CN110437232A - Double and ring ureas nucleocapsid inhibitor and its medicinal usage - Google Patents
Double and ring ureas nucleocapsid inhibitor and its medicinal usage Download PDFInfo
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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Abstract
The present invention relates to a kind of pair and ring nucleoid capsid inhibitors are used to treat the purposes of hepatitis B with it as drug.Specifically, the invention discloses a kind of compounds with structure shown in chemical formula A that can make HBV inhibitor or its stereoisomer or tautomer or its pharmaceutically acceptable salt, hydrate or solvate, the definition of each group to be detailed in specification.The invention further relates to the pharmaceutical composition comprising above compound and its purposes in treatment hepatitis B.
Description
Technical field
The invention belongs to field of medicaments, in particular it relates to aryl and cyclic amides class for treating hepatitis B
Compound and application thereof.
Background technique
Hepatitis type B virus (HBV) is a kind of tunicary, dsdna segment (dsDNA), Hepadna Virus DNA family
The virus of (hepatovirus section (Hepadnaviridae)).Its genome includes 4 overlapping open reading frames: pronucleus/karyogene, polymerization
Enzyme gene, UM and S gene (they encode three envelope proteins) and X gene.When before infection, the dsdna segment base
Because (open-circle DNA, rcDNA) is changed into covalently closed circular DNA (cccDNA) and virus mRNA to group in host cell nuclear
It is transcribed.Once the pregenome RNA (pgRNA) (it is also core protein and Pol coding) is used as template by encapsidate
In reverse transcription, this reverse transcription regenerates part dsDNA genome (rcDNA) in nucleocapsid.
HBV causes epidemic disease in some areas in Asia and Africa, and it is endemic in China.HBV is
About 2,000,000,000 people are infected in the whole world, wherein about 3.5 hundred million people are developed into chronic infectious disease.The virus causes hepatitis B
To increase risk associated for disease and chronic infectious disease and the development of cirrhosis and liver cancer high.
The Spreading source of hepatitis type B virus has in serum efficient in being exposed to communicable blood or body fluid
Viral DNA is detected in the saliva of the chronic carriers of valence DNA, tear and urine.
Although presently, there are vaccine a kind of effective and with good tolerability, the selection directly treated is current
It is also limited to interferon and antiviral agent below；Tenofovir, Lamivudine, adefovirdipivoxil, Entecavir and for than husband
It is fixed.
Press down in addition, heteroaryl dihydro-pyrimidin (HAPs) is authenticated in tissue cultures and animal model as a kind of HBV
Preparation.WO 2013/006394 (being disclosed on January 10th, 2013) and WO 2013/096744 (being disclosed on June 27th, 2013)
It also discloses and is related to sulfamoyl-aryl amide of Anti-HBV effect.
However, what can be encountered in these direct HBV antiviral agents is toxicity, mutagenicity, shortage selectivity, curative effect
The problems such as difference, difficult poor bioavailability and synthesis.
Therefore, this field needs to develop the HBV inhibitor having the advantages that as potency is high, toxicity is more low.
Summary of the invention
The object of the present invention is to provide a kind of potency height, the lower HBV inhibitor of toxicity.
The first aspect of the present invention provides a kind of chemical formula A compound represented or its stereoisomer or mutually variation
Structure body or its pharmaceutically acceptable salt, hydrate or solvate,
Wherein, the B ring is substituted or unsubstituted 8-20 membered bicyclic and ring structure；Wherein, the substitution refers to base
One or more hydrogen atoms in group are replaced by substituent group selected from the group below: halogen ,-CN, hydroxyl, amino, carboxyl ,-(C=O)-
Substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, replaces substituted or unsubstituted C1-C8 alkyl
Or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino radical, substituted or unsubstituted C1-C8 alkoxyl, substitution
Or unsubstituted C3-C10 naphthenic base, the substituted or unsubstituted heteroatomic 3-10 member that N, S and O are selected from the group with 1-3
Heterocyclylalkyl, substituted or unsubstituted C6-C10 aryl and substituted or unsubstituted there is 1-3 to be selected from the group the miscellaneous of N, S and O
The 5-10 unit's heteroaryl of atom；
C ring is substituted or unsubstituted 5-12 member ring；
R1、R2It is each independently selected from the following group: hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-
C10 naphthenic base (including monocycle and ring or caged scaffold), the substituted or unsubstituted hetero atom that N, S and O are selected from 1-3
3-10 circle heterocyclic ring base (including monocycle, and ring or caged scaffold), substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted
The heteroatomic 5-10 unit's heteroaryls that N, S and O are selected from the group with 1-3；
Or R1、R2With the nitrogen-atoms being connected with them collectively form it is substituted or unsubstituted have 1 N and 0-3 selected from N,
The heteroatomic 3-10 circle heterocyclic ring base (including monocycle and ring or caged scaffold) of S and O；
