WO2009103552A1 - Substituted indole derivatives - Google Patents

Substituted indole derivatives Download PDF

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Publication number
WO2009103552A1
WO2009103552A1 PCT/EP2009/001232 EP2009001232W WO2009103552A1 WO 2009103552 A1 WO2009103552 A1 WO 2009103552A1 EP 2009001232 W EP2009001232 W EP 2009001232W WO 2009103552 A1 WO2009103552 A1 WO 2009103552A1
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Prior art keywords
methyl
dimethylamino
indol
piperidin
phenylpiperidin
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PCT/EP2009/001232
Other languages
French (fr)
Inventor
Stefan Schunk
Stefan OBERBÖRSCH
Werner Englberger
Bernd Sundermann
Original Assignee
Grünenthal GmbH
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Publication date
Application filed by Grünenthal GmbH filed Critical Grünenthal GmbH
Priority to AU2009216920A priority Critical patent/AU2009216920B2/en
Priority to CN200980115064.3A priority patent/CN102015683B/en
Priority to CA2716270A priority patent/CA2716270C/en
Priority to MX2010009045A priority patent/MX2010009045A/en
Priority to RU2010138838/04A priority patent/RU2500677C2/en
Priority to EP09713555.2A priority patent/EP2254883B1/en
Priority to JP2010547116A priority patent/JP5635914B2/en
Publication of WO2009103552A1 publication Critical patent/WO2009103552A1/en
Priority to IL207684A priority patent/IL207684A/en
Priority to HK11104071.1A priority patent/HK1149762A1/en

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Definitions

  • the present invention relates to substituted indole derivatives, processes for the preparation thereof, medicinal products containing these compounds and the use of substituted indole derivatives for the preparation of medicinal products.
  • 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, is to be found in many regions of the brain and spinal cord, and has a high affinity for the ORL1 receptor.
  • the ORL1 receptor is homologous to the ⁇ , K and ⁇ opioid receptors and the amino acid sequence of the nociceptin peptide displays a strong similarity to those of the known opioid peptides.
  • the nociceptin peptide After intercerebroventicular application, the nociceptin peptide exhibits pronociceptive and hyperalgesic activity in various animal models (Reinscheid et al., Science 270, 1995, p. 792- 794). These findings can be explained as an inhibition of stress-induced analgesia (Mogil et al., Neuroscience 75, 1996, p. 333-337). Anxiolytic activity of the nociceptin could also be demonstrated in this connection, (Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854- 14858).
  • nociceptin has an antinociceptive effect in various pain models, for example in the tail flick test in mice (King et al., Neurosci. Lett., 223, 1997, 113-116).
  • an antinociceptive effect of nociceptin could likewise be detected and was particularly beneficial since the effectiveness of nociceptin increases after axotomy of spinal nerves. This contrasts with conventional opioids, the effectiveness of which decreases under these conditions (Abdulla and Smith, J. Neurosci., 18, 1998, p. 9685-9694).
  • the ORL1 receptor is also involved in the regulation of further physiological and pathophysiological processes. These include inter alia learning and memory (Manabe et al., Nature, 394, 1997, p. 577-581), hearing capacity (Nishi et al., EMBO J., 16, 1997, p. 1858- 1864) and numerous further processes.
  • a synopsis by CaIo et al. (Br. J. Pharmacol., 129, 2000, 1261 - 1283) gives an overview of the indications or biological processes in which the ORL1 -receptor plays a part or very probably plays a part.
  • analgesics stimulation and regulation of food intake, effect on ⁇ -agonists such as morphine, treatment of withdrawal symptoms, reduction of the addiction potential of opioids, anxiolysis, modulation of motor activity, memory disorders, epilepsy; modulation of neurotransmitter release, in particular of glutamate, serotonin and dopamine, and hence neurodegenerative diseases; influence on the cardiovascular system, triggering of an erection, diuresis, antinatriuresis, electrolyte balance, arterial blood pressure, water retention disorders, intestinal motility (diarrhoea), relaxation of the respiratory tract, micturation reflex (urinary incontinence).
  • agonists and antagonists as anorectics, analgesics (also when coadministered with opioids) or nootropics is also discussed.
  • opioid receptors such as the ⁇ - receptor, but also the other subtypes of these opioid receptors, namely ⁇ and K, play an important part in the field of pain therapy and also other of the aforementioned indications. It is accordingly desirable if the compound also has an effect on these opioid receptors.
  • the object of the present invention was to provide medicinal products which act on the nociceptin/ORL1 receptor system.
  • substituted indole derivatives having the general formula I act on the nociceptin/ORL1 receptor system and are suitable for the treatment of pain, anxiety conditions and other diseases.
  • R 1 and R 2 mutually independently denote C 1-3 alkyl or H or the radicals R 1 and R 2 form a ring with inclusion of the N atom and together denote (CH 2 ) 3 or (CH 2 )-*;
  • R 3 denotes aryl or heteroaryl, each optionally bound by a C 1-3 alkyl chain, each unsubstituted or mono- or polysubstituted; or C 1-6 alkyl, unsubstituted or mono- or polysubstituted;
  • R 4 denotes H; C 1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl, heteroaryl or cycloaryl, each optionally bound by a C 1-3 alkyl chain;
  • R 5a c and R 6a c mutually independently stand for H; F, CN, OH, OCH 3 , OCF 3 ; C 1-6 alkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C 3-8 cycloalkyl, aryl or heteroaryl, each unsubstituted or mono- or polysubstituted; or for a C 3-8 cycloalkyl, aryl or heteroaryl radical bound by a C 1-3 alkyl chain, each unsubstituted or mono- or polysubstituted; or one of the radicals R 5a c or R 6a" c forms a five-, six- or seven-membered ring with the radical R 4 with inclusion of the nitrogen atom, which ring can itself be substituted or unsubstituted or can be fused to a further five-, six- or seven-membered ring, which can be aromatic or non
  • y independently stand for H; F, CN, OH, OCH 3 , OCF 3 ; C 1-6 alkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C 3-8 cycloalkyl, aryl or heteroaryl, each unsubstituted or mono- or polysub- stituted; or for a C 3-8 cycloalkyl, aryl or heteroaryl radical bound by a C 1-3 alkyl chain, each unsubstituted or mono- or polysubstituted;
  • radicals R 7a'c or R 8a c forms a five-, six- or seven-membered unsaturated ring with a substituent in the 2 or 3 position of the indolyl ring X,
  • R 3 stands for a phenyl radical which is substituted in the 3 position with OH or OCOC 1-8 alkyl are excluded from protection, in the form of the racemate; the enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a single enantiomer or diastereomer; the bases and/or salts of physiologically compatible acids or cations.
  • the compounds according to the invention exhibit good binding to the ORL1 receptor but also to the ⁇ -opioid receptor.
  • C 1-6 alkyl and “C 1-3 alkyl” include acyclic saturated or unsaturated hydrocarbon radicals, which can be branched or straight- chain and unsubstituted or mono- or polysubstituted, having respectively 1 , 2, 3, 4, 5 or 6 C atoms or 1 , 2 or 3 C atoms, i.e. C 1-5 alkanyls, C 2-5 alkenyls and C 2- S alkynyls or Ci -3 alkanyls, C 2-3 alkenyls and C 2-3 alkynyls.
  • Alkenyls have at least one C-C double bond and alkynyls have at least one C-C triple bond.
  • cycloalkyl or "C 3-8 cycloalkyl” denotes cyclic hydrocarbons having 3, 4, 5, 6, 7 or 8 carbon atoms, wherein the hydrocarbons can be saturated or unsaturated (but not aromatic), unsubstituted or mono- or polysubstituted.
  • C 3-8 cycloalkyl is advantageously selected from the group including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Cyclobutyl, cyclopentyl and cyclohexyl are particularly preferred within the meaning of this invention.
  • (CH 2 J 3-6 is understood to mean -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 -.
  • aryl denotes carbocyclic ring systems having up to 14 ring members with at least one aromatic ring, but without heteroatoms in only one of the rings, inter alia phenyls, naphthyls and phenanthrenyls.
  • the aryl radicals can also be fused to other saturated, (partially) unsaturated or aromatic ring systems.
  • Each aryl radical can be present in unsubstituted or mono- or polysubstituted form, wherein the aryl substituents can be identical or different and can be at any desired and possible position of the aryl. Phenyl or naphthyl radicals are particularly advantageous.
  • heteroaryl stands for a 5-, 6- or 7-membered cyclic aromatic radical containing at least 1 , optionally also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms can be identical or different and the heterocyclic compound can be unsubstituted or mono- or polysubstituted; if the heterocyclic compound is substituted, the substituents can be identical or different and can be at any desired and possible position of the heteroaryl.
  • the heterocyclic compound can also be part of a bicyclic or polycyclic system having up to 14 ring members. Preferred heteroatoms are nitrogen, oxygen and sulfur.
  • heteroaryl radical is selected from the group including pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazolyl, benzothiazolyl, benzo- triazolyl, benzodioxolanyl, benzodioxanyl, phthalazinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl or oxadiazolyl, wherein the binding to the compounds having
  • alkyl denotes “Ci -6 alkyl” unless otherwise specified.
  • alkyl and "cycloalkyl”
  • substituted within the meaning of this invention is understood to mean the substitution of one or more hydrogen radicals with F, Cl, Br, I, -CN, NH 2 , NH-alkyl, NH-aryl, NH-heteroaryl, NH-cycloalkyl, NH-alkyl-aryl, NH-alkyl- heteroaryl, NH-alkyl-OH, N(alkyl) 2 , N(alkyl-aryl) 2 , N(alkyl-heteroaryl) 2 , N(cycloalkyl) 2 , N(alkyl- OH) 2 , NO 2 , SH, S-alkyl, S-aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl, S-cycloalkyl, S- alkyl-OH, S-alkyl-SH, OH,
  • CH(OH)-CH CH-CHCI 2 .
  • the polysubstitution can take place with identical or with different substituents.
  • a substituent can also optionally itself be substituted, so -O alkyl also includes -0-CH 2 -CH 2 -O-CH 2 -CH 2 -OH.
  • alkyl or cycloalkyl prefferably substituted with F 1 Cl 1 Br, I 1 CN, CH 3 , C 2 H 5 , NH 2 , NO 2 , SH, CF 3 , OH, OCH 3 , cyclopentyl, cyclohexyl, OC 2 H 5 Or N(CH 3 J 2 , preferably F, Cl 1 Br 1 I 1 CN, CH 3 , C 2 H 5 , NH 2 , NO 2 , SH, CF 3 , OH 1 OCH 3 , OC 2 H 5 or N(CH 3 J 2 . It is most particularly preferred for alkyl or cycloalkyl to be substituted with OH, OCH 3 or OC 2 H 5 .
  • aryl indolyl or “heteroaryl”, “mono- or polysubstituted” within the meaning of this invention is understood to mean the single or multiple, e.g. two, three, four or five times, substitution of one or more hydrogen atoms in the ring system with F, Cl, Br, I, CN, NH 2 , NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-cycloalkyl, NH-alkyl-OH, N(alkyl) 2 , N(alkyl-aryl) 2 , N(alkyl-heteroaryl) 2 , N(cycloalkyl) 2 , N(alkyl-OH) 2 , NO 2 , SH, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-alkyl-ary
  • the polysubstitution is performed with identical or with different substituents. If an aryl, indolyl or heteroaryl radical is itself substituted with an aryl or heteroaryl radical optionally bound via a bridge, this substituent is preferably itself unsubstituted or mono- or polysubstituted with F, Cl, Br, I, CN, CH 3 , C 2 H 5 , NH 2 , NO 2 , SH, CF 3 , OH, OCH 3 , OC 2 H 5 Or N(CH 3 J 2 .
  • aryl, indolyl or heteroaryl to be substituted with F, Cl, Br, I, CN, CH 3 , C 2 H 5 , NH 2 , NO 2 , SH, CF 3 , OH, OCH 3 , OC 2 H 5 or N(CH 3 ) 2 .
  • salt is understood to mean any form of the active ingredient according to the invention in which it assumes an ionic form or is charged and is coupled to a counterion (a cation or anion) or is in solution. Also included here are complexes of the active ingredient with other molecules and ions, in particular complexes which are complexed by means of ionic interactions. It means in particular (and this is also a preferred embodiment of this invention) physiologically compatible salts, in particular physiologically compatible salts with cations or bases and physiologically compatible salts with anions or acids or also a salt formed with a physiologically compatible acid or a physiologically compatible cation.
  • physiologically compatible salt with anions or acids is understood to mean salts of at least one of the compounds according to the invention - mostly protonated, for example on nitrogen - as cation with at least one anion, which are physiologically - particularly when used in humans and/or mammals - compatible.
  • this is particularly understood to mean the salt formed with a physiologically compatible acid, namely salts of the individual active ingredient with inorganic or organic acids which are physiologically - particularly when used in humans and/or mammals - compatible.
  • physiologically compatible salts of certain acids are salts of: 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, saccharinic acid, monomethyl sebacic acid, 5- oxoproline, hexane-1 -sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6- trimethylbenzoic acid, ⁇ -lipoic acid, acetylglycine, acetyl salicylic acid, hippuric acid and/or aspartic acid.
  • the hydrochloride salt, the citrate and the hemicitrate are particularly preferred.
  • salt formed with a physiologically compatible acid is understood to mean salts of the individual active ingredient with inorganic or organic acids which are physiologically - particularly when used in humans and/or mammals - compatible.
  • the hydrochloride and the citrate are particularly preferred.
  • physiologically compatible 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, saccharinic acid,- monomethyl sebacic acid, 5-oxoproline, hexane-1 -sulfonic acid, nicotinic acid, 2-, 3- or 4- aminobenzoic acid, 2,4,6-trimethylbenzoic acid, ⁇ -lipoic acid, acetylglycine, acetyl salicylic acid, hippuric acid and/or aspartic acid.
  • physiologically compatible salt with cations or bases is understood to mean salts of at least one of the compounds according to the invention - mostly a (deprotonated) acid - as anion with at least one, preferably inorganic, cation, which are physiologically - particularly when used in humans and/or mammals - compatible.
  • Particularly preferred are the salts of the alkali and alkaline-earth metals, but also ammonium salts, but in particular (mono) or (di)sodium, (mono) or (di)potassium, magnesium or calcium salts.
  • salt formed with a physiologically compatible cation is understood to mean salts of at least one of the compounds as anion with at least one inorganic cation, which is physiologically - particularly when used in humans and/or mammals - compatible.
  • Particularly preferred are the salts of the alkali and alkaline-earth metals, but also ammonium salts, but in particular (mono) or (di)sodium, (mono) or (di)potassium, magnesium or calcium salts.
  • CF 3 C 1-6 alkyl, pyrrolidinyl, piperidinyl, morpholinyl, benzyloxy, phenoxy, phenyl, pyridyl, alkylaryl, thienyl or furyl, wherein aryl and heteroaryl substituents can themselves be substituted with F, Cl, Br, I 1 CN, CH 3 , C 2 H 5 , NH 2 , NO 2 , SH, CF 3 , OH, OCH 3 , OC 2 H 5 or N(CH 3 ) 2 ;
  • the enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a single enantiomer or diastereomer in the form of the racemate; the enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a single enantiomer or diastereomer; the bases and/or salts of physiologically compatible acids or cations.
  • Substituted indole derivatives are preferred wherein X stands for indolyl, unsubstituted or mono- or polysubstituted with F, Cl, Br 1 I 1 CN 1 CH 3 , C 2 H 5 , C 3 H 8 , NH 2 , NO 2 , SH, CF 3 , OH, OCH 3 , OC 2 H 5 , N(CH 3 ) 2 or phenyl, unsubstituted or mono- or polysubstituted with F, Cl, Br, I 1 CN, CH 3 , C 2 H 5 , NH 2 , NO 2 , SH, CF 3 , OH, OCH 3 , OC 2 H 5 Or N(CH 3 J 2 .
  • Substituted indole derivatives are particularly preferred wherein X stands for indole, 1- methylindole, 5-fluoroindole, 5-methoxyindole, 5-bromoindole, 6-chloroinidole, 6-fluoroindole, 6-methoxy-1,2-dimethylindole, 1 ,2-dimethylindole, 2-(4-fluorophenyl)indole, 2-phenylindole, 5-chloroindole or 6-/so-propylindole.
  • X stands for indole, 1- methylindole, 5-fluoroindole, 5-methoxyindole, 5-bromoindole, 6-chloroinidole, 6-fluoroindole, 6-methoxy-1,2-dimethylindole, 1 ,2-dimethylindole, 2-(4-fluorophenyl)indole, 2-
  • R 1 and R 2 mutually independently denote methyl or H or the radicals R 1 and R 2 form a ring with inclusion of the N atom and denote (CH 2 ) 3 or (CH 2 ) 4 .
  • R 1 and R 2 mutually independently denote methyl or H, preferably methyl.
  • R 3 stands for phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted at the ring; C 1 ⁇ alkyl, unsubstituted or mono- or polysubstituted; pyridyl, thienyl, thiazolyl, imidazolyl, 1 ,2,4-triazolyl or benzimidazolyl, unsubstituted or mono- or polysubstituted.
  • R 3 stands for phenyl, benzyl, phenethyl, thienyl, pyridyl, thiazolyl, imidazolyl, 1 ,2,4-triazolyl, benzimidazolyl or benzyl, unsubstituted or mono- or polysubstituted with F, Cl, Br 1 CN, CH 3 , C 2 H 5 , NH 2 , NO 2 , SH 1 CF 3 , OH, OCH 3 , OC 2 H 5 Or N(CH 3 J 2 ; ethyl, n-propyl, 2-propyl, allyl, n- butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, cyclopentyl or cyclohex
  • thienyl, pyridyl, thiazolyl, imidazolyl, 1,2,4-triazolyl and benzimidazolyl are preferably unsubstituted;
  • phenyl unsubstituted or monosubstituted with F, Cl, CN, CH 3 ; thienyl; or n-butyl, unsubstituted or mono- or polysubstituted with OCH 3 , OH or OC 2 H 5 , in particular with OCH 3 .
  • substituted indole derivatives wherein R 4 denotes H, CH 3 or benzyl, in particular H. Further preferred are substituted indole derivatives wherein
  • R 5a -° and R 6 ⁇ stand for H.
  • y independently denotes H; Ci -6 alkyl, saturated or unsaturated, branched or unbranched,
  • R 7a c or R 8a'c forms a five-, six- or seven-membered unsaturated ring with a substituent in the 3 position of the indolyl ring X, such that a structural element having the general formulae lla-f is produced:
  • substituted indole derivatives having the general formula I 1 wherein R 7a - c R ⁇ a - c mutua
  • y independently stand for H; CH 3 , ethyl or propyl;
  • substituted indole derivatives from the group comprising
  • the enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a single enantiomer or diastereomer in the form of the racemate; the enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a single enantiomer or diastereomer; the bases and/or salts of physiologically compatible acids or cations.
  • the substances according to the invention act for example on the ORL1 receptor of relevance in connection with various diseases, such that they are suitable as a pharmaceutical active ingredient in a medicinal product.
  • the invention therefore also provides medicinal products containing at least one substituted indole derivative according to the invention, optionally along with suitable additives and/or auxiliary substances and/or optionally further active ingredients.
  • the medicinal products according to the invention optionally contain, in addition to at least one substituted indole derivative according to the invention, suitable additives and/or auxiliary substances, including carrier materials, fillers, solvents, diluents, dyes and/or binders, and can be administered as liquid dosage forms in the form of injection solutions, drops or juices, as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, plasters/spray plasters or aerosols.
  • suitable additives and/or auxiliary substances including carrier materials, fillers, solvents, diluents, dyes and/or binders
  • auxiliary substances etc., and the amount thereof to use depend on whether the medicinal product is to be administered by oral, peroral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal or local means, for example on the skin, mucous membranes or in the eyes.
  • Preparations in the form of tablets, pastilles, capsules, granules, drops, juices and syrups are suitable for oral administration; solutions, suspensions, easily reconstitutable dry preparations and sprays are suitable for parenteral, topical and inhalative administration.
  • Substituted indole derivatives according to the invention in a depot formulation, in dissolved form or in a plaster, optionally with addition of agents promoting skin penetration, are suitable preparations for percutaneous administration.
  • Preparation forms suitable for oral or percutaneous administration can deliver the substituted indole derivatives according to the invention on a delayed release basis.
  • the substituted indole derivatives according to the invention can also be used in parenteral long-term depot forms, such as implants or implanted pumps, for example.
  • Other additional active ingredients known to the person skilled in the art can be added in principle to the medicinal products according to the invention.
  • the amount of active ingredient to be administered to the patient varies according to the weight of the patient, the type of administration, the indication and the severity of the illness. 0.00005 to 50 mg/kg, preferably 0.001 to 0.5 mg/kg, of at least one substituted indole derivative according to the invention are conventionally administered.
  • a preferred form of the medicinal product contains a substituted indole derivative according to the invention as a pure diastereomer and/or enantiomer, as a racemate or as a non- equimolar or equimolar mixture of diastereomers and/or enantiomers.
  • Substituted indole derivatives according to the invention can accordingly be used for the preparation of a medicinal product for the treatment of pain, in particular acute, neuropathic or chronic pain.
  • the invention therefore also provides the use of a substituted indole derivative according to the invention to prepare a medicinal product for the treatment of pain, in particular acute, visceral, neuropathic or chronic pain.
  • the invention also provides the use of a substituted indole derivative according to the invention to prepare a medicinal product for the treatment of anxiety conditions, stress and stress-related syndromes, depression, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunctions, learning and memory disorders (as a nootropic), withdrawal symptoms, alcohol and/or drug and/or prescription drug abuse and/or dependency, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinnitus, pruritus, migraine, hearing impairment, gastrointestinal motility disorders, food intake disorders, anorexia, obesity, locomotive disorders, diarrhoea, cachexia, urinary incontinence, or as a muscle relaxant, anticonvulsant or anaesthetic, or for coadministration in treatment with an opioid analgesic or with an anaesthetic, for diuresis or antinatriuresis, anxiolysis, for the modulation of motor activity, for the modulation of neurotransmitter release and treatment of associated neurodegenerative diseases, for the treatment of
  • a substituted indole derivative that is used can be in the form of a pure diastereomer and/or enantiomer, a racemate or a non-equimolar or equimolar mixture of diastereomers and/or enantiomers.
  • the invention also provides a process for the treatment, in particular in one of the aforementioned indications, of a non-human mammal or human requiring treatment of pain, in particular chronic pain, by administration of a therapeutically active dose of a substituted indole derivative according to the invention or of a medicinal product according to the invention.
  • the present invention also provides a process for preparing the substituted indole compounds according to the invention.
  • the chemicals and reaction components used in the reactions described are available commercially or can be produced by methods known to the person skilled in the art.
  • the compounds having the general formula AA can be converted to compounds having the formula AMD, SAM and AMN.
  • the protective group in formula A, B and III is a suitable nitrogen protective group, preferably benzyl or tert-butyloxycarbonyl.
  • stage 1 compounds known from the literature having the general formula A in at least one solvent, preferably selected from the group consisting of methanol, ethanol, dioxane, diethyl ether, tetrahydrofuran, water and dimethyl formamide, are reacted with an amine having the general formula HNR 1 R 2 , wherein R 1 and R 2 have the meaning given above, and potassium cyanide or sodium cyanide, with addition of at least one acid, preferably selected from the group consisting of sodium hydrogen sulfite, acetic acid, trifluoroacetic acid, hydrochloric acid and sulfuric acid, at temperatures of preferably 0 0 C to 60 0 C 1 to form compounds having the general formula B.
  • solvent preferably selected from the group consisting of methanol, ethanol, dioxane, diethyl ether, tetrahydrofuran, water and dimethyl formamide
  • stage 2 compounds having the general formula B in at least one solvent, preferably selected from the group consisting of tetrahydrofuran, diethyl ether and dioxane, are reacted with a Grignard reagent R 3 MgBr or R 3 MgCI, wherein R 3 has the meaning given above, at temperatures of preferably 0 0 C to 80 0 C, to form compounds having the general formula III.
  • a Grignard reagent R 3 MgBr or R 3 MgCI wherein R 3 has the meaning given above
  • the protective group is benzyl
  • the conversion to compounds having the general formula IV takes place in 2 steps.
