TW201006823A - Use of pyrimidylaminobenzamide derivatives for the treatment of fibrosis - Google Patents
Use of pyrimidylaminobenzamide derivatives for the treatment of fibrosis Download PDFInfo
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- TW201006823A TW201006823A TW098123638A TW98123638A TW201006823A TW 201006823 A TW201006823 A TW 201006823A TW 098123638 A TW098123638 A TW 098123638A TW 98123638 A TW98123638 A TW 98123638A TW 201006823 A TW201006823 A TW 201006823A
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- Prior art keywords
- group
- lower alkyl
- phenyl
- fibrosis
- amine
- Prior art date
Links
- 206010016654 Fibrosis Diseases 0.000 title claims abstract description 28
- 230000004761 fibrosis Effects 0.000 title claims abstract description 28
- 238000011282 treatment Methods 0.000 title claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 12
- 241001465754 Metazoa Species 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 206010019668 Hepatic fibrosis Diseases 0.000 claims abstract 2
- 125000000217 alkyl group Chemical group 0.000 claims description 89
- -1 3-acridinyl Chemical group 0.000 claims description 56
- 229910052799 carbon Inorganic materials 0.000 claims description 32
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 150000001412 amines Chemical class 0.000 claims description 21
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
- 125000002950 monocyclic group Chemical group 0.000 claims description 11
- 125000002619 bicyclic group Chemical group 0.000 claims description 10
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- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 9
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- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 claims description 8
- FHZJQFANTTXVTA-UHFFFAOYSA-N 2-aminobenzamide pyrimidine Chemical compound C1=CN=CN=C1.NC(=O)C1=CC=CC=C1N FHZJQFANTTXVTA-UHFFFAOYSA-N 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
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- 229910052736 halogen Inorganic materials 0.000 claims description 7
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- QBRCMHSAOZCHQH-UHFFFAOYSA-N n-pyrimidin-2-ylbenzamide Chemical compound C=1C=CC=CC=1C(=O)NC1=NC=CC=N1 QBRCMHSAOZCHQH-UHFFFAOYSA-N 0.000 claims description 7
