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WO2004060873A1 - Nouveaux derives de 5-hydroxyindole-3-carboxylate - Google Patents

Nouveaux derives de 5-hydroxyindole-3-carboxylate Download PDF

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Publication number
WO2004060873A1
WO2004060873A1 PCT/CN2003/000481 CN0300481W WO2004060873A1 WO 2004060873 A1 WO2004060873 A1 WO 2004060873A1 CN 0300481 W CN0300481 W CN 0300481W WO 2004060873 A1 WO2004060873 A1 WO 2004060873A1
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Prior art keywords
methyl
indole
hydroxy
thio
bromo
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Ceased
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PCT/CN2003/000481
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English (en)
Chinese (zh)
Inventor
Ping Gong
Dun Wang
Yangfang Zhao
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SHENYAND PHARMACEUTICAL UNIVERSITY
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SHENYAND PHARMACEUTICAL UNIVERSITY
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Priority to AU2003303648A priority Critical patent/AU2003303648A1/en
Publication of WO2004060873A1 publication Critical patent/WO2004060873A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P31/12—Antivirals
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • the present invention relates to a novel 5-hydroxy-3-carboxylic acid ester indole derivative and a pharmaceutically acceptable salt thereof, and also relates to a pharmaceutical composition using the compound as an active ingredient, as an antiviral agent, for influenza viruses and Respiratory viruses have significant inhibitory effects and their use as anti-influenza virus agents and in the treatment and prevention of acute viral respiratory infections.
  • the invention also relates to a method for their preparation. Background technique
  • Influenza is an acute viral inspiratory infectious disease caused by the influenza virus, which mainly affects the elderly and people with compromised immune systems.
  • Influenza virus belongs to the family Orthomyxoviridae, and is divided into three types: A, B, and C according to different antigens.
  • Type A often appears in epidemic forms and can cause worldwide pandemics.
  • Type B often causes local outbreaks and type C.
  • influenza virus variability and multi-drug resistance of influenza virus strains Due to the virus variability and multi-drug resistance of influenza virus strains, the originally effective influenza vaccines quickly failed; the current types and quantities of anti-influenza drugs are limited, and they usually have drug resistance and toxic side effects. To address these issues, many studies have been conducted to develop new anti-influenza virus chemotherapeutics with potent anti-influenza virus activity and lower toxicity.
  • R for. Alkyl, C 3 -C 7 cyclofluorenyl
  • R 2 is C, ⁇ C 4 fluorenyl
  • Z is CH 2 SR 5 and CH 2 NR 6 R 7 ;
  • R 5 is phenyl optionally substituted with 1 to 3 R 8 ;
  • R 5 is a monocyclic or polycyclic saturated ring having 4 to 10 atoms or 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, or a heteroaromatic ring containing 5 to 10 atoms, wherein the saturated
  • the ring and heteroaryl ring may be optionally substituted with 1 to 3 R 8 ;
  • '' or 15 is an alkyl group,. 3 ⁇ cyclofluorenyl, C 2 -C ,. Alkenyl, C 2 -C 1Q alkynyl, which may be optionally substituted by 1 to 3;
  • 13 ⁇ 4 and 14 are independently selected from H, amino, or a group as defined in 5 ;
  • R 3 , 1 4 and 1 ⁇ together form a guanidyl group, or a 4 to 10 membered monocyclic or polycyclic saturated ring or a 5 to 10 membered heteroaryl ring, wherein the saturated ring and heteroaryl ring optionally include 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, in addition to 1 3 and the attached nitrogen atom, the saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, the saturated ring and heteroaryl The ring may be optionally substituted by 1 to 3;
  • And 17 are independently selected from H, an amino group, or a group R 5 as defined above;
  • 1, 7 and 1 ⁇ together form a guanidyl group, or a 4 to 10 membered monocyclic or polycyclic saturated ring or a 5 to 10 membered heteroaromatic ring, wherein the saturated ring and heteroaromatic ring optionally include 1 to 4 members Heteroatoms from nitrogen, oxygen and sulfur, except! Outside the nitrogen atom to which 6 and ⁇ are connected, the saturated ring optionally includes 1 or 2 carbon-carbon double bonds or triple bonds, and the saturated ring and heteroaryl ring may be optionally substituted by 1 to 3;
  • X represents H, halogen
