US20150353519A1 - Therapeutic agent for disease based on inhibitory effect of macrophage migration inhibitory factor - Google Patents

Therapeutic agent for disease based on inhibitory effect of macrophage migration inhibitory factor Download PDF

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US20150353519A1
US20150353519A1 US14/647,931 US201414647931A US2015353519A1 US 20150353519 A1 US20150353519 A1 US 20150353519A1 US 201414647931 A US201414647931 A US 201414647931A US 2015353519 A1 US2015353519 A1 US 2015353519A1
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benzopyran
mif
amino
oxo
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Keiichi Tanaka
Kimiko Morimoto
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Toyama Chemical Co Ltd
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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
    • A61K31/335—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
    • A61K31/352—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 condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones

Definitions

  • the present invention relates to a method of using a benzopyran derivative having macrophage migration inhibitory factor (hereinafter referred to as MIF) inhibitory activity or a salt thereof for a therapeutic or preventive treatment of a nervous system disease such as neuropathic pain or multiple sclerosis. Furthermore, it relates to a pharmaceutical composition containing a benzopyran derivative or a salt thereof useful for a therapeutic or preventive treatment of a nervous system disease.
  • MIF macrophage migration inhibitory factor
  • NP Neuropathic pain
  • QOL quality of life
  • NP narcotic analgesic
  • NP is induced by a damage of peripheral and/or central nerve.
  • NP is treated for purposes of relieving the pain, increasing the functional capacity of the patient, and improving his/her activity.
  • administration of an antidepressant, a narcotic analgesic or the like, a nerve block treatment, and an acupuncture and moxibustion treatment are performed.
  • any excellent therapeutic method based on the developing mechanism of NP has not been known, and an excellent therapeutic method for NP is desired.
  • MS Multiple sclerosis
  • a central nerve system such as a brain or a spinal cord
  • various neurological symptoms such as visual disturbance, dyskinesia, hypesthesia, dysesthesia, pain, dysequilibrium, shivering, dysuria, sexual dysfunction, fatigue, and emotional disorder.
  • MS is divided, depending on the progressive mode of a patient's condition, into a “relapsing-remitting type” wherein relapse and remission are repeated, and a “chronic progressive type” that the symptom is gradually worsened.
  • the chronic progressive type is further divided into a “secondary progressive type” that the relapsing-remitting MS subsequently shows chronic progression, and a “primary progressive type” that obvious relapse does not occur but the symptom is gradually worsened from the initial stage of the onset.
  • a therapeutic method for MS is divided into three categories, that is, inhibition of inflammation in an acute period, inhibition of relapse or progression, and relief of the symptoms.
  • glucocorticoid a steroid anti-inflammatory drug
  • MS is a disease difficult to completely recover because relapse and remission repeatedly occur.
  • Various immunological treatments based on the pathogenetic mechanism of MS have been studied (Non Patent Document 2), and it is presumed that interferon ⁇ and immunosuppressive agents are effective. However, a sufficiently effective and safe therapeutic method has not been established. In particular, an excellent therapeutic method for MS at the time of relapse is desired.
  • MIF is a cytokine secreted from activated lymphocytes and having various biological activities. It is known to exhibit activities for, for example, an immune system, an endocrine system, and proliferation and differentiation of cells. Particularly, MIF plays a significant role in systemic inflammation and immune response, and is a factor pertaining also to a delayed hypersensitivity reaction for inhibiting random migration of macrophages. Besides, MIF has dopachrome tautomerase activity (Non Patent Document 3).
  • MIF is known to have homology to glutathione S-transferase, to show detoxification, to be secreted from adenohypophysis at the time of endotoxic shock, to be induced by a low level of glucocorticoid, and to oppose its immunosuppressive effect (Non Patent Document 4).
  • MIF inhibits the activity of glucocorticoid, antagonizes the anti-inflammatory effect of endogenous or therapeutically administered glucocorticoid, and works also as a cause or an aggravating factor of an inflammatory disease and an inflammatory state.
  • MIF is indispensable for activation of T cells, is expressed in various cells, and is strongly expressed particularly in the nerve system.
  • an MIF inhibitor relieves an allodynia symptom of an animal model for NP.
