TW202304464A - 新穎糖皮質素受體激動劑 - Google Patents
新穎糖皮質素受體激動劑 Download PDFInfo
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- TW202304464A TW202304464A TW111109388A TW111109388A TW202304464A TW 202304464 A TW202304464 A TW 202304464A TW 111109388 A TW111109388 A TW 111109388A TW 111109388 A TW111109388 A TW 111109388A TW 202304464 A TW202304464 A TW 202304464A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/0026—Oxygen-containing hetero ring cyclic ketals
- C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J17/005—Glycosides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Urology & Nephrology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pain & Pain Management (AREA)
- Transplantation (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Steroid Compounds (AREA)
Abstract
Description
本發明提供作為糖皮質素受體激動劑且適用於治療自體免疫及發炎性疾病(諸如異位性皮膚炎、發炎性腸病、全身性紅斑狼瘡、狼瘡性腎炎及類風濕性關節炎)之化合物、製備此等化合物之方法、包含此等化合物之醫藥組合物,且亦提供使用此等化合物及組合物之方法。
異位性皮膚炎係一種慢性、瘙癢性的復發緩解型發炎性皮膚病,其頻繁發生在兒童中,且亦影響許多成人。異位性皮膚炎之當前治療包括光療法、含有皮質類固醇或鈣調神經磷酸酶抑制劑之外用乳膏或被稱為度匹魯單抗(dupilumab)之皮下可注射生物製劑。儘管在治療異位性皮膚炎方面取得進展,但仍非常需要用以治療異位性皮膚炎及其他發炎性及自體免疫疾病之新穎化合物。
WO2017/210471揭示適用於治療自體免疫或發炎性疾病之某些糖皮質素受體激動劑及其免疫結合物。WO2018/089373揭示新穎類固醇、其蛋白質結合物以及用於治療疾病、病症及病況之方法,該等方法包含投與該等類固醇及結合物。
本發明提供作為糖皮質素受體激動劑之某些新穎化合物。本發明進一步提供作為糖皮質素受體激動劑之前藥的某些新穎化合物。另外,本發明提供作為糖皮質素受體激動劑且適用於治療自體免疫及發炎性疾病之某些新穎化合物,該等自體免疫及發炎性疾病諸如異位性皮膚炎、發炎性腸病、類風濕性關節炎、全身性紅斑狼瘡及狼瘡性腎炎。
在一實施例中,R為氫。
在一實施例中,R為-P(=O)(OH)
2。
在一實施例中,本發明亦提供一種治療需要此類治療之患者之發炎性疾病的方法,其包含向該患者投與有效量的式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明亦提供一種治療需要此類治療之患者之異位性皮膚炎的方法,其包含向該患者投與有效量的式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明進一步提供一種治療需要此類治療之患者之發炎性腸病的方法,其包含向該患者投與有效量的式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明進一步提供一種治療需要此類治療之患者之類風濕性關節炎的方法,其包含向該患者投與有效量的式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明亦提供一種治療需要此類治療之患者之全身性紅斑狼瘡的方法,其包含向該患者投與有效量的式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明亦提供一種治療需要此類治療之患者之狼瘡性腎炎的方法,其包含向該患者投與有效量的式I化合物或其醫藥學上可接受之鹽。
在一實施例中,本發明進一步提供一種用於療法中之式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明提供一種用於治療發炎性疾病之式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明提供一種用於治療異位性皮膚炎之式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明提供一種用於治療類風濕性關節炎之式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明提供一種用於治療發炎性腸病之式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明提供一種用於治療狼瘡性腎炎之式I化合物或其醫藥學上可接受之鹽。在一實施例中,本發明提供一種用於治療全身性紅斑狼瘡之式I化合物或其醫藥學上可接受之鹽。
