmethyl) -1-phenyl-cyclohexane-1,4-diamine are obtained as a cis / trans mixture.
    [515] Example 33: N, N-dimethyl-N '-(1-methyl-1H-indol-3-ylmethyl) -1-phenyl-cyclohexane-1,4-diamine, polar diastereomer
    [516] As described in Example 32, the polar diastereomer N, N-dimethyl-N '-(1-methyl-1H-indol-3-ylmethyl) -1-phenyl-cyclohexane-1,4- 106 mg of diamine are also obtained.
    [517] Example 34 N '-(2-benzo [b] thiophen-3-yl-ethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, cis / trans mixture
    [518] Lithium aluminum hydroxide (1.16 g, 30.3 mmol) is suspended in anhydrous diethyl ether (100 mL). Anhydrous aluminum chloride (4.04 g, 30.3 mmol) is added to the suspension under argon. After 5 minutes, a benzo [b] thiophene-3-acetonitrile solution (5.25 g, 30.3 mmol) in anhydrous diethyl ether (70 mL) is added. After the addition is complete, the mixture is heated at reflux for 4 days. Lithium aluminum hydroxide (930 mmol) and aluminum chloride (500 mg) are added again to the reaction mixture and the mixture is heated under reflux for an additional 8 hours. During workup, it is neutralized with an aqueous solution of potassium sodium tartrate (80 mL, 20% by weight). Once gas evolution is complete, the phases are separated and the cloudy aqueous phase is suction filtered off through a glass frit. The residue on the frit is washed with ethyl acetate and the clear aqueous phase is extracted with ethyl acetate (3 x 50 mL). The organic phase is dried over sodium sulfate, filtered and the filtrate is concentrated. Crude benzo [b] thiophen-3-ylethylamine (3.7 g) is obtained as reddish brown oil. Treatment with methanolic hydrochloric acid yields a viscous hydrochloride, which is immediately converted back to the free base. 794 mg (15%) of benzo [b] thiophen-3-ylethylamine are obtained as a yellow oil, which is used in further synthesis.
    [519] Benzo [b] thiophen-3-ylethylamine (289 mg, 1.6 mmol) was dissolved in anhydrous 1,2-dichloroethane (10 mL) under argon and 4-dimethylamino-4-phenylcyclohexanone (354 mg, 1.6 mmol) and sodium sulfate (2 g) are added, and then the mixture is stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (440 mg, 2.0 mmol) is then added in part to the reaction mixture. After 3 days, glacial acetic acid (4 mmol) is added and the mixture is stirred for an additional 24 hours at room temperature. During workup, water (20 mL) is added and the reaction mixture is suction filtered. The obtained solid is dissolved in 2M sodium carbonate solution and ethyl acetate. The organic phase is separated off, dried over sodium sulfate, filtered and the filtrate is concentrated. A solid other than the obtained (213 mg) viscous residue was dissolved in 2-butanone (5 mL) and ethanol HCl (500 μl, 1.5 mmol) was added at room temperature. After 2 hours, the solution is concentrated to dryness and the residue is suspended in diethyl ether (5 mL), then filtered off with suction and washed with diethyl ether (3 x 3 mL). Cis-N '-(2-benzo [b] thiophen-3-yl-ethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride and trans-N'-( 2-benzo [b] thiophen-3-yl-ethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride (217 mg, melting point: 164 to 167 ° C.) was beige- Obtained as a brown solid.
    [520] Example 35 N '-(2-benzo [b] thiophen-3-yl-ethyl) -1-benzyl-N, N-dimethyl-cyclohexane-1,4-diamine dihydrochloride, cis / trans mixture
    [521] Benzo [b] thiophen-3-ylethylamine (350 mg, 1.9 mmol) was dissolved in anhydrous 1,2-dichloroethane (10 mL) under argon and 4-benzyl-4-dimethylamino-cyclohexanone (463 mg, 2 mmol), glacial acetic acid (2 mmol) and anhydrous sodium sulfate (2 g) are added, and then the mixture is stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (550 mg, 2.5 mmol) is then added in one portion and the mixture is stirred at room temperature for 4 days. During workup, the mixture is diluted with 1,2-dichloroethane (10 mL) and water (15 mL). Residual precipitate (379 mg, melting point: 225 to 233 ° C.) is suction filtered off. The aqueous phase is extracted and adjusted to pH 11 with 5 M sodium hydroxide solution and ethyl acetate to give 353 mg of yellow oil. From the amount of two portions, dissolved with dilute hydrochloric acid, extracted with diethyl ether (2 x 15 mL), the aqueous phase was adjusted to pH 11 with 5 M sodium hydroxide solution, and the crude product isolated (438 mg, viscous oil) By extraction with ethyl acetate (3 × 20 mL). 366 mg of the obtained diastereomeric mixture is dissolved in 2-butanone (30 mL), and ethanol hydrochloric acid (847 mu l, 2.8 mmol) is added at room temperature. A precipitate forms, which quickly dissolves again and precipitates again for the post-stirring time (4 days at room temperature). After an additional 3 minutes in the freezer, the precipitate is suction filtered off, washed with cold 2-butanone (3 x 3 mL) and dried. The pale yellow solid obtained was cis-N '-(2-benzo [b] thiophen-3-yl-ethyl) -1-benzyl-N, N-dimethyl-cyclohexane-1,4-diamine dihydrochloride and trans -N '-(2-benzo [b] thiophen-3-yl-ethyl) -1-benzyl-N, N-dimethyl-cyclohexane-1,4-diamine dihydrochloride (338 mg, melting point: 225 to 229) ° C).
    [522] Example 36 N'-acenaphthen-1-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomers
    [523] 339 mg of acenaphthen-1-ylamine and 435 mg of 4-dimethylamino-4-phenyl-cyclohexanone are dissolved in anhydrous 1,2-dichloroethane (20 mL) under argon. 600 mg glacial acetic acid (2 mmol) and sodium triacetoxyborohydride are added to the mixture and the mixture is stirred at room temperature for 24 hours. During workup, the reaction mixture is concentrated and the residue is adjusted to pH 11 with 5M sodium hydroxide solution. The alkaline phase is diluted with water (10 mL) and extracted with ethyl acetate (4 x 20 mL). The combined extracts are dried over sodium sulphate, filtered and then concentrated. The crude product is chromatographed on silica gel using ethyl acetate / ethanol (1: 1). 130 mg of the polar diastereomer N'-acenaphthen-1-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine are obtained as a white solid and the corresponding dihydrochloride is 2-butanone ( 5 mL) is precipitated using 1.85 M ethanol hydrochloric acid (0.5 mL) (151 mg, melting point: 214-216 ° C.).
    [524] Example 37 N'-acenaphthen-1-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer
    [525] As described in Example 36, 250 mg of the nonpolar diastereomer N'-acenaphthen-1-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine are also obtained as a white solid The corresponding dihydrochloride is precipitated using 1.85 M ethanol hydrochloric acid (0.9 mL) in 2-butanone (10 mL) (300 mg, melting point: 190-192 ° C.).
    [526] Example 38 N'-benzo [b] thiophen-5-yl-1-benzyl-N, N-dimethyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer
    [527] 300 mg of 5-aminobenzothiophene and 463 mg of 4-benzyl-4-dimethylamino-cyclohexanone are dissolved in anhydrous 1,2-dichloroethane (20 mL) under argon. 600 mg glacial acetic acid (2 mmol) and sodium triacetoxyborohydride are added to the mixture and the mixture is stirred at room temperature for 24 hours. During workup, the reaction mixture is concentrated and the residue is adjusted to pH 11 with 5M sodium hydroxide solution. The alkaline phase is diluted with water (10 mL) and extracted with ethyl acetate (6 x 20 mL). The combined extracts are dried over sodium sulfate, filtered and the filtrate is concentrated. The crude product is chromatographed on silica gel using ethyl acetate / ethanol (1: 1). 520 mg of the nonpolar diastereomer N'-benzo [b] thiophen-5-yl-N, N-dimethyl-cyclohexane-1,4-diamine is obtained as a white solid and the corresponding dihydrochloride is 2-butanone. Precipitates (621 mg, melting point: 140-142 ° C.) using 1.85 M ethanol hydrochloric acid (1.93 mL) in (15 mL).
    [528] Example 39 N'-benzo [b] thiophen-5-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer
    [529] 300 mg of 5-aminobenzothiophene and 435 mg of 4-benzyl-4-dimethylamino-cyclohexanone are dissolved in anhydrous 1,2-dichloroethane (20 mL) under argon. 600 mg glacial acetic acid (2 mmol) and sodium triacetoxyborohydride are added to the mixture and the mixture is stirred at room temperature for 24 hours. During workup, the reaction mixture is concentrated and the residue is adjusted to pH 11 with 5M sodium hydroxide solution. The alkaline phase is diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts are dried over sodium sulfate, filtered and the filtrate is concentrated. The crude product is chromatographed on silica gel using ethyl acetate / ethanol (1: 1). 230 mg of a nonpolar diastereomer N'-benzo [b] thiophen-5-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine are obtained as a white solid and the corresponding dihydrochloride is Precipitates using 2.85 M ethanol hydrochloric acid (0.54 mL) in 2-butanone (8 mL) (243 mg, melting point: 155-157 ° C.).
    [530] Example 40 N'-benzothiazol-6-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer
    [531] 300 mg of 6-aminobenzothiazole and 435 mg of 4-dimethylamino-4-phenyl-cyclohexanone are dissolved in anhydrous 1,2-dichloroethane (20 mL) under argon. 600 mg glacial acetic acid (2 mmol) and sodium triacetoxyborohydride are added to the mixture and the mixture is stirred at room temperature for 24 hours. During workup, the reaction mixture is concentrated and the residue is adjusted to pH 11 with 5M sodium hydroxide solution. The alkaline phase is diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts are dried over sodium sulfate, filtered and the filtrate is concentrated. The crude product is chromatographed on silica gel using ethyl acetate / ethanol (1: 1). 220 mg of the nonpolar diastereomer N'-benzothiazol-6-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine is obtained as a yellow solid and the corresponding dihydrochloride is 2-butane Precipitates using 1.85 M ethanol hydrochloric acid (0.83 mL) in warm (10 mL) (197 mg, melting point: 144-147 ° C.).
    [532] Example 41 N'-Benzo [1,2,5] thiadiazol-4-yl-N, N-dimethyl-1-phenyl-cyclohexane-1, 4-diamine dihydrochloride, polar diastereomers
    [533] 302 mg of benzo [1,2,5] thiadiazol-4-ylamine and 435 mg of 4-dimethylamino-4-phenyl-cyclohexanone are dissolved in anhydrous 1,2-dichloroethane (20 mL) under argon. 600 mg glacial acetic acid (2 mmol) and sodium triacetoxyborohydride are added to the mixture and the mixture is stirred at room temperature for 24 hours. During workup, the reaction mixture is concentrated and the residue is adjusted to pH 11 with 5M sodium hydroxide solution. The alkaline phase is diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts are dried over sodium sulfate, filtered and the filtrate is concentrated. The crude product is chromatographed on silica gel using ethyl acetate / ethanol (1: 1). 40 mg of a nonpolar diastereomer N'-benzo [1,2,5] thiadiazol-4-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine is obtained as a red solid, The corresponding hydrochloride is precipitated using 1.85 M ethanol hydrochloric acid (0.15 mL) in 2-butanone (2 mL) (35 mg, melting point: 122-125 ° C.).
    [534] Example 42 N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar Diastereomers
    [535] DL-α-methyltryptamine (3.00 g, 17.2 mmol) is dissolved in anhydrous 1,2-dichloroethane (10 mL) under argon. After addition of 4-dimethylamino-4-phenyl-cyclohexanone (3.70 g) and glacial acetic acid (1.5 mL), the mixture is stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (4.7 g) is then added and the suspension is stirred at room temperature for 4 days. During workup, 1,2-dichloroethane (20 mL) and water (50 mL) are added to the reaction mixture. The clear phase is separated and the aqueous phase is washed with ether (2 × 20 mL) and then made strongly alkaline using 5 M sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate (5 x 30 mL) and the combined extracts are dried over sodium sulphate and then filtered and the filtrate is concentrated. The crude product obtained (5.8 g of a beigeish brown solid) was first coarsely fractionated with silica gel using methanol / triethylamine (199: 1) and then finely purified again. 1.20 g of nonpolar diastereomer N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine (melting point) : 158 to 160 ° C.). From 1 g of the compound, the corresponding dihydrochloride is precipitated using chlorotrimethylsilane (840 μL) in 2-butanol / acetone (100 mL / 30 mL) (977 mg, melting point: 170-174 ° C.).
    [536] Example 43 N'-adamantan-2-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride
    [537] 302 mg of 2-adamantylamine and 434 mg of 4-dimethylamino-4-phenyl-cyclohexanone are dissolved in anhydrous tetrahydrofuran (15 mL) and 1,2-dichloroethane (5 mL) under argon. Sodium triacetoxyborohydride (600 mg) is added to the mixture and the mixture is stirred at room temperature for 23 hours. During workup, the reaction mixture is concentrated and the residue is adjusted with 1M hydrochloric acid (20 mL) and ether (40 mL). The aqueous phase is washed with ether (2 x 20 mL), rendered alkaline with 5 M sodium hydroxide solution and then extracted with ether (3 x 30 mL). The combined extracts are dried over sodium sulfate, filtered and the filtrate is concentrated. The crude product is chromatographed on silica gel using ethyl acetate / methanol (4: 1). 130 mg of N'-adamantan-2-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine are obtained as a beige solid and the corresponding dihydrochloride decomposed upon heating at 237 ° C. ( 132 mL) is precipitated using 3.3 M ethanol hydrochloric acid (0.34 mL) in 2-butanone (6 mL).
    [538] Example 44 N '-(9-ethyl-9H-carbazol-3-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1, 4-diamine dihydrochloride, nonpolar diastereomer
    [539] 421 mg of 3-amino-9-ethylcarbazole and 435 mg of 4-dimethylamino-4-phenyl-cyclohexanone are dissolved in anhydrous 1,2-dichloroethane (20 mL) under argon. 600 mg glacial acetic acid (2 mmol) and sodium triacetoxyborohydride are added to the mixture and the mixture is stirred at room temperature for 24 hours. During workup, the reaction mixture is concentrated and the residue is adjusted to pH 11 with 5M sodium hydroxide solution. The alkaline phase is diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts are dried over sodium sulfate, filtered and the filtrate is concentrated. The crude product is chromatographed on silica gel using ethyl acetate / ethanol (1: 1). 288 mg of the nonpolar diastereomer N '-(9-ethyl-9H-carbazol-3-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine is obtained as a brown solid and the corresponding The dihydrochloride salt is precipitated using 1.85 M ethanol hydrochloric acid (0.95 mL) in 2-butanone (10 mL) (339 mg, melting point: 145-150 ° C.).
    [540] Example 45 N '-(3H-benzotriazol-5-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine hydrochloride, nonpolar diastereomer
    [541] 268 mg of 5-aminobenzotriazole and 435 mg of 4-dimethylamino-4-phenyl-cyclohexanone are dissolved in anhydrous 1,2-dichloroethane (20 mL) under argon. 600 mg glacial acetic acid (2 mmol) and sodium triacetoxyborohydride are added to the mixture and the mixture is stirred at room temperature for 24 hours. During workup, the reaction mixture is concentrated and the residue is adjusted to pH 11 with 5M sodium hydroxide solution. The alkaline phase is diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts are dried over sodium sulfate, filtered and the filtrate is concentrated. The crude product is chromatographed on silica gel using ethyl acetate / ethanol (1: 1). 135 mg of a nonpolar diastereomer N '-(3H-benzotriazol-5-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine are obtained as a white solid and the corresponding hydrochloride is Precipitates (98 mg, melting point: 168-173 ° C.) using 1.85 M ethanol hydrochloric acid (0.54 mL) in 2-butanone (5 mL).
    [542] Example 46 N '-(3H-benzotriazol-5-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1, 4-diamine hydrochloride, polar diastereomer
    [543] As described in Example 45, 122 mg of the polar diastereomer N '-(3H-benzotriazol-5-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine Obtained as a white solid, the corresponding dihydrochloride is precipitated using 1.85 M ethanol hydrochloric acid (0.5 mL) in 2-butanone (5 mL) (119 mg, melting point: 185-189 ° C.).
    [544] Example 47 N '-(9H-fluorene-9-yl) -N, N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, cis / trans mixture
    [545] 2-iodothiophene (2.9 g) is dissolved in THF (80 mL) under argon and 2 M isopropylmagnesium chloride (35.7 mL) is added thereto at 0 ° C. over 30 minutes. After 1 hour reaction time at 3 to 5 ° C., 8-dimethylamino-1,4-dioxa-spiro [4.5] decane-8-carbonitrile (10 g) dissolved in tetrahydrofuran (20 mL) was added, Stir at room temperature for 20 hours. During workup, saturated NH 4 Cl (85 mL) was added and the mixture was extracted using diethyl ether (3 × 100 mL), then the combined extracts were washed with water (50 mL) and saturated NaCl (50 mL), After drying, it is concentrated. The obtained crude product (21.3 g of pale brown oil) was dissolved in 2-butanone (140 mL), and dimethyl- (8-thiophen-2-yl-1,4-dioxa was obtained using chlorotrimethylsilane (9.1 mL). -Spiro [4.5] deck-8-yl) -amine hydrochloride (white solid; 8.74 g).
    [546] Dimethyl- (8-thiophen-2-yl-1,4-dioxa-spiro [4.5] dec-8-yl) -amine hydrochloride (8.68 g) is dissolved in 7.5 M hydrochloric acid (29 mL) and room temperature Stir for 48 h then extract with diethyl ether (2 × 50 mL). The aqueous phase is made alkaline with 5 M sodium hydroxide solution while cooling with ice, extracted with dichloromethane (3 x 50 mL), dried and concentrated. Thus, 4-dimethylamino-4-thiophen-2-yl-cyclohexanone is obtained as a yellow solid (5.66 g; melting point: 108 to 110 ° C).
    [547] 362 mg 9-aminofluorene and 434 mg 4-dimethylamino-4-thiophen-2-yl-cyclohexanone are dissolved in anhydrous 1,2-dichloroethane (10 mL) under argon. 600 mg glacial acetic acid (2 mmol) and sodium triacetoxyborohydride are added to the mixture and the mixture is stirred at room temperature for 24 hours. During workup, the mixture is concentrated and the residue is adjusted to pH 11 with 5M sodium hydroxide solution. The alkaline phase is diluted with water (10 mL) and extracted with ethyl acetate (5 x 20 mL). The combined extracts are dried over sodium sulfate, filtered and the filtrate is concentrated. The crude product is chromatographed on silica gel using ethyl acetate / ethanol (1: 1). 440 mg of a cis / trans mixture of N '-(9H-fluoren-9-yl) -N, N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine are obtained as a white solid, The corresponding dihydrochloride is precipitated using 1.85 M ethanol HCl (1.55 mL) in 2-butanone (1.55 mL) (460 mg, melting point: 202-205 ° C.).
    [548] Example 48 N'-cyclooctyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride
    [549] 254 mg of cyclooctylamine and 434 mg of 4-dimethylamino-4-phenyl-cyclohexanone are dissolved in anhydrous tetrahydrofuran (15 mL) and 1,2-dichloroethane (5 mL) under argon. Glacial acetic acid (120 mg) and sodium triacetoxyborohydride 600 mg are added to the mixture and the mixture is stirred at room temperature for 18 hours. During workup, the reaction mixture is concentrated and the residue is washed with 1M hydrochloric acid (20 mL) and ether (2 x 30 mL). The aqueous phase is made alkaline with 5 M sodium hydroxide solution and extracted with ether (3 x 30 mL). The combined extracts are dried over sodium sulfate, filtered and the filtrate is concentrated. The crude product (515 mg) is chromatographed on silica gel with methanol. 108 mg of N'-cyclooctyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine are obtained as a colorless oil, the corresponding dihydrochloride being 3.3 M ethanol in 2-butanone (2 mL) Precipitates with hydrochloric acid (0.25 mL) (102 mg, melting point: 247-249 ° C.).
    [550] Example 49 N '-(1H-indol-3-ylmethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer
    [551] 970 mg of C- (1H-indol-3-yl) -methylamine and 1.44 mg of 4-dimethylamino-4-phenyl-cyclohexanone were dissolved in anhydrous tetrahydrofuran (15 mL) and 1,2-dichloroethane (50 mL). Dissolved in. Glacial acetic acid (13.2 mmol) and 1.82 g of sodium triacetoxyborohydride are added to the mixture and the mixture is stirred at room temperature for 72 hours. During workup, the reaction mixture is concentrated, water (20 mL) and ether (30 mL) are added to the residue, then the mixture is vigorously stirred. The aqueous phase is separated off, washed with ether (2 x 15 mL), brought to pH 11 with 5 M sodium hydroxide solution and extracted with ethyl acetate (4 x 25 mL). The combined extracts are dried over sodium sulfate, filtered and the filtrate is concentrated. The crude product (2.11 g) is chromatographed on silica gel using methanol / triethylamine (199: 1). Obtained 465 mg (melting point: 182-184 degreeC) of N '-(1H- indol-3-ylmethyl) -N, N- dimethyl- 1-phenyl- cyclohexane- 1, 4- diamine which is a nonpolar diastereomer, The corresponding dihydrochloride is precipitated using chlorotrimethylsilane (443 μl) in 2-butanone / acetone (20 mL / 50 mL) (498 mg, melting point: 164-168 ° C.).
    [552] Example 50 N '-(1H-indol-3-ylmethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomers
    [553] As described in Example 49, 360 mg of the polar diastereomer N '-(1H-indol-3-ylmethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained. The corresponding dihydrochloride is precipitated using chlorotrimethylsilane (328 μl) in 2-butanone / acetone (10 mL / 25 mL) (435 mg, melting point: 185-188 ° C.).
    [554] Example 51 N'-Benzo [b] thiophen-3-ylmethyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer
    [555] Benzothiophene-3-carbaldehyde (4.0 g, 24.6 mmol) is dissolved in a mixture of pyridine (25 mL) and ethanol (25 mL). Hydroxyamine hydrochloride (3.4 g, 49.2 mmol) is added with stirring. The mixture is stirred at rt for 30 min and heated at reflux for 8 h. A reddish brown solid is formed. During workup, the solution is concentrated and the residue is distilled with ethanol (3 x 50 mL) to leave no residual pyridine. Water (50 mL) is added to the oily residue and the mixture is stirred vigorously overnight. The pink solid present is suction filtered off, washed with water and dried in vacuo. 4.3 g (melting point: 87-89 ° C.) of benzothiophene-3-carbaldehyde oxime are obtained.
    [556] Benzothiophene-3-carbaldehyde oxime (3.96 g, 22.3 mmol) was dissolved in methanol (100 mL) and 5 M sodium hydroxide solution (100 mL), and Devarda alloy (14.1 g) was partially added to the mixture under argon. Add. When heated, the hydrogen generated here is released. The mixture is stirred for 16 hours. The workup is carried out by the slow addition of water (100 mL) and the vigorous reaction is started again. The mixture is filtered through celite, methanol is removed in vacuo, and the remaining aqueous phase is extracted with diethyl ether (3 x 50 mL). After concentration of the organic phase, 1.43 g of C-benzo [b] thiophen-3-yl methylamine remain as green oil. When 3,3 M ethanol hydrochloric acid (3.6 mL, 12 mmol) was added to this amine solution (1.3 g, 8 mmol), 1.18 g of C-benzo [b] thiophen-3-yl-methylamine hydrochloride (melting point) was obtained as white crystals. : 254-256 degreeC) precipitates.
