WO2010069150A1 - Derives d'acide acrylique de para-hydroxybenzene et utilisations associees - Google Patents

Derives d'acide acrylique de para-hydroxybenzene et utilisations associees Download PDF

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WO2010069150A1
WO2010069150A1 PCT/CN2009/001500 CN2009001500W WO2010069150A1 WO 2010069150 A1 WO2010069150 A1 WO 2010069150A1 CN 2009001500 W CN2009001500 W CN 2009001500W WO 2010069150 A1 WO2010069150 A1 WO 2010069150A1
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group
hydrogen
aminosulfonylphenyl
methoxy
amino
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PCT/CN2009/001500
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English (en)
Chinese (zh)
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毛近隆
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Mao Jinlong
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/51—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D307/58—One oxygen atom, e.g. butenolide

Definitions

  • the present invention relates to a p-hydroxyphenylacrylic acid derivative and its use, in particular to a compound of the formula (I), a pharmaceutically acceptable salt and a hydrate, a process for the preparation thereof, and a composition comprising one or more of these compounds, And the use of the compound in the manufacture of a medicament for the treatment and prevention of an inflammation or inflammation-related disorder, in particular for the preparation of a cyclooxygenase and/or lipoxygenase selective inhibitory medicament.
  • Non-steroidal anti-inflammatory drugs are widely used in the treatment of inflammation, pain, rheumatic diseases and sports injuries due to their defined anti-inflammatory and analgesic effects, but gastrointestinal complications are the most common for long-term use of NSAIDs. Side effects, including life-threatening ulcers, limit the use of non-steroidal anti-inflammatory drugs.
  • COX-2 cyclooxygenase
  • Representative drugs include Merck. The company's rofecoxib and Pfizer's celecoxib.
  • the compound of the present invention is a p-hydroxyphenylacrylic acid derivative and a pharmaceutically acceptable salt thereof.
  • the p-hydroxyphenylacrylic acid derivative has good cardiovascular safety, and its structural feature is that two benzene rings are attached to the olefin double bond, one of which has a hydroxyl group at the para position, and the carboxyl group on the olefin double bond forms a p-hydroxybenzene.
  • the structure of acrylic acid has another acyl group at the para position of the benzene ring, and the two benzene rings are on the same side of the olefin double bond.
  • the p-hydroxystyrene in the structure of the compound of the present invention can interact with various active centers of the enzyme, and the hydroxyl group at the para position of the benzene ring is related to the inhibition of prostaglandins (PGs), and its activity is significantly reduced after removing the hydroxyl group (Chem. Pharm. Bull. 34 (1986): 121-129); olefinic double bonds conjugated to benzene rings can also increase the activity of inhibiting prostaglandins (PGs), and if reduced to saturated alkanes, activity will disappear (Chem. Pharm. Bull) 34(1986): 1619-1627.
  • PGs prostaglandins
  • Another sulfonyl group on the phenyl ring is a pharmacological group for selective inhibition of cyclooxygenase (COX-2) (J. Med. Chem. 40 (1997) ): 1347-1365. ).
  • COX-2 cyclooxygenase
  • p-hydroxystyrene also exhibits strong lipoxygenase (LOX) selective inhibitory activity (US4440784; US4971996), and synergistic inhibition of cyclooxygenase and lipoxygenase is beneficial to reduce cardiovascular risk (Cancer Prev. Res. 2 (2009): 288-290, ).
  • caffeic acid and ferulic acid are active ingredients of traditional Chinese medicine having a structure of p-hydroxyphenylacrylic acid, wherein caffeic acid is 3,4-dihydroxyphenylacrylic acid and ferulic acid is 3-methoxy-4-hydroxyphenylacrylic acid.
  • Caffeic acid has the effect of shortening the time of blood coagulation and bleeding, and has better hemostatic effect on the internal organs and less toxicity. Caffeic acid also has a wide range of antibacterial and antiviral activities, and has a strong inhibitory effect on adenovirus and parainfluenza.
  • Benzyl acrylate is an active ingredient in honeycomb wax, which is an ester formed by caffeic acid. It has antiviral, anti-inflammatory, anti-oxidant and immune-modulating functions, and can inhibit tumor cell proliferation and induce apoptosis. Inhibitory effect of caffeic acid phenethyl ester on the proliferation of activated rat vascular smooth muscle cells. Chinese Journal of Heart Disease, 05(2007): 513-516).
  • Chlorogenic acid is one of the antibacterial effective components of honeysuckle, and it is also an ester formed by caffeic acid. It has significant pharmacological activities such as antibacterial, antiviral, antimutagenic, antitumor and liver protection.
  • ferulic acid In addition to its anti-inflammatory and antibacterial effects, ferulic acid also has excellent activity in reducing blood fat, anti-thrombosis, and preventing coronary heart disease, and has less toxic side effects. It has now been found that ferulic acid has the following physiological effects: antibacterial anti-inflammatory, anti-atherosclerosis, anti-platelet aggregation and thrombosis, anti-tumor, anti-mutation, ferulic acid can be absorbed by the body and easily discharged from the urine
  • the p-hydroxyphenylacrylic acid derivative also has strong vasodilator activity and exhibits certain potassium channel open activity, which is promising for the treatment and prevention of hypertension (synthesis of ⁇ -phenyl substituted cinnamamides and potassium thereof) Channel open activity. Journal of Pharmaceutical Sciences, 36(2001): 502-506).
  • the invention provides a novel p-hydroxyphenylacrylic acid derivative and a pharmaceutically acceptable salt thereof.
  • the experiment shows that the p-hydroxyphenylacrylic acid derivative can reduce the side effects of the stomach while treating inflammation, and has good safety in cardiovascular terms.
  • the compounds of the invention will have a promising future as prodrugs for the treatment of inflammation or inflammation related conditions.
  • a further object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising one or more of the p-hydroxyphenylacrylic acid derivative, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable hydrate thereof, and a compound or a mixture thereof;
  • a further object of the present invention is to provide a use of the p-hydroxyphenylacrylic acid derivative and a pharmaceutically acceptable salt thereof for the treatment and prevention of inflammation or inflammation-related disorders.
  • a further object of the present invention is to provide a p-hydroxyphenylacrylic acid derivative and a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating and preventing an inflammation or inflammation-related disorder, particularly in the preparation of a cyclooxygenase And/or the use of lipoxygenase to selectively inhibit the drug.
  • R 1 is selected from the group consisting of: (a) hydrogen, (b) hydrocarbyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylhydrocarbyl, epoxy hydrocarbyl, carbonyl, hydrocarbylcarbonyl, aromatic hydrocarbyl, hydrocarbyloxycarbonyl An acyl group, a hydrocarbylsulfinyl group or a hydrocarbylsulfonyl group, wherein the group may be optionally substituted by the same or different 1-5 substituents selected from the group consisting of a hydroxyl group, a halogen group, an amino group, a fluorenyl group, and an azide group.
