US20170000767A1 - Therapeutic or prophylactic agent for multiple sclerosis - Google Patents

Therapeutic or prophylactic agent for multiple sclerosis Download PDF

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US20170000767A1
US20170000767A1 US15/114,874 US201515114874A US2017000767A1 US 20170000767 A1 US20170000767 A1 US 20170000767A1 US 201515114874 A US201515114874 A US 201515114874A US 2017000767 A1 US2017000767 A1 US 2017000767A1
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multiple sclerosis
therapeutic
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hydroxyl
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Kozue Takagaki
Mie Kaino
Hiroe Hirokawa
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Toray Industries Inc
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61P25/28—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

Definitions

  • This disclosure relates to a therapeutic or prophylactic agent for multiple sclerosis.
  • Multiple sclerosis is a disease that characteristically shows demyelination, in which myelin sheaths covering nerve fibers of the brain, spinal cord, optic nerves, and the like are destroyed. In this disease, progression of disorders occurs while recurrence and remission are repeated. It is known that the symptoms of this disease vary depending on the lesion area, and examples of the symptoms include various nervous symptoms such as visual impairment, quadriplegia, sensory disturbances, and gait disturbances (Aranami et al., Cell Technology, Vol. 30, No. 10, 2011, pp. 1060-1063).
  • adrenocortical hormones are used for acute-phase treatment
  • interferon ⁇ -1b and interferon ⁇ -1a are used for prevention of recurrence (Kira et al., “Multiple Sclerosis Treatment Guidelines 2010,” 2010, pp. 11-15).
  • Multiple sclerosis shows enhancement of the coagulation system, and it is known that the symptoms can be ameliorated with a thrombin inhibitor hirudin in a disease model for multiple sclerosis (Han et al., Nature, Vol. 451, 2008, pp. 1076-1081).
  • WO 2011/126903 reports a low molecular weight compound having thrombin inhibition activity.
  • WO '903 does not show usefulness of the compound against multiple sclerosis, and shows no specific data on its pharmacological effect.
  • cyclohexane derivatives represented by the following Formula are known to be effective as an analgesic and therapeutic agent for neurogenic pain (WO 2010/050577), therapeutic agent for fibromyalgia (WO 2011/125836), therapeutic agent for urine storage dysfunction (WO 2011/125838), therapeutic agent for Alzheimer's disease (WO 2011/136318), and therapeutic agent for neuropathic pain (WO 2012/015027):
  • A represents substituted or unsubstituted 1,5-diaryl-1H-pyrazol-3-yl, 4,5-diaryloxazol-2-yl, or the like;
  • R 4 represents a fluorine atom, hydroxyl, or the like.
  • R 5 and R 6 each independently represent a hydrogen atom, hydroxyl, carboxyl, or the like.
  • Interferon ⁇ -1b and interferon ⁇ -1a are used to prevent recurrence of multiple sclerosis. Since these are biological preparations, they are expensive. However, their therapeutic effect cannot necessarily be expected for all patients, and those preparations are known to be ineffective for some patients (Aranami et al., Cell Technology, Vol. 30, No. 10, 2011, pp. 1060-1063 and Kira et al., “Multiple Sclerosis Treatment Guidelines 2010,” 2010, pp. 11-15).
  • a cyclohexane derivative or a pharmaceutically acceptable salt thereof has an excellent therapeutic effect and prophylactic effect on multiple sclerosis.
  • a therapeutic or prophylactic agent for multiple sclerosis comprising, as an effective component, a cyclohexane derivative represented by Formula (I), or a pharmaceutically acceptable salt thereof:
  • A is a substituent represented by Formula (IIa) or (IIb):
  • R 1 and R 2 are each independently a hydrogen atom, chlorine atom, C 1 -C 3 haloalkyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or cyano;
  • R 3 is a hydrogen atom or chlorine atom;
  • R 4 is a fluorine atom, hydroxymethyl, or hydroxyl;
  • R 5 and R 6 are each independently a hydrogen atom, fluorine atom, C 1 -C 3 haloalkyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, C 1 -C 4 alkoxy, hydroxyl, or C 2 -C 5 alkylcarbonyloxy, or optionally together form oxo;
  • R 7 and R 8 are each independently a hydrogen atom or fluorine atom;
  • Y is an oxygen atom or sulfur atom; and
  • Z is a nitrogen atom or methine.
