# Patent

## Title
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.

## Background
RELATED PATENT APPLICATIONS
This application is a divisional application of U.S. patent application Ser. No. 09/649,596, filed Aug. 29, 2000, now U.S. Pat. No. 6,541,470.


FIELD OF THE INVENTION
This invetion related to a group of 1,2-disubstituted 1,4-dihydro-4-oxoquinoline compounds and the use of said compounds as an antiviral agent.
BACKGROUND OF THE INVENTION
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.
SUMMARY OF THE INVENTION
The present invention provides a 1,2-disubstituted 1,4-dihydro-4-oxoquinoline compound of Formula I; 




wherein each R1 is a member independently selected from the group consisting of alkyl, cycloalkyl, phenyl, alkoxy, cycloalkyloxy, phenoxy, methylenedioxy, trifluoromethyl, halogen, OH, NO2, NH2, mono- or dialkylamino, pyrrolidino, piperidino, piperazino, 4-hydroxypiperazino, 4-methylpiperazino, 4-acetylpiperazino, morpholino, pyridyl, pyridyloxy, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiomorpholino, dialkylaminoalkylamino, N-alkylaminoalkyl-N-alkylamino, N-hydroxyalkyl-N-alkylamino, dialkylaminoalkoxy, acetoxy, hydroxycarbonyloxy, alkoxycarbonyloxy, hydroxycarbonylmethoxy and alkoxycarbonylmethoxy, and n is 1,2 or 3
wherein R2 is a member selected from the group consisting of alkyl, pyridyl, pyrazinyl, furyl, N-alkylpyrrolyl, thiazolyl, thienyl which may be optionally substituted with alkyl or halogen, and phenyl which may be optionally substituted with up to two substituents independently selected from the group consisting of halogen, OH, alkyl, alkoxy, trifluorometlyl and acetoxy;
wherein R3 is a member selected from the group consisting of hydrogen, alkyl, phenyl, alkoxy, alkoxycarbonyl, alkylsulfonyl, CN and acetyl; or
if R2 is a phenyl group optionally substituted with halo, alkyl or alkoxy groups, R3 may represent a bridging group between the 3rd position of the quinoline ring and said phenyl group at a position next to the ring carbon atom at which said phenyl group is directly connected to the quinoline ring, said bridging group being selected from the group consisting of methylene, carbonyl, hydroxyiminomethylidene, alkoxyiminomethylidene, alkanoylaminomethylidene, aminomethylidene, hydroxymethylidene, 1-hydroxy-1,1-alkylidene, α-hydroxybenzylidene, 1-alkoxy-1,1-alkylidene, α-alkoxybenzylidene, 1,2-ethylidene and 1,3-propylidene; or
if R2 is 2-thienyl, 4- or 5-alkyl-2-thienyl or N-alkylpyrrol-3-yl, R3 may represent methylene bridge between the 3rd position of the quinoline ring and said thienyl group at the 3rd position or said pyrrolyl group at the 2nd position, and

    
    
        wherein R4 is a member selected from the group consisting of alkyl, alkenyl, benzyl and phenyl optionally substituted with halo, alkyl or alkoxy.
    
    


In a preferred embodiment, the compound of the present invention has Formula I-a: 




wherein R2′ is phenyl or substituted phenyl having up to two substituents independly selected from the group consisting of halo, OH, alkyl, alkoxy, trifluoromethyl and acetoxy;
R3′ is hydrogen, alkyl, phenyl, alkoxy, alkoxycarbonyl, alkyl-sulfonyl, CN or acetyl; and
R1, R4 and n are as defined above.
In another embodiment, the compound of the present invention has Formula I-b: 




wherein R2′′ is alkyl, pyridyl, pyrazinyl, furyl, N-alkylpyrrolyl, thienyl, substituted thienyl having up to two halo- or alkyl substituents, or thiazolyl; and
R1, R3′, R4 and n are as defined above.
In other embodiments, if R2 is pheny or substituted phenyl in the formula I, R3 may be a bridge forming a fused ring system including the quinoline and benzene rings.
When the bridge is formed of a single carbon atom, the compound of the present invention is a derivative of 5,6-dihydro-11H-indeno[1,2-b]quinoline of Formula I-c: 




wherein R5 is a member independly selected from the group consisting of hydrogen, halo, alkyl and alkoxy;
R6 and R7 together with the carbon atom to which they are attached represent a bridge selected from the group consisting of methylene, carbonyl, hydroxyiminomethylidene, alkoxyiminomethylidene, alkanoylaminomethylidene, aminomethylidene, hydroxymethylidene, 1-hydroxy-1,1-alkylidene, α-hydroxybenzylidene, 1-alkoxy-1,1-alkylidene and α-alkoxybenzylidene;
m is 1 or 2; and
R1, R4 and n are as defined above.
When the bridge is 1,2-ethylidene, the compound of the present invention is a derivative of 6,12-dihydrobenzo[c]-acridine of Formula I-d: 




wherein R1, R4, R5, n and m are as defined above.
When the bridge is 1,3-propylidene, the compound of the present invention is a derivative of 5,6,7,13-tetrahydro-8H-benzo[6,7]cyclohepta[1,2-b]quinoline of Formula I-e; 




wherein R1, R4, R5, n and m are as defined above.
In further embodiments, if R2 is thienyl, 4- or 5-alkyl-2-thienyl or N-alkyl-pyrrol-3-yl, R3 may be a methylene bridge forming a fused ring system including the quinoline ring and the thiophene or pyrrole ring. Thus, the compounds of the present invention include a derivative of thieno[3′, 2′:4,5]-cyclopenta[1,2-b]quinoline-5-one of Formula I-f: 




wherein R8 is hydrogen or alkyl; and
R1, R4 and n are as defined above.
Also included in the compounds of the present invention is a derivative of pyrrolo[3′,2′:4,5]cyclopenta[1,2-b]quinoline-5-one of Formula I-g: 




wherein R9 is alkyl, and R1, R4 and n are as define.
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.


DETAILED DESCRIPTION OF THE INVENTION
Throughout the specification and claims, several terms are difined as follows.
Alkyl including the alkyl moiety of alkoxy refers to a straight chain or branched alkyl of up to 8, preferably 6 carbon atoms.
Alkenyl refers to an alkenyl of 2-6, preferably 3-4 carbon atoms.
Cycloalkyl refers to a cycloalkyl of 5-7 carbon atoms, preferably cyclohexyl.
Halogen refers to fluorine, chlorine or bromine.
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 R4I in the presence of sodium hydride. Method A is applicable to the synthesis of the compounds of Formula I-a. Scheme I. Method 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 R4 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 R4 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 R4 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.
In Method B1 for the preparation of the compounds of Formula I-a, the ketone compound may be represented by the formula: R2′C(O)CH2R3′, wherein R2′ is phenyl or substituted phenyl having one or two substituents independently selected from the group consisting of halo, OH, alkyl, alkoxy, trifluoromethyl and acetoxy; and R3′ is hydrogen, alkyl, phenyl, alkoxy, alkoxycarbonyl, alkylsulfonyl, CN or acetyl. The reaction involved in Method B1 is shown in Scheme III. 




Similarly, Method B2 for the preparation of the compounds I-b, a ketone of the formula: R2′′C(O)CH2R3′, wherein R2′′ is alkyl, pyridyl, pyrazinyl, furyl, N-alkylpyrrolyl, thienyl, substituted thienyl having up to two halo- or alkyl substituent or thiazolyl; and R3′ is as defined above is used. The reaction involved in Method B2 is shown in Scheme IV. 




The compounds of Formula I-c wherein both R6 and R7 are hydrogen as well as the compounds of Formula I-d and Formula I-e are prepared by Method B3 shown in Scheme V. 




Specifically, the oxo compound XIII are 1-indanones for the compounds of Formula I-c(x=1, R6, R7=H), 1-tetralones for the compounds Formula I-d (x=2) and 1-oxobenzosuberones (x=3), respectively.
The compounds of Formula I-c wherein R6 and R7 together represent oxo may be prepared by reacting the isatoic anhydride VIII with a 1,3-indandione XIV to obtain 5,10-dihydro-11H-indeno[1,2-b]quinolin-10, 11-dione compounds XV as shown in Scheme VI. 




The 11-oxo compounds XV may be further manipulated using known methodoloy to obtain the compounds of Formula I-c wherein R6 and R7 are other than oxo. Reaction of 11-oxo compounds XV with hydroxylamine gives a corresponding oxime. Reaction of oxime with an alkylating agent in the presence of sodium hydride gives a 11-alkoxyimino compound. The oxime further gives a 11-alkanoylamino compound by acylation with an acylating agent such as acetyl anhydride in a reducing atomosphere. Saponification of 11-alkanoylamino compound leads to 11-amino compound.
The 11-oxo compounds XV may be converted into a 11-hydroxy compound by the reaction with sodium borohydride. Reaction of 11-oxo compounds XV with alkyl- or phenyl magnesium halide leads to a 11-hydroxy-11-alkyl or phenyl devivative. The hydroxy group at position 11 may further be alkylated in the presence of sodium hydride to give a 11-alkoxy-11-alkyl or phenyl derivative. The hydroxy group at position 11 may be removed by the reaction with sodium iodide and trimethylsilyl chloride to give 11-alkyl or phenyl derivative.
Finally, the compounds of Formula I-f and Formula I-g may be prepared by Method B4 as shown in Scheme VII. The compounds of Formula I-f are prepared by the reaction of isatoic anhydride VIII with 4,5-dihydro-6H-cyclopenta[b]-thiophen-6-one XVI in the presence of n-BuLi and TMEDA. Reaction of isatoic anhydride VIII with 1-methyl-5,6-dihydro-4H-cyclopenta[b]pyrrol-4-one XVII in the presence of n-BuLi and TMEDA gives the compounds of Formula I-g. 




EXAMPLES
The following examples are given for illustrative purposes only.

Part A. 