  • CbzCI carbobenzoxychloride
  • solvent preferably selected from the group consisting of methanol, ethanol, diethyl ether, tetrahydrofuran, acetonitrile, dimethyl formamide and dimethyl sulfoxide
  • a catalyst preferably selected from the group consisting of palladium on carbon, palladium hydroxide, palladium acetate and palladium black
  • the protective group is te/f-butyloxycarbonyl (Boc)
  • the compounds having the general formula III in at least one solvent preferably selected from the group consisting of methanol, ethanol, dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, dioxane, dimethyl formamide and dimethyl sulfoxide, are reacted with an acid, preferably selected from the group consisting of trifluoroacetic acid, sulfuric acid and hydrochloric acid, at temperatures of preferably 0 0 C to 80 0 C, to form compounds having the general formula IV.
  • the compounds having the general formula IV in at least one solvent are reacted with a suitable alkyl halide in the presence of an excess of a base, preferably selected from the group consisting of caesium carbonate, calcium carbonate, potassium carbonate, triethylamine, diisopropyl ethylamine and pyridine, at temperatures of preferably 0 0 C to 8O 0 C, to form compounds having the general formula V.
  • a suitable alkyl halide preferably selected from the group consisting of caesium carbonate, calcium carbonate, potassium carbonate, triethylamine, diisopropyl ethylamine and pyridine, at temperatures of preferably 0 0 C to 8O 0 C, to form compounds having the general formula V.
  • compounds having the general formula IV are reacted with a suitable aldehyde in at least one organic solvent, preferably selected from the group consisting of diethyl ether, tetrahydrofuran, methanol, ethanol, dichloroethane, dichloromethane and toluene, with addition of at least one reducing agent, preferably selected from the group consisting of borane-pyridine complex, sodium boron hydride, sodium triacetoxyboron hydride, sodium cyanoboron hydride and triethylsilane, optionally in the presence of at least one acid, preferably selected from the group consisting of formic acid, acetic acid, hydrochloric acid and trifluoroacetic acid, at temperatures of preferably -70 0 C to 100 0 C, to form compounds having the general formula V.
  • organic solvent preferably selected from the group consisting of diethyl ether, tetrahydrofuran, methanol, ethanol, dichloroethane,
  • compounds having the general formula IV in at least one solvent are reacted with acids having the general formula protective group-NR 4 -T-CO 2 H, wherein protective group, R 4 and T have the meanings given above, with addition of at least one coupling reagent, preferably selected from the group consisting of carbonyl diimidazole (CDI), 2-chloro-1-methylpyridinium iodide (Mukaiyama reagent), ⁇ /-(3-dimethylaminopropyl)- ⁇ /'-ethylcarbodiimide (EDCI), O-(benzotriazoM-yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /'-tetramethyluronium tetrafluoroborate (TBTU), ⁇ /./V-dicyclohe
  • CDI carbonyl diimidazole
  • EDCI 2-chloro-1-methylpyridinium iodide
  • EDCI ⁇ /-(3-dimethylaminoprop
  • the protective group is not H, the protective group is eliminated. If the protective group is terf-butyloxycarbonyl, then the compounds having the general formula V in at least one solvent, preferably selected from the group consisting of diethyl ether, tetrahydrofuran, methanol, ethanol, dichloromethane, dioxane and dimethyl formamide, are reacted with an acid, preferably selected from the group consisting of trifluoroacetic acid, hydrochloric acid and sulfuric acid, at temperatures of preferably 0 0 C to 80 0 C, to form compounds having the general formula AA.
  • solvent preferably selected from the group consisting of diethyl ether, tetrahydrofuran, methanol, ethanol, dichloromethane, dioxane and dimethyl formamide
  • stage 6 compounds having the general formula AA in at least one solvent, preferably selected from the group consisting of dichloromethane, acetonitrile, dimethyl formamide, diethyl ether, dioxane and tetrahydrofuran, are reacted with acids having the general formula X-Q-CO 2 H, wherein X and Q have the meanings given above, with addition of at least one coupling reagent, preferably selected from the group consisting of carbonyl diimidazole (CDI), 2-chloro-1-methylpyridinium iodide (Mukaiyama reagent), ⁇ /-(3-dimethylaminopropyl)- /V-ethylcarbodiimide (EDCI), O-(benzotriazol-1-yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /'-tetramethyluronium tetrafluoroborate (TBTU), ⁇ /. ⁇ /'-dicyclohexylcarbod
  • Step-1 Dimethylamine (10 eq.) was added to a solution of 1 ,4-Cyclohexanedione monoethylene acetal (12.8 mmol) in methanol (5 ml) and acetic acid (3 ml) at 0 0 C. Then potassium cyanide (2.5 eq.) was added to the reaction mixture through solid addition funnel and stiired for another 16 h. The reaction mixture was slowly quenched with NH 4 OH solution (50 g ice + 50 ml liquor ammonia) and stirred at 0 0 C for another half an hour. The reaction mixture was extracted with ethylacetate. Organic layer was washed with water, satd. FeSO 4 , brine successively and dried over anh. Sodium sulfate and concentrated under reduced pressure to give the pure desired product. Yield: 94%
  • Step-2 A solution of step-1 product (2 mmol) in THF (5 ml) was added to an ice-cold solution of thiophene-2-magnesium bromide (5 eq, freshly prepared from 2-bromothiophene, Mg and catalytic amount of I 2 in 30 ml THF) and the reaction mixture was allowed to stir at RT for 16 h under nitrogen atmosphere. The reaction mixture was quenched with satd. Ammonia solution under ice-cold condition and extracted with ethylacetate. Organic layer was washed with water, brine successively and dried over anh. Sodium sulfate and concentrated under reduced pressure to give the crude product.
  • thiophene-2-magnesium bromide 5 eq, freshly prepared from 2-bromothiophene, Mg and catalytic amount of I 2 in 30 ml THF
  • step-2 product was purified by silica gel column chromatography (EtOH/Hexane) to give the desired step-2 product. Yield: 30% Step-3: To a solution of step-2 product (1.64 mmol) in DCM (5 ml) was added TFA (1 ml) at 0 0 C and stirred for 2 h at RT. Then the reaction mixture was concentrated and the crude mass was azeotroped twice with dry toluene to give the TFA salt of the amine that was used as such for the coupling reactions.
  • Step-1 Dimethylamine (10 eq.) was added to a solution of 1 ,4-Cyclohexanedione monoethylene acetal (12.8 mmol) in methanol (5 ml) and acetic acid (3 ml) at 0 0 C. Then potassium cyanide (2.5 eq.) was added to the reaction mixture through solid addition funnel and stiired for another 16 h. The reaction mixture was slowly quenched with NH4OH solution (50 g ice + 50 ml liquor ammonia) and stirred at 0 0 C for another half an hour. The reaction mixture was extracted with ethylacetate. Organic layer was washed with water, satd. FeSO4, brine successively and dried over anh. Sodium sulfate and concentrated under reduced pressure to give the pure desired product. Yield: 94%
  • Step-2 A solution of step-1 product (2 mmol) in THF (5 ml) was added to an ice-cold solution of phenyl magnesium bromide (5 eq. 1M solution in THF) and the reaction mixture was allowed to stir at RT for 16 h under nitrogen atmosphere. The reaction mixture was quenched with satd. Ammonia solution under ice-cold condition and extracted with ethylacetate.
  • Step-3 To a solution of step-2 product (1.64 mmol) in DCM (5 ml) was added TFA (1 ml) at 0 0 C and stirred for 2 h at RT. Then the reaction mixture was concentrated and the crude mass was azeotroped twice with dry toluene to give the TFA salt of the amine that was used as such for the coupling reactions.
  • Step-1 Methyl-3 indole carboxylate (17.1 mmmol) was placed in a 50 ml round bottom flask with NaH (1.5 eq.) and cooled to an ice-bath. THF (20 ml) was added with stirring. After 30 minutes Boc-anhydride (1.5 eq.) was added and stirred for overnight. The reaction mixture was quenched with satd. Ammonium chloride solution, diluted with ether and washed with water. The organic layer was dried with anh. sodium sulfate and concentrated. The crude mass was purified by column chromatography (EA/ hexane) to give the desired product. Yield: 98%
  • Step-2 The Step-1 product was hydrogenated (8 mmol) in parr-shaker with 5% Pd/C (1 g) using 60 psi hydrogen pressure in a mixture of ethyl acetate (30 ml) and methanol (10 ml) for 3 days. The reaction mixture was filtered and filtrate was concentrated. The crude mass was purified by column chromatography (EA/ hexane) to give the desired product. Yield: 98%
  • Step-3 To a suspension of Step-2 product (11.75 mmol) in methanol (40 ml), tetrahydrofuran (40ml) and water (30 ml) was added LiOH-H 2 O (5 eq) and the reaction mixture was allowed to stir at 25 0 C for overnight. Methanol and THF were completely evaporated; aqueous layer was acidified with 1(N) HCI and filtered. The white solid was taken in a mixture of 350 ml acetone and 50 ml methanol and stirred for 1 h. After filtration the white solid was dried under vacuum to give desired acid intermediate. Yield: 84%
  • Structural unit AA-1 ⁇ /./V-Dimethvl-1-(2-(methvlamino)ethyl)-4-phenvlpiperidin-4-amine tris hydrochloride
  • HCI gas was passed through a solution of 9 g (1 eq) terf-butyl 2-(4-(dimethylamino)-4- phenylpiperidin-1-yl)ethyl(methyl)carbamate in 600 ml CH 3 CI for 30 min.
  • the reaction course was monitored by thin-layer chromatography (20% MeOH/CHCI 3 ).
  • the passage of HCI gas was continued for a further 30 min and the completeness of the conversion again monitored by thin-layer chromatography (20% MeOH/CHCI 3 ).
  • the solvent was removed under reduced pressure and 7.2 g (96%) of the desired product obtained in the form of a white solid.
  • Structural unit AA -2 ⁇ /-methvl-2-(4-phenvl-4-(pvrrolidin-1-vl)piperidin-1-vl)ethanamine tris hydrochloride
  • Stage 5 4-Phenyl-4-(pyrrolidin-1-yl)piperidine bishydrochloride HCI gas was passed through a solution of 9 g (1 eq) 4-phenyl-4-(pyrrolidin-1-yl)piperidine in 180 ml chloroform for ⁇ 30 min until the reaction mixture reached a pH of ⁇ 2. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCI 3 ). Once the conversion was complete, the solvent was removed under reduced pressure and the residue washed with ethyl acetate (3 x 100 ml) and dried. 9 g (76%) of product were obtained in the form of a solid.
  • HCI gas was passed through a solution of 8 g (1 eq) te/f-butyl methyl(2-(4-phenyl-4- (pyrrolidin-1-yl)piperidin-1-yl)ethyl)carbamate in 160 ml chloroform at 0 0 C for ⁇ 30 min until the reaction mixture reached a pH of ⁇ 2.
  • the reaction mixture was then stirred at room temperature for 4 hours.
  • the reaction course was monitored by thin-layer chromatography (10% MeOH/CHCI 3 ). Once the conversion was complete, the solvent was removed under reduced pressure and 8 g (97%) of product were obtained in the form of a white solid.
  • Structural unit AA-3 1-(2-Aminoethvn- ⁇ /. ⁇ /-dimethvl-4-(thiophen-2-vQpiperidin-4-amine tris hydrochloride
  • Stage 1 tert-Butyloxycarbonyl-4-cyano-4-(dimethylamino)piperidine 500 ml (10 eq) dimethylamine solution and 109.9 g (5 eq) dimethylamine hydrochloride were added to a solution of 50 g (1 eq) te ⁇ t-butyloxycarbonyl-4-oxopiperidine in 100 ml methanol and the mixture was cooled to 5°C. 5 ml (0.1 eq) hydrochloric acid were then added dropwise to the reaction mixture over a period of 10 min and the mixture was stirred for 60 min at room temperature.
  • the Grignard reagent prepared in the preceding step was added dropwise to a solution of 20 g (1 eq) tert-butyloxycarbonyl-4-cyano-4-(dimethylamino)- piperidine dissolved in 200 ml THF and stirred overnight at room temperature.
  • the reaction course was monitored by thin-layer chromatography (50% EtOAc/hexane). Once the conversion was complete, the reaction solution was cooled to 0 0 C, mixed with saturated NH 4 CI solution, extracted with ethyl acetate (3 x 100 ml) and the combined organic phases were dried with Na 2 SO 4 . Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (Alox neutral; 30% EtOAc/hexane). 6.1 g (25%) of product were obtained in the form of a white solid.
  • HCI gas was passed through a solution of 9 g (1 eq) terf-butyl 2-(4-(dimethylamino)-4- (thiophen-2-yl)pipehdin-1-yl)ethylcarbamate in chloroform at O 0 C for ⁇ 30 min.
  • the reaction mixture was then stirred at room temperature for one hour.
  • the reaction course was monitored by thin-layer chromatography (10% MeOH/CHCI 3 ). Once the conversion was complete, the solvent was removed under reduced pressure and 9 g (97%) of product were obtained in the form of a white solid.
  • Structural unit A A -4 4-Butyl- ⁇ /. ⁇ /-dimethvl-1-(2-(methvlamino)ethyl)piperidin-4-amine tris hydrochloride
  • reaction solution was cooled to 0 0 C, mixed with saturated NH 4 CI solution, filtered over celite, extracted with ethyl acetate (3 x 200 ml) and the combined organic phases were dried over Na 2 SO 4 . Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (aluminium oxide neutral; hexane). 18.2 g (53%) of product were obtained in the form of an oil.
  • reaction mixture was cooled to 0 0 C and adjusted to a pH of ⁇ 5 with acetic acid.
  • 2 g tert-butyl formylmethyl methylcarbamate and 1.7 g sodium cyanoboron hydride were again added and the reaction mixture was stirred for a further 60 min at room temperature.
  • the methanol was then distilled off, 100 ml saturated NaHCO 3 solution were added and the mixture obtained was extracted with ethyl acetate (2 x 200 ml) and the combined organic phases were dried over Na 2 SO 4 . Following removal of the solvent under reduced pressure, 10.5 g of crude product were obtained in the form of a pale yellow oil.
  • HCI gas was passed through a solution of 10.5 g (1 eq) tert-butyl 2-(4-butyl-4-(dimethyl- amino)piperidin-1-yl)ethyl(methyl)carbamate in 1000 ml chloroform at 0 0 C for ⁇ 1 h.
  • the reaction mixture was then stirred for 12 hours at room temperature.
  • the reaction course was monitored by thin-layer chromatography (20% MeOH/CHCI 3 ). Once the conversion was complete, the solvent was removed under reduced pressure and the residue washed with hexane (3 x 50 ml) and ethyl acetate (3 x 50 ml) and dried. 9 g (87%) of product were obtained in the form of a white solid.
  • Structural unit AA -5 ⁇ /,W-Dimethyl-1-(3-(methylamino)propyl)-4-phenylpiperidin-4- amine tris hydrochloride
  • Stage 1 tert-Butyl 3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)propyl(methyl)- carbamate 11.1 g (1.3 eq) terf-butyl methyl(3-oxopropyl)carbamate were added to a solution of 11 g (1 eq) ⁇ /, ⁇ /-dimethyl-4-phenylpiperidin-4-amine dihydrochloride in 110 ml methanol at 0°C and the reaction mixture was stirred for 15 min at 0 0 C. 6.2 g (3 eq) sodium cyanoboron hydride were then added in portions and the mixture was stirred for 30 min at room temperature.
  • the reaction mixture obtained was adjusted to a pH of 5-6 with acetic acid and stirred for 12 h at room temperature.
  • the reaction course was monitored by thin-layer chromatography (20% MeOH/CHCI 3 ).
  • 2.4 g sodium cyanoboron hydride were added and the reaction mixture obtained was adjusted to pH 5-6 with acetic acid and stirred for 60 min at room temperature.
  • the methanol was distilled off, the mixture was made alkaline with saturated NaHCO 3 solution, the mixture obtained was extracted with chloroform (3 x 100 ml) and the combined organic phases were dried over Na 2 SO 4 . Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 5% MeOH/CHCI 3 ). 9 g (60%) of product were obtained.
  • HCI gas was passed through a solution of 9 g (1 eq) terf-butyl 3-(4-(dimethylamino)-4- phenylpiperidin-1-yl)propyl(methyl)carbamate in 100 ml chloroform at 0 0 C for 1 h.
  • the reaction course was monitored by thin-layer chromatography (20% MeOH/CHCI 3 ). Once the conversion was complete, the solvent was removed under reduced pressure and after trituration with diethyl ether 10 g (100%) of product were obtained in the form of a white solid.
  • Structural unit AA -6 W,W-Dimethyl-1 -(3-(methylamino)propyl)-4-(thiophen-2- yl)piperidin-4-amine tris hydrochloride
  • reaction mixture was filtered over celite and the filtrate mixed with 200 ml water and extracted with dichloromethane. The combined organic phases were dried over Na 2 SO 4 . Following removal of the solvent under reduced pressure,
  • reaction mixture was quenched with saturated NH 4 CI solution and then extracted with ethyl acetate. The combined organic phases were dried over Na 2 SO 4 . Following removal of the solvent under reduced pressure, 48 g (92%) of product were obtained in the form of an oil.
  • the mixture was cooled to O 0 C, 50 ml dilute acetic acid were added over a period of 20 min and the mixture was stirred for a further 1 h at 0 0 C
  • the reaction course was monitored by thin- layer chromatography (10% EtOAc/ hexane). Once the conversion was almost complete, the reaction mixture was concentrated under reduced pressure, adjusted to a pH of ⁇ 9 with Na 2 CO 3 solution and extracted with 10% IPA/CH 3 CI. The combined organic phases were dried over Na 2 SO 4 . Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 10% EtOAc/hexane). 40 g (66%) of product were obtained in the form of a colourless oil.
  • a catalytic amount of TEMPO was added to a mixture of 20 g (1 eq) terf-butyl 3-hydroxy- propyl(methyl)carbamate in 200 ml dichloromethane and 17.7 g (2 eq) sodium hydrogen carbonate in 100 ml water at 0°C. 140 ml (7 eq) NaOCI were then added dropwise over a period of 30 min to the solution at a temperature of 0°C and the reaction mixture obtained was stirred for a further 15 min at 0 0 C. The reaction course was monitored by thin-layer chromatography (40% EtOAc/hexane).
  • HCI gas was passed through a solution of 6 g (1 eq) tert-butyloxycarbonyl-4-(dimethylamino)- 4-(thiophen-2-yl)piperidine in 120 ml chloroform at 0 0 C for 1 h.
  • the reaction course was monitored by thin-layer chromatography (75% EtOAc/hexane). Once the conversion was complete, the solvent was removed under reduced pressure and 5.3 g (98%) of product were obtained in the form of a white solid.
  • Stage 7 tert-Butyl 3-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1- yl)propyl(methyl)carbamate 6.4 g (1.3 eq) tert-butyl methyl(3-oxopropyl)carbamate were added to a solution of 7.5 g (1 eq) ⁇ /, ⁇ /-dimethyl-4-(thiophen-2-yl)piperidin-4-amine bis hydrochloride in 75 ml methanol at O 0 C and the reaction mixture was stirred for 15 min at 0 0 C.
  • Stage 8 W, ⁇ /-Dimethyl-1-(3-(methylamino)propyl)-4-(thiophen-2-yl)piperidin-4-amine tris hydrochloride HCI gas was passed through a solution of 1.5 g (1 eq) tert-butyl 3-(4-(dimethylamino)-4- (thiophen-2-yl)piperidin-1-yl)propyl(methyl)carbamate in 30 ml chloroform at 0 0 C for ⁇ 30 min. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCI 3 ). Once the conversion was complete, the solvent was removed under reduced pressure. After trituration with diethyl ether, 1.5 g (98%) of product were obtained in the form of a white solid.
  • Amine Building Block AA-7 3-Amino-1-(4-(dimethvlamino)-4-phenylpiperidin-1- yl)propan-1-one dihydrochloride
  • Amine Building Block AA -9 3-Amino-1-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin- 1-yl)-3-phenylpropan-1-one trihydrochloride
  • Amine Building Block AA-10 1-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)-3-methyl-2- (methylamino)butan-i-one trihydrochloride (i) 2-(te/?-Butoxycarbonyl(methyl)amino)-3-methylbutanoic acid was converted with N 1 N- dimethyl-4-phehylpiperidin-4-amine trifluoroacetate according to general procedure no. 1 to yield the desired product (51%).
  • Amine Building Block AA-11 1-(4-(Dimethvlamino)-4-(thiophen-2-vl)piperidin-1-yl)-2-
  • Amine Building Block AA-12 4-(Dimethvlamino)-4-phenvlpiperidin-1-vl)(piperidin-3- yl)methanone trihydrochloride (i) 1-(fert-Butoxycarbonyl)piperidine-3-carboxylic acid was converted with N,N-dimethyl-4- phenylpiperidin-4-amine trifluoroacetate according to general procedure no. 1 to yield the desired product (65%).
  • Amine Building Block AA-13 (4-(Dimethylamino)-4-phenylpiperidin-1-yl)(indolin-3- yl)methanone trihydrochloride
  • ALD-13 1 H-lndole-6-carbaldehyde
  • ALD-14 1 H-lndole-7-carbaldehyde
  • reaction mixture was washed 3 times with saturated sodium hydrogen carbonate solution and the organic phase was dried over magnesium sulfate. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (alumina neutral; 1% MeOH/CH 2 CI 2 ). 198 mg (76%) of product were obtained in the form of a yellow oil.
  • reaction course was monitored by thin-layer chromatography (75% EtOAc/hexane). Once the conversion was complete, the reaction mixture was washed 3 times with saturated sodium hydrogen carbonate solution and the organic phase was dried over magnesium sulfate. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (alumina neutral; 1% MeOH/CH 2 CI 2 ). 143 mg (67%) of product were obtained in the form of a yellow oil.
  • reaction course was monitored by thin-layer chromatography (75% EtOAc/hexane). Once the conversion was complete, the reaction mixture was washed 3 times with saturated sodium hydrogen carbonate solution and the organic phase was dried over magnesium sulfate. Following removal of the solvent under reduced pressure, the residue was purified by 5
  • the amine structural units AA were converted by parallel synthesis both with acids (ACI) and with aldehydes (ALD) to the acylated (AMD) and reductively aminated (AMN) products.
  • MassLynx Single Quadrupol MS Detector Column: Nucleodur Gravity C18 30 x 2 mm, 5 ⁇ m; CoI. temp.: 40°C, Eluent A: purified water + 0.1% formic acid; Eluent B: methanol (gradient grade) +
  • MassLynx Single Quadrupol MS Detector Column: Waters AtlantisTM dC18, 3 ⁇ m, 2.1 x 30 mm; CoI. temp.: 40 0 C, Eluent A: purified water + 0.1% formic acid; Eluent B: acetonitrile(gradient grade) +
  • a solution of the indole carboxylic acid derivative ACI (150 ⁇ mol) in 1.6 ml dichloromethane was prepared at room temperature and a solution of carbonyldiimidazole (160 ⁇ mol) in 1 ml dichloromethane was added.
  • the reaction mixture was shaken for 1 hour at room temperature and then a solution of the corresponding amine AA (100 ⁇ mol) in a mixture of 500 ⁇ mol N-ethyl-diisopropylamine and 0.5 ml dichloromethane was added.
  • the reaction mixture was shaken for 12 hours at room temperature.
  • the solvent was then removed under vacuum in a vacuum centrifuge (GeneVac).
  • the final purification was performed by HPLC- MS.
  • the final analysis was performed by LC-MS.
  • a solution of the amine AA (100 ⁇ mol) in 1.0 ml methanol was prepared at room temperature and a solution of the corresponding aldehyde ALD (100 ⁇ mol) in 1.0 ml methanol was added.
  • the reaction mixture obtained was mixed with 41 mg aluminium oxide and shaken for 2 hours at room temperature. 10.1 ⁇ l borane-pyridine complex were then added and the reaction mixture was shaken for 3 days at room temperature.
  • the cyclohexane derivatives having the general formula I were investigated in a receptor binding assay with 3 H-nociceptin/orphanin FQ with membranes of recombinant CHO-ORL1 cells.
  • This test system was conducted in accordance with the method described by Ardati et al. (MoI. Pharmacol., 51 , 1997, p. 816-824).
  • the concentration of 3 H-nociceptin/orphanin FQ in these tests was 0.5 nM.
  • the binding assays were carried out with 20 ⁇ g amounts of membrane protein per 200 ⁇ l batch in 50 mM Hepes, pH 7.4, 10 mM MgCI 2 and 1 mM EDTA.
