The present invention relates to a genus of novel phenylmethylpiperazines compounds and a method for preparing such compounds; and also relates the use of the compounds in the manufacture of antiviral drugs; in particular, the use of the compounds in the manufacture of drugs against HCV viruses.
Viral diseases are the most common infectious diseases, and have become global public health problems due to their features of high infectivity and high variability. Effect targets of the existing antiviral drugs are mostly viral enzymes. Viral enzyme inhibitors drugs have advantages such as explicit targets, high specificity, and strong efficacy, and apparent shortages of narrow antiviral spectrum, and problem of drug resistance leaded by the trends of the high variability of the viruses. The emerging of the new virus variants and unknown viruses make existing antiviral drugs, which have frequent problems of drug resistance, powerless. Therefore, the development of new antiviral drugs is imminent.
The inventors discovered and confirmed that a new genus of substituted phenylmethylpiperazines compounds had strong inhibitory activity on HCV replication, and initial mechanism of action studies showed that it did not act on the replication process of HCV, which is quite different from the mechanism of action of the current direct antiviral drugs. The compounds of the invention and their roles are not reported by relevant literature domestically and abroad to date.
The main object of the present invention is to screen a new genus of antiviral compounds and pharmaceutically acceptable salts thereof by medicinal chemistry studies of substituted phenylmethylpiperazines, and the compounds not only have significant antiviral activity, but also have the advantages of low cytotoxicity and high selectivity index.
To achieve the above object, the invention employs the following technical means:
At first, the present invention provides compounds having the structure represented by the following general formula I or a pharmaceutically acceptable salt thereof:
Wherein, preferably, the compounds or pharmaceutically acceptable salts thereof have the structure shown in the following general formula II:
wherein, n=1-3, R7, R8 are each H, alkyl, or substituted alkyl, respectively, or R7 and R8, together with the nitrogen atom to which they are bonded, form a cyclic group or a cyclic group substituted with a substituent selected from the group consisting of alkyl, alkylamino, dialkylamino, and heterocyclyl, such as pyrrolidinyl, the cyclic group is a three-, four-, five-, six-, or seven-membered saturated or unsaturated cyclic group containing 1 or 2 nitrogen atoms, for example, the three-membered cyclic group is selected from aziridinyl, the four-membered cyclic group is selected from azetidinyl, the five membered cyclic group is selected from the group consisting of pyrrolyl, pyrrolidinyl, imidazolyl, and oxazolyl groups, the six-membered cyclic group is selected from the group consisting of morpholine, piperazine, piperidine, pyridine, and pyrimidine groups, and the seven-membered cyclic group is 1,4-diazepanyl;
In the general formula II, preferably, when R4 is
R4 is
n=2 or 3, R10 is H; or R4 is
n=2, 3 or 4, and R9 is H.
In the general formula II, preferably, R5, R4 and the nitrogen atom to which they are bonded together form a saturated heterocycle or a saturated heterocycle substituted by a substituent, and the heterocycle is a five-, six- or seven-membered heterocycle containing one or two heteroatoms, the five-membered heterocycle is selected from the group consisting of pyrrolidinyl, pyrrolyl, imidazolyl, imidazolidinyl, and oxazolyl groups, the six-membered heterocycle is selected from the group consisting of morpholine, piperazine, and piperidine, and the seven-membered heterocycle is selected from 1,4-diazepane; the substituents are selected from the group consisting of alkyl containing 1 to 4 carbon atoms, di-C1-C4 alkylamino, cycloalkyl containing 3 to 5 carbon atoms, and heterocyclic groups containing 3 to 5 carbon atoms and one nitrogen, such as methyl, ethyl, methylamino, ethylamino, dimethyl amino, diethylamino, cyclopropyl, or pyrrolidinyl.
