[go: up one dir, main page]

WO2008035956A1 - Nouveau dérivé de benzoxazole, son procédé de préparation et composition pharmaceutique le renfermant - Google Patents

Nouveau dérivé de benzoxazole, son procédé de préparation et composition pharmaceutique le renfermant Download PDF

Info

Publication number
WO2008035956A1
WO2008035956A1 PCT/KR2007/004681 KR2007004681W WO2008035956A1 WO 2008035956 A1 WO2008035956 A1 WO 2008035956A1 KR 2007004681 W KR2007004681 W KR 2007004681W WO 2008035956 A1 WO2008035956 A1 WO 2008035956A1
Authority
WO
WIPO (PCT)
Prior art keywords
benzoxazole derivative
leukotriene
acid
pharmaceutical composition
ethylphenyl
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/KR2007/004681
Other languages
English (en)
Inventor
Hae-Young Park Choo
Hyeong-Kyu Lee
Sei-Ryang Oh
Kyungseop Ahn
Gyoonhee Han
Joo Heon Kim
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ewha Womans University
Original Assignee
Ewha Womans University
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 Ewha Womans University filed Critical Ewha Womans University
Publication of WO2008035956A1 publication Critical patent/WO2008035956A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or 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
    • 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
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • 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
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • the present invention relates to a new benzoxazole derivative, a process for the preparation thereof, and a pharmaceutical composition comprising the same.
  • Leukotriene is an oxidized polyunsaturated fatty acid having several bioactivities, and metabolized from arachidonic acid liberated from cell membrane by calcium action via multiple steps, so as to be biosynthesized as one of inflammatory mediators exerting a variety of biological activities.
  • the leukotriene B (LTB ) formed through the first pathway is a bioactive compound enzymatically formed by hydration of LTA .
  • the compound has chemotactic activity for inflammatory cells such as polymorphonuclear leukocyte, and causes degranulation and aggregation of inflammatory cells. Further, leukotriene B increases vascular permeability, resulting in edema formation.
  • LTC 4 leukotriene C 4
  • LTD 4 leukotriene D 4
  • LTE 4 leukotriene E 4
  • 5-lipoxygenase is limited to neutrophils, eosinophils, basophils, monocytes, macrophages, mast cells, and B lymphocytes.
  • LTA hydrolase and LTC synthase enzymes are more widely distributed in various tissues.
  • Zileuton has been recently developed as a drug to inhibit 5-lipoxygenase, and in addition, substances such as E6080, A-61443, BW-755c, A-63162, MK-886, MK-591, WY-50,295, and ZD5138 have been under development and clinical trials as a 5-lipoxygenase inhibitor.
  • Zileuton is a drug synthesized at Abbott Laboratories, and has been applied for
  • E6080 is a powerful 5-lipoxygenase inhibitor developed by Eisai Co. Ltd. (Japan), which has high selectivity, is orally administrable and inhibits the release of LTB and LTC .
  • the present inventors have developed a pharmaceutical composition having 5-lipoxygenase inhibitory activity in Korean Patent Registration No. 10-0544901.
  • a new benzoxazole derivative having excellent 5-lipoxygenase inhibitory activity has been synthesized, and it was found that the compound significantly reduces the degree of airway hypersensitivity, levels of cytokines IL-4, IL-5, and IL- 13, Ova-specific IgE in serum, and degree of the peribronchial and perivascular inflammation, statistically significantly reduces the number of TRAP(+) MNCs, and significantly inhibits osteoclastogenesis in a co-culture system of bone marrow cells and osteoblasts, thereby completing the present invention.
  • the present invention provides a new benzoxazole derivative having
  • FIG. 1 is a drawing showing the effect of a benzoxazole derivative of the present invention on osteoclast-inhibitory activity. Best Mode for Carrying Out the Invention
  • the present invention provides a benzoxazole derivative represented by the following Formula 1.
  • the compounds of the present invention may be prepared in the form of a pharmaceutically acceptable salt and a solvate according to the conventional method in the related art.
  • acid addition salts produced with free acids are preferred.
  • the acid addition salts are prepared by the conventional method, for example, a method comprising the steps of dissolving a compound in an excessive amount of acid aqueous solution, and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • Acid or alcohol for example, glycol monomethyl ether
