WO2012133489A1 - Composition pharmaceutique pour le traitement ou la prophylaxie de maladies neurogènes - Google Patents

Composition pharmaceutique pour le traitement ou la prophylaxie de maladies neurogènes Download PDF

Info

Publication number
WO2012133489A1
WO2012133489A1 PCT/JP2012/058067 JP2012058067W WO2012133489A1 WO 2012133489 A1 WO2012133489 A1 WO 2012133489A1 JP 2012058067 W JP2012058067 W JP 2012058067W WO 2012133489 A1 WO2012133489 A1 WO 2012133489A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
aminopyridin
fluorophenyl
tetrahydro
pyrazole
Prior art date
Application number
PCT/JP2012/058067
Other languages
English (en)
Japanese (ja)
Inventor
萩原　昌彦
博文 松永
善俊 粕谷
香奈 並木
Original Assignee
宇部興産株式会社
国立大学法人 千葉大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 宇部興産株式会社, 国立大学法人 千葉大学 filed Critical 宇部興産株式会社
Publication of WO2012133489A1 publication Critical patent/WO2012133489A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • 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

Definitions

  • MAP Mitogen Activated Protein
  • ⁇ ⁇ Multiple sclerosis which is a neurological disease, is one of the central demyelinating diseases characterized by local disruption of the myelin sheath (demyelination). In this disease, lesions occur in the brain, spinal cord, optic nerve, etc., and various neurological symptoms repeat relapses and remissions. Many of them develop acutely, but they sometimes follow a slow and continuous path of progression. Symptoms of this disease vary depending on the site of demyelination of the central nervous system, and include symptoms such as visual impairment, eye movement disorders, movement disorders, sensory disorders, ataxia, and bladder and rectal disorders. Although the cause of this disease is still unclear, the possibility of an autoimmune disease has been suggested by the finding of immunological abnormalities. In recent years, various specific cytokines and proteins such as interleukin-17 (hereinafter abbreviated as IL-17) have attracted attention as factors that induce autoimmune diseases.
  • IL-17 interleukin-17
  • steroids are instilled as an acute treatment, and subcutaneous injection of interferon ⁇ and immunosuppressants are used for preventing recurrence and suppressing progression. Yes.
  • none of these drugs has a sufficient therapeutic effect on multiple sclerosis, and there are problems that the side effects are strong and there are many restrictions on the dosage form. Therefore, there is an urgent need for a medicament that has a sufficient therapeutic effect and has a safer autoimmunity suppressing action.
  • p38 MAP kinase cloned as a homolog of MAP kinase is involved in the control of the production of inflammatory cytokines such as IL-1, IL-6, and IL-8, and the signal transduction system coupled to these receptors.
  • Inflammatory cytokine inhibitors by inhibiting p38 MAP kinase include new generation antipyretic / analgesic / anti-inflammatory drugs with different mechanisms of action, autoimmune diseases such as rheumatoid arthritis, bone diseases such as osteoporosis, and other cytokines. It is expected as a therapeutic agent for the diseases involved.
  • a p38 MAP kinase inhibitor having a chemical structure different from a pharmacologically acceptable salt thereof is an experimental autoimmune encephalomyelitis (hereinafter referred to as EAE), which is a mouse experimental model of multiple sclerosis. Have been reported to have an effect (see Non-Patent Document 1).
  • EAE experimental autoimmune encephalomyelitis
  • the present invention relates to 4- (2-aminopyridin-4-yl) -3- (4-fluorophenyl) -1- (1,4,5,6-tetrahydro-6-oxopyridazin-3-yl) -1H -A pharmaceutical composition for treating or preventing multiple sclerosis comprising pyrazole or a pharmacologically acceptable salt thereof as an active ingredient.
  • 4- (2-Aminopyridin-4-yl) -3- (4-fluorophenyl) -1- (1,4,5,6-tetrahydro-6-oxopyridazine which is an active ingredient of the pharmaceutical composition of the present invention -3-yl) -1H-pyrazole or a pharmacologically acceptable salt thereof has an excellent autoimmune inhibitory action because it exhibits a suppressive action on the production of cytokines such as IL-17 in addition to a potent p38 MAP kinase inhibitory action.
  • the pharmaceutical composition of the present invention is useful as a medicament for the treatment or prevention of multiple sclerosis because it has few side effects, high safety, and excellent oral absorption.
  • 4- (2-Aminopyridin-4-yl) -3- (4-fluorophenyl) -1- (1,4,5,6-tetrahydro-6-oxopyridazine which is an active ingredient of the pharmaceutical composition of the present invention -3-yl) -1H-pyrazole or a pharmacologically acceptable salt thereof can be easily produced according to a known method (for example, WO 2004/029043 or WO 2010/029938) or a method analogous thereto. it can.
  • inorganic acid salts such as phosphates; or acetate, propionate, butyrate, benzoate, phthalate, oxalate, malonate, succinate, maleate, fumarate, tartrate Citrate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate, 2,4-dimethylbenzenesulfonate, 2,4,6-trimethylbenzenesulfonate, -Organic acid salts such as toluene sulfonic acid, 4-ethylbenzene sulfonate, 2-naphthalene sulfonic acid, glutamate or aspartate, preferably, hydrochloride, hydrobromide, sulfate, Examples thereof include methanesulfonate and benzenesulfonate, and particularly preferably, methanesulfonate.
  • inorganic acid salts such as
  • the pharmaceutical composition of the present invention comprises tablets, capsules, granules, pills, powders, solutions, syrups, troches, suspensions, emulsions and the like, or injections, suppositories or patches. It can be administered in a dosage form for parenteral administration such as an agent, which is pharmacologically and pharmaceutically acceptable. Of these, dosage forms for oral administration such as tablets and capsules are preferred.
  • additives that can be used when preparing the pharmaceutical compositions of the above various dosage forms include, for example, various excipients, lubricants ordinarily used in oral dosage forms and parenteral dosage forms.
  • examples include binders, disintegrants, emulsifiers, stabilizers, flavoring agents, diluents or solvents for injection.
