公开(公告)号：US5371077A

公开(公告)日：1994-12-06

申请号：US923423

申请日：1992-08-03

申请人： George J. Schroepfer, Jr. ,  Josef E. Herz ,  Shankar Swaminathan ,  William K. Wilson

发明人： George J. Schroepfer, Jr. ,  Josef E. Herz ,  Shankar Swaminathan ,  William K. Wilson

IPC分类号： C12N9/99 ,  A61K31/575 ,  A61P3/06 ,  A61P43/00 ,  C07J9/00 ,  C07J31/00 ,  C07J41/00 ,  C07J75/00 ,  A61K31/56

CPC分类号： C07J9/005 ,  A61K31/575 ,  C07J31/006 ,  C07J41/0055 ,  C07J9/00

摘要： Pharmaceutical compositions are provided for lowering the activity of HMG-CoA reductase and/or lowering serum cholesterol, comprising an amount effective to lower the activity of HMG-CoA reductase and/or lower serum cholesterol of a side chain derivatized 15-oxygenated sterol having the formula (I): ##STR1## the basic ring structure being saturated or unsaturated, wherein R.sub.1 is --OH, .dbd.O, --OR.sub.7, ##STR2## a sulfate group, a sugar moiety, or a Mg, Na, or K salt of a sulfate group;R.sub.2 is --H, --OH, .dbd.O, mono- or di-halogen, or a C.sub.1 to C.sub.6 alkyl group, which may be unsaturated or substituted with halogen;R.sub.3 is --H, --OH, halogen, or a C.sub.1 to C.sub.6 alkyl group, which may be unsaturated or substituted with halogen;R.sub.4 is nonexistent when there is a double bond between the 8 and 14 carbons or .alpha.H, .beta.H, or an .alpha.C.sub.1 to C.sub.6 alkyl group;R.sub.5 is --OH, .dbd.O, .dbd.NOH, or ##STR3## R.sub.6 is --CH.sub.2 CH(CH.sub.3).sub.2 or CH.sub.2 N(CH.sub.3).sub.2, in which one or more of the hydrogen atoms is replaced by OH or halogen;R.sub.7 is a C.sub.1 to C.sub.6 alkyl group;R.sub.8 is a C.sub.1 to C.sub.20 aliphatic group, which may be substituted or unsubstituted, or a phenyl group; andn is an integer of from 2 to 6; andoptionally a pharmaceutically acceptable carrier or excipient, with the proviso that R.sub.6 is not --CH.sub.2 CH(CH.sub.3)(CH.sub.2 OH). Methods of using the pharmaceutical compositions containing the side chain derivatized 15-oxygenated sterols are also provided.A new process is also provided for preparing side chain derivatized 15-oxygenated sterols. This process includes oxidative cleavage of the saturated side chain of the sterol with trifluoroperacetic acid to give a side chain trifluoroacetate and subsequent hydrolysis of this ester. The resultant side chain alcohol is a valuable and advanced intermediate for the preparation of side chain derivatives of 15-oxygenated sterols.

摘要翻译： 提供了用于降低HMG-CoA还原酶和/或降低血清胆固醇的活性的药物组合物，其包含有效降低HMG-CoA还原酶的活性和/或降低侧链衍生的15-氧化甾醇的血清胆固醇的量，其具有 式（I）：饱和或不饱和的，其中R 1是-OH，= O，-OR 7，硫酸根基团，糖基团或硫酸根基团的Mg，Na或K盐; R2是-H，-OH，= O，单 - 或二 - 卤素，或可以是不饱和的或被卤素取代的C1-C6烷基; R3是-H，-OH，卤素或C1-C6烷基，其可以是不饱和的或被卤素取代的; 在8和14碳之间存在双键或αH，βH或αC1至C6烷基时，R4不存在; R 5是-OH，= O，= NOH，或者R 6是-CH 2 CH（CH 3）2或CH 2 N（CH 3）2，其中一个或多个氢原子被OH或卤素取代; R7是C1-C6烷基; R8是可以是取代或未取代的C1〜C20脂肪族基团或苯基; n为2〜6的整数。 和任选的药学上可接受的载体或赋形剂，条件是R 6不是-CH 2 CH（CH 3）（CH 2 OH）。 还提供了使用含有侧链衍生的15-氧化甾醇的药物组合物的方法。 还提供了用于制备侧链衍生的15-氧化甾醇的新方法。 该方法包括用三氟过乙酸氧化裂解固醇的饱和侧链，得到侧链三氟乙酸盐，随后水解该酯。 所得的侧链醇是制备15-氧化甾醇的侧链衍生物的有价值和先进的中间体。