R4、R5And R6Be each independently be located at C ring on any position substituent group selected from the group below: hydrogen, halogen ,-CN,
Hydroxyl, amino, carboxyl ,-(C=O)-substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkyl, replace or
Unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino radical, replace or not
Substituted C1-C8 alkoxyl, substituted or unsubstituted there are 1-3 to be selected from the group at substituted or unsubstituted C3-C10 naphthenic base
N, the heteroatomic 3-10 membered heterocycloalkyl of S and O, substituted or unsubstituted C6-C10 aryl and substituted or unsubstituted have
1-3 are selected from the group the heteroatomic 5-10 unit's heteroaryl of N, S and O；
X is NR9；Wherein, R9For hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 naphthenic base；
Wherein, described " substitution " refers to replaced one or more (such as 2,3,4 etc.) substituent groups selected from the group below: halogen
Element, C1-C6 alkyl, halogenated C1-C6 alkyl ,-CN, hydroxyl, amino, carboxyl；
Y is carbonyl (- (CO) -)；
Unless stated otherwise, " substitution " refers to by one or more (such as 2,3,4 selected from the group below
Deng) replaced substituent group: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy,
C3-C8 naphthenic base, halogenated C3-C8 naphthenic base, oxo ,-CN, hydroxyl, hydroxyl-C1-C6 alkyl, amino, carboxyl, C6-C10 virtue
Base, halogenated C6-C10 aryl, the unsubstituted or miscellaneous originals that N, S and O are selected from 1-3 that are replaced by substituent group selected from the group below
The 5-10 unit's heteroaryl of son: halogen, phenyl.
In another preferred example, the compound is not compound selected from the group below:
In another preferred example, the 3-10 circle heterocyclic ring base is selected from the group: monocycle base, two ring groups, condensed ring radical, bridged ring
Base, loop coil base.
In another preferred example, the C ring is that substituted or unsubstituted phenyl ring or substituted or unsubstituted 5-7 member are miscellaneous
Aromatic ring.
In another preferred example, the B ring is five yuan and five-membered ring.
In another preferred example, the B ring is five yuan and hexatomic ring.
In another preferred example, the B ring is hexa-atomic and hexatomic ring.
In another preferred example, the B ring is five yuan and heptatomic ring.
In another preferred example, the B ring is saturated rings, part unsaturated ring or aromatic rings.
In another preferred example, the C ring is 5-7 member ring.
In another preferred example, the C ring is phenyl ring.
In another preferred example, each chiral centre in compound of formula I is each independently R type or S type.
In another preferred example, the R4、R5And R6It is each independently and is located at any position on C ring and is selected from the group
Substituent group: hydrogen, halogen ,-CN, hydroxyl, amino, carboxyl, substituted or unsubstituted C1-C8 alkyl.
In another preferred example, the compound has the structure as shown in following formula I:
Wherein, W1It is selected from the group: CR10R11、CR10, O, S or NR12；
W2It is selected from the group: CR10Or N；
W3For CR10R11、CR10, N or NR12；
N is 0,1 or 2；
Dotted line is chemical bond or nothing；
R10And R11The substituent group selected from the group below being each independently: hydrogen, halogen ,-CN, hydroxyl, amino, carboxyl ,-(C
=O)-substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl,
Substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino radical, substituted or unsubstituted C1-C8 alkoxyl,
Substituted or unsubstituted C3-C10 naphthenic base, the substituted or unsubstituted heteroatomic 3- that N, S and O are selected from the group with 1-3
10 membered heterocycloalkyls, substituted or unsubstituted C6-C10 aryl and substituted or unsubstituted there is 1-3 to be selected from the group N, S and O
Heteroatomic 5-10 unit's heteroaryl；
R12The substituent group selected from the group below being each independently: hydrogen ,-CN, hydroxyl, amino, carboxyl ,-(C=O)-replace or
Unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, replaces or does not take substituted or unsubstituted C1-C8 alkyl
The C2-C6 alkynyl in generation, substituted or unsubstituted C1-C8 alkylamino radical, substituted or unsubstituted C1-C8 alkoxyl, substitution do not take
The C3-C10 naphthenic base in generation, the substituted or unsubstituted heteroatomic 3-10 circle heterocyclic ring alkane that N, S and O are selected from the group with 1-3
Base, substituted or unsubstituted C6-C10 aryl and substituted or unsubstituted there is 1-3 to be selected from the group the heteroatomic of N, S and O
5-10 unit's heteroaryl；
R3For positioned at and ring structure on one or more (preferably 1,2,3,4 or 5) substituent group selected from the group below: H,
Halogen ,-CN, hydroxyl, amino, carboxyl ,-(C=O)-substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkane
Base, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino radical,
Substituted or unsubstituted C1-C8 alkoxyl, substituted or unsubstituted has 1-3 at substituted or unsubstituted C3-C10 naphthenic base
It is selected from the group heteroatomic 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl and the substitution of N, S and O or does not take
The heteroatomic 5-10 unit's heteroaryl that N, S and O are selected from the group with 1-3 in generation.
