WO2006011719A1 - Derives d'acide sulfamoylbenzoique n-substitue, leur procede de preparation et composition pharmaceutique antivirale les contenant - Google Patents

Derives d'acide sulfamoylbenzoique n-substitue, leur procede de preparation et composition pharmaceutique antivirale les contenant Download PDF

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Publication number
WO2006011719A1
WO2006011719A1 PCT/KR2005/002257 KR2005002257W WO2006011719A1 WO 2006011719 A1 WO2006011719 A1 WO 2006011719A1 KR 2005002257 W KR2005002257 W KR 2005002257W WO 2006011719 A1 WO2006011719 A1 WO 2006011719A1
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Prior art keywords
morpholino
phenyl
group
sulfamoyl
substituted
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PCT/KR2005/002257
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English (en)
Inventor
Jong Woo Kim
Sang Wook Lee
Geun Hyung Lee
Jae Jin Han
Sang Jin Park
Eul Yong Park
Joong Chul Shin
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B & C Biopharm Co., Ltd.
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Publication of WO2006011719A1 publication Critical patent/WO2006011719A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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
    • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to ⁇ f-substituted-sulfamoylbenzoic acid derivatives useful as an antiviral agent, and more particularly novel N - substituted-sulfamoylbenzoic acid derivatives having an excellent inhibitory effect on replication of Hepatitis C virus (HCV), represented by the following formula I:
  • R i represents hydroxy group or -NR R group
  • R represents hydrogen atom, C -C straight or branched alkyl group
  • R 4 represents phenyl group or heterocyclic ring, and m represents an integer between 0 and 4; and R represents C -C straight or branched
  • n represents an integer between 0 and 4, to a method for preparing the compounds, and to an antiviral pharmaceutical composition comprising the same as an active ingredient.
  • Hepatitis C virus is the major etiological agent of non-A and non-B viral hepatitis, mainly being post- transfusion and community-acquired.
  • HCV Hepatitis C virus
  • HCV is a member of the Flaviviridae family. More specifically, HCV has about
  • RNA genome consists of an untranslational region at 5' and 3' ends (UTR) and a long open reading frame (ORF).
  • This ORF is expressed as a polyprotein including 3,010 to 3,040 amino acids by host cell enzymes and divided into 3 structural proteins and 6 nonstructural proteins by host cell enzymes and its own protease. Also, there is a uniformly conserved region in the 5' and 3' end of the genome, respectively. This region is believed to play an important role for protein expression and RNA replication of the virus.
  • the long ORF is expressed as a polyprotein, and through co-translational or post- translational processing, it is processed into structural proteins, i.e. core antigen protein (core) and surface antigen protein (El, E2), and nonstructural proteins, NS2 (protease), NS3 (serine protease, helicase), NS4A (serine protease cofactor), NS4B (protease cofactor, involved in resistance), NS5A, and NS5B (RNA dependent RNA polymerase, RdRp), each contributing to replication of virus.
  • the structural proteins are divided into core, El, and E2 by signal peptidase of the host cell.
  • nonstructural proteins are processed by serine protease (NS3) and cofactor (NS2, NS4A, and NS4B) of the virus.
  • NS3 and NS5B serine protease
  • the core antigen protein together with surface antigen protein of the structural protein compose a capsid of the virus, and the nonstructural proteins like NS3 and NS5B play an important role of the RNA replication of the virus (Reference: Bartenschager, R., 1997, Molecular targets in inhibition of hepatitis C virus replication, Antivir. Chem. Chemother. 8: 281-301).
  • the 5' and 3' ends of the virus RNA has a uniformly conserved untranslational region (UTR). Generally, this region is known to play a very important role in replication of the virus.
  • the 5' end has 5'-UTR composed of 341 nu ⁇ cleotides, and this part has the structure of 4 stem and loop (I, II, III, and IV). Actually, this functions as an internal ribosome entry site (IRES) necessary for translation processing to express protein.
  • IRS internal ribosome entry site
  • stem III which has the biggest and the most stable structure with a conserved sequence, has been reported to play the most essential part for ribosome binding.
  • the 3' end has 3'-UTR composed of 318 nucleotides.
  • This part is known to play a very important role in the initiation step of binding of NS5B, an essential enzyme of RNA replication.
  • the 3'-UTR is composed of three different parts: -X-tail-5' starting from the 5' end to 98th nucleotide (98nt.), -poly (U)- having UTP consecutively, and the rest of 3'-UTR-. More specifically, X-tail-5' part consists of 98 nucleotides having a very conserved sequence, and has three stem and loop structures, thereby forming a very stable tertiary structure.
