CN101775003A - Benzothiophene derivative, preparation method and application thereof - Google Patents
Benzothiophene derivative, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a compound with general formula (I) structure or salt which can be received in pharmacy. The compound or the salt which can be received in pharmacy can restrain hepatitis C virus NS5B polymerase in vitro with high efficiency, can have anti-hepatitis C virus activity in vivo, and has higher inhibitory activity when being compared with NS5B polymerase inhibitors with the similar structure.
Description
Technical field
The present invention relates to thionaphthene carboxylic acid cpd and method for making and purposes, especially its inhibitor of duplicating as hepatitis C virus (HCV) as Anti-virus agent.
Background technology
It is the major cause that hepatic diseases is brought out in the whole world that hepatitis C virus (HCV) infects, estimate according to The World Health Organization (WHO), there is 1.7 hundred million to 200,000,000 chronic hepatitis C infection person in the whole world at present, accounts for 3% of global population, and annual newly-increased third hepatopath 3,000,000～4,000,000 people.According to U.S. disease prevention and control center (CDC) statistics, only the chronic hepatitis C patient of the U.S. is just near 3,000,000 people, and the whole America is annual to increase third hepatopath, 300,000 people newly.In China, enquiry data shows that the c-hepatitis antibody positive rate is 3.2%, and 4,000 ten thousand patients are arranged approximately.Though the acute third liver clinical manifestation is lighter, easily develop into chronicly, the patient of about 50-80% can develop into chronic hepatitis even liver cirrhosis and liver cancer, it is reported, infects behind third liver 20 years, and liver cirrhosis occurs as 10-15%.The third liver number of the infected of China report in 2008 is about 120,000, is 6 times in 2003.The present third liver mortality ratio comes the tenth in all diseases of the whole world, in China, the third liver mortality ratio comes the 5th.
At present, the standard treatments of third liver is that Peg-Intron (PEG-IFN) share with ribavirin.The PEG-IFN that sells on the market comprises the PEG-Intron of Schering Plough company, the Pegasys of Roche Holding Ag; Ribavirin comprises the Rebetol of Schering Plough company, the Copegus of Roche Holding Ag, and various imitation medicine.But from continuing rate of virological response (SVR), present this standard treatments effect is not very desirable, and clinical cure rate is about 50%.And the administration time of present this therapy is long, third hepatopath such as the HCVI type, need 48 weeks of continuous use, serious adverse effects also often takes place simultaneously, as with the problem of spiritual aspect, flu-like symptoms occurs and produce haematics toxicity, thereby cause the successful curative ratio of existing therapy to be less than 10%, therefore, develop a kind of new mechanism, the HCV inhibitor of high-efficiency low-toxicity seems particularly important more.
The HCV genome is a kind of single stranded RNA (+) of flaviviridae, about 9600 base pairs common 3009-3030 amino acid whose polypeptide of having encoded.This polypeptide is 10 albumen with difference in functionality by the proteolytic enzyme cutting, comprising core protein---Core, shell glycoprotein---E1, E2, unstructuredness albumen---NS2, NS3 (having serine protease, helicase activity), NS4A, NS4B, NS5A, NS5B (having the RdRP activity), and the albumen of 1 Unknown Function---p7 (it may be a kind of ionic channel for recent findings) is in the albumen ripening process, Core, E1, the cutting between E2 and p7 relies on intracellular signal peptidase to finish, the cysteine protease activity of self that then relies on NS2 and NS3 realizes the autocatalysis fracture, and the NS3 of the cutting between all the other albumen after by maturation finishes.(Michael?P.Manns?et?al.，Nature?Reviews?Drug?Discovery，6，991-1001(2007))。
Virogene replicative enzyme NS5B is the rna dependent rna polysaccharase of virus, and having with RNA is the rna replicon activity of template, is responsible for that HCV is genomic to be duplicated.The NS5B gene is that HCV is peculiar, high conservative all in the HCV of range gene type virus, and also it lacks corresponding gene in the mammalian cell genome.The common RNA (RaffaeleDe Francesco, Antiviral Research, 58:1-16 (2003)) that relies on of expressed rna not of the cell of Gan Raning not, therefore, NS5B becomes the desirable target spot of treatment hepatitis C.
The seventies in last century, the investigator finds the part patient because a kind of new pathogenic agent has been infected in blood transfusion.Non-A appears in infected person, the non-B hepatitis symptom, so will cause this para-infectious pathogenic agent called after C type (third type) hepatitis virus (hepatitis C virus, HCV).1989, the just separated for the first time and affirmation of the genome of HCV.Nowadays, 6 kinds of HCV genotype (1-6 type) and a hypotype surplus in the of 70 have been found in the global range.The distribution of different genes C-type virus C in the whole world also exists than big-difference, and wherein 1,2,3 C-type virus Cs are distribution on global, and the European and American areas is based on the 1a type, and comprises the Far East Area of China, 1b, and 2a, the 2b type is more common, and wherein the 1b type is main dominant strain.1a and 1b account for 78.1% of all infected numbers.(Peter?Simmonds?et?al.，Hepathology，42：962-973(2005))。Based on this, be necessary to develop the HCV inhibitor that can suppress 1a and 1b hypotype.In the former document, reported thiophene carboxylic acid's compounds can be used as the HCV inhibitor that acts on the NS5B polysaccharase (WO2002/100851, WO2005/063734, WO2007/071434).
Summary of the invention
The object of the invention is to provide a kind of compound of brand-new inhibition hepatitis c virus infection to be used to carry out the treatment that HCV infects, and provides a kind of brand-new treatment means and mechanism, for the treatment hepatitis c virus infection provides new selection.
In order to solve these problems of the prior art, technical scheme provided by the invention is:
A kind of compound or its pharmacy acceptable salt with general formula (I) structure,
Wherein, R
1Be selected from the C1-C12 alkyl, C2-C12 thiazolinyl, C2-C12 alkynyl, C6-C14 aryl, C3-C12 heterocycle, C3-C18 heteroarylalkyl, C6-C18 arylalkyl or C3-C7 cycloalkyl;
R
2Be selected from hydrogen, C1-C12 alkyl, C2-C12 thiazolinyl, C2-C12 alkynyl, C3-C12 heterocycle, C3-C18 heteroarylalkyl, C6-C18 arylalkyl or C3-C7 cycloalkyl;
R
3Be selected from hydrogen, halogen, nitro ,-NR
aR
b,-SO
2R
c,-SO
2NR
dR
e,-CONR
fR
g,-NR
hCOR
i,-NR
jSO
2R
k, azido-, cyano group, trifluoromethyl, trifluoromethoxy, the C1-C6 alkyl or-OR
l
R
4Be selected from hydrogen, halogen, nitro ,-NR
aR
b,-SO
2R
c,-SO
2NR
dR
e,-CONR
fR
g,-NR
hCOR
i,-NR
jSO
2R
k, azido-, cyano group, trifluoromethyl, trifluoromethoxy, the C1-C6 alkyl or-OR
l
R
5Be selected from hydrogen, halogen, nitro ,-NR
aR
b,-SO
2R
c,-SO
2NR
dR
e,-CONR
fR
g,-NR
hCOR
i,-NR
jSO
2R
k, azido-, cyano group, trifluoromethyl, trifluoromethoxy, the C1-C6 alkyl or-OR
l
R
6Be selected from hydrogen, halogen, C1-C12 alkyl, C2-C12 thiazolinyl, C6-C14 aryl, C5-C14 heteroaryl, C6-C14 arylalkyl, C5-C14 heteroarylalkyl, C3-C12 heterocycle, C3-C7 cycloalkyl or C3-C7 cycloalkenyl group;
A is selected from-NR
jSO
2R
k,-OR
n,-NR
oSO
2NR
pR
qB is selected from-CO-,-SO
2-;
R
1, R
6Can be chosen wantonly replacement by one or more following group when non-hydrogen: halogen, nitro ,-NR
aR
b,-SO
2R
c,-SO
2NR
dR
e,-CONR
fR
g,-NR
hCOR
i,-NR
jSO
2R
k, azido-, cyano group, trifluoromethyl, trifluoromethoxy, the C1-C6 alkyl or-OR
lR
2Can be chosen wantonly replacement by one or more following group when non-hydrogen: halogen or-OR
m
In above-mentioned, R
a, R
b, R
c, R
d, R
e, R
f, R
g, R
h, R
i, R
j, R
k, R
l, R
n, R
o, R
p, R
qBe independently selected from hydrogen or C1-C6 alkyl or C6-C14 aryl; R
mBe independently selected from hydrogen or C1-C6 alkyl.
