TWI405572B - 新穎的胺基菸酸及異菸酸衍生物 - Google Patents
新穎的胺基菸酸及異菸酸衍生物 Download PDFInfo
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- TWI405572B TWI405572B TW096148215A TW96148215A TWI405572B TW I405572 B TWI405572 B TW I405572B TW 096148215 A TW096148215 A TW 096148215A TW 96148215 A TW96148215 A TW 96148215A TW I405572 B TWI405572 B TW I405572B
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- ylamino
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- nicotinic acid
- acid
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- KPIVDNYJNOPGBE-UHFFFAOYSA-N 2-aminonicotinic acid Chemical compound NC1=NC=CC=C1C(O)=O KPIVDNYJNOPGBE-UHFFFAOYSA-N 0.000 title 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical class OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 85
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 4
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 52
- -1 Nicotinate 2-(3-methyl-3'-(trifluoromethoxy)biphenyl-4-ylamino)nicotinic acid 2 -(3-chloro-3'-methoxybiphenyl-4-ylamino)nicotinic acid Chemical compound 0.000 claims description 46
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 45
- 125000005843 halogen group Chemical group 0.000 claims description 43
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 35
- 125000001424 substituent group Chemical group 0.000 claims description 35
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 32
- 235000001968 nicotinic acid Nutrition 0.000 claims description 29
- 239000011664 nicotinic acid Substances 0.000 claims description 29
- 201000010099 disease Diseases 0.000 claims description 27
- 125000001153 fluoro group Chemical group F* 0.000 claims description 25
- 239000003112 inhibitor Substances 0.000 claims description 25
- 229960003512 nicotinic acid Drugs 0.000 claims description 25
- 239000002253 acid Substances 0.000 claims description 24
- 108010052167 Dihydroorotate Dehydrogenase Proteins 0.000 claims description 23
- 102100032823 Dihydroorotate dehydrogenase (quinone), mitochondrial Human genes 0.000 claims description 23
- 229910052731 fluorine Inorganic materials 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 238000011282 treatment Methods 0.000 claims description 20
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 15
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 14
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 13
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 13
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 13
- 230000005764 inhibitory process Effects 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 claims description 12
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- 201000006417 multiple sclerosis Diseases 0.000 claims description 12
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- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 150000001768 cations Chemical class 0.000 claims description 8
- 125000004429 atom Chemical group 0.000 claims description 7
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
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- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
- 108010022394 Threonine synthase Proteins 0.000 claims description 6
- 102000004419 dihydrofolate reductase Human genes 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
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- 229960004641 rituximab Drugs 0.000 claims description 5
- HMLGSIZOMSVISS-ONJSNURVSA-N (7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-(2,2-dimethylpropanoyloxymethoxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound N([C@@H]1C(N2C(=C(C=C)CSC21)C(O)=O)=O)C(=O)\C(=N/OCOC(=O)C(C)(C)C)C1=CSC(N)=N1 HMLGSIZOMSVISS-ONJSNURVSA-N 0.000 claims description 4
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 4
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- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- BGISFYHWLSYDCI-UHFFFAOYSA-M lithium;pyridine-3-carboxylate Chemical compound [Li+].[O-]C(=O)C1=CC=CN=C1 BGISFYHWLSYDCI-UHFFFAOYSA-M 0.000 claims description 4
- UEJMTWHXKJKXEU-UHFFFAOYSA-N lithium;pyridine-4-carboxylic acid Chemical compound [Li].OC(=O)C1=CC=NC=C1 UEJMTWHXKJKXEU-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 claims description 3
- ZVCGCHFXVUBZIC-UHFFFAOYSA-N 2-[2,3,5,6-tetrafluoro-4-(3-methoxyphenyl)anilino]pyridine-3-carboxylic acid Chemical compound COC1=CC=CC(C=2C(=C(F)C(NC=3C(=CC=CN=3)C(O)=O)=C(F)C=2F)F)=C1 ZVCGCHFXVUBZIC-UHFFFAOYSA-N 0.000 claims description 3
- JBNWDYGOTHQHOZ-UHFFFAOYSA-N 2-[5-[4-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]-6-methoxy-1-methylindol-3-yl]-n,n-dimethyl-2-oxoacetamide Chemical compound COC1=CC=2N(C)C=C(C(=O)C(=O)N(C)C)C=2C=C1C(=O)N(CC1)CCC1CC1=CC=C(F)C=C1 JBNWDYGOTHQHOZ-UHFFFAOYSA-N 0.000 claims description 3
- RQVKVJIRFKVPBF-VWLOTQADSA-N 2-[[(2s)-2-amino-3-phenylpropyl]amino]-3-methyl-5-naphthalen-2-yl-6-pyridin-4-ylpyrimidin-4-one Chemical compound C([C@H](N)CNC=1N(C(C(C=2C=C3C=CC=CC3=CC=2)=C(C=2C=CN=CC=2)N=1)=O)C)C1=CC=CC=C1 RQVKVJIRFKVPBF-VWLOTQADSA-N 0.000 claims description 3
- QSUSKMBNZQHHPA-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-1-(3-phenylpropyl)-5-pyridin-4-ylimidazol-2-yl]but-3-yn-1-ol Chemical compound C=1C=CC=CC=1CCCN1C(C#CCCO)=NC(C=2C=CC(F)=CC=2)=C1C1=CC=NC=C1 QSUSKMBNZQHHPA-UHFFFAOYSA-N 0.000 claims description 3
- IFGWYHGYNVGVRB-UHFFFAOYSA-N 5-(2,4-difluorophenoxy)-n-[2-(dimethylamino)ethyl]-1-(2-methylpropyl)indazole-6-carboxamide Chemical compound CN(C)CCNC(=O)C=1C=C2N(CC(C)C)N=CC2=CC=1OC1=CC=C(F)C=C1F IFGWYHGYNVGVRB-UHFFFAOYSA-N 0.000 claims description 3
- QZSUASFQOGKQPZ-UHFFFAOYSA-N 5-bromo-2-[2-fluoro-4-[3-(trifluoromethoxy)phenyl]anilino]pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC(Br)=CN=C1NC1=CC=C(C=2C=C(OC(F)(F)F)C=CC=2)C=C1F QZSUASFQOGKQPZ-UHFFFAOYSA-N 0.000 claims description 3
- 229940124292 CD20 monoclonal antibody Drugs 0.000 claims description 3
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- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 3
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- ICIJBYYMEBOTQP-UHFFFAOYSA-N n-[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]-2-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]-2-oxoacetamide;hydrochloride Chemical compound Cl.C1=C(C(C)(C)C)C=C(NS(C)(=O)=O)C(OC)=C1NC(=O)C(=O)C(C1=CC=CC=C11)=CC=C1OCCN1CCOCC1 ICIJBYYMEBOTQP-UHFFFAOYSA-N 0.000 claims description 3
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- OMPATGZMNFWVOH-UHFFFAOYSA-N 2-[2,6-difluoro-4-(3-methoxyphenyl)anilino]pyridine-3-carboxylic acid Chemical compound COC1=CC=CC(C=2C=C(F)C(NC=3C(=CC=CN=3)C(O)=O)=C(F)C=2)=C1 OMPATGZMNFWVOH-UHFFFAOYSA-N 0.000 claims description 2
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Description
本發明是關於新穎的二氫乳清酸脫氫酶(dihydroorotate dehydrogenase,DHODH)抑制劑。所述化合物適用於治療、預防或抑止已知易由二氫乳清酸脫氫酶之抑制改善的疾病及病症,諸如自體免疫疾病、免疫及發炎性疾病、破壞性骨病、惡性贅生性疾病、血管生成相關病症、病毒性疾病以及感染性疾病。
酶二氫乳清酸脫氫酶(DHODH)為催化嘧啶生物合成途徑中之第四步的酶,所述第四步即二氫乳清酸(dihydroorotate)轉化為乳清酸(orotate),其中伴隨電子經由黃素單核苷酸(flavin mononucleotide)中間體轉移至泛醌(ubiquinone)(輔因子Q)(Loffler等人,Mol Cell Biochem,1997)。與僅具有所述從無到有途徑作為嘧啶源之寄生蟲(惡性瘧原蟲(Plasmodium falciparum))(McRobert等人,Mol Biochem Parasitol 2002)及細菌(大腸桿菌(E.coli))對比,哺乳動物細胞具有另一補救途徑。穩態增殖期間,不依賴於DHODH之補救途徑似乎足以細胞性供應嘧啶鹼基。只有具有高轉換率之細胞且尤其T及B淋巴細胞需要從無到有途徑來進行增殖。在所述細胞中,DHODH抑制使細胞週期進程停止,從而抑止DNA合成且因此抑止細胞增殖(Breedveld FC等人,Ann Rheum Dis 2000)。
因此,DHODH抑制劑在以引起慢性炎症及組織毀壞之異常及不可控細胞增殖為特徵的人類疾病中展示有利的免疫抑制及抗增殖效應。