Example 1
1-Ethyl-2-phenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquinoline(Compound A37)
Step 1. 2-phenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquinoline
To polyphosphoric acid (1.5 g) heated to 160° C. were added dropwise a solution of 4-isopropylaniline(0.5 g, 3.6 mmol) and ethyl 2-benzoylpropionate (1.52 g, 7.3 mmol) in ethanol with stirring. The mixture was stirred at 160° C. for 3 hours. After cooling, a cold solution of 10% hydrochloric acid was added to the mixture. The resulting precipitate was recovered by filtration, dissolved in methanol and treated with active carbon. After evaporating in vacuo, the residue was recrystallized from ethyl acetate to give the title compound in a yield of 81%. 1H-NMR(DMSO-d6) δ 1.28 (6H, d, CH(CH3)2), 2.0 (3H, s, CH3), 3.07 (1H, septet, CH), 7.61 (5H, s, Ar—H), 7.6-7.7 (2H, m, H-7,8), 8.13 (1H, s, H-5), 12.67 (1H, s, NH)
Step 2. 1-ethyl-2-phenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquinoline
To a solution of 0.28 g(1 mmol) of 2-phenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquiline in DMF (10 mL) were added potassium carbonate(3 mmol) and ethyl iodide(5 mmol). The mixture was heated with stirring for 4.5 hours. After removing the solvent, the residue was dissolved in water and extracted with ethyl acetate twice. The combined organic layers were washed with water and then saturated sodium chloride solution followed by drying with sodium sulfate and evaporation in vacuo. The residue was purified by silica gel-column chromatography(hexane:ethyl acetate=2:1) to yield the title compound. 1H-NMR (CDCl3) δ 1.1-1.4 (3H, t, NCH2CH3), 1.3-1.5 (6H, d, CH(CH3)2), 1.8 (3H, s, CH3), 2.7-3.4 (1H, m, CH), 3.8-4.2 (2H, q, NCH2), 7.1-7.8 (7H, m, Ar—H), 8.3-8.6 (1H, s, H-5).
Example 2
1-Ethyl-2-(3-methyl-4-methoxyphenyl)-3,5-dimethyl-6-isobutoxy-1,4-dihydro-4-oxoquinoline (Compound A191)
Step 1. 3′-Methyl-4′-methoxyacetophenone
To an ice-cooled solution of 3′-methyl-4′-hydroxyacetophenone (15 g, 100 mmol) in 100 mL of DMF was added 60% sodium hydride (2.4 g, 101 mmol) under argon atmosphere with stirring. After 30 minutes, methyl iodide(7.5 mL, 120 mmol) was added to the solution and allowed to react overnight at room temperature with stirring. The reaction mixture was evaporated to remove the solvent. The residue was dissolved in water and extracted with diethyl ether thrice. The combined organic layers were sequentially washed with water and saturated sodium chloride solution, dried with sodium sulfate and distilled under reduced pressure (116° C./0.2 mmHg) to obain the title compound in a yield of 71%. 1H-NMR (CDCl3) δ 2.24 (3H, s, CH3), 2.54 (3H, s, COCH3), 3.90 (3H, s, OCH3), 6.84 (1H, d, H-5′), 7.77 (1H, dd, H-2′), 7.82 (1H, dd, H-6′)
Step 2. 3-Methyl-4-methoxybenzoic Acid
To a suspension of bleaching powder(72 g, 500 mmol) in 270 mL of water was added a solution of potassium hydroxide (14 g, 250 mmol) and potassium carbonate (50.5 g 365 mmol) in 150 mL of water. The suspension was stirred for 2 hours under sealing and the filtered to remove precipitated calcium salt. The precipitate was washed with a small amount of water and washing was combined with the above filtrate. To the filtrate was added 3′-methyl-4′-methoxyacetophenone (27.3 g, 166 mmol) while stirring vigorously. The mixture was stirred overnight at room temperature. After adding sodium bisulfate (17.8 g 171 mmol), the reaction mixture was washed twice with diethyl ether. The aqueous layer was acidified with hydrochloric acid. The resulting crystals were filtered off followed by drying under reduce pressure to yield the title compound.
1H-NMR (CDCl3) δ 2,18 (3H, s, CH3), 3.89 (3H, s, OCH3), 7.02 (1H, d, H-5), 7.74 (1H, dd, H-2), 7.81 (1H, dd, H-6)
Step 3. Ethyl 3-methyl-4-methoxybenzoate
A solution of 3-methyl-4-methoxybenzoic acid (20 g,120 mmol) and ethyl orthoformate (19.6 g 132 mmol) in 300 mL of ethanol was refluxed overnight with the addition of concentrated sulfuric acid (4 mL) followed by evaporation in vacuo to remove the solvent. The residue was dissolved in water. The solution was made alkaline with sodium carbonate and extracted thrice with chloroform. The combined organic layers were sequentially washed with saturated sodium carbonate solution, water and saturated sodium chloride solution, dried with sodium sulfate and distilled under reduced pressure (185-190° C./0.3 mmHg) to give the title compound. 1H-NMR (CDCl3) δ 1,38 (3H, t, CH2CH3), 2.23 (3H, s, 3-CH3), 3.87 (3H, s, OCH3), 4.34 (2H, dq, CH2CH3), 6.82 (1H, d, H-5), 7.83 (1H, dd, H-2), 7.89 (1H, dd, H-6)
Step 4. Ethyl 2-(3-methyl-4-methoxybenzoyl)propionate
To a mixture of ethyl 3-methyl-4-methoxybenzoate (24.8 g 128 mmol) and 60% sodium hydride (3.1 g, 128 mmol) under argon atmosphere was added dropwise a solution of ethyl propionate (6.5 g, 64 mmol) in 200 mL of n-butyl ether with stirring while keeping the inner temperature at 90-100° C. Stirring was continued for additional 3 hours at 130° C. After cooling to room temperature, excessive sodium hydride in the reaction mixture was decomposed with ethanol. After the addition of water, the reaction mixture was neutrallized with hydrochloric acid and extracted with diethyl ether thrice. The combined organic layers were sequentially washed with saturated sodium carbonate solution, water and saturated sodium chloride solution followed by drying with sodium sulfate. Distillation of the organic layers under reduced pressure (185-190° C./0.3 mmHg) gave the title compound. 1H-NMR (CDCl3) δ 1.19 (3H, t, CH2CH3), 1.47 (3H, d, CHCH3), 2,25 (3H, s, 3′-CH3), 3.90 (3H, s, OCH3), 4.15 (2H, dq, CH2CH3), 4.34 (1H, q, CH), 6.86 (1H, d, H-5′), 7.80 (1H, dd, H-2′), 7.86 (1H, dd, H-6′)
Step 5. 3-Methyl-4-isobutoxynitrobenzene
Isobutyl alcohol (1.5 g, 5 mmol) was dissolved in anhydrous DMF under argon atmosphere and cooled to −15° C. To this solution was added 60% sodium hydride (0.37 g, 15.5 mmol) with stirring followed by 2-nitro-5-fluorotoluene (2 g, 13 mmol) after 30 minutes. The mixture was stirred for additional 2 hours at the same temperature followed by distilling off DMF. The residue was diluted with water and extracted with chloroform thrice. The combined organic layers were was sequentially washed with water and saturated sodium chloride solution, dried with sodium sulfate and purified by silica gel-column chromatography (chloroform) to give the titel compound. 1H-NMR (CDCl3) δ 1.07 (6H, d, (CH3) 2), 2.16 (1H, septet, CH), 2.29 (3H, s, 3-CH3), 3.83 (2H, d, CH2), 6.82 (1H, d, H-5), 8.04 (1H, d, H-2), 8.08 (1H, dd, H-6)
Step 6. 3-methyl-4-isobutoxyaniline
To a solution of 3-methyl-4-isobutoxynitrobenzene (2.72 g, 13 mmol) in ethanol (25 mL) were added iron powder (13 g), water (1.5 mL) and concentrated hydrochloric acid (0.13 mL). The mixture was refluxed for 1 hour and then filtered while hot. The filtrate was concentrated in vacuo. The residue was dissolved in chloroform followed by drying with sodium sulfate. Removal of chloroform by evaporation gave the title compound. 1H-NMR (CDCl3) δ 1.01 (6H, d, CH(CH3)2), 2.06 (1H, septet, CH), 2.17 (3H, s, 3-CH3), 3.33 (2H,brs,NH2), 3.63 (2H, d, CH2), 6.53 (1H, d, H-2), 6.63 (1H, d, H-5), 6.67 (1H, dd, H-6)
Step 7. 2-(3-Methyl-4-methoxyphenyl)-3,5-dimethyl-6-isobutoxy-1,4-dihydro-4-oxoquinoline
To polyphosphoric acid (3 g) heated to 160° C. was added dropwise a solution of ethyl 2-(3-methyl-4-methoxybenzoyl) propionate (3,4 g,13.4 mmol) and 3-methyl-4-isobutoxyaniline (1.2 g, 6.7 mmol) in ethanol (2 mL) with stirring.
The mixture was stirred for additional 1 hour and allowed to cool to room temperature. An amount of crashed ice and 20% hydrochloric acid were added to the reaction mixture and extracted with chloroform. The organic layer was washed sequentially with saturated sodoium carbonate solution, water and saturated sodium chloride solution followed by drying with sodium sulfate. The residue resulting from evaporation of chloroform was roughly purified by silica gel-column chromatography(chloroform: acetone=20:1).
The title compound was obtained by crystallizing the crude product from diethyl ether. 1H-NMR (CDCl3) δ 1.08 (6H, d, CH(CH3)2), 1.87 (3H, s, 3-CH3), 2.07 (3H, s, 3′-CH3), 2,14 (1H, septet, CH), 2.91 (3H, s, 5-CH3), 3.75 (2H, d, CH2), 3.76 (3H, s, OCH3), 6.65 (1H, s, H-5′), 7.11 (1H, d, H-2′), 7.13 (1H, dd, H-6′), 7.21 (1H, d, H-8), 7.48 (1H, d, H-7), 9.78 (1H, s, NH)
Step 8. 1-Ethyl-2-(3-methyl-4-methoxyphenyl)-3,5-dimethyl-6-isobutoxy-1,4-dihydro-4-oxoquinoline
2-(3-Methyl-4-methoxyphenyl)-3,5-dimethyl-6-isobutoxy-1,4-dihydro-4-oxoquinoline(0.18 g, 0.5 mmol) was dissolved in anhydrous DMF under argon atmosphere.
