WO1994011355A1 - Derive de 3,4-dihydro-1(2-hydroxyphenyl)-2(1h)-quinoxalinone et compose associe - Google Patents

Derive de 3,4-dihydro-1(2-hydroxyphenyl)-2(1h)-quinoxalinone et compose associe Download PDF

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WO1994011355A1
WO1994011355A1 PCT/JP1993/001646 JP9301646W WO9411355A1 WO 1994011355 A1 WO1994011355 A1 WO 1994011355A1 JP 9301646 W JP9301646 W JP 9301646W WO 9411355 A1 WO9411355 A1 WO 9411355A1
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group
alkyl group
substituted
hydrogen atom
atom
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PCT/JP1993/001646
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English (en)
Japanese (ja)
Inventor
Motoji Kawasaki
Tadahiro Sawayama
Tomohiro Nigo
Shinya Nagata
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Dainippon Pharmaceutical Co., Ltd.
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Priority to AU54335/94A priority Critical patent/AU5433594A/en
Publication of WO1994011355A1 publication Critical patent/WO1994011355A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines 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 to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C07D239/96—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring

Definitions

  • the present invention relates to a novel 3,4-dihydro-11- (2-hydroxyphenyl) -12 (1H) -quinoxalinone derivative represented by the following formula (I), which has a smooth muscle relaxing action, a related compound, and a compound thereof. Related to metal salts.
  • R 3 is hydrogen, alkyl, halogen, hydroxy. Cyano, carboxyl, trifluoromethyl, etc.
  • Ring A is a benzene or pyridine ring which may have up to 4 R 3 .
  • West German Patent Application Publication No. 2652144 discloses that compounds represented by the following formula [B] and their physiologically acceptable acid addition salts and quaternary salts have anti-inflammatory, sedative and analgesic effects. However, there is no description about a compound having a hydroxyphenyl group or a 2-alkoxy-15-substituted phenyl group as R 1 .
  • R 1 represents C! -C 6 alkyl, alkoxycarbonyl, hydroxy, etc., and when R 2 is a hydrogen atom and R 3 is halogen, methoxyphenyl, ethoxyphenyl or 3,4-xylyl; When R 2 is fuunyl substituted with benzyl or methyl, it may be a hydrogen atom.
  • R 2 means benzyl, pyridyl or the like, and when R 1 is methoxyphenyl, ethoxyphenyl or 3,4-xylyl and R 3 is halogen, it is a hydrogen atom.
  • R 3 represents a hydrogen atom or a halogen. However, when R 1 is methoxyphenyl, ethoxyphenyl or 3,4-xylyl and R 2 is a hydrogen atom, R 3 is halogen. ]
  • R 1 represents a phenyl group, a substituted phenyl group (where the substituent is 1 or 2 selected from halogen, lower alkyl, lower alkoxy and trifluoromethyl) or a cyclohexyl group
  • R 2 represents an alkyl group, a substituted alkyl group or an unsaturated alkyl group.
  • Japanese Patent Application Publication No. 477819 discloses a 1- (2-hydroxy or mercaptophenyl) -1H-benzimidazol-2-one derivative represented by the following formula [D]: They are C a 2 + -dependent forces It is stated to have a channel opening effect.
  • the compound of the present invention is different from the compound described in the above publication in that quinoxaline, benzoxazine or quinazoline is used as a basic skeleton. Are clearly different.
  • R 1 is hydrogen, d- 6 alkyl, etc.
  • X is 0, S or NCN
  • Y is 0 or S
  • R 4 , R 5 , R 6 and R 7 are each independently hydrogen, halogen, trifluoromethyl, hydroxy, S 0 2 NR 1 R 1 ′ (where R ′ and R M are independently hydrogen or C — Is 6 alkyl)
  • R 11 is hydrogen, halogen, nitro, etc.
  • R 13 is hydrogen, halogen, etc.
  • R 12 is hydrogen, or aromatic taken together with R 13, or partially optionally saturated C 4 - 7 to form a carbocyclic ring,
  • R 14 is hydrogen, or R 13 together such connexion aromatic and, or partially form an optionally C 4 7 carbon ring which may be saturated.
  • Compounds having a smooth muscle relaxing action are mainly used as therapeutic agents for cardiovascular, respiratory, digestive, urinary disorders and the like.
  • calcium channel antagonists Antidrugs and potassium channel openers are known.
  • diphedipine, diltiazem, verabamil and the like are known as calcium channel antagonists [for example, Anne M. Keogh & John S. Schroeder: J.C. 6, s28-s35 (1990); Y. Ouchi & H. 0 rimo: J. Cardiovas c. Pharma col., 16 supp 1.
  • potassium channel openers for example, Buckingham, JC et al .: J. Cardiovas c. Pharma col., 8, 798-804 (1986); E scande D. & Cavero I .: Trends Ph. rma col. Sci., 1_3_, 269-272 (1992); Go od, MD et al. : Br. J. Pharmacol., 105_. 933-940 (1992)].
  • these drugs are not always satisfactory in terms of efficacy or side effects, and the development of new types of smooth muscle relaxants is desired.
  • the present inventors have conducted intensive studies to obtain a compound having a new chemical structure and an excellent smooth muscle relaxing action. As a result, the present inventors have found that 3,4-dihydro 1- (2-hydroxyphenyl) 1 2 The present inventors have found that (1H) monoquinoxalinone derivatives and related compounds have a smooth muscle relaxing action, and have completed the present invention.