  • excipients include organic excipients and inorganic excipients.
  • organic excipients include sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starches such as corn starch, potato starch, ⁇ -starch, or dextrin and derivatives thereof; cellulose derivatives such as crystalline cellulose; Gum arabic; dextran; or pullulan.
  • inorganic excipient include silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate or magnesium metasilicate aluminate; calcium hydrogen phosphate or phosphate; calcium carbonate or carbonate; or calcium sulfate or sulfuric acid Salt.
  • lubricants include stearic acid; stearic acid metal salts such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as beeswax or gay wax; boric acid; adipic acid; sulfates such as sodium sulfate.
  • binder examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the compounds exemplified as the excipient.
  • disintegrants include cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium or internally crosslinked sodium carboxymethylcellulose; crosslinked polyvinylpyrrolidone; or chemically modified starch / cellulose such as carboxymethyl starch or carboxymethyl starch sodium.
  • cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium or internally crosslinked sodium carboxymethylcellulose; crosslinked polyvinylpyrrolidone; or chemically modified starch / cellulose such as carboxymethyl starch or carboxymethyl starch sodium.
  • emulsifier examples include colloidal clay such as bentonite or bee gum; alkali metal or alkaline earth metal hydroxide such as magnesium hydroxide or aluminum hydroxide; anionic surfactant such as sodium lauryl sulfate or calcium stearate; Cationic surfactants such as benzalkonium chloride; or nonionic surfactants such as polyoxyethylene alkyl ethers or polyoxyethylene sorbitan fatty acid esters.
  • colloidal clay such as bentonite or bee gum
  • alkali metal or alkaline earth metal hydroxide such as magnesium hydroxide or aluminum hydroxide
  • anionic surfactant such as sodium lauryl sulfate or calcium stearate
  • Cationic surfactants such as benzalkonium chloride
  • nonionic surfactants such as polyoxyethylene alkyl ethers or polyoxyethylene sorbitan fatty acid esters.
  • the stabilizer examples include parahydroxybenzoates such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol, or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; Acetic acid; or sorbic acid.
  • parahydroxybenzoates such as methylparaben or propylparaben
  • alcohols such as chlorobutanol, benzyl alcohol, or phenylethyl alcohol
  • benzalkonium chloride examples include phenols such as phenol or cresol; thimerosal; Acetic acid; or sorbic acid.
  • sweeteners such as saccharin sodium or aspartame
  • acidulants such as citric acid or malic acid
  • fragrances such as menthol, lemon extract or orange extract.
  • diluent examples include compounds usually used as a diluent.
  • lactose lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, polyvinyl pyrrolidone, magnesium metasilicate aluminate or these A mixture is mentioned.
  • Examples of the solvent for injection include water, ethanol, glycerin and the like.
  • the dose of the active ingredient of the pharmaceutical composition of the present invention varies depending on symptoms, age, administration method, etc.
  • 0.1 mg to 1000 mg preferably 0.5 mg to 500 mg per dose.
  • 0.01 mg to 500 mg, preferably 0.05 mg to 300 mg per administration is administered once to 6 times a day for an adult weighing 60 kg depending on symptoms. can do.
  • Test Example 1 Mouse EAE Test 1 Induction of EAE Induction of EAE was performed according to the method of Tokuhara et al. (Journal of Biological Chemistry, 285, 33294 (2010)). Freund's complete adjuvant suspension was prepared by suspending 25 mg of tuberculosis killed bacteria H37Ra (product number 231141, manufactured by DIFCO) in 5 ml of Freund's incomplete adjuvant (product number 263910, manufactured by DIFCO).
  • the total score is the sum of each clinical sign score of one mouse after immunization, and the numerical value is from 0 (no clinical sign) to a maximum value of 27.5 (when all clinical signs are shown).
  • FIG. 1 the average value of the total score in 7 post-immunization mice used in the test is plotted.
  • ** indicates a significant difference p ⁇ 0.01 in Student's t-test.
  • mice Immunization of mice was performed according to the method of Tokuhara et al. (Journal of Biological Chemistry, 285, 33294 (2010)).
  • Freund's complete adjuvant suspension was prepared by suspending 15 mg of tuberculosis killed bacteria H37Ra (product number 231141, manufactured by DIFCO) in 3 ml of Freund's incomplete adjuvant (product number 263910, manufactured by DIFCO).
  • mice were euthanized under ether anesthesia, thoroughly sterilized with 70% alcohol, and then cervical and extremity regional lymph nodes (Superficial clinical node, Axillary) node, Brachial node, and Inguinal node) were extracted into ice-cooled sterile PBS, and tissue pieces such as adipose tissue were removed under a stereomicroscope.
  • lymphocytes were separated by breaking the capsule of the lymph node, and then filtered through a cell strainer (product number 352340, manufactured by FALCON) having a mesh size of 40 ⁇ m, and 10% fat bovine serum (hereinafter abbreviated as FBS) and 55 ⁇ M.
  • FBS fat bovine serum
  • RPMI 1640 Rowell Park Memorial Institute 1640 (hereinafter abbreviated as RPMI 1640) medium (product number 680554, manufactured by Nissui) containing 2-mercaptoethanol (hereinafter abbreviated as 2-M ⁇ ; product number 137-06862, manufactured by Wako Pure Chemical Industries, Ltd.)
  • 2-M ⁇ 2-mercaptoethanol
  • a lymphocyte suspension containing 1.5 ⁇ 10 7 lymphocytes / ml was prepared.
  • lymphocyte suspension prepared in 2) was seeded in a 24-well culture plate (manufactured by FALCON) in an amount of 500 ⁇ l / well, and then myelin oligosaccharide.
  • RPMI 1640 medium containing 10% FBS and 55 ⁇ M 2-ME
  • myelin oligoglycoprotein MOG 35-55 final concentration 5 ⁇ g / mL
  • 0.2% aqueous dimethyl sulfoxide solution was used.
  • the culture broth was collected and centrifuged (400 g, 10 minutes) to separate the supernatant, and the amount of IL-17 produced was measured using an ELISA method (Product No. 432501, manufactured by Biolegend). .

