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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• • A—HUMAN NECESSITIES
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  • A61P17/00—Drugs for dermatological disorders
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/04—Antipruritics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents

Definitions

• compositions of [2-(3-methoxyphenyl)-cyclohexylmethyl]-dimethylamine and the metabolites thereof for treating anxiety, anxiety attacks and disorders as well as depression are also provided, including methods of administering the active compound(s) as adjuvant(s) to at least one antidepressant.
• Anxiety disorders are illnesses of which the main symptoms are manifestations of unrealistic or excessively pronounced anxiety.
• phobias to the sub-types of which so-called simple phobias, social anxiety disorders and agoraphobias belong, the anxiety attacks are associated with particular objects or situations.
• pronounced anxiety attacks can also occur without being triggered by specific situations or circumstances.
• panic disorders are distinguished by recurring, pronounced anxiety attacks which are not foreseeable and therefore lead to anticipatory anxiety.
• Generalized anxiety disorders are floating, lasting anxieties with diverse, in particular vegetative symptoms. Patients who suffer from posttraumatic stress disorders (PTSD) were exposed to a brief or long-lasting event or occurrence of exceptional threat or with catastrophic proportions. This event would induce a deep-seated despair in virtually anyone.
• PTSD posttraumatic stress disorders
• Obsessive compulsive disorders are characterized by recurring unpleasant thoughts, impulses or actions which last several weeks, are experienced as being part of the self and against which at least partial resistance is given since the person affected finds them senseless.
• Mixed anxiety disorders or anxiety disorders accompanied with depressions very often exist.
• Depressions are affectivity disorders in which a depressive syndrome is of prime significance, depressive meaning associated with depression or of sad mood.
• the depressive illnesses include unipolar severe depressions with or without delusion, moderate depressions, mild depressions, dysthymia, melancholy, bipolar depressions (bipolar illness I, mania and severe depression; bipolar illness II, hypomania and severe depressions; cyclothymic personality disorders, hypomania and mild depressions).
• Those pharmaceutical formulations with an anxiolytic and antidepressant action based on an inhibition of the reuptake of the monoamines noradrenaline and/or serotonin are widely used for therapy of anxiety disorders and depressions (Pacher, P., Kohegyi, E., Kecskemeti, V., Furst, S., Current Medicinal Chemistry 2001, 8, 89-100; Goddard, A. W., Coplan, J. D. Gorman, J. M., Charney, D. S., in: Neurobiology of mental illness, Charney, D. S., Nestler, E. J., Bunney, B. S. (eds.), Oxford University Press, New York, 1999, p. 548-563).
• a great disadvantage in this context is that the monoamine reuptake inhibitors display their anxiolytic and antidepressant action only after several weeks of treatment and achieve their full activity only after approx. 3-4 weeks.
• standard medications frequently intensify or induce anxiety states, unrest, increased irritability and thoughts of suicide.
• These psychomotor states of excitation and thoughts of suicide occur particularly frequently in the first days after the start of therapy both with tricyclic antidepressants, selective serotonin reuptake inhibitors (so-called SSRIs) and with mixed serotonin-noradrenalin reuptake inhibitors, and are associated with an increased risk of suicide (Jick, H., Kaye, J.
• the monoamine reuptake inhibitors used for therapy of anxiety disorders and depressions are also used for treatment of chronic pain patients.
• reuptake inhibitors of noradrenaline and serotonin lead to an independent analgesic action in that descending pain inhibition pathways at the level of the spinal marrow are activated.
• Monoamine reuptake inhibitors are employed clinically for monotherapy of neuropathic pain, and also as an adjuvant to opiates for treatment of chronic pain (inter alia inflammatory pain, tumour pain, fibromyalgia) (Sindrup, in: Yaksh, T. L., et al., Anesthesia. Biological foundations.
• One object of the present invention is to provide substances, in particular opioid substance, which are suitable for therapy of anxiety disorders, depressions or mixed forms of anxiety and depression with or without chronic pain.
• the invention provides compounds with an earlier onset of action compared with the monoamine reuptake inhibitors widely used for anxiety disorders and depressions.