  • R 8 represents C r C 6 fluorenyl, C 3 ⁇ C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxyl, 6 methoxy, C 2 -alkenyloxy, 6 alkynyloxy, mercapto, alkylthio embankment ⁇ 6, 6 alkenylthio group, a phenyl group, a benzyl group, a free, salified, esterified and amidated carboxy, halogen, trifluoromethyl, embankment acyl, nitro Group, cyano, amino or amino substituted by mono or di (C, -C 6 fluorenyl);
  • R 5 is not p-chlorophenyl, Ethoxyphenyl, p-ethylphenyl, p-methylphenyl, o-nitrophenyl, benzyl, 2-pyridyl, 4-hydroxy-3,5-di-t-butylphenyl, cyclohexyl, 2-thienyl, phenyl, 3-thienyl; when X is a bromine atom,!
  • ⁇ Is methyl is ethyl
  • NR 3 R 4 is 1-morpholinyl
  • Z is CH 2 NR 6 R 7 , where R fi and R 7 are either H or methyl, and the other Not p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl;
  • X is a bromine atom
  • 1 is a methyl group
  • 14 are both a methyl group
  • Z is CH 2 NR 6 R 7 , wherein R 6 and R 7 are either H or methyl
  • R 6 and R 7 are either H or methyl
  • Z is 2 NR 6 7 when CH R, wherein, R 6, R 7 can not both be H, methyl, ethyl, NR 6 R 7 is not a morpholinyl group; when Z is CH 2 SR 5 , wherein R 5 is not phenyl and benzyl.
  • Preferred R is preferably C ⁇ fluorenyl, especially methyl, ethyl, propyl, isopropyl, cyclopropyl; preferred Z is CH 2 SR 5;
  • R 5 is unsubstituted phenyl or 1 to 3 selected from hydroxy, C, -C 4 alkyl, ⁇ - ⁇ fluorenyloxy, halogen, trifluoromethyl, nitro, cyano or amino.
  • R 5 is phenyl substituted with 1 to 3 halogen atoms
  • R 5 is pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazine Groups, indolyl, benzofuranyl, benzothienyl, quinolinyl, and purine base residues;
  • 1 3 and R 4 are independently selected from H, methyl, ethyl, propyl, cyclopropyl, butyl, cyclopentyl, cyclohexyl, n-octyl;
  • Preferred R 3 and RPN are guanidyl, pyrrolyl, pyrazolyl, imidazolyl, 2-methylimidazolyl, pyrrolidin, piperidinyl, piperazinyl, 4-methylpiperazinyl, Phosphono
  • X represents H and a bromine atom
  • 5-hydroxy-3-carboxylic acid ester indole derivatives of the above formula I include:
  • the 5-hydroxy-3-carboxylic acid ester indole derivative of the above formula I of the present invention may form an pharmaceutically acceptable salt thereof with an acid.
  • Acids can include inorganic or organic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid Acid, p-toluenesulfonic acid, etc.
  • Another object of the present invention is to provide a compound of formula II or a pharmaceutically acceptable compound thereof.
  • the method for preparing a salt is characterized in that: a compound of the general formula III is obtained by reacting HR 3 R 4 .
  • R 3 , 14 and ⁇ together are a guanidino group, or a heteroaryl ring containing 5 to 10 atoms, wherein the heteroaryl ring It optionally includes 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and may be optionally substituted by 1 to 3; R and R 'are independently selected from H,. Alkyl, ⁇ . 7 Huanyuanji.
  • the 5-hydroxy-3-carboxylic acid ester indole compound of the above formula I according to the present invention has potential anti-influenza virus and anti-respiratory virus effects, it is clinically used as an anti-influenza virus agent and for Treatment and prevention of acute viral respiratory infections, particularly caused by the following viruses such as influenza A virus, influenza B virus, respiratory syncytial virus, parainfluenza virus, rhinovirus and adenovirus.
  • the compound according to the present invention can be used as an active ingredient for treating or preventing influenza and acute viral respiratory infections.
  • the present invention also provides a method for treating or preventing the above-mentioned diseases, which comprises administering a therapeutically effective amount of Compounds according to the invention.
  • the present invention includes a pharmaceutical composition containing the 5-hydroxy-3-carboxylic acid ester indole compound of the above formula I or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient refers to any diluent, adjuvant and / or carrier that can be used in the pharmaceutical field.
  • the compounds of the present invention can be used in combination with other active ingredients, as long as they do not cause other adverse effects, such as allergic reactions.
  • the pharmaceutical composition of the present invention When used clinically, it can be formulated into several dosage forms, which contain some excipients commonly used in the pharmaceutical field; for example, oral preparations (such as tablets, capsules, dragees, solutions or Suspensions); Injectable preparations (such as injectable solutions or suspensions, or injectable dry powders, which can be used immediately after adding water for injection); Topical preparations (such as ointments or solutions).
  • oral preparations such as tablets, capsules, dragees, solutions or Suspensions
