EP1169310A1 - Procede de preparation de mkc-442 - Google Patents

Procede de preparation de mkc-442

Info

Publication number
EP1169310A1
EP1169310A1 EP00925979A EP00925979A EP1169310A1 EP 1169310 A1 EP1169310 A1 EP 1169310A1 EP 00925979 A EP00925979 A EP 00925979A EP 00925979 A EP00925979 A EP 00925979A EP 1169310 A1 EP1169310 A1 EP 1169310A1
Authority
EP
European Patent Office
Prior art keywords
disubstituted
reaction
mkc
thiourea
thiouracil
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.)
Withdrawn
Application number
EP00925979A
Other languages
German (de)
English (en)
Inventor
Darryl G. Cleary
Frank Waligora
Merrick R. Almond
Rose O'mahony
Terrence Mungal
Michael Kuzemko
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.)
Gilead Sciences Inc
DSM Pharmaceuticals Inc
Original Assignee
Triangle Pharmaceuticals Inc
Catalytica Pharmaceuticals Inc
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 Triangle Pharmaceuticals Inc, Catalytica Pharmaceuticals Inc filed Critical Triangle Pharmaceuticals Inc
Publication of EP1169310A1 publication Critical patent/EP1169310A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals

Definitions

  • HIV human immunodeficiency virus
  • the first enzyme reverse transcriptase
  • the first enzyme is active early in the replication cycle of HIV and allows the virus, which is made of RNA, to produce DNA necessary for continued replication.
  • This enzyme can be inhibited by two general classes of drugs defined by their structure as well as their mechanism of action.
  • the first general class, nucleoside analogue reverse transcriptase inhibitors such as 3'-azido-3'-deoxythymidine (AZT), 2',3'- dideoxyinosine (ddl), 2',3'-dideoxycytidine (ddC), and (-)-cis-2-hydroxymethyl-5-(cytosin-l- yl)-l,3-oxathiolane (3TC) bear a strong chemical resemblance to the natural building blocks (nucleosides) of DNA and interfere with the function of the enzyme by displacing the natural nucleosides used by the enzyme.
  • the second general class, non-nucleoside reverse transcriptase inhibitors, such as MKC-442 and nevirapine, is composed of an extremely diverse group of chemicals that act by binding to the enzyme and modifying it so that it functions less efficiently.
  • nucleoside reverse transcriptase inhibitors including AZT, ddl, ddC, 3TC, 2',3'-dideoxy-2',3'-didehydrothymidine (D4T), and cis-2-hydroxymethyl-5- (5-fluorocytosin-l-yl)-l,3-oxathiolane (FTC), have been proven to be effective against HIV. After cellular phosphorylation to the 5'-triphosphate by cellular kinases, these synthetic nucleosides are also incorporated into a growing strand of viral DNA, causing chain termination due to the absence of the 3'-hydroxyl group.
  • D4T 2',3'-dideoxy-2',3'-didehydrothymidine
  • FTC cis-2-hydroxymethyl-5- (5-fluorocytosin-l-yl)-l,3-oxathiolane
  • MKC-442 functions as a non-nucleoside reverse transcriptase inhibitor.
  • MKC-442 is considered an allosteric inhibitor because it appears to exert its activity by binding to an "allosteric position", i.e., one other than the binding site, of the enzyme.
  • Preclinical tests suggest that MKC-442 may possess characteristics that address several of the therapeutic challenges of HIV. When tested in cell culture assay systems against wild-type (drug- sensitive) and several mutant strains of HIV known to be resistant to established non- nucleoside reverse transcriptase inhibitors, MKC-442 retained much of its ability to inhibit HIV replication. In these studies, MKC-442 displayed greater potency than nevirapine against wild-type and mutant strains of HIV.
  • Preclinical studies of MKC-442 in two drug combinations with AZT or with ddl and in three drug combinations with AZT and saquinavir have demonstrated synergistic inhibition of HIV replication.
  • a Phase I study evaluated the pharmacokinetics and tolerance of single escalating doses of MKC-442 in HIV-infected volunteers.
  • the compound was generally well tolerated, with only a few participants experiencing minor adverse effects at the higher dose levels.