  • a mouse model showing a stimulus sensitivity reaction aggravated by stress can be produced by injecting recombinant MIF to a normal mouse (Non Patent Document 5).
  • MIF is highly expressed in the ipsilateral dorsal horn of spinal cord, and signaling molecules on the downstream side from MIF are activated (Non Patent Document 6).
  • MIF knockout mouse the allodynia induced by sciatic nerve ligation is eliminated (Non Patent Documents 5 and 6). Accordingly, MIF is presumed to be indispensable for expression of the symptoms of NP.
  • EAE that is, the animal model for MS, includes a model for reproducing primary onset of an acute period (monophasic) and a model for reproducing chronic relapsing/remitting condition, and in general, rats are used for the former and mice are used for the latter to construct the model.
  • Non Patent Document 9 It is reported, for example, that cyclophosphamide of an immunosuppressive agent inhibits the onset of acute EAE in rats but is ineffective for relapsing type or chronic progressive type of EAE in mice (Non Patent Document 9).
  • Non Patent Documents 10 and 11 a rat or mouse anti- ⁇ 4 integrin antibody equivalent to an MS therapeutic agent, natalizumab, delayed the onset and reduced the severity of the disease with respect to the acute EAE in rats, and inhibited the EAE onset in mice by administration for preventing EAE, but the symptoms were aggravated by therapeutic administration.
  • a benzopyran derivative exhibits an antiarthritic effect (Patent Document 1), an inhibitory effect for production of inflammatory cytokines, such as interleukin- ⁇ and interleukin-6, and an immunomodulatory effect (Non Patent Documents 12, 13 and 14), and is known to be useful for a treatment of rheumatoid arthritis and other arthritis, and autoimmune diseases (Patent Document 2). Besides, it is known to be effective for the acute EAE in rats (Non Patent Document 15).
  • Patent Document 1 JP 02-049778 A
  • Patent Document 2 Pamphlet of International Publication No. WO 94/23714
  • Non Patent Document 1 Lancet, 1999, vol. 353, pp. 1959-1964
  • Non Patent Document 2 N. Engl. J. Med., 2000, vol. 343, pp. 938-952
  • Non Patent Document 3 Nat. Rev. Drug Discov., 2006, vol. 5, pp. 399-410
  • Non Patent Document 4 Molecular Medicine, 1996, vol. 2, pp. 143-149
  • Non Patent Document 5 Exp. Neurol., 2012, vol. 236, pp. 351-362
  • Non Patent Document 6 Anesthesiology, 2011, vol. 114, pp. 643-659
  • Non Patent Document 7 J. Neurol. Sci., 2000, vol. 179, pp. 127-131
  • Non Patent Document 8 J. Immunol., 2005, vol. 175, pp. 5611-5614
  • Non Patent Document 9 Clin. Exp. Immunol., 2009, vol. 159, pp.159-168
  • Non Patent Document 10 J. Pharmacol. Exp. Ther., 2003, vol. 305, pp. 1150-62
  • Non Patent Document 11 J. Clin. Invest., 2001, vol. 107, pp. 995-1006
  • Non Patent Document 12 Chem. Pharm. Bull., 2000, vol. 48, pp. 131-139
  • Non Patent Document 13 J. Pharamcobiodyn., 1992, vol. 15, pp. 649-655
  • Non Patent Document 14 Int. J. Immunotherapy, 1993, vol. 9, pp. 69-78
  • Non Patent Document 15 J. Neuroimmunol., 1998, vol. 89, pp. 35-42
  • a medical product useful for a therapeutic or preventive treatment of diseases such as NP and MS is desired, and a pharmaceutical composition for inhibiting MIF, that is, a factor significant as the cause of these diseases, is desired.
  • compositions useful for a therapeutic or preventive treatment of NP, relapsing MS and the like is desired.
  • a benzopyran derivative represented by the following general formula [1] or a salt thereof binds to MIF, exhibits an MIF inhibitory effect, and hence is useful for a therapeutic or preventive treatment of a disease for which the inhibition of MIF is effective, resulting in accomplishing the present invention:
  • R 1 represents an optionally substituted C 1 - 6 alkyl group
  • one of R 2 and R 3 represents a hydrogen atom
  • the other of R 2 and R 3 represents a hydrogen atom, an optionally substituted amino group, an optionally substituted acylamino group, an optionally substituted carbamoyl group or an optionally substituted aryl group.
