WO2010126022A1 - Dérivé d'imidazole - Google Patents

Dérivé d'imidazole Download PDF

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Publication number
WO2010126022A1
WO2010126022A1 PCT/JP2010/057418 JP2010057418W WO2010126022A1 WO 2010126022 A1 WO2010126022 A1 WO 2010126022A1 JP 2010057418 W JP2010057418 W JP 2010057418W WO 2010126022 A1 WO2010126022 A1 WO 2010126022A1
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WO
WIPO (PCT)
Prior art keywords
acid
tgf
added
benzothiazole
methoxy
Prior art date
Application number
PCT/JP2010/057418
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English (en)
Japanese (ja)
Inventor
肇 浅沼
武史 小網
喜功 関口
直哉 小野
明子 中尾
Original Assignee
大正製薬株式会社
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 大正製薬株式会社 filed Critical 大正製薬株式会社
Priority to JP2011511400A priority Critical patent/JP5569816B2/ja
Publication of WO2010126022A1 publication Critical patent/WO2010126022A1/fr

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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
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory 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
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a compound having an inhibitory action on activin receptor-like kinase 5 (ALK5), which is a type I receptor for TGF- ⁇ .
  • ALK5 activin receptor-like kinase 5
  • TGF- ⁇ Transforming growth factor- ⁇
  • BMP activin
  • TGF- ⁇ is a molecule belonging to the TGF- ⁇ superfamily together with activin, BMP and the like.
  • type II receptor phosphorylates the type I receptor, resulting in activation of the type I receptor and signaling to the nucleus via the Smad2 / 3 pathway or TAB1 / TAK1 pathway Is transmitted.
  • TGF- ⁇ has been shown to have a wide variety of physiological effects. One of them is that it has the effect of accumulating extracellular matrix in tissues through the promotion of production and suppression of degradation of extracellular matrix constituent proteins. Is well known (Non-Patent Document 1). For this reason, continuous enhancement of TGF- ⁇ production and activation of the signal transduction system are causes of many fibrotic diseases.
  • TGF- ⁇ is deeply involved in renal interstitial fibrosis and glomerulosclerosis in renal diseases such as glomerulonephritis and diabetic nephropathy (Non-patent Documents 2 and 3)
  • TGF- ⁇ promotes the production of extracellular matrix of nonparenchymal cells and is involved in the development of liver fibrosis and cirrhosis (Non-patent Document 4).
  • a fibrosis such as pulmonary fibrosis, proliferative vitreoretinopathy, scleroderma
  • accumulation of extracellular matrix due to hyperfunction of TGF- ⁇ can be mentioned.
  • Non-Patent Documents 5 to 7 Inhibitors of ALK5 have been reported to suppress the accumulation of extracellular matrix induced by TGF- ⁇ by blocking the TGF- ⁇ / Smad signal. It is considered useful as a pharmaceutical for treatment or prevention of various diseases associated with fibrosis such as lungs.
  • Non-patent Document 1 TGF- ⁇ is known to exhibit a strong growth inhibitory action against many cells such as epithelial cells, vascular endothelial cells, blood cells and lymphocytes.
  • Non-patent Documents 8 and 9 The applicant of the present application reported that an inhibitor of ALK5 inhibits hair follicle cell growth suppression by TGF- ⁇ (Patent Document 1). Therefore, ALK5 inhibitors are considered useful as hair follicle cell growth promoters, hair growth agents, and hair growth agents.
  • Patent Document 1 describes a group of compounds having a structure similar to the compound of the present invention. Compounds are not described.
  • the present invention relates to glomerulonephritis, diabetic nephropathy, hepatic fibrosis, cirrhosis, pulmonary fibrosis, proliferative vitreoretinopathy, strong, based on the inhibitory action of AGF5 which is a type I receptor of TGF- ⁇ .
  • the object is to provide a novel compound or a pharmaceutically acceptable salt thereof useful for the prevention or treatment of diseases such as dermatosis and alopecia.
  • the present inventors have found that the compound of the present invention has an ALK5 inhibitory action and completed the present invention.