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 6
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- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 claims description 3
- VVZRKVYGKNFTRR-UHFFFAOYSA-N 12h-benzo[a]xanthene Chemical group C1=CC=CC2=C3CC4=CC=CC=C4OC3=CC=C21 VVZRKVYGKNFTRR-UHFFFAOYSA-N 0.000 claims description 2
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- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 claims description 2
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- VTDCYOLLYVAJSY-UHFFFAOYSA-N cyclohexyl propan-2-yl carbonate Chemical compound CC(C)OC(=O)OC1CCCCC1 VTDCYOLLYVAJSY-UHFFFAOYSA-N 0.000 claims description 2
- 208000002672 hepatitis B Diseases 0.000 claims description 2
- 230000002503 metabolic effect Effects 0.000 claims description 2
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 2
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 2
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- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 claims 2
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 claims 1
- 208000022309 Alcoholic Liver disease Diseases 0.000 claims 1
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/4164—1,3-Diazoles
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- C—CHEMISTRY; METALLURGY
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
- C07D239/12—Nitrogen atoms not forming part of a nitro radical
- C07D239/14—Nitrogen atoms not forming part of a nitro radical with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to said nitrogen atoms
Landscapes
- Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
201006823 六、發明說明: 【發明所屬之技術領域】 本發明係關於一種以如下定義之式I之0i咬胺基笨甲酿 胺或其醫藥可接受之鹽於製備用於治療纖維化之醫藥組合 物上之用途,關於一種以式I之嘧啶胺基苯甲醯胺或其醫 藥可接受之鹽於治療纖維化上之用途,關於一種治療患有 纖維化之溫血動物(包括人)之方法,其係對需要如此治療 之動物投與有效劑量之式I之嘧啶胺基苯甲醯胺或其醫藥 可接受之鹽。 【先前技術】 纖維化係特徵在於皮膚及内臟(包括腎、心、肺、肝、 皮膚及關節)中沉積胞外基質成分之病症。 文中所用之術語「纖維化」涵蓋但不限於肺纖維化、肝 纖維化、腎纖維化、心臟纖維化及硬皮病。在較佳實施例 中,纖維化係經一種或多種DDR1(盤狀結構域受體丨)、 DDR2(盤狀結構域受體2)及PDGFR(血小板衍生之生長因子 受體)激酶活性調節。 在實施例中,本發明係關於治療肺纖維化。 肺纖維化為對非特異性炎症後局部纖維化之普通病理反 歧在間質性肺炎巾發生之特定過程。纖維化變化可引起 功能性功能障礙並歸類為疾病(例如,間質性肺炎及支氣 管擴張)。 肺纖維化可呈五種不同形式屮. U々式出現支氣管、間質性、實 質性、胸膜及血管纖维化。兮τ门”,l 該不同形式即可大概決定功能 141240.doc 201006823 障礙類型,且常會一起出現。 -支氣管纖維化將產生與彌漫阻塞性氣腫有M + π 1稱之功能改 變。 -間質性纖維化主要產生彌漫性障礙。 -血管纖維化將產生肺高壓。 -胸膜纖維化將產生某種程度之換氣功能障礙,同時產 生較高程度之實質性纖維化。 肺纖維化為發病率及死亡率之主要原因。