  • A represents an oxygen atom, a carbonyl group or NR 1 , wherein R 1 is a hydrogen atom, a lower alkyl group, a hydroxy-substituted lower alkyl group, a lower alkoxy-substituted lower alkyl group, a lower alkyl group
  • B represents a NR 2 or CR 3 R, wherein R 2 is a hydrogen atom, a lower alkyl group, a hydroxy-substituted lower alkyl group, a lower alkoxy-substituted lower alkyl group, or R 3 and R 4 are the same or different and are the same or different and represent a hydrogen atom, a lower alkyl group, a hydroxy-substituted lower alkyl group, a lower alkoxy-substituted lower alkyl group, a nitroxy-substituted lower alkyl group, a phenyl-substituted group; Lower alkyl group
  • X 1 and X 2 represent at least one atom or group other than a hydrogen atom, which is the same or different and is a hydrogen atom, a halogen atom, a trifluoromethyl group, a dinitro group, a cyano group, a lower alkoxycarbonyl group, carboxyl group, 5-tetrazolyl group, a force Rubamoiru group, hydroxy group, -C 2 Furuoroa Alkoxy group, sulfamoyl group, lower alkylsulfamoyl group, di-lower alkylsulfamoyl group or benzoyl group,
  • Y 1 represents a hydrogen atom, a halogen atom or a nitro group
  • Y 2 represents a hydrogen atom, or together with Y 3 together with the benzene ring to which they are attached to form a naphthalene ring;
  • Y 3 represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a nitro group or a phenyl group,
  • Y 4 represents a hydrogen atom or a lower alkyl group, or together with Y 3 together with the benzene ring to which they are attached, forms a naphthalene ring
  • z represents a hydrogen atom, a lower alkyl group, a lower alkoxy substitution. It means a lower alkyl group, a hydroxy-substituted lower alkyl group, a nitroquine-substituted lower alkyl group, or a group that can be converted to a hydrogen atom in vivo.
  • alkali metal salt of the compound represented by the formula (I) examples include a lithium salt, a sodium salt, and a potassium salt. Since the compounds of formula (I) and salts thereof may exist in the form of hydrates or solvates, these hydrates and solvates are also included in the compounds of the present invention.
  • the group which can be converted into a hydrogen atom in a living body in the compound represented by the formula (I) is, for example, an acetyl group, a propionyl group, a benzoyl group, an ethoxycarbo group. And an acyl group such as an amino group and an amino acid residue.
  • a compound having such a group may be referred to as a prodrug.
  • the compounds of formula (I) optionally have one or more asymmetric carbon atoms, it is possible that several stereoisomers may exist. These stereoisomers, their mixtures and racemates are included in the compounds of the present invention.
  • lower alkyl group means a straight-chain or branched alkyl group having 1 to 6 carbon atoms unless otherwise specified, and a lower alkyl group having 1 to 3 carbon atoms is preferable.
  • Lower alkanoyl group means a saturated aliphatic carboxylic acid residue having 2 to 6 carbon atoms.
  • aroyl group means an unsubstituted or substituted aromatic carboxylic acid residue, for example, a halogen atom, a lower alkyl group or a lower alkoxy group as a substituent such as benzoyl, chlorobenzoyl, methylbenzoyl or methoxybenzoyl. And a benzoic acid residue which may have the like.
  • R la is a hydrogen atom, a C, to C 3 alkyl group, a hydroxy-substituted d
  • R 3a and R 4a are the same or different and each represent a hydrogen atom, a ⁇ C 3 alkyl group, Human Dorokishi substituted d -C 3 alkyl group, d -C 3 alkoxy-substituted C, ⁇ c 3 alkyl group, nitroxy substituted to c 3 alkyl group, phenyl substituted
  • Ci -C 3 alkyl group human Dorokishifuweniru substituted D ⁇ c 3 alkyl group, D ⁇ c 3 alkoxy phenylalanine substituted c! To c 3 alkyl group, phenyl group,
  • R 3a Means ci to c 3 alkoxy substituent Fuweniru group or a halogen-substituted Fuweniru group, or R 3a is optionally form a double bond between 3 and 4-position of the 3, 4 Jihi Dorokinokisarin ring together with R la In that case, R 4a also means a hydroxy group or a d-C 3 alkoxy group,
  • W represents an oxygen atom or a sulfur atom
  • One of X la and X 2a is a halogen atom, a trifluoromethyl group, a nitro group, a cyano group, a C! To C 3 alkoxycarbonyl group, a carboxyl group, a 5-tetrazolyl group, a carbamoyl group or a Ci to C 2 full group.
  • Y la represents a hydrogen atom, a halogen atom or a nitro group
  • Y 2a represents a hydrogen atom, or together with Y 3a, together with the benzene ring to which they are attached, forms a naphthalene ring,
  • Y 3a represents a hydrogen atom, a halogen atom, a trifluoromethyl group or a fuunyl group
  • Y a represents a hydrogen atom or a d-C 3 alkyl group, or forms a naphthalene ring together with Y 3a together with the benzene ring to which they are attached;
  • Z a represents a hydrogen atom, a C 3 alkyl group, a C 3 alkoxy substitution d a C 3 alkyl group, a hydroxy substitution C! ⁇ C 3 alkyl group, a nitroxy substitution ⁇ ⁇ (: a 3 alkyl group or an acyl group Yes.]
  • Another preferred compound of the present invention has the general formula (Ib)
  • R 3b is a hydrogen atom, Ci to C 3 alkyl group, hydroxy substituted d to C 3 alkyl group, d to C 3 alkoxy substituted d to C 3 alkyl group, nitroxy substituted d to (: 3 alkyl group, phenyl substituted C ⁇ C 3 alkyl group, hydroxyphenyl substituted C! ⁇ (: 3 alkyl group or ⁇ C 3 alkoxyphenyl substituted C ⁇ ⁇ (: 3 alkyl group, R 4b is a hydrogen atom, C! ⁇ C 3 ⁇ alkyl group, human Dorokishi substituted d -C 3 alkyl group, d -C 3 alkoxy-substituted c!
  • w represents an oxygen atom or a sulfur atom
  • One of which is a halogen atom, a trifluoromethyl group, a nitro group, a cyano group,
  • Ci Ci to C 3 alkoxyl radical, carbonyl group, 5-tetrazolyl group or rubamoyl group; the other means a hydrogen atom or a halogen atom; Y 3a represents a hydrogen atom, a halogen atom, a trifluoromethyl group or a phenyl group,
  • Y b represents a hydrogen atom or, together with Y 3b , forms a naphthalene ring together with the benzene ring to which they are bound,
  • z b represents a hydrogen atom, a -c 3 alkyl group or an acyl group.
