ZA200401223B - Substituted 4-aminocyclohexanol derivatives - Google Patents

Substituted 4-aminocyclohexanol derivatives Download PDF

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ZA200401223B
ZA200401223B ZA2004/01223A ZA200401223A ZA200401223B ZA 200401223 B ZA200401223 B ZA 200401223B ZA 2004/01223 A ZA2004/01223 A ZA 2004/01223A ZA 200401223 A ZA200401223 A ZA 200401223A ZA 200401223 B ZA200401223 B ZA 200401223B
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polysubstituted
mono
chosen
unsubstituted
case
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ZA2004/01223A
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Heinrich Hennies Hagen
Yvonne Kogel Babette
Sundermann Bernd
Wnendt Stephan
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Gruenenthal Chemie
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Priority claimed from PCT/EP2002/007849 external-priority patent/WO2003008371A1/en
Application filed by Gruenenthal Chemie filed Critical Gruenenthal Chemie
Publication of ZA200401223B publication Critical patent/ZA200401223B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

) J4Qblo! ® WO 03/008371 PCT/EP02/07849
Patent Application of Griinenthal GmbH, D-52078 Aachen (Applicant's reference G 3041)
Substituted 4-aminocyclohexanol derivatives } 5 .
The present invention relates to substituted 4- aminocyclohexanol derivatives, processes for their preparation, medicaments comprising these compounds and the use of substituted 4-aminocyclohexanol derivatives for the preparation of medicaments for treatment of diverse : indications, in particular pain.
The heptadecapeptide nociceptin is an endogenous ligand of the ORL1 (opioid receptor-like) receptor (Meunier et al.,
Nature 377, 1995, p. 532-535), which belongs to the family of opioid receptors and is to be found in many regions of the brain and spinal cord (Mollereau et al., FEBS Letters, 341, 1994, p. 33-38, Darland et al., Trends in
Neurosciences, 21, 1998, p. 215-221). The peptide is characterized by a high affinity, with a Kg value of approximately 56 pM (Ardati et al., Mol. Pharmacol. 51, p. 816-824), and by a high selectivity for the ORL1 receptor.
The ORL1 receptor is homologous to the uy, k and & opioid receptors and the amino acid sequence of the nociceptin peptide has a high similarity with those of the known opioid peptides. The activation of the receptor induced by nociceptin leads, via coupling with Gis, proteins, to an inhibition of adenylate cyclase (Meunier et al., Nature 377, 1995, p. 532-535). Functional similarities of the yu, x and & opioid receptors with the ORL1 receptor are also present at the cell level in respect of activation of the potassium channel (Matthes et al., Mol. Pharmacol. 50,
® WO 03/008371 PCT/EP02/07849 1996, p. 447-450; Vaughan et al., Br. J. Pharmacol. 117, 1996, p. 1609-1611) and inhibition of the L-, N- and P/Q- type calcium channels (Conner et al., Br. J. Pharmacol. 118, 1996, p. 205-207; Knoflach et al., J. Neuroscience 16, 1996, p. 6657-6664).
The nociceptin peptide shows a pronociceptive and hyperalgesic activity after intercerebroventicular administration in various animal models (Reinscheid et al.,
Science 270, 1995, p. 792-794; Hara et al,. Br. J.
Pharmacol. 121, 1997, p. 401-408). These findings can be explained as inhibition of stress-induced analgesia (Mogil et al., Neurosci. Letters 214, 1996, pl31-134; and
Neuroscience 75, 1996, p. 333-337). In this connection it has also been possible to demonstrate an anxiolytic activity of nociceptin (Jenck et al., Proc. Natl. Acad.
Sci. USA 94, 1997, 14854-14858).
On the other hand, it has also been possible to show an antinociceptive effect of nociceptin in various animal models, in particular after intrathecal administration.
Nociceptin inhibits the activity of kainate- or glutamate- stimulated dorsal root ganglia neurones (Shu et al.,
Neuropeptides, 32, 1998, 567-571) or glutamate-stimulated spinal cord neurones (Faber et al., Br. J. Pharmacol., 119, 1996, p. 189-190); it has an antinociceptive action in the tail flick test in the mouse (King at al., Neurosci. Lett., 223, 1997, 113-116), in the flexor-reflex model in the rat (Xu et al., NeuroReport, 7, 1996, 2092-2094) and in the formalin test on the rat (Yamamoto et al., Neuroscience, 81, 1997, p. 249-254). In models for neuropathic pain it
® WO 03/008371 PCT/EP02/07849 has also been possible to demonstrate an antinociceptive action of nociceptin (Yamamoto and Nozaki-Taguchi,
Anesthesiology, 87, 1997), which is of interest in as much as the activity of nociceptin increases after axotomy of spinal nerves. This is in contrast to conventional opioids, the activity of which decreases under these conditions (Abdulla and Smith, J. Neurosci., 18, 1998, p. 9685-9694).
