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WO2006046683A1 - Antagonistes des récepteurs de leucotriène et de prostaglandine d2 dérivés de thiazolylbenzofurane - Google Patents

Antagonistes des récepteurs de leucotriène et de prostaglandine d2 dérivés de thiazolylbenzofurane Download PDF

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Publication number
WO2006046683A1
WO2006046683A1 PCT/JP2005/019854 JP2005019854W WO2006046683A1 WO 2006046683 A1 WO2006046683 A1 WO 2006046683A1 JP 2005019854 W JP2005019854 W JP 2005019854W WO 2006046683 A1 WO2006046683 A1 WO 2006046683A1
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WO
WIPO (PCT)
Prior art keywords
methyl
tert
butyl
indol
compound
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/JP2005/019854
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English (en)
Inventor
Shinji Shigenaga
Koichi Higuchi
Koichiro Mukoyoshi
Daisuke Tanabe
Takayuki Inoue
Kentaro Sato
Yoshiyuki Tenda
Susumu Tsujimoto
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.)
Astellas Pharma Inc
Original Assignee
Astellas Pharma Inc
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
Priority claimed from AU2004906155A external-priority patent/AU2004906155A0/en
Application filed by Astellas Pharma Inc filed Critical Astellas Pharma Inc
Publication of WO2006046683A1 publication Critical patent/WO2006046683A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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

