U.S. patent application number 15/685150 was filed with the patent office on 2017-12-07 for derivatives of betulin.
The applicant listed for this patent is GLAXOSMITHKLINE LLC. Invention is credited to Mark Andrew HATCHER, Brian Alvin Johns, Michael Tolar Martin, Elie Amine Tabet, Jun Tang.
Application Number | 20170348324 15/685150 |
Document ID | / |
Family ID | 48613199 |
Filed Date | 2017-12-07 |
United States Patent
Application |
20170348324 |
Kind Code |
A1 |
HATCHER; Mark Andrew ; et
al. |
December 7, 2017 |
DERIVATIVES OF BETULIN
Abstract
The present invention relates to compounds characterized by
having a structure according to the following Formula I:
##STR00001## , or a pharmaceutically acceptable salt thereof.
Compounds of the present invention are useful for the treatment or
prevention of HIV.
Inventors: |
HATCHER; Mark Andrew;
(Durham, NC) ; Johns; Brian Alvin; (Durham,
NC) ; Martin; Michael Tolar; (Durham, NC) ;
Tabet; Elie Amine; (Durham, NC) ; Tang; Jun;
(Durham, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GLAXOSMITHKLINE LLC |
Wilmington |
DE |
US |
|
|
Family ID: |
48613199 |
Appl. No.: |
15/685150 |
Filed: |
August 24, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14757754 |
Dec 23, 2015 |
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15685150 |
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14365802 |
Jun 16, 2014 |
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PCT/US12/69637 |
Dec 14, 2012 |
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14757754 |
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61576448 |
Dec 16, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 265/30 20130101;
C07D 207/09 20130101; A61K 31/225 20130101; C07C 2603/52 20170501;
C07C 225/14 20130101; A61K 31/44 20130101; A61K 31/551 20130101;
A61K 31/397 20130101; A61K 31/505 20130101; C07C 211/10 20130101;
C07D 239/48 20130101; A61K 31/568 20130101; C07D 498/14 20130101;
C07J 63/008 20130101; C07C 219/24 20130101; C07C 2601/02 20170501;
A61K 31/506 20130101; A61K 45/06 20130101; A61P 31/12 20180101;
C07C 233/33 20130101; C07C 215/08 20130101; A61K 31/222 20130101;
A61K 31/58 20130101; C07D 239/26 20130101; A61K 31/5375 20130101;
A61K 31/472 20130101; C07D 413/06 20130101; C07C 69/34 20130101;
A61K 31/495 20130101; C07C 211/38 20130101; C07C 2601/14 20170501;
C07D 217/04 20130101; A61K 31/54 20130101; C07J 53/002 20130101;
A61K 31/4985 20130101; C07D 243/08 20130101; A61P 31/18 20180101;
A61K 31/40 20130101; A61K 31/56 20130101; A61P 31/00 20180101; C07D
265/32 20130101; C07D 213/40 20130101; C07C 217/26 20130101; C07D
205/04 20130101; C07C 211/04 20130101; C07C 219/06 20130101 |
International
Class: |
A61K 31/568 20060101
A61K031/568; C07J 53/00 20060101 C07J053/00; A61K 31/222 20060101
A61K031/222; A61K 31/225 20060101 A61K031/225; A61K 31/397 20060101
A61K031/397; C07D 498/14 20060101 C07D498/14; C07D 413/06 20060101
C07D413/06; C07D 265/32 20060101 C07D265/32; C07D 265/30 20060101
C07D265/30; C07D 243/08 20060101 C07D243/08; C07D 239/48 20060101
C07D239/48; C07D 239/26 20060101 C07D239/26; C07D 217/04 20060101
C07D217/04; C07D 213/40 20060101 C07D213/40; C07D 207/09 20060101
C07D207/09; C07D 205/04 20060101 C07D205/04; C07C 233/33 20060101
C07C233/33; C07C 225/14 20060101 C07C225/14; C07C 219/24 20060101
C07C219/24; C07C 219/06 20060101 C07C219/06; C07C 217/26 20060101
C07C217/26; C07C 215/08 20060101 C07C215/08; C07C 211/38 20060101
C07C211/38; C07C 211/10 20060101 C07C211/10; C07C 211/04 20060101
C07C211/04; C07C 69/34 20060101 C07C069/34; A61K 45/06 20060101
A61K045/06; A61K 31/58 20060101 A61K031/58; A61K 31/551 20060101
A61K031/551; A61K 31/54 20060101 A61K031/54; A61K 31/5375 20060101
A61K031/5375; A61K 31/506 20060101 A61K031/506; A61K 31/505
20060101 A61K031/505; A61K 31/4985 20060101 A61K031/4985; A61K
31/495 20060101 A61K031/495; A61K 31/472 20060101 A61K031/472; A61K
31/44 20060101 A61K031/44; A61K 31/40 20060101 A61K031/40; C07J
63/00 20060101 C07J063/00 |
Claims
1. A compound having the structure of Formula I: ##STR00758## or a
pharmaceutically acceptable salt thereof, wherein: A is
##STR00759## L.sub.1 and L.sub.2 are independently selected from a
bond or [C(R.sup.6R.sup.6')].sub.q; each instance of Q is
independently selected from--CH.sub.2-- or --C(.dbd.O)--; W is
selected from a bond or O; R.sup.1 is selected from the group
consisting of --H, (C.sub.1-C.sub.12)alkyl, --C(O)R.sup.5,
--CH.sub.2--O--(C.sub.1-C.sub.6)alkyl, 2-tetrahydro-2H-pyran, and
##STR00760## R.sup.2 is selected from the group consisting of --H,
(C.sub.1-C.sub.12)alkyl, --(C.sub.1-C.sub.6)alkyl-OR.sup.4,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.5,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, and
--(CH.sub.2).sub.rN.sup.+(R.sup.4).sub.3, wherein when W is O,
R.sup.1 and R.sup.2 can optionally be taken together with the O and
N to which they are respectively joined to form a 4 to 8 membered
heterocyclyl ring, wherein the heterocyclyl ring may be optionally
substituted by one to two R.sup.11 groups; R.sup.3 is selected from
the group consisting of hydrogen, (C.sub.1-C.sub.12)alkyl,
--NR.sup.1R.sup.2, --OR.sup.5, ##STR00761## wherein: X is a
monocyclic or bicyclic (C.sub.6-C.sub.1a)aryl, Y is selected from a
monocyclic or bicyclic (C.sub.2-C.sub.6)heterocyclyl or monocyclic
or bicyclic (C.sub.2-C.sub.6)heteroaryl, each having one to three
heteroatoms selected from S, N or O, and Z is a monocyclic or
bicyclic (C.sub.3-C.sub.8)cycloalkyl; R.sup.2 and R.sup.3 can
optionally be taken together with the nitrogen and L.sub.2 to which
they are respectively joined to form a 4 to 8 membered heterocyclyl
ring, wherein the heterocyclyl ring may be optionally substituted
by one to two R.sup.11 groups; R.sup.4 is selected from the group
consisting of --H and (C.sub.1-C.sub.6)alkyl; R.sup.5 is selected
from the group consisting of --H, (C.sub.1-C.sub.6)alkyl,
--R.sup.3, --(CH.sub.2).sub.rNR.sup.7R.sup.8, and
--(CH.sub.2).sub.rOR.sup.7. R.sup.6 and R.sup.6' are independently
selected from the group consisting of --H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, haloalkyl,
--Y, --(CH.sub.2).sub.rNR.sup.7R.sup.8, --C(O)OH, and
--C(O)NH.sub.2, wherein the R.sup.6 and R.sup.6' groups can
optionally be taken together with the carbon to which they are
joined to form a 3 to 8 membered cycloalkyl ring, and wherein the
cycloalkyl ring may be optionally substituted by one to three
R.sup.11 groups; R.sup.7 and R.sup.8 are independently selected
from the group consisting of --H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, -Q-aryl-(R.sup.4).sub.n,
--NR.sup.14R.sup.15, --C(O)CH.sub.3, wherein R.sup.7 and R.sup.8
can optionally be taken together with the nitrogen to which they
are joined to form a 4 to 8 membered heterocyclyl or heteroaryl
ring containing one to three heteroatoms selected from
--NR.sup.5--, --O--, --S--, --S(O)--, or --SO.sub.2--, wherein the
heterocyclyl or heteroaryl ring may be optionally substituted by
one to three R.sup.11 groups; R.sup.9 is halo; R.sup.10 is
--N(R.sup.16).sub.2; R.sup.11, R.sup.12, and R.sup.13 are
independently selected from the group consisting of oxo, hydroxyl,
halo, (C.sub.1-C.sub.6)alkoxy, --R.sup.6(R.sup.9).sub.q,
--OR.sup.6(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.10, --R.sup.4YR.sup.6,
--CO(O)R.sup.4, and --CO(O)R.sup.5, wherein any two R.sup.11,
R.sup.12 or R.sup.13 groups can optionally join to form a 3 to 8
membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring, wherein
the heterocyclyl or heteroaryl ring may contain one to three
heteroatoms selected from --NR.sup.5--, --O--, --S--, --S(O)--, or
--SO.sub.2--, and wherein the cycloalkyl, aryl, heterocyclyl or
heteroaryl ring may be optionally substituted by one to three
R.sup.16 groups; R.sup.14 and R.sup.15 are independently selected
from the group consisting of --H, (C.sub.1--C--.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy,
--[C(R.sup.6).sub.2].sub.r--, --O[C(R.sup.6).sub.2].sub.r--, oxo,
hydroxyl, halo, --C(O)R.sup.7, --R.sup.10, and --CO(O)R.sup.2,
wherein R.sup.14 and R.sup.15 can optionally be taken together with
the carbon to which they are joined to form a 3 to 8 membered
cycloalkyl ring or 4 to 8 membered heterocyclyl ring containing one
to three heteroatoms selected from --NR.sup.5--, --O--, --S--,
--S(O)--, or --SO.sub.2--, wherein the cycloalkyl ring or
heterocyclyl ring may be optionally substituted by one to three
R.sup.16 groups; R.sup.16 is independently selected from the group
consisting of --H, halo, oxo, hydroxyl, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
--R.sup.6(R.sup.9).sub.q, --OR.sup.6(R.sup.9).sub.q,
--N(R.sup.4).sub.2, --(CH.sub.2).sub.r-heterocyclyl, --C(O)OH,
--C(O)NH.sub.2, --R.sup.5(R.sup.9).sub.q,
--OR.sup.5(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
--C(O)R.sup.10, and --CO(O)R.sup.4; m and n in each instance are
independently 0, 1, 2, 3, or 4; p is independently 0, 1, 2, 3, or
4; and r and q in each instance are independently 0, 1, 2, 3, or
4.
2. The compound of claim 1, wherein L.sub.1 and L.sub.2 are both
[C(R.sup.6R.sup.6')].sub.q.
3. The compound of claim 1, wherein L.sub.1 and L.sub.2 are both
--CH.sub.2--.
4. The compound of claim 1, wherein each instance of q is
independently 1, 2, or 3.
5. The compound of claim 1, wherein q is 1.
6. The compound of claim 1, wherein W is O.
7. The compound of claim 1, wherein W is a bond.
8. The compound of claim 1, wherein when W is a bond, then R.sup.1
is --H.
9. The compound of claim 1, wherein when W is O, then R.sup.1 is
--H.
10. The compound of claim 1, wherein Q.sub.m in the A group is
absent and Q, in the A group is --CH.sub.2-- and the Q in the
Formula I structure is C(.dbd.O)
11. The compound of claim 1, wherein R.sup.1 is --H.
12. The compound of claim 1, wherein R.sup.2 is
--(CH.sub.2).sub.rNR.sup.7R.sup.8.
13. The compound of claim 1, wherein R.sup.2 is
(dimethylamino)ethyl.
14. The compound of claim 1, wherein each instance of r is
independently 0, 1, 2, or 3.
15. The compound of claim 1, wherein r is 2.
16. The compound of claim 1, wherein R.sup.3 is ##STR00762##
17. The compound of claim 1, wherein X is a monocyclic
(C.sub.5-C.sub.14)aryl.
