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  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/06—Phosphorus compounds without P—C bonds
  • C07F9/08—Esters of oxyacids of phosphorus
  • C07F9/09—Esters of phosphoric acids
  • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/06—Phosphorus compounds without P—C bonds
  • C07F9/22—Amides of acids of phosphorus
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• • 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
  • A61P25/18—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
  • A61P25/30—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
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/32—Alcohol-abuse
• • 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
  • A61P25/36—Opioid-abuse
• • 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

• the present invention provides a novel ⁇ 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenoxy ⁇ phosphate or a pharmaceutically acceptable salt thereof, a preparation method thereof and an active ingredient thereof. It relates to a pharmaceutical composition for preventing and treating central nervous system diseases.
• neurotransmitters include cholinergic neurons that secrete acetylcholine by stimulation in the central and peripheral nervous systems, and adrenergic neurons that secrete noradrenaline.
• neurotransmitters that are important in the central nervous system, including dopamine and serotonin.
• GABA ⁇ -aminobutyl acid
• serotonin nervous system is closely related to mental disorders such as worry, anxiety and depression. It is known that the distribution of the receptor is significantly reduced in patients with schizophrenia and dementia.
• the brain's serotonin system is an important neurotransmitter that controls behaviors and physical functions, including anxiety and emotional anxiety, and is known to regulate various physiological and mental states.
• serotonin In the central nervous system, serotonin (5-HT) is associated with the etiology of many diseases, particularly depression, anxiety, schizophrenia, eating disorders, obsessive compulsive disorder. It is known to be an important cause of psychosis, such as migraine and panic disorder. Recent advances in pharmacy, molecular biology, and genetics of the serotonin nervous system have enabled the development of more advanced drug therapies for the treatment of certain central nervous system diseases. In fact, the general treatment for these diseases is currently believed to work by modulating the physiological activity of serotonergic substances.
• Venlafaxine metabolite O-key (venlafaxine) - desmethylvenlafaxine (O -desmethylvenlafaxine, hereinafter "ODV") blocks the reuptake of serotonin and norepinephrine [Klamerus, such as KJ, "Introduction of the Composite Parameter to the Pharmacokinetics of Venlafaxine and its Active O -Desmethyl Metabolite ", J. Clin. Pharmacol. 32: 716-724 (1992).
• the ODV is used for the treatment of central nervous system diseases, in particular depression, generalized anxiety disorders (see US 5,916,923; US 6,444,708; US 6,274,171; US 6,403,120; US 6,419,958; US 6,310,101).
• Venlafaxine hydrochloride tablets are sold under the trade name EFFEXOR.
• the ODV has the chemical name 1- [2- (dimethylamino) -1- (4-phenol) ethyl] cyclohexanol and is exemplified as fumarate salt in US Pat. No. 4,535,186.
• the fumarate salt of ODV has inadequate physicochemical and permeable properties.
• ODV is also illustrated as the free base in WO 00/32555.
• WO 02/064543 A2 discloses a formulation showing the use of hydroxypropyl methylcellulose (HPMC) as a hydrogel matrix.
• HPMC hydroxypropyl methylcellulose
• US 4,535,186 discloses ( R / S ) -1- [2- (dimethylamino) -1- (4-methoxyphenyl) ethyl] cyclohexanol and its metabolite 1- [2- (dimethylamino) -1- (4-hydroxyphenyl) ethyl] cyclohexanol and 1- [1- (4-methoxyphenyl) -2- (methylamino) ethyl] cyclohexanol are disclosed.
• US 5,530,013 discloses the use of venlafaxine in inducing cognitive enhancement.
• US 5,506,270 discloses the use of venlafaxine in a method of treating hypothalamic amenorrhea in women who are not depressed.
• the present inventors are studying to synthesize ODV derivatives having high solubility in water while maintaining the activity of ODV.
• the present invention was completed by synthesizing a phosphate compound of, having a high solubility in water, and showing an activity equal to or higher than that of a conventional ODV.
• Another object of the present invention is to provide a method for preparing the phosphate compound of 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenol.
• Another object of the present invention is a pharmaceutical composition for preventing and treating central nervous system diseases containing the phosphate compound of 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenol as an active ingredient. To provide.
• the present invention provides novel ⁇ 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenoxy ⁇ phosphate or a pharmaceutically acceptable salt thereof.
• the present invention reacts the compound of formula (2) with phosphorylation reagent in the presence of a reaction solvent and an amine to form ⁇ 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenoxy ⁇ phosphate. It provides a method for preparing ⁇ 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenoxy ⁇ phosphate.
• the present invention is a central nervous system disease containing the ⁇ 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenoxy ⁇ phosphate or a pharmaceutically acceptable salt thereof as an active ingredient.
• a prophylactic and therapeutic pharmaceutical composition is provided.
