CN101575314A - Dihydropyridine compounds and application thereof on preparing drugs for curing and/or preventing virus diseases - Google Patents
Dihydropyridine compounds and application thereof on preparing drugs for curing and/or preventing virus diseases Download PDFInfo
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- CN101575314A CN101575314A CNA200910148629XA CN200910148629A CN101575314A CN 101575314 A CN101575314 A CN 101575314A CN A200910148629X A CNA200910148629X A CN A200910148629XA CN 200910148629 A CN200910148629 A CN 200910148629A CN 101575314 A CN101575314 A CN 101575314A
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- Prior art keywords
- nitro
- methyl
- dihydropyridine
- carboxylic acid
- ethyl ester
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention relates to dihydropyridine compound and application thereof on preparing drugs for curing and/or preventing virus diseases, in particular to a compound shown as general formula (1) and isomers, salts for medicinal purpose or hydrate thereof, and each variable is defined in a specification. The invention also relates to a preparing method of a compound shown as general formula (1), and an application of compound shown as general formula (1) and isomers, salts for medicinal purpose or hydrate thereof, in particular to application in preparing drugs for curing and/or preventing hepatitis B.
Description
Technical field
The present invention relates to dihydropyridine compounds of general formula (I) and preparation method thereof, the pharmaceutical composition that comprises above-claimed cpd, and this compounds or its isomer or its pharmacologically acceptable salt or hydrate are as the medicine purposes of antiviral for example, especially as the purposes that is used for the treatment of and/or prevents the medicine of hepatitis B.
Background technology
Chronic hepatitis B is caused by hepatitis B virus (HBV), and pandemic a kind of serious transmissible disease in the world wide is closely related with the generation of liver cirrhosis and liver cancer.China is high incidence of hepatitis b, and 1992-1995 whole nation viral hepatitis seroepidemiological survey result shows that population of China hepatitis B virus surface antigen (HBsAg) carrying rate is 9.7%, estimates that about 1.3 hundred million people are the HBV carrier.To discovering of the popular present situation of China's viral hepatitis, hepatitis B annual report sickness rate from 21.9/10 ten thousand of nineteen ninety be elevated to 2003 53.3/10 ten thousand, be obvious ascendant trend (Wang Xiaojun, Zhang Rongzhen, disease surveillance such as Hu Yuansheng, 2004,19 (8): 290-292).Chronic hepatitis B not only has a strong impact on HUMAN HEALTH, and causes heavy economical load for family, society, and chronic hepatitis B has become one of great public health problem of China.
The medicine that is used for the treatment of chronic viral hepatitis B mainly contains two classes---immunomodulator and ucleosides archaeal dna polymerase inhibitor (Loomba R., Liang T.J., Antivir.Ther., 2006,11 (1): 1-15).The former comprises: interferon-' alpha ' 2b (IFN-α 2b, Intron
) and polyoxyethylene glycol interferon-' alpha ' 2a (peg-IFN-α 2a,
); The latter comprises: lamivudine (Lamivudine, Epivir-
), adefovir ester (Adefovir Dipivoxil,
), Entecavir (Entecavir,
), Telbivudine (Telbivudine,
), tynofovir (Tenofovir,
) and L-FMAU (Clevudine,
).Comparatively speaking can be also seldom for the medicament categories that is used for the treatment of hepatitis B of clinical application and quantity, the therefore continuous new antiviral safely and effectively of research and development, the medicine that especially has brand-new mechanism of action has crucial meaning.
Dihydropyridine compounds has physiologically active widely, as can be used as N type calcium-ion channel antagonists (US6350762) and L type calcium-ion channel antagonists (US6001857).While 3-[4-(2-first imidazolyl [4,5-c] pyridine) valeric acid]-5-(N-pyridine-2-carbamyl)-1, the 4-dihydropyridine compounds has antianaphylaxis, anti-inflammatory action (US4904671).But do not see 1, the relevant report of 4-dihydropyridine compounds anti-hepatitis B virus.
Summary of the invention
The inventor finds that the dihydropyridine compound of the general formula of a class novelty provided by the invention (I) has the particularly effect of anti-hepatitis B virus of effective antivirus action, the present invention is based on above-mentioned discovery and is accomplished.
Summary of the invention:
First aspect present invention provides general formula (I) compound,
Wherein:
R
1Represent hydrogen, (C
1-C
6)-alkyl, (C
2-C
6)-alkenyl, (C
1-C
6)-acyl group, alkylsulfonyl;
R
2Representative (C
1-C
6)-alkyl;
R
3Represent aryl or heteroaryl, it is optional to be selected from following substituting group independently of one another and to replace by one or more: hydrogen, halogen, trifluoromethyl, trifluoromethoxy, trifyl, nitro, cyano group, carboxyl, hydroxyl, amino, (C
1-C
6)-alkylamino, (C
1-C
6)-dialkyl amido, (C
1-C
6)-amido, (C
1-C
6)-alkyl, (C
1-C
6)-alkoxyl group, (C
1-C
6)-carbalkoxy, (C
1-C
6)-carbamyl, wherein said alkyl can be had aryl, the halogen, (C of 6-10 carbon atom
1-C
6)-alkoxyl group, (C
1-C
6)-alkylamino, amide group replace;
R
4Represent aryl or heteroaryl, it is optional to be selected from following substituting group independently of one another and to replace by one or more: hydrogen, halogen, hydroxyl, cyano group, carboxyl, trifluoromethyl, nitro, benzyl, (C
1-C
6)-alkyl, (C
1-C
6)-alkoxyl group, (C
1-C
6)-alkylthio, (C
1-C
6)-carbalkoxy, (C
1-C
6)-acyloxy, amino, (C
1-C
6)-alkylamino or (C
1-C
6)-dialkyl amido, (C
1-C
6)-acyl amino, (C
1-C
6)-carbamyl,
Or its isomer, pharmacologically acceptable salt or hydrate.
According to general formula (I) compound of first aspect present invention, wherein:
R
1Represent hydrogen, (C
1-C
3)-alkyl, formyl radical, ethanoyl, benzoyl, methylsulfonyl, benzene methylsulfonyl, p-toluenesulfonyl;
R
2Representative (C
1-C
4)-alkyl;
R
3Represent aryl or heteroaryl, it is optional to be selected from following substituting group independently of one another and to replace by one or more: hydrogen, halogen, trifluoromethyl, trifluoromethoxy, trifyl, nitro, cyano group, carboxyl, hydroxyl, amino, (C
1-C
4)-alkylamino, (C
1-C
4)-dialkyl amido, (C
1-C
4)-amido, (C
1-C
4)-alkoxy carbonyl, (C
1-C
4)-alkoxyl group, (C
1-C
4)-alkyl, (C
1-C
4)-carbamyl;
R
4Represent aryl or heteroaryl, it is optional to be selected from following substituting group independently of one another and to replace by one or more: hydrogen, halogen, nitro, cyano group, hydroxyl, trifluoromethyl, carboxyl, (C
1-C
3)-alkyl, (C
1-C
3)-alkoxyl group, (C
1-C
3)-carbalkoxy, amino, (C
1-C
3)-alkylamino, (C
1-C
3)-dialkyl amido, (C
1-C
3)-acyl amino, (C
1-C
3)-carbamyl.
Or its isomer, pharmacologically acceptable salt or hydrate.
According to general formula (I) compound of first aspect present invention, wherein:
R
1Represent hydrogen, methyl, formyl radical, ethanoyl, methylsulfonyl, benzoyl;
R
2Represent methylidene, ethyl, propyl group, sec.-propyl;
R
3Represent aryl or heteroaryl, it is optional to be selected from following substituting group independently of one another and to replace by one or more: hydrogen, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, trifyl, nitro, cyano group, carboxyl, hydroxyl, amino, methylamino-, dimethylamino, formamido-, acetamido, ethylamino, methoxycarbonyl, methoxyl group, oxyethyl group, methyl, ethyl, propyl group;
R
4Represent aryl or heteroaryl, it is optional to be selected from following substituting group independently of one another and to replace by one or more: hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl group, sec.-propyl, hydroxyl, carboxyl, methoxyl group, oxyethyl group, methoxycarbonyl, ethoxycarbonyl, nitro, amino, methylamino-, dimethylamino, formamido-, ethylamino, acetamido.
