WO1998008820A1 - Composes de benzenesulfone et sels de ces derniers - Google Patents

Composes de benzenesulfone et sels de ces derniers Download PDF

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Publication number
WO1998008820A1
WO1998008820A1 PCT/JP1997/002934 JP9702934W WO9808820A1 WO 1998008820 A1 WO1998008820 A1 WO 1998008820A1 JP 9702934 W JP9702934 W JP 9702934W WO 9808820 A1 WO9808820 A1 WO 9808820A1
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Prior art keywords
group
phenyl
substituted
quinolyl
added
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PCT/JP1997/002934
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English (en)
Japanese (ja)
Inventor
Masaki Yokota
Souichirou Kawazoe
Yoshinori Okamoto
Hirokazu Kubota
Ryo Naito
Yasuhito Arakida
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Yamanouchi Pharmaceutical Co., Ltd.
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Priority to AU38684/97A priority Critical patent/AU3868497A/en
Publication of WO1998008820A1 publication Critical patent/WO1998008820A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms

Definitions

  • the present invention is useful as a medicament, in particular, a prophylactic or therapeutic agent for a disease associated with leukotriene (L Ts) antagonism and toxin oxoxane (TX) A 2 antagonism, in which these mediators are involved.
  • L Ts leukotriene
  • TX toxin oxoxane
  • mediator inhibitors among anti-inflammatory drugs For example, PAF antagonists, thromboxane A 9 (TXA 2 ) antagonists, and leukotriene (LT s) antagonists have been applied to asthma and their efficacy Is being recognized.
  • TXA 2 thromboxane A 9
  • LT s leukotriene
  • both mediators LTs and TXAQ is strongly induced airway resistance increase due to exacerbated and bronchoconstriction effects of the inflammatory response, further TXA 2 is known to be involved into the airway hyperresponsiveness
  • TXA 2 is known to be involved into the airway hyperresponsiveness
  • Japanese Patent Application Laid-Open No. 4-154766 discloses a funoxyacetic acid derivative represented by the following formula having both TXA 2 antagonistic activity and LTs antagonistic activity. Further, JP-5 - 279336 and JP-off phenoxy acetic acid derivatives which antagonize TXA 2 and LTs in Gazette and JP-A-5 262 736 JP-A-3 258 759 is disclosed. However, clinically both mediation evening one inhibitor usefulness was confirmed LTs and TXA 2 has not yet been reported, the creation of the two mediators inhibitors having high inhibitory effect and good oral absorbability crave Have been.
  • JP-A-5-105664, JP-A-5-105665, JP-A-5-25135 and EP 233763 disclose quinoline derivatives having leukotriene antagonistic activity.
  • Japanese Patent Application Laid-Open No. 5-105665 discloses a compound having a clinical trial number of MK-476 (Example 161) which is being developed as an oral cotriene antagonist represented by the following formula.
  • these quinoline derivatives have LTs antagonism but do not have T XA 2 antagonism and are not multiple mediator inhibitors, and are therefore useful with the compounds of the present invention. Sex is completely different. Further, the compounds of the present invention differ from these compounds in that they have a benzene sulfone or benzene sulfonamide structure. Disclosure of the invention
  • An object of the present invention is to provide a compound useful as a multiple mediator inhibitor having both TXA 2 antagonism and LTs antagonism, and a medicament containing the compound as an active ingredient.
  • the present inventors have found that by creating drugs that inhibit two or more mediators (multiple mediator inhibitors), multiple mediator inhibitors can be effective drugs for allergic diseases such as asthma with a high effective rate. think, predicted to be particularly TXA 0 antagonism and L in case of having both the both effects of Ts antagonism as an antiasthmatic synergistic therapeutic effect can be expected, it has extensive research. As a result, they have found that the novel benzenesulfone compound represented by the following general formula (I) or a salt thereof has both of the above two effects and has good oral absorption, and LTs and TXA. Both The present inventors have found that they can be effective and powerful anti-asthmatics in a wide range as a data inhibitor, and have completed the present invention.
  • the present invention relates to a benzenesulfone compound represented by the following general formula (I) or a salt thereof, a pharmaceutical composition containing the compound as an active ingredient, preferably leukotriene and thromboxane A: 2 For both antagonists.
  • a 1 , A 2 One of them is a methylene group which may be substituted or an ethylene group which may be substituted, and the other is a single bond, a methylene group which may be substituted or a substituted group.
  • Y is a phenylene group which may be substituted, A 1 and ⁇ may both be a single bond;
  • ⁇ a phenylene group which may be substituted, a phenylene group which may be substituted or a spirocyclopropynyl group which may be substituted;
  • R carboxyl group or tet which may be substituted by ester residue Lazolyl group
  • B force halogen atom, hydroxyl group, lower alkoxy group, cyano group, amino group, mono- or di-lower alkylamino group, nitro group and lower alkyl group (the lower alkyl group is , A halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono or di-lower alkylamino group, a nitro group, an aryloxy group and an aralkyloxy group.
  • a quinolyl group which may be substituted with a group selected from the group consisting of: a D atom, a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono or Di-lower alkylamino group, nitro group and lower alkyl group (the lower alkyl group is a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono- or di-alkyl group).
  • the optionally substituted phenylene group, the optionally substituted phenyleneoxy group or the optionally substituted spirocyclopropyl group may be a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, respectively.
  • An optionally substituted methylene group or an optionally substituted ethylene group is a halogen atom, a hydroxyl group, a lower alkoxy group, an aryl group or a lower alkyl group (the lower alkyl group is a halogen atom, a hydroxyl group, One or more groups selected from a lower alkoxy group, an amino group, a mono or di-lower alkylamino group, an aryloxy group and an aryl group.
  • B-force is a 2-quinolyl group which may be substituted with a halogen atom, and which may be substituted with a D-force, ', a halogen atom, a lower alkoxy group, a nitro group and a halogen atom.