  • the binding to the ORL1 receptor was determined using 1 mg amounts of WGA-SPA beads (Amersham-Pharmacia, Freiburg, Germany), by incubation of the batch for one hour at room temperature and subsequent measurement in a Trilux scintillation counter (Wallac, Finland).
  • the receptor affinity to the human ⁇ -opiate receptor was determined in a homogeneous batch in microtitre plates. To this end, dilution series of the substituted indole derivative to be tested were incubated for 90 minutes at room temperature with a receptor membrane preparation (15 - 40 ⁇ g protein per 250 ⁇ l incubation batch) of CHO-K1 cells, which express the human ⁇ -opiate receptor (RB-HOM receptor membrane preparation from NEN, Zaventem, Belgium), in the presence of 1 nmol/l of the radioactive ligand [ 3 H] naloxone (NET719, NEN, Zaventem, Belgium) and 1 mg of WGA-SPA beads (wheat germ agglutinin SPA beads from Amersham/Pharmacia, Freiburg, Germany) in a total volume of 250 ⁇ l.
  • a receptor membrane preparation 15 - 40 ⁇ g protein per 250 ⁇ l incubation batch
  • CHO-K1 cells which express the human ⁇ -opiate receptor (RB-HO
  • 38 g of one of the substituted indole derivatives according to the invention, in this case example 3, are dissolved in 1 I of water for injection at room temperature and then adjusted to isotonic conditions by the addition of anhydrous glucose for injection.

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Abstract

The present invention relates to substituted indole derivatives having the general formula (I) which act on the ORL 1 receptor wherein A and B mutually independently denote CH2, C=O or SO2, X stands for indolyl, unsubstituted or mono- or polysubstituted; T stands for (CR5a-cR6a-c)n, n = 1, 2 or 3, and Q stands for (CR7a-cR8a-c)m, m = 0,1, 2 or 3, processes for the preparation thereof, medicinal products containing these compounds and the use of substituted indole derivatives for the preparation of medicinal products.

Description

Substituted indole derivatives
The present invention relates to substituted indole derivatives, processes for the preparation thereof, medicinal products containing these compounds and the use of substituted indole derivatives for the preparation of medicinal products.
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, is to be found in many regions of the brain and spinal cord, and has a high affinity for the ORL1 receptor. The ORL1 receptor is homologous to the μ, K and δ opioid receptors and the amino acid sequence of the nociceptin peptide displays a strong similarity to those of the known opioid peptides. The activation of the receptor induced by nociceptin leads via the coupling with G,/o proteins to an inhibition of the adenylate cyclase (Meunier et al., Nature 377, 1995, p. 532-535).
After intercerebroventicular application, the nociceptin peptide exhibits pronociceptive and hyperalgesic activity in various animal models (Reinscheid et al., Science 270, 1995, p. 792- 794). These findings can be explained as an inhibition of stress-induced analgesia (Mogil et al., Neuroscience 75, 1996, p. 333-337). Anxiolytic activity of the nociceptin could also be demonstrated in this connection, (Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854- 14858).
On the other hand, an antinociceptive effect of nociceptin could also be demonstrated in various animal models, in particular after intrathaecal application. Nociceptin has an antinociceptive effect in various pain models, for example in the tail flick test in mice (King et al., Neurosci. Lett., 223, 1997, 113-116). In models of neuropathic pain, an antinociceptive effect of nociceptin could likewise be detected and was particularly beneficial since the effectiveness of nociceptin increases after axotomy of spinal nerves. This contrasts with conventional opioids, the effectiveness of which decreases under these conditions (Abdulla and Smith, J. Neurosci., 18, 1998, p. 9685-9694).
The ORL1 receptor is also involved in the regulation of further physiological and pathophysiological processes. These include inter alia learning and memory (Manabe et al., Nature, 394, 1997, p. 577-581), hearing capacity (Nishi et al., EMBO J., 16, 1997, p. 1858- 1864) and numerous further processes. A synopsis by CaIo et al. (Br. J. Pharmacol., 129, 2000, 1261 - 1283) gives an overview of the indications or biological processes in which the ORL1 -receptor plays a part or very probably plays a part. Mentioned inter alia are: analgesics, stimulation and regulation of food intake, effect on μ-agonists such as morphine, treatment of withdrawal symptoms, reduction of the addiction potential of opioids, anxiolysis, modulation of motor activity, memory disorders, epilepsy; modulation of neurotransmitter release, in particular of glutamate, serotonin and dopamine, and hence neurodegenerative diseases; influence on the cardiovascular system, triggering of an erection, diuresis, antinatriuresis, electrolyte balance, arterial blood pressure, water retention disorders, intestinal motility (diarrhoea), relaxation of the respiratory tract, micturation reflex (urinary incontinence). The use of agonists and antagonists as anorectics, analgesics (also when coadministered with opioids) or nootropics is also discussed.
The possible applications of compounds that bind to the ORL1 receptor and activate or inhibit it are correspondingly diverse. In addition, however, opioid receptors such as the μ- receptor, but also the other subtypes of these opioid receptors, namely δ and K, play an important part in the field of pain therapy and also other of the aforementioned indications. It is accordingly desirable if the compound also has an effect on these opioid receptors.
The object of the present invention was to provide medicinal products which act on the nociceptin/ORL1 receptor system.
Surprisingly it has now been found that substituted indole derivatives having the general formula I act on the nociceptin/ORL1 receptor system and are suitable for the treatment of pain, anxiety conditions and other diseases.
The invention therefore provides substituted indole derivatives having the general formula I,
Ri
Figure imgf000003_0001
wherein
A and B mutually independently denote CH2, C=O or SO2 X stands for indolyl, unsubstituted or mono- or polysubstituted;
T stands for (CR^R63"0),, , n = 1 , 2 or 3
Q stands for (CR^R83^),,, , m = 0,1 , 2 or 3
R1 and R2 mutually independently denote C1-3 alkyl or H or the radicals R1 and R2 form a ring with inclusion of the N atom and together denote (CH2)3 or (CH2)-*;
R3 denotes aryl or heteroaryl, each optionally bound by a C1-3 alkyl chain, each unsubstituted or mono- or polysubstituted; or C1-6 alkyl, unsubstituted or mono- or polysubstituted;
R4 denotes H; C1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl, heteroaryl or cycloaryl, each optionally bound by a C1-3 alkyl chain;
R5a c and R6a c mutually independently stand for H; F, CN, OH, OCH3, OCF3; C1-6 alkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C3-8 cycloalkyl, aryl or heteroaryl, each unsubstituted or mono- or polysubstituted; or for a C3-8 cycloalkyl, aryl or heteroaryl radical bound by a C1-3 alkyl chain, each unsubstituted or mono- or polysubstituted; or one of the radicals R5a c or R6a" c forms a five-, six- or seven-membered ring with the radical R4 with inclusion of the nitrogen atom, which ring can itself be substituted or unsubstituted or can be fused to a further five-, six- or seven-membered ring, which can be aromatic or non-aromatic;
R 7a-c R βa-c mutua||y independently stand for H; F, CN, OH, OCH3, OCF3; C1-6 alkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C3-8 cycloalkyl, aryl or heteroaryl, each unsubstituted or mono- or polysub- stituted; or for a C3-8 cycloalkyl, aryl or heteroaryl radical bound by a C1-3 alkyl chain, each unsubstituted or mono- or polysubstituted;
or one of the radicals R7a'c or R8a c forms a five-, six- or seven-membered unsaturated ring with a substituent in the 2 or 3 position of the indolyl ring X,
with the proviso that compounds in which R3 stands for a phenyl radical which is substituted in the 3 position with OH or OCOC1-8 alkyl are excluded from protection, in the form of the racemate; the enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a single enantiomer or diastereomer; the bases and/or salts of physiologically compatible acids or cations.
The compounds according to the invention exhibit good binding to the ORL1 receptor but also to the μ-opioid receptor.
Within the meaning of this invention the expressions "C1-6 alkyl" and "C1-3 alkyl" include acyclic saturated or unsaturated hydrocarbon radicals, which can be branched or straight- chain and unsubstituted or mono- or polysubstituted, having respectively 1 , 2, 3, 4, 5 or 6 C atoms or 1 , 2 or 3 C atoms, i.e. C1-5 alkanyls, C2-5 alkenyls and C2-S alkynyls or Ci-3 alkanyls, C2-3 alkenyls and C2-3 alkynyls. Alkenyls have at least one C-C double bond and alkynyls have at least one C-C triple bond. Alkyl is advantageously selected from the group comprising methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl; ethylenyl (vinyl), ethynyl, propenyl (-CH2CH=CH2, -CH=CH-CH3, -C(=CH2)-CH3), propynyl (-CH-C≡ CH, -C≡ C-CH3), 1 ,1-dimethylethyl, 1 ,1-dimethylpropyl, butenyl, butynyl, pentenyl, pentynyl, hexyl, hexenyl or hexynyl. Methyl and ethyl are particularly preferred within the meaning of this invention.
For the purposes of this invention the expression "cycloalkyl" or "C3-8 cycloalkyl" denotes cyclic hydrocarbons having 3, 4, 5, 6, 7 or 8 carbon atoms, wherein the hydrocarbons can be saturated or unsaturated (but not aromatic), unsubstituted or mono- or polysubstituted. C3-8 cycloalkyl is advantageously selected from the group including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Cyclobutyl, cyclopentyl and cyclohexyl are particularly preferred within the meaning of this invention.
The term (CH2J3-6 is understood to mean -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2- and CH2-CH2-CH2-CH2-CH2-CH2-.
Within the meaning of this invention the expression "aryl" denotes carbocyclic ring systems having up to 14 ring members with at least one aromatic ring, but without heteroatoms in only one of the rings, inter alia phenyls, naphthyls and phenanthrenyls. The aryl radicals can also be fused to other saturated, (partially) unsaturated or aromatic ring systems. Each aryl radical can be present in unsubstituted or mono- or polysubstituted form, wherein the aryl substituents can be identical or different and can be at any desired and possible position of the aryl. Phenyl or naphthyl radicals are particularly advantageous.
The expression "heteroaryl" stands for a 5-, 6- or 7-membered cyclic aromatic radical containing at least 1 , optionally also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms can be identical or different and the heterocyclic compound can be unsubstituted or mono- or polysubstituted; if the heterocyclic compound is substituted, the substituents can be identical or different and can be at any desired and possible position of the heteroaryl. The heterocyclic compound can also be part of a bicyclic or polycyclic system having up to 14 ring members. Preferred heteroatoms are nitrogen, oxygen and sulfur. It is preferable for the heteroaryl radical to be selected from the group including pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazolyl, benzothiazolyl, benzo- triazolyl, benzodioxolanyl, benzodioxanyl, phthalazinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl or oxadiazolyl, wherein the binding to the compounds having the general structure I can be made via any desired and possible ring member of the heteroaryl radical.
In connection with definitions of substituents, "alkyl" denotes "Ci-6 alkyl" unless otherwise specified.
In connection with "alkyl" and "cycloalkyl", the term "substituted" within the meaning of this invention is understood to mean the substitution of one or more hydrogen radicals with F, Cl, Br, I, -CN, NH2, NH-alkyl, NH-aryl, NH-heteroaryl, NH-cycloalkyl, NH-alkyl-aryl, NH-alkyl- heteroaryl, NH-alkyl-OH, N(alkyl)2, N(alkyl-aryl)2, N(alkyl-heteroaryl)2, N(cycloalkyl)2, N(alkyl- OH)2, NO2, SH, S-alkyl, S-aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl, S-cycloalkyl, S- alkyl-OH, S-alkyl-SH, OH, O-alkyl, O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, O- cycloalkyl, 0-alkyl-OH, CHO1 C(=O)C1-6 alkyl, C(=S)C1-6 alkyl, C(=O)aryl, C(=S)aryl, Ct=O)C1- 6 alkyl-aryl, C(=S)d-6 alkyl-aryl, C(=O)-heteroaryl, C(=S)-heteroaryl, C(=O)-cycloalkyl, C(=S)- cycloalkyl, CO2H, CO2 alkyl, CO2 alkyl-aryl, C(=O)NH2, C(=O)NH-alkyl, C(=O)NH-aryl, C(=O)NH-cycloalkyl, C(=O)N(alkyl)2, C(=O)N(alkyl-aryl)2, C(=O)N(alkyl-heteroaryl)2, C(=O)N(cycloalkyl)2, SO-alkyl, SO2-alkyl, SO2NH2, SO3H, PO(O-C1-6 alkyl)2 =0, =S, wherein polysubstituted radicals are understood to mean radicals which are either substituted multiple times, e.g. twice or three times, at different or the same atoms, for example three times at the same C atom, as in the case of CF3 or -CH2CF3, or at different sites, as in the case of -
CH(OH)-CH=CH-CHCI2. The polysubstitution can take place with identical or with different substituents. A substituent can also optionally itself be substituted, so -O alkyl also includes -0-CH2-CH2-O-CH2-CH2-OH. It is preferable within the meaning of this invention for alkyl or cycloalkyl to be substituted with F1 Cl1 Br, I1 CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, cyclopentyl, cyclohexyl, OC2H5 Or N(CH3J2, preferably F, Cl1 Br1 I1 CN, CH3, C2H5, NH2, NO2, SH, CF3, OH1 OCH3, OC2H5 or N(CH3J2. It is most particularly preferred for alkyl or cycloalkyl to be substituted with OH, OCH3 or OC2H5.
In connection with "aryl", "indolyl" or "heteroaryl", "mono- or polysubstituted" within the meaning of this invention is understood to mean the single or multiple, e.g. two, three, four or five times, substitution of one or more hydrogen atoms in the ring system with F, Cl, Br, I, CN, NH2, NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-cycloalkyl, NH-alkyl-OH, N(alkyl)2, N(alkyl-aryl)2, N(alkyl-heteroaryl)2, N(cycloalkyl)2, N(alkyl-OH)2, NO2, SH, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl, S-cycloalkyl, S- alkyl-OH, S-alkyl-SH, OH, O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl- heteroaryl, O-cycloalkyl, 0-alkyl-OH, CHO, C(=0)C1-6 alkyl, C(=S)Ci-6 alkyl, C(=O)aryl, C(=S)aryl, C(=0)-Ci-6 alkyl-aryl, C(=S)Ci-6 alkyl-aryl, C(=O)-heteroaryl, C(=S)-heteroaryl, C(=O)-cycloalkyl, C(=S)-cycloalkyl, CO2H, CO2-alkyl, CO2-alkyl-aryl, C(=O)NH2, C(=0)NH- alkyl, C(=O)NH-aryl, C(=0)NH-cycloalkyl, C(=O)N(alkyl)2, C(=O)N(alkyl-aryl)2, C(=O)N(alkyl- heteroaryl)2, C(=O)N(cycloalkyl)2, S(O)-alkyl, S(O)-aryl, SO2-alkyl, SO2-aryl, SO2NH2, SO3H, CF3; alkyl, cycloalkyl, aryl and/or heteroaryl; at one or optionally different atoms (wherein a substituent can optionally itself be substituted). The polysubstitution is performed with identical or with different substituents. If an aryl, indolyl or heteroaryl radical is itself substituted with an aryl or heteroaryl radical optionally bound via a bridge, this substituent is preferably itself unsubstituted or mono- or polysubstituted with F, Cl, Br, I, CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OC2H5 Or N(CH3J2.
It is particularly preferred within the meaning of this invention for aryl, indolyl or heteroaryl to be substituted with F, Cl, Br, I, CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OC2H5 or N(CH3)2.
The term salt is understood to mean any form of the active ingredient according to the invention in which it assumes an ionic form or is charged and is coupled to a counterion (a cation or anion) or is in solution. Also included here are complexes of the active ingredient with other molecules and ions, in particular complexes which are complexed by means of ionic interactions. It means in particular (and this is also a preferred embodiment of this invention) physiologically compatible salts, in particular physiologically compatible salts with cations or bases and physiologically compatible salts with anions or acids or also a salt formed with a physiologically compatible acid or a physiologically compatible cation. Within the meaning of this invention the term "physiologically compatible salt with anions or acids" is understood to mean salts of at least one of the compounds according to the invention - mostly protonated, for example on nitrogen - as cation with at least one anion, which are physiologically - particularly when used in humans and/or mammals - compatible. Within the meaning of this invention this is particularly understood to mean the salt formed with a physiologically compatible acid, namely salts of the individual active ingredient with inorganic or organic acids which are physiologically - particularly when used in humans and/or mammals - compatible. Examples of physiologically compatible salts of certain acids are salts of: 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, saccharinic acid, monomethyl sebacic acid, 5- oxoproline, hexane-1 -sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6- trimethylbenzoic acid, α-lipoic acid, acetylglycine, acetyl salicylic acid, hippuric acid and/or aspartic acid. The hydrochloride salt, the citrate and the hemicitrate are particularly preferred.
Within the meaning of this invention the term "salt formed with a physiologically compatible acid" is understood to mean salts of the individual active ingredient with inorganic or organic acids which are physiologically - particularly when used in humans and/or mammals - compatible. The hydrochloride and the citrate are particularly preferred. Examples of physiologically compatible 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, saccharinic acid,- monomethyl sebacic acid, 5-oxoproline, hexane-1 -sulfonic acid, nicotinic acid, 2-, 3- or 4- aminobenzoic acid, 2,4,6-trimethylbenzoic acid, α-lipoic acid, acetylglycine, acetyl salicylic acid, hippuric acid and/or aspartic acid.
Within the meaning of this invention the term "physiologically compatible salt with cations or bases" is understood to mean salts of at least one of the compounds according to the invention - mostly a (deprotonated) acid - as anion with at least one, preferably inorganic, cation, which are physiologically - particularly when used in humans and/or mammals - compatible. Particularly preferred are the salts of the alkali and alkaline-earth metals, but also ammonium salts, but in particular (mono) or (di)sodium, (mono) or (di)potassium, magnesium or calcium salts.
Within the meaning of this invention the term "salt formed with a physiologically compatible cation" is understood to mean salts of at least one of the compounds as anion with at least one inorganic cation, which is physiologically - particularly when used in humans and/or mammals - compatible. Particularly preferred are the salts of the alkali and alkaline-earth metals, but also ammonium salts, but in particular (mono) or (di)sodium, (mono) or (di)potassium, magnesium or calcium salts.
Preferred within the meaning of this invention are substituted indole derivatives wherein
"alkyl substituted" and "cycloalkyl substituted" stands for the substitution of a hydrogen radical with F, Cl, Br, I, -CN, NH2, NH-Ci-6 alkyl, NH-C1-6 alkyl-OH, C1-6 alkyl, N(C1-6 alkyl)2, N(C1-6 alkyl-OH)2l NO2, SH, S-C1-6 alkyl, S-benzyl, 0-C1-6 alkyl, OH1 0-C1-6 alkyl-OH, =0, O- benzyl, C(=O)C1-6 alkyl, C(=O)OC1-6 alkyl, phenyl or benzyl,
and "aryl substituted", "indolyl substituted" and "heteroaryl substituted" stands for the single or multiple, e.g. two, three or four times, substitution of one or more hydrogen atoms in the ring system with F, Cl, Br, I, CN, NH2, NH-C1-6 alkyl, NH-C1-6 alkyl-OH, N(C1-6 alkyl)2, N(C1-6 alkyl-OH)2, NO2, SH, S-C1-6 alkyl, OH, 0-C1-6 alkyl, 0-C1-6 alkyl-OH, C(=O)-aryl; C(=O)C1-6 alkyl, C(=O)NHC1-6 alkyl; C(=0)-N-morpholine; C(=O)-piperidine; (C=O)-pyrrolidine; (C=O)- piperazine; NHSO2C1-6 alkyl, NHCOC1-6 alkyl, CO2H, CH2SO2 phenyl, CO2-C1-6 alkyl, OCF3,
CF3,
Figure imgf000009_0001
, C1-6 alkyl, pyrrolidinyl, piperidinyl, morpholinyl, benzyloxy, phenoxy, phenyl, pyridyl, alkylaryl, thienyl or furyl, wherein aryl and heteroaryl substituents can themselves be substituted with F, Cl, Br, I1 CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OC2H5 or N(CH3)2;
in the form of the racemate; the enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a single enantiomer or diastereomer; the bases and/or salts of physiologically compatible acids or cations.
For a preferred embodiment of the substituted indole derivatives according to the invention,
A and B mutually independently denote CH2 or C=O.
It is particularly preferable for A to denote CH2 and B to denote CH2 or C=O.
Substituted indole derivatives are preferred wherein X stands for indolyl, unsubstituted or mono- or polysubstituted with F, Cl, Br1 I1 CN1 CH3, C2H5, C3H8, NH2, NO2, SH, CF3, OH, OCH3, OC2H5, N(CH3)2 or phenyl, unsubstituted or mono- or polysubstituted with F, Cl, Br, I1 CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OC2H5 Or N(CH3J2.
Substituted indole derivatives are particularly preferred wherein X stands for indole, 1- methylindole, 5-fluoroindole, 5-methoxyindole, 5-bromoindole, 6-chloroinidole, 6-fluoroindole, 6-methoxy-1,2-dimethylindole, 1 ,2-dimethylindole, 2-(4-fluorophenyl)indole, 2-phenylindole, 5-chloroindole or 6-/so-propylindole.
Also preferred are substituted indole derivatives wherein R1 and R2 mutually independently denote methyl or H or the radicals R1 and R2 form a ring with inclusion of the N atom and denote (CH2)3 or (CH2)4.
Most particularly preferred are substituted indole derivatives wherein R1 and R2 mutually independently denote methyl or H, preferably methyl.
Also preferred are substituted indole derivatives wherein R3 stands for phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted at the ring; C1^ alkyl, unsubstituted or mono- or polysubstituted; pyridyl, thienyl, thiazolyl, imidazolyl, 1 ,2,4-triazolyl or benzimidazolyl, unsubstituted or mono- or polysubstituted.
Particularly preferred are substituted indole derivatives having the general formula I, wherein R3 stands for phenyl, benzyl, phenethyl, thienyl, pyridyl, thiazolyl, imidazolyl, 1 ,2,4-triazolyl, benzimidazolyl or benzyl, unsubstituted or mono- or polysubstituted with F, Cl, Br1 CN, CH3, C2H5, NH2, NO2, SH1 CF3, OH, OCH3, OC2H5 Or N(CH3J2; ethyl, n-propyl, 2-propyl, allyl, n- butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, cyclopentyl or cyclohexyl, each unsubstituted or mono- or polysubstituted with OH, OCH3 or OC2H5,
wherein thienyl, pyridyl, thiazolyl, imidazolyl, 1,2,4-triazolyl and benzimidazolyl are preferably unsubstituted;
in particular
phenyl, unsubstituted or monosubstituted with F, Cl, CN, CH3; thienyl; or n-butyl, unsubstituted or mono- or polysubstituted with OCH3, OH or OC2H5, in particular with OCH3.
Also preferred are substituted indole derivatives wherein R4 denotes H, CH3 or benzyl, in particular H. Further preferred are substituted indole derivatives wherein
R5a-° and R6^ stand for H.