  • the free acids organic acids and inorganic acids may be used.
  • Examples of the inorganic acids include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, and tartaric acid
  • examples of the organic acids include methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycollic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid, vanillic acid, and hydroiodic acid, but are not limited thereto.
  • a pharmaceutically acceptable metal salt can be prepared using a base.
  • An alkali metal salt and alkaline earth metal salt can be obtained by a method, for example, the method comprising the steps of dissolving a compound in an excessive amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved salt, and then evaporating and drying the filtrate.
  • sodium, potassium, or calcium salt is pharmaceutically preferable, and the corresponding silver salt is obtained by reacting alkali metal salt or alkaline earth metal salt with a suitable silver salt (e.g. silver nitrate).
  • a pharmaceutically acceptable salt of the compound represented by Formula 1 includes salts of acidic or basic groups, which can be present in the compound of Formula 1, as long as particular mention is not made.
  • the pharmaceutically acceptable salt includes sodium salt, calcium salt, and potassium salt of hydroxy group
  • other pharmaceutically acceptable salt of amino group includes hy- drobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate).
  • the salts can be prepared by a preparation method or preparation process thereof known in the related art.
  • the present invention provides a process for the preparation of the benzoxazole derivative represented by Formula 1, comprising the steps of:
  • 2-amino-4-methylphenol used as a starting material can be prepared by reduction reaction of 4-methyl-2-nitrophenol with Pd/C or purchased from com-schreibally available sources.
  • step 1) 2-amino-4-methylphenol and 4-ethylphenyl isocyanate are dissolved in an organic solvent, and then reacted for about 24 hours to prepare a N- (2-hydroxy-5-methylphenyl)-N'-(4-ethylphenyl)thiourea compound.
  • Examples of the organic solvent used in the step include methanol, ethanol, and ether, most preferably methanol.
  • step 2) about 5 equivalent weights of potassium peroxide is preferably used based on 1 equivalent weight of the N- (2-hydroxy-5-methylphenyl)-N'-(4-ethylphenyl)thiourea compound.
  • the present invention provides a pharmaceutical composition for preventing and treating diseases induced by leukotriene, comprising the benzoxazole derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • Examples of diseases induced by leukotriene include asthma, pertussis, psoriasis, arthritis, inflammatory bowel disease, cystic fibrosis, chronic bronchitis, allergic rhinitis, gout, rheumatoid arthritis, sepsis, myocardial ischemia, heart anaphylaxis, cerebral vasospasm, ischemic attack, osteoporosis, breast cancer, pancreatic cancer, or pain.
  • the benzoxazole derivative according to the present invention significantly reduces the degree of airway hypersensitivity, levels of cytokines IL-4, IL-5, and IL- 13, Ova-specific IgE in serum, and degree of the peribronchial and perivascular inflammation.
  • the number of TRAP(+) MNCs is statistically significantly reduced (**p ⁇ 0.01 compared to a control), and osteoclastogenesis is significantly inhibited in a co-culture system of bone marrow cells and osteoblasts.
  • the benzoxazole derivative according to the present invention can be used to prevent and treat diseases induced by leukotriene, in particular, inflammatory diseases including asthma or osteoporosis.
  • composition of the present invention may contain one or more active ingredients having the effects of preventing and treating diseases induced by leukotriene in addition to the benzoxazole derivative of Formula 1.
  • the composition of the invention can be prepared including at least one pharmaceutically acceptable carrier, in addition to the active ingredients as described above.
  • the pharmaceutically acceptable carrier include saline solution, sterile water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol and a mixture of two or more thereof.
  • the composition may also contain other conventional additives, such as antioxidants, buffers, and bacteriostatic agents.
  • the composition may additionally contain diluents, dispersants, surfactants, binders, and lubricants in order to formulate it into injectable formulations, such as aqueous solution, suspension, and emulsion, pills, capsules, granules and tablets.
  • injectable formulations such as aqueous solution, suspension, and emulsion, pills, capsules, granules and tablets.
