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CN107848986A - Pyridazinone compound, its preparation method, pharmaceutical composition and purposes - Google Patents

Pyridazinone compound, its preparation method, pharmaceutical composition and purposes Download PDF

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Publication number
CN107848986A
CN107848986A CN201680040315.6A CN201680040315A CN107848986A CN 107848986 A CN107848986 A CN 107848986A CN 201680040315 A CN201680040315 A CN 201680040315A CN 107848986 A CN107848986 A CN 107848986A
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ring
methyl
propyl
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general formula
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Inventor
胡有洪
左建平
陆栋
唐炜
邢唯强
杨莉
王浪
王亚娟
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Shanghai Institute of Materia Medica of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

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Abstract

Pyridazinone compound or its pharmaceutically acceptable salt, its preparation method, pharmaceutical composition shown in a kind of below formula I and its purposes in preparing hepatitis type B virus inhibitor and prevention and/or treating the medicine of hepatitis B.

Description

Pyridazinone compound, preparation method, pharmaceutical composition and purposes
Cross reference
This application claims in the priority and right of the application for a patent for invention CN201510512718.3 submitted to China State Intellectual Property Office on the 19th of August in 2015, all the contents of the application are incorporated herein by the following way herein, as recording herein.
Technical field
The invention belongs to field of medicinal chemistry.Specifically, the present invention relates to a kind of pyridazinone compound or its pharmaceutically acceptable salt, preparation method, pharmaceutical composition and purposes.Such compound or its pharmaceutical composition can be used for preparing hepatitis type B virus inhibitor, to prevent and/or treat hepatitis B.
Background technique
According to the statistics of the World Health Organization, the whole world has had 2,000,000,000 people to infect hepatitis type B virus (HBV) at present, and about hundred million Genus Homo of 3.5-4.0 is in chronic infection.Annual about 1,000,000 people die of cirrhosis, liver function the energy metabolism not complication such as complete, liver cancer because infecting hepatitis B.Therefore, hepatitis b virus infected is still a kind of worldwide disease for seriously endangering public health.
Currently, interferon and ucleosides anti-hepatitis virus medicine are two kinds of hepatitis b virus infected main means for the treatment of.But the disadvantages of interferon is there are poor resistance, adverse reaction is more, somewhat expensive；And the 6 kinds of nucleoside medicines (Lamivudine, Aldoforwe ester, entecavir grace, Sebivo, tenofovir and Clevudine) listed at present act on the reverse transcriptase of hepatitis type B virus, different degrees of drug resistance and side effect can be generated in long-term treatment, greatly limit the application of this kind of drug.
Therefore, the non-nucleoside small molecule hepatitis B virus resisting medicine that research and development more acts on novel targets, new mechanism and brand new parent nucleus is increasingly urgent to, it is the hot spot of current field of medicinal chemistry research, and there is highly important theoretical, economy and society meaning.
Summary of the invention
It is an object of the present invention to provide a kind of pyridazinone compound or its pharmaceutically acceptable salts.
It is a further object to provide the preparation methods of the compounds of this invention.
A further object of the present invention is to provide pyridazinone compound or its pharmaceutically acceptable salt of the invention as hepatitis type B virus inhibitor and the purposes in the drug that preparation prevents and treats hepatitis B.
It is also another object of the present invention to provide a kind of prevention and/or the methods for the treatment of hepatitis B.
According to an aspect of the present invention, the present invention provides pyridazinone compound or its pharmaceutically acceptable salts shown in a kind of following general formula I:
Wherein,
R1、R2It is each independently H, C1-C7 linear or branched alkyl group, C3-C6 naphthenic base or 6-10 member aryl or R1And R2It is formed together with the carbon atom being connected containing the 1-3 heteroatomic 5-7 member hetero-aromatic rings or non-aromatic heterocyclic rings in N, O and S,
Preferably, R1、R2It is each independently H, C1-C4 linear or branched alkyl group, C3-C6 naphthenic base or phenyl or R1And R2It is formed together with the carbon atom being connected containing 1-2 5-7 member hetero-aromatic rings heteroatomic in N, O and S or non-aromatic heterocyclic rings,
It is highly preferred that R1、R2It is each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl or R1And R2Pyrrole ring, thiphene ring, furan nucleus, pyridine ring, nafoxidine ring, thiophane ring or tetrahydrofuran ring are formed together with the carbon atom being connected；
Heteroatomic 5-10 member hetero-aromatic ring of the A for 6-10 member aromatic ring or containing 1-3 in N, O and S,
Preferably, heteroatomic 5-10 member hetero-aromatic ring of the A for phenyl ring or containing 1-2 in N, O and S,
It is highly preferred that A is phenyl ring, pyridine ring, pyrrole ring, pyrimidine ring, pyridine ring, pyridazine ring, thiphene ring, furan nucleus, pyrazole ring, imidazole ring, oxazole ring, thiazole ring, indole ring, azaindole ring, naphthyridines ring, benzimidazole ring, imidazopyridine ring or imidazopyrimidine ring or quinoline ring；
It is highly preferred that A is phenyl ring, pyridine ring, pyrimidine ring, pyridine ring, pyrazole ring, pyridazine ring, indole ring, azaindole ring, naphthyridines ring, imidazo [1,2-a] pyridine ring or imidazo [1,2-a] pyrimidine ring or quinoline ring；
R3Indicate one or more substituent groups, it is preferred that indicating 1,2 or 3 substituent group, the substituent group is each independently selected from H, halogen, cyano, nitro, C1-C7 linear or branched alkyl group, C1-C6 straight or branched alkoxyl, by two C1-C7 linear or branched alkyl groups, preferably C1-C4 alkyl, the more preferable alkyl-substituted amino of C1-C2 (preferably dimethylamino), the first saturated heterocyclyl (more preferable oxetanyl, azetidinyl) of heteroatomic 3-8 (preferably 3-5) containing 1-3 in N, O and S
Wherein, n is selected from integer of 0 to 10, it is preferable that n is the integer selected from 0 to 7, it is highly preferred that n is 0,1,2,3 or 4；
R4For H, halogen, C1-C7 linear or branched alkyl group, C3-C6 naphthenic base, 6-10 member aryl, the heteroatomic 5-10 unit's heteroaryl containing 1-3 in N, O and S, heteroatomic 3-8 member saturated heterocyclyl containing 1-3 in N, O and S, the unsubstituted or amino that is replaced by 1-2 substituent group；Wherein, the substituent group in described " amino replaced by 1-2 substituent group " is C1-C7 linear or branched alkyl group, preferably methyl, ethyl, propyl or butyl；
Preferably, R4It for H, halogen, methyl, ethyl, propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, cyclopropyl, oxetanyl, azetidinyl or is the amino replaced by the 1-2 substituent groups in methyl, ethyl, propyl or butyl.
Preferably, pyridazinone compound shown in general formula I is selected from the compound with structure shown in one of following general formula I-I to I-VIII:
Wherein, R1、R2、R3Definition it is identical as the definition in general formula I.
Preferably, in general formula I-I, R1、R2It is each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl or R1And R2Pyrrole ring, thiphene ring, furan nucleus, pyridine ring, nafoxidine ring, thiophane ring or tetrahydrofuran ring are formed together with the carbon atom being connected；R3Indicate 1,2 or 3 substituent group, the substituent group be each independently selected from H, halogen, cyano, nitro, C1-C7 linear or branched alkyl group, C1-C6 straight or branched alkoxyl,Wherein, 0,1,2,3 or 4 n；R4It for H, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or is the amino replaced by the 1-2 substituent groups in methyl, ethyl, propyl or butyl.
Preferably, in general formula I-II, R1、R2It is each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl Or phenyl；R3Indicate 1 or 2 substituent group, the substituent group is each independently selected from H, halogen, cyano, nitro, C1-C7 linear or branched alkyl group, C1-C6 straight or branched alkoxyl, by two C1-C7 linear or branched alkyl groups, it is preferred that C1-C4 alkyl, the more preferable alkyl-substituted amino of C1-C2 (preferably dimethylamino), the first saturated heterocyclyl (more preferable oxetanyl, azetidinyl) of heteroatomic 3-8 (preferably 3-5) containing 1-3 in N, O and SWherein, 0,1,2,3 or 4 n；R4For H, halogen, methyl, ethyl, propyl, isopropyl, normal-butyl, tert-butyl, cyclopropyl, oxetanyl, azetidinyl or isobutyl group.