Also preferred are substituted indole derivatives wherein
R 7a-c R βa-c muuja||y independently denotes H; Ci-6 alkyl, saturated or unsaturated, branched or unbranched,
or one of the radicals R7a c or R8a'c forms a five-, six- or seven-membered unsaturated ring with a substituent in the 3 position of the indolyl ring X, such that a structural element having the general formulae lla-f is produced:
Figure imgf000011_0001
Ma Hb Hc
Figure imgf000011_0002
Hd He Hf
Particularly preferred are substituted indole derivatives having the general formula I1 wherein R 7a-c R βa-c mutua||y independently stand for H; CH3, ethyl or propyl;
or one of the radicals R7a"c or R8a"c forms a six-membered unsaturated ring with a substituent in the 3 position of the indolyl ring X, such that the structural element having the general formula Ha is produced:
Figure imgf000012_0001
Na
Most particularly preferred are substituted indole derivatives from the group comprising
. N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-N-methyl-1 H-indole-6- carboxamide
2 N-(2-(4-(Dimethylamino)-4-(thiophen-2-yl)pipehdin-1-yl)ethyl)-3-(1 H-indol-3-yl)-4- methylpentanamide
N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-5-fluoro-N-methyl-1 H-indole-2- carboxamide
. N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-3-(1 H-indol-3-yl)-N- methylpropanamide
5 N-(2-(4-(Dimethylamino)-4-(thiophen-2-yl)pipehdin-1 -yl)ethyl)-3-(1 H-indol-3- yl)propanamide
6 N-(2-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)ethyl)-3-(1 H-indol-3-yl)-4- methylpentanamide
_ 6-Chloro-N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)ethyl)-2,3,4,9- tetrahydro-1 H-carbazole-1-carboxamide
8 N-(2-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)ethyl)-2-(6-fluoro-1 H-indol-3- yl)acetamide g N-(2-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)ethyl)-1-methyl-1H-indole-6- carboxamide
10 N-(2-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)ethyl)-1-methyl-1H-indole-4- carboxamide
. . N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl)-N-methyl-1 H-indole-3- carboxamide
12 N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-N-methyl-1 H-indole-3- carboxamide
13 N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl)-N-methyl-3-(1-methyl-1 H- indol-3-yl)propanamide
14 N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-N-methyl-3-(1-methyl-1 H-indol-3- yl)propanamide 15 N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl)-5-fluoro-N-methyl-1 H- indole-2-carboxamide
N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-5-fluoro-N-methyl-1 H-indole-2- carboxamide
. N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl)-N-methyl-1H-indole-6- carboxamide
1 R N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-N-methyl-1 H-indole-6- carboxamide
19 N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl)-3-(1 H-indol-3-yl)-N- methylbutanamide
20 N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-3-(1 H-indol-3-yl)-N- methylbutanamide
21 N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl)-3-(1 H-indol-3-yl)-N- methylpropanamide
__ N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1 -yl)propyl)-5-methoxy-N-methyl-1 H- indole-2-carboxamide
23 N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl)-3-(1 H-indol-3-yl)-N,4- dimethylpentanamide
24 N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-3-(1H-indol-3-yl)-N,4- dimethylpentanamide
25 6-Chloro-N-(2-(4-(dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-N-methyl-2, 3,4,9- tetrahydro-1H-carbazole-1 -carboxamide
26 N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl)-2-(6-fIuoro-1 H-indol-3-yl)- N-methylacetamide
_7 N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-2-(6-fluoro-1H-indol-3-yl)-N- methylacetamide
28 N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl)-N,1-dimethyl-1H-indole- 6-carboxamide
2g N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-N,1-dimethyl-1 H-indole-6- carboxamide
30 N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl)-N,1-dimethyl-1 H-indole- 4-carboxamide
31 N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-N,1-dimethyl-1 H-indole-4- carboxamide
32 3-(1H-lndol-3-yl)-N,4-dimethyl-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1- yl)ethyl)pentanamide
33 N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-3-(1 H-indol-3-yl)-N,4- dimethylpentanamide _ . N-(3-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)propyl)-3-(1 H-indol-3-yl)-N,4- dimethylpentanamide
^1. 6-Chloro-N-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)propyl)-N-methyl-2, 3,4,9- tetrahydro-1 H-carbazole-1 -carboxamide
36 2-(6-Fluoro-1 H-indol-3-yl)-N-methyl-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1- yl)ethyt)acetamide
37 N.I-Dimethyl-N^^-phenyM^pyrrolidin-i-yOpiperidin-i-yOethyO-I H-indole-θ- carboxamide
38 N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-N,1-dimethyl-1H-indole-6- carboxamide
3g N-(3-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)propyl)-N,1-dimethyl-1 H-indole-6- carboxamide
40 N,1-Dimethyl-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1-yl)ethyl)-1 H-indole-4- carboxamide
41 N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-N,1-dimethyl-1 H-indole-4- carboxamide
42 6-Chloro-N-methyl-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1-yl)ethyl)-2,3,4,9- tetrahydro-1 H-carbazole-1 -carboxamide
43 N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-6-chloro-N-methyl-2, 3,4,9- tetrahydro-1 H-carbazole-1 -carboxamide
44 N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-2-(6-fluoro-1 H-indol-3-yl)-N- methylacetamide
4(- N-(3-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)propyl)-2-(6-fluoro-1 H-indol-3-yl)-N- methylacetamide
46 N-Methyl-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1-yl)ethyl)-1 H-indole-3-carboxamide
47 N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-N-methyl-1 H-indole-3-carboxamide
48 N-Methyl-3-(1-methyl-1 H-indol-3-yl)-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1- yl)ethyl)propanamide
49 N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-N-methyl-3-(1-methyl-1 H-indol-3- yl)propanamide
50 N-(3-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)propyl)-N-methyl-3-(1-methyl-1 H-indol-3- yl)propanamide
_. 5-Fluoro-N-methyl-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1-yl)ethyl)-1H-indole-2- carboxamide N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-5-fluoro-N-methyl-1H-indole-2- carboxamide N-(3-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)propyl)-5-fluoro-N-methyl-1 H-indole-2- carboxamide
N-Methyl-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1-yl)ethyl)-1 H-indole-6-carboxamide
N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-N-methyl-1H-indole-6-carboxamide N-(3-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)propyl)-N-methyl-1 H-indole-6- carboxamide 3-(1H-lndol-3-yl)-N-methyl-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1- yl)ethyl)butanamide N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-3-(1 H-indol-3-yl)-N- methylbutanamide N-(3-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)propyl)-3-(1 H-indol-3-yl)-N- methylbutanamide N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-3-(1 H-indol-3-yl)-N- methylpropanamide N-(3-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)propyl)-3-(1 H-indol-3-yl)-N- methylpropanamide 2-(5-Bromo-1 H-indol-3-yl)-N-methyl-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1- yl)ethyl)acetamide 2-(5-Bromo-1H-indol-3-yl)-N-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)propyl)-N- methylacetamide 5-Methoxy-N-methyl-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1-yl)ethyl)-1 H-indole-2- carboxamide N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-5-methoxy-N-methyl-1H-indole-2- carboxamide N-(3-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)propyl)-5-methoxy-N-methyl-1 H-indole-2- carboxamide 1-(3-(((6-lsopropyl-1H-indol-3-yl)methyl)(methyl)amino)propyl)-N,N-dimethyl-4-(thiophen- 2-yl)piperidin-4-amine 1-(2-(((1 H-lndol-5-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4-phenylpiperidin-4- amine 1-(2-((1 H-lndol-5-yl)methylamino)ethyl)-N,N-dimethyl-4-(thiophen-2-yl)piperidin-4-amine 1-(2-(((2-(4-Fluorophenyl)-1H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine N,N-Dimethyl-1-(2-(methyl((2-phenyl-1H-indol-3-yl)methyl)amino)ethyl)-4- phenylpiperidin-4-amine 72 1-(2-((5-Chloro-1 H-indol-3-yl)methylamino)ethyl)-N,N-dimethyl-4-(thiophen-2-yl)piperidin- 4-amine
73 1-(2-(((6-lsopropyl-1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine
1-(2-((6-lsopropyl-1H-indol-3-yl)methylamino)ethyl)-N,N-dimethyl-4-(thiophen-2- yl)piperidin-4-amine
75 1-(2-(((5-Methoxy-1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine
76 1-(2-((5-Methoxy-1H-indol-3-yl)methylamino)ethyl)-N,N-dimethyl-4-(thiophen-2- yl)piperidin-4-amine
77 1-(2-(((1-Benzyl-5-methoxy-2-methyl-1H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N- dimethyl-4-phenylpiperidin-4-amine
78 1-(2-((1-Benzyl-5-methoxy-2-methyl-1 H-indol-3-yl)methylamino)ethyl)-N,N-dimethyl-4- (thiophen-2-yl)piperidin-4-amine
79 1-(2-(((1 ,2-Dimethyl-1H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine
80 1-(2-((1 ,2-Dimethyl-1 H-indol-3-yl)methylamino)ethyl)-N,N-dimethyl-4-(thiophen-2- yl)piperidin-4-amine
O 1 1-(3-(((1 ,2-Dimethyl-1 H-indol-3-yl)methyl)(methyl)amino)propyl)-N,N-dimethyl-4- (thiophen-2-yl)piperidin-4-amine
82 N-(1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-2-(6-fluoro- 1H-indol-3-yl)-N-methylacetamide
83 2-(5-bromo-1 H-indol-3-yl)-N-(1-(4-(dimethylannino)-4-phenylpiperidin-1-yl)-3-methyl-1- oxobutan-2-yl)-N-methylacetamide
04 N-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-oxopropyl)-3-(1 H-indol-3-yl)-4- methylpentanamide
05 N-(3-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-3-oxo-1-phenylpropyl)-3-(1H- indol-3-yl)-4-methylpentanamide
06 1-(3-(4-(dimethylamino)-4-phenylpiperidine-1-carbonyl)indolin-1-yl)-2-(6-fluoro-1H-indol- 3-yl)ethanone
07 N-(2-(4-(dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-3-(1H-indol-3-yl)-N,4- dimethylpentanamide
Q8 N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-2-oxoethyl)-3-(1 H-indol-3-yl)-4- methylpentanamide 1-(3-(4-(dimethylamino)-4-phenylpiperidine-1-carbonyl)indolin-1-yl)-3-(1 H-indol-3-yl)-4- methylpentan-1-one
N-(2-(4-(dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-2-(6-fIuoro-1 H-indol-3-yl)-N- methylacetamide
N-(3-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-3-oxo-1-phenylpropyl)-3-(1H- indol-3-yl)butanamide
Q2 N-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-oxopropyl)-3-(1 H-indol-3- yl)butanamide
N-(3-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-3-oxo-1-phenylpropyl)-2-(6- fluoro-1 H-indol-3-yl)acetamide
N-(1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-(1 H-indol-3- yl)-N-methylpropanamide
N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-2-oxo-1-phenylethyl)-2-(6-fluoro- 1 H-indol-3-yl)-N-methylacetamide
Q6 N-(3-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-3-oxo-1-phenylpropyl)-1 H- indole-6-carboxamide
Q7 e-chloro-N^S^^dimethylamino^-^hiophen^-ylJpiperidin-i-yO-S-oxo-i-phenylpropyl)- 2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide
Qo N-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-oxopropyl)-3-(1H-indol-3- yl)propanamide go N-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-oxopropyl)-1-methyl-1 H-indole-6- carboxamide
100 2-(5-bromo-1 H-indol-3-yl)-N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-2-oxo- 1-phenylethyl)-N-methylacetamide
101 N-(3-(4"(dimethy|am'no)"4-(th'°Phen-2"y|)piperidin-1-yl)-3-oxo-1-phenylpropyl)-1 -methyl- 1 H-indole-6-carboxamide i n« N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-2-oxo-1-phenylethyl)-N-methyl- 1 H-indole-6-carboxamide
10« (6-chloro-2,3,4,9-tetrahydro-1 H-carbazol-1-yl)(3-(4-(dimethylamino)-4-phenylpiperidine- 1 -carbonyl)piperidin-1 -yl)methanone
104 (4-(d'methy|am'no)"4"Pheny|P'Per'd'n"1"y|)('|-(5-fluoro-1 H-indole-2-carbonyl)piperidin-3- yl)methanone N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-2-oxo-1-phenylethyl)-3-(1 H- indol-3-yl)-N,4-dimethylpentanamide
1-(3-(4-(dimethylamino)-4-phenylpiperidine-1-carbonyl)piperidin-1-yl)-3-(1H-indol-3-yl)-4- methylpentan-1-one
6-chloro-N-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-oxopropyl)-2,3,4,9-tetrahydro- 1 H-carbazole-1-carboxamide
N-(3-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-3-oxo-1-phenylpropyl)-1-methyl- 1 H-indole-4-carboxamide
N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-2-oxoethyl)-1-methyl-1 H-indole- 6-carboxamide
1 10 N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-2-oxo-1-phenylethyl)-3-(1 H- indol-3-yl)-N-methylpropanamide
1.. N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-2-oxo-1-phenylethyl)-N,1- dimethyl-1H-indole-6-carboxamide
1 12 N-(2-(4-butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-2-(6-fluoro-1 H-indol-3-yl)-N- methylacetamide
113 N-(3-(4-(dimethylamino)-4-phenylpiperidin-1 -yl)-3-oxopropyl)-1 H-indole-6-carboxamide
114 (4-(dimethylamino)-4-phenylpiperidin-1-yl)(1-(1-methyl-1 H-indole-4-carbonyl)indolin-3- yl)methanone
1 15 2-(5-bromo-1 H-indol-3-yl)-1-(3-(4-(dimethylamino)-4-phenylpiperidine-1- carbonyl)piperidin-1-yl)ethanone
. .6 6-chloro-N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1 -yl)-2-oxoethyl)-2, 3,4,9- tetrahydro-1 H-carbazole-1-carboxamide
1 17 N-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-oxopropyl)-3-(1-methyl-1 H-indol-3- yl)propanamide
1 18 (4-(dimethylamino)-4-phenylpiperidin-1-yl)(1-(1-methyl-1 H-indole-6-carbonyl)indolin-3- yl)methanone
1 19 N-(2-(4-(dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-N,1-dimethyl-1 H-indole-6- carboxamide
120 6-(dirnethylamino)-N-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-oxopropyl)-1 H- indole-2-carboxamide N-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-oxopropyl)-1-methyl-1H-indole-4- carboxamide
1-(3-(4-(dimethylamino)-4-phenylpiperidine-1-carbonyl)piperidin-1-yl)-3-(1 H-indol-3- yl)butan-1-one
1-(3-(4-(dimethylamino)-4-phenylpiperidine-1-carbonyl)piperidin-1-yl)-3-(1H-indol-3- yl)propan-1-one
1-(3-(4-(dimethylamino)-4-phenylpiperidine-1-carbonyl)piperidin-1-yl)-2-(6-fluoro-1H- indol-3-yl)ethanone
(1-(1 H-indole-6-carbonyl)piperidin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-1- yl)methanone
N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1 -yl)-2-oxo-1 -phenylethyl)-N-methyl- 3-( 1 -methyl- 1 H-indol-3-yl)propanamide
6-chloro-N-(2-(4-(dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-N-methyl-2,3,4,9- tetrahydro-I H-carbazole-i-carboxamide
128 (4-(dimethylannino)-4-phenylpiperidin-1-yl)(1-(1-methyl-1 H-indole-6-carbonyl)piperidin-3- yl)methanone
12g N-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-oxopropyl)-5-methoxy-1 H-indole-2- carboxamide
130 (4-(dimethylannino)-4-phenylpiperidin-1-yl)(1-(1-methyl-1 H-indole-4-carbonyl)piperidin-3- yl)methanone
131 C-('|H-indole-3-carbonyl)piperidin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-1- yl)methanone
132 N-(1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-N-methyl-3- (1-methyl-1H-indol-3-yl)propanamide
133 1"(3"(4"(c|imethylamino)-4-phenylpiperidine-1-carbonyl)piperidin-1-yl)-3-(1-methyl-1 H- indol-3-yl)propan-1-one
134 6-chloro-N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-2-oxo-1-phenylethyl)-N- methyl-2,3,4,9-tetrahydro-1 H-carbazole-1 -carboxamide
135 N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-2-oxoethyl)-1-methyl-1 H-indole- 4-carboxamide
136 (6-(dimethylamino)-1 H-indol-2-yl)(3-(4-(dimethylamino)-4-phenylpiperidine-1- carbonyl)piperidin-1-yl)methanone N-((1H-indol-3-yl)methyl)-N-methyl-2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1- yl)ethanamine
138 1-(2-(((1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-4-butyl-N,N-dimethylpiperidin-4-amine
3-((1H-indol-3-yl)methylannino)-1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)propan-1- 1 jy one
140 N-((1 H-'ndo|-5-y|)methyl)-N-methyl-2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1- yl)ethanamine
141 1-(2-(((1 H-indol-5-yl)nnethyl)(methyl)amino)ethyl)-4-butyl-N,N-dimethylpiperidin-4-amine
142 3-((1 H-indol-5-yl)methylamino)-1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)propan-1- one
143 N-((1H-'nc|ol-6-yl)methyl)-N-methyl-2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1- yl)ethanamine
144 1-(2-(((1H-indol-6-yl)methyl)(methyl)amino)ethyl)-4-butyl-N,N-dimethylpiperidin-4-amine
AΛC 3-((1H-indol-6-yl)methylamino)-1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)propan-1-
145 one
14fi 2-(((1H-indol-5-yl)methyl)(methyl)amino)-1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3- methylbutan-1-one
147 2-(((1H-indol-5-yl)methyl)(methyl)amino)-1-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin- 1 -yl)-2-phenylethanone
148 C|"(CH-indol-5-yl)methyl)piperidin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-1- yl)methanone
149 2-(((1H-indol-6-yl)methyl)(methyl)amino)-1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3- methylbutan-1-one
150 2-(((1H-indol-6-yl)methyl)(methyl)amino)-1-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin- 1 -yl)-2-phenylethanone
151 (1-((1 H-indol-3-yl)methyl)piperidin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-1- yl)methanone
152 C-((1 H"'ndol"6-y|)methyl)piperidin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-1- yl)methanone N-^S-bromo-I H-indol-S-yOmethylJ-N-methyl-Σ^-phenyl^-Cpyrrolidin-i-yOpiperidin-i- yl)ethanamine
1-(2-(((5-bromo-1H-indol-3-yl)methyl)(methyl)amino)ethyl)-4-butyl-N,N-dimethylpiperidin- 4-amine
155 (1-((5-bromo-1H-indol-3-yl)methyl)piperidin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-1- yl)methanone
156 (4-(dinfiethylamino)-4-phenylpiperidin-1-yl)(1-((2-methyl-1H-indol-3-yl)methyl)piperidin-3- yl)methanone
157 1-(2-(((1 H-indol-7-yl)methyl)(methyl)amino)ethyl)-4-butyl-N,N-dimethylpiperidin-4-amine
158 (1-((1 H-indol"7"y')rnethyl)piperidin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-1- yl)methanone
159 N-((1 H-indol-4-yl)methyl)-N-methyl-2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1- yl)ethanamine
160 1-(2-(((1H-indol-4-yl)methyl)(methyl)amino)ethyl)-4-butyl-N,N-dimethylpiperidin-4-amine
161 (1-((1 H-indol-4-yl)methyl)piperidin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-1- yl)methanone
... 3-((5-bromo-1H-indol-3-yl)methylamino)-1-(4-(dimethylamino)-4-phenylpiperidin-1- yl)propan-1-one
1 β3 3-((5-bromo-1 H-indol-3-yl)methylamino)-1-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin- 1-yl)-3-phenylpropan-1-one
164 3-((1 H-indol-3-yl)methylamino)-1-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-3- phenylpropan-1 -one
165 3-((1H-indol-5-yl)methylamino)-1-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-3- phenylpropan-1 -one
166 C|-((1 H"'nclol"5"y|)fTiethyl)indolin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-1- yl)methanone
1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-((2-methyl-1H-indol-3- yl)methylamino)propan-1-one
168 1-(4"(d'metny|amino)"4"(tnioPnen"2-yl)piperidin-1-yl)-3-((2-methyl-1 H-indol-3- yl)methylamino)-3-phenylpropan-1-one S-^IH-indol-e-yOmethylaminoJ-i^^dimethylaminoJ-Φ^hiophen^-ylJpiperidin-i-yO-S- phenylpropan-1-one
(1-((1 H-indol-6-yl)methyl)indolin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-1- yl)methanone
171 3-((1H-indol-7-yl)methylamino)-1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)propan -1- one
172 2-((1 H-indol-7-yl)methylamino)-1-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1- yl)ethanone
17_ 3-((1H-indol-7-yl)methylamino)-1-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-3- phenylpropan-1-one
3-((1H-indol-4-yl)methylamino)-1-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-3- phenylpropan-1-one
(1 -((1 H-indol-4-yl)methyl)indolin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-1 - yl)methanone
176 (4-(dimethylamino)-4-phenylpiperidin-1-yl)(1-((6-methoxy-1 ,2-dimethyl-1 H-indol-3- yl)methyl)piperidin-3-yl)methanone
177 (4-(dimethylamino)-4-phenylpiperidin-1-yl)(1-((2-(4-fluorophenyl)-1H-indol-3- yl)methyl)piperidin-3-yl)methanone
178 i^-^S-chloro-IH-indol-S-yOmethylaminoJethylJ-N.N-dimethyl^thiophen^-yOpiperidin- 4-amine
179 1-(2-((1H-indol-3-yl)methylamino)ethyl)-N,N-dimethyl-4-(thiophen-2-yl)piperidin-4-amine
180 1-(2-(((6-isopropyl-1H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine
181 1-(2-(((1 H-indol-6-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4-phenylpiperidin-4- amine
1-(2-(((5-chloro-1H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine
8 1-(2-(((5-chloro-1H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine
184 1-(2-(((1H-indol-6-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4-phenylpiperidin-4- amine 1 -(2-(((5-bromo- 1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-N , N-dimethyl-4- phenylpiperidin-4-amine
186 1-(2-(((1 H-'ndo|-3-y|)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4-phenylpiperidin-4- amine
187 1-(2-(((1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4-phenylpiperidin-4- amine
18o 1-(2-((5-methoxy-1H-indol-3-yl)methylamino)ethyl)-N,N-dimethyl-4-(thiophen-2- yl)piperidin-4-amine
189 1-(2-(((1 ,2-dimethyl-1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine
190 1-(2-(((5-methoxy-1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine
191 1-(2-(((5-methoxy-1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine
192 1-(2-(((5-|Tietnoχy-1 H-indo|-3-y|)fTiethyl)(methyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine
193 1-(2-(((1-benzyl-5-methoxy-2-methyl-1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N- dimethyl-4-phenylpiperidin-4-amine
1 Q4 1-(2-(((1H-indol-4-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4-phenylpiperidin-4- amine
195 #'-(2-(((1H-indol-4-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4-phenylpiperidin-4- amine
in the form of the racemate; the enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a single enantiomer or diastereomer; the bases and/or salts of physiologically compatible acids or cations.
The substances according to the invention act for example on the ORL1 receptor of relevance in connection with various diseases, such that they are suitable as a pharmaceutical active ingredient in a medicinal product. The invention therefore also provides medicinal products containing at least one substituted indole derivative according to the invention, optionally along with suitable additives and/or auxiliary substances and/or optionally further active ingredients. The medicinal products according to the invention optionally contain, in addition to at least one substituted indole derivative according to the invention, suitable additives and/or auxiliary substances, including carrier materials, fillers, solvents, diluents, dyes and/or binders, and can be administered as liquid dosage forms in the form of injection solutions, drops or juices, as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, plasters/spray plasters or aerosols. The choice of auxiliary substances, etc., and the amount thereof to use depend on whether the medicinal product is to be administered by oral, peroral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal or local means, for example on the skin, mucous membranes or in the eyes. Preparations in the form of tablets, pastilles, capsules, granules, drops, juices and syrups are suitable for oral administration; solutions, suspensions, easily reconstitutable dry preparations and sprays are suitable for parenteral, topical and inhalative administration. Substituted indole derivatives according to the invention in a depot formulation, in dissolved form or in a plaster, optionally with addition of agents promoting skin penetration, are suitable preparations for percutaneous administration. Preparation forms suitable for oral or percutaneous administration can deliver the substituted indole derivatives according to the invention on a delayed release basis. The substituted indole derivatives according to the invention can also be used in parenteral long-term depot forms, such as implants or implanted pumps, for example. Other additional active ingredients known to the person skilled in the art can be added in principle to the medicinal products according to the invention.
The amount of active ingredient to be administered to the patient varies according to the weight of the patient, the type of administration, the indication and the severity of the illness. 0.00005 to 50 mg/kg, preferably 0.001 to 0.5 mg/kg, of at least one substituted indole derivative according to the invention are conventionally administered.
A preferred form of the medicinal product contains a substituted indole derivative according to the invention as a pure diastereomer and/or enantiomer, as a racemate or as a non- equimolar or equimolar mixture of diastereomers and/or enantiomers.
As was mentioned in the introduction in respect of the prior art, the ORL1 receptor has been identified in particular in the pain mechanism. Substituted indole derivatives according to the invention can accordingly be used for the preparation of a medicinal product for the treatment of pain, in particular acute, neuropathic or chronic pain. The invention therefore also provides the use of a substituted indole derivative according to the invention to prepare a medicinal product for the treatment of pain, in particular acute, visceral, neuropathic or chronic pain.
