TW200524612A

TW200524612A - Combinations of a pyrimidine containing NNRTI with RT inhibitors

Info

Publication number: TW200524612A
Application number: TW093126446A
Authority: TW
Inventors: Paul Stoffels
Original assignee: Tibotec Pharm Ltd
Priority date: 2003-09-03
Filing date: 2004-09-02
Publication date: 2005-08-01
Also published as: DK1663240T3; DK1663240T4; HUE025576T2; CN102319433A; TWI365744B; KR20130127515A; SI1663240T2; EA200600522A1; PT1663240E; KR101638999B1; EA014840B1; SI1663240T1; KR101539245B1; ES2542017T3; ES2542017T5; KR20110132475A

Abstract

The present invention concerns combinations of a pyrimidine containing NNRTI with nucleoside reverse transcriptase inhibitors and/or nucleotide reverse transcriptase inhibitors useful for the treatment of HIV infected patients or for the prevention of HIV transmission or infection.

Description

200524612 九、發明說明：【發明所屬之技術領域】本發明係有關一種含NNRTI之嘧啶與核苷逆轉錄酶抑制劑與/或核苷酸逆轉錄酶抑制劑之組合，其適用於治療感染HIV之患者或用於預防HIV傳播或感染。【先前技術】 15 20 儘管在引進H A A RT療法（高活性抗逆轉錄病毒療法)上已有長足進步，但HIV病毒對核苷逆轉錄酶抑制劑(>fRTIs)、非核苷逆轉錄酶抑制劑(NNRTIs)、核苦酸逆轉錄酶抑制劑(NtRTIs)、蛋白酶抑制劑，甚至最近之驊合抑制劑之抗性仍為療法失敗之主因。例如：接受抗HIV組合療法之患者中，有半數對治療沒有反應，其主因為病毒對所採用之一種致多種藥物出現抗性。此外，已發現抗性病毒出現在新感染之個體上，使此等未曾接受過藥物之患者所能選擇之療法受到極大限制。在2〇〇3年7月， =巴黎舉行之崎AIDS會議中，研究者在所提丨目前對細8 藥物之抗性所進行之最大研究中發現，歐洲有約⑽新感染之患者含有抗藥性菌株。舊金山之高危險市中心曾進行一項工型式驗來別疋抗性之分佈性。此試驗顯示，最高抗性程度達π%。、市面上可取知之許多種抗逆轉錄病毒劑之藥物動力學圖形醫療劑量。不良之藥物動力學圖形經常與抗逆〜毋谷解度性質結合，造成AIDS患者之高度服荜負者。此外，甚至二;Γ 或第一線療法特別不樂見醫師追加血料轉=雜合躲之AIDS^會促使復其對抗突變之度’以使該抗逆轉錄病毒劑得以恢負擔。追加血之有效性，其結果卻造成更高之服藥 ' 水/辰X亦提高患者對所採用療法不適應性之危 25 200524612 險，並增加副作用。目前已進行數種嘗試來設計組合療程。例如：蘭弗唆 (lamivudine)(—種核普RT抑制劑，亦稱為3TC)i 15〇 mg劑量與去弗咬(zidovudine)(—種核苷酸RT抑制劑，亦稱為AZT)之 5 300 mg劑量之組合，其係調配物成口服錠劑，一天投藥2次，或阿巴卡菲（abacavir)硫酸鹽在等於300 mg阿巴卡菲 (abacavir)(—種核苷RT抑制劑)之劑量下與蘭弗啶(lamivudine) 之150 mg劑量及去弗啶(zidovudine)之300 mg劑量之組合，其係調配成口服錠劑，一天投藥兩次。 10 WO 93/23021說明一種治療HIV感染之醫療組合中包含去弗啶（zidovudine)及一種可加強對抗原本可能對去弗啶 (zidovudine)產生抗性之HIV族群之抗病毒活性之藥劑。 WO 96/01110說明一種含去弗σ定（zid〇vudine)、蘭弗口定 (lamivudine)與洛維得(loviride)之三重組合，後者為α_ΑΡΑ類之 15 非核苷RT抑制劑。有關新穎抗逆轉錄病毒藥物之說明示於 am/ ⑽ 2003· Vol· 9 : 3, ρρ· 186-193。 03/016306明確揭示超過250種具有抑制HIV複製性質而可作為非核苷RT抑制劑(NNRTIs)之嘧啶衍生物，其有能力同 20 /時抑制野生型與突變型之複製。其中一種該NNRps為 / 4_[[4-[[4-(2_氰基乙烯基)-2,6·二甲基苯基]_胺基]_2^4基]胺給基]-芋基氰(本文中稱為TMC29)。WO〇3/0163〇6亦搞示合成此等化合物之方法。其亦揭示該NNRTIs與甚:典抗逆轉续病毒劑之組合，亦即蘇拉明（suramine)、本他咬(pentamidine)、賽本口定 25 (thymopentin)、卡塔普明（castanospermine)、葡聚糖（葡聚糖硫酸鹽）、福卡米（foscamet)-鈉（亞磷羧基曱酸三鈉）、去弗啶 (zidovudine)(3’_疊氮基-3，-去氧胸腺核苷，AZT)、達諾辛 200524612 (didanosine) (2丨，3丨_二-去氧肌苦；ddl)、賽他本(zaicitabine)(二去氧胞嘧啶核苷，ddC)、蘭弗啶(iamivudine)(2，-3，-二去氧-3，-硫雜胞哺咬核音’ 3TC)、斯弗咬(stavudine) (2’，3’_二去氫-3’·去氧胸腺核皆’ d4T)、阿巴卡菲⑽acavir)、尼拉本(nevirapine)(ii, 丙基-5，11·二氫·4-甲基-6H_二吡啶并_[3,2-b: 2，，3^][1，4]二吖呼-6-酮）、抑弗靈（efavirenz)、狄菲啶(delavirdine)、TMC120、TMC125、丹諾菲(tenofovir)、（3)-8-氣_4,5_6,7_四氫-5-甲基-6-(3-甲基-2_丁烯基)咪唑并-[4,5，l-jk][l，4]苯并二吖呼·2(1Η)-硫酮、α-[(2-硝基笨基)胺基]-2,6-二氯-苯乙醯胺、RO_5_3335、英達菲(indinavir)、利拿菲（ritonavir)、散克菲（saquinavir)、洛平菲（1〇pinavir) (ABT·378)、尼納菲(neiflnavir)、安普菲(&吨代⑽也）、頂ο%、 BMS-232632、VX-175、Τ-20、T_1249、AMD-31〇〇與羥基脲。主儘管現在已有組合療法，但仍然需要一種改良之抗逆轉錄病 15 20 :療法’更特定言之aids療法。不僅特別急需對野生型HIV病常有效之療法，而且亦需對日漸增多之一般抗性病毒之有效療法。目此第_線療法特別需要設計—種服藥負擔低之組合療法，其應可限钱壓抑抗藥性病毒復發，且可長财效使用。、本發明一項目的為提供一種包含一種以上醫療上有效之抗毒藥物之組合’該組合可長期用於未曾接受藥物治療之患者之第一線療法。 2明之目的亦在提供包含一種以上醫療上有效之抗逆轉圖^毒^之組合’其中該抗逆轉錄病毒藥物具有互補之抗性患者二療屏障，因此得以使未曾接受藥物治療之逆轉種以上醫療活性之抗物可-夭: 合中各該活性抗逆轉錄病毒藥天投樂一次，因此可降低患者之服藥負擔。 25 200524612 本發明另一項目的為提供一種包含一種以上醫療活性之抗逆轉錄病毒藥物之組合，其中組合中各該活性抗逆轉錄病毒藥物可共同調配。本發明另一項目的為提供一種包含一種以上醫療上活性抗 5 逆轉錄病毒藥物之組合，其中組合中各該醫療有效量之活性抗逆轉錄病毒藥物可共同調配成單--種醫藥調配物。本發明另一項目的為提供一種包含一種以上活性抗逆轉錄病毒藥物之組合，其中該組合可用於預防人類之HIV傳播或感染。 1〇本文中所摘錄之所有參考文獻均以引用之方式完全併入本文中。【發明内容】因此’本發明第一方面提供一種組合，其包含⑴TMC278或 15 其立體異構型；或其醫藥上可接受之鹽；或其前藥；與(ii)核苷逆轉錄酶抑制劑與/或核苷酸逆轉錄酶抑制劑；其中TMC278與核苷酸逆轉錄酶抑制劑與/或核苦逆轉錄酶抑制劑在一天投藥一次之劑量下，為醫療上有效之HIV抑制劑。因此，本發明第二方面提供一種組合，其包含⑴TMC278 2〇 *其立體異構型；或其醫藥上可接受之鹽；或其前藥；與⑻核苷逆，錄酶抑制劑；其中TMC278與核苦逆轉錄酶抑制劑在一天才又藥-次之劑量下，為醫療上有效之請抑制劑。本七月第一方面提供一種組合，其包含⑴或其立體異構型；或其醫藥上可接受之鹽；或其前藥物；與⑻核普酸 " 逆轉錄酶抑制劑；其中™⑽與核《逆轉錄酶抑制劑在一天投藥-次之劑量下，為醫療上有效之贈抑制劑。本發明第四方面提供一種三重組合，其包含⑴麗278或 200524612 其立體異構型；或其醫藥上可接受之鹽；或其前藥；與(ii)核苷逆轉錄酶抑制劑；與(出）核苷酸逆轉錄酶抑制劑；其中TMC278 與核苷酸逆轉錄酶抑制劑與核苷逆轉錄酶抑制劑在一天投藥一次之劑量下，為醫療上有效之HIV抑制劑。 5 本發明第五方面提供一種三重組合，其包含(i) TMC278或其立體異構型；或其醫藥上可接受之鹽；或其前藥；與出)核苷逆轉錄酶抑制劑；與(iii)不同於(ii)之核苷逆轉錄酶抑制劑之第二種核苷逆轉錄酶抑制劑；其中TMC278與該第一種與第二種核苷逆轉錄酶抑制劑在一天投藥一次之劑量下，為醫療上有效之HIV 10 抑制劑。另一方面，提供一種醫藥調配物，其包含醫藥上可接受之載劑與本文中明確說明之組合。本發明亦有關一種以本文中明確說明之組合作為HIV抑制劑之用途及其用於治療感染HIV之患者或用於預防HIV傳播或 15 感染上之用途。本發明之依據為發現TMC278係一種強效逆轉錄酶抑制劑，其具有極高之基因屏障，組合了有利之醫藥動力學圖形，可以一天投藥一次。已驚人地發現TMC278具有所有此等性質。此點並不尋常，因為無法預估特定藥物會在HIV-1基因組中選 20 擇何種突變，突變之病毒在藥物壓力下是否有任何存活機會，需要多少藥物方得以限制或壓抑此等突變之病毒復發，及此等藥物在何種投藥頻率下方得以壓抑突破藥物之基因屏障之抗性病毒之發展。 25 【實施方式】本文所採用術語，在一天投藥一次之劑量下，為醫療上有效之HIV抑制劑，意指該mv抑制劑適合每24小時投藥。術語，每 200524612 二小時，意指mv抑制劑可以每24小日紐藥—次，使血浆中，有效活性成分濃度，以便在24小時期間有效_爾感染。本發明所使狀HIV抑制劑可每24小時投藥。 TMC278或4-[[4·[[4-(2-氰基乙烯基)2,6二甲基苯基卜胺 5 土]2嘧啶基>胺基]笨基氰為已知之NNRTI，其可依 W003/016^)6之說明製備。TMc278可呈驗型使用，或較佳為呈。適之面藥上可射之鹽型，特定言之呈酸加成鹽型。醫藥上可接又之加成鹽型指醫療活性無毒性鹽型。酸加成鹽型之製法可由驗型經適當酸處理，如··無機酸，例如：氮函酸，例如·· 10 鹽酸、氳漠酸，等等；硫酸；硝酸；魏，等等；或有機酸，例如.乙酸、丙酸、羥基乙酸、2_經基丙酸、2_氧代丙酸、草酸、丙謂、琥賴、馬來酸、富馬酸、蘋果酸、酒石酸、請基-U,3-丙二紐、甲續酸、乙續酸、笨續酸、4·甲基苯確酸、環己胺續酸、2_經基苯甲酸、4-胺基_2_經基苯甲酸，等等。較適用於本發 15 明為鼠鹵酸鹽類，特定言之鹽酸鹽。 TMC278會出現立體異構型，更特定言之E_與厶異構型。兩種異構物均可用於本發明之組合。本文中不論何時提及之 TMC278均包括E-與Z-型，及其任何混合物。 TMC278較適用於本發明之型式為E-異構物，亦即 20 ⑹-4-[[4-[[4-(2_氰基乙烯基)-2,6·二曱基苯基]-胺基]-2-嘧啶基]- 胺基]-苯基氰(下文稱為E-TMC278)。TMC278之Z-異構物，亦即（Z)-4-[[4-[[4_(2-氰基乙烯基>2,6_二曱基苯基胺基]_2·嘧啶基]-胺基]-苯基氰(下文中稱為化合物Z—TMC278)亦可使用。其對野生型HIV-1具有相當高效力，但對抗單一及雙重突變株之活 25 性則低於異構物。表1出示TMC278之E與Z-異構物之IC50 值，以nM表示。 200524612 表1200524612 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a combination of NNRTI-containing pyrimidine and nucleoside reverse transcriptase inhibitor and / or nucleotide reverse transcriptase inhibitor, which is suitable for treating HIV infection Patients may be used to prevent HIV transmission or infection. [Previous technology] 15 20 Although there has been considerable progress in the introduction of HAA RT therapy (highly active antiretroviral therapy), the HIV virus inhibits nucleoside reverse transcriptase inhibitors (> fRTIs), non-nucleoside reverse transcriptase Resistance to agents (NNRTIs), ribopic acid reverse transcriptase inhibitors (NtRTIs), protease inhibitors, and even more recently inhibitors of conjugation inhibitors are still the main causes of treatment failure. For example, half of the patients who received anti-HIV combination therapy did not respond to treatment, mainly because the virus became resistant to one of the drugs used to cause it. In addition, the emergence of resistant viruses in newly infected individuals has greatly limited the options available to these patients who have not received the drug. In July 2003, at the Sakis AIDS conference held in Paris, the researchers found in the largest study currently conducted on the resistance of the 8 drugs, that about 30% of newly infected patients in Europe contained anti- Medicinal strains. A high-risk downtown in San Francisco has undergone a type test to identify the distribution of resistance. This test showed that the highest degree of resistance was π%. Pharmacokinetic patterns of many antiretroviral agents available in the market. Medical doses. Poor pharmacokinetic patterns are often combined with stress resistance and resolution properties, resulting in a high degree of service for AIDS patients. In addition, even two; Γ or first-line therapy is particularly unpleasant. Physician's additional blood transfer = AIDS of heterozygous hiding will promote its degree of resistance to mutation 'to make the antiretroviral agent affordable. The effectiveness of additional blood has resulted in higher medications. Water / Chen X also increases the risk of patients' incompatibility with the therapy used and increases side effects. Several attempts have been made to design a combination course. For example: lamivudine (a nuclear RT inhibitor, also known as 3TC) i 15 mg dose and zidovudine (a nucleotide RT inhibitor, also known as AZT) 5 300 mg dose combination, which is formulated as an oral lozenge, administered twice a day, or abacavir sulfate is equal to 300 mg abacavir (a nucleoside RT inhibitor ) Is combined with a 150 mg dose of lamivudine and a 300 mg dose of zidovudine, which are formulated as oral tablets and administered twice a day. 10 WO 93/23021 describes a medical combination for the treatment of HIV infections comprising zidovudine and an agent that enhances the antiviral activity of HIV populations that may be resistant to zidovudine. WO 96/01110 describes a triple combination containing zidovudine, lamivudine and loviride, the latter being a 15-nucleoside RT inhibitor of the α-APA class. A description of novel antiretroviral drugs is shown in am / ⑽ 2003 · Vol · 9: 3, ρρ · 186-193. 03/016306 clearly revealed that more than 250 kinds of pyrimidine derivatives that have the property of inhibiting HIV replication and can be used as non-nucleoside RT inhibitors (NNRTIs), have the ability to inhibit wild-type and mutant-type replication at 20 / hour. One of the NNRps is / 4 _ [[4-[[4- (2-_cyanovinyl) -2,6 · dimethylphenyl] _amino] _2 ^ 4yl] amine giving group] -taroyl Cyanide (referred to herein as TMC29). WO03 / 0163〇6 also shows a method for synthesizing these compounds. It also revealed the combination of the NNRTIs and the anti-retroviral agents, namely suramine, pentamidine, thymopentin, castanospermine, Dextran (dextran sulfate), foscamet-sodium (trisodium phosphorocarboxylate), zidovudine (3'_azido-3, -deoxythymidine AZT), Danoxin 200524612 (didanosine) (2 丨, 3 丨 _di-deoxymuscarinone; ddl), zaicitabine (dideoxycytosine nucleoside, ddC), lanphoridine (iamivudine) (2, -3, -dideoxy-3, -sulfur nucleus bite nuclear sound '3TC), stavudine (2', 3'_didehydro-3 '· deoxy Thymic nucleus are all 'd4T), abacafi⑽acavir), nevirapine (ii, propyl-5,11 · dihydro · 4-methyl-6H_dipyrido_ [3,2-b : 2, 3 ^] [1,4] diazepine-6-one), efavirenz, delavirdine, TMC120, TMC125, tenofovir, (3)- 8-Gas_4,5_6,7_Tetrahydro-5-methyl-6- (3-methyl-2-butenyl) imidazo- [4,5, l-jk] [l, 4] benzene Benzodiazepine · 2 (1Η) -thione α-[(2-Nitrobenzyl) amino] -2,6-dichloro-phenethylamine, RO_5_3335, Indinavir, ritonavir, saquinavir, 10pinavir (ABT · 378), neiflnavir, & Teflon, BMS-232632, VX-175, T-20, T_1249 , AMD-3100 and hydroxyurea. Although the Lord already has combination therapies, there is still a need for an improved antiretroviral disease 15 20: Therapy 'and more specifically aids therapy. Not only is there a particularly urgent need for treatments that are often effective against wild-type HIV, but also effective treatments for an increasing number of general resistant viruses. At present, the first line therapy needs to be designed—a combination therapy with a low burden of medication, which should be able to limit money to suppress the recurrence of drug-resistant viruses and can be used with long-term benefits. An object of the present invention is to provide a combination comprising more than one medically effective anti-drug, which can be used as a first-line therapy for a patient who has not received drug treatment for a long time. The purpose of 2 Ming is also to provide a combination containing more than one medically effective anti-reversal map ^ poison ^ 'wherein the antiretroviral drug has complementary resistance to the second-treatment barrier in patients with resistance, thus enabling the reversion of drugs that have never been treated with drugs. Medically active anti-cans-夭: Each of the active antiretroviral drugs in the combination is injected once a day, so it can reduce the burden of medication for patients. 25 200524612 Another item of the present invention is to provide a combination comprising more than one medically active antiretroviral drug, wherein each of the active antiretroviral drugs in the combination can be formulated together. Another item of the present invention is to provide a combination including more than one medically active anti-5 retroviral drug, wherein each of the medically effective amount of the active antiretroviral drug in the combination can be jointly formulated into a single-medicine formulation . Another item of the present invention is to provide a combination comprising more than one active antiretroviral drug, wherein the combination can be used for preventing HIV transmission or infection in humans. 10 All references cited herein are fully incorporated by reference. [Summary of the Invention] Therefore, 'the first aspect of the present invention provides a combination comprising ⑴TMC278 or 15 in a stereoisomeric form; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and (ii) nucleoside reverse transcriptase inhibition Agents and / or nucleotide reverse transcriptase inhibitors; TMC278 and nucleotide reverse transcriptase inhibitors and / or nuclear bitter reverse transcriptase inhibitors are medically effective HIV inhibitors at a dose of once a day . Therefore, the second aspect of the present invention provides a combination comprising ⑴TMC278 2 ** its stereoisomeric form; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and a nucleoside inverse enzyme recording enzyme; wherein TMC278 With nuclear bitter reverse transcriptase inhibitors in one day and the second dose, the inhibitors are medically effective. The first aspect of this July provides a combination comprising thallium or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and thorium nuclear acid " a reverse transcriptase inhibitor; of which With the nuclear "reverse transcriptase inhibitor", it is a medically effective inhibitor at a dose of once a day. The fourth aspect of the present invention provides a triple combination, which comprises Lili 278 or 200524612, a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and (ii) a nucleoside reverse transcriptase inhibitor; and (Out) nucleotide reverse transcriptase inhibitor; TMC278, nucleotide reverse transcriptase inhibitor and nucleoside reverse transcriptase inhibitor are medically effective HIV inhibitors at a dose of once a day. 5 The fifth aspect of the present invention provides a triple combination comprising (i) TMC278 or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and) a nucleoside reverse transcriptase inhibitor; and (iii) a second nucleoside reverse transcriptase inhibitor different from the nucleoside reverse transcriptase inhibitor of (ii); wherein TMC278 and the first and second nucleoside reverse transcriptase inhibitors are administered once a day At the dosage, it is a medically effective HIV 10 inhibitor. In another aspect, a pharmaceutical formulation is provided that comprises a pharmaceutically acceptable carrier in combination with a formulation explicitly described herein. The invention also relates to the use of a combination explicitly described herein as an HIV inhibitor and its use in the treatment of patients infected with HIV or in the prevention of HIV transmission or infection. The basis of the present invention is to discover that TMC278 is a potent reverse transcriptase inhibitor, which has a very high genetic barrier, combines favorable pharmacokinetic patterns, and can be administered once a day. It has been surprisingly found that TMC278 has all these properties. This is unusual because it is not possible to predict which mutations a particular drug will choose in the HIV-1 genome, whether the mutated virus has any chance of survival under drug pressure, and how many drugs are needed to limit or suppress these mutations. The recurrence of viruses and the frequency under which these drugs are administered can suppress the development of resistant viruses that break the drug's genetic barrier. [Embodiment] The term used herein is a medically effective HIV inhibitor at a dose of once a day, which means that the mv inhibitor is suitable for administration every 24 hours. The term, two hours per 200524612, means that the mv inhibitor can be used as a new drug every 24 hours, so that the concentration of the active ingredient in the plasma can be effective in a 24-hour period. The HIV inhibitor used in the present invention can be administered every 24 hours. TMC278 or 4-[[4 · [[4- (2-cyanoethenyl) 2,6dimethylphenylblymine 5 earth] 2pyrimidyl > amino] benzyl cyanide is known as NNRTI, which It can be prepared according to the instructions of W003 / 016 ^) 6. TMc278 can be used in a test form, or preferably. The salt type that can be sprayed on the noodles, especially the acid addition salt type. Additive salt type in medicine refers to medically active non-toxic salt type. The method of acid addition salt type can be treated by appropriate acid treatment, such as inorganic acids, such as: nitrogen acid, such as hydrochloric acid, desertic acid, etc .; sulfuric acid; nitric acid; Wei, etc .; or Organic acids, for example, acetic acid, propionic acid, glycolic acid, 2-acrylic acid, 2-oxopropionic acid, oxalic acid, propane, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, benzyl -U, 3-propanedioic acid, formic acid, acetic acid, stearic acid, 4-methylbenzoic acid, cyclohexylamino acid, 2-Aminobenzoic acid, 4-Amino-2_A Benzoic acid, and so on. It is more suitable for the present invention to be rat halates, specifically the hydrochloride. TMC278 will appear stereo isomeric, more specifically E_ and hydrazone isomeric. Both isomers can be used in the combination of the present invention. Whenever mentioned herein, TMC278 includes E- and Z-types, and any mixtures thereof. TMC278 is more suitable for the present invention in the form of E-isomer, that is, 20 ⑹-4-[[4-[[4- (2-_cyanovinyl) -2,6 · difluorenylphenyl]- Amino] -2-pyrimidinyl] -amino] -phenylcyanine (hereinafter referred to as E-TMC278). The Z-isomer of TMC278, that is, (Z) -4-[[4-[[4_ (2-cyanovinyl > 2,6_diamidinophenylamino] _2 · pyrimidinyl]- Amine] -phenyl cyanide (hereinafter referred to as compound Z-TMC278) can also be used. It is quite potent against wild-type HIV-1, but its activity against single and double mutants is lower than that of isomers. Table 1 shows the IC50 values of E and Z-isomers of TMC278, expressed in nM. 200524612 Table 1

