[go: up one dir, main page]

WO2008154819A1 - Thiazolyl-dihydropyrimidines à substitution carbéthoxy - Google Patents

Thiazolyl-dihydropyrimidines à substitution carbéthoxy Download PDF

Info

Publication number
WO2008154819A1
WO2008154819A1 PCT/CN2008/001189 CN2008001189W WO2008154819A1 WO 2008154819 A1 WO2008154819 A1 WO 2008154819A1 CN 2008001189 W CN2008001189 W CN 2008001189W WO 2008154819 A1 WO2008154819 A1 WO 2008154819A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
composition
salt
hepatitis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2008/001189
Other languages
English (en)
French (fr)
Inventor
Goldmann Siegfried
Jing Li
Yisong Liu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ZHANG ZHONGNENG
Original Assignee
ZHANG ZHONGNENG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by ZHANG ZHONGNENG filed Critical ZHANG ZHONGNENG
Publication of WO2008154819A1 publication Critical patent/WO2008154819A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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

Definitions

  • the present invention relates to a novel ethoxycarbonyl-substituted thiazolyl dihydropyrimidine, a process for the preparation thereof and its use as a medicament, especially as a medicament for the treatment and prevention of hepatitis B virus infection.
  • the invention further relates to compositions of these dihydropyrimidines with other antiviral agents and, where appropriate, immunomodulators, and medicaments containing such compositions, especially compositions for the treatment and prevention of HBV infections such as hepatitis B. Background technique
  • Hepatitis B virus belongs to the family of hepatic viruses. It can cause acute and/or persistent/progressive chronic conditions. Hepatitis B virus also causes many other clinical signs in pathological morphology - especially chronic inflammation of the liver, cirrhosis of the liver and carcinogenesis of hepatocytes. In addition, co-infection with hepatitis D can have an adverse effect in the development of the disease.
  • Interferon and lamivudine are conventional drugs approved for the treatment of chronic hepatitis. However, interferon is only moderately active and has harmful side effects; although lamivudine has good activity, its resistance develops rapidly during treatment and often has a rebound effect after stopping treatment. Lamivudine (3-butyl 0> has an IC 5 Q value of 300 nM (Science, 299 (2003), 893-896).
  • No. 7,074,784 discloses 6-aminoalkyldihydropyrimidines and their use as medicaments, especially for the treatment and prevention of hepatitis B virus infection.
  • This patent discloses 54 different examples, and almost all of them (50) are compounds having a fluorine-substituted 2-pyridine residue at the position of R6.
  • R3 is a methyl group.
  • the present invention relates to a compound represented by the formula (I) and an isomer thereof (la)
  • R 1 is o-chloro
  • R 2 is p-chloro
  • R 3 is C 2 -C 3 alkyl
  • R 6 is thiazol-2-yl
  • X is methylene
  • Z is morpholinyl.
  • R 1 is o-chloro
  • R 2 is p-chloro
  • R 3 is ethyl
  • R 6 is thiazol-2-yl
  • X is methylene
  • Z is morpholinyl.
  • the invention also relates to enantiomers of the above compounds and to their respective mixtures.
  • the racemic form can be separated by known means, which is essentially a homogeneous component of the stereoisomer.
  • the compounds of the invention comprise isomers of the formulae (I) and (la) and mixtures thereof.
  • the compounds of the invention may also be in the form of a salt.
  • a physiologically acceptable salt is preferred.
  • the physiologically acceptable salt may be a mineral acid salt or an organic acid salt.
  • the physiologically acceptable salt may also be a metal or ammonium salt of a compound of the invention.
  • Particularly preferred examples are sodium, potassium, magnesium, or calcium salts, and from ammonia or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, An ammonium salt formed by arginine, lysine, ethylenediamine, or 2-phenylethylamine.
  • the compound (I) of the present invention can be produced by the following method:
  • R 6 means as described above, or
  • RR 2 , R 3 and R 6 have the same meanings as defined above, and Y is a nucleophilic substituent such as chloride, bromide, iodide, methanesulfonyl or tosyl, and morpholine (VII)
  • the reaction is carried out with or without the addition of a base, as appropriate, in the presence of an inert solvent.
  • a base as appropriate, in the presence of an inert solvent.
  • the compound (VI) can be produced, for example, by using the compound of the formula (VIII)
  • R 1 , R 2 , R 3 and R 6 have the same meanings as defined above, and a brominating agent such as N-bromosuccinate; imine, preferably in an inert solution, to give a compound of the formula (IX)
  • R 3 , X and Z have the same meanings as defined above, and the oxime represented by the formula (V) has or does not carry a base adduct.
  • R 3 has the same meaning as described above.
  • Compound (V) is known and can be prepared as described in WO-A-99/54326 and WO-A-99/54329.
  • Morpholine (VII) is commercially available.
  • inert organic solvents are suitable for the eight, B, C and D steps.
  • Preferred among them are alcohols such as methanol, ethanol, isopropanol, ethers such as dioxins, diethyl ether, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, carboxylic acids such as glacial acetic acid, or dimethyl.
  • Alcohols such as methanol, ethanol, isopropanol
  • ethers such as dioxins, diethyl ether, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, carboxylic acids such as glacial acetic acid, or dimethyl.
  • the reaction temperature can be varied within a relatively wide range.
  • a temperature between 20 and 150 ° C is usually used, but is preferably at the boiling temperature of the selected solvent.
  • the reaction can be carried out under atmospheric pressure or under high pressure. It is usually carried out under atmospheric pressure.
  • the reaction can be carried out in the presence or absence of an acid or a base; however, it is preferred to carry out the reaction in the presence of a weak acid such as acetic acid or formic acid.
  • a weak acid such as acetic acid or formic acid.
  • One embodiment of the invention relates to the use of A) at least one of the above-described dihydropyrimidines,
  • a detailed embodiment of the invention relates to a composition
  • a composition comprising A) a dihydropyrimidine, a B) HBV polymerase inhibitor and, if appropriate, a C) immunomodulator.
  • Preferred immunomodulators C) include, for example, all interferons such as alpha-, beta- and gamma-interferons, especially a-2a- and a-2b-interferon, interleukins such as interleukin-2 Polypeptides such as thymosin-ct-1 and thymoctonan, imidazoquinoline derivatives such as 8 levamisole, immunoglobulins and therapeutic vaccines. .
  • the present invention also relates to such compositions for the treatment and prevention of HBV infection and their use in the treatment of diseases caused by HBV.
  • compositions of the invention are beneficial for the treatment of HBV-induced diseases, primarily synergistic antiviral activity, and Tox-50 relative to a single component (50% cell viability toxicity) relative to a single treatment of a single compound. Scope)
  • the compositions of the invention are well tolerated.
  • HBV polymerase inhibitors used to achieve the objects of the present invention are in Ph. A. Furman et al., Antimicrobial Agents and Chemotherapy Vol. 36 (No. 12), 2688 (1992). Those materials disclosed in the endogenous polymerase experiments, as well as those described below, inhibit the formation of HBV DNA duplexes, resulting in a maximum of 50% of the activity values of zero.
  • HBV virions from culture suspensions integrate nucleoside 5'-triphosphate in vitro
  • the DNA of HBV is in the positive strand.
  • agarose gel electrophoresis the product in which [ ⁇ - 32 P]-deoxynucleoside 5'-triphosphate was incorporated into the virus 3.2 kb DNA was found, and there was no potential HBV polymerase-inhibiting property. substance.
  • One part by volume of the clarified cell culture suspension was mixed with 1/4 part by volume of an aqueous solution containing 50% by weight of polyethylene glycol 8000 and 0.6 M of sodium chloride.
  • the pellet was centrifuged at 2500 x g for 15 minutes, and the precipitate was resuspended in 2 ml of a buffer containing 0.05 M tris-HCl M (H 7.5), and dialyzed against the buffer containing 100 mM potassium chloride.
  • the sample was frozen at -80 Torr.
  • Each reaction mixture (100 ⁇ ) contains at least 10 5 HBV virions, 50 mM tris-HCl (p.sub.H 7.5), 300 mM potassium chloride, 50 mM magnesium chloride, 0.1%® Nonident P-40 (non-ion Type of washing, Boehringer Mannheim) > ⁇ ⁇ ⁇ , 10 ⁇ dGTP , 10 ⁇ dTTP; 10 ⁇ [ 32 P]dCTP (3000 Ci/mmol; final concentration 33 nM) and 1 ⁇ triphosphate form of polymerase potential inhibition Agent.
  • the samples were incubated at 37 C for one hour and then stopped by the addition of 50 mM EDTA.
