TW381079B - Biaryl acetylenes as inhibitors of matrix metalloproteases - Google Patents
Biaryl acetylenes as inhibitors of matrix metalloproteases Download PDFInfo
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Description
第861 〇6283號專利申請案 中文説明書修正頁(87年11月)五、發明説明(i ) A7 B7 87. ίί.[ 經濟部中央標準局員工消費合作社印?私 _背景 發明範圍 本發明係關於酶抑制南i 甘❻ ^ ’更特足地説’是關於用於抑制 基免金屬蛋白酶的新穎的本、 、)0 W方基乙炔的化合物或其衍生 物。 相關技藝説明 基θ至屬蛋白酶(a_k’a.基質金屬内切蛋白酶,或稱MMps) 是鋅内切蛋白酶系,包括,但不限於,間質膠原酶 ah.MMPM),溶基質素(a k a蛋白聚糖酶,蠢素職⑻ 或MMP :) ’明膠酶A(a.k‘a. 72 kDa_明膠酶或:ΜΜρ·2)及明 膠酶B(a.k_a. 9:> kDa-明膠酶或ΜΜρ_9)。此等MMps係由各 種細胞,包括纖维細胞及敕骨細胞,與稱作打^11>5(金屬 白酶的組織抑制劑)的天然蛋白質性質的抑制劑一起分泌來。 所有此等MMPs都能破壞關節軟骨或基底膜的結缔組織叫 分。每一種MMP都是以非活性的酶原形式分y出,在發揮 其蛋白質分解活性前必須先行裂解。除了其基;質破壞作 外,有些MMP,如MMP-3,曾被指出關連於作爲其〜 MMPs(如MMP-1及MMP-9)的活體内激活劑(It〇, et al,Arch Biochem. Biophys. 267., 21 1, 1988 ; Ogata, et al., J. Biol Chem. 2 67, 358 1,1 992) 3所以過量的MMP-3可i激發一連串 的蛋白質分解活動。因之,特定的MMP·3抑制_應能限希 其他不直接受此抑制劑作用的MMPs的活動。 也有人報告,MMP·3能分裂,因而使其他蛋白酶,如召 蛋 出 成 他 ---------< ’衣-- (讀先閱讀背面之注意事項再填寫本頁) 訂 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 第861 〇6283號專利申請案 中文説明書修正頁(87年11月)五、發明説明(i ) A7 B7 87. ίί.[ 經濟部中央標準局員工消費合作社印?私 _背景 發明範圍 本發明係關於酶抑制南i 甘❻ ^ ’更特足地説’是關於用於抑制 基免金屬蛋白酶的新穎的本、 、)0 W方基乙炔的化合物或其衍生 物。 相關技藝説明 基θ至屬蛋白酶(a_k’a.基質金屬内切蛋白酶,或稱MMps) 是鋅内切蛋白酶系,包括,但不限於,間質膠原酶 ah.MMPM),溶基質素(a k a蛋白聚糖酶,蠢素職⑻ 或MMP :) ’明膠酶A(a.k‘a. 72 kDa_明膠酶或:ΜΜρ·2)及明 膠酶B(a.k_a. 9:> kDa-明膠酶或ΜΜρ_9)。此等MMps係由各 種細胞,包括纖维細胞及敕骨細胞,與稱作打^11>5(金屬 白酶的組織抑制劑)的天然蛋白質性質的抑制劑一起分泌來。 所有此等MMPs都能破壞關節軟骨或基底膜的結缔組織叫 分。每一種MMP都是以非活性的酶原形式分y出,在發揮 其蛋白質分解活性前必須先行裂解。除了其基;質破壞作 外,有些MMP,如MMP-3,曾被指出關連於作爲其〜 MMPs(如MMP-1及MMP-9)的活體内激活劑(It〇, et al,Arch Biochem. Biophys. 267., 21 1, 1988 ; Ogata, et al., J. Biol Chem. 2 67, 358 1,1 992) 3所以過量的MMP-3可i激發一連串 的蛋白質分解活動。因之,特定的MMP·3抑制_應能限希 其他不直接受此抑制劑作用的MMPs的活動。 也有人報告,MMP·3能分裂,因而使其他蛋白酶,如召 蛋 出 成 他 ---------< ’衣-- (讀先閱讀背面之注意事項再填寫本頁) 訂 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 第S61 〇6283號專利申請案 中文説明書修正頁(S7年11月) A7 B7Patent Application No. 861 〇6283 Revised page of Chinese specification (November 1987) V. Description of invention (i) A7 B7 87. ίί. [Printed by Staff Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs? BACKGROUND OF THE INVENTION The present invention relates to the enzyme inhibitory glycosaminoglycan ^ 'more specifically' is a novel compound, or its derivative, or a derivative thereof for the inhibition of metalloproteinases. . Relevant technical descriptions are based on θ to genus proteases (a_k'a. Matrix metalloprotease, or MMps) are zinc endoprotease series, including, but not limited to, interstitial collagenase ah.MMPM), matrix soluble (aka Proteoglycans, stupins, or MMPs :) 'Gelatinase A (ak'a. 72 kDa_gelatinase or: Μρ · 2) and gelatinase B (a.k_a. 9:> kDa-gelatinase Or MMρ_9). These MMps are secreted by various cells, including fibroblasts and sacrum cells, together with natural proteinaceous inhibitors called ^ 11 > 5 (tissue inhibitor of metalloproteinase). All these MMPs can damage the articular cartilage or connective tissue of the basement membrane. Each MMP is separated in the form of an inactive zymogen and must be cleaved before exerting its proteolytic activity. In addition to its basic damage, some MMPs, such as MMP-3, have been shown to be linked to in vivo activators (It〇, et al, Arch Biochem) as their ~ MMPs (such as MMP-1 and MMP-9). Biophys. 267., 21 1, 1988; Ogata, et al., J. Biol Chem. 2 67, 358 1, 1, 992) 3 So excess MMP-3 can stimulate a series of proteolytic activities. Therefore, specific MMP · 3 inhibition should limit the activity of other MMPs that are not directly affected by this inhibitor. It has also been reported that MMP · 3 can split, so that other proteases, such as calling eggs out of him --------- < 'yi-(read the precautions on the back before filling this page) Order This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) No. 861 〇6283 patent application Chinese amendment page (November 87) V. Description of the invention (i) A7 B7 87. ίί. [ Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs? BACKGROUND OF THE INVENTION The present invention relates to the enzyme inhibitory glycosaminoglycan ^ 'more specifically' is a novel compound, or its derivative, or a derivative thereof for the inhibition of metalloproteinases. . Relevant technical descriptions are based on θ to genus proteases (a_k'a. Matrix metalloprotease, or MMps) are zinc endoprotease series, including, but not limited to, interstitial collagenase ah.MMPM), matrix lysin (aka Proteoglycans, glucosamine or MMP :) 'Gelatinase A (ak'a. 72 kDa_gelatinase or: Μρ · 2) and gelatinase B (a.k_a. 9: > kDa-gelatinase Or MMρ_9). These MMps are secreted by various cells, including fibroblasts and sacrum cells, together with natural proteinaceous inhibitors called ^ 11 > 5 (tissue inhibitor of metalloproteinase). All these MMPs can damage the articular cartilage or connective tissue of the basement membrane. Each MMP is separated in the form of an inactive zymogen and must be cleaved before exerting its proteolytic activity. In addition to its basic damage, some MMPs, such as MMP-3, have been shown to be linked to in vivo activators (It〇, et al, Arch Biochem) as their ~ MMPs (such as MMP-1 and MMP-9). Biophys. 267., 21 1, 1988; Ogata, et al., J. Biol Chem. 2 67, 358 1, 1, 992) 3 So excess MMP-3 can stimulate a series of proteolytic activities. Therefore, specific MMP · 3 inhibition should limit the activity of other MMPs that are not directly affected by this inhibitor. It has also been reported that MMP · 3 can split, so that other proteases, such as calling eggs out of him --------- < 'yi-(read the precautions on the back before filling this page) Order This paper size applies Chinese National Standard (CNS) A4 specification (210X297mm) No. S61 〇6283 Patent Application Chinese Manual Correction Page (November S7) A7 B7
五、發明説明( 18V. Description of the invention (18
R2 0 RJ { Η I Ί "N-C^N—R R2 Ο l II n ~N-C-〇R3 Ό (Rl)u R2 > , N-R2 以及對應的雜芳基,其中含芳基的R7基團 土) 個N,0,或S雜原子。於.r7基團中 S ; R1之定義如上述’^0,1,或2,先決 是 /~^CR)U —N Y V_/ 或 ..R2 N R1 R2 0 —N-C-R2R2 0 RJ {Η I Ί " NC ^ N—R R2 Ο l II n ~ NC-〇R3 Ό (Rl) u R2 >, N-R2 and the corresponding heteroaryl group, which contains the R7 group of aryl group Soil) N, 0, or S heteroatoms. The definition of S; R1 in the .r7 group is as described above, '^ 0, 1, or 2; the prerequisite is / ~ ^ CR) U —N Y V_ / or ..R2 N R1 R2 0 —N-C-R2
含4 - 9個碳及 ,Y代表0或 條件是在R7 及A單位是苯基,B單位是伸基,m是1,[ι是2及t爲0 時,則X是1或2。 1 3)-(CH2)vZR8,其中v是1至4的整數,:ζ代表_ -S(O)- ’ -S02- ’或-0-,及R8係選自包括1至12個碳的 燒基,6至10個竣的芳基,含4-9個後及至少一個N, (請先閱讀背面之注意事項再填寫本頁) 訂 j 經濟部中央標李局員工消費合作社印製 0,或S雜原子的雜芳基;芳基烷基,其中芳 1 2個碳而烷基部分含1 - 4個碳;雜芳基烷基 基部分含6 - 1 2個碳及至少一個N,0,或S雜原子,而烷 基部分含1 - 4個碳;-C(0)R9,其中R9代表2至6個碳的烷 基,芳基爲6至10個碳的,含4-9個碳及至 ◦,或S雜原子的雜芳基;及芳基烷基,其中 6-10個破或是含4-9個碳及至少一個N,0, 基郅分含6 -,其中雜芳 少一個N, 芳基部分含 或S雜原子 的雜芳基,而烷基部分含丨至4個碳,先決條件是在R8是- -21 本紙張尺度適用中國國家標隼(CNS ) A4規格(210X297公瘦〉 五、發明説明(2 ) A7 B7 性蛋白酶,的内生性抑制劑不被活化(Winyard, et al.,;FEBS Letts, 1, 91, 1"1)。是以MMP-3抑制劑土藉其改變内 生性抑制劑含量而影響其他破壞性蛋白酶的活性 一般認爲有些疾病係由過量的或不需要的基質破壞性金 屬蛋白酶活性所引起,或由MMPs與TIMPs的比如不平衡所 引起。此等疾病包括:a)骨性關節炎(Woessner, et al·, J. Biol. Chem., 259(6). 3633, 1984 ; Phadke Rheumatol. 10, 852, 1983),b)類風濕關節炎(M Biochim. Biophys. Acta 695. 117,1983 ; Wo Arthritis Rheum. 20., 1231, 1977 ; Gravallese, et Rheum. 11,1076, 1991),c)化膿性關節炎(Wii et al., J. ullins, et al., olley, et al., al., Arthritis liams, et al.,Contains 4 to 9 carbons and Y represents 0 or with the proviso that when R7 and A are phenyl, B is extrinsic, m is 1, [ι is 2 and t is 0, then X is 1 or 2. 1 3)-(CH2) vZR8, where v is an integer from 1 to 4, ζ represents _ -S (O)-'-S02-' or -0, and R8 is selected from the group consisting of 1 to 12 carbons Burning base, 6 to 10 complete aryl groups, containing 4-9 after and at least one N, (Please read the notes on the back before filling this page) Order j Printed by the Central Consumer Bureau of the Ministry of Economy Staff Consumer Cooperatives 0 , Or S heteroatom heteroaryl; arylalkyl, where aryl is 12 carbons and the alkyl portion contains 1-4 carbons; heteroarylalkyl group contains 6-12 carbons and at least one N , 0, or S heteroatoms, and the alkyl portion contains 1-4 carbons; -C (0) R9, where R9 represents an alkyl group of 2 to 6 carbons, and the aryl group is 6 to 10 carbons, containing 4 -9 carbons and heteroaryl groups up to ◦, or S heteroatoms; and arylalkyl groups, of which 6-10 are broken or contain 4-9 carbons and at least one N, 0, the radical containing 6-, Wherein the heteroaryl has one N, the aryl part contains a heteroaryl group with S or heteroatoms, and the alkyl part contains 丨 to 4 carbons, the prerequisite is that R8 is--21 This paper applies the Chinese national standard (CNS) ) A4 specification (210X297 male thin) V. Description of the invention (2) A7 B7 protease, endogenous The formulation is not activated (Winyard, et al., FEBS Letts, 1, 91, 1 " 1). MMP-3 inhibitors are used to change the content of endogenous inhibitors and affect the activity of other destructive proteases. Some diseases are caused by excessive or unwanted matrix destructive metalloproteinase activity, or caused by, for example, imbalance of MMPs and TIMPs. These diseases include: a) Osteoarthritis (Woessner, et al. ,, J. Biol. Chem., 259 (6). 3633, 1984; Phadke Rheumatol. 10, 852, 1983), b) Rheumatoid arthritis (M Biochim. Biophys. Acta 695. 117, 1983; Wo Arthritis Rheum. 20 ., 1231, 1977; Gravallese, et Rheum. 11, 1076, 1991), c) septic arthritis (Wii et al., J. ullins, et al., Olley, et al., Al., Arthritis liams, et al.,
Arthritis Rheum. 11, 533,1990),d)腫瘤轉移(Reich, et al.,Arthritis Rheum. 11, 533, 1990), d) tumor metastasis (Reich, et al.,
Cancer Res., 48., 3307, 1988, and Matrisian, et al., Proc.Cancer Res., 48., 3307, 1988, and Matrisian, et al., Proc.
Nat'l. Acad. Sci., USA 83. 9413, 1986) ’ e)牙周病(Overall, et al., J. Periodontal Res. 22., 81, 1987),f)角膜漬 al., Invest. Opthalmol ; Vis. Sci. 3_0, 1569, 1989 瘍·(Burns,et hf)蛋白尿 (Baricos, et al., Biochem. J. 254. 609,1988),h)由粥狀動脈 ------------f I裝-- (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 硬化斑破裂引起的冠狀動脈栓塞(Henney, Mat'l ; . Acad, Sci. USA U, 8154-8158, 1991) > et al., Proc. i)動脈瘤性 主動脈疾病(Vine, et al.,Clin· Sci, 81, 233,1991),.j)生育 控制(Woessner, et al., Steroids 54., 491, 1989), k)營養不良 性表皮鬆弛大疱(Kronberger,et al·, Invest. E,ermatol_ 79, 208, 1982),及1)關節受傷後發生的退行性軟骨 致發炎反應的疾病,由MMP活性引起的骨質減 損失,m)導 少,η)顧頷 -5 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ297公釐) 罘跖1〇6283號專利申請案 中文説明書修正頁(87年11月) A7 B7 五'發明説明( 19Nat'l. Acad. Sci., USA 83. 9413, 1986) 'e) Periodontal disease (Overall, et al., J. Periodontal Res. 22., 81, 1987), f) Corneal stains al., Invest Opthalmol; Vis. Sci. 3_0, 1569, 1989 Urine (Burns, et hf) proteinuria (Baricos, et al., Biochem. J. 254.609, 1988), h) from the atheromatous artery ---- -------- f I pack-(Please read the precautions on the back before filling out this page) Order printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs to print coronary emboli caused by ruptured sclerosis (Henney, Mat ' l;. Acad, Sci. USA U, 8154-8158, 1991) > et al., Proc. i) aneurysmal aortic disease (Vine, et al., Clin · Sci, 81, 233, 1991), .j) fertility control (Woessner, et al., Steroids 54., 491, 1989), k) malnourished epidermal sagging bullae (Kronberger, et al ·, Invest. E, ermatol_ 79, 208, 1982), and 1) Diseases caused by degenerative cartilage inflammation after joint injury, bone loss caused by MMP activity, m) less conduction, η) Gu 本 -5 This paper applies Chinese National Standard (CNS) A4 specification (210 × 297) Mm) 罘 跖 106283 Chinese Patent Application text modification page specification (87 November) A7 B7 Five-described invention (19
C(0)R9時,z 是-S-或;在 Z 是-〇_ 時 (CqH2q〇)rR5,及在A單位是苯基,B單位是 1,η是2,及v是0時,則X是1或2 ;及 14)-(CH2)wSiR103,其中w是1至3的整數,又ί0代表ί至2 個唉的娱:基。 此外,任何Τ或R6基團的芳基或雜芳基部分可視需要帶 有達二個的取代基,此等取代基選自包括: -(CH2)yC(Ru)(R12)〇H , -(CH2)yORn , -(CH2)ySRn , -(CH2)yS(0)Rn » -(CH2)yS(0)2Ru » -(CH2)yi502N(Rn) '(C H 2 )yN(R'*)2 » -(C H2 )yN(R'!)C0R12 ? -〇C(R R8也可是-ί申苯基,m是 )2〇_ 2 7 其中 (請先閱讀背面之注意事項再填寫本頁)When C (0) R9, z is -S- or; when Z is -〇_ (CqH2q〇) rR5, and when A is phenyl, B is 1, η is 2, and v is 0, Then X is 1 or 2; and 14)-(CH2) wSiR103, where w is an integer from 1 to 3, and ί0 represents 2 to 2 唉 entertainment: base. In addition, the aryl or heteroaryl portion of any T or R6 group may carry up to two substituents as required. These substituents are selected from the group consisting of:-(CH2) yC (Ru) (R12) OH,-( CH2) yORn,-(CH2) ySRn,-(CH2) yS (0) Rn »-(CH2) yS (0) 2Ru»-(CH2) yi502N (Rn) '(CH 2) yN (R' *) 2 »-(C H2) yN (R '!) C0R12? -〇C (R R8 can also be -ί phenyl, m is) 2〇_ 2 7 Of which (Please read the precautions on the back before filling this page)
個氧原子都是聯於芳基環上,_(CH2;)yC〇R 11 -(CH2)yCON(R")2,-(CH2)yC02R",-(CH2)yd 素,-CH0,-CF3,-N〇2,-CN,及-R12,其中 y 代衣H或1 - 4個碳的娱》基;及R 1 2代表1 _ 4個竣的燒基 於通式(L)中’ G代表-P〇3H2,-M, 11 COR11,-卣 是0-4 ; R11All oxygen atoms are linked to the aryl ring, _ (CH2;) yC〇R 11-(CH2) yCON (R ") 2,-(CH2) yC02R ",-(CH2) yd element, -CH0,- CF3, -N02, -CN, and -R12, where y substitutes H or 1 to 4 carbon atoms; and R 1 2 represents 1 to 4 carbon atoms based on the general formula (L) ' G represents -P〇3H2, -M, 11 COR11,-卣 is 0-4; R11
?t(l —C-NjM? t (l —C-NjM
訂 經濟部中央標準局員工消費合作社印製 及R13代表 側鏈= 也在本發明 且幸文佳是幾 其中 M 代表- CO2H,-CON(Rn)2,或_c〇2R12 : 天然出現於胺基酸上的1 9個非環形側鏈的任— 此等屬於通式(L)化合物的醫藥上可接受的璧 範圍内= G單位最佳是於D單位的召碳上聯於e單位, 22- 本紙法尺度適用中國國家標準(CNS ) A4規格(210X 297公缝 五、發明説明(3 A7 B7 ry, et al., J. 經濟部中央標準局員工消費合作社印製Ordered by the Central Standards Bureau of the Ministry of Economic Affairs, printed by the employee consumer cooperative and the R13 representative side chain = is also in the present invention and Xing Wenjia is a few of which M represents-CO2H, -CON (Rn) 2, or _c〇2R12: naturally occurring in the amine group Any of the 19 non-cyclic side chains on the acid-these are within the pharmaceutically acceptable range of the compound of general formula (L) = G units are best linked to e units on the carbon of D units, 22 -The size of the paper method is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 5. Description of the invention (3 A7 B7 ry, et al., J. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs
關節疾病,Ο)神經系統脱髓鞘疾病(chan Neurochem. 50., 688, 1988)。 關節疾病尤需新的治療。骨性關節炎(OA) 炎(RA)及化膿性關節炎的初發性官能病變即+關節軟骨損 失因而失去關節功能所致。雖則非類固醇藥物(NSAIDs)能 控制疼痛和腫脹,現在尚沒有明顯的醫藥劑能預防或減緩 此種軟骨損失。此等疾病的最後結果是完全失去關節功 能,只能藉關節置換手術治療。MMP抑制劑期望能停止或 倒轉軟骨損失的進行,避免或延緩外科干擾。 在腫瘤轉移過程的幾個階段中蛋白酶是重要因素。於此 過程中,基底膜結構性蛋白質的蛋白酶分解降解使原發部 位的腫瘤得以擴散,由原發部位侵入第二部位 瘤所致的血管生成是腫瘤生長所需,也有賴於 織的再塑。以各種類型的蛋白酶作交叉感染實驗,顯示基 質金屬蛋白酶,特別是明膠酶A及B (分別Λ MMP - 2及 ΜΜΡ-9)在此過程中扮演主要角色。有關此方面的參考見: Mullins, et al., Biochim. Biophys. Acta 695. 177 et al., Eur. Respir. J. 7, 2062, 1994 : Birkedal-H Crit. Rev. Oral Biol. Med.生,197, 1993。 此外,實驗(Moses, et al., Science 248, 140_, 1990)還顯 示,以天然的基質金屬蛋白酶抑制劑TIMP-2( 對細胞外基質降解的抑制可停止癌的生長(DeC 類風濕關節 。而且,腫 蛋白酶解組 ,1983 ; Ray. ansen, et al., -種蛋白質) lerck, et al.,Joint disease, 0) Nervous system demyelination disease (chan Neurochem. 50., 688, 1988). New treatments are particularly needed for joint diseases. The primary functional lesion of osteoarthritis (OA) inflammation (RA) and septic arthritis is + joint cartilage loss and loss of joint function. Although nonsteroidal drugs (NSAIDs) can control pain and swelling, there are no obvious medical agents that can prevent or slow this type of cartilage loss. The end result of these diseases is total loss of joint function and can only be treated with joint replacement surgery. MMP inhibitors are expected to stop or reverse cartilage loss and avoid or delay surgical intervention. Proteases are important factors in several stages of the tumor metastasis process. In this process, the proteolytic degradation of structural proteins of the basement membrane allows the tumor at the primary site to spread. The angiogenesis caused by the invasion of the primary site into the tumor at the second site is required for tumor growth and also depends on remodeling . Cross-infection experiments with various types of proteases have shown that matrix metalloproteinases, especially gelatinases A and B (Λ MMP-2 and MMP-9, respectively) play a major role in this process. For reference in this regard, see: Mullins, et al., Biochim. Biophys. Acta 695. 177 et al., Eur. Respir. J. 7, 2062, 1994: Birkedal-H Crit. Rev. Oral Biol. Med. , 197, 1993. In addition, experiments (Moses, et al., Science 248, 140_, 1990) have shown that the natural matrix metalloproteinase inhibitor TIMP-2 (inhibition of extracellular matrix degradation can stop cancer growth (DeC rheumatoid joints). Moreover, the proteolytic group, 1983; Ray. Ansen, et al.,-Proteins) Lerck, et al.,
Cancer Res. 52, 701, 1992),並且顯示,TIMP-2抑制腫瘤引 起的血管生成。參考:DeClerck, et al., Ann. N. Y. Acad. Sci. -1 I ll u Ί - —1- - - i 1^11 n I (請先閲讀背面之注意事項再填寫本頁) 訂 -6 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 第86106283號專利申請案 中文說明書修正頁(87年11月) A7 B7 五 '發明説明(24 ) 芳基部分含6-1〇個碳;6-10個碳的芳惠 _C02r3 ; _CON(R2)2 ; -(CH2)tR7,其中丈是 數;及-(CH2)vZR8,其中V是〇或;1_3的整數 或-0-,R1,R7,及R8之定義如前述。 較佳的通式(L)化合物,其中—或多個取代 及非螺旋壤之形成’有如下構造之E單位. COR/ ; 〕或1 - 4的整 而Z代表-S 基R6基團灰 I-Cancer Res. 52, 701, 1992) and showed that TIMP-2 inhibits tumor-induced angiogenesis. Reference: DeClerck, et al., Ann. NY Acad. Sci. -1 I ll u Ί-—1---i 1 ^ 11 n I (Please read the notes on the back before filling this page) Order -6 copies Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) No. 86106283 Patent Application Chinese Specification Correction Sheet (November 87) A7 B7 Five 'Invention Description (24) Aromatic part contains 6-10 Carbon; 6-10 carbons Fanghui_C02r3; _CON (R2) 2;-(CH2) tR7, where Zhang is a number; and-(CH2) vZR8, where V is 0 or; an integer of 1-3 or -0, R1, R7, and R8 are as defined above. Preferred compounds of the general formula (L), in which-or more substituted and non-spiral soils are formed E units having the following structure. COR /;] or 1-4 integers and Z represents -S group R6 group ash I-
(Hj^Rs.C) \ (H (CRe.H,Jd- -(CRe6H,J. I- (H^R%C) * \ tH^RebC>-(Hj ^ Rs.C) \ (H (CRe.H, Jd--(CRe6H, J. I- (H ^ R% C) * \ tH ^ RebC >-
(CR(CR
-iCR'K 、(C,H 以 / i七) 經濟部中央標準局員工消費合作社印製 (,CRe.H2_Jd一I \ -—其中 a,b,c,d,(c + d),e,g,i,k,R U,及R14之定義如前述。 取代基T基團較佳是含乙炔的基,有如下的g式 R3〇(CH2)n.C ^C- 此處η,是1 - 4,R30係選自包括:|"10-,1^0-CH3C02-,CH3CH2OC〇2-,H02C-,〇HC-,Ph|·,3-HO-Ph-及PhCH20-,先決條件是在R3Q是Ph或3-H0-Ph時,n,= 0 最佳是,T 是 MeOCH2C = C-,( τ; -Pr)2NCH2C 兰 C-, CH3C02CH2C = C- ^ Et0C02CH2C = C- » H0CH2C = C-ΗΟ((:Η2;)2(: = (:_,(:Η3(:〇2(:(:ίί2)2(: = (:_,HC^CiCE^hCEC-, OHC(CH2)3C = C- ^ HO(CH2)4C = C- » PhC = C- -27- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 基囷總數 (n-Pr)2N-,-iCR'K, (C, H to / iVII) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (, CRe.H2_Jd-I \--of which a, b, c, d, (c + d), e , G, i, k, RU, and R14 are as defined above. The substituent T group is preferably an acetylene-containing group, and has the following g formula R3〇 (CH2) nC ^ C- where η is 1- 4, R30 is selected from the group consisting of: " 10-, 1 ^ 0-CH3C02-, CH3CH2OC〇2-, H02C-, oHC-, Ph |, 3-HO-Ph- and PhCH20-, the prerequisites are When R3Q is Ph or 3-H0-Ph, n, = 0 is best, T is MeOCH2C = C-, (τ; -Pr) 2NCH2C blue C-, CH3C02CH2C = C- ^ Et0C02CH2C = C- »H0CH2C = C-ΗΟ ((: Η2;) 2 (: = (: _, (: Η3 (: 〇2 (:(: ί2) 2 (: = (: _, HC ^ CiCE ^ hCEC-, OHC (CH2) 3C = C- ^ HO (CH2) 4C = C- »PhC = C- -27- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) The total number of bases (n-Pr) 2N-,
3-HO-PhC 一 私 . 訂------J (請先閱讀背面之注意事項再填寫本頁) 五、發明説明(4 ) A7 B7 732. 222, 1994。並且進一步顯示,於裸鼠,杜腹腔内給予 合成的基質金屬蛋白酶抑制劑巴提瑪斯(batimastat)時,抑 制人結腸腫瘤的生長及原位擴散(\\^叫.6131.,€&1^61:^8· M, 4726, 1994),並延長帶有人卵巢癌移植物约鼠的存活期 (Davies et al., Cancer Res. 53., 2087, 1993)。有關此化合物 及相關化合物的使用見Brown, et al., WO-932H42 A2。 有幾個專利及專利申請聲稱金屬蛋白酶抑制劑在滯緩腫 瘤轉移、促使腫瘤退縮、抑制腫瘤細胞繁殖 減緩或預防 骨性關節炎所致的軟骨損失上的用途,或治療上述其他疾 病上的用途(例如,Levy,et al.,WO-95199653-HO-PhC A private. Order ------ J (Please read the notes on the back before filling this page) V. Description of the invention (4) A7 B7 732. 222, 1994. It was further shown that when a synthetic matrix metalloproteinase inhibitor batimastat is administered intraperitoneally in nude mice, it inhibits the growth and spread of human colon tumors in situ (\\ ^ 叫 .6131., € & 1 ^ 61: ^ 8 · M, 4726, 1994), and prolong the survival of mice bearing human ovarian cancer grafts (Davies et al., Cancer Res. 53., 2087, 1993). For the use of this compound and related compounds, see Brown, et al., WO-932H42 A2. Several patents and patent applications claim the use of metalloproteinase inhibitors to retard tumor metastasis, promote tumor shrinkage, inhibit tumor cell proliferation, slow or prevent cartilage loss caused by osteoarthritis, or treat other diseases mentioned above (E.g. Levy, et al., WO-9519965
Al ; Beckett, et al., WO-9519956 Al ; Beckett, et al., WO-9519957 Al ; Beckett, et al·,WO-9519961 Al ; Brown, et ?丄 wr»-Q321942 A2 ; crimmin, et al., WO-9421625 Al ; Dickeni, et al., U.S. Pat. No. 4,599,361 ; Hughes, et al., U.S. Pat. No. 5,190,937 ; Broadhurst, et al” EP 574758 Al ; Ero只Hh'”rst, et al·, EP 276436 ; and Myers, et al., EP 520573 Al)。此等專 利較佳的化合物有一肽架(backbone),其一端有鋅複合基團 (異羥肟酸,硫醇,羧酸或以亞磷爲基礎的酸) 支鏈,這都是見於天然胺基酸的,並有新穎官 ---------^ 1¾衣------1T------^ (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 ^並有各種 能基團。此 類小肽常不易吸收,經口給予時生物利用率較低。而且這 些化合物都是很快蛋白酶甲代謝的,是以其半 舉例説,如巴提瑪斯(batimastat),Brown, 9321942 A2所述的化合物,只能作腹腔内給予 有些3 -二苯醯'基丙酸及4 -二芳醯基丁酸在文 衰期很短。 et al., WO- 獻中稱爲抗 -7 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 經濟部中央標準局員工消費合作社印製 五、發明説明(5 ) 發炎劑,抗血小板凝固劑,抗炎劑,抗增生 劑,柷風濕劑,止痛劑,及降血膽固醇劑·。 對MMP的抑制,供作上述治療。有些有關的 液體晶體的中間體。 特別是,Tomcufcik, et al.,US、Pat. No. 3,7 定的經取代的苯甲醯基丙酸用於治療發炎與批 合物包括下面所示的3·二苯醯基-丙酸( (fenbufen)) °Al; Beckett, et al., WO-9519956 Al; Beckett, et al., WO-9519957 Al; Beckett, et al., WO-9519961 Al; Brown, et 丄 wr »-Q321942 A2; crimmin, et al ., WO-9421625 Al; Dickeni, et al., US Pat. No. 4,599,361; Hughes, et al., US Pat. No. 5,190,937; Broadhurst, et al "EP 574758 Al; Ero only Hh '" rst, et al., EP 276436; and Myers, et al., EP 520573 Al). The preferred compounds of these patents have a peptide backbone with a zinc complex (hydroxamic acid, thiol, carboxylic acid, or phosphorous-based acid) branch at one end, all of which are found in natural amines. Based on acid, and has a new official --------- ^ 1¾ clothing ------ 1T ------ ^ (Please read the precautions on the back before filling this page) Central Ministry of Economic Affairs It is printed by the Consumer Bureau of Standards Bureau and has various energy groups. Such small peptides are often not easily absorbed and have low bioavailability when administered orally. Moreover, these compounds are rapidly metabolized by protease A. For example, the compounds described in Batimastat, Brown, 9321942 A2 can only be used for intraperitoneal administration of some 3-diphenylhydrazones. Propanoic acid and 4-diarylfluorenyl butyric acid have very short lifetimes. et al., called WO-7 in anti-paper This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (5) Inflammatory agents, Antiplatelet coagulants, anti-inflammatory agents, antiproliferative agents, rheumatoid agents, analgesics, and cholesterol lowering agents. Inhibition of MMP for the above treatment. Some related liquid crystal intermediates. In particular, Tomcufcik, et al., US, Pat. No. 3,7, substituted benzamidine propanoic acid for the treatment of inflammation and batches including the 3-diphenylamyl-propane group shown below Acid ((fenbufen)) °
分布芬 劑,降血脂 一例曾述及 φ合物也用作 無 斗4,701聲稱特 痛。此等化 斗.k.a.芬布芬Dispensing agent, hypolipidemic case One case was described in which the φ compound was also used as a non-combatant 4,701 claiming special pain. K.a.finbufen
Child, et al., J. Pharm. Sci., 66., 466,1977説明 芬類以物的構造與活性間的關係。此等化合物 環經取代的化合物或丙酸部分以苯基、南素、 取代的化合物,或羧酸或羰基官.能基團轉化而 合物。但並未述及含4 '-經取代的二苯基及經取 分同時出現於一分子内的化合物。其説明中 物XLIX及LXXVII)及曱基(化合物XLVII)取代的 活性的。 了幾種芬布 包括二苯基 巍基或甲基 ^的各種化 代的丙酸部 爲苯基(化合 化合物是非 -------------41¾衣------1T------^ (請先閲讀背面之注意事項再填寫本頁) 8 本紙張尺度適用中國國家標準(CNS ) A4規格(21〇 X 297公釐) 經濟部中央標準局員工消費合作社印製Child, et al., J. Pharm. Sci., 66., 466, 1977 illustrate the relationship between the structure and activity of fens. These compounds are cyclically substituted compounds or propionic acid moieties converted to phenyl, sulfonin, substituted compounds, or carboxylic acid or carbonyl functional groups. It does not address compounds containing 4'-substituted diphenyl groups and fractions present in one molecule at the same time. It illustrates the activity of the substitution of the compounds XLIX and LXXVII) and fluorenyl (compound XLVII). Several kinds of fenbu including diphenylpropenyl or methyl ^ various propionates are phenyl (the compound is not ------------ 41¾ clothing ----- -1T ------ ^ (Please read the notes on the back before filling out this page) 8 This paper size applies to China National Standard (CNS) A4 (21 × X 297 mm) Employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by a cooperative
1.1-------.-41 裝------訂------z' (請先閲讀背面之注意事項再填寫本頁) 五、發明説明(7 ) A7 B7 經濟部中央標準局員工消費合作社印製1.1 -------.- 41 Install ------ order ------ z '(Please read the notes on the back before filling this page) V. Description of the invention (7) A7 B7 Economy Printed by the Consumer Standards Cooperative of the Ministry of Standards
^n. - In 1 I - - 1— I - - (. I n^— (請先閱讀背面之注意事項再填寫本頁)^ n.-In 1 I--1— I--(. I n ^ — (Please read the notes on the back before filling out this page)
、1T 五、發明説明(8 ) A7 B7 其中R 1是1 -1 0個碳的烷基。 Thyes, et al·,DE Pat. No. 2854475使用如·下的化合物作爲 中間體。二苯基是未經取代的。(1) V. Description of the invention (8) A7 B7 wherein R 1 is an alkyl group of 1 to 10 carbons. Thyes, et al., DE Pat. No. 2854475 used compounds as intermediates. Diphenyl is unsubstituted.
