TW318850B - - Google Patents

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Publication number
TW318850B
TW318850B TW084111436A TW84111436A TW318850B TW 318850 B TW318850 B TW 318850B TW 084111436 A TW084111436 A TW 084111436A TW 84111436 A TW84111436 A TW 84111436A TW 318850 B TW318850 B TW 318850B
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TW
Taiwan
Prior art keywords
aryl
alkyl
group
hydrogen
compound
Prior art date
Application number
TW084111436A
Other languages
English (en)
Inventor
Louis Plamondon
Original Assignee
Proscript Inc
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Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26987313&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=TW318850(B) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Proscript Inc filed Critical Proscript Inc
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Publication of TW318850B publication Critical patent/TW318850B/zh

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    • 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
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
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    • 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
    • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
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    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • 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
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06043—Leu-amino acid
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    • C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
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  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Immunology (AREA)
  • Rheumatology (AREA)
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  • Oncology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Virology (AREA)
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  • Pulmonology (AREA)
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  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

318850 A8 B8 C8 D8 々、申請專利範圍 c6_10芳基、c6_10芳（Ci-6)烷基、Ch6烷（c6_1〇)芳基或雜環中 之任一者之環部分可選擇性地經取代；且 (請先閱讀背面之注意事項再填寫本頁) A係0、1或2。 3 ·如申請專利範圍第2項之化合物，其中： p係r7-c(o)-或r7-so2-，其中R7係喹啉基、喹噁啉基 、吡啶基、吡嗪基、呋喃基或吡咯基中之一者，或當P係 R7-C(0)時，R7亦可係N-嗎啉基。 4·如申請專利範圍第2項之化合物，其中p係喹啉擬基 、口比D定鑛基、喹啉礦驢基、喹B惡琳鐵基、D奎H惡琳礦酿基、D比嗪 羰基、吡嗪磺醯基、呋喃羰基、呋喃磺醯基或N-嗎啉羰基中 之一者。 5·如申請專利範圍第4項之化合物，其中P係8_喹啉羰 基、8-喹啉磺醯基、2-喹噁啉羰基、2-喹噁啉磺醯基、2-吡嗪 羰基、2-吡嗪磺醯基、3-呋喃羰基、3-呋喃磺醯基或N-嗎啉 鑛基中之一者。 6.如申請專利範圍第2項之化合物，其中A係〇。 7·如申請專利範圍第2項之化合物，其中R係氫或Cl_8 烷基。 經濟部智慧財產局員工消費合作社印製 8.如申請專利範圍第2項之化合物，其中： R2係氫、C!-8烷基、C3_1G環烷基、C6-1G芳基、5_、6-、9-或10-節雜芳基、或-CH2_R5中之一者； R5 係 C6.1G 芳基、C6-10 芳（Ci-6)院基、Ci_6院（C6_10)芳基 、C3-IG環院基、Ci_8院氧基、Ci-8院硫基或5-、6-、9 -或 10-節雜芳基中之一者； 其中R2及R5之該芳基、芳烷基、烷芳基或5-、6-、9- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）-4 - 318850 A8 B8 C8 D8 六、申請專利範圍 (請先閱·#背面之注意事項再填寫本頁) 或10-節雜芳基中任一者之環部分可視情況經一個或兩個各 選自烷基、C3_8環烷基、Cu烷基（C3.8)環烷基、（:2_8 烯基、C2_8炔基、氰基、胺基、c!_6烷胺基、二（(^_6)烷胺 基、苄胺基、二苄胺基、硝基、羧基、羰基（<^_6)烷氧基、 三氟甲基、鹵素、Cb6烷氧基、c6_1()芳基、C6_1()芳（Ci.6)烷 基、C6_1G芳（Ci-6)院氧基、經基、Ci_6院硫基、Ci_6院亞礦 醯基、Ch6烷磺醯基、C6_1G芳硫基、C6_1G芳亞磺醯、c6_10 芳磺醯基、C6_1G芳基、Cu烷基（c6_1G)芳基及鹵基（c6_1G)芳 基中之取代基所取代。 9·如申請專利範圍第2項之化合物，其中R3係異丁基 〇 10. 如申請專利範圍第2項之化合物，其中R2係異丁基 、2-萘甲基、3-哦啶甲基、2-吼啶甲基、6-喹啉甲基、3-D引D朵 甲基、苄基、4-氟苄基、4-羥苄基、4-(2，-吡啶甲氧）苄基、 4-(苄氧）苄基、苄萘甲基或苯乙基中之一者。 11. 如申請專利範圍第2項之化合物，其中Z1及Z2各係 ◦ 1- 6^71：基、經基或Ci_6院氧基中之一*者。 經濟部智慧財產局員工消費合作社印製 12. 如申請專利範圍第n項之化合物，其中Ζι及z2皆 係羥基。 13·如申請專利範圍第2項之化合物，其中Z1及Z2 —起 形成由選自噸那醇（pinacol )、全氟噸哪醇、蒎烷二醇、乙 二醇、二伸乙基二醇、1，2 -環己烷二醇、1，3 -丙二醇、2 ，3-丁二醇、甘油或二乙醇胺中之二羥基化合物所衍生之部 分。 14.如申請專利範圍第2項之化合物，其中該化合物係 本&張尺度逋用中國國家襟準（CNS ) A4規格（210X297公釐）_ 5 - ' 318850 A8 B8 C8 D8 經濟部智慧財產局員工消費合作社印製 六、申請專利範圍 下列者之一： N-(2-吡嗪）羰基-L-苯基丙胺酸-L-白胺酸腿酸， N-(2-喹啉）磺醯-L-高苯基丙胺酸-L-白胺酸臓酸， N-(3-吡啶）羰基-L-苯基丙胺酸-L·白胺酸腿酸， N-(4-嗎啉）羰基-L-苯基丙胺酸-L-白胺酸画酸， N-(4-嗎啉）羰基·β·(1_萘基）-L-丙胺酸-L-白胺酸腿酸， N-(8-喹啉）磺醯-β-(1-萘基）-L-丙胺酸-L-白胺酸願酸， N-(4-嗎啉）羰基-(0-苄基）-L-酪胺酸-L-白胺酸哪酸， N-(4-嗎啉）羰基-L-酪胺酸-L·白胺酸臓酸， N - (4 -嗎啉）碳基-〔0 · (2 -卩比D定甲基）〕-L -酪胺酸-L -白胺酸願酸 ， 或其藥學上可接受之鹽。 1 5 .如申請專利範圍第1 4項之化合物，其中該化合物係 N-(2-吡嗉）羰基-L-苯基丙胺基-L-白胺酸腿酸。 16·如申請專利範圍第1項之化合物，其中 P爲氫或胺基保護部份； R2爲萘甲基，吡啶甲基或喹啉甲基； A爲0，1或2。 17·如申請專利範圍第16項之化合物，其中p係r7_ c(o)-、r7_so2-、r7-nh-c(o)-或 r7-o-c(o)_，且 R7係C6-10芳基、C6_10#(Ci-6)院基、5-至10-節雜芳基 或5-至10-節雜芳（Cl_6)烷基中之一者，其中任一者皆可視 情況經取代，或當P係R7-C(0)-時，R7亦可係N_嗎啉基。 1 8 ·如申請專利範圍第1 7項之化合物，其中P係 R7-C(0)-或 r7_s〇2-;且 本紙張尺度適用中國國家襟準（CNS ) A4規格（210X297公釐）-6 - . 訂 (請先閱讀背面之注意事項再填寫本頁) 318850 A8 B8 C8 D8 六、申請專利範圍 (請先閱讀背面之注意事項再填寫本頁) R係C6_l〇芳基、C6-10方（Ci_6)院基、5 -至10 -節雜芳基 或5-至10-節雜芳基（Chd烷基，其中任一者皆可視情況經 取代，或當P係R7-C(0)-時，R7亦可係N-嗎啉基。 19.如申請專利範圍第16項之化合物，其中A係零。 2 0 .如申請專利範圍第1 6項之化合物，其中R2係喹啉甲 基。 