  • a benzopyran derivative represented by general formula [1] or a salt thereof exhibits an MIF inhibitory effect and is useful for a therapeutic or preventive treatment of diseases for which the inhibition of MIF is effective, such as NP and the relapsing-remitting and secondary progressive MS at the time of relapse.
  • a halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • a C 1-6 alkyl group means a linear or branched C 1-6 alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group and a hexyl group.
  • a C 1-6 alkoxy group means a linear or branched C 1-6 alkyloxy group such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group and a hexyloxy group.
  • a C 2-12 alkanoyl group means a linear or branched C 2-12 alkanoyl group such as an acetyl group, a propionyl group, a valeryl group, an isovaleryl group and a pivaloyl group.
  • An aroyl group means a benzoyl group or a naphthoyl group.
  • a heterocyclic carbonyl group means a nicotinoyl group, a tenoyl group, a pyrrolizinocarbonyl group or a furoyl group.
  • An ( ⁇ -substituted) aminoacetyl group means an ( ⁇ -substituted) aminoacetyl group which is derived from an amino acid (such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine, tyrosine, tryptophan, proline and hydroxyproline) and which may have a protected N-terminal.
  • an amino acid such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine,
  • An acyl group means a formyl group, a succinyl group, a glutaryl group, a maleoyl group, a phthaloyl group, a C 2-12 alkanoyl group, an aroyl group, a heterocyclic carbonyl group or an ( ⁇ -substituted) aminoacetyl group.
  • An acylamino group means an amino group substituted with an acyl group.
  • An aryl group means a phenyl group, a naphthyl group, an indanyl group, an indenyl group, a tetrahydronaphthyl group or the like.
  • the C 1-6 alkyl group of R 1 may be substituted with one or more halogen atoms.
  • the amino group or the carbamoyl group of R 2 and R 3 may be substituted with one or more C 1-6 alkyl groups.
  • the acylamino group of R 2 and R 3 may be substituted with one or more halogen atoms.
  • the aryl group of R 2 and R 3 may be substituted with one or more groups selected from a halogen atom, an amino group, a hydroxyl group, a C 1-6 alkyl group which may be substituted with one or more halogen atoms, and a C 1-6 alkoxy group which may be substituted with one or more halogen atoms.
  • benzopyran derivative represented by general formula [1] of the present invention include compounds described below.
  • R 1 is an optionally substituted C 1-6 alkyl group; one of R 2 and R 3 is a hydrogen atom; and the other of R 2 and R 3 is an optionally substituted acylamino group is preferred.
  • the benzopyran derivative of general formula [1] used in the present invention is produced by combining the publicly acknowledged methods, and can be produced by, for example, a method described in Patent Document 1.
  • Examples of the salt of the benzopyran derivative of general formula [1] include a salt with an alkali metal such as sodium or potassium; a salt with an alkali earth metal such as calcium and magnesium; an ammonium salt; and a salt with a nitrogen-containing organic base such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-efenamine and N,N′-dibenzylethylenediamine.
  • an alkali metal such as sodium or potassium
  • a salt with an alkali earth metal such as calcium and magnesium
  • an ammonium salt and a salt with a nitrogen-containing organic base
  • a nitrogen-containing organic base such as trimethylamine, triethylamine, tributylamine,
  • MIF has high homology to a bacterial tautomerase, and catalyzes a dopachrome tautomerase reaction (Molecular Medicine, 1996, vol. 2, pp. 143-149). Therefore, the biological activity of MIF can be evaluated by using a tautomerase reaction with a dopachrome as a substrate.
  • the benzopyran derivative of general formula [1] or the salt thereof of the present invention has an effect to inhibit the MIF tautomerase activity (namely, an MIF inhibitory effect), and a drug containing the benzopyran derivative of general formula [1] or the salt thereof is useful for a therapeutic or preventive treatment of diseases for which the MIF inhibition is effective.
  • Examples of the disease for which the MIF inhibition is effective include NP and the relapsing-remitting and secondary progressive MS at the time of relapse, and preferably include NP.