  • concentrations of the drug in the plasma reached levels much higher than the levels required to suppress 90% of the virus in culture.
  • U.S. Patent No. 5,604,209 issued on February 18, 1997 to Ubasawa et al., and assigned to Mitsubishi Chemical Corporation, discloses that certain 6-benzyl-l- ethoxymethyl-5-substituted uracil derivatives, including MKC-442, and certain 2',3'- dideoxyribonucleosides, including 2',3'-dideoxyinosine (ddl), 3'-azido-3'-deoxythymidine (AZT), AZT triphosphate, and 2',3'-dideoxycytidine (ddC), exhibit a synergistic effect against HIV.
  • ddl 2',3'-dideoxyinosine
  • AZT 3'-azido-3'-deoxythymidine
  • ddC 2',3'-dideoxycytidine
  • MKC-442 is a 5,6-substituted uracil derivative that has an alkoxyalkyl group in the 1 position (see Figure 1), methods for its synthesis must include steps to add these three 1,5,6-substituents.
  • Typical synthetic routes to MKC-442 have included condensation of the alkoxyalkyl moiety with a 5-substituted thiouracil, followed by desulfurization of the thiouracil, lithiation at the 6-position, reaction with benzaldehyde, subsequent acetylation and eventual reduction of the hydroxy group using hydrogeno lysis to yield MKC-442 . Rosowsky, et al., J.
  • the ⁇ -keto ester is then condensed with thiourea in the presence of sodium ethoxide to form a 2- thiouracil which is refluxed with chloroacetic acid in aqueous acetic acid overnight to give 6- benzyl-5-ethyluracil.
  • Silylation of the uracil is required prior to condensation with an alkylating agent of choice.
  • the Danel method has substantial drawbacks for the manufacturing scale preparation of MKC-442, as it requires a large excess of Zn and the use of sodium metal to generate the base in situ, which is a serious safety concern. Also, a 20-fold excess of the ethoxide was specified in the article, which is not reasonable for industrial scale-up.
  • the Danel method required the use of fifteen equivalents of thiourea, which prevents a clean crystallization of the thiouracil derivative.
  • the thiouracil intermediate was not at all soluble in the chloroacetic acid solution used, and when the material was heated to reflux, a sticky mass formed and coated the agitator and flask walls.
  • the desulfurization reaction was homogenized using either alcohols or tetrahydroftiran, the thiouracil was converted to an undetermined impurity.
  • the yield of MKC-442 dropped dramatically, providing only 25-50% product having only 90% purity.
  • MKC-442 is useful in the treatment of HIV-infected patients, there is a need to develop cost effective and scalable methods for manufacturing pure MKC- 442 in large quantity, high purity, and high yield. It is therefore an object of the present invention to provide an improved synthetic process for preparing 6-benzy l-l-(ethoxymethyl)- 5-isopropyluracil (MKC-442) in high yield and greater purity.
  • a 5,6-disubstituted uracil can be produced in good yield by the reaction of an appropriate ⁇ -keto ester with thiourea in the presence of potassium t- butoxide.
  • the ⁇ -keto ester is ethyl-2-isopropyl-3-oxo-4-phenyl-butyrate
  • the resulting product is 6-benzyl-l-(ethoxymethyl)-5-isopropyluracil, also known as MKC-442.
  • a method for producing a 5,6-disubstituted uracil includes the use of two bases simultaneously to effectively synthesize the 5,6- disubstituted uracil in high yield from a ⁇ -keto ester.
  • Preferred bases include potassium carbonate and potassium t-butoxide as the co-bases in acetonitrile. This embodiment is depicted in Scheme 3.
  • an isopropyl ⁇ -keto ester such as ethyl-2-isopropyl-3-oxo-4-phenyl-butyrate can be synthesized using any known method, including from benzyl cyanide and ethyl-2-bromo-3,3-dimethyl-propionate with activated zinc in a Reformatsky reaction.
  • the ⁇ -keto ester is then reacted with a two-base system, including but not limited to potassium carbonate and potassium t-butoxide, in a solvent, for example acetonitrile.
  • the reaction is a single-step process that proceeds to form a product in greater than 80% yield .
  • the two-base system results in products of greater purity.