Preferably, in general formula I-III, R1、R2It is each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl；R3Indicate 1 or 2 substituent group, the substituent group be each independently selected from H, halogen, cyano, nitro, C1-C7 linear or branched alkyl group, C1-C6 straight or branched alkoxyl,Wherein, 0,1,2,3 or 4 n；R4For H, halogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl group.
Preferably, in general formula I-IV, R1、R2It is each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl；R3Indicate 1 or 2 substituent group, the substituent group be each independently selected from H, halogen, cyano, nitro, C1-C7 linear or branched alkyl group, C1-C6 straight or branched alkoxyl orWherein, 0,1,2,3 or 4 n；R4For H, halogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl group.
Preferably, in general formula I-V, R1、R2It is each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl；R3Indicate 1 or 2 substituent group, the substituent group be each independently selected from H, halogen, cyano, nitro, C1-C6 linear or branched alkyl group, C1-C6 straight or branched alkoxyl,Wherein, 0,1,2,3 or 4 n；R4For H, halogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl group.
Preferably, in general formula I-VI, R1、R2It is each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl；R3Indicate 1 or 2 substituent group, the substituent group be each independently selected from H, halogen, cyano, nitro, C1-C7 linear or branched alkyl group, C1-C6 straight or branched alkoxyl,Wherein, 0,1,2,3 or 4 n；R4For H, halogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl group.
Preferably, in general formula I-VII, R1、R2It is each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl；R3Indicate 1 or 2 substituent group, the substituent group be each independently selected from H, halogen, cyano, nitro, C1-C7 linear or branched alkyl group, C1-C6 straight or branched alkoxyl orWherein, 0,1,2,3 or 4 n；R4For H, halogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl group.
Preferably, in general formula I-VIII, R1、R2It is each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl；R3Indicate that 1 or 2 substituent group, the substituent group are each independently selected from H, halogen, cyano, nitro, C1-C7 linear or branched alkyl group or C1-C6 straight or branched alkoxyl.
In the present invention, unless otherwise specifically indicated, the meaning of substituent group is made as given a definition:
The halogen atom refers to F, Cl, Br or I.
The C1-C7 linear or branched alkyl group refers to the linear or branched alkyl group with 1 to 7 carbon atom, its specific example includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1- methyl butyl, 2- methyl butyl, 3- methyl butyl, isopentyl, 1- ethyl propyl, neopentyl, n-hexyl, 1- methyl amyl, 2- methyl amyl, 3- methyl amyl, isohesyl, 1, 1- dimethylbutyl, 2, 2- dimethylbutyl, 3, 3- dimethylbutyl, 1, 2- dimethylbutyl, 1, 3- dimethylbutyl, 2, 3- dimethylbutyl, 2- ethyl-butyl, n-heptyl, 2- methylhexyl, 3- methylhexyl, 2, 2- dimethyl amyl group, 3, 3- dimethyl amyl group, 2, 3- dimethyl amyl group , 2,4- dimethyl amyl group, 3- ethylpentyl, 2,2,3- trimethyl butyl etc..Term " C1-C4 linear or branched alkyl group " has similar meaning.
The C1-C6 straight or branched alkoxyl refers to the straight or branched alkoxyl with 1 to 6 carbon atom, and specific example includes methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isoamoxy, neopentyl oxygen, positive hexyloxy, dissident's oxygroup, 3- methyl amoxy etc..
The C3-C6 naphthenic base refers to the aliphatic carbon ring group on ring with 3 to 6 carbon atoms, and specific example includes cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc..
The 6-10 member aryl refers to the armaticity carbocylic radical on ring with 6 to 10 carbon atoms, and specific example includes phenyl, naphthalene etc..
The heteroatomic armaticity ring referred to containing the 1-3 heteroatomic 5-10 member hetero-aromatic rings in N, O and S on ring with 5 to 10 atoms and comprising 1-3 in N, O, S, it can be monocycle or bicyclic, such as pyridine ring, pyrrole ring, pyrimidine ring, pyridine ring, pyridazine ring, thiphene ring, furan nucleus, pyrazole ring, imidazole ring, oxazole ring, thiazole ring, indole ring, azaindole ring, naphthyridines ring, benzimidazole ring, pyridine-imidazole ring, pyrimido imidazole ring or quinoline ring etc..Term " containing 1-2 selected from N, O and the heteroatomic 5-10 member hetero-aromatic ring in S " has similar meaning.
The heteroatomic armaticity ring, such as pyridine ring, pyrrole ring, pyrimidine ring, pyridine ring, pyridazine ring, thiphene ring, furan nucleus, pyrazole ring, imidazole ring, oxazole ring, thiazole ring etc. referred to containing the 1-3 heteroatomic 5-7 member hetero-aromatic rings in N, O and S on ring with 5 to 7 atoms and comprising 1-3 in N, O, S.Term " containing 1-2 selected from N, O and the heteroatomic 5-7 member hetero-aromatic ring in S " has similar meaning.
The heteroatomic nonaro-maticity ring group, such as nafoxidine ring, thiophane ring or tetrahydrofuran ring etc. referred to comprising the 1-3 heteroatomic 5-7 member non-aromatic heterocyclic rings in N, O and S on ring with 5 to 7 atoms and comprising 1-3 in N, O, S.Term " containing 1-2 selected from N, O and the heteroatomic 5-7 member non-aromatic heterocyclic rings in S " has similar meaning.
In the present invention, particularly preferred particular compound is one of following compounds:
The pharmaceutically acceptable salt, such as can be alkali metal salt (for example, sodium salt, sylvite, lithium salts, cesium salt etc.)；Alkali salt (such as calcium salt, magnesium salts, strontium salt etc.) etc.；Ammonium salt；With salt formed by organic base, such as with three (rudimentary) alkylamines (such as trimethylamine, triethylamine, N- ethyl diisopropylamine etc.), pyridine, quinoline, piperidines, imidazoles, picoline, dimethylamino naphthyridine, dimethylaniline, N- (rudimentary) alkyl morpholine (such as N-methylmorpholine etc.), 1,5- diazabicyclo [4.3.0] nonene -5 (DBN), 1, salt formed by 8- diazabicyclo [5.4.0] endecatylene -7 (DBU), Isosorbide-5-Nitrae-diazabicyclo [2.2.2] octane (DABCO) etc.；Inorganic acid salt, such as hydrochloride, hydrobromate, hydriodate, sulfate, nitrate, phosphate, carbonate etc.；Acylate, such as formates, acetate, propionic acid Salt, oxalates, malonate, succinate, fumarate, maleate, lactate, malate, citrate, citrate, tartrate, carbonate, picrate, mesylate, esilate, tosilate, glutamate, embonate etc..
The pharmaceutically acceptable salt of pyridazinone compound shown in general formula I provided by the invention can be prepared and being dissolved in pyridazinone compound shown in general formula I with being reacted in the alcoholic solution of corresponding acid saturation, such as: pyridazinone compound provided by the invention is dissolved in the methanol solution of HCl saturation, it is stirred at room temperature 30 minutes, solvent is evaporated, corresponding hydrochloride is obtained.
Pyridazinone compound of the invention or its pharmaceutically acceptable salt be not in the case where influencing its application effect; it can further be used in the form of its isomers, prodrug or solvate etc., it should be understood by those skilled in the art that the above-mentioned form of pyridazinone compound of the invention is also within protection scope of the present invention.
The isomers includes geometric isomer, stereoisomer etc..
The prodrug refers to the compound that the inactive in vitro or active smaller conversion in vivo through enzyme or non-enzymatic that drug obtains after modifying for chemical structure releases active medicine and plays drug effect.Prodrug forms in the present invention are not specially limited, as long as it discharges active raw medicine through enzyme or chemical action in vivo, to play expected pharmacological action, can be precursor carrier drug or bioprecursor.