  • NP examples include fibromyalgia, postherpetic pain, diabetic neuropathy, post-spinal cord injury pain, postapoplectic pain, chronic pain, complex regional pain syndrome, backache for which NSAIDs are insufficiently effective, sciatica, pelvic pain, trigeminal neuralgia, osteoarthritis pain for which NSAIDs are insufficiently effective, deafferentation pain syndrome, pain due to myositis, pain due to fasciitis, and pain due to seronegative arthritis.
  • deafferentation pain syndrome include thalamic pain, pain due to MS, pain after avulsion injury, phantom limb pain, and postoperative pain syndrome.
  • the pain due to seronegative arthritis include pain due to axial joint disorder, pain due to ankylosing spondylitis, pain due to sacroiliac joint disorder, and pain due to seronegative spondylitis.
  • Preferable examples include fibromyalgia, postherpetic pain, diabetic neuropathy, backache for which NSAIDs are insufficiently effective, osteoarthritis pain for which NSAIDs are insufficiently effective, pain due to myositis, pain due to fasciitis, and pain due to seronegative arthritis, and more preferable examples include postherpetic pain, diabetic neuropathy, backache for which NSAIDs are insufficiently effective, osteoarthritis pain for which NSAIDs are insufficiently effective, pain due to myositis, pain due to fasciitis, and pain due to seronegative arthritis.
  • the relapsing-remitting MS has a characteristic that it is ameliorated over several weeks or several months after a neurological symptom having acutely appeared reaches the fastigium, and then it relapses to reproduce or aggravate the neurological symptom. A remission period follows the relapse. A relapse occurred every several months or years and a slow or gradual remission are repeated.
  • the secondary progressive MS has a characteristic that a remission state of a patient having initially developed the relapsing-remitting MS is gradually aggravated while the relapse and the remission are repeated.
  • Examples of the symptoms of the relapsing-remitting MS and secondary progressive MS at the time of relapse include reduced vision, motor paralysis, sensory disturbance, multiple vision, dysuria and dysarthria.
  • the compound of the present invention can be formed into pharmaceutical formulations such as an oral preparation (including a tablet, a capsule, a powder, a granule, a fine granule, a pill, a suspension, an emulsion, a liquid and a syrup), an injection and an eye drop by mixing with various pharmaceutical additives such as an excipient, a binder, a disintegrant, a disintegration inhibitor, an anti-caking agent, a lubricant, a carrier, a solvent, an expander, a tonicity adjusting agent, a solubilizing agent, an emulsifier, a suspending agent, a thickener, a coating agent, an absorption enhancer, a gelling enhancer, a coagulation accelerator, a light stabilizer, a preservative, a desiccating agent, an emulsion stabilizer, a suspension stabilizer, a dispersion stabilizer, a coloring inhibitor, an oxygen absorber, an antioxidant, a taste masking
  • An oral solid formulation such as a tablet, a powder and a granule may be formulated by a usual method using a pharmaceutical additive of, for example, an excipient such as lactose, saccharose, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, anhydrous dibasic calcium phosphate, partly pregelatinized starch, corn starch and alginic acid; a binder such as a simple syrup, a glucose solution, a starch solution, a gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinyl pyrrolidone, carboxymethyl cellulose, shellac, methyl cellulose, ethyl cellulose, sodium alginate, acacia, hydroxypropyl methyl cellulose and hydroxypropyl cellulose; a disintegrant such as dry starch, alginic acid, powdered agar, starch, cross-linked polyvinyl pyrrolidone, cross-linked carboxy
  • the tablet may be formed, if necessary, into a general coated tablet, such as a sugar coated tablet, a gelatin coated tablet, a gastric soluble coated tablet, an enteric coated tablet and a water-soluble film coated tablet.
  • a general coated tablet such as a sugar coated tablet, a gelatin coated tablet, a gastric soluble coated tablet, an enteric coated tablet and a water-soluble film coated tablet.
  • the capsule is prepared by filling a hard gelatin capsule, a soft capsule and the like with any of the aforementioned various pharmaceutical additives.
  • a pharmaceutical additive such as a solvent, an expander, a tonicity adjusting agent, a solubilizing agent, an emulsifier, a suspending agent and a thickener may be used for preparation by a usual method to obtain an aqueous or oil suspension, a solution, a syrup and an elixir.