  • the present invention (1) 7-methoxy-6- [5- (4-methyl-thiazol-2-yl) -3H-imidazol-4-yl] -benzothiazole or a pharmaceutically acceptable salt thereof.
  • a prophylactic or therapeutic agent for diseases such as spherical nephritis, diabetic nephropathy, liver fibrosis, cirrhosis, pulmonary fibrosis, proliferative vitreoretinopathy, scleroderma, or alopecia.
  • Hair comprising 7-methoxy-6- [5- (4-methyl-thiazol-2-yl) -3H-imidazol-4-yl] -benzothiazole or a pharmaceutically acceptable salt thereof as an active ingredient
  • a follicle cell growth promoter, hair growth agent, or hair growth agent It is.
  • the compound of the present invention Since the compound of the present invention has an ALK5 inhibitory action, it can block the TGF- ⁇ / Smad signal.
  • the compound of the present invention 7-methoxy-6- [5- (4-methyl-thiazol-2-yl) -3H-imidazol-4-yl] -benzothiazole, is a compound having the following structure.
  • “pharmaceutically acceptable salt” means acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethyl succinic acid, lactobionic acid, gluconic acid , Glucoheptonic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, lauryl sulfuric acid, malic acid, aspartic acid, glutamic acid, adipic acid, cysteine, N-acetyl
  • Examples include salts with cysteine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydrogen iodide, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, undecano
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may exist as a solvate.
  • the hydrate of a compound, the hydrate of the pharmaceutically acceptable salt of a compound, etc. are mentioned. These are all included in the present invention.
  • the compound of the present invention is added with usual excipients, extenders, pH adjusters, solubilizers, etc., and tablets, granules, pills, capsules are added by conventional formulation techniques. , Powders, solutions, suspensions, injections, coatings, etc., and can be administered orally, transdermally or intravenously.
  • the compound of the present invention can be administered to an adult patient at a dose of 0.01 to 100 mg / kg per day in 1 to several divided doses. This dose can be appropriately increased or decreased depending on the type of disease, patient age, weight, symptoms and the like.
  • the compound of the present invention can be synthesized, for example, by the method shown below.
  • Example 1 7-Methoxy-6- [5- (4-methyl-thiazol-2-yl) -3H-imidazol-4-yl] -benzothiazole (1) Synthesis of 6,6-dibromo-5,6-dihydro-4H-benzothiazol-7-one A solution of 5,6-dihydro-4H-benzothiazol-7-one (100.0 g) in acetic acid (880 mL) Bromine (70.2 mL) was added dropwise to the suspension in which hydrobromic acid (35.4 ml, 48%) was added dropwise at room temperature over 1 hour. The reaction mixture was stirred at 40 ° C. to 45 ° C.
  • Test Example 1 Solubility Test As a test compound, 7-methoxy-6- [5- (4-methyl-thiazol-2-yl) -3H-imidazol-4-yl] -benzothiazole synthesized in Example 1 above was used. And 6- [5- (4-methyl-thiazol-2-yl) -3H-imidazol-4-yl] -benzothiazole (hereinafter referred to as Comparative Example 1) described in WO2005 / 085241 was used. The structure of Comparative Example 1 is shown below.
  • 1,3-butylene glycol (10 g) was weighed and placed in a graduated cylinder, EtOH (79 mL) was added and stirred to homogenize, and then water was added to a total volume of 100 mL to prepare a base. Add an excess amount of the test compound to the test tube, add the base prepared above, stir at room temperature for 24 hours, filter through a membrane filter (0.45 ⁇ m), and dilute the resulting filtrate with 50% acetonitrile / water mixture. Then, quantification was performed by HPLC, and the obtained value was defined as solubility.
  • the solubility of Comparative Example 1 was 14.9 mg / mL, and the solubility of Example 1 was 51.8 mg / mL.
  • Test Example 2 [Skin Smad2 Phosphorylation Inhibition Test] As test compounds, Example 1 and Comparative Example 1 were used as in Test Example 1. The back of C57BL / 6 mice was removed, and the base prepared in Test Example 1 or the test compound solution dissolved in the base was applied and administered 16 days later, and the skin was collected 1 hour and 8 hours after administration. The concentration of the test compound was 1.5% which is the maximum dissolution concentration in Comparative Example 1, and 3% in Example 1. 50 mM Tris-HCl (pH 7.6) containing 1% NP-40 and 150 mM sodium chloride was added to each skin sample, homogenized, and then centrifuged at 3,000 rpm for 15 minutes, and the supernatant was used. Western blot analysis was performed.