Or its isomer, pharmacologically acceptable salt or hydrate.
According to general formula (I) compound of first aspect present invention, wherein:
R
1Represent hydrogen, ethanoyl;
R
2Represent methylidene, ethyl;
R
3Represent single the replacement or polysubstituted optional identical or different substituent aryl: hydrogen, chlorine, fluorine, bromine, trifluoromethyl, methyl, methoxyl group, carboxyl, cyano group, hydroxyl from following radicals;
R
4Represent single the replacement or polysubstituted optional identical or different substituent phenyl, thienyl, thiazolyl: hydrogen, fluorine, methyl, hydroxyl, methoxyl group, methoxycarbonyl, nitro, amino, methylamino-, formamido-, acetamido from following radicals.Or its isomer, pharmacologically acceptable salt or hydrate.
According to general formula (I) compound of first aspect present invention, it is selected from:
(1) 2-methyl-4-phenyl-5-nitro-6-(4-aminomethyl phenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(2) 2-methyl-4-(2-chloro-phenyl-)-5-nitro-6-(4-aminomethyl phenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(3) 2-methyl-4-(3-chloro-phenyl-)-5-nitro-6-(4-aminomethyl phenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(4) 2-methyl-4-(2-chloro-phenyl-)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(5) 2-methyl-4-(3-chloro-phenyl-)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(6) 2-methyl-4-(2-chloro-phenyl-)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(7) 2-methyl-4-(4-fluorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(8) 2-methyl-4-(2-p-methoxy-phenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(9) 2-methyl-4-(2-bromophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(10) 2-methyl-4-(3-chloro-phenyl-)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(11) 2-methyl-4-(4-chloro-phenyl-)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(12) 2-methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(13) 2-methyl-4-(2-p-methoxy-phenyl)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(14) 2-methyl-4-(2-bromophenyl)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(15) 2-methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(16) 2-methyl-4-(4-chloro-phenyl-)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(17) 2-methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylate methyl ester;
(18) 2-methyl-4-(2-aminomethyl phenyl)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(19) 2-methyl-4-(2-aminomethyl phenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester; With
(20) 1-ethanoyl-2-methyl-4-(2-aminomethyl phenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester,
Or its isomer, pharmacologically acceptable salt or hydrate.
Second aspect present invention provides the method for preparing each described general formula (I) compound of first aspect present invention, and it comprises:
Steps A) under the situation that adds or do not add alkali or acid, in suitable inert solvent, the olefinic amine compound of general formula (II)
Aldehyde with general formula (III)
R
3CHO (III)
And the reaction of the compound of general formula (IV),
Obtain R wherein
1General formula (I) compound for hydrogen; With, optional
Step B) under alkaline condition, in suitable inert solvent, above-mentioned steps A) product and formula R
1The compound reaction that X represents obtains general formula (I) compound,
Wherein, X represents halogen (for example fluorine, chlorine, bromine and iodine), R
1, R
2, R
3, and R
4Separately with the definition in each described general formula (I) compound of first aspect present invention.
Third aspect present invention provides a kind of pharmaceutical composition, and it comprises the compound of each the described general formula (I) of first aspect present invention that treats and/or prevents significant quantity, optional pharmaceutically useful carrier, and optional other medicines active compound.
The compound that fourth aspect present invention provides each described general formula (I) of first aspect present invention preparation be used for the treatment of and/or the medicine of prophylaxis of acute or chronic viral disease in purposes.
The compound that fifth aspect present invention provides each described general formula (I) of first aspect present invention preparation be used for the treatment of and/or the medicine of prophylaxis of acute or chronic HBV infection in purposes.
Sixth aspect present invention provides the method acute or the chronic viral disease that treats and/or prevents, and it comprises the compound to each described general formula (I) of first aspect present invention of experimenter's administering therapeutic that needs are arranged and/or prevention significant quantity.
Seventh aspect present invention provides the method that treats and/or prevents acute or chronic HBV infection, and it comprises the compound to each described general formula (I) of first aspect present invention of experimenter's administering therapeutic that needs are arranged and/or prevention significant quantity.
Detailed Description Of The Invention:
All documents that the present invention quoted from, their full content is incorporated this paper by reference into, and if the expressed implication of these documents and the present invention when inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this more detailed description and interpretation to be made in these terms and phrase, term of mentioning and phrase are as the criterion with the implication that the present invention was explained if any inconsistent with known implication.
In the specification sheets of the present invention, term " halogen " or " halo " are meant fluorine, chlorine, bromine and iodine.
In the specification sheets of the present invention, term " (C
2-C
6)-alkenyl " be meant straight or branched thiazolinyl with 2-6 carbon atom, the straight or branched thiazolinyl of preferred 3-4 carbon atom, but comprise and be not limited to vinyl, propenyl, just pentenyl, n-hexylene base.
In the specification sheets of the present invention, term " (C
1-C
6)-acyl group " be meant straight or branched acyl group with 1-6 carbon atom, preferably have the straight or branched acyl group of 2-4 carbon atom.
In the specification sheets of the present invention, term " aryl " typically refers to the aromatic ring system of 5-14 unit, maybe may comprise condensed dicyclo or trinucleated aromatic ring system, but comprises and be not limited to phenyl and naphthyl.
In the specification sheets of the present invention, term " heteroaryl " typically refers to the 5-14 unit aromatic ring system that contains heteroatoms N, O, S etc., maybe may comprise condensed dicyclo or trinucleated aromatic ring system.
In the specification sheets of the present invention, term " (C
1-C
6)-alkyl " be meant and the group that contains 1-6 carbon atom of straight or branched include but are not limited to: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-and the tertiary butyl etc.
In the specification sheets of the present invention, term " (C
1-C
6)-alkoxyl group " be meant the straight or branched alkoxyl group that contains 1-6 carbon atom; preferably have the straight or branched alkoxyl group of 1-4 carbon atom, include but are not limited to: methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy and tert.-butoxy etc.
In the specification sheets of the present invention, term " (C
1-C
6)-alkylthio " be meant the straight or branched alkylthio that contains 1-6 carbon atom, preferably have the straight or branched alkylthio of 1-4 carbon atom.
In the specification sheets of the present invention, term " (C
1-C
6)-carbalkoxy " be meant straight or branched carbalkoxy with 1-6 carbon atom; preferably have the straight or branched carbalkoxy of 1-4 carbon atom, include but are not limited to: methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, the different third oxygen carbonyl, butoxy carbonyl, isobutyl boc and tertbutyloxycarbonyl etc.
The compounds of this invention can exist with the optical isomer form, can be enantiomer or diastereomer relation between the described optical isomer form.The present invention relates to these enantiomers or diastereomer and their mixture.As diastereomer, racemic modification can split into the single component of optical isomer by currently known methods, as utilize the nitrogen-atoms that has alkalescence in the The compounds of this invention molecule to split with the salifiable method of acid chiral selectors, this method specifically describes as follows: invention compound and resolution reagent are used organic solvent dissolution respectively, mix then, place, separate out solid.Separate solid and solution are handled with alkali lye respectively, and organic solvent extraction promptly gets a pair of enantiomer.
Acid chiral selectors is including, but not limited to dextrocamphoric acid, the camphorsulfonic acid of R or S configuration, the tartrate of D or L configuration, lactic acid, oxysuccinic acid, natural or alpha-non-natural amino acid and derivative thereof etc.
The used organic solvent of above-mentioned method for splitting includes but are not limited to: methyl alcohol, ethanol, acetone, ethyl acetate, ether, sherwood oil, methylene dichloride, trichloromethane etc.
Perhaps introduce another chiral radicals in the molecule of invention compound, it is become a pair ofly be easy to isolating diastereomer, thereby the chiral radicals of removing introducing after the separation and purification obtains optically pure enantiomer, this method specifically describes as follows:
1) add under the situation of alkali, in suitable inert solvent, general formula (I) compound (R wherein
1Be hydrogen) with molecule in contain the acyl chlorides or the anhydride reaction of the acid of a chiral centre at least, perhaps general formula (I) compound (R wherein
1Be hydrogen) with molecule in contain a chiral centre at least acid in the presence of suitable condensing agent, react, obtain leading to formula V and (VI) mixture.Recrystallization in appropriate solvent, or through column chromatographic isolation and purification obtains pure (V) and (VI) respectively.