  • the use of potassium carbonate and potassium t-butoxide in acetonitrile results in a product having a purity of 90- 95%.
  • bases of high pK b alone destroy the starting ⁇ -keto ester and have higher levels of impurities.
  • use of bases with high pK b alone leads to products of lower yield.
  • Bases of lower pK S tend to have longer reaction times and tend to contain residual starting material. It is therefore beneficial to use a two- base system to counteract these tendencies.
  • Bases useful in the two-base system of the present invention include, but are not limited to potassium carbonate, potassium t-butoxide, sodium carbonate, di-isopropyl amine, triethyl amine, 2,6-dimethyl pyridine, sodium acetate, potassium acetate, ammonia, potassium ethoxide, and potassium cyanide.
  • the bases are used in combination with a solvent.
  • Solvents useful in the two-base system of the present invention include, but are not limited to acetonitrile, butyronitrile, isobutyronitrile, chloroacetonitrile and other alkyl nitrile solvents, isopropyl alcohol, methanol, ethanol, propanol, butanol, and other alcohol solvents.
  • a method for producing a 5,6- disubstituted uracil includes reacting a ⁇ -keto ester with thiourea in the presence of potassium t-butoxide, preferably in iso-propyl alcohol. This embodiment of this reaction is depicted in Scheme 4.
  • an isopropyl ⁇ -ketoester such as ethyl-2-isopropyl-3-oxo-4-phenyl-butyrate
  • an isopropyl ⁇ -ketoester such as ethyl-2-isopropyl-3-oxo-4-phenyl-butyrate
  • any known method including from benzyl cyanide and ethyl-2-brorno-3,3-dimethyl-propionate with activated zinc in a Reformatsky reaction, and then the ethyl-2-isopropyl-3-oxo-4-phenyl- butyrate is condensed with thiourea in the presence of potassium t-butoxide in process step (A) of the present invention to form a benzyl isopropyl thiouracil, which is desulfurized in process step (B), and then the benzyl isopropyl uracil is alkoxyalkylated in process step (C)
  • BuOK for NaOEt in the cyclocondensation reaction of step (A) affords a dramatically purer product.
  • the increased yields gained with t-BuOK have precedent in the literature, however the increased purity of the product obtained is heretofore unknown and unexpected.
  • the substitution of t-BuOK for NaOEt afforded a tractable, crude thiouracil, making the workup both manageable and scalable. It is also surprising that this reaction of step (A) occurs with a sub-stoichiometric amount of t-BuOK.
  • step (C) the use of diethoxy methane in the presence of an acid catalyst such as sulfuric acid of step (C), rather than the very toxic TMS triflate or chloromethyl ether used in the prior art, offers a cost advantage as well as a safety benefit.
  • the slow and controlled evolution of hydrogen sulfide in the desulfurization reaction of step (B) is also unexpected. A rapid and uncontrollable gas evolution would prevent scale up and commercialization of the process.
  • step (C) has two unexpected aspects associated with it. First, it is surprising that this reaction proceeds so efficiently in the presence of sub- stoichiometric amounts of sulfuric acid. Secondly, it is extremely convenient that the removal of HMDS is not necessary. The alkylation proceeds in an efficient fashion with sub- stoichiometric amounts of sulfuric acid, even in the presence of HMDS.
  • a first process for preparing a 5,6-disubstituted uracil, preferably MKC-442, via the reaction of a ⁇ -keto ester with thiourea in a two-base system includes the use of two bases simultaneously to effectively synthesize the 5,6-disubstituted uracil.
  • the process includes reacting a ⁇ -keto ester with thiourea in the presence of a two-base system and a solvent at temperatures ranging from 80-85 ° C.
  • the one-step process of this first process of the present invention comprises reacting a 2,4-disubstituted-3-oxo-butyrate, preferably ethyl-2-isopropyl-3-oxo-4-phenylbutyrate, with thiourea in a two-base system and a solvent.
  • Preferred bases for the two-base system include, but are not limited to, potassium t-butoxide and potassium carbonate.
  • a preferred solvent for the reaction includes, but is not limited to, acetonitrile.
  • the reaction proceeds at a temperature from 80 °C to 85 °C. A preferred reaction temperature is about 85 °C.