  • the gel therein is dried or transformed into a membrane using Southern transformation techniques.
  • a maximum 50% concentration of the control group indicates the presence of an HBV polymerase inhibitor.
  • Abacavir (-)-(lS-cis)-4-[ 2 -amino-6-(cyclopropylamine)-9H-indol-9-yl]-2-yl-cyclopentene- 1-methanol, cf.
  • FTC (2R-cis)-4-amino-5-fluoro-l-[2-(hydroxymethyl)-1.3-oxothio-5-yl]-p-pyrimidine-2(1H)-one, Cf.
  • WO 92/14743 US 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;
  • a more preferred embodiment of the invention relates to a composition comprising the above dihydropyrimidines (I) and (la) and B) lamivudine.
  • Another preferred HBV antiviral agent B contains, for example, phenylacrylamide represented by the following formula
  • R 1 and R 2 independently of each other, d- -fluorenyl or, together with the nitrogen atom at the position thereof, form a ring having 5 to 6 ring atoms including carbon and/or oxygen atoms.
  • R 3 to R 12 are independently hydrogen, cyano, C r C 4 -alkyl, optionally substituted for C r C 4 -nonyloxy, nitro, cyano or trifluoromethyl.
  • R 13 is hydrogen, C r C 4 -alkyl, dC 7 -acyl or aralkyl, and X is halogen or an optionally substituted C r C 4 -fluorenyl group.
  • AT-61 is a compound
  • Preferred immunomodulators C) include, for example, all interfering agents such as ⁇ -, ⁇ - and ⁇ -interferons, in particular a-2a- and a-2b-interfering, interleukins such as interleukin-2 , polypeptides such as thymosin-ot-1 and thymoctonan, imidazoquinoline derivatives such as 8 levamisole, immunoglobulins and therapeutic vaccines.
  • interfering agents such as ⁇ -, ⁇ - and ⁇ -interferons, in particular a-2a- and a-2b-interfering, interleukins such as interleukin-2 , polypeptides such as thymosin-ot-1 and thymoctonan, imidazoquinoline derivatives such as 8 levamisole, immunoglobulins and therapeutic vaccines.
  • Another preferred embodiment of the invention relates to a composition
  • a composition comprising A) the above-described dihydropyrimidines (I) and (la); B) lamivudine; and, where appropriate, C) interferon.
  • Antiviral testing was performed on 96-well microtiter plates. The first column only received medium and HepG2.2.15 cells as a virus control.
  • the mother liquor of the test compound (50 mM) was first dissolved in DMSO and then diluted with HepG2.2.15 medium. Typically, a 100 ⁇ test concentration (1 st test concentration) of the compound of the invention is pipetted into the second test column of the microtiter plate each time, and then added to the medium in which 2% by weight fetal calf serum (25 ⁇ l in volume) is added. Diluted 2 1Q times in two steps.
  • Each well of the microtiter plate containing 2% by weight of fetal bovine serum contained 225 l of HepG 2.2.15 cell suspension (5 x 10 4 cdls/ml). The test mixture was incubated for 4 days at 37 ° C, 5% C0 2 (v/v).
  • the surface suspension was then aspirated and discarded, and 225 ⁇ M of freshly prepared medium was added to the wells. A 25 ⁇ volume of a 1/10 concentration solution of the compound of the invention was added. The mixture was continued for 4 days.
  • cytotoxic or cytotoxic changes induced by substances in HepG2.2.15 cells for example, changes in cell morphology under a light microscope. Changes in these substances in HepG2.2.15 cells are evident compared to untreated cells, such as cytolysis, vacuoles, or changes in cell morphology.
  • 50% toxicity (TOX.-50) means that 50% of the cells exhibit a morphology compared to the corresponding control cells.
  • the tolerance of some of the compounds of the invention is tested by other host cells such as, for example, HeLa cells, primary human peripheral hematopoietic cells or transformed cell lines such as H-9 cells. No change in cytotoxin was detected at concentrations of the compounds of the invention > 10 ⁇ 1 . Determination of antiviral effect
  • the intracellular or extracellular suspension of HepG2.2.15 cells was denatured (1.5 M NaCl/0.5 N NaOH), neutralized ( 3 M NaCl/0.5 M Tris HCl, pH 7.5), then rinse (2xSSC) o
  • the DNA was dried onto the membrane by incubating the filter at 120 °C for 2-4 hours.
  • Viral DNA from treated HepG2.2.15 cells on nylon filters is typically detected by a non-radioactive, digoxin-labeled hepatitis B-specific DNA probe, labeled with digoxin, and according to the manufacturer Instructions for purification and hybridization.
  • Pre-hybridization is at 60. C was run for 30 minutes and then specifically hybridized with 20 to 40 ng/ml of digoxin-labeled, denatured HBV-specific DNA (14 hours, 60 °C). Wash the filter. Detection of HBV-DNA with digoxin antibody
  • Immunodetection of digoxin-labeled DNA was performed according to the manufacturer's instructions: The wash filter was hybridized in a blocking reagent (according to the manufacturer's instructions). Hybridization was then carried out using an anti-DIG antibody coupled to alkaline phosphatase for 30 minutes. After the washing step, the substrate of alkaline phosphatase, CSPD, was incubated with the filter for 5 minutes, then coated with a plastic film, and for another 15 minutes at 37 ° C. The filter was exposed to the X-ray layer.
  • HBV DNA was seen emission signal (incubation depending on signal strength: 10 to 2 minutes) at half maximum inhibitory concentration (IC 5 o, 50% inhibitory concentration) of a 50% reduction compared to the compounds of the present invention and an untreated sample.
  • IC 5 o half maximum inhibitory concentration
  • the compounds of the present invention exhibited an effective antiviral effect of IC 5 () below 1 nM, which was unexpected.
  • the compounds of the invention are useful in the treatment of viral-induced diseases, particularly acute and chronic persistent HBV viral infections.
  • Chronic viral disease caused by HBV It can lead to serious morbidity, and chronic hepatitis B virus infection can lead to cirrhosis and/or hepatocellular carcinogenesis in many cases.
  • the indicated regions that may be mentioned are, for example, the treatment of acute and chronic viral infections that may result in infectious hepatitis, for example, hepatitis B virus infection.
  • the compounds of the invention are especially suitable for the treatment of chronic hepatitis B infection and acute and chronic hepatitis B virus infection.
  • the invention includes a pharmaceutical preparation comprising, in addition to a non-toxic, inert, pharmaceutically suitable carrier, one or more compounds (I) or (la) or compositions of the invention or one or more activities Ingredient (I) or (la) or a composition of the invention.
  • the active ingredients (I) and (Ia) used in the above pharmaceutical preparations have a concentration of from about 0.1 to 99.5% by weight, preferably from about 0.5 to 95% by weight, based on the whole of the mixture.
  • the above pharmaceutical preparations may also contain other active pharmaceutical ingredients other than the compounds (I) and (la).
  • the content ratio of components A, B and suitable C in the composition of the invention may vary within wide limits, preferably from 5 to 500 mg of A/10 to 1000 mg of B, especially from 10 to 200 mg. A/20-400 mg of B.
  • Component C if appropriate, can also be used, preferably in an amount of from 1 to 10 million, more preferably from 2 to 7 million, I.U. (international unit), three times a week for a period of more than one year.
  • the compound or composition of the present invention for use in the above pharmaceutical preparations is usually present in a concentration of from about 0.1% to about 99.5%, preferably from about 0.5% to about 95%, by weight based on the total of the mixture.
  • the above pharmaceutical preparations can be prepared by a known conventional method, for example, by mixing the active ingredient with a carrier.
  • a total dose of from about 0.05 to about 500, preferably from 0.1 to 100 mg/kg body weight per 24 hours, whether in humans or veterinary, for a single dose of multiple doses.
  • the active ingredient contained in a single dose is preferably in a total amount of from about 0.1 to about 80, preferably from 0.1 to 30 mg/kg of body weight. No It is necessary to vary the above dosage, especially depending on the type and weight of the subject to be treated, the nature and severity of the condition, the type of preparation, the manner in which the medicine is administered, and the time or interval at which the medicine is administered.
  • the present invention also relates to the above compounds and compositions for use in the control of diseases.
  • the invention further relates to a medicament comprising at least one of the above compounds or compositions and, where appropriate, one or more other active pharmaceutical ingredients.
  • the invention further relates to the use of the above compounds and compositions for the preparation of a medicament for the treatment and prevention of the above mentioned diseases, in particular viral diseases, in particular hepatitis B.
  • the anti-HBV active compounds of Example 3 were all enantiomers with a longer retention time.
  • the activity data for the compounds of the invention are listed below:

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Virology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

一种乙氧碳酰基 -取代噻唑二氢嘧啶 技术领域
本发明涉及一种新的乙氧碳酰基-取代噻唑二氢嘧啶， 其制备方 法及其作为药物，尤其是作为治疗和预防乙型肝炎病毒感染的药物的 用途。 本发明还涉及这些二氢嘧啶同其他抗病毒剂和， 适当情况下， 免疫调节剂的组合物， 以及含有这些组合物尤其是治疗和预防 HBV 感染诸如乙型肝炎的组合物的药物。 背景技术
乙型肝炎病毒属于肝病毒科。它可引起急性的和或持续 /渐进的 慢性病。 B型肝炎病毒还引起病理形态中的许多其他的临床病征一一 尤其是肝脏的慢性炎症、 肝硬化和肝细胞的癌变。 另外， 与丁型肝炎 的共同感染在疾病的发展过程中会产生不利影响。
干扰素和拉米夫定（lamivudine )是批准用于治疗慢性肝炎治疗 的常规药物。然而，干扰素只具有中等的活性，并具有有害的副反应； 虽然拉米夫定 （lamivudine )具有良好的活性， 但其在治疗中抗性发 展迅速，并在停止治疗之后常常出现反弹效应，拉米夫定（ lamivudine ) (3-丁0>的 IC5Q 值为 300 nM(Science, 299 (2003)， 893-896)。
US 7074784公开了 6-胺基烷基二氢嘧啶及其作为药物的应用， 尤其是用于治疗和预防乙型肝炎病毒感染。
该专利公布了 54个不同的实施例， 它们几乎全部 （50个）都是 在 R6的位置具有氟取代 2 -吡啶残基的化合物。 该专利的所有实施 例 （54个） 中 R3 均为甲基。
该专利指出具有较长的烷基连（如乙基） 的化合物是弱活性或甚 至是惰性的。
该专利 中 的具有下述结构的 9 个化合物 （ 实施例 1,5,7,9,12,24,31,34,45 )其中八个具 8有 6位的氟取代 2 -吡啶残基。 只有一个实施例 （实施例 45) 的 R6= 噻唑 -2-基。
Figure imgf000003_0001
发明内容
我们惊人地发现了具有噻唾 -2-基取代基（(R6= 噻唑 -2-基） 乙酯 (R3=乙基） 的该专利的实施例 45 (Rl =邻-氯 和 R2=对-氯 ）， 产 生了 3倍高活性的衍生物， 即 IC5。低于 l nM。 （见表 1 )
Figure imgf000003_0002
Figure imgf000003_0003
因此， 本发明涉及通式 （I)所示的化合物及其同分异构体 (la)
Figure imgf000004_0001
其中
R1是邻 -氯， R2是对 -氯， R3是 C2-C3烷基， R6是噻唑 -2-基， X是 亚甲基， 和 Z是吗啉基。
优选地， 在本发明的通式 (I)和 (la)所示的化合物中：
R1是邻 -氯， R2是对 -氯， R3是乙基， R6是噻唑 -2-基， X是亚甲 基， 以及 Z是吗啉基。
本发明还涉及上述化合物的对映异构体及其各自的混合物。外消 旋体能通过已知的手段分离出来，本质上说它是立体异构体中的均一 成分。
本发明的化合物包含通式 （I)和 （la) 的异构体及其混合物。 本 发明的化合物也可以是盐的形式。在本发明中， 生理上可接受的盐是 优选的。
生理上可接受的盐可以是无机酸盐或者有机酸盐。优选的是无机 酸的盐， 诸如， 例如盐酸、 氢溴酸、 磷酸或硫酸等， 或者有机羧酸或 磺酸， 例如醋酸、 马来酸、 反丁烯二酸、 苹果酸、 柠檬酸、 酒石酸、 乳酸、 苯甲酸或甲磺酸、 乙磺酸、 苯磺酸、 甲苯磺酸或萘-二硫磺酸 等形成的盐。
生理上可接受的盐还可以是本发明化合物的金属盐或者铵盐。尤 其优选的实例是纳、钾、镁、或钙盐， 以及由氨或有机胺， 诸如乙胺， 二 -或三乙胺， 二-或三乙醇胺， 二环己基胺， 二甲基氨基乙醇， 精氨 酸， 赖氨酸， 乙二胺， 或 2-苯乙胺等生成的铵盐。
本发明的化合物 (I)可由下述方法制备：
[A]首先将苯甲醛 (II)与通式 (III)所示的 β-酮酯在加入或不加入碱 或酸， 适当时在惰性有机溶剂存在下进行反应转化成通式（IV )所示 的苯亚甲基化合物：
Figure imgf000005_0001
其中 Κλ R2 、 R3、 X和 Z的含义如前所述。
然后， 将后者与通式（V )所示的脒或者其盐 (诸如， 例如盐酸盐 或醋酸盐)， 在加入或不加入碱或酸， 适当时在存在惰性有机溶剂的 情况下， 进行反应
Figure imgf000005_0002
其中 R6含义如前所述， 或
[B]将通式 （III)所示化合物同醛（Π )和脒 （V)或它们的盐 （诸 如， 盐酸盐或醋酸盐）在加入或不加入碱或酸， 适当时在存在惰性有 机溶剂的情况下， 进行一步反应； 或
[C]当通式 （I) 中的 X是亚甲基， 将通式 （VI )所示化合物
Figure imgf000006_0001
其中 R R2、 R3 和 R6含义如前所述， Y是亲核取代基团， 诸如氯化物，溴化物，碘化物， 甲磺酰基或甲苯磺酰基， 与吗啉（VII )
Figure imgf000006_0002
在加入或不加入碱， 适当时存在惰性溶剂的条件下进行反应。 化合物 (VI)的制备可以通过， 例如， 用通式 （VIII )所示化合物
Figure imgf000006_0003
其中 R1, R2, R3 和 R6含义如前所述， 和溴化剂诸如， N-溴琥 ；亚胺， 优选在惰性溶液中进行反应， 得到通式（IX )所示化合物
Figure imgf000006_0004
将具有亲核取代基团的后者直接或者按照文献中所述的常规方 法进一步转变之后， 与吗啉 (VII)反应。
[D] 通式 （II )所示的醛与通式 （X )所示的化合物， 当适合时 在惰性溶剂中反应，
Figure imgf000007_0001
其中 R3， X和 Z含义如前所述， 通式 （V)所示的脒带有或不带 有碱基加成物。
为制备本发明的通式 (I)所示化合物， 其中 X是亚甲基， z是吗 啉基， 可将通式（XI )所示的氯乙酸酯与吗啉 (VII)反应来制备相应的 β-酮羧酸酯（ΠΙ )
Figure imgf000007_0002
其中 R3含义如前所述。