在一實施例中,本發明亦提供一種式I化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療發炎性疾病所用之藥劑。在一實施例中,本發明提供一種式I化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療異位性皮膚炎所用之藥劑。在一實施例中,本發明提供一種式I化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療類風濕性關節炎所用之藥劑。在一實施例中,本發明進一步提供一種式I化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療發炎性腸病所用之藥劑。在一實施例中,本發明進一步提供一種式I化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療狼瘡性腎炎所用之藥劑。在一實施例中,本發明亦提供一種式I化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療全身性紅斑狼瘡所用之藥劑。
在一實施例中,本發明進一步提供一種醫藥組合物,其包含式I化合物或其醫藥學上可接受之鹽以及一或多種醫藥學上可接受之載劑、稀釋劑或賦形劑。在一實施例中,本發明進一步提供一種用於製備醫藥組合物之方法,其包含摻合式I化合物或其醫藥學上可接受之鹽與一或多種醫藥學上可接受之載劑、稀釋劑或賦形劑。在一實施例中,本發明亦涵蓋用於合成式I化合物之新穎中間物及方法。
本申請案主張2021年3月23日申請之美國申請案第63/164,603號的優先權益,該申請案之內容以全文引用之方式併入。
如本文所使用,術語「治療(treating/treatment)」或「以治療(to treat)」包括限制、減緩、遏止或逆轉現有症狀或病症之進展或嚴重程度。
如本文所使用,術語「患者」係指哺乳動物,尤其人類。
如本文所使用,術語「有效量」係指當向患者投與單一或多個劑量時,在診斷或治療之患者中提供所要效果之本發明化合物或其醫藥學上可接受之鹽的量或劑量。
有效量可由熟習此項技術者藉由使用已知技術且藉由在類似情況下獲得的觀測結果來確定。在確定用於患者之有效量時,主治診斷醫師考慮多個因素,包括(但不限於):患者之物種;其體型、年齡及一般健康狀況;所涉及之特定疾病或病症;疾病或病症之累及程度或嚴重程度;個別患者之反應;所投與之特定化合物;投與模式;所投與之製劑之生物可用性特徵;所選擇之劑量方案;伴隨藥品之使用;及其他相關情形。
如本文所使用,應理解,式I涵蓋式Ia、Ib及Ic,且本文中對式I之提及皆應理解為包括式Ia、Ib及Ic。
本發明之化合物可調配為藉由任何途徑投與之醫藥組合物,該途徑使化合物生物可用,包括外用投與。另外,本發明之化合物可調配為抗體藥物結合物(ADC),其中某些式I化合物由熟習此項技術者識別為ADC之有效負載部分。此類ADC係藉由注射,尤其皮下注射投與。此外,在C21封端處具有羥基的本發明化合物(其中R為-P(=O)(OH)
2、
)
表現為前藥,且在活體外或活體內代謝以提供其中R為氫的活性糖皮質素受體激動劑。此類醫藥組合物、ADC及其製備方法為此項技術中熟知的(參見例如Remington: The Science and Practice of Pharmacy, L.V. Allen編, 第22版, Pharmaceutical Press, 2012;WO 2017/062271及WO 2017/210471)。
式I之醫藥學上可接受之鹽包括在本發明之範疇內。本發明化合物(諸如式I化合物)的醫藥學上可接受之鹽可例如藉由使本發明化合物之適當游離鹼與適當的醫藥學上可接受之酸在適合溶劑(諸如二***)中在此項技術中熟知的標準條件下反應而形成。參見例如Berge, S.M.等人, 「Pharmaceutical Salts」,
Journal of Pharmaceutical Sciences,
66: 1-19, (1977)。
某些縮寫定義如下:「DMSO」係指二甲亞碸;「DCM」係指二氯甲烷(methylene chloride/dichloromethane);「g」係指公克;「rt」係指室溫;「g」係指公克;「hr」係指小時;「mg」係指毫克;「min」係指分鐘;「mL」係指毫升;「mol」係指莫耳;「mmol」係指毫莫耳;「nm」係指奈米;「ES/MS」係指電噴霧質譜分析;且「m/z」係指質譜分析之質荷比。
本發明化合物或其鹽可容易地藉由一般熟習此項技術者已知的各種程序來製備,其中一些在以下製備方案及實例中加以說明。一般熟習此項技術者咸了解,所描述途徑中之每一者之特定合成步驟可依不同方式組合或與不同流程之步驟結合,以製備本發明化合物或其鹽。各步驟之產物可藉由此項技術中熟知之習知方法回收,包括萃取、蒸發、沈澱、層析、過濾、濕磨及結晶。除非另外指明,否則所有取代基如先前所定義。試劑及起始物質係一般熟習此項技術者容易獲得。以下製備方案、實例及分析進一步說明本發明,但不應以任何方式構成限制本發明之範疇。
將(4-(溴甲基)苯基)胺基甲酸三級丁酯(3.4 g,11.6 mmol)、2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)苯甲醛(1.9 g,7.7 mmol)及碳酸鉀(39 g,285 mmol)溶解於甲苯(50 mL,470 mmol)及水(10 mL,560 mmol)中。藉由抽真空且用氮氣回填三次而使溶液脫氣。添加1,1'-雙(二苯基膦基)二茂鐵二氯化鈀(II)二氯甲烷錯合物(0.977 g,1.2 mmol),且將反應物加熱至回流後保持18小時。在將反應物重新冷卻至室溫之後,添加水(100 mL)及乙酸乙酯(150 mL)。分離各層,有機層經硫酸鎂乾燥,過濾且減壓濃縮。殘餘物藉由正相純化法(矽膠),用4:1之庚烷:乙酸乙酯溶離純化,得到標題化合物(1.36 g,53%產率)。ES/MS m/z 328.2 (M-H)。