21·如申請專利範圍第16項之化合物，其中該化合物係 下述者之一： N-(4-嗎啉）羰基-β-(1-萘基）-L-丙胺酸-L-白胺酸腦酸，或 N-(8-喹啉）磺醯基- β-(1-萘基）-L-丙胺酸-L-白胺酸腿酸。 22·如申請專利範圍第1項之化合物，其中 P爲氫或胺基保護基部分； R與R2 —起形成含氮之單-、雙-、或三-環、飽和或部 分飽和之具有4 -1 4個ig自卩之纟哀系統，其可選擇性經一*個或 兩個酮基、羥基、C!_8烷基、C6-1Q芳基、C6_1G芳（Ci-6)烷基 、（：丨_8烷氧基或C6_1()芳氧基所取代； R3爲氮、Ci-8院基、或-CH2_(C6-1Q)芳基； A爲0 〇 經濟部智慧財產局員工消費合作社印製 23 .如申請專利範圍第.22項之化合物，其中該含氮之環 系統係選自下列者： 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）-7 - 318850 六 A8 B8 C8 D8 、申請專刊範圍
R -c(0)、、R7-S〇2-、R7-nh-c(〇)-或 R7-0-C(0)_，且 •如申請專利範圍第2 2項之化合物，其中p係 (請先閲讀背面之注意事項再填寫本頁) \ 、τ Γ R係C6-i〇芳基、c6-i〇芳（Ci-6)烷基、5-至10-節雜芳基 或 5 _革 1 if. 一 1〇、節雜芳（<^_6)烷基中之一者，其中任一者皆可視情 況糸111取代’或當P係R7-C(0)_時，R7亦可係N-嗎啉基。 經濟部智慧財產局員工消費合作社印製 25 ·如申請專利範圍第24項之化合物，其中p係 R _e⑼·或 H7-S〇2-;且 尺7係C11Q芳基、C6_1Q芳（Ci-6)烷基、5-至10-節雜芳基 或5_至1(K節雜芳基（Cl_6)烷基中之一者，其中任一者皆可 視情況經取代，或當P係R7-C(0)-時，R7亦可係N-嗎啉基 〇 26·如申請專利範圍第22項之化合物，其中P係氫。 27·如申請專利範圍第22項之化合物，其中該化合物係 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）-8 - 318850 A8 B8 C8 D8 六、申請專利範圍 L-脯胺酸-L-白胺酸腿酸。 (請先閱讀背面之注意事項再填寫本頁) 28.如申請專利範圍第1項之化合物，其中 P爲氫或胺基保護基部分； R1各係氫或烷基； R2係：
其中R9係氫、烷基、環烷基、芳基、芳烷基、雜芳基或雜 芳烷基中之一者，其中烷基視情況經CU6烷基、鹵素、單鹵 基（C!·6)烷基、及三氟甲基中之一者所取代； 經濟部智慧財產局員工消費合作社印製 且其中該環烷基、芳基、芳烷基、雜芳基及雜芳基烷基可視 情況經一個或兩個Cu烷基、C3_8環烷基、Cl 6烷基（c3_8) 環院基、C2-8儲基、C2-8炔基、氰基、胺基、Ci-6院胺基、 二（CL6)烷胺基、苄胺基、二苄胺基、硝基、羧基、羰基（ Ci-6)垸氧基、三氟甲基、鹵素、Cl-6垸氧基、C6-10芳基、 C6-1G芳基（Cl-6)院基、C6-10方基（Ci_6)院氧基、經基、Ci_6 烷硫基、Ci_6烷亞磺醯基、¢^6烷磺醯基、C6_1G芳硫基、 C6_10芳亞磺醯基、C5-1()芳磺醯基、C6-10芳基、Cu烷基 (C6_1G)芳基、及鹵基（C6_1G)芳基所取代； A1及A2各係氫、鹵素、Cu烷基、單鹵基（Cm)烷基， 或三氟甲基中之一者； A係0、1或2。 本紙張尺度適用中國國家標準（CNS ) A4規格(210X297公釐）_ 一 ^ 318850 A8 B8 C8 D8 六、申請專利範圍 29·如申請專利範圍第28項之化合物，其中p係 R7-C(0)、、r7_s〇2_、r7_nh-C(0)-或 R7-0-C(0)_，且 (請先閱讀背面之注意事項再填寫本頁) R係C6_1G芳基、C6_1G芳（Cb6)烷基、5_至1〇-節雜芳基 或5-至10-節雜芳（C^)烷基中之一者，其中任一者皆可視 ^況經取代，或當p係R7-C(0)-時，R7亦可係N-嗎啉基。 3 〇·如申請專利範圍第29項之化合物，其中p係 r7-c(〇)1 r7-S02-;且 R係C6_1G芳基、C6.1G芳（Ci-6)烷基、5 -至10 -節雜芳基 或5_至10-節雜芳基（(^_0)烷基，其中任一者皆可視情況經 取代’或當P係R7-C(0)-時，R7亦可係1嗎啉基。 3 1·如申請專利範圍第28項之化合物，其中R2係 其中 A1及A2各係氫、Cl_6烷基、鹵素、單鹵基（Ci6)烷基或 三氟甲基中之一者； 經濟部智慧財產局員工消費合作社印製 R9係Cu烷基、c3_1G環烷基、Cn。芳基、C6_1G芳（ C!-6)烷基、5-至10-節雜芳基或5-至10-節雜芳基（Cl_6)院基 中之~'者。 32·如申請專利範圍第28項之化合物，其中A係零。 3 3 ·如申請專利範圍第2 8項之化合物，其中該化合物係： Ν-(4·嗎啉）羰基-(0-苄基）-L-酪胺酸-L-白胺酸酸， N-(4-嗎啉）羰基-L-酪胺酸-L-白胺酸腿酸，或 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）-1〇_ 318850 經濟部智慧財產局員工消費合作社印製 A8 B8 C8 D8 々、申請專利範圍 N-(4-嗎啉）羰基-〔〇-(2-吡啶甲基）〕-L-酪胺酸-L-白胺酸腿酸 〇 34.