患者—般呈現 咳嗷及呼吸困難的症狀;當病症進展時,通常繼而產生慢 性呼吸困難。儘管一些形式之已知來源之肺纖維化具有^ 好預後,但特發性肺纖維化(IPF)為很少(若有)能自行消除 之漸進性病症。在大系列中,患有IPF之病人5年存活率少 於5〇%。然而,儘管開展了積極研究,治療ιρ]ρ之結果依舊 不佳。 【發明内容】 本發明係回應對治療肺纖維化(尤其間質性纖維化及特 發性肺纖維化)之替代性療法之需求。 在實施例中,本發明係關於治療肝纖維化。 文令所引用之肝纖維化包括但不限於患有下列疾病之患 者k〖生B型肝炎、c型肝炎、非酒精性脂肪肝、 酒精陡肝病、代謝性肝病(WU_氏疾病、血色素沉著 )膽汁阻塞(先天或後天)或與未知原因之纖維化有關之 肝病。 "fell tb T ’本發明係關於硬皮病,其係經DDR1(盤 141240.doc 201006823 狀結構域受體υ或DDR2(盤狀結構域受體2)激酶活性調 節。 現已發現以下定義之式I之嘧啶胺基苯甲醯胺可調節纖 維化疾病,因此給患者帶來益處。 因此,本發明係關於一種以式I之嘧啶胺基苯甲醢胺或 其醫藥可接受之鹽(單獨或與另一活性化合物組合)於製備 用於治療纖維化之醫藥組合物上之用途
其中 (a) py表示3-吡啶基,
Ri表示氫、低碳數烷基、低碳數烷氧基-低碳數烷基、 酿氧基-低碳數烷基、羧基-低碳數烷基、低碳數烷氧羰基-低碳數烷基,或苯基-低碳數烷基; I表示氫、低碳數烷基(其視需要經一個或多個相同或 不同基團R3取代)' 環烷基、苯并環烷基、雜環基、芳 基,或包含0、1、2或3個環氮原子及0或1個氧原子及〇或1 個硫原子之單環或二環雜芳基,該等基團分別未經取代或 經單或多取代;及 I表示羥基、低碳數烷氧基' 醯氧基、羧基、低碳數烷 141240.doc 201006823 氧幾基、胺甲醢基、N_單-或N,N•二取代胺甲酿基、胺 基'單或二取代胺基、環烷基、雜環基、芳基,或包含 〇、1、2或3個環氮原子及個氧原子及〇或丨個硫原子之 單環或二環雜芳基,該等基團分別未經取代或經單或 代; 或其中Ri及R2—起表不具有4、5或6個碳原子之伸烷 基,其視需要經低碳數烷基、環烷基、雜環基 '苯基 '羥 基、低碳數烷氧基、胺基、單或二取代胺基、側氧基、吡 啶基、吡嗪基或嘧啶基單或二取代;具有4或5個碳原子之 苯并伸烷基;具有1個氧原子及3或4個碳原子之氧雜伸烷 基;或具有1個氮原子及3或4個碳原子之氮雜伸烷基,其 中氮未經取代或經低碳數烷基、苯基-低碳數烷基、低碳 數烷氧羰基-低碜數烷基、羧基_低碳數烷基、胺甲醯基-低 碳數烷基、N-單-或N,N-二取代胺甲醯基-低碳數烷基、環 烷基、低碳數烷氧羰基、羧基、苯基、經取代之苯基、吡 啶基 '嘧啶基或吡嗪基取代; R4表示氫,低碳數烷基或鹵素;或 (b) py表示5-嘧啶基,R!為氫,尺2為[[(3S)_3_(二甲基 胺基)-1-。比咯烷基]甲基]-3-(三氟曱基)苯基及尺4為曱基。 較佳係式I之嘧啶胺基苯甲醯胺,其中py為3_吡啶基, 且其中彼此獨立之基團具有以下定義: • Ri表示氫、低碳數烷基、低碳數烷氧基-低碳數烷基、 醯氧基-低碳數烷基、羧基-低碳數烷基、低碳數烷氧 羰基-低碳數烷基,或苯基-低碳數烷基;以氫更佳; 141240.doc 201006823 • R2表示氫、低碳數烷基(其視需要經一個或多個相同气 不同基團R·3取代)、環烷基、笨并環烷基、雜環基、芳 基’或包含0、1、2或3個環氮原子及〇或1個氧原子及 0或1個硫原子之單環或二環雜芳基,該等基團分別未 經取代或經單或多取代; • R3表示羥基、低碳數烷氧基、醯氧基、羧基、低碳數 烷氧羰基、胺甲醯基、N-單-或n,N-二取代胺甲酿 基、胺基、單或二取代之胺基、環烷基、雜環基、芳 基,或包含0、1、2或3個環氮原子及〇或丨個氧原子及 0或1個硫原子之單環或二環雜芳基,該等基團分別未 經取代或經單或多取代;及 • R_4表示低碳數烷基,尤指曱基。 一種較佳嘧啶胺基苯甲醯胺為4_甲基_3_[〔 4_(3_吡啶 基)-2-嘧啶基]胺基〕-N-[5-(4-曱基·1Η-咪唑-i_基)_3_(三氣 甲基)苯基]苯甲醯胺,其亦稱為「尼祿替尼(nil〇tinib)」。 上文及下文使用之通用術語在本發明範圍内較佳地具有 以下意義,除非另作說明: 字首「低碳數」表示具有至多且包括最多7個碳原子(尤 其至多且包括最多4個碳原子)之基團,論述中之基團或為 直鏈或具單一或多重支鏈。 當使用複數形式之化合物、鹽等等時,此亦指單一化合 物、鹽等等。 低碳數烷基較佳係具有自丨個開始且包括丨個至包括7個 (較佳係1個開始至包括4個)碳原子,且為直鍵或分支鏈之 141240.doc 201006823 烷基;較佳地,低碳數烷基為丁基,諸如正丁基、第二丁 基、異丁基、第三丁基、丙基(諸如正丙基或異丙基)、乙 基或甲基。低碳數烷基較佳係曱基、丙基或第三丁基。 低碳數醯基較佳係甲醯基或低碳數烷基羰基,特定言之 乙醯基。 芳基為經一個位於基團之芳環碳原子上之化學鍵連接至 分子之芳香基。