CN101775003B - Benzothiophene derivative, preparation method and application thereof - Google Patents
Benzothiophene derivative, preparation method and application thereof Download PDFInfo
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- CN101775003B CN101775003B CN2010101068450A CN201010106845A CN101775003B CN 101775003 B CN101775003 B CN 101775003B CN 2010101068450 A CN2010101068450 A CN 2010101068450A CN 201010106845 A CN201010106845 A CN 201010106845A CN 101775003 B CN101775003 B CN 101775003B
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- 0 *c([s]c1ccccc11)c1N Chemical compound *c([s]c1ccccc11)c1N 0.000 description 3
- SMNBHWRWAUPMMI-UHFFFAOYSA-N CC(C)N(C(C1CCC(C)CC1)=O)c1c(C(O)=O)[s]c2c1cccc2-c(cc1)ccc1OC(F)(F)F Chemical compound CC(C)N(C(C1CCC(C)CC1)=O)c1c(C(O)=O)[s]c2c1cccc2-c(cc1)ccc1OC(F)(F)F SMNBHWRWAUPMMI-UHFFFAOYSA-N 0.000 description 1
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 as Anti-virus agent, the inhibitor that especially it copies as hepatitis C virus (HCV).
Background technology
It is the major cause that hepatic diseases is brought out in the whole world that hepatitis C virus (HCV) infects, according to the World Health Organization (WHO), estimate, 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 population in the world, and annual newly-increased the third hepatopath 3,000,000～4,000,000 people.According to U.S. disease prevention and control center (CDC) statistics, only the patients with chronic hepatitis C of the U.S. just approaches 3,000,000 people, annual newly-increased the third hepatopath 300,000 people in the whole America.In China, the enquiry data demonstration, the c-hepatitis antibody positive rate is 3.2%, and 4,000 ten thousand patients are approximately arranged.Although acute the 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 after the third liver 20 years, and liver cirrhosis occurs as 10-15%.The third liver number of the infected of China report in 2008 approximately 120,000 is 6 times in 2003.Current the third liver mortality ratio comes the tenth in all diseases in the whole world, and in China, the third liver mortality ratio comes the 5th.
At present, the standard treatments of the third liver is that Peg-Intron (PEG-IFN) share with ribavirin.The PEG-IFN sold on 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), current this standard treatments effect is not very desirable, and clinical cure rate is about 50%.And the administration time of current this therapy is long, the third hepatopath such as the HCVI type, need continuous use 48 weeks, serious untoward reaction also often occurs simultaneously, as the problem with 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, approximately 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 (has serine protease, helicase activity), NS4A, NS4B, NS5A, NS5B (thering is 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 protein maturation process, Core, E1, cutting between E2 and p7 relies on intracellular signal peptidase to complete, the cysteine protease activity of self that relies on NS2 and NS3 realizes the autocatalysis fracture, the NS3 of cutting between all the other albumen after by maturation completes.(Michael?P.Manns?et?al.，Nature?Reviews?Drug?Discovery，6，991-1001(2007))。
Virogene replicative enzyme NS5B is viral rna dependent rna polysaccharase, has to take the rna replicon activity that RNA is template, is responsible for that HCV is genomic to be copied.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 cell the do not infected RNA (RaffaeleDe Francesco, Antiviral Research, 58:1-16 (2003)) that expressed rna does not rely on usually, therefore, NS5B becomes the desirable target spot for the treatment of hepatitis C.
The seventies in last century, the investigator find some patients were because blood transfusion infection a kind of new pathogenic agent.Non-A appears in infected person, and the non-B hepatitis symptom, so will cause this para-infectious pathogenic agent called after C type (the third type) hepatitis virus (hepatitis C virus, HCV).1989, the genome of HCV is separated and confirmation for the first time.Nowadays, 6 kinds of HCV genotype (1-6 type) and more than 70 hypotypes have been found in global range.Also there is larger difference in the different genes C-type virus C in global distribution, and wherein 1,2,3 C-type virus Cs are distribution on global, and the 1a type be take as main in European and American areas, and comprises the Far East Area of China, 1b, and 2a, the 2b type is more common, and wherein the 1b type is the main advantage 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 former document, reported that thiophene carboxylic acid's compounds can be used as the HCV inhibitor (WO2002/100851, WO2005/063734, WO2007/071434) that acts on the NS5B polysaccharase.