18. The compound of claim 1, wherein X is phenyl.
19. The compound of claim 1, wherein R.sup.4 is --H.
20. The compound of claim 1, wherein each instance of m is
independently 0 or 1.
21. The compound of claim 1, wherein m is 0.
22. The compound of claim 1, wherein m is 1.
23. The compound of claim 1, wherein n is 1.
24. The compound of claim 1, wherein R.sup.6 and R.sup.6' are both
--H.
25. The compound of claim 1, wherein R.sup.7 and R.sup.8 are both
(C.sub.1-C.sub.6)alkyl.
26. The compound of claim 1, wherein R.sup.7 is methyl.
27. The compound of claim 1, wherein R.sup.8 is methyl.
28. The compound of claim 1, wherein R.sup.7 and R.sup.8 are both
methyl.
29. The compound of claim 1, wherein R.sup.11 is halo.
30. The compound of claim 1, wherein R.sup.11 is selected from
chloro, bromo, or fluoro.
31. The compound of claim 1, wherein R.sup.11 is chloro.
32. The compound of claim, wherein R.sup.11 is absent.
33. The compound of claim 1, wherein R.sup.14 and R.sup.15 are both
(C.sub.1-C.sub.6)alkyl.
34. The compound of claim 1, wherein R.sup.14 and R.sup.15 are both
methyl.
35. The compound of claim 1, wherein A is ##STR00763##
36. The compound of claim 1, wherein A is ##STR00764##
37. The compound of claim 1, wherein A is ##STR00765##
38. The compound of claim 1, wherein A is ##STR00766##
39. A compound having the structure of Formula I: ##STR00767## or a
pharmaceutically acceptable salt thereof, wherein: A is
##STR00768## L.sub.1 and L.sub.2 are [C(R.sup.6R.sup.6')].sub.q;
each Q is independently selected from--CH.sub.2-- or --C(.dbd.O)--;
W is selected from a bond or O; R.sup.1 is selected from the group
consisting of --H, (C.sub.1-C.sub.6)alkyl, --C(O)R.sup.4, and
##STR00769## R.sup.2 is selected from the group consisting of --H,
(C.sub.1-C.sub.6)alkyl, --(C.sub.1-C.sub.6)alkyl-OR.sup.4,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.5,
and --(CH.sub.2).sub.rNR.sup.7R.sup.8, and
--(CH.sub.2).sub.rN.sup.+(R.sup.4).sub.3; R.sup.3 is selected from
the group consisting of --H, (C.sub.1-C.sub.12)alkyl,
--NR.sup.1R.sup.2, --OR.sup.5, ##STR00770## wherein: X is a
monocyclic or bicyclic (C.sub.5-C.sub.14)aryl, Y is selected from a
monocyclic or bicyclic (C.sub.2-C.sub.9)heterocyclyl or monocyclic
or bicyclic (C.sub.2-C.sub.9)heteroaryl, each having one to three
heteroatoms selected from S, N or O, and Z is a monocyclic or
bicyclic (C.sub.3-C.sub.8)cycloalkyl; R.sup.4 is selected from the
group consisting of --H and (C.sub.1-C.sub.6)alkyl; R.sup.5 is
selected from the group consisting of (C.sub.1-C.sub.6)alkyl,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, and --(CH.sub.2).sub.rOR.sup.7;
R.sup.6 and R.sup.6' are independently selected from the group
consisting of --H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, haloalkyl,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, --C(O)OH, and --C(O)NH.sub.2,
wherein the R.sup.6 and R.sup.6' groups can optionally be taken
together with the carbon to which they are joined to form a 3 to 8
membered cycloalkyl ring, and wherein the cycloalkyl ring may be
optionally substituted by one to three R.sup.11 groups; R.sup.7 and
R.sup.8 are independently selected from the group consisting of
--H, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
--NR.sup.14R.sup.15, and --C(O)CH.sub.3; R.sup.9 is halo; R.sup.10
is --N(R.sup.16).sub.2; R.sup.11, R.sup.12, and R.sup.13 are
independently selected from the group consisting of oxo, hydroxyl,
halo, (C.sub.1-C.sub.6)alkoxy, --R.sup.6(R.sup.9).sub.q,
--OR.sup.6(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.10, --R.sup.4YR.sup.6,
--CO(O)R.sup.4, and --CO(O)R.sup.5; R.sup.14 and R.sup.15 are
independently selected from the group consisting of --H,
(C.sub.1--C--.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.6)alkoxy, --[C(R.sup.6).sub.2].sub.r--,
--O[C(R.sup.6).sub.2].sub.r--, oxo, hydroxyl, halo, --C(O)R.sup.7,
--R.sup.10, and --CO(O)R.sup.2; R.sup.16 is independently selected
from the group consisting of --H, oxo, halo, hydroxyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.8)cycloalkyl, --R.sup.6(R.sup.9).sub.q,
--OR.sup.6(R.sup.9).sub.q, --N(R.sup.4).sub.2,
--(CH.sub.2).sub.r-heterocyclyl, --C(O)OH, --C(O)NH.sub.2,
--R.sup.5(R.sup.9).sub.q, --OR.sup.5(R.sup.9).sub.q, nitro,
--SO.sub.2R.sup.6, --C(O)R.sup.10, and --CO(O)R.sup.4; m and n in
each instance are independently 0, 1, 2, 3, or 4; p is
independently 0, 1, 2, 3, or 4; and r and q in each instance are
independently 0, 1, 2, 3, or 4.
40. A compound having the structure of Formula I: ##STR00771## or a
pharmaceutically acceptable salt thereof, wherein: A is
##STR00772## L.sub.1 and L.sub.2 are both (--CH.sub.2--); Q is
--C(.dbd.O)--; W is O; R.sup.1 is --H; R.sup.2 is selected from the
group consisting of --H, (C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkyl-OR.sup.4,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.5,
and --(CH.sub.2).sub.rNR.sup.7R.sup.8; R.sup.3 is selected from the
group consisting of --H, (C.sub.1-C.sub.12)alkyl,
--NR.sup.1R.sup.2, --OR.sup.5, ##STR00773## wherein: X is a
monocyclic or bicyclic (C.sub.5-C.sub.14)aryl, Y is selected from a
monocyclic or bicyclic (C.sub.2-C.sub.9)heterocyclyl or monocyclic
or bicyclic (C.sub.2-C.sub.9)heteroaryl, each having one to three
heteroatoms selected from S, N or O, and Z is a monocyclic or
bicyclic (C.sub.3-C.sub.8)cycloalkyl; R.sup.4 is selected from the
group consisting of --H and (C.sub.1-C.sub.6)alkyl; R.sup.5 is
selected from the group consisting of (C.sub.1-C.sub.6)alkyl,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, and --(CH.sub.2).sub.rOR.sup.7;
R.sup.6 and R.sup.6' are independently selected from the group
consisting of --H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, haloalkyl,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, --C(O)OH, and --C(O)NH.sub.2;
R.sup.7 and R.sup.8 are independently selected from the group
consisting of --H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, --NR.sup.14R.sup.15, and
--C(O)CH.sub.3; R.sup.9 is halo; R.sup.10 is --N(R.sup.16).sub.2;
R.sup.11, R.sup.12, and R.sup.13 are independently selected from
the group consisting of oxo, hydroxyl, halo,
(C.sub.1-C.sub.6)alkoxy, --R.sup.6(R.sup.9).sub.q,
--OR.sup.6(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.10, --R.sup.4YR.sup.6,
--CO(O)R.sup.4, and --CO(O)R.sup.5; R.sup.14 and R.sup.15 are
independently selected from the group consisting of --H,
(C.sub.1--C--.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.6)alkoxy, --[C(R.sup.6).sub.2].sub.r--,
--O[C(R.sup.6).sub.2].sub.r--, oxo, hydroxyl, halo, --C(O)R.sup.7,
--R.sup.10, and --CO(O)R.sup.2; R.sup.16 is independently selected
from the group consisting of --H, oxo, halo, hydroxyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.8)cycloalkyl, --R.sup.6(R.sup.9).sub.q,
--OR.sup.6(R.sup.9).sub.q, --N(R.sup.4).sub.2,
--(CH.sub.2).sub.r-heterocyclyl, --C(O)OH, --C(O)NH.sub.2,
--R.sup.5(R.sup.9).sub.q, --OR.sup.5(R.sup.9).sub.q, nitro,
--SO.sub.2R.sup.6, --C(O)R.sup.10, and --CO(O)R.sup.4; m and n in
each instance are independently 0, 1, or 2; p is independently 0,
1, or 2; and r and q in each instance are independently 0, 1, 2, or
3.
41. A compound having the structure of Formula I: ##STR00774## or a
pharmaceutically acceptable salt thereof, wherein: A is
##STR00775## L.sub.1 and L.sub.2 are both (--CH.sub.2--); Q is
--C(.dbd.O)--; W is O; R.sup.1 is --H; R.sup.2 is selected from the
group consisting of --H, (C.sub.1-C.sub.6)alkyl, --C(O)R.sup.5, and
--(CH.sub.2).sub.rNR.sup.7R.sup.8; R.sup.3 is ##STR00776## wherein
X is a monocyclic or bicyclic (C.sub.5-C.sub.14)aryl; R.sup.4 is
selected from the group consisting of --H and
(C.sub.1-C.sub.6)alkyl; R.sup.5 is selected from the group
consisting of (C.sub.1-C.sub.6)alkyl,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, and --(CH.sub.2).sub.rOR.sup.7;
R.sup.6 is selected from the group consisting of --H,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.6)alkoxy, haloalkyl,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, --C(O)OH, and --C(O)NH.sub.2;
R.sup.7 and R.sup.8 are independently selected from the group
consisting of --H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, --NR.sup.14R.sup.15, and
--C(O)CH.sub.3; R.sup.9 is halo; R.sup.10 is --N(R.sup.16).sub.2;
R.sup.11, R.sup.12, and R.sup.13 are independently selected from
the group consisting of oxo, hydroxyl, halo,
(C.sub.1-C.sub.6)alkoxy, --R.sup.6(R.sup.9).sub.q,
--OR.sup.6(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.10, --CO(O)R.sup.4, and
--CO(O)R.sup.5; R.sup.14 and R.sup.15 are independently selected
from the group consisting of --H, (C.sub.1--C--.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy,
--[C(R.sup.6).sub.2].sub.r--, --O[C(R.sup.6).sub.2].sub.r--, oxo,
hydroxyl, halo, --C(O)R.sup.7, --R.sup.10, and --CO(O)R.sup.2;
R.sup.16 is independently selected from the group consisting of
--H, oxo, halo, hydroxyl, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
--R.sup.6(R.sup.9).sub.q, --OR.sup.6(R.sup.9).sub.q,
--N(R.sup.4).sub.2, --(CH.sub.2).sub.r-heterocyclyl, --C(O)OH,
--C(O)NH.sub.2, --R.sup.5(R.sup.9).sub.q,
--OR.sup.5(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
--C(O)R.sup.10, and --CO(O)R.sup.4; m and n in each instance are
independently 0, 1, or 2; p is independently 0, 1, or 2; and r and
q in each instance are independently 0, 1, 2, or 3.
42. A compound having the structure of Formula I: ##STR00777## or a
pharmaceutically acceptable salt thereof, wherein: A is
##STR00778## L.sub.1 and L.sub.2 are both (--CH.sub.2--); Q is
--C(.dbd.O)--; W is O; R.sup.1 is --H; R.sup.2 is
--(CH.sub.2).sub.rNR.sup.7R.sup.8; R.sup.3 is ##STR00779## wherein
X is phenyl; R.sup.7 and R.sup.8 are independently selected from
the group consisting of --H and methyl; R.sup.9 is selected from
the group consisting of chloro, bromo, and fluoro; R.sup.11 is
selected from the group consisting of chloro, bromo, and fluoro; m
is independently 0, 1, or 2; and r is independently 1, 2, or 3.