55

10 本文中不論何時提及之TMC278之匕型（亦即e_tmc278)，均包括純E-異構物或以E_型為主之e-與z_型之任物，亦即異構物混合物中之E-型含量占50%以上或特定言之肋^ 以上或甚至超過90%以上。特別有利為實質上不含z_型之型。此時，”實質上不含"意指E-Z-混合物中沒有或幾乎沒有z_ 型，例如：E-型含量占高達90%，特定言之95%或甚至98%或之異構物混合物。同樣地，本文中不論何時提及之TMC278 之厶型（亦即Z-TMC278)，均包括純z_異構物或以&型為主之 E-與Z_型之任何異構物混合物，亦即異構物混合物中之z_型含里占50%以上或特定言之80%以上或甚至超過90%以上。特別有利為實質上不含E-型之Z-型。此時，，實質上不含，意指E-Z-混合物中沒有或幾乎沒有E-型，例如：Z·型含量占高達90〇/〇，特定言之95%或甚至98%或99%之異構物混合物。本發明亦包括使用TMC278之異構物型之鹽，特定言之上述鹽類。特別有利為Z-TMC278鹽酸鹽與明確言之E-TMC278 -11- 15 200524612 鹽酸鹽。核苷酸逆轉錄酶抑制劑與核苷逆轉錄酶抑制劑宜在逆轉錄酶中選擇*會對TMC278產生抗性之突變。因此本文中所說明特別有利之任何組合，其中（1)TMC278與核苷/核苷酸逆轉錄酶抑制劑或抑制劑群為醫療上有效之HIV抑制劑之劑量可一天投藥-次’與(2)核普/核:g：酸逆轉錄酶抑制劑或抑制劑群在逆轉錄酶中選擇不會對TMC278產生抗性之突變。、明確言之，在一項具體實施例中提供一種組合，其包含 ⑴TMC278或其立體異構型或醫藥上可接《之鹽或其前藥，與⑼ 核皆逆轉_抑侧，其巾（1)TMC278與㈣逆轉麟抑制劑在一天投藥一次之劑量下，為醫療上有效之HIV抑制劑，與(2) 核苷逆轉錄酶抑制劑在逆轉錄酶中選擇不會對TMC278產生抗性之突變。另一項具體實施例中，提供一種組合，其包含⑴TMC278 或其立體異構物型或醫藥上可接受之鹽或其前藥，與⑼核苷酸逆轉錄酶抑制劑，其中⑴TMC278與核苷酸逆轉錄酶抑制劑在一天投藥一次之劑量下，為醫療上有效之mv抑制劑，與(2)核苷酸逆轉錄酶抑制劑在逆轉錄酶中選擇不會對TMC278產生抗性之突變。較佳具體實施例中，提供一種三重組合，其包含⑴TMC278 或其立體異構型或醫藥上可接受之鹽或其前藥，與⑴)核苷逆轉錄酶抑制劑，與(111)核苷酸逆轉錄酶抑制劑，其中與核苷酸逆轉錄酶抑制劑與核苷逆轉錄酶抑制劑在一天投藥一次之劑量下，為醫療上有效之HIV抑制劑，與(2)核苷酸逆轉錄酶抑制劑與核苷逆轉錄酶抑制劑在逆轉錄酶中選擇不會對 TMC278產生抗性之突變。另一項較佳具體實施例中，提供一種三重組合，其包含 -12- 200524612 (i)TMC278或其立體異構型或醫藥上可接受之鹽或其前藥，與⑼· 核苷逆轉錄酶抑制劑，與(iii)不同於(ii)之核苷逆轉錄酶抑制劑之第二種核苷逆轉錄酶抑制劑；其中（1)TMC278與核苷逆轉錄酶抑制劑在一天投藥一次之劑量下，為醫療上有效之mv抑制 5 劑’與(2)核苷逆轉錄酶抑制劑在逆轉錄酶中選擇不會對TMC278 產生抗性之突變。較適用於本發明之組合之核苷酸逆轉錄酶抑制劑包括丹諾菲(tenofovir)與其前藥丹諾菲(tenofovir)二異丙氧基(dis〇pr〇xil) 富馬酸鹽。 10 丹諾菲(tenofovir)為目前可自市面上取得之腺苷核苷酸類似鲁物’具有對抗逆轉錄病毒之活性。丹諾菲(tenofovir)二異丙氧基富馬酸鹽（丹諾菲(tenofovir)DF)為丹諾菲(tenofovir)之前藥，一天口服一次。丹諾菲(tenofovir) DF必需水解成ANP類似物後，磷酸化成活性二磷酸酯部份基團，方具有抗病毒活性[Arimim 15 Antiviral Chemistry and Chemotherapy 1997, 8 :6(557-564)；10 Whenever mentioned herein, the dagger type of TMC278 (ie, e_tmc278) includes pure E-isomers or any of the e- and z_-types that are mainly E_-types, that is, mixtures of isomers. The E-type content in it is more than 50%, or more specifically, more than 90% or even more than 90%. It is particularly advantageous to be a type substantially free of the z-type. At this time, "substantially free" means that there is no or almost no z-type in the EZ-mixture, for example, the E-type content accounts for up to 90%, specifically 95% or even 98% or a mixture of isomers. Similarly, whenever this article refers to the T-type of TMC278 (that is, Z-TMC278), it includes pure z-isomers or any isomer mixtures of E- and Z-types dominated by & That is, the z-type in the isomer mixture contains more than 50% or specifically 80% or even more than 90%. It is particularly advantageous to be a Z-type that does not substantially contain E-type. At this time, , Substantially free, means that there is no or almost no E-type in the EZ-mixture, for example: Z-type content accounts for up to 90/0, specifically 95% or even 98% or 99% of the isomer mixture The invention also includes the use of salts of the isomeric form of TMC278, in particular the aforementioned salts. Particularly advantageous are Z-TMC278 hydrochloride and explicitly E-TMC278 -11-15 200524612 hydrochloride. Nucleotides Reverse transcriptase inhibitors and nucleoside reverse transcriptase inhibitors should preferably be selected among the reverse transcriptases * Mutations that are resistant to TMC278. Therefore, the descriptions herein are particularly Advantageously any combination wherein the dose of (1) TMC278 and a nucleoside / nucleotide reverse transcriptase inhibitor or inhibitor group is a medically effective HIV inhibitor can be administered once a day 'and (2) nuclear universal / nuclear : g: acid reverse transcriptase inhibitors or groups of inhibitors choose mutations in the reverse transcriptase that do not develop resistance to TMC278., Specifically, in a specific embodiment, a combination is provided, which comprises ⑴TMC278 or Stereoisomeric or pharmacologically acceptable salt or its prodrugs, and the nucleus are reversed _ inhibitory side, its towel (1) TMC278 and osmium reversion Lin inhibitors are medically effective at a dose of once a day HIV inhibitor, and (2) a nucleoside reverse transcriptase inhibitor selected from the reverse transcriptase mutations that do not have resistance to TMC278. In another specific embodiment, a combination is provided, which comprises ⑴TMC278 or a stereo Isomers or pharmaceutically acceptable salts or their prodrugs, and ⑼nucleotide reverse transcriptase inhibitors, of which CTMC278 and nucleotide reverse transcriptase inhibitors are medically effective at a dose of once a day Mv inhibitor, with (2) nucleotide reverse transcription The inhibitor selects a mutation in the reverse transcriptase that does not cause resistance to TMC278. In a preferred embodiment, a triple combination is provided, which comprises ⑴TMC278 or a stereoisomer thereof or a pharmaceutically acceptable salt or a prodrug thereof. , And ⑴) a nucleoside reverse transcriptase inhibitor and a (111) nucleotide reverse transcriptase inhibitor, wherein the nucleotide reverse transcriptase inhibitor and the nucleoside reverse transcriptase inhibitor are administered at a dose of once a day As a medically effective HIV inhibitor, (2) a nucleotide reverse transcriptase inhibitor and a nucleoside reverse transcriptase inhibitor are selected among reverse transcriptase mutations that do not have resistance to TMC278. In another preferred embodiment, a triple combination is provided, which comprises -12-200524612 (i) TMC278 or a stereoisomeric or pharmaceutically acceptable salt thereof or a prodrug thereof, and reverse transcription of ⑼ · nucleoside Enzyme inhibitor, and (iii) a second nucleoside reverse transcriptase inhibitor different from (ii) a nucleoside reverse transcriptase inhibitor; of which (1) TMC278 and a nucleoside reverse transcriptase inhibitor are administered once a day At the dosage, 5 agents that are medically effective mv 'and (2) a nucleoside reverse transcriptase inhibitor are selected among the reverse transcriptase mutations that do not produce resistance to TMC278. Nucleotide reverse transcriptase inhibitors that are more suitable for the combination of the present invention include tenofovir and its prodrug tenofovir diisopropoxyl fumarate. 10 Tenofovir is an adenosine nucleotide analogue that is currently available on the market and has antiretroviral activity. Tenofovir diisopropoxy fumarate (tenofovir DF) is a prodrug of tenofovir and is taken orally once a day. Tenofovir DF must be hydrolyzed to an ANP analog, and then phosphorylated into an active diphosphate moiety to have antiviral activity [Arimim 15 Antiviral Chemistry and Chemotherapy 1997, 8: 6 (557-564);