Summary of the invention
The object of the invention is to provide a kind of compound of brand-new inhibition hepatitis c virus infection for carrying out the treatment of HCV infection, 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;
Be selected from-NR of A
jSO
2R
k,-OR
n,-NR
oSO
2NR
pR
qBe selected from-CO-of B ,-SO
2-;
R
1, R
6During non-hydrogen, can optionally be replaced 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
2During non-hydrogen, can be replaced by one or more following group institute is optional: 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
qIndependently selected from hydrogen or C1-C6 alkyl or C6-C14 aryl; R
mIndependently 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 optionally be replaced 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
2During non-hydrogen, can be replaced by one or more following group institute is optional: 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
lIndependently selected from hydrogen or C1-C6 alkyl or C6-C14 aryl; R
mIndependently 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 optionally be replaced 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
2During non-hydrogen, can be replaced by one or more following group institute is optional: halogen or-OR
m
A is 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
lIndependently selected from hydrogen or C1-C6 alkyl or C6-C14 aryl; R
mIndependently selected from hydrogen or C1-C6 alkyl.
Preferably, described compound is selected from 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-phenyl benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl 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-isopropyl-4-methyl cyclohexyl formamido-)-7-(naphthyl-1-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(xenyl-4-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(1 hydrogen-indoles-5-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(pyridine-3-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(cumarone-2-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(4-Trifluoromethoxyphen-l) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(furyl-2-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(3, the 5-bis trifluoromethyl phenyl) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(thionaphthene-2-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(4-chloro-phenyl-) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(4-tert-butyl-phenyl) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(4-fluorophenyl) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(thienyl-2-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(2-chloro-phenyl-) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl 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) reacts the compound of the formula of obtaining (V) after the alkali deprotonation with the iodo thing
(4) compound by (V) obtains the compound of formula (I) after the Suzuki linked reaction with the highly basic saponification
Above 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) compound by (V) obtains the compound of formula (I) after the Suzuki linked reaction with the highly basic saponification
Above 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 appropriate mineral alkali, as diethylamine, and triethylamine, diisopropylethylamine, pyridine, quinoline etc., or organic bases, as salt of wormwood, sodium carbonate, cesium carbonate, potassium hydroxide, in the situation that sodium hydroxide etc. exist; In described step (3), alkali is selected from organic bases, as salt of wormwood, and sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride KH, butyllithium, lithium diisopropylamine, LHMDS, 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.
Application aspect the medicine that another purpose of the present invention is to provide a kind of described compound or its pharmacy acceptable salt to copy at preparation inhibition hepatitis C virus.
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 in the present invention generally has following meaning:
Term " alkyl " refers to that straight or branched is saturated, aliphatic hydrocarbon group that contain 1-8 carbon atom (preferably 1-6 carbon atom); The C1-n alkyl means the saturated aliphatic radical of 1-n carbon atom, comprise straight chain and branched group (for example " C1-20 alkyl ", refer to that this group is alkyl, and the carbochain amount of carbon atom of alkyl is between 1～20, containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms etc., until comprise the alkyl of 20 carbon atoms.And the restriction of this 1-20 does not comprise the carbonatoms of the replacement on alkyl, as replace " alkyl " in alkylamino, when being not particularly limited its carbonatoms, the carbonatoms that only refers to the moieties that wherein indicates is 1-20, and does not comprise substituent carbonatoms on alkyl and other the substituent carbonatomss on amino.Adopt the statement of " C1-8 alkyl " to mean the alkyl that contains 1～8 carbon atom in this alkyl.) " 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, mean the alkyl that halogen atom replaces, and this replacement comprises monosubstituted and polysubstituted, and wherein the concept of alkyl as mentioned above.C1～8 haloalkyls, the carbonatoms that refers to the alkyl in haloalkyl is 1～8.Haloalkyl refers to the group that on alkyl, the H atom is replaced by halogen atom; As perfluoroalkyl refers to the group that the H on alkyl is all replaced by F.
