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31. 发明授权

US07501417B2 Aminocarbonyl-derivatives as novel inhibitors of histone deacetylase 有权
标题翻译：氨基羰基衍生物作为组蛋白脱乙酰酶的新型抑制剂
公开(公告)号：US07501417B2
公开(公告)日：2009-03-10
申请号：US10507271
申请日：2003-03-11
申请人： Kristof Van Emelen , Hans Louis Jos De Winter , Alexey Borisovich Dyatkin , Marc Gustaaf Celine Verdonck , Lieven Meerpoel , Jimmy Arnold Viviane Van heusden
发明人： Kristof Van Emelen , Hans Louis Jos De Winter , Alexey Borisovich Dyatkin , Marc Gustaaf Celine Verdonck , Lieven Meerpoel , Jimmy Arnold Viviane Van heusden
IPC分类号： C07D239/42 , C07D295/20 , A61K31/506 , A61P35/00
CPC分类号： C07D413/12 , A61K31/40 , A61K31/402 , A61K31/435 , A61K31/4427 , A61K31/454 , A61K31/4545 , A61K31/472 , A61K31/495 , A61K31/496 , A61K31/506 , A61K31/5377 , A61K31/55 , A61K45/06 , C07D207/09 , C07D207/14 , C07D211/14 , C07D211/58 , C07D213/78 , C07D217/02 , C07D217/04 , C07D217/16 , C07D239/42 , C07D295/155 , C07D295/26 , C07D307/68 , C07D401/04 , C07D401/12 , C07D403/04 , C07D403/12 , C07D405/06 , C07D409/12 , C07D409/14 , C07D413/04 , C07D471/04 , C07D471/10 , C07D513/04 , C12Q1/34 , C12Q1/48
摘要： This invention comprises the novel compounds of formula (I) wherein n, R1, R2, R3, R4, L, Q, X, Y, Z and have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.
摘要翻译：本发明包括具有组蛋白脱乙酰酶抑制酶活性的式（I）的新化合物，其中n，R 1，R 2，R 3，R 4，L，Q，X，Y，Z具有定义的含义; 其制剂，含有它们的组合物及其作为药物的用途。

32. 发明申请

US20090124646A1 SUBSTITUTED INDOLYL ALKYL AMINO DERIVATIVES AS NOVEL INHIBITORS OF HISTONE DEACETYLASE 有权
标题翻译：取代的吲哚基氨基酸衍生物作为HISTONE脱乙酰基酶的新型抑制剂
公开(公告)号：US20090124646A1
公开(公告)日：2009-05-14
申请号：US11572563
申请日：2005-07-25
申请人： Marc Gustaaf Celine Verdonck , Patrick Rene Angibaud , Bruno Roux , Isabelle Noelle Constance Pilatte , Peter Ten Holte , Janine Arts , Kristof Van Emelen
发明人： Marc Gustaaf Celine Verdonck , Patrick Rene Angibaud , Bruno Roux , Isabelle Noelle Constance Pilatte , Peter Ten Holte , Janine Arts , Kristof Van Emelen
IPC分类号： A61K31/506 , C07D401/14
CPC分类号： A61K31/506 , A61K31/454 , A61K31/4545 , C07D401/14 , C07D405/14 , C07D409/14 , C07D491/04 , C07D491/056
摘要： This invention comprises the novel compounds of formula (I) wherein R1, R2, R3, X and Y have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.
摘要翻译：本发明包括式（I）的新化合物，其中R1，R2，R3，X和Y具有定义的含义，具有组蛋白脱乙酰酶抑制酶活性; 其制剂，含有它们的组合物及其作为药物的用途。