  • a phenyl group which may be substituted with a group selected from good lower alkyl groups, and a phenylene group which may be substituted with a group selected from halogen atoms and lower alkoxy groups; A phenyleneoxy group or a spironcropropyl group, wherein A 1 or A may be substituted with a group selected from a lower alkyl group, an aryl group and an aralkyl group; An ethylene group which may be substituted with a group selected from an alkyl group, an aryl group and an aralkyl group, and the other is a single bond, a methylene group or an ethylene group, provided that 1 is 1 and Y is When a phenylene group may be filed by A 1 and A 2 are both single bonds, Z force, the formula - CH CH-, wherein _ CH 2 - CH.
  • X is a sulfur atom, a benzenesulfone compound or a pharmaceutically acceptable salt thereof
  • Particularly preferred compounds include
  • the “optionally substituted quinolyl group” in B is quinolyl. Any carbon atom on the ring of the phenyl group is substituted with 1 to 6 substituents or an unsubstituted quinolyl group.
  • the substituent is a general substituent that can be substituted on a quinolyl group, and specifically, for example, a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono- or mono- or G-lower alkylamino group, nitro group, lower alkyl group (the lower alkyl group is a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono- or lower G-alkylamino group, May be substituted with a group selected from a toro group, an aryloxy group and an aralkyloxy group).
  • halogen atom a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group, or a lower alkyl group substituted with a halogen atom, more preferably a halogen atom.
  • the bond of the quinolyl group to Z may come from any carbon atom on the quinoline ring, but is preferably a 2-quinolyl group or a 3-quinolyl group, more preferably a 2-quinolyl group. It is a ril group.
  • the “optionally substituted phenyl group” in D is an unsubstituted phenyl group in which any carbon atom on the ring of the phenyl group is substituted with 1 to 6 substituents.
  • the substituent is a general substituent that can be substituted on a phenyl group, and specifically includes, for example, a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono- or di-lower alkylamino group.
  • a lower alkyl group such as a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono or di-lower alkylamino group, a nitro group; , An aryloxy group and an aralkyloxy group which may be substituted).
  • a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group, a lower alkyl group (the lower alkyl group may be substituted with a group selected from a halogen atom and a lower alkoxy group) And more preferably a halogen atom, a lower alkoxy group, a nitrogen atom, or a halogen atom.
  • a lower alkyl group which may be substituted with a substituent.
  • the “optionally substituted methylene group or the optionally substituted ethylene group” refers to any one or more hydrogen atoms of a methylene group or an ethylene group; Preferably, one or two are a methylene group or an ethylene group substituted with an arbitrary substituent, and an unsubstituted methylene group or an ethylene group.
  • the substituent is a general substituent capable of substituting for a methylene group or an ethylene group, and specifically, for example, a halogen atom, a hydroxyl group, a lower alkoxy group, an aryl group, a lower alkyl group (for example, The lower alkyl group is substituted with a group selected from a halogen atom, a hydroxyl group, a lower alkoxy group, an amino group, a mono- or di-lower alkylamino group, an aryloxy group and an aryl group. And the like).
  • it is a halogen atom, a lower alkoxy group, an aryl group or a lower alkyl group (the lower alkyl group may be substituted with a group selected from a halogen atom, a lower alkoxy group and an aryl group). And more preferably a lower alkyl group, an aryl group or an aralkyl group.
  • the “carboxyl group optionally substituted by an ester residue” in R is an unsubstituted carboxyl group or a carboxyl group substituted by an ester residue.
  • ester residue includes a lower alkyl group, a lower alkenyl group, a halogeno lower alkyl group (such as a chloromethyl group and a trifluoromethyl group), and an aralkyl group (such as a benzyl group and a lower alkoxybenzyl group).
  • Ester residues such as benzyl group, nitrobenzyl group, benzhydrinole group, lower alkoxybenzylhydryl group, phenethyl group, and 1-naphthylmethyl group), or are hydrolyzed by metabolism in vivo.
  • Ester residues such as lower alkanoyloxy lower alkyl groups (such as acetyloxymethyl group, acetyloxyxethyl group, tert-butanoloxymethyl group), lower alkenyl lower alkyl groups (vinyl carboxymethyl group, vinyl group) Carbonylethyl group, etc.), cycloalkylcar Bonyloxy lower alkyl groups (cyclopropylcarbonyloxymethyl group, cyclobutylcarbonyloxy group, cyclopentylcarbonyloxymethyl group, etc.), lower alkenyloxy lower alkyl groups (vinylcarbonyloxymethyl group, vinylcarbonyloxy group) A lower alkoxy lower alkyl group (a methoxymethyl group, a methoxyxyl group, an ethoxymethyl group, etc.), a lower alkoxy lower alkoxy lower alkyl group (a methoxymethoxy methyl group, etc.), a lower alkoxycarbonyl group,
  • Oxy-lower alkyl groups (methoxycarbonyloxymethyl group, ethoxycarbonylmethyl group, tert-butoxycarboxyloxymethyl group, etc.), benzoyloxy lower alkyl groups (benzoyloxymethyl group, benzoylo group Ixetyl group, etc.), 2—year-old oxotetrahydrofuran-1-5-yl group, 2-oxo-1-5-lower alkyl-1,1-alkyl
  • Examples include lahydrofuranylcarbonyloxymethyl group and phthalidyl group.
  • lower alkyl group Preferably, lower alkyl group, aralkyl group, lower alkanoyloxy lower alkyl group, phthalidyl group, 2-oxo-15-lower alkyl—1,3, -dioxolen-14-ylmethyl group, lower alkoxycarbonyloxy lower alkyl group Group.
  • lower alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group and butyl group are preferred.
  • the “optionally substituted phenylene group” in Y means that any carbon atom on the ring of the phenylene group is substituted with 1 to 4 substituents or unsubstituted phenylene group. is there.
  • the substituent is a general substituent that can be substituted on a phenylene group, and specifically includes, for example, a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, and a monohydroxy group.
  • Di-lower alkylamino group, nitro group, lower alkyl Group (the lower alkyl group is a group selected from a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono- or di-lower alkylamino group, a dinitro group, an aryloxy group and an aralkyloxy group. May be substituted).
  • a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group or a lower alkyl group (the lower alkyl group may be substituted by a group selected from a halogen atom and a lower alkoxy group). And more preferably a halogen atom or a lower alkoxy group.