—種具下式之化合物： γΐο_Ν_χ13_ H R13 (2a) 及其藥學上可接受之鹽； 其中 Y 係 r8-c(o)-、r8-so2-、r8_nh-c(0)-或 R8-0-C(0)-中 之一者，其中R8係Cu烷基、Cn❹芳基、Cu烷（C6_1())芳 基、C6_1()芳（Chd烷基中之一者，其中任一者可視情況經取 代，或當γ係r8-c(o)-或r8_so2-，貝ϋ r8亦可係視情況經 取代之5至1 0節飽和、部分不飽和或芳族雜環； X13係共價鍵結或-c(0)-ch2-; R13 係氣、Ci_8 院基、-CH2-(C6-1Q)方基； Z1及Z2各係Cb8烷基、羥基、或（^_8烷氧基、或一起 形成由具有至少兩個被至少兩個鏈中或環中聯結原子所分隔 之羥基的二羥基化合物，該鏈或環包含碳原子及選擇性之氮 原子； 先決條件係當Y係R8-C(0)-時，R8不爲苯基、苄基或 Ci-Cs烷基。 3 5 ·如申請專利範圍第3 4項之化合物，其中γ 1 0係 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）-11 - (請先閱讀背面之注意事項再填寫本頁)
中之一者’其中R4係C6-12烷基。 3 6 . —種具下式之化合物： Y—N—X3—CH—B^XZ2) H R3 (2a) 及其藥學上可接受之鹽； 其中 Y是 p—CHj-CH—C-—; I II r1 o (3a)
P 係 R7-C(0)-、R7-S02-、R7-NH-C(0)-或 R7-〇-C
I I n I I n I — I n I I I I ^ (請先閱p背面之注意事項再填寫本頁J 經濟部智慧財產局員工消費合作社印製 (〇)中 之一者，其中 &7係Cb8烷基、C6_1()芳基、Cb6烷（c6_1G)芳基、 C6-1G芳（c^6)烷基中之一者，其中任一者可視情況經取代， 或當Y係R7-C(0)-或R7-S〇2_時，R7亦可係視情況經取代之 5至1 0節飽和、部分不飽和或芳族雜環； X3係共價鍵結或-c(o)-ch2-; R1各係氫、Ci-8垸基、C3_1()環院基、c6_1G芳基、5至 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）-12 - 争 318850 A8 B8 C8 D8 六、申請專利範圍 (請先閱,背面之注意事項再填寫本頁) 10節飽和、部分不飽和或芳族雜環或-CH5中之〜者， 其中’該芳基或雜環中任一者之環部分可選擇性地經取代； R3係氫、Cu烷基、c3_1G環烷基、c6_1G芳基、5至10 節飽和、部分不飽和或芳族雜環或-CH5中之一者，其中 該芳基或雜環中之任一者可選擇性地經取代； R5各係c6·!。芳基、Ch。芳（Cu)院基、Cu烷（c6_1Q)芳 基，C3_1G環烷基、5至10節飽和、部分飽和或芳族雜環或 -W-R6中之一者，其中W係硫屬且尺6係Ci_8烷基，其中該 C6-1()芳基、C6_IG芳（Cu)烷基、Cl_6烷（C6_1())芳基或雜環中 之任一者之環部分可選擇性地經取代；且 Z1及Z2各係Ci-8烷基、羥基、Cl_8烷氧基中之一者， 或Z1及Z2 —起形成由具有至少兩個被至少兩個鏈中或環中 之聯結原子分隔之羥基的二羥基化合物所衍生之部分，該鏈 或環包含碳原子及選擇性之氮原子。 3 7 ·如申請專利範圍第3 6項之化合物，其中Y係 經濟部智慧財產局員工消費合作社印製
0〇 _ 3 8 · —種用於抑制哺乳類蛋白酶體功能之藥學組合物， 其包含如申請專利範圍第1或34或36項之化合物及其藥學 上可接受之載體或稀釋劑。 39.如申請專利範圍第38項之藥學組合物，其中該化合 物之存在量係可有效地抑制晡乳類體內之蛋白酶體功能。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）-13 - 318850 A8 B8 C8 D8 六、申請專利範圍 40.—種抑制癌細胞生長之藥學組成物，其包括可有效 抑制生長之量之如申請專利範圍第1或34或36項之化合物 〇 4 1 . 一種降低細胞內肌肉蛋白降解速率之藥學組成物， 其包括有效量之具下式之蛋白酶體抑制劑： pio 一n—B11-X11 R10 R11 CH——X12 —CH——B(Z11)(Z12) R12 R13 A10 (lb) (請先閱讀背面之注意事項再填寫本頁)
或其藥學上可接受之鹽 其中 p1 ^係氫或胺基保護部分； B11，各係 CH ; X11，各係-C(〇)-NH-; X12 係-C(0)-NH-; R1Q係氫或C"烷基，或當係零時，與相鄰R!2 一 起形成含氮之單-、雙-或三環、飽和或部分飽和之具有4-14 個環節之環系統，其可選擇性經一個或兩個酮基、趣基、 C!_8烷基、。芳基、。芳（Ci_6)烷基、Cl_8烷氧基或 C 6 - 1 0芳氧基所取代； R11各係氫或C! _8烷基； R12係氫、C"烷基、c3_1G環烷基、C6_1G芳基、5、1〇節 飽和、部分不飽和或芳族雜環或_CH2_r15中之一者，其中該 C6-1Q芳基、或雜環中任—者之環部分可選擇性地經取 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇χ297公董）_ 14 訂 争 經濟部智慧財產局員工消費合作社印製 A8 B8 C8 D8 318850 六、申請專利範圍 R13 係氫、Ci_8 院基、或- CH2-(C6_1())芳基； R15 各係 C6_1G 芳基、C6-1G 芳（CU6)烷基、Ci 6 院（(^ 〕 芳基、C3 _ 1 〇環院基、5 -1 0節飽和、邰分飽和或芳族雜環戌 _w1g-r16中之一者，其中w1G係硫屬且尺“係Ci 8烷基，其 中該C6_l〇芳基、C6-l〇芳（Ci_6)烷基、Cu烷（C6_1〇)芳基或雜 環中之任一者之環部分可選擇性地經取代； Z11及Z12各係C!