製備 2三乙酸(2R,3S,4S,5R,6R)-2-(乙醯氧基甲基)-6-(2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-胺基苯甲基)-2-氟苯基)-7-羥基-6a,8a-二甲基-4-側氧基-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氫-8bH-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-8b-基)-2-側氧基乙氧基)四氫-2H-哌喃-3,4,5-三基酯
將分子篩(3Å,0.5 g)、(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-胺基苯甲基)-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮(異構體1) (200 mg,0.34 mmol,參見實例1)及2,3,4,6-四-O-乙醯基-α-D-半乳哌喃糖基溴化物(175 mg,0.43 mmol)溶解於二氯甲烷(7 mL,109 mmol)中,且在室溫下攪拌1小時。將反應物冷卻至0℃且一次添加全量氧化銀(I) (160 mg,0.68 mmol),接著經3分鐘逐滴添加三氟甲磺酸三甲基矽酯(65 μL,0.35 mmol),同時劇烈攪拌反應物30分鐘。粗反應物用20 mL二氯甲烷稀釋,且添加2 mL水。溶液經矽藻土過濾,且用二氯甲烷、乙酸乙酯及甲醇洗滌。將粗物質溶液減壓濃縮,得到殘餘物。殘餘物藉由逆相層析純化,用1:9之10 mM碳酸氫銨水+5%甲醇:乙腈溶離,得到標題化合物(85 mg,27%產率)。ES/MS m/z 918.4 (M)。
製備 3三乙酸(2R,3R,4S,5S,6S)-2-(2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-胺基苯甲基)-2-氟苯基)-7-羥基-6a,8a-二甲基-4-側氧基-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氫-8bH-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-8b-基)-2-側氧基乙氧基)-6-(甲氧基羰基)四氫-2H-哌喃-3,4,5-三基酯
將分子篩(3Å,0.5 g)、(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-胺基苯甲基)-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮(異構體1) (200 mg,0.34 mmol,參見實例1)及2,3,4,6-四-乙醯溴-α-D-葡萄糖醛酸甲酯(182 mg,0.43 mmol)溶解於二氯甲烷(7 mL,109 mmol)中,且在室溫下攪拌1小時。將反應物冷卻至0℃且一次添加全量氧化銀(I) (160 mg,0.68 mmol),接著一次添加全量三氟甲磺酸三甲基矽酯(65 μL,0.35 mmol)。將反應物在0℃下攪拌40分鐘,且接著使其升溫至室溫後保持10分鐘。粗反應物用15 mL二氯甲烷稀釋,且添加2 mL水。溶液經矽藻土過濾,且用二氯甲烷、乙酸乙酯及甲醇洗滌。將粗物質溶液減壓濃縮,得到殘餘物。殘餘物藉由逆相層析純化,用1:9之10 mM碳酸氫銨水+5%甲醇:乙腈溶離,得到標題化合物(44 mg,14%產率)。ES/MS m/z 904.4 (M+H)。
在0℃下向N-[4-[(3-氟-4-甲醯基-苯基)甲基]苯基]胺基甲酸三級丁酯(3.7 mg,13 mmol,參見製備1)於乙腈(40 mL)及水(10 mL)中之溶液中一次添加全量碳酸氫鈉(1.9 g,23 mmol)及氯甲酸9-茀基甲酯(3.3 g,12 mmol)。在添加之後使反應物升溫至15℃且攪拌12小時。將粗物質溶液減壓濃縮,得到殘餘物。將殘餘物再懸浮於水(50 mL)中且用乙酸乙酯(50 mL×3)萃取。合併之有機層用鹽水(40 mL)洗滌,經硫酸鈉乾燥,過濾且減壓濃縮。殘餘物藉由正相層析(矽膠)純化,用9:1之石油醚:乙酸乙酯溶離,得到標題化合物(1.6 g,24%產率)。ES/MS m/z 452.4 (M+H)。
製備 5(4-(3-氟-4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-4-側氧基-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-10-基)苯甲基)苯基)胺基甲酸(9H-茀-9-基)甲酯
在0℃下向N-[4-[(3-氟-4-甲醯基-苯基)甲基]苯基]胺基甲酸9H-茀-9-基甲酯(1.5 g,2.9 mmol,參見製備4)及(8S,9S,10R,11S,13S,14S,16R,17S)-11,16,17-三羥基-17-(2-羥基乙醯基)-10,13-二甲基-7,8,9,11,12,14,15,16-八氫-6H-環戊并[a]菲-3-酮(1.3 g,3.5 mmol)於乙腈(15 mL,290 mmol)中之溶液中逐滴添加過氯酸(70%水溶液,1.3 mL,17 mmol)。將反應物在0℃下攪拌30分鐘,且使其經6小時升溫至室溫。將反應物倒入30 mL飽和碳酸氫鈉水溶液中。將粗物質溶液減壓濃縮,得到殘餘物。將殘餘物溶解於乙酸乙酯(50 mL)及水(30 mL)中,且用乙酸乙酯(50 mL × 2)萃取。合併之有機層用鹽水(50 mL)洗滌,經硫酸鈉乾燥,過濾且減壓濃縮。殘餘物藉由正相層析(矽膠)純化,用9:1之二氯甲烷:甲醇溶離,得到標題化合物(1.5 g,61%產率)。ES/MS m/z 810.3 (M+H)。