  • Further preferred compounds of the present invention include compounds of the general formula (Ic)
  • R 2a, Y la, Y 2a, Y a, Z a denotes the same supra
  • one of X lb and X 2b denotes a halogen atom, triflate Ruo Russia methyl group or a nitro group, the other is a hydrogen atom or a halogen atom
  • Upsilon 3 means halogen atom, triflate Ruo Russia methyl or Fuweniru group.
  • Suitable compounds include the compounds in Tables 1 to 5 below and metal salts thereof.
  • the compound of the present invention can be produced, for example, by the following method. Production method (a)
  • a 1 has an oxygen atom or NH
  • R 31 has a hydrogen atom or a lower alkyl group.
  • R 41 represents a hydrogen atom, a lower alkyl group, a phenyl group, a lower alkoxy-substituted phenyl group or a halogen-substituted phenyl group
  • ⁇ is the same or different and represents a hydrogen atom, a halogen atom, a trifluoromethyl group, Toromoto, human Dorokishi group means a C!
  • This ring closure reaction is performed without a solvent or in an appropriate solvent.
  • the solvent include alcohols such as methanol and ethanol, ethers such as diisopropyl ether and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as benzene, and dimethylformamide. Dimethyl sulfoxide, and acetonitrile.
  • the reaction temperature is usually about 10 ° C to about 200 ° C, preferably about 60 ° C to about 150 ° C.
  • This ring closure reaction is accelerated in the presence of an acid or a base.
  • the acid used include hydrogen chloride, hydrogen bromide, sulfuric acid, p-toluenesulfonic acid, and camphorsulfonic acid.
  • Specific examples of the base include sodium bicarbonate, bicarbonate lime, and the like. Alkali carbonates such as sodium bicarbonate, sodium carbonate and carbonated carbonate, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine Tertiary amines may be mentioned.
  • the reaction temperature is usually about 0 ° C to about 200 ° C, preferably about 20 ° C to about 150 ° C.
  • the ring-closing reaction of the compound of the formula (II) wherein A 1 is NH is preferably carried out in an inert atmosphere, for example, in a stream of nitrogen or argon.
  • the reaction is carried out in a suitable solvent in the presence of a reagent suitable for funolic ether cleavage, preferably inert. Under atmosphere (for example, (In a stream of nitrogen or argon).
  • a reagent suitable for funolic ether cleavage preferably inert. Under atmosphere (for example, (In a stream of nitrogen or argon).
  • the combination of the reagent and the solvent should be appropriately selected according to the type of the compound (III). Specific examples thereof include trimethylsilane iodide chloroform, sodium ethanethiolate / dimethylformamide, and cyanide.
  • the reaction temperature varies depending on the type of the compound (III) and / or the reagent.
  • boron tribromide it is usually about 180 ° C. to about 40 ° C.
  • aluminum bromide, boron trifluoride / getyl ether complex The temperature is usually about 5 ° C. to about 35 ° C. for trimethylsilane, usually about 5 ° C. to about 50 ° C. for trimethyl iodide, and usually the heating reflux temperature for other reagents.
  • X 11 and X 21 in the formula (III) are atoms or groups other than a nitro group, and the protecting group in Z is a benzyl group, they can also be eliminated by catalytic reduction.
  • catalysts for catalytic reduction include palladium-carbon, palladium-barium sulfate, palladium-calcium carbonate, platinum oxide, and Raney nickel. Ethanol, acetic acid, etc. are used as solvents, and the reaction temperature is usually about 10 ° C to about 50 ° C.
  • a compound in which Z is a lower alkoxy-substituted lower alkyl group, a hydroxy-substituted lower alkyl group or a nitroxy-substituted lower alkyl group is obtained by cleaving the ether bond of the compound in which Z is a lower alkyl group.
  • a compound in which Z is a lower alkyl group may be converted to another compound in which Z is a lower alkyl group.
  • This alkylation reaction is carried out in a suitable solvent in the presence of a base.
  • a suitable solvent include ethers such as tetrahydrofuran and dioxane, dimethylformamide, and dimethylsulfoxide.
  • ethers such as tetrahydrofuran and dioxane
  • dimethylformamide such as dimethylsulfoxide.
  • the base include alkali metal hydrides such as lithium hydride and sodium hydride, and alkali carbonates such as sodium carbonate and lithium carbonate.
  • alkylating agent examples include lower alkyl halides such as methyl iodide, halogenated ethers such as 2-iodoethyl methyl ether, benzyl halides such as benzyl bromide, and methyl methanesulfonate.
  • Lower alkyl esters of lower alkyl sulfonic acids, and lower alkyl esters of aryl sulfonic acids such as methyl ⁇ -toluenesulfonic acid are exemplified.
  • the reaction temperature is usually about 150 ° C to about 100 ° C, preferably about 120 ° C to about 50 ° C.
  • the compound in which A 1 is NH in the formula (III) it is preferable that the compound is subjected to the present alkylation reaction with its amino group protected.
  • the amino-protecting group include acyl groups such as trifluoroacetyl and trichloroacetyl.
  • the compound of the formula (III) wherein Z is a hydrogen atom can also be converted to a prodrug by reacting the compound with an acylating agent in a suitable solvent in the presence of a base.
  • a suitable solvent include ethers such as diisopropyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as methylene chloride, chloroform, and chlorinated ethylene, dimethylformamide, dimethyl sulfoxide, and acetonitrile.
  • the base include alkali bicarbonate such as sodium bicarbonate and potassium bicarbonate, and alkali carbonate such as sodium carbonate and lithium carbonate.
  • acylating agent examples include acetic anhydride, acetyl chloride, propionyl chloride, and benzoyl chloride.
  • the reaction temperature is generally about 45 ° C to about 100 ° C, preferably about 120 ° C to about 50 ° C.
  • the compound in which A 1 is NH in the formula (II), which is a starting compound of the production method (a), can be produced, for example, by the method shown in the following scheme 1.
  • R 31 , R 41 , X 11 , X 21 , Y 1 , ⁇ 2 , ⁇ 3 , Y 4 , L 1 and Z have the same meanings as described above, and L 2 is a halogen atom, lower alkyl. It means the reactive ester residue of alcohol such as sulfonyloxy and arylsulfonyloxy.