33. 发明授权

US08318929B2 4-aryl-2-anilino-pyrimidines 有权
标题翻译： 4-芳基-2-苯胺基 - 嘧啶
公开(公告)号：US08318929B2
公开(公告)日：2012-11-27
申请号：US12921499
申请日：2009-03-09
申请人： Peter Jacobus Johannes Antonius Buijnsters , Marc Gustaaf Celine Verdonck , Kristof Van Emelen , Pascal Ghislain André Bonnet
发明人： Peter Jacobus Johannes Antonius Buijnsters , Marc Gustaaf Celine Verdonck , Kristof Van Emelen , Pascal Ghislain André Bonnet
IPC分类号： C07D345/00
CPC分类号： C07D471/08 , C07D471/18 , C07D471/22 , C07D498/08 , C07D498/18
摘要： The present invention relates to compounds of Formula (Ia) or (Ib), the N-oxide forms, pharmaceutically acceptable addition salts, quaternary amines, stereoisomers, tautomers, racemics, metabolites, prodrugs, hydrates, or solvates thereof, wherein Y1, m, n, R1; X1; X2; R2; X3; X4; R3; and R4 have the meaning defined in the claims. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use in therapy. The invention particularly relates to compounds that are kinase inhibitors useful for the treatment of disease states mediated by kinase, especially PLK4, in particular such compounds that are useful in the treatment of pathological processes which involve an aberrant cellular proliferation, such as tumor growth, rheumatoid arthritis, restenosis and atherosclerosis.
摘要翻译：本发明涉及式（Ia）或（Ib）的化合物，N-氧化物形式，药学上可接受的加成盐，季胺，立体异构体，互变异构体，外消旋学，代谢物，前药，水合物或溶剂化物，其中Y1，，n，R1; X1; X2; R2; X3; X4; R3; 和R4具有权利要求中限定的含义。本发明还涉及制备所述化合物的方法，含有它们的药物组合物及其在治疗中的用途。本发明特别涉及可用于治疗由激酶，特别是PLK4介导的疾病状态的激酶抑制剂的化合物，特别是可用于治疗涉及异常细胞增殖的病理过程的化合物，例如肿瘤生长，类风湿关节炎，再狭窄和动脉粥样硬化。

34. 发明申请

US20100190786A1 INDOLIN-2-ONES AND AZA-INDOLIN-2-ONES 有权
标题翻译：吲哚-2-ONES和AZA-INDOLIN-2-ONES
公开(公告)号：US20100190786A1
公开(公告)日：2010-07-29
申请号：US12663158
申请日：2008-06-20
申请人： Gaston Stanislas Marcella Diels , Marc Gustaaf Celine Verdonck , Peter Jacobus Johannes Antonius Buijnsters , Kristof Van Emelen
发明人： Gaston Stanislas Marcella Diels , Marc Gustaaf Celine Verdonck , Peter Jacobus Johannes Antonius Buijnsters , Kristof Van Emelen
IPC分类号： A61K31/5377 , A61K31/497 , A61K31/529 , C07D498/18 , A61P19/02 , A61P35/04
CPC分类号： C07D209/34 , C07D471/04 , C07D487/04
摘要： The present invention relates to compounds or pharmaceutically-acceptable salts thereof, processes for preparing them, pharmaceutical compositions containing them and their use in therapy. The invention particularly relates to certain indolin-2-ones and aza-indolin-2-ones which possess anti-tumour activity and are accordingly useful in methods of treatment of the human or animal body, in particular such compounds are useful in the treatment of pathological processes which involve an aberrant cellular proliferation, such as tumor growth, rheumatoid arthritis, restenosis and atherosclerosis.
摘要翻译：本发明涉及其化合物或药学上可接受的盐，其制备方法，含有它们的药物组合物及其在治疗中的用途。本发明特别涉及具有抗肿瘤活性的某些二氢吲哚-2-酮和氮杂 - 二氢吲哚-2-酮，因此可用于人或动物体的治疗方法，特别是这些化合物可用于治疗涉及异常细胞增殖的病理过程，例如肿瘤生长，类风湿性关节炎，再狭窄和动脉粥样硬化。