  • Base nitro, cyano, trihalomethyl, carboxy, hydrocarbyl, aryl, heteroaryl, hydroxyalkyl, hydrocarbyloxy, cycloalkoxy, aryloxy, acyl, acyloxy, alkoxycarbonyl , an aryloxycarbonyl group, a hydrocarbylsulfinyl group or a hydrocarbylsulfonyl group;
  • R 2 , R 2 ', R 3 , R 3 ' are each independently selected from the group consisting of hydrogen, hydroxy, halogen, amino, fluorenyl, azide, nitro, cyano, trihalomethyl, carboxy, hydrocarbyl, hydrocarbyloxy Or a hydrocarbylthio group;
  • Two adjacent groups on the phenyl ring may together form a dioxymethyl or dioxyethyl group
  • G is selected from a disubstituted phenyl group, a disubstituted naphthyl group or a disubstituted heteroaryl group such as a group (A), (B) or (C);
  • R 4 is selected from an amino group, a mercapto group, a hydrocarbyl group, an amide group, a hydrocarbylcarbonylamino group or a hydrocarbylsulfonylamino group, wherein the group may be optionally substituted by the same or different 1-5 substituents selected from the group consisting of a hydroxyl group, a halogen, an amino group, a fluorenyl group, an azide group, a nitro group, a cyano group, a trihalomethyl group, a carboxyl group, a hydrocarbon group, an aryl group, a heteroaryl group, a hydrocarbyloxy group, an acyl group or an acyloxy group;
  • R 4 ' is selected from (a) hydrogen, (b) hydrocarbyl, cycloalkyl, aryl, arene, acyl or hydrocarbylsulfonyl, wherein the group may be optionally substituted by the same or different 1-5 Substituted, the substituent is selected from the group consisting of hydroxyl, halogen, amino, decyl, nitro, cyano, trihalomethyl, carboxy, hydrocarbyl, aryl, heteroaryl, alkoxy, acyl or acyloxy; R 5 Selected from hydrogen, hydroxy, halogen, amino, decyl, azide, nitro, trifluoromethyl, carboxy, hydrocarbyl or hydrocarbon n is 1 or 2;
  • X is selected from the group consisting of: (a) hydrogen,
  • Y is selected from the group consisting of: (a) hydrogen, halogen, hydroxy or azide, (b) amino, mercapto, hydrocarbyl, cycloalkyl, heterocyclyl, hydrocarbyloxy, cycloalkyloxy, aryloxy, aryl a hydrocarbyloxy group, an N-hydrocarbylamino group, an N-cycloalkylamino group, an N-arylamino group, an N-arylhydrocarbylamino group, an anthracene, a fluorenyl-dihydrocarbylamino group or a heterocyclic amino group, wherein said group is optionally Substituted by the same or different 1-5 substituents selected from the group consisting of hydroxy, halogen, amino, fluorenyl, azide, nitro, cyano, trihalomethyl, carboxy, hydrocarbyl, cycloalkyl, aryl Or a heterocyclic group, a heteroary
  • R 1 is selected from the group consisting of: (a) hydrogen, (b) mercapto, alkenyl, cyclodecyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, arylalkyl, arylalkenyl, epoxy An indenyl group, a carbonyl group; a mercaptocarbonyl group, a decyloxycarbonyl group, an aralkenylcarbonyl group, an acyl group, an alkylsulfinyl group or an alkylsulfonyl group, wherein the groups may be optionally the same or different from 1 to 5 Substituted by a substituent selected from the group consisting of hydroxy, halogen, amino, decyl, azide, nitro, cyano, trihalomethyl, carboxy, alkyl, alkenyl, cyclodecyl, cycloalkenyl, aromatic Or a heterocyclic group, a
  • R 2 , R 2 ⁇ R 3 , R 3 ' are each independently selected from the group consisting of hydrogen, hydroxy, halogen, amino, fluorenyl, azide, nitro, cyano, trihalomethyl, carboxy, decyl, alkenyl , mercaptooxy or mercaptothio;
  • Two adjacent groups on the phenyl ring may together form a dioxymethyl or dioxyethyl group
  • G is selected from disubstituted phenyl, disubstituted naphthyl or disubstituted heteroaryl, preferably from group (D), (E) or (F):
  • R 4 is selected from the group consisting of an amino group, a fluorenyl group, a fluorenyl group, an amide group, a fluorenylcarbonylamino group or an alkylsulfonylamino group, wherein the group is Optionally substituted by the same or different 1-5 substituents selected from the group consisting of hydroxy, halo, amino, decyl, azide, nitro, cyano, trihalomethyl, carboxy, fluorenyl , aryl, heteroaryl, decyloxy, acyl or acyloxy;
  • R 4 ' is selected from the group consisting of: (a) hydrogen, (b) mercapto, cycloalkyl, aryl, aryl sulfonyl, acyl or decylsulfonyl, wherein the groups may be optionally the same or different Substituted with 1-5 substituents selected from hydroxy, halo, amino, decyl, azide, nitro, cyano, trihalomethyl, carboxy, decyl, aryl, heteroaryl, alkoxy a group, an acyl group or an acyloxy group;
  • R 5 is selected from the group consisting of hydrogen, hydroxy, halogen, amino, decyl, azide, nitro, trifluoromethyl, carboxy, decyl or alkyloxy;
  • n 1 or 2;
  • X is selected from the group consisting of: (a) hydrogen, halogen or hydroxy, (b) amino, decyl, oxy, decyl, alkenyl, cyclodecyl, cycloalkenyl, hydroxyindenyl, decyloxy, carbonyl, acyl, An acyloxy group, an acyloxy fluorenyl group or a methoxy acyloxy fluorenyl group, wherein the group may be optionally substituted by the same or different 1-5 substituents selected from the group consisting of a hydroxyl group, a halogen, Amino, nitro, cyano, trihalomethyl, carboxy, decyl, alkenyl, cyclodecyl, cycloalkenyl, aryl, heteroaryl, decyloxy, nitrooxy, acyl or acyloxy Base
  • Y is selected from the group consisting of: (a) hydrogen, halogen or hydroxy, (b) amino, fluorenyl, oxy, decyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, arylalkyl, arylene , fluorenyloxy, cycloalkyloxy, aryloxy, aralkyloxy, arylalkenyloxy, N-decylamino, N-cyclodecylamino, N-arylamino, N An arylalkylamino, hydrazine, hydrazine-dialkylamino or heterocyclic amine group, wherein the group may be optionally substituted by the same or different 1-5 substituents selected from the group consisting of hydroxyl groups, Halogen, amino, mercapto, azide, nitro, cyano, trihalomethyl, carboxy, decyl, alkenyl, cycloalkyl
  • R 1 is selected from the group consisting of: (a) hydrogen, (b) fluorenyl, cycloalkyl, aryl fluorenyl, epoxy fluorenyl, carbonyl or acyl, wherein the groups may be optionally the same or different 1 Substituted with 5 substituents selected from hydroxy, halo, amino, cyano, trihalomethyl, carboxy, alkyl, aryl, hydroxyalkyl, alkyloxy, acyl, acyloxy, oxirane a carbonyl or aryloxycarbonyl group;
  • R 2 , R 2 ', R 3 , R 3 ' are each independently selected from hydrogen, hydroxy, halogen, alkyl or decyloxy; two adjacent groups on the phenyl ring may together form a dioxymethyl group or Dioxyethyl group;
  • G is selected from a disubstituted phenyl group, preferably from a group (M), ( ) or (L):
  • R 4 is selected from amino, decyl, alkyl, amide or decyl sulfonamide, wherein the group may be optionally substituted by the same or different 1-5 substituents selected from the group consisting of hydroxyl groups, Halogen, amino, cyano, trihalomethyl, carboxy, decyl, aryl, alkyloxy, acyl or acyloxy; R 4 'is selected from hydrogen or sulfhydryl;
  • R 5 is selected from hydrogen, halogen, alkyl or alkyloxy; n is 1 or 2;
  • X is selected from: (a) hydrogen, halogen or hydroxy, (b) amino, alkyl, cycloalkyl, cycloalkenyl, hydroxyalkyl, carbonyl, acyl or acyloxy, wherein said group is optionally Substituted by the same or different 1-5 substituents, the substituent is selected from the group consisting of hydroxyl, halogen, amino, fluorenyl, 'azido, nitro, cyano, trihalomethyl, carboxy, fluorenyl, aryl a base, a heteroaryl group, an alkyloxy group, an acyl group or an acyloxy group;
  • Y is selected from: (a) hydrogen or hydroxy, (b) amino, alkyl, alkyloxy, decylamino or heterocyclic amino, wherein the groups may be optionally the same or different from 1 to 5 Substituted by a substituent selected from the group consisting of hydroxyl, halogen, amino, cyanide , trihalomethyl, carboxy, alkyl, aryl, alkyloxy, acyl, acyloxy, decyloxycarbonyl, N-decylaminocarbonyl or N,N-dialkylaminocarbonyl;
  • R 6 , R 7 are each independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, trihalomethyl, carboxy, amino, alkyl, aryl, alkyloxy, hydroxyalkyl, aminoalkyl, acyl or acyl An oxy group; or R 6 and R 7 may together form a 3 to 7 membered carbocyclic or heterocyclic ring;
  • R 8 selected from hydrogen, hydroxy, cyano, trihalomethyl, carboxy, decyl, aryl, alkyloxy, acyl, acyloxy, alkoxycarbonyl or alkylaminocarbonyl;
  • a further preferred form of the compound of the above p-hydroxyphenylacrylic acid derivative is:
  • R 1 is selected from hydrogen, methyl, ethyl, ethenyl or cinnamoyl;
  • R 2 , R 2 ', R 3 , R 3 ' are each independently selected from the group consisting of hydrogen, hydroxy, halogen, methyl, methoxy, Trifluoromethyl or tert-butyl;
  • I 1 , R 2 may together form a dioxymethyl or dioxyethyl group;
  • G is selected from a disubstituted phenyl group, preferably from a group (M) or (N);
  • R 4 is selected from amino, decyl, alkyl, amide or alkylsulfonylamino; R 4 'is hydrogen; R 5 is hydrogen; n is 2; X, Y two groups form lactone, lactam,
  • the anhydride or the diimide may also be two independent groups, preferably free from the formula (VII), (VDI) or (IV):
  • X is hydrogen;
  • Y is selected from hydrogen, hydroxy, amino, methoxy, ethoxy or phenethyloxy;
  • a still further preferred form of the above-mentioned p-hydroxyphenylacrylic acid derivative is represented by the structural formula (W), (WI) or (IV):
  • R 1 is selected from hydrogen, methyl, acetyl or cinnamoyl;
  • R 2 , R 2 ' , R 3 > R 3 ' are each independently selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, bromo, methoxy or t-butyl; and I 1 and R 2 may together represent a dioxymethyl group;
  • G is selected from disubstituted phenyl, preferably from group (M); R 4 is selected from methyl, amino, acetamido or trifluoroacetamido; R 5 is hydrogen; n is 2;
  • X is hydrogen; Y is selected from hydrogen, hydroxy, amino, ethoxy or phenethyloxy;
  • the above p-hydroxyphenylacrylic acid derivative is most preferably one of the following compounds:
  • the term "optionally substituted by the same or different 1-5 substituents” is used to include both unsubstituted and substituted, and each substitutable carbon in a given moiety.