  • X-tail-5' part is considered very essential of NS5B binding.
  • -poly (U)- part induces a pyrimidine track, facilitating RNA polymerase effect.
  • the rest part of 3'-UTR has the tertiary structure of loop and plays an important role in NS5B binding.
  • its structure is known somewhat unstable.
  • the 3' end region of HCV RNA is known to have an essential structure in NS5B binding when the RNA replication starts (Reference: Yamada et al., 1996, Genetic organization and diversity of the hepatitis C virus genome, Virology 223:255-281).
  • NS5B is the one that is directly involved in RNA replication and thus it is very important.
  • NS5B is an enzyme consisting of 591 amino acids having the molecular weight of about 68kDa.
  • RBDl RNA-binding domains
  • RBD2 RNA-binding domains
  • essential motif amino acids for RNA binding and activity are 'Asp' (amino acid number 220), 'GIy' (amino acid number 283), 'GIy' (amino acid number 317), 'Asp' (amino acid number 318), 'Asp' (amino acid number 319), and 'Lys' (amino acid number 346).
  • this enzyme can lead a polymerization reaction without another primer (Reference: Lohmann, V. et al., 1997, Biochemical properties of hepatitis C virus NS5B RNA dependent RNA polymerase and identification of amino acid sequence motifs essential for enzymatic activity, /. viral. 71:8416-8428).
  • RNA genome of HCV was isolated in 1989 by molecular cloning (Reference: Choo,
  • HCV hepatitis C.
  • HCV patients are prevalent in the world, and its frequency to be progressed to hepatic cirrhosis and/or liver cancer is much higher than HBV.
  • HBV chronic hepatitis
  • the research on infection mechanism of the virus is still under progress. People are infected with HCV through blood transfusion or medication via phleboclysis or tattooing, but most of cases HCV infection takes place through a direct blood contact. However, 40 ⁇ 50% of the HCV patients still do not exactly know how they became infected.
  • HCV human immunodeficiency virus
  • HCV human immunodeficiency virus
  • ⁇ -interferon alpha interferon
  • NS3 protease/helicase and NS5B RNA polymerase of HCV are very useful for developing anti-HCV agent since these types of enzyme is not necessary for the host cell but essential for its own replication.
  • NS5B of HCV RNA dependent RNA polymerase ⁇ is an essential enzyme for HCV, and this makes the enzyme a good target for suppressing the replication of HCV.
  • HCV subtype found in patient world wide is 1 (Ia, Ib) that is not easily treated by interferon, compared to 2 and 3 subtypes.
  • Ia, Ib the most HCV subtype found in patient world wide
  • ribavirin the treatment effect was doubled.
  • ribavirin is that when it was used alone, it showed little effect on HCV and rather, caused side effects like erythroclastic anemia.
  • ribavirin was prescribed only when the interferon therapy was no good or relapsed into Hepatitis C again. So far, no one actually developed an antiviral agent for treating hepatitis C by suppressing the replication of HCV.
  • the present invention is directed to develop a nonnucleoside small molecule having low toxicity and side effect but manifesting excellent antiviral activity against HCV, by studying any possible compound that inhibits the activity of the re ⁇ combinant HCV RNA polymerase (NS5B, RNA polymerase).
  • Another object of the present invention is to provide a pharmaceutical composition comprising the above compound as an effective component, which has little side effect and is economical, for prevention and treatment of hepatitis C.
  • the present invention provides novel ⁇ -substituted sulfamoylbenzoic acidderivatives, represented by the following formula I:
  • R represents hydroxy group or -NR R group
  • R represents hydrogen atom, C -C straight or branched alkyl group
  • R 4 represents phenyl group or heterocyclic ring, and m represents an integer between 0 and 4; and R represents C -C straight or branched
  • n represents an integer between 0 and 4.
  • the above compounds can be used in form of pharmaceutically acceptable salts.
  • an acid addition salts that are prepared by pharma ⁇ ceutically acceptable free acids are available.
  • the compounds with the chemical formula I can make pharmaceutically acceptable acid addition salts following the con ⁇ ventional method in the related art.
  • free acids both organic acids and inorganic acids can be used.
  • inorganic acids include hydrochloric acid, hy- drobromic acid, sulfuric acid, and phosphoric acid.
  • Organic acids include citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, benzenesulfonic acid, glutamic acid or aspartic acid.
  • the present invention provides a method for preparing N - substituted-sulfamoylbenzoic acid derivatives of the formula I, represented by the following scheme I;