  • two-base system refers to the use of two bases simultaneously in the presence of a solvent.
  • bases included in the two-base system are potassium carbonate, potassium t-butoxide, sodium carbonate, di- isopropyl amine, triethyl amine, 2,6-dimethyl pyridine, sodium acetate, potassium acetate, ammonia, potassium ethoxide, and potassium cyanide.
  • the bases are used in combination with a solvent.
  • Solvents useful in the two-base system of the present invention include, but are not limited to acetonitrile, butyronitrile, isobutyronitrile, chloroacetonitrile and other alkyl nitrile solvents, isopropyl alcohol, methanol, ethanol, propanol, butanol, and other alcohol solvents.
  • step (i) a step (A) that includes the preparation of a 5,6-disubstituted thiouracil via the reaction of a 2,4-disubstituted-3-oxo-butyrate ester with thiourea in the presence of potassium t-butoxide in an organic solvent, wherein the intermediate is a 5,6-disubstituted-2-thio-uracil;
  • step (ii) the process of step (A) wherein the solvent is an alcohol, preferably isopropyl alcohol;
  • step (A) wherein molar ratio of thiourea to 2,4-disubstituted-3- keto-butyrate is not greater than approximately 10% excess, and more preferably no more than 5% excess;
  • step (iv) the process of step (A) wherein the reaction is quenched with water and acetic acid;
  • step (v) a step (B) that includes the process of step (A) further including desulfurizing the 5,6-disubstituted-2-thiouracil to a 5,6-disubstituted-uracil, preferably using 10% chloroacetic acid (aq) in acetic acid;
  • step (vi) the process of step (B) further including isolating the thiouracil prior to desulfurization;
  • step (vii) the process of step (B) wherein the acetic acid is between approximately 25 and 40% of the total solvent volume used, and preferably, approximately 35%;
  • step (viii) the process of step (B) wherein the reaction is heated to between 85° C and 105° C to form a solution;
  • step (ix) a step (C) that includes the silylation of the 5,6-disubstituted uracil of step (v) with any suitable reagent according to known methods;
  • step (x) the process of step (C) wherein the reagent is a silylating agent such as hexamethyldisilizane;
  • step (xi) the process of step (x) wherein the hexamethyldisilizane is reacted in the presence of a catalytic amount of ammonium sulfate;
  • step C reacting the product of step C with an alkylating or alkoxyalkylating agent, for example, diethoxy methane;
  • an alkylating or alkoxyalkylating agent for example, diethoxy methane
  • step (xiii) the process of step (xii) wherein the reaction is accomplished in sulfuric acid or methanesulfonic acid;
  • step (xiv) the process of step (xiii), wherein sub-stoichiometric equivalent amounts of sulfuric acid are used, and preferably, between 0.25 and 0.5 equivalent amounts;
  • step (xv) the process of step (xiv), wherein the reaction is run in refluxing acetonitrile (or other alkyl nitriles), preferably for 2-5 hours.
  • the two-stage process of the second process of the present invention comprises steps (A) and (B) in Stage I.
  • Step (A) comprises cyclizing isopropyl- ⁇ -ketoester with thiourea and potassium tert-butoxide in isopropyl alcohol at reflux to produce benzyl isopropyl thiouracil.
  • the benzyl thiouracil is then desulfurized under reflux in step (B) to produce benzyl isopropyl uracil (BIU) using chloroacetic solution, 10% ClAcOH (aq), AcOH.
  • the reaction work up involves a quench with water and acetic acid, then filtration of a crystalline solid in 70-80% yield.
  • the Stage I process differs from Danefs process (J. Med. Chem. 1996, 39,2427- 2431 ) by eliminating the use of sodium metal, used by Danel to generate the base in situ. Elimination of the sodium resolved a serious safety concerns during scale up. Danel also specified a 20-fold excess of the ethoxide while only a 5%-20% excess is required by the process of the present invention. Additionally, the Danel process produces a thiouracil intermediate which, when heated to reflux, forms a sticky mass which coats the agitator and flask walls. In contrast, using discretely isolated thiouracil produced by the process of step (A) of the present invention, conversion and purity are increased.