In the general formula II, preferably, R5, R4 together with the nitrogen atom to which they are bonded form
wherein n=1 or 2, R13 is alkyl containing 1-4 carbons or cycloalkyl containing 3 to 5 carbons, and the alkyl containing 1-4 carbon is, such as methyl, ethyl;
wherein n=1 or 2, R14 and R15 are alkyl groups containing 1 to 4 carbons; or R5, R4 together with the nitrogen atom to which they are bonded form
wherein R16 is a diC1-C4 alkylamino group, such as dimethylamino, diethylamino, or a saturated five-membered heterocyclic ring containing one nitrogen, such as pyrrolidinyl;
R16 is a diC1-C4 alkylamino, e.g., dimethylamino, diethylamino.
Wherein, preferably, the compounds or pharmaceutically acceptable salts thereof have the structure shown in the following general formula III:
1Aryl is the same as or different from 2Aryl, 1Aryl and 2Aryl are each a benzene ring or aza aromatic ring or a substituted benzene ring or aza aromatic ring, the aza aromatic ring is a heteroaromatic ring containing 1 to 2 nitrogen atoms, preferably pyridine rings and pyrimidine rings, the substitution is that 1 to 2 substituents are at any position on the ring, and the substituents are selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxy, phenoxy or substituted phenoxy, alkylthio, phenylthio, phenylthio or substituted phenylthio, haloalkyl, cyano and halogen;
In the general formula III, preferably, R4 is
wherein, n=1-3, R7 and R8 are H or alkyl or substituted alkyl, or R7 and R8 together with the nitrogen atom to which they are bonded form a cyclic group or substituted cyclic group, the substituent is selected from the group consisting of alkyl, alkylamino, dialkylamino and heterocyclic group, such as pyrrolidinyl, the cyclic group is three-, four-, five-, six- or seven-membered saturated or unsaturated cyclic group containing 1 or 2 nitrogen atoms, for example, the three-membered cyclic group is selected from aziridinyl, and the four-membered cyclic group is selected from azetidinyl, the five-membered cyclic group is selected from the group consisting of pyrrolyl, pyrrolidinyl, imidazolyl and oxazolyl groups, and the six-membered cyclic group is selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, pyridinyl, and pyrimidinyl groups, the seven-membered cyclic group is 1,4-diazepanyl;
In the general formula III, preferably, when R4 is
R4 is
n=2 or 3, R10 is H; or R4 is
n=2, 3 or 4, and R9 is H.
In the general formula III, preferably, R5, R4 and the nitrogen atom to which they are bonded together form a saturated heterocycle or a saturated heterocycle substituted by a substituent, and the heterocycle is a five-, six- or seven-membered heterocycle containing one or two heteroatoms, the five-membered heterocycle is selected from the group consisting of pyrrolidinyl, pyrrolyl, imidazolyl, imidazolidinyl, and oxazolyl groups, the six-membered heterocycle is selected from the group consisting of morpholine, piperazine, and piperidine, and the seven-membered heterocycle is selected from 1,4-diazepane; the substituents are selected from the group consisting of alkyl containing 1 to 4 carbon atoms, di-C1-C4 alkylamino, cycloalkyl containing 3 to 5 carbon atoms, and heterocyclic groups containing 3 to 5 carbon atoms and one nitrogen, such as methyl, ethyl, alkylamino, dimethylamino, diethyl amino, cyclopropyl, or pyrrolidinyl.
In the general formula III, preferably, R5, R4 together with the nitrogen atom to which they are bonded form
wherein n=1 or 2, R13 is alkyl containing 1-4 carbons or cycloalkyl containing 3 to 5 carbons, and the alkyl containing 1-4 carbon is, such as methyl, ethyl;
wherein n=1 or 2, R14 and R15 are alkyl groups containing 1 to 4 carbons;
wherein R16 is a diC1-C4 alkylamino group, such as dimethylamino, diethylamino, or a saturated five-membered heterocyclic ring containing one nitrogen, such as pyrrolidinyl;
R16 is a diC1-C4 alkylamino, e.g., dimethylamino, diethylamino.