  • SRSA Stretrachloro-1-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminopyrrolizine and pyridoindolizine derivatives having activites as prostaglandin receptor antagonist, more particularly, prostaglandin D 2 receptor (hereinafter referred to as DP receptor) antagonists have been known, for example, in International Publication No. WO 2004/039807.
  • DP receptor prostaglandin D 2 receptor
  • Another object of this invention is to provide a method oftreatmentand/orpreventionforallergyand/orinflammation including administering a therapeutically effective amount ofthecompoundorthepharmaceuticallyacceptablesaltthereof of this invention to a patient.
  • thiazolylbenzofuran derivatives of this invention can be represented by the following general formula (I):
  • R 3 is loweralkoxy substitutedwithloweralkylcarbamoyl, or pharmaceutically acceptable salts thereof.
  • Some of the compounds of formula (I) may contain one or more asymmetric centers andthus theycan exist as enantiomers or diastereoisomers. This invention includes both mixtures and separated individual isomers.
  • the compounds of the formula (I) may also exist in tautomeric forms and the invention includes bothmixtures and separated individual tautomers.
  • the compounds of the formula (I) and its salts can be in a form of a solvate, which is included within the scope of the present invention.
  • the solvate preferably include a hydrate and an ethanolate.
  • Also includedinthe scopeof invention areradiolabelled derivatives of compounds of formula (I) which are suitable for biological studies.
  • suitable examples, of the various definitions to be includedwithin the scope of the invention are explained in detail in the following.
  • the term "lower” is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
  • Suitable "lower alkyl” , and lower alkyl moiety in the term “lower alkylcarbamoyl” may be a linear or branched one, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, or the like.
  • Suitable “lower alkoxy” may be a linear or branched one, such as methoxy, ethoxy, propoxy, isopropoxy (or 1-methylethoxy) ; butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, or the like.
  • Suitable “esterified carboxy” may be lower alkoxycarbonyl (e.g.
  • aryloxycarbonyl e.g. phenoxycarbonyl, naphtyloxycarbonyl, tolyloxy ⁇ arbonyl, cumenyloxycarbonyl, xylyloxycarbonyl, etc.
  • substituted or unsubstituted aryl(lower)alkoxycarbonyl e.g.
  • Suitable “loweralkylcarbamoyl” maybemethylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, and. the like, in which preferable one is methylcarbamoyl.
  • Preferred “lower alkyl” for R 1 may be tert-butyl.
  • Preferred "lower alkyl substituted with a substituent selected from the group consisting of carboxy and esterified carboxy” for R 2 may be methyl and isopropyl, each of which is substituted with carboxy or methoxycarbonyl.
  • Preferred “lower alkoxy subustituted with lower alkylcarbamoyl” for R 3 may be methoxy and isopropoxy, each of which is substituted with methylcarbamoyl.
  • the compound of the present invention may form a salt, which is included in the present invention as long as pharmaceutically acceptable.
  • the salt includeadditionsaltswithamineralacidsuchashydrochloric acid, hydrobromicacid, hydroiodicacid, sulfuricacid, nitric acid , phosphoric acid, and the like, or an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonicacid, succinic acid, fumaricacid, maleicacid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like; salts with an inorganic base such as sodium, potassium, magnesium, calcium, and the like; or an organic base such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and the like;
  • Transformedhuman embryonickidney (HEK) 293 cells which stably expressed human DP receptor were homogenized in the sucrose buffer by using ultrasonic homogenizer. The homogenate was centrifuged (300 g, 10 min) to remove tissue clumps andthe supernatantwas centrifuged (100,000g, 30min) .
  • mice Specific pathogen-free male BALB/ ⁇ mice were used. Mice were actively sensitized by intraperitoneal injection of 8 ⁇ g ovalbumin (OA) with 2 mg aluminum hydroxide hydrate gel suspension on day 0 and day 5. OA-immunized mice were challenged by an intranasal administration of 40 ⁇ L of saline containing 12.8 ⁇ g OA under pentobarbital sodium anesthesia. Sham-challenged mice were administered saline under the same condition. The compound was dissolved in saline and subcutaneously administrated twice a day on day 12 and day 13.
  • OA ovalbumin
  • bronchoalveolar lavage fluid was collected by lavaging whole-lung three times with 0.5 mL aliquots of Ca 2+ and Mg 2+ free phosphate buffered saline (PBS) via the tracheal cannula.
  • the BALF was centrifuged, and separated cells were resuspended in PBS. The cells were counted with a hemacytometer and cells were cytocentrifuged ontoaglass slide. CellswerestainedwithHemacolor® (Merck) , andthreehundredcellsweredifferentiatedbylightmicroscopy based on conventional morphological criteria, (ii) Test Result:
  • the compound (I) orapharmaceuticallyacceptable salt thereof of the present invention have antagonistic and inhibitory activities for both of leukotriene and DP receptors, and are useful for the treatment and/or prevention of allergy or inflammation inhumanbeings oranimals, andmoreparticularly for prevention and/or treatment of asthma, psoriasis, hepatitis, bronchitis, gastritis, esophagitis, pancreatic, arthritis, nephritis, inflammatoryboweldisease, shock (e.g.
  • septic shock e.g. allergic rhinitis, etc.
  • arteriosclerosis myocardial infarction
  • cerebral vasospasm e.g. allergic rhinitis, etc.
  • conjunctivitis eczema
  • ischemic cerebral disease chronic obstructive pulmonary disease
  • cerebraledema adult respiratorydistress syndrome
  • neonatal pulmonary hypertension Chrohri's disease
  • dermatitis e.g. atopic dermatitis, etc.
  • rheumatism gastric ulcer, peptic ulcer, gout, sinusitis, food allergy, systemic mastocytosis, urticaria, ulcerative colitis and the like.
  • the compound (I) and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid, semi-solid or liquid excipient suitable for oral, parenteral or external (topical) administration.
  • a pharmaceutically acceptable carrier such as an organic or inorganic solid, semi-solid or liquid excipient suitable for oral, parenteral or external (topical) administration.
  • the pharmaceutical preparations may be capsules, tablets including chewable tablets, dragees, granules, suppositories, solution, lotion, inhalant, ophthalmic preparations, collunarium, suspension, emulsion, ointment, gel, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.
  • an average single dose of about 0.01 rag, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating the above-mentioned diseases.
  • amounts between 0.01 mg/bpdy and about 1,000 mg/body may be administered per a day.
  • the compound (I) and a salt thereof of the present invention can be prepared by the following processes.
  • the compound and its pharmaceutically acceptable salt can be prepared by various known synthesis methods, using characteristics based on its basic skeleton or the kinds of functional groups.
  • the representative preparation methods will be explained in detail as below.
  • a suitable protection group i.e. , a group that can be easily converted into the functional group, in the step of a preparation of starting material or intermediate. Then, if necessary, the protection group is removed to obtain a desired compound.
  • the functional group include hydroxy, carboxy, and amino
  • examples of the protection group include those described in "Protective Groups in Organic Synthesis ", third edition, edited by Greene and Wuts. It is preferable to suitably use them depending on reaction conditions.
  • R 1 is as defined in the foregoing,
  • R 21 is as loweralkyl substitutedwithesterifiedcarboxy
  • R 22 is lower alkyl substituted with carboxy
  • R 3 is loweralkoxysubstitutedwithloweralkylcarbamoyl
  • R 4 is lower alkyl
  • Starting material (Ia) of this method and related compounds are described in WO 97/27190.
  • acompound (Ib) canbe obtainedbyhydrolysis of a compound (Ia) .
  • the compound of the invention (I-a) canbepreparedby the aminolysis of acompound (Ib) with (Ic).
  • hydrolysis reagent for the first step NaOH aq, KOH aq, and the like can be used.
  • the reaction is carried out in an inert organic solvent such as an alcohol including MeOH, EtOH, andthelike; oraetherincludingtetrahydrofuran (THF) , dioxane, diglyme and the like, under cooling, cooling to ambient temperature, or ambient temperature to heating.
  • an inert organic solvent such as an alcohol including MeOH, EtOH, andthelike; oraetherincludingtetrahydrofuran (THF) , dioxane, diglyme and the like
  • Aminolysis of the second step can be carried out in an inert organic solvent such as an alcohol; an ether; and the like, undercooling, coolingtoambienttemperature, orambient temperaturetoheating.
  • an inert organic solvent such as an alcohol; an ether; and the like
  • methylester, ethylester, or the like is preferably used as esterified carboxy in "X" of the formula (I) .
  • the deprotection of the first step can be carried out in an inert organic solvent such as a halogenated hydrocarbon including dichloromethane, dichloroethane, chloroform and the like,- an aromatic hydrocarbon including benzene, toluene, xylene and the like; an ether including diethylether, THF, dioxane, diglyme and the like; an ester including ethyl acetate; N,N-dimethylformamide (DMF); dimethylsulfoxide (DMSO); and the like, under cooling, cooling to ambient temperature, or ambient temperature to heating.
  • an inert organic solvent such as a halogenated hydrocarbon including dichloromethane, dichloroethane, chloroform and the like,- an aromatic hydrocarbon including benzene, toluene, xylene and the like; an ether including diethylether, THF, dioxane, diglyme and the like; an ester including ethy
  • the reaction it is preferable to carry out the reaction using a condensing agent such as dicylcohexylcarbodiimide, carbonyldiimidazole, diphenylphosphorylazide, diethylphosphorylcyanide, or 1-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) , andphosphorous oxychlorideinpyridine solvent, orthelike.
  • a condensing agent such as dicylcohexylcarbodiimide, carbonyldiimidazole, diphenylphosphorylazide, diethylphosphorylcyanide, or 1-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI)
  • EDCI 1-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride
  • EDCI 1-ethyl-3- (3-di