To the solution were added while ice cooling and stirring 60% sodium hydride (0.013 g, 0.54 mmol). After 30 minutes, ethyl iodide (0.12 g, 0.75 mmol) was added to the mixture followed by stirring overnight. After removing DMF by distillation, water was added to the reaction mixture followed by extraction with ethyl acetate thrice. The combined organic layers were washed sequentially with water and saturated sodium chloride solution, dried with sodium sulfate and then concentrated in vacuo. The residue was purified by silica gel-column chromatography (n-hexane:ethyl acetate=3:1) to give the title compound. 1H-NMR (CDCl3) δ 1.08 (6H, d, CH(CH3)2), 1.19 (3H, t, CH2CH3), 1.77 (3H, s, 3-CH3), 2.15 (1H, septet, CH), 2.28 (3H, s, 3′-CH3), 2.98 (3H, s, 5-CH3), 3.78 (2H, d, OCH2), 3.91 (3H, s, OCH3), 3.96 (3H, q, CH2CH3), 6.93 (1H, d, H-5′), 7.03 (1H, d, H-2′), 7.05 (1H, dd, H-6′), 7.25 (1H, d, H-8), 7.33 (1H, d, H-7)
Example 3
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 (5.2 g, 38 mmol) in acetic acid was added while ice-cooling and stirring acetic anhydride (4 ml, 42 mmol). 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. 1H-NMR (CDCl3) δ 1.22 (6H, d, CH(CH3)2), 2.15 (3H, s, NHCOCH3), 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-isopropyl-acetanilide (2.5 g, 5 mmol), 4-chlorobromobenzene (2.97 g, 15.5 mmol), cupric iodide (2.95 g, 15.5 mmol) and potassium carbonate (1.5 g, 10.9 mmol) 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.
1H-NMR (CDCl3) δ 1.25 (6H, d, CH(CH3)2), 2.05 (3H, s, NCOCH3), 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 (2.91 g, 10 mmol) in ethanol (35 mL) was mixed with 15 mL 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. 1H-NMR (CDCl3) δ 1.24 (6H, d, CH(CH3)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 (2.29 g, 9.3 mmol) in dry benzene under argon atmosphere was added oxalyl chloride (1.42 mL, 16.3 mmol) 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 (1.28 g, 9.6 mmol) in portions. The mixture was stirred at room temperature overnight and then gradually poured into ice-water (40 mL) containing 10 mL 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, 1H-NMR (CDCl3) δ 1.24 (6H, d, CH(CH3)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 (1.5 g, 5.0 mmol) in methylene chloride was added dropwise to a solution of m-chloroperbenzoic acid (907 mg, 5.3 mmol) 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. 1H-NMR (CDCl3) δ 1.24 (6H, d, CH(CH3)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-oxoquinoline
Tetramethylethylenediamine (1.05 mL, 6.94 mmol) was gradially added with stirring into a solution of 1.55M hexane solution of n-butyl lithium (4.5 mL, 6.94 mmol) under argon atmosphere. Then a solution of propiophenone (936 mg, 6.94 mmol) 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 (1.10 g, 3.47 mmol) 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. 1H-NMR (CDCl3) δ 1.31 (6H, d, CH(CH3)2), 1.91 (3H, s, CH3), 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 4
1,2-Diphenyl-3-methyl-6-isopropyl-1,4-dihydro-4-oxoquinoline (Compound A320)
Step 1. 4-Isopropylisonitrosoacetanilide
A solution of chloral hydrate (9.0 g, 54 mmol) and anhydrous sodium sulfate (57 g) in 190 mL of water was heated to 60° C. . To this solution were added a warmed solution (70° C.) of 4-isopropylaniline (6.8 g, 50 mmol) and concentrated hydrochloric acid (4.3 mL, 52 mmol) in 150 mL of water followed by a warmed solution of hydroxylamine hydrochloride (11.0 g, 158 mmol) in 50 mL 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. 1H-NMR (CDCl3) δ 1.21 (6H, d, CH3), 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
30 mL of concentrated sulfuric acid was heated to 50° C. To this was added 4-isopropylnitrosoacetanilide (8.4 g, 41 mmol) 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 300 g). The resulting precipitate was filtered off, washed with cold water and dried under reduced pressure to give the title compound. 1H-NMR (CDCl3) δ 1.21 (6H, d, CH2), 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 (500 mg, 2.6 mmol), bromobenzene(10 mmol) and cupric iodide (420 mg, 5.3 mmol) 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. 1H-NMR (CDCl3) δ 1.25 (6H, d, CH(CH3)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 3. 1H-NMR (CDCl3) δ 1.31 (6H, d, CH(CH3)2), 1.93 (3H, s, CH3), 3.05 (1H, septet, CH), 6.69 (1H, d, H-8), 7.04-7.33 (1H, m, Ar—H)
Example 5
1-Methyl-2-phenyl-3-ethoxycarbonyl-6-isopropyl-1,4-dihydro-4-oxoquinoline (Compound A50)
Step 1. 6-Isopropylisatoic Anhydride
To a solution of m-chloroperbenzoic acid (5 g, 28.5 mmol) in THF (20 mL) was added dropwise a solution of 5-isopropylisatin (2.7 g, 14.3 mmol) in THF (50 mL) under ice-cooling and stirring. After stirring for additional 3 hours under ice-cooling, the reaction mixture was treated with 10% sodium hydrogen sulfite solution (60 mL) to decompose excessive m-CPBA. The solution was poured into ice water (200 mL) and extracted with ethyl acetate several times. The combined organic layers were washed with water and saturated sodium chloride solution, dried with sodium sulfate and concentrated in vacuo. The resulting residue was crystallized from diethyl ether to give the title compound.
1H-NMR (CDCl3) δ 1.23 (6H, d, CH(CH3)2), 2.88 (1H, septet, CH), 6.95 (1H, d, H-7), 7.43 (1H, dd, H-6), 7.47 (1H, d, H-4)
Step 2. 1-Methyl-6-isopropylisatoic Anhydride
To a suspension of 60% sodium hydride (0.54 g, 13.4 mmol) in anhydrous DMF(30 mL), 6-isopropylisatoic anhydride (2.5 g, 12.2 mmol) was added at room temperature under argon atmosphere with stirring. After 30 minutes, methyl iodide (1.9 g, 13.4 mmol) was added to the reaction mixture followed by stirring at room temperature overnight. The reaction mixture was evaporated to remove DMF and extracted with chloroform. The extract was washed with water and saturates sodoium chloride solution, dried with sodium sulfate and evaporated in vacuo to dryness. The titled compound was obtained by crystalling the residue from diethyl ether. 1H-NMR (CDCl3) δ 1.28 (6H, d, CH(CH3)2), 2.99 (1H, septet, CH), 3.57 (3H, s, N—CH3), 7.12 (1H, d, H-8), 7.64 (1H, dd, H-7), 8.01 (1H, d, H-5)
Step 3. 1-Methyl-2-phenyl-3-ethoxycarbonyl-6-isopropyl-1,4-dihydro-4-oxoquinoline
To a suspension of 60% sodium hydride (0.06 g, 1.5 mmol) in anhydrous DMF (10 mL) was added ethyl benzoylacetate (0.29 g, 1,5 mmol) at room temperature under argon atmosphere with stirring. After 30 minutes, 1-metyl-6-isopropylisatoic anhydride (0.33 g, 1,5 mmol) was added to the mixture at 60° C. with stirring. The temperature was raised to 120° C. over 1 hour. The stirring was continued at the same temperature for additional 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel-chromatography (chloroform: acetone=9:1) followed by crystallization from diethyl ether to obtain the desired compound. 1H-NMR (CDCl3) δ 0.93 (3H, t, CH2CH3), 1.35 (6H, d, CH(CH3)2, 3.09 (1H, septet, CH), 3.98 (2H, q, OCH3), 7.39-7.41 (2H, m,H-2′,6′), 7.47-7.50 (4H, m, H-3′,4′,5′,8′), 7.61 (1H, dd, H-7), 8.40 (1H, d, H-5)
Example 6
1-Ethyl-2-(2-furyl)-6-isopropyl-1,4-dihydro-4-oxoquinoline (Compound A304)
Step 1. 1-Ethyl-6-isopropylisatoic Anhydride
6-Propylisatoic anhydride was reacted with ethyl iodide in the presence of sodium hydride in a manner analogous to step 2 of Example 5 to prepare the title compound. 1H-NMR (CDCl3) δ 1.28 (6H, d, CH(CH3)2), 1.38 (3H, t, CH2CH3), 2.99 (1H, septet, CH), 4.13 (2H, q, NCH2), 7.14 (1H, d, H-8), 7.64 (1H, dd, H-7), 8.01 (1H, d, H-5)
Step 2. 1-Ethyl-2-(2-furyl)-6-isopropyl-1,4-dihydro-4-oxoquinoline
To a 1.6M solution of n-butyl lithium in hexane (1,38 mL, 2,2 mmol) was added tetramethylethylenediamine (0.3 mL, 2,2 mmol) under argon atmosphere at room temperature with stirring. Then 2-acetylfuran (242 mg, 2,2 mmol) in anhydrous THF was added dropwise to the mixture under ice cooling followed by stirring for 1 hour. To this mixture was added 1-ethyl-6-isopropylisatoic anhydride (250 mg, 1.1 mmol) in anhydrous THF. After stirring at room temperature overnight, the reaction mixture was diluted with saturated aqueous solution of ammonium chloride. The resulting organic layer was separated and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and then washed with saturated sodium chloride solution followed by drying with sodium sulfate. After removing ethyl acetate by evaporation in vacuo, the residue was subjected to preparative TLC(n-hexane:ethyl acetate=2:1) to separate the title compound followed by crystallization from diethyl ether. 1H-NMR (CDCl3) δ 1.33 (6H, d, CH(CH3)2), 1.55 (3H, t, CH2CH3), 3.08 (1H,septet,CH), 4.17 (2H, q, NCH2), 6.48 (1H, s, H-3), 6.56-6.58 (1H, m, furan H-4′), 6.76 (1H, dd, furan H-5′), 7.54 (1H, d, H-8), 7.59 (1H, dd, H-7), 7.63 (1H, dd, furan H-3′), 8.34 (1H, d, H-5)
The following compounds have been produced in a manner analogous to that described in the preceding examples. 
















