TW201737943A - 使用fasn抑制劑之方法 - Google Patents
使用fasn抑制劑之方法 Download PDFInfo
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- TW201737943A TW201737943A TW106113737A TW106113737A TW201737943A TW 201737943 A TW201737943 A TW 201737943A TW 106113737 A TW106113737 A TW 106113737A TW 106113737 A TW106113737 A TW 106113737A TW 201737943 A TW201737943 A TW 201737943A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本發明係關於治療、預防或改善TH17-或CSF1介導之疾病或病症(例如癌症、免疫病症及肥胖症)之方法,其係藉由向有需要之患者投與治療有效量之FASN抑制劑或其醫藥上可接受之鹽、水合物、溶劑合物、前藥、立體異構物或互變異構物達成。
Description
已報導在人類患者中NAFL至NASH之進展與肝中TH
17細胞之頻率顯著增加相關,Rau, M.等人,J. Immunol.
2016;196
(1):97-105。在小鼠NAFL模型中,已發現TH
17細胞所產生之肥胖症驅動型IL-17產生對NAFL至脂肪性肝炎之發展及進展至關重要。 已知IL-17受體活化誘導促發炎細胞介素之分泌且IL-17在肝星狀細胞中誘導I型膠原產生(Tan, Z.等人,J Immunol.
2013;191
(4):1835-44)。因此,預計IL-17之抑制或中和影響IL-17介導之發炎及纖維化(Tan, Z.,J Immunol.
1835-44)。 利用CSF-1分化之M2樣巨噬細胞可獲取促纖維化及免疫抑制性質。M2樣巨噬細胞及CSF-1信號轉導參與纖維化且參與腫瘤微環境中抗腫瘤反應之回避。 因此,業內需要用於治療TH
17-及CSF1驅動之病症之新穎TH
17細胞及M2巨噬細胞抑制劑。
已驚奇且意外地觀察到當在TH
17極化條件下在FASN抑制劑存在下培養人類CD4+ T細胞時,顯著抑制IL-17之產生。 本發明之第一態樣係關於治療與TH
17介導之發炎相關之病況或疾病之方法。該方法包含向需要針對與TH
17介導之發炎相關之病況或疾病進行治療之患者投與有效量之FASN抑制劑。 本發明之另一態樣係關於治療與IL-17受體活化相關之病況或疾病之方法。該方法包含向需要針對與IL-17受體活化相關之病況或疾病進行治療之患者投與有效量之FASN抑制劑。 本發明之另一態樣係關於治療器官移植患者以減少器官排斥之方法。該方法包含向需要針對減少器官排斥進行治療之患者投與有效量之FASN抑制劑。 本發明之另一態樣係關於抑制CSF-1依賴性巨噬細胞分化之方法。該方法包含使細胞與有效量之FASN抑制劑接觸。 本發明之另一態樣係關於治療與CSF-1依賴性巨噬細胞分化相關之病況或疾病之方法。該方法包含向需要針對與CSF-1依賴性巨噬細胞分化相關之病況或疾病進行治療之患者投與有效量之FASN抑制劑。
優先權之主張
本申請案主張2016年4月25日提出申請之美國申請案第62/327,167號之優先權,該案之內容以全文引用方式併入。定義
本發明化合物包括上文通常闡述之彼等化合物,且藉由本文所揭示之種類、子類及物質來進一步闡釋。如本文所使用,除非另有說明,否則以下定義應適用。出於本發明之目的,根據元素週期表,CAS版,Handbook of Chemistry and Physics,第75版來識別化學元素。此外,有機化學之一般原則闡述於「Organic Chemistry」, Thomas Sorrell, University Science Books, Sausalito: 1999及「March's Advanced Organic Chemistry」,第5版,編者:Smith, M.B.及March, J., John Wiley & Sons, New York: 2001中,該等文獻之全部內容以引用方式併入本文中。 本文所用之縮寫具有其化學及生物領域內之習用含義。根據化學領域中已知化學化合價之標準規則來構建本文所陳述之化學結構及式。 應瞭解,除非另有指示,否則上文及本發明通篇使用之以下術語具有以下含義:若缺少定義,則以熟習此項技術者已知之常規定義為準。 如本文所用術語「投與」通常係指向個體或系統投與組合物或化合物。熟習此項技術者將意識到在適當情形中可用於投與個體(例如人類)之各種途徑。舉例而言,在一些實施例中,投與可為經眼、經口、非經腸、經局部等。在一些特定實施例中,投與可為經支氣管(例如,藉由支氣管滴注)、經頰、經真皮(其可為或包含(例如)局部投與至真皮、真皮內(intradermal)、真皮內(interdermal)、經皮等中之一或多者)、經腸、動脈內、真皮內、胃內、髓內、肌內、鼻內、腹膜內、鞘內、靜脈內、室內、在特定器官內(例如肝內)、經黏膜、經鼻、經口、直腸、皮下、舌下、局部、經氣管(例如,藉由氣管內滴注)、經陰道、經玻璃體等。在一些實施例中,投與可涉及為間歇性(例如,適時隔開之複數個劑量)及/或週期性(例如,間隔相同時間段之個別劑量)投藥之投藥。在一些實施例中,投與可涉及連續投藥(例如,灌注)達至少所選時間段。在一些實施例中,特定化合物之投與可藉由投與包括該化合物之組合物達成或以其他方式將該化合物遞送至個體或系統(或至其相關部分或其中的位點)。因此,在一些實施例中,化合物之投與可藉由投與包含該化合物之組合物達成。或者或另外,在一些實施例中,化合物之投與可藉由投與達成該化合物之遞送之組合物(例如,包括在投與組合物時代謝為該化合物之該化合物前藥或其他變體之組合物)達成。 如本文所用術語「患者」或「個體」係指出於(例如)實驗、診斷、預防及/或治療目的根據本發明向其投與一或多種本文所述化合物之任何生物體,且其包括哺乳動物及非哺乳動物。哺乳動物之實例包括(但不限於)任何哺乳動物綱成員:人類、非人靈長類,例如黑猩猩及其他猿及猴物種;農場動物,例如牛、馬、綿羊、山羊、豬;家畜,例如兔、狗及貓;實驗室動物,包括齧齒動物,例如大鼠、小鼠及天竺鼠及諸如此類。非哺乳動物之實例包括(但不限於)鳥、魚及諸如此類。在本發明之一個實施例中,哺乳動物係人類。在一些實施例中,個體可罹患疾病、病症及/或病況及/或易受其影響。 術語「FASN」係指脂肪酸合酶之所有種類、類型、亞型、同型、區段、變體及突變體形式。 如本文所用術語「抑制劑」係指存在、含量、程度、類型或形式與另一藥劑(即,受抑藥劑或靶標)之降低之含量或活性相關之藥劑、條件或事件。一般而言,抑制劑可為或包括任一化學種類之藥劑,包括(例如)小分子、多肽、核酸、碳水化合物、脂質、金屬及/或任何其他顯示相關抑制活性之實體、條件或事件。在一些實施例中,抑制劑可為直接抑制劑(在該情形下其藉由(例如)結合至靶標而對其靶標直接施加其影響);在一些實施例中,抑制劑可為間接抑制劑(在該情形下其藉由與靶標之調節劑相互作用及/或以其他方式改變靶標之調節劑,使得靶標之含量及/或活性降低來施加其影響)。 術語「有效量」或「治療有效量」係指藥劑足以提供期望之生物結果之量。結果可為體徵、症狀或病因之減少及/或緩解或生物系統之任何其他期望之改變。例如,對於治療用途之「有效量」係使疾病、病症及/或病況在臨床上顯著減輕所需之包含本文所揭示化合物之組合物之量。可由熟習此項技術者使用常規實驗來確定在任一個別病例中之適當「有效」量。因此,表述「有效量」通常係指活性物質具有治療效應之量。 「哺乳動物」意指人類及其他哺乳動物。 如本文所用術語「預防(prevent或prevention)在與疾病、病症及/或病況之發生結合使用時係指降低疾病、病症及/或病況發生之風險及/或延遲疾病、病症或病況之一或多種特徵或症狀之發作。當疾病、病症或病況之發作延遲預定時間段時,預防可視為完全的。 本文所用術語「治療(treat或treatment)」與術語「預防」同義且意欲指示延遲疾病發展、預防疾病發生及/或降低該等將預計或預計發展之症狀之嚴重性。因此,該等術語包括改善現有疾病症狀、預防其他症狀、改善或預防症狀之潛在代謝原因、抑制病症或疾病,例如,停止病症或疾病之發展、減輕病症或疾病、使得病症或疾病消退、減輕由疾病或病症造成之病況,或終止或緩和疾病或病症之症狀。 「醫藥上可接受」意指在生物上或在其他方面並非不合意之材料,該材料可投與個體而不會造成任何不合意生物效應或與組合物中所含有之任何組份以有害方式相互作用。 「載劑材料」或亦稱為「賦形劑」者包括在醫藥中常用之任何賦形劑且應基於期望劑型之相容性及釋放曲線性質來選擇。例示性載劑材料包括(例如)黏合劑、懸浮劑、崩解劑、填充劑、表面活性劑、增溶劑、穩定劑、潤滑劑、潤濕劑、稀釋劑及諸如此類。「醫藥上相容之載劑材料」可包含(例如)阿拉伯樹膠、明膠、膠體二氧化矽、甘油磷酸鈣、乳酸鈣、麥芽糊精、甘油、矽酸鎂、酪蛋白酸鈉、大豆卵磷脂、氯化鈉、磷酸三鈣、磷酸氫二鉀、硬脂醯基乳酸鈉、卡拉膠(carrageenan)、單甘油酯、甘油二酯、預膠化澱粉及諸如此類。例如參見Hoover, John E.,Remington’s Pharmaceutical Sciences,
Mack Publishing Co., Easton, Pa. 1975。 如本文所用術語「脂肪族」或「脂肪族基團」意指完全飽和或含有一或多個不飽和單元之直鏈(即,無支鏈)或具支鏈、經取代或未經取代之烴鏈,或完全飽和或含有一或多個不飽和單元但不為芳香族的單環烴或雙環烴(在本文中亦稱作「碳環基」、「環脂族」或「環烷基」),其具有至分子剩餘部分之單一附接點。除非另有說明,否則脂肪族基團含有1至6個脂肪族碳原子。在一些實施例中,脂肪族基團含有1至5個脂肪族碳原子。在一些實施例中,脂肪族基團含有1至4個脂肪族碳原子。在一些實施例中,脂肪族基團含有1至3個脂肪族碳原子,且在再其他實施例中,脂肪族基團含有1至2個脂肪族碳原子。 術語「雜原子」意指氧、硫、氮、磷或矽中之一或多者(包括氮、硫、磷、或矽之任一氧化形式;任一鹼性氮之四級銨化形式;或雜環之可取代氮,例如N (如在3,4-二氫-2H
-吡咯基中)、NH (如在吡咯啶基中)或NR+
(如在N-取代之吡咯啶基中))。 本文所用術語「不飽和」意指具有一或多個不飽和單元之部分。 如本文所用「烷基」意指具有1至10個碳原子之直鏈或具支鏈飽和鏈。代表性飽和烷基包括(但不限於)甲基、乙基、正丙基、異丙基、2-甲基-1-丙基、2-甲基-2-丙基、2-甲基-1-丁基、3-甲基-1-丁基、2-甲基-3-丁基、2,2-二甲基-1-丙基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-1-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-1-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基、丁基、異丁基、第三丁基、正戊基、異戊基、新戊基、正己基及諸如此類,及更長烷基,例如庚基及辛基及諸如此類。烷基可未經取代或經取代。含有三個或更多個碳原子之烷基可為直鏈、具支鏈或環狀烷基。如本文所用「低碳烷基」意指具有1至6個碳原子之烷基。 本文所用「烯基」包括其中具有一或多個雙鍵之無支鏈或具支鏈烴鏈。烯基之雙鍵可不結合或結合至另一不飽和基團。闡釋性烯基包括(但不限於)(C2
-C8
)烯基、例如乙烯基(ethylenyl、vinyl)、烯丙基、丁烯基、戊烯基、己烯基、丁二烯基、戊二烯基、己二烯基、2-乙基己烯基、2-丙基-2-丁烯基、4-(2-甲基-3-丁烯)-戊烯基及諸如此類。烯基可未經取代或經取代。 如本文所用之「炔基」包括其中具有一或多個三鍵之無支鏈或具支鏈烴鏈。炔基之三鍵可不結合或結合至另一不飽和基團。適宜炔基包括(但不限於)(C2