    [557] 449 mg of C-benzo [b] thiophen-3-yl-methylamine and 434 mg of 4-dimethylamino-4-phenyl-cyclohexanone were dried under argon with anhydrous tetrahydrofuran (20 mL) and 1,2-dichloroethane (7 mL). Dissolved in. Glacial acetic acid (165 mmol) and 825 mg sodium triacetoxyborohydride are added to the mixture and the mixture is stirred at room temperature for 41 hours. During workup, the reaction mixture is concentrated and the residue is washed with 1M hydrochloric acid (20 mL) and ether (2 x 20 mL). The aqueous phase is adjusted to pH 8-9 with 1 M sodium hydroxide solution and the filtrate is concentrated. The crude product (787 mg), which is yellow crystals, is dissolved in methanol (7 mg) for chromatographic separation, whereby nonpolar diastereomers precipitate. 247 mg of a nonpolar diastereomer, N'-benzo [b] thiophen-3-ylmethyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, as a white solid (melting point: 138-140 ° C.) And the corresponding dihydrochloride is precipitated with 3.3 M ethanol hydrochloric acid (0.8 mL) in 2-butanol (25 mL) (187 mg, melting point: 225-230 ° C.).
    [558] Example 52 N'-Benzo [b] thiophen-3-ylmethyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomers
    [559] As described in Example 51, the methanolic solution of the crude product is chromatographed on silica gel using methanol. 113 mg of the polar diastereomer N'-benzo [b] thiophen-3-ylmethyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine are obtained, with the corresponding dihydrochloride being 2- Precipitated as a white solid using 3.3 M ethanol hydrochloric acid (0.28 mL) in butanone (10 mL) (120 mg, melting point: 252-254 ° C.).
    [560] Example 53 N'-anthracen-2-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine hydrochloride, nonpolar diastereomer
    [561] 386 mg of 2-aminoanthracene and 434 mg of 4-dimethylamino-4-phenyl-cyclohexanone are dissolved in anhydrous 1,2-dichloroethane (20 mL) under argon. 600 mg glacial acetic acid (2 mmol) and sodium triacetoxyborohydride are added to the mixture and the mixture is stirred at room temperature for 24 hours. During workup, the reaction mixture is concentrated and the residue is brought to pH 11 with 5 M sodium hydroxide solution and then extracted with ethyl acetate (4 x 20 mL). The combined extracts are dried over sodium sulfate, filtered and the filtrate is concentrated. The crude product is chromatographed on silica gel using ethyl acetate / ethanol (1: 1). 132 mg of the nonpolar diastereomer N'-anthracen-2-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine is obtained as a green solid and the corresponding hydrochloride is 2-butanone (5 mL Precipitate (104 mg, melting point: 169-172 ° C.) with 1.85 M ethanol hydrochloric acid (0.46 mL).
    [562] Example 54 N'-benzo [b] thiophen-3-ylmethyl-1-benzyl-N, N-dimethyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer
    [563] 391 mg of C-benzo [b] thiophen-3-yl-methylamine and 554 mg of 4-benzyl-4-dimethylamino-cyclohexanone were dried under argon with anhydrous tetrahydrofuran (18 mL) and 1,2-dichloroethane (6 mL). Dissolved in. 720 mg of glacial acetic acid (144 mmol) and sodium triacetoxyborohydride are added to the mixture, and the mixture is stirred at room temperature for 22 hours. During workup, the reaction mixture is concentrated and the residue is dissolved in 1M hydrochloric acid (20 mL) and then the mixture is washed with ether (2 x 20 mL). The aqueous phase is adjusted to pH 8-9 with 1 M sodium hydroxide solution and extracted with ether (3 x 20 mL). The combined extracts are dried over sodium sulfate, filtered and the filtrate is concentrated. The pale yellow oil (904 mg) obtained is chromatographed on silica gel with methanol. 368 mg of N'-benzo [b] thiophen-3-ylmethyl-1-benzyl-N, N-dimethyl-cyclohexane-1,4-diamine as a nonpolar diastereomer is obtained, and the corresponding dihydrochloride is 2- Precipitates with 3.3 M ethanol hydrochloric acid (0.88 mL) in butanol (25 mL) (364 mg, Melting Point: 246-255 ° C).
    [564] Example 55 N'-benzo [b] thiophen-3-ylmethyl-1-benzyl-N, N-dimethyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomers
    [565] As described in Example 54, 347 mg of the polar diastereomer N'-benzo [b] thiophen-3-ylmethyl-1-benzyl-N, N-dimethyl-cyclohexane-1,4-diamine And the corresponding dihydrochloride is precipitated using 3.3 M ethanol hydrochloric acid (0.83 mL) in 2-butanone (25 mL) (418 mg, melting point: 242-248 ° C.).
    [566] Example 56 N '-[2- (1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-naphthalen-2-yl-cyclohexane-1,4-diamine dihydrochloride, nonpolar Diastereomers
    [567] Grignard solution is prepared from anhydrous tetrahydrofuran (65 mL) from magnesium (2.05 g) and 2-bromonaphthalene (17.7 g). This Grignard solution is stirred for an additional hour at boiling point. Subsequently, 8-dimethylamino-1,4-dioxa-spiro [4.5] decane-8-carbonitrile (9.0 g) dissolved in anhydrous tetrahydrofuran (70 mL) was added dropwise at room temperature, and the mixture was overnight at room temperature. Stir. When the reaction is complete, the batch is quenched with saturated ammonium chloride while cooling with ice, extracted with diethyl ether (2 x 70 mL), dried over Na 2 S0 4 and concentrated. During workup, the crude product (24,2 g) is dissolved in 2-butanone (130 mL) and Me 3 SiCl (14.8 mL) is added thereto while cooling with ice. After 6 hours, precipitated dimethyl- (8-naphthalen-2-yl-1,4-dioxa-spiro [4.5] dec-8-yl) -amine dimethyl (8-naphthalin-2-yl-1,4 Dioxa-spiro [4.5] dec-8-yl) -amine is filtered off with suction (white solid; 6.09 g).
    [568] Dimethyl- (8-naphthalen-2-yl-1,4-dioxa-spiro [4.5] dec-8-yl) -amine hydrochloride (6.09 g) is dissolved in 7.5N hydrochloric acid and is allowed to stand at room temperature for 32 hours. After stirring, it is extracted with diethyl ether (3 × 30 mL). The aqueous phase is made alkaline with 25% ammonia solution while cooling with ice and extracted with 1,2-dichloroethane (3 x 30 mL). The combined extracts are dried over Na 2 S0 4 and concentrated. 4.48 g of 4-dimethylamino-4-naphthalen-2-yl-cyclohexanone are obtained as a white solid (melting point: 81-83 ° C.).
    [569] The nonpolar diastereomer N '-[2- (1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-naphthalen-2-yl-cyclohexane-1,4-diamine dihydrochloride Similar to the example described above is obtained by reductive amination of 4-dimethylamino-4-naphthalen-2-yl-cyclohexanone with tryptamine.
    [570] Example 57 N '-[2- (1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dichlorohydride, nonpolar diastereomer
    [571] 1.12 g of tryptamine and 1.52 g of 4-dimethylamino-4-phenylcyclohexanone are dissolved in anhydrous tetrahydrofuran (12 mL) and 1,2-dichloroethane (40 mL) under argon. Glacial acetic acid (801 μl) and 19.2 g of sodium triacetoxyborohydride are added to the mixture and the mixture is stirred at room temperature for 4 days. During workup, the reaction mixture is concentrated and the residue is dissolved in water (20 mL), 2M hydrochloric acid (5 mL) and ether (35 mL). The aqueous phase is separated off, washed with ether (2 x 15 mL), then adjusted to pH 11 with sodium hydroxide solution and extracted with ethyl acetate (3 x 20 mL). The combined extracts are dried over sodium sulfate, filtered and the filtrate is concentrated. The obtained beigeish brown residue (2.0 g) is chromatographed on silica gel using methanol containing 0.75% by volume triethylamine. Obtain 553 mg of the nonpolar diastereomer N '-[2- (1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, with the corresponding dichloride The acid salt is obtained using chlorotrimethylsilane in 2-butanone / acetone (20 mL / 50 mL) (600 mg, melting point: 216-218 ° C.).
    [572] Example 58 N '-[2- (1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomer
    [573] As described in Example 57, the polar diastereomer N '-[2- (1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4 536 mg (melting point: 175-180 ° C.) of diamine are obtained and the corresponding dihydrochloride is obtained using chlorotrimethylsilane (573 μl) in 2-butanone / acetone (3 mL / 30 mL) (520 mg, melting point: 223). To 229 ° C.).
    [574] Example 59: N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar Diastereomers
    [575] As described in Example 42, the polar diastereomer N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-phenyl-cyclohexane 546 mg (melting point: 50-55 ° C.) of −1,4-diamine are obtained and the corresponding dihydrochloride is obtained as a pale pink solid using chlorotrimethylsilane (1.0 mL) in 2-butanone (50 mL) (1.1 g, melting point: 194 to 199 ° C).
    [576] Example 60 Methyl 2- (4-dimethylamino-4-phenyl-cyclohexylamino) -3- (1H-indol-3-yl) -propionate dihydrochloride, nonpolar diastereomer
    [577] 4-dimethylamino-4-phenylcyclohexanone (435 mg, 2 mmol), glacial acetic acid (57 μl) and red sodium sulfate (2 g) were added to L-tryptophan methyl ester (438 mg, 2 mmol) in 1,2-dichloroethane (20 mL). Add. After 2 hours of stirring at room temperature, sodium triacetoxyborohydride (660 mg, 3 mmol) is added and stirring is continued. After 3 days, the reaction mixture is concentrated and the residue is suspended in diethyl ether (20 mL) and 1M NaOH (5 mL). After extracting the aqueous phase using diethyl ether and ethyl acetate (3 x 10 mL each), the combined organic phases are washed twice in a separating funnel with 1 M NaOH (5 mL), dried and concentrated. Let's do it. Viscous residue (718 mg) was subjected to flash chromatography [silica gel: 50 g; Eluent: ethyl acetate / methanol (3: 1) and ethyl acetate / MeOH (1: 1)] twice and the diastereomers are separated thereby.
    [578] 270 mg of methyl 2- (4-dimethylamino-4-phenyl-cyclohexylamino) -3- (1H-indol-3-yl) -propionate as a nonpolar diastereomer is obtained, and the corresponding dihydrochloride is 2- Obtained as a white solid (291 mg, melting point: 175-180 ° C.) using chlorotrimethylsilane (244 μl) in butanone / acetone (8 mL / 4 mL).
    [579] Example 61 Methyl 2- (4-dimethylamino-4-phenyl-cyclohexylamino) -3- (1H-indol-3-yl) -propionate dihydrochloride, polar diastereomers
    [580] As described in Example 60, methyl 2- (4-dimethylamino-4-phenyl-cyclohexylamino) -3- (1H-indol-3-yl) -propionate (140 mg) as a polar diastereomer , Melting point: 60-65 ° C.) is also obtained and the corresponding dihydrochloride is obtained as a white solid using chlorotrimethylsilane (126 μl) in 2-butanone / acetone (7 mL / 3 mL) (129 mg, melting point: 180 to 185 ° C).
    [581] Example 62 N '-[2- (1H-Indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-naphthalen-2-yl-cyclohexane-1,4-diamine di Hydrochloride, nonpolar diastereomers
    [582] 4-Dimethylamino-4-naphthalen-2-yl-cyclohexanone (534 mg) and DL-α-methyltryptamine (348 mg) were dissolved in argon with tetrahydrofuran (20 mL) and 1,2-dichloroethane (5 mL). Dissolve in a mixture with water. Acetic acid (120 mg) is added and after 15 minutes reaction time, sodium triacetoxyborohydride (600 mg) is added thereto. After 64 hours, the reaction mixture is suction filtered. After dissolution, a white solid is obtained in 1 M sodium hydroxide solution (20 mL), extracted with diethyl ether (3 x 20 mL), then the anhydrous mixed extract is concentrated and an oily residue (520 mg) is obtained. Separation of the mixture by chromatography first gives 295 mg (melting point: 68-70 ° C.) of the nonpolar diastereomer as white solid using methanol. Dissolving nonpolar diamine in 2-butanone (5 mL) and adding 3.3 N ethanol hydrochloric acid (0.52 mL) to this precipitates an oily solid. After the reaction mixture was concentrated and diethyl ether was added, the nonpolar diastereomer N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-naphthalene- Crystalline dihydrochloride (319 mg, melting point: 206 to 210 ° C.) of 2-yl-cyclohexane-1,4-diamine is obtained.
    [583] Example 63 N'-benzo [1,3] dioxol-5-ylmethyl-N, N-dimethyl-1-1phenyl-cyclohexane-1,4-diamine dihydrochloride, cis / trans mixture
    [584] 3,4- (methylenedioxy) benzylamine (250 μl) and dimethylamino-4-phenylcyclohexanone (434 mg) are dissolved in 1,2-dichloroethane (10 mL) using only oxygen. Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) are added to the mixture. Agitation is then performed at room temperature for 24 hours. During workup, the mixture is concentrated, adjusted to pH 11 with 5M NaOH, then diluted with water (10 mL) and extracted with ethyl acetate (4 x 20 mL). The combined organic extracts are dried over Na 2 S0 4 and concentrated. The resulting colorless oil (795 mg) was dissolved in 2-butanone (13 mL), and N'-benzo [1,3] dioxol-5-yl-N, N-dimethyl-1-phenyl-cyclohexane-1, 4-diamine dihydrochloride is obtained as a mixture of cis / trans isomers with chlorotrimethylsilane (719 μl) (white solid: 790 mg, melting point: 128-131 ° C.).
    [585] Example 64 N '-[2- (6-Fluoro-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, Nonpolar Diastereomers
    [586] 6-fluorotryptamine (410 mg) and 4-dimethylamino-4-phenylcyclohexanone (545 mg) were dissolved in THF (18 mL) and 1,2-dichloroethane (6 mL) under argon, acetic acid (138 mg) Is added to the solution. After 15 minutes, sodium triacetoxyborohydride (690 mg) and THF (5 mL) are added. After 40 hours, the mixture is concentrated and the residue is dissolved in 1M hydrochloric acid (20 mL) and then extracted with ether (2 x 20 mL). The aqueous phase is made alkaline with 1 M sodium hydroxide solution (30 mL) and extracted with ether (3 x 30 mL). A white solid (785 mg) precipitates out between phases and is separated off. Solids are mixtures of two diastereomers, which sometimes occur when the ethereal phase is concentrated. The mixture (985 g) is separated together by column chromatography using methanol / conc. Ammonia (500: 1). Nonpolar diastereomers are obtained as a white solid (321 mg, melting point: 185-187 ° C.), dissolved in ethanol (20 mL) with heating, and then 3.3 N ethanol HCl (0.79 mL) is added thereto. After stirring for several hours at room temperature, N '-[2- (6-fluoro-1 H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1 is a nonpolar diamine. Obtain white dihydrochloride of, 4-diamine (344 mg, melting point: 190-195 ° C.).
    [587] Example 65 N '-[2- (6-Fluoro-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, Polar diastereomers
    [588] As described in Example 64, the polar diastereomer N '-[2- (6-fluoro-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclo 305 mg of hexane-1,4-diamine are also obtained and the corresponding dihydrochloride is obtained in ethanol (20 mL) using 3.3 N ethanol HCl (0.73 mL) (270 mg, melting point: 208-211 ° C.).
    [589] Example 66 N '-[2- (1H-indol-3-yl) -ethyl] -N, N, N'-trimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar moiety Stereoisomer
    [590] N-ω-methyltryptamine ([2- (1H-indol-3-yl) ethyl] methylamine (348 mg) is dissolved in anhydrous 1,2-dichloroethane (10 mL) under argon. After addition of 4-phenylcyclohexanone (435 mg) and glacial acetic acid (114 [mu] l), a bulk precipitate is formed, after stirring the suspension for 2 hours at room temperature, sodium triacetoxyborohydride (660 mg) is added. The reaction mixture is stirred at room temperature for 2 days and after workup, the residue is dissolved in water (15 mL) and diethyl ether (20 mL) and the organic phase is separated off. Extract with ether (2 × 10 mL) and adjust to pH 10 with 1 M NaOH where white solid precipitates, is filtered off with suction, washed and dried (174 mg, melting point: 208-210 ° C., nonpolar portion) Stereoisomer), brought to pH 11 with 1 M NaOH, and with ethyl acetate (4 x 25 mL). . Causes output that The extracts were combined, dried over Na 2 SO 4, then concentrated under vacuum and the residue (469mg) in methanol / triethylamine (990: 1).. Then separated by flash chromatography using the in this way The resulting nonpolar diastereomer (172 mg) was dissolved at elevated temperature in 2-butanone / acetone (15 mL / 15 mL), and N '-[2- (1H-indol-3-yl) -ethyl] -N, N, Hydrochloride of N'-trimethyl-1-phenyl-cyclohexane-1,4-diamine is precipitated as a white solid at room temperature using chlorotrimethylsilane (174 μl) (173 mg, melting point: 195-198 ° C.).
    [591] Example 67 N '-[2- (1H-indol-3-yl) -ethyl] -N, N, N'-trimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar portion Stereoisomer
    [592] As described in Example 66, the polar diastereomer N '-[2- (1H-indol-3-yl) -ethyl] -N, N, N'-trimethyl-1-phenyl-cyclohexane- 129 mg of 1,4-diamine are also obtained and converted to the corresponding dihydrochloride salt by raising the temperature in 2-butanone / acetone (15 mL / 3 mL) using chlorotrimethylsilane (121 μl) (white solid; 141 mg, melting point: 198 to 206 ° C).
    [593] Example 68: N, N-dimethyl-N '-[2- (7-methyl-1H-indol-3-yl) -ethyl] -1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar Diastereomers
    [594] 7-Methyltryptamine (348 mg) and 4-dimethylamino-4-phenylcyclohexaone (435 mg) are dissolved in anhydrous 1,2-dichloroethane (5 mL) and tetrahydrofuran (15 mL) using only oxygen. . Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) are added to the mixture and the mixture is stirred at room temperature for 24 hours. During workup, the mixture is concentrated, 1M HCl (20 mL) and diethyl ether (40 mL) are added to the batch, the acidic aqueous phase is extracted with diethyl ether (2 x 20 mL) and brought to pH 11 with 5M NaOH. Adjust The alkaline phase is diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts are dried over Na 2 SO 4 , concentrated and the resulting crude product is separated on silica gel using EtOH / NH 3 (500: 1). Nonpolar diastereomers are obtained as brown oil (321 mg), dissolved in 2-butanone (10 mL) and then converted to dihydrochloride using chlorotrimethylsilane (270 μL) (white solid: 420 mg, melting point: 189). To 191 ° C.).
    [595] Example 69 N, N-dimethyl-N '-[2- (7-methyl-1H-indol-3-yl) -ethyl] -1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar Diastereomers
    [596] As described in Example 68, 144 mg of the polar diastereomer is obtained as a brown oil, dissolved in 2-butanone (5 mL) and then converted to hydrochloride using chlorotrimethylsilane (121 μl) (white Solid: 146 mg, melting point: 244-246 ° C.).
    [597] Example 70 N '-[2- (5-Fluoro-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, Nonpolar Diastereomers
    [598] To a mixture of tetrahydrofuran (12 mL) and 1,2-dichloroethane (4 mL), firstly 2- (5-fluoro-1H-indol-3-yl) ethylamine (282 mg) and 4-dimethylamino-4 -Phenylcyclohexanone (343 mg) is added under argon and acetic acid (0.09 mL) is added thereto. After 15 minutes, NaBH (OAc) 3 (474 mg) is added and stirred at room temperature for 40 hours. The reaction mixture is concentrated and the residue is dissolved in 1M hydrochloric acid (20 mL) and then extracted with ether (2 x 30 mL). A white precipitate (191 mg) is separated out here and separated off. The aqueous solution is then made alkaline with 1 M NaOH (28 mL) and extracted with ether (2 x 30 mL) and ethyl acetate (2 x 30 mL). The combined organic extracts are dried over sodium sulfate and concentrated. The residue (468 mg) consists of two products very similar to the solid previously separated off. They are separated together by column chromatography using (459 mg) methanol / ammonia (500: 1). The nonpolar diastereomer is obtained as a white solid (218 mg, melting point: 191 to 192 ° C.), dissolved in ethanol (15 mL) while heating, and then 3.3 N ethanol hydrochloric acid (0.47 mL, 1.56 mmol) is added thereto. Since no solid precipitates after 90 minutes, 2-butanone (5 mL) is added. The hydrochloride then begins to crystallize after a short time (184 mg, melting point: 230-237 ° C.).
    [599] Example 71 N '-[2- (5-Fluoro-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, Polar diastereomers
    [600] As described in Example 70, polar diastereomers (189 mg, melting point: 200 to 201 ° C.) were obtained, of which 159 mg were dissolved in ethanol (15 mL) and 2-butanone (5 mL), followed by 3.3 Convert to dihydrochloride with ethanol hydrochloric acid (0.38 mL) of N (124 mg, melting point: 262-265 ° C.).
    [601] Example 72 N'-acenaphthene-5-ylmethyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer
    [602] Acenaphthene-5-ylmethylamine (366 mg) and 4-dimethylamino-4-phenylcyclohexanone (434 mg) are dissolved in anhydrous 1,2-dichloroethane (10 mL) using only oxygen. Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) are added to the mixture and the mixture is stirred at room temperature for 24 hours. During workup, the mixture is concentrated and the pH is adjusted to 11 with 5M HCl. The alkaline phase is diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic phases are dried over Na 2 S0 4 and concentrated. The crude product obtained is purified by chromatography on silica gel using ethyl acetate / EtOH (1: 1). Non-polar diastereomers are obtained as colorless oil (330 mg), dissolved in 2-butanone (10 mL) and then converted to the corresponding dihydrochloride salt using chlorotrimethylsilane (272 μL) (white solid: 393 mg, melting point). : 164 to 167 ° C).
    [603] Example 73 N '-[2- (1H-Indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine Dihydrochloride, Nonpolar Diastereomers
    [604] DL-α-methyltryptamine (N '-[2- (1H-indol-3-yl) -1-methylethyl] -N, N-dimethyl-1-thiophen-2-yl-cyclohexane-1 , 4-diamine, 348 mg) is dissolved in anhydrous 1,2-dichloroethane (20 mL) under argon. After addition of 4-dimethylamino-4-thiophen-2-yl-cyclohexanone (447 mg) and glacial acetic acid (114 [mu] l), a bulky precipitate is formed. The suspension is stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (660 mg) is then added and the reaction mixture is stirred for 2 days at room temperature. During workup, the mixture is diluted with 1,2-dichloroethane (10 mL) and water (15 mL), the organic phase is separated off and the aqueous phase is extracted again with 1,2-dichloroethane (2 x 5 mL) and , Alkaline with 5M NaOH, and then extracted with ethyl acetate (4 x 15 mL). The combined organic phases are dried, concentrated and purified by flash chromatography [50 g of silica gel 60, eluent: methanol / NEt 3 (99: 1)]. Nonpolar diastereomers (202 mg, melting point: 158-161 ° C.) are dissolved in 2-butanol (5 mL) and converted to the corresponding dihydrochloride salt using chlorotrimethylsilane (202 μl) (white solid, 207 mg, melting point: 162 to 165 ° C).
    [605] Example 74 N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine Dihydrochloride, cis / trans mixture
    [606] As described in Example 73, the mixture of diastereomers was separated again (195 mg), dissolved in 2-butanone (4 mL), and then the corresponding dihydrochloride salt using chlorotrimethylsilane (194 μl). Convert (white solid, 232 mg, polar / non-polar = 70/30).
    [607] Example 75: N '-[2- (7-benzyloxy-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, Nonpolar Diastereomers
    [608] 7-benzyloxytryptamine (200 mg) is dissolved in anhydrous 1,2-dichloroethane (10 mL) and THF (10 mL) under argon. After addition of 4-dimethylamino-4-phenylcyclohexanone (180 mg) and glacial acetic acid (43 μl), the mixture is stirred at room temperature for 1 hour and then sodium triacetoxyborohydride (462 mg) is added thereto. The reaction mixture is stirred for 3 days at room temperature. During workup, the mixture is concentrated, the residue is dissolved in water (15 mL), 2N HCl (2 mL) and diethyl ether (20 mL), the organic phase is separated off and the aqueous phase is diethyl ether (2 x 15 mL). ), Adjust to pH 11 with 1 M NaOH, and then extract with ethyl acetate (4 x 10 mL). The combined ethyl acetate extracts are dried, concentrated and the residue obtained (351 mg) is purified by flash chromatography [45 g of silica gel 60, eluent: MeOH / NEt 3 (99: 1)]. The nonpolar diastereomer (188 mg) is dissolved in 2-butanol / acetone (6 mL / 6 mL) at elevated temperature and converted to the corresponding dihydrochloride salt using chlorotrimethylsilane (147 μl) (white solid, 176 mg, melting point: 162). To 165 ° C.).