除制止淋巴細胞增殖外,DHODH抑制劑(亦即,特立氟胺(teriflunomide)、馬力提穆斯(Maritimus)(FK778)以及布喹那(brequinar))亦因抑制細胞激素之產生以及核因子(NF)-kB-信號轉導、單核細胞遷移以及轉型生長因子β-1之產生的增加而具有消炎作用,且其誘導1型T輔助細胞(Thelper cell type 1,Th1)轉變為2型(Th2)之子群分化(Manna等人,JImmunol 2000)(Dimitrova等人,J.Immunol 2002)。此外,由RANKL介導之蝕骨細胞分化因DHODH抑制而減輕(Urushibara等人,Arthrititis Rheum 2004)。
在兩種已進入臨床試驗之DHODH抑制劑布喹那(Dexter D.L.等人;Cancer Res.1985)及特立氟胺(A77-1726)的共結晶實驗中,可見兩者結合於共同位點,亦咸信所述共同位點為輔因子泛醌之結合位點(Liu等人;Struc.Fold.Des.2000)。
以商品名稱Arava(EP 0 780 128,WO 97/34600)銷售之來氟米特(Leflunomide)為第一種進入市場之DHODH抑制劑。來氟米特為特立氟胺之前藥,而特立氟胺為以適度效能抑制人類DHODH之活性代謝物(Fox等人,J.Rheumatol.增刊,1998)。
來氟米特為來自Aventis之疾病調節抗風濕藥物(disease modifying anti-rheumatic drug,DMARD),其已於1998年經美國食品與藥品管理局(FDA)批准用於治療類風濕性關節炎且已於2004年經歐洲藥品監管局(EMEA)批准用於治療牛皮癬性關節炎。目前,來氟米特正被積極開發用於治療全身性紅斑狼瘡、韋格納肉芽腫病(Wegener's granulomatosis)(Metzler等人;Rheumatology 2004;43(3),315-320)以及HIV感染。此外,其活性代謝物特立氟胺有效用於多發性硬化症且此時正處於臨床試驗第III階段(O'Connor等人;Neurology 2006)。
其他密切相關疾病中出現其他資料,所述疾病諸如強直性脊柱炎(Haibel等人;Ann.Rheum.Dis.2005)、多關節炎性青少年特發性關節炎(Silverman等人;Arthritis Rheum.2005)以及肉狀瘤病(Baughman等人;Sarcoidosis Vasc.Diffuse Lung Dis.2004)。此外,來氟米特及FK778已對於細胞巨大病毒展示極佳的抗病毒活性。目前,指定來氟米特為器官移植後細胞巨大病毒疾病之二線療法(John等人;Transplantation 2004)。另外,來氟米特在可由習知給藥獲得之濃度下使HIV複製降低約75%(SchlapferE等人;AIDS 2003)。
鑒於由抑制二氫乳清酸脫氫酶介導之生理學效應,最近已揭露數種DHODH抑制劑用於治療或預防自體免疫疾病、免疫及發炎性疾病、破壞性骨病、惡性贅生性疾病、血管生成相關病症、病毒性疾病以及感染性疾病。參見,例如WO 06/044741、WO 06/022442、WO 06/001961、WO 04/056747、WO 04/056746、WO 03/006425、WO 02/080897以及WO 99/45926。
DHODH抑制在其中起作用之疾病或病症包含(但不限於)自體免疫疾病、免疫及發炎性疾病、破壞性骨病、惡性贅生性疾病、血管生成相關病症、病毒性疾病以及感染性疾病。
可預防或治療之自體免疫疾病包含(但不限於)類風濕性關節炎、牛皮癬性關節炎、全身性紅斑狼瘡、多發性硬化症、牛皮癬、強直性脊柱炎、韋格納肉芽腫病、多關節炎性青少年特發性關節炎、諸如潰瘍性結腸炎及克羅恩氏症(Crohn's disease)之發炎性腸疾病、萊特氏症候群(Reiter's syndrome)、肌肉纖維疼痛以及1型糖尿病。
可預防或治療之免疫及發炎性疾病包含(但不限於)哮喘、慢性阻塞性肺部疾病(COPD)、呼吸窘迫症候群、急性或慢性胰腺炎、移植抗宿主疾病、慢性肉狀瘤病、移植排斥反應、接觸性皮炎、異位性皮炎、過敏性鼻炎、過敏性結膜炎、貝塞特氏症候群(Behcet syndrome)、諸如結膜炎及葡萄膜炎之發炎性眼病。
可預防或治療之破壞性骨病包含(但不限於)骨質疏鬆症、骨關節炎及多發性骨髓瘤相關骨病。
可預防或治療之惡性贅生性疾病包含(但不限於)前列腺癌、卵巢癌以及腦癌。
可預防或治療之血管生成相關病症包含(但不限於)血管瘤、眼睛新血管生成、黃斑退化或糖尿病性視網膜病。
可預防或治療之病毒性疾病包含(但不限於)人體免疫缺損病毒(HIV)感染、肝炎以及細胞巨大病毒感染。
可預防或治療之感染性疾病包含(但不限於)敗血症、敗血性休克、內毒素休克、革蘭氏陰性敗血症(Gram negative sepsis)、中毒性休克症候群、志賀桿菌病(Shigellosis)以及諸如瘧疾之其他原蟲侵染。
現已發現某些胺基(異)菸酸衍生物為新穎有效的DHODH抑制劑且因此可用於治療或預防所述疾病。
本發明之其他目的在於提供一種製備所述化合物之方法;包括有效量之所述化合物的醫藥組合物;所述化合物在製造供治療易由DHODH之抑制改善的病理學病狀或疾病用之藥劑中的用途,其中所述病理學病狀或疾病是選自:類風濕性關節炎、牛皮癬性關節炎、強直性脊柱炎、多發性硬化症、韋格納肉芽腫病、全身性紅斑狼瘡、牛皮癬以及肉狀瘤病;以及治療易由DHODH之抑制改善的病理學病狀或疾病之方法,其中所述病理學病狀或疾病是選自:類風濕性關節炎、牛皮癬性關節炎、強直性脊柱炎、多發性硬化症、韋格納肉芽腫病、全身性紅斑狼瘡、牛皮癬以及肉狀瘤病,所述方法包括向需要治療之受檢者投與本發明之化合物。
因此,本發明是關於新穎的式(I)胺基(異)菸酸衍生物:
其中:.基團G1
中之一個表示氮原子或基團CRc
且另一個表示基團CRc
.G2
表示氮原子或基團CRd
.R1
表示選自以下各基之基團:氫原子、鹵素原子、可視情況經1、2或3個選自鹵素原子及羥基之取代基取代的C1-4
烷基以及可視情況經1、2或3個選自鹵素原子及羥基之取代基取代的C3-8
環烷基.R2
表示選自以下各基之基團:氫原子、鹵素原子、羥基、可視情況經1、2或3個選自鹵素原子及羥基之取代基取代的C1-4
烷基、可視情況經1、2或3個選自鹵素原子及羥基之取代基取代的C1-4
烷氧基以及可視情況經1、2或3個選自鹵素原子及羥基之取代基取代的C3-8
環烷基.Ra
、Rb
以及Rc
獨立地表示選自以下各基之基團:氫原子、鹵素原子、可視情況經1、2或3個選自鹵素原子及羥基之取代基取代的C1-4
烷基以及可視情況經1、2或3個選自鹵素原子及羥基之取代基取代的C1-4
烷氧基.Rd
表示選自以下各基之基團:氫原子、鹵素原子、羥基、可視情況經1、2或3個選自鹵素原子及羥基之取代基取代的C1-4
烷基以及可視情況經1、2或3個選自鹵素原子及羥基之取代基取代的C1-4
烷氧基以及可視情況經1、2或3個選自鹵素原子及羥基之取代基取代的C3-8
環烷氧基.基團G3
及G4
中之一個為氮原子且另一個為CH基團.M為氫原子或醫藥學上可接受之陽離子其中限制條件為當基團Ra
及Rb
中之至少一個表示氫原子且G2
為基團CRd
時,則Rd
表示選自以下各基之基團:可視情況經1、2或3個選自鹵素原子及羥基之取代基取代的C1-4
烷氧基、可視情況經1、2或3個選自鹵素原子及羥基之取代基取代的C3-8
環烷氧基;以及其醫藥學上可接受之鹽及N-氧化物。
如本文所使用,術語烷基包括具有1至4個碳原子之視情況經取代之直鏈或支鏈烴基。烷基上之較佳取代基為鹵素原子及羥基,且更佳為鹵素原子。
實例包含甲基、乙基、正丙基、異丙基、正丁基、第二丁基以及第三丁基。
如本文所使用,術語烷氧基包括各具有1至4個碳原子之視情況經取代之直鏈或支鏈含氧基團。烷氧基上之較佳取代基為鹵素原子及羥基,且更佳為鹵素原子。
實例包含甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、第二丁氧基以及第三丁氧基。
如本文所使用,術語環烷基包括飽和碳環基,且除非另有說明,否則環烷基通常具有3至8個碳原子。
實例包含環丙基、環丁基、環戊基、環已基以及環庚基。當環烷基帶有兩個或兩個以上取代基時,取代基可相同或不同。環烷基上之較佳取代基為鹵素原子及羥基,且更佳為鹵素原子。
如本文所使用,術語環烷氧基包括飽和含氧碳環基,且除非另有說明,否則環烷氧基通常具有3至8個碳原子。
實例包含環丙氧基、環丁氧基、環戊氧基、環已氧基以及環庚氧基。當環烷氧基帶有兩個或兩個以上取代基時,取代基可相同或不同。環烷氧基上之較佳取代基為鹵素原子及羥基,且更佳為鹵素原子。
如本文所使用,本發明之通用結構中所存在之原子、基團、部分、鏈或環中的一些可“視情況經取代”。此意謂所述原子、基團、部分、鏈或環可未經取代或在任何位置經一或多個(例如1、2、3或4個)取代基取代,由此與未經取代之原子、基團、部分、鏈或環結合之氫原子經化學上可接受之原子、基團、部分、鏈或環置換。當存在兩個或兩個以上取代基時,各取代基可相同或不同。
如本文所使用,術語鹵素原子包括氯、氟、溴或碘原子,通常為氟、氯或溴原子,最佳為溴或氟。當術語鹵代用作前綴時,具有相同含義。
M可為氫原子或醫藥學上可接受之陽離子。當M為醫藥學上可接受之陽離子時,由式(I)表示之化合物另外可由下式(I*
)表示。
如本文所使用,術語醫藥學上可接受之陽離子包括無機陽離子,例如鹼金屬陽離子(Li+
、Na+
、K+
)、鹼土金屬陽離子(Ca2+
、Mg2+
)以及此項技術已知之其他醫藥學上可接受之無機陽離子(Zn2+
、Al3+
);與有機陽離子,例如銨離子(亦即,NH4 +
)及經取代銨離子,諸如NH3
R1+
、NH2
(R1
)2 +
、NH(R1
)3 +
以及N(R1
)4 +
,其中R1
各自獨立地選自苯基、苄基、C1-4
烷基以及C3-8
環烷基。
一些合適的經取代銨離子之實例為EtNH3 +
、Et2
NH2 +
、Et3
NH+
、(C6
H11
)2
NH2 +
、CH3
CH2
CH2
CH2
NH3 +
、PhCH2
NH3 +
以及(Ph)(PhCH2
)NH2 +
。常見四級銨離子之實例為N(CH3
)4 +
。
M通常為氫原子或選自Li+
、Na+
、K+
、Ca2+
以及Mg2+
之醫藥學上可接受之陽離子。M較佳為氫原子或選自Li+
、Na+
以及K+
之醫藥學上可接受之陽離子。M更佳為氫原子或Li+
,且最佳為其中M為氫原子。
若式(I)之M為具有大於+1之電荷的醫藥學上可接受之陽離子,則存在其他陰離子以維持化合物之電中性。抗衡陰離子可為如下所定義之陰離子X-
或上式(I*
)中所表示之陰離子。
如本文所使用,術語醫藥學上可接受之鹽包括與醫藥學上可接受之酸或鹼形成之鹽。醫藥學上可接受之酸包含無機酸,例如鹽酸、硫酸、磷酸、二磷酸、氫溴酸、氫碘酸以及硝酸;與有機酸,例如檸檬酸、反丁烯二酸、順丁烯二酸、蘋果酸、扁桃酸、抗壞血酸、草酸、丁二酸、酒石酸、苯甲酸、乙酸、甲烷磺酸、乙烷磺酸、苯磺酸、環己基胺磺酸(cyclohexylsulfamic)(環拉酸(cyclamic))或對甲苯磺酸。醫藥學上可接受之鹼包含鹼金屬(例如,鈉或鉀)及鹼土金屬(例如,鈣或鎂)氫氧化物以及有機鹼,例如烷基胺、芳基烷基胺以及雜環胺。
本發明之其他較佳鹽為四級銨化合物,其中等量的陰離子(X-
)與N原子之正電荷締合。X-
可為各種礦物酸之陰離子,諸如氯離子、溴離子、碘離子、硫酸根、硝酸根、磷酸根;或有機酸之陰離子,諸如乙酸根、順丁烯二酸根、反丁烯二酸根、檸檬酸根、草酸根、丁二酸根、酒石酸根、蘋果酸根、扁桃酸根、三氟乙酸根、甲烷磺酸根以及對甲苯磺酸根。X-
較佳為選自以下離子之陰離子:氯離子、溴離子、碘離子、硫酸根、硝酸根、乙酸根、順丁烯二酸根、草酸根、丁二酸根或三氟乙酸根。X-
更佳為氯離子、溴離子、三氟乙酸根或甲烷磺酸根。
如本文所使用,N-氧化物是由分子中所存在之三級鹼性胺或亞胺使用便利氧化劑而形成。
在本發明之一實施例中,R1
是選自由氫、溴及氟原子、甲基、乙基、環丙基以及環丁基組成的族群。
在本發明之另一實施例中,G3
表示氮原子且G4
表示基團CH。
在本發明之又一實施例中,G3
表示基團CH且G4
表示氮原子。
在本發明之又一實施例中,兩個基團G1
均表示基團CRc
。
在本發明之另一實施例中,Rc
各自獨立地選自由氫原子、氟原子、氯原子以及C1-3
烷基組成的族群。
在本發明之又一實施例中,基團G2
表示基團CRd
。
在本發明之又一實施例中,Rd
是選自由羥基、C1-3
烷氧基、2,2,2-三氟乙氧基以及C3-4
環烷氧基組成的族群。C1-3
烷氧基、2,2,2-三氟乙氧基以及C3-4
環烷氧基較佳。
在本發明之另一實施例中,Ra
是選自由氟原子、甲基以及三氟甲氧基組成的族群。
在本發明之又一實施例中,Rb
是選自由氫原子、氟原子以及氯原子組成的族群。
在本發明之又一實施例中,R2
是選自由氫原子及鹵素原子、較佳氫原子及氟原子組成的族群。
在本發明之一較佳實施例中,兩個基團G1
均表示C(Rc
)基團,G2
表示C(Rd
)基團,G2
較佳為選自C(OH)、C(OMe)以及C(OEt)之基團;Ra
為氟原子,Rb
是選自由氫原子及氟原子組成的族群且R1
是選自由氫、溴及氟原子、甲基、乙基以及環丙基組成的族群;較佳地,兩個G1
均表示CH基團,G2
為選自C(OMe)及C(OEt)之基團;Ra
為氟原子,Rb
是選自由氫原子及氟原子組成的族群且R1
是選自由氫、溴及氟原子、甲基、乙基以及環丙基組成的族群。
在本發明之一較佳實施例中,Rc
為氫原子,Rd
為羥基或C1-3
烷氧基且R2
為氫原子;較佳地,Rc
為氫原子,Rd
為C1-3
烷氧基且R2
為氫原子。
其中G3
表示氮原子,G4
表示基團CH且Rb
為氟原子之化合物以及其中G3
表示基團CH,G4
表示氮原子之化合物尤其較佳。
在本發明之一較佳實施例中,兩個基團G1
均表示C(Rc
)基團,G2
表示C(Rd
)基團,Ra
為氟原子,Rb
是選自由氫原子及氟原子組成的族群且R1
是選自由氫、溴及氟原子、甲基、乙基以及環丙基組成的族群;較佳地,Rc
為氫原子,Rd
是選自由C1-3
烷氧基及C3-4
環烷氧基組成的族群且R2
為氫原子。其中G3
表示氮原子,G4
表示基團CH且Rb
為氟原子之化合物以及其中G3
表示基團CH,G4
表示氮原子之化合物尤其較佳。
本發明之特殊個別化合物包含:2-(3-氟-3'-甲氧基聯苯-4-基胺基)菸酸2-(3'-乙氧基-3-氟聯苯-4-基胺基)菸酸2-(3-氟-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(3'-乙氧基-3-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(3'-甲氧基-3-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(2,5-二氟-3'-甲氧基聯苯-4-基胺基)菸酸2-(3'-乙氧基-2,5-二氟聯苯-4-基胺基)菸酸2-(2',3-二氟-3'-甲氧基聯苯-4-基胺基)菸酸2-(2-甲基-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(3-氯-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(3-氯-3'-乙氧基聯苯-4-基胺基)菸酸2-(3-甲基-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(3-氯-3'-甲氧基聯苯-4-基胺基)菸酸2-(3'-(二氟甲氧基)-3-氟聯苯-4-基胺基)菸酸2-(3'-環丁氧基-3-氟聯苯-4-基胺基)菸酸2-(3-氟-3'-(2,2,2-三氟乙氧基)聯苯-4-基胺基)菸酸2-(3'-環丁氧基-3,5-二氟聯苯-4-基胺基)菸酸2-(3,5-二氟-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(3'-乙氧基-3,5-二氟聯苯-4-基胺基)菸酸2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)菸酸3-(3'-乙氧基-3-氟聯苯-4-基胺基)異菸酸鋰3-(3-氟-3'-甲氧基聯苯-4-基胺基)異菸酸鋰3-(3'-甲氧基-3-(三氟甲氧基)聯苯-4-基胺基)異菸酸鋰3-(3-氟-3'-(三氟甲氧基)聯苯-4-基胺基)異菸酸鋰2-(3'-乙氧基聯苯-4-基胺基)菸酸2-(5-氟-2-甲基-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(2',3-二氟-5'-異丙氧基聯苯-4-基胺基)菸酸2-(3-氟-3'-甲氧基聯苯-4-基胺基)-5-甲基菸酸2-(3,5-二氟-3'-羥基聯苯-4-基胺基)菸酸5-溴-2-(3-氟-3'-甲氧基聯苯-4-基胺基)菸酸5-溴-2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)菸酸5-溴-2-(3-氟-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(3-氟-3'-(三氟甲氧基)聯苯-4-基胺基)-5-甲基菸酸5-環丙基-2-(3-氟-3'-甲氧基聯苯-4-基胺基)菸酸2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)-5-甲基菸酸2-(3'-乙氧基-5-氟-2-甲基聯苯-4-基胺基)菸酸2-(5-氟-3'-甲氧基-2-甲基聯苯-4-基胺基)菸酸2-(3'-乙氧基-3,5-二氟聯苯-4-基胺基)-5-甲基菸酸5-環丙基-2-(3'-乙氧基-3,5-二氟聯苯-4-基胺基)菸酸2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)-5-乙基菸酸5-溴-2-(3'-乙氧基-2,5-二氟聯苯-4-基胺基)菸酸5-環丙基-2-(3'-乙氧基-2,5-二氟聯苯-4-基胺基)菸酸2-(5-氟-3'-甲氧基-2-甲基聯苯-4-基胺基)-5-甲基菸酸5-環丙基-2-(5-氟-3'-甲氧基-2-甲基聯苯-4-基胺基)菸酸2-(2',3,5-三氟-3'-甲氧基聯苯-4-基胺基)菸酸2-(2'-氯-3,5-二氟聯苯-4-基胺基)菸酸2-(3'-環丙氧基-3,5-二氟聯苯-4-基胺基)菸酸2-(3,5-二氟-2-甲基聯苯-4-基胺基)菸酸5-環丙基-2-(2,5-二氟-3'-甲氧基聯苯-4-基胺基)菸酸2-(3'-環丙氧基-3,5-二氟聯苯-4-基胺基)-5-環丙基菸酸5-氯-2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)菸酸5-環丙基-2-(3,5-二氟-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(2,3,5-三氟-3'-甲氧基聯苯-4-基胺基)菸酸2-(2'-氯-3,5-二氟聯苯-4-基胺基)-5-環丙基菸酸2-(3,5-二氟-3'-甲氧基-2-甲基聯苯-4-基胺基)菸酸2-(3,5-二氟-2-甲基-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(2'-氯-3,5-二氟-2-甲基聯苯-4-基胺基)菸酸5-氯-2-(3,5-二氟聯苯-4-基胺基)菸酸5-氯-2-(2'-氯-3,5-二氟聯苯-4-基胺基)菸酸2-(2,3,5,6-四氟-3'-甲氧基聯苯-4-基胺基)菸酸2-(3,5-二氟-2'-甲基聯苯-4-基胺基)菸酸3-(3'-環丙氧基-3-氟聯苯-4-基胺基)異菸酸。