-C6
)炔基,例如乙炔基、丙炔基、丁炔基、戊炔基、己炔基、甲基丙炔基、4-甲基-1-丁炔基、4-丙基-2-戊炔基、4-丁基-2-己炔基及諸如此類。炔基可未經取代或經取代。 術語「三氟甲基」、「磺醯基」及「羧基」分別包括CF3
、SO2
及CO2
H。 術語「羥基」意指OH基團。 術語烷基羥基或羥基烷基意指如上文所定義之烷基,其中烷基在其上安置有OH基團。 如本文所用術語「烷氧基」包括—O-(烷基),其中烷基係如上文所定義。 如本文所用術語「胺基烷基」意指具有一或多個氮原子且在氮上具有一或多個如上文所定義烷基之基團。 「芳烷基」或「芳基烷基」意指芳基及烷基係如前所述之芳基-烷基。較佳芳烷基包含低碳數烷基。適宜芳烷基之非限制性實例包括苄基、2-苯乙基及萘基甲基。與母體部分之鍵結係藉助烷基達成。 「雜芳基烷基」意指經由烷基部分(如上文所定義)連接至母體核心之如本文所定義之雜芳基部分。適宜雜芳基之非限制性實例包括2-吡啶基甲基、喹啉基甲基及諸如此類。 「雜環基烷基」意指經由烷基部分(如上文所定義)連接至母體核心之如本文所定義之雜環基部分。適宜雜環基烷基之非限制性實例包括六氫吡啶基甲基、六氫吡嗪基甲基及諸如此類。 亦應注意,對於本文之文字說明、方案、實例及表中之任何具有不飽和化合價之碳原子以及雜原子,皆假定其具有足夠氫原子數量以使化合價達到飽和。 在任何變量(例如芳基、雜環、R2
等)在任何成份或各式中出現一次以上時,其每次出現時之定義皆獨立於其在其他每個情況下出現時之定義。 如本文中所使用,術語「組合物」意欲涵蓋包含指定量之指定成分之產物以及直接或間接源自指定量之指定成分之組合之任何產物。 如本文所用術語「氘」意指氫之具有奇數個質子及中子之穩定同位素。 如本文所用術語「鹵基」意指具有至少一個選自氟、氯、溴及碘之鹵素之取代基。 如本文所用術語「氰基」意指碳原子藉由三鍵接合至氮原子之取代基。 如本文所用術語「胺基」意指含有至少一個氮原子之取代基。 如本文所用術語「(胺基)烷氧基」意指具有至少一個胺基及至少一個烷氧基之取代基。 如本文所用術語「芳基氧基」意指形式Ar-O-
之取代基,其中Ar係如本文所定義之芳基。 如本文所用術語「亞甲基二氧基」意指藉由兩個化學鍵經由氧連接至分子且具有結構式-O-CH2
-O-之官能基。 如本文所用之「烷氧基烷基」意指-(烷基)-O-(烷基),其中每一「烷基」獨立地係上文所定義之烷基。 如本文所用術語「(烷氧基烷基)胺基」意指具有至少一個如上文所定義之烷氧基烷基及至少一個如上文所定義之胺基之取代基。 如本文所用術語「芳基」在單獨或作為較大部分之一部分(如在「芳烷基」、「芳烷氧基」或「芳基氧基烷基」中)使用時係指具有6至24個環原子之單環或稠合多環芳香族碳環(環原子皆為碳之環結構),且該碳環包括總共具有5至10個環成員之單環及二環系統,其中系統中之至少一個環為芳香族且其中系統中之每一環含有三至七個環成員。術語「芳基」可與術語「芳基環」互換使用。在一些實施例中,8至10員二環芳基係視情況經取代之萘基環。在本發明之某些實施例中,「芳基」係指芳香族環系統,其包括(但不限於)苯基、聯苯基、萘基、蒽基及諸如此類,其可具有一或多個取代基。如本文所用,在術語「芳基」之範圍內亦包括芳香族環稠合至一或多個非芳香族環之基團,例如二氫茚基、鄰苯二甲醯亞胺基、萘二甲醯亞胺基、菲啶基或四氫萘基及諸如此類。芳基之闡釋性實例包括(但不限於)以下部分: 及諸如此類。闡釋性經取代芳基包括: 及諸如此類。 單獨或作為較大部分之一部分使用之術語「雜芳基」和「雜芳-」(例如,「雜芳烷基」或「雜芳烷氧基」)係指具有5至24個環原子之基團,且包括具有5至10個環原子、較佳5個、6個或9個環原子;具有6個、10個或14個在環狀陣列中共享之π電子;且除碳原子以外具有1至5個雜原子之彼等。雜芳基包括(但不限於)噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、三唑基、四唑基、噁唑基、異噁唑基、噁二唑基、噻唑基、異噻唑基、噻二唑基、吡啶基、嗒嗪基、嘧啶基、吡嗪基、吲嗪基、嘌呤基、萘啶基及蝶啶基。本文所用術語「雜芳基」和「雜芳-」亦包括雜芳香族環稠合至一或多個芳基、環脂族或雜環基環之基團,其中基團或附接點在雜芳香族環上。非限制性實例包括吲哚基、異吲哚基、苯并噻吩基、苯并呋喃基、二苯并呋喃基、吲唑基、苯并咪唑基、苯并噻唑基、喹啉基、異喹啉基、㖕啉基、酞嗪基、喹唑啉基、喹喏啉基、4H-
喹嗪基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基、四氫喹啉基、四氫異喹啉基和吡啶并[2,3-b]-1,4-噁嗪-3(4H)-酮。雜芳基可為單環或雙環。術語「雜芳基」可與術語「雜芳基環」、「雜芳基」或「雜芳香族」互換使用,該等術語中之任一者包括視情況經取代之環。術語「雜芳烷基」係指經雜芳基取代之烷基,其中烷基及雜芳基部分獨立地視情況經取代。雜芳基及經取代雜芳基之闡釋性實例包括(但不限於)以下部分: 及諸如此類。 如本文所用術語「環烷基」係指具有3至24個環原子之飽和或部分飽和、單環或稠合或螺多環碳環。在一些實施例中,「碳脂肪族」 (或「碳環基」或「環烷基」)係指完全飽和或含有一或多個不飽和單元但不為芳香族的單環C3
-C7
烴,其具有至分子其餘部分之單一附接點。環烷基之闡釋性實例包括(但不限於)以下部分: 及諸如此類。 如本文所用術語「雜環烷基」係指飽和或部分飽和且具有3至24個選自C原子及N、O及S雜原子之環原子之單環或稠合的或螺的多環結構。在一些實施例中,術語「雜環」、「雜環基」、「雜環基團」及「雜環」可互換使用且係指穩定的5員至7員單環或7員至10員雙環雜環部分,其飽和或部分不飽和且除碳原子外具有一或多個、較佳1至4個如上文所定義之雜原子。在關於雜環之環原子使用時,術語「氮」包括經取代之氮。作為實例,在具有0至3個選自氧、硫或氮之雜原子之飽和或部分不飽和環中,氮可為N (如在3,4-二氫-2H-
吡咯基中)、NH (如在吡咯啶基中)或+
NR (如在N-
取代之吡咯啶基中)。雜環可在產生穩定結構之任一雜原子或碳原子處附接至其側基,且任一環原子可視情況經取代。雜環烷基及經取代雜環烷基之闡釋性實例包括(但不限於): 及諸如此類。 本文所用術語「部分不飽和」係指包括至少一個雙鍵或三鍵之環部分。術語「部分不飽和」意欲涵蓋具有多個不飽和位點之環,但不欲包括如本文所定義之芳基或雜芳基部分。 本文所用術語「醫藥上可接受之鹽」係指彼等在正確醫學判斷範圍內適用於接觸人類及低等動物組織而不會產生過度毒性、刺激、過敏反應及諸如此類且與合理益處/風險比相稱之鹽。醫藥上可接受之鹽已為業內所熟知。舉例而言,S. M.Berge等人在J. Pharmaceutical Sciences, 1977, 66, 1-19中詳細闡述醫藥上可接受之鹽,該文獻以引用方式併入本文中。 本文所用數值範圍意欲包括連續整數。舉例而言,表示為「0至4」之範圍可包括0、1、2、3及4。 本文所用術語「單環、二環或三環芳基、雜芳基、環烷基或雜環烷基」意指在鄰位或鄰位及迫位稠合系統中二環或三環結構中之任一環可獨立地為芳基、雜芳基、環烷基或雜環烷基。 如本文所用術語「經取代」意指指定基團或部分具有一或多個適宜取代基,其中取代基可在一或多個位置連接至指定基團或部分。舉例而言,經環烷基取代之芳基可指示,環烷基利用鍵或藉由與芳基稠合且共有兩個或更多個共同原子連接至芳基之一個原子。 如本文所用術語「未經取代」意指指定基團沒有取代基。 如本文所用術語「視情況經取代」意指指定基團未經取代或經一或多個取代基取代。 當顯示多官能部分時,至核心之附接點可藉由線來標識。例如對於(環烷基氧基)烷基-而言係指烷基為至核心之附接點,而環烷基係經由氧基附接至烷基。在不存在線下,可假定在任一位置附接。 必須注意,如說明書及隨附申請專利範圍中所使用,除非上下文另有明確指示,否則單數形式「一(a、an)」及「該」包括複數個指示物。 在本文所闡述之FASN (FASN)之抑制劑用作治療劑時,其可與一或多種生理上可接受之賦形劑一起來投與。生理上可接受之載劑或賦形劑係可將化合物添加至其中以溶解該化合物或以其他方式促進該化合物投與之調配物。 本發明之劑型可含有一或多種本發明化合物之混合物,且可包括熟習此項技術者已知之其他材料作為醫藥賦形劑。可將穩定添加劑納入遞送劑溶液中。在一些藥物之情況下,該等添加劑之存在促進藥劑在溶液中之穩定性及可分散性。穩定添加劑可以在約0.1% (W/V)與5% (W/V)範圍內、較佳約0.5% (W/V)之濃度使用。穩定添加劑之適宜但非限制性實例包括阿拉伯樹膠(gum acacia)、明膠、甲基纖維素、聚乙二醇、羧酸及其鹽及聚離胺酸。較佳穩定添加劑係阿拉伯樹膠、明膠及甲基纖維素。 酸化劑(乙酸、冰乙酸、檸檬酸、富馬酸、鹽酸、稀鹽酸、蘋果酸、硝酸、磷酸、稀磷酸、硫酸、酒石酸);氣溶膠推進劑(丁烷、二氯二氟-甲烷、二氯四氟乙烷、異丁烷、丙烷、三氯單氟甲烷);空氣置換物(二氧化碳、氮);醇變性劑(苯甲地那銨(denatonium benzoate)、甲基異丁基酮、蔗糖八乙酸酯);鹼化劑(強氨溶液、碳酸銨、二乙醇胺、二異丙醇胺、氫氧化鉀、碳酸氫鈉、硼酸鈉、碳酸鈉、氫氧化鈉、三乙醇胺);防結塊劑(參見助流劑
);消泡劑(聚二甲基矽氧烷、二甲基矽油);抗微生物防腐劑(氯化苄烷銨、氯化苄烷銨溶液、苄索氯銨、苯甲酸、苄醇、對羥苯甲酸丁基酯、氯化鯨蠟基吡啶鎓、氯丁醇、氯甲酚、甲酚、脫氫乙酸、對羥苯甲酸乙酯、對羥苯甲酸甲酯、對羥苯甲酸甲酯鈉、酚、苯基乙基醇、乙酸苯汞、硝酸苯汞、苯甲酸鉀、山梨酸鉀、對羥苯甲酸丙基酯、對羥苯甲酸丙基酯鈉、苯甲酸鈉、脫氫乙酸鈉、丙酸鈉、山梨酸、硫柳汞、瑞香草酚);抗氧化劑(抗壞血酸、抗壞血酸棕櫚酸酯、丁基化羥基茴香醚、二丁基羥基甲苯、次磷酸、一硫代甘油、沒食子酸丙基酯、甲醛次硫酸鈉、偏亞硫酸氫鈉、硫代硫酸鈉、二氧化硫、生育酚、生育酚賦形劑);緩衝劑(乙酸、碳酸銨、磷酸銨、硼酸、檸檬酸、乳酸、磷酸、檸檬酸鉀、偏磷酸鉀、磷酸二氫鉀、乙酸鈉、檸檬酸鈉、乳酸鈉溶液、磷酸氫二鈉、磷酸二氫鈉);膠囊潤滑劑(參見錠劑及膠囊潤滑劑