Fridland 等人· ΛαβαλΆ 1997，34]。前藥進入淋巴球或巨嗟細胞中後’全部轉化成類似物母體丹諾菲(tenofovir)，填酸化成單-與二-磷酸酯代謝物。負責此藥物之鱗酸化作用之細胞酵 φ 素為腺嘌呤核苷酸激酶與核苷二磷酸激酶[Robbins等人. 20 Antimicrobial Agents and Chemotherapy 1995, 39:10 (2304-2308)；Fridland et al. ΛαβαλΆ 1997, 34]. After the prodrug enters the lymphocytes or macrophage cells, all of the prodrugs are converted into the analog parent tenofovir, which is filled with acid to form mono- and di-phosphate metabolites. The cellular enzyme responsible for the scale acidification of this drug is adenine nucleotide kinase and nucleoside diphosphate kinase [Robbins et al. 20 Antimicrobial Agents and Chemotherapy 1995, 39:10 (2304-2308);

Kobbins 等人· Antimicrobial Agents amd Chemotherapy 1998, 42 :3 (612-617)]。不同於其他核苷類似物，如：去弗^(zidovudine) 或斯弗啶(stavudine)兩者之磷酸化作用均依賴細胞循環，丹諾菲 (tenofovir)之有效填酸化作用在靜止及循環中之周邊血液淋巴球 25 中均可進行[Robbins等人· 1998]。丹諾菲(tenofovir)可在不同 HIV目標細胞型態中抑制HIV-1複製，包括原生人類血液淋巴球與巨嗤細胞[Pemo 等人· 1992 (289-304); -13- 200524612Kobbins et al. Antimicrobial Agents amd Chemotherapy 1998, 42: 3 (612-617)]. Unlike other nucleoside analogs, such as: zidovudine or stavudine, the phosphorylation of both depends on the cell cycle, and the effective acidification of tenofovir is at rest and in circulation Peripheral blood lymphocytes can be performed in 25 [Robbins et al. 1998]. Tenofovir inhibits HIV-1 replication in different HIV target cell types, including native human hemolymph and giant cymbal cells [Pemo et al. 1992 (289-304); -13- 200524612

Perno 等人· Mo/ecw/arP/zarmaco/ogy 1996, 50 :2 (359-366)]。丹諾菲（tenofovir)二磷酸之主要目標為逆轉錄酶(RT)。丹諾菲 (tenofovir)二磷酸為去氧腺苷三磷酸進入新生之前病毒DNA鍵中之競爭性抑制劑。丹諾菲(tenofovir)二填酸抑制HIV-1 RT之抑 5 制常數為約〇·9 μΜ，若該類似物進入生長中病毒DNA鏈中時，其可肖b終止病毒鍵進一步延長。丹諾菲(tenofovir)抑制病毒汉了之有效性遠高於其抑制細胞DNA聚合酶之有效性[Suo等人 ⑽nza/ CAemzWr;; 1998, 273 ; 42 (2750-2758)]。在淋巴球與巨噬細胞之細胞型態(MT-2、CEM、ACH8)中抑制多種 10 不同HIV_1菌株複製達50%(EC50)時所需濃度範圍為〇·2至 10μΜ。抗病拳效果可在丹諾菲(tenofovir)之無毒劑量下達成(選擇性指數範圍為100至2000)。丹諾菲(tenofovir)DF目前可取得 300 mg錠劑，一天投藥一次。病毒於活體外對丹諾菲(tenofovir)抗性之出現速度緩慢。表 15 現K65R突變之重組病毒於活體外對丹諾菲(tenofovir)之感受性降低 3 倍。[Cherrington 等人 /加⑼⑽ Antimicrobial Agents and Chemotherapy 1997, 37 th]。Μ注意，在 RT上表現M184V蘭弗唆(lamivudine)·相關抗性突變之臨床HIV 菌株於活體外對丹諾菲(tenofovir)展現野生型或提高之感受性， 2〇與其突變株酵素之Ki變化無關[Miller等人Perno et al. Mo / ecw / arP / zarmaco / ogy 1996, 50: 2 (359-366)]. The main target of tenofovir diphosphate is reverse transcriptase (RT). Tenofovir diphosphate is a competitive inhibitor of viral DNA bonds before deoxyadenosine triphosphate enters newborns. The inhibitory constant of tenofovir dibasic acid to inhibit HIV-1 RT is about 0.9 μM. If the analogue enters the growing viral DNA chain, it can further terminate the viral bond. Danofovir (tenofovir) is much more effective at inhibiting viral infection than it is at inhibiting cellular DNA polymerase [Suo et al. ⑽nza / CAemzWr ;; 1998, 273; 42 (2750-2758)]. In the cell types of lymphocytes and macrophages (MT-2, CEM, ACH8), the required concentration range for inhibition of multiple 10 different HIV_1 strains to 50% (EC50) is from 0.2 to 10 μM. The anti-disease effect can be achieved at a non-toxic dose of tenofovir (selectivity index range is 100 to 2000). Tenofovir DF is currently available in 300 mg lozenges and is administered once a day. Virus resistance to tenofovir appears slowly in vitro. Table 15 Recombinant K65R mutant virus has three-fold reduced in vitro susceptibility to tenofovir. [Cherrington et al / Plus Antimicrobial Agents and Chemotherapy 1997, 37 th]. Note that clinical HIV strains exhibiting M184V lamivudine-related resistance mutations on RT exhibited wild-type or improved susceptibility to tenofovir in vitro, and Ki changes in enzymes of their mutant strains Not relevant [Miller et al.

Conference on Antimicrobial Agents amd Chemotherapy \99名]。新生之恆河猴接種猿類免疫缺乏症病毒後3周起，使用丹諾菲 (tenofovir)長期治療(5至15週)(劑量30 mg/kg)時，使所出現之 SIV對丹諾菲(tenofovir)之感受性下降約5倍[Van Rompay等人 25 Antimicrobial Agents and Chemotherapy 1996， 40 ： 11(2586-2591)]。這種低度抗性與K65R突變之出現有關。較佳具體實施例中，提供一種組合，其包含(i) TMC278或 200524612 其立體異構型或醫藥上可接受之鹽或其前藥，與⑻丹諾菲 (tenofovnr)或其前藥丹諾菲(ten〇f〇vir)二異丙氧基富馬酸鹽，其中 TMC278與丹諾菲(tenof〇vir)或其前藥丹諾菲細—的二^丙氧基富馬酸鹽在-天投藥一次之劑量下，為醫療上有效之請 5 抑制劑。另一項較佳具體實施例中，提供一種三重組合，其包含 ⑴TMC278或其立體異構型或醫藥上可接受之鹽或其前藥，與⑻ 核苷逆轉錄酶抑制劑與(iii)丹諾菲(ten〇f〇vir)二異丙氧基富馬酸鹽，其中TMC278與核苷逆轉錄酶抑制劑與丹諾菲(ten〇f〇vir)二 0 異丙氧基富馬酸鹽在一天投藥一次之劑量下，為醫療上有效之 HIV抑制劑。本發明組合可使用之較佳核苷逆轉錄酶抑制劑包括阿巴卡菲(abacavir)或其醫藥上可接受之鹽、恩奇本卜加如咖⑹）、消旋性FTC與蘭弗咬(lamivudine)(亦稱為3TC)。 5 恩奇本(emtricitabine)或㈠-FTC為消旋性FTC或(土)-順式-4- fe基_5_氟小[2_(經曱基)_1，3_氧硫戊環I基]^(出)』密咬酮(FTc) 之左旋(-)對映異構物。其係可自商品取得之核苷類似物，具有對抗 HIV-1 之活性[Hoong 等人c/ie論吵 1992 (5563-5565) ; Jeong 等人 /⑽而/ CT^m加1993，〇 36:2 (181-195) ； Vm Roey 等尺 Antiviral Chemistry and 1993, 4 :6 (369-375)]。FTC 之㈠♦對映異構物之活體外抗HIV-1活性據報告指出，高於(+)_β_對映異構物之2〇倍’且(+)-對映異構物對脊髓子代細胞之毒性顯著高於對映異填物[Schinazi 等人 Antimicrobial Agents and Chemotherapy ; 1992, 36 :11 (2423-2431 )]。HIV-1 對 FTC 之抗性潛力之分析法係由病毒於人類PBMCs與MT-2細胞中，在逐漸提高藥物濃度下進行一系列傳代下進行。經過兩次或多次感染循環後，複製 200524612 之病毒族群中會顯著出現高抗藥性之HIV-l變異株。衍生自抗藥性病毒粒子之RT對FTC之5，-三磷酸鹽之感受性比衍生自藥物感受性病毒母株之酵素低15至50倍。由抗性病毒擴增得到之RT基因之DMA序列分析一致證 5 實，字碼子 184 由 Met (ATG)突變成 Val(GTG 或 GTA)[Schinazi 專尺 Antimicrobial Agents and Chemotherapy \99?>, YJ ; 4 (875-881) ； Tisdale 等人及以1993, 20 :Suppl 1 ;Conference on Antimicrobial Agents amd Chemotherapy \ 99 names]. Newborn rhesus monkeys were immunized with simian immunodeficiency virus from 3 weeks, and the long-term treatment of tenofovir (5 to 15 weeks) (dose 30 mg / kg) was used to make the SIV appear on Danofi (tenofovir) decreased about 5 times [Van Rompay et al. 25 Antimicrobial Agents and Chemotherapy 1996, 40: 11 (2586-2591)]. This low resistance is related to the appearance of the K65R mutation. In a preferred embodiment, a combination is provided which comprises (i) a stereoisomeric or pharmaceutically acceptable salt of TMC278 or 200524612 or a prodrug thereof, and tenofovnr or a prodrug of Dano Pheno (vir) diisopropoxy fumarate, of which TMC278 and danofo (tenofovir) or its prodrug danofo di-propoxy fumarate are in- It is medically effective at the dosage of once a day. 5 inhibitors. In another preferred embodiment, a triple combination is provided, which comprises ⑴TMC278 or a stereoisomeric or pharmaceutically acceptable salt thereof or a prodrug thereof, and ⑻ a nucleoside reverse transcriptase inhibitor and (iii) Dan Tenfofir diisopropoxy fumarate, of which TMC278 and nucleoside reverse transcriptase inhibitors and tenfofir di0 isopropoxy fumarate It is a medically effective HIV inhibitor at a dose of once a day. Preferred nucleoside reverse transcriptase inhibitors that can be used in combination with the present invention include abacavir or a pharmaceutically acceptable salt thereof, Enkibenga, such as calyx), racemic FTC, and Lange Bite (lamivudine) (also known as 3TC). 5 Emtricitabine or ㈠-FTC is a racemic FTC or (Earth) -cis-4- feyl_5_fluorosmall [2_ (Ethyl) _1,3_oxetanyl I ] ^ (出) "L-(-) enantiomer of ptidone (FTc). It is a nucleoside analogue that is available from commercial products and has anti-HIV-1 activity [Hoong et al. C / ie Talk No. 1992 (5563-5565); Jeong et al./⑽ Er / CT ^ m plus 1993, 〇36 : 2 (181-195); Vm Roey Isometric Antiviral Chemistry and 1993, 4: 6 (369-375)]. The in vitro anti-HIV-1 activity of FTC enantiomers has been reported to be 20 times higher than (+) _ β_enantiomers and (+)-enantiomers against spinal cord Progeny cells are significantly more toxic than enantiomeric [Schinazi et al. Antimicrobial Agents and Chemotherapy; 1992, 36:11 (2423-2431)]. The analysis of the resistance potential of HIV-1 to FTC was performed by a series of passages in human PBMCs and MT-2 cells with increasing drug concentration. After two or more cycles of infection, HIV-l variants with high drug resistance will be noticeably present in the virus population that replicated 200524612. The sensitivity of RT derived from drug-resistant virus particles to FTC 5,3-triphosphate is 15 to 50 times lower than the enzyme derived from drug-sensitive virus mother strains. The DMA sequence analysis of the RT gene amplified by the resistant virus is consistent with the 5 evidences. The word code 184 is mutated from Met (ATG) to Val (GTG or GTA). 4 (875-881); Tisdale et al. And 1993, 20: Suppl 1;

