TW470750B - Reversible cysteine protease inhibitors - Google Patents
Reversible cysteine protease inhibitors Download PDFInfo
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- TW470750B TW470750B TW085104392A TW85104392A TW470750B TW 470750 B TW470750 B TW 470750B TW 085104392 A TW085104392 A TW 085104392A TW 85104392 A TW85104392 A TW 85104392A TW 470750 B TW470750 B TW 470750B
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- 239000002852 cysteine proteinase inhibitor Substances 0.000 title description 22
- 230000002441 reversible effect Effects 0.000 title description 9
- -1 morpholinecarbonyl Chemical group 0.000 claims abstract description 240
- 150000001875 compounds Chemical class 0.000 claims abstract description 181
- 239000000203 mixture Substances 0.000 claims abstract description 110
- 101000749287 Clitocybe nebularis Clitocypin Proteins 0.000 claims abstract description 70
- 101000767029 Clitocybe nebularis Clitocypin-1 Proteins 0.000 claims abstract description 70
- 229940094664 Cysteine protease inhibitor Drugs 0.000 claims abstract description 70
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 64
- 239000001257 hydrogen Substances 0.000 claims abstract description 63
- 150000003839 salts Chemical class 0.000 claims abstract description 57
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 49
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 45
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 41
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 29
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 19
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- 125000001475 halogen functional group Chemical group 0.000 claims abstract 2
- 239000003112 inhibitor Substances 0.000 claims description 72
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- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000001010 sulfinic acid amide group Chemical group 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium Chemical compound [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- SJODCYRYHPVMMQ-ZDUSSCGKSA-N tert-butyl n-[(2s)-1-hydroxy-4-phenylbutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](CO)CCC1=CC=CC=C1 SJODCYRYHPVMMQ-ZDUSSCGKSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000008354 tissue degradation Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
- C07F9/6533—Six-membered rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
Description
470750 經濟部中央樣準局員工消費合作杜印製 A7 B7五、發明説明(1 ) 發明範疇 本發明有關一種新穎之可逆蛋白酶抑制劑。該抑制劑 對半胱胺酸蛋白酶具有選擇性 發明背景 半胱胺酸或硫醇蛋白酶在負責蛋白質水解之活性部位 上含有半胱胺酸殘基。因爲半胱胺酸蛋白酶與數種疾病有 關,包括關節炎、肌肉失養症、發炎、腫瘤發作、絲球體 性腎炎、虐疾、及其他寄生蟲性感染,選擇性且可逆地使 其滅能之方法針對新藥候選者提供機會。參照例如Esser, R. E. et a 1. ,Arthritis & Rheumatism ( 1 9 9 4) 37, 236; Meijers,Μ.Η.M. et a 1., Agents Actions (1993) ,39(Special Conference Issue), C219; Machleidt, W. et al. M.J., Clin. Exp. Metastasis (1992), 10 , 145; Rosenthal, P.J., Wollish, li.S., Palmer, J.T., Rasnick, D. , J. Clin. I nvestigations( 1 99 1 ), 88, 1467; Baricos, W.H. et al., Arch. Biochem. Biophys. (1991), 288,468; Thornberry, N.A. et al., Nature (1992), 356, 768。 Rich,蛋白酶抑制劑(第4章,"半胱胺酸蛋白 酶之抑制劑〃 )Elsevier Science Publishers (1986)已 描述半胱胺酸蛋白酶之低分子量抑制劑。此等抑制劑包括 胜肽醛,其與蛋白酶活性部位之半晄胺酸形成半硫代乙縮 酸。參照例如 Cheng, H.,Keitz,P., and Jones, J. 本紙張尺度適用中國國家標準(CNS ) A4規格(21 OX297公釐) —•In I---------* 訂 (請先閱讀背面之注意事項再填寫本頁) -4 - 470750 A7 B7 五、發明説明(2 ) B.,J. Org.. Chem. (1994),59 ,7671。酸之缺點係其 體內及化學不安定性。 醛已藉下文所述之Wi t t i g反應之Wadsworth -Emmons - Horner改良法轉化成2,—不飽和酯及硕< Wadsworth, W. S. Emmous, W. D. (J. Am. Chem.470750 Consumption Cooperation by Employees of the Central Procurement Bureau of the Ministry of Economic Affairs, Du printed A7 B7 V. Invention Description (1) Scope of the Invention The present invention relates to a novel reversible protease inhibitor. This inhibitor is selective for cysteine proteases. BACKGROUND OF THE INVENTION Cysteine or thiol proteases contain cysteine residues at the active site responsible for proteolysis. Because cysteine protease is associated with several diseases, including arthritis, muscular dystrophy, inflammation, tumor attack, filamentous nephritis, malaria, and other parasitic infections, it selectively and reversibly disables it This approach provides opportunities for new drug candidates. Refer to, for example, Esser, RE et a 1., Arthritis & Rheumatism (1 9 9 4) 37, 236; Meijers, M.Η.M. et a 1., Agents Actions (1993), 39 (Special Conference Issue), C219; Machleidt, W. et al. MJ, Clin. Exp. Metastasis (1992), 10, 145; Rosenthal, PJ, Wollish, li.S., Palmer, JT, Rasnick, D., J. Clin. I nvestigations (1 99 1), 88, 1467; Baricos, WH et al., Arch. Biochem. Biophys. (1991), 288,468; Thornberry, NA et al., Nature (1992), 356, 768. Rich, Protease Inhibitors (Chapter 4, " Inhibitors of Cysteine Enzymes〃) Elsevier Science Publishers (1986) has described low molecular weight inhibitors of cysteine proteases. These inhibitors include peptide aldehydes, which form hemithioacetic acid with the hemiamidic acid of the protease active site. Refer to, for example, Cheng, H., Keitz, P., and Jones, J. This paper size applies the Chinese National Standard (CNS) A4 specification (21 OX297 mm) — • In I --------- * Order (Please read the precautions on the back before filling this page) -4-470750 A7 B7 V. Description of the Invention (2) B., J. Org .. Chem. (1994), 59,7671. The disadvantage of acids is their in vivo and chemical instability. Aldehydes have been converted to 2, by the Wadsworth-Emmons-Horner modification of the Wit t ig reaction described below, unsaturated esters and < Wadsworth, W. S. Emmous, W. D. (J. Am. Chem.
Soc. ( 1 9 6 1 ), 83 , 1 733 ) 〇 oII 4· EtO-P、Soc. (196 1), 83, 1 733) 〇II 4. · EtO-P,
,EWG 鹼, EWG base
EWGEWG
RR
EtO (請先閱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R=烷基、芳基等。 EWG = C00Et,S02Me 等。 α ,召一不飽和酯(Hanzlik et al.,J. Med. Chem., 27(6):7 1 1 - 7 1 2 ( 1 984 ),Thompsοn et al., J. Med. Chem. 29:104-111(1986), Liu et al., J. Med. Chem., 35(6):1067(1992)及 a ’ /S —不飽和碉( 丁110111?8 0 11等人,前述者,;11\1等人,前述者) 係以兩個半胱胺酸蛋白酶(木爪蛋白酶及二肽基胺基一肽 酶I (亦稱爲組織蛋白酶C ))之抑制劑的形式試驗。然 而,藉此等a,y3 —不飽和化合物抑制木瓜蛋白酶時顯示 較差之抑制性,其係由a,0 -不飽和酯之低於 1M -1 s e c-1至低於γΟΜ-^ e c-1及·之低於 2 OM-h e c-1至低於6 0M-1 s e c-1之二次速率常 數證明。 此外,此等化學在對應於甘胺酸者以外之2 -胺基酸 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -5 - 470750 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明(3 ) 衍生物上,或酯、苯基丙胺酸上未獲證實。因而,此等化 合物之對常性對甘胺酸衍生物而言不存在,而對苯基丙胺 酸衍生物而言並不清楚。因爲酶之抑制通常要對掌性化合 物,故此點極爲重要。 已有人建議2 -胺基磺酸爲潛在之抑制化合物,雖然 其抑制效果未經記錄,但已製得數種(Me 1 1 wa i η等人, J. Chem. Soc. 75(1941))。 此外,已記錄使亞磺酸、醛、及胺甲酸乙酯Mannieh 縮合,以形成胺基甲酸乙酯(Engberts Recueil 84:942 ( 1965)。 其他選擇性且可逆地抑制半胱胺酸蛋白酶之方法係藉 胜肽 2 —氟甲基酮(Rasnick,D. Anal. Biochem (1985) ,149,416)、重氮甲基酮(Kirschke, Η.,Shaw,E. Biochem. Biphys. tes.Commun ( 1 98 1 ),1 0 1, 454 )、焼氧 甲基酮(Krantz, A.等人,生物化學(1991),30, 4678 ; Krontz,A.等人,美國專利 5 ,0 5 5,4 5 1 ,1 9 9 1年1 0月8日提出)及酮基碉鑷鹽(Walker, B. , Shaw, E. , Fed. Proc. Fed. Am. Soc. Exp. Biol., ( 1 985 ),44, 1 433 )烷基化。 其他種類之半胱胺酸蛋白酶抑制劑包括環氧琥珀基胜 肽,包括£ — 6 4及其同質物(1^113(13,1(.6士&1., Agric. Biol. Chem (1978), 42, 523; Sumiya, S. et al., Chem. Pharnt. Bull. ( 1 9 9 2 ),40,2 9 9 Gour-Salin, B. J. et al., J. Med. Chem·, (1993), 36, 720)、 2- .訂 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS ) A4規格(21 OX 297公釐) 一 6 - 470750 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明(4 ) 二羰基化合物(Mehdi,S.,生物有機化學(1993) ,21,249所評論者)及N-肽基一0-醯基氧肪酸 酯(B r 〇 m m e,D.,N e u m a η η,U.,K i r s c h k e, Η ·,D e m u t h, H - U ·,B i o c h i m. B i o p h y s · A c t a,( 1 9 9 3 ),1 2 0 2,2 7 1。 近來已有人編輯可逆地及不可逆地抑制半胱胺酸蛋白酶之 方法的其他摘要;參照Shaw, E.,酵素學之進展及分子 生物學之相關範疇(1990) ,63,271。 發明概述 本發明一方面係一種蛋白酶抑制劑,其包含經由兩個 碳原子鏈鍵結於吸電子基上之定靶基,其中,以該抑制劑 抑制蛋白酶之解離常數(K i )不大於約1 〇 〇 。 本發明另一方面係一種蛋白酶抑制劑,其包含直接或 經由鍵結基鍵結於砚基之定靶基,該鍵結基係選自中間碳 原子或兩個碳原子鏈,其中以該抑制劑抑制該蛋白酶之解 離常數(K i )不大於約1 0 0 。 本發明另一方面係一種式I之化合物,較佳蛋白酶抑 制劑: \a^ \s(0);R2 I 其中: n係0至1 3 ; Α-Β 表示選自—C (Ο) NR3、— CH2NR3、 _C (0) CH2—及一NR3C (Ο)—中之鍵結,'其中 本紙張尺度適用中關家標準(CNS ) Α4规格(21GX297公釐) ~ ' (請先聞讀背面之注意事項再填寫本頁) 470750 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明(5 ) R 3係氫或如下文所定義; X表示鍵結、伸甲基、或鍵結—CH2CH (R4)—,其 中R4係氫、烷基或芳烷基; Y係一 CH (R5)—或-NR5—,其中R5係氫或如下 文定義; Z 係(CH2).2—、— C ( R 6 ) ( R 7 )—或 _N (R7) — ’其中R β係氫或甲基,且R 7如下文所定 義; Z1 係—(CH2) 2—、一C(R6) (R8)-或 —N (R8) —,其中R 8係氫或甲基,且R 8如下文所定 義; R1係氫、烷氧羰基烷醯基、烷氧羰基、光醯基(選擇性 地經選自羰基、烷氧羰基及雜環烷基烷醯胺基中之基團所 取代)、環烷羰基、雜環烷羥基(選擇性地經選自羥基、 烷基、烷醯基、烷氧羥基、芳烷氣羥基及雜環烷羰基中之 基團所取代)、芳烷氧羰基、胺甲醯基、烷基胺甲醯基、 二烷基胺甲醯基、芳基胺甲醯基、芳烷基胺甲醯基、芳烷 醯基、芳醯基、烷磺醯基、二烷胺基磺醯基、芳磺醯基或 雜芳基磺醯基; R 7及R 8各係氫、烷基(選擇性地經選自羥基、胺基、烷 胺基、二烷胺基、脲基、锍基、烷硫基、羥基、胺甲醯基 、烷基胺甲醯基、二烷基胺甲醯基、烷磺醯基及胍基、或 其經保護之衍生物中之基團所取代)、環烷基、環烷基烷 基、雜芳基、雜芳烷基、選自芳基及芳烷基中之基團(該 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) -------------袭----^---1T------〆 (請先閱讀背面之注意事項再填寫本頁) 470750 經濟部中央標準局員工消費合作社印製 A7 __B7___五、發明説明(6 ) 基團之芳基環選擇性地經一個至三個選自羥基、胺基、胍 基、_基、選擇性地經鹵基取代之烷基、烷氧基及芳基' 或其經保護之衍生物中之基團所取代),或與相鄰之R3 或R5—起形成選自(C3-C4)伸甲基及1 ,2 —苯二伸 甲基中之二價基團(該基團選擇性地經羥基或其經保護之 衍生物,或合氧基所取代):且 R 2係氫、烷基(選擇性地經一個或多個選自胺基、胍基 、鹵基、羥基、烷氧基、硝基、烷磺醯基及芳磺醯基,或 其經保護之衍生物中之基團所取代)、環烷基、環烷基烷 基或選自芳基及芳烷基中之基團(該基團之芳基環選擇性 地經一個至兩個選自胺基、鹵基、羥基、選擇性地經鹵基 取代之烷基、烷氧基、硝基、烷磺醯基、芳磺醯基、或其 經保護之化合物所取代):及其藥學上可接受之鹽,其個 別異構物或異構物混合物,較佳以該抑制劑抑制該蛋白酶 時之解離常數(K i )不大於約1 〇 〇 am。 本發明另一方面係一種式II化合物,較佳蛋白酶抑 制劑:丨〆\ζ/Α(β/Ζ、^Β\ζ丨^ II 其中: 該基團如前定義且 R9係氰基、—C (0) OR1。、— Ρ (〇) (OR1。)2 ' -S (◦) (NR10) R10、C (0) R11、 -S (0) R11、- C (〇) NR12R13、 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) (請先閱讀背面之注意事項再填寫本頁) 47G750 經濟部中央標準局員工消費合作社印製 A7 B7 _五、發明説明(7 ) -S (0)2NR12R13、-C (0) NHR14 或 —S (02) NHR14’其中各Ri。個別係氫、烷基(選 擇性地經一個或多個選自胺基、鹵基、羥基、烷氧基、硝 基、烷磺醯基及芳磺醯基、或其經保護衍生物中之基團所 取代)、環烷基、環烷基烷基或選自芳基及芳烷基中之基 團(該基團之芳基環係選擇性地經一個至兩個選自胺基、 鹵基、羥基、選擇性經鹵基取代之烷基、烷氧基、硝基、 烷磺醯基及芳磺醯基、或其經保護之衍生物中之基團取代 )’R11係氫、烷基、全氟烷基、環烷基、環烷基烷基、 全氟芳基、全氟芳烷基或選自芳基及芳烷基中之基團(該 基團之芳基環選擇性地經一個或兩個選自胺基、_基、羥 基、選擇性地經鹵基取代之烷基、烷氧基、硝基、烷磺醯 基或芳磺醯基、或其經保護之衍生物中之基團所取代), R12及R 13各係氫、烷基、環烷基、環烷基烷基、芳基或 芳烷基,且R 14係一C ( 0 ) 0 R 10,其中R 1G如前定義 ,或係選自式(a)及(b)中之基團: 0人 〇R- ο (a) (b) (其中n、A、B、Y、Z、R1及R1。各如前定義,及 藥學上可接受之鹽;其個別異構物及異構物之混合物,較 佳係其中以該抑制劑抑制該蛋白酶之解離常數(K i )不 大於約100jc/m。 本發明另一方面係一種式III之化合物,較佳蛋白 本紙張尺度適用中國國家標準(CNS )八4規格(2丨〇'乂297公釐) (請先閱讀背面之注意事項再填寫本頁) 470750 A7 B7 五、發明説明(8 ) 酶抑制劑EtO (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs where R = alkyl, aryl, etc. EWG = C00Et, S02Me, etc. α, a mono-unsaturated ester (Hanzlik et al., J. Med. Chem., 27 (6): 7 1 1-7 1 2 (1 984), Thompsοn et al., J. Med. Chem. 29: 104-111 (1986), Liu et al., J. Med. Chem., 35 (6): 1067 (1992) and a '/ S-unsaturated europium (Ding 110111 ~ 8 0 11 et al., The former, 11 \ 1 et al., The former) were tested as inhibitors of two cysteine proteases (xyloprotease and dipeptidylamino-peptidase I (also known as cathepsin C)). However, Thus, a, y3 —unsaturated compounds exhibit poor inhibitory properties when inhibiting papain, which ranges from less than 1M -1 se c-1 to less than γOM- ^ e c- Proof of the secondary rate constant of 1 and · below 2 OM-h e c-1 to below 60 M-1 se c-1. In addition, these chemistries are 2-amine groups other than those corresponding to glycine The size of the acid paper is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) -5-470750 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (3) Derivatives, or esters, phenyl Alanine has not been confirmed. Therefore, these compounds It does not exist for normal glycine derivatives, but it is not clear for phenylalanine derivatives. This is important because inhibition of enzymes usually requires palm compounds. It has been suggested that 2-amines Sulfosulfonic acid is a potential inhibitory compound. Although its inhibitory effect has not been recorded, several kinds have been prepared (Me 1 1 wa i η et al., J. Chem. Soc. 75 (1941)). In addition, it has been recorded that Mannieh condensation of sulfinic acid, aldehyde, and urethane to form urethane (Engberts Recueil 84: 942 (1965). Other methods that selectively and reversibly inhibit cysteine proteases are peptides 2 —Fluoromethyl ketone (Rasnick, D. Anal. Biochem (1985), 149,416), diazomethyl ketone (Kirschke, Η., Shaw, E. Biochem. Biphys. Tes. Commun (1 98 1), 1 0 1, 454), oxymethyl ketone (Krantz, A. et al., Biochemistry (1991), 30, 4678; Krontz, A. et al., U.S. Patent 5, 0 5 5, 4 5 1, 1 9 9 Proposed on October 8, 2011) and Ketone Tweezer Salts (Walker, B., Shaw, E., Fed. Proc. Fed. Am. Soc. Exp. Biol., (1 985), 44, 1 433 )Alkylation. Other types of cysteine protease inhibitors include epoxy succinic peptides, including £ -6 4 and its homologs (1 ^ 113 (13, 1 (.6 ± & 1., Agric. Biol. Chem ( (1978), 42, 523; Sumiya, S. et al., Chem. Pharnt. Bull. (199.2), 40, 29.9 Gour-Salin, BJ et al., J. Med. Chem., ( 1993), 36, 720), 2-. Order (please read the notes on the back before filling in this page) This paper size applies to China National Standard (CNS) A4 (21 OX 297 mm)-6-470750 Ministry of Economic Affairs Printed by A7 B7, Consumer Cooperatives of the Central Bureau of Standards 5. Description of the Invention (4) Dicarbonyl compounds (Mehdi, S., Bioorganic Chemistry (1993), 21, 249 reviewers) and N-peptidyl 0-fluorenyl Oxo fatty acid esters (B r 0mme, D., N euma η η, U., Kirschke, Η ·, Demuth, H-U ·, B iochi m. B iophys · A cta, (1 9 9 3 ), 1 2 0 2, 2 7 1. Others have recently edited other abstracts of methods for reversibly and irreversibly inhibiting cysteine proteases; see Shaw, E., Advances in Enzymology and Related Categories of Molecular Biology ( 199 0), 63, 271. SUMMARY OF THE INVENTION One aspect of the present invention is a protease inhibitor comprising a target group bonded to an electron withdrawing group via a chain of two carbon atoms, wherein the inhibitor inhibits the dissociation constant of the protease. (K i) is not more than about 100. Another aspect of the present invention is a protease inhibitor, which comprises a target group bonded to a fluorenyl group directly or via a bonding group, the bonding group being selected from intermediate carbon atoms Or two carbon atom chains, wherein the inhibitor inhibits the dissociation constant (K i) of the protease by not more than about 100. Another aspect of the present invention is a compound of formula I, preferably a protease inhibitor: \ a ^ \ s (0); R2 I where: n is 0 to 1 3; A-B represents a bond selected from —C (Ο) NR3, —CH2NR3, _C (0) CH2—and one NR3C (Ο) — , 'Among which the paper size applies the Zhongguanjia Standard (CNS) Α4 specification (21GX297 mm) ~' (Please read the precautions on the back before filling out this page) 470750 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (5) R 3 is hydrogen or as defined below; X represents bonding, methyl extension Or bonding—CH2CH (R4) —, where R4 is hydrogen, alkyl or aralkyl; Y is a CH (R5) —or —NR5—, where R5 is hydrogen or as defined below; Z is (CH2). 2 — 、 — C (R 6) (R 7) — or _N (R7) — 'where R β is hydrogen or methyl, and R 7 is as defined below; Z1 —— (CH2) 2—, a C (R6) (R8)-or —N (R8) —, where R 8 is hydrogen or methyl, and R 8 is as defined below; R 1 is hydrogen, alkoxycarbonylalkylfluorenyl, alkoxycarbonyl, photofluorenyl (Optionally substituted with a group selected from the group consisting of carbonyl, alkoxycarbonyl, and heterocycloalkylalkylamino), cycloalkylcarbonyl, and heterocycloalkylhydroxy (optionally selected from hydroxy, alkyl, and alkyl (Replaced by groups in fluorenyl, alkoxyhydroxy, aralkyloxy, and heterocycloalkylcarbonyl), aralkyloxycarbonyl, carbamoyl, alkylaminomethyl, dialkylaminomethyl, aryl R amidinomethylamidino, aralkylaminomethylamidino, aralkylamidino, arylamidino, alkanesulfinomethyl, dialkylaminosulfinomethyl, arylsulfinomethyl or heteroarylsulfinomethyl; R 7 And R 8 are each hydrogen, alkyl (optionally selected from the group consisting of hydroxyl, amine, and alkylamino) , Dialkylamino, ureido, fluorenyl, alkylthio, hydroxy, carbamoyl, alkylaminomethyl, dialkylaminomethyl, alkylsulfonyl and guanidino, or protected Substituted by groups in its derivatives), cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, groups selected from aryl and aralkyl (the dimensions of this paper are applicable to the country of China Standard (CNS) A4 specification (210 X 297 mm) ------------- Attack ---- ^ --- 1T ------ 〆 (Please read the note on the back first Please fill in this page again) 470750 Printed by A7 __B7___ of the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (6) The aryl ring of the group is optionally passed through one to three selected from hydroxyl, amine, and guanidino , _, Optionally substituted with a halogen-substituted alkyl, alkoxy, and aryl group (or a group in a protected derivative thereof), or together with adjacent R3 or R5 to form a selected group (C3-C4) a divalent group in methyl and 1,2-phenylenediyl (this group is optionally substituted with a hydroxyl group or a protected derivative thereof, or a oxy group): and R 2 is hydrogen, alkyl (optionally Or more selected from the group consisting of amine, guanidino, halo, hydroxy, alkoxy, nitro, alkanesulfonyl, and arylsulfonyl, or substituted groups thereof), naphthenes Group, cycloalkylalkyl, or a group selected from aryl and aralkyl (the group's aryl ring is optionally passed through one or two selected from amine, halo, hydroxyl, and optionally Halo-substituted alkyl, alkoxy, nitro, alkanesulfonyl, arylsulfonyl, or protected compounds thereof): and pharmaceutically acceptable salts thereof, individual isomers or isomeric The structure mixture preferably has a dissociation constant (K i) when the protease is inhibited by the inhibitor is not more than about 1000 am. Another aspect of the present invention is a compound of formula II, preferably a protease inhibitor: 丨 〆 \ ζ / Α (β / Z, ^ Β \ ζ 丨 ^ II where: the group is as defined above and R9 is a cyano group,- C (0) OR1., — P (〇) (OR1.) 2 '-S (◦) (NR10) R10, C (0) R11, -S (0) R11,-C (〇) NR12R13, this paper Standards are applicable to China National Standard (CNS) A4 specifications (210X297 mm) (Please read the precautions on the back before filling out this page) 47G750 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 _V. Invention Description (7)- S (0) 2NR12R13, -C (0) NHR14 or -S (02) NHR14 'each Ri. Individual hydrogen, alkyl (optionally via one or more selected from amine, halo, hydroxyl, alkane Oxy, nitro, alkanesulfonyl and arylenesulfonyl, or substituted with a group in a protected derivative thereof), cycloalkyl, cycloalkylalkyl, or a group selected from aryl and aralkyl Group (the aryl ring system of this group is optionally substituted by one or two selected from amine, halo, hydroxyl, alkyl substituted with halo, alkoxy, nitro, alkanesulfonyl And aromatic sulfonyl, or Substituted by a group in a protected derivative) 'R11 is hydrogen, alkyl, perfluoroalkyl, cycloalkyl, cycloalkylalkyl, perfluoroaryl, perfluoroaralkyl, or selected from aryl and A group in an aralkyl group (the aryl ring of this group is optionally substituted by one or two selected from the group consisting of amine, _, hydroxy, and optionally substituted by halogen, alkyl, alkoxy, nitro , Alkylsulfonyl or arylsulfonyl, or a protected derivative thereof), R12 and R13 are each hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl or Aralkyl, and R 14 is C (0) 0 R 10, wherein R 1G is as defined above, or is a group selected from the group consisting of formulas (a) and (b): 0 person 〇R- ο (a) (b) (wherein n, A, B, Y, Z, R1, and R1. Each is as defined above, and a pharmaceutically acceptable salt; its individual isomers and mixtures of isomers, preferably those in which The inhibitors inhibit the dissociation constant (K i) of the protease not more than about 100 jc / m. Another aspect of the present invention is a compound of formula III, and the preferred protein is a Chinese paper standard applicable to China National Standard (CNS) 8-4 (2 丨〇 '乂 297 mm) (Please Note the back surface of the page read and re-fill) 470750 A7 B7 V. Description of the Invention (8) inhibitor
III 經濟部中央標準局員工消費合作社印裝 其中: 該基團如前定義且 R15係氫、甲基、氟或選自前文所定義之式(a )及(b )之基團,且R16係選自苯基或(5 - 6 )雜芳基(該基 團選擇性地經至少一個選自烷基胺甲醯基、二烷基胺甲醯 基、烷氧羥基、烷基胺基亞磺醯基、二烷基胺基亞磺醯基 、烷磺醯基、羧基、硝基、胺基亞磺醯基、磺基、胺甲醯 基、亞磷羧基、烷氧膦基、二烷氧膦基、烷醯基、氰基、 烷亞磺醯基、胺磺醯基、烷基胺磺醯基、二烷基胺磺醯基 、烷氧磺醢基、芳基、雜芳基、羥基、烷氧基、選擇性地 經鹵基取代之烷基、芳烷基、鹵基、_+N ( R17) 3或 —N (R18) 2中之基團所取代,其中各係烷基、芳 基或芳烷基,而其中R18各係氫、烷基、芳基或芳烷基) :及藥學上可接受之鹽;其個別異構物或異構物之混合物 ,較佳其中以該抑制劑抑制該蛋白酶之解離常數(K i ) 不大於約100//m。 本發明另一方面係一種藥學組成物,其包含治療有效 量之本發明半胱胺酸蛋白酶抑制劑,或其個別異構物、異 構物之混合物、或藥學上可接受之鹽或鹽類,並與一或多 (請先閱讀背面之注意事項再填寫本頁) 丁 本紙張尺度適用中國國家標準(CNS ) A4规格(210X297公釐) 470750 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明(9 ) 種藥學上可接受之輔劑結合》 本發明另一方面係一種於具有彼種需求之動物體內藉 著胱胺酸半胱胺酸蛋白酶而治療可ameli or at ion之狀況 的方法,該法包括給予該動物治療有效量之本發明半胱胺 酸蛋白酶抑制劑,或其個別異構物、異構物之混合物,或 藥學上可接受之鹽或鹽類。 本發明另一方面係一種偵測試樣中之半胱胺酸蛋白酶 的方法,該法包括: (a )使用蛋白酶受質檢定試樣之蛋白酶活性; (b )在已知濃度之本發明半胱胺酸蛋白酶抑制劑存 在下檢定蛋白酶活性;及 (c )計算在a )項與b )項之間之差異,以決定由 半胱胺酸蛋白酶所產生之蛋白酶活性。 本發明一方面係一種製備本發明半胱胺酸蛋白酶抑制 劑之方法。 附圖簡述 圖1表示意圖1 ,當X係鍵結時之式I化合物的合成 。合成步驟步下:a) HC02H,H20 ; b) HB r/ 乙酸;c) 4_甲基碼啉,氯甲酸異丁酯,Mu — R〇H ;及4 )層析純化。基團如本發明之定義。 圖2表示意圖2,當X係伸甲基時之式I化合物的合 成。合成步驟如下a) 4 —甲基嗎啉、氯甲酸異丁酯,隨 後係於水/THF中以N a BH4還原;b ) 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) (請先閲讀背面之注意事項再填寫本頁) -12 - 470750 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明(ίο) CH3S02Cj?,三乙胺,CH2c 芡 2; c) RiSH , NaH,CH3〇H,THF,熱;d) 4 —氯過笮酸, CH2Cj?2; e) HC 又 / 二噁烷或 p — CH3CeH4S〇3H / 乙醚·,及 f ) Mu_r〇h , 4 一 甲基嗎啉,氯甲酸異丁酯β 圖3表示意圓3,當X係伸甲基時之式I化合物的合 成。合成步驟如下:a) (CH3) 3CH2CH2SH ' NaH、Me〇H、THF、熱;b)4—氯過苄酸; c ) ( n — CaHjj) 4N+F -,THF,之後是 BrCH2Cj?,熱;d) He 又 / 二噁烷或 4_ CH3CeH4S03H /乙醚,及;e) 4 —甲基嗎啉’氯 甲酸異丁酯,Mu—Phe〇H。 圖4表示意圖4,式I I化合物之合成。合成步驟如 下· a) Cj? H2H+(CH3) OCH3,二環己基碳化 二亞胺,E t3N/CH2Ci2; b) L i Aj2H4/ THF; c)NaH/THF;d)HC^/二噁烷/ CH2Cj?2; e) 4 —甲基嗎啉,氯甲酸異丁酯/ THF :及 f)H2,5%Pd/c。 圖5示意圖5 ’當X係伸乙基時之式I化合物之合成 。合成步驟如下:a) (CH20)n,HCj?,二噁烷, 例如當Ar = 2—某基時;b) (E t 0) 3P ; c) C Η 3 C Ο 3 H ’ C Η 2 C β 2 ' d ) NaH ’ THF '< e ) P~CH3C6H4S〇3H ' E t 2 〇 ; f ) 4 —甲基碼琳 ,氯甲酸異丁酯;及g) H2,Pd/C。 (請先閱讀背面之注意事項再填寫本頁) 装. 、11 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -13 - 470750 經濟部中央標隼局員工消費合作社印製 A7 B7 _五、發明説明(11) 圖6表其中R8係一 COOH之式I I化合物之合成 〇 圖7表其中R 9係一 P (0) (R1Q)2之式I I化合 物之合成。合成示意圖如下:a) NaH/THF ; b) 無水P — CH3CeH4S03H /乙醚;c) 4 —甲基嗎啉 ,氯甲酸異丁酯/THF,及;d) H2,pd/C。 圖8表其中R9係—C (0) NHR14之式I I化合 物之合成。合成示意圖如下:a)NaOH/EtOH, 隨後係HCj?/H20 ; b )笮胺,二環己基碳化二亞胺 ,CH2Cj?2; c) NaH/THF ,苄基醯胺申甲基膦 酸二乙酯;d) HCj? /二噁烷;e) 4 —甲基碼啉,氯 甲酸異丁酯,THF ; f) H2,Pd/C,由經前述示 意圖6所合成之羧酸鹽開始之代用製備法;及g)苯胺、 二環己基碳化二亞胺,CH2cp2。 圖9表示式I I化合物之一般合成法。 圖10表示式I I I化合物之合成。合成步驟如下: a)CH3CN或其化適當溶劑,回流;b)H20, NaOH,隨後萃取於有機介質中;c)磷烷’ THF ( Wi t t i g 反應);d) P — CH3CeH4S03H ’ 乙 醚;e) Mu — PheOH,4 —甲基碼啉,氯甲酸異丁 酯,THF;及 f)H2,Pd/C。 定義 除非另有陳述,否則說明書及申請專利範圍中所用之 本紙張尺度適用中國國家標準(〇阳)八4規格(210父297公釐)_1/(_ (請先閲讀背面之注意事項再填寫本頁) 470750 A7 B7 經濟部中央標準局員工消費合作社印製 五、, 發明説明( 12) 1 1 下 列 辭 句 皆 視 本 發 明 之 巨 的 定 義 > 且 具 有 下 列 意 義 1 1 於 院 基 、 烷 氧 基 、 烷 硫 基 、 烷 擴 Off/if 醯 基 、 烷 基 胺 甲 醯 基 1 1 、 二 烷 基 胺 甲 醯 基 > 雜 芳 烷 基 、 芳 烷 基 等 基 中 之 院 基 ft 1 I 請 1 | 思 指 具 有 1 至 1 0 個 碳 原 子或 具 所 示 數 之 碳 原 子 之 直 鏈 閲 I I 讀 1 或 支 鏈 、 飽 和 或 不 飽 和 烴 基 ( 例 如 甲 基 、 乙 基 、 丙 基 、 異 背 面 1 之 1 丙 基 丁 基 、 第 二 丁 基 、 異 丁 基 、 第 三 丁 基 乙 烯 基 、 烯 注 意 1 1 丙 基 1 — 丙 烯 基 > 異 丙 烯 基 \ 1 — 丁 烯 基 \ 2 — 丁 烯 基 事 項 再 1 1 、 3 — 丁 烯 基 、 2 — 甲 基 烯 丙 基 、 乙 炔 基 、 1 — 丙 炔 基 > 填 寫 裝 2 — 丙 炔 基 等 ) 0 頁 '«W〆 1 1 烷 氧 膦 基 及 二 院 氧 膦 基 rf 個 別 意指 基 團 1 I — P ( 0 ) ( 0 Η ) 0 R 及 一 P ( 0 ) ( 0 R ) 2 其中 1 I R 係 前 文 所 定 義 之 烷 基 〇 1 訂 I 於 烷 醯 基 、 院 釅 氧 基 雜 環 烷 基 烷 醯 胺 基 等 基 中 之 VV 1 1 院 醯 基 » 意 指 基 團 — C ( 0 ) R 其 中 R 係 總 共 具 有 1 至 1 1 1 1 個 碳 原 子 或 所 示 之 碳 原 子 數 之前 述 院 基 ( 例 如 ( 1 1 C 1 — 烷醯基 >包括甲醯基 、乙醯基 、丙醯基 、異丙醯 I 基 、 丁 醯 基 、 異 丁 醯 基 、 巴 豆 醯 基 、 異 巴 豆 醯 基 等 ) 0 1 1 I 芳 基 意 指 含 有 6 至 1 4 個 碳 原 子 或 所 示 之 碳 原 子 1 1 數 之 芳 族 單 壞 或 多 壞 烴 基 > 及 其 碳 環 酮 或 硫 酮 衍 生 物 > 其 1 中 具 有 白 由 價 之 碳 原 子 係 芳 族 環 之 — 員 ( 例 如 > 芳 基 包 括 1 苯 基 、 菓 基 、 Μ 基 菲 基 、 1 9 2 > 3 4 — 四 氫 — 5 — 1 I 棻 基 、 1 — 合 氧 基 — 1 y 2 — 二 氫 — 5 — 棻 基 、 1 一 硫 代 1 I — 1 > 2 — 二 氫 5 — 某 基 等 ) 0 1 1 1 A 芳 醯 基 意 指 基 團 — C ( 0 ) A r 其 中 A r 係 前 1 1 I 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) ---- 1 470750 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明(l3) 文所定義之芳基,具有總數由7個至1 5個之碳原子或所 示之碳原子數(例如,(C^n)芳醯基包括苄醯基、菓 醯基等)。 在環烷基及環烷基烷基中之"環烷基〃意指含有3至 2 0個碳原子或所示之碳原子數之飽和或不飽和、單環或 多環烴基,其中具有自由價之碳原子係非芳族環之一員’ 及其任何一種碳環酮及硫酮衍生物(例如,環烷基一詞用 以包括環丙基、環丁基、環戊基、環己基、環己烯基、雙 環〔2,2,2〕辛基、1,2,3,4 一四氫—1—菓 基,二氧基環己基,硫代環己基、9 一芴基等)。 a鹵基〃意指氟、氯、溴或碘。 在雜環烷基、雜環烷基烷醯胺基、雜環烷羰基、雜環 烷羰基等基中之"雜環烷基"意指其中1個至5個所示之 碳原子經選自N、0、S、P或A s中之雜原子所取代之 前文所定義之環烷基,其中其有自由價之原子係非芳族環 中之一員,及其任何一種雜環酮、硫酮、硕或亞硕衍生物 (例如雜環烷基係包括哌啶基、吡咯啶基、吡咯啉基、咪 唑啶基、蚓跺啉基、奎寧環基、嗎啉基、哌嗪基、N -甲 基哌嗪基、哌若症基(P i pe r ad i ny 1 ) 、4, 4-二氧基—4 一硫雜哌啶基、1 ,2 ,3,4 —四氫— 3 -異晻啉基、2,4 —二氮雜-3 —氧基-7-硫雜― 6 —雙環〔3,3 ,0〕辛基等)。因此,雜(C6)環 烷基包括基團嗎啉基 '哌嗪基、哌啶基等。 "雜芳基"意指含有總數5至14個原子或所示之原 本紙張尺度適^中國國家標準(CNsTa4規格(210X297公釐) (請先聞讀背面之注意事項再填寫本育) 装· 訂 470750 A7 B7 ___五、發明説明(14) 子數之芳族單環或多環烴基,其中1個至5個碳原子係經 選自N、0、S、P或As中之雜原子所取代,其中具有 自由价之原子係芳族環之一員,及任何一種其雜環酮及硫 酮衍生物(例如雜芳基包括卩塞嗯基、呋喃基、吡咯基、嘧 啶基、異噁唑基、噁唑基、蚓跺基、苯並〔b〕_嗯基、 異苯並呋喃基、嘌呤基、異喹啉基、蝶啶基、嘧啶基、咪 唑基、吡啶基、吡唑基、吡暸基、4 ~氧基—1,2 —二 氯—1—条基、4—硫基一 1 ’ 2 -二氣—1—秦基等) 。因此,雜(C β )芳基包括基團吡啶基、嘧啶基等。 "1 ,2 —苯二伸甲基"意指具下式 —CH2C6H4CH2_之二價基。例如,其中Υ係—Ν ( R 5 ) ,Z係一 C H ( R 7 ) —,A係羰基且R 7與R 5—起 形成1 ,2_苯二伸甲基之基團RiY — Z — A — 〃意指 具下式之基團: (請先聞讀背面之注意事項再填寫本頁)III Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs: The group is as defined above and R15 is hydrogen, methyl, fluorine or a group selected from the formulas (a) and (b) defined above, and R16 is Selected from phenyl or (5-6) heteroaryl (this group is optionally via at least one selected from alkylaminomethylsulfanyl, dialkylaminomethylsulfanyl, alkoxyhydroxyl, alkylaminosulfinyl Fluorenyl, dialkylaminosulfinyl, alkylsulfonyl, carboxyl, nitro, aminesulfinyl, sulfo, carbamoyl, phosphorous carboxyl, alkoxyphosphino, dialkoxy Phosphino, alkylsulfonyl, cyano, alkylsulfinyl, sulfanyl, alkylaminesulfonyl, dialkylaminosulfonyl, alkoxysulfonyl, aryl, heteroaryl, hydroxyl , Alkoxy, optionally substituted with halo, alkyl, aralkyl, halo, _ + N (R17) 3 or -N (R18) 2 groups, each of which is an alkyl group, Aryl or aralkyl, wherein each of R18 is hydrogen, alkyl, aryl, or aralkyl): and pharmaceutically acceptable salts; individual isomers or mixtures of isomers thereof, preferably the Inhibitor inhibits the protein The dissociation constant (K i) is no greater than about 100 // m. Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a cysteine protease inhibitor of the present invention, or an individual isomer, a mixture of isomers, or a pharmaceutically acceptable salt or salt thereof. And one or more (please read the notes on the back before filling this page) The paper size of this paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 470750 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (9) Combination of pharmaceutically acceptable adjuvants Another aspect of the present invention is the treatment of ameli or at ion by cystine cysteine protease in an animal with the same needs. A method of treating a condition comprising administering to the animal a therapeutically effective amount of a cysteine protease inhibitor of the invention, or an individual isomer, mixture of isomers, or a pharmaceutically acceptable salt or salt thereof. Another aspect of the present invention is a method for detecting a cysteine protease in a sample, the method comprising: (a) using a protease to test the protease activity of a sample; (b) a half of the present invention at a known concentration Detecting protease activity in the presence of a cysteine protease inhibitor; and (c) calculating the difference between items a) and b) to determine the protease activity produced by the cysteine protease. One aspect of the present invention is a method for preparing a cysteine protease inhibitor of the present invention. Brief Description of the Drawings Figure 1 is a schematic diagram of Table 1, the synthesis of a compound of formula I when X is bonded. The synthetic steps are as follows: a) HC02H, H20; b) HB r / acetic acid; c) 4-methyl codeline, isobutyl chloroformate, Mu-ROH; and 4) chromatographic purification. Group is as defined in the present invention. Fig. 2 is a schematic diagram showing the synthesis of a compound of formula I when X is a methyl group. The synthesis steps are as follows: a) 4-Methylmorpholine and isobutyl chloroformate, which are then reduced with Na BH4 in water / THF; b) This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) -12-470750 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (ίο) CH3S02Cj ?, triethylamine, CH2c 芡 2; c) RiSH , NaH, CH3OH, THF, heat; d) 4-chloroperacetic acid, CH2Cj? 2; e) HC / dioxane or p-CH3CeH4S03H / ether ·, and f) Mu_r0h, 4 Monomethylmorpholine, isobutyl chloroformate β Figure 3 shows the meaning of circle 3, the synthesis of a compound of formula I when the X is methyl. The synthesis steps are as follows: a) (CH3) 3CH2CH2SH 'NaH, MeOH, THF, heat; b) 4-chloroperbenzoic acid; c) (n — CaHjj) 4N + F-, THF, followed by BrCH2Cj ?, heat D) He / dioxane or 4-CH3CeH4S03H / ether, and; e) 4-methylmorpholine'isobutyl chloroformate, Mu-PheOH. Figure 4 is a schematic diagram of the synthesis of compounds of formula II. The synthesis steps are as follows: a) Cj? H2H + (CH3) OCH3, dicyclohexylcarbodiimide, E t3N / CH2Ci2; b) L i Aj2H4 / THF; c) NaH / THF; d) HC ^ / dioxane / CH2Cj? 2; e) 4-methylmorpholine, isobutyl chloroformate / THF: and f) H2, 5% Pd / c. Fig. 5 is a schematic diagram 5 'of the synthesis of a compound of formula I when X is ethylene. The synthesis steps are as follows: a) (CH20) n, HCj ?, dioxane, for example, when Ar = 2-a certain group; b) (E t 0) 3P; c) C Η 3 C Ο 3 H 'C Η 2 C β 2 'd) NaH' THF '< e) P ~ CH3C6H4S03H' E t 2 0; f) 4 -methyl codeline, isobutyl chloroformate; and g) H2, Pd / C. (Please read the precautions on the back before filling out this page). 