尤其關注的是:2-(3'-乙氧基-3-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(3'-甲氧基-3-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(3'-乙氧基-3,5-二氟聯苯-4-基胺基)菸酸2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)菸酸3-(3'-乙氧基-3-氟聯苯-4-基胺基)異菸酸鋰3-(3-氟-3'-甲氧基聯苯-4-基胺基)異菸酸鋰3-(3'-甲氧基-3-(三氟甲氧基)聯苯-4-基胺基)異菸酸鋰2-(3-氟-3'-甲氧基聯苯-4-基胺基)-5-甲基菸酸5-溴-2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)菸酸5-環丙基-2-(3-氟-3'-甲氧基聯苯-4-基胺基)菸酸2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)-5-甲基菸酸2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)-5-乙基菸酸2-(2'-氯-3,5-二氟聯苯-4-基胺基)菸酸2-(3'-環丙氧基-3,5-二氟聯苯-4-基胺基)菸酸2-(3,5-二氟-2-甲基聯苯-4-基胺基)菸酸5-環丙基-2-(2,5-二氟-3'-甲氧基聯苯-4-基胺基)菸酸5-環丙基-2-(3,5-二氟-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(2'-氯-3,5-二氟聯苯-4-基胺基)-5-環丙基菸酸2-(2,3,5,6-四氟-3'-甲氧基聯苯-4-基胺基)菸酸。
通式(I)化合物可根據圖1中所描繪之合成流程製備。
可藉由在100℃至160℃之溫度下在酸介質(諸如作為溶劑之乙酸,或含有諸如水、二甲苯、乙氧基乙醇、DME或DMF之高沸點溶劑之乙酸或對甲苯磺酸)中,使所述中間體(II)與相應氯菸酸(III)反應製備通式(Ia)化合物(菸酸衍生物)。亦可在諸如DBU、DIEA或Cs2
CO3
之鹼性介質中在諸如二甲苯、乙氧基乙醇、DMF或NMP之高沸點溶劑中製備所述化合物。
在0℃至50℃之溫度下使用可與水混溶之溶劑(諸如乙醇或甲醇),藉由使相應甲基酯(V)與諸如氫氧化鋰或氫氧化鈉之鹼皂化反應得到相應鹽可製備通式(Ib)化合物(異菸酸衍生物)。
藉由使聯芳基苯胺(II)與相應氯異菸酸甲酯(IV)偶合可得到式(V)化合物。所述反應可在80℃至溶劑沸點之溫度下在諸如甲苯、二噁烷或二甲基甲醯胺之惰性溶劑中在諸如9,9-二甲基-4,5-雙(二苯基膦基)-9H-二苯並哌喃之配位基存在下且在諸如碳酸銫之無機鹼存在下由諸如參(二亞苄基丙酮)-二鈀(0)之鈀觸媒催化。
式(II)之聯芳基苯胺可根據圖2中所描繪之合成流程製備。
在其中G5
表示硼酸或硼酸酯之Suzuki反應(Miyaura,N.;Suzuki,A.Chem.Rev.1995,95,2457)條件下或在其中G5
表示錫烷之Stille反應條件下,使式(VI)溴衍生物與相應式(VII)芳基衍生物偶合。所述反應可在80℃至140℃之溫度下在諸如二噁烷、甲苯、DMF或DME之質子惰性有機溶劑中且在諸如碳酸銫、碳酸鈉、碳酸鉀或磷酸鉀之鹼存在下由諸如[1,1'-雙(二苯基膦基)-二茂鐵]二氯鈀(II)錯合物與二氯甲烷(1:1)、肆(三苯基膦)鈀(0)、雙(三苯基膦)氯化鈀(II)或參(二亞苄基丙酮)二鈀(0)之鈀觸媒催化。
在Ra
及Rb
均不同於氫之特殊情況下,式(Ia)化合物可根據圖3中所示之合成途徑獲得。
在其中G5
表示硼酸或硼酸酯之Suzuki反應(Miyaura,N.;Suzuki,A.Chem.Rev.1995,95,2457)條件下或在其中G5
表示錫烷之Stille反應條件下,可自式(IX)之2-(4-溴苯基胺基)菸酸及相應式(VII)芳基衍生物得到式(Ia)化合物。
可藉由在100℃至160℃之溫度下在諸如作為溶劑之乙酸之酸介質中或在諸如二甲苯、乙氧基乙醇或DMF之高沸點溶劑存在下,使式(VIII)溴苯胺與相應氯菸酸(III)反應得到式(IX)之2-(4-溴苯基胺基)菸酸。或者,可在諸如DBU、DIEA或Cs2
CO3
之鹼性介質中在諸如二甲苯、乙氧基乙醇、DMF或NMP之高沸點溶劑中進行所述反應。
在G2
為CRd
且Rd
為羥基之特殊情況下,式(Ia2)化合物可根據圖4中所示之合成途徑製備。
在0至溶劑沸點之溫度下在諸如碳酸氫鈉之無機鹼存在下在諸如丙酮之溶劑中,使式(XII)菸酸與諸如硫酸二甲酯之甲基化試劑反應得到式(XI)菸酸甲酯化合物。
藉由標準方法使式(XI)菸酸甲酯與其中Rd
如上文所定義且X為諸如氯或溴原子之離去基團之式(XIII)烷基化劑反應得到式(X)化合物。
最後,在0℃至50℃之溫度下在諸如甲醇或乙醇之質子性溶劑中在諸如氫氧化鋰或氫氧化鈉之鹼存在下,使式(X)菸酸甲酯水解得到所需的式(Ia2)化合物。
在R1
為C1-4
烷基或C3-8
環烷基之特殊情況中,可根據圖5及6中所示之合成途徑製備式(Ia3)化合物。
圖5
在其中G5
表示硼酸或硼酸酯之Suzuki反應(Miyaura,N.;Suzuki,A.Chem.Rev.1995,95,2457)條件下或在其中G5
表示錫烷之Stille反應條件下,使式(XV)溴菸酸與相應式(XIV)烷基硼酸、硼酸酯或錫烷反應得到所需的通式(Ia3)化合物。
在其中G5
表示硼酸或硼酸酯之Suzuki反應(Miyaura,N.;Suzuki,A.Chem.Rev.1995,95,2457)條件下或在其中G5
表示錫烷之Stille反應條件下,使式(XVII)溴菸酸甲酯與相應式(XIV)烷基硼酸、硼酸酯或錫烷反應得到通式(XVI)化合物。在0℃至50℃之溫度下在諸如甲醇或乙醇之質子性溶劑中在諸如氫氧化鋰或氫氧化鈉之鹼存在下,使所得式(XVI)菸酸酯水解得到式(IV)菸酸衍生物。可藉由在100℃至160℃之溫度下在諸如作為溶劑之乙酸之酸介質中或在諸如二甲苯、乙氧基乙醇或DMF之高沸點溶劑存在下,使所述式(IV)菸酸與相應式(II)苯胺反應得到式(Ia3)最終化合物。或者,可在諸如DBU、DIEA或Cs2
CO3
之鹼性介質中在諸如二甲苯、乙氧基乙醇、DMF或NMP之高沸點溶劑中進行所述反應。
由包含製備實例(中間體1至51)之以下實例(1至62)說明本發明之化合物以及其中所使用之中間體的合成,所述實例無論如何不限制本發明之範疇。
在Varian Mercury 200光譜儀上記錄1
H核磁共振光譜。使用ESI離子化在Micromass ZMD質譜儀上記錄低解析度質譜(m/z)。使用配備有Symmetry C18(2.1×10毫米,3.5毫莫耳濃度)管柱之Waters 2690系統獲得層析分離。移動相為甲酸(0.4毫升)、氨水(0.1毫升)、甲醇(500毫升)以及乙腈(500毫升)(B)與甲酸(0.46毫升)、氨水(0.115毫升)以及水(1000毫升)(A):最初0% B歷時0.5分鐘,隨後0%至95% B歷時6.5分鐘,隨後95% B歷時1分鐘。兩個注射之間的重新平衡時間為1分鐘。流率為0.4毫升/分鐘。注射體積為5微升。在210奈米下收集二極體陣列層析圖。
中間體13'-乙氧基-3-氟聯苯-4-胺
在氮氣氛下,向4-溴-2-氟苯胺(3.2公克,17.05毫莫耳)、2莫耳濃度K2
CO3
(24毫升,48.00毫莫耳)、Pd(PPh3
)4
(1.2公克,1.02毫莫耳)於甲苯(120毫升)中之溶液中逐滴添加3-乙氧基苯基硼酸(4.25公克,25.61毫莫耳)於31毫升MeOH中之溶液。將混合物加熱至80℃隔夜,隨後冷卻至室溫。添加乙酸乙酯且用K2
CO3
水溶液洗滌兩次。將有機層用鹽水洗滌,經硫酸鎂乾燥,過濾且在真空下蒸發溶劑。將所獲得之殘餘物經急驟層析用己烷/AcOEt(10/1至8/1)溶離純化。將所獲得之固體於己烷中再結晶得到3.78公克呈白色固體之所需化合物。產率=72%。
LRMS:m/z 232(M+1)+
。
滯留時間:6.44分鐘
1
H NMR(250 MHz,CDCl3
)δ ppm:1.4(t,J=6.9 Hz,3H);4.1(q,J=6.9 Hz,2H);6.8(m,2H);7.1(m,2H);7.2-7.3(m,3H)。
中間體23-氟-3'-(三氟甲氧基)聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴-2-氟苯胺及3-(三氟甲氧基)苯基硼酸獲得(54%)。
LRMS:m/z 272(M+1)+
。
滯留時間:6.81分鐘
1
H NMR(250 MHz,CDCl3
)δ ppm:6.8(m,1H);7.2(m,3H);7.4(m,3H)。
中間體33'-乙氧基-3-(三氟甲氧基)聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴-2-(三氟甲氧基)苯胺及3-乙氧基苯基硼酸獲得(40%)。
LRMS:m/z 298(M+1)+
。
滯留時間:7.04分鐘
1
H NMR(200 MHz,CDCl3
)δ ppm:1.4(t,J=7.0 Hz,3 H);3.9(s,2 H);4.1(q,J=7.0 Hz,2 H);6.8(m,2 H);7.1(m,2 H);7.3(m,3 H)。
中間體43-氟-3'-甲氧基聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴-2-氟苯胺及3-甲氧基苯基硼酸獲得(35%)。
LRMS:m/z 218(M+1)+
。
1
H NMR(250 MHz,CDCl3
.)δ ppm:3.9(s,3H);6.8(m,2H);7.1(m,2H);7.3(m,3H)。
中間體53'-甲氧基-3-(三氟甲氧基)聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴-2-(三氟甲氧基)苯胺及3-甲氧基苯基硼酸獲得(56%)。
LRMS:m/z 284(M+1)+
。
1
H NMR(250 MHz,CDCl3
).δ ppm:3.8(s,3H);6.8(m,2H);7.0(m,1H);7.1(m,1H);7.3-7.4(m,3H)。
中間體62,5-二氟-3'-甲氧基聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴-2,5-二氟苯胺及3-甲氧基苯基硼酸獲得(84%)。
LRMS:m/z 236(M+1)+
。
滯留時間:6.20分鐘
中間體73'-乙氧基-2,5-二氟聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴-2,5-二氟苯胺及3-乙氧基苯基硼酸獲得(66%)。
LRMS:m/z 250(M+1)+
。
滯留時間:6.58分鐘
中間體82',3-二氟-3'-甲氧基聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴-2-氟苯胺及2-氟-3-甲氧基苯基硼酸獲得(54%)。
LRMS:m/z 236(M+1)+
。
滯留時間:5.93分鐘
1
H NMR(200 MHz,CDCl3
)δ ppm:3.8(s,2 H);3.9(s,3 H);6.9(m,3 H);7.1(m,3 H)。
中間體92-甲基-3'-(三氟甲氧基)聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴-3-甲基苯胺及3-(三氟甲氧基)苯基硼酸獲得(86%)。
LRMS:m/z 268(M+1)+
。
滯留時間:6.54分鐘
1
H NMR(200 MHz,CDCl3
)δ ppm:2.2(s,3 H);3.7(s,2 H);6.6(m,2 H);7.0(d,J
=8.2 Hz,1 H);7.2(m,3 H);7.4(m,1 H)。
中間體103-氯-3'-(三氟甲氧基)聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴-2-氯苯胺及3-(三氟甲氧基)苯基硼酸獲得(78%)。
LRMS:m/z 288(M+1)+
。
滯留時間:7.12分鐘
1
H NMR(200 MHz,DMSO-D6
)δ ppm:5.6(s,2 H);6.9(d,J
=8.6 Hz,1 H);7.2(m,J
=8.2 Hz,1 H);7.5(m,5 H)。
中間體113-氯-3'-乙氧基聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴-2-氯苯胺及3-乙氧基苯基硼酸獲得(79%)。
LRMS:m/z 248(M+1)+
。
滯留時間:6.75分鐘
1
H NMR(200 MHz,DMSO-D6
)δ ppm:1.3(t,J
=7.0 Hz,3 H);4.1(q,J
=7.0 Hz,2 H);5.5(s,2 H)6.8(m,2 H);7.1(m,2 H);7.3(t,J
=7.8 Hz,1 H);7.4(dd,J
=8.4,2.1 Hz,1 H);7.5(d,J
=2.3 Hz,1 H)。
中間體123'-乙氧基聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴苯胺及3-乙氧基苯基硼酸獲得(91%)。
LRMS:m/z 214(M+1)+
。
滯留時間:5.73分鐘
1
H NMR(200 MHz,CDCl3
)δ ppm:1.4(t,J
=7.0 Hz,3 H);3.7(s,2 H);4.1(q,J
=7.0 Hz,2 H);6.8(m,3 H);7.1(m,2 H);7.4(m,3 H)。
中間體133-甲基-3'-(三氟甲氧基)聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴-2-甲基苯胺及3-(三氟甲氧基)苯基硼酸獲得(83%)。
LRMS:m/z 268(M+1)+
。
滯留時間:6.82分鐘
1
H NMR(200 MHz,CDCl3
)δ ppm:2.2(s,3 H);3.7(s,2 H);6.7(d,J
=9.0 Hz,1 H);7.1(m,J
=7.8 Hz,1 H);7.4(m,5 H)。
中間體143-氯-3'-甲氧基聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴-2-氯苯胺及3-甲氧基苯基硼酸獲得(87%)。
LRMS:m/z 234(M+1)+
。
滯留時間:6.44分鐘
1
H NMR(200 MHz,CDCl3
)δ ppm:3.9(s,3 H);4.1(s,2 H);6.8(m,2 H);7.1(m,2 H);7.3(m,2 H);7.5(d,J
=2.3 Hz,1 H)。
中間體153'-(二氟甲氧基)-3-氟聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴-2-氟苯胺及2-(3-(二氟甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼戊環獲得(76%)。
LRMS:m/z 254(M+1)+
。
滯留時間:6.24分鐘
1
H NMR(200 MHz,CDCl3
)δ ppm:3.9(s,2 H);6.5(t,J
=73.8 Hz,1 H);6.8(m,1 H);7.1(m,1 H);7.3(m,3 H);7.4(m,2 H)。