The ORL1 receptor is moreover also involved in the regulation of further physiological and pathophysiological processes. These include, inter alia, learning and memory formation (Sandin et al., Eur. J. Neurosci., 9, 1997, p. 194-197; Manabe et al., Nature, 394, 1997, p. 577-581), hearing ability (Nishi et al., EMBO J., 16, 1997, p. 1858- 1864), food intake (Pomonis et al., NeuroReport, 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, 1977, p. 309-312), epilepsy (Gutiérrez 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). In a review article by Calo et al. (Br. J. Pharmacol., 129, 2000, 1261-1283) an overview of the indications or biological processes in which the ORL1l receptor plays or with high probability could play a role is given. There are mentioned, inter alia: analgesia, stimulation and regulation of food intake, influence on p-agonists, such as morphine, treatment of withdrawal symptoms, reduction in the addiction potential of morphines, anxiolysis, modulation of motor activity,
memory disorders, epilepsy; modulation of neurotransmitter secretion, in particular of glutamate, serotonin and dopamine, and therefore neurodegenerative diseases; influencing of the cardiovascular system, initiation of an erection, diuresis, antinatriuresis, electrolyte balance, aterial blood pressure, water retention diseases, intestinal motility (diarrhoea), relaxing effects on the respiratory tract, micturation reflex (urinary incontinence). The use of agonists and antagonists as anoretics, analgesics (also in co-administration with opioids) or nootropics, and also as antitussives is furthermore discussed.
The possible uses of compounds which bond to the ORL] receptor and activate or inhibit this are correspondingly diverse.
The object of the present invention was to provide active compounds which act on the nociceptin/ORL1 receptor system and are therefore suitable for medicaments, in particular for treatment of the various diseases which, according to the prior art, are connected with this system, or for use in the indications mentioned there.
The invention therefore provides substituted 4- aminocyclohexanol derivatives according to the general formula I
R* OH 8 .R?
RON
1
I wherein : R! and. R? independently of one another are chosen from 5 H; Cj-g—alkyl or Csg-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl-, or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or aryl, Cs-g-cycloalkyl or heteroaryl bonded via C;-z3—alkylene and in each case mono- or polysubstituted or unsubstituted; wherein R! and R? may not both be H, or the radicals R! and R? together form a ring and denote CH,CH,0CH»CH>, CH,CH,NR®CH,CH, or (CH3) 3-6, where R® is chosen from H; Ci.g—alkyl or Cs_g- cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl-, or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or aryl, Cs_g-cycloalkyl or heteroaryl bonded via Cj;-3-alkylene and in each case mono- or polysubstituted or unsubstituted;
® WO 03/008371 PCT/EP02/07849 - R® is chosen from Ci.g—alkyl or Cs-g—cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or aryl,
Cs-g—cycloalkyl or heteroaryl bonded via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C;-4—alkyl group and in each case unsubstituted or mono- or polysubstituted;
RY is chosen from Cs-g-cycloalkyl, aryl or heteroaryl, : 10 in each case unsubstituted or mono- or polysubstituted; -CHR®R’, -CHR®-CH.R’, -CHR®-CH,-CH,R’, —CHR®-CH,~CH,-CH,R’, -C(Y)R’, —C(Y)-CH,R’, —C(Y)-CHp-CHR’ or -C(Y)-CHp-CHp-CH;R”; or -R®-L-R’ where Y = 0, S or Hy, where R® is chosen from
H, Ci-;—alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C(0)0-C;-¢—alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; and where R7 is chosen from
H; Cs.g—cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted, where R® is chosen from
. aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted, where L is chosen from -C (0) -NH-, =-NH-C(O)-, -C(O)-0-, -0-C(O)-, -0O-, -S- or -5(0)2- where R® is chosen from } aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted, optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; : in the form shown or in the form of their acids or their bases or in the form of their salts, in particular the physiologically acceptable salts, or in the form of their solvates, in particular the hydrates.