  • the composition may preferably be formulated depending on particular diseases and its components, using the method described in Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA., which is a suitable method in the relevant field of art.
  • composition of the invention may be administered orally or parenterally (for example, intravein, subcutaneous, intraperitoneal, or topical application) depending on the purpose of the invention, and the dosage of the composition can vary depending on various factors, including patient's weight, age, sex, health condition, and diet, and administration time, administration route, secretion rate, disease severity, etc..
  • the compound of Formula 1 is administered at a daily dosage of about 10 to 1000 mg/kg, more preferably once or several times.
  • composition of the invention may be used alone or in combination with surgical operations, hormone therapies, chemical therapies, and other methods using biological reaction regulators in order to prevent and treat diseases induced by leukotriene.
  • a Pd/C catalyst was added to 4-methyl-2-nitrophenol, and air was completely removed by using a pump. Then, methanol was injected thereto to dissolve reagents, and connected to a hydrogen-filled balloon to be substituted with hydrogen. After strongly stirring for 5 hours at room temperature, the resultant was filtered to completely remove Pd/C, and the filtrate was concentrated under reduced pressure to obtain 2-amino-4-methylphenol.
  • mice Two female BALB/c mice (5-6 weeks old) were sterilized with 71% ethanol, and femurs were separated from the mice. A 25G needle was put into the femur, and then bone-marrow was flushed out with 25 D of RPMI to be centrifuged (1000 rpm, 5 mins). The supernatant was discarded, and the bone-marrow mast cells were cultured in RPMI 1640/10% FBS. After about 1 day, the cells were observed to be subcultured. After 90% or more of cell growth was confirmed, the following experiments were performed with BMMC.
  • BMMC was cultured for 3 weeks or more, and then transferred to a 50 D falcon tube to be centrifuged (1000 rpm, 5 min, 4 0 C). The supernatant was discarded, and RPMI 1640 was added thereto. 50 D of supernatant sample, 50 D of LTCAChE tracer, and 50 D of LTC antiserum were aliquoted into a well, and an EIA buffer solution was used for dilution. 100 D of EIA buffer solution, 50 D of LT 4CAChE tracer, and 50 D of LTC 4 antiserum were aliquoted into a NSB well. After culturing at room temperature for 16 to 20 hours, the cells were washed with 200 D of wash buffer about 5 times. 200 D of
  • mice The sterilized 6 week-old healthy female BALB/c mice (Korean Research Institute of Chemistry Technology, Daejeon, Korea) were bred in laminar flow cabinets.
  • the BALB/c mice were divided into 3 groups, each group with 6 mice: group I, sham- sensitization plus challenge with phosphate-buffered saline (PBS; ipNeb); group II, sensitization plus challenge with OVA (ovalbumin: Sigma A5503; Sigma, St. Louis, MO) (ipNeb); group III, sensitization with OVA (ip) plus challenge with OVA (Neb) and samples (po).
  • the degree of airway hypersensitivity was represented as the increased ratio, by comparing an enhanced r pause (Penh) value (Penh MCH ), which was measured after administration of each concentration of methacholine, with a Penh value (Penh ), which was measured after inhalation of saline solution.
  • Penh MCH enhanced r pause
  • Penh MCH Penh value
  • Penh [Expiratory time (Te) / Relaxation time (RT)-I] x [Peak expiratory flow (PEF) / Peak inspiratory flow (PIF)]
  • mice were sacrificed using an excessive amount of pentobarbital, and then a tracheotomy was performed. The chests of mice were excised to expose trachea, and the upper portion of the trachea was excised. Then, a tube was carefully inserted to be ligatured. 0.5 D of cold PBS was injected to trachea-lung, and the recovered bronchoalveolar lavage fluid (BALF) was collected to be centrifuged at 4 0 C. The supernatant was separately stored at -7O 0 C.
  • BALF bronchoalveolar lavage fluid
  • the plasma was obtained by a cardiac puncture after performing the tracheotomy.
  • the level of Ova-specific IgE in serum (BD Biosciences Pharmingen Inc., San Dieogo, CA, USA) was quantified and examined by the ELISA method.
  • the degree of the peribronchial and perivascular inflammation was evaluated by a objective scale of 0-3. A value of 0 was assigned when no inflammation was detectable, a value of 1 was assigned for occasional cuffing with inflammatory cells, a value of 2 was assigned for most bronchi or vessels surrounded by a thin layer (one to five cells), and a value of 3 was assigned for most bronchi or vessels surrounded by a thick layer (more than five cells thick). Total lung inflammation was defined as the average of the peribronchial and perivascular inflammation scores.