43. A compound having the structure of Formula (II): ##STR00780##
or a pharmaceutically acceptable salt thereof, wherein: A is
##STR00781## L.sub.1 and L.sub.2 are independently selected from a
bond or [C(R.sup.6R.sup.6')].sub.q; each instance of Q is
independently selected from--CH.sub.2-- or --C(.dbd.O)--; W is
selected from a bond or O; R.sup.1 is selected from the group
consisting of --H, (C.sub.1-C.sub.12)alkyl, --C(O)R.sup.5,
--CH.sub.2--O--(C.sub.1-C.sub.6)alkyl, 2-tetrahydro-2H-pyran, and
##STR00782## R.sup.2 is selected from the group consisting of --H,
--(C.sub.1-C.sub.6)alkyl-OR.sup.4,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.5,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, and
--(CH.sub.2).sub.rN.sup.+(R.sup.4).sub.3, wherein when W is O,
R.sup.1 and R.sup.2 can optionally be taken together with the O and
N to which they are respectively joined to form a 4 to 8 membered
heterocyclyl ring, wherein the heterocyclyl ring may be optionally
substituted by one to two R.sup.11 groups; R.sup.3 is selected from
the group consisting of --H, (C.sub.1-C.sub.12)alkyl,
--NR.sup.1R.sup.2, --OR.sup.5, ##STR00783## wherein: X is a
monocyclic or bicyclic (C.sub.6-C.sub.1a)aryl, Y is selected from a
monocyclic or bicyclic (C.sub.2-C.sub.6)heterocyclyl or monocyclic
or bicyclic (C.sub.2-C.sub.6)heteroaryl, each having one to three
heteroatoms selected from S, N or O, and Z is a monocyclic or
bicyclic (C.sub.3-C.sub.8)cycloalkyl; R.sup.2 and R.sup.3 can
optionally be taken together with the nitrogen and L.sub.2 to which
they are respectively joined to form a 4 to 8 membered heterocyclyl
ring wherein the heterocyclyl ring may be optionally substituted by
one to two R.sup.11 groups; R.sup.4 is selected from the group
consisting of --H and (C.sub.1-C.sub.6)alkyl; R.sup.5 is selected
from the group consisting of --H, (C.sub.1-C.sub.6)alkyl,
--R.sup.3, --(CH.sub.2).sub.rNR.sup.7R.sup.8, and
--(CH.sub.2).sub.rOR.sup.7. R.sup.6 and R.sup.6' are independently
selected from the group consisting of --H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, haloalkyl,
--Y, --(CH.sub.2).sub.rNR.sup.7R.sup.8, --C(O)OH, and
--C(O)NH.sub.2, wherein the R.sup.6 and R.sup.6' groups can
optionally be taken together with the carbon to which they are
joined to form a 3 to 8 membered cycloalkyl ring, and wherein the
cycloalkyl ring may be optionally substituted by one to three
R.sup.11 groups; R.sup.7 and R.sup.8 are independently selected
from the group consisting of --H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, -Q-aryl-(R.sup.4).sub.n,
--NR.sup.14R.sup.15, --C(O)CH.sub.3, wherein R.sup.7 and R.sup.8
can optionally be taken together with the nitrogen to which they
are joined to form a 4 to 8 membered heterocyclyl or heteroaryl
ring containing one to three heteroatoms selected from
--NR.sup.5--, --O--, --S--, --S(O)--, or --SO.sub.2--, wherein the
heterocyclyl or heteroaryl ring may be optionally substituted by
one to three R.sup.11 groups; R.sup.9 is halo; R.sup.10 is
--N(R.sup.16).sub.2; R.sup.11, R.sup.12, and R.sup.13 are
independently selected from the group consisting of oxo, hydroxyl,
halo, (C.sub.1-C.sub.6)alkoxy, --R.sup.6(R.sup.9).sub.q,
--OR.sup.6(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.10, --R.sup.4YR.sup.6,
--CO(O)R.sup.4, and --CO(O)R.sup.5, wherein any two R.sup.11,
R.sup.12 or R.sup.13 groups can optionally join to form a 3 to 8
membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring, wherein
the heterocyclyl or heteroaryl ring may contain one to three
heteroatoms selected from --NR.sup.5--, --O--, --S--, --S(O)--, or
--SO.sub.2--, and wherein the cycloalkyl, aryl, heterocyclyl or
heteroaryl ring may be optionally substituted by one to three
R.sup.16 groups; R.sup.14 and R.sup.15 are independently selected
from the group consisting of --H, (C.sub.1--C--.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy,
--[C(R.sup.6).sub.2].sub.r--, --O[C(R.sup.6).sub.2].sub.r--, oxo,
hydroxyl, halo, --C(O)R.sup.7, --R.sup.10, and --CO(O)R.sup.2,
wherein R.sup.14 and R.sup.15 can optionally be taken together with
the carbon to which they are joined to form a 3 to 8 membered
cycloalkyl ring or 4 to 8 membered heterocyclyl ring containing one
to three heteroatoms selected from --NR.sup.5--, --O--, --S--,
--S(O)--, or --SO.sub.2--, wherein the cycloalkyl ring or
heterocyclyl ring may be optionally substituted by one to three
R.sup.16 groups; R.sup.16 is independently selected from the group
consisting of --H, halo, oxo, hydroxyl, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
--R.sup.6(R.sup.9).sub.q, --OR.sup.6(R.sup.9).sub.q,
--N(R.sup.4).sub.2, --(CH.sub.2).sub.r-heterocyclyl, --C(O)OH,
--C(O)NH.sub.2, --R.sup.5(R.sup.9).sub.q,
--OR.sup.5(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
--C(O)R.sup.10, and --CO(O)R.sup.4; m and n in each instance are
independently 0, 1, 2, 3, or 4; p is independently 0, 1, 2, 3, or
4; and r and q in each instance are independently 0, 1, 2, 3, or
4.
44. A compound having the structure of Formula (II): ##STR00784##
or a pharmaceutically acceptable salt thereof, wherein: A is
##STR00785## L.sub.1 and L.sub.2 are [C(R.sup.6R.sup.6')].sub.q;
each instance of Q is independently selected from--CH.sub.2-- or
--C(.dbd.O)--; W is selected from a bond or O; R.sup.1 is selected
from the group consisting of --H, (C.sub.1-C.sub.6)alkyl,
--C(O)R.sup.4, and ##STR00786## R.sup.2 is selected from the group
consisting of --H, (C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkyl-OR.sup.4,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.5,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, and
--(CH.sub.2).sub.rN.sup.+(R.sup.4).sub.3; R.sup.3 is selected from
the group consisting of --H, (C.sub.1-C.sub.12)alkyl,
--NR.sup.1R.sup.2, --OR.sup.5, ##STR00787## wherein: X is a
monocyclic or bicyclic (C.sub.5-C.sub.14)aryl, Y is selected from a
monocyclic or bicyclic (C.sub.2-C.sub.9)heterocyclyl or monocyclic
or bicyclic (C.sub.2-C.sub.9)heteroaryl, each having one to three
heteroatoms selected from S, N or O, and Z is a monocyclic or
bicyclic (C.sub.3-C.sub.8)cycloalkyl; R.sup.4 is selected from the
group consisting of --H and (C.sub.1-C.sub.6)alkyl; R.sup.5 is
selected from the group consisting of (C.sub.1-C.sub.6)alkyl,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, and --(CH.sub.2).sub.rOR.sup.7;
R.sup.6 and R.sup.6' are independently selected from the group
consisting of --H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, haloalkyl,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, --C(O)OH, and --C(O)NH.sub.2,
wherein the R.sup.6 and R.sup.6' groups can optionally be taken
together with the carbon to which they are joined to form a 3 to 8
membered cycloalkyl ring, and wherein the cycloalkyl ring may be
optionally substituted by one to three R.sup.11 groups; R.sup.7 and
R.sup.8 are independently selected from the group consisting of
--H, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
--NR.sup.14R.sup.15, and --C(O)CH.sub.3; R.sup.9 is halo; R.sup.10
is --N(R.sup.16).sub.2; R.sup.11, R.sup.12, and R.sup.13 are
independently selected from the group consisting of oxo, hydroxyl,
halo, (C.sub.1-C.sub.6)alkoxy, --R.sup.6(R.sup.9).sub.q,
--OR.sup.6(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.10, --R.sup.4YR.sup.6,
--CO(O)R.sup.4, and --CO(O)R.sup.6; R.sup.14 and R.sup.15 are
independently selected from the group consisting of --H,
(C.sub.1--C--.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.6)alkoxy, --[C(R.sup.6).sub.2].sub.r--,
--O[C(R.sup.6).sub.2].sub.r--, oxo, hydroxyl, halo, --C(O)R.sup.7,
--R.sup.10, and --CO(O)R.sup.2; R.sup.16 is independently selected
from the group consisting of --H, oxo, halo, hydroxyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.8)cycloalkyl, --R.sup.6(R.sup.9).sub.q,
--OR.sup.6(R.sup.9).sub.q, --N(R.sup.4).sub.2,
--(CH.sub.2).sub.r-heterocyclyl, --C(O)OH, --C(O)NH.sub.2,
--R.sup.5(R.sup.9).sub.q, --OR.sup.5(R.sup.9).sub.q, nitro,
--SO.sub.2R.sup.6, --C(O)R.sup.10, and --CO(O)R.sup.4; m and n in
each instance are independently 0, 1, 2, 3, or 4; p is
independently 0, 1, 2, 3, or 4; and r and q in each instance are
independently 0, 1, 2, 3, or 4.
45. A compound having the structure of Formula (II): ##STR00788##
or a pharmaceutically acceptable salt thereof, wherein: A is
##STR00789## L.sub.1 and L.sub.2 are both (--CH.sub.2--); Q is
--C(.dbd.O)--; W is O; R.sup.1 is --H; R.sup.2 is selected from the
group consisting of --H, (C.sub.1-C.sub.6)alkyl, --C(O)R.sup.5, and
--(CH.sub.2).sub.rNR.sup.7R.sup.8; R.sup.3 is ##STR00790## wherein
X is a monocyclic or bicyclic (C.sub.5-C.sub.14)aryl; R.sup.4 is
selected from the group consisting of --H and
(C.sub.1-C.sub.6)alkyl; R.sup.5 is selected from the group
consisting of (C.sub.1-C.sub.6)alkyl,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, and --(CH.sub.2).sub.rOR.sup.7;
R.sup.6 is selected from the group consisting of --H,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.6)alkoxy, haloalkyl,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, --C(O)OH, and --C(O)NH.sub.2;
R.sup.7 and R.sup.8 are independently selected from the group
consisting of --H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, --NR.sup.14R.sup.15, and
--C(O)CH.sub.3; R.sup.9 is halo; R.sup.10 is --N(R.sup.16).sub.2;
R.sup.11, R.sup.12, and R.sup.13 are independently selected from
the group consisting of oxo, hydroxyl, halo,
(C.sub.1-C.sub.6)alkoxy, --R.sup.6(R.sup.9).sub.q,
--OR.sup.6(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.10, --CO(O)R.sup.4, and
--CO(O)R.sup.5; R.sup.14 and R.sup.15 are independently selected
from the group consisting of --H, (C.sub.1---C--.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy,
--[C(R.sup.6).sub.2].sub.r--, --O[C(R.sup.6).sub.2].sub.r--, oxo,
hydroxyl, halo, --C(O)R.sup.7, --R.sup.10, and --CO(O)R.sup.2;
R.sup.16 is independently selected from the group consisting of
--H, oxo, halo, hydroxyl, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
--R.sup.6(R.sup.9).sub.q, --OR.sup.6(R.sup.9).sub.q,
--N(R.sup.4).sub.2, --(CH.sub.2).sub.r-heterocycle, --C(O)OH,
--C(O)NH.sub.2, --R.sup.5(R.sup.9).sub.q,
--OR.sup.5(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
--C(O)R.sup.10, and --CO(O)R.sup.4; m and n in each instance are
independently 0, 1, or 2; p is independently 0, 1, or 2; and r and
q in each instance are independently 0, 1, 2, or 3.
