Macrocyclic compounds having aspartic protease inhibiting activity and pharmaceutical uses thereof
申请人:Betschart Claudia
公开号:US20060223745A1
公开(公告)日:2006-10-05
The present invention relates to macrocyclic compounds of formula (I), wherein R
1
, is (C
1-8
)alkyl, (C
1-4
)alkoxy(C
1-4
)alkyl, hydroxy(C
1-6
)alkyl, (C
1-4
)alkylthio(C
1-4
)alkyl, (C
1-6
)alkenyl, (C
3-7
)cycloalkyl, (C
3-7
)cycloalkyl(C
1-4
)alkyl, piperidinyl or pyrrolidinyl, R
2
and R
4
, independently, are hydrogen or optionally substituted (C
1-8
)alkyl, (C
3-7
)cycloalkyl, (C
3-7
)cycloalkyl(C
1-4
)alkyl, aryl, aryl(C
1-4
)alkyl, heteroaryl or heteroaryl(C
1-4
)alkyl, or R
2
and R
4
, together with the nitrogen to which they are attached, form an optionally substituted piperidino, pyrrolidinyl, morpholino or piperazinyl group, R
3
is hydrogen or (C
1-4
)alkyl, X
1
is CH
2
, X
2
is CH
2
, O, S, CO, COO, OCO, NHCO, CONH, or NR, R being hydrogen or (C
1-4
)alkyl, Y is (C
1-8
)alkylen or (C
1-8
)alkylenoxy(C
1-6
)alkylen, (C
1-8
)alkenylen or (C
1-6
)alkenylenoxy(C
1-6
)alkylen, Ar is a phenyl ring optionally mono- di or trisubstituted by, independently, hydroxy or halogen, whereby X
1
, and X
2
are in meta or para position to each other, and either Z is CO, AA is a natural or unnatural alpha-amino-acid, and n is 0 or 1, or Z is SO
2
, AA is an optionally substituted ethylencarbonyl group (derived from a natural or unnatural alpha-amino acid by replacement of the nitrogen by a methylen group), and n is 1; processes for the preparation of these compounds; pharmaceutical compositions and combinations comprising the same; and their use in the treatment of neurological and vascular disorders related to beta-amyloid generation and/or aggregation.
本发明涉及式(I)的大环化合物,其中R1为(C1-8)烷基,(C1-4)烷氧基(C1-4)烷基,羟基(C1-6)烷基,(C1-4)烷基硫基(C1-4)烷基,(C1-6)烯基,(C3-7)环烷基,(C3-7)环烷基(C1-4)烷基,哌啶基或吡咯烷基,R2和R4独立地为氢或可选取代的(C1-8)烷基,(C3-7)环烷基,(C3-7)环烷基(C1-4)烷基,芳基,芳基(C1-4)烷基,杂环芳基或杂环芳基(C1-4)烷基,或R2和R4与它们附着的氮一起形成可选取代的哌啶基,吡咯烷基,吗啉基或哌嗪基,R3为氢或(C1-4)烷基,X1为CH2,X2为CH2,O,S,CO,COO,OCO,NHCO,CONH或NR,其中R为氢或(C1-4)烷基,Y为(C1-8)烷基或(C1-8)烷氧基(C1-6)烷基,(C1-8)烯基或(C1-6)烯氧基(C1-6)烷基,Ar为苯环,可选取代,独立地为羟基或卤素,其中X1和X2在彼此的间位或对位,且Z为CO时,AA为天然或非天然α-氨基酸,n为0或1,或Z为SO2时,AA为可选取代的乙烯羰基(通过将氮替换为甲基烷基而来自天然或非天然α-氨基酸),n为1;制备这些化合物的方法;包含它们的制药组合物和组合物;以及它们在治疗与β-淀粉样蛋白生成和/或聚集有关的神经和血管疾病中的用途。