The term of this paper " aryl " refers to aromatic systems, can be monocycle or condense or many aromatic rings that link together originally, thereby at least a portion is condensed or the ring that connects forms the virtue system of conjugation.Aromatic yl group includes, but are not limited to: phenyl, naphthyl, tetralyl.Aryl can be optionally substituted, as be selected from the aryl that group replaced or the heterocycle of lower group 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, refer to the 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, can be also 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 applicable pharmacy acceptable salt of formula (I) compound can be the acid salt of formula (I) compound, can include, but is not limited to the salt formed with following mineral acid: example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the salt formed with organic acid, organic acid refers to acetic acid, oxalic acid, succinic acid, tartrate, methylsulfonic acid and toxilic acid; Can be the salt of formula (I) compound with enough acidity, as an alkali metal salt or alkaline earth salt (calcium salt, magnesium salts or ammonium salt etc.).The applicable pharmacy acceptable salt of another kind of formula (I) compound can be the salt formed in human or animal body after 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 study discovery through the contriver, compound of the present invention can be, but not limited to following two kinds of modes and synthesizes, and the cyanophenyl derivative (II) that one of them can replace by the ortho position fluorine and Methyl Thioglycolate are processed and formed 3-amino-benzene thiophthene derivative (III) with sodium carbonate.3-amino-benzene thiophthene derivative (III) and acyl chlorides condensation are obtained to amide derivatives (IV), and then after processing with NaH, dropping iodo thing can obtain intermediate (V).Intermediate (V) next occurs can to obtain required target molecule (VII) with the highly basic saponification after the Suzuki coupling with boric acid thereupon, the compound that this target molecule is preferred formula (I) a kind of.Its synthetic route (1) is as follows:
After the cyanophenyl derivative (II) that another kind of preparation method can replace by the ortho position fluorine and Methyl Thioglycolate are processed formation 3-amino-benzene thiophthene derivative (III) with sodium carbonate, 3-amino-benzene thiophthene derivative (III) obtains sulfonamide derivatives (VI) with aldehyde, ketone or enol by reductive amination process (addition reaction).Then sulfonamide derivatives (VI) and acyl chlorides condensation are obtained to intermediate (V).Intermediate (V) next occurs can to obtain required target molecule (VII) with the highly basic saponification after the Suzuki coupling with boric acid thereupon, the compound that this target molecule is preferred formula (I) a kind of.Its synthetic route (2) is as follows:
Indication and medication
The present invention also comprises pharmaceutical composition and methods for the treatment of, 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 having an appointment 20-50% ethanol), or carry out the parenteral administration with sterile injectable solution or form of suspension (containing the 0.05-5% suspension agent of having an appointment waiting in oozing medium).For example, these pharmaceutical preparations can contain the approximately 25-90% mixed with carrier, usually are about the activeconstituents of 5%-60% (weight).
The effective dose of activeconstituents used can change with the severity of the pattern of compound used, administration and disease to be treated.Yet, usually, 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, preferably with the dosage separated for 2-4 time, give 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 and active compound solid-state or the intimately mixed about 0.5-500mg of liquid pharmaceutically acceptable carrier.Can regulate this dosage to provide optimal treatment to reply.For example, by an urgent demand for the treatment of 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 the administration such as subcutaneous.Solid-state carrier comprises: starch, lactose, Si Liaodengji dicalcium phosphate feed grade, 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 applicable to the characteristic of activeconstituents and required specific administration mode.In pharmaceutical compositions, normally used adjuvant also can advantageously be included, and for example seasonings, pigment, sanitas and antioxidant are as vitamin-E, vitamins C, BHT and BHA.
From being easy to the position of preparation and administration, preferred pharmaceutical composition is solid-state composition, especially the capsule of tablet and solid-filling or liquid filling.The oral administration of compound is preferred.
But these active compounds are parenteral or intraperitoneal administration also.Also can in the water that suitably is mixed with tensio-active agent (as hydroxypropylcellulose), prepare solution or the suspension of 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 conventional storage and working conditions, contain sanitas in these preparations to prevent microorganism growth.
The medicament forms that is adapted to injection comprises: aseptic aqueous solution or dispersion liquid and aseptic powder (for prepare 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.Must be stable under manufacture and condition of storage, 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 after deliberation, and thionaphthene carboxylic acid compound of the present invention can act on the NS5B polysaccharase, and suppresses efficiently HCV virus in vivo.While hepatitis C virus being exposed in the compound of effective concentration, hepatitis C virus can effectively be killed.So compound of the present invention can, for the preparation of the medicine that is used for the treatment of the HCV infection, certainly, can comprise pharmaceutically acceptable carrier in 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 in vitro efficiently, thereby may have in vivo anti-hepatitis C virus activity.With the NS5B AG14361 of similar structures, compare, 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 not limited to limit the scope of the invention for the present invention is described.The implementation condition adopted in embodiment can be done further adjustment according to the condition of concrete producer, and not marked implementation condition is generally the condition in normal experiment.