Sammour, et al., Egypt. J. Chem. 1^., 311, 197 et al‘,Bull. Soc. Chim. 么 3196, 1971説明- 基取代的二苯醯苯丙酸。二苯基無一是經取代 2 及 Couquelet, -些二烷基胺 的0 ------------^ I 裝-- (請先閱讀背面之注意事項再填寫本頁)Sammour, et al., Egypt. J. Chem. 1 ^., 311, 197 et al., Bull. Soc. Chim. Mod. 3196, 1971 illustrates -disubstituted phenylphenylpropanoic acid. None of the diphenyls are substituted 2 and Couquelet, 0 of some dialkylamines ------------ ^ I Pack-(Please read the precautions on the back before filling this page)
0H0H
、1T 經濟部中央標準局員工消費合作社印製 其中R1,R2 =烷基,苄基,Η,或與氮共同成_嗎啉基 還有人揭示一系列含二苯基的羧酸,可以如下化合物説 明,此等化合物抑制神經内切肽酶(ΝΕΡ24.11]|,爲束缚於 膜上的鋅金屬蛋白酶(818111:011,€1&1.,6丨00巧· Lett. 4, 539, 1994 ; Lombaert, et al., Bioorg. Lett. 4, 2715, 1994 ; Lombaert, et al.? Bioorg. Lett.芝,145,1995 ; Lombaert,et al·, Bioorg. Lett. Ul,1995) 〇 〇, 1T printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs where R1, R2 = alkyl, benzyl, hydrazone, or together with nitrogen to form _morpholinyl. Some people have also revealed a series of diphenyl-containing carboxylic acids. It is shown that these compounds inhibit neuroendopeptidase (NEP24.11] |, which is a zinc metalloproteinase bound to the membrane (818111: 011, € 1 & 1., 6 丨 0000 · Lett. 4, 539, 1994 Lombaert, et al., Bioorg. Lett. 4, 2715, 1994; Lombaert, et al.? Bioorg. Lett. Shiba, 145, 1995; Lombaert, et al., Bioorg. Lett. Ul, 1995).
Med. Chem. Med. Chem. Med. Chem. Med. Chem. J :Med. Chem. Med. Chem. Med. Chem. Med. Chem. J:
〇 II Ph〇 — P、 PhO〇 II Ph〇 — P, PhO
^\^C〇2H^ \ ^ C〇2H
本紙張尺度適用中國國家標準(CNS )'A4規格(210X297公釐) A7 B7 五、發明説明(9 ) 衍生物,以 72kDA明膠酶 -9529689)。 有人報告含二苯基乙基甘胺酸的Ν·羧基烷| 下不化合物説明,爲溶基質素(ΜΜρ_3)· (ΜΜΡ-2)及膠原酶的抑制劑(Durene,et幻,w〇This paper size applies Chinese National Standard (CNS) 'A4 specification (210X297 mm) A7 B7 V. Description of the invention (9) Derivatives, 72kDA gelatinase -9529689). It has been reported that N · carboxyalkane containing diphenylethylglycine is described below as a compound that is a matrix solubilin (MMP_3) · (MMP-2) and an inhibitor of collagenase (Durene, et al., W.
CH3 此種化合物 MP活性引起 節炎,化膿 經濟部中央標準局貝工消費合作社印製 現在需要一種有效的MMP抑制劑,此抑制劑與前此技藝 已有的以肽爲基礎的化合物相比,有較好的^物利用率及 生物安定性,並適於姆抗特定的MMPs目標。 爲本發明的目的。 有效的MMP抑制劑的開發會提供對由過量μ 的疾病的新治療,包括骨性關節炎,類風濕軺 性關節炎,腫瘤轉移,牙週病,角膜潰瘍,及蛋白尿。文 獻中曾説明幾種MMPs抑制劑,包括硫醇^682&111;,6131.,1· Med. Chem. 11,4030, 1993),異羥肪酸(Wahl, etal., Bioorg. Med. Chem. Lett. 5., 349, 1995 ; Conway, et al., J. Exp. Med. 182. 449, 1995 ; Porter, et al., Bioorg. Med. Cliem. Lett. 4, 2741, 1994 ; Tomczuk, et al., Bioorg. Med. Cliem. Lett. 5., 12- 本紙張尺度適用中國國家標準(CNS ) A4规格(210X297公釐) A7 B7 五、發明説明(10 y 27, 4299, 1988)。但此等抑制劑一般含有肽支架,由於咮收不佳及快 速蛋白酶解所致的半衰期短的關係,其經口生物活性較 低。是以需要一種改良的MMP抑制劑 本發明概述 本發明提供有基質金屬蛋白酶抑制活性的1合物。此等 化合物可用於抑制基質金屬蛋白酶,所以可治療由MMP's 引起的疾病。因之,本發明也提供治療此類4病的醫藥组 合物及方法 經濟部中央榡率局員工消費合作衽印製 343, 1995 ; Castelhano, et al., Bioorg. Med. Chem. Lett, i, 1415,1995),以亞鱗爲基礎的酸(Bird, et al.,I. Med. Chem. 37., 158, 1994 ; Morphy, et al., Bioorg. Med. Chem. Lett. 4, 2747, 1994 ; Kortylewicz, et al., J. Med. Cliem. 33., 263, 1990) ’ 及幾酸(Chapman, et al., J· Med. ch«:m. 36., 4293, 1993 ; Brown et al., J. Med. Chem. 37, 674, 1<»94 ; Morphy, et al., Bioorg. Med. Chem. Lett. 4, 2747, 1994 ; Stack, et al., Arch. Biochem. Biophys. 287. 240,1991 ; Ye, et al., J. Med. Chem. 37., 206, 1994 ; Crobelny, et al., Biochemistry 24, 6145, 1985 ; Mookhtiar, et al., Biochemistry 所述化合物係關於治療哺乳動物的方法,其包括給予哺 乳動物以基質金屬蛋白酶抑制量的本發明化合物足以 性關節炎, 脈病,營養 病,由MMP 系統脱髓鞠 (請先閲讀背面之注意事項再填寫本頁) a)減輕骨性關節炎,類風濕關節炎,化臈 牙週病,角膜潰療,蛋白尿,動脈瘤性主動 不良性上皮鬆·弛,大疱,導致發炎反應的疾 活性引起的骨質減少,顳頷關節疾病,神經 13- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 五、發明説明(11 ) 疾病 A7 B7 經 b) 阻止腫瘤轉移或關節受傷後發生^退行性軟骨損 c) 降低由粥狀動脈硬化斑破裂引起的冠狀動脈栓塞 或 d) 控制生育力。 本發明化合物也是供活體内及活體外研究^質金屬蛋白 酶的功能及作用機轉的有用的科學研究工具 抑制活性,此等化合物可用於調整MMp作用 ㈣ 人員觀察研究中的實驗系統中MMP活性減少所發生的 響。 本發明係關於有基質金屬蛋白酶抑制活性化合物 下的通式: τ ΤχΑ-Β-D-E-G 於上述通式α)中,τχΑ代表經取代的或未纪取代的芳香 族6-員環或含1-2個獨立選自Ν,〇 族5 - 6員環。Τ代表經取代的乙炔基 於通式(L)中,Β代表芳香族6_員環或含有卜 失 。由於其MMP 由而使研究 如 或S的原子的雜芳香 請 先 閱 讀 背 之 注CH3 The MP activity of this compound causes arthritis, which is printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Purgation and now requires an effective MMP inhibitor. This inhibitor is compared with the peptide-based compounds already available in this technology. It has good bioavailability and biostability, and is suitable for specific MMPs targets. For the purpose of this invention. The development of effective MMP inhibitors will provide new treatments for diseases caused by excess μ, including osteoarthritis, rheumatoid arthritis, tumor metastasis, periodontal disease, corneal ulcers, and proteinuria. Several MMPs inhibitors have been described in the literature, including thiol ^ 682 &111;, 6131., 1. Med. Chem. 11, 4030, 1993), isohydroxy fatty acids (Wahl, etal., Bioorg. Med. Chem Lett. 5., 349, 1995; Conway, et al., J. Exp. Med. 182. 449, 1995; Porter, et al., Bioorg. Med. Cliem. Lett. 4, 2741, 1994; Tomczuk, et al., Bioorg. Med. Cliem. Lett. 5., 12- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of the invention (10 y 27, 4299, 1988). However, these inhibitors generally contain peptide scaffolds, which have a low oral biological activity due to the short half-life caused by poor harvesting and rapid proteolysis. Therefore, an improved MMP inhibitor is needed. SUMMARY OF THE INVENTION The present invention provides Compound 1 with matrix metalloproteinase inhibitory activity. These compounds can be used to inhibit matrix metalloproteinases, so they can treat diseases caused by MMP's. Therefore, the present invention also provides pharmaceutical compositions and methods for treating these 4 diseases. Printed by the Central Government Office on Consumer Cooperatives, 343, 1995; Castelhano, et al., Bioorg. Med. Chem. Lett, i, 1415, 1995), subscale-based acids (Bird, et al., I. Med. Chem. 37., 158, 1994; Morphy, et al., Bioorg. Med. Chem. Lett. 4, 2747, 1994; Kortylewicz, et al., J. Med. Cliem. 33., 263, 1990) 'and several acids (Chapman, et al., J. Med. Ch :: m. 36., 4293, 1993; Brown et al., J. Med. Chem. 37, 674, 1 <»94; Morphy, et al., Bioorg. Med. Chem. Lett. 4, 2747, 1994; Stack, et al. ,, Arch. Biochem. Biophys. 287. 240, 1991; Ye, et al., J. Med. Chem. 37., 206, 1994; Crobelny, et al., Biochemistry 24, 6145, 1985; Mookhtiar, et al., The compound described in Biochemistry is a method for treating mammals, which comprises administering a matrix metalloproteinase-inhibiting amount of a compound of the present invention to mammals to suffocate arthritis, vein disease, nutritional disease, and demyelination by MMP system (please read the Note: Please fill in this page again) a) Reduce osteoarthritis, rheumatoid arthritis, periodontal disease, corneal ulceration, proteinuria, aneurysmal active adverse epithelial loosening, bullae, and inflammation Disease reduction of bone caused by disease activity, temporomandibular joint disease, nerve 13- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) V. Description of the invention (11) Disease A7 B7 via b) Prevent tumor metastasis or joints ^ Degenerative cartilage damage after injury c) reduce coronary artery embolism caused by atherosclerotic plaque rupture or d) control fertility. The compounds of the present invention are also useful scientific research tools for in vivo and in vitro studies on the function and mechanism of cytoplasmic metalloproteinases. These compounds can be used to adjust the effects of MMPs. What happened. The present invention relates to a general formula with a matrix metalloproteinase-inhibiting compound: τ ΤχΑ-Β-DEG In the above general formula α), τχΑ represents a substituted or unsubstituted aromatic 6-membered ring or containing 1- Two independently selected from the N, 0 family of 5-6 member rings. T represents a substituted ethynyl group. In the general formula (L), B represents an aromatic 6-membered ring or contains a loss. Due to its MMP, the heteroaromaticity of atoms such as or S is studied. Please read the back note
I t 裝 訂 中 央 標 準 局 員 工 消 費 合 作 杜 印 製 弋 c Β;, ' " 0 1 [ 2 個 Ν,0,==芳香族Η員環。稱爲Β環❹單位。在Β環上 ,- …ν —> ^ J3 早有Ν與S或〇時,此等雜原子以至少—個碳原子 於通式(L)中,D代表 隔離 C = 〇It binds the central government bureau's consumer cooperation du print 弋 c Β ;, '" 0 1 [2 Ν, 0, == aromatic aromatic member ring. It is called a B ring unit. On the B ring, -... ν — > ^ J3 When N and S or 〇 are long before, these heteroatoms have at least one carbon atom in the general formula (L), D stands for isolation C = 〇
C=NOH C=SC = NOH C = S
C .ΗC .Η
OH 1-------- -14- '度侧中國國家轉(CNS )八4祕(21GX297公釐) 五、發明説明(12 A7 B7 於通式(L)中,E代表η個碳原予鏈,帶杏m個取代基 R6,其中R6是獨立的取代基,或形成螺旋·或泎螺旋環。各 個可以一種方式形成:a)二個R 6基團相聯,與此二個R 6基 團相聯的鏈原子及任何插入的鏈原子形成3_7 一個R6基團聯於此R6基團相聯處聯於鏈上, 聯的鏈原子及任何插入的鏈原子形成3_7員的環。鏈上鏈 原子的數m是2或3,R6取代基的數爲1—3的^數。r6基團 的總碳數至少爲2。 每一 R6基團是燒基,晞基,块基,雜芳基 及視需要以一或多個下述的雜原子取代的雜午香環。於通 式(L)中’ E是視需要由一或多個雜原子經取代的單_或二 雙環基。於通式(L)中,G代表-Ρ03Η2,-M, 員的環;或b ) 與R6基團相 非芳•香環 (請先聞讀背面之注意事項再填寫本頁) γ丨裝· 訂 -C-N-C-M ΗOH 1 -------- -14- 'Secret China National Transfer (CNS) Eighty-four Secrets (21GX297 mm) 5. Description of the invention (12 A7 B7 In the general formula (L), E represents η Carbon source chain, with m substituents R6, where R6 is an independent substituent, or forming a spiral or helical spiral ring. Each can be formed in one way: a) two R 6 groups are connected, and this two Each R 6 group linked atom and any inserted chain atom form 3_7 An R6 group linked to this R6 group is linked to the chain, the linked chain atom and any inserted chain atom form a 3_7 member ring. The number m of on-chain atoms is 2 or 3, and the number of R6 substituents is 1-3. The total carbon number of the r6 group is at least two. Each R6 group is an alkyl group, a fluorenyl group, a bulk group, a heteroaryl group, and a heteroepicyclic ring substituted with one or more heteroatoms as described below as necessary. In general formula (L), 'E is a mono- or bi-bicyclic group optionally substituted with one or more heteroatoms. In general formula (L), G represents -P03Η2, -M, member ring; or b) non-aromatic and fragrant ring with R6 group (please read the precautions on the back before filling this page) · Order-CNCM Η
R 13 •HM ,或R 13 • HM, or
經濟部中央標準局員工消費合作社印製 其中 Μ代表-C02H,-CON(Rn)2,或-C02R12, 然出現於胺基酸上的19種非環形支鏈。 本發明最佳的化合物是:Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, where M stands for -C02H, -CON (Rn) 2, or -C02R12, of which 19 non-cyclic branched chains appear on amino acids. The most preferred compounds of this invention are:
〇 R16 R -C=C〇 R16 R -C = C
及R13代表天 其中 R15 是選自:HOCH2,MeOCH2,(n CH3C02CH2 » Et0C02CH2 ^ HO(CH2)2 , CH3(b〇2(CH2)2And R13 represents day, where R15 is selected from: HOCH2, MeOCH2, (n CH3C02CH2 »Et0C02CH2 ^ HO (CH2) 2, CH3 (b〇2 (CH2) 2
Pr)2NCH2 -15- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 五、發明説明(13 ) A7 B7 H02C(CH2)2,OHC(CH2)3,HO(CH2)4Ph,i-H〇-Ph,及 PhCH2OCH2 ;及R16是 .Ph 或Pr) 2NCH2 -15- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) V. Description of the invention (13) A7 B7 H02C (CH2) 2, OHC (CH2) 3, HO (CH2) 4Ph, iH〇-Ph, and PhCH2OCH2; and R16 is .Ph or
經濟部中央標準局員工消費合作社印製 此等化合物醫藥上可接受的鹽也屬於本發明 前此技藝中關係最近的參考化合物中,分子中的聯苯基 部分是未經取代的’而丙酸或丁酸部分是未經取代的或有 一個甲基或苯基。曾有人報告,有較大的苯基出現時或此 动此技藝化合物不具抗炎止痛活性。見,例如,Child,e. al·,J. Pharm. Sci.妓,466 (1977)。相反的,現已發現,展 現有效的MMP抑制活性的化合物於分子之丙酸或丁酸部分 * 含的取代基很大。此最佳MMP抑制劑之聯苯基部分較佳於 4 W立也含取代基,雖則當丙酸或丁睃部分作適宜的取代 時,本發明未經取代的聯苯基化合物仍有足夠的活性 認作是票物候選者。 前述説明只是總結本發明的特定方面,絕非 不可理解爲,對本發明的限制。此説明中所引 利及其他公告全文於此一併附上供參考。 較佳具體實施例説明 更特定地説,本發明化合物是有基質金屬蛋 性的物質,有如下的通式:The medically acceptable salts of these compounds printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economics also belong to the reference compounds with the closest relationship in this technology before the present invention. The biphenyl moiety in the molecule is unsubstituted. Either the butyric acid moiety is unsubstituted or has a methyl or phenyl group. It has been reported that this compound does not have anti-inflammatory and analgesic activity when larger phenyl groups are present or moved. See, for example, Child, e. Al., J. Pharm. Sci. Prostitute, 466 (1977). In contrast, it has been found that compounds exhibiting effective MMP inhibitory activity have a large number of substituents in the propionic or butyric acid portion of the molecule *. The biphenyl moiety of this best MMP inhibitor is better than 4W and also contains a substituent, although the unsubstituted biphenyl compound of the present invention is still sufficient when the propionic acid or butylamidine moiety is suitably substituted. Active is considered a ticket candidate. The foregoing description merely summarizes certain aspects of the invention and is by no means to be understood as limiting the invention. The full text of the benefits and other announcements cited in this note are hereby attached for reference. Description of preferred embodiments More specifically, the compound of the present invention is a matrix metal egg-like substance, and has the following general formula:
ΤχΑ-Β-D-E-G 16- 本紙張尺度適用中國國家標準&叫从麟(2!〇><297公着) 範圍内 意爲,也衾 用的所有4 白酶抑制ΤχΑ-Β-D-E-G 16- This paper size applies to the Chinese national standard & called Conglin (2! 〇 > < 297), which means that all 4 enzymes also used for inhibition
(I m- —JT· - I n- —Bn (請先閲讀背面之注意事項再填寫本頁) -*° 4 A7 B7 五、發明説明(14 ) 其中Tx A代表經取代的或未經取代的芳香族本團或雜芳香 族基團,選自包括: ‘(I m- —JT ·-I n- —Bn (Please read the notes on the back before filling this page)-* ° 4 A7 B7 V. Description of the invention (14) where Tx A represents substituted or unsubstituted Aromatic group or heteroaromatic group selected from the group consisting of: ''
T广N RT Guang N R
NN
T T,,T T ,,
ΝΝ
NN
T,、S R1 τ Λ Τχ飞〆 Τ, , - 1 (請先閲讀背面之注意事項再填寫本頁) 訂 其中R1代表Η或1-3個碳的烷基。 於整個本説明中,在所示化學構造中,開4键表示此構 造聯於另一基團上的點。例如 J · 經濟部中央標準局員工消費合作社印製 在其R5()是 時,其構造爲 〇r r50T ,, S R1 τ Λ Τχ 〆 〆, T,,-1 (Please read the notes on the back before filling out this page) Order Where R1 represents Η or an alkyl group of 1-3 carbons. Throughout this description, in the chemical structure shown, opening a 4 bond indicates the point at which this structure is linked to another group. For example, J. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. When its R5 () is, its structure is 〇r r50
-17- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 五、發明説明(15 A7 B7 於此等構造中,芳香環稱爲A環或A單位,每一 T代表取 代基,稱爲T基團或T單位。T是經取代的乙炔基,X是1。 通式(L )中的B環是經取代的或未取代的芳+環或雜芳香 V 環’其中,任何取代基是不使分子不適合於目標酶的活性 位’或擾亂A及B環相對構造以緣被傷害的基[§。此類取代 基可以是基團的一邵分(m〇ieties),如低燒基,低统氧基 CN ’ N〇2,鹵素等,但並不限於此等基圏。 於通式(L)中,B代表下列芳香或雜芳香環4團之一:-17- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297 mm) 5. Description of the invention (15 A7 B7 In these structures, the aromatic ring is called A ring or A unit, each T represents substitution Group, called T group or T unit. T is a substituted ethynyl group and X is 1. The ring B in the general formula (L) is a substituted or unsubstituted aryl + ring or a heteroaromatic V ring. Any substituent is a group that does not make the molecule unsuitable for the active site of the target enzyme 'or disrupts the relative structure of the A and B rings [§. Such substituents can be a moieties of the group , Such as low-carbyl, lower-oxyl CN ′ No, halogen, etc., but is not limited to these groups 圏. In the general formula (L), B represents one of the following four groups of aromatic or heteroaromatic rings:
R1 N-R1 N-
〇 -N Λ丨 0〇 -N Λ 丨 0
...... ... I —II i — -1 ‘:: —ί I ^ I I I - (請先閲讀背面之注意事囔再填寫本頁; 0...... ... I —II i — -1 ‘:: — ί I ^ I I I-(Please read the notes on the back before filling this page; 0
N R1 -11*N R1 -11 *
•0 Ν• 0 Ν
R1 ΝR1 Ν
0 Ν0 Ν
Ν R1Ν R1
Rl J : 經濟部中央標準局員工消費合作社印製 •Ν Ν=^\又Ν、 ΝRl J: Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs • Ν Ν = ^ \ 又 Ν 、 Ν
Ν·Ν ·
Ν XTΝ XT
λΤ Ν· .ΝλΤ Ν · .Ν
、νΝ, ΝΝ
Xr 其中R之疋義如上述。此等環稱爲Β環或Β單位 -18- 本紙張Α度適用中國國家標準(CNS ) A4規格(21〇X2^^yXr wherein R is as defined above. These rings are called B-rings or B-units. -18- This paper A degree is applicable to Chinese National Standard (CNS) A4 specifications (21〇X2 ^^ y
、發明説明(16 於通式(L)中,D代表如下之基 團 ,C=〇Description of the invention (16 In the general formula (L), D represents the following group, C = 〇