製備 6(4-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-8b-(2-((二三級丁氧基磷醯基)氧基)乙醯基)-7-羥基-6a,8a-二甲基-4-側氧基-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-10-基)-3-氟苯甲基)苯基)胺基甲酸(9H-茀-9-基)甲酯
在室溫下在氮氣氛圍下,將1H-四唑(520 mg,7.3 mmol)及N-二三級丁氧基磷醯基-N-乙基-乙胺(1.9 g,7.1 mmol)一次添加全量至(4-(3-氟-4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-4-側氧基-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-10-基)苯甲基)苯基)胺基甲酸(9H-茀-9-基)甲酯(650 mg,0.75 mmol,參見製備5)於二甲基甲醯胺(7 mL,90 mmol)中之溶液中。3小時後,將反應物冷卻至0℃且添加過氧化氫(1.9 g,7.5 mmol),且使反應物經4小時重新升溫至室溫。反應物藉由添加硫代硫酸鈉(10 mL)而淬滅,將其倒入水(15 mL)中,且用乙酸乙酯(25 mL)萃取三次。合併之有機層用鹽水(50 mL)洗滌,經硫酸鈉乾燥,且減壓濃縮,得到殘餘物。殘餘物藉由正相層析(矽膠)純化,用1:1之石油醚:乙酸乙酯溶離,得到標題化合物(250 mg,33%產率)。ES/MS m/z 1002.3 (M+H)。
製備 7磷酸2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-胺基苯甲基)-2-氟苯基)-7-羥基-6a,8a-二甲基-4-側氧基-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氫-8bH-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-8b-基)-2-側氧基乙酯二三級丁酯
將(4-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-8b-(2-((二三級丁氧基磷醯基)氧基)乙醯基)-7-羥基-6a,8a-二甲基-4-側氧基-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-10-基)-3-氟苯甲基)苯基)胺基甲酸(9H-茀-9-基)甲酯(250 mg,0.25 mmol,參見製備6)溶解於乙腈(4 mL,76 mmol)中,且添加哌啶(200 µL,2.0 mmol)。在室溫下攪拌反應物20分鐘。將粗物質溶液減壓濃縮,得到殘餘物。將殘餘物溶解於10 mL石油醚中且攪拌2小時。藉由過濾收集所得固體且減壓乾燥,得到標題化合物(165 mg,77%產率)。ES/MS m/z 780.3 (M+H)。
製備 8三乙酸(2R,3R,4S,5R,6R)-2-(乙醯氧基甲基)-6-(2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-胺基苯甲基)-2-氟苯基)-7-羥基-6a,8a-二甲基-4-側氧基-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氫-8bH-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-8b-基)-2-側氧基乙氧基)四氫-2H-哌喃-3,4,5-三基酯
將分子篩(3Å,0.5 g)、(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-胺基苯甲基)-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮(異構體1) (300 mg,0.51 mmol,參見實例1)及2,3,4,6-四-O-乙醯基-α-D-葡糖哌喃糖基溴化物(320 mg,0.77 mmol)溶解於二氯甲烷(7 mL)中,且在室溫下攪拌1小時。將反應物冷卻至0℃。添加氧化銀(I) (240 mg,1.0 mmol)及三氟甲磺酸三甲基矽酯(100 μL,0.54 mmol)。30分鐘後,反應物用飽和碳酸氫鈉水溶液淬滅,經矽藻土過濾,且用DCM (10 mL)及MeOH (10 mL)沖洗。將合併之有機層減壓濃縮,得到殘餘物。殘餘物藉由逆相層析純化,用1:2之10 mM碳酸氫銨水+5%甲醇:乙腈溶離,得到標題化合物(120 mg,26%產率)。MS m/z 918.4 (M)。
實例 1(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-胺基苯甲基)-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮(異構體1)