Embodiment:
Embodiment 1 Compound I a:3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-phenyl benzo [b] thiophene-2-carboxylic acid
First 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 nitrogen protection by the bromo-2-fluorobenzene of 3-cyanogen (5.0g; 25.1mmol) be dissolved in 20.0 milliliters of DMF; add sodium carbonate (5.3g; 50.0mmol) be cooled to 0 ℃, drip Methyl Thioglycolate (2.9g, 27.5mmol) under the condition stirred; reaction soln is risen to room temperature, and stirring is spent the night.After adding water, separate out white solid, filter, water, petroleum ether solid, obtain white powder (6.4g), yield 89.5% after 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
The bromo-3-of 7-(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, reflux 2 hours, and cool to room temperature.Concentration of reaction solution, keep somewhere stand-by.
Step b: under the nitrogen protection effect; by intermediate III a (5.0g; 17.5mmol) be dissolved in anhydrous methylene dichloride (60ml); add triethylamine (7.3ml; 52.6mmol) be cooled to 0 ℃; dropping be dissolved in 10 milliliters of methylene dichloride trans-4-methyl cyclohexane formyl chloride (3.6g, 22.7mmol), stirring is spent the night.Concentration of reaction solution, add water and ethyl acetate, extracts three times.Organic phase washes with water, saturated common salt washing, Na
2SO
4Drying, filtering and concentrating obtains 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
The bromo-3-of 7-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-) benzo [b] thiophene-2-carboxylic acid isopropyl ester
Under nitrogen protection, intermediate compound IV a (2.0g, 4.9mmol) is dissolved in anhydrous 60 milliliters of DMF, add sodium hydride (1.4g, 35.0mmol), cooling.After adding Iso-Propyl iodide (8.3g, 49mmol), stirring is spent the night.Add the shrend reaction of going out, be extracted with ethyl acetate, organic phase makes water, saturated common salt washing, Na
2SO
4Drying, used ethyl acetate and sherwood oil (1/15-1/8) column chromatography after 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 intermediate Va (100mg, 0.21mmol) in tube sealing, phenylo boric acid (38mg, 0.31mmol), Pd (PPh
3)
4(12mg, 0.01mmol), sodium carbonate (45mg, 0.42mmol), ethylene glycol monomethyl ether (0.8ml), water (0.4ml), react 6 hours at 100 ℃ after adding.Cool to room temperature, add sodium hydroxide (15mg), and dioxane stirs and spends the night.Add 1N hydrochloric acid in reaction solution, regulate pH to 3-4, make to be extracted with ethyl acetate, with saturated common salt washing, Na
2SO
4Drying, obtain solid after concentrating, and with sherwood oil and ethyl acetate washing solid, obtains powdered compounds.
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-isopropyl-4-methyl cyclohexyl 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 nitrogen protection by the bromo-2-fluorobenzene of 4-cyanogen (5.0g; 25.1mmol) be dissolved in 20.0ml DMF; add sodium carbonate (5.3g; 50.0mmol) be cooled to 0 ℃, drip Methyl Thioglycolate (2.9g, 27.5mmol) under the condition stirred; reaction soln is risen to room temperature, and stirring is spent the night.After adding water, separate out white solid, filter, water, petroleum ether solid, obtain white powder (6.0g), yield 83.9% after 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
+)。
The following steps, according to preparing the method for Compound I a in 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 in 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, then by intermediate VIa synthesising target compound.
According to synthetic route (2), under nitrogen protection, the intermediate III b (290mg, 1mmol) produced in embodiment 2 is dissolved in to 5 milliliter 1; in the 2-ethylene dichloride, add phenyl aldehyde (424mg, 4mmol); acetic acid (240mg, 4mmol), stirring at room.Add three acetic acid sodium borohydrides (1.3g, 6mmol), reaction is spent the night.Concentration of reaction solution, add water, the ethyl acetate extraction, and organic layer is successively with saturated sodium bicarbonate, water, saturated common salt washing.With ethyl acetate and sherwood oil (1/20-1/15) column chromatography, obtain target product intermediate (273mg), yield 73% after concentrated ethyl acetate.