  • a hetero atom if present, may be independently unsubstituted or monosubstituted or polysubstituted by one or more such substituents which may be the same or different at each occurrence and which result in a stable structure .
  • the term "1-5 substituents” means one substitution, two substitutions, three substitutions, four substitutions, five substitutions.
  • substituted arylalkyl includes substitutions on the phenyl ring and substitutions on the thiol group.
  • hydrocarbon may be alkyl, alkenyl, alkynyl and the like. Either alone or in combination with other terms (e.g., "hydroxyalkyl”, “hydrocarbylsulfonyl”, etc.) include one or two or three of decyl, alkenyl and alkynyl groups or a combination thereof.
  • mercapto includes straight or branched chain groups of 1 to 10 carbon atoms or Joint form. More preferred alkyl groups are lower alkyl groups of 1 to 6 carbon atoms. Examples of sulfhydryl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, Heptyl, octyl and the like.
  • alkenyl includes straight-chain or branched fluorenyl groups of 2 to 10 carbon atoms containing at least one carbon-carbon double bond, preferably an alkyl group having 2 to 6 carbon atoms. Examples of such groups include ethenyl, n-propenyl, butenyl and the like.
  • alkynyl includes straight-chain or branched alkyl or alkenyl groups of 2 to 10 carbon atoms containing at least one carbon-carbon triple bond, preferably fluorenyl groups having 2 to 6 carbon atoms. Examples of such groups include ethynyl, n-propynyl, butynyl and the like.
  • halogen refers to a halogen element such as a fluorine, chlorine, bromine or iodine atom.
  • cycloalkyl includes groups having from 3 to 10 carbon atoms. More preferred cycloalkyl groups are "lower cycloalkyl” groups having from 3 to 7 carbon atoms. Examples include groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • cycloalkenyl includes unsaturated cyclic groups having 3 to 10 carbon atoms such as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and the like.
  • aryl when used alone or in combination, includes carbocyclic aromatic systems containing 1, 2 or 3 rings, wherein the rings may be joined together in a side chain manner or may be fused.
  • aryl includes aryl groups such as phenyl, naphthyl and biphenyl.
  • the above “aryl group” may have 1 to 4 substituents such as lower alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, hydroxy, amino and lower decylamino, lower decyloxy, halogen, lower Thioguanidino and acyl.
  • hetero includes groups of one or more 0, S or deuterium atoms.
  • heterocyclic groups and heteroaryl groups.
  • heterocyclyl and heterocycle include saturated, partially saturated, and unsaturated cyclic groups derived from nitrogen, sulfur, and oxygen.
  • the saturated heterocyclic group includes a saturated 3-7 membered heterocyclic ring containing one or more hetero atoms selected from the group consisting of ruthenium, 0 and S, and may be a group in which a hydrogen atom is removed from a hydrogen such as an alkylene oxide group, or may be A group in which a hetero atom is removed from a hydrogen such as a heterocyclic amine group or the like.
  • alkylene oxide saturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, hexahydropyridyl, hexahydropyrazinyl, hexahydropyridazinyl, hexahydropyrimidine. Base and similar groups.
  • unsaturated heterocyclic groups include, but are not limited to, cycloethylenimine (azacyclopropenyl), azetidinyl, pyrrolidinyl, imidazolinyl, piperidinyl, piperazinyl, 2-oxo Depiperidinyl, 4-oxopiperidinyl, 2-oxopiperrazinyl, 3-oxopyridinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl, azepine a group, a hydrazine, an oxazepine group, a thiazepine group, an oxazolyl group, a thiazolidinyl group, and the like; examples of a partially saturated heterocyclic group include dihydrothiophene, Hydropyran, dihydrofuran, dihydrothiazole and the like.
  • heterocyclic group may have 1 to 4 substituents such as lower alkyl, haloalkyl, dihalofluorenyl, trihaloalkyl, hydroxy, amino and lower alkylamine.
  • Base lower decyloxy, halogen, lower thioindolyl, acyl group.
  • preferred heterocyclic groups include tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, hexahydropyridyl, hexahydropyrazinyl and the like.
  • heteroaryl includes unsaturated heterocyclic groups.
  • unsaturated heterocyclic group also referred to as “heteroaryl”
  • examples of the unsaturated heterocyclic group include an unsaturated 5-6 membered monoheterocyclic group, a fused polycyclic heteroaryl group or one or more selected from 0, N, S.
  • a fused polycyclic heterocyclic group of a hetero atom include an unsaturated 5-6 membered monoheterocyclic group, a fused polycyclic heteroaryl group or one or more selected from 0, N, S.
  • a fused polycyclic heterocyclic group of a hetero atom include an unsaturated 5-6 membered monoheterocyclic group, a fused polycyclic heteroaryl group or one or more selected from 0, N, S.
  • Examples of such groups include 1 chloropyrazine, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridine, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazine , triazolyl (such as 4 ⁇ -1,2,3-triazolyl, 1 ⁇ -1,2,3-tetrazolyl, etc.), fluorenyl, isodecyl, indanyl, benzo Furanyl, 2,3-dihydrobenzofuranyl, chromanyl, benzopyranyl, thiochromanyl, benzothiopyranyl, benzodifuran Benzo benzodioxanyl, pyridyl, thienyl, benzothienyl, oxazolyl, benzimidazolyl, decyl, isodecyl carbazolyl, benzotriazolyl, tetra
  • heteroaryl group may have 1 to 4 substituents such as a lower alkyl group, a halogenated fluorenyl group, a dihaloalkyl group, a trihaloalkyl group, a hydroxyl group, an amino group and a lower fluorenylamino group, a lower decyloxy group, a halogen group. , lower thioalkyl, acyl group.
  • heteroaryl groups examples include benzofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl, fluorenyl, indanyl, chromanyl, benzene Pyranyl, thiochromanyl, benzothiopyranyl, benzofuranyl, benzodigethylene, pyridyl, thienyl, thiazolyl, oxazolyl , furyl, pyrazinyl, pyridazinyl, quinazolinyl, quinolyl, isoquinolyl, benzoxazolyl, benzothiazolyl and the like.
  • hydroxy means - ⁇ .
  • oxy denotes -0- after removal of a hydrogen atom from a hydroxy group, and may be used alone or in combination with other groups, such as a decyloxy group, which is attached to the oxy group by a thiol group as defined above. .