  • a therapeutic or prophylactic agent for multiple sclerosis comprising, as an effective component, a cyclohexane derivative represented by Formula (I), or a pharmaceutically acceptable salt thereof:
  • A is a substituent represented by General Formula (IIc) or (IId):
  • R 1 and R 2 are each independently a hydrogen atom, chlorine atom, C 1 -C 3 haloalkyl, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;
  • R 3 is a hydrogen atom or chlorine atom;
  • R 4 is a fluorine atom, hydroxymethyl, or hydroxyl;
  • R 5 and R 6 are each independently a hydrogen atom, fluorine atom, C 1 -C 3 haloalkyl, carboxyl, C 1 -C 4 alkoxy, hydroxyl, or C 2 -C 5 alkylcarbonyloxy, or optionally together form oxo;
  • Y is an oxygen atom or sulfur atom; and
  • Z is a nitrogen atom or methine.
  • R 1 and R 2 are each independently a hydrogen atom, chlorine atom, C 1 -C 3 haloalkyl, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;
  • R 5 and R 6 are each independently a hydrogen atom, fluorine atom, C 1 -C 3 haloalkyl, carboxyl, C 1 -C 4 alkoxy, hydroxyl, or C 2 -C 5 alkylcarbonyloxy, or optionally together form oxo; and each of R 7 and R 8 is a hydrogen atom.
  • R 1 and R 2 are each independently trifluoromethyl, methyl, or methoxy;
  • R 3 is a hydrogen atom;
  • R 4 is hydroxymethyl or hydroxyl;
  • R 5 and R 6 are each independently a hydrogen atom, fluorine atom, trifluoromethyl, carboxyl, methoxy, hydroxyl, or acetyloxy (or optionally together form oxo).
  • the therapeutic or prophylactic agent for multiple sclerosis enables remarkable suppression of exacerbation of symptoms of multiple sclerosis, and effective treatment or prevention of multiple sclerosis.
  • FIG. 1 is a diagram showing the inhibitory effect of 30 mg/kg Compound 3 against an increase in the neurological symptom score in a myelin oligodendrocyte glycoprotein-induced mouse experimental autoimmune encephalomyelitis model.
  • FIG. 2 is a diagram showing the inhibitory effect of 3 mg/kg and 10 mg/kg Compound 3 against an increase in the neurological symptom score in a myelin oligodendrocyte glycoprotein-induced mouse experimental autoimmune encephalomyelitis model.
  • FIG. 3 is a diagram showing the inhibitory effect of Compound 3 against an increase in the neurological symptom score in a proteolipid protein-induced mouse experimental autoimmune encephalomyelitis model.
  • FIG. 4 is a diagram showing the action of Compound 3 against the thrombin activity.
  • the therapeutic or prophylactic agent for multiple sclerosis comprises, as an effective component, a cyclohexane derivative represented by Formula (I), or a pharmaceutically acceptable salt thereof:
  • A is a substituent represented by the following General Formula (IIa) or (IIb):
  • R 1 and R 2 are each independently a hydrogen atom, chlorine atom, C 1 -C 3 haloalkyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or cyano;
  • R 3 is a hydrogen atom or chlorine atom;
  • R 4 is a fluorine atom, hydroxymethyl, or hydroxyl;
  • R 5 and R 6 are each independently a hydrogen atom, fluorine atom, C 1 -C 3 haloalkyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, C 1 -C 4 alkoxy, hydroxyl, or C 2 -C 5 alkylcarbonyloxy, or optionally together form oxo;
  • R 7 and R 8 are each independently a hydrogen atom or fluorine atom;
  • Y is an oxygen atom or sulfur atom; and
  • Z is a nitrogen atom or methine.