In another preferred example, as n=2, the compound has the structure as shown in following formula A2:
In another preferred example, R3For positioned at and ring structure on one or more substituent groups selected from the group below: H, halogen
Element ,-CN, hydroxyl, amino, carboxyl ,-(C=O)-substituted or unsubstituted C1-C4 alkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-
C4 alkynyl, C1-C4 alkylamino radical, C1-C4 alkoxy.
In another preferred example, the compound is selected from the group formula A-1, A-2, A-3 or A-4:
W1For CR10R11, S, O or NR12；W2For CR10Or N；W3For N or NR12；W4For CR11Or (- (CO) -).
In another preferred example, the compound have be selected from the group I, II, III, IV, V, VI, VII, VIII, IXX,
Structure shown in XI:
Wherein, the R is selected from the group: halogen, C1-C4 alkyl.
In another preferred example, the C ring is 5-7 member ring.
In another preferred example, the C ring is saturated rings, part unsaturated ring or aromatic rings.
In another preferred example, the R1For C1-C4 alkyl that is halogenated or being optionally substituted by a hydroxyl group, and the R2For H.
In another preferred example, the compound is selected from compound described in table 1.
The second aspect of the present invention provides a kind of pharmaceutical composition, and it includes changes described in (1) first aspect present invention
Close object or its stereoisomer or tautomer or its pharmaceutically acceptable salt, hydrate or solvate；(2) medicine
Acceptable carrier on.
In another preferred example, described pharmaceutical composition also includes other for preventing and/or treating hepatitis type B virus
The drug of infection.
In another preferred example, described other to can be selected from for preventing and/or treat hepatitis b virus infected drug
The following group: the stimulant of immunomodulator (such as interferon-' alpha ' (IFN-α), glycol interferon-α) or innate immune system
(such as Toll-like receptor 7 and/or 8 agonists).
In another preferred example, described other to can be selected from for preventing and/or treat hepatitis b virus infected drug
The following group: tenofovir, Lamivudine, adefovirdipivoxil, Entecavir, Sebivo, or combinations thereof.
The third aspect of the present invention provides a kind of compound as described in the first aspect of the invention or its alloisomerism
Body or tautomer or its pharmaceutically acceptable salt, hydrate or solvate or as described in respect of the second aspect of the invention
The purposes of pharmaceutical composition, which is characterized in that be used to prepare prevention and/or treat hepatitis b virus infected drug.
The fourth aspect of the present invention, provides a kind of hepatitis type B virus inhibitor, and the inhibitor includes the present invention the
Compound described in one side or its stereoisomer or tautomer or its pharmaceutically acceptable salt, hydrate or molten
Agent compound.
The fifth aspect of the present invention provides and a kind of prepares compound as described in the first aspect of the invention or its solid is different
The method of structure body or tautomer or its pharmaceutically acceptable salt, hydrate or solvate, shown formula A compound are
- 1 compound represented of Formula XIII, the method includes the steps:
In atent solvent, is reacted with formula A1 compound and formula A2 compound, obtain formula A compound.
In another preferred example, shown formula A compound is -2 compound represented of Formula X, the method includes the steps:
The sixth aspect of the present invention provides a kind of method prevented and/or treat hepatitis B, comprising steps of to institute
Need patient apply first aspect present invention described in compound or its stereoisomer or tautomer or its pharmaceutically may be used
Pharmaceutical composition described in salt, hydrate or the solvate or second aspect of the present invention of receiving.
The seventh aspect of the present invention provides a kind of external method for inhibiting hepatitis type B virus, comprising steps of this is sent out
Compound described in bright first aspect or its stereoisomer or tautomer or its pharmaceutically acceptable salt, hydrate
Or solvate, it is contacted with hepatitis type B virus, to inhibit hepatitis B.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, In
This no longer tires out one by one states.
Specific embodiment
The present inventor is after extensive and in-depth study, it was found that a kind of to have excellent therapeutic effect to hepatitis B
New compound.On this basis, inventor completes the present invention.
Definition
As used herein, term " alkyl " includes the alkyl of linear chain or branched chain.Such as C1-C8Alkyl indicates there is 1-8 carbon
Alkyl of the linear chain or branched chain of atom, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl etc..
As used herein, term " alkenyl " includes the alkenyl of linear chain or branched chain.Such as C2-C6Alkenyl refers to former with 2-6 carbon
Son linear chain or branched chain alkenyl, such as vinyl, allyl, 1- acrylic, isopropenyl, 1- cyclobutenyl, 2- cyclobutenyl or
Similar group.
As used herein, term " alkynyl " includes the alkynyl of linear chain or branched chain.Such as C2-C6Alkynyl refers to 2-6 carbon
The alkynyl of the linear chain or branched chain of atom, such as acetenyl, propinyl, butynyl or similar group.