  • the “phenylene group” includes 1,2-phenylene group, 1,3-phenylene group and 1,4-phenylene group. It is preferably a 1,3-phenylene group or a 1,4-phenylene group, and more preferably a 1,4-phenylene group.
  • the “optionally substituted phenylene group” is a group in which an optionally substituted phenylene group is further bonded to a phenyl group.
  • the group represented by is preferred.
  • the “optionally substituted spirocyclopropyl group” for Y includes a spirocyclopropyl group in which any carbon atom on the ring of the spirocyclopropyl group is substituted with 1 to 4 substituents or unsubstituted. It is.
  • the substituent is a general substituent that can be substituted on a spirocyclopropyl group, and specifically, for example, a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono- or mono- or G lower alkylamino group, nitro group, lower alkyl group (the lower alkyl group is a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono- or di-lower alkylamino group) Group, Nitro group, aryloxy May be substituted with a group selected from a group and an aralkyloxy group).
  • a halogen atom Preferably, a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group or a lower alkyl group (the lower alkyl group may be substituted with a group selected from a halogen atom and a lower alkoxy group) And more preferably a halogen atom or a lower alkoxy group.
  • the “lower alkyl group” includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl Group, 2-methylpentyl group, 3-methylpentyl group, 1,1 dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethyl group T-butyl group, 3,3—dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2—trimethylpropyl group, 1,2,
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Preferably, they are a fluorine atom and a chlorine atom.
  • the “lower alkyl group substituted by a halogen atom” includes chloromethyl group, bromomethyl group, fluoromethyl group, trifluoromethyl group, 1-chloroethyl group, 2,2-dichloroethyl group, and 3-octyl group. Examples thereof include a ropyl pill group, and a trifluoromethyl group is preferable.
  • Examples of the “lower alkoxy group” include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, sec —butoxy group, tert —butoxy group, pentyloxy (amiroxy) group, isopentyloxy group, tert —pentyloxy group, neopentyloquine group, 2-methylbutoxy group, 1,2-dimethylpropo
  • Examples thereof include a xy group, a 1-ethylpropoxy group, and a hexyloxy group. Among them, those having 1 to 4 carbon atoms are preferable, and a methoxy group and an ethoxy group are particularly preferable.
  • the “mono or di-lower alkylamino group” is an amino group in which one or two hydrogen atoms have been substituted with the above-mentioned alkyl group.
  • the two alkyl groups may be the same or different.
  • the mono-lower alkylamino group include a methylamino group, an ethylamino group, a propylamino group, a poramino group, a butylamino group, an isobutylamino group, and a poramino group.
  • di-lower alkylamino group examples include dimethylamino group, getylamino group, dipropylamino group, methylethylamino group, methylpropylamino group, methylisopropylamino group, and methylisopropylamino group.
  • dimethylamino group getylamino group, dipropylamino group, methylethylamino group, methylpropylamino group, methylisopropylamino group, and methylisopropylamino group.
  • the “lower alkenyl group” is a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, an aryl group, a 1-propenyl group, a 1-methylvinyl group, Butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methylaryl, 1-methyl-1-propenyl, 1-methylaryl, 1-pentenyl, 2- Pentenyl group, 3-pentenyl group, 4-pentenyl group, 3-methyl-1-butenyl group, 3-methyl-2-butenyl group, 3-methyl-13-butenyl group, 2-methyl-1-butenyl group, 1,, 1-dimethylaryl group, 1,2-dimethyl-1-propenyl group, 1-ethyl-2-propenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 1,1-Dimethyl-3-butenyl group, 3,3-
  • aryl group means an aromatic hydrocarbon ring group, preferably an aryl group having 6 to 14 carbon atoms, specifically, a phenyl group or a naphthyl group. , An indenyl group, an anthryl group, a phenyl group and the like. Preferable is a phenyl group and a naphthyl group, and more preferable is a fuunyl group.
  • the “aralkyl group” is a group in which an arbitrary hydrogen atom of the above “lower alkyl group” is substituted with the above “aryl group”. Specifically, a benzyl group, a phenethyl group, —Phenylenyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylbutyl, 5-phenylpentyl, 1-naphthylmethyl, 2-naphthylmethyl and the like. It is preferably a benzyl group.
  • aralkyloxy group is a group in which a hydrogen atom of a hydroxyl group is substituted with the above-mentioned aralkyl group, and examples thereof include a benzyloxy group, a phenethyloxy group, and a naphthylmethyloxy group. Preferable is a benzyloxy group.
  • aryloxy group is a group in which a hydrogen atom of a hydroxyl group is substituted with the above-mentioned aryl group, and examples thereof include a phenoxy group and a naphthyloxy group. Preferably it is a phenyl group.
  • the compound of the general formula (I) of the present invention may form a salt.
  • the present invention includes these pharmaceutically acceptable salts.
  • examples of such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid.
  • salts with organic acids such as acids.
  • examples of the salt with a base include inorganic bases such as sodium, potassium, magnesium, potassium, and aluminum; organic bases such as methylamine, ethylamine, and ethanolamine; Examples include salts with basic amino acids such as gin, arginine, and ornithine, and ammonium salts.
  • the compound of the general formula (I) may have an asymmetric carbon atom or a double bond depending on the type of the substituent, and the present invention provides an optical isomer, a geometric isomer and a tautomer based on these. It includes isolated isomers of various isomers such as sex forms and mixtures thereof.
  • the compound of the general formula (I) of the present invention may be used as a hydrate thereof or as various solvates such as an ethanol solvate. Since the compound of the general formula (I) of the present invention may be isolated as a substance having a form, the compound of the general formula (I) of the present invention may have any of these hydrates. Contains substances.
  • the compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods, utilizing characteristics based on the basic skeleton or the types of substituents.
  • an appropriate protecting group that is, a group that can be easily converted to the functional group at the stage of the raw material or intermediate. May be important.
  • the desired compound can be obtained by removing the protecting group as necessary.
  • Examples of such a functional group include a hydroxyl group and a carboxyl group, and examples of such a protective group include Green and Wuts.
  • Protective Groups in Organic Synthetic. s ", and the protecting groups described in the second edition can be used, and these may be appropriately used according to the reaction conditions.