在較佳實施例中,芳基為具有6至14個碳 原子之芳香基,尤指苯基、萘基、四氫萘基、芴基或菲 基,且係未經取代或經一個或多個,較佳為經至多3個, 尤指1或2個特別選自下列之取代基取代:胺基、經單_或 二取代之胺基、齒素、低碳數烷基、經取代之低碳數烷 基、低奴數烯基、低碳數炔基、苯基、經基、醚化或醋化 羥基、硝基、氰基、羧基、酯化羧基、烧醢基、苯曱醯 基、胺甲醯基、N-單-或N,N-二取代之胺曱醯基、肺基、 胍基、脲基、鲸基、磺基、低碳數烷基硫基、苯基硫基、 笨基-低碳數烧基硫基、低峻數燒基苯基硫基、低碳數院 基亞磺醯基、苯基亞磺醯基、苯基-低碳數烷基亞磺醯 基、低碳數烷基苯基亞磺醯基、低碳數烷基磺醯基、苯續 醯、苯基-低碳數炫基續醯基、低碳數炫基苯基績醯基、 鹵素-低碳數烷基巯基、齒素_低碳數烷基磺酿基,諸如尤 其三氟甲基磺醯基、二羥基硼基(_B(OH)2)、雜環基、單 或二環雜芳基及結合在環中相鄰碳原子之低碳數伸燒基二 氧基,諸如亞甲二氧基。芳基更佳係苯基、萘基或四氫萘 基’其分別未經取代或獨立地經選自包括如下之群之一個 141240.doc 201006823 或兩個取代基取代:齒素,尤其氟、氣或溴;羥基;經低 碳數烧基(例如甲基)、i素-低碳數烷基(例如三氟甲基)或 苯基_化的羥基;連接至兩個相鄰碳原子之低碳數伸烷基 二氧基,例如亞甲二氧基,低碳數烷基,例如曱基或丙 基,齒素-低碳數烷基,例如三氟曱基;羥基-低碳數烷 基’例如羥甲基或2-羥基-2-丙基;低碳數烷氧基_低碳數 烧基;例如甲氧基曱基或2_甲氧基乙基;低碳數烷氧基羰 基-低碳數烷基’例如’甲氧基羰基甲基;低碳數炔基, 諸如1·丙炔基;酯化羧基,尤指低碳數烷氧基羰基,例 如’甲氧基羰基’正丙氧基羰基或異丙氧基羰基;N_單取 代之胺曱酿基’特定言之經低碳數烧基(例如甲基、正丙 基或異丙基)單取代之胺甲醯基;胺基;低碳數烷基胺 基’例如甲基胺基;二低碳數烷基胺基,例如二甲基胺基 或二乙基胺基;低碳數伸烧基-胺基,例如,。比咯燒基或 哌啶基;低碳數氧雜伸烷基-胺基,例如嗎啉基,低碳數 氮雜伸烧基-胺基’例如η底唤基,醯基胺基,例如,乙醯 基胺基或本曱酿基胺基,低碳數烧基績酿基,例如,曱確 醯基;胺磺酿基;或苯磺醢基。 環烷基較佳係環丙基、環戊基、環己基或環庚基,及可 未經取代或經一個或多個(尤其一個或兩個)選自如上所定 義芳基之取代基之群取代,最佳係經低碳數烷基(諸如甲 基)、低碳數院氧基(諸如甲氧基或乙氧基)或經基取代,及 進一步經側氧基取代或稠合成苯并環,諸如苯并環戊基或 苯并環己基。 141240.doc -10- 201006823 經取代烷基為如上所定義之烷基’尤其低碳數烷基,較 佳係甲基;其中可出現一個或多個(尤其至多三個)取代 基’其主要係選自鹵素(尤其氟)、胺基、N-低碳數烷基胺 基、N,N-二-低碳數烷基胺基、N_低碳數烷醯基胺基、羥 基、氰基、羧基、低碳數烷氧基羰基及苯基-低碳數烷氧 基羰基之群。以三氟曱基特別佳。 早或一 _取代胺基尤指經一個或兩個彼此獨立地選自如 下之取代基取代之胺基:低碳數烷基,諸如甲基;羥基 -低碳數烷基,諸如2-羥乙基;低碳數烷氧基-低碳數烷 基’諸如甲氧基乙基;苯基-低碳數烷基,諸如笨甲基或2-苯乙基;低碳數烷醯基,諸如乙醢基;苯甲醯基;經取代 之苯甲醯基,其中苯基尤其經一個或多個,較佳為1或2個 選自硝基、胺基、鹵素、N-低碳數烷基胺基、N,N-二-低 碳數烧基胺基、經基、氰基、缓基、低碳數烧氧基幾基、 低碳數烷醯基及胺甲醯基之取代基取代;及苯基_低碳數 烷氧基羰基,其中苯基未經取代或尤其經一個或多個(較 佳係一個或兩個)選自硝基、胺基、鹵素、N-低碳數烷基 胺基、N,N-二-低碳數烷基胺基、羥基、氰基、羧基、低 碳數烷氧基羰基、低碳數烷醯基及胺甲醯基之取代基取 代;較佳係N-低碳數烷基胺基(諸如N-曱基胺基)、羥基-低 碳數烷基胺基(諸如2·羥乙基胺基或2-羥丙基)、低碳數烷 氧基-低碳數烷基(諸如甲氧基乙基)、苯基·低碳數烷基胺 基(諸如苯曱基胺基)、N,N-二-低碳數烷基胺基、N-苯基 -低碳數烷基-N-低碳數烷基胺基、N,N-二-低碳數烷基苯基 141240.doc -11 - 201006823 胺基、低碳數烷醯基胺基(諸如乙醯基胺基),或為選自包 括苯甲醯基胺基及苯基-低碳數烷氧基羰基胺基之群之取 代基’其中苯基分別未經取代或尤其係經硝基或胺基取 代,或亦經鹵素、胺基、N-低碳數烷基胺基、n,N-二-低 碳數烧基胺基、幾基、氰基、叛基、低碳數烧氧基幾基、 低碳數烷醯基及胺甲醯基或胺基羰基胺基取代。二取代胺 基亦為低碳數伸烧基-胺基’例如,π比洛烧基、2 -側氧基n比 咯烷基或哌啶基;低碳數氧雜伸烷基-胺基,例如:嗎啉 基,或低碳數氮雜伸烧基-胺基,例如:派嘻基或Ν_經取 ◎ 代哌嗪基,諸如Ν-曱基哌嗪基或Ν_甲氧基羰基哌嗪基。 鹵素尤其為氟、氣、溴或碘,尤其為氟、氣或溴。 醚化羥基尤指Cs-Cm烷氧基,諸如正癸氧基,低碳數烷 氧基(較佳),諸如甲氧基、乙氧基、異丙氧基,或第三丁 氧基,苯基-低碳數烷氧基,諸如苄氧基、苯氧基,鹵素 -低碳數烷氧基,諸如三氟甲氧基、2,2,2_三氟乙氧基或 1,1,2,2-四氟乙氧基,或經包含一個或兩個氮原子之單或 雙環雜芳基取代之低碳數烷氧基,較佳係經下列取代基取Ο 代之低碳數烷氧基:咪唑基(諸如1H咪唑_丨·基)、吡咯 基、苯并咪唑基(諸如i•苯并咪唑基)、吡啶基(尤其2·、3_ 或4-吼啶基)、嘧啶基(尤其2·嘧啶基)、β比嗪基、異喹啉基 (尤其3-異喹啉基)、喹啉基、吲哚基或噻唑基。 S旨化經基尤指低碳數㈣氧基、苯甲醯氧基、低碳數烧 氧基叛基氧基,諸如第三τ氧基幾基氧基,或苯基·低礙 數烷氧基羰基氧基,諸如节氧基羰基氧基。 141240.doc •12· 201006823 s曰化叛基尤其為低ί反數烧氧基幾基,諸如第三丁氧基獄 基、異丙氧基羰基、甲氧基羰基或乙氧基羰基、苯基_低 碳數烷氧基羰基或苯氧基羰基。 