  • step (B) accomplished two tasks: it allowed for the formation of a solution when heated to 95°C; it served as a recrystailization cosolvent when the reaction was scaled.
  • the process of the present invention eliminates the sticky mass formed by the Danel process, making the improved process scalable to production sized equipment.
  • the BIU was recovered in approximately 90% yield of >98% pure material.
  • BIU is silylated with 1,1,1,3,3,3- hexamethyldisilazane (HMDS) in the presence of a catalytic amount of ammonium sulfate, followed by alkylation with diethoxymethane in acetonitrile containing sulfuric acid.
  • HMDS hexamethyldisilazane
  • step (C) hexamethyldisilazane
  • methanesulfonic acid as the acid catalyst.
  • the conditions were optimized to employ sub-stoichiometric amounts (0.25 - 0.5 equivalents) of concentrated sulfuric acid at reflux in acetonitrile for 2-5 hours in order to effect alkylation. Typical reaction profiles showed MKC-442 at 90-95% yields possessing ⁇ 3% BIU as an impurity.
  • the two-stage process of the present invention provides several improvements over the prior art processes.
  • the substitution of t-BuOK for NaOEt in the cyclocondensation reaction of step (A) affords a dramatically purer product.
  • the increased yields gained with t- BuOK has literature precedence, but in this case, the increased purity of the product obtained was unexpected.
  • the substitution of t-BuOK for the NaOEt unexpectedly afforded a tractable, crude thiouracil, making the workup both manageable and scalable. With the NaOEt, an intractable, sticky mass was obtained, making scale-up difficult. Also, it is surprising that this reaction occurs with a sub-stoichiometric amount of t-BuOK.
  • Another advantage to the process of the present invention is the slow and controlled evolution of hydrogen sulfide in the desulfurization reaction of step (B).
  • a rapid and difficult-to-control gas evolution would have severely limited the scalability of the process.
  • step (C) has several unexpected aspects associated with it. First, it is surprising that this reaction proceeds so efficiently in the presence of sub- stoichiometric amounts of sulfuric acid. Second, it is unexpected and quite convenient that the removal of the HMDS is unnecessary. The alkylation proceeds in an efficient fashion, with sub-stoichiometric amounts of sulfuric acid, even in the presence of HMDS. Finally, the use of diethoxymethane as an alkylating agent offers a significant advantage over the prior art processes which employ trimethylsilyl triflate or chloromethyl ether. Not only is the diethoxymethane less expensive, it is also a significantly less toxic reagent, making its use safer than the reagents of the prior art.
  • a 12 liter reaction flask fitted with a mechanical stirrer and twin condensers was purged with argon and charged with -100 mesh zinc metal (301 g, 4.6 mol) and 5000 ml tetrahydroftiran (THF).
  • a catalytic amount of iodine (3.0 g) was added and the suspension was stirred until the color faded.
  • the activated zinc suspension was then treated with benzyl cyanide (179 g, 1.53 mol) and the mix was heated to 60°C.
  • the reaction was then treated with ethyl 2-bromoisovalerate (481 g, 2.30 mol). Approximately 50 g of the bromo ester were added, and the reaction was allowed to initiate, raising the batch temperature to 69°C after five minutes. The remaining ester was then added over 35 minutes, so that a minimal reflux was maintained. Following the addition, the reaction was left to stir at 65°C for one hour.
  • a 1L 3 neck round bottom flask was charged with 6-benzyl-5-i-propyl uracil (BIU) (50 g, 0.20 mol), ammonium sulfate (0.5 g, catalytic) and 1,1,1,3,3,3-hexamethyldisilazane (258 g, 1.6 mol).
  • BIU 6-benzyl-5-i-propyl uracil
  • ammonium sulfate 0.5 g, catalytic
  • 1,1,1,3,3,3-hexamethyldisilazane 258 g, 1.6 mol
  • the slurry was heated to reflux (125-130°C) under argon for four hours.
  • the resulting solution was concentrated to a thick oil (about 125 ml) under reduced pressure (85°C, 30 mm Hg).
  • the oil was resuspended in 350 ml acetonitrile.
  • the remaining slurry was diluted with 175 ml ethyl acetate and the layers were split.