11 Paper sizes are applicable to Chinese National Standard (CNS) A4 specifications (210X297 mm) -13-470750 Printed by A7, Consumers Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs B7 _V. Description of the invention (11) Figure 6 shows the synthesis of a compound of formula II in which R8 is a COOH. Figure 7 shows the synthesis of a compound of formula II in which R 9 is a P (0) (R1Q) 2. The synthesis scheme is as follows: a) NaH / THF; b) anhydrous P-CH3CeH4S03H / ether; c) 4-methylmorpholine, isobutyl chloroformate / THF, and; d) H2, pd / C. Figure 8 shows the synthesis of compounds of formula I I where R9 is -C (0) NHR14. The synthesis scheme is as follows: a) NaOH / EtOH, followed by HCj? / H20; b) sulfonamide, dicyclohexylcarbodiimide, CH2Cj? 2; c) NaH / THF, benzyl sulfonamide and methylphosphonic acid diethyl ester D) HCj? / Dioxane; e) 4-methyl codeline, isobutyl chloroformate, THF; f) H2, Pd / C, prepared by substitution starting from the carboxylate synthesized by the aforementioned scheme 6 Method; and g) aniline, dicyclohexylcarbodiimide, CH2cp2. Fig. 9 shows a general method for synthesizing a compound of formula II. Figure 10 shows the synthesis of compounds of formula I I I. The synthesis steps are as follows: a) CH3CN or its appropriate solvent, reflux; b) H20, NaOH, followed by extraction in an organic medium; c) phosphane 'THF (Wi ttig reaction); d) P — CH3CeH4S03H' ether; e) Mu — PheOH, 4-methyl codeline, isobutyl chloroformate, THF; and f) H2, Pd / C. Definition Unless otherwise stated, the paper size used in the specification and patent application scope is applicable to the Chinese National Standard (〇 阳) 8 4 specifications (210 father 297 mm) _1 / (_ (Please read the precautions on the back before filling (This page) 470750 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (12) 1 1 The following words are all based on the definition of the invention > and have the following meanings 1 1 Oxy, alkylthio, alkane Off / if fluorenyl, alkylaminomethyl 1 1, dialkylaminomethyl > heteroaryl, aralkyl and other groups in the group ft 1 I Please 1 | Think of a straight chain with 1 to 10 carbon atoms or the number of carbon atoms shown II Read 1 or branched, saturated or unsaturated hydrocarbon group (such as methyl, ethyl, propyl, isomeric 1 to 1 propylbutyl, second butyl, isobutyl , 3rd butyl vinyl, alkenes Note 1 1 propyl 1 —propenyl> isopropenyl \ 1 —butenyl 2 — butenyl matters again 1 1, 3 — butenyl, 2 — methyl Allyl, ethynyl, 1-propynyl > fill in 2-propynyl, etc.) 0 pages' «W〆1 1 alkoxyphosphino and dihodophosphino rf individually mean the group 1 I — P (0) (0 Η) 0 R and a P (0) (0 R) 2 where 1 IR is an alkyl group as defined above. VV 1 1 in an amino group and the like »means a group — C (0) R where R is the aforementioned group having a total of 1 to 1 1 1 1 carbon atoms or the number of carbon atoms shown (eg (1 1 C 1-Alkyl)> includes methyl, ethyl, propyl, propyl, isopropyl, butyl, butyl, isobutyl, crotonyl, isocrotonyl, etc.) 0 1 1 I Aryl means an aromatic mono- or multi-bad hydrocarbon group containing 6 to 14 carbon atoms or the number of carbon atoms shown 1 1 and its carbocyclic ketone or thioketone derivative > wherein 1 has a Valence carbon atom is a member of the aromatic ring—for example,> aryl includes 1 phenyl, phenyl, methyl, phenanthryl, 1 9 2 > 3 4 — tetrahydro — 5 — 1 I amidino, 1 — Hexyloxy — 1 y 2 —dihydro — 5 —fluorenyl, 1 monothio 1 I — 1 > 2 —dihydro 5 — certain group, etc.) 0 1 1 1 A Arylfluorenyl means group — C (0) A r where A r is the first 1 1 I This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) ---- 1 470750 A7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Description of the invention (l3) The aryl group defined in the text has a total of 7 to 15 carbon atoms or the number of carbon atoms shown (for example, (C ^ n) arylfluorenyl includes benzylfluorenyl and perylene Wait). "Cycloalkyl" in cycloalkyl and cycloalkylalkyl means a saturated or unsaturated, monocyclic or polycyclic hydrocarbon group containing 3 to 20 carbon atoms or the number of carbon atoms shown, wherein A free-valent carbon atom is a member of a non-aromatic ring 'and any of its carbocyclic ketone and thioketone derivatives (for example, the term cycloalkyl is used to include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , Cyclohexenyl, bicyclo [2,2,2] octyl, 1,2,3,4 tetrahydro-1-fruityl, dioxycyclohexyl, thiocyclohexyl, 9-fluorenyl, etc.) . a Halofluorene means fluorine, chlorine, bromine or iodine. "Heterocycloalkyl" in heterocycloalkyl, heterocycloalkylalkylamino, heterocycloalkylcarbonyl, heterocyclocarbonyl and the like means that one to five of the carbon atoms shown in A heteroatom selected from N, 0, S, P or As is substituted for a cycloalkyl group as previously defined, in which the free-valent atom is a member of a non-aromatic ring, and any of its heterocyclic ketones , Thioketones, sulfones, or bis-derivatives (e.g., heterocycloalkyls include piperidinyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, earthworm, quinuclidinyl, morpholinyl, piperazine , N-methylpiperazinyl, piperazine (P i pe ad ad ny 1), 4, 4-dioxy-4 monothiapiperidinyl, 1,2, 3, 4-tetra Hydrogen—3-isodolinolinyl, 2,4-diaza-3—oxy-7-thia-6—bicyclo [3,3,0] octyl, etc.). Thus, hetero (C6) cycloalkyl includes the groups morpholinyl'piperazinyl, piperidinyl and the like. " heteroaryl " means that the original paper contains a total of 5 to 14 atoms or is shown in the original paper size ^ Chinese National Standard (CNsTa4 specification (210X297 mm) (please read the notes on the back before filling in this education) Binding · 470750 A7 B7 ___ V. Description of the invention (14) Aromatic monocyclic or polycyclic hydrocarbon group with a number of members, in which 1 to 5 carbon atoms are selected from N, 0, S, P or As A heteroatom is substituted, in which the atom having a free valence is a member of the aromatic ring, and any of its heterocyclic ketones and thioketone derivatives (for example, the heteroaryl group includes threonyl, furyl, pyrrolyl, pyrimidinyl, Isoxazolyl, oxazolyl, vermicarbyl, benzo [b] -umyl, isobenzofuranyl, purinyl, isoquinolinyl, pteridinyl, pyrimidinyl, imidazolyl, pyridyl, pyridine Oxazolyl, pyridyl, 4 ~ oxy-1,2-dichloro-1-yl, 4-thio-1'2-digas-1-yl, etc.). Therefore, hetero (C β) Aryl includes groups such as pyridyl, pyrimidinyl, etc. " 1,2-phenylenedimethyl " means a divalent radical having the formula -CH2C6H4CH2_. For example, where the fluorene is -N ( R 5), Z is a group CH (R 7) —, A is a carbonyl group and R 7 and R 5 together form a 1,2-phenylenedimethyl group RiY — Z — A — 〃 means having the formula Group: (Please read the notes on the back before filling out this page)
經濟部中央標準爲員工消費合作社印製 及其經取代之衍生物及個別之立體異構物及立體異構物之 混合物。1 ,2 —苯二伸甲基二價基團之經取代衍生物在 環系統內之任何碳上或在任何一個不飽和環碳原子之合氧 基上可含有羥基。 ^亞磷羧基"意指基圑—P (〇) (OH) 2。 在(C3_4)伸甲基〃及a (C3_7)伸甲基"中之 a伸甲基"意指具有所示之碳原子數之直鏈飽和二價基; 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) ~ ~一 470750 經濟部中央標準局員工消費合作社印裝 A7 ____B7___ 五、發明説明(15) a (C3_4)伸甲基〃包括三伸甲基(一(CH2) 3_) 及四伸甲基(_ (ch2) 4—)。例如,本發明較佳具體 實例利用脯胺酸殘基充作A_B-Z基團,其中A — B表 示CH2— NR3,且R3與R7或R8—起形成C3伸甲基。 因此,其中 Y 係一(NR5) —,Z 係一CH (R7)— ’ A係羰基且R 7與R 5—起形成三伸甲基之基團R1— Y — Z_A意指具下式之基團:The central standard of the Ministry of Economic Affairs is printed by employee consumer cooperatives and their substituted derivatives and individual stereoisomers and mixtures of stereoisomers. Substituted derivatives of 1,2-benzenedienemethyl divalent groups may contain a hydroxyl group on any carbon in the ring system or on the oxygen group of any unsaturated ring carbon atom. ^ Phosphorous carboxyl refers to the group 圑 —P (〇) (OH) 2. In (C3_4) methylamine and a (C3_7) methylamine, "a methyl" means a straight-chain saturated divalent group with the number of carbon atoms shown; this paper standard applies to Chinese national standards (CNS) A4 specification (210X297 mm) ~ ~ 470750 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ____B7___ V. Description of the invention (15) a (C3_4) Methylmethyl, including trimethylol ) 3_) and tetramethyl (_ (ch2) 4—). For example, the preferred embodiment of the present invention utilizes a proline residue as the A_B-Z group, where A-B represents CH2-NR3, and R3 and R7 or R8 together form a C3 methyl group. Therefore, where Y is a (NR5) —, Z is a CH (R7) — 'A is a carbonyl group and R 7 and R 5 — form a trimethyl group — R1 — Y — Z_A means having the formula Group:
及其個別立體異體物及立體異構物之混合物。三伸甲基及 四伸甲基二價基團之經取代衍生物可在任何一個環碳原子 '上含有羥基、或其經保護之衍生物、或氧基。適當之羥基 保護基係如下文所定義。 "氧雜(c3_7)伸甲基〃及”氮雜(c3_7)伸甲基 "意指其中一個所表示碳原子各經氧或氮原子取代之前述 伸甲基。例如,"氧雜(C 5 )伸m"包括3 —氧雜五 伸甲基(一CHsCHsOCHsC^z-)及2 —氧雜五伸 甲基(一CH2OCH2CH2CH2—)。因此,當 R21 及 R 22—起形成3 _氧雜五伸甲基時, —C (0) NR21R22意指基團4 —嗎啉羰基,當R21及 R 22—起形成3 —氮雜伸甲基時,則係基團1 ~哌嗪羰基 〇 在"R7與相鄰R3—起"一辭中所用之"相鄰〃意指 本紙張尺度適用中國國家標準(CNS ) A4規格(2丨OX297公釐) — In I I I , K "^衣— I I I I I I I —-^ (請先閲讀背面之注意事項再填寫本頁) 470750 A7 B7 經濟部中央標準局員工消費合作社印製 五、 發明説明( 16) R 7及R 3 所 個 別附 著之 原 子 依序彼 此 附 著 〇 ,動 物 包括 人類 、 非 人類 哺乳 類 ( 例如 犬 、 貓、 免 牛 、馬 、 羊 、山 羊、 豬 、 鹿等 ) 及 非 哺 乳類 ( 例 如島 類 等 ) 0 ,疾 病 特別包括 動 物 或其部 分 之 任何一 種 不 健康 狀 況 並包括 由 施於 動物 身 上 之醫 學 或 獸 醫 治療 所 致 或所 容 易 產 生之 不 健 康狀況, 即 彼等 治 療 之 副作 用 0 Λ吸 電 子 基' (Ε W G )意 指 在 最 廣 泛之 定 義 下之 官 能 基 係可 在 介 於其 自身 與 彼 所附 著 之 碳 之 間之 鍵 結 上, 產 生 極 化力 使 該電 子順 應 該 吸電 子 基 地 極 化之 基 團 。雖 未 受 限 於任 何 特 定理 論, 但 相 信該 極 化 性 質 可使 吸 電 子基 參 與 半 胱胺 酸 蛋 白酶 之活 性 部 位進 行 之 疏 水性或 氧 鍵 結相 互 作 用 ,而 抑 制 該酶 。通 常 當一 個 部 分 存 於一 般 結 構 P h 3P = c (R ) EWG之鱗炔化物之ί 2 -位置時,若 具 有 足以 使 炔 化物 對抗 與 氧 、水 氫 鹵 酸 、醇 等 進 行之 分 解 應 而安 定 化 之極 化, 則 適 於充 作 吸 電 子 基。 較 佳 吸電 子 基 係 相同 地 使 通式 (〇 R ) 2 Ρ (〇 ) C (R ) E W G之 炔 化 物安 定 化 者。 適當 之 吸 電子 基 包括 氣 基、 — S (〇 ) 2 R 2、 -C ( 0 )〇 R 10 — Ρ ( 0 ) ( 0 R 10) 2 » -S (〇 ) (N R 1 0〕 R 1 0 C (〇〕 R 1 1 \ — S ( 0 ) R 1 1 、 — C ( 0 ) Ν R 1 2 R 13, 一 S (〇 ) 2N R 1 2 R 1 3 、 — -C (〇 ) N H R 1 A -S ( 0 ) 2N R 1 4 、苯基及 ( :5 -6 ) 雜 芳 基 , 其中 R 2 R 1 〇 、 R 1 1 X R 1 2 、R 13及 R 1 4 各如 發 明 簡 述 中所 述 之 最廣 義 訂 球 本紙張尺度適用中國國家標準(CNS ) A4規格(21〇Χ29ί7公釐) 請 先 聞 ft 背 之 注 意 事 項 再 填 I裝 頁 19 - 470750 Α7 Β7 經濟部中央標準局員工消費合作社印製 五、發明説明(17) 之定義中所定義者。當吸電子基係苯基或(c5-e)雜芳 基時,該環可經一個或多個間位定向取代基(例如烷基羰 基、烷基胺基亞磺醯基、二烷基胺基亞磺醯基、烷磺醯基 、羧基、硝基、胺基亞磺醯基、磺基、亞磷羧基、烷氧膦 基、二烷氧膦基、烷醯基、氰基、烷亞磺醢基、胺磺醯基 、烷基胺磺醯基、二烷基胺磺醯基、烷氧磺醯基、二經取 代之胺基、三經取代之a m m ο n i 0等)、原位及對位 定向取代基(例如羥基、烷氧基、選擇性經_基取代之烷 基、芳基、芳烷基、鹵基等)及吸電子部分(例如烷基胺 甲醯基、二烷基胺甲醯基、烷氧羰基、烷基胺基亞磺醯基 、二烷基胺基亞磺醯基、烷磺醯基、羧基、硝基、胺基亞 磺醯基、磺基、胺甲醯基、亞磷羧基、烷氧基膦基、二烷 氧基膦基、烷醯基、氰基、烷基亞磺醯基、胺基磺醯基、 烷基胺磺醯基、二烷基胺磺醯基、烷氧磺醯基、芳基、雜 芳基等)所取代。 4脫離基A具有合成機化學所習用之定義,即可在烷 基化條件下置換之原子或基團,包括_基及烷一或烯磺醯 氧基,諸如甲磺醯氧基,乙磺醯氧基,苯磺醯氧基及甲苯 磺醢氧基、及烷磺醯胺基、烷羰胺基、胺磺醯胺基、胺羰 胺基等。 ' 異構化係其中化合物具有相同分子式,但原子鍵結之 性質或序列或其原子於空間中之排列相異之現象,原子在 空間中排列相異之異構物稱爲"立體異構物〃。彼此非鏡 像之立體異構物稱爲A非鏡像異構物",而非可重疊之鏡 (請先閱讀背面之注意事項再填寫本頁) 4口 本紙張尺度適用中_家鱗Μ規格⑺咖公餐) 470750 經濟部中央標率局員工消費合作社印製 A7 ______B7__五、發明説明(18) 像的立體異體物稱爲"鏡像異構物〃或有時稱爲"光學異 構物"。鍵結於四個不同取代基之碳原子稱爲對掌中心 ” 〇 具有一個具有兩種相反對掌性之鏡像異構形式之對掌 中心之化合物稱爲Α消旋混合物〃。具有多於一個之對掌 中心之化合物具有2"-1對鏡像異構物對,其中η係對掌 中心之數目。 式I 、 II 、 III之化合物可係個別立體異構物或 立體異構物混合物之形式。例如,式I 、I I及I I I之 化合物在附著取代基R 8之碳上含有對掌中心。此外,其 中Ζ係-C (Re) (R7)之式I 、I I及I I I化合物 在附有R 7取代基之碳上含有對掌中心。因此,例如,其 η 係 0 且 Ζ 係—C (Re) (R7)之式 I 、I I 及 I I I 化合物具有兩個對掌中心,且可有四種個別之立體異構物 或任何一種其混合物。 個別立體異構物可由其對掌中心之絕對結構定義。絕 對結構意指附於對掌中心之取代基於空間中之排列。附於 所1討論之對掌中心之取代基係根據Cahn, Ingold及 Pre 1 og之序列規則排列,若三個最高階取代基於空間中 由高至低極性順時鐘排列於空間中(第四個最低階之取化 基定向於遠離觀察者之方向),則定爲絕對描述符R,而 絕對描述符S則定爲逆時針排列。當描述含有一個對掌中 心之個別立體異構物時,在括弧中列出絕對描述符R或S ,之後是連字符號及化合物之化學名稱。本發明中,描述 本紙張尺度適用中國國家標準(CNS ) A4規格(2丨0X297公釐) —ί I I * n II 訂— — II^, (請先閱讀背面之注意事項再填寫本頁) 470750 A7 _B7___五、發明説明(19) 含有兩個或多個對掌原子之個別立體異構物或立體異構物 之混合物時,在適當之位置後立即列出絕對描述符!^或5 。由天然胺基酸所衍生之醯基意指由描寫符L所前導之胺 基酸基(例如L-苯基丙胺酸)。胺基酸醯基之非天然鏡 像異構物係由描述符D所前導。因爲酶之立體選擇性’故 較佳胺基酸側鏈係(S )或L -型,但某些情況下可使用 D -型。當對掌中心未列出絕對描述符時,該描述係同時 * 包括兩結構及其混合物、消旋物等。因此,例如’具下式 之化合物 (請先聞讀背面之注意事項再填寫本頁)And its individual stereoisomers and mixtures of stereoisomers. The substituted derivatives of tris-methyl and tetras-methyl groups may contain a hydroxyl group, or a protected derivative thereof, or an oxy group on any one ring carbon atom. Suitable hydroxy protecting groups are as defined below. " Oxa (c3_7) methyl and " aza (c3_7) methyl " mean the aforementioned methyl group in which each of the carbon atoms represented is replaced with an oxygen or nitrogen atom. For example, " oxa (C 5) m " includes 3-oxapentamethyl (1-CHsCHsOCHsC ^ z-) and 2-oxapentamethyl (1-CH2OCH2CH2CH2—). Therefore, when R21 and R 22- together form 3 _ In the case of oxapentamethyl, —C (0) NR21R22 means the group 4 —morpholine carbonyl. When R21 and R 22 together form a 3 —azatetramethyl, it is a group 1 to piperazinecarbonyl. 〇Used in the terms “R7 and adjacent R3—from” “Adjacent” means that the paper size applies the Chinese National Standard (CNS) A4 specification (2 丨 OX297 mm) — In III, K " ^ 衣 — IIIIIII —- ^ (Please read the notes on the back before filling out this page) 470750 A7 B7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (16) Individually attached to R 7 and R 3 The atoms are sequentially attached to each other. Animals include humans, non-human mammals (such as dogs, , Free of cattle, horses, sheep, goats, pigs, deer, etc.) and non-mammalian species (such as islands, etc.) 0, the disease particularly includes any unhealthy condition of the animal or part thereof and includes medical or veterinary treatment applied to the animal Unhealthy conditions caused or prone to occur, that is, side effects of their treatment 0 Λ electron-withdrawing group (E WG) means that the functional group under the broadest definition can be between itself and the carbon to which it is attached On the bond between them, a polarizing force is generated to make the electron conform to the group polarized by the electron-withdrawing base. Although not limited to any particular theory, it is believed that the polarization property can allow the electron-withdrawing group to participate in cysteine Hydrophobic or oxygen-bonding interactions at the active site of a protease inhibit the enzyme. Usually when a part is present in the 2 -position of the phosphonium compound of the general structure Ph 3P = c (R) EWG, if it has Enough to acetylate Confrontation with the decomposition of the oxygen feed line, hydrohalic acid, water, alcohol or the like to be given the safety of the polarization is adapted to be charged electron withdrawing group. A better electron-acceptor group is one which stabilizes an alkynide of the general formula (〇 R) 2 P (〇) C (R) E W G in the same way. Suitable electron withdrawing groups include a gas group, -S (〇) 2 R 2, -C (0) 〇R 10-P (0) (0 R 10) 2 »-S (〇) (NR 1 0) R 1 0 C (〇) R 1 1 — — S (0) R 1 1, — C (0) NR 1 2 R 13, —S (〇) 2N R 1 2 R 1 3, — -C (〇) NHR 1 A -S (0) 2N R 1 4, phenyl and (: 5 -6) heteroaryl, wherein R 2 R 1 〇, R 1 1 XR 1 2, R 13 and R 1 4 are as described in the brief description of the invention In the broadest sense, the paper size applies to the Chinese National Standard (CNS) A4 specification (21〇 × 29ί7mm). Please read the notes on ft before filling in I. Page 19-470750 Α7 Β7 Staff Consumption of the Central Standards Bureau of the Ministry of Economic Affairs Cooperative prints 5. As defined in the definition of invention description (17). When the electron withdrawing group is phenyl or (c5-e) heteroaryl, the ring may be substituted by one or more meta-oriented substituents (for example, Alkylcarbonyl, alkylaminosulfinyl, dialkylaminosulfinyl, alkylsulfinyl, carboxyl, nitro, aminosulfinyl, sulfo, phosphorous carboxyl, alkoxyphosphine Dialkoxy Alkyl, alkylsulfonyl, cyano, alkylsulfinyl, sulfamoyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkoxysulfinyl, disubstituted amine, tris Substituted amm ο ni 0, etc.), in situ and para-oriented substituents (such as hydroxyl, alkoxy, optionally substituted alkyl, aryl, aralkyl, halo, etc.) and electron withdrawing moieties (E.g. alkylaminomethylsulfanyl, dialkylaminomethylsulfanyl, alkoxycarbonyl, alkylaminosulfinylsulfanyl, dialkylaminosulfinylsulfanyl, alkylsulfanyl, carboxyl, nitro, Aminosulfinyl, sulfo, carbamoyl, phosphorous carboxyl, alkoxyphosphino, dialkoxyphosphino, alkylsulfo, cyano, alkylsulfinamido, aminosulfo Group, alkylaminesulfonyl, dialkylaminosulfonyl, alkoxysulfanyl, aryl, heteroaryl, etc.) 4Leaving group A has the definition commonly used in synthetic chemistry, and can be used in Atoms or groups substituted under alkylation conditions, including radicals and alkanyl or alkenesulfonyloxy groups, such as methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy and tosylsulfonyloxy, Alkanes Amine group, alkylcarbonylamino group, sulfamoylamino group, aminocarbonylamino group, etc. 'Isomerization is where the compounds have the same molecular formula, but the nature or sequence of atomic bonding or the arrangement of their atoms in space are different. Phenomenon, the isomers with different arrangement of atoms in space are called "stereoisomers". The stereoisomers that are not mirror images of each other are called A non-mirror isomers ", but not mirrors that can be overlapped (please read the precautions on the back before filling this page). Meal meal) 470750 A7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ______B7__ V. Description of the invention (18) The stereoscopic foreign body of the image is called " mirror isomer " or sometimes " optical alien Structure ". A carbon atom bonded to four different substituents is called a palmar center. "A compound having a palmar center with two mirror-isomeric forms of opposite palmarity is called an A racemic mixture. It has more than one The compound of the palm center has 2 " -1 mirror image isomer pairs, where η is the number of palm center. The compounds of formula I, II, III can be in the form of individual stereoisomers or stereoisomer mixtures. For example, compounds of formulae I, II, and III contain a palm center on the carbon to which the substituent R 8 is attached. In addition, compounds of formulae I, II, and III of the Z series-C (Re) (R7) are attached with R The carbon of the 7 substituent has a palm center. Therefore, for example, a compound of formulas I, II, and III in which η is 0 and Z is —C (Re) (R7) has two palm centers, and may have four types. Individual stereoisomers or any one of their mixtures. Individual stereoisomers can be defined by their absolute structure in the center of the palm. Absolute structure means that the substitution attached to the center of the palm is based on the arrangement in space. Attached to the discussion of 1 The substituent of the center of the palm is according to Cahn, The sequence of Ingold and Pre 1 og is regularly arranged. If the three highest order substitutions are arranged in space in a clockwise order based on the highest to low polarity in the space (the fourth lowest order basis is oriented away from the observer), then Is the absolute descriptor R, and the absolute descriptor S is set counterclockwise. When describing the individual stereoisomers that contain a pair of palm centers, list the absolute descriptor R or S in parentheses, followed by the hyphen and Chemical name of the compound. In the present invention, the paper size is described in accordance with the Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm) —ί II * n II Order — — II ^, (Please read the precautions on the back before (Fill in this page) 470750 A7 _B7___ V. Description of the invention (19) When the individual stereoisomers or mixtures of stereoisomers containing two or more palm atoms are listed, the absolute descriptors are listed immediately after the appropriate position ^ Or 5. The fluorenyl group derived from a natural amino acid means an amino acid group (such as L-phenylalanine) preceded by the descriptor L. An unnatural mirror image isomer of an amino fluorenyl group Is preceded by descriptor D. Because The stereoselectivity of the enzyme is therefore preferred for the amino acid side chain (S) or L-type, but in some cases D-type can be used. When absolute descriptors are not listed in the center of the palm, the description is simultaneously * Including two structures and their mixtures, racemates, etc. Therefore, for example, 'compounds with the formula (please read the precautions on the back before filling this page)
經濟部中央標準局負工消費合作社印裝 名稱爲: 當R 1係4 _嗎啉羰基,R 8係2 —苯乙基且位於參考平面 與R 7取代基同一側處,R 7係笮基且R 19係苯磺醯基時, 稱爲N2— (4 —嗎啉激基)— N1—〔 3 —苯基—1 S — (2 -苯磺醯乙基)丙基〕—L 一苯基丙胺醯胺; 當R1係4-嗎啉羰基,R8係2 —苯乙基且位於參考平面 之任一面或兩面上,R 7係笮基且R1 9係苯磺醯基時,稱 爲N2 - 4 -嗎啉羰基—N1—〔3 -苯基一 1_ (2 —苯 磺醯乙基)丙基〕-L-苯基丙胺醯胺; 當R1係4 _嗎啉羰基,R8係2 -苯乙基且位於參考平面 與R 7取代基同側處,R 7係2 —棻甲基且R 19係苯磺醯基 時’則稱爲N2—4_嗎啉羰基—N -〔 3 —苯基—1 S ϋ張尺度適用中國國家標準(cns ) A4规格(21 〇 X 297公釐) 470750 經濟部中央標準局員工消費合作社印製 A7 __B7___ 五、發明説明(20) -(2 —苯磺醯乙基)丙基〕—石一(2 —菓基)一L 一 丙胺醯胺;且當R 1係4 —嗎啉羰基’ R 8係2 —苯乙基且 位於參考平面與R7取代基同側處’ R7係苄基且R19係乙 氧鑛基時,則係4 S — ( N — 4 —嗎啉鐵基一 L —苯基丙 胺醯胺基)一6—苯乙酸乙酯。 較佳具體實例中,本發明組成物係純非鏡像具構物° 或者,該組成物含有非鏡像異構物之混合物。較佳之具體 實例具有高於約7 0%之單一非鏡像異構物’而至少約 9 0 %特佳》 *保護基〃具有在合成有機化學中所習用之意義,即 ,阻隔化合物反應性部位之基團。參照’ G r e e η等人 之有機合成中之保護基,第2版,John Wiley & Sons, 1991,在此供作參考。羥基保護基之實例包括芳氧羰基’ 諸如苄氧羰基等,芳醯基,諸如笮醯基等,及氧羥基,諸 如乙氧羥基及9 -芴基甲氧羰基等。胍基保護基之實例包 括磺醯基,諸如2,3,5 —三甲基—4 一甲氧苯基磺醯 基等。適於形成酯部分之羧基保護基之實例係總數4至8 個碳原子之烷氧羰基,特別係第三丁氧羰基(B0C)或 苄氧羰基(CBZ,Z),尤其是環中總數4至8個原子 之環烷胺羥基或氧維環烷胺羥基,尤其是4 —嗎啉羰基( M u ) 等。 在化合物基團中之^經保護'意指其中反應性部位被 保護基阻斷之化合物或基團之衍生物。 、選擇性〃或'^選擇性地"意指後續所述之狀況或條 _本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) ~~~^ -23 - -------------<装----^----1T------# (請先閱讀背面之注意事項再填寫本頁) 470750 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明(21) 件可能發生或不發生,而該敘述包括發生該狀況或條件之 情況及未發生之情況。例如,"選擇性地另外經一個或多 個官能基取代"意指該取代基可存在或不存在,而所述之 化合物仍落於本發明範疇內,而本發明包括其中存有一個 或多個官能基之化合物及其中無官能基之化合物。 本發明中"半胱胺酸蛋白酶所併發之疾病"意指由半 胱胺酸蛋白酶所併發之病理狀況。某些疾病中,該狀況伴 有半胱胺酸蛋白酶之濃度增高;例如,關節炎、肌肉失癢 症、發炎、腫瘤發作、及絲球體性腎炎皆伴有半胱胺酸蛋 白酶之濃度增加。其他障礙或疾病中,該狀況係伴隨著未 存於正常組織中之胞外半胱胺酸蛋白酶活性之出現。其他 具體實例中,半胱胺酸蛋白酶伴生病原(諸如病毒)在宿 主器官內感染或複製之能力。 半胱胺酸蛋白酶所併發之疾病的特例包括(但不限於 )關節炎、肌肉失癢症、發炎、腫瘤發作、絲球體性腎炎 、瘧疾、阿耳茲海默氏症、癌症轉移、外傷、發炎、齒齦 炎、萊什曼病、絲蟲病、及其他由細菌及寄生蟲所產生之 感染。尤其包括間白素1 Θ轉化酶(I CE)所併發之疾 病。 $藥學上可接受〃意指可用於製備大體上安全、無毒 且既非生物上亦非其他方面所不期望之藥學組成物,包括 獸醫及人類藥學用途可接受者。 a藥學上可接受之鹽〃意指如前定義藥學上可接受且 具有所期望之藥學活性之鹽。此等鹽包括使用無機酸所形 本紙張尺度適用中國國家標準(CNS ) A4规格(210X297公釐) --------------¾衣-------II------# (請先閲讀背面之注意事項再填寫本頁) -24 - 470750 經濟部中央標準局員工消費合作社印製 A7 B7__五、發明説明(22) 成之酸加成鹽,諸如鹽酸、氫溴酸、硫酸、硝酸、磷酸等 :或使用有機酸者,諸如乙酸、丙酸、.己酸、庚酸、環戊 烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、蘋果 酸、馬來酸、富馬酸、酒石酸、檸檬酸、苄酸、鄰—( 4 -羥笮醯)笮酸、肉桂酸、馬得酸(made lie acid)、 甲磺酸、乙磺酸、1 ,2 —乙二磺酸、2_羥基乙磺酸、 苯磺酸、對氯苯磺酸、2 -某磺酸、對甲苯磺酸 '樟腦磺 酸、4_甲基雙環〔2,2,2〕辛一 2 —烯_1 一羧酸 、葡庚糖酸,4,4< —伸甲基雙(3 —羥基一 2 —烯一 1_羧酸)、3 —苯基丙酸、三甲基乙酸、第三丁基乙酸 、月桂基硫酸、葡糖酸、榖胺酸、羥基棻酸、水楊酸、硬 脂酸、粘康酸等。 藥學上可接受之鹽亦包括當存有可與無機或有機鹼反 應之酸性質子時,可形成之鹼加成鹽。可接受之無機鹼包 括氫氧化鈉、碳酸鈉、氫氧化鉀、氫氧化鋁及氫氧化銘。 可接受之有機鹼包括乙醇胺、二乙醇胺、三乙醇胺、托美 胺(tromethamine) 、N —甲基糖胺等。 "治療有效量Λ意指在給予動物以治療疾病之量’包 括: (1 )預防可能罹患病病,但尙未出現或顯示疾病症 狀之動物身上發生疾病。 (2)抑制疾病,即,遏止其發展,或 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)Α4规格(210x297公釐) 470750 A7 B7 五、發明説明(23) (3 )改善該疾病,即,造成疾病之退化 發明詳述 本發明有關一種新穎之半胱胺酸蛋白酶抑制劑。在未 限於理論下,相信該抑制劑根據下列示意圖鍵結於半胱胺 酸蛋白酶上。The printed name of the Consumer Work Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs is: when R 1 is a 4-morpholine carbonyl group, R 8 is a 2-phenethyl group and is located on the same side of the reference plane as the R 7 substituent, and R 7 is a fluorenyl group When R 19 is benzenesulfonyl, it is called N2— (4-morpholinyl) —N1— [3-phenyl-1S— (2-phenylsulfonylethyl) propyl] —L-benzene R1 is 4-morpholine carbonyl, R8 is 2-phenethyl and is located on either or both sides of the reference plane, R 7 is fluorenyl and R1 9 is phenylsulfonyl -4 -morpholine carbonyl—N1— [3-phenyl-1— (2-phenylsulfonylethyl) propyl] -L-phenylpropylamine amide; when R1 is 4-morpholine carbonyl and R8 is 2- Phenethyl and the reference plane are on the same side as the R 7 substituent. When R 7 is a 2-fluorenylmethyl group and R 19 is a phenylsulfonyl group, it is called N 2-4_morpholinecarbonyl group -N-[3 — Phenyl — 1 S is in accordance with Chinese National Standard (cns) A4 specifications (21 OX 297 mm) 470750 Printed by A7 __B7___, Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (20)-(2 —Benzene Sulfoethyl) propyl] —Shiyi (2 — (Fructyl) -L-propylamine amide; and when R 1 is 4-morpholinecarbonyl 'R 8 is 2-phenethyl and is located on the same side of the reference plane as the R7 substituent' R7 is benzyl and R19 is ethoxy When it is mineral-based, it is 4 S — (N — 4 —morpholine iron group — L —phenylpropylamine amine group) — 6 —phenylacetate. In a preferred embodiment, the composition of the present invention is a pure non-mirror structure. Alternatively, the composition contains a mixture of non-mirror isomers. Preferred specific examples have a single non-mirromeric isomer that is higher than about 70%, and at least about 90% is particularly preferred. "* Protective group 〃 has the meaning commonly used in synthetic organic chemistry, that is, to block the reactive site of a compound Of groups. Reference is made to the protecting group in organic synthesis of ‘Gre e η et al., 2nd edition, John Wiley & Sons, 1991, which is hereby incorporated by reference. Examples of the hydroxy protecting group include aryloxycarbonyl 'such as benzyloxycarbonyl and the like, arylfluorenyl such as fluorenyl and the like, and oxyhydroxy such as ethoxyhydroxy and 9-fluorenylmethoxycarbonyl and the like. Examples of the guanidino protecting group include sulfonyl groups such as 2,3,5-trimethyl-4 monomethoxyphenylsulfonyl and the like. Examples of carboxy protecting groups suitable for forming the ester moiety are alkoxycarbonyl groups having a total of 4 to 8 carbon atoms, especially a third butoxycarbonyl group (B0C) or a benzyloxycarbonyl group (CBZ, Z), especially the total number of 4 in the ring Cycloalkylamine or oxyretidinylamine to 8 atoms, especially 4-morpholinecarbonyl (Mu) and the like. ^ Protected 'in a compound group means a compound or a derivative of a group in which a reactive site is blocked by a protecting group. , Selective 〃 or '^ optionally " means the conditions or conditions described later _ This paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) ~~~ ^ -23----- --------- < equipment ---- ^ ---- 1T ------ # (Please read the precautions on the back before filling out this page) 470750 Staff Consumption of Central Bureau of Standards, Ministry of Economic Affairs Cooperatives print A7 B7 V. Invention description (21) The item may or may not occur, and the narrative includes the situation or condition that occurred or the situation that did not occur. For example, " optionally further substituted by one or more functional groups " means that the substituent may be present or absent, and the compound described still falls within the scope of the present invention, and the present invention includes Or more functional compounds and compounds without functional groups. In the present invention, "disease complicated by cysteine protease" means a pathological condition complicated by cysteine protease. In some diseases, this condition is accompanied by an increase in the concentration of cysteine protease; for example, arthritis, muscle itching, inflammation, tumor attacks, and filamentous nephritis are all accompanied by increased cysteine protease concentrations. In other disorders or diseases, the condition is accompanied by the appearance of extracellular cysteine protease activity that is not present in normal tissues. In other specific examples, the ability of cysteine protease-associated pathogens (such as viruses) to infect or replicate in host organs. Specific examples of diseases complicated by cysteine protease include (but are not limited to) arthritis, itching muscles, inflammation, tumor attacks, filamentous nephritis, malaria, Alzheimer's disease, cancer metastasis, trauma, Inflammation, gingivitis, Leishmaniasis, filariasis, and other infections caused by bacteria and parasites. In particular, diseases that are complicated by melanin 1 Θ converting enzyme (I CE) are included. $ Pharmaceutically acceptable means that it can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, and neither biologically nor otherwise undesirable, including those acceptable for veterinary and human pharmaceutical use. a A pharmaceutically acceptable salt means a salt that is pharmaceutically acceptable and has the desired pharmacological activity as defined above. These salts include the size of the paper formed by using inorganic acids. Applicable to China National Standard (CNS) A4 specifications (210X297 mm) -------------- ¾ clothing ------- II ------ # (Please read the precautions on the back before filling this page) -24-470750 A7 B7 printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs _V. Description of the invention (22) Sulfuric acid addition salt , Such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. or those using organic acids, such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvate, lactic acid, malonic acid Acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzyl acid, o- (4-hydroxyammonium) arsinic acid, cinnamic acid, made lie acid, methanesulfonic acid Acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-sulfonic acid, p-toluenesulfonic acid, 'camphorsulfonic acid, 4_formaldehyde Bicyclo [2,2,2] octyl-2-ene-1 monocarboxylic acid, glucoheptanoic acid, 4,4 < -methylenebis (3-hydroxy-2-2-ene-1carboxylic acid), 3 —Phenylpropionic acid, trimethylacetic acid, tert-butyl Glycolic acid, lauryl sulfuric acid, gluconic acid, ammonium acid, hydroxyammonium acid, salicylic acid, stearic acid, muconic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which can be formed when an acidic proton is present which can react with an inorganic or organic base. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and sodium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, and the like. " Therapeutically effective amount Λ means an amount administered to an animal to treat a disease ', including: (1) preventing the occurrence of a disease in an animal that may be sick, but does not show or show symptoms of the disease. (2) Inhibit the disease, that is, stop its development, or (please read the precautions on the back before filling this page) This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 470750 A7 B7 V. Description of the invention (23) (3) Ameliorating the disease, that is, causing deterioration of the disease. Detailed description of the invention The present invention relates to a novel cysteine protease inhibitor. Without being bound by theory, it is believed that the inhibitor is bound to a cysteine protease according to the following schematic.