  • hydroxyindenyl embraces a straight or branched alkyl group containing from 1 to 10 carbon atoms, wherein any one of the carbon atoms on the alkyl group may be substituted with one or more hydroxyl groups. More preferred hydroxymethyl groups are "lower hydroxy fluorenyl” groups having from 1 to 6 carbon atoms and one or more hydroxy groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl and hydroxyhexyl groups.
  • alkyloxy includes an oxygen-containing group to which a straight or branched chain is bonded, and the thiol moiety of each group is from 1 to 10 carbon atoms.
  • Preferred oxiranyl groups are "lower alkoxy” groups having from 1 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.
  • the "decyloxy” group may further include a substituent having one or more halogen atoms (e.g., a fluorine atom, a chlorine atom or a bromine atom) to constitute a "halogenated methoxy group” group.
  • Examples of such groups include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and the like.
  • dioxymethyl or “dioxyethyl” means that the methyl or ethyl group is bonded to the other group through two oxygen atoms. Examples of such groups include dioxymethyl groups which form a benzo group on the phenyl ring. Dioxane.
  • mercaptothio includes a sulfur-containing group to which a straight or branched chain is bonded, and the alkyl moiety of each group is from 1 to 10 carbon atoms. Preferred are "lower thiol” groups containing from 1 to 6 carbon atoms. Examples of such groups include methylthio, ethylthio and tert-butylthio.
  • aryl fluorenyl includes a "lower aralkyl” group having an aryl group attached to a fluorenyl group having 1 to 6 carbon atoms.
  • examples of such groups include benzyl, diphenylmethyl, triphenylmethyl, phenethyl, diphenylethyl and the like.
  • the aryl group in the above aralkyl group may further have a halogen, a mercapto group, an alkoxy group, a halogenated alkoxy group, a hydroxyl group, an amino group, an alkoxycarbonyl group and the like.
  • benzyl and benzyl are interchangeable.
  • acyl refers to a group provided by residues remaining after removal of a hydroxyl group from an organic acid, and includes, but is not limited to, a substituted or unsubstituted group selected from formyl, acetyl, propionyl, butanoyl. , isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, benzoyl, cinnamoyl or the like.
  • acyl group may have 1 to 4 substituents such as lower alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, hydroxy, amino and lower alkylamino, lower alkoxy, halogen, lower sulfur Alkenyl, acyl groups.
  • acyloxy denotes an oxygen-containing group to which an acyl group is attached
  • amino group-containing group to which an acyl group is attached.
  • mercaptocarbonyl includes a group having an alkyl group attached to the carbonyl group such as the above acyl or decanoyl group.
  • alkoxycarbonyl means a group containing the above decyloxy group, wherein the alkoxy group is a carbonyl group.
  • lower oxocarbonyl includes a decyloxy group having from 1 to 6 carbon atoms.
  • lower methoxycarbonyl ester groups include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl groups.
  • aminocarbonyl means a group having an amino substituent attached to a carbonyl group.
  • N-fluorenylaminocarbonyl and “deuterium, fluorenyl-dialkylaminocarbonyl” denote an aminocarbonyl group having one mercapto substituent group and two alkyl substituent groups, respectively.
  • a "lower alkylaminocarbonyl group” having a lower mercapto group as defined above attached to an aminocarbonyl group.
  • the terms “anthracene-arylaminocarbonyl” and “nonyl-fluorenyl-fluorene-arylaminocarbonyl” mean an aminocarbonyl group having one aryl substituent or having one fluorenyl group and one aryl substituent group, respectively.
  • alkylsulfonyl refers to the divalent radical 3 ⁇ 4-S0 2 -.
  • sulfinyl whether used alone or in combination with other terms (e.g., fluorenylsulfinyl), refers to the divalent group -SO-.
  • Alkylsulfonyl includes the attachment of a fluorenyl group as defined above to a sulfonyl group. More preferred alkylsulfonyl groups are lower alkylsulfonyl groups of 1 to 6 carbon atoms.
  • lower alkylsulfonyl groups examples include methylsulfonyl, ethylsulfonyl and propylsulfonyl groups.
  • Mercaptosulfinyl includes the attachment of a fluorenyl group as defined above to a sulfinyl group.
  • lower sulfhydrylsulfinyl groups include methylsulfinyl, ethylsulfinyl and propylsulfinyl.
  • arylsulfonyl includes the attachment of an aryl group as defined above to a sulfonyl group. Examples of such groups include phenylsulfonyl.
  • phosphoryl whether used alone or in combination with other terms (such as alkylphosphoryl), refers to the divalent group -P0 2 -.
  • phosphoryl whether used alone or in combination with other terms (eg, mercaptophosphoryl), refers to the divalent group -PO-.
  • amino denotes -NH 2
  • N-nonylamino and “N,N-dialkylamino” denote an amino group having one alkyl substituent and two alkyl substituents, respectively.
  • Preferred alkylamino groups are "lower alkylamino” groups having one or two mercapto groups having from 1 to 6 carbon atoms attached to the nitrogen atom.
  • Suitable "alkylamino” groups can be hydrazine, hydrazine-dimethylamino, hydrazine, hydrazine-diethylamino or the like.
  • arylamino denotes an amino group having one or two aryl substituent ' groups, such as an anthracene-benzylamino group.
  • the "arylamino” group can also be further substituted in its aromatic ring moiety.
  • sulfamoyl and “sulfonamido” are used either alone or in combination with other terms (eg “N-alkylaminosulfonyl", “anthracene, fluorenyl-didecylaminosulfonyl”), A sulfonamide (-S0 2 NH 2 ) formed by substitution of a sulfonyl group with an amino group.
  • deuterium, fluorenyl-dimercaptoaminosulfonyl means a substituent to which the sulfamoyl group is attached to an alkyl group or two alkyl groups, respectively.
  • a more preferred mercaptoaminosulfonyl group is a "lower alkylaminosulfonyl group" having 1 to 6 carbon atoms.
  • lower mercaptoaminosulfonyl groups include anthracene-methylaminosulfonyl group, anthracene-ethylaminosulfonyl group, anthracene-methyl-indole-ethylaminosulfonyl group and the like.
  • mercapto denotes - ⁇ -, whether alone or in combination with other groups, may be suitably substituted by other groups, such as alkyl fluorenyl, which is attached to the fluorenyl group by a thiol group as defined above. On the regiment.
  • mercapto denotes -SH, "thio group,” meaning -S-, which may be used alone or in combination with other groups, for example, a mercaptothio group, which is attached to a thio group by a mercapto group as defined above.
  • disubstituted phenyl, disubstituted naphthyl or disubstituted heteroaryl means two substituents on a benzene ring, a naphthalene ring or a heteroaryl ring, which may be ortho, meta or para.
  • substituents include, but are not limited to, a sulfonyl group, a sulfinyl group, a sulfoximine group, a phosphoryl group or a phosphoryl group, and the above group is hydrogen, an amino group, a decyl group, a decyl group, an amide group or a decyl sulfonamide.
  • the base substitution is preferably a methylsulfonyl group, an aminosulfonyl group, an acetylaminosulfonyl group or a trifluoroacetylaminosulfonyl group, preferably in the para position of the phenyl ring.
  • substituents include, but are not limited to, hydrogen, hydroxy, halogen, amino, decyl, nitro, trifluoromethyl, carboxy, alkyl or decyloxy, preferably hydrogen or halogen.
  • substituted phenylacetic acid means that the acetic acid and acetamide are linked to the above-mentioned “disubstituted phenyl group”.
  • substituted naphthaleneacetic acid means that the acetic acid and acetyl are bonded to the above-mentioned "disubstituted naphthyl group”.