Preferably, described R
1Be selected from the C6-C14 aryl, C3-C12 heterocycle, C3-C18 heteroarylalkyl, C6-C18 arylalkyl or C3-C7 cycloalkyl;
R
2Be selected from the C1-C12 alkyl, C2-C12 thiazolinyl, C2-C12 alkynyl, C3-C12 heterocycle, C3-C18 heteroarylalkyl, C6-C18 arylalkyl or C3-C7 cycloalkyl;
R
6Be selected from the C6-C14 aryl, C5-C14 heteroaryl, C6-C14 arylalkyl, C5-C14 heteroarylalkyl, C3-C12 heterocycle, C3-C7 cycloalkyl or C3-C7 cycloalkenyl group;
R
1, R
6Can be chosen wantonly replacement by one or more following group: halogen, nitro ,-NR
aR
b,-SO
2R
c,-SO
2NR
dR
e,-CONR
fR
g,-NR
hCOR
i,-NR
jSO
2R
k, azido-, cyano group, trifluoromethyl, trifluoromethoxy, the C1-C6 alkyl or-OR
lR
2Can be chosen wantonly replacement by one or more following group when non-hydrogen: halogen or-OR
m
In above-mentioned, R
a, R
b, R
c, R
d, R
e, R
f, R
g, R
h, R
i, R
j, R
k, R
lBe independently selected from hydrogen or C1-C6 alkyl or C6-C14 aryl; R
mBe independently selected from hydrogen or C1-C6 alkyl.
Preferably, described R
1Be selected from the C6-C14 aryl, C3-C12 heterocycle, C3-C18 heteroarylalkyl, C6-C18 arylalkyl or C3-C7 cycloalkyl;
R
2Be selected from the C1-C12 alkyl, C2-C12 thiazolinyl, C2-C12 alkynyl, C3-C12 heterocycle, C3-C18 heteroarylalkyl, C6-C18 arylalkyl or C3-C7 cycloalkyl;
R
6Be selected from the C6-C14 aryl, C5-C14 heteroaryl, C6-C14 arylalkyl, C5-C14 heteroarylalkyl, C3-C12 heterocycle, C3-C7 cycloalkyl or C3-C7 cycloalkenyl group;
R
1, R
6Can be chosen wantonly replacement by one or more following group: halogen, nitro ,-NR
aR
b,-SO
2R
c,-SO
2NR
dR
e,-CONR
fR
g,-NR
hCOR
i,-NR
jSO
2R
k, azido-, cyano group, trifluoromethyl, trifluoromethoxy, the C1-C6 alkyl or-OR
lR
2Can be chosen wantonly replacement by one or more following group when non-hydrogen: halogen or-OR
m
A is a hydroxyl;
In above-mentioned, R
a, R
b, R
c, R
d, R
e, R
f, R
g, R
h, R
i, R
j, R
k, R
lBe independently selected from hydrogen or C1-C6 alkyl or C6-C14 aryl; R
mBe independently selected from hydrogen or C1-C6 alkyl.
Preferably, described compound is selected from 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-phenyl benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-6-phenyl benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-ethyl-4-methylcyclohexyl formamido-)-6-phenyl benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-benzyl-4-methylcyclohexyl formamido-)-6-phenyl benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-4-methylcyclohexyl formamido-)-7-phenyl benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-4-Methyl benzenesulfonyl amido)-7-phenyl benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(naphthyl-1-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(xenyl-4-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(1 hydrogen-indoles-5-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(pyridine-3-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(cumarone-2-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(4-Trifluoromethoxyphen-l) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(furyl-2-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(3, the 5-bis trifluoromethyl phenyl) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(thionaphthene-2-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(4-chloro-phenyl-) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(4-tert-butyl-phenyl) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(4-fluorophenyl) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(thienyl-2-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(2-chloro-phenyl-) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-bromobenzene is [b] thiophene-2-carboxylic acid also.
Another object of the present invention is to provide a kind of method for preparing the compound of described general formula (I) structure, it is characterized in that said method comprising the steps of:
(1) compound of formula (II)
Under alkaline environment with the compound of Methyl Thioglycolate generation cyclization production (III)
(2) compound of formula (III) and carboxylic acid halides condensation form the compound of formula (IV)
(3) compound of formula (IV) obtains the compound of formula V with the reaction of iodo thing after the alkali deprotonation
(4) after the Suzuki linked reaction, obtain the compound of formula (I) by the compound of (V) with the highly basic saponification
More than various in, R
1, R
2, R
3, R
4, R
5, R
6, A, B define with claim 1.
Another purpose of the present invention is to provide a kind of method for preparing the compound of described general formula (I) structure, it is characterized in that said method comprising the steps of:
(1) compound of formula (II)
Under alkaline environment with the compound of Methyl Thioglycolate generation cyclization production (III)
(2) compound of formula (III) obtains the compound of formula (VI) through reductive amination process
(3) compound of formula (VI) and carboxylic acid halides condensation obtain the compound of formula V
(4) after the Suzuki linked reaction, obtain the compound of formula (I) by the compound of (V) with the highly basic saponification
More than various in, R
1, R
2, R
3, R
4, R
5, R
6, A, B define with claim 1.
Preferably, described step (1) neutral and alkali environment is having an amount of mineral alkali, as diethylamine, and triethylamine, diisopropylethylamine, pyridine, quinoline etc., or organic bases, as salt of wormwood, yellow soda ash, cesium carbonate, potassium hydroxide is under the situation that sodium hydroxide etc. exist; Alkali is selected from organic bases in the described step (3), as salt of wormwood, and yellow soda ash, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride KH, butyllithium, lithium diisopropylamine, hexamethyl two silica-based amido lithiums, sodium hexamethyldisilazide, potassium hexamethyldisilazide etc.
Another purpose of the present invention is to provide a kind of medicinal compositions, it is characterized in that, described composition contains pharmaceutically acceptable carrier and pharmaceutically described formula (I) compound or its pharmacy acceptable salt of significant quantity.
Another purpose of the present invention is to provide a kind of described compound or its pharmacy acceptable salt to suppress application aspect the medicine that hepatitis C virus duplicates in preparation.
Another purpose of the present invention is to provide a kind of described compound or the application of its pharmacy acceptable salt aspect the medicine of preparation control hepatitis c virus infection.