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酶抑制劑 錯合物 (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 相信.該 之相互 作用而 此 有選擇 不抑制 體實例 有活性 程度較 此 之間之 基間產 下文所 酶可藉抑制 作用,且藉 可逆地抑制 種可逆抑制 性。通常, 絲胺酸、天 中,本發明 ,諸如絲胺 低。 外,式I之 電子極化, 生氫鍵,而 通述者。已 劑之R、Y及Z部分與酶之鍵結部分間 硕與活性部位胺基酸側鍵間之氫鍵相互 〇 之機構使酶抑制劑對半胱胺酸蛋白酶具 本發明抑制劑抑制半胱胺酸蛋白酶,而 冬胺醯基及鋅蛋白酶"然而,在某些具 蛋白酶抑制劑可對其他種類之蛋白酶具 酸、天冬胺醯基或其他金屬蛋白酶,但 硕基之吸電子性在砚基與彼所附著之碳 使其本身與絲胺酸蛋白酶之活性部位殘 使抑制劑與半晄胺酸之間緊密鍵結,如 知硫原子及氧原子之間大概有額外之吸 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -26 - 470750 經濟部中央標準局員工消費合作杜印製 A7 B7五、發明説明(24) 電子性或電子極化,使氧原子參與蛋白酶活性部位殘基之 氫鍵,而進一步地抑制該酶。 本發明大體上提供一種新穎之以胜肽爲底質及擬肽類 半胱胺酸蛋白酶抑制劑,其充作可逆之半胱胺酸蛋白酶抑 制劑。本發明中a半胱胺酸蛋白酶抑制劑〃意指抑制蛋白 酶抑制劑之抑制劑。較佳具體實例中,半胱胺酸蛋白酶抑 制劑對半胱胺酸蛋白酶具有專一性;即,不抑制其他種類 之蛋白酶,諸如絲胺酸、天冬胺醯基、或其他金屬蛋白酶 。然而,在替用之具體實例中,本發明半胱胺酸蛋白酶抑 制劑亦可抑制其他種類之蛋白酶。 本發明"可逆之〃意指該抑制劑係非共價地鍵結於該 酶上,而與不可逆之抑制明顯不同。參照Wa 1 sh,酶 催性反應機構,Freeman & Co.,N. Y.,1 979。本發明中 "可逆之'係熟習此技藝者所已知之辭。此外,可逆之半 胱胺酸蛋白酶抑制劑係競爭性抑制劑,即,其可逆地鍵結 於酶上時,與受質競爭,抑制劑與受質之鍵結彼此排斥。 此外,抑制之計量係1 : 1 ;即,單一抑制劑即足以抑制 單一酶分子。 本發明之半胱胺酸蛋白酶抑制劑係設計成可逆地鍵結 於半胱胺酸蛋白酶上。此種鍵結係使用以胜肽爲底或擬肽 結構作爲定靶基而達成,其係模擬天然受質及/或抑制劑 。本發明之A擬肽"意指胺基酸胜肽狀結構,但其中一個 或多個胜肽鍵結(即,—C (0) NR —)經等排形式取 代,即—CH2NR —,— C (0) CH2- 或 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) ---------.襄------1T------# (請先閲讀背面之注意事項再填寫本頁) -27 - 經濟部中央標準局員工消費合作社印製 470750 A7 ___B7 _ 五、發明説明(25) 一 NRC (◦) -且/或其中存有非天然胺基酸取代基。 本發明之a定靶基〃意指半胱胺酸蛋白酶抑制劑上使 該抑制劑鍵結於半胱胺酸蛋白酶上之胜肽或擬肽殘基。較 佳具體實例中,半胱胺酸蛋白酶抑制劑之定靶基包含至少 兩個經由胜肽鍵結或等排物鍵結之胺基酸側鏈或側鏈同質 物。定靶基可包含高達約1 5個胺基酸或同質物,但抑制 劑通常係約1至7個胺基酸或同質物,因爲治療應用中通 常期望較小之抑制劑。因此,在式I 、 II及III中, η較佳係由〇至1 3,而由0至5較佳,由0至3特佳。 如式I 、I I及I I I所示,定靶基可由具下式之天 然或非天然胜肽殘基表示: R7 R、入/ 丫 R8 其中R 8及R 7成份表示天然或非天然胺基酸同質物或取代 基,如下文所詳述者。該抑制劑之定靶基亦含有其他官能 基,如R1及本文所述者。 雖不受限於任何特別之理論,但相信定靶基之胺基酸 取代基與蛋白酶之表面鍵部位相互作用,以促進鍵結。亦 相信接近。及電子基(例如上式之R8)之胺基酸取代基 會佔據受質鍵結部位之S 1位置,因此稱爲抑制劑之P i殘 基。相同地,次位相鄰之胺基酸取代基(例如,具前式之 R 7 )則佔據受質鍵結部位之S 2位置,且稱爲抑制劑之 P2殘留基。若存有額外之胺基酸取代基,則其占據受質 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) •裝 訂 冰 (請先閲讀背面之注意事項再填寫本頁) 470750 經濟部中央標準局員工消費合作社印製 A7 __B7_ 五、發明説明(26) 鍵結部位之S 3、S 4等位置,且稱爲抑制劑之P 3、P 4等 殘基。其他之定靶基可附於吸電子基,若存有其胺基酸取 代基,則佔有受質鍵結部位之S i > 、S 2 >等位置,且個 別稱爲抑制劑之P 3 β、P 4 >等殘基。 通常,有擇性酶之定靶基係由在半胱胺酸蛋白酶中支 配受質選擇性之規則所決定(例如,參照Barret等人在 細胞及組織生理學之研究專題論文中之"蛋白酶抑制劑" ,第1 2冊,第4章:半胱胺酸蛋白酶之抑制劑,Daniel Rich, Elsevier, New York ;及前述之 Thornberry 等 人所著者,在此供作參考)。例如,間白素- 1轉化酶( I CE)在Pi位置上接受壓各胺酸取代基(即2 —羧乙 基),而P2位置上則爲丙胺酸(甲基)、纈胺酸(異丙 基)或組織胺酸(4 -咪唑甲基)取代基。木瓜蛋白酶則 於Pi位置上接受精胺酸、離胺酸、N_笮氧羰基離胺酸 (即,4 —苄氧羰基胺丁基)、高苯基丙胺酸(即2 —苯 乙基)、胍基苯基丙胺酸(即,4 -胍基苄基)或正白胺 酸(即丁基)取代基,且P 2位置爲苯基丙胺酸、酪胺酸 、点一(2_某基)丙胺酸(即2 —某基)、白胺酸、正 白胺酸、異白胺酸或丙胺酸取代基。組織蛋白酶B之P i 位置接受精胺酸、離胺酸、N -苄氧羰基離胺酸、胍基苯 基丙胺酸、高苯基丙胺酸或正白胺酸取代基,而P 2位置 則係苯基丙胺酸、酪胺酸、3,5 -二碘基酪胺酸(即, 3,5_二碘基_4 一羥笮基)、/3— (2_某基)丙胺 酸、粗胺酸、胍苯基丙胺酸或瓜胺酸(即’ 3 -脲丙基) 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) ^ ~~ -29 - -------------i----^----1T------^ (請先閲讀背面之注意事項再填寫本頁} 470750 經濟部中央標準局員工消費合作社印製 A7 _____B7五、發明説明(27) 取代基。組織蛋白酶L及卡汪酶(c r u z a i η)於 Ρ i位置上接受精胺酸、離胺酸、高苯基丙胺酸、胍苯基 丙胺酸、瓜胺酸或正白胺酸取代基,而P 2位置上則係苯 基丙胺酸、酪胺酸或(2 —某基)丙胺酸取代基。組 統蛋白酶SM Pi位置上接受精胺酸、離胺酸、高苯基丙 胺酸、胍苯基丙胺酸、瓜胺酸或正白胺酸取代基,而p2 位置上則是苯基丙胺酸、酪胺酸、(2 -棻基)丙胺 酸、纈胺酸、白胺酸、正白胺酸、異白胺酸或丙胺酸取代 基。DPP — 1於Pi位置上接受苯基丙胺酸或酪胺酸取 代基,而P 2位置則無取代基或係丙胺酸。卡盤酶( calpain)於Ρι位置上接受苯基丙胺酸、酪胺酸 、甲硫胺酸、Θ —甲磺醯基甲基丙胺酸(即,2 —甲磺醯 乙基)或纈胺酸取代基,而P 2位置上則係纈胺酸、白胺 酸、正白胺酸或異百胺酸取代基。 因此,R 7及R 8各係氫、烷基(選擇性地經選自羥基 、胺基、烷胺基、二烷胺基、脲基、锍基、烷硫基、羧基 、胺甲醯基、烷基胺甲醯基、二烷基胺甲醯基、烷磺醯基 或弧基中之量團所取代,或其經保護之衍生物)、環烷基 、環烷基烷基、雜芳基、雜芳基烷基、選自芳基及芳基烷 基之基團(該基團之芳基環選擇性地經一個至三個選自羥 基、胺基、胍基、鹵基、選擇性經鹵基取代之烷基、烷氧 基及芳基中之基團所取代,或其經保護之衍生物)或與相 鄰之R3或R5—起形成選自(C3 — 4)伸甲基及1,2 — 伸苯基二伸甲基(此基團選擇性地經羥基取代,或其經保 ---------‘裝-------訂------球 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家襟準(CNS ) A4規格(21〇Χ297公釐) -〇0 - 470750 A7 B7 五、發明説明(28) 護之衍生物)中之二價基團。 因此,較佳之R 7及R 8基團係天然胺基酸側鏈及同質 衍生物。此者包括(但不限於)兩胺酸(甲基)、精胺酸 (3 —胍丙基)、天冬醯胺(胺甲醯甲基)、瓜胺酸(3 一脲丙基)、天冬醯胺(羧甲基)、半胱胺酸(酼甲基) 、殼胺酸(2 —羧乙基)、殼胺醯胺(2 -胺甲醯乙基) 、甘胺酸(氫)、組織胺酸(4一咪唑甲基)、高苯基丙 胺酸(2 —苯乙基)、高絲胺酸(2 -羥乙基)、異百胺 酸(1 一甲基丙基)、百胺酸(異丁基)、離胺酸(4 一 胺丁基)、甲硫胺酸(2 -甲硫乙基)、y3 — (1-菓基 )丙胺酸(1—棻甲基)、石一(2 —棻基)丙胺酸(2 —棻甲基)、正百胺酸(丁基)、正纈胺酸(丙基)、鳥 胺酸(3 -胺丙基)、苯基丙胺酸(笮基)、脯胺酸(本 發明所述者)、肌胺酸(甲胺甲基)、絲胺酸(羥甲基) 、蘇胺酸(1_羥乙基)、色胺酸(3 — D引跺甲基)、酪 胺酸(4 一羥苄基)、及纈胺酸(異丙基)。 經濟部中央標準局員工消費合作社印裂 (請先閱讀背面之注意事項再填寫本頁) 雖發明簡述中列有本發明最廣義之定義,但特定本發 明化合物較佳。例如,一般較佳式I、I I及I I I化合 物係其中η係0至5 ; A — B表示選自一C (0) NR3 一之鍵結’中R3係氫或如下文所定義;Υ係—N (R5) -’其中R5係氫或如下文所定義;ζ係-(CH2) 2 -或一 C ( R 6 ) ( R 7 ) — ; Z1 係-CH ( R 8 ) - ; R 1 係氫’總數3至1 0個碳原子之烷氧羰基烷醯基、( C卜9)烷氧羰基、(C 烷醯基(選擇性地經選自 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -31 - 470750 A7 B7 經濟部中央標準局員工消費合作社印簞 五、發明説明(29) 羥基、(c^q)烷氧碳基及雜(c4_s)環烷基(c2 —10 )烷醯胺基中之基團所取代)、(c4_9)環烷碳基、雜 (C4_8)環烷碳基(選擇性地經選自羥基、(Ci-s)烷 基、(C 1_5)烷基、(C 1_5)烷醯基、(c卜5)烷氧 羰基、(ce_10)芳基(Cn)烷氧羰基及雜(c4_8) 環烷羰基中之基團所取代)、(Ce^y)芳基(Ci-5) 烷氧羰基、胺甲醢基、(Ci-5)烷基胺甲醯基、二( Ci-5)烷基胺甲醯基、(c6_10)芳基胺甲醯基、( Ce —10)芳基(Ci_5)烷基胺甲醯基、(ce-10)芳基 (Ci-5)烷醯基、(Cm)芳醯基、((^_5)烷磺醯 基、二(Ci_5)烷胺磺醯基、(ce_10)芳磺醯基或雜 (C 5_8)芳磺醯基;且R 7及R 8個別係(C 1_5)烷基( 選擇性地經選自羥基、胺基、烷胺基、二烷胺基、脲基、 毓基、烷硫基、羧基、胺甲醯基、烷基胺甲醯基、二烷基 胺甲醯基、烷磺醯基及胍基中之基團所取代,或其經保護 之衍生物)、(c3_7)環烷基、(c3_7)環烷基( C卜5 )烷基、吡啶基、卩塞嗯基、呋喃基、咪唑基、吲跺 基、吡啶基(c 1 -6 )烷基、卩塞嗯基(C 1 _6 )烷基、呋喃 基(Ci_e)烷基、咪唑基(Ci-6)烷基、蚓跺基( C Ρβ)烷基、選自苯基、棻基、苯基(c H)烷基、棻 基(C n)烷基(該基團選擇性地於芳基環上經一個至 三個選自羥基、胺基、氯一溴、碘、氟、甲基、三氟甲基 、甲氧基及苯基中之基團所取代’或其經保護之衍生物) 或與相鄰之R 3或R 4一起形成選自(C 3-4)伸甲基及1 {請先閱讀背面之注^|^項再填寫本頁) -裝. 、π I冰_ 本紙張尺度適用中國國家標準(匚飑)八4規格(2丨0父297公釐)_ —UU _ 470750 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明(30) ’ 2 -伸苯基二伸甲基(該基團選擇性地經羥基或其經保 護之衍生物或氧基所取代)。 更佳之式I 、I I及I I I化合物係其中η係〇至2 ;Α — Β表示選自一 C (0) NR3—之鍵結,其中R3係 氫或如下文定義;Υ係—N (R5)—,其中R5係氫或如 下文定義;Ζ 係—(CH2)2 —或一 C (R6) ( R 7 )— (先決條件係當η爲〇時,Z非-(C Η 2 ) 2- ) ; Ζ 1 係一 CH (R” - ; R1係氫、(c4_8)烷氧碳基、( C 2 —6)烷醯基(選擇性地經選自羧基、(C >5)烷氧激 基及雜(C 4_8)環烷基(C 4_6)烷醯胺基中之基團所取 代)、—C (0) NR21R22,其中 R21 及 R22 —起形成 氮雜(C2_e)伸甲基、氧雜(C2_e)伸甲基或(C3_7 )伸甲基、(C 4_8 )環烷羰基、苄氧羰基、乙醢基、笮 醯基或二甲胺磺醯基;且R 8及R 7個別係(C 5_6 )環烷 基、(C 5 _ β )環烷基甲基、3 —吡啶基、2 — H塞嗯基、 2 -呋喃基、4 一咪唑基、3 - D引跺基、3 —吡啶甲基、 2 — P塞嗯甲基、2 —呋喃甲基、4 一咪唑甲基、3 引晚 甲基、(Ci—5)烷基(選擇性地經選自锍基、羧基、胺 基、甲硫基、甲磺醯基、胺甲醯基、二甲基胺甲醯基、胍 基及羥基或其經保護衍生物中之基團所取代)、選自苯基 、1-某基、1-某基、笮基、1-某甲基、2 —某甲基 及2 -苯乙基中之基團(該基團選擇性地於芳族環上經一 個選自羥基、胺基、氯、溴及氟中之基團所取代,或其經 保護衍生物)或與相鄰之R 3或R 5—起形成選自(C 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) (請先閲讀背面之注意事項再填寫本頁) -33 - 470750 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(31) )伸甲基及1 ,2 —伸苯基二伸甲基中之基團(該基團選 擇性地經羥基或其經保護之衍生物所取代)。 特佳式I 、I I及I I I化合物係其中η係〇至1 ; A — Β表示選自-(0) NR3-之鍵結;γ係—N (R5 )-,其中R5係氫或如下文定義;ζ係一C (R6) (R7) — ; Ζ1 係—CH (R8) — ; Ri 係氫,第三丁氧 羥基、笮氧羥基、乙醯基、3 —羧丙醯基、3_甲氧羰基 丙醯基、生物素胺基乙醯基、苯乙醯基、笮醯基、二甲胺 磺醯基、笮磺醯基、1_哌_羥基、4 一甲基哌嗪一1 — 基羥基或4 —嗎啉羥基;R 7係3 -吡啶甲基、2 — H塞嗯 甲基、2 —呋喃甲基、4 —咪唑甲基、3-邛跺甲基、( Ci _5)烷基(選擇性地經選自锍基、羧基、胺基、甲硫 基、甲磺醯基、胺甲醯基、二甲基胺甲醯基、胍基及羥基 、或其經保護之衍生物中之基團所取代)、選自笮基、卜 菓甲基、2 _菓甲基及2 —苯乙基中之基團(該基團之芳 基環選擇性地經一個選自羥基、胺基、氯、溴及氟、或其 經保護形式中之基團所取代)或與相鄰R 3或R 5一起形成 選自(C3_4)伸甲基及1 ,2 —伸苯基二伸甲基中之二 价基(該基團選擇性地經羥基或其經保護之衍生物或氧基 所取代):且8係丁基、2—苯乙基、2—甲磺醯乙基、 2 —第三丁氧羰乙基、2 —第三丁氧羰甲基、4 一第三丁 氧羰胺丁基、4 -苄醯胺丁基或苄氧甲基。 特佳式I 、I I及I I I化合物係其中η係0 ; A — Β表示選自-C (Ο) ΝΗ-之鍵結;γ〇 — ΝΗ- ; Ζ 本紙張尺度適用中國國家標準(CNS ) Α4规格(210X297公釐) — -34 - II ‘^*衣 I n 訂 I I n I 球 (請先閲讀背面之注意事項再填寫本頁) 470750 經濟部中央標準局員工消費合作社印製 A7 B7_五、發明説明(32) 係—CH (R7) — ; Z1 係—CH (R8) — ; R1 係氫、 第三丁氧羰基、苄氧羰基、生物素胺基己醯基、苄醯基、 哌嗪—1 —基羰基、4~甲基哌嗪—1 一基羥基或4 —碼 啉經基;R 7係(C i — 5 )烷基、選擇性經取代之苄基、1 一棻甲基、2 —棻甲基、3_吡啶甲基或2 —甲磺硫乙基 :且R8係丁基、2 —苯乙基或2-甲磺醯乙基。 最佳式I 、I I及I I I化合物係其中η係〇 ; A — B表示選自_C (Ο) NH —之鍵結;Y係一 NH — ; Z 係一 C H ( R 7 ) — ; Z 1 係-c H ( R 8) - ; R 1 係 1 — 哌嗪經基、4 -甲基- 1 —哌嗪羥基或4 —嗎啉羥基; R 7係選擇性經取代之书基、1 —菓甲基或2 -棻甲基; 且R 8係苯乙基。 —般較佳式I化合物係其中R2各係(Ci_5)烷基( 選擇性經一個或2個選自胺基、氯、溴、氟、羥基及甲氧 基、或其經保護之衍生物中之基團所取代)、全鹵基( Ci-5)烷基、(C3_7)環烷基、(c3—7)環烷基( Ci-5)烷基或選自苯基 '五氟苯基、棻基及苯基( )烷基中之基團(該基團之芳基環選擇性經1個至二個選 自胺基、氯、溴、氟、羥基、甲氧及選擇性經鹵基取代之 甲基或其經保護之衍生物中之基團所取代)且R 4係氫、 (—5)烷基或(Ce^。)芳基(Ci_5)烷基。更佳之 式I化合物係其中R 2係(C 1 —5 )烷基(選擇性地經一個 或二個選自胺基、氯、溴、氟及羥基或其經保護衍生物中 之基團所取代)、全氟(Ci_5)烷基、(C5 —β)環烷基 本紙張尺度適用中國國家標準(€泌)八4規格(210父297公釐)_ n n ' I I I I 訂—— ^ (請先聞讀背面之注意事項再填寫本頁) 470750 經濟部中央標準局員工消費合作社印製 A7 B7___五、發明説明(33) 、(C5_6)環烷基甲基或選自苯基、某基及苄基中之基 團(該基團選擇性地經1個選自胺基、羥基、氯、溴或氟 、或其經保護之衍生物中之基團所取代)且R4係氫或甲 基。特佳之式I化合物係其中R2係甲基、二氣甲基、選 擇性經取代之苯基、2 -棻基或2 -苯乙基。最佳之式I 化合物係其中R 2係苯基、2 -菓基或2 -苯乙基,尤其 是苯基或2—棻基,且R 4係氫。 . 一般其中 R 9係一 C (0) OR1。、 —P(O) ( 0 R 10 ) 2 、- S(0) (NR10) R 10 > -C (0) NHC (0) R10或 —S (0) 2NHC (0) R1。之較佳式I I化合物係其 中各R1D各係(Ci _5)烷基(選擇性地經1個或2個選 自胺基、氯、溴、氟、羥基及甲氧基或其經保護衍生物中 之基團所取代)、(C3_7)環烷基、(C3_7)環烷基( Ci-5)烷基,或選自苯基或苯基(Ci-e)烷基中之基團 (該基團之苯環選擇地經一個至兩個選自胺基、氯、溴、 氟、羥基、甲氧及選擇性經鹵基取代之甲基、或其經保護 之衍生物中之基團所取代)。其中R 9係 -C(0)〇R10、-P(0) (OR10) 2 ' -S (0) (NR10) R10、 -C (0) NHC (0) R 10或 —S (0) 2NHC (0) R1Q之更佳式I I化合物係其 中R1。係乙基、(C5_6)環烷基、(C5_6)環烷基甲基 或選自苯基及笮基中之基團(該基團之苯環選擇性地經一 I紙&尺度適用中國國家標準("0NS ) A4規格(210X297公釐) ~ ' (請先閲讀背面之注意事項再填寫本頁) 470750 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明(34) 個選自胺羥基、氯、溴或氟、或其經保護衍生物中之基團 所取代)。 其中R9係C (0) R11或一 S (0) R11之一般較 佳式1 I化合物係其中R11係(Ci —5)烷基、(C3 —7) 環fee基、(C3_7)環院基(C:i_5)院基或選自苯基及苯 基(Ci-e)烷基中之基團(該基團之芳基環選擇性地經 一至二個選自胺基、氯、溴、氟、羥基、甲基、三氟甲基 及甲氧基中之基團所取代)、其中R11係C (0) R11或 —S (0) RU之更佳式I I化合物係其中係乙基、 環(C5_e)烷基、環(C5_e)烷基甲基或自苯基及笮基 中之基團(該基團之苯環選擇性地經一個選自胺羥基、氯 、溴或氟中之基團,或其經保護之衍生物所取代)。 其中 R9 係—C (0) NR12R13 或 —S (COsNRuru之一般較佳式I j化合物係其中 R12及R13各係(Ci — 5)烷基、(C3_7)環烷基、( C3_7)環烷基(烷基或選自苯基及苯基(Cp6 )烷基中之基團(該基團之苯環係選擇性地經1至2個選 自胺基、氯、氟、羥基、甲氧基及選擇性經鹵基取代之甲 基中之基團所取代)。其中R9係一 C (0) NR12Ru 或一S (0)2NRi2R13之更佳式I I化合物係其中 R12及R13各係乙基、(C5-e)環烷基、(C5_e)環烷 基甲基或選自苯基及苄基中之基團(該基團之苯環係選擇 性地經1個選自胺基羥基、氯、溴或氟中之基團、或其經 保護之衍生物所取代)。 (請先閲讀背面之注意事項再填寫本頁) -裝-Enzyme inhibitor complex (please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. The interaction between this and the selective non-inhibitor instance is more active than this. The enzymes in the interbasin production can inhibit the reversible inhibition of species by reversing. Generally, serine, tianzhong, the present invention, such as seramine, is low. In addition, the electron polarization of formula I, hydrogen generation The mechanism of the hydrogen bond between the R, Y, and Z parts of the agent and the binding part of the enzyme and the side bond of the amino acid side of the active site is made by the enzyme inhibitor to the cysteine protease. With the inhibitors of the present invention inhibiting cysteine proteases, and asparagine and zinc protease " However, in some certain protease inhibitors can be acidic, aspartyl or other metalloproteinases for other kinds of proteases, However, the electron-withdrawing property of Shuoji is that the carbon and the carbon attached to it make it itself and the active site of serine protease, leaving a tight bond between the inhibitor and hemi-amino acid, such as the sulfur and oxygen atoms. Large There are additional paper sizes applicable to Chinese National Standard (CNS) A4 specifications (210X297 mm) -26-470750 Staff consumption cooperation of the Central Standards Bureau of the Ministry of Economic Affairs, printed A7 B7 V. Description of invention (24) Electronic or electronic pole The oxygen atom participates in the hydrogen bonding of the residues in the active site of the protease, and further inhibits the enzyme. The present invention generally provides a novel peptide-based substrate and peptidyl cysteine protease inhibitor, which has As a reversible cysteine protease inhibitor. In the present invention, a cysteine protease inhibitor 〃 means an inhibitor that inhibits a protease inhibitor. In a preferred embodiment, a cysteine protease inhibitor is a cysteamine inhibitor. Acid proteases are specific; that is, they do not inhibit other kinds of proteases, such as serine, asparagine, or other metalloproteinases. However, in alternative specific examples, the cysteine protease inhibitors of the present invention It can also inhibit other kinds of proteases. The present invention " reversibly " means that the inhibitor is non-covalently bonded to the enzyme, and is significantly different from irreversible inhibition. Wa 1sh, an enzymatic reaction mechanism, Freeman & Co., NY, 1 979. "Reversible" in the present invention is a word known to those skilled in the art. In addition, a reversible cysteine protease inhibitor It is a competitive inhibitor, that is, when it reversibly binds to an enzyme, it competes with the substrate, and the inhibitor and the substrate are mutually exclusive. In addition, the amount of inhibition is 1: 1; that is, a single inhibitor is Enough to inhibit a single enzyme molecule. The cysteine protease inhibitor system of the present invention is designed to reversibly bind to a cysteine protease. This type of binding system uses a peptide as a base or a peptidomimetic structure as a target base. This is achieved by simulating natural substrates and / or inhibitors. A peptidomimetic of the present invention means an amino peptide-like structure, but one or more of the peptides are bonded (ie, -C (0 ) NR —) is replaced by an isocratic form, ie —CH2NR —, — C (0) CH2- or this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ---------. Xiang ------ 1T ------ # (Please read the notes on the back before filling this page) -27-Member of the Central Standards Bureau of the Ministry of Economic Affairs Co-op printed 470750 A7 ___B7 _ V. invention is described in (25) a NRC (◦) - and / or non-natural amino acid in which there substituents. The "targeting group" of the present invention means a peptide or peptidomimetic residue on a cysteine protease inhibitor which binds the inhibitor to cysteine protease. In a preferred embodiment, the targeting group of the cysteine protease inhibitor comprises at least two amino acid side chains or side chain homogens which are bonded via peptide bonds or isosteres. Targeting groups may contain up to about 15 amino acids or homogeneous species, but inhibitors are typically about 1 to 7 amino acids or homogeneous species, as smaller inhibitors are often desired in therapeutic applications. Therefore, in the formulae I, II and III, η is preferably from 0 to 13 and more preferably from 0 to 5 and particularly preferably from 0 to 3. As shown in formulas I, II and III, the targeting group can be represented by natural or unnatural peptide residues of the formula: R7 R, R / R R8 where R 8 and R 7 components represent natural or unnatural amino acids Homologs or substituents, as detailed below. The target group of the inhibitor also contains other functional groups, such as R1 and those described herein. Although not limited to any particular theory, it is believed that the targeted amino group substituents interact with the surface bond sites of the protease to promote bonding. Also believe in approaching. The amino group substituent of the electron group (such as R8 in the above formula) will occupy the S 1 position of the mass-bonding site, and is therefore called the P i residue of the inhibitor. Similarly, amino acid substituents adjacent to the second position (for example, R 7 of the foregoing formula) occupy the S 2 position of the mass-bonding site and are referred to as the P 2 residue of the inhibitor. If there are additional amino acid substituents, the paper size is subject to Chinese National Standard (CNS) A4 (210 X 297 mm). • Binding ice (please read the precautions on the back before filling this page) ) 470750 A7 __B7_ printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (26) S, S 4 and other positions of the bonding site, and are called residues P 3 and P 4 of the inhibitor. Other target groups can be attached to the electron withdrawing group. If there is an amino acid substituent, they occupy positions S i > and S 2 > of the bonding site of the mass, and are individually referred to as P of the inhibitor. 3 β, P 4 > and other residues. In general, the targeting of selective enzymes is determined by the rules governing the selectivity of substrates in cysteine proteases (for example, see "Protease in Barret et al.'S Monograph on Cell and Tissue Physiology Research" Inhibitors ", Volume 12, Chapter 4: Inhibitors of Cysteine Proteases, Daniel Rich, Elsevier, New York; and the aforementioned author by Thornberry et al., Hereby incorporated by reference). For example, melanin-1 converting enzyme (ICE) accepts each amino acid substituent (ie, 2-carboxyethyl) at the Pi position, while alanine (methyl), valine ( Isopropyl) or histidine (4-imidazolylmethyl) substituents. Papain accepts spermine, lysine, N-fluorenyloxycarbonyl lysine (ie, 4-benzyloxycarbonylaminobutyl), and homophenylalanine (ie, 2-phenethyl) at the Pi position. , Guanidinophenylalanine (ie, 4-guanidinobenzyl) or n-leucine (ie, butyl) substituents, and the P 2 position is phenylalanine, tyrosine, point one (2_some Group) alanine (ie, a certain group), leucine, n-leucine, isoleucine or alanine substituents. Cathepsin B accepts spermine, lysine, N-benzyloxycarbonyl lysine, guanidylphenylalanine, homophenylalanine or n-leucine substituents at the P i position, while the P 2 position Are phenylalanine, tyrosine, 3,5-diiodotyrosine (ie, 3,5_diiodo_4 monohydroxyfluorenyl), / 3- (2_some) alanine, Crude amino acid, guanyl phenylalanine or citrulline (that is, '3 -ureidopropyl) This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ^ ~~ -29---- ---------- i ---- ^ ---- 1T ------ ^ (Please read the notes on the back before filling out this page} 470750 Staff Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs Print A7 _____B7 V. Description of the invention (27) Substituents. Cathepsin L and cruzai η accept spermine, lysine, homophenylalanine, guanylphenylalanine at the position p i , Citrullic acid or n-leucine substitution, and the P 2 position is a phenylalanine, tyrosine or (2-base) alanine substituent. The systemic protease SM Pi accepts arginine , Lysine, homophenylalanine, guanidine Phenylalanine, citrulline or n-leucine substituents, and p2-position is phenylalanine, tyrosine, (2-fluorenyl) alanine, valine, leucine, n-leucine Acid, isoleucine, or alanine substituents. DPP — 1 accepts phenylalanine or tyrosine substituents at the Pi position, while P 2 has no substituents or alanine. Calpain Accepts phenylalanine, tyrosine, methionine, Θ-methanesulfonylmethylalanine (ie, 2-methanesulfonylethyl) or valine acid substituents at the P1 position, and P 2 In the position, it is a valine, leucine, n-leucine or isovaleric acid substituent. Therefore, each of R 7 and R 8 is a hydrogen or an alkyl group (optionally selected from a hydroxyl group, an amine group, and an alkane group). Amino group, dialkylamino group, urea group, fluorenyl group, alkylthio group, carboxyl group, carbamoyl group, alkylaminomethyl group, dialkylaminomethyl group, alkylsulfonyl group, or arcyl group Group, or a protected derivative thereof), cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, a group selected from aryl and arylalkyl Aryl ring selection With one to three groups selected from the group consisting of hydroxyl, amine, guanidino, halo, optionally substituted halo-substituted alkyl, alkoxy, and aryl, or protected derivatives thereof) Or together with adjacent R3 or R5 to form a group selected from (C3-4) dimethyl and 1,2 phenylphenyl dimethyl (this group is optionally substituted with a hydroxyl group, or its ------- 'Pack ------- Order ------ Ball (Please read the notes on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 specifications (21〇 × 297mm) -〇0-470750 A7 B7 V. Description of the invention (28) Protected derivatives) Divalent group. Therefore, preferred R 7 and R 8 groups are natural amino acid side chains and homogeneous derivatives. This includes (but is not limited to) diamine (methyl), arginine (3-guanidinopropyl), asparagine (carbamidine methyl), citrulline (3-monouretyl), Asparagine (carboxymethyl), cysteine (fluorenylmethyl), chitosan (2-carboxyethyl), chitosan (2-aminomethylethyl), glycine (hydrogen ), Histamine (4-imidazolylmethyl), Homophenylalanine (2-phenethyl), Homoserine (2-hydroxyethyl), Isoglutamine (1-methylpropyl), L-amino acid (isobutyl), lysine (4-monoaminobutyl), methionine (2-methylthioethyl), y3 — (1-fructyl) alanine (1-methyl) , Stone mono (2-methyl) alanine (2-methyl), n-glutamic acid (butyl), n-valine (propyl), ornithine (3-aminopropyl), phenyl Alanine (fluorenyl), proline (the one described in the present invention), sarcosine (methylamine methyl), serine (hydroxymethyl), threonine (1-hydroxyethyl), tryptamine Acid (3-D), tyrosine (4-hydroxybenzyl), and valine (isopropyl). Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page). Although the broadest definition of the invention is listed in the brief description of the invention, certain compounds of the invention are preferred. For example, compounds of formulae I, II and III are generally preferred wherein η is 0 to 5; A — B represents a hydrogen atom selected from the group consisting of —C (0) NR3 — or R3 is hydrogen or as defined below; N (R5)-'wherein R5 is hydrogen or as defined below; ζ is-(CH2) 2-or -C (R 6) (R 7) —; Z1 is -CH (R 8)-; R 1 is Hydrogen's total number of alkoxycarbonylalkanoyl groups of 3 to 10 carbon atoms, (C9) alkoxycarbonyl groups, (C alkanoyl groups (optionally selected from the paper standard applicable Chinese National Standard (CNS) A4 Specifications (210X297 mm) -31-470750 A7 B7 Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China. 5. Description of the Invention (29) Hydroxyl, (c ^ q) alkoxycarbon and hetero (c4_s) cycloalkyl (c2 —10) substituted by a group in an alkylamino group, (c4-9) cycloalkylcarbon group, hetero (C4_8) cycloalkylcarbon group (optionally selected from hydroxyl group, (Ci-s) alkyl group, (C 1_5) alkyl, (C 1_5) alkyl, (c_5) alkoxycarbonyl, (ce_10) aryl (Cn) alkoxycarbonyl and hetero (c4_8) cycloalkylcarbonyl substituted with groups), ( Ce ^ y) aryl (Ci-5) alkoxycarbonyl, carbamoyl, (Ci-5) alkylamine Fluorenyl, bis (Ci-5) alkylaminomethane, (c6_10) arylaminomethane, (Ce-10) aryl (Ci_5) alkylaminomethane, and (ce-10) aryl (Ci-5) alkylfluorenyl, (Cm) arylsulfonyl, ((^ _5) alkylsulfonyl, bis (Ci_5) alkylaminesulfonyl, (ce_10) arylsulfonyl or hetero (C 5_8) aryl Sulfofluorenyl; and R 7 and R 8 are each (C 1_5) alkyl (optionally selected from the group consisting of hydroxyl, amine, alkylamino, dialkylamino, urea, fluorenyl, alkylthio, and carboxyl , Substituted with amine formamidine, alkyl amine formamyl, dialkyl amine formamyl, alkanesulfonyl and guanidino groups, or protected derivatives thereof), (c3_7) cycloalkyl (C3_7) cycloalkyl (Cb5) alkyl, pyridyl, fluorenyl, furanyl, imidazolyl, indinoyl, pyridyl (c1-6) alkyl, fluorenyl (C 1_6) alkyl, furanyl (Ci_e) alkyl, imidazolyl (Ci-6) alkyl, vermido (Cp) alkyl, selected from phenyl, fluorenyl, and phenyl (cH) alkyl , Fluorenyl (C n) alkyl (this group is optionally on the aryl ring through one to three selected from hydroxyl, amine, chloro-bromo, iodine, fluorine Methyl, trifluoromethyl, methoxy, and phenyl groups, or their protected derivatives) or together with adjacent R 3 or R 4 to form a group selected from (C 3-4) Methyl and 1 (please read the note ^ | ^ on the back before filling this page) -pack., Π I ice _ This paper size applies to Chinese national standard (匚 飑) 8 4 specifications (2 丨 0 parent 297 mm ) —UU _ 470750 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (30) '2 -Phenyldimethyl (This group is selectively derived from a hydroxyl group or a protected derivative thereof Or oxygen). More preferred compounds of formulae I, II and III are those wherein η is 0 to 2; A-B represents a bond selected from the group consisting of -C (0) NR3-, wherein R3 is hydrogen or as defined below; Υ-N (R5) —, Where R5 is hydrogen or as defined below; Z is — (CH2) 2 — or —C (R6) (R 7) — (Prerequisite is when η is 0, Z is not-(C Η 2) 2- ); Z 1 is a CH (R "-; R1 is hydrogen, (c4_8) alkoxycarbon, (C 2-6) alkanoyl (selectively selected from carboxyl, (C > 5) alkoxy) Excimer and hetero (C 4_8) cycloalkyl (C 4_6) alkylamino group substituted), —C (0) NR21R22, where R21 and R22 together form aza (C2_e) methyl, Oxa (C2_e) methyl or (C3_7) methyl, (C4_8) cycloalkylcarbonyl, benzyloxycarbonyl, ethylfluorenyl, fluorenyl, or dimethylaminesulfonyl; and R8 and R7 individually (C 5_6) cycloalkyl, (C 5_ β) cycloalkylmethyl, 3-pyridyl, 2-H singyl, 2-furanyl, 4-imidazolyl, 3-D fluorenyl, 3-Pyridylmethyl, 2-Psynmethyl, 2-furanmethyl, 4-imidazolylmethyl, 3-methylamine, (Ci-5) alkane (Selectively via a group selected from the group consisting of fluorenyl, carboxyl, amine, methylthio, mesylsulfonyl, carbamoyl, dimethylaminocarbamyl, guanidino, and hydroxyl or a protected derivative Substituted by a group), a group selected from phenyl, 1-a certain group, 1-a certain group, fluorenyl group, 1-a certain methyl group, 2 a certain methyl group, and 2 phenethyl group (the group is selective Is substituted on the aromatic ring by a group selected from the group consisting of hydroxyl, amine, chlorine, bromine and fluorine, or a protected derivative thereof) or together with adjacent R 3 or R 5 to form a member selected from ( C This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the notes on the back before filling this page) -33-470750 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Explanation (31)) The groups in dimethyl and 1,2-phenylene dimethyl (this group is optionally substituted by a hydroxyl group or a protected derivative thereof). Particularly preferred formulae I, II And III compounds wherein η is 0 to 1; A-B represents a bond selected from-(0) NR3-; γ-N (R5)-, wherein R5 is hydrogen or as defined below; ζ is a C ( R6) (R7) —; ZO1 —CH (R8) —; Ri is hydrogen, tertiary butoxyhydroxy group, fluorenyl hydroxy group, ethenyl group, 3-carboxypropionyl group, 3-methoxycarbonylpropionyl group, biotin Amine ethyl fluorenyl, phenethyl fluorenyl, fluorenyl, dimethylamine sulfonyl, sulfonyl sulfonyl, 1-piperazine-hydroxyl, 4-methylpiperazine- 1-ylhydroxyl or 4-morpholinehydroxyl ; R 7 is 3-pyridylmethyl, 2-Hsammonyl, 2-furanmethyl, 4-imidazolylmethyl, 3-fluorenylmethyl, (Ci_5) alkyl (optionally selected from Fluorenyl, carboxyl, amine, methylthio, methanesulfonyl, carbamoyl, dimethylaminoformamyl, guanidino, and hydroxy, or a group derived from a protected derivative thereof), A group selected from the group consisting of fluorenyl, bismethyl, 2-fluoromethyl, and 2-phenethyl (the aryl ring of this group is optionally substituted by a group selected from hydroxyl, amine, chlorine, bromine, and fluorine , Or substituted by a group in a protected form) or together with adjacent R 3 or R 5 to form a divalent group selected from (C3_4) methyl and 1,2-phenylene dimethyl This group is optionally hydroxy or its protected derivative or oxy (Replaced): and 8-series butyl, 2-phenethyl, 2-methanesulfonylethyl, 2-third-butoxycarbonylethyl, 2-third-butoxycarbonylmethyl, 4-third-butoxy Carboxamide, 4-benzylamine butyl or benzyloxymethyl. Particularly preferred compounds of the formulae I, II and III are those in which η is 0; A-B represents a bond selected from -C (Ο) ΝΗ-; γ〇- ΝΗ-; Z This paper size applies Chinese National Standard (CNS) Α4 Specifications (210X297 mm) — -34-II '^ * 衣 I n Order II n I ball (Please read the precautions on the back before filling this page) 470750 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7_F Description of the invention (32) system —CH (R7) —; Z1 system —CH (R8) —; R1 system hydrogen, third butoxycarbonyl, benzyloxycarbonyl, biotinaminohexyl, benzamidine, piperazine Azine-1-ylcarbonyl, 4-methylpiperazine-1 monohydroxy or 4-codeolinyl; R 7 is (C i-5) alkyl, optionally substituted benzyl, 1-methyl Group, 2-fluorenylmethyl, 3-pyridylmethyl or 2-methanesulfanylethyl: and R8 is butyl, 2-phenethyl or 2-methanesulfanylethyl. The most preferred compounds of formula I, II and III are wherein η is 0; A-B represents a bond selected from _C (Ο) NH-; Y is -NH-; Z is -CH (R 7)-; Z 1 -C H (R 8)-; R 1 is 1-piperazinyl, 4-methyl-1 -piperazine hydroxyl or 4-morpholine hydroxyl; R 7 is a selectively substituted book base, 1- Fruit methyl or 2-methylmethyl; and R 8 is phenethyl. -Generally preferred compounds of formula I wherein each R2 is (Ci_5) alkyl (optionally via one or two selected from amine, chlorine, bromine, fluorine, hydroxyl and methoxy, or protected derivatives thereof) Substituted by its group), perhalo (Ci-5) alkyl, (C3_7) cycloalkyl, (c3-7) cycloalkyl (Ci-5) alkyl or selected from phenyl 'pentafluorophenyl , Fluorenyl, and phenyl () alkyl groups (the aryl ring of this group is optionally selected from one to two selected from amino, chlorine, bromine, fluorine, hydroxyl, methoxy, and optionally halogen Methyl substituted with a methyl group or a protected derivative thereof) and R 4 is hydrogen, (-5) alkyl or (Ce ^.) Aryl (Ci_5) alkyl. More preferred compounds of formula I are those wherein R 2 is (C 1 -5) alkyl (optionally via one or two groups selected from the group consisting of amine, chlorine, bromine, fluorine and hydroxyl or protected derivatives thereof). Substitute), perfluoro (Ci_5) alkyl, (C5 —β) cycloalkyl This paper size applies the Chinese national standard (Europe) 8 4 specifications (210 parent 297 mm) _ nn 'IIII Order-^ (please first Please read the notes on the back of the page and fill in this page) 470750 A7 B7___ printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (33), (C5_6) cycloalkylmethyl or selected from phenyl, a certain group and A group in benzyl (this group is optionally substituted with a group selected from amine, hydroxyl, chlorine, bromine or fluorine, or a protected derivative thereof) and R4 is hydrogen or methyl . Particularly preferred compounds of formula I are those in which R2 is methyl, diaminomethyl, optionally substituted phenyl, 2-fluorenyl or 2-phenethyl. The most preferred compounds of formula I are those in which R 2 is phenyl, 2-fruit or 2-phenethyl, especially phenyl or 2-fluorenyl, and R 4 is hydrogen. In general, R 9 is a C (0) OR1. , —P (O) (0 R 10) 2, -S (0) (NR10) R 10 > -C (0) NHC (0) R10 or —S (0) 2NHC (0) R1. Preferred compounds of the formula II are wherein each R1D is a (Ci_5) alkyl group (optionally via one or two selected from the group consisting of amine, chlorine, bromine, fluorine, hydroxyl, and methoxy, or protected derivatives thereof). (C3_7) cycloalkyl, (C3_7) cycloalkyl (Ci-5) alkyl, or a group selected from phenyl or phenyl (Ci-e) alkyl (this The benzene ring of the group is optionally substituted by one or two groups selected from the group consisting of amine, chlorine, bromine, fluorine, hydroxyl, methoxy, and methyl substituted with a halogen group, or a protected derivative thereof. Instead). Where R 9 is -C (0) 〇R10, -P (0) (OR10) 2 '-S (0) (NR10) R10, -C (0) NHC (0) R 10 or -S (0) 2NHC (0) R1Q is more preferably a compound of formula II wherein R1. Ethyl, (C5_6) cycloalkyl, (C5_6) cycloalkylmethyl, or a group selected from phenyl and fluorenyl (the benzene ring of this group is selectively passed through a paper & standard for China National Standard (" 0NS) A4 specification (210X297 mm) ~ '(Please read the precautions on the back before filling this page) 470750 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of inventions (34) Selected from the group consisting of amine hydroxyl, chlorine, bromine or fluorine, or a protected derivative thereof). Among them, R9 is C (0) R11 or one S (0) R11. Generally, the compound of formula 1 is I. Among them, R11 is (Ci-5) alkyl, (C3-7) ring fee group, (C3_7) ring compound group. (C: i_5) a radical or a group selected from phenyl and phenyl (Ci-e) alkyl (the aryl ring of this group is optionally Fluorine, hydroxy, methyl, trifluoromethyl, and methoxy groups are substituted), wherein R11 is more preferably C (0) R11 or —S (0) RU. Compounds of formula II are ethyl, Ring (C5_e) alkyl, ring (C5_e) alkylmethyl or a group from phenyl and fluorenyl (the benzene ring of this group is Group, or a protected derivative thereof). Wherein R9 is -C (0) NR12R13 or -S (COsNRuru is generally preferred compound of formula I j wherein R12 and R13 are each (Ci-5) alkyl, (C3_7) cycloalkyl, (C3_7) cycloalkyl (Alkyl or a group selected from phenyl and phenyl (Cp6) alkyl (the benzene ring of this group is optionally selected from 1 to 2 selected from amine, chlorine, fluorine, hydroxyl, methoxy And optionally substituted by a group in a methyl group which is substituted with a halogen group. Among them, R9 is a more preferred C (0) NR12Ru or S (0) 2NRi2R13 compound of formula II wherein R12 and R13 are each ethyl, (C5-e) cycloalkyl, (C5_e) cycloalkylmethyl or a group selected from phenyl and benzyl (the benzene ring system of this group is optionally , Bromine or fluorine, or their protected derivatives). (Please read the notes on the back before filling out this page)-装-