  • Anti-phosphorylated Smad2 antibody or anti-Smad2 antibody as the primary antibody HRP-labeled anti-rabbit IgG antibody as the secondary antibody, and ECL Plus Western Blotting Detection Reagents (GE Healthcare) as the detection reagent, Lumi-Imager F1 (The amount of luminescence of phosphorylated Smad2 and Smad2 was measured using Roche Diagnostics). The test was conducted in 5 cases in each group. The phosphorylated Smad2 level was expressed as a relative value when the average value of phosphorylated Smad2 / Smad2 in the base administration group was 1.
  • the inhibition rate of Smad2 phosphorylation in Comparative Example 1 was 80.4% after 1 hour and 28.3% after 8 hours. Further, the result after 8 hours could not be said to significantly suppress phosphorylation of Smad2. On the other hand, the inhibition rate of Smad2 phosphorylation in Example 1 was 78.8% after 1 hour and 72.6% after 8 hours, and both significantly suppressed phosphorylation of Smad2. The results are shown in the figure.
  • Example 1 since Example 1 has improved solubility in the base compared to Comparative Example 1, it can be dissolved in the base at a high dose, and has a more sustained skin Smad2 phosphorylation inhibitory action. I found out.
  • the compound of the present invention has an inhibitory effect on ALK5, it blocks glomerulonephritis, diabetic nephropathy, liver fibrosis, cirrhosis, pulmonary fibrosis, proliferative vitreous retina by blocking the TGF- ⁇ / Smad signal It is useful as a prophylactic or therapeutic agent for diseases such as dermatosis, scleroderma, or alopecia, and further as a hair follicle cell growth promoter, hair growth agent, or hair restorer.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Urology & Nephrology (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention porte sur le nouveau composé 7-méthoxy-6-[5-(4-méthylthiazol-2-yl)-3H-imidazol-4-yl]­benzothiazole et sur les sels pharmaceutiquement acceptables de celui-ci. Ce nouveau composé et ses sels sont utiles pour la prévention ou le traitement de maladies, telles que la glomérulonéphrite, la néphropathie diabétique, et fibrose hépatique, la cirrhose hépatique, la fibrose pulmonaire, la vitréorétinopathie proliférative, la sclérodermie et la calvitie, la prévention ou le traitement étant basé sur une action inhibitrice sur ALK 5, qui est un récepteur I de TGF-β.
PCT/JP2010/057418 2009-04-28 2010-04-27 Dérivé d'imidazole WO2010126022A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2011511400A JP5569816B2 (ja) 2009-04-28 2010-04-27 イミダゾール誘導体

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Application Number Priority Date Filing Date Title
JP2009109712 2009-04-28
JP2009-109712 2009-04-28

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WO2010126022A1 true WO2010126022A1 (fr) 2010-11-04

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022251359A1 (fr) * 2021-05-26 2022-12-01 Theravance Biopharma R&D Ip, Llc Inhibiteurs bicycliques de l'alk5 et procédés d'utilisation
US11903310B2 (en) 2019-11-05 2024-02-13 Samsung Display Co., Ltd. Organic light-emitting device and method of manufacturing the same

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005085241A1 (fr) * 2004-03-05 2005-09-15 Taisho Pharmaceutical Co., Ltd. Derive de thiazole

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005085241A1 (fr) * 2004-03-05 2005-09-15 Taisho Pharmaceutical Co., Ltd. Derive de thiazole

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11903310B2 (en) 2019-11-05 2024-02-13 Samsung Display Co., Ltd. Organic light-emitting device and method of manufacturing the same
WO2022251359A1 (fr) * 2021-05-26 2022-12-01 Theravance Biopharma R&D Ip, Llc Inhibiteurs bicycliques de l'alk5 et procédés d'utilisation

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JPWO2010126022A1 (ja) 2012-11-01
JP5569816B2 (ja) 2014-08-13

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