The invention also provides the use of a substituted indole derivative according to the invention to prepare a medicinal product for the treatment of anxiety conditions, stress and stress-related syndromes, depression, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunctions, learning and memory disorders (as a nootropic), withdrawal symptoms, alcohol and/or drug and/or prescription drug abuse and/or dependency, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinnitus, pruritus, migraine, hearing impairment, gastrointestinal motility disorders, food intake disorders, anorexia, obesity, locomotive disorders, diarrhoea, cachexia, urinary incontinence, or as a muscle relaxant, anticonvulsant or anaesthetic, or for coadministration in treatment with an opioid analgesic or with an anaesthetic, for diuresis or antinatriuresis, anxiolysis, for the modulation of motor activity, for the modulation of neurotransmitter release and treatment of associated neurodegenerative diseases, for the treatment of withdrawal symptoms and/or for the reduction of the addiction potential of opioids.
In one of the above uses it can be preferable for a substituted indole derivative that is used to be in the form of a pure diastereomer and/or enantiomer, a racemate or a non-equimolar or equimolar mixture of diastereomers and/or enantiomers.
The invention also provides a process for the treatment, in particular in one of the aforementioned indications, of a non-human mammal or human requiring treatment of pain, in particular chronic pain, by administration of a therapeutically active dose of a substituted indole derivative according to the invention or of a medicinal product according to the invention.
The present invention also provides a process for preparing the substituted indole compounds according to the invention. The chemicals and reaction components used in the reactions described are available commercially or can be produced by methods known to the person skilled in the art.
General process for preparing compounds having the general formula I Stage 1
Protective group -
Figure imgf000026_0001
O^
III
Stage 3
Figure imgf000026_0002
AA IV
Figure imgf000026_0003
Figure 1: Synthesis routes
The compounds having the general formula AA, as shown in Figure 1 , can be converted to compounds having the formula AMD, SAM and AMN.
The protective group in formula A, B and III is a suitable nitrogen protective group, preferably benzyl or tert-butyloxycarbonyl.
In stage 1 , compounds known from the literature having the general formula A in at least one solvent, preferably selected from the group consisting of methanol, ethanol, dioxane, diethyl ether, tetrahydrofuran, water and dimethyl formamide, are reacted with an amine having the general formula HNR1R2, wherein R1 and R2 have the meaning given above, and potassium cyanide or sodium cyanide, with addition of at least one acid, preferably selected from the group consisting of sodium hydrogen sulfite, acetic acid, trifluoroacetic acid, hydrochloric acid and sulfuric acid, at temperatures of preferably 00C to 600C1 to form compounds having the general formula B.
In stage 2, compounds having the general formula B in at least one solvent, preferably selected from the group consisting of tetrahydrofuran, diethyl ether and dioxane, are reacted with a Grignard reagent R3MgBr or R3MgCI, wherein R3 has the meaning given above, at temperatures of preferably 00C to 800C, to form compounds having the general formula III.
In stage 3, compounds having the general formula III are converted to compounds having the general formula IV by elimination of the protective group.
If the protective group is benzyl, the conversion to compounds having the general formula IV takes place in 2 steps. First of all the compounds having the general formula III (protective group = benzyl) in at least one solvent, preferably selected from the group consisting of chloroform, diethyl ether, tetrahydrofuran, acetonitrile, acetone and dimethyl formamide, are reacted with carbobenzoxychloride (CbzCI) at temperatures of preferably 00C to 8O0C to form compounds having the general formula III (protective group = Cbz). Then the compounds having the general formula III (protective group = Cbz) in at least one solvent, preferably selected from the group consisting of methanol, ethanol, diethyl ether, tetrahydrofuran, acetonitrile, dimethyl formamide and dimethyl sulfoxide, are reacted with an inorganic base, preferably selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide, at temperatures of preferably 00C to 800C, to form compounds having the general formula IV.
Alternatively, compounds having the general formula III (protective group = benzyl) in at least one solvent, preferably selected from the group consisting of methanol, ethanol, ethyl acetate, chloroform, diethyl ether, tetrahydrofuran, acetone and dimethyl formamide in the presence of a catalyst, preferably selected from the group consisting of palladium on carbon, palladium hydroxide, palladium acetate and palladium black, are reacted with a suitable hydrogen source, preferably selected from the group consisting of hydrogen, formic acid, 1 ,3- cyclohexadiene and ammonium formate, at temperatures of preferably 0°C to 800C, to form compounds having the general formula IV.
If the protective group is te/f-butyloxycarbonyl (Boc), then the compounds having the general formula III in at least one solvent, preferably selected from the group consisting of methanol, ethanol, dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, dioxane, dimethyl formamide and dimethyl sulfoxide, are reacted with an acid, preferably selected from the group consisting of trifluoroacetic acid, sulfuric acid and hydrochloric acid, at temperatures of preferably 00C to 800C, to form compounds having the general formula IV.
In stage 4, the compounds having the general formula IV in at least one solvent, preferably selected from the group consisting of dioxane, diethyl ether, tetrahydrofuran, acetonitrile and dimethyl formamide, are reacted with a suitable alkyl halide in the presence of an excess of a base, preferably selected from the group consisting of caesium carbonate, calcium carbonate, potassium carbonate, triethylamine, diisopropyl ethylamine and pyridine, at temperatures of preferably 00C to 8O0C, to form compounds having the general formula V.
Alternatively, compounds having the general formula IV are reacted with a suitable aldehyde in at least one organic solvent, preferably selected from the group consisting of diethyl ether, tetrahydrofuran, methanol, ethanol, dichloroethane, dichloromethane and toluene, with addition of at least one reducing agent, preferably selected from the group consisting of borane-pyridine complex, sodium boron hydride, sodium triacetoxyboron hydride, sodium cyanoboron hydride and triethylsilane, optionally in the presence of at least one acid, preferably selected from the group consisting of formic acid, acetic acid, hydrochloric acid and trifluoroacetic acid, at temperatures of preferably -700C to 1000C, to form compounds having the general formula V.
Alternatively, compounds having the general formula IV in at least one solvent, preferably selected from the group consisting of dichloromethane, acetonitrile, dimethyl formamide, diethyl ether, dioxane and tetrahydrofuran, are reacted with acids having the general formula protective group-NR4-T-CO2H, wherein protective group, R4 and T have the meanings given above, with addition of at least one coupling reagent, preferably selected from the group consisting of carbonyl diimidazole (CDI), 2-chloro-1-methylpyridinium iodide (Mukaiyama reagent), Λ/-(3-dimethylaminopropyl)-Λ/'-ethylcarbodiimide (EDCI), O-(benzotriazoM-yl)- Λ/,Λ/,Λ/',Λ/'-tetramethyluronium tetrafluoroborate (TBTU), Λ/./V-dicyclohexylcarbodiimide (DCC) and 1-benzotriazolyloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), optionally in the presence of at least one inorganic base, preferably selected from the group consisting of potassium carbonate and caesium carbonate, or an organic base, preferably selected from the group consisting of triethylamine, diisopropylethylamine and pyridine, and optionally with addition of 4-(dimethylamino)pyridine or 1-hydroxybenzotriazole, to form compounds having the general formula V.
In stage 5, if the protective group is not H, the protective group is eliminated. If the protective group is terf-butyloxycarbonyl, then the compounds having the general formula V in at least one solvent, preferably selected from the group consisting of diethyl ether, tetrahydrofuran, methanol, ethanol, dichloromethane, dioxane and dimethyl formamide, are reacted with an acid, preferably selected from the group consisting of trifluoroacetic acid, hydrochloric acid and sulfuric acid, at temperatures of preferably 00C to 800C, to form compounds having the general formula AA.
In stage 6, compounds having the general formula AA in at least one solvent, preferably selected from the group consisting of dichloromethane, acetonitrile, dimethyl formamide, diethyl ether, dioxane and tetrahydrofuran, are reacted with acids having the general formula X-Q-CO2H, wherein X and Q have the meanings given above, with addition of at least one coupling reagent, preferably selected from the group consisting of carbonyl diimidazole (CDI), 2-chloro-1-methylpyridinium iodide (Mukaiyama reagent), Λ/-(3-dimethylaminopropyl)- /V-ethylcarbodiimide (EDCI), O-(benzotriazol-1-yl)-Λ/,Λ/,Λ/',Λ/'-tetramethyluronium tetrafluoroborate (TBTU), Λ/.Λ/'-dicyclohexylcarbodiimide (DCC) and 1-benzotriazolyloxy-tris- (dimethylamino)-phosphonium hexafluorophosphate (BOP), optionally in the presence of at least one inorganic base, preferably selected from the group consisting of potassium carbonate and caesium carbonate, or an organic base, preferably selected from the group consisting of triethylamine, diisopropylethylamine and pyridine, and optionally with addition of 4-(dimethylamino)pyridine or 1-hydroxybenzotriazole, to form compounds having the general formula AMD.
In stage 7, compounds having the general formula AA are reacted with aldehydes having the general formula X-Q-CHO, wherein X and Q have the meanings given above, in at least one organic solvent, preferably selected from the group consisting of diethyl ether, tetrahydrofuran, methanol, ethanol, dichloroethane, dichloromethane and toluene, with addition of at least one reducing agent, preferably selected from the group consisting of borane-pyridine complex, sodium boron hydride, sodium triacetoxyboron hydride, sodium cyanoboron hydride and triethylsilane, optionally in the presence of at least one acid, preferably selected from the group consisting of formic acid, acetic acid, hydrochloric acid and trifluoroacetic acid, at temperatures of preferably -700C to 100°C, to form compounds having the general formula AMN.
In stage 8, compounds having the general formula AA are reacted with sulfonyl chlorides having the general formula X-Q-SO2CI, wherein X and Q have the meanings given above, in at least one organic solvent, preferably selected from the group consisting of dichloromethane, acetonitrile, dimethyl formamide, diethyl ether, dioxane, tetrahydrofuran, methanol, ethanol and toluene, in the presence of an excess of a base, preferably selected from the group consisting of caesium carbonate, calcium carbonate, potassium carbonate, triethylamine, diisopropylethylamine and pyridine, at temperatures of preferably -700C to 1000C, to form compounds having the general formula SAM.
Examples
Amine Building Blocks AA:
Common Intermediates and general procedures
Synthesis of N, N -Dimethyl-4-(thiophen-2-yl)piperidin-4-amine trifluoroacetate:
Figure imgf000030_0001
N,N-Dimethyl-4-(thiophen-2- yl)piperidin-4-amine
Trifluoroacetate
Step-1: Dimethylamine (10 eq.) was added to a solution of 1 ,4-Cyclohexanedione monoethylene acetal (12.8 mmol) in methanol (5 ml) and acetic acid (3 ml) at 0 0C. Then potassium cyanide (2.5 eq.) was added to the reaction mixture through solid addition funnel and stiired for another 16 h. The reaction mixture was slowly quenched with NH4OH solution (50 g ice + 50 ml liquor ammonia) and stirred at 0 0C for another half an hour. The reaction mixture was extracted with ethylacetate. Organic layer was washed with water, satd. FeSO4, brine successively and dried over anh. Sodium sulfate and concentrated under reduced pressure to give the pure desired product. Yield: 94%
Step-2: A solution of step-1 product (2 mmol) in THF (5 ml) was added to an ice-cold solution of thiophene-2-magnesium bromide (5 eq, freshly prepared from 2-bromothiophene, Mg and catalytic amount of I2 in 30 ml THF) and the reaction mixture was allowed to stir at RT for 16 h under nitrogen atmosphere. The reaction mixture was quenched with satd. Ammonia solution under ice-cold condition and extracted with ethylacetate. Organic layer was washed with water, brine successively and dried over anh. Sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (EtOH/Hexane) to give the desired step-2 product. Yield: 30% Step-3: To a solution of step-2 product (1.64 mmol) in DCM (5 ml) was added TFA (1 ml) at 0 0C and stirred for 2 h at RT. Then the reaction mixture was concentrated and the crude mass was azeotroped twice with dry toluene to give the TFA salt of the amine that was used as such for the coupling reactions.
Synthesis of N,N-Dimethyl-4-phenylpiperidin-4-amine trifluoroacetate
Figure imgf000031_0001
N,W-Dimethyl-4- phenylpiperidin-4-amine
Trifluoroacetate
Step-1: Dimethylamine (10 eq.) was added to a solution of 1 ,4-Cyclohexanedione monoethylene acetal (12.8 mmol) in methanol (5 ml) and acetic acid (3 ml) at 0 0C. Then potassium cyanide (2.5 eq.) was added to the reaction mixture through solid addition funnel and stiired for another 16 h. The reaction mixture was slowly quenched with NH4OH solution (50 g ice + 50 ml liquor ammonia) and stirred at 0 0C for another half an hour. The reaction mixture was extracted with ethylacetate. Organic layer was washed with water, satd. FeSO4, brine successively and dried over anh. Sodium sulfate and concentrated under reduced pressure to give the pure desired product. Yield: 94%
Step-2: A solution of step-1 product (2 mmol) in THF (5 ml) was added to an ice-cold solution of phenyl magnesium bromide (5 eq. 1M solution in THF) and the reaction mixture was allowed to stir at RT for 16 h under nitrogen atmosphere. The reaction mixture was quenched with satd. Ammonia solution under ice-cold condition and extracted with ethylacetate.
Organic layer was washed with water, brine successively and dried over anh. Sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (EtOH/Hexane) to give the desired step-2 product. Yield: 20%
Step-3: To a solution of step-2 product (1.64 mmol) in DCM (5 ml) was added TFA (1 ml) at 0 0C and stirred for 2 h at RT. Then the reaction mixture was concentrated and the crude mass was azeotroped twice with dry toluene to give the TFA salt of the amine that was used as such for the coupling reactions. Synthesis of i-ftert-Butoxycarbonytyindoline-S-carboxylic acid
Figure imgf000032_0001
Step-1: Methyl-3 indole carboxylate (17.1 mmmol) was placed in a 50 ml round bottom flask with NaH (1.5 eq.) and cooled to an ice-bath. THF (20 ml) was added with stirring. After 30 minutes Boc-anhydride (1.5 eq.) was added and stirred for overnight. The reaction mixture was quenched with satd. Ammonium chloride solution, diluted with ether and washed with water. The organic layer was dried with anh. sodium sulfate and concentrated. The crude mass was purified by column chromatography (EA/ hexane) to give the desired product. Yield: 98%
Step-2: The Step-1 product was hydrogenated (8 mmol) in parr-shaker with 5% Pd/C (1 g) using 60 psi hydrogen pressure in a mixture of ethyl acetate (30 ml) and methanol (10 ml) for 3 days. The reaction mixture was filtered and filtrate was concentrated. The crude mass was purified by column chromatography (EA/ hexane) to give the desired product. Yield: 98%
Step-3: To a suspension of Step-2 product (11.75 mmol) in methanol (40 ml), tetrahydrofuran (40ml) and water (30 ml) was added LiOH-H2O (5 eq) and the reaction mixture was allowed to stir at 25 0C for overnight. Methanol and THF were completely evaporated; aqueous layer was acidified with 1(N) HCI and filtered. The white solid was taken in a mixture of 350 ml acetone and 50 ml methanol and stirred for 1 h. After filtration the white solid was dried under vacuum to give desired acid intermediate. Yield: 84%
General procedure No. 1 - Amidation reaction:
To a dichloromethane solution (3 ml/mmol) of N-boc-amino acid (1 eq.) was added EDCI (1.5 eq.), HOBT (1 eq.), DIPEA (2.5 eq.) and the resulting reaction mixture was allowed to stir for 15 minutes at 250C. In another round bottom flask, TFA salt of N,N-dimethyl-4-(thiophen-2- yl)piperidin-4-amine trifluoroacetate (1.5 eq) in dichloromethane (1 ml/ mmol) was cooled in ice bath, treated with DIPEA (4 eq.) and it was added to the reaction mixture. The reaction mixture was allowed to stir at 250C for 16 hrs and diluted with dichloromethane. Organic layer was successively washed with aqueous ammonium chloride, sodium bicarbonate and brine and finally dried over sodium sulfate. Evaporation of organic layer under reduced pressure gave the crude product, which was purified by column chromatography on neutral alumina using MeOH/DCM as eluent.
General procedure No. 2 - Boc-deprotection: At 00C, 5-10 equiv of acetylchloride were added to a solution of the boc protected amine in methanol. Progress of the reaction was followed via TLC. The solvent was removed under reduced pressure, after complete conversion. The desired product was obtained as hydrochloride and utilized in the subsequent reactions without further purification.
1) Amine structural units AA:
Structural unit AA-1 : Λ/./V-Dimethvl-1-(2-(methvlamino)ethyl)-4-phenvlpiperidin-4-amine tris hydrochloride
Stage 1: 1-Benzyl-Λ/,Λ/-dimethyl-4-phenylpiperidin-4-amine
A little iodine was added to a mixture of 34.5 g (3.5 eq) magnesium and 100 ml dry diethyl ether, followed over a period of 10 min by 10 g (0.15 eq) bromobenzene, and the mixture was stirred for a further 10 min. Once the reaction had started, 183 g (2.85 eq) bromo- benzene dissolved in 500 ml diethyl ether were added dropwise over a period of 2 h and the mixture was stirred for a further 15 min. 100 g (1 eq) 1-benzyl-4-(dimethylamino)piperidine-4- carbonithle dissolved in 900 ml diethyl ether were added over a period of 2 h to the Grignard reagent prepared in the preceding step and the mixture was then heated for 12 h at 800C. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCI3). Once the conversion was complete, the reaction solution was cooled to 0°C, mixed with saturated NH4CI solution, extracted with ethyl acetate (3 x 300 ml) and the combined organic phases were dried with Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 1% MeOH/CHCI3). 30 g (35%) of product were obtained in the form of a yellow solid.
Stage 2: Benzyloxycarbonyl-4-(dimethylamino)-4-phenylpiperidine
500 ml (10 eq) Cbz chloride were added dropwise to 50 g (1 eq) 1-benzyl-Λ/,Λ/-dimethyl-4- phenylpiperidin-4-amine over a period of 1 h and the reaction mixture obtained was stirred for 2 h at room temperature. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCI3). Once the conversion was complete, the reaction mixture was cooled to 00C, made alkaline with saturated sodium hydrogen carbonate solution and extracted 3 times with 300 ml EtOAc. The combined organic phases were dried with Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 50% EtOAc/heptane). 12 g (21%) of product were obtained in the form of an oil.
Stage 3: fert-Butyloxycarbonyl-4-(dimethylamino)-4-phenylpiperidine
12.2 g KOH were added to a solution of 12 g (1 eq) benzyloxycarbonyl-4-(dimethylamino)-4- phenylpiperidine in 120 ml ethanol and the reaction mixture was refluxed for 48 h. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCI3).
Once the conversion was complete, the solvent was distilled off completely, the residue suspended in ethyl acetate, filtered, and the organic phase dried over sodium sulfate. Following removal of the solvent under reduced pressure, the crude product was dissolved in dioxane, mixed with saturated sodium hydrogen carbonate solution and 11.9 g (1.5 eq) of Boc anhydride and stirred for 30 min at room temperature. Once the conversion was complete, the reaction mixture was extracted with 3 x 200 ml ethyl acetate and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, 8.5 g (77%) of crude product were obtained in the form of a colourless solid.
Stage 4: Λ/,Λ/-Dimethyl-4-phenylpiperidin-4-amine bishydrochloride
10 equivalents of acetyl chloride were added to a solution of tert-butyloxycarbonyl-4- (dimethylamino)-4-phenylpiperidine in methanol at O0C. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCI3). Once the conversion was complete, the solvent was removed under reduced pressure and the product obtained in the form of a solid.
Stage 5: ferf-Butyl 2-(4-(dimethylamino)-4-phenylpiperidin-1-yl)ethyl(methyl)carbamate
7 g (1 eq) Λ/,Λ/-dimethyl-4-phenylpiperidin-4-amine were added in portions to a solution of 6.5 g (1.5 eq) terf-butyl methyl(2-oxoethyl)carbamate in 60 ml methanol. This reaction mixture was cooled to 00C, 3.97 g (2.5 eq) sodium cyanoboron hydride were added in portions and then the mixture was stirred for 10 min at room temperature. The reaction mixture obtained was adjusted to a pH of ~ 5 with acetic acid and stirred for 12 h at room temperature. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCI3). As the conversion was still not complete, 1.5 g sodium cyanoboron hydride and acetic acid were added and the reaction mixture was stirred for a further 30 to 45 min. Once the conversion was complete, the methanol was distilled off, 100 ml saturated NaHCO3 solution were added and the mixture obtained was extracted with chloroform (2 x 200 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 5% MeOH/CHCI3). 8 g (64%) of product were obtained in the form of an oil.
Stage 6: Λ/,Λ/-Dimethyl-1-(2-(methylamino)ethyl)-4-phenylpiperidin-4-amine tris hydrochloride
HCI gas was passed through a solution of 9 g (1 eq) terf-butyl 2-(4-(dimethylamino)-4- phenylpiperidin-1-yl)ethyl(methyl)carbamate in 600 ml CH3CI for 30 min. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCI3). Once the conversion was complete, the passage of HCI gas was continued for a further 30 min and the completeness of the conversion again monitored by thin-layer chromatography (20% MeOH/CHCI3). Once the conversion was complete, the solvent was removed under reduced pressure and 7.2 g (96%) of the desired product obtained in the form of a white solid.
Structural unit AA -2: Λ/-methvl-2-(4-phenvl-4-(pvrrolidin-1-vl)piperidin-1-vl)ethanamine tris hydrochloride
Stage 1 : 1-Benzyl-4-(pyrrolidin-1-yl)piperidine-4-carbonitrile
100 g (5 eq) pyrrolidine were added to a solution of 50 g (1 eq) 1-benzylpiperidin-4-one in 250 ml ethanol and the mixture was stirred for 10 min at room temperature. 25 ml (0.5 eq) hydrochloric acid were then added dropwise to the reaction mixture over a period of 10 min and the mixture was stirred for 30 min at room temperature. 55 g (3 eq) potassium cyanide dissolved in 250 ml water were added to this reaction mixture and it was stirred for three days at room temperature. The reaction course was monitored by thin-layer chromatography (50% EtOAc/heptane). Once the conversion was complete, the solid that had formed was filtered off and washed with iced water (3 x 150 ml). The solid obtained was then suspended in ethyl acetate and dried with Na2SO4. Following removal of the solvent under reduced pressure, 70 g of crude product were obtained in the form of a solid.
Stage 2: 1-Benzyl-4-phenyl-4-(pyrrolidin-1-yl)piperidine
A little iodine was added to a mixture of 31.2 g (5 eq) magnesium and 100 ml dry THF, followed over a period of 10 min by 10 g (0.25 eq) bromobenzene, and the mixture was stirred for a further 10 min. Once the reaction had started, 194.2 g (4.75 eq) bromobenzene dissolved in 500 ml THF were added dropwise over a period of 2 h and the mixture was stirred for a further 15 min. 70 g (1 eq) 1-benzyl-4-(pyrrolidin-1-yl)piperidine-4-carbonitrile dissolved in 450 ml THF were added over a period of 2 h to the Grignard reagent prepared in the preceding step and the mixture was then heated for 12 h at 800C. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCI3). Once the conversion was complete, the reaction solution was cooled to 00C1 mixed with saturated NH4CI solution, extracted with ethyl acetate (3 x 200 ml) and the combined organic phases were dried with Na2SO4. Following removal of the solvent under reduced pressure, 33 g (40%) of crude product were obtained in the form of an oil.
Stage 3: Benzyloxycarbonyl-4-phenyl-4-(pyrrolidin-1-yl)piperidine
60 g (3.5 eq) Cbz chloride were added dropwise to a solution of 33 g (1 eq) 1-benzyl-4- phenyl-4-(pyrrolidin-1-yl)piperidine in 330 ml chloroform over a period of 10 min and the reaction mixture obtained was stirred for 30 min at room temperature. The reaction course was monitored by thin-layer chromatography (ethyl acetate). Once the conversion was complete, the solvent was distilled off completely and the residue adjusted to a pH of ~ 6 with 10% HCI solution and washed 3 times with 100 ml EtOAc. In an ice bath the aqueous solution was adjusted to a pH of ~ 9 with NaOH solution and then extracted 3 times with 100 ml chloroform. The combined organic phases were dried with Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 20% EtOAc/heptane). 11 g (29%) of product were obtained in the form of a yellow solid.
Stage 4: 4-Phenyl-4-(pyrrolidin-1-yl)piperidine
11 g KOH were added to a solution of 7.3 g (1 eq) benzyloxycarbonyl-4-phenyl-4-(pyrrolidin- 1-yl)piperidine in 100 ml ethanol and the reaction mixture was refluxed for 24 h. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCI3). Once the conversion was complete, the solvent was distilled off completely and the residue mixed with 100 ml water and extracted 3 times with 100 ml CHCI3. The combined organic phases were dried with Na2SO4. Following removal of the solvent under reduced pressure, 7 g of crude product were obtained in the form of an oil.