  • the therapeutic or prophylactic agent for multiple sclerosis also comprises, as an effective component, a cyclohexane derivative represented by Formula (I), or a pharmaceutically acceptable salt thereof:
  • A is a substituent represented by General Formula (IIc) or (IId):
  • R 1 and R 2 are each independently a hydrogen atom, chlorine atom, C 1 -C 3 haloalkyl, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;
  • R 3 is a hydrogen atom or chlorine atom;
  • R 4 is a fluorine atom, hydroxymethyl, or hydroxyl;
  • R 5 and R 6 are each independently a hydrogen atom, fluorine atom, C 1 -C 3 haloalkyl, carboxyl, C 1 -C 4 alkoxy, hydroxyl, or C 2 -C 5 alkylcarbonyloxy, or optionally together form oxo;
  • Y is an oxygen atom or sulfur atom; and
  • Z is a nitrogen atom or methine.
  • C 1 -C 4 alkyl means a linear, branched, or cyclic alkyl group having 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, sec-butyl, or tert-butyl.
  • C 1 -C 4 alkoxy means a linear, branched, or cyclic alkyl-oxy group having 1 to 4 carbon atoms, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, cyclopropyloxy, n-butoxy, sec-butoxy, or tert-butoxy.
  • the “C 1 -C 3 haloalkyl” means a linear alkyl group having 1 to 3 carbon atoms whose hydrogen atoms are partially or entirely substituted by a halogen atom(s) (the halogen atom means a fluorine atom, chlorine atom, bromine atom, or iodine atom).
  • the “C 1 -C 3 haloalkyl” include monochloromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, and pentafluoroethyl.
  • C 2 -C 5 alkylcarbonyloxy examples include acetyloxy, ethanoyloxy, propanoyloxy, isopropanoyloxy, butanoyloxy, isobutanoyloxy, and pivaloyloxy.
  • A is preferably Formula (IIa); Y is preferably an oxygen atom; and Z is preferably methine.
  • R 1 is preferably a hydrogen atom, chlorine atom, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propyloxy, or isopropyloxy; more preferably trifluoromethyl, methyl, or methoxy; still more preferably methyl.
  • R 2 is preferably a hydrogen atom, chlorine atom, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propyloxy, or isopropyloxy; more preferably methoxy.
  • R 3 is preferably a hydrogen atom.
  • R 4 is preferably hydroxymethyl or hydroxyl, more preferably hydroxyl.
  • R 5 is preferably a hydrogen atom, fluorine atom, trifluoromethyl, carboxyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, hydroxyl, acetyloxy, propanoyloxy, butanoyloxy, or isobutanoyloxy; more preferably a hydrogen atom, hydroxyl, or carboxyl; still more preferably hydroxyl.
  • R 6 is preferably a hydrogen atom, fluorine atom, trifluoromethyl, carboxyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, hydroxyl, acetyloxy, propanoyloxy, butanoyloxy, or isobutanoyloxy; more preferably a hydrogen atom or hydroxyl; still more preferably a hydrogen atom.
  • R 5 and R 6 may together form oxo.
  • each of R 7 and R 8 is preferably a hydrogen atom.
  • cyclohexane derivative (I) Preferred specific examples of cyclohexane derivatives represented by Formula (I) (hereinafter referred to as cyclohexane derivative (I)) are shown in Tables 1-1 to 1-4. It should be noted that these do not restrict this disclosure or its contents.
  • cyclohexane derivative (I) or the pharmaceutically acceptable salt thereof has an asymmetric carbon, all enantiomers and mixtures thereof are included in the cyclohexane derivative (I) or the pharmaceutically acceptable salt thereof.
  • Examples of the “pharmaceutically acceptable salt” include inorganic acid salts such as hydrochloric acid salt, sulfuric acid salt, phosphoric acid salt, and hydrobromic acid salt; organic acid salts such as oxalic acid salt, malonic acid salt, citric acid salt, fumaric acid salt, lactic acid salt, salt, malic acid salt, succinic acid salt, tartaric acid salt, acetic acid salt, trifluoroacetic acid salt, maleic acid salt, gluconic acid salt, benzoic acid salt, ascorbic acid salt, methanesulfonic acid salt, p-toluenesulfonic acid salt, and cinnamic acid salt; inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, and ammonium salt; and organic base salts such as methylamine salt, diethylamine salt, trimethylamine salt, triethylamine salt, pyridinium salt, triethanolamine salt, ethylenediamine salt, and guan
  • cyclohexane derivative (I) or the pharmaceutically acceptable salt thereof can be synthesized according to, for example, the method described in WO 2010/050577.