All these compounds or compound groups according to the invention show outstanding binding to the ORL1 receptor.
Compounds which show a certain remote structural relationship to the compounds proposed here are known from the following publications:
® WO 03/008371 PCT/EP02/07849 ". DE-0S-28 39 891 or the parallel US patent US 4,366,172 (Lednicer et al.). In this the compounds mentioned are described as analgesically active, without reference being made to the ORL1 receptor. ® The parallel articles: - D. Lednicer and P.F. von Voightlander, J. Med. Chem. 1979, 22, 1157, - D. Lednicer, P.F. von Voightlander and D.E. Emmert, J.
Med. Chem. 1980, 23, 424, and i : 10 - D. Lednicer, P.F. von Voightlander and D.E. Emmert, J.
Med. Chem. 1981, 24, 404, - D. Lednicer, P.F. von Voightlander and D.E. Emmert, J.
Med. Chem. 1981, 24, 340, - P.F. VonVoightlander, D. Lednicer, R.A. Lewis and D.D.
Gay, "Endogenous and Exogenous Opiate Agonists and
Antagonists", Proc. Int. Narc. Res. Club Conf. (1980),
Meeting Date 1979, Way E.Long (Ed), Publisher: Pergamon,
Elmsford, N.Y.International, Pergamon, 1980, 17-21, = Kamenka et al., EurJd.Med.Chem.Chim. Ther. ; FR; 19;3;1984;255-260 and ®= Rao M.N.A. and Rao S.C. Indian Drugs, 1985, 22 (5), 252- 257.
In the context of this invention, alkyl or cycloalkyl radicals are understood as meaning saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which can be unsubstituted or mono- or polysubstituted. Here, Cj-alkyl represents Cl- or Cc2- alkyl, Ci-3—alkyl represents Cl-, C2- or C3-alkyl, Ci-g—alkyl represents Cl-, C2-, C3- or Cd-alkyl, Ci-s~—alkyl represents ci-, C2-, C3-, C4- or C5-alkyl, Ci-e¢—alkyl represents Cl-,

Claims (1)

  1. ® WO 03/008371 PCT/EP02/07849 Patent claims
    1. Substituted 4-aminocyclohexanol derivatives of the general formula I R* OH
    3 .R? R®* TN bo I wherein R! and R? independently of one another are chosen . from H; Ci-g—alkyl or Cjz_g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl-, or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or aryl, Csz-g- cycloalkyl or heteroaryl bonded via C;.z-alkylene and in each case mono- or polysubstituted or unsubstituted; wherein R' and R? may not both be H, or the radicals R! and R® together form a ring and denote CH,CH,0CH>CH>, CH,CH,NR>CH,CH, or (CH) 3-6, where R® is chosen from H; Ci_g—alkyl or Cs.g- cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl-,
    ® WO 03/008371 PCT/EP02/07849
    . or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or aryl, Ci-g—-cycloalkyl or heteroaryl bonded via Cji-3— alkylene and in each case mono- or polysubstituted or unsubstituted; R® is chosen from Ci-g—alkyl or Csz-g—cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or aryl, Csg-cycloalkyl or heteroaryl bonded via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C;_4~alkyl group and in each case unsubstituted or mono- or polysubstituted; R? is chosen from Ci-g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; —-CHR®R, -CHR®-CH,R’, ~CHR®-CH,- CH2R’, -CHR®-CH,-CH,~CH2R’, -C(Y)R’, -C(Y)-CH.R’, ~C(Y) =CHp-CH,R” or -C(Y)~-CH,-CH;-CH;R’; or -R®-L-R® where Y = 0, S$ or Hp, ‘where R® is chosen from H, Ci-gs-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C(0)0- C;-¢—alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
    ® WO 03/008371 PCT/EP02/07849 and where R7 is chosen from : H; Cs-g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted, where R® is chosen from aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted, where L is chosen from -C(0)~-NH-, -NH-C(O)-, -C(O)-0-, =-0-C(O)-, -0-, =-S- or -S(0O)2- where R® is chosen from aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted, optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; in the form shown or in the form of their acids or their bases or in the form of their salts, in particular the physiologically acceptable salts, or in
    ® WO 03/008371 PCT/EP02/07849 - the form of their solvates, in particular the hydrates.