在室溫下將過氯酸(70%水溶液,3 mL)添加至含(8S,9S,10R,11S,13S,14S,16R,17S)-11,16,17-三羥基-17-(2-羥基乙醯基)-10,13-二甲基-7,8,9,11,12,14,15,16-八氫-6H-環戊并[a]菲-3-酮(2.5 g,6.6 mmol)及N-[4-[(3-氟-4-甲醯基-苯基)甲基]苯基]胺基甲酸三級丁酯(2.2 g,6.7 mmol,參見製備1)之乙腈(50 mL)中並攪拌。18小時後,將反應物用飽和碳酸氫鈉水溶液淬滅,且用9:1之二氯甲烷:異丙醇萃取。合併有機層,經硫酸鎂乾燥,過濾且減壓濃縮,得到殘餘物。殘餘物藉由逆相層析純化,用1:1之10 mM碳酸氫銨水+5%甲醇:乙腈溶離,得到標題化合物(異構體1,峰1) (2.25 g,58%產率)。ES/MS m/z 588.4 (M+H)。
1H NMR (500.11 MHz, d
6-DMSO) δ 0.86 (s, 3H); 1.06-1.01 (m, 2H), 1.39 (s, 3H), 1.80-1.73 (m, 5H), 2.16-2.13 (m, 2H), 2.38-2.28 (m, 1H), 2.59-2.53 (m, 1H), 3.74 (s, 2H), 4.20-4.15 (m, 1H), 4.30-4.29 (m, 1H), 4.50-4.45 (m, 1H), 4.94-4.79 (m, 4H), 5.12 (t, J= 6.0 Hz, 1H), 5.59 (s, 1H), 5.93 (s, 1H), 6.16 (dd, J= 1.8, 10.1 Hz, 1H), 6.49-6.46 (m, 2H), 6.86 (d, J= 8.3 Hz, 2H), 7.06-7.00 (m, 2H), 7.32-7.30 (m, 1H), 7.46 (t, J= 7.7 Hz, 1H)
實例1 (其他製備) (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-胺基苯甲基)-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮
將過氯酸(70% w/w水溶液,12 mL,140 mmol,3.5當量)逐滴添加至(8S,9S,10R,11S,13S,14S,16R,17S)-11,16,17-三羥基-17-(2-羥基乙醯基)-10,13-二甲基-7,8,9,11,12,14,15,16-八氫-6H-環戊并[a]菲-3-酮(15.00 g,39.85 mmol)及N-[4-[(3-氟-4-甲醯基-苯基)甲基]苯基]胺基甲酸三級丁酯(13.12 g,39.85 mmol,參見製備1)之混合物於乙腈(750 mL,589 g,50體積,360當量,14.34 mol)中之冷(0至3℃)漿液中。10分鐘後,移除冷卻浴,且在環境溫度下攪拌混合物18小時。逐份添加固體NaHCO
3(16.8 g,200 mmol),且將pH調節至中性。在攪拌1小時之後,過濾混合物且用50 mL乙腈洗滌。然後將澄清溶液用®-anicyphos (10.84 g,39.85 mmol)於甲醇(325 mL)中之溶液一次性處理,且用大約5 mg鹽處理。將混合物在環境溫度下攪拌16小時,且過濾所得懸浮液,用乙腈(3 × 50 mL)洗滌,且在45℃下真空乾燥,得到17.8 g呈白色固體狀之(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-胺基苯甲基)-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮-(R)-anicyphos鹽(52%產率)。固體之HPLC-MS在215/242 nm處 (校正0.68處之anicyphos峰)顯示:1.69 min;95.5/96面積% a/a (所需異構體);1.75 min;1.3/1.4面積% a/a (非所需異構體)。
將(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-胺基苯甲基)-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮-(R)-anicyphos鹽(20 g,23 mmol)與200 mL DCM及200 mL飽和NaHCO
3水溶液之混合物劇烈攪拌,直至所有固體溶解(通常隔夜)。然後分離各層,且用2×50 mL DCM萃取水層。合併之有機相用2×50 mL飽和NaCl洗滌,經無水Na
2SO
4乾燥,且在45℃下真空濃縮,得到12.5 g呈白色固體狀之標題化合物(91%產率)。HPLC純度:215 nm處96.6%;242 nm處96.9%。ES/MS m/z 588.2 (M+1)。Q-NMR (9.5 mg產物 + 3.0 mg TCNB (MW 260.89)。純度90% w/w。殘餘DCM 1% w/w。
1H NMR (500.11 MHz, CDCl
3) δ 0.95 (s, 3H); 1.20-1.03 (m, 2H), 1.44-1.37 (m, 4H) , 1.84-1.56 (m, 3H), 1.97-1.90 (m, 1H), 2.25-2.00 (m, 3H), 2.38-2.29 (m, 1H), 2.62-2.50 (m, 1H), 3.08-2.90 (m, 1H), 3.68-3.47 (m, 1H), 3.82 (s, 2H), 4.32-4.23 (d, 1H), 4.49 (m, 1H), 4.65-4.58 (d, 1H), 5.08-5.03 (d, 1H), 5.63 (s, 1H), 6.00 (s, 1H), 6.27-6.23 (d, J = 8.3 Hz, 1H), 6.60 (d, J= 8.3 Hz, 2H), 6.99-6.82 (m, 3H), 7.23-7.16 (m, 1H), 7.35 (t, J= 7.7 Hz, 1H)。