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; by intermediate VIa (225mg; 0.6mmol) be dissolved in methylene dichloride; add diisopropylethylamine (232mg, 1.8mmol), add the acyl chlorides (192mg of preparation; 1.2mmol); triphenylphosphine (188mg, 0.72mmol), room temperature reaction spends the night.Concentration of reaction solution, add water and ethyl acetate extraction, 1N hydrochloric acid, saturated common salt washing for organic layer, concentrated organic layer.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 above-mentioned intermediate Vd (110mg, 0.2mmol) in tube sealing, phenylo boric acid (37mg, 0.3mmol), Pd (PPh
3)
4(12mg, 0.01mmol), sodium carbonate (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 reaction solution, regulate pH to 3-4, be extracted with ethyl acetate, the saturated common salt washing, the Na2SO4 drying, obtain solid after concentrating, and with sherwood oil and re-crystallizing in ethyl acetate solid, obtains powdered compounds.
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
Method according to Compound I a in Preparation Example 1 can prepare Compound I e.
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
Method according to Compound I a in Preparation Example 1 can prepare Compound I f.
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-isopropyl-4-methyl cyclohexyl formamido-)-7-(naphthyl-1-position) benzo [b] thiophene-2-carboxylic acid
Method according to Compound I a in Preparation Example 1 can prepare Compound I g.
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-isopropyl-4-methyl cyclohexyl formamido-)-7-(xenyl-4-position) benzo [b] thiophene-2-carboxylic acid
Method according to Compound I a in Preparation Example 1 can prepare Compound I h.
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-isopropyl-4-methyl cyclohexyl formamido-)-7-(1 hydrogen-indoles-5-position) benzo [b] thiophene-2-carboxylic acid
Method according to Compound I a in Preparation Example 1 can prepare Compound I i.
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-isopropyl-4-methyl cyclohexyl formamido-)-7-(pyridine-3-position) benzo [b] thiophene-2-carboxylic acid
Method according to Compound I a in Preparation Example 1 can prepare Compound I j.
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-isopropyl-4-methyl cyclohexyl formamido-)-7-(cumarone-2-position) benzo [b] thiophene-2-carboxylic acid
Method according to Compound I a in Preparation Example 1 can prepare Compound I k.
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-isopropyl-4-methyl cyclohexyl formamido-)-7-(4-Trifluoromethoxyphen-l) benzo [b] thiophene-2-carboxylic acid
Method according to Compound I a in Preparation Example 1 can prepare Compound I l.
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-isopropyl-4-methyl cyclohexyl formamido-)-7-(furyl-2-position) benzo [b] thiophene-2-carboxylic acid
Method according to Compound I a in Preparation Example 1 can prepare Compound I m.
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-isopropyl-4-methyl cyclohexyl formamido-)-7-(3,5-bis trifluoromethyl phenyl) benzo [b] thiophene-2-carboxylic acid
Method according to Compound I a in Preparation Example 1 can prepare Compound I n.
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-isopropyl-4-methyl cyclohexyl formamido-)-7-(thionaphthene-2-position) benzo [b] thiophene-2-carboxylic acid
Method according to Compound I a in Preparation Example 1 can prepare Compound I o.
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-isopropyl-4-methyl cyclohexyl formamido-)-7-(4-chloro-phenyl-) benzo [b] thiophene-2-carboxylic acid
Method according to Compound I a in Preparation Example 1 can prepare Compound I p.
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-isopropyl-4-methyl cyclohexyl formamido-)-7-(4-tert-butyl-phenyl) benzo [b] thiophene-2-carboxylic acid
Method according to Compound I a in Preparation Example 1 can prepare Compound I q.
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-isopropyl-4-methyl cyclohexyl formamido-)-7-(4-fluorophenyl) benzo [b] thiophene-2-carboxylic acid
Method according to Compound I a in Preparation Example 1 can prepare Compound I r.
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-isopropyl-4-methyl cyclohexyl formamido-)-7-(thienyl-2-position) benzo [b] thiophene-2-carboxylic acid
Method according to Compound I a in Preparation Example 1 can prepare Compound I s.
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-isopropyl-4-methyl cyclohexyl formamido-)-7-(2-chloro-phenyl-) benzo [b] thiophene-2-carboxylic acid
Method according to Compound I a in Preparation Example 1 can prepare Compound I t.
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-isopropyl-4-methyl cyclohexyl formamido-)-7-bromobenzene is [b] thiophene-2-carboxylic acid also
Method according to Compound I a in Preparation Example 1 can prepare Compound I u.
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; Control compound is selected following compound
This compound prepares by the method for WO2002100851.
The ability that inhibition HCV copies proves by following experiment in vitro.
The A.NS5B polysaccharase suppresses experiment
The inhibition experiment of the NS5B polysaccharase of standard is as follows: the reaction solution of 20uL, containing the Tris-HCl of 20mM, 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.The EDTA that this reaction solution reacts after 2 hours the 0.45M by adding 2uL under 25 ℃ stops, and clean plate for several times.After washing, in conjunction with radioactivity by scintillometer, count.