  • ⁇ -MEM Minimal essential medium alpha modification
  • FBS fetal bovine serum
  • penicillin streptomycin
  • trypsin-EDTA used for cell culture were purchased from Gibco-BRL.
  • 1,25(OH) D dex- amethasone
  • TRAP Temporal resistant acid phosphatase staining kit and other chemical reagents were purchased from Sigma- Aldrich.
  • New born ICR mice were purchased from Biolinks Co. (Korea), and 6 week-old ddY mice were purchased from Charles River Japan Lab (Japan).
  • the compounds prepared in Example 1 were dissolved in DMSO, and diluted with culture medium containing a 0.1% solvent.
  • the osteoclast formation index was measured by counting the number of TRAP- positive multinucleated osteoclasts (TRAP(+) MNCs). Bone marrow cells (2.5 xlO cells/D) and calvaria-derived osteoblasts (4 x l ⁇ cells/D) were co-cultured in ⁇ -MEM containing the compounds prepared in Example 1 (0.01, 0.1 and 1 D/D) and 10% FBS in the presence of 1,25(OH) D (10 M) and dexamethasone (10 M) for 7 days.
  • TRAP(+) MNCs The osteoclast formation index was measured by counting the number of TRAP- positive multinucleated osteoclasts (TRAP(+) MNCs). Bone marrow cells (2.5 xlO cells/D) and calvaria-derived osteoblasts (4 x l ⁇ cells/D) were co-cultured in ⁇ -MEM containing the compounds prepared in Example 1 (0.01, 0.1 and 1 D/D) and 10% FBS
  • Bone marrow cells were isolated from the femora of 6 week-old ddY mice, and osteoblasts were isolated from calvaria of new born ICR mice by sequential digestions with 0.2% collagenase. The media were changed with fresh media every two days. On the 6th day, the cells were fixed with 10% formaldehyde, and stained for TRAP. The number of TRAP(+) MNCs containing 6-7 nuclei was observed using an electron microscope (ZEISS Axiovert 25, Swiss).
  • An injectable liquid formulation containing 10 mg of the active ingredient was prepared as the following method. [114] 1 g of the compound of the formula 1, 0.6 g of sodium chloride, and 0.1 g of ascorbic acid were dissolved in distilled water to be 100 ml. The solution was put into a bottle, and heated to be sterilized at 2O 0 C for 30 minutes. [115] The composition of the injectable liquid formulation is as follows.
  • a syrup formulation containing the compound of the formula 1 as an active ingredient was prepared as the following method.
  • the compound of the formula 1, saccharin, and sugar were dissolved in 80 g of warm water. The solution was cooled, and a solution containing glycerin, saccharin, flavor, ethanol, sorbic acid, and distilled water was added thereto. Water was added to the mixture to be 100 ml.
  • composition of the syrup formulation is as follows.
  • a tablet formulation containing 15 mg of the active ingredient was prepared as the following method.
  • composition of the tablet formulation is as follows.
  • 5-lipoxygenase inhibitory activity reduces the degree of airway hypersensitivity, levels of cytokines IL-4, IL-5, and IL- 13, Ova-specific IgE in serum, and degree of the peribronchial and perivascular inflammation, statistically significantly reduces the number of TRAP(+) MNCs, and significantly inhibits osteoclastogenesis in a co- culture system of bone marrow cells and osteoblasts, thereby being used to prevent and treat diseases induced by leukotriene, in particular, inflammatory diseases including asthma or osteoporosis.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Immunology (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau dérivé de benzoxazole ayant une activité inhibitrice de 5-lipoxygénase, son procédé de préparation et une composition pharmaceutique le renfermant. Le dérivé de benzoxazole selon l'invention possède une excellente activité inhibitrice de 5-lipoxygénase, réduit le degré d'hypersensibilité bronchique, les taux de cytokines IL-4, IL-5 et IL- 13, d'IgE spécifique à l'OVA dans le sérum et le degré de l'inflammation péribronchique et périvasculaire, réduit sensiblement sur le plan statistique le nombre de TRAP(+) MNCs et empêche sensiblement l'ostéoclastogenèse dans un système de co-culture de cellules de moelle osseuse et d'ostéoblastes, que l'on utilise alors pour empêcher et pour traiter des maladies induites par le leucotriène, en particulier des maladies inflammatoires dont l'asthme et l'ostéoporose.
PCT/KR2007/004681 2006-09-22 2007-09-21 Nouveau dérivé de benzoxazole, son procédé de préparation et composition pharmaceutique le renfermant Ceased WO2008035956A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20060092326 2006-09-22
KR10-2006-0092326 2006-09-22