As used herein, term " C3-C10Naphthenic base " refers to the naphthenic base with 3-10 carbon atom.It can be monocycle,
Such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl or similar group.It is also possible to bi-cyclic form, such as bridged ring or loop coil shape
Formula.
As used herein, term " C1-C8Alkylamino radical " refers to by C1-C8Amido replaced alkyl, can be it is monosubstituted or
It is disubstituted；For example, methylamino, ethylamino-, Propylamino, isopropylamine base, butylamine base, isobutyl amine, tert-butylamine base, dimethylamine
Base, diethylin, dipropyl amido, diisopropylamino, dibutyl amino, di-iso-butylmanice base, two tert-butylamine bases etc..
As used herein, term " C1-C8Alkoxy " refers to the alkoxy of the linear chain or branched chain with 1-8 carbon atom；Example
Such as, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, tert-butoxy etc..
As used herein, term " the heteroatomic 3-10 membered heterocycloalkyl of N, S and O are selected from 1-3 " refers to have
3-10 atom and wherein 1-3 atom is the cyclic group of heteroatomic saturation or fractional saturation selected from N, S and O.Its
It can be monocycle, be also possible to bi-cyclic form, such as bridged ring or loop coil form.Specific example can be oxetanes, nitrogen
Azetidine, tetrahydro -2H- pyranose, piperidyl, tetrahydrofuran base, morpholinyl and pyrrolidinyl etc..
As used herein, term " C6-C10Aryl " refers to the aryl with 6-10 carbon atom, for example, phenyl or naphthyl
Deng similar group.
As used herein, term " the heteroatomic 5-10 unit's heteroaryl of N, S and O are selected from 1-3 " refers to 5-10
A atom and wherein 1-3 atom is the heteroatomic cyclic aromatic groups selected from N, S and O.It can be monocycle, can also be with
It is condensed ring form.Specific example can for pyridyl group, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical, pyrrole radicals, pyrazolyl,
Imidazole radicals, (1,2,3)-triazolyl and (1,2,4)-triazolyl, tetrazole radical, furyl, thienyl, isoxazolyl, thiazolyl,
Oxazolyl etc..
Group of the present invention is " substituted or unsubstituted " unless stated otherwise, otherwise group of the invention
Replaced substituent group selected from the group below: halogen, itrile group, nitro, hydroxyl, amino, C1-C6Alkyl-amino, C1-C6Alkyl, C2-
C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, halogenated C1-C6Alkyl, halogenated C2-C6Alkenyl, halogenated C2-C6Alkynyl, halogenated C1-C6
Alkoxy, allyl, benzyl, C6-C12Aryl, C1-C6Alkoxy -C1-C6Alkyl, C1-C6Alkoxy-carbonyl, carbobenzoxy,
C2-C6Alkynyl-carbonyl, C2-C6Alkenyl-carbonyl, C3-C6Cycloalkyl-carbonyl, C1-C6Alkyl-sulfonyl base etc..
As used herein, " halogen " or " halogen atom " refers to F, Cl, Br and I.More preferably, halogen or halogen atom are selected from F, Cl
And Br." halogenated " refers to replaced the atom selected from F, Cl, Br and I.
Unless stated otherwise, structural formula described in the invention is intended to include that (such as mapping is different for all isomeric forms
Structure, diastereo-isomerism and geometric isomer (or conformer)): such as R, S configuration containing asymmetric center, double bond
(Z), (E) isomers etc..Therefore, the single three-dimensional chemical isomer of the compounds of this invention or its enantiomter, diastereomeric different
The mixture of structure body or geometric isomer (or conformer) belongs to the scope of the present invention.
As used herein, term " tautomer " indicates that with different energy structural isomer can be more than low
Energy barrier, thus mutual inversion of phases.For example, proton tautomer (i.e. prototropic change) includes carrying out interconversion by proton transfer, such as
1H- indazole and 2H- indazole.Valence tautomers include recombinating to carry out interconversion by some bonding electrons.
As used herein, term " solvate " refers to that the compounds of this invention and solvent molecule are coordinated to form special ratios
Complex.
As used herein, term " hydrate " refers to that the compounds of this invention and water carry out the complex of coordination formation.
Active constituent
As used herein, " the compounds of this invention " refers to formula (A) compound represented, and further includes formula (A) compound
Various crystalline forms, pharmaceutically acceptable salt, hydrate or solvate:
As used herein, " pharmaceutically acceptable salt " refers to that the compounds of this invention and acid or alkali are formed by and are suitable as medicine
The salt of object.Pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferred salt is that the compounds of this invention and acid are formed
Salt.The acid for suitably forming salt includes but is not limited to: the inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid,
Formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, hardship
Sour, methanesulfonic acid, benzene methanesulfonic acid, the organic acids such as benzene sulfonic acid；And the acidic amino acids such as aspartic acid, glutamic acid.
In another preferred example, the B ring, C ring, X, Y, R1、R2、R4、R5And R6It is each independently eachization in table 1
Close group corresponding to object.
