CN101328169A - Diethylcarbamyl-substituted thiazole dihydropyrimidine - Google Patents

Diethylcarbamyl-substituted thiazole dihydropyrimidine Download PDF

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CN101328169A
CN101328169A CNA2008101257239A CN200810125723A CN101328169A CN 101328169 A CN101328169 A CN 101328169A CN A2008101257239 A CNA2008101257239 A CN A2008101257239A CN 200810125723 A CN200810125723 A CN 200810125723A CN 101328169 A CN101328169 A CN 101328169A
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CN101328169B (en
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S·戈尔德曼
李静
刘遗松
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Guangdong HEC Pharmaceutical
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ZHANG ZHONGNENG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

The invention relates to a novel ethoxycarbonyl-substituted thiazolyldihydropyrimidine applicable to acting against hepatitis B virus (HBV) infection and a composition of the same and other antiviral agents.

Description

A kind of ethoxy carbonic acyl radical-substituted thiazole dihydropyrimidine
Technical field
The present invention relates to a kind of new ethoxy carbonic acyl radical-substituted thiazole dihydropyrimidine, its preparation method and as medicine is especially as the treatment and the purposes of preventing hepatitis b virus infected medicine.The invention still further relates to these dihydro-pyrimidins with other antiviral agents and, suitably under the situation, the composition of immunomodulator, and contain these compositions and especially treat and prevent HBV to infect medicine such as the composition of hepatitis B.
Background technology
Hepatitis B virus belongs to hepatovirus section.It can cause acute and or continue/progressive chronic disease.Hepatitis B virus also causes many other clinical symptom---especially chronic inflammatory diseases, liver cirrhosis and the hepatocellular cancerations of liver in the pathomorphism.In addition, the co-infected with hepatitis D can have a negative impact in the advancing of disease process.
Interferon, rabbit and lamivudine (lamivudine) are the conventional medicines that approval is used for the treatment of chronic hepatitis treatment.Yet Interferon, rabbit only has medium activity, and has deleterious side reaction; Though lamivudine (lamivudine) has good activity, its resistance development in treatment is rapid, and after stopping treatment the effect that usually has a rebound, lamivudine (lamivudine) (3-TC)＞IC 50The value for 300nM (Science, 299 (2003), 893-896).
US 7074784 discloses 6-amido alkyl dihydro-pyrimidin and as the application of medicine, in particular for treatment with prevent hepatitis b virus infected.
This patent has been announced 54 different embodiment, they almost all (50) have the compound that fluorine replaces 2-pyridine residue in the position of R6.R3 is methyl among all embodiment of this patent (54).
It is weak activity or or even inert that this patent is pointed out to have than the long alkyl even compound of (as ethyl).
9 compounds with following structure (embodiment 1,5,7,9,12,24,31,34,45) in this patent wherein eight tools 8 have 6 fluorine to replace 2-pyridine residue.The R that has only an embodiment (embodiment 45) 6=thiazol-2-yl.
Figure A20081012572300081
Summary of the invention
We have shockingly found to have thiazol-2-yl substituting group ((R 6=thiazol-2-yl) ethyl ester (R 3Embodiment 45 (the R of this patent=ethyl) 1=neighbour-chlorine and R 2=right-chlorine), 3 times of highly active derivatives, i.e. IC have been produced 50Be lower than 1nM.(seeing Table 1)
Figure A20081012572300082
Table 1
Embodiment R 1 R 2 R 3 IC 50(nM)
1 Cl Cl CH 3 2
2 Cl Cl CH 3CH 2 0.6
Therefore, the present invention relates to compound shown in the general formula (I) and isomers (Ia) thereof
Figure A20081012572300091
Wherein
R 1Be neighbour-chlorine, R 2Be right-chlorine, R 3Be C 2-C 3Alkyl, R 6Be thiazol-2-yl, X is that methylene radical and Z are morpholinyls.
Preferably, at general formula of the present invention (I) with in the compound (Ia):
R 1Be neighbour-chlorine, R 2Be right-chlorine, R 3Be ethyl, R 6Be thiazol-2-yl, X is a methylene radical, and Z is a morpholinyl.