    [609] Example 76 N'-cyclooctyl-N, N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer
    [610] 4-dimethylamino-4-phenylcyclohexanone (447 mg, 2 mmol) is dissolved in 1,2-dichloroethane (25 mL) under argon, and cyclooctylamine (254 mg) and acetic acid (120 mg) are added to the solution. The mixture is stirred at room temperature for 15 minutes and sodium triacetoxyborohydride (600 mg) is added. After 48 hours at room temperature, the reaction mixture is concentrated on a rotary evaporator and the residue is dissolved in 1M hydrochloric acid (20 mL) and then washed with diethyl ether (2 x 30 mL). The aqueous solution is then made alkaline with 1 M NaOH (28 mL) and extracted with Et 2 O (3 × 30 mL). The combined organic extracts are dried over sodium sulfate and concentrated. The oily residue (586 mg) is purified by chromatography using methanol / ammonia (500: 1). The nonpolar product is a colorless oil (280 mg), dissolved in 2-butanol (20 mL) and converted to the corresponding dihydrochloride using 3.3 N ethanol hydrochloric acid (0.76 mL) (white solid, 273 mg, melting point: 205). To 207 ° C).
    [611] Example 77 N'-adamantan-2-yl-N, N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer
    [612] 2-adamantyl-amine (302 mg) and 4-dimethylamino-4-phenylcyclohexanone (446 mg) are dissolved in a mixture of THF (15 mL) and 1,2-dichloroethane (5 mL) under argon. After 15 minutes, sodium triacetoxyborohydride (600 mg) is added to the mixture and stirred at room temperature for 45 hours. During workup, the reaction mixture is concentrated and the residue is dissolved in 1M hydrochloric acid (20 mL) and diethyl ether (40 mL), then the phases are separated and the aqueous phase is washed with diethyl ether (2 x 30 mL). . The aqueous phase is made alkaline with 5 M sodium hydroxide solution and extracted with diethyl ether (3 x 30 mL). After concentration of the combined organic extracts, the obtained crude product is separated by chromatography using methanol. Nonpolar diastereomers (286 mg) are dissolved in 2-butanol (15 mL) and converted using 3.3 M ethanol hydrochloric acid (0.34 mL) (white solid, 300 mg, melting point: 266 ° C.).
    [613] Example 78: 3- [2- (4-Dimethylamino-4-phenyl-cyclohexylamino) -ethyl] -1 H-indol-5-ol dihydrochloride, nonpolar diastereomer
    [614] Serotonin (405 mg) was dissolved in 1,2-dichloroethane / THF (5 mL / 20 mL), 4-dimethylamino-4-phenylcyclohexanone (500 mg), glacial acetic acid (131 μl) and red sodium sulfate (2 g) were added thereto. Add. After 1 hour of stirring at room temperature, sodium triacetoxyborohydride (759 mg) is added and stirring is continued for an additional 2 days. During workup, the mixture is concentrated and the residue is suspended in diethyl ether (15 mL), water (10 mL) and 2M HCl (1 mL), then additional diethyl ether (20 mL) is added and the organic phase is coarsely separated. Remove The aqueous phase is first brought to pH 9 with 1M NaOH, extracted with ethyl acetate (3 × 5 mL), then adjusted to pH 11, and extracted again with ethyl acetate (5 × 10 mL). The organic extract is dried, concentrated and the residue is purified by flash chromatography [eluent: MeOH / NEt 3 (99.5: 0.5)]. 267 mg of nonpolar diastereomer (melting point: 90-100 ° C.) were isolated, dissolved in ethanol / 2-butanone (3 mL / 15 mL), and then the corresponding dihydrochloride using 3.3 M ethanol HCl (642 μl). (White solid, 304 mg, melting point: 215-217 ° C.).
    [615] Example 79: 3- [2- (4-Dimethylamino-4-phenyl-cyclohexylamino) -ethyl] -1 H-indol-5-ol dihydrochloride, polar diastereomers
    [616] As described in Example 78, 124 mg of polar diastereomers (melting point: 185 to 187 ° C.) were also obtained and dissolved in ethanol / 2-butanone (6 mL / 15 mL) followed by 3.3 M ethanol HCl. (298 μl) is used to convert to the corresponding dihydrochloride (white solid, 123 mg, melting point: 230-233 ° C.).
    [617] Example 80: N '-[2- (5-methoxy-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, Nonpolar Diastereomers
    [618] 6-methoxytrytamine (495 mg) is dissolved under argon in anhydrous 1,2-dichloroethane and THF (5 mL / 15 mL) until clear. 4-dimethylamino-4-phenylcyclohexanone (565 mg) and glacial acetic acid (148 μl) were added, followed by stirring at room temperature for 2 hours, followed by sodium triacetoxyborohydride (858 mg). The reaction mixture is stirred for 2 days at room temperature. During workup, water (15 mL) and 5.5 M HCl (1.5 mL) are added to the reaction mixture. The phases are separated and the aqueous phase (pH 3) is dissolved in diethyl ether (3 x 10 mL), then brought to pH 11 with 1 M NaOH and extracted with ethyl acetate (5 x 15 mL). The combined extracts are dried over Na 2 S0 4 and concentrated. The residue (1.0 g, melting point: 129-153 ° C.) is purified by flash chromatography [eluent: MeOH / NEt 3 (99.25: 0.75)]. The nonpolar diastereomer (550 mg, melting point: 164-169 ° C.) was transparently separated off, dissolved in 2-butanol / acetone (15 mL / 16 mL) at elevated temperature, and then the corresponding using chlorotrimethylsilane (533 μl). Convert to dihydrochloride (white solid, 633 mg, melting point: 165-175 ° C.).
    [619] Example 81: N '-[2- (5-methoxy-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, Polar diastereomers
    [620] As described in Example 80, polar diastereomers (320 mg, melting point: 136-140 ° C.) were also obtained and dissolved in 2-butanone / acetone (15 mL / 3 mL) followed by chlorotrimethylsilane (310). Μl) is used to convert to the corresponding dihydrochloride (white solid, 362 mg, melting point: 206-210 ° C.).
    [621] Example 82: N, N-dimethyl-N '-[2- (5-methyl-1H-indol-3-yl) -ethyl] -1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar Diastereomers
    [622] 5-Methyltryptamine (348 mg) and 4-dimethylamino-4-phenylcyclohexaone (435 mg) are dissolved in anhydrous 1,2-dichloroethane (5 mL) and tetrahydrofuran (15 mL) using only oxygen. . Glacial acetic acid (114 μl) and sodium triacetoxyborohydride (600 mg) are added to the mixture and the mixture is stirred at room temperature for 24 hours. During workup, the mixture is concentrated and the residue is dissolved in 1M HCl (20 mL) and diethyl ether (40 mL), then the phases are separated and the aqueous phase is extracted with diethyl ether (2 x 20 mL), Adjust to pH 11 with 5M NaOH. The aqueous phase is diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts are dried over Na 2 S0 4 and concentrated. The residue is purified by chromatography using MeOH / NH 3 (500: 1). Non-polar diastereomers (brown oil, 379 mg) are dissolved in 2-butanone (10 mL) and then converted to the corresponding dihydrochloride salt by addition of chlorotrimethylsilane (319 μl) (white solid: 405 mg, melting point: 234-23). 236 ° C.).
    [623] Example 83 N, N-dimethyl-N '-[2- (5-methoxy-1 H-indol-3-yl) -ethyl] -1-phenyl-cyclohexane-1,4-diamine dihydrochloride, Polar diastereomers
    [624] As described in Example 82, polar diastereomers (266 mg) were dissolved in 2-butanone (10 mL) and converted to the corresponding dihydrochloride salt using Me 3 SiCl (224 μL, 1.76 mmol) ( White solid, 272 mg, melting point: 248-250 ° C.).
    [625] Example 84: Dimethyl- [1-phenyl-4- (1,3,4,9-tetrahydro-b-carboline-2-yl) -cyclohexyl] -amine dihydrochloride
    [626] 2,3,4,9-tetrahydro-1H-β-carboline (345 mg) and 4-dimethylamino-4-phenylcyclohexanone (435 mg) were dissolved under argon with THF (10 mL) and 1,2-dichloroethane ( 15 mL) and acetic acid (120 mg, 2 mmol) is added thereto. After 15 minutes, NaBH (OAc) 3 (600 mg) was added and stirred for 68 hours, then the reaction mixture was concentrated, the residue was dissolved in 1N hydrochloric acid (20 mL) and then washed with ether (2 × 20 mL). do. The aqueous solution is made alkaline with 1M NaOH (30 mL) and extracted with ether (3 x 30 mL). After the combined extracts are dried and concentrated, a semisolid crude product is obtained, which is separated by column chromatography using methanol / NH 3 (500: 3) to give a nonpolar diastereomer (334 mg, melting point: 147-150 ° C.). ) Is dissolved in 2-butanol (20 mL) and ethanol (10 mL) on heating and converted to the corresponding dihydrochloride with 3.3 M ethanol hydrochloric acid (0.8 mL) (335 mg, melting point: 264-269 ° C.). ).
    [627] Example 85: N- (4-Dimethylamino-4-phenyl-cyclohexyl) -N- [2- (4-fluoro-phenyl) -ethyl] -acetamide hydrochloride, nonpolar diastereomers
    [628] 4- (fluorophenyl) ethylamine (1.15 g) and 4-dimethylamino-4-phenylcyclohexanone (1.8 g) were used with only oxygen and anhydrous 1,2-dichloroethane (20 mL) and tetrahydrofuran ( 60 mL). Glacial acetic acid (8.28 mmol) and sodium triacetoxyborohydride (2.48 g, 11.59 mmol) are added to the mixture and the mixture is stirred at room temperature for 24 hours. During workup, the mixture was concentrated, 1M HCl (20 mL) and diethyl ether (40 mL) were added to the batch, then the phases were separated and the aqueous phase was extracted with diethyl ether (2 x 20 mL), then 5M NaOH Adjust to pH 11 using. The aqueous phase is diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts are dried over Na 2 S0 4 , concentrated and the residue is purified by chromatography on silica gel with methanol. Nonpolar diastereomers (531 mg, 1.55 mmol) are dissolved in anhydrous pyridine (10 mL) and acetic anhydride (1.59 g, 15.59 mmol) is added thereto with stirring. After 24 hours, a few pieces of ice are added to the reaction mixture and the reaction mixture is concentrated in a rotary evaporator as much as possible. 1M NaOH (20 mL) is added to the residue. The aqueous phase is extracted with ethyl acetate (3 × 30 mL) and the combined organic extracts are dried over Na 2 SO 4 and then concentrated. The resulting acetamide (545 mg) was dissolved in 2-butanone (10 mL) and then converted to the corresponding hydrochloride using chlorotrimethylsilane (0.270 mL) (white solid: 302 mg, melting point: 196 to 201 ° C.).
    [629] Example 86 2- (4-Dimethylamino-4-phenyl-cyclohexylamino) -3- (5-fluoro-1 H-indol-3-yl) -propionic acid methyl ester dihydrochloride, nonpolar diastereomers
    [630] 4-dimethylamino-4-phenyl-cyclohexanone (935 mg), sodium sulfate (4 g) and glacial acetic acid (245 μl, 4.4 mmol) in rac-5-fluorotryptophan in 1,2-dichloroethane (about 40 mL) under argon. To methyl ester (1,030 mg). After stirring for 1 hour at room temperature, sodium triacetoxyborohydride (1.4 g, 6.5 mmol) is added. The mixture is stirred for 3 days at room temperature. During workup, the mixture is concentrated and the residue is dissolved in ethyl acetate (40 mL) and 1N NaOH (35 mL) and then extracted three times with ethyl acetate (10 mL each time). The combined extracts are dried, concentrated and the residue obtained is purified by flash chromatography [eluent: MeOH / EtOAc (1: 3)]. The resulting nonpolar diastereomer (911 mg, melting point: 55-62 ° C.) is dissolved in 2-butanone / acetone (7 mL / 1 mL) and converted to the corresponding dihydrochloride using chlorotrimethylsilane (174 μl) ( Beige solid: 135 mg, melting point: 172-182 ° C.).
    [631] Example 87 N- (4-dimethylamino-4-phenyl-cyclohexyl) -N- (3-phenyl-propyl) -acetamide hydrochloride, nonpolar diastereomers
    [632] 3-phenylpropylamine (676 mg) and 4-dimethylamino-4-phenylcyclohexaone (1.086 g) are dissolved in anhydrous 1,2-dichloroethane (5 mL) and tetrahydrofuran (15 mL) using only oxygen. . Glacial acetic acid (5 mmol) and sodium triacetoxyborohydride (1.5 g, 7 mmol) are added to the mixture and the mixture is stirred at room temperature for 24 hours. During workup, the mixture is concentrated and 1M HCl (20 mL) and diethyl ether (40 mL) are added to the batch. The aqueous phase is washed with diethyl ether (2 x 20 mL), separated off, adjusted to pH 11 with 5N NaOH, diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts are dried over Na 2 SO 4 and concentrated. The crude product obtained is purified by chromatography on silica gel using methanol. 761 mg of nonpolar diastereomer is obtained. 453 mg is dissolved in anhydrous pyridine (10 mL) and acetic anhydride (1.374 g) is added with stirring. After stirring for 24 hours at room temperature, a few pieces of ice are added and the mixture is concentrated in a rotary evaporator as much as possible. 1M NaOH (20 mL) is added to the residue and the mixture is extracted with ethyl acetate (3 x 30 mL). The combined organic extracts are dried over Na 2 S0 4 and concentrated. The obtained acetamide (528 mg) is dissolved in 2-butanone (10 mL) and converted to the corresponding hydrochloride using chlorotrimethylsilane (0.353 mL) (white solid: 282 mg, melting point: 206-211 ° C.).
    [633] Example 88 2- (4-Dimethylamino-4-phenyl-cyclohexylamino) -3- (6-fluoro-1 H-indol-3-yl) -propionic acid methyl ester dihydrochloride, nonpolar diastereomers
    [634] 4-dimethylamino-4-phenyl-cyclohexanone (877 mg), sodium sulfate (2 g) and glacial acetic acid (230 μl, 4 mmol) were dissolved in rac-6-fluorotryptophan methyl in 1,2-dichloroethane (about 30 mL) under argon. To ester (952 mg). After stirring for 1 hour at room temperature, sodium triacetoxyborohydride (1.33 g, 6 mmol) is added and the mixture is stirred at room temperature for 2 days. During workup, the mixture is concentrated and the residue is dissolved in ethyl acetate (30 mL) and 1M NaOH (25 mL), then the clear phase is separated in a separating funnel and the aqueous phase is extracted three times with ethyl acetate (10 mL each time). The combined extracts are then dried and concentrated by evaporation. The obtained residue (1.72 g) was subjected to flash chromatography [eluent: MeOH / EtOAc (1: 2), followed by MeOH / EtOAc (1: 1) and MeOH / NH 3 (400: 1)]. Some of the nonpolar diastereomers (868 mg) (261 mg) are dissolved in 2-butanone (7 mL) and the corresponding dihydrochloride is precipitated using chlorotrimethylsilane (227 μL) (white solid, 224 mg, melting point: 164). To 169 ° C.).
    [635] Example 89 N- (4-dimethylamino-4-phenyl-cyclohexyl) -2- (1H-indol-3-yl) -acetamide hydrochloride, polar diastereomers
    [636] 4-Dimethylamino-4-phenyl-cyclohexanone (10 g) and hydroxylamine hydrochloride (4.8 g) were dissolved in anhydrous ethanol (120 mL), and a basic ion exchanger Amberlyst A 21 (30.7 g) was added to the solution. Stir overnight at room temperature. The ion exchanger is filtered off and washed with ethanol (3 x 50 mL) on frit. Ethanol is removed under vacuum and the residue is adjusted to pH 11 with 5M NaOH, diluted with water and then extracted with ethyl acetate (4 x 30 mL). The combined extracts are dried over Na 2 S0 4 and concentrated. 11 g of 4-dimethylamino-4-phenyl-cyclohexanone oxime are obtained.
    [637] 4-Dimethylamino-4-phenyl-cyclooxane oxime (11 g) is dissolved in methanol (200 mL) and diluted with 5M NaOH (200 mL). A Devada alloy (30 g) is added in part to the mixture. Reaction temperature is 50-60 degreeC. 15 minutes after completion of addition the mixture is diluted with water (150 mL), methanol is removed in vacuo, and the aqueous solution is extracted with ether (5 x 50 mL). The combined extracts are dried over Na 2 S0 4 and concentrated. N, N-dimethyl-1-phenylcyclohexane-1,4-diamine is obtained as a yellow oil (10.0 g).
    [638] N-methylmorpholine (235 μl, 2.1 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (371 mg, 2.11 mmol) indole-3-yl in dry THF (10 mL) To acetic acid (257 mg) solution. Then it is stirred for 1 hour at room temperature. Polar diastereomer N, N-dimethyl-1-phenylcyclohexane-1,4-diamine (320 mg) is added to the batch and stirred at room temperature for 12 hours. During workup, the mixture is concentrated, the batch is adjusted to pH 11 with 5M NaOH, the phases are separated and the aqueous phase is diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts are dried over Na 2 S0 4 and concentrated. Purification by column chromatography using ethyl acetate / ethanol (1: 1), the obtained amide was dissolved in 2-butanone (3 mL) and then converted to the corresponding hydrochloride with chlorotrimethylsilane (61 μl). (White solid, 128 mg, melting point: 100-102 DEG C).
    [639] Example 90 2- (4-Dimethylamino-4-thiophen-2-yl-cyclohexylamino) -3- (1H-indol-3-yl) -propionic acid methyl ester dihydrochloride, nonpolar diastereomers
    [640] Hydrochloride of L-Tryptophan methyl ester (1.01 g) was vigorously stirred with 1,2-dichloroethane (20 mL) and NaHCO 3 solution (20 mL) for 15 minutes and the aqueous phase was 1,2-dichloroethane (2 x 20 mL). Extract immediately. After drying with Na 2 SO 4 , the organic phase is concentrated to 40 mL and 4-dimethylamino-4-phenylcyclohexanone (893 mg, 4 mmol) is added thereto under argon. Glacial acetic acid (0.228 mL, 4 mmol) and Na 2 SO 4 (2 g) are added to the clear solution. After 15 minutes of reaction time, NaBH (OAc) 3 (1.2 g) is added to the reaction mixture and stirred for 4 days at room temperature. During workup, saturated NaHCO 3 (40 mL) is added and stirred for 15 minutes. The aqueous phase is extracted with dichloromethane (2 x 20 mL). The combined organic phases are dried and concentrated to give a light brown oil. Purification by column chromatography using ethyl acetate and methanol. Nonpolar diastereomers (918 mg, melting point: 108-112 ° C.) are dissolved in 2-butanone (15 mL) and converted to the corresponding dihydrochloride salt using chlorotrimethylsilane (0.4 mL) (white solid, 326 mg, melting point). : 197 to 202 ° C.).
    [641] Example 91 N- (4-dimethylamino-4-phenyl-cyclohexyl) -2- (5-methoxy-1H-indol-3-yl) -acetamide hydrochloride, nonpolar diastereomer
    [642] Nonpolar diastereomers N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine (387 mg) and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl)- 4-Methyl-morpholinium chloride (267 mg, 2.0 mmol) was added to a solution of (5-methoxy-1H-indol-3-yl) acetic acid (364 mg) in anhydrous methanol (20 mL). Then it is stirred at room temperature for 24 hours. During workup, the mixture is concentrated, the batch is diluted with water (10 mL) and the mixture is adjusted to pH 11 with 5M NaOH and then extracted with ethyl acetate (3 x 20 mL). The combined organic extracts are dried over Na 2 SO 4 and concentrated to evaporate. After column chromatography using MeOH, the nonpolar amide (154 mg; colorless oil) is dissolved in 2-butanone (5 mL) and converted to the corresponding hydrochloride using chlorotrimethylsilane (72 μL) (white solid, 168 mg, Melting Point: 143-145 ° C.
    [643] Example 92:
    [644] ORL1 binding measurements
    [645] Cyclohexane-1,4-diamine derivatives of formula (I) are investigated in a receptor binding assay using 3 H-nociceptin / opanin FQ with recombinant CHO-ORL1 cells. The test system is described in Ardati et al. (Mol. Pharmacol., 51, 1997, p. 816-824) The concentration of 3 H-nociceptin / opanin FQ in these experiments is 0.5 nM. In each case, 50 mM Hepes, Binding assays are performed using 20 μg of membrane protein per 200 μl bath in pH 7.4, 10 mM MgCl 2 and 1 mM EDTA, binding to ORL1 receptor was performed using 1 mg WGA-SPA beads (Amesham-Pharmacia, Freiburg), respectively. The bath is incubated for 1 hour at room temperature and then determined by measuring with a Trilux scintillation counter (Wallac, Finland) The affinity is expressed as K i of μM.
    [646]
    [647]
    [648]
    [649]
    [650] ORL1 binding measurements
    [651] Cyclohexane-1,4-diamine derivatives of formula (I) are investigated in a receptor binding assay using 3 H-nociceptin / opanin FQ with recombinant CHO-ORL1 cells. The test system is described in Ardati et al. (Mol. Pharmacol., 51, 1997, p. 816-824) The concentration of 3 H-nociceptin / opanin FQ in these experiments is 0.5 nM. In each case, 50 mM Hepes, Binding assays are performed using 20 μg membrane protein per 200 μl bath in pH 7.4, 10 mM MgCl 2 and 1 mM EDTA, binding to the ORL1 receptor was performed using 1 mg WGA-SPA beads (Amesham-Pharmacia, Freiburg), respectively. The bath is incubated for 1 hour at room temperature and then determined by measuring with a Trilux scintillation counter (Wallac, Finland) The affinity is expressed as K i of μM.
    [652] Example 93:
    [653] Analgesia Test in the Tail Slap Test of Mice
    [654] Mice are each placed in a separate test cage and the base of the tail is exposed to the focused heating wire of the electric lamp (tail-beat type 50/80 / 1.bc, Labtec, Dr. Hess). The intensity of the lamp is adjusted so that the time from lighting of the lamp to sudden cramping of the tail (latency of pain) in untreated mice is 3 to 5 seconds. Prior to administration of a solution comprising a compound according to the invention or a particular comparative solution, mice are preliminary tested twice over 5 minutes and these measurements are calculated as preliminary test values.
    [655] Solutions of the compounds of formula (I) and comparative solutions according to the invention are then administered intravenously. In each case, pain measurements are performed 10, 20, 40 and 60 minutes after intravenous administration. Painless activity is determined as an increase in latency of pain (% of the maximum possible pain inhibitory effect) according to Equation 1 below.
    [656]
    [657] In Equation 1 above,
    [658] T 0 is the incubation period prior to administration,
    [659] Time T 1 is the incubation period following administration of the active substance combination,
    [660] Time T 2 is the maximum exposure time (12 seconds).
    [661] An in-depth study of analgesia activity is performed in the tail beating test in mice as described above.
    [662] The compounds tested according to the invention exhibit analgesic activity. Selected test results are also listed in the table below.
    [663] Example number% Pain Suppression Activity for Control Group * One98 (10) 340 (10) 444 (10) 7100 (1) 1247 (10) 2749 (2.15) 60100 (1) 8591 (1) 86100 (1) 88100 (10) 8937 (1) 9094 (1) 91100 (1)
    [664] Intravenous doses of mg / kg are shown in parentheses in each case.
    [665] Study compounds according to the invention exhibit good analgesic activity.
    [666] Example 94:
    [667] Parenteral solutions of substituted cyclohexane-1,4-diamine derivatives according to the invention
    [668] As in Example 91, 38 g of the substituted cyclohexane-1,4-diamine derivative according to the present invention is dissolved in 1 L of water for injection at room temperature, and then the solution is adjusted to an isotonic condition by adding anhydrous glucose for injection. .
    权利要求:
    Claims (62)
    [1" claim-type="Currently amended] Substituted cyclohexane-1,4-diamine derivatives of formula (I), optionally racemic forms thereof, pure stereoisomers, in particular enantiomeric or diastereomeric forms, or mixtures of stereoisomers, in particular enantiomers or parts In the form of stereoisomeric mixtures; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or solvates thereof, especially hydrate forms.
    Formula I