Preferred the compounds of this invention is as shown in table 1:
Pharmaceutical composition and method of administration
Since the compounds of this invention has the inhibitory activity of excellent hepatitis type B virus (HBV), chemical combination of the present invention
Object and its various crystal forms, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and contain chemical combination of the present invention
Object is that the pharmaceutical composition of main active can be used for preventing and/or treating and (stablize, mitigate or cure) hepatitis type B virus
Infection or for prevent and/or treat (stablize, mitigate or cure) hepatitis type B virus related disease (for example, hepatitis B, into
Malleability liver fibrosis, the inflammation for leading to cirrhosis and necrosis, end-stage liver disease, ethyl liver cancer).
Pharmaceutical composition of the invention is comprising the compounds of this invention within the scope of safe and effective amount and can pharmaceutically receive
Excipient or carrier.Wherein " safe and effective amount " refers to: the amount of compound is enough to be obviously improved the state of an illness, and is unlikely to generate
Serious side effect.In general, pharmaceutical composition contains 1-2000mg the compounds of this invention/agent, more preferably, contain 10-200mg sheet
Invention compound/agent.Preferably, described is " one " for a capsule or tablet.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solids or liquid filler or gelatinous mass,
They are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " referred to herein as composition
Middle each component energy and the compounds of this invention and they between mutually admix, and significantly reduce the drug effect of compound.Pharmaceutically
Acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose
Acetic acid esters etc.), gelatin, talcum, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame
Oil, peanut oil, olive oil etc.), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbierite), emulsifier (such as ), profit
Humectant (such as lauryl sodium sulfate), colorant, flavoring agent, stabilizer, antioxidant, preservative, apirogen water.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representative method of application includes
(but being not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulations
In type, reactive compound is mixed at least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with
Following compositions mixing: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) it bonds
Agent, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；(c) moisturizer, example
Such as, glycerol；(d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, certain composition silicates,
And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti
Pure and mild glycerin monostearate；(h) adsorbent, for example, kaolin；(i) lubricant, for example, talcum, calcium stearate, tristearin
Or mixtures thereof sour magnesium, solid polyethylene glycol, lauryl sodium sulfate,.In capsule, tablet and pill, dosage form also may include
Buffer.
Coating and shell material preparation can be used in solid dosage forms such as tablet, sugar-pill, capsule, pill and granule, such as casing and
Other materials well known in the art.They may include opacifying agent, also, reactive compound or compound in this composition
Release can discharge in certain a part in the digestive tract in a delayed fashion.The example of adoptable embedding component is polymeric material
And wax material.When necessary, reactive compound can also be with one of above-mentioned excipient or a variety of formation microencapsulation forms.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture.
In addition to active compounds, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, increase
Solvent and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethyl formyl
The mixture of amine and oil, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances
Deng.
Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweet taste
Agent, corrigent and fragrance.
In addition to active compounds, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene
Sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or the mixture of these substances etc..
Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid,
Suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.It is suitable aqueous and
Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
The compounds of this invention can be administered alone, or with other pharmaceutically acceptable compounds (such as anti-HBV agent)
It is administered in combination.
When administering drug combinations, described pharmaceutical composition further include with it is one or more (2 kinds, 3 kinds, 4 kinds, or more) other
Pharmaceutically acceptable compound (such as anti-HBV agent).In other pharmaceutically acceptable compounds (such as anti-HBV agent)
It is one or more (2 kinds, 3 kinds, 4 kinds, or more) can be with the compound of the present invention simultaneously, separately or be sequentially used for preventing
And/or treat HBV infection or HBV related disease.
It is the mammal that the compounds of this invention of safe and effective amount is applicable to treatment when using pharmaceutical composition
(such as people), wherein dosage is the effective dosage pharmaceutically thought when application, for the people of 60kg weight, day is to medicament
Amount is usually 1~2000mg, preferably 20~500mg.Certainly, specific dosage is also contemplated that administration route, patient health situation etc.
Factor, within the scope of these are all skilled practitioners technical ability.
Main advantages of the present invention include:
1. the compound of the present invention structure novel and having the function of excellent anti-hepatitis virus infection.
2. the compound of the present invention is very low to the toxicity of normal cell.
3. the compounds of this invention and containing the compounds of this invention be main active pharmaceutical composition can be used for it is pre-
Prevent and/or treats hepatitis b virus infected.
4. the compounds of this invention and containing the compounds of this invention be main active pharmaceutical composition can be used for it is pre-
Anti- and/or treatment hepatitis type B virus related disease is (for example, hepatitis B, progressivity liver fibrosis, the inflammation for leading to cirrhosis
With necrosis, end-stage liver disease, ethyl liver cancer).
Term explanation
Unless otherwise defined, otherwise whole technologies used herein and scientific term all have such as fields of the present invention
The normally understood identical meanings of those of ordinary skill.