  • Injectable preparations such as injectable solutions or suspensions, or injectable dry powders, which can be used immediately after adding water for injection
  • Topical preparations such as ointments or solutions.
  • the carriers used in the pharmaceutical composition of the present invention are common types available in the pharmaceutical field and include: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, pigment-free for oral preparations , Flavoring agents, etc .; preservatives, solubilizers, stabilizers, etc. for injectable preparations; bases, diluents, lubricants, preservatives, etc. for topical preparations.
  • Pharmaceutical preparations can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally, or topically). If certain drugs are unstable under gastric conditions, they can be formulated as enteric-coated tablets.
  • the clinical dosage of the 5-hydroxy-3-carboxylic acid ester indole compounds of the above formula I for patients can be based on- The therapeutic efficacy and bioavailability of active ingredients in the body, their metabolism and excretion rates, and the age, sex, and disease stage of the patient are appropriately adjusted, but the daily dose for adults should generally be 10 ⁇ 500mg, preferably 50 ⁇ 300mg . Therefore, when the pharmaceutical composition of the present invention is made into a unit dosage form, in consideration of the above effective dose, each unit preparation should contain 10 to 500 mg of the 5-hydroxy-3-carboxylate indole compound of the above formula I, preferably 5 (K300mg.
  • these preparations can be administered at intervals (preferably one to six times).
  • the following synthetic routes A to C describe the preparation of the compound of formula I of the present invention. All the raw materials are Are prepared by the methods described in these schemes, by methods well known to those skilled in the art of organic chemistry, or are commercially available. All final compounds of the present invention are prepared by the methods described in these schemes or by methods analogous thereto, These methods are well known to those of ordinary skill in the art of organic chemistry. All variable factors applied in these diagrams are as defined below or as defined in the claims.
  • Z is 01 2 31 5 or 0 ⁇ 7
  • the substituents R ,, R 2 , R 5 , and 17 are as defined above, wherein R 3 , R 4 is independently selected from H, amino, -C ⁇ embankment group, C 3 ⁇ C 7 cycloalkyl group embankment, C 2 -C 1 () alkenyl, C 2 -C 1Q alkynyl group which may be substituted with 1 to 3 R 8 Optionally substituted; or R 3 , 11 4 and N together form a monocyclic or polycyclic saturated ring of 4 to 10 atoms, wherein the saturated ring optionally includes 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, In addition to the nitrogen atom to which 3 ⁇ 4 is attached, the saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, which may be optionally substituted by 1 to 3 R 8 ;
  • the substituted amine is added to the acetoacetate, and the reaction is heated to form the compound 3-amino-2-butenoate (A-1).
  • the compound A-1 and p-benzoquinone are in 1,2-dichloroacetamidine.
  • the substituent X is a hydrogen, fluorine, chlorine atom, and other substituents are defined as the substituents of the compound in the route A.
  • Ethyl chloroacetate is commercially available, and it can be reacted with 13 ⁇ 4 ⁇ or 1 ⁇ 6 1 7 (substituted thiophenol or amine) under basic conditions at room temperature to obtain compound B-1.
  • the amine was refluxed for 12 to 24 hours in 1,2-dichloroethane to obtain compound B-2, and then was refluxed for 6 to 12 hours in reaction with p-benzoquinone in 1,2-dichloroethane.
  • Compound Manganese Formula B-4 is obtained by Mannich reaction.
  • Z is as defined for compounds of formula I
  • X is H or halogen
  • R 3 , 1 4 and: ⁇ are guanidino together, or contain 5 to 10 membered heteroaromatic rings, which may be optionally substituted by 1 to 3 members.
  • R and R ' are independently selected from H, -C ,. Alkyl,. 3 ⁇ cycloalkyl.
  • Step B Preparation of ethyl 1,2-dimethyl-5-hydroxyindole-3-carboxylic acid (2)
  • Step C Preparation of 6-bromo-2- (bromomethyl) -5-hydroxy small methyl-1H-indole-3-carboxylic acid ethyl ester (3)
  • compound (2) 65.0 g (0.28 mol) to To 400 ml of carbon tetrachloride, add 3 pieces of benzoyl peroxide, dropwise add 40.0 ml (0.70 mol) of bromine, reflux after dripping for 4 h, complete the reaction, leave to stand, cool, suction filter, and recrystallize ethyl acetate 94.9 g of compound (3) was obtained with a yield of 86.7%,
  • Step D Preparation of 6-bromo-5-hydroxy-1-methyl-2-[(phenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl ester (4)
  • Step E 6-bromo-4- (diethylamino) methyl-5-hydroxy-1-methyl-2- (phenylthiomethyl) -1H-indole-3-carboxylic acid ethyl ester hydrochloride
