TW509668B - Arylsulfonylamino hydroxamic acid derivatives and pharmaceutical composition comprising same - Google Patents
Arylsulfonylamino hydroxamic acid derivatives and pharmaceutical composition comprising same Download PDFInfo
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Description
經濟部中央標李局員工消費合作社印製 509668 A7 —一 —_ B7__ 五、發明説明(1 ) 說明 本發明係有關芳基磺醯基胺基異羥肪酸衍生物,其爲 母質金屬蛋白酶或產生腫瘤壞死因子(TNF)之抑制劑,因 而可用於治療選自關節炎、癌症、組織潰瘍、斑退化、再 狹窄、齒骨膜疾病、大泡性表皮鬆懈、鞏膜炎及其他以母 質金屬蛋白酶活性特徵化之疾病、AIDS、敗血病、敗血性 休克及其他涉及TNF產生之疾病之病況。此外,本發明化 合物可與標準非類固醇消炎藥(後文稱NSAID,S)及類似物組 备使用治療關節炎’及與胞毒性藥物如阿霉素 (adriamycin)、紅比霉素(daunomycin)、順氣氨銷(cis-platinum)、衣托塞(et〇p〇side)、紫杉紛(taxol)、泰索泰拓 (taxotere)及其他生物驗如長春新驗(vincristine)組合用以治療 癌症。 本發明亦有關一種使用此種化合物以治療哺乳類尤其是 人類之上述疾病之方法,及有關其可用之醫藥組合物。 有數種酵素可有效損壞結構蛋白質且爲結構相關之金屬 蛋白酶。母質降解之金屬蛋白酶如明膠酶、思托密利辛 (stromelysin)及膠原酶涉及組織母質降解作用(如膠原虛脱) 且與涉及異常結缔組織及基膜母質代謝之許多生理狀況相 關,如關節炎(例如骨關節炎及風濕性關節炎)、組織潰瘍 (如角膜、表皮及胃潰瘍)、異常傷口癒合、齒骨膜疾病、 骨疾病(如柏棋氏(paget‘s)疾病及骨質疏鬆症)、腫瘤轉移 或侵入’以及HIV -感染(].Leuk. Biol.. 52(2):244-248 ^ 1992) 〇 -4- 本紙張尺度適用中國國家標準(CNS ) Λ4規格(210X 297公釐) (請先閱讀背面之注意事項#填寫本頁) •^^1. 訂 509668 A7 B7 五、發明説明(2 ) 腫瘤壞死因子被認爲與許多感染性及自動免疫性疾病有 關(W. Fiers,EJEBS Letters, 1991,281, 199)。再者,已顯示 TNF爲敗血病及敗血性休克中所見之發炎反應之主要調節 物(C.E· Spooner等人之Clinical Immunology and Immunopath〇1r>gy 1992, ^ISll) 〇 本發明係有關下式之化合物或其醫藥可接受性鹽:
其中 R1及R 2各獨立選自(C卜C6)燒基、三氟甲基、三氟甲基 (Ci-C6)烷基,(d-Cs)烷基(二氟亞甲基)、(ChCd烷基(二 氟亞甲基HCVC3)烷基、(c卜c10)芳基、(c2-C9)雜芳基、 (C6-C1G)芳基(Cl-C6)烷基、(C2-C9)雜芳基(Cl-C6)烷基; 或R1與R2可合而形成(C3-C6)環烷基或‘苯并稠合之(C3-C6) 環烷基環或下式之基: (請先閲讀背面之注意事項典、填寫本頁) ΛΙ. 經濟部中央標準局員工消費合作社印製 (CH2)n (CH2)w 其中11及111獨立爲1或2及X爲CF2,S,Ο或NR3,其中R3爲 氫、(Ci-C6)烷基、(C6-C1())芳基、(C2-C9)雜芳基、(C6-C10) -5- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 509668 A7 B7 五、發明説明(3 經濟部中央標隼局員工消費合作社印製 方基(Ci-C6)燒基、(c2-c9)㈣基(Ci_c6)i完基、(C1_C6)烷 橫釀基、(CVC1G)芳橫酿基或醯基;及 J爲關燒基食1〇)芳基、(〜崎 f 基(C6-Cl。)万基(C6_Ci。)芳基、(C6-Cu))芳基(c6-cl0) 芳基(Ci-CO烷基、(c6-c…芳基(〇2<9)雜芳基、(C6_Ci〇) 芳氧基(C2-C9)雜芳基、(C2_C9)雜芳基、(C2_C9)雜芳基 (c2-c9)雜芳基、(C2-C9)雜芳基(cvc⑹芳基、(C1_C6)烷 基(CVCiG)芳基、(Ci-co 烷氧基(x;6_Ci())芳基、(C6_CiG)芳 基(Ci-Ce)烷氧基(C6-C1G)芳基.、(C6-CiG)芳基(Ci_C6)燒氧 基(C卜c6)烷基、(C2-C9)雜芳氧基(C6_CiG)芳基、(Ci_C6) 烷基(C2-C9)雜芳基、(ChCQ烷氧基(C2_C9)雜芳基、(c6-c1〇)芳基(d-Cd烷氧基(c2_C9)雜芳基、(C2_C9)雜芳氧基 (C2-C9)雜芳基、(C6-C1G)芳氧基(Cl_C6)燒基、(C2-C9)雜 方氧基(C卜C6)烷基、(c卜c6)烷基(c6-Cio)芳氧基(C6-Cl0) 方基、(C卜C6)烷基(C2-C9)雜芳氧基(C6_ClG)芳基、(Ch_C6) 燒基(C6-C1G)芳氧基(c2-c9)雜芳基、(Cl_c6)烷氧基(C6-Ci〇) 芳氧基(C6-C10)芳基、(c卜C6)烷氧基(0-C9)雜芳氧基(c6-C10)芳基或(C1-C6)坑氧基(C6-C1G)芳氧基(C2-C9)雜芳基, 其中各芳基係視情況經氟、氣、溴、(C1-C6)烷基、(C1-C6) 烷氧基或全氟(Ci-C3)烷基取代。 本文所用之“烷基,,一詞,除非另有説明,否則包含具有 直鍵、合枝或ί募狀邵份或其組合之飽和單價煙基。 本文所用之“坑氧基’,一詞包含〇 -纟充基,其中“垸基,,如 上述定義。 -6 - 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X297公釐) (請先閲讀背面之注*意事項界填寫本頁) 、1Τ S. 509668 經濟部中央標準局員Η消費合作社印製 -Λ 7 _____ Β7 五、發明説明(4 ) 本文所用“芳基’’,除非另有説明,否則包含衍生自芳族 烴藉移除一個氫所得之有機基,如苯基或莕基,其視情況 經1至3個選自氟、氯、三氟甲基、(c卜c6)烷氧基、