R wherein
2, R
3, R
4Define together above, the R representative contains the acyl group or the sulfonic group of a chiral centre at least,
2) logical formula V or (VI) in appropriate solvent with highly basic such as sodium alkoxide react a pair of enantiomer of general formula (I) compound.
R wherein
2, R
3, R
4Define the same, R
1Be hydrogen,
At least the acid that contains a chiral centre in the molecule includes but are not limited to: tartrate, lactic acid, oxysuccinic acid, natural or the alpha-non-natural amino acid and the derivative thereof etc. of the dextrocamphoric acid of R or S configuration, camphorsulfonic acid, D or L configuration.
Condensing agent includes but are not limited to: dicyclohexylcarbodiimide (DCC), DIC (DIC), N, N '-carbonyl dimidazoles (CDI), 1-ethyl-3-[3-(dimethylin) propyl group] carbodiimide (EDCI), BOP (blocking special condensing agent) etc.
Utilize following reaction scheme to illustrate the chiral separation method of The compounds of this invention:
The compounds of this invention can also be the form of salt.Its pharmaceutically useful salt is preferred.
But wherein pharmaceutically useful salt comprises and being not limited to, the salt that is become with mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, Hydrogen bromide and nitric acid, and the salt that is become with various organic acids such as toxilic acid, fumaric acid, oxysuccinic acid, fumaric acid, succsinic acid, tartrate, citric acid, acetate, lactic acid, phenylformic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, tosic acid, palmitinic acid etc.
Its pharmaceutically useful salt also includes but are not limited to: metal-salt such as sodium salt, sylvite, magnesium salts or the calcium salt of The compounds of this invention, or the ammonium salt that becomes with ammonia or organic amine such as ethamine, diethylamine, triethylamine, diethanolamine, trolamine, dicyclohexylamine, dimethylaminoethanol, arginine, Methionin, quadrol or 2-phenyl-ethyl amine etc.
Some compounds possibility water or various organic solvent crystallization or recrystallizations among the present invention in this case, may form all kinds of SOLVENTS thing.The present invention includes those stoichiometric solvates, comprise hydrate, be also included within the compound that comprises variable water gaging that forms when preparing with lyophylization.
Though offer some clarification at summary of the invention part general formula (I) compound to the first aspect of the present invention, the China invites the person still is further described at this.Specifically, the general formula that the present invention is defined as follows (I) compound or its isomer and their salt or hydrate are preferred,
Wherein:
R
1Represent hydrogen, (C
1-C
3)-alkyl, formyl radical, ethanoyl, benzoyl, methylsulfonyl, benzene methylsulfonyl, p-toluenesulfonyl;
R
2Representative (C
1-C
4)-alkyl;
R
3Represent aryl or heteroaryl, it is optional to be selected from following substituting group independently of one another and to replace by one or more: hydrogen, halogen, trifluoromethyl, trifluoromethoxy, trifyl, nitro, cyano group, carboxyl, hydroxyl, amino, (C
1-C
4)-alkylamino, (C
1-C
4)-dialkyl amido, (C
1-C
4)-amido, (C
1-C
4)-alkoxy carbonyl, (C
1-C
4)-alkoxyl group, (C
1-C
4)-alkyl, (C
1-C
4)-carbamyl;
R
4Represent aryl or heteroaryl, it is optional to be selected from following substituting group independently of one another and to replace by one or more: hydrogen, halogen, nitro, cyano group, hydroxyl, trifluoromethyl, carboxyl, (C
1-C
3)-alkyl, (C
1-C
3)-alkoxyl group, (C
1-C
3)-carbalkoxy, amino, (C
1-C
3)-alkylamino, (C
1-C
3)-dialkyl amido, (C
1-C
3)-acyl amino, (C
1-C
3)-carbamyl.
In addition, the general formula that is defined as follows (I) compound or its isomer and their salt or hydrate are particularly preferred, wherein:
R
1Represent hydrogen, methyl, formyl radical, ethanoyl, methylsulfonyl, benzoyl;
R
2Represent methylidene, ethyl, propyl group, sec.-propyl;
R
3Represent aryl or heteroaryl, it is optional to be selected from following substituting group independently of one another and to replace by one or more: hydrogen, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, trifyl, nitro, cyano group, carboxyl, hydroxyl, amino, methylamino-, dimethylamino, formamido-, acetamido, ethylamino, methoxycarbonyl, methoxyl group, oxyethyl group, methyl, ethyl, propyl group;
R
4Represent aryl or heteroaryl, it is optional to be selected from following substituting group independently of one another and to replace by one or more: hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl group, sec.-propyl, hydroxyl, carboxyl, methoxyl group, oxyethyl group, methoxycarbonyl, ethoxycarbonyl, nitro, amino, methylamino-, dimethylamino, formamido-, ethylamino, acetamido.
Further, the general formula that is defined as follows (I) compound or its isomer and their salt or hydrate are very particularly preferred, wherein:
R
1Represent hydrogen, ethanoyl;
R
2Represent methylidene, ethyl;
R
3Represent single the replacement or polysubstituted optional identical or different substituent aryl: hydrogen, chlorine, fluorine, bromine, trifluoromethyl, methyl, methoxyl group, carboxyl, cyano group, hydroxyl from following radicals;
R
4Represent single the replacement or polysubstituted optional identical or different substituent phenyl, thienyl, thiazolyl: hydrogen, fluorine, methyl, hydroxyl, methoxyl group, methoxycarbonyl, nitro, amino, methylamino-, formamido-, acetamido from following radicals.
Compound below the particularly preferred general formula of the present invention (I) compound or its isomer or its pharmacologically acceptable salt or hydrate are preferred:
(1) 2-methyl-4-phenyl-5-nitro-6-(4-aminomethyl phenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(2) 2-methyl-4-(2-chloro-phenyl-)-5-nitro-6-(4-aminomethyl phenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(3) 2-methyl-4-(3-chloro-phenyl-)-5-nitro-6-(4-aminomethyl phenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(4) 2-methyl-4-(2-chloro-phenyl-)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(5) 2-methyl-4-(3-chloro-phenyl-)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(6) 2-methyl-4-(2-chloro-phenyl-)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(7) 2-methyl-4-(4-fluorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(8) 2-methyl-4-(2-p-methoxy-phenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(9) 2-methyl-4-(2-bromophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(10) 2-methyl-4-(3-chloro-phenyl-)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(11) 2-methyl-4-(4-chloro-phenyl-)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(12) 2-methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(13) 2-methyl-4-(2-p-methoxy-phenyl)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(14) 2-methyl-4-(2-bromophenyl)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(15) 2-methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(16) 2-methyl-4-(4-chloro-phenyl-)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(17) 2-methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylate methyl ester;
(18) 2-methyl-4-(2-aminomethyl phenyl)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(19) 2-methyl-4-(2-aminomethyl phenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester; With
(20) 1-ethanoyl-2-methyl-4-(2-aminomethyl phenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester.
The compounds of this invention general formula (I) compound can prepare by following method:
A) under the situation that adds or do not add alkali or acid,, in suitable inert solvent, make the olefinic amine compound of general formula (II) in 20-150 ℃
R wherein
2Define the same,
With general formula R
3CHO (III) aldehyde
R wherein
3Define the same,
And general formula (IV) reaction,
R wherein
4Define the same,
React general formula (I) compound
R wherein
1Be hydrogen,
B) under alkaline condition, in suitable inert solvent, above-mentioned steps product and general formula R
1The X reaction obtains general formula (I) compound, wherein R
1Define the samely, X is for example fluorine, chlorine, bromine and an iodine of halogen.
Can utilize following reaction scheme to illustrate the inventive method:
For this reaction, the solvent that is suitable for is all inert organic solvents.These solvents preferably include alcohols such as ethanol, methyl alcohol, Virahol, ethers such as dioxane, ether, tetrahydrofuran (THF), methyl glycol, glycol dimethyl ether or Glacial acetic acid, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile, pyridine and hexamethylphosphoramide.