  • Effectiveness of the cyclohexane derivative (I) or the pharmaceutically acceptable salt thereof for treatment or prevention of multiple sclerosis can be evaluated using a disease model.
  • the disease model include experimental autoimmune encephalomyelitis models (Journal of Neuroscience Research, 2006, Vol. 84, pp. 1225-1234; International Immunology, 1997, Vol. 9, pp. 1243-1251).
  • Experimental autoimmune encephalomyelitis models are animal models prepared by immunizing laboratory animals with myelin oligodendrocyte glycoprotein (hereinafter referred to as MOG) or proteolipid protein (hereinafter referred to as PLP), or a partial peptide thereof, to induce neuropathy such as hind limb paralysis due to demyelination of the central nervous system. Because of similarity of symptoms and pathological findings in these animal models to those in humans, these models are widely used to study the pharmacological effects of therapeutic agents and prophylactic agents for multiple sclerosis. The effectiveness for treatment or prevention of multiple sclerosis can be evaluated with the above-described experimental autoimmune encephalomyelitis models using, for example, as an index, a decrease in the neurological symptom score, which is a characteristic index of multiple sclerosis.
  • MOG myelin oligodendrocyte glycoprotein
  • PLP proteolipid protein
  • the action of the cyclohexane derivative (I) or the pharmaceutically acceptable salt thereof on the thrombin activity can be evaluated using an in vitro test.
  • the in vitro test include a method in which the protease activity of thrombin is measured.
  • the method of evaluating the protease activity of thrombin include a method in which cleavage of a substrate by thrombin is measured utilizing fluorescence resonance energy transfer (FRET) (Advanced Functional Materials, Vol. 20, No. 18, 2010, pp. 3175-3182).
  • FRET fluorescence resonance energy transfer
  • the therapeutic or prophylactic agent for multiple sclerosis described above may be used as an excellent pharmaceutical product which is useful for treatment and prevention of multiple sclerosis in mammals (for example, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, or human).
  • mammals for example, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, or human.
  • the cyclohexane derivative (I) or the pharmaceutically acceptable salt thereof may be orally or parenterally administered as it is, or as a mixture with a pharmaceutically acceptable carrier.
  • examples of its dosage form include tablets (including sugar-coated tablets and film-coated tablets), balls, granules, powders, capsules (including soft capsules and microcapsules), syrups, emulsions, and suspensions.
  • examples of the dosage form include injection solutions, infusions, drops, and suppositories.
  • the cyclohexane derivative (I) or the pharmaceutically acceptable salt thereof may also be effectively used in combination with an appropriate base (for example, butyric acid polymer, glycolic acid polymer, butyric acid/glycolic acid copolymer, mixture of butyric acid polymer and glycolic acid polymer, or polyglycerol fatty acid ester) to provide a sustained-release formulation.
  • an appropriate base for example, butyric acid polymer, glycolic acid polymer, butyric acid/glycolic acid copolymer, mixture of butyric acid polymer and glycolic acid polymer, or polyglycerol fatty acid ester
  • the formulation in the above-described dosage form containing the cyclohexane derivative (I) or the pharmaceutically acceptable salt thereof may be prepared according to a known production method commonly used in the field of pharmaceutical preparations.
  • the formulation may be prepared by including, if necessary, one or more of diluents, binders, lubricants, disintegrators, sweeteners, surfactants, suspending agents, emulsifiers, and the like that are commonly used in the field of pharmaceutical preparations.
  • one or more of diluents, binders, disintegrators, lubricants and the like may be included.
  • diluents, binders, disintegrators, lubricants and the like may be included in the preparation of balls and granules.
  • one or more of diluents, binders, disintegrators and the like may be included in the preparation of powders and capsules.