The invention still further relates to the enantiomer of above-claimed cpd and mixture separately thereof.The racemize physical efficiency is separated by known means, says that in essence it is a homogeneous composition in the steric isomer.
Compound of the present invention comprises general formula (I) and isomer (Ia) and composition thereof.Compound of the present invention also can be the form of salt.In the present invention, physiologically acceptable salt is preferred.
Physiologically acceptable salt can be inorganic acid salt or organic acid salt.The salt of mineral acid preferably, such as, for example hydrochloric acid, Hydrogen bromide, phosphoric acid or sulfuric acid etc., perhaps organic carboxyl acid or sulfonic acid, for example salt that forms such as acetic acid, toxilic acid, FUMARIC ACID TECH GRADE, oxysuccinic acid, citric acid, tartrate, lactic acid, phenylformic acid or methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, toluenesulphonic acids or naphthalene-two thiosulfonic acid.
Physiologically acceptable salt can also be the metal-salt or the ammonium salt of The compounds of this invention.Especially preferred example is sodium, potassium, magnesium or calcium salt, and by ammonia or organic amine, such as ethamine, and two-or triethylamine, two-or trolamine, dicyclohexylamine, dimethylaminoethanol, arginine, Methionin, quadrol, or the ammonium salt that generates such as 2-phenylethylamine.
Compound of the present invention (I) can be prepared by following method:
[A] at first adding or do not adding alkali or acid with phenyl aldehyde (II) and the 'beta '-ketoester shown in the general formula (III), reacts in the time of suitably to change into the Ben Yajiaji compound shown in the general formula (IV) in the presence of inert organic solvents:
Figure A20081012572300101
R wherein 1, R 2, R 3, X and Z implication as previously mentioned.
Then, with the amidine shown in the latter and the logical formula V or its salt (such as, for example hydrochloride or acetate), adding or do not add alkali or acid, existing under the situation of inert organic solvents, react in the time of suitably
Figure A20081012572300102
R wherein 6Implication as previously mentioned, or
[B] with the same aldehyde of compound (II) shown in the general formula (III) and amidine (V) or their salt (such as, hydrochloride or acetate) adding or do not add alkali or acid, existing under the situation of inert organic solvents, carry out single step reaction in the time of suitably; Or
[C] X in general formula (I) is a methylene radical, with compound shown in the general formula (VI)
Figure A20081012572300111
R wherein 1, R 2, R 3And R 6Implication as previously mentioned, Y is the nucleophilic substitution group, such as muriate, bromide, iodide, methylsulfonyl or tosyl group are with morpholine (VII)
Figure A20081012572300112
Adding or do not adding alkali, existing in the time of suitably under the condition of inert solvent and react.The preparation of compound (VI) can be passed through, for example, and with compound shown in the general formula (VIII)
Figure A20081012572300113
R wherein 1, R 2, R 3And R 6Implication as previously mentioned and bromizating agent such as, N-bromine succinimide preferably reacts in inertia solution, obtains compound shown in the general formula (IX)
Figure A20081012572300114
The latter that will have a nucleophilic substitution group reacts with morpholine (VII) after further changing directly or according to the ordinary method described in the document.
Compound shown in aldehyde shown in [D] general formula (II) and the general formula (X) reacts in inert solvent when suitable,
Figure A20081012572300121
R wherein 3, X and Z implication are led to the amidine shown in the formula V and are had or do not have the base affixture as previously mentioned.
For preparing compound shown in the general formula of the present invention (I), wherein X is a methylene radical, and Z is a morpholinyl, chloracetate shown in the general formula (XI) and morpholine (VII) reaction can be prepared corresponding β-esters of keto-carboxylic acid (III)
Figure A20081012572300122
R wherein 3Implication as previously mentioned.
2-chloro-4-fluoro-phenyl aldehyde (II) as starting raw material can obtain by commercial sources.
β-esters of keto-carboxylic acid (III) as starting raw material is known, or can from the currently known methods that document is announced, analogize make [as, D.Borrmann, " Umsetzung vonDiketen mit Alkoholen; Phenolen und Mercaptanen ", in " Methoden derorganischen Chemie " (Houben-Weyl), vol.VII/4,230 ff (1968); Y.Oikawa, K.Sugano und O.Yonemitsu, J.Org.Chem.43,2087 (1978)].