Wherein, preferably, the compounds or pharmaceutically acceptable salts thereof have the structure shown in the following general formula IV:
In the general formula IV, preferably, R4 is
wherein, n=1-3, R7 and R8 are H or alkyl or substituted alkyl, or R7 and R8 together with the nitrogen atom to which they are bonded form a cyclic group or substituted cyclic group, the substituent is selected from the group consisting of alkyl, alkylamino, dialkylamino and heterocyclic group, such as pyrrolidinyl, such as pyrrolidin-1-yl, the cyclic group is three-, four-, five-, six- or seven-membered saturated or unsaturated cyclic group containing 1 or 2 nitrogen atoms, for example, the three-membered cyclic group is selected from aziridinyl, and the four-membered cyclic group is selected from azetidinyl, the five-membered cyclic group is selected from the group consisting of pyrrolyl, pyrrolidinyl, imidazolyl and oxazolyl groups, and the six-membered cyclic group is selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, pyridinyl, and pyrimidinyl groups, the seven-membered cyclic group is 1,4-diazepanyl;
wherein R12 is alkyl containing 1-4 carbon atoms, such as methyl, ethyl;
In the general formula IV, preferably, When R4 is
R4 is
n=2 or 3, R10 is H; or R4 is
n=2, 3 or 4, and R9 is H.
In the general formula IV, preferably, R5, R4 and the nitrogen atom to which they are bonded together form a saturated heterocycle or a saturated heterocycle substituted by a substituent, and the heterocycle is a five-, six- or seven-membered heterocycle containing one or two heteroatoms, the five-membered heterocycle is selected from the group consisting of pyrrolidinyl, pyrrolyl, imidazolyl, imidazolidinyl, and oxazolyl groups, the six-membered heterocycle is selected from the group consisting of morpholine, piperazine, and piperidine, and the seven-membered heterocycle is selected from 1,4-diazepane; the substituents are selected from the group consisting of alkyl containing 1 to 4 carbon atoms, di-C1-C4 alkylamino, cycloalkyl containing 3 to 5 carbon atoms, and heterocyclic groups containing 3 to 5 carbon atoms and one nitrogen, such as methyl, ethyl, alkylamino, dimethylamino, diethyl amino, cyclopropyl, or pyrrolidinyl.
In the general formula IV, preferably, R5, R4 together with the nitrogen atom to which they are bonded form
wherein n=1 or 2, R13 is alkyl containing 1-4 carbons or cycloalkyl containing 3 to 5 carbons, and the alkyl containing 1-4 carbon is, such as methyl, ethyl;
wherein n=1 or 2, R14 and R15 are alkyl groups containing 1 to 4 carbons;
wherein R16 is a diC1-C4 alkylamino group, such as dimethylamino, diethylamino, or a saturated five-membered heterocyclic ring containing one nitrogen, such as pyrrolidinyl;
R16 is a diC1-C4 alkylamino, e.g., dimethylamino, diethylamino.
In specific embodiments of the present invention, the compounds can be selected from:
Further, the invention also provides a method for preparing the compounds or pharmaceutically acceptable salts thereof, comprising the steps of:
Further, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds as mentioned in the present invention or a pharmaceutically acceptable salt thereof, and comprising one or more pharmaceutically acceptable excipients.
Wherein, preferably, the pharmaceutically acceptable salts refer to the product from salt forming reaction of a compound of the present invention with an acid, including inorganic acid salts such as hydrochloride, hydrobromide or sulfate and the like; organic acid salts such as acetate, lactate, succinate, fumarate, maleate, citrate, benzoate, methanesulfonate, or 4-methylbenzoate salt.
Wherein, preferably, the compounds of the present invention or a pharmaceutically acceptable salt thereof is used as an active ingredient, and present in an amount of 0.1% to 99.5% by weight of the pharmaceutical composition. Preferably, the pharmaceutical composition contains 0.5%-99.5% by weight of the active ingredient.
Further, the present invention also provides the use of the compounds or pharmaceutically acceptable salt thereof or the pharmaceutical composition in the manufacture of a medicament against virus, wherein the virus is a DNA virus and/or a RNA virus, or a hepatitis virus.
Wherein, preferably, the DNA viruses are herpes viruses, hepatotropic viruses, adenoviruses, or papilloma viruses; and the RNA viruses are mumps viruses, influenza viruses, coronaviruses, retroviruses, enterovirus or flaviviruses, or, the viruses are hepatitis C viruses.