  • the compound of the present invention (la) is obtained by deprotecting the phthalimide derivative represented by the general formula ( ⁇ ) and then subjecting it to a sulfonamidation reaction to remove the protecting group if desired. Is the way.
  • Solvents used for the deprotection of 1) include protonic solvents such as methanol, ethanol, propanol, and water; diisopropyl ether; tetrahydrofuran; 4 Non-dioxane, benzene, toluene, xylene, pyridine, dichloromethane, cycloform, 1,2-dichloroethane, acetonitrile, dimethylformamide, dimethylsulfoxide Protonic solvents and their mixtures are used.
  • As the reaction reagent ammonia, hydrazine, methylhydrazine, methylamine, ethylamine, etc. are used in an amount of 1 equivalent to an excess amount at room temperature or under heating conditions. Alternatively, it is deprotected by using the conditions of hydrolysis. Deprotection can also be achieved by reductive treatment using sodium borohydride or the like, followed by acidic conditions such as acetic acid.
  • the sulfonyl chloride is a reactive derivative of sulfonamide Id ⁇ sulfonic anhydride derivatives and the like can be used, and 1 equivalent to an excess amount thereof can be used under ice cooling to room temperature or room temperature to heating conditions.
  • Solvents used are diisopropyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, pyridine, dichloromethane, chloroform, 1,2-dichloroethane, and acetone.
  • Reactive solvents such as tonitrile, dimethylformamide, dimethylsulfoxide, and water are used.
  • organic bases such as triethylamine, pyridine, picolin, norethidine, N, N-dimethylaniline, N-methylmorpholine, cesium carbonate, lithium carbonate, sodium hydrogencarbonate
  • organic bases such as triethylamine, pyridine, picolin, norethidine, N, N-dimethylaniline, N-methylmorpholine, cesium carbonate, lithium carbonate, sodium hydrogencarbonate
  • an inorganic base such as sodium hydroxide or sodium hydroxide in an amount of 1 equivalent to an excessive amount may be advantageous for smoothly proceeding the reaction.
  • deprotection of the carboxylic acid ester is performed by a conventional method in organic chemistry.
  • a conventional method of acid hydrolysis can be applied, and the reaction is preferably carried out at room temperature to 100 ° C.
  • a hydrogenation reaction or a method using a strong acid such as trifluoroacetic acid can be used.
  • the benzenesulfone compound represented by the general formula (m) is reacted with the alcohol or thiol derivative represented by the general formula (IV), and the protecting group is removed as required. It is a method to obtain I b).
  • the hydroxyl group of compound (III) or the hydroxyl group or mercapto group of compound (IV) may be converted to an active group and used.
  • the conversion is the same as in 2) of the first production method, in the solvent, temperature, and catalyst. It can be performed under the following conditions.
  • Activating reagents include thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, oxalyl chloride, carbon tetrachloride and triphenylphosphine, carbon tetrabromide and trichloride.
  • halogenating reagents such as phenylphosphine, sulfonylating reagents using alkyl or arylsulfonyl chloride, and dialkylazodicarboxylic acids and triphenylphosphine.
  • the reaction with the compound represented by the general formula (IV) can be carried out under the same conditions as in 2) of the first production method, in a solvent and at the same temperature.
  • the organic base or inorganic compound mentioned in 2) of the first production method is used.
  • organometallic reagents such as sodium hydrogen butyl lithium, inorganic salts such as sodium iodide, lithium iodide, and potassium bromide, tetrabutyl bromide
  • Layer transfer catalysts such as ammonium and tetrabutylammonium iodide; mineral acids such as sulfuric acid and phosphoric acid; organic acids such as trifluoracetic acid and trifluoromethansulfonic acid; boron trifluoride; It may be advantageous to add a Lewis acid such as titanium chloride, alone or simultaneously, in a catalytic amount to 1 equivalent or 1 equivalent to excess in order to make the reaction proceed smoothly.
  • reaction solvent examples include ethers such as ethyl ether and tetrahydrofuran, toluene, hexane, N-methylbiperidone, dimethylformamide, and dimethylsulfoxy. Inactive in reactions of N, N, N'-dimethylimigzolinone It is preferable to use a neutral solvent alone or as a mixture.
  • the reaction temperature varies depending on the reaction, and the reaction is suitably carried out at a temperature of from 178 to ice cooling, from ice cooling to room temperature, or from room temperature to heating.
  • a 1 , A 2 , B, D, X, Y, Z, 1, m and n are as described above, and R ′ represents a lower alkyl group or an aryl group.
  • the third production method comprises the steps of: i) reacting a compound represented by the general formula (m) with a cyano compound represented by the formula (X); ii) further reacting a trialkyltin azide represented by the general formula (XI); This is a process for obtaining the compound (Ic) of the present invention by reacting a free tin azide or a sodium azide.
  • the reaction of i) with the cyano compound can be carried out in the same manner as in the second production method.
  • the reaction (ii) is carried out in the presence of trialkyltin azide or triaryltin azide in an inert solvent such as benzene or toluene at room temperature or under reflux conditions for several days to several hours. be able to. It can also be synthesized by stirring in dimethylformamide in the presence of sodium azide and ammonium chloride at room temperature or under reflux for several hours to several days. 4th manufacturing method
  • Cormorants can and child.
  • organic acids such as acetic acid, propionic acid, trifluoroacetic acid, 4-toluenesulfonic acid and methansulfonic acid, boron trifluoride getyl ether complex, Louis iodide and zinc chloride, etc.
  • Acid triethylamine, diisopropylamine, N-methylmorpholine, piperidine, pyrrolidine, morpholine, butylamine, isoptilamine, isopropylamine,
  • Organic bases such as propylamine, sodium acetate, acetic acid
  • Organic acid salts such as sodium, alkali metal reagents such as sodium hydride and butyllithium, inorganic bases such as potassium carbonate, sodium carbonate and sodium hydroxide, tetrakis (Triphenylphosphine)
  • Addition of a transition metal reagent such as palladium or palladium chloride (II) in a catalytic amount or 1 equivalent to an excess amount may be advantageous for smooth progress of the reaction. .