  • substituted ⁇ -haloacetophenone means acetophenone or benzaldehyde para hydroxyl group, *; a mercapto group, a substituted oxy or substituted mercapto group and the like, examples of the substituents include, but are not limited to, hydroxy, mercapto, methoxy, ethoxy, acetoxy, and cinnamoyl group;
  • the ortho or meta position of acetophenone or benzaldehyde may have 1 to 4 identical or different substituents, and examples of the substituent include, but are not limited to, a hydroxyl group, a halogen, an amino group, a fluorenyl group, an azide group, a nitro group, A cyano group, a trihalomethyl group,
  • R 1 is hydrogen, methyl, acetyl
  • a compound represented by "cinnamyl, R 2 , R 2 ', RR 3 'is a compound of hydrogen, methoxy, chloro or bromo" is (E)-2-(4-methylsulfonylphenyl)-3-(3) -Methoxy-4-acetoxyphenyl)acrylic acid, (E)-2-(4-.methylsulfonylphenyl)-3-(3,4-dimethoxyphenyl)acrylic acid, (E) -2-(4-Methylsulfone phenyl)-3-(3-methoxy-4-trans-carnityloxyphenyl)acrylic acid, (E)-2-(4-methylsulfonyl
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
  • Salts derived from inorganic bases include, for example, sodium, potassium, rubidium, calcium, magnesium, zinc salts, aluminum, copper, iron, ferrous, lithium, manganese and divalent manganese, particularly preferably sodium, potassium, ammonium, calcium and magnesium. salt.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include the salts of the following bases: primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such bases, For example, arginine, betaine, caffeine, choline, guanidine, guanidine dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, hydrazine- Ethyl phthalocyanine, hydrazine-ethylpiperidine, glucosamine, glucosamine, histidine, hexamine, isopropylamine, lysine, methyl glucosamine, morpholine, piperazine, piperidine, poly Amine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropyl
  • the compound of the present invention When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable acids including inorganic acids and organic acids.
  • acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid.
  • isethionethane lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, palmitic acid, pantothenic acid, succinic acid, tartaric acid, quinic acid and p-toluenesulfonic acid, etc., particularly preferably hydrochloric acid, hydrogen Bromo acid, sulfuric acid, phosphoric acid, benzenesulfonic acid, maleic acid, citric acid, tartaric acid and quinic acid.
  • the pharmaceutical composition of the present invention is included as The active ingredient of a compound of formula (I), or a pharmaceutically acceptable salt thereof, may also contain a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients, it being understood that in the therapeutic methods discussed below, the compound also includes Use salt.
  • Some of the compounds described herein contain a plurality of double bonds, and thus can give the oxime / oxime isomers and other conformational isomers.
  • the invention includes all such possible isomers as well as mixtures of such isomers.
  • Some of the compounds described herein contain a plurality of centers that are not opposite to the spines, and thus can give diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
  • the above formula (I) does not give a defined stereochemistry at a specific position, and the present invention includes all stereoisomers of the compound of the formula (I) and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. In the synthetic process used to prepare such compounds, or in the use of racemization or epimerization isomerization processes known to those skilled in the art, the products of such processes may be stereoisomers. mixture.
  • the object of the present invention is to provide a use of a compound of the formula (I) and a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and prevention of inflammation or inflammation-related disorders, in particular for the preparation of cyclooxygenase and/or lipoxygenase selectivity
  • the use of the drug is inhibited, and the dosage form of the drug is mainly a tablet, a capsule, a water injection or a powder.
  • Another object of the present invention is to provide a compound of formula (I) and a pharmaceutically acceptable salt thereof for treating and preventing common cold, fever, pain, headache, toothache, neck pain, sprain and strain, dysmenorrhea, menstrual cramps in a mammal.
  • arthritis arthritis, rheumatoid arthritis, osteoarthritis, spondyloarthropathy, gout arthritis, systemic lupus erythematosus, inhibition of prostaglandin-induced smooth muscle contraction or prevention of colorectal cancer, ovarian cancer, cervical cancer, prostate cancer
  • a further object of the present invention is to provide a compound of formula (I) and a pharmaceutically acceptable salt thereof for use in a method of treatment in a mammal, particularly for treating and preventing a common cold, fever, pain, headache, toothache, neck in a mammal Pain, sprains and strains, dysmenorrhea, menstrual cramps, arthritis, rheumatoid arthritis, osteoarthritis, spondyloarthropathy, gout arthritis, systemic lupus erythematosus, inhibition of prostaglandin-induced smooth muscle contraction or Prevention of colorectal cancer, ovarian cancer, cervical cancer, prostate cancer, bladder cancer, small bowel cancer, pancreatic cancer, stomach cancer, chest cancer, lung cancer, lip cancer, oral cancer, esophageal cancer or skin cancer.
  • the compounds of formula (I) of the invention are useful in the treatment and prevention of conditions associated with inflammation and inflammation by administering to a patient a therapeutic dose of a compound of formula (I).
  • Inflammation is associated with many conditions, including fever caused by rheumatism, symptoms associated with influenza or other viral infections, common cold, lower back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, menstrual cramps ⁇ , premature delivery.
  • Such compounds are also useful in the treatment of arthritis including, but not limited to, rheumatoid arthritis, spondyloarthropathy, gout arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis. They can also be used to treat dermatological conditions such as psoriasis, eczema, burns and dermatitis.
  • the compound of the formula (I) of the present invention inhibits tumor transformation of a cell and growth of a metastatic tumor, and thus is useful for the treatment and prevention of cancer.
  • the invention provides a method of treating a prostaglandin producing tumor by treating a patient with a therapeutic dose of a compound of formula (I). Therefore, the compounds of the present invention are useful for the prevention and treatment of cancer such as colorectal cancer, ovarian cancer, cervical cancer, prostate cancer, bladder cancer, small bowel cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, lip cancer, oral cancer, esophageal cancer or Skin cancer, etc.
  • Such compounds are also useful in the treatment of inflammation of the following diseases such as vascular disease, migraine, nodular aneuredulitis, thyroiditis, aplastic anemia, Hodgkin's disease, scleroderma, fever caused by rheumatism, Type I diabetes, neuromuscular junction disease (including myasthenia gravis), white matter disease (including multiple sclerosis), sarcoma-like disease, nephropathy complications, Becht's complications, polymyositis, gingivitis, nephritis, allergies Symptoms, swelling after injury, myocardial ischemia and so on.
  • diseases such as vascular disease, migraine, nodular aneuredulitis, thyroiditis, aplastic anemia, Hodgkin's disease, scleroderma, fever caused by rheumatism, Type I diabetes, neuromuscular junction disease (including myasthenia gravis), white matter disease (including multiple sclerosis), sarcoma-like disease, nephropathy complications
  • the compounds are also useful in the treatment of ophthalmic diseases such as retinitis, retinopathy, uveitis, photophobia, and acute ocular tissue damage. They can also be used for the treatment of lung inflammation (such as inflammation associated with viral infections) and bladder fibrosis.
  • the compound of the formula (I) of the present invention can treat and prevent a pharmaceutical composition of a patient suffering from a cardiovascular event of thrombosis, in the case of a cardiovascular event of thrombosis, such as stroke, myocardial ischemia, myocardial infarction, angina pectoris, Transient ischemic attack (TIA; - temporal sputum), reversible ischemic neurological disorder, and any similar thrombotic event in any vascular bed (viscera, kidney, aorta, etc.).
  • TIA Transient ischemic attack
  • reversible ischemic neurological disorder reversible ischemic neurological disorder
  • any similar thrombotic event in any vascular bed viscera, kidney, aorta, etc.
  • patients with chronic inflammatory conditions such as rheumatoid arthritis and systemic lupus erythematosus
  • dementia including Alzheimer's disease and senile dementia, especially dementia associated with Alzheimer's disease (i
  • the compound of the formula (I) of the present invention can also be used as a substitute for commonly used NSAIDs, especially in those cases where non-steroidal anti-inflammatory drugs are contraindicated, such as ulcers for treating gastrointestinal diseases, gastritis, local enteritis, ulcerative conjunctivitis, Patients with diverticulitis, Crohn's disease, enteritis complications and stress bowel complications, gastrointestinal bleeding and coagulopathy, kidney disease (eg renal insufficiency), preoperative or patients taking anticoagulants, and Patients who are sensitive to NSAIDs.
  • non-steroidal anti-inflammatory drugs are contraindicated, such as ulcers for treating gastrointestinal diseases, gastritis, local enteritis, ulcerative conjunctivitis, Patients with diverticulitis, Crohn's disease, enteritis complications and stress bowel complications, gastrointestinal bleeding and coagulopathy, kidney disease (eg renal insufficiency), preoperative or patients taking anticoagulants, and Patients who are sensitive to NSAIDs.