Cio)芳氧基、三氟甲氧基、二氟甲氧基及(Ci-C6)烷基之組 群之取代基所取代。 本文所用之‘‘雜芳基,,,除非另有説明,否則包含衍生自 芳族雜環化合物藉移除一個氫所得之有機基,如吡啶基、 吱喃基、峨哈基、魂吩基、異p塞哇基、咪峻基、苯幷咪唑 基、四唑基、吡嗜基、嘧啶基、喳諾基、異喹諾基、苯幷 唉喃基、異苯并吱喃基、苯并魂吩基、p比峻基、啕嗓基、 異㈣味基、嗓吟基、叶嗤基、異号嗤基、p塞嗤基、吟唾 基、苯并隹嗤基或苯幷呤唑基,其視情況經1或2個選自 氣、氯、三氟甲基、(c卜c6)烷氧基、(c6_Cl0)芳氧基、三 氣甲氧基、二氟甲氧基及(Ci-C6)烷基之取代基所取代。 本文所用之‘‘醯基,,一詞,除非另有説明,否則包含通式 RCO之基,其中R爲烷基、烷氧基、芳基、芳烷基或芳烷 氧基且“烷基,,或“芳基,,如前述定義。‘' 本文所用之“醯氧基,,包含Ο -醯基,其中“醯基,,如前述 定義。 式1化合物可具有對掌中心且因此呈現不同之對映異構 態°本發明係有關式1化合物之所有光學異構物及立體異 構物及其混合物。 幸父佳式1化合物包含其中R1及R2合而形成(C3-C6)環烷基 或苯并稠合之(C3-C〇環烷基環或下式之基者·· 本紙張尺度適财關家縣(CNS )續 ίϋχ 297公及〉 (請先閲讀背面之注意事項吾填寫本頁) ^^1. 訂 509668 A7 B7 五、發明説明( 其中η及m獨立爲1或2及X爲CF2,S,Ο或NR3,其中汉3爲 氣、(Cl-C6)fei 基、(C6-Cl〇)芳基、(C2-C9)雜芳基、(C6-Ci〇) 芳基(¢:^6)烷基、(C2-C9)雜芳基(d-Ce)烷基、(C卜c6)境 %酿基、(C6-ClG)芳續酿基或醯基。 其他較佳式1化合物包含其中R1及R2合而形成(Cs C6)環 烷基或苯并稠合之(C3-C〇環熔基環者。 其他較佳式1化合物包含其中Q爲(C6-C1G)芳基、(C6-C1(^ 芳基(C6-C10)芳基、(C6-C10)芳氧基(C6-C10)芳基、(c6-cl0) 芳氧基(C2-C9)雜芳基、(c2-c9)雜芳基、(C2_c9)雜芳基 (c2-c9)雜芳基、(C6-Cn))芳基(c2-c9)雜芳基、(c2-c9)雜 芳基(C6-C10)芳基或(C2-C9)雜芳氧基(c6-c1())芳基者。 其他較佳式1化合物包含其中Q爲(c6-c1(>)芳氧基(C6-C1q) 芳基者。 其他較佳式1化合物包含其中R1及R2各獨立爲完 基者。 · t\ 更佳之式1化合物包含其中R1及R2合而形成(C3-C6)環境 基或苯幷稠合之(C3-C6)環烷基環下式之基者:
(請先閱讀背面之¾意事項填l>f本百C 經濟部中央標準局員工消費合作社印製 <CHp)n <ch2), 其中η及m獨立爲1或2及X爲cf2,S,Ο或NR3,其中r3 λ 本紙張尺度適用中國國家標率(CNS ) Α4規格(210X297公釐) A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明(6 ) 现、(C1-C6)烷基、(C6-C1())芳基、(C2-C9)雜芳基、(C6-Ci〇) 1 基(CVC6)烷基、(C2-C9)雜芳基(d-C6)烷基、(C1-C6)烷 續驢基、(C6-C1G)芳磺醯基或醯基;及Q爲(C6-ClG)芳基、 (C6-C1())芳基(c6_Ci〇)芳基、(C6-Cl〇)芳氧基(C6-ClG)芳 基、(CVCho)芳氧基(C2-C9)雜芳基、(C2-C9)雜芳基、(C2-C9)雜芳基(C2-C9)雜芳基、(C6-C1(>)芳基(C2-C9)雜芳基、 (C2-C9)雜芳基(c6-ClQ)芳基或(C2_C9)雜芳氧基(C6_C⑹芳 0 % '一 * 更佳之式1化合物包含其中R1&R2合而形成(C3-C6)環烷 基或苯并稠合之(Cs-C:6)環烷基環;爲(C6_CiG)芳基、 (C6-C1())芳基(C6_Cl〇)芳基、(C6-Ci〇)芳氧基(C6_C⑷芳 基、(C6-C1())芳氧基(C2_C9)雜芳基、(C2_C9)雜芳基、(c2_ C9)雜芳基(C2_C9)雜芳基、(C6_CiQ)芳基(C2_c〇雜芳基、 (c2-c9),雜芳基(C6_Cig)芳基或(C2_C9)雜芳氧基(c^c芳 基者。 更佳<式1化合物包含其中⑷及^各獨立爲(Ci_c〇烷 基;及 Q 爲(c6_Ci〇)芳基、(C6_ClG)芳'基(C6_CiG)芳基、 (c6-Cl。)芳氧基(C6_Ci。)芳基、(C6-Ci〇)芳氧基(C2_⑸雜芳 基、iC2-C9)雜芳基、(ChC9)雜芳基(c2-c9)雜芳基、(C6_
Cl〇)万基(C2_C9)雜芳基、(C2-C9)雜芳基(C6-C1G)芳基或 (C2-C9)雜芳氧基(C6_Ci〇)芳基者。 更佳足式1化合物包含其中…及化2各獨立 基;及Q爲(cvCl0)芳氧基(C6.Cl0)芳基者。 社 特佳之式1化合物包含下列: 9- ----------磡 II (請先閲讀背面之注意事項再填寫本頁) -5 本紙張尺度適用中_家縣(CNS)⑽見格 (210X 297公t ) 509668 .A 7 B7 五、發明説明(7 ) 3 - [4-(4-氟苯氧基)苯橫醯基胺基]υ丫丁淀-3-複酸輕酉盛 胺; 4-[4-(4-氟苯氧基)苯續醯基胺基]六氫p比症-4-幾酸輕醯 胺; 1-[4-(4-氟苯氧基)苯續醯基胺基]環丙燒-1-複酸輕醯 胺; 1-[4-(4-氯苯氧基)苯續基胺基]環丙燒-1-獲酸幾醯 胺; > 一 1-[4-(4-氟苯氧基)苯續醢基胺基]環丁燒^-1-致酸經酉遙 胺; 1 -[4-(4-氣苯氧基)苯續龜基胺基]環丁燒-1-叛酸經醯 胺; 1-[4-(4-氟苯氧基)苯績醯基胺基]環戊燒^-1-複酸禮醯 胺; 1- [4-(4-氟苯氧基)苯續醯基胺基]環己貌-1-瘦酸經醯 胺; 2- [4-(4 -氟苯氧基)苯橫醯基胺基]-‘N1-護基-2-甲基丙醯 胺; 經濟部中央標隼局員工消費合作社印製 (讀先閱讀背面之注货事項再填寫本頁) 2-[4-(4-氯苯氧基)苯磺醯基胺基]-N-羥基-2-甲基丙醯 胺; N-經基-2-甲基-2-(5-吡啶-2-基違吩-2-確醯基胺基)丙醯 胺; 1-(5 -峨淀-2 -基p塞吩-2 -續酿基胺基)環戊燒-1-叛酸經酿 胺; 10- 本紙張尺度適用中國國家標準(CNS ) Λ4規格(210X 297公漦) 509668 A7 B7 五 、發明説明(8 經濟部中央標準局員工消費合作社印製 1 氟聯苯基-4-磺醯基胺基)環丙烷-1 -羧酸羥醯胺; -氣聯苯基-4 -續酿基胺基)環丁:fe-Ι -幾酸幾醯胺; K(4k氟聯苯基-4-磺醯基胺基)環戊烷-1 -羧酸幾gs胺; 2-(4-甲氧基苯橫醯基胺基)印滿-2-叛酸幾醯胺;及 2<4_(4-氟苯氧基)苯磺醯基胺基]茚滿-2-羧酸幾醯胺。 本發明亦有關一種醫藥組合物,係用以(a)治療選自關節 炎、癌症(與胞毒性抗癌劑協同使用)、組織潰瘍、斑退 化、再狹窄、齒骨膜疾病、大泡隹奏皮鬆懈、鞏膜炎(與 標準NSAID,S之類似物組合)及其他以母質金屬蛋白酶活性 特徵化之疾病、AIDS、敗血病、敗血性休克及其他涉及腫 瘤壞死因子(TNF)產生之疾病之病況,或(b)抑制哺乳類包 含人類之母質金屬蛋白酶或產生腫瘤壞死因子(TNF),該 組合物包括有效治療量之式i化合物或其醫藥可接受性鹽 •及醫藥可接受性載體。 1 本發明亦有關一種抑制哺乳類包含人類之(a)母質金屬蛋 白酶或(b)腫瘤壞死因子(TNF)產生之方法,包括對該哺乳 類投與有效量之式1化合物或其醫藥可接受性鹽。 本發明亦有關一種治療選自關節炎、癌症、組織潰瘍、 斑退化、再狹窄、齒骨膜疾病、大泡性表皮鬆懈、鞏膜炎 之病況芡方法,或1化合物可與標準1^8八11),8及類似物組 合使用及與胞毒性抗癌劑組合使用,及用以治療哺乳類包 含人類之其他以母質金屬蛋白酶活性特徵化之疾病、 AIDS敗血病敗血性休克及其他涉及腫瘤壞死因子 (TNF)產生 < 疾病心方法,包括對該哺乳類投與治療此等 -11 - 本紙張尺度適用中國國家標準(CNS ) (請先閱讀背面之注意事項再填寫本頁) 、1Τ άφ. 509668 A7 B7 五、發明説明(9 病況有效量之式1化合物或其醫藥可接受性職。
下列反應圖説明本發明化合物之製備。瓜A 降非另有說明 否則反應圖及後述討論中之R1,R2及Q如前述定義。 <对先閲讀背面之注意事項#填寫本頁) 訂 參. 經濟部中央標隼局員工消费合作社印製 -12 本紙張尺度適用中國國家標率(CNS〉A4規格(210X297公釐) 509668 A7 B7 五、發明説明(10
製法A 0 H0
NH; R1 R ‘ 〇r
III
V (請先閲讀背面之注-意事項再填寫本頁) ^^1.