、1T 丨腺 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X297公釐) -37 - 470750 經濟部中央標準局員工消費合作社印裝 A7 __B7_五、發明説明(35) 其中R9係一C (0) NHR 14或 一 S (0)2NHR14 (其中R14係選自式(a)及(b )中之基團)之較佳式I I化合物係其中各個η、A、B 、Y ' Z、R1及111(>係如前述較佳式I 、I I及I I I 化合物所定義》 一般較佳式I I I化合物係其中R15係選自2 —呋喃 基、2 -卩塞嗯基、2 —吡咯基、2 -磷戊環、2 —砷醯基 、3 -吡啶基或3 -磷炔基中之基團(該基團係選擇性地 經至少一個選自(C i — 5)烷基胺甲醯基、二(C i—5)烷 基胺甲醯基、(Ci_5)烷氧羰基、(c^5)烷基胺基亞 磺醯基、二(Ci—5)烷基胺基亞磺醯基、(Ci-5)烷磺 醯基、羧基、硝基、胺基亞磺醯基、磺基、胺甲醯基、亞 磷羧基、(C )烷氧膦基、二(C ^5 )烷氧膦基、( Ci-5)烷醯基、氰基、(Ci — 5)烷亞磺醯基、胺磺醯基 、(Ci-s)烷基胺磺醯基、二(Cn)烷基胺磺醯基、 (Ci_5)烷氧磺醯基、(Cl—5)苯基、棻基、吡啶基、 瞎嗯基、呋喃基、咪唑基、蚓跺基、羥基、(c i _ 5 )院 氧基、選擇性經鹵基取代之(C 1_5)烷基、韦基、鹵基 、—+n(rm)3 (其中各R17各係(Ci —5)烷基、苯 基或苄基)、或一N(R18)2(其中各r18各係氫、( C1-5)烷基、苯基或苄基)中之基團所取代)。更佳之 式I I I化合物係其中R 1 0係選自2 —呋喃基、2 — u塞嗯 基、2 -卩塞嗯基、2_吡咯基、2 -磷戊環、2 —砷醯基 、3 —吡啶基或3 —磷炔基中之基團(該基團選擇性地經 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) ~ · ~~—— ----------裝------訂------^ (請先閱讀背面之注意事項再填寫本頁) . 470750 經濟部中央標準局員工消費合作社印裂 A7 ___—_ B7五、發明説明(36) 由至少一個選自甲基胺甲醯基、二甲基胺甲醯基、甲氧羰 基、甲基胺亞磺醯基、二甲基胺亞磺醯基、甲磺醯基、羧 基、硝基、胺亞磺醯基、磺基、胺甲醯基、亞磷羧基、甲 氧磷炔基、二甲氧磷炔基、甲醯基、氰基、甲基亞磺醯基 、胺磺醯基、甲基胺磺醯基、二甲基胺磺醢基、甲氧磺醯 基、甲基磺醯亞胺基、苯基、棻基 '吡啶基、卩塞嗯基 '呋 喃基、咪唑基、D引跺基、羥基、甲氧基、甲基、三氟甲基 、苄基鹵基、—+N (R17) 3(其中各各係甲基、苯 基或苄基),或-N (R18) 2(其中各R18各係氫、甲 基、苯基或苄基)中之基團所取代)。一般較佳之式 I I I化合物(其中R16係選自式(a )及(b)中之.基 團)係其中η、A、B、Y、Z、R1及Ri°各如前式I 、I I及I I I之化合物所定義。 通常,較佳本發明半胱胺酸蛋白酶抑制劑係其中各對 掌中心之絕對構型係(S)-構型者。然而,其中η係〇 之較佳式I化合物係其中R 7取代基所附著之對掌中心之 絕對構型係(R) -構型者》例如,較佳之式I化合物包 括:Ν2 -(4 —嗎啉羰基)一 Ν1— (3 —苯基一 1R — 苯磺醯丙基)一 L 一苯基丙胺醯胺(化合物1 ) 、Ν2 — (4 —嗎啉羰基)—Ν1— (3_苯基_1 S —苯磺醯丙 基)—L 一苯基丙胺醯胺(化合物2) 、Ν2_ (4_嗎 啉羰基)—Ν1— (3_苯基_1_苯磺醯丙基)—L — 苯基丙胺醯胺(化合物3) 、Ν2— (4 -嗎啉羰基)— Ν1— (3 —苯基_1_笮磺醯丙基)一L_白胺醯胺( 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) (請先閱讀背面之注意事項再填寫本頁} 470750 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明(37) 化合物4) 、N2- (4 -嗎啉羰基)一N1— (3 -苯基 一 1 一三氟磺醢丙基)一 L 一苯基丙胺醯胺(化合物5 ) 、N2— (4 —嗎啉幾基)—N1— (3 -苯基_1 一苯擴 醯丙基)—L —苯基丙胺醯胺(化合物6) 、N2— (4 一嗎啉羰基)— N1- (3 -苯基-1—苯磺醯丙基)一 L —白胺醯胺(化合物7 ) 、N 2 - ( 4 -嗎啉羰基)— N1- (3-苯基一 1—氟甲磺醯丙基)—L—苯基丙胺 醯胺(化合物8) 、N2 -(4 -嗎啉羰基)一 N1-(3 一苯基一 1 S -苯磺醯甲基丙基)一 L 一苯基丙胺醯胺( 化合物9) ; N2— (4 -嗎啉羰基)一N1— { 3 —苯基 一 1S —〔2 —(2 —苯乙磺醯)乙基〕丙基} _L_苯 基丙胺醯胺(化合物1 ) ; N 2 — ( 4 —嗎啉羰基)_ N 1 一 {3 -苯基_1 S -〔2 -(2 —某磺醯)乙基〕丙基 (2 -某基)_L 一丙胺醯胺(化合物11); N2 —苯乙醯一 N1— { 3_苯基—1 S — (2_苯磺醯乙 基)丙基} —L —苯基丙胺醯胺(化合物1 2) ,N2 - (N—爷氧幾基—Θ -丙胺醯基)— N1—〔―苯基一 1 S —(2 —苯磺醯乙基)丙基〕一 L 一苯基丙胺醯胺( 化合物13) 、3— {2 —苯基一 lS—〔3 —苯基— 1 S- ( 2 —苯磺醯乙基)丙基胺甲醯基〕乙基胺甲醯基 }两酸(化合物14) ; 3— {2 —苯基一1S —〔3 — 苯基一 1 S -( 2 -苯磺醯乙基)丙基胺甲醯〕乙基胺甲 醯}丙酸(化合物1 5) ; N2- (4_嗎啉羰基)一 N1 -丨3 -苯基一 1S -〔2— (2 —某磺醯)乙基〕丙基 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) ---------'裝 訂 地 (請先聞讀背面之注意事項再填寫本頁) -40 - 470750 A7 _______ B7五、發明説明(38) } — L—酪胺醯胺(化合物16) ; 3— {2-苯基— 1 S —〔 3 —苯基—1 S —(2 —苯磺醯乙基)丙基胺甲 醯〕乙基胺甲醯丨丙酸甲酯(化合物1 7) ; N2— (4 —嗎琳鑛基)—N1—〔 3 —苯基—1 S — (2 —苯擴酿 乙基)丙基〕一 L—苯基丙胺醯胺(化合物1 8) ; N 2 (石一丙胺醯)、 1T 丨 The size of this paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297mm) -37-470750 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 __B7_ V. Description of the invention (35) where R9 is a C (0) NHR 14 or -S (0) 2NHR14 (where R14 is a group selected from the group consisting of formulae (a) and (b)), wherein each compound η, A, B, Y ′ Z, R1 and 111 (> are as defined in the aforementioned preferred compounds of formulae I, II and III ". Generally preferred compounds of formula III are those in which R15 is selected from 2-furanyl, 2-pyrenyl, 2-pyrrolyl, A group in 2-phosphopentyl ring, 2-arsenyl, 3-pyridyl, or 3-phosphoalkynyl (this group is optionally via at least one member selected from (C i -5) alkylamine formamidine , Di (C i-5) alkylaminomethylsulfenyl, (Ci_5) alkoxycarbonyl, (c ^ 5) alkylaminosulfinyl sulfenyl, di (Ci-5) alkylaminosulfinyl sulfenyl (Ci-5) alkylsulfonyl, carboxyl, nitro, aminosulfinyl, sulfo, carbamoyl, phosphorous carboxyl, (C) alkoxyphosphino, di (C ^ 5) Alkoxyphosphino, (Ci-5) alkanoyl, cyano, (Ci 5) Alkylenesulfinyl, sulfamoyl, (Ci-s) alkylaminosulfonyl, di (Cn) alkylaminosulfonyl, (Ci_5) alkoxysulfanyl, (Cl-5) Phenyl, fluorenyl, pyridyl, blindyl, furanyl, imidazolyl, arsenyl, hydroxyl, (ci_5) oxy, (C 1_5) alkyl optionally substituted with halo, Weiben , Halo, — + n (rm) 3 (wherein each R17 is (Ci-5) alkyl, phenyl or benzyl), or N (R18) 2 (wherein each r18 is hydrogen, (C1- 5) an alkyl group, a phenyl group or a benzyl group). More preferably, the compound of the formula III is wherein R 1 0 is selected from 2-furanyl, 2-uthenyl, 2-pinthenyl , 2-pyrrolyl, 2-phosphapentyl, 2-arsenyl, 3-pyridyl, or 3-phosphoalkynyl groups (this group selectively applies the Chinese National Standard (CNS) A4 via this paper standard) Specifications (210X297mm) ~ · ~~ —— ---------- install ------ order ------ ^ (Please read the precautions on the back before filling this page) . 470750 Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs print A7 ___ —_ B7 V. Description of the invention (36) At least one selected from A Aminomethylsulfonyl, dimethylaminomethylsulfanyl, methoxycarbonyl, methylaminesulfinyl, dimethylaminesulfinyl, methylsulfinyl, carboxyl, nitro, aminesulfinyl, Sulfo, amidino, phosphorous carboxyl, methoxyphosphonyl, dimethoxyphosphonyl, methylamidino, cyano, methylsulfinyl, sulfamoyl, methylaminosulfonyl , Dimethylaminosulfonyl, methoxysulfinyl, methylsulfinamido, phenyl, fluorenyl'pyridyl, fluorenyl'furanyl, imidazolyl, fluorenyl, hydroxyl, Methoxy, methyl, trifluoromethyl, benzyl halide,-+ N (R17) 3 (where each is methyl, phenyl or benzyl), or -N (R18) 2 (where each R18 Hydrogen, methyl, phenyl or benzyl). Generally preferred compounds of formula III (wherein R16 is selected from the group of formulae (a) and (b)) are those in which η, A, B, Y, Z, R1 and Ri ° are each as described in formulae I, II and III compounds. Generally, it is preferred that the cysteine protease inhibitor of the present invention is the absolute configuration (S) -configuration of each palm center. However, the preferred compound of formula I in which η is 0 is the absolute configuration of the center of the palm where the R 7 substituent is attached. For example, preferred compounds of formula I include: N 2-(4 —Morpholinecarbonyl) —N1— (3-phenyl—1R—benzenesulfonylpropyl) —L—phenylpropylamine amine (Compound 1), N2— (4-morpholinecarbonyl) —N1— (3_ Phenyl_1 S —benzenesulfonylpropyl) —L monophenylpropylamine (compound 2), N2_ (4_morpholinecarbonyl) —N1 — (3_phenyl_1_benzenesulfonylpropyl) —L — Phenylpropylamine (Compound 3), Ν2 -— (4-morpholinecarbonyl) — Ν1— (3-Phenyl_1_sulfonamidinopropyl) -L_leukoamine (this paper is standard Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (Please read the notes on the back before filling out this page} 470750 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (37) Compounds 4), N2- (4-morpholine carbonyl) -N1- (3-phenyl-1, trifluorosulfonylpropyl) -L-phenylpropylamine amide (compound 5), N2- (4-morpholine A few bases)-N1 (3-Phenyl-1-monophenylpropanyl) -L-phenylpropylamine sulfonamide (Compound 6), N2- (4-morpholinecarbonyl) —N1- (3-phenyl-1-benzenesulfonyl) Propyl) -L-leukoamine (compound 7), N 2-(4-morpholinecarbonyl) -N1- (3-phenyl-1-fluoromethanesulfonylpropyl) -L-phenylpropylamine Amine (compound 8), N2- (4-morpholinecarbonyl) -N1- (3-phenyl-1S-benzenesulfonylmethylpropyl) -L-phenylpropylamine sulfonamide (compound 9); N2— (4 -morpholinecarbonyl) -N1— {3-phenyl-1S— [2-((2-phenylethylsulfonium) ethyl] propyl) _L_phenylpropylamine amide (compound 1); N 2 — (4-Morpholinecarbonyl) _N1- {3-phenyl_1S- [2- (2-Sulfosulfonyl) ethyl] propyl (2-Syl) _L-propylamine sulfonamide (compound 11) N2 —phenethylhydrazine-N1— {3_phenyl-1 S — (2_benzenesulfonylethyl) propyl} —L —phenylpropylamine amidamine (compound 1 2), N2-(N-ye Oxoyl — Θ -propylaminofluorenyl) — N1 — [— phenyl-1S — (2-phenylsulfonylethyl) propyl] -L-phenylpropylaminofluorene (Compound 13) 3, {2-phenyl-1S- [3-phenyl-1S- (2-benzenesulfonylethyl) propylaminomethylamidino] ethylaminomethylamido} dicarboxylic acid (compound 14); 3— {2-phenyl-1S— [3-phenyl-1S— (2-benzenesulfonylethyl) propylaminoformamidine] ethylamineformamidine} propionic acid (Compound 1 5); N2- (4_morpholinecarbonyl) -N1-丨 3-phenyl-1S-[2- (2—a sulfofluorenyl) ethyl] propyl This paper is sized to the Chinese National Standard (CNS) A4 (210X297 mm)- -------- 'Binding (please read the precautions on the back before filling out this page) -40-470750 A7 _______ B7 V. Description of the invention (38)} — L-Tyramine (Compound 16 ); 3- {2-phenyl-1 S — [3-phenyl-1 S — (2-benzenesulfonylethyl) propylamine formamidine] ethylamine formamidine 丨 propionic acid methyl ester (Compound 1 7); N2— (4-Morinite-based) —N1— [3-Phenyl-1 S— (2-Benzylbenzene ethyl) propyl] -L-phenylpropylamine (Compound 1 8) ; N 2 (stone-propylamine hydrazone)
N —苯基一1 S — (2 -苯 磺醯乙基)丙基〕-L —苯基丙胺醯胺(化合物1 9 ); 及5 —苯磺醯—3S— {N —〔N— (N —乙醯—L —酪 胺醯)一L —顧胺醢〕一 L 一丙胺酸醯胺}成酸(化合物 20)。較佳之式I I化合物包括:4S— (N —;磺醢 —石一(2 —棻基)一L —丙胺醯胺)—6 —苯基己酸乙 酯(化合物2 1) 基胺甲醯—(2 _某基)一 L —丙胺醯胺)一 6 —苯基己酸乙酯(化合物 22) ; 4S —〔N —(4 —嗎啉碳基)—石—2—(菓 基—L 一丙胺醢胺〕一 6 —苯基己酸乙醋(化合物2 3 );4S_ (N —苄基胺甲醯一 L —苯基丙胺醯胺)—6_N-phenyl-1S- (2-benzenesulfonylethyl) propyl] -L-phenylpropylamine sulfonamide (compound 1 9); and 5-phenylbenzenesulfonium—3S— {N — [N— ( N—Ethylamine—L—Tyramine 醯) —L—Guamine 醢] —L—Alanine amidinamide} to form an acid (Compound 20). Preferred compounds of formula II include: 4S— (N —; sulfonyl—stilbene— (2—fluorenyl) —L—propylamine sulfonamide) —6—phenylhexanoic acid ethyl ester (compound 2 1) (2 _ some group) -L -propylamine amide) -6-phenylhexanoic acid ethyl ester (compound 22); 4S — [N — (4-morpholine carbon group) —stone—2— (fruit group—L Monopropylammonium amine] -6-phenylhexanoic acid ethyl acetate (compound 2 3); 4S_ (N —benzylamine formamidine-L —phenylpropylamine amine) — 6_
苯基己酸乙酯(化合物24) ; 4 S N — ( 4 —嗎啉 —I· Κ ^^^1 ^^^^1 m —^^1 I In 1^1^1 ^^—^1 nn ,一5^-I i (請先閱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 羰基)一L_苯基丙胺醯胺)_6—苯基己酸乙酯(化合 物25) ;N2— (4 -嗎啉羥基)一Nl— r〇 L d -奈基— IS— (2_苯基胺甲醯乙基)丙基〕^ ^ ^ L ~苯基丙胺醯 胺(化合物2 6);及Ν2— (4 -嗎啉羥基)—νι_〔 3 —菓基一 1 S— (2 —苄基胺甲醯乙基)丙基〕_l — 苯基丙胺醯胺(化合物27)。較佳武】τ τ/,八 ~ 1 1 I化合物包括 :Ν2 -(4 —嗎啉經基)—Ν1— { 3-_难甘 本基〜1 s 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ297公釐)^ ~ 41 470750 A7 ____B7 _五、發明説明(39) (2 —(4 一甲氧苯基)乙基〕丙基丨一 L —苯基丙胺醯 胺(化合物28):及N2 -(4 —嗎啉羥基)— Ni-i 3 —苯基—IS —〔2 -(4 —胺苯基)乙基〕丙基丨一 L_苯基丙胺醯胺(化合物2 9)。 如技藝界所熟知者,式I包括下文所示之較佳種類 I V所表示之結構。 R7 0Ethyl phenylhexanoate (compound 24); 4 SN — (4 —morpholine — I · K ^^^ 1 ^^^^ 1 m — ^^ 1 I In 1 ^ 1 ^ 1 ^^ — ^ 1 nn , 5 ^ -I i (Please read the precautions on the back before filling out this page) Carbonyl printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs) -L_phenylpropylamine hydrazine) _6-phenylphenylhexanoate Compound 25); N2- (4-morpholinehydroxyl) -Nl-rOL d-nayl-IS- (2-phenylamine formamidineethyl) propyl] ^^^^ L ~ phenylpropylamine amidamine (Compound 2 6); and N2- (4-morpholinehydroxyl) —νι_ [3 —fructyl-1 S— (2-benzylamine formamidineethyl) propyl] -1 —phenylpropanamine (compound 27). Better Wu] τ τ /, eight ~ 1 1 I compounds include: Ν2--(4-morpholino)-Ν1-{3-_ difficult Ganbenji ~ 1 s This paper size applies Chinese National Standard (CNS) Α4 specifications (210 × 297 mm) ^ ~ 41 470750 A7 ____B7 _V. Description of the invention (39) (2- (4-monomethoxyphenyl) ethyl] propyl 丨 L-phenylpropylamine amide (compound 28): and N2- (4-morpholinehydroxyl) -Ni-i3-phenyl-IS- [2- (4-aminophenyl) ethyl] propyl-L-phenylpropylamine amide (compound 2 9). As is well known in the art world, Formula I includes the structure represented by the preferred category IV shown below. R7 0
經濟部中央標準局—工消費合作社印製 其中Μ係零、壹或兩個碳原子,Α-Β係如前定義,R1 、R2、R7及R8如前定義,且Q係ΝΗ或CH2。較佳具 體實例採用在B位置上含有氮之A - B鍵結。此具體實例 中’介於附著R 8基之碳與硕基之硫原子間之碳原子數決 定該化合物係a—胺基硕、/3 —胺基硕、或7 -胺基硕。 如以下實例所討論者,化合物可使用胺基酸之名稱或使用 化學名稱而稱之爲胺基砚。 因此,例如,種類V係α _胺基硕:Printed by the Central Standards Bureau of the Ministry of Economy—Industrial and Consumer Cooperatives where M is zero, one or two carbon atoms, A-B is as defined above, R1, R2, R7 and R8 are as previously defined, and Q is ΝΗ or CH2. A preferred specific example uses an A-B bond containing nitrogen at the B position. In this specific example, the number of carbon atoms between the carbon to which the R 8 group is attached and the sulfur atom of the base group determines whether the compound is a-amino group, / 3-amino group, or 7-amino group. As discussed in the examples below, the compounds may be referred to as aminophosphonium by the name of the amino acid or by the chemical name. So, for example, the class V is α_amino group:
種類VI係万一胺基硕: 本紙張尺度適用中國國家標準(CNS )八4規格(210X297公釐)_ μ '--------裝-------1Τ------^ (請先閱讀背面之注意事項再填寫本頁) 470750 A7 B7 五、發明説明(4〇) R7 R,\Type VI is a monoamine-based master: This paper size is applicable to China National Standard (CNS) 8 4 specifications (210X297 mm) _ μ '-------- install ------- 1T --- --- ^ (Please read the notes on the back before filling this page) 470750 A7 B7 V. Description of the invention (4〇) R7 R, \
、Q A 计 種類νι ι係r—胺基硕 R1、, Q A meter type νι ι r-amine based R1
式I I包括種類VI I I之結構,稱爲胺基類 尤其係R9爲吸電子基時:Formula I I includes the structure of type VI I I, which is called amine group. Especially when R9 is an electron withdrawing group:
經濟部中央標準局員工消費合作社印製 較佳具體實例中,使用本發明抑制劑抑制蛋白酶之解 離常數,技藝界通常WKi表示’最高ι 0 〇 。本發 明中 ''鍵結常數〃或 '"解離常數〃或文法相當物意指抑制 劑與酶之可逆締合約的平衡解離常數。解離常數如下所定 義及測定。 解離常數之測定係技藝已知者。例如,就;_ Μ Ϋ #曰月 者之可逆抑制反應而言,反應示意圖如下: 式3 Ε + Ι~^ Ε <_ - 1¾ 本紙張尺度適用中國國家標準(CNS ) A4规格(210X297公釐) ---------•裝-------訂------4 (請先閱讀背面之注意事項再填寫本頁) -43 470750 經濟部中央標準局員工消費合作社印黎 A7 B7五、發明説明(41) 該酶及抑制劑結合產生酶-抑制劑複體E . I 。推測 此步驟係迅速且可逆,未產生任何化學變化;該酶及抑制 劑係藉非共價力保持在一起。此反應中,k i係形成 Ε · I可逆複體之二次速率常數。1^2係可逆之E · I複 體解離之一速平常數。此反應中, 平衡常數ki之測定係根據技藝界熟知之技術進行, 如實例所述。例如,檢定通常使用合成之發色或產生螢光 之受質。 個別k 2值可使用lrwin Segel在酶動力學:快速平 衡且穩態之酶系統之行爲及分析,1 9 7 5,1丨16丫-Imterscience Publication, John Wiley & Sons, New York,或就競爭式鍵結抑制劑而言,係根據下列計算: 式4 l-CVi/V。),"〕/!::!" KI(1+(CS]/KM))) 其中 V。係無抑制劑時之受質水解速率,而V i係存有競爭性抑 制劑時之速率。 已知解離常數係特別可用於評定酶與特定受質或抑制 劑之效率之方式,經常以該方式用於技藝界中。若抑制劑 具有極低之K I,則其係有效之抑制劑。因此’本發明半 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)~~~~~~-44 - ----------------A--------ΐτ------t (請先閱讀背面之注意事項再填寫本頁) 470750 經濟部中央標準局員工消費合作杜印製 A7 ____B7 ___五、發明説明(42) 胱胺酸蛋白酶抑制劑之解離常數Kz最高約1 〇 〇 βΜ。 較佳具體實例之抑制劑的解離常數最高約1 〇 ’而最 佳具體實例之解離常數最高約1 //Μ。 化學 本發明抑制劑之合成如下進行。其中X表示鍵結之式 I化合物可藉圖1之示意圖1所示之方法製備。 於甲酸水溶液存在下,以諸如異丁醛或氫肉桂醛之適 當醛及諸如苯亞磺酸(Aldrich Chemical Co.)之適當磺 酸之鈉鹽處理胺甲酸第三丁酯或胺甲酸苄酯’產生對應之 N -經保護胺甲基碉。經苇氧羰基保護之胺甲基硕於乙酸 中以溴化氫脫保護。與適當之N -經保護胺基酸或胜肽或 其擬肽衍生物偶聯,產生其中X表示鍵結之式I化合物。 或者,適當之N終端經保護之胺基酸或其擬肽衍生物之胜 肽,諸如N _( 4 -嗎啉羰基)苯基丙胺醯胺於甲酸水溶 液在下與適當之醛與適當亞磺酸之鈉鹽反應,產生其中X 表示鍵結之式I化合物。 其中X表示伸甲基鍵結之式1化合物可藉個別示於圖 2及3示意圖2及3中之方法製備。 適當之N -經保護胺基酸或其擬肽衍生物以硼氫化鈉 處理,產生對應之Θ -胺基乙醇。於三乙胺存在下以甲磺 醯氯處理該醇,產生對應之甲磺酸酯。根據Spaltenstein ,A·, Carpion, P., Miyalce, F·,及 Hopkings, P.B., J. Org. Chem( 1 987) 52,3759之方法,使用硫醇陰離子, ^紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 一 " ' _ 45 一 ----------裝-------訂------^ (請先閱讀背面之注意事項再填寫本頁) 470750 經濟部中央標準局員工消費合作社印裝 A7 _B7__五、發明説明(43) 諸如硫代苯酚進行親核性置換,產生對應之/3 —胺基硫。 該硫化物藉4 -氯過笮酸氧化,產生對應之N -經保護yS -胺乙基砚。在特定情況下,甲磺酸酯以諸如由2—(三 甲基甲矽烷基)乙硫醇所衍化之硫醇鹽離子(其合成係如 Anderson,Μ.B., Ranasinghe, Μ.B., Palmer, J.T., Fuchs, P.L_,J· Org. Chem. ( 1 988 ) 53,3 1 25 所述般)處 理,產生對應之—胺乙基2 —三甲基甲矽烷乙基硫。2 一三甲基矽烷乙基硫還原成對應之Θ _胺乙基2 -三甲基 甲矽烷乙基硕,進行由氟化物調節之切除,產生三甲基甲 矽烷基氟及乙烯之氣體副產物,及中間亞磺酸酯,該亞磺 酸酯於原位以適當之含鹵素物種(諸如溴化氯甲烷)烷基 化,產生對應之N_經保護/5 —胺乙基鹵甲基硕。此種N -經保護;5 -胺乙基砚經脫保護,隨後與適當之N —經保 護胺基酸或胜肽或擬肽衍生物偶聯,產生其中X係伸甲基 之式I化合物。 其中X表伸乙基之式I I及式I化合物可藉式5,6 及7所表示之方法製備。 式5 (請先閲讀背面之注意事項再填寫本頁) 〇 ΟPrinted by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. In a preferred embodiment, the inhibitor of the present invention is used to inhibit the dissociation constant of the protease. Generally, WKi in the art world indicates ‘highest ι 0 〇. In the present invention, "bond constant" or "" dissociation constant" or grammatical equivalent means the equilibrium dissociation constant of the reversible contract between the inhibitor and the enzyme. The dissociation constant is defined and measured as follows. The measurement of the dissociation constant is known in the art. For example, in the case of; _ Μ Ϋ # 月 月 者 的 逆 回流。 The schematic diagram of the reaction is as follows: Formula 3 Ε + Ι ~ ^ Ε < _-1¾ This paper size applies the Chinese National Standard (CNS) A4 specification (210X297) (Li) --------- • Equipment ------- Order ------ 4 (Please read the notes on the back before filling out this page) -43 470750 Employees of the Central Standards Bureau of the Ministry of Economic Affairs Consumption cooperatives Yinli A7 B7 V. Description of the invention (41) The enzyme and inhibitor combine to produce an enzyme-inhibitor complex E.I. It is speculated that this step is rapid and reversible without any chemical changes; the enzyme and inhibitor are held together by non-covalent forces. In this reaction, k i is a quadratic rate constant that forms an EI · I reversible complex. 1 ^ 2 is a reshaping constant of E · I complex dissociation. In this reaction, the determination of the equilibrium constant ki is performed according to techniques well known in the art, as described in the examples. For example, tests often use synthetic hair colors or fluorescent-generating substrates. For individual k 2 values, use lrwin Segel in enzyme kinetics: fast-balanced and steady-state enzyme system behavior and analysis, 1 9 7 5, 1 丨 16-Imterscience Publication, John Wiley & Sons, New York, or just For competitive bond inhibitors, it is calculated based on: Formula 4 l-CVi / V. ), &Quot;] /! ::! &Quot; KI (1+ (CS) / KM))) where V. It is the rate of mass hydrolysis when there is no inhibitor, and Vi is the rate when competitive inhibitors are present. Known dissociation constants are a method that is particularly useful for assessing the efficiency of enzymes and specific substrates or inhibitors and is often used in the art world in this way. If the inhibitor has a very low K I, it is an effective inhibitor. Therefore, 'The paper size of the present invention is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) ~~~~~~ -44----------------- A-- ------ ΐτ ------ t (Please read the notes on the back before filling in this page) 470750 Duty printing of employee cooperation of the Central Standards Bureau of the Ministry of Economic Affairs A7 ____B7 ___ V. Description of Invention (42) The dissociation constant Kz of the cystine protease inhibitor is up to about 100βM. The dissociation constant of the inhibitor of the preferred embodiment is up to about 10 'and the dissociation constant of the preferred embodiment is up to about 1 // M. Chemistry The synthesis of the inhibitors of the present invention proceeds as follows. Compounds of formula I in which X represents a bond can be prepared by the method shown in Scheme 1 in FIG. Treat the third butyl carbamate or benzyl carbamate with an appropriate aldehyde such as isobutyraldehyde or hydrocinnamaldehyde and a suitable sodium salt such as benzenesulfinic acid (Aldrich Chemical Co.) in the presence of an aqueous formic acid solution ' A corresponding N-protected amine methyl amidine is produced. The amine methyl group protected with reed oxo was deprotected in acetic acid with hydrogen bromide. Coupling with a suitable N-protected amino acid or peptide or its peptidomimetic derivative yields a compound of formula I where X represents a bond. Alternatively, a suitable N-terminal protected amino acid or a peptide derivative of a peptidomimetic derivative thereof, such as N_ (4-morpholinecarbonyl) phenylpropylamine, in an aqueous formic acid solution with a suitable aldehyde and a suitable sulfinic acid The sodium salt reacts to produce a compound of formula I where X represents a bond. Compounds of formula 1 in which X represents a methyl group bond can be prepared by methods shown individually in Figures 2 and 3 in Schemes 2 and 3. Appropriate N-protected amino acids or peptidomimetic derivatives are treated with sodium borohydride to produce the corresponding Θ-aminoethanol. Treatment of the alcohol with methanesulfonium chloride in the presence of triethylamine yields the corresponding mesylate. According to the method of Spaltenstein, A ·, Carpion, P., Miyalce, F ·, and Hopkings, PB, J. Org. Chem (1 987) 52,3759, the thiol anion is used. ^ The paper standard is applicable to the Chinese National Standard (CNS ) A4 specification (210X297 mm) A " '_ 45 A ---------- install ------- order ------ ^ (Please read the precautions on the back before (Fill in this page) 470750 Printed by A7 _B7__ of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the Invention (43) Nucleophilic substitution such as thiophenols will produce the corresponding / 3-aminosulfur. The sulfide is oxidized with 4-chloroperacetic acid to produce the corresponding N-protected yS-aminoethylphosphonium. In particular cases, the mesylate is thiolate ion derived from, for example, 2- (trimethylsilyl) ethyl mercaptan (synthesis is such as Anderson, M.B., Ranasinghe, M.B. , Palmer, JT, Fuchs, P.L_, J. Org. Chem. (1 988) 53, 3 1 25)) treatment to produce the corresponding -amine ethyl 2-trimethylsilyl ethyl sulfur. 2 Trimethylsilylethylsulfur is reduced to the corresponding Θ_aminoethyl 2-trimethylsilylethyl group, which is subjected to removal by fluoride adjustment to produce trimethylsilyl fluoride and ethylene gas vice Products, and intermediate sulfinates, which are alkylated in situ with a suitable halogen-containing species (such as methyl bromide) to produce the corresponding N_protected / 5-aminoethylhalomethyl large. This N-protected; 5-aminoethylamidine is deprotected and then coupled with the appropriate N-protected amino acid or peptide or peptidomimetic derivative to produce a compound of formula I in which the X is methyl. . Compounds of formula I I and formula I in which X is ethylene, can be prepared by the methods represented by formulae 5, 6 and 7. Formula 5 (Please read the precautions on the back before filling this page) 〇 〇
OH a)OH a)
BocBoc
NN
Boc - b) R8Boc-b) R8
H 其中 a) Cj^— H2N + (Me) OMe 二亞胺,三乙胺;及b )氫化鋰鋁。 式6 二環己基碳化 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -46 - 470750 A7 B7 五、發明説明(44)H wherein a) Cj ^ —H2N + (Me) OMe diimine, triethylamine; and b) lithium aluminum hydride. Formula 6 Dicyclohexyl carbonization The paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) -46-470750 A7 B7 V. Description of Invention (44)
ΟΗ II Boc—N、 IIΟΗ II Boc—N, II
0 R’O丨丨 /P、 RO0 R’O 丨 丨 / P, RO
,EWG R8, EWG R8
Boc—i8Boc—i8
.EWG 式7 R8 EWG H2/Pd Boc R8 (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 適當之N -第三丁羰基胺基酸或其擬肽衍生物轉化成 對應之胺甲基醛(例如,參照Fehrentz, J-A及Castro ,Β·之方法(Synthesis, (1 9 8 3 ) ’6 7 6;式 5 )。該醛經Wittig反應或WittU反應(例如參照 Wadsworth 等人,J. Amer. Chem. Sec.8 3 : 1 7 3 3 (1 9 9 1 );式 6 )之Wadsworth-Emmons-Horner改良 法轉化成對應之含乙烯基之化合物。含乙烯基之化合物藉 催化氫化(例如參照式7 )還原,並脫保護,與適當之N -經保護胺基酸或胜肽或其擬肽衍生物偶聯,產生對應之 式I或I I化合物。或者,該含乙烯基之化合物使用N — 經保護之胺基酸或胜肽或其擬肽衍生物脫保護並偶聯,產 生對應之含乙烯基之縮合產物,其隨後還原產生對應之式 I或I I化合物。 式I I化合物可藉圖4示意圖4所示之方法製備。 泰紙張尺度適用中國國家標準(CNS ) A4规格(210X297公釐) -Λ7 470750 經濟部中央標準局員工消費合作社印製 A7 _B7 _五、發明説明(45) ' 較佳,由N -第三丁氧羰基胺基酸或其擬衍生物至對 應之胺甲基醛之轉化係於二氯甲烷中,於三乙胺及二環己 基碳化二亞胺存在下,使用N,0 -二甲基羥胺鹽酸鹽進 行。或者,該轉化係使用三乙胺及偶聯劑六氟磷酸苯並三 唑一 1 一基氧三(二甲胺基)鱗(BOP)處理胺基酸或 其擬肽衍生物,並使用氫化鋰鋁還原,產生對應之醛而進 行(例如,參照 Fehrentz Castro,B. ;Synthesis,( 1983) ,676—678之方法)。由醛至對應之含 乙烯基之酯之轉化可使用亞磷羧乙酸三乙酯之鈉陰離子進 行。含乙烯基之酯之脫保護可於二噁烷中使用氯化氫進行 。氫化一般係於鈀存在下進行。 其中X係伸乙基之式I化合物可藉圖5示意圖5所示 方法而簡便地製備。 如式5所述般製備之適當N -第三丁氧羰基-α —胺 基醛以適當之磺醯甲烷膦酸酯之鈉陰離子(SMP)(例 如苯磺醢甲膦酸二乙酯、2 —某磺醯甲膦酸二乙酯、甲磺 醯甲膦酸二乙酯等)處理產生對應之含乙烯之硕。該硕於 乙醚中以無水對甲苯磺醯脫保護,隨後與Ν -經保護之胺 基酸或胜肽或其擬肽衍生物偶聯,產生對應之含乙烯之縮 合產物,隨後還原產生對應之式I化合物。適當之芳磺醯 甲膦酸酯可藉於氯化氫存在下,以對甲醛處理芳基硫醇, 與亞磷酸三乙酯反應產生對應之二乙基磷羧甲基芳基硫, 然後氧化該硫化物。或者,可工業化地得到適當之硫醚( 例如 Aldrich Chemical Co.,所售之二乙基亞磷羧甲基 _本紙張尺度適用中國國家標準(CNS > A4規格(210X297公釐) '~~—_ 48 - (請先閱讀背面之注意事項再填寫本頁) -裝· 訂 470750 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(46) 甲硫醚,二乙基亞磷羧甲基苯硫醚等),並氧化其對應之 硼。 其中R9係一 COOH之式I ;[化合物可藉圖6示意 圖6所列之方法製備。 通常,其中R9係一COORi。之式丨丨化合物之皂 化產生對應之羧酸酯’以酸處理時產生對應之羧酸。 其中R9係—p (〇) (r1〇)2之式! j化合物可藉 示意圓6般加工而如τκ意圖7 (圖7 )般地製備,而以適 當之伸甲基二膦酸酯之鈉陰離子(例如苄基醯胺伸甲基磷 酸二乙酯等)取代SMP。 其中尺9係—C (0) NHR"之式化合物可藉 著如示意圖5般加工而如示意圖8 (圖8 )般製備,但以 適當之醯胺伸甲基膦酸二乙酯(例如笮醯胺伸甲基膦酸二 乙酯等)取代SMP。 適當之醯胺伸甲基膦酸酯可藉亞磷羧乙酸三乙醋之岂 化產物適當胺反應而製備。或者,其中尺9係 —C (◦) NHR14之式I I化合物可藉其中r9係 一 COOH之式I化合物與適當胺反應而製備。例如,於 一氯甲院中於一環己基碳化二亞胺存在下進行反應,或藉 任何一種熟習此技藝者已知之其他胜肽偶聯反應而製備。 通常,式I1化合物可藉示意圖9 (圖9)所示之方 法製備,並置換結構I —V I I所示之原料。.EWG 7 R8 EWG H2 / Pd Boc R8 (Please read the precautions on the back before filling out this page) The Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs printed the appropriate N-tert-butycarbonylamino acid or its peptidomimetic derivative The product is converted into the corresponding amine methylaldehyde (for example, refer to the method of Fehrentz, JA and Castro, Beta) (Synthesis, (1 9 8 3) '6 7 6; Formula 5). The aldehyde is subjected to the Wittig reaction or the WittU reaction ( For example, refer to Wadsworth et al., J. Amer. Chem. Sec. 8 3: 1 7 3 3 (19 9 1); Formula 6) modified Wadsworth-Emmons-Horner conversion method to corresponding vinyl-containing compounds. Vinyl compounds are reduced by catalytic hydrogenation (see, for example, Formula 7) and deprotected, and coupled with the appropriate N-protected amino acid or peptide or peptidomimetic derivative, to produce corresponding compounds of Formula I or II. Alternatively, the vinyl-containing compound is deprotected and coupled using N-protected amino acid or peptide or peptidomimetic derivative to produce the corresponding vinyl-containing condensation product, which is subsequently reduced to produce the corresponding formula I Or II compounds. Compounds of formula II can be prepared by the method shown in Figure 4 and Scheme 4. Thai Paper size applies Chinese National Standard (CNS) A4 (210X297 mm)-Λ7 470750 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 _B7 _ V. Description of the invention (45) 'Better, by N-three-butoxy The conversion of carbonylamino acid or its pseudo-derivative to the corresponding amine methylaldehyde is in methylene chloride in the presence of triethylamine and dicyclohexylcarbodiimide using N, 0-dimethylhydroxylamine salt Alternatively, the conversion system is treated with triethylamine and coupling agent benzotriazole hexafluorophosphate-1 1-oxytris (dimethylamino) scale (BOP) to treat the amino acid or its peptidomimetic derivative And use lithium aluminum hydride reduction to produce the corresponding aldehyde (for example, refer to the method of Fehrentz Castro, B .; Synthesis, (1983), 676-678). The conversion from aldehyde to the corresponding vinyl-containing ester can be It is carried out using the sodium anion of triethyl phosphorous carboxyacetate. The deprotection of vinyl-containing esters can be carried out in dioxane using hydrogen chloride. The hydrogenation is generally carried out in the presence of palladium. Among them, X is an ethylidene compound of formula I It can be easily prepared by the method shown in Figure 5 and Figure 5. A suitable N-tert-butoxycarbonyl-α-amino aldehyde prepared as described in Formula 5 with a suitable sodium anion (SMP) of —Diethyl sulfomethylmethonate, diethyl methanesulfonate methylphosphonate, etc.) treatment to produce the corresponding ethylene-containing masterbatch. The masterbatch was deprotected with anhydrous p-toluenesulfonium in ether, and then treated with N- The protected amino acid or peptide or its peptidomimetic derivative is coupled to produce the corresponding ethylene-containing condensation product, which is subsequently reduced to produce the corresponding compound of formula I. Appropriate sulfonium methylphosphonate can be used to treat aryl mercaptan with formaldehyde in the presence of hydrogen chloride, and react with triethyl phosphite to produce the corresponding diethylphosphocarboxymethylaryl sulfide, and then oxidize the sulfur Thing. Alternatively, suitable thioethers can be obtained industrially (for example, the diethyl phosphorous carboxymethyl sold by Aldrich Chemical Co. _ this paper size applies to Chinese national standards (CNS > A4 size (210X297 mm) '~~ —_ 48-(Please read the precautions on the back before filling this page)-Binding · 470750 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (46) Methyl sulfide, diethylphosphine Carboxymethyl phenyl sulfide, etc.), and oxidize the corresponding boron. Among them, R9 is a formula of COOH I; [Compounds can be prepared by the methods listed in the schematic diagram of Figure 6. Generally, R9 is a COORi. Formula 丨丨 The saponification of the compound produces the corresponding carboxylic acid ester, which results in the corresponding carboxylic acid when treated with an acid. Among them, R9 is the formula of p (〇) (r1〇) 2! J Compounds can be processed by schematic circle 6 as τκ intention 7 (Figure 7), and replace the SMP with an appropriate sodium anion of methyl bisphosphonate (such as benzylamidine and methyl diethyl phosphate). Among them, Rule 9-C (0) Compounds of the formula NHR " can be prepared as shown in Scheme 5 (Figure 8) by processing as shown in Scheme 5, Replace SMP with an appropriate diethylammonium methylphosphonate (eg diethylammonium methylphosphonate, etc.). An appropriate diammonium methylphosphonate can be triethyl phosphonocarboxacetate. The chemical product is prepared by reacting an appropriate amine. Alternatively, a compound of formula II in which the 9-series (C) NHR14 is prepared can be prepared by reacting a compound of formula I in which r9 is a COOH with an appropriate amine. For example, in methyl chloride The reaction is carried out in the presence of a cyclohexylcarbodiimide, or by any other peptide coupling reaction known to those skilled in the art. Generally, the compound of formula I1 can be obtained by the method shown in Figure 9 (Figure 9). Prepare and replace the starting materials shown in structures I-VII.