35. 发明申请

US20100048588A1 AMINOCARBONYL-DERIVATIVES AS NOVEL INHIBITORS OF HISTONE DEACETYLASE 有权
标题翻译：氨苄青霉素衍生物作为HISTONE脱乙酰壳多糖的新型抑制剂
公开(公告)号：US20100048588A1
公开(公告)日：2010-02-25
申请号：US12360139
申请日：2009-01-27
申请人： Kristof Van Emelen , Hans Louis Jos De Winter , Alexy Borisovich Dyatkin , Marc Gustaaf Celine Verdonck , Lieven Meerpoel , Jimmy Arnold Viviane Van heusden
发明人： Kristof Van Emelen , Hans Louis Jos De Winter , Alexy Borisovich Dyatkin , Marc Gustaaf Celine Verdonck , Lieven Meerpoel , Jimmy Arnold Viviane Van heusden
IPC分类号： A61K31/4965 , C07D241/04
CPC分类号： C07D413/12 , A61K31/40 , A61K31/402 , A61K31/435 , A61K31/4427 , A61K31/454 , A61K31/4545 , A61K31/472 , A61K31/495 , A61K31/496 , A61K31/506 , A61K31/5377 , A61K31/55 , A61K45/06 , C07D207/09 , C07D207/14 , C07D211/14 , C07D211/58 , C07D213/78 , C07D217/02 , C07D217/04 , C07D217/16 , C07D239/42 , C07D295/155 , C07D295/26 , C07D307/68 , C07D401/04 , C07D401/12 , C07D403/04 , C07D403/12 , C07D405/06 , C07D409/12 , C07D409/14 , C07D413/04 , C07D471/04 , C07D471/10 , C07D513/04 , C12Q1/34 , C12Q1/48
摘要： This invention comprises the novel compounds of formula (I) wherein n, R1, R2, R3, R4, L, Q, X, Y, Z and have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.
摘要翻译：本发明包括具有组蛋白脱乙酰酶抑制酶活性的式（I）的新化合物，其中n，R 1，R 2，R 3，R 4，L，Q，X，Y，Z具有定义的含义; 其制剂，含有它们的组合物及其作为药物的用途。