實例 2(6aR,6bS,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(4-(4-胺基苯甲基)-2-氟苯基)-7-羥基-8b-(2-羥基乙醯基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮(異構體2)
根據實例1,殘餘物藉由逆相層析純化,用1:1之10 mM碳酸氫銨水+5%甲醇:乙腈溶離,得到標題化合物(異構體2,峰2) (225 mg,9%產率)。ES/MS m/z 588.4 (M+H)。
1H NMR (500.11 MHz, d
6-DMSO) d 0.86 (s, 3H), 1.05 (dd, J= 3.0, 11.1 Hz, 1H), 1.25-1.20 (m, 2H), 1.38 (s, 4H), 1.85-1.78 (m, 5H), 2.09-2.00 (m, 2H), 2.32-2.29 (m, 1H), 2.56-2.53 (m, 1H), 3.73 (s, 2H), 4.02-3.97 (m, 1H), 4.22-4.17 (m, 1H), 4.30-4.29 (m, 1H), 4.78 (d, J= 3.1 Hz, 1H), 4.87 (s, 2H), 4.98 (t, J= 6.0 Hz, 1H), 5.28 (d, J= 6.8 Hz, 1H), 5.93 (s, 1H), 6.16 (dd, J= 1.7, 10.1 Hz, 1H), 6.23 (s, 1H), 6.47 (d, J= 8.2 Hz, 2H), 6.84 (d, J= 8.2 Hz, 2H), 6.99-6.95 (m, 2H), 7.16 (t, J= 7.7 Hz, 1H), 7.32-7.30 (m, 1H)。
實例 3(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-胺基苯甲基)-2-氟苯基)-7-羥基-6a,8a-二甲基-8b-(2-(((2R,3R,4S,5R,6R)-3,4,5-三羥基-6-(羥甲基)四氫-2H-哌喃-2-基)氧基)乙醯基)-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮
將三乙酸(2R,3S,4S,5R,6R)-2-(乙醯氧基甲基)-6-(2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-胺基苯甲基)-2-氟苯基)-7-羥基-6a,8a-二甲基-4-側氧基-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氫-8bH-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-8b-基)-2-側氧基乙氧基)四氫-2H-哌喃-3,4,5-三基酯(45 mg,0.05 mmol,參見製備2)、甲醇(2 mL)及碳酸鉀(25 mg,0.25 mmol)添加至燒瓶中,且在室溫下攪拌1小時。將粗物質溶液減壓濃縮,得到殘餘物。殘餘物藉由逆相層析純化,用3:7之10 mM碳酸氫銨水+5%甲醇:乙腈溶離,得到標題化合物(23 mg,63%產率)。ES/MS m/z 750.4 (M+H)。
1H NMR (500.11 MHz, d
6-DMSO) δ 0.88 (s, 3H); 1.06-1.03 (m, 2H), 1.40 (s, 3H), 1.77-1.69 (m, 3H), 1.81 (d, J= 1.8 Hz, 2H), 2.04-2.00 (m, 1H), 2.17-2.14 (m, 1H), 2.38-2.32 (m, 1H), 2.58-2.53 (m, 1H), 3.18 (d, J= 5.4 Hz, 1H), 3.31-3.26 (m, 1H), 3.39-3.34 (m, 1H), 3.55-3.47 (m, 2H), 3.63 (t, J= 4.1 Hz, 1H), 3.74 (s, 2H), 4.20 (d, J= 7.6 Hz, 1H), 4.31-4.30 (m, 1H), 4.47-4.41 (m, 2H), 4.65 (t, J= 5.5 Hz, 1H), 4.78-4.72 (m, 3H), 4.89 (s, 2H), 4.94 (dd, J= 5.0, 9.9 Hz, 2H), 5.64 (s, 1H), 5.93 (s, 1H), 6.17 (dd, J= 1.8, 10.1 Hz, 1H), 6.49-6.46 (m, 2H), 6.86 (d, J= 8.3 Hz, 2H), 7.06-7.01 (m, 2H), 7.32 (d, J= 10.0 Hz, 1H), 7.47 (t, J= 7.7 Hz, 1H)。
實例 4(2S,3S,4S,5R,6R)-6-(2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-胺基苯甲基)-2-氟苯基)-7-羥基-6a,8a-二甲基-4-側氧基-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氫-8bH-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-8b-基)-2-側氧基乙氧基)-3,4,5-三羥基四氫-2H-哌喃-2-甲酸