  • the injection may be prepared by a usual method using a pharmaceutical additive of, for example, a diluent such as water, ethyl alcohol, macrogol, propylene glycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid and sodium hydroxide; a pH buffer and a pH adjuster such as sodium citrate, sodium acetate and sodium phosphate; an emulsion stabilizer, a suspension stabilizer and a dispersion stabilizer such as sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid and thiolactic acid; a tonicity adjusting agent such as common salt, glucose, mannitol and glycerin; a solubilizing agent such as carboxymethyl cellulose sodium, propylene glycol, sodium benzoate, benzyl benzoate, urethane, ethanolamine and glycerin; a soothing agent such as calcium gluconate, chloro
  • the eye drop may be prepared by a usual method by appropriately mixing with a preservative such as chlorobutanol, sodium dehydroacetate, benzalkonium chloride, cetylpyridinium chloride, phenethyl alcohol, methyl paraoxybenzoate and benzethonium chloride; a pH buffer and a pH adjustor such as borax, boric acid and potassium dihydrogenphosphate; a thickener such as methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, carboxymethyl cellulose sodium and chondroitin sulfate; a solubilizing agent such as polysorbate 80 and polyoxyethylene hardened castor oil 60; an emulsion stabilizer, a suspension stabilizer and a dispersion stabilizer such as sodium edetate and sodium hydrogen sulfite; and a tonicity adjusting agent such as sodium chloride, potassium chloride and glycerin.
  • An administration method of the formulation is not especially limited, and is appropriately determined in accordance with the form of the formulation, the age, sex and other conditions of a patient, and the degree of the symptom of the patient.
  • a dose of an active ingredient of the present formulation is appropriately selected in accordance with the usage, the age and sex of a patient, the form of a disease and the other conditions, and generally, it may be administered at a dose of 0.1 to 500 mg, preferably 10 to 200 mg per day once or dividedly several times a day for an adult.
  • EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • EDTA ethylenediaminetetraacetic acid
  • PLP Proteolipid protein
  • THP-1 cells were cultured for about 6 hours in PRMI 1640 medium containing 1% fetal bovine serum and 50 ⁇ mol/L 2-mercaptoethanol. Then, lipopolysaccharide ( E. coli 0127:B8, Sigma Aldrich) was added to the culture plate at a final concentration of 1 ⁇ g/mL, and the cells were cultured for about 30 minutes.
  • lipopolysaccharide E. coli 0127:B8, Sigma Aldrich
  • the cells were harvested and washed with phosphate buffered saline, and mixed with about 2-fold volume of cell lysis buffer (20 mmol/L Tris, 150 mmol/L sodium chloride, 1 mmol/L magnesium chloride, 0.1% NP-40, 1 mmol/L dithiothreitol, 0.1% Triton X-100, pH 7.4).
  • the resultant mixture was placed on ice with occasional stirring for about 30 minutes, and was centrifuged (20000 ⁇ g, 4° C., 8 minutes). The separated and gained supernatant was used as cell lysate. Protein concentration of the cell lysate was measured with BCA protein assay reagent (Thermo Fisher Scientific K.K.) in accordance with its manual.
  • the beads were washed with 0.5 mL of DMF twice, and then, 0.94 mL of DMF and 0.060 mL of 2-aminoethanol were added thereto, followed by shaking at room temperature for 2 hours.
  • the beads were washed with 0.5 mL of DMF twice, and then washed with 1 mL of 0.05 mol/L phosphate buffer (pH 6) four times, and thus, beads to which Compound A was bound via a linker were obtained (hereinafter referred to as the compound beads).
  • beads obtained by a similar reaction without adding 4-amino-N-[7-[(methylsulfonyl)amino]-4-oxo-6-phenoxy-4H-1-benzopyran-3-yl]butanamide hydrochloride were used as control beads.
  • Each type of these beads was suspended in 1 mL of 0.05 mol/L phosphate buffer (pH 6) to be stored in a refrigerator until use. Just before use, a part of the beads was separated and washed with cell lysis buffer three times.