The solvate, such as can be hydrate, ethanolates etc., preferred solvate is hydrate.
According to another aspect of the present invention, the present invention provides the preparation method of pyridazinone compound shown in general formula I, this method is realized by one of following formulas:
Route 1:
Route 2:
Route 3:
Wherein A, R1、R2、R3Definition it is identical as its definition in general formula I,
Each route is specific as follows:
Route 1: hydrazine hydrate cyclization obtains compound shown in general formula 2 after 1 compound represented of general formula, with pyruvic acid condensation, then obtains pyridazinone compound shown in general formula 4 with nucleophilic substitution is carried out to benzyl chloride chlorine；
Route 2: 5 compound represented of general formula, the compound represented of general formula 6 and 7 is obtained after hydrolysis, 7 compound represented of general formula obtains 8 compound represented of general formula with to benzyl chloride chlorine progress nucleophilic substitution, finally under the action of metallic catalyst or alkali, by coupling reaction (suzuki reaction), pyridazinone compound shown in general formula 9 is obtained；
Route 3: hydrazine hydrate cyclization obtains 10 compound represented of general formula after 1 compound represented of general formula, with glyoxalic acid condensation, with grignard reagent R1MgBr carries out Michael addition reaction and obtains 11 compound represented of general formula, finally obtains pyridazinone compound shown in general formula 12 with to benzyl chloride chlorine progress nucleophilic substitution.
Nucleophilic substitution described in route 1, route 2 and route 3 can carry out in such as acetonitrile, N,N-dimethylformamide, tetrahydrofuran equal solvent in the presence of the alkali such as such as potassium carbonate, cesium carbonate, sodium hydride, hydrofining, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide；
Hydrolysis condition described in route 2 is to carry out in a solvent under acid or alkaline condition；The acid is preferably one of acetic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid or a variety of；The alkali is preferably one of potassium hydroxide, sodium hydroxide, potassium acetate, sodium acetate, potassium tert-butoxide, sodium tert-butoxide or a variety of；The solvent is preferably one of ethyl alcohol, methanol, water, acetic acid or a variety of.
Coupling reaction condition described in route 2 is the conventional selection of those skilled in the art.In general, selecting such as DMF (n,N-Dimethylformamide), toluene, Isosorbide-5-Nitrae-dioxane is solvent, it is performed under heating conditions in the presence of metallic catalyst, alkali and ligand.The heating condition is known to those skilled in the art, such as can be heated to reflux or use microwave heating.The alkali is known to those skilled in the art, such as cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide.The metallic catalyst is known to those skilled in the art, such as palladium acetate, Pd (PPh3)4、Pd(dppf)2Cl2Deng.The ligand is known to those skilled in the art, such as triphenylphosphine, DPPP (1, bis- (diphenylphosphine) ferrocene of 1'-), BINAP (dinaphthalene diphenylphosphine), Sphos (2- dicyclohexylphosphontetrafluoroborate -2 ', 6 '-dimethoxy-biphenyls), Davephos (2- dicyclohexylphosphino -2'- (N, TMSDMA N dimethylamine)-biphenyl) etc..
Grignard reagent R described in route 31MgBr is known to those skilled in the art, such as alkyl bromination magnesium, naphthenic base magnesium bromide, aryl magnesium bromide, such as methyl-magnesium-bromide, ethylmagnesium bromide, isopropyl magnesium bromide, normal-butyl magnesium bromide, cyclopropyl magnesium bromide, cyclohexyl magnesium bromide, phenyl-magnesium-bromide.
Michael addition reaction condition described in route 3 carries out under solvent；The solvent is preferably tetrahydrofuran, 2- methyltetrahydrofuran, ether, toluene, benzene.
According to another aspect of the invention, the present invention provides the purposes of pyridazinone compound shown in general formula I or its pharmaceutically acceptable salt in preparation hepatitis type B virus inhibitor, and are preparing the purposes in the drug for preventing and/or treating hepatitis B disease.
In accordance with a further aspect of the present invention, one of pyridazinone compound or its pharmaceutically acceptable salt or a variety of pharmaceutical compositions shown in the present invention also provides a kind of general formula I comprising therapeutically effective amount.Described pharmaceutical composition can be used as hepatitis type B virus inhibitor, and for preventing and/or treating hepatitis B, further, which can optionally include pharmaceutically acceptable carrier or excipient.
Above-mentioned pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, such as: diluent, such as water；Filler, such as starch, sucrose；Adhesive, such as cellulose derivative, alginates, gelatin, polyvinylpyrrolidone；Wetting agent, such as glycerol；Disintegrating agent, such as agar, calcium carbonate and sodium bicarbonate；Sorbefacient, such as quaternary ammonium compound；Surfactant, such as hexadecanol；Absorption carrier, such as kaolin and soap clay；Lubricant, such as talcum powder, calcium stearate and magnesium stearate and polyethylene glycol.Furthermore it is also possible to other adjuvants be added in aforementioned pharmaceutical compositions, such as flavouring agent and sweetener.
According to another aspect of the invention, the present invention also provides the methods prevented and/or treat hepatitis B disease, and the method includes applying one of pyridazinone compound or its pharmaceutically acceptable salt shown in the general formula I of therapeutically effective amount or a variety of or of the invention aforementioned pharmaceutical compositions to patient.
Compound or composition provided by the invention can be applied to the patient for needing this treatment by way of oral, rectum or parenteral administration.When for taking orally, it can be made into conventional solid pharmaceutical preparation, such as tablet, pulvis, granula, capsule, or liquid preparation is made, such as water or oil-suspending agent or other liquid preparations, such as syrup；When for parenteral administration, solution, water or oleaginous suspension of injection etc. can be made into.
The method have the advantages that:
Compound is to the toxicity of HepG2.2.15 cell and the active detection of inhibition HBV DNA through the invention, inventor's discovery: in the compound that above-mentioned general formula I is indicated, the HBV DNA inhibitory activity of multiple compounds is at 3 μM hereinafter, best compound inhibitory activity is less than 0.4 μM.Therefore, the compound that general formula I is indicated is effective hepatitis type B virus inhibitor.
Specific embodiment
The following examples are used to specifically describe the preparation of pyridazinone compound provided by the invention as well as the biological activity of hepatitis type B virus inhibitor, but the invention is not limited to these embodiments.
In the examples below, nuclear magnetic resonance spectroscopy BrukerAMX-400 type, Gemini-300 type or AMX -600 type Nuclear Magnetic Resonance record, the unit of chemical shift δ are ppm.Specific rotatory power is measured by Perkin-Elmer241 type automatic polarimeter, and microwave used is CEM-discovery microwave reactor.Unless otherwise instructed, all reaction dissolvents are conventionally purified.Column silica gel for chromatography (200-300 mesh) is the production of Qingdao Haiyang chemical industry subsidiary factory.Thin-layer chromatography uses the efficient plate of GF254, produces for Yantai chemical institute.Preparative thin-layer chromatography plate is prepared by Shanghai Pharmaceutical Inst., Chinese Academy of Sciences; stationary phase is prepared using GF254 (HG/T2354-92) silica gel and sodium carboxymethylcellulose (800-1200), respectively Qingdao Marine Chemical Co., Ltd. and China Medicine's production.As without especially mark, all solvents are analytical reagents, and agents useful for same is purchased from Sinopharm Chemical Reagent Co., Ltd..It is developed the color using the methods of iodine, Ultraluminescence.Organic solvent is removed under reduced pressure to carry out in Rotary Evaporators.
