專利名稱：用于治療阿爾茨海默病的肽類β分泌酶抑制劑及其用途的制作方法
技術領域：
本發(fā)明涉及醫(yī)藥化工領域，具體涉及一類肽類β分泌酶抑制劑及其用于β分泌酶相關疾病(如阿爾茨海默病)的用途。
背景技術：
阿爾茨海默病(Alzheimer's disease，AD)，是老年人由于腦功能障礙而產生的獲得性智能障礙綜合癥。阿爾茨海默病的主要特征是腦部淀粉樣蛋白以胞外斑塊和胞內神經原纖維纏結形式異常沉積。其致病過程非常復雜，目前對該疾病的致病機制和生化變化原因尚缺乏全面的實質性認識，僅有幾種假說解釋AD的成因。其中，β淀粉樣蛋白學說越來越受到普遍接受。淀粉樣蛋白累積率是形成、積聚和從腦部流出速率的綜合反映。淀粉樣蛋白斑塊(senile plaque, SP)的主要成分是淀粉樣蛋白(β-amylod，Aβ )。Αβ是由淀粉樣前體蛋白(amyloid precursor protein, APP)經 β 分泌酶(β secretases，或 β amyloid cleaving enzyme, BACE)裂角軍得至Ij CTF99 (99-amino-acidC-terminal fragment)，CTF99 經 Y分泌酶剪切得到Αβ4(1和Αβ42。其中Αβ4(1與比率為9 1^日42更易相互聚合， 形成淀粉樣蛋白斑塊，在腦中異常沉積，從而形成了阿爾茨海默病的主要病理癥狀(Dermis JS. Amyloid beta-protein and the genetics of Alzheimer ' sdisease[J]. J. Biol. Chem，1996,271 :18295-18298 ；Christian H, Bart DS. The presenilins in Alzheimer' s disease-proteolysis holds the key [J] · Science，1999，286 :916-919)。因此，抑制 β 分泌酶活性的藥物可用于治療阿爾茨海默病(Bart DS, Gerhard K. A firm basefor drug development[J]. Nature, 1999,402 :471-472 ；Dennis JS. Alzheimer' s Disease :Genes, Proteins, and Therapy[J]. Physiological Reviews. 2001,81(2) :741-766)。本發(fā)明的化合物可通過抑制β分泌酶的活性而阻止Αβ的形成并阻止產生SP，從而用于治療阿爾茨海默病。

發(fā)明內容
本發(fā)明涉及一類具有β分泌酶抑制劑活性的肽類化合物，包含這些化合物的藥物組合物以及這些化合物和藥物組合物在治療β分泌酶相關疾病中的用途。本發(fā)明涉及式(I)的化合物、其立體異構體、其無生理毒性的鹽或前藥。
權利要求
1. ー種式(I)的化合物、其立體異構體、其無生理毒性的鹽或前藥
2.根據權利要求1的化合物，其中， A為氨基，B1缺失；或A為氨基，B1缺失，化為缺失、-CH2-或-CH2-CH2-；或A為氨基，B1缺失，化為缺失、-CH2-或-CH2-CH2-, R1為異丙基，R2為異丁基或環(huán)己烷甲基，其中&優(yōu)選為異丁基。
3.根據權利要求1的化合物，其中，D為缺失、-NHCO-或-NHCO-R4，其中R4選自式(VII) 結構中的一種
4.根據權利要求1的化合物，其中，Q為天然氨基酸殘基，或選自式(VIII)結構中的一種，其中手性碳原子的構型為R或 S，其中 R9 為-0Η, -Cl，-Br, -NO3, -NH2, -F 或-I ；R10 為-OH 或-NH2
5.根據權利要求ι的化合物，其中，G 為-Asp，-Asp-Ala，-Asp-Ala-Glu，-Asp-Ala-Glu-Phe，或選自式(IX)結構中的一種， 其中 R11 和 R1/為各自獨立的-C00H，-CONH2,-0H,-Cl,-F,-Br,-!,-CF3,-NO2,-COCF3,-CONHS
6.根據權利要求5的化合物，G為-Asp，-Asp-Ala,-Asp-Ala-Glu 或-Asp-Ala-Glu-Phe0