    In Formula I above,
    R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono- or polysubstituted, saturated or unsaturated branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    R 4 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; And C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , wherein X is O or S and R 7 Is H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated, branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkylbutab, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; mono or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, each saturated or unsaturated, branched or straight chain; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, each bonded through C 1 -C 3 -alkylene, or Heteroaryl) or (CH 2 ) 3-6 , and R 9 is each saturated or unsaturated straight or branched mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H; Saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And each unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl; or
    R 4 and R 5 together form a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms, wherein the heterocyclic radical may optionally be fused with an additional ring. Forming,
    Provided that when R 3 is substituted or unsubstituted phenyl and at least one of R 1 and R 2 is H or C 1 -C 8 -alkyl, R 4 is not alkyl and R 4 and R 5 together are heterocyclic radicals Does not form
    When R 3 is unsubstituted phenyl and R 1 and R 2 together are (CH 2 ) 5 and R 4 is selected from H and C 1 -C 8 -alkyl, Y is not O or S and R 5 is C 1 -C 6 -alkyl is not.
    [2" claim-type="Currently amended] Substituted cyclohexane-1,4-diamine derivatives of formula (I), optionally racemic forms thereof, pure stereoisomers, in particular enantiomeric or diastereomeric forms, or mixtures of stereoisomers, in particular enantiomers or parts In the form of stereoisomeric mixtures; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or solvates thereof, especially hydrate forms.
    Formula I