TABLE I





Com-







pound




m.p.


No.
R1
X
R3′
R4
(° C.)







A12
6-Br
H
H
CH3
166-168


A13
5-OH
H
CH3
CH3
282-283


A14
6-OH
H
CH3
CH3
>300 


A15
7-OH
H
CH3
CH3
>300 


A16
8-OH
H
CH3
CH3
240-242


A17
6-CH3
H
H
C2H5
169-170


A18
6-CH3
H
CH3
C2H5
167-170


A19
5-CH3O
H
CH3
CH3
141-142


A20
6-CH3O
H
CH3
CH3
154-156


A21
6-CH3O
3-CH3
H
C2H5
193-194




4-CH3O


A22
6-CH3O
3-CH3
H
C2H5
140-142




4-i-C3H7O


A23
6-CH3O
3-CH3
H
C2H5
144-145




4-i-C4H9O


A24
7-CH3O
H
CH3
CH3
188-191


A25
8-CH3O
H
CH3
CH3
131-133


A26
6-C2H5
H
CH3
C2H5
151-154


A27
6-C2H5O
H
H
CH3
156-159


A28
6-C2H5O
H
CH3
C2H5
165-167


A29
6-C3H7
H
CH3
CH3
127


A30
6-C3H7
R
CH3
C2H5
133-134


A31
6-C3H7O
H
CH3
CH3
162-163


A32
6-C3H7O
H
CH3
C2H5
136-140


A33
5-i-C3H7
H
CH3
CH3
153-155


A34
5-i-C3H7
H
CH3
C2H5
144


A35
6-i-C3H7
H
H
CH3
140-141


A36
6-i-C3H7
H
CH3
CH3
197-199


A37
6-i-C3H7
H
CH3
C2H5
159-165


A38
6-i-C3H7
H
CH3
i-C3H7
184-186


A39
6-i-C3H7
H
CH3O
CH3
169-173


A40
6-i-C3H7
H
C2H5
CH3
172


A41
6-i-C3H7
H
C2H5
C2H5
129-130


A42
6-i-C3H7
H
C3H7
CH3
102-103


A43
6-i-C3H7
H
C3H7
C2H5
oil


A44
6-i-C3H7
H
i-C3H7
CH3
177-179


A45
6-i-C3H7
H
i-C3H7
C2H5
148


A46
6-i-C3H7
H
C4H9
CH3
136-137


A47
6-i-C3H7
H
C4H9
C2H5
oil


A48
6-i-C3H7
H
C6H13
CH3
84-86


A49
6-i-C3H7
H
C6H13
C2H5
oil


A50
6-i-C3H7
H
C2H5OCO
CH3
164-165


A51
6-i-C3H7
H
CH3SO2
CH3
245-247


A52
6-i-C3H7
H
CN
CH3
250-251


A53
6-i-C3H7
H
CH3CO
CH3
169-171


A54
6-i-C3H7
3-Cl
CH3
C2H5
159-160


A55
6-i-C3H7
4-Cl
H
CH3
149-152


A56
6-i-C3H7
4-Cl
H
C2H5
172-173


A57
6-i-C3H7
4-Cl
CH3
CH3
231-232


A58
6-i-C3H7
4-Cl
CH3
C2H5
204-205


A59
6-i-C3H7
3-F
CH3
CH3
263


A60
6-i-C3H7
3-F
CH3
C2H5
174-175


A61
6-i-C3H7
3,4-diCl
H
CH3
207-210


A62
6-i-C3H7
3,4-diCl
CH3
CH3
268-270


A63
6-i-C3H7
3,4-diCl
H
C2H5
160-162


A64
6-i-C3H7
3,4-diCl
CH3
C2H5
197-198


A65
6-i-C3H7
3,4-diF
CH3
CH3
278-279


A66
6-i-C3H7
3,4-diF
CH3
C2H5
194-196


A67
6-i-C3H7
3-CF3
CH3
CH3
200-201


A68
6-i-C3H7
3-CF3
CH3
C2H5
179


A69
6-i-C3H7
4-CF3
CH3
CH3
>300 


A70
6-i-C3H7
4-CF3
CH3
C2H5
218-219


A71
6-i-C3H7
2-OH
H
CH3
>300 


A72
6-i-C3H7
3-OH
H
CH3
248-249


A73
6-i-C3H7
4-OH
H
CH3
>300 


A74
6-i-C3H7
4-OH
CH3
CH3
>300 


A75
6-i-C3H7
2-CH3
CH3
C2H5
157-159


A76
6-i-C3H7
3-CH3
CH3
CH3
181-183


A77
6-i-C3H7
3-CH3
CH3
C2H5
140-144


A78
6-i-C3H7
3-CH3O
CH3
C2H5
130-132


A79
6-i-C3H7
4-CH3
CH3
CH3
180-181


A80
6-i-C3H7
4-CH3
CH3
C2H5
171-172


A81
6-i-C3H7
4-CH3O
CH3
CH3
177-178


A82
6-i-C3H7
4-CH3O
CH3
C2H5
193-196


A83
6-i-C3H7
4-CH3O
CH3
C3H7
199-202


A84
6-i-C3H7
4-C2H5
CH3
CH3
193-194


A85
6-i-C3H7
4-C2H5
CH3
C2H5
148-150


A86
6-i-C3H7
4-C2H5O
CH3
CH3
169-170


A87
6-i-C3H7
4-C2H5O
CH3
C2H5
173-175


A88
6-i-C3H7
4-C3H7
CH3
CH3
181-183


A89
6-i-C3H7
4-C3H7
CH3
C2H5
88-91


A90
6-i-C3H7
4-C3H7O
CH3
CH3
164-166


A91
6-i-C3H7
4-C3H7O
CH3
C2H5
125-127


A92
6-i-C3H7
4-C3H11
CH3
CH3
159-160


A93
6-i-C3H7
4-C5H11
CH3
C2H5
110-113


A94
6-i-C3H7
4-C5H11O
CH3
CH3
137-138


A95
6-i-C3H7
4-C5H11O
CH3
C2H5
255-257


A96
6-i-C3H7
3-CH3
H
CH3
248-250




4-OH


A97
6-i-C3H7
3-CH3
H
CH3
209-210




4-CH3O


A98
6-i-C3H7
3-CH3
H
C2H5
128-129




4-CH3O


A99
6-i-C3H7
3-CH3
H
CH3
134-135




4-C2H5O


A100
6-i-C3H7
3-CH3
H
CH3
130-131




4-i-C3H7O


A101
6-i-C3H7
3-CH3O
H
CH3
293-295




4-OH


A102
6-i-C3H7
3-C2H5
H
CH3
155-157




4-CH3O


A103
6-i-C3H7
3-C2H5
H
CH3
147-150




4-i-C3H7O


A104
6-i-C3H7
3-C2H5
H
CH3
149-153




4-




CH3COO


A105
6-i-C3H7
3-i-C3H7
H
CH3
180-182




4-CH3O


A106
6-i-C3H7
2,3-diCH3
CH3
CH3
185-187


A107
6-i-C3H7
2,4-diCH3
CH3
CH3
151-152


A108
6-i-C3H7
2,4-diCH3
CH3
C2H5
121


A109
6-i-C3H7
2,5-diCH3
CH3
CH3
143-145


A110
6-i-C3H7
3,4-diCH3
CH3
CH3
154-156


A111
6-i-C3H7
3,4-diCH3
CH3
C2H5
119-121


A112
6-i-C3H7
3,5-diCH3
CH3
C2H5
151-155


A113
6-i-C3H7
3-OH
CH3
CH3
295




4-CH3


A114
6-i-C3H7
3-OH
CH3
CH3
227-228




4-CH3O


A115
6-i-C3H7
3-CH3
CH3
C2H5
158-160




4-CH3O


A116
6-i-C3H7
3-CH3
C2H5OCO
C2H5
179-180




4-CH3O


A117
6-i-C3H7
3-CH3O
CH3
CH3
166




4-CH3


A118
6-i-C3H7
3-CH3O
CH3
C2H5
164-166




4-CH3


A119
6-i-C3H7O
3-CH3
H
C2H5
177-178




4-CH3O


A120
6-i-C3H7O
3-CH3
H
C2H5
123-124




4-i-C3H7O


A121
7-i-C3H7
H
CH3
CH3
156-157


A122
7-i-C3H7
H
CH3
C2H5
142-144


A123
7-i-C4H9O
H
CH3
CH3
179-182


A124
6-C4H9
H
CH3
CH3
140


A125
6-C4H9
H
CH3
C2H5
85-86


A126
6-C4H9O
H
CH3
CH3
126-128


A127
6-C4H9O
H
CH3
C2H5
136-138


A128
6-i-C4H9
H
CH3
C2H5
121-125


A129
6-i-C4H9O
H
CH3
CH3
oil


A130
6-i-C4H9O
H
CH3
C2H5
106-107


A131
6-i-C4H9O
H
CH3
2-
97-101






butenyl


A132
6-i-C4H9O
H
CH3
benzyl
178-181


A133
6-i-C4H9O
3-CH3
H
CH3
167-168




4-CH3O


A134
6-i-C4H9O
3-CH3
H
C2H5
169-170




4-CH3O


A135
6-i-C4H9O
3-CH3
CH3
C2H5
180-182




4-CH3O


A136
6-i-C4H9O
3-CH3
H
C2H5
116-118




4-C4H9O


A137
6-C5H11
H
CH3
CH3
138-140


A138
6-C5H11
H
CH3
C2H5
94-96


A139
6-C5H11O
H
CH3
CH3
115-117


A140
6-i-C5H11
H
CH3
CH3
138-139


A141
6-i-C5H11
H
CH3
C2H5
101-103


A142
6-i-C5H11O
H
CH3
CH3
112-113


A143
6-i-C5H11O
H
CH3
C2H5
128-130


A144
6-C5H13
H
OH3
CH3
123-125


A145
6-C5H13
H
CH3
C2H5
oil


A146
6-C5H13O
H
CH3
CH3
100-102


A147
6-C5H13O
H
CH3
C2H5
96-98


A148
6-i-C5H13O
H
CH3
CH3
106-109


A149
6-C8H17
H
CH3
CH3
105-107


A150
6-C8H17
H
CH3
C2H5
oil


A151
6-cyclohexyl
H
CH3
CH3
221-222


A152
6-cyclohexyl
H
CH3
C2H5
154-156


A153
6-NO2
H
CH3
CH3
279







(dec)


A154
6-NH2
H
CH3
CH3
227


A155
6-(CH3)2N
H
CH3
CH3
179-183


A156
6-N-(2-dimethyl
H
CH3
CH3
methyl-



aminoethylamino



iodide







285







(dec)


A157
6-i-C4H9NH
H
CH3
CH3
183-186









A158
Compound No. 157  2HCl.1⁄2H2O
194




(dec)












A159
6-i-C4H9NH
H
CH3
C2H5
H2O







162


A160
6-i-C4H9NH
H
CH3
C2H5
HCl







183


A161
6-pyrrolidino
H
CH3
CH3
157-167


A162
6-pyrrolidino
H
CH3
C2H5
122-130


A163
6-piperazino
H
CH3
CH3
186-196


A164
6-piperazino
H
CH3
C2H5
186-189


A165
6-(4-methyl
H
CH3
C2H5
111-113



piperazino)


A166
6-(4-acetyl
H
CH3
CH3
220-225



piperazino)


A167
6-(4-acetyl
H
CH3
C2H5
200-204



piperazino)


A168
6-morpholino
H
CH3
CH3
241-243


A169
6-morpholino
H
CH3
C2H5
195-196


A170
6-C6H5
H
CH3
CH3
164-169


A171
6-C6H5
H
CH3
C2H5
192-194


A172
6-(3-pyridyl)
H
H
CH3
oil


A173
6-Cl
H
CH3
CH3
187-189


A174
6-Cl
H
CH3
C2H5
160-161


A175
6-F
H
CH3
CH3
192-193


A176
6-F
H
CH3
C2H5
193-196


A177
7-F
H
CH3
CH3
219-221


A178
5-Cl
H
CH3
CH3
207-208



6-i-C4H9O


A179
5-Cl
H
CH3
C2H5
174-176



6-i-C4H9O


A180
5-Cl
3-CH3
CH3
CH3
179-180



6-i-C4H9O


A181
5-Cl
3-CH3
CH3
C2H5
167-167



6-i-C4H9O


A182
5-F
H
CH3
CH3
172-173



6-i-C4H9O


A183
5-F
4-O2H5
CH3
CH3
205-207



6-i-C4H9O


A184
5-CH3
3-CH3
CH3
C2H5
165-167



6-CH3O
4-CH3


A185
5-CH3
3-CH3
CH3
C2H5
175-176



6-i-C3H7O
4-i-C3H7O


A186
5-CH3
H
H
CH3
127



6-i-C4H9O


A187
5-CH3
H
H
C2H5
182-184



6-i-C4H9O


A188
5-CH3
H
CH3
C2H5
154-156



6-i-C4H9O


A189
5-CH3
3-CH3
H
C2H5
185-186



6-i-C4H9O
4-CH3O


A190
5-CH3
3-CH3
CH3
CH3
150-151



6-i-C4H9O
4-CH3O


A191
5-CH3
3-CH3
CH3
C2H5
149



6-i-C4H9O
4-CH3O


A192
5-CH3
3-CH3
CH3
C2H5
169-171



6-i-C4H9O
4-i-C3H7O


A193
5-CH3
3-CH3
H
C2H5
114-115



6-i-C4H9O
4-i-C3H7O


A194
5-NH2
H
CH3
CH3
HCl



6-i-C4H9O



130-131


A195
5-i-C3H7
H
CH3
CH3
153-155



6-CH3O


A196
5-CH3O
H
CH3
CH3
130-131



6-i-C4H9O


A197
5-i-C4H9O
H
CH3
CH3
oil



6-F


A198
5-(N-methyl-N-
H
CH3
CH3
120-122



(2-dimethyl-



amino-



ethyl)amino)



6-F


A199
5,7-diF
H
CH3
CH3
218-220


A200
5,7-diCH3O
H
CH3
CH3
220


A201
5-i-C4H9O
H
CH3
CH3
120



7-F


A202
6,7-diF
H
CH3
CH3
194-197


A203
6-F
H
CH3
CH3
216-219



7-i-C4H9O


A204
6-F
H
CH3
CH3
189-194



7-piperidino


A205
6-F,7-(4-hydro-
H
CH3
CH3
>300 



xypiperidino)


A206
6-F
H
CH3
CH3
221-225



7-pyrrolidino


A207
6-F
H
CH3
CH3
251-252



7-morpholino


A208
6-F
H
CH3
CH3
223-226



7-piperazino


A209
6-F
H
CH3
CH3
202-205



7-(4-methyl-



piperazino)


A210
6-F
H
CH3
CH3
215-218



7-(4-acetyl-



piperadino)


A211
6-F,7-[N-methyl-
H
CH3
CH3
189-190



N-(2-hydroxy-



ethyl)amino


A212
6-OH
H
CH3
CH3
>300 



7-F


A213
6-OH
H
CH3
CH3
>300 



7-i-O3H7


A214
6-CH3O
H
CH3
CH3
210-213



7-F


A215
6-C2H5O
H
CH3
CH3
266-267



7-F


A216
6-C3H7O
H
CH3
CH3
198-200



7-F


A217
6-C4H9O
H
CH3
CH3
146-148



7-F


A218
6,7-OCH2O—
H
CH3
CH3
185-189


A219
6,7-
H
CH3
CH3
273-274



OC2H4N(CH3)—


A220
6,7-diCH3O
H
CH3
CH3
282-283


A221
6,7-diC2H5O
H
CH3
CH3
219-221


A222
6,7-diC3H7O
H
CH3
CH3
187-189


A223
6,7-di-i-C4H9O
H
CH3
CH3
218-220


A224
6-CH3O
H
CH3
CH3
202-206



7-C3H5


A225
6-CH3O
H
CH3
CH3
175-177



7-C3H7


A226
6-CH3O
H
CH3
CH3
174-177



7-i-C3H7


A227
6-CH3O
H
CH3
C2H5
133-134



7-i-C3H7


A228
6-CH3O
4-C2H5
CH3
CH3
172-175



7-i-C3H7


A229
6-CH3O
4-i-C3H7
CH3
CH3
182-183



7-i-C3H7


A230
6-CH3O
3-CH3
H
CH3
197-199



7-i-C3H7
4-CH3O


A231
6-CH3O
3-CH3
CH3
CH3
200



7-i-C3H7
4-CH3O


A232
6-CH3O
3-CH3
CH3
C2H5
170-171



7-i-C3H7
4-CH3O


A233
6-i-C4H9O
H
H
CH3
156-157



7-CH3


A234
6-i-C4H9O
H
CH3
CH3
202-204



7-CH3


A235
6-i-C4H9O
H
CH3
C2H5
142-144



7-CH3


A236
6-i-C4H9O
3-CH3
H
CH3
219-220



7-CH3
4-CH3O


A237
6-i-C4H9O
3-CH3
CH3
CH3
178-179



7-CH3
4-CH3O


A238
6-i-C4H9O
3-CH3
CH3
C2H5
196



7-CH3
4-CH3O


A239
6-CH3O
H
CH3
CH3
239-242



7-CH3H5O


A240
6-CH3O
H
CH3
CH3
215-222



7-C3H7O


A241
6-CH3O
H
CH3
CH3
213-216



7-i-C4H9O


A242
6-CH3O
H
CH3
CH3
210-213



7-CF3


A243
6-CH3O
H
CH3
CH3
229-231



7-cyclohexyloxy


A244
6-CH3O
H
CH3
CH3
216-218



7-C6H5O


A245
6-CH3O
H
CH3
CH3
>300 



7-(4-pyridyl)oxy


A246
6-CH3O
H
CH3
CH3
215-217



7-pyrrolidino


A247
6-CH3O
H
CH3
CH3
230-237



7-piperidino


A248
6-CH3O
H
CH3
CH3
246-248



7-morpholino


A249
6-CH3O
H
CH3
CH3
234-236



7-thiomorpholino


A250
6-CH3O
H
CH3
CH3
217-220



7-piperazino


A251
6-CH3O
H
CH3
CH3
231-233



7-(4-methyl-



piperazino)