7.根據權利要求1-6任一項的化合物，其選自以下的化合物、其立體異構體、其無生理毒性的鹽或前藥中的至少一種(1)Glu-Val-Leu-Pro-Asp-Ala-Glu-Phe(2)Glu-Val-Leu-D-Pro-Asp-Ala-Glu-Phe(3)Glu-Val-Leu-Ser-Asp-Ala-Glu-Phe(4)Glu-Val-Leu-D-Ser-Asp-Ala-Glu-Phe(5)Glu-Val-Leu-Thr-Asp-Ala-Glu-Phe(6)Glu-Val-Leu-Tyr-Asp-Ala-Glu-Phe(7)Glu-Val-Leu-His-Asp-Ala-Glu-Phe(8)Glu-Val-Leu-Trp-Asp-Ala-Glu-Phe(9)Glu-Val-Leu-D-Trp-Asp-Ala-Glu-Phe(10)Glu-Val-Leu-Met-Asp-Ala-Glu-Phe(11)Glu-Val-Leu-Phe-Asp-Ala-Glu-Phe(12)Glu-Val-Leu-D-Phe-Asp-Ala-Glu-Phe(13)Glu-Val-Leu-Phe (4-N02) -Asp-Ala-Glu-Phe(14)Glu-Val-Leu-D-Phe (4-N02) -Asp-Ala-Glu-Phe(15)Glu-Val-Leu-Phe (4-NH2) -Asp-Ala-Glu-Phe(16)Glu-Val-Leu-D-Phe (4-NH2) -Asp-Ala-Glu-Phe(17)Glu-Val-Leu-Phe(4-C1)-Asp-Ala-Glu-Phe(18)Glu-Val-Leu-D-Phe(4-C1)-Asp-Ala-Glu-Phe(19)Glu-Val-Leu-Phe (3_N02) -Asp-Ala-Glu-Phe(20)Glu-Val-Leu-Phe (3_NH2) -Asp-Ala-Glu-Phe(21)Glu-Val-Leu-Phe(2-F)-Asp-Ala-Glu-Phe(22)Glu-Val-Leu-Phe(3-F)-Asp-Ala-Glu-Phe(23)Glu-Val-Leu-Phe(4-F)-Asp-Ala-Glu-Phe(24)Glu-Val-Leu-Phe(2-C1)-Asp-Ala-Glu-Phe(25)Glu-Val-Leu-Phe(3-C1)-Asp-Ala-Glu-Phe(26)Glu-Val-Leu-Phe(2_Br)-Asp-Ala-Glu-Phe(27)Glu-Val-Leu-Phe(3-Br)-Asp-Ala-Glu-Phe(28)Glu-Val-Leu-Phe(4-Br)-Asp-Ala-Glu-Phe(29)Glu-Val-Leu-Phe (2-CH3) -Asp-Ala-Glu-Phe(30)Glu-Val-Leu-Phe (3_CH3) -Asp-Ala-Glu-Phe(31)Glu-Val-Leu-Phe (4-CH3) -Asp-Ala-Glu-Phe(32)Glu-Val-Leu-Phe(2，3-difluorine)-Asp-Ala-Glu-Phe(33)Glu-Val-Leu-Phe(2,4-difluorine)-Asp-Ala-Glu-Phe(34)Glu-Val-Leu-Phe(3,4-difluorine)-Asp-Ala-Glu-Phe(35)Glu-Val-Leu-Phe(2,4-dichlorine)-Asp-Ala-Glu-Phe(36)Glu-Val-Leu-Phe(3,4-dichlorine)-Asp-Ala-Glu-Phe(37)Glu-Val-Leu-Phe(2，3-dichlorine)-Asp-Ala-Glu-Phe(38)Glu-Val-Leu-Phe(2，4-dibromine)-Asp-Ala-Glu-Phe(39)Glu-Val-Leu-Phe(3,4-dibromine)-Asp-Ala-Glu-Phe(40)Glu-Val-Leu-Phe(2，3-dibromine)-Asp-Ala-Glu-Phe(41)Glu-Val-Leu-Phe(2，4-dimethyl)-Asp-Ala-Glu-Phe(42)Glu-Val-Leu-Phe(3,4-dimethyl)-Asp-Ala-Glu-Phe(43)Glu-Val-Leu-Phe(2，3-dimethyl)-Asp-Ala-Glu-Phe(44)Glu-Val-Leu-Phe(3-Br,4-C1)-Asp-Ala-Glu-Phe(45)Glu-Val-Leu-Phe(2-Br,4-C1)-Asp-Ala-Glu-Phe(46)Glu-Val-Leu-Phe(3-C1，4-Br)-Asp-Ala-Glu-Phe(47)Glu-Val-Leu-Phe(3-F,4-C1)-Asp-Ala-Glu-Phe(48)Glu-Val-Leu-Phe(2-F,4-C1)-Asp-Ala-Glu-Phe(49)Glu-Val-Leu-Phe(3-C1，4_F)-Asp-Ala-Glu-Phe(50)Glu-Val-Leu-2-Nal-Asp-Ala-Glu-Phe(51)Glu-Val-Leu-D-2-Nal-Asp-Ala-Glu-Phe(52)Glu-Val-Leu- y - (trans, L) -Pro (4-NH2) -Asp-Ala-Glu-Phe(53)Glu-Val-Leu- y-(cis, L) -Pro (4_NH2) -Asp-Ala-Glu-Phe(54)Glu-Val-Leu- y - (trans, D) -Pro (4_NH2) -Asp-Ala-Glu-Phe(55)Glu-Val-Leu- y-(cis, D) -Pro (4_NH2) -Asp-Ala-Glu-Phe(56)Glu-Val-Leu-(trans,L)-Pro (4-OH)-Asp-Ala-Glu-Phe(57)Glu-Val-Leu-(cis,L)-Pro (4-OH)-Asp-Ala-Glu-Phe(58)Glu-Val-Leu-(trans,D)-Pro (4-OH)-Asp-Ala-Glu-Phe(59)Glu-Val-Leu-(cis,D)-Pro (4-OH)-Asp-Ala-Glu-Phe(60)Glu-Val-Leu- (trans, L) -Pro (4-NH2) -Asp-Ala-Glu-Phe (61)Glu-Val-Leu-(cis, L) -Pro (4-NH2) -Asp-Ala-Glu-Phe(62)Glu-Val-Leu- (trans, D) -Pro (4_NH2) -Asp-Ala-Glu-Phe(63)Glu-Val-Leu- (cis, D) -Pro (4_NH2) -Asp-Ala-Glu-Phe(64)Glu-Val-Leu-Phe-D-Pro-Asp-Ala-Glu-Phe(65)Glu-Val-Leu-Phe-(cis,D)-Pro (4-OH)-Asp-Ala-Glu-Phe66Glu--Va-Leu--Phe--(cis，D) -Pro (4-NH2) -Asp-Ala-Glu-Phe67Glu--Va-Leu--Phe--(cis, D)-y -Pro (4_NH2) -Asp-Ala-Glu-Phe68Glu--Va-Leu--Phe--(trans, D)-Pro (4_0H)-Asp-Ala-Glu-Phe69Glu--Va-Leu--Phe--(trans, D) -Pro (4_NH2) -Asp-Ala-Glu-Phe70Glu--Va-Leu--Phe--(trans, D)- y -Pro (4_NH2) -Asp-Ala-Glu-Phe71Glu--Va-Leu--Phe--(cis, D)-Pro (5-0H)-Asp-Ala-Glu-Phe72Glu--Va-Leu--Phe--(cis, D) - ω -Pro (5_NH2) -Asp-Ala-Glu-Phe73Glu--Va-Leu--Phe--(cis, D) -Pro (5-NH2) -Asp-Ala-Glu-Phe74Glu--Va-Leu--Phe--(trans, D)-Pro (5_0H)-Asp-Ala-Glu-Phe75Glu--Va-Leu--Phe--(trans, D) - ω -Pro (5_NH2) -Asp-Ala-Glu-Phe76Glu--Va-Leu--Phe--(trans, D) -Pro (5_NH2) -Asp-Ala-Glu-Phe77Glu--Va-Leu-Tyr-D-Pro-Asp-Ala-Glu-Phe78Glu--Va-Leu-His-D-Pro-Asp-Ala-Glu-Phe79Glu--Va-Leu-Trp--D-Pro-Asp-Ala-Glu-Phe80Glu--Va-Leu--Phe4-N02)-D-Pro-Asp-Ala-Glu-Phe81Glu--Va-Leu--Phe4-NH2)-D-Pro-Asp-Ala-Glu-Phe82Glu--Va-Leu--Phe4-C1)-D-Pro-Asp-Ala-Glu-Phe83Glu--Va-Leu--Phe4-Br)-D-Pro-Asp-Ala-Glu-Phe84Glu--Va-Leu--Phe3-N02)-D-Pro-Asp-Ala-Glu-Phe85Glu--Va-Leu--Phe3-NH2)-D-Pro-Asp-Ala-Glu-Phe86Glu--Va-Leu--Phe2-F)-D-Pro-Asp-Ala-Glu-Phe87Glu--Va-Leu--Phe3-F)-D-Pro-Asp-Ala-Glu-Phe88Glu--Va-Leu--Phe4-F)-D-Pro-Asp-Ala-Glu-Phe89Glu--Va-Leu--Phe2-C1)-D-Pro-Asp-Ala-Glu-Phe90Glu--Va-Leu--Phe3-C1)-D-Pro-Asp-Ala-Glu-Phe91Glu--Va-Leu--Phe2-Br)-D-Pro-Asp-Ala-Glu-Phe92Glu--Va-Leu--Phe3-Br)-D-Pro-Asp-Ala-Glu-Phe93Glu--Va-Leu--Phe4-Br)-D-Pro-Asp-Ala-Glu-Phe94Glu--Va-Leu--Phe2-CH3)-D-Pro-Asp-Ala-Glu-Phe95Glu--Va-Leu--Phe3- ) -D-Pro-Asp-Ala-Glu-Phe96Glu--Va-Leu--Phe4- ) -D-Pro-Asp-Ala-Glu-Phe97Glu--Va-Leu--Phe2,3-difluorine)-D-Pro-Asp-Ala-Glu-Phe98Glu--Va-Leu--Phe2,4-difluorine)-D-Pro-Asp-Ala-Glu-Phe99Glu--Va-Leu--Phe3,4-difluorine)-D-Pro-Asp-Ala-Glu-Phe100)Glu-Val-Leu-Phe(2,4-dichlorine)-D-Pro-Asp-Ala-Glu-Phe101)Glu-Val-Leu-Phe(3,4-dichlorine)-D-Pro-Asp-Ala-Glu-Phe102)Glu-Val-Leu-Phe(2,3-dichlorine)-D-Pro-Asp-Ala-Glu-Phe103)Glu-Val-Leu-Phe(2，4-dibromine)-D-Pro-Asp-Ala-Glu-Phe104)Glu-Val-Leu-Phe(3,4-dibromine)-D-Pro-Asp-Ala—Glu—Phe105Glu--Va-Leu-Phe (2,3-dibromine)-D-Pro-Asp-Ala-Glu-Phe106Glu--Va-Leu-Phe (2,4-dimethyl)-D-Pro-Asp-Ala-Glu-Phe107Glu--Va-Leu-Phe (3,4-dimethyl)-D-Pro-Asp-Ala-Glu-Phe108Glu--Va-Leu-Phe(2，3-dimethyl)-D-Pro-Asp-Ala-Glu-Phe109Glu--Va-Leu-Phe(3_Br，4_C1)-D-Pro-Asp-Ala-Glu-Phe110Glu--Va-Leu-Phe(2_Br，4_C1)-D-Pro-Asp-Ala-Glu-Phe111Glu--Va-Leu-Phe (3-C1，4-Br)-D-Pro-Asp-Ala-Glu-Phe112Glu--Va-Leu-Phe(3_F，4-C1)-D-Pro-Asp-Ala-Glu-Phe113Glu--Va-Leu-Phe (2-F,4-C1)-D-Pro-Asp-Ala-Glu-Phe114Glu--Va-Leu-Phe(3-C1，4_F)-D-Pro-Asp-Ala-Glu-Phe115Glu--Va-Leu-2-Nal-D-Pro-Asp-Ala-Glu-Phe116Glu--Va-Leu-Tyr-Asp117Glu--Va-Leu-His-Asp118Glu--Va-Leu-Trp-Asp120Glu--Va-Leu-Met-Asp121Glu--Va-Leu-Phe-Asp122Glu--Va-Leu-Phe (4_N02) -Asp123Glu--Va-Leu-Phe (4-NH2) -Asp124Glu--Va-Leu-Phe(4-C1)-Asp125Glu--Va-Leu-Phe (3_N02) -Asp126Glu--Va-Leu-Phe (3_NH2) -Asp127Glu--Va-Leu-Phe(2-F)-Asp128Glu--Va-Leu-Phe(3_F)-Asp129Glu--Va-Leu-Phe(4_F)-Asp130Glu--Va-Leu-Phe(2-C1)-Asp131Glu--Va-Leu-Phe(3-C1)-Asp132Glu--Va-Leu-Phe(2_Br)-Asp133Glu--Va-Leu-Phe(3_Br)-Asp134Glu--Va-Leu-Phe(4_Br)-Asp135Glu--Va-Leu-Phe (2-CH3) -Asp136Glu--Va-Leu-Phe (3_CH3) -Asp137Glu--Va-Leu-Phe (4-CH3) -Asp138Glu--Va-Leu-Phe(2,3-difluorine)-Asp139Glu--Va-Leu-Phe (2,4-difluorine)-Asp140Glu--Va-Leu-Phe (3,4-difluorine)-Asp141Glu--Va-Leu-Phe(2,4-dichlorine)-Asp142Glu--Va-Leu-Phe(3,4-dichlorine)-Asp143Glu--Va-Leu-Phe (2,3-dichlorine)-Asp144Glu--Va-Leu-Phe (2,4-dibromine)-Asp(145Glu--Va-Leu-Phe(3,4-dibromine)-Asp(146Glu--Va-Leu-Phe (2,3-dibromine)-Asp(147Glu--Va-Leu-Phe (2,4-dimethyl)-Asp(148Glu--Va-Leu-Phe (3,4-dimethyl)-Asp(149Glu--Va-Leu-Phe(2,3-dimethyl)-Asp(150Glu--Va-Leu-Phe(3-Br,4-C1)-Asp(151Glu--Va-Leu-Phe(2-Br,4-C1)-Asp(152Glu--Va-Leu-Phe(3-C1，4_Br)-Asp(153Glu--Va-Leu-Phe(3_F，4-C1)-Asp(154Glu--Va-Leu-Phe(2-F,4-C1)-Asp(155Glu--Va-Leu-Phe(3-C1，4_F)-Asp(156Glu--Va-Leu-2-Nal-Asp(157Glu--Va-Leu-Phe-D-Pro-Asp-Ala-Glu-Phe(158Glu--Va-Leu-Phe-(c i s，D)-Pro(4-OH)-Asp(159Glu--Va-Leu-Phe- (cis, D) -Pro (4_NH2) -Asp(160Glu--Va-Leu-Phe-(cis, D)- y -Pro (4_NH2)-Asp(161Glu--Va-Leu-Phe-(trans, D)-Pro(4-OH)-Asp(162Glu--Va-Leu-Phe- (trans, D) -Pro (4_NH2) -Asp(163Glu--Va-Leu-Phe- (trans, D)- y -Pro (4_NH2) -Asp(164Glu--Va-Leu-Phe- (cis, D) -Pro (5-0H) -Asp(165Glu--Va-Leu-Phe- (c i s, D) - ω -Pro (5_NH2) -Asp(166Glu--Va-Leu-Phe- (cis, D) -Pro (5_NH2) -Asp(167Glu--Va-Leu-Phe- (trans, D) -Pro (5-OH) -Asp(168Glu--Va-Leu-Phe- (trans, D) - ω -Pro (5_NH2) -Asp(169Glu--Va-Leu-Phe- (trans, D) -Pro (5_NH2) -Asp(170Glu--Va-Leu-Tyr-D-Pro-Asp(171Glu--Va-Leu-His-D-Pro-Asp(172Glu--Va-Leu-Trp-D-Pro-Asp(173Glu--Va-Leu-Phe (4_N02) -D-Pro-Asp(174Glu--Va-Leu-Phe (4_NH2) -D-Pro-Asp(175Glu--Va-Leu-Phe(4-C1)-D-Pro-Asp(176Glu--Va-Leu-Phe (4_Br)-D-Pro-Asp(177Glu--Va-Leu-Phe (3_N02) -D-Pro-Asp(178Glu--Va-Leu-Phe (3_NH2) -D-Pro-Asp(179Glu--Va-Leu-Phe(2-F)-D-Pro-Asp(180Glu--Va-Leu-Phe (3_F)-D-Pro-Asp(181Glu--Va-Leu-Phe(4_F)-D-Pro-Asp(182Glu--Va-Leu-Phe (2-C1)-D-Pro-Asp(183Glu--Va-Leu-Phe (3—C1)-D-Pro-Asp(184)Glu-Val-Leu--Phe2-Br)-D-Pro-Asp(185)Glu-Val-Leu--Phe3-Br)-D-Pro-Asp(186)Glu-Val-Leu--Phe4-Br)-D-Pro-Asp(187)Glu-Val-Leu--Phe2-CH3) -D-Pro-Asp(188)Glu-Val-Leu--Phe3- ) -D-Pro-Asp(189)Glu-Val-Leu--Phe4- ) -D-Pro-Asp(190)Glu-Val-Leu--Phe2,3-difluorine)-D-Pro-Asp(191)Glu-Val-Leu--Phe2,4-difluorine)-D-Pro-Asp(192)Glu-Val-Leu--Phe3,4-difluorine)-D-Pro-Asp(193)Glu-Val-Leu--Phe2,4-dichlorine)-D-Pro-Asp(194)Glu-Val-Leu--Phe3,4-dichlorine)-D-Pro-Asp(195)Glu-Val-Leu--Phe2,3-dichlorine)-D-Pro-Asp(196)Glu-Val-Leu--Phe2,4-dibromine)-D-Pro-Asp(197)Glu-Val-Leu--Phe3,4-dibromine)-D-Pro-Asp(198)Glu-Val-Leu--Phe2,3-dibromine)-D-Pro-Asp(199)Glu-Val-Leu--Phe2,4-dimethyl)-D-Pro-Asp(200)Glu-Val-Leu--Phe3,4-dimethyl)-D-Pro-Asp(221)Glu-Val-Leu--Phe2,3-dimethyl)-D-Pro-Asp(222)Glu-Val-Leu--Phe3-Br,4-C1)-D-Pro-Asp(223)Glu-Val-Leu--Phe2-Br,4-C1)-D-Pro-Asp(224)Glu-Val-Leu--Phe3-Cl,4-Br)-D-Pro-Asp(225)Glu-Val-Leu--Phe3-F,4-Cl)-D-Pro-Asp(226)Glu-Val-Leu--Phe2-F,4-Cl)-D-Pro-Asp(227)Glu-Val-Leu--Phe3-Cl，4-F)-D-Pro-Asp(228)Glu-Val-Leu--2-Nal-D-Pro-Asp(229)Glu-Val-Leu--Pro--Asp(230)Glu-Val-Leu--D-Pro-Asp
8.藥物組合物，其含有至少一種權利要求1-7任一項的化合物以及可藥用載體或賦形劑或輔劑。
9.權利要求1-7任一項的化合物用于制備抑制哺乳動物β分泌酶活性，預防或治療 β分泌酶相關疾病(如阿爾茨海默病)的藥物的用途。
10.權利要求1-7任一項的化合物用于制備β分泌酶抑制劑的用途。
全文摘要
本發(fā)明涉及一類具有β分泌酶抑制活性的通式I的肽類化合物及其立體異構體、無生理毒性的鹽或前藥；包含通式I化合物或其立體異構體或其無生理毒性的鹽或其前藥的藥物組合物；通式I化合物或其立體異構體或其無生理毒性的鹽或其前藥用于制備藥物的用途，所述藥物用于抑制β分泌酶活性，預防或治療β分泌酶相關疾病(如阿爾茨海默病)。
文檔編號A61P25/28GK102344485SQ20101024592
公開日2012年2月8日 申請日期2010年8月5日 優(yōu)先權日2010年8月5日
發(fā)明者何軍林, 劉克良, 周文霞, 張永祥, 徐亮, 程軍平, 門秀峰 申請人:中國人民解放軍軍事醫(yī)學科學院毒物藥物研究所