Smith 等人 /⑽，似/ 〇/F/ra/ogy 1997, 71 :3(2357-2362) ; Harrer 專 k Journal of Infectious Diseases \996，\Ί?> ..2 {ΑΊβ^ΑΊ9、·， 10 'Tisdale 等尺 Proceedings of the National Academy of Sciences of 1993, 90 :12 (5653-5656)]。基於感染 HIV之患者中逆轉錄酶之YMDD觀察到此單一突變，因此㈠-FTC並不適合單一療法，且需要與其他抗逆轉錄病毒劑組合投藥，以有效治療感染HIV之患者。恩奇本(emtricitabine)可取 15 得200mg膠囊，一天投藥一次。蘭弗^(lamivudine)之化學名稱為㈠-2’，3’-二去氧_3’-硫雜胞嘧啶核苷，且說明於例如：EP-382 526，為一種抗病毒核苷類似物。其亦為一種已詳細確認且有用之抗逆轉錄病毒劑，可自商品取得例如：150 mg 口服鍵劑。亦可在商品上取得蘭弗咬 20 (lamivudine)與去弗咬（zidovudine)之組合（300 mg 去弗口定 (zidovudine)/150 mg 蘭弗啶（lamivudine))，及與蘭弗口定 (lamivudine)與阿巴卡菲(abacavir)硫酸鹽之組合(300 mg去弗α定 (zidovudine)/150 mg 蘭弗^(lamivudine)/300 mg 當量阿巴卡菲 (abacavir)) ° 25 阿巴卡菲(abacavir)為已詳細確認且有用之抗逆轉錄病毒劑，可自商品取得例如··阿巴卡菲(abacavir)硫酸鹽之口服液，其強度等於20 mg阿巴卡菲（abacavir)鹼/ml，或阿巴卡菲 200524612 (abacavir)硫酸鹽之口服錠劑，其強度等於300mg阿巴卡菲 (abacavir)鹼。亦可在商品上取得阿巴卡菲(abacavir)硫酸鹽與蘭弗啶(lamivudine)及去弗啶(zidovudine)之組合(300 mg去弗啶 (zidovudine)/150 mg 蘭弗啶(lamivudine)/300 mg 當量阿巴卡菲 5 (abacavir)) 〇阿巴卡菲(abacavir)為一種具有強力選擇性抗HIV活性之碳環核苷。呈光學活性型之阿巴卡菲(abacavir)揭示於EP-434 450 中。絕對立體化學組態未明確之阿巴卡菲(abacavir)順式異構物說明於EP-349 242。阿巴卡菲(abacavir)為目前所發展之最強效 10 NRTI。在短期之阿巴卡菲(abacavir)單一療法後，平均可使病毒量降低1·4 log 10 RNA套數/ml以上。在活體外，抗性病毒無法被阿巴卡菲（abacavir)快速選出。野生型或去弗啶(zidovudine)_ 抗性HIV-1菌株需在MT-4細胞中經過8至10次傳代後，方可觀察到其對阿巴卡菲(abacavir)之感受性顯著下降。在於活體外 15 傳代期間，使用阿巴卡菲(abacavir)在HIV逆轉錄酶(RT)字碼子 65R、74V、115F與/或184V選出一組抗性突變，且HIV之實驗至菌株需要此等突變組合方可使阿巴卡菲(abacavir)之感受性下降10倍。當提高阿巴卡菲(abacavir)濃度時，在HIV-1傳代時所檢測到之第一種突變為M184V，其僅使HIV-1感受性下降3倍。 20 對3TC之表型抗性及/或184V突變之存在並未防止病毒量對阿巴卡菲(abacavir)療法之反應。對多重核苷之抗性與對阿巴卡菲 (abacavir)之反應降低或缺乏有關[Kumar等人如— dgenh 1999，43:3 (603-608) ; Lanier 等人Smith et al./⑽, like / 〇 / F / ra / ogy 1997, 71: 3 (2357-2362); Harrer Journal of Infectious Diseases \ 996, \ Ί? &Gt; .. 2 {ΑΊβ ^ ΑΊ9, · , 10 'Tisdale Isometric Proceedings of the National Academy of Sciences of 1993, 90:12 (5653-5656)]. This single mutation was observed with YMDD of reverse transcriptase in HIV-infected patients, so ㈠-FTC is not suitable for monotherapy and needs to be administered in combination with other antiretroviral agents to effectively treat HIV-infected patients. Emtricitabine can take 15 to get 200mg capsules, once a day. The chemical name of lamivudine is ㈠-2 ', 3'-dideoxy_3'-thiacytosine nucleoside, and is described in, for example, EP-382 526, which is an antiviral nucleoside analog . It is also a well-established and useful antiretroviral agent that can be obtained from commercial products such as: 150 mg oral bond. A combination of lamivudine 20 and zidovudine (300 mg zidovudine / 150 mg lamivudine) is also available on the product. lamivudine) and abacavir sulfate combination (300 mg zidovudine / 150 mg lamivudine / 300 mg equivalent abacavir) ° 25 abacavir Abacavir is a well-recognized and useful antiretroviral agent. Oral solutions of abacavir sulfate can be obtained from commercial products. Its strength is equal to 20 mg of abacavir base. / ml, or oral tablet of abacavir 200524612 (abacavir) sulfate, its strength is equal to 300 mg of abacavir base. Combinations of abacavir sulfate with lamivudine and zidovudine (300 mg zidovudine / 150 mg lamivudine / 300 mg equivalent of abacavir 5 o Abacavir is a carbocyclic nucleoside with strong selective anti-HIV activity. Abacavir, which is optically active, is disclosed in EP-434 450. Abacavir cis isomers whose absolute stereochemical configuration is unknown are described in EP-349 242. Abacavir is the most powerful 10 NRTI currently developed. After short-term abacavir monotherapy, the average amount of virus can be reduced by more than 1.4 log 10 RNA sets / ml. In vitro, resistant viruses cannot be quickly selected by abacavir. The wild-type or zidovudine_resistant HIV-1 strain needs 8 to 10 passages in MT-4 cells before it can observe a significant decrease in its sensitivity to abacavir. During 15 passages in vitro, a set of resistance mutations were selected using the abacavir in HIV reverse transcriptase (RT) coders 65R, 74V, 115F, and / or 184V, and this is required for HIV experiments to the strain The combination of mutations can decrease the sensitivity of abacavir by 10 times. When the abacavir concentration was increased, the first mutation detected at the time of HIV-1 passage was M184V, which only reduced HIV-1 sensitivity by a factor of three. 20 Phenotypic resistance to 3TC and / or the presence of 184V mutations did not prevent the amount of virus from responding to abacavir therapy. Resistance to multiple nucleosides is associated with reduced or lack of response to abacavir [Kumar et al., Eg — dgenh 1999, 43: 3 (603-608); Lanier et al.

International Conference on Retroviruses and Opportunistic 25 Infections 1998, 5th:Chicago ； 1999 年 4 月 16 日發表]。較佳具體實施例中，提供一種組合，其包含(i)TMC278或其立體異構型；或其醫藥上可接受之鹽；或其前藥，與(ii)恩奇本 200524612 (emtricitabine)，其中 TMC278 與恩奇本(emtricitabine)在一天投藥一次之劑量下，為醫療上有效之mv抑制劑。較佳具體實施例中，提供一種組合，其包含⑴TMC278或其立體異構型；或其醫藥上可接受之鹽；或其前藥；及(ii)蘭弗 5 啶(lamivudine)，其中TMC278與蘭弗啶(lamivudine)在一天投藥一次之劑量下，為醫療上有效之HIV抑制劑。另一項較佳具體實施例中，提供一種組合，其包含⑴ TMC278或其立體異構型；或其醫藥上可接受之鹽；或其前藥；與⑼阿巴卡菲(abacavir)或其醫藥上可接受之鹽，其特徵在於 10 ™C278與阿巴卡菲(abacavir)在一天投藥一次之劑量下，為醫療上有效之HIV抑制劑。另一項較佳具體實施例中，提供一種組合，其包含⑴ TMC278或其立體異構型；或其醫藥上可接受之鹽；或其前藥；與⑼阿巴卡菲(abacavir)硫酸鹽，其特徵在於丁“^冗與阿巴卡 15 菲(abacavir)硫酸鹽在一天投藥一次之劑量下，為醫療上有效之 HIV抑制劑。另一項較佳具體實施例中，提供一種三重組合，其包含 (i)TMC278或其立體異構型；或其醫藥上可接受之鹽；或其前藥；與(ii)恩奇本(emtricitabine)，與(iii)核苷酸逆轉錄酶抑制 20 劑，其中TMC278與核苷酸逆轉錄酶抑制劑與恩奇本 (emtricitabine)在一天投藥一次之劑量下，為醫療上有效之mv 抑制劑。另一項較佳具體實施例中，提供一種三重組合，其包含 (i)TMC278或其立體異構型；或其醫藥上可接受之鹽；或其前 25 藥；與⑼蘭弗啶(lamivudine)，與⑽核苷酸逆轉錄酶抑制劑，其中TMC278與核苷酸逆轉錄酶抑制劑與蘭弗啶(iamivudine)在一天投藥一次之劑量下，為醫療上有效之HIV抑制劑。 200524612 另一項較佳具體實施例中，提供一種三重組合，其包含 ⑴TMC278或其立體異構型；或其醫藥上可接受之鹽；或其前藥；與⑼阿巴卡菲(abacavir)或其醫藥上可接受之鹽，或較佳為阿巴卡菲(abacavir)硫酸鹽，與(iii)核苦酸逆轉錄酶抑制劑，其中 TMC278與核苷酸逆轉錄酶抑制劑與阿巴卡菲(abacavir)或其醫藥上可接受之鹽，或較佳為阿巴卡菲(abacavir)硫酸鹽，在一天投藥一次之劑量下，為醫療上有效之HIV抑制劑。另一項較佳具體實施例中，提供一種三重組合，其包含 ⑴TMC278或其立體異構型，·或其醫藥上可接受之鹽；或其前藥；與⑼恩奇本(emtricitabine)，與(iii)丹諾菲(ten〇f〇vir)或其前藥丹諾菲(tenofovir)二異丙氧基富馬酸鹽，其中TMC278與恩奇本(emtricitabine)與丹諾菲(tenofovir)或其前藥丹諾菲(ten〇f〇vir) 二異丙氧基富馬酸鹽在一天投藥一次之劑量下，為醫療上有效之HIV抑制劑。另一項較佳具體實施例中，提供一種三重組合，其包含 (i)TMC278或其立體異構型；或其醫藥上可接受之鹽；或其前藥；與⑻蘭弗啶(lamivudine)與(iii)丹諾菲(ten〇f〇vir)或其前藥丹諾菲(tenofovir)二異丙氧基富馬酸鹽，其中TMC278與蘭弗啶 (lamivudine)與丹諾菲(ten0f0vir)或其前藥丹諾菲(ten〇f〇vir)二異丙氧基富馬酸鹽在一天投藥一次之劑量下，為醫療上有效之HIV 抑制劑。另一項較佳具體實施例中，提供一種三重組合，其包含 (i)TMC278或其立體異構型；或其醫藥上可接受之鹽或其前藥；與(ii)阿巴卡菲(abacavir)或其醫藥上可接受之鹽型，較佳為阿巴卡菲(abacavir)硫酸鹽；與(iii)丹諾菲(ten〇f〇vir)或其前藥丹諾菲 (tenofovir)二異丙氧基富馬酸鹽，其中TMC278與阿巴卡菲 (abacavir)或醫藥上可接受之鹽型，較佳為阿巴卡菲（abacavir)硫 200524612 酸鹽與丹諾菲(tenofovir)或其前藥丹諾菲(ten〇f〇vir)二異丙氧基富馬酸鹽在一天投藥一次之劑量下，為醫療上有效之扭¥抑$ 劑。亦包括下列較佳三重組合： 5 (a) TMC278或其立體異構型；或其醫藥上可接受之鹽；或其前藥；與恩奇本(emtridtabine)與丹諾菲(ten〇f〇vir)二異丙氧基富馬酸鹽； (b) TMC278或其立體異構型；或其醫藥上可接受之鹽；或其前藥；與蘭弗啶(lamivudine)與丹諾菲(tenof〇vir)二異丙氧基富 10 馬酸鹽； @ (c) TMC278或其立體異構型；或其醫藥上可接受之鹽；或其前藥；與阿巴卡菲(abacavir)硫酸鹽與丹諾菲(ten〇f〇vir)二異丙氧基富馬酸鹽； (d) TMC278或其立體異構型；或其醫藥上可接受之鹽；或其前 15 藥；與恩奇本(emtrieitabine)與蘭弗啶(iamivudine); (e) TMC278或其立體異構型；或其醫藥上可接受之鹽；或其前藥；恩奇本(emtridtabine)與阿巴卡菲⑽⑽狀的或其醫藥上可接受之鹽，較佳為阿巴卡菲(abacavir)硫酸鹽； (f) TMC278或其立體異構型；或其醫藥上可接受之鹽；或其前 20 藥；阿巴卡菲(abacavir)或其醫藥上可接受之鹽，較佳為阿巴卡菲(abacavir)硫酸鹽與蘭弗〇定(iamivudine)。特定έ之，各組合(a) - (f)中，活性成分，特定言之TMC278、恩奇本(emtridtabine) ' 蘭弗。定(lamivudine)、阿巴卡菲(abacavir) 或其醫藥上可接受之鹽，較佳為阿巴卡菲(abacavir)硫酸鹽，與 25 丹諾菲(ten〇f〇vir)或其前藥丹諾菲(tenofovir)二異丙氧基富馬酸鹽在一天投藥一次之劑量下，為醫療上有效之HIV抑制劑。本發明之雙重組合可另包含一種或多種其他活性成分，其可 -20- 200524612 為適用於治療感染HIV之患者之活性劑或其他活性劑。本發明之三重組合同樣可包含一種或多種其他活性成分，其可為適用於治療感染HIV之患者之活性劑或其他活性劑。任何此等其他藥劑最好在一天投藥一次之劑量下具有醫療有效性。本發明組合中之活性成分可同時、併行或順序投藥。同時投藥法可採用單一醫藥調配物或分開之醫藥調配物進行。通常，該組合可局部、經口、直腸、經靜脈内、皮下或肌内途徑投藥。 HIV感染之第一線療法中，同時投藥法最好採用單一醫藥調配物。因此另一方面，提供一種產品，其包含本文所說明組合作為修供同時、分開或順序投藥對抗HIV感染之組合製劑。本發明亦提供一種產品，其包含⑴TMC278或其立體異構型，或其醫藥上可接受之鹽；或其前藥；與⑴）核苷逆轉錄酶抑制劑與/或核苷酸逆轉錄酶抑制劑；，其中TMC278與核苷酸逆轉錄酶抑制劑與/或核苷逆轉錄酶抑制劑在一天投藥一次之劑量下，為醫療上有效之HIV抑制劑；作為供同時、分開或順序投藥對抗HIV感染之組合製劑。另一方面提供一種產品，其包含(i) TMC278或其立體異構型或其醫藥上可接受之鹽；或其前藥；與⑻㈣逆轉錄酶_ · 劑，其中TMC278與核苷逆轉錄酶抑制劑在一天投藥一次之劑量下，為醫療上有效之HIV抑制劑；作為供同時、分開投藥對抗HIV感染之組合製劑。序 ,另一方面提供一種產品，其包含(i) TMC278或其立體異構型；或其醫藥上可接受之鹽；或其前藥；與(ii)核苷酸逆轉錄酶 I7制齊]其中TMC278與核普酸逆轉錄酶抑制劑在一天投藥一次之劑量下，為醫療上有效之mv抑制劑；作為供同時、分開或順序投藥對抗HIV感染之組合製劑。 -21 - 200524612 10 15 型之::其二(：!TMC278或其，構土丨十卜^ 之孤，或其刖樂；與⑴)核苷逆轉錄_如 /、㈣核普酸逆轉錄酶抑制劑；其中TMC278與核芽酸轉錄酶抑制劑與核普逆轉錄酶抑制劑在—天投藥—次^ ί,ΓπΓνΓ™ 型·：：::提供一種產品，其包含(i) ™C278或其立體異構 ίΐ#Ι Γγ ；； ”㈣不同於(u)之㈣逆轉錄酶抑糊之第三種核錄酶抑制劑；其中TMC278與核普逆轉錄酶抑制劑在—天投藥一次之劑量下，為醫療上有效之贈抑制劑；作為供同時、分開或順序投藥對抗HIV感染之組合製劑。本發明產品中蹄成分含量為祕有效量；後者意指其用量足以在-段時間内’亦即在每次服甩調配物之間之時間期内，較佳為約24小時内，保持充分抑制HIV之效果。International Conference on Retroviruses and Opportunistic 25 Infections 1998, 5th: Chicago; published April 16, 1999]. In a preferred embodiment, a combination is provided, which comprises (i) TMC278 or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; or a prodrug thereof, and (ii) Enchiben 200524612 (emtricitabine), Among them, TMC278 and emtricitabine are medically effective mv inhibitors at a dose of once a day. In a preferred embodiment, a combination is provided which comprises ⑴TMC278 or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and (ii) lamivudine, wherein TMC278 and Lamivudine is a medically effective HIV inhibitor at a once-a-day dose. In another preferred embodiment, a combination is provided, which comprises ⑴ TMC278 or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and ⑼abacavir or its A pharmaceutically acceptable salt, characterized by 10 ™ C278 and abacavir, is a medically effective HIV inhibitor at a dose of once a day. In another preferred embodiment, a combination is provided, which comprises ⑴ TMC278 or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and ⑼abacavir sulfate It is characterized in that it is a medically effective HIV inhibitor at a dosage of once a day and abacavir sulfate, which is administered once a day. In another preferred embodiment, a triple combination is provided. Comprising (i) TMC278 or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and (ii) emtricitabine, and (iii) nucleotide reverse transcriptase inhibition 20 doses, of which TMC278, nucleotide reverse transcriptase inhibitor and emtricitabine are medically effective mv inhibitors at a dose of once a day. In another preferred embodiment, a kind of A triple combination comprising (i) TMC278 or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; or a pro 25 drug thereof; and lamivudine, and a nucleoside reverse transcriptase inhibitor Of which TMC278 and nucleotide reverse transcriptase inhibitors and lamividine (iamivudi ne) It is a medically effective HIV inhibitor at a dose of once a day. 200524612 In another preferred embodiment, a triple combination is provided, which comprises ⑴TMC278 or a stereoisomeric form thereof; or a pharmaceutically acceptable Accepted salts; or prodrugs thereof; and ⑼ abacavir or a pharmaceutically acceptable salt thereof, or preferably abacavir sulfate, and (iii) reverse transcription Enzyme inhibitors, including TMC278 and nucleotide reverse transcriptase inhibitors and abacavir or its pharmaceutically acceptable salt, or preferably abacavir sulfate, administered once a day At a dosage, it is a medically effective HIV inhibitor. In another preferred embodiment, a triple combination is provided, which comprises ⑴TMC278 or a stereoisomeric form thereof, or a pharmaceutically acceptable salt thereof; or Prodrug; with emtricitabine, and (iii) tenofovir or its prodrug tenofovir diisopropoxy fumarate, of which TMC278 is Emtricitabine and tenofovir or their prodrug tenofovir Diisopropoxyfumarate is a medically effective HIV inhibitor at a dose of once a day. In another preferred embodiment, a triple combination is provided, which comprises (i) TMC278 or its stereo Isoform; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and lamivudine and (iii) tenofovir or its prodrug tenofovir Diisopropoxy fumarate, in which TMC278 and lamivudine and tenofovir (ten0f0vir) or its prodrug danofovir diisopropoxyfumarate are It is a medically effective HIV inhibitor at a dose of once a day. In another preferred embodiment, a triple combination is provided, which comprises (i) TMC278 or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof or a prodrug thereof; and (ii) abacafi ( abacavir) or a pharmaceutically acceptable salt form thereof, preferably abacavir sulfate; and (iii) tenofovir or its prodrug tenofovir Isopropoxy fumarate, of which TMC278 and abacavir or a pharmaceutically acceptable salt form, preferably abacavir sulfur 200524612 or tenofovir or Its prodrug, danofovir diisopropoxy fumarate, is a medically effective drug that is effective at a dose of once a day. Also included are the following preferred triple combinations: 5 (a) TMC278 or its stereoisomeric form; or its pharmaceutically acceptable salt; or its prodrug; with emtridtabine and tenofib. vir) diisopropoxy fumarate; (b) TMC278 or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and lamivudine and tenof 〇vir) diisopropoxy-rich 10 maleate; @ (c) TMC278 or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and abacavir sulfate With tenofovir diisopropoxy fumarate; (d) TMC278 or its stereoisomeric form; or its pharmaceutically acceptable salt; or its top 15 drugs; and Enki Emtrieitabine and iamivudine; (e) TMC278 or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; emtridtabine and abacafil Or its pharmaceutically acceptable salt, preferably abacavir sulfate; (f) TMC278 or its stereoisomeric form; or its pharmaceutically acceptable salt; or its first 20 drugs; A Bakafi (abacavir) or a pharmaceutically acceptable salt thereof, preferably abacavir sulfate and iamivudine. Specifically, in each combination (a)-(f), the active ingredient is specifically TMC278, emtridtabine 'Lamfer. Lamivudine, abacavir, or a pharmaceutically acceptable salt thereof, preferably abacavir sulfate, and 25 danofovir or a prodrug thereof Tenofovir diisopropoxy fumarate is a medically effective HIV inhibitor at a dose of once a day. The dual combination of the present invention may further include one or more other active ingredients, which may be -20-200524612 active agents or other active agents suitable for treating patients infected with HIV. The triple combination of the present invention may also include one or more other active ingredients, which may be active agents or other active agents suitable for treating patients infected with HIV. Any of these other agents is preferably medically effective at a dose of once a day. The active ingredients in the combination of the present invention can be administered simultaneously, concurrently, or sequentially. Simultaneous administration can be carried out using a single pharmaceutical formulation or separate pharmaceutical formulations. Generally, the combination can be administered topically, orally, rectally, intravenously, subcutaneously, or intramuscularly. Among first-line treatments for HIV infection, a single-drug formulation is best for simultaneous administration. Accordingly, in another aspect, a product is provided comprising a combination described herein as a combination formulation that provides simultaneous, separate, or sequential administration against HIV infection. The present invention also provides a product comprising ⑴TMC278 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and ⑴) a nucleoside reverse transcriptase inhibitor and / or a nucleotide reverse transcriptase Inhibitors; TMC278 and nucleotide reverse transcriptase inhibitors and / or nucleoside reverse transcriptase inhibitors are medically effective HIV inhibitors at a dose of once a day; as simultaneous, separate or sequential administrations Combination preparation against HIV infection. Another aspect provides a product comprising (i) TMC278 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and a ⑻㈣ reverse transcriptase agent, wherein TMC278 and a nucleoside reverse transcriptase The inhibitor is a medically effective HIV inhibitor at a dose of once a day; it is a combined preparation for simultaneous and separate administration against HIV infection. In another aspect, there is provided a product comprising (i) TMC278 or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and (ii) a nucleotide reverse transcriptase I7] Among them, TMC278 and a nuclear acid reverse transcriptase inhibitor are medically effective mv inhibitors at a dose of once a day; as a combined preparation for simultaneous, separate or sequential administration against HIV infection. -21-200524612 10 Type 15 :: Second (:! TMC278 or its structure, 丨 Shibo ^ solitary, or its music; and ⑴) nucleoside reverse transcription _ such as /, ㈣ nuclear acid reverse transcription Enzyme inhibitors; TMC278 and ribotranscriptase inhibitors and nuclear reverse transcriptase inhibitors—day administration—times ^, ΓπΓνΓ ™ type :::: Providing a product containing (i) ™ C278 Or its stereoisomer ίΐ # Ι Γγ; ”㈣ is different from (u) the third ribozyme inhibitor of reverse transcriptase inhibition; of which TMC278 and nuclear general reverse transcriptase inhibitors are administered once a day At the dosage, it is a medically effective gift inhibitor; as a combined preparation for simultaneous, separate or sequential administration against HIV infection. The content of the hoof component in the product of the present invention is a secret effective amount; the latter means that the amount is sufficient in a period of time Within, that is, within a period of time between each serving of the formulation, preferably within about 24 hours, the effect of adequate HIV suppression is maintained.