·8烷基、羥基、或山_8烷氧基中之〜 者，或Z11及Z12 —起形成由具有至少兩個被至少兩個鏈中 或環中之聯結原子分隔之羥基的二羥基化合物所衍生之部分 ，該鏈或環包含碳原子及任意之氮原子；且 A1G 係 0、1 或 2。 42.—種降低細胞內NF-kB( nuclear factor-kB，核因子 k Β)活性之藥學組成物，其包括有效量之下式蛋白酶體抑制 劑·· 1 -I «n n_i ml —^ϋ ml an n I ^^1 i (請先閱讀背面之注意事項再填寫本頁} pio—ν—Β11—X11 I R11 ·—CH—X12—CH—Β(Ζ11)(Ζ12】R12 R13 Α10 ⑽ 争 經濟部智慧財產局員工消費合作社印製 或其藥學上可接受之鹽； 其中 Ριυ係氫或胺基保護部分； Β11，各係 CH ; X11，各係-C(0)-NH-; X12 係-C(0)-NH-; 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）-15 - 318850 A8 B8 C8 D8 經濟部智慧財產局員工消費合作社印製 夂、申請專利範圍 R1()係氫或Cm烷基，或當A1()係零時，與相鄰Rl2s 起形成含氮之單-、雙-或三環、飽和或部分飽和之具有4-i4 個環節之環系統，其可選擇性經一個或兩個酮基、羥基、 Cl-8院基、C6_10芳基、C6_10芳（Ci-6)院基、Ci-8院氧基或 C 6 _ ! 〇芳氧基所取代； R11各係氯或Ci_8院基； R12係氫、C"烷基、c3_1G環烷基、C6_1G芳基、5-10節 飽和、部分不飽和或芳族雜環或-CHpR15中之一者，其中 該C6_1G芳基、或雜環中任一者之環部分可選擇性地經取代 R13 係氫、Ci-8 院基、或- CH2-(C6-1G)芳基； R15 各係 c6_10 芳基、c6_10 芳（Cu)烷基、Cb6 烷（C6-10) 芳基、〇環烷基、5-10節飽和、部分飽和或芳族雜環或 -W1G-R16中之一者，其中W1G係硫屬且R16係Ch烷基， 其中該Cnc芳基、C6_1()芳（Cm)烷基、Cu烷（C6_1G)芳基或 雜環中之任一者之環部分可選擇性地經取代； Z11及Z12各係山_8烷基、羥基、或Cu烷氧基中之一 者，或Z11及Z12 —起形成由具有至少兩個被至少兩個鏈中 或環中之聯結原子分隔之羥基的二羥基化合物所衍生之部分 ，該鏈或環包含碳原子及任意之氮原子；且 A10 係 〇、1 或 2。 43. —種降低細胞內蛋白質破壞之藥學組成物，其包括 有效量之下式蛋白酶體抑制劑： 财關緖準（CNS ) A4· ( 210X297公釐）_ 16 · ^ 、訂 I ^^1 (請先閎讀背面之注意事項再填、寫本頁j 318850 A8 B8 C8 D8 六、申請專利範圍 p10-N一 I R10 B11—X”「CH—χη—CH—Β(Ζ11)02) R11 A10 (lb) 經濟部智慧財產局員工消費合作社印製 或其藥學上可接受之鹽； 其中 p1()係氫或胺基保護部分； B11，各係 CH ; X11，各係-C(0)-NH-; X12 係-C(0)-NH-; R1G係氫或CU8烷基，或當A1G係零時，與相鄰R 起形成含氮之單-、雙-或三環、飽和或部分飽和之具有4-14 個環節之環系統，其可選擇性經一個或兩個酮基、羥基、 Cb8烷基、。芳基、C“1()芳（Cl_6)烷基、Cm烷氧基或 C6-10芳氧基所取代； R11各係氫或C!_8烷基； R12係氫、Cm烷基、C3-1G環烷基、C6_1()芳基、5-10節 飽和、部分不飽和或芳族雜環或- CH2_R15中之一者，其中該 C6_1Q芳基、或雜環中任一者之環部分可選擇性地經取代； R13係氫、Ch烷基、或-ch2-(c6_1())芳基； R 各係 C6_1G 芳基、C6-10 芳（Ci_6)院基、C1-6 院（06 ι〇) 方基、C3 _ i 〇 ί哀烷基、5 -1 0節飽和、部分飽和或芳族雜環或 -W1G-R16中之一者，其中wi〇係硫屬且Rl6係I 8烷其， 其中該。芳基、c6.1()芳（Cl_6)烷基、〇16烷（(^芳基或 雜環中之任一者之環部分可選擇性地經取代； & 1 2 (請先閱讀背面之注意事項再填寫本頁) 318850 A8 B8 C8 D8 、申請專利範圍 Z11及Z12各係Cu烷基、羥基、或Cl.8烷氧基中之一 者，或Z11及Z12 —起形成由具有至少兩個被至少兩個鏈中 或環中之聯結原子分隔之羥基的二羥基化合物所衍生之部分 ，該鏈或環包含碳原子及任意之氮原子；且 A10 係 0、1 或 2。 44· 一種降低細胞內p53蛋白質（tumor suppressor protein p53，腫瘤抑制劑蛋白質p53)之降解速率的藥學組成 物，其包括有效量之下式蛋白酶體抑制劑： (請先閱讀背面之注意事項再填寫本頁) pio—n—
I R10 B11——X11