);螯合劑(依地酸二鈉、乙二胺四乙酸及鹽、乙二胺四乙酸);包覆劑(羧甲基纖維素鈉、乙酸纖維素、鄰苯二甲酸乙酸纖維素、乙基纖維素、明膠、醫藥釉、羥基丙基纖維素、羥基丙基甲基纖維素、羥基丙基甲基纖維素鄰苯二甲酸酯、甲基丙烯酸共聚物、甲基纖維素、聚乙二醇、鄰苯二甲酸乙酸聚乙烯、蟲膠、蔗糖、二氧化鈦、棕櫚蠟、微晶蠟、玉米蛋白);著色劑(焦糖、氧化鐵紅、氧化鐵黃、氧化鐵黑或其摻合物);錯合劑(乙二胺四乙酸及鹽(EDTA)、乙二胺四乙酸、龍膽酸乙醇醯胺、硫酸氧基喹啉);乾燥劑(氯化鈣、硫酸鈣、二氧化矽);乳化劑及/或增溶劑(阿拉伯樹膠、膽固醇、二乙醇胺(附加劑)、單硬脂酸甘油基酯、羊毛脂醇、卵磷脂、單甘油酯及甘油二酯、單乙醇胺(附加劑)、油酸(附加劑)、油醇(穩定劑)、泊洛沙姆(poloxamer)、聚氧乙烯50硬脂酸酯、聚烴氧35蓖麻油、聚烴氧40氫化蓖麻油、聚烴氧10油醚、聚烴氧20鯨蠟硬脂醯基醚、聚烴氧40硬脂酸酯、聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯80、丙二醇二乙酸酯、丙二醇單硬脂酸酯、月桂基硫酸鈉、硬脂酸鈉、去水山梨醇單月桂酸酯、去水山梨醇單油酸酯、去水山梨醇單棕櫚酸酯、去水山梨醇單硬脂酸酯、硬脂酸、三乙醇胺、乳化蠟);過濾助劑(粉末狀纖維素、純化矽藻土);矯味劑及香料(茴香腦、苯甲醛、乙基香草醛、薄荷醇、柳酸甲酯、麩胺酸一鈉、橙花油、薄荷、薄荷油、薄荷醑、玫瑰油、濃玫瑰水、瑞香草酚、妥魯香脂(tolu balsam)酊劑、香草、香草酊劑、香草醛);助流劑及/或防結塊劑(矽酸鈣、矽酸鎂、膠體二氧化矽、滑石);保濕劑(甘油、己二醇、丙二醇、山梨醇);塑化劑(蓖麻油、二乙醯基化單甘油酯、鄰苯二甲酸二乙酯、甘油、單乙醯基化及二乙醯基化單甘油酯、聚乙二醇、丙二醇、三乙酸甘油酯、檸檬酸三乙酯);聚合物(例如,乙酸纖維素、烷基纖維素、羥基烷基纖維素、丙烯酸聚合物及共聚物);溶劑(丙酮、醇、稀醇、戊烯水合物、苯甲酸苄基酯、丁基醇、四氯化碳、氯仿、玉米油、棉籽油、乙酸乙酯、甘油、己二醇、異丙醇、甲基醇、二氯甲烷、甲基異丁基酮、礦物油、花生油、聚乙二醇、碳酸伸丙酯、丙二醇、芝麻油、注射用水、無菌注射用水、灌洗用無菌水、純化水);吸附劑(粉末狀纖維素、木炭、純化矽藻土);二氧化碳吸附劑(鋇氫氧化物石灰、鹼石灰);硬化劑(氫化蓖麻油、鯨蠟硬脂醇、鯨蠟醇、鯨蠟基酯蠟、硬脂、石蠟、聚乙烯賦形劑、十八烷醇、乳化蠟、白蠟、黃蠟);懸浮劑及/或增黏劑(阿拉伯樹膠、瓊脂、海藻酸、單硬脂酸鋁、膨潤土、純化膨潤土、岩漿膨潤土、卡波姆934p (carbomer 934p)、羧甲基纖維素鈣、羧甲基纖維素鈉、羧甲基纖維素鈉12、卡拉膠、微晶及羧甲基纖維素鈉纖維素、糊精、明膠、瓜爾膠(guar gum)、羥乙基纖維素、羥基丙基纖維素、羥基丙基甲基纖維素、鎂矽酸鋁、甲基纖維素、果膠、聚氧化乙烯、聚乙烯醇、聚維酮(povidone)、丙二醇海藻酸酯、二氧化矽、膠體二氧化矽、海藻酸鈉、黃蓍膠、黃原膠);甜味劑(阿斯巴甜(aspartame)、葡萄糖結合劑、右旋糖、賦形劑右旋糖、果糖、甘露醇、糖精、鈣糖精、鈉糖精、山梨醇、溶液山梨醇、蔗糖、可壓縮糖、特細精糖粉(confectioner’s sugar)、糖漿);錠劑黏合劑(阿拉伯樹膠、海藻酸、羧甲基纖維素鈉、微晶纖維素、糊精、乙基纖維素、明膠、液體葡萄糖、瓜爾膠、羥基丙基甲基纖維素、甲基纖維素、聚氧化乙烯、聚維酮、預膠化澱粉、糖漿);錠劑及/或膠囊稀釋劑(碳酸鈣、磷酸氫二鈣、磷酸三鈣、硫酸鈣、微晶纖維素、粉末狀纖維素、葡萄糖結合劑、糊精、右旋糖賦形劑、果糖、高嶺土、乳糖、甘露醇、山梨醇、澱粉、預膠化澱粉、蔗糖、可壓縮糖、特細精糖粉);錠劑崩解劑(海藻酸、微晶纖維素、交聯羧甲基纖維素鈉、交聯聚維酮、波拉克林鉀(polacrilin potassium)、羥乙酸澱粉鈉、澱粉、預膠化澱粉);錠劑及/或膠囊潤滑劑(硬脂酸鈣、山崳酸甘油酯、硬脂酸鎂、輕質礦物油、聚乙二醇、硬脂醯基富馬酸鈉、硬脂酸、純化硬脂酸、滑石、氫化植物油、硬脂酸鋅);張力劑(右旋糖、甘油、甘露醇、氯化鉀、氯化鈉);媒劑:矯味媒劑及/或甜味化媒劑(芳香族酏劑、化合物苯甲醛酏劑、等醇酏劑、薄荷水、山梨醇溶液、糖漿、妥魯香脂糖漿);媒劑:油質媒劑(杏仁油、玉米油、棉籽油、油酸乙酯、肉豆蔻酸異丙酯、棕櫚酸異丙酯、礦物油、輕質礦物油、肉豆蔻醇、辛基十二烷醇、橄欖油、花生油、桃仁油、芝麻油、大豆油、角鯊烷);媒劑:固體載劑(糖球);媒劑:無菌媒劑(注射用抑菌水、抑菌氯化鈉注射液);增黏劑(參見懸浮劑
);疏水劑(環聚甲基矽氧烷、聚二甲基矽氧烷、二甲基矽油);及潤濕劑及/或增溶劑(氯化苄烷銨、氯化本索寧(benzethonium chloride)、氯化鯨蠟基吡啶鎓、多庫酯鈉(docusate sodium)、壬苯醇醚9、壬苯醇醚10、辛苯醇醚9、泊洛沙姆、聚烴氧35蓖麻油、聚烴氧40氫化蓖麻油、聚烴氧50硬脂酸酯、聚烴氧10油醚、聚烴氧20、鯨蠟硬脂醯基醚、聚烴氧40硬脂酸酯、聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯80、月桂基硫酸鈉、去水山梨醇單月桂酸酯、去水山梨醇單油酸酯、去水山梨醇單棕櫚酸酯、去水山梨醇單硬脂酸酯、泰洛沙泊(tyloxapol))可用作賦形劑。此列表並非意欲具有排他性,而是僅代表賦形劑及可用於本發明劑型中之特定賦形劑之種類。 式I、I-A、I-B、I-C、I-D及I-E及其亞類之化合物可形成亦落在本發明之範圍內之鹽。應瞭解,除非另外指明,否則本文提及之各式化合物包括提及其鹽。本文所使用術語「鹽」表示利用無機酸及/或有機酸形成之酸性鹽以及利用無機鹼及/或有機鹼形成之鹼性鹽。此外,在各式之化合物含有鹼性部分(例如但不限於吡啶或咪唑)及酸性部分(例如但不限於羧酸)二者時,可形成兩性離子(「線性鹽」)且包括在本文所使用之術語「鹽」之內。醫藥上可接受(亦即無毒、生理上可接受)之鹽較佳,但亦可使用其他鹽。舉例而言,可藉由使一式化合物與一定量(例如1當量量)之酸或鹼在諸如可沈澱鹽之介質等介質中或在水性介質中反應然後凍乾來形成該式化合物之鹽。 實例性酸加成鹽包括乙酸鹽、抗壞血酸鹽、苯甲酸鹽、苯磺酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、檸檬酸鹽、樟腦酸鹽、樟腦磺酸鹽、富馬酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽、乳酸鹽、馬來酸鹽、甲磺酸鹽、萘磺酸鹽、硝酸鹽、草酸鹽、磷酸鹽、丙酸鹽、水楊酸鹽、琥珀酸鹽、硫酸鹽、酒石酸鹽、硫氰酸鹽、甲苯磺酸鹽(toluenesulfonate,亦稱為tosylate)及諸如此類。此外,通常被視為適於自鹼性醫藥化合物形成醫藥上有用的鹽之酸論述於(例如) P. Stahl等人,Camille G.(編輯)Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH;S. Berge等人,Journal of Pharmaceutical Sciences (1977) 66(1) 1-19;P. Gould, International J. of Pharmaceutics (1986) 33 201-217;Anderson等人,The Practice of Medicinal Chemistry (1996), Academic Press, New York;及The Orange Book (Food & Drug Administration, Washington, D.C.,在其網站上)。該等揭示內容以引用方式併入本文中。 實例性鹼性鹽包括銨鹽、鹼金屬鹽(例如鈉、鋰及鉀鹽)、鹼土金屬鹽(例如鈣及鎂鹽)、與有機鹼(例如,有機胺,例如二環己基胺、第三丁基胺)形成之鹽及與胺基酸(例如,精胺酸、離胺酸及諸如此類)形成之鹽。可使用諸如以下等試劑使鹼性含氮基團四級銨化:低碳數烷基鹵化物(例如甲基、乙基及丁基之氯化物、溴化物及碘化物)、硫酸二烷基酯(例如硫酸二甲基酯、硫酸二乙基酯及硫酸二丁基酯)、長鏈鹵化物(例如癸基、月桂基及硬脂醯基之氯化物、溴化物及碘化物)、芳烷基鹵化物(例如苄基及苯乙基之溴化物)及其他試劑。 出於本發明之目的,所有該等酸性鹽及鹼性鹽皆意欲係在本發明範圍內之醫藥上可接受之鹽,且認為所有酸性鹽及鹼性鹽皆等效於相應化合物之游離形式。 各式化合物及其鹽、溶劑合物、酯及前藥可以其互變異構形式(例如,作為醯胺或亞胺基醚)存在。本文涵蓋所有該等互變異構物形式作為本發明之一部分。 除非另有說明,否則本文所描繪之結構亦意欲包括該結構之所有異構(例如,鏡像異構、非鏡像異構及幾何異構(或構象異構))形式;例如,每一不對稱中心之R及S構型、Z及E雙鍵異構物及Z及E構象異構物。因此,本發明化合物之單一立體化學異構物以及鏡像異構物、非鏡像異構物及幾何(構象)混合物在本發明之範圍內。除非另有說明,否則本發明化合物之所有互變異構物形式皆在本發明之範圍內。此外,除非另有說明,否則本文所繪示之結構亦欲包括僅在一或多個同位素富集原子存在時不同之化合物。舉例而言,具有包括用氘或氚替代氫或用13
C或14
C富集碳替代碳之本發明結構之化合物在本發明之範圍內。根據本發明,所述化合物可用作(例如)分析工具、作為生物分析中之探針或作為治療劑。 符號「」除在用作繪示未知或混合立體化學之鍵時以外,表示化學部分與分子或化學式之剩餘部分之附接點。某些實施例之詳細闡述
本發明尤其係關於治療、預防或改善TH
17-或CSF1介導之疾病或病症之方法,其係藉由向有需要之患者投與治療有效量之FASN抑制劑或其醫藥上可接受之鹽、水合物、溶劑合物、前藥、立體異構物或互變異構物達成。在一些實施例中,本發明之方法可用於治療各種TH
17或CSF1依賴性疾病及病症。為治療TH
17-或CSF1介導之疾病或病症對FASN之抑制提供治療、預防或改善疾病(包括(但不限於)癌症、免疫病症及肥胖症)之新穎方法。 在一些實施例中,本發明提供抑制IL-17分泌之方法,其包含使能夠分泌IL-17之細胞與FASN抑制劑接觸。 在一些實施例中,本發明提供治療與IL-17相關之病況及疾病之方法,其包含向有需要之患者投與FASN抑制劑。在一些實施例中,可用於該等方法中之FASN抑制劑係在與在TH
17極化條件下在細胞介素存在下培養之經活化CD4+ T細胞一起培育時抑制IL-17之產生之彼等。 在一態樣中,本發明係關於治療與TH
17介導之發炎相關之病況或疾病之方法。該方法包含向需要針對與TH
17介導之發炎相關之病況或疾病進行治療之患者投與有效量之FASN抑制劑。 本發明之另一態樣係關於治療與IL-17受體活化相關之病況或疾病之方法。該方法包含向需要針對與IL-17受體活化相關之病況或疾病進行治療之患者投與有效量之FASN抑制劑。 在一些實施例中,IL-17分泌被抑制至少1%。在一些實施例中,IL-17分泌被抑制至少5%。在一些實施例中,IL-17分泌被抑制至少10%。在一些實施例中,IL-17分泌被抑制至少25%。在一些實施例中,IL-17分泌被抑制至少30%。在一些實施例中,IL-17分泌被抑制至少35%。在一些實施例中,IL-17分泌被抑制至少40%。在一些實施例中,IL-17分泌被抑制至少45%。在一些實施例中,IL-17分泌被抑制至少50%。在一些實施例中,IL-17分泌被抑制至少55%。在一些實施例中,IL-17分泌被抑制至少60%。在一些實施例中,IL-17分泌被抑制至少65%。在一些實施例中,IL-17分泌被抑制至少70%。在一些實施例中,IL-17分泌被抑制至少75%。在一些實施例中,IL-17分泌被抑制至少80%。在一些實施例中,IL-17分泌被抑制至少85%。在一些實施例中,IL-17分泌被抑制至少90%。在一些實施例中,IL-17分泌被抑制至少95%。在一些實施例中,IL-17分泌被抑制至少99%。 在一些實施例中,FASN抑制劑係揭示於WO 2014/164749中之彼等。 本文所揭示之化合物可以類似於闡述於US 2016/0002188中之程序之方式來製備,該案之全部內容係以引用方式併入本文中。 在一些實施例中,FASN抑制劑包含式I之化合物:或其醫藥上可接受之鹽,其中 R1
係未經取代或經-CH3
或-CHz
F3-z
取代之C1
-C3
羥基-烷基、未經取代或經選自由氘、-Rp
、-ORp
及-NRp
Rp1
組成之群之取代基取代之5員環烷基,或3員或4員環烷基或雜環烷基,其中(i)該3員或4員雜環烷基之雜原子環成員獨立地選自O、S或N,且(ii) 3或4員環烷基或雜環烷基未經取代或視情況經選自由氘、-Ra
、-ORa
及-NRa
Ra1
組成之群之取代基取代; L係5至10員單環或二環烷基或雜烷基,其中(i)該5至10員單環或二環雜烷基之雜原子環成員獨立地選自O、S或N,且(ii) 5至10員單環或二環烷基或雜烷基中之每一者未經取代或視情況經選自由氘及-Rb
組成之群之取代基取代; A及B獨立地係O或S; Ar1
係4至10員單環或二環芳基、雜芳基或雜環烷基,其中(i)該4至10員單環或二環雜芳基或雜環烷基具有1個、2個、3個或4個獨立地選自N、S或O之雜原子,且(ii)該4至10員單環或二環芳基、雜芳基或雜環烷基中之每一者未經取代或視情況獨立地經1或多個可相同或不同且獨立地選自由氘及-Rq
組成之群之取代基取代; R2