  • the aqueous layer was washed with ethyl acetate (50 ml) and the organic fractions combined.
  • the organic fractions were concentrated to a volume of about 75 ml, then were chased with 75 ml ethanol to a volume of about 75 ml.
  • the crude MKC-442 was then taken up in an additional 100 ml EtOH at 85°C and was diluted with 60 ml H2O, cooled to ambient and crystallized. After 2 hours, the crude material was filtered and washed with 25 ml 25% EtOH in water. 52 g, 94% HPLC AUC. The material was then taken up in 115 ml EtOH at 85°C, diluted with 50 ml H O, and the product was left to cool to ambient temperature and crystallize. The product was filtered and washed twice with 25 ml 25% EtOH in water to leave 45 g, 99.8% AUC, with 0.10% (AUC) BIU.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de 6-benzyl-1-(éthoxyméthyl)-5-isopropyluracil, appelé MKC-442. Ce procédé consiste à faire la synthèse d'un isopropyl ß-cétoester, notamment un éthyl-2-isopropyl-3-oxo-4-phényl-butyrate, grâce au procédé connu consistant à inclure un phénylacétonitrile et éthyl-2-bromo-3,3-diméthyl-propionate avec un zinc activé dans une réaction Reformatsky. L'éthyl-2-isopropyl-3-oxo-4-phényl-butyrate est condensé par la suite avec une thiourée de deux manières. D'après la première, l'éthyl-2-isopropyl-3-oxo-4-phényl-butyrate est condensé avec la thiourée dans un système à double base en présence d'un solvant et d'après la seconde, il est condensé avec une thiourée en présence d'un potassium t-butoxyde afin d'obtenir un benzyl isopropyl thiouracil, qui est désulfuré à l'étape (B). Le benzyl isopropyl uracil obtenu est soumis à une alcoxyalkylation afin d'obtenir un MKC-442.
EP00925979A 1999-04-13 2000-04-13 Procede de preparation de mkc-442 Withdrawn EP1169310A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US12892599P 1999-04-13 1999-04-13
US128925P 1999-04-13
PCT/US2000/009965 WO2000061566A1 (fr) 1999-04-13 2000-04-13 Procede de preparation de mkc-442

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EP (1) EP1169310A1 (fr)
JP (1) JP2002541247A (fr)
KR (1) KR20020040657A (fr)
CN (1) CN1352637A (fr)
AU (1) AU4459000A (fr)
CA (1) CA2369698A1 (fr)
IL (1) IL145791A0 (fr)
WO (1) WO2000061566A1 (fr)

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GB0504079D0 (en) * 2005-02-28 2005-04-06 Davy Process Techn Ltd Process
CN102206187B (zh) * 2010-03-31 2013-01-02 北京大学 6-苄基-1-乙氧甲基-5-异丙基尿嘧啶及其类似物的合成方法
CN102295608B (zh) * 2010-06-24 2014-09-24 北京大学 新型hept类hiv-1逆转录酶抑制剂的制备及其应用
CN102838549A (zh) * 2011-06-23 2012-12-26 北京大学 具有抗hiv病毒作用的新一类1,5,6-取代嘧啶衍生物
CN104119283B (zh) * 2013-04-24 2016-06-22 北京大学 Hiv逆转录酶/整合酶双靶点抑制剂6-苯甲酰基取代尿嘧啶类化合物的制备及应用
CN103601768B (zh) * 2013-11-13 2015-09-30 齐鲁天和惠世制药有限公司 一种阿米卡星的制备方法
EP3681873A4 (fr) * 2017-09-15 2021-05-26 The Regents of the University of California Compositions et procédés d'inhibition de la n-smase2

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JPH10130244A (ja) * 1996-09-06 1998-05-19 Mitsubishi Chem Corp アシクロヌクレオシドの製造方法

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IL145791A0 (en) 2002-07-25
KR20020040657A (ko) 2002-05-30
WO2000061566A1 (fr) 2000-10-19
CN1352637A (zh) 2002-06-05
CA2369698A1 (fr) 2000-10-19
AU4459000A (en) 2000-11-14
JP2002541247A (ja) 2002-12-03

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