36. 发明授权

US06509339B2 N-substituted 4-((4′-aminobenzoyl)-oxymethyl)-piperidines having gastric prokinetic properties 有权
标题翻译： N-取代的4 - （（4'-氨基苯甲酰基） - 氧甲基） - 哌啶具有胃动力学性质
公开(公告)号：US06509339B2
公开(公告)日：2003-01-21
申请号：US09933094
申请日：2001-08-20
申请人： Jean-Paul René Marie Bosmans , Christopher John Love , Marc Gustaaf Celine Verdonck , Joannes Adrianus Jacobus Schuurkes
发明人： Jean-Paul René Marie Bosmans , Christopher John Love , Marc Gustaaf Celine Verdonck , Joannes Adrianus Jacobus Schuurkes
IPC分类号： C07D40514
CPC分类号： C07D401/06 , C07D211/22 , C07D401/12 , C07D405/12 , C07D405/14 , C07D417/14
摘要： This invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein R1 is C1-6alkyloxy, C2-6alkenyloxy or C2-6alkynyloxy; R2 is hydrogen or C1-6alkyloxy, or when taken together R1 and R2 may form a bivalent radical of formula wherein in said bivalent radicals one or two hydrogen atoms may be substituted with C1-6alkyl, R3 is hydrogen or halo; L is C3-6cycloalkyl, C5-6cycloalkanone, C2-6alkenyl optionally substituted with aryl, or L is a radical of formula -Alk-R4, -Alk-NR5R6, 1-R6-4-piperidinyl, Alk-X—R7, -Alk-Y—C(═O)—R9, or -Alk-Y—C(═O)—NR11R12 wherein each Alk is C1-12alkanediyl; R4 is hydrogen, C1-6alkylsulfonylamino, C3-6cycloalkyl, C5-6cycloalkanone, Ar-, di(Ar)methyl, Ar-oxy- or Het1; R5 is hydrogen or C1-6alkyl; R6 is Het2; R7 is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C3-6cycloalkyl, Ar or Het2; X is O, S, SO2 or NR8; said R8 being hydrogen, C1-6alkyl or Ar; R9 is hydrogen, C1-6alkyl, C3-6cycloalkyl, Ar, ArC1-6alkyl, di(Ar)methyl, C1-6alkyloxy or hydroxy; Y is NR10 or a direct bond; said R10 being hydrogen, C1-6alkyl or Ar; R11 and R12 each independently are hydrogen, C1-6alkyl, C3-6cycloalkyl, Ar or ArC1-6alkyl, or R11 and R12 combined with the nitrogen atom bearing R11 and R12 may form a pyrrolidinyl or piperidinyl ring both being optionally substituted with C1-6alkyl, amino or mono or di(C1-6alkyl)amino, or said R11 and R12 combined with the nitrogen bearing R11 and R12 may form a piperazinyl or 4-morpholinyl radical both being optionally substituted with C1-6alkyl. Processes for preparing said products, formulations comprising said products and their use as a medicine are disclosed, in particular for treating conditions which are related to impairment of gastric emptying.
摘要翻译：本发明涉及配制N-氧化物形式的化合物，其药学上可接受的酸加成盐及其立体化学异构形式，其中R 1为C 1-6烷氧基，C 2-6烯氧基或C 2-6炔基氧基; R 2是氢或C 1-6烷氧基，或者当R 1和R 2一起形成式2的二价基团时，其中在所述二价基团中，一个或两个氢原子可以被C 1-6烷基取代，R 3是氢或卤素; L是C3-6环烷基，C5-6环烷酮，任选被芳基取代的C2-6烯基，或L是式-Alk-R4，-Alk-NR5R6，1-R6-4-哌啶基，Alk-X-R7， - Alk-YC（= O）-R9或-Alk-YC（= O）-NR11R12，其中每个Alk是C1-12烷二基; R4是氢，C1-6烷基磺酰氨基，C3-6环烷基，C5-6环烷酮，Ar-，二（Ar）甲基，Ar-氧基或Het1; R5是氢或C1-6烷基; R6是Het2; R 7是氢，C 1-6烷基，羟基C 1-6烷基，C 3-6环烷基，Ar或Het 2; X是O，S，SO 2或NR 8; 所述R8为氢，C1-6烷基或Ar; R 9为氢，C 1-6烷基，C 3-6环烷基，Ar，ArC 1-6烷基，二（Ar）甲基，C 1-6烷氧基或羟基; Y是NR10或直接键; 所述R 10为氢，C 1-6烷基或Ar; R 11和R 12各自独立地为氢，C 1-6烷基，C 3-6环烷基，Ar或ArC 1-6烷基，或R 11和R 12与带有R 11和R 12的氮原子结合可以形成吡咯烷基或哌啶基环，其两者均被C 1-6烷基，氨基或单或

37. 发明授权

US08114999B2 Aminocarbonyl-derivatives as novel inhibitors of histone deacetylase 有权
标题翻译：氨基羰基衍生物作为组蛋白脱乙酰酶的新型抑制剂
公开(公告)号：US08114999B2
公开(公告)日：2012-02-14
申请号：US12360139
申请日：2009-01-27
申请人： Kristof Van Emelen , Hans Louis Jos De Winter , Alexy Borisovich Dyatkin , Marc Gustaaf Celine Verdonck , Lieven Meerpoel , Jimmy Arnold Viviane Van heusden
发明人： Kristof Van Emelen , Hans Louis Jos De Winter , Alexy Borisovich Dyatkin , Marc Gustaaf Celine Verdonck , Lieven Meerpoel , Jimmy Arnold Viviane Van heusden
IPC分类号： C07D295/205 , A61K31/495 , A61P35/00
CPC分类号： C07D413/12 , A61K31/40 , A61K31/402 , A61K31/435 , A61K31/4427 , A61K31/454 , A61K31/4545 , A61K31/472 , A61K31/495 , A61K31/496 , A61K31/506 , A61K31/5377 , A61K31/55 , A61K45/06 , C07D207/09 , C07D207/14 , C07D211/14 , C07D211/58 , C07D213/78 , C07D217/02 , C07D217/04 , C07D217/16 , C07D239/42 , C07D295/155 , C07D295/26 , C07D307/68 , C07D401/04 , C07D401/12 , C07D403/04 , C07D403/12 , C07D405/06 , C07D409/12 , C07D409/14 , C07D413/04 , C07D471/04 , C07D471/10 , C07D513/04 , C12Q1/34 , C12Q1/48
摘要： This invention comprises the novel compounds of formula (I) wherein n, R1, R2, R3, R4, L, Q, X, Y, Z and have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.
摘要翻译：本发明包括具有组蛋白脱乙酰酶抑制酶活性的式（I）的新化合物，其中n，R 1，R 2，R 3，R 4，L，Q，X，Y，Z具有定义的含义; 其制剂，含有它们的组合物及其作为药物的用途。

