1,2-disubstituted 1,4-dihydro-4-oxoquinoline compounds

Abstract: The present invention relates to substituted 1,4-dihydro-4-oxoquinolines having antiviral activity. The substituents are present at positions 1, 2 and at least one of 5-8 positions of the quinoline ring.

Description: This invention relates to a group of 1,2-disubstituted 1,4-dihydro-4-oxoquinoline compounds and the use of said compounds as an antiviral agent. The enteroviruses, rhinoviruses and hepatovirus are three groups within the family Picornaviridae which cause a wide range of human viral disease. The enterovirus group comprises 67 distinct serotypes, including 3 strains of poliovirus, 23 group A and 6 group B coxsackieviruses, 31 echoviruses, and 4 the newer numbered enteroviruses. Enteroviruses cause a broader range disease syndrome including "summer flu", upper respiratory illness, acute hemorrhagic conjunctivitis, hand, foot and mouth disease, myocarditis, aseptic meningitis, and poliomyelitis. Hepatitis A virus (HAV) was provisionally classified as enterovirus type 72. However, later studies have demonstrated several characteristics that distinguish HAV from other picornaviruses. It is concluded that HAV is a unique member of the family Picornaviridae, resulting in its classification into a new genus, Hepatovirus. HAV is a common cause of both sporadic and epidemic acute hepatitis in humans, produces substantial morbidity. Among the agents of viral hepatitis, HAV is most prevalent, but it is clinically less important than the hepatitis B and C virus. The clinical manifestations of HAV infection in humans can vary greatly, ranging from asymptomatic infection, commonly seen in young children, to fulminant hepatitis, which in some cases can result in death. Human rhinovirus (HRV), which include over 100 different serotypes are the most important etiological agents of the common cold. Infection of the upper respiratory tract by members of the HRV group represents perhaps the most common viral, affliction of humans, accounting for some 40 to 50 % of common colds. Although HRV-induced upper respiratory illnesses often mild and self-limiting, severe disease can occur in subjects predisposed to respiratory problems, such as asthmatics. From an economic standpoint, rhinovirus infections of humans represent a significant health problem in terms of numbers of physicians' office visits, costs associated with symptomatic treatments and days lost from work and school. Thus, infections with more than 200 different serotypes of picornavirus cause significant morbidity and mortality. The vast serotypic diversity of these viruses precludes development of vaccines for the control of human infection by these virus groups except for poliovirus and hepatitis A virus. Currently, there is no specific antiviral therapy to treat or prevent picornavirus infections. Rotaviruses are the single most important etiologic agents of severe diarrheal illness of infant and young children world-wide. Although diarrheal diseases are one of the most common illness of infant and young children throughout the world, they assume a special significance in less developed countries, where they constitute a major cauase of mortality among the young. Rotavirus infection produces a spectrum of responses that vary from subclinical infection to mild diarrhea to a severe and occasionally fatal dehydrating illness. At present, neither a vaccine nor specific antiviral medication has been discovered for human rotavirus infections. We have found that a group of 1,4-dihydro-4-oxoquinoline derivatives have a potent antiviral activity against picornaviruses and rotaviruses. US-A 5,175,151, GB 1,191,443 and M. P. Wendtland et al., J. Med. Chem. 1993, Vol. 36, 1580-1596 disclose antiviral compounds possessing a 4-oxoquinoline