The explanation of term
Each group among the present invention generally has following meaning:
Term " alkyl " refers to straight or branched aliphatic hydrocarbon group saturated, that contain 1-8 carbon atom (preferably 1-6 carbon atom); The C1-n alkyl is then represented the saturated aliphatic radical of 1-n carbon atom, comprise straight chain and branched group (for example " C1-20 alkyl ", be meant that this group is an alkyl, and the carbochain amount of carbon atom of alkyl is between 1～20, promptly contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms etc., until the alkyl that comprises 20 carbon atoms.And the restriction of this 1-20 does not comprise the carbonatoms of the replacement on the alkyl, as replace " alkyl " in the alkylamino, when being not particularly limited its carbonatoms, only refer to that wherein the carbonatoms of indicated moieties is 1-20, and do not comprise substituent carbonatoms on the alkyl and other the substituent carbonatomss on the amino.Adopt the statement of " C1-8 alkyl " then to represent to contain in this alkyl the alkyl of 1～8 carbon atom.) " thiazolinyl " comprise straight chain and the branched hydrocarbyl that contains at least one carbon-carbon double bond and 2-8 carbon atom (preferably 2-6 carbon atom); " alkynyl " comprises straight chain and the branched hydrocarbyl that contains at least one carbon carbon triple bond and 2-8 carbon atom (preferably 2-6 carbon atom).Haloalkyl, the alkyl that the expression halogen atom replaces, this replacement comprises single replacement and polysubstituted, wherein the notion of alkyl is as mentioned above.C1～8 haloalkyls, the carbonatoms that is meant the alkyl in the haloalkyl is 1～8.Haloalkyl refers to the group that the H atom is replaced by halogen atom on the alkyl; Be meant the group that the H on the alkyl is all replaced by F as perfluoroalkyl.
The term of this paper " aryl " refers to aromatic systems, can be monocycle or originally condensed or many aromatic rings of linking together, thereby at least a portion is condensed or the ring that connects forms conjugated virtue system.Aromatic yl group includes, but are not limited to: phenyl, naphthyl, tetralyl.Aryl can be optionally substituted, as being selected from down aryl that group replaced or the heterocycle of organizing by 1-4: halogen, CN, OH, NO
2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxyl group, aryloxy, replacement alkoxyl group, alkyl-carbonyl, alkyl carboxyl, alkylamino or arylthio.Preferably, substituting group is halogen, C1-C4 alkyl.
Heterocyclic radical is meant heteroatomic cyclic groups by 3 to 8 annular atomses such as containing N, O, S, and in this group, heteroatoms can only contain the N atom, also can contain O or S atom.Wherein heteroatomic number can be one, also can be for a plurality of.This heterocycle can be saturated class cycloalkanes structure, also can be undersaturated aromatic ring class formation.More specifically, this term nitrogen heterocycle includes but not limited to pyrryl, Pyrrolidine base, piperidyl, piperazinyl, morpholinyl, piperazinyl, pyrimidyl, imidazolyl etc.Heterocycle also can comprise any many rings, and wherein arbitrary above-mentioned heterocycle can condense in aromatic ring.
Halogen refers to F, Cl, Br or I.
Should be clear that some formula (I) compound can present tautomerism.Formula (I) compound can exist with the form of solvation not, also can exist with the form of solvation.Even can there be heteromorphism in some formula of the present invention (I) compound.
The pharmacy acceptable salt that is fit to of formula (I) compound can be the acid salt of formula (I) compound, can include, but is not limited to salt with following mineral acid formation: example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the salt that forms with organic acid, organic acid then refers to acetate, oxalic acid, Succinic Acid, tartrate, methylsulfonic acid and toxilic acid; Can be salt, as an alkali metal salt or alkaline earth salt (calcium salt, magnesium salts or ammonium salt etc.) with enough tart formulas (I) compound.The pharmacy acceptable salt that the another kind of formula (I) compound is fit to can be the salt that forms in human or animal body behind giving construction (I) compound.This compound also can be with the form (when with this form administration, can change into active part in vivo) of " prodrug " of ester, carbamate or other routines.
The synthetic route of compound
Repeatedly discover through the contriver, compound of the present invention can but be not limited to following dual mode and synthesize, the benzene carbonitrile derivatives (II) that one of them can replace by the ortho position fluorine and Methyl Thioglycolate are handled with yellow soda ash and are formed 3-amino benzothiophene derivative (III).Amino benzothiophene derivative of 3-(III) and acyl chlorides condensation are obtained amide derivatives (IV), and then can obtain intermediate (V) with NaH processing back dropping iodo thing.Intermediate (V) next takes place can to obtain required target molecule (VII) with the highly basic saponification after the Suzuki coupling with boric acid thereupon, and this target molecule is compound a kind of of preferred formula (I).Its synthetic route (1) is as follows:
Benzene carbonitrile derivatives (II) that another kind of preparation method can replace by the ortho position fluorine and Methyl Thioglycolate with yellow soda ash handle form the amino benzothiophene derivative of 3-(III) after, amino benzothiophene derivative of 3-(III) and aldehyde, ketone or enol obtain sulfonamide derivatives (VI) by reductive amination process (addition reaction).Then sulfonamide derivatives (VI) and acyl chlorides condensation are obtained intermediate (V).Intermediate (V) next takes place can to obtain required target molecule (VII) with the highly basic saponification after the Suzuki coupling with boric acid thereupon, and this target molecule is compound a kind of of preferred formula (I).Its synthetic route (2) is as follows:
Indication and medication
The present invention also comprises pharmaceutical composition and methods of treatment, and it comprises the formula I compound to the administration significant quantity.Compound of the present invention can be used for treatment: HCV to be infected.Preferably, described Mammals is the people.
When compound is used for such use; they can with one or more pharmaceutically acceptable carrier or mixed with excipients; as solvent, thinner etc.; and can be with following form oral administration: tablet, capsule, dispersible powder, particle or suspension (containing 0.05-5% suspension agent according to appointment), syrup (containing 10-50% sugar according to appointment) and elixir (containing the 20-50% ethanol of having an appointment), perhaps carry out the parenteral administration with sterile injectable solution or form of suspension (containing the 0.05-5% suspension agent of having an appointment in the medium waiting to ooze).For example, these pharmaceutical preparations can contain and the about 25-90% of carrier blended, are about the activeconstituents of 5%-60% (weight) usually.
The effective dose of used activeconstituents can change with the severity of the pattern of used compound, administration and disease to be treated.Yet, when compound of the present invention every day gives with the dosage of about 0.5-500mg/kg the weight of animals, can obtain gratifying effect usually, preferably give with the dosage that separates for 2-4 time every day, or with the slowly-releasing form administration.For most of large mammal, the total dose of every day is about 1-100mg, preferably is about 2-80mg.Be applicable to dosage form for oral administration, comprise active compound with the intimately mixed about 0.5-500mg of solid-state or liquid pharmaceutically acceptable carrier.Can regulate this dosage replys so that optimal treatment to be provided.For example, by an urgent demand of treatment situation, but give the dosage that several times separate every day, or dosage is reduced pari passu.
These active compounds can be by oral and intravenously, intramuscular or administration such as subcutaneous.Solid-state carrier comprises: starch, lactose, Lin Suanergai, Microcrystalline Cellulose, sucrose and white bole, and liquid carrier comprises: sterilized water, polyoxyethylene glycol, nonionic surface active agent and edible oil (as Semen Maydis oil, peanut oil and sesame oil), as long as be fit to the characteristic of activeconstituents and required specific administration mode.Normally used adjuvant also can advantageously be comprised in pharmaceutical compositions, for example seasonings, pigment, sanitas and antioxidant such as vitamin-E, vitamins C, BHT and BHA.
From being easy to prepare the position with administration, preferred pharmaceutical composition is a solid-state composition, and especially tablet and solid are filled or the capsule of liquid filling.The oral administration of compound is preferred.