38. 发明授权

US6100262A (2-morpholinylmethyl) benzamide derivatives 有权
标题翻译：（2-吗啉基甲基）苯甲酰胺衍生物
公开(公告)号：US6100262A
公开(公告)日：2000-08-08
申请号：US401729
申请日：1999-09-22
申请人： Marie-Louise Hendrickx , Kurt Godfried Cornelius Emile Van Daele , Peter Jules Victor Van Daele , Glenn Kurt Ludo Van Daele , Frans Maria Alfons Van den Keybus , Marc Gustaaf Celine Verdonck
发明人： Marie-Louise Hendrickx , Kurt Godfried Cornelius Emile Van Daele , Peter Jules Victor Van Daele , Glenn Kurt Ludo Van Daele , Frans Maria Alfons Van den Keybus , Marc Gustaaf Celine Verdonck
IPC分类号： C07D265/32 , A61K31/535 , A61K31/5375 , A61P1/00 , C07D265/30 , C07D413/06
CPC分类号： C07D265/30
摘要： The present invention concerns novel (2-morpholinylmethyl)benzamide derivatives having the formula ##STR1## the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein R.sup.1 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; R.sup.2 is hydrogen, halo or C.sub.1-6 alkylsulfonylamino; R.sup.3 is hydrogen or C.sub.1-6 alkyl; L is a radical of formula R.sup.4 --C(.dbd.O)--Alk-- (a); R.sup.5 --C(.dbd.O)--N(R.sup.6)--Alk-- (b); or R.sup.7 --C(.dbd.O)--O--Alk-- (c); wherein each Alk is independently C.sub.1-12 alkanediyl; R.sup.4 is hydrogen, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, amino, mono- or di(C.sub.1-6 alkyl)amino or an optionally substituted heterocyclic ring; R.sup.5 and R.sup.7 each independently are hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, amino, mono- or di(C.sub.1-6 alkyl)amino or an optionally substituted heterocyclic ring; R.sup.6 is hydrogen or C.sub.1-6 alkyl; and aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents selected from halo, C.sub.1-6 alkyl or C.sub.1-6 alkyloxy. It further relates to pharmaceutical compositions comprising them, processes for preparing said compounds and compositions, and the use thereof as a medicine, in particular in the conditions involving a decreased gastric emptying.
摘要翻译：本发明涉及具有N-氧化物形式的新型（2-吗啉基甲基）苯甲酰胺衍生物，其药学上可接受的加成盐和立体化学异构形式，其中R 1为C 1-6烷基，C 2-6烯基或C 2-6炔基; R2是氢，卤素或C1-6烷基磺酰基氨基; R3是氢或C1-6烷基; L是式R4-C（= O）-Alk-（a）的基团; R5-C（= O）-N（R6）-Alk-（b）; 或R 7 -C（= O）-O-Alk-（c）; 其中每个Alk独立地为C 1-12烷二基; R4是氢，羟基，C1-6烷基，C1-6烷氧基，氨基，单或二（C1-6烷基）氨基或任选取代的杂环; R5和R7各自独立地为氢，C1-6烷基，C1-6烷氧基，氨基，单或二（C1-6烷基）氨基或任选取代的杂环; R6是氢或C1-6烷基; 并且芳基是苯基或被1,2或3个选自卤素，C 1-6烷基或C 1-6烷氧基的取代基取代的苯基。它还涉及包含它们的药物组合物，制备所述化合物和组合物的方法及其作为药物的用途，特别是涉及胃排空减少的病症。