The test-results of the formula I compound (IC that suppresses the NS5B polysaccharase
50Value) list in table 1, wherein A means its IC
50Value is less than 1uM, and B means its IC
50Value is between 1uM to 10uM, and C means its IC
50Value is between 10uM to 50uM, and D means 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 is only explanation technical conceive of the present invention and characteristics, and its purpose is to allow the person skilled in the art can understand content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalent transformations that spirit is done according to the present invention or modification, within all should being encompassed in protection scope of the present invention.
Claims (10)
1. compound or its pharmacy acceptable salt with general formula (I) structure,
Wherein, R
lBe selected from the C1-C12 alkyl, C6-C14 aryl, or C3-C7 cycloalkyl;
R
2Be selected from hydrogen, C1-C12 alkyl, C6-C18 arylalkyl;
R
3Be selected from hydrogen, the C1-C6 alkyl;
R
4Be selected from hydrogen, the C1-C6 alkyl;
R
5Be selected from hydrogen, the C1-C6 alkyl;
R
6Be selected from phenyl, naphthyl, Trifluoromethoxyphen-l;
Be selected from-OR of A
nBe selected from-CO-of B ,-S0
2-;
R
nBe selected from hydrogen or C1-C6 alkyl or C6-C14 aryl;
Perhaps described compound is selected from 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(xenyl-4-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(pyridine-3-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(cumarone-2-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(furyl-2-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(thionaphthene-2-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(thienyl-2-position) benzo [b] thiophene-2-carboxylic acid.
2. compound according to claim 1, is characterized in that R in described compound
1Be selected from the C6-C14 aryl, the C3-C7 cycloalkyl;
R
2Be selected from the C1-C12 alkyl, the C6-C18 arylalkyl;
R
6Be selected from phenyl, naphthyl, Trifluoromethoxyphen-l.
3. compound according to claim 1, is characterized in that in described compound, A is hydroxyl.
4. compound according to claim 1, it is characterized in that described compound is selected from 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-phenyl benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl 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-isopropyl-4-methyl cyclohexyl formamido-)-7-(naphthyl-1-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(xenyl-4-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(pyridine-3-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(cumarone-2-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(4-Trifluoromethoxyphen-l) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(furyl-2-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(3, the 5-bis trifluoromethyl phenyl) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(thionaphthene-2-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(4-tert-butyl-phenyl) benzo [b1 thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(4-fluorophenyl) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(thienyl-2-position) benzo [b] thiophene-2-carboxylic acid, 3-(nitrogen-isopropyl-4-methyl cyclohexyl formamido-)-7-(2-chloro-phenyl-) benzo [b] thiophene-2-carboxylic acid.
5. a 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) reacts the compound of the formula of obtaining (V) after the alkali deprotonation with the iodo thing
(4) compound by (V) obtains the compound of formula (I) after the Suzuki linked reaction with the highly basic saponification
Above various in, R
1, R
2, R
3, R
4, R
s, R
6, A, B define with claim 1.
6. a 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) compound by (V) obtains the compound of formula (I) after the Suzuki linked reaction with the highly basic saponification
Above various in, R
1, R
2, R
3, R
4, R
s, R
6, A, B define with claim 1.
7. according to the described method of claim 5 or 6, it is characterized in that described step (1) neutral and alkali environment is selected from the situation that have appropriate diethylamine, triethylamine, diisopropylethylamine, pyridine, quinoline, salt of wormwood, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide existence; In described step (3), alkali is selected from salt of wormwood, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride KH, butyllithium, lithium diisopropylamine, LHMDS, sodium hexamethyldisilazide, potassium hexamethyldisilazide.
8. a medicinal compositions, is characterized in that, described composition contains pharmaceutically acceptable carrier and pharmaceutically compound claimed in claim 1 or its pharmacy acceptable salt of significant quantity.
9. the application aspect the medicine that a compound claimed in claim 1 or its pharmacy acceptable salt copy at preparation inhibition hepatitis C virus.
10. a compound claimed in claim 1 or its pharmacy acceptable salt application aspect the medicine of preparation control hepatitis c virus infection.
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| CN105254611B (en) * | 2015-11-09 | 2017-10-31 | 江西仁明医药化工有限公司 | The preparation method of the carboxylic acid of benzothiophene 2 |
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