  • the reaction of the compound of the formula (IV) with the compound of the formula (V) is usually carried out in a solvent such as tetrahydrofuran in the presence of a base such as triethylamine.
  • the reaction temperature is usually about 120 ° C to about 100 ° C.
  • the compound ( ⁇ may be used in the form of an acid addition salt to form a free base in the reaction system.
  • the compound in which A 1 is an oxygen atom in the formula (II), which is a starting compound of the production method (a), can be produced, for example, by the method shown in the following scheme 2. '
  • the compound of the formula ( ⁇ ⁇ I) can be produced by a method known per se, and the compound of the formula (VII) is commercially available or is produced by a method known per se.
  • Can be The reaction of the compound of the formula (VI) with the compound of the formula (VI I) is usually carried out in the presence of copper powder or cuprous iodide and a base such as potassium carbonate, without solvent or in a solvent such as dimethylformamide. Done in The reaction temperature is usually about
  • This reaction is usually performed in a solvent such as methanol in the presence of a base such as sodium methoxide.
  • the reaction temperature is usually about 0 ° C to about 150 ° C.
  • This step can be carried out in the same manner as in the method of Scheme 1, except that sodium hydride, potassium carbonate or the like can be further used as a base.
  • the compound in which A 1 is an oxygen atom in the formula (II), which is a starting compound of the production method (a), can also be produced, for example, by the method shown in Scheme 3 below.
  • R 31 , R 41 , X 11 , X 21 , Y 1 , Y 2 , Y 3 , Y 4 , L 1 , L 3 and Z mean the same as described above, and R 51 is a lower alkyl group. Or a benzyl group.
  • the compound of the formula (X) can be produced by a method known per se, and the compound of the formula (XI) is commercially available or can be produced by a method known per se.
  • the reaction of the compound of the formula (X) with the compound of the formula (XI) is usually carried out in the presence of copper powder or cuprous iodide and a base such as carbonated rim, without solvent or in a solvent such as dimethylformamide. Done.
  • the reaction temperature is usually about 20 ° C to about 250 ° C. .
  • This step can be performed in the same manner as in step 3 of scheme 2.
  • the ring-closure reaction from the compound of the formula (XIV) to the compound of the formula (XV) is carried out under an inert atmosphere (for example, in a stream of nitrogen or argon) without a solvent or in a suitable solvent.
  • the solvent the solvent described in the production method (a) can be used as it is.
  • This reaction is carried out in the presence of a base as necessary.
  • the base include alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, and water such as sodium hydroxide and potassium hydroxide.
  • Alkali metal alkoxides such as alkali oxide and sodium methoxide, alkali carbonates such as sodium carbonate and potassium carbonate, alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, triethylamine, diisopropylethylamine, pyridine, 2,4-dimethyl pyridine Organic bases.
  • the reaction temperature is usually about -45 ° Ci to about 150 ° C, preferably about 0 ° C to about 100 ° C.
  • the compound of the formula (XIV), which is the starting compound of the production method (b) can be produced, for example, by the method shown in Scheme 4 below.
  • L 4 is a carboxylic acid halide, This refers to the residue obtained by removing the acyl group from the reactive derivative of sulfonic acid such as a symmetrical anhydride or a mixed anhydride.
  • the compound of the formula (XVI) can be produced, for example, according to the method described in EP-A-478197 or by a method known per se. It is used in a state where the functional hydroxyl group is protected with an ether-based protecting group, if necessary. Further, the compound of the formula (XVII) is commercially available or can be produced by a method known per se.
  • Reaction of a compound of formula (XVI) compounds with formula (XV II) is preferably in the presence of a base such as pyridine, c reaction temperature is carried out in a solvent such as as tetrahydrofuran is about normal C ⁇ about a 20 ° 100 ° C.
  • This reduction step is carried out by reacting a compound of the formula (XVIII) ′ with a reducing agent in an appropriate solvent, or by catalytically reducing a compound of the formula (XVIII) in the presence of a catalyst.
  • Examples of the reducing agent include a combination of a metal (eg, zinc powder, tin powder, tin samar gum) and an acid (eg, hydrochloric acid, acetic acid).
  • Examples of the catalyst for catalytic reduction include palladium-carbon, palladium-barium sulfate, palladium-calcium carbonate, platinum oxide, and Raney nickel.
  • the solvent used should be appropriately selected according to the type of the reducing agent or the reducing means, and includes, for example, ethanol and acetic acid.
  • the reaction temperature varies depending on the type of the reducing agent or the reducing means. The reaction temperature is usually about -20 ° C to about 100 ° C, and in the case of catalytic reduction, preferably about 10 ° C to about 50 ° C.
  • the hydrogen atom is converted to a lower alkyl group, a hydroxy-substituted lower alkyl group, a lower alkoxy-substituted lower alkyl group, a nitroxy-substituted lower alkyl group, a phenyl-substituted lower alkyl group, or a hydroxyphenyl-substituted lower alkyl group.
  • Alkyl group or lower alcohol The compound of the present invention substituted with a xylixunyl-substituted lower alkyl group can be produced.
  • This reaction is performed in a suitable solvent in the presence of a base.
  • a suitable solvent include ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, and dioxane, and aromatic hydrocarbons such as toluene and xylene.
  • ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, and dioxane
  • aromatic hydrocarbons such as toluene and xylene.
  • Specific examples of the base include lithium diisopropylamide and lithium hexamethyldisilazide.
  • alkylating agent examples include lower alkyl halides such as methyl iodide, halogenated ethers such as 2-iodoethyl methyl ether, benzyl halides such as benzyl bromide, and methyl methanesulfonate.
  • Lower alkyl esters of lower alkyl sulfonic acids, and lower alkyl esters of aryl sulfonic acids such as methyl ⁇ -toluenesulfonic acid are exemplified.
  • the reaction temperature is generally about -150 ° C to about 100 ° C, preferably about 100 ° C to about 50 ° C.
  • the raw material compound used in the present alkylation reaction is the corresponding raw material compound.