    2. Substituted 4-aminocyclohexanol derivatives according to claim 1, characterized in that R! and R? independently of one another are chosen from H; Ci-g—alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; where R! and R? may not both be . y or the radicals R! and R? together form a ring and denote CH;CH»,OCH,CH2, CH,CH,NR®CH,CH, or (CHa) 3-6, where R® is chosen from H; Ci-g—alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, preferably R! and R? independently of one another are chosen from H; C;-4~alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; where R! and R? may not both be H, or the radicals R' and R? together form a ring and denote (CH) s-5,
    ® WO 03/008371 PCT/EP02/07849
    . in particular R! and R? independently of one another are chosen from methyl or ethyl or the radicals R' and R? together form a ring and denote (CHz)s.
    3. Substituted 4-aminocyclohexanol derivatives according to one of claims 1 or 2, characterized in that R® is chosen from Cs.g-cycloalkyl, unsubstituted or mono- or polysubstituted; or aryl, Csz.g—cycloalkyl or heteroaryl bonded via a saturated or unsaturated, unbranched, substituted or unsubstituted Ci-4-alkyl group and in each case unsubstituted or mono- or polysubstituted; preferably R® is chosen from Cs_g-cycloalkyl, unsubstituted or mono- or polysubstituted; or Cs-g-cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, pyridyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl bonded via a saturated, unbranched C;-»—-alkyl group and in each case unsubstituted or mono- or polysubstituted; in particular R® is chosen from phenyl, pyridyl, furyl or thiophenyl bonded via a saturated, unbranched
    ® WO 03/008371 PCT/EP02/07849 : C;-z—alkyl group and in each case unsubstituted or mono- or polysubstituted.
    4. Substituted 4-aminocyclohexanol derivatives according to one of claims 1 to 3, characterized in that R? is chosen from Csg-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; or -R%®-L-R° : 10 preferably R? is chosen from cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl or benzo[1l,2,5]thiazolyl or 1,2- dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolinonyl, oxopyrazolinonyl, dioxolanyl, adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl or quinazolinyl, in each case unsubstituted or mono- or polysubstituted; or -R®-L-R’ in particular
    ® WO 03/008371 PCT/EP02/07849 - R? is chosen from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzothiazolyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, : 5 benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, in each case unsubstituted or mono- or polysubstituted; or -R8-1-R®.
    5. Substituted 4-aminocyclohexanol derivatives according to claim 4, characterized in that R® is chosen from indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl or benzo[l,2,5]thiazolyl or 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolinonyl, oxopyrazolinonyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl or quinazolinyl, in each case unsubstituted or mono- or polysubstituted, L is chosen from
    ® WO 03/008371 PCT/EP02/07849
    . -C(0)-NH-, -NH-C(0O)-, -C(O)-0-, -0-C(O)-, -0-, -S- OR -S5(0),-, and/or R® is chosen from indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl or benzo[l,2,5]thiazolyl or 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolinonyl, oxopyrazolinonyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl or gquinazolinyl, in each case unsubstituted or mono- or polysubstituted, preferably R® is chosen from indolyl, benzothiophenyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, in each case unsubstituted or mono- or polysubstituted, L is chosen from
    ® WO 03/008371 PCT/EP02/07849 -C(0)-NH-, -NH-C(0)-, -C(0)-0-, -0-C(0)- or ) -S5(0)2—, and/or R® is chosen from indolyl, benzothiophenyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, in each case unsubstituted or mono- or polysubstituted, in particular R® is chosen from indolyl, unubstituted, L is chosen from -S (0) 2- and R® is chosen from phenyl, unsubstituted.
    6. Substituted 4-aminocyclohexanol derivatives according to one of claims 1 to 3, characterized in that R? is chosen from -CHR®R’, -CHR®-CH,R’, -CHR®-CH,- CH,R’, -CHR®-CH,-CH,-CHR’, -C(Y)R’, -C(Y)-CH.R, ~C(Y) -CHp-CH,R’ or -C(Y)-CHp-CH,-CH,R’
    - where Y¥Y = O, S or Hj, preferably R?! is chosen from -CHR®R’, -CHR®-CH,R’, -CHR®-CH:- CH,R”, -C(Y)R’, -C(Y)-CH;R’ or -C(Y)-CHy-CH,R’ where Y = O or S, : 10 in particular R* is chosen from -CHR®R’, -CHR®-CH,R’, -C(Y)R’ or -C (Y) ~-CH3R’ where Y = O.