I R11 CH—
I
Ri2 A10 (lb)
B 經濟部智慧財產局員工消費合作社印製 或其藥學上可接受之鹽； 其中 p1 ^係氫或胺基保護部分； 各係CH ; X11，各係-C(0)-NH-; X12 係-C(0)-NH-; R1G係氫或Cu烷基，或當A1G係零時，與相鄰R12 — 起形成含氮之單-、雙-或三環、飽和或部分飽和之具有 個環節之環系統，其可選擇性經一個或兩個酮基、羥基、 Cu院基、C6_1G芳基、c6_1G芳（Cy)烷基、c!_8烷氧基或 c 6 · 1 0芳氧基所取代； R11各係氫或Cu烷基； 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 18 _ 318850 A8 B8 C8 D8 、申請專利範圍 R12係氫、匕_8烷基、c3_1G環烷基、c6_1G芳基、5-10節 飽和、部分不飽和或芳族雜環或_CH2_R15中之—者，其中 該C6_1G芳基、或雜環中任一者之環部分可選擇性地經取代 R13係氫、烷基、或_CH2-(C6 lQ)芳基； R15 各係 c6_1()芳基、c6“。芳（Cl 6)院基、Ci 6 烷（c6 i〇) 方基、C3 _ 1 〇環烷基、5 -1 0節飽和、部分飽和或芳族雜環或 -W1G-R16中之一者，其中wl〇係硫屬且r16係Ci_8烷基， 其中該Cno芳基、C6-1()芳（CU6)烷基、Cu烷（c6_1())芳基或 雜環中之任一者之環部分可選擇性地經取代； Z11及Z12各係Ci_8烷基、羥基、或Ci_8烷氧基中之一 者，或Z11及Z12 —起形成由具有至少兩個被至少兩個鏈中 或環中之聯結原子分隔之羥基的二羥基化合物所衍生之部分 ’該鏈或環包含碳原子及任意之氮原子；且 A1 υ 係 0、1 或 2。 45.—種抑制細胞內塞克林（eyelin )降解之藥學組成物 其包括有效量之下式蛋白酶體抑制劑” (請先閱讀背面之注意事項再填寫本頁) 訂- 經濟部智慧財產局員工消費合作社印製 ρΐο_μ—rB11—X11I I R10 R11 CH—X12 —CH—日) A10 (lb) 或其藥學上可接受之鹽； 其中 P1()係氫或胺基保護部分； 本紙張尺度適用中國國家襟準（〇奶）八4規格（210/297公釐）-19- 318850 A8 B8 C8 D8 六、申請專利範圍 B11，各係 CH ; X11，各係-C(0)-NH-; (請先閱讀背面之注意事項再填寫本頁) X12 係-C(0)-NH-; R1()係氫或（^_8烷基，或當係零時，與相鄰R!2 一 起形成含氮之單-、雙-或三環、飽和或部分飽和之具有4_14 個壤卽之ί哀系統，其可選擇性經一個或兩個酮基、羥基、 Ci-8烷基、C6_1G芳基、Ch。芳（Cu)烷基、Cl_8烷氧基或 C 6 _ i 〇芳氧基所取代； R11各係氫或Cm烷基； R1 2係氫、C 1 · 8烷基、c 3 _】〇環烷基、C 6 _ i 〇芳基、5 -1 0節 飽和、部分不飽和或芳族雜環或-CHyR15中之一者，其中該 C 6 · 1 〇芳基、或雜環中任一者之環部分可選擇性地經取代； R13係氫、c"烷基、或-ch2-(c6-1g)芳基； 經濟部智慧財產局員工消費合作社印製 R15 各係 c6_10 芳基、C6_10 芳（Ci_6)院基、Ci_6 烷（C6_10) 芳基、Cm環烷基、5-10節飽和、部分飽和或芳族雜環或 -Wig-r16中之一者，其中wlG係硫屬且Rl6係Ci 8烷基， 其中該c6_1()芳基、c6_1()芳（Ci-6)烷基、Cu烷（c6_1())芳基或 雜環中之任一者之環部分可選擇性地經取代； Z11及Z12各係山-8烷基、羥基、或Cl_8烷氧基中之一 者’或Z11及Z12 —起形成由具有至少兩個被至少兩個鏈中 或環中之聯結原子分隔之羥基的二羥基化合物所衍生之部分 ，該鏈或環包含碳原子及任意之氮原子；且 A1Q 係 0、1 或 2。 4 6. —種預防或治療需治療患者之發炎狀況的藥學組成 本紙張尺度適用中國國家襟準（CNS ) A4規格（210X297公釐）-20 · 318850 A8 B8 C8 D8 六、申請專利範圍 物，其包括有效量之下式蛋白酶體抑制劑 pio—N—B11——X11 R10 R11 —CH—X12—CH—B(211)(Z12) R12 R13 A10 (lb) 或其藥學上可接受之鹽； 其中 P1()係氫或胺基保護部分
B 各係CH ; (請先閱讀背面之注意事項再填寫本頁} 經濟部智慧財產局員工消費合作社印製 X11，各係-C(0)-NH-; X12 係-C(0)-NH-; R1Q係氫或烷基，或當A1G係零時，與相鄰_ 起形成含氮之單-、雙-或三環、飽和或部分飽和之具有4_14 個環節之環系統，其可選擇性經一個或兩個酮基、翔基、 Ci-8院基、C6-1G芳基、C6-1。芳（Ci_6)院基、Ci-8院氧基戌 c6-1G芳氧基所取代； R11各係氫或Ch烷基； R12係氫、c"烷基、Cn。環烷基、c6_1G芳基、5·1〇節 飽和、部分不飽和或芳族雜環或-CH2_R15中之一者，其中該 C 6 -1 0方基、或雜環中任一者之環部分可選擇性地經取代； R 係氣、C1-8院基、或-CH2-(C6-ig)方基； R15各係C6_1G芳基、C6·〗。