將三乙酸(2R,3R,4S,5S,6S)-2-(2-((6aR,6bS,7S,8aS,8bS, 10R,11aR,12aS,12bS)-10-(4-(4-胺基苯甲基)-2-氟苯基)-7-羥基-6a,8a-二甲基-4-側氧基-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氫-8bH-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-8b-基)-2-側氧基乙氧基)-6-(甲氧基羰基)四氫-2H-哌喃-3,4,5-三基酯(44 mg,0.05 mmol,參見製備3)、甲醇(2 mL)及碳酸鉀(25 mg,0.25 mmol)添加在一起,且在室溫下攪拌2.5小時。將粗物質溶液減壓濃縮,得到殘餘物。殘餘物藉由逆相層析純化,用1:1之10 mM碳酸氫銨水+5%甲醇:乙腈溶離,得到標題化合物(24 mg,65%產率)。ES/MS m/z 764.4 (M+H)。1H NMR (500.11 MHz, d
6-DMSO) d 0.84 (s, 3H), 1.07-0.98 (m, 2H), 1.41 (s, 3H), 1.76-1.66 (m, 4H), 2.16-2.11 (m, 2H), 2.45-2.44 (m, 1H), 2.60-2.55 (m, 1H), 3.05-3.04 (m, 1H), 3.20-3.18 (m, 2H), 3.74 (s, 2H), 4.40-4.30 (m, 2H), 4.58-4.52 (m, 1H), 4.82-4.78 (m, 1H), 4.95-4.92 (m, 2H), 5.13-5.11 (m, 2H), 5.64 (s, 1H), 5.92 (s, 1H), 6.16 (dd, J= 1.3, 10.0 Hz, 1H), 6.48 (d, J= 8.1 Hz, 2H), 6.86 (d, J= 8.1 Hz, 2H), 7.11-7.09 (m, 2H), 7.36-7.32 (m, 1H), 7.51-7.45 (m, 1H)。
實例 5磷酸二氫2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-胺基苯甲基)-2-氟苯基)-7-羥基-6a,8a-二甲基-4-側氧基-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氫-8bH-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-8b-基)-2-側氧基乙酯
將磷酸2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-胺基苯甲基)-2-氟苯基)-7-羥基-6a,8a-二甲基-4-側氧基-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氫-8bH-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-8b-基)-2-側氧基乙酯二三級丁酯(165 mg,0.19 mmol,參見製備7)溶解於二氯甲烷(2 mL)中,且添加三氟乙酸(1 mL)。在室溫下攪拌反應物1小時。將粗物質溶液用飽和碳酸氫鈉水溶液中和且用乙酸乙酯萃取。合併之有機層經硫酸鈉乾燥,過濾且減壓濃縮,得到殘餘物。殘餘物藉由逆相層析純化,用7:3之10 mM碳酸氫銨水:乙腈溶離,得到標題化合物(34 mg,26%產率)。ES/MS m/z 668.2 (M+H)。1H NMR (500.11 MHz, d
6-DMSO) d 0.79-0.72 (m, 1H), 0.89 (s, 4H), 1.38 (s, 3H), 1.66-1.55 (m, 1H), 1.73-1.67 (m, 2H), 2.10-2.08 (m, 2H), 2.27-2.22 (m, 2H), 3.67 (s, 2H), 3.67 (brs, 4H), 4.19 (d, J= 1.8 Hz, 1H), 4.78-4.69 (m, 2H), 4.94 (d, J= 4.9 Hz, 1H), 5.58 (s, 1H), 5.88 (s, 1H), 6.11-6.08 (m, 1H), 6.46 (d, J= 8.3 Hz, 2H), 6.87-6.80 (m, 4H), 7.38-7.28 (m, 5H)。
實例 6(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-胺基苯甲基)-2-氟苯基)-7-羥基-6a,8a-二甲基-8b-(2-(((2R,3R,4S,5S,6R)-3,4,5-三羥基-6-(羥甲基)四氫-2H-哌喃-2-基)氧基)乙醯基)-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氫-4H-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-4-酮