結構I 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X297公釐) -------------ά------、1Τ----- ^ (請先閲讀背面之注意事項再填寫本頁} -49 470750 Α7 Β7 五、發明説明(47)Structure I This paper size applies the Chinese National Standard (CNS) Α4 specification (210X297 mm) ------------- ά ------, 1Τ ----- ^ (please first Read the notes on the back and fill out this page} -49 470750 Α7 Β7 V. Description of the invention (47)
QHsO^HQHsO ^ H
酮之合成係藉B 〇 c - α -胺基酸與適 之Wadsworth-Emmons反應進行’隨後於把 化還原。通常,醛部分係如前述般地合成。 則膦酸酯係藉氯膦酸二乙酯處理甲基或經取 諸如丙酮或二苯甲酮)之烯醇鹽陰離子處理 醇鹽陰離子係例如藉·丁基鋰處理二異丙胺 液,隨後於二異丙基醯胺鋰(LDA)溶液 0. House, Modern Synthetic React ions, Benjamin, Inc., Menlo Park, CA,第 9章 鹽後,添加氯膦酸二乙酯。烯醇鹽與氯磷酸 結果,形成Wadsworth - Emmons試劑。 合成半胱胺酸蛋白酶抑制劑時,使用睛 之 E W G ·· 結構I IKetone synthesis is carried out by reaction of Boc-?-Amino acid with a suitable Wadsworth-Emmons' followed by reduction. Generally, the aldehyde moiety is synthesized as described above. Then the phosphonate is treated with diethyl chlorophosphonate or treated with enolate anion such as acetone or benzophenone). The alkoxide anion is treated with diisopropylamine solution by Lithium diisopropylamidamine (LDA) solution 0. House, Modern Synthetic React ions, Benjamin, Inc., Menlo Park, CA, Chapter 9 After the salt, diethyl chlorophosphonate was added. Enolate and chlorophosphoric acid As a result, a Wadsworth-Emmons reagent is formed. When synthesizing cysteine protease inhibitors, use E W G ·· Structure I I
當之膦酸酯間 存在下以氫催 若非市售者, 代之甲基酮( 而 成。該烯 之四氫呋喃溶 中添加酮(Η. 2nd Ed. (ff. )。形成烯醇 二乙酯偶聯之 充作結構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 明〇^|| 腈之合成係藉B 〇 c - α -胺基醛與適當之膦酸酯間 之Wadsworth - Emmons反應進行,隨後於適當之觸媒存 在下氫化。通常,醛部分係如前述般地合成。膦酸酯係市 售者。 本纸張尺度適用中國國家標準(CNS ) A4規格(21〇χ:297公釐) -50 - 470750 A7 B7In the presence of phosphonates, hydrogen is used to urge non-marketers to replace methyl ketones. The ketone (Η. 2nd Ed. (Ff.)) Is added to the tetrahydrofuran solution of the olefin. Diethyl enol is formed Coupling is used as structure II (please read the notes on the back before filling this page) -β Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. The Wadsworth-Emmons reaction between the aldehyde and the appropriate phosphonate is carried out, followed by hydrogenation in the presence of a suitable catalyst. Usually, the aldehyde moiety is synthesized as described above. The phosphonate is commercially available. This paper is scaled to China National Standard (CNS) A4 specification (21 ×: 297 mm) -50-470750 A7 B7
五、發明説明(48) 合成半胱胺酸蛋白酶抑制劑時 I I I 之 E W G : 結構I I I 使用亞硕充作結構 ο οcmj II XR' 亞砚之合成係藉B o c — α —胺基醛及適當膦酸酯間 之Wadsworth - Emmous反應進彳了 ’隨後於適當觸媒存在 下氫化。通常,醛部分係如前述般地合成。膦酸酯係藉氯 磷酸二乙酯處理甲基亞硕之陰離子而合成。藉於二異丙胺 中添加B u L i而產生陰離子,隨後添加甲基亞硕。 合成半胱胺酸蛋白酶抑制劑時’使用磺醯胺充作 結構I V之E W G : 結構I V 0 0 c2h5〇、|| c2h5o/P"^ |Γνηκ'4 ο I I I I I . I n ^ I I I I I 丨 球 (請先聞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 磺醯胺之合成係藉Β ο c — α -胺基醛及適當膦酸酯間之 Wadsworth - Emmous反應,隨後於適當觸媒存在下氫化 而進行。通常,醛部分係如前述般地合成。膦酸酯係例如 藉諸如下述 a ) Lett., 28:1 1 04- 1 1 08( 1 987 ))之方法所製備之甲擴酸二 乙基磷醯酯藉五氯化磷處理轉化成磺醯氯(^91^&(^1卜 eg, ^ Methoden der Organische Chemic ( Houben - Ulieyl 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 470750 經濟部中央標準局員工消費合作社印製 A7 B7 _五、發明説明(49) )^ ,ed .E. Muller .Thieme Verlag, Stuttgart, 4th Ed.,1955, Vol IX,第 14 章);或 b)以諸如氨、一 級胺(包括胺基酸衍生物)或二級胺之胺處理磺醯氯,形 成磺醯胺(Quaedvlieg,前述者,第1 9章)。磺醯胺膦 酸酯隨後與B 〇 c - α—胺基醛根據Wadsworth -Emmous 反應而反應,形成標靶化合物。 合成半胱胺酸蛋白酶抑制劑時,使用亞磺醯胺充作結 構V之E W G : 結構V 0 0 明\11 II /P\ ΧΝΗΐί2 亞硼之合成係藉Β ο c _ α -胺基醛及適當之膦酸酯間之 Wadsworth - Emmous反應進行,隨後於適當觸媒存在下 氫化。通常,醛部分係如前述般地合成。膦酸酯可使用下 列方法中之一者合成。於氯化鋁存在下使用亞硫醯氯處理 膦酸中酯二烷酯(諸如止售之膦酸甲酯二乙酯(Aldrich )’產生二院基磷醯甲亞礎醯氯(Vennstra et al., Synthesis (1975) 519. See also Anderson, Compre-hensive Organic Chemistry ( Pergamon Press) ^, Vol. 3,Chapter 11.18,(1979)。或者,使用胺處理二 院基磷醯亞擴醯氯(Stirling, Internat. Sulfur Chem. (B) 6 : 277 (1971))產生二烷基磷醯 亞磺醯胺。 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) (請先閱讀背面之注意事項再填寫本頁) -52 - 470750 經濟部中央標準局員工消費合作社印製 A7 B7___五、發明説明(5〇) 合成半胱胺酸蛋白酶抑制劑時,使用亞硼亞胺充作結 構V I之E W G : 結構V I 0 0明0\丨丨II 10 /S—R10 Nv xr'° 亞碉亞胺之合成係藉Β ο c - α -胺基醛及適當膦酸 酯間之Wadsworth - Emmous反應進行,隨後於適當觸媒 存在下氫化。通常,醛部分係如前述般地合成。膦酸酯可 根據各種方式合成。例如N -烷基或N -芳基苯基甲基亞 石亞胺係藉 Johnson 於 A Comprehensive Organic C h e m i s t r y ( P e r g a m ο η P r e s s ),前述者,第 1 1 · 1 1 章中所述之方法製造。或者,化合物之鋰陰離子,諸如N -烷基苯基甲基亞碉亞胺係於T H F中藉丁基鋰處理中性 化合物而製備(Cram等人,J. Amer. Chem. Soc. 9 2 :736 9 (1970))。該鋰陰離子與氯磷酸二烷酯 (諸如市售氯磷酸二乙酯(Aldrich))反應產生合成亞 硼亜胺化合物所必要之Wadsworth - Emmous試劑。 合成半胱胺酸蛋白酶抑制劑時,使用磺酸酯充作結構 V I I 之 E W G : 結構V . I I 0cwxjl /S〇3-M+ 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)_ 53 _ !| 批衣— II 訂 备 (請先閱讀背面之注意事項再.¾寫本頁) 470750 經濟部中央標率局員工消費合作社印製 A7 B7五、發明説明(51 ) 磺酸酯亞硕之合成係藉B 〇 c - α -胺基醛與適當膦 酸酯(例如甲磺酸二之乙基磷醯酯)間之Wadsworth -Emmous反應進行·,隨後於諸如Raney鎳之適當觸媒存在 下氫化。如下合成膦酸酯。膦酸甲酯二烷酯之陰離子,諸 如市售膦酸甲酯二乙酯(Aldrich),係藉以諸如L D A 之強鹼處理該膦酸酯而產生。形成之陰離子以三氧化硫/ 三甲胺複體礎酸化(Carreto等人,Tetrahedron Lett., 28 : 110 4 — 1108 (1987)形成甲磺酸二乙 基磷醯酯,其可於Wadsworth - Emmous方法中使用醒類 反應形成a,yS —不飽和磺酸酯。 式I I化合物可藉示意圖10 (圖10)所示之方法 製備。 含r8及r9之氯化物化合物通常使用市售試劑及產物 並使用熟習此技藝者之技術製造。該反應通常產生順式及 反式構型之混合物,而反式異構物佔優勢》還原成本具體 實例之半胱胺酸蛋白酶抑制劑時,順式一反式異構化消失 ,則定義形成單一化合物。 一個具體實例中,本發明半胱胺酸蛋白酶抑制劑於合 成後視需要純化,例如用以去除未反應之物質。例如,本 發明半胱胺酸蛋白酶抑制劑可結晶,或使用溶劑混合物通 經氧化矽層析管柱,以洗提純抑制劑。 簡言之,製備本發明化合物之方法如下: —I I I I I I I I I —-訂— 备 (請先閲讀背面之注意事項再丨、寫本頁) 本紙張尺度適用中國國家標準(CNS > A4規格(210XW7公釐) -54 - 470750 A7 B7 五、發明説明(52 ) (A )製備式I V時: 0 R8V. Description of the invention (48) EWG III when synthesizing cysteine protease inhibitors: Structure III uses ASUS as the structure ο ο cmj II XR 'sulfonium is synthesized by B oc — α —amino aldehyde and appropriate phosphine The Wadsworth-Emmous reaction between the acid esters was initiated, followed by hydrogenation in the presence of a suitable catalyst. Generally, the aldehyde moiety is synthesized as described above. Phosphonates are synthesized by treating methyl anion with chlorodiethyl phosphate. An anion is generated by the addition of Bu Li to diisopropylamine, followed by the addition of methylasyl. When synthesizing cysteine protease inhibitors, 'sulfamethoxamine was used as the EWG of structure IV: Structure IV 0 0 c2h50, || c2h5o / P " ^ | Γνηκ'4 ο IIIII. I n ^ IIIII 丨 ball (please First read the notes on the back and then fill out this page.) The synthesis of sulfonamide produced by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs is based on the Wadsworth-Emmous reaction between β ο c — α-amino aldehyde and the appropriate phosphonate. This is followed by hydrogenation in the presence of a suitable catalyst. Generally, the aldehyde moiety is synthesized as described above. Phosphonates are, for example, converted to diethylphosphonium methoate prepared by a method such as the following a) Lett., 28: 1 1 04- 1 1 08 (1 987)) by phosphorus pentachloride treatment Sulfonium chloride (^ 91 ^ & (^ 1 卜 eg, ^ Methoden der Organische Chemic (Houben-Ulieyl) This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 470750 Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Print A7 B7 _V. Description of the Invention (49)) ^, ed.E. Muller. Thieme Verlag, Stuttgart, 4th Ed., 1955, Vol IX, Chapter 14); or b) For example, ammonia, primary amine ( Including amine derivatives) or secondary amines, sulfonium chloride is treated to form sulfonamide (Quaedvlieg, aforementioned, Chapter 19). Sulfonamidophosphonate is then reacted with Boc-α-aminoaldehyde according to the Wadsworth-Emmous reaction to form the target compound. When synthesizing cysteine protease inhibitors, sulfinamide is used as the EWG of structure V: Structure V 0 0 Ming \ 11 II / P \ ΧΝΗΐί 2 The synthesis of boron is based on β ο c _ α -amino aldehyde and The Wadsworth-Emmous reaction between the appropriate phosphonates proceeds, followed by hydrogenation in the presence of a suitable catalyst. Generally, the aldehyde moiety is synthesized as described above. The phosphonate can be synthesized using one of the following methods. Treatment of dialkyl phosphonic acid dialkyl esters (such as methyl ethyl diphosphonate (Aldrich) ', which is not sold, with a thionyl chloride in the presence of aluminum chloride) to produce a dibasic phosphonium phosphine subbasic chloride (Vennstra et al ., Synthesis (1975) 519. See also Anderson, Compre-hensive Organic Chemistry (Pergamon Press), Vol. 3, Chapter 11.18, (1979). , Internat. Sulfur Chem. (B) 6: 277 (1971)) produces dialkylphosphonium sulfenamidine. This paper size applies the Chinese National Standard (CNS) A4 size (210X297 mm) (Please read the back Note: Please fill in this page again) -52-470750 A7 B7___ printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (50) When synthesizing cysteine protease inhibitors, use boronimine as the structure The EWG of VI: Structure VI 0 0 Ming 0 \ 丨 丨 II 10 / S-R10 Nv xr '° The synthesis of iminoimine is by B ο c-α -amino aldehyde and the appropriate phosphonate between Wadsworth-Emmous The reaction proceeds, followed by hydrogenation in the presence of a suitable catalyst. Generally, the aldehyde moiety is combined as previously described. The phosphonate can be synthesized according to various methods. For example, N-alkyl or N-arylphenylmethylimineimide is based on Johnson's A Comprehensive Organic C hemistry (Pergam ο η P ress), the former, Manufactured by the method described in Chapter 11.1.1. Alternatively, the lithium anion of the compound, such as N-alkylphenylmethylimide, is prepared by treating a neutral compound with butyl lithium in THF (Cram Et al., J. Amer. Chem. Soc. 9 2: 736 9 (1970)). The lithium anion is reacted with a dialkyl chlorophosphate, such as a commercially available diethyl chlorophosphate (Aldrich), to produce a synthetic boroxamine. Wadsworth-Emmous reagents necessary for compounds. When synthesizing cysteine protease inhibitors, the sulfonate is used as the EWG of structure VII: Structure V. II 0cwxjl / S〇3-M + This paper standard applies to Chinese national standards (CNS ) A4 size (210X297mm) _ 53 _! | Approval—II order (please read the precautions on the back before writing this page) 470750 Printed by A7 B7, Cooperative of Staff of Central Standards Bureau of Ministry of Economic Affairs DESCRIPTION OF THE INVENTION (51) The synthesis of sulfonate ASSO was borrowed from B. The Wadsworth-Emmous reaction between c-α-amino aldehyde and a suitable phosphonate (for example, diethylphosphonium mesylate) proceeds, followed by hydrogenation in the presence of a suitable catalyst such as Raney nickel. The phosphonate was synthesized as follows. The anion of methyl phosphonate dialkyl, such as commercially available methyl phosphonate diethyl (Aldrich), is generated by treating the phosphonate with a strong base such as L D A. The anion formed is acidified with sulfur trioxide / trimethylamine complex (Carreto et al., Tetrahedron Lett., 28: 110 4 — 1108 (1987) to form diethylphosphonium mesylate, which can be used in the Wadsworth-Emmous method In the reaction, a, yS—unsaturated sulfonate is used. Compounds of formula II can be prepared by the method shown in Figure 10 (Figure 10). Chloride compounds containing r8 and r9 are usually used commercially available reagents and products and used Familiar with the techniques of this artist. The reaction usually produces a mixture of cis and trans configurations, and the trans isomers dominate. "When the cost of a cysteine protease inhibitor is a specific example, cis-trans The disappearance of isomerization is defined as the formation of a single compound. In a specific example, the cysteine protease inhibitor of the present invention is purified as needed after synthesis, for example, to remove unreacted substances. For example, the cysteine protease of the present invention The inhibitor can be crystallized, or the solvent mixture can be passed through a silica chromatography column to purify the inhibitor. In short, the method for preparing the compound of the present invention is as follows: -IIIIIIIII —-Order— Preparation (Please read the precautions on the back before writing this page) This paper size applies to Chinese national standards (CNS > A4 size (210XW7 mm) -54-470750 A7 B7 V. Description of the invention (52 ) (A) When formula IV is prepared: 0 R8
經濟部中央標準局員工消費合作社印製 其 中 η 係 0至 1 2 » R 2 0 係 氰基,—s ( 0 )2R 2 ) — C Η 2S ( c 丨) 2 R 2 , — C Η 2 C H ( ;R 4 ) S ( 0 )2R 2, — ( C H 2) 2 C ( 0 ) 0 R 10、 — ( C H 2) 2 P ( 0 ) ( 0 R 10) 2 , — ( C H 2) 2 s ( 0 ) ( N R 1 0 ) R 11 0, — C H 2) 2 C ( 0 ) R 11 > 一(C H 2 ) 2 S (0 ) R 11 9 — ( C H 2) 2 c ( 0 ) N R 1 2 R 1 3 , — ( C H 2) 2 s ( 0 ) 2N R 12R 13、 — ( C H 2) 2 c ( 0 ) N H R 14, — ( C H 2) 2 s ( 0 ) 2 N H R 14 或— C Η 2 C H R 1 5 R 16 且 各 A 、 B 、 X 、 Y 、 Z 、 R 1、R 8、 R 1 , • R 8、 R 2、 R 10 、 R 11 、 R 12 、 R 13 、 R 14、R 1 5及 R 1 e如發 明簡 述 中 針 對 式 I 、 I I 及 I I I 之化合物及其 藥 學上可 接受 之 鹽 、 個 別 異構 物 及 其 異 構 物 混合物之定義 9 式v之胺:Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs where η is 0 to 1 2 »R 2 0 is cyano, —s (0) 2R 2) — C Η 2S (c 丨) 2 R 2, — C Η 2 CH (; R 4) S (0) 2R 2, — (CH 2) 2 C (0) 0 R 10, — (CH 2) 2 P (0) (0 R 10) 2, — (CH 2) 2 s (0) (NR 1 0) R 11 0, — CH 2) 2 C (0) R 11 > One (CH 2) 2 S (0) R 11 9 — (CH 2) 2 c (0) NR 1 2 R 1 3, — (CH 2) 2 s (0) 2N R 12R 13, — (CH 2) 2 c (0) NHR 14, — (CH 2) 2 s (0) 2 NHR 14 or — C Η 2 CHR 1 5 R 16 and each of A, B, X, Y, Z, R 1, R 8, R 1, • R 8, R 2, R 10, R 11, R 12, R 13, R 14, R 15 and R 1 e are as defined in the brief description of the compounds of formulae I, II and III and their pharmaceutically acceptable salts, individual isomers and mixtures of isomers thereof 9 amines of formula v:
與式V I之化合物反應: ------------裝------訂------線 (請先閱讀背面之注意事項莽,\寫本頁) 本紙張尺度適用中國國家標準(CNS ) A4规格(210X 297公釐)# 二' 55 -- 470750 A7 —____B7 五、發明説明(&3)Reaction with the compound of formula VI: ------------ install ------ order ------ line (please read the precautions on the back first, write this page) Paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) # 2 '55-470750 A7 —____ B7 5. Description of the invention (& 3)
VI 其中η、A、B、X、Y、Z、R 1、R 8及R 2°如前定義 (B)製備式I V之化合物(其中R2。係一S (0) 2R2 )及其藥學上可接受之鹽、個別異構物及異構物混合物時 式V I I I化合物: 〇 人 NH2VI wherein η, A, B, X, Y, Z, R 1, R 8 and R 2 ° are as defined above (B) to prepare a compound of formula IV (where R 2 is a S (0) 2R 2) and its pharmacy Acceptable salts, individual isomers and mixtures of isomers: Compounds of formula VIII: o Human NH2
VII 與式R8CH0之醛及式R2S (〇) 〇Na之亞磺醯鈉反 應,其中η、A、B、X、Y、Z、R1及R8如前定義; (C)製備式IV化合物(其中R 2。係 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項f...舄本頁) 一 S (0) 2R2)及其藥學上可接受之鹽、個別異構物及 異構物之混合物時, (1 )式NH2P之化合物(其中P係保護基)與式 R8CH0之醛及式R2S (0) ONa之亞磺醯鈉反應, 隨後脫保護,產生式VIII之化合物:VII reacts with an aldehyde of the formula R8CH0 and sodium sulfenylsulfonate of the formula R2S (〇) 〇Na, wherein η, A, B, X, Y, Z, R1 and R8 are as defined above; (C) preparing a compound of formula IV (where R 2. It is printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the note on the back f ... 舄 this page)-S (0) 2R2) and its pharmaceutically acceptable salts and individual isomers When it is a mixture of isomers, (1) a compound of formula NH2P (wherein P is a protecting group) is reacted with an aldehyde of formula R8CH0 and sodium sulfenylsulfonate of formula R2S (0) ONa, followed by deprotection to produce a compound of formula VIII :
本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 470750 經濟部中央標準局員工消費合作社印製 A7 _______ B7_ 五、發明説明(54 ) 其中R 2及R 8各如發明簡述中針對式I之定養;及 (2)式VI1I之化合物與式¥1之化合物反應, 其中η ' A、B、X、γ、Z及R 1各如前定義·, (D )製備式I V化合物(其中尺2°係 一 CH2S (0)2R2及其藥學上可接受之鹽、個別異構 物及異構物混合物時, (1 )式X之化合物This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 470750 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 _______ B7_ V. Description of the invention (54) where R 2 and R 8 are as specified in the brief description of the invention And (2) reacting a compound of formula VI1I with a compound of formula ¥ 1, wherein η ′ A, B, X, γ, Z, and R 1 are each as defined above; Wherein 2 ° is a CH2S (0) 2R2 and its pharmaceutically acceptable salts, individual isomers and mixtures of isomers, (1) a compound of formula X
與式R2S-之硫醇鹽陰離子反應,其中L係脫離基· R 且R 8如前定義,產生式X之化合物:Reacting with a thiolate anion of formula R2S-, where L is a leaving group · R and R 8 is as previously defined, yielding a compound of formula X:
KsKs
(2 )使式X之化合物氧化,產生式X I之化合物:(2) oxidizing a compound of formula X to produce a compound of formula X I:
(3 )式X I之化合物與式V I之化合物反應’其中 η、A、B、X、Y、Z及P1各如前定義; (E )製備式I V化合物(其中R 2 °係氰基 -(C H 2) 2 S (0) 2R2, I : i. . 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -57 一(3) reacting a compound of formula XI with a compound of formula VI 'wherein η, A, B, X, Y, Z and P1 are each as defined above; (E) preparing a compound of formula IV (where R 2 ° is cyano- ( CH 2) 2 S (0) 2R2, I: i.. This paper size applies to China National Standard (CNS) A4 (210X297 mm) -57 一
It-------裝------訂------涑 (請先閱讀背面之注意事項再却寫本頁) 470750 A7 __B7___ 五、發明説明(55 ) -(CH2) 2C (0) OR10- -(C Η 2 ) 2 P ( 0 ) (OR10) 2 ' -(C H 2 ) 2 S ( 0 ) (NR10) R 10 > -(CH2) 2C (0) R11,- (CH2) 2S (0) R1 ,—(C H 2 ) 2 C 0 ) N R 12R 13 - -(CH2) 2S (0) 2NR12R13, -(CH2) 2C (0) NHR 14或—(CH2) 2S (0) 2NHR14)及其藥學上可接受之 鹽、個別異構物及異構物混合物時,(1 )式X I I之醛It ------- install ------ order ------ 涑 (Please read the notes on the back before writing this page) 470750 A7 __B7___ V. Description of the invention (55)-(CH2 ) 2C (0) OR10--(C Η 2) 2 P (0) (OR10) 2 '-(CH 2) 2 S (0) (NR10) R 10 >-(CH2) 2C (0) R11, -(CH2) 2S (0) R1, — (CH 2) 2 C 0) NR 12R 13--(CH2) 2S (0) 2NR12R13,-(CH2) 2C (0) NHR 14 or — (CH2) 2S ( 0) 2NHR14) and pharmaceutically acceptable salts, individual isomers and mixtures of isomers thereof, (1) an aldehyde of formula XII
PHNPHN
CHO 與選自式XIII及XIV化合物反應 R2io、 〇 R2' , R21\丨丨 R2丨R2|/P、 520 ,20 --------裝------訂------線 (請先閱讀背面之注意事項寫本頁) 經濟部中央標準局員工消費合作社印製 XIII xiv其中R 8及R 2 °如前定義,隨後脫保護產生式XV之化合 物CHO reacts with compounds selected from formulas XIII and XIV R2io, 〇R2 ', R21 \ 丨 丨 R2 丨 R2 | / P, 520, 20 -------- install ------ order ---- --Line (please read the notes on the back to write this page first) XIII xiv printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economics where R 8 and R 2 ° are as defined previously, and then deprotected to produce the compound of formula XV
XV (2 )式XV之化合物與式V I之化合物反應’其中 η、A、B、X、Y、Z及R1各如前定義’及 本紙張尺度適用中國國家標率(CNS ) A4規格(210X297公釐) -58 - 470750 A7 ____B7___五、發明説明(56 ) (3 )還原; (F )製備式I V化合物(其中R 2°係 —C H2C HR15R16)及藥學上可接受之鹽,個別異構 物及異構物混合物時, (1)式XI I之醛與式XVI之化合物反應: V=P(Ph)3 R16 XVI 其中R8、R1 5及R1 6如前定義,隨後脫保護產生式 X V I I之化合物: (請先閲讀背面之注意事項再寫本頁) R8 R15XV (2) The compound of formula XV reacts with the compound of formula VI 'where η, A, B, X, Y, Z, and R1 are each as defined previously' and the Chinese standard (CNS) A4 specification (210X297) for this paper size (Mm) -58-470750 A7 ____B7___ V. Description of the invention (56) (3) Reduction; (F) Preparation of compound of formula IV (where R 2 ° -C H2C HR15R16) and pharmaceutically acceptable salts, individual differences When the structure and the mixture of isomers are reacted, (1) the aldehyde of formula XI I reacts with the compound of formula XVI: V = P (Ph) 3 R16 XVI where R8, R1 5 and R1 6 are defined as before, and then deprotected to produce the formula XVII compounds: (Please read the precautions on the back before writing this page) R8 R15
XVII 經濟部中央標準局員工消費合作社印裝 (2)式XVI I之化合物與式VI之化合物反應, 其中η、A、B、X、Y、Z及R1各如前定義,及 (3 )還原; (G )選擇性地將式I V化合物之非鹽形式進一步轉化成 藥學上可接受之鹽; 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -59 - 470750 經濟部中央標準局員工消費合作社印製 A7 __B7五、發明説明(q (Η )選擇性地將式I V化合物之非鹽形式進一步轉化成 非鹽形式;及 (Η)選擇性地將式I V化合物進一步分離成個別立體異 構物。 其中一個具體實例中,本發明半胱胺酸蛋白酶抑制劑 經標記。本發明"經標記之半胱胺酸蛋白酶抑制劑〃係意 指半胱胺酸蛋白酶抑制劑,其附有至少一個元素、同位素 或化學化合物,以偵測鍵結於半胱胺酸蛋白酶之半胱胺酸 蛋白酶抑制劑或半胱胺酸蛋白酶抑制劑。通常,標記分成 三類:a )同位素標記,其可係放射活性或重同位素; b )免疫標記,其可係抗體或抗原;及c )有色或螢光染 料。該標記可摻入半胱胺酸蛋白酶抑制劑之任何一個位置 。例如,標記可附著成爲式1中之"R1"基,或摻入任 何位置之放射同位素。可用之標記之實例包括14C、3H 、生物素、及螢光標記》 藥理學及用途 本發明半胱胺酸蛋白酶抑制劑一旦製成則可輕易篩檢 其抑制效果。該抑制劑先針對半胱胺酸蛋白酶試驗,而如 前述般地選擇抑制劑之定靶基。或者,許多半胱胺酸蛋白 酶及其對應之發色受質係市售者。因此,於半胱胺酸蛋白 酶抑制劑存在或不存在下,使用合成之發色受質使用技藝 界熟知之技術定期檢定各種半胱胺酸蛋白酶,以確認該化 ---------—裝------訂------旅 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 一 60 - 470750 經濟部中央標準局員工消費合作社印製 A7 B7_五、發明説明(58) 合物之抑制作用。隨後使有效之蛋白酶進行動力分析’以 計算κ t值,而測定解離常數。 若化合物抑制至少一種半胱胺酸蛋白酶’則其係本發 明目的之半胱胺酸蛋白酶抑制劑。較佳具體實例係具有可 對至少一種標靶半胱胺酸蛋白酶具有正確之動力參數之抑 制劑。 某些情況下,半胱胺酸蛋白酶半非以純型販售。本發 明之半胱胺酸蛋白酶抑制劑亦可使用生物檢定法檢定效力 。例如,該抑制劑可添加於含有半胱胺酸蛋白酶之細胞或 組織中,並測定生物效果。 其中一個具體實例中,本發明半胱胺酸蛋白酶抑制劑 係經合成或條飾,而減少或預防抑制劑之體內及體外蛋白 水解降解。通常,以係經由併入合成之胺基酸、衍生物或 取代基於半胱胺酸蛋白酶抑制劑中而完成。較少,僅於半 胱胺酸蛋白酶抑制劑內併入一個非天然胺基酸或胺基酸側 鏈,使抑制劑對酶之定靶不致有重大之影響。然而,使用 含有數個定靶殘基之較長鏈半胱胺酸蛋白酶抑制劑之某此 具體實例可容許一個以上之合成衍生物。此外,非天然胺 基酸取代可設計成模擬天然側鏈對該酶之鍵結,而能容許 一個以上之合成取代基。或者,使用胜狀等排物以減低或 預防抑制劑降解。 此具體實例中,可試驗經修飾半胱胺酸蛋白酶抑制劑 對各種已知市售蛋白酶之體外阳抗,以擇定其蛋白水解安 定性。可於動物模型中定期篩檢有希望之候選者,例如使 _本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)~~~ ~ -〇 1 ;- 1._^--------^------1T------# (請先閱讀背面之注意事項寫本頁) 470750 經濟部中央橾準局員工消費合作社印製 A 7 · __B7 ______五、發明説明(59) 用經標記之抑制劑,以決定體內安定性及功效。 可藉本發明抑制劑抑制之選擇性半胱胺酸蛋白酶係於 活性部位具有硫醇基之半胱胺酸蛋白酶。此類蛋白酶係見 於細菌、病毒、真核微生物、植物、及動物體內。半晄胺 酸蛋白酶可大體分離爲屬於四個或更多個不同超科中之一 者。可藉本發明新穎半胱胺酸蛋白酶抑制劑抑制之半胱胺 酸蛋白酶實例包括(但不限於)植物半胱胺酸蛋白酶,諸 如木瓜蛋白酶、無花果蛋白酶、油桐蛋白酶、稻蛋白酶及 彌猴桃蛋白酶:哺乳類半胱胺酸蛋白酶,諸如組織蛋白酶 B、H、 J 、L、N、S、T、0及C (組織蛋白酶C亦 稱爲二肽基肽酶I )、間白素轉化酶(I C E )、經鈣活 化之中性蛋白酶、卡盤酶(c a 1 p a i η ) I及I I ; 博菜徽素水解酶、病毒半胱胺酸蛋白酶,諸如細小核糖核 酸病毒蛋白酶2 A及3 C、口瘡病毒肽鏈內切酶.、心病毒 肽鏈內切酶、豇豆花葉病毒肽鏈內切酶、馬鈴薯y病毒肽 鏈內切酶I及II 、腺病毒肽鏈內切酶、板栗枯萎病病毒 、披膜病毒半胱胺酸肽鏈內切酶,以及脊髓灰質炎病毒及 鼻病毒之半胱胺酸蛋白酶;及已知寄生蟲生命週期所必要 之半胱胺酸蛋白酶,諸如來自瘧原蟲屬、阿朱巴屬、蟠尾 絲蟲屬、錐蟲屬、萊什曼原蟲屬、扭轉線蟲屬、Dietyos-telium、Therileria及血吸蟲屬,諸如併發瘧疾(Ρ· falciparium)、錐蟲(T. cruzi,該酶亦稱爲卡任酶( cruzain)或卡吉盤(cruzipain))、鼠 P. vinckei 及 c. el egans半胱胺酸蛋白酶。可藉半胱胺酸蛋白酶抑制劑 本紙張尺度適用中國國家標準(CNS )八4規格(210X297公瘦) ---------袭--------訂------冰 (請先閱讀背面之注意事項再填寫本頁) -62 - 470750 經濟部中央標準局員工消費合作社印裂 A7 B7__ 五、發明説明(60) 抑制之半胱胺酸蛋白酶之徹底列示參照 Rawlings等人 ’ B i 〇 c h e in. J· 290 .205- 218 (1993) ’ 在此供作參考。 因此,半胱胺酸蛋白酶之抑制劑可有廣於用途。例如 ,本發明抑制劑係用於定量試樣中之半胱胺酸蛋白酶含量 ,因此係用於血液、淋巴、唾液、或其他組織試樣’及細 菌、黴菌、植物、酵母、病毒或哺乳類細胞培養物中之半 胱胺酸蛋白酶定量之檢定及診斷套裝物。較佳具體實例中 ,使用標準蛋白酶受質檢定試樣。添加已知濃度之半胱胺 酸蛋白酶抑制劑,使之鍵結於特定半胱胺酸蛋白酶。再進 行蛋白酶檢定,活性損失係使用熟習此技藝者已知之技術 校正或半胱胺酸蛋白酶活性。 半胱胺酸蛋白酶抑制劑亦可用於去除或抑制試樣中污 染性半胱胺酸蛋白酶。例如,本發明半胱胺酸蛋白酶抑制 劑添加於不希望被污染性半胱胺酸蛋白酶所蛋白質水解降 解之試樣中。或者,本發明半胱胺酸蛋白酶抑制劑可使用 技藝界已知之技術鍵結於層析擔體上,以形成親和力層析 管柱。含有不期望之半胱胺酸蛋白酶之試樣通經管柱以去 除蛋白酶。 較佳具體實例中,半胱胺酸蛋白酶抑制劑可用於抑制 涉及數種疾病之半胱胺酸蛋白酶。尤其,抑制組織蛋白酶 B、L及S、卡任酶(cruzain)、卡盤酶I及 I I 、及間白素1 yS轉化酶。該酶係多種具有組織降解特 色之疾病中溶酶體半胱胺酸蛋白酶之實例。該種疾病包括 本紙張尺度適用中國國家標準(CNS ) A4規格(210:^97公釐) (請先閲讀背面之注意事項再填寫本頁) 裝- 470750 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(61) (但不限於)關節炎、肌肉失癢、發炎、腫瘤發作、絲球 體性腎炎' 寄生蟲所產生之感染、阿爾茲海默氏症、齒齦 疾病、及癌症轉移。例如,哺乳類溶酶體硫醇蛋白酶在蛋 白質胞內降解及某些胜肽激素之加工中扮演重要角色。類 似組織蛋白酶B及L之酶係由腫瘤釋放,且可能渉及腫瘤 轉移。組織蛋白酶L係存於罹病人類滑液及轉形組織中。 相同地,於創傷及發炎中發現由多形核粒性細胞及巨噬細 胞釋放組織蛋白酶B及其他溶酶體蛋白酶。 半胱胺酸蛋白酶抑制劑亦可應用於多種其他病病,包 括(但不限於)齒齦炎、瘧疾、萊什曼體病、絲蟲病、及 其他細菌及寄生蟲產生之感染。化合物亦可應用於病毒疾 病,其係以病毒複製所需之抑制蛋白酶的研究爲主。例如 ,許多細小核糖核酸病毒,包括脊髓灰質炎病毒、足及口 疾病病毒、及鼻病毒編碼切病毒多蛋白所需之半胱胺酸蛋 白酶。 此外,此等化合物可應用於疾病中,包括間白素一 1冷轉化酶(ICE)、可處理間白素1/5之半胱胺酸蛋 白酶;例如,治療肺、氣管、中樞神經系統及周圍薄膜、 眼、耳、關節、骨骼、連結組織、心血管系統(包括心囊 、腸胃及泌尿生殖系統)、皮膚及粘膜之發炎及免疫性疾 病。此類疾病包括在任何身體部位之活性感染的感染性疾 病,諸如腦髓膜炎及輸卵管炎;感染之併發病,包括敗血 性休克、多發性靜脈內凝固,及/或成人呼吸困難症狀; 因抗原、抗體及/或補體沈積所致之急性或慢性發炎;發 本紙張尺度適用中國國家標準(〇呢)六4規格(210父297公釐)_从 ----------t.— (請先閲讀背面之注意事項再填寫本頁) 訂- 線. 470750 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明(62) 炎狀況’包括關節炎、Chalangitis、結腸炎、腦炎、心 內膜炎、絲球體性腎炎、肝炎、心肌炎、胰炎、心包炎、 再灌流損傷及脈管炎。基於免疫之疾病包括(但不限於) 包括T -細胞N及/或巨噬細胞所涉及之狀況,諸如急性 及延時過敏、移植排斥、及移植物一對一宿主之疾病;自 體免疫疾病,包括第I類糖尿病及多發性硬化。骨骼及軟 骨再吸收及造成胞外基質之過度沈積之疾病,諸如組織間 隙肺纖維變性、肝變化、全身性硬化、及瘢瘤形成亦可使 用本發明抑制劑治療。該抑制劑亦可用於治療產生1 L 1 以作爲autocrine生長因子之特定腫瘤,並預防特定腫 瘤所產生之惡病質。Apoptosis及細胞死之亦併有I C.E 及I C E狀活性,可使用本發明抑制劑治療。 此外,本發明半胱胺酸蛋白酶抑制劑可應用於藥物用 途。例如,諸如抗生素或抗腫瘤藥劑之治療藥劑可藉內源 半胱胺酸蛋白酶經由蛋白質分解而滅能,而使所給之藥物 較無效或滅能。例如,已發現博菜霉素、抗腫瘤藥物可藉 博菜黴素水解酶、半胱胺酸蛋白酶水解(參照Sebti等 人,Cancer Res· January 1991 ,第 227—232 頁)。因此,本發明半胱胺酸蛋白酶抑制劑可與療劑一起 給予患者,以增加或增加藥物活性。此種共同給藥法可係 同時給藥,諸如半胱胺酸蛋白酶抑制劑與藥物之混合物, 或個別同時或依序給藥。 此外,已發現半胱胺酸蛋白酶抑制劑可抑制細菌生長 ,尤其是人類病原細菌(參照Bjorck等人,Nature U3 (請先聞讀背面之注意事項再填寫本頁) 、-^ 丁 本紙張尺度適用中國國家標準(CNS ) A4规格(210 X 297公釐) c c -00 470750 經濟部中央標準局員工消費合作杜印製 A7 B7五、發明説明(6$ 337 ·· 385 (1989) )»因此,本發明半胱胺酸 蛋白酶抑制劑可充作抗菌劑,以延阻或抑制特定細菌之生 長。 本發明半胱胺酸蛋白酶抑制劑亦可充作降低細菌半胱 胺酸蛋白酶對宿主生物之損害的藥劑。例如,葡萄球菌生 產使不可溶之彈性蛋白降解之極高活性胞外半胱胺酸蛋白 酶,可能係因於諸如敗血症、敗血性關節炎及耳炎之細菌 感染中所產生之聯結組織破壞。參見Potempa等人,J. Biol. Chem_ 263(6) :2664—2667( 1 9 8 8 )。因此,本發明半胱胺酸蛋白酶抑制劑可用於 治療細菌感染,以防止組織受損。 給藥及藥學組成物 逋常,本發明半胱胺酸蛋白酶抑制劑係經由任何一種 技藝界已知之一般可接受模式給予治療有效量,可係單獨 或與另一種本發明半胱胺酸蛋白酶抑制劑或與另一種療劑 結合給藥。治療有效量可視患者之疾病嚴重性、年齡及相 對健康、所用化合物之效用及其他因素而大幅變化。本發 明半胱胺酸蛋白酶抑制劑之有效量範圍係每日每公斤體重 1 0微克(Mg/kg)至每公斤體1 0毫克(mg/ kg),一般係 10〇Aig/kg / 日至 lmg/kg/ 日。因此,對8 0 k g之人類而言,治療有效量範圍係由 lmg/日至l〇〇mg/日,一般係10mg/日至 1 0 0 m g / 日。 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) ----------裝------訂------冰 (請先閱讀背面之注意事項再填寫本頁) 470750 經濟部中央棣準局員工消費合作社印製 C7 D7 五、創作説明(64) 一般熟習治療該疾病之技藝者可根據個人知識及本發 明之發現而不需過度實驗,即可確定本發明半胱胺酸蛋白 酶抑制劑對特定疾病之治療有效量。 通常,本發明半胱胺酸蛋白酶抑制劑係藉以下路徑中 之一種以藥學組成物形式給藥:經口、全身(例如經皮、 鼻內、肺內、或栓劑)或非經腸(例如肌內、靜脈內、肺 內或皮下)。組成物可採取錠劑、丸劑、膠囊、半固體、 粉末、持續釋放之配製劑、溶液、懸浮液、酊劑、氣溶膠 或任何一種其他適當之組成物,其通常包含本發明半胱胺 酸蛋白酶抑制劑,並結合有至少一種藥學上可接受之輔劑 。可接受之輔劑係非毒性、輔助給藥,且對本發明半胱胺 酸蛋白酶抑制劑之治療優點不致有不良影響。該輔劑可係 任何固體、液體、半固體或(若係氣溶膠組成物)熟習此 技藝者一般可得之氣體輔劑。 固體藥學輔劑包括澱粉、纖維素、滑石、葡萄糖、乳 糖、蔗糖、明膠、麥芽糖、稻、麵粉、白垔、矽膠、硬脂 酸鎂、硬脂酸鈉、甘油單硬脂酸酯、氯化鈉、乾燥之脫脂 奶粉等。液體及半固體輔劑可選自水、乙醇、甘油、丙二 醇及各種油、包括石油、動物、植物或合成來源(例如花 生油、大豆油、礦油、芝麻油等)。較佳液體載體,尤其 是注射溶液,包括水、鹽、葡萄糖水溶液及甘醇。 可使用壓縮氣體,以將本發明半胱胺酸蛋白酶抑制劑 分散成氣溶膠形成。適於此目的之惰性氣體係氮、二氧化 碳、一氧化二氮等。其他適當之藥學載體及其配製劑係述 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)C7XVII Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (2) The compound of formula XVI I reacts with the compound of formula VI, where η, A, B, X, Y, Z, and R1 are each as defined above, and (3) reduction (G) Selectively convert the non-salt form of the compound of Formula IV into a pharmaceutically acceptable salt; This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -59-470750 Central Standard of the Ministry of Economic Affairs A7 __B7 printed by the Bureau ’s Consumer Cooperatives V. Description of the invention (q (Η) selectively converts the non-salt form of the compound of formula IV into a non-salt form; and (ii) selectively separates the compound of formula IV further into individual Stereoisomers. In one specific example, the cysteine protease inhibitor of the present invention is labeled. The "labeled cysteine protease inhibitor" of the present invention means a cysteine protease inhibitor, which Attach at least one element, isotope or chemical compound to detect cysteine protease inhibitors or cysteine protease inhibitors bound to cysteine proteases. Generally, labels are divided into three categories: a ) Isotope labeling, which may be radioactive or heavy isotope; b) immunolabeling, which may be an antibody or antigen; and c) colored or fluorescent dyes. The label can be incorporated at any position of the cysteine protease inhibitor. For example, the label may be attached to the "R1" group in Formula 1, or a radioisotope incorporated in any position. Examples of usable labels include 14C, 3H, biotin, and fluorescent labels. Pharmacology and use Once the cysteine protease inhibitor of the present invention is made, its inhibitory effect can be easily screened. The inhibitor was first tested for cysteine protease, and the target group of the inhibitor was selected as before. Alternatively, many cysteine protease enzymes and their corresponding hair color receptors are commercially available. Therefore, in the presence or absence of a cysteine protease inhibitor, synthetic hair color and texture are used to periodically test various cysteine proteases using techniques well-known in the art to confirm the transformation -------- --- Packing ------ Order ------ Brigade (Please read the notes on the back before filling out this page) This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm)-60- 470750 A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs V. Description of Invention (58) The inhibitory effect of the compound. The effective protease was then subjected to a kinetic analysis' to calculate the κt value and the dissociation constant was determined. If the compound inhibits at least one cysteine protease ', it is a cysteine protease inhibitor for the purposes of the present invention. A preferred embodiment is an inhibitor having the correct kinetic parameters for at least one target cysteine protease. In some cases, cysteine proteases are sold in pure form. The cysteine protease inhibitors of the present invention can also be tested for efficacy using a bioassay. For example, the inhibitor can be added to a cell or tissue containing a cysteine protease and the biological effect can be measured. In one specific example, the cysteine protease inhibitor of the present invention is synthesized or decorated to reduce or prevent proteolytic degradation of the inhibitor in vivo and in vitro. Generally, this is accomplished by incorporating synthetic amino acids, derivatives or substitutions into cysteine-based protease inhibitors. Rarely, an unnatural amino acid or amino acid side chain is incorporated into the cysteine protease inhibitor only, so that the inhibitor does not have a significant impact on the targeting of the enzyme. However, using this specific example of a longer chain cysteine protease inhibitor containing several targeted residues may allow for more than one synthetic derivative. In addition, unnatural amino acid substitutions can be designed to mimic the binding of natural side chains to the enzyme, while allowing more than one synthetic substituent. Alternatively, winches and the like are used to reduce or prevent inhibitor degradation. In this specific example, a modified cysteine protease inhibitor can be tested for its in vitro positive resistance to various known commercially available proteases to determine its proteolytic stability. Prospective candidates can be regularly screened in animal models, such as making _ this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ~~~ ~ -〇1;-1 ._ ^ --- ----- ^ ------ 1T ------ # (Please read the notes on the back to write this page first) 470750 Printed by the Consumers' Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs A 7 · __B7 ______ V. Description of the invention (59) Use labeled inhibitors to determine stability and efficacy in the body. The selective cysteine protease which can be inhibited by the inhibitor of the present invention is a cysteine protease having a thiol group at the active site. Such proteases are found in bacteria, viruses, eukaryotic microorganisms, plants, and animals. Hemiprotease can be roughly separated into one of four or more different subfamilies. Examples of cysteine proteases that can be inhibited by the novel cysteine protease inhibitors of the present invention include, but are not limited to, plant cysteine proteases such as papain, fig protease, tung protease, rice protease, and kiwifruit. Proteases: mammalian cysteine proteases, such as cathepsins B, H, J, L, N, S, T, 0, and C (cathepsin C is also known as dipeptidyl peptidase I), melanin converting enzyme ( ICE), calcium-activated neutral proteases, ca 1 pai η I and II; brussels hydrolyzing enzymes, viral cysteine proteases, such as picornavirus proteases 2 A and 3 C, Aphthous virus endonucleases, cardiovirus endonucleases, cowpea mosaic virus endonucleases, potato y virus peptide endonucleases I and II, adenovirus peptide endonucleases, chestnut wilt Viruses, mantle virus cysteine endopeptidases, and cysteine proteases of polio and rhinoviruses; and cysteine proteases necessary for the life cycle of known parasites, such as from malaria Worms, ajuba, Onchocerca, Trypanosoma, Leishmania, Reverse Nematode, Dietos-telium, Therileria and Schistosoma, such as concurrent malaria (P. falciparium), trypanosoma (T. cruzi, this enzyme is also known as Cruzain or cruzipain), mouse P. vinckei and c. El egans cysteine proteases. Can be borrowed cysteine protease inhibitors This paper size applies to China National Standard (CNS) 8 4 specifications (210X297 male thin) --------- Attack -------- Order ---- --Bing (please read the notes on the back before filling this page) -62-470750 Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs printed A7 B7__ V. Description of the invention (60) Complete list of inhibited cysteine proteases See Rawlings et al. 'Biche in. J. 290.205-218 (1993)' for reference. Therefore, inhibitors of cysteine proteases have a wide range of uses. For example, the inhibitors of the present invention are used to quantify the content of cysteine protease in a sample, and are therefore used in blood, lymph, saliva, or other tissue samples' and bacteria, molds, plants, yeast, viruses, or mammalian cells Assay and diagnostic kit for quantification of cysteine protease in culture. In a preferred embodiment, a standard protease test sample is used. A known concentration of a cysteine protease inhibitor is added to bind to a specific cysteine protease. Protease assays are performed, and loss of activity is corrected or cysteine protease activity using techniques known to those skilled in the art. Cysteine inhibitors can also be used to remove or inhibit contaminating cysteine proteases from samples. For example, the cysteine protease inhibitor of the present invention is added to a sample which is not expected to be hydrolyzed and degraded by a contaminating cysteine protease. Alternatively, the cysteine protease inhibitor of the present invention may be bonded to a chromatographic support using a technique known in the art to form an affinity chromatography column. Samples containing undesired cysteine proteases were passed through the column to remove proteases. In a preferred embodiment, a cysteine protease inhibitor can be used to inhibit cysteine protease involved in several diseases. In particular, it inhibits cathepsins B, L, and S, cruzain, chuckase I and I I, and melanin 1 yS converting enzyme. This enzyme is an example of lysosomal cysteine protease in various diseases with tissue degradation characteristics. This disease includes the Chinese paper standard (CNS) A4 specification (210: ^ 97 mm) of this paper standard (please read the precautions on the back before filling this page) Pack-470750 Printed by the Consumer Cooperative of the Central Standards Bureau, Ministry of Economic Affairs A7 B7 5. Description of the invention (61) (but not limited to) arthritis, itching of muscles, inflammation, tumor attack, filamentous nephritis, infections caused by parasites, Alzheimer's disease, gum disease, and cancer Transfer. For example, mammalian lysosomal thiol proteases play an important role in the intracellular degradation of proteins and the processing of certain peptide hormones. Enzymes like cathepsins B and L are released by tumors and may affect tumor metastasis. Cathepsin L is found in synovial fluid and transformed tissues of patients. Similarly, cathepsin B and other lysosomal proteases are released by polymorphonuclear granulocytes and macrophages during trauma and inflammation. Cysteine inhibitors can also be used in a variety of other diseases, including (but not limited to) gingivitis, malaria, Leishmaniasis, filariasis, and other bacterial and parasitic infections. The compounds can also be used in viral diseases, which are mainly based on the research of protease inhibitors required for viral replication. For example, many parvoviruses include polioviruses, foot and mouth disease viruses, and rhinoviruses that encode the cysteine protease enzymes required to cut viral polyproteins. In addition, these compounds can be used in diseases including melatonin-1 cold invertase (ICE), cysteine proteases that can treat melanin 1/5; for example, the treatment of lung, trachea, central nervous system and Peripheral membranes, eyes, ears, joints, bones, connected tissues, cardiovascular system (including the heart capsule, gastrointestinal and urogenital systems), skin and mucosal inflammation and immune diseases. Such diseases include infectious diseases of active infections in any part of the body, such as meningitis and salpingitis; concurrent infections include septic shock, multiple intravenous coagulation, and / or symptoms of dyspnea in adults; due to antigens Acute or chronic inflammation caused by the deposition of antibodies, antibodies and / or complements; the size of the paper is applicable to the Chinese National Standard (〇 呢) 6 4 specifications (210 father 297 mm) _from ---------- t .— (Please read the notes on the back before filling out this page) Order-Line. 470750 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (62) Inflammatory conditions including arthritis, Chalangitis, colitis , Encephalitis, endocarditis, filamentous nephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury and vasculitis. Immune-based diseases include, but are not limited to, conditions involving T-cell N and / or macrophages, such as acute and prolonged allergies, transplant rejection, and graft-to-host disease; autoimmune diseases, Includes type I diabetes and multiple sclerosis. Bone and cartilage resorption and diseases causing excessive deposition of extracellular matrix, such as interstitial lung fibrosis, liver changes, systemic sclerosis, and keloid formation can also be treated with the inhibitors of the present invention. The inhibitor can also be used to treat specific tumors that produce 1 L 1 as an autocrine growth factor, and to prevent cachexia produced by specific tumors. Apoptosis and cell death also have I C.E and I C E-like activities, which can be treated with the inhibitors of the present invention. In addition, the cysteine protease inhibitor of the present invention is applicable to pharmaceutical applications. For example, therapeutic agents such as antibiotics or antineoplastic agents can be rendered ineffective or inactivated by the endogenous cysteine protease through proteolytic breakdown. For example, it has been found that bleomycin and antineoplastic drugs can be hydrolyzed by bleomycin hydrolase and cysteine protease (see Sebti et al. Cancer Res. January 1991, pp. 227-232). Therefore, the cysteine protease inhibitor of the present invention can be administered to a patient together with a therapeutic agent to increase or increase drug activity. Such co-administration may be administered simultaneously, such as a mixture of a cysteine protease inhibitor and a drug, or they may be administered simultaneously or sequentially. In addition, cysteine protease inhibitors have been found to inhibit bacterial growth, especially human pathogenic bacteria (see Bjorck et al., Nature U3 (please read the precautions on the back before filling out this page),-^ Paper size Applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) cc -00 470750 Employees' cooperation cooperation with the Central Standards Bureau of the Ministry of Economic Affairs Du printed A7 B7 5. Invention Description (6 $ 337 ·· 385 (1989)) »Therefore The cysteine protease inhibitor of the present invention can be used as an antibacterial agent to retard or inhibit the growth of specific bacteria. The cysteine protease inhibitor of the present invention can also be used to reduce the effect of bacterial cysteine protease on host organisms. Harmful agents. For example, staphylococci produce extremely active extracellular cysteine proteases that degrade insoluble elastin, which may be due to associations in bacterial infections such as sepsis, septic arthritis, and otitis Tissue destruction. See Potempa et al., J. Biol. Chem. 263 (6): 2664-2667 (19 8 8). Therefore, the cysteine protease inhibitors of the present invention can be used to treat bacterial infections, to The cysteine protease inhibitor of the present invention is usually administered in a therapeutically effective amount via any one of the generally accepted modes known in the art, and can be used alone or in combination with another half of the present invention. Cysteine protease inhibitors may be administered in combination with another therapeutic agent. A therapeutically effective amount may vary greatly depending on the severity of the patient's disease, age and relative health, the effectiveness of the compound used, and other factors. The cysteine protease inhibition of the present invention The effective amount of the agent ranges from 10 micrograms (Mg / kg) per kilogram of body weight to 10 milligrams (mg / kg) per kilogram of body weight per day, and generally ranges from 100 Aig / kg / day to 1 mg / kg / day. Therefore, For humans of 80 kg, the therapeutically effective amount ranges from 1 mg / day to 100 mg / day, and generally ranges from 10 mg / day to 100 mg / day. This paper standard applies Chinese National Standard (CNS) A4 Specifications (210X297 mm) ---------- install ------ order ------ ice (please read the precautions on the back before filling this page) 470750 C7 D7 printed by the Bureau ’s Consumer Cooperatives V. Creation Instructions (64) General familiarity with treating the disease The skilled artisan can determine the therapeutically effective amount of the cysteine protease inhibitor of the present invention for a specific disease based on personal knowledge and the discovery of the present invention without undue experimentation. Generally, the cysteine protease inhibitor of the present invention is Administration is in the form of a pharmaceutical composition by one of the following routes: oral, systemic (eg, percutaneous, intranasal, pulmonary, or suppository) or parenteral (eg, intramuscular, intravenous, intrapulmonary, or subcutaneous). The composition may be in the form of a tablet, pill, capsule, semi-solid, powder, sustained release formulation, solution, suspension, elixir, aerosol or any other suitable composition, which usually contains the cysteine protease of the present invention Inhibitor, combined with at least one pharmaceutically acceptable adjuvant. Acceptable adjuvants are non-toxic, adjuvant and do not adversely affect the therapeutic advantages of the cysteine protease inhibitors of the present invention. The adjuvant can be any solid, liquid, semi-solid or (if aerosol composition) gas adjuvant generally available to those skilled in the art. Solid pharmaceutical adjuvants include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, maltose, rice, flour, paeony, silicone, magnesium stearate, sodium stearate, glycerol monostearate, chlorinated Sodium, dry skimmed milk powder, etc. Liquid and semi-solid adjuvants can be selected from water, ethanol, glycerol, glycerol and various oils, including petroleum, animal, vegetable or synthetic sources (such as flower oil, soybean oil, mineral oil, sesame oil, etc.). Preferred liquid carriers, especially injectable solutions, include water, salts, aqueous dextrose and glycols. Compressed gas can be used to disperse the cysteine protease inhibitor of the present invention into an aerosol. Inert gas systems suitable for this purpose include nitrogen, carbon dioxide, nitrous oxide, and the like. Description of Other Suitable Pharmaceutical Carriers and Their Formulations The paper size applies to the Chinese National Standard (CNS) A4 (210X297 mm) C7
-D I (請先閱讀背面之注意事項再¥爲本頁) r 470750 C7 D7 經濟部中央梯準局負工消費合作社印製 五、創作説明(65) 於 A.R. Alfonso Reminton’s Pharmacent i ca 1 Sciences 1985 ,第 17 版,Easton, Pa. : Mack Publishing Compang,在此供作參考。 本發明半胱胺酸蛋白酶抑制劑之用量可視配製劑種類 、單元劑型之大小、輔劑種類及其他熟習藥物科學者,已 知之因素而大幅變化。通常,最終組成物係包含 0 · 1 % W至1 0 % W半胱胺酸蛋白酶抑制劑,較佳 l%w至1 〇%w,餘者係輔劑及輔群。 較佳藥學組成物係以單元劑型給藥以供連續處理,或 當特別需要舒緩症狀時,以單元劑型任意給藥。含有本發 明半胱胺酸蛋白酶抑制劑之代表性藥學配製劑係述於以下 實例2 0。 以下實例係用於充分描述使用前述發明之方式,並列 出用於進行本發明各個方面之最大模式。已知此實例絕不 限制本發明之實際範疇,而僅用於說明。本文所列之所有 參考資料在此供作參考。 實.施例 使用下列縮寫習慣以簡化實例。 Mu =嗎啉脲 X a a ! =相對於酶之活性部位係位於Pi位置上之 胺基酸 X a a 2 =相對於酶之活性部位係位於P i位置上之 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)_ 68 _ (請先閱讀背面之注意事項再V鳥本頁) •裝. 訂 i線 470750 C7 五、創作説明(66) 胺基酸 r - -c 0 2 E t = r _胺 基 乙酯 Ύ - -s 0 2 P h =具 有苯 基 終端之r -胺基硕 r - -c 0 2h = r -胺 基 羧酸根 r ~ -P E t = r. -胺 基 膦酸酯 r - -A M =r -胺 基 醯胺 r - -A r (Sub) γ - -胺基芳族化合物(適當地經取 代) β — s 0 2 P h = 具 有 苯 基 取 代 基 之 β - 胺基碉 a 一 s 0 2 P h - 具 有苯 基 取 代 基 之 a — 胺基砚 Η Ρ h 高 苯 基 丙 胺 酸 Ρ S M P = 苯 磺 醯 伸 甲 基 膦 酸 二乙 酯 Ν Ρ 2 = 2 — 某 基 苯 胺 S 〇 2 2 ! N p = 具 有 2 — m 基 終 端 之硼 Ρ h a c = 苯 乙 醯 基 β — A 1 a β — 丙 胺 酸 Μ e 〇 S 11 c = 甲 氧 Μ 珀 醯 基 例 如,1\/111- -P h e - -Η p h - -β - -S 0 2 中 X a a 2 = P h e ( 苯 基 丙 胺 酸 ) 且X a a 1 = 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再,¾寫本頁) 高苯基丙胺酸))根據實例所述之方法轉化成胺基苯 石風。 實施例1 含有r -胺基酯以充作EWG之 本紙張i度適用中國國家標準(CNS ) A4規格(210X297公釐)_ 69 _ 470750 經濟部中央操準局®;工消費合作社印製-DI (Please read the notes on the back before ¥ for this page) r 470750 C7 D7 Printed by the Central Consumers ’Association of the Ministry of Economic Affairs and Consumer Cooperatives. V. Creative Instructions (65) In AR Alfonso Reminton's Pharmacent i ca 1 Sciences 1985, 17th edition, Easton, Pa.: Mack Publishing Compang, here for reference. The dosage of the cysteine protease inhibitor of the present invention may vary greatly depending on the type of formulation, the size of the unit dosage form, the type of adjuvant, and other factors known to those skilled in the pharmaceutical sciences. Generally, the final composition contains 0.1 to 10% W cysteine protease inhibitors, preferably 1% to 10% w, and the rest are adjuvants and auxiliary groups. Preferably, the pharmaceutical composition is administered in a unit dosage form for continuous treatment, or when the symptoms are particularly required to be relieved, it is optionally administered in a unit dosage form. A representative pharmaceutical formulation containing a cysteine protease inhibitor of the present invention is described in Example 20 below. The following examples are provided to fully describe the manner in which the foregoing invention is used, and to list the largest modes for carrying out various aspects of the invention. It is known that this example does not limit the practical scope of the present invention in any way, but is only used for illustration. All references listed in this article are here for reference. Examples Use the following abbreviation conventions to simplify the examples. Mu = Morpholine urea X aa! = Amino acid X aa 2 located at Pi position relative to the active site of the enzyme X = aa 2 = P i position relative to the active site of the enzyme The Chinese paper standard (CNS) ) A4 size (210X297mm) _ 68 _ (please read the precautions on the back before V bird page) • Install. Order i-line 470750 C7 V. Creation instructions (66) Amino acid r--c 0 2 E t = r _aminoethyl hydrazone--s 0 2 P h = r -amino group with phenyl terminal r--c 0 2h = r -aminocarboxylate r ~ -PE t = r. -amine Phosphonate r--AM = r -aminoaminoamine r--A r (Sub) γ--amino aromatic compound (appropriately substituted) β — s 0 2 P h = with phenyl substituent Β-amino group a-s 0 2 P h-a with phenyl substituent a —amino group P h homophenylalanine P SMP = benzenesulfonyl methylphosphonic acid diethyl ester NP 2 = 2 — some aniline S 〇2 2! N p = boron with 2 —m terminal P hac = phenethylfluorenyl β — A 1 a β — alanine M e 〇S 1 1 c = Methoxymethane, for example, 1 \ / 111- -P he--Η ph--β--S 0 2 in X aa 2 = P he (phenylalanine) and X aa 1 = economic Printed by the Ministry of Standards and Staff ’s Consumer Cooperatives (please read the precautions on the back, and write this page). Phenylalanine)) is converted into amine benzene stone according to the method described in the example. Example 1 This paper containing r-amino ester as an EWG is suitable for the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 69 _ 470750 Central Office of the Ministry of Economic Affairs®; printed by the Industrial and Consumer Cooperative
Cl D7 五、創作説明(67) 半胱胺酸蛋白酶抑制劑之合成 除非另有陳述,否則所有反應皆係於室溫下於氬或氮 之惰性氣氛下進行。由二苯甲酮·鈉K e t y 1蒸餾 THF。使用所有其他溶劑及市售試劑,而不加純化。 (S) — 4 — (4 —嗎啉羰基苯基丙胺醯)—胺基— 6 —苯基己酸乙酯一簡稱Mu — P h e — H p h — r — C Ο 2 E t _之合成如下。除非另有陳述,否則所有試劑 皆係得到Aldrich,Inc.。亞磷羧基乙酸三乙酯( 2. 20g,9. 82mmoi?)於 THF(50mi?) 中之溶液於一10 °C下添加0. 3 9 3 g氫化鈉之60% 礦油分散液(9. 8 2mm〇P)。混合物攪拌15分鐘 ,於彼處添加Boc -高苯基丙胺酸醛(Boc-HphH) (2. 3 5 g ) 9 . 82mmo 芡,使用Cl D7 V. Creative Instructions (67) Synthesis of Cysteine Protease Inhibitors Unless otherwise stated, all reactions are performed at room temperature under an inert atmosphere of argon or nitrogen. THF was distilled from benzophenone · sodium K ety 1. All other solvents and commercially available reagents were used without purification. (S) — 4 — (4 —morpholinecarbonylphenylpropylamine hydrazone) —amino — 6 —phenylhexanoic acid ethyl ester—Mu — P he — H ph — r — C Ο 2 E t _ is synthesized as follows . Unless otherwise stated, all reagents were obtained from Aldrich, Inc. A solution of phosphorous carboxytriethyl acetate (2.20g, 9.82mmoi?) In THF (50mi?) At a temperature of 10 ° C was added with 0.39 3g of sodium hydride 60% mineral oil dispersion (9 8 2mm〇P). The mixture was stirred for 15 minutes. Boc-HphH (2. 3 5 g) 9. 82mmo 芡 was added there.