The preparation of compound:
Embodiment 1:
Step 1:
5g 4- fluoro acetophenone is added in 3.76ml pyruvic acid, after stirring 10h at 120 DEG C, is cooled to room temperature, under ice bath, ammonium hydroxide tune pH to 8-9 is added, aqueous layer with ethyl acetate extracts unreacted 4- fluoro acetophenone.After 4ml hydrazine hydrate (85%) is added in water layer, 100 DEG C are refluxed overnight.Next day cools down reaction solution, has solid precipitation at this time, filters to obtain 5.2g white solid (compound 2) (yield 72%).1H NMR(300MHz,CDCl3) (s, the 3H) of δ 11.39 (s, 1H), 7.86-7.71 (m, 2H), 7.57 (s, 1H), 7.15 (t, J=8.7Hz, 2H), 2.32
Step 2:
100mg midbody compound 2 is dissolved in 30ml N, in dinethylformamide (DMF), add 94mg p-chlorobenzylchloride and 190mg cesium carbonate, reaction solution reacts 5-6 hours at 50 DEG C, and TLC shows that substrate completely disappears, and stops reacting and being cooled to room temperature reaction solution, reaction solution is extracted with ethyl acetate, organic layer is dry with anhydrous sodium sulfate after washing 3 times, and concentration, column chromatographs to obtain 100mg white solid (compound I-1) (yield 62%).1H NMR(300MHz,CDCl3) δ 7.75 (dd, J=8.6,5.6Hz, 2H), 7.49 (s, 1H), 7.44 (d, J=8.2Hz, 2H), 7.30 (d, J=8.3Hz, 2H), 7.14 (t, J=8.7Hz, 2H), 5.34 (s, 2H), 2.27 (s, 3H)
Following compound is prepared in the same manner as in Example 1:
Embodiment 2
Step 1:
By 10g 3, the chloro- 4- methyl pyridazine of 6- bis- is dissolved in 100ml acetic acid, and 120 DEG C of reflux 4h, TLC show that substrate completely disappears, and stops reacting and being cooled to room temperature reaction solution, decompression boils off acetic acid and obtains solid.200ml ethyl acetate is added, by insoluble solid filtering, gained white solid is midbody compound 7 (3g, yield 33%).1H NMR(300MHz,DMSO)δ13.02(s,1H),6.89(s,1H),2.16(s,3H).
Filtrate is dry, concentration, column chromatograph white solid is midbody compound 6 (4g, yield 44%).1H NMR (300MHz, DMSO) δ 13.03 (s, 1H), 7.43 (d, J=1.3Hz, 1H), 2.04 (d, J=1.2Hz, 3H)
Step 2:
500mg midbody compound 7 is dissolved in 50ml N, in dinethylformamide (DMF), add 670mg p-chlorobenzylchloride and 1.35g cesium carbonate, reaction solution reacts 5-6 hours at 50 DEG C, and TLC shows that substrate completely disappears, and stops reacting and being cooled to room temperature reaction solution, reaction solution is extracted with ethyl acetate, organic layer is dry with anhydrous sodium sulfate after washing 3 times, and concentration, column chromatographs to obtain 700mg white solid (compound 8a) (yield 75%).1H NMR (300MHz, CDCl3) δ 7.41 (s, 1H), 7.38 (s, 1H), 7.30 (d, J=8.5Hz, 2H), 7.06 (d, J=1.2Hz, 1H), 5.20 (s, 2H), 2.20 (d, J=1.2Hz, 3H)
Step 3:
100mg compound 8a is dissolved in 30ml Isosorbide-5-Nitrae-dioxane (Isosorbide-5-Nitrae-dioxane) and 3ml water, sequentially adds 62mg to fluorobenzoic boric acid, 30mg Pd (dppf)2Cl2([1,1'- bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex) and 197mg potassium phosphate are replaced 3 times with nitrogen, and 100 DEG C of reactions are overnight.TLC shows that substrate completely disappears, and stops reacting and being cooled to room temperature reaction solution, and reaction solution is extracted with ethyl acetate, and organic layer uses anhydrous slufuric acid after washing 3 times Sodium is dry, and concentration, column chromatographs to obtain 72mg white solid (compound I-2) (yield 60%).1H NMR(400MHz,CDCl3) δ 8.92 (s, 1H), 7.42 (ddd, J=23.2,18.5,8.1Hz, 6H), 7.23 (t, J=7.9Hz, 2H), 7.05 (d, J=1.2Hz, 1H), 6.87 (t, J=7.3Hz, 1H), 5.14 (s, 2H), 2.10 (d, J=0.9Hz, 3H)
Embodiment 3
Step 1:
500mg intermediate 6 (preparing in embodiment 2) is dissolved in 50ml DMF, add 670mg p-chlorobenzylchloride and 1.35g cesium carbonate, reaction solution reacts 5-6 hours at 50 DEG C, TLC shows that substrate completely disappears, stop reacting and being cooled to room temperature reaction solution, reaction solution is extracted with ethyl acetate, and organic layer is dry with anhydrous sodium sulfate after washing 3 times, concentration, column chromatograph to obtain 700mg white solid (compound 8b) (yield 75%).1H NMR(300MHz,CDCl3) (d, J=1.2Hz, the 3H) of δ 7.41 (s, 1H), 7.38 (s, 1H), 7.30 (d, J=8.5Hz, 2H), 7.06 (d, J=1.2Hz, 1H), 5.20 (s, 2H), 2.20
Step 2:
100mg compound 8b is dissolved in 30ml DMF and 3ml water, sequentially adds 93mg 1- methyl -4- (4,4,5,5- tetramethyls -1,3,2- dioxaborolan -2- base) -1H- pyrazoles, 30mg Pd (dppf)2Cl2([1,1'- bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex) and 197mg potassium phosphate are replaced 3 times with nitrogen, and 100 DEG C of reactions are overnight.TLC shows that substrate completely disappears, stop reacting and being cooled to room temperature reaction solution, reaction solution is extracted with ethyl acetate, and organic layer is dry with anhydrous sodium sulfate after washing 3 times, concentration, column chromatograph to obtain 68mg white solid (compound I-19) (yield 58%).1H NMR(300MHz,CDCl3) δ 7.60 (s, 1H), 7.53 (d, J=4.7Hz, 1H), 7.44 (s, 1H), 7.41 (s, 2H), 7.32-7.23 (m, 3H), 5.32 (s, 2H), 2.26 (s, 3H)
Following compound is prepared in method same as Example 3:
Embodiment 4:
150mg compound I-18 (preparing in embodiment 1) is dissolved in 95% ethyl alcohol of 25ml, 94.4mg reduced iron powder and 1.56ml acetic acid is added, flow back 4h.TLC shows that substrate completely disappears, and filters out solid, and filtrate decompression is distilled off, and is extracted with ethyl acetate, and organic layer is dry with anhydrous sodium sulfate after washing 3 times, concentration, and column chromatographs to obtain 80mg Huang Color solid (compound I-32) (yield 60%).1H NMR (300MHz, DMSO) δ 7.83 (s, 1H), 7.54 (d, J=8.4Hz, 2H), 7.39-7.29 (m, 4H), 6.59 (d, J=8.2Hz, 2H), 5.48 (s, 2H), 5.24 (s, 2H), 2.12 (s, 3H)1H NMR(300MHz,D2O) δ 7.59 (d, J=8.7Hz, 2H), 7.48-7.44 (m, 2H), 7.42 (s, 1H), 7.30 (s, 1H), 7.27 (d, J=1.9Hz, 1H), 6.73 (d, J=8.8Hz, 2H), 5.32 (s, 2H), 4.77-4.68 (m, 1H), 3.91-3.83 (m, 1H), 2.25 (d, J=1.2Hz, 3H)
Embodiment 5:
60mg compound I-20 (preparing in embodiment 3) is dissolved in 20ml methylene chloride, 20 μ l chloroacetic chlorides and 30 μ l pyridines are added, are stirred overnight at room temperature.TLC shows that substrate completely disappears, and reaction solution is dry with anhydrous sodium sulfate after being washed with water 3 times, and concentration, column chromatographs to obtain 20mg white solid (compound I-33) (yield 30%).1H NMR(400MHz,CDCl3) δ 8.66 (d, J=2.3Hz, 1H), 8.29 (d, J=8.7Hz, 1H), 8.09 (dd, J=8.8,2.3Hz, 1H), 8.05 (s, 1H), 7.49 (s, 1H), 7.44 (d, J=8.3Hz, 2H), 7.30 (d, J=8.4Hz, 2H), 5.35 (s, 2H), 2.28 (s, 3H), 2.25 (s, 3H)