中間體162-(3-氟-3'-羥基聯苯-4-基胺基)菸酸甲酯
向2-(3-氟-3'-羥基聯苯-4-基胺基)菸酸(1公克,3.08毫莫耳)及NaHCO3
(0.5公克,6.17毫莫耳)於丙酮(20毫升)中之混合物中逐滴添加硫酸二甲酯(0.47公克,3.70毫莫耳)。將混合物加熱至回流隔夜,隨後濃縮。將乙酸乙酯添加至粗產物中且用4% NaHCO3
溶液及鹽水洗滌兩次。隨後將有機相經MgSO4
乾燥且在真空下濃縮得到0.4公克米色固體,所述固體足夠純可用於下一合成步驟中。產率=36%。
LRMS:m/z 339(M+1)+
。
滯留時間:7.02分鐘
中間體172-(3,5-二氟-3'-羥基聯苯-4-基胺基)菸酸甲酯
根據對於中間體16所述之實驗程序,自2-(3,5-二氟-3'-羥基聯苯-4-基胺基)菸酸獲得(52%)。
LRMS:m/z 357(M+1)+
。
滯留時間:6.26分鐘
中間體182-(3-氟-3'-(2,2,2-三氟乙氧基)聯苯-4-基胺基)菸酸甲酯
在120℃下在氮氣氛下,將中間體16(0.36公克,1.06毫莫耳)、2-溴-1,1,1-三氟乙烷(0.26公克,1.6毫莫耳)以及碳酸鉀(0.29公克,2.13毫莫耳)於DMF中之混合物攪拌隔夜。添加水且用EtOAc(2×)萃取混合物。將組合有機相用水及鹽水洗滌,經MgSO4
乾燥且在真空下濃縮。經管柱層析(於己烷中之10% EtOAc)純化得到呈黃色固體之所需化合物。產率=27%。
LRMS:m/z 421(M+1)+
。
滯留時間:7.73分鐘
中間體192-(3'-環丁氧基-3-氟聯苯-4-基胺基)菸酸甲酯
根據對於中間體18所述之實驗程序,自中間體16及溴環丁烷獲得(48%)。
LRMS:m/z 393(M+1)+
。
滯留時間:8.08分鐘
中間體202-(3'-環丁氧基-3,5-二氟聯苯-4-基胺基)菸酸甲酯
根據對於中間體18所述之實驗程序,自中間體17及溴環丁烷獲得(26%)。
LRMS:m/z 411(M+1)+
。
滯留時間:7.53分鐘
中間體212-(4-溴-2,6-二氟苯基胺基)菸酸
在氮氣氛下,將2-氯菸酸(1.6公克,10.15毫莫耳)及4-溴-2,6-二氟苯胺(3.24公克,15.58毫莫耳)於乙酸(40毫升)中之混合物在130℃下加熱隔夜。將混合物冷卻至室溫得到沈澱。將混合物過濾且將固體用乙酸清洗得到2-羥基菸酸(副產物)。當將濾液部分濃縮時第二固體沈澱,得到另一沈澱,其對應於N-(4-溴-2,6-二氟苯基)乙醯胺(另一副產物)。最後,將濾液濃縮至乾燥且得到3.14公克呈固體之所需化合物,雖然所述固體含部分乙醯胺,但使用所述混合物進行下一合成步驟。
LRMS:m/z 329,331(M+1)+
。
滯留時間:6.09分鐘
中間體223-(3'-乙氧基-3-氟聯苯-4-基胺基)異菸酸甲酯
在氬氣氛下,將3-氯異菸酸甲酯(1.00公克,5.83毫莫耳)、中間體1(1.35公克,5.83毫莫耳)、Cs2
CO3
(2.66公克,8.16毫莫耳)以及Xantphos(0.68公克,1.17毫莫耳)於二噁烷(20毫升)中之混合物攪拌10分鐘。隨後添加Pd2
(dba)3
(0.53公克,0.58毫莫耳)且在氬氣氛下在120℃下將混合物攪拌隔夜。將反應混合物經矽藻土過濾且用CH2
Cl2
洗滌。將濾液濃縮且經管柱層析用EtOAc/己烷/Et3
N(20/79/1)溶離純化且得到所需化合物。產率=51%。
LRMS:m/z 367(M+1)+
。
1
H NMR(250 MHz,CDCl3
)δ ppm:9.26(s,1H);8.8(s,1H);8.25(d,J=5.3 Hz,1H);7.87(d,J=5.3 Hz,1H);7.72-7.45(m,4H);7.3(d,J=8.2 Hz,1H);7.26(s,1H);7.05(dd,J=8.2,J=1.8 Hz,1H);4.25(c,J=7 Hz,2H);4.12(s,3H);1.61(t,J=7 Hz,3H)。
中間體233-(3-氟-3'-甲氧基聯苯-4-基胺基)異菸酸甲酯
根據對於中間體22所述之實驗程序,自3-氯異菸酸甲酯及中間體4獲得(57%)。
LRMS:m/z 353(M+1)+
。
1
H NMR(250 MHz,CDCl3
)δ ppm:9.11(s,1H);8.65(s,1H);8.1(d,J=4.9 Hz,1H);7.72(d,J=5.2 Hz,1H);7.58-7.27(m,4H);7.16(d,J=7.4 Hz,1H);7.1(t,J=1.7 Hz,1H);6.9(dd,J=8.2,J=2.5 Hz,1H);3.96(s,3H);3.87(s,3H)。
中間體243-(3'-甲氧基-3-(三氟甲氧基)聯苯-4-基胺基)異菸酸甲酯
根據對於中間體22所述之實驗程序,自3-氯異菸酸甲酯及中間體5獲得(76%)。
LRMS:m/z 419(M+1)+
。
1
H NMR(250 MHz,CDCl3
)δ ppm:9.44(s,1H);8.95(s,1H);8.3(d,J=5.2 Hz,1H);7.9(d,J=4.9 Hz,1H);7.72(m,3H);7.53(m,1H);7.32(d,J=8.2 Hz,1H);7.27(m,1H);7.07(d,J=9 Hz,1H);4.12(s,3H);4.03(s,3H)。
中間體253-(3-氟-3'-(三氟甲氧基)聯苯-4-基胺基)異菸酸甲酯
根據對於中間體22所述之實驗程序,自3-氯異菸酸甲酯及中間體2獲得(92%)。
LRMS:m/z 407(M+1)+
。
1
H NMR(250 MHz,CDCl3
)δ ppm:8.98(s,1H);8.5(s,1H);7.95(d,J=4.9 Hz,1H);7.58(d,J=4.9 Hz,1H);7.46-7.15(m,6H);7.06(m,1H);3.81(s,3H)。
中間體263'-乙氧基-5-氟-2-甲基聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴-2-氟-5-甲基苯胺及3-乙氧基苯基硼酸獲得(80%)。
LRMS:m/z 246(M+1)+
。
滯留時間:6.36分鐘
1
H NMR(200 MHz,CDCl3
)δ ppm:1.4(t,J
=6.8 Hz,3 H);2.2(s,3 H);3.7(s,2 H);4.1(q,J
=7.0 Hz,2 H);6.7(d,J
=9.0 Hz,1 H);6.9(m,4 H);7.3(m,1 H)
中間體275-氟-2-甲基-3'-(三氟甲氧基)聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴-2-氟-5-甲基苯胺及3-(三氟甲氧基)苯基硼酸獲得(92%)。
LRMS:m/z 286(M+1)+
。
滯留時間:6.96分鐘
1
H NMR(200 MHz,CDCl3
)δ ppm:2.2(s,3 H);3.7(s,2 H);6.7(d,J
=9.0 Hz,1 H);6.9(d,J
=11.7 Hz,1 H);7.2(m,3 H);7.4(m,1 H)。
中間體282',3-二氟-5'-異丙氧基聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴-2-氟苯胺及2-氟-5-異丙氧基苯基硼酸獲得(95%)。
LRMS:m/z 264(M+1)+
。
滯留時間:6.67分鐘
1
H NMR(200 MHz,CDCl3
)δ ppm:1.3(d,J
=6.2 Hz,6 H);3.8(s,2 H);4.5(m,1 H);6.8(m,3 H);7.0(m,1 H);7.2(m,2 H)。
中間體293,5-二氟-3'-甲氧基聯苯-4-胺
根據對於中間體1所述之實驗程序,由4-溴-2,6-二氟苯胺及3-甲氧基苯基硼酸獲得(91%)。
LRMS:m/z236(M+1)+
。
滯留時間:6.34分鐘
1
H NMR(200 MHz,CDCl3
)δ ppm:3.8(s,2 H);3.9(s,3 H);6.9(m,1 H);7.1(m,4 H);7.3(t,J
=8.0 Hz,1 H)。
中間體305-氟-3'-甲氧基-2-甲基聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴-2-氟-5-甲基苯胺及3-甲氧基苯基硼酸獲得(80%)。
LRMS:m/z 232(M+1)+
。
滯留時間:6.00分鐘
1
H NMR(200 MHz,DMSO-D6
)δ ppm:2.1(s,3 H);3.7(s,3 H);5.1(s,2 H);6.6(d,J
=9.4 Hz,1 H);6.8(m,4 H);7.3(t,J
=7.8 Hz,1 H)。
中間體312-氯-5-甲基菸酸甲酯
在氮氣氛下,向5-溴-2-氯菸酸甲酯(1.05公克,4.19毫莫耳)、K3
PO4
(2.95公克,13.90毫莫耳)、甲基硼酸(0.32公克,5.26毫莫耳)以及三環己基膦(0.11公克,0.39毫莫耳)於甲苯/水(16毫升/0.8毫升)中之溶液中添加Pd(OAc)2
(0.04公克,0.18毫莫耳)。在氮氣氛下,將混合物在100℃下加熱隔夜。隨後將反應混合物冷卻至室溫且真空濃縮。將乙酸乙酯添加至殘餘物中且將所述有機層用水、鹽水洗滌,經MgSO4
乾燥,過濾且在真空下蒸發溶劑得到呈黃色油狀物之所需產物。產率=87%。
LRMS:m/z 186(M+1)+
。
滯留時間:4.84分鐘
中間體322-氯-5-甲基菸酸
將中間體31(0.38公克,1.81毫莫耳)溶解於MeOH(2毫升)中且添加2N NaOH溶液(1.81毫升,3.62毫莫耳)且在室溫下將混合物攪拌2小時。將反應混合物濃縮至乾燥且將殘餘物再溶解於EtOAc/水中。將有機層分離,經硫酸鎂乾燥且真空濃縮得到呈白色固體之所需產物。產率=94%。
LRMS:m/z 172(M+1)+
。
滯留時間:3.25分鐘
1
H NMR(200 MHz,DMSO-D6
)δ ppm:2.2(s,3 H);7.6(d,J
=2.53 Hz,1 H);8.0(d,J
=2.53 Hz,1 H)。
中間體332-(3'-(環丙基甲氧基)-3,5-二氟聯苯-4-基胺基)菸酸甲酯
根據對於中間體18所述之實驗程序,自中間體17及溴環丁烷獲得(83%)。
LRMS:m/z 411(M+1)+
。
滯留時間:7.48分鐘
中間體345-溴-2-(3'-乙氧基-3,5-二氟聯苯-4-基胺基)菸酸
在氮氣氛下,將5-溴-2-氯菸酸(1.42公克,6.01毫莫耳)、中間體21(1.0公克,4.01毫莫耳)以及對甲苯磺酸(0.5公克,2.42毫莫耳)於水(10毫升)中之混合物在110℃下加熱隔夜。將反應混合物冷卻至室溫且形成沈澱。將所形成之固體過濾,用熱水、隨後冷MeOH洗滌。最後,將固體用二異丙醚洗滌且在真空烘箱中乾燥。產率=63%。
LRMS:m/z 449,451(M+1)+
。
滯留時間:7.52分鐘
中間體355-溴-2-(5-氟-3'-甲氧基-2-甲基聯苯-4-基胺基)菸酸
根據對於中間體34所述之實驗程序,自中間體30及5-溴-2-氯菸酸獲得(73%)。
LRMS:m/z 431,433(M+1)+
。
滯留時間:7.98分鐘
中間體361-溴-3-環丙氧基苯
將3-溴苯酚(2.4公克,13.9毫莫耳)、溴環丙烷(6.66毫升,83毫莫耳)以及碳酸鉀(9.6公克,69.5毫莫耳)於DMF(16毫升)中之混合物在微波烘箱中在180℃下加熱8小時。將反應混合物用乙醚與水之混合物稀釋。將有機層分離,用水、鹽水洗滌,經Na2
SO4
乾燥,過濾且蒸發。得到2.87公克純度為81%之油狀物。將所述中間體用於下一反應中。
滯留時間:6.91分鐘
中間體372-(3-環丙氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼戊環
在氮氣氛下,將中間體36(2.87公克,10.9毫莫耳)、雙(頻哪醇根基)二硼(4.16公克,16.4毫莫耳)以及乙酸鉀(3.2公克,32.7毫莫耳)於無水二噁烷中之混合物攪拌,隨後添加PdCl2
dppf.CH2
Cl2
(0.5公克,0.55毫莫耳)。將反應混合物在100℃下加熱3小時。隨後將粗產物經矽藻土過濾,用二噁烷洗滌且在減壓下蒸發。將所獲得之殘餘物經逆相層析用水與AcN/MeOH(1/1)(0%至100% AcN/MeOH(1/1))之梯度溶離純化。得到呈黃色油狀物之所需產物。產率=55%。
LRMS:m/z 261(M+1)+
。
滯留時間:7.23分鐘
中間體383,5-二氟-2-甲基聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴-2,6-二氟-3-甲基苯胺及苯基硼酸獲得(92%)。
LRMS:m/z 220(M+1)+
。
滯留時間:6.73分鐘
中間體395-溴-2-(2,5-二氟-3'-甲氧基聯苯-4-基胺基)菸酸
根據對於中間體34所述之實驗程序,自中間體6及5-溴-2-氯菸酸獲得(78%)。
LRMS:m/z 433,435(M+1)+
。
滯留時間:7.77分鐘
中間體402-氯-5-環丙基菸酸甲酯
根據對於中間體31所述之實驗程序,自5-溴-2-氯菸酸甲酯及環丙基硼酸獲得(99%)。
LRMS:m/z 212(M+1)+
。
滯留時間:5.46分鐘
中間體412-氯-5-環丙基菸酸
根據對於中間體32所述之實驗程序,自中間體40獲得(65%)。
LRMS:m/z 198(M+1)+
。
滯留時間:4.29分鐘
中間體422-(4-溴-2,6-二氟苯基胺基)-5-環丙基菸酸
根據對於中間體34所述之實驗程序,自中間體41及4-溴-2,6-二氟苯胺獲得(65%)。
LRMS:m/z 369,371(M+1)+
。
滯留時間:7.06分鐘
中間體432,3,5-三氟-3'-甲氧基聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴-2,3,6-三氟苯胺及3-甲氧基苯基硼酸獲得(60%)。
LRMS:m/z 254(M+1)+
。
滯留時間:6.45分鐘
中間體444-溴-2,6-二氟-3-甲基苯胺
在55℃下,向2,6-二氟-3-甲基苯胺(5公克,34.9毫莫耳)於乙酸(50毫升)中之溶液中逐滴添加溴(1.97毫升,38.4毫莫耳)於乙酸(10毫升)中之溶液。將反應混合物攪拌1小時,隨後傾入水/冰中。將固體過濾,用水洗滌且在真空烘箱中乾燥。得到6.3公克黑色固體(產率=81%)。
滯留時間:6.28分鐘
中間體452-(4-溴-2,6-二氟-3-甲基苯基胺基)菸酸
根據對於中間體34所述之實驗程序,自中間體44及2-氯菸酸獲得(46%)。
LRMS:m/z 343,345(M+1)+
。
滯留時間:6.50分鐘
中間體462-(4-溴-2,6-二氟苯基胺基)-5-氯菸酸
根據對於中間體34所述之實驗程序,自4-溴-2,6-二氟苯胺及2,5-二氯菸酸獲得(36%)。
LRMS:m/z 363,365(M+1)+
。
滯留時間:7.09分鐘
中間體472,3,5,6-四氟-3'-甲氧基聯苯-4-胺
根據對於中間體1所述之實驗程序,自4-溴-2,3,5,6-四氟苯胺及3-甲氧基苯基硼酸獲得(91%)。
LRMS:m/z 272(M+1)+
。
滯留時間:6.49分鐘
中間體483-(2-氟苯基胺基)異菸酸甲酯
根據對於中間體22所述之實驗程序,自3-氯異菸酸甲酯及2-氟苯胺獲得(34%)。
LRMS:m/z 247(M+1)+
。
中間體493-(4-溴-2-氟苯基胺基)異菸酸甲酯
根據對於中間體44所述之實驗程序,自中間體48獲得(90%)。
LRMS:m/z 323,325(M+1)+
。
1
H NMR(250MHz,CDCl3
)δ ppm:3.9(s,3H);7.3(m,3H);7.7(d,J=7.5 Hz,1H);8.1(d,J=7.5 Hz,1H);8.5(s,1H);9.0(s,1H)。
中間體503-(2'-氯-3-氟聯苯-4-基胺基)異菸酸甲酯
根據對於中間體1所述之實驗程序,自中間體49及2-氯苯基硼酸獲得(29%)。
LRMS:m/z 357(M+1)+
。
中間體513-(3'-環丙氧基-3-氟聯苯-4-基胺基)異菸酸甲酯
根據對於中間體1所述之實驗程序,自中間體50及2-(3-環丙氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼戊環獲得(56%)。
LRMS:m/z 379(M+1)+
。
滯留時間:7.44分鐘
實例12-(3-氟-3'-甲氧基聯苯-4-基胺基)菸酸
在氮氣氛下,將2-氯菸酸(4.86公克,30.89毫莫耳)及中間體4(10.06公克,46.34毫莫耳)於乙酸(160毫升)中之混合物在130℃下加熱隔夜。將反應混合物冷卻至室溫且形成沈澱。將所形成之黃色固體過濾,用乙酸及乙醚洗滌且在真空烘箱中乾燥。產率=65%。
1
H NMR(200MHz,CD3
OD)δ ppm:3.9(s,3H);7.0(m,1H);7.21(m,3H);7.41(t,1H);7.71(m,3H);8.15(dd,J=6.05,1.76 Hz,1H);8.83(dd,J=7.61,1.76 Hz,1H)。
LRMS:m/z 339(M+1)+
。
滯留時間:7.09分鐘
實例22-(3'-乙氧基-3-氟聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自2-氯菸酸及中間體1獲得(43%)。
1
H NMR(400 MHz,DMSO-D6.