    7. Substituted 4-aminocyclohexanol derivatives according to claim 6, characterized in that R® is chosen from H, Ci-s-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C(O)O- Ci-¢—alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; preferably
    9 WO 03/008371 PCT/EP02/07849 : H, Ci-4-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; in particular H, CHs and CjHs.
    8. Substituted 4-aminocyclohexanol derivatives according to claim 6, characterized in that R’ is chosen from Cs.g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; preferably R’ is chosen from cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, .pyrazinyl or pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl or benzo[1l,2,5]thiazolyl or 1,2- dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolinonyl, oxopyrazolinonyl, dioxolanyl, adamantyl, pyrimidinyl, gquinolinyl, isoquinolinyl, phthalazinyl or quinazolinyl, in each case unsubstituted or mono- or polysubstituted; in particular R’ is chosen from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, : 10 carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, in each case unsubstituted or mono- or polysubstituted.
    9. Substituted 4-aminocyclohexanol derivatives according to one of claims 1 to 8, characterized in that they are chosen from the following group: e 4-benzyl-4-dimethylamino-l-phenethylcyclohexanol and the corresponding hydrochloride, J 4-dimethylamino-1, 4-diphenethylcyclohexanol and the corresponding hydrochloride, eo 4-benzyl-4-dimethylamino-1-[2-(2- fluorophenyl)ethyl]cyclohexanol and the corresponding hydrochloride, e 4-benzyl-4-dimethylamino-1-{2-(4- fluorophenyl)ethyl]cyclohexanol and the corresponding hydrochloride, e 4-dimethylamino-4-(2-fluorobenzyl)-1- phenethylcyclohexanol and the corresponding hydrochloride,
    : e 4-dimethylamino-4-(3-fluorobenzyl)-1- : phenethylcyclohexanol and the corresponding hydrochloride,
    eo 4-dimethylamino-4-(4-fluorobenzyl)-1-
    phenethylcyclohexanol and the corresponding hydrochloride,
    e 4-benzyl-4-dimethylamino-1-[2- (3~- fluorophenyl)ethyl]lcyclohexanol and the corresponding hydrochloride-
    e 4-benzyl-4-dimethylamino-1-(2- fluorobenzyl)cyclohexanol and the corresponding hydrochloride,
    e¢ 4-(allylmethylamino)-4-benzyl-1- phenethylcyclohexanol and the corresponding hydrochloride,
    e 4-penzyl-4-dimethylamino-1-(3- fluorobenzyl) cyclohexanol and the corresponding hydrochloride,
    oe 4-benzyl-4-dimethylamino-1-(4-
    fluorobenzyl) cyclohexanol and the corresponding
    + hydrochloride,
    eo l-benzyl-4-dimethylamino-4-(3- fluorobenzyl) cyclohexanol and the corresponding hydrochloride or oe 4-benzyl-l-phenethyl-4-pyrrolidin-1l-ylcyclohexanol and the corresponding hydrochloride oe 4-benzyl-4-dimethylamino-1-(l-methyl-1H-indol-2- yl) cyclohexanol e 1-benzo[b]thiophen-2-yl-4-benzyl-4-
    dimethylaminocyclohexanol
    © e 1l-benzo[b]thiophen-3-yl-4-benzyl-4- dimethylaminocyclohexanol e l-benzofuran-2-yl-4-benzyl-4-dimethylamino- cyclohexanol : optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; in the form shown or in the form of their acids or their bases or in the form of their salts, in particular the physiologically acceptable salts, or in the form of their solvates, in particular the hydrates.
    10. Medicaments comprising at least one substituted 4- aminocyclohexanol derivative according to one of claims 1 to 9, optionally in the form of its racemate, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; in the form shown or in the form of the acids or the bases or in the form of the salts, in particular the : physiologically acceptable salts, or in the form of the solvates, in particular the hydrates; and optionally suitable additives and/or auxiliary substances and/or optionally further active compounds.
    11. Medicament according to claim 10, characterized in that in addition to at least one substituted 4- aminocyclohexanol derivative, the medicament also comprises an opioid, preferably a potent opioid, in particular morphine, or an anaesthetic, preferably hexobarbital or halothane.
    12. Use of a substituted 4-aminocyclohexanol derivative according to one of claims 1 to 9, optionally in the : form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; in the form shown or in the form of its acids or its bases or in the form of its salts, in particular the physiologically acceptable salts, or in the form of its solvates, in particular the hydrates; for the preparation of a medicament for treatment of pain, in particular acute, visceral, neuropathic or chronic pain.