  • a 1 , A 2 , B, D, R, Y, Z, 1, m, p and n are as described above, and U is a halogen atom, a lower alkylsulfonyloxy group, an arylsulfonyl A leaving group such as an oxy group, a formyl group, a carboxyl group or a lower alkyloxy group.
  • This production method comprises the steps of: i) alkylating an amino group of an amino derivative represented by the general formula (XV) with a compound represented by the general formula (XVI); and ii) carboxylic acid represented by the general formula (XVII).
  • the reaction of i) can be carried out in a solvent inert to the same reaction as the solvent exemplified in 1) of the first production method, under the conditions of from 178 to ice cooling to room temperature to reflux temperature.
  • U is a formyl group
  • the reaction is carried out by catalytic hydrogenation using a metal such as platinum, palladium, rhodium or Raney nickel, sodium borohydride, lithium borohydride, This can be performed by a hydride reduction reaction using lithium aluminum hydride, sodium triacetoxyborohydride, or the like.
  • organic acids such as formic acid, acetic acid, and propionic acid; ammonium salts such as ammonium chloride and ammonium formate; mineral acids such as hydrochloric acid and sulfuric acid; and Louis acids such as iron chloride ( ⁇ ) and cerium chloride ( ⁇ ).
  • An organic base such as an acid, triethylamine, piberidine, pyrrolidine, morpholine, butylamine, isopropylamine, or propylamine may be added in a catalytic amount or 1 equivalent to an excess amount. In some cases, it is advantageous for the reaction to proceed smoothly.
  • U When U is a carboxyl group or a lower alkyloxycarbonyl group, it can be produced by a reduction reaction after passing through an amide derivative by an amidation reaction.
  • the amidation reaction can be carried out by a conventional method such as a thermal method, various active esterification methods, an acid chloride method, and an azidation method.
  • the reduction reaction is performed by a hydride reduction method using lithium aluminum hydride, sodium borohydride, a borane complex, or the like, or by reaction with thionyl chloride, phosphorus pentachloride, or the like. After that, a method easily understood by those skilled in the art, such as a method using a hydride reduction method, is applied.
  • an organic base such as triethylamine, diisopropylethylamine, or an inorganic base such as potassium carbonate, sodium hydroxide, or potassium hydroxide
  • the reaction can be carried out by using an alkali metal reagent such as lithium or butyllithium, and optionally adding sodium iodide, potassium iodide, and various interlayer transfer catalysts.
  • the amidation reaction of ii) can be carried out in the same manner as the amidation reaction described in i) above. 6th manufacturing method
  • amidation is carried out using a carboxylic acid derivative represented by the general formula (XVI) and an amine derivative represented by the general formula (XIX), and a protective group is removed as required.
  • a carboxylic acid derivative represented by the general formula (XVI) and an amine derivative represented by the general formula (XIX)
  • a protective group is removed as required.
  • the amidation reaction can be carried out in the same manner as the amidation reaction described in the fifth production method i).
  • a compound in which R is a carboxyl group can be converted to a compound of the present invention in which R is a carboxyl group substituted with an ester residue by esterification.
  • Esterification can be easily carried out by a conventional esterification reaction using an esterifying agent such as an alcohol or a halide thereof, a sulfate, or a diazo compound.
  • Other esters can be introduced using a conventional transesterification reaction.
  • the raw material for producing the compound of the present invention can be easily produced by a conventional method known to those skilled in the art. A typical manufacturing method is described below. (Production method A of raw material compounds)
  • the compound ( ⁇ ) is converted from the amide compound represented by the general formula (VI) to an alcohol or thiol derivative represented by the general formula (IV), and then the raw material intermediate ( This is a method for obtaining the phthalimide derivative of the above (ii).
  • a reagent of an orthophthalic acid derivative such as phthalic anhydride or ⁇ -carboethoxyphthalimide is used.
  • the reaction conditions are 2) of the first production method, a solvent,
  • the reaction may be carried out under similar conditions at temperature and catalyst, or only the reagent may be reacted without adding solvent.
  • the reaction may proceed smoothly.
  • the reaction from compound (W) to compound (II) is performed in the same manner as in the second production method. (Production method B of raw material compounds)
  • the carbonylethene derivative represented by the general formula () is sulfonated or sulfonamided.
  • a benzenesulfone or benzenesulfonamide derivative of the general formula (K) is obtained and further reduced to obtain a benzenesulfone compound as a raw material intermediate (II).
  • the solvent and temperature are the same as in the first production method 2).
  • the reaction reagent sulfonamide derivatives and alkali metal salts of sulfinic acid or sulfinic acid are used, and organic bases such as triethylamine, N, N-dimethylaniline, N-methylmorpholine, and carbonic acid are used.
  • organic bases such as triethylamine, N, N-dimethylaniline, N-methylmorpholine, and carbonic acid are used.
  • Inorganic bases such as cesium, potassium carbonate and sodium hydroxide, alkali metal reagents such as sodium hydride and potassium tert-butoxide, or organic acids such as acetic acid and propionic acid are used. It may be advantageous to add an equivalent amount or an excess amount to make the reaction proceed smoothly.
  • the solvent and temperature are the same as in the first production method 1).
  • the reaction reagent those used in general reduction reactions are used.
  • Hydrogenation reaction under normal pressure or pressure using a metal hydride reagent, palladium, platinum or rhodium catalyst.
  • an optically active ligand is added at the same time, or an optically active compound is prepared by using an optically active reducing reagent.
  • the compound represented by the general formula (Xla) is obtained by i) simultaneous addition or stepwise addition of nitromethane and an alcohol or thiol derivative represented by the general formula (IV) to a benzaldehyde derivative represented by the general formula (XX).
  • the compound (XIV) is obtained by the reaction, followed by ii) reduction of the nitro group, and further iii) sulfonation of the amino group and, if desired, removal of the protecting group.
  • the reaction i) can be carried out in a solvent inert to the same reaction as the solvent exemplified in 1) of the first production method, at room temperature to reflux temperature.