A252
6-CH3O
H
CH3
CH3
247-249



7-(4-acetyl-



piperazino)


A253
6-CH3O
H
CH3
CH3
252-254



7-pyrrolyl


A254
6-CH3O
H
CH3
CH3
180-182



7-(1-pyrazolyl)


A255
6-CH3O
H
CH3
CH3
254-257



7-(1-imidazolyl)


A256
6-CH3O
H
CH3
CH3
241-245



7-(1-triazolyl)


A257
6-C2H5O
H
CH3
CH3
128-130



7-i-C3H7


A258
6-i-C3H7O
H
CH3
CH3
126-128



7-i-C3H7


A259
6-i-C3H7O
H
CH3
CH3
126-128



7-i-C3H7


A260
6-i-C4H9O
H
CH3
CH3
241-242



7-CH3O


A261
6-i-C4H9O
H
CH3
CH3
134-137



7-i-C3H7


A262
6-i-C4H9O
H
CH3
CH3
176-177



7-CF3


A263
6-i-C4H9O
H
CH3
CH3
198-203



7-pyrrolidino


A264
6-i-C4H9O
H
CH3
CH3
224-225



7-piperidino


A265
6-i-C4H9O
H
CH3
CH3
216-219



7-morpholino


A266
6-acetoxy
H
CH3
CH3
139



7-CH3


A267
6-hydroxy-
H
CH3
CH3
>300 



carbonyloxy



7-CH3


A268
6-ethoxy-
H
CH3
CH3
169-170



carbonyloxy



7-CH3


A269
6-hydroxy-
H
CH3
CH3
>300 



carbonylmethoxy



7-CH3


A270
6-i-C3H7
H
CH3
C2H5
232



7-CH3O


A271
6-ethoxy-
H
CH3
CH3
183-184



carbonyloxy



7-i-C3H7


A272
7,8-diF
H
CH3
CH3
226-228


A273
7-i-C3H7
H
CH3
CH3
144-145



8-CH3O


A274
7-i-C3H7
4-C2H5
CH3
CH3
152-155



8-CH3O


A275
7-i-C4H9
H
CH3
CH3
oil



8-F


A276
5,7-diCl
H
CH3
CH3
223-226



8-CH3O


A277
5,7-diCl
H
CH3
C2H5
180-182



6-CH3O


A278
5,7-diCl
H
CH3
CH3
196-199



6-i-C4H9O


A279
5,7-diCl
H
CH3
C2H5
193-194



6-i-C4H9O


A280
5-Cl
H
CH3
CH3
184-186



6-CH3O



7-i-C3H7


A281
5-Cl
H
CH3
C2H5
154-155



6-CH3O



7-i-C3H7


A282
5-Cl
H
CH3
CH3
188-189



6- i-C4H9O



7-CH3


A283
5-Cl
H
CH3
C2H5
205-207



6-i-C4H9O



7-CH3


A284
5-Cl
H
CH3
C2H5
183-186



6-i-C4H9O



7-Cl


A285
5,7-diCH3
H
H
CH3
170-172



6-i-C4H9O
H


A286
5,7-diCH3
H
CH3
CH3
158-160



6-i-C4H9O


A287
5,7-diCH3
H
CH3
C2H5
175-178



6-i-C4H9O


A288
5,7-diCH3
3-CH3
CH3
CH3
155-157



6-i-C4H9O
4-CH3O


A289
5,7-diCH3
3-CH3
CH3
C2H5
154-157



6-i-C4H9O
4-CH3O


























TABLE II





Com-







pound




m.p. 


No.
R1
R2′
R3′
R4
(° C.)







A290
6-C3H7
CH3
C6H5
CH3
241-245


A291
6-i-C3H7
CH3
CH3
CH3
188-189


A292
6-i-C3H7
CH3
C4H9
CH3
106-107


A293
6-i-C3H7
CH3
C4H9
C2H5
oil


A294
6-i-C3H7
C3H7
H
CH3
132-134


A295
6-i-C3H7
2-pyridyl
H
CH3
124-126


A296
6-i-C3H7
2-pyridyl
H
C2H5
144-146


A297
6-i-C3H7
3-pyridyl
H
CH3
164-166


A298
6-i-C3H7
3-pyridyl
H
C2H5
148-149


A299
6-i-C3H7
3-pyridyl
CH3
CH3
242-243


A300
6-i-C3H7
4-pyridyl
H
CH3
192-193


A301
6-i-C3H7
4-pyridyl
H
C2H5
229-230


A302
6-i-C3H7
2-pyradinyl
H
C2H5
 94-96


A303
6-i-C3H7
2-furyl
H
CH3
 86-88


A304
6-i-C3H7
2-furyl
H
C2H5
 70-73


A305
6-i-C3H7
N—CH3-
H
C2H5
101-104




2-pyrrolyl


A306
6-i-C3H7
N—CH3-
H
CH3
173-176




3-pyrrolyl


A307
6-i-C3H7
N—CH3-
H
C2H5
132-134




3-pyrrolyl


A308
6-i-C3H7
2-thienyl
H
CH3
111-113


A309
6-i-C3H7
2-thienyl
H
C2H5
 95-96


A310
6-i-C3H7
2-thienyl
CH3
CH3
136-137


A311
6-i-C3H7
2-thienyl
CH3
C2H5
169-173


A312
6-i-C3H7
3-thienyl
H
CH3
164-166


A313
6-i-C3H7
3-thienyl
H
C2H5
118-120


A314
6-i-C3H7
5-CH3-
H
CH3
132




2-thienyl


A315
6-i-C3H7
5-CH3-
H
C2H5
121-122




2-thienyl


A316
6-i-C3H7
5-Br-2-thienyl
H
CH3
183-185


A317
6-i-C3H7
5-Br-2-thienyl
H
C2H5
oil


A318
5-CH3
2-thiernyl
CH3
CH3
111-112



6-i-C4H9O


A319
6-i-C3H7
2-thiazolyl
H
C2H5
 91-93


A320
6-i-C3H7
C6H5
CH3
C6H5
225


A321
6-i-C3H7
C6H5
CH3
2-F—C6H4
205-207


A322
6-i-C3H7
C6H5
CH3
3-F—C6H4
248-251


A323
6-i-C3H7
C6H5
CH3
4-F—C6H4
224-229


A324
6-i-C3H7
C6H5
CH3
4-Cl—C6H4
233-235


A325
6-i-C3H7
C6H5
CH3
4-CH3—C6H4
203-205


A326
6-i-C3H7
C6H5
CH3
4-CH3O—
204-208






C6H4









Part B. 




Example 7
5-Ethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one(Compound B2)
To a 1.6M solution of n-butyl lithium in hexane (6.6 mL, 10.5 mmol) was added tetramethylethylenediamine (1.58 mL, 10.5 mmol) under argon atomosphere at room temperature with stirring. To this was added with ice cooling a solution of 1-indanone (1.38 g, 10.5 mmol) in anhydrous THF followed by stirring at room temperature for 1 hour. After ice cooling the mixture, a solution of 1-ethyl-6-isopropylisatoic anhydride prepared in step 1 of Example 6 (1.22 g, 5.2 mmol) in anhydrous THF was added dropwise thereto. The mixture was stirred at room temperature overnight and then duluted with saturated aqueous solution of ammonium chloride. The organic layer was separated and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated sodium chloride solution and dried with sodium sulfate followed by evaporating to remove the solvent. The residue was purified by silica gel-chromatography (chloroform) and crystallization from diethyl ether to obtain the desired compound. 1H-NMR (CDCl3) δ 1.32 (6H, d, CH(CH3)2), 1.70 (3H, t, CH2CH3), 3.09 (1H, septet, CH), 3.91 (2H, s, H-11), 4.71 (2H, q, NCH2), 7.47-7.94 (6H, m, Ar—H), 8.44 (1H, s, H-9)
Example 8
2.5-Diethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one (Compound B9)
Step 1. 3-Chloro-1-(4-ethylphenyl)-1-propanone
To a solution of anhydrous aluminum chloride (20 g, 0.15 mmol) in nitrobenzene(50 mL) was added dropwise a solution (30 mL) of ethylbenzene(13.5 mL, 0.11 mmol) and 3-chloropropionyl chloride (25 g, 0.20 mmol) in nitrobenzene. The mixture was stirred at room temperature for 3 hours and then poured into ice-water (600 mL) containing 100 mL of concentrated hydrochloric acid followed by extraction with diethyl ether. The combined organic layers were washed with water and saturated sodium chloride solution, dried with sodium sulfate and evoparated to remove diethyl ether and nitrobenzene under reduced pressure. The residue was crystallized from n-hexane to give the title compound (9.1 g, 42.1%). 1H-NMR (CDCl3) δ 1.26 (3H, t, CH2CH3), 2.72 (2H, q, CH2CH3), 3.44 (2H,t,COCH2), 3.93 (2H, t, CH2Cl), 7.31 (2H, d, Ar—H), 7.89 (2H, d, Ar—H)
Step 2. 5-Ethyl-1-indanone
3-Chloro-1-(4-ethylphenyl)-1-propanone (9.1 g, 46.3 mmol) was dissolved in 50 mL of conc. H2SO4 and heated at 100° C. for 30 minutes with stirring. The reaction mixture was poured onto crashed ice (500 g). The resulting precipitate was filtered off, washed with water and then dissolved in diethyl ether. The solution was washed with water and saturated sodium chloride solution, dried with sodium sulfate and evaporated to dryness. The title compound was obtained by crystallizing the residue from n-hexane. 1H-NMR (CDCl3) δ 1.28 (3H, t, CH2CH3), 2.67-2.70 (2H, m,H-3), 2.74 (2H, q, CH2CH3), 3.11 (2H, dd, H-2), 7.21 (1H, d, Ar—H), 7.30 (1H, s, H-4), 7.68 (1H, d, Ar—H)
Step 3. 2,5-Diethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one
To a 1.53M solution of n-butyl lithium in hexane (13.2 mL, 20.2 mmol) was added TMEDA (3.1 mL, 20.2 mmol) under argon atmosphere at room temperature with stirring. To this was added with ice cooling a solution of 5-ethyl-1-indanone(3.24 g,20.2 mmol) in anhydrous THF followed by stirring at room temperature for 1 hour. After ice cooling the mixture, a solution of 1-ethyl-6-isopropylisatoic anhydride (Example 6, step 1) (2.35 g, 10.1 mmol) in anhydrous THF was added dropwise thereto. The mixture was stirred at room temperature overnight and diluted with saturated aqueous solution of ammonium chloride. The orgaic layer was separated and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated sodium chloride solution and dried with sodium sulfate. After removing the solvent, the residue was purified by silica gel-chromatography (chloroform:acetone=20:1) and crystallization from diethyl ether to give the desired compound. 1H-NMR (CDCl3) δ 1.32 (3H, t, CH2CH3), 1.34 (6H, d, CH(CH3)2), 1.70 (3H, t, NCH2CH3), 2.78 (2H, q, CH2CH3), 3.10 (1H, septet, CH), 3.91 (2H, s, H-11), 4.72 (2H, q, NCH2), 7.30-7.85 (5H, m, Ar—H), 8.45 (1H, s, H-9)
Example 9
2-Ethyl-9-isopropyl-6,12-dihydrobenzo[c]acridin-7 (5H)-one (Compund B25)
To a 1.6M solution of n-butyl lithium in hexane (1.6 mL, 2.6 mmol) was added TMEDA (0.4 mL, 2.6 mmol) under argon atmosphere at room temperature with stirring. To this was added with ice cooling a solution of 1-tetralone (0.38 g, 2.6 mmol) in anhydrous THF followed by stirring for 1 hour under ice cooling. Thereafter, a solution of 1-ethyl-6-i-propylisatoic anhydride (0.3 g, 1.3 mmol) in anhydrous THF was added dropwise followed by stirring at room temperature for 1.5 hours. The reaction mixture was diluted with saturated aqueous solution of ammonium chloride. The organic layer was separated and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium chloride solution and dried with sodium sulfate. After removing the solvent, the residue was purified by silica gel-chromatography (chloroform) followed by crystallization from petroleum ether to give the desired compound. 1H-NMR (CDCl3) δ 1.15 (3H, t, NCH2CH3), 1.33 (6H, d, CH(CH3)2), 2.79-2.86 (4H, m, CH2CH2), 3.07 (1H, septet, CH), 4.62 (2H, q, NCH2), 7.32-7.60 (6H, m, Ar—H), 8.33 (1H, d, H-8)
The following compounds have been synthesized in a manner analogous to Examples 7-9. 