46. A compound having the structure of Formula (II): ##STR00791##
or a pharmaceutically acceptable salt thereof, wherein: A is
##STR00792## L.sub.1 and L.sub.2 are both (--CH.sub.2--); Q is
--C(.dbd.O)--; W is O; R.sup.1 is --H; R.sup.2 is
--(CH.sub.2).sub.rNR.sup.7R.sup.8; R.sup.3 is ##STR00793## wherein
X is phenyl; R.sup.7 and R.sup.8 are independently selected from
the group consisting of --H and methyl; R.sup.9 is selected from
the group consisting of chloro, bromo, and fluoro; R.sup.11 is
selected from the group consisting of chloro, bromo, and fluoro; m
is 0, 1, or 2; and r is 1, 2, or 3.
47. A compound having the structure: ##STR00794## or a
pharmaceutically acceptable salt thereof.
48. A compound having the structure: ##STR00795## or a
pharmaceutically acceptable salt thereof.
49. A compound having the structure: ##STR00796## or a
pharmaceutically acceptable salt thereof.
50. A compound having the structure: ##STR00797## or a
pharmaceutically acceptable salt thereof.
51. A compound or a pharmaceutically acceptable salt thereof
selected from the group consisting of: TABLE-US-00007 Parent
Structure Chemical Name ##STR00798## 4-[(1R)-1-
[(1R,2R,5R,10S,13R,14R,17S,19R)- 17-[(3-carboxy-3,3-
dimethylpropanoyl)oxy]- 1,2,14,18,18-pentamethyl-7-oxo-
8-(propan-2-yl)pentacyclo [11.8.0.0{circumflex over (
)}{1,10}.0{circumflex over ( )}{5,9}.0{circumflex over ( )} {14,
19}]henicos-8-en-5-yl]-2- {[(4- chlorophenyl)methyl]amino}ethoxy]-
2,2-dimethyl-4-oxobutanoic acid ##STR00799## 4-[(1R)-1-
[(1R,2R,5R,10S,13R,14R,17S,19R)- 17-[(3-carboxy-3,3-
dimethylpropanoyl)oxy]- 1,2,14,18,18-pentamethyl-7-oxo-
8-(propan-2-yl)pentacyclo [11.8.0.0{circumflex over (
)}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over ( )}
{14,19}]henicos-8-en-5-yl]-2- {[(4-chlorophenyl)methyl][2-
(dimethylamino)ethyl]amino}eth- oxy]-2,2-dimethyl-4-oxobutanoic
acid ##STR00800## 4-[(1S)-1- [(1R,2R,5R,10S,13R,14R,17S,19R)-
17-[(3-carboxy-3,3- dimethylpropanyl)oxy]-
1,2,14,18,18-pentamethyl-7-oxo- 8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-5-yl]-2-
{[(4- chlorophenyl)methyl]amino}ethoxy]- 2,2-dimethyl-4-oxobutanoic
acid ##STR00801## 4-[(1S)-1- [(1R,2R,5R,10S,13R,14R,17S,19R)-
17-[(3-carboxy-3,3- dimethylpropanyl)oxy]-
1,2,14,18,18-pentamethyl-7-oxo- 8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-5-yl]-2-
{[(4-chlorophenyl)methyl][2- (dimethylamino)ethyl]amino}eth-
oxy]-2,2-dimethyl-4-oxobutanoic acid ##STR00802## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-(2-{[(4-
chlorophenyl)methyl]amino}ethyl)- 1,2,14,18,18-pentamethyl-7-oxo-
8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex over (
)}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over ( )}
{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00803## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)-
5-[2-(benzylamino)ethyl]- 1,2,14,18,18-pentamethyl-7-oxo-
8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex over (
)}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00804## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-(2-{[(3-
chlorophenyl)methyl]amino}ethyl)- 1,2,14,18,18-pentamethyl-7-oxo-
8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex over (
)}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy]-2,2-dimethyl-4-oxobutanoic acid
##STR00805## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)-
5-(2-{[(3-chloro-2- fluorophenyl)methyl]amino}ethyl)-
1,2,14,18,18-pentamethyl-7-oxo- 8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00806## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-(2-{[1-(4-
chlorophenyl)cyclopropyl]amino}eth- yl)-1,2,14,18,18-pentamethyl-7-
oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex over (
)}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00807## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-(2-{[(4-
chlorophenyl)methyl][2- (dimethylamino)ethyl]amino}ethyl)-
1,2,14,18,18-pentamethyl-7-oxo- 8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00808## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-(2-{[1-(4-
chlorophenyl)cyclopropyl][2- (dimethylamino)ethyl]amino}ethyl)-
1,2,14,18,18-pentamethyl-7-oxo- 8-(propan-2-
y)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00809## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-(2-{[(4-
chlorophenyl)methyl](methyl)amino} ethyl)-1,2,14,18,18-pentamethyl-
7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex over (
)}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00810## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-(2-{N-[(4-
chlorophenyl)methyl]acetamido}eth- yl)-1,2,14,18,18-pentamethyl-7-
oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex over (
)}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00811## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1R)-2-{[(4-
chlorophenyl)methyl]amino}-1- hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2.10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00812## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1S)-2-{[(4-
chlorophenyl)methyl]amino}-1- hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00813## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1S)-2-{[(4-
chlorophenyl)methyl]amino}-1- hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00814## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)-
5-[(1R)-1-(acetyloxy)-2-{[(4- chlorophenyl)methyl]amino}ethyl]-
1,2,14,18,18-pentamethyl-7-oxo- 8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00815## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1R)-2-{[(4-
chlorophenyl)methyl][2- (dimethylamino)ethyl]amino}-1-
hydroxyethyl]-1,2,14,18,18- pentamethyl-7-oxo-8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00816## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1S)-2-{[(4-
chlorophenyl)methyl][2- (dimethylamino)ethyl]amino}-1-
hydroxyethyl]-1,2,14,18,18- pentamethyl-7-oxo-8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00817## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1S)-1-(acetyloxy)-2-{[(4-
chlorophenyl)methyl][2- (dimethylamino)ethyl]amino}ethyl]-
1,2,14,18,18-pentamethyl-7-oxo- 8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00818## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1R)-1-(acetyloxy)-2-{[(4-
chlorophenyl)methyl][2- (dimethylamino)ethyl]amino}ethyl]-
1,2,14,18,18-pentamethyl-7-oxo- 8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00819## 5-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1R)-2-{[(4-
chlorophenyl)methyl][2- (dimethylamino)ethyl]amino}-1-
hydroxyethyl]-1,2,14,18,18- pentamethyl-7-oxo-8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-3,3-dimethyl-5- oxopentanoic acid ##STR00820## 5-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1S)-2-{[(4-
chlorophenyl)methyl][2- (dimethylamino)ethyl]amino}-1-
hydroxyethyl]-1,2,14,18,18- pentamethyl-7-oxo-8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-3,3-dimethyl-5- oxopentanoic acid ##STR00821## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1S)-2-{[(2-
chlorophenyl)methyl]amino}-1- hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00822## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1R)-2-{[(2-
chlorophenyl)methyl]amino}-1- hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00823## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)-
5-[(1S)-1-(acetyloxy)-2-{[(4- fluorophenyl)methyl]amino}ethyl]-
1,2,14,18,18-pentamethyl-7-oxo- 8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00824## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1R)-1-(acetyloxy)-2-{[(4-
fluorophenyl)methyl]amino}ethyl]- 1,2,14,18,18-pentamethyl-7-oxo-
8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex over (
)}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00825## 4- (((3aR,5aR,5bR,7aR,9S,11aR,11bR,
13aS)-3a-((S)-1-acetoxy-2-((4- fluorobenzyl)(methyl)amino)ethyl)-
1-isopropyl-5a,5b,8,8,11a- pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a, 11b,12,13,13a-octadecahydro-
2H-cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00826## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1S)-2-{[(4-
chlorophenyl)methyl](methyl)amino}- 1-hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00827## 4- (((3aR,5aR,5bR,7aR,9S,11aR,11bR,
13aS)-3a-((R)-1-Acetoxy-2-((4- chlorobenzyl)(methyl)amino)ethyl)-
1-isopropyl-5a,5b,8,8,11a- pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a, 11b,12,13,13a-octadecahydro-
2H-cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00828## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1R)-2-{[(4-
chlorophenyl)methyl](methyl)amino}- 1-hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00829## 4- (((3aR,5aR,5bR,7aR,9S,11aR,11bR,
13aS)-3a-((S)-1-Acetoxy-2-(N- (4-chlorobenzyl)acetamido)ethyl)-
1-isopropyl-5a,5b,8,8,11a- pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a, 11b,12,13,13a-octadecahydro-
2H-cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00830## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1S)-2-{N-[(4-
chlorophenyl)methyl]acetamido}- 1-hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00831## 4- (((3aR,5aR,5bR,7aR,9S,11aR,11bR,
13aS)-3a-((S)-2-(N-(4- Chlorobenzyl)acetamido)-1-
hydroxyethyl)-1-isopropyl- 5a,5b,8,8,11a-pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a, 11b,12,13,13a-octadecahydro-
2H-cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00832## 4- (((3aR,5aR,5bR,7aR,9S,11aR,11bR,
13aS)-3a-((R)-2-(N-(4- Chlorobenzyl)acetamido)-1-
hydroxyethyl)-1-isopropyl- 5a,5b,8,8,11a-pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a, 11b,12,13,13a-octadecahydro-
2H-cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00833## 4- (((3aR,5aR,5bR,7aR,9S,11aR,11bR,
13aS)-3a-((S)-2-(N-(2- Chlorobenzyl)acetamido)-1-
hydroxyethyl)-1-isopropyl- 5a,5b,8,8,11a-pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a, 11b,12,13,13a-octadecahydro-
2H-cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00834## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)-
5-[(1S)-1-(acetyloxy)-2-{[(2- chlorophenyl)methyl][2-
(dimethylamino)ethyl]amino}ethyl]- 1,2,14,18,18-pentamethyl-7-oxo-
8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex over (
)}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00835## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1S)-2-{[(3-
chlorophenyl)methyl]amino}-1- hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic
acid
##STR00836## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1R)-2-{[(3-
chlorophenyl)methyl]amino}-1- hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00837## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1S)-2-{[(3-
chlorophenyl)methyl][2- (dimethylamino)ethyl]amino}-1-
hydroxyethyl]-1,2,14,18,18- pentamethyl-7-oxo-8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00838## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1R)-2-{[(3-
chlorophenyl)methyl][2- (dimethylamino)ethyl]amino}-1-
hydroxyethyl]-1,2,14,18,18- pentamethyl-7-oxo-8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00839## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1S)-1-(acetyloxy)-2-{[(3-
chlorophenyl)methyl]amino}ethyl]- 1,2,14,18,18-pentamethyl-7-oxo-
8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex over (
)}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00840## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)-
5-[(1R)-1-(acetyloxy)-2-{[(3- chlorophenyl)methyl]amino}ethyl]-
1,2,14,18,18-pentamethyl-7-oxo- 8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14.19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00841## 4-
(((3aR,5aR,5bR,7aR,9S,11aR,11bR, 13aS)-3a-((S)-1-acetoxy-2-((3-
chlorobenzyl)(2- (dimethylamino)ethyl)amino)ethyl)-
1-isopropyl-5a,5b,8,8,11a- pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a, 11b,12,13,13a-octadecahydro-
2H-cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-osobutanoic acid
##STR00842## 4- (((3aR,5aR,5bR,7aR,9S,11aR,11bR,
13aS)-3a-((R)-1-acetoxy-2-((3- chlorobenzyl)(2-
(dimethylamino)ethyl)amino)ethyl)- 1-isopropyl-5a,5b,8,8,11a-
pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,
11b,12,13,13a-octadecahydro- 2H-cyclopenta[a]chrysen-9-
yl)oxy)-2,2-dimethyl-4-oxobutanoic acid ##STR00843## 4-
(((3aR,5aR,5bR,7aR,9S,11aR,11bR, 13aS)-3a-((R)-2-((3-
chlorobenzyl)(ethyl)amino)-1- hydroxyethyl)-1-isopropyl-
5a,5b,8,8,11a-pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a, 11b,12,13,13a-octadecahydro-
2H-cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00844## 4- (((3aR,5aR,5bR,7aR,9S,11aR,11bR,
13aS)-3a-((S)-2-((3- Chlorobenzyl)(2-
(dimethylamino)ethyl)amino)-1- hydroxyethyl)-1-isopropyl-
5a,5b,8,8,11a-pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a, 11b,12,13,13a-octadecahydro-
2H-cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00845## 4- (((3aR,5aR,5bR,7aR,9S,11aR,
11bR,13aS)-3a-((R)-2-((3- Chlorobenzyl)(2-
(dimethylamino)ethyl)amino)-1- hydroxyethyl)-1-isopropyl-
5a,5b,8,8,11a-pentamethyl-2- oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,
11a,11b,12,13,13a- octadecahydro-2H-
cyclopenta[a]chrysen-9-yl)oxy)- 2,2-dimethyl-4-oxobutanoic acid.