Temperature of reaction can change in the scope of broad.Usually this is reflected at 20-150 ℃ and carries out, but preferably carries out at the boiling point of each solvent.
This reaction can be at normal pressure, but also can carry out under elevated pressure.Usually this is reflected under the normal pressure and carries out.
This reaction can be carried out under the condition that adds or do not add alkali or acid.Organic acid such as formic acid, Glacial acetic acid, methylsulfonic acid, tosic acid, mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid etc.But the present invention reacts preferably and carries out in the presence of weak relatively acid such as acetate or formic acid.
The alkali that this reaction is suitable for preferably includes organic alkali such as triethylamine, methyl-diethyl-amine, pyridine, hexahydropyridine, morpholine, and mineral alkali such as yellow soda ash, salt of wormwood, sodium bicarbonate, acetic acid are received, sodium hydroxide, potassium hydroxide.
The enamine that is used as the general formula (II) of initial substance is known in some cases, perhaps can prepare according to the currently known methods of putting down in writing in the document (referring to Mara E.F.B., Hugo S.B., Lauri M, et al.Synthesis, 1994,898-900).
As the general formula (IV) of initial substance be known, perhaps can according to the currently known methods preparation of putting down in writing in the document (David C.Baker, Sterling R.Synthesis, 1978,6,478-479.).
General formula of the present invention (I) compound can be single synthetic with ordinary method, also mixed-the separating method or the parallel synthetic method of available combination chemistry (contain two at least with the storehouse in each storehouse, or 5-1000,10-100 compound preferably) synthetic for unit, promptly can in liquid phase, synthesize also and can use solid phase synthesis process.
See embodiment about the more detailed data of preparation general formula (I) compound.
The antivirus action of The compounds of this invention is pressed people such as Sells (M.A.Sells, M.L.Chen, G.Proc.Natl.Acad.Sci.1987,84,1005-1009) and (B.E.Korba, J.L.Gerin Antiviral Research 1992 such as Korba, 19,55-70) method of describing is measured.
In 96 hole microtiter plates, carry out antivirus test.The first perpendicular row of this plate only contains growth medium and HepG 2.2.15 cell, as blank.
At first the stock solution (50 mmole) with test compound is dissolved among the DMSO, prepares further diluent with HepG 2.2.15 cell growth medium.Usually compound of the present invention is inhaled in each hole that moves on to the microtiter plate second perpendicular experimental with the experimental concentration (the 1st experimental concentration) of 100 μ g/ml, adding 2% foetal calf serum (25 μ l) with growth medium then dilutes, 2 times of each dilutions, dilution is up to 2
10Doubly.
Then 225 μ l HepG 2.2.15 cells are added suspension (5 * 10 in 2% foetal calf serum at growth medium
4Individual cell/ml) be added in each hole of this 96 hole microtiter plate.
This test mixture is at 37 ℃, 5%CO
2Cultivated 4 days under the condition.Sucking-off supernatant liquor and discarding adds the freshly prepd growth medium of 225 μ l in each hole then.Add The compounds of this invention once more, liquor capacity 25 μ l.This mixture was cultivated 4 days again.
Investigating the HepG2.2.15 cytotoxicity with light microscope technique or biological chemistry detection method (as Alamar Blue dyeing or Trypan Blue dyeing) before the results supernatant liquor is measured antiviral effect changes.
Collect supernatant liquor then, and it is absorbed (by manufacturer's operation instruction) in the Dot blot chamber, 96 hole that covers with nylon membrane with vacuum.
Cytotoxic assay
Cytotoxicity in HepG 2.2.15 cell of being brought out by material or the variation that suppresses cell for example can adopt light microscope technique to measure, and represent with the variation of cellular form.It is significantly that the variation that this class is brought out by material in HepG 2.2.15 cell is compared with undressed cell, and for example cytolysis, cavity form or cellular form changes.With the observation of cell pathology is index, 8 days microscopically observation of cell pathologies, and completely destroy is 4; 75% is 3; 50% is 2; 25% is 1; Anosisly become 0.Calculate average cell lesion degree and inhibition percentage ratio under each concentration.Press Reed ﹠amp; The Muench method is calculated the poisonous concentration (TC of half
50), maximal non-toxic concentration (TC
0).
TC
50Be meant the concentration of the The compounds of this invention when 50% cell has the form similar to corresponding cell contrast.
Antiviral activity is measured
After supernatant liquor being transferred on the nylon membrane of spot device (referring to above), with supernatant liquor sex change (1.5M NaCl/0.5M NaOH), the neutralization (3MNaCl/0.5M Tris HCl, pH 7.5) of HepG2.2.15 cell with wash (2xSSC).DNA was baked on this film in 2-4 hour 120 ℃ of insulations filter membrane then.
DNA hybridization
Usually the hepatitis B specificity DNA probing needle of the active digoxigenin mark of employing non-radioactive is measured the viral DNA of the HepG 2.2.15 cell after handling on the nylon leaching film.Wherein, at every turn all be according to manufacturer's operation instruction with described probe with digoxigenin mark, purifying and hybridization.
Briefly, hydridization and hydridization are to carry out prehybridization and hybridization in 5 * SSC, 1 * encapsulant, 0.1%N-Sarkosyl L, 0.02%SDS and 100 μ g black carp sperm DNAs in advance.Carry out 30 minutes prehybridizations at 60 ℃, carry out specific hybrid (14 hours, 60 ℃) with the sex change HBV specific DNA of 20-40ng/ml digoxigeninization.Then filtering membrane is washed, carry out the digoxigenin antibody test of HBV DNA.
The immunology detection of the DNA of digoxigenin mark is undertaken by manufacturer's explanation.
Briefly, this filter membrane washs with encapsulant and prehybridization (by the explanation of manufacturers), hybridizes 30 minutes with the anti--DIG antibody that is coupled in advance on the alkaline phosphatase then.After the washing, add alkaline phosphate ester enzyme substrates CSPD, cultivated 5 minutes, wrap in the plastics film then, and cultivated again 15 minutes at 37 ℃ with filter.Strainer is exposed to the chemiluminescence signal (cultivating 10 minutes to 2 hours according to strength of signal) of measuring the specific DNA of hepatitis B on the x-ray film, calculation of half inhibitory concentration (IC
50).
Half-inhibition concentration (IC
50) be meant with untreated samples and compare, make hepatitis B specificity band reduce the concentration of 50% o'clock The compounds of this invention.
Compound exhibits of the present invention goes out stronger antivirus action.This compounds has antiviral activity beyond expectation to hepatitis B (HBV), therefore is suitable for being used for treating the various diseases that virus causes, the disease that especially acute and chronic persistence HBV virus infection causes.The chronic viral disease that is caused by HBV can cause the syndrome of various different severity, and is well-known, chronic HBV infection can cause liver cirrhosis and (or) hepatocellular carcinoma.
The example of the indication of available The compounds of this invention treatment has:
Treatment can cause the acute and chronic viral infection of infectious hepatitis, and is for example hepatitis b virus infected.Particularly preferably be the treatment of chronic hepatitis B infection and the treatment of acute hepatitis b virus infection.
The pharmaceutical composition of The compounds of this invention, any-mode that can following aspect is granted: in oral, spraying suction, rectal administration, intranasal administration, vagina administration, topical, parenterai administration such as subcutaneous, vein, intramuscular, intraperitoneal, the sheath, in the ventricle, in the breastbone or intracranial injection or input, or by a kind of reservoir medication of outer planting, wherein preferred oral, intramuscular injection, intraperitoneal or intravenously application method.
The compounds of this invention or contain the pharmaceutical composition of The compounds of this invention can the unit dosage form administration.Form of administration can be liquid dosage form, solid dosage.Liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.Other formulations are tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, suppository, lyophilized injectable powder, inclusion compound, implants, patch, liniment etc. for example.
Can also contain carrier commonly used in the pharmaceutical composition of the present invention, pharmaceutically acceptable carrier described here is including, but not limited to ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein such as human serum protein, buffer substance such as phosphoric acid salt, glycerine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloided silica, Magnesium Trisilicate, polyvinylpyrrolidone, cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, beeswax, wool grease etc.The content of carrier in pharmaceutical composition can be 1%-98% weight, accounts for 80% weight usually greatly.For simplicity, local anesthetic, sanitas, buffer reagents etc. can directly be dissolved in the carrier.