• novel ⁇ 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenoxy ⁇ phosphate (ODV phosphate) or pharmaceutically acceptable salts thereof according to the invention are known in the art. It exhibits the same activity as the biological and pharmaceutical activity of venlafaxine and its salts, and has very low toxicity, and in particular, solubility in water compared to conventional venlafaxine derivatives can be used to treat or alleviate central nervous system diseases in which ODV compounds are used. have. In addition, it can be usefully used in the induction of cognitive enhancement and prescription for smoking cessation or other tobacco use.
• the present invention provides novel ⁇ 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenoxy ⁇ phosphate (hereinafter referred to as ODV phosphate) represented by Formula 1 below, and its pharmaceutically acceptable Salts or isomers thereof.
• the compound of Formula 1 is a pharmaceutically active phosphate of 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenol which is a venlafaxine metabolite, and the molecular formula is C 16 H 26 NO 5 P It is a colorless solid with a molecular weight of 343.36.
• the present invention includes not only the compound of Formula 1 or a pharmaceutically acceptable salt thereof, but also all possible isomers, solvates, and hydrates that can be prepared therefrom.
• the compound of formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
• Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanediodes. Obtained from non-toxic organic acids such as acids, aromatic acids, aliphatic and aromatic sulfonic acids.
• Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide.
• the acid addition salts according to the invention are dissolved in conventional methods, for example, by dissolving a compound of formula 1 in an excess of aqueous acid solution and using the water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation.
• water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation.
• Equivalent amounts of the compound of formula 1 and the acid or alcohol in water may be heated and then the mixture is evaporated to dryness or prepared by suction filtration of the precipitated salt.
• Bases can also be used to make pharmaceutically acceptable metal salts.
• Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium salt, potassium salt or calcium salt as the metal salt.
• Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).
• the present invention also provides a process for producing novel ⁇ 4- [2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl] phenoxy ⁇ phosphate (hereinafter ODV phosphate).
• novel ODV phosphate according to the present invention can be prepared by reacting a compound of formula 2 with a phosphorylation reagent in the presence of a reaction solvent and an amine, as represented by Scheme 1 below.
• the starting material 1- [2- (diamino) -1- (4-hydroxyphenyl) ethyl] cyclohexanol racemic compound of Formula 2 was prepared by the method disclosed in Example 26 of US Patent No. 4,535,186. Can be.
• the enantiomers can be separated from one another by standard resolution techniques known in the art, and alternatively, the separated enantiomers of venlafaxine using boron tribromide or ethanethiol anion. Obtained by O- demethylation.
• the reaction solvent may be an inert solvent such as acetonitrile, tetrahydrofuran, dimethylformamide, but is not limited thereto.
• the amine may be triethylamine (TEA), diethylamine (DEA), diisopropylethylamine, cyclohexylamine, diisopropylamine, etc., but is not limited thereto. .
• the phosphorylation reagent may be phosphorus oxy chloride, halo phosphate diester and the like, but is not limited thereto, and may be used as a reagent capable of phosphorylating phenols.
• the reaction is preferably carried out at 0 ⁇ 5 °C bar, if out of the temperature range there is a problem that the reaction efficiency is lowered and side reactions occur.
• the present invention provides a composition for preventing and treating central nervous system diseases containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
• the present invention also provides a method of treating a central nervous system disease in a treatment subject comprising administering an effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof to the treatment subject.
• composition containing the compound of formula 1 according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient exhibits the same activity as the biological and pharmaceutical activities of venlafaxine and salts thereof known in the art, and is nontoxic and especially conventional Solubility in water is better than that of venlafaxine derivatives.
• Depression including major depressive disorders, bipolar disorder and case depression
• fibromyalgia anxiety, panic disorder, agoraphobia, post-traumatic stress disorder
• premenstrual dysphoric disorder premenstrual syndrome
• attention deficit disorder obsessive-compulsive personality disorder
• hair growth Social anxiety disorders, panic anxiety disorders, autism, schizophrenia, obesity, anorexia nervosa, bulimia nervosa, Gilles de la Tourette Syndrome, vasomotor flushing, cocaine and alcoholism, sexual dysfunction (including premature ejaculation)
• Borderline personality disorder chronic fatigue syndrome, urinary incontinence, pain (including migraine, chronic low back pain, ring pain, central pain, neuropathic pain such as diabetic neuropathy and postherpetic neuropathy), Raynaud's syndrome It can be used to treat or alleviate central nervous system diseases, including the like.
• it can be usefully used in the induction of cognitive enhancement and prescription for smoking cessation or other tobacco use.
• composition containing the compound of formula 1 according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient may be used in the form of a general pharmaceutical preparation.
• the compound of formula 1 according to the present invention can be administered in various formulations, oral and parenteral, in actual clinical administration.
• it when formulated, in addition to the active ingredient, it may be prepared by including one or more pharmaceutically acceptable carriers.
• Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, if necessary, as antioxidants, buffers And other conventional additives such as bacteriostatic agents can be added.
• Solid preparations for oral administration may include tablets, pills, powders, granules, capsules, and the like, which may comprise at least one excipient in the compound, for example starch, calcium carbonate, sucrose (Sucrose) or lactose (Lactose), gelatin, etc. are mixed and prepared.