Compound (V) is known, and can prepare according to the description of WO-A-99/54326 and WO-A-99/54329.
Morpholine (VII) can obtain by commercial sources.
Compound (VIII) and (X) can make according to the step of describing among the WO-A-99/54326 [A] or [B].
All inert organic solvents all are applicable to A, B, C and D step.Wherein preferably comprise alcohol as, methyl alcohol, ethanol, Virahol, ether such as dioxan, diethyl ether, tetrahydrofuran (THF), ethylene glycol monomethyl ether, glycol dimethyl ether, carboxylic acid such as Glacial acetic acid or dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile, pyridine and HMPA.
Temperature of reaction can change in quite wide scope.Usually the temperature between using 20 to 150 ℃, but preferably in the boiling temperature of selected solvent.
Reaction can under atmospheric pressure be carried out, and also can under high pressure carry out.Usually under atmospheric pressure carry out.
Reaction can be carried out under the environment that adds or do not add acid or alkali; But reacting in the presence of weak acid such as acetic acid or formic acid etc. is preferably.
A kind of embodiment of the present invention relates to and contains A) at least a above-mentioned dihydro-pyrimidin, B) at least a and A) composition of different other antiviral agents.
A detailed embodiment of the present invention relates to and contains A) above-mentioned dihydro-pyrimidin, B) the HBV AG14361 and and suitable situation under, the C) composition of immunomodulator.
Preferred immunomodulator C) comprise, for example, all Interferon, rabbit such as α-, β-and gamma-interferon, especially α-2a-and α-2b-Interferon, rabbit, interleukin-is such as interleukin II, polypeptide such as thymosin-α-1 and Thymoctonan (thymoctonan), the imidazole quinoline derivative such as
Figure A20081012572300131
Immunoglobulin (Ig) and treatment vaccine..
Therefore, the invention still further relates to these compositions and the purposes on the disease that treatment HBV causes thereof that is used for the treatment of and prevents the HBV infection.
Single therapy with respect to the simplification compound, the use of the present composition is useful to the disease that treatment HBV causes, it mainly is the antiviral activity of working in coordination with, and with respect to the Tox-50 of single composition (toxicity range that 50% cell survival is arranged), composition of the present invention has good tolerability.
The HBV AG14361 B that is used to realize the object of the invention at Ph.A.Furman etc. at " anti-microbial agents and embolic chemotherapy " (Antimicrobial Agents andChemotherapy) Vol.36 (No.12), those materials that disclose in the interior living polysaccharase experiment in 2688 (1992), and those are described hereinafter, suppressing the formation of HBVDNA two strands, is those zero materials thereby cause maximum 50% activity value.
From the HBV virion of culture suspension external with nucleosides 5 '-triphosphate is incorporated in the DNA normal chain of HBV.By using the gelose gel electrophoresis, find wherein to exist [α- 32P]-deoxynucleoside 5 '-triphosphate is incorporated into the product among the viral 3.2kb DNA, do not have the material with potential HBV polysaccharase-inhibition activity.From the cell cultures suspended substance of HepG2.2.15 cell, with polyethylene glycol precipitation, the concentrated HBV virion that obtains.The aqueous solution that contains 50% (weight) polyoxyethylene glycol 8000 and 0.6M sodium-chlor of the clarification cell cultures suspended substance of 1 parts by volume and 1/4 parts by volume.2500 * g centrifugation 15 minutes, throw out is dialysed with this damping fluid that contains 100mM Repone K with the damping fluid resuspending that 2ml contains 0.05M tris-HCl M (pH 7.5).Sample is freezing in the time of-80 ℃.Each reaction mixture (100 μ l) contains at least 10 5HBV virion, 50mM tris-HCl (p.sub.H 7.5), 300mM Repone K, 50mM magnesium chloride,
Figure A20081012572300141
Nonident P-40 (non-ionic detergent, Boehringer Mannheim), 10 μ M dATP, 10 μ M dGTP, 10 μ MdTTP; 10 μ Ci[ 32P] dCTP (3000Ci/mmol; Ultimate density is 33nM) and the polysaccharase potential inhibitor of 1 μ M triphosphoric acid form.Sample was cultivated one hour down at 37 ℃, added 50mM EDTA stopped reaction then.Adding 10% weight/volume SDS solution (every 90ml water contains 10g SDS) is 1% (volume) (based on overall solution volume) to final concentration, and adding Proteinase K to ultimate density is 1mg/ml.37 ℃ of incubations 1 hour, extract with isopyknic phenol/chloroform/primary isoamyl alcohol (volume ratio is 25: 24: 1) solution then, DNA is precipitated out from containing the alcoholic acid aqueous phase.The DNA bead is suspended in the 10 μ l gel buffer liquid (containing 10.8g tris, 5.5g boric acid and 0.75g EDTA (=TBE buffer) in 1 premium on currency), and separates with agarose gel electrophoresis.Wherein gel drying or employing Southern transformation technology are changed film forming with nucleic acid wherein.Relatively detect the amount of the marker DNA two strands of generation then with negative control (=carry out endo-pol reaction) with blank or inertia contrast.If have maximum 50% concentration of control group then show and have the HBV AG14361.