C = N〇H ,c=s Η 於通式(L)中,ε代表帶有111個取代基R6的 鏈,稱爲R6基團或R6單位。R6基團是獨立&取代基,或 1個碳原子的 構成螺旋會非螺旋環。此等環可以二種方式形 a)二個R6基團相聯,與此二個R6基團相聯的 成·· 錢原子8及任何 插入的鏈原子形成3 -7員的環;或b) —個R6基團聯於此R6 (請先聞讀背面之注意事項再填寫本頁) - Γ ι^ϋ n l· - .1. IA< I - - .1. - I I— m I .-. 經濟部中央標準局員工消費合作社印製 基團相聯處聯於鏈上,與R6基團相聯的鏈原 的鏈原子形成3-7員的環。鏈上碳原子的數η 取代基的數爲1_3的整數。r6基團的總碳數至 每一 R6基團係獨立選自包括下述1) -1 4 )所列 1) 1 -1 0個碳原子的烷基,先決條件是,如果A單位是 苯基,B單位是伸苯基,瓜是!,ns2,烷^係位於 單位而言的α碳上,則x是1或2 ; 2 ) 6 - 1 〇個碳的芳基,先決條件是,如果 基,B單位是伸苯基,芳基為苯基,η是2 2,則X是1或2 ; ' 3) 有4-9個碳及至少一個Ν,〇,或S雜原子 4) 芳基烷基,其中芳、基部分含6 -1 〇個碳而 1 - 8個碳; 5) 雜芳基烷基,其中雜芳基部分含4-9個碳 Ν ’ 〇 或S雜原子,而燒基部分含1-8個碳; 及任何插入 是2或3,R6 少爲2。 的取代基。 Α單位是苯 ,而m是1或 的雜芳基; 燒基部分含 及至少一個 、1T_ -19- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) A7 B7 分含 碳及至少τ 五、發明説明(17 ) 6 ) 2 - 1 0個碳的締基; 7)芳基晞基’其中芳基部分含6_10個碳而晞基部 2-5個碳; 8) 雜芳基晞基,其中雜芳基部分含4_9個碳及至少—個 N,〇,或S雜原子,而烯基部分含2_5個碳 9) 2-10個碳的炔基; 10) 芳基炔基,其中芳基部分含6-10個碳$烯基部分含 2 · 5個碳; 11) 雜芳基炔基,其中雜芳基部分含4-9偃 個N,〇,或S雜原子,而块基部分含2-5個破; -i ^1. 1 {請先閎讀背面之注意事項再填寫本頁} 12)- (C Η 2 )tR7,其中t是0或1-5的整數,R 如下的基團: 7是選自包括 、-° 0 —N 6C = N0H, c = s Η In the general formula (L), ε represents a chain with 111 substituents R6, which is called R6 group or R6 unit. The R6 group is an independent & substituent, or one carbon atom constitutes a spiral non-spiral ring. These rings can be shaped in two ways: a) two R6 groups are connected, and the two R6 groups are connected to form a money atom 8 and any inserted chain atom to form a 3-7 member ring; or b ) — An R6 group is connected to this R6 (please read the notes on the back before filling this page)-Γ ι ^ ϋ nl ·-.1. IA < I--.1.-II— m I .- The printed group of the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs is connected to the chain, and the chain atoms of the chain original linked to the R6 group form a 3-7 member ring. The number of carbon atoms on the chain η The number of substituents is an integer of 1-3. The total carbon number of the r6 group to each R6 group is independently selected from the following alkyl groups including 1) to 1) listed in 1) 1 to 10 carbon atoms, the prerequisite is that if the A unit is benzene Base, B unit is phenylene, melons are! , Ns2, alkane is located on the α carbon of the unit, then x is 1 or 2; 2) 6-10 carbon aryl, the prerequisite is that if the group, the B unit is phenylene, aryl Is phenyl, η is 2 2, then X is 1 or 2; '3) has 4-9 carbons and at least one N, 0, or S heteroatom 4) arylalkyl, in which the aryl and base portions contain 6 -10 carbons and 1-8 carbons; 5) heteroarylalkyl, wherein the heteroaryl portion contains 4-9 carbons N′0 or S heteroatoms, and the alkyl group contains 1-8 carbons; And any insertion is 2 or 3, and R6 is less than 2. Substituents. The unit of Α is benzene, and m is 1 or heteroaryl; the calcined part contains at least one, 1T_ -19- This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) A7 B7 carbon And at least τ V. Description of the invention (17) 6) Alkenyl groups of 2 to 10 carbons; 7) aryl fluorenyl group in which the aryl moiety contains 6-10 carbons and the fluorene base has 2-5 carbons; 8) heteroaryl Amidino, where the heteroaryl moiety contains 4-9 carbons and at least one N, 0, or S heteroatom, and the alkenyl moiety contains 2-5 carbons 9) alkynyl with 2-10 carbons; 10) arylalkyne Group, in which the aryl moiety contains 6-10 carbons; the alkenyl moiety contains 2.5 carbons; 11) heteroarylalkynyl, in which the heteroaryl moiety contains 4-9 偃 N, 0, or S heteroatoms , And the base of the block contains 2-5 breaks; -i ^ 1. 1 {Please read the precautions on the back before filling out this page} 12)-(C Η 2) tR7, where t is 0 or 1-5 Integer, R is a group of: 7 is selected from the group consisting of,-° 0 -N 6
一NOne N
Ο 0 經濟部中央標準局員工消費合作社印製 0 N .N Λ-R2Ο 0 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 0 N .N Λ-R2
0 〇 -N: Ο -κ Ο /^•NR2 —Jv/ I , Ο -20- 本紙張尺度適用中國國家標準(CNS > Α4規格(21 ΟΧ297公釐) 第S61 〇6283號專利申請案 中文説明書修正頁(S7年11月) A7 B70 〇-N: Ο -κ Ο / ^ • NR2 —Jv / I, 〇 -20- This paper size applies to Chinese National Standards (CNS > A4 Specification (21 〇 × 297mm) No. S61 〇6283 Chinese Patent Application Manual revision page (November S7) A7 B7
五、發明説明( 18V. Description of the invention (18
R2 0 RJ { Η I Ί "N-C^N—R R2 Ο l II n ~N-C-〇R3 Ό (Rl)u R2 > , N-R2 以及對應的雜芳基,其中含芳基的R7基團 土) 個N,0,或S雜原子。於.r7基團中 S ; R1之定義如上述’^0,1,或2,先決 是 /~^CR)U —N Y V_/ 或 ..R2 N R1 R2 0 —N-C-R2R2 0 RJ {Η I Ί " NC ^ N—R R2 Ο l II n ~ NC-〇R3 Ό (Rl) u R2 >, N-R2 and the corresponding heteroaryl group, which contains the R7 group of aryl group Soil) N, 0, or S heteroatoms. The definition of S; R1 in the .r7 group is as described above, '^ 0, 1, or 2; the prerequisite is / ~ ^ CR) U —N Y V_ / or ..R2 N R1 R2 0 —N-C-R2
含4 - 9個碳及 ,Y代表0或 條件是在R7 及A單位是苯基,B單位是伸基,m是1,[ι是2及t爲0 時,則X是1或2。 1 3)-(CH2)vZR8,其中v是1至4的整數,:ζ代表_ -S(O)- ’ -S02- ’或-0-,及R8係選自包括1至12個碳的 燒基,6至10個竣的芳基,含4-9個後及至少一個N, (請先閱讀背面之注意事項再填寫本頁) 訂 j 經濟部中央標李局員工消費合作社印製 0,或S雜原子的雜芳基;芳基烷基,其中芳 1 2個碳而烷基部分含1 - 4個碳;雜芳基烷基 基部分含6 - 1 2個碳及至少一個N,0,或S雜原子,而烷 基部分含1 - 4個碳;-C(0)R9,其中R9代表2至6個碳的烷 基,芳基爲6至10個碳的,含4-9個碳及至 ◦,或S雜原子的雜芳基;及芳基烷基,其中 6-10個破或是含4-9個碳及至少一個N,0, 基郅分含6 -,其中雜芳 少一個N, 芳基部分含 或S雜原子 的雜芳基,而烷基部分含丨至4個碳,先決條件是在R8是- -21 本紙張尺度適用中國國家標隼(CNS ) A4規格(210X297公瘦〉 罘跖1〇6283號專利申請案 中文説明書修正頁(87年11月) A7 B7 五'發明説明( 19Contains 4 to 9 carbons and Y represents 0 or with the proviso that when R7 and A are phenyl, B is extrinsic, m is 1, [ι is 2 and t is 0, then X is 1 or 2. 1 3)-(CH2) vZR8, where v is an integer from 1 to 4, ζ represents _ -S (O)-'-S02-' or -0, and R8 is selected from the group consisting of 1 to 12 carbons Burning base, 6 to 10 complete aryl groups, containing 4-9 after and at least one N, (Please read the notes on the back before filling this page) Order j Printed by the Central Consumer Bureau of the Ministry of Economy Staff Consumer Cooperatives 0 , Or S heteroatom heteroaryl; arylalkyl, where aryl is 12 carbons and the alkyl portion contains 1-4 carbons; heteroarylalkyl group contains 6-12 carbons and at least one N , 0, or S heteroatoms, and the alkyl portion contains 1-4 carbons; -C (0) R9, where R9 represents an alkyl group of 2 to 6 carbons, and the aryl group is 6 to 10 carbons, containing 4 -9 carbons and heteroaryl groups up to ◦, or S heteroatoms; and arylalkyl groups, of which 6-10 are broken or contain 4-9 carbons and at least one N, 0, the radical containing 6-, Wherein the heteroaryl has one N, the aryl part contains a heteroaryl group with S or heteroatoms, and the alkyl part contains 丨 to 4 carbons, the prerequisite is that R8 is--21 This paper applies the Chinese national standard (CNS) ) A4 size (210X297 male thin) 修正 No. 106283 Patent Application Chinese Specification Revision Page (8 November 7) A7 B7 Five 'invention description (19
C(0)R9時,z 是-S-或;在 Z 是-〇_ 時 (CqH2q〇)rR5,及在A單位是苯基,B單位是 1,η是2,及v是0時,則X是1或2 ;及 14)-(CH2)wSiR103,其中w是1至3的整數,又ί0代表ί至2 個唉的娱:基。 此外,任何Τ或R6基團的芳基或雜芳基部分可視需要帶 有達二個的取代基,此等取代基選自包括: -(CH2)yC(Ru)(R12)〇H , -(CH2)yORn , -(CH2)ySRn , -(CH2)yS(0)Rn » -(CH2)yS(0)2Ru » -(CH2)yi502N(Rn) '(C H 2 )yN(R'*)2 » -(C H2 )yN(R'!)C0R12 ? -〇C(R R8也可是-ί申苯基,m是 )2〇_ 2 7 其中 (請先閱讀背面之注意事項再填寫本頁)When C (0) R9, z is -S- or; when Z is -〇_ (CqH2q〇) rR5, and when A is phenyl, B is 1, η is 2, and v is 0, Then X is 1 or 2; and 14)-(CH2) wSiR103, where w is an integer from 1 to 3, and ί0 represents 2 to 2 唉 entertainment: base. In addition, the aryl or heteroaryl portion of any T or R6 group may carry up to two substituents as required. These substituents are selected from the group consisting of:-(CH2) yC (Ru) (R12) OH,-( CH2) yORn,-(CH2) ySRn,-(CH2) yS (0) Rn »-(CH2) yS (0) 2Ru»-(CH2) yi502N (Rn) '(CH 2) yN (R' *) 2 »-(C H2) yN (R '!) C0R12? -〇C (R R8 can also be -ί phenyl, m is) 2〇_ 2 7 Of which (Please read the precautions on the back before filling this page)
個氧原子都是聯於芳基環上,_(CH2;)yC〇R 11 -(CH2)yCON(R")2,-(CH2)yC02R",-(CH2)yd 素,-CH0,-CF3,-N〇2,-CN,及-R12,其中 y 代衣H或1 - 4個碳的娱》基;及R 1 2代表1 _ 4個竣的燒基 於通式(L)中’ G代表-P〇3H2,-M, 11 COR11,-卣 是0-4 ; R11All oxygen atoms are linked to the aryl ring, _ (CH2;) yC〇R 11-(CH2) yCON (R ") 2,-(CH2) yC02R ",-(CH2) yd element, -CH0,- CF3, -N02, -CN, and -R12, where y substitutes H or 1 to 4 carbon atoms; and R 1 2 represents 1 to 4 carbon atoms based on the general formula (L) ' G represents -P〇3H2, -M, 11 COR11,-卣 is 0-4; R11
?t(l —C-NjM? t (l —C-NjM
訂 經濟部中央標準局員工消費合作社印製 及R13代表 側鏈= 也在本發明 且幸文佳是幾 其中 M 代表- CO2H,-CON(Rn)2,或_c〇2R12 : 天然出現於胺基酸上的1 9個非環形側鏈的任— 此等屬於通式(L)化合物的醫藥上可接受的璧 範圍内= G單位最佳是於D單位的召碳上聯於e單位, 22- 本紙法尺度適用中國國家標準(CNS ) A4規格(210X 297公缝 經濟部中央棣準局員工消費合作杜印製 五、發明説明(2〇 ) G單位最佳是於D單位的卢碳上聯於£單位 酸基。 應了解到,此處所謂,,烷基"一詞意爲直鏈、一 或多環形物質。"鹵烷基"—詞音爲3 』 J心馬#为或元聲鹵素化的烷 基,如-(CH2)2C1,-CF3,&_c6F13。 於其一個具體實施例中,本發明係關於通式 其中至少A,B單位之—及R6含有雜芳香環‘ 雜芳香環的化合物是這樣的化合物,其中雜如基是4_9個 碳的5-6員的雜芳基,在環爲5_員的時含冇〇,s,或 NR 1,在裱爲6 -員的時含有N。特佳的含有雜芳香環的化 合物是這樣的化合物,其中至少A&B單位之一含有嘍吩 環。在A單位是遠吩環時,較佳是於2 ·位聯於B單位上 且較佳是羧 支鏈、環形 L)化合物, 較佳的含有 並於5 -位帶有取代基T。在B單位是嘍吩環時 經由2 -及5 -位聯於D及A單位上。 於通式(L)中,A及B環較佳分別是苯基或柃苯基,a環 較佳於距聯接B環最遠處帶有τ取代基,D單 基,G單位較佳是羧基 於另一較佳具體實施例中,本發明係關於通式(L)化合 物’於其E單位中η是2,m是1。所以此等化合物於D單位 及F單位間有二個碳原子,於此二碳鏈上帶 基 於另一較佳具體實施例中,本發明係關於遊式(L )化合 物,其中A環是經取代的或未經取代的苯基 較佳是分別 位較佳是羰 有一個取代 B環是伸苯 基,任何含由芳基的R6基的芳基部分在環上只含有碳。是 -23- 各紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) I ---------^—裝-- (請先閲讀背面之注意事項再填寫本頁) 訂 A7 經濟部中央標隼局員工消費合作社印¾ 五、發明説明(21 以此等化合物不含雜芳香環 於另-較佳具體實施例中,本發明係關於“式⑹化合 物,其中m是1 ’ R6獨立是取代基。此等化合物是於e單位 上只含單,一取代基R 6的物質,而此取代基與壞 次類中較佳的化合物有如下的式Ordered by the Central Standards Bureau of the Ministry of Economic Affairs, printed by the employee consumer cooperative and the R13 representative side chain = is also in the present invention and Xing Wenjia is a few of which M represents-CO2H, -CON (Rn) 2, or _c〇2R12: naturally occurring in the amine group Any of the 19 non-cyclic side chains on the acid-these are within the pharmaceutically acceptable range of the compound of general formula (L) = G units are best linked to e units on the carbon of D units, 22 -The size of the paper method is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 quilt of the Ministry of Economic Affairs of the Central Bureau of Quasi-Employees for consumer cooperation. Du V. Invention Description (20) The G unit is best on the D carbon of D unit It is linked to the unit acid group. It should be understood that the term "alkyl group" means a linear, one or more ring-shaped substance. "Haloalkyl" —the pronunciation is 3 『J 心 马 # Is a halogenated alkyl group such as-(CH2) 2C1, -CF3, & _c6F13. In a specific embodiment, the present invention relates to the general formula in which at least A, B units-and R6 contain hetero Aromatic ring 'Heteroaromatic ring compounds are compounds in which the heterocyclic group is a 5-6 membered heteroaryl group of 4 to 9 carbons. When it is 5 members, it contains 冇 〇, s, or NR 1, and when it is 6-members, it contains N. Particularly preferred compounds containing heteroaromatic rings are compounds in which at least one of the A & B units contains A phenphen ring. When the A unit is a distant phen ring, it is preferably at a position of 2 · The B unit and is preferably a carboxyl branched, cyclic L) compound, preferably containing and substituted at the 5-position. Radical T. When the B unit is a phenphen ring, it is linked to the D and A units via the 2- and 5-positions. In the general formula (L), the A and B rings are preferably phenyl or fluorenyl groups, respectively, and the a ring preferably has a τ substituent, the D single group, and the G unit are farthest away from the ring B. In another preferred embodiment, the carboxyl group relates to a compound of the general formula (L) in which η is 2 and m is 1. Therefore, these compounds have two carbon atoms between the D unit and the F unit. The two carbon chains are based on another preferred embodiment. The present invention relates to compounds of formula (L), in which the A ring is A substituted or unsubstituted phenyl group is preferably a carbonyl group having a substituted B ring and a phenyl group, and any aryl moiety containing an R6 group consisting of an aryl group contains only carbon on the ring. Yes-23- Each paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) I --------- ^ — Packing-(Please read the precautions on the back before filling this page) Order A7 Printed by the Consumers' Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs Ⅴ. Description of the invention (21 These compounds do not contain heteroaromatic rings in another-preferred embodiments, the present invention relates to "compounds of formula ⑹, where m is 1 'R6 is independently a substituent. These compounds are substances containing only a single, one substituent R 6 in the e unit, and this substituent has the following formula with the better compounds in the bad class.
C-ClI,CHR6CO〇H 無關。於此 其中X是1,取代基T,相對於A環及B環的聯結 位於A環的4-位上。此次類的對位取代基τ較佳 下列基團的乙炔:Me〇CH2C三C-,( 7; _Ργ)2Ν CH3C02CH2C = C- » Et〇C02CH2C ^ C- ^ H〇CH2C ^ C-HO(CH2)2C-C- ’ CH3C〇2(CH2)2C = C-,H02C(CH2)2C 兰 c_ OHC(CH2)3C = C- » HO(CH2)4C = c- » Phc = c-C及PhCH2OCH2C = C-。 其他R 6是-(c H2 )tR7的通式(L)化合物之t爲 '較佳的R6是-(CH2)VZR8的通式(L)化合物之 數,而Z爲-S-或-〇-。另外的通式(L)化合物 烷基,於該烷基上含4或多個碳,以及R6是芳基坑基的通 式(L)化合物,其芳基烷塞的烷基部分含2-3個碳 於另一較佳具體實施例中,本發明係關於通式(L)化合 物’其中E單位上取代基的爪數是2或3 ;當瓜是〗時,二個 R基團疋獨互的取代基,或共同構成螺旋環,或一個尺6基 團是獨立的取代基而另一個構成螺旋環;當讯是3時,二個 點而言,是 是含有選自 CH2C ξ C-, —:--------r —^II (請先聞讀背面之注意事項再填寫本頁) ,11 3-HO-PhC = -5的整數。 V是1 - 4的整 ,其中R6是C-ClI, CHR6CO〇H have nothing to do. Here, X is 1, and the substituent T is located at the 4-position of the A ring with respect to the connection of the A ring and the B ring. The para-substituent group τ this time is preferably acetylene of the following group: MeOCH2C tri-C-, (7; _Ργ) 2N CH3C02CH2C = C- »Et〇C02CH2C ^ C- ^ H OH 2 C ^ C-HO CH2) 2C-C- 'CH3C〇2 (CH2) 2C = C-, H02C (CH2) 2C Blue c_ OHC (CH2) 3C = C- »HO (CH2) 4C = c-» Phc = cC and PhCH2OCH2C = C -. Other compounds of general formula (L) where R 6 is-(c H2) tR7, where t is' preferred R6 is the number of compounds of general formula (L) where-(CH2) VZR8, and Z is -S- or-. -. Another compound of the general formula (L) is an alkyl group having 4 or more carbons on the alkyl group, and R6 is a compound of the general formula (L) having an aryl pit group, and the alkyl portion of the aryl alkane contains 2- 3 carbons in another preferred embodiment, the present invention relates to a compound of the general formula (L) in which the number of claws of substituents on the E unit is 2 or 3; Unique substituents, or together form a helical ring, or one foot 6 group is an independent substituent and the other constitutes a helical ring; when the news is 3, for two points, it contains a group selected from CH2C ξ C -, —: -------- r — ^ II (Please read the notes on the back before filling in this page), 11 3-HO-PhC = -5 integer. V is an integer of 1-4, where R6 is
J 24 本紙張尺度適用中國國家榡準(CNS〉A4規格(210X297公釐) Α7 Β7 五、發明説明(22 ) R6基團是獨立的取代基,一個R6基團構成一.環,或二個 R6基團構成一環而一個R6基團是獨立的取代基,或三個 R6基團是獨立的取代基。所以此次類含這樣的化合物,其 中E單位是二-或三-取代的,且在爲二取代的時,由一或 二個R 6基團構成的任何環是螺旋環,在爲三取代的時,R 6 基團可構成螺旋環或非螺旋環。 於另一較佳具體實施例中,本發明係關於通式(L)化合 物,其中E單位上取代基的„!數是;當時,R6基 團構成非螺旋環;當m是2時,二個r6基團共肖構成非螺 旋環,或-個是獨立的取代基而另_韻成非螺旋 環。所以此次類含這樣的化合物,其中E單位蒂 二個R 6取代基,且至少此等取代基彡 , 叭丞艾—涉及非螺旋環。J 24 The standard of this paper is applicable to Chinese National Standards (CNS> A4 specification (210X297 mm) A7 B7 V. Description of the invention (22) R6 group is an independent substituent, one R6 group forms one ring, or two The R6 group forms a ring and one R6 group is an independent substituent, or three R6 groups are independent substituents. So this class contains compounds in which the E unit is di- or tri-substituted, and When it is di-substituted, any ring formed by one or two R 6 groups is a helical ring. When it is tri-substituted, R 6 group may constitute a helical ring or a non-helical ring. In the embodiments, the present invention relates to compounds of general formula (L), in which the number of substituents on the E unit is; at that time, the R6 group constitutes a non-spiral ring; when m is 2, the two r6 groups are in common. Form a non-spiral ring, or one is an independent substituent and the other is a non-spiral ring. So this class contains compounds in which the E unit has two R 6 substituents, and at least these substituents 彡,丞 丞 丞-involving non-spiral loops.