將三乙酸(2R,3R,4S,5R,6R)-2-(乙醯氧基甲基)-6-(2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-胺基苯甲基)-2-氟苯基)-7-羥基-6a,8a-二甲基-4-側氧基-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-十二氫-8bH-萘并[2',1':4,5]茚并[1,2-d][1,3]間二氧雜環戊烯-8b-基)-2-側氧基乙氧基)四氫-2H-哌喃-3,4,5-三基酯(120 mg,0.13 mmol,參見製備8)、甲醇(2 mL)及碳酸鉀(65 mg,0.66 mmol)添加至圓底燒瓶中,且在室溫下攪拌1小時。將粗物質溶液裝載至矽藻土上,且藉由逆相層析純化,用3:7之10 mM碳酸氫銨水+5%甲醇:乙腈溶離,得到標題化合物(78 mg,78%產率)。MS m/z 750.4 (M+H)。1H NMR (500.11 MHz, d
6-DMSO) δ 7.48-7.45 (m, 1H), 7.34-7.30 (m, 1H), 7.07-7.01 (m, 2H), 6.86 (d, J= 8.3 Hz, 2H), 6.48 (d, J= 8.3 Hz, 2H), 6.25-6.16 (m, 1H), 5.95-5.93 (m, 1H), 5.66 (s, 1H), 5.11 (d, J= 4.9 Hz, 1H), 4.98-4.88 (m, 5H), 4.79-4.74 (m, 2H), 4.62-4.59 (m, 1H), 4.50-4.46 (m, 1H), 4.38-4.29 (m, 1H), 4.25-4.23 (m, 1H), 3.74 (s, 2H), 3.71-3.67 (m, 1H), 3.50-3.48 (m, 1H), 3.17-3.13 (m, 4H), 2.38-2.34 (m, 1H), 2.16-2.14 (m, 2H), 1.84-1.75 (m, 5H), 1.40 (s, 3H), 1.07-1.05 (m, 2H), 0.89-0.88 (m, 3H)。
hGR 共活化劑募集分析使用來自Life Technologies之LanthaScreen TR-Fret GR共活化劑分析(A15899)來量測糖皮質素化合物之活性。以3倍10點連續稀釋將化合物聲學轉移至分析盤中,最高濃度為200 nM。將十微升GR-LBD之2×溶液添加至化合物盤中且培育10分鐘。接著將十微升經螢光素-SRC1-4及Tb標記之抗GST抗體之2×溶液添加至盤中。將盤避光培育兩小時,接著在Envision盤讀取器上讀數,其中在340 nm下激發且在520 nm (螢光素)及490 nm (鋱)下發射。在Genedata中分析520/490之發射比率。為了獲得活性百分比,將資料與DMSO之陰性對照及4 µM***(dexamethasone)之陽性對照進行比較。
遵循如上文基本上所描述之程序,實例1之化合物得到2.07 nM之相對IC
50,且實例2之化合物得到13.1 nM之相對IC
50。
Claims (34)
- 如請求項1之化合物,其中R為氫,或其醫藥學上可接受之鹽。
- 如請求項1之化合物,其中R為-P(=O)(OH) 2,或其醫藥學上可接受之鹽。
- 一種治療患者之異位性皮膚炎的方法,其包含向需要此類治療之患者投與有效量的如請求項1至16中任一項之化合物或其醫藥學上可接受之鹽。
- 一種治療患者之全身性紅斑狼瘡的方法,其包含向需要此類治療之患者投與有效量的如請求項1至16中任一項之化合物或其醫藥學上可接受之鹽。
- 一種治療患者之類風濕性關節炎的方法,其包含向需要此類治療之患者投與有效量的如請求項1至16中任一項之化合物或其醫藥學上可接受之鹽。
- 一種治療患者之狼瘡性腎炎的方法,其包含向需要此類治療之患者投與有效量的如請求項1至16中任一項之化合物或其醫藥學上可接受之鹽。
- 一種治療患者之發炎性腸病的方法,其包含向需要此類治療之患者投與有效量的如請求項1至16中任一項之化合物或其醫藥學上可接受之鹽。
- 如請求項1至16中任一項之化合物或其醫藥學上可接受之鹽,其用於療法中。
- 如請求項1至16中任一項之化合物或其醫藥學上可接受之鹽,其用於治療異位性皮膚炎。
- 如請求項1至16中任一項之化合物或其醫藥學上可接受之鹽,其用於治療全身性紅斑狼瘡。
- 如請求項1至16中任一項之化合物或其醫藥學上可接受之鹽,其用於治療狼瘡性腎炎。
- 如請求項1至16中任一項之化合物或其醫藥學上可接受之鹽,其用於治療類風濕性關節炎。
- 如請求項1至16中任一項之化合物或其醫藥學上可接受之鹽,其用於治療發炎性腸病。
- 一種如請求項1至16中任一項之化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療異位性皮膚炎之藥劑。
- 一種如請求項1至16中任一項之化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療全身性紅斑狼瘡之藥劑。
- 一種如請求項1至16中任一項之化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療狼瘡性腎炎之藥劑。
- 一種如請求項1至16中任一項之化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療類風濕性關節炎之藥劑。
- 一種如請求項1至16中任一項之化合物或其醫藥學上可接受之鹽的用途,其用於製造供治療發炎性腸病之藥劑。
- 一種醫藥組合物,其包含如請求項1至16中任一項之化合物或其醫藥學上可接受之鹽及一或多種醫藥學上可接受之載劑、稀釋劑或賦形劑。
- 一種製備醫藥組合物之方法,其包含摻合如請求項1至16中任一項之化合物或其醫藥學上可接受之鹽與一或多種醫藥學上可接受之載劑、稀釋劑或賦形劑。
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