• the use according to the invention of the compounds mentioned is a particularly effective treatment possibility precisely also for pharmaco-resistant anxiety and depression patients.
• the invention accordingly provides the use of
• salt is to be understood as meaning any form of the active compound according to the invention in which this assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution.
• a counter-ion a cation or anion
• complexes of the active compound with other molecules and ions in particular complexes which are complexed via ionic interactions.
• physiologically acceptable salts in particular physiologically acceptable salts with cations or bases and physiologically acceptable salts with anions or acids or also a salt formed with a physiologically acceptable acid or a physiologically acceptable cation.
• the preferred salt of the compounds used is the hydrochloride.
• Physiologically acceptable is to be understood as meaning that the substance, in particular the salt as such, is acceptable when used on humans or mammals, that is to say, for example, does not have a non-physiological (e.g. toxic) action.
• physiologically acceptable salt with anions or acids is understood as meaning salts of at least one of the compounds according to the invention—usually protonated, for example on the nitrogen—as the cation with at least one anion which is physiologically acceptable—in particular when used on humans and/or mammals.
• this is understood as meaning the salt formed with a physiologically acceptable acid, namely salts of the particular active compound with inorganic or organic acids which are physiologically acceptable—in particular when used on humans and/or mammals.
• physiologically acceptable salts of particular 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, 1,1-dioxo-1,2-dihydro-1 ⁇ 6 -benzo[d]isothiazol-3-one (saccharin), monomethylsebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, ⁇ -liponic acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid.
• the hydrochloride salt is particularly preferred.
• the term salt formed with a physiologically acceptable acid is understood as meaning salts of the particular active compound with inorganic or organic acids which are physiologically acceptable - in particular when used on humans and/or mammals.
• the hydrochloride is particularly preferred.
• physiologically acceptable acids are: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydro-1 ⁇ 6 -benzo[d]isothiazol-3-one (saccharin), monomethylsebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, ⁇ -liponic acid, acetyl
• physiologically acceptable salt with cations or bases is understood as meaning at least one of the compounds according to the invention—usually a (deprotonated) acid—as the anion with at least one, preferably inorganic cation, which are physiologically acceptable—in particular when used on humans and/or mammals.
• Particularly preferred salts are the salts of the alkali metals and alkaline earth metals, but also with NH 4 +, in particular (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium or calcium salts.
• salt formed with a physiologically acceptable cation is understood as meaning salts of at least one of the particular compounds as the anion with at least one inorganic cation which is physiologically acceptable—in particular when used on humans and/or mammals.
• Particularly preferred salts are the salts of the alkali metals and alkaline earth metals, but also NH 4 +, in particular (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium or calcium salts.
• the present invention also provides a method for treatment of anxiety disorders in a mammal and/or human, in which a therapeutically active amount of a compound used according to the invention is administered.
• the present invention also provides a method for treatment of anxiety disorders or depressions, in which a compound used according to the invention is administered as an adjuvant to standard antidepressants, in order to inhibit the psychomotor states of excitation induced by the antidepressants at the start of therapy and the increased risk of suicide.
• standard antidepressants are understood as meaning all the approved antidepressants.
• the substances used are potent anxiolytics, antidepressants and analgesics, that is to say have an additional and clinically relevant anxiolytic action component.
• the compounds used according to the invention can moreover also be employed for the preparation of a pharmaceutical formulation for treatment of obsessive compulsive disorders, migraine, fibromyalgia, eating disorders, bulimia, hyperactivity, drug dependency, addiction and withdrawal, trichotillomania, Tourette's syndrome, skin diseases, in particular postherapeutic neuralgia and pruritus, psychoses, impaired memory, cognitive disorders and/or Alzheimer's disease.
• Suitable additives and/or auxiliary substances to the compounds used according to the invention in the process for the preparation of the pharmaceutical formulation are all the substances known to the expert from the prior art for achieving galenical formulations.
• the choice of these auxiliary substances and the amounts thereof to be employed depend on whether the pharmaceutical formulation is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or locally.
• Formulations in the form of tablets, chewable tablets, coated tablets, capsules, granules, drops, juices or syrups are suitable for oral administration, and solutions, suspensions, easily reconstitutable dry formulations and sprays are suitable for parenteral, topical and inhalatory administration.