更特定説,通式(L)代表性的化合物,其中—衣 6 取代基涉及於構成非螺旋環,有如下構造的E H S、多個R (請先閲讀背面之注意事項再填寫本頁) 7— 裝. 訂 經濟部中央標準局員工消費合作社印製 -25-More specifically, the representative compound of general formula (L), in which the -6 substituent is involved in forming a non-spiral ring, has the following structure EHS, multiple R (please read the precautions on the back before filling this page) 7 — Packing. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs-25-
五、發明説明(23 I一 '(H2JRe.C) Ν〇·Η2( I- (H2-tRe·^ iH^RflbCh (H2^r\C) \ (Hi^bC)- (H2j.R".C)\ κι Β7 (CR*,H2J)i一| x Tv 〜 \ -/-(RiA s · i^y (CR'HjJa—丨 '(9^1-b) T。)1 7 (CAfleH2「山—f / ^ 严Vw -(HtJfc v iHh·* ~Y(Rl4)n -(H,.bR%Cr-C^cR9bHvb, \ ;-^~(Rh)h iCRatH2^)d- i-b) (CRe,H2J„- / (C'F^d (R14)«.及 乂),i.H,.ybcr—' iH^Rebpj^V. Description of the invention (23 I-'(H2JRe.C) Ν〇 · Η2 (I- (H2-tRe · ^ iH ^ RflbCh (H2 ^ r \ C) \ (Hi ^ bC)-(H2j.R ". C) \ κι Β7 (CR *, H2J) i 一 | x Tv ~ \-/-(RiA s · i ^ y (CR'HjJa— 丨 '(9 ^ 1-b) T.) 1 7 (CAfleH2 「 Mountain — f / ^ Yan Vw-(HtJfc v iHh · * ~ Y (Rl4) n-(H, .bR% Cr-C ^ cR9bHvb, \;-^ ~ (Rh) h iCRatH2 ^) d- ib) ( CRe, H2J „-/ (C'F ^ d (R14)«. And 乂), iH, .ybcr— 'iH ^ Rebpj ^
Λ IHh,. \ (Hh-. (CRebHΛ IHh,. \ (Hh-. (CRebH
V I- n--]--J I 裝— 11--"―訂— —----^ (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 其中a是0,1,或2 ; b是0或1 ;C是0或1 ; d是 是0或 1 ; e是 1-5 ; f是 1-4 ; g是3-5 ; h是2-4 是0-3 ; k是0-2 ; R6基圑的總數是〇,1,或2 S,或NR1 ;及z是1或2 ;每一 R1 4基團係獨立 1-9個碳的烷基,·芳基烷基,其中烷基部分含 基部分含6 - 1 0個碳;2 - 9個碳的烯基;芳基取 其中烯基部分含2-4個碳,芳基部分含6-1〇 碳的块基.,·芳基取代的块基,其中块基邵分含 〇戒 1 ; c + d ;1是〇-4 ; j ;0代表0, 遽自包括: l|-7個碳,芳 代的烯基, 碳;2 - 9個 2-4個碳, 侗 -26- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 第86106283號專利申請案 中文說明書修正頁(87年11月) A7 B7 五 '發明説明(24 ) 芳基部分含6-1〇個碳;6-10個碳的芳惠 _C02r3 ; _CON(R2)2 ; -(CH2)tR7,其中丈是 數;及-(CH2)vZR8,其中V是〇或;1_3的整數 或-0-,R1,R7,及R8之定義如前述。 較佳的通式(L)化合物,其中—或多個取代 及非螺旋壤之形成’有如下構造之E單位. COR/ ; 〕或1 - 4的整 而Z代表-S 基R6基團灰 I-V I- n-]-JI equipment — 11-" ―Order— —---- ^ (Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs a is 0, 1, or 2; b is 0 or 1; C is 0 or 1; d is 0 or 1; e is 1-5; f is 1-4; g is 3-5; h is 2- 4 is 0-3; k is 0-2; the total number of R6 radicals is 0, 1, or 2 S, or NR1; and z is 1 or 2; each R1 4 group is independently 1-9 carbons Alkyl, arylalkyl, in which the alkyl portion contains 6-10 carbons; the alkenyl group contains 2-9 carbons; the aryl group contains 2-4 carbons in the alkenyl portion, and the aryl portion Blocks containing 6 to 10 carbons. · Aryl-substituted blocks, in which the block contains 0 or 1; c + d; 1 is 0-4; j; 0 represents 0, and 遽 includes: l | -7 carbons, aryl alkenyl, carbon; 2-9 2-4 carbons, 侗 -26- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) Patent Application No. 86106283 Revised page of the Chinese manual for the case (November 87) A7 B7 Five 'invention description (24) The aryl part contains 6-10 carbons; 6-10 carbons are aromatic _C02r3; _CON (R2) 2;-(CH2 ) tR7, which Is the number of feet; and - (CH2) vZR8, wherein V is square or; 1_3 integer or -0-, R1, R7, and R8 are as defined in the foregoing. Preferred compounds of the general formula (L), in which-or more substituted and non-spiral soils are formed E units having the following structure. COR /;] or 1-4 integers and Z represents -S group R6 group ash I-
(Hj^Rs.C) \ (H (CRe.H,Jd- -(CRe6H,J. I- (H^R%C) * \ tH^RebC>-(Hj ^ Rs.C) \ (H (CRe.H, Jd--(CRe6H, J. I- (H ^ R% C) * \ tH ^ RebC >-
(CR(CR
-iCR'K 、(C,H 以 / i七) 經濟部中央標準局員工消費合作社印製 (,CRe.H2_Jd一I \ -—其中 a,b,c,d,(c + d),e,g,i,k,R U,及R14之定義如前述。 取代基T基團較佳是含乙炔的基,有如下的g式 R3〇(CH2)n.C ^C- 此處η,是1 - 4,R30係選自包括:|"10-,1^0-CH3C02-,CH3CH2OC〇2-,H02C-,〇HC-,Ph|·,3-HO-Ph-及PhCH20-,先決條件是在R3Q是Ph或3-H0-Ph時,n,= 0 最佳是,T 是 MeOCH2C = C-,( τ; -Pr)2NCH2C 兰 C-, CH3C02CH2C = C- ^ Et0C02CH2C = C- » H0CH2C = C-ΗΟ((:Η2;)2(: = (:_,(:Η3(:〇2(:(:ίί2)2(: = (:_,HC^CiCE^hCEC-, OHC(CH2)3C = C- ^ HO(CH2)4C = C- » PhC = C- -27- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 基囷總數 (n-Pr)2N-,-iCR'K, (C, H to / iVII) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (, CRe.H2_Jd-I \--of which a, b, c, d, (c + d), e , G, i, k, RU, and R14 are as defined above. The substituent T group is preferably an acetylene-containing group, and has the following g formula R3〇 (CH2) nC ^ C- where η is 1- 4, R30 is selected from the group consisting of: " 10-, 1 ^ 0-CH3C02-, CH3CH2OC〇2-, H02C-, oHC-, Ph |, 3-HO-Ph- and PhCH20-, the prerequisites are When R3Q is Ph or 3-H0-Ph, n, = 0 is best, T is MeOCH2C = C-, (τ; -Pr) 2NCH2C blue C-, CH3C02CH2C = C- ^ Et0C02CH2C = C- »H0CH2C = C-ΗΟ ((: Η2;) 2 (: = (: _, (: Η3 (: 〇2 (:(: ί2) 2 (: = (: _, HC ^ CiCE ^ hCEC-, OHC (CH2) 3C = C- ^ HO (CH2) 4C = C- »PhC = C- -27- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) The total number of bases (n-Pr) 2N-,
3-HO-PhC 一 私 . 訂------J (請先閱讀背面之注意事項再填寫本頁) 經 濟 部 中 央 準 局 員 工 合 作 社 印 製 卜 _A7 Γ ~~~~—--~~___ Β7 ' 五、發明説明(25 ) C-及PhCH2OCH2CsC-。 界足T取代基數目的下標X較佳是1或2,最 (圭是1,且當 X疋1時,Τ較佳是位於Α環的4_位上。 A環較佳是苯基或嘍吩環,最佳是苯基環。 較佳是1,4·伸苯基或2,5_嘧吩環,最佶 是1,4 _伸苯 基。 D單位最佳是羰基。 於E基團中,R6較佳是: U芳基烷基,其中芳基部分含6_10個碳, 烷基部分含 1-8個碳; 2卜(CH2)tR7,其中t是0或1-5的整數,R 7是含香族殘 基的亞胺醯基;或 3)-(CH2)vZR8,其中v是〇或ι_4的整數, z是S或〇, 及R8是6-10個碳的芳基或芳基烷基,其中芳 基部分含6 - 1 2個碳,烷基部分含4個碳。 R6基團最佳是如下的基團,其中任何芳香基彰 :佳是經取代 的; 1)芳基烷基,其中芳基部分是苯基,烷基1 卩分含1 - 4個 碳; 2)-(CH2)tR7,其中t是1-3的整數,及r7. LN-(1,2-荅 -二羧亞胺醯基),N-(2,3-茬-二羧亞胺越 -基),或N_ (1,8 -審-二叛亞胺酿基);或N -苯二醯亞胺@| ί基, 3 ) - (C Η 2) v ZR8,其中v是1-3的整數,z是 :S,及R8是 苯基。 -28- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) A7 、發明説明(26 更佳的通式(L)化合物由如下構造的R6單位: • Ph 或3-HO-PhC A private. Order ------ J (Please read the notes on the back before filling out this page) Printed by the Staff Cooperative of the Central Bureau of the Ministry of Economic Affairs_A7 Γ ~~~~ ------ ~ ~ ___ Β7 'V. Description of the invention (25) C- and PhCH2OCH2CsC-. The subscript X of the number of bound T substituents is preferably 1 or 2, most preferably (1, and when X 疋 1, T is preferably located at the 4-position of the A ring. The A ring is preferably phenyl or The phene ring is preferably a phenyl ring. A 1,4-phenylene or 2,5-pyrimidine ring is preferred, and the 1,4-phenylene ring is most preferred. The D unit is preferably a carbonyl group. E In the group, R6 is preferably: U arylalkyl, wherein the aryl part contains 6-10 carbons, and the alkyl part contains 1-8 carbons; 2 (CH2) tR7, where t is 0 or 1-5 An integer, R 7 is an iminofluorenyl group containing an aromatic residue; or 3)-(CH2) vZR8, where v is an integer of 0 or ι_4, z is S or 0, and R8 is an aromatic group of 6-10 carbons Or arylalkyl, where the aryl moiety contains 6 to 12 carbons and the alkyl moiety contains 4 carbons. The R6 group is preferably the following group, in which any aromatic group is preferably substituted; 1) an arylalkyl group, wherein the aryl part is phenyl, the alkyl group 1 contains 1 to 4 carbons; 2)-(CH2) tR7, where t is an integer of 1-3, and r7. LN- (1,2-fluorene-dicarboximidine group), N- (2,3-carbo-dicarboximide) (Vietyl-based), or N_ (1,8-triene-diamine imine); or N-phenylenediimide @ | ί 基, 3)-(C Η 2) v ZR8, where v is 1 An integer of -3, z is: S, and R8 is phenyl. -28- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) A7, Description of Invention (26 A better general formula (L) compound is composed of R6 units as follows: • Ph or
精於此技藝者會了解,本發明化合物係以 像互體異構物形式存在,此技藝都知道此種立體異構物於 生物系统中一般展現不同活性。本發b月包括片·有具對mmp 有抑制活性的可能的立體異構物,不管甚麼樣的立體異構 物’以及立體異構物混合物,其.中至少一種成員是具抑制 活性的。 本發明最佳的化合物如.下表所列: I) R/S 4、(3-控基-1-丙決基)_r_氧基-<5 基)-[1,1·-二苯基]-4-丁酸, 對映體或非鏡 經濟部中央標準局員工消費合作社印製 II) S-4'-(3-羥基-1_丙炔基hr-氧基· 基)-[1,1·-二苯基]-4-丁酸, III) R-4、(3-羥基-1-丙块基)-r -氧基-α 基)-[1,1· -二苯基]-4-丁酸, 4’-(3-甲氧基-1-丙炔基)-7*-氧基-« 基)-[1,1·-二苯基]-4-丁酸, 厂-氧基-α - (3 -苯基丙基)-4·-.(3 -丙基-[1,1,-二苯基]-4-丁酸, 4·-[3-(乙醯氧基)-1-丙炔基]-r-氧基-丙基)-[1,1,-二苯基]-4-丁酸, VII) 4'-[3_(乙氧基羧基)氧基]-1-丙炔基] IV) V) VI) -29 本紙張尺度適用中國國家標準(CNS〉Α4規格(2!0Χ297公釐) a -(3 -苯基丙 (3-苯基丙 (3-苯基丙 -(3 -苯基两 1 -己块基)_ α _(3 -苯基 --氧基-α _ —i ---il! 11^ --- - 訂---I--^ (請先閲讀背面之注意事項再填寫本頁) 五、 發明説明(27 A7 B7 丁酸, -本基丙基)_ 躂濟部中夬榡隼局員W消費合作衽印製 (3-苯基丙基)-[1,1,-[1,1,_二苯基]-4 VIII) 4,-[4 -羥基-1-丁炔基]-r -氧基-Λ _(3 [1,1·-二苯基]-4-丁酸, Ιχ) 4'-[3-(乙醯氧基)-1-丙炔基]氧基 丙基)-[1,1,-二苯基]-4-丁酸’ Χ) 4·-(4-羧基-1 - 丁 炔基]-r -氧基-Λ _(3 [Ι,Γ-二苯基]-4-丁酸, Xl) ?*-氧基-4,-(5-氧基-1-戌炔基)-汉-(3 [1 ,1 二苯基]-4- 丁酸, ΧΙΙ) 4,·(6-羥基-1-己块基]-r-氧基-α-(3 [1,1·-二苯基]-4-丁酸, ΧΙΙΙ) 氧基-4’-(苯基乙炔基苯基 二苯基]-4-丁酸及 XIV) 4'-[3-(羥基苯基)乙炔基]-r-氧基-基)-[1,1·-二苯基]-4-丁酸, XV) 1,3-二氫-1,3-二氧基-從-[2-氧基-2-[4,-[(3-苯基 甲氧基)-1-丙炔基][1,1'-二苯基]-4_基)]乙基]-2H_ 異吲哚-2 - 丁酸,及 XVI) 1,3·二氫-[2-[4'-(羥基乙炔基)[1, 4_基]-2 -氧基乙基]-1 ,3 -二氧基- 2Η-異β哚_2_ 酸。 —般製備方法: 本發明化合物可以已知化學反應及工序製伟。下述一般 製備方法有助精於此技藝者合成此等抑制劑 -β - ( 3 -苯基 -苯基丙基)- -苯基丙基)- -苯基丙基)- 丙基)-[1,1 '_ a (3 -苯基丙 1, 苯基]- 更詳細的實 (請先聞讀背面之注意事項再填寫本頁) "丨裝·Those skilled in the art will understand that the compounds of the present invention exist as tautomers. It is known in the art that such stereoisomers generally exhibit different activities in biological systems. This month b includes tablets. There are possible stereoisomers with inhibitory activity on mmp. No matter what kind of stereoisomers' and stereoisomer mixtures, at least one of the members is inhibitory. The best compounds of the present invention are listed in the following table: I) R / S 4, (3-Controll-1-propenyl) _r_oxy- < 5 group)-[1,1 · -di Phenyl] -4-butanoic acid, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy or Enantiomer II) S-4 '-(3-hydroxy-1_propynyl hr-oxy · yl)- [1,1 · -diphenyl] -4-butanoic acid, III) R-4, (3-hydroxy-1-propanyl) -r-oxy-α group)-[1,1 · -di Phenyl] -4-butanoic acid, 4 '-(3-methoxy-1-propynyl) -7 * -oxy- «yl)-[1,1 · -diphenyl] -4-but Acid, plant-oxy-α- (3-phenylpropyl) -4 ·-. (3-propyl- [1,1, -diphenyl] -4-butanoic acid, 4 ·-[3- (Ethyloxy) -1-propynyl] -r-oxy-propyl)-[1,1, -diphenyl] -4-butanoic acid, VII) 4 '-[3_ (ethoxy Carboxy) oxy] -1-propynyl] IV) V) VI) -29 This paper size applies to Chinese national standard (CNS> A4 specification (2! 0 × 297 mm) a-(3-phenylphenyl (3- Phenylpropane (3-phenylpropane- (3-phenylbis 1-hexyl) _α_ (3-phenyl--oxy-α_ —i --- il! 11 ^ ---- Order --- I-^ (Please read the notes on the back before filling out this page) V. Description of the invention (27 A7 B7 Butyric acid, -benzylpropyl) _ Printed by (3-phenylpropyl)-[1,1,-[1,1, _diphenyl]- 4 VIII) 4,-[4-hydroxy-1-butynyl] -r-oxy-Λ_ (3 [1,1 · -diphenyl] -4-butanoic acid, Ιχ) 4 '-[3 -(Ethoxy) -1-propynyl] oxypropyl)-[1,1, -diphenyl] -4-butanoic acid 'χ) 4 ·-(4-carboxy-1 -butyne Group] -r-oxy-Λ_ (3 [Ι, Γ-diphenyl] -4-butanoic acid, Xl)? *-Oxy-4,-(5-oxy-1-fluorenyl) -Han- (3 [1,1 diphenyl] -4-butanoic acid, χΙΙ) 4, · (6-hydroxy-1-hexyl) -r-oxy-α- (3 [1,1 · -Diphenyl] -4-butanoic acid, XIIIII) oxy-4 '-(phenylethynylphenyldiphenyl] -4-butanoic acid and XIV) 4'-[3- (hydroxyphenyl) acetylene Group] -r-oxy-yl)-[1,1 · -diphenyl] -4-butanoic acid, XV) 1,3-dihydro-1,3-dioxy-from- [2-oxy Yl-2- [4,-[(3-phenylmethoxy) -1-propynyl] [1,1'-diphenyl] -4-yl)] ethyl] -2H_ isoindole- 2-butyric acid, and XVI) 1,3 · dihydro- [2- [4 '-(hydroxyethynyl) [1,4-yl] -2 -oxyethyl] -1, 3-dioxy -2Η-isoβ-doline_2_ acid. -General preparation method: The compounds of the present invention can be made known by chemical reactions and procedures. The following general preparation method will help those skilled in the art to synthesize these inhibitors -β-(3-phenyl-phenylpropyl)--phenylpropyl)--phenylpropyl) -propyl)- [1,1 '_ a (3-Phenylpropane 1, Phenyl]-More detailed information (please read the precautions on the back before filling this page) "
、1T -30- 五、發明説明(28 ) Α7 Β7 例見下述實驗段所述的工作例。此等方法的各種基團,如 非特別説明,係以其屬名表示。各可變的下標n係於每一 方法中獨立表示。當在一給予構造中可變的釭團以給予的 經濟部中央標準局員工消費合作社印製 符號(即R 9)作一次以上的使用時,應了解到 團是可在其定義範圍内獨立變化的 通法A -本發明此等化合物,其中a及Β環分別是經取代 的苯基及伸苯基’可用;Friedel -Crafts反應以經取代的二苯 基MII與活化的含酿基的中間體,如丁二酸或戍二酸酐衍生 物ΜΙΠ或酿基氣MIV在有路易士酸催化劑,如三氣化銘, 之存在下於非質子溶劑,如1,1,2,2-四氣乙烷内反應製備。 週知的Friedel -Crafts反應可用多種溶劑及酸催化劑完成, 如 Berliner所著〇rg. React·, 1,229,1949及Heaney 所著Comp 〇rg. Synth. 2_, 733, 1991所述。 如果酐Mill是以不對稱方式作單取代或多取 產物MI-A常因在二個羰基上發生不同酐聯結而 合物形式存在。這樣生成的異構物可以結晶或色譜分析月 此技藝所知的標準方法純化。 如在市場上不能購得時,丁二酸酐Mill可用Stobbe縮合;: 以丁二酸二烷基酯與醛或酮(於測鏈R6上生成 行催化氫化,將半酯中間體水解成二酸,再以 酸酐轉化成酐Mill。或者以亞硫醯氯或草醯氯 間體,轉化成醯基氣MIV。有關Stobbe縮合,溶劑及驗見 Johnson and Daub. Org. React.色,1 每一此等基 代的,原半 以異構物碎 反應,然1 乙醯氣或i 處理半酯1 包括適宜< 1951。 此法在使用於MIII(R6=H,異丁基及Η,正戍基)製備 本紙張尺度適用中國國家標準(CNS )八4規格(2〖0Χ297公釐) -----------^ _ 裝------訂------^ (請先聞讀背面之注意事項再填寫本頁) A7 B7 五、發明説明(29 )1T -30- V. Description of the invention (28) Α7 Β7 Examples See the working examples described in the experimental section below. The various groups of these methods are indicated by their generic names unless otherwise specified. Each variable subscript n is represented independently in each method. When a variable group in a given structure is given to the printed symbol (ie, R 9) of the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs for more than one use, it should be understood that the group can be independently changed within its definition. General Method A-These compounds of the present invention, in which rings a and B are substituted phenyl and phenylene, respectively, are available; Friedel-Crafts reaction takes the middle of substituted diphenyl MII with activated brewing group Succinic acid or succinic anhydride derivative MI, or base gas MIV in the presence of a Lewis acid catalyst, such as Sanqihuaming, in an aprotic solvent, such as 1,1,2,2-tetrakis Prepared by reaction in ethane. The well-known Friedel-Crafts reaction can be accomplished with a variety of solvents and acid catalysts, as described by Berliner, Org. React., 1,229,1949 and Heaney, Comp., Synth. 2_, 733, 1991. If the anhydride Mill is monosubstituted or multiply obtained in an asymmetric manner, the product MI-A often exists in the form of a compound due to different anhydride linkages on two carbonyl groups. The isomers thus formed can be purified by crystallization or chromatographic analysis using standard methods known in the art. If it is not available on the market, Mill succinic anhydride can be condensed with Stobbe ;: Dialkyl succinate and aldehyde or ketone (produced on the test chain R6 to catalyze hydrogenation, the half ester intermediate is hydrolyzed to diacid Then, it is converted into Mill by anhydride. Or it is converted into sulfenyl chloride MIV by thionyl chloride or chloramphenicol. For Stobbe condensation, solvents and tests see Johnson and Daub. Org. React. Color, 1 each For these basic groups, the original half is crushed with isomers, but 1 is treated with acetylene or i. 1 includes suitable <1951. This method is used in MIII (R6 = H, isobutyl and fluorene, n戍 Base) The size of this paper is prepared in accordance with Chinese National Standard (CNS) 8-4 specifications (2 〖0 × 297mm) ----------- ^ _ Packing ------ Order ----- -^ (Please read the notes on the back before filling this page) A7 B7 V. Description of Invention (29)
面見评〇131^11,61狂1.,美:國專利4,771,038所述。 方法AMeet the comment 〇131 ^ 11,61 Mad 1., the United States: National Patent 4,771,038. Method A
.MI-A-3. M1II-A n = 0-3 —^t· n^i ml. a- - ^111 —^n ^in HI a^i— 1^1 I - l^i、一 n^i m· I In (請先閲讀背面之注意事項再填寫本頁) 驗 經 濟 部 中 Jt 標 準 局 % 工 消 費 合 社 印 製.MI-A-3. M1II-A n = 0-3 — ^ t · n ^ i ml. A--^ 111 — ^ n ^ in HI a ^ i— 1 ^ 1 I-l ^ i 、 一 n ^ im · I In (Please read the notes on the back before filling this page) Printed by Jt Standards Bureau, Ministry of Economic Affairs
MI-A-4 方法A特別適宜用於環形化合物’如ΜΙ·Α-3 R6基團聯於亞甲基鏈形成3 -7員的環’的製備 員的)只能以其順式異構物購得’生成本發明 -32 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 0 (CHz)MI-A-4 Method A is particularly suitable for use in the preparation of cyclic compounds 'such as those of the MI · A-3 R6 group linked to the methylene chain to form a 3-7 membered ring') which can only be isomerized in cis The material is purchased to generate the present invention-32 The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 0 (CHz)
^COjH^ COjH
R1 ,其中二個。小環(3 - 5 順式化合物 經 部 中 央 標 準 扃 員 工 合 作 社 印 製 A7 B7 . 五、發明説明(3〇 ) MI-A-3。用鹼,如 DBU,THF 内處理 MI-A-3 即 Γ製得反式化 合物MI-A-4。此經取代的四員環起始物奸,.丨 (αΜΙΠ-Α-l, 係以如下所示光化學2 + 2反應製成。此法特另j 適用於製備 R14是乙醯氧基或乙醯氧基亞甲基的化合物 。在 Friedel - Crafts反應後,醋酸根可作鹼性水解除去並轉 化成2 -(三甲 基矽烷基)乙基酯保護羧基。生成的有r14 = c] 12 0 Η的中間 體可用其他的R1 4基以通法G所述方法轉化成 物。 本發明化合 °\>° + V MV 乙赌 t μπι-α-ι \14 在丁酿鏈(例如,來自馬來酸肝或1 -環戊晞 1,2 -二幾酸 酐)之C-2及C-3有雙鍵或於側鏈上有雙鍵時 ’此 Friedel - Crafts法特別有用,如使用衣康酸肝作起始物 質製備二個 R6基團位於一側鏈碳上共同形成外亞甲基(= 時。此等化合物之後的用途於方法D中敘述。 - Η 2 )的產物 通法B ·或者,化合物MI可以一聯串反應製命 丨’包括將丙 二酸二烷基酯MVI以燒*基鹵素.行單烷基化 4·成中間體 .MVII,再用鹵甲基二苯基酮MVIII行烷基化, 生成中間體 MIX。再用水性鹼將構造MIX化合物水解,再 -將丙二酸中 間體加熱脱羧酸’生成MI-B-2(方法B - 1)。使 -用一當量的 。水性鹼製得R1 2爲烷基的酯MI-B-2,使用一 當量以上的 鹼,製得.酸化合物(R12 = H)。有.時不加熱製靖 -33- 卜二酸或酸酯 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公瘦)R1, two of them. Small ring (3-5 cis compounds are printed by the central standard of the Ministry of Labor 扃 A7 B7. V. Description of the invention (3〇) MI-A-3. MI-A-3 is treated with a base such as DBU, THF, ie The trans compound MI-A-4 was prepared by Γ. This substituted four-membered ring starter,. (ΑΜΙΠ-Α-1, was prepared by a photochemical 2 + 2 reaction as shown below. This method Another j is suitable for the preparation of compounds where R14 is ethoxyl or ethoxyl methylene. After Friedel-Crafts reaction, acetate can be removed by alkaline hydrolysis and converted into 2- (trimethylsilyl) Ethyl ester protects the carboxyl group. The intermediate formed with r14 = c] 12 0 可用 can be converted into other R1 4 groups by the method described in General Method G. The compound of the present invention ° \ > ° + V MV μπι-α-ι \ 14 Double bonds in C-2 and C-3 in Dingshang chain (for example, from maleic acid liver or 1-cyclopentanidine 1,2-di-chinoanhydride) or on side chains In the case of double bonds, this Friedel-Crafts method is particularly useful, such as using itaconic acid liver as a starting material to prepare two R6 groups on one side of the carbon to form an outer methylene group (= h). The subsequent use of the compound is described in Method D.-Η 2) Product General Method B · Or, compound MI can be prepared in a series of reactions 丨 'including the dialkyl malonate MVI to burn the * halogen. Monoalkylation is performed to form an intermediate. MVII, and then alkylated with halomethyldiphenyl ketone MVIII to form an intermediate MIX. The structural MIX compound is hydrolyzed with an aqueous base, and then malonic acid is intermediated. Decarboxylation by bulk heating to produce MI-B-2 (method B-1). Use-one equivalent. An aqueous base is used to obtain the ester MI-B-2 where R1 is an alkyl group. The acid compound is obtained (R12 = H). If there is no heating, it can be produced without jing-33- phthalic acid or acid ester. The paper size is applicable to Chinese National Standard (CNS) A4 (210X297 male thin)
Λ發明説明(31 H)(Dezeil,Λ Description of the Invention (31 H) (Dezeil,
Ml-B-i 〇 或者,二酯中間體MIX可用強酸,如濃鹽^,在醋酸中 木封閉的管内於110°c加熱约2 4小時製得MI-E -1 (R12= η )。 或者,之反應可在與烷基齒素反g之前反應, 製得相同的MIX(方法B-2)。 或者,可將含R 1 2 =埽丙基的二酯中間體河以乂在有吡咯 咬之存在下曝露於Pd催化劑生成MI-B^R12:Ml-B-i 〇 Alternatively, the diester intermediate MIX can be prepared from MI-E -1 (R12 = η) by heating it at 110 ° C for about 24 hours with a strong acid, such as a concentrated salt ^, in a tube closed in acetic acid. Alternatively, the reaction can be carried out before reacting with the alkyl halide to obtain the same MIX (Method B-2). Alternatively, MI-B ^ R12 can be formed by exposing the diester intermediate containing R 1 2 = propyl to the Pd catalyst in the presence of pyrrole bites:
Tetrahedron Lett. 28, 4371, 1990)。 中間體MVn係用二苯基Mil以Friedel -Craft反應與鹵乙醯 _素,如溴乙醯溴或氣乙醯氯,反應製成。或者,二苯基 可與乙醯氯或脆酸酐反應,再將生成的產物與,例如,溴 反應使鹵素化,生成中間體MVIII(X=Br)。 方法B的優點是能生產單一區域異構物(regi〇 is〇mers), 而万法A產生混合物。在側鏈尺6含芳香或雜芳香環時,方 法B特別有用,如果用方法a,此等芳香或雜芳香環會介入 分子内醯化反應,生成副產物。在鄰近終產化 的R6基團含雜原子,如氧,硫,或氮時,或含 能基團,如亞醯胺環時,此法也很有用。 ------------------ 1^.—— (請先聞讀背面之注意事項再填寫本頁) 訂 合物的羧基 更複雜的官 經濟部中央標準局員工消費合作社印製 -34 本紙張尺度適财關家辟(π^ϋ:(210χ297公鲞 經濟部中央標準局員工消費合作社印製Tetrahedron Lett. 28, 4371, 1990). Intermediate MVn is prepared by reacting diphenyl Mil with Friedel-Craft reaction with haloacetamidine, such as bromoacetammonium bromide or acetamidine chloride. Alternatively, the diphenyl group can be reacted with acetyl chloride or brittle anhydride, and the resulting product can be reacted with, for example, bromine to halogenate to form intermediate MVIII (X = Br). The advantage of method B is the ability to produce single regioisomers, while method A produces a mixture. Method B is particularly useful when the side chain rule 6 contains an aromatic or heteroaromatic ring. If method a is used, these aromatic or heteroaromatic rings may intervene in the molecular dehydration reaction to generate by-products. This method is also useful when the adjacent R6 group contains heteroatoms, such as oxygen, sulfur, or nitrogen, or when it contains energetic groups, such as an imidene ring. ------------------ 1 ^ .—— (Please read the precautions on the back before filling out this page) The carboxyl group of the compound is more complicated. Printed by the Bureau's Consumer Cooperatives-34 This paper is suitable for financial affairs and family protection (π ^ ϋ: (210 × 297)
I- --------f — 裝-- (讀先閲讀背面之注意事項再填寫本頁} 五、發明説明(33I- -------- f — Install-(Read the precautions on the back before filling out this page} 5. Description of the invention (33
Ru0 A7 B7 然後 異戊二烯基溴 12 2)03,CH2g2 然後 NaBHa, MeOH Ο Ο 3) Milsunobu -MVI 3)CBr4l or ,Ph3P 4)烷基化Ru0 A7 B7 then isoprenyl bromide 12 2) 03, CH2g2 then NaBHa, MeOH Ο Ο Ο 3) Milsunobu -MVI 3) CBr4l or, Ph3P 4) alkylation
通法c-特別有用的是使用對掌性HPLC分離外消旋產物混 合物的對映體(見,例如,Arit,et al·; Chem. :[nt. Ed_ Engl. 11,30, 1991)。本發明化合物可用對掌性輔助途徑製成純對 經濟部中央標準局員工消費合作社印製 映體。見,例如,Evans, Aldrichimica Act 1982,及其他精於此技藝者所知的類似參考文 通法D -化合物,其中R6是烷基-或芳基-或 基-或雜芳基獄基-硫基亞甲基,係用類似WO 90/05719所述 方法製備。將經取代的衣康酸酐MXVI(n=])在Friedel -Crafts條件下反應,生成酸MI-D-1,此可藉色講分析或用少 量異構的MI-D-5結晶分離。或用本發明化合物ΜΙ-π-4(由方 法Α至C製得)與曱醛在有鹼之存在下反應製成MI-D-5s。 然後將化合物MI-D-1或MI-D-5與氫硫基衍生物MXVII或 MXVIII在有催化劑,如碳酸鉀,乙基二異丁基胺,氟化四 丁基銨或游離根激發劑,如偶氮二異丁腈(AIBN)之存在下 於類如二乙基曱醯胺或四氫呋喃.之溶劑内反應 明化合物MI-D-2,MI-D-3,MI-D-6,或MI-D-7 a,11(2),23, 獻。 雜芳基-或酿 生成本發 (請先聞讀背面之注意事項再填寫本頁) -36- 本纸張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 經濟部中央標準局員工消費合作社印製General method c-is particularly useful for the separation of enantiomers of racemic product mixtures using p-palladium HPLC (see, for example, Arit, et al .; Chem .: [nt. Ed_ Engl. 11, 30, 1991). The compound of the present invention can be made into a purely pair-printed enantiomer of a consumer cooperative of employees of the Central Bureau of Standards of the Ministry of Economic Affairs by means of an auxiliary assistant approach. See, for example, Evans, Aldrichimica Act 1982, and other similar reference D-compounds known to those skilled in the art, where R6 is alkyl- or aryl- or aryl- or heteroarylhexyl-thio Methylene is prepared by a method similar to that described in WO 90/05719. The substituted itaconic anhydride MXVI (n =]) is reacted under Friedel-Crafts conditions to form the acid MI-D-1, which can be analyzed by color analysis or separated with a small amount of isomeric MI-D-5 crystals. Alternatively, MI-D-5s can be prepared by reacting the compound of the present invention MI-π-4 (made by methods A to C) with formaldehyde in the presence of a base. Then compound MI-D-1 or MI-D-5 with hydrogen thio derivative MXVII or MXVIII in the presence of a catalyst such as potassium carbonate, ethyl diisobutylamine, tetrabutylammonium fluoride or a free radical activator In the presence of azobisisobutyronitrile (AIBN), the compounds MI-D-2, MI-D-3, MI-D-6 are reacted in solvents such as diethylamidamine or tetrahydrofuran. Or MI-D-7 a, 11 (2), 23, dedication. Heteroaryl- or fermented hair (please read the notes on the back before filling out this page) -36- This paper size applies to China National Standard (CNS) A4 (210X297 mm) Employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by Consumer Cooperatives
I-1--^------J I 裝-- (請先閱讀背面之注意事項再填寫本頁) -β ~ί ' 五、發明説明(35 ) A7 B7 經濟部中央標準局員工消費合作社印製 通法E - 聯芳基化合物,如本申請書之此類化合'物 或雜芳基金屬化合物,其中金屬爲鋅;’錫,鑲 砂,銅’,叙等,與芳1基雜芳基鹵素或三氟甲 Suzuki或Stille交叉偶合反應製備。與下面方程 X爲金屬,其他爲画素化物或三氟甲烷磺 Pd(com)爲赵的可溶的複合物,如氯化-肆(三苯 或雙(三苯基膦)-鈀(III)。此等方法是精於此_藝者所週知 的。見,例如,Suziki, Pure Appl. Chem. 63., 213, 1994 ; Suziki, Pure Appl. Chem. 63_, 419, 1991 ;及Far:.na and Roth, "Metal-Organic Chemistry" Volume 5 (Chapter 1 起始物質MXXIII(B = 1,4-伸苯基)可用類似方 或D輕易製備,但用画苯代替二苯基作爲起始 時,X爲鹵的物料可用此技藝週知的方法轉化爲X位金屬 的物料,如用六甲基錫及鈀肆三苯基膦於曱苯内將溴中間 體加熱處理,即生成三曱基錫中間體< ΜΧΧΙΙΙ(Β =雜芳基)最易由方法C製備,唯用易 芳基而非用二苯基起始物質。中間體ΜΧΧΙΙ可 用可購得的物料以此技藝週知的方法製備 方法Ε 也可用芳基 鋰,硼, 燒續酸醋作 式中,Met或 酸醋(OTf)。 基膦)-把(0) ),1994。 法A,Β,C 物質。需要 起始物質 於講得的雜 以購得也可 m· I t —^ϋ ϊί 1^. n n (請先閱讀背面之注意事項再填寫本頁) 訂 (T)XA-Met ΜΧΧΙΙ +I-1-^ ------ JI equipment-(Please read the precautions on the back before filling out this page) -β ~ ί 'V. Description of invention (35) A7 B7 Employees ’consumption by the Central Standards Bureau of the Ministry of Economic Affairs Cooperatives print general method E-biaryl compounds, such as this compound 'compounds or heteroaryl metal compounds in this application, where the metal is zinc;' tin, sand setting, copper ', Syria, etc., and aryl 1 groups Heteroaryl halide or trifluoromethyl Suzuki or Stille cross coupling reaction. With the following equation X is a metal, others are pigment compounds or trifluoromethanesulfonate Pd (com) is a soluble complex of Zhao, such as chlorinated-tris (triphenyl or bis (triphenylphosphine) -palladium (III) These methods are well-known to the artist. See, for example, Suziki, Pure Appl. Chem. 63., 213, 1994; Suziki, Pure Appl. Chem. 63_, 419, 1991; and Far: .na and Roth, " Metal-Organic Chemistry " Volume 5 (Chapter 1 starting material MXXIII (B = 1,4-phenylene) can be easily prepared by analogues or D, but using benzene instead of diphenyl as starting material At the beginning, materials with X as halogen can be converted into materials with X position metal by well-known methods. For example, hexamethyltin and palladium triphenylphosphine are used to heat the bromine intermediate in toluene to form three compounds. The fluorenyltin intermediate < MXXIII (B = heteroaryl) is the easiest to prepare by Method C, using only an aryl group instead of a diphenyl starting material. Intermediate MXXII can use commercially available materials as a skill week Known method Preparation method E can also use aryl lithium, boron, and scorched acid vinegar in the formula, Met or acid vinegar (OTf). Phosphine)-((0)), 1 994. Method A, B, C Substance. Requires starting material. It can also be purchased as mentioned. M · I t — ^ ϋ ϊί 1 ^. N n (Please read the precautions on the back before filling this page) Order (T) XA-Met ΜΧΧΙΙ +
X-B-E-G MXXIH -►X-B-E-G MXXIH -►
Pd(com)Pd (com)
(T)XA-B-D-E-G MI-E T,x,A,B,E及G如構造(L)中之定義 Met=金.屬及X =鹵化物或三氟甲燒績酸酉旨 38- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 經濟部中央標準局員工消費合作社印製 五、發明説明(36 ) 或 Met=由化物或三氟甲烷磺酸酯及χ=金屬 此等通法可用於製備此等化合物,此等; Crafts反應,如法A,B,C,或D,會導致各 式的混合物。方法E也特別適用於製備這樣 中芳基,A或B,含一或多個雜原子(雜芳基) 呋喃,吡啶,噚唑,嘧唑,嘧啶或吡啡環等 化合物。 通法F_當方法F的R6基團共同形成4_7員的^ 中間體MXXV所示,可用二當量的強鹼,如 鐘或六甲基梦贫基酸胺链等,除去與嗣共轆的 酸停止反應,製得構造爲MXXVI的化合物。 方法,以MXXVI與氫硫基衍生物反應生成環 F-1 或MI-F-2。 的 以 备中 Friedel · 芳基醯化形 化合物,其 如含p塞吩, 代替苯基的 n 形 環時,如下 異丙基醯胺 雙鍵,再以 類似通法D 化合物MI- ——•nn H1UI4 I 1 I—I— n I n τ 一 U3.-δ (請先聞讀背面之注意事項再填寫本頁) 39- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)(T) XA-BDEG MI-E T, x, A, B, E and G as defined in the structure (L) Met = gold. Genus and X = halide or trifluoromethane Paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (36) or Met = by compound or trifluoromethanesulfonate and χ = metal Isotactic methods can be used to prepare these compounds, and so on; Crafts reactions, such as Method A, B, C, or D, can lead to various mixtures. Process E is also particularly suitable for the preparation of compounds such as aryl, A or B, containing one or more heteroatoms (heteroaryl) furans, pyridines, pyrazoles, pyrazoles, pyrimidines, or pyrene rings. General method F_ When the R6 group of method F together forms a 4-7 member ^ Intermediate MXXV, two equivalents of a strong base, such as bell or hexamethyl dreamanyl amine chain can be used to remove The acid stopped the reaction to prepare a compound structured as MXXVI. Method: MXXVI is reacted with a hydrogen thio derivative to form ring F-1 or MI-F-2. In the preparation of Friedel · aryl halogenated compounds, such as p-phene, instead of the n-ring of phenyl, the following isopropylamidine double bond, and then similar to the general method D compound MI- —— • nn H1UI4 I 1 I—I— n I n τ a U3.-δ (please read the precautions on the back before filling out this page) 39- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm)
五 '發明説明(37V. Description of the invention (37
方法FMethod F
經濟部中央檩準局員工消費合作社印製 I.-------1 -裝—— (請先閱讀背面之注意事項再填寫本頁} 訂 通法G-本發明化合物,其中二個R6基團相勒成經取代的 5 -員的環,最易用方法G製得。於此法中,押Tetrahedron U,Suppl·,411,1981所述方案製得酸CII(R=3)。用偶合 劑,如1-(3 -二曱基胺基丙基)-3 -乙基碳化二亞胺鹽酸 鹽,使此酸以酯的形式被保護[例如,R=苄基(Bn)或2-(三基甲基矽烷基)乙基(TMSE)],此方法是精於此技藝者週 知的。經取代的溴二苯基cm再以鎂處理轉化成格雷格納 試劑,再與c I反應,生成醇C VI。醇C VI經由用其曱基確酸Printed by the Consumers' Cooperative of the Central Government Bureau of the Ministry of Economic Affairs I .--------- 1-Pack—— (Please read the precautions on the back before filling out this page} Order G- Compound of the invention, two of which The R6 group forms a substituted 5-membered ring, which is most easily obtained by method G. In this method, acid CII is prepared by the scheme described by Tetrahedron U, Suppl ·, 411, 1981 (R = 3) Protect this acid as an ester with a coupling agent, such as 1- (3-diamidoaminopropyl) -3-ethylcarbodiimide hydrochloride [eg, R = benzyl (Bn ) Or 2- (triylmethylsilyl) ethyl (TMSE)], this method is well known to those skilled in the art. Substituted bromodiphenyl cm is then treated with magnesium to convert to Gregner reagent, and Reacts with c I to produce alcohol C VI. Alcohol C VI
I ®日作驗以精於此技藝者所知方命處理後,生成烯烴。 或者’將CIII於低溫(-7 8 C )以正丁基鐘使其.溴化物作原始 -40 本紙張尺度適用中國國家標隼(CNS ) A4規格(210X297公釐) 經濟部中央標準局員工消費合作社印製I ® is tested daily to produce olefins when processed by a person skilled in the art. Or 'make CIII at low temperature (-7 8 C) with n-butyl bell. Bromide as the original -40 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) Employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by Consumer Cooperatives
------I---J I 批衣-- (請先閱讀背面之注意事項再填寫本頁) 、-=5 J : A7 B7 五、發明説明(39 ) 關鍵中間體cvin之轉化成本發明目標化合物係以幾種方 式完成’視側鏈官能基Z而定。以CVIII與魏惕格(Wittig)試 劑反應,再行氫化生成Z是烷基或芳基烷基的產物。醛 C VIII與還原劑,如氫化參[(3_乙基_3_戊基)氧基]鋁鋰 (LTEPA)作選擇性反應生成醇CIX。此醇再於精於此技藝者 週知的 Mitsunobu條件(見Mistunobu, Synthesis, 1,1981)下 轉化成苯基醚或用於產生側鏈Z的各種雜原子取代的衍化 物。或者,以精於此技藝者所週知的條件將^乂轉化成離 去基’如甲苯續酸酯或溴化物,然後再用適宜的親核劑取 代離去基。此型反應的幾種例可見於N〇rman,et ai,j Med. Chem. 12, 2552,1994。將醇CIX直接醯化即生成本發明化 合物,其中Z = OAcyl,以此醇與各種烷基鹵素在有鹼之存 在下反應即生成烷基醚。在任何情形下都是視R及Z的安定 性用不同的方法除去酸阻斷基R以生成酸(R = H),但在所 有情形下都是用精於此技藝者所知的方法行鹼水解除去芊 (請先閱讀背面之注意事項再填寫本頁) γ—裝. 經濟部中央標準局員工消費合作社印製 基,或用氟化四丁基銨處理除去2-(甲基矽烷 通法Η -本發明酸的醯胺可藉在適宜的溶劑 或二甲基甲醯胺,内用初級或二級胺及糅合齊 碳化二亞胺處理此酸製備。此胺成分可只是烷 取代的胺,也可是胺基酸衍化物,其中羧基是阻斷的而胺基 是游離的。 通法I-本發明化合物,其中(τ)χ是炔基或 基,可根據通法I製備(Austin,J. 〇rg. Che )乙基。 如二氯曱烷 如二環己基 基或芳基燒 經取代的炔 46, 2280, 1981)。中間體MX係根據方法A,B,C,D或G以市場上 -42- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)------ I --- JI approved clothing-- (Please read the precautions on the back before filling this page),-= 5 J: A7 B7 V. Description of the invention (39) Conversion cost of key intermediate cvin The target compounds of the invention are accomplished in several ways depending on the side chain functional group Z. CVIII is reacted with Wittig reagent, and then hydrogenated to produce a product in which Z is an alkyl group or an arylalkyl group. Aldehyde C VIII reacts selectively with a reducing agent, such as lithium hydride [(3-ethyl_3-pentyl) oxy] aluminum lithium (LTEPA), to generate alcohol CIX. This alcohol is further converted to phenyl ether or various heteroatom-derived derivatives used to produce the side chain Z under Mitsunobu conditions (see Mistunobu, Synthesis, 1, 1981) known to the artisan. Alternatively, ^ 乂 is converted to a leaving group such as toluate or bromide under conditions well known to those skilled in the art, and then the leaving group is replaced with a suitable nucleophile. Several examples of this type of reaction can be found in Norman, et ai, j Med. Chem. 12, 2552, 1994. The alcohol of CIX is directly deuterated to form the compound of the present invention, where Z = OAcyl, and the alcohol is reacted with various alkyl halides in the presence of a base to form an alkyl ether. In any case, depending on the stability of R and Z, the acid-blocking group R is removed by different methods to form an acid (R = H), but in all cases, it is performed by methods known to those skilled in the art. Alkaline hydrolysis to remove plutonium (please read the precautions on the back before filling this page) γ-pack. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, or treated with tetrabutylammonium fluoride to remove 2- (methylsilane General method-The amidine of the acid of the present invention can be prepared by treating the acid with a primary or secondary amine and a hydrazide carbodiimide in a suitable solvent or dimethylformamide. The amine component may be substituted by alkane only. The amine may also be an amino acid derivative, in which the carboxyl group is blocked and the amine group is free. General method I-the compound of the present invention, wherein (τ) χ is an alkynyl group or a group, which can be prepared according to the general method I ( Austin, J. Org. Che) ethyl. For example, dichloromethane such as dicyclohexyl or aryl is substituted alkyne 46, 2280, 1981). Intermediate MX is on the market according to method A, B, C, D or G. -42- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm)
J 五、發明説明(4〇 ) A7 B7J V. Description of the invention (40) A7 B7
可購得的MIIRRkBr)起始製備。以MX與經取代的乙炔 MXI在有Cu(I)/鈀試劑之存在下反應,生成本發明化合物 MI-I-1。於特定情形下,r3可以是三蜣基曱妒烷基阻斷的 醇。此時.,曱矽烷基可用酸,如·三氟醋酸,或HF -吡啶試 劑處理除去。 方法ICommercially available MIIRRkBr) was initially prepared. Reaction of MX with substituted acetylene MXI in the presence of a Cu (I) / palladium reagent yields the compound MI-I-1 of the present invention. Under certain circumstances, r3 may be a tris (fluorenyl) alkyl-blocked alcohol. At this time, the arsenyl silyl group can be removed by treatment with an acid such as trifluoroacetic acid or HF-pyridine reagent. Method I
R3(CH2y-CSCH (Et),N~~—' Cul反式-一乳雙三苯基 膦鈀 0 R3(CH2)b-C=C,R3 (CH2y-CSCH (Et), N ~~ — 'Cul trans-a milk bistriphenylphosphine palladium 0 R3 (CH2) b-C = C,
MI-I-1 本發明化合物適宜的醫藥上可接受的鹽包括與有機或無 經濟部中央標準局員工消費合作社印製 機鹼所成的加成鹽。由此等鹼所衍生的形成鹽 是金屬離子,例如鋁,鹼金屬離子,如鈉或針 金屬離子’如釣或鎮離子,或胺鹽離子、其中 技藝已知的。其例包括銨鹽,芳基烷基胺如 N,N-二苄基伸乙基二胺,低烷基胺如甲基胺 胺,普魯卡因,低烷基六氫吡啶如N_乙基六氫吡啶,環烷 基胺如環己基胺或二環己基胺,i•金剛烷基胺, benzathine,或由胺基酸如精胺酸或賴胺酸等所 此等生理上可接受的鹽,如鈉或鉀鹽及胺基酸 述的醫學使用,且也是較佳的 此等鹽及其他並非生理上可接受的鹽可用於 下述目的.所用的產物。例如_,使用市場上可購 的離子可以 離子,驗土 有許多是此 二节基胺及 ,三級丁基 衍生的鹽。 鹽,可作下 分離或純化 得的對映體 43- 本纸張尺度適用中國國家標準(CNS ) A4規格(210Χ297公董) 經濟部中央標率局員工消費合作社印裝 9溶劑内可生 3反的對映體 ”。由於本發 其對映體爲 留於液體相 •量的能供應 • ’或於水性 ‘可用鹽以習 〇 酶 MMP-3, 丨抑制,所以 -其他的前面 特別是在催 IPs也有不同 分上的取代 的取代基會 的化合物可 病理情況有 MMPs。 實行於展現 用時,ΐ 多種醫I 及其他馬 五、發明説明(41 上的純胺,如( + )-辛可寧(cinch〇nine)於合適白 成本發明化合物的單一對映體的鹽結晶,將才 留於溶液内,此法即爲通常所謂的”經典解析 明特定化合物的一種對映體的生理效果通常車 大,此活性異構物即可以結晶方式純化出或 内。此類鹽係以本發明化合物的酸的形式與, 鹼性離子的鹼在能沉澱出鹽的介質内反應製4 介貧内製備然後再凍乾。而游離態的酸的形纟 用的中和技術製備,例如用硫酸氫卸,鹽酸等 現已發現本發明化合物抑制基質金屬蛋白 ΜΜΡ-9及ΜΜΡ-2,並能對ΜΜΙΜ作較小程度分 可用於治療或預防於背景段所述的疾病。由索 未列出的MMPs與列出的MMPs有高度共同性 化邵位,可以設想本發明化合物對其他的 程度的抑制。現已顯示,改變分子中聯芳基_ 基,以及改變聲稱化合物上的丙酸或丁酸鏈上 影響前列MMPs的相對抑制性。所以,這—類 藉選擇特定的取代基加以”調整",以使與特定 關的MMP(S)的抑制得到加強,而不影響無關的 治療由基質金屬蛋白酶引起的疾病的方法 此疾病的哺乳動物,包括人。 本發明抑制劑可使用於獸及人。作此目的使 於醫藥組合物,此组合物含有活性成分及—或 可接受的載劑,稀釋劑,填充劑,結合劑 (請先閲讀背面之注意事項再填寫本頁)MI-I-1 Suitable pharmaceutically acceptable salts of the compounds of the present invention include addition salts formed with organic bases produced by the consumer cooperatives of the Central Standards Bureau of the Ministry of Organic or Non-Economics. Salts derived from such bases are metal ions, such as aluminum, alkali metal ions, such as sodium or needle metal ions, such as fishing or ballast ions, or amine salt ions, of which the techniques are known. Examples include ammonium salts, arylalkylamines such as N, N-dibenzylethylenediamine, lower alkylamines such as methylamineamine, procaine, lower alkylhexahydropyridines such as N-ethyl Hexahydropyridine, cycloalkylamines such as cyclohexylamine or dicyclohexylamine, i-adamantylamine, benzathine, or physiologically acceptable salts of amino acids such as arginine or lysine Such as the sodium or potassium salts and amino acids described for medical use, and also these salts and other non-physiologically acceptable salts can be used for the following purposes. Products used. For example, ions can be ionized using commercially available ions. Many of the test soils are derived from these dibasic amines and tertiary butyl. Salt, which can be separated or purified as the enantiomer. 43- This paper size is applicable to Chinese National Standard (CNS) A4 (210 × 297). Printed by the staff of the Central Standards Bureau of the Ministry of Economic Affairs. The opposite enantiomer ". Since this enantiomer is left in the liquid phase, the amount of energy can be supplied," or in water, "the salt can be used to inhibit the enzyme MMP-3, so-the other fronts are especially In the case of IPs, there are also different substituents on the compounds. The pathological conditions are MMPs. When applied to display, a variety of medical I and other Ma Wu, invention description (41 pure amines, such as (+)- The crystals of the single enantiomer of cinchonine in a suitable compound of the invention will remain in solution. This method is commonly known as "classical analysis of the physiology of an enantiomer of a specific compound. The effect is usually large, and the active isomer can be purified or crystallized. This type of salt is reacted in the form of an acid of the compound of the present invention with a base of a basic ion in a medium capable of precipitating the salt. Lean internal preparation It is then lyophilized, and the free acid form is prepared by neutralization techniques, such as dehydration with hydrogen sulfate, hydrochloric acid, etc. It has now been found that the compounds of the present invention inhibit matrix metalloproteins MMP-9 and MMP-2, and can be compared to MIMIM A small degree can be used to treat or prevent the diseases described in the background paragraph. From the fact that MMPs not listed have a high degree of commonality with the listed MMPs, it is conceivable that the compounds of the present invention inhibit other degrees of inhibition. Now It is shown that changing the biaryl group in the molecule, and changing the relative inhibitory effect of the propionate or butyrate chain on the claimed compound affects the forefront MMPs. So, this kind of "select" and "adjust" by selecting specific substituents to Enhancing the inhibition of MMP (S) in a specific way without affecting the irrelevant method for treating a disease caused by matrix metalloproteinases Mammals of this disease, including humans. The inhibitors of the present invention can be used in animals and humans. This purpose is for pharmaceutical compositions that contain active ingredients and—or acceptable carriers, diluents, fillers, binding agents (please read the precautions on the back before filling this )