As used herein, in use, term " about " means that the value can be from enumerating in mentioning the numerical value specifically enumerated
Value changes not more than 1%.For example, as used herein, statement " about 100 " include 99 and 101 and between whole values (for example,
99.1,99.2,99.3,99.4 etc.).
As used herein, term " containing " or " including (including) " can be open, semi-enclosed and enclosed.It changes
Yan Zhi, the term also include " substantially by ... constitute " or " by ... constitute ".
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.
Experimental material used in following embodiment and reagent can obtain unless otherwise instructed from commercially available channel.
Each embodiment is the synthesis of 100 class compounds below:
The synthesis of 1 compound 100a of embodiment
Step 1:
87 (50mg) are dissolved in acetonitrile (3ml), triethylamine (50mg) is added, 99 (60mg) 80 degree of reactions is added.Reaction knot
Shu Hou crosses column (heptane:EA=3:1) 10mg after being spin-dried for.ESI-MS (M+H=451)
The synthetic method of root embodiment 1 has synthesized following 100 class series compound again:
Biological examples -- anti-HBV activity experiment
Experiment one: effect on hepatitics B virus in vitro nucleocapsid assembling activity test method
Main agents and raw material:
C150 albumen is that Yao Ming Kant company expresses and purifies；
FL is purchased from Thermo Fischer Scient Inc..
Protein fluorescence label:
150 μ L 2%w/v skim milks are added to the every hole of 96 orifice plates, are incubated at room temperature 2 hours.Skim milk is sopped up, is spent
It is dried after ionized water cleaning, room temperature preservation.C150 albumen (3 milligrams of every pipe) is used into 5ml Hitrap desalting column desalination.To every pipe
50mM is added in C150 albumen after desalination20 μ l of FL fluorescent dye is uniformly mixed, and 4 DEG C are protected from light overnight incubation.With
Sephadex G-25 gel filtration removes the fluorescent dye not in conjunction with C150.The fluorescent label efficiency of C150 is calculated, formula is such as
Under:
[FL]=A504/78,000M-1；
[C150Bo]=(A280- [FL]x 1300M-1)/60,900M-1；
Fluorescent label efficiency=[FL]/[C150Bo]；
Wherein,
[FL] indicate fluorescent marker concentration；
The concentration of [C150Bo] expression fluorescent marker protein；
The light absorption value of A504 expression wavelength 504nM；
The light absorption value of A280 expression wavelength 280nM；
M-1Indicate the inverse of molar concentration.
Diluted chemical compound:
Compound stock solutions are diluted to 6mM with DMSO, then are diluted to 600 μM with 50mM HEPES, then use 10%DMSO/
Further 3 times of 50mM HEPES are serially diluted 8 concentration.
C150Bo is diluted to 2 μM with 50mM HEPES.Take the compound of 37.5 μ L C150Bo and the 2.5 each concentration of μ L
It is added in 96 hole reaction plates and mixes, be incubated at room temperature 15 minutes.The 750mM NaCl/50mM HEPES of 10 μ l is taken to be added to reaction
The final concentration of 150mM of Kong Zhong, NaCl.
0% albumen assembles control wells, and the final concentration of 0mM of the 50mM HEPES, NaCl of 10 μ L is added.
100% albumen assembles control wells, and the final concentration of 1M of 5M the NaCl/50mM HEPES, NaCl of 10 μ L is added.
DMSO final concentration of 0.5%, final concentration of 30 μM of compound highest, final concentration of 1.5 μM of C150Bo.Incubation at room temperature
1 hour.Measure fluorescence signal (exciting light 485nm；Emit light 535nm).
Data analysis
% albumen assembling=[1- (sample fluorescence value -1M NaCl fluorescent value)/(0M NaCl fluorescent value -1MNaCl fluorescence
Value)] × 100.
IC50Value is calculated by prism software, and equation is as follows:
Y=Bottom+ (Top-Bottom)/(1+10((LogIC50-X)*HillSlope))；
Wherein,
X indicates the logarithm of concentration, and Y indicates effect value, and Y is originated from bottom and is fitted to top with S type；
Bottom indicates the bottom of curve；
Top indicates that Top indicates the top of curve；
HillSlope is indicated: the absolute value of the greatest gradient of curve.
Experiment two: it is measured in the anti-hepatitis B activity of HepG2.2.15 cell
Main agents:
QIAamp 96DNA Blood Kit (12) (Qiagen, article No. 51162)；
FastStart Universal Probe Master (Roche, article No. 04914058001)；
Cell-titer Glo detection reagent (Promega, article No. G7573).
Diluted chemical compound: external Anti-HBV effect experiment is serially diluted with equal 3 times of all compounds of cytotoxicity experiment, and 8
Concentration.The final initial concentration of test-compound is 30 μM, and the final initial concentration of reference compound GLS4 is 1 μM, DMSO final concentration
It is 0.5%.
Kind HepG2.2.15 cell (4 × 104Cells/well) to 96 orifice plates, at 37 DEG C, 5%CO2Overnight incubation.Second day,
The fresh medium of the compound containing various concentration is added into culture hole.5th day, culture solution old in culture hole is absorbed, is added
The fresh medium of the compound containing various concentration.