• Suppositories for use in the rectum are a further possibility.
• the use in a depot in dissolved form, a carrier film or a patch, optionally with the addition of agents which promote penetration through the skin are examples of suitable forms for percutaneous administration.
• suitable forms for percutaneous administration are examples of auxiliary substances and additives for the oral administration forms.
• auxiliary substances and additives for the oral administration forms are disintegrating agents, lubricants, binders, fillers, mould release agents, optionally solvents, flavourings, sugars, in particular carrier agents, diluents, dyestuffs, antioxidants etc.
• waxes and fatty acid esters can be used, and for parenteral administration compositions carrier substances, preservatives, suspension auxiliaries etc. can be used.
• the amounts of active compound to be administered to patients vary as a function of the weight of the patient, the mode of administration and the severity of the disease.
• the compounds used according to the invention can be released in a delayed manner from formulation forms which can be used orally, rectally or percutaneously.
• Corresponding sustained-release formulations, in particular in the form of a “once daily” preparation which has to be taken only once a day, are particularly preferred for the indication according to the invention.
• compositions which comprise at least 0.05 to 90.0% of the active compound, in particular low active dosages, in order to avoid side effects or analgesic actions, are preferred.
• 0.1 to 5,000 mg/kg, in particular 1 to 500 mg/kg, preferably 2 to 250 mg/kg of body weight of a least one compound used according to the invention are conventionally administered.
• the administration of 0.01- 5 mg/kg, preferably 0.03 to 2 mg/kg, in particular 0.05 to 1 mg/kg is also preferred and conventional.
• Auxiliary substances can be, for example: water, ethanol, 2-propanol, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, sucrose, dextrose, molasses, starch, modified starch, gelatine, sorbitol, inositol, mannitol, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, cellulose acetate, shellac, cetyl alcohol, polyvinylpyrrolidone, paraffins, waxes, naturally occurring and synthetic gums, gum acacia, alginates, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glyceryl stearate, sodium lauryl sulfate, edible oils, sesame oil, coconut oil, groundnut oil, soya bean oil, lecithin, sodium lactate, polyoxyethylene
• compositions are prepared with the aid of means, devices, methods and processes which are well-known in the prior art of pharmaceutical formulation, such as are described, for example, in “Remington's Pharmaceutical Sciences”, ed. A. R. Gennaro, 17th ed., Mack Publishing Company, Easton, Pa. (1985), in particular in part 8, chapter 76 to 93.
• Homogeneous distribution is understood here as meaning that the active compound is uniformly distributed over the entire composition, so that this can easily be divided into unit dose forms, such as tablets, pills or capsules, having the same activity.
• the solid composition is then divided into unit dose forms.
• the tablets or pills of the pharmaceutical formulation according to the invention or of the compositions according to the invention can also be coated or compounded in another manner in order to provide a dose form with delayed release.
• Suitable coating compositions are, inter alia, polymeric acids and mixtures of polymeric acids with materials such as e.g. shellac, cetyl alcohol and/or cellulose acetate.
• the purification and enantiomer separation in all the processes mentioned as an example are carried out at the various stages by column chromatography or, predominantly, HPLC, where appropriate on chiral stationary phases.
• the residue was taken up in 192.5 ml ethylene glycol and 46 ml sodium hydroxide solution (5N) and the mixture was stirred at 110° C. for a total of 8 hours, it being topped up twice with 10 ml sodium hydroxide solution (5N) each time. After cooling, it was diluted with 100 ml distilled water and extracted three times with 50 ml methylene chloride each time. The extracts were washed with distilled water and a saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo and the residue was dried.
• the residue (5.03 g) was dissolved in 32.3 ml 2-butanone, 2.7 ml trimethylchlorosilane were added to the solution and the mixture was stirred for 15 minutes.