-44 - A7 B7 五、發明説明(42 劑,視給予方式及劑形而定。 關節内給 用以取得血 抑制劑的給予可以是精於此技藝者所知的_何適宜的方 式。適宜的非經腸給予的例包括靜脈内给予 予,皮下給予,及肌肉内給予。靜脈内給予 漿内藥物濃度高峰的快速調整。藥物半衰期^改進及使藥 物達於關節腔内可藉將藥物包於脂質體之助 特定滑液大分子上的脂質體外面加配位體,γ改進脂質體 達於關節腔的性質。或者,肌肉内、關節内、或皮下長效 注射液’不管疋否將藥物包裹微球體(例如含聚(D l _丙交 酯-共-乙交酯的微球體)内,可用以使藥物延長釋出。爲使 劑形方便使用,可用腹腔内植入儲器及隔,如可從 Pharmacia 購得的 Percuseal system。使用注射筆(inject〇r 如由 Bioject, 便並減少病 投送入滑液 下植入的渗 經濟部中央標準局負工消費合作社印製 pens)(例如Novo pin或Q-pen)或無針的注射器(例 Mediject,或Becton Dickinson各得者)也可更方 人痛苦。使用可植入的系,使藥物經由一管子 腔,可準確地控制藥物的釋出。此類例包括成 透泵,此泵可從ALZA購得,如ALZET滲透泵。 將藥物加於生物粘性顆粒載劑内(<2〇〇微米〕 素’聚丙晞酸醋或polycarbophil的生物枯性顆 ,如含纖維 粒載劑,再 同時使用合適的吸附增強劑,如磷脂質或醯基肉鹼,可作 os Nova所發 經鼻投送。可購得的系統包括DanBiosys及Scl· 展出的系統。 與本申請書前面背景段所述的各種肽化合物相較,本發 明化合物値得注意的性質是此等化合物的經口给予活性 -45- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 經濟部中央標準局員工消費合作社印製 五、發明説明(43 特疋化合物的於各種動物模型的經口生物 〇 、’么口技送可藉將藥物加於鍵、塗覆的紀、糖衣錠、 硬及軟明膠膠囊、溶液、乳液、或懸浮液内迷成。經口投 运也可藉將藥物加於腸衣膠囊内達成,此種膠囊可使藥物 釋入消化蛋白酶活性較低的結腸内。此類例 ALZA 及 Scherer Drug Delivery Systems 購 CT/Osmet™及PULSINCAP™系統。其他系統使用由結腸細 菌氮還原酶降解的氮交聯聚合物,或對pH敏感的聚丙烯酸 酿聚合物,此種聚合物在結腸内p Η增高時會被活化。上述 系統可與各種易購得的吸收增強劑合用。 經直腸投送可藉將藥加於塞劑内達成。 本發明化合物可藉加各種精於此技藝者所知的治療上爲 惰性的、無機的或有機的載劑製成上述的調_物。此類載 劑的例包括,但不限於,乳糖,玉米澱粉或^衍生物,滑 石粉,植物油,蠟,脂肪,多元醇如聚乙二 糖,醇,甘油等。爲幫助調配物的穩定,或| 利用率達90· 包括分別由 得的OROS- (請先閲讀背面之注意事項再填寫本頁) 丨裝· 訂 醇,水,蔗 幫助活性成 分的生物利用率,或爲在經口給予時使調配 道及氣味,調配物内也可加各種防腐劑,乳 劑,矯味劑,濕潤劑,抗氧化劑,甘味劑,增 劑,鹽,緩衝劑等。 此醫藥組合物的使用量視蜮形劑及所治的病 量可由精於此技藝者所知的方案決定。或者, 的目標酶的量計算需要量,此目標酶是治療疾 的。 有較好的味 化劑,分散 色劑,安定 而定。需要 也可以測得 病必須抑制 46- 本紙張尺度適用中國國家標隼(CNS ) Α4規格(210X 297公釐) 五、發明説明(44 本發明基貝金屬蛋白西备 、, 每不僅可用於治療前迟的生理上的 疾病,也可用於金屬Iώ 、 、 屬蛋白酶的純化及試驗基質金屬蛋白酶 、f此種/錄試驗可用天然的或合成的酶製劑於活體外 進行’也可用,例如,動物模型於活體内進行,此動物模 型中可自然地發現不正常的破壞性酶(使用基㈣變的動物 或基因轉移的動物)’或是給予外生性劑或以外科破壞關節 穩定所致而有不正常的破壞性酶。 實例 下述實例只用作説明性目的,無意,也不^理解爲對本 發明的限制。 通法: 濃縮指使用 所有反應,除非另有説明,都是於火燄乾燥的或爐乾燥 的玻璃器内在氬氣的正壓下且是用磁性攪拌進行。敏感液 體及溶液是用注射筒或管穿過橡皮隔引入反應器内。除非 另有説明,反應產物溶液係使用Buchi減壓 Buchi迴轉蒸發器内濃縮。 材料: 經濟部中央標準局員工消費合作社印製 二氯甲 有機或有機 st saint Paul M Science, 使用商業級試劑及溶劑,不進一步純化,唯乙酸及四氫 呋喃(THF)—般係用二苯基酮羰游基在氬氣下^餾 烷係用氫化鈣在氬氣下CaH蒸餾。多數特定的 金屬起始物質及試劑係購自Aldrich,1001 We Avenue, Milwaukee, WI 53233。溶劑多是取自 E 由 VWR Scientific銷售。 色譜分析: -47- 表紙張又度適用中國國家標準(CNS ) Α4規格(210X297公釐) 五、發明説明(45 ) A7 B7 完成,此儀器 -254250微米 線照明,(b) 分析性薄層色譜分析(TLC)係於Whatman®上 有預塗覆的以玻璃爲底的二氧化矽膠60A F 板。點之目測係以如下技術之一完成:(a)紫夕 曝露於碘氣下,(c)加熱將板浸入1 〇%的磷鉬酸於乙醇内的 溶液中,及(d)將板浸入含有〇. 5 %的濃硫酸的3 %的對-茴 香醛於乙醇内之溶液内,然後加熱。 柱色譜分析係用230-400網眼的EM Science 成。 分析用高效液體色譜分析(HPLC)係於1 4升/分鐘於 4.6x250毫米Microsorb®柱完成,以288毫微米監測,半製備 用HPLC係以24毫升/分鐘於21.4x250毫米Micnisorb®柱上完 成,以288毫微米監測。 儀器: 熔點(mp)以Thomas-Hoover溶點儀測定,未作 質子(士)核磁共振(NMR)譜係用General OMEGA 300 (300 MHz)分光計測定,碳十三( 係用 General Electric GN-OMEGA 300(75 MH 定。下述實驗中合成的多數的化合物都作NMI^分析,每一 例的光譜都與設想的構造一致。 氧化矽膠完 校訂。 Electric GN-C) NMR 譜 z)分光計測 (請先閲讀背面之注意事項再填寫本頁)-44-A7 B7 V. Explanation of the invention (42 doses, depending on the administration method and dosage form. Intra-articular administration to obtain blood inhibitors can be any suitable method known to those skilled in the art. Suitable Examples of parenteral administration include intravenous administration, subcutaneous administration, and intramuscular administration. Rapid adjustment of peak plasma drug concentrations in intravenous administration. Improvement of drug half-life ^ and improvement of the drug's reach in the joint cavity Adding ligands to the liposomes on the specific synovial macromolecules of the liposomes, γ improves the properties of the liposomes to reach the joint cavity. Or, intramuscular, intra-articular, or subcutaneous long-acting injections, regardless of whether or not Drug-coated microspheres (such as poly (D l_lactide-co-glycolide-containing microspheres)) can be used to prolong the release of the drug. For convenient use of the dosage form, a reservoir can be implanted intraperitoneally and Separately, such as the Percuseal system available from Pharmacia. Use an injection pen (inject〇r, such as by Bioject, and reduce the incidence of disease into the synovial fluid implanted pens printed by the Central Bureau of Standards of the Ministry of Economic Affairs and Consumer Cooperatives) (E.g. Novo pin or Q-pen) or needleless syringes (such as Mediject, or Becton Dickinson) can also be more painful. Using an implantable system, the drug is passed through a tube cavity, which can accurately control the release of the drug Such examples include osmotic pumps, which are commercially available from ALZA, such as ALZET osmotic pumps. The drug is added to a biocohesive particulate carrier (< 200 micrometers) of a biocide or polycarbophil Lacky particles, such as fiber-containing granules, and a suitable adsorption enhancer, such as phospholipids or amyl carnitine, can be used for nasal delivery by os Nova. Commercially available systems include DanBiosys and Scl · Compared with the various peptide compounds described in the background section of the present application, the noticeable property of the compounds of the present invention is the oral administration activity of these compounds -45- This paper is in accordance with the Chinese National Standard (CNS ) A4 size (210X297 mm) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (43 Special oral compounds in various animal models. Oral technology can be used to add drugs to the bond, Coated tablets, sugar-coated tablets, hard and soft gelatin capsules, solutions, emulsions, or suspensions. Oral delivery can also be achieved by adding drugs to enteric-coated capsules, which allow the drug to be released into digestive proteases Less active in the colon. Such examples include CT / Osmet ™ and PULSINCAP ™ systems from ALZA and Scherer Drug Delivery Systems. Other systems use nitrogen-crosslinked polymers degraded by colonic bacteria nitrogen reductase, or pH-sensitive polyacrylic acid A polymer that is activated when pΗ increases in the colon. The system described above can be used in combination with various commercially available absorption enhancers. Rectal delivery can be achieved by adding the drug to a suppository. The compounds of the present invention can be prepared by adding a variety of therapeutically inert, inorganic or organic carriers known to those skilled in the art. Examples of such carriers include, but are not limited to, lactose, corn starch or derivatives, talc, vegetable oils, waxes, fats, polyols such as polyethylene glycol, alcohol, glycerin, and the like. In order to help the stability of the formulation, or | Utilization rate up to 90 · Including separately derived OROS- (Please read the precautions on the back before filling out this page) 丨 Ordering alcohol, water, cane to help the bioavailability of active ingredients Or, in order to make the preparation channel and odor during oral administration, various preservatives, emulsions, flavoring agents, wetting agents, antioxidants, sweeteners, builders, salts, buffers, etc. can also be added to the preparations. The amount of the pharmaceutical composition to be used depends on the elixir and the amount of the disease to be treated, which can be determined by a scheme known to those skilled in the art. Alternatively, calculate the required amount of the target enzyme, and this target enzyme is for treating diseases. There are better flavoring agents, dispersing colorants, depending on stability. The disease can be measured if necessary. It must be suppressed. 46- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm). 5. Description of the invention Late physiological diseases can also be used for the purification and testing of metalloproteinases and metalloproteinases. This type of test can be performed in vitro using natural or synthetic enzyme preparations. It can also be used, for example, animal models Performed in vivo, abnormal destructive enzymes can be found naturally in this animal model (using animals that have undergone metastasis or gene transfer), or caused by the administration of exogenous agents or surgically destabilizing joints. Normal destructive enzymes. Examples The following examples are for illustrative purposes only and are not intended to be understood as a limitation on the present invention. General method: Concentration refers to the use of all reactions, unless otherwise specified, are flame-dried or Furnace dried glassware is under positive pressure of argon and is magnetically stirred. Sensitive liquids and solutions are introduced into the reaction through a rubber septum with a syringe or tube Unless otherwise stated, the reaction product solution is concentrated in a Buchi decompression Buchi rotary evaporator. Materials: Printed with chloroform organic or organic st saint Paul M Science by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, using commercial grade reagents And solvent, without further purification, only acetic acid and tetrahydrofuran (THF)-generally diphenyl ketone carbonyl group under argon distillation alkane series with calcium hydride under argon CaH distillation. Most specific metal starting materials The reagents and reagents were purchased from Aldrich, 1001 We Avenue, Milwaukee, WI 53233. Most of the solvents were taken from E and sold by VWR Scientific. Chromatographic analysis: -47- Table paper is also applicable to China National Standard (CNS) A4 specification (210X297 mm) ) 5. Description of the invention (45) A7 B7 is completed, this instrument is -254250 micron line illumination, (b) Analytical thin layer chromatography (TLC) is pre-coated glass-based silica dioxide on Whatman® 60A F plate. The visual inspection of the point was done by one of the following techniques: (a) Zixi was exposed to iodine, (c) the plate was immersed in a solution of 10% phosphomolybdic acid in ethanol by heating, and (d Dip the board Into a solution of 3% p-anisaldehyde in ethanol containing 0.5% concentrated sulfuric acid, and then heated. Column chromatography was performed using 230-400 mesh EM Science. High-performance liquid chromatography analysis (HPLC ) Was completed at 14 liters / minute on a 4.6 x 250 mm Microsorb® column and monitored at 288 nm. Semi-preparative HPLC was performed at 24 ml / min on a 21.4 x 250 mm Micnisorb® column and monitored at 288 nm. Apparatus: Melting point (mp) is determined by Thomas-Hoover melting point apparatus, without proton (±) nuclear magnetic resonance (NMR) spectrum measurement using General OMEGA 300 (300 MHz) spectrometer, carbon thirteen (using General Electric GN-OMEGA 300 (75 MH determination. Most of the compounds synthesized in the following experiments were analyzed by NMI ^, and the spectrum of each case was consistent with the expected structure. Silicon oxide was revised. Electric GN-C) NMR spectrum z) spectrometer (please (Read the notes on the back before filling out this page)
經濟部中央標準局員工消費合作社印I 質譜(MS),數據係用Kratos Concept 1-H分光計以液體卸 二級離子(LCIMS)(新型的快速原子撞擊(FABj取得。多數 下述實例合成的化合物都用低解析質譜分析 想的構造一致 通論 48 - 本紙張尺度適用中國囤家標準(CNS)八4賴_ (2丨0><297公瘦) 光譜都與設 五、發明説明(46 於多步驟方法中,序列步驟以數字表示 實例1 -化合物I之劁借Mass spectrometry (MS) of the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. The data is obtained using a Kratos Concept 1-H spectrometer with liquid desorption secondary ions (LCIMS) (a new type of fast atomic impact (obtained by FABj. Most of the following examples are synthesized All compounds are analyzed by low-resolution mass spectrometry. 48-This paper is in accordance with Chinese standards (CNS) 8 4 Lai _ (2 丨 0 > < 297 male thin). The spectra are the same as those set forth in the fifth, the invention description (46 In a multi-step method, the sequence steps are represented numerically by Example 1-Compound I
OEt 經濟部中央標準局員工消費合作社印裝 步驟1 ·於乾燥的2公升圓底三頸燒-瓶上裝配攪拌棒,等 壓加料漏斗,氬氣輸入口及溫度計。此燒瓶内載入氫化鈉 (8·4克95o/o的NaH;約0.33莫耳)於無水THF(700毫升)内之懸 浮液’用冰水浴冷卻。由加料漏斗用2 5分鐘滴加丙二酸二 乙酯(48.54克,0.30莫耳)。繼續攪拌15小時,然後經加料 管用10分鐘加1-漠-3-苯基丙烷(47毫升,約61克,約〇.3〇 莫耳)·於此反應混合物内加加料漏斗洗液(THf,2χ1〇毫 升),繼續攪拌3 0分鐘。用回流·濃縮器及塞換 及溫度計,反應物於回流加熱1 9小時。游混 溫,再用冰水浴冷卻。在攪拌下緩慢加蒸餾水 分離各層,水相用氣仿(100毫升)萃取。合併 10% HC1(250毫升)洗,分離出之水相再用氣仿〔1〇〇毫升)反 萃取。合併之有機物用飽和NaHC〇3( 250毫升)洗,分離出 之水相再用氯仿(100毫升)反萃取。將有機物乾燥 (Na2S〇4),濃縮,製得黃色'油體,於Vigreux柱 蒸餾純化。於124-138°C沸騰的部分即爲清潔 (57.21克,0.206莫耳;產出率68%)。TLC(50%己烷·二氣甲 嫁):Rf=0.32。 裝加料漏斗 合物冷至室 (400毫升)。 之有機物用 減壓(0.4拖) 的所需產物 f請先聞讀背面之注意事¾再壤窝本頁j i i Λ— n^— I I w .訂· 49- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 五、發明説明(47 ) A7 B7 0OEt Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economics Step 1 · Equip a dry 2 liter round-bottomed three-neck burner-bottle with a stir bar, an isocratic addition funnel, an argon input port, and a thermometer. This flask was charged with a suspension of sodium hydride (8.4 g of 95o / o NaH; about 0.33 moles) in anhydrous THF (700 ml) and cooled with an ice-water bath. Diethyl malonate (48.54 g, 0.30 mole) was added dropwise from the addition funnel over 25 minutes. Stirring was continued for 15 hours, and then 1-benz-3-phenylpropane (47 ml, about 61 g, about 0.30 mol) was added through the feeding tube over 10 minutes. To this reaction mixture was added a funnel washing solution (THf , 2 × 10 ml), stirring was continued for 30 minutes. Using a reflux concentrator, stopper and thermometer, the reaction was heated at reflux for 19 hours. Allow to mix and cool with ice-water bath. Distilled water was added slowly with stirring to separate the layers, and the aqueous phase was extracted with aerosol (100 ml). The combined 10% HC1 (250 ml) was washed, and the separated aqueous phase was back-extracted with gas-form (100 ml). The combined organics were washed with saturated NaHC03 (250 ml), and the separated aqueous phase was back-extracted with chloroform (100 ml). The organics were dried (Na2SO4) and concentrated to give a yellow 'oil, which was purified by distillation on a Vigreux column. The part that boils at 124-138 ° C is clean (57.21 g, 0.206 mol; yield 68%). TLC (50% hexane · dichloromethane): Rf = 0.32. Fill the addition funnel and cool the mixture to the chamber (400 ml). The required product of decompression (0.4 tow) of organic matter f Please read the notes on the back first ¾ then the home page jii Λ— n ^ — II w. Order · 49- This paper size applies to Chinese National Standard (CNS ) A4 specification (210X297 mm) 5. Description of the invention (47) A7 B7 0
Br 步驟2. 於1公升圓底燒瓶上裝配橡皮隔及氳氣輸入口。 此燒瓶内載入市場上可購得的4:溴二苯基(5C.00克,0.215 莫耳)於二氣甲烷(1 〇〇毫升)内之溶液。用注身-筒加溴乙醯 漠(21.0¾升’ 48.7克’ 0.^30莫耳),用冰水^浴冷至〇°C,同 時分批加A1C13(34.3克,0.258莫耳)。由此混漸橄欖綠之反 應混合物内有氣體排出。於室溫過2 4小時後 物小心倒入冷飽和NaHC03水溶液内。生成之:^合物用醋酸 乙酯(3 x200毫升)萃取,合併之有機層於1^2{;〇4上乾燥, 濃縮,製得所需產物,.爲黃色固體,產±5率定量 TLC(30%二氯曱烷-己烷):Rf=0 30。 將反應混合 經濟部中央標準局員工消費合作社印製Br Step 2. Attach a rubber septum and a radon inlet to a 1 liter round bottom flask. This flask was charged with a commercially available solution of 4: bromodiphenyl (5C.00 g, 0.215 mol) in digas methane (100 ml). Add bromoacetam (21.0¾ liters '48.7 grams' 0. ^ 30 moles) in a syringe-cylinder, cool to 0 ° C with ice water bath, and add A1C13 (34.3 grams, 0.258 moles) in portions. . As a result, gas is discharged from the reaction mixture of olive green. After 24 hours at room temperature, the contents were carefully poured into a cold saturated aqueous NaHC03 solution. The resulting: ^ compound was extracted with ethyl acetate (3 x 200 ml), the combined organic layers were dried over 1 ^ 2 {; 04, concentrated, to obtain the desired product, as a yellow solid, yield ± 5 rate quantitative TLC (30% dichloromethane-hexane): Rf = 30. Mixed response Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs
步骤3. 於2公升圓底三頸燒瓶上裝配磁攪拌棒,氬氣輸 入口’等壓加料漏斗。此燒瓶内載入步驟1產物(63.0克, 0.227莫耳)於THF(500毫升)内之溶液。將反應 器用冰水浴 -50- 本紙張尺度適用中國國家標隼(CNS >八4規格(21〇x 297公釐) (請先閲讀背面之注意事項再填寫本頁)Step 3. A 2 liter round-bottomed three-necked flask was equipped with a magnetic stir bar and an argon inlet ' isobaric addition funnel. This flask was charged with a solution of the product from Step 1 (63.0 g, 0.227 mol) in THF (500 ml). Use ice-water bath for reactor -50- This paper size is applicable to Chinese national standard (CNS > 8-4 size (21 × 297 mm)) (Please read the precautions on the back before filling this page)
A7 B7 五、發明説明(48 ) 冷卻。同時小心分批加氫化鈉(5_40克95%的HaIi,0214莫 耳)。此反應混合物於〇。(:攪拌1小時,再經由加料漏斗用約 20分鐘加步驟2產物(80.0克,0.215莫耳)於無水THF(3〇〇 毫升)内之溶液。將此深橘色反應混合物於室溫在氬氣下携 拌3小時。將反應器於冰水浴内冷卻,同時小心加蒸館水 (150毫升)。水相用醋酸乙酯(3>^300毫升)萃取,合併之有 機相於MgS〇4上乾燥,濃縮,製得124克暗橘包油體。此物 料直接用於下一操作,不必純化。 内’再加於 此反應混合 再於室溫攪 ^ϋ). * m n^i I - -- —^ϋ (請先閲讀背面之注意事項再填寫本頁) 將橘色油體溶於400毫升1 : 1的THF :甲醇 NaOH水溶液(4當量,500毫升,2.00莫耳)内。 物於室溫攪拌2 4小時,於5 0 攪拌4 8小時, 訂- 摔24小時。眞空除去大部分MeOH,殘餘物用2〇〇毫升j : i 醋酸乙酯:己嫁及200毫升己燒萃取。水相用]ici酸化,用 二份200毫升及三份1〇〇毫升醋酸乙酯萃取。合併之有機相 於MgS〇4上乾燥,濃縮,製得定暈產出率的二酸 TLC(10%甲醇-氯仿及1 %醋酸):Rf=〇.45。A7 B7 5. Description of the invention (48) Cooling. At the same time, careful addition of sodium hydride (5-40 g of 95% HaIi, 0214 mol) was performed in small portions. This reaction mixture was at 0 ° C. (: Stir for 1 hour, and then add a solution of the product from Step 2 (80.0 g, 0.215 mol) in anhydrous THF (300 ml) via an addition funnel over about 20 minutes. This dark orange reaction mixture was kept at room temperature at room temperature. Stir for 3 hours under argon. Cool the reactor in an ice-water bath while carefully adding steaming water (150 ml). The aqueous phase is extracted with ethyl acetate (3> 300 ml), and the combined organic phases are in MgS. It was dried and concentrated on 4 to obtain 124 g of dark orange oil-wrapped body. This material was used directly in the next operation without purification. Internally, it was added to the reaction mixture and stirred at room temperature). * Mn ^ i I --— ^ Ϋ (Please read the precautions on the back before filling this page) Dissolve the orange oil in 400 ml of 1: 1 THF: methanol NaOH aqueous solution (4 equivalents, 500 ml, 2.00 mol). Stir at room temperature for 24 hours, stir at 50 for 4 8 hours, and order-drop for 24 hours. Most of the MeOH was removed by emptying, and the residue was extracted with 200 ml of j: i ethyl acetate: hexane and 200 ml of hexane. The aqueous phase was acidified with ici and extracted with two 200 ml portions and three 100 ml portions of ethyl acetate. The combined organic phases were dried over MgS04 and concentrated to obtain a diacid TLC (10% methanol-chloroform and 1% acetic acid) with a fixed halo yield: Rf = 0.45.
經濟部中央標準局員工消費合作社印製 内,加熱至回流2 4小時。眞空除去溶劑,將1 c 二氧化矽廢上作色譜分析(以10-50%醋酸乙酯 步驟4 _ 將步骤3未純化的二酸溶於1,4 -二〃号燒(5〇〇毫升) 克殘餘物於 己烷,含1% 51 五、發明説明(49 醋酸作梯度洗離),製得0.840克(10%)所需產 體。熔點174°C。 物,爲黃色固Printed in the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, heated to reflux for 24 hours. The solvent was removed in vacuo, and 1 c of silica was used for chromatographic analysis (using 10-50% ethyl acetate in step 4). The unpurified diacid in step 3 was dissolved in 1,4-dioxane (500 ml). ) Gram of the residue in hexane, containing 1% 51 V. Description of the invention (49 acetic acid was used as gradient washing off) to obtain 0.840 g (10%) of the desired product. Melting point 174 ° C. The product is a yellow solid.