  • organic acids such as acetic acid, propionic acid, trifluoroacetic acid, 4-toluenesulfonic acid and methanesulfonic acid, boron trifluoride-diethyl ether complex, ruisic acid such as zinc iodide and zinc chloride, Triethylamine, diisopropylethylamine, N-methylmorpholine, piperidine, pyrrolidine, morpholine, butylamine, isobutylamine, isopropylamine, propylamine Addition of a catalytic amount or 1 equivalent to an excessive amount of an organic base such as min, an organic acid salt such as sodium acetate or potassium acetate, or an ammonium salt such as ammonium acetate or ammonium chloride is performed. There are cases where
  • the reduction reaction of the nitro group of ii) can be carried out at room temperature to reflux temperature using a solvent which is inert to the same reaction as the solvent exemplified in 1) of the first production method.
  • the reaction is carried out by catalytic hydrogenation using metals such as platinum, palladium, rhodium and Raney nickel, gold reduction using zinc, tin, iron, tin chloride ( ⁇ ), etc., sodium sulfide, and hydrosulfur.
  • metals such as platinum, palladium, rhodium and Raney nickel
  • gold reduction using zinc, tin, iron, tin chloride ( ⁇ ), etc. gold reduction using zinc, tin, iron, tin chloride ( ⁇ ), etc., sodium sulfide, and hydrosulfur.
  • Conventional methods such as a reduction method using a sulfur compound using sodium or the like and a hydride reduction method using lithium aluminum hydride or sodium borohydride can be applied.
  • reaction addition of a catalytic amount, 1 equivalent or an excess amount of an organic acid such as acetic acid or formic acid, a mineral acid such as hydrochloric acid or sulfuric acid, or a Lewis acid such as nickel chloride ( ⁇ ) or titanium tetrachloride is performed. It may be advantageous for smooth progress.
  • organic acid such as acetic acid or formic acid
  • mineral acid such as hydrochloric acid or sulfuric acid
  • Lewis acid such as nickel chloride ( ⁇ ) or titanium tetrachloride
  • reaction of i i i) can be carried out in the same manner as in 2) of the first production method.
  • optical resolution using an organic acid may be performed on an appropriate intermediate compound.
  • the compound represented by the general formula (Cor) has the following formulas in the first, second, third and fifth production methods, where ⁇ and ⁇ are as described above.
  • reaction products obtained by each of the above methods are isolated and purified as various solvates such as free compounds, their salts or hydrates.
  • the salt can be produced by subjecting it to a usual salt formation reaction.
  • Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
  • Various isomers can be isolated by a conventional method using the physicochemical difference between the isomers.
  • the optical isomers can be separated by a common method of resolving in a semi-semiconductor such as fractional crystallization or chromatography.
  • Optical isomers can also be synthesized from appropriate optically active starting compounds.
  • fractional crystallization fractional crystallization using an optically active organic acid such as a tartaric acid derivative, a mandelic acid derivative, or a camphorsulfonic acid derivative is suitably performed.
  • the solvent a solvent that can efficiently perform optical resolution is appropriately selected. Industrial applicability
  • the compound of the present invention is a drug that has both TXA 2 antagonistic action and LTs antagonistic action and has good oral absorbability. Accordingly the present invention compounds prevention of diseases involving disorders and LTs which TXA 2 is involved.
  • a therapeutic agent useful for example, allergic diseases (e.g. bronchial asthma, allergic rhinitis, urticaria, etc.), ischemic It is useful as a preventive and therapeutic agent for heart disease, brain disease, thrombosis, angina pectoris, inflammatory peptic ulcer, and liver disease. It is particularly useful for the prevention or treatment of allergic diseases involving both mediators (eg, bronchial asthma, allergic rhinitis, urticaria, etc.), ischemic heart / brain disease, and thrombosis.
  • Hartley male guinea pigs (500 to 800 g) were anesthetized with urethane (1.2 gZ kg, i.p.), fixed in a dorsal position, and tracheal force neurons were introduced.
  • Spontaneous respiration was stopped with gallamine (lmg / kg, i.v.), and artificial respiration was performed at a rate of 60 strokes / min, volume 1 ml / 100 g body weight / cycle.
  • U-46619 (3 g / kg) was administered intravenously in the common jugular vein, and the increasing airway resistance was measured with a respiratory function measurement device (Model 6, Buxco Electronics Inc.). The drug was orally administered 1 hour before administration of U-46619 as a dimethyl sulfoxide solution or as a methylcellulose suspension.
  • LTD 4 suppresses vascular hyperpermeability
  • a 1% aqueous solution of Evans blue (lmlZanimal) was intravenously administered to male Hartley guinea pigs whose backs were shaved.
  • LTD 4 (5 ng / site) was administered intradermally to the back of the guinea pig, and 30 minutes later, the animals were killed by decapitation.
  • Skin LTD 4 intradermal sites were collected and extracted leaked dye intradermally. The amount of the leaked dye was calculated by measuring the absorbance at 620 nm and used as an index of vascular permeability.
  • test drug was orally administered as a dimethyl sulfoxide solution one hour before intradermal administration of LTD 4 .
  • the results were calculated as the inhibition rate after lmgZkg of the drug.
  • Table 2 shows the results of representative compounds.
  • Hartley male guinea pigs were sensitized by intraperitoneal administration of ovalbumin (OA) and Al (OH) 3 as antigens three times at 2-week intervals.
  • OA ovalbumin
  • OH Al
  • Galamine 10 minutes before antigen administration
  • indomethacin 2 mgZkg
  • mepyramin 2 mgZkg
  • oral branolol O. SmgZkg
  • the test drug was orally administered 1 hour before the antigen administration.
  • the rate of change in airway resistance after antigen administration was calculated, and the effect of the test drug was examined using the inhibitory effect on airway resistance increase as an index.
  • the compound of the present invention had a good inhibitory effect on the increase in airway resistance.
  • compositions containing one or more of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be prepared by using a commonly used carrier or excipient for a pharmaceutical preparation. Tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, ointments, patches, etc., using other additives, orally or parenterally. Is administered.
  • the clinical dose of the compound of the present invention to humans is appropriately determined in consideration of the symptoms, weight, age, sex, etc. of the patient to which the compound is applied. ⁇ 500mg, parenteral 0.01 ⁇ :! OOmg, given once or divided into several doses. Since the dose varies under various conditions, a dose smaller than the above range may be sufficient.