Oral tablet and capsule can contain vehicle such as tackiness agent, as syrup, and gum arabic, sorbyl alcohol, tragacanth, or polyvinylpyrrolidone, weighting agent is as lactose, sucrose, W-Gum, calcium phosphate, sorbyl alcohol, Padil, lubricant, as Magnesium Stearate, talcum, polyoxyethylene glycol, tripoli, disintegrating agent, as yam starch, or acceptable dibutyl phthalate, as bay sodium alkoxide vitriol.Tablet can be with known method dressing on the pharmacopedics.
Oral liquid can be made the suspension of water and oil, solution, and emulsion, syrup or elixir also can be made dry product, with preceding make up water or other suitable medium.This liquid preparation can comprise conventional additive, as suspension agent, and sorbyl alcohol, Walsroder MC 20000S, dextrose syrup, gel, Natvosol, carboxymethyl cellulose, aluminium stearate gel, hydrogenant food oils, emulsifying agent, as Yelkin TTS, sorb gathers candy list oleate, gum arabic; Or nonaqueous carrier (may comprise edible oil), as Prunus amygdalus oil, grease such as glycerine, ethylene glycol, or ethanol; Sanitas is as methyl p-hydroxybenzoate or propyl ester, Sorbic Acid.Can add seasonings or tinting material as needs.
Suppository can comprise conventional suppository base, as cocoa butter or other glyceryl ester.
Stomach is offerd medicine outward, and liquid formulation is made by compound and a kind of disinfectant carrier usually.The first-selected water of carrier.Different according to selected carrier and drug level, compound had both dissolved in and also can be made into aaerosol solution in the carrier, and was earlier that compound is soluble in water when making injection solution, packed into after the filter-sterilized and sealed in bottle or the ampoule.
When topical application, The compounds of this invention can be made suitable ointment, lotion, or the form of creme, and wherein activeconstituents suspends or is dissolved in one or more the carrier.Wherein the operable carrier of ointment formulation is including, but not limited to mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion and creme includes but not limited to: mineral oil, and sorbitan monostearate, polysorbate60, the n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
The concentration that exists at the active compound of said medicine preparation formula of (I) should be the about 0.1～99.5% of this mixture total weight amount, preferred about 0.5～95% (weight).
The said medicine preparation also can further comprise other pharmaceutical active compounds except the compound that comprises general formula (I).
Generally speaking, verified advantageously no matter at human body medicine or in veterinary drug, the administration total amount of active compound of the present invention was about 0.5-500mg in per 24 hours, preferred 1-100mg/kg body weight, if suitable, single dose administration several times is to reach desired effect.The amount that contains active compound in the single dose is preferably about 1-80mg, 1-50mg/kg body weight more preferably, but also can be not according to above-mentioned dosage, the character and severity, the type of preparation and the administering mode of medicine that promptly depend on the kind of treatment target and body weight, disease, and the administration cycle or the timed interval.
Embodiment
Further specify the present invention below by specific embodiment, still, should be understood to, these embodiment are only used for the more detailed usefulness that specifically describes, and are used for limiting in any form the present invention and should not be construed as.
The present invention carries out generality and/or concrete description to the material and the test method that are used in the test.Though for realizing that employed many materials of the object of the invention and working method are well known in the art, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if do not specify that material therefor of the present invention and working method are well known in the art.
The fusing point of compound is measured by RY-1 fusing point instrument, and thermometer is calibration not.Mass spectrum is measured by Micromass ZabSpec high resolution mass spectrometer (resolving power 1000).
1H NMR is measured by JNM-ECA-400 SUPERCONDUCTING NMR instrument, operating frequency
1H NMR 400MHz.
Embodiment
Embodiment 1:2-methyl-4-phenyl-5-nitro-6-(4-aminomethyl phenyl)-1, the 4-dihydropyridine
-3-carboxylic acid, ethyl ester
Step 1:2-nitro is synthetic to the toluene ethyl ketone
5.68g (94mmol) Nitromethane 99Min. is slowly splashed in the 20ml anhydrous THF solution of 0.96gNaH (24mmol), drip and finish, stirring at room is emerged to no longer including bubble, places standby.
With 2.72g paratolunitrile (20mmol), 3.89g phosphinylidyne diimidazole (24mmol) 1h that refluxes in the anhydrous THF of 50ml, the TLC detection reaction is complete.Reaction solution is slowly dropped in the above-mentioned reserve liquid, drip and finish backflow 16h.Cooling is filtered, the 150ml water dissolution, and hydrochloric acid transfers pH to about 3.0.Ethyl acetate extraction merges organic layer for several times, concentrates, and obtains crude product.Crude product is dissolved in ethyl acetate, adds sherwood oil, separates out crystal.Filtration drying promptly gets little yellow crystal 1.79g.Yield: 50%.Fusing point: 145-147 ℃.
Synthesizing of step 2:3-amino-2-butylene acetoacetic ester
13.0g methyl aceto acetate, 3.0g polynite k-10 are added in the reaction flask stirring at room.Slowly splash into 10.0g ammoniacal liquor, stirring is spent the night.The washed with dichloromethane extraction adds anhydrous MgSO
4Dry.Filter, concentrate, obtain little yellow solid 10.0g.Yield: 79.5%.Fusing point: 107 ℃.
Step 3:2-methyl-4-phenyl-5-nitro-6-(4-aminomethyl phenyl)-1,4-dihydropyridine-3-carboxylic
Synthesizing of acetoacetic ester
The 2-nitro is added in the 40ml toluene toluene ethyl ketone 5mmol, phenyl aldehyde 8mmol, Beta-alanine 0.07g, splash into the 4ml Glacial acetic acid, stirring and refluxing.Reaction 3h concentrates, and residue is weighed, and adds the 3-amino-2-butylene acetoacetic ester 5mmol of equimolar amount, 15ml Glacial acetic acid, stirring at room 20h.Concentrate, column chromatography gets yellow crystal 0.7g (yield 38.9%).m.p.193-194℃。
1H NMR(DMSO-d
6)(ppm)：1.169-1.204(3H，t，CH
3)，2.311(3H，s，CH
3)，2.374(3H，s，ArCH
3)，4.070-4.088(2H，m，CH
2)，5.312(1H，s，CH)，7.285-7.313(9H，m，ArH)，9.758(1H，s，NH)。MS(FAB)379.1(M
+)。
Embodiment 2:2-methyl-4-(2-chloro-phenyl-)-5-nitro-6-(4-aminomethyl phenyl)-1, the 4-dihydro
The pyridine-3-carboxylic acid ethyl ester
Adopt the method for embodiment 1, change wherein phenyl aldehyde into the 2-chlorobenzaldehyde, the 0.25g yellow crystal, yield 12.1%, m.p.205-206 ℃.
1H NMR(DMSO-d6)(ppm)：1.107-1.143(3H，t，CH
3)，2.494(3H，s，CH
3)，2.498(3H，s，ArCH
3)，4.002-4.019(2H，m，CH
2)，5.689(1H，s，CH)，7.226-7.353(8H，m，ArH)，9.750(1H，s，NH)。MS(FAB)413.1(M
+)。
Embodiment 3:2-methyl-4-(3-chloro-phenyl-)-5-nitro-6-(4-aminomethyl phenyl)-1, the 4-dihydro
The pyridine-3-carboxylic acid ethyl ester
Adopt the method for embodiment 1, change wherein phenyl aldehyde into the 2-chlorobenzaldehyde, the 0.21g yellow crystal, yield 10.2%, m.p.141-142 ℃.
1H NMR(DMSO-d6)(ppm)：1.171-1.207(3H，t，CH
3)，2.328(3H，s，CH
3)，2.376(3H，s，ArCH
3)，4.061-4.092(2H，m，CH
2)，5.299(1H，s，CH)，7.280-7.316(8H，m，ArH)，9.818(1H，s，NH)。MS(FAB)413.0(M
+)。
Embodiment 4:2-methyl-4-(2-chloro-phenyl-)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-
Dihydropyridine-3-carboxylic acid, ethyl ester
The Beta-alanine of 2-chlorobenzaldehyde 8mmol, 2-nitrotrimethylolmethane fluoro acetophenone 5mmol, 0.07g is added in the 40ml toluene, splash into the 4ml Glacial acetic acid, stirring and refluxing.Reaction 3h concentrates, and residue is weighed, and adds the 3-amino-2-butylene acetoacetic ester 6.7mmol of equimolar amount, 15ml Glacial acetic acid, stirring at room 20h.Concentrate, column chromatography gets yellow powder 0.4g.Yield: 17.7%.M.p.176-177 ℃ of product fusing point.