Further, the present invention also provides the method for treating viral infections, which comprises administering to the patient a therapeutically effective amount of the compounds of the present invention or pharmaceutically acceptable salt thereof or the pharmaceutical composition, wherein the virus is a DNA virus and/or a RNA virus, or a hepatitis virus.
Wherein, preferably, the DNA viruses are herpes viruses, hepatotropic viruses, adenoviruses, or papilloma viruses; and the RNA viruses are mumps viruses, influenza viruses, coronaviruses, retroviruses, enterovirus or flaviviruses, or, the viruses are hepatitis C viruses.
The terms involved in this paper have the following meanings without specific definitions:
“Substituted” means, but is not limited to, being substituted with one or more substituents selected from the group consisting of halogen, alkoxy, hydroxy, alkyl, amino, alkylamino, aminoalkyl, alkenyl and phenyl. For example, “substituted piperazine” may be, but is not limited to, piperazine substituted at each substitutable position with a substituent selected from the group consisting of halogen, alkoxy, hydroxy, alkyl, amino, alkenyl, phenyl and substituted amino. As another example, “substituted benzene ring” can be, but is not limited to, benzene rings substituted by one substituent, such as alkyl, alkoxy, hydroxyl, amino, phenoxy, phenylthio, halogen, or polysubstituted benzene rings with these substituents in different positions thereof.
“Alkyl” may be, but not limited to straight or branched chain alkyl with number of carbon atoms of 1-6, more preferably C1-C4 lower alkyl, for example, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl and the like.
“Alkoxy” may be, but not limited to alkoxy with number of carbon atoms of 1 to 6, more preferably C1-C4 lower alkoxy, for example, methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentyloxy, n-hexyloxy, iso-hexyloxy and the like.
“Alkenyl” may be, but not limited to alkenyl with number of carbon atoms of 2 to 4, e.g., vinyl, propenyl, allyl, 1-butenyl, 2-butenyl, isobutenyl. Allyl is more preferable.
“Halo” or “halogen” may be fluoro, chloro, bromo or iodo. Fluoro, chloro or bromo is more preferable.
“Aminoalkyl” may be, but not limited to alkyl with number of carbon atoms of 1-6 substituted by amino, e.g., amino methyl, amino ethyl, amino isopropyl, amino n-propyl, amino n-butyl, amino isobutyl, amino sec-butyl, amino tert-butyl, amino n-pentyl, amino isopentyl, amino n-hexyl, amino isohexyl and the like. Amino (C1-C4) alkyl is more preferable.
“Amino”, “Aminoalkyl” and “dialkylamino” respectively refer to —NH2, —NHR and —NR2, and R is alkyl as defined above. Two alkyls connected to the nitrogen atom in dialkyl moiety may be the same or different.
The present invention will be described in further detail by reference to the following specific examples, but the present invention is not limited to the following specific examples.
305 μL 5-fluoro-2-(trifluoromethyl)benzyl bromide was dissolved in 6 mL acetone, added 617 mg 1-(bis(4-fluorophenyl)methyl)piperazine and 805 mg anhydrous potassium carbonate under stirring, and reacted at room temperature for 2.5 hours. After the reaction was completed, the reaction system was filtered by suction, the solvent of the filtrate was removed by rotary distillation, and 6 mL ethyl acetate and 3 mL distilled water were added for extraction, the organic phase was washed with saturated sodium chloride solution, then anhydrous magnesium sulfate was added for drying, and then filtered, concentrated, purified by column chromatography (petroleum ether:ethyl acetate=10:1) to obtain intermediate1-(bis(4-fluorophenyl)methyl)-4-(5-fluoro-2-(trifluoromethyl)benzyl)piperazine (80% yield). 232 mg of 1-(bis(4-fluorophenyl)methyl)-4-(5-fluoro-2-(trifluoro-methyl)benzyl)piperazine was dispersed in 4 mL of anhydrous DMSO, the mixture was placed in a 15 mL pressure-resistant tube, and 187 μL N-methylhomopiperazine and 207 mg anhydrous potassium carbonate were added, the reaction was conducted at 120° C. for 96 hours under airtight conditions, and the raw materials monitored by TLC had completely disappeared. The reaction system was filtered, the filtrate was extracted with ethyl acetate and water, and the organic layer was washed with water and saturated sodium chloride solution, added anhydrous magnesium sulfate to dry and then filtered, purified by column chromatography (dichloromethane:methanol=10:1) to obtain product 1-(3-((4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)methyl)-4-(trifluoromethyl) phenyl)-4-methyl-1,4-diazepane (58% yield), mass spectrum (ESI+): m/z=559.3 (M+H)+.