Stage 5: 4-Phenyl-4-(pyrrolidin-1-yl)piperidine bishydrochloride HCI gas was passed through a solution of 9 g (1 eq) 4-phenyl-4-(pyrrolidin-1-yl)piperidine in 180 ml chloroform for ~ 30 min until the reaction mixture reached a pH of ~ 2. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCI3). Once the conversion was complete, the solvent was removed under reduced pressure and the residue washed with ethyl acetate (3 x 100 ml) and dried. 9 g (76%) of product were obtained in the form of a solid.
Stage 6: tert-Butyl methyl(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1-yl)ethyl)carbamate
7 g (1 eq) 4-phenyl-4-(pyrrolidin-1-yl)piperidine bishydrochloride were added to a solution of 4.4 g (1.1 eq) terf-butyl-methyl(2-oxoethyl)carbamate in 70 ml methanol under a nitrogen atmosphere and the reaction mixture was stirred for 10 min at 00C. 3.62 g (2.5 eq) sodium cyanoboron hydride were then added and the mixture was stirred for 30 min at room temperature. The reaction mixture obtained was adjusted to a pH of 5-6 with acetic acid and stirred for 14 h at room temperature. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCI3). Once the conversion was complete, the methanol was distilled off, saturated NaHCO3 solution was added and the mixture obtained was extracted with chloroform (3 x 50 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 50% EtOAc/heptane). 8 g (89%) of product were obtained in the form of a red oil.
Stage 7: tert-Butyl methyl(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1-yl)ethyl)carbamate tris hydrochloride
HCI gas was passed through a solution of 8 g (1 eq) te/f-butyl methyl(2-(4-phenyl-4- (pyrrolidin-1-yl)piperidin-1-yl)ethyl)carbamate in 160 ml chloroform at 00C for ~ 30 min until the reaction mixture reached a pH of ~ 2. The reaction mixture was then stirred at room temperature for 4 hours. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCI3). Once the conversion was complete, the solvent was removed under reduced pressure and 8 g (97%) of product were obtained in the form of a white solid.
Structural unit AA-3: 1-(2-Aminoethvn-Λ/.Λ/-dimethvl-4-(thiophen-2-vQpiperidin-4-amine tris hydrochloride
Stage 1 : tert-Butyloxycarbonyl-4-cyano-4-(dimethylamino)piperidine 500 ml (10 eq) dimethylamine solution and 109.9 g (5 eq) dimethylamine hydrochloride were added to a solution of 50 g (1 eq) teΛt-butyloxycarbonyl-4-oxopiperidine in 100 ml methanol and the mixture was cooled to 5°C. 5 ml (0.1 eq) hydrochloric acid were then added dropwise to the reaction mixture over a period of 10 min and the mixture was stirred for 60 min at room temperature. 48.9 g (3 eq) potassium cyanide were added in portions to this reaction mixture and the mixture was stirred for 24 h at room temperature. The reaction course was monitored by thin-layer chromatography (50% EtOAc/hexane). Once the conversion was complete, 150 ml water were added to the reaction mixture and it was extracted 3 times with 100 ml ethyl acetate. The combined organic phases were dried with Na2SO4. Following removal of the solvent under reduced pressure, crude product was obtained which was recrystallised out of hexane. 57 g (90%) of product were obtained in the form of a colourless solid.
Stage 2: tert-Butyloxycarbonyl-4-(dimethylamino)-4-(thiophen-2-yl)piperidine
A little iodine was added to a mixture of 5.6 g (3 eq) magnesium and 20 ml dry diethyl ether, followed over a period of 10 min by 5 g 2-bromothiophene, and the mixture was stirred for a further 10 min. Once the reaction had started, 33.5 g (2.6 eq) 2-bromothiophene dissolved in 80 ml diethyl ether were added dropwise and the mixture was stirred for a period of 2 h at room temperature. The Grignard reagent prepared in the preceding step was added dropwise to a solution of 20 g (1 eq) tert-butyloxycarbonyl-4-cyano-4-(dimethylamino)- piperidine dissolved in 200 ml THF and stirred overnight at room temperature. The reaction course was monitored by thin-layer chromatography (50% EtOAc/hexane). Once the conversion was complete, the reaction solution was cooled to 00C, mixed with saturated NH4CI solution, extracted with ethyl acetate (3 x 100 ml) and the combined organic phases were dried with Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (Alox neutral; 30% EtOAc/hexane). 6.1 g (25%) of product were obtained in the form of a white solid.
Stage 3: Λ/,Λ/-Dimethyl-4-(thiophen-2-yl)piperidin-4-amine
HCI gas was passed through a solution of 10 g (1 eq) terf-butyloxycarbonyl-4-(dimethyl- amino)-4-(thiophen-2-yl)piperidine in chloroform at O0C for ~ 1 h. The reaction course was monitored by thin-layer chromatography (75% EtOAc/hexane). Once the conversion was complete, 200 ml water were added to the reaction mixture, it was adjusted to a pH of ~ 8 with Na2CO3 and then extracted with 15% IPA/CHCI3. The combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, 6 g (89%) of product were obtained in the form of a white solid. Stage 4: tert-Butyl 2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)ethylcarbamate
11.1 g (1.5 eq) tert-butyl-2-bromoethylcarbamate dissolved in 65 ml THF and 9.19 g (2 eq) potassium carbonate were added to a solution of 7 g (1 eq) Λ/,Λ/-dimethyl-4-(thiophen-2- yl)piperidin-4-amine in 40 ml THF. The reaction mixture was heated for 6 h at 700C. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCI3). Once the conversion was complete, the solvent was distilled off completely, the residue mixed with 200 ml water and the aqueous phase extracted with 20% IPA/CHCI3. The combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 10% MeOH/CHCI3). 9 g (76%) of product were obtained in the form of an oil.
Stage 5: 1-(2-Aminoethyl)-A/,Λ/-dimethyl-4-(thiophen-2-yl)piperidin-4-amine tris hydrochloride
HCI gas was passed through a solution of 9 g (1 eq) terf-butyl 2-(4-(dimethylamino)-4- (thiophen-2-yl)pipehdin-1-yl)ethylcarbamate in chloroform at O0C for ~ 30 min. The reaction mixture was then stirred at room temperature for one hour. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCI3). Once the conversion was complete, the solvent was removed under reduced pressure and 9 g (97%) of product were obtained in the form of a white solid.
Structural unit A A -4: 4-Butyl-Λ/.Λ/-dimethvl-1-(2-(methvlamino)ethyl)piperidin-4-amine tris hydrochloride
Stage 1 : 1-Benzyl-4-(dimethylamino)piperidine-4-carbonitrile
208 g (3 eq) Λ/,Λ/-dimethylamine hydrochloride, 154 g (3 eq) potassium cyanide in 154 ml water and 1050 ml (7 eq) of a 40% dimethylamine solution were added to a solution of 150 g (1 eq) 1-benzylpiperidin-4-one in 300 ml methanol and the mixture was cooled to O0C. 75 ml (0.5 eq) concentrated hydrochloric acid were then added at 0°C and the reaction mixture was stirred for 24 h at room temperature. The reaction course was monitored by thin-layer chromatography (20% EtOAc/hexane). Once the conversion was complete, the solid that had formed was filtered off and washed with iced water (4 I). The solid obtained was then dissolved in ethyl acetate and dried with Na2SO4. Following removal of the solvent under reduced pressure, 165 g (85%) of crude product were obtained in the form of a solid. 3
Stage 2: 1-Benzyl-4-butyl-Λ/,Λ/-dimethylpiperidin-4-amine
A little iodine was added to a mixture of 17.7 g (6 eq) magnesium and 50 ml dry ether, followed over a period of 1 h by 100 g (6 eq) bromobutane dissolved in 100 ml dry ether. This reaction mixture was stirred for 1 h at room temperature. The Grignard reagent produced in the preceding step was added over a period of 20 min to a solution of 30 g (1 eq) 1-benzyl-4- (dimethylamino)piperidine-4-carbonitrile dissolved in 210 ml dry THF and the reaction mixture obtained was then stirred for 12 h at room temperature. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCI3). Once the conversion was complete, the reaction solution was cooled to 00C, mixed with saturated NH4CI solution, filtered over celite, extracted with ethyl acetate (3 x 200 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (aluminium oxide neutral; hexane). 18.2 g (53%) of product were obtained in the form of an oil.
Stage 3: 4-Butyl-Λ/,Λ/-dimethylpiperidin-4-amine bis hydrochloride
1.5 g 20% Pd(OH)2/C and 6.95 g (3 eq) ammonium formate were added to a solution of 10 g (1 eq) 1-benzyl-4-butyl-Λ/,Λ/-dimethylpiperidin-4-amine in 100 ml MeOH. The reaction mixture obtained was refluxed for 30 min. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCI3). Once the conversion was complete, the reaction solution was cooled to room temperature, filtered over celite and rewashed with methanol. The methanol is distilled off, the residue taken up in ethyl acetate/hexane, the solvent decanted off and toluene added. The organic phase thus obtained was concentrated under reduced pressure and the residue taken up in 150 ml dichloromethane. HCI gas was passed through the dichloromethane solution for 20 min, the solvent was distilled off and 7 g (74%) of product were obtained in this way as a white solid.
Stage 4: ferf-Butyl 2-(4-butyl-4-(dimethylamino)piperidin-1-yl)ethyl(methyl)carbamate
A solution of 4.73 g (1 eq) tert-butyl methyl(2-oxoethyl)carbamate in 20 ml methanol was added to a solution of 7 g (1 eq) 4-butyl-Λ/,Λ/-dimethylpiperidin-4-amine bis hydrochloride in 50 ml methanol at room temperature and the reaction mixture obtained was stirred for 50 min at room temperature. 3.43 g (2 eq) sodium cyanoboron hydride were added in portions to this reaction mixture and it was then stirred for 12 h at room temperature. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCI3). Once the conversion was complete, the reaction mixture was cooled to 00C and adjusted to a pH of ~ 5 with acetic acid. 2 g tert-butyl formylmethyl methylcarbamate and 1.7 g sodium cyanoboron hydride were again added and the reaction mixture was stirred for a further 60 min at room temperature. The methanol was then distilled off, 100 ml saturated NaHCO3 solution were added and the mixture obtained was extracted with ethyl acetate (2 x 200 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, 10.5 g of crude product were obtained in the form of a pale yellow oil.
Stage 5: 4-Butyl-Λ/,Λ/-dimethyl-1-(2-(methylamino)ethyl)piperidin-4-amine tris hydrochloride
HCI gas was passed through a solution of 10.5 g (1 eq) tert-butyl 2-(4-butyl-4-(dimethyl- amino)piperidin-1-yl)ethyl(methyl)carbamate in 1000 ml chloroform at 00C for ~ 1 h. The reaction mixture was then stirred for 12 hours at room temperature. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCI3). Once the conversion was complete, the solvent was removed under reduced pressure and the residue washed with hexane (3 x 50 ml) and ethyl acetate (3 x 50 ml) and dried. 9 g (87%) of product were obtained in the form of a white solid.
Structural unit AA -5: Λ/,W-Dimethyl-1-(3-(methylamino)propyl)-4-phenylpiperidin-4- amine tris hydrochloride
Stage 1 : tert-Butyl 3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)propyl(methyl)- carbamate 11.1 g (1.3 eq) terf-butyl methyl(3-oxopropyl)carbamate were added to a solution of 11 g (1 eq) Λ/,Λ/-dimethyl-4-phenylpiperidin-4-amine dihydrochloride in 110 ml methanol at 0°C and the reaction mixture was stirred for 15 min at 00C. 6.2 g (3 eq) sodium cyanoboron hydride were then added in portions and the mixture was stirred for 30 min at room temperature. The reaction mixture obtained was adjusted to a pH of 5-6 with acetic acid and stirred for 12 h at room temperature. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCI3). As the conversion was still not complete, 2.4 g sodium cyanoboron hydride were added and the reaction mixture obtained was adjusted to pH 5-6 with acetic acid and stirred for 60 min at room temperature. Once the conversion was complete, the methanol was distilled off, the mixture was made alkaline with saturated NaHCO3 solution, the mixture obtained was extracted with chloroform (3 x 100 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 5% MeOH/CHCI3). 9 g (60%) of product were obtained.
Stage 2: Λ/,Λ/-Dimethyl-1-(3-(methylamino)propyl)-4-phenylpiperidin-4-amine hydrochloride
HCI gas was passed through a solution of 9 g (1 eq) terf-butyl 3-(4-(dimethylamino)-4- phenylpiperidin-1-yl)propyl(methyl)carbamate in 100 ml chloroform at 00C for 1 h. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCI3). Once the conversion was complete, the solvent was removed under reduced pressure and after trituration with diethyl ether 10 g (100%) of product were obtained in the form of a white solid.
Structural unit AA -6: W,W-Dimethyl-1 -(3-(methylamino)propyl)-4-(thiophen-2- yl)piperidin-4-amine tris hydrochloride
Stage 1 : tert-Butyl 3-hydroxypropyl(methyl)carbamate
84.2 g (1.2 eq) sodium carbonate followed by 100 ml water were added in portions to a solution of 50 g (1 eq) 3-aminopropan-1-ol in 500 ml THF at 00C. 156.5 ml (1.02 eq) di- tert-butyl dicarbonate were added dropwise over a period of 30 min to the solution at 0°C. On completion of the addition, the mixture was stirred for 30 min at room temperature. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCI3). Once the conversion was complete, the reaction mixture was filtered over celite and the filtrate concentrated under reduced pressure. The residue was mixed with 300 ml water and extracted with 2 x 250 ml ethyl acetate. The combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, 116 g (100%) of product were obtained in the form of an oil.
Stage 2: tert-Butyl-3-(tert-butyldimethylsilyloxy)propylcarbamate
11.6 g (1.3 eq) imidazole were added to a solution of 23 g (1 eq) tert-butyl 3-hydroxypropyl- carbamate in 230 ml dichloromethane. The reaction solution was stirred for 10 min at room temperature and then cooled to 00C. 21.79 g (1.1 eq) TBDMSCI were added to this solution at 00C and on completion of the addition the mixture was stirred for 1 h at room temperature.
The reaction course was monitored by thin-layer chromatography (30% EtOAc/hexane).
Once the conversion was complete, the reaction mixture was filtered over celite and the filtrate mixed with 200 ml water and extracted with dichloromethane. The combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure,
32 g (84%) of product were obtained in the form of an oil. Stage 3: tert-Butyl 3-(tert-butyldimethylsilyloxy)propyl(methyl)carbamate
50 g (1 eq) te/f-butyl 3-(tert-butyldimethylsilyloxy)propylcarbamate dissolved in 200 ml THF were added dropwise to a mixture of 20.7 g (5 eq) sodium hydride and 300 ml THF at 00C. After heating the reaction mixture to 100C1 32.3 ml (3 eq) methyl iodide were added dropwise. On completion of the addition, the mixture was stirred for 3 h at room temperature. The reaction course was monitored by thin-layer chromatography (30% EtOAc/hexane). Once the conversion was complete, the reaction mixture was quenched with saturated NH4CI solution and then extracted with ethyl acetate. The combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, 48 g (92%) of product were obtained in the form of an oil.
Stage 4: ferf-Butyl 3-hydroxypropyl(methyl)carbamate
482.5 ml (5 eq) acetic acid dissolved in 386 ml water were added dropwise over a period of 45 min to a solution of 95.6 g (1 eq) terf-butyl 3-(tert-butyldimethylsilyloxy)propyl(methyl)- carbamate dissolved in 386 ml THF at 00C and the reaction mixture was then stirred for 20 h at room temperature. As the starting product had not yet been completely converted, the mixture was cooled to O0C, 50 ml dilute acetic acid were added over a period of 20 min and the mixture was stirred for a further 1 h at 00C The reaction course was monitored by thin- layer chromatography (10% EtOAc/ hexane). Once the conversion was almost complete, the reaction mixture was concentrated under reduced pressure, adjusted to a pH of ~ 9 with Na2CO3 solution and extracted with 10% IPA/CH3CI. The combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 10% EtOAc/hexane). 40 g (66%) of product were obtained in the form of a colourless oil.
Stage 5: tert-Butyl methyl(3-oxopropyl)carbamate
A catalytic amount of TEMPO was added to a mixture of 20 g (1 eq) terf-butyl 3-hydroxy- propyl(methyl)carbamate in 200 ml dichloromethane and 17.7 g (2 eq) sodium hydrogen carbonate in 100 ml water at 0°C. 140 ml (7 eq) NaOCI were then added dropwise over a period of 30 min to the solution at a temperature of 0°C and the reaction mixture obtained was stirred for a further 15 min at 00C. The reaction course was monitored by thin-layer chromatography (40% EtOAc/hexane).
Once the conversion was complete, the reaction mixture was mixed with 150 ml water and the phases were separated. The organic phase was dried over Na2SO4. Following removal of the solvent under reduced pressure, 16 g (85%) of product were obtained in the form of a yellowish oil. Stage 6: A/,Λ/-Dimethyl-4-(thiophen-2-yl)piperidin-4-amine bis hydrochloride
HCI gas was passed through a solution of 6 g (1 eq) tert-butyloxycarbonyl-4-(dimethylamino)- 4-(thiophen-2-yl)piperidine in 120 ml chloroform at 00C for 1 h. The reaction course was monitored by thin-layer chromatography (75% EtOAc/hexane). Once the conversion was complete, the solvent was removed under reduced pressure and 5.3 g (98%) of product were obtained in the form of a white solid.
Stage 7: tert-Butyl 3-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1- yl)propyl(methyl)carbamate 6.4 g (1.3 eq) tert-butyl methyl(3-oxopropyl)carbamate were added to a solution of 7.5 g (1 eq) Λ/,Λ/-dimethyl-4-(thiophen-2-yl)piperidin-4-amine bis hydrochloride in 75 ml methanol at O0C and the reaction mixture was stirred for 15 min at 00C. 4.9 g (3 eq) sodium cyanoboron hydride were then added in portions and the mixture was stirred for 90 min at room temperature. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCI3). As the conversion was not yet complete, the pH of the reaction mixture was adjusted to 5-6 with acetic acid and the mixture was stirred for 12 h at room temperature. Once the conversion was complete, the methanol was distilled off, water was added, the mixture obtained was extracted with IPA/chloroform (2 x 100 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 5% MeOH/CHCI3). 8.5 g (84%) of product were obtained.
Stage 8: W,Λ/-Dimethyl-1-(3-(methylamino)propyl)-4-(thiophen-2-yl)piperidin-4-amine tris hydrochloride HCI gas was passed through a solution of 1.5 g (1 eq) tert-butyl 3-(4-(dimethylamino)-4- (thiophen-2-yl)piperidin-1-yl)propyl(methyl)carbamate in 30 ml chloroform at 00C for ~ 30 min. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCI3). Once the conversion was complete, the solvent was removed under reduced pressure. After trituration with diethyl ether, 1.5 g (98%) of product were obtained in the form of a white solid.
Amine Building Block AA-7: 3-Amino-1-(4-(dimethvlamino)-4-phenylpiperidin-1- yl)propan-1-one dihydrochloride
(i) 3-(terf-Butoxycarbonylamino)propanoic acid was converted with N,N-dimethyl-4- phenylpiperidin-4-amine trifluoroacetate according to general procedure no. 1 to yield the desired product (49%).
(ii) The product obtained above was reacted according to general procedure no. 2, to yield the desired product (6.07 g, 102 %). Amine Building Block AA-8: 2-Amino-1 -(4-(dimethylamino)-4-(thiophen-2-yl)piperidin- 1-yl)ethanone
(i) 2-(te/f-Butoxycarbonylamino)acetic acid was converted with N,N-dimethyl-4-(thiophen-2- yl)piperidin-4-amine trifluoroacetate according to general procedure no. 1 to yield the desired product (53%).
(ii) The product obtained above was reacted according to general procedure no. 2, to yield the desired product (4.82 g, 85 %).
Amine Building Block AA -9: 3-Amino-1-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin- 1-yl)-3-phenylpropan-1-one trihydrochloride
(i) 3-(tert-Butoxycarbonylamino)-3-phenylpropanoic acid was converted with N,N-dimethyl-4- (thiophen-2-yl)piperidin-4-amine trifluoroacetate according to general procedure no. 1 to yield the desired product (40%). (ii) The product obtained above was reacted according to general procedure no. 2, to yield the desired product (5.84 g, 91 %).
Amine Building Block AA-10: 1-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)-3-methyl-2- (methylamino)butan-i-one trihydrochloride (i) 2-(te/?-Butoxycarbonyl(methyl)amino)-3-methylbutanoic acid was converted with N1N- dimethyl-4-phehylpiperidin-4-amine trifluoroacetate according to general procedure no. 1 to yield the desired product (51%).
(ii) The product obtained above was reacted according to general procedure no. 2, to yield the desired product (8.92 g, 102 %).
Amine Building Block AA-11 : 1-(4-(Dimethvlamino)-4-(thiophen-2-vl)piperidin-1-yl)-2-
(methylamino)-2-phenylethanone trihydrochloride
(i) 2-(te/?-Butoxycarbonyl(methyl)amino)-2-phenylacetic acid was converted with N1N- dimethyl-4-(thiophen-2-yl)piperidin-4-amine trifluoroacetate according to general procedure no. 1 to yield the desired product (40%).
(ii) The product obtained above was reacted according to general procedure no. 2, to yield the desired product (6.92 g, 104 %).
Amine Building Block AA-12: 4-(Dimethvlamino)-4-phenvlpiperidin-1-vl)(piperidin-3- yl)methanone trihydrochloride (i) 1-(fert-Butoxycarbonyl)piperidine-3-carboxylic acid was converted with N,N-dimethyl-4- phenylpiperidin-4-amine trifluoroacetate according to general procedure no. 1 to yield the desired product (65%).
(ii) The product obtained above was reacted according to general procedure no. 2, to yield the desired product (7.17 g, 97 %).
Amine Building Block AA-13: (4-(Dimethylamino)-4-phenylpiperidin-1-yl)(indolin-3- yl)methanone trihydrochloride
(i) 1-(tert-Butoxycarbonyl)indoline-3-carboxylic acid was converted with N,N-dimethyl-4- phenylpiperidin-4-amine trifluoroacetate according to general procedure no. 1 to yield the desired product (51%).
(ii) The product obtained above was reacted according to general procedure no. 2, to yield the desired product (4.82 g, 90 %).
Amine
Structure Building Amine Building Block Name Block No
N,N-Dimethyl-1-(2-(methylamino)ethyl)-4- phenylpiperidin-4-amine trihydrochloride
N-Methyl-2-(4-phenyl-4-(pyrrolidin-1 -yl)piperidin-1 - yl)ethanamine trihydrochloride
1-(2-Aminoethyl)-N,N-dimethyl-4-(thiophen-2- yl)piperidin-4-amine trihydrochloride
4-Butyl-N,N-dimethyl-1 -(2-
(methylamino)ethyl)piperidin-4-amine trihydrochloride
Figure imgf000046_0001
H— α H— a N,N-Dimethyl-1 -(3-(methylamino)propyl)-4- phenylpiperidin-4-amine trihydrochloride
N,N-Dimethyl-1-(3-(methylamino)propyl)-4- (thiophen-2-yl)piperidin-4-amine
3-Amino-1 -(4-(dimethylamino)-4-phenylpiperidin-1 - yl)propan-1-one dihydrochloride
2-Amino-1-(4-(dimethylamiπo)-4-(thiophen-2- yl)piperidin-1 -yl)ethanone
Figure imgf000047_0001
H-Cl 3-Amino-1-(4-(dimethylamino)-4-(thiophen-2- H-Cl AA-9 yl)piperidin-1 -yl)-3-phenylpropan-1 -one H-Cl trihydrochloride
Figure imgf000047_0002
Q α 1 -(4-(Dimethylamino)-4-phenylpiperidin-1 -yl)-3-
AA-10 methyl-2-(methylamino)butan-1-one α trihydrochloride
Figure imgf000047_0003
1-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-
H— α AA-11 yl)-2-(methylamino)-2-phenylethanone trihydrochloride
Figure imgf000047_0004
(4-(Dimethylamino)-4-phenylpiperidin-1- yl)(piperidin-3-yl)methanone trihydrochloride
Figure imgf000047_0005
(4-(Dimethylamino)-4-phenylpiperidin-1-yl)(indolin-
AA-13 3-yl)methanone trihydrochloride
Figure imgf000048_0001
2 Indole structural units ACI
All indole building blocks (ACI) were commercially available at the time of synthesis.