But these active compounds are parenteral or intraperitoneal administration also.The solution or the suspension that also can in the water that suitably is mixed with tensio-active agent (as hydroxypropylcellulose), prepare these active compounds (as free alkali or pharmacy acceptable salt).Also can in glycerine, liquid, polyoxyethylene glycol and the mixture in oil thereof, prepare dispersion liquid.Under routine storage and working conditions, contain sanitas in these preparations to prevent microorganism growth.
The medicament forms that is adapted to inject comprises: aseptic aqueous solution or dispersion liquid and aseptic powder (being used for preparing aseptic injectable solution or dispersion liquid) temporarily.In all situations, these forms must be aseptic and must be that fluid is discharged fluid to be easy to syringe.Under manufacturing and condition of storage must be stable, and must be able to prevent the pollution effect of microorganism (as bacterium and fungi).Carrier can be solvent or dispersion medium, wherein contains just like water, alcohol (as glycerine, propylene glycol and liquid polyethylene glycol), their suitable mixture and vegetables oil.
The inventor finds that after deliberation thionaphthene carboxylic acid compound of the present invention can act on the NS5B polysaccharase, and suppresses HCV virus efficiently in vivo.When hepatitis C virus being exposed in the compound of effective concentration, hepatitis C virus can effectively be killed.Be used for the treatment of the medicine that HCV infects so compound of the present invention can be used to prepare, certainly, can comprise pharmaceutically acceptable carrier in the medicine.
With respect to scheme of the prior art, advantage of the present invention is:
The present invention has found a kind of compound of brand-new molecular structure, and making us unexpected is that it can suppress hepatitis C virus NS 5 B polysaccharase efficiently external, thereby may have anti-hepatitis C virus activity in vivo.Compare with the NS5B AG14361 of similar structures, it is higher that it suppresses activity.
Embodiment
Below in conjunction with specific embodiment such scheme is described further.Should be understood that these embodiment are used to the present invention is described and are not limited to limit the scope of the invention.The implementation condition that adopts among the embodiment can be done further adjustment according to the condition of concrete producer, and not marked implementation condition is generally the condition in the normal experiment.
Embodiment:
Embodiment 1 Compound I a:3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-phenyl benzo [b] thiophene-2-carboxylic acid
Earlier want also [b] thiophene-2-carboxylic acid methyl esters of synthetic intermediate IIIa:3-amino-7-bromobenzene, by intermediate III a synthesising target compound.
According to synthetic route (1); under the nitrogen protection with 3-bromo-2-fluorobenzene cyanogen (5.0g; 25.1mmol) be dissolved among 20.0 milliliters of DMF; add yellow soda ash (5.3g; 50.0mmol) be cooled to 0 ℃, under stirring condition, drip Methyl Thioglycolate (2.9g, 27.5mmol); reaction soln is risen to room temperature, and stirring is spent the night.After adding entry, separate out white solid, filter, water, petroleum ether solid get white powder (6.4g), yield 89.5% after the drying.
1H?NMR(CDCl
3，300MHz)δ7.64-7.60(m，2H)，7.29-7.24(m，1H)，5.86(br，2H)，3.90(s，3H)；ESI-MS?m/z?284(M-H)
-。
Intermediate compound IV a's is synthetic
7-bromo-3-(4-methylcyclohexyl formamido-) benzo [b] thiophene-2-carboxylic acid methyl esters
Step a: trans-4-methyl cyclohexane formic acid (5.2g 32.4mmol) is dissolved in 60 milliliters of methylene dichloride, under the nitrogen protection condition, adds 30 milliliters of sulfur oxychlorides, refluxes cool to room temperature 2 hours.Concentration of reaction solution is kept somewhere stand-by.
Step b: under the nitrogen protection effect; with intermediate III a (5.0g; 17.5mmol) be dissolved in the anhydrous methylene dichloride (60ml); add triethylamine (7.3ml; 52.6mmol) be cooled to 0 ℃; dropping is dissolved in trans-4-methyl cyclohexane formyl chloride in 10 milliliters of methylene dichloride, and (3.6g, 22.7mmol), stirring is spent the night.Concentration of reaction solution adds entry and ethyl acetate, extracts three times.Organic phase washes with water, saturated common salt washing, Na
2SO
4Drying, filtering and concentrating gets solid.Use recrystallizing methanol, obtain intermediate compound IV a (5.0g), yield 70%.
1H?NMR(CDCl
3，300MHz)δ9.58(s，1H)，8.08(d，J＝8.1Hz，1H)，7.65(d，J＝7.5Hz，1H)，7.32-7.28(m，1H)，3.97(s，3H)，2.43-2.36(m，1H)，2.17-2.12(m，2H)，1.89-1.85(m，2H)，1.70-1.62(m，2H)，1.45-1.30(m，2H)，1.12-1.04(m，1H)，0.95(d，J＝6.6Hz，3H)；ESI-MS?m/z?410(M+H)
+。
Intermediate Va's is synthetic
7-bromo-3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-) benzo [b] thiophene-2-carboxylic acid isopropyl ester
Under nitrogen protection, (2.0g 4.9mmol) is dissolved among anhydrous 60 milliliters of DMF, and (1.4g 35.0mmol), cools off to add sodium hydride with intermediate compound IV a.(8.3g, 49mmol) back is stirred and is spent the night to add Iso-Propyl iodide.Add the shrend reaction of going out, use ethyl acetate extraction, organic phase makes water, saturated common salt washing, Na
2SO
4Drying is used ethyl acetate and sherwood oil (1/15-1/8) column chromatography after the filtering and concentrating, obtain target product intermediate Va (1.3g), yield 56%.
1H?NMR(CDCl
3，300MHz)δ7.69-7.65(m，2H)，7.37-7.32(m，1H)，5.27-5.19(m，1H)，4.82-4.72(m，1H)，1.78-1.74(m，2H)，1.60-1.47(m，6H)，1.34(d，J＝3.9Hz，6H)，1.19(d，J
AB＝6.3Hz，3H)，0.96(d，J＝6.3Hz，3H)，0.69(d，J＝6.3Hz，3H)，0.58-0.54(m，1H)，0.41-0.38(m，1H)；ESI-MS?m/z?480(M+H)
+。
Compound I a's is synthetic
Under nitrogen protection, add in the tube sealing intermediate Va (100mg, 0.21mmol), phenylo boric acid (38mg, 0.31mmol), Pd (PPh
3)
4(12mg, 0.01mmol), yellow soda ash (45mg, 0.42mmol), ethylene glycol monomethyl ether (0.8ml), water (0.4ml) adds the back 100 ℃ of reactions 6 hours.Cool to room temperature adds sodium hydroxide (15mg), and dioxane stirs and spends the night.Add 1N hydrochloric acid in the reaction solution, regulate pH to 3-4, use ethyl acetate extraction, with saturated common salt washing, Na
2SO
4Drying obtains solid after concentrating, and obtains powdered compounds with sherwood oil and ethyl acetate washing solid.
1H?NMR(DMSO-d6，300MHz)δ8.61(s，1H)，7.88-7.58(m，8H)，4.77-4.72(m，1H)，1.87-1.75(m，2H)，1.65-1.47(m，5H)，1.22(d，J＝6.6Hz，3H)，1.07(d，J＝6.6Hz，3H)，1.00-0.95(m，1H)，0.76(d，J＝6.6Hz，3H)，0.62-0.58(m，1H)，0.45-0.41(m，1H)；ESI-MS?m/z?434(M-H)
-。
Embodiment 2 compounds ibs: 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-6-phenyl benzo [b] thiophene-2-carboxylic acid
Intermediate III b's is synthetic
3-amino-6-bromobenzene is [b] thiophene-2-carboxylic acid methyl esters also
According to synthetic route (1); under the nitrogen protection with 4-bromo-2-fluorobenzene cyanogen (5.0g; 25.1mmol) be dissolved in 20.0ml DMF; add yellow soda ash (5.3g; 50.0mmol) be cooled to 0 ℃, under stirring condition, drip Methyl Thioglycolate (2.9g, 27.5mmol); reaction soln is risen to room temperature, and stirring is spent the night.After adding entry, separate out white solid, filter, water, petroleum ether solid get white powder (6.0g), yield 83.9% after the drying.