The numbering of various substituents are those of respective fused ring systems, namely indeno[1,2-b]quinoline(x=1),benzo[c]acridine(x=2) and benzo[6,7]cyclohepta[1,2-b]quinoline, respectively.












TABLE III





Com-







pound


No.
x
R4
R5
R1







B1
1
CH3
H
8-i-C3H7
249







(dec)


B2
1
C2H5
H
8-i-C3H7
152-155


B3
1
Compound


175-177




B2,




HCl salt


B4
1
C2H5
H
8-CH3O
205-207


B5
1
C2H5
H
6-F
241-243


B6
1
CH3
H
8-CH3O
297






9-i-C3H7
(dec)


B7
1
C2H5
H
8-CH3O
217-218






9-i-C3H7


B8
1
CH3
2-C2H5
8-i-C3H7
220







(dec)


B9
1
C2H5
2-C2H5
8-i-C3H7
205


B10
1
C2H5
2-CH3O
8-i-C3H7
202-204


B11
1
CH3
2-CH3O
8-i-C4H9
218


B12
1
C2H5
2-CH3O
8-i-C4H9
216-217


B13
1
CH3
2-CH3O
8-i-C3H7
215-222


B15
1
C2H5
2-CH3O
8-i-C4H9
189-190


B16
1
CH3
2-Cl
8-i-C3H7
265







(dec)


B17
1
C2H5
2-Cl
8-i-C3H7
186







(dec)


B18
1
CH3
2-Br
8-i-C3H7
280







(dec)


B19
1
C2H5
2-Br
8-i-C3H7
225







(dec)


B20
1
C2H5
2-OCH3
8-i-C3H7
217





3-CH3

(dec)


B21
1
CH3
2,3-diCH3O
8-i-C3H7
253-254


B22
1
C2H5
2,3-diCH3O
8-i-C3H7
208


B23
1
C2H5
1,2-diCl
8-i-C3H7
235







(dec)


B24
2
CH3
H
9-i-C3H7
199-203


B25
2
C2H5
H
9-i-C3H7
oil


B26
2
CH3
H
9-i-C4H9O
160


B27
2
C2H5
H
9-i-C4H9O
 61


B28
3
CH3
H
10-i-C3H7
167


B29
1
4-FC6H4
2-CH3O
8-i-C3H7
285







(dec)


B30
1
4-FC6H4
2-C2H5
8-i-C3H7
270







(dec)


B31
1
C6H4
2-CH3O
8-i-C3H7
208-210


B32
1
C2H5
2-CH3O
7-i-C3H7
224-225






8-CH3O


B33
1
C2H5
2-C2H5
7-i-C3H7
210-212






8-CH3O


B34
1
C2H5
H
7,9-diCH3
184






8-i-C4H9


B35
1
C2H5
2-CH3O
7,9-diCH3
203-204






8-i-C4H9


B36
1
C2H5
2-C2H5
7,9-diCH3
140






8-i-C4H9


B37
1
C2H5
1,3-diCH3
8-i-C3H7
201





2-CH3O


B38
1
4-FC6H4
2-C2H5
7-i-C3H7
281






8-CH3O
(dec)


B39
1
C2H5
H
8-i-C4H9O
239-240






9-CH3









Part C. 




Example 10
5-Ethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (Compound C47)
Under argon atmosphere, 60% sodium hydride (82 mg, 2.0 mmol) was added to a solution of 1,3-indandione (300 mg,2.0 mmol) in anhydrous DMF with ice cooling and stirring followed by stirring for additional 1 hour. To the mixture was added dropwise a solution of 1-ethyl-6-isopropylisatoic anhydride (238 mg,1.0 mmol) in anhydrous DMF followed by stirring at 60° C. for 3 hours. The reaction mixture was poured into ice-water. The resulting precipitate was filtered off, washed with water and dissolved in chloroform. The chloroform solution was washed with saturated sodium chloride solution and dried with sodium sulfate followed by evaporation to remove chloroform. The title compound was obtained by crystallizing from diethyl ether. 1H-NMR (CDCl3) δ 1.30 (6H, d, CH(CH3)2, 1.73 (3H, t, NCH2CH3), 3.03 (1H, septet, CH), 4.69 (2H, q, NCH2), 7.46-7.71 (6H, m, Ar—H), 8.33 (1H, s, H-9)
Example 11
5-Ethyl-8-isopropyl-11-hydroxyimino-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one (Compound C48)
5-Ethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (300 mg, 0.95 mmol) was dissolved in a solution of hydroxylamine hydrochloride (525 mg, 7.6 mmol) and triethylamine (0.5 mL) in 20 mL of ethanol. The solution was refluxed overnight and then concentrated dryness. The residue was diluted with water and extracted with chloroform twice. The combined organic layers were washed with saturated sodium chloride solution, dried with sodium sulfate followed by evaporation to remove the solvent. The title compound was obtained by subjecting the resulting residue to silica gel-chromatography (chloroform:actone=20:1) and then to crystallization from diethyl ether. 1H-NMR (CDCl3) δ 1.32 (6H, d, CH(CH3)2, 1.73 (3H, t, NCH2CH3), 3.03 (1H, septet, CH), 4.79 (2H, q, NCH2), 7.41-8.00 (6H, m, Ar—H), 8.25 (1H, s, H-9), 15.31 (1H, s, N═OH)
Example 12
5-Ethyl-8-isopropyl-11-hydroxy-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one (Compound C43)
To an ethanolic solution of 5-ethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (500 mg, 1,58 mmol) was added sodium borohydride (62 mg, 1.64 mmol) in portions followed by stirring at room temperature for 1 hour. After removing ethanol, the reaction mixture was diluted with water and extracted with chloroform twice. The combined organic layers were washed with saturated sodium chloride solution and dried with sodium sulfate followed by evaporating to remove chloroform. The title compound was obtained by crystallizing the residue from acetone-diethyl ether mixture. 1H-NMR (CDCl3) δ 1.35 (6H, d, CH(CH3)2), 1.72 (3H, t, NCH2CH3), 3.11 (1H, septet, CH), 4.79 (2H, q, NCH2), 5.86 (1H, s, H-11), 7.52-7.63 (3H, m, Ar—H), 7.85 (1H, dd, H-9)
Example 13
5-Ethyl-8-isopropyl-11-hydroxy-11-phenyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one (Compound C45)
2M solution of phenyl magnesium bromide in THF (1.07 mL, 1.87 mmol) was dissolved in anhydrous methylene chloride. To this solution was added dropwise a solution of 5-ethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (500 mg, 1.58 mmol) in anhydrous methylene chloride with ice cooling and stirring followed by stirring at room temperature overnight. The reaction mixture was treated with 10% hydrochloric acid. The organic layer was separated, washed sequentially with diluted hydrochloric acid and saturated sodium chloride solution and dried with sodium sulfate followed by evaporation to remove methylene chloride. The title compound was isolated by subjecting the residue to silica gel-chromatography (chloroform) and crystallization from diethyl ether. 1H-NMR (CDCl3) δ 1.30 (6H, d, CH(CH3)2), 1,79 (3H, t, NCH2CH3), 3.05 (1H, septet, CH), 4.81 (2H, q, NCH2), 5.18 (1H, s, H-11), 7.16-7.64 (10H, m, Ar—H), 7.96 (1H, d, H-6), 8.37 (1H, d, H-9)
Example 14
5-Ethyl-8-isopropyl-11-phenyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one (Compound C44)
To a mixture of trimethylsilyl chloride (0.19 mL, 1.5 mmol), sodium iodide (224 mg, 1.5 mmol) and acetonitrile (61 mg, 1.5 mmol) was added dropwise a solution of 5-ethyl-8-isopropyl-11-hydroxy-11-phenyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one in 1,2-dichloroethane with stirring at room temperature. The mixture was stirred at 50° C. overnight followed by allowing to cool to room temperature. The reaction mixture was treated diluted aqueous solution of sodium sulfite. The separated organic layer was washed with water four times and then with saturated sodium chloride solution followed by drying with sodium sulfate. After removing the solvent, the residue was purified by silica gel-chromatography (chloroform) followed by crystallization from diethyl ether to give the title compound. 1H-NMR (CDCl3) δ 1.30 (6H, d, CH(CH3)2), 1.79 (3H, t, NCH2CH3), 3.05 (1H, septet, CH), 4.81 (2H, q, NCH2), 5.18 (1H, s, H-11), 7.16-7.64 (10H, m, Ar—H), 7.96 (1H, d, H-6), 8.37 (1H, d, H-9)
Example 14
5-Ethyl-8-methoxy-9-methyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (Compound C60)
Step 1. 3-Methyl-4-methoxynitrobenzene
A solution of 2-fluoro-5-nitrotoluene (7.0 g, 45 mmol) in anhydrous DMF was added to a 28% methanolic solution of sodium methoxide (10.45 g, 54 mmol) under ice-cooling with stirring. The reaction mixture was stirred at room temperature overnight and then poured into ice water. The resulting precipitate was filtered off and dissolved in diethyl ether. This solution was washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated to dryness to give the desired compound. 1H-NMR (CDCl3) δ 2,27 (3H, s, CH3), 3.94 (3H, s, OCH3), 6.87 (1H, d, H-5), 8.03 (1H, d, H-2), 8.11 (1H, dd, H-6)
Step 2. 2-Bromo-4-methoxy-5-methylaniline
To a solution of 3-methyl-4-methoxynitrobenzene(7.59 g, 45 mmol) in ethanol was added-iron powder (35 g), water(5 mL) and concentrated hydrochloric acid (0.4 mL). The mixture was refluxed for 1 hour and then filtered while hot. The filtrate was concentrated to dryness. The residue was dissolved in chloroform. The chloroform solution was dried with sodium sulfated and evaporated to give 3-methyl-4-methoxyaniline (7.59 g). To a solution of this compound (6.17 g, 45 mmol) in acetic acid (55 mL) were added dropwise acetic anhydride (4,4 mL, 46 mmol) at room temperature with stirring and then bromine(2,4 mL, 46 mmol) at 50° C. with stirring. The reaction mixture was stirred at the same temperature for 2 hours and poured into ice-water. The resulting precipitate was filtered off, washed with water and dissolved in ethyl acetate. This solution was washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated to dryness to give 2-bromo-4-methoxy-5-methylacetanilide as a crude product. Crystallization from diethyl ether gave pure product (8.27 g).
This product was dissolved in ethanol and concentrated hydrochoric acid (26 mL) was added thereto. The mixture was refluxed for 2 hours and then concentrated to dryness. The residue was made weak alkaline with sodium hydroxide. The resulting precipitate was filtered off, washed with water and dried under reduced pressure to give the desired compound. 1H-NMR (CDCl3) δ 2.11 (3H, s, CH3), 3,74 (3H, s, OCH3), 3.74 (2H, m, NH2), 6.61 (1H, d, Ar—H), 6.87 (1H, s, Ar—H)
Step 3. 5-Methyl-6-methoxy-8-bromoisatoic Anhydride
The title compound was prepared from 2-bromo-4-methoxy-5-methylaniline via 4-methyl-5-methoxy-7-bromoisatin in a manner analogous to that described in Example 5.
Step 4. 1-Ethyl-5-methyl-6-methoxyisatoic Anhydride
5-methyl-6-methoxy-8-bromoisatoic anhydride (1,39 g, 4.8 mmol) in DMF was hydrogenated in the presence of 5% Pd—C overnight. After filtering, the reaction mixture was concentrated to dryness and dissolved in ethyl acetate. This solution was washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated to dryness to give 5-methyl-6-methoxyisatoic anhydride. Reaction of this compound with ethyl iodide in the presence of sodium hydride gave the title compound.
Step 5. 5-Ethyl-8-methoxy-9-methyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione
1-Ethyl-5-methyl-6-methoxyisatoic anhydride was reacted with 1,3-indandione as in Example 10 to give the desired compound. 1H-NMR (CDCl3) δ 1.70 (3H, t, NCH2CH3), 2.83 (3H, s, CH3), 3.88 (3H, s, OCH3), 4.64 (2H, q, NCH2), 7.18-7.69 (6H, m, Ar—H)
Example 15
5-Ethyl-8-isobutoxy-9-methyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (Compound C61)
To a solution of boron tribromide (0.3 mL, 3,3 mmol) in methylene chloride was added dropwise a solution of 5-ethyl-8-methoxy-9-methyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione(325 mg, 1.0 mmol) in methylene chloride under ice cooling with stirring followed by stirring at room temperature overnight. The reaction mixture was poured into a 10% aqueous solution of sodium hydroxide. The aqueous layer was acidified with hydrochloric acid to yield a precipitate. This precipitate was filtered off, washed with water and dried under reduced pressure to give the corresponding 8-hydroxy compound (331 mmg, 100%). This product (331 mg, 1.0 mmol) was dissolved in anhydrous DMF and 60% sodium hydride (48 mg, 1.2 mmol) was added thereto at room teperature with stirring.After stirring for 1 hour, the reaction mixture was allowed to react with isobutyl bromide (0.1 mL, 1.5 mmol) added thereto at 60° C. overnight with stirring. The reaction mixture was concentrated to dryness and the residue was dissolved in chloroform. The chloroform solution was washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated to dryness. The residue was purifie by silida gel-chromatography (chloroform:methanol=30:1) to obtain the desired compound. 1H-NMR (CDCl3) δ 1.08 (6H, d, OCH2CH(CH3)2), 1.67 (3H, t, NCH2CH3), 2.13 (1H, m,OCH2CH(CH3)2), 2.80 (3H, s, CH3), 3.72 (2H, d, OCH2CH(CH3)2), 4.64 (2H, q, NCH2), 7.10-7.63 (6H, m, Ar—H)
Example 16
5-Ethyl-8-isobutoxy-9-methyl-11-hydroxy-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one (Compound C62)
5-Ethyl-8-isobutoxy-9-methyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione was treated as in Example 12 to give the title compound. 1H-NMR (CDCl3) δ 1.10 (6H, d, OCH2CH(CH3)2), 1.69 (3H, t, NCH2CH3), 2.17 (1H, m,OCH2CH(CH3)2), 3.00 (3H, s, CH3), 3,81 (2H, d, OCH2CH(CH3)2), 4.31 (1H, s, H-11), 4.65 (2H, q, NCH2), 5,80 (1H, s, OH), 7.28-7.74 (6H, m, Ar—H)
Starting from 5-ethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (Compound C47), the following compound have been prepared using known methodology.
5-Ethyl-8-isopropyl-11-methyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one (Compound C40) mp 152-154;
5-Ethyl-8-isopropyl-11-amino-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one dihydrochloride (Compound C41), mp 200° C. (decomp);
5-Ethyl-8-isoproypl-11-methoxyimino-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one (Compound C49) mp 150° C.
5-Ethyl-8-isopropyl-11-acetylamino-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one (Compound C42), mp215° C. (decomp); and
5-Ethyl-8-isopropyl-11-methoxy-11-phenyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one, (Compound C46), mp 237-239. 