  • the one or more active substances may include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch. , Polyvinylpyrrolidone, metasilicate, and magnesium aluminate.
  • the composition may contain additives other than inert diluents, for example, lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, and stabilizers such as lactose.
  • solubilizing or solubilizing agents such as glutamate or aspartic acid.
  • the pills and pills are gastric-soluble, such as sucrose, gelatin, hydroxypropylcellulose, and hydroxypropylmethylcellulose phthalate, as necessary. Alternatively, it may be coated with a film of an enteric substance.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, and commonly used inert diluents. Contains, for example, purified water and ethyl alcohol.
  • the composition may contain, in addition to the inert diluent, solubilizing or solubilizing agents, wetting agents, auxiliary agents such as suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Diluents for aqueous solutions and suspensions include, for example, distilled water for injections and physiological saline. Non-water-soluble solutions.
  • diluents for suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, and polysol. There are 80 (brand name) etc.
  • Such compositions may also contain additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing aids. Good.
  • a solubilization treatment may be performed.
  • known methods applicable to pharmaceutical preparations for example, surfactants (polyoxyethylene hydrogenated castor oils, polyoxyethylene sorbitan higher fatty acid esters, polyoxyethylene polyoxypropylene glycols, sucrose) Fatty acid esters, etc.), drugs and solubilizers such as polymers (hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), etc.
  • surfactants polyoxyethylene hydrogenated castor oils, polyoxyethylene sorbitan higher fatty acid esters, polyoxyethylene polyoxypropylene glycols, sucrose) Fatty acid esters, etc.
  • drugs and solubilizers such as polymers (hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), etc.
  • CMEC hydroxypropylmethyl cellulose
  • HPMCP hydroxypropyl methylcellulose cellulose phthalate
  • a method of forming a solid dispersion with a phosphoric acid copolymer an enteric polymer such as Eudragit L, S, trade name; manufactured by Rohm and Haas Co.
  • a method of forming a soluble salt, a method of forming an inclusion compound using cyclodextrin, or the like can also be employed.
  • the method of solubilization can be changed as appropriate depending on the target drug ["Recent drug technology and its application I", Isamu Utsumi, Pharmaceutical Journal 157-159 (1983) and “Pharmaceutical Monograph No. 1, Bioavailability ”, Tsuneji Nagai et al., Soft Science, 78-82 (1988)].
  • the organic layer was washed successively with a 5% aqueous solution of potassium carbonate and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was dissolved in 30 ml of 1,2-dichloroethane, and cooled to 5 ° C, and 0.51 ml (3.6 mmol) of triethylamine, 0.61 g (2.9 mmol) of 4-benzene-sulfonyl chloride was obtained. ) Was added to the solution and reacted for 12 hours.
  • the reaction mixture was distilled off, a 10% aqueous solution of potassium carbonate and ethyl acetate were added, and the obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then the solvent was distilled off. did.
  • the obtained residue was dissolved in 10 ml of toluene. 223 mg of 4-chlorophenyl isocyanate was added, and the mixture was stirred at room temperature for 3 days. Water and ethyl acetate were added to the reaction mixture, and the obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off.
  • (+ Or one) —4-1 [[[2-amino-1 ([3- (1,3-dioxolan-1-2-yl) fu Xnil] ethyl] thio] methyl] methyl benzoate
  • a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to 1.80 g of toluene (+) toluene oil tartrate, and the obtained organic layer was washed with water and saturated saline solution in that order, and then washed with sodium sulfate anhydride.
  • reaction solution was concentrated under reduced pressure, distilled water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and concentrated under reduced pressure. Dissolve 18. lg of the residue in 150 ml of dichloroethane, add 12.1 ml (86.8 mmol) of triethylamine and 6.13 m of methanesulfonyl chloride (79.2 mmol) under ice-cooling, and keep at that temperature for 30 minutes. Stirred. Reaction liquid Distilled water was added to the mixture, and the mixture was separated. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure.
  • Ethyl acetate hydrochloride 500 mg (1.16 mmol) was desalted, and the obtained compound (405 mg) was added. It was dissolved in 8.0 ml of tetrahydrofuran and 4.0 ml of methanol, and 1N aqueous sodium hydroxide solution 905 ⁇ 1 was added under ice-cooling, followed by stirring at room temperature for 30 minutes. 40 ml of a 10% aqueous solution of citric acid was added to the reaction solution, and the mixture was stirred.
  • reaction solution was cooled to room temperature, added with a 10% aqueous solution of citric acid, and extracted three times with 50 ml of ethyl acetate. The obtained organic layer was washed with water and dried over anhydrous magnesium sulfate.
  • (+) — 4 [[[2-Amino 1— (3—hydroxymethyl-phenyl) ethyl] thio] methyl] Methyl benzoate (+) — G p-toluoyl D -Tartrate is suspended in ethyl acetate, 1N aqueous sodium hydroxide solution is added to extract the solution, and the mixture is extracted. The organic layer is washed with saturated saline and dried over magnesium sulfate.
  • Example 74 [[[2- (4-chlorophenylsulfonylamino) 1-1- [3 — [(E) —2— (7— Chloro-2-quinolyl) vinyl] phenyl] ethyl] thio] methyl] benzoic acid was obtained.
  • (+)-4-1 [[[2- (4-chlorophenylsulfonylamino) 1-1- [3 — [(E) —2— (7— Chloro-2-quinolyl) vinyl] phenyl] ethyl] thio] methyl] benzoic acid was obtained.
  • (+)-4-1 [[[2- (4-chlorophenylsulfonylamino) 1-1- [3 — [(E) —2— (7— Chloro-2-quinolyl) vinyl] phenyl] ethyl] thio] methyl] benzoic acid was obtained.
  • Example 74 [[[2- (4-chlorophenyl
  • (+) — 4 — [[[2- (4-chlorophenylsulfonylamino) 1 1-[3 — [(E) 1 2— (7-chloro-2-quinolyl) vinyl] [Phenyl] ethyl] thio] methyl] benzoic acid 500 mg, 0.770 mmol was suspended in ethanol (5 ml), 1N aqueous sodium hydroxide solution 770 ⁇ 1 (0.770 mmol) was added, and ethanol (5 ml) was further added. The mixture was stirred at room temperature for 1 ⁇ .