##STR00846## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1R)-2-{N-[(3-
chlorophenyl)methyl]acetamido)- 1-hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00847## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1S)-2-{N-[(3-
chlorophenyl)methyl]acetamido}- 1-hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00848## 4- (((3aR,5aR,5bR,7aR,9S,11aR,11bR,
13aS)-3a-((R)-1-acetoxy-2-((2- chlorobenzyl)(2-
(dimethylamino)ethyl)amino)ethyl)- 1-isopropyl-5a,5b,8,8,11a-
pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,
11b,12,13,13a-octadecahydro- 2H-cyclopenta[a]chrysen-9-
yl)oxy)-2,2-dimethyl-4-oxobutanoic acid ##STR00849## 4-
(((3aR,5aR,5bR,7aR,9S,11aR,11bR, 13aS)-3a-((R)-2-((2-
chlorobenzyl)(ethyl)amino)-1- hydroxyethyl)-1-isopropyl-
5a,5b,8,8,11a-pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a, 11b,12,13,13a-octadecahydro-
2H-cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00850## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1R)-2-{[(2-
chlorophenyl)methyl][2- (dimethylamino)ethyl]amino}-1-
hydroxyethyl]-1,2,14,18,18- pentamethyl-7-oxo-8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00851## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1S)-2-{[(2-
chlorophenyl)methyl][2- (dimethylamino)ethyl]amino}-1-
hydroxyethyl]-1,2,14,18,18- pentamethyl-7-oxo-8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00852## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1R)-1-(acetyloxy)-2-
(benzylamino)ethyl]-1,2,14,18,18- pentamethyl-7-oxo-8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00853## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1S)-1-(acetyloxy)2-
(benzylamino)ethyl]-1,2,14,18,18- pentamethyl-7-oxo-8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00854## 4-
(((3aR,5aR,5bR,7aR,9S,11aR,11bR, 13aS)-3a-((R)-2-((3-Chloro-2-
fluorobenzyl)amino)-1- hydroxyethyl)-1-isopropyl-
5a,5b,8,8,11a-pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a, 11b,12,13,13a-octadecahydro-
2H-cylcopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00855## 4- (((3aR,5aR,5bR,7aR,9S,11aR,11bR,
13aS)-3a-((S)-2-((3-chloro-2- fluorobenzyl)amino)-1-
hydroxyethyl)-1-isopropyl- 5a,5b,8,8,11a-pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a, 11b,12,13,13a-octadecahydro-
2H-cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
##STR00856## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)-
5-[(1R)-2-{[(3-chloro-2- fluorophenyl)methyl][2-
(dimethylamino)ethyl]amino}-1- hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00857## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)-
5-[(1S)-2-{[(3-chloro-2- fluorophenyl)methyl][2-
(dimethylamino)ethyl]amino}-1- hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00858## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)-
5-[(1R)-1-hydroxy-2-[(propan- 2-yl)amino]ethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00859## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)-
5-[(1R)-2-(cyclohexylamino)-1- hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00860## 4- {[(1R,2R,5S,10S,13R,14R,17S,19R)-
5-[1-hydroxy-2-(4- methylpiperazin-1-yl)ethyl]-
1,2,14,18,18-pentamethyl-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00861## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-(2-{[(4-
chlorophenyl)methyl]amino}ethyl)- 1,2,14,18,18-pentamethyl-8-
(propan-2- yl)pentacyclo[11.8.0.0{circumflex over (
)}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00862## 4- {[(1R,2R,5S,10S,13R,14R,17S,19R)- 5-[(1S)-2-{[(4-
chlorophenyl)methyl]amino}-1- hydroxyethyl]-1,2,14,18,18-
pentamethyl-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex over (
)}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00863## 4- {[(1R,2R,5S,10S,13R,14R,17S,19R)- 5-[(1S)-2-
[(cyclohexylmethyl)amino]-1- hydroxyethyl]-1,2,14,18,18-
pentamethyl-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex over (
)}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00864## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)-
5-[(1S)-2-(cyclohexylamino)-1- hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00865## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)-
5-[(1R)-1-hydroxy-2-(1,2,3,4- tetrahydroisoquinolin-2-yl)ethyl]-
1,2,14,18,18-pentamethyl-7-oxo- 8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00866## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1S)-1-hydroxy-2-(1,2,3,4-
tetrahydroisoquinolin-2-yl)ethyl]- 1,2,14,18,18-pentamethyl-7-oxo-
8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex over (
)}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00867## 4- {[(1R,2R,10S,13R,14R,17S,19R)-
5-[(5S)-3-[1-(5-chloropyrimidin-2- yl)cyclopropyl]-2-oxo-1,3-
oxazolidin-5-yl]-1,2,14,18,18- pentamethyl-7-oxo-8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00868## 4-
{[(1R,2R,10S,13R,14R,17S,19R)- 5-[(5R)-3-[1-(5-chloropyrimidin-2-
yl)cyclopropyl]-2-oxo-1,3- oxazolidin-5-yl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00869## 5- {[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1S)-2-{[(4-
chlorophenyl)methyl]amino}-1- hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-3,3-dimethyl-5- oxopentanoic
acid ##STR00870## 4- (((3aR,5aR,5bR,7aR,9S,11aR,11bR,
13aS)-3a-((R)-2-(3,4- dihydroisoquinolin-2(1H)-yl)-1-
hydroxyethyl)-1-isopropyl- 5a,5b,8,8,11a-pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a, 11b,12,13,13a-octadecahydro-
2H-cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00871## 4- (((3aR,5aR,5bR,7aR,9S,11aR,11bR,
13aS)-3a-((S)-2-(3,4- dihydroisoquinolin-2(1H)-yl)-1-
hydorxyethyl)-1-isopropyl- 5a,5b,8,8,11a-pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a, 11b,12,13,13a-octadecahydro-
2H-cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
##STR00872## 4- (((3aS,5aR,5bR,7aR,9S,11aR,11bR,
13aS)-3a-((R)-1-hydroxy-2-(4- methylpiperazin-1-yl)ethyl)-1-
isopropyl-5a,5b,8,8,11a- pentamethyl-
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a, 11b,12,13,13a-octadecahydro-
2H-cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
##STR00873## 4- (((3aR,5aR,5bR,7aR,9S,11aR,11bR, 13aS)-3a-(2-((4-
chlorobenzyl)amino)ethyl)-1- isopropyl-5a,5b,8,8,11a- pentamethyl-
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a, 11b,12,13,13a-octadecahydro-
2H-cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
##STR00874## 4- (((3aS,5aR,5bR,7aR,9S,11aR,11bR, 13aS)-3a-((S)-2-
((cyclohexylmethyl)amino)-1- hydroxyethyl)-1-isopropyl-
5a,5b,8,8,11a-pentamethyl- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,
11b,12,13,13a-octadecahydro- 2H-cyclopenta[a]chrysen-9-
yl)oxy)-2,2-dimethyl-4-oxobutanoic acid. ##STR00875## 4-
(((3aR,5aR,5bR,7aR,9S,11aR,11bR, 13aS)-3a-((S)-2-
(cyclohexylamino)-1- hydroxyethyl)-1-isopropyl-
5a,5b,8,8,11a-pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,
11b,12,13,13a-octadecahydro- 2H-cyclopenta[a]chrysen-9-
yl)oxy)-2,2-dimethyl-4-oxobutanoic acid ##STR00876## 4-
(((3aR,5aR,5bR,7aR,9S,11aR,11bR, 13aS)-3a-((S)-2-(benzyl(2-
(dimethylamino)ethyl)amino)-1- hydroxyethyl)-1-isopropyl-
5a,5b,8,8,11a-pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a, 11b,12,13,13a-octadecahydro-
2H-cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00877## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)-
5-[(1S)-1-(acetyloxy)-2-{[2- (dimethylamino)ethyl][(4-
fluorophenyl)methyl]amino}ethyl]- 1,2,14,18,18-pentamethyl-7-oxo-
8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex over (
)}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00878## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)-
5-[(1R)-1-(acetyloxy)-2-{[2- (dimethylamino)ethyl][(4-
fluorophenyl)methyl]amino}ethyl]- 1,2,14,18,18-pentamethyl-7-oxo-
8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex over (
)}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00879## 5- {[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1R)-2-{[(4-
chlorophenyl)methyl]amino}-1- hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-3,3-dimethyl-5- oxopentanoic
acid ##STR00880## 5- (((3aR,5aR,5bR,7aR,9S,11aR,11bR,
13aS)-3a-((S)-2-((4- chlorobenzyl)amino)-1-
hydroxyethyl)-1-isopropyl- 5a,5b,8,8,11a-pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a, 11b,12,13,13a-octadecahydro-
2H-cyclopenta[a]chrysen-9- yl)oxy)-3,3-dimethyl-5- oxopentanoic
acid ##STR00881## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)-
5-[(1S)-2-{[(2,4- dichlorophenyl)methyl][2-
(dimethylamino)ethyl]amino}-1- hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00882## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)-
5-[(1R)-2-{benzyl[2- (dimethylamino)ethyl]amino}-1-
hydroxyethyl]-1,2,14,18,18- pentamethyl-7-oxo-8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00883## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1R)-2-{[2-
(dimethylamino)ethyl][(4- fluorophenyl)methyl]amino}-1-
hydroxyethyl]-1,2,14,18,18- pentamethyl-7-oxo-8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00884## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1R)-2-{[(4-
fluorophenyl)methyl]amino}-1- hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00885## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1S)-2-{[2-
(dimethylamino)ethyl][(4- fluorophenyl)methyl]amino}-1-
hydroxyethyl]-1,2,14,18,18- pentamethyl-7-oxo-8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00886## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1S)-2-{[(4-
fluorophenyl)methyl]amino}-1- hydroxyethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00887## 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1R)-2-{[(2,4-
dichlorophenyl)methyl][2- (dimethylamino)ethyl]amino}-1-
hydroxyethyl]-1,2,14,18,18- pentamethyl-7-oxo-8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00888## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-[(1R)-2-[1-(4-chlorophenyl)-
N-[2- (dimethylamino)ethyl]formamido]-
1-hydroxyethyl]-1,2,14,18,18- pentamethyl-7-oxo-8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}-2,2-dimethyl-4-oxobutanoic acid ##STR00889## 4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 5-(2-{[(2-
chlorophenyl)methyl]amino}ethyl)- 1,2,14,18,18-pentamethyl-7-oxo-
8-(propan-2- yl)pentacyclo[11.8.0.0{circumflex over (
)}{2,10}.0{circumflex over ( )}{5, 9}.0{circumflex over (
)}{14,19}]henicos-8-en-17- yl]oxy}-2,2-dimethyl-4-oxobutanoic acid
##STR00890## 2,2-dimethyl-4-oxo-4-
{[(1R,2R,5R,10S,13R,14R,17S,19R)- 1,2,14,18,18-pentamethyl-7-
oxo-5-[2-(phenylformamido)ethyl]- 8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,10}.0{circumflex over
( )}{5, 9}.0{circumflex over ( )}{14,19}]henicos-8-en-17-
yl]oxy}butanoic acid
52. The compound of claims 1-51, wherein the pharmaceutically
acceptable salt is a base salt.