Indole Building Block
Structure Indole Building Block Name ACI No.
ACI-1 IH-lndole-3-carboxylic acid
ACI-2 3-(1-Methyl-1 H-indol-3-yl)propanoic acid
ACI-3 3-(1 H-lndol-3-yl)butanoic acid
ACI-4 3-(1 H-lndol-3-yl)-4-methylpentanoic acid
ACI-5 3-(1H-lndol-3-yl)propanoic acid
Figure imgf000048_0002
ACI-6 2-(5-Bromo-1 H-indol-3-yl)acetic acid
Figure imgf000049_0001
H-carbazole-
Figure imgf000049_0002
ACI-8 2-(6-Fluoro-1H-indol-3-yl)acetic acid
ACI-9 1 -Methyl-1 H-indole-6-carboxylic acid
ACI-10 1 -Methyl-1 H-indole-4-carboxylic acid
ACI-11 5-Fluoro-1 H-indole-2-carboxylic acid
ACI-12 5-Methoxy-1 H-indole-2-carboxylic acid
ACI-13 I H-lndole-6-carboxylic acid
Figure imgf000049_0003
H-indole-2-carboxylic
Figure imgf000050_0001
3) Indole structural units ALD
All indole building blocks (ALD) were commercially available at the time of synthesis.
Indole Building Block
Structure Indole Building Block Name ALD No.
ALD-1 5-Bromo-1 H-indole-3-carbaldehyde
Figure imgf000050_0002
1 H-lndole-3-carbaldehyde
6-Methoxy-1 ,2-dimethyl-1 H-indole-3- carbaldehyde
1 -Benzyl-5-methoxy-2-methyl-1 H-indole- 3-carbaldehyde
1 ,2-Dimethyl-1 H-indole-3-carbaldehyde
Figure imgf000050_0003
ALD-6 1 H-lndole-5-carbaldehyde
2-(4-Fluorophenyl)-1 H-indole-3-
ALD-7 carbaldehyde
ALD-8 5-Methoxy-1 H-indole-3-carbaldehyde
ALD-9 2-Phenyl-1 H-indole-3-carbaldehyde
ALD-10 5-Chloro-1 H-indole-3-carbaldehyde
ALD-11 6-lsopropyl-1 H-indole-3-carbaldehyde
ALD-12 2-Methyl-1 H-indole-3-carbaldehyde
ALD-13 1 H-lndole-6-carbaldehyde
Figure imgf000051_0001
ALD-14 1 H-lndole-7-carbaldehyde
ALD-15 1 H-lndole-4-carbaldehyde
Figure imgf000052_0001
Solid substances
Example 1 : N-(2-(4-(Dimethylamino)-4-phenvlpiperidin-1 -vl)ethvl)-N-methvl-1H-indol-6- amide
A solution of I H-indole-6-carboxylic acid (1 eq/0.637 mmol/102 mg), 1-hydroxybenzotriazole hydrate (1 eq/0.637 mmol/84 mg) and N-ethyl diisopropylamine (5 eq/3.185 mmol/0.54 ml) in 5 ml tetrahydrofuran was cooled to 0°C, mixed with 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (1.5 eq/0.956 mmol/181 mg) and stirred for 15 min at 00C. Λ/,Λ/-Dimethyl-1-(2-(methylamino)ethyl)-4-phenylpiperidin-4-amine (1.5 eq/0.956 mmol/250 mg) was added to this reaction mixture and it was heated to room temperature and stirred for 12 h.
The reaction course was monitored by thin-layer chromatography (75% EtOAc/hexane).
Once the conversion was complete, the reaction mixture was washed 3 times with saturated sodium hydrogen carbonate solution and the organic phase was dried over magnesium sulfate. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (alumina neutral; 1% MeOH/CH2CI2). 198 mg (76%) of product were obtained in the form of a yellow oil.
HPLC/MS analysis1: R, = 1.8 min; purity (UV 200-400 nm) 99%; m/z = 405.3 [MH]+, 360.3 [M-
[1J Equipment and methods for HPLC-MS analysis: HPLC: Waters Alliance 2795 with PDA Waters 996; MS. ZQ 2000 MassLynx Single Quadrupol MS Detector; Column: Waters Atlantis™ dC18, 3 μm, 2.1 x 30 mm; Column temperature: 400C, Eluent A: purified water + 0.1% formic acid; Eluent B: acetonitrile (gradient grade) + 0.1% formic acid; Gradient: Wo B to 100% B in 8.8 min, 100% B for 0.4 min, 100% B to 0% B in 0.01 min, 0% B for 0.8 min; Flow: 1.0 ml/min; Ionization: ES+, 25 V; Make-up. 100 μl/min 70% methanol + 0.2% formic acid; UV: 200 - 400 nm. N(CHs)2]*
Example 2: N-(2-(4-(Dimethylamino)-4-(thiophen-2-vl)piperidin-1-vl)ethyl)-3-(1H-indol-3- yl)-4-methylpentanamide A solution of 3-(1H-indol-3-yl)-4-methylpentanoic acid (1 eq/0.459 mmol/106 mg),
1-hydroxybenzotriazole hydrate (1 eq/0.459 mmol/61 mg) and N-ethyl diisopropylamine (5 eq/2.295 mmol/0.4 ml) in 3.5 ml tetrahydrofuran was cooled to O0C, mixed with 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 eq/0.689 mmol/130 mg) and stirred for 15 min at 00C. 1-(2-Aminoethyl)-Λ/,Λ/-dimethyl-4-(thiophen-2-yl)piperidin-4-amine trihydrochloride (1.5 eq/0.689 mmol/250 mg) was added to this reaction mixture and it was heated to room temperature and stirred for 12 h.
The reaction course was monitored by thin-layer chromatography (75% EtOAc/hexane). Once the conversion was complete, the reaction mixture was washed 3 times with saturated sodium hydrogen carbonate solution and the organic phase was dried over magnesium sulfate. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (alumina neutral; 1% MeOH/CH2CI2). 143 mg (67%) of product were obtained in the form of a yellow oil.
HPLC/MS analysis111: R, = 2.4 min; purity (UV 200-400 nm) 99%; m/z = 467.3 [MH]+, 422.3 [M-N(CH3)2]+
Example 3: N-(2-(4-(Dimethylamino)-4-phenvlpiperidin-1-vl)ethvl)-5-fluoro-N-methyl-1H- indol-2-amide
A solution of δ-fluoro-IH-indole^-carboxylic acid (1 eq/0.637 mmol/114 mg), 1-hydroxybenzotriazole hydrate (1 eq/0.637 mmol/84 mg) and N-ethyl diisopropylamine (5 eq/3.185 mmol/0.54 ml) in 5 ml tetrahydrofuran was cooled to O0C, mixed with 1-(3- dimethylarninopropyl)-3-ethylcarbodiimide hydrochloride (1.5 eq/0.956 mmol/181 mg) and stirred for 15 min at 00C. Λ/,Λ/-Dimethyl-1-(2-(methylamino)ethyl)-4-phenylpiperidin-4-amine (1.5 eq/0.956 mmol/250 mg) was added to this reaction mixture and it was heated to room temperature and stirred for 12 h.
The reaction course was monitored by thin-layer chromatography (75% EtOAc/hexane). Once the conversion was complete, the reaction mixture was washed 3 times with saturated sodium hydrogen carbonate solution and the organic phase was dried over magnesium sulfate. Following removal of the solvent under reduced pressure, the residue was purified by 5
column chromatography (alumina neutral; 1% MeOH/CH2CI2). 138 mg (51%) of product were obtained in the form of a white solid.
HPLC/MS analysis'11: R, = 2.1 min; purity (UV 200-400 nm) 99%; m/z = 423.3 [MH]+, 378.3 [M-N(CH3)2]+
Library substances
Parallel synthesis of acylated and reductively aminated piperidine derivatives
General:
R1
Figure imgf000054_0001
AA ACI AMD
Figure imgf000054_0002
AA ALX) AMN
In accordance with the scheme above, the amine structural units AA were converted by parallel synthesis both with acids (ACI) and with aldehydes (ALD) to the acylated (AMD) and reductively aminated (AMN) products.
The crude products of the parallel synthesis were analysed by HPLC-MS'21 and then purified by reverse phase HPLC-MS'31. The products were able to be identified by means of analytical HPLC-MS measurements'21.
[2] Equipments and methods for HPLC-MS analysis:
Parallel synthesis method 1: HPLC: Waters Alliance 2795 with PDA Waters 996; MS: ZQ 2000
MassLynx Single Quadrupol MS Detector; Column: Nucleodur Gravity C18 30 x 2 mm, 5μm; CoI. temp.: 40°C, Eluent A: purified water + 0.1% formic acid; Eluent B: methanol (gradient grade) +
0.1% formic acid; Gradient: 0% B to 100% B in 2.3 min, 100% B for 0.4 min, 100% B to 0% B in
0.01 min, 0% B for 0.8 min; Flow: 1.0 ml/min; Ionisation: ES+, 25V; make up: 100 μl/min 70% methanol + 0.2% formic acid; UV: 200 - 400 nm
Parallel synthesis method 2: HPLC: Waters Alliance 2795 with PDA Waters 996; MS: ZQ 2000
MassLynx Single Quadrupol MS Detector; Column: Waters Atlantis™ dC18, 3 μm, 2.1 x 30 mm; CoI. temp.: 400C, Eluent A: purified water + 0.1% formic acid; Eluent B: acetonitrile(gradient grade) +
0.1% formic acid; Gradient: 0% B to 100% B in 2.0 min, 100% B for 0.1 min, 100% B to 0% B in Parallel synthesis method 1 :
Synthesis procedure for the acylation of the amino piperidine derivatives (AA) with indole carboxylic acids (ACI)
Synthesis procedure for method 1 :
A solution of the indole carboxylic acid derivative ACI (150 μmol) in 1.6 ml dichloromethane was prepared at room temperature and a solution of carbonyldiimidazole (160 μmol) in 1 ml dichloromethane was added. The reaction mixture was shaken for 1 hour at room temperature and then a solution of the corresponding amine AA (100 μmol) in a mixture of 500 μmol N-ethyl-diisopropylamine and 0.5 ml dichloromethane was added. The reaction mixture was shaken for 12 hours at room temperature. The solvent was then removed under vacuum in a vacuum centrifuge (GeneVac). The final purification was performed by HPLC- MS. The final analysis was performed by LC-MS.
Parallel synthesis method 2:
Synthesis procedure for the reductive amination of the amino piperidine derivatives
(AA) with indole aldehydes (ALD)
Synthesis procedure for method 2:
A solution of the amine AA (100 μmol) in 1.0 ml methanol was prepared at room temperature and a solution of the corresponding aldehyde ALD (100 μmol) in 1.0 ml methanol was added. The reaction mixture obtained was mixed with 41 mg aluminium oxide and shaken for 2 hours at room temperature. 10.1 μl borane-pyridine complex were then added and the reaction mixture was shaken for 3 days at room temperature.
For the purposes of processing, 1.5 ml of ΛA concentrated hydrochloric acid were added to the batches and they were shaken for 15 minutes at room temperature. Then 1 ml 6 M sodium hydroxide solution and 3 ml ethyl acetate were added. Further processing took place on a Myriad-Allex processing system (Mettler-Toledo). After mixing thoroughly, the organic phase was separated off, the aqueous phase extracted with 3
0.01 min, 0% B for 0.5 min; Flow: 1.2 ml/min; Ionisation: ES+, 25V; make up: 100 μl/min 70% methanol + 0.2% formic acid; UV: 200 - 400 nm
[3] Equipment and methods for HPLC-MS purification: Prep Pump: Waters 2525; Make Up Pump: Waters 515; Auxiliary Detector: Waters DAD 2487; MS Detector: Waters Micromass ZQ; Injector/Fraction Collector: Waters Sample Manager 2767; Gradient: Initial: 50Vo Water 50% Methanol -> 2-17 min. 0% Water 100% Methanol; Flow: 35 ml/min Column: Phenomenex Gemini, C18, 100x21.2 mm, Axia, HOA, 5μ ml ethyl acetate and the organic phases combined. Removal of the solvent took place under vacuum in a vacuum centrifuge (GeneVac). Purification was performed by HPLC-MS. Analysis was performed by LC-MS.
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
In the following example, the free base of building block AA was always utilized in parallel synthesis method 2.
Figure imgf000067_0002
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Investigations into the effectiveness of the compounds according to the invention:
The data resulting from the following assays and models is summarised in Table 1.
Measurement of ORL1 binding
The cyclohexane derivatives having the general formula I were investigated in a receptor binding assay with 3H-nociceptin/orphanin FQ with membranes of recombinant CHO-ORL1 cells. This test system was conducted in accordance with the method described by Ardati et al. (MoI. Pharmacol., 51 , 1997, p. 816-824). The concentration of 3H-nociceptin/orphanin FQ in these tests was 0.5 nM. The binding assays were carried out with 20 μg amounts of membrane protein per 200 μl batch in 50 mM Hepes, pH 7.4, 10 mM MgCI2 and 1 mM EDTA. The binding to the ORL1 receptor was determined using 1 mg amounts of WGA-SPA beads (Amersham-Pharmacia, Freiburg, Germany), by incubation of the batch for one hour at room temperature and subsequent measurement in a Trilux scintillation counter (Wallac, Finland). The affinity is given in Table 1 as the nanomolar K1 value or in % inhibition at c=1 μM.
Measurement of u binding
The receptor affinity to the human μ-opiate receptor was determined in a homogeneous batch in microtitre plates. To this end, dilution series of the substituted indole derivative to be tested were incubated for 90 minutes at room temperature with a receptor membrane preparation (15 - 40 μg protein per 250 μl incubation batch) of CHO-K1 cells, which express the human μ-opiate receptor (RB-HOM receptor membrane preparation from NEN, Zaventem, Belgium), in the presence of 1 nmol/l of the radioactive ligand [3H] naloxone (NET719, NEN, Zaventem, Belgium) and 1 mg of WGA-SPA beads (wheat germ agglutinin SPA beads from Amersham/Pharmacia, Freiburg, Germany) in a total volume of 250 μl. 50 mmol/l tris-HCI supplemented with 0.05 wt.% sodium azide and 0.06 wt.% bovine serum albumin were used as the incubation buffer. In order to determine the non-specific binding, 25 μmol/l of naloxone were also added. At the end of the ninety-minute incubation period the microtitre plates were centrifuged for 20 minutes at 1000 g and the radioactivity was measured in a β counter (Microbeta-Trilux, PerkinElmer Wallac, Freiburg, Germany). The percentage displacement of the radioactive ligand from its binding to the human μ-opiate receptor was determined at a test substance concentration of 1 μmol/l and stated as the percentage inhibition (% inhibition) of the specific binding. In some cases the percentage displacement due to differing concentrations of the compounds having the general formula I to be tested was used to calculate the IC50 inhibition concentrations which bring about a 50- percent displacement of the radioactive ligand. K1 values for the test substances were obtained by extrapolation using the Cheng-Prusoff equation.
Figure imgf000076_0001
Figure imgf000076_0002
Figure imgf000077_0001
Figure imgf000077_0002
Figure imgf000078_0001
Figure imgf000078_0002
Figure imgf000079_0002
Figure imgf000079_0001
Parenteral solution of a substituted indole derivative according to the invention
38 g of one of the substituted indole derivatives according to the invention, in this case example 3, are dissolved in 1 I of water for injection at room temperature and then adjusted to isotonic conditions by the addition of anhydrous glucose for injection.

Claims

Claims:
1. Substituted indole derivatives having the general formula I1
Figure imgf000080_0001
I
wherein
A and B mutually independently denote CH2, C=O or SO2,
X stands for indolyl, unsubstituted or mono- or polysubstituted;
T stands for (CR5a cR6a-c)n , n = 1 , 2 or 3,
Q stands for (CR7a cR8a"c)m , m = 0,1 , 2 or 3,
R1 and R2 mutually independently denote C1-3 alkyl or H or the radicals R1 and R2 form a ring with inclusion of the N atom and together denote (CH2)3 or (CH2)4;
R3 denotes aryl or heteroaryl, each optionally bound by a C1-3 alkyl chain, each unsubstituted or mono- or polysubstituted; or Ci-6 alkyl, unsubstituted or mono- or polysubstituted;
R4 denotes H; C1-6 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl, heteroaryl or cycloaryl, each optionally bound by a Ci-3 alkyl chain;
R5a"c and R6a c mutually independently stand for H, F, CN, OH, OCH3, OCF3, C1-6 alkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C3-8 cycloalkyl, aryl or heteroaryl, each unsubstituted or mono- or polysubstituted; or for a C3-8 cycloalkyl, aryl or heteroaryl radical bound by a C1-3 alkyl chain, each unsubstituted or mono- or polysubstituted; or one of the radicals R53"0 or R6a"° forms a five-, six- or seven-membered ring with the radical R4 with inclusion of the nitrogen atom, which ring can itself be substituted or unsubstituted or can be fused to a further five-, six- or seven-membered ring, which can be aromatic or non-aromatic;
R 7a-c R βa-c mutua||y independently stand for H; F, CN, OH, OCH3, OCF3, C1-6 alkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly- substituted; C3-8 cycloalkyl, aryl or heteroaryl, each unsubstituted or mono- or poly- substituted; or for a C3-8 cycloalkyl, aryl or heteroaryl radical bound by a C1-3 alkyl chain, each unsubstituted or mono- or polysubstituted;
or one of the radicals R7a~° or R8a c forms a five-, six- or seven-membered unsaturated ring with a substituent in the 2 or 3 position of the indolyl ring X,
with the proviso that compounds in which R3 stands for a phenyl radical which is substituted in the 3 position with OH or OCOCi-8 alkyl are excluded from protection,
in the form of the racemate; the enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a single enantiomer or diastereomer; the bases and/or salts of physiologically compatible acids or cations.
2. Substituted indole derivatives according to claim 1 , wherein
"alkyl substituted" and "cycloalkyl substituted" stands for the substitution of a hydrogen radical with F, Cl, Br, I, -CN, NH2, NH-C1-6 alkyl, NH-C1-6 alkyl-OH, C1-6 alkyl, N(C1-6 alkyl)2, N(C1-6 alkyl-OH)2, NO2, SH1 S-C1-6 alkyl, S-benzyl, 0-C1-6 alkyl, OH, 0-C1-6 alkyl-OH, =0, O- benzyl, C(=O)C1-6 alkyl, C(=O)OC1-6 alkyl, phenyl or benzyl,
and "aryl substituted", "indolyl substituted" and "heteroaryl substituted" stands for the single or multiple, e.g. two, three or four times, substitution of one or more hydrogen atoms in the ring system with F, Cl, Br, I, CN, NH2, NH-Ci-6 alkyl, NH-C1-6 alkyl-OH, N(C1-6 alkyl)2, N(C1-6 alkyl-OH)2, NO2, SH1 S-Ci-6 alkyl, OH, 0-Ci-6 alkyl, 0-C1-6 alkyl-OH, C(=O)-aryl; C(=O)C1-6 alkyl, C(=O)NHC1-6 alkyl; C(=O)-N-morpholine; C(=O)-piperidine; (C=O)-pyrrolidine; (C=O)- piperazine; NHSO2C1-6 alkyl, NHCOCi-6 alkyl, CO2H, CH2SO2 phenyl, CO2-C1-6 alkyl, OCF3,
CF3, ' / , / , C1-6 alkyl, pyrrolidinyl, piperidinyl, morpholinyl, benzyloxy, phenoxy, phenyl, pyridyl, alkylaryl, thienyl or furyl, wherein aryl and heteroaryl substituents can themselves be substituted with F1 Cl, Br1 I1 CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OC2H5 or N(CH3)2.
3. Substituted indole derivatives according to one of claims 1 or 2, wherein A denotes CH2 and B denotes CH2 or C=O.
4. Substituted indole derivatives according to one of claims 1 or 2, wherein X stands for indolyl, unsubstituted or mono- or polysubstituted with F, Cl, Br, I, CN, CH3, C2H5, C3H8, NH2, NO2, SH, CF3, OH, OCH3, OC2H5, N(CH3)2 or phenyl, unsubstituted or mono- or polysubstituted with F, Cl1 Br, I, CN, CH3, C2H5, NH2, NO2, SH1 CF3, OH, OCH3, OC2H5 Or N(CH3)2.
5. Substituted indole derivatives according to one of claims 1 or 2, wherein R1 and R2 mutually independently denote methyl or H.
6. Substituted indole derivatives according to one of claims 1 or 2, wherein
R3 stands for phenyl, benzyl, phenethyl, thienyl, pyridyl, thiazolyl, imidazolyl, 1 ,2,4-triazolyl, benzimidazolyl or benzyl, unsubstituted or mono- or polysubstituted with F1 Cl, Br, CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OC2H5 Or N(CH3)2; ethyl, n-propyl, 2-propyl, allyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, cyclopentyl or cyclohexyl, each unsubstituted or mono- or polysubstituted with OH, OCH3 or OC2H5.
7. Substituted indole derivatives according to one of claims 1 or 2, wherein R4 denotes H, CH3 or benzyl.
8. Substituted indole derivatives according to one of claims 1 or 2, wherein
R5a c and R6a-° stand for H.