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention a pour objet un composé de formule (I), ou un sel de qualité pharmaceutique de ce composé, qui peuvent être employés comme médicaments : où R1 représente un groupement alkyle court, R2 représente un groupement alkyle court substitué par un substituant sélectionné au sein du groupe constitué par les groupements carboxy et carboxy estérifié, et R3 représente un groupement alcoxy court substitué par un groupement alkylcarbamoyle court.
PCT/JP2005/019854 2004-10-25 2005-10-24 Antagonistes des récepteurs de leucotriène et de prostaglandine d2 dérivés de thiazolylbenzofurane Ceased WO2006046683A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2004906155A AU2004906155A0 (en) 2004-10-25 Thiazolylbenzofuran Derivatives
AU2004906155 2004-10-25

Publications (1)

Publication Number Publication Date
WO2006046683A1 true WO2006046683A1 (fr) 2006-05-04

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010127452A1 (fr) * 2009-05-04 2010-11-11 The Royal Institution For The Advancement Of Learning/Mcgill University Composés antagonistes des récepteurs 5-oxo-ete
CN107635961A (zh) * 2015-03-31 2018-01-26 皇家学习促进学会/麦吉尔大学 作为5‑氧代‑ete受体拮抗剂的吲哚类似物及其使用方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0528337A1 (fr) * 1991-08-16 1993-02-24 Fujisawa Pharmaceutical Co., Ltd. Dérivés de thiazolylbenzofuranes, procédé de préparation et compositions pharmaceutiques les contenant
WO1997027190A1 (fr) * 1996-01-22 1997-07-31 Fujisawa Pharmaceutical Co., Ltd. Derives du thiazolylbenzofuranne et compositions pharmaceutiques les contenant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0528337A1 (fr) * 1991-08-16 1993-02-24 Fujisawa Pharmaceutical Co., Ltd. Dérivés de thiazolylbenzofuranes, procédé de préparation et compositions pharmaceutiques les contenant
WO1997027190A1 (fr) * 1996-01-22 1997-07-31 Fujisawa Pharmaceutical Co., Ltd. Derives du thiazolylbenzofuranne et compositions pharmaceutiques les contenant

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010127452A1 (fr) * 2009-05-04 2010-11-11 The Royal Institution For The Advancement Of Learning/Mcgill University Composés antagonistes des récepteurs 5-oxo-ete
US8809382B2 (en) 2009-05-04 2014-08-19 The Royal Institution For The Advancement Of Learning/Mcgill University 5-oxo-ETE receptor antagonist compounds
US9464048B2 (en) 2009-05-04 2016-10-11 Florida Institute Of Technology 5-oxo-ETE receptor antagonist compounds
CN107635961A (zh) * 2015-03-31 2018-01-26 皇家学习促进学会/麦吉尔大学 作为5‑氧代‑ete受体拮抗剂的吲哚类似物及其使用方法
CN107635961B (zh) * 2015-03-31 2021-07-20 皇家学习促进学会/麦吉尔大学 作为5-氧代-ete受体拮抗剂的吲哚类似物及其使用方法

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