HOCHjCHCHOCHjCHC
經濟部中央標準局員工消費合作社印裝 步驟5. 於裝有橡皮隔及氬氣輸入口的15毫升的一頸燒 瓶内載入2.6毫升二乙基胺,步驟4產物(0.3 〇|)克,0.667莫 耳),炔丙醇(1.0毫升,17毫莫耳),碘化鋼(ι)(〇·〇220克, 〇-115莫耳),及反式-二氯雙(三苯.基膦)鈀(〇_11〇克,〇.157毫 莫耳)。此混合物'於室溫攪拌4小時。將反應混合物濃縮 (290毫克殘餘物),部分殘餘物(90毫克)於50克二氧化矽 膠上作色譜分析(20%醋酸乙酯-己烷,含0.5% 偶合產物,爲白色固體(0.035克,40%)偶合固 固體。熔點130°C 〇 實例2及實例3 -化合物II及III之製備 實例2及實例3係用Chiralcel AD®柱(2公分‘ χ2 EtOH,4.75% Η20及0.095% HOAc於CH3CN内殊對掌分離至 備,流速2 0毫升/分鐘。 實例2 :第一次流出Chiralcel AD®柱;1 H NMR CDC13) 8.02 (d, J=8.4 Hz, 2H), 7.67 (d, J=8 7.58 (d, J=8.7 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 5H), 4.54 (s,2H),3.46 (dd,ϊ=8.1,16.8 Hz,1I|),3.14.3.02 (m,2H),2.65 (t,J=7.2 Hz,2H), 1.64-1.84(m,4H) 蝻酸),至得 體,爲白色 5公分)以5% (300 MHz, .7 Hz,2H), 7.17-7.33 (m (請先閲讀背面之注意事項再填寫本頁) 7丨裝· ',ιτ- -52- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 。生成的混 A7 B7 五、發明説明(5〇 ) 實例 3 :第二次流出 Chiralcel AD®柱;1 H NMR (300 MHz, CDC13) ¢51 8.02 (d,J=8.4 Hz,2H),7.67 (d,J=i;.7 Hz,2H), 7.58 (d, J=8.7 Hz,2H), 7.53 (d, J=8.4 Hz,2H),7.17-7.33 (m, 5H), 4.54 (s, 2H), 3.46 (dd, J=8.1,16.8 Hz,III),3.14-3.02 (m,2H),2.65 (t,J = 7.2 Hz,2H),1.64-1.84(m, 4H)。 會例6-化合物VI之製備 於裝有橡皮隔及氬氣輸入口的10毫升的一_燒瓶内載入 0.5毫升p比咬,實例1 (0.0070克’ 0.014毫莫耳),及醋酸舒 (0.020毫升,22毫克,0.21毫莫耳)。此反應混合物於室Printing by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Step 5. In a 15-ml one-neck flask equipped with a rubber septum and an argon inlet, load 2.6 ml of diethylamine, and the product of step 4 (0.3 〇 |) g 0.667 mol), propargyl alcohol (1.0 ml, 17 mmol), steel iodide (ι) (0.0220 g, 〇-115 mol), and trans-dichlorobis (triphenyl.yl) Phosphine) Palladium (0-11 g, 0.157 mmol). This mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated (290 mg residue), and a portion of the residue (90 mg) was chromatographed on 50 g of silica (20% ethyl acetate-hexane containing 0.5% of the coupling product as a white solid (0.035 g (40%) coupled solids. Melting point 130 ° C 〇 Example 2 and Example 3-Preparation of Compounds II and III Example 2 and Example 3 were performed using a Chiralcel AD® column (2 cm 'χ 2 EtOH, 4.75% Η20 and 0.095% HOAc Separate with palms in CH3CN and prepare it at a flow rate of 20 mL / min. Example 2: First flow out of Chiralcel AD® column; 1 H NMR CDC13) 8.02 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8 7.58 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 5H), 4.54 (s, 2H), 3.46 (dd, ϊ = 8.1, 16.8 Hz, 1I | ), 3.14.3.02 (m, 2H), 2.65 (t, J = 7.2 Hz, 2H), 1.64-1.84 (m, 4H) acetic acid), decent, white 5 cm) at 5% (300 MHz, .7 Hz, 2H), 7.17-7.33 (m (please read the precautions on the back before filling out this page) 7 丨 Installation · ', ιτ- -52- This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm). The resulting mixed A7 B7 V. Description of the invention (50) Example 3: Chiralcel AD® column flowing out for the second time; 1 H NMR (300 MHz, CDC13) ¢ 51 8.02 (d, J = 8.4 Hz, 2H), 7.67 (d, J = i; .7 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.17-7.33 (m, 5H), 4.54 (s, 2H), 3.46 (dd, J = 8.1, 16.8 Hz , III), 3.14-3.02 (m, 2H), 2.65 (t, J = 7.2 Hz, 2H), 1.64-1.84 (m, 4H). Example 6-Compound VI was prepared with rubber septum and argon A 10 ml one-flask of the inlet was charged with 0.5 ml p-bite, Example 1 (0.0070 g '0.014 mmol), and acetic acid (0.020 ml, 22 mg, 0.21 mmol). This reaction mixture was used in room
溫攪拌2小時,然後加於30毫升1當量的HC1A 合物用三份30毫升醋酸乙酯萃取,合併之有機相於MgS04 上乾燥,濃縮。用HPLC純化(2.5%醋酸乙酯-二氯甲烷,含 0.01%三氟醋酸),製得3毫克(38%)實例6產^。熔點137 〇C。 實例7-化合物VII之製備 於裝有橡皮隔及氬氣輸入口的15毫升的一 1|:燒瓶内載入 2毫升三乙基胺,2毫升THF,化合物1(0.〇570克,0_134毫莫 耳),及乳甲酸乙醋(0.032毫升,36毫克,0.3 4毫莫耳)。 此反應混合物於室溫攪拌1 6小時,然後加於5 0毫升1當量 的H C1内。生成的混合物用三份5 〇毫升醋酸乙酯萃取,合 併之有機相於MgS04上乾燥,濃縮。於1〇克二氧化矽膠上 作柱色譜分析(40%醋酸乙酯-己烷,含〇·5% E:OAc),再作 HPLC純化(1.5%醋酸乙酯-二氣甲烷,含〇·〇ι%三氟醋酸), 製得 1 毫克(1.5%)實例 7 產物。MS (FAB-LSIMS) 499 -53- 本紙張尺度適用中國囤家標準(CNS ) A4規格(210X297公釐 ------------f It-- 一 ' (請先聞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 -ΙΓ n IL . A7 B7 _ 五、發明説明(51 ) [M+H]+。 實例11-化合物XI之製備 於装有橡皮隔及氬氣輸入口的25毫升的一,燒瓶内載入 1 毫升 CH2C12,實例 12 產物(0.012 克,0.026 Dess-Martin試劑(1 6毫克,0.038毫莫耳)(此試劑係根據Dess, et al·, J. Org. Chem. 41, 4156, 1983製備)。此反應混合物於 二份2 0毫升 。作HPLC純 酸),製得1 〇°C攪拌30分鐘,用30毫升醋酸乙酯稀釋,用 1當量的HC1洗。有機層於MgS04上乾燥,濃縮 化(1 .5%醋酸乙酯-二氣甲烷,含0.01%三氟醋 毫克(9%)實例 1 1 產物。NMR (300 Mhz, CDC13) (ί 9.70 (t, J=1.3 Hz, 1H), 8.05 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.15-7.35 (m, 5H), 3.46 (dd, J=8.1, 16.8 Hz, 1H), 3.14-3.02 (m, 2H), 2.67 (t, J=7.2 Hz, 2H), 2.48 (t, J=7.5 HZ, :!H), 2.41 (dt, J=l.3 Hz及6.3 Hz, 2H), 1.96 (m, 2H),1.64-1.84〔m,4H) 上述製備實例1,實例2,實例6,實例7,及實例i i方法 用以製備下述含二苯基的化合物。 經濟部中央標準局員工消費合作社印製 -54 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 經濟部中央標準局員工消費合作社印袋Stir for 2 hours, then add to 30 ml of 1 equivalent of HC1A compound and extract with three 30 ml portions of ethyl acetate. The combined organic phases are dried over MgS04 and concentrated. Purification by HPLC (2.5% ethyl acetate-dichloromethane containing 0.01% trifluoroacetic acid) yielded 3 mg (38%) of Example 6. Melting point: 137 ° C. Example 7-Preparation of Compound VII In a 15 ml of 1: 1 with a rubber septum and an argon inlet: 2 ml of triethylamine, 2 ml of THF, compound 1 (0.0570 g, 0_134 Millimoles), and ethyl lactate (0.032 ml, 36 mg, 0.3 4 millimoles). The reaction mixture was stirred at room temperature for 16 hours and then added to 50 ml of 1 equivalent of H C1. The resulting mixture was extracted with three 50 ml portions of ethyl acetate, and the combined organic phases were dried over MgS04 and concentrated. Column chromatography was performed on 10 g of silica (40% ethyl acetate-hexane, containing 0.5% E: OAc), and then purified by HPLC (1.5% ethyl acetate-digas methane, containing 0 · 0% trifluoroacetic acid) to give 1 mg (1.5%) of the product of Example 7. MS (FAB-LSIMS) 499 -53- This paper size is applicable to China Standards (CNS) A4 specification (210X297mm ------------ f It-- a '(Please read first Note on the back, please fill out this page again) Order printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs-ΙΓ n IL. A7 B7 _ V. Description of the Invention (51) [M + H] +. Example 11-Preparation of Compound XI in 25 ml of one with rubber septum and argon inlet, 1 ml of CH2C12, flask 12 was loaded with the product of Example 12 (0.012 g, 0.026 Dess-Martin reagent (16 mg, 0.038 mmol)) (this reagent is based on Dess, et al., J. Org. Chem. 41, 4156, 1983). This reaction mixture was prepared in 20 ml portions (as pure HPLC acid). The resulting mixture was stirred at 10 ° C for 30 minutes, and 30 ml of acetic acid was used. The ethyl acetate was diluted and washed with 1 equivalent of HC1. The organic layer was dried over MgS04 and concentrated (1.5% ethyl acetate-digasmethane containing 0.01% trifluoroacetic acid mg (9%) of the product of Example 1 1. NMR (300 Mhz, CDC13) (ί 9.70 (t, J = 1.3 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.15-7.35 (m, 5 H), 3.46 (dd, J = 8.1, 16.8 Hz, 1H), 3.14-3.02 (m, 2H), 2.67 (t, J = 7.2 Hz, 2H), 2.48 (t, J = 7.5 HZ,:! H ), 2.41 (dt, J = 1.3 Hz and 6.3 Hz, 2H), 1.96 (m, 2H), 1.64-1.84 [m, 4H) The above-mentioned preparation example 1, example 2, example 6, example 7, and example Method ii is used to prepare the following diphenyl-containing compounds. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economics -54 This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm). Cooperative printed bags
化合物 R 異構物 m.p.(°cy其他定性Compound R isomer m.p. (° cy other qualitative
I II hoch2c=c hoch2c=c R,S sI II hoch2c = c hoch2c = c R, S s
IU HOCHjChC R IV MeOCHjC=C R,S V (/i-Pr)2NCH2OC R,S VI CH3C02CH2ChC R.S VII Et0C02CH2C=C R,S vra HO(CH2)2C=C R,S DC CH3C02(CH2)2C=C R,S X HOACHAOC R,S XI OHC(CH2)3ChC R,S 130 'H NMR (300 MHZ, CDC13) δ 8.02 (d, J = 8.4 Hz, 2 H), 7.67 (d, J = B.7 Hz, 2 H), 7.58 (d, J = 8.7 Hz, 2 H), 7.53 (d, J = 8.4 Hz, 2 H), 7.17- 7.33 (m, 5 H), 4.54 (i, 2 H), 3.46 (dd, J =8.1, 16.8 Hz, 1 H), 3.02-3.14 (m, 2 H), 2.65 (t, J = 7.2 Hz, 2 Η), 1.64-1.84 (m, 4 H). Ή NMR (300 MHz, CDCl^) δ 8.02 (d, J = 8.4 Hz, 2 H), 7.67 (d, J = 8Hz, 2 H), 7 (d, J = 8.7 Hz, 2 H), 7.53 (d J = 8.4 Hz, 2 H), 7.17- 7.33 (m, 5 H), 4.54 (s 2-H), 3.46 (dd, J =8.1,16.8 Hz, 1 H), 3.02-3 14 (m, 2 H), 2.65 (t, J = 7.2 Hz, 2 H), 1.64-1.^4 (m, 4 H). 136 I MS (FAB-LSIMS) 5|i0 [M+H]^ 137 MS (FAB-LSIMS) 4^9 [M+H]* 124 MS (FAB-LSIMS) 483 [M+H]*. 184 Ή NMR (300 MHz, CDClL) δ 9.70 (t, y ^ 1.3 Hz, 1 H), 8.05 (d,J= 8.4 Hz, 2 H), 7.70 (d, J = 8.4 Hz, 2 H), 7.65 (d, J = 8.4 Hz, 2 H), 7.44 (d, J= 8.4 Hz, 2 H), 7.15-7.35 (m, 5 H), 3.46 (dd, J= 8.1, 16.8 Hz, H), 3.14-3.02 (m, 2 H), 2.67 (t, ./= 7.2 Hz 2 H), 2.48 (t,J =7.5 Hz, 2 H), 2.41 (dt, J = 1.3 Hz and 6.3 Hz, 2 Η), 1.96 (m, 2 H), 1.6Ί1.84 (in, 4 H). -55- 本紙張尺度適用中國國家標準(CNS )八4^格(210X297公釐) -----------1 I装-- (請先閲讀背面之注意事項再填寫本頁) 訂 j 五、發明説明(53IU HOCHjChC R IV MeOCHjC = CR, SV (/ i-Pr) 2NCH2OC R, S VI CH3C02CH2ChC RS VII Et0C02CH2C = CR, S vra HO (CH2) 2C = CR, S DC CH3C02 (CH2) 2C = CR, SX HOACHAOC R , S XI OHC (CH2) 3ChC R, S 130 'H NMR (300 MHZ, CDC13) δ 8.02 (d, J = 8.4 Hz, 2 H), 7.67 (d, J = B.7 Hz, 2 H), 7.58 (d, J = 8.7 Hz, 2 H), 7.53 (d, J = 8.4 Hz, 2 H), 7.17- 7.33 (m, 5 H), 4.54 (i, 2 H), 3.46 (dd, J = 8.1, 16.8 Hz, 1 H), 3.02-3.14 (m, 2 H), 2.65 (t, J = 7.2 Hz, 2 Η), 1.64-1.84 (m, 4 H). Ή NMR (300 MHz, CDCl ^ ) δ 8.02 (d, J = 8.4 Hz, 2 H), 7.67 (d, J = 8Hz, 2 H), 7 (d, J = 8.7 Hz, 2 H), 7.53 (d J = 8.4 Hz, 2 H ), 7.17- 7.33 (m, 5 H), 4.54 (s 2-H), 3.46 (dd, J = 8.1, 16.8 Hz, 1 H), 3.02-3 14 (m, 2 H), 2.65 (t, J = 7.2 Hz, 2 H), 1.64-1. ^ 4 (m, 4 H). 136 I MS (FAB-LSIMS) 5 | i0 [M + H] ^ 137 MS (FAB-LSIMS) 4 ^ 9 [ M + H] * 124 MS (FAB-LSIMS) 483 [M + H] *. 184 Ή NMR (300 MHz, CDClL) δ 9.70 (t, y ^ 1.3 Hz, 1 H), 8.05 (d, J = 8.4 Hz, 2 H), 7.70 (d, J = 8.4 Hz, 2 H), 7.65 (d, J = 8.4 Hz, 2 H), 7.44 (d, J = 8.4 Hz, 2 H), 7.15-7.35 (m , 5 H), 3.46 ( dd, J = 8.1, 16.8 Hz, H), 3.14-3.02 (m, 2 H), 2.67 (t, ./= 7.2 Hz 2 H), 2.48 (t, J = 7.5 Hz, 2 H), 2.41 ( dt, J = 1.3 Hz and 6.3 Hz, 2 Η), 1.96 (m, 2 H), 1.6 Ί 1.84 (in, 4 H). -55- This paper size applies Chinese National Standard (CNS) 8 4 ^ divisions (210X297mm) ----------- 1 I equipment-(Please read the notes on the back before filling this page) Order j V. Description of the invention (53
XII HO(CH2)4C = C XIII PhC 三 C XIV 3-HO-PhOCXII HO (CH2) 4C = C XIII PhC Three C XIV 3-HO-PhOC
R,S R,S R,S ιφ 15 23 實例15-化合物XV之劁借_R, S R, S R, S φ 15 23 Example 15-Borrowing of Compound XV_
Ν —^n-i Tn· ml I ^^—^1 n (請先閱讀背面之注意事項再填寫本頁) 步驟1.將氫化納(4.35克,181毫莫耳)於新蒸餘的 THF(100毫升)内之溶液冷至〇。(:,用市場上^購得的丙二 酸二烯丙基(35.0克,190毫莫耳)經由滴漏斗處理4〇分鐘 於室溫攪拌30分鐘後,將N-(2-溴乙基)苯鄰 (43.9克,247毫莫耳)一次加於此溶液内,將混 回流。4 8小時後將此溶液冷至〇 °C,用2當量的H C1使停止 反應,濃縮至原容積的20%。濃縮物以醋酸乙 稀釋,相繼用飽和K2C03水溶液及NaCl飽和溶 相於MgS〇4上乾燥,過遽,減壓濃縮。作閃柱 5-25%醋酸乙酯-己烷梯度洗離),製得2-苯鄰 基乙基丙二酸二烯丙酯(41.2克,64%),爲 !H NMR (300 MHz, CDC13) ά 7.82 (m, 2Η), 7 5.85 (m, 2H), 5.30 (m, 2H), 5.22 (m, 2H), 4.60 ( -56- 本紙張尺度適用中國國家標隼(CNS )八4規格(公釐) 訂 二甲醯亞胺 合物加熱至 經濟部中央樣準局員工消費合作社印製 酯(300毫升) 液洗。有機 色譜分析以 二甲醯亞胺 無四油體。 .72 (m, 2H), 4H), 3.80Ν — ^ ni Tn · ml I ^^ — ^ 1 n (Please read the notes on the back before filling this page) Step 1. Place sodium hydride (4.35 g, 181 mmol) in freshly distilled THF (100 The solution was cooled to zero. (: Commercially available diallyl malonate (35.0 g, 190 mmol) was treated through a dropping funnel for 40 minutes and stirred at room temperature for 30 minutes, and then N- (2-bromoethyl ) Benzyl (43.9 g, 247 mmol) was added to this solution once, and the mixture was refluxed. After 48 hours, the solution was cooled to 0 ° C, and the reaction was stopped with 2 equivalents of H C1, and concentrated to the original volume. 20%. The concentrate was diluted with ethyl acetate, successively dried over MgS04 with saturated K2C03 aqueous solution and NaCl saturated solution, concentrated under reduced pressure, washed as a flash column with 5-25% ethyl acetate-hexane gradient washing. Ion) to obtain diallyl 2-phenanthrylethylmalonate (41.2 g, 64%) as! H NMR (300 MHz, CDC13) ά 7.82 (m, 2Η), 7 5.85 (m, 2H), 5.30 (m, 2H), 5.22 (m, 2H), 4.60 (-56- This paper size is applicable to China National Standard (CNS) 8-4 (mm). Ester (300 ml) printed by the Consumer Cooperative of the Central Sample Bureau of the Ministry of Economic Affairs, liquid washing. Dimethyimine-free tetra-oil body was analyzed by organic chromatography. 72 (m, 2H), 4H), 3.80
、發明説明(54 於新蒸餾的 J=6.6 Hz, 2H), 3.46 (t, J=7.2 Hz, 1H), 2.3() (dd, J=13.8, 6 9 Hz,2H)。Description of the invention (54 for newly distilled J = 6.6 Hz, 2H), 3.46 (t, J = 7.2 Hz, 1H), 2.3 () (dd, J = 13.8, 6 9 Hz, 2H).
步驟2. 將步驟1產物(5.20克,14.6毫莫耳 THF(l〇〇毫升)内之溶液冷至〇 ,同時緩慢加NaH(385毫 克’ 16.1毫莫耳)。4 0分鐘後將反應混合物升至室溫,分批 加實例1步驟2產物(4.55克,14.6毫莫耳),將此混合物攪拌 2 4小時。再將反應混合物冷至〇。匸,用2當量 升)使緩慢停止反應,用一份150毫升二氣甲燒及二份1〇〇毫 升二氯甲烷萃取。合併之有機相於MgS04上乾 濃縮,製得6.50克(71%)所需產物,不必純化用於步驟3。 TLC(30%醋酸乙酯-級烷):Rf;〇 4。 -—1% It— I - 1^1 I I I (請先閲讀背面之注意事項再填寫本頁) 、-β 經濟部中央標準局員工消費合作社印製Step 2. The solution of the product from Step 1 (5.20 g, 14.6 mmoles in THF (100 mL) was cooled to zero while NaH (385 mg '16.1 mmoles) was slowly added. The reaction mixture was added after 40 minutes. The temperature was raised to room temperature, and the product of Step 2 of Example 1 (4.55 g, 14.6 mmol) was added portionwise, and the mixture was stirred for 24 hours. The reaction mixture was cooled to 0 ° C, and 2 equivalents were used to slowly stop the reaction. It was extracted with 150 ml of dichloromethane and 100 ml of dichloromethane. The combined organic phases were dried over MgS04 and concentrated to give 6.50 g (71%) of the desired product, which was used without purification in step 3. TLC (30% ethyl acetate-grade alkane): Rf; 04. -—1% It— I-1 ^ 1 I I I (Please read the precautions on the back before filling out this page), -β Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs
步驟3. 將步驟2產物(6.50克,1〇·4毫莫耳)於 (100毫升)内之溶液冷至0。(:,相繼加肆( (0.180克.,M6毫莫耳)及p比洛咬(2.40毫升,29卫 1,4 -二崎垸 苯基膦)鈀 毫莫耳)。於 __! -57- 本紙張;^度適用中國國家標準(CNS ) A4規格(210X297公釐) A7 B7 >昆合物倒入2 100毫升二氣 滤,濃縮, 質的樣品溶 。冷至室溫 上作色譜分 製得所需酸 產出率,由 熔點 209-210 五、發明説明(55 〇°C攪拌2小時及於室溫攪拌4小時後,將反應 當量的HC1(100毫升)内。生成之混合物用四份 甲燒萃取’合併之有機相於MgS〇4上乾燥,過 製得二酸,,爲黃色固體(9 7〇克)。將3 _ 8克此物 於1,4 -二噚烷(150毫升)内,於回流加熱i小_ 後,將溶液濃縮,殘餘物於300克二氧化矽 析,(以5 % -15%甲醇-二氣甲烷作梯度洗離), (〇.3〇〇克),再重結晶純化,製得〇.17〇克(59%雒 步驟2開始計算)所需產物,爲白色結晶固體 °C 〇 (請先閲讀背面之注意事項再填寫本頁) 裝- 0、Step 3. The solution of the product from Step 2 (6.50 g, 10.4 mmol) in (100 ml) was cooled to zero. (:, Successively added ((0.180 g., M6 millimoles) and p bilo bite (2.40 ml, 29 Wei 1,4-Di-Dicrazylphenylphosphine) palladium millimoles). In __!- 57- This paper; ^ degrees are applicable to Chinese National Standard (CNS) A4 specifications (210X297 mm) A7 B7 > Kun compound is poured into 2 100 ml two-air filtration, concentrated, and the quality sample is dissolved. Cool to room temperature to make Chromatography was used to obtain the desired acid yield, from the melting point of 209-210 V. Description of the invention (stirred at 55 ° C for 2 hours and at room temperature for 4 hours, the reaction equivalent of HC1 (100 ml) was generated. The mixture was extracted with four portions of methane, and the combined organic phases were dried over MgSO and dried to give the diacid as a yellow solid (970 g). 3-8 g of this material was added to 1,4-dioxane. In hexane (150 ml), the solution was concentrated under reflux, and the solution was concentrated, and the residue was precipitated in 300 g of silica (washed off with a gradient of 5% to 15% methanol-digas methane), (0. (300 g), and then recrystallized and purified to obtain 0.170 g (59% (calculated from step 2)) of the desired product, which is a white crystalline solid ° C. (Please read the precautions on the back before filling (Write this page) Pack-0,
-C=CH -訂 輸入口的100 耳),冷至0 經濟部中央標準局員工消費合作社印製 莫耳)’此混 内,用一份 (t, J=2.4 Hz, 步驟4. 於含2毫升THF之裝有橡皮隔及氬氣 毫升的一頸燒瓶内載入NaH(435毫克17.2毫莫 °C,同時以注射筒用約5分鐘時間加快丙醇(1.0毫升,〇.963 克,17_2毫莫耳)。此混合物於〇°C攪拌10分餘及於室溫擾 拌3 0分鐘。加苄基溴(1.8毫升,2.59克,15.1毫 合物於室溫攪拌3 6小時,倒入戊烷(150毫升) 100毫升鹽水洗。蒸發移去溶劑.,殘餘物(3.5克黃色油)直 接用於步驟5。4 NMR (300 MHz CDC13) ‘d 7.36-7.31 (m. 5H), 4.61 (s, 2H), 4.17 (d, J=2.4 Hz, 2H), 2.47 1H)。 58- 本紙張尺度適用中國國家樣隼(CNS ) M規格(21(rx297公釐 五 、發明説明(56 A7 B7-C = CH-order 100 ears of the input port), cold to 0 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, printed by Moore) 'this mix, use a copy (t, J = 2.4 Hz, step 4. A 2 ml THF filled flask with a rubber septum and argon ml was charged with NaH (435 mg 17.2 mmol ° C), while the propanol (1.0 ml, 0.963 g, 17_2 mmol). The mixture was stirred at 0 ° C for 10 minutes and stirred at room temperature for 30 minutes. Add benzyl bromide (1.8 ml, 2.59 g, 15.1 mmol) and stir at room temperature for 3 6 hours. Pour Pentane (150 ml) was washed with 100 ml of brine. The solvent was removed by evaporation. The residue (3.5 g of yellow oil) was used directly in step 5. 4 NMR (300 MHz CDC13) 'd 7.36-7.31 (m. 5H), 4.61 (s, 2H), 4.17 (d, J = 2.4 Hz, 2H), 2.47 1H). 58- This paper size is applicable to China National Samples (CNS) M specification (21 (rx297 mm. V. Description of the invention (56 A7 B7
步驟3產物作 起始物質製備實例15產物。熔點151°C 复圾1 6化合物XVI之製備 t-BuMqSiO、The product of Step 3 was used as starting material to prepare the product of Example 15. Melting point 151 ° C Preparation of 16 compound XVI t-BuMqSiO,
C = CH (請先閲讀背面之注意事項再填寫本頁) -裝· 經濟部中央標準局員工消費合作社印製 步驟1. 於裝有橡皮隔及氬氣針輸入口的10+毫升的一頸 燒瓶内載入炔丙酮(1.0毫升,0.963克,17.2毫_耳)’醚(20 毫升),冷至0°C,同時缓慢加NaH(435毫克,17.2毫莫耳) 此混合物於室溫攪拌1小時,加·三級丁基貳甲基矽烷基氯 (2.6克,17.2毫莫耳)。此反應混合物於室溫攪泮6小時,倒 入己烷(150毫升)内,用1當量的HC1洗。有機相於MgS〇4 上乾燥,濃縮,製得2.8 8克黃色固體,不必純化直接用於 步驟2。iH NMR (300 MHz, CDC13)汐 4.29 (d,J=2.1 Hz, 2H), 2.37 (t, J=2,l Hz, 1H), 0.89 (s, 9H), 0.11(s, 3H) 、νβ 59- 本紙張尺度適用中國國家標率(CNS ) A4規格(210X297公釐) 五、發明説明(57 A7 B7 步驟2 · 用實例1步驟2方法使用市場上可跗得的4 -碘 笨基及乙醯氯製得所需乙醯基二苯基。TLC(l·〕%醋酸乙酯-己坑):Rf=0.3。 0 -C.C 替 ^ 步驟3 . 用實例1步驟5方法使用步驟1產物 製得所需二苯基乙炔。TLC(10%醋酸乙酯己 烷 殳步驟2產物 ):Rf=0.4。 (請先閲讀背面之注意事項再填寫本頁)C = CH (Please read the precautions on the back before filling out this page)-Packing · Printing by Employee Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs 1. At a neck of 10+ ml with rubber septum and argon needle input port The flask was charged with acetylene acetone (1.0 mL, 0.963 g, 17.2 mmol), ether (20 mL), and cooled to 0 ° C while slowly adding NaH (435 mg, 17.2 mmol). The mixture was stirred at room temperature. For 1 hour, add tertiary butylphosphonium methylsilyl chloride (2.6 g, 17.2 mmol). The reaction mixture was stirred at room temperature for 6 hours, poured into hexane (150 ml), and washed with 1 equivalent of HC1. The organic phase was dried over MgS04 and concentrated to give 2.88 g of a yellow solid, which was used in step 2 without purification. iH NMR (300 MHz, CDC13) 4.29 (d, J = 2.1 Hz, 2H), 2.37 (t, J = 2, l Hz, 1H), 0.89 (s, 9H), 0.11 (s, 3H), νβ 59- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) V. Description of the invention (57 A7 B7 Step 2 · Use Example 1 Step 2 method using commercially available 4-iodobenzyl and Acetyl chloride is used to obtain the desired ethyl fluorenyl diphenyl. TLC (l ·]% ethyl acetate-hexane): Rf = 0.3. 0 -CC instead ^ Step 3. Use the product of Step 1 using the method of Example 1 Step 5 The required diphenylacetylene was obtained. TLC (product of step 2 of 10% ethyl acetate hexane 殳): Rf = 0.4. (Please read the precautions on the back before filling this page)
-C三C-C three C
經濟部中央標準局貝工消費合作社印裝 (|毫升的一頸 94毫莫耳), 此化鉀(617毫 30分鐘,用 4〇 克,2.94 毫 此混合物升 毫莫耳),任 混合物倒入 升二氣甲烷 於200克二氧 己烷梯度洗 酸乙酯-己Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (| ml of a neck of 94 millimoles), this potassium (617 milliseconds, using 40 grams, 2.94 milliliters of this mixture liter millimoles), let the mixture pour Dilute methane with 200 g of dioxane gradient
t-BuMc^SiO 步驟4. 於裝有橡皮隔及氬氣針輸入口的5 燒瓶内載入5毫升THF,步驟3產物(1.06克,2. 冷至-78 °C,同時用注射筒滴加六甲基二矽 克,2.94毫莫耳)。此反應混合物於_ 7 8 °C攪拌 注射筒滴加三甲基矽烷基氣(Θ:374毫升,0.3 莫耳),生成混合物於-7 8 °C攪拌3小時。再將 至0°C 1小時,加N -溴丁二醯胺(0.540克,2.94 此混合物升至室溫,並攪拌1 6小時。將此反應 —份100毫升飽和NH4C1水溶液内,用三份50齋 萃取。合併之有機相於MgS04上乾燥,濃縮 化矽膠上作柱色譜分析(用〇 - 5 %醋酸乙酯 離),製得0.264克(20%)溴甲基酮。TLC(10〇/〇‘ 烷):Rf=0.5。 -60 本紙張尺度適用中國國家標率(CNS ) A4规格(2KTX297公釐) 五、發明説明(58t-BuMc ^ SiO Step 4. Load 5 ml of THF into a 5 flask equipped with a rubber septum and an argon needle input port. The product from Step 3 (1.06 g, 2. Cool to -78 ° C, while dripping with a syringe. Add hexamethyldisic, 2.94 millimoles). The reaction mixture was stirred at -7 ° C. Trimethylsilyl gas (Θ: 374 ml, 0.3 mol) was added dropwise to the syringe, and the resulting mixture was stirred at -7 ° C for 3 hours. Add another 1 hour to 0 ° C, add N-bromobutanediamine (0.540 g, 2.94). The mixture is warmed to room temperature and stirred for 16 hours. This reaction is taken in 100 ml of saturated NH4C1 aqueous solution. Extracted at 50 mg. The combined organic phases were dried over MgS04, and analyzed by column chromatography on concentrated silica gel (with 0-5% ethyl acetate) to obtain 0.264 g (20%) of bromomethyl ketone. TLC (100%) / 〇 'alkane): Rf = 0.5. -60 This paper size applies to China's national standard (CNS) A4 specification (2KTX297 mm) 5. Description of the invention (58
t-BuMe^SiO A7 B7t-BuMe ^ SiO A7 B7
-CEC-CEC
步驟5. 用實例1 5步驟2-3方法使用步驟41 二苯基苯鄰二甲亞醯胺。TLC(50%醋酸乙酯-醋酸):Rf=0.3。 物製得所需 己烷,含1 〇/。 (請先聞讀背面之注意事項再填寫本頁) C----Γ I 裝·Step 5. The method of Example 1, Step 5 and Step 2-3 was used, and Step 41 was used. TLC (50% ethyl acetate-acetic acid): Rf = 0.3. The desired hexane was obtained, containing 10%. (Please read the notes on the back before filling this page) C ---- Γ I