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un produit pharmaceutique qui possède un effet curatif suffisant sur la sclérose en plaques et une excellente activité inhibitrice auto-immune, tout en permettant une diminution des effets secondaires découlant des agents stéroïdes et de l'interféron β. La présente invention porte en particulier sur une composition pharmaceutique destinée au traitement ou à la prophylaxie de la sclérose en plaques contenant, en tant qu'agent actif, 4-(2-aminopyridin-4-yl)-3-(4-fluorophényle)-1-(1,4,5,6-tétrahydro-6-oxopyridazin-3-yl)-1H-pyrazole ou son sel pharmacologiquement acceptable.
PCT/JP2012/058067 2011-03-29 2012-03-28 Composition pharmaceutique pour le traitement ou la prophylaxie de maladies neurogènes WO2012133489A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2011-071464 2011-03-29
JP2011071464A JP2014114213A (ja) 2011-03-29 2011-03-29 神経性疾患の治療又は予防のための医薬組成物

Publications (1)

Publication Number Publication Date
WO2012133489A1 true WO2012133489A1 (fr) 2012-10-04

Family

ID=46931198

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2012/058067 WO2012133489A1 (fr) 2011-03-29 2012-03-28 Composition pharmaceutique pour le traitement ou la prophylaxie de maladies neurogènes

Country Status (2)