  • one or more of diluents and the like may be included.
  • sweeteners and the like may be included.
  • emulsions or suspensions one or more of surfactants, suspending agents, emulsifiers and the like may be included.
  • diluents examples include lactose, glucose, starch, sucrose, microcrystalline cellulose, powdered glycyrrhiza, mannitol, sodium hydrogen carbonate, calcium phosphate, and calcium sulfate.
  • binders examples include starch paste liquids, gum arabic liquids, gelatin liquids, tragacanth liquids, carboxymethylcellulose liquids, sodium alginate liquids, and glycerin.
  • disintegrators examples include starch and calcium carbonate.
  • lubricants examples include magnesium stearate, stearic acid, calcium stearate, and purified talc.
  • sweeteners examples include glucose, fructose, invert sugar, sorbitol, xylitol, glycerol, and simple syrup.
  • surfactants examples include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid esters, and polyoxyl 40 stearate.
  • suspending agents examples include gum arabic, sodium alginate, sodium carboxymethylcellulose, methyl cellulose, and bentonite.
  • emulsifiers examples include gum arabic, tragacanth, gelatin, and polysorbate 80.
  • one or more of coloring agents, preservatives, aromatics, correctives, stabilizers, thickeners, and the like, which are commonly used in the field of formulations, may be added thereto.
  • the daily dose of the formulation varies depending on the conditions and the body weight of the patient, the type of the compound, the administration route, and the like.
  • the formulation in oral administration to an adult (with a body weight of about 60 kg), the formulation is preferably administered at a daily dose 1 mg to 1000 mg, at one time or dividedly in two or three times.
  • parenteral administration using an injection solution the formulation is preferably administered by intravenous injection at a daily dose of 0.01 to 100 mg/kg body weight.
  • the therapeutic or prophylactic agent for multiple sclerosis described above may also be used in combination with one or more other therapeutic or prophylactic agents for multiple sclerosis, or with one or more therapeutic or prophylactic agents for a symptom(s) such as convulsion or spasm in patients with multiple sclerosis.
  • Examples of the other therapeutic or prophylactic agents for multiple sclerosis include adrenocortical steroids (such as prednisolone and methylprednisolone), immunosuppresssants (such as fingolimod, methotrexate, azathioprine, cyclophosphamide, cyclosporin A, tacrolimus, mizoribine, and leflunomide), interferon preparations (such as interferon ⁇ , interferon ⁇ -1b, and interferon ⁇ -1a), copolymer I, immunoglobulin, mitoxantrone, glatiramer acetate, T cell receptor vaccines, adhesion molecule inhibitors, analgesics (such as indomethacin and diclofenac), and muscle relaxants (such as tizanidine, eperisone, afloqualone, baclofen, diazepam, and dantrolene sodium).
  • Examples of the therapeutic or prophylactic agents for a symptom(s) such as convulsion or spasm in patients with multiple sclerosis include anticonvulsants (such as carbamazepine, phenytoin, clonazepam, and amitriptyline).
  • anticonvulsants such as carbamazepine, phenytoin, clonazepam, and amitriptyline.
  • the action of the cyclohexane derivative (I) or the pharmaceutically acceptable salt thereof against an increase in the neurological symptom score in a MOG-induced mouse experimental autoimmune encephalomyelitis model was evaluated.
  • the mouse experimental autoimmune encephalomyelitis model was prepared according to the method described in Journal of Neuroscience Research, 2006, Vol. 84, pp. 1225-1234 with partial modification.
  • a MOG 35-55 administration solution which was prepared by mixing equal volumes of a PBS solution containing a partially synthesized peptide of MOG (MOG 35-55; CS Bio Company Inc.) whose concentration was adjusted to 4 mg/mL and Freund's complete adjuvant, was intracutaneously inoculated to both lateral regions of each C57BL/6J mouse (male, 7-weeks old) (Charles River Laboratories Japan) in a total amount of 0.1 mL (0.05 mL per side). Further, on the day of inoculation of the MOG 35-55 administration solution, and two days thereafter, 200 ⁇ L of pertussis toxin (Sigma) whose concentration was adjusted to 1 ⁇ g/mL was intraperitoneally administered to each mouse.