20 、特別具體實施例為上述產品中包含一種或多種本文說明之活性成分，如：恩奇本(emtricitabine)、消旋性ftc、蘭弗啶 (lammidine)、丹諾菲(tenofovir)與其前藥丹諾菲如也响二異丙氧基富馬酸鹽。 ' 上述產品可包含活性成分之分開調配物，或可共同調配兩種或多種活性成分。20. A particularly specific embodiment is that the above product contains one or more of the active ingredients described herein, such as: emtricitabine, racemic ftc, lammidine, tenofovir and its prodrugs Danofi also sounds diisopropoxy fumarate. '' The aforementioned products may contain separate formulations of the active ingredients, or they may be formulated in combination of two or more active ingredients.

本發明另一方面提供一種醫藥調配物，其包含本文所說明之組合與合適載劑。另一方面，提供一種醫藥調配物，其包含醫藥上可接受之載劑與作為活性成分之⑴TMC278或其立體異構型；或其醫藥上可接受之鹽，或其前藥；與(ii)核苷逆轉錄酶抑制劑與/或核苷酸逆轉錄酶抑制劑，·其中TMC278與核苷逆轉錄酶抑制劑與/或核苷 -22- 25 200524612 酸逆轉錄酶抑制劑在一天投藥一次之劑量下，為醫療上有效之 HIV抑制劑。本發明另提供一種醫藥調配物，其包含醫藥上可接受之載劑與作為活性成分之⑴TMC278或其立體異構型；或其醫藥上可接受之鹽；或其前藥；與(ii)核苷逆轉錄酶抑制劑；其中tmc278 與核苷逆轉錄酶抑制劑在一天投藥一次之劑量下，為醫療上有效之HIV抑制劑。 ’、 10 15 20 ^ w，坑识一禋醫樂調配物，其包含醫藥上可接受之f 劑與作為活性成分之⑴TMC278或其立體異構型；或其醫藥』可接受之鹽；或其前藥；肖⑼核普酸逆轉錄酶抑制劑，其今 TMC278與核芽逆轉錄酶抑制劑與核芽酸逆轉錄酶抑制劑在一天投藥一次之劑量下，為醫療上有效之HIV抑制劑。另-方面，提供一種醫藥調配物，其包含醫藥上可劑與作為雜齡之(i) TMC278或其立體異翻；或 2受之鹽；或其前藥；與⑻歸逆轉錄酶抑制劑,·盘㈣核技逆轉錄酶抑_ ;其中TMC278 ___ _ 核普酸逆轉_抑侧在—天投藥—奴 ^ 效之HIV抑制劑。 #醫療上有另一方面，提供一種醫藥調配物，其包劑與作為活性成分之⑴TMC278或其立體異=上之載可接受之鹽;或其前藥;與⑼核苦逆轉錄酶:制劑:醫樂^ 同於⑻之核苷逆轉錄酶抑制劑之第二種與㈣不八中TMC278與核苷逆轉錄酶抑制劑在 :田下，為醫療上有效之HIV抑制劑。又” 人之劑1 本發明醫藥調配物中活性成分含量為醫旦其用量料在-段時間内，亦即在每“里’後者忍指期内，較佳㈣小時之時間Another aspect of the invention provides a pharmaceutical formulation comprising a combination as described herein and a suitable carrier. In another aspect, there is provided a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and ⑴TMC278 or a stereoisomeric form thereof as an active ingredient; or a pharmaceutically acceptable salt thereof, or a prodrug thereof; and (ii) Nucleoside reverse transcriptase inhibitor and / or nucleotide reverse transcriptase inhibitor, of which TMC278 and nucleoside reverse transcriptase inhibitor and / or nucleoside-22- 25 200524612 acid reverse transcriptase inhibitor is administered once a day At the dosage, it is a medically effective HIV inhibitor. The present invention further provides a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and ⑴TMC278 or a stereoisomeric form thereof as an active ingredient; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and (ii) a core Glycoside reverse transcriptase inhibitors; tmc278 and nucleoside reverse transcriptase inhibitors are medically effective HIV inhibitors at a dose of once a day. ', 10 15 20 ^ w, a conscious medical formula, which contains a pharmaceutically acceptable f agent and ⑴TMC278 or its stereoisomeric form as an active ingredient; or a pharmaceutically acceptable salt thereof; or Prodrug; Xiao Qiao Nupu acid reverse transcriptase inhibitor, its current TMC278, nuclear bud reverse transcriptase inhibitor and nuclear bud reverse transcriptase inhibitor are medically effective HIV inhibitors at a dose of once a day . In another aspect, a pharmaceutical formulation is provided, which comprises a pharmaceutically acceptable agent and (i) TMC278 or its stereoisoversion as a heterogeneous agent; or a 2-accepted salt; or a prodrug thereof; and Zigui reverse transcriptase inhibitor ················································· for TMC278 for nuclear reversal of nuclear acid, which is an inhibitor of HIV that is effective at day-to-day administration. #Medically, there is another aspect, and a pharmaceutical formulation is provided, the package of which is an active ingredient of ⑴TMC278 or its steric isopropyl salt; or a prodrug thereof; and ⑼ nuclear bitter reverse transcriptase: preparation : Yiyue ^ The second nucleoside reverse transcriptase inhibitor, which is the same as ⑻, TMC278 and nucleoside reverse transcriptase inhibitor in Hebubazhong. It is a medically effective HIV inhibitor. Moreover, the dose of human 1 The active ingredient content in the pharmaceutical formulation of the present invention is Yidan, and its dosage is within a period of time, that is, within the period of the latter tolerance period, preferably within a period of one hour.