53. The compound of claim 52, wherein the pharmaceutically
acceptable salt is a Lysine salt.
54. A compound having the structure: ##STR00891##
55. A compound having the structure: ##STR00892##
56. A compound having the structure: ##STR00893##
57. A compound having the structure: ##STR00894##
58. A pharmaceutical composition comprising a compound of any of
claims 1-57, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable excipient.
59. The composition of claim 58, wherein the compound is present in
an amorphous form.
60. The composition of claim 58, wherein the composition is in a
tablet form.
61. The composition of claim 58, wherein the compound is present as
a spray dried dispersion.
62. A method of treating an HIV infection in a subject comprising
administering to the subject a compound of any of claims 1-57, or a
pharmaceutically acceptable salt thereof.
63. A method of treating an HIV infection in a subject comprising
administering to the subject a pharmaceutical composition according
to claim 58.
64. A method of preventing an HIV infection in a subject at risk
for developing an HIV infection, comprising administering to the
subject a compound of any of claims 1-57, or a pharmaceutically
acceptable salt thereof.
65. A method of preventing an HIV infection in a subject at risk
for developing an HIV infection, comprising administering to the
subject a pharmaceutical composition according to claim 58.
66. The method of claims 62-65, further comprising administration
of one or more additional agents active against HIV.
67. The method of claim 66, wherein said one or more additional
agents active against HIV is selected from the group consisting of
zidovudine, didanosine, lamivudine, zalcitabine, abacavir,
stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil,
emtricitabine, alovudine, amdoxovir, elvucitabine, nevirapine,
delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine,
lersivirine, GSK2248761, TMC-278, TMC-125, etravirine, saquinavir,
ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir,
brecanavir, darunavir, atazanavir, tipranavir, palinavir,
lasinavir, enfuvirtide, T-20, T-1249, PRO-542, PRO-140, TNX-355,
BMS-806, BMS-663068 and BMS-626529, 5-Helix, raltegravir,
elvitegravir, GSK1349572, GSK1265744, vicriviroc (Sch-C), Sch-D,
TAK779, maraviroc, TAK449, didanosine, tenofovir, lopinavir, and
darunavir.
68. The use of a compound or salt as defined in any of claims 1-57
in the manufacture of a medicament for use in the treatment of an
HIV infection in a human.
69. A process for preparing a compound of Formula (I) having the
structure: ##STR00895## comprising the steps of: (1) saponifying a
compound having the structure: ##STR00896## in the presence of a
first metal catalyst, in order to provide a compound having the
structure: ##STR00897## (2) reacting the compound product of Step
(1), with a compound having the structure: ##STR00898## in the
presence of an acid chloride and a tertiary amine in order to
provide a compound having the structure: ##STR00899## (3) reacting
nitromethane with the compound product of Step (2) in the presence
of a chiral ligand, an optional base, and a second metal catalyst
in order to provide a compound having the structure: ##STR00900##
(4) reducing the compound product of Step (3), in the presence of a
third metal catalyst and hydrogen gas in order to provide a
compound having the structure: ##STR00901## (5) reacting
p-chlorobenzaldehyde with the compound product of Step (4), in the
presence of a metal hydride, to provide a compound having the
structure: ##STR00902## (6) acidifying the compound product of Step
(5), in the presence of an acid in order to provide the compound
having the structure: ##STR00903## (7) reacting the compound
product of Step (6) with a compound having the structure according
to Formula III: ##STR00904## wherein A.sup.1 is either optionally
absent or is selected from the group consisting --H, methyl, and
ethyl; and A.sup.2 is selected from the group consisting of --H,
methoxy, ethoxy, hydroxyl, and --SO.sub.3.sup.-Na.sup.+; while in
the presence of a metal hydride in order to provide the compound
having the structure: ##STR00905##
70. The process according to claim 69, wherein one or more of Steps
(1)-(7) are conducted in the presence of a solvent.
71. The process according to claim 69, wherein one or more of Steps
(1)-(7) are conducted in the presence of an organic solvent.
72. The process according to claim 69, wherein one or more of Steps
(1)-(7) are conducted in the presence of a solvent that is selected
from the group consisting of water, dichloromethyl, methanol,
tetrahydrofuran, tetrahydrofuran acetate, ethanol, ethyl acetate,
heptane, isopropanol, tert-butanol, toluene, acetonitrile, and
tert-butyl methyl ether.
73. The process according to claim 69, wherein the first metal
catalyst of Step (1) is a metal halide.
74. The process according to claim 69, wherein the first metal
catalyst of Step (1) is zirconium tetrachloride.
75. The process according to claim 69, wherein the acid chloride of
Step (2) is selected from the group consisting of benzoyl chloride
and methoxybenzoyl chloride.
76. The process according to claim 69, wherein the acid chloride of
Step (2) is methoxybenzoyl chloride.
77. The process according to claim 69, wherein the tertiary amine
of Step (2) is a tertiary amine coupling agent.
78. The process according to claim 69, wherein the tertiary amine
of Step (2) is selected from the group consisting of triethylamine,
N,N-diisopropylethylamine, and
1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride.
79. The process according to claim 69, wherein the tertiary amine
of Step (2) is 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide
hydrochloride.
80. The process according to claim 69, wherein the tertiary amine
of Step (2) is triethylamine.
81. The process according to claim 69, wherein the second metal
catalyst of Step (3) is a compound comprising a metal selected from
the group consisting of Zn, Co, Cu, Mg, and Cr.
82. The process according to claim 69, wherein the second metal
catalyst of Step (3) is a compound comprising a metal selected from
the group consisting of Cu(I) and Cu(II).
83. The process according to claim 69, wherein the second metal
catalyst of Step (3) is a compound comprising Cu(I).
84. The process according to claim 69, wherein the second metal
catalyst of Step (3) is selected from the group consisting of
Copper(I) acetate and Cu(II) acetate.
85. The process according to claim 69, wherein the second metal
catalyst of Step (3) is Copper(I) acetate.
86. The process according to claim 69, wherein the second metal
catalyst of Step (3) is Copper(II) acetate.
87. The process according to claim 69, wherein the optional base of
Step (3) is selected from the group consisting of alkali metal
hydroxides, alkoxides, carbonates, fluoride anions, and nonionic
organic amine bases.
88. The process according to claim 69, wherein the optional base of
Step (3) is .sup.iPr.sub.2Net.
89. The process according to claim 69, wherein the chiral ligand of
Step (3) is a derivative of S-Camphor.
90. The process according to claim 69, wherein the chiral ligand of
Step (3) is a compound having the structure: ##STR00906##
91. The process according to claim 69, wherein the third metal
catalyst of Step (4) is selected from the group consisting of Raney
Nickel, nickel, nickel chloride, aluminum, palladium, copper, zinc,
chromium, iridium, rhodium, platinum, and combinations thereof.
92. The process according to claim 69, wherein the third metal
catalyst of Step (4) is Raney Nickel.
93. The process according to claim 69, wherein the hydrogen of Step
(4) is hydrogen gas.
94. The process according to claim 69, wherein the metal hydride of
Step (5) is a borohydride.
95. The process according to claim 69, wherein the metal hydride of
Step (5) is selected from the group consisting of NaBH.sub.4 and
NaBH(OAc).sub.3.
96. The process according to claim 69, wherein the metal hydride of
Step (5) is NaBH.sub.4.
97. The process according to claim 69, wherein the metal hydride of
Step (5) is NaBH(OAc).sub.3.
98. The process according to claim 69, wherein the acid of Step (6)
is selected from the group consisting of trifluoroacetic acid, HCl,
and trichloroacetic acid,
99. The process according to claim 69, wherein the acid of Step (6)
is trifluoroacetic acid.
100. The process according to claim 69, wherein the A.sup.2 of Step
(7) is --SO.sub.3Na.
101. The process according to claim 69, wherein the A.sup.2 of Step
(7) is --H.
102. The process according to claim 69, wherein the A.sup.1 of Step
(7) is absent.
103. The process according to claim 69, wherein the A.sup.1 of Step
(7) is --H.
104. The process according to claim 69, wherein the compound of
Formula III of Step (7) has the following structure:
##STR00907##
105. The process according to claim 69, wherein the compound of
Formula III of Step (7) has the following structure:
##STR00908##
106. The process according to claim 69, wherein the compound of
Formula III of Step (7) has the following structure:
##STR00909##
107. The process according to claim 69, wherein the compound of
Formula III of Step (7) has the following structure:
##STR00910##
108. The process according to claim 69, wherein the metal hydride
of Step (7) is a borohydride.
109. The process according to claim 69, wherein the metal hydride
of Step (7) is NaBH.sub.3CN.
110. A process for preparing a compound having the structure:
##STR00911## comprising the steps of: (1) saponifying a compound
having the structure: ##STR00912## in the presence of a first metal
catalyst, in order to provide a compound having the structure:
##STR00913## (2) reacting the compound product of Step (1), with a
compound having the structure: ##STR00914## in the presence of an
acid chloride and a tertiary amine in order to provide a compound
having the structure: ##STR00915## (3) reacting nitromethane with
the compound product of Step (2) in the presence of a chiral ligand
and a base and a second metal catalyst in order to provide a
compound having the structure: ##STR00916## (4) reducing the
compound product of Step (3), in the presence of a third metal
catalyst and hydrogen gas in order to provide a compound having the
structure: ##STR00917## (5) reacting p-chlorobenzaldehyde with the
compound product of Step (4), in the presence of a metal hydride
and a tertiary amine, to provide a compound having the structure:
##STR00918## (6) reacting the compound product of Step (5) with a
compound having the structure according to Formula III:
##STR00919## wherein A.sup.1 is either optionally absent or is
selected from the group consisting --H, methyl, and ethyl; and
A.sup.2 is selected from the group consisting of --H, methoxy,
ethoxy, hydroxyl, and --SO.sub.3.sup.-Na.sup.+; while in the
presence of a metal hydride in order to provide the compound having
the structure: ##STR00920## (7) acidifying the compound product of
Step (6), in the presence of an acid in order to provide the
compound having the structure: ##STR00921##
111. The process according to claim 110, wherein one or more of
Steps (1)-(7) are conducted in the presence of a solvent.
112. The process according to claim 110, wherein one or more of
Steps (1)-(7) are conducted in the presence of an organic
solvent.
113. The process according to claim 110, wherein one or more of
Steps (1)-(7) are conducted in the presence of a solvent that is
selected from the group consisting of water, dichloromethyl,
methanol, tetrahydrofuran, tetrahydrofuran acetate, ethanol, ethyl
acetate, heptane, isopropanol, tert-butanol, toluene, acetonitrile,
and tert-butyl methyl ether.
114. The process according to claim 110, wherein the base of Step
(3) is selected from the group consisting of alkali metal
hydroxides, alkoxides, carbonates, fluoride anions, and nonionic
organic amine bases.
115. The process according to claim 110, wherein the base of Step
(3) is .sup.iPr.sub.2Net.
116. The process according to claim 110, wherein the tertiary amine
of Step (5) is selected from the group consisting of triethylamine,
N,N-diisopropylethylamine, and
1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride.
117. The process according to claim 110, wherein the tertiary amine
of Step (5) is triethylamine.
118. The process according to claim 110, wherein the metal hydride
of Step (5) is a borohydride.
119. The process according to claim 110, wherein the metal hydride
of Step (5) is selected from the group consisting of NaBH.sub.4 and
NaBH(OAc).sub.3.
120. The process according to claim 110, wherein the metal hydride
of Step (5) is NaBH.sub.4.
121. The process according to claim 110, wherein the tertiary amine
of Step (6) is triethylamine.