  • R represents hydrogen atom, C -C straight or branched alkyl group, or
  • amine compounds represented by HNR R of Formula 5 used in the step (ii) are appropriate reagents to introduce substituents to target compounds and can be suitably selected, depending on substituents to be introduced, by a person possessing ordinary knowledge in the art.
  • the reaction is performed in the presence of an organic base such as pyridine, N,N - dimethylaniline, ⁇ /,./V-diethylaniline, 2,6-lutidine, 2,4,6-collidine, 2,6-di-tert - butyl-4-methylpyridine and the like which is relatively weak base, in an organic solvent such as dichloromethane, chloroform, acetonitrile, ⁇ /,./V-dimethylformamide, ⁇ /,./V-dimethylacetamide, dimethylsulfoxide, l-methyl-2-pyrrolidinone, ethyl ether, isopropyl ether, tetrahydrofuran, acetone and the like, at a temperature in the range of 0 ⁇ 35°C within 5 hours.
  • an organic base such as pyridine, N,N - dimethylaniline, ⁇ /,./V-diethylaniline, 2,6-lutidine, 2,4,6-col
  • the reaction is performed in the presence of an organic base such as triethylamine, tribenzylamine, ⁇ /,./V-diisopropylethylamine, 4-methylmorpholine, 4-ethylmorpholine, 1-methylpiperidine, 1-ethylpiperidine, 1,1,3,3-tetramethylguanidine and the like which is relatively strong base, in an organic solvent such as dichloromethane, chloroform, acetonitrile, ⁇ /,./V-dimethylformamide, ⁇ -dimethylacetamide, dimethylsulfoxide, l-methyl-2-pyrrolidinone, ethyl ether, isopropyl ether, tetrahydrofuran, acetone and the like, or in a mixed solvent.
  • an organic base such as triethylamine, tribenzylamine, ⁇ /,./V-diisopropylethylamine, 4-methylmorpholine, 4-ethylmorph
  • step (ii) The reaction of the step (ii) is completed within 1 hour to 30 hours at a temperature in the range of 0 ⁇ 80°C, depending on reactivity of selected amine compounds represented by HNR R of Formula 5 and kinds of selected solvents.
  • the present invention also provides the pharmaceutical compositions for treatment and prevention of hepatitis C, which contains the TV-substituted-sulfamoylbenzoic acid derivatives represented by the chemical formula I and/or its pharmaceutically acceptable salts as an active ingredient.
  • the compounds of the chemical formula I as the therapeutics for hepatitis C may be administered orally as well as through other routes in clinical uses, and can be used in form of general drugs. If it needs to be prepared, a generally used diluent including filler, builder, binder, humectant, dis -integration agent or surfactant, or excipient can be employed.
  • the solid preparation for oral administration includes tablets, pills, powder, granules or capsules. This solid preparation involves more than one compound of the chemical formula I and more than one excipient, for example, starch, calcium carbonate, sucrose or lactose, or gelatin.
  • liquid preparation for oral administration suspension, solution, oily medicine or syrup can be used, but it can also employ a simple diluent, namely water, liquid paraffin, or other kinds of excipient, e.g. humectant, sweetening agent, odorant, or preservative.
  • a simple diluent namely water, liquid paraffin, or other kinds of excipient, e.g. humectant, sweetening agent, odorant, or preservative.
  • liquid preparation for non-oral administration sterilized water solution, non-aqueous solvent, suspension or oily medicine.
  • non-aqueous solvent and suspension is propylene glycol, polyethylene glycol, vegetable oil like olive oil, and injectable esters like ethyl oleate.
  • the effective dose of the compounds of the chemical formula I is controlled depending on the patient's sex, age and condition. In general, it can be dosed to adults 10 to 1000 mg/day, more preferably 20 to 500 mg/day, or one to three times dividedly per day.
  • novel TV-substituted-sulfamoylbenzoic acid derivatives according to the present invention represented by the chemical Formula I have excellent inhibitory effect on replication of hepatitis C virus and low cytotoxicity. Best Mode for Carrying Out the Invention
  • Example 4 Preparation of 4-[ TV -[4-(4-morpholino)phenyl]sulfamoyl]- TV -
  • Example 1 and 1.0 ml of triethylamine were added in sequence to mixed solvent of 40 ml of chloroform and 40 ml of acetonitrile, stirred to dissolve and stirred at 20 ⁇ 30°C for 2 hours after adding 0.91 g of 3,5-dichloro-2-hydroxybenzenesulfonyl chloride. Then, 0.4 ml of 2-(aminomethyl)pyridine was added to the mixture, heated up slowly and stirred at 50 ⁇ 60°C for 24 hours more. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was crystallized by 25 ml of methanol and 75 ml of water. The mixture was stirred at room temperature for 5 hours, filtered, washed with 30 ml of water, to give a crystalline product. The product was dried in vacuo at 40 ⁇ 50°C to give 1.28 g of the desired compound (85% yield).
  • Example 8 Preparation of 4-[ TV -[4-(4-morpholino)phenyl]sulfamoyl]- N' JV '- bis[(2-pyridyl)methyl]benzamide [73] 1 g of 4-[TV-[4-(4-morpholino)phenyl]sulfamoyl]benzoic acid prepared in Example