skeleton. The present invention provides a 1,2-disubstituted 1,4-dihydro-4-oxoquinoline selected from the group consisting of: 1,2-diphenyl-3-methyl-6-isopropyl-1,4-dihydro-4oxoquinoline, 1-(2-fluorophenyl)-2-phenyl-3-methyl-6-isopropyl-1,4dihydro4-oxoquinoline, 1-(3-fluorophenyl)-2-phenyl-3-methyl-6-isopropyl-1,4dihydro-4-oxoquinoline, 1-(4-fluorophenyl)-2-phenyl-3-methyl-6-isopropyl-1,4dihydro-4-oxoquinoline, 1-(4-chlorophenyl)-2-phenyl-3-methyl-6-isopropyl-1,4dihydro-4-oxoquinoline, 1-(4-tolyl)-2-phenyl-3-methyl-6-isopropyl-1,4dihydro-4-oxoquinoline, 1-(4-methoxyphenyl)-2-phenyl-3-methyl-6-isopropyl1,4-dihydro-4-oxoquinoline. The compounds have the formula I wherein (R 1 ) n is 6-isopropyl, R 2 is phenyl, R 3 is methyl and R 4 is selected from the group consisting of C 6 H 5 , 2-F-C 6 H 4 , 3-F-C 6 H 4 , 4-F-C 6 H4, 4-Cl-C 6 H 4 , 4-CH 3 -C 6 H 4 , and 4-CH 3 O-C 6 H 4 The compounds of the present invention also include a pharmaceutically acceptable acid addition salt or quaternary ammonium salt thereof. The invention also relates to a pharmaceutical composition comprising a compound of Formula I above and a pharmaceutically acceptable carrier. The pharmaceutical composition of the invention is useful in the prophylaxis and the treatment of viral infections of Picornavirus and human rotavirus. The compounds of Formula I may be synthesized by use of known chemical reactions and procedures starting from appropriately substituted aniline II. Generally, the synthesis of the compounds of Formula I follows either Method A or Method B, In Method A, substituted anilines II are reacted with 2-benzoylalkanoic acid ethyl ester III in the presence of polyphosphoric acid to give 2-phenyl-4-oxoquinoline derivatives (IV) followed by the reaction with R 4 I in the presence of sodium hydride. Method A is applicable to the synthesis of the compounds of Formula I-a. In Method B, the compounds of Formula I are prepared from substituted anilines II via N-substituted isatoic anhydrides VIII. The intermediate VIII, in turn, may be synthesized by two methods as shown in Scheme II below. Substituted anilines II are reacted with chloral hydrate and hydroxylamine to yield nitrosoacetanilide V. Cyclization of V into substituted isatins VI followed by introduction of R at position 1 yields N-substituted isatins VII. N-substituted isatoic anhydrides VIII are obtained by treating VII with m-chloroperbenzoic acid(m-CPBA). Alternatively, N-substituted isatoic anhydride VIII may be prepared by reacting isatins VI with m-CPBA to produce N-unsubstituted isatoic anhydrides IX followed by introduction of R 4 at position 1. N-substituted isatins VII may also be prepared by reacting N-substituted anilines XII with oxalyl chloride followed by aluminum chloride. N-substituted anilines XII, in turn, may be prepared by acetylating substituted anilines II, reacting the resulting acetanilides X with an alkylating agent to introduce R 4 followed by deacetylation of the N-substituted acetanilides XI. N-Substituted isatoic anhydrides VIII are used in Method B for the synthesis of the compounds of Formula I by the reaction with an appropriate ketone in the presence of n-butyl lithium and tetramethylethylenediamine (TMEDA) or in the presence of sodium hydride. The ketone compound may be represented by the formula: R 2 C(O)CH 2 R 3 , wherein R 2 is phenyl or substituted phenyl; and R 3 is methyl. The reaction is shown in Scheme III. EXAMPLES The following examples are given for illustrative purposes only. Example 1. 1-(4-chlorophenyl)-2-phenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquinoline(Compound A324) Step 1. 