  • the compound of the formula (I) of the present invention as an active ingredient can be intimately mixed with a pharmaceutical carrier according to a conventional pharmaceutical mixing technique.
  • the carrier may take a wide variety of forms depending on the form of preparation required for administration such as oral or parenteral administration (including intravenous).
  • the pharmaceutical composition of the present invention may be a discrete unit suitable for oral administration such as a capsule, sachet or tablet, each of which contains a predetermined amount of the active ingredient.
  • compositions may be in the form of a powder, a granule, a solution, a suspension present in an aqueous liquid, a nonaqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion.
  • the compounds of formula (I) of the present invention may also be administered by controlled release means and / or delivery means.
  • compositions of the present invention which are suitable for oral administration can be prepared by any of the methods known in the art for preparing pharmaceutical compositions.
  • these compositions may contain one or more selected from sweeteners, flavored.
  • the tablet contains the active ingredient of the present invention and a non-toxic pharmaceutically acceptable excipient suitable for the preparation of a tablet.
  • excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or arabic a lubricant, such as magnesium stearate, stearic acid or talc, which may be uncoated or coated by known methods to delay disintegration and absorption in the gastrointestinal tract for a longer period of time. Provide a lasting effect.
  • a time delaying substance such as glyceryl monostearate or glyceryl distearate may be used.
  • the preparation for oral use can also be in the form of a hard capsule, wherein the active ingredient of the present invention is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in the form of a soft capsule, wherein the active ingredient of the present invention is in the form of a soft capsule.
  • an oily medium such as peanut oil, liquid paraffin or olive oil.
  • compositions of the invention suitable for injectable use include sterile aqueous solutions or dispersions. Further, these compositions may be in the form of a sterilized powder for the temporary preparation of such sterile injectable solutions or dispersions. In all cases, the final form of injection must be sterile and must be an effective liquid that is easy to inject.
  • the pharmaceutical composition must be stable under the conditions of manufacture and storage; therefore, the preferred storage should protect against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.
  • the pharmaceutical composition of the invention may be an aqueous suspension or an oil suspension.
  • the aqueous suspension contains the active ingredient of the present invention and an excipient therewith suitable for the preparation of the aqueous suspension.
  • These capping agents are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia; dispersing or wetting agents It may be a naturally occurring phospholipid, such as lecithin, or a condensation product of an alkylene oxide with a fatty acid, such as polyoxyethylene stearate, or a condensation product of an epoxy oxime with a long chain fatty alcohol, such as heptadecyloxy ten a condensation product of hexamethylol, or a partial ester of ethylene oxide with a fatty acid and a hexitol, such as a polyoxyethylene sorbitan monooleate, or
  • Condensation products such as polyethylene sorbitan monooleate.
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • preservatives for example ethyl or n-propyl p-hydroxybenzoate
  • coloring agents for example, sucrose, saccharin or aspartame.
  • the oily suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil, coconut oil, or mineral oil such as liquid paraffin.
  • the oil suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • compositions of the invention may also be in the form of an oil-in-water emulsion.
  • Oil phase It may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids such as esters or partial esters of soy, lecithin, fatty acids and hexitol anhydrides.
  • the pharmaceutical composition of the present invention may be in a form suitable for topical use, for example, an aerosol, a cream, an ointment, a lotion, a dusting powder, and the like. Mouthwashes and gargles are included within the scope of topical use for the purposes of the present invention. Further, these compositions may be in a form suitable for administration in a transdermal device ; ⁇ is prepared by a conventional treatment method, for example, a cream or ointment is prepared by mixing a hydrophilic substance and water, and about 5% to about 10% by weight of the compound to prepare a cream or ointment having a desired consistency.
  • the pharmaceutical composition of the invention may be in a form suitable for rectal administration wherein the carrier is a solid.
  • the mixture forms a unit dose of a suppository.
  • Suitable carriers include those which are lipophilic and are commonly used in the art.
  • a suppository can be prepared by first mixing the composition with a softened or melted carrier(s), followed by cooling and shaping in a mold.
  • the pharmaceutical composition of the present invention may be mixed with a carrier material to prepare an amount of the active ingredient in a single dosage form, depending on the subject to be treated and the particular mode of administration.
  • a formulation for oral administration to a human can conveniently: have from about 0.5 mg to about 5 g of the active ingredient, admixed with a suitable amount of carrier material, such that the amount of the carrier can comprise from about 5 to about 95% of the total composition .
  • the unit dosage form generally contains from about 0.01 mg to about 1000 mg of the active ingredient, typically in an amount of 0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg. Or 1000mg.
  • the p-hydroxyphenylacrylic acid derivative of the present invention can be produced by the following method:
  • the solvent used in the condensation reaction is acetic anhydride, acetonitrile, ethanol, methanol, water, dichloromethane, chloroform, etc., and the reaction temperature is between 0 and 150 ° C.
  • the reaction time is from 15 minutes to 15 hours.
  • R 1 is hydrogen, alkyl or acyl
  • R 2 , R 2 ', RR 3 ' are each independently selected from hydrogen, hydroxy, halogen or decyloxy.
  • G is a disubstituted aryl group, as defined in claim 1. .
  • the substituted benzene is reacted with a suitable acid halide to obtain a substituted aromatic ketone compound, and then introduced into a hydroxyl group by a reaction with a base such as NaOH under the action of a phase transfer catalyst such as Aliquat 336 TM in an aqueous organic solvent.
  • a phase transfer catalyst such as Aliquat 336 TM in an aqueous organic solvent.
  • the solvent used in the condensation reaction is acetic anhydride, acetonitrile, ethanol, methanol, water, dichloromethane or chloroform, and the reaction temperature is between 0 and 150 ° C, and the reaction time is from 15 minutes to 15 hours.
  • R 6 , R 7 are each independently selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, trifluoromethyl, carboxy, amino, decyl, alkyloxy, etc., and R 6 and R 7 may be cleaved by a thiol or an oxy group. Carbon ring of 3 to 7 atoms)
  • R 8 is hydrogen, fluorenyl, acyl, etc.
  • the substituted benzaldehyde and the substituted phenylacetic acid are reacted in acetic anhydride under the catalysis of triethylamine, DBU, sodium hydroxide, sodium ethoxide or the like to obtain a carboxylic acid p-hydroxyphenylacrylic acid derivative (Ketcham R, Jambotkar D, J. Org. Chem. 28 (1963) 1034-1037; J. Chem. Soc. 1955, 3445), reacting with an alcohol or a halogenated hydrocarbon to give an ester of a p-hydroxyphenylacrylic acid derivative (J. Am. Chem. Soc. 77 (1955) : 6214-6215; J. Med. Chem.
  • the solvent used in the condensation reaction is acetic anhydride, acetonitrile, ethanol, methanol, water, dichloromethane, chloroform, etc.
  • the reaction temperature is between 0 and 150 ° C
  • the reaction time is from 15 minutes to 15 hours.
  • R is a group such as an alkyl group, an alkenyl group, an aryl group or an aryl group.
  • Ketcham study found that the product of the E configuration was mainly catalyzed by triethylamine in acetic anhydride. It is also possible to determine the product of the E configuration from the displacement of the isolated hydrogen on the double bond (Org. Syn. CV4, 777; Can. J. Chem. 73 (1990) 1660-1665; J. Org. Chem. 46 (1981) 2514-2520).
  • the substituted benzaldehyde is reacted with a substituted phenylacetic acid to prepare an ⁇ , ⁇ -diphenylacrylic compound.
  • the compound is reacted with methanesulfonyl chloride to obtain a m-sulfonyl-based p-hydroxyphenylacrylic acid derivative; and a reagent such as chlorosulfonic acid or aqueous ammonia is reacted to prepare a sulfamic acid-based p-hydroxyphenylacrylic acid derivative.
  • Method G The thioether compound is reacted with an oxidizing agent to be converted into a sulfoxide, a sulfoxide compound and an imidizing reagent to obtain a sulfoxide gold amine compound.
  • the oxidant has reagents such as 0 2 , peracetic acid, m-chloroperbenzoic acid, potassium hydrogen persulfate, sodium tungstate, etc.
  • the imidization reagent is sodium sulfate and concentrated sulfuric acid.