  • the compound in which A is an oxygen atom is prepared by the production method (a), and the compound in which A is NR 1 is produced by the production method (a) or ( b).
  • the starting compound was protected with an ether-based protecting group, if necessary, or when A was NH, protected with an amino-protecting group such as methoxymethyl, benzyloxymethyl, and trimethylsilylethoxymethyl. As such, it is subjected to an alkylation reaction.
  • the compound obtained by the present alkylation reaction is obtained by removing the protecting group, if any, in the compound and subjecting the compound to an alkylation reaction or an acylation reaction, if necessary, to obtain the compound of the present invention.
  • the elimination of the protecting group for the amino group is carried out in a suitable solvent under acidic conditions.
  • the solvent alcohols such as methanol, ethanol, propanol, and butanol, or a mixture of these with water is used.
  • the reaction temperature is usually about -40 ° C to about 150 ° C, preferably about 0 ° C to about 100 ° C.
  • A is NR 1
  • B is CR 3 R 43
  • R 3 is linked to R 1 to form a double bond between the 3- and 4-positions of the 3,4-dihydroquinoxaline ring.
  • the compound in which W is an oxygen atom has the general formula (Id)
  • R 43 is a hydrogen atom, a lower alkyl group, a hydroxy-substituted lower alkyl group, Lower alkoxy-substituted lower alkyl group, nitroxy-substituted lower alkyl group, fuunyl-substituted lower alkyl group, hydroxyphenyl-substituted lower alkyl group, lower alkoxyphenyl-substituted lower alkyl group, phenyl group, lower alkoxy-substituted phenyl group or halogen substitution
  • a compound represented by) is oxidized under mild conditions, and then, if a protecting group is present, the protecting group is removed.
  • the compound is subjected to an alkylation reaction or an acylation reaction. It can be manufactured by attaching.
  • This oxidation reaction is a method of treating with dichlorodisianoparabenzoquinone (DDQ) Z methanol at about 0 ° C to about 50 ° C, oxygen gas Z alcohol at about 0 ° C to about 50 ° C, and acidic conditions. (E.g., methanol, ethanol), and nitrobenzene at the reflux temperature.
  • DDQ dichlorodisianoparabenzoquinone
  • the compound of the formula (Id) can be produced by the production method (a), (b) or (c) using the corresponding starting compound.
  • the compound of the formula (Ie) can be produced, for example, according to the method described in EP-A-477819 or by a method known per se.
  • the compound of the formula (V ') is commercially available or can be produced by a method known per se.
  • the reaction of the compound of the formula (Ie) with the compound of the formula (V ') is usually carried out in the presence of an acid without solvent or in a suitable solvent.
  • an acid without solvent or in a suitable solvent.
  • specific examples of the solvent Te Jerusalemi Dorofuran, methylene chloride, ethanol, specific examples of the c acid methanol may be mentioned hydrochloric acid, sulfuric acid, c reaction temperature include p- toluenesulfonic acid is usually about a 45 ° C To about 150 ° C, preferably from about 120 ° C to about 100 ° C.
  • Compound (Ie) may be used in the form of an acid addition salt.
  • the product can be produced by adding a nucleophile thereto and, when protected, removing the protecting group and, if necessary, subjecting it to an alkylation reaction or an acylation reaction.
  • This reaction is carried out in a suitable solvent in the presence of a nucleophile.
  • the nucleophile include alkyl magnesium halides and lithium dialkyl copper (I) complexes. Specific examples include methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium bromide, and phenyl magnesium. Butyl amide, orthobromophenylmagnesium bromide ", paramethoxyphenylmagnesium bromide, dimethyl copper (I) lithium complex, and getyl copper (I) lithium complex.
  • the solvent include ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, and dioxane, and aromatic hydrocarbons such as benzene, toluene, and xylene.
  • the reaction temperature is usually about a 100 ° Celsius to about 100 ° C, preferably about one 50 Q Celsius to about 50 ° C.
  • the compound of the formula (If) can be produced by the production method (d) or (e) using the corresponding starting compound.
  • a 1 , R 3 , R 4 , Y 1 , Y 2 , Y 3 , ⁇ 4 and ⁇ mean the same as described above, and X 13 and X 23 are the same or different, and represent a hydrogen atom, a halogen atom, except atom, triflate Ruo Russia methyl, C! -C 2 full O b alkoxy group, it means a hydroxycarboxylic group or a sulfamoyl group. However, in the case of X 13 and X 23 are both hydrogen atoms.
  • the compound represented by is protected with an ether-based protecting group, if necessary, and then reacted with phosphorus pentasulfide in a suitable solvent. If protected, the protecting group is eliminated, and if necessary, It can be produced by subjecting it to an alkylation reaction or an acylation reaction.
  • the reaction temperature is usually about 20 ° C to about 200 ° C, preferably about 20 ° C to about 150 ° C.
  • reaction of the compound of the formula (I g) wherein A 1 is NH is preferably carried out under an inert atmosphere, for example, in a stream of nitrogen or argon.
  • the compound of the formula (Ig) can be produced by the production methods (a), (b), (c), (d), (e) and (f) using the corresponding starting compounds.
  • This reaction is usually performed in the presence of a base, without a solvent, or in an appropriate solvent.
  • a base include dioxane, diglyme, toluene, xylene, nitrobenzene, and dimethylformamide.
  • Specific examples of the base include potassium acetate, potassium carbonate, potassium tert-butoxide, 4-dimethylaminopyridine, sodium hydride, and potassium hydride.
  • the reaction temperature is usually about 0 ° C. to about 250 ° C., preferably about 50 ° C. to about 200 ° C.
  • the compound represented by the formula (Ih), which is a starting compound of the production method (h), can be produced, for example, by the method shown in the following scheme 5.
  • R 31 , R 41 , X 11 , X 21 , ⁇ 1 , ⁇ 2 , ⁇ 3 , ⁇ 4 , L 1 , L 2 , L 3 and ⁇ mean the same as described above.
  • the compounds represented by the formulas (XIX) and (V) are commercially available, or can be produced by a method known per se.