4-Isopropylacetanilide To a solution of 4-isopropylaniline (5.2g, 38mmol) in acetic acid was added while ice-cooling and stirring acetic anhydride (4ml, 42mmol). After stirring at room temperature overnight, the reaction mixture was poured into ice water. The resulting precipitate was filtered off, washed with water and then dried under reduced pressure to give the title compound. 1 H-NMR(CDCl 3 ) δ 1.22(6H,d,CH(C H 3 ) 2 ), 2.15(3H,s,NHCO CH 3 ), 2.87(1H,septet,CH), 7.28(4H,d,Ar-H) Step 2. 1-(4-Chlorophenyl)-4-isopropylacetanilide Under argon atmosphere, a mixture of 4-isopropylacetanilide (2.5g, 5mmol), 4-chlorobromobenzene (2.97g, 15.5mmol), cupric iodide (2.95g, 15.5mmol) and potassium carbonate (1.5g, 10.9mmol) was heated at 160-180°C for 30 hours followed by allowing to cool. The reaction mixture was diluted with water and diethyl ether and filtered to remove insolubles. The organic layer was separated, washed with water and saturated sodium chloride solution and dried with sodium sulfate. After removing the solvent, the residue was purified by silica gel-column chromatography (chloroform) to yield the title compound. 1 H-NMR(CDCl 3 )δ 1.25(6H,d,CH( CH 3 ) 2 ), 2.05(3H,s,NCOCH 3 ), 2.92(4H,septet,CH), 7.15-7.28(8H,m,Ar-H) Step 3. 1-(4-Chlorophenyl)-4-isopropylaniline A solution of 1-(4-chlorophenyl)-4-isopropylacetanilide (2.91g, 10mmol) in ethanol (35mL) was mixed with 15mL of concentrated hydrochloric acid. The mixture was refluxed overnight and evaporated to remove ethanol. The resulting residue was diluted with water and made alkaline with sodium hydroxide. This solution was extracted with diethyl ether twice. The combined organic layers were sequentially washed with water and saturated sodium chloride solution, dried with sodium sulfate and evaporated in vacuo to give the title compound. 1 H-NMR(CDCl 3 )δ 1.24(6H,d,CH( CH 3 ) 2 ), 2.87(1H,septet,CH), 5,59(1H,s,NH), 6.91-7.19(8H,m,Ar-H) Step 4. 1-(4-Chlorophenyl)-5-isopropylisatin To a solution of 1-(4-chlorophenyl)-4-isopropylaniline (2.29g, 9.3mmol) in dry benzene under argon atmosphere was added oxalyl chloride (1.42mL, 16.3mmol) while ice cooling and stirring. The mixture was stirred at room temperature for additional 2 hours followed by evaporation under reduced pressure to remove excessive oxalyl chloride. The residue was dissolved in 1,2-dichloroethane. To this solution was added under argon atmosphere anhydrous aluminum chloride (1.28g, 9.6mmol) in portions. The mixture was stirred at room temperature overnight and then gradually poured into ice-water (40mL) containing 10mL of 2N hydrochloric acid solution. The organic phase was separated, sequentially washed with 2N sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried with sodium sulfate and evaporated under reduced pressure to remove 1,2-dichloroethane. The title compound was obtained by crystalizing the residue from diethyl ether, 1 H-NMR(CDCl 3 )δ 1.24(6H,d,CH( CH 3 ) 2 , 2,92(1H,septet,CH), 6.82(1H,d,H-7), 7.36-7.55(4H,m,Ar-H), 7.42(1H,dd,H-6), 7.59(1H,d,H-4) Step 5. 1-(4-Chlorophenyl)-6-isopropylisatoic anhydride A solution of 1-(4-chlorophenyl)-5-isopropylisatin (1.5g, 5.0mmol) in methylene chloride was added dropwise to a solution of m-chloroperbenzoic acid (907mg, 5.3mmol) in methylene chloride. The mixture was stirred at room temperature for 2 hours and then poured into ice-water containing 3 equivalents of sodium hydrogen sulfite followed by extraction with methylene chloride. The methylene chloride layer was sequentially washed with 1% sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried with sodium sulfate and then evaporated to remove methylene chloride. The title compound was obtained by crystallizing the residue from diethyl ether. 1 H-NMR(CDCl 3 )δ 1.24(6H,d,CH( CH 3 ) 2 ), 2.95(1H,septet,CH ), 6.49(1H,d,H-8), 6.98(1H,dd,H-7), 7.26-7.60(4H,m,Ar-H), 8.03(1H,d,H-5) Step 6. 