    13. Use of a substituted 4-aminocyclohexanol derivative according to one of claims 1 to 9, optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; in the form shown or in the form of its acids or its bases or in the form of its salts, in particular the physiologically acceptable salts, or in the form of its solvates, in particular the hydrates;
    : for the preparation of a medicament for treatment of anxiety states, of stress and stress-associated syndromes, depressions, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunctions, learning and memory difficulties (as a nootropic), withdrawal symptoms, alcohol and/or drug and/or medicament abuse and/or dependency, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinitus, pruritus, migraine, impaired hearing, deficient intestinal motility, impaired food intake, anorexia, obesity, locomotor disorders, diarrhoea, cachexia, urinary incontinence or as a muscle relaxant, anticonvulsive, antitussive or anaesthetic or for co-administration in treatment with an opioid analgesic or with an anaesthetic, for diuresis or antinatriuresis and/or anxiolysis.
    14. Process for the preparation of a substituted 4- aminocyclohexanol derivative according to one of claims 1 to 9 with the following steps:
    a. a cyclohexane-1,4-dione, protected with the groups st and S%, according to formula II is reacted with a cyanide, preferably potassium cyanide, in the presence of a compound of the formula HNR'R% to give a : protected N-substituted l-amino-4-oxo- cyclohexanecarbonitrile derivative according to formula III;
    o WO 03/008371 PCT/EP02/07849 9 RN = ro1-N =~ —_— IT III optionally acylation, alkylation or sulfonation is then carried out in any desired sequence and optionally repeatedly, and/or in the case of compounds where R°' and/or R% and/or R°® = H protected with a protective group, at least once a protective group is split off and optionally acylation, alkylation or sulfonation is carried out, and/or in the case of a compounds where R® and/or R%? and/or R% = H, at least once a protective group is introduced and optionally acylation, alkylation or sulfonation is carried out,
    b. the aminonitrile according to formula III is reacted with organometallic reagents, preferably Grignard or organolithium reagents, of the formula metal-R®, so that a compound according to formula IVa is formed; R02 R02 —N | a : i y got-N R gs? _ 2 1 _ 2 ~o0” No S 5 ) S IIT Iva optionally acylation, alkylation or sulfonation is then carried out in any desired sequence and optionally repeatedly, and/or in the case of compounds
    Co where R% and/or R% and/or R%° = H protected with a protective group, at least once a protective group is split off and optionally acylation, alkylation or sulfonation is carried out, and/or in the case of a compounds where R% and/or R% and/or R°® = H, at least once a protective group is introduced and optionally acylation, alkylation or sulfonation is carried out,
    Cc. on the compound according to formula IVa according to formula III, the protective groups S' and S? are split off so that a 4-substituted 4-aminocyclohexanone derivative according to formula IV is formed; R%2 R2 Ne) cor N i” —_— s'e 82 ol oO ©O ) Iva Iv optionally acylation, alkylation or sulfonation is then carried out in any desired Sequence and optionally repeatedly, and/or in the case of compounds where R% and/or R° and/or R°® = H protected with a protective group, at least once a protective group is split off and optionally acylation, alkylation or sulfonation is carried out, and/or in the case of a compounds where R% and/or R%? and/or R% = H, at least once a protective group is introduced and optionally acylation, alkylation or sulfonation is carried out,
    d.. the 4-substituted 4-aminocyclohexanone derivative according to formula IV is reacted with organometallic reagents, preferably Grignard or organolithium reagents, of the formula metal-R?® so that a compound according to formula V is formed; RO? Re? br =k : —_— : S RO4 OH iv Vv optionally acylation, alkylation or sulfonation is then carried out in any desired sequence and optionally repeatedly, and/or in the case of compounds where R°' and/or R% and/or R% and/or R®°® and/or R% = H protected with a protective group, at least once a protective group is split off and optionally acylation, alkylation or sulfonation is carried out, and/or in the case of a compounds where R® and/or R°? and/or R% and/or R%° and/or R% = H, at least once a protective group is introduced and optionally acylation, alkylation or sulfonation is carried out, until a compound according to formula I is formed,
    wherein R', R®>, R?, R® and R® have the meaning given in claim 1 and
    9 WO 03/008371 PCT/EP02/07849