  • the beads were lightly rinsed with cell lysis buffer, were mixed with 15 ⁇ L of SDS-PAGE sample buffer (2ME+) (Wako Pure Chemical Industries, Ltd.), which had been diluted to 4 times, and were heated at about 95° C. for 5 minutes. Thereafter, supernatants separated from the beads by using a magnet were collected as Heat-eluted fraction.
  • SDS-PAGE sample buffer (2ME+) (Wako Pure Chemical Industries, Ltd.)
  • Both of a part of the Flow-through fraction and a part of the Compound A-eluate obtained as described above in (4) were respectively mixed with the SDS-PAGE sample buffer (2ME+), and were heated. These heat-treated samples and the Heat-eluted fraction were electrophoresed on SDS-PAGE gel (SuperSep Ace 15%, Wako Pure Chemical Industries, Ltd.) at 30 to 50 mA for about 80 minutes, and then were electrophoretically transferred to a PVDF membrane (Hybond-P, GE Healthcare Japan Corporation) at 100 mA for about 60 minutes.
  • SDS-PAGE gel SuperSep Ace 15%, Wako Pure Chemical Industries, Ltd.
  • the protein-transferred membrane was immersed and gently shaken in TBST solution (10 mmol/L Tris, 100 mmol/L sodium chloride, 0.1% Tween-20, pH 7.5) containing 5% skim milk at room temperature for about 1 hour. Thereafter, the membrane was immersed in TBST solution containing 1/50000 volume of anti-MIF antibody (Abcam Plc.) and 5% skim milk, and was reacted overnight at 4° C. with gentle mixing.
  • FIG. 1 shows a photograph of the membrane on which binding reactants of MIF and the antibody are detected by chemiluminescence.
  • Lane 4 recombinant MIF (Abeam Plc.)
  • Lane 5 Flow-through fraction of the control beads
  • the Compound A-eluate of the compound beads contains proteins that have binding capacity to the compound beads and is relieved from the compound beads in the presence of an excessive amount of Compound A.
  • a band detected in the Compound A-eluate i.e., Lane 2 was proved to be MIF because it was bound to the anti-MIF antibody and was in a position corresponding to the same molecular weight as recombinant MIF.
  • MIF has binding capacity to the compound beads.
  • both of the Compound A-eluate of the control beads and the Heat-eluted fraction of the control beads contain proteins having binding capacity to the control beads. Since MIF was not detected in these fractions (namely, Lanes 6 and 7), it was shown that MIF has no binding capacity to the control beads.
  • test substances against tautomerase activity of MIF was evaluated by referring to a method of Healy et al. (Cancer Epidemiology Biomarkers and Prevention, 2011, vol. 20, pp. 1516-1523).
  • MIF As an enzyme source, recombinant MIF manufactured by Abcam Plc. or MIF produced and purified by referring to a method of Lubetsky et al. (The Journal of Biological Chemistry, 2002, vol. 277, pp. 24976-24982) was used. A purification method for MIF is described below.
  • the pET15b vector (Merck) into which the full length gene sequence of MIF had been inserted was transfected E. coli BL21 Star (DE3) strain (Life Technologies Corporation).
  • the E. coli was cultured until the culture medium exhibited absorbance (at 600 nm) of 0.5 to 0.8, isopropyl- ⁇ -thiogalactopyranoside (Wako Pure Chemical Industries, Ltd.) was added thereto to a final concentration of 0.1 mmol/L, and the protein expression was induced for 4 hours.
  • coli were resuspended in buffer (pH 7.5) containing 20 mmol/L Tris (Wako Pure Chemical Industries, Ltd.), 20 mmol/L sodium chloride (Wako Pure Chemical Industries, Ltd.) and 1 mmol/L dithiothreitol (Wako Pure Chemical Industries, Ltd.), and the resultant was subjected to ultrasonic lysis and centrifugation at 15000 rpm for 10 minutes. The thus obtained supernatant was filtered using a 0.20 ⁇ m filter, and was allowed to pass through HiTrap Q HP and HiTrap SP HP columns (GE Healthcare Japan Corporation), so as to separate flow-through fractions each of 5 mL.