  • the compound of the formula (XIX) may be used in a protected state, if necessary. Is done.
  • reaction of the compound of the formula (XIX) with the compound of the formula (V) is usually carried out in the presence of a base such as sodium hydride, in the absence of a solvent or in the presence of a solvent such as dimethylformamide. Performed in a medium.
  • the reaction temperature is usually about 150 ° C to about 100 ° C.
  • This step is performed in the presence of a base such as potassium tert-butoxide, without a solvent, or in a solvent such as dimethylformamide.
  • the reaction temperature is usually about 150 ° C to about 150 ° C.
  • the compound in which A is a carbonyl group and B is NR 2 is a compound represented by the general formula (XXI) protected with an ether-based protecting group, if necessary.
  • Y 1 , Y 2 , Y 3 , ⁇ 4 and ⁇ mean the same as described above, and R 5 means a lower alkyl group.
  • the compound can be produced by reacting with a compound represented by the formula (1) and, when protected, removing the protecting group and subjecting it to an alkylation reaction or an acylation reaction, if necessary.
  • the compound of the formula (XXI) and the compound of the formula (XXII) are commercially available or can be produced by a method known per se.
  • reaction between compound (XXI) and compound (XXI I) is carried out without a solvent or in an appropriate solvent.
  • the solvent include diisopropyl ether, tetrahydrofuran, dioxane, diglyme, benzene, toluene, xylene, dimethylformamide, and dimethylsulfoxide.
  • This reaction is preferably performed in the presence of a base.
  • the base include sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, and 4-diethylbenzene. Methylamino pyridine is mentioned.
  • the reaction temperature is generally about 120 ° C to about 200 ° C, preferably about 50 ° C to about 150 ° C.
  • A is an oxygen atom or NR 1
  • B is a compound of CR 3 R 4, or R 1 is a hydrogen atom or a lower alkyl group, or R 3 and 3 become one cord
  • 4 Forms a double bond between the 3- and 4-positions of the dihydroquinoxaline ring.
  • the compound in which X 1 or X 2 is a trifluoromethyl group can convert this trifluoromethyl group into a carboxyl group or a lower alkoxycarbonyl group by a conventional method.
  • A is an oxygen atom or NR 1
  • B is a compound of CR 3 R 4, or R 1 is a hydrogen atom or a lower alkyl group, or R 3 and 3 become one cord
  • a compound in which a double bond is formed between the 3- and 4-positions of the 4-dihydroquinoxaline ring and X 1 or X 2 is a bromine atom is converted to a cyano group or a carbamoyl group by a conventional method.
  • A is at NR 1
  • B is CR 3 R
  • R 1 and R 3 together 3, 4-dihydroquinoxaline sarin ring 3, 4 between the form a double bond
  • a compound in which A is NH and B is CHR 4 in the formula (I) can be produced.
  • a compound in which A is NH and B is CH 2 is an alkylating agent R 5 L 3 (R 5 is a lower alkyl group, and L 3 means a halogen atom) in an oxygen stream.
  • Alkylation proceeds simultaneously with oxidation under the conditions of normal alkylation using, and in formula (I), A is NR 1 , B is CR 3 R, and R 1 and R 3 are taken together.
  • A is NR 1
  • B is CR 3 R
  • R 1 and R 3 are taken together.
  • a compound can be produced in which a double bond is formed between the 3,4-position of the 3,4-dihydroquinoxaline ring and R 4 is a lower alkoxy group.
  • R 4 is a hydroxy group can be produced by cleaving the ether bond of R 4 by a conventional method.
  • the product obtained by each of the above production methods can be isolated and purified by a conventional method such as chromatography, recrystallization, and reprecipitation.
  • the compound of the present invention represented by the formula (I) can be converted to an alkali metal salt by treating it with an alkali metal compound.
  • a tool for metal compounds examples include alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, lithium methoxide, sodium methoxide and potassium tert.
  • Metal alkoxides such as butoxide and sodium amide.
  • salts is carried out according to a conventional method, for example, water, alcohols (eg, methanol, ethanol, isopropyl alcohol), ethers (eg, getyl ether, tetrahydrofuran, dioxane, diisopropyl ether), aromatic hydrocarbons (eg, The reaction is carried out by contacting the compound (I) with an appropriate alkali metal compound at about 120 ° C to about 50 ° C in benzene, toluene or a mixture thereof.
  • alcohols eg, methanol, ethanol, isopropyl alcohol
  • ethers eg, getyl ether, tetrahydrofuran, dioxane, diisopropyl ether
  • aromatic hydrocarbons eg, The reaction is carried out by contacting the compound (I) with an appropriate alkali metal compound at about 120 ° C to about 50 ° C in benzene, toluene or a mixture thereof.
  • a spontaneously developing male hypertension rat (SHR) weighing about 300 g (16 weeks old) was subjected to a heparin-containing catheter (polyethylene tube; PE-50) for blood pressure measurement under inhalation anesthesia with getyl ether.
  • a heparin-containing catheter polyethylene tube; PE-50
  • the test compound suspended in a tragacanth solution containing 30% polyethylene glycol was orally administered at a dose of 10 mg / kg, and blood pressure was measured.
  • Blood pressure was measured using a real-time automatic measurement method by converting it into a digital electric signal via a pressure transducer, an amplifier and an AZD converter and taking it into a computer in order to remove noise and perform an accurate measurement.
  • Test compound Delta MBP * ⁇ S.E the most decreased blood pressure after administration (represented by the example number) ⁇ , mmHg time (hr
  • the thoracic aorta of a male Std-Wi star (body weight about 280 g) was excised, and a spiral specimen was prepared by a conventional method. After the specimen was peeled endothelial cells in cotton, modified Krebs solution (118mM N a C 1, 4. 7mM KC 1, 2. 5mM C a C 12, 1. 2mM KH 2 P0 4, 25mM NaHC0 3, 1. 2 mM Mg S 0 4 ⁇ 7H 2 0, 11 mM glucose) was suspended in a bus (1 OML) filled with. The resting tension 50 Omg loaded induced contractions in the winter two Refurin (10- 7 M). After the contraction was stabilized, the test compound was added cumulatively to examine the relaxation effect.