•Q cr
Rr
HN
、1T
I I
VI 經濟部中央標準局員工消費合作社印製 -13- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 509668 A7 B7 五、發明説明(11) 反應圖1
(請先閲讀背面之注意事項再填寫本頁) 訂 經濟部中央標準局員工消費合作社印製 製法i之反應1中,以苄醇及式HX之酸(其中x較好爲仁 甲苯續酸根);於情性溶劑如苯或甲苯(以甲苯較佳)中, 處理式III之胺基酸,得式v之對應苄酯酸鹽。此反應一般 在所用溶劑之 >弗點溫度進行約1小時至:約24小時。反應進 行期間形成之水一般收集於丁-斯達克阱中。 製法I之反應2之中,藉使V與磺酸(QS02〇H)之反應性 官能基衍生物,如磺醯氣(QS〇2C1),在鹼如氫氧化鉀或三 乙胺存在下及於溶劑如二氣甲烷、四氫呋喃、二嘮烷、水 或乙腈(較好爲二嘮烷與水之混合物)中反應,而使式V化 合物轉化成對應之式VI化合物。此反應混合物係在約〇 t 至約50°C,較好在室溫攪拌約1〇分鐘至約2天,較好約6〇 -14- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 經濟部中央標隼局員工消費合作社印製 A7 '^ -----B7 五、發明説明(12 ) 分鐘。 製法i之反應3中,式ντ Φ p弓儿人w > I中間化合物經虱解而得式II中間 物0此反應係在溶劑如乙醢由 如卜产^ U G%中,在氫氣壓(較好3大氣壓) 下使用觸媒如1G%!E/活性碳進行。此反應混合物—般在室 溫攪動約30分鐘至約24小時,較好约15小時。 反應圖反應1中,藉使式m與式qs〇2〇h之磺酸反應性 耳能基衍生物(其中Q如前述定義)如確醯氯(qs〇2ci),在 鹼如氫氧化鈉或三乙胺,夂極I溶劑如四氫呋喃、二呤 ^水或乙腈(較好爲了二嗲烷與水之混合物)存在下反 應,使式III之胺基酸化合物轉化成對應之式Π化合物。此 反應混合物在約(TC至約50X:之溫度,較好在室溫下,擺摔 10分鐘至約2天,較好約60分鐘。 反應圖L之反應2中,藉由在極性溶劑如N,N _二甲基甲 醯胺中以1-(3-二甲胺基丙基卜3_乙基碳二醯亞胺及^羥 基苯并三唑處理II,再於約15分鐘至約1小時,較好約3〇 分鐘後添加羥胺至反應混合物中而使式13[之羧酸轉化成式 1之異幾B酸化合物。羥胺較好於鹼如兰乙胺存在下自鹽 悲就地產生,如羥胺鹽酸鹽。或者,可使用其中羥基以第 二丁基、苄基、晞丙基或2 -三甲基矽燒基乙醚保護之邊胺 或其鹽態之經保護衍生物取代羥胺或羥胺鹽。羥基保護基 之移除對苄基保護基係以氫解反應(5 %鈀在硫酸鋇上爲較 佳觸媒)或對第三丁基保護基係以強.酸如三、氟乙酸處理而 進行。晞丙基保護基可在觸媒氣化雙(三苯膦)鈀(11)存在 下以氫化三丁基錫及乙酸處理而移除。2 -三甲基矽烷基乙 -15- 本紙張尺度適用中國國家標準(CNS ) Λ4規格(210X 297公釐) (請先閱讀背面之注意事項再填寫本頁) •^^1.