  • a final concentration of 10 to 50 nmol/L of MIF and a final concentration of 30 ⁇ mol/L of each test substance or 0.5% dimethyl sulfoxide (Wako Pure Chemical Industries, Ltd.) as a control were added to buffer (pH 6.2) containing 50 mmol/L Bis-Tris (Dojindo Laboratories) and 1 mmol/L EDTA (Dojindo Laboratories), and reaction was performed at room temperature for 15 minutes to give a reaction solution 1.
  • reaction solution 2 1/20 volume of 12 mmol/L L-3,4-dihydroxyphenylalanine methyl ester (Sigma Aldrich) and 1/20 volume of 24 mmol/L sodium periodate (Wako Pure Chemical Industries, Ltd.) were added to buffer having the same composition as that used for obtaining the reaction solution 1, to give a reaction solution 2.
  • reaction solution 1 and the reaction solution 2 were mixed, and the temporal change of absorbance at 475 nm of the obtained mixture was immediately measured.
  • Compound A was used as a test substance, and celecoxib, one of NSAIDs, was used as a reference substance.
  • the compound A was administered at a dose of 30 mg/kg (Compound A group).
  • the celecoxib was administered at a dose of 30 mg/kg (celecoxib group).
  • a 0.5% methyl cellulose aqueous solution used as a vehicle was administered.
  • von Frey test pain sense (mechanical allodynia) of the footpad of left hind paw was evaluated by von Frey test. Briefly, von Frey filaments respectively having various flexibilities (Semmes-Weinstein Von Frey Anesthesiometer (manufactured by Danmic Global, LCC)) were vertically pressed against the footpad of the left hind paw successively in order from one having a lightest elasticity, and the elastic force of the filament against which the rat showed a withdrawal response was determined as a pain threshold value.
  • the pain threshold value of the Compound A group was increased to 13.5 g 14 days after the start of the administration (on the 30th day after the operation), and thus, Compound A inhibited the symptom of the mechanical allodynia as compared with that in the control group.
  • Compound A was selected as a test substance, and salazosulfapyridine (hereinafter referred to as SASP) was selected as a comparative control agent.
  • Compound A was administered at a dose of 30 mg/kg (Compound A group).
  • SASP was administered at a dose of 300 mg/kg (SASP group).
  • the chronic relapsing EAE was induced in SJL/J female mice by immunization with partial PLP peptide.
  • an emulsion was prepared by mixing equivalent volumes of phosphate buffer saline containing 1 mg/mL of the peptide corresponding to residues 139-151 of the PLP and Freund's incomplete adjuvant containing 4 mg/mL of killed M. Tuberculosis H37Ra.
  • the emulsion was intradermically injected (50 ⁇ g of PLP per mouse) into four positions on the back for immunization, and additionally, on the day of the immunization and two days after, pertussis toxin was intraperitoneally injected in each amount of 150 ng per mouse, twice in total.
  • the vehicle, the test substance or the reference article was orally administered continuously for 44 days once daily from the day of the immunization.
  • the symptom was evaluated in accordance with a report of Weaver et al. (FASEB Journal, 2005, vol. 19, p. 1668). Briefly, paralysis of all of the four limbs and the tail was evaluated by scoring in 4 ranks of scores of 0 to 3 and in 3 ranks of scores of 0 to 2, respectively, and the sum of the scores was determined as EAE score (the maximum score 14).
  • Incidence rates (the number of mice having developed the disease/the number of used mice) and the average of EAE score of each group were measured at the period of initial onset (on the 15th day after the immunization) and at the period of relapse (on the 38th day after the immunization). The results are shown in Table 4.
  • the incidence rate was low both at the period of initial onset and at the period of relapse, and the EAE score was obviously low too.
  • the compound of general formula [1] or the salt thereof is useful as an MIF inhibitor, and is also useful for a therapeutic or preventive treatment of a disease for which the inhibition of MIF is effective, such as NP and a relapse period of the relapsing-remitting and secondary progressive MS.
  • FIG. 1 is a photograph of a membrane on which reactants resulting from binding between MIF and the antibody are detected by chemiluminescence.
  • a benzopyran derivative represented by general formula [1] or a salt thereof binds to MIF, exhibits an MIF inhibitory effect, and is useful for a therapeutic or preventive treatment of a disease for which the inhibition of MIF is effective.

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