係H或4至15員單環、二環或三環芳基、雜芳基、環烷基或雜環烷基,其中(i)該4至15員單環、二環或三環雜芳基或雜環烷基具有1個、2個、3個、4個、5個、6個、7個或8個獨立地選自N、S或O之雜原子,且(ii)該芳基、雜芳基、環烷基或雜環烷基視情況經r個Re
之例子取代; 每一Rp
及Rp1
獨立地係H、C1
-C4
烷基或C3
-C4
環烷基; 每一Ra
及Ra1
獨立地係H、C1
-C4
烷基或C3
-C4
環烷基; 每一Rb
獨立地係鹵基、C1
-C4
烷基、C1
-C3
羥基-烷基或C3
-C4
環烷基; 每一Re
獨立地係鹵基、氰基、硝基、羥基、羥基-烷基、羥基環烷基、羥基、雜環烷基、羥基-芳基、羥基-雜芳基、胺基、胺基烷基、(胺基)烷氧基、-CONH2
、-C(O)NH(烷基)、-C(O)N(烷基)2
、-C(O)NH(芳基)、-C(O)N(芳基)2
、-CHz
F3-z
、-OCHz
F3-z
、烷基、烷氧基、烯基、炔基、芳基氧基、(烷氧基烷基)胺基、環烷基、雜環烷基、(雜環烷基)烷基、芳基、雜芳基、-O(烷基)、-O(環烷基)、-O(雜環烷基)、-O(芳基)、-O(雜芳基)、-ONH2
、-C(O)NH(烷基)、-C(O)N(芳基)2
、-C(O)NH(環烷基)、-NH(CO)環烷基、-NH(SO2
)、-NH(SO2
)烷基、-NH(SO2
)芳基、-NH(SO2
)雜芳基、-N(SO2
)環烷基、-C(O)N(烷基)2
、(芳基)烷基、(雜芳基)烷基、-S(O)2
-烷基、-S(O)2
-芳基、-S(O)2
-環烷基、-C(O)N(烷基)2
、-C(O)烷基、-NH-C(O)-烷基、-NH-C(O)-環烷基、-NH-C(O)-雜環烷基、-NH-C(O)-雜環烷基-Rd
、-NH-C(O)-Rd
、-NH-C(O)-芳基、-NH-C(O)-NH-烷基、-NH-C(O)-NH-環烷基、-NH2
(CO)環烷基、-NH-C(O)-NH-芳基、-NH-C(O)-O-烷基、-NH-C(O)-NH-環烷基、-NH-C(O)-O-環烷基、-N(Rd
)-C(O)-烷基、-N(Rd
)-C(O)-芳基、-N(Rd
)-S(O2
)環烷基、-S(O2
)NH2
、-S(O2
)NH(烷基)、-S(O2
)N(Rd
)環烷基、-S(O2
)N(烷基)2
、-C(O)N(H)(烷基)、-C(O)N(Rd
)(環烷基)、亞甲基二氧基、-CHz
F3-z
或-OCHz
F3-z
; 每一Rq
獨立地係鹵基、烷基、-CHz
F3-z
、氰基、硝基、羥基、羥基烷基、胺基、胺基烷基、(胺基)烷氧基、-CONH2
、-C(O)NH(烷基)、-C(O)N(烷基)2
、-C(O)NH(芳基)、-C(O)N(芳基)2
、-OCHz
F3-z
、烷基、烯基、炔基、烷氧基、(烷氧基烷基)胺基、-N(Rc
)-C(O)-烷基、-N(Rc
)-C(O)-芳基、環烷基、雜環烷基、芳基或雜芳基; 每一Rc
獨立地係H、鹵基、C1
-C4
烷基或C3
-C4
環烷基; 每一Rd
獨立地係H、鹵基、C1
-C4
烷基或C3
-C4
環烷基; 前提係兩個毗鄰環雜原子不皆為S或O; m為1、2、3或4; n為1、2、3或4; r為1、2、3或4 且z為0、1、2、3或4; 或其溶劑合物、酯、前藥或異構物。 在一些實施例中,FASN抑制劑包含式I-A之化合物:其中: Ar1
、R1
、R2
、Ra
、Ra1
、Rd
、Re
、Rp
、Rp1
、Rq
、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中; 或其醫藥上可接受之鹽、溶劑合物、酯、前藥或異構物。 在一些實施例中,FASN抑制劑包含式I-B之化合物:其中: Ar1
、R2
、Rc
、Rd
、Re
、Rq
、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中; 或其溶劑合物、酯、前藥或異構物。 在一些實施例中,FASN抑制劑包含式I-C之化合物:其中: R1
、R2
、Ra
、Ra1
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中;Rq
係H、鹵基、C1
-C4
烷基或C3
-C4
環烷基; 或其溶劑合物、酯、前藥或異構物。 在一些實施例中,FASN抑制劑包含式I-C’之化合物:其中: R1
、Ra
、Ra1
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中; 或其溶劑合物、酯、前藥或異構物。 在一些實施例中,FASN抑制劑包含式I-C’’之化合物:其中: R1
、Ra
、Ra1
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中; 或其溶劑合物、酯、前藥或異構物。 在一些實施例中,FASN抑制劑包含式I-D之化合物:其中: R1
’係OH或NH2
; Ar1
、R2
、Rc
、Rd
、Re
、Rq
、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中; 或其溶劑合物、酯、前藥或異構物。 在一些實施例中,FASN抑制劑包含式I-E之化合物:其中: R1
、R2
、Ra
、Ra1
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中; 或其溶劑合物、酯、前藥或異構物。 在一些實施例中,FASN抑制劑包含式I-F之化合物:R1
、R2
、Rp
、Rp1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中; 或其溶劑合物、酯、前藥或異構物。 在一些實施例中,FASN抑制劑包含式I-F’之化合物:其中: R1
、Rp
、Rp1
、Ra
、Ra1
、Rc
、Rd
、Re
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中; 或其溶劑合物、酯、前藥或異構物。 在一些實施例中,FASN抑制劑包含式I-F’’之化合物:其中: R1
、Rp
、Rp1
、Ra
、Ra1
、Rc
、Rd
、Re
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中; 或其溶劑合物、酯、前藥或異構物。 以下實施例係關於本文所闡述之任何式(若適用)。對於未特定定義之任何部分,以先前定義為準。此外,該等實施例中之部分芳基、雜芳基及雜環烷基可如早前所闡述獨立地未經取代或視情況經取代或視情況經稠合。 在一些實施例中,R1
係未經取代或經-CH3
或-CHz
F3-z
取代之C1
-C3
羥基-烷基,且A、B、L、Ar1
、R2
、Rp
、Rp1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Rq
及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R1
係5員未經取代或經羥基取代之環烷基,且A、B、L、Ar1
、R2
、Rp
、Rp1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Rq
及z係如上文所定義之且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R1
係3或4員環烷基,且A、B、L、Ar1
、R2
、Rp
、Rp1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Rq
及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R1
係3或4員雜環烷基,且A、B、L、Ar1
、R2
、Rp
、Rp1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Rq
及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R1
係 或。 且A、B、L、Ar1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R1
係 或。 且A、B、L、Ar1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R1
係,且A、B、L、Ar1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R1
係 或,且A、B、L、Ar1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,A及B係O,且L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,A及B係S,且L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,A或B係O,另一者係S,且L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,L係5至10員單環烷基,且A、B、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,L係5至10員二環烷基,且A、B、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,L係5至10員單環雜烷基,且A、B、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,L係5至10員二環雜烷基,且A、B、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,L係,m係1、2或3,n係0、1、2或3,且A、B、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,L係,且A、B、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,L係,且A、B、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ar1
係芳基,且A、B、L、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ar1
係雜芳基,且A、B、L、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ar1
係5至10員單環芳基,且A、B、L、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ar1
係5至10員二環芳基,且A、B、L、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ar1
係5至10員單環雜芳基,且A、B、L、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ar1
係5至10員二環雜芳基,且A、B、L、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ar1
係經取代或未經取代之5員單環芳基或雜芳基且該雜芳基具有1或2個獨立地係S或N之雜原子,且A、B、L、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ar1
係之經取代或未經取代形式,且A、B、L、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ar1