1H?NMR(CDCl
3，300MHz)δ7.88(s，1H)，7.48(s，2H)，5.88(s，2H)，3.89(s，3H)；ESI-MS?m/z?284(M
+-H
+)。
Below several steps according to the method for preparing Compound I a among the embodiment 1, can prepare compounds ib with intermediate III b.
1H?NMR(DMSO-d6，300MHz)δ8.02(s，1H)，7.65-7.58(m，3H)，7.45-7.38(m，4H)，4.15-4.12(m，1H)，1.95-1.84(m，2H)，1.62-1.42(m，6H)，1.27(d，J＝6.6Hz，6H)，0.98(d，J＝6.6Hz，3H)，0.58-0.57(m，1H)，0.44-0.40(m，1H)；ESI-MSm/z?434(M-H)
-。
Embodiment 3 Compound I c:3-(nitrogen-ethyl-4-methylcyclohexyl formamido-)-6-phenyl benzo [b] thiophene-2-carboxylic acid
Can prepare Compound I c according to the method for preparing compounds ib among the embodiment 2.
1H?NMR(DMSO-d6，300MHz)δ8.40(s，1H)，7.86-7.74(m，4H)，7.53-7.41(m，3H)，3.82-3.58(m，2H)，2.10-2.02(m，1H)，1.84-1.80(m，3H)，1.66-1.63(m，3H)，1.43-1.24(m，6H)，0.83(d，J＝6.6Hz，3H)；ESI-MS?m/z?422(M+H)
+。
Embodiment 4 Compound I d:3-(nitrogen-benzyl-4-methylcyclohexyl formamido-)-6-phenyl benzo [b] thiophene-2-carboxylic acid
Its synthetic thinking is also [b] thiophene-2-carboxylic acid methyl esters of first synthetic intermediate VIa:3-(nitrogen-benzyl)-6-bromobenzene, again by intermediate VIa synthesising target compound.
According to synthetic route (2), under nitrogen protection, with the intermediate III b that produces among the embodiment 2 (290mg 1mmol) is dissolved in 5 milliliter 1, in the 2-ethylene dichloride, add phenyl aldehyde (424mg, 4mmol), acetate (240mg, 4mmol), stirring at room.(1.3g, 6mmol), reaction is spent the night to add three acetic acid sodium borohydrides.Concentration of reaction solution adds entry, and ethyl acetate extraction, organic layer are successively with saturated sodium bicarbonate, water, saturated common salt washing.Use ethyl acetate and sherwood oil (1/20-1/15) column chromatography after concentrating ethyl acetate, obtain target product intermediate (273mg), yield 73%.
ESI-MS?m/z?374(M-H)
-。
Intermediate Vd's is synthetic
3-(nitrogen-benzyl-4-methylcyclohexyl formamido-)-6-bromobenzene is [b] thiophene-2-carboxylic acid methyl esters also
Under the nitrogen protection effect, (225mg 0.6mmol) is dissolved in the methylene dichloride, adds diisopropylethylamine (232mg with intermediate VIa; 1.8mmol), the acyl chlorides of adding preparation (192mg, 1.2mmol); (188mg, 0.72mmol), room temperature reaction spends the night triphenylphosphine.Concentration of reaction solution adds entry and ethyl acetate extraction, and organic layer concentrates organic layer with 1N hydrochloric acid, saturated common salt washing.With sherwood oil and ethyl acetate (1/10-1/5) column chromatography, obtain target product intermediate (179mg), yield 60%.
1H?NMR(CDCl
3，300MHz)δ7.97(s，1H)，7.38(d，J＝8.7Hz，1H)，7.16-7.08(m，6H)，4.97(d，J＝13.8Hz，1H)，4.75(d，J＝13.8Hz，1H)，3.71(s，3H)，2.01-1.96(m，2H)，1.80-1.73(m，2H)，1.50-1.25(m，3H)，0.88(d，J＝6.6Hz，3H)，0.60-0.56(m，1H)，0.45-0.40(m，1H)；ESI-MS?m/z?498(M-H)
-。
Compound I d's is synthetic
Under nitrogen protection, add in the tube sealing above-mentioned intermediate Vd (110mg, 0.2mmol), phenylo boric acid (37mg, 0.3mmol), Pd (PPh
3)
4(12mg, 0.01mmol), yellow soda ash (53mg, 0.5mmol), ethylene glycol monomethyl ether (0.8ml), water (0.4ml) was 100 ℃ of reactions 6 hours.Cool to room temperature.Add 1N hydrochloric acid in the reaction solution, regulate pH to 3-4, use ethyl acetate extraction, the saturated common salt washing, the Na2SO4 drying obtains solid after concentrating, and obtains powdered compounds with sherwood oil and re-crystallizing in ethyl acetate solid.
1H?NMR(DMSO-d6，300MHz)δ8.32(s，1H)，7.73(d，J＝8.1Hz，2H)，7.64(d，J＝8.4Hz，1H)，7.49-7.28(m，4H)，7.14-7.12(m，5H)，5.23(d，J＝13.8Hz，1H)，4.51(d，J＝13.8Hz，1H)，1.90-1.80(m，1H)，1.65-1.21(m，7H)，0.67(d，J＝6.0Hz，3H)，0.60-0.50(m，1H)，0.37-0.33(m，1H)；ESI-MS?m/z?482(M-H)
-。
Embodiment 5 Compound I e:3-(nitrogen-4-methylcyclohexyl formamido-)-7-phenyl benzo [b] thiophene-2-carboxylic acid
Can prepare Compound I e according to the method for preparing Compound I a among the embodiment 1.
1H?NMR(DMSO-d6，300MHz)δ9.99(s，1H)，7.82-7.79(m，3H)，7.67-7.59(m，5H)，2.51-2.48(m，1H)，2.08-2.04(m，2H)，1.88-1.84(m，2H)，1.66-1.44(m，3H)，1.12-1.07(m，2H)，1.00(d，J＝6.3Hz，3H)；ESI-MS?m/z?392(M-H)
-。
Embodiment 6 Compound I f:3-(nitrogen-4-Methyl benzenesulfonyl amido)-7-phenyl benzo [b] thiophene-2-carboxylic acid
Can prepare Compound I f according to the method for preparing Compound I a among the embodiment 1.
1H?NMR(DMSO-d6，300MHz)δ7.89-7.82(m，4H)，7.71-7.60(m，4H)，7.50-7.47(m，3H)，7.33-7.28(m，1H)，2.53(s，3H)；ESI-MS?m/z?422(M-H)
-。
Embodiment 7 Compound I g:3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(naphthyl-1-position) benzo [b] thiophene-2-carboxylic acid
Can prepare Compound I g according to the method for preparing Compound I a among the embodiment 1.
1H?NMR(DMSO-d6，300MHz)δ8.11-8.06(m，2H)，7.92-7.82(m，1H)，7.71-7.44(m，7H)，4.72-4.62(m，1H)，1.82-1.74(m，1H)，1.68-1.62(m，1H)，1.54-1.34(m，5H)，1.19(d，J＝6.6Hz，3H)，1.01(d，J＝6.6Hz，3H)，0.86-0.79(m，1H)，0.70(d，J＝6.6Hz，3H)，0.55-0.49(m，1H)，0.39-0.34(m，1H)；ESI-MS?m/z?484(M-H)
-。
Embodiment 8 Compound I h:3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(xenyl-4-position) benzo [b] thiophene-2-carboxylic acid
Can prepare Compound I h according to the method for preparing Compound I a among the embodiment 1.