Publications (1)

Publication Number Publication Date
WO2008035956A1 true WO2008035956A1 (fr) 2008-03-27

Family

ID=39200729

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2007/004681 Ceased WO2008035956A1 (fr) 2006-09-22 2007-09-21 Nouveau dérivé de benzoxazole, son procédé de préparation et composition pharmaceutique le renfermant

Country Status (2)

Country Link
KR (1) KR20080027191A (fr)
WO (1) WO2008035956A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8466186B2 (en) 2010-12-10 2013-06-18 Boehringer Ingelheim International Gmbh Compounds
US8486968B2 (en) 2010-12-10 2013-07-16 Boehringer Ingelheim International Gmbh Compounds
US8586604B2 (en) 2010-08-20 2013-11-19 Boehringer Ingelheim International Gmbh Inhibitors of the microsomal prostaglandin E2 synthase-1
US8598190B2 (en) 2008-09-25 2013-12-03 Boehringer Ingelheim International Gmbh 3H-imidazo [4, 5-C] pyridine-6-carboxamides as anti-inflammatory agents
US8674113B2 (en) 2010-12-10 2014-03-18 Boehringer Ingelheim International Gmbh Compounds
US8759537B2 (en) 2010-08-20 2014-06-24 Boehringer Ingelheim International Gmbh 3H-imidazo [4, 5-C] pyridine-6-carboxamides as anti-inflammatory agents
US8921405B2 (en) 2009-03-05 2014-12-30 Orexo Ab Compounds
CN104292179A (zh) * 2014-10-19 2015-01-21 湖南华腾制药有限公司 一种2-氯苯并[d]恶唑-5-甲醛的制备方法
CN104311544A (zh) * 2014-09-22 2015-01-28 湖南华腾制药有限公司 一种苯并恶唑衍生物的制备方法
CN104327061A (zh) * 2014-10-19 2015-02-04 湖南华腾制药有限公司 一种溴苯并[d]恶唑衍生物的制备方法
JP2023503217A (ja) * 2019-10-02 2023-01-27 克洛索科学公司 抗老化遺伝子ｋｌｏｔｈｏの発現を誘導する化合物およびその用途