Following compound is prepared in method same as Example 5:
Embodiment 6:
100mg compound I-15 (preparing in embodiment 1) is dissolved in 30ml toluene, sequentially adds 26mg methylamine hydrochloride, 48mg Pd2(dba)3(three (double BENZYLIDENE ACETONEs) two palladiums), 41mg S-Phos (2- dicyclohexylphosphontetrafluoroborate -2 ', 6 '-dimethoxy-biphenyls) and 127mg cesium carbonate, it is replaced 3 times with nitrogen, 100 DEG C of reactions are overnight.TLC shows that substrate completely disappears, stop reacting and being cooled to room temperature reaction solution, reaction solution is extracted with ethyl acetate, and organic layer is dry with anhydrous sodium sulfate after washing 3 times, concentration, column chromatograph to obtain 50mg white solid (compound I-36) (yield 56%).1H NMR(300MHz,CDCl3) δ 7.62 (d, J=8.7Hz, 2H), 7.46 (d, J=5.2Hz, 1H), 7.43 (s, 1H), 7.30 (s, 1H), 7.26 (s, 2H), 6.64 (d, J=8.7Hz, 2H), 5.33 (s, 2H), 3.97 (s, 1H), 2.89 (s, 3H), 2.25 (s, 2H)
Following compound is prepared to the same method as example 6:
Embodiment 7:
Step 1:
2g compound I-15 (preparing in embodiment 1) is dissolved in 100ml N, N- dimethyl sulfoxide (DMSO), sequentially add 24ml methanol, 345mg palladium acetate, 433mg dppf ([1, bis- (diphenylphosphine) ferrocene of 1'-) and 5.9ml triethylamine, it is replaced 3 times with CO, 100 DEG C of reactions are overnight.TLC shows that substrate completely disappears, stop reacting and being cooled to room temperature reaction solution, reaction solution is extracted with ethyl acetate, and organic layer is dry with anhydrous sodium sulfate after washing 3 times, concentration, column chromatograph to obtain 1.1g white solid (compound 13) (yield 58%).1H NMR(300MHz,CDCl3) δ 8.11 (d, J=6.2Hz, 2H), 7.85 (d, J=6.1Hz, 2H), 7.56 (s, 1H), 7.45 (d, J=6.4Hz, 2H), 7.34-7.28 (m, 2H), 5.37 (s, 2H), 3.95 (d, J=2.6Hz, 3H), 2.29 (s, 3H)
Step 2:
250mg compound 13 is dissolved in 30ml tetrahydrofuran (THF) and 20ml water, 70mg lithium hydroxide is added, is stirred overnight at room temperature.TLC shows that substrate completely disappears, and vacuum distillation removes solvent, is extracted with ethyl acetate, and organic layer is dry with anhydrous sodium sulfate after washing 3 times, and concentration, column chromatographs to obtain 230mg white solid (compound I-38) (yield 96%).1H NMR (300MHz, CDCl3) δ 8.19 (d, J=8.4Hz, 1H), 7.89 (d, J=8.0Hz, 1H), 7.59 (s, 1H), 7.46 (d, J=8.4Hz, 1H), 7.33 (s, 1H), 5.38 (s, 1H), 2.30 (d, J=2.8Hz, 1H)
Step 3:
50mg compound I-38 is dissolved in 20ml methylene chloride, 23mg methylamine hydrochloride, 32mg EDC (1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate), 23mg HOBT (I-hydroxybenzotriazole) and 100 μ l triethylamines are added, are stirred overnight at room temperature.TLC shows that substrate completely disappears, and reaction solution is dry with anhydrous sodium sulfate after being washed with water 3 times, and concentration, column chromatographs to obtain 30mg white solid (compound I-39) (yield 58%).1H NMR(300MHz,CDCl3) δ 7.84 (s, 4H), 7.55 (s, 1H), 7.44 (d, J=8.3Hz, 2H), 7.30 (d, J=8.4Hz, 2H), 6.23 (s, 1H), 5.36 (s, 2H), 3.05 (d, J=4.9Hz, 3H), 2.28 (s, 3H)
Following compound is prepared in method same as Example 7:
Embodiment 8:
Step 1:
250ml round-bottomed flask is added after stirring 10h at 120 DEG C in 5g 4- fluoro acetophenone and mono- glyoxylic acid of 13.3g to be cooled to room temperature, under ice bath, ammonium hydroxide tune pH to 8-9 is added, aqueous layer with ethyl acetate extracts unreacted 4- fluoro acetophenone.After 4ml hydrazine hydrate (85%) is added in water layer, 100 DEG C are refluxed overnight.Next day cools down reaction solution, has solid precipitation at this time, filters to obtain 5g white solid (compound 10) (yield 73%).
Step 2:
2.6ml 2M n-propyl grignard reagent is dissolved in the 2- methyltetrahydrofuran of 30ml, adds 200mg compound 10, is replaced 3 times with nitrogen, 90 DEG C of reactions are overnight.TLC shows that substrate completely disappears, stop reacting and being cooled to room temperature reaction solution, reaction solution is extracted with ethyl acetate, and organic layer is dry with anhydrous sodium sulfate after washing 3 times, concentration, column chromatograph to obtain 130mg white solid (compound 11) (yield 55%).1H NMR(300MHz,CDCl3)δ11.27(s,1H), 7.81-7.74 (m, 2H), 7.50 (d, J=2.6Hz, 1H), 7.15 (t, J=8.5Hz, 2H), 2.69-2.60 (m, 2H), 1.73 (dd, J=15.1,7.6Hz, 2H), 1.03 (t, J=7.3Hz, 3H)
Step 3:
100mg compound 11 is dissolved in 30ml DMF, add 84mg p-chlorobenzylchloride and 168mg cesium carbonate, reaction solution reacts 5-6 hours at 50 DEG C, TLC shows that substrate completely disappears, stop reacting and being cooled to room temperature reaction solution, reaction solution is extracted with ethyl acetate, and organic layer is dry with anhydrous sodium sulfate after washing 3 times, concentration, column chromatograph to obtain 90mg white solid (compound I-45) (yield 59%).1H NMR (300MHz, Acetone) δ 8.03-7.92 (m, 2H), 7.80 (s, 1H), 7.49 (d, J=8.3Hz, 2H), 7.37 (d, J=8.4Hz, 2H), 7.24 (t, J=8.8Hz, 2H), 5.38 (d, J=6.9Hz, 2H), 2.59 (t, J=7.5Hz, 2H), 1.68 (dd, J=15.0,7.6Hz, 2H), 0.97 (t, J=7.3Hz, 3H)
Following compound is prepared in method same as Example 8:
Embodiment 9:
Step 1:
By 5g 3,4- thiophene dicarboxylic acid is dissolved in 50ml dehydrated alcohol, is added 0.5ml hydrazine hydrate (85%), and reflux is cooled to room temperature after 4 hours, filters to obtain 4.5g white solid (compound 14) (yield 97%).
Step 2:
4.5g compound 14 is dissolved in 50ml thionyl chloride, reflux is cooled to room temperature after 7 hours, after vacuum distillation removes thionyl chloride, ice water is added into residue, then (2x50mL) is extracted with ethyl acetate, organic layer is dry with anhydrous sodium sulfate after washing 3 times, and concentration, column chromatographs to obtain 1g white solid (compound 15) (yield 19%).
Step 3:
1g compound 15 is dissolved in 20mL glacial acetic acid, reflux is cooled to room temperature after 4 hours, obtains white solid (compound 16) about 1g (yield > 100%) after solvent is removed under reduced pressure.
Step 4:
260mg compound 16 is dissolved in 20mL DMF, 225mg is added to benzyl chloride rate and 455mg cesium carbonate, 50 DEG C are reacted 5 hours, TLC shows that substrate completely disappears, stop reacting and being cooled to room temperature reaction solution, reaction solution is extracted with ethyl acetate, and organic layer is dry with anhydrous sodium sulfate after washing 3 times, concentration, column chromatograph to obtain 120mg white solid (compound 17) (yield 28%).