Example 17
10-Ethyl-7-isopropyl-2-methyl-5,10-dihydro-4H-thieno[3′,2′:4,5]cyclopenta[1,2-b]quinolin-5-one (Compound D51)
Step 1. 3-Chloro-1-(5-methyl-2-thienyl)-1-propanone
To a suspension of anhydrous aluminum chloride (4 g,0.03 mol) in nitrobenzene (10 mL) was added dropwise a solution of 2-methylthiophene (2.0 g, 0.02 mol) and 3-chloropropionyl chloride (3.8 g, 0.20 mol) in nitrobenzene (10 mL). After stirring for 3 hours, the reaction mixture was poured into ice-water (200 mL) containing concentrated hydrochloric acid (20 mL) followed by extraction with diethyl ether. The orgaic layer was sequentially washed with water and saturated sodium chloride solution dried with sodium sulfate and evaporated to remove diethyl ether. The residue was further evaporated under reduced pressure to remove nitrobenzene and purified by silica gel-chromatography (hexane:ethyl acetate=19:1) to give the desired compound (2.5 g, 66.2%). 1H-NMR (CDCl3) δ 2.54 (3H, s, CH3), 3.32 (2H, t, CH2Cl), 3,89 (2H,t,COCH2), 6.81-6.83 (1H, m,H-4), 7.56 (1H, d, H-3)
Step 2. 2-Methyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one
3-Chloro-1-(5-methyl-2-thienyl)-1-propanone (2,5 g,13.2 mmol) was heated in concentrated sulfuric acid (20 mL) at 100° C. for 50 minutes with stirring. The reaction mixture was gradually poured into ice-water (200 g) and extracted with diethyl ether. The organic layer was sequnetially washed with water and saturated sodium chloride solution, dried with sodium sulfate and evaporated to dryness. The residue was purified by silica gel-chromatography (chloroform) to give the desired compound.
1H-NMR (CDCl3) δ 2.57 (3H, s, CH3), 2.87-2.97 (4H, m,COCH2CH2), 6.75 (1H, s, H-3)
Step 3. 10-Ethyl-7-isopropyl-2-methyl-5,10-dihydro-4H-thieno[3′,2′:4,5]cyclopenta[1,2-b]quinolin-5-one
To a 1.53M solution of n-butyl lithium in hexane (0.47 mL, 0.72 mmol) were added under argon atmosphere TMEDA (0.11 mL, 0.72 mmol) at room temperature and then 2-methyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one (0.11 g, 0.72 mmol) in anhydrous THF dropwise with ice cooling and stirring. The reaction mixture was stirred at room temperature for 1 hour and ice-cooled again. To this was added dropwise a solution of 1-ethyl-6-isopropylisatoic anhydride (Example 6, step 1) (0.11 g, 0.48 mmol) in anhydrous THF. The reaction mixture was stirred at room temperature for 2 hours and diluted with saturated aqueous solution of ammonium chloride. The organic layer was concentrated to dryness and the residue was dissolved in ethyl acetate. This solution was washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated again. The residue was subjected to silica gel-chromatography (chloroform: acetone=9:1) and crystallization from diethyl ether to give the title compound. 1H-NMR (CDCl3) δ 1.33 (6H, d, CH(CH3)2), 1.58 (3H, t, CH2CH3), 2.64 (3H, s, CH3), 3.10 (1H, septet, CH), 3,78 (2H, s, H-4), 4,49 (2H, q, NCH2), 6.97 (1H, s, H-3), 7.49 (1H, d, H-9), 7.56 (1H, dd, H-8), 8.45 (1H, d, H-6)
The following compounds have been synthesized in a manner analogous to that described in Example 17.
10-Ethyl-7-isopropyl-5,10-dihydro-4H-thieno[3′,2′:4,5]cyclopenta[1,2-b]quinolin-5-one (Compound D50), mp 168-169° C.
10-Ethyl-7-isopropyl-3-methyl-5,10-dihydro-4H-thieno[3′,2′:4,5]cyclopenta[1,2-b]quinolin-5-one (compound D52), mp 195° C. (decomp); and
4-Ethyl-7-isopropyl-1-methyl-4,9-dihydro-10H-pyrrolo[2′,3′:4,5]cyclopenta[1,2-b]quinolin-9-one (Compound D53), mp 91-93° C.
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 2.0×104 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 CO2 incubator to form monolayer. The growth medium in the plates was removed and a serial 0.5 log10 dilutions of the test compound in 50 μl 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 50 μl 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 calorimetric 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 μl 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 18 hr. 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 (IC50) 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: [(AT)v−(Ac) v/(Ac)mock−(Ac)v]×100%, where (AT)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 (CC50), 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.
A majority of the compounds of the present invention exhibited anti-picornavirus activities as shown in table IV-VI.







TABLE IV







in vitro Anti-picornavirus activity









IC50(μg/ml)














Com-









pound
Polio 1
Echo 11
CA7
CB4
HRV1B
HRV2
HRV89

















A30
1.0
0.42
1.2
1.8
1.6
0.48
1.0


A32
0.93
0.40
1.9
>3.3
1.0
0.55
0.77


A37
1.1
0.91
3.8
6.7
1.0
0.83
0.54


A60
1.1
0.52
2.5
2.8
0.59
0.52
1.1


A61
0.73
0.40
>4
>4
0.64
0.65
0.38


A78
1.3
1.2
7.1
2.6
5.6
1.7
2.9


A81
0.78
0.52
0.78
2.2
1.7
0.86
0.55


A97
0.54
0.3
2.1
1.4
0.58
0.61
0.14


A98
0.66
0.26
2.9
1.2
0.78
0.42
0.36


A99
0.55
0.20
1.8
1.1
0.63
0.50
0.14


A100
0.57
0.24
4.5
1.4
0.85
0.43
0.20


A122
1.2
0.54
6.9
5.5
0.59
0.43
0.35


A130
0.86
0.32
0.17
>4
0.90
0.65
0.72


A157
0.59
0.27
3.8
4.9
1.0
0.56
1.3


A159
0.51
0.26
2.7
3.0
0.78
0.48
0.73


A160
0.55
0.27
2.7
2.9
0.73
0.45
0.78


A169
4.3
1.1
>50
18
8.2
1.0
5.4


A171
0.52
0.22
1.9
2.0
0.43
0.76
0.39


A179
0.29
0.20
2.4
1.2
0.86
0.87
0.37


A181
0.39
0.24
2.4
1.8
1.6
0.94
0.46


A186
0.67
0.27
3.0
1.2
1.1
>1.7
0.26


A187
0.53
0.21
3.0
0.99
0.71
0.57
0.15


A188
0.31
0.27
1.2
1.1
0.81
0.33
0.25


A190
0.58
0.23
3.2
2.4
2.0
0.57
0.28


A191
0.40
0.19
2.5
1.6
1.3
0.15
0.20


A194
0.58
0.45
1.7
1.3
0.05
0.49
0.18


A196
1.1
0.44
9.7
1.9
5.9
1.8
0.86


A226
0.93
0.33
9.7
>3.3
1.6
0.73
<0.033


A234
0.89
0.25
3.8
2.5
1.0
0.26
0.32


A235
0.72
0.27
2.8
2.9
0.75
0.24
0.35


A237
1.1
0.40
>4
2.9
2.0
0.29
0.46


A258
0.62
0.23
4.9
>1.6
0.62
0.45
0.66


A285
0.69
0.2
3.1
1.9
0.68
0.18
0.46


A286
1.3
0.57
>5
1.4
0.87
0.23
0.61


A296
5.1
1.7
20
17
4.5
2.0
4.8


A303
1.4
0.83
6.5
3.6
1.4
0.97
1.9


A304
0.80
0.35
3.6
1.9
0.76
0.34
0.90


A306
0.83
0.49
2.9
2.1
0.89
0.73
0.88


A307
0.79
0.34
1.9
1.3
0.83
0.39
0.86


A308
0.87
0.31
3.9
1.6
0.81
0.36
0.94


A309
0.76
0.28
3.3
1.5
0.48
0.25
0.58


A311
0.67
0.42
3.3
2.0
1.0
0.53
1.2


A313
0.94
0.35
3.8
3.0
0.90
0.33
0.96


A314
0.60
0.51
1.5
0.82
0.56
0.55
0.38


A315
0.54
0.30
1.2
0.63
0.52
0.28
0.26


A316
0.78
0.39
1.2
1.1
0.56
0.29
0.27


A317
0.81
0.35
2.6
1.1
0.82
0.43
0.40


A318
0.47
0.27
2.0
0.65
0.45
0.38
0.16


A319
2.0
0.81
8.9
9.4
1.5
0.80
2.0


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
















TABLE V-1







in vitro Anti-picornavirus activity









IC50(μg/ml)

