作为起始原料的 2-氯 -4-氟-苯甲醛（Π)可通过商业途径获得。 用作起始原料的 β-酮羧酸酯（III )是公知的， 或者是能够从文献 公布的已知方法中类推制得的 [如， D. Borrmann， "Umsetzung von Diketen mit Alkoholen, Phenolen und Mercaptanen"， in "Methoden der organischen Chemie" (Houben- Weyl) , vol. VII/4 , 230 ff (1968); Y. Oikawa, K. Sugano und O. Yonemitsu, J. Org. Chem. 43, 2087 (1978)]。
化合物 （V)是 已知 的 ， 并可根据 WO-A-99/54326 和 WO-A-99/54329 的描述来制备。
吗啉 (VII)可通过商业途径获得。
化合物 (VIII)和 (X)可根据 WO-A-99/54326 中描述的步骤 [A]或 [B ]制得。
所有的惰性有机溶剂都适用于八、 B、 C和 D步骤。 其中优选的 包括醇如， 甲醇、 乙醇、 异丙醇， 醚如二恶垸、 二乙醚、 四氢呋喃、 乙二醇单甲醚， 乙二醇二甲醚， 羧酸诸如冰醋酸、 或二甲基甲酰胺、 二甲基亚砜、 乙腈、 吡啶和六甲基磷酰三胺。
反应温度可以在相当宽的范围内变化。 通常使用 20到 150°C之 间的温度， 但优选的是在所选溶剂的沸点温度。
反应可以在大气压下进行， 也可以在高压下进行。 通常在大气压 下进行。
反应可以在加入或者不加入酸或者碱的环境下进行； 但是， 在弱 酸诸如醋酸或者蚁酸等的存在下进行反应是较好的。
本发明的一种实施方案涉及含有 A ) 至少一种上述的二氢嘧啶，
B)至少一种与 A )不同的其他抗病毒剂的组合物。
本发明的一个详细的实施方案涉及含有 A )上述二氢嘧啶， B ) HBV聚合酶抑制剂和， 和合适的情况下， C ) 免疫调节剂的组合物。
优选的免疫调节剂 C)包括， 例如， 所有的干扰素诸如 α -， β- 和 γ-干扰素，尤其是 a -2a-和 a -2b-干扰素， 白细胞介素诸如白细胞 介素 -2, 多肽诸如胸腺素 - ct -1 和胸腺托南 （thymoctonan ), 咪唑喹 啉衍生物诸如 ⑧左咪唑， 免疫球蛋白和治疗疫苗。 .
因此， 本发明还涉及用于治疗和预防 HBV感染的这些组合物及 其在治疗 HBV引发的疾病上的用途。
相对于单一化合物的单一治疗，本发明组合物的使用对治疗 HBV 引发的疾病是有益的， 主要是协同的抗病毒活性， 以及相对于单个成 分的 Tox-50 (有 50 %的细胞存活的毒性范围）来说， 本发明的组合 物具有良好的耐受性。
用于实现本发明目的的 HBV聚合酶抑制剂 Β为在 Ph. A. Furman 等在 《抗微生物制剂与化疗方法》 （ Antimicrobial Agents and Chemotherapy ) Vol. 36 (No. 12), 2688 (1992)中的内生聚合酶实验中 揭示的那些物质， 以及那些在下文中描述的， 抑制 HBV DNA双链的 形成， 从而导致最大 50%活性值为零的那些物质。
来自培养悬浮液的 HBV 毒粒在体外将核苷 5'-三磷酸盐整合到 HBV 的 DNA正链中。 通过使用琼酯糖凝胶电泳， 发现其中存在 [ α -32P]-脱氧核苷 5'-三磷酸盐掺入到病毒 3.2 kb DNA中的产物，不存在 具有潜在 HBV聚合酶 -抑制性质的物质。 从 HepG2.2.15 细胞的细 胞培养悬浮物中， 用聚乙二醇沉淀、 浓缩得到 HBV毒粒。 1体积份 的澄清细胞培养悬浮物与 1 / 4体积份的含有 50 % (重量）聚乙二醇 8000 和 0.6M氯化钠的水溶液混合。 2500 X g离心沉淀 15分钟， 沉 淀物用 2ml含有 0.05 M tris-HCl M ( H 7.5)的缓冲液再悬浮， 用含有 lOOmM氯化钾的该缓冲液透析。样品在 -80Ό时冷冻。 每个反应混合 物（100 μΐ)含有至少 105 HBV毒粒、 50 mM tris-HCl (p.sub.H 7.5)、 300 mM氯化钾、 50 mM氯化镁、 0.1%® Nonident P-40 (非离子型洗 洚剩， Boehringer Mannheim) > ΙΟ μΜ άΑΤΡ, 10 μΜ dGTP , 10 μΜ dTTP; 10 μΟΊ [32P]dCTP (3000 Ci/mmol; 最终浓度为 33nM)和 1 μΜ 三磷酸形式的聚合酶潜在抑制剂。 样品在 37 C下培养一个小时， 然 后加入 50 mM EDTA中止反应。 加入 10% 重量 /体积 SDS 溶液 （每 90 ml水含有 lO g SDS)到终浓度为 1% (体积 )(基于溶液总体积)，加入 蛋白酶 K至最终浓度为 lmg/ml。 然后在 37°C温育 1小时， 用等体积 的苯酚 /氯仿 /异戊醇（体积比为 25:24:1 )溶液提取， DNA从含有 乙醇的水相中沉淀出来。 将 DNA小球悬浮在 ΙΟ μΙ凝胶缓冲液 (1升 水中含有 10.8 g tris、 5.5 g硼酸和 0.75g EDTA(=TBE buffer))中 , 并 用琼脂糖凝胶电泳分离。将其中的凝胶干燥或者釆用 Southern转化技 术将其中的核酸转变成膜。然后与阴性对照 (=与空白或惰性对照物进 行 endo-pol反应）比较来检测生成的标记 DNA双链的量。 如果存在 对照组的最大 50 %浓度则表明存在 HBV聚合酶抑制剂。
优选的 HBV 聚合酶抑制剂 B) 包括， 例如， 3TCHi米夫定 ( lamivudine ) =4-氨基 -1-[(2R-顺式) -2- (羟甲基) -1.3-氧硫茂 -5-基-] -嘧 啶 -2(1H)-酮， cf. EP-B 382 526 (=U.S. Pat. No. 5,047,407) 和 WO 91/11186 (=U.S. Pat. No. 5,204,466); 阿德福韦酯（ Adefovir dipivoxil ) =9-[2- [双 (特戊酰羟甲氧基)膦酰 甲氧基]乙基]腺嘌呤， cf. EP-B 481 214 (=U.S. Pat. Nos. 5,663,159 和 5,792,756), U.S. Pat. Nos. 4,724,233和 4，808，716;