烷醯基主要為烷基羰基,尤其低碳數烷醯基,例如乙醯 基。 Ν-單-或Ν,Ν-二取代胺曱醯基係尤其經一個或兩個分別 選自如下之取代基取代:低碳數烷基、苯基_低碳數烷基 及羥基-低碳數烷基,或低碳數伸烷基、氧雜_低碳數伸烷 基或於末端氮原子上視需要取代之氧雜_低碳數伸烷基。 包含〇、1、2或3個環氮原子及0或丨個氧原子及個硫 原子之單或雙環雜芳基(該基團分別未經取代或經單或多 取代)係:ί曰其中雜芳基結合至中分子其餘部分之環位置 為不飽和之雜環部分,及較佳環為在結合之環中(視需要 亦在任何稠合之環中),至少一個碳原子被選自包括氮、 氧及硫之群之雜原子置換;其中結合環較佳係具有5至12 個更佳係5或6個環原子;及其未經取代或可經一個或多 個(尤其一個或兩個)選自如上所定義芳基之取代基之群取 代最佳係經低碳數烷基(諸如甲基)、低碳數烷氧基(諸如 甲氧基或乙氧基)或羥基取代。較佳地,該單或二環雜芳 基係選自:2Η-°比咯基、σ比咯基、咪唑基、苯并咪唑基、 唑基吲唑基、嘌呤基、°比咬基、η比嗅基、喷咬基、建 嗪基、4Η·喹嗪基、異喹啉基、喹啉基、酞嗪基、喹啶 基、喹喔啉基、喹唑啉基、喹諾啉基、蝶啶基、吲哚嗪 基、3Η-吲哚基、吲哚基、異吲哚基、噁唑基、異噁唑 141240.doc •13· 201006823 基嘆唾基、異嗟峻基、三啥基、四β坐基、咬咱基苯并 [d]比唾基、嘆吩基及吱„南基。更佳地,該單或二環雜芳基 係選自》比略基、β米咬基(諸如1H__唾卜基)、苯并味。坐基 (諸如1·苯并_ 4基)H基(尤其5_。弓卜坐基)"比咬基(尤 其2_,3-或4_°比啶基)、嘧啶基(尤其2-嘧啶基)、吼嗪基、異 喹啉基(尤其3-異喹啉基)、喹啉基(尤其4或8_喹啉基)、吲 哚基(尤其3-吲哚基)、噻唑基、苯并[dp比唑基、噻吩基、 及咬味基。在本發明之一個較佳實施例中,^比咬基中氮 原子之鄰位上經經基取代,因此係至少部分呈η比咬_(1 Η): — 酮之對應互變異構體之形式存在。 在另一較佳實施例中,嘧啶基之位置2及4同時經羥基取 代及因此係呈右干互變異構物形式.(如,呈嘴t^_(iH,3H) 2,4-二酮)存在。 雜環基尤其為具有選自包括氮、氧及硫之群之一個或兩 個雜原子之五、六或七員雜環系,其可為不飽和或完全或 部分飽和,且未經取代或尤其經如下取代基取代:低碳數 烷基(諸如甲基)、苯基_低碳數炫基(諸如苯甲基)、侧氧 基、或雜芳基(諸如2-哌嗪基);雜環基尤其為2_或3_吡咯 烷基、2-側氧基_5_吡咯烷基、哌啶基、N_苯甲基哌啶 基、N-低碳數烷基_4_哌啶基、N_低碳數烷基_哌嗪基、嗎 啉基(例如2-或3-嗎啉基)、2-側氧基-1H-氮雜環庚烯 基、2-四氫呋喃、或孓曱基_丨,3·二氧戊環_2_基。 式I範圍内之嘧啶胺基苯甲醯胺,其中py為3-比啶基及 其製備方法已揭示於2004年1月15日公告之w〇 〇4/()()5281 141240.doc -14- 201006823 中,其内容已透過引用之方式併入本發明。 式I之嘧啶胺基苯甲醯胺(其中py表示5·嘧啶基,心為 氫,R2為[[(3S)-3-(二甲基胺基)-ΐ·〇比洛燒基]甲基]_3 (:氣 甲基)笨基及R_4為甲基)亦稱為ΙΝΝΟ-406。該化合物、其製 備及適合其投與之醫藥組合物在EP 1533304A中有揭示。 式I之嘧啶胺基苯甲醯胺之醫藥可接受之鹽(其中”為3· 吡啶基)尤其為彼等揭示於WO 2007/015871中者。在較佳 實施例中,尼祿替尼(nilotinib)係以其鹽酸鹽單水合物形 式使用。WO 2007/015870揭不某些適用於本發明之尼祿替 尼(nilotinib)之多晶形及其醫藥可接受之鹽。 式I之嘧啶胺基苯甲醯胺(其中py為3_吡啶基)可經任何途 徑投與’包括經口、非經腸胃式’例如腹膜内、靜脈内、 肌内、皮下 '腫瘤内或直腸,或經腸内投與。較佳地,式 I之嘧啶胺基苯甲醯胺(其中py為3-吡啶基)較佳係以每曰劑 量50至2000 mg經口投與。一種尼祿替尼(nii〇tinib)之較佳 每曰口服劑量為200至1200 mg(例如800 mg),尼祿替尼 (nilotinib)作為單一劑量或分成多劑量(諸如每曰兩次劑量) 投與。INNO-406可每日兩次以200至300 mg(例如240 mg) 之劑量經口投與。 通常’最初投與小劑量’然後逐漸增加劑量,直至達到 確定用於治療病人之最佳劑量。劑量上限係受副作用限 制,且可由接受治療之病人之試驗決定。 術語「治療」或」療法」係指文中揭示疾病之預防性或 較佳係治療性(包括但不限於減輕、治療、減緩症狀、減 141240.doc 15 201006823 少症狀、調節激酶及/或抑制激酶)處理。 在進步之態樣中,本發明係關於一種組合(諸如組合 製劑或醫藥組合物),其包含⑷至少-種式I之嘴咬胺基苯 甲酿胺,及(b)選自ΑΤι受體抬抗劑及AcE抑制劑之至少一 種化°物其中活性成分係彼此獨立地呈游離形式或呈醫 藥可接又之鹽之形式存在,&包含視需要選用之至少一種 醫藥可接受之用於同時、分開或依序使用。下文中 稱該組合為本發明之組合。 本發明之組合特別適用於治療肝纖維化。 々驚奇地相較於僅使用本發明之組合中一種醫藥活 陡成/7之單一療法,本發明之組合之活體内投藥不僅產生 有益效果(尤其協同治療效果,例如在減慢 '阻止或逆轉 纖維化方面還進—步產生令人驚奇的有益效果,例如 較少副作用、改進生活品質及減少死亡率及發病率。 