    In Formula I above,
    R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono- or polysubstituted, saturated or unsaturated branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    R 4 is H, C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 where X is O or S And R 7 is H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated straight or branched mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is unsubstituted or mono- or polysubstituted C 3 -C, respectively. 8 -cycloalkyl, aryl and heteroaryl.
    [3" claim-type="Currently amended] Substituted cyclohexane-1,4-diamine derivatives of formula (I), optionally racemate forms thereof, pure stereoisomers, in particular enantiomeric or diastereomeric forms, or mixtures of stereoisomers, in particular enantiomers or parts In the form of stereoisomeric mixtures; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or solvates thereof, especially hydrate forms.
    Formula I

    In Formula I above,
    R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except for hydrogen at the same time,
    R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    R 4 is H, C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 where X is O or S R 7 is H, saturated or unsaturated, branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated straight or branched mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively.
    [4" claim-type="Currently amended] Substituted cyclohexane-1,4-diamine derivatives of formula (I), optionally racemic forms thereof, pure stereoisomers, in particular enantiomeric or diastereomeric forms, or mixtures of stereoisomers, in particular enantiomers or parts In the form of stereoisomeric mixtures; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or solvates thereof, especially hydrate forms.
    Formula I

    In Formula I above,
    R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted, mono- or polysubstituted heteroaryl; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    R 4 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; And C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , wherein X is O or S and R 7 Is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated straight or branched mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or monosubstituted or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And each unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl; or
    R 4 and R 5 together form a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms, wherein the heterocyclic radical may optionally be fused with an additional ring. Form.
    [5" claim-type="Currently amended] Substituted cyclohexane-1,4-diamine derivatives of formula (I), optionally racemic forms thereof, pure stereoisomers, in particular enantiomeric or diastereomeric forms, or mixtures of stereoisomers, in particular enantiomers or parts In the form of stereoisomeric mixtures; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or solvates thereof, especially hydrate forms.
    Formula I