BMS 200 475=[1S-(L. alpha., 3..alpha., 4..beta.)]-2-氨基 -1.9-二氢 -9-[4-羟基 -3- (羟甲基) -2-亚甲基-环戊基] -6H-嘌呤 -6-酮， cf. EP-B 481 754 (=U.S. Pat. Nos. 5,206,244 和 5,340,816)， WO 98/09964 和 99/41275;
阿巴卡韦 （Abacavir ) =(-)-(lS-顺式) -4-[2_氨基 -6- (环丙胺) -9H-嘌 呤 -9-基] -2-基-环戊烯 -1-甲醇， cf. EP-B 349 242 (=U.S. Pat. No. 5,049,671)和 EP-B 434 450 (=U.S. Pat. No. 5,034,394);
FTC=(2R-顺式) -4-氨基 -5-氟 -l-[2- (羟甲基) -1.3-氧硫茂 -5-基] -p-嘧 啶 -2(1H)-酮， 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)和 WO 92/18517;
P-L-FDDC=5-(6-氨基 -2-氟 -9H-嘌呤 -9-基) -四氢 -2-呋喃甲醇， cf. WO 94/27616 (=U.S. Pat. Nos. 5,627,160; 5,561,120; 5,631,239 和 5， 830, 881); L-FMAU=l-(2-脱氧 -2-氟 -.beta.-L-阿拉伯呋喃糖 )-5-甲基- 嘧啶 e—2.4(lH，3H)-二酮， cf. WO 99/05157， WO 99/05158 和 U.S. Pat.
Figure imgf000010_0001
本发明的一个更优选的实施方案涉及含有 Α )上述二氢嘧啶 （I) 和 (la)及 B)拉米夫定（lamivudine ) 的组合物。
另一个优选的 HBV抗病毒剂 B 含有， 例如， 下述通式所示的 苯基丙烯酰胺
Figure imgf000011_0001
其中
R1 和 R2 ， 分别独立地为， d- -垸基或者， 与其所在位置上 的氮原子一起， 形成具有 5-6个环原子包括碳和 /或氧原子的环。 R3 至 R12, 分别独立地为氢， 素， CrC4-烷基， 任意的取代 CrC4-垸 氧基， 硝基， 氰基 或三氟甲基。 R13是氢， CrC4-烷基， d-C7-酰基 或芳烷基， 且 X是卤素或任意的取代 CrC4-垸基。
这些苯基丙烯酰胺及其制备方法已在 WO 98/33501中公开，这里 提及是为了公开的目的。 AT-61 是化合物
Figure imgf000011_0002
优选的免疫调节剂 C)包括例如， 所有的干扰如， α -, β-和 γ- 干扰素， 尤其还可以是 a -2a-和 a -2b-干扰， 白细胞介素如白细胞介 素 -2， 多肽如胸腺素 - ot -1 和胸腺托南 （thymoctonan ), 咪唑喹啉衍 生物如⑧左咪唑， 免疫球蛋白和治疗疫苗。
本发明的另一个优选的实施方式涉及含有 A) 上述二氢嘧啶 （I) 和 （la); B)拉米夫定 （lamivudine ); 以及合适的情况下 C) 干扰素 的组合物。 实验描述
基于 M. A. Sells Proc. Natl. Acad. Sci. 84， 1005 1009 (1987)以及 B. E. Korba等.， Antiviral Research 19, 55 70 (1992) 等描述的方法研究 本发明的化合物对乙型肝炎病毒的抗病毒作用。
抗病毒测试在 96-孔微量滴定板上进行。 第一直列只接受培养基 和 HepG2.2.15 细胞， 作为病毒对照.
将测试化合物的母液 (50 mM)先溶解在 DMSO 中， 然后用 HepG2.2.15 培养基稀释。 通常每次用移液管移取 100 μΜ 测试浓度 (1st测试浓度)的本发明化合物到微量滴定板的第二测试列， 然后在 加入 2% 重量胎牛血清（体积 25 μ1 ) 的培养基中分两步稀释 21Q倍。
微量滴定板的每个加入了 2% 重量胎牛血清的培养基的孔中都 含有 225 l HepG2.2.15 细胞悬浮液 (5 x 104 cdls/ml)。 37°C、 5% C02 (v/v)培养测试混合物 4天。
然后将表面悬浮物吸出丟弃， 向孔中加入 225 μΐ新制备的培养 基。 重新加入 25 μΐ体积的 1/10浓度的本发明化合物的溶液。 混合物 继续培养 4天。
在收集悬浮物测试抗病毒效果之前，先在光学显微镜下或者通过 生物化学检测方法 (例如 Alamar Blue stain或 Trypan Blue stain)检 测 HepG2.2.15细胞细胞毒素的变化。
收集表面悬浮物和 /或细胞并用抽真空的方法在 96-孔斑点室上 覆盖一层尼龙膜（根据制造商的信息） 细胞毒素的测定
检测 HepG2.2.15 细胞中物质引发的细胞毒素或抑制细胞的变 化， 例如， 在光学显微镜下细胞形态的改变。 HepG2.2.15 细胞的这 些物质引发的变化与未处理过的细胞相比起来是明显的， 例如， 细胞 溶解，液泡或者细胞形态的改变。 50%毒性 (TOX.-50)是指与相应的对 照细胞相比 50% 的细胞表现出一种形态学。
通过其他的宿主细胞诸如， 例如 HeLa细胞， 初级人外周造血细 胞或转化细胞系如 H-9 细胞上测试本发明的一些化合物的耐受性。 在本发明的化合物浓度>10 ^1 时没有检测到细胞毒素的改变。 抗病毒作用的测定
在将表面悬浮物或溶解的细胞转移到点装置（如上述）的尼龙膜 上之后，将 HepG2.2.15细胞的胞内或胞外悬浮物变性 (1.5 M NaCl/0.5 N NaOH), 中和 (3 M NaCl/0.5 M Tris HCl, pH 7.5) ， 然后冲洗 (2xSSC)o通过在 120 °C下温育过滤器 2-4小时，将 DNA烘干至膜上。
DNA杂交
通常通过非放射性， 地高辛 -标记的乙型肝炎-特异性 DNA探针 检测来自尼龙过滤器上已处理的 HepG2.2.15 细胞的病毒 DNA , DNA 探针用地高辛标记， 并且根据制造商的说明书进行纯化和杂交。
预杂交和杂交在 5xSSC， lx封闭试剂， 0.1% (重量） N-月桂酰 肌氨酸， 0.02% (重量） SDS 和 100 μβ鯡鱼精 DNA中进行。 预杂 交在 60。C进行 30 分钟， 然后与 20 至 40 ng/ml地高辛标记的、 变性 的 HBV -特异性 DNA (14小时， 60°C)进行特定杂交。 洗涤过滤器。 用地高辛抗体检测 HBV-DNA