• excipients for example starch, calcium carbonate, sucrose (Sucrose) or lactose (Lactose), gelatin, etc.
• lubricants such as magnesium styrate talc are also used.
• liquid preparations for oral administration include suspending agents, liquid solutions, emulsions, and syrups, and various excipients, for example, wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents, water and liquid paraffin. This may be included.
• Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilizers, suppositories.
• non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
• As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
• compositions of the present invention can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection or intramuscular injection.
• parenteral administration is by subcutaneous injection, intravenous injection or intramuscular injection.
• the compounds are mixed in water with stabilizers or buffers to prepare solutions or suspensions, which are formulated in unit dosage forms of ampoules or vials.
• the compound according to the invention is preferably included in 0.1 to 50% by weight relative to the total weight of the composition.
• the composition as described above is not necessarily limited thereto, and may vary according to the condition of the patient, the type of disease, and the degree of progression.
• Preferred dosages of the compounds according to the invention depend on the condition and body weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, but may be appropriately selected by those skilled in the art. However, for the desired effect, it is preferable to administer from 0.01 mg / kg to 10 g / kg, preferably from 1 mg / kg to 1 g / kg per day. Administration may be administered once a day or may be divided several times.
• ODV phosphate compounds prepared in the Examples were diluted in 100 ml of water to prepare ODV phosphate solutions at concentrations of 0.4, 0.5, and 0.6 mg / ml.
• the calibration curve was set by analyzing the ODV phosphate solution and the internal standard by HPLC to measure the peak area ratio of the ODV phosphate and the internal standard according to the ODV phosphate concentration.
• the calibration curve was set to the average value measured by repeating the HPLC analysis several times.
• HPLC analysis conditions are as shown in Table 1 and Table 2.
• the undissolved compound was filtered to prepare a saturated solution.
• Water was added to 1 ml of the saturated solution and diluted to 20 ml.
• the saturated solution was diluted so that the dilution factor was 800 times, and the solution and the internal standard were analyzed by HPLC to determine the peak area ratio of the ODV phosphate and the internal standard.
• the solubility was measured by substituting the measured value into the calibration curve, calculating the concentration when the dilution factor was 800 times, and multiplying the dilution factor.
• a conventionally used ODV succinate compound was used as a comparative example.
• the solubility was measured by the same method except that the concentrations were set at 0.1, 0.15 and 0.2 mg / ml when the calibration curve was set. The results are shown in Table 3. .
• the ODV phosphate compound according to the present invention had a solubility in water of 313.4 mg / ml, which was about 4 times higher than the conventional ODV compound (84,2 mg / ml).
• ICR mice SPF, producer: KOATEC
• ODV succinate H 2 O ODV succinate hydrate
• the acute toxicity of the compound was determined by measuring the number of mice that were dissolved in 100% distilled water at a dose and intraperitoneally injected (IP) or injected only with distilled water as a control and observed for 7 days. The results are shown in Table 4 below.
• ODV succinate hydrate had 2 mice died on day 1 when the dose was 350 mg / kg, and 8 mice on day 1 when 450 mg / kg. Although all died, the ODV phosphate compound according to the present invention was found to be absent for 7 days even when the dose is 450 mg / kg. Therefore, the ODV phosphate compound according to the present invention was found to be safe and very low toxicity.
• mice Male SD rats (SPF, produced by KOATEC) weighing 320 ⁇ 20 g, 9 weeks old, were used as experimental animals. Using three experimental animals, ODV phosphate compound prepared in Example was dissolved in a solvent [100% distilled water] and administered orally 120 mg / kg. After oral administration, blood was collected after 0.08, 0.25, 0.5, 1, 2, 3, 4, 6 and 8 hours, and the collected blood was centrifuged to separate plasma. The separated plasma was measured for drug concentration using LC / MS / MS. As a comparative example, ODV succinate hydrate was also tested in the same manner as above. The results are shown in Table 5 below.
• C max peak blood concentration
• T max peak blood concentration reaching time
• AUC 0-t area under the blood concentration-time curve up to measurement time
• AUC 0-inf area under the blood concentration-time curve
• t 1 / 2 half-life
• MRT inf of drug in vivo mean residence time of drug.
• the ODV phosphate compound according to the present invention exhibits excellent solubility in water, is very safe due to its low toxicity, and exhibits the same activity as the pharmaceutical activity of the conventional ODV compound, thereby preventing the use of ODV in place of the conventional ODV compound. It can be usefully used for treatment.
• the airtight cloth was filled to prepare a powder.
• tablets were prepared by tableting according to a conventional method for producing tablets.
• the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.
• the compound of formula 1 was dissolved in an appropriate volume of sodium chloride BP for injection, and the pH of the resulting solution was adjusted to pH 3.5 with dilute hydrochloric acid BP, and the volume was adjusted with sodium chloride BP for injection and thoroughly mixed.
• the solution was filled into a 5 ml Type I ampoule made of clear glass, encapsulated under an upper grid of air by dissolving the glass and sterilized by autoclaving at 120 ° C. for at least 15 minutes to prepare an injection solution.

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