  • Step B Preparation of 4-phenylthio-2-methylamino-2-butenoic acid ethyl ester
  • Methylamine gas (about 0.14 mol) was passed into a solution of 16.7 g (0.07 mol) of ethyl phenylthioacetoacetate in 150 ml of 1,2-dichloroacetamidine, and the reaction was carried out at 50-60 ° C for 18 hours. After the reaction was completed, washing , Dried, and evaporated to dryness to obtain 15 g of 4-phenylthio-2-methylamino-2-butenoic acid ethyl ester in a yield of 86%.
  • Step C Preparation of 5-hydroxy-1-methyl-2- (phenylthiomethyl) -1H-indole-3-carboxylic acid ethyl ester
  • Step D 4- (dimethylamino) methyl-5-hydroxy-1-methyl-2- (phenylthio) methyl-1H-indole-3- 81
  • 6-bromo-4- (dimethylamino) methyl-5-lightyl-1-methyl-2-[(4-chlorophenyl) thio] methyl-1H- was prepared according to the method of Example 1.
  • Indole-3-carboxylic acid ethyl ester, 10.2 g (0.02 mol) of the compound was added to 80 mL of ethanol, stirred to dissolve, 3.4 g (0.05 mol) of imidazole was added, heated under reflux for 4 h, and concentrated under reduced pressure to obtain an oil. After reacting with ether hydrochloride, a solid was obtained, and the target compound was recrystallized to obtain 9.7 g of the target compound in a yield of 91%.
  • CPE cytopathic effect
  • MDCK cells were plated at 400,000 ⁇ 96-well plates, 37 ° C, 5% C0 2 culture 24h, test compounds were added, Arbidol, adamantyl amine embankment and ribavirin, were diluted with 4000 g / ml ⁇ 31.3 g / ml, inoculate 3 wells per concentration, 100 ⁇ l per well. At the same time, a normal cell control was set. Incubate at 37 ° C and 5% C0 2 for 5-7 days. The morphological changes of cells were observed under an inverted microscope every 24 hours, and the morphological changes of cells (CPE) were recorded: the change below 25% was +, the change from 26% to 50% was ++, 51 ° /.
  • CPE morphological changes of cells
  • Hela cells were seeded in a 96-well culture plate at a concentration of 400,000 / ml, and cultured at 37 ° C and 5% CO 2 for 24 hours.
  • the test compounds, Arbidol, amantadine, and ribavirin were added and diluted to 4000 yg / ml ⁇ 31.3 yg / ml, inoculate 3 wells per concentration, 100 ⁇ l per well.
  • a normal cell control was set. Incubate at 37 ° C and 5% CO 2 for 5-7 days. The morphological changes of the cells were observed under an inverted microscope every 24 hours, and the morphological changes of the cells were recorded.
  • the Reed-Muench method was used to calculate the half poisoning concentration of the drug (TD 5 ) and the maximum non-toxic concentration (TD.). The test was repeated twice.
  • MDCK cells at a concentration of 400,000 per ml of culture were seeded in 96-well plates, 37 ° C5% C0 2 culture 24h, added A3 virus, virus 1: 10-1: 40, diluted with 4 concentrations, each concentration in 3 wells, each well 100 ⁇ 1.
  • a normal cell control was set and cultured at 5% C0 2 at 33 ° C for 5-7 days.
  • the morphological changes of the cells were observed under an inverted microscope every 24 hours, and the morphological changes of the cells were recorded.
  • the Reed-Muench method was used to calculate the half infection concentration TCID 5 of the virus. .
  • Hela cells were cultured at a concentration of 400,000 per ml were seeded in 96-well pull, 37 ⁇ culture 24h, RSV virus was added, diluted 10-fold concentrations 10_i ⁇ 10- 7, 3 wells per concentration per well of 100 ⁇ 1.
  • a normal cell control was set. Incubate at 37 ° C for 5 ⁇ 7 days. Cell morphology CPE was observed, and Reed-Muench method was used to calculate the virus infection concentration TCID 5 . .
  • MDCK and Hela cells were seeded in 96-well culture plates at a concentration of 400,000 / ml, 37. After C-culture for 24-48 hours, discard the culture medium and add 1:30 A3 virus solution, 100 ⁇ l / 33 for 1.5 h, and 100 TCID 5 per well. RSV virus solution, 100 ⁇ l / well, adsorbed at 37 ° C for 1 h. Discard the virus solution. Add test compound and Arbidol solution with the maximum non-toxic concentration (TD Q ) to the cells, dilute 8 ⁇ 10 concentrations, 3 wells per concentration, 100 L per well. The positive control is amantadine and ribavirin.
  • the concentration is 500 yg / ml ⁇ 0.97 wg / ml, diluted twice, 3 wells per concentration, 100 L per well, virus control and normal cell control are set at 33 ⁇ and 37, respectively.
  • Example 1 7.8 ⁇ 0 15.6 ⁇ 0 8 3.9 ⁇ 0 15.6 ⁇ 0 8
  • Example 2 ⁇ 3.9 ⁇ 0 3.9 ⁇ 0 64 ⁇ 3.9 ⁇ 0 3.9 ⁇ 0 64
  • Example 3 3.9 ⁇ 0 7.8 ⁇ 0 256 ⁇ 3.9 ⁇ 0 3.9 ⁇ 0 513
  • Example 4 7.8 ⁇ 0 15.6 ⁇ 0 128 3.9 ⁇ 0 7.8 ⁇ 0 256
  • Example 5 15.6 ⁇ 0 31.3 ⁇ 0 64 15.6 ⁇ 0 31.3 ⁇ 0 64
  • Example 6 ⁇ 3.9 ⁇ 0 3.9 ⁇ 0 0 0 0 512 ⁇ 3.9 ⁇ 0 3.9 ⁇ 0 512
  • Example 7 ⁇ 3.9 ⁇ 0 3.9 ⁇ 0 512 3.9 ⁇ 0 7.8 ⁇ 0 256
  • Example S ⁇ 3.9 ⁇ 0 3.9 ⁇ 0 256 3.9 ⁇ 0