按照造制造商的说明进行地高辛 -标记 DNA的免疫检测： 洗涤过滤器在封闭试剂中杂交 (依照制造商的说明)。 然后利用与 碱性磷酸酶耦合的抗 - DIG抗体杂交 30分钟。 在洗涤步骤之后， 加 入碱性磷酸酶的底物， CSPD, 与过滤器一起温育 5 分钟， 然后包上 塑料膜， 37°C下另外 15分钟. 将过滤器曝光在 X射线层下， 可看见 乙型肝炎 DNA的发光信号 (温育取决于信号强度： 10 分钟至 2小时). 最大半抑制浓度 （IC5o，50%抑制浓度)为与未处理样本相比本发 明化合物降低 50 %胞内或胞外乙肝病毒群的浓度。
本发明的化合物表现出 IC5()低于 1 nM的有效的抗病毒作用， 这 是没有预料到的。 因此， 本发明的化合物适用于病毒引发的疾病尤其 是急性和慢性持续的 HBV病毒感染的治疗。 HBV引发的慢性病毒病 可能导致病态变得严重，慢性乙型肝炎病毒感染在许多情况下可导致 肝硬化和 /或肝细胞癌变。
对本发明的化合物来说， 可能被提及的指示区域是， 例如： 可能 导致传染性肝炎的急性和慢性病毒感染的治疗，例如，乙肝病毒感染。 本发明的化合物尤其适合治疗慢性乙肝感染和急性和慢性乙肝病毒 感染。
本发明包括药物制剂， 除了无毒， 惰性的制药学上合适的载体之 外，还含有一种或多种本发明的化合物 （I) 或 (la)或组合物或含有一 种或多种活性成分 (I)或 (la)或本发明的组合物。
用于上述药物制剂中的活性成分 (I)和 (Ia)， 其浓度相对于整个混 合物约为 0.1至 99.5% (重量）， 优选约为 0.5 至 95% (重量）。
上述药物制剂也可以包含化合物 （I) 和 （la)以外的其他活性药 物成分。
本发明的组合物中组分 A、 B和合适的 C的含量比例可以在较宽 的限制范围内变化， 优选 5-500 mg的 A/10-1000 mg的 B， 尤其是 10-200 mg的 A/20-400 mg的 B。
组分 C, 适当的时候也可使用， 其用量优选 1至 10百万， 更优 选 2至 7百万， I.U. (国际单位)， 在超过一年的时期内每周 3次。
用于上述药物制剂的本发明的化合物或组合物，其浓度相对于整 个混合物通常为约 0.1%至 99.5%， 优选约 0.5%至 95%， （重量百分 比）。
上述药物制剂可以通过公知的常规方法来制备，例如将活性成分 和载体混合。
无论是在人体还是在兽医学上每 24小时服用总剂量为约 0.05至 约 500， 优选 0.1至 100mg/kg体重的活性成分已经被普遍证明是有 益的， 合适单剂量的多次服用， 可以达到理想的效果。 单剂量含有的 活性成分优选在总量约 0.1 至约 80, 优选 0.1至 30mg/kg体重。 无 论如何， 尤其是根据待治疗受试者的种类和体重， 病症的特性和严重 程度， 制剂的类型， 药物服用的方式以及药物服用的时间或间隔来改 变上述的剂量是必要的。
因此， 本发明还涉及用于控制疾病的上述化合物和组合物。
本发明还涉及至少含有一种上述化合物或组合物和适当的情况 下， 含有一种或几种其他活性药物成分的药物。
本发明还涉及，用于上述化合物和组合物用于制备治疗和预防上 述疾病尤其是病毒性疾病特别是乙型肝炎的药物的用途。
除特别指明的外， 下述实施例中的百分数均是重量百分数。 混合 溶液中溶剂的比例均指体积比。
实施例
A.中间体 实施例 1
乙基 4-(2，4-二氯苯基 ）-2- (噻唑 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯
Figure imgf000015_0001
将 10.0 g (57.1 mmol) of 2， 4-二氯苯甲醛, 7.4 g (57.1 mmol) 乙 基乙酰乙酸， 9.3 g (57.1 mmol) 2-脒基-噻唑盐酸盐和 5.7 g (69.5 mmol) 醋酸钠溶解或悬浮于 500 ml乙醇中沸腾回流 16小时。 冷却至室温， 抽气过滤， 水洗残渣去除无机盐。 得产物 11.8 g (52.5%)
溶点： 164-166。 C。 实施例 2 乙基 6-溴甲基 4-(2，4-二氯苯基 ）-2- (噻唑 -2-基) -1,4-二氢嘧啶 -5-羧酸 酯
Figure imgf000016_0001
将实施例 1 制得的 8.0 g (20.2 mmol) 乙基 4 -(2, 4-二氯苯 基）-2- (噻唑 -2-基) -6-甲基 -1，4-二氢嘧啶 -5-羧酸酯加入到 140ml 四氯 化碳中， 氩气氛围下加热至 50。 C, 得到澄清溶液。 在此温度， 加入 4.36 g (24.2 mmol) N-溴琥珀酰亚胺， 保持在该温度混合 10分钟。 立 刻冷却，室温下抽气过滤，减压浓缩。 HPLC检测产物纯度高于 90%， 并作为下一步的原料。
RiN).68 (石油醚 /乙酸乙酯 =8:2)
B. 制备实施例 实施例 3
乙基 4-(2，4-二氯苯基 ）-2- (噻唑 -2-基) -6-(4-吗啉甲基) -1,4-二氢嘧啶-
Figure imgf000016_0002
将 5.0 g 实施例 2 新制备的乙基 -6-溴甲基- 4-(2-氯 4-氯苯 基 ）-2- (噻唑 -2-基) -1,4-二氢嘧啶 -5-羧酸酯加入到 60 ml甲醇中形成溶 液， 同 5倍量的吗啉混合， 室温下搅拌 30分钟。 溶液用水稀释， 乙 酸乙酯萃取。
产量: 4.1g
熔点： 155-157°C。
Rf = 0.48 (石油醚 /乙酸乙酯 = 8 : 2)
实施例 3制得的对映异构体在手性柱 （Daicel ChiralpakAS-H， 流 动相： 正己烷 / 乙醇 = 99/1)上分离
实施例 3中的抗 -HBV活性化合物均是保留时间较长的对映体。 本发明的化合物的活性数据列表如下:
实施例 No. IC50(nM)
3 0.6
(-)-3 0.3 使用本发明的化合物治疗乙型肝炎病毒产生的 HepG2.2.15 细胞 导致了胞内和 /或胞外病毒 DNA的减少。 工业实用性
实验表明本发明化合物表现出 IC5。低于 1 nM的有效的抗病毒作 用，因而，可以按照本发明所述的方法或本领域技术人员所知的方法， 将本发明化合物用于病毒引发的疾病尤其是急性和慢性持续的 HBV 病毒感染的治疗。