    In Formula I above,
    R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    R 4 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; And C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , wherein X is O or S and R 7 Is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated straight or branched mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is unsubstituted or mono- or polysubstituted C 3 -C, respectively. 8 -cycloalkyl, aryl and heteroaryl; or
    R 4 and R 5 together form a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms, wherein the heterocyclic radical may optionally be fused with an additional ring. Form.
    [6" claim-type="Currently amended] The method according to any one of claims 1, 2 and 4,
    R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl, except when R 1 and R 2 are hydrogen at the same time, or
    R 1 and R 2 together represent the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 , wherein R 6 is H; and a saturated or unsaturated branched or straight chain mono- or polysubstituted Is unsubstituted C 1 -C 8 -alkyl) or (CH 2 ) 3-6 to form a ring,
    Preferably, R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl, except when R 1 and R 2 are hydrogen at the same time, or R 1 and R 2 are Together form a ring of formula (CH 2 ) 4-5 ,
    In particular, substituted cyclohexane-1,4-diamine derivatives wherein R 1 and R 2 are independently selected from methyl and ethyl or R 1 and R 2 together form a ring of formula (CH 2 ) 5 .
    [7" claim-type="Currently amended] The method of claim 5,
    R 1 and R 2 taken together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 , wherein R 6 is H; and a saturated or unsaturated branched or straight chain mono- or polysubstituted Is unsubstituted C 1 -C 8 -alkyl) or (CH 2 ) 3-6 to form a ring,
    Preferably, R 1 and R 2 together form a ring of formula (CH 2 ) 4-5 ,
    In particular, substituted cyclohexane-1,4-diamine derivatives wherein R 1 and R 2 together form a ring of formula (CH 2 ) 5 .
    [8" claim-type="Currently amended] The method of claim 3,
    R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl, except when R 1 and R 2 are hydrogen at the same time,
    Preferably, R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl, except when R 1 and R 2 are hydrogen at the same time,
    In particular, substituted cyclohexane-1,4-diamine derivatives wherein R 1 and R 2 are independently selected from methyl and ethyl.
    [9" claim-type="Currently amended] The method according to any one of claims 1 to 3 and 5,
    Each R 3 is bonded via an unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, and a saturated or unsaturated branched or straight-chain substituted or unsubstituted C 1 -C 2 -alkyl group, respectively Unsubstituted or mono- or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl,
    Preferably, R 3 is unsubstituted or mono- or polysubstituted C 5 -C 6 -cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxola Nil, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl; And unsubstituted or monosubstituted or monosubstituted C 5 -C 6 -cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothio, each bonded via a saturated straight chain C 1 -C 2 -alkyl group Phenyl, pyridyl, furyl, benzofuranyl, benzodioxolanil, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl,
    In particular, R 3 is unsubstituted or mono- or polysubstituted phenyl, furyl, thiophenyl, cyclohexanyl, naphthyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pi Rollyl, pyrimidyl, pyrazinyl or benzothiophenyl; And substituted cyclohexane-1,4-diamine derivatives which are bonded through a saturated straight chain C 1 -C 2 -alkyl group and are each selected from unsubstituted or mono- or polysubstituted phenyl, furyl or thiophenyl.
    [10" claim-type="Currently amended] The method of claim 4, wherein
    Each R 3 is bonded via an unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl or heteroaryl, and a saturated or unsaturated straight-chain substituted or unsubstituted C 1 -C 4 -alkyl group Each selected from unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl or heteroaryl,
    Preferably, R 3 is unsubstituted or mono- or polysubstituted C 5 -C 6 -cycloalkyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolalanyl, indolyl, indanyl, Benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl; And unsubstituted or monosubstituted or monosubstituted C 5 -C 6 -cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothio, each bonded via a saturated straight chain C 1 -C 2 -alkyl group Phenyl, pyridyl, furyl, benzofuranyl, benzodioxolanil, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl,
    In particular, R 3 is unsubstituted or mono- or polysubstituted furyl, thiophenyl, cyclohexanyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pyrrolyl, pyrimidyl, Pyrazinyl or benzothiophenyl; And substituted cyclohexane-1,4-diamine derivatives which are bonded through a saturated straight chain C 1 -C 2 -alkyl group and are each selected from unsubstituted or mono- or polysubstituted phenyl, furyl or thiophenyl.
    [11" claim-type="Currently amended] The substituted cyclohexane-1, 4-diamine derivative according to claim 1, wherein R 4 is H. 12.
    [12" claim-type="Currently amended] The method according to any one of claims 1 to 10,
    R 4 is H, C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , where X is O or S Is selected from
    Preferably, R 4 is selected from H, C (X) R 7 , C (X) NR 7 R 8 and C (X) OR 9 , wherein X is O,
    In particular, R 4 is selected from H and C (O) R 7 wherein R 7 is H; and saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; Preferably selected from H; and saturated branched or straight chain unsubstituted C 1 -C 3 -alkyl; in particular CH 3 .
    [13" claim-type="Currently amended] The method according to any one of claims 1, 4 and 5,
    R 4 and R 5 together may be a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms; Preferably, in addition to the essential atom N, having 5 to 7 ring atoms, 0 or 1 heteroatom further selected from N, S and O is further present in the ring and is monocyclic or polysubstituted or unsubstituted heterocyclic radical [Here, the heterocyclic radicals formed by R 4 and R 5 together may optionally be fused with further rings, preferably aromatic and / or heteroaromatic rings, wherein these rings can in turn be fused with further aromatic and / or heteroaromatic rings. Can be fused together, in particular the heterocyclic radicals formed by R 4 and R 5 together with one or two further rings, preferably heterocyclic formed by R 4 and R 5 The radical is fused with two further rings such that R 4 and R 5 together form To represent a radical of the substituted cyclohexane-1,4-diamine derivative.
    [14" claim-type="Currently amended] The method according to any one of claims 1, 4 and 5,
    R 4 is H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl,
    Preferably, H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 6 -alkyl,
    In particular, H; And a substituted, cyclohexane-1,4-diamine derivative selected from saturated straight chain unsubstituted C 1 -C 3 -alkyl.
    [15" claim-type="Currently amended] The method according to any one of claims 1 to 14,
    R 5 is each selected from unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl and heteroaryl,
    Preferably, R 5 is unsubstituted or monosubstituted or monosubstituted cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothio Phenyl, indanyl, benzodioxanyl, benzodioxolanil, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthenyl, benzo Thiazolyl, benzotriazolyl, benzo [1,2,5] thiazolyl, 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolononyl, oxopyrazolinonyl, dioxolanyl , Adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl and quinazolinyl,
    In particular, R 5 is unsubstituted or mono- or polysubstituted cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxa Substituted cyclohexane-1,4-diamine derivatives selected from nil, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl and pyrimidyl.
    [16" claim-type="Currently amended] The method according to any one of claims 1 to 14,
    R 5 is -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O , S or H 2 ),
    Preferably, R 5 is -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 and —C (Y) —CH 2 —CH 2 R 12 , wherein Y is O or S,
    In particular, R 5 is -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -C (Y) R 12 and -C (Y) -CH 2 R 12 Substituted cyclohexane-1,4-diamine derivative, wherein Y is O.
    [17" claim-type="Currently amended] The method of claim 16,
    R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 4 -alkyl,
    Preferably, H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl; And saturated straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 2 -alkyl,
    In particular substituted cyclohexane-1,4-diamine derivatives selected from H, CH 3 , C 2 H 5 and C (O) O—CH 3 .
    [18" claim-type="Currently amended] The method of claim 16,
    R 12 is each selected from unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl and heteroaryl,
    Preferably, R 12 is unsubstituted or mono- or polysubstituted cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothio Phenyl, indanyl, benzodioxanyl, benzodioxolanil, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthenyl, benzo Thiazolyl, benzotriazolyl, benzo [1,2,5] thiazolyl, 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolononyl, oxopyrazolinonyl, dioxolanyl , Adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl and quinazolinyl,
    In particular, R 12 is unsubstituted or mono- or polysubstituted cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxa Substituted cyclohexane-1,4-diamine derivatives selected from nil, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl and pyrimidyl.
    [19" claim-type="Currently amended] The method according to any one of claims 1 to 18,
    N'-benzyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine hydrochloride, nonpolar diastereomers,
    N'-benzyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine hydrochloride, polar diastereomers,
    1, N'-dibenzyl-N, N-dimethyl-cyclohexane-1,4-diamine hydrochloride, nonpolar diastereomers,
    1, N'-dibenzyl-N, N-dimethyl-cyclohexane-1,4-diamine hydrochloride, polar diastereomers,
    N- (4-benzyl-4-dimethylamino-cyclohexyl) -N-propyl-benzamide hydrochloride,
    N, N-dimethyl-1-phenyl-N'-propyl-cyclohexane-1,4-diamine hydrochloride, nonpolar diastereomers,
    N- (4-dimethylamino-4-phenyl-cyclohexyl) -N-propyl-benzamide hydrochloride, nonpolar diastereomers,
    N- (4-dimethylamino-4-phenyl-cyclohexyl) -N-propyl-benzamide hydrochloride, polar diastereomers,
    1, N'-dibenzyl-N, N, N'-trimethyl-cyclohexane-1,4-diamine hydrochloride, nonpolar diastereomers,
    1, N'-dibenzyl-N, N, N'-trimethyl-cyclohexane-1,4-diamine hydrochloride, polar diastereomers,
    N- (4-benzyl-4-dimethylamino-cyclohexyl) -N-methyl-benzamide hydrochloride, polar diastereomers,
    N- (4-benzyl-4-dimethylamino-cyclohexyl) -N-ethyl-benzamide hydrochloride, polar diastereomers,
    1-benzyl-N '-(1H-indol-3-ylmethyl) -N, N-dimethyl-cyclohexane-1,4-diamine dihydrochloride,
    1-benzyl-N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-cyclohexane-1,4-diamine, cis / trans mixture,
    1-benzyl-N'-indan-5-yl-N, N-dimethyl-cyclohexane-1,4-diamine hydrochloride,
    1-benzyl-N'-indan-1-yl-N, N-dimethyl-cyclohexane-1,4-diamine dihydrochloride, cis / trans mixture,
    N'-indan-1-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine,
    N '-(1H-indol-5-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine,
    N '-(1H-indol-3-ylmethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, cis / trans mixture,
    N '-(1H-indol-3-ylmethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, nonpolar diastereomer,
    N '-[2- (1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, nonpolar diastereomer,
    N '-[2- (1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, cis / trans mixture,
    N'-indan-5-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, nonpolar diastereomer,
    N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, nonpolar diastereomer,
    N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, cis / trans mixture,
    N '-[2- (5-benzyloxy-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine, cis / trans mixture,
    N '-(9H-fluoren-1-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride,
    N'-indan-2-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, cis / trans mixture,
    N '-(9H-fluoren-9-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, cis / trans mixture,
    1-benzyl-N '-(9-fluoren-9-yl) -N, N-dimethyl-cyclohexane-1,4-diamine,
    1-benzyl-N '-(1H-indol-3-ylmethyl) -N, N-dimethyl-cyclohexane-1,4-diamine, cis / trans mixture,
    N, N-dimethyl-N '-(1-methyl-1H-indol-3-ylmethyl) -1-phenyl-cyclohexane-1,4-diamine, cis / trans mixture,
    N, N-dimethyl-N '-(1-methyl-1H-indol-3-ylmethyl) -1-phenyl-cyclohexane-1,4-diamine, polar diastereomer,
    N '-(2-benzo [b] thiophen-3-yl-ethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, cis / trans mixture,
    N '-(2-benzo [b] thiophen-3-yl-ethyl) -1-benzyl-N, N-dimethylcyclohexane-1,4-diamine dihydrochloride, cis / trans mixture,
    N'-acenaphthen-1-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomers,
    N'-acenaphthen-1-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomers,
    N'-benzo [b] thiophen-5-yl-1-benzyl-N, N-dimethyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomers,
    N'-benzo [b] thiophen-5-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine hydrochloride, nonpolar diastereomers,
    N'-benzothiazol-6-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomers,
    N'-benzo [1,2,5] thiadiazol-4-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomers,
    N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    N'-adamantan-2-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride,
    N '-(9-ethyl-9H-carbazol-3-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    N '-(3H-benzotriazol-5-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine hydrochloride, nonpolar diastereomers,
    N '-(3H-benzotriazol-5-yl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine hydrochloride, polar diastereomers,
    N '-(9H-fluoren-9-yl) -N, N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, cis / trans mixture,
    N'-cyclooctyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride,
    N '-(1H-indol-3-ylmethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    N '-(1H-indol-3-ylmethyl) -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomers,
    N'-benzo [b] thiophen-3-ylmethyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    N'-benzo [b] thiophen-3-ylmethyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomers,
    N'-anthracen-2-yl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine hydrochloride, nonpolar diastereomers,
    N'-benzo [b] thiophen-3-ylmethyl-1-benzyl-N, N-dimethyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomers,
    N'-benzo [b] thiophen-3-ylmethyl-1-benzyl-N, N-dimethyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomers,
    N '-[2- (1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-naphthalen-2-yl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    N '-[2- (1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    N '-[2- (1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomer,
    N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomer,
    Methyl 2- (4-dimethylamino-4-phenyl-cyclohexylamino) -3- (1H-indol-3-yl) -propionate dihydrochloride, nonpolar diastereomers,
    Methyl 2- (4-dimethylamino-4-phenyl-cyclohexylamino) -3- (1H-indol-3-yl) -propionate dihydrochloride, polar diastereomers,
    N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-naphthalen-2-yl-cyclohexane-1,4-diamine dihydrochloride, nonpolar Diastereomer,
    N'-benzo [1,3] dioxol-5-ylmethyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, cis / trans mixture,
    N '-[2- (6-Fluoro-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer ,
    N '-[2- (6-Fluoro-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomer ,
    N '-[2- (1H-indol-3-yl) -ethyl] -N, N, N'-trimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    N '-[2- (1H-indol-3-yl) -ethyl] -N, N, N'-trimethyl-1-phenyl-cyclohexane-1, 4-diamine dihydrochloride, polar diastereomer,
    N, N-dimethyl-N '-[2- (7-methyl-1H-indol-3-yl) -ethyl] -1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    N, N-dimethyl-N '-[2- (7-methyl-1H-indol-3-yl) -ethyl] -1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomer,
    N '-[2- (5-Fluoro-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer ,
    N '-[2- (5-Fluoro-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1, 4-diamine dihydrochloride, polar diastereomer ,
    N'-acenaphthene-5-ylmethyl-N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, Nonpolar diastereomers,
    N '-[2- (1H-indol-3-yl) -1-methyl-ethyl] -N, N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, Cis / trans mixture,
    N '-[2- (7-benzyloxy-1H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer ,
    N'-cyclooctyl-N, N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomers,
    N'-adamantan-2-yl-N, N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    3- [2- (4-dimethylamino-4-phenyl-cyclohexylamino) -ethyl] -1 H-indol-5-ol dihydrochloride, nonpolar diastereomer,
    3- [2- (4-dimethylamino-4-phenyl-cyclohexylamino) -ethyl] -1 H-indol-5-ol dihydrochloride, polar diastereomer,
    N '-[2- (5-methoxy-1 H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1, 4-diamine dihydrochloride, nonpolar diastereomer ,
    N '-[2- (5-methoxy-1 H-indol-3-yl) -ethyl] -N, N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomer ,
    N, N-dimethyl-N '-[2- (5-methyl-1H-indol-3-yl) -ethyl] -1-phenyl-cyclohexane-1,4-diamine dihydrochloride, nonpolar diastereomer,
    N, N-dimethyl-N '-[2- (5-methyl-1H-indol-3-yl) -ethyl] -1-phenyl-cyclohexane-1,4-diamine dihydrochloride, polar diastereomer,
    Dimethyl- [1-phenyl-4- (1,3,4,9-tetrahydro-b-carboline-2-yl) -cyclohexyl] -amine dihydrochloride,
    N- (4-dimethylamino-4-phenyl-cyclohexyl) -N- [2- (4-fluoro-phenyl) -ethyl] -acetamide hydrochloride, nonpolar diastereomers,
    2- (4-dimethylamino-4-phenyl-cyclohexylamino) -3- (5-fluoro-1 H-indol-3-yl) -propionic acid methyl ester dihydrochloride, nonpolar diastereomers,
    N- (4-dimethylamino-4-phenyl-cyclohexyl) -N- (3-phenyl-propyl) -acetamide hydrochloride, nonpolar diastereomers,
    2- (4-dimethylamino-4-phenyl-cyclohexylamino) -3- (6-fluoro-1 H-indol-3-yl) -propionic acid methyl ester dihydrochloride, nonpolar diastereomers,
    N- (4-dimethylamino-4-phenyl-cyclohexyl) -2- (1H-indol-3-yl) -acetamide hydrochloride, polar diastereomers,
    2- (4-dimethylamino-4-thiophen-2-yl-cyclohexylamino) -3- (1H-indol-3-yl) -propionic acid methyl ester dihydrochloride, nonpolar diastereomers and
    N- (4-dimethylamino-4-phenyl-cyclohexyl) -2- (5-methoxy-1 H-indol-3-yl) -acetamide hydrochloride, substituted cyclo selected from the group consisting of nonpolar diastereomers Hexane-1,4-diamine derivatives.
    [20" claim-type="Currently amended] One or more substituted cyclohexane-1,4-diamine derivatives of formula I, optionally racemic forms, pure stereoisomers, in particular enantiomers or diastereomeric forms, or mixtures of stereoisomers, in particular enantiomers Or in the form of diastereomeric mixtures; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or a solvate, in particular a hydrate form thereof, and optionally a suitable additive and / or adjuvant material and / or optionally further active compounds.
    Formula I

    In Formula I above,
    R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    R 4 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; And C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , wherein X is O or S and R 7 Is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated straight or branched mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And each unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl; or
    R 4 and R 5 together form a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms, wherein the heterocyclic radical may optionally be fused with an additional ring. Forming,
    Provided that when R 3 is substituted or unsubstituted phenyl and at least one of R 1 and R 2 is H or C 1 -C 8 -alkyl, R 4 is not alkyl and R 4 and R 5 together are heterocyclic radicals Does not form.
    [21" claim-type="Currently amended] One or more substituted cyclohexane-1,4-diamine derivatives of formula I, optionally racemic forms, pure stereoisomers, in particular enantiomers or diastereomeric forms, or mixtures of stereoisomers, in particular enantiomers Or in the form of diastereomeric mixtures; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or a solvate, in particular a hydrate form thereof, and optionally a suitable additive and / or adjuvant material and / or optionally further active compounds.
    Formula I

    In Formula I above,
    R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl, or heteroaryl, which are bonded via a saturated or unsaturated branched or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    R 4 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; And C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , wherein X is O or S and R 7 Is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated straight or branched mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And each unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl; or
    R 4 and R 5 together form a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms, wherein the heterocyclic radical may optionally be fused with an additional ring. Form.
    [22" claim-type="Currently amended] One or more substituted cyclohexane-1,4-diamine derivatives of formula I, optionally racemic forms, pure stereoisomers, in particular enantiomers or diastereomeric forms, or mixtures of stereoisomers, in particular enantiomers Or in the form of diastereomeric mixtures; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or a solvate, in particular a hydrate form thereof, and optionally a suitable additive and / or adjuvant material and / or optionally further active compounds.
    Formula I

    In Formula I above,
    R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    R 4 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; And C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , wherein X is O or S and R 7 Is H, saturated or unsaturated, branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated straight or branched mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And each unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl; or
    R 4 and R 5 together form a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms, wherein the heterocyclic radical may optionally be fused with an additional ring. Form.
    [23" claim-type="Currently amended] One or more substituted cyclohexane-1,4-diamine derivatives of formula I, optionally racemic forms, pure stereoisomers, in particular enantiomers or diastereomeric forms, or mixtures of stereoisomers, in particular enantiomers Or in the form of diastereomeric mixtures; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or a solvate, in particular a hydrate form thereof, and optionally a suitable additive and / or adjuvant material and / or optionally further active compounds.
    Formula I