1H NMR(DMSO-d6)(ppm)：1.111-1.147(3H，t，CH
3)，2.497(3H，s，CH
3)，4.021-4.039(2H，m，CH
2)，5.784(1H，s，CH)，7.329-7.460(6H，m，ArH)，10.081(1H，s，NH)。MS(FAB)453.0(M
+)。
Embodiment 5:2-methyl-4-(3-chloro-phenyl-)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-
Dihydropyridine-3-carboxylic acid, ethyl ester
Adopt the method for embodiment 4, wherein the 2-chlorobenzaldehyde changes the 3-chlorobenzaldehyde into, gets 0.2g orange needle crystal, yield 17.8%, m.p.150-151 ℃.
1H NMR(DMSO-d6)(ppm)：1.181-1.217(3H，t，CH
3)，2.302(3H，s，CH
3)，4.087-4.118(2H，m，CH
2)，5.378(1H，s，CH)，7.299-7.354(6H，m，ArH)，10.166(1H，s，NH)。MS(FAB)453.0(M
+)。
Embodiment 6:2-methyl-4-(2-chloro-phenyl-)-5-nitro-6-(2-thienyl)-1,4-dihydro pyrrole
Pyridine-3-carboxylic acid, ethyl ester
The Beta-alanine of 2-chlorobenzaldehyde 8mmol, 2-nitrothiophene ethyl ketone 5mmol, 0.07g is added in the 40ml toluene, splash into the 4ml Glacial acetic acid, stirring and refluxing.Reaction 3h concentrates, and residue is weighed, and adds the 3-amino-2-butylene acetoacetic ester 8mmol of equimolar amount, 15ml Glacial acetic acid, stirring at room 20h.Concentrate, column chromatography gets orange crystallization 0.2g.Yield: 9.9%.M.p.146-147 ℃ of product fusing point.
1H NMR (DMSO-d6)(ppm)：1.105-1.140(3H，t，CH
3)，2.301(3H，s，CH
3)，3.990-4.025(2H，q，CH
2)，5.682(1H，s，CH)，7.183-7.443(6H，m，ArH，C
4H
3SH)，7.804-7.820(1H，q，C
4H
3SH)，9.862(1H，s，NH)。MS(FAB)405.1(M
+)。
Embodiment 7:2-methyl-4-(4-fluorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydro pyrrole
Pyridine-3-carboxylic acid, ethyl ester
Adopt the method for embodiment 6, wherein the 2-chlorobenzaldehyde changes the 4-fluorobenzaldehyde into, gets the 0.25g yellow crystal, yield 12.6%, m.p.145-146 ℃.
1H NMR(DMSO-d6)(ppm)：1.160-1.196(3H，t，CH
3)，2.338(3H，s，CH
3)，4.075-4.092(2H，m，CH
2)，5.294(1H，s，CH)，7.159-7.393(6H，m，ArH，C
4H
3SH)，7.845-7.858(1H，q，C
4H
3SH)，9.952(1H，s，NH)。MS(FAB)389.1(M
+)。
Embodiment 8:2-methyl-4-(2-p-methoxy-phenyl)-5-nitro-6-(2-thienyl)-1,4-
Dihydropyridine-3-carboxylic acid, ethyl ester
Adopt the method for embodiment 6, change wherein 2-chlorobenzaldehyde into the 2-methoxybenzaldehyde, the red crystallization of 0.32g, yield 16%, m.p.173-174 ℃.
1H NMR(DMSO-d6)(ppm)：1.137-1.173(3H，t，CH
3)，2.255(3H，s，CH
3)，3.749(3H，s，OCH
3)，3.992-4.028(2H，q，CH
2)，5.459(1H，s，CH)，7.172-7.219(5H，m，ArH，C
4H
3SH)，7.310-7.318(1H，d，C
4H
3SH)，7.797-7.809(1H，d，C
4H
3SH)，9.807(1H，s，NH)。MS(FAB)401.1(M
+)。
Embodiment 9:2-methyl-4-(2-bromophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydro pyrrole
Pyridine-3-carboxylic acid, ethyl ester
Adopt the method for embodiment 6, wherein the 2-chlorobenzaldehyde changes the 2-bromobenzaldehyde into, gets the red crystallization of 0.31g, yield 13.8%, m.p.144-145 ℃.
1H NMR(DMSO-d6)(ppm)：1.106-1.141(3H，t，CH
3)，2.295(3H，s，CH
3)，4.017-4.035(2H，m，CH
2)，5.662(1H，s，CH)，7.167-7.440(5H，m，ArH，C
4H
3SH)，7.533-7.551(1H，d，C
4H
3SH)，7.800-7.814(1H，q，C
4H
3SH)，9.827(1H，s，NH)。MS(FAB)451.0(M
+)。
Embodiment 10:2-methyl-4-(3-chloro-phenyl-)-5-nitro-6-(2-thienyl)-1, the 4-dihydro
The pyridine-3-carboxylic acid ethyl ester
Adopt the method for embodiment 6, change wherein 2-chlorobenzaldehyde into the 3-chlorobenzaldehyde, the red crystallization of 0.6g, yield 29.7%, m.p.130-131 ℃.
1H NMR(DMSO-d6)(ppm)：1.174-1.210(3H，t，CH
3)，2.346(3H，s，CH
3)，4.086-4.119(2H，m，CH
2)，5.287(1H，s，CH)，7.264-7.416(6H，m，ArH，C
4H
3SH)，7.861-7.874(1H，m，C
4H
3SH)，10.012(1H，s，NH)。MS(FAB)405.0(M
+)。
Embodiment 11:2-methyl-4-(4-chloro-phenyl-)-5-nitro-6-(2-thienyl)-1, the 4-dihydro
The pyridine-3-carboxylic acid ethyl ester
Adopt the method for embodiment 6, change wherein 2-chlorobenzaldehyde into the 4-chlorobenzaldehyde, the 0.18g yellow crystal, yield 9%, m.p.148-149 ℃.
1H NMR(DMSO-d6)(ppm)：1.162-1.197(3H，t，CH
3)，2.339(3H，s，CH
3)，4.070-4.088(2H，m，CH
2)，5.283(1H，s，CH)，7.280-7.411(6H，m，ArH，C
4H
3SH)，7.849-7.862(1H，m，C
4H
3SH)，9.971(1H，s，NH)。MS(FAB)405.1(M
+)。
Embodiment 12:2-methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2-thienyl)-1,4-
Dihydropyridine-3-carboxylic acid, ethyl ester
Adopt the method for embodiment 6, change wherein 2-chlorobenzaldehyde into 2-chloro-4-fluorobenzaldehyde, the red crystallization of 0.3g, yield 14.2%, m.p.152-153 ℃.
1H NMR(DMSO-d6)(ppm)：1.109-1.144(3H，t，CH
3)，2.305(3H，s，CH
3)，3.995-4.031(2H，q，CH
2)，5.656(1H，s，CH)，7.162-7.347(4H，m，ArH，C
4H
3SH)，7.439-7.477(1H，q，C
4H
3SH)，7.806-7.822(1H，q，C
4H
3SH)，9.886(1H，s，NH)。MS(FAB)423.1(M
+)。
Embodiment 13:2-methyl-4-(2-p-methoxy-phenyl)-5-nitro-6-(2,4, the 6-trifluoro-benzene
Base)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester
Adopt the method for embodiment 4, change wherein 2-chlorobenzaldehyde into the 2-methoxybenzaldehyde, the 0.6g yellow crystal, yield 27%, m.p.163-164 ℃.