  • the solvent used is water, acetic acid, acetonitrile, dichloro Formazan, acetone, ethanol, etc., the reaction temperature is between 0 and 150 ° C, and the reaction time is from 15 minutes to 15 hours.
  • a suitable alkyne is reacted with CO and 3 ⁇ 40 to give the p-hydroxybenzoic acid derivative A.
  • the catalysts used are palladium carbon, nickel, platinum, ! ⁇ (.0) 12, etc., reaction temperature 50-20CTC, reaction pressure 5-150 atmosphere, solvent tetrahydrofuran, acetone, acetonitrile, benzene, ethanol, methanol, etc. (J. Am. Chem. Soc. 88 (1966) ): 1289-1292)o
  • the substituted phenylacetyl chloride and bis(3-butenyl) cadmium are reacted to obtain a ketone, which is then oxidatively decomposed to obtain a ketone aldehyde.
  • the condensation reaction is carried out with a base to obtain a cyclopentenone, which is then reacted with an aryllithium or an argon bromide reagent.
  • An allyl alcohol compound is obtained, which is oxidized with pyridinium chlorochromate (PCC) to give a 2,3-disubstituted cyclohexenone.
  • PCC pyridinium chlorochromate
  • the synthesis method of the present invention is not limited to the above-described synthetic route, and includes furanone or pyrrolidone to obtain a compound of the present invention by substitution or the like, a glycoside compound or other form of compound to obtain a compound of the present invention by hydrolysis, in a mammal
  • the form of the metabolite forms the compound of the present invention and the like.
  • the biological activity of the p-hydroxyphenylacrylic acid derivative of the present invention can be tested by the following methods:
  • Kunming mice (18 to 22 g) were randomly divided into groups of 6 to 8 according to the protocol described in the literature (Chinese Journal of Medicinal Chemistry, 38 (2000): 242-246).
  • the experiment included a blank control group, indomethacin (a commercially available oral preparation) positive control group and a test compound group.
  • the test compound group was 5%.
  • CMC-Na was formulated as a suspension and administered intragastrically. The blank group was used in an equivalent amount of 5%.
  • CMC-Na positive control with indomethacin.
  • 50 ⁇ l of xylene was uniformly applied to both sides of the right ear of the mouse, and the left ear was used as a control.
  • SD rats (180 to 200 g - ) were randomly grouped according to the protocol described in Journal of China Pharmaceutical University, 33 (2002): 460-465, with 6 to 8 per group.
  • the experiment included a blank control group and a test compound group.
  • the drug preparation and dosage were the same as the anti-inflammatory activity test.
  • the rats were administered by continuous intragastric administration for 7 days, and fasted for 12 hours before the last intragastric administration. After 1 hour of administration, the cervical vertebrae were dislocated and immediately opened. The abdominal cavity was opened immediately, and the pylorus was ligated 2 cm away. 10% formaldehyde was injected from the cardia.
  • SD rats (180 to 200 g) were randomly divided into groups of 6 to 8 per group according to the protocol described in Chinese Journal of Pathophysiology, 19 (2003): 386-390.
  • the experiment included a blank control group and a test compound group.
  • the drug was formulated and administered at the same dose as the anti-inflammatory activity test. Rats were intragastrically administered once every other day for 6 times (11 days). Toxic responses in rats were observed including body weight, behavior, eating, fur, respiration, limb activity, and the like.
  • the rats were anesthetized with sodium pentobarbital, then sacrificed by cervical dislocation, the pericardial cavity was opened, the heart was removed and washed with phosphate buffer, and the left ventricular free wall middle ventricular muscle was taken along the long axis of the heart. Specimens, light microscopy and transmission electron microscopy were used to observe changes in myocardial tissue. The experimental results are shown in Table 3.
  • NMYY 100 1/6 The present invention is exemplified without obvious abnormalities.
  • Compounds CPY and NMYY were compared with the blank group, except for one death in the compound NMYY group, and the other rats had no abnormal body weight, eating, and activity. Other toxic reactions occur. Light microscopy of the cardiac muscle tissue did not reveal significant differences or abnormal changes.
  • Its structure is characterized by the ethylene bridge linking two benzene rings and the cyclooxygenase structure on the benzene ring.
  • the group is a mesyl group, but the heterocyclic bridge connection such as a furan ring has not been studied.
  • the core structure of the study is an ethylene bridge instead of a p-hydroxyphenylacrylic acid derivative.
  • the compound of the formula (I) of the present invention is deeply studied on the basis of p-hydroxyphenylacrylic acid, and it is clearly proposed that the p-hydroxyphenylacrylic acid derivative is a core structure, and the two benzene rings are connected by an unsaturated heterocyclic bridge, and also include impurities.
  • the cyclooxygenase structure-constituting group on the benzene ring is an aminosulfonyl group and a methylsulfonyl group, and the structure-constituting group of the lipoxygenase is p-hydroxystyrene.
  • the structural feature of the present invention is that the benzene ring at the ⁇ -position of the p-hydroxyphenylacrylic acid derivative and the benzene ring at the ⁇ -position are located on the same side of the unsaturated heterocyclic ring, and the amino group at the para position of the X-position benzene ring
  • An acyl group such as an acyl group has an oxygen atom at the para position of the ⁇ -position benzene ring to form a p-hydroxyphenylacrylic acid structure with an unsaturated bond.
  • the cyclooxygenase structure-active group of rofecoxib is a methylsulfonyl group and is on the 4-position benzene ring of the furan ring, and the structure-active group also has a good selective activity on the 3-position benzene ring.
  • the cyclooxygenase structure of the celecoxib (such as the formula ( ⁇ )) is a sulfamoyl group, and the aminosulfonyl group has a better apoptosis-inducing activity compared with the methanesulfonyl group, celecoxib. Cardiovascular safety is better than rofecoxib, 'this also illustrates certain properties of sulfamoyl groups (J. Natl. Cancer Inst. 94 (23): 1745-1757).
  • the pharmaceutical composition of the compound of the formula (I) of the present invention treats and prevents inflammation and inflammation-related diseases, and reduces cardiovascular side effects while reducing gastrointestinal side effects.
  • Example 1 3-(4-Methanesulfonylphenyl)-4-(4-acetoxyphenyl)-2(5H)-furanone and 3-(4-methanesulfonylphenyl)-4- (4-acetoxyphenyl)-2,5-furandione
  • methanesulfonyl chloride 34.5 g, 0.3 mol, about 23 ml
  • Phenylacetic acid (10.5 g, 0.075 mol) was added in portions, and gradually heated to 60 ° C for 2 hours. It was poured into ice water, and the solid was precipitated, filtered, dried, and recrystallized from ethanol to give white crystals, 14.2 g, mp.
  • Step 4 2-(4-acetoxyphenyl)-2-oxoethyl-4-methanesulfonylphenylacetate
  • Step 5 3-(4-Methanesulfonylphenyl)-4-(4-acetoxyphenyl)-2(5H)-furanone and 3-(4-methanesulfonylphenyl)-4-( 4-acetoxyphenyl)-2,5-furandione'
  • the ester product of the previous step (0.39 g, 1 mmol) was dissolved in 6 ml of acetonitrile, cooled in an ice water bath, then 0.15 ml of diazabicyclohexane (DBU) was added, reacted for 50 minutes, and then adjusted to acidity with 5% HCl. In 30 ml of ice water, a solid product was precipitated, which was filtered, dried, and eluted with ethyl acetate and n-hexane.
  • DBU diazabicyclohexane
  • Step 3 3-(4-Methanesulfonylphenyl)-4-(4-methoxyphenyl)-2,5-furandione
  • Step 2 (E)-2-(4-(N-Acetylaminosulfonyl)phenyl)-3-(3-methoxy-4-acetoxyphenyl)acrylic acid 4-aminosulfonylbenzene Acetic acid (0.22 g, 1 mmol), 3-methoxy-4-hydroxybenzaldehyde (0.25 g, 1.3 mmol) and triethylamine 0.4 ml were added to 5 mL of acetic anhydride, and the reaction was stirred at 130 ° C for 4 hours.