    R” and R% independently of one another are chosen from H; H provided with a protective group; Cji-s- alkyl or Cs-g-cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl-, or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or aryl, Ci-g-cycloalkyl or heteroaryl bonded via Cj;-3-alkylene and in each case mono- or polysubstituted or unsubstituted;
    or the radicals R® and R% together form a ring and denote CH,CH,OCH,CH,, CH,CH,NR®°CH,CH, or (CHz) 3-6, where R% is chosen from H; H provided with a protective group; Ci;_g-alkyl or Ciz_g- cycloalkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl-, or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or aryl, Cis-g—cycloalkyl or heteroaryl bonded via Cj_3- alkylene and in each case mono- or polysubstituted or unsubstituted;
    R% is chosen from H, H provided with a protective group; Cs_g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; -CHR®R’, ~CHR®-CH,R’, -CHR®-CH,- CHzR’, -CHR®-CH,-CH,-CHzR’, -C(Y)R’, -C(Y)-CHyR’, -C(Y)-CH,-CH,R" or -C(Y)-CHp-CH;-CH,R’; or -R%-L-R°
    \
    where Y = 0, S or H,, where R® is chosen from
    H, C;-s-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; or C(0)O- Ci-¢—alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; and where R7 is chosen from H; Cs-g-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or mono- or : polysubstituted, where R® is chosen from aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted, where L is chosen from
    -C (0) -NH-, -NH-C(O0)-, -C(0)-0-, -0-C{(0O}-, -0-, -S- or -S5(0)2- where R’? is chosen from
    18 PCT/EP02/07849 aryl or heteroaryl, in each case “unsubstituted or mono- or polysubstituted, and s! ana &? independently of one another are chosen from protective groups or together denote a protective group, preferably monoacetal.
    15. Process for the preparation of a substituted 4- aminocyclohexanol derivative according to claim 14, characterized in that the protective groups on H in ROL, r0Z, r04 and/or RY are chosen from alkyl, benzyl or carbamates, for example FMOC, Z or Boc.
    16. A substance or composition for use in a method for treatment of pain, in particular acute, visceral, neuropathic or chronic pain, said substance or composition comprising a substituted 4- aminocyclohexanol derivative according to one of claims 1 to 9, optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; in the form shown or in the form of its acids or its bases or in the form of its salts, in particular the physiologically acceptable salts, or in the form of its solvates, in particular the hydrates; and said method comprising administering said substance or composition.
    17. A substance or composition for use in a method for the treatment of anxiety states, of stress and stress- associated syndromes, depressions, epilepsy, Alzheimer’s disease, senile dementia, general cognitive dysfunctions, learning and memory AMENDED SHEET .
    EJ PCT/EP02/07849 difficulties (as a nootropic), withdrawal symptoms, alcohol and/or drug and/or medicament abuse and/or dependency, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinitus, pruritus, migraine, impaired hearing, deficient intestinal motility, impaired food intake, anorexia, obesity, locomotor disorders, diarrhoea, cachexia, urinary incontinence or as a muscle relaxant, anticonvulsive, antitussive or anaesthetic or for co- administration in treatment with an opioid analgesic or with an anaesthetic, for diuresis or antinatriuresis and/or anxiolysis, said substance or composition comprising a substituted 4 - aminocyclohexanol derivative according to one of claims 1 to 9, optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; in the form shown or in the form of its acids or its bases or in the form of its salts, in _ particular the physiologically acceptable salts, or in the form of its solvates, in particular the hydrates; and said method comprising administering said substance or composition.
    18. A derivative according to any one of claims 1 to 9, substantially as herein described and illustrated.
    19. A medicament according to claim 10 or claim 11, substantially as herein described and illustrated.
    20. Use according to claim 12 or claim 13, substantially as herein described and illustrated. AMENDED SHEET
    & PCT/EP02/07849
    21. A process according to claim 14 or claim 15, substantially as herein described and illustrated.
    22. A substance or composition for use in a method of treatment according to claim 16 or claim 17, substantially as herein described and illustrated.
    23. A new derivative, a new medicament, a new use of a derivative as claimed in any one of claims 1 to 9, a new process for the preparation of a derivative, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
ZA2004/01223A 2001-07-17 2004-02-16 Substituted 4-aminocyclohexanol derivatives ZA200401223B (en)

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DE101356358 2001-07-17
DE101356374 2001-07-17
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