)δ ppm:1.4(t,J=6.9 Hz,3 H);4.1(q,J=6.9 Hz,2 H);6.9(d,J=8.3 Hz,1 H);7.0(m,1 H);7.2(d,J=1.7 Hz,1 H);7.3(d,J=7.8 Hz,1 H);7.4(t,J=7.8 Hz,1 H);7.5(d,J=8.3 Hz,1 H);7.7(d,J=12.8 Hz,1 H);8.3(m,1 H);8.5(m,1 H);8.7(t,J=8.8 Hz,1 H);10.8(s,1 H)。
LRMS:m/z 353(M+1)+
。
滯留時間:7.39分鐘
實例32-(3-氟-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體2及2-氯菸酸獲得(37%)。
1
H NMR(200 MHz,DMSO-D6
)δ ppm:7.0(dd,J
=7.8,4.7 Hz,1 H);7.4(d,J
=8.2 Hz,1 H);7.7(m,5 H);8.3(dd,J
=7.8,2.0 Hz,1 H);8.5(dd,J
=4.7,2.0 Hz,1 H);8.8(t,J
=8.8 Hz,1 H);10.8(d,J
=3.1 Hz,1 H)。
LRMS:m/z 393(M+1)+
。
滯留時間:7.63分鐘
實例42-(3'-乙氧基-3-(三氟甲氧基)聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體3及2-氯菸酸獲得(18%)。
1
H NMR(200 MHz,DMSO-D6
)δ ppm:1.4(t,J=7.0 Hz,3 H);4.1(q,J=7.0 Hz,2 H);7.0(m,2 H);7.3(m,3 H);7.7(m,2 H);8.3(m,1 H);8.5(m,1 H);8.9(d,J=8.6 Hz,1 H);11.2(s,1 H)。
LRMS:m/z 417(M-1)-
。
滯留時間:7.65分鐘
實例52-(3'-甲氧基-3-(三氟甲氧基)聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體5及2-氯菸酸獲得(14%)。
LRMS:m/z 405(M+1)+
。
滯留時間:7.44分鐘
實例62-(2,5-二氟-3'-甲氧基聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體6及2-氯菸酸獲得(12%)。
1
H NMR(200 MHz,DMSO-D6
)δ ppm:3.8(s,3 H);7.0(m,4 H);7.4(t,J=8.0 Hz,1 H);7.6(dd,J=12.1,7.4 Hz,1 H);8.3(dd,J=7.8,2.0 Hz,1 H);8.5(dd,J=4.7,2.0 Hz,1 H);8.7(dd,J=13.7,7.0 Hz,1 H);11.0(s,1 H)。
LRMS:m/z 357(M+1)+
。
滯留時間:7.35分鐘
實例72-(3'-乙氧基-2,5-二氟聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體7及2-氯菸酸獲得(36%)。
1
H NMR(200 MHz,DMSO-D6
)δ ppm:1.4(t,J=6.9 Hz,3 H);4.1(q,J=6.9 Hz,2 H);7.0(m,4 H);7.4(t,J=7.8 Hz,1 H);7.6(dd,J=12.3,7.2 Hz,1 H);8.3(dd,J=7.4,2.0 Hz,1 H);8.5(dd,J=5.1,2.0 Hz,1 H);8.7(dd,J=13.7,7.0 Hz,1 H);11.0(s,1 H)。
LRMS:m/z 371(M+1)+
。
滯留時間:7.51分鐘
實例82-(2',3-二氟-3'-甲氧基聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體8及2-氯菸酸獲得(31%)。
1
H NMR(200 MHz,DMSO-D6
).:δ ppm 3.9(s,3 H);7.1(m,4 H);7.4(m,2 H);8.3(dd,J
=7.8,2.0 Hz,1 H);8.5(dd,J
=4.9,1.8 Hz,1 H);8.7(t,J
=8.8 Hz,1 H);10.8(d,J
=2.7 Hz,1 H)。
LRMS:m/z 357(M+1)+
。
滯留時間:7.04分鐘
實例92-(2-甲基-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體9及2-氯菸酸獲得(61%)。
1
H NMR(200 MHz,CDCl3
):δ ppm 2.3(s,3H);6.8(dd,J
=7.8,4.7 Hz,1 H);7.2(m,4 H)7.5(m,3 H);8.4(m,2 H);10.0(s,1 H)。
LRMS:m/z 389(M+1)+
。
滯留時間:7.51分鐘
實例102-(3-氯-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體10及2-氯菸酸獲得(44%)。
1
H NMR(200 MHz,CDCl3
):δ ppm 6.9(dd,J
=7.8,5.1 Hz,1 H);7.3(m,2 H);7.5(m,3 H);7.7(d,J
=2.0 Hz,1 H);8.4(dd,J
=7.8,2.0 Hz,1 H);8.5(dd,J
=4.7,2.0 Hz,1 H);8.8(d,J
=8.6 Hz,1 H);10.6(s,1 H)。
LRMS:m/z 409(M+1)+
。
滯留時間:7.74分鐘
實例112-(3-氯-3'-乙氧基聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體11及2-氯菸酸獲得(48%)。
1
H NMR(200 MHz,CDCl3
):δ ppm 1.5(t,J
=6.9.0 Hz,3 H);4.1(q,J
=6.9 Hz,2 H);6.9(m,2 H);7.1(m,2 H);7.3(t,J
=7.8 Hz,1 H);7.5(dd,J
=8.6,2.0 Hz,1 H);7.7(d,J
=2.3 Hz,1 H);8.4(dd,J
=7.8,2.3 Hz,1 H);8.5(dd,J
=4.7,2.0 Hz,1 H);8.7(d,J
=9.0 Hz,1 H);10.5(s,1 H)。
LRMS:m/z 369(M+1)+
。
滯留時間:7.57分鐘
實例122-(3-甲基-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體13及2-氯菸酸獲得(41%)。
1
H NMR(200 MHz,CDCl3
):δ ppm 2.4(s,3 H);6.8(m,J
=7.8,4.7 Hz,1 H);7.2(m,J
=1.6 Hz,1 H);7.3(m,1 H);7.5(m,4 H);8.2(d,J
=9.4 Hz,1 H);8.3(dd,J
=7.8,2.0 Hz,1 H);8.4(dd,J
=4.7,2.0 Hz,1 H);10.0(s,1 H)。
LRMS:m/z 389(M+1)+
。
滯留時間:7.62分鐘
實例132-(3-氯-3'-甲氧基聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體14及2-氯菸酸獲得(36%)。
1
H NMR(200 MHz,CDCl3
):δ ppm 3.9(s,3 H);6.9(m,2 H);7.1(m,2 H);7.4(m,1 H);7.5(dd,J
=8.6,2.3 Hz,1 H);7.7(d,J
=2.0 Hz,1 H);8.4(dd,J
=7.8,2.0 Hz,1 H);8.5(dd,J
=4.9,2.1 Hz,1 H);8.7(d,J
=8.6 Hz,1 H);10.5(s,1 H)。
LRMS:m/z 355(M+1)+
。
滯留時間:7.53分鐘
實例142-(3'-(二氟甲氧基)-3-氟聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體15及2-氯菸酸獲得(10%)。
1
H NMR(200 MHz,DMSO-D6
):δ ppm 7.0(dd,J
=7.6,4.7 Hz,1 H);7.2(d,J
=7.8 Hz,1 H);7.3(t,J=74.1 Hz,1H);7.6(m,5 H);8.3(dd,J
=7.8,2.0 Hz,1 H);8.5(dd,J
=4.7,2.0 Hz,1 H);8.7(t,J
=8.8 Hz,1 H);10.9(s,1 H)。
LRMS:m/z 375(M+1)+
。
滯留時間:7.43分鐘
實例152-(3'-環丁氧基-3-氟聯苯-4-基胺基)菸酸
將中間體19(0.28公克,0.63毫莫耳)溶解於MeOH(10毫升)中,且添加2N NaOH(2毫升)。在室溫下將混合物攪拌隔夜。將反應混合物濃縮且經逆相管柱層析純化得到呈黃色固體之所需化合物。產率=12%。
LRMS:m/z 379(M+1)+
。
滯留時間:7.68分鐘
1
H NMR(200 MHz,CD3
OD):δ ppm 1.8(m,2 H);2.1(m,2 H);2.5(m,2 H);4.7(m,1 H);6.8(m,2 H);7.2(m,5 H);8.4(m,J
=7.8 Hz,2 H);8.6(t,J
=8.4 Hz,1 H)。
實例162-(3-氟-3'-(2,2,2-三氟乙氧基)聯苯-4-基胺基)菸酸
根據實例15中所述之實驗程序,自中間體18獲得(57%)。
LRMS:m/z 407(M+1)+
。
滯留時間:7.36分鐘
1
H NMR(200 MHz,CD3
OD):δ ppm 4.5(q,J
=8.6 Hz,2 H);6.8(m,2 H);7.3(m,5 H);8.3(m,2 H);8.6(t,J
=8.8 Hz,1 H)。
實例172-(3'-環丁氧基-3,5-二氟聯苯-4-基胺基)菸酸
根據實例15中所述之實驗程序,自中間體20獲得(55%)。
LRMS:m/z 397(M+1)+
。
滯留時間:6.87分鐘
1
H NMR(200 MHz,DMSO-D6
):δ ppm 1.8(m,2 H);2.1(m,2 H);2.5(m,2 H);4.9(m,1 H);6.9(t,J
=6.4 Hz,2 H);7.2(s,1 H);7.4(m,2 H);7.6(d,J
=9.4 Hz,2 H);8.3(d,J
=4.3 Hz,2 H);9.7(s,1 H)。
實例182-(3,5-二氟-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸
在氮氣氛下,向中間體21(0.2公克,0.61毫莫耳)、3-(三氟甲氧基)苯基硼酸(0.19公克,0.91毫莫耳)、碳酸鉀(0.17公克,1.21毫莫耳)於11毫升二噁烷/水(10/1)中之混合物中添加Pd(PPh3
)4
(0.25公克,0.22毫莫耳)。將混合物加熱至回流隔夜,隨後經矽藻土過濾且用乙酸乙酯洗滌。將有機相用水洗滌兩次,用鹽水洗滌,經硫酸鎂乾燥,過濾且真空蒸發得到油狀物。將此粗產物經製備型HPLC純化得到60毫克呈白色固體之所需化合物。產率=24%。
1
H NMR(200 MHz,DMSO-D6
):δ ppm 6.9(m,1H);7.4(m,1H);7.6(m,3H);7.8(m,2H);8.2(m,2H)。
LRMS:m/z 409(M-1)-
。
滯留時間:7.27分鐘
實例192-(3'-乙氧基-3,5-二氟聯苯-4-基胺基)菸酸
根據實例18中所述之實驗程序,自中間體21及3-乙氧基苯基硼酸獲得(28%)。
1
H NMR(200 MHz,DMSO-D6
):δ ppm 1.4(t,J
=6.9 Hz,3 H);4.1(q,J
=6.9 Hz,2 H);6.9(dd,J
=7.8,4.7 Hz,1 H);7.0(m,1 H);7.4(m,5 H);8.2(m,2 H);9.5(s,1 H)。
LRMS:m/z 371(M+1)+
。
滯留時間:6.91分鐘
實例202-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體29及2-氯菸酸獲得(31%)。
1
H NMR(200 MHz,DMSO-D6
)δ ppm:3.8(s,3 H);6.9(dd,J=7.8,4.7 Hz,1 H);7.0(m,1 H);7.4(m,3 H);7.5(m,2 H);8.2(m,2 H);9.5(s,1 H);13.6(s,1 H)。
LRMS:m/z 357(M+1)+
。
滯留時間:6.79分鐘
實例213-(3'-乙氧基-3-氟聯苯-4-基胺基)異菸酸鋰
在0℃下,向中間體22(0.12公克,0.33毫莫耳)於THF(4毫升)中之溶液中添加0.39 M LiOH水溶液(0.02公克,0.39毫莫耳),且在室溫下將混合物攪拌1小時。將反應混合物經管柱層析用MeOH/DCM(30%至50%)混合物溶離純化且得到呈白色固體之所需產物。產率=76%。
1
H NMR(250 MHz,DMSO-D6
)δ ppm:1.2(t,3H);4.1(q,2H);6.9(m,1H);7.2(m,2H);7.4(t,1H);7.6(m,3H);7.8(d,1H);8.0(d,1H);8.6(s,1H);11.2(bs,1H)。
LRMS:m/z 353(M+1)+
。
滯留時間:5.95分鐘
實例223-(3-氟-3'-甲氧基聯苯-4-基胺基)異菸酸鋰
根據實例21中所述之實驗程序,自中間體23獲得(80%)。
1
H NMR(250 MHz,DMSO-D6
)δ ppm:3.8(s,3H);6.9(m,1H);7.3(m,3H);7.5(m,3H);7.8(d,J=6.5Hz,1H);8.0(d,J=6.5Hz,1H)8.5(s,1H);11.1(bs,1H)。
LRMS:m/z 339(M+1)+
。
滯留時間:5.43分鐘
實例233-(3'-甲氧基-3-(三氟甲氧基)聯苯-4-基胺基)異菸酸鋰
根據實例21中所述之實驗程序,自中間體24獲得(70%)。
1
H NMR(250 MHz,DMSO-D6
):δ ppm 3.8(s,3H);6.9(m,1H);7.2(m,2H);7.4(t,1H);7.7(m,3H);7.8(d,1H);8.0(d,1H);8.6(s,1H);11.4(bs,1H)。
LRMS:m/z 405(M+1)+
。
滯留時間:6.26分鐘
實例243-(3-氟-3'-(三氟甲氧基)聯苯-4-基胺基)異菸酸鋰
根據實例21中所述之實驗程序,自中間體25獲得(39%)。
1
H NMR(250 MHz,DMSO-D6
)δ ppm:7.3(m,1H);7.7(m,7H);8.0(m,1H);8.6(s,1H);10.9(bs,1H)。
LRMS:m/z 393(M+1)+
。
滯留時間:6.53分鐘
實例252-(3'-乙氧基聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體12及2-氯菸酸獲得(25%)。
1
H NMR(200 MHz,CDCl3
)δ ppm:1.5(t,J
=7.0 Hz,3 H);4.1(q,J
=7.0 Hz,2 H);6.8(m,1 H);6.9(m,1 H);7.2(m,2 H);7.3(m,1 H);7.6(d,J
=8.8 Hz,2 H);7.8(d,J
=8.8 Hz,2 H);8.3(dd,J
=7.8,2.0 Hz,1 H);8.5(dd,J
=4.7,2.0 Hz,1 H);10.1(s,1 H)。
LRMS:m/z 335(M+1)+
。
滯留時間:6.97分鐘
實例262-(5-氟-2-甲基-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體27及2-氯菸酸獲得(42%)。
1
H NMR(200 MHz,DMSO-D6
):δ ppm 2.3(s,3 H);7.0(dd,J
=7.8,4.7 Hz,1 H);7.2(d,J
=12.1 Hz,1 H);7.4(m,J
=1.0 Hz,3 H);7.6(d,J
=9.0 Hz,1 H);8.3(dd,J
=7.4,2.0 Hz,1 H);8.5(m,2 H);10.7(d,J
=2.7 Hz,1 H)。
LRMS:m/z 407(M+1)+
。
滯留時間:7.63分鐘
實例272-(2',3-二氟-5'-異丙氧基聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體28及2-氯菸酸獲得(57%)。
1
H NMR(200 MHz,DMSO-D6
):δ ppm 1.3(d,J
=6.2 Hz,6 H);4.7(m,1 H);7.0(m,3 H);7.2(m,1 H);7.5(m,2 H);8.3(dd,J
=7.8,2.0 Hz,1 H);8.5(dd,J
=4.7,2.0 Hz,1 H);8.7(t,J
=8.8 Hz,1 H);10.9(d,J
=2.7 Hz,1 H)。
LRMS:m/z 385(M+1)+
。
滯留時間:7.51分鐘
實例282-(3-氟-3'-甲氧基聯苯-4-基胺基)-5-甲基菸酸
根據實例1中所述之實驗程序,自中間體4及中間體32獲得(13%)。
LRMS:m/z 353(M+1)+
。
滯留時間:7.00分鐘
1
H NMR(200 MHz,CD3
OD):δ ppm 2.2(s,3 H);3.8(s,3 H);6.8(m,J
=8.2,2.3 Hz,1 H);7.1(m,2 H);7.3(m,3 H);8.1(m,2 H);8.5(t,J
=8.6 Hz,1 H)。
實例292-(3,5-二氟-3'-羥基聯苯-4-基胺基)菸酸
根據實例18中所述之實驗程序,自中間體21及3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯酚獲得(46%)。
LRMS:m/z 343(M+1)+
。
滯留時間:5.71分鐘
1
H NMR(200 MHz,DMSO-D6
):δ ppm 6.8(dd,J
=7.6,4.9 Hz,2 H);7.1(m,2 H);7.3(t,J
=7.8 Hz,1 H);7.4(d,J
=9.4 Hz,2 H);8.2(m,2 H);10.2(s,1H)。
實例305-溴-2-(3-氟-3'-甲氧基聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體4及5-溴-2-氯菸酸獲得(34%)。
LRMS:m/z 417-419(M+1)+
。
滯留時間:7.71分鐘
實例315-溴-2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體29及5-溴-2-氯菸酸獲得(13%)。
LRMS:m/z 435-437(M+1)+
。
滯留時間:6.93分鐘
1
H NMR(200 MHz,DMSO-D6
):δ ppm 3.8(s,3 H);7.0(m,1 H);7.4(m,3 H)7.6(d,J
=9.8 Hz,2 H);8.3(d,J
=2.7 Hz,1 H);8.4(d,J
=2.3 Hz,1 H);9.6(s,1 H)。
實例325-溴-2-(3-氟-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體2及5-溴-2-氯菸酸獲得(27%)。
LRMS:m/z 471-473(M+1)+
。
滯留時間:8.04分鐘
實例332-(3-氟-3'-(三氟甲氧基)聯苯-4-基胺基)-5-甲基菸酸
在氮氣氛下,向實例32(0.1公克,0.21毫莫耳)、K3
PO4
(204毫克,0.96毫莫耳)、甲基硼酸(20毫克,0.33毫莫耳)以及三環己基膦(14毫克,0.04毫莫耳)於甲苯/水(2毫升/0.1毫升)中之溶液中添加Pd(OAc)2
(5毫克,0.02毫莫耳)。將混合物加熱至100℃隔夜,隨後冷卻至室溫。將反應混合物濃縮且將殘餘物再溶解於乙酸乙酯及水中。將有機層用水及鹽水洗滌,經硫酸鎂乾燥,過濾且在真空下蒸發溶劑。將所獲得之殘餘物經逆相層析用水與AcN/MeOH(1/1)(0%至70% AcN/MeOH(1/1))之梯度溶離純化。得到呈黃色固體之所需產物。產率=28%。
LRMS:m/z 407(M+1)+
。
滯留時間:7.80分鐘
1
H NMR(200 MHz,CD3
OD):δ ppm 2.2(s,3 H);7.1(d,J
=7.5 Hz,1 H);7.5(m,5 H);8.1(d,J
=11.4 Hz,2 H);8.6(t,J
=8.4 Hz,1 H)。
實例345-環丙基-2-(3-氟-3'-甲氧基聯苯-4-基胺基)菸酸
根據實例33中所述之實驗程序,自實例30及環丙基硼酸獲得(10%)。
LRMS:m/z 379(M+1)+
。
滯留時間:7.59分鐘
1
H NMR(200 MHz,DMSO-D6
):δ ppm 0.7(m,2 H);1.0(m,2 H);2.0(m,1 H);3.8(s,3 H);6.9(m,1 H);7.3(m,3 H);7.6(m,2 H);8.0(d,J
=2.5 Hz,1 H);8.3(d,J
=2.5 Hz,1 H);8.7(t,J
=8.8 Hz,1 H);10.7(d,J
=2.0 Hz,1 H)。
實例352-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)-5-甲基菸酸
根據實例33中所述之實驗程序,自實例31及甲基硼酸獲得(10%)。
LRMS:m/z 370(M+1)+
。
滯留時間:6.57分鐘
1
H NMR(400 MHz,DMSO-D6.