1-(4-Chlorphenyl)-2-phenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoguinoline Tetramethylethylenediamine(1.05mL, 6.94mmol) was gradially added with stirring into a solution of 1.55M hexane solution of n-butyl lithium (4.5mL, 6.94mmol) under argon atmosphere. Then a solution of propiophenone(936mg, 6.94mmol) in anhydrous THF was aded to the mixture while ice cooling and stirring. The reaction mixture was stirred for additional 3 hours at room temperatured and then ice-cooled. To this was added dropwise a solution of 1-(4-chlorophenyl)-6-isopropylisatoic anhydride (1.10g, 3.47mmol) in anhydrous THF. The reaction mixture was stirred overnight at room temperature and diluted with saturated ammonium chloride. The organic layer was separated and concentrated in vacuo. The residue was dissolved in ethyl acetate. The resulting solution was washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated to remove the solvent. The residue was purified by silica gel-column chromatography (chloroform:acetone=20: 1) followed by crystallization from diethyl ether to give the title compound. 1 -H-NMR(CDCl 3 )δ 1.31(6H,d,CH( CH 3 ) 2 ), 1.91(3H,s,CH 3 ), 3.05(1H,septet,CH), 6.67(1H,d,H-8), 7.01-7.28(9H,m,Ar-H), 7.33(1H,dd,H-7), 8.39(1H,d,H-5) Example 2. 1,2-Diphenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquinoline (Compound A320) Step 1. 4-Isopropylisonitrosoacetanilide A solution of chloral hydrate (9.0g, 54mmol) and anhydrous sodium sulfate (57g) in 190mL of water was heated to 60°C. To this solution were added a warmed solution (70 °C)of 4-isopropylaniline (6.8g, 50mmol) and concentrated hydrochloric acid (4.3mL, 52mmol) in 150mL of water followed by a warmed solution of hydroxyl'amine hydrochloride (11.0g, 158mmol) in 50mL of water. The resulting solution was heated to boiling temperature over 40 minutes and then refluxed for 2 minutes. After cooling with tap water, the resulting precipitate was filtered off, washed with cold water and dried under reduced pressure to give the title compound. 1 H-NMR(CDCl 3 )δ 1.21(6H,d,CH 3 ), 2.96(1H,septet,CH) , 6.72(1H,brs,OH), 7.18(2H,d,H-3.5), 7.47(2H,d,H-2,6), 7.58(1H,s,CH=N), 8.34(1H,s,NH) Step 2. 5-Isopropylisatin 30mL of concentrated sulfuric acid was heated to 50°C. To this was added 4-isopropylnitrosoacetanilide (8.4g, 41mmol) in portions while maintaing the inner temperature at 60-70°C. The reaction mixture was heated at 80°C for 10 minutes with stirring, allowed to cool to room temperature and poured into ice(about 300g). The resulting precipitate was filtered off, washed with cold water and dried under reduced pressure to give the title compound. 1 H-NMR(CDCl 3 )δ 1.21(6H,d,CH 3 ), 2.96(1H,septet,CH), 7.10(1H,d,H-8), 7.67(1H,d,H-7), 7.74(1H,d,H-5). 11.66(1H,brs,NH) Step 3. 1-Phenyl-5-isopropylisatin A solution of 5-isopropylisatin (500mg, 2.6mmol), bromobenzene(10mmol) and cupric iodide (420mg, 5.3mmol) in DMF was heated at 180 °C for 5.5 hours with stirring. The reaction mixture was filtered while hot and the filtrate was concentrated in vacuo. The residue was dissolved in chloroform followed by drying with sodium sulfate. The chloroform solution was evaporated to remove the solvent and the residue was purified by silica gel-chromatography (chloroform) to give the title compound. 1 H-NMR(CDCl 3 ) δ 1.25(6H,d,CH( CH 3 ) 2 , 2.92(1H,septet,CH), 6.83(1H,d,H-7), 7.38-7.57(6H,m,Ar-H), 7.59(1H,d,H-4) Steps 4 and 5. 1,2-Diphenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquinoline The title compound was prepared from 1-phenyl-5-isopropylisatin in a manner analogous to steps 5 and 6 of Example 1. 1 H-NMR(CDCl 3 ) δ 1.31(6H,d,CH( CH 3 ) 2 ), 1.93(3H,s,CH 3 ), 3.05(1H,septet,CH), 6.69(1H,d,H-8), 7.04-7.33(11H,m,Ar-H) The following compounds have been produced in a manner analogous to that described in the preceding examples. Compound No. R 1 X R 3 ' R 4 m.p.