Fehrentz法將B o c_ —高苯基丙胺酸(Synthetech)轉 化成其N,0 —二甲基羥胺,隨後以氫化鋰鋁還原而製備 )於THF (20m$)中之溶液。混合物攪拌45分鐘 。添加IMHCj? (30mJ?)。產物以乙酸乙酯( 50m5)萃取,以飽和NaHC03水溶液(30mj? )洗滌,以Mg S ◦ 4乾燥、過濾並蒸乾。乾燥物質溶於 CH2CJ?2(10m$),並添加HCj?於二噁烷中之 4 . 0M溶液(20mJ?)。混合物攪拌30分鐘。在減 壓下去除溶劑’並泵乾殘留物(S) — 4 -胺基一 6 —苯 基-.2 —己烯酸乙酯鹽酸鹽。 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)_ π _ 一~~~~ 訂 線 (請先閱讀背面之注意事項再丨.烏本頁) 470750 A7 B7 經濟部中央標準局負工消費合作社印製 五、發明説明( 68) 1 1 4 — 嗎 啉 羰 苯 基 丙 胺 酸 ( Μ U — P h e 0 Η 1 1 2 7 4 g 9 8 2 m m 0 义 根 據 Esser, R.等人 1 1 , Ar th r i t i S & Pheumat i sm (1 9 4 I— [) ,3 7, /—ν 1 I 2 3 6 所 述 之 方 法 製 備 ) 溶 於 — 1 0 °C 之 τ H F ( 請 kj 閲 1 1 5 0 m Si ) 中 0 添 加 4 — 甲 基 碼 啉 ( 1 0 8 m 义, 背 1 I 9 8 2 m m 0 ) 隨 後 是 氯 甲 酸 異 丁 酯 ( 之 注 意 1 1 1 1 2 7 m ) 9 8 2 m m 0 i? ) 0 混 合 酐攪 拌1 0分 事 項 再 1 臨 趣 於 彼 處 添 加 先 -.W· 刖 步 驟 所 得 之 ( S ) — 4 -胺 基- 6 — 填 寫 1 裝 苯 基 — 2 — 己 烯 酸 乙 酯 鹽 酸 η·Λ* 鹽 在 D Μ F ( 1 0 m i?) 中之 頁 1 溶 液 隨 後 是 4 — 甲 基 嗎 啉 ( 1 0 8 m 又 1 I 9 8 2 m m 0 ) 〇 混 合 物 攪 拌 1 小 時 〇 添加 1 I 1 Μ Η C ( 5 0 m ) 0 產 物 以 乙 酸 乙 酯 (1 0 0 m芡 1 訂 1 ) 萃 取 以 飽 和 Ν a Η C 0 3水溶液 (E )0 m ^ ) 洗滌, 1 1 1 以 Μ g S 0 4乾燥並以炭 (D A R C 0 ) 脫色,過濾並蒸 1 1 乾 產 生 3 8 0 g 中 間 物 ( 由 Β 0 C 一 高 苯基 丙胺 酸醛 1 開 始 產 率 8 0 % ) 0 、银 1 該 中 間 物 ( 1 4 5 m il 3 0 9 m m ο 艾) 於乙 1 I 醇 ( 2 5 m ) 中 之 溶 液 中 添 加 5 % 於 活 性 碳上 之鈀 ( 1 I 0 5 g ) 〇 混 合 物 於 P a r r 氫 化 器 上 還 原3 6小 時。 1 1 '思 m 濾 該 溶 液 於 減 壓 下 去 除 溶 劑 產 生 1 9 1 g ( 1 1 8 2 % ) 產 物 0 1 1 於 各 試 樣 上 進 行 薄 層 層 析 ( Τ L C ) 〇 藉2 5 4 η τη 1 I 之 U V 光 > 隨 後 係 第 二 酮 、 溴 化 甲 酚 綠 、 或 對茴 香醛 染料 1 I 而 達 成 顯 影 〇 Μ U — Ρ h e — Η Ρ h — r — C 0 2e t之 1 1 1 不紙珉凡度通州T囤囤豕標準(CMS J A4現格(210 X297公釐J -71 - 470750 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明( 69) 1 | 滯 留 因 子 ( R f ) 係 0 .3 5 (5 % M e 0 Η / 1 1 C Η 2 C ^ 1 2 ) 0 1 1 於 Var i an Gem i n i 300MHZ裝置上記錄NMR S 1 1 光 譜 請 1 0 此 例 及 後 續 實 例 之所有 1 Η NMR數據皆記錄成 閲 1 I 相 對 於 內 部 四 甲 基 矽 烷 (以粗 體字 標 示之尖峰 )之每 百萬 讀 背 ιέ 1 分 數 之 1 之份 的 δ 值 0 使 用 以下縮 寫: S ,單重線 ;d, 雙重 注 意 1 線 事 1 t , 二 重 線 q 四重線 ;b r ,寬峰。 星號( *) 項 再 1 表 示 該 訊 息 模 糊 或 隱 藏 於另一 個共 振 下。 填‘ 寫 本 裝 頁 ____» 1 | 實 施 例 2 1 1 含 有 r — 胺 基 硼 以 充 作 E W G 之半 胱 胺酸蛋白 酶抑制 劑之 1 1 合 成 ( S ) — 3 — 第 三 丁氧羰 胺基 — 5 -苯基 -1 - 苯磺 訂 1 醯 戊 烷 ( B 0 C — Η 0 h — r —S 0 2 P h )之合成 1 I P S Μ Ρ ( 8 8 7 m j? ,3 0 3 4m m 〇芡 )於 1 1 1 T Η F ( 1 5 0 m ) 中之溶 液於 0 °C下添加 氫化鈉 ( 1 I 1 2 1 g 6 0 % 礦 油分散 液) 0 混合物攪 拌2 0 分鐘 1 1 * 於 彼 添 加 藉 •、h 刖 述 Fehrentz 及Costro方法 所合成 之 1 1 B 0 C — 高 苯 基 丙 胺 酸 醛(7 .9 9 g , 1 1 3 0 • 3 4 m m 0 Si ) 於T Η F ( 2 0 m 5 ) 中之溶 液。 1 1 溶 液 於 0 °C 下 攪 拌 3 0 分鐘。 添加 1 Μ H C 9.( 1 I 1 0 0 m 9. ) 〇 產 物 萃 取於乙 酸乙 酯 (10 0 mi ) 中, 1 I 以 飽 和 碳 酸 量 鈉 水 溶 液 (10 0 m ),.鹽水 (50 m 9. 1 1 I ) 洗 滌 以 Μ g S 0 4乾燥,過濾 ,並於減壓下去除溶劑 1 1 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -72 - 470750 經濟部中央標準局ωκ;工消費合作社印f. A7 B7五、發明説明(70 ) 。殘留物溶於乙醇(lOOmj?)中,並移至裝有5%在 活性炭上之鈀(0· 92g)之Parr瓶中。混合物 Pa r r裝置上還原24小時。溶液濾經Ce 1 i t e, 在減壓下去除溶劑。產物之T L C顯示有定量產率之單一 產物,Rf=0. 29 (30%乙酸乙酯/己烷),使用 對茴香醛噴酒染成白色。 實施例3 含有r -胺基硼充作EWG之半胱胺酸蛋白酶抑制劑之合 成 (S ) — 3 —胺基_ 5 _苯基一 1 一苯擴酿—戊院鹽 酸鹽(HCi? .Hph-r_S02Ph)之合成。於 Boc-Hph-r-S02Ph ( (12. 24mj?, 30. 34mmoj?)於二氯甲烷(20m义)中之溶液 中添加在二噁烷中之氯化氫(5 Omj?之4 . 0M溶液) 。混合物攪拌9 0分鐘。於減壓下去除溶劑,殘留物溶於 C H 2 C 5 2 ( 5 0 m又)中》溶液小心地添加於攪拌中之 乙醚(500mj?)中。濾出固體,以乙醚(5〇mj?) 洗滌,並於真空中乾燥。 實施例4 含有r胺基砚爲E W G之半胱胺酸蛋白酶抑制劑之合 成 I 11 n 1 n 111 11 線 (請先聞讀背面之注意事項再4寫本頁) 本紙張尺度適用中國國家標準(CNS ) A4规格(210X297公釐)刊 -(〇 470750 經濟部中央橾準扃員工消費合作社印製 A7 ____ B7 _五、發明説明(71) (S) - 3™ (4 -嗎啉羰苯基丙胺醯)—胺基—S 一苯基—1_苯磺醯戊烷(Mu_Ph e— Hph — r — S02Ph)之合成。Mu — PheOH ( 2 . 94g ’ 1〇· 56mm〇5)於THF(75m芡)中之溶液於 一 10 下添加4 一甲基碼啉(1_ 16m]?, 1〇_ 56mm〇e)及氯甲酸異丁酯(1. 37mi2’ 10. 56mm〇i2)。混合物攪拌5分鐘。添加藉 B 〇 c —高苯基丙胺酸醒間之Wadsworth - Emmous縮合 與對甲苯磺酸脫保護所合成之(S) —(E) - 3 -胺基 一 5 —苯基—1 一苯磺醯一 1 一戊烯對甲苯磺酸酯( 5 0 0 g > 1 〇 . 5 6 m m 〇 ^ ),隨後係4-甲基碼啉 (1 - 16mj?,10. 56mm〇i?) » 混合物攪拌 45分鐘。溶液以乙酸乙酯(l〇〇mj)稀釋,以 lMHCj? (2x5〇m$)、飽和碳酸氫鈉水溶液( 5 0 m j?),鹽水(5〇mi2)洗滌,以MgS04乾燥 ,過濾,並於減壓下去除溶劑。殘留物由CH2C又2/乙 醚結晶產生4. 27g/(72%)中間物。1. 17g 此物質(2. O8mm〇i2)溶於乙醇(25m^)中。 溶液移至裝有5%在活性炭上之鈀(0. 30g)之 Pa r r瓶。混合物於室溫下於Pa r r搖動機上氫化過 夜。添加乙酸乙酯於產物之懸浮液中,該產物係由反應混 合物結晶。過濾溶液並於真空中濃縮,隨後由CH2Cj?2 / 己烷再結晶。Μ_ Ρ· =176— 178 °C«TLC( 50% 乙酸乙酯/ CH2Cj?2)Rf=〇. 24。 -η - 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X297公釐) ί--------餐---------、1Τ-------^ (請先聞讀背面之注意事項-Τ4寫本頁) 470750 A7 B7 經濟部中央標準爲員工消費合作社印製 五、發明説明(72) 實施例5 含有r -胺基硕作爲E W G之半胱胺酸蛋白酶抑制劑之合 成 (S) — 3- (4 —嗎啉羰基酪胺醯)—胺基一 5 — 苯基-1 —苯磺醯戊烷(Mu — Ty r — Hph — r_ S〇2Ph)之合成。4 —嗎啉羰基酪胺酸(Mu — Ty r OH ’ 根據 Esser,R.等人,Arthritis & Rheumatism (1994) , 37, 236 之方法合成, 〇 5 0 g - 1 . 70mmoj?)MTHF(10mj?) 中之溶液於一1 0 °C下添加4 一甲基嗎啉( 〇_ 187mj?,l. 70mmoj?)及氯甲酸異丁酯( 0. 2 2 m > 1 . 70mm〇i2) 。5 分鐘後,添加 HCi? · Hph-r-S02Ph (0. 5 7 7 g ' 1 · 70mm〇i?,實例3所述),隨後係4 —甲基碼啉 (0. 187mj?,1. 70mmo 又)。混合物攪拌 45分鐘》添加乙酸乙酯(50mj2)。溶液以 INHCj?、飽和碳酸氫鈉水溶液、及鹽(各30ιηβ) 洗滌,於Mg S 04上乾燥,過濾,並於減壓下去除溶劑 。殘留物由CH2C52 /乙醚沈澱產生0. 58g ( 59%) Mu — Ty r - Hph-r_S02Ph。 MP104— 107〇C°TLC: (10%MeOH/ CH2Cj?2) Rf=0. 59。 1._〆--------t.-------IT------.^ (請先閱讀背面之注意事項再从寫本頁) 本紙張尺度適用中國國家標準(CNS ) A4規格(21 OX297公釐)_ 75 470750 經濟部中央標準局員工消費合作社印製 A7 ________ B7五、發明説明( 實施例6 含有r -胺基砚以充作E W G之半胱胺酸蛋白酶抑制劑之 合成 (S) — 3— (4 —嗎啉羰基—2 —棻基丙胺醯)-胺基—5 —苯基—1_ (2 —棻磺醯)戊烷(Mu — Np2 — Hph — r — S02Np)之合成。將 2 —棻硫 醇(9. 64g/60. 16mmoj?)溶於甲苯( 75m义)中。添加對甲醛(3. 9 7 g > 132mmo 艾)及 HCj? /二噁烷(33m^ 4. OM溶液)。混合物於室溫下攪拌數日。在減壓下去 除溶劑,殘留物懸浮於己烷(200mj?)中,於 M g S 04上乾燥,過濾,並蒸乾。此物質一粗氯甲基2 一某硫醚一與亞磷酸三乙酯(10. 9g,65mmo又 )結合,並回流加熱4小時。混合物冷卻至室溫,以乙醚 (200mj?)稀釋,以IMHCj?、飽和碳酸氫鈉水溶 液、及鹽水(各1 50mj)洗滌,於MgS04上乾燥 ,過濾’,並於真空中濃縮,產生17. 35g(93%粗 產率)2-某基硫代伸甲基膦酸二乙酯。該物溶質 C H 2 C 2 ( 3 0 0 m i?)中並冷卻至0 °C。小心添加過 乙酸(23. 5mj? 3 2 %稀乙酸溶液,Aldrich Chemical Co.)。混合物於溫至室溫下殘留物過液。溶液 以初製、飽和亞酸氫鈉水溶液(1 0 0 m ί )洗滌。隨後 請 閱 背 之 注 意 畢 項 再 填: 寫 本 頁 本紙張尺度適用中國國家襟準(CNS ) A4規格(210X297公釐) 76 - 470750 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明(74) 以數份飽和碳酸氫鈉水溶液洗滌,直至水相變鹼性。有機 相以M g S 0 4乾燥,過濾並於減壓下去除溶劑。於6 0 —2 0 0目矽膠上層析(0 — 1 0%乙酸乙酯/ CH2C j?2)產生 6 · 5 g ( 3 4%)純 Wadsworth -Emmons試劑2 -某磺醯伸甲基膦酸二乙酯,與約等質量 之不純物》TLC (20%乙酸乙酯/CH2Ci?2) Rf = 0.37。 2_棻磺醯伸甲基膦酸二乙酯(3. 91g, 11. 42mmo又)於THF(60mj?)中之溶液於 0 °C下添加氫化鈉(0 . 4 5 7 g 6 0 %礦油分散液) 。混合物攪拌1 5分鐘,於彼添加B 〇 c —高苯基丙胺酸 醛(3. 00g,ll. 42mmo 芡)於 THF( 5mj)中之溶液。混合物攪拌30分鐘。添加 IMHCj? (100m及)。產物以乙酸乙酯( 1 0 0 m $ )萃取,以飽和碳酸氫鈉水溶液(7 5 m ) 、鹽水(50mj?)洗滌,於MgS04上乾燥,過濾, 並於減壓下去除溶劑。殘留物溶於二氯甲烷(1 0m义) 中,於彼添加HCj? /二噁烷(25mj? 4. 0M溶液 )。混合物於室溫下攪拌1小時,倒入乙醚(3 0 0 m义 )中,並過濾。該固體以乙醚(2x5 Omj)洗滌並於 真空中乾燥產生3 . 3 0 g (始自B 〇 c -高苯基丙胺酸 醛,74%) (S)-(E)_3—胺基—5 —苯基一 1 一(2 —菓磺醯)_1一戊烯。 Boc-2 —某丙胺酸(2.68g, -77 - 本紙張尺度適用中國國家標準(CNS ) A4規格(2丨0'乂297公釐) -----.---裝------ΐτ-------m (請先閲讀背面之注意事項再¾寫本頁) 470750 經濟部中央標準局貞工消費合作社印製 A7 B7__ _五、發明説明(μ) 8. 51mm〇P ( S y η ΐ h e t e c h,0 r e g ο η )於 T H F ( 50mj?)中之溶液於_l〇°C下添加4 —甲基碼啉( 0. 936mi?,8. 51mmoj?)及氯甲酸異丁酯( 1. 1 3 m » 8 . 51mmoj?)。混合物攪拌5分鐘 ,於彼添加(S) - (E) - 3-胺基_5 —苯基—1 — (2 —某磺醯)一 1-戊烯(3. 30g’ 8. 5 1 m m 〇 j?),隨後係4 —甲基碼啉(〇. 936 mj?,8. 5 1 m m 〇 )。混合物攪拌45分鐘,以乙 酸乙酯(lOOmi?)稀釋,以 IMHCj? (50m£) 、飽和碳酸氫鈉水溶液(50mj?)、及鹽水(50m义 )洗滌,於Mg S 04上乾燥,過濾,並於減壓下去除溶 劑。中間物(S)-(E)—3—(第三丁氧羰基一2— 菓基丙胺醯基)胺基—5 —苯基-1— (2_棻磺醯)一 1 _戊烯由適當混合物CH2C j?2/乙醚/己烷結晶,產 率 69% 形成之物質(3. 83g ,5. 9〇mmoJ2) 溶於CH2Ci?2(5mi2)中,並以HC^/二噁烷( 1 5 m 4 . 0M溶液)處理。混合物於室溫下攪拌1 小時。溶液於攪拌下倒入乙醚(5 0 〇m又)中並過濾。 固體以乙醚(2 X 5 0mP )洗滌並於真空中乾燥,產生 中間物(S) — (E) _3 -(2-¾两胺酶).,一胺基― 5—苯基一1_(2 —某擴醢)—1—戊嫌,3. 41g ,9 9 %產率。 2. 00g 該物質(3. 42mm〇^)溶於 THF (1 5 m ]?)中,並冷卻至0 °C。添加4 —甲基嗎啉羰基 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)~~~~ IK--------裝-------訂--------線 (請先閱讀背面之注意事項WV4寫本頁) 470750 經濟部中央標準爲員工消費合作社印袋 A7 B7 五、發明説明(76〉 氯(0· 40πιβ,3. 42mmo义)及三乙胺( 0 . 9 5 3 m m ο $ )。混合物於0 °C下攪拌1小時’隨 後於室溫下2小時,添加乙酸乙酯(5 0 m j?)。溶液以 IMHCj? (30mj?)、飽和碳酸氫鈉水溶液( 3 0 m )、鹽水(30m)2)洗滌,於MgS04上乾 燥,過濾並蒸乾,產生1. 58 (69%)中間物(S) —(E) — 3_ (4 —嗎啉羰基—2_棻丙胺醯)胺基— 5 —苯基一1— (2 —棻磺醯)一1—戊烯。TLC :( 50%乙酸乙酯/己烷)Rf=0. 37。 將0. 73g(l. lOmmoi?)此物質溶於乙醇 (20m义)中,並移至裝有5%碳上鈀(0. 3〇g) 之Pa r r瓶中。混合物於Pa r r氫化器上還原36小 時。過濾溶液,並於減壓下去除溶劑。產物於6 0 — 2 0 0目矽膠上管柱層析(5 0%乙酸乙酯/ CH2C $2爲洗 提劑)純化產生0· 14g(19%)純產物,Mu-A Fehrentz method was used to convert a solution of Boc_-homophenylalanine (Synthetech) to its N, 0-dimethylhydroxylamine, followed by reduction with lithium aluminum hydride, in THF (20 m $). The mixture was stirred for 45 minutes. Add IMHCj? (30mJ?). The product was extracted with ethyl acetate (50m5), washed with a saturated NaHC03 aqueous solution (30mj?), Dried over MgS◦4, filtered, and evaporated to dryness. The dried material was dissolved in CH2CJ? 2 (10m $), and a 4.0M solution (20mJ?) Of HCj? In dioxane was added. The mixture was stirred for 30 minutes. The solvent 'was removed under reduced pressure and the residue (S) —4-amino-6-phenyl-.2-hexanoic acid ethyl ester hydrochloride was pump-dried. This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) _ _ _ 1 ~~~~ Thread setting (please read the precautions on the back first, then this page). 470750 A7 B7 Central Bureau of Standards, Ministry of Economic Affairs Printed by the Consumers ’Cooperative Cooperative V. Description of the invention (68) 1 1 4 —Morpholine carbonylphenylalanine (M U — P he 0 Η 1 1 2 7 4 g 9 8 2 mm 0 Meaning according to Esser, R., etc. Human 1 1, Ar th riti S & Pheumat i sm (1 9 4 I— [), 37, / —ν 1 I 2 3 6) Prepared in τ HF (-10 ° C) ( Please kj read 1 1 5 0 m Si) and add 4 — methyl codeline (1 0 8 m meaning, back 1 I 9 8 2 mm 0) followed by isobutyl chloroformate (note 1 1 1 1 2 7 m) 9 8 2 mm 0 i?) 0 mixed with anhydride, stirred for 10 minutes, and then added 1 where (-) W- 刖 step (S) — 4 -amino — 6 — filled in 1 pack Phenyl-2-hexenoate ethyl hydrochloride η · Λ * salt in D MF (10 mi?) Page 1 solution followed by 4-Methylmorpholine (108 m and 1 I 9 8 2 mm 0). The mixture was stirred for 1 hour. 1 I 1 M Η C (50 m) was added. The product was ethyl acetate (1 0 0 m 芡). 1 order 1) Extraction was washed with saturated N a Η C 0 3 aqueous solution (E) 0 m ^), 1 1 1 was dried with Mg S 0 4 and decolorized with charcoal (DARC 0), filtered and steamed 1 1 dried to produce 3 80 g of intermediate (80% yield starting from B 0 C-homophenylalanine 1) 0, silver 1 The intermediate (1 4 5 m il 3 0 9 mm ο) in ethanol 1 I alcohol To the solution in (25 m) was added 5% palladium (1 105 g) on activated carbon. The mixture was reduced on a Parr hydrogenator for 36 hours. 1 1 'm filtered the solution under reduced pressure to remove the solvent to produce 191 g (1182%) of the product. 0 1 1 TLC was performed on each sample. 2 5 4 η UV light of τη 1 I > is then developed by the second ketone, bromocresol green, or p-anisaldehyde dye 1 I U M — P he — Η P h — r — C 0 2e t of 1 1 1 Non-paper Fandu Tongzhou T hoarding standard (CMS J A4 is now available (210 X297 mm J-71-470750 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (69) 1 | Stay The factor (R f) is 0.3 5 (5% Me 0 Η / 1 1 C Η 2 C ^ 1 2) 0 1 1 Record the NMR S 1 1 on a Var i an Gem ini 300MHZ device. The spectrum please 1 0 this All 1 Η NMR data of the examples and subsequent examples are recorded as 1 1 δ value of 1 part of 1 fraction per million read back relative to the internal tetramethylsilane (the peaks marked in bold type) 0 Use The following shrink Write: S, single line; d, double attention 1 line matter 1 t, double line q quartet line; br, wide peak. An asterisk (*) term followed by 1 indicates that the message is blurred or hidden under another resonance. Fill in the writing page____ »1 | Example 2 1 1 1 containing r —aminoboron to act as EWG's cysteine protease inhibitor 1 1 Synthesis (S) — 3 — third butoxycarbonylamino group — Synthesis of 5 -phenyl-1 -benzenesulfonidine 1 pentane (B 0 C — Η 0 h — r —S 0 2 P h) 1 IPS Μ Ρ (8 8 7 mj ?, 3 0 3 4m m 〇 芡) Sodium hydride (1 I 1 2 1 g 60 0% mineral oil dispersion) was added to the solution in 1 1 1 T Η F (150 m) at 0 ° C. The mixture was stirred for 2 0 minutes 1 1 * Add 1 1 B 0 C —Homophenylalanine (7.99 g, 1 1 3 0 • 3 4 mm 0 Si) synthesized by Fe • Hentz and Costro method to T Η Solution in F (20 m5). 1 1 Stir the solution at 0 ° C for 30 minutes. 1 M HC 9. (1 I 100 m 9.) was added. The product was extracted in ethyl acetate (100 mi), 1 I was a saturated sodium carbonate aqueous solution (100 m), and brine (50 m 9). 1 1 I) Wash and dry with MG S 0 4, filter, and remove the solvent under reduced pressure. 1 1 This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) -72-470750 Central Standard of the Ministry of Economic Affairs Bureau ωκ; Printing by Industrial and Consumer Cooperatives f. A7 B7 V. Description of Invention (70). The residue was dissolved in ethanol (100 mj?) And transferred to a Parr bottle containing 5% palladium (0.92 g) on activated carbon. The mixture was reduced on a Parr device for 24 hours. The solution was filtered through Ce 1 ite and the solvent was removed under reduced pressure. The product's T L C showed a single product in quantitative yield, Rf = 0.29 (30% ethyl acetate / hexane), and was dyed white with p-anisaldehyde. Example 3 Synthesis of a Cysteine Protease Inhibitor Containing r-Amine Boron as EWG (S) — 3 —Amine — 5 —Phenyl — 1 —Benzene Expansion — Ethyl Hydrochloride (HCi? .Hph-r_S02Ph) Synthesis. To a solution of Boc-Hph-r-S02Ph ((12. 24mj ?, 30. 34mmoj?) In dichloromethane (20m), was added hydrogen chloride in dioxane (5.0Mm? Of 4.0M solution). The mixture was stirred for 90 minutes. The solvent was removed under reduced pressure, and the residue was dissolved in CH 2 C 5 2 (50 m). The solution was carefully added to the stirred ether (500mj?). The solid was filtered off, Wash with ether (50mj?) And dry in vacuum. Example 4 Synthetic I 11 n 1 n 111 11 thread containing ramine group cysteine protease inhibitor EWG (please read the back first) Please pay attention to this page and write this page again.) This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm)-(〇470750 printed by the Central Ministry of Economic Affairs of the People's Republic of China and the Consumer Consumption Cooperative A7 __ B7 _V. Description of the invention (71) Synthesis of (S)-3 ™ (4-morpholine carbonylphenylpropylamine hydrazone) -amino-S-phenyl-1 -benzenesulfonylpentane (Mu_Ph e—Hph — r — S02Ph). Mu — A solution of PheOH (2.94g '10 .56mm〇5) in THF (75m 芡) was added with 4 -methyl codeline (1-16m] ?, 10-56mmoe) and chloroformic acid under 10 different Butyl ester (1.37mi2 '10. 56mm〇i2). The mixture was stirred for 5 minutes. Addition Wasworth-Emmous condensation of B oc-homophenylalanine and deprotection of p-toluenesulfonic acid (S) — (E)-3 -amino- 5 -phenyl-1 -benzenesulfenamidine-1 -pentene p-toluenesulfonate (500 g > 1 0.56 mm 〇 ^), followed by 4 -Methylcodeline (1-16mj ?, 10.56mm〇i?) »The mixture was stirred for 45 minutes. The solution was diluted with ethyl acetate (100mj), and 1MHCj? (2x50m $), saturated bicarbonate Aqueous sodium solution (50 mj?), Brine (50 mi2), washed with MgS04, filtered, and the solvent was removed under reduced pressure. The residue was crystallized from CH2C and 2 / ether to produce 4.27g / (72%) intermediate 1.17g This material (2.08mm〇i2) was dissolved in ethanol (25m ^). The solution was transferred to a Parr bottle filled with 5% palladium (0.30g) on activated carbon. The mixture was at room temperature Hydrogenated overnight on a Parr shaker. Ethyl acetate was added to a suspension of the product, which was crystallized from the reaction mixture. The solution was filtered and concentrated in vacuo, followed by recrystallization from CH 2 Cj 2 / hexane. Μ_Ρ · = 176—178 ° C «TLC (50% ethyl acetate / CH2Cj? 2) Rf = 0.24. -η-This paper size applies Chinese National Standard (CNS) Α4 specification (210X297 mm) ί -------- Meals ---------, 1Τ ------- ^ ( Please read the precautions on the back first-write this page on T4) 470750 A7 B7 Printed by the Central Standard of the Ministry of Economy for Employees' Cooperatives V. Description of the Invention (72) Example 5 Containing r-Aminosulfone as EWG Cysteine Synthesis of Protease Inhibitors (S) — 3- (4-morpholinecarbonyltyrosine hydrazone) —amino-5 —phenyl-1 —benzenesulfonylpentane (Mu — Ty r — Hph — r_ S〇2Ph) Of synthesis. 4-Morpholine carbonyl tyrosine (Mu — Ty r OH 'was synthesized according to the method of Esser, R. et al., Arthritis & Rheumatism (1994), 37, 236, 0 0 0 g-1. 70 mmoj?) MTHF ( 10mj?) Was added at a temperature of 10 ° C 4 monomethylmorpholine (〇_ 187mj ?, 1. 70mmoj?) And isobutyl chloroformate (0.22 m > 1. 70mm〇i2 ). After 5 minutes, HCI? · Hph-r-S02Ph (0.57 7 g '1 · 70mm〇i ?, described in Example 3) was added, followed by 4-methyl codeline (0. 187mj ?, 1. 70mmo again). The mixture was stirred for 45 minutes. Ethyl acetate (50 mj2) was added. The solution was washed with INHCj ?, a saturated aqueous solution of sodium bicarbonate, and a salt (30 ηβ each), dried over Mg S 04, filtered, and the solvent was removed under reduced pressure. The residue was precipitated from CH2C52 / ether to give 0.58 g (59%) of Mu-Tyr-Hph-r_S02Ph. MP104-107 ° C TLC: (10% MeOH / CH2Cj? 2) Rf = 0.59. 1._〆 -------- t .------- IT ------. ^ (Please read the notes on the back before writing this page) This paper size is applicable to China Standard (CNS) A4 specification (21 OX297 mm) _ 75 470750 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 ________ B7 V. Description of the invention (Example 6 Contains r-aminoamidine to be used as cysteamine of EWG Synthesis of Acid Protease Inhibitors (S) — 3- (4-morpholinecarbonyl-2—fluorenylpropylamine 醯) -amino-5-phenyl—1— (2 —sulfonylsulfonium) pentane (Mu — Np2 — Synthesis of Hph — r — S02Np). Dissolve 2-mercaptan mercaptan (9. 64g / 60. 16mmoj?) In toluene (75m). Add para-formaldehyde (3.97 g > 132mmo Ai) and HCj / Dioxane (33m ^ 4. OM solution). The mixture was stirred at room temperature for several days. The solvent was removed under reduced pressure, and the residue was suspended in hexane (200mj?) And dried on Mg S 04. Filtered and evaporated to dryness. This material-crude chloromethyl 2-a certain sulfide-was combined with triethyl phosphite (19.9 g, 65 mmo again) and heated at reflux for 4 hours. The mixture was cooled to room temperature, and ether ( 200mj?) Diluted to IMHCj ?, Saturated aqueous sodium bicarbonate solution and brine (150mj each) were washed, dried over MgS04, filtered ', and concentrated in vacuo to yield 17.35g (93% crude yield) 2-a thiothiomethylphosphine Diethyl acid. This material was dissolved in CH 2 C 2 (300 mi?) And cooled to 0 ° C. Peracetic acid (23. 5mj? 3 2% dilute acetic acid solution, Aldrich Chemical Co.) was carefully added. Mixture Residues are allowed to flow at room temperature to room temperature. The solution is washed with an initial, saturated aqueous solution of sodium hydrogen sulfite (100 m ί). Please read the notes at the back and fill in the following: Write this page This paper is for China National Standard (CNS) A4 specification (210X297 mm) 76-470750 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (74) Wash with several saturated aqueous sodium bicarbonate solution until the water phase becomes alkaline The organic phase was dried over M g S 0 4, filtered and the solvent was removed under reduced pressure. Chromatography on a 60-200 mesh silica gel (0-10% ethyl acetate / CH2C j? 2) yielded 6 5 g (34%) pure Wadsworth-Emmons reagent 2-a diethyl sulfonylidene methylphosphonic acid, and an impurity of about equal quality TLC (20% ethyl acetate / CH2Ci? 2) Rf = 0.37. A solution of diethylsulfonium methylphosphonic acid diethyl ester (3.91 g, 11.42 mmo) in THF (60 mj?) Was added at 0 ° C, sodium hydride (0.4 5 7 g 6 0% Mineral oil dispersion). The mixture was stirred for 15 minutes, and a solution of Boc-homophenylalanine (3.0 g, 11.42 mmo) in THF (5 mj) was added thereto. The mixture was stirred for 30 minutes. Add IMHCj? (100m and up). The product was extracted with ethyl acetate (100 m $), washed with a saturated aqueous sodium bicarbonate solution (75 m), brine (50 mj?), Dried over MgS04, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (10m sense), and HCj? / Dioxane (25mj? 4.0M solution) was added thereto. The mixture was stirred at room temperature for 1 hour, poured into diethyl ether (300 m), and filtered. The solid was washed with diethyl ether (2x5 Omj) and dried in vacuo to give 3.30 g (from Boc-homophenylalanine, 74%) (S)-(E) _3-Amino-5 —Phenyl-1 1- (2-sulfosulfuronium) _1-pentene. Boc-2 —Alanine (2.68g, -77-This paper size is applicable to China National Standard (CNS) A4 specification (2 丨 0 '乂 297mm) -----.--- Package ---- --ΐτ ------- m (Please read the precautions on the back before writing this page) 470750 Printed by Zhengong Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs, A7 B7__ _V. Description of the invention (μ) 8. 51mm 〇P (S y η ΐ hetech, 0 reg ο η) in THF (50mj?) Solution at -10 ° C was added 4-methyl codeline (0. 936mi ?, 8. 51mmoj?) And chlorine Isobutyl formate (1.13 m »8. 51mmoj?). The mixture was stirred for 5 minutes, and (S)-(E)-3-amino_5 —phenyl — 1 — (2 — a sulfonic acid) was added to the mixture. Ii) 1-pentene (3.30 g '8. 5 1 mm 〇j?), Followed by 4-methyl codeline (0.936 mj ?, 8. 5 1 mm 0). The mixture was stirred for 45 minutes, Diluted with ethyl acetate (100m?), Washed with IMHCj? (50m £), saturated aqueous sodium bicarbonate solution (50mj?), And brine (50m), dried over Mg S04, filtered, and under reduced pressure Remove the solvent. Intermediate (S)-(E) —3- (Third-butoxycarbonyl-2—fructylpropylamino) amino-5 Phenyl-1— (2-sulfenamidine)-1-pentene was crystallized from a suitable mixture of CH2C j? 2 / ether / hexane with a yield of 69% (3. 83g, 5.90mmoJ2). In CH2Ci? 2 (5mi2) and treated with HC ^ / dioxane (15 m 4.0 solution). The mixture was stirred at room temperature for 1 hour. The solution was poured into ether (500 m with stirring). ) And filtered. The solid was washed with diethyl ether (2 X 50 mP) and dried in vacuo to produce the intermediate (S) — (E) — 3 — (2-¾diaminase)., Monoamine — 5-benzene The base 1_ (2—a certain fluorene) —1—pentanthene, 3.41g, 99% yield. 2. 00g of this material (3.42mm) is dissolved in THF (1 5 m)?), And cooled to 0 ° C. The size of the basic paper added with 4-methylmorpholine carbonyl is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) ~~~~ IK -------- installation ---- --- Order -------- line (please read the note on the back WV4 first to write this page) 470750 The central standard of the Ministry of Economic Affairs is the printing bag A7 B7 of the consumer consumer cooperative V. Description of the invention (76> Chlorine (0 · 40πιβ, 3.42mmo) and triethylamine (0.953 mm). The mixture was stirred at 0 ° C for 1 hour 'and then at room temperature for 2 hours, and ethyl acetate (50 m j?) Was added. The solution was washed with IMHCj? (30mj?), Saturated aqueous sodium bicarbonate solution (30m), brine (30m) 2), dried over MgS04, filtered and evaporated to dryness, yielding 1.58 (69%) of intermediate (S ) — (E) — 3_ (4 —morpholinecarbonyl — 2 —propylpropylamine 醯) amino — 5 —phenyl — 1 — (2 —sulfonylsulfonium) — 1-pentene. TLC: (50% ethyl acetate / hexane) Rf = 0.37. 0.73 g (1.0 mmoi?) Of this material was dissolved in ethanol (20 m) and transferred to a Parr bottle containing 5% palladium on carbon (0.30 g). The mixture was reduced on a Parr hydrogenator for 36 hours. The solution was filtered and the solvent was removed under reduced pressure. The product was purified by column chromatography on 60—200 mesh silica gel (50% ethyl acetate / CH2C $ 2 as eluent) to yield 0.14 g (19%) of pure product, Mu-
Np2 — Hph—r — S022 Np ’ 及不純物。TLC =(50% 乙酸乙酯/ CH2Cj?2) Rf=〇. 34。 實施例7 含有r _胺基硼充作EWG之半胱胺酸蛋白酶抑制劑之合 成 3 -乙醯酪胺醯纈胺醯丙胺醯胺基-4 -羥羰基- 1 —苯磺醯丁烷(Ac— Tyr— Va 1— A1 a—Asp 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)_ 79 (請先閲讀背面之注意事項-Τ4寫本頁) 裝·Np2 — Hph—r — S022 Np ′ and impurities. TLC = (50% ethyl acetate / CH2Cj? 2) Rf = 0.34. Example 7 Synthesis of Cysteine Protease Inhibitor Containing r-Amine Boron as EWG Ac— Tyr— Va 1— A1 a—Asp The paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 79 (Please read the precautions on the back first-write this page on T4)
、1T 470750 經濟部中央標準局員工消費合作社印掣 A7 ____________B7五、發明説明(77) —T — SOsPh)之合成。將氫化鈉(〇. 489s 60%礦油分散液,i2_ 23mmoj?)添加於苯磺醯 伸甲基膦酸二乙酯(3. 58g,12_ 23mm〇i?) 於50mJ?THF中之〇°C溶液中。混合物攪拌1 5分鐘 。添加 B〇c-AsPH(iS_Ot— Bu)( 3· 〇4g’ll. 12mmo 爻,藉將 B〇c-Asp (石一 0 — t ~B u)轉化成其N,◦一二甲基羥醯胺並 以氫化鋰鋁還原而製備)於THF ( 1 〇mj?)中之溶液 。混合物攪拌1小時。於彼添加1MHC々 (30mj?) 。產物以乙酸乙酯(1 〇 〇mj?)萃取,以飽和 NaHC03水溶液(30mj?)、鹽水(30m^洗滌 ),於M g S 0 4上乾燥,過瀘,並蒸乾產生中間物。於 矽膠上層析(20 — 30%乙酸乙酯/己烷,梯度洗提) 產生 2. 07g 45%)中間物(S)_(E)— 3 — 第二丁氧鐵胺基—4 _第三丁氧幾基一 1 一苯擴醯一 1 — 丁烯。該物質溶於乙醚(2mj?)中,並以無水對甲苯磺 酸(1· 〇g,5. 87mmoj2)於乙醚(2mj?)中 之溶液處理。混合物於室溫下攪拌過夜,隨後以乙醚( 2 5 m β )稀釋。濾出沈澱物,以乙醚洗滌’並於真空中 乾燥產生0_ 80g(95%)後續中間物(s) — (Ε )一 3 —胺基—4_第三丁氧羰基—1 一苯磺醯_1— 丁 烯一對甲苯磺酸酯。 使用混合酐化學,將該物質偶聯於A c — T y r — V a 1 — A 1 a OH (藉標準化學製備)產生後續中間物 I _ - "丨 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) ----------裝------訂------線 (請先閱讀背面之注意事項再填寫本頁) 470750 經濟部中央標率局員工消費合作社印製 A7 ______B7_五、發明説明(78) (S) —(E) —3 —乙醯酪胺醯纈胺醯丙胺醯胺—4 — 第二丁氧鑛基—1 一苯礎醯—1 一 丁嫌。 該材料以三氟乙酸處理去除天冬胺酸側鏈之第三丁酯 ’產生(E)_.3 —乙醯酪胺醯纈胺醯丙胺醯胺一 4 —經 羰基—1—苯磺醯—1— 丁烯。將〇. 28g ( 0. 444mmoj?)此物質溶於乙醇(l〇mj?)。溶 液移至Parr瓶(裝有5%碳上鈀0· lg)中。溶液 於P a r r氫化器上還原過夜。過濾溶液並於減壓下去除 溶劑。殘留物溶於甲醇(5m$)中並以4〇xl : 1 C H2C j?2/乙醚稀釋,形成膠狀沈澱物,收集於 Buchner漏斗上,產生0. 18 (64%)產量。相對於 A s p殘基之S對R異構物比例以NMR有關Ty r殘基 之芳族區之雙重線之積分計約3:1。 實施例8 以r -胺基羧酸酯爲EWG之半胱胺酸蛋白酶抑制劑之合 成 (S ) - 4 — ( 4 _嗎啉羰苯基丙胺醢)胺基—6 _ 苯基己酸Mu — Ph e— Hph — r — C02H之合成。 根據實例1所述之方法所製之Mu_P h e — Hp h— r -C 0 2 E t ( 0 . 5g’l· 06mm〇i)之溶液中 添加N a Ο H水溶液(1 m 2 M溶液)。4小時後反應 完全。同時添加1MHC)2 (4mi2)與水(l〇mi?) _ _ 1 I’ .— -......... 本紙張尺度適用中國國家標準(CNS) A4規格(2丨OX 297公釐)-81 _ (請先閱讀背面之注意事項再填寫本頁) 470750 A7 B7 經濟部中央標準局員工消費合作社印製 五、 發明説明 ( ) 1 I 〇 產 物 以 C Η 2 C j? 2 ( 2 X 1 0 m ) > T Η F ( 15 ) 1 1 萃 取 以 Μ g S 0 4乾燥 ,於減壓下去除溶劑 ,殘留物 1 1 Μ U — P h e — Η Ρ h — r — c 0 2h泵成固體 •產量= ί | 請 1 0 3 0 ( 6 0 % ) 0 胡 1 1 背 1 | 例 之 1 實 施 9 意 1 1 以 r — 胺 基 膦 酸 酯 爲 E W G 之 半 胱 胺 酸 蛋 白 酶 抑 制 劑之 合 事 項 β 1 1 成 冩 本 1 裝 頁 '—^ 1 I ( S ) — 4 — ( 嗎 啉 羰 基 苯丙 胺 醯 ) 胺 基 — 6 -苯 基 1 1 1 己 膦 酸 二 乙 酯 之合 成法 如 下 〇 伸 甲 基 二 膦 酸 四 乙 酯 ( 1 I 2 0 0 g 6 9 4 m m 0 ) 於 T Η F ( 3 0 m j? ) 訂 I 中 之 溶 液 中 添 加 氫 化 鈉 ( 0 2 7 8 g 6 0 % 礦 油分 散 1 1 | 液 » 6 9 4 m m 0 ) 〇 混 合 物 迅 速 發 泡 隨 後 並澄 清 1 1 I 0 5 分 鍾 後 添 加 Β 0 C — Η P h Η ( 1 8 3 g 5 1 1 線 1 6 9 4 m m 0 ) 於 T Η F ( 5 m 父 ) 中 之 溶 液 。混 合 物 攪 拌 1 小 時 0 添 加 1 Μ Η C Si ( 2 0 m ) 〇 產 物萃 取 1 1 於 乙 酸 乙 酯 ( 5 0 m 又 ) 中 以 飽 和 N a Η C 0 3水溶液 1 | ( 2 0 m i? ) 鹽 水 ( 1 0 m il ) 洗 滌 於 Μ g S 〇 4上 1 I 乾 燥 過 濾 並 蒸 乾 產 生 2 4 6 g ( 8 9 % ) 中 間物 ( 1 1 I S ) ~ < E ) — 4 — 第 三 丁 氧 羰 胺 基 — 6 一 苯 基 — 2 - 己 1 1 烯 膦 酸 二 乙 酯 〇 於 此 物 質 於 C Η 2C ] 1 2 中 之 溶 液 ( 3 m 9. 1 1 ) 中 添 加 1 0 m il 4 0 Μ Η C 二 噁 烷 溶 液 。混 合 1 1 物 於 至 溫 下 攪 拌 1 5 小 時 0 於 減 壓 下 去 除 溶 劑 殘留 物 1 1 本紙張尺度適用中國國家標準(CNSM4規格(加謂公釐)_ 82 一 470750 A7 B7 經濟部中央標準局員工消費合作社印製 五、 發明説明 (80 ) 1 溶 於 甲 醇 ( 1 0 m ) 中 〇 溶 液 倒 入 乙 醚 ( 4 0 0 m il ) 1 1 中 0 沈 澱 物 收 集 於 Buc hn e r 漏斗上 ,以乙醚 (2 X 1 1 2 0 m 2 ) 洗 滌 並 泵 乾 產 生 1 2 5 g ( 6 0 % ) 中 間 1 1 物 請 \ 1 ( S ) 一 ( E ) — 4 — 胺 基 — 6 — 苯 基 — 2 — 己 烯 膦 酸 閲 I | 酯 讀 1 一 乙 鹽 酸 鹽 0 Μ U — P h e 0 Η ( 1 0 4 S 背 1 1 3 7 之 1 4 m m 0 2 ) 於 T Η F ( 1 5 m it ) 中 之 溶 液 於 注 意 1 I — 1 0 °C 下 添 加 4 — 甲 基 嗎 啉 ( 0 4 1 2 m 事 項 1 1 I 3 7 4 m m 0 Si ) 隨 後 係 氯 甲 酸 異 丁 酯 ( % 本 1 0 4 8 6 m il 3 7 4 m m 0 ) 〇 混 合 酐 攪 拌 5 分 頁 1 1 鍾 於 彼 添 加 ( S ) — ( Ε ) — 4 — 胺 基 — 6 — 苯 基 — 2 1 1 一 己 烯 膦 酸 酯 鹽 酸 鹽 ( 1 2 5 g 3 7 4 m m 0 又 ) 1 1 於 D Μ F ( 5 m ) 中 之 溶 液 隨 後 係 4 — 甲 基 嗎 啉 ( 訂 I 0 4 1 2 m il 3 7 4 m m 0 ) 0 混 合 物 攪 拌 1 小 1 1 I 時 0 添 加 乙 酸 乙 酯 ( 5 0 m ) 0 溶 液 以 1 Μ Η C ( 1 1 1 2 5 m ) 、 飽 和 N a Η C 0 3水溶液 (Σ )1 )m \ 1 ) 及水 1 1 線 1 ( 1 0 m ) 洗 滌 於 Μ g S 0 4乾燥 ,過濾 ,並蒸乾 > 以 C Η 2 C义2 / 乙 醚 / 己 烷 ( 3 1 5 m 5 1 5 2 0 0 1 1 ·· 1 0 0 比 例 ) 處 理 時 產 物 形 成 油 > 其 於 乾 燥 時 固 化 成 1 | 1 4 4 g ( 6 9 % ) ( S ) — ( E ) — 4 — ( 4 — 嗎 啉 1 I 羰 苯 基 丙 胺 醯 ) 胺 基 — 6 一 苯 基 — 2 — 己 烯 膦 酸 二 乙 酯 〇 1 i I 0 8 5 g 此 物 質 溶 於 乙 醇 ( 1 0 m ) 中 並 移 至 裝 有 1 1 5 % 於 活性炭 上 之 鈀 之 Ρ a r r 瓶 內 〇 溶 液 於 Ρ a r r 氫 1 化 器 上 還 原 3 6 小 時 0 溶 液 經 C el i t e 過 濾 於 減 壓 下 去 1 1 除 溶 劑 產 生 0 6 6 g ( 7 6 % ) 油 狀 最 終 產 物 0 1 1 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)_ 470750 A7 B7 五、發明説明(81 ) TLC: (5%MeOH/CH2CJ?2) Rf=0. 27 實施例1 Ο ’ 以r 一胺基醯胺爲ewg之半胱胺酸蛋白酶抑制劑之合成 (S) — 3 -(4 —嗎啉羰苯基丙胺醯)—胺基一 6 一苯基己醯胺(Mu — Ph e— Hp h_r— AMB z 1 )之合成。Wadsworth - Emmons試劑辛醯胺鑛基伸甲基 膦酸二乙酯分兩階合成,先將亞磷羧乙酸三乙酯皂化成亞 磷羧乙酸二乙酯,隨後溶於乙酸乙酯中成爲0· 2M濃度 ,以1當量笮胺、0. 1當量4-二甲胺基吡啶、及1當 量二環己基碳化二亞胺處理。此Wadsworth - Emmons試 劑(2. 59g’9. 08mm〇i?)於 THF( 4 〇 m又)中之溶液於0 °C下添加氫化納(〇 . 3 6 3 g 6 0%礦油分散液,9. 08mmoj?)。混合物於室溫 下攪拌1 5分鐘,於彼添加B 〇 c -高苯基丙胺酸醛( 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再,Η本頁) 2. 39g,9. 08mmo^)於 THF(l〇m 义) 中之溶液。混合物攪拌1小時。添加1 Μ H C j?