The following compounds were obtained by the methods similar to that in Example 1:
mass spectrum (ESI+): m/z=539.2 (M+H)+
mass spectrum (ESI+): m/z=481.2 (M+H)+
mass spectrum (ESI+): m/z=513.2 (M+H)+
mass spectrum (ESI+): m/z=495.2 (M+H)+
mass spectrum (ESI+): m/z=519.3 (M+H)+
mass spectrum (ESI+): m/z=501.2 (M+H)+
mass spectrum (ESI+): m/z=480.2 (M+H)+
mass spectrum (ESI+): m/z=541.2 (M+H)+
mass spectrum (ESI+): m/z=483.2 (M+H)+
mass spectrum (ESI+): m/z=449.3 (M+H)+
mass spectrum (ESI+): m/z=455.2 (M+H)+
mass spectrum (ESI+): m/z=499.2 (M+H)+
mass spectrum (ESI+): m/z=495.2 (M+H)+
mass spectrum (ESI+): m/z=481.2 (M+H)+
mass spectrum (ESI+): m/z=467.2 (M+H)+
mass spectrum (ESI+): m/z=525.2 (M+H)+
mass spectrum (ESI+): m/z=495.2 (M+H)+
mass spectrum (ESI+): m/z=533.1 (M+H)+
mass spectrum (ESI+): m/z=481.2 (M+H)+
mass spectrum (ESI+): m/z=507.2 (M+H)+
mass spectrum (ESI+): m/z=467.2 (M+H)+
mass spectrum (ESI+): m/z=453.2 (M+H)+
mass spectrum (ESI+): m/z=495.2 (M+H)+
mass spectrum (ESI+): m/z=549.2 (M+H)+
mass spectrum (ESI+): m/z=581.2 (M+H)+
mass spectrum (ESI+): m/z=543.3. (M+H)+
mass spectrum (ESI+): m/z=495.2 (M+H)+
mass spectrum (ESI+): m/z=451.2 (M+H)+
mass spectrum (ESI+): m/z=485.2 (M+H)+
mass spectrum (ESI+): m/z=533.1 (M+H)+
mass spectrum (ESI+): m/z=480.2 (M+H)+
mass spectrum (ESI+): m/z=481.2 (M+H)+
mass spectrum (ESI+): m/z=473.2 (M+H)+
mass spectrum (ESI+): m/z=488.2 (M+H)+
mass spectrum (ESI+): m/z=480.2 (M+H)+
mass spectrum (ESI+): m/z=551.3 (M+H)+
mass spectrum (ESI+): m/z=591.2 (M+H)+
mass spectrum (ESI+): m/z=679.1 (M+H)+
mass spectrum (ESI+): m/z=607.4 (M+H)+
mass spectrum (ESI+): m/z=591.4 (M+H)+
mass spectrum (ESI+): m/z=591.2 (M+H)+
mass spectrum (ESI+): m/z=541.3 (M+H)+
mass spectrum (ESI+): m/z=579.2 (M+H)+
mass spectrum (ESI+): m/z=647.3 (M+H)+
mass spectrum (ESI+): m/z=545.3 (M+H)+
mass spectrum (ESI+): m/z=577.2 (M+H)+
mass spectrum (ESI+): m/z=558.3 (M+H)+
mass spectrum (ESI+): m/z=524.3 (M+H)+
mass spectrum (ESI+): m/z=571.3 (M+H)+
mass spectrum (ESI+): m/z=607.2 (M+H)+
mass spectrum (ESI+): m/z=573.3 (M+H)+
mass spectrum (ESI+): m/z=605.2 (M+H)+
mass spectrum (ESI+): m/z=605.2 (M+H)+
mass spectrum (ESI+): m/z=605.2 (M+H)+
mass spectrum (ESI+): m/z=577.2 (M+H)+
mass spectrum (ESI+): m/z=539.3 (M+H)+
mass spectrum (ESI+): m/z=547.3 (M+H)+
mass spectrum (ESI+): m/z=605.2 (M+H)+
mass spectrum (ESI+): m/z=665.1 (M+H)+
mass spectrum (ESI+): m/z=573.3 (M+H)+