係經取代或未經取代之6員單環芳基或雜芳基且該雜芳基具有1或2個為N之雜原子,且A、B、L、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ar1
係之經取代或未經取代形式,Ph1
係苯基、吡啶基、吡嗪基或嘧啶基,Re
係H、鹵基或C1
-C3
烷基,且A、B、L、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ar1
係或之經取代或未經取代形式,且A、B、L、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ar1
係經取代或未經取代之6員單環芳基,且A、B、L、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ar1
係,Re
係H、鹵基或C1
-C3
烷基,且A、B、L、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ar1
係 或,且A、B、L、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ar1
係經取代或未經取代之9員6,5-二環雜芳基且該雜芳基具有1個、2個或3個獨立地為O、S或N之雜原子,且A、B、L、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ar1
係 或之經取代或未經取代形式且該雜芳基具有1個、2個或3個獨立地為S或N之雜原子,且A、B、L、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R2
係經取代或未經取代之芳基,且A、B、L、Ar1
、R1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R2
係經取代或未經取代之雜芳基,且A、B、L、Ar1
、R1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R2
係經取代或未經取代之環烷基,且A、B、L、Ar1
、R1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R2
係經取代或未經取代之雜環烷基,且A、B、L、Ar1
、R1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R2
係經取代或未經取代之單環或二環5至10員芳基或雜芳基,且A、B、L、Ar1
、R1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R2
係未經取代或經取代之單環6員芳基,且A、B、L、Ar1
、R1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R2
係 或,且A、B、L、Ar1
、R1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Rp
、Rp1
、Rq
、n、m及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R2
係經取代或未經取代之二環8-10員芳基或8-10員雜芳基,且A、B、L、Ar1
、R1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R2
係經取代或未經取代之8員5,5二環雜芳基且該雜芳基具有1個、2個、3個或4個雜原子且該等雜原子獨立地係O、S或N,且A、B、L、Ar1
、R1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R2
係 或之經取代或未經取代形式,且A、B、L、Ar1
、R1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R2
係經取代或未經取代之9員6,5二環雜芳基且該雜芳基具有1個、2個、3個或4個雜原子且該等雜原子獨立地係O、S或N,且A、B、L、Ar1
、R1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R2
係 或之經取代或未經取代形式,且A、B、L、Ar1
、R1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R2
係經取代或未經取代之10員6,6二環芳基或雜芳基且該雜芳基具有1個、2個、3個或4個雜原子且該等雜原子係O、S或N,且A、B、L、Ar1
、R1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R2
係 或之經取代或未經取代形式,且A、B、L、Ar1
、R1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R2
係視情況經取代苯并噁唑基,且A、B、L、Ar1
、R1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,R2
係視情況經取代苯并咪唑基,且A、B、L、Ar1
、R1
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rp
係H,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp1
、Rq
、n、m、r及z係如上文所定義之且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rp
係鹵基,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rp
係C1
-C4
烷基,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rp
係C3
-C4
環烷基,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rp1
係H,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rp1
係鹵基,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rp1
係C1
-C4
烷基,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rp1
係C3
-C4
環烷基,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ra
係H,且A、B、L、Ar1
、R1
、R2
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ra
係鹵基,且A、B、L、Ar1
、R1
、R2
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ra
係C1
-C4
烷基,且A、B、L、Ar1
、R1
、R2
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ra
係C3
-C4
環烷基,且A、B、L、Ar1
、R1
、R2
、Ra1
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ra1
係H,且A、B、L、Ar1
、R1
、R2
、Ra
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ra1
係鹵基,且A、B、L、Ar1
、R1
、R2
、Ra
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ra1
係C1
-C4
烷基,且A、B、L、Ar1
、R1
、R2
、Ra
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Ra1
係C3
-C4
環烷基,且A、B、L、Ar1
、R1
、R2
、Ra
、Rb
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rb
係H,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rb
係鹵基,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rb
係C1
-C4
烷基,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rb
係C1
-C3
羥基-烷基,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rb
係C3
-C4
環烷基,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rc
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rc
係H,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rc
係鹵基,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rc
係C1
-C4
烷基,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rc
係C3
-C4
環烷基,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rd
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rd
係H,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rd
係鹵基,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rd
係C1
-C4
烷基,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rd
係C3
-C4
環烷基,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Re
、Rp
、Rp1
、Rq
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rq
係H,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Re
、Rp
、Rp1
、Rd
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rq
係鹵基,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Re
、Rp
、Rp1
、Rd
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rq
係C1
-C4
烷基,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Re
、Rp
、Rp1
、Rd
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,Rq
係C3
-C4
環烷基,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Re
、Rp
、Rp1
、Rd