Country Link
JP (1) JP2014114213A (fr)
WO (1) WO2012133489A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9018153B1 (en) 2013-11-13 2015-04-28 The Clorox Company Mesitylene sulfonate compositions and methods thereof
WO2015072988A1 (fr) * 2013-11-13 2015-05-21 The Clorox Company Compositions de sulfonate de mésitylène et méthodes associées
WO2015072986A1 (fr) * 2013-11-13 2015-05-21 The Clorox Company Compositions de sulfonate de mésitylène et procédés correspondants
US9074166B1 (en) 2013-11-13 2015-07-07 The Clorox Company Method for bleaching a surface with a mesitylene sulfonate composition

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004029043A1 (fr) * 2002-09-25 2004-04-08 Ube Industries, Ltd. Composes pyrazole

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004029043A1 (fr) * 2002-09-25 2004-04-08 Ube Industries, Ltd. Composes pyrazole

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LU, L. ET AL.: "Role of SMAD and Non-SMAD Signals in the Development of Th17 and Regulatory T Cells", JOURNAL OF IMMUNOLOGY, vol. 184, 2010, pages 4295 - 4306 *
NAMIKI, K. ET AL.: "Role of p38 in experimental autoimmune encephalomyelitis", JOURNAL OF PHARMACOLOGICAL SCIENCES, vol. 109, no. 1, 2009, pages 102P *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9018153B1 (en) 2013-11-13 2015-04-28 The Clorox Company Mesitylene sulfonate compositions and methods thereof
WO2015072988A1 (fr) * 2013-11-13 2015-05-21 The Clorox Company Compositions de sulfonate de mésitylène et méthodes associées
WO2015072986A1 (fr) * 2013-11-13 2015-05-21 The Clorox Company Compositions de sulfonate de mésitylène et procédés correspondants
US9074165B1 (en) 2013-11-13 2015-07-07 The Clorox Company Liquid mesitylene sulfonate compositions and methods thereof
US9074166B1 (en) 2013-11-13 2015-07-07 The Clorox Company Method for bleaching a surface with a mesitylene sulfonate composition
US9120999B2 (en) 2013-11-13 2015-09-01 The Clorox Company Mesitylene sulfonate compositions and methods for cleaning a surface

Also Published As

Publication number Publication date
JP2014114213A (ja) 2014-06-26

Similar Documents

Publication Publication Date Title
KR101918669B1 (ko) 신경 장애 치료용 신규 조성물
KR101937782B1 (ko) 바클로펜 및 아캄프로세이트에 기초한 신경 장애의 치료
EP2579879B1 (fr) Dérivés de triazine pour retarder l'apparition du diabète de type 1
TWI436768B (zh) 第２型糖尿病之治療
KR20160067103A (ko) 신경 장애를 치료하기 위한 토라세미드 및 바클로펜을 포함하는 조성물
KR20140003659A (ko) 폐경전 성욕 장애의 치료를 위한 플리반세린의 용도
WO2012133489A1 (fr) Composition pharmaceutique pour le traitement ou la prophylaxie de maladies neurogènes
EA028300B1 (ru) Композиции, содержащие вортиоксетин и донепезил
WO2006090759A1 (fr) Agent pharmaceutique comprenant de la solifenacine
JPWO2019225740A1 (ja) インドール化合物を含む多発性硬化症の治療又は予防剤
JP2019516699A (ja) 純粋な５−ｈｔ６受容体アンタゴニストとアセチルコリンエステラーゼ阻害剤の組合せ
KR101834005B1 (ko) 티오우레아 유도체를 포함하는 자가면역질환 예방 또는 치료용 약학적 조성물
KR102076137B1 (ko) 수축력 저하 수반성 배뇨근 과활동 개선제
JP2008255064A (ja) 睡眠障害予防治療剤
WO2023182298A1 (fr) Médicament thérapeutique ou prophylactique contre le syndrome de l'x fragile
KR20190054549A (ko) 말초신경의 나트륨-채널병증을 예방 또는 치료하기 위한 카바메이트 화합물의 용도
TW201806601A (zh) σ受體配體在皰疹後遺疼痛中的用途
JP6430445B2 (ja) バクロフェンおよびアカンプロセートに基づく神経疾患の治療
KR20220126122A (ko) 섬유증의 치료 또는 완화용 약학 조성물
KR20030019634A (ko) 2-아릴-8-옥소디히드로푸린 유도체를 유효성분으로 하는치매증 치료제
KR20220108123A (ko) 치매 환자의 행동 및 심리적 증상 치료
AU2021399925A1 (en) Masitinib for the treatment of alzheimer's disease
MX2007014396A (es) Composicion farmaceutica que comprende 1-(3-clorofenil)-3- alquilpiperazina para el tratamiento de trastorno alimenticio.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12764029

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12764029

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP