WO1998033501A1 - Derives de 2-benzoylamino-3-phenylpropenamide et leurs procedes d'utilisation - Google Patents

Derives de 2-benzoylamino-3-phenylpropenamide et leurs procedes d'utilisation Download PDF

Info

Publication number
WO1998033501A1
WO1998033501A1 PCT/US1998/000986 US9800986W WO9833501A1 WO 1998033501 A1 WO1998033501 A1 WO 1998033501A1 US 9800986 W US9800986 W US 9800986W WO 9833501 A1 WO9833501 A1 WO 9833501A1
Authority
WO
WIPO (PCT)
Prior art keywords
piperidinyl
alkyl
nitrogen atom
compound
attached form
Prior art date
Application number
PCT/US1998/000986
Other languages
English (en)
Inventor
Robert B. Perni
Samuel C. Conway
Original Assignee
Avid Therapeutics Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Avid Therapeutics Inc. filed Critical Avid Therapeutics Inc.
Priority to AU59239/98A priority Critical patent/AU5923998A/en
Publication of WO1998033501A1 publication Critical patent/WO1998033501A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings 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
    • C07D263/36—One oxygen atom
    • C07D263/42—One oxygen atom attached in position 5
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to certain 2-benzoylamino- 3-phenylpropenamide derivatives which are useful as antiviral agents.
  • the present invention also relates to methods of treating of viral infections, in particular hepatitis.
  • the present invention further relates to pharmaceutical compositions useful for treating viral infections, in particular hepatitis.
  • Viral diseases include such diseases as AIDS, yellow fever, rabies, and poliomyelitis.
  • Viral infections include some of the most common of all human ailments, including the common acute respiratory and gastrointestinal infections, as well as such important chronic infections as hepatitis and genital herpes.
  • HAV Natural hepatitis A virus
  • HAV infection is usually caused by ingestion of feces-contaminated material.
  • the course of HAV infection is extremely variable, with the onset of jaundice sometimes preceded by a prodromal state of several days to more than a week characterized by fever.
  • Human hepatitis B virus (HBV) is a member of the hepadnavirus family which is characterized by a circular,
  • HBV induced disease that of the approximately 300 million individuals worldwide who are chronic carriers of HBV, one million die annually from HBV induced disease (Lau, J.Y.N., et al, Lancet, vol. 342, pp.
  • Hepatitis C virus has recently been identified as the principal agent for transfusion-associated non-A, non-B hepatitis.
  • the mean incubation period for acute HCV infection is intermediate between those of hepatitis A and hepatitis B and the clinical course for acute HCV is similar to those of hepatitis A and hepatitis B.
  • treatment with ⁇ - interferon leads to some improvement, as indicated by reduced alanine amino transferase (ALT) activity, a significant number of patients suffer relapse upon termination of the treatment.
  • ALT alanine amino transferase
  • Hepatitis Delta virus has been identified as the causative agent of delta or type D hepatitis. As in the cases of HBV and HCV, interferon treatment has been found to give only transient, beneficial results.
  • Human papillomaviruses HPV have been implicated in skin warts, epidermodysplasia verruciformis , infections of the genital tract, and anogenital warts, as well as cervical intraepithelial neoplasia and cancer of the cervix. HPV infections of the respiratory tract and oral cavity have also been reported. Although most warts regress spontaneously, there is no treatment which will cure all warts.
  • R 1 and R 2 are C ⁇ C., alkyl, or together with the nitrogen atom to which they are attached form a ring containing 5-6 atoms, including C and/or o;
  • R 3 -R 12 are hydrogen, halogen, C,-C 4 alkyl, C,-C 4 alkoxyl, substituted C, . -C 4 alkoxyl, nitro, cyano, or trifluoromethyl;
  • R J3 is hydrogen, C,-C 4 alkyl, arylalkyl, or C 2 -C- acyl; and X is halogen, Cj-C + alkyl, or substituted 0,-C,, alkyl, or a pharmaceutically acceptable salt thereof.
  • the present invention provides novel methods for the treatment of viral infections, by administering an effective amount of a compound of formula (I) .
  • the viral infections which may be treated by the present method include hepatitis (including hepatitis A, B, C, and Delta virus) and papillomavirus .
  • the present method involves treatment of hepatitis, in particular hepatitis B.
  • Examples of the C,-C 4 alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert- butyl.
  • Examples of the 5-6 membered rings which may be formed by R and R z together with the nitrogen atom to which they are attached include 1-piperidinyl, N-morpholinyl, and 1- pyrrolidinyl.
  • Examples of halogen include F, Cl, and Br.
  • Examples of C -C. alkoxyl include methoxy1, ethoxyl, n-propoxyl, iso-propoxyl, n-butoxyl, iso-butoxyl, sec-butoxyl, and tert-butoxyl.
  • Examples of substituted Cj-C,, alkoxyl include fl ⁇ orinated C,-C 4 alkoxyl such as trifluoromethoxyl and other perfluorinated C z -C 4 alkoxyl groups.
  • Examples of arylalkyl include benzyl, C,-C 4 alkyl substituted benzyl, and nitro substituted benzyl.
  • C 2 -C- acyl examples include acetyl, benzoyl, and nitro substituted benzoyl.
  • substituted C,-C 4 alkyl examples include trifluoromethyl and perfluorinated 0,-C,, alkyl groups.
  • a preferred set of compounds to be used in the present method are those in which R 1 and R 2 together with the nitrogen atom to which they are attached form a 1-piperidinyl group; and one to three of R -R ,z are halogen, N0 2 , or C,-C 4 alkoxyl, with the remainder of R 3 -R 12 being hydrogen; R 13 is hydrogen; and X is Cl or Br.
  • Another preferred set of compounds for use in the present method includes those compounds in which all of R 3 -R 12 are hydrogen; R l and R 2 together with the nitrogen atom to which they are attached form a 1-piperidinyl , 1-pyrrolidinyl, or N- morpholinyl group; X is Cl or Br; and R *J is hydrogen.
  • Another preferred set of compounds for use in the present method includes those compounds in which one of R 8 -R 12 is fluoro, methyl, methoxyl, chloro, or nitro, with the remainder of R -R )2 being hydrogen; all of R 3 -R are hydrogen; R 13 is hydrogen; X is chloro or bromo; and R 1 and R2 together with the nitrogen atom to which they are attached form a 1-piperidinyl group .
  • R ⁇ -R 12 are hydrogen; one or two or R 3 -R are chloro, fluoro, methoxyl, methyl, bromo, nitro, or cyano, with the remainder of R 3 -R being hydrogen; R 13 is hydrogen; X is chloro or bromo; and R 1 and R 2 together with the nitrogen atom to which they are attached form a 1-piperidinyl group.
  • Another preferred set of compounds for use in the present method includes those compounds in which one or two (preferably one) R ⁇ -R 12 of are fluoro, methyl, methoxyl, chloro, or nitro, with the remainder of R s -R 32 being hydrogen; one of R 2 -R is nitro, cyano, bromo, or methyl, with the remainder of R 3 -R 7 being hydrogen; R 23 is hydrogen; X is bromo; and R 1 and R 2 together with the nitrogen atom to which they are attached form a 1-piperidinyl group.
  • Another preferred set of compounds for use in the present method includes those compounds given in Table 1 in the Examples below.
  • R 10 is not methoxyl, chloro, or methyl. In the case of treating hepatitis B, it is also preferred that, when X is chloro, R 10 is hydrogen or fluoro.
  • an antiviral effective amount of a compound according to formula (I) is administered to a subject in need thereof.
  • the compound of formula (I) may be administered orally, parenterally, subcutaneously, intraveneously , topically, or via a suppository or an aerosol spray.
  • the compound of formula (I) is preferably administered orally.
  • a suitable dosage for an adult is 20 mg to 4 g per day, preferably 100 mg to 1500 mg per day, more preferably 250 mg to 750 mg per day.
  • the daily dosage may be given once per day or in small portions.
  • the present method is carried out by administering a compound of formula (I) which is effective for the treatment of the viral infection.
  • the compound is effective for the treatment of the viral infection at a dosage which can be tolerated by the subject being treated.
  • the compound is preferably effective at a dose which is not toxic to the subject.
  • the relative efficacy and toxicity may be determined by routine experimentation. For example in the case of hepatitis B, the relative efficacy and toxicity may be determined using the assays given in the Examples below.
  • the compounds in Table 1 are all effective at doses (EC i0 and/or EC 90 values) which are significantly less than the doses which result in significant cell death (TC 50 values) or significant inhibition of cell replication (IC 50 values) .
  • the present method may also be carried out by coad inistering the compound of formula (I) with one or more Known antiviral agents, such as interferons, ⁇ -thymosin, 3TC, FTC, ganiclovir, (S) -9- (3-hydroxy-2- phosphonylmethoxypropyl) adenine (HPMPA) , and penciclovir. Good results have been achieved with the combined use of 3TC and compound AT-61 in Table 1.
  • Known antiviral agents such as interferons, ⁇ -thymosin, 3TC, FTC, ganiclovir, (S) -9- (3-hydroxy-2- phosphonylmethoxypropyl) adenine (HPMPA)
  • the subject being treated by the present method may be any animal suffering from a viral infection, including dogs, cats, cows, horses, pigs, chickens, turkeys, apes, monkeys or humans .
  • the present invention provides novel compounds.
  • the novel compounds of the present invention are those having formula (II)
  • R 1 and R 2 are C,-C 4 alkyl, or together with the nitrogen atom to which they are attached form a ring containing 5-6 atoms, including C and/or 0;
  • R 3 -R 12 are hydrogen, halogen, C t -C 4 alkyl, C,-C 4 alkoxyl, substituted C,-C 4 alkoxyl, nitro, cyano, or trifluoromethyl;
  • R 13 is hydrogen, C,-C 4 alkyl, arylalkyl, or C-C- acyl
  • X is halogen, C,-c 4 alkyl, or substituted C,-C + alkyl, or a pharmaceutically acceptable salt thereof; with the proviso that, when R 1 and R z together with the nitrogen atom to which they are attached form an N-morpholinyl group, at least one of R 3 -R 12 is not hydrogen.
  • Step one in Scheme A is a slight modification of the procedure described by Buck and Ide in Organic Synthesis , vol.
  • the present invention provides novel pharmaceutical compositions which comprise at least one compound of formulae (I) or (II) and a pharmaceutically acceptable carrier.
  • the present compositions may be in any form which is suitable for the intended route of administration.
  • the present composition may be a sterile solution or suspension suitable for injection; a lotion cream or ointment suitable for topical application; a tablet, pill, capsule, or elixer suitable for ingestion; or a solution or suspension suitable for inhalation.
  • the pharmaceutical composition may also be in the form of a patch for transdermal administration, encapsulated for subcutaneous implantation, or in the form of a suppository.
  • the pharmaceutical composition will be formulated so as to deliver 5 mg to 4 g, preferably 10 mg to 1500 mg, more preferably 50 mg to 750 mg, of the compound of formulae (I) or (II) per unit dosage.
  • the present pharmaceutical compositions may also contain one or more known antiviral agents such as interferons, c_-thymosin, 3TC, FTC, ganciclovir, HPMPA, and penciclovir .
  • hippuric acid derivatives can be prepared according to one or both of the preceding two procedures.
  • Hep AD38 cells were maintained in Dulbecco's Modified Eagle 's/F-12 Medium (DMEM/F-12, Gibco BRL/Life Technologies, Gaithersburg, MD) supplemented with 10% fetal bovine serum (FBS) , 50 ⁇ g/ml penicillin, 50 ⁇ g/ml streptomycin, 100 ⁇ g/ml kanamycin (PSK) at 37°C and 5% carbon dioxide.
  • FBS fetal bovine serum
  • PSK kanamycin
  • Hep AD38 cells were grown in the presence of 0.3 ⁇ g/ml tetracycline and 400 ⁇ g/ml G418 (Gibco BRL/Life Technologies, Gaithersburg, MD) .
  • the 2.2.15 cells (Acs, G. , et al., Proc . Natl . Acad . Sci . USA , vol. 84, pp.
  • Dr. George Acs were maintained in RPMI 1640 medium with 10% FBS, PSK and 400 ⁇ g/ml G418.
  • Hep G2 cells (4 x 10 " cells/35 mm plate) were co- transfected with 0.3 ⁇ g of pUHD 15-lneo (Gossen, M. , et al., Proc . Natl . Acad . Sci . USA , vol. 89, pp. 5547-5551 (1992)) and
  • ptetHBV ptetHBV using a liposome transfection kit as directed by the manufacturer (Transfectace, GIBCO BRL/Life Technologies, Gaithersburg, MD) .
  • Transfected cells were selected in DMEM/F-12 medium containing 10% FBS, 1 ⁇ g/ml of tetracycline and 400 ⁇ g/ml of G418 until individual clones could be identified by visual inspection of the plates (approximately one month) .
  • Individual clones were isolated and maintained in DMEM/F-12 medium supplemented with 10% FBS, PSK, 0.3 ⁇ g/ml tetracycline, and 400 ⁇ g/ml G418.
  • B Plas id constructs
  • Plasmid ptetHBV was created by replacing the cytomegalovirus immediate early (CMV-IE) promoter in pCMVhbv (Fallows, D. A., et al. J . Virol . , vol. 69(5), pp. 3067-73
  • pCMVhbv was created by the fusion of HBV sequences (subtype ayw, Christman, J. K. , et al., Proc .
  • Polyadenylated RNA was isolated from Hep AD38 cells with a modified "fast track" method (In Vitrogen, San Diego, CA) . Briefly, cells were washed twice with PBS and lysed with 10 ml of lysis buffer (0.2 MM Tris HCl pH 7.5, 0.2 M NaCl, 2% SDS , 25 mM EDTA and 0.2 mg/ml proteinase K) /T162 flask. The cell lysate was sheared by repeated (10 times) passage through an 18 gauge needle and incubated at 50°C for 1 hour.
  • lysis buffer 0.2 MM Tris HCl pH 7.5, 0.2 M NaCl, 2% SDS , 25 mM EDTA and 0.2 mg/ml proteinase K
  • oligo (dT) cellulose (Stratagene, La Jolla, CA) in 1 ml of binding buffer (0.5 M NaCl, 10 mM Tris HCl pH 7.5 and 0.1 mM EDTA) on a shaking platform for 1 hour at room temperature.
  • binding buffer 0.5 M NaCl, 10 mM Tris HCl pH 7.5 and 0.1 mM EDTA
  • the oligo (dT) cellulose was pelleted and washed four times with 10 ml of binding buffer, resuspended in 0.5 ml of binding buffer and transferred to a spin column.
  • RNA were eluted with 0.4 ml of elution buffer (10 mM Tris HCl pH 7.5 , 1 mM EDTA) at 65°C, precipitated with ethanol and resuspended in 0.05 ml of DEPC- treated water.
  • elution buffer 10 mM Tris HCl pH 7.5 , 1 mM EDTA
  • One microgram of poly-A selected RNA was electrophoresed through a 1% formaldehyde agarose gel, transferred to a nylon membrane (Hybond-N, Amersham, Arlington Heights, IL) and hybridized with a :: P-labeled HBV RNA probe.
  • ccc covalently closed circular DNA
  • the cells were lysed in 1 ml of lysis buffer without pronase.
  • protein-detergent complexes such as the DNA intermediates of HBV replication
  • 0.25 ml of 2.5 M KCl was added to the lysate.
  • the supernatant containing the ccc DNA was extracted with phenol and ethanol precipitated.
  • the centrifuged pellets were resuspended in 80 ⁇ l of TE and analyzed as described above.
  • the supernatants of Hep AD38 and 2.2.15 cells were clarified of cellular debris of centrifugation (Sorval RT-6000D centrifuge 2000 RMP's for 10 minutes). Virus particles were precipitated from the cleared supernatants with PEG and DNA isolated as described above for viral DNA.
  • HepAD38 cells were plated into 96-well microtiter plates (6 x 10" cells/well) and grown for three days in the presence of 0.3 ⁇ g/ml of tetracycline. On day zero, the cells were washed several times with PBS and treated with tetracycline- free medium that contained either test or control compounds. Each test compound was screened at two, three or six concentrations in quadruplicate. On day three, the medium was removed and replaced with fresh medium containing compound.
  • Radioactivity was quantified with a Bio-Rad GS-363 phospho ⁇ mager .
  • concentration of compound that inhibited HBV replication by 50 or 90% was determined by linear regression.
  • the cell monolayer was washed with PBS and tested for cell viability using a cell proliferation assay kit as directed by the manufacturer (CellTiter 96 Non-Radioactive Cell Proliferation Assay, Promega, Madison, I) .
  • the concentrations of compound that inhibited cell viability by 50 or 90% were determined by linear regression.
  • DPBS fPulbeccos's phosphate buffered saline 0.2 g/1 KCl, 8 g/L NaCl, 0.2 g/L KH 2 P0 4 , 1.15 g/L Na 2 HP0 4 , 133 mg/L CaCL j -2H 2 0, 100 mg/L MgCl z -6H 2 0); bring up to volume with RT deionized water, adjust pH to 7.35 using 1M HCl or 1M NaOH if necessary. Pre-made solution is also acceptable.
  • MTS reagent available from Promega in the CellTiter 96 Aqueous Non-radioactive Cell Proliferation Assay; 2mg/ml in DPBS, filter sterilized with 0.2 ⁇ m pore filter. Store at -20° in a light-protected container. MTS reagent powder must be stored at 4 ; C in a light- protected container. The results of the assays are shown in Tables 1 and 2. Table 1
  • EC ?0 concentration of drug which inhibits synthesis of viral DNA by 50%.
  • EC 90 concentration of drug which inhibits synthesis of viral DNA by 90%.
  • TC 50 concentration of drug which reduces the number -*• of viable cells by 50%.
  • d IC 5e concentration of drug which inhibits the replication of cells by 50%.
  • EG f0 concentration of drug which inhibits synthesis of viral DNA by 50%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Emergency Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux 2-benzoylamino-3-phénylpropénamides servant d'agents antiviraux. L'invention concerne également des compositions contenant lesdits 2-benzoylamino-3-phénylpropénamides et des méthodes pour traiter des maladies virales, telles que l'hépatite, au moyen desdits 2-benzoylamino-3-phénylpropénamides.
PCT/US1998/000986 1997-01-31 1998-01-29 Derives de 2-benzoylamino-3-phenylpropenamide et leurs procedes d'utilisation WO1998033501A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU59239/98A AU5923998A (en) 1997-01-31 1998-01-29 2-benzoylamino-3-phenylpropenamide derivatives and methods of using the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US79427497A 1997-01-31 1997-01-31
US08/794,274 1997-01-31

Publications (1)

Publication Number Publication Date
WO1998033501A1 true WO1998033501A1 (fr) 1998-08-06

Family

ID=25162190

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/000986 WO1998033501A1 (fr) 1997-01-31 1998-01-29 Derives de 2-benzoylamino-3-phenylpropenamide et leurs procedes d'utilisation

Country Status (2)

Country Link
AU (1) AU5923998A (fr)
WO (1) WO1998033501A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000024392A1 (fr) * 1998-10-26 2000-05-04 Sumitomo Pharmaceuticals Company, Limited Inhibiteur de la formation de beta-amyloide
WO2001045712A1 (fr) * 1999-12-22 2001-06-28 Bayer Aktiengesellschaft Combinaison de medicaments pour lutter contre des maladies virales
WO2004050613A3 (fr) * 2002-12-02 2004-09-23 Gilead Sciences Inc Derives de 3-propenamide substitue en 2 et procedes d'utilisation de ces derives
US6930106B2 (en) 2002-07-01 2005-08-16 Pharmacia & Upjohn Company Inhibitors of HCV NS5B polymerase
US7026339B2 (en) 2003-11-07 2006-04-11 Fan Yang Inhibitors of HCV NS5B polymerase
US7041690B2 (en) 2002-07-01 2006-05-09 Pharmacia & Upjohn Company, Llc Inhibitors of HCV NS5B polymerase
JP2008528600A (ja) * 2005-01-26 2008-07-31 アラーガン、インコーポレイテッド 鎮痛活性および／または免疫賦活活性を有する３−アリール−３−ヒドロキシ−２−アミノ−プロピオン酸アミド、３−ヘテロアリール−３−ヒドロキシ−２−アミノ−プロピオン酸アミドおよび関連化合物
EP2514750A1 (fr) 2007-06-18 2012-10-24 Sunshine Lake Pharma Co., Ltd Thiazolyl-dihydropyrimidines a substitution bromo-phenyle
CN107011206A (zh) * 2017-03-06 2017-08-04 徐州医科大学 一种丙烯酰胺类化合物、其制备方法及医药用途
WO2018085619A1 (fr) 2016-11-07 2018-05-11 Arbutus Biopharma, Inc. Composés tricycliques contenant de la pyridinone substituée, et procédés les utilisant
WO2018172852A1 (fr) 2017-03-21 2018-09-27 Arbutus Biopharma Corporation Dihydroindène-4-carboxamides substitués, leurs analogues et procédés d'utilisation correspondant
WO2020023710A1 (fr) 2018-07-27 2020-01-30 Arbutus Biopharma Corporation Tétrahydrocyclopenta[c]pyrroles substituées, dihydropyrrolizines substituées, analogues de celles-ci, et procédés les utilisant
WO2020123674A1 (fr) 2018-12-12 2020-06-18 Arbutus Biopharma Corporation Arylméthylurées et hétéroarylméthylurées substituées, analogues de ces dernières et procédés d'utilisation de celles-ci

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4310517A (en) * 1976-12-28 1982-01-12 Troponwerke Gmbh & Co., Kg Tumor-resolving and histolytic medicaments and their use

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4310517A (en) * 1976-12-28 1982-01-12 Troponwerke Gmbh & Co., Kg Tumor-resolving and histolytic medicaments and their use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KNOWLES A.M., ET AL.: "ACTION OF OXAZOL-5(4H)-ONES AND 4,5-DIHYDRO-5-OXO-OXAZOLIUM PERCHLORATES ON ENAMINES.", JOURNAL OF THE CHEMICAL SOCIETY, CHEMICAL SOCIETY, LETCHWORTH; GB, vol. 03., 1 January 1971 (1971-01-01), LETCHWORTH; GB, pages 598 - 603., XP002913465, ISSN: 0368-1769 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000024392A1 (fr) * 1998-10-26 2000-05-04 Sumitomo Pharmaceuticals Company, Limited Inhibiteur de la formation de beta-amyloide
WO2001045712A1 (fr) * 1999-12-22 2001-06-28 Bayer Aktiengesellschaft Combinaison de medicaments pour lutter contre des maladies virales
US6930106B2 (en) 2002-07-01 2005-08-16 Pharmacia & Upjohn Company Inhibitors of HCV NS5B polymerase
US7041690B2 (en) 2002-07-01 2006-05-09 Pharmacia & Upjohn Company, Llc Inhibitors of HCV NS5B polymerase
WO2004050613A3 (fr) * 2002-12-02 2004-09-23 Gilead Sciences Inc Derives de 3-propenamide substitue en 2 et procedes d'utilisation de ces derives
US7026339B2 (en) 2003-11-07 2006-04-11 Fan Yang Inhibitors of HCV NS5B polymerase
US8927589B2 (en) 2005-01-26 2015-01-06 Allergan, Inc. 3-aryl-3-hydroxy-2-amino-propionic acid amides, 3-heteroaryl-3-hydroxy-2-aminopropionic acid amides and related compounds having analgesic and/or immuno stimulant activity
JP2008528600A (ja) * 2005-01-26 2008-07-31 アラーガン、インコーポレイテッド 鎮痛活性および／または免疫賦活活性を有する３−アリール−３−ヒドロキシ−２−アミノ−プロピオン酸アミド、３−ヘテロアリール−３−ヒドロキシ−２−アミノ−プロピオン酸アミドおよび関連化合物
US8288556B2 (en) 2005-01-26 2012-10-16 Allergan, Inc. 3-aryl-3-hydroxy-2-amino-propionic acid amides, 3-heteroaryl-3-hydroxy-2-amino-propionic acid amides and related compounds having analgesic and/or immuno stimulant activity
KR101395382B1 (ko) * 2005-01-26 2014-05-14 알러간, 인코포레이티드 3-아릴-3-히드록시-2-아미노-프로피온산 아미드,3-헤테로아릴-3-히드록시-2-아미노-프로피온산 아미드 및진통 및/또는 면역자극 활성을 갖는 관련 화합물
EP2514750A1 (fr) 2007-06-18 2012-10-24 Sunshine Lake Pharma Co., Ltd Thiazolyl-dihydropyrimidines a substitution bromo-phenyle
WO2018085619A1 (fr) 2016-11-07 2018-05-11 Arbutus Biopharma, Inc. Composés tricycliques contenant de la pyridinone substituée, et procédés les utilisant
CN107011206A (zh) * 2017-03-06 2017-08-04 徐州医科大学 一种丙烯酰胺类化合物、其制备方法及医药用途
CN107011206B (zh) * 2017-03-06 2020-01-03 徐州医科大学 一种丙烯酰胺类化合物、其制备方法及医药用途
WO2018172852A1 (fr) 2017-03-21 2018-09-27 Arbutus Biopharma Corporation Dihydroindène-4-carboxamides substitués, leurs analogues et procédés d'utilisation correspondant
WO2020023710A1 (fr) 2018-07-27 2020-01-30 Arbutus Biopharma Corporation Tétrahydrocyclopenta[c]pyrroles substituées, dihydropyrrolizines substituées, analogues de celles-ci, et procédés les utilisant
WO2020123674A1 (fr) 2018-12-12 2020-06-18 Arbutus Biopharma Corporation Arylméthylurées et hétéroarylméthylurées substituées, analogues de ces dernières et procédés d'utilisation de celles-ci