、1T 509668 Α7 Β7 13 五、發明説明( 醚可藉與強酸如三氟乙酸反應或與氟源如三氟化硼醚化物 反應而移除。II與羥胺、羥胺鹽、羥胺之經保護衍生物或 羥胺之經保護衍生物鹽間反應亦可在(苯幷三唑_ i _基氧基) 參(二甲胺基)鱗六氟磷酸鹽及鹼如三乙胺,之存在下,在情 性洛劑如二氣甲烷中進行。此反應混合物在約〇 π至約 C之度,較好在室溫搅拌約1小時至約3天,較好約1 天。化合物II轉化成化合物〗之較佳程序係使π.〇_苄基羥 胺鹽酸鹽,在(苯并三唑-丨_基氧、、基參(二甲胺基)鳞二^ 磷酸鹽及三乙胺存在下,使甩二氯甲烷甲烷作爲溶劑而進 行。接著在室溫及3大氫氣壓下使用5%^/^鋇作爲觸媒 進行氳解而隨後移除〇-苄基保護基,得式j化合物。較 佳足落劑爲甲醇。反應時間可自約1小時至約5小時間變化 (以3 . 5小時較佳)。 於某些例中,較好藉由羥胺、羥胺鹽、羥胺之經保護衍 生物或每胺之經保護衍生物之鹽與式IV之活化酯反應,而 得式I化合物,如反應圖丨之反應3所示。此反應係於情性 落劑如N,N _二甲基甲醯胺,在約室溫皇約8〇。〇範圍内,較 好在約50 C進行約1小時至約2天。若使用羥胺之經保護衍 生物或羥胺之經保護衍生物之鹽,則如前所述進行保護基 移除。藉由以(苯并三唑基氧基)參(二甲胺基)鳞六氟 $ 鹽及驗如二乙胺,在情性溶劑如二氣甲燒中處理式Η 化合物,可得式IVi活化酯衍生物(反應圖Γ,反應4)。此 反應混合物在約〇。(:至約50Χ:,較好在室溫攪拌約1小時至 3天,較好約1天。 -16 - 本紙張尺度適用中國國家標準(CNS ) Λ4規格(210X 297公潑) (請先閲讀背面之注意事項再填寫本頁)
、1T 經濟部中央標準局員工消費合作社印製 509668 經濟部中央標準局員工消費合作社印黧 A7 五、發明説明(14 ) 本發明之酸性化合物之醫藥可接受性鹽係與鹼形成之 鹽’亦即陽離子性鹽如鹼及鹼土金屬鹽如鈉、鋰、卸、 鈣、鎂,及銨鹽,如銨、三甲銨、二乙銨及參(禮甲基)甲 按鹽。 類似之酸加成鹽,如無機酸、有機羧酸及有機磺酸如鹽 酸、甲磺酸、馬來酸,亦可提供鹼性基如吡啶基,而構成 結構之一部份。 式1化合物或其醫藥可接受尨鹽(後文簡稱爲本發明化合 物)抑制母質金屬蛋白酶或腫瘤壞死因子(丁NF)產生之能力 且隨後證明其可有效治療由母質金屬蛋白酶或腫瘤壞死因 子產生所特徵化之疾病之試管内分析測試如下。 生物分折 人類膠原酶(MMP-1)之抑制 使用下列比例之胰蛋白酶活化人類重組膠原酶;每1 〇〇 械克膠原酶使用1 〇微克胰蛋白酶。胰蛋白酶與膠原酶在室 培養1〇分鐘再添5倍過量(5〇微克/1〇微克胰蛋白酶)之大 豆胰蛋白酶抑制劑。 於二曱基亞颯中構成抑制劑之丨〇 mM原液再使用下列程 序稀釋:
10mM…>120 “Μ…>12 …>1·2 …>0·12 //M 25微升备濃度重複3次添加至96洞微生物盤之適宜洞 中,添加酵素及基質後,抑制劑之終濃度爲1 : 4稀釋。於 D1 D6洞中叹足呩性對照組(酵素,無抑制劑)及在d7_d ! 2 洞中设定芝白組(無酵素亦無抑制劑)。 膠原酶稀釋至4〇〇毫微克/毫升並添加25 ^ 1於微生物盤 -17- 本紙張尺度適用中國國家標準(CNS ) A4規格(2丨〇><297公釐) (請先閱讀背面之注*意事項再填寫本頁} •^^1. 訂 A7 ~~____ B7 五、發明説明(15 ) 足適宜洞中。分析時膠原酶終濃度爲i⑽毫微克/微升。 基質(DNP-Pro-Cha-Gly_Cys(Me)-His-Ala-Lys(NMA)-NH2) 於二甲基亞礙中作成5 mM原液,接著於分析緩衝液中稀 釋成2〇 aM。藉於微生物盤各洞中添加5〇微升基質而起 始分析,得10 " μ終濃度。 在時間0及在20分窬間隔時讀取螢光値(36〇 ηΜ激發,46〇 nm放射)。在室溫以3小時之典型分析時間進行分析。 對S白組及含膠原酶之樣品之螢光値對時間作圖(以三 次測定數値之平均値)。提供良好訊號(空白組)及在曲線 直線邵份之時間點(一般在12〇分鐘左右)選用以決定IC5〇 値。對各化合物之各濃度之零時間作爲空白組且由12〇分 鐘之數値減去該等値。數據以抑制劑濃度對%對照組 (抑制螢光値除以膠原酶單獨之螢光値χ 1〇〇)作圖。由得 到對照組之50%訊號之抑制劑濃度決定爲IC5G值。 若IC5G値小於0.03 A Μ,則抑制劑在0.3 v M,0.03 # M, 〇·〇3 "Μ及0·003 之濃度分析。 明膠酶(MMP-2WP.制柞阐 使用 Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-LyS(NMA)-NH2 基 質(10 # M)在如人類膠原酶(MMP-1)抑制作用之相同條件下 分析明膠酶活性之抑制作用。 以ΙηΜ ΑΡΜΑ(乙酸對-胺基苯基汞)在4°C活化72kD明膠 酶15小時,並稀釋以得分析中終濃度爲1〇〇亳微克/毫升。 如人類膠原酶(MMP-1)抑制作用般稀釋抑制劑得分析中終 濃度爲30 "Μ,3 "Μ,0·3 //M及0·03 "M。各濃度重複進 -18 - 本紙張尺度適用中國國家標準(CNS ) Λ4規格(210χ 297公釐) (請先閱讀背面之注意事項再填寫本頁) 訂 經濟部中央榡準局員工消費合作社印製 509668 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明(16 ) 行三次。 在0時間及在20分鐘間隔時讀取螢光値(360 nm激發,460 放射)4小時。 如人類膠原酶(MMP -1)每次抑制作用般決定ICsg。若IC50 爲小於 0.03 a Μ,則抑制劑在0·3 a Μ,0.03 // Μ,0.003 # Μ 及0.0003 αΜ之終濃度分析。 思托密利辛(Stromelysin)活性(ΜΜΡ-3)抑制作用 依據 Weingarten 及 Feder(We 丨 ngarJenL H·及 Feder,對脊椎 動物膠原酶之分光計分析,生化分析期刊(J.,Spectropho-tometric Assay for Vertebrate Collagenase,Anal. Biochem.) X42, 437-440(1985))所述之修正之分光訂分析進行思托密 利辛,活性抑制作用。硫胜肽類(thio peptolide)基度[Ac-Pro-Leu-Gly-SCH[CH2CH(CH3)2]CO-Leu-Gly-OC2H5]水解產 生可在伊門氏(Ellman‘s)試劑存在下追踪之硫醇片斷。 以胰蛋白酶使用每26微克思托密利辛1微升1〇毫克/毫升 胰蛋白酶原液之比例活化人類重組思托密利辛原 (prostromelysin)。胰蛋白酶與思托密科辛在37°C培養1 5分 鐘,再於37°C添加10微升10毫克/毫升大豆胰蛋白酶抑制劑 10分鐘,以終止騰蛋白酶活性。 