訂 經濟部中央標準局員工消費合作杜印製 步驟6. 於裝有橡皮隔及氬氣針輸入口的5C 燒瓶内載入10毫升CH2C12,歩驟5產物(〇.〇4( 莫耳),及2毫升H F - p比咬。此混合物於室虛檀 用75毫升水稀釋,再用75毫升(:112(:12萃取 MgS〇4上乾燥,濃縮。於5克二氧化矽膠上作 (用25%醋酸乙酯-己烷含1 % HOAc洗離),製得 例1 6產物。熔點145°C。 實例1 7 本發明化合物之生物學鑑定 毫升的一頸 克,0.067 摔1 0分鐘 。有機 柱色譜 6 克(19%) 毫 相 於 分析 實 -61 - 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 五、發明説明(59 ) A7 B7 經濟部中央標隼局負工消費合作社印裝 MMP抑制之P218猝滅熒光鑑定 P218猝滅的熒光鑑定(顯微熒光計輪廓鑑定)是Knight等於 FEBS Lett. 296, 263, 1992最初就樣品池内相關物質及各種 基質金屬蛋白酶(MMPs)所述的鑑定的改進。+鑑定是用每 一發明化合物及三種MMPs(MMP-3,MMP-9 平行分析,使用9 6凹的微滴定碟及Hamiltoif ATW工作站 (workstation)。 P218熒光團基質:P218爲合成的被作用物,與(N-端位置含 有4-乙醯基-7-甲氧基香豆素(MCA)基團,其 二硝基苯基]-L-2,3-二胺基丙醯基(DPA) (1992)所報告的用作基質金屬酶被作用物的多 一旦P218多肽被裂解(於Ala-Leu鍵的推定截除 基的熒光即可以熒光計測出’於328毫微米興 微米發射。目前有BACHEM生產P218 ’專門供應Bayer。P218 的構造是: H-MCA-Pro-Lys-Pro-Leu-Ala-Leu-DPA-Ala-Ai 量1332.2) 重組人CHO溶基質素(MMP-3) 重組人CH〇 Pro-MMP·3 ·· Houseley,et al·,j268. 4481,1993説明人 CHO pro-溶基質素-257 的表現於純化。 pro-MMP_3的活化·於5 mM Tris, ρΉ 7.5, 5 nj mM NaCl,及0.005% Brij_35 活化緩衝 内有3-[2,4-此爲Knight 肽的改良。 位)後,MCA 奮並於393毫 g-NH2 (分子Order the consumer cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs. Du Printing Step 6. In a 5C flask equipped with a rubber septum and an argon needle input port, load 10 ml of CH2C12, step 5 product (0.04 (mol)), And 2 ml of HF-p ratio bite. This mixture was diluted with 75 ml of water in the chamber, and then dried with 75 ml (: 112 (: 12 extracted MgS04) and concentrated. It was prepared on 5 g of silicon dioxide (using 25% ethyl acetate-hexane containing 1% HOAc was washed off) to obtain the product of Example 16. The melting point was 145 ° C. Example 17 Biological identification of the compound of the present invention One milligram of milliliter, 0.067 drop for 10 minutes. Organic column chromatography 6 g (19%) is exactly the same as the analysis result -61-This paper size is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) 5. Explanation of the invention (59) A7 B7 P218 quenched fluorescence identification of MMP inhibition printed by the Industrial and Commercial Cooperatives. The fluorescence identification of P218 quenching (microfluorometer profile identification) is Knight equal to FEBS Lett. 296, 263, 1992. Initially, the related substances in the sample pool and various matrix metalloproteinases ( MMPs) improvement of identification. + Identification is with each round Compounds and three MMPs (MMP-3, MMP-9 were analyzed in parallel, using a 96-well microtiter plate and a Hamiltoif ATW workstation. P218 fluorophore matrix: P218 is a synthetic substrate, and (N-terminal Contains 4-Ethyl-7-methoxycoumarin (MCA) group at its position, as reported by its dinitrophenyl] -L-2,3-diaminopropionyl (DPA) (1992) Once the P218 polypeptide is cleaved as the substrate for the substrate metalloenzyme (the fluorescence of the presumed truncation group at the Ala-Leu bond can be measured with a fluorometer, the emission is at 328 nanometers and the micrometers. Currently, BACHEM produces P218. Supply Bayer. The structure of P218 is: H-MCA-Pro-Lys-Pro-Leu-Ala-Leu-DPA-Ala-Ai Amount 1332.2) Recombinant human CHO stromin (MMP-3) Recombinant human CHO Pro-MMP · 3 ·· Houseley, et al ·, j268. 4481, 1993 illustrates the performance of human CHO pro-lysin-257 in purification. Activation of pro-MMP_3 at 5 mM Tris, ρΉ 7.5, 5 nj mM NaCl, and After the 0.005% Brij_35 activation buffer contains 3- [2,4- this is an improvement of the Knight peptide.) MCA is bound to 393 mg-NH2 (molecule
Biol. Chem. (pro-MMP-3) M CaCl2,25 液内1.72 μΜ (100微克/毫升)的Pro-MMP_3可藉TPCK(N_甲苯磺醯基-(L·)- 62- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公幻 ---r--,-----f -^------ΐτ------f - - (請先聞讀背面之注意事項再填寫本頁) 五、發明説明(60 A7 B7 苯丙胺酸氣甲基酮)胰蛋白酶(1 : 100重量 /重量與pro- MMP-3的比)於2 5 °C培養3 0分鐘活化。此反蛛可藉加大豆 胰蛋白酶抑制劑(SBTI ; 5 : 1重量/重量與胰蛋白酶濃度比) 停止。此活化方法導致45kDa活性MMP-3的生丰,此活化的 MMP- 3仍含酶的C -端部分。 人重組膠原酶A(Pro-MMP-2)的製備 重组人pro-MMP-2 :依據Fridman, et al_, J 267. 15398, 1992,所述方法使用牛痘表現系蛛製備人膠原 酶A(pro-MMP-2)。 pro-MMP-2之活化:將252毫克/毫升的pro mM的 Tris溶液,pΗ 7.5,5 mM CaCl2,150 mM NaCl,及 0.005% Brij-3 5 (MMP-2活化緩衝液)以1 : 5稀釋至終濃度 爲5 0微克/毫升。製成10mM(3.5毫克/毫升)的 内的醋酸對位胺基苯基汞(ΑΡΜΑ)。以1 / 2 0 ΑΡΜΑ溶液,使ΑΡΜΑ終濃度爲0.5 mM,此酶 3 0分鐘。以2公升MMP-2活化缓衝液透析活 (1 5毫升)二次(透析膜先以MMP- 2活化缓衝液 BSA處理1分鐘,再用H20徹底洗)。用Centric .Biol. chem. -MMP-2 以 25 於 0.05NaOH 反應容積加 於3 7 °C培養 化的MMP-2 内含有0.1% pn濃縮器(濃 —^ϋ. I -.1 !-1 - - 1 ΐ·! - — IX 1 - I— I - - (請先閱讀背面之注意事項再填寫本頁) 訂Biol. Chem. (Pro-MMP-3) M CaCl2, 1.72 μM (100 μg / ml) of Pro-MMP_3 in 25 liquids can be borrowed from TPCK (N_toluenesulfonyl- (L ·)-62- Applicable to China National Standard (CNS) A4 specification (210X297 public magic --- r-, ----- f-^ ------ ΐτ ------ f--(Please read the back first Please note this page and fill in this page again) 5. Description of the invention (60 A7 B7 phenylalanine methyl ketone) Trypsin (1: 100 weight / weight to pro-MMP-3 ratio) Incubate at 25 ° C for 30 minutes Activation. This anti-spider can be stopped by adding soybean trypsin inhibitor (SBTI; 5: 1 weight / weight to trypsin concentration ratio). This activation method results in the growth of 45 kDa active MMP-3, and this activated MMP-3 remains Contains the C-terminal part of the enzyme. Preparation of human recombinant collagenase A (Pro-MMP-2) Recombinant human pro-MMP-2: According to Fridman, et al_, J 267. 15398, 1992, the method uses a vaccinia expression line Spider prepares human collagenase A (pro-MMP-2). Activation of pro-MMP-2: 252 mg / ml of pro mM Tris solution, p 7.5, 5 mM CaCl2, 150 mM NaCl, and 0.005% Brij- 3 5 (MMP-2 activation buffer) diluted 1: 5 to a final concentration of 50 G / ml. 10 mM (3.5 mg / ml) of para-aminophenylmercury acetate (APMA) was prepared. With 1/20 APMA solution, the final concentration of APMA was 0.5 mM, and this enzyme was 30 minutes. Dialyze (15 ml) twice with 2 liters of MMP-2 activation buffer (dialysis membrane is first treated with MMP-2 activation buffer BSA for 1 minute, then washed thoroughly with H20). Centric. Biol. Chem. -MMP -2 Add 0.1% pn concentrator (concentrated — ^ ϋ. I -.1! -1--1 ΐ ·!-— IX) to MMP-2 cultured at 37 ° C with 25 to 0.05NaOH reaction volume. 1-I— I--(Please read the notes on the back before filling this page) Order
J 經濟部中央標準局員工消費合作杜印製 縮器也先用MMP- 2活化緩衝液内含有0.1 % _SA處理1分 鐘,再用H20洗,再用MMP-2活化緩衝液洗j濃縮酶,再 稀釋,再濃縮,重覆二次。用MMP-2活化緩^液將酶稀釋 至7.5毫升(原始容積的0.5倍)。 人重組膠原酶B (MMP- 9 )之製備 重组人 pro-MMP-9 : Wilhelm., et al., J. Biol. chem. 264. -63- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 經 央 標 準 局 員 工 消 費 合 作 社 印 製 A7 B7 五、發明説明⑼) 17213, 1989,説明人膠原酶 B(pro-MMI' -9)衍生自 U937cDNA,用桿狀病毒蛋白質表現系統表 現爲全長形 式。此酶原係用 Hibbs,et al., J. Biol. Chem. 26 0, 2493, 1984 所述方法純化。 pro-MMP-9 之活化:將 50 mM Tris,pH 7.4 » 10 mM CaCl2,150 mM Naa,及0.005% Brij-35 (MM P-9活化緩衝 液)内的pro-MMP-2 20微克/毫升用0.5mM醋 酸對位胺基苯 基汞(ΑΡΜΑ)於37°C培養3.5小時使活化。此_ t係用相同的 緩衝液透析除去ΑΡΜΑ。 儀器裝設 Hamilton Microlab AT Plus : ΜΜΡ輪廓鑑定 y 系以 Hamilton MicroLab AT Plus® 全自動完成。給 Hamilton 設計的程式 是:(1)以100% DMSO内的2.5mM的儲液自動痛 釋至11種可 能的抑制劑;(2)分佈被作用物於9 6凹Cytofl our碟内,再 分佈抑制刮至此碟内;(3 )加單一酶至碟内並g L合以開使反 應。於加被作用物的點重新開始此程式,自食 給另外的酶 製成另外的碟,重新混合稀釋的抑制劑,再 加酶開始反 應。這樣,用相同的抑制劑稀釋液完成MMP鑑 定。 Millipore Cytoflour II :經培養後,於 Cytofl fur II熒光計 碟讀數計上讀碟,於340毫微米興奮,於395¾ :微米發射, 放大倍數定於80。 緩衝液 顯微熒火計反應缓衝液(MRB) ··供顯微熒光 *計鑑定用的 試驗化合物稀釋液,酶,及P218被作用物係《 >顯微熒光計 -64- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 請 先 閲 讀 背 Φ} 之 注 意 事 項 再 填 寫 本 頁 A7 B7 嗎啉基)乙烷 581079 五、發明説明(62 ) 反應緩衝液製成,此緩衝液内含50 mM 2-(N-橫酸(MES),pH 65,10 mM CaCl2,150 mM NaCl,0.005%J Consumption cooperation staff of the Central Bureau of Standards, Ministry of Economic Affairs, Du printed shrink device was also treated with MMP-2 activation buffer containing 0.1% _SA for 1 minute, then washed with H20, and then washed with MMP-2 activation buffer. Dilute again, concentrate again, and repeat twice. The enzyme was diluted to 7.5 ml (0.5 times the original volume) with MMP-2 activation buffer. Preparation of Human Recombinant Collagenase B (MMP-9) Recombinant human pro-MMP-9: Wilhelm., Et al., J. Biol. Chem. 264. -63- This paper size applies to China National Standard (CNS) A4 (210X297 mm) A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards 5. Description of the invention ⑼) 17213, 1989, showing that human collagenase B (pro-MMI '-9) is derived from U937cDNA and expressed by the baculovirus protein system Shown as a full-length form. This zymogen was purified by the method described in Hibbs, et al., J. Biol. Chem. 26 0, 2493, 1984. Pro-MMP-9 activation: Pro-MMP-2 in 50 mM Tris, pH 7.4 »10 mM CaCl2, 150 mM Naa, and 0.005% Brij-35 (MM P-9 activation buffer) 20 μg / ml Activation was performed by incubation with 0.5 mM p-aminophenylmercury (APMA) at 37 ° C for 3.5 hours. This t was dialyzed to remove APMA with the same buffer. Instrument Setup Hamilton Microlab AT Plus: The MMP profile identification is performed fully automatically with Hamilton MicroLab AT Plus®. The program designed for Hamilton is: (1) automatic pain release to 11 possible inhibitors with a 2.5 mM stock solution in 100% DMSO; (2) distributing the substrate in a 96-well Cytofl our dish and redistribution Inhibit scraping into this dish; (3) Add a single enzyme to the dish and combine g L to start the reaction. Restart the program at the point where the substrate is added, make another plate for the other enzyme, mix the diluted inhibitor, and start the reaction with the enzyme. In this way, the same inhibitor dilution was used to complete the MMP assay. Millipore Cytoflour II: After incubation, read the disc on a Cytofl fur II fluorometer dish reader, excite at 340 nm, emit at 395¾: micron, and set the magnification at 80. Buffer Microfluorescein Reaction Buffer (MRB) ·· Dilution of test compounds, enzymes, and P218 substrates for identification of microfluorescein * meter > Microfluorimeter-64- Paper size Applicable to China National Standard (CNS) A4 specification (210X 297 mm) Please read the notes on the back Φ} before filling in this page A7 B7 morpholinyl) ethane 581079 V. Description of the invention (62) Made of reaction buffer, This buffer contains 50 mM 2- (N-trans acid (MES), pH 65, 10 mM CaCl2, 150 mM NaCl, 0.005%
Brij-35及1% DMSO。 方法 MMP顯微熒光計輪廓鑑定:此鑑定係用被作用物mis終 濃度爲6 μΜ及約0.5至0.8 nM的MMP以不同的藥物濃度完 成。將Hamilton設計成在鑑定中能由2.5 mM儲液(100% DMSO)至1 0倍化合物終濃度系列稀釋達1 1種化合物。開始 時,儀器投送不同量的顯微熒光劑反應緩衝液(MRB)至1毫 升Marsh稀釋試管的9 6隻試管架。然後此儀器由樣品架取 2 0微升抑制劑(2 _ 5 mM)與Marsh架上A排内的緩衝液混合, 製成50μΜ的藥物濃度。再將抑制劑系列稀釋成1 〇,5, 1,0.2,0.05及0.01 μΜ。樣品架上的1號位只含DMSO供鑑 定中"只有酶"的凹使用,這樣,從A排至Η排的第1列不含 抑制劑。儀器然後分佈107微升Ρ218被作用物(8·2μΜ,於 MRB内)至單一 96凹的Cyt〇flour微滴定碟。儀器重混合,並 將14.5微升稀釋的化合物由Marsh架的A排至G排載入微滴 定碟的對應的排。(Η排代表"背景"排,只給予39.5微升 MRB,不給予藥物或酶)。每一凹(η排(,,背景排")除外)内 由BSA處理過的試劑儲液槽加2 5微升適宜的酶(酶終濃度的 5_86倍)開始反應。(酶儲液槽先以5〇 mM Tris(pH 7.5,含 150 mM NaCl)内的1%的BSA於室溫處理1小時),再以H2〇 徹底洗過,於室溫乾燥)。 在將酶加入並混合後,將碟蓋上,於37 t培養25分鐘 -65- 本紙張尺度適用中國國家標準(CNS ) Μ^Μ~{2^Γ29η^ ) —^1 · ·<ί· --1In 1^1 1^,- Is —^n I - - (請先閱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袋 ^81073 ------ 五、發明説明(63 A7 B7Brij-35 and 1% DMSO. Methods MMP microfluorescein profile identification: This identification was performed with MMPs with a final mis concentration of 6 μM and about 0.5 to 0.8 nM at different drug concentrations. Hamilton was designed to serially dilute 11 compounds from 2.5 mM stock solution (100% DMSO) to 10 times the final compound concentration in the identification. To begin, the instrument delivers different amounts of Microfluorescein Reaction Buffer (MRB) to 96 tubes of 1 ml Marsh-diluted tubes. The instrument then took 20 microliters of inhibitor (2-5 mM) from the sample rack and mixed it with the buffer in row A on the Marsh rack to make a drug concentration of 50 μM. The inhibitors were serially diluted to 10, 5, 1, 0.2, 0.05 and 0.01 μM. Position 1 on the sample rack contains only DMSO for identification "only enzyme" recess, so that the first row from row A to row 8 does not contain inhibitors. The instrument then distributes 107 microliters of P218 substrate (8.2 μM in MRB) to a single 96-well Cytoflour microtiter plate. The instrument was remixed and 14.5 microliters of the diluted compound was loaded from row A to row G of the Marsh rack into the corresponding row of the microtiter plate. (Representative " Background " row, given only 39.5 microliters of MRB, no drugs or enzymes). In each recess (except the η row (,, background row)), the reaction was started by adding 25 microliters of appropriate enzyme (5-86 times the final enzyme concentration) to the BSA-treated reagent reservoir. (The enzyme storage tank was first treated with 1% BSA in 50 mM Tris (pH 7.5, containing 150 mM NaCl) at room temperature for 1 hour), and then thoroughly washed with H20 and dried at room temperature. After adding the enzyme and mixing, cover the dish and incubate it at 37 t for 25 minutes -65- This paper size applies Chinese National Standard (CNS) Μ ^ Μ ~ {2 ^ Γ29η ^) — ^ 1 · · < ί · --1In 1 ^ 1 1 ^,-Is — ^ n I--(Please read the notes on the back before filling out this page) Order the printed bag of the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ^ 81073 ------ V. Description of the invention (63 A7 B7
X相同方式’藉Hamilton程式將P218被作用物分佈至微滴 疋碟’然後再與藥物混合並由相同的Marsh架分佈至微滴定 碟,忒驗其他的酶。然後將要試驗的第二(或 MMP由試劑架分佈至微滴定碟並混合,再蓋起,培養。所 有的其他的MMP都以此法試驗 〜、微费光计鐘定中的IC50測定:將Cytoflou】 據由輸出CSV"構案複製於主Excei散佈頁(spreadsheet) 自動計算由幾種不同的MMps取得的數據(每一MMP-9 6凹 的碟)。比較含化合物的凹的水解量(水解2 5分鐘產生的熒 光單位)與1列"只含酶"的凹的水甲量就每一鈐物濃度測出 抑制百分比。減去背景,以下述公式計算抑制((對照値-治療値)/對照値)X10C 就抑制劑濃度5,1,〇 5,〇」,〇 〇2,〇 〇〇5及〕〇〇1μΜ藥物 測定出抑制百分比。以此抑制百分比的線性谢歸分析與對 數抑制劑濃度比較求得j c 5 〇値 表II r II產生的數 百分比 I-r---------f —^------ΐτ * - (請先閱讀背面之注意事項再填寫本頁)In the same way, ‘the Hamilton program is used to distribute the P218 substrate to the droplet 疋 disk’ and then mix it with the drug and distribute it to the microtiter plate from the same Marsh rack to test other enzymes. Then the second to be tested (or MMP is distributed from the reagent rack to the microtiter dish and mixed, then covered and cultured. All other MMPs are tested in this way ~, IC50 determination in the micrometer meter: Cytoflou] Based on the output CSV " copy from the main Excei spread sheet, the data obtained from several different MMps (each 6-concave discs for MMP-9) are automatically calculated. The amount of hydrolysis of the compound-containing concavities (hydrolysis 2 The fluorescence unit generated in 5 minutes) and the amount of concave water nails containing "enzyme only" in one column were used to measure the percentage of inhibition for each substance concentration. Subtract the background and calculate the inhibition using the following formula ((control 値 -treatment) ) / Control 値) X10C The inhibitory percentages were determined with respect to the inhibitor concentrations of 5, 1, 05, 0, 2, 0, 05 and 1 μM. Linear regression analysis and logarithm of the inhibitory percentages were performed using this method. Inhibitor concentration comparison to obtain jc 5 〇 値 Table II r II produced percentages Ir --------- f — ^ ------ ΐτ *-(Please read the precautions on the back before filling (This page)
21 ΜΜΡ-9生熒光團的 IC50 MMlf-2生熒光團的 IC50 經濟部中央標隼局員工消費合作社印製 I ΗΠΙΙνννΙνΙΙ 106 2184 -3 5% 252 5 38 327 36 67 37 704 2630 834 2460 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X 297公釐) 21 235 14 103 -66- S81079 A7 B7 五、發明説明(64 ) VIII 32 122 6 IX 57 542 37 X 203 1=27% 108 XI 1730 1=24% 596 XII 56.6 614 36 XIII 405 245 XIV 125 1=46% 85 XV 11 40 5 XVI 4 2 1 精於此技藝者由此説明或此處所揭示的本軎 了解到其他具體實施例。此説明及實例只4 質,下述申請專利範圍説明本發明的眞範圍及 明的實例會 舉例説明性 精神。 (請先閲讀背面之注意事項再填寫本頁) J —裝_ 、?! 經濟部中央標準扃員工消費合作社印製 67- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)21 IC50 of MMMP-9 fluorophore IC50 of MMlf-2 fluorophore Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economy 106 2184 -3 5% 252 5 38 327 36 67 37 704 2630 834 2460 Paper size Applicable to China National Standard (CNS) A4 specification (210X 297 mm) 21 235 14 103 -66- S81079 A7 B7 V. Description of invention (64) VIII 32 122 6 IX 57 542 37 X 203 1 = 27% 108 XI 1730 1 = 24% 596 XII 56.6 614 36 XIII 405 245 XIV 125 1 = 46% 85 XV 11 40 5 XVI 4 2 1 Those skilled in the art can understand other specific embodiments from this description or the present disclosure disclosed herein. These descriptions and examples are only 4 qualities. The following patent application scope illustrates the scope of the present invention and the examples will exemplify the spirit. (Please read the precautions on the back before filling out this page) J — Equipment _ 、?! Printed by the Central Standard of the Ministry of Economic Affairs 消费 Printed by the Employee Consumer Cooperatives 67- This paper size applies to China National Standard (CNS) A4 (210X297 mm)
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EP (1) | EP0912496A1 (en) |
JP (1) | JP3090957B2 (en) |
CN (1) | CN1139570C (en) |
AR (1) | AR007097A1 (en) |
AU (1) | AU710759B2 (en) |
BR (1) | BR9709077A (en) |
CA (1) | CA2253796C (en) |
CO (1) | CO5080759A1 (en) |
HN (1) | HN1997000088A (en) |
HR (1) | HRP970245B1 (en) |
ID (1) | ID16910A (en) |
PA (1) | PA8429301A1 (en) |
SV (1) | SV1997000035A (en) |
TN (1) | TNSN97084A1 (en) |
TW (1) | TW381079B (en) |
WO (1) | WO1997043245A1 (en) |
YU (1) | YU18697A (en) |
ZA (1) | ZA974031B (en) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6288063B1 (en) | 1998-05-27 | 2001-09-11 | Bayer Corporation | Substituted 4-biarylbutyric and 5-biarylpentanoic acid derivatives as matrix metalloprotease inhibitors |
AR035478A1 (en) * | 1999-01-27 | 2004-06-02 | Wyeth Corp | AMIDA-HYDROXAMIC ACID, ACETYLLENE, BETA-SULPHONAMIDE AND PHOSPHINIC ACID AS INHIBITORS OF TACE, USE OF THE SAME FOR THE MANUFACTURE OF A MEDICINAL PRODUCT AND PHARMACEUTICAL COMPOSITION CONTAINING THEM |
US6326516B1 (en) | 1999-01-27 | 2001-12-04 | American Cyanamid Company | Acetylenic β-sulfonamido and phosphinic acid amide hydroxamic acid TACE inhibitors |
EP1031349A1 (en) * | 1999-02-25 | 2000-08-30 | Bayer Aktiengesellschaft | Use of substituted 4-biarylbutyric and 5-biarylpentanoic acid derivatives for the treatment of cerebral diseases |
US7141607B1 (en) | 2000-03-10 | 2006-11-28 | Insite Vision Incorporated | Methods and compositions for treating and inhibiting retinal neovascularization |
CA2804918C (en) | 2010-07-08 | 2018-03-06 | Kaken Pharmaceutical Co., Ltd. | N-hydroxyformamide derivative and medicament containing same |
CN106458938A (en) | 2014-04-03 | 2017-02-22 | 拜耳制药股份公司 | Chiral 2,5-disubstituted cyclopentanecarboxylic acid derivatives and use thereof |
CA2944614A1 (en) | 2014-04-03 | 2015-10-08 | Bayer Pharma Aktiengesellschaft | 2,5-disubstituted cyclopentane carboxylic acids for the treatment of respiratoy tract diseases |
EP3126339A1 (en) | 2014-04-03 | 2017-02-08 | Bayer Pharma Aktiengesellschaft | 2,5-disubstituted cyclopentane carboxylic acids and use thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3784701A (en) * | 1970-09-21 | 1974-01-08 | American Cyanamid Co | Compositions containing substituted benzoylpropionic acids and method of use to treat inflammation and pain |
DE2112716A1 (en) * | 1971-03-17 | 1972-10-05 | Thomae Gmbh Dr K | Biphenylyl-butyric acid derivs. - anti phlogistics |
US5789434A (en) * | 1994-11-15 | 1998-08-04 | Bayer Corporation | Derivatives of substituted 4-biarylbutyric acid as matrix metalloprotease inhibitors |
-
1997
- 1997-05-09 CO CO97025172A patent/CO5080759A1/en unknown
- 1997-05-09 ZA ZA9704031A patent/ZA974031B/en unknown
- 1997-05-09 TN TNTNSN97084A patent/TNSN97084A1/en unknown
- 1997-05-09 HR HR970245A patent/HRP970245B1/en not_active IP Right Cessation
- 1997-05-12 CA CA002253796A patent/CA2253796C/en not_active Expired - Fee Related
- 1997-05-12 HN HN1997000088A patent/HN1997000088A/en unknown
- 1997-05-12 EP EP97923622A patent/EP0912496A1/en not_active Withdrawn
- 1997-05-12 CN CNB971964564A patent/CN1139570C/en not_active Expired - Fee Related
- 1997-05-12 YU YU18697A patent/YU18697A/en unknown
- 1997-05-12 PA PA19978429301A patent/PA8429301A1/en unknown
- 1997-05-12 TW TW086106283A patent/TW381079B/en not_active IP Right Cessation
- 1997-05-12 JP JP09540980A patent/JP3090957B2/en not_active Expired - Fee Related
- 1997-05-12 WO PCT/US1997/007921 patent/WO1997043245A1/en not_active Application Discontinuation
- 1997-05-12 AR ARP970101977A patent/AR007097A1/en unknown
- 1997-05-12 BR BR9709077A patent/BR9709077A/en not_active Application Discontinuation
- 1997-05-12 SV SV1997000035A patent/SV1997000035A/en unknown
- 1997-05-12 AU AU29386/97A patent/AU710759B2/en not_active Ceased
- 1997-05-14 ID IDP971606A patent/ID16910A/en unknown
Also Published As
Publication number | Publication date |
---|---|
CA2253796A1 (en) | 1997-11-20 |
CN1139570C (en) | 2004-02-25 |
CN1225623A (en) | 1999-08-11 |
HRP970245B1 (en) | 2002-06-30 |
ID16910A (en) | 1997-11-20 |
CO5080759A1 (en) | 2001-09-25 |
WO1997043245A1 (en) | 1997-11-20 |
HRP970245A2 (en) | 1998-04-30 |
SV1997000035A (en) | 1999-01-14 |
BR9709077A (en) | 1999-08-03 |
EP0912496A1 (en) | 1999-05-06 |
HN1997000088A (en) | 1997-06-18 |
JPH11511179A (en) | 1999-09-28 |
AU710759B2 (en) | 1999-09-30 |
PA8429301A1 (en) | 2000-05-24 |
AU2938697A (en) | 1997-12-05 |
ZA974031B (en) | 1998-02-19 |
AR007097A1 (en) | 1999-10-13 |
YU18697A (en) | 1999-11-22 |
CA2253796C (en) | 2003-10-28 |
TNSN97084A1 (en) | 2005-03-15 |
JP3090957B2 (en) | 2000-09-25 |
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