Also Published As

Publication number Publication date
AU5923998A (en) 1998-08-25

Similar Documents

Publication Publication Date Title
TWI336694B (en) Phthalazinone derivatives
JP5068813B2 (ja) 新規なベンゾチアジノン誘導体、及び抗菌剤としてのその使用
US20150292045A1 (en) Alternative uses for hbv assembly effectors
WO1998033501A1 (fr) Derives de 2-benzoylamino-3-phenylpropenamide et leurs procedes d'utilisation
WO2007147336A1 (fr) Composés non nucléosidiques hétérocycliques, leur préparation, compositions pharmaceutiques, et leur utilisation en tant qu'agents antiviraux
JP6437119B2 (ja) 選択的ｓ１ｐ１レセプターアゴニストを含む薬学的合剤
WO2017219915A1 (fr) Promédicament de phosphonate pour dérivé d'adénine et ses applications médicales
RU2264387C2 (ru) Производные амидоксимов пропенкарбоновых кислот, способ их получения и содержащие их фармацевтические композиции
EP1115697B1 (fr) Derives d'acide hydroximique insatures utilises comme inhibiteurs de parp
EP1605939B1 (fr) Utilisation pharmaceutique de 1-azabicyclo ¬2.2.2 octanes et procede d'essai de composes concernant la capacite d'activation de wt p53 inactif
JP2008543735A (ja) 抗腫瘍化合物及びその医薬組成物
EP1220848B1 (fr) Composes de n-arymethylthioanilide utiles pour inhiber la replication du vih
RU2666727C1 (ru) Ингибитор вируса гепатита В (ВГВ)
ES2390053T3 (es) Derivado de ácido fenilacético, procedimiento para producir el mismo y uso
EP3974418A1 (fr) Forme cristalline de 1,4-[bis(1,2-benzisosélénazol-3(2h)-one)]butane, son procédé de préparation et son utilisation
WO2021212010A2 (fr) Traitement par médicament antiviral à petites molécules pour des infections par papillomavirus humain
MXPA02008418A (es) Medicamentos para enfermedades virales.
JP3702382B2 (ja) ＮＦ−κＢ活性化阻害剤
RU2726456C1 (ru) Ингибитор вируса гепатита В (ВГВ)
US20050203176A1 (en) Carbamates as HIV anti-viral agents
RU2736975C1 (ru) Ингибитор вируса гепатита В (ВГВ)
RU2738848C1 (ru) Ингибитор вируса гепатита В (ВГВ), представляющий собой производные N-{ 3-[6-(диалкиламино)пиридазин-3-ил]фенил} арилсульфонамида и производные N-{ 4-[6-(диалкиламино)пиридазин-3-ил]фенил} арилсульфонамида
CN112979705B (zh) 核苷酸类似物化合物及其盐、制备方法及其药物用途
WO2024114709A1 (fr) Forme cristalline d'un composé dérivé d'hétérocycle fusionné
WO2019071105A1 (fr) Composés cristallins et procédés de traitement d'infections virales

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: CA

122 Ep: pct application non-entry in european phase