• Sulfuric acid mono-[3-(2-dimethylaminomethyl-cyclohexyl)-phenyl] ester or sulfuric acid mono-(1R,2R)-[3-(2-dimethylaminomethyl-cyclohexyl)-phenyl] ester was prepared as follows:
• 6-[3-(2-Dimethylaminomethyl-cyclohexyl)-phenoxy]-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid and 6-[(1R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenoxy]-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid were prepared as follows:
• Method 1 BuLi moreover means the synthesis, well-known to the expert, via bromine-lithium exchange with BuLi reagents and Method 2 Grignard means the synthesis, well-known to the expert, via Mg reagents.
• a mammal was injected with [2-(3-methoxyphenyl)-cyclohexylmethyl]-dimethylamine hydrochloride and in a further example (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol hydrochloride.
• Blood was taken from the mammal and, after separating off corpuscular constituents, was separated via HPLC and the metabolites in the fractions were identified via NMR and then isolated from the fractions.
• the receptor affinity for the human ⁇ -opiate receptor is determined in a homogeneous set-up in microtitre plates. For this, dilution series of the substances to be tested are incubated with a receptor membrane preparation (15-40 ⁇ g protein/250 ⁇ l incubation batch) of CHO-K1 cells which express the human ⁇ -opiate receptor (RB-HOM receptor membrane preparation from Perkin Elmer, Zaventem, Belgium) in the presence of 1 nmol/l of the radioactive ligand [ 3 H]-naloxone (NET719, Perkin Elmer, Zaventem, Belgium) and 1 mg WGA-SPA-Beads (wheat germ agglutinin SPA beads from Amersham/Pharmacia, Freiburg, Germany) in a total volume of 250 ⁇ l for 90 minutes at room temperature.
• a receptor membrane preparation 15-40 ⁇ g protein/250 ⁇ l incubation batch
• CHO-K1 cells which express the human ⁇ -opiate receptor (RB-HOM receptor membrane
• the incubation buffer 50 mmol/l Tris-HCl supplemented with 0.05% sodium azide and with 0.06% bovine serum albumin is used as the incubation buffer. 25 ⁇ mol/l naloxone are additionally added for determination of the non-specific binding. After the end of the ninety-minute incubation time, the microtitre plates are centrifuged for 20 minutes at 1,000 g and the radioactivity is measured in a ⁇ -counter (Microbeta-Trilux, PerkinElmer Wallac, Freiburg, Germany). The percentage displacement of t h e radioactive ligand from its binding to the human ⁇ -opiate receptor is determined at a concentration of the test substances of 1 ⁇ mol/l and stated as the percentage inhibition of the specific binding.
• synaptosomes are freshly isolated from areas of the rat brain.
• P 2 a so-called “P 2 ” fraction, which is prepared exactly in accordance with the instructions of Gray and Whittaker (1962), is used.
• NA NA reuptake
• 5-HT 5-HT reuptake from the medulla+pons region of male rat brains.
• IC 50 values are obtained by this means, and can be converted into inhibitor constants (K i ) in accordance with the “Cheng-Prusoff equation” (Cheng and Prusoff 1973).
• the IC 50 values were obtained with the aid of the computer program “ Figure P” (version 6.0, Biosoft, Cambridge, England). Km values were calculated in accordance with the method of Lineweaver and Burk (1934).
• the computer program “Ligand” version 4, Biosoft, England was used to display K D values.
• the apparatus was placed approx. 1 m above the floor and comprised four arms arranged in a cross, two opposite arms being open and two closed.
• the rats were placed individually in the central square compartment, from where access to all four arms was possible, and the behaviour of the animals was observed for 5 minutes. The duration of stay and the number of entries into the open arms were evaluated.
• the group size was 10-15 animals.
• the single administration of the test substances or of the control vehicle took place 30 min before testing.
• the typical disadvantages of monoamine reuptake inhibitors in the therapy of anxiety patients namely the delayed onset of action and the initially anxiogenic-like effects, can thus be followed in the elevated plus maze test on rats.
• the elevated plus maze test is therefore a suitable animal model for the investigation of new therapies which have the aim of accelerating the onset of action of monoamine reuptake inhibitors.
• Diazepam caused an increase in the duration of stay and the entries into the open arms.
• the mixed serotonin and noradrenaline reuptake inhibitor venlafaxine showed no anxiolytic action after a single administration.

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