8th day, the supernatant in culture hole is collected, the HBV DNA, qPCR for extracting in supernatant detect HepG2.2.15
HBV DNA content in supernatant.After collecting supernatant, then supplemented medium and Cell-titer Glo reagent into culture hole, enzyme
Mark instrument detects the values of chemiluminescence in each hole.
Active calculation formula is as follows:
Y=Bottom+ (Top-Bottom)/(1+10((LogIC50-X)*HillSlope))；
Wherein,
X indicates the logarithm of concentration, and Y indicates effect value, and Y is originated from bottom and is fitted to top with S type；
The bottom of Bottom expression curve；
The top of Top expression curve；
HillSlope is indicated: the absolute value of the greatest gradient of curve.
Experiment three: cytotoxicity assay
The cytotoxicity of untested compound is tested using HepG2 cell, by these cells in untested compound
In the presence of be incubated for 4 days.Cell viability is assessed using resazurin measurement.
The result shows that: the effect on hepatitics B virus in vitro nucleocapsid assembling activity and anti-hepatitis B activity of the compound of the present invention
Well, and cytotoxicity is low.
It can be seen that the compound of the application has excellent anti-hepatitis B activity.
The activity data of experiment one to experiment three is shown in Table 2:
Table 2
Wherein, in second column of table:
+++ indicate IC50<1μM；
++ indicate IC50It is 1~100 μM；
+ indicate IC50It is > 100 μM.
In table third column:
++++indicate EC50<0.1nM；
+++ indicate EC500.1~100nM；
++ indicate EC50For 100~1000nM；
+ indicate EC50For > 1000nM.
It can be seen that the compound of the application has excellent anti-hepatitis B activity.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (11)
1. a kind of chemical formula A compound represented or its stereoisomer or tautomer or its is pharmaceutically acceptable
Salt, hydrate or solvate,
Wherein, the B ring is substituted or unsubstituted 8-20 membered bicyclic and ring structure；Wherein, the substitution refers on group
One or more hydrogen atoms replaced by substituent group selected from the group below: halogen ,-CN, hydroxyl, amino, carboxyl ,-(C=O)-replace
Or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, replace or not
Substituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino radical, substituted or unsubstituted C1-C8 alkoxyl, substitution or not
Substituted C3-C10 naphthenic base, the substituted or unsubstituted heteroatomic 3-10 circle heterocyclic ring that N, S and O are selected from the group with 1-3
Alkyl, substituted or unsubstituted C6-C10 aryl and the substituted or unsubstituted hetero atom that N, S and O are selected from the group with 1-3
5-10 unit's heteroaryl；
C ring is substituted or unsubstituted 5-12 member ring；
R1、R2It is each independently selected from the following group: hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 ring
It is alkyl, the substituted or unsubstituted heteroatomic 3-10 circle heterocyclic ring base with 1-3 selected from N, S and O, substituted or unsubstituted
C6-C10 aryl, the substituted or unsubstituted heteroatomic 5-10 unit's heteroaryl that N, S and O are selected from the group with 1-3；Or R1、R2
Collectively forming with the nitrogen-atoms being connected with them substituted or unsubstituted has 1 N and 0-3 selected from the heteroatomic of N, S and O
3-10 circle heterocyclic ring base；
R4、R5And R6Be each independently be located at C ring on any position substituent group selected from the group below: hydrogen, halogen ,-CN, hydroxyl,
Amino ,-(C=O)-substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkyl, replaces or does not take carboxyl
It is the C2-C6 alkenyl in generation, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino radical, substituted or unsubstituted
C1-C8 alkoxyl, substituted or unsubstituted C3-C10 naphthenic base, it is substituted or unsubstituted have 1-3 be selected from the group N, S and
The heteroatomic 3-10 membered heterocycloalkyl of O, substituted or unsubstituted C6-C10 aryl and substituted or unsubstituted there are 1-3
It is selected from the group the heteroatomic 5-10 unit's heteroaryl of N, S and O；
X is NR9；Wherein, R9For hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 naphthenic base；Wherein,
" substitution " refers to replaced one or more (such as 2,3,4 etc.) substituent groups selected from the group below: halogen, C1-
C6 alkyl, halogenated C1-C6 alkyl ,-CN, hydroxyl, amino, carboxyl；
Y is carbonyl (- (CO) -)；
Unless stated otherwise, " substitution " refers to is taken by one or more (such as 2,3,4 etc.) selected from the group below
Replaced Dai Ji: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8
Naphthenic base, halogenated C3-C8 naphthenic base, oxo ,-CN, hydroxyl, hydroxyl-C1-C6 alkyl, amino, carboxyl, C6-C10 aryl, halogen
The C6-C10 aryl in generation, it is unsubstituted or by substituent group selected from the group below replace with 1-3 selected from the heteroatomic of N, S and O
5-10 unit's heteroaryl: halogen, phenyl.