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101666727B1 (ko) 2013-12-30 2016-10-14 이화여자대학교 산학협력단 신경세포의 분화 또는 재생, 신경손상 또는 신경질환의 치료 효과가 있는 신규한 물질, 이의 제조방법 및 이를 포함하는 약학 조성물
KR102064611B1 (ko) 2017-10-13 2020-01-09 이화여자대학교 산학협력단 벤즈옥사졸 유도체, 이의 제조 방법 및 이를 포함하는 약학적 조성물

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002051821A1 (fr) * 2000-12-22 2002-07-04 Astrazeneca Ab Composes therapeutiques
WO2004063177A1 (fr) * 2003-01-13 2004-07-29 F. Hoffmann-La Roche Ag Derives de benzoxazole et leur utilisation en tant que ligands des recepteurs de l'adenosine
KR20040086698A (ko) * 2003-04-03 2004-10-12 학교법인 이화학당 벤족사졸 유사체의 제조방법
KR20050007056A (ko) * 2003-07-11 2005-01-17 학교법인 이화학당 5-리폭시게나제 억제용 약학적 조성물

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002051821A1 (fr) * 2000-12-22 2002-07-04 Astrazeneca Ab Composes therapeutiques
WO2004063177A1 (fr) * 2003-01-13 2004-07-29 F. Hoffmann-La Roche Ag Derives de benzoxazole et leur utilisation en tant que ligands des recepteurs de l'adenosine
KR20040086698A (ko) * 2003-04-03 2004-10-12 학교법인 이화학당 벤족사졸 유사체의 제조방법
KR20050007056A (ko) * 2003-07-11 2005-01-17 학교법인 이화학당 5-리폭시게나제 억제용 약학적 조성물

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8703796B2 (en) 2008-09-25 2014-04-22 Boehringer Ingelheim International Gmbh 3H-imidazo [4, 5-B] pyridine-6-carboxamides as anti-inflammatory agents
US9040565B2 (en) 2008-09-25 2015-05-26 Orexo Ab 1H-benzimidazole-5-carboxamides as anti-inflammatory agents
US8598190B2 (en) 2008-09-25 2013-12-03 Boehringer Ingelheim International Gmbh 3H-imidazo [4, 5-C] pyridine-6-carboxamides as anti-inflammatory agents
US8916599B2 (en) 2008-09-25 2014-12-23 Orexo Ab 1H-benz imidazole-5-carboxamides as anti-inflammatory agents
US8921405B2 (en) 2009-03-05 2014-12-30 Orexo Ab Compounds
US8759537B2 (en) 2010-08-20 2014-06-24 Boehringer Ingelheim International Gmbh 3H-imidazo [4, 5-C] pyridine-6-carboxamides as anti-inflammatory agents
US8586604B2 (en) 2010-08-20 2013-11-19 Boehringer Ingelheim International Gmbh Inhibitors of the microsomal prostaglandin E2 synthase-1
US8466186B2 (en) 2010-12-10 2013-06-18 Boehringer Ingelheim International Gmbh Compounds
US8674113B2 (en) 2010-12-10 2014-03-18 Boehringer Ingelheim International Gmbh Compounds
US8486968B2 (en) 2010-12-10 2013-07-16 Boehringer Ingelheim International Gmbh Compounds
CN104311544A (zh) * 2014-09-22 2015-01-28 湖南华腾制药有限公司 一种苯并恶唑衍生物的制备方法
CN104292179A (zh) * 2014-10-19 2015-01-21 湖南华腾制药有限公司 一种2-氯苯并[d]恶唑-5-甲醛的制备方法
CN104327061A (zh) * 2014-10-19 2015-02-04 湖南华腾制药有限公司 一种溴苯并[d]恶唑衍生物的制备方法
JP2023503217A (ja) * 2019-10-02 2023-01-27 克洛索科学公司 抗老化遺伝子ｋｌｏｔｈｏの発現を誘導する化合物およびその用途
JP7412546B2 (ja) 2019-10-02 2024-01-12 克洛索科学公司 抗老化遺伝子ｋｌｏｔｈｏの発現を誘導する化合物およびその用途