122. A process for preparing a compound having the structure:
##STR00922## comprising the steps of: (1) reacting a compound
having the structure: ##STR00923## with a compound having the
structure according to Formula III: ##STR00924## wherein A.sup.1 is
either optionally absent or is selected from the group consisting
--H, methyl, and ethyl; and A.sup.2 is selected from the group
consisting of --H, methoxy, ethoxy, hydroxyl, and
--SO.sub.3.sup.-Na.sup.+; while in the presence of a metal hydride
in order to provide the compound having the structure:
##STR00925##
123. A process for preparing a compound having the structure:
##STR00926## comprising the steps of: (1) acidifying a compound
having the structure: ##STR00927## in the presence of an acid in
order to provide the compound having the structure:
##STR00928##
124. A process for preparing a compound having the structure:
##STR00929## comprising the steps of: (1) reacting
p-chlorobenzaldehyde with a compound having the structure:
##STR00930## in the presence of a metal hydride to provide the
compound having the structure: ##STR00931##
125. A process for preparing a compound having the structure:
##STR00932## comprising the steps of: (1) reducing a compound
having the structure: ##STR00933## in the presence of a metal
catalyst and hydrogen gas in order to provide the compound having
the structure: ##STR00934##
126. A process for preparing a compound having the structure:
##STR00935## comprising the steps of: (1) reacting nitromethane
with a compound having the structure: ##STR00936## in the presence
of a chiral ligand and a metal catalyst in order to provide a
compound having the structure: ##STR00937##
127. A process for preparing a compound having the structure:
##STR00938## comprising the steps of: (1) reacting a compound
having the structure: ##STR00939## with a compound having the
structure: ##STR00940## in the presence of an acid chloride and a
tertiary amine in order to provide the computer having the
structure: ##STR00941##
128. A process for preparing a compound having the structure:
##STR00942## comprising the steps of: (1) saponifying a compound
having the structure: ##STR00943## in the presence of a metal
catalyst, in order to provide the compound having the structure:
##STR00944##
129. The use of a compound or salt as defined in any of claims 1-57
in the manufacture of a medicament for use in therapy.
130. The method according to claims 62-67, wherein the subject is a
human.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to compounds, pharmaceutical
compositions, and methods of use thereof for (i) inhibiting HIV
replication in a subject infected with HIV, or (ii) treating a
subject infected with HIV, by administering such compounds.
BACKGROUND OF THE INVENTION
[0002] Human immunodeficiency virus type 1 (HIV-1) leads to the
contraction of acquired immune deficiency disease (AIDS). The
number of cases of HIV continues to rise, and currently over
twenty-five million individuals worldwide suffer from the virus.
Presently, long-term suppression of viral replication with
antiretroviral drugs is the only option for treating HIV-1
infection. Indeed, the U.S. Food and Drug Administration has
approved twenty-five drugs over six different inhibitor classes,
which have been shown to greatly increase patient survival and
quality of life. However, additional therapies are still required
because of undesirable drug-drug interactions; drug-food
interactions; non-adherence to therapy; and drug resistance due to
mutation of the enzyme target.
[0003] Currently, almost all HIV positive patients are treated with
therapeutic regimens of antiretroviral drug combinations termed,
highly active antiretroviral therapy ("HAART"). However, HAART
therapies are often complex because a combination of different
drugs must be administered often daily to the patient to avoid the
rapid emergence of drug-resistant HIV-1 variants. Despite the
positive impact of HAART on patient survival, drug resistance can
still occur. The emergence of multidrug-resistant HIV-1 isolates
has serious clinical consequences and must be suppressed with a new
drug regimen, known as salvage therapy.
[0004] Current guidelines recommend that salvage therapy includes
at least two, and preferably three, fully active drugs. Typically,
first-line therapies combine three to four drugs targeting the
viral enzymes reverse transcriptase and protease. One option for
salvage therapy is to administer different combinations of drugs
from the same mechanistic class that remain active against the
resistant isolates. However, the options for this approach are
often limited, as resistant mutations frequently confer broad
cross-resistance to different drugs in the same class. Alternative
therapeutic strategies have recently become available with the
development of fusion, entry, and integrase inhibitors. However,
resistance to all three new drug classes has already been reported
both in the lab and in patients. Sustained successful treatment of
HIV-1-infected patients with antiretroviral drugs will therefore
require the continued development of new and improved drugs with
new targets and mechanisms of action.
[0005] Presently, long-term suppression of viral replication with
antiretroviral drugs is the only option for treating HIV-1
infection. To date, a number of approved drugs have been shown to
greatly increase patient survival. However, therapeutic regimens
known as highly active antiretroviral therapy (HAART) are often
complex because a combination of different drugs must be
administered to the patient to avoid the rapid emergence of
drug-resistant HIV-1 variants. Despite the positive impact of HAART
on patient survival, drug resistance can still occur.
[0006] The HIV Gag polyprotein precursor (Pr55Gag), which is
composed of four protein domains--matrix (MA), capsid (CA),
nucleocapsid (NC) and p6--and two spacer peptides, SP1 and SP2,
represents a new therapeutic target. Although the cleavage of the
Gag polyprotein plays a central role in the progression of
infectious virus particle production, to date, no antiretroviral
drug has been approved for this mechanism.
[0007] In most cell types, assembly occurs at the plasma membrane,
and the MA domain of Gag mediates membrane binding. Assembly is
completed by budding of the immature particle from the cell.
Concomitant with particle release, the virally encoded PR cleaves
Gag into the four mature protein domains, MA, CA, NC and p6, and
the two spacer peptides, SP1 and SP2. Gag-Pol is also cleaved by
PR, liberating the viral enzymes PR, RT and IN. Gag proteolytic
processing induces a morphological rearrangement within the
particle, known as maturation. Maturation converts the immature,
donut-shaped particle to the mature virion, which contains a
condensed conical core composed of a CA shell surrounding the viral
RNA genome in a complex with NC and the viral enzymes RT and IN.
Maturation prepares the virus for infection of a new cell and is
absolutely essential for particle infectivity.
[0008] Bevirimat (PA-457) is a maturation inhibitor that inhibits
the final step in the processing of Gag, the conversion of
capsid-SP1 (p25) to capsid, which is required for the formation of
infectious viral particles. Bevirimat has activity against
ART-resistant and wild-type HIV, and has shown synergy with
antiretrovirals from all classes. Bevirimat reduced HIV viral load
by a mean of 1.3 log.sub.10/mL in patients who achieved trough
levels of >=20 .mu.g/mL and who did not have any of the key
baseline Gag polymorphisms at Q369, V370 or T371. However,
Bevirimat users with Gag polymorphisms at Q369, V370 or T371
demonstrated significantly lower load reductions than patients
without Gag polymorphisms at these sites.
[0009] Other examples of maturation inhibitors can be found in PCT
Patent Application No. WO2011/100308, "Derivatives of Betulin"; PCT
Patent Application No. PCT/US2012/024288, "Novel Anti-HIV Compounds
and Methods of Use Thereof"; Chinese PCT Application No.
PCT/CN2011/001302, "Carbonyl Derivatives of Betulin"; Chinese PCT
Application No. PCT/CN2011/001303, "Methylene Derivatives of
Betulin"; Chinese PCT Application Nos. PCT/CN2011/002105 and
PCT/CN2011/002159, "Propenoate Derivatives of Betulin". Maturation
inhibitors in the prior art leave open gaps in the areas of
polymorphism coverage whereby potency against a broad range of
clinically relevant gag sequences is extremely important, along
with overall potency including the clinically relevant protein
adjusted antiviral activity that will be required for robust
efficacy in long term durability trials. To date, no maturation
inhibitor has achieved an optimal balance of these properties.
[0010] It would therefore be an advance in the art to discover
alternative compounds that are an effective balance of the
aforementioned properties for the prevention and/or treatment of
HIV infections.
SUMMARY OF THE INVENTION
[0011] In accordance with one embodiment of the present invention,
there is provided a compound of Formula I:
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein:
[0012] A is
##STR00003##
[0013] L.sub.1 and L.sub.2 are independently selected from a bond
or [C(R.sup.6R.sup.6')].sub.q;
[0014] each instance of Q is independently selected from
--CH.sub.2-- or --C(.dbd.O)--;
[0015] W is selected from a bond or O;
[0016] R.sup.1 is selected from the group consisting of hydrogen,
(C.sub.1-C.sub.12)alkyl, --C(O)R.sup.5,
--CH.sub.2'O--(C.sub.1-C.sub.6)alkyl, 2-tetrahydro-2H-pyran,
and
##STR00004##
[0017] R.sup.2 is selected from the group consisting of --H,
(C.sub.1-C.sub.12)alkyl, --(C.sub.1-C.sub.6)alkyl-OR.sup.4,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.5,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, and
--(CH.sub.2).sub.rN.sup.+(R.sup.4).sub.3, wherein when W is O,
R.sup.1 and R.sup.2 can optionally be taken together with the O and
N to which they are respectively joined to form a 4 to 8 membered
heterocyclyl ring, wherein the heterocyclyl ring may be optionally
substituted by one to two R.sup.11 groups;
[0018] R.sup.3 is selected from the group consisting of hydrogen,
(C.sub.1-C.sub.12)alkyl, --NR.sup.1R.sup.2, --OR.sup.5,
##STR00005##
wherein: [0019] X is a monocyclic or bicyclic
(C.sub.5-C.sub.14)aryl, [0020] Y is selected from a monocyclic or
bicyclic (C.sub.2-C.sub.9)heterocyclyl or monocyclic or bicyclic
(C.sub.2-C.sub.9)heteroaryl, each having one to three heteroatoms
selected from S, N or O, and [0021] Z is a monocyclic or bicyclic
(C.sub.3-C.sub.8)cycloalkyl;
[0022] R.sup.2 and R.sup.3 can optionally be taken together with
the nitrogen and L.sub.2 to which they are respectively joined to
form a 4 to 8 membered heterocyclyl ring, wherein the heterocyclyl
ring may be optionally substituted by one to two R.sup.11
groups;
[0023] R.sup.4 is selected from the group consisting of --H and
(C.sub.1-C.sub.6)alkyl;
[0024] R.sup.5 is selected from the group consisting of --H,
(C.sub.1-C.sub.6)alkyl, --R.sup.3,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, and
--(CH.sub.2).sub.rOR.sup.7.
[0025] R.sup.6 and R.sup.6' are independently selected from the
group consisting of --H, (C.sub.1--C--.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, haloalkyl,
--Y, --(CH.sub.2).sub.rNR.sup.7R.sup.8, --C(O)OH, and
--C(O)NH.sub.2, wherein the R.sup.6 and R.sup.6' groups can
optionally be taken together with the carbon to which they are
joined to form a 3 to 8 membered cycloalkyl ring, and wherein the
cycloalkyl ring may be optionally substituted by one to three
R.sup.11 groups;
[0026] R.sup.7 and R.sup.8 are independently selected from the
group consisting of --H, (C.sub.1--C--.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, -Q-aryl-(R.sup.4).sub.n,
--NR.sup.14R.sup.15, --C(O)CH.sub.3, wherein R.sup.7 and R.sup.8
can optionally be taken together with the nitrogen to which they
are joined to form a 4 to 8 membered heterocyclyl or heteroaryl
ring containing one to three heteroatoms selected from
--NR.sup.5--, --O--, --S--, --S(O)--, or --SO.sub.2--, wherein the
heterocyclyl or heteroaryl ring may be optionally substituted by
one to three R.sup.11 groups;
[0027] R.sup.9 is halo;
[0028] R.sup.10 is --N(R.sup.16).sub.2;
[0029] R.sup.11, R.sup.12, and R.sup.13 are independently selected
from the group consisting of oxo, hydroxyl, halo,
(C.sub.1-C.sub.6)alkoxy, --R.sup.6(R.sup.9).sub.q,
--OR.sup.6(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.10, --R.sup.4YR.sup.6,
--CO(O)R.sup.4, and --CO(O)R.sup.5, wherein any two R.sup.11,
R.sup.12 or R.sup.13 groups can optionally join to form a 3 to 8
membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring, wherein
the heterocyclyl or heteroaryl ring may contain one to three
heteroatoms selected from --NR.sup.5--, --O--, --S--, --S(O)--, or
--SO.sub.2--, and wherein the cycloalkyl, aryl, heterocyclyl or
heteroaryl ring may be optionally substituted by one to three
R.sup.16 groups;
[0030] R.sup.14 and R.sup.15 are independently selected from the
group consisting of --H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy,
--[C(R.sup.6).sub.2].sub.r--, --O[C(R.sup.6).sub.2].sub.r--, oxo,
hydroxyl, halo, --C(O)R.sup.7, --R.sup.10, and --CO(O)R.sup.2,
wherein R.sup.14 and R.sup.15 can optionally be taken together with
the carbon to which they are joined to form a 3 to 8 membered
cycloalkyl ring or 4 to 8 membered heterocyclyl ring containing one
to three heteroatoms selected from --NR.sup.5--, --O--, --S--,
--S(O)--, or --SO.sub.2--, wherein the cycloalkyl ring or
heterocyclyl ring may be optionally substituted by one to three
R.sup.16 groups;
[0031] R.sup.16 is independently selected from the group consisting
of --H, halo, oxo, hydroxyl, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
--R.sup.6(R.sup.9).sub.q, --OR.sup.6(R.sup.9).sub.q,
--N(R.sup.4).sub.2, --(CH.sub.2).sub.r-heterocyclyl, --C(O)OH,
--C(O)NH.sub.2, --R.sup.5(R.sup.9).sub.q,
--OR.sup.5(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
--C(O)R.sup.10, and --CO(O)R.sup.4;
[0032] m and n in each instance are independently 0, 1, 2, 3, or
4;
[0033] p is independently 0, 1, 2, 3, or 4; and
[0034] r and q in each instance are independently 0, 1, 2, 3, or
4.