)δ ppm 2.2(s,3 H);3.8(s,3 H;7.0(dd,J
=7.8,1.7 Hz,1 H);7.4(m,3 H);7.5(d,J
=9.4 Hz,2 H);8.1(dd,J
=20.2,1.7 Hz,2 H);9.3(s,1 H);13.6(s,1 H)。
實例362-(3'-乙氧基-5-氟-2-甲基聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體26及2-氯菸酸獲得(67%)。
LRMS:m/z 367
滯留時間:7.08分鐘
1
H NMR(200 MHz,DMSO-D6
)δ ppm:1.3(t,J
=6.8 Hz,3 H);2.2(s,3 H);4.0(q,J
=6.8 Hz,2 H);6.9(m,4 H);7.1(d,J
=12.1 Hz,1 H);7.3(t,J
=7.8 Hz,1 H);8.3(dd,J
=7.8,2.0 Hz,1 H);8.4(m,2 H);10.6(d,J
=2.3 Hz,1 H)。
實例372-(5-氟-3'-甲氧基-2-甲基聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自中間體30及2-氯菸酸獲得(73%)。
LRMS:m/z 353
滯留時間:6.75分鐘
1
H NMR(200 MHz,DMSO-D6
):δ ppm 2.2(s,3 H);3.8(s,3 H);6.9(m,4 H);7.1(d,J
=12.1 Hz,1 H);7.3(t,J
=7.8 Hz,1 H);8.4(m,3 H);10.6(d,J
=2.3 Hz,1 H)。
實例382-(3'-乙氧基-3,5-二氟聯苯-4-基胺基)-5-甲基菸酸
根據實例33中所述之實驗程序,自中間體34及甲基硼酸獲得(6%)。
LRMS:m/z 385(M+1)+
。
滯留時間:7.06分鐘
1
H NMR(200 MHz,DMSO-D6
)δ ppm 1.4(t,J=6.8 Hz,3 H)2.2(s,3 H)4.1(d,J=6.8 Hz,2 H)7.0(d,J=1.6 Hz,1 H)7.4(m,5 H)8.1(d,J=7.0 Hz,2 H)9.4(s,1 H)。
實例395-環丙基-2-(3'-乙氧基-3,5-二氟聯苯-4-基胺基)菸酸
根據實例33中所述之實驗程序,自中間體34及環丙基硼酸獲得(14%)。
LRMS:m/z 411(M+1)+
。
滯留時間:7.33分鐘
1
H NMR(200 MHz,DMSO-D6
)δ ppm 0.6(m,2 H)0.9(m,2 H)1.4(t,J=6.9 Hz,3 H)1.9(m,1 H)4.1(q,J=6.9 Hz,2 H)7.0(m,1 H)7.4(m,5 H)7.9(d,J=2.5 Hz,1 H)8.1(d,J=2.5Hz,1 H)9.4(s,1 H)。
實例402-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)-5-乙基菸酸
在氮氣氛下,向實例31(200毫克,0.46毫莫耳)及三丁基(乙烯基)錫烷(209毫克,0.66毫莫耳)於DMF(8毫升)中之溶液中添加Pd(PPh3
)4
(37毫克,0.07毫莫耳)。將混合物加熱至100℃隔夜,隨後冷卻至室溫。將反應混合物濃縮且將殘餘物再溶解於乙酸乙酯及水中。將有機層用水及鹽水洗滌,經硫酸鎂乾燥,過濾且在真空下蒸發溶劑。將所獲得之殘餘物經急驟層析用己烷/AcOEt(1/0至1/1)溶離純化。將所獲得之固體再溶解於EtOH(10毫升)中且添加Pd/C(46毫克,0.04毫莫耳)且在氫氣氛下將反應混合物攪拌隔夜。將粗產物經矽藻土過濾且蒸發。將所獲得之殘餘物經逆相層析用水與AcN/MeOH(1/1)(0%至70% AcN/MeOH(1/1))之梯度溶離純化。得到呈黃色固體之所需產物。產率=23%。
LRMS:m/z 385(M+1)+
。
滯留時間:7.01分鐘
1
H NMR(200 MHz,DMSO-D6
)δ ppm 1.2(t,J=7.4 Hz,3 H)3.8(m,3 H)7.0(m,J=8.2 Hz,1 H)7.3(m,3 H)7.5(d,J=9.4 Hz,2 H)8.1(m,2 H)9.6(s,1 H)。
實例415-溴-2-(3'-乙氧基-2,5-二氟聯苯-4-基胺基)菸酸
根據中間體34中所述之實驗程序,自中間體7及5-溴-2-氯菸酸獲得(70%)。
LRMS:m/z 447,449(M+1)+
。
滯留時間:7.91分鐘
1
H NMR(200 MHz,DMSO-D6
)δ ppm 1.4(t,J=6.9 Hz,3 H)4.1(d,J=6.9 Hz,2 H)7.0(m,3 H)7.4(t,J=7.6 Hz,1 H)7.5(dd,J=11.9,7.6 Hz,1 H)8.4(d,J=2.0 Hz,1 H)8.6(m,2 H)10.9(s,1 H)。
實例425-環丙基-2-(3'-乙氧基-2,5-二氟聯苯-4-基胺基)菸酸
根據實例33中所述之實驗程序,自實例41及環丙基硼酸獲得(26%)。
LRMS:m/z 411(M+1)+
。
滯留時間:6.71分鐘
1
H NMR(200 MHz,DMSO-D6
)δ ppm 0.7(m,2 H)1.0(m,2 H)1.4(t,J=7.0 Hz,3 H)2.0(m,1 H)4.1(q,J=7.0 Hz,2 H)6.9(m,1 H)7.1(m,J=10.5 Hz,2 H)7.4(t,J=8.0 Hz,1 H)7.5(dd,J=12.1,7.4 Hz,1 H)8.0(d,J=2.3 Hz,1 H)8.4(d,J=2.3 Hz,1 H)8.7(dd,J=14.1,7.0 Hz,1 H)10.9(s,1 H)。
實例432-(5-氟-3'-甲氧基-2-甲基聯苯-4-基胺基)-5-甲基菸酸
根據實例33中所述之實驗程序,自中間體35及甲基硼酸獲得(20%)。
LRMS:m/z 367(M+1)+
。
滯留時間:7.35分鐘
1
H NMR(200 MHz,DMSO-D6
)δ ppm 2.2(2s,6 H)3.8(s,3 H)6.9(m,3 H)7.1(d,J=12.5 Hz,1 H)7.4(m,1 H)8.1(d,J=2.3 Hz,1 H)8.3(d,J=2.3 Hz,1 H)8.5(d,J=8.6 Hz,1 H)10.9(s,1 H)。
實例445-環丙基-2-(5-氟-3'-甲氧基-2-甲基聯苯-4-基胺基)菸酸
根據實例33中所述之實驗程序,自中間體35及環丙基硼酸獲得(6%)。
LRMS:m/z 393(M+1)+
。
滯留時間:7.62分鐘
1
H NMR(200 MHz,DMSO-D6
)δ ppm 0.7(m,2 H)0.9(m,2 H)1.9(m,1 H)2.2(s,3 H)3.8(s,3 H)6.9(m,3 H)7.1(d,J=12.5 Hz,1 H)7.4(t,J=7.8 Hz,1 H)7.9(d,J=2.3 Hz,1 H)8.3(d,J=2.3 Hz,1 H)8.5(d,J=8.2 Hz,1 H)10.6(s,1 H)。
實例452-(2',3,5-三氟-3'-甲氧基聯苯-4-基胺基)菸酸
根據實例18中所述之實驗程序,自中間體21及(2-氟-3-甲氧基苯基)硼酸獲得(73%)。
LRMS:m/z 375(M+1)+
。
滯留時間:6.50分鐘
1
H NMR(200 MHz,DMSO-D6
)δ ppm 3.9(s,3 H)6.9(dd,J=7.8,4.7 Hz,1 H)7.2(m,3 H)7.4(d,J=8.2 Hz,2 H)8.2(m,2 H)9.6(s,1 H)。
實例462-(2'-氯-3,5-二氟聯苯-4-基胺基)菸酸
根據實例18中所述之實驗程序,自中間體21及2-氯苯基硼酸獲得(73%)。
LRMS:m/z 361(M+1)+
。
滯留時間:6.75分鐘
1
H NMR(200 MHz,DMSO-D6
)δ ppm 6.9(dd,J=7.8,4.7 Hz,1 H)7.3(d,J=8.6 Hz,2 H)7.5(m,4 H)8.3(m,2 H)9.6(s,1 H)。
實例472-(3'-環丙氧基-3,5-二氟聯苯-4-基胺基)菸酸
根據實例18中所述之實驗程序,自中間體21及中間體37獲得(53%)。
LRMS:m/z 383(M+1)+
。
滯留時間:7.06分鐘
1
H NMR(400 MHz,DMSO-D6
)δ ppm 0.7(m,2 H)0.8(m,2 H)4.0(m,1 H)6.9(dd,J=7.4,4.7 Hz,1 H)7.1(m,1 H)7.4(m,3 H)7.5(d,J=9.4 Hz,2 H)8.2(m,2 H)9.5(s,1 H)13.6(s,1 H)。
實例482-(3,5-二氟-2-甲基聯苯-4-基胺基)菸酸
根據實例1中所述之實驗程序,自2-氯菸酸及中間體38獲得(33%)。
LRMS:m/z 341(M+1)+
。
滯留時間:7.02分鐘
1
H NMR(200 MHz,DMSO-D6
)δ ppm 2.1(s,3 H)6.9(dd,J=7.8,4.7 Hz,1 H)7.1(dd,J=10.5,2.0 Hz,1 H)7.4(m,5 H)8.2(m,2 H)9.5(s,1 H)。
實例495-環丙基-2-(2,5-二氟-3'-甲氧基聯苯-4-基胺基)菸酸
根據實例33中所述之實驗程序,自中間體39及環丙基硼酸獲得(7%)。
LRMS:m/z 397(M+1)+
。
滯留時間:7.77分鐘
1
H NMR(400 MHz,DMSO-D6
)δ ppm 0.7(d,J=5.2 Hz,2 H)1.0(d,J=8.3 Hz,2 H)2.0(m,1 H)3.8(s,3 H)7.0(d,J=7.2 Hz,1 H)7.1(m,2 H)7.4(t,J=7.9 Hz,1 H)7.5(dd,J=12.1,7.4 Hz,1 H)8.0(s,1 H)8.4(s,1 H)8.7(dd,J=13.7,7.0 Hz,1 H)10.8(s,1 H)13.9(s,1 H)。
實例502-(3'-環丙氧基-3,5-二氟聯苯-4-基胺基)-5-環丙基菸酸
根據實例18中所述之實驗程序,自中間體42及中間體37獲得(30%)。
LRMS:m/z 423(M+1)+
。
滯留時間:7.44分鐘
1
H NMR(200 MHz,DMSO-D6
)δ ppm 0.8(m,8 H)1.9(m,1 H)4.0(m,1 H)7.1(m,1 H)7.4(m,5 H)7.9(d,J=2.3 Hz,1 H)8.1(d,J=2.3 Hz,1 H)9.3(s,1 H)13.6(s,1 H)。
實例515-氯-2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)菸酸
根據中間體34中所述之實驗程序,自中間體29及2,5-二氯菸酸獲得(19%)。
LRMS:m/z 391(M+1)+
。
滯留時間:7.28分鐘
1
H NMR(400 MHz,DMSO-D6
)ppm 3.8(s,3 H)7.0(dd,J=7.8,1.6 Hz,1 H)7.4(m,3 H)7.6(2s,2 H)8.2(d,J=2.5 Hz,1 H)8.3(d,J=2.5 Hz,1 H)9.5(s,1 H)。
實例525-環丙基-2-(3,5-二氟-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸
根據實例18中所述之實驗程序,自中間體42及3-(三氟甲氧基)苯基硼酸獲得(48%)。
LRMS:m/z 451(M+1)+
。
滯留時間:7.48分鐘
1
H NMR(400 MHz,DMSO-D6
)δ ppm 0.6(m,2 H)0.9(m,2 H)1.9(m,1 H)7.4(m,1 H)7.6(m,3 H)7.8(s,1 H)7.8(dd,J=7.4,1.2 Hz,1 H)7.9(d,J=2.3 Hz,1 H)8.1(d,J=2.7 Hz,1 H)9.4(s,1 H)13.6(s,1 H)。
實例532-(2,3,5-三氟-3'-甲氧基聯苯-4-基胺基)菸酸
根據中間體34中所述之實驗程序,自中間體43及2-氯菸酸獲得(6%)。
LRMS:m/z 375(M+1)+
。
滯留時間:6.79分鐘
1
H NMR(400 MHz,DMSO-D6
)δ ppm 3.8(s,3 H)6.7(m,1 H)7.1(m,3 H)7.4(m,2 H)8.0(s,1 H)8.2(m,1 H)11.8(s,1 H)。
實例542-(2'-氯-3,5-二氟聯苯-4-基胺基)-5-環丙基菸酸
根據實例18中所述之實驗程序,自中間體42及2-氯苯基硼酸獲得(38%)。
LRMS:m/z 401(M+1)+
。
滯留時間:7.27分鐘
1
H NMR(400 MHz,DMSO-D6
)δ ppm 0.7(m,2 H)0.9(m,2 H)1.9(m,1 H)7.3(2s,2 H)7.5(m,3 H)7.6(dd,J=5.8,3.6 Hz,1 H)7.9(d,J=2.6 Hz,1 H)8.1(d,J=2.6 Hz,1 H)9.4(s,1 H)13.6(s,1 H)。
實例552-(3,5-二氟-3'-甲氧基-2-甲基聯苯-4-基胺基)菸酸
根據實例18中所述之實驗程序,自中間體45及3-甲氧基苯基硼酸獲得(68%)。
LRMS:m/z 371(M+1)+
。
滯留時間:6.76分鐘
1
H NMR(200 MHz,DMSO-D6
)δ ppm 2.1(d,J=2.0 Hz,3 H)3.8(s,3 H)6.8(dd,J=7.6,4.9 Hz,1 H)7.0(m,4 H)7.4(t,J=8.2 Hz,1 H)8.2(m,2 H)9.7(s,1 H)。
實例562-(3,5-二氟-2-甲基-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸
根據實例18中所述之實驗程序,自中間體45及3-(三氟甲氧基)苯基硼酸獲得(63%)。
LRMS:m/z 425(M+1)+
。
滯留時間:7.31分鐘
1
H NMR(200 MHz,DMSO-D6
)δ ppm 2.1(d,J=2.0 Hz,3 H)6.9(dd,J=7.8,5.1 Hz,1 H)7.1(dd,J=10.3,1.8 Hz,1 H)7.5(m,3 H)7.6(d,J=7.8 Hz,1 H)8.2(m,2 H)9.6(s,1 H)。
實例572-(2'-氯-3,5-二氟-2-甲基聯苯-4-基胺基)菸酸
根據實例18中所述之實驗程序,自中間體45及2-氯苯基硼酸獲得(63%)。
LRMS:m/z 375(M+1)+
。
滯留時間:6.99分鐘
1
H NMR(200 MHz,DMSO-D6
)δ ppm 2.0(s,3 H)6.9(dd,J=7.6,4.9 Hz,1 H)7.0(m,1 H)7.4(m,3 H)7.6(dd,J=5.9,3.1 Hz,1 H)8.3(m,2 H)9.6(s,1 H)。
實例585-氯-2-(3,5-二氟聯苯-4-基胺基)菸酸
根據實例18中所述之實驗程序,自中間體46及苯基硼酸獲得(23%)。
LRMS:m/z 361(M+1)+
。
滯留時間:7.37分鐘
1
H NMR(400 MHz,DMSO-D6
)δ ppm 7.4(t,J=7.4 Hz,1 H)7.5(m,4 H)7.8(d,J=7.4 Hz,2 H)8.2(d,J=2.7 Hz,1 H)8.3(d,J=2.7 Hz,1 H)9.5(s,1 H)。
實例595-氯-2-(2'-氯-3,5-二氟聯苯-4-基胺基)菸酸
根據實例18中所述之實驗程序,自中間體46及2-氯苯基硼酸獲得(15%)。
LRMS:m/z 395(M+1)+
。
滯留時間:7.48分鐘
1
H NMR(400 MHz,DMSO-D6
)δ ppm 7.3(d,J=8.7 Hz,2 H)7.5(m,3 H)7.6(m,1 H)8.2(d,J=2.5 Hz,1 H)8.3(d,J=2.5 Hz,1 H)9.6(s,1 H)14.0(s,1 H)。
實例602-(2,3,5,6-四氟-3'-甲氧基聯苯-4-基胺基)菸酸
根據中間體34中所述之實驗程序,自中間體47及2-氯菸酸獲得(3%)。
LRMS:m/z 393(M+1)+
。
滯留時間:6.97分鐘
1
H NMR(200 MHz,DMSO-D6
)δ ppm 3.8(s,3 H)6.9(dd,J=7.6,4.9 Hz,1 H)7.1(m,3 H)7.5(t,J=8.2 Hz,1 H)8.3(m,2 H)10.2(s,1 H)。
實例612-(3,5-二氟-2'-甲基聯苯-4-基胺基)菸酸
根據實例18中所述之實驗程序,自中間體21及鄰甲苯基硼酸獲得(63%)。
LRMS:m/z 341(M+1)+
。
滯留時間:6.91分鐘
1