-23- 25 200524612 特別具體實施例為上述醫藥調配物中包含一種或多種本文說明之活性成分，如·恩奇本(emtricitabine)、消旋性FTC、蘭弗啶(lamivudine)、丹諾菲(tenofovir)與其前藥丹諾菲(ten〇f〇vir) 二異丙氧基富馬酸鹽。本發明醫藥調配物可調配成多種不同投藥型態。製備本發明醫藥調配物時，由有效量活性成分(可視需要呈加成鹽型)與醫藥上可接受之載劑均勻混合，該載劑可隨所需之投藥劑型呈現多種不同型式。本發明醫藥調配物最好調配成特定言之適合經口、直腸、經皮膚或非經腸式注射之單位劑型。例如：製成口服劑型調配物時，任何常用之醫藥介質均可使用，如，例如：水、甘醇、油類、醇類，等等，可用於製備口服用液體製劑，如：懸浮液、糖漿、酏劑、乳液與溶液；或固態載劑如：澱粉、糖類、高嶺土、稀釋劑、潤滑劑、結合劑、崩解劑，等等，可用於製備粉劑、丸劑、膠囊、與錠劑。由於錠劑與膠囊方便投藥，因此代表最有利之口服單位劑型，此時通常使用固態醫藥載劑。非經腸式組合物中之載劑通常包括無菌水，至少佔絕大部份，但亦可包含其他成份，例如：有助於溶解之成份。例如：可製備注射液，其中載劑則包括生理食鹽水溶液、葡萄糖溶液或生理食鹽水與葡萄糖溶液之混合物。亦可製備注射用懸浮液，此時可使用適當液態載劑、懸浮劑，等等。本發明一方面，本組合可調配成口服錠劑型，其另包含重量範圍在150 mg與600 mg之間之醫藥上可接受之賦形劑，合適範圍為200與400 mg之間。一般口服錠劑型中根據本發明活性成刀之通稱總重1耗圍在200 mg與1500 mg之間，合適範圍為 500 mg與1250 mg之間，更合適為600與11〇〇 mg之間。本發明醫藥調配物之優點在於本組合中各成分可共同調配成一個醫藥調配物，且不需要分開投藥。此等共同調配之單— 200524612 合之成分中，每曰抗逆轉錄病毒劑醫療量最好呈早—I位劑型，但若需要時，亦可投與多重單位劑型，如； L3^、5或更多單位劑型投藥。醫師可考量患者之條件及患重、性別及其他可能參數如：麵對各藥物之吸收性、生物分佈性、代謝性與***率之差異及f此相關技藝之人士已知之其他因素，決定確實之劑量。本發明亦提供-種治絲染HIV之患者之方法，該方法包括投與本文說明之組合。 10 15 20 亦提供-種治療感染HIV之患者之方法，該方法包括投與 ™c278 $其立體異構型或醫藥上可接受之鹽或其前t，與核普逆轉錄酶抑制劑與/或核:g：酸逆轉錄酶抑制劑之組合，該方法中醫療有效置之TMC278與核苷逆轉錄酶抑制劑與/或核苷酸逆轉錄酶抑制劑可一天投藥一次。此外亦提供一種治療感染HIV之患者之方法，該方法包括投與TMC278或其立體異翻或醫藥上可接受之鹽或其前藥，與核苷逆轉錄酶抑制劑之組合，該方法中，醫療有效量之 TMC278與核苷逆轉錄酶抑制劑可一天投藥一次。本發明另一方面係有關一種治療感染HIV之患者之方法，該方法包括投與TMC278或其立體異構型或醫藥上可接受之鹽或其前藥，與核苷酸逆轉錄酶抑制劑，該方法中醫療有效量之 TMC278與核苷酸逆轉錄酶抑制劑可一天投藥一次。本發明另一方面包括一種治療感染HIV之患者之方法，該方法包括投與TMC278或其立體異構型或醫藥上可接受之鹽或其則藥’與核苷逆轉錄酶抑制劑與核苷酸逆轉錄酶抑制劑之組合’該方法中，醫療有效量之TMC278、核苷酸逆轉錄酶抑制劑與核苷逆轉錄酶抑制劑可一天投藥一次。本發明另一方面包括一種治療感染HIV之患者之方法，該-23- 25 200524612 A specific embodiment is one or more of the active ingredients described herein, such as emtricitabine, racemic FTC, lamivudine, Danofi ( tenofovir) and its prodrug tenofovir diisopropoxy fumarate. The pharmaceutical preparations of the present invention can be formulated into a variety of different dosage forms. When preparing the pharmaceutical formulation of the present invention, an effective amount of the active ingredient (in the form of an addition salt if necessary) is uniformly mixed with a pharmaceutically acceptable carrier, and the carrier can take on a variety of different forms depending on the required dosage form. The pharmaceutical formulations of the present invention are preferably formulated into unit dosage forms specifically suitable for oral, rectal, transdermal or parenteral injection. For example, when making oral dosage formulations, any commonly used pharmaceutical medium can be used, such as, for example, water, glycol, oils, alcohols, etc., and can be used to prepare liquid preparations for oral use, such as suspensions, Syrups, elixirs, emulsions and solutions; or solid carriers such as starch, sugars, kaolin, diluents, lubricants, binders, disintegrating agents, etc., can be used to prepare powders, pills, capsules, and lozenges. Because tablets and capsules are convenient for administration, they represent the most advantageous oral unit dosage form, in which case solid pharmaceutical carriers are usually used. Carriers in parenteral compositions usually include sterile water, at least in most cases, but may also contain other ingredients, such as ingredients that help dissolve. For example: Injectable solutions can be prepared where the carrier includes a physiological saline solution, a glucose solution, or a mixture of a physiological saline solution and a glucose solution. Suspensions for injection can also be prepared, in which case appropriate liquid carriers, suspensions, etc. can be used. In one aspect of the present invention, the combination can be formulated into an oral lozenge form, which further comprises pharmaceutically acceptable excipients in a weight range between 150 mg and 600 mg, with a suitable range between 200 and 400 mg. In the general oral tablet dosage form, the active weight of the knife according to the present invention is generally between 1 and 200 mg and 1500 mg, suitable range is between 500 mg and 1250 mg, and more preferably between 600 and 1 100 mg. The medicinal formulation of the present invention has the advantage that the components in the combination can be jointly formulated into one medicinal formulation and do not need to be administered separately. Among these jointly formulated single-200524612 combined ingredients, the medical dose of antiretroviral agents should preferably be in the early-I dosage form, but multiple unit dosage forms can also be administered if needed, such as; L3 ^, 5 Or more unit dosage forms. Physicians can consider the patient's condition and weight, gender, and other possible parameters such as: the differences in absorption, biodistribution, metabolism, and excretion rate of each drug and other factors known to those skilled in the relevant arts Of dosage. The invention also provides a method of treating a patient with silkworm HIV, which method comprises administering a combination described herein. 10 15 20 Also provides a method for treating patients infected with HIV, the method comprising administering ™ c278 $ its stereoisomeric or pharmaceutically acceptable salt or its pre-t, and nuclear universal reverse transcriptase inhibitors and / Or nuclear: g: a combination of acid reverse transcriptase inhibitors. In this method, TMC278 and nucleoside reverse transcriptase inhibitors and / or nucleotide reverse transcriptase inhibitors can be administered once a day. Also provided is a method for treating a patient infected with HIV, which method comprises administering a combination of TMC278 or a stereoisomere or a pharmaceutically acceptable salt or a prodrug thereof, and a nucleoside reverse transcriptase inhibitor. In the method, A medically effective amount of TMC278 and a nucleoside reverse transcriptase inhibitor can be administered once a day. Another aspect of the present invention relates to a method for treating a patient infected with HIV, which method comprises administering TMC278 or a stereoisomeric or pharmaceutically acceptable salt thereof or a prodrug thereof, and a nucleotide reverse transcriptase inhibitor, In this method, a medically effective amount of TMC278 and a nucleotide reverse transcriptase inhibitor can be administered once a day. Another aspect of the present invention includes a method for treating a patient infected with HIV, which method comprises administering TMC278 or a stereoisomeric or pharmaceutically acceptable salt thereof or a drug thereof, and a nucleoside reverse transcriptase inhibitor and a nucleoside Combination of acid reverse transcriptase inhibitors' In this method, a medically effective amount of TMC278, a nucleotide reverse transcriptase inhibitor and a nucleoside reverse transcriptase inhibitor can be administered once a day. Another aspect of the invention includes a method for treating a patient infected with HIV, the

-25 - 25 200524612 5 10 15 20 括投與TMC278或其讀異構型或醫紅可接受之鹽或、别樂’與核脊逆轉騎抑_，與不同於前—種料逆轉錄酶抑制，之第二種核芽逆轉錄酶抑制劑之組合，該方法中，醫療有效量之TMC278、核苷逆轉錄酶抑制劑可一天投藥一次。本發明方法之活性成分係軸醫療有效量，後者意指其用量足以在-段時間内，亦即在每次服用調配物之間之時間期内，較佳為約24小時内，保持充分抑制贈之效果。特別具體實施例為如上述方法，其中投與一種或多種如本文中說明之活性於，如··恩奇本(贈以⑽㈣、舰性ftc、蘭弗唆(lamivudine)、丹諾菲(tenof〇vir)與其前藥丹諾菲(_ 二異丙氧基富馬酸鹽。本發明一項具體實施例係有關用為醫藥之本組合。另一項具體實施例係有關驗製造供治療絲mv之患者之醫藥之本發明組合。特別強調本文說明之任何組合，或任何以該組合為主之產品、醫藥調配物、單位劑型、方法與用途，其中TMC278為 E-TMC287,或較佳為TMC278鹽酸鹽或更佳為E_TMC278鹽酸鹽。-25-25 200524612 5 10 15 20 Including the administration of TMC278 or its isomerized or medically acceptable salt or, Bile 'and nuclear spine reverse ride inhibition, and different from the pre-seed reverse transcriptase inhibition The second combination of nuclear bud reverse transcriptase inhibitors. In this method, a medically effective amount of TMC278 and a nucleoside reverse transcriptase inhibitor can be administered once a day. The active ingredient of the method of the present invention is a medically effective amount of the axis, the latter means that its amount is sufficient to maintain sufficient inhibition within a period of time, that is, within the time period between each taking of the formulation, preferably about 24 hours Gift effect. A particularly specific embodiment is the method as described above, wherein one or more of the actives as described herein are administered, such as ... Enkiben (gift ⑽㈣, navy ftc, lamivudine, tenofi) 〇vir) and its prodrug Danofi (_ diisopropoxyfumarate). A specific embodiment of the present invention relates to the present combination for use in medicine. Another specific embodiment relates to the manufacture of therapeutic filaments. The combination of the invention of the medicine of the patient of MV. Special emphasis is placed on any combination described herein, or any product, pharmaceutical formulation, unit dosage form, method and use based on the combination, in which TMC278 is E-TMC287, or preferably TMC278 hydrochloride or more preferably E_TMC278 hydrochloride.

本發明之組合特別適用於治療aids與相關之臨床病症，如：AIDS相關併發症(ARC)、漸進性全身淋巴結病(PGL)或AIDS 相關神經病症如：多發性硬化。本三重組合特別適用於治療未曾接受過藥物治療之感染HIV之患者。本發明之組合亦適用於預防人類HIV傳播或感染，特定言之性傳染。因此，本發明係有關以根據本發明之組合於製造醫藥，供預防HIV感染或經由***或伴侣之間相關親密接觸傳染 HIV上之用途。本發明亦有關一種預防hiv感染或經由***或伴侣之間相關親密接觸傳染HIV上之方法，其包括對有此需要 -26- 25 200524612 之個體投與有效量之根據本發明任何組合。根據本發明組合中各活性成分之個別一日劑量範圍可在10 mg至800 mg之間，較佳為50至400 mg之間，更佳為50至300 mg之間，或100至300 mg之間。特定言之TMC278之一曰劑 5 量範圍可在10 mg至500 mg之間，較佳為10至30〇，更佳為 50至250 mg，亦更佳為50至200 mg，例如：約1〇〇 mg。以一日劑量為主之三重組合中每一對成分之重量比可在 1/10至1(V1之範圍内變化。每一對成分之合適重量比宜在1/6 至6/1之間變化，更適合在1/4至4/1之間，較佳為1/3至3/1 10 之間，更佳為1/2至2/1之間。表2出示化合物E-TMC278、恩奇本(emtricitabine)與丹諾菲(tenofovir)之組合中各活性成分之一日劑量之一些實例。組合編號 E-TMC278 恩奇本丹諾菲 1 50 mp 200 mg 2 50 mg 議 300 mg 3 ---- 100 mg 200 mg 麵 4 — 100 mg 300 mg 5 — 200 mg 200 mg 6 200 mg 300 mg 7 50 mg 200 mg 300 mg 8 100 mg 200 mg 300 mg 9 ----—_ 200 mg —200 mg 300 mg 表3出示TMC278、阿巴卡菲(abacavir)與蘭弗ο定(iamivudine) 之組合中各活性成分之一日劑量之一些實例，其中表中所示阿巴卡菲(abacavii*)硫酸鹽之劑量係指阿巴卡菲(abacavi]r)驗之當量 200524612 劑量。組合編號 E-TMC278 蘭弗淀阿巴卡菲硫酸鹽 1 50 mp 150 mg 300 mg 2 100 mg 150 mg 300 mg 3 200 mg 150 mg 300 mg 因此，根據本發明之有利組合中包含一日劑量範圍在10 mg 至5〇0 mg之化合物E-(A)，一日劑量為150 mg之蘭弗啶 (lamivudine)與一曰劑量為300 mg當量阿巴卡菲(abacavir)驗。此等組合宜調配成單一劑型。另一項有利之根據本發明組合包括一日劑量範圍在5〇 mg 至250 mg之化合物E-(A)、一曰劑量為150 mg蘭弗啶(lamivudine) 與一日劑篁為300 mg當量阿巴卡菲(abacavir)驗。此等組合宜調配成單一劑型。本發明亦有關適合投藥至***位置或可能發生相關之親密接觸之位置之醫藥組合物劑型，如：生殖器、直腸、口腔、手、下腹部、上腿部，尤指***與口腔，其包含醫藥上可接受之劑與作為活性成分之有效量之根據本發·合。適當之^ 式組合物可為所有常***、直腸、口腔與皮廣之組人如，例如：凝膠、轉、乳霜、油f、則、海錦、 ***環、子宮頸套、直腸或***用塞劑、***或直腸或^ 旋劑、漱Π水。製備此等㈣組合物時，由在三重組合^ 活性成分之有效量之各特定化合物與醫藥上可 *、、、混合，該載劑可呈多種不同型式，端賴投藥型式而定1均句長此等醫藥組合物在投藥位置之滯留時間，可能 /、了延添加生__，特定言之生物膠雜聚合物。生物 200524612 疋義為可崎在活生物細如，例如··_或皮膚輯之物質。、因此，本發明亦有關-種醫藥組合物，其包含醫藥上可接受之載劑與在本三重組合中作為活性成分之有效量之各特定化合物，其特徵在於該醫藥組合物在施藥位置具有生物膠黏性。較 5 佳者’補位置為***、直腸、口腔或皮膚，最佳為***。The combination of the present invention is particularly suitable for treating aids and related clinical conditions, such as: AIDS-related complications (ARC), progressive systemic lymphadenopathy (PGL), or AIDS-related neurological conditions such as multiple sclerosis. This triple combination is particularly suitable for treating HIV-infected patients who have not been treated with drugs. The combination of the invention is also suitable for the prevention of HIV transmission or infection in humans, specifically sexual transmission. Therefore, the present invention relates to the use of the combination according to the present invention in the manufacture of medicines for preventing HIV infection or transmitting HIV through sexual intercourse or related intimate contact between partners. The invention also relates to a method for preventing HIV infection or transmission of HIV through sexual intercourse or related intimate contact between partners, which comprises administering to a subject in need thereof an effective amount of any combination according to the invention. The individual daily dosage range of each active ingredient in the combination according to the present invention may be between 10 mg and 800 mg, preferably between 50 and 400 mg, more preferably between 50 and 300 mg, or between 100 and 300 mg. between. Specifically, the amount of one of TMC278 5 can range from 10 mg to 500 mg, preferably 10 to 30 mg, more preferably 50 to 250 mg, and still more preferably 50 to 200 mg, for example: about 1 〇〇mg. The weight ratio of each pair of ingredients in a triple combination based on a daily dose can vary from 1/10 to 1 (V1. The appropriate weight ratio of each pair of ingredients should be between 1/6 and 6/1 The change is more suitable between 1/4 and 4/1, preferably between 1/3 and 3/1 10, and more preferably between 1/2 and 2/1. Table 2 shows compounds E-TMC278, Some examples of one daily dose of each active ingredient in a combination of emtricitabine and tenofovir. Combination number E-TMC278 Enkiben Danofi 1 50 mp 200 mg 2 50 mg Negotiable 300 mg 3 ---- 100 mg 200 mg noodle 4-100 mg 300 mg 5-200 mg 200 mg 6 200 mg 300 mg 7 50 mg 200 mg 300 mg 8 100 mg 200 mg 300 mg 9 ------ 200 mg- 200 mg 300 mg Table 3 shows some examples of one daily dose of each active ingredient in the combination of TMC278, abacavir and iamivudine. Among them, abacavii * ) Sulfate dosage refers to the equivalent of 200524612 by abacavir. Combination No. E-TMC278 Lanford Lake Abacafi sulfate 1 50 mp 150 mg 300 mg 2 100 mg 150 mg 300 mg 3 200 mg 150 mg 300 mg Therefore, an advantageous combination according to the present invention comprises Compound E- (A) in a daily dose ranging from 10 mg to 5000 mg, and a daily dose of 150 mg of lamivudine and The daily dose is 300 mg equivalent abacavir test. These combinations should be formulated into a single dosage form. Another advantageous combination according to the invention comprises compound E- in a daily dosage range of 50 mg to 250 mg. (A). A dose of 150 mg lamivudine and a daily dose of 300 mg equivalent abacavir are tested. These combinations should be formulated into a single dosage form. The present invention is also related to suitable for administration to Pharmaceutical composition dosage forms such as genitals, rectum, oral cavity, hands, lower abdomen, upper legs, especially vagina and oral cavity, including sexual intercourse or locations where intimate contact may occur, including pharmaceutically acceptable agents and acts The effective amount of the active ingredient is based on the present invention. Appropriate composition can be all groups of people who are usually vaginal, rectal, oral and skin wide, such as: gel, transfer, cream, oil, Broccoli, vaginal ring, cervical sleeve, rectum or yin With suppositories, or vaginal or rectal ^ spin agent, Π rinse water. In the preparation of these hydrazone compositions, the effective amount of each specific compound in a triple combination ^ of the active ingredients can be mixed with the medicine, and the carrier can be in a variety of different forms, depending on the type of administration. Increasing the residence time of these pharmaceutical compositions at the administration site may / and delay the addition of bio-polymers, specifically biopolymers. Creature 200524612 疋 means a substance that can be found in living creatures such as ... or skin. Therefore, the present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and each specific compound in an effective amount as an active ingredient in the triple combination, which is characterized in that the pharmaceutical composition is at the application site With bio-adhesive. The better place is the vagina, rectum, mouth, or skin, and the best is the vagina.