1H?NMR(DMSO-d6，300MHz)δ7.90(s，4H)，7.80-7.77(m，2H)，7.71-7.65(m，3H)，7.54-7.49(m，2H)，7.44-7.38(m，1H)，4.71-4.62(m，1H)，1.80-1.68(m，2H)，1.54-1.36(m，5H)，1.14(d，J＝6.6Hz，3H)，0.99(d，J＝6.6Hz，3H)，0.86-0.82(m，1H)，0.69(d，J＝6.9Hz，3H)，0.57-0.46(m，1H)，0.38-0.28(m，1H)；ESI-MSm/z?510(M-H)
-。
Embodiment 9 Compound I i:3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(1 hydrogen-indoles-5-position) benzo [b] thiophene-2-carboxylic acid
Can prepare Compound I i according to the method for preparing Compound I a among the embodiment 1.
1H?NMR(DMSO-d6，300MHz)δ11.3(s，1H)，7.96(d，J＝1.5Hz，1H)，7.68-7.57(m，4H)，7.48-7.45(m，2H)，6.56-6.55(m，1H)，4.71-4.61(m，1H)，1.78-1.64(m，2H)，1.54-1.38(m，5H)，1.19-1.12(m，1H)，1.15(d，J＝6.9Hz，3H)，0.98(d，J＝6.9Hz，3H)，0.69(d，J＝6.9Hz，3H)，0.55-0.49(m，1H)，0.38-0.28(m，1H)；ESI-MS?m/z?473(M-H)
-。
Embodiment 10 Compound I j:3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(pyridine-3-position) benzo [b] thiophene-2-carboxylic acid
Can prepare Compound I j according to the method for preparing Compound I a among the embodiment 1.
1H?NMR(DMSO-d6，300MHz)δ8.97(s，1H)，8.74-8.72(m，1H)，8.26(d，J＝10.2Hz，1H)，7.84-7.81(m，1H)，7.77-7.59(m，3H)，4.73-4.64(m，1H)，1.79-1.64(m，2H)，1.56-1.36(m，5H)，1.25-1.20(m，1H)，1.13(d，J＝6.6Hz，3H)，0.99(d，J＝6.6Hz，3H)，0.69(d，J＝6.3Hz，3H)，0.60-0.50(m，1H)，0.45-0.35(m，1H)；ESI-MS?m/z?435(M-H)
-。
Embodiment 11 Compound I k:3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(cumarone-2-position) benzo [b] thiophene-2-carboxylic acid
Can prepare Compound I k according to the method for preparing Compound I a among the embodiment 1.
1H?NMR(DMSO-d6，300MHz)δ8.25(d，J＝6.9Hz，1H)，7.84-7.69(m，5H)，7.45-7.32(m，2H)，4.73-4.64(m，1H)，1.75-1.64(m，2H)，1.55-1.35(m，5H)，1.13(d，J＝6.6Hz，3H)，0.99(d，J＝6.6Hz，3H)，0.89-0.79(m，1H)，0.66(d，J＝6.9Hz，3H)，0.58-0.45(m，1H)，0.38-0.23(m，1H)；ESI-MS?m/z?474(M-H)
-。
Embodiment 12 Compound I l:3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(4-Trifluoromethoxyphen-l) benzo [b] thiophene-2-carboxylic acid
Can prepare Compound I l according to the method for preparing Compound I a among the embodiment 1.
1H?NMR(DMSO-d6，300MHz)δ7.94(d，J＝8.4Hz，2H)，7.80-7.77(m，1H)，7.71-7.67(m，2H)，7.60(d，J＝8.4Hz，2H)，6.55(s，1H)，4.71-4.62(m，1H)，1.77-1.62(m，2H)，1.54-1.35(m，5H)，1.14(d，J＝6.9Hz，3H)，0.98(d，J＝6.9Hz，3H)，0.88-0.77(m，1H)，0.68(d，J＝6.6Hz，3H)，0.57-0.50(m，1H)，0.39-0.31(m，1H)；ESI-MS?m/z?518(M-H)
-。
Embodiment 13 Compound I m:3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(furyl-2-position) benzo [b] thiophene-2-carboxylic acid
Can prepare Compound I m according to the method for preparing Compound I a among the embodiment 1.
1H?NMR(DMSO-d6，300MHz)δ8.02-8.00(m，1H)，7.72-7.54(m，3H)，7.23-7.21(m，1H)，6.78-6.76(m，1H)，4.70-4.60(m，1H)，1.74-1.62(m，2H)，1.54-1.39(m，5H)，1.12(d，J＝6.9Hz，3H)，0.97(d，J＝6.9Hz，3H)，0.93-0.79(m，1H)，0.66(d，J＝6.3Hz，3H)，0.56-0.43(m，1H)，0.36-0.24(m，1H)；ESI-MS?m/z?424(M-H)
-。
Embodiment 14 Compound I n:3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(3, the 5-bis trifluoromethyl phenyl) benzo [b] thiophene-2-carboxylic acid
Can prepare Compound I n according to the method for preparing Compound I a among the embodiment 1.
1H?NMR(DMSO-d6，300MHz)δ8.48(s，2H)，8.28(s，1H)，7.86-7.82(m，2H)，7.73-7.68(m，1H)，4.72-4.63(m，1H)，1.82-1.65(m，2H)，1.54-1.37(m，5H)，1.22-1.17(m，1H)，1.13(d，J＝6.9Hz，3H)，0.98(d，J＝6.9Hz，3H)，0.69(d，J＝6.3Hz，3H)，0.61-0.47(m，1H)，0.43-0.30(m，1H)；ESI-MS?m/z?570(M-H)
-。
Embodiment 15 Compound I o:3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(thionaphthene-2-position) benzo [b] thiophene-2-carboxylic acid
Can prepare Compound I o according to the method for preparing Compound I a among the embodiment 1.
1H?NMR(DMSO-d6，300MHz)δ8.11(s，1H)，8.10-8.08(m，1H)，8.04-8.01(m，1H)，7.95(d，J＝7.5Hz，1H)，7.82(d，J＝8.1Hz，1H)，7.78-7.66(m，1H)，7.56-7.46(m，2H)，4.72-4.63(m，1H)，1.78-1.61(m，2H)，1.54-1.36(m，5H)，1.22-1.18(m，1H)，1.14(d，J＝6.6Hz，3H)，0.99(d，J＝6.6Hz，3H)，0.68(d，J＝6.0Hz，3H)，0.56-0.46(m，1H)，0.41-0.29(m，1H)；ESI-MS?m/z?490(M-H)
-。
Embodiment 16 Compound I p:3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(4-chloro-phenyl-) benzo [b] thiophene-2-carboxylic acid
Can prepare Compound I p according to the method for preparing Compound I a among the embodiment 1.
1H?NMR(DMSO-d6，300MHz)δ7.83-7.76(m，3H)，7.67-7.64(m，4H)，4.72-4.62(m，1H)，1.77-1.63(m，2H)，1.55-1.36(m，5H)，1.19-1.14(m，1H)，1.13(d，J＝6.6Hz，3H)，0.98(d，J＝6.6Hz，3H)，0.68(d，J＝6.6Hz，3H)，0.58-0.45(m，1H)，0.39-0.31(m，1H)；ESI-MS?m/z?468(M-H)
-。
Embodiment 17 Compound I q:3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(4-tert-butyl-phenyl) benzo [b] thiophene-2-carboxylic acid
Can prepare Compound I q according to the method for preparing Compound I a among the embodiment 1.