    In Formula I above,
    R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    R 4 is H, C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 where X is O or S R 7 is H, saturated or unsaturated, branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated straight or branched mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively.
    [24" claim-type="Currently amended] The method of claim 20 or 21,
    R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl, except when R 1 and R 2 are hydrogen at the same time, or
    R 1 and R 2 together represent the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 , wherein R 6 is H; and a saturated or unsaturated branched or straight chain mono- or polysubstituted Is unsubstituted C 1 -C 8 -alkyl) or (CH 2 ) 3-6 to form a ring,
    Preferably, R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl, except when R 1 and R 2 are hydrogen at the same time, or R 1 and R 2 are Together form a ring of formula (CH 2 ) 4-5 ,
    In particular, they contain substituted cyclohexane-1,4-diamine derivatives in which R 1 and R 2 are independently selected from methyl and ethyl or R 1 and R 2 together form a ring of formula (CH 2 ) 5 Drugs characterized in that.
    [25" claim-type="Currently amended] The method of claim 22,
    R 1 and R 2 taken together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 , wherein R 6 is H; and a saturated or unsaturated branched or straight chain mono- or polysubstituted Is unsubstituted C 1 -C 8 -alkyl) or (CH 2 ) 3-6 to form a ring,
    Preferably, R 1 and R 2 together form a ring of formula (CH 2 ) 4-5 ,
    In particular, a medicament characterized by containing a substituted cyclohexane-1,4-diamine derivative, wherein R 1 and R 2 together form a ring of formula (CH 2 ) 5 .
    [26" claim-type="Currently amended] The method of claim 23, wherein
    R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl, except when R 1 and R 2 are hydrogen at the same time,
    Preferably, R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl, except when R 1 and R 2 are hydrogen at the same time,
    In particular, R 1 and R 2 are each independently selected from methyl and ethyl,
    R 1 and R 2 together represent the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 , wherein R 6 is H; and a saturated or unsaturated branched or straight chain mono- or polysubstituted Is unsubstituted C 1 -C 8 -alkyl) or (CH 2 ) 3-6 to form a ring,
    Preferably, R 1 and R 2 together form a ring of formula (CH 2 ) 4-5 ,
    In particular, a medicament characterized by containing a substituted cyclohexane-1,4-diamine derivative, wherein R 1 and R 2 together form a ring of formula (CH 2 ) 5 .
    [27" claim-type="Currently amended] The method according to any one of claims 20, 22 and 23,
    Each R 3 is bonded via an unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl and a saturated or unsaturated straight or substituted C 1 -C 2 -alkyl group And are each selected from unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl, or heteroaryl,
    Preferably, R 3 is unsubstituted or mono- or polysubstituted C 5 -C 6 -cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxola Nil, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl; And unsubstituted or monosubstituted or monosubstituted C 5 -C 6 -cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothio, each bonded via a saturated straight chain C 1 -C 2 -alkyl group Phenyl, pyridyl, furyl, benzofuranyl, benzodioxolanil, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl,
    In particular, R 3 is unsubstituted or mono- or polysubstituted phenyl, furyl, thiophenyl, cyclohexanyl, naphthyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pi Rollyl, pyrimidyl, pyrazinyl or benzothiophenyl; And substituted cyclohexane-1,4-diamine derivatives bonded through a saturated straight chain C 1 -C 2 -alkyl group and each selected from unsubstituted or mono- or polysubstituted phenyl, furyl or thiophenyl A medicament characterized in that it contains.
    [28" claim-type="Currently amended] The method of claim 21,
    Each R 3 is bonded through an unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl or heteroaryl, and a saturated or unsaturated straight-chain substituted or unsubstituted C 1 -C 4 -alkyl group Each selected from unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl or heteroaryl,
    Preferably, R 3 is unsubstituted or mono- or polysubstituted C 5 -C 6 -cycloalkyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolalanyl, indolyl, indanyl, Benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl; And unsubstituted or monosubstituted or monosubstituted C 5 -C 6 -cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothio, each bonded via a saturated straight chain C 1 -C 2 -alkyl group Phenyl, pyridyl, furyl, benzofuranyl, benzodioxolanil, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl,
    In particular, R 3 is unsubstituted or mono- or polysubstituted furyl, thiophenyl, cyclohexanyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pyrrolyl, pyrimidyl, Pyrazinyl or benzothiophenyl; And substituted cyclohexane-1,4-diamine derivatives bonded through a saturated straight chain C 1 -C 2 -alkyl group and each selected from unsubstituted or mono- or polysubstituted phenyl, furyl or thiophenyl A medicament characterized in that it contains.
    [29" claim-type="Currently amended] 29. A medicament according to any one of claims 20 to 28, wherein a substituted cyclohexane-1, 4-diamine derivative is contained, wherein R 4 is H.
    [30" claim-type="Currently amended] The method according to any one of claims 20 to 28, wherein
    R 4 is H, C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , where X is O or S Is selected from
    Preferably, R 4 is selected from H, C (X) R 7 , C (X) NR 7 R 8 and C (X) OR 9 , wherein X is O,
    In particular, R 4 is selected from H and C (O) R 7 where R 7 is H; and saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; Preferably substituted H, and substituted cyclohexane-1,4-diamine derivatives selected from saturated branched or straight chain unsubstituted C 1 -C 3 -alkyl; in particular CH 3 ). Characterized in that the pharmaceutical.
    [31" claim-type="Currently amended] The method according to any one of claims 20 to 22,
    R 4 and R 5 together may be a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms; Preferably, in addition to the essential atom N, having 5 to 7 ring atoms, 0 or 1 heteroatom further selected from N, S and O is further present in the ring and is monocyclic or polysubstituted or unsubstituted heterocyclic radical [Here, the heterocyclic radicals formed by R 4 and R 5 together may optionally be fused with further rings, preferably aromatic and / or heteroaromatic rings, wherein these rings can in turn be fused with further aromatic and / or heteroaromatic rings. Can be fused together, in particular the heterocyclic radicals formed by R 4 and R 5 together with one or two further rings, preferably heterocyclic formed by R 4 and R 5 The radical is fused with two further rings such that R 4 and R 5 together form And a substituted cyclohexane-1,4-diamine derivative, which forms a radical thereof.
    [32" claim-type="Currently amended] The method according to any one of claims 20 to 22,
    R 4 is H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl,
    Preferably, H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 6 -alkyl,
    In particular, H; And substituted cyclohexane-1,4-diamine derivatives selected from saturated straight chain unsubstituted C 1 -C 3 -alkyl.
    [33" claim-type="Currently amended] The method according to any one of claims 20 to 32,
    R 5 is each selected from unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl and heteroaryl,
    Preferably, R 5 is unsubstituted or monosubstituted or monosubstituted cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothio Phenyl, indanyl, benzodioxanyl, benzodioxolanil, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthenyl, benzo Thiazolyl, benzotriazolyl, benzo [1,2,5] thiazolyl, 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolononyl, oxopyrazolinonyl, dioxolanyl , Adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl and quinazolinyl,
    In particular, R 5 is unsubstituted or mono- or polysubstituted cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxa Containing substituted cyclohexane-1,4-diamine derivatives selected from nil, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl and pyrimidyl Characterized in that the pharmaceutical.
    [34" claim-type="Currently amended] The method according to any one of claims 20 to 32,
    R 5 is -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O , S or H 2 ),
    Preferably, R 5 is -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 and —C (Y) —CH 2 —CH 2 R 12 , wherein Y is O or S,
    In particular, R 5 is -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -C (Y) R 12 and -C (Y) -CH 2 R 12 A medicament characterized by containing a substituted cyclohexane-1,4-diamine derivative, wherein Y is O.
    [35" claim-type="Currently amended] The method of claim 34, wherein
    R 11 is H; Saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 4 -alkyl,
    Preferably, H; Saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl; And saturated straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 2 -alkyl,
    In particular, a medicament characterized by containing a substituted cyclohexane-1,4-diamine derivative selected from H, CH 3 , C 2 H 5 and C (O) O-CH 3 .
    [36" claim-type="Currently amended] The method of claim 34, wherein
    R 12 is each selected from unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl,
    Preferably, R 12 is unsubstituted or mono- or polysubstituted cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothio Phenyl, indanyl, benzodioxanyl, benzodioxolanil, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthenyl, benzo Thiazolyl, benzotriazolyl, benzo [1,2,5] thiazolyl, 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolononyl, oxopyrazolinonyl, dioxolanyl , Adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl and quinazolinyl,
    In particular, R 12 is unsubstituted or mono- or polysubstituted cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxa Containing substituted cyclohexane-1,4-diamine derivatives selected from nil, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl and pyrimidyl Characterized in that the pharmaceutical.
    [37" claim-type="Currently amended] 37. The opioid, preferably an effective opioid, in particular a morphine, or an anesthetic, preferably hexobarbital, in addition to at least one substituted cyclohexane-1,4-diamine derivative. Or a halotan.
    [38" claim-type="Currently amended] Substituted cyclohexane-1,4-diamine derivatives of formula (I), optionally racemic forms, pure stereoisomers, especially enantiomers or parts, for the manufacture of a medicament for the treatment of pain, in particular acute, neuropathic or chronic pain Stereoisomeric forms or mixtures of stereoisomers in a particular mixing ratio, in particular enantiomers or diastereomeric mixtures; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or their solvates, especially in the form of hydrates.
    Formula I

    In Formula I above,
    R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    R 4 is H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; And C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , wherein X is O or S and R 7 Is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated, branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or monosubstituted or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And each unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl; or
    R 4 and R 5 together form a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms, wherein the heterocyclic radical may optionally be fused with an additional ring. Forming,
    Provided that when R 3 is substituted or unsubstituted phenyl and at least one of R 1 and R 2 is H or C 1 -C 8 -alkyl, R 4 is not alkyl and R 4 and R 5 together are heterocyclic radicals Does not form.
    [39" claim-type="Currently amended] Substituted cyclohexane-1,4-diamine derivatives of formula (I), optionally racemic forms, pure stereoisomers, especially enantiomers or parts, for the manufacture of a medicament for the treatment of pain, in particular acute, neuropathic or chronic pain Stereoisomeric forms or mixtures of stereoisomers in a particular mixing ratio, in particular enantiomers or diastereomeric mixtures; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or their solvates, especially in the form of hydrates.
    Formula I

    In Formula I above,
    R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    R 4 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; And C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , wherein X is O or S and R 7 Is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated straight or branched mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And each unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl; or
    R 4 and R 5 together form a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms, wherein the heterocyclic radical may optionally be fused with an additional ring. Form.
    [40" claim-type="Currently amended] Substituted cyclohexane-1,4-diamine derivatives of formula (I), optionally racemic forms, pure stereoisomers, especially enantiomers or parts, for the manufacture of a medicament for the treatment of pain, in particular acute, neuropathic or chronic pain Stereoisomeric forms or mixtures of stereoisomers in a particular mixing ratio, in particular enantiomers or diastereomeric mixtures; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or their solvates, especially in the form of hydrates.
    Formula I

    In Formula I above,
    R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    R 4 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; And C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , wherein X is O or S and R 7 Is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated, branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H; Saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And each unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl; or
    R 4 and R 5 together form a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms, wherein the heterocyclic radical may optionally be fused with an additional ring. Form.
    [41" claim-type="Currently amended] Substituted cyclohexane-1,4-diamine derivatives of formula (I), optionally racemic forms, pure stereoisomers, especially enantiomers or parts, for the manufacture of a medicament for the treatment of pain, in particular acute, neuropathic or chronic pain Stereoisomeric forms or mixtures of stereoisomers in a particular mixing ratio, in particular enantiomers or diastereomeric mixtures; Acid or base formulations or forms thereof, or salt forms thereof, especially salt forms of physiologically acceptable salts or physiologically acceptable acids or cations; Or their solvates, especially in the form of hydrates.
    Formula I

    In Formula I above,
    R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    R 4 is H, C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 where X is O or S R 7 is H, saturated or unsaturated, branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated, branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively.
    [42" claim-type="Currently amended] Anxiety, stress and stress-related syndromes, depression, epilepsy, Alzheimer's disease, elderly dementia, general cognitive dysfunction, learning and memory disorders (as brain supplements), withdrawal symptoms, alcohol and / or drug and / or drug abuse and / or Dependence, sexual dysfunction, cardiovascular disease, hypotension, hypertension, tinnitus, itching, migraine, hearing impairment, intestinal motility, eating insufficiency, anorexia, vomiting, exercise disorders, diarrhea, cachexia and incontinence medications, or muscle relaxants, Substituted cyclohexane-1,4- to prepare a medicament as an anticonvulsant or anesthetic, or a medicament for use in combination with an opioid analgesic or anesthesia, a diuretic or antisodium urinary stimulation and / or antianxiety agent Diamine derivatives, optionally racemic forms thereof, pure stereoisomers, in particular enantiomer or diastereomeric forms, or stereoisomeric mixtures of a specific mixing ratio Water, in particular enantiomer or diastereomer mixture forms; Their acid or base formulations or forms, or salt forms thereof, in particular physiologically acceptable salts or salt forms of physiologically acceptable acids or cations; or their solvates, in particular hydrate forms.
    Formula I