Claims

权利要求书
1、 通式 （I )及其同分异构体 (la)所示的化合物以及其对映异构 体及它们的盐：
Figure imgf000018_0001
其中：
R1 是邻 -氯， R2是对 -氯， R3是 d-C4烷基， R6是噻唑基 -2-基， X是亚甲基， 以及 Z是吗啉基。
2、 如权利要求 1所述的化合物及其对映异构体及它们的盐， 其 中： R1是邻 -氯， R2是对 -氯， R3是甲基或乙基， R6是噻唑基 -2-基, X是亚甲基， 以及 Z是吗啉基。
3、 具有下述结构的化合物及其对映异构体、 其互变异构体 （la) 及其盐
Figure imgf000018_0002
4、 制备权利要求 1所述化合物的方法， 包括步骤：
[A] 首先将通式 (Π)所示苯甲醛与通式（III )所示 β-酮酯反应生 成通式 (IV)所示的苯亚甲基化合物:
Figure imgf000019_0001
其中： I 1 、 R2 、 R3、 X和 Z具有权利要求 1中所述的含义， 且 然后将通式 (IV)所示苯亚甲基化合物与通式 (V)所示的脒或其盐， 或其它化合物反应，
Figure imgf000019_0002
其中 R6 具有权利要求 1中所述的含义；
[B] 将通式 （III)所示化合物同醛 （II)和脒 （V)或其盐，或其它化 合物通过一步法进行反应，
[C] 当通式 （I) 中 X是亚甲基时， 将通式 （VI)所示化合物和 吗啉 (VII)或其盐反应：
Figure imgf000019_0003
其中， R1, R2, R3 和 R6 具有上述的含义， Y是亲核取代基，
[D] 将通式 （II) 所示醛与通式 (X)所示化合物及通式 （V) 所示 的脒或其盐反应：
NH2 (X)
其中， R3、 X和 Z具有权利要求 1中所述的含义。
5、 通式 (XII)所示的化合物：
Figure imgf000020_0001
其中 R1, R2, R3 和 R6具有杈利要求 1-3中所述的含义并且所 述化合物用作合成化合物 （I)或 （la)的中间体。
6、 权利要求 1-3之任一所述的用于控制疾病的化合物。
7、 一种药物， 该药物含有至少一种权利要求 1至 3所述的化合 物， 适当时， 进一步含有其它活性药物组分。
8、 权利要求 1至 3所述的化合物在制备治疗和预防病毒性疾病 的药物中的用途。
9、 权利要求 1至 3所述的化合物在制备治疗和预防乙型肝炎感 染的药物中的用途。
10、 一种治疗乙型肝炎的方法， 包括给予哺乳动物有效量的权利 要求 1所述的化合物。
11、 一种治疗由乙型肝炎感染引起的疾病的方法， 包括给予哺 乳动物有效量的权利要求 1所述的化合物。
12、 如权利要求 11所述的方法， 其中所述的疾病是肝炎。
13、 如权利要求 11所述的方法， 其中所述的疾病是肝硬化。
14、 如权利要求 11所述的方法， 其中所述的疾病是肝细胞癌变。
15、 一种药物制剂， 其包含一种或多种权利要求 1所述的化合物 及一种药学上可接受的载体。
16、 一种组合物由下列组分组成：
A)至少一种如杈利要求 1至 3之任一所述的二氢嘧啶，
B)至少一种不同于 A的 HBV抗病毒剂和， 适当情况下，
C)至少一种免疫调节剂。
17、 如权利要求 16所述的组合物， 其中组分 B 是 HBV聚合酶 抑制剂。
18、 如权利要求 16 所述的组合物， 其中组分 B 是 拉米夫定 ( lamivudine ) .
19、 如权利要求 16所述的组合物， 其中组分 B选自下述通式所 示的化合物及其盐
Figure imgf000021_0001
其中
R1 和 R2 ， 分别独立地为， d-C4 -烷基或者， 与其所在位置上 的氣原子一起， 形成具有 5-6个环原子包括碳和 /或氧原子的环，
R3 至 R12，分别独立地为氢，卤素， 烷基，任意的取代 d-C4- 烷氧基， 硝基， 氰基或三氟甲基，
R13是氢， CrC4-垸基， CrC7-酰基或芳烷基， 且 X是卤素或任 意的取代 d-C 烷基。
20、 如权利要求 19所述的组合物， 其中化合物具有如下结构：
Figure imgf000022_0001
21、 如杈利要求 16至 20之任一所述的组合物， 其中免疫调节剂 C包括干扰素。
22、 一种组合物， 其由下述物质组成：
A)权利要求 1至 3所述的二氢嘧啶，
B)拉米夫定 （lamivudine )和， 适当时，
C)干扰素。
23、 一种如权利要求 16至 22之任一所述的组合物的制备方法， 其特征在于， 以适合方式组合或混合组分 A， B和， 适当情况下的组 分(。
24、 如权利要求 16至 22之任一所述的用于控制疾病的组合物。
25、 一种药物， 其包含至少一种如权利要求 16至 22 之任一所 述的组合物， 且适当情况下， 其他活性药物成分。
26、如权利要求 16至 22之任一所述的组合物在制备治疗和预防 病毒性疾病的药物中的用途。
27、如杈利要求 16至 22之任一所述的组合物在制备治疗和预防 乙型肝炎感染的药物中的用途。
PCT/CN2008/001189 2007-06-18 2008-06-18 Thiazolyl-dihydropyrimidines à substitution carbéthoxy Ceased WO2008154819A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200710119017.9 2007-06-18
CN200710119017 2007-06-18

Publications (1)

Publication Number Publication Date
WO2008154819A1 true WO2008154819A1 (fr) 2008-12-24

Family

ID=40155888

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2008/001189 Ceased WO2008154819A1 (fr) 2007-06-18 2008-06-18 Thiazolyl-dihydropyrimidines à substitution carbéthoxy

Country Status (2)

Country Link
CN (1) CN101328169B (zh)
WO (1) WO2008154819A1 (zh)

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010069147A1 (zh) * 2008-12-17 2010-06-24 张中能 二氢嘧啶类化合物、其组合物及其应用
US8236797B2 (en) 2007-06-18 2012-08-07 Sunshine Lake Pharma Co., Ltd. Bromo-phenyl substituted thiazolyl dihydropyrimidines
WO2014029193A1 (en) 2012-08-24 2014-02-27 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
JP2015531354A (ja) * 2012-09-27 2015-11-02 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． ジヒドロピリミジン誘導体の結晶形
US9447086B2 (en) 2012-09-10 2016-09-20 Hoffmann-La Roche Inc. 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection
US9498479B2 (en) 2013-11-19 2016-11-22 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
US9573941B2 (en) 2013-11-27 2017-02-21 Sunshine Lake Pharma Co., Ltd. Processes for preparing dihydropyrimidine derivatives and intermediates thereof
US9771358B2 (en) 2014-03-28 2017-09-26 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
US9856247B2 (en) 2012-03-31 2018-01-02 Hoffmann-La Roche Inc. 4-methyl-dihydropyrimidines for the treatment and prophylaxis of Hepatitis B virus infection
US9873671B2 (en) 2014-01-16 2018-01-23 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9884818B2 (en) 2013-05-17 2018-02-06 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9895349B2 (en) 2013-04-03 2018-02-20 Janssen Sciences Ireland Us N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
WO2018036941A1 (en) 2016-08-24 2018-03-01 F. Hoffmann-La Roche Ag Combination therapy of an hbv capsid assembly inhibitor and a nucleos(t)ide analogue
US10071961B2 (en) 2013-10-23 2018-09-11 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10077239B2 (en) 2015-09-29 2018-09-18 Novira Therapeutics, Inc. Crystalline forms of a hepatitis B antiviral agent
US10098889B2 (en) 2015-02-07 2018-10-16 Sunshine Lake Pharma Co., Ltd. Complexes and salts of dihydropyrimidine derivatives and their application in pharmaceuticals
US10125094B2 (en) 2013-02-28 2018-11-13 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10160743B2 (en) 2013-05-17 2018-12-25 Janssen Sciences Ireland Uc Sulphamoylthiophenamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10196376B2 (en) 2011-12-21 2019-02-05 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US10213420B2 (en) 2014-02-05 2019-02-26 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
US10392349B2 (en) 2014-01-16 2019-08-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10441589B2 (en) 2016-04-15 2019-10-15 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
US10450270B2 (en) 2013-07-25 2019-10-22 Janssen Sciences Ireland Uc Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10537580B2 (en) 2015-03-19 2020-01-21 Novira Therapeutics, Inc. Azocane and azonane derivatives and methods of treating hepatitis B infections
US10596173B2 (en) 2015-11-03 2020-03-24 Hoffmann-La Roche Inc. Combination therapy of an HBV capsid assembly inhibitor and an interferon
WO2020087107A1 (en) 2018-10-31 2020-05-07 The University Of Sydney Compositions and methods for treating viral infections
US10676429B2 (en) 2012-08-28 2020-06-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10875876B2 (en) 2015-07-02 2020-12-29 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10973801B2 (en) 2018-03-14 2021-04-13 Janssen Sciences Ireland Unlimited Company Capsid assembly modulator dosing regimen
US11078193B2 (en) 2014-02-06 2021-08-03 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US11096931B2 (en) 2019-02-22 2021-08-24 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
US11491148B2 (en) 2019-05-06 2022-11-08 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103664925B (zh) * 2012-09-07 2018-01-23 广东东阳光药业有限公司 杂芳基取代的二氢嘧啶类化合物及其在药物中的应用
BR112015028873A2 (pt) * 2013-05-17 2017-07-25 Hoffmann La Roche heteroaril-diidro-pirimidinas interligados na posição 6, para o tratamento e profilaxia de infecção pelo vírus da hepatite b

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068640A1 (de) * 2000-03-16 2001-09-20 Bayer Aktiengesellschaft Arzneimittel gegen virale erkrankungen
WO2001068642A1 (de) * 2000-03-16 2001-09-20 Bayer Aktiengesellschaft Dihydropyrimidine und ihre verwendung als arzneimittel zur behandlung von hepatitis b
WO2001068639A1 (de) * 2000-03-17 2001-09-20 Bayer Aktiengesellschaft Dihydropyrimidin-5-carbonsäureester und ihre verwendung als arzneimittel gegen virale erkrankungen
WO2001068641A1 (de) * 2000-03-17 2001-09-20 Bayer Aktiengesellschaft 6-aminoalkyl-dihydroppyrimidine und ihre verwendung als arzneimittel gegen virale erkrankungen