1H?NMR(DMSO-d6，300MHz)δ7.74-7.61(m，7H)，4.72-4.63(m，1H)，1.78-1.65(m，2H)，1.58-1.42(m，5H)，1.38(s，9H)，1.16(d，J＝6.6Hz，3H)，1.00(d，J＝6.6Hz，3H)，0.89-0.83(m，1H)，0.70(d，J＝6.9Hz，3H)，0.59-0.49(m，1H)，0.41-0.31(m，1H)；ESI-MS?m/z?490(M-H)
-。
Embodiment 18 Compound I r:3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(4-fluorophenyl) benzo [b] thiophene-2-carboxylic acid
Can prepare Compound I r according to the method for preparing Compound I a among the embodiment 1.
1H?NMR(DMSO-d6，300MHz)δ7.86-7.82(m，2H)，7.77-7.73(m，1H)，7.69-7.65(m，2H)，7.46-7.40(m，2H)，4.71-4.62(m，1H)，1.78-1.64(m，2H)，1.55-1.36(m，5H)，1.21-1.16(m，1H)，1.14(d，J＝6.6Hz，3H)，0.98(d，J＝6.6Hz，3H)，0.69(d，J＝6.3Hz，3H)，0.59-0.46(m，1H)，0.41-0.28(m，1H)；ESI-MS?m/z?452(M-H)
-。
Embodiment 19 Compound I s:3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(thienyl-2-position) benzo [b] thiophene-2-carboxylic acid
Can prepare Compound I s according to the method for preparing Compound I a among the embodiment 1.
1H?NMR(DMSO-d6，300MHz)δ8.11(d，J＝8.1Hz，1H)，7.75-7.54(m，5H)，4.70-4.60(m，1H)，1.72-1.58(m，2H)，1.54-1.33(m，5H)，1.22-1.17(m，1H)，1.11(d，J＝6.6Hz，3H)，0.95(d，J＝6.6Hz，3H)，0.67(d，J＝6.6Hz，3H)，0.56-0.46(m，1H)，0.33-0.25(m，1H)；ESI-MS?m/z?440(M-H)
-。
Embodiment 20 Compound I t:3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(2-chloro-phenyl-) benzo [b] thiophene-2-carboxylic acid
Can prepare Compound I t according to the method for preparing Compound I a among the embodiment 1.
1H?NMR(DMSO-d6，300MHz)δ7.82(d，J＝8.4Hz，1H)，7.71-7.54(m，6H)，4.70-4.60(m，1H)，1.79-1.62(m，2H)，1.55-1.34(m，5H)，1.29-1.25(m，1H)，1.16(d，J＝6.6Hz，3H)，0.98(d，J＝6.6Hz，3H)，0.69(d，J＝6.3Hz，3H)，0.58-0.46(m，1H)，0.36-0.24(m，1H)；ESI-MS?m/z?468(M-H)
-。
Embodiment 21 Compound I u:3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-bromobenzene is [b] thiophene-2-carboxylic acid also
Can prepare Compound I u according to the method for preparing Compound I a among the embodiment 1.
1H?NMR(DMSO-d6，300MHz)δ7.90(d，J＝7.5Hz，1H)，7.87(d，J＝8.4Hz，1H)，7.55-7.50(m，1H)，4.71-4.62(m，1H)，1.73-1.60(m，2H)，1.54-1.35(m，5H)，1.20-1.10(m，1H)，1.08(d，J＝6.6Hz，3H)，0.95(d，J＝6.6Hz，3H)，0.68(d，J＝6.6Hz，3H)，0.60-0.47(m，1H)，0.37-0.27(m，1H)；ESI-MS?m/z?436(M-H)
-。
The biological activity test of embodiment 22 compounds
The compound of formula I is selected Compound I a, compounds ib, Compound I c, Compound I d, Compound I e, the Compound I f of embodiment 1～6 gained for use; Control compound is selected following compound for use
This compound prepares by the method for WO2002100851.
The ability that inhibition HCV duplicates proves by following experiment in vitro.
The A.NS5B polysaccharase suppresses experiment
The experiment of the inhibition of standard N S5B polysaccharase is as follows: the reaction solution of 20uL, contain the Tris-HCl of 20mM, and pH 7.0,5mM MgCl
2, 5mM MnCl
2, 5mM DTT, 5U RNAsin, 100ug/mL BSA, the NS5B albumen of 400-500ng, 0.2ug poly (C) template, 10mMGTP and 1mCi[α-
33P]-GTP.This reaction solution passes through the 0.45M of adding 2uL in reaction under 25 ℃ after 2 hours EDTA stops, the clean plate several.After the washing, the bonded radioactivity is counted by scintillometer.
The test-results of the formula I compound (IC that suppresses the NS5B polysaccharase
50Value) list in table 1, wherein A represents its IC
50Value is less than 1uM, and B represents its IC
50Value is between 1uM to 10uM, and C represents its IC
50Value is between 10uM to 50uM, and D represents its IC
50Value is greater than 50uM.
Table 1 compound suppresses the result of NS5B polysaccharase
B.HCV replicon (Replicon) experiment
The HCV that the method that formula I compound provides according to document is tested them suppresses ability (ChiakiOkuse, Jo Ann Rinaudo, Kristine Farrar, Frances Wells and Brent E.Korba, Antiviral Research 2005,65 (1), 23-34).
Above-mentioned example only is explanation technical conceive of the present invention and characteristics, and its purpose is to allow the people who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalent transformations that spirit is done according to the present invention or modification all should be encompassed within protection scope of the present invention.
Claims (10)
1. compound or its pharmacy acceptable salt with general formula (I) structure,
Wherein, R
1Be selected from the C1-C12 alkyl, C2-C12 thiazolinyl, C2-C12 alkynyl, C6-C14 aryl, C3-C12 heterocycle, C3-C18 heteroarylalkyl, C6-C18 arylalkyl or C3-C7 cycloalkyl;
R
2Be selected from hydrogen, C1-C12 alkyl, C2-C12 thiazolinyl, C2-C12 alkynyl, C3-C12 heterocycle, C3-C18 heteroarylalkyl, C6-C18 arylalkyl or C3-C7 cycloalkyl;
R
3Be selected from hydrogen, halogen, nitro ,-NR
aR
b,-SO
2R
c,-SO
2NR
dR
e,-CONR
fR
g,-NR
hCOR
i,-NR
iSO
2R
k, azido-, cyano group, trifluoromethyl, trifluoromethoxy, the C1-C6 alkyl or-OR
l
R
4Be selected from hydrogen, halogen, nitro ,-NR
aR
b,-SO
2R
c,-SO
2NR
dR
e,-CONR
fR
g,-NR
hCOR
i,-NR
jSO
2R
k, azido-, cyano group, trifluoromethyl, trifluoromethoxy, the C1-C6 alkyl or-OR
l
R
5Be selected from hydrogen, halogen, nitro ,-NR
aR
b,-SO
2R
c,-SO
2NR
dR
e,-CONR
fR
g,-NR
hCOR
i,-NR
jSO
2R
k, azido-, cyano group, trifluoromethyl, trifluoromethoxy, the C1-C6 alkyl or-OR
l
R
6Be selected from hydrogen, halogen, C1-C12 alkyl, C2-C12 thiazolinyl, C6-C14 aryl, C5-C14 heteroaryl, C6-C14 arylalkyl, C5-C14 heteroarylalkyl, C3-C12 heterocycle, C3-C7 cycloalkyl or C3-C7 cycloalkenyl group;
A is selected from-NR
jSO
2R
k,-OR
n,-NR
oSO
2NR
pR
qB is selected from-CO-,-SO
2-;
R
1, R
6Can be chosen wantonly replacement by one or more following group when non-hydrogen: halogen, nitro ,-NR
aR
b,-SO
2R
c,-SO
2NR
dR
e,-CONR
fR
g,-NR
hCOR
i,-NR
jSO
2R
k, azido-, cyano group, trifluoromethyl, trifluoromethoxy, the C1-C6 alkyl or-OR
lR
2Can be chosen wantonly replacement by one or more following group when non-hydrogen: halogen or-OR
m
In above-mentioned, R
a, R
b, R
c, R
d, R
e, R
f, R
g, R
h, R
i, R
j, R
k, R
l, R
n, R
o, R
p, R
qBe independently selected from hydrogen or C1-C6 alkyl or C6-C14 aryl; R
mBe independently selected from hydrogen or C1-C6 alkyl.