  • Compound 3 1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexane-cis-1,4-diol (hereinafter referred to as Compound 3), which is represented by the following chemical formula, was used.
  • Compound 3 was synthesized according to the method described in WO 2010/050577.
  • Comparative Control Compound 1 which is represented by Comparative Chemical Formula 1
  • Comparative Control Compound 2 which is represented by the following chemical formula, was synthesized based on the synthesis method of Comparative Example 2 described in WO 2010/050577.
  • Compound 3 was orally administered to mice twice daily at a dose of 30 mg/kg for 16 successive days.
  • Compound 3 was used as a suspension in 0.5% methylcellulose solution.
  • the group in which Compound 3 was administered to mice was provided as the Compound 3 administration group.
  • 0.5% methylcellulose solution was administered in the same manner.
  • the neurological symptom score was scored (0: normal, 1: limp tail or hind limb weakness, 2: limp tail and hind limb weakness, 3: partial hind limb paralysis, 4: complete hind limb paralysis, 5: moribund state). Scoring was carried out using the method described in Current Protocols in Immunology (John Wiley & Sons, Inc., 2000, pp. 15.1.1-15.1.20).
  • FIG. 1 The results are shown in FIG. 1 .
  • “Vehicle” indicates the group in which 0.5% methylcellulose solution was orally administered to the mice to which the MOG 35-55 administration solution was inoculated (vehicle administration group)
  • “Compound 3” indicates the group in which Compound 3 was orally administered twice daily at a dose of 30 mg/kg to the mice to which the MOG 35-55 administration solution was inoculated (Compound 3 administration group).
  • the inoculation of the MOG 35-55 administration solution caused an increase in the neurological symptom score to 2.8.
  • the increase in the neurological symptom score was remarkably suppressed.
  • the rate of suppression of exacerbation of neurological symptoms by Compound 3 was 85.7%.
  • Comparative Control Compound 1 and Comparative Control Compound 2 were similarly evaluated. That is, from three days before inoculation of the MOG 35-55 administration solution, Comparative Control Compound 1 or Comparative Control Compound 2 suspended in 0.5% methylcellulose solution was orally administered to mice twice daily at a dose of 30 mg/kg for 16 successive days. Thirteen days after inoculation of the MOG 35-55 administration solution, the neurological symptom score was scored. The rates of suppression of exacerbation of neurological symptoms by Comparative Control Compound 1 and Comparative Control Compound 2 were 3.3% and 6.5%, respectively.
  • a MOG 35-55 administration solution which was prepared by mixing equal volumes of a PBS solution containing a partially synthesized peptide of MOG (MOG 35-55; CS Bio Company Inc.) whose concentration was adjusted to 4 mg/mL and Freund's complete adjuvant, was intracutaneously inoculated to both lateral regions of each C57BL/6J mouse (male, 10-weeks old) (Charles River Laboratories Japan) in a total amount of 0.1 mL (0.05 mL per side). Further, on the day of inoculation of the MOG 35-55 administration solution, and two days thereafter, 200 ⁇ L of pertussis toxin (Sigma) whose concentration was adjusted to 1 ⁇ g/mL was intraperitoneally administered to each mouse. As a test compound, Compound 3 was used.
  • Compound 3 was orally administered to mice twice daily at a dose of 3 mg/kg and 10 mg/kg for 12 successive days.
  • Compound 3 was used as a suspension in 0.5% methylcellulose solution.
  • the group in which Compound 3 was administered to mice was provided as the Compound 3 administration group.
  • 0.5% methylcellulose solution was administered in the same manner.
  • the neurological symptom score was scored (0: normal, 1: limp tail or hind limb weakness, 2: limp tail and hind limb weakness, 3: partial hind limb paralysis, 4: complete hind limb paralysis, 5: moribund state). Scoring was carried out using the method described in Current Protocols in Immunology (John Wiley & Sons, Inc., 2000, pp. 15.1.1-15.1.20).