Preferred HBV AG14361 B) comprises, for example, 3TC=lamivudine (lamivudine)=4-amino-1-[(2R-cis)-and 2-(methylol)-1.3-oxygen sulphur is luxuriant-the 5-base-]-pyrimidine-2 (1H)-ketone, cf.EP-B 382526 (=U.S.Pat.No.5,047,407) and WO91/11186 (=U.S.Pat.No.5,204,466);
Two (pivaloyl hydroxyl methoxyl group) the phosphono methoxyl groups of adefovir ester (Adefovir dipivoxil)=9-[2-[] ethyl] VITAMIN B4, cf.EP-B 481214 (=U.S.Pat.Nos.5,663,159 and 5,792,756), U.S.Pat.Nos.4,724,233 and 4,808,716;
BMS 200475=[1S-(1..alpha., 3..alpha., 4..beta.)]-2-amino-1.9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical-cyclopentyl]-the 6H-purine-6-one, cf.EP-B 481754 (=U.S.Pat.Nos.5,206,244 and 5,340,816), WO 98/09964 and 99/41275;
Abacavir (Abacavir)=(-)-(1S-cis)-4-[2-amino-6-(cyclopropylamine)-9H-purine-9-yl]-2-base-cyclopentenes-1-methyl alcohol, cf.EP-B 349 242 (=U.S.Pat.No.5,049,671) and EP-B 434 450 (=U.S.Pat.No.5,034,394);
FTC=(2R-cis)-4-amino-5-fluoro-1-[2-(methylol)-1.3-oxygen sulphur is luxuriant-the 5-yl]-p-pyrimidine-2 (1H)-ketone, cf.WO 92/14743 (=U.S.Pat.Nos.5,204,466; 5,210,085; 5,539,116; 5,700,937; 5,728,575; 5,814,639; 5,827,727; 5,852,027; 5,892,025; 5,914,331; 5,914,400) and WO 92/18517;
β-L-FDDC=5-(6-amino-2-fluoro-9H-purine-9-yl)-tetrahydrochysene-2-furfuralcohol, cf.WO 94/27616 (=U.S.Pat.Nos.5,627,160; 5,561,120; 5,631,239 and 5,830,881); L-FMAU=1-(2-deoxidation-2-fluoro-.beta.-L-arbinofuranose)-5-methyl-pyrimidine e--2.4 (1H, 3H)-diketone, cf.WO 99/05157, WO 99/05158 and U.S.Pat.No.5,753,789.
A preferred embodiment of the present invention relates to and contains A) above-mentioned dihydro-pyrimidin (I) and (Ia) and B) composition of lamivudine (lamivudine).
Another preferred HBV antiviral agent B contains, for example, and the Phenyl Acrylamide shown in the following general formula
Figure A20081012572300161
Wherein
R 1And R 2, be C respectively independently 1-C 4-alkyl or, the nitrogen-atoms on its position forms and to have the ring that 5-6 annular atoms comprises carbon and/or Sauerstoffatom.R 3To R 12, be hydrogen independently respectively, halogen, C 1-C 4-alkyl replaces C arbitrarily 1-C 4-alkoxyl group, nitro, cyano group or trifluoromethyl.R 13Be hydrogen, C 1-C 4-alkyl, C 1-C 7-acyl group or aralkyl, and X is halogen or replaces C arbitrarily 1-C 4-alkyl.