H NMR(400 MHz,DMSO-D6
)δ ppm 2.3(s,3 H)6.9(dd,J=7.6,4.9 Hz,1 H)7.2(d,J=8.6 Hz,2 H)7.3(m,4 H)8.2(dd,J=7.6,1.9 Hz,1 H)8.3(dd,J=4.7,1.9 Hz,1 H)9.5(s,1 H)。
實例623-(3'-環丙氧基-3-氟聯苯-4-基胺基)異菸酸
在0℃下,向中間體51(0.13公克,0.34毫莫耳)於THF(5毫升)中之溶液中添加0.39 M LiOH水溶液(0.02公克,0.41毫莫耳),且在室溫下將混合物攪拌隔夜。蒸發THF且將殘餘物用水稀釋。藉由添加5 N HCl溶液將pH值調節至4-5,且將所形成之固體過濾且用DCM洗滌。得到呈黃色固體之所需產物。產率=62%。
LRMS:m/z 365(M+1)+
。
滯留時間:6.42分鐘
1
H NMR(400 MHz,DMSO-D6
)δ ppm 0.7(s,2 H)0.8(m,2 H)4.0(m,1 H)7.1(m,1 H)7.4(m,3 H)7.6(m,4 H)8.1(d,J=5.1 Hz,1 H)8.5(s,1 H)9.3(s,1 H)。
使用色原還原檢定用2,6-二氯酚-靛酚(2,6-dichlorophenol-indophenol,DCIP)研究DHODH活性及其抑制。受質氧化(二氫乳清酸,L-DHO)以及輔受質還原(輔酶Q,CoQ)與色原還原相關,因此酶活性使得600奈米下之色原吸光度降低。
將酶萃取物(8微升,約1.5微克人類蛋白)在96孔板中培育。檢定混合物(200微升)含有於檢定緩衝液(100毫莫耳濃度HEPES(pH 8.0)、150毫莫耳濃度NaCl、10% Glicerol、0.05% Triton X-100)中之200微莫耳濃度CoQD、100微莫耳濃度L-DHO、120微莫耳濃度DCIP以及2微升測試化合物。將化合物溶解於DMSO中,儲備濃度為1毫莫耳濃度,且在10微莫耳濃度至1皮莫耳濃度變化之不同濃度下進行測試以計算IC50
(抑制50%所需之抑制劑濃度)。
藉由添加酶起始反應,隨後在室溫下培育10分鐘,之後藉由使用標準儀器(Spectramax)計數600奈米下吸光度之降低來量測DCIP還原。
所有反應進行雙份,且使用ABase軟體繪製表明各化合物之IC50
值的曲線圖。
表2展示一些本發明之化合物在人類DHODH抑制檢定中之活性,展示所述化合物為有效的DHODH抑制劑。
使用Ficoll密度離心製備健康志願者之周邊血液單核細胞(peripheral blood mononuclear cells,PBMC)。將細胞接種於96孔平底板中之補充有5%胎牛血清、2毫莫耳濃度L-麩胺醯胺以及青黴素/鏈黴素之RPMI 1640中,每孔1×105
個細胞。隨後,用1微克/毫升植物血球凝集素(PHA,Sigma)激活PBMC,且用不同濃度之測試化合物之連續稀釋液培育3天。此後,將細胞用每孔0.5 μ Ci氚化胸腺嘧啶脈衝且培育隔夜。接著,將培養物收集在濾紙上且用B計數器計數。由劑量反應曲線計算各化合物之IC50
值。
已使用所述檢定測試之本發明化合物之IC50
小於10微莫耳濃度。本發明之較佳化合物之IC50
小於4微莫耳濃度,較佳小於2微莫耳濃度,最佳小於1微莫耳濃度。
如這些結果所示,本發明之化合物有效抑制DHODH,從而抑制具有高轉換率之細胞、尤其淋巴細胞之增殖。
本發明之胺基(異)菸酸適用於治療或預防已知易由二氫乳清酸脫氫酶抑制劑所進行之治療改善的疾病。所述疾病包含(但不限於)類風濕性關節炎、牛皮癬性關節炎、強直性脊柱炎、多發性硬化症、韋格納肉芽腫病、全身性紅斑狼瘡、牛皮癬以及肉狀瘤病。
因此,本發明之胺基(異)菸酸衍生物及包括所述化合物及/或其鹽之醫藥組合物可用於治療人體或動物體病症之方法中,所述方法包括向需要所述治療之受檢者投與有效量之本發明之胺基(異)菸酸衍生物或其醫藥學上可接受之鹽。
本發明之胺基(異)菸酸衍生物亦可與其他活性化合物組合治療已知易由二氫乳清酸脫氫酶抑制劑所進行之治療改善之疾病。
本發明之組合可視情況包括一或多種已知適用於治療自體免疫疾病、免疫及發炎性疾病、破壞性骨病、惡性贅生性疾病、血管生成相關病症、病毒性疾病以及感染性疾病之其他活性物質,諸如(a)抗TNF-α單株抗體,諸如英利昔單抗(Infliximab)、塞妥珠單抗(Certolizumab pegol)、戈利木單抗(Golimumab)、阿達木單抗(Adalimumab)以及來自Applied Molecular Evolution之AME-527;(b)抗代謝物化合物,諸如咪唑立賓(Mizoribine)、環磷醯胺(Cyclophosphamide)以及硫唑嘌呤(Azathioprine);(c)鈣調神經磷酸酶(PP-2B)抑制劑/INS表現抑制劑,諸如環孢素A(cyclosporine A)、他克莫司(Tacrolimus)以及來自Isotechnika之ISA-247;(d)環加氧酶抑制劑,諸如醋氯芬酸(Aceclofenac)、雙氯芬酸(Diclofenac)、塞來昔布(Celecoxib)、羅非昔布(Rofecoxib)、依託昔布(Etoricoxib)、伐地昔布(Valdecoxib)、魯米昔布(Lumiracoxib)、西米昔布(Cimicoxib)以及來自Laboratorios Almirall,S.A之LAS-34475;(e)TNF-α拮抗劑,諸如依那西普(Etanercept)、來那西普(Lenercept)、奧那西普(Onercept)以及培那西普(Pegsunercept);(f)NF-κ B(NFKB)激活抑制劑,諸如柳氮磺吡啶(Sulfasalazine)及艾拉莫德(Iguratimod);(g)IL-1受體拮抗劑,諸如阿那白滯素(Anakinra)及來自Amgen之AMG-719;(h)二氫葉酸還原酶(Dihydrofolate Reductase,DHFR)抑制劑,諸如甲胺喋呤(Methotrexate)、胺基喋呤(Aminopterin)以及來自Chelsea之CH-1504;(i)肌苷5'-單磷酸脫氫酶(Inosine 5'-Monophosphate Dehydrogenase,IMPDH)抑制劑,諸如咪唑立賓、病毒唑(Ribavirin)、噻唑呋啉(Tiazofurin)、阿米替韋(Amitivir)、黴酚酸酯(Mycophenolate mofetil)、利巴米定(Ribamidine)以及美泊地布(Merimepodib);(j)糖皮質激素,諸如潑尼龍(Prednisolone)、甲潑尼龍(methylprednisolone)、地塞米松(Dexamethasone)、皮質醇(Cortisol)、氫化可的松(Hydrocortisone)、曲安奈德(Triamcinolone acetonide)、醋酸氟輕鬆(Fluocinolone acetonide)、氟輕鬆(Fluocinonide)、特戊酸氯可托龍(Clocortolone pivalate)、醋丙氫可的松(Hydrocortisone aceponate)、磺庚甲潑尼龍(Methylprednisolone suleptanate)、丁酸丙酸倍他米松(Betamethasone butyrate propionate)、δ可的松(Deltacortisone)、δ去氫可的松(Deltadehydrocortisone)、潑尼松(Prednisone)、地塞米松磷酸鈉(Dexamethasone sodium phosphate)、曲安西龍(Triamcinolone)、戊酸倍他米松(Betamethasone valerate)、倍他米松(Betamethasone)、氫化可的松丁二酸鈉(Hydrocortisone sodium succinate)、潑尼龍磷酸鈉(Prednisolone sodium phosphate)、氫化可的松(Hydrocortisone probutate)以及二氟潑尼酯(Difluprednate);(k)抗CD20單株抗體,諸如利妥昔單抗(Rituximab)、奧吐穆單抗(Ofatumumab)、奧利珠單抗(Ocrelizumab)以及來自Trubion Pharmaceuticals之TRU-015;(1)B-靶細胞治療劑,諸如BLYSS、BAFF、TACI-Ig以及APRIL;(m)p38抑制劑,諸如AMG-548(來自Amgen)、ARRY-797(來自Array Biopharma)、乙二磺酸氯美噻唑(Chlormethiazole edisylate)、多瑪皮莫(Doramapimod)、PS-540446(來自BMS)、SB-203580、SB-242235、SB-235699、SB-281832、SB-681323、SB-856553(全部來自GlaxoSmithKline)、KC-706(來自Kemia)、LEO-1606、LEO-15520(全部來自Leo)、SC-80036、SD-06(全部來自Pfizer)、RWJ-67657(來自R.W.Johnson)、RO-3201195、RO-4402257(全部來自Roche)、AVE-9940(來自Aventis)、SCIO-323、SCIO-469(全部來自Scios)、TA-5493(來自Tanabe Seiyaku)以及VX-745及VX-702(全部來自Vertex)以及西班牙專利申請案第P200600396號及第P200602174號中所主張或所述之化合物;(n)Jak3抑制劑,諸如來自Pfizer之CP690550;(o)Syk抑制劑,諸如R-112、R-406以及R-788,全部來自Rigel;(p)MEK抑制劑,諸如ARRY-142886、ARRY-438162(全部來自Array Biopharma)、AZD-6244(來自AstraZeneca)、PD-098059、PD-0325901(全部來自Pfizer);(q)P2X7受體拮抗劑,諸如來自AstraZeneca之AZD-9056;(r)S1P1激動劑,諸如非格利莫(Fingolimod)、來自Sankyo之CS-0777以及來自Actelion之R-3477;(s)抗CD49單株抗體,諸如那他珠單抗(Natalizumab);(t)整合素抑制劑,諸如西侖吉肽(Cilengitide)、非特司特(Firategrast)、伐特司特鹽酸鹽(Valategrast hydrochloride)、SB-273005、SB-683698(全部來自Glaxo)、來自Sanofi-Aventis之HMR-1031、來自Roche之R-1295、來自BMS之BMS-587101以及來自UCB Celltech之CDP-323;(u)抗CD88單株抗體,諸如依利珠單抗(Eculizumab)以及培利珠單抗(Pexelizumab);(v)IL-6受體拮抗劑,諸如來自InKine之CBP-1011及來自Amgen之C-326;(w)抗IL-6單株抗體,諸如艾斯利單抗(Elsilimomab)、來自Centocor之CNTO-328以及來自Vaccinex之VX-30;(x)抗CD152單株抗體,諸如伊皮利單抗(Ipilimumab)及替西利單抗(Ticilimumab);(y)包括與部分人類免疫球蛋白G1聯結之人類細胞毒素T淋巴細胞相關抗原4(CTLA-4)之胞外域的融合蛋白,諸如阿巴他昔(Abatacept);(z)適用於治療骨病之藥劑,諸如雙膦酸鹽,諸如替魯膦酸二鈉(Tiludronate disodium)、氯屈膦酸二鈉(Clodronate disodium)、帕米膦酸二鈉(Disodium pamidronate)、依替膦酸二鈉(Etidronate disodium)、西地風(Xydiphone)(鉀鹽、鈉鹽)、阿侖膦酸鈉(Alendronate sodium)、奈立膦酸鹽(Neridronate)、二甲基-APD、奧帕膦酸鈉鹽(Olpadronic acid sodium salt)、米諾膦酸(Minodronic acid)、阿樸嗎啡(Apomine)、伊班膦酸鈉水合物(Ibandronate sodium hydrate)以及利塞膦酸鈉(Risedronate sodium);(aa)VEGF Try激酶抑制劑,諸如哌加他尼八鈉(Pegaptanib octasodium)、丁二酸凡塔藍尼(Vatalanib succinate)、索拉非尼(Sorafenib)、範得它尼(Vandetanib)、蘋果酸舒尼替尼(Sunitinib malate)、西地尼布(Cediranib)、鹽酸帕佐帕尼(Pazopanib hydrochloride)以及來自AEterna Zentaris之AE-941;(bb)對自體免疫疾病有效之其他化合物,諸如金鹽(Gold salt)、羥氯喹啉(hydroxychloroquine)、青黴胺(Penicilamine)、K-832、SMP114以及AD452;(cc)嘌呤-核苷磷酸化酶抑制劑,諸如福羅德辛鹽酸鹽(Forodesine hydrochloride)、來自Albert Einstein College of Medicine之R-3421、來自Pfizer之CI-972以及CI-1000;(dd)抗RANKL單株抗體,諸如狄諾單抗(Denosumab);(ee)抗CD25單株抗體,諸如伊諾莫單抗(Inolimomab)、達昔單抗(Dacliximab)、巴利昔單抗(Basiliximab)以及來自US National Cancer Institute之LMB-2;(ff)組蛋白脫乙醯基酶(Histone Deacetylase,HDAC)抑制劑,諸如雙丙戊酸鈉(Divalproex sodium)、乙醯基地那林(Acetyldinaline)、酯肽(Depsipeptide)、丁酸鈉、苯基丁酸鈉、沃利斯他(Vorinostat)、來自Mitsui之MS-27-275、丙戊酸(Valproic acid)、吡羅麥德(Pyroxamide)、三丁酸甘油酯(Tributyrin)、來自TopoTarget之PX-105684、來自MethylGene之MG-0103、來自TopoTarget之G2M-777以及來自Celera之CG-781;以及(gg)抗集落刺激因子(GM-CSF)單株抗體,諸如來自KaloBios之KB-002。
當本發明之胺基(異)菸酸衍生物用於治療類風濕性關節炎、牛皮癬性關節炎、強直性脊柱炎、多發性硬化症、韋格納肉芽腫病、全身性紅斑狼瘡、牛皮癬以及肉狀瘤病時,將其與已知適用於治療諸如類風濕性關節炎、牛皮癬性關節炎、強直性脊柱炎、多發性硬化症、韋格納肉芽腫病、全身性紅斑狼瘡、牛皮癬以及肉狀瘤病之所述疾病的其他活性化合物組合使用可能為有利的。
欲與本發明之胺基(異)菸酸衍生物組合治療或預防類風濕性關節炎、牛皮癬性關節炎、強直性脊柱炎、多發性硬化症、韋格納肉芽腫病、全身性紅斑狼瘡、牛皮癬或肉狀瘤病之尤其較佳的活性劑為(a)抗TNF-α單株抗體,諸如英利昔單抗、塞妥珠單抗、戈利木單抗、阿達木單抗以及來自Applied Molecular Evolution之AME-527;(b)TNF-α拮抗劑,諸如依那西普、來那西普、奧那西普以及培那西普;(c)鈣調神經磷酸酶(PP-2B)抑制劑/INS表現抑制劑,諸如環孢素A、他克莫司以及來自Isotechnika之ISA-247;(d)IL-1受體拮抗劑,諸如阿那白滯素及來自Amgen之AMG-719;(e)抗CD20單株抗體,諸如利妥昔單抗、奧吐穆單抗、奧利珠單抗以及來自Trubion Pharmaceuticals之TRU-015;(f)p38抑制劑,諸如AMG-548(來自Amgen)、ARRY-797(來自Array Biopharma)、乙二磺酸氯美噻唑、多瑪皮莫、PS-540446(來自BMS)、SB-203580、SB-242235、SB-235699、SB-281832、SB-681323、SB-856553(全部來自GlaxoSmithKline)、KC-706(來自Kemia)、LEO-1606、LEO-15520(全部來自Leo)、SC-80036、SD-06(全部來自Pfizer)、RWJ-67657(來自R.W.Johnson)、RO-3201195、RO-4402257(全部來自Roche)、AVE-9940(來自Aventis)、SCIO-323、SCIO-469(全部來自Scios)、TA-5493(來自Tanabe Seiyaku)以及VX-745及VX-702(全部來自Vertex)以及西班牙專利申請案第P200600396號及第P200602174號中所主張或所述之化合物;(g)NF-κ B(NFKB)激活抑制劑,諸如柳氮磺吡啶及艾拉莫德;以及(h)二氫葉酸還原酶(DHFR)抑制劑,諸如甲胺喋呤、胺基喋呤以及來自Chelsea之CH-1504。