  • FIG. 2 The results are shown in FIG. 2 .
  • “Vehicle” indicates the group in which 0.5% methylcellulose solution was orally administered to the mice to which the MOG 35-55 administration solution was inoculated (vehicle administration group)
  • “Compound 3” indicates the group in which Compound 3 was orally administered twice daily at a dose of 3 mg/kg and 10 mg/kg to the mice to which the MOG 35-55 administration solution was inoculated (Compound 3 administration group).
  • the mouse experimental autoimmune encephalomyelitis model was prepared according to the method described in International Immunology, 1997, Vol. 9, pp. 1243-1251 with partial modification.
  • a PLP 139-151 administration solution which was prepared by mixing equal volumes of a PBS solution containing a partially synthesized peptide of PLP (PLP 139-151; Kokusan Chemical Co., Ltd.) whose concentration was adjusted to 2 mg/mL and Freund's complete adjuvant, was intracutaneously inoculated to both lateral regions of each SJL mouse (female, 6-weeks old) (Charles River Laboratories Japan) in a total amount of 0.1 mL (0.05 mL per side).
  • Compound 3 was orally administered to mice twice daily at a dose of 10 mg/kg for 7 successive days.
  • Compound 3 was used as a suspension in 0.5% methylcellulose solution.
  • the group in which Compound 3 was administered to mice was provided as the Compound 3 administration group.
  • 0.5% methylcellulose solution was administered in the same manner.
  • the neurological symptom score was scored (0: normal, 1: limp tail or hind limb weakness, 2: limp tail and hind limb weakness, 3: partial hind limb paralysis, 4: complete hind limb paralysis, 5: moribund state). Scoring was carried out using the method described in Current Protocols in Immunology (John Wiley & Sons, Inc., 2000, pp. 15.1.1-15.1.20).
  • FIG. 3 The results are shown in FIG. 3 .
  • “Vehicle” indicates the group in which 0.5% methylcellulose solution was orally administered to the mice to which the PLP 139-151 administration solution was inoculated (vehicle administration group)
  • “Compound 3” indicates the group in which Compound 3 was orally administered twice daily at a dose of 10 mg/kg to the mice to which the PLP 139-151 administration solution was inoculated (Compound 3 administration group).
  • the action of the cyclohexane derivative (I) or the pharmaceutically acceptable salt thereof on the thrombin activity was evaluated using a SensoLyte (registered trademark) 520 thrombin activity assay kit manufactured by Anaspec Inc., which utilizes fluorescence resonance energy transfer (FRET).
  • SensoLyte registered trademark
  • FRET fluorescence resonance energy transfer
  • test compound was dissolved in dimethylsulfoxide (hereinafter referred to as DMSO), and diluted with the assay buffer included in the kit to a final DMSO concentration of 0.5 to 1%.
  • DMSO dimethylsulfoxide
  • the test compound final concentration, 0.1 nmol/L to 30 ⁇ mol/L
  • thrombin diluted with the assay buffer (final concentration, 300 ng/mL) were added, and the plate was then incubated at room temperature for 10 minutes.
  • 5-FAM/QXL 520 thrombin substrate diluted with the assay buffer (final concentration, 300 nmol/L) was added, and the resulting mixtures were incubated at room temperature for 2 hours. Thereafter, the fluorescence value was measured by excitation at 485 nm and detection at 520 nm.
  • test compound Compound 3, which is included in the cyclohexane derivative (I) or the pharmaceutically acceptable salt thereof, was used.
  • Argatroban which is a selective thrombin inhibitor, was used.
  • the thrombin activity inhibition rate (%) was calculated according to Equation 1, and regression analysis was carried out to obtain a sigmoid curve (variable slope), thereby calculating the IC50 value of the thrombin activity inhibition by the test compound:
  • the results are shown in FIG. 4 .
  • the abscissa represents the test compound concentration (nmol/L).
  • the cyclohexane derivative (I) or the pharmaceutically acceptable salt thereof remarkably suppresses exacerbation of symptoms of multiple sclerosis, it can be used as a therapeutic or prophylactic agent for multiple sclerosis.

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