These Phenyl Acrylamide and preparation method thereof are open in WO 98/33501, mention it being for disclosed purpose here.AT-61 is a compound
Figure A20081012572300162
Preferred immunomodulator C) for example comprise, all interference as, α-, β-and gamma-interferon, especially can also be that α-2a-and α-2b-disturbs interleukin-such as interleukin II, polypeptide such as thymosin-α-1 and Thymoctonan (thymoctonan), the imidazole quinoline derivative as
Figure A20081012572300163
Immunoglobulin (Ig) and treatment vaccine.
Of the present invention another preferred embodiment relates to and contains A) above-mentioned dihydro-pyrimidin (I) and (Ia); B) lamivudine (lamivudine); And C under the suitable situation) composition of Interferon, rabbit.
Experiment is described
Based on M.A.Sells Proc.Natl.Acad.Sci.84,10051009 (1987) and B.E.Korba etc., the method for descriptions such as Antiviral Research 19,5570 (1992) is studied the antivirus action of compound of the present invention to hepatitis B virus.
Antiviral test is carried out on the microtiter plate of 96-hole.First array is only accepted substratum and HepG2.2.15 cell, as virus control.
The mother liquor (50mM) of test compounds is dissolved in earlier among the DMSO, then with the dilution of HepG2.2.15 substratum.Usually pipette second tests column of the The compounds of this invention of 100 μ M test concentrations (1st test concentrations) with transfer pipet at every turn, in the substratum that adds 2% weight foetal calf serum (volume 25 μ l), dilute 2 in two steps then to microtiter plate 10Doubly.
Each of microtiter plate added in the hole of substratum of 2% weight foetal calf serum and all contained 225 μ l HepG2.2.15 cell suspending liquids (5 * 10 4Cells/ml).37 ℃, 5%CO 2(v/v) cultivated the test mixing thing 4 days.
Then the sucking-off of surfactant suspension thing is abandoned, Xiang Kongzhong adds the freshly prepd substratum of 225 μ l.Again the solution of The compounds of this invention that adds 1/10 concentration of 25 μ l volumes.Mixture continues to cultivate 4 days.
Before collecting suspended substance test antiviral effect, earlier under opticmicroscope or detect the variation of HepG2.2.15 cell toxin by biological chemistry detection method (for example Alamar Blue stain or Trypan Blue stain).
Collect surfactant suspension thing and/or cell and on spot chamber, 96-hole, cover one deck nylon membrane (according to the information of manufacturers) with the method that vacuumizes
Cytotoxic mensuration
Detect the variation of the cytotoxin or the inhibition cell of material initiation in the HepG2.2.15 cell, for example, the change of cellular form under opticmicroscope.It is significantly that the variation that these materials of HepG2.2.15 cell cause is compared mutually with untreated cell, for example, and cytolysis, the change of vacuole or cellular form.50% toxicity (Tox.-50) is meant that comparing 50% cell with corresponding control cells shows a kind of morphology.
By other host cell such as, HeLa cell for example, the tolerance of test compounds more of the present invention on primary human procedure for peripheral blood cell or transformation cell lines such as the H-9 cell.
When compound concentration of the present invention＞10 μ M, do not detect cytotoxic change.The mensuration of antivirus action
With after surfactant suspension thing or dissolved cell transfer are to the nylon membrane of point apparatus (as above-mentioned), with in the born of the same parents of HepG2.2.15 cell or the outer suspended substance sex change (1.5M NaCl/0.5N NaOH) of born of the same parents, neutralization (3M NaCl/0.5M Tris HCl, pH 7.5), flushing (2 * SSC) then.By 120 ℃ of following incubation strainers 2-4 hour, DNA is dried to film.
DNA hybridization
Usually pass through on-radiation, the hepatitis B of digoxin-mark-specificity DNA probing needle detects the viral DNA from the HepG2.2.15 cell of having handled on the nylon filter, the dna probe digoxigenin labeled, and carry out purifying and hybridization according to the specification sheets of manufacturers.