芳（Cm)烷基、Cu烷（c 八 V L 6 - 1 〇 ) 芳基、C3_1G環烷基、5-1〇節飽和、部分飽和或芳族雜環或 -W1G_r16中之一者，其中wlG係硫屬且^6係Ci_8烷基，其 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）-21 318850 A8 B8 C8 D8 六、申請專利範圍 中該c6_10芳基、C6_10芳（Ci-6)院基、Ci_6院（c6_10)芳基或雜 環中之任一者之環部分可選擇性地經取代； Z11及Z12各係Cl_8烷基、羥基、或Cl_8烷氧基中之一 者’或Z11及Z12 —起形成由具有至少兩個被至少兩個鏈中 或環中之聯結原子分隔之羥基的二羥基化合物所衍生之部分 ，該鏈或環包含碳原子及任意之氮原子；且 A1C)係 〇、1 或 2。 47.如申請專利範圍第46項之藥學組成物，其中該患者 係經診斷具有選自組織排斥、器官排斥、關節炎、感染、皮 膚病、發炎性腸疾、及自體免疫疾病中之狀況或發展彼者之 危險。 4 8.—種抑制細胞內抗原表現之藥學組成物，其包括有 效量之下式蛋白酶體抑制劑： P10_N_B11_X11_CH—_CH—B(Z11)(Zi2) R10 R” fU R13 • JA10 或其藥學上可接受之鹽； 其中 P1()係氫或胺基保護部分； B11，各係 CH ; X11，各係-C(0)-NH-; X12 係-C(0)-NH-; R1 0係氫或C ! _ 8烷基，或當A 1G係零時，與相鄰R12 — 起形成含氮之單-、雙-或三環、飽和或部分飽和之具有4_14 本紙張尺度適用中國國家標準（〇灿）八4規格（210父297公釐）_22- (請先閱讀背面之注意事項再填寫本頁) 訂 (lb) 經濟部智慧財產局員工消費合作社印製 318850 A8 B8 C8 D8 經濟部智慧財產局員工消費合作社印製 六、申請專利範圍 個環節之環系統，其可選擇性經一個或兩個酮基、經基、 CU8院基、Cq。芳基、。芳（Cl_6)烷基、Cl_8烷氧基或 c 6 - 1 Q芳氧基所取代； R11各係氫或6_8烷基； R 係氫、C1-8院基、C3-1()環院基、C6-10芳基、5-10節 飽和、部分不飽和或芳族雜環或-CH^R15中之一者，其中該 C6_1Q芳基、或雜環中任一者之環部分可選擇性地經取代； R13 係氫、CU8 烷基、或-CH2-(C6_1())芳基； R15 各係 C6_1G 芳基、C6_1G 芳（Cm)烷基、Cu6 烷（CVl〇) 芳基、C3_1()環烷基、5-10節飽和、部分飽和或芳族雜環或 -Wi、Rl6中之一者，其中wlG係硫屬且Rl6係山_8烷基，其 中該C6-1G芳基、C6_1()芳（Cm)烷基、Cu烷（C6-1G)芳基或雜 環中之任一者之環部分可選擇性地經取代； Z11及Z12各係Cm烷基、羥基、或Cu烷氧基中之一 者，或Z11及Z12 —起形成由具有至少兩個被至少兩個鏈中 或環中之聯結原子分隔之羥基的二羥基化合物所衍生之部分 ，該鏈或環包含碳原子及任意之氮原子；且 A1G 係 0、1 或 2。 49·一種於需該抑制之動物體內抑制可誘發之與NF-kB 有關之細胞黏連的藥學組成物，其包括有效量之下式蛋白酶 體抑制劑： pio一N—B11一X11I I R1〇 R11 CH—X12—CH—B(Z11)(Z^) R12 R13 (lb) 本紙張尺度適用中國國家襟準（CNS ) A4規格（21〇Χ297公釐）-23 - (請先閲讀背面之注意事項再填寫本頁) 訂- 參· A8 B8 C8 D8 318850 六、申請專利範圍 或其藥學上可接受之鹽； 其中 p 1""係氫或胺基保護部分； B11，各係 CH ; X"，各係-C(0)-NH-; X12 係-C(0)-NH-;
RlG係氫或Cu烷基，或當A1G係零時，與相鄰R12 — 起形成含氮之單-、雙-或三環、飽和或部分飽和之具有4 個環節之環系統，其可選擇性經一個或兩個酮基、殘基、 Ci-8院基、C6-10芳基、C6-10芳（Ci-6)院基、Ci-8院氧基或 C6-1()芳氧基所取代； RU各係氫或Ci.8烷基； R12係氫、Cm烷基、C3_1G環烷基、C6-1G芳基、5_1〇節 飽和、部分不飽和或芳族雜環或-CHrR15中之一者，其中該 C6-1G芳基、或雜環中任一者之環部分可選擇性地經取代；
Ri3係氫、Cu烷基、或-CH2-(C6_1())芳基； R15 各係 c6.1()芳基、c6·!。芳（Ci_6)院基、Cu 院（c 、 八 V L 6 · 1 〇 ) 芳基、C^o環烷基、5-10節飽和、部分飽和或芳族雜環或 -W1()-R16中之一者，其中W1G係硫屬且R!6係Cu8烷基，其 中該c6_1()芳基、c6_1()芳（Ci_6)院基、CU6院（c6_1())芳基或雜 環中之任一者之環部分可選擇性地經取代； Z11及Z12各係Cl_8烷基、羥基、或Cl_8烷氧基中之一 者，或Z11及Z12 —起形成由具有至少兩個被至少兩個鏈中 或環中之聯結原子分隔之羥基的二羥基化合物所衍生之部分 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）· 24 - (請先閱讀背面之注意事項再填寫本頁)