1H NMR(DMSO-d6)(ppm)：1.131-1.166(3H，t，CH
3)，2.231(3H，s，CH
3)，3.754(3H，s，OCH
3)，3.981-4.016(2H，q，CH
2)，5.595(1H，s，CH)，6.849-6.887(1H，t，ArH)，6.955-6.976(1H，d，ArH)，7.173-7.241(2H，m，ArH)，7.351-7.430(2H，q，ArH)，9.948(1H，s，NH)。MS(FAB)449.1(M
+)。
Embodiment 14:2-methyl-4-(2-bromophenyl)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-
Dihydropyridine-3-carboxylic acid, ethyl ester
Adopt the method for embodiment 4, wherein the 2-chlorobenzaldehyde changes the 2-bromobenzaldehyde into, gets the 0.63g yellow crystal, yield 25%, m.p.173-174 ℃.
1H NMR(DMSO-d6)(ppm)：1.120-1.155(3H，t，CH
3)，2.276(3H，s，CH
3)，4.050-4.068(2H，m，CH
2)，5.760(1H，s，CH)，7.118-7.159(1H，m，ArH)，7.378-7.536(5H，m，ArH)，10.086(1H，s，NH)。MS(FAB)497.0(M
+)。
Embodiment 15:2-methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2,4, the 6-trifluoro-benzene
Base)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester
Adopt the method for embodiment 4, change wherein 2-chlorobenzaldehyde into 2-chloro-4-fluorobenzaldehyde, the 0.3g yellow crystal, yield 13%, m.p.185-186 ℃.
1H NMR(DMSO-d6)(ppm)：1.117-1.153(3H，t，CH
3)，2.287(3H，s，CH
3)，4.009-4.043(2H，q，CH
2)，5.759(1H，s，CH)，7.238-7.245(1H，m，ArH)，7.324-7.493(4H，m，ArH)，10.152(1H，s，NH)。MS(FAB)471.1(M
+)。
Embodiment 16:2-methyl-4-(4-chloro-phenyl-)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-
Dihydropyridine-3-carboxylic acid, ethyl ester
Adopt the method for embodiment 4, change wherein 2-chlorobenzaldehyde into the 4-chlorobenzaldehyde respectively, the 0.15g yellow crystal, yield 7%, m.p.160-161 ℃.
1H NMR(DMSO-d6)(ppm)：1.166-1.201(3H，t，CH
3)，2.300(3H，s，CH
3)，4.053-4.071(2H，m，CH
2)，5.366(1H，s，CH)，7.312-7.334(2H，d，ArH)，7.390-7.411(4H，m，ArH)，10.158(1H，s，NH)。MS(FAB)453.1(M
+)。
Embodiment 17:2-methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2,4, the 6-trifluoro-benzene
Base)-1,4-dihydropyridine-3-carboxylate methyl ester
Adopt the method for embodiment 4, change wherein 2-chlorobenzaldehyde and 3-amino-2-butylene acetoacetic ester into 2-chloro-4-fluorobenzaldehyde 2-amino-2-butylene acid methyl esters respectively, the 0.36g yellow crystal.Yield 16%, m.p.154-155.
1HNMR(DMSO-d6)(ppm)：2.284(3H，s，CH
3)，3.572(3H，s，CH
3)，5.761(1H，s，CH)，7.216-7.265(1H，m，ArH)，7.323-7.484(4H，m，ArH)，10.170(1H，s，NH)。MS(FAB)457.0(M
+)。
Embodiment 18:2-methyl-4-(2-aminomethyl phenyl)-5-nitro-6-(2,4, the 6-trifluoro-benzene
Base)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester
Adopt the method for embodiment 4, change wherein 2-chlorobenzaldehyde into the 2-tolyl aldehyde, the 0.7g yellow crystal, yield 32%, m.p.177-178 ℃.
1H NMR(DMSO-d6)(ppm)：1.122-1.158(3H，t，CH
3)，2.291(3H，s，CH
3)，2.503-2.567(3H，d，ArCH
3)，4.022-4.057(2H，q，CH
2)，5.551(1H，s，CH)，7.076-7.447(6H，m，ArH)，10.035(1H，s，NH)。MS(FAB)433.1(M
+)。
Embodiment 19:2-methyl-4-(2-aminomethyl phenyl)-5-nitro-6-(2-thienyl)-1,4-two
Pyridinium hydroxide-3-carboxylic acid, ethyl ester
Adopt the method for embodiment 6, change wherein 2-chlorobenzaldehyde into the 2-tolyl aldehyde, the 0.7g yellow crystal, yield 36%, m.p.171-172 ℃.
1H NMR(DMSO-d6)(ppm)：1.115-1.151(3H，t，CH
3)，2.316(3H，s，CH
3)，2.499-2.507(3H，d，ArCH
3)，4.012-4.047(2H，q，CH
2)，5.457(1H，s，CH)，7.085-7.336(6H，m，ArH)，7.811-7.824(1H，d，C
4H
3SH)，9.812(1H，s，NH)。MS(FAB)385.1(M
+)。
Embodiment 20:1-ethanoyl-2-methyl-4-(2-aminomethyl phenyl)-5-nitro-6-(2-thiophene
Base)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester
Product 0.2 gram of embodiment 19 is dissolved among the anhydrous tetrahydro furan 5ml, adds sodium hydride 22mg, emerge to no longer including bubble, add Acetyl Chloride 98Min. 0.05ml, room temperature reaction 1 hour adds the water termination reaction.Concentrate residue water, ethyl acetate separatory, organic phase dried over sodium sulfate.Filter, the evaporating column chromatography gets faint yellow solid 0.18 gram.Yield 81%.
1H NMR(DMSO-d6)(ppm)：1.12-1.15(3H，t，CH
3)，2.04(3H，s，CH
3)，2.33(3H，s，CH
3)，2.50-2.52(3H，d，ArCH
3)，4.02-4.07(2H，q，CH
2)，5.46(1H，s，CH)，7.09-7.34(6H，m，ArH)，7.81-7.83(1H，d，C
4H
3SH)。MS(FAB)426.1(M
+)。
Embodiment 21: the cytotoxicity of compound and antiviral activity are measured
Cytotoxicity and antiviral activity according to method mensuration The compounds of this invention mentioned above the results are shown in Table 1.
Table 1: compound is to the restraining effect of HBV DNA
| The experimental example numbering | Inhibiting rate ＊ | IC 50(μg/ml) | TC 50(μg/ml) | SI |
| 1 | 12.91％ | - | 1.92 | |
| 10 | 28.93％ | - | 5.75 | |
| 11 | 17.81％ | - | 17.25 | |
| 12 | 24.77％ | - | 22.22 | |
| 13 | 32.66％ | - | 22.22 | |
| 14 | 10.73％ | - | 12.83 | |
| 15 | 41.07％ | 0.42 | 5.75 | 13.69 |
| 16 | 22.02 | - | 5.75 |
*0.27 under the μ g/ml concentration, compound is to the inhibiting rate of HBV DNA.
Claims (10)
1, general formula (I) compound,
Wherein:
R
1Represent hydrogen, (C
1-C
6)-alkyl, (C
2-C
6)-alkenyl, (C
1-C
6)-acyl group, alkylsulfonyl;
R
2Representative (C
1-C
6)-alkyl;
R
3Represent aryl or heteroaryl, it is optional to be selected from following substituting group independently of one another and to replace by one or more: hydrogen, halogen, trifluoromethyl, trifluoromethoxy, trifyl, nitro, cyano group, carboxyl, hydroxyl, amino, (C
1-C
6)-alkylamino, (C
1-C
6)-dialkyl amido, (C
1-C
6)-amido, (C
1-C
6)-alkyl, (C
1-C
6)-alkoxyl group, (C
1-C
6)-carbalkoxy, (C
1-C
6)-carbamyl, wherein said alkyl can be had aryl, the halogen, (C of 6-10 carbon atom
1-C
6)-alkoxyl group, (C
1-C
6)-alkylamino, amide group replace;
R
4Represent aryl or heteroaryl, it is optional to be selected from following substituting group independently of one another and to replace by one or more: hydrogen, halogen, hydroxyl, cyano group, carboxyl, trifluoromethyl, nitro, benzyl, (C
1-C
6)-alkyl, (C
1-C
6)-alkoxyl group, (C
1-C
6)-alkylthio, (C
1-C
6)-carbalkoxy, (C
1-C
6)-acyloxy, amino, (C
1-C
6)-alkylamino or (C
1-C
6)-dialkyl amido, (C
1-C
6)-acyl amino, (C
1-C
6)-carbamyl,
Or its isomer, pharmacologically acceptable salt or hydrate.