polio
Echo


HRV
HRV
HRV
HRV
HRV


Compd.
1
11
CA7
CB4
1A
1B
2
14
89



















B2
0.58
0.19
3.1
0.97
5.0
0.54
0.15
0.65
0.48


B3
0.72
0.35
2.1
0.82
2.6
0.30
0.54
0.74
0.57


B7
0.42
0.25
1.4
0.52
1.7
0.17
0.36
0.49
0.30


B8
0.19
0.17
0.70
0.60
>1
0.24
0.22
0.40
0.12


B9
0.18
0.18
0.71
0.56
>1
0.25
0.20
0.58
0.21


B10
0.17
0.14
1.4
0.57
1.9
0.25
0.16
0.52
0.33


B11
0.45
0.28
>2
1.6
1.7
0.36
0.34
0.78
0.31


B12
0.39
0.19
2.0
0.63
>2.5
0.25
0.31
0.43
0.31


B15
0.49
0.27
2.2
1.9
>2.5
0.36
0.44
0.84
0.39


B20
0.40
0.28
1.4
0.60
>2.5
0.23
0.19
0.51
0.18


B22
0.54
0.39
1.9
1.3
>5.9
0.44
0.55
0.86
0.36
















TABLE V-2







in vitro Anti-picornavirus activity









IC50(μg/ml)

















polio
Echo


HRV
HRV
HRV
HRV
HRV


Compd.
1
11
CA7
CB4
1A
1B
2
14
89



















C40
0.54
0.24
>3.3
1.7
>3.3
0.51
0.54
1.1
0.56


C43
1.5
0.54
>5
2.9
>5
1.5
0.67
2.5
0.86


C49
0.52
0.26
9.2
2.3
>10
1.9
1.7
5.5
2.1
















TABLE V-3







in vitro Anti-picornavirus activity









IC50(μg/ml)

















polio
Echo


HRV
HRV
HRV
HRV
HRV


Compd.
1
11
CA7
CB4
1A
1B
2
14
89



















D50
0.64
0.27
1.9
0.82
2.2
0.25
0.20
1.3
0.41


D51
0.28
0.21
1.1
0.72
3.1
0.59
0.27
0.82
0.35


D52
1.0
0.55
>5
3.0
3.1
0.89
0.86
1.1
0.85


D53
1.8
0.68
>10
>3.3
>10
1.6
0.91
2.3
1.4
















TABLE VI-1







Cytotoxicity









CC50(μg/ml)












Compound
HeLa-S3
HeLa
HeLa(Ohio)
















A30
6.5
6.0
5.8



A32
>10
9.7
>10



A37
12
11
11



A60
7.0
5.3
5.7



A61
>4
>4
>4



A78
>8
>8
>8



A81
7.6
6.5
5.8



A97
>10
5.1
4.5



A98
>4
>4
>4



A99
5.8
5.4
5.7



A100
>5
>5
>5



A122
>10
>10
>10



A130
>4
>4
>4



A157
>5
>5
>5



A159
>5
>5
>5



A160
>5
>5
>5



A169
>50
>50
>50



A171
>2.5
>2.5
>2.5



A179
>4
>4
>4



A181
>2.5
>2.5
>2.5



A186
>5
>5
5.0



A187
>4
>4
>4



A188
>5
>5
>5



A190
>4
>4
>4



A191
>4
>4
>4



A194
>2.5
>2.5
>2.5



A196
>10
>10
>10



A226
>10
>10
>10



A234
>5
>5
>5



A235
>4
>4
>4



A237
>4
>4
>4



A258
>5
4.5
4.9



A285
>4
>4
>4



A286
>5
>5
>5



A296
>100
75
68



A303
>20
>20
>20



A304
>20
18
19



A306
26
14
25



A307
>20
>20
18



A308
16
11
11



A309
18
12
14



A311
>10
6.8
>10



A313
>20
18
15



A314
>10
7.0
>10



A315
>10
7.1
>10



A316
>5
>5
>5



A317
>5
>5
>5



A318
>2.5
>2.5
>2.5



A319
>50
35
32



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

















TABLE VI-2







Cytotoxicity









CC50(μg/ml)












Compound
HeLa-S3
HeLa
HeLa(Ohio)
















B2
>10
>10
>10



B3
>4
>4
>4



B7
>2.5
>2.5
>2.5



B8
>1
>1
>1



B9
>1
>1
>1



B10
>2.5
>2.5
>2.5



B11
>2
>2
>2



B12
>2.5
>2.5
>2.5



B15
>2.5
>2.5
>2.5



B20
>2.5
>2.5
>2.5



B22
>10
>10
>10

















TABLE VI-3







Cytotoxicity









CC50(μg/ml)












Compound
HeLa-S3
HeLa
HeLa(Ohio)
















D50
>10
7.8
>10



D51
>5
>5
>5



D52
>5
>5
>5



D53
>10
>10
>10










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 VII and VIII, some of the compounds exhibit potent activity against a broad spectrum of rhinovirus serotypes.







TABLE VII







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
0.017
0.017
0.030


isolated


strain
















TABLE VIII







Anti-Rhinovirus activity

















Compd.
Compd.
Compd.
Compd.
Compd.
Compd.
Compd.


Virus
Compd. B3
B7
B9
B10
B12
B15
B20
B22


















HRV1A
2.6
1.7
>1.0
1.9
>2.5
>2.5
>2.5
>5.9


HRV1B
0.30
0.20
0.25
0.25
0.25
0.36
0.23
0.44


HRV2
0.54
0.36
0.20
0.16
0.31
0.44
0.19
0.50


HRV3
2.9
0.49
0.23
0.48
0.52
1.1
0.50
0.97


HRV5
0.36
0.22
0.17
0.24
0.29
0.39
0.23
0.43


HRV8
0.46
0.32
0.15
0.20
0.32
0.38
0.29
0.46


HRV10
1.8
0.41
0.47
0.41
0.43
1.1
0.42
0.53


HRV13
0.17
0.13
0.14
0.12
0.091
0.18
0.13
0.13


HRV14
0.74
0.49
0.58
0.52
0.43
0.84
0.51
0.86


HRV16
2.3
0.98
0.47
0.57
1.4
1.2
0.44
1.2


HRV21
0.20
0.11
0.16
0.16
0.17
0.34
0.14
0.18


HRV29
1.5
0.43
0.19
0.44
0.44
0.67
0.44
0.56


HRV31
0.29
0.13
0.15
0.15
0.11
0.38
0.18
0.14


HRV32
0.61
0.30
0.13
0.36
0.33
0.65
0.29
0.19


HRV33
0.20
0.097
0.094
0.11
0.12
0.29
0.097
0.16


HRV36
0.30
0.16
0.16
0.17
0.21
0.32
0.20
0.25


HRV39
1.7
0.38
0.20
0.39
0.38
0.46
0.35
0.46


HRV41
0.20
0.064
0.13
0.007
0.11
0.18
0.12
0.14


HRV50
0.20
0.12
0.13
0.10
0.12
0.28
0.18
0.17


HRV61
0.80
0.28
0.16
0.24
0.31
0.39
0.31
0.34


HRV89
0.57
0.30
0.21
0.33
0.31
0.39
0.18
0.36


Clinical
1.9
0.50
0.31
0.75
0.46
1.1
0.49
0.43


isolated


strain









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 1.5 hr) 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 IC50, 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 IX.







TABLE IX







Anti-rotavirus activity










IC50(μg/mL)












Compound
HRoV(Odelia)
SRoV(SA11)















A323
1.30
0.90



B9
0.56
0.59

## Claims

1. A 1,2-disubstituted 1,4-dihydro-4-oxoquinoline compound of Formula I: 



wherein each R1 is a member independently selected from the group consisting of alkyl, cycloalkyl, phenyl, alkoxy, cycloalkyloxy, phenoxy, methylenedioxy, trifluoromethyl, halogen, OH, NO2, NH2, mono- or dialkylamino, pyrrolidino, methylpiperazino, 4-acetylpiperazino, morpholino, pyridyl, pyridyloxy, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiomorpholino, dialkylaminoalkylamino, N-alkylaminoalkyl-N-alkylamino, N-hydroxyalkyl-N-alkylamino, dialkylamino alkoxy, acetoxy, hydroxycarbonyloxy, alkoxycarbonyloxy, hydroxycarbonylmethoxy and alkoxycarbonylmethoxy, and n is 1, 2 or 3; 
wherein R2 is a member selected from the group consisting of alkyl, pyridyl, pyrazinyl, furyl, N-alkylpyrrolyl, thiazolyl, thienyl which may be optionally substituted with alkyl or halogen, and phenyl which may be optionally substituted with up to two substituents independently selected from the group consisting of halogen, OH, alkyl, alkoxy, trifluoromethyl and acetoxy; 
wherein R3 is a member selected from the group consisting of hydrogen, alkyl, phenyl, alkoxy, alkoxycarbonyl, alkylsulfonyl, CN and acetyl; or 
if R2 is a phenyl group optionally substituted with halo, alkyl or alkoxy groups, R3 may represent a bridging group between the 3rd position of the quinoline ring and said phenyl group at a position next to the ring carbon atom at which said phenyl group is directly connected to the quinoline ring, said bridging group being selected from the group consisting of methylene, carbonyl, hydroxyiminomethylidene, alkoxyiminomethylidene, alkanoylaminomethylidene, aminomethylidene, hydroxymethylidene, 1-hydroxy-1,1-alkylidene, α-hydroxybenzylidene, 1-alkoxy-1,1-alkylidene, α-alkoxybenzylidene, 1,2-ethylidene and 1,3-propylidene; or 
if R2 is 2-thienyl, 4- or 5-alkyl-2-thienyl or N-alkylpyrrol-3-yl, R3 may represent methylene bridge between the 3rd position of the quinoline ring and said thienyl group at the 3rd position or said pyrrolyl group at the 2nd position, and 
wherein R4 is a member selected from the group consisting of alkyl, alkenyl, benzyl and phenyl optionally substituted with halo, alkyl or alkoxy.

2. A compound according to claim 1 of Formula I-a: 



wherein R2′ is phenyl or substituted phenyl having up to two substituents independly selected from the group consisting of halo, OH, alkyl, alkoxy, trifluoromethyl and acetoxy; 
R3′ is hydrogen, alkyl, phenyl, alkoxy, alkoxycarbonyl, alkylsulfonyl, CN or acetyl; and 
R1, R4 and n are as defined above.

3. A compund according to claim 1 of Formula I-b: 



wherein R2′′ is alkyl, pyridyl, pyrazinyl, furyl, N-alkylpyrrolyl, thienyl, substituted thienyl having up to two halo- or alkyl substituents, or thiazolyl; and 
R1, R3′, R4 and n are as defined above.

4. A compound according to claim 1 of Formula I-c: 



wherein R5 is a member independly selected from the group consisting of hydrogen, halo, alkyl and alkoxy; 
R6 and R7 together with the carbon atom to which they are attached represent a bridge selected from the group consisting of methylene, carbonyl, hydroxyiminomethylidene, alkoxyiminomethylidene, alkanoylaminomethylidene, aminomethylidene, hydroxymethylidene, 1-hydroxy-1,1-alkylidene, α-hydroxybenzylidene, 1-alkoxy-1,1-alkylidene and α-alkoxybenzylidene; 
m is 1 or 2; and 
R1, R4 and n are as defined above.

5. A compound according to claim 1 of Fomula I-d: 



wherein R1, R4, R5, n and m are as defined above.

6. A compound according to claim 1 of Formula I-c: 



wherein R1, R4, R5, n and m are as defined above.

7. A compound according to claim 1 of Formula I-f: 



wherein R8 is hydrogen or alkyl; and 
R1, R4 and n are as defined above.