、1T 經濟部智慧財產局員工消費合作社印製 318850 A8 B8 C8 D8 、申請專利範圍 ，該鍵或ί哀包含碳原子及任意之氣原子，且 A1G 係 0、1 或 2。 50· —種於需要該抑制之動物體內抑制 HIV(human immunodeficiency virus，人類免疫缺乏症病毒）複製之藥學 組成物，其包括有效量之下式蛋白酶體抑制劑： pio —N- R10 B11—χ11 I R” ，CH—X12—CH—B(Z11)(Z12) R13 A10 (lb) (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 I紙張尺度適用中國國家標準（CNS) Α4· ( 210x297公羡)乂 25 一 或其藥學上可接受之鹽； 其中 p1 ^係氫或胺基保護部分； B11，各係 CH ; X11，各係-C(0)-NH-; X12 係-C(0)-NH-; R1G係氫或Cy烷基，或當A1()係零時，與相鄰Ru — 起形成含氮之單-、雙·或三環、飽和或部分飽和之具有4_14 個環節之環系統，其可選擇性經一個或兩個酮基、羥基、 Cl-8 it兀基、C6-10芳基、C6-10芳（Ci_6)院基、Ci_8院氧基戌 C 6 - ! 〇芳氧基所取代； R11各係氫或（^_8烷基； R12係氫、C"烷基、c3.1()環烷基、c6_1()芳基、5_1〇節 飽和、部分不飽和或芳族雜環或_CH2-R15中之一者，其中琴 芳基、或雜環中任一者之環部分可選擇性地經 318850 A8 B8 C8 D8 六、申請專利範圍 R13係氫、Cb8烷基、或-CH2-(C6.1Q)芳基； (請先閱讀背面之注意事項再填寫本頁) R15各係C6-1G芳基、C6_i〇芳（Cm)烷基、Cl_6院彳^⑼) 芳基、c3 _ i 0環烷基、5 -1 G節飽和、部分飽和或芳族雜環或 _w1g-r16中之一者，其中w1G係硫屬且尺“係Ci8烷基，其 中該C6_10芳基、C6_10芳（Cu)烷基、Cb6烷（c6_10)芳基或雜 環中之任一者之環部分可選擇性地經取代； Z11及Z12各係Cm烷基、羥基、或Cl_8烷氧基中之一 者，或Z11及Z12 —起形成由具有至少兩個被至少兩個鏈中 或環中之聯結原子分隔之經基的二經基化合物所衍生之部分 ，該鏈或環包含碳原子及任意之氮原子；且 A10 係 0、1 或 2。 51.如申請專利範圍第 40、41、42、43、44、45、46、 48、49及50項中任一項之藥學組成物，其中該蛋白酶體抑 制劑係下述者之一： N-(2-吡嗪）羰基苯基丙胺酸-L-白胺酸腿酸， N-(2-喹啉）磺醯-L-高苯基丙胺酸-L-白胺酸腿酸， N-(3-吡啶）羰基-L-苯基丙胺酸-L-白胺酸硼酸， 經濟部智慧財產局員工消費合作社印製 N - (4 -嗎琳）鑛基-L -苯基丙胺酸-L -白胺酸腿酸’ N-(4-嗎啉）羰基-β-(1-萘基）-L-丙胺酸-L-白胺酸腦酸， N-(8-喹啉）磺醯-β-(1-萘基）-L-丙胺酸-L-白胺酸哪酸’ N-(4-嗎啉）羰基-(〇-苄基）-L-酪胺酸-L-白胺酸哪酸， N-(4-嗎啉）羰基-L-酪胺酸-L-白胺酸硼酸，或 N-(4-嗎啉）羰基-〔0-(2-吡啶甲基）〕-L-酪胺酸-L-白胺酸鹏酸 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 26 - 318850 A8 B8 C8 D8 々、申請專利範圍 5 2.—種降低細胞內肌肉蛋白質降解速率之藥學組成 物，其包括有效量之如申請專利範圍第34或36項之化合物 (請先閲讀背面之注意事項再填寫本頁) 〇 5 3.—種降低細胞內NF-kB活性之藥學組成物，其包括 有效量之如申請專利範圍第34或36項之化合物。 5 4. —種降低細胞內蛋白質破壞速率之藥學組成物，其 包括有效量之如申請專利範圍第34或36項之化合物。 55.—種降低細胞內p53蛋白質降解速率的藥學組成物 ，其包括有效量之如申請專利範圍第34或36項之化合物。 56·—種抑制細胞內塞克林（cyclin )降解之藥學組成物 ，其包括有效量之如申請專利範圍第3 4或3 6項之化合物。 5 7.—種於需治療之患者體內預防或治療發炎狀況之藥 學組成物，包括有效量之如申請專利範圍第34或36項之化 合物。 經濟部智慧財產局員工消費合作社印製 58.如申請專利範圍第57項之藥學組成物，其中該患者 係經診斷具有選自組織排斥、器官排斥、關節炎、感染、皮 膚炎、發炎性腸疾、氣喘、骨質疏鬆症、骨關節炎及自體免 疫疾病中之狀況或有發展彼者之危險。 5 9.—種抑制癌細胞生長之藥學組成物，其包括有效量 之如申請專利範圍第34或36項之化合物。 60. —種抑制細胞內抗原表現之藥學組成物，其包括有 效量之如申請專利範圍第34或36項之化合物。 6 1.—種抑制動物體內與NF-kB有關之細胞粘連的藥學 組成物，其包括有效量之如申請專利範圍第34或36項之化 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 27 - 318850 as C8 D8 六、申請專利範圍 合物。 62.—種抑制動物體內之HIV複製的藥學組成物，其包 括有效量之如申請專利範圍第3 4或3 6項之化合物。 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產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（210X297公釐）-28 -
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