於9 6 -洞微滴定盤中以總體積爲2 5 0微升之分析緩衝液 (200 mM 氯化鈉、50 mM MES 及 1 OmM 氯化躬,pH 6.0)進 行分析。活化之思托密利辛於分析緩衝液中稀釋至2 5毫微 克/毫升。伊門氏試劑(3 -羧基-4 -硝基苯二硫化物)於二甲 基甲醯胺中作成1M原液並於分析緩衝液中稀釋成5 mM, -19 - 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) (請先閲讀背面之注·意事項再填寫本頁 •^1. 訂 -線 經濟部中央標準局員工消費合作社印製 509668 A7 _____ B7 五、發明説明(1?) 而在1 mM終濃度時每洞產生5〇微升。 於一甲基亞颯中作成1〇 mM之抑制劑原液並於分析缓衝 液中連續稀釋,因而於適宜洞中添加5 〇微升後產生3 # Μ,0·3 ,0.003 αΜ&0·〇〇〇3 之終濃度。所有條件重 複三次。 胜肽基負之300 mM二甲基亞颯原液於分析缓衝液中稀釋 至15 mM並於各洞中添加5〇微升使終濃度爲3 mM基質而開 始分析。空白組由胜肽基質及伊門民試劑組成但不含酵 素。以分子裝置UVmax板讀取計在405 nm追腙產物形成。 以如膠原酶之相同方法測定IC5〇値。 MMP-13之抑制作用
以2mM ΑΡΜΑ(乙酸對-胺基苯基汞)在3 7 活化人類重 組MMP-13共1·5小時,並於分析緩衝液(5〇mM Tris,pH 7·5,200 mM氣化鈉、5 mM氣化鈣、20 "Μ氯化鋅、0.02〇/〇 bnj)中稀釋至400毫克/毫升。96洞微生物盤各洞中添加25 微升之稀釋酵素。接著藉添加抑制劑及基質使酵素於分析 中以1 : 4比例稀釋而得100毫克/毫升之分析終濃度。 於二甲基亞砜中構成10 mM抑制劑原液且接著如抑制人 類膠原酶(MMP-1)之每抑制劑稀釋流程般於分析緩衝液中 稀釋:於微生物盤中添加25微升各濃度重複三次。分析中 之終濃度爲 30 "M,3 "M,0.3 及 0.03 "M。 如人類膠原酶(MMP-1)抑制作用般製備基質(Dnp_Pr〇-
Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2)並於各洞中添加 50微升得1 〇 " Μ之分析終濃度。在〇時間及每5分鐘計1小 -20 _ 本紙張尺度中國國家標隼( CNS ) A4規格(210 X 297公釐)~ ~ (請先閱讀背面之注意事項#填寫本頁 訂 509668 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(18 ) 時内讀取螢光値(36〇 nM激發;450發射)。 陽性對照組由酵素及基質所構成但不含抑制劑,及空白 組僅由基質構成。 如人類膠原酶(MMP-1)抑制作用般測定IC50,若IC5g小於 0·03 " Μ,則抑制劑在 〇·3 " μ,0.03 γ Μ,0.003 # Μ及 0·0003 #Μ之終濃度分析。 TNF產生之抑制作用 本化合物及其醫藥可接受惟鹽抑.(TNF產生之能力及隨 後證明其可有效治療涉及TNF產生之疾病之試管内分析方 法如下: 使用單步驟之Fieoll-hypaque分離技術自抗凝集之人類血 液中單離出人類單核細胞。(2)此單核細胞於漢克斯(fjanks) 之以二價陽離子平衡之鹽溶液(HBSS)洗滌3次,並再懸浮 於含1% BBA之HBBS中成密度2 X 106/亳升。使用Abbott Cell Dyn 3500分析儀測定之微分數顯示該等製劑中單細胞 量爲全部細胞之17至24%。 180微升細胞懸浮液取入平底96洞盤(Costar)中。添加化 合物及LPS(100毫微克/毫升終濃度)而得終體積爲200微升。 所有條件進行3次。在3 7 °C及濕化之C〇2培養器中培養4小 時後移開盤並離心(在約250 xg 10分鐘)並移開上溶液及使 用R&D ELISA套組分析TNF汉。 對包含人類之哺乳類投藥以抑制母質金屬蛋白酶或腫瘤 壞死因子(TNF)產生而言,可使用多種習知途徑,包含口 服、非經腸道及局部投藥。通常’活性化合物口服或非經 -21- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) (請先閱讀背面之¾意事項I填寫本頁)
、1T 經濟部中央標準局員工消費合作社印製 509668 A7 _________B7 __ 五、發明説明(19 ) 腸道投藥劑量爲每天約〇·!至25毫克/公斤之欲治療目標物體 重’較好約0.3至5亳克/公斤。但視欲治療之目標物病沉必 要時可改變此劑量。結果,負責投藥者將可對個別目標物 決定適宜劑量。 本發明化合物可以廣泛種類之劑型投藥,通常,此種劑 型中存在治療有效之本發明化合物濃度爲自約5 0%至約7〇0/〇 重量。 就口服投藥而言,可使用食各零賦型劑如微晶纖維素、 檸檬酸納、碳酸鈣、磷酸二鈣及甘油之錠劑並與各種崩解 劑如澱粉(且較好爲玉米、馬鈐薯或樹薯澱粉)、藻朊酸及 某種複合矽酸鹽及與造粒粘合劑如聚乙晞吡咯酮、蔗糖、 明膠及阿拉伯膠組合使用。此外,對製錠目的經常利用潤 滑劑如硬脂酸鎂、月桂基硫酸鈉及滑石。類似種類之固體 組合物亦可於明膠膠囊中使用作爲填料;就此而言,較佳 之物質亦包含乳糖或牛奶糖及高分子量聚乙二醇類。當需 要水性懸浮液及/或酣酏劑口服投藥時,活性成分可與各 種甜味劑或矯味劑、著色劑或染料及若需要之乳化劑及/ 或懸浮劑,乃與稀釋劑如水、乙醇、丙二醇、甘油及其各 種類似組合一起組合使用。在動物之例中,可有利地含於 動物飼料或飲水中,濃度爲5_5〇〇〇 ppm,較好25至 p p m 〇 對非經腸道投藥(肌肉内、腹膜内、皮下及靜脈内投藥) 而。,以活性成分之無菌注射溶液較佳。可使用本發明治 療性化合物於芝麻油或花生油或於水性丙二醇中之^液: -22- 本紙ί長尺度適用中國國家標準(CNS ) A4規格(2丨0X297公釐) (請先閱讀背面之注意事項#填寫本頁)
經濟部中央標準局員工消費合作社印製 J^668 A7 〜__ B7 "- — _~~— --- — T _….."~一 1 ' 五、發明説明(20 ) 水溶液須適用調整並緩衝,較好在pH大於8,若需要,此 液體稀釋劑可先作成等張。該等水溶液適於靜脈内注射。 油性溶液適用於關節内、肌肉内及皮下注射。所有該等溶 液藉本技藝悉知之標準醫藥技術於無菌條件下完成製備。 在動物之例中,化合物可以約0.1至50毫克/公斤/天劑量靜 脈内或皮下注射,較好0.2至10毫克/公斤/天,可以單一劑 量或分3次劑量投藥。 本發明以下列實例加以説明,但不〖艮於該細節。