    In Formula I above,
    R 1 and R 2 are independently of each other H; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which is bonded via C 1 -C 3 -alkylene, respectively, wherein R 1 and R 2 are Except hydrogen at the same time, or
    R 1 and R 2 together may be represented by the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 (wherein R 6 is H; mono or polysubstituted, saturated or unsaturated, branched or straight chain, respectively; Unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; mono- or polysubstituted or unsubstituted aryl or heteroaryl; and are bonded through C 1 -C 3 -alkylene, respectively Mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl) or (CH 2 ) 3-6 to form a ring,
    R 3 is a saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    R 4 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; And C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , wherein X is O or S and R 7 Is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from R 8 is H; And saturated or unsaturated branched or straight chain mono- or poly-substituted or unsubstituted C 1 -C 4 -alkyl, or R 7 and R 8 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 , wherein R 10 is H; saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono- or poly-substituted or unsubstituted aryl or heteroaryl, and mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or hetero, bonded through C 1 -C 3 -alkylene, respectively; Aryl) or (CH 2 ) 3-6 , and R 9 is saturated or unsaturated, branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl; Unsubstituted or mono- or polysubstituted aryl or heteroaryl, respectively; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Selected from;
    R 5 is unsubstituted or mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; And -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O, S Or H 2 , R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 6 -alkyl, R 12 is H; And each unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl; or
    R 4 and R 5 together form a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms, wherein the heterocyclic radical may optionally be fused with an additional ring. Form.
    [43" claim-type="Currently amended] The method according to any one of claims 38, 39 and 42,
    R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl, except when R 1 and R 2 are hydrogen at the same time, or
    R 1 and R 2 together represent the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 , wherein R 6 is H; and a saturated or unsaturated branched or straight chain mono- or polysubstituted Is unsubstituted C 1 -C 8 -alkyl) or (CH 2 ) 3-6 to form a ring,
    Preferably, R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl, except when R 1 and R 2 are hydrogen at the same time, or R 1 and R 2 are Together form a ring of formula (CH 2 ) 4-5 ,
    In particular, substituted cyclohexane-1,4-diamine derivatives are used in which R 1 and R 2 are independently selected from methyl and ethyl, or R 1 and R 2 together form a ring of formula (CH 2 ) 5 Use characterized by.
    [44" claim-type="Currently amended] The method of claim 40,
    R 1 and R 2 together represent the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 , wherein R 6 is H; and a saturated or unsaturated branched or straight chain mono- or polysubstituted Is unsubstituted C 1 -C 8 -alkyl) or (CH 2 ) 3-6 to form a ring,
    Preferably, R 1 and R 2 together form a ring of formula (CH 2 ) 4-5 ,
    In particular, substituted cyclohexane-1,4-diamine derivatives are used, wherein R 1 and R 2 together form a ring of formula (CH 2 ) 5 .
    [45" claim-type="Currently amended] The method of claim 41, wherein
    R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl, except when R 1 and R 2 are hydrogen at the same time,
    Preferably, R 1 and R 2 are independently of each other H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl, except when R 1 and R 2 are hydrogen at the same time,
    In particular, R 1 and R 2 are each independently selected from methyl and ethyl,
    R 1 and R 2 together represent the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 , wherein R 6 is H; and a saturated or unsaturated branched or straight chain mono- or polysubstituted Is unsubstituted C 1 -C 8 -alkyl) or (CH 2 ) 3-6 to form a ring,
    Preferably, R 1 and R 2 together form a ring of formula (CH 2 ) 4-5 ,
    In particular, substituted cyclohexane-1,4-diamine derivatives are used, wherein R 1 and R 2 together form a ring of (CH 2 ) 5 .
    [46" claim-type="Currently amended] 43. The method of any one of claims 38 and 40-42,
    C 3 -C 8 -cycloalkyl, aryl or heteroaryl, wherein each R 3 is unsubstituted or mono- or polysubstituted; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated straight or branched substituted or unsubstituted C 1 -C 2 -alkyl group, respectively. Is selected from,
    Preferably, R 3 is unsubstituted or mono- or polysubstituted C 5 -C 6 -cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxola Nil, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl; And unsubstituted or monosubstituted or monosubstituted C 5 -C 6 -cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothio, each bonded via a saturated straight chain C 1 -C 2 -alkyl group Phenyl, pyridyl, furyl, benzofuranyl, benzodioxolanil, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl,
    In particular, R 3 is unsubstituted or mono- or polysubstituted phenyl, furyl, thiophenyl, cyclohexanyl, naphthyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pi Rollyl, pyrimidyl, pyrazinyl or benzothiophenyl; And substituted cyclohexane-1,4-diamine derivatives bonded through a saturated straight chain C 1 -C 2 -alkyl group and each selected from unsubstituted or mono- or polysubstituted phenyl, furyl or thiophenyl Use characterized by being used.
    [47" claim-type="Currently amended] The method of claim 39,
    R 3 is unsubstituted or each substituted or multi-substituted C 3 -C 8 - cycloalkyl, or heteroaryl; And unsubstituted or monosubstituted or polysubstituted aryl, C 3 -C 8 -cycloalkyl or heteroaryl, which are bonded via a saturated or unsaturated side or straight chain substituted or unsubstituted C 1 -C 4 -alkyl group, respectively. Is selected from,
    Preferably, R 3 is unsubstituted or mono- or polysubstituted C 5 -C 6 -cycloalkyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolalanyl, indolyl, indanyl, Benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl; And unsubstituted or monosubstituted or monosubstituted C 5 -C 6 -cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothio, each bonded via a saturated straight chain C 1 -C 2 -alkyl group Phenyl, pyridyl, furyl, benzofuranyl, benzodioxolanil, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl,
    In particular, R 3 is unsubstituted or mono- or polysubstituted furyl, thiophenyl, cyclohexanyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pyrrolyl, pyrimidyl, Pyrazinyl or benzothiophenyl; And substituted cyclohexane-1,4-diamine derivatives bonded through a saturated straight chain C 1 -C 2 -alkyl group and each selected from unsubstituted or mono- or polysubstituted phenyl, furyl or thiophenyl Use characterized by being used.
    [48" claim-type="Currently amended] 48. The use according to any one of claims 38 to 47, wherein substituted cyclohexane-1,4-diamine derivatives are used in which R 4 is H.
    [49" claim-type="Currently amended] The method according to any one of claims 38 to 47,
    R 4 is H, C (X) R 7 , C (X) NR 7 R 8 , C (X) OR 9 , C (X) SR 9 and S (O 2 ) R 9 , where X is O or S Is selected from
    Preferably, R 4 is selected from H, C (X) R 7 , C (X) NR 7 R 8 and C (X) OR 9 , wherein X is O,
    In particular, R 4 is selected from H and C (O) R 7 where R 7 is H; and saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl; Preferably, substituted cyclohexane-1,4-diamine derivatives are selected from H; and selected from saturated branched or straight chain unsubstituted C 1 -C 3 -alkyl; in particular CH 3 ). Characteristic uses.
    [50" claim-type="Currently amended] The method according to any one of claims 38 to 40 and 42,
    R 4 and R 5 together may be a saturated or unsaturated monocyclic or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms; Preferably, in addition to the essential atom N, having 5 to 7 ring atoms, 0 or 1 heteroatom further selected from N, S and O is further present in the ring and is monocyclic or polysubstituted or unsubstituted heterocyclic radical [Here, the heterocyclic radicals formed by R 4 and R 5 together may optionally be fused with further rings, preferably aromatic and / or heteroaromatic rings, wherein these rings can in turn be fused with further aromatic and / or heteroaromatic rings. Can be fused together, in particular the heterocyclic radicals formed by R 4 and R 5 together with one or two further rings, preferably heterocyclic formed by R 4 and R 5 The radical is further fused with two rings such that R 4 and R 5 together form Used to form a substituted cyclohexane-1,4-diamine derivative.
    [51" claim-type="Currently amended] The method according to any one of claims 38 to 40 and 42,
    R 4 is H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl,
    Preferably, H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 6 -alkyl,
    In particular, H; And substituted cyclohexane-1,4-diamine derivatives selected from saturated straight chain unsubstituted C 1 -C 3 -alkyl.
    [52" claim-type="Currently amended] The compound according to any one of claims 38 to 51,
    R 5 is each selected from unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl and heteroaryl,
    Preferably, R 5 is unsubstituted or monosubstituted or monosubstituted cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothio Phenyl, indanyl, benzodioxanyl, benzodioxolanil, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthenyl, benzo Thiazolyl, benzotriazolyl, benzo [1,2,5] thiazolyl, 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolononyl, oxopyrazolinonyl, dioxolanyl , Adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl and quinazolinyl,
    In particular, R 5 is unsubstituted or mono- or polysubstituted cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxa Substituted cyclohexane-1,4-diamine derivatives are used, which are selected from nil, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl and pyrimidyl. Characteristic uses.
    [53" claim-type="Currently amended] The compound according to any one of claims 38 to 51,
    R 5 is -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is O , S or H 2 ),
    Preferably, R 5 is -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 and —C (Y) —CH 2 —CH 2 R 12 , wherein Y is O or S,
    In particular, R 5 is -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -C (Y) R 12 and -C (Y) -CH 2 R 12 Wherein a substituted cyclohexane-1,4-diamine derivative is used, wherein Y is O.
    [54" claim-type="Currently amended] The method of claim 53,
    R 11 is H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 4 -alkyl,
    Preferably, H, saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 4 -alkyl; And saturated straight chain mono- or polysubstituted or unsubstituted C (O) OC 1 -C 2 -alkyl,
    In particular a substituted cyclohexane-1,4-diamine derivative is used, which is selected from H, CH 3 , C 2 H 5 and C (O) O—CH 3 .
    [55" claim-type="Currently amended] The method of claim 53,
    R 12 is each selected from unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl and heteroaryl,
    Preferably, R 12 is unsubstituted or mono- or polysubstituted cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothio Phenyl, indanyl, benzodioxanyl, benzodioxolanil, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthenyl, benzo Thiazolyl, benzotriazolyl, benzo [1,2,5] thiazolyl, 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolononyl, oxopyrazolinonyl, dioxolanyl , Adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl and quinazolinyl,
    In particular, R 12 is unsubstituted or mono- or polysubstituted cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxa Substituted cyclohexane-1,4-diamine derivatives are used, which are selected from nil, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl and pyrimidyl. Characteristic uses.
    [56" claim-type="Currently amended] The substituted cyclohexane-1,4-diamine derivative, medicament or method of any one of claims 1-55, wherein R 4 and R 5 together do not form a heterocyclic radical.
    [57" claim-type="Currently amended] Protected N-substituted compounds of formula III by reacting cyclohexane-1,4-dione of formula II protected with groups S 1 and S 2 with cyanide, preferably potassium cyanide, in the presence of a compound of formula HNR 01 R 02 The resulting 1-amino-4-oxo-cyclohexane-carbonitrile derivative, optionally, subsequently, in any desired order and, optionally, repeatedly, and acylation, alkylation or sulfonation For compounds wherein R 01 and / or R 02 and / or R 06 are H protected with a protecting group, one or more protecting groups are separated off and optionally acylated, alkylated or sulfonated, and / or R 01 And / or for compounds in which R 02 and / or R 06 is H, introducing one or more protecting groups and optionally performing acylation, alkylation or sulfonation, (a),
    The aminonitrile of formula III is reacted with an organometallic reagent of formula metal-R 3 , preferably a Grignard reagent or an organolithium reagent, to form a compound of formula IVa, optionally, subsequently, in any desired order and , Optionally, repeatedly, acylation, alkylation or sulfonation, and / or in the case of compounds wherein R 01 and / or R 02 and / or R 06 are protected with a protecting group, isolating at least one protecting group And optionally perform acylation, alkylation or sulfonation, and / or for compounds wherein R 01 and / or R 02 and / or R 06 are H, introduce one or more protecting groups, and acylate, alkylate or sulfonate (B) arbitrarily performing
    In the compound of formula IVa, protecting groups S 1 and S 2 are separated off to form a 4-substituted 4-aminocyclohexanone derivative of formula IV, optionally, subsequently, in any desired order and optionally , Repeatedly performing acylation, alkylation or sulfonation, and / or for compounds wherein R 01 and / or R 02 and / or R 06 are protected with a protecting group, isolating one or more protecting groups, Optionally perform acylation, alkylation or sulfonation, and / or for compounds wherein R 01 and / or R 02 and / or R 06 are H, introduce one or more protecting groups and optionally acylation, alkylation or sulfonation. Performing step (c) and
    Reductively amination of the 4-substituted 4-aminocyclohexanone derivative of Formula IVa with a compound of Formula HNR 04 R 05 to form a cyclohexane-1,4-diamine derivative of Formula V; A process for the preparation of the substituted cyclohexane-1, 4-diamine derivatives according to any one of claims 1 to 19.
    Scheme 1

    II III
    Scheme 2

    III IVa
    Scheme 3

    IVa IV
    Scheme 4

    IV V
    In Schemes 1-4 above,
    R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 1,
    R 01 and R 02 are each independently of the other H; H protected with a protecting group; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or heteroaryl, which is bonded through C 1 -C 3 -alkylene, respectively,
    R 01 and R 02 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 06 CH 2 CH 2 (wherein R 06 is H; protected with a protecting group; each saturated or unsaturated side chain or straight chain) Mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl of mono- or polysubstituted or unsubstituted aryl or heteroaryl, and C 1 -C 3 -alkyl, respectively And are monocyclic or polysubstituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or heteroaryl, each of which is bonded through a ene) or forms a ring of (CH 2 ) 3-6 ,
    R 04 is H protected by a protecting group; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl,
    R 05 is H protected by a protecting group; Unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; And -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is H 2 , R 11 is H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl, R 12 is H; And each unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl; or
    R 04 and R 05 together form a saturated or unsaturated, mono or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms,
    S 1 and S 2 are independently selected from a protecting group or together represent a protecting group, preferably monoacetal.
    [58" claim-type="Currently amended] Cyclohexane-1,4-dione of formula (II) protected by groups S 1 and S 2 is subjected to reductive amination with a compound of formula HNR 04 R 05 to form a 4-aminocyclohexanone derivative of formula VI, optionally, Subsequently, in the compound in any desired order and optionally, repeatedly, acylation, alkylation or sulfonation is performed and / or R 04 and / or R 05 is H protected with a protecting group, one Isolating at least one protecting group, optionally performing acylation, alkylation or sulfonation, and / or in the case of compounds where R 04 and / or R 05 is H, introduce at least one protecting group and (A) arbitrarily performing the phoneization;
    Reacting the 4-aminocyclohexanone derivative of formula VI with a cyanide, preferably potassium cyanide, in the presence of a compound of formula HNR 01 R 02 to give a cyclohexanone-nitrile derivative of formula VII, optionally, subsequently , Acylation, alkylation or sulfonation in any desired order and optionally, repeatedly, and / or R 01 and / or R 02 and / or R 04 and / or R 05 and / or R 06 For compounds that are H protected with a protecting group, one or more of the protecting groups are separated off and optionally subjected to acylation, alkylation or sulfonation, and / or R 01 and / or R 02 and / or R 04 and / or R For compounds wherein 05 and / or R 06 is H, introducing one or more protecting groups and optionally performing acylation, alkylation or sulfonation, (b),
    The cyclohexanone-nitrile derivative of formula VII is reacted with an organometallic reagent of formula metal-R 3 , preferably a Grignard reagent or an organolithium reagent, and finally, the protective groups S 1 and S 2 are separated off to form To form a cyclohexane-1,4-diamine derivative of and optionally undergo subsequent acylation, alkylation or sulfonation in any desired order and, optionally, repeatedly, and / or R 01 and / Or in the case of a compound in which R 02 and / or R 04 and / or R 05 and / or R 06 are H protected with a protecting group, one or more protecting groups are separated off and optionally acylated, alkylated or sulfonated And / or for compounds wherein R 01 and / or R 02 and / or R 04 and / or R 05 and / or R 06 are H, introduce one or more protecting groups and optionally perform acylation, alkylation or sulfonation Thereby forming a compound of formula 20. A process for the preparation of the substituted cyclohexane-1,4-diamine derivatives according to any one of claims 1 to 19, comprising the step (c).
    Scheme 5

    II VI
    Scheme 6

    VI VII
    Scheme 7

    VII V
    In Scheme 5-7 above,
    R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 1,
    R 01 and R 02 are each independently of the other H; H protected with a protecting group; Saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl, respectively; Mono or polysubstituted or unsubstituted aryl or heteroaryl, respectively; And mono- or poly-substituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or heteroaryl, which is bonded through C 1 -C 3 -alkylene, respectively,
    R 01 and R 02 together are of the formula CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 06 CH 2 CH 2 (wherein R 06 is H; protected with a protecting group; each saturated or unsaturated side chain or straight chain) Mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl or C 3 -C 8 -cycloalkyl of mono- or polysubstituted or unsubstituted aryl or heteroaryl, and C 1 -C 3 -alkyl, respectively And are monocyclic or polysubstituted or unsubstituted aryl, C 3 -C 8 -cycloalkyl, or heteroaryl, each of which is bonded through a ene) or forms a ring of (CH 2 ) 3-6 ,
    R 04 is H protected by a protecting group; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 8 -alkyl,
    R 05 is H protected by a protecting group; Unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl, respectively; And -CHR 11 R 12 , -CHR 11 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 R 12 , -CHR 11 -CH 2 -CH 2 -CH 2 R 12 , -C (Y) R 12 , -C (Y) -CH 2 R 12 , -C (Y) -CH 2 -CH 2 R 12 and -C (Y) -CH 2 -CH 2 -CH 2 R 12 , wherein Y is H 2 , R 11 is H; And saturated or unsaturated branched or straight chain mono- or polysubstituted or unsubstituted C 1 -C 7 -alkyl, R 12 is H; And each unsubstituted, mono- or polysubstituted C 3 -C 8 -cycloalkyl, aryl or heteroaryl; or
    R 04 and R 05 together form a saturated or unsaturated, mono or polysubstituted or unsubstituted heterocyclic radical having 3 to 8 ring atoms,
    S 1 and S 2 are independently selected from a protecting group or together represent a protecting group, preferably monoacetal.
    [59" claim-type="Currently amended] 59. The process of claim 57 or 58 wherein the protecting group on H in R 01 , R 02 , R 04 , R 05 and / or R 06 is selected from alkyl, benzyl and carbamate, for example FMOC, Z and Boc. Characterized in that the process for the preparation of substituted cyclohexane-1,4-diamine derivatives.
    [60" claim-type="Currently amended] The process of claim 57, wherein the reductive amination in step (d) is carried out in the presence of ammonium formate, ammonium acetate or NaCNBH 3 .
    [61" claim-type="Currently amended] 58. The substituted cyclone of claim 57, wherein instead of reductive amination with HNR 04 R 05 in step (d), the compound of formula IV is reacted with hydroxylamine and reduction is performed after oxime formation. Method for preparing hexane-1,4-diamine derivative.
    [62" claim-type="Currently amended] The process of claim 58, wherein in step (b) the radical R 01 in formula HNR 01 R 02 is H and the reaction with the cyanide is carried out using TMSCN, optionally, subsequently a protecting group is introduced onto R 01 . Method for producing a substituted cyclohexane-1,4-diamine derivative, characterized in that.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-05-09|Priority to DE10123163A
    2001-05-09|Priority to DE10123163.6
    2002-05-08|Application filed by 그뤼넨탈 게엠베하
    2002-05-08|Priority to PCT/EP2002/005051
    2004-02-26|Publication of KR20040017214A
    2009-05-08|Application granted
    2009-05-08|Publication of KR100895778B1
    优先权:
    申请号 | 申请日 | 专利标题
    DE10123163A|DE10123163A1|2001-05-09|2001-05-09|Substituted cyclohexane-1,4-diamine derivatives|
    DE10123163.6|2001-05-09|
    PCT/EP2002/005051|WO2002090317A1|2001-05-09|2002-05-08|Substituted cyclohexane-1,4-diamine derivatives|
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