另個益處為本發明之組合中活性成分劑量可以降低, 例如’不僅所需之劑量通常較低,而且其施用次數亦減 少’或可用於消除副作用之發生。此點符合待治療患者之 需要及要求。 應理解AT 1受體拮抗劑(亦為▲管緊張素11受體枯抗劑)為 連接至血管緊張素„受體之AT〗受體亞型,但不會造成受 體活化之彼等活性成分。由於ΑΤι受體抑制之結果,該等 心抗劑可例如’作為抗高血壓藥物使用或用於治療充也性 心力衰竭。 AT,受體括抗劑類包括具有不同結構特徵之化合物基 141240.doc 201006823 本上較佳的為彼等非肽類。例如,可提及選自卞列各物所 組成群中之化合物:綠沙坦(valsartan)(如在歐洲專利申請 案第0 443 983號或美國專利第5,399,578號-CAS : 137862-53 4中有敍述,商品名稱:Di〇van)、氣沙坦(i〇sartan)(如 在歐洲專利申請案第Ep 2533 1〇號中有敍述)、坎地沙坦 (candesartan)(如在歐洲專利申請案第459136號中有敍 述)、依普羅沙坦(eprosartan)(如在歐洲專利申請案第 ^^^^^號中有敍述”厄貝沙坦&^加⑽乂如在歐洲專利 申叫案第4545 11號中有敍述)、奥美沙坦(〇imesartan)(如在 歐洲專利申請案第503785號中有敍述)、他索沙坦 (tasosartan)(如在歐洲專利申請案第539〇86號中有敍述)、 替米沙坦七111^&1^11)(如在歐洲專利申請案第522314號中 有敍述)或西來替昔酯(cilexetil)。 ACE抑制劑類包含具有不同結構特徵之化合物。例如, 可提及選自下列各物所組成群中之化合物:阿拉普利 (alacepril)、貝那普利(benazepril)、貝那普利拉 (benazeprilat)、卡托普利(capt〇prii)、西羅普利 (ceronapril)、西拉普利(Ciiazaprii)、地拉普利(delapril)、 依拉普利(enalapril)、依拉普利拉(enaprilat)、福辛普利 (fosinopril)、依米普利(imidapril)、賴諾普利(lisinopril)、 莫維普利(moveltopril)、培哚普利(perindopril)、喹那普利 (quinapril)、雷米普利(ramipril)、螺普利(spiraprii)、替莫 普利(temocapril)及群多普利(trandolapril),或其各醫藥可 接受之鹽。較佳ACE抑制劑為彼等已上市之藥劑,最佳係 141240.doc 201006823 貝那普利(benazepril)及依拉普利(enaiapril)。 應理解’所提及之組合物對象亦包括化合物之醫藥可接 受之鹽。 以代碼、類別名稱或商品名稱標識之活性劑之結構可自 現行版本之標準綱要「Merek指南(Merck index)」或自資 料庫例如國際專利(例如IMS世界出版物)獲得。其相應内 容已以引用之方式併入。 當本文中揭示之組合中所使用組合對象係以作為單一藥 物上市之形式施用時,其劑量及投與方式可按照各市售藥© 物之藥品說明書上之資訊而進行,以產生文中敍述之有益 效果’除非本文中另有說明。 I在最佳實施例中,血管緊張素受體阻斷劑為纈沙坦。纈 4坦為強力之口服活性血管緊張素π受體括抗劑,其在每 :一次80及160 mg劑量下’當用於治療輕度及中度原發性 问血壓時’已顯示與常用之ACE抑制劑(包括依拉普利卜 樣有效’且具有更佳耐受性。根據本發明之組合之織沙坦 之較佳每日口服劑量為40至⑽mg之間,較佳係8〇至16〇❹ mg。 因 jit,jfe 5 _ . 組人、 項較佳態樣中,本發明係關於如上敍述之 曱酿胺用::方法’其中⑷為至少-種式1之嘧啶胺基苯 需H其尼祿替尼(nilotinib)’及(b)為纈沙坦,且視 沙挺呈塞嗓化物。令人驚奇地,作為組合對象⑻之顯 ㈦相互促有進果人預料之效果’例如,組合對象⑷及 進之政果’尤其協同作用,例如,超過加成效 I41240.doc •18· 201006823 應、額外的有益效果、較少副作用、非有效劑量下之一種 或兩種組合對象(a)及(b)所產生之組合療效,及極佳係組 合對象(a)及(b)之強力協同作用。 本發明進一步係關於一種以該組合於製備用於治療纖維 化之藥物上之用途,一種商業包裝或產品,其包含該組合 及說明書,形成組合製劑,供同時、分開或依序施用該組 合,治療纖維化,並有關一種治療纖維化之方法。 • 文中所用之術語「組合製劑」尤其定義為「成分套 組」,其疋義為如上定義之組合對象(a)及(b)可獨立投與劑 量,或使用各自獨立用量之組合對象0)及(b)之不同固定 組合投與劑量,亦即同時或在不同時間點投藥。成分套組 之成分進而可例如同時或按時程先後交錯投與,亦即對於 成分套組之成分,在不同時間點及使用相同或不同時間間 隔投藥。極佳地,選擇時間間隔,以使組合施用之成分所 治療疾病之效果大於僅施用組合對象(a)及(b)中任何一種 φ 可此單獨獲得之效果。組合製劑中待投與之組合對象(a)與 組σ對象(b)之總量比例可以變化,例如以配合待治療患者 亞群之需要或單一患者之需要(其需要可能隨患者特定疾 病、年齡、性別、體重等而不同)。較佳地,存在至少一 種有益效果’例如組合對象(a)及(b)相互促進之效果尤 其協同作用,例如,超過加成效果、額外的有益效果較 少副作用、非有效劑量之一種或兩種組合對象(a)及化)之 組合療效,及極佳係組合對象(a)及(b)之強力協同作用。 因此’在另一實施例中’本發明提供一種治療已罹患或 141240.doc •19· 201006823 可能罹患纖維化疾、虑+、β , i 七土 、病之&血動物(尤其人)(尤其治療肝纖唯 化)之方法,其包括啦外▲ 梁奸纖.准 括對该動物投與一種組合,其 明之組合及視需要潠+ s , 、匕3本發 為要選用t至少—種醫藥可Μ 合(諸如組合製劑或醫藥組合物)。 、, 本發月之自目標為提供一種醫藥組合物 纖維化疾病(尤a肝敏給儿、* 匕3紂對 组a。在^ Γ )為組合治療有效量之本發明之 組合對象⑷及(b)可呈