mass spectrum (ESI+): m/z=607.2 (M+H)+
mass spectrum (ESI+): m/z=604.3 (M+H)+
mass spectrum (ESI+): m/z=578.2 (M+H)+
mass spectrum (ESI+): m/z=666.1 (M+H)+
mass spectrum (ESI+): m/z=467.2 (M+H)+
mass spectrum (ESI+): m/z=675.2 (M+H)+
mass spectrum (ESI+): m/z=597.3 (M+H)+
mass spectrum (ESI+): m/z=545.2 (M+H)+
mass spectrum (ESI+): m/z=616.3 (M+H)+
mass spectrum (ESI+): m/z=753.3 (M+H)+
mass spectrum (ESI+): m/z=673.3 (M+H)+
mass spectrum (ESI+): m/z=474.3 (M+H)+
mass spectrum (ESI+): m/z=489.2 (M+H)+
mass spectrum (ESI+): m/z=469.2 (M+H)+
mass spectrum (ESI+): m/z=501.1 (M+H)+
642 mg 5-fluoro-2-cyanobenzyl bromide (3.0 mmol) was dissolved in 10 mL acetone, added 808 mg 1-(3,4-dichlorobenzyl)piperazine (3.3 mmol) and 1242 mg anhydrous potassium carbonate (9.0 mmol) under stirring, and reacted at room temperature for 3 hours. After the reaction was completed, the reaction system was filtered by suction, the solvent of the filtrate was removed by rotary distillation, after 6 mL ethyl acetate was added to dissolve, 3 mL distilled water was added and stirred fully before standing and stratifying, the organic phase was washed again with saturated sodium chloride solution, an appropriate amount of anhydrous magnesium sulfate was added for drying, and then filtered, purified by column chromatography (petroleum ether:ethyl acetate=10:1) to obtain intermediate 2-((4-(3,4-dichlorobenzyl)piperazin-1-yl)methyl)-4-fluoro-benzonitrile (75% yield). 378 mg of 2-((4-(3,4-dichlorobenzyl) piperazin-1-yl) methyl)-4-fluoro-benzonitrile was dissolved ultrasonically in 3.0 mL anhydrous DMSO, the mixture was placed in a 15 mL pressure-resistant tube, 354 μL 3-(1H-pyrrol-1-yl)propan-1-amine (3.0 mmol) and 414 mg anhydrous potassium carbonate (3.0 mmol) were added under stirring, the reaction was conducted at 120° C. for 8 hours under airtight conditions, and the raw materials monitored by TLC had completely disappeared. The reaction system was filtered, the filtrate was dried to remove the solvent, and the remaining was dissolved by adding 6 mL ethyl acetate, then washed with water and saturated sodium chloride solution successively, added anhydrous magnesium sulfate to dry and then filtered, purified by column chromatography (dichloromethane:methanol=8:1) to obtain product 4-((3-(1H-pyrrol-1-yl)propyl)amino)-2-((4-(3,4-dichlorobenzyl)piperazin-1-yl)methyl)benzonitrile (47% yield), mass spectrum (ESI+): m/z=482.2 (M+H)+.