本發明之組合可用於治療易由二氫乳清酸脫氫酶之抑制改善之病症。因此,本申請案涵蓋治療所述病症之方法以及本發明之組合在製造用於治療所述病症之藥劑中的用途。
所述病症之較佳實例為類風濕性關節炎、牛皮癬性關節炎、強直性脊柱炎、多發性硬化症、韋格納肉芽腫病、全身性紅斑狼瘡、牛皮癬以及肉狀瘤病,更佳為類風濕性關節炎、牛皮癬性關節炎以及牛皮癬且最佳為類風濕性關節炎。
本發明之組合中的活性化合物視待治療之病症之性質而定可由任何合適途徑投與,例如經口投與(以糖漿、錠劑、膠囊、口含劑、控釋製劑、速溶製劑等形式);局部投與(以乳膏、軟膏、洗劑、鼻用噴霧或氣霧劑等形式);注射(皮下、真皮內、肌肉內、靜脈內等)或吸入(以乾粉、溶液、分散液等形式)。
組合中之活性化合物(亦即,本發明之二氫乳清酸脫氫酶之抑制劑)及其他可選活性化合物可於同一醫藥組合物中一起投與或於意欲分開、同時、相伴或相繼投與之不同組合物中經相同或不同途徑投與。
本發明之一種執行形式是由多部件套組組成,所述套組包括本發明之二氫乳清酸脫氫酶抑制劑以及說明與適用於治療類風濕性關節炎、牛皮癬性關節炎、強直性脊柱炎、多發性硬化症、韋格納肉芽腫病、全身性紅斑狼瘡、牛皮癬以及肉狀瘤病之另一種活性化合物同時、並行、分開或相繼使用之說明書。
本發明之另一種執行形式是由包括式(I)之二氫乳清酸脫氫酶抑制劑以及適用於治療類風濕性關節炎、牛皮癬性關節炎、強直性脊柱炎、多發性硬化症、韋格納肉芽腫病、全身性紅斑狼瘡、牛皮癬以及肉狀瘤病之另一種活性化合物的封裝組成。
醫藥調配物可方便地以單位劑型提供且可由藥劑學技術中熟知之任何方法製備。
適於經口投與之本發明之調配物可以如下形式提供:離散單元,諸如膠囊、扁囊劑或錠劑,其各自含有預定量之活性成份;散劑或顆粒劑;於水性液體或非水性液體中之溶液或懸浮液;或水包油型液體乳液或油包水型液體乳液。活性成份亦可以大丸劑、糖劑或糊劑形式提供。
糖漿調配物通常將由化合物或鹽於液體載劑(例如乙醇、花生油、橄欖油、甘油或水)中之懸浮液或溶液以及調味劑或著色劑組成。
當組合物呈錠劑形式時,可使用製備固體調配物通常所用之任何醫藥載劑。所述載劑之實例包含硬脂酸鎂、滑石、明膠、阿拉伯膠(acacia)、硬脂酸、澱粉、乳糖以及蔗糖。
可藉由視情況與一或多種配合劑壓縮或模製來製造錠劑。可藉由在合適機器中將視情況與黏合劑、潤滑劑(lubricant)、惰性稀釋劑、潤滑劑(lubricating agent)、表面活性劑或分散劑混合之自由流動形式(諸如散劑或顆粒劑)之活性成份壓縮來製備壓縮錠劑。可藉由在合適機器中使經惰性液體稀釋劑濕潤之粉末狀化合物之混合物模製來製造模製錠劑。可視情況將錠劑包衣或刻痕且錠劑可經調配以提供其中之活性成份之緩釋或控釋。
當組合物呈膠囊形式時,任何常規封裝均為合適的,例如於硬質明膠膠囊中使用上述載劑。當組合物呈軟質明膠膠囊形式時,可考慮通常用於製備分散液或懸浮液之任何醫藥載劑,例如水性樹膠、纖維素、矽酸鹽或油類,且可將其併入軟質明膠膠囊中。
用於藉由吸入局部傳送至肺之乾粉組合物可(例如)於用於吸入器或吹入器中之明膠膠囊及藥筒或層壓鋁箔發泡包裝中提供。調配物通常含有本發明之化合物與諸如乳糖或澱粉之合適粉末基質(載劑物質)之用於吸入的粉末混合物。較佳使用乳糖。各膠囊或藥筒通常可含有2微克與150微克之間的各治療活性成份。或者,可提供無賦形劑之活性成份。
用於吸入之調配物之封裝可藉由使用諸如Novolizer SD2FL之合適吸入器裝置進行,此描述於以下專利申請案中:WO 97/000703、WO 03/000325以及WO 03/061742。
經鼻傳送之典型組合物包含以上所提及之用於吸入之組合物且更包含呈於諸如水之惰性媒劑中之溶液或懸浮液形式的可經鼻用泵投與之非加壓組合物,所述惰性媒劑視情況與諸如緩衝液、抗微生物劑、張力調節劑以及黏度調節劑之習知賦形劑組合。
典型皮膚用及經皮調配物包括例如乳膏、軟膏、洗劑或糊劑之習知水性或非水性媒劑或呈藥用硬膏劑、貼片或膜形式。組合物較佳為單位劑型,例如錠劑、膠囊或計量氣霧劑劑量,如此患者可投與單劑量。
實現治療效應所需之各活性劑之量當然將隨特定活性劑、投藥途徑、所治療之受檢者以及所治療之特定病症或疾病而變化。
有效劑量通常在每天2-2000毫克活性成份範圍內。每日劑量可以每天一或多次治療、較佳1至4次治療投與。較佳地,1天投與1次或2次活性成份。
當使用活性劑之組合時,預期所有活性劑應同時或以極靠近之時間投與。或者,一或兩種活性劑可在上午服用且其他活性劑在當日稍後服用。或在另一方案中,一或兩種活性劑可每日服用兩次,且其他活性劑每日服用一次,可與進行每天兩次之給藥中的一次同時服用或分開服用。較佳至少兩種且更佳所有活性劑應同時一起服用。較佳至少兩種且更佳所有活性劑應以混合物形式投與。
引用以下製劑形式作為調配物實例:
根據以下配方製備50,000顆膠囊,各自含有100毫克2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)-5-甲基菸酸(活性成份):
經60目篩篩分上述成份,且將其裝載於合適的混合器中且填充於50,000顆明膠膠囊中。
根據以下配方製備50,000顆錠劑,各自含有50毫克2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)-5-甲基菸酸(活性成份):
使所有粉末穿過孔徑為0.6毫米之篩網,隨後於合適混合器中混合20分鐘且使用9毫米圓形且平坦之斜刃衝頭壓縮成300毫克錠劑。錠劑之崩解時間為約3分鐘。
Claims (27)
- 一種式(I)化合物:
- 如申請專利範圍第1項所述之化合物,其中所述C1-4 烷基、所述C3-8 環烷基、所述C1-4 烷氧基以及所述C3-8 環烷氧基各自視情況經1、2或3個鹵素原子取代。
- 如申請專利範圍第1項所述之化合物,其中R1 是選自由氫、溴及氟原子、甲基、乙基、環丙基以及環丁基組成的族群。
- 如申請專利範圍第1項所述之化合物,其中G3 表示氮原子且G4 表示基團CH。
- 如申請專利範圍第1項所述之化合物,其中G3 表示基團CH且G4 表示氮原子。
- 如申請專利範圍第1項所述之化合物,其中Rc 各自獨立地選自由氫原子、氟原子、氯原子以及C1-3 烷基組成的族群。
- 如申請專利範圍第1項所述之化合物,其中Rd 是選自由羥基、C1-3 烷氧基、2,2,2-三氟乙氧基以及C3-4 環烷氧基組成的族群。
- 如申請專利範圍第7項所述之化合物,其中Rd 是選自由C1-3 烷氧基、2,2,2-三氟乙氧基以及C3-4 環烷氧基組成的族群。
- 如申請專利範圍第1項所述之化合物,其中Ra 是選自由氟原子、甲基以及三氟甲氧基組成的族群。
- 如申請專利範圍第1項所述之化合物,其中Rb 是選自由氫原子、氟原子以及氯原子組成的族群。
- 如申請專利範圍第1項所述之化合物,其中R2 是選自由氫原子及鹵素原子組成的族群。
- 如申請專利範圍第11項所述之化合物,其中R2 是選自由氫原子及氟原子組成的族群。
- 如申請專利範圍第1項所述之化合物,其中兩個基團G1 均表示C(Rc )基團,G2 表示C(Rd )基團,Ra 為氟原子,Rb 是選自由氫原子及氟原子組成的族群且R1 是選自由氫、溴及氟原子、甲基、乙基以及環丙基組成的族群。
- 如申請專利範圍第13項所述之化合物,其中G2 為選自C(OH)、C(OMe)以及C(OEt)的基團。
- 如申請專利範圍第13項所述之化合物,其中兩個G1 均表示CH基團且G2 為選自C(OMe)及C(OEt)的基團。
- 如申請專利範圍第15項所述之化合物,其中Rc 為氫原子,Rd 是選自由C1-3 烷氧基及C3-4 環烷氧基組成的族群且R2 為氫原子。
- 如申請專利範圍第16項所述之化合物,其中Rd 為羥基或C1-3 烷氧基。
- 如申請專利範圍第17項所述之化合物,其中Rd 為C1-3 烷氧基。
- 如申請專利範圍第1項所述之化合物,其中G3 表示氮原子,G4 表示基團CH且Rb 為氟原子。
- 如申請專利範圍第1項所述之化合物,其中G3 表示基團CH,G4 表示氮原子。
- 如申請專利範圍第1項所述之化合物,其為以下各物中之一種:2-(3-氟-3'-甲氧基聯苯-4-基胺基)菸酸2-(3'-乙氧基-3-氟聯苯-4-基胺基)菸酸2-(3-氟-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(3'-乙氧基-3-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(3'-甲氧基-3-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(2,5-二氟-3'-甲氧基聯苯-4-基胺基)菸酸2-(3'-乙氧基-2,5-二氟聯苯-4-基胺基)菸酸2-(2',3-二氟-3'-甲氧基聯苯-4-基胺基)菸酸2-(2-甲基-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(3-氯-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(3-氯-3'-乙氧基聯苯-4-基胺基)菸酸2-(3-甲基-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(3-氯-3'-甲氧基聯苯-4-基胺基)菸酸2-(3'-(二氟甲氧基)-3-氟聯苯-4-基胺基)菸酸2-(3'-環丁氧基-3-氟聯苯-4-基胺基)菸酸 2-(3-氟-3'-(2,2,2-三氟乙氧基)聯苯-4-基胺基)菸酸2-(3'-環丁氧基-3,5-二氟聯苯-4-基胺基)菸酸2-(3,5-二氟-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(3'-乙氧基-3,5-二氟聯苯-4-基胺基)菸酸2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)菸酸3-(3'-乙氧基-3-氟聯苯-4-基胺基)異菸酸鋰3-(3-氟-3'-甲氧基聯苯-4-基胺基)異菸酸鋰3-(3'-甲氧基-3-(三氟甲氧基)聯苯-4-基胺基)異菸酸鋰3-(3-氟-3'-(三氟甲氧基)聯苯-4-基胺基)異菸酸鋰2-(3'-乙氧基聯苯-4-基胺基)菸酸2-(5-氟-2-甲基-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(2',3-二氟-5'-異丙氧基聯苯-4-基胺基)菸酸2-(3-氟-3'-甲氧基聯苯-4-基胺基)-5-甲基菸酸2-(3,5-二氟-3'-羥基聯苯-4-基胺基)菸酸5-溴-2-(3-氟-3'-甲氧基聯苯-4-基胺基)菸酸5-溴-2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)菸酸5-溴-2-(3-氟-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(3-氟-3'-(三氟甲氧基)聯苯-4-基胺基)-5-甲基菸酸5-環丙基-2-(3-氟-3'-甲氧基聯苯-4-基胺基)菸酸2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)-5-甲基菸酸2-(3'-乙氧基-5-氟-2-甲基聯苯-4-基胺基)菸酸2-(5-氟-3'-甲氧基-2-甲基聯苯-4-基胺基)菸酸2-(3'-乙氧基-3,5-二氟聯苯-4-基胺基)-5-甲基菸酸5-環丙基-2-(3'-乙氧基-3,5-二氟聯苯-4-基胺基)菸酸2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)-5-乙基菸酸 5-溴-2-(3'-乙氧基-2,5-二氟聯苯-4-基胺基)菸酸5-環丙基-2-(3'-乙氧基-2,5-二氟聯苯-4-基胺基)菸酸2-(5-氟-3'-甲氧基-2-甲基聯苯-4-基胺基)-5-甲基菸酸5-環丙基-2-(5-氟-3'-甲氧基-2-甲基聯苯-4-基胺基)菸酸2-(2',3,5-三氟-3'-甲氧基聯苯-4-基胺基)菸酸2-(2'-氯-3,5-二氟聯苯-4-基胺基)菸酸2-(3'-環丙氧基-3,5-二氟聯苯-4-基胺基)菸酸2-(3,5-二氟-2-甲基聯苯-4-基胺基)菸酸5-環丙基-2-(2,5-二氟-3'-甲氧基聯苯-4-基胺基)菸酸2-(3'-環丙氧基-3,5-二氟聯苯-4-基胺基)-5-環丙基菸酸5-氯-2-(3,5-二氟-3'-甲氧基聯苯-4-基胺基)菸酸5-環丙基-2-(3,5-二氟-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(2,3,5-三氟-3'-甲氧基聯苯-4-基胺基)菸酸2-(2'-氯-3,5-二氟聯苯-4-基胺基)-5-環丙基菸酸2-(3,5-二氟-3'-甲氧基-2-甲基聯苯-4-基胺基)菸酸2-(3,5-二氟-2-甲基-3'-(三氟甲氧基)聯苯-4-基胺基)菸酸2-(2'-氯-3,5-二氟-2-甲基聯苯-4-基胺基)菸酸5-氯-2-(3,5-二氟聯苯-4-基胺基)菸酸5-氯-2-(2'-氯-3,5-二氟聯苯-4-基胺基)菸酸2-(2,3,5,6-四氟-3'-甲氧基聯苯-4-基胺基)菸酸2-(3,5-二氟-2'-甲基聯苯-4-基胺基)菸酸3-(3'-環丙氧基-3-氟聯苯-4-基胺基)異菸酸。
- 如申請專利範圍第1至21項中任一項所述之化合物,其用於對人體或動物體進行治療。
- 如申請專利範圍第1至21項中任一項所述之化合物,其用於治療由二氫乳清酸脫氫酶之抑制改善的病理學病狀或疾病。
- 如申請專利範圍第23項所述之化合物,其中所述病理學病狀或疾病是選自類風濕性關節炎、牛皮癬性關節炎、強直性脊柱炎、多發性硬化症、韋格納肉芽腫病(Wegener's granulomatosis)、全身性紅斑狼瘡、牛皮癬以及肉狀瘤病。
- 一種醫藥組合物,其包括如申請專利範圍第1至21項中任一項所述之化合物以及醫藥學上可接受之稀釋劑或載劑。
- 一種如申請專利範圍第1至21項中任一項所述之化合物的用途,其用於製造供治療如申請專利範圍第23或24項所述之病理學病狀或疾病用的藥劑。
- 一種組合產品,其包括(i)如申請專利範圍第1至21項中任一項所述之化合物;以及(ii)另一種選自以下各物之化合物:a)抗TNF-α單株抗體,諸如英利昔單抗(Infliximab)、塞妥珠單抗(Certolizumab pegol)、戈利木單抗(Golimumab)、阿達木單抗(Adalimumab)以及來自Applied Molecular Evolution之AME-527 b)TNF-α拮抗劑,諸如依那西普(Etanercept)、來那西普(Lenercept)、奧那西普(Onercept)以及培那西普(Pegsunercept)c)鈣調神經磷酸酶(PP-2B)抑制劑/INS表現抑制劑,諸如環孢素A(cyclosporine A)、他克莫司(Tacrolimus)以及來自Isotechnika之ISA-247 d)IL-1受體拮抗劑,諸如阿那白滯素(Anakinra)及來自Amgen之AMG-719 e)抗CD20單株抗體,諸如利妥昔單抗(Rituximab)、奧吐穆單抗(Ofatumumab)、奧利珠單抗(Ocrelizumab)以及來自Trubion Pharmaceuticals之TRU-015 f)p38抑制劑,諸如AMG-548(來自Amgen)、ARRY-797(來自Array Biopharma)、乙二磺酸氯美噻唑(Chlormethiazole edisylate)、多瑪皮莫(Doramapimod)、PS-540446(來自BMS)、SB-203580、SB-242235、SB-235699、SB-281832、SB-681323、SB-856553(全部來自GlaxoSmithKline)、KC-706(來自Kemia)、LEO-1606、LEO-15520(全部來自Leo)、SC-80036、SD-06(全部來自Pfizer)、RWJ-67657(來自R.W. Johnson)、RO-3201195、RO-4402257(全部來自Roche)、AVE-9940(來自Aventis)、SCIO-323、SCIO-469(全部來自Scios)、TA-5493(來自Tanabe Seiyaku)以及VX-745及VX-702(全部來自Vertex)g)NF-κB(NFKB)激活抑制劑,諸如柳氮磺吡啶(Sulfasalazine)及艾拉莫德(Iguratimod)h)二氫葉酸還原酶(Dihydrofolate Reductase,DHFR)抑制劑,諸如甲胺喋呤(Methotrexate)、胺基喋呤(Aminopterin)以及來自Chelsea之CH-1504。
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