、n、m、r及z係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,z係0,且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Re
、Rp
、Rp1
、Rq
、Rd
、n、m及r係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,z係1且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Re
、Rp
、Rp1
、Rq
、Rd
、n、m及r係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在一些實施例中,z係2且A、B、L、Ar1
、R1
、R2
、Ra
、Ra1
、Rb
、Rc
、Re
、Rp
、Rp1
、Rq
、Rd
、n、m及r係如上文所定義且單獨及以組合闡述於本文之種類及子類中。 在本文所提供方法之一些實施例中,對於如在上文各式中所闡述之化合物,R2
不為之經取代或未經取代形式,其中X係N或CH。 在本文所提供方法之一些實施例中,對於如在上文各式中所闡述之化合物,當AR1
係在1位連接至之,且X1
及X2
獨立地係N或C-Rz
,且Ry
及Rz
係任一取代基時,則Rx
不包括炔基、烯基、芳基、5-14員雜環、5-14員雜芳香族或4-9員碳環。 在本文所提供方法之一些實施例中,對於如在上文各式中所闡述之化合物,當R2
係時,Ar1
不為以下之經取代或未經取代形式: 或。 在本文所提供方法之一些實施例中,對於如在上文各式中所闡述之化合物,當Ar1
係5員雜芳基之經取代或未經取代形式時,Ar1
係。 在一些實施例中,可用於所提供方法中之FASN抑制劑選自由以下組成之群:化合物1 化合物2化合物3 化合物4化合物5 化合物6化合物7 化合物8化合物9 化合物10化合物11化合物12化合物13 及 化合物14 或其醫藥上可接受之鹽。 在其他實施例中,FASN抑制劑包括(但不限於) TVB-2640;GSK2194069;GSK1995010;GSK837149A;JNJ54302833;BI00179;IPI-9119;奧利司他(Orlistat);淺藍菌素(Cerulenin)及C75 (4-亞甲基-2-辛基-5-側氧基四氫呋喃-3-甲酸);以及揭示於WO 2014/146747中之FASN抑制劑,該案係以全文引用方式併入。 在一些實施例中,FASN抑制劑係揭示於WO 2014/164749中之彼等。 在一些實施例中,與IL-17相關之病況及疾病係與TH
17介導之發炎相關之病況及疾病。 在一些實施例中,與IL-17相關之病況及疾病係與IL-17受體活化相關之病況及疾病。 在一些實施例中,藉由所提供方法治療之疾病係癌症。在一些實施例中,該癌症選自由以下組成之群:前列腺癌、卵巢癌、胰臟癌、食管癌、甲狀腺癌、膀胱癌、骨癌、膽管癌、睪丸癌、子宮癌、頭癌、頸癌、唾液腺癌、子宮頸癌、結腸癌、乳房癌、肺癌、胃癌、血液癌(例如(但不限於)白血病、淋巴瘤及多發性骨髓瘤);中線癌、間葉性腫瘤、肝腫瘤、腎腫瘤及神經腫瘤;及黑色素瘤、鱗狀細胞癌及皮膚T細胞淋巴瘤;及小細胞及非小細胞肺癌、去勢抵抗性前列腺癌、神經膠母細胞瘤、星細胞瘤、神經管胚細胞瘤、神經胚細胞瘤、神經纖維瘤病、默克爾細胞癌(merkel cell carcinoma)、軟組織肉瘤、骨肉瘤、尤因氏肉瘤(Ewing’s sarcoma)及膽道癌。 用於治療 NASH 之用途
NASH係具有不同程度之發炎及纖維化之慢性肝病,其可進展至硬化及晚期肝併發症。該疾病在影響美國1600多萬人且係美國第二大肝移植原因。此外,NASH係2型糖尿病、心血管疾病及晚期腎病之強力預測子。目前沒有批準用於治療NASH之藥理學藥劑,此代表巨大健康照護負擔。NASH之發病機制與肥胖症或異常代謝症候群相關。靶向所有三個病理過程(脂肪變性、發炎及纖維化)之策略可最有效地管控此疾病。 FASN係藉由利用丙二醯基-CoA作為受質合成棕櫚酸酯來催化DNL之最終步驟之重要酶。在小鼠(FASNLKO小鼠)中肝特異性燒蝕編碼FASN之基因使得肝中之丙二醯基-CoA增加及棕櫚酸酯降低。另外,與瘦小鼠對照相比,在缺乏瘦素之肥胖小鼠(ob/ob小鼠)中,肝FASN基因表現及肝FASN活性增加。在ob/ob小鼠中肝特異性抑制生脂肪性轉錄因子碳水化合物反應元件結合蛋白(ChREBP)之後,發生肝脂質累積及肝DNL之進一步減少。令人驚訝的是,FASNLKO小鼠顯示正常肝甘油三酯含量,表明DNL可分配在健康肝中且FASN抑制可不負面影響未患病肝之功能。 FASN控制DNL之最後步驟,且與健康志願者相比,在NASH患者中該FASN之基因表現程度異常升高。不受控DNL係脂肪肝變性之關鍵貢獻因素。肝細胞內肝DNL之長期活化及游離脂肪酸運輸之增加可導致生成有毒脂質代謝物。該等脂毒性代謝物充當活性含氧物(ROS),觸發肝駐留型細胞、肝細胞、庫弗氏細胞(Kupffer cell)及肝星狀細胞(HSC)中之內質網(ER)應力、細胞凋亡及壞死。因此,升高之FASN活性可因脂毒性介導之組織損傷及細胞死亡而為NASH之主要貢獻因素。 FASN除在脂肪變性及脂毒性中之作用以外,其可促成發炎及纖維化之進程。脂肪酸合成路徑之末端產物棕櫚酸酯在原代肝細胞及庫弗氏細胞中上調TLR4促發炎細胞介素及腫瘤壞死因子-α (TNF-α)產生。因此,DNL生成TH
17細胞分化及功能所必需之脂肪酸。人類肝中增加之TH
17細胞含量與非酒精性脂肪肝(NAFL)至NASH之進展相關。在小鼠肝病模型(四氯化碳(CCl4
)誘導之肝損傷模型)中,IL-17亦藉助肝星狀細胞活化及後續膠原產生而促進肝纖維化。在小鼠中HSC活化之刺激係藉由IL-17之升高及棕櫚酸酯進行。 在NASH中DNL路徑之重要性係藉由該路徑中其他酶(例如乙醯基-CoA羧化酶1/2 (ACC))之抑制劑來證實。ACC1係直接位於FASN上游之酶,其催化丙二醯基-CoA自乙醯基-CoA之產生。在臨床前NASH模型中,ACC1/2之小分子抑制劑(例如NDI-010976 (Nimbus Therapeutics/Gilead))減少脂肪變性及纖維化,但其可攜載不期望之脂肪酸β-氧化之機械風險。 不希望受限於任何具體理論,據信靶向FASN代表藉由減少脂肪變性及TH
17依賴性發炎及纖維化來治療NASH之潛在強大的多模態方法。 在某些實施例中,本發明提供治療選自纖維變性疾病或纖維化、發炎疾病、病症或病況或自體免疫疾病、病症或病況之疾病、病症或病況之方法,其包含向有需要之患者投與FASN抑制劑(例如,式I化合物)。 在某些實施例中,本發明提供治療NASH之方法,其包含向有需要之患者投與FASN抑制劑(例如,式I化合物)。 其他用途
在一些實施例中,本發明提供治療與TH
17介導之發炎相關之疾病、病症或病況之方法,該方法包含向有需要之患者投與FASN抑制劑。 在一些實施例中,本發明提供治療與IL-17受體活化相關之疾病、病症或病況之方法,該方法包含向有需要之患者投與FASN抑制劑。 在一些實施例中,疾病係NASH。 在一些實施例中,該病況或疾病係肥胖症(Berndt等人,Diabetologia
, 2007, 50: 1472-1480;Lodhi等人,Cell Metabolism
, 2012, 16, 189-201)。在其他實施例中,該病況或疾病係II型糖尿病。 在一些實施例中,該疾病選自由發炎性腸病及慢性阻塞性肺病組成之群。 在一些實施例中,該疾病選自由過敏性接觸性皮膚炎及自體免疫肌炎組成之群。 在另一實施例中,該疾病選自由以下組成之群:全身或組織發炎、對感染或低氧之發炎反應、細胞活化及增殖、脂質代謝、纖維化及病毒感染之預防及治療。 在另一實施例中,該疾病選自由慢性及發炎病況組成之群,包括(但不限於)類風濕性關節炎、骨關節炎、齒根骨膜炎、急性痛風、牛皮癬、牛皮癬關節炎、關節黏連性脊椎炎、HIV相關性腎病變、肌肉萎縮性脊髓側索硬化症、肺動脈高血壓、急性同種異體移植排斥、慢性器官移植排斥、全身性紅斑狼瘡、狼瘡性腎炎、多發性硬化、克隆氏病(Crohn’s disease)、潰瘍性結腸炎、嚴重腹腔/腹部疾病、氣喘、慢性阻塞性氣道疾病、肺炎、心肌炎、心包炎、肌炎、濕疹、皮膚炎、脫髪、白斑病、大皰性皮膚病、腎炎、血管炎、動脈粥樣硬化、阿茲海默氏病(Alzheimer’s disease)、抑鬱症、薛格連氏症候群(Sjogren’s syndrome)、涎腺炎、視網膜中央靜脈阻塞、視網膜分支靜脈阻塞、歐文-加斯症候群(Irvine-Gass syndrome)、旁中心凹毛細血管擴張、色素性視網膜炎、睫狀體平坦部炎、散射狀視網膜脈絡膜病變、黃斑前膜、囊性黃斑水腫、黃斑病變、玻璃體黃斑牽拉症候群、視網膜脫落、視神經網膜炎、特發性黃斑水腫、視網膜炎、乾眼病、春季角膜結膜炎、特應性角膜結膜炎、前眼色素層炎、全葡萄膜炎、後眼色素層炎、眼色素層炎相關黃斑水腫、鞏膜炎、糖尿病性視網膜病變、糖尿病性黃斑水腫、年齡相關性黃斑失養症、肝炎、胰臟炎、原發性膽汁性肝硬化、硬化性膽管炎、艾迪森氏病(Addison’s disease)、垂體炎、甲狀腺炎、I型糖尿病及移植器官之急性排斥。 在另一實施例中,該疾病選自由以下組成之群:急性發炎病況,例如急性痛風;巨細胞動脈炎;腎炎(包括狼瘡性腎炎);腎小球性腎炎;及血管炎,包括巨細胞動脈炎、華格納氏肉芽病(Wegner’s granulomatosis)、結節性多動脈炎、貝塞氏病(Becet’s disease)、川崎氏病(Kawasaki disease)、高安氏動脈炎(Takayasu’s arteritis)、壞疽性膿皮症、涉及器官之血管炎及移植器官之急性排斥。 在另一實施例中,該疾病選自由以下組成之群:對細菌、病毒、真菌、寄生蟲或其毒素之感染之發炎反應,例如(但不限於)敗血症、敗血症症候群、敗血性休克、內毒素血症、全身發炎反應症候群、多器官功能障礙症候群、中毒性休克症候群、急性肺損傷、急性呼吸窘迫症候群、急性腎衰竭、猛暴型肝炎、燒傷、急性胰臟炎、手術後症候群、類肉瘤病、赫氏反應(Herxheimer reaction)、腦炎、脊髓炎、腦膜炎、瘧疾;與病毒感染相關之全身發炎反應,例如(但不限於)流行性感冒、帶狀皰疹、單純皰疹及冠狀病毒。 本發明之另一實施例係關於治療與全身發炎反應症候群相關之疾病(例如(但不限於)敗血症、燒傷、胰臟炎、嚴重創傷、出血及缺血)之方法,該方法包含投與FASN抑制劑。 本文亦提供治療器官移植患者以減少器官排斥之方法,該方法包含向需要其之患者投與FASN抑制劑。 本發明之另一態樣係關於治療器官移植患者以減少器官排斥之方法。該方法包含向需要針對減少器官排斥進行治療之患者投與有效量之FASN抑制劑。 本發明之另一態樣係關於抑制CSF-1依賴性巨噬細胞分化之方法。該方法包含使細胞與有效量之FASN抑制劑接觸。 本發明之另一態樣係關於治療與CSF-1依賴性巨噬細胞分化相關之病況或疾病之方法。該方法包含向需要針對與CSF-1依賴性巨噬細胞分化相關之病況或疾病進行治療之患者投與有效量之FASN抑制劑。 在一些實施例中,該病況及疾病選自由骨關節炎及疼痛組成之群。 在一些實施例中,該病況或疾病係惡性黑色素瘤。 在一些實施例中,該病況或疾病係發炎性疾病。 在一些實施例中,該病況或疾病係發炎性腸病。在一個實施例中,發炎性腸病係克羅恩氏病(Crohn's disease)。在其他實施例中,發炎性腸病係潰瘍性結腸炎。在另一實施例中,發炎性疾病係類風濕性關節炎。 在另一實施例中,FASN抑制劑選自顯示於表 A
中之化合物,該表列示該等化合物之IUPAC名稱及結構。表 A. 醫藥組合物
在另一態樣中,本發明包含治療可與IL-17或TH