  • Example 9 A procedure for the preparation of (E)-2-(4-(N-acetylaminosulfonyl)phenyl)-3-(3,4-diacetoxyphenyl)acrylic acid was similar to that of Example 3. 4-Aminosulfonylphenylacetic acid and 3,4-dihydroxybenzaldehyde were combined to give a white solid, mp 225-227 ° C o ⁇ -NMR 5 (ppm): 1.95 (3H, s), 2.19 (3H, s ), 2.22(3H,s), 6.82(l H,s), 6.95 (lH, s), 7.13 (lH, d), 7.44 (2H, d), 7.81 (lH, s), 7.90 (2H, d), 12.16 (lH, s), 13.02 (lH, s).
  • Example 10 (E)-2-(4-(N-Acetylaminosulfonyl)phenyl)-3-(3,4-dimethoxyphenyl)acrylic acid was prepared in a similar manner to Example 3. 4-Aminosulfonylphenylacetic acid and 3,4-dimethoxybenzaldehyde were combined to give a pale yellow solid, mp 236-238.
  • Example 12 The preparation method was similar to that of Example 12. 0.2 g of the compound of Example 4 was hydrolyzed in a 5% NaOH solution, acidified with 5% HCl, and a brown solid was precipitated, which was carbonized and decomposed at m.p. MS (m/z): 335.3 [M + H] +.
  • Example 15 (E)- 4-Methoxybenzyl-2-(4-methanesulfonylphenyl)-3-(3-methoxy-4-acetoxyphenyl)acrylate
  • Step 1 The preparation method was similar to that of Example 4. Reaction of 4-aminosulfonylphenylacetic acid with vanillin affords a white solid, mp 224-226 ° C, (E)-2-(4-methanesulfonylphenyl)-3-(3-methoxy- 4-acetoxyphenyl)acrylic acid.
  • Step 2 In a single-mouth bottle, 0.2 g of the previous product, 0.3 ml of 4-methoxybenzyl chloride, 0.5 ml of triethylamine and 5 ml of acetonitrile were mixed, and the reaction was stirred at room temperature for 6 hours, and then acidified with 5% HCl. The mixture was poured into 20 ml of water, and the precipitate was precipitated, filtered, dried, and then recrystallized from methanol to afford white solid, mp 253-255 °C.
  • Step 1 0.2 g of (E)-2-(4-methanesulfonylphenyl)-3-(3-methoxy-4-acetoxyphenyl)acrylic acid in Example 15 was added to 5 ml of water and 1 ml of 5% NaOH solution, reacted in a water bath at 80 ° C for 2 hours, acidified with 5% HCl, mp 220-223 ° C, (E)-2-(4-methanesulfonylphenyl)-3-(3 -Methoxy-4-hydroxyphenyl)acrylic acid.
  • Step 2 Method 1, in a single-mouth bottle, 0.2 g of the previous product, 0.25 ml of phenylethyl alcohol, 0.25 ml of benzenesulfonyl chloride and 3 ml of pyridine are mixed, reacted at room temperature for 6 hours, then acidified with 5% HCl, and put into 20 ml. In water, a precipitate precipitated to give a white solid.
  • 0.2 g of the product of the previous step and 3 ml of absolute ethanol were added, and 5 drops of concentrated sulfuric acid was added dropwise, and then the reaction was refluxed in a water bath at 80 ° C for 2 hours, cooled to room temperature, and adjusted to 5% NaOH.
  • Example 17 (E)-2-(4-sulfonamidophenyl)-3-(3,4-methylenedioxybenzene)acrylic acid T N2009/001500 0.18 g (0.0015 mol) of 3,4-methylenedioxybenzaldehyde was added to 10 mL of acetonitrile solvent, 0.40 mL of triethylamine was added, and then 0.22 g (0.001 mol) of p-sulfonamidophenylacetic acid was added. The reaction was stirred for 1 hour, then DBU was added, and the reaction was further stirred for 1 hour. The reaction was quenched, and 1N hydrochloric acid (1 mL) was added, extracted with ethyl acetate, layered, ethyl acetate solution washed with water, dried and concentrated to give product.
  • Example 18 (E)-(4-(N-Acetylaminosulfonyl)phenyl)-3-(3-methoxy-4-acetoxyphenyl)acrylate sodium (E)- 2-(4-(N-Acetylaminosulfonyl)phenyl)-3-(3-methoxy-4-acetoxyphenyl)acrylic acid O. lg was added to 3 ml of water at room temperature, dropwise 5 % NaOH solution, adjust the pH to about 10, heat and stir at 50 ° C for 10 minutes, then vacuum dry to obtain a solid residue, add a small amount of ethanol to dissolve, add diethyl ether to precipitate a solid, and vacuum to obtain a product. Sodium salt. Similarly, the potassium salt, calcium salt, and ammonium salt are synthesized in the same manner as above.
  • Phenylacetic acid (7.8 g, 0.05 mol), ⁇ -bromo-p-methoxyacetophenone (11.4 g, 0.05 mol), triethylamine 3 ml and acetonitrile 20 ml were mixed, and the reaction was stirred at room temperature for 2 hours, and then the reaction was carried out.
  • the container was transferred to an ice water bath, and the reaction mixture was stirred for 50 minutes, and the mixture was reacted with 5% HCl to give a solid solid.
  • Dichlorosulfonic acid (4.5 g, 0.04 mol) was diluted with 10 ml of benzene, and cooled at about -10 Torr.
  • the product of the previous step (2.7 g, O. Olmol) was added in portions, stirred for 30 minutes, and then reacted at room temperature for 2 hours. Into the water, filter, and dry.
  • the product of the previous step was added to 5 ml of cold ammonia water, and the mixture was stirred and heated in an 80 ⁇ water bath for 1 hour, then cooled to room temperature, diluted with water, acidified to neutral with 5% HCl, and a yellow solid product was precipitated, mpl 58-160°. C.
  • Example 22 3-(4-(N-Acetylaminosulfonyl)phenyl)-4-(4-acetoxyphenyl)-2(5H)-furanone 4-aminosulfonylphenylacetic acid ( 0.22g, lmmol), ⁇ -bromo-4-hydroxyacetophenone (0.37g, 1.5mmol), triethylamine 0.4ml and acetonitrile ⁇ were mixed, stirred for 1 hour, acidified with 5% HCl, and put into water. The solid was precipitated, filtered and dried to give a white solid.
  • A-bromo-p-acetoxyacetophenone (0.51 g, 2 mmol), 4-methanesulfonylphenylacetamide (0.43 g, 2 mmol) and 6 ml of acetonitrile were added to a three-necked flask, stirred and dissolved, and triethylamine 0.2 ml was added.
  • the reaction was stirred at room temperature for 1 hour.
  • the mixture was acidified with 5% HCl, and poured into 30 ml of ice water to precipitate a solid, which was filtered and dried to give an off-white solid.

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Abstract

L'invention concerne des dérivés d'acide acrylique de para-hydrobenzène de formule (I) et des sels pharmaceutiquement acceptables, des procédés de préparation, des compositions pharmaceutiques les contenant ainsi que leurs utilisations dans la préparation de médicaments destinés au traitement et à la prévention des inflammations ou des maladies associées aux inflammations. L'invention concerne en particulier les utilisations de ces dérivés dans la préparation de médicaments inhibiteurs sélectifs de la cyclo-oxygénase et/ou de la lipoxygénase.
PCT/CN2009/001500 2008-12-18 2009-12-18 Derives d'acide acrylique de para-hydroxybenzene et utilisations associees WO2010069150A1 (fr)

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WO2008140251A2 (fr) * 2007-05-14 2008-11-20 University-Industry Cooperation Group Of Kyung Hee University Inhibiteurs de la cyclooxygénase-2
CN101429181A (zh) * 2008-12-18 2009-05-13 毛近隆 对羟基苯丙烯酸衍生物及其应用

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US5474995A (en) * 1993-06-24 1995-12-12 Merck Frosst Canada, Inc. Phenyl heterocycles as cox-2 inhibitors

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CN1762994A (zh) * 2005-09-26 2006-04-26 山东大学 含有磺酰基二苯基乙烯桥化合物及其制法和药物应用
WO2008140251A2 (fr) * 2007-05-14 2008-11-20 University-Industry Cooperation Group Of Kyung Hee University Inhibiteurs de la cyclooxygénase-2
CN101429181A (zh) * 2008-12-18 2009-05-13 毛近隆 对羟基苯丙烯酸衍生物及其应用

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