9. Substituted indole derivatives according to one of claims 1 or 2, wherein
R 7a-c R βa-c mutua||y independently denotes H; C1-6 alkyl, saturated or unsaturated, branched or unbranched,
or one of the radicals R7a~° or R8a"c forms a five-, six- or seven-membered unsaturated ring with a substituent in the 3 position of the indolyl ring X, such that a structural element having the general formulae lla-f is produced:
Figure imgf000083_0001
Ma lib Mc
Figure imgf000083_0002
Md Me Mf
10. Substituted indole derivatives according to claim 1 , from the group comprising
N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-N-methyl-1 H-indole-6-
1 carboxamide
N-(2-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)ethyl)-3-(1 H-indol-3-yl)-4- 2 methylpentanamide
N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-5-fluoro-N-methyl-1 H-indole-2- 3 carboxamide
N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-3-(1H-indol-3-yl)-N- methylpropanamide
N-(2-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1 -yl)ethyl)-3-(1 H-indol-3- yl)propanamide
6 N-(2-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)ethyl)-3-(1 H-indol-3-yl)-4- methylpentanamide
_ 6-Chloro-N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)ethyl)-2, 3,4,9- tetrahydro-1 H-carbazole-1 -carboxamide
8 N-(2-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1 -yl)ethyl)-2-(6-fluoro-1 H-indol-3- yl)acetamide
N-(2-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)ethyl)-1-methyl-1 H-indole-6- carboxamide
10 N-(2-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)ethyl)-1-methyl-1 H-indole-4- carboxamide
N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl)-N-methyl-1H-indole-3-
1 1 carboxamide
12 N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-N-methyl-1 H-indole-3- carboxamide
13 N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl)-N-methyl-3-(1-methyl- 1 H-indol-3-yl)propanamide
14 N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-N-methyl-3-(1-methyl-1 H-indol-3- yl)propanamide
. N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl)-5-fluoro-N-methyl-1 H- indole-2-carboxamide 16 N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-5-fluoro-N-methyl-1 H-indole-2- carboxamide . N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl)-N-nnethyl-1H-indole-6- carboxamide
18 N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-N-methyl-1 H-indole-6- carboxamide
19 N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl)-3-(1H-indol-3-yl)-N- methylbutanamide
20 N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-3-(1H-indol-3-yl)-N- methylbutanamide
21 N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl)-3-(1H-indol-3-yl)-N- methylpropanamide
22 N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl)-5-methoxy-N-methyl- 1 H-indole-2-carboxamide
23 N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1 -yl)propyl)-3-(1 H-indol-3-yl)-N,4- dimethylpentanamide
24 N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-3-(1H-indol-3-yl)-N,4- dimethylpentanamide
25 6-Chloro-N-(2-(4-(dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-N-methyl-2,3,4,9- tetrahydro-1 H-carbazole-1 -carboxamide
OR N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl)-2-(6-fluoro-1H-indol-3- yl)-N-methylacetamide
27 N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1 -yl)ethyl)-2-(6-fluoro-1 H-indol-3-yl)-N- methylacetamide
28 N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl)-N,1-dimethyl-1 H-indole- 6-carboxamide
2Q N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-N,1-dimethyl-1 H-indole-6- carboxamide 30 N-(3-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl)-N,1-dimethyl-1 H-indole-
4-carboxamide
„.. N-(2-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-N,1-dimethyl-1 H-indole-4- carboxamide
32 3-(1H-lndol-3-yl)-N,4-dimethyl-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1- yl)ethyl)pentanamide
33 N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-3-(1H-indol-3-yl)-N,4- dimethylpentanamide
34 N-(3-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)propyl)-3-(1 H-indol-3-yl)-N,4- dimethylpentanamide
35 6-Chloro-N-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)propyl)-N-methyl-2, 3,4,9- tetrahydro-1 H-carbazole-1 -carboxamide
36 2-(6-Fluoro-1 H-indol-3-yl)-N-methyl-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1- yl)ethyl)acetamide
37 N,1-Dimethyl-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1-yl)ethyl)-1 H-indole-6- carboxamide
„0 N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-N,1-dimethyl-1 H-indole-6- carboxamide
3g N-(3-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)propyl)-N,1-dimethyl-1 H-indole-6- carboxamide N,1-Dimethyl-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1-yl)ethyl)-1 H-indole-4- carboxamide
N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-N,1-dimethyl-1 H-indole-4- carboxamide
6-Chloro-N-methyl-N-(2-(4-phenyl-4-(pyrrolidin-1 -yl)piperidin-1 -yl)ethyl)-2,3,4,9- tetrahydro-1 H-carbazole-1 -carboxamide
43 N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-6-chloro-N-methyl-2, 3,4,9- tetrahydro-1 H-carbazole-1 -carboxamide
44 N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-2-(6-fluoro-1 H-indol-3-yl)-N- methylacetamide
45 N-(3-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)propyl)-2-(6-fluoro-1H-indol-3-yl)-N- methylacetamide
46 N-Methyl-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1-yl)ethyl)-1H-indole-3- carboxamide
47 N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-N-methyl-1 H-indole-3-carboxamide
48 N-Methyl-3-(1-methyl-1 H-indol-3-yl)-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1- yl)ethyl)propanamide
4Q N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-N-methyl-3-(1-methyl-1 H-indol-3- yl)propanamide
50 N-(3-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)propyl)-N-methyl-3-(1-methyl-1 H-indol- 3-yl)propanamide
51 5-Fluoro-N-methyl-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1-yl)ethyl)-1 H-indole-2- carboxamide
52 N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-5-fluoro-N-methyl-1H-indole-2- carboxamide
53 N-(3-(4-(Dimethylamino)-4-phenylpiperidin-1 -yl)propyl)-5-fluoro-N-methyl-1 H-indole-2- carboxamide
54 N-Methyl-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1-yl)ethyl)-1 H-indole-6- carboxamide
55 N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-N-methyl-1H-indole-6-carboxamide
5β N-(3-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)propyl)-N-methyl-1 H-indole-6- carboxamide
3-(1 H-lndol-3-yl)-N-methyl-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1- yl)ethyl)butanamide
58 N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-3-(1 H-indol-3-yl)-N- methylbutanamide
5g N-(3-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)propyl)-3-(1 H-indol-3-yl)-N- methylbutanamide
60 N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-3-(1 H-indol-3-yl)-N- methylpropanamide β1 N-(3-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)propyl)-3-(1H-indol-3-yl)-N- methylpropanamide R_ 2-(5-Bromo-1 H-indol-3-yl)-N-methyl-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1- yl)ethyl)acetamide 63 2-(5-Bromo-1 H-indol-3-yl)-N-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)propyl)-N- methylacetamide β4 5-Methoxy-N-methyl-N-(2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1-yl)ethyl)-1 H-indole-2- carboxamide
_5 N-(2-(4-Butyl-4-(dimethylamino)piperidin-1-yl)ethyl)-5-methoxy-N-methyl-1 H-indole-2- carboxamide β6 N-(3-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)propyl)-5-methoxy-N-methyl-1 H-indole- 2-carboxamide g_ 1-(3-(((6-lsopropyl-1H-indol-3-yl)methyl)(methyl)amino)propyl)-N,N-dimethyl-4- (thiophen-2-yl)piperidin-4-amine
68 1-(2-(((1 H-lndol-5-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4-phenylpiperidin-4- amine
6g 1-(2-((1H-lndol-5-yl)methylamino)ethyl)-N,N-dimethyl-4-(thiophen-2-yl)piperidin-4- amine
70 1-(2-(((2-(4-Fluorophenyl)-1H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine
71 N,N-Dimethyl-1-(2-(methyl((2-phenyl-1H-indol-3-yl)methyl)amino)ethyl)-4- phenylpiperidin-4-amine
1-(2-((5-Chloro-1H-indol-3-yl)methylamino)ethyl)-N,N-dimethyl-4-(thiophen-2- yl)piperidin-4-amine
73 1-(2-(((6-lsopropyl-1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine
74 1-(2-((6-lsopropyl-1H-indol-3-yl)methylamino)ethyl)-N,N-dimethyl-4-(thiophen-2- yl)piperidin-4-amine
75 1-(2-(((5-Methoxy-1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine
76 1-(2-((5-Methoxy-1 H-indol-3-yl)methylamino)ethyl)-N,N-dimethyl-4-(thiophen-2- yl)piperidin-4-amine
1-(2-(((1-Benzyl-5-methoxy-2-methyl-1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N- dimethyl-4-phenylpiperidin-4-amine
7_ 1-(2-((1-Benzyl-5-methoxy-2-methyl-1 H-indol-3-yl)methylamino)ethyl)-N,N-dimethyl-4- (thiophen-2-yl)piperidin-4-amine
79 1-(2-(((1 ,2-Dimethyl-1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine
80 1-(2-((1 ,2-Dimethyl-1 H-indol-3-yl)methylamino)ethyl)-N,N-dimethyl-4-(thiophen-2- yl)piperidin-4-amine
81 1-(3-(((1 ,2-Dimethyl-1H-indol-3-yl)methyl)(methyl)amino)propyl)-N,N-dimethyl-4- (thiophen-2-yl)piperidin-4-amine g2 N-(1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-2-(6-fluoro- 1H-indol-3-yl)-N-methylacetamide
83 2-(5-bromo-1 H-indol-3-yl)-N-(1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-methyl-1- oxobutan-2-yl)-N-methylacetamide
84 N-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-oxopropyl)-3-(1 H-indol-3-yl)-4- methylpentanamide
8 N-(3-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-3-oxo-1-phenylpropyl)-3-(1 H- indol-3-yl)-4-methylpentanamide O6 1-(3-(4-(dimethylamino)-4-phenylpiperidine-1-carbonyl)indolin-1-yl)-2-(6-fluoro-1H- indol-3-yl)ethanone
87 N-(2-(4-(dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-3-(1H-indol-3-yl)-N,4- dimethylpentanamide
88 N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-2-oxoethyl)-3-(1H-indol-3-yl)-4- methylpentanamide
8Q 1-(3-(4-(dimethylamino)-4-phenylpiperidine-1-carbonyl)indolin-1-yl)-3-(1 H-indol-3-yl)-4- methylpentan-1-one N-(2-(4-(dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-2-(6-fIuoro-1 H-indol-3-yl)-N- methylacetamide
N-(3-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-3-oxo-1-phenylpropyl)-3-(1H- indol-3-yl)butanamide g2 N-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-oxopropyl)-3-(1 H-indol-3- yl)butanamide
N-CS^^dimethylaminoH-Ohiophen-Z-yOpiperidin-i-yO-S-oxo-i-phenylpropyO^^Θ- fluoro-1 H-indol-3-yl)acetamide
N-(1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-(1H-indol-
3-yl)-N-methylpropanamide 95 N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1 -yl)-2-oxo-1 -phenylethyl)-2-(6- fluoro-1 H-indol-3-yl)-N-methylacetamide Q6 N-(3-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1 -yl)-3-oxo-1 -phenylpropyl)-1 H- indole-6-carboxamide θ-chloro-N^S^^dimethylaminoM-Ohiophen^-yOpiperidin-i-yO-S-oxo-i- phenylpropyl)-2,3,4,9-tetrahydro-1 H-carbazole-1-carboxamide P8 N-(3-(4-(dimethylamino)-4-phenylpiperidin-1 -yl)-3-oxopropyl)-3-(1 H-indol-3- yl)propanamide Q9 N-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-oxopropyl)-1-methyl-1 H-indole-6- carboxamide
100 2-(5-bromo-1H-indol-3-yl)-N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-2- oxo-1-phenylethyl)-N-methylacetamide
101 N-(3-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-3-oxo-1-phenylpropyl)-1- methyl-1 H-indole-6-carboxamide
102 N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-2-oxo-1-phenylethyl)-N-methyl- 1 H-indole-6-carboxamide
103 (6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)(3-(4-(dimethylamino)-4-phenylpiperidine- 1-carbonyl)piperidin-1-yl)methanone
104 (4"(dimethylamino)-4-phenylpiperidin-1-yl)(1-(5-fluoro-1 H-indole-2-carbonyl)piperidin-3- yl)methanone
105 N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-2-oxo-1-phenylethyl)-3-(1H- indol-3-yl)-N,4-dimethylpentanamide
106 ''"(^-(^-(dimethylaminoH-phenylpiperidine-i-carbonyOpiperidin-i-ylJ-S-CIH-indol-S-yl)- 4-methylpentan-1-one
10 6-chloro-N-(3-(4-(dimethylamino)-4-phenylpiperidin-1 -yl)-3-oxopropyl)-2, 3,4,9- tetrahydro-1 H-carbazole-1-carboxamide 108 N-(3-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-3-oxo-1-phenylpropyl)-1- methyl-1 H-indole-4-carboxamide 1 og N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-2-oxoethyl)-1 -methyl-1 H- indole-6-carboxamide .10 N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-2-oxo-1-phenylethyl)-3-(1 H- indol-3-yl)-N-methylpropanamide 1 N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-2-oxo-1-phenylethyl)-N,1- dimethyl-1 H-indole-6-carboxamide
1 12 N-(2-(4-butyl-4-(dimethylamino)piperidin-1 -yl)ethyl)-2-(6-fluoro-1 H-indol-3-yl)-N- methylacetamide
113 N-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-oxopropyl)-1 H-indole-6-carboxamide
114 (^-(dimethylaminoM-phenylpiperidin-i-ylXI-O-methyl-I H-indole^-carbonylJindolin-S- yl)methanone
1 15 2-(5-bromo-1 H-indol-3-yl)-1-(3-(4-(dimethylamino)-4-phenylpiperidine-1- carbonyl)piperidin-1-yl)ethanone
1 16 6-chloro-N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-2-oxoethyl)-2, 3,4,9- tetrahydro-1H-carbazole-1-carboxamide
1 17 N-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-oxopropyl)-3-(1-methyl-1 H-indol-3- yl)propanamide
118 (4-(dimethylamino)-4-phenylpiperidin-1-yl)(1-(1-methyl-1 H-indole-6-carbonyl)indolin-3- yl)methanone 1 i q N-(2-(4-(dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-N,1-dimethyl-1 H-indole-6- carboxamide
6-(dimethylamino)-N-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-oxopropyl)-1 H- indole-2-carboxamide 121 N-^-^-CdimethylaminoM-phenylpiperidin-i -yl)-3-oxopropyl)-1 -methyl-1 H-indole-4- carboxamide .__ 1-(3-(4-(dimethylamino)-4-phenylpiperidine-1-carbonyl)piperidin-1-yl)-3-(1 H-indol-3- yl)butan-1-one
1 -(3-(4-(dimethylamino)-4-phenylpiperidine-1 -carbonyl)piperidin-1 -yl)-3-(1 H-indol-3- yl)propan-1-one
124 1-(3-(4-(dimethylamino)-4-phenylpiperidine-1-carbonyl)piperidin-1-yl)-2-(6-fluoro-1 H- indol-3-yl)ethanone
125 (1-(1 H-incOle-6-carbonyl)piperidin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-1- yl)methanone
126 N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-2-oxo-1-phenylethyl)-N-methyl- 3-( 1 -methyl- 1 H-indol-3-yl)propanamide
127 6-chloro-N-(2-(4-(dimethylamino)-4-phenylpiperidin-1 -yl)ethyl)-N-methyl-2, 3,4,9- tetrahydro-1 H-carbazole-1 -carboxamide
128 (4-(dimethylamino)-4-phenylpiperidin-1-yl)(1-(1-methyl-1 H-indole-6-carbonyl)piperidin- 3-yl)methanone
129 N-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-oxopropyl)-5-methoxy-1H-indole-2- carboxamide
130 (4-(d'methy|amino)-4"Pheny|P'Per'd'n"1"y|)(1-(1-methyl-1 H-indole-4-carbonyl)piperidin- 3-yl)methanone
131 (1-(1 H-incOle-3-carbonyl)piperidin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-1- yl)methanone
,,. N-(1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-N-methyl-3- (1-methyl-1H-indol-3-yl)propanamide
133 1 "(3-(4-(dimethylamino)-4-phenylpiperidine-1-carbonyl)piperidin-1-yl)-3-(1 -methyl-1 H- indol-3-yl)propan-1-one
134 6-chloro-N-(2-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-2-oxo-1-phenylethyl)- N-methyl^.S^.Θ-tetrahydro-I H-carbazole-i -carboxamide
135 N"(2"(4"(d'met'1y|amiπo)"4"(t'1iophen-2-yl)piperidin-1-yl)-2-oxoethyl)-1 -methyl-1 H- indole-4-carboxamide
136 (6-(dimethylamino)-1 H-indol-2-yl)(3-(4-(dimethylamino)-4-phenylpiperidine-1- carbonyl)piperidin-1-yl)methanone
13 N-((1H-indol-3-yl)methyl)-N-methyl-2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1- yl)ethanamine
138 1-(2-(((1H-indol-3-yl)methyl)(methyl)amino)ethyl)-4-butyl-N,N-dimethylpiperidin-4- amine
139 3-((1H-indol-3-yl)methylamino)-1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)propan-1- one
140 N-((1H-'nclol-5-yl)methyl)-N-methyl-2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1- yl)ethanamine
141 1-(2-(((1H-indol-5-yl)methyl)(methyl)amino)ethyl)-4-butyl-N,N-dimethylpiperidin-4- amine
14? 3-((1H-indol-5-yl)methylamino)-1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)propan-1- one
143 N-((1H-indol-6-yl)methyl)-N-methyl-2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1- yl)ethanamine
144 1-(2-(((1H-indol-6-yl)methyl)(methyl)amino)ethyl)-4-butyl-N,N-dimethylpiperidin-4- amine
145 3-((1H-indol-6-yl)methylamino)-1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)propan-1- one
146 2-(((1H-indol-5-yl)methyl)(methyl)amino)-1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)- 3-methylbutan-1 -one
2-(((1 H-indol-5-yl)methyl)(methyl)amino)-1-(4-(dimethylamino)-4-(thiophen-2- yl)piperidin-1-yl)-2-phenylethanone
(1-((1 H-indol-5-yl)methyl)piperidin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-1- yl)methanone
2-(((1 H-indol-6-yl)methyl)(methyl)amino)-1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-
3-methylbutan-1-one 150 2-(((1 H-indol-6-yl)methyl)(methyl)amino)-1-(4-(dimethylamino)-4-(thiophen-2- yl)piperidin-1-yl)-2-phenylethanone Λ Ci (HO H-indol-3-yl)methyl)piperidin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-1- yl)methanone 2 (1-((1 H-indol-6-yl)methyl)piperidin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-1- yl)methanone 153 N-((5-bromo-1 H-indol-3-yl)methyl)-N-methyl-2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1- yl)ethanamine
1-(2-(((5-bromo-1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-4-butyl-N,N- dimethylpiperidin-4-amine 155 C-((5-bromo"1 H-indol-3-yl)methyl)piperidin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-
1-yl)methanone 15β (4-(dimethylamino)-4-phenylpiperidin-1-yl)(1-((2-methyl-1 H-indol-3-yl)methyl)piperidin-
3-yl)methanone 1 ς7 1-(2-(((1H-indol-7-yl)methyl)(methyl)amino)ethyl)-4-butyl-N,N-dimethylpiperidin-4- amine 1EO (1-((1H-indol-7-yl)methyl)piperidin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-1- yl)methanone
159 N-((1 H"incOI-4-yl)methyl)-N-methyl-2-(4-phenyl-4-(pyrrolidin-1-yl)piperidin-1- yl)ethanamine
160 1-(2-(((1H-indol-4-yl)methyl)(methyl)amino)ethyl)-4-butyl-N,N-dimethylpiperidin-4- amine
... (1-((1 H-indol-4-yl)methyl)piperidin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-1- yl)methanone -1 Q2 3-((5-brom°-'I H-'nc'ol-3-yl)rriethylamino)-1-(4-(dimethylamino)-4-phenylpiperidin-1- yl)propan-1-one
163 3-((5-bromo-1H-indol-3-yl)methylamino)-1-(4-(dimethylamino)-4-(thiophen-2- yl)piperidin-1-yl)-3-phenylpropan-1-one
164 3-((1 H-indol-3-yl)methylamino)-1-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-3- phenylpropan-1 -one
1 fi(. 3-((1 H-indol-5-yl)methylamino)-1-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-3- phenylpropan-1-one 166 (1-((1 H-incOI-5-yl)methyl)indolin-3-yl)(4-(dimethylamino)-4-phenylpipendin-1- yl)methanone 1 fi7 1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-3-((2-methyl-1 H-indol-3- yl)methylamino)propan-1 -one
168 1"(4"(c'imethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-3-((2-methyl-1 H-indol-3- yl)methylamino)-3-phenylpropan-1-one
169 3"((1 H"'ndol"6"y')methylamino)-1-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-3- phenylpropan-1-one
(1-((1 H-indol-6-yl)methyl)indolin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-1- yl)methanone
171 3-((1H-indol-7-yl)methylamino)-1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)propan-1- one
172 2-((1 H-indol-7-yl)methylamino)-1-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1- yl)ethanone
. 3-((1H-indol-7-yl)methylamino)-1-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-3- phenylpropan-1 -one 174 3-((1 H-indol-4-yl)methylamino)-1-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)-3- phenylpropan-1-one
(1-((1H-indol-4-yl)methyl)indolin-3-yl)(4-(dimethylamino)-4-phenylpiperidin-1- yl)methanone
(4-(dimethylamino)-4-phenylpiperidin-1 -yl)(1 -((6-methoxy-1 ,2-dimethyl-1 H-indol-3- yl)methyl)piperidin-3-yl)methanone 177 (4-(dimethylamino)-4-phenylpiperidin-1-yl)(1-((2-(4-fluorophenyl)-1 H-indol-3- yl)methyl)piperidin-3-yl)methanone
1-(2-((5-chloro-1 H-indol-3-yl)methylamino)ethyl)-N,N-dimethyl-4-(thiophen-2- yl)piperidin-4-amine 17g 1-(2-((1 H-indol-3-yl)methylamino)ethyl)-N,N-dimethyl-4-(thiophen-2-yl)piperidin-4- amine
180 1-(2-(((6-isoProPy|-1 H-indo|-3-y|)rnethyl)(fτiethyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine
181 1-(2-(((1 H-indol-6-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4-phenylpiperidin-4- amine
2 1 -(2-(((5-chloro-1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-N , N-dimethyl-4- phenylpiperidin-4-amine
1-(2-(((5-chloro-1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine
184 1-(2-(((1 H-indol-6-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4-phenylpiperidin-4- amine
185 1-(2-(((5-bromo-'I H-'ndo|-3-y|)methyl)(methyl)amino)ethyl)-NlN-dimethyl-4- phenylpiperidin-4-amine
186 1-(2-(((1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4-phenylpiperidin-4- amine
. _ 1-(2-(((1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4-phenylpiperidin-4- amine
188 ''"(2"((5-methoxy-1 H-indol-3-yl)methylamino)ethyl)-N,N-dimethyl-4-(thiophen-2- yl)piperidin-4-amine
189 1-(2-(((1 ,2-dimethyl-1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine
190 1-(2-(((5-methoxy-1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine
191 1-(2-(((5-methoxy-1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine
192 1-(2-(((5-metnoχy-1 H-'ndo|-3-y|)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4- phenylpiperidin-4-amine
193 1 "(2'^(1 -benzyl-δ-methoxy^-methyl- 1 H-indol-3-yl)methyl)(methyl)amino)ethyl)-N , N- dimethyl-4-phenylpiperidin-4-amine
1-(2-(((1H-indol-4-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4-phenylpiperidin-4- amine
195 1-(2"((CH-indol-4-yl)methyl)(methyl)amino)ethyl)-N,N-dimethyl-4-phenylpiperidin-4- amine
in the form of the racemate; the enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a single enantiomer or diastereomer; the bases and/or salts of physiologically compatible acids or cations.
11. Process for the preparation of substituted indole derivatives according to claim 1 ,
Figure imgf000091_0001
wherein compounds having the general formula AA in at least one solvent, preferably selected from the group consisting of dichloromethane, acetonitrile, dimethyl formamide, diethyl ether, dioxane and tetrahydrofuran, are reacted with acids having the general formula X-Q-CO2H1 wherein X and Q have the meanings given above, with addition of at least one coupling reagent, preferably selected from the group consisting of carbonyl diimidazole (CDI), 2-chloro-1-methylpyridinium iodide (Mukaiyama reagent), Λ/-(3-dimethylaminopropyl)-Λ/'-ethylcarbodiimide (EDCI), O- (benzotriazol-1-yl)-Λ/,Λ/,Λ/',Λ/'-tetramethyluronium tetrafluoroborate (TBTU), Λ/,Λ/'- dicyclohexylcarbodiimide (DCC) and i-benzotriazolyloxy-tris-(dimethylamino)- phosphonium hexafluorophosphate (BOP), optionally in the presence of at least one inorganic base, preferably selected from the group consisting of potassium carbonate and caesium carbonate, or an organic base, preferably selected from the group consisting of triethylamine, diisopropylethylamine and pyridine, and optionally with addition of 4-(dimethylamino)pyridine or 1-hydroxybenzotriazole, to form compounds having the general formula AMD,
or compounds having the general formula AA are reacted with sulfonyl chlorides having the general formula X-Q-SO2CI, wherein X and Q have the meanings given above, in at least one organic solvent, preferably selected from the group consisting of dichloromethane, acetonitrile, dimethyl formamide, diethyl ether, dioxane, tetrahydrofuran, methanol, ethanol and toluene, in the presence of an excess of a base, preferably selected from the group consisting of caesium carbonate, calcium carbonate, potassium carbonate, triethylamine, diisopropylethylamine and pyridine, at temperatures of preferably -700C to 1000C, to form compounds having the general formula SAM,
or compounds having the general formula AA are reacted with aldehydes having the general formula X-Q-CHO, wherein X and Q have the meanings given above, in at least one organic solvent, preferably selected from the group consisting of diethyl ether, tetrahydrofuran, methanol, ethanol, dichloroethane, dichloromethane and toluene, with addition of at least one reducing agent, preferably selected from the group consisting of borane-pyridine complex, sodium boron hydride, sodium triacetoxyboron hydride, sodium cyanoboron hydride and triethylsilane, optionally in the presence of at least one acid, preferably selected from the group consisting of formic acid, acetic acid, hydrochloric acid and trifluoroacetic acid, at temperatures of preferably -70°C to 1000C, to form compounds having the general formula AMN.
12. Medicinal product containing at least one substituted indole derivative according to one of claims 1 to 10 and optionally containing suitable additives and/or auxiliary substances and/or optionally further active ingredients.
13. Use of a substituted indole derivative according to one of claims 1 to 10 to prepare a medicinal product for the treatment of pain, in particular acute, neuropathic or chronic pain.
14. Use of a substituted indole derivative according to one of claims 1 to 10 to prepare a medicinal product for the treatment of anxiety conditions, stress and stress-related syndromes, depression, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunctions, learning and memory disorders (as a nootropic), withdrawal symptoms, alcohol and/or drug and/or prescription drug abuse and/or dependency, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinnitus, pruritus, migraine, hearing impairment, gastrointestinal motility disorders, food intake disorders, anorexia, obesity, locomotive disorders, diarrhoea, cachexia, urinary incontinence, or as a muscle relaxant, anticonvulsant or anaesthetic, or for coadministration in treatment with an opioid analgesic or with an anaesthetic, for diuresis or antinatriuresis, anxiolysis, for the modulation of motor activity, for the modulation of neurotransmitter release and treatment of associated neurodegenerative diseases, for the treatment of withdrawal symptoms and/or for the reduction of the addiction potential of opioids.
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