2. compound as described in claim 1, which is characterized in that the compound has the structure as shown in following formula I:
Wherein, W1It is selected from the group: CR10R11、CR10, O, S or NR12；
W2It is selected from the group: CR10Or N；
W3For CR10R11、CR10, N or NR12；
N is 0,1 or 2；
Dotted line is chemical bond or nothing；
R10And R11The substituent group selected from the group below being each independently: hydrogen, halogen ,-CN, hydroxyl, amino, carboxyl ,-(C=O)-
Substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, replaces substituted or unsubstituted C1-C8 alkyl
Or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino radical, substituted or unsubstituted C1-C8 alkoxyl, substitution
Or unsubstituted C3-C10 naphthenic base, the substituted or unsubstituted heteroatomic 3-10 member that N, S and O are selected from the group with 1-3
Heterocyclylalkyl, substituted or unsubstituted C6-C10 aryl and substituted or unsubstituted there is 1-3 to be selected from the group the miscellaneous of N, S and O
The 5-10 unit's heteroaryl of atom；
R12The substituent group selected from the group below being each independently: hydrogen ,-CN, hydroxyl, amino, carboxyl ,-(C=O)-substitution do not take
It is the C1-C8 alkyl in generation, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted
It is C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino radical, substituted or unsubstituted C1-C8 alkoxyl, substituted or unsubstituted
C3-C10 naphthenic base substituted or unsubstituted there is 1-3 to be selected from the group the heteroatomic 3-10 membered heterocycloalkyl of N, S and O, take
Generation or unsubstituted C6-C10 aryl and the substituted or unsubstituted heteroatomic 5-10 that N, S and O are selected from the group with 1-3
Unit's heteroaryl；
R3For positioned at and ring structure on one or more substituent groups selected from the group below: H, halogen ,-CN, hydroxyl, amino, carboxyl ,-
(C=O)-substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkene
Base, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino radical, substituted or unsubstituted C1-C8 alcoxyl
Base, substituted or unsubstituted there is 1-3 to be selected from the group the heteroatomic of N, S and O at substituted or unsubstituted C3-C10 naphthenic base
3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl and substituted or unsubstituted there is 1-3 to be selected from the group N, S
With the heteroatomic 5-10 unit's heteroaryl of O.
3. compound as described in claim 1, which is characterized in that the C ring is 5-7 member ring.
4. compound as described in claim 1, which is characterized in that the R1For C1-C4 alkane that is halogenated or being optionally substituted by a hydroxyl group
Base, and the R2For H.
5. compound as described in claim 1, which is characterized in that the compound is selected from the group:
6. a kind of pharmaceutical composition, it includes (1) compound described in claim 1 or its stereoisomers or tautomerism
Body or its pharmaceutically acceptable salt, hydrate or solvate；(2) pharmaceutically acceptable carrier.
7. compound as described in claim 1 or its stereoisomer or tautomer or its is pharmaceutically acceptable
The purposes of salt, hydrate or solvate or pharmaceutical composition as claimed in claim 6, which is characterized in that be used to prepare pre-
Prevent and/or treat hepatitis b virus infected drug.
8. a kind of hepatitis type B virus inhibitor, which is characterized in that the inhibitor include compound described in claim 1,
Or its stereoisomer or tautomer or its pharmaceutically acceptable salt, hydrate or solvate.
9. a kind of compound as described in claim 1 or its stereoisomer or tautomer or its of preparing can pharmaceutically connect
The method of salt, hydrate or the solvate received, shown formula A compound are -1 compound represented of Formula XIII, the method packet
Include step:
In atent solvent, is reacted with formula A1 compound and formula A2 compound, obtain formula A compound.
10. a kind of method of prevention and/or treatment hepatitis B, comprising steps of being applied to required patient described in claim 1
Compound or its stereoisomer or tautomer or its pharmaceutically acceptable salt, hydrate or solvate or right
It is required that pharmaceutical composition described in 6.
11. a kind of external method for inhibiting hepatitis type B virus, which is characterized in that comprising steps of by described in claim 1ization
Object or its stereoisomer or tautomer or its pharmaceutically acceptable salt, hydrate or solvate are closed, and it is B-mode
Hepatitis virus contact, to inhibit hepatitis B.
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| PCT/CN2019/085559 WO2019210880A1 (en) | 2018-05-04 | 2019-05-05 | Dicyclourea nucleocapsid inhibitor and pharmaceutical use thereof |
| CN201980030320.2A CN112074518B (en) | 2018-05-04 | 2019-05-05 | Di-parallel cyclic urea nucleocapsid inhibitor and its pharmaceutical use |
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| CN112074518B (en) | 2023-09-19 |
| CN110437232B (en) | 2022-04-12 |
| WO2019210880A1 (en) | 2019-11-07 |
| CN112074518A (en) | 2020-12-11 |
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