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068640A1 (de) * 2000-03-16 2001-09-20 Bayer Aktiengesellschaft Arzneimittel gegen virale erkrankungen
WO2001068642A1 (de) * 2000-03-16 2001-09-20 Bayer Aktiengesellschaft Dihydropyrimidine und ihre verwendung als arzneimittel zur behandlung von hepatitis b
WO2001068639A1 (de) * 2000-03-17 2001-09-20 Bayer Aktiengesellschaft Dihydropyrimidin-5-carbonsäureester und ihre verwendung als arzneimittel gegen virale erkrankungen
WO2001068641A1 (de) * 2000-03-17 2001-09-20 Bayer Aktiengesellschaft 6-aminoalkyl-dihydroppyrimidine und ihre verwendung als arzneimittel gegen virale erkrankungen

Cited By (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8236797B2 (en) 2007-06-18 2012-08-07 Sunshine Lake Pharma Co., Ltd. Bromo-phenyl substituted thiazolyl dihydropyrimidines
US8343969B2 (en) 2007-06-18 2013-01-01 Sunshine Lake Pharma Co., Ltd. Bromo-phenyl substituted thiazolyl dihydropyrimidines
USRE44987E1 (en) 2007-06-18 2014-07-01 Sunshine Lake Pharma Co., Ltd. Bromo-phenyl substituted thiazolyl dihydropyrimidines
USRE45004E1 (en) 2007-06-18 2014-07-08 Sunshine Lake Pharma Co., Ltd. Bromo-phenyl substituted thiazolyl dihydropyrimidines
WO2010069147A1 (zh) * 2008-12-17 2010-06-24 张中能 二氢嘧啶类化合物、其组合物及其应用
US10196376B2 (en) 2011-12-21 2019-02-05 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US9856247B2 (en) 2012-03-31 2018-01-02 Hoffmann-La Roche Inc. 4-methyl-dihydropyrimidines for the treatment and prophylaxis of Hepatitis B virus infection
US9340538B2 (en) 2012-08-24 2016-05-17 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
EP2888241A4 (en) * 2012-08-24 2016-05-25 Sunshine Lake Pharma Co Ltd DIHYDROPYRIMIDIN COMPOUNDS AND THEIR USE AS PHARMACEUTICALS
WO2014029193A1 (en) 2012-08-24 2014-02-27 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
US10676429B2 (en) 2012-08-28 2020-06-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10995064B2 (en) 2012-08-28 2021-05-04 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US9447086B2 (en) 2012-09-10 2016-09-20 Hoffmann-La Roche Inc. 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection
JP2015531354A (ja) * 2012-09-27 2015-11-02 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． ジヒドロピリミジン誘導体の結晶形
US9403814B2 (en) 2012-09-27 2016-08-02 Sunshine Lake Pharma Co., Ltd. Crystalline forms of dihydropyrimidine derivatives
US10941113B2 (en) 2013-02-28 2021-03-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10125094B2 (en) 2013-02-28 2018-11-13 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US9895349B2 (en) 2013-04-03 2018-02-20 Janssen Sciences Ireland Us N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10398677B2 (en) 2013-04-03 2019-09-03 Janssen Sciences Ireland Uc N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10457638B2 (en) 2013-05-17 2019-10-29 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9884818B2 (en) 2013-05-17 2018-02-06 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10160743B2 (en) 2013-05-17 2018-12-25 Janssen Sciences Ireland Uc Sulphamoylthiophenamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10450270B2 (en) 2013-07-25 2019-10-22 Janssen Sciences Ireland Uc Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10071961B2 (en) 2013-10-23 2018-09-11 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10377709B2 (en) 2013-10-23 2019-08-13 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9498479B2 (en) 2013-11-19 2016-11-22 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
US9617252B2 (en) 2013-11-27 2017-04-11 Sunshine Lake Pharma Co., Ltd. Processes for preparing dihydropyrimidine derivatives and intermediates thereof
US9643962B2 (en) 2013-11-27 2017-05-09 Sunshine Lake Pharma Co., Ltd. Processes for preparing dihydropyrimidine derivatives and intermediates thereof
US9573941B2 (en) 2013-11-27 2017-02-21 Sunshine Lake Pharma Co., Ltd. Processes for preparing dihydropyrimidine derivatives and intermediates thereof
US9873671B2 (en) 2014-01-16 2018-01-23 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10392349B2 (en) 2014-01-16 2019-08-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10632112B2 (en) 2014-02-05 2020-04-28 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
US10213420B2 (en) 2014-02-05 2019-02-26 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
US11078193B2 (en) 2014-02-06 2021-08-03 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9771358B2 (en) 2014-03-28 2017-09-26 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
US10098889B2 (en) 2015-02-07 2018-10-16 Sunshine Lake Pharma Co., Ltd. Complexes and salts of dihydropyrimidine derivatives and their application in pharmaceuticals
US10537580B2 (en) 2015-03-19 2020-01-21 Novira Therapeutics, Inc. Azocane and azonane derivatives and methods of treating hepatitis B infections
US10875876B2 (en) 2015-07-02 2020-12-29 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10077239B2 (en) 2015-09-29 2018-09-18 Novira Therapeutics, Inc. Crystalline forms of a hepatitis B antiviral agent
US10596173B2 (en) 2015-11-03 2020-03-24 Hoffmann-La Roche Inc. Combination therapy of an HBV capsid assembly inhibitor and an interferon
US10441589B2 (en) 2016-04-15 2019-10-15 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
US11129834B2 (en) 2016-04-15 2021-09-28 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
WO2018036941A1 (en) 2016-08-24 2018-03-01 F. Hoffmann-La Roche Ag Combination therapy of an hbv capsid assembly inhibitor and a nucleos(t)ide analogue
US10973801B2 (en) 2018-03-14 2021-04-13 Janssen Sciences Ireland Unlimited Company Capsid assembly modulator dosing regimen
WO2020087107A1 (en) 2018-10-31 2020-05-07 The University Of Sydney Compositions and methods for treating viral infections
US11096931B2 (en) 2019-02-22 2021-08-24 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
US11491148B2 (en) 2019-05-06 2022-11-08 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases

Also Published As

Publication number Publication date
CN101328169A (zh) 2008-12-24
CN101328169B (zh) 2011-05-25

Similar Documents

Publication Publication Date Title
WO2008154819A1 (fr) Thiazolyl-dihydropyrimidines à substitution carbéthoxy
JP5970421B2 (ja) ブロモフェニル置換チアゾリルジヒドロピリミジン
WO2008154818A1 (fr) Thiazolyl-dihydropyrimidines à substitution fluorophényle
WO2008154820A1 (fr) Thiazolyl-dihydropyrimidines à substitution carbéthoxy
US7074784B2 (en) Medicaments against viral diseases
WO2010069147A1 (zh) 二氢嘧啶类化合物、其组合物及其应用
JP2002512233A (ja) 薬剤としてのジヒドロピリミジン類の使用及び新規な物質
WO2008009209A1 (en) Dihydropyrimidine compounds and their uses in preparation of medicaments for treating and preventing antiviral diseases
HK1125646A (zh) 一种溴苯基-取代的噻唑二氢嘧啶
HK1174035B (zh) 一种溴苯基取代的噻唑二氢嘧啶
JP2003514896A (ja) 新規な５−ピリミジンカルボキサミド誘導体及び該誘導体を含む製薬組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08757465

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08757465

Country of ref document: EP

Kind code of ref document: A1