2. compound according to claim 1 is characterized in that described R
1Be selected from the C6-C14 aryl, C3-C12 heterocycle, C3-C18 heteroarylalkyl, C6-C18 arylalkyl or C3-C7 cycloalkyl;
R
2Be selected from the C1-C12 alkyl, C2-C12 thiazolinyl, C2-C12 alkynyl, C3-C12 heterocycle, C3-C18 heteroarylalkyl, C6-C18 arylalkyl or C3-C7 cycloalkyl;
R
6Be selected from the C6-C14 aryl, C5-C14 heteroaryl, C6-C14 arylalkyl, C5-C14 heteroarylalkyl, C3-C12 heterocycle, C3-C7 cycloalkyl or C3-C7 cycloalkenyl group;
R
1, R
6Can be chosen wantonly replacement by one or more following group: halogen, nitro ,-NR
aR
b,-SO
2R
c,-SO
2NR
dR
e,-CONR
fR
g,-NR
hCOR
i,-NR
jSO
2R
k, azido-, cyano group, trifluoromethyl, trifluoromethoxy, the C1-C6 alkyl or-OR
lR
2Can be chosen wantonly replacement by one or more following group when non-hydrogen: halogen or-OR
m
In above-mentioned, R
a, R
b, R
c, R
d, R
e, R
f, R
g, R
h, R
i, R
j, R
k, R
lBe independently selected from hydrogen or C1-C6 alkyl or C6-C14 aryl; R
mBe independently selected from hydrogen or C1-C6 alkyl.
3. compound according to claim 1 is characterized in that described R
1Be selected from the C6-C14 aryl, C3-C12 heterocycle, C3-C18 heteroarylalkyl, C6-C18 arylalkyl or C3-C7 cycloalkyl;
R
2Be selected from the C1-C12 alkyl, C2-C12 thiazolinyl, C2-C12 alkynyl, C3-C12 heterocycle, C3-C18 heteroarylalkyl, C6-C18 arylalkyl or C3-C7 cycloalkyl;
R
6Be selected from the C6-C14 aryl, C5-C14 heteroaryl, C6-C14 arylalkyl, C5-C14 heteroarylalkyl, C3-C12 heterocycle, C3-C7 cycloalkyl or C3-C7 cycloalkenyl group;
R
1, R
6Can be chosen wantonly replacement by one or more following group: halogen, nitro ,-NR
aR
b,-SO
2R
c,-SO
2NR
dR
e,-CONR
fR
g,-NR
hCOR
i,-NR
jSO
2R
k, azido-, cyano group, trifluoromethyl, trifluoromethoxy, the C1-C6 alkyl or-OR
lR
2Can be chosen wantonly replacement by one or more following group when non-hydrogen: halogen or-OR
m
A is a hydroxyl;
In above-mentioned, R
a, R
b, R
c, R
d, R
e, R
f, R
g, R
h, R
i, R
j, R
k, R
lBe independently selected from hydrogen or C1-C6 alkyl or C6-C14 aryl; R
mBe independently selected from hydrogen or C1-C6 alkyl.
4. compound according to claim 1, it is characterized in that described compound is selected from 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-phenyl benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-6-phenyl benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-ethyl-4-methylcyclohexyl formamido-)-6-phenyl benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-benzyl-4-methylcyclohexyl formamido-)-6-phenyl benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-4-methylcyclohexyl formamido-)-7-phenyl benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-4-Methyl benzenesulfonyl amido)-7-phenyl benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(naphthyl-1-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(xenyl-4-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(1 hydrogen-indoles-5-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(pyridine-3-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(cumarone-2-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(4-Trifluoromethoxyphen-l) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(furyl-2-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(3, the 5-bis trifluoromethyl phenyl) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(thionaphthene-2-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(4-chloro-phenyl-) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(4-tert-butyl-phenyl) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(4-fluorophenyl) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(thienyl-2-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-(2-chloro-phenyl-) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-sec.-propyl-4-methylcyclohexyl formamido-)-7-bromobenzene is [b] thiophene-2-carboxylic acid also.
5. method for preparing the compound of the described general formula of claim 1 (I) structure is characterized in that said method comprising the steps of:
(1) compound of formula (II)
Under alkaline environment with the compound of Methyl Thioglycolate generation cyclization production (III)
(2) compound of formula (III) and carboxylic acid halides condensation form the compound of formula (IV)
(3) compound of formula (IV) obtains the compound of formula V with the reaction of iodo thing after the alkali deprotonation
(4) after the Suzuki linked reaction, obtain the compound of formula (I) by the compound of (V) with the highly basic saponification
More than various in, R
1, R
2, R
3, R
4, R
5, R
6, A, B define with claim 1.
6. method for preparing the compound of the described general formula of claim 1 (I) structure is characterized in that said method comprising the steps of:
(1) compound of formula (II)
Under alkaline environment with the compound of Methyl Thioglycolate generation cyclization production (III)
(2) compound of formula (III) obtains the compound of formula (VI) through reductive amination process
(3) compound of formula (VI) and carboxylic acid halides condensation obtain the compound of formula V
(4) after the Suzuki linked reaction, obtain the compound of formula (I) by the compound of (V) with the highly basic saponification
More than various in, R
1, R
2, R
3, R
4, R
5, R
6, A, B define with claim 1.
7. according to claim 5 or 6 described methods, it is characterized in that described step (1) neutral and alkali environment is selected under the situation with an amount of diethylamine, triethylamine, diisopropylethylamine, pyridine, quinoline, salt of wormwood, yellow soda ash, cesium carbonate, potassium hydroxide, sodium hydroxide existence; Alkali is selected from salt of wormwood, yellow soda ash, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride KH, butyllithium, lithium diisopropylamine, hexamethyl two silica-based amido lithiums, sodium hexamethyldisilazide, potassium hexamethyldisilazide in the described step (3).
8. a medicinal compositions is characterized in that, described composition contains pharmaceutically acceptable carrier and the pharmaceutically described compound of claim 1 or its pharmacy acceptable salt of significant quantity.
9. the described compound of claim 1 or its pharmacy acceptable salt suppress application aspect the medicine that hepatitis C virus duplicates in preparation.
10. the described compound of claim 1 or its pharmacy acceptable salt application aspect the medicine of preparation control hepatitis c virus infection.
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| EP2335700A1 (en) * | 2001-07-25 | 2011-06-22 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis C virus polymerase inhibitors with a heterobicylic structure |
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| CN105254611A (en) * | 2015-11-09 | 2016-01-20 | 江西仁明医药化工有限公司 | Preparation method for benzothiophene-2-carboxylic acid |
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