The following compounds were obtained by the methods similar to that in Example 2:
mass spectrum (ESI+): m/z=452.2 (M+H)+
mass spectrum (ESI+): m/z=450.2 (M+H)+
mass spectrum (ESI+): m/z=454.3 (M+H)+
mass spectrum (ESI+): m/z=432.3 (M+H)+
mass spectrum (ESI+): m/z=474.3 (M+H)+
mass spectrum (ESI+): m/z=494.3 (M+H)+
mass spectrum (ESI+): m/z=472.3 (M+H)+
mass spectrum (ESI+): m/z=536.2 (M+H)+
mass spectrum (ESI+): m/z=540.3 (M+H)+
mass spectrum (ESI+): m/z=516.3 (M+H)+
mass spectrum (ESI+): m/z=548.2 (M+H)+
mass spectrum (ESI+): m/z=559.2 (M+H)+
mass spectrum (ESI+): m/z=470.3 (M+H)+
mass spectrum (ESI+): m/z=534.2 (M+H)+
mass spectrum (ESI+): m/z=552.4 (M+H)+
mass spectrum (ESI+): m/z=580.4 (M+H)+
mass spectrum (ESI+): m/z=624.1 (M+H)+
mass spectrum (ESI+): m/z=548.4 (M+H)+
mass spectrum (ESI+): m/z=548.2 (M+H)+
mass spectrum (ESI+): m/z=562.2 (M+H)+
mass spectrum (ESI+): m/z=534.2 (M+H)+
mass spectrum (ESI+): m/z=514.3 (M+H)+
mass spectrum (ESI+): m/z=515.3 (M+H)+
mass spectrum (ESI+): m/z=535.2 (M+H)+
mass spectrum (ESI+): m/z=515.3 (M+H)+
mass spectrum (ESI+): m/z=422.3 (M+H)+
mass spectrum (ESI+): m/z=564.3 (M+H)+
mass spectrum (ESI+): m/z=492.3 (M+H)+
mass spectrum (ESI+): m/z=536.3 (M+H)+
mass spectrum (ESI+): m/z=560.3 (M+H)+
mass spectrum (ESI+): m/z=485.3 (M+H)+
mass spectrum (ESI+): m/z=559.2 (M+H)+
100 μL Huh7.5 cells were seeded at a density of 1×105/mL in a 96-well cell culture plate and incubated in an incubator at 37° C., 5% CO2 and saturated humidity for 6 hrs. Then, while infecting Huh7.5 cells with viral solution containing HCV virus particles, the compounds of the present invention (including all specific compounds listed herein) were added at a concentration of 1 μM, respectively. After continuing incubation for 96 hrs, the total intracellular RNA was extracted separately, and the content of intracellular HCV RNA was measured by one-step quantitative RT-PCR, compared with the RNA level of the viral control, and the inhibition rate of the compounds against HCV was calculated. The results of some compounds are shown in Table 1.
The results of the anti-HCV activity assay of the compounds of the present invention and synthesized in cell culture are shown in Table 1
#The effective digits of molecular weights of all compounds in the table are retained to three digits and rounded off.
Filing Document | Filing Date | Country | Kind |
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PCT/CN2019/000232 | 11/29/2019 | WO |
Publishing Document | Publishing Date | Country | Kind |
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WO2021/102600 | 6/3/2021 | WO | A |
Number | Name | Date | Kind |
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10252987 | Li | Apr 2019 | B2 |
Number | Date | Country |
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104447625 | Mar 2015 | CN |
106467501 | Mar 2017 | CN |
110698432 | Jan 2020 | CN |
WO2010118367 | Oct 2010 | WO |
WO-2017028472 | Feb 2017 | WO |
Entry |
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International Search Report (English and Chinese) and Written Opinion of PCT/CN2019/000232 dated Aug. 20, 2020, 11 pages. |
Romero, D.L. et al., Discovery, Synthesis, and Bioactivity of Bis(heteroaryl)piperazines. 1. A Novel Class of Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors, Journal of Medicinal Chemistry, 1994, pp. 999-1014, vol. 37, No. 7, Miami, US. |
Number | Date | Country | |
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20230024612 A1 | Jan 2023 | US |