(°C) A320 6-i-C 3 H 7 C 6 H 5 CH 3 C 6 H 5 225 A321 6-i-C 3 H 7 C 6 H 5 CH 3 2-F-C 6 H 4 205-207 A322 6-i-C 3 H 7 C 6 H 5 CH 3 3-F-C 6 H 4 248-251 A323 6-i-C 3 H 7 C 6 H 5 CH 3 4-F-C 6 S 4 224-229 A324 6-i-C 3 H 7 C 6 H 5 CH 3 4-Cl-C 6 H 4 233-235 A325 6-i-C 3 H 7 C 6 H 5 CH 3 4-CH 3 -C 6 H 4 203-205 A326 6-i-C 3 H 7 C 6 H 5 CH 3 4-CH 3 O-C 6 H 4 204-208 BIOLOGICAL EXAMPLES 1. In vitro anti-picornavirus activity Poliovirus type 1(Polio 1, Sabin), echovirus type 11(Echo 11, Gregory), coxsackievirus type A7 (CA7), coxsackievirus type B4 (CB4,JVB), human rhinovirus type 1B (HRV 1B, B632), HRV 2 (HGP), and HRV 89 (41617-Gallo) were used. Polio 1, Echo 11, and CA7 were assayed in HeLa-S3 cells with the exception of the CB4, which were assayed in HeLa cells; all numbered HRV serotypes were assayed in HeLa (Ohio strain)cells. Cells were seeded at 2.0 x 10 4 cells/well (in Eagle MEM plus 7 % fetal bovine serum, growth medium) in 96-well tissue culture plate and were incubated for 24 hr. at 37°C in a CO 2 incubator to form monolayer. The growth medium in the plates was removed and a serial 0.5 log 10 dilutions of the test compound in 50µl maintenance medium (Eagle MEM plus 2% heat-inactivated fetal bovine serum) was added to the wells. Each drug concentration was run in quadruplicate. Immediately after addition of compounds, the cells in 96-well plate were infected with appropriate virus at 300-1,000 plaque forming units (PFU) per well in 50µl of maintenance medium and were incubated at 33°C for HRVs or 37 °C for enteroviruses. Uninfected cells and cells that received virus in the absence of compound were included on each plate. The anti-picornavirus activities of the compounds were examined by colorimetric assay based on the cells as monitored by reduction of 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) to formazan. After 3-5 days, 20 µl of MTT solution (4 mg/ml) in phosphate buffered saline (PBS) was added to each well, and the incubation was continued for an additional 2.5-4 hr. After incubation, 100 µ of 15 % SDS in 0.01 N HCl was added to each well to solubilize the bluish violet crystal of formazan and the plates were incubated at 37°C for an additional 18hr. The absorbency of formazan at 600 nm with a reference wave length of 660 nm was measured by a computer-controlled microplate reader. The 50 % inhibitory concentration (IC 50 ) by the MTT method was defined as the concentration of compound that protected 50 % of the cell monolayer from virus-induced cytopathic effect. The percentage protection was calculated by the following equation: [ (A T )v-(Ac) v/(Ac) mock -(Ac)v] X 100 %, where (A T )v, (Ac)v, (Ac) mock indicate absorbencies of the test sample, the virus-infected control (no compound) and mock-infected control, respectively. The cytotoxicity of the compound was determined as described above without inoculation of the virus and expressed as the 50 % cytotoxic concentration (CC 50 ), i.e., the concentration required to reduce the viability of untreated cells by 50 %. The cells were exposed to various concentrations of the test compounds in the maintenance medium and incubated for 4 days. The compounds of the present invention exhibited anti-picornavirus activities as shown in table II. in vitro Anti-picornavirus activity IC 50 ( µg/ml) Compound. Polio 1 Echo 11 CA7 CB4 HRV1B HRV2 HRV89 A320 >5 0.15 >5 >5 0.12 0.051 0.051 A321 NT NT NT NT 0.60 0.056 0.066 A322 NT NT NT NT 0.18 0.030 0.034 A323 >2 >2 >2 >2 0.27 0.038 0.011 A324 NT NT NT NT 0.53 0.12 0.046 A325 >2.5 >2.5 >2.5 >2.5 >2.5 0.066 0.022 A326 >2.5 >2.5 >2.5 >2.5 >2.5 0.48 0.067 Cytotoxicity CC 50 ( µg/ml) Compound HeLa-S3 HeLa HeLa(Ohio) A320 >5 >5 >5 A321 NT NT >1 A322 NT NT >1 A323 >2 >2 >2 A324 NT NT >1 A325 >2.5 >2.5 >2.5 A326 >2.5 >2.5 >2.5 2. Anti-rhinovirus spectrum In the above cell-based assays, some compounds demonstrate