( 3〇mj?)。產物萃取於乙酸乙酯(lOOmj?)中,以 飽和碳酸氫鈉水溶液(50mP)、鹽水(30mj)洗 滌,於MgSO4上乾燥、過濾、濃縮,由乙醚/己烷結 晶產生 1. 81g(51%) (S) — (E)-3 —第三 丁氧羰胺基- 6 -苯基-2 -己烯醯胺苄酯。此物溶於 _____ I________ 本紙張尺度適用中國國家標準(CNS ) A4規格(210X_297公釐_) " — '~~~ 4707^° 經濟部中央標準局員工消費合作社印製 A7 __ B7 7、發明説明(82厂 CH2Ci?2(5mj2)中。於溶液中添加HCi? /二嚼烷 (1 0 m 5 4 . Ο Μ溶液)。混合物於室溫下攪拌3小時 。於減壓下去除溶劑。殘留物溶於甲醇(5mi?)中,並 列入乙醚(3〇〇m又)中,於彼分離油狀中間物(S) 一(E) - 3 —胺基—6 —苯基—2 —己烯醯胺笮酯鹽酸 锻,產率82%(1· 25g) »Mu-PheOH( 1. 05g,3. 78mmoj^)於丁 HF(15m5) 中之溶液於一 10 °c下添加4 —甲基碼啉(〇_ 416 mi?,3· 78mmoi?)及氯甲酸異丁酯( 0. 49mj?,3. 78mmoJ?)。混合物攪拌 1〇 分 鐘,彼於添加(S) -(E) -3_胺基一 6 -苯基一 2 一己烯醯胺笮酯鹽酸鹽(1_ 25g,3. 78mm〇·? )於THF (3mJ2)中之溶液,隨後係4 一甲基嗎啉( 0 4 1 6 m j? » 3 . 7 8 m m o )。混合物攪拌 45 分鐘’添加乙酸乙酯(40m又)。溶液以iMHCj?( l〇mj?)、飽和碳酸氫鈉水溶液(i〇mp)、鹽水( 5mi)洗滌,於MgS04上乾燥,過濾並蒸乾《中間 物(S) — (E) — 3 — (4 —嗎啉羰苯基丙胺醯)胺基 —6 —苯基一2 —己烯醯胺由CH2C又2/乙醚沈澱,產 率 56%。〇. 48g(0. 865mmoj?)此物質溶 於乙醇(1 〇mj )中’並移至裝有5%於活性碳上之鈀 之p a r r瓶中。混合物於P a r r氫化器上還原4小時 。溶液經C e 1 i t e過濾’於減壓下去餘溶劑。最終產 物(Mu-Phe— Hph — r— AMBz 1 )由乙醚/ 本'4張尺度適用中國國家標準(CNS ) A4^ ( 21GX297公釐) I----------裝------訂------線 (請先聞讀背面之注意事項一一::,寫本頁} 470750 A7 B7 經濟部中央標準局員工消費合作社印製 五、 發明説明(83 1 | 己 院 結 晶 得 到 0 2 5 ( 5 2 % ) 。Τ L C - (5 0 %乙 1 1 酸 乙 酯 / 己 烷 ) R f = =( 〕. 4 £ ) > 1 1 | /—n 請 1 ! 實 施 例 1 1 闡 | 基 讀 1 1 以 r 一 胺 醯 胺 爲 E W G 之半 胱 胺 酸蛋 白 酶 抑 制劑 之合成 背 1 | 之 1 注 意 1 | ( S ) — 3 — ( 4 — 嗎啉 羰 苯 基丙 胺 醯 ) 胺基 —6 — 事 項 1 1 I 苯 基 己 醯 胺 苯 酯 ( Μ U — P h e — Η ρ h — r 一 A Μ P h % 本 1 装 I ) 之 合 成 0 Μ U 一 Ρ h e -Η P h -r — C 0 2h ( 頁 •s' 1 1 0 3 0 S 如 實 例 8 般 製備 ) 於 ΤΗ F ( 5 m艾 )中之 1 1 溶 液 於 — 1 0 °c 下 添 加 三 乙胺 ( 9 0 β 1 e q ),隨 1 1 後 添 加 氯 甲 酸 異 丁 酯 ( 0 • 0 8 3 m J? 1 e q ) » 5分 訂 | 鍾 後 添 加 苯 胺 ( 0 0 5 8 m )° 去 除 冷卻浴 ,反應 1 I 於 室 溫 下 攪 拌 2 小 時 0 添 加C Η 2 C芡2 ( 3 0 m 9. )。溶 1 1 I 液 以 1 Μ Η C 及 飽 和 碳 酸氫 鈉 水 溶液 ( 各 1 0 m β)洗 1 1 滌 於 Μ g S 0 4上乾燥 ,並於減壓下去除溶劑。殘留物 線 1 以 E t 2◦碾製, 過濾 並於真空中乾燥產生< 3 . 2 9 g 1 I ( 8 5 % ) 產 物 Μ U — P h e — Η p h — r — AM P h 。 1 I Τ L C ( 1 0 % Μ e 0 Η / c Η 2 1 :又2) R f = 0 · 7 0 ( 1 I 0 大 量 吸 收 U V ( 2 5 4 n m ) , I 2 > 1 1 實 施 例 1 2 1 1 1 以 r — 芳 族 物 充 作 E W G 之半 胱 胺 酸蛋 白 酶 抑 制劑 之合成 1 1 ( S ) — 4 — 胺 苯 基 — 3 j -( 4 — 嗎啉 羰 苯 基 丙胺 醯基) 1 1 本紙張尺度適用中國國家標準(CMS〉A4規格(210X297公釐) -86 - 470750 經濟部中央標準局工消費合作社印製 A7 -____ B7_ 五、發明説明(84 ) 胺基—5 -苯基戊烷鹽酸鹽(Mu — P h e — hPhe-r — C6H4NHZ · HCe)之合成 二本膦(38. 17g’〇. i46moj?)及 4 — 硝基笮基氯(2 5g ’ 〇_ 146m〇e)溶於 CH3CN (lOOmj?)中並回流加熱2小時,使之冷 卻至室溫。反應混合物以E t20 ( 3 0 Om又)稀釋, 濾出白色固體’以Et2〇 (200m$)洗滌,並真空 中乾燥於TLC上產生53. 3g (84%)氯化4~硝 基3Ϊ?基之苯鱗之單點:(Rf=〇. 71,4 : 1 : 1 丁 醇;乙酸:水)elH — NMR(de-DMSO): 5. 4 0 - 5. 50 (2H,d,CH2P,J = 2 0 Hz) ; 7 . 20 — 7. 40 ( 2H,dd,芳族物 );7. 40-7. 80(12H,m,芳族物); 7. 9 0 - 8. 0 0(311,111,芳族物);8_ 10 — 8.20(211,(1,芳族物)。 氯化4_硝笮基三苯鱗(10. 02g, 23. lmmoi)於 CH2Cj?2(100mj?)中之攪 拌懸浮液中添加4 —甲基嗎啉(2. 5 4 m ^ > 23. Ιιηιηοβ)。當所有固體溶解時,添加Boc — H p h Η ( 4 . 04g,15. 4mmoj?) 。24 小時 後,反應混合物以CH2C j?2( 2 0 )稀釋並過濾 。濾液以1MHCJ? (200mS)飽和碳酸氫鈉水溶液 (200mV)洗滌;於MgS04乾燥,過濾並於減壓 下濃縮,產生4. 0 0g粗中間物’其部分藉層析純化( 本紙張尺度適用中國國家標準(CNS ) A4規格(2!〇X297公釐〉_ f ~ I I II ! I I I n ^ II I —^ 線 (請先閱讀背面之注意事項再舄本頁) 470750 五、發明説明(85 ) A7 B7 經濟部中央標準局員工消費合作社印製 梯 度 洗 提 * 1 0 — 3 0 % 乙 酸 乙 酯/ 己 烷) 以 進行中間 物 之 N Μ R 分 析 > ( S ) ~~ 第 二 丁 氧凝 基 一 3 — 胺基—1 — ( 4 — 硝 苯 基 ) — 5 — 苯 基 — 1 -戊 烯 。Τ L C :( 3 0 % E t 0 A c / 己 院 ) R f ~~ 1 0 . 4 ί )° |此物質1 2 * 7 6 S 9 7 2 m m 0 9. ) 於E t 2 0丨 〔2 5 m 芡) 中 之 溶 液 中 添 加 /fm*. m 水 對 甲 苯 嫡 酸 (2 7 g 1 6 0 m m 0 ) 於 E t 2〇 (1 0 m j?) 中之溶液。 1 反 應 攪 拌 1 6 小 時 > 過 濾 以 E t 2 1 0 (2 5 m义)洗滌 固 體 並 於 真 空 中 乾 燥 產 生 2 S ( 6 1 % ) (S )- 3 一 胺 基 — 1 — ( 4 — 硝 苯 基 ) — 5 — 苯 基— 1 —戊烯, 於 T L C 上 爲 單 點 ( R f = =0 . 4 9 > 10%MeOH/ C Η 2c j? 2) 〇 Μ U — P h e 0 Η ( 1 2 9 g 1 4 . 6 3 m m 〇 % ) 於 Τ Η F ( 2 0 m 父 ) 中 之 溶 液中 添 加4 — 甲基碼啉 ( 0 5 1 m 父 > 4 6 3 m m 0 交) 及 氯甲 酸 異丁酯( 0 6 1 m 9 4 6 3 m m 0 又) 0 3分 鐘 後,(S ) — 3 — 胺 基 — 1 — ( 4 一 硝 苯 基 )- 5 -苯 基 - 1 -戊 烯 鹽 tm. 酸 鹽 ( 藉 ( S ) — 3 — 第 三 丁 氧鐵 ί胺 基— 1 一(4 一 硝 苯 基 ) - 5 — 苯 基 — 1 — 戊 烯 先 質之 .由 H C 又 /二噁烷 調 節 之 脫 保 護 而 製 備 » 1 3 4 g ,4 - 2 0 m m 〇 j?) 於 C Η 2 C j? 2 ( 2 0 m 又 ) 中 之 溶 液, 隨 後係 4 一甲基嗎 啉 ( 0 5 1 m > 4 6 3 m m 〇又 ) 。混 合 物邊溫至 室 溫 邊 攪 拌 々扭 m 夜 0 溶 液 混 合物 以 C Η 2 C兑2 ( 1 0 0 m又 ) 稀 釋 > 以 1 Μ Η c 9. ( 2 1 0 0 m 又) 、 飽和 碳 酸氫鈉水 溶 本紙張尺度適用中國國家標準(CNS ) A4規格(2IOX297公g ) 一 88 — I ----------裝------訂------線 (請先閱讀背面之注意事項-"、.寫本頁) 470750 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明(86 ) 液(2 0 Omj?)洗滌,於Mg S〇4乾燥’過濾,並於 減壓下濃縮,產生黃色油。此物由CH2C $2 /乙醚(2 :100,20mj?)結晶產生 1. 00g(40%)( S ) — 3 — ( 4 —嗎啉羰苯基丙胺醯)胺基—1 — ( 4 — 硝苯基)—5_苯基一 1_戊烯之約4 : 1 E/Z混合 物。0. 27g(0. 49mmoj?)此物溶於乙醇( 50m5)中,移至裝有5%碳上鈀(0. l〇g)之 P a r r瓶中,並於Pa r r氫化器上述原8小時。將混 合物過濾,於減壓下去除溶劑。殘留物溶於4 : 1乙醚/ CH2Cj?2( 1 〇〇mj?)中,於彼添加 HCj?/二噁院 (0. 136m^4. 0M 溶液)。濾出產物]\411 — Ph e-Hph-r-C6H4NH2. HCj?並於真空中 乾燥。產量=0. 1 5 g (54%) °TLC: (1〇% 甲醇/CH2CJ?2)Rf=0. 31。 實施例1 3 以β -胺基硕爲E W G之半胱胺酸蛋白酶抑制劑之合成 (S ) — 2 _( 4 —嗎啉羰苯基丙胺醯)胺基一 4 一 苯基一1—苯磺醯丁烷(Mu_Ph e_Hph_/S — S 02P h )之合成。根據前述 Spaltenstein,Carpino, Miyake,及Hopkins所記錄之示意圖製備B o c -高苯 基丙胺酸醇(Bo c-Hph-iS — OH)及(S) - 2 一第三丁氧羰胺基一 1 一甲磺醯氧一 1 一苯基丁烷( (請先閱讀背面之注意事項/ ‘.寫本頁) -裝. -訂 —線_ 本紙張尺度適用中國國家標準(CNS ) A4規格(21〇X297公釐)-89 ~ 470750 A7 B7 五、發明説明(87) (請先閲讀背面之注意事項、寫本頁)、 1T 470750 A7 ____________ B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. V. Synthesis of the invention (77) —T — SOsPh). Sodium hydride (.489s 60% mineral oil dispersion, i2_23mmoj?) Was added to benzylsulfonium methylphosphonic acid diethyl ester (3.58g, 12_23mmoi?) In 50mJ? THF 0 ° C solution. The mixture was stirred for 15 minutes. Add B〇c-AsPH (iS_Ot—Bu) (3.04g'll. 12mmo 爻, by converting B〇c-Asp (石 一 0 — t ~ B u) to its N, ◦ dimethyl hydroxyl Prepare ammonium amine and reduce it with lithium aluminum hydride) in THF (10 mj?). The mixture was stirred for 1 hour. Add 1MHC々 (30mj?) To him. The product was extracted with ethyl acetate (100 mj?), Saturated with a saturated aqueous solution of NaHC03 (30 mj?), Brine (30 m ^), dried over MgS04, dried over water, and evaporated to give an intermediate. Chromatography on silica gel (20-30% ethyl acetate / hexane, gradient elution) yielded 2.07g 45%) intermediate (S) _ (E) — 3 — second butoxyferoxamine — 4 — The third butyloxy-1,1-benzene fluorene, 1-butene. This material was dissolved in ether (2mj?) And treated with a solution of anhydrous p-toluenesulfonic acid (1.0 g, 5.87mmoj2) in ether (2mj?). The mixture was stirred at room temperature overnight and then diluted with diethyl ether (2.5 m β). The precipitate was filtered off, washed with ether and dried in vacuo to yield 0_80g (95%) of the subsequent intermediate (s) — (E) — 3 —amino — 4 — butoxycarbonyl — 1 benzenesulfonium _1- Butene p-toluenesulfonate. Using mixed anhydride chemistry, this substance is coupled to A c — T yr — V a 1 — A 1 a OH (prepared by standard chemistry) to produce subsequent intermediates I _-" 丨 This paper size applies Chinese national standards (CNS ) A4 specification (210X 297 mm) ---------- install ------ order ------ line (Please read the precautions on the back before filling this page) 470750 Ministry of Economic Affairs Printed by the Consumer Standards of the Central Standards Bureau A7 ______B7_ V. Description of the invention (78) (S) — (E) —3 — Ethyl tyramine, valamine, propylamine, amine — 4 — Second butoxymine-based — 1 Benzene base 1 1 suspicion. The material was treated with trifluoroacetic acid to remove the third butyl ester of the aspartic acid side chain to produce (E) _. 3 —Ethylacetamide, valamine, propylamine, amine-1, 4—via carbonyl—1—benzenesulfonium —1— Butene. 0.28 g (0.444 mmoj?) Of this material was dissolved in ethanol (10 mj?). The solution was transferred to a Parr bottle (filled with 5% palladium on carbon 0 · lg). The solution was reduced on a Parr hydrogenator overnight. The solution was filtered and the solvent was removed under reduced pressure. The residue was dissolved in methanol (5m $) and diluted with 40 × l: 1 C H2C j? 2 / ether to form a gelatinous precipitate, which was collected on a Buchner funnel to yield 0.18 (64%) yield. The ratio of the S to R isomers relative to the As p residue is approximately 3: 1 based on the integral of the double line of the aromatic region of the Ty r residue in NMR. Example 8 Synthesis of Cysteine Protease Inhibitor Using E-amino Carboxylate as EWG (S)-4- (4-morpholinecarbonylphenylpropylamine fluorene) amino-6-phenylhexanoic acid Mu — Ph e — Hph — r — C02H Synthesis. To a solution of Mu_P he — Hp h — r -C 0 2 E t (0.5 g'l · 06 mm), prepared according to the method described in Example 1, was added a Na 0 H aqueous solution (1 m 2 M solution) . The reaction was complete after 4 hours. Simultaneously add 1MHC) 2 (4mi2) and water (l0mi?) _ _ 1 I '. — -......... This paper size applies Chinese National Standard (CNS) A4 specification (2 丨 OX 297 Mm) -81 _ (Please read the notes on the back before filling out this page) 470750 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () 1 I 〇 The product is C Η 2 C j? 2 (2 X 1 0 m) > T Η F (15) 1 1 Extraction was dried with MG S 0 4 and the solvent was removed under reduced pressure. The residue 1 1 Μ U — P he — Η Ρ h — r — c 0 2h pump into solid • Yield = ί | please 1 0 3 0 (60%) 0 Hu 1 1 back 1 | example 1 implementation 9 meaning 1 1 r-aminophosphonate is cysteine of EWG Protease inhibitors β 1 1 transcripts 1 Sheet '— ^ 1 I (S) — 4 — (morpholine carbonyl phenylpropyl Amine 醯) Amino-6-phenyl 1 1 1 Diethyl hexaphosphonate is synthesized as follows: Tetraethyl methyldiphosphonate (1 I 2 0 0 g 6 9 4 mm 0) at T Η F (3 0 mj?) Add sodium hydride (0 2 7 8 g 6 0% mineral oil dispersion 1 1 | liquid »6 9 4 mm 0) in the solution of the formula I. The mixture foams quickly and then clarifies 1 1 I 0 After 5 minutes, add a solution of Β 0 C — Η P h Η (1 8 3 g 5 1 1 thread 1 6 9 4 mm 0) in T Η F (5 m parent). The mixture was stirred for 1 hour. 0 Μ Η C Si (2 0 m) was added. The product was extracted 1 1 in ethyl acetate (5 0 m) with saturated Na Η C 0 3 aqueous solution 1 | (2 0 mi?) Brine. (10 m il) washed on MG S04, 1 I dried, filtered and evaporated to yield 2 4.6 g (89%) intermediate (1 1 IS) ~ < E)-4-third butoxy Carboxamido — 6 monophenyl — 2 -hexyl 1 1 diethylenephosphonate. 0 m il 4 0 was added to a solution of this material in C Η 2C] 1 2 (3 m 9. 1 1). M Η C dioxane solution. Mix 1 1 Stir at room temperature for 15 hours 0 Remove solvent residues under reduced pressure 1 1 This paper size applies to Chinese national standards (CNSM4 specifications (plus millimeters) _ 82 470750 A7 B7 Central Bureau of Standards, Ministry of Economic Affairs Printed by the employee consumer cooperative V. Description of the invention (80) 1 Dissolved in methanol (10 m) 0 The solution was poured into ether (400 m il) 1 1 in 0 The precipitate was collected on a Buc hn er funnel with ether (2 X 1 1 2 0 m 2) Wash and pump dry to produce 1 2 5 g (60 0%) Intermediate 1 1 please \ 1 (S) a (E) — 4 — amino — 6 — phenyl — 2 — Hexenephosphonic acid I | Ester 1 Monoethyl hydrochloride 0 Μ U — P he 0 Η (1 0 4 S back 1 1 3 7 1 4 mm 0 2) at T Η F (1 5 m it The solution in) is added with 1-4-methylmorpholine (0 4 1 2 m matter 1 1 I 3 7 4 mm 0 Si) at 1 I — 10 ° C, followed by isobutyl chloroformate (% 1 0 4 8 6 m il 3 7 4 mm 0) 〇 mixed anhydride and stir for 5 pages 1 1 min. (S) — (E) — 4 —amino — 6 —phenyl — 2 1 1 monohexenephosphonic acid Ester hydrochloride (1 2 5 g 3 7 4 mm 0 again) 1 1 The solution in D MF (5 m) is then 4-methylmorpholine (order I 0 4 1 2 m il 3 7 4 mm 0) 0 The mixture was stirred for 1 h 1 1 1 h 0 ethyl acetate (50 m) was added 0 The solution was 1 M C (1 1 1 2 5 m), saturated Na a Η C 0 3 aqueous solution (Σ) 1) m \ 1) and water 1 1 line 1 (1 0 m) washed with MG g 0 4 dried, filtered, and evaporated to dryness> C 以 2 C 2 / ether / hexane (3 1 5 m 5 1 5 2 0 0 1 1 ·· 1 0 0 ratio) The product forms an oil when treated> It solidifies to 1 | 1 4 4 g (6 9%) (S) — (E) — 4 — (4 — Morpholine 1 I carbonylphenylpropylamine 醯) amino-6 monophenyl-2-diethylhexenephosphonic acid 〇1 i I 0 8 5 g This material is dissolved in ethanol (1 0 m) and Into a Parr bottle containing 1 15% palladium on activated carbon. The solution was reduced on a Parr hydrogenator for 36 hours. 0 The solution was filtered through Celite under reduced pressure. 1 1 Solvent removal yielded 0 6 6 g (76%) Oily final product 0 1 1 This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 470750 A7 B7 V. Description of the invention (81) TLC: (5% MeOH / CH2CJ? 2) Rf = 0. 27 Example 1 0 ′ Synthesis of Cysteine Protease Inhibitor with r-Amineamine as ewg (S) — 3-(4 —morpholinecarbonylphenylpropylamine 醯) —amine Synthesis of phenyl-6-phenylhexylamine (Mu — Ph e — Hp h — r — AMB z 1). The Wadsworth-Emmons reagent octylamine-based methylenediphosphonic acid diethyl ester is synthesized in two stages. First, triethylphosphorocarboxacetate is saponified into diethylphosphorocarboxacetate, and then dissolved in ethyl acetate to become 0 ·. 2M concentration, treated with 1 equivalent of amidine, 0.1 equivalent of 4-dimethylaminopyridine, and 1 equivalent of dicyclohexylcarbodiimide. A solution of this Wadsworth-Emmons reagent (2.59g'9.08mm〇i?) In THF (400m) was added with sodium hydride (0.36 3g 6 0% mineral oil dispersion) at 0 ° C. , 9. 08mmoj?). The mixture was stirred at room temperature for 15 minutes, and B oc-homophenylalanine was added to it (printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back, and then click this page) 2. 39g, 9.08mmo) in THF (10m). The mixture was stirred for 1 hour. 1 M H C j? (30 mj?) Was added. The product was extracted in ethyl acetate (100mj?), Washed with a saturated aqueous sodium bicarbonate solution (50mP), brine (30mj), dried over MgSO4, filtered, and concentrated. Crystallization from ether / hexane yielded 1.81g (51% ) (S) — (E) -3 —Third-butoxycarbonylamino-6-phenyl-2 -hexenamidamine benzyl ester. This material is soluble in _____ I________ This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X_297mm_) " — '~~~ 4707 ^ ° Printed by A7 __ B7, a consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 7, Description of the invention (82 plant CH2Ci? 2 (5mj2). HCI? / Dioxane (1 0 m 5 4. 0 M solution) was added to the solution. The mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in methanol (5 mi?) And listed in diethyl ether (300 m 又), and the oily intermediate (S)-(E) -3-amino-6-phenyl-2 was separated therefrom. —Hexenamidamine hydrochloride forging, yield 82% (1.25g) »Mu-PheOH (1.05g, 3.78mmoj ^) in butyl HF (15m5) solution was added at a temperature of 10 ° C 4 —Methyl codeline (〇_ 416 mi ?, 3.78mmoi?) And isobutyl chloroformate (0.49mj ?, 3.78mmoJ?). The mixture was stirred for 10 minutes, and (S)-(E ) -3-Amino-6-phenyl-2 2-hexenamidamine hydrochloride (1-25 g, 3.78mm ··) in THF (3mJ2), followed by 4-methylmorpholine (0 4 1 6 mj? »3. 7 8 mmo). The mixture was stirred for 45 minutes. 'Ethyl acetate (40m) was added. The solution was washed with iMHCj? (10mj?), Saturated aqueous sodium bicarbonate solution (iomp), brine (5mi), dried over MgS04, filtered and evaporated to dryness. (S) — (E) — 3 — (4-morpholinecarbonylphenylpropylamine hydrazone) Amino-6-phenyl-2-hexenamidamine was precipitated from CH2C and 2 / ethyl ether with a yield of 56%. 48g (0.865mmoj?) Of this material was dissolved in ethanol (10mj) and transferred to a parr bottle containing 5% palladium on activated carbon. The mixture was reduced on a Parr hydrogenator for 4 hours. The solution was passed through C e 1 ite is filtered under reduced pressure and the remaining solvent is removed. The final product (Mu-Phe—Hph — r— AMBz 1) is made of ether / this' 4-sheet scale applies Chinese National Standard (CNS) A4 ^ (21GX297 mm) I ---------- install ------ order ------ line (please read and read the notes on the back one by one ::, write this page) 470750 A7 B7 Central Standard of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperatives V. Description of the Invention (83 1 | Owned by the hospital to get 0 2 5 (5 2%). Τ LC-(50% ethyl 1 1 ethyl acetate / hexane) R f = = (). 4 £) > 1 1 | / —n Please 1! Example 1 1 Explanation | Monoamine amine is a synthesis of cysteine protease inhibitor of EWG 1 | -1 Note 1 | (S) — 3 — (4 — morpholine carbonylphenylpropylamine hydrazone) Amine — 6 — Item 1 1 I Synthesis of Phenylhexamidine Phenyl Ester (Μ U — P he — Η ρ h — r-A Μ P h% of this product) 1 Μ U-P he-Η P h -r — C 0 2h (Page • s' 1 1 0 3 0 S was prepared as in Example 8) Triethylamine (9 0 β 1 eq) was added to the 1 1 solution in T F (5 m Ai) at -10 ° C, with 1 1 Then add isobutyl chloroformate (0 • 0 8 3 m J? 1 eq) »5 min order | Add aniline (0 0 5 8 m) after 15 minutes. Remove the cooling bath, react 1 I stir at room temperature for 2 hours 0 Add C Η 2 C 芡 2 (30 m 9.). The 1 1 I solution was washed with 1 MΗC and a saturated sodium bicarbonate water solution (each 10 m β), washed with 1 1 and dried on M g S 0 4, and the solvent was removed under reduced pressure. The residue line 1 was milled with E t 2 ◦, filtered and dried in vacuum to produce < 3.2 9 g 1 I (85%) product MU — Phe — e ph — r — AM Ph. 1 I Τ LC (1 0% Μ e 0 Η / c Η 2 1: again 2) R f = 0 · 7 0 (1 I 0 absorbs UV (2 5 4 nm) in a large amount, I 2 > 1 1 Example 1 2 1 1 1 Synthesis of Cysteine Protease Inhibitors with R — Aromatics as EWG 1 1 (S) — 4 — Aminophenyl — 3 j-(4 —Morpholinecarbonylphenylpropylamine amidino ) 1 1 This paper size applies to Chinese national standards (CMS> A4 size (210X297 mm) -86-470750 Printed by the Industrial and Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 -____ B7_ V. Description of the invention (84) Amine-based -5- Synthesis of diphenylphosphine (38. 17g'〇.i46moj?) And 4-nitronitrochloro (2 5g '〇_) from phenylpentane hydrochloride (Mu — P he — hPhe-r — C6H4NHZ · HCe) 146m〇e) was dissolved in CH3CN (100mj?) And heated at reflux for 2 hours, allowed to cool to room temperature. The reaction mixture was diluted with Et20 (300m) again, and the white solid was filtered off as Et20 (200m $) Washed and dried in vacuo on TLC to produce 53.3 g (84%) of benzene scale of 4 ~ nitro 3 fluorenyl chloride single point: (Rf = 0.71, 4: 1: 1 butanol; acetic acid : Water) elH — NMR (de-DMSO): 5. 4 0-5. 50 (2H, d, CH2P, J = 2 0 Hz); 7. 20 — 7. 40 (2H, dd, aromatics) ; 7. 40-7. 80 (12H, m, aromatics); 7. 9 0-8. 0 0 (311, 111, aromatics); 8_ 10 — 8.20 (211, (1, aromatics) 4) Nitrosyltriphenyl chloride (10. 02g, 23. lmmoi) in a stirred suspension in CH2Cj? 2 (100mj?) Was added with 4-methylmorpholine (2.5 5 m ^ & gt 23. Ιηιηοβ). When all solids are dissolved, add Boc — H ph Η (4.04 g, 15.4 mmoj?). After 24 hours, the reaction mixture was diluted with CH2C j? 2 (20) and filtered. The filtrate was filtered with 1MHCJ? (200mS) saturated sodium bicarbonate aqueous solution (200mV) was washed; dried in MgS04, filtered and concentrated under reduced pressure to produce 4.00g of crude intermediate 'part of which was purified by chromatography (this paper scale applies to Chinese national standards (CNS) A4 specifications (2! 〇X297mm> _ f ~ II II! III n ^ II I — ^ cable (please read the precautions on the back before clicking this page) 470750 V. Description of the invention (85) A7 B7 Gradient elution printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs * 1 0 — 30% ethyl acetate / hexane) for N MR analysis of intermediates> (S) ~~ Second butoxy condensing group 3 —amino group 1 — (4 — nitrophenyl) — 5-Phenyl-1-pentene. Τ LC: (30% E t 0 A c / 院 院) R f ~~ 1 0. 4 ί) ° | This substance 1 2 * 7 6 S 9 7 2 mm 0 9.) in E t 2 0 丨〔2 5 m 芡) was added to the solution in /fm*.m water p-toluenic acid (27 g 1 60 mm 0) in E t 2〇 (10 mj?). 1 Reaction stirred for 16 hours > filtered to wash the solid with E t 2 1 0 (2 5 m) and dried in vacuum to produce 2 S (6 1%) (S)-3 monoamine — 1 — (4 — Nitrophenyl) — 5 —phenyl — 1 —pentene, single point on TLC (R f == 0. 4 9 > 10% MeOH / C Η 2c j? 2) 〇Μ U — P he 0 Η (1 2 9 g 1 4. 6 3 mm 〇%) was added to the solution in Τ Η F (2 0 m parent) 4-methyl codeline (0 5 1 m parent> 4 6 3 mm 0 cross ) And isobutyl chloroformate (0 6 1 m 9 4 6 3 mm 0 again) After 3 minutes, (S) — 3 —amino — 1 — (4 mononitrophenyl)-5 -phenyl-1 -Pentene salt tm. Acid salt (borrowed by (S) — 3 — third butoxy iron amine — 1 — (4-nitrophenyl) — 5 — phenyl — 1 — pentene precursor. By HC / Dioxane-regulated deprotection to prepare »1 3 4 g, 4-20 mm 〇j?) In C Η 2 C j? 2 (20 m), followed by 4-monomethyl Morpholine (0 5 1 m > 4 6 3 m m 〇 and). The mixture was stirred while warming to room temperature. The solution mixture was diluted with C Η 2 C to 2 (100 m) again > with 1 M Η c 9. (2 1 0 0 m), saturated carbonic acid Sodium hydride water-soluble paper size applicable to Chinese National Standard (CNS) A4 specifications (2IOX297 g) 88-I ---------- installation ------ order ------ line ( Please read the precautions on the back-", write this page) 470750 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economy Dry'filtered and concentrated under reduced pressure to give a yellow oil. This product was crystallized from CH2C $ 2 / ether (2: 100, 20mj?) To produce 1. 00g (40%) (S) — 3 — (4 —morpholinecarbonylphenylpropylamine hydrazone) amino — 1 — (4 — nitrate Phenyl) -5_phenyl-1_pentene in an approximately 4: 1 E / Z mixture. 0.27g (0.49mmoj?) This material was dissolved in ethanol (50m5), transferred to a Parr bottle filled with 5% palladium on carbon (0.10g), and the original 8 above in a Parr hydrogenator. hour. The mixture was filtered and the solvent was removed under reduced pressure. The residue was dissolved in 4: 1 ether / CH2Cj? 2 (100mj?), And HCj? / Dioxin (0.136m ^ 4.0M solution) was added thereto. The product was filtered off] \ 411 — Ph e-Hph-r-C6H4NH2. HCj? And dried under vacuum. Yield = 0.15 g (54%) ° TLC: (10% methanol / CH2CJ? 2) Rf = 0.31. Example 1 3 Synthesis of Cysteine Protease Inhibitor Using β-Aminosulfone as EWG (S) — 2 — (4-morpholinecarbonylphenylpropylamine 醯) Amine — 4 —Phenyl — 1 —Benzene Synthesis of sulfobutane (Mu_Ph e_Hph_ / S — S 02P h). According to the schematic diagrams recorded by the aforementioned Spaltenstein, Carpino, Miyake, and Hopkins, B oc -Homo-phenylalanine (Bo c-Hph-iS — OH) and (S)-2-third butoxycarbonylamino-1 Methanesulfonyloxy-1 monophenylbutane ((Please read the precautions on the back / '.Write this page)-Install.-Order-thread _ This paper size applies to China National Standard (CNS) A4 specifications (21 〇X297mm) -89 ~ 470750 A7 B7 V. Description of the invention (87) (Please read the precautions on the back and write this page)
Bo c-Hph — 万-OMs或Bo c -高苯基丙胺酸醇 甲磺酸酯)《Boc —高苯基丙胺酸(10. 29g, 36. 84mmoj2)於 THFClOOmj?)中之溶液 於一10 °C下添加4 -甲基嗎啉(4. 05m又, 3 6 84mmoj?)及氯甲酸異丁酯(4_ 7 8 m . 3 6. 84mmoj?) »溶液攪拌10分鐘,之後過濾。 濾液小心添加於硼氫化鈉(2 . 7 7 g, 73. 67mm〇j?)於水(lOOmj?)中之 〇°C 攪動 溶液中。混合物攪拌3 0分鐘。添加飽和碳酸氫鈉水溶液 (200m 义)。產物以 CH2Cj?2(2xl00mj2) 萃取,以M g S Ο 4乾燥,過濾,於減壓下去除溶劑,產 生9. 78g (100%) Bo c -高苯基丙胺酸醇。 TLC : (30%乙酸乙酯/己烷)Rf=0. 15。 5· 83g (21. 97mmoj?)此物質溶於 CH2C52(150mj?)中,冷卻至0°C,並以甲磺醯 氯(4. 15m又,53. 71mm〇5)及三乙胺( 9. 24mj?,66. 3mmoj?)處理。混合物攪拌 經濟部中央標準局員工消費合作社印製 3 0分鐘。添加水(1 0 0 m 3?);混合物劇烈攪拌。分 離有機相,以M g S 04乾燥,過濾,並於減壓下去除溶 劑,產生 7. 31g(97%)產量。TLC: (30% 乙酸乙酯/己烷)Rf=0. 2 1。採用類似方法以製備 對應之B 〇 c-Hph — A — OH之苯磺酸酯。 硫苯酚(0. 653m 又,6_ 36mmoJ?)於 THF(5mJ?)中之溶液中添加氫化鈉(0. 254g _ . I_—.— _ 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)_ 470750 經濟部中央標準局員工消費合作社印製 A7 B7 _____五、發明説明(⑽) ’6. 36mmoj?,60%礦油分散液)。混合物攪拌 1 0分鐘。添加B 〇 c -高苯基丙胺酸醇苯磺酸酯( 2 · 58g,6. 36mmo 芡)於 THF(5mj?)中 之溶液。溶液於室溫下攪拌1 〇分鐘。隨後添加甲醇( 2 m j?) ’混合物回流加熱1小時。將溶液冷卻,以 1M NaOH(25nlj^)稀釋,以CH2C义2( 1 OOmJ?)萃取’以MgS04乾燥,過濾,並於減壓 下去除溶劑。殘留於溶於CH2C$2(35mi?)中並冷 卻至0°C。溶液中添加4 一氯過笮酸(3. 7 1 g 1 13. 99mmo$,估計過酸含量65%)。混合物攪 拌1小時,添加1 0 % N a Ο Η ( 3 5 m又)及飽和 NaHS03水溶液(35mj?)。混合物以CH2Cj?2 (3x50mj?部分)萃取,以MgS04乾燥,過濾, 並於減壓下去除溶劑產生蠟狀固體(S ) - 2 -第三丁氧 羰胺基—4 —苯基—1—苯磺醯丁烷。TLC : (30% 乙酸乙酯/己烷)Rf=0. 32。1. 25g此物質溶 於 CH2C^2(5mJ2)中並以 HCi? /二噁烷(5mj? 4. 0M溶液)處理。混合物於室溫下攪拌2小時。溶液 倒入乙醚(200mj?)中,形成油狀殘油留物。丟棄上 清液。殘留物再溶於CH2C$2( 1 Omj?)中,並倒入 乙醚(200m又)中。析出中間物(S) — 2 —胺基一 4 —苯基一 1 -苯磺醯丁烷鹽酸鹽。濾出固體,並於真空 中乾燥產生0. 4〇g材料(38%產率,始自B 〇 c — 高苯基丙胺酸醇苯磺峻酯。 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) ---------t--------IT------i (請先閲讀背面之注意事項声.寫本頁)Bo c-Hph — 10,000-OMs or Bo c-homophenylalanine mesylate) "Boc-homophenylalanine (10. 29g, 36. 84mmoj2) in THFClOOmj?) In a 10 Add 4-methylmorpholine (4.05m, 3 6 84mmoj?) And isobutyl chloroformate (4_7 8 m. 3 6.84mmoj?) At ° C »The solution was stirred for 10 minutes, and then filtered. The filtrate was carefully added to a 0 ° C agitated solution of sodium borohydride (2.77 g, 73.67 mm) in water (100 mj ·). The mixture was stirred for 30 minutes. Add a saturated aqueous sodium bicarbonate solution (200m). The product was extracted with CH2Cj? 2 (2xl00mj2), dried over MgS04, filtered, and the solvent was removed under reduced pressure, yielding 9.78g (100%) of Boc-homophenylalaninol. TLC: (30% ethyl acetate / hexane) Rf = 0.15. 5.83g (21. 97mmoj?) This material was dissolved in CH2C52 (150mj?), Cooled to 0 ° C, and treated with methanesulfonyl chloride (4.15m, 53.71mm05) and triethylamine (9 24mj ?, 66.3mmoj?). Mixing and mixing 30 minutes printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Water (100 m 3?) Was added; the mixture was stirred vigorously. The organic phase was separated, dried over MgS04, filtered, and the solvent was removed under reduced pressure, yielding 7.31 g (97%). TLC: (30% ethyl acetate / hexane) Rf = 0.21. A similar method was used to prepare the corresponding Boc-Hph-A-OH benzenesulfonate. Add thiophenol (0. 653m, 6_ 36mmoJ?) To THF (5mJ?) In a solution of sodium hydride (0. 254g _. I_—. — _ This paper size applies Chinese National Standard (CNS) A4 specification (210X297 Mm) 470 750 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs _____ V. Invention Description (⑽) '6. 36mmoj ?, 60% mineral oil dispersion). The mixture was stirred for 10 minutes. A solution of Boc-homophenylalanine benzene sulfonate (2.58 g, 6.36 mmo 芡) in THF (5 mj?) Was added. The solution was stirred at room temperature for 10 minutes. Methanol (2 mj?) 'Was then added and the mixture was heated at reflux for 1 hour. The solution was cooled, diluted with 1M NaOH (25nlj ^), extracted with CH2C2 (100mJ?) ', Dried over MgS04, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in CH2C $ 2 (35mi?) And cooled to 0 ° C. Add 4 monochloroperacetic acid (3.71 g 1 13.99mmo $, estimated peracid content 65%) to the solution. The mixture was stirred for 1 hour, and 10% NaOH (35 m) was added and a saturated aqueous NaHS03 solution (35 mj?) Was added. The mixture was extracted with CH2Cj? 2 (3x50mj? Part), dried over MgS04, filtered, and the solvent was removed under reduced pressure to give a waxy solid (S)-2-tert-butoxycarbonylamino-4 -phenyl-1- Toluene butane. TLC: (30% ethyl acetate / hexane) Rf = 0. 32. 1. 25g This material was dissolved in CH2C ^ 2 (5mJ2) and treated with HCi? / Dioxane (5mj? 4.0M solution). The mixture was stirred at room temperature for 2 hours. The solution was poured into ether (200mj?) To form an oily residue. Discard the supernatant. The residue was redissolved in CH2C $ 2 (1 Omj?) And poured into diethyl ether (200m). The intermediate (S) is precipitated as 2-amino-4-phenyl- 1-benzenesulfobutane hydrochloride. The solid was filtered off and dried in a vacuum to produce 0.40 g of material (38% yield, starting from B oc — homophenylalanine benzyl sulfonate. This paper is dimensioned to the Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) --------- t -------- IT ------ i (Please read the notes on the back first. Write this page)