Step 5:
100mg compound 17 is dissolved in 30ml Isosorbide-5-Nitrae-dioxane and 3ml water, sequentially adds 62mg to fluorobenzoic boric acid, 30mg Pd (dppf)2Cl2([1,1'- bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex) and 137mg potassium phosphate are replaced 3 times with nitrogen, and 100 DEG C of reactions are overnight.TLC shows that substrate completely disappears, stop reacting and being cooled to room temperature reaction solution, reaction solution is extracted with ethyl acetate, and organic layer is dry with anhydrous sodium sulfate after washing 3 times, concentration, column chromatograph to obtain 80mg white solid (compound I-49) (yield 67%).1H NMR(300MHz,CDCl3) δ 8.46 (s, 1H), 7.81 (s, 1H), 7.75-7.66 (m, 2H), 7.44 (d, J=8.4Hz, 2H), 7.29 (d, J=8.4Hz, 2H), 7.21 (t, J=8.5Hz, 2H), 5.35 (s, 2H)
Following compound is prepared in method same as Example 9:
Testing example 1: the influence of Compounds on Hepatitis B viral dna replication ability obtained in the embodiment of the present invention
1, experimental material
1.1 screening systems
The human liver cancer cell HepG2.2.15 cell strain (offer of institute of materia medica, the Chinese Academy of Sciences) of stable transfection overall length HBV
1.2 laboratory apparatus
Incubator (ThermoForma3111)；Microplate reader (Molecular Devices Spectra Max 190)；Electronic balance；Microscope；Biohazard Safety Equipment (Heal Force safe15)；Centrifuge (Eppendorf Centrifuge 5810R)；Real-Time PCR(FASTA GEN-DNA fast2000)
1.3 experimental drugs and reagent
Positive drug and configuration: Lamivudine (3TC), it is combined by Chinese Academy of Sciences's Shanghai institute of materia medica pharmaceutical chemistry, it is stand-by that 40mM liquid storage is configured to DMEM/High Glucose culture solution (Dulbecco ' s modified Eagle ' s medium, Hyclone company).
Other solution and configuration:
DMEM/High Glucose culture solution: 1 × (Hyclone of Dulbecco ' s modified Eagle ' s medium Company) phosphate buffer (PBS, pH7.3,1L): NaCl, 8.0g；Na2HPO4, 1.16g；KH2PO4, 0.2g；KCl:0.2g；
MTT solution: MTT (Sigma company) is configured to 5mg/ml with PBS；
DNA extraction agent box:Blood&Tissue (Qiagen company)
2, experimental method
2.1 cell culture
HepG2.2.15 cell subculture according to a conventional method.The culture medium utilized is DMEM, inside contains 10% (v/v) cow's serum and selection antibiotic G418, at 37 DEG C, 5%CO2Incubator in cultivate 8 days (changing liquid within the 4th day).
The preparation of 2.2 untested compounds and positive drug
Untested compound is configured to the stock solution of 40mM with DMSO, contains 10%HycloneTMThe DMEM culture solution of Fetal Bovine Serum is made into solution and the dilution of specified maximum concentration；Positive drug is Lamivudine, equally to contain 10%HycloneTMThe DMEM culture solution of Fetal Bovine Serum is made into prescribed concentration.
2.3 MTT measure cytotoxicity
HepG2.2.15 cell is with 5 × 103Cells/well is inoculated in 96 orifice plates, cultivates eight days under drug effect according to the above method, and MTT solution is added after taking out 200 μ l of supernatant, is added lysate after cultivating 4h, cultivates and measures OD with microplate reader after 12h570, be compared with the absorbance of control wells, calculating survivaling cell percentage, and calculate cause half cytotoxicity needed for concentration C C50。
The measurement of HBV DNA content in 2.4 cells and supernatants
HepG2.2.15 cell draws culture supernatant after compound effects 8 days (changing liquid within the 4th day) of various concentration, using the HBV DNA contained in mature virion in real-time PCR (Real-time PCR) standard measure detection supernatant.
Column mention HepG2.2.15 cell conditioned medium DNA (Qiagen,Blood&Tissue Handbook)
1) 96 orifice plate supernatant DNA are received, the 200 every holes μ l collect multiple holes into the same EP pipe, and 4000rcf*5min centrifugation takes supernatant；
2) take 200 supernatants, be added in 1.5ml EP pipe, be added 20 μ l Proteinase Ks and 200 μ l Buffer AL (Qiagen,Blood&Tissue Kit), vortex mixes it completely, 56 DEG C of incubation 10min；
3) 200 ethyl alcohol are added, vortex mixes it completely；
4) liquid of the 3) step is all added be placed in 2ml waste collection pipe DNeasy Mini spin column (Qiagen,Blood&Tissue Kit), 6000rcf*1min centrifugation discards supernatant；
5) DNeasy Mini spin column is placed in new 2ml waste collection pipe, be added 500 μ l Buffer AW1 (Qiagen,Blood&Tissue Kit), 6000rcf*1min centrifugation discards supernatant；
6) DNeasy Mini spin column is placed in new 2ml waste collection pipe, 500 μ l Buffer AW2 are added, (Qiagen,Blood&Tissue Kit) 20000rcf*3min centrifugation, it discards supernatant；
7) DNeasy Mini spin column is placed in new 1.5ml EP pipe, 50 μ l Buffer AE of absorption (Qiagen, Blood&Tissue Kit) it is directly added on the film of DNeasy Mini spin column, it is being placed at room temperature for 5min, the DNA on 6000rcf*1min centrifugation elution film discards DNeasy Mini spin column, collects DNA sample to -20 DEG C.
Real-time PCR detection supernatant HBV DNA (anisotropic HBV nucleic acid immue quantitative detection reagent box, up to peace gene)
1) standard curve: 1e7-1e4IU/ml, 1 μ l loading, is arranged a blank well, to detect whether reaction system pollutes；
2) add 1 μ l of DNA sample in order；
3) enzyme and reaction buffer is added: first two tube reaction liquid being added in enzyme, slightly centrifugation is placed on ice after mixing, and is added 19 μ l of enzyme reaction solution after introduction of the sample, and when addition, which ensures not touch DNA sample, to be polluted；
4) sealer is sticked, is centrifuged；
5) PCR reacts:
First stage: 93 DEG C, 2min
Second stage: 10 circulations
Step 1: 93 DEG C, 45s
Step 2: 55 DEG C, 1min
Phase III: 45 circulations
Step 1: 93 DEG C, 30s
Step 2: 55 DEG C, 45s
Sample: 20 μ l
Detection: data are collected afterwards in the second step (55 DEG C, 45s) for completing the phase III.
2.8 data processing
Experimental data is counted using Origin software, calculates IC50
Experimental result:
Experimental result is as shown in table 1.