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Abstract

La présente invention concerne de nouveaux dérivés de 5-hydroxyindole-3-carboxylate, et en particulier de nouveaux dérivés de 5-hydroxyindole-3-carboxylate représentés par la formule générale (1). Dans cette formule, R1, R2, Z, R3, R4 et X sont tels que définis dans les descriptions. Cette invention concerne aussi des sels de ces composés répondant aux normes pharmaceutiques et des compositions pharmaceutiques contenant ces composés comme principes actifs. Ces composés ont des effets inhibiteurs éminents sur le virus de la grippe A et sur un virus de maladie respiratoire aigue en tant qu'agent antiviral. Cette invention concerne aussi l'utilisation de ces composés comme agent antigrippal et l'utilisation de ceux-ci pour le traitement et la prophylaxie d'infection respiratoire virale aigue. Cette invention concerne enfin une technique de préparation de ces dérivés.
PCT/CN2003/000481 2003-01-04 2003-06-20 Nouveaux derives de 5-hydroxyindole-3-carboxylate Ceased WO2004060873A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003303648A AU2003303648A1 (en) 2003-01-04 2003-06-20 Novel 5-hydroxyindole-3-carboxylate derivatives

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CNB031108032A CN100361975C (zh) 2003-01-04 2003-01-04 5－羟基－3－羧酸酯吲哚类衍生物及其制备方法
CN03110803.2 2003-01-04

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WO2004060873A1 true WO2004060873A1 (fr) 2004-07-22

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Cited By (4)