製備例A K 4-氟苯氣基)苯磺醯氣 在機械攪拌下,將氣磺酸(26毫升,0.392莫耳)滴加至冰 冷卻之4_氟苯氧基苯(36.9克,0.196莫耳)中。滴加完後,混 合物在室溫擾摔4小時。混合物倒入冰水中,過據收集產 物4-(4-氟苯氧基)苯橫gf氯(18.6克,33%)並於空氣中乾燥。
製備例B 4-(3-甲基丁氧基)笨磺酸鈉 含4-堯基苯磺酸(10.0克,43」亳莫耳)及氳氧化鋼(3.3 克’ 83¾莫耳)之水(40毫升)溶液與食丨-碘^-甲基丁燒 (11.3氅升’ 86.4耄莫耳)之異丙醇(60毫升)溶液混合,且 所得混合物回流加熱2天。眞空下蒸除異丙醇。過滅收集 標題化合物1〇.〇克(87%)並以異丙醇洗滌。
製備例C 生-(3 -甲基丁氧基)笨墙醯氣 含4-(3-甲基丁氧基)苯磺酸鈉(2·5克,9·4毫莫耳)、亞罐 -23- 本紙張尺度適用中國國家標準(CNS ) A4規格(2丨0X 297公釐) ---~~~ - c請先閲讀背面之注意事項香填寫本頁} 、\10 509668 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(21 ) 醯氯(10毫升)及5滴N,N-二甲基甲醯胺之混合物加熱回流5 小時。冷卻後,瘵除過量亞硫醯氣且殘留物置於乙酸乙酯 中、溶液於冰浴中冷卻並添加水。分離有機相並以水及食 鹽水洗。以硫酸鈉乾燥後,蒸除溶劑得油狀標題化合物 2.34克(95%)。
製備例D ϋ 2 —環戊基乙氣某、笑 含4·羥基苯磺酸(6·5克,?8·2.寒耳)及氫氧化鈉(2.2 克,55毫莫耳)之水(15毫升)落液與含2_(溴乙基)環戊烷 (15.0克,84.7毫莫耳)之異丙醇(40毫升)溶液混合,且所 得混合物回流加熱2天。眞空蒸除異丙醇,過濾收集標題 化合物4.7克(57%)並以異丙醇洗滌。 製備例Ε -甲基丁氧基)策錯醢1 含4-(2-%戊基乙氧基)冬>%故鈉(2.5克,86亳莫耳)、亞 續醯氯(15毫升)及數滴Ν,Ν·二甲基甲醯胺之混合物加熱回 流5小時。冷卻後,蒸除過量亞硫醯氯且殘留物置於Ζ酸 乙酯中、溶液於冰浴中冷卻並添加水。分離有機相並以水 及食鹽水洗。以硫酸鈉乾燥後,蒸除溶劑得油狀標題化合 物 2.24克(90%)。 α
製備例F 4 ’ -氟聯本基續酿氧 在攪拌及冰浴中,使氣磺酸(8.7毫升,〇 η贫瓦、、, • a 〇吴斗)滴加至 4-氟聯苯(10.2克,59毫莫耳)中。以冰冷卻繼續攪拌〇5小 -24- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) (諸先閱讀背面之注意事項奔填寫本頁) 訂 Φ. A7 ____B7 五、發明説明(22 ) ^ (請先閱讀背面之注意事項再填寫本頁 t,接著反應混合物倒至冰上。過濾收集所得沈澱並溶於 氣仿中。氣仿溶液以水及食鹽水洗滌,以硫酸鎂乾燥並濃 ’得白色固體。使所需產物4,_氟聯苯磺醯氯(43克, 27%)與4’-氟聯苯磺酸(不期望之副產物)分離,使後者自 乙酸乙酯中結晶並使剩餘物自己烷中結晶。
製備例G 生-(4-氟节氧基)苯績酸鋼 於含4-羥基苯磺酸(5.13克>,2^毫莫耳)之in氫氧化鈉 水落液(23毫升)中添加含4-氟苄基溴(3.3亳升,26.5亳莫 耳)之乙醇(2 0毫升)溶液。所得混合物加熱回流2天,冷卻 及靜置時,沈澱出白色固體。過濾收集沈澱之產物氟 τ氧基)苯磺酸鈉4 95克(74%)並以乙酸乙酯及乙醚洗滌。 訂 製備例Η 氟苄氧基)笨磺醯氯 經濟部中央標準局員工消費合作社印製 於含4-(4-氟苄氧基)苯磺酸鈉(〇·5克,164毫莫耳)之二 氣甲:fe (5毫升)漿液中添加五氣化磷(275亳克,ι·3毫莫 耳)。所得混合物加熱回流7小時。於泳浴中冷卻及以水 (15毫升)終止反應後,混合物以乙酸乙酯萃取。有機相以 食鹽水洗滌、以硫酸鈉乾燥並濃縮得白色固體之4_(4_氟苄 氧基)苯磺醯氯(130毫克,26%)。
製備例I 生-(4-氟苯氧基)苯續醯氣、 在室溫攪拌下,氣磺酸(9·7毫升,〇147莫耳)滴加至仁氯 苯氧基苯(12.6毫升,73·4毫莫耳)中。添加完成時,混合 -25 - 本紙張尺度適用中國國家標牟(CNS ) Λ4規格(210X 297公釐) 509668 Λ 7 _ Β7 五、發明説明(23 ) 物在室溫攪拌1小時接著倒入冰水中。過濾收集固體,於 空氣中乾燥並自石油醚及乙酸乙酯中再結晶’得4-(4-氯苯 氧基)苯磺醯氯(7.43克,33%)。 實例1 1-(4-甲氧苯磺醯基胺基)環戊烷毯,,,,,羥醯胺 ㈧於含1-胺基環戊烷羧酸(6·0克,46.5毫莫耳)及三乙 胺(14毫升,1〇〇毫莫耳)之二呤烷(90毫升)及水(90毫升)溶 液中添加4-甲氧基苯磺醯氯(10五克-,51.3毫莫耳)。所得 混合物在室溫攪拌4小時,以1Ν鹽酸水溶液酸化,並以乙 酸乙酯萃取兩次。合併之乙酸乙酯萃取液以食鹽水洗,以 硫酸鎂乾燥並濃縮得褐色固體,其以氯仿分散,得白色固 體之1-(4-甲氧基苯磺醯基胺基)環戊烷-1-羧酸,5·42克 (39%) 〇 經濟部中央標準局員工消費合作社印製 (Β)於含1-(4-甲氧基苯磺醯基胺基)環戊烷-1-羧酸(4.65克, 15·2毫莫耳)及三乙胺(2.5毫升,17·9毫莫耳)之二氯甲烷 (120毫升)溶液中添加(苯幷三唑-1-基氧基)參(二甲胺基) 鳞六氟磷酸鹽(7.4克,16.3毫莫耳)。所'得混合物在室溫攪 拌2.5天。蒸除溶劑且殘留物置於乙酸乙酯中。溶液依序 以0.5Ν鹽酸水溶液、水及食鹽水洗滌。以硫酸鎂乾燥後, 瘵除溶劑’得黃色固體之1-(4-甲氧基苯續醯基胺基)環戊燒 羧酸苯幷三唑-1-基酯。此溶於N,N-二甲基甲醯胺(12〇毫升) 中並於所得溶液中添加二異丙基乙胺(5·3毫升,3〇毫莫耳) 及〇-苄基羥胺鹽酸鹽(3.2克,20亳莫耳)。混合物在5(TC油 浴中加熱20小時。蒸除溶劑並添加乙酸乙酯。過濾混合物 -26 - 本紙張尺度適用中國國家標準(CNS ) Λ4規格(210x 297公釐) · ~~ 509668 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(24 ) 收集白色固體。濾液依序以〇·5Ν鹽酸水溶液、飽和碳酸氫 銅水落液及食鹽水洗滌。蒸除溶劑後,得固體,其與藉過 滤分離者合併並分散於乙酸乙酯中,得白色固體之^(‘甲 氧基苯磺醯基胺基)環戊烷-1-羧酸苄氧基醯胺,2.92克 (47%) 〇 (C)含1-(4-甲氧基苯磺醯基胺基)環戊烷-:^羧酸苄氧基醯胺 (1.50克,3.71毫莫耳)之甲醇(200毫升)溶液以5%鈀/硫酸鋇 (〇.75克)處理並在帕爾(?&1:1:)搖晃器中在3大氣壓下氫化3.5小 時。通過0 · 4 5微米耐綸濾紙移除觸媒並濃縮濾液,得白色固 體之1-(4-甲氧基苯續gf基胺基)環戊燒-1-痩酸經醯胺,1.13 克(97%),MS ·· 313(M-1)。 依實例1之類似方法使用所示試劑,製備實例2-8之標題 化合物。 實例2 1-(4 -甲氧基苯橫醯基胺基)環己燒数酸巍醯胺 1-胺基環己烷-1-羧酸;4-甲氧基苯磺醯氯。MS : 327(M-1” … 實例3 144-(4-氟苯氧基)苯磺醯基胺基1環戊烷_ 1 -羧酸羥醯胺 1-胺基環戊烷-1-羧酸;4-(4-氟苯氧基)苯磺醯氯。MS : 393(^-1)。對(:181119卩^〇58.0.25 112〇分析計算値:€54.19,11 4.93,N 7.02,實測値:C 54·20,Η 5.13,N 7.08。、 實例4 1-「4-(4 -氣冬氧基)苯績g產基胺基1環己fe-l -複酸龜酿胺 -27- 本紙張尺度適/f]中國國家標準(CNS ) Λ4規格(210X 297公釐) (請先閱讀背面之注意事項再填寫本頁)