I 470750 經濟部中央標準局員工消費合作社印製 A7 B7 _______五、發明説明(89 ) Mu-PheOH (〇. 3 4 2 g * 1. 23mmoJ2)於 THF(l〇mj?)中之溶液於 —10 °C下添加4 —甲基嗎啉(0. 135mi?’ 1. 23mmoj2)及氯甲酸異丁酯(〇. 159m义’ 1. 2 3 m m 〇 32 )。混合物攪拌10分鐘,添加(S) 一 2-胺基—4 一苯基一 1 一苯磺醯丁烷鹽酸鹽( 4 0 g > 1 . 23mm〇i2),隨後係4 —甲基嗎啉( 0. 135mi2,l. 23mmoj?)。混合物攪拌 45 分鐘。添加lMHCj? (15mi?)。產物以乙酸乙酯( 3〇mi?)萃取,以飽和碳酸氫鈉水溶液(15m5)、 鹽水(1 5mi?)洗滌,以MgS04乾燥,過濾,並於 減壓下去除溶劑。最終產物Mu — P‘h e-Hph —汐一 S02Ph 重 0. 68g (100% 產率)。 實施例1 4 以石-胺基硼充作E W G之半胱胺酸蛋白酶抑制劑之合成 (S) _2 -第三丁氧羰胺基一 4 —苯基一 1 一( 1 三甲基甲矽烷乙基)一磺醯基丁烷(Boc — Hph —召一S〇2CH2CH2TMS)之合成 2 —三甲 基甲矽烷乙硫醇(0. 86g,6. 41mmoj?)如前 述 Anderson, Ranasinghe,Palmer,及 Fachs 所述般地 合成)於THF ( 1 〇mj?)中之溶液中添加氫化鈉( 0_ 256g,6. 41mm〇i,60%礦油分散液) 本紙張尺度適用中國國家標準(CNS ) A4規格(210x^97公釐丁 —Q2 - :--------1-------IT------▲ (請先閲讀背面之注意事項具 冩本頁) 470750 經濟部中央標準局負工消費合作社印裝 A7 B7 . - I I - ' - ' -.—.I -五、發明説明(90 ) 。混合物攪拌1 〇分鐘。添加B o c -高苯基丙胺酸醇甲 擴峻酯(2. 00g,5. 82mmo芡,如前述實例 1 3所述般地合成)。溶液攪拌2小時。添加乙酸乙酯( 50m$) *溶液以各3〇m$之1MHCP、飽和碳酸 氫鈉水溶液、及鹽水洗滌,以M g S 0 4乾燥、過濾、並 於減壓下去除溶劑,產生中間物(S) _2 —第三丁氧幾 胺基一 4-苯其丁基三甲基甲矽烷乙硫醚。TLC:( 5%乙酸乙酯/己烷)Rf=0. 22。此物溶於 CH2Cj?2(50mj2),冷卻至一10 °C,並以 4 -氯 過笮酸(3. 24g,12. 22mmo又,估預65% 過酸含量)處理。混合物攪拌過夜。過濾懸浮液,小心地 將飽和NaHS03水溶液(4〇mj?)及飽和碳酸氫鈉 水溶液(5 0 m j )添加於濾液中。分離有機相,以 Mg SO 4乾燥,過濾,並於減壓下去除溶劑’由甲磺酸 酯定量地回收產生產物B 〇 c_Hp h —冷一 S02CH2CH2TMS。TLC : ( 3 0% 乙酸乙酯 / 己烷)Rf=〇. 49。 實施例1 5 以沒-胺基硕爲EWG之半胱胺酸蛋白酶抑制劑之合成(S) - 2_ (4 —嗎啉羰苯基丙胺醯)胺基一 1—氯甲 磺醯一4 —苯基丁烷(Mu-Ph e — Hp h —召一 S02CH2Ci2)之合成。B〇 c — Hph-/3 — 本紙張尺度適用中國國家標準(CNS ) A4规格(210 XM7公釐) (請先閲讀背面之注意事項7、寫本頁) 裝. -訂 線 470750 A7 B7 經濟部中央擦準局員工消費合作杜印製 五、 發明説明 ( )1 1 1 S 0 2 C Η 2 C Η 2 Τ Μ S (0 . 9 ( )g 1 1 2 1 8 m m 0 > 如 實 例 1 4所 述) 於 Τ Η F ( 2 ΙΪ1 1 1 ) 中 之 溶 液 中 添 加 氟 化 四 丁 Jbh m (8 .7 m β 1 0 Μ ✓-N I 請 1 T Η F 溶 液 ) 及 數 種 分 子 篩 ο 混合 物於 室 溫 下 攪 拌 iSSL 過 夜 0 閲 ί I 讀 1 添 加 溴 基 氯 基 甲 烷 ( 5 m ίί ) 。混 合物 回 流 加 熱 1 小 時 > 背 1 1 之 1 冷卻 並 於 減 壓 下 去 除 揮 發 性成份 。殘 留 物 溶 於 乙 酸 乙 酯 注 意 1 Ψ 1 ( 7 5 m ) 中 以 1 Μ Η C 5 (5 0 ΙΪ1 9. ) 洗 滌 以 項 ιε I Μ g S 0 4乾燥 •過濾 、並於減壓下去除溶劑 殘留物粗 窝 1 裝 頁 1 ( S ) — 2 — 第 三 丁 氧 羰 胺 基 -1 _氯 甲 磺 醯 4 — 苯 基 1 丁 烷 溶 於 乙 醚 ( 3 m 9. ) 中 0 添加 無水 4 — 甲 苯 磺 酸 ( 1 1 0 8 0 g 4 7 0 m m 0 H ) 於乙 醚 ( 3 m ) 中 之 1 1 溶 液 〇 混 合 物 於 室 溫 下 攪 拌 過 夜。 添加 乙 醚 ( 1 0 0 m 訂 1 ) 0 濾 出 囿 體 中 間 物 ( S ) — 2 - 胺基 — 1 — 氯 甲 基 — 磺 1 1 醯 — 4 — 苯 基 丁 烷 — 4 — 甲 苯 磺酸 酯( T S 〇 Η Η P h 1 | — β — S 〇 2 C Η 2 C ) 固 體以 乙醚 ( 2 X 2 0 m i? ) ] 線 洗 滌 , 並 於 真 空 中 乾 燥 產 生 0 .1 9 3 物 質 ( 由 Β 0 C 1 I Η Ρ h — β — S 0 2 C Η 2 C Η 2TMS開始係2 4%) 0 1 1 I Μ U — Ρ h e 0 Η ( 0 * 10 9 g 1 1 0 3 9 2 m m 0 ) 於 T Η F ( 3 m 义 ) 中 之 溶 液 於 1 1 — 1 0 °C 下 添 加 4 — 甲 基 嗎 啉 (4 3 β L 1 0 3 9 2 m m 0 9. ) 及 氯 甲 酸異 丁酯 ( 5 1 β L 1 I 0 3 9 2 τη m 0 ) 0 混 合 物攪 拌1 0 分 鐘 添 加 1 I Τ S 〇 Η Η Ρ h — β — S 0 2 C H 2 C il ( 0 * 1 7 g > 1 1 1 0 3 9 2 m m 0 ) 隨 後 係4 一甲 基 嗎 啉 ( 4 3 β L 1 1 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -94 - 經濟部中央標準局員工消費合作社印製 A7 —__B7 五、發明説明(92 ) 0 392mmoj2)。混合物攪拌45分鐘。添加乙 酸乙酯(20mj?) ^溶液以IMHCj?、飽和碳酸氫鈉 水溶液及鹽水(各2m$)洗滌,以MgS04乾燥、過 媳、並於減壓下去除溶劑,產生最終產物Mu_Ph e-Hph-/S — S.02CH2C 芡(90mg ,48% 產率) ο 實施例1 6 以α -胺基碉爲E W G之半胱胺酸蛋白酶抑制劑之合成 1—(第三丁氧羰基)胺基—2 —甲基一 1—苯磺醯 基丙烷(Boc— Va l—α — S02Ph)之合成。胺 甲酸第三丁酯(2. 34g,20mmoj?)及苯亞磺酸 鈉(3. 28g,20mm〇5)於水(20m5)中之 攪動懸浮液中添加異丁醛(2. 00m5,22mmo又 )於甲酸(5m{)中之溶液。混合物於室溫下攪拌過夜 。濾出沈澱物,以水(2 X 5 Omj?)洗滌並由異丙醇/ 水結晶產生4. 72g (7 5%)產物。 混合物1 7 以α -胺基碉爲EWG之半胱胺酸蛋白酶抑制劑之合成 1 —苄氧羰胺基一3 —苯基一 1 一苯磺醯丙烷(Ζ-Hph — a — S02Ph)之合成。苯亞磺酸鈉(1 0 g 本紙張尺度適用中國國家標準(CNS ) A4規格(X 297公釐)_ 95 一 ------------裝-------訂-------線 (請先閱讀背面之注意事項声‘.寫本頁) 470750 A7 B7 經濟部中央標準局員工消費合作社印製 五、 發明説明 (93 ) 1 I 6 0 9 m m 0 又 ) 及 胺 甲 酸 苄酯 ( 9 2 1 g > 1 1 6 0 9 m m 0 9. ) 於水 ( 4 0 m 9. ) 中 之 懸浮 液 中 添 加 1 1 於 甲 酸 ( 1 0 m ίί ) 中 之 氫 肉 桂 醛( 8 8 m j? > I 請 6 7 m m 0 父 ) 0 混 合 物 於 7 0 0C下 加 熱 1 小時 9 冷卻 至 閲 | 室 溫 過 夜 0 產 物 結 晶 析 出 » 濾 出 彼者 並 由 熱 異丙 醇 再 結 晶 讀 背 面 1 I 產 生 2 3 g ( 1 0 0 % ) 產 量 0 T L C ( 3 0 % 乙 酸 乙 之 注 意 1 1 I 酯 / 己 院 ) R f = C )· r 5 7 事 項 1 1 | k 本 百 1 Λ I 實 施 例 1 8 貝 1 1 以 a — 胺 基 硕 爲 Ε W G 之 半 胱 胺 酸蛋 白 酶 抑 制劑 之 合 成 1 1 1 ( R ) — 1 — ( 4 — 嗎 啉 羰 苯基 丙 胺 醯 )胺 基 — 3 — 1 訂 I 苯 基 — 1 一 苯 磺 醯 丙 烷 及 ( S ) -1 — ( 4 -嗎 啉 羰 苯 基 1 1 I 丙 胺 醯 ) 胺 基 — 3 — 苯 基 — 1 — 苯擴 鹽 丙 院 (Μ U — 1 1 I P h e 一 Η P h — a — S 0 2ph,分離之差向異構物) 1 t i 線 之 合 成 〇 方 法 A Z — Η P h 一 a — S 0 2Ϊ 3 h ( 1 1 0 g , 2 4 4 m m 0 9. ) 於乙 酸 ( 1 5 m 又 ) 中 以 1 1 3 0 % 溴 化 氫 處 理 0 3 0 分 趣 後 ,混 合 物 以 乙醚 ( 1 3 0 0 m ) 稀 釋 , m 濾 以 乙 醚( 2 X 3 0 m β ) 洗 滌 1 I » 並 於 真 空 中 乾 燥 產 生 0 7 4 g ( 8 6 % )1 — 胺 基 — I 3 — 苯 基 — 1 — 苯 擴 醯 丙 院 溴 化 氫鹽 ( Η Β r · Η Ρ h — 1 1 I a — S 0 2 P h ) » Μ 1 - -] P h e 0 Η ( D . 6 4 g > 1 1 2 3 ΤΠ ΤΠ 0 ) 於 τ Η F ( 1 5 m ) 中 之溶 液 中 添 加 1 1 4 — 甲 基 嗎 啉 ( 0 3 0 2 m ,2 3 m m o J2 ) 及 氯 1 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 470750 Α7 Β7 經濟部中央標準局員工消費合作社印製 五、發明説明(94) 甲酸異丁酯(〇. 312mi2,2. 3mm〇5)。混合 物攪拌10分鐘。添加HBr .Hph — α - S02Ph (0. 74g,2. 1 m m o j?),隨後係4 -甲基嗎啉 (0. 3 0 2 m » 2 . 3 m m o ) 。45 分鐘後’混 合物以乙酸乙酯(30mj?)稀釋,以各15mj? 1 Μ H C 5、飽和碳酸氫鈉水溶液、及鹽水洗滌,以 Mg SO 4乾燥,過濾,並於減壓下去除溶劑,產生 0. 75g(65%)產物Mu — Phe— Hph — α — S Ο 2 Ρ h。 方法Β :苯基丙胺酸醯胺鹽酸鹽(10g, 5〇mmoi2)於 DMF (50mi)及 CH2C^2( 50m义)中之溶液中添加三乙胺(1 3. 9mj? ’ lOOmmo又)及4 —嗎啉羰基氯(5. 9mi2 , 50mm〇5)。混合物攪拌過夜。於減壓下去除溶劑° 殘留物溶於乙酸乙酯(5 Οιηβ ),並過濾。將乙醚添加 於濾液中,直至溶液變成混濁。7. 2g(80%產率) 中間物4 一嗎啉羰苯基丙胺酸醯胺(Mu — Ph e-NH2)於3日後由溶液結晶。Mu-Ph eNH2( 2. 2 4 g * 8 . lmmoi?)於甲酸(5m芡)中之溶 液於攪拌下添加氫肉桂醛(1. 17mj?, 8. 9mmop)。混合物攪拌5小時,於彼添加苯亞磺 酸鈉(1. 33m^,8. lmmoj?)。混合物以5分 鐘迅速加熱至回流,並使之冷卻至室溫。溶液攪拌3日。 添加等體積之水。產物以CH2CP2(3xi〇〇mj?) (請先閲讀背面之注意事項Η,、寫本頁) •裝. 訂 -線 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐〉 -y r - 470750 經濟部中央標準局負工消費合作社印製 A7 B7五、發明説明(95 ) 萃取,以M g S 0 4乾燥,過濾,並於減壓下去除溶劑。 產物非鏡像(R) _及(S) — 1— (4-嗎啉羰苯基丙 胺醯)胺基一 3 —苯磺醯一 1 一苯基丙烷之產率係 3_ 9g(90%) °TLC(50%乙酸乙酯/ CH2Cj^2)Rf=〇. 27,0. 34。 藉於230 — 400目矽膠上快速層析(20 — 5 0 %乙酸乙酯/ C H2C j? 2,梯度洗提)分離非鏡像異 構物。 實施例1 9 使用本發明抑制劑之半胱胺酸蛋白酶之抑制劑 組織蛋白酶B用之條件:5 0 m Μ磷酸鹽, ΡΗ6. 0,2. 5mM EDTA>2. 5mM DTT。受質:〔Z — Arg-Arg—AMC〕= 50mM(Km=190mM)。於25°C下之檢定係藉 添加cat L(最終濃度約InM)而開始,追踪於 3 8 0 nm下激發下之4 5 0 nm螢光增量2分鐘。註上 在添加不同濃度抑制劑後對受質水解速率之抑制劑。在所 觀察之整體範圍內,該檢定係線性。進行雙次測定。 組織蛋白酶S用之條件:50mM磷酸鹽, p Η 6 . 5,2. 5 η M EDTA’2_ 5 m N DTT,受質:〔Z—Va l—Va 1 — Arg - AMC 〕=1 〇mM (Km=l 8mM)。於 2 5°C 下之檢定係 本紙張尺度適用中國國家標準(CNS ) A4規格UlOXW7公釐)_ 98 = I I n I n ϋ 訂— n 線 (請先閱讀背面之注意事項/¾寫本頁) 470750 A7 B7 五、發明説明(96 ) 藉添加c a t S (最終濃度約3〇pM)而開始,於 3 8 0 nm下激發下之4 5 0 nm螢光增量係追踪2分鐘 。註上在添加各種濃度之抑制劑後,對受質水解之速率的 抑制劑。在所觀察所有範圍內,該檢定係線性。進行雙次 測定。 卡任酶用之條件係同於組織蛋白酶L,不同處係受質 之K m係1 m Μ。 如Irwin Segel於酶動力學:迅速平衡及穩態系統 之行爲及分析,1 9 7 5 ’ Wiley - Interscience Publication ,John Wiley & Sons, Nwe York 中所述般 地使用Dixon圖估計各K i值》 結果列於表2 I. n n I I 1 (請先聞讀背面之注意事項声'寫本頁) 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS ) A4規格(21 〇 X 297公釐) -99 - 471^750I 470750 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs _______ V. Description of the invention (89) Mu-PheOH (0.32 2 g * 1. 23mmoJ2) in THF (10mj?) At -10 ° C, 4-methylmorpholine (0.135 mi? '1. 23 mmoj2) and isobutyl chloroformate (0.159 m' 1.23 mm 0.32) were added. The mixture was stirred for 10 minutes, and (S) 2-amino-4, 4-phenyl, 1-benzenesulfobutane hydrochloride (40 g > 1.23 mm2) was added, followed by 4-methyl. Porphyrin (0.135 mi2, 1.23 mmoj?). The mixture was stirred for 45 minutes. Add lMHCj? (15mi?). The product was extracted with ethyl acetate (30 mi?), Washed with a saturated aqueous sodium bicarbonate solution (15 m?), Brine (15 mi?), Dried over MgS04, filtered, and the solvent was removed under reduced pressure. The final product Mu — P’h e-Hph — Xiyi S02Ph weighed 0.68 g (100% yield). Example 14 Synthesis of a Cysteine Protease Inhibitor Filled with Stone-Amine Boron as EWG (S) _2 -Third-Butoxycarbonylamino- 4 -phenyl-1 1-(1 Trimethylsilane Ethyl) Monosulfobutane (Boc — Hph — Synthesize 2-Trimethylsilylethanethiol (0.86g, 6.41mmoj?) As described in Anderson, Ranasinghe, Palmer, Synthesized as described by Fachs) Sodium hydride (0_256g, 6.41mm〇i, 60% mineral oil dispersion) was added to the solution in THF (10mj?). The paper size is applicable to Chinese National Standard (CNS) A4 specification (210x ^ 97mm Ding-Q2-: -------- 1 ------- IT ------ ▲ (Please read the precautions on the back first page) 470750 A7 B7.-II-'-'-. —.I-Printing of the Consumer Work Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (90). Stir the mixture for 10 minutes. Add B oc-homophenylalanine Alcohol methyl ester (2.00 g, 5.82 mmo, synthesized as described in Example 13 above). The solution was stirred for 2 hours. Ethyl acetate (50 m $) was added. The solution was 1 MHCP at 30 m $ each. Water-soluble saturated sodium bicarbonate , And washed with brine, dried with M g S 0 4, filtered, and the solvent was removed under reduced pressure to produce an intermediate (S) _2 — tertiary butyloxy amine amino 4-benzyl butyl trimethylsilane Ethyl sulfide. TLC: (5% ethyl acetate / hexane) Rf = 0.22. This material was dissolved in CH2Cj? 2 (50mj2), cooled to a temperature of 10 ° C, and treated with 4-chloroperacetic acid (3 24g, 12.22mmo, estimated 65% peracid content) treatment. The mixture was stirred overnight. The suspension was filtered and the saturated NaHS03 aqueous solution (40mj?) And saturated sodium bicarbonate aqueous solution (50mj) were carefully added. In the filtrate. The organic phase was separated, dried over Mg SO 4, filtered, and the solvent was removed under reduced pressure. The product B was quantitatively recovered from the mesylate to produce 〇c_Hp h —Chilled S02CH2CH2TMS. TLC: (30% acetic acid Ethyl ester / hexane) Rf = 0.49. Example 1 5 Synthesis of Cysteine Protease Inhibitor with E-amino group as EWG (S)-2-(4-morpholinecarbonylphenylpropylamine hydrazone) Synthesis of Amine 1-chloromethanesulfonium-4-phenylbutane (Mu-Ph e — Hp h —Zhaoyi S02CH2Ci2). Boc — Hph- / 3 — This paper standard is applicable to Chinese national standards (C NS) A4 specification (210 XM7 mm) (please read the precautions on the back 7. Write this page).-Thread 470750 A7 B7 Printed by the consumer cooperation department of the Central Bureau of Correction of the Ministry of Economic Affairs. 5. Description of the invention () 1 1 1 S 0 2 C Η 2 C Η 2 ΤΜS (0.9 () g 1 1 2 1 8 mm 0 > as described in Example 1 4) in T Τ F (2 Ι 1 1 1) Add tetrabutyl fluoride Jbh m (8. 7 m β 1 0 M ✓-NI please 1 T Η F solution) and several molecular sieves to the solution. The mixture was stirred at room temperature for iSSL overnight. 0 Read I Read 1 Add bromo group Chloromethane (5 m ίί). The mixture is refluxed and heated for 1 hour > the back 1 to 1 is cooled and the volatile components are removed under reduced pressure. The residue was dissolved in ethyl acetate. Note 1 Ψ 1 (7.5 m) was washed with 1 M Η C 5 (50 0 Ι Ϊ 1 9.) was washed with the term ι ε Μ g S 0 4 • filtered, and removed under reduced pressure. Solvent residues rough nest 1 Loading sheet 1 (S) — 2 — third butoxycarbonylamino-1 _chloromethanesulfonium 4 —phenyl 1 butane dissolved in ether (3 m 9.) 0 added anhydrous 4 — Toluenesulfonic acid (1 0 0 0 0 g 4 7 0 mm 0 H) in diethyl ether (3 m) in 1 1 solution. The mixture was stirred at room temperature overnight. Add diethyl ether (100 m order 1) 0 Filter out the carbohydrate intermediate (S) — 2-amino — 1 — chloromethyl — sulfo 1 1 醯 — 4 — phenylbutane — 4 — tosylate (TS 〇Η Η P h 1 | — β — S 〇 2 C Η 2 C) The solid was washed with ether (2 X 2 0 mi?)] Line, and dried in vacuum to produce 0.1 9 3 substance (by β 0 C 1 I Η ρ h — β — S 0 2 C Η 2 C Η 2 TMS starting system 2 4%) 0 1 1 I Μ U — Ρ he 0 Η (0 * 10 9 g 1 1 0 3 9 2 mm 0 ) The solution in T Η F (3 m) was added at 1 1-10 ° C with 4-methylmorpholine (4 3 β L 1 0 3 9 2 mm 0 9.) and isobutyl chloroformate. (5 1 β L 1 I 0 3 9 2 τη m 0) 0 Stir the mixture for 10 minutes and add 1 I Τ S 〇Η Ρ ρ h — β — S 0 2 CH 2 C il (0 * 1 7 g > 1 1 1 0 3 9 2 mm 0) followed by 4 monomethylmorpholine (4 3 β L 1 1 This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -94-Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 —__ B7 V. Description of Invention (92) 0 392mmoj2). The mixture was stirred for 45 minutes. Ethyl acetate (20mj?) Was added, and the solution was washed with IMHCj ?, saturated sodium bicarbonate aqueous solution and brine (2m $ each), dried over MgS04, filtered, and the solvent was removed under reduced pressure to produce the final product Mu_Ph e-Hph -/ S — S.02CH2C 芡 (90mg, 48% yield) ο Example 16 Synthesis of 1- (Third Butoxycarbonyl) amino Group Using α-Aminopyrene as EWG's Cysteine Protease Inhibitor —2 —Methyl- 1-benzenesulfonylpropane (Boc-Val-α-S02Ph) Synthesis. A third suspension of butyl carbamate (2.34g, 20mmoj?) And sodium benzenesulfinate (3.28g, 20mm05) in water (20m5) was added to an isobutyraldehyde (2.00m5, 22mmo) And) a solution in formic acid (5m {). The mixture was stirred at room temperature overnight. The precipitate was filtered off, washed with water (2 X 5 Omj?) And crystallized from isopropanol / water to give 4.72 g (7 5%) of the product. Mixture 17 Synthesis of Cysteine Protease Inhibitor with α-Aminopyrene as EWG 1—Benzyloxycarbonylamino-3—phenyl-1—benzenesulfonylpropane (Z-Hph — a — S02Ph) synthesis. Sodium benzene sulfinate (10 g) This paper size is applicable to China National Standard (CNS) A4 specification (X 297 mm) Order ------- line (please read the note on the back first '. Write this page) 470750 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (93) 1 I 6 0 9 mm 0 and) and benzyl carbamate (9 2 1 g > 1 16 0 9 mm 0 9.) To a suspension in water (40 m 9.) was added 1 1 to formic acid (1 0 m ί) Hydrogen cinnamaldehyde (8 8 mj? ≫ I please 6 7 mm 0 parent) 0 The mixture was heated at 7 0 0C for 1 hour 9 cooled to room temperature | overnight at room temperature 0 product crystals precipitated out »filtered by the other Isopropanol recrystallization reads back 1 I produces 2 3 g (100%) yield 0 TLC (30% ethyl acetate Note 1 1 I ester / hexahedron) R f = C) r 5 7 Matters 1 1 | k Benbai 1 Λ I Example 1 8 Bay 1 1 with a —amino group as Ε WG Synthesis of Cysteine Protease Inhibitors 1 1 1 (R) — 1 — (4 —morpholinecarbonylphenylpropylamine fluorene) amino — 3 — 1 Order I phenyl — 1 monobenzenesulfonylpropane and (S) -1 — (4 -morpholinecarbonylphenyl 1 1 I propylamine hydrazone) amino — 3 — phenyl — 1 — benzene salt salt (M U — 1 1 IP he Η P h — a — S 0 2ph, separated epimer) 1 Synthesis of ti line 〇Method AZ — Η P h — a — S 0 2Ϊ 3 h (1 1 0 g, 2 4 4 mm 0 9.) in acetic acid (1 5 m)) treated with 1 130% hydrogen bromide for 0 3 0 minutes, the mixture was diluted with diethyl ether (13 0 0 m), and filtered with ether (2 X 3 0 m β) and washed 1 I » And dried in vacuum to produce 0 7 4 g (86%) 1 —amino — I 3 — phenyl — 1 — benzene dihydrogen bromide (Η Β r · Η Ρ h — 1 1 I a — S 0 2 P h) »Μ 1--] P he 0 Η (D. 6 4 g > 1 1 2 3 ΤΠ ΤΠ 0) at τ Η F ( 1 5 m) and 1 1 4 —methylmorpholine (0 3 0 2 m, 2 3 mmo J2) and chlorine 1 are added to the solution. The paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 470750 Α7 Β7 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. 5. Description of the invention (94) Isobutyl formate (0.312mi2, 2.3mm). The mixture was stirred for 10 minutes. HBr .Hph — α-S02Ph (0.74 g, 2.1 m m o j?) Was added, followed by 4-methylmorpholine (0.3 2 m »2.3 m m o). After 45 minutes, the mixture was diluted with ethyl acetate (30mj?), Washed with 15mj? 1M HC5, saturated aqueous sodium bicarbonate solution, and brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. 0.75 g (65%) of the product Mu — Phe — Hph — α — S Ο 2 Ρ h was produced. Method B: Triethylamine (13.9mj? '100mmo again) was added to a solution of phenylalanine ammonium hydrochloride (10g, 50mmoi2) in DMF (50mi) and CH2C ^ 2 (50moi). And 4-morpholine carbonyl chloride (5.9 mi2, 50 mm). The mixture was stirred overnight. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (50 μηβ) and filtered. Diethyl ether was added to the filtrate until the solution became cloudy. 7.2 g (80% yield) Intermediate 4 Monomorpholine phenylalanine amidoamine (Mu — Ph e-NH2) crystallized from the solution after 3 days. A solution of Mu-Ph eNH2 (2.2 4 g * 8. lmmoi?) In formic acid (5m 芡) was added with stirring to add cinnamaldehyde (1.17mj ?, 8.9mmop). The mixture was stirred for 5 hours, and sodium phenylsulfinate (1.33m ^, 8. lmmoj?) Was added thereto. The mixture was quickly heated to reflux in 5 minutes and allowed to cool to room temperature. The solution was stirred for 3 days. Add an equal volume of water. The product is based on CH2CP2 (3xi〇〇mj?) (Please read the notes on the back Η, and write this page) • Binding. Binding-line paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm> -yr -470750 Printing of A7 B7 printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (95) Extraction, drying with M g S 0 4, filtration, and removal of the solvent under reduced pressure. Product non-mirror (R) _ and The yield of (S) — 1 — (4-morpholinecarbonylphenylpropylamine hydrazone) amine — 3 —benzenesulfonium — 1 monophenylpropane is 3-9 g (90%) ° TLC (50% ethyl acetate / CH2Cj ^ 2) Rf = 0.27, 0.34. Non-mirror isomers were separated by flash chromatography on 230-400 mesh silica gel (20-50% ethyl acetate / C H2C j? 2, gradient elution). Example 19 Cathepsin B inhibitor using cysteine protease inhibitor of the present invention Conditions for use: 50 m Μ phosphate, pH 6.0, 2.5 EDTA > 2.5 mM DTT. Substrate : [Z — Arg-Arg-AMC] = 50 mM (Km = 190 mM). The test at 25 ° C was started by adding cat L (final concentration of about InM) and traced to 4 under excitation at 380 nm. 5 0 nm fluorescence increment 2 minutes. Note the inhibitor of the hydrolysis rate of the substrate after adding different concentrations of inhibitors. Within the overall range observed, the assay is linear. Two measurements were performed. Conditions for cathepsin S: 50 mM phosphate, p Η 6.5, 2.5 η M EDTA'2_ 5 m N DTT, substrate: [Z-Va l-Va 1 — Arg-AMC] = 10 mM (Km = 18 mM). At 2 5 ° The verification under C is based on the Chinese standard (CNS) A4 size UlOXW7 mm for this paper size_ 98 = II n I n ϋ Order — n line (Please read the precautions on the back / write this page first) 470750 A7 B7 V. Description of the invention (96) Started by adding cat S (final concentration of about 30 pM), the 450 nm fluorescence increment under excitation at 3800 nm was tracked for 2 minutes. Note the inhibitors on the rate of hydrolysis of the substrate after adding various concentrations of inhibitors. The test is linear over all observed ranges. A double determination was performed. The conditions for calenzyme are the same as those for cathepsin L, except that the Km of the substrate is 1 mM. Dixon plots were used to estimate each K i value as described in Irwin Segel in Enzyme Kinetics: Rapid Equilibrium and Steady-State System Behavior and Analysis, 195 5 'Wiley-Interscience Publication, John Wiley & Sons, Nwe York 》 The results are listed in Table 2. I. nn II 1 (please read the note on the back first, write this page) The paper printed by the Central Consumers' Bureau of the Ministry of Economic Affairs, the Consumer Cooperatives, applies the Chinese National Standard (CNS) A4 specification (21 〇X 297 mm) -99-471 ^ 750
A 五、發明説明(97 )表 2 經濟部中央標準局員工消費合作社印製A V. Description of Invention (97) Table 2 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs
Inhibitor · 組嫌蛋白明B (Κ·μΜ) 組織翬白醃L 粗歎蛋3酶s 卡任》 Mu-Phe-(DL)HphaS02Ph 3,000 13 5 15 Mu-Phe-HphaS02Ph - 2.6 _ Mu-Phe-(DL)HphaS02Ph, - - 3.7 - Mu-Leu-HphaS02Ph 16 1,3 1.6 0.27 Mu-Leu-HphaS02Bzl 54 0.60 4.2 076 Mu-Phe-HphaS02CH2F 170 1.5 2.8 2,0 Mu-Phe-HphaS02Bzl 77 1.2 5.2 0.92 Mu-Phe-HphaS02CR3 50 0.18 2.2 0.23 Mu-Phe-HphpS02Ph 1,100 29 0.94 5.7 Mu-Phe-HphYS02Ph 48 10 0.16 4.3 Phac-Phe-HphYS02Ph »10 0.41 12.5 1.8 Mu-Np2-HphvS022Np 20 0.26 0.53 0.10 Mu-Phe-HphYS02EtPh 190 0.17 0.082 5.9 Suc-Phe-HphYS02Ph >1000 1.0 0.07 1.5 Me0Suc-Phe-HphYS02Ph 81 3.2 1.2 4.7 Suc-Np2-HphvS02Ph >1000 2,3 0.50 0.78 Suc-Np2-HphvSOp2Np >1000 0.11 0.24 0.23 1 .............. 1 _, Z-p-Ala-Phe-HphYS02Ph 52 079 3.0 0.54 1 p-Ala-Phe-HphyS02Ph »50 14 11 14 Mu-Tyr-HphYS02Ph 2.3 9.5 20 Mu-Phe-HphYCO?Et 1.6 0.48 0.19 0.91 Mu-Phe-HphYCONHPh 2.6 2.0 1.3 0.13 Mu-Phe-HphYCONHBzl »50 19 30 7.7 Mu-Phe-HphYP0(0?Et)2 17 3.0 1.4 15 Mu-Phe-Hph-YPh-OMe 4.8 0.94 0.37 0.89 Mu-Phe-Hph-vPh-NH? »50 2.9 9,1 3,0 (請先閱讀背面之注意事項J;'舄本頁) _1一 >~ -a Γ ^^t^W(CNS)A^(21〇X297^! ι〇〇 _ 470750 A7 B7五、發明説明(98 ) 下列者係含有本發明半胱胺酸蛋白酶抑制劑之代表性 藥學配製劑。 經口配製劑 經口給藥用之代表性溶液含有: 半胱胺酸蛋白酶抑制劑 100至1000 檸檬酸單水合物 105mgInhibitor · Histone B (K · μΜ) Tissue White Pickled L Coarse Egg 3 Enzymes Carmen Mu-Phe- (DL) HphaS02Ph 3,000 13 5 15 Mu-Phe-HphaS02Ph-2.6 _ Mu-Phe- (DL) HphaS02Ph,--3.7-Mu-Leu-HphaS02Ph 16 1,3 1.6 0.27 Mu-Leu-HphaS02Bzl 54 0.60 4.2 076 Mu-Phe-HphaS02CH2F 170 1.5 2.8 2,0 Mu-Phe-HphaS02Bzl 77 1.2 5.2 0.92 Mu -Phe-HphaS02CR3 50 0.18 2.2 0.23 Mu-Phe-HphpS02Ph 1,100 29 0.94 5.7 Mu-Phe-HphYS02Ph 48 10 0.16 4.3 Phac-Phe-HphYS02Ph »10 0.41 12.5 1.8 Mu-Np2-HphvS022Np 20 0.26 0.53 0.10 Mu-PheE-HP 190 0.17 0.082 5.9 Suc-Phe-HphYS02Ph > 1000 1.0 0.07 1.5 Me0Suc-Phe-HphYS02Ph 81 3.2 1.2 4.7 Suc-Np2-HphvS02Ph > 1000 2,3 0.50 0.78 Suc-Np2-HphvSOp2Np > 1000 1 .1 0.24 0.23 ............. 1 _, Zp-Ala-Phe-HphYS02Ph 52 079 3.0 0.54 1 p-Ala-Phe-HphyS02Ph »50 14 11 14 Mu-Tyr-HphYS02Ph 2.3 9.5 20 Mu- Phe-HphYCO? Et 1.6 0.48 0.19 0.91 Mu-Phe-HphYCONHPh 2.6 2.0 1.3 0.13 Mu-Phe-HphYCONHBzl »50 19 30 7.7 Mu-Phe-HphYP0 (0? Et) 2 17 3.0 1.4 15 Mu-Phe-Hph-YPh -OMe 4 .8 0.94 0.37 0.89 Mu-Phe-Hph-vPh-NH? »50 2.9 9,1 3,0 (Please read the precautions on the back J; '舄 This page) _1 一 > ~ -a Γ ^^ t ^ W (CNS) A ^ (21〇X297 ^! Ι〇〇_470750 A7 B7 V. Description of the Invention (98) The following are representative pharmaceutical formulations containing the cysteine protease inhibitor of the present invention. Oral formulations Representative solutions for oral administration contain: Cysteine protease inhibitor 100 to 1000 citric acid monohydrate 105mg
S 氫氧化鈉 調味劑 水 1 8 m g 適量使之成爲1 0 0 靜脈內配製劑 靜脈內給藥用之代表性溶液含有: (請先閲讀背面之注意事項声寫本頁) 經濟部中央標準局員工消費合作社印製 半胱胺酸蛋白酶抑制劑 葡萄糖單水合物 檸檬酸單水合物 氫氧化鈉 注射用之鹽水 錠劑配製劑 代表性錠劑可含有: 半胱胺酸蛋白酶抑制劑 微晶纖維素 1 0 至 1 0 0 適量使之等張 1 . 0 5 m g 0 . 1 8 m g 適量使之成1 1 % 7 3 % 本紙張尺度適用中國國家標準(CNS ) A4規格(210X2.97公釐) g 101 470750 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(") 硬脂酸 2 5 % 膠態氧化矽 1 % (請先閱讀背面之注意事項再填寫本頁) -102 - 本紙張尺度適用中國國家標準(CNS ) A4规格(210Χ297公釐)S Sodium hydroxide flavoring water 18 mg appropriate amount to make it a 100% intravenous formulation. Representative solutions for intravenous administration contain: (Please read the notes on the back first and dictate this page) Central Bureau of Standards, Ministry of Economic Affairs Employee Consumer Cooperative printed cysteine protease inhibitor glucose monohydrate citrate monohydrate sodium hydroxide injection saline lozenge formulations for injection. Representative lozenges may contain: Cysteine protease inhibitor microcrystalline cellulose 10 to 100 0 in the right amount makes it equal to 1.0 0.5 mg 0. 1 8 mg in the right amount makes it 11% 7 3% This paper size applies the Chinese National Standard (CNS) A4 size (210X2.97 mm) g 101 470750 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention " Stearic acid 2 5% Colloidal silica 1% (Please read the precautions on the back before filling this page) -This paper size applies to China National Standard (CNS) A4 (210 × 297 mm)
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JP (1) | JPH11503417A (en) |
KR (1) | KR19980703261A (en) |
CN (1) | CN1071751C (en) |
AU (1) | AU713492B2 (en) |
CA (1) | CA2216151A1 (en) |
CZ (1) | CZ298197A3 (en) |
IL (1) | IL117638A0 (en) |
MY (1) | MY113489A (en) |
NO (1) | NO311573B1 (en) |
NZ (1) | NZ305626A (en) |
PL (1) | PL322409A1 (en) |
TW (1) | TW470750B (en) |
WO (1) | WO1996030353A1 (en) |
ZA (1) | ZA962336B (en) |
Families Citing this family (28)
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PT912601E (en) | 1996-04-22 | 2004-04-30 | Massachusetts Inst Technology | DELETING THE IMUNE RESPONSE FROM CATEPSIN S INHIBITION |
NZ333713A (en) * | 1996-07-30 | 2000-12-22 | Axys Pharm Inc | Compounds for treating diseases associated with tryptase activity |
DE19817461A1 (en) | 1998-04-20 | 1999-10-21 | Basf Ag | New benzamide derivatives useful as cysteine protease inhibitors for treating neurodegenerative diseases, neuronal damage, stroke, cranial trauma, Alzheimer's disease, etc. |
EP1159273A1 (en) | 1999-03-02 | 2001-12-05 | Boehringer Ingelheim Pharmaceuticals Inc. | Compounds useful as reversible inhibitors of cathepsin s |
US6420364B1 (en) | 1999-09-13 | 2002-07-16 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compound useful as reversible inhibitors of cysteine proteases |
ATE244235T1 (en) * | 1999-09-13 | 2003-07-15 | Boehringer Ingelheim Pharma | HETEROCYCLIC COMPOUNDS AS REVERSIBLE INHIBITORS OF CYSTEINE PROTEASES |
JP2003514524A (en) | 1999-11-18 | 2003-04-22 | コルバス・インターナショナル・インコーポレイテッド | Nucleic acid encoding an endoceliase, endotheliase and uses thereof |
US7700341B2 (en) | 2000-02-03 | 2010-04-20 | Dendreon Corporation | Nucleic acid molecules encoding transmembrane serine proteases, the encoded proteins and methods based thereon |
EP1309591B1 (en) | 2000-08-14 | 2007-01-24 | Ortho-McNeil Pharmaceutical, Inc. | Substituted pyrazoles |
MXPA03001420A (en) | 2000-08-14 | 2004-01-26 | Johnson & Johnson | Substituted pyrazoles. |
CZ307185B6 (en) | 2000-08-14 | 2018-03-07 | Ortho Mcneil Pharmaceutical, Inc. | Substituted pyrazole, a pharmaceutical composition containing it and their medical applications |
US7332494B2 (en) | 2000-08-14 | 2008-02-19 | Janssen Pharmaceutica, N.V. | Method for treating allergies using substituted pyrazoles |
CN1642973A (en) | 2000-09-06 | 2005-07-20 | 奥索-麦克尼尔药品公司 | A method for treating allergies |
US20020107266A1 (en) * | 2000-12-12 | 2002-08-08 | Marguerita Lim-Wilby | Compounds, compositions and methods for treatment of parasitic infections |
US7030116B2 (en) | 2000-12-22 | 2006-04-18 | Aventis Pharmaceuticals Inc. | Compounds and compositions as cathepsin inhibitors |
CA2433520A1 (en) | 2000-12-22 | 2002-07-04 | Axys Pharmaceuticals, Inc. | Novel compounds and compositions as cathepsin inhibitors |
US6900237B2 (en) | 2001-09-14 | 2005-05-31 | Axys Pharmaceuticals, Inc. | Sulfonamide compounds as protease inhibitors |
BR0212535A (en) * | 2001-09-14 | 2004-10-19 | Aventis Pharma Inc | Compounds and compositions as cathepsin inhibitors |
RU2004117877A (en) | 2001-11-14 | 2006-01-10 | Авентис Фармасьютикалз Инк. (Us) | OLIGOPEPTIDES AND COMPOSITIONS CONTAINING THEM, AS CATATEPSIN S INHIBITORS |
GB0311406D0 (en) * | 2003-05-17 | 2003-06-25 | Queen Mary & Westfield College | Substituted phosphonate fluorescent sensors,and use thereof |
DK2288615T3 (en) * | 2008-05-21 | 2017-09-04 | Genesis Tech Ltd | SELECTIVE CASPASE INHIBITORS AND APPLICATIONS THEREOF |
WO2010133000A1 (en) | 2009-05-21 | 2010-11-25 | New World Laboratories Inc. | Selective caspase inhibitors and uses thereof |
US8895497B2 (en) | 2009-12-04 | 2014-11-25 | Dcb-Usa, Llc | Cathepsin S inhibitors |
ES2665301T3 (en) | 2011-04-15 | 2018-04-25 | Genesis Technologies Limited | Selective cysteine prorease inhibitors and their uses |
KR101309578B1 (en) * | 2011-05-06 | 2013-09-17 | 연세대학교 산학협력단 | Dityrosine compounds having selectivity for cysteine proteases and method for monitoring cysteine proteases using the same |
KR101385855B1 (en) * | 2012-10-16 | 2014-04-22 | 이동익 | Diaromatic amino acid-based substrate for detecting cathepsins |
WO2019142890A1 (en) * | 2018-01-19 | 2019-07-25 | 株式会社大阪ソーダ | Organosilicon compound and rubber composition including same |
EP3553521A1 (en) * | 2018-04-12 | 2019-10-16 | Koninklijke Philips N.V. | Gingivitis diagnostic methods, uses and kits |
-
1996
- 1996-03-21 CA CA002216151A patent/CA2216151A1/en not_active Abandoned
- 1996-03-21 WO PCT/US1996/003844 patent/WO1996030353A1/en not_active Application Discontinuation
- 1996-03-21 AU AU53674/96A patent/AU713492B2/en not_active Ceased
- 1996-03-21 NZ NZ305626A patent/NZ305626A/en unknown
- 1996-03-21 JP JP8529509A patent/JPH11503417A/en active Pending
- 1996-03-21 PL PL96322409A patent/PL322409A1/en unknown
- 1996-03-21 KR KR1019970706665A patent/KR19980703261A/en not_active Application Discontinuation
- 1996-03-21 CN CN96193951A patent/CN1071751C/en not_active Expired - Fee Related
- 1996-03-21 EP EP96910499A patent/EP0817778A1/en not_active Withdrawn
- 1996-03-21 CZ CZ972981A patent/CZ298197A3/en unknown
- 1996-03-22 MY MYPI96001076A patent/MY113489A/en unknown
- 1996-03-22 ZA ZA962336A patent/ZA962336B/en unknown
- 1996-03-24 IL IL11763896A patent/IL117638A0/en unknown
- 1996-04-12 TW TW085104392A patent/TW470750B/en active
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1997
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AU5367496A (en) | 1996-10-16 |
NO974403D0 (en) | 1997-09-23 |
WO1996030353A1 (en) | 1996-10-03 |
KR19980703261A (en) | 1998-10-15 |
CA2216151A1 (en) | 1996-10-03 |
NO311573B1 (en) | 2001-12-10 |
PL322409A1 (en) | 1998-01-19 |
IL117638A0 (en) | 1996-07-23 |
EP0817778A1 (en) | 1998-01-14 |
NO974403L (en) | 1997-11-17 |
JPH11503417A (en) | 1999-03-26 |
CZ298197A3 (en) | 1998-03-18 |
ZA962336B (en) | 1996-07-31 |
AU713492B2 (en) | 1999-12-02 |
NZ305626A (en) | 2000-01-28 |
MY113489A (en) | 2002-03-30 |
CN1071751C (en) | 2001-09-26 |
CN1184472A (en) | 1998-06-10 |
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