Prehybridization and hybridization at 5 * SSC, 1 * closed reagent, 0.1% (weight) N-Sarkosyl L carries out in 0.02% (weight) SDS and the 100 μ g herring sperm dnas.Prehybridization carried out 30 minutes at 60 ℃, carried out specific cross with 20 to 40ng/ml HBV-specific DNAs digoxigenin labeled, sex change (14 hours, 60 ℃) then.Washing filter.
With digoxin antibody test HBV-DNA
Carry out the immunodetection of digoxin-marker DNA according to the explanation of making manufacturers:
Washing filter is hybridized (according to the explanation of manufacturers) in closed reagent.Utilize then with the alkaline phosphatase coupled anti--DIG antibody hybridization 30 minutes.After washing step, the substrate that adds alkaline phosphatase, CSPD, with strainer incubation 5 minutes, wrap plastic film then, 37 ℃ were descended other 15 minutes. the strainer exposure under the X ray layer, can be seen the luminous signal (incubation depends on strength of signal: 10 minutes to 2 hours) of hepatitis B DNA.
Maximum half inhibition concentration (IC 50, 50% inhibition concentration) reduce in 50% born of the same parents or the outer hepatitis B virus group's of born of the same parents concentration for compare The compounds of this invention with the sample that is untreated.
Compound of the present invention shows IC 50Be lower than the effective antivirus action of 1nM, this does not reckon with.Therefore, compound of the present invention is applicable to the treatment of the especially acute and chronic lasting HBV virus infection of disease that virus causes.The chronic disease viral disease that HBV causes may cause morbid state to become seriously, and chronic HBV infection can cause liver cirrhosis and/or canceration of hepatic cell in many cases.
Concerning compound of the present invention, the indicating area that may be mentioned is, for example: may cause the treatment of the acute and chronic viral infection of infectious hepatitis, and for example, hepatitis B virus infection.Compound of the present invention especially is fit to the treatment chronic viral hepatitis B to be infected and acute and chronic hbv-infection.
The present invention includes pharmaceutical preparation,, on the inert pharmacopedics outside the suitable carriers, also contain one or more compounds of the present invention (I) or (Ia) or composition or contain one or more activeconstituentss (I) or (Ia) or composition of the present invention except nontoxic.
Be used for the activeconstituents (I) of said medicine preparation and (Ia), its concentration is about 0.1 to 99.5% (weight) with respect to whole mixture, preferably is about 0.5 to 95% (weight).
The said medicine preparation also can inclusion compound (I) and (Ia) in addition other active pharmaceutical ingredients.
The content ratio of component A, B and appropriate C can change in the limited field of broad in the composition of the present invention, the B of the A/20-400mg of B, the especially 10-200mg of the A/10-1000mg of preferred 5-500mg.
Component C also can use in the time of suitable, and its consumption is preferred 1 to 1,000 ten thousand, and more preferably 2 to 700 ten thousand, I.U. (international unit) is surpassing in the period in 1 year 3 times weekly.
The compound of the present invention or the composition that are used for the said medicine preparation, its concentration is generally about 0.1% to 99.5% with respect to whole mixture, and is preferred about 0.5% to 95%, (weight percent).
The said medicine preparation can prepare by known ordinary method, for example activeconstituents and carrier is mixed.
No matter be to be about 0.05 to about 500 at human body or veterinarily taking total dose in per 24 hours, the activeconstituents of preferred 0.1 to 100mg/kg body weight is generally proved useful, and repeatedly taking of suitable single dose can reach the ideal effect.The activeconstituents that single dose contains preferably in total amount about 0.1 to about 80, preferred 0.1 to 30mg/kg body weight.In any case, especially according to experimenter's to be treated kind and body weight, the characteristic of illness and severity, the type of preparation, the mode of drug administration and the time of drug administration or to change above-mentioned dosage at interval be necessary.
Therefore, the invention still further relates to above-claimed cpd and the composition that is used for control disease.
The invention still further relates to and contain at least under a kind of above-claimed cpd or composition and the suitable situation, contain the medicine of one or more other active pharmaceutical ingredients.
The invention still further relates to, be used for above-claimed cpd and composition and be used to prepare treatment and prevent the especially virus disease purposes of the medicine of hepatitis B particularly of above-mentioned disease.
Except that specializing, the percentage number average among the following embodiment is a weight percentage.The ratio of solvent all refers to volume ratio in the mixing solutions.