Table 1: the part of compounds of the embodiment of the present invention is to the toxicity of HepG2.2.15 cell and the activity of inhibition HBV DNA
Compound CC<sub>50</sub>(μM) IC<sub>50</sub>(μM)
I-1 >100 3.3
I-2 >100 6.5
I-3 >100 7.0
I-4 >100 26.7
I-5 >100 45.4
I-6 >100 6.32
I-7 >100 4.26
I-8 >100 7.27
I-9 70.5 11.8
I-10 55.6 6.24
I-11 52.4 6.8
I-12 24.7 4.4
I-13 50.9 13.8
I-14 66.5 17.6
I-15 42.2 4.3
I-16 51.8 15.0
I-17 82.5 15.6
I-18 50.9 2.6
I-19 >100 10.1
I-20 33.8 1.2
I-21 >100 2.9
I-22 41.3 6.6
I-23 33.3 3.2
I-24 70.5 11.8
I-25 >100 2.6
I-26 23.3 1.5
I-27 82.2 11.8
I-28 32.5 3.9
I-29 11.1 7.1
I-30 47.6 6.8
I-31 38.2 31.7
I-32 31.4 5.8
I-33 62.4 11.1
I-34 >100 1.1
I-35 >100 33
I-36 35.7 6.1
I-37 10.0 2.8
I-38 >100 19.8
I-39 84.7 3.6
I-40 51.9 4.5
I-41 78.6 2.6
I-42 70.4 4.2
I-43 10.7 3.7
I-44 10.0 1.2
I-45 77 22.1
I-46 33.6 18.8
I-47 88.6 28.7
I-48 >100 43.4
I-49 >100 20.2
I-50 >100 10.4
I-51 >100 7.7
I-52 >100 4.6
I-53 >100 24.6
I-54 >100 25.7
I-55 >100 13.6
I-56 67.7 7.8
I-57 >100 15.8
I-58 50.6 16.8
I-59 46.9 11.3
I-60 77.9 3.2
I-61 33.5 1.6
I-62 >100 6.9
I-63 >100 4.7
I-64 >100 22.4
I-65 >100 20.1
I-66 44.9 4.4
I-67 34.4 1.6
I-68 >100 0.5
I-69 >100 2.9
I-70 >100 0.05
I-71 >100 10.8
I-72 38.8 4.6
I-73 >100 5.1
I-74 >100 1.3
I-75 37.3 4.9
I-76 33.3 30
I-77 >100 1.1
I-78 8.1 1.6
I-79 34.4 0.2
I-80 6.7 0.26
I-81 42 3.6
I-82 25.7 0.9
I-83 30.3 0.22
I-84 24.3 0.9
I-85 33.3 1.2
I-86 >100 2.5
I-87 19.7 2.0
I-88 27.6 0.3
I-89 48.8 0.1
I-90 >100 4.56
I-91 93.2 5.1
I-92 32.1 3.6
I-93 22.7 2.1
I-94 27.9 0.4
Note: CC50Influence for example pharmaceuticals to the growth of HepG2.2.15 cell, half (50%) lethasl concentration.
IC50Concentration when half (50%) is reached to the inhibition that hepatitis B virus DNA replicates for example pharmaceuticals.
From test result it can be seen that such compound largely all have on a cellular level in until excellent inhibition HBV DNA replication dna activity, wherein the IC of 57 compounds50Less than 10 μM.
Only illustratively, the scope of the present invention is not limited thereto for above-described embodiment.Modify to one skilled in the art is it will be apparent that the present invention is only limited by attached rights require scope.

Claims (10)

  1. Pyridazinone compound or its pharmaceutically acceptable salt shown in following general formula I:
    Wherein,
    R1、R2It is each independently H, C1-C7 linear or branched alkyl group, C3-C6 naphthenic base or 6-10 member aryl or R1And R2It is formed together with the carbon atom being connected containing the 1-3 heteroatomic 5-7 member hetero-aromatic rings or non-aromatic heterocyclic rings in N, O and S,
    Heteroatomic 5-10 member hetero-aromatic ring of the A for 6-10 member aromatic ring or containing 1-3 in N, O and S,
    R3Indicate one or more substituent groups, it is preferred that indicating 1,2 or 3 substituent group, the substituent group is each independently selected from H, halogen, cyano, nitro, C1-C7 linear or branched alkyl group, C1-C6 straight or branched alkoxyl, the amino replaced by two C1-C7 linear or branched alkyl groups, heteroatomic 3-8 member saturated heterocyclyl containing 1-3 in N, O and S
    Wherein, n is selected from integer of 0 to 10；
    R4For H, halogen, C1-C7 linear or branched alkyl group, C3-C6 naphthenic base, 6-10 member aryl, the heteroatomic 5-10 unit's heteroaryl containing 1-3 in N, O and S, heteroatomic 3-8 member saturated heterocyclyl containing 1-3 in N, O and S, the unsubstituted or amino that is replaced by 1-2 substituent group；Wherein, the substituent group in described " amino replaced by 1-2 substituent group " is C1-C7 linear or branched alkyl group.
  2. Pyridazinone compound according to claim 1 or its pharmaceutically acceptable salt, which is characterized in that
    R1、R2It is each independently H, C1-C4 linear or branched alkyl group, C3-C6 naphthenic base or phenyl or R1And R2It is formed together with the carbon atom being connected containing 1-2 5-7 member hetero-aromatic rings heteroatomic in N, O and S or non-aromatic heterocyclic rings,
    Heteroatomic 5-10 member hetero-aromatic ring of the A for phenyl ring or containing 1-2 in N, O and S,
    R3Indicate one or more substituent groups, it is preferred that indicating 1,2 or 3 substituent group, the substituent group is each independently selected from H, halogen, cyano, nitro, C1-C7 linear or branched alkyl group, C1-C6 straight or branched alkoxyl, the amino replaced by two C1-C4 linear or branched alkyl groups, the heteroatomic 3-5 member containing 1-3 in N, O or S Saturated heterocyclyl,
    Wherein, n is the integer selected from 0 to 7；
    R4For H, halogen, C1-C7 linear or branched alkyl group, C3-C6 naphthenic base, 6-10 member aryl, the heteroatomic 5-10 unit's heteroaryl containing 1-3 in N, O and S, heteroatomic 3-8 member saturated heterocyclyl containing 1-3 in N, O and S, the unsubstituted or amino that is replaced by 1-2 substituent group；Wherein, the substituent group in described " amino replaced by 1-2 substituent group " is methyl, ethyl, propyl or butyl.
  3. Pyridazinone compound according to claim 1 or its pharmaceutically acceptable salt, which is characterized in that
    R1、R2It is each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl or R1And R2Pyrrole ring, thiphene ring, furan nucleus, pyridine ring, nafoxidine ring, thiophane ring or tetrahydrofuran ring are formed together with the carbon atom being connected；
    A is phenyl ring, pyridine ring, pyrrole ring, pyrimidine ring, pyridine ring, pyridazine ring, thiphene ring, furan nucleus, pyrazole ring, imidazole ring, oxazole ring, thiazole ring, indole ring, azaindole ring, naphthyridines ring, quinoline ring, benzimidazole ring, imidazopyridine ring or imidazopyrimidine ring；
    R3Indicate one or more substituent groups, it is preferred that indicating 1,2 or 3 substituent group, the substituent group is each independently selected from H, halogen, cyano, nitro, C1-C7 linear or branched alkyl group, C1-C6 straight or branched alkoxyl, the amino replaced by two C1-C2 linear or branched alkyl groups, contains the 1-3 heteroatomic 3-5 member saturated heterocyclyls in N, O or S
    Wherein, 0,1,2,3 or 4 n；
    R4It for H, halogen, methyl, ethyl, propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, cyclopropyl, oxetanyl, azetidinyl or is the amino replaced by the 1-2 substituent groups in methyl, ethyl, propyl or butyl.
  4. Pyridazinone compound according to claim 1 or its pharmaceutically acceptable salt, which is characterized in that
    R1、R2It is each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl or R1And R2Pyrrole ring, thiphene ring, furan nucleus, pyridine ring, nafoxidine ring, thiophane ring or tetrahydrofuran ring are formed together with the carbon atom being connected；
    A is phenyl ring, pyridine ring, pyrimidine ring, pyridine ring, pyrazole ring, pyridazine ring, indole ring, azaindole ring, naphthyridines ring, quinoline ring, imidazo [1,2-a] pyridine ring or imidazo [1,2-a] pyrimidine ring；
    R3It indicates one or more substituent groups, preferably indicates 1,2 or 3 substituent group, the substituent group is each independently Selected from H, halogen, cyano, nitro, C1-C7 linear or branched alkyl group, C1-C6 straight or branched alkoxyl, dimethylamino, oxetanyl, azetidinyl,
    Wherein, 0,1,2,3 or 4 n；
    R4It for H, halogen, methyl, ethyl, propyl, isopropyl, normal-butyl, isobutyl group, cyclopropyl, tert-butyl, oxetanyl, azetidinyl or is the amino replaced by the 1-2 substituent groups in methyl, ethyl, propyl or butyl.