Otten RA 專人於細卿，< 巧._办（2_)，74(2〇)， 9771-9775 與 Witvrouw M 等人於血敝以（2〇〇〇)，’ 46(3)，215_221中揭示丹諾菲(ten〇f〇vir)在高危險性性接觸後延遲HIV病毒侵入之能力。 10 Pam A 等人於 Antivim! Chemistry & Chemotgerapy (2001)， 12(SuPPl. 1)，51-59中說明蘭弗啶(lamivudine)延遲病毒侵入之能力。 TMC278預防經由***或伴侣之間相關之親密接觸感染 HIV之能力可於下列試驗中證實。衍生自未成熟單核細胞之樹 15 突細胞(immM0_DC)代表一種間質樹突細胞之良好模式，其係性傳染HIV期間之早期目標，且為免疫反應之重要起始物。此等 immMO-DC即用於”於活體外”模式，試驗對經由***或伴侣之間相關之親密接觸感染HIV之預防效果。其中一種模式說明於實驗部份中，且顯示TMC278強力抑制HIV在MO-DC/CD4(+) 20 T細胞共培養物中之複製。實例膏例1 : E-TMC278之藥物動力學設計雙盲隨機，以安慰劑為對照組之I期試驗來分析單一劑 25 量之化合物E_TMC278於健康男性自願者之安全性、耐受性及活體外藥物動力學。口服劑量12.5、25與50 mg係於PEG 400 中調配，與標準餐一起服用。其藥物動力學結果示於表4。 -29- 200524612 另一項雙盲機，以安慰劑為對照組之Z期試驗進行4個投藥期，來分析100 mg與200 mg單一口服劑量之化合物 E-TMC278於健康男性者之安全性、耐受性、藥物動力學與活體外藥效學，結果亦不於表4。隨機分佈法使得每一投藥期有6位受試者接受相同劑量化合物E-TMC278，3位接受安慰劑。每個投藥期之間間隔約14天。表4顯示得到尚度反應且隨劑量成比例變化。5 Cmax數據點之相關係數為0.9897，〇至48小時曲線下面積(AUCV48小時) 為0.9952。血漿濃度半衰期範圍在37至39小時之間。自願者對化合物之耐受性良好。沒有觀察到藥物相關不良反應。表4 參數 12.5 mg 25 mg 50 mg 100 mg ,200 mg Cmax(ng/ml) 73 土 14 149 土 32 267土27 482土 121 807土207 Tmax(hr) 4·0 土 0 4.0+1.3 4.0+1.3 4.3+0.8 4.3 土 0.8 AUC〇.4 小時(nghr/ml) 1337土 310 2805+496 5094土 509 8162±2251 15592±2746 AUC〇.〇〇(nghr/ihl) 2210 土473 463 7土1164 8872土 1342 15844土4592 Ti/2 (hr) 37.1 38.7 45 土 9 55 土 18Otten RA by Yu Qingqing, < Qiao. _ Office (2_), 74 (2〇), 9771-9775, and Witvrouw M, et al. (2), '46 (3), 215_221 Revealed the ability of tenofovir to delay HIV invasion after high-risk sexual contact. 10 Pam A et al. In Antivim! Chemistry & Chemotgerapy (2001), 12 (SuPPl. 1), 51-59 illustrate the ability of lamivudine to delay virus invasion. The ability of TMC278 to prevent HIV infection through sexual intercourse or related intimate contact between partners can be demonstrated in the following tests. Dendritic cells derived from immature monocytes (immM0_DC) represent a good model of interstitial dendritic cells, which are early targets during sexual transmission of HIV and are important initiators of the immune response. These immMO-DCs are used in an "in vitro" mode to test the prevention of HIV infection through sexual intercourse or intimate contact between partners. One of these modes is described in the experimental section and shows that TMC278 strongly inhibits HIV replication in MO-DC / CD4 (+) 20 T cell co-cultures. Example Paste Example 1: The pharmacokinetic design of E-TMC278 is a double-blind, randomized, phase I trial using a placebo as a control group to analyze the safety, tolerability, and liveness of a single dose of 25 compounds E_TMC278 in healthy male volunteers Outer Pharmacokinetics. Oral doses of 12.5, 25 and 50 mg are formulated in PEG 400 and taken with a standard meal. The pharmacokinetic results are shown in Table 4. -29- 200524612 Another double-blind machine, using a placebo as a control group, in a phase Z trial of 4 dosing periods to analyze the safety of 100 mg and 200 mg of a single oral dose of compound E-TMC278 in healthy men, The results of tolerance, pharmacokinetics and in vitro pharmacodynamics are also shown in Table 4. The randomized distribution method resulted in 6 subjects receiving the same dose of compound E-TMC278 and 3 subjects receiving placebo per dosing period. The interval between each administration period is about 14 days. Table 4 shows that a modest response is obtained and varies proportionally with dose. The correlation coefficient for the 5 Cmax data points was 0.9897, and the area under the 0-48 hour curve (AUCV 48 hours) was 0.9952. The plasma concentration half-life ranges between 37 and 39 hours. Volunteers were well tolerated by the compounds. No drug-related adverse reactions were observed. Table 4 Parameters 4.3 + 0.8 4.3 soil 0.8 AUC0.4 hours (nghr / ml) 1337 soil 310 2805 + 496 5094 soil 509 8162 ± 2251 15592 ± 2746 AUC〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇 (〇nghr / ihl) 2210 soil 473 463 7 soil 1164 8872 soil 1342 15844 soil 4592 Ti / 2 (hr) 37.1 38.7 45 soil 9 55 soil 18

15 實例2 :化合物E-TMC278之病奏學圖形在以細胞為主之分析法中，採用HIV之天然宿主細胞試驗化合物E-TMC278。以HIV-1 (野生型或突變株)感染MT-4細胞(人類T細胞之細胞株），於10%胎牛血清之存在下，曝露在不同濃度抗病毒化合物中。另一平行試驗中，以抗病毒活性決定細胞 20 毒性，因此可分析該抗病毒效果之選擇性。活性化合物必需滲入細胞膜中以干擾細胞内之複製步驟。 -30- 200524612 於37°C下培養4天後，採用以四唑鑌鹽為主之自動化比色 · 分析法分析感染HIV之細胞與偽感染之細胞之活力。此方法可以計算抑制病毒細胞致病性達50%之抑制濃度(IC5〇)、IC9〇、與 50%細胞毒性濃度(CC50)。CC50/IC50比例亦稱為選擇性指數^ 5 代表抗病毒效果之專一性。所試驗之HIV菌株包括:野生型(wt) HIV-1 ; —組由定點誘變法(SDM)得到之單一與雙重突變株，及一組臨床單離株，供選拔對NNRTIs之抗性。数野生型奧SDM突#蜂之法枨 10 採用定點誘變法(S D Μ)與同系重組技術構築一組有限制之鲁 HIV-1突變株。測試化合物E-TMC278對另一組已知對自商品取得之NNRTIs產生抗性之單一與雙重突變株之活性。其中包括尼拉本(nevirapine)(NVP)與抑弗靈(efavirenz)(EFV)作為對照組。其結果示於表5(所示數值為IC50值，以nM表示）。野生型 15 病骨得到之1C5〇為〇·4 ηΜ(0·15 ng/ml)，IC90 為 1.3 ηΜ(0·48 ng/ml)。在此選擇性作用中對化合物E-TMC278之選擇性最低之 HIV菌株為雙重突變株1〇〇I+1〇3N，其IC5〇約8 nM，IC90約 16 nM 〇 20 表5 NVP EFV 化合物E-TMC278 野生型 81 1.4 0.4 1001 597 35 0.4 101E 547 5 1.6 103N 2,879 28 0.3 106A 2,983 23 0.2 -31 - 200524612 NVP EFV 化合物E-TMC278 1081 - 2 0.3 138K 64 1.3 0.4 179D 161 6 0.6 179E 158 5 0.4 181C 10,000 2 1.3 188C 3,764 5 0.1 188H 241 9 0.2 188L 10,000 78 2.0 190A 4,101 8 0.3 190S 10,000 275 0.1 225H 171 2 0.3 227C 1,816 36 2.0 227L 78 0.3 0.3 2341 45 NT 0.3 236L 41 1 0.3 100I+103N 10,000 10,000 7.9 101E+103N 7,033 84 0.5 103N+181I 10,000 37 1.0 227L+106A 10,000 8 1.015 Example 2: Graphical study of compound E-TMC278 In a cell-based analysis, natural host cells of HIV were used to test compound E-TMC278. MT-4 cells (human T cell line) were infected with HIV-1 (wild type or mutant strain) and exposed to antiviral compounds at different concentrations in the presence of 10% fetal bovine serum. In another parallel experiment, antiviral activity was used to determine cell 20 toxicity, so the selectivity of this antiviral effect could be analyzed. The active compound must penetrate the cell membrane to interfere with intracellular replication steps. -30- 200524612 After 4 days of incubation at 37 ° C, the viability of HIV-infected cells and pseudo-infected cells was analyzed using an automated colorimetric assay based on tetrazolium salt. This method can be used to calculate the inhibitory concentration (IC50), IC90, and 50% cytotoxic concentration (CC50) of virus cells that are 50% pathogenic. The CC50 / IC50 ratio is also known as the selectivity index ^ 5 represents the specificity of the antiviral effect. The tested HIV strains include: wild-type (wt) HIV-1;-a group of single and double mutants obtained by site-directed mutagenesis (SDM), and a group of clinical single isolates for selection for resistance to NNRTIs. The method of counting wild-type Austrian SDM ## 蜂之枨 10 A site-specific mutagenesis method (SDM) and homologous recombination technology were used to construct a restricted set of HIV-1 mutant strains. The test compound E-TMC278 was active against another group of single and double mutants known to be resistant to commercially available NNRTIs. These included nevirapine (NVP) and efavirenz (EFV) as controls. The results are shown in Table 5 (the values shown are IC50 values, expressed in nM). The 1C50 obtained from wild type 15 diseased bone was 0.4 ηM (0.15 ng / ml), and the IC90 was 1.3 ηM (0.48 ng / ml). The HIV strain with the lowest selectivity for compound E-TMC278 in this selective action is the double mutant strain 1001 + 10N, with IC50 of about 8 nM and IC90 of about 16 nM. Table 5 NVP EFV Compound E -TMC278 wild type 81 1.4 0.4 1001 597 35 0.4 101E 547 5 1.6 103N 2,879 28 0.3 106A 2,983 23 0.2 -31-200524612 NVP EFV compound E-TMC278 1081-2 0.3 138K 64 1.3 0.4 179D 161 6 0.6 179E 158 5 0.4 181C 10,000 2 1.3 188C 3,764 5 0.1 188H 241 9 0.2 188L 10,000 78 2.0 190A 4,101 8 0.3 190S 10,000 275 0.1 225H 171 2 0.3 227C 1,816 36 2.0 227L 78 0.3 0.3 2341 45 NT 0.3 236L 41 1 0.3 100I + 103N 10,000 10,000 7.9 101E + 103N 7,033 84 0.5 103N + 181I 10,000 37 1.0 227L + 106A 10,000 8 1.0

活體外抗性之發展 NNRTIs為HIV-1之高選擇性抑制劑，但其目前之臨床用途卻受限於NNRTI (交又-)抗性之產生快速。因此於活體外比較對化合物E-TMC278與第一代NNRTIs尼拉本(nevirapine)與抑弗靈 (efavirenz)之抗性形成率。在不同濃度化合物 E-TMC278(40、200、1000 與 5000 X IC50) -32- 200524612 之存在下’以咼感染比例（每個細胞感染之病毒數Μ，以放大病毒族群之基因多樣性)之野生型mV-l感染“Μ細胞，每週追蹤 2次病毒之複製情形。收集所產生之表型與基因型病毒。沒有出現病毒複製證據之培養物進一步在相同濃度抑制劑冬存在下進 5 行次培養，共為期30天(傳代10次）。在所有试驗濃度下，對尼拉本(nevirapine)之抗性在34天内出現。入侵之病毒停留在典型之Y18lc突變。以抑弗靈(efavirenz) 進行相同试驗，結果在所有濃度下(至高5μΜ)，於3至7天内即選擇G190E。使用野生型病毒之化合物E_TMC278在3〇天内均 10 沒有抗性病毒選擇。若採用雙重抗性突變株K103N+Y181C · (IC50 0.8nM)替代野生型病毒時，所有試驗濃度均未出現抗性。由單一突變株 Y181C(IC50 1·3ηΜ)或 103N (IC50 0·3ηΜ)開始測试’病毒未在40與200 ηΜ時侵入，但在1〇 ηΜ時侵入。在此高基因多樣性之實驗設定下，對第一代NNRTIs具有抗 15 性之HIV-1之選擇極快速。抗性病毒僅停留在一種突變。反之，對化合物E-TMC278具有抗性之HIV-1則延後出現或沒有出現。化合物E-TMC278之心jk管及肺部安令神 · 化合物E-TMC278於活體内，在涵蓋及超過人體目標血漿 20 濃度之血漿濃度下，及於活體外，在涵蓋或超過活體外抗病毒濃度下，對心血管及肺部參數之影響很小或沒有影響。 .實例3 jjj言左化合物E-TMC278對預防綞由***或侔侶之間相關巍査接觸威染HIV之能力之活體外模式 25 例如：在一種模式中，取衍生自單核細胞之樹突細胞Development of in vitro resistance NNRTIs are highly selective inhibitors of HIV-1, but their current clinical use is limited by the rapid generation of NNRTI (cross-) resistance. Therefore, the resistance formation rates of the compound E-TMC278 and the first generation NNRTIs nevirapine and efavirenz were compared in vitro. In the presence of different concentrations of the compound E-TMC278 (40, 200, 1000, and 5000 X IC50) -32- 200524612, the ratio of infection with tadpoles (the number of viruses infected per cell is MM to amplify the genetic diversity of the virus population). Wild-type mV-1 infects M cells, and tracks virus replication twice a week. The resulting phenotype and genotype viruses are collected. Cultures without evidence of virus replication are further advanced in the presence of the same concentration of inhibitor winter 5 Subcultures were carried out for a total of 30 days (10 passages). At all concentrations tested, resistance to nevirapine appeared within 34 days. The invading virus stayed at the typical Y18lc mutation. Yifu Efavirenz performed the same test, and at all concentrations (up to 5 μM), G190E was selected within 3 to 7 days. The wild-type virus compound E_TMC278 was used for 10 days without resistance virus selection. If dual is used, When the resistant mutant strain K103N + Y181C · (IC50 0.8nM) replaced the wild-type virus, no resistance appeared at all concentrations tested. The test was started with a single mutant strain Y181C (IC50 1 · 3ηΜ) or 103N (IC50 0 · 3ηΜ). 'virus It does not invade at 40 and 200 ηM, but invades at 10 ηM. Under this experimental setting of high genetic diversity, the selection of HIV-1 with resistance to 15 for first-generation NNRTIs is extremely fast. Resistant virus only It stays in a mutation. Conversely, HIV-1, which is resistant to compound E-TMC278, appears late or does not appear. Compound E-TMC278's heart jk tube and lungs are reassuring. Compound E-TMC278 is in vivo, At plasma concentrations that cover and exceed human target plasma concentrations of 20 and in vitro, and that they cover or exceed in vitro antiviral concentrations, they have little or no effect on cardiovascular and pulmonary parameters. Example 3 jjj 言The in vitro model of the left compound E-TMC278 on the ability to prevent HIV infection by sexual intercourse or related investigations of exposure to HIV infection 25 Example: In one model, dendritic cells derived from monocytes