Embodiment
A. intermediate
Embodiment 1
Ethyl 4-(2,4 dichloro benzene base)-2-(thiazol-2-yl)-6-methyl isophthalic acid, 4-dihydro-pyrimidin-5-carboxylicesters
Figure A20081012572300201
With 10.0g (57.1mmol) of 2,4 dichloro benzene formaldehyde, 7.4g (57.1mmol) ethyl acetoacetic acid, 9.3g (57.1mmol) 2-amidino groups-thiazole hydrochloride and 5.7g (69.5mmol) sodium-acetate dissolving or be suspended in the 500ml ethanol boiling reflux 16 hours.Be cooled to room temperature, the filtration of bleeding, rinsing residue is removed inorganic salt.Get product 11.8g (52.5%)
Fusing point: 164-166 ℃.
Embodiment 2
Ethyl 6-brooethyl 4-(2,4 dichloro benzene base)-2-(thiazol-2-yl)-1,4-dihydro-pyrimidin-5-carboxylicesters
Figure A20081012572300211
With 8.0g (20.2mmol) ethyl 4-(2,4 dichloro benzene base)-2-(thiazol-2-yl)-6-methyl isophthalic acid that embodiment 1 makes, 4-dihydro-pyrimidin-5-carboxylicesters joins in the 140ml tetracol phenixin, is heated to 50 ℃ under the argon atmosphere, obtains settled solution.In this temperature, add 4.36g (24.2mmol) N-bromine succinimide, remain on this temperature and mixed 10 minutes.Cooling at once, the room temperature lower pumping filters, concentrating under reduced pressure.HPLC detects product purity and is higher than 90%, and as next step raw material.
Rf=0.68 (petrol ether/ethyl acetate=8: 2)
B. prepare embodiment
Embodiment 3
Ethyl 4-(2,4 dichloro benzene base)-2-(thiazol-2-yl)-6-(4-morpholine methyl)-1,4-dihydro-pyrimidin-5-carboxylicesters
With 5.0g embodiment 2 freshly prepd ethyl-6-brooethyl-4-(2-chlorine 4-chloro-phenyl-)-2-(thiazol-2-yl)-1,4-dihydro-pyrimidin-5-carboxylicesters joins in the 60ml methyl alcohol and forms solution, with the morpholine mixing of 5 times of amounts, stirs 30 minutes under the room temperature.The solution with water dilution, ethyl acetate extraction.
Output: 4.1g
Fusing point: 155-157 ℃.
R f=0.48 (petrol ether/ethyl acetate=8: 2)
The enantiomer that embodiment 3 makes is in chiral column (Daicel Chiralpak AS-H, moving phase: normal hexane/ethanol=99/1) go up separation
Anti--HBV active compound among the embodiment 3 all is the long enantiomorphs of retention time.
The activity data of compound of the present invention is listed as follows:
Figure A20081012572300221
The HepG2.2.15 cell that uses compounds for treating hepatitis B virus of the present invention to produce has caused in the born of the same parents and/or the minimizing of extracellular virus DNA.

Claims (27)

1, the compound shown in general formula (I) and the isomers (Ia) thereof with and enantiomer and their salt:
Figure A2008101257230002C1
Wherein:
R 1Be neighbour-chlorine, R 2Be right-chlorine, R 3Be C 1-C 4Alkyl, R 6Be thiazolyl-2-base, X is a methylene radical, and Z is a morpholinyl.
2, compound as claimed in claim 1 and enantiomer thereof and their salt, wherein: R 1Be neighbour-chlorine, R 2Be right-chlorine, R 3Be methyl or ethyl, R 6Be thiazolyl-2-base, X is a methylene radical, and Z is a morpholinyl.