2, according to the compound of claim 1, wherein:
R
1Represent hydrogen, (C
1-C
3)-alkyl, formyl radical, ethanoyl, benzoyl, methylsulfonyl, benzene methylsulfonyl, p-toluenesulfonyl;
R
2Representative (C
1-C
4)-alkyl;
R
3Represent aryl or heteroaryl, it is optional to be selected from following substituting group independently of one another and to replace by one or more: hydrogen, halogen, trifluoromethyl, trifluoromethoxy, trifyl, nitro, cyano group, carboxyl, hydroxyl, amino, (C
1-C
4)-alkylamino, (C
1-C
4)-dialkyl amido, (C
1-C
4)-amido, (C
1-C
4)-alkoxy carbonyl, (C
1-C
4)-alkoxyl group, (C
1-C
4)-alkyl, (C
1-C
4)-carbamyl;
R
4Represent aryl or heteroaryl, it is optional to be selected from following substituting group independently of one another and to replace by one or more: hydrogen, halogen, nitro, cyano group, hydroxyl, trifluoromethyl, carboxyl, (C
1-C
3)-alkyl, (C
1-C
3)-alkoxyl group, (C
1-C
3)-carbalkoxy, amino, (C
1-C
3)-alkylamino, (C
1-C
3)-dialkyl amido, (C
1-C
3)-acyl amino, (C
1-C
3)-carbamyl.
Or its isomer, pharmacologically acceptable salt or hydrate.
3, according to the compound of claim 1, wherein:
R
1Represent hydrogen, methyl, formyl radical, ethanoyl, methylsulfonyl, benzoyl;
R
2Represent methylidene, ethyl, propyl group, sec.-propyl;
R
3Represent aryl or heteroaryl, it is optional to be selected from following substituting group independently of one another and to replace by one or more: hydrogen, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, trifyl, nitro, cyano group, carboxyl, hydroxyl, amino, methylamino-, dimethylamino, formamido-, acetamido, ethylamino, methoxycarbonyl, methoxyl group, oxyethyl group, methyl, ethyl, propyl group;
R
4Represent aryl or heteroaryl, it is optional to be selected from following substituting group independently of one another and to replace by one or more: hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl group, sec.-propyl, hydroxyl, carboxyl, methoxyl group, oxyethyl group, methoxycarbonyl, ethoxycarbonyl, nitro, amino, methylamino-, dimethylamino, formamido-, ethylamino, acetamido.
Or its isomer, pharmacologically acceptable salt or hydrate.
4, according to the compound of claim 1, wherein:
R
1Represent hydrogen, ethanoyl;
R
2Represent methylidene, ethyl;
R
3Represent single the replacement or polysubstituted optional identical or different substituent aryl: hydrogen, chlorine, fluorine, bromine, trifluoromethyl, methyl, methoxyl group, carboxyl, cyano group, hydroxyl from following radicals;
R
4Represent single the replacement or polysubstituted optional identical or different substituent phenyl, thienyl, thiazolyl: hydrogen, fluorine, methyl, hydroxyl, methoxyl group, methoxycarbonyl, nitro, amino, methylamino-, formamido-, acetamido from following radicals.
Or its isomer, pharmacologically acceptable salt or hydrate.
5, according to the compound of claim 1, it is selected from:
(1) 2-methyl-4-phenyl-5-nitro-6-(4-aminomethyl phenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(2) 2-methyl-4-(2-chloro-phenyl-)-5-nitro-6-(4-aminomethyl phenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(3) 2-methyl-4-(3-chloro-phenyl-)-5-nitro-6-(4-aminomethyl phenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(4) 2-methyl-4-(2-chloro-phenyl-)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(5) 2-methyl-4-(3-chloro-phenyl-)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(6) 2-methyl-4-(2-chloro-phenyl-)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(7) 2-methyl-4-(4-fluorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(8) 2-methyl-4-(2-p-methoxy-phenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(9) 2-methyl-4-(2-bromophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(10) 2-methyl-4-(3-chloro-phenyl-)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(11) 2-methyl-4-(4-chloro-phenyl-)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(12) 2-methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(13) 2-methyl-4-(2-p-methoxy-phenyl)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(14) 2-methyl-4-(2-bromophenyl)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(15) 2-methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(16) 2-methyl-4-(4-chloro-phenyl-)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(17) 2-methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylate methyl ester;
(18) 2-methyl-4-(2-aminomethyl phenyl)-5-nitro-6-(2,4, the 6-trifluorophenyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester;
(19) 2-methyl-4-(2-aminomethyl phenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester; With
(20) 1-ethanoyl-2-methyl-4-(2-aminomethyl phenyl)-5-nitro-6-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, ethyl ester,
Or its isomer, pharmacologically acceptable salt or hydrate.
6, prepare the method for each described compound of claim 1-5, it comprises:
Steps A) under the situation that adds or do not add alkali or acid, in suitable inert solvent, the olefinic amine compound of general formula (II)
Aldehyde with general formula (III)
R
3CHO (III)
And the reaction of the compound of general formula (IV),
Obtain R wherein
1General formula (I) compound for hydrogen; With, optional
Step B) under alkaline condition, in suitable inert solvent, above-mentioned steps A) product and formula R
1The compound reaction that X represents obtains general formula (I) compound,
Wherein, X represents halogen (for example fluorine, chlorine, bromine and iodine), R
1, R
2, R
3, and R
4Separately with the definition in each described compound of claim 1-4.
7, a kind of pharmaceutical composition, it comprises each the described compound of claim 1-4 that treats and/or prevents significant quantity, optional pharmaceutically useful carrier, and optional other medicines active compound.
8, each described compound of claim 1-4 preparation be used for the treatment of and/or the medicine of prophylaxis of acute or chronic viral disease in purposes.
9, each described compound of claim 1-4 preparation be used for the treatment of and/or the medicine of prophylaxis of acute or chronic HBV infection in purposes.
10 treat and/or prevent the method that acute or chronic viral disease particularly treats and/or prevents acute or chronic HBV infection, and it comprises the compound to each described general formula (I) of first aspect present invention of experimenter's administering therapeutic that needs are arranged and/or prevention significant quantity.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010148632A1 (en) * | 2009-06-25 | 2010-12-29 | 中国人民解放军军事医学科学院毒物药物研究所 | Dihydropyridine compounds and preparation methods, pharmaceutical compositions and uses thereof |
| US9447086B2 (en) | 2012-09-10 | 2016-09-20 | Hoffmann-La Roche Inc. | 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection |
| US9856247B2 (en) | 2012-03-31 | 2018-01-02 | Hoffmann-La Roche Inc. | 4-methyl-dihydropyrimidines for the treatment and prophylaxis of Hepatitis B virus infection |
| CN108840800A (en) * | 2018-05-28 | 2018-11-20 | 上海华堇生物技术有限责任公司 | A kind of new preparation process of phenyl nitro ethyl ketone |
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| EP1052990A2 (en) * | 1997-11-14 | 2000-11-22 | Neurosearch A/S | Chemical compounds having ion channel blocking activity for the treatment of immune dysfunction |
| CN101575314B (en) * | 2009-06-25 | 2011-05-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Dihydropyridine compounds and application thereof on preparing drugs for curing and/or preventing virus diseases |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010148632A1 (en) * | 2009-06-25 | 2010-12-29 | 中国人民解放军军事医学科学院毒物药物研究所 | Dihydropyridine compounds and preparation methods, pharmaceutical compositions and uses thereof |
| US9856247B2 (en) | 2012-03-31 | 2018-01-02 | Hoffmann-La Roche Inc. | 4-methyl-dihydropyrimidines for the treatment and prophylaxis of Hepatitis B virus infection |
| US9447086B2 (en) | 2012-09-10 | 2016-09-20 | Hoffmann-La Roche Inc. | 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection |
| CN108840800A (en) * | 2018-05-28 | 2018-11-20 | 上海华堇生物技术有限责任公司 | A kind of new preparation process of phenyl nitro ethyl ketone |
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