  • 2,2'-dipicolylamine and 0.43 ml of triethylamine were added in sequence at 0 ⁇ 5°C and stirred at 0 ⁇ 5°C for 30 minutes, followed by stirring at 20 ⁇ 25°C for 20 hours.
  • the reaction mixture was washed with 60 ml of water 2 times and the separated organic layer was concentrated under reduced pressure. The residue was dissolved in 5 ml of dichloromethane and crystallized by adding 25 ml of isopropyl ether and 25 ml of hexane. The mixture was stirred at room temperature for 3 hours, filtered, washed with 10 ml of hexane, to give a crystalline product.
  • the product was dried in vacuo at 30 ⁇ 35°C to give 0.9 g of the desired compound (60% yield).
  • Example 8 except that TV -benzyl-TV,TV-dimethylethylenediamine was substituted for 2,2'-dipicolylamine.
  • HCV RNA polymerase was prepared as follows.
  • HCV cDNA was obtained from the blood of HCV- Ib type HCV patient and NS5B region (1773bps) was amplified by PCR and cloned into pVLHIS, a baculovirus transfer vector, to prepare a recombinant transfer vector.
  • the prepared transfer vector and the wild-type AcNPV vector were cotransfected into Sf 9 insect cell line to yield a recombinant baculovirus with the histidine-tagged recombinant vector pVLHIS-NS5B.
  • Sufficiently cultured insect cells were infected with the resulting recombinant baculovirus and cultured in Grace s medium containing 10% FBS for 3 to 4 days.
  • the culture broth was centrifuged to obtain only the infected cells.
  • the cells were washed three times with PBS and resuspended in binding buffer [5OmM Na-phosphate (pH 8.0), 3OmM NaCl, 1OmM imidazole, ImM DTT, 10% glycerol, 1% NP-40], sonicated and the clearized lysate was obtained.
  • Recombinant NS5B was purified by affinity column chromatography using a Ni-NTA His bind resin (Novagen) to produce pure NS5B protein.
  • the (His) -tagged NS5B was bound to Ni-NTA resin and washed with
  • the binding buffer containing 5OmM imidazole was eluted with the binding buffer containing imidazole in a step-gradient manner (100 ⁇ 300mM).
  • the NS5B protein fractions were dialyzed against buffer [5OmM Tris-HCl, 5OmM NaCl, ImM DTT, 5mg MgCl , 10% glycerol], followed by at -70°C in a small aliquot.
  • RNA template containing HCV 3' end (3'-UTR) was prepared as follows.
  • the 3'UTR cDNA (220bp) of HCV was obtained from Ib HCV RNA of the blood of a hepatitis C patient by PCR and cloned into pcDNA3 vector.
  • Linearized DNA fragment containing the 3'-UTR was prepared using the restriction enzyme, Eco RI and used as a template for in vitro transcription using T7 RNA ploymerase to prepare RNA fragment containing 3'-UTR.
  • a streptavidin-coated well plate was prepared suitable for the sample to be examined.
  • 25 ⁇ l of 2x assay buffer [5OmM Tris-Cl (pH 7.5), 10OmM NaCl, 1OmM MgCl , 2OmM KCl, ImM EDTA, ImM DTT] and 10 ⁇ l of purified HCV RNA polymerase 200 ng and 3'-UTR template RNA were added to each well. Then, 5 ⁇ l of the sample to be examined was added to have final concentrations of 10, 1, 0.1 and 0.01 ⁇ g/ml.
  • RNA template of HCV 3'-UTR RNA 10 ⁇ l of a reactant solution containing DIG-(digoxigenin)-UTP, biotin-UTP, ATP, CTP, GTP, and UTP as a nucleotide for the ploymerase reaction with the RNA template of HCV 3'-UTR RNA was added to each well. The reaction mixture was incubated at 22°C for 60 minutes. By the action of HCV polymerase, newly generated RNAs including UTP conjugated with biotin and DIG were copied and these new RNAs could bind to streptavidin coated on the well by biotin- conjugated UTP.
  • the plate was washed three times with 200 ⁇ l of a washing buffer (pH 7.0, Roche Co.) to remove unreacted substances and impurities. Then, 100 ⁇ l of the secondary antibody anti-DIG-POD (peroxidase, Roche Co.) was added to each well and incubated at 37 0 C for 1 hour. Again, the well plate was washed with the washing buffer. Finally, 100 ⁇ l of ABTS (Roche Co.) as a POD substrate was added to each well and reacted for 15 to 30 minutes. The optical density (OD) was measured using an ELISA reader (Bio-Tek instrument Co.) at 405nm. The inhibitory effect on the activity of HCV polymerase was calculated by subtracting the OD of the positive control without the sample. The results are shown in Table 1 below.
  • the compounds according to the present invention show excellent inhibitory effects on activity of HCV RNA polymerase which plays an important role in reproduction of HCV, thereby inhibiting replication of HCV by this property. Also, the compounds according to the present invention can be advantageously used as a therapeutic or prophylactic agent of hepatitis C.
  • the novel ⁇ f-substituted-sulfamoylbenzoic acid derivatives according to the present invention represented by the chemical Formula I have excellent inhibitory effect on replication of hepatitis C virus and low cytotoxicity. Therefore, they can be advantageously used as a therapeutic or prophylactic agent of hepatitis C.