* Cited by examiner, † Cited by third party
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WO2007136300A2 (fr) 2006-05-23 2007-11-29 Alla Chem, Llc Indoles substitués et procédé de production et d'utilisation de ceux-ci
WO2007136302A3 (fr) * 2006-05-23 2008-02-14 Alla Chem Llc Substances actives, composition pharmaceutique et procédé de fabrication et d'utilisations correspondants
RU2338531C1 (ru) * 2007-02-16 2008-11-20 Алла Хем, Ллс Активные субстанции, фармацевтическая композиция, способ получения и применения
EP1970061A4 (fr) * 2005-12-28 2009-04-08 Zakrytoe Aktsionernoe Obschest Produit medicamenteux destine au traitement d'infections virales

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CN1560035A (zh) * 2004-03-12 2005-01-05 沈阳药科大学 5－羟基吲哚－3－羧酸脂类衍生物
RU2330018C2 (ru) * 2006-04-18 2008-07-27 Общество с ограниченной ответственностью "МБФ" Производные 4-аминометил-6-бром-5-гидроксииндол-3-карбоксилатов, способы их получения (варианты) и применение
RU2386616C2 (ru) 2008-04-23 2010-04-20 Общество С Ограниченной Ответственностью "Бинатех" Производные 5-гидрокси-4-аминометил-1-циклогексил (или циклогептил)-3-алкоксикарбонилиндолов, их фармацевтически приемлемые соли, обладающие противовирусной активностью, и способ их получения
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CN104479286A (zh) * 2014-12-19 2015-04-01 江苏华宏实业集团有限公司 一种抗菌塑料
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Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU1685933A1 (ru) * 1974-11-27 1991-10-23 Всесоюзный Научно-Исследовательский Химико-Фармацевтический Институт Им.С.Орджоникидзе Хлоргидрат 1-метил-2-фенилтиометил-3-карбэтокси-4-диметиламинометил-5-окси-6-броминдола, обладающий противовирусным действием, и способ его получени
WO1990008135A1 (fr) * 1989-01-12 1990-07-26 Vsesojuzny Nauchno-Issledovatelsky Khimiko-Farmatsevtichesky Institut Imeni S.Ordzhonikidze (Vnikhfi) Monohydrate d'hydrochlorure d'acide ethyle ester 6-brome-5-hydroxy-4-dimethyle-aminomethyle-1-methyle-2-phenylthiomethyle indole-3-carboxylique, son procede d'obtention et preparation pharmaceutique presentant une activite antivirale, de stimulation d'interferon et d'immunomodulation basee sur ledit compose

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 107, no. 39560, 1987, Columbus, Ohio, US; *
CHEMICAL ABSTRACTS, vol. 116, no. 255437, 1992, Columbus, Ohio, US; *
CHEMICAL ABSTRACTS, vol. 124, no. 29656, 1994, Columbus, Ohio, US; *
CHEMICAL ABSTRACTS, vol. 124, no. 86729, 1995, Columbus, Ohio, US; *
GRINEV A.N. ET AL, KHIM.-FARM.ZH, vol. 21, no. 1, pages 52 - 55 *
ZOTOVA S.A. ET AL, KHIM.-FARM.ZH, vol. 26, no. 1, pages 52 - 55 *
ZOTOVA S.A. ET AL, KHIM.-FARM.ZH, vol. 28, no. 2, pages 22 - 24 *
ZOTOVA S.A. ET AL, KHIM.-FARM.ZH, vol. 29, no. 1, pages 53 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1970061A4 (fr) * 2005-12-28 2009-04-08 Zakrytoe Aktsionernoe Obschest Produit medicamenteux destine au traitement d'infections virales
WO2007136300A2 (fr) 2006-05-23 2007-11-29 Alla Chem, Llc Indoles substitués et procédé de production et d'utilisation de ceux-ci
WO2007136302A3 (fr) * 2006-05-23 2008-02-14 Alla Chem Llc Substances actives, composition pharmaceutique et procédé de fabrication et d'utilisations correspondants
US8329689B2 (en) 2006-05-23 2012-12-11 Alexandre Vasilievich Ivachtchenko Substituted indoles and a method for the production and use thereof
RU2338531C1 (ru) * 2007-02-16 2008-11-20 Алла Хем, Ллс Активные субстанции, фармацевтическая композиция, способ получения и применения

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