  • modified Krebs solution 118mM N a C 1, 4. 7mM KC 1, 2. 5mM C a C 12, 1. 2mM KH 2 P0 4, 25mM NaHC0 3, 1. 2 mM Mg S 0 4 ⁇ 7H 2 0, 11 m
  • test compound was dissolved in a mixed solvent of polyethylene glycol: dimethyl sulfoxide (9: 1) or ethanol. It was appropriately diluted with purified water. Winter two Refurin (10- 7 M) due to shrinkage and high as 100%, Searching for the relaxation response as percent inhibition 50% inhibition concentration
  • the compound of the formula (I) and an alkali metal salt thereof (hereinafter sometimes referred to as the compound of the present invention) have an excellent vasodilating action, hypotensive action, etc. based on a smooth muscle relaxing action, and therefore have high blood pressure. It is useful for the prevention and treatment of ischemic heart diseases such as arteriosclerosis, angina pectoris, myocardial infarction and congestive heart failure, arrhythmias, and alopecia.
  • the compounds of the present invention may also be used in addition to cardiovascular diseases, such as cerebrovascular disorders (eg, cerebral vasospasm, migraine, dizziness), respiratory disorders.
  • Harms eg, reversible airway obstruction, irritable airway obstruction, bronchial asthma
  • gastrointestinal disorders eg, neuro-gastrointestinal disorders, irritable bowel diseases
  • urinary disorders eg, frequent urination, dysuria, incontinence
  • the administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, but oral administration is preferred.
  • the dose varies depending on the type of compound, the administration method, the patient's symptoms and age, etc., but is usually 0.1 to 50 mg Zg g Z, preferably 0.2 to: L O mg / k.
  • the compound of the present invention is usually administered in the form of a preparation prepared by mixing with a preparation carrier.
  • a preparation carrier a substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used. Specifically, for example, lactose, glucose, mannitol, starch, sucrose, magnesium aluminate metasilicate, synthetic aluminum gaterate, crystalline cellulose, carboxymethylcellulose sodium, hydroxypropyl starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin , Arabic rubber, Hydroxypropylpropylcellulose, Low-substituted hydroquinpropylcellulose, Hydroxypropylmethylcellulose, Polyvinylpyrrolidone, Polyvinyl alcohol, Light gay anhydride, Magnesium stearate, talc, Carboxy vinyl Nil polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin este
  • Dosage forms include tablets, capsules, granules, powders, syrups, suspensions, suppositories, injections and the like. These preparations are prepared according to a conventional method. In the case of liquid preparations, they may be dissolved or suspended in water or other appropriate medium at the time of use. Tablets and granules may be coated by a well-known method. These preparations can contain the compound of the present invention in a proportion of 0.1% or more, preferably 0.5 to 70%. These formulations may also contain other therapeutically active ingredients.
  • Example 4 In the same manner as in Example 4, 1- (5-chloro-2-methoxyphenyl) -13,4-dihydroxy 6-trifluoromethyl-2 (1H) -quinoxalinone obtained in Example 1 was used as a starting material. 1- (5-Chloro-2-methoxyphenyl) -1-6-trifluoromethyl-12 (1H) -quinoxalinone was obtained. 160-163 ° C
  • Example 6 In the same manner as in Example 2, 11- (5-chloro-1--2-methoxyphenyl) -16-trifluoromethyl-2 (1H) -quinoxalinone obtained in Example 6 was used as a starting material. 5-Chloro-2-hydroxyphenyl-1-6-trifluoromethyl-12 (1H) -quinoxalinone was obtained. Melting point 220-2 22 ° C
  • Example 1 Using 1- (5-chloro-2-methoxyphenyl) -1,3-dihydro-3,3-dimethyl-6-trifluoromethyl-2 (1H) -quinoxalinone obtained in Example 17 as a raw material, In the same manner as in 2, 2- (1-chloro-2-hydroxyphenyl) -1,3-dihydro-3,3-dimethyl-16-trifluoromethyl-2 (1H) -quinoxalinone was obtained. Melting point 169-: 170.
  • Example 2 Using 4-acetyl-1-1 (5-chloro-1--2-methoxyphenyl) -13,4-dihydro-6-trifluoromethyl-12 (1H) -quinoxalinone obtained in Example 19 as a raw material
  • 41-acetyl-1-1 (5-chloro-2-hydroxyphenyl) -13,4-dihydro-16-trifluoromethyl-2 (1H) -quinoxalinone was obtained. Melting point 210-2 12 ° C
  • Example 1 1- (5-chloro-2-methoxyphenyl) -1,3,4-dihydro-6-trifluoromethyl-1 2 (1H) -quinoxalinone 2.0 g (5.6 mmo 1) obtained in Example 1 was used. The solution was dissolved in 20 ml of concentrated sulfuric acid, and 10 ml of a concentrated sulfuric acid solution containing 0.85 g (8.4 mmo 1) of potassium nitrate was added at 0 ° C., followed by stirring for 30 minutes. The reaction solution was poured into ice water and stirred for a while, and the deposited precipitate was collected by filtration, washed with water, and dried.
  • reaction solution is concentrated under reduced pressure, ethyl acetate is added, washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 5-bromo-2- (5-chloro-2-methoxyphenyl). 94 g (2.8 mmo 1) of aminoaniline were obtained as a colorless oil.