17相關或如本文另外闡述之病況及疾病,其包含投與包含所提供化合物視情況與醫藥上可接受之賦形劑(例如載劑)之組合之醫藥組合物。 適宜醫藥組合物包括本文所揭示化合物之光學異構物、非鏡像異構物或醫藥上可接受之鹽。舉例而言,在一些實施例中,醫藥組合物包括醫藥上可接受之鹽。包括在醫藥組合物中之化合物可共價附接至醫藥上可接受之載劑。或者,包括在醫藥組合物中之本發明化合物不共價連接至醫藥上可接受之載劑。 如本文所用「醫藥上可接受之載劑」係指並不有害地與根據所提供方法使用之化合物發生反應且適於經腸或非經腸施用之醫藥賦形劑,例如,醫藥上、生理上可接受之有機或無機載劑物質。適宜之醫藥上可接受之載劑包括水、鹽溶液(例如林格氏溶液(Ringer's solution))、醇、油、明膠及碳水化合物(例如乳糖、直鏈澱粉或澱粉)、脂肪酸酯、羥甲基纖維素及聚乙烯基吡咯啶。可將該等製劑滅菌且若期望將其與輔助劑(例如潤滑劑、防腐劑、穩定劑、潤濕劑、乳化劑、用於影響滲透壓之鹽、緩衝劑、著色劑及/或芳族物質及諸如此類並不有害地與根據本文所提供方法使用之化合物發生反應者)混合。 化合物可單獨投與或可連同一或多種其他藥物一起共投與患者。共投與意欲包括同時或依序投與個別或組合之化合物(一種以上化合物)。在一些實施例中,製劑係與其他活性物質組合(例如以減少代謝降解)。調配物
在另一態樣中,本發明包含治療可與IL-17或TH
17相關或如本文另外闡述之病況及疾病,其包含投與本文所闡述化合物或組合物之調配物。可製備適宜調配物並以各種口服、非經腸及局部劑型投與。在一些實施例中,可藉由注射(例如靜脈內、肌內、皮內、皮下、十二指腸內或腹膜腔內)投與所提供之化合物。在一些實施例中,藉由吸入(例如,以鼻內方式)投與本文所闡述之化合物。在一些實施例中,經皮投與所提供之化合物。亦設想可使用多種投與途徑(例如肌內、經口、經皮)投與本發明之化合物。本發明亦提供包含一或多種所提供化合物及一或多種醫藥上可接受之載劑或賦形劑之醫藥組合物。 醫藥上可接受之載劑可為固體或液體。固體形式製劑包括粉末、錠劑、丸劑、膠囊、扁囊劑、栓劑及可分散顆粒。在一些實施例中,固體載劑為一或多種物質,其亦可用作稀釋劑、矯味劑、黏合劑、防腐劑、錠劑崩解劑或囊封材料。 在一些實施例中,當組合物係粉末時,載劑係與微細活性組份混合之微細固體。在一些實施例中,當將組合物調配成錠劑時,將活性組份與具有必需結合性質之載劑以適宜比例混合並以期望之形狀及大小將其壓緊。 在一些實施例中,粉末及錠劑含有5%至70%之活性化合物。適宜載劑包括碳酸鎂、硬脂酸鎂、滑石、糖、乳糖、果膠、糊精、澱粉、明膠、黃蓍膠、甲基纖維素、羧甲基纖維素鈉、低熔點蠟、可可脂及諸如此類。在一些實施例中,將組合物調配成扁囊劑或菱形錠劑。在一些實施例中,使用錠劑、粉末、膠囊、丸劑、扁囊劑及/或菱形錠劑作為適於經口投與之固體劑型。 在一些實施例中,為製備栓劑,首先將低熔點蠟(例如脂肪酸甘油酯混合物或可可脂)熔化且使活性組份均勻分散在其中。然後將熔化之均質混合物倒入便利大小之模具中,使其冷卻以固化。 液體形式製劑包括溶液、懸浮液及乳液,例如水或水/丙二醇溶液。在一些實施例中,對於非經腸注射而言,液體製劑可調配成於聚乙二醇水溶液中之溶液。 在需要或期望非經腸施用時,尤其適於本發明化合物之混合物係可注射、無菌溶液、較佳地油性溶液或水溶液以及懸浮液、乳液或植入物(包括栓劑)。具體而言,用於非經腸投與之載劑包括右旋糖水溶液、鹽水、純水、乙醇、甘油、丙二醇、花生油、芝麻油、聚氧乙烯-嵌段聚合物及諸如此類。安瓿係便利單位劑量。可用於所提供方法中之化合物亦可納入脂質體中或經由經皮幫浦或貼片來投與。適用於本發明中之醫藥混合物包括闡述於(例如)Pharmaceutical Sciences
(第17版, Mack Pub. Co., Easton, PA)及WO 96/05309中之彼等,該等文獻中之每一者均一引用方式併入本文中。 可藉由將活性組份溶解於水中並視需要添加適宜著色劑、矯味劑、穩定劑及增稠劑來製備適於經口使用之水溶液。可藉由將微細活性組份與黏性材料(例如天然或合成膠、樹脂、甲基纖維素、羧甲基纖維素鈉及其他熟知懸浮劑)一起分散於水中來製備適於經口使用之水性懸浮液。 亦包括意欲在使用前不久轉化為供經口投與之液體形式製劑之固體形式製劑。該等液體形式包括溶液、懸浮液及乳液。該等製劑除含有活性組份外亦可含有著色劑、矯味劑、穩定劑、緩衝劑、人工及天然甜味劑、分散劑、增稠劑、增溶劑及諸如此類。 在一些實施例中,醫藥組合物係呈單位劑型。在該形式中,將組合物再分為含有適當量活性組份之單位劑量。單位劑型可為包裝製劑,該包裝含有離散量之醫藥組合物,例如經包裝錠劑、膠囊及存於小瓶或安瓿中之粉末。在一些實施例中,單位劑型係膠囊、錠劑、扁囊劑或菱形錠劑自身,或其可為適當量之任何該等包裝形式。 根據具體應用及活性組份之效力,單位劑型中之活性組份之量可在0.1 mg至10000 mg、更通常1.0 mg至1000 mg、最通常10 mg至500 mg中有所變化或加以調節。在一些實施例中,所提供組合物含有其他相容治療劑。 一些化合物在水中可具有有限溶解性且可在組合物中需要表面活性劑或其他適當共溶劑。該等共溶劑包括:聚山梨醇酯20、60及80;Pluronic F-68、F-84及P-103;環糊精;及聚烴氧35蓖麻油。該等共溶劑通常以介於約0.01重量%與約2重量%之間之含量使用。 在一些實施例中,可期望黏度大於簡單水溶液以降低在分配調配物中之可變性,以降低調配物之懸浮液或乳液中組份之物理分離,及/或以其他方式改良調配物。該等黏度增效劑包括(例如)聚乙烯醇、聚乙烯基吡咯啶酮、甲基纖維素、羥丙基甲基纖維素、羥乙基纖維素、羧甲基纖維素、羥丙基纖維素、硫酸軟骨素及其鹽、透明質酸及其鹽及前述物質之組合。該等試劑通常以介於約0.01重量%與約2重量%之間之含量使用。 所提供方法中所使用之組合物可另外包括提供持續釋放及/或舒適感之組份。該等組份包括高分子量陰離子型擬黏膜聚合物、膠凝多糖及微細藥物載劑基質。該等組份更詳細論述於美國專利第4,911,920號、第5,403,841號、第5,212,162號及第4,861,760號中。出於所有目的,該等專利之全部內容以全文引用方式併入本文中。 組合
在一些實施例中,所提供方法進一步包含投與另一治療劑。在一些實施例中,本發明包含治療可與IL-17或TH
17相關或如本文另外闡述之病況及疾病,其包含與其他治療劑組合投與FASN抑制劑。在一個實施例中,該其他治療劑係BRAF抑制劑。在另一實施例中,該其他治療劑係PD1/PDL1抑制劑。 在一些實施例中,BRAF抑制劑係GDC-0879/SB590885;恩拉菲尼(Encorafenib) (LGX818);RAF265 (CHIR-265);達拉菲尼(Dabrafenib) (GSK2118436);TAK-632;PLX-4720;CEP-32496;甲苯磺酸索拉菲尼(Sorafenib Tosylate);索拉菲尼;威羅菲尼(Vemurafenib) (PLX4032, RG7204);或AZ 628。 在一些實施例中,PD1/PDL1抑制劑選自由以下組成之群:PD1抑制劑派姆單抗(Pembrolizumab)及尼沃魯單抗(Nivolumab);及PDL1抑制劑阿替珠單抗(Atezolizumab)、MEDI4736、阿維魯單抗(Avelumab)及PDR001。 在另一態樣中,本發明因此提供包含本文所述化合物或其醫藥上可接受之鹽以及至少一種其他治療劑之組合。在實例性實施例中,該其他治療劑係本發明之化合物。 當本文所闡述之化合物與針對相同疾病狀態具有活性之另一治療劑組合使用時,每一化合物之劑量可不同於當單獨使用該化合物時之劑量。熟悉此項技術者將容易地瞭解適當劑量。將瞭解,用於治療所需之化合物之量將隨所治療病況之性質及患者之年齡及狀況而變化,且最終將由會診醫師來決定。 有效劑量
本發明之醫藥組合物包括其中含有治療有效量(亦即有效達成其預期目的之量)之活性成份之組合物。用於具體應用之實際有效量將尤其取決於所治療病況。 所投與化合物之劑量及頻率(單一或多個劑量)可端視各種因素而變化:包括投與途徑;接受者之大小、年齡、性別、健康、體重、身體質量指數及飲食;所治療疾病症狀之性質及程度;其他疾病或其他健康相關問題之存在;同時治療之種類;及來自任一疾病或治療方案之併發症。其他治療方案或治療劑可與本發明之方法及化合物結合使用。 對於本文所闡述之任一化合物而言,可最初自細胞培養分析測定治療有效量。目標濃度將為例如使用所闡述方法測得的能殺死寄生蟲及/或控制其生長或繁殖之活性化合物之彼等濃度。 可根據動物模型來確定用於人類中之治療有效量。舉例而言,用於人類之劑量可經調配以達成發現在動物中有效之濃度。人類中之劑量可如上文所闡述藉由監測激酶抑制並向上或向下調節劑量來調節。用於動物(例如,牛)中之治療有效量可自動物模型(例如,小鼠模型)來測定。 劑量可端視患者之需求及所採用化合物而變化。在本發明上下文中,投與患者之劑量應足以隨時間在患者中實現有益治療反應。亦將藉由任何不利副作用之存在、性質及程度來確定劑量大小。通常,利用小於該化合物之最佳劑量之更小劑量開始治療。此後,逐步以小增量增加劑量直至達到該等情況下之最佳效應為止。在一些實施例中,劑量範圍為0.001% w/v至10% w/v。在一些實施例中,劑量範圍為0.1% w/v至5% w/v。 可個別地調節劑量量及間隔以提供有效用於所治療特定臨床適應症之所投與化合物之量。此將提供與個別疾病狀態之嚴重程度一致之治療方案。 藉由以下實例進一步闡釋本發明,該等實例不應視為將本發明之範圍或精神限於本文所闡述之特定程序。應瞭解,提供該等實例以闡釋某些實施例且並非意欲將本發明之範圍限於此。應進一步瞭解可採用本身可由熟習此項技術者提出之各個其他實施例、其修改形式及等效形式,而不背離本發明之精神及/或隨附申請專利範圍之範圍。實例
以下係本發明之某些實施例之闡釋性但非限制性實例。闡述在活體外在分化之TH
17細胞中測試對IL-17分泌之抑制及評估FASN抑制劑對CSF-1介導之M2巨噬細胞分化之效應之分析的過程及結果。實例 1. TH
17 分化分析:
使用CD4+ T細胞分離套組(Miltenyi Biotech)分離CD4+ T細胞,利用CD3/CD28微珠粒活化,並在IL-1β、IL-6、IL-21、IL-23及TGFβ及測試化合物存在下培養7至10天。使用在有DMSO或沒有細胞介素之情況下培養之細胞及/或微珠粒作為陰性對照。 讀出:(1)在第7-10天,收集上清液並針對可溶性IL-17進行測試。(2)亦收穫細胞並針對細胞內IL-17A進行染色。(3)亦針對細胞存活率藉由膜聯蛋白/PI對細胞進行單獨染色。(4)針對每一條件對培養物進行拍照。表 1.1. 在活體外對分化之 TH
17 細胞中 IL-17 分泌之抑制 實例 2. 評估 FASN 抑制劑對 CSF-1 介導之 M2 巨噬細胞分化之效應之方案
藉由使用單核球分離套組(Miltenyi Biotec Inc.)自PBMC分離原代人類單核球。在細胞培養基中在hMCSF (50 ng/mL)存在下將單核球以1.5 × 106
個細胞/孔平鋪於6孔板中。在平鋪時利用各個濃度之FASN抑制劑或淺藍菌素(0.001 µM、0.01 µM、0.1 µM、1 µM或10 µM)處理該等細胞。具有0.1% DMSO之細胞充當對照。將該等細胞維持6天以促進分化為巨噬細胞。在第6天,收穫細胞用於qPCR且針對M1標記物(IL-1β)、M2標記物(CD206)及充當管家對照之TBP進行分析。 儘管已結合上述特定實施例闡述了本發明,但熟習此項技術者將明瞭本發明之許多替代形式、修改形式及其他變化形式。所有該等替代形式、修改形式及變化形式皆意欲在本發明之精神及範圍內。
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Claims (40)
- 一種FASN抑制劑之用途,其用於製造用以治療與TH 17介導之發炎相關之病況或疾病之藥劑。