、1T 509668 經濟部中央標準局員工消費合作社印製 Α7 Β7 i、發明説明(25 ) 1-胺基環己烷-1-羧酸;4-(4-氟苯氧基)苯磺醯氣。自氯 仿再結晶。MP : 174°C ; MS : 407(M_1)。 實例5 144-(4-氟苯氧基)苯磺醯基胺基1環丙烷-1-羧酸羥醯胺 1-胺基環丙烷-1-羧酸;4-(4-氟苯氧基)苯磺醯氯。MP ·· 184°C ·’ MS 365(M-1);對 C16H15FN2〇5S ·· C 52·45,Η 4·13,N 7·65,實測値:C 52·20,Η 4·34,Ν 7·44。 實例6 '. . · Μ4、氟聯苯基-4-磺醯基胺基)環戊烷-1 -羧酸羥醯胺 1-胺基環戊烷-1-羧酸;4、氟聯苯基磺醯氯。自氯仿再結 晶。MP 159°C ; MS : 377(Μ·1)。 實例7 1-『4-(4 -氟苯乳基)苯續酿基胺基1環丁燒-1-複酸與酿胺 1-胺基環丁:fe-Ι -瘦酸;4-(氟苯氧基)苯續醯氯。MS : 379(M-1) 〇 實例8 1 -『4-(4-氟辛氧基)苯續醯基胺基1環呙垸幾酸與醮脖 1-胺基彡哀丙燒-l-叛酸;4-(4-氟节氧基)苯續釀氣。]yjs ·· 379(M-1)。 實例9 HI基-2-(4-甲氧基苯磺贐基胺基)-2-甲i丙醯胺 ㈧含2-胺基-2-甲基丙酸苄酯鹽酸鹽(12.0克,52.2毫莫耳) 及4-甲氧基苯磺醯氣(11·9克,57.6毫莫耳)之二号燒(1〇〇 毫升)及水(1 〇 〇愛升)溶液於冰浴中冷卻。添加三乙胺(1 8 2 -28- 本紙張尺度適用中國國家標準(CNS ) Α4規格(2丨0X297公釐) (請先閱讀背面之注,意事項再填寫本頁) ^^1. 、1Τ A7 B7
(請先閱讀背面之注意事項再、填寫本頁} $升’ 0.13毫莫耳)。移開冰浴並使反應混合物在室溫攪拌 2天。眞空移除溶劑且殘留物置於乙酸乙酯及水中。分離 '^層並以乙故乙酯萃取2次。合併之有機層以飽和碳酸氫 鋼水溶液、1 N鹽酸水溶液及食鹽水洗滌。以硫酸鈉乾燥 後’蒸除溶劑得黃色油(丨9.3克)其一部份(10克)以矽膠上 層析以3 : 7乙酸乙g旨/己燒溶離,自乙酸乙酯/己燒中再結 晶後’得白色固體之2-(4-甲氧基苯磺醯基胺基)-2-甲基丙 酸苄酯,6.59克(67%)。
、1T (B)含2-(4-甲氧基苯磺醯基胺基)_2_甲基丙酸苄酯(15 克’ 4· 13亳莫耳)之乙醇(80毫升)溶液以1〇%鈀/碳(〇17克) 處理並於帕爾搖晃機中在3大氣壓下氫化1.5小時。經〇 45 微米耐倫濾紙移除觸媒並濃縮濾液,得白色固體之2_(仁甲 氧基苯磺醯基胺基)-2-甲基丙酸,1.09克(96%)。 (〇含2-(4-甲氧基苯磺醯基胺基)-2-曱基丙酸(1·〇8克, 經濟部中央標準局員工消费合作社印製 3.95耄莫耳)之二氯甲貌(12〇毫升)溶液於冰浴中冷卻。依 序添加三乙胺(2.2毫升,15.8毫莫耳)、(苯幷三唑-1-基氧 基)參(二甲胺基)鳞六氟磷酸鹽(2·6克,5·88毫莫耳)及〇-节 基羥胺鹽酸鹽(〇·95克,5.59毫莫耳):所得混合物在室溫 攪拌16小時。蒸除溶劑且殘留物置於乙酸乙酯中。溶液依 序以1Ν鹽酸水溶液、碳酸氫鈉飽和水溶液、水及食鹽水洗 滌。以硫酸鈉乾燥後,蒸除溶劑,得油狀物,在矽膠上層 析以1 : 2乙酸乙酯/己烷溶離後,得白色固體之所需產物 Ν-Τ氧基-2-(4-甲氧基苯續酿基胺基)-2-甲基丙醯胺(1.41 克,95%) 〇 (D)含N-苄氧基-2-(4-甲氧基苯磺醯基胺基)-2-甲基丙醯胺 -29- 本紙張尺度適用中國國家標準( CNS ) A4規格(210X 297公釐) 509668 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(27 ) (1.40克,3.70毫莫耳)之甲醇(8〇毫升)溶液以5%!巴/硫酸 鋇(〇·75克)處理並在帕爾搖晃器中在3大氣壓下氫化丨· 5小 時。經由0 · 4 5微米耐倫濾紙移除觸媒並濃縮濾液,得白色 固體之N -羥基- 2-(4-甲氧基苯磺醯基胺基)_2_甲基丙醯 胺,1.06 克(100%)。MP : 122-125°C。MS ·· 289(M+1):對 C11H16N2O5S分析計算値:C,45.82 ; Η,5·59 ; N,9·72 ;實剛 値:C,45·88 ; Η,5·60 ; Ν,9·69。 依實例9之類似方法使用所示試劑夢備實例1042之標題 化合物。 f例1 0 氟苯氧基)笨磺醯基胺基ι·Ν_羥基_2_甲基丙醯胺 2-胺基-2-甲基丙酸苄酯鹽酸鹽;4-(4-氟苯氧基)苯磺醯 氯。MP ·· 133-134°C,MS ·· 369(M+1),對 CMHnFNsCbS分析計算 ‘値:C,52.17 ; Η,4·65 ; N,7.60 ;實測値:C,52.21 ; Η,4.83 ; Ν,7.80。 實例1 1 Μι輕基-2-甲基甲基丁氣基)苯磺醯基胺基1丙醯胺 ~^...................... ~~ 胺基-2-甲基丙酸苄酯鹽酸鹽;4-(3-甲基丁氧基)-苯磺醯 氯,自乙酸乙酯/己烷再結晶,MP 126.5-128X:。MS : 343(M-1);對 Ci5H24N2〇5S分析計算値:c,52·31 ; Η,7.02 ; N,8.31 ;實 測値:C,52.30 ; Η,7.07 ; Ν,8J6。 實例1 2 2-[4-(2-環戊基乙氧基)笨確醯基胺基甲基丙醯胺 2-胺基-2-甲基丙酸苄酯鹽酸鹽;4-(2-環戊基乙氧基)苯磺 醯氯,自乙酸乙酯/己烷中再結晶。MP 126-127°C。MS : ___ -30- 本紙張尺度適用中國國家標準(CNS ) A4規格(2丨0'乂297公藶) (請先閱讀背面之注意事項再填寫本頁) 、11 線一 509668 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(28 ) 369(M-1),對 C17H26N2O5S分析計算値:c,55.12 ; Η,7.07 ; N, 7.56 ;實測値:C,55.46 ; Η,7.09 ; Ν,7.38。 