(MO-DC) ’採用單向轉變性HIV菌株Ba-L，依感染比例(MOI) 10·3 進行感染2小時。感染後，洗滌細胞6次，再懸浮於1〇% BCS -33· 200524612 部胞中，400,000個細胞/ml。自與MO-DC相同之溶析液之淋巴球份中純化出自體CD4(+)T細胞，使用濃度為2X106個細 /ml(MO-DC/CD4(+) T 比例：1/5)。取經一系列稀釋之式（I)化合物（試驗化合物）加至 MO-DC/CD4(+) T細胞共培養物中。各實驗係於96孔分析板中進行，其中各孔包含50μ1 MO-DC、50μ1 CD4(+) Τ細胞與 10(MO-DC) 'A unidirectional transforming HIV strain Ba-L was used, and the infection was performed for 2 hours according to the infection ratio (MOI) 10.3. After infection, cells were washed 6 times and resuspended in 10% BCS-33.200524612 cells at 400,000 cells / ml. Autologous CD4 (+) T cells were purified from the lymphosphere fraction of the same lysate as MO-DC, using a concentration of 2X106 cells / ml (MO-DC / CD4 (+) T ratio: 1/5). A series of diluted compounds of formula (I) (test compounds) were added to the MO-DC / CD4 (+) T cell co-culture. Each experiment was performed in a 96-well analysis plate, where each well contained 50 μ1 MO-DC, 50 μ1 CD4 (+) T cells and 10

ΙΟΟμΙ試驗化合物。含試驗化合物之培養基中，每週更換半量2 次。培養14天後，取上澄液進行ELISA。決定抗病毒活性時，在第一次培養物結束時，測定壓抑50%病毒複製時所需試驗化合物濃度(EC50)。化合物E-TMC278之EC50值為0.55 nM。 15 20 實例4:調配物錠劑調配物之組成如下：恩奇本(emtricitabine) 丹諾菲(tenofovir)二異丙氧基富馬酸鹽 E-TMC278鹽酸鹽 HPMC 2910 15 mPa.s 聚山梨酸酯20 乂聯聚乙稀11比嘻π定綱(Crosspolyvidone) 乳糖單水合物硬脂酸鎂滑石6 mg 300 mg 300 mg 110 mg 24 mg 6 mg 18 mg 43 mg 3 mg100 μl test compound. In the medium containing the test compound, the half amount is changed twice a week. After 14 days of culture, the supernatant was taken for ELISA. When determining antiviral activity, at the end of the first culture, the concentration of the test compound (EC50) required to suppress 50% of viral replication was determined. Compound E-TMC278 had an EC50 value of 0.55 nM. 15 20 Example 4: Formulations Tablets The composition of the formulation is as follows: emtricitabine tenofovir diisopropoxy fumarate E-TMC278 hydrochloride HPMC 2910 15 mPa.s polysorbate Ester 20 Polyethylene 11 Cross Polyvidone Lactose Monohydrate Magnesium Stearate 6 mg 300 mg 300 mg 110 mg 24 mg 6 mg 18 mg 43 mg 3 mg

取活性成分與乳糖流體化，噴灑含HPMC與聚山梨酸酯之水溶液(等於120 ml/錠）。然後添加交聯聚乙烯吼洛。定酮，同時流體化。然後添加硬脂酸鎂與滑石。所得顆粒採用標準壓縮設備壓縮成13 mm圓柱型鍵劑。 -34-The active ingredient is fluidized with lactose and sprayed with an aqueous solution of HPMC and polysorbate (equal to 120 ml / tablet). Then add cross-linked polyethylene. Ketone while fluidizing. Then add magnesium stearate and talc. The granules obtained were compressed into a 13 mm cylindrical bond using standard compression equipment. -34-

Claims

200524612 、申請專利範圍： 1· 一種組合，其包含 ⑴^[[4_(2_氰基乙·)26二曱基笨基]爛_2_射土 l·胺基]•篆基氰，亦稱為TMCr78，或其立體異構或其醫藥上可接受之鹽；或其前藥；與 ⑻核苦逆轉錄酶抑制劑與/或核苷酸逆轉錄酶抑制劑；其中TMC278與核苦酸逆轉錄酶抑制劑與核苦逆轉錄酶抑制劑在-天投藥—次之劑量下，為醫療上有效之爾抑制劑。 2. 根據申請專利範圍第β之組合，其包含 ⑴TMC278 ’或其立體異構型；或其醫或其前藥；與 *又之瓜， ⑻核苷逆轉錄酶抑制劑;其中麗278與核苷逆轉錄酶抑制劑在-天投藥一次之劑量下，為醫療上有效之勝 15 20 抑制劑。 3. 根據申請專利範圍第丨項之組合，其包含 ⑴TMC278 ’或其立體異構型；或其醫藥上可接受之越；或其前藥；與 1 ’ ⑻核㈣逆轉錄_卩軸；射聽278與料酸逆酶抑制劑在-天投藥一次之劑量下，為醫療上之 HIV抑制劑。力双々 4·根據申請專利範圍第1項之組合，其包含 (i) TMC278，或其立體異構型；或其醫藥上可接受之鹽；或其前藥；與 I’ (11)核苷逆轉錄酶抑制劑；與 Μ核苷酸逆轉錄酶抑制劑；其中tmc278與核苷酸逆轉錄酶抑制劑與核苦逆轉錄酶抑制劑在一天投藥_次之劑 -35- 25 200524612 量下’為醫療上有效之HIV抑制劑。 5·根據申請專利範圍第1項之組合，其包含 ⑴TMC278，《其立體異構型；或其醫藥上可接受之鹽；或其前藥；與 5 (ϋ)核苷逆轉錄酶抑制劑；與 (111)不同於(ii)之核苷逆轉錄酶抑制劑之第二種核苷逆轉錄酶抑制劑；其中TMC278與核苷逆轉錄酶抑制劑在一天投藥一次之劑量下，為醫療上有效之HIV抑制劑。 6·根據申請專利範圍第1至5項中任一項之組合，其中 10 TMC278呈其Ε_異構型。 ’、 7·根據申請專利範圍第1至6項中任一項之組合，其中核苷酸逆轉錄酶抑制劑與/或核苷逆轉錄酶抑制劑或抑制劑群在逆轉錄酶中選擇不會對TMC278產生抗性之突變。 8·根據申請專利範圍第1至7項中任一項之組合，其中核苷酸 15 逆轉錄酶抑制劑為丹諾菲（tenofovir)或其前藥丹諾菲 (tenofovir)二異丙氧基富馬酸鹽。 9·根據申請專利範圍第1至7項中任一項之組合，其中核苷逆轉錄酶抑制劑為恩奇本(emtricitabine)、消旋性FTC、蘭弗《定 (lamivudine)(亦稱為3TC)、阿巴卡菲(abacavir)或其醫藥上可 20 接受之鹽。 10·根據申請專利範圍第1至7項中任一項之組合，其中核苷逆轉錄8#抑制劑為恩奇本(emtricitabine)。 11.根據申請專利範圍第1至7項中任一項之組合，其中該組合包含 25 ⑴TMC278或其醫藥上可接受之鹽，與 (ii)丹諾菲(tenofovir)或其前藥丹諾菲(ten〇f〇vir)二異丙氧基富馬酸鹽，與 -36- 200524612 (iii)恩奇本(emtricitabine) 〇 12. 根據申請專利範圍第1至7項中任一項之組合，其中核苷逆轉錄酶抑制劑為蘭弗^(lamivudine)。 13. 根據申請專利範圍第8項之組合，其中該組合包含 5 ⑴TMC278或其醫藥上可接受之鹽，與 (ii) 丹諾菲(tenofovir)或其前藥丹諾菲(tenofovir)二異丙氧基富馬酸鹽， (iii) 蘭弗口定(lamivudine) 〇 14. 根據申請專利範圍第1至7項中任一項之組合，其中核苷逆 10 轉錄酶抑制劑為阿巴卡菲(abacavir)或其醫藥上可接受之鹽。 15. 根據申請專利範圍第14項之組合，其中該組合包含 (i) TMC278或其醫藥上可接受之鹽，與 (ii) 丹諾菲(tenofovir)或其前藥丹諾菲(tenofovir)二異丙氧 15 基富馬酸鹽，與 (iii) 阿巴卡菲(abacavir)或其醫藥上可接受之鹽。 16. 根據申請專利範圍第1至7項中任一項之組合，其中該組合包含 (i) TMC278或其醫藥上可接受之鹽，與 20 (ii)蘭弗唆(lamivudine)，與 (iii)恩奇本(emtricitabine)。 17. 根據申請專利範圍第1至7項中任一項之組合，其中該組合包含 (i) TMC278或其醫藥上可接受之鹽，與 25 (ii)阿巴卡菲(abacavir)，或其醫藥上可接受之鹽；與 (iii)恩奇本(emtricitabine) 〇 18. 根據申請專利範圍第1至7項中任一項之組合，其中該組合 -37- 4200524612 包含 (i) TMC278或其醫藥上可接受之鹽，與 (ii) 蘭弗 ^(lamivudine)，與㈣阿巴卡菲(―），或其醫藥 19.根據申請專利範圍第丨至18 π 现。 π— 煩甲任~項之組合，其中一 f 投樂-次之三重組合中每對成分之重量比範圍内變化。 10 2〇. -種包含根據申請專利範圍第i至19項中任一項之組合之產品’其係供同時、分開或順序投藥對抗請感染。儿-，醫藥調配物，其包含醫藥上可接受之載劑與根據申請專利範圍第1至18項中任一項之組合。 22·根據申請專利範圍帛21項之調配物，其包含作為活性成分，(〇 TMC278或其立體频贱㈣上可接*之鹽或其前 15 藥’與⑻核苷逆轉錄酶抑制劑，與㈣核苷酸逆轉錄酶抑劑0 23.根據申請專利範圍第i至18項中任一項之組合其係醫藥。 ’ 24· -種以根據巾請專利範圍第丨至18項巾任κ组合於製 20 造醫藥’供預防經由***或伴彳g之間相關親雜觸感染播HIV上之用途。 ^ -38- 200524612 七、指定代表圖： (一）本案指定代表圖為：第（）圖。（無） (二) 本代表圖之元件符號簡單說明：無八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：無200524612 Scope of patent application: 1. A combination, which contains ⑴ ^ [[4_ (2_cyanoethyl ·) 26 difluorenylbenzyl] _2_2_ 射土 l · amino] • fluorenyl cyanide, also Called TMCr78, or its stereoisomers or pharmaceutically acceptable salts thereof; or its prodrugs; and tritium nuclear bitter reverse transcriptase inhibitors and / or nucleotide reverse transcriptase inhibitors; of which TMC278 and nuclear picric acid Reverse transcriptase inhibitors and nuclear bitter reverse transcriptase inhibitors are medically effective inhibitors at the second dose. 2. According to the combination of the scope of application patent β, which contains ⑴TMC278 'or its stereoisomeric form; or its medicine or its prodrug; and * you melon, ⑻nucleoside reverse transcriptase inhibitor; of which Li 278 and nuclear Glycoside reverse transcriptase inhibitors are medically effective over 15 20 inhibitors at a once-day dose. 3. The combination according to item 丨 of the scope of patent application, which includes ⑴TMC278 'or a stereoisomeric form thereof; or a pharmaceutically acceptable residue thereof; or a prodrug thereof; and 1' ⑻ nuclear ㈣ reverse transcription _ 卩 axis; Ting 278 and feed acid reverse enzyme inhibitors are medical HIV inhibitors at a dose of once a day. Lishuangpi 4. The combination according to item 1 of the scope of patent application, which contains (i) TMC278, or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and I '(11) nuclear Glycoside reverse transcriptase inhibitors; and M nucleotide reverse transcriptase inhibitors; tmc278, nucleotide reverse transcriptase inhibitors and nuclear bitter reverse transcriptase inhibitors are administered in one day_ 次的剂 -35- 25 200524612 Amount Next 'is a medically effective HIV inhibitor. 5. The combination according to item 1 of the scope of the patent application, which includes ⑴TMC278, "its stereoisomeric form; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and 5 (i) a nucleoside reverse transcriptase inhibitor; A second nucleoside reverse transcriptase inhibitor different from (111) in (111); TMC278 and nucleoside reverse transcriptase inhibitors are medically administered at a dose of once a day Effective HIV inhibitor. 6. The combination according to any one of claims 1 to 5, wherein 10 TMC278 is in its E-isomer form. ', 7. The combination according to any one of claims 1 to 6, wherein the nucleotide reverse transcriptase inhibitor and / or the nucleoside reverse transcriptase inhibitor or inhibitor group choose not to Mutations that are resistant to TMC278. 8. The combination according to any one of items 1 to 7 of the scope of the applied patent, wherein the nucleotide 15 reverse transcriptase inhibitor is tenofovir or its prodrug tenofovir diisopropoxy Fumarate. 9. The combination according to any one of the claims 1 to 7, wherein the nucleoside reverse transcriptase inhibitor is emtricitabine, racemic FTC, lamivudine (also known as 3TC), abacavir or its pharmaceutically acceptable salt. 10. The combination according to any one of items 1 to 7 of the scope of the patent application, wherein the nucleoside reverse transcription 8 # inhibitor is emtricitabine. 11. A combination according to any one of claims 1 to 7, wherein the combination comprises 25 ⑴TMC278 or a pharmaceutically acceptable salt thereof, and (ii) tenofovir or a prodrug of it (ten〇f〇vir) diisopropoxy fumarate, and -36- 200524612 (iii) emtricitabine 〇 12. According to any one of the scope of the application for patents 1 to 7, The nucleoside reverse transcriptase inhibitor is lamivudine. 13. The combination according to item 8 of the scope of patent application, wherein the combination contains 5 ⑴TMC278 or a pharmaceutically acceptable salt thereof, and (ii) tenofovir or its prodrug tenofovir diisopropyl Oxyfumarate, (iii) lamivudine 〇14. The combination according to any one of claims 1 to 7, wherein the nucleoside reverse 10 transcriptase inhibitor is abacafi (abacavir) or a pharmaceutically acceptable salt thereof. 15. The combination according to item 14 of the scope of patent application, wherein the combination comprises (i) TMC278 or a pharmaceutically acceptable salt thereof, and (ii) tenofovir or its prodrug tenofovir II Isopropoxy 15-based fumarate, and (iii) abacavir or its pharmaceutically acceptable salt. 16. A combination according to any one of claims 1 to 7, wherein the combination comprises (i) TMC278 or a pharmaceutically acceptable salt thereof, and 20 (ii) lamivudine, and (iii ) Emtricitabine. 17. The combination according to any one of claims 1 to 7, wherein the combination comprises (i) TMC278 or a pharmaceutically acceptable salt thereof, and 25 (ii) abacavir, or A pharmaceutically acceptable salt; and (iii) emtricitabine 〇18. A combination according to any one of claims 1 to 7, wherein the combination -37-4200524612 contains (i) TMC278 or Pharmaceutically acceptable salts, and (ii) lamivudine, and 巴 abakafi (―), or their medicines 19. According to the scope of application for patents No. 丨 to 18 π. π— A combination of irritability and any one of the terms, in which the weight ratio of each pair of components in a triple combination of f fou music and second is changed. 10 2〇.-A product comprising a combination according to any one of claims i to 19 of the scope of patent application ', which is for simultaneous, separate or sequential administration against infection. -A pharmaceutical formulation comprising a combination of a pharmaceutically acceptable carrier and any one of items 1 to 18 according to the scope of patent application. 22. A formulation according to 21 of the scope of the patent application, which contains as active ingredients (〇TMC278 or a stereo-acceptable salt thereof or a pro- 15 drug 'and a nucleoside reverse transcriptase inhibitor, With the nucleoside reverse transcriptase inhibitor 0 23. It is a medicine according to the combination of any one of items i to 18 of the scope of patent application. The κ combination is used in the manufacture of 20 medicines for preventing the transmission of HIV through sexual intercourse or related intimate contact infection with 彳 g. ^ -38- 200524612 7. Designated Representative Map: (1) The designated representative map in this case is: () Figure. (None) (B) Brief description of the component symbols of this representative figure: No 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: None