potent antiviral activities against 3 HRV serotypes tested. Therefore, we expanded our assessment of the antiviral activity of the compounds to a larger panel of HRV serotypes. HRV1A (E28), HRV3(FEB), HRV50, HRV8(MRH), HRV10(204-CV14), HRV13(353), HRV14(1059), HRV16(11757), HRV21(47), HRV29(5582), HRV31(41F), HRV32(363), HRV33(1200) , HRV36(342H), HRV39(209), HRV41(56110), HRV50(A2#58), HRV61(6669-CV39), and clinical isolate (89229T) were tested in the same method described above for sensitivity to the compounds. As shown in Table IV, some of the compounds exhibit potent activity against a broad spectrum of rhinovirus serotypes. Anti-rhinovirus activity Rhinovirus Serotype Compd.A320 Compd. A322 Compd. A323 HRV1A >5.0 >1.0 >2.0 HRV1B 0.12 0.18 0.27 HRV2 0.051 0.030 0.038 HRV3 >5.0 >1.0 >2.0 HRV5 >5.0 >1.0 >2.0 HRV8 >5.0 >1.0 >2.0 HRV10 0.021 0.013 0.032 HRV13 0.23 0.029 0.12 HRV14 >5.0 >1.0 >2.0 HRV16 0.023 0.030 0.033 HRV21 0.024 0.048 0.067 HRV29 0.079 0.080 0.11 HRV31 0.046 0.045 0.088 HRV32 0.051 0.020 0.077 HRV33 0.23 0.17 0.30 HRV36 0.082 0.085 0.13 HRV39 <0.017 0.012 0.018 HRV41 0.066 0.034 0.058 HRV50 0.020 0.023 0.038 HRV61 0.21 0.29 0.30 HRV89 0.051 0.034 0.011 Clinically isolated strain 0.017 0.017 0.030 3. In vitro anti-Rotavirus activity Human rotavirus (HRoV, Odelia) and simian rotavirus (SRoV, SA11) were used in this experiment. Confluent monolayers of MA104 cells in 6-well multiplate were washed with Eagle MEM containing 0.5 µg/ml of trypsin and were infected with tripsinized-rotavirus (treated with 10 µg/ml of tripsin at 37°C for 1.5hr) at 50 PFU per well. After 1 hr of adsorption, the virus inoculum was removed, and the monolayers were washed with Eagle MEM containing 0.5 µg/ml of trypsin and overlaid with Eagle MEM containing 1 µg/ml of trypsin, 0.6 % purified agar and the test compounds at various concentrations. The cultures were incubated at 37 °C for 3 days and same overlay medium was added. Four days after infection, the cell sheets were washed with PBS and stained with 1.3 % crystal violet in 95 % ethanol. The antiviral efficacy of the compounds was expressed as the IC 50 , that is the concentration of the compounds required to reduce the number of plaques to 50 % in the control (virus-infected, but not untreated). The compounds tested specifically inhibited the multiplication of HRoV (Odelie) and SRoV (SA11) as shown in Table V. Anti-rotavirus activity IC 50 ( µg/mL) Compound HRoV(Odelia) SRoV(SA11) A323 1.30 0.90

Claims: A substituted 1,4 dihydro-4-oxoquinoline compound selected from the group consisting of : 1,2-diphenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquinoline, 1-(2-fluorophenyl)-2-phenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquinoline, 1-(3-fluorophenyl)-2-phenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquinoline, 1-(4-fluorophenyl)-2-phenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquinoline, 1-(4-chiorophenyl)-2-phenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquinoline, 1-(4-tolyl)-2-phenyl-3-methyl-6-isopropyl-1,4dihydro-4-oxoquinoline, and 1-(4-methoxyphenyl)-2-phenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquinoline. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. The use of a compound according to claim 1 in the manufacture of a pharmaceutical composition for use in the prophylaxis and the treatment of Picornavirus and human rotavirus infections.

Inventors: AGOH MASANOBU, AGOH YUMI, KURIYAMA HARUO, MORI TERUYO, SOGA MANABU, TAMURA TAKASHI, AGOH, MASANOBU, AGOH, YUMI, KURIYAMA, HARUO, MORI, TERUYO, SOGA, MANABU, TAMURA, TAKASHI
Applicants: MARUISHI PHARMA, MARUISHI PHARMACEUTICAL CO., LTD.
Application year: 2000
Main classification: C07D215
IPC codes: C07D491, C07D498, C07D471, C07D215, C07D401, A61P31, C07D409, C07D417, C07D495, C07D221, C07D405