- 一種FASN抑制劑之用途,其用於製造用以治療與IL-17受體活化相關之病況或疾病之藥劑。
- 一種FASN抑制劑之用途,其用於製造用以治療器官移植患者以減少器官排斥之藥劑。
- 一種FASN抑制劑之用途,其用於製造用以抑制CSF-1依賴性巨噬細胞分化之藥劑。
- 一種FASN抑制劑之用途,其用於製造用以治療與CSF-1依賴性巨噬細胞分化相關之病況或疾病之藥劑。
- 一種FASN抑制劑之用途,其用於製造用以治療NASH之藥劑。
- 如請求項1至6中任一項之用途,其中該FASN抑制劑係式I之化合物:或其醫藥上可接受之鹽,其中 R1 係視情況經-CH3 或-CHz F3-z 取代之C1 -C3 羥基-烷基、視情況經選自由鹵基、C1 -C4 烷基、C3 -C4 環烷基、-ORp 及-NRp Rp1 組成之群之取代基取代之5員環烷基,或3員或4員環烷基或雜環烷基,其中(i)該3員或4員雜環烷基之雜原子環成員獨立地選自O、S或N,且(ii)該3員或4員環烷基或雜環烷基視情況經選自由鹵基、C1 -C4 烷基、C3 -C4 環烷基、-ORa 及-NRa Ra1 組成之群之取代基取代; L係5至10員單環或二環烷基或雜烷基,其中(i)該5至10員單環或二環雜烷基之雜原子環成員獨立地選自O、S或N,且(ii)該5至10員單環或二環烷基或雜烷基中之每一者視情況經m個-Rb 之例子取代; A及B獨立地係O或S; Ar1 係4至10員單環或二環芳基、雜芳基或雜環烷基,其中(i)該4至10員單環或二環雜芳基或雜環烷基具有1個、2個、3個或4個獨立地選自N、S或O之雜原子,且(ii)該4至10員單環或二環芳基、雜芳基或雜環烷基視情況經n個Rq 之例子取代; R2 係H或4至15員單環、二環或三環芳基、雜芳基、環烷基或雜環烷基,其中(i)該4至15員單環、二環或三環雜芳基或雜環烷基具有1個、2個、3個、4個、5個、6個、7個或8個獨立地選自N、S或O之雜原子,且(ii)該芳基、雜芳基、環烷基或雜環烷基視情況經r個Re 之例子取代; 每一Rp 及Rp1 獨立地係H、C1 -C4 烷基或C3 -C4 環烷基; 每一Ra 及Ra1 獨立地係H、C1 -C4 烷基或C3 -C4 環烷基; 每一Rb 獨立地係鹵基、C1 -C4 烷基、C1 -C3 羥基-烷基或C3 -C4 環烷基; 每一Re 獨立地係鹵基、氰基、硝基、羥基、羥基-烷基、羥基環烷基、羥基、雜環烷基、羥基-芳基、羥基-雜芳基、胺基、胺基烷基、(胺基)烷氧基、-CONH2 、-C(O)NH(烷基)、-C(O)N(烷基)2 、-C(O)NH(芳基)、-C(O)N(芳基)2 、-CHz F3-z 、-OCHz F3-z 、烷基、烷氧基、烯基、炔基、芳基氧基、(烷氧基烷基)胺基、環烷基、雜環烷基、(雜環烷基)烷基、芳基、雜芳基、-O(烷基)、-O(環烷基)、-O(雜環烷基)、-O(芳基)、-O(雜芳基)、-ONH2 、-C(O)NH(烷基)、-C(O)N(芳基)2 、-C(O)NH(環烷基)、-NH(CO)環烷基、-NH(SO2 )、-NH(SO2 )烷基、-NH(SO2 )芳基、-NH(SO2 )雜芳基、-N(SO2 )環烷基、-C(O)N(烷基)2 、(芳基)烷基、(雜芳基)烷基、-S(O)2 -烷基、-S(O)2 -芳基、-S(O)2 -環烷基、-C(O)N(烷基)2 、-C(O)烷基、-NH-C(O)-烷基、-NH-C(O)-環烷基、-NH-C(O)-雜環烷基、-NH-C(O)-雜環烷基-Rd 、-NH-C(O)-Rd 、-NH-C(O)-芳基、-NH-C(O)-NH-烷基、-NH-C(O)-NH-環烷基、-NH2 (CO)環烷基、-NH-C(O)-NH-芳基、-NH-C(O)-O-烷基、-NH-C(O)-NH-環烷基、-NH-C(O)-O-環烷基、-N(Rd )-C(O)-烷基、-N(Rd )-C(O)-芳基、-N(Rd )-S(O2 )環烷基、-S(O2 )NH2 、-S(O2 )NH(烷基)、-S(O2 )N(Rd )環烷基、-S(O2 )N(烷基)2 、-C(O)N(H)(烷基)、-C(O)N(Rd )(環烷基)、亞甲基二氧基、-CHz F3-z 或-OCHz F3-z ; 每一Rq 獨立地係鹵基、烷基、-CHz F3-z 、氰基、硝基、羥基、羥基烷基、胺基、胺基烷基、(胺基)烷氧基、-CONH2 、-C(O)NH(烷基)、-C(O)N(烷基)2 、-C(O)NH(芳基)、-C(O)N(芳基)2 、-OCHz F3-z 、烷基、烯基、炔基、烷氧基、(烷氧基烷基)胺基、-N(Rc )-C(O)-烷基、-N(Rc )-C(O)-芳基、環烷基、雜環烷基、芳基或雜芳基; 每一Rc 獨立地係H、鹵基、C1 -C4 烷基或C3 -C4 環烷基; 每一Rd 獨立地係H、鹵基、C1 -C4 烷基或C3 -C4 環烷基; 前提係兩個毗鄰環雜原子不皆為S或O; m為1、2、3或4; n為1、2、3或4; r為1、2、3或4 且z為0、1、2、3或4。
- 如請求項7之用途,其中該FASN抑制劑具有式I-F:I-F。
- 如請求項7之用途,其中該FASN抑制劑具有式I-E:I-E。
- 如請求項8之用途,其中n為1。
- 如請求項8之用途,其中n為2。
- 如請求項10或11之用途,其中Rb 係甲基。
- 如請求項1至6中任一項之用途,其中該化合物選自表1。
- 如請求項7之用途,其中該FASN抑制劑係選自化合物1 化合物2化合物3 化合物4化合物5 化合物6化合物7 化合物8化合物9 化合物10化合物11 化合物12及化合物13 化合物14 或其醫藥上可接受之鹽。
- 如請求項1至6中任一項之用途,其中該FASN抑制劑選自由以下組成之群:TVB-2640、GSK2194069、GSK1995010、GSK837149A、JNJ54302833、BI00179、IPI-9119、奧利司他(Orlistat)、淺藍菌素(Cerulenin)及C75 (4-亞甲基-2-辛基-5-側氧基四氫呋喃-3-甲酸)。
- 如請求項1或2之用途,其中該疾病係NASH。
- 如請求項7至15中任一項之用途,其中該疾病係NASH。
- 如請求項1或2之用途,其中該疾病係選自由發炎性腸病及慢性阻塞性肺病組成之群。
- 如請求項1或2之用途,其中該疾病係選自由過敏性接觸性皮膚炎及自體免疫肌炎組成之群。
- 如請求項1或2之用途,其中該疾病係選自由以下組成之群:全身或組織發炎、對感染或低氧之發炎反應、細胞活化及增殖、脂質代謝、纖維化及病毒感染。
- 如請求項1或2之用途,其中該疾病係選自由慢性及發炎病況組成之群,包括但不限於類風濕性關節炎、骨關節炎、齒根骨膜炎、急性痛風、牛皮癬、牛皮癬關節炎、關節黏連性脊椎炎、HIV相關性腎病變、肌肉萎縮性脊髓側索硬化症、肺動脈高血壓、急性同種異體移植排斥、慢性器官移植排斥、全身性紅斑狼瘡、狼瘡性腎炎、多發性硬化、克隆氏病(Crohn’s disease)、潰瘍性結腸炎、嚴重腹腔/腹部疾病、氣喘、慢性阻塞性氣道疾病、肺炎、心肌炎、心包炎、肌炎、濕疹、皮膚炎、脫髪、白斑病、大皰性皮膚病、腎炎、血管炎、動脈粥樣硬化、阿茲海默氏病(Alzheimer’s disease)、抑鬱症、薛格連氏症候群(Sjogren’s syndrome)、涎腺炎、視網膜中央靜脈阻塞、視網膜分支靜脈阻塞、歐文-加斯症候群(Irvine-Gass syndrome)、旁中心凹毛細血管擴張(parafoveal telangiectasis)、色素性視網膜炎、睫狀體平坦部炎、散射狀視網膜脈絡膜病變、黃斑前膜、囊性黃斑水腫、黃斑病變、玻璃體黃斑牽拉症候群、視網膜脫落、視神經網膜炎、特發性黃斑水腫、視網膜炎、乾眼病、春季角膜結膜炎、特應性角膜結膜炎、前眼色素層炎、全葡萄膜炎、後眼色素層炎、眼色素層炎相關黃斑水腫、鞏膜炎、糖尿病性視網膜病變、糖尿病性黃斑水腫、年齡相關性黃斑失養症、肝炎、胰臟炎、原發性膽汁性肝硬化、硬化性膽管炎、艾迪森氏病(Addison’s disease)、垂體炎、甲狀腺炎、I型糖尿病及移植器官之急性排斥。
- 如請求項1或2之用途,其中該疾病係選自由急性發炎病況組成之群,例如急性痛風;巨細胞動脈炎;腎炎,包括狼瘡性腎炎;涉及器官之血管炎,例如腎小球性腎炎;血管炎,包括巨細胞動脈炎;華格納氏肉芽病(Wegner’s granulomatosis);結節性多動脈炎;貝塞氏病(Becet’s disease);川崎氏病(Kawasaki disease);高安氏動脈炎(Takayasu’s arteritis);壞疽性膿皮症;涉及器官之血管炎;及移植器官之急性排斥。
- 如請求項1或2之用途,其中該疾病係選自由以下組成之群:對細菌、病毒、真菌、寄生蟲或其毒素之感染之發炎反應,例如但不限於敗血症、敗血症症候群、敗血性休克、內毒素血症、全身發炎反應症候群、多器官功能障礙症候群、中毒性休克症候群、急性肺損傷、急性呼吸窘迫症候群、急性腎衰竭、猛暴型肝炎、燒傷、急性胰臟炎、手術後症候群、類肉瘤病、赫氏反應(Herxheimer reaction)、腦炎、脊髓炎、腦膜炎、瘧疾;與病毒感染相關之全身發炎反應,例如但不限於流行性感冒、帶狀皰疹、單純皰疹及冠狀病毒。
- 如請求項1或2之用途,其中該疾病係與全身發炎反應症候群相關之疾病,例如但不限於敗血症、燒傷、胰臟炎、嚴重創傷、出血及缺血。
- 2或5之用途,其中該疾病係選自由骨關節炎及疼痛組成之群。
- 如請求項25之用途,其中該疼痛係手術後疼痛、骨癌疼痛、類風濕性關節炎疼痛、骨關節炎疼痛或發炎性疼痛。
- 如請求項5之用途,其中該疾病係惡性黑色素瘤。
- 2或5之用途,其中該疾病係發炎性疾病。
- 如請求項27之用途,其中該藥劑係與另一治療劑組合使用。
- 如請求項29之用途,其中該另一治療劑係BRAF抑制劑。
- 如請求項30之用途,其中該BRAF抑制劑係GDC-0879、SB590885;恩拉菲尼(Encorafenib) (LGX818);RAF265 (CHIR-265);達拉菲尼(Dabrafenib) (GSK2118436);TAK-632;PLX-4720;CEP-32496;甲苯磺酸索拉菲尼(Sorafenib Tosylate);索拉菲尼;威羅菲尼(Vemurafenib) (PLX4032, RG7204);或AZ 628。
- 2或5之用途,其中該疾病係發炎性腸病。
- 如請求項32之用途,其中該發炎性腸病係克隆氏病。
- 如請求項32之用途,其中該發炎性腸病係潰瘍性結腸炎。
- 如請求項28之用途,其中該發炎性疾病係類風濕性關節炎。
- 如請求項29之用途,其中該另一治療劑係PD1/PDL1抑制劑。
- 如請求項29之用途,其中該PD1/PDL1抑制劑係選自由以下組成之群:PD1抑制劑派姆單抗(Pembrolizumab)及尼沃魯單抗(Nivolumab);及PDL1抑制劑阿替珠單抗(Atezolizumab)、MEDI4736、阿維魯單抗(Avelumab)及PDR001。
- 如請求項1或2之用途,其中該病況或疾病係肥胖症。
- 如請求項1或2之用途,其中該病況或疾病係II型糖尿病。
- 一種抑制CSF-1依賴性巨噬細胞分化之活體外方法,其包含使細胞與FASN抑制劑接觸。
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US11040027B2 (en) | 2017-01-17 | 2021-06-22 | Heparegenix Gmbh | Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death |
TWI767148B (zh) | 2018-10-10 | 2022-06-11 | 美商弗瑪治療公司 | 抑制脂肪酸合成酶(fasn) |
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