實例1 3 Μι·象.基_2-『5·吡淀_-2·基嘍兮^磺醯基胺基)丙醯胺 (A)於含2-胺基-2-甲基丙酸(2.0克,19·4毫莫耳)之1N氫氧 化鈉水溶液(45毫升)及二嘮烷(45毫升)溶液中添加5_吡啶_ 2-基違吩-2-磺醯氣(8.41克,32·4亳莫耳)。所得混合物在 室溫攪拌1 6小時。再於反應混合物中添加i Ν氫氧化鈉水 落液(45亳升),再以乙醚萃取。丟棄有機萃取物。水層以 1Ν鹽酸溶液酸化並以乙酸乙酯萃取,乙酸乙酯部份以食鹽 水洗滌’以硫酸鎂乾燥並濃縮,得白色固體之甲基·2_ (5-吡咬>2-基嘍吩-2-磺醯基胺基)丙酸(2.18克,34%)。 ⑽於含2-甲基-2-( 5-吡啶-2-基噻吩-2-磺醯基胺基)丙酸 (1·60克,4·91亳莫耳)之二氯甲烷(16〇毫升)溶液中,添加 三乙胺(2·3亳升,16.5毫莫耳)、(苯幷三唑基氧基)參 (二甲胺基)鳞六氟磷酸鹽(2.4克,5.41毫莫耳)及〇-(2-三 甲基石夕燒基乙基)藉胺鹽酸鹽(〇·92克,5.41毫莫耳)。所得 混合物在室溫攪拌16小時。蒸除溶劑且殘留物置於乙酸乙 酉旨中。溶液以水、飽和碳酸氫鈉水溶液及食鹽水洗滌。以 硫酸鎂乾燥後,蒸除溶劑得白色泡沫,於矽膠上層析以 3 ·· 2乙酸乙酯/己烷溶離單離得所需產物2_甲基_2_(5_吡啶_ 2-基噻吩-2-磺醯基胺基(2-三甲基矽烷基乙氧基)丙 醯胺之白色固體(2 2 0毫克,1 〇 % )。 、 (0 2-甲基-2-(5-吡啶-2-基噻吩-2-磺醯基胺基)-N-(2-三甲 基石夕基乙氧基)丙醯胺(8〇亳克,〇18毫莫耳)溶於三氟乙 _____^ ·31- 本紙張尺度適财( CNS) A4^^( 21Qx 297公楚) (請先閱讀背面之注-ώ·思事唷I填寫本頁)
、1T 線麵 509668 A7 —- __ B7____ 五、發明説明(29 ) 酸中且所得溶液在室溫攪拌1 6小時。眞空下蒸除三氟乙 酸’以甲醇追洗,得黃色油之N-羥基-2 -甲基-2-(5-吡啶-2-基嘍吩-2-磺醯基胺基)丙酼胺(60毫克,97%),其自乙 醇中結晶。MP 165-166〇C,MS : 342(M+1) 0 依實例13之類似方法使用所示試劑,製備實例14-15之標 題化合物。 實例1 4 -2-基嘧吩-2-磺醯基胺基)環戊烷-1-羧酸羥醯胺 1-胺基彡衣戊:t克-1-竣酸;5 -ρ比淀-2 -基0塞吩-2 -橫酿氯。 MS : 368(M+1) 〇 實例1 5 氣苯氧基)苯磺醯基胺基1環丙烷-1 -羧酸羥醯胺 1-胺基環丙烷-1-羧酸;4-(4-氯苯氧基)苯磺醯氯。MS : 381(M-1) 〇 (請先閱讀背面之注·意事項-¾填寫本頁) 、τ 經濟部中央標準局員工消費合作社印製 -32- 本紙張尺度適用中國國家標準(CNS ) Λ4規格(210X297公釐)
Claims (1)
- 509668 第8710Π96號專利申請案 A8 中文申請專利範圍修正本(9丄專2月)_思 .................. . D8X、申請專利範圍 公告本一種下式之化合物: 〇 R1 Η 0-Ν II I C-C- H R2或其醫藥上可接受鹽 其中 Rl&R2各獨立選自(Ci-CO烷基、或R1與R2可合而形 成(c^c:6)環烷基或苯并稠合之(C3-C6)環烷基環,其中 1個奴原子選擇性地被氧原子取代; Q為苯基、聯苯基、苯氧苯基、苯(c \ _ c 6)烷氧基 苯基、(C 3 - 6)環烷(c i - C 4 )烷氧基苯基、以及(5員或_ 6員)雜環(5員或-6員)雜環基,其中5員雜環係選自噻 吩、呋喃、與吡咯,而6員雜環則含有氮原子。 2 ·根據申請專利範圍第丨項之化合物,其中該化合物係選 自下列組群: 1-[4-(4-氟苯氧基)苯磺醯基胺基]環丙烷_丨_羧酸羥醯 胺; 1-[4-(4-氯苯氧基)苯磺醯基胺基]環丙烷_ι_羧酸羥醯 胺; 1-[4-(4-氟苯氧基)苯磺醯基胺基]環丁烷羧酸羥醯 胺; 1 [4-(4-氯苯氧基)苯磺醯基胺基]環丁烷“ί —複酸輕醯 胺; 本紙張尺巧财目S家標準(CNS)_ _:規格(2iG X 297公釐)-----裝50966^ 8 8 8 8 AB c D 六、申請專利範圍 1-[4-(4-氟苯氧基)苯磺醯基胺基]環戊烷-1-羧酸羥醯 胺; 1- [4-(4-氟苯氧基)苯磺醯基胺基]環己烷-1-羧酸羥醯 胺; 2- [4-(4-氟苯氧基)苯磺醯基胺基]-N-羥基-2-甲基丙醯 胺; 2-[4-(4-氯苯氧基)苯磺醯基胺基]-N-羥基-2-甲基丙醯 胺; N-羥基-2-甲基-2-(5-吡啶-2-基嘧吩-2-磺醯基胺基)丙 醯胺; 1 -(5-吡啶-2-基噻吩-2-磺醯基胺基)環戊烷-1 -羧酸羥 醯胺; 1-(4’-氟聯苯基-4-磺醯基胺基)環丙烷-1-羧酸羥醯 胺; 1 _(4’-氟聯苯基-4-磺醯基胺基)環丁烷-1-羧酸羥醯 胺; 1- (4’-氟聯苯基-4-磺醯基胺基)環戊烷-1-羧酸羥醯 胺; 2- [4-(2-環戊基乙氧基)苯磺醯基胺基]-N-羥基-2-甲基丙 醯胺。 3 · —種治療以母質金屬蛋白酶活性特徵化疾病之醫藥組合物,其 與標準NSAID'S及類似物,以及胞毒性抗癌劑組合,該組合 物包括有效治療量之根據申請專利範圍第1項之化合物作為活 性成份或其醫藥上可接受鹽及醫藥上可接受載體。 -2- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)六、申請專利範圍 ~ 一 4. 一種治療涉及腫瘤壞死因子(Tnf)產生的疾病之醫藥醫組合 物,其與標準NSAID,S及類似物,以及胞毒性抗癌劑組合, 藏組合物包括有效治療量之根據申請專利範圍第1項之化合物 作為活性成份或其醫藥上可接受鹽及醫藥上可接受載體。 5·根據申請專利範圍第3項之醫藥組合物,其中該疾病係選自下 列所組成之群組:關節炎、癌症、組織潰瘍、斑退化、再狹 窄、齒骨膜疾病、大泡性表皮鬆懈、鞏膜炎。 | 6.根據申請專利範圍第4項之醫藥組合物,其中該疾病係選自下 列所組成之群組:AIDS、敗血病、休克。 7.—種用於抑制哺乳類(含人類)中母質金屬蛋白酶活性之醫藥組 合物,包括有效抑制量之根據申請專利範園第丨項之化合物作 為活性成份及其醫藥上可接受載體。 8·—種用於抑制哺乳類(含人類)中腫瘤壞死因子(TNF)產生之醫 藥醫組合物,包括有效抑制量之根據申請專利範圍第丨項之化 合物作為活性成份及其醫藥上可接受載體。 本紙银尺度適用中國國家榡準(CNS) A4規格(210X297公釐)
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