  5. Pyridazinone compound described in any one of -4 or its pharmaceutically acceptable salt according to claim 1, which is characterized in that the compound is selected from the compound of structure shown in one of following general formula I-I to I-VIII:
    Wherein, R1、R2、R3Definition and respective right require the definition in formula of I identical；
    Preferably, in general formula I-I, R1、R2It is each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl or R1And R2Pyrrole ring, thiphene ring, furan nucleus, pyridine ring, nafoxidine ring, thiophane ring or tetrahydrofuran ring are formed together with the carbon atom being connected；R3Indicate 1,2 or 3 substituent group, the substituent group be each independently selected from H, halogen, cyano, nitro, C1-C7 linear or branched alkyl group, C1-C6 straight or branched alkoxyl,Wherein, 0,1,2,3 or 4 n； R4It for H, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or is the amino replaced by the 1-2 substituent groups in methyl, ethyl, propyl or butyl；
    Preferably, in general formula I-II, R1、R2It is each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl；R3Indicate 1 or 2 substituent group, the substituent group is each independently selected from H, halogen, cyano, nitro, C1-C7 linear or branched alkyl group, C1-C6 straight or branched alkoxyl, the amino replaced by two C1-C7 linear or branched alkyl groups, the heteroatomic 3-8 member saturated heterocyclyl containing 1-3 in N, O or S Wherein, 0,1,2,3 or 4 n；R4For H, halogen, methyl, ethyl, propyl, isopropyl, normal-butyl, tert-butyl, cyclopropyl, oxetanyl, azetidinyl or isobutyl group；
    Preferably, in general formula I-III, R1、R2It is each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl；R3Indicate 1 or 2 substituent group, the substituent group be each independently selected from H, halogen, cyano, nitro, C1-C7 linear or branched alkyl group, C1-C6 straight or branched alkoxyl,Wherein, 0,1,2,3 or 4 n；R4For H, halogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl group；
    Preferably, in general formula I-IV, R1、R2It is each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl；R3Indicate 1 or 2 substituent group, the substituent group be each independently selected from H, halogen, cyano, nitro, C1-C7 linear or branched alkyl group, C1-C6 straight or branched alkoxyl orWherein, 0,1,2,3 or 4 n；R4For H, halogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl group；
    Preferably, in general formula I-V, R1、R2It is each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl；R3Indicate 1 or 2 substituent group, the substituent group be each independently selected from H, halogen, cyano, nitro, C1-C6 linear or branched alkyl group, C1-C6 straight or branched alkoxyl,Wherein, 0,1,2,3 or 4 n；R4For H, halogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl group；
    Preferably, in general formula I-VI, R1、R2It is each independently H, methyl, n-propyl, cyclopropyl, hexamethylene Base or phenyl；R3Indicate 1 or 2 substituent group, the substituent group be each independently selected from H, halogen, cyano, nitro, C1-C7 linear or branched alkyl group, C1-C6 straight or branched alkoxyl,Wherein, 0,1,2,3 or 4 n；R4For H, halogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl group；
    Preferably, in general formula I-VII, R1、R2It is each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl；R3Indicate 1 or 2 substituent group, the substituent group be each independently selected from H, halogen, cyano, nitro, C1-C7 linear or branched alkyl group, C1-C6 straight or branched alkoxyl orWherein, 0,1,2,3 or 4 n；R4For H, halogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl group；
    Preferably, in general formula I-VIII, R1、R2It is each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl；R3Indicate that 1 or 2 substituent group, the substituent group are each independently selected from H, halogen, cyano, nitro, C1-C7 linear or branched alkyl group or C1-C6 straight or branched alkoxyl.
  6. Pyridazinone compound according to claim 1 or its pharmaceutically acceptable salt, which is characterized in that the compound is one of following compounds:
  7. A method of pyridazinone compound of any of claims 1-6 being prepared, the method is realized by one of following formulas:
    Route 1:
    Route 2:
    Route 3:
    Wherein A, R1、R2、R3Definition with reference respective right requirement in definition it is identical,
    Wherein:
    Route 1: hydrazine hydrate cyclization obtains compound shown in general formula 2 after 1 compound represented of general formula, with pyruvic acid condensation, then obtains pyridazinone compound shown in general formula 4 with nucleophilic substitution is carried out to benzyl chloride chlorine；
    Route 2: 5 compound represented of general formula, the compound represented of general formula 6 and 7 is obtained after hydrolysis, 7 compound represented of general formula obtains 8 compound represented of general formula with to benzyl chloride chlorine progress nucleophilic substitution, finally under the action of metallic catalyst or alkali, by coupling reaction, pyridazinone compound shown in general formula 9 is obtained；
    Route 3: hydrazine hydrate cyclization obtains 10 compound represented of general formula after 1 compound represented of general formula, with glyoxalic acid condensation, with grignard reagent R1MgBr carries out Michael addition reaction and obtains 11 compound represented of general formula, finally obtains pyridazinone compound shown in general formula 12 with to benzyl chloride chlorine progress nucleophilic substitution；
    Preferably, nucleophilic substitution described in route 1, route 2 and route 3 carries out in a solvent in the presence of a base；The alkali is preferably one of potassium carbonate, cesium carbonate, sodium hydride, hydrofining, potassium tert-butoxide, sodium tert-butoxide or sodium hydroxide or a variety of；The solvent is preferably one of acetonitrile, N,N-dimethylformamide or tetrahydrofuran or a variety of；
    Preferably, hydrolysis described in route 2 carries out in a solvent under acid or alkaline condition；The acid is selected from one of acetic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid or a variety of；The alkali is selected from one of potassium hydroxide, sodium hydroxide, potassium acetate, sodium acetate, potassium tert-butoxide, sodium tert-butoxide or a variety of；The solvent is selected from one of ethyl alcohol, methanol, water, acetic acid or a variety of；
    Preferably, coupling reaction described in route 2 in a solvent, is performed under heating conditions in the presence of metallic catalyst, alkali and ligand；The solvent is preferably n,N-Dimethylformamide, toluene or Isosorbide-5-Nitrae-dioxane, and the heating condition is to be heated to reflux or use microwave heating；The alkali is preferably one of cesium carbonate, potassium carbonate, potassium tert-butoxide and sodium tert-butoxide or a variety of；The metallic catalyst is preferably palladium acetate, Pd (PPh3)4Or Pd (dppf)2Cl2One of or it is a variety of；The ligand is preferably triphenylphosphine, 1, bis- (diphenylphosphine) ferrocene of 1'-, dinaphthalene diphenylphosphine, 2- dicyclohexylphosphontetrafluoroborate -2 ', one of 6 '-dimethoxy-biphenyls and 2- dicyclohexylphosphino -2'- (N, TMSDMA N dimethylamine)-biphenyl are a variety of；
    Preferably, grignard reagent R described in route 31MgBr is selected from alkyl bromination magnesium, naphthenic base magnesium bromide or aryl magnesium bromide, more preferably methyl-magnesium-bromide, ethylmagnesium bromide, isopropyl magnesium bromide, normal-butyl magnesium bromide, cyclopropyl magnesium bromide, cyclohexyl magnesium bromide or phenyl-magnesium-bromide；
    Preferably, Michael addition reaction condition described in route 3 carries out under solvent；The solvent is selected from one of tetrahydrofuran, 2- methyltetrahydrofuran, ether, toluene or benzene or a variety of.
  8. Pyridazinone compound according to any one of claim 1 to 6 or its pharmaceutically acceptable salt are preparing the purposes in the drug for preventing and/or treating hepatitis B disease.
  9. A kind of pharmaceutical composition, it includes one of pyridazinone compounds or its pharmaceutically acceptable salt according to any one of claim 1 to 6 of therapeutically effective amount or a variety of.
  10. A kind of hepatitis type B virus inhibitor, it includes one of pyridazinone compounds or its pharmaceutically acceptable salt according to any one of claim 1 to 6 of therapeutically effective amount or a variety of.
CN201680040315.6A 2015-08-19 2016-08-18 Pyridazinone compound, its preparation method, pharmaceutical composition and purposes Pending CN107848986A (en)

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