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Abstract

Cette invention concerne des dérivés d'acide sulfamoylbenzoïque N-substitué utilisés comme agent antiviral et concerne en particulier de nouveaux dérivés d'acide sulfamoylbenzoïque N-substitué présentant un excellent effet inhibiteur sur la réplication du virus de l'hépatite C (VHC) ainsi que des sels pharmaceutiquement acceptables de ces dérivés. Cette invention concerne également un procédé de préparation de ces dérivés ainsi qu'une composition pharmaceutique antivirale comprenant ce composé comme ingrédient actif. Les dérivés d'acide sulfamoylbenzoïque N-substitué de cette invention présentent un excellent effet inhibiteur sur la réplication du virus de l'hépatite C (VHC) et peuvent ainsi être utilisés comme agent thérapeutique ou prophylactique contre l'hépatite C.
PCT/KR2005/002257 2004-07-28 2005-07-13 Derives d'acide sulfamoylbenzoique n-substitue, leur procede de preparation et composition pharmaceutique antivirale les contenant WO2006011719A1 (fr)

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KR10-2004-0059038 2004-07-28
KR1020040059038A KR100638709B1 (ko) 2004-07-28 2004-07-28 Ｎ－치환된－ 설파모일벤조산 유도체, 그 제조방법 및이를 포함하는 항바이러스용 약학적 조성물

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2494991A1 (fr) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Polythérapie pour le traitement de l'infection par VHC

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0515128A1 (fr) * 1991-05-23 1992-11-25 Konica Corporation Matériau à l'halogénure d'argent pour photographie en couleurs
WO2004018414A2 (fr) * 2002-08-23 2004-03-04 Pharmacia & Upjohn Company Llc Agents antibacteriens

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0515128A1 (fr) * 1991-05-23 1992-11-25 Konica Corporation Matériau à l'halogénure d'argent pour photographie en couleurs
WO2004018414A2 (fr) * 2002-08-23 2004-03-04 Pharmacia & Upjohn Company Llc Agents antibacteriens

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2494991A1 (fr) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Polythérapie pour le traitement de l'infection par VHC

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KR20060010370A (ko) 2006-02-02

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