  • Example 78 By performing the same operation as in Example 76, 3- [N-[(4-cyclobenzenebenzenesulfonylamino) acetyl] -1-N— [3-[2- (7-cyclo1-2-quino) Ryl) vinyl] phenyl] aminomethyl] phenyl acetic acid / 1Z dihydrate was obtained.
  • Example 78
  • the physicochemical properties of the reference compound are shown in Tables 3 to 8, and the structural formulas and physicochemical properties of the compounds of Examples 1 to 2, 36 to 57 and 69 to 72 are shown in Table 9. 35.
  • the structural formulas and physicochemical properties of the compounds of 58, 61-68 and 73-75 are shown in Table 10, the structural formulas and physicochemical properties of the compounds of Examples 59 and 60 are shown in Table 11, and Examples 76-78.
  • Table 12 shows the structural formulas and physicochemical properties of the compounds of Table 1.

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Abstract

L'invention a pour objet des composés de benzènesulfone représentés par la formule générale (I) ou des sels pharmaceutiquement acceptables de ces derniers. Ces composés sont utiles comme produits pharmaceutiques présentant un antagonisme du leucotriène combiné à un antoganisme du thromboxane A2 et une bonne absorbabilité par voie orale. Ils sont particulièrement utiles comme agents pour prévenir et traiter les maladies dans lesquelles le leucotriène et la thromboxane A2 jouent un rôle, par exemple, l'asthme bronchique. Dans la figure (I), B représente un groupe quinolyle éventuellement substitué; D représente un groupe phényle éventuellement substitué; E représente un groupe représenté par les formules (a), (b) ou (c). Un élément parmi A1 et A2 représente un groupe méthylène éventuellement substitué ou un groupe éthylène éventuellement substitué, tandis que l'autre élément représente une simple liaison, un groupe méthylène éventuellement substitué, ou un groupe éthylène éventuellement substitué, à condition que lorsque 1 représente 1 et Y représente un groupe phénylène éventuellement substitué, chaque élément parmi A1 et A2 représente une simple liaison; X représente un atome d'oxygène ou un atome de soufre; Y représente un groupe phénylène éventuellement substitué, un groupe phénylèneoxy éventuellement substitué ou un groupe spirocyclopropinyle éventuellement substitué; Z représente un groupe représenté par la formule -CH=CH-, -CH¿2?-CH2-, -CH2O-, ou -O-CH2-; R représente un groupe carboxyle ou un groupe tétrazolyle qui peut être éventuellement substitué avec un résidu d'ester; 1, n, p et g peuvent être identiques ou différents, et représentent chacun 0 ou 1; et m représente 1, 2 ou 3.
PCT/JP1997/002934 1996-08-26 1997-08-25 Composes de benzenesulfone et sels de ces derniers WO1998008820A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009090976A1 (fr) * 2008-01-16 2009-07-23 Kaken Pharmaceutical Co., Ltd. Préparation thérapeutique transmucosale pour une obstruction nasale
EP2287165A2 (fr) 2003-07-14 2011-02-23 Arena Pharmaceuticals, Inc. Dérivés d'hétéroaryle et aryle fusionné en tant que modulateurs du métabolisme et prophylaxie et traitement des troubles associés
WO2013051024A3 (fr) * 2011-07-26 2013-07-04 Sun Pharma Advanced Research Company Ltd. Antagonistes des cystéinyl leucotriènes
CN104109122A (zh) * 2013-04-16 2014-10-22 浙江奥翔药业有限公司 用于合成孟鲁司特的中间体化合物及其制备方法
CN114728075A (zh) * 2019-12-02 2022-07-08 尹图赛利有限公司 与分子缀合相关的组合物和方法

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JPH05105664A (ja) * 1990-10-12 1993-04-27 Merck Frosst Canada Inc ロイコトリエン拮抗剤としてのヒドロキシアルキルキノリンエーテル酸

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2287165A2 (fr) 2003-07-14 2011-02-23 Arena Pharmaceuticals, Inc. Dérivés d'hétéroaryle et aryle fusionné en tant que modulateurs du métabolisme et prophylaxie et traitement des troubles associés
EP2287166A2 (fr) 2003-07-14 2011-02-23 Arena Pharmaceuticals, Inc. Dérivés d'hétéroaryle et aryle fusionné en tant que modulateurs du métabolisme et prophylaxie et traitement des troubles associés
EP2292620A2 (fr) 2003-07-14 2011-03-09 Arena Pharmaceuticals, Inc. Dérivés d'hétéroaryle et aryle fusionné en tant que modulateurs du métabolisme et prophylaxie et traitement des troubles associés
WO2009090976A1 (fr) * 2008-01-16 2009-07-23 Kaken Pharmaceutical Co., Ltd. Préparation thérapeutique transmucosale pour une obstruction nasale
WO2013051024A3 (fr) * 2011-07-26 2013-07-04 Sun Pharma Advanced Research Company Ltd. Antagonistes des cystéinyl leucotriènes
CN103842344A (zh) * 2011-07-26 2014-06-04 太阳医药高级研究有限公司 基于喹啉、喹喔啉或苯并[c]噻唑的半胱氨酰白三烯拮抗剂
US9102665B2 (en) 2011-07-26 2015-08-11 Sun Pharma Advanced Research Company Ltd. Cysteinyl leukotriene antagonists
CN103842344B (zh) * 2011-07-26 2016-08-03 太阳医药高级研究有限公司 基于喹啉、喹喔啉或苯并[c]噻唑的半胱氨酰白三烯拮抗剂
CN104109122A (zh) * 2013-04-16 2014-10-22 浙江奥翔药业有限公司 用于合成孟鲁司特的中间体化合物及其制备方法
CN104109122B (zh) * 2013-04-16 2017-03-29 浙江奥翔药业股份有限公司 用于合成孟鲁司特的中间体化合物及其制备方法
CN114728075A (zh) * 2019-12-02 2022-07-08 尹图赛利有限公司 与分子缀合相关的组合物和方法

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