單位劑量形式或兩個分開之單位劑量形式共同、接連:分 開投藥。單位劑量形式亦可為固定組合。 連或刀 :於“u又與組合對象⑷及⑻及用於以固定組合 =含至少兩種組合對象⑷及⑻之單一蓋侖製劑組合物)投 醫樂組合物可根據本發明本身已知之方式製備,且為 <等適(諸如經口、直腸)及非經腸式投與包括人之 °“L動物(溫血動物)’其包含單獨或與-種或多種醫藥可 ,又之載劑組合之治療有效量之至少—種藥理活性組合對 ,尤其適合經腸或非經腸式施用。
。新穎醫藥組合物包含例如:約1〇%至1〇〇%(較佳係自約 20/。至60%)之活性成分1於經腸或非經腸式投與醫藥製 劑之組合療法為例如彼等呈單位劑型(諸如糖衣錠劑:錠 劑膠囊或栓劑及安瓶)者。若未說明,彼等係依本身已 知之方式製備,例如:f用之混合、製粒、包糖衣、溶解 或束乾法。應理解:由於可由投與多個劑量單元達到必要 :有效量’因此每一劑型之單一劑量中所包含組合對象之 早位含量本身不一定構成有效量。 141240.doc •20· 201006823 特定言之’本發明組合中各組合對象之治療有效量可同 時或依序及依任何順序投與,且成分可分開或形成固定組 合投與。本發明之組合之單獨組合對象可於治療過程期 間,在不同時間分開投與,或呈分開或單一組合形式同時 投與。而且,術語」投與」亦涵蓋施用可在活體内轉換成 該組合對象之前體藥物。因此,本發明應理解其包括所有 該等同時或交替性治療法,且術語「投與」亦可作相 釋。 應用於本發明之組合之每—組合對象之有效劑量可依施 用之特定化合物或醫藥組合物、投與方式、待治療病症、 待治療病症之嚴重性而變化。因此,本發明之組合之劑量 療法係根據包括投與途徑及患者腎及肝⑽之諸多因素而 選擇。習此相關技藝之醫生、臨床人員或獸醫很容易即可 ^並開立用於預防、對抗或阻止病症進展所需有效量之 單一活性成分處方。需要以活性成分在標無位置之可利用 性動力學為主之療程才可在沒有毒性下產生功效之活性成 分濃度範圍内達到最佳精確性。 此外,本發明提供包含作為活性成分之本發明之组合之 商業包裝’其連同說明’供同時、分開或依序用於治^纖 維化疾病或延遲其進展。 【實施方式】 熟悉相關技術者完全能夠選擇有關測試模型,以證明上 文及下文所闡明之治療適應症及有益效果。藥理學^性係 在例如已確立的活體外及活體内測試法中或在下文中主要 141240.doc -21 - 201006823 敍述之臨床研究中證實。例如,如根據以下敍述之方法或 由 Driscoll KE 等人於 Toxico.I Appl. Pharmacol. (1992) 116: 30-7中敍述之方法,於活體内測試顯示,式I之嘧啶胺基苯 曱醯胺或其醫藥可接受之鹽可抑制小鼠經石棉所誘發肺部 疤痕之形成或顯著減少小鼠經釩所誘發之肺纖維化(亦即 抑制纖維母細胞增殖,減少羥脯胺酸累積)。用於肺纖維 化之另一已確立的模式為由E.White等人公開於Am J Respir Crit Care Med. 2006,173:112-121之大鼠博來黴素模 式。 實例 實例1-大鼠博來黴素模式中之尼祿替尼(nilotinib) (AMN107) 僅使用博來黴素及使用博來黴素與若干其他化合物(包 括AMN107)之組合,藉由天狼猩紅染色法,進行測定肺部 間質中膠原沉積濃度之組織學分析。其結果示於圖1。如 圖1所示,由天狼猩紅染色組織學所測定肺部組織中間質 性膠原濃度(統計分析:曼-懷氏(Man-Whitney)分級總和試 驗法)顯示,共同投與AMN107可減少博來黴素之效應超過 50%。 【圖式簡單說明】 圖1顯示利用天狼猩紅染色測定之肺間質性膠原之相對 面積及強度(人工記分)(統計分析:曼-懷氏(Man-Whitney) 分級總和試驗法)。 141240.doc -22-
Claims (1)
- 201006823 七、申請專利範圍: 1. 一種式I之嘧啶胺基苯甲醯胺或其醫藥可接受之鹽之用 途,其中 (a) py表示3-吼啶基, Ri表示氫、低碳數烷基、低碳數烷氧基-低碳數烷 基、醯氧基-低碳數烷基、羧基-低碳數烷基、低 碳數烷氧羰基-低碳數烷基,或苯基-低碳數烷 基; 尺2表示氫、低碳數烷基(其視需要經一個或多個相 同或不同基團R3取代)、環烷基、苯并環烷基、 雜環基、芳基,或包含0、1、2或3個環氮原子及 0或1個氧原子及0或1個硫原子之單環或二環雜芳 基,該等基團分別未經取代或經單或多取代;且 R3表示羥基、低碳數烷氧基、釅氧基、羧基、低碳 數院氧羰基、胺曱醯基、N_單-或N,N-二取代胺 曱醯基、胺基、單或二取代胺基、環烷基、雜環 基、芳基,或包含0、i、2或3個環氣原子及⑷ 個氧原子及0或1個硫原子之單環或二環雜芳基, 141240.doc 201006823 該等基團分別未經取代或經單或多取代; 或其中Ri及R2—起表示具有4、5或6個碳原子之 伸烷基,其視需要經低碳數烷基、環烷基、雜環 基、苯基、羥基、低碳數烷氧基、胺基、單或二 