Also Published As

Publication number Publication date
KR20080027191A (ko) 2008-03-26

Similar Documents

Publication Publication Date Title
WO2008035956A1 (fr) Nouveau dérivé de benzoxazole, son procédé de préparation et composition pharmaceutique le renfermant
JP6448562B2 (ja) 線維症を治療するための置換芳香族化合物及び関連方法
US8642656B2 (en) Calixarene-based peptide conformation mimetics, methods of use, and methods of making
KR20160040452A (ko) 폐 섬유증, 간 섬유증, 피부 섬유증 및 심장 섬유증의 치료를 위한 치환된 방향족 화합물
EP3098224B1 (fr) Dérivé de pyranochroményl phénol, et composition pharmaceutique pour le traitement d'un syndrome métabolique ou d'une maladie inflammatoire
JP6917649B2 (ja) 新規化合物及びそれを有効成分として含有する、線維症または非アルコール性脂肪肝炎の予防、改善または治療用組成物
CA2983312A1 (fr) Derives de l'acide propionique tetrahydronaphthyridinyle et leurs utilisations
CN116947756B (zh) 环丁烯二酮基喹啉类化合物及其制备方法、药物组合物和应用
CN118598820B (zh) 一种二苯基三嗪类化合物及其制备方法和应用
CN107721924A (zh) 加替沙星衍生物及其制备方法和用途
US20230322837A1 (en) Preparation method for and application of class of stellate bifunctional compounds targeting spike protein against respiratory tract infection virus and salt thereof
CN113072484B (zh) 含有琥珀酸酯的磺胺苯甲酰胺类化合物及其制备方法与应用
US20070066577A1 (en) Benzoxazole derivative or analogue thereof for inhibiting 5-lipoxygenase and pharmaceutical composition containing same
RU2642426C1 (ru) 1-Этил-6-фтор-4-оксо-7-(8-этокси-2-оксо-2Н-хромен-3-ил)-1,4-дигидрохинолин-3-карбоновая кислота, обладающая противотуберкулезной активностью
CN102432607A (zh) 一种吡嗪异喹啉衍生物在制备治疗血吸虫药物中的应用
JP7472139B2 (ja) フェノキシカルボン酸化合物およびその医薬用途
CN101486659B (zh) α1-肾上腺素受体拮抗剂及其制备方法和医药用途
CN114315930A (zh) 化合物或其可药用盐、药物组合物及用途
KR102727491B1 (ko) RORα의 활성자로서의 신규한 티오우레아 유도체 및 이를 포함하는 약학적 조성물
CN114181225B (zh) 一种含笑内酯衍生物及其药物组合物、制备方法和用途
KR20090032372A (ko) 2,4,5-삼중치환-1,3-티아졸 유도체 및 약제학적으로 허용가능한 그의 염, 그의 제조방법 및 그를 유효성분으로함유하는 ｓｐｃ 수용체 활성으로 유발되는 염증관련 질환치료제
WO2019080842A1 (fr) Composé d'acide uronique, son procédé de préparation et son utilisation
WO2020249139A1 (fr) Forme cristalline b de sel de potassium d'inhibiteur de phosphodiestérase de type 5, son procédé de préparation et son utilisation
WO2025092340A1 (fr) Utilisation d'un composé de pyrrolotriazine dans la préparation d'un médicament pour la prévention et/ou le traitement de la fibrose ou d'une maladie associée
KR101051077B1 (ko) 2-피페라지노-4,5-이중치환-1,3-티아졸 유도체, 그의 제조방법 및 그를 유효성분으로 함유하는 ｓｐｃ 수용체 활성으로 유발되는 염증관련질환 치료제

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: 07808443

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: 07808443

Country of ref document: EP

Kind code of ref document: A1