  • Example 26 Using 1- (5-chloro-2-hydroxyphenyl) -13-methyl-16-trifluoromethyl-2 (1H) -1-quinoxalinone obtained in Example 26 as a raw material, 1 1- (2-acetoxy-5-chlorophenyl) -1-methyl-6-trifluoromethyl-2 (1H) -quinoxalinone was obtained. Melting point 169-171 ° C
  • Example 2 Using the 4- (5-chloro-2-methoxyfuryl) -17-trifluoromethyl-1 2H-1,4-benzoxazine-13 (4H) -one obtained in Example 32 as the starting material, Example 2 In the same manner as described above, 4- (5-chloro-2-hydroxyfurnyl) -17-trifluoromethyl-1 2H-1,4-benzoxazin-13 (4H) -one was obtained. Melting point 198 ⁇ 199 ° C
  • Example 39 The same procedure as in Example 2 was carried out except that the 6-bromo-1- (5-chloro-2-methoxif: nil) -1-H-1,4-benzoxazine-13 (4H) one obtained in Example 37 was used as a raw material. This gave 6-promo 41- (5-chloro-1-2-hydroxyphenyl) -12H-1,4-benzoxazine-13 (4H) one. 258-260 ° C
  • 6-bromo-1- 5-chloro-2-methoxif: nil
  • Example 4 The same procedure as in Example 2 was carried out using 6-force rubamoyl-4-1 (5-chloro-2-methoxyphenyl) -1-2H-1,4-benzodoxazine-13 (4H) -one obtained in Example 40 as a raw material. 6-force rubamoyl-41- (5-chloro-2-hydroxyphenyl) -1-2H-1,4-benzoxazine-13 (4H) -one was obtained. 285-287 ° C
  • 6-Carboxy-41- (5-chloro-2-hydroxyphenyl) -1-H-1.4-Benzoxazine-13 (4H) one obtained in Example 46 0.30 g (0.94 mmo 1) was converted to methanol. It was dissolved in a mixed solvent of 8 ml and 2 ml of toluene, 4 ml of a hexane solution of trimethylsilyldiazomethane (2 M) was added, and the mixture was stirred at room temperature for a while.
  • Example 2 The same procedure as in Example 2 was carried out, except that 1- (5-chloro-1--2-methoxyphenyl) -6-trifluoromethyl-2,4 (1H, 3H) -quinazolinedione obtained in Example 50 was used as a raw material. 1- (5-chloro-1--2-hydroxyphenyl) -1-6-trifluoromethyl-2,4 (1H, 3H) -quinazolinedione was obtained. Melting point 238-239
  • Example 5 The same procedure as in Example 2 was carried out except that the 1- (5-chloro-1--2-methoxyphenyl) -17-trifluoromethyl-2,4 (1H, 3H) -quinazolinedione obtained in Example 56 was used as a raw material. There was obtained 1- (5-chloro-1--2-hydroxyphenyl) -17-trifluoromethyl-2,4 (1H, 3H) -quinazolinedione. Melting point 249-251 ° C
  • the compound (I) and the alkali metal salt thereof of the present invention have excellent vasodilatory and hypotensive effects based on smooth muscle relaxing effects, and are therefore useful as drugs such as therapeutic drugs for cardiovascular diseases.

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Abstract

Dérivé de 3,4-dihydro-1-(2-hydroxyphényl)-2(1H)-quinoxalinone réprésenté par la formule générale (I), ou ses sels de métal alcalin. Dans ladite formule, A représente oxygène, carbonyle ou NR1; B représente NR?2 ou CR3R4; R3¿ représente hydrogène, etc. ou est associé à R1 pour former une liaison double entre A et B; W représente oxygène ou soufre; chacun de X1 et X2 représente trifluorométhyle, etc., Y1 représente hydrogène, etc.; Y2 représente hydrogène, etc.; Y3 représente halogène, etc.; Y4 représente hydrogène, etc.; et Z représente hydrogène, alkyle inférieur, alkyle inférieur substitué ou un groupe pouvant être éliminé in vivo pour laisser l'hydrogène; à condition que si A représente oxygène ou NR1, alors B représente CR3R4, et si A représente carbonyle, alors B représente NR2 et W représente oxygène. Le composé (I) et ses sels présentent une activité vasodilatatrice et hypotensive basée sur l'effet de dépresseur des fibres lisses, et sont donc utilisables comme médicament dans le traitement des maladies cardio-vasculaires ou analogue.
PCT/JP1993/001646 1992-11-19 1993-11-11 Derive de 3,4-dihydro-1(2-hydroxyphenyl)-2(1h)-quinoxalinone et compose associe WO1994011355A1 (fr)

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JP4/335288 1992-11-19
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WO2017112950A1 (fr) 2015-12-24 2017-06-29 The Regents Of The University Of California Régulateurs cftr et méthodes pour les utiliser
US11839616B2 (en) 2017-08-24 2023-12-12 The Regents Of The University Of California Ocular pharmaceutical compositions

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TW202315613A (zh) * 2021-08-12 2023-04-16 大陸商浙江同源康醫藥股份有限公司 多環類化合物及其用途

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JPH04305568A (ja) * 1990-09-24 1992-10-28 Neurosearch As ベンズイミダゾール誘導体、その製造方法及びその使用方法

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Publication number Priority date Publication date Assignee Title
JPH04305568A (ja) * 1990-09-24 1992-10-28 Neurosearch As ベンズイミダゾール誘導体、その製造方法及びその使用方法

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017112950A1 (fr) 2015-12-24 2017-06-29 The Regents Of The University Of California Régulateurs cftr et méthodes pour les utiliser
JP2018538352A (ja) * 2015-12-24 2018-12-27 ザ・リージエンツ・オブ・ザ・ユニバーシテイー・オブ・カリフオルニア Ｃｆｔｒ制御因子及びこの使用方法
EP3394046A4 (fr) * 2015-12-24 2019-06-19 The Regents of the University of California, A California Corporation Régulateurs cftr et méthodes pour les utiliser
RU2730855C2 (ru) * 2015-12-24 2020-08-26 Дзе Риджентс Оф Дзе Юниверсити Оф Калифорниа Кфтр регуляторы и способы их применения
AU2016377785B2 (en) * 2015-12-24 2021-07-01 The Regents Of The University Of California CFTR regulators and methods of use thereof
US11084795B2 (en) 2015-12-24 2021-08-10 The Regents Of The University Of California CFTR regulators and methods of use thereof
JP2021185186A (ja) * 2015-12-24 2021-12-09 ザ・リージエンツ・オブ・ザ・ユニバーシテイー・オブ・カリフオルニア Ｃｆｔｒ制御因子及びこの使用方法
US11839616B2 (en) 2017-08-24 2023-12-12 The Regents Of The University Of California Ocular pharmaceutical compositions

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