取代胺基、側氧基、吡啶基、吡嗪基或嘧啶基單 或二取代;具有4或5個碳原子之苯并伸烷基;具 有1個氧原子及3或4個碳原子之氧雜伸烷基;或 具有1個氮原子及3或4個碳原子之氮雜伸烷基, 其中氮未經取代或經低碳數烷基、苯基_低碳數 烷基、低碳數烷氧羰基-低碳數烷基、羧基-低碳 數烷基、胺甲醯基-低碳數烷基、N-單-或Ν,Ν-二 取代胺甲醯基-低碳數烷基、環烷基、低碳數烷 氧羰基、羧基、苯基、經取代之苯基、吼啶基、 嘧咬基或"比嗪基取代; 尺4表示氫’低碳數烷基或鹵素;或 (b) py表示5-嘧啶基’ R】為氫,心為[[(38)·3·(二曱基胺 基)-1-°比洛烷基]甲基]-3-(三氟甲基)苯基及r4為曱 基; 其中字首「低碳數」表示具有至多7個且包括最多7個 碳原子之基團, 其係用於製備供治療纖維化之醫藥組合物,其中纖維 化係選自肺纖維化及肝纖維化。 2.如請求項1之用途,其中式I之嘧啶胺基苯甲醯胺為4_曱 基-3-[[4-(3-吼啶基)·2-嘧啶基]胺基_N-[5-(4-甲基-1H-咪 141240.doc -2- 201006823 唑-1-基)_3·(三氟曱基)苯基]苯甲醯胺。 3. 如請求項2之用途,其中該嘧啶胺基苯甲醯胺係呈其鹽 酸鹽單水合物之形式使用。 4. 一種治療或預防肺纖維化或肝纖維化之方法,其包括投 與式I之嘧啶胺基苯甲醯胺罾 其中 (a) py表示3-°比咬基,艮表示氫、低碳數烷基、低碳數烷氧基-低碳數烷 基、醯氧基-低碳數烷基、羧基-低碳數烷基、低 碳數烷氧羰基-低碳數烷基,或苯基-低碳數烷 基; R2表示氫、低碳數烧基(其視需要經一個或多個相 同或不同基團R3取代)、環烷基、苯并環烷基、 雜環基、芳基’或包含0、1、2或3個環氮原子及 0或1個氧原子及0或1個硫原子之單環或二環雜芳 基’該等基團分別未經取代或經單或多取代;且 R3表示羥基、低碳數烷氧基、醯氧基、羧基、低碳 數烧氧魏基、胺甲醯基、N-單或N,N-二取代胺曱 141240.doc 201006823 醯基、胺基、單或二取代胺基、環烷基、雜環 基、芳基,或包含0、1、2或3個環氮原子及 個氧原子及0或1個硫原子之單環或二環雜芳基, 該等基團分別未經取代或經單或多取代;或 1^及112—起表示具有4、5或6個碳原子之伸烷基,其 視需要經低碳數烷基、環烷基、雜環基、苯基、 羥基、低碳數烷氧基、胺基、單或二取代胺基、 侧氧基、"比啶基、η比嗪基或嘧啶基單或二取代; 具有4或5個瑞原子之苯并伸烷基;具有1個氧原 Q 子及3或4個碳原子之氧雜伸烷基;或具有1個氮 原子及3或4個碳原子之氮雜伸烷基,其中氮未經 取代或經低碳數烷基、苯基-低碳數烷基 '低碳 數烷氧羰基-低碳數烷基、羧基·低碳數烷基、胺 甲酿基-低碳數烧基、Ν-單或Ν,Ν-二基取代胺甲 酿基-低碳數烷基、環烷基、低碳數烷氧羰基、 叛基、苯基、經取代之苯基、η比咬基、嘴咬基或 吡嗪基取代; Ρ 表不風’低碳數烧基或齒素;或 (b) py表示5-嘧啶基,R,為氫,r2為[[(3S)_3_(二甲基胺 基)-1-D比咯烷基]曱基]·3-(三氟甲基)苯基及r4為甲 基; 或該化合物之醫藥可接受之鹽。 5.如明求項4之用途,其中該嘧啶胺基苯甲醯胺為4_甲基_ 3 [[4'(3-»比啶基)_2_嘧啶基]胺基]_N-[5-(4-曱基-1H-咪唑- 141240.doc • 4 - 201006823 1基)3-(二氟甲基)苯基]苯甲醯胺。 ”求員5之用途’其中該嘧啶胺基苯甲醯胺係呈其鹽 酸鹽單水合物之形式使用。 .θ求項1至3中任一項之用途或如請求項4至6中任一項 =方法,其中該纖維化係經至少-種DDR1(盤狀結構域 又體1)、DDR2(盤狀結構域受體U及(血小板衍生 之生長因子受體)激酶活性調節。8.種組合’其包含⑷至少-種如請求項!定義之式工之嘧 啶胺基苯甲醯胺及(b)選自ΑΤι受體拮抗劑及抑制劑 之至^種化合物,其中活性成分係分別獨立呈游離形 弋或呈省藥可接受之鹽之形式存在,及包含視需要選用 之至少—種醫藥可接受之載劑;用於同時、分開或依序 施用。 9·如請求項8之組合,其中該ΑΤι受體拮抗劑係選自纈沙坦 (valSartan)、氯沙坦(losartan)、坎地沙坦 依普羅沙坦(eprosartan)、厄貝沙坦(irbesartan)、奥美沙 坦(olmesartan)、他索沙坦(tasosartan)、替米沙坦 (telmisartan)或西來替昔醋(cilexetil)。 10. 如請求項9之組合,其中該ΑΤι受體拮抗劑為纈沙坦。 11. 如請求項8至1〇中任一項之組合’其中該嘴咬胺基苯甲 醯胺為4·曱基-3-[〔 4-(3-吡啶基)-2-嘧啶基]胺基·Ν_[5·(4_ 曱基·1Η-0米唾-1-基)-3-(三曱基)苯基]笨甲酿胺。 12. —種治療已罹患或可能罹患肺纖維化或肝纖維化之溫企 動物(尤其人)之方法,其包括對該動物投與如請求項8至 141240.doc 201006823 11中任/項之組合, 受之載劑。 及視需要選用之至少 〜種醫藥可接 治療肝纖維化 13. —種以如請求項8至11中任一項之組合於 上之用途。 14.如請求項1至3或13中任—項之用途,其 於為患有慢性 B型肝炎、C型肝炎、非酒精性脂肪肝、酒精性肝病、代 謝性肝病、膽汁阻塞或與未知原因之纖維化有關之肝病 之病人治療肝纖維化。 141240.doc
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