39. 发明授权

US08338422B2 Indolin-2-ones and aza-indolin-2-ones 有权
标题翻译：二氢吲哚-2-酮和氮杂 - 二氢吲哚-2-酮
公开(公告)号：US08338422B2
公开(公告)日：2012-12-25
申请号：US12663158
申请日：2008-06-20
申请人： Gaston Stanislas Marcella Diels , Marc Gustaaf Celine Verdonck , Peter Jacobus Johannes Antonius Buijnsters , Kristof Van Emelen
发明人： Gaston Stanislas Marcella Diels , Marc Gustaaf Celine Verdonck , Peter Jacobus Johannes Antonius Buijnsters , Kristof Van Emelen
IPC分类号： C07D209/34 , C07D471/04 , C07D487/04 , A61K31/404 , A61K31/407 , A61P35/00
CPC分类号： C07D209/34 , C07D471/04 , C07D487/04
摘要： The present invention relates to compounds or pharmaceutically-acceptable salts thereof, processes for preparing them, pharmaceutical compositions containing them and their use in therapy. The invention particularly relates to certain indolin-2-ones and aza-indolin-2-ones which possess anti-tumor activity and are accordingly useful in methods of treatment of the human or animal body, in particular such compounds are useful in the treatment of pathological processes which involve an aberrant cellular proliferation, such as tumor growth, rheumatoid arthritis, restenosis and atherosclerosis.
摘要翻译：本发明涉及其化合物或药学上可接受的盐，其制备方法，含有它们的药物组合物及其在治疗中的用途。本发明特别涉及具有抗肿瘤活性的某些二氢吲哚-2-酮和氮杂 - 二氢吲哚-2-酮，因此可用于人或动物体的治疗方法，特别是这些化合物可用于治疗涉及异常细胞增殖的病理过程，例如肿瘤生长，类风湿性关节炎，再狭窄和动脉粥样硬化。

40. 发明申请

US20110009404A1 4-ARYL-2-ANILINO-PYRIMIDINES 有权
公开(公告)号：US20110009404A1
公开(公告)日：2011-01-13
申请号：US12921499
申请日：2009-03-09
申请人： Peter Jacobus Johannes Buijnsters , Marc Gustaaf Celine Verdonck , Kristof Van Emelen , Pascal Ghislain André Bonnet
发明人： Peter Jacobus Johannes Buijnsters , Marc Gustaaf Celine Verdonck , Kristof Van Emelen , Pascal Ghislain André Bonnet
IPC分类号： A61K31/5377 , C07D487/14 , C07D487/04 , A61K31/519 , A61K31/496 , A61P35/00
CPC分类号： C07D471/08 , C07D471/18 , C07D471/22 , C07D498/08 , C07D498/18
摘要： The present invention relates to compounds of Formula (Ia) or (Ib), the N-oxide forms, pharmaceutically acceptable addition salts, quaternary amines, stereoisomers, tautomers, racemics, metabolites, prodrugs, hydrates, or solvates thereof, wherein Y1, m, n, R1; X1; X2; R2; X3; X4; R3; and R4 have the meaning defined in the claims.The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use in therapy. The invention particularly relates to compounds that are kinase inhibitors useful for the treatment of disease states mediated by kinase, especially PLK4, in particular such compounds that are useful in the treatment of pathological processes which involve an aberrant cellular proliferation, such as tumor growth, rheumatoid arthritis, restenosis and atherosclerosis.
摘要翻译：本发明涉及式（Ia）或（Ib）的化合物，N-氧化物形式，药学上可接受的加成盐，季胺，立体异构体，互变异构体，外消旋学，代谢物，前药，水合物或溶剂化物，其中Y1，，n，R1; X1; X2; R2; X3; X4; R3; 和R4具有权利要求中限定的含义。本发明还涉及制备所述化合物的方法，含有它们的药物组合物及其在治疗中的用途。本发明特别涉及可用于治疗由激酶，特别是PLK4介导的疾病状态的激酶抑制剂的化合物，特别是可用于治疗涉及异常细胞增殖的病理过程的化合物，例如肿瘤生长，类风湿关节炎，再狭窄和动脉粥样硬化。

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