3, the compound and enantiomer, its tautomer (Ia) and the salt thereof that have following structure
Figure A2008101257230002C2
4, prepare the method for the described compound of claim 1, comprise step:
[A] at first generates the Ben Yajiaji compound shown in the general formula (IV) with the reaction of 'beta '-ketoester shown in phenyl aldehyde shown in the general formula (II) and the general formula (III):
Figure A2008101257230003C1
Wherein: R 1, R 2, R 3, X and Z have the implication described in the claim 1, and
Then with amidine or its salt shown in Ben Yajiaji compound shown in the general formula (IV) and the logical formula V, or other compound reaction,
R wherein 6Has the implication described in the claim 1;
[B] with the same aldehyde of compound (II) shown in the general formula (III) and amidine (V) or its salt, or other compound reacts by single stage method,
When [C] X in the general formula (I) is methylene radical, with compound shown in the general formula (VI) and morpholine (VII) or its reactant salt:
Figure A2008101257230003C3
Wherein, R 1, R 2, R 3And R 6Have above-mentioned implication, Y is the nucleophilic substitution base,
[D] is with compound shown in aldehyde shown in the general formula (II) and the general formula (X) and lead to amidine or its reactant salt shown in the formula V:
Figure A2008101257230004C1
Wherein, R 3, X and Z have the implication described in the claim 1.
5. the compound shown in the general formula (XII):
Figure A2008101257230004C2
R wherein 1, R 2, R 3And R 6Have implication described in the claim 1-3 and described compound as synthetic compound (I) or intermediate (Ia).
6. the arbitrary described compound that is used for control disease of claim 1-3.
7. medicine, this medicine contains the described compound of at least a claim 1 to 3, in the time of suitably, further contains other active medicine component.
8. the purposes of the described compound of claim 1 to 3 in the medicine of preparation treatment and prophylaxis of viral diseases.
9. the purposes of the described compound of claim 1 to 3 in the medicine of preparation treatment and prevention hepatitis B infection.
10. a method for the treatment of hepatitis B comprises the described compound of the claim 1 that gives the Mammals significant quantity.
11. the method for the disease that a treatment is caused by hepatitis B infection comprises the described compound of the claim 1 that gives the Mammals significant quantity.
12. method as claimed in claim 11, wherein said disease is a hepatitis.
13. method as claimed in claim 11, wherein said disease is a liver cirrhosis.
14. method as claimed in claim 11, wherein said disease is a canceration of hepatic cell.
15. a pharmaceutical preparation, it comprises the described compound of one or more claims 1 and a kind of pharmaceutically acceptable carrier.
16. a composition is made up of following component:
A) at least a arbitrary described dihydro-pyrimidin as claim 1 to 3,
B) at least a HBV antiviral agent that is different from A and, suitably under the situation,
C) at least a immunomodulator.
17. composition as claimed in claim 16, wherein B component is the HBV AG14361.
18. composition as claimed in claim 16, wherein B component is lamivudine (lamivudine).
19. composition as claimed in claim 16, wherein B component is selected from compound shown in the following general formula and salt thereof
Figure A2008101257230005C1
Wherein
R 1And R 2, be C respectively independently 1-C 4-alkyl or, the nitrogen-atoms on its position forms and to have the ring that 5-6 annular atoms comprises carbon and/or Sauerstoffatom,
R 3To R 12, be hydrogen independently respectively, halogen, C 1-C 4-alkyl replaces C arbitrarily 1-C 4-alkoxyl group, nitro, cyano group or trifluoromethyl,
R 13Be hydrogen, C 1-C 4-alkyl, C 1-C 7-acyl group or aralkyl, and X is halogen or replaces C arbitrarily 1-C 4-alkyl.
20, composition as claimed in claim 19, wherein compound has following structure:
21, as the arbitrary described composition of claim 16 to 20, wherein immunomodulator C comprises Interferon, rabbit.
22, a kind of composition, it is made up of following substances:
A) the described dihydro-pyrimidin of claim 1 to 3,
B) lamivudine (lamivudine) and, in the time of suitably,
C) Interferon, rabbit.
23, a kind of arbitrary described preparation of compositions method as claim 16 to 22 is characterized in that, make up or blending ingredients A to be fit to mode, B and, the suitable component C under the situation.
24. the arbitrary described composition that is used for control disease as claim 16 to 22.
25. a medicine, it comprises at least a arbitrary described composition as claim 16 to 22, and under the suitable situation, other active pharmaceutical ingredients.
26. the purposes of arbitrary described composition in the medicine of preparation treatment and prophylaxis of viral diseases as claim 16 to 22.
27. the purposes of arbitrary described composition in the medicine of preparation treatment and prevention hepatitis B infection as claim 16 to 22.
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