[0035] In a second aspect, the present invention relates to a
pharmaceutical composition comprising a) the compound of Formula I
or Formula II or a pharmaceutically acceptable salt the thereof;
and b) a pharmaceutically acceptable excipient.
[0036] In a third aspect, the present invention is a method of
treating an HIV infection comprising administering to a subject
suffering therefrom a compound of Formula I or Formula II, or a
pharmaceutically acceptable salt thereof.
[0037] Compounds of the present invention are useful for the
treatment of subjects with an HIV infection or for the treatment of
subjects at risk of acquiring an HIV infection.
BRIEF DESCRIPTION OF THE FIGURES
[0038] FIG. 1 shows a bar graph representing a comparison between
Bevirimat and compound 51 of their relative ability to inhibit HIV
reverse transcriptase activity across a broad panel of HIV-1
isolates.
[0039] FIG. 2 shows a bar graph representing a comparison between
compound 51 and compound C of their relative ability to inhibit HIV
reverse transcriptase activity across a broad panel of HIV-1
isolates.
[0040] FIG. 3 shows a line graph representing an extrapolation of
Bevirimat normalized IC.sub.50 values to 100% human serum.
[0041] FIG. 4 shows a line graph representing an extrapolation of
compound B normalized IC.sub.50 values to 100% human serum.
[0042] FIG. 5 shows a line graph representing an extrapolation of
compound 51 normalized IC.sub.50 values to 100% human serum.
DETAILED DESCRIPTION OF REPRESENTATIVE EMBODIMENTS
[0043] Throughout this application, references are made to various
embodiments relating to compounds, compositions, and methods. The
various embodiments described are meant to provide a variety of
illustrative examples and should not be construed as descriptions
of alternative species. Rather it should be noted that the
descriptions of various embodiments provided herein may be of
overlapping scope. The embodiments discussed herein are merely
illustrative and are not meant to limit the scope of the present
invention.
[0044] It is to be understood that the terminology used herein is
for the purpose of describing particular embodiments only and is
not intended to limit the scope of the present invention. In this
specification and in the claims that follow, reference will be made
to a number of terms that shall be defined to have the following
meanings.
[0045] As used herein unless otherwise specified, "alkyl" refers to
to a monovalent saturated aliphatic hydrocarbyl group having from 1
to 14 carbon atoms and, in some embodiments, from 1 to 6 carbon
atoms. "(C.sub.x-C.sub.y)alkyl" refers to alkyl groups having from
x to y carbon atoms. The term "alkyl"includes, by way of example,
linear and branched hydrocarbyl groups such as methyl (CH.sub.3--),
ethyl (CH.sub.3CH.sub.2--), n-propyl (CH.sub.3CH.sub.2CH.sub.2--),
isopropyl ((CH.sub.3).sub.2CH--), n-butyl
(CH.sub.3CH.sub.2CH.sub.2CH.sub.2--), isobutyl
((CH.sub.3).sub.2CHCH.sub.2--), sec-butyl
((CH.sub.3)(CH.sub.3CH.sub.2)CH--), t-butyl ((CH.sub.3).sub.3C--),
n-pentyl (CH.sub.3CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), and
neopentyl ((CH.sub.3).sub.3CCH.sub.2--).
[0046] "Alkylene" or "alkylene" refers to divalent saturated
aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and,
in some embodiments, from 1 to 6 carbon atoms.
"(C.sub.u-C.sub.v)alkylene" refers to alkylene groups having from u
to v carbon atoms. The alkylene groups include branched and
straight chain hydrocarbyl groups. For example,
"(C.sub.1-C.sub.6)alkylene" is meant to include methylene,
ethylene, propylene, 2-methylpropylene, dimethylethylene,
pentylene, and so forth. As such, the term "propylene" could be
exemplified by the following structure:
##STR00006##
Likewise, the term "dimethylbutylene" could be exemplified by any
of the following three structures or more:
##STR00007##
Furthermore, the term "(C.sub.1-C.sub.6)alkylene" is meant to
include such branched chain hydrocarbyl groups as
cyclopropylmethylene, which could be exemplified by the following
structure:
##STR00008##
[0047] "Alkenyl" refers to a linear or branched hydrocarbyl group
having from 2 to 10 carbon atoms and in some embodiments from 2 to
6 carbon atoms or 2 to 4 carbon atoms and having at least 1 site of
vinyl unsaturation (>C.dbd.C<). For example,
(C.sub.x-C.sub.y)alkenyl refers to alkenyl groups having from x to
y carbon atoms and is meant to include for example, ethenyl,
propenyl, isopropylene, 1,3-butadienyl, and the like.
[0048] "Alkynyl" refers to a linear monovalent hydrocarbon radical
or a branched monovalent hydrocarbon radical containing at least
one triple bond. The term "alkynyl" is also meant to include those
hydrocarbyl groups having one triple bond and one double bond. For
example, (C.sub.2-C.sub.6)alkynyl is meant to include ethynyl,
propynyl, and the like.
[0049] "Alkoxy" refers to the group --O-alkyl wherein alkyl is
defined herein. Alkoxy includes, by way of example, methoxy,
ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and
n-pentoxy.
[0050] "Acyl" refers to the groups H--C(O)--, alkyl-C(O)--,
alkenyl-C(O)--, alkynyl-C(O)--, cycloalkyl-C(O)--, aryl-C(O)--,
heteroaryl-C(O)--, and heterocyclic-C(O)--. Acyl includes the
"acetyl" group CH.sub.3C(O)--.
[0051] "Acylamino" refers to the groups --NR.sup.20C(O)alkyl,
--NR.sup.20C(O)cycloalkyl, --NR.sup.20C(O)alkenyl,
--NR.sup.20C(O)alkynyl, --NR.sup.20C(O)aryl,
--NR.sup.20C(O)heteroaryl, and --NR.sup.20C(O)heterocyclic, wherein
R.sup.10 is hydrogen or alkyl.
[0052] "Acyloxy" refers to the groups alkyl-C(O)O--,
alkenyl-C(O)O--, alkynyl-C(O)O--, aryl-C(O)O--, cycloalkyl-C(O)O--,
heteroaryl-C(O)O--, and heterocyclic-C(O)O--.
[0053] "Amino" refers to the group --NR.sup.21R.sup.22 where
R.sup.21 and R.sup.22 are independently selected from hydrogen,
alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl,
heterocyclic, --SO.sub.2-alkyl, --SO.sub.2-alkenyl,
--SO.sub.2-cycloalkyl, --SO.sub.2-aryl, --SO.sub.2-heteroaryl, and
--SO.sub.2-heterocyclic, and wherein R.sup.21 and R.sup.22 are
optionally joined together with the nitrogen bound thereto to form
a heterocyclic group. When R.sup.21 is hydrogen and R.sup.22 is
alkyl, the amino group is sometimes referred to herein as
alkylamino. When R.sup.21 and R.sup.22 are alkyl, the amino group
is sometimes referred to herein as dialkylamino. When referring to
a monosubstituted amino, it is meant that either R.sup.21 or
R.sup.22 is hydrogen but not both. When referring to a
disubstituted amino, it is meant that neither R.sup.21 nor R.sup.22
are hydrogen.
[0054] "Hydroxyamino" refers to the group --NHOH.
[0055] "Alkoxyamino" refers to the group --NHO-alkyl wherein alkyl
is defined herein.
[0056] "Aminocarbonyl" refers to the group --C(O)NR.sup.26R.sup.27
where R.sup.26 and R.sup.27 are independently selected from
hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl,
heterocyclic, hydroxy, alkoxy, amino, and acylamino, and where
R.sup.26 and R.sup.27 are optionally joined together with the
nitrogen bound thereto to form a heterocyclic group.
[0057] "Aryl" refers to an aromatic group of from 6 to 14 carbon
atoms and no ring heteroatoms and having a single ring (e.g.,
phenyl) or multiple condensed (fused) rings (e.g., naphthyl or
anthryl). For multiple ring systems, including fused, bridged, and
spiro ring systems having aromatic and non-aromatic rings that have
no ring heteroatoms, the term "Aryl" or "Ar" applies when the point
of attachment is at an aromatic carbon atom (e.g., 5,6,7,8
tetrahydronaphthalene-2-yl is an aryl group as its point of
attachment is at the 2-position of the aromatic phenyl ring).
[0058] "AUC" refers to the area under the plot of plasma
concentration of drug (not logarithm of the concentration) against
time after drug administration.
[0059] "EC.sub.50" refers to the concentration of a drug that gives
half-maximal response.
[0060] "IC.sub.50" refers to the half-maximal inhibitory
concentration of a drug. Sometimes, it is also converted to the
pIC.sub.50 scale (-log IC.sub.50), in which higher values indicate
exponentially greater potency.
[0061] "Clade" refers to a hypothetical construct based on
experimental data. Clades are found using multiple (sometimes
hundreds) of traits from a number of species (or specimens) and
analyzing them statistically to find the most likely phylogenetic
tree for the group.
[0062] "Cyano" or "nitrile" refers to the group --CN.
[0063] "Cycloalkyl" refers to a saturated or partially saturated
cyclic group of from 3 to 14 carbon atoms and no ring heteroatoms
and having a single ring or multiple rings including fused,
bridged, and spiro ring systems. For multiple ring systems having
aromatic and non-aromatic rings that have no ring heteroatoms, the
term "cycloalkyl" applies when the point of attachment is at a
non-aromatic carbon atom (e.g.
5,6,7,8,-tetrahydronaphthalene-5-yl). The term "Cycloalkyl"
includes cycloalkenyl groups, such as cyclohexenyl. Examples of
cycloalkyl groups include, for instance, adamantyl, cyclopropyl,
cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and
cyclohexenyl. Examples of cycloalkyl groups that include multiple
bicycloalkyl ring systems are bicyclohexyl, bicyclopentyl,
bicyclooctyl, and the like. Two such bicycloalkyl multiple ring
structures are exemplified and named below:
##STR00009##
[0064] "(C.sub.u-C.sub.v)cycloalkyl" refers to cycloalkyl groups
having u to v carbon atoms.
[0065] "Spiro cycloalkyl" refers to a 3 to 10 member cyclic
substituent formed by replacement of two hydrogen atoms at a common
carbon atom in a cyclic ring structure or in an alkylene group
having 2 to 9 carbon atoms, as exemplified by the following
structure wherein the group shown here attached to bonds marked
with wavy lines is substituted with a spiro cycloalkyl group:
##STR00010##
[0066] "Fused cycloalkyl" refers to a 3 to 10 member cyclic
substituent formed by the replacement of two hydrogen atoms at
different carbon atoms in a cycloalkyl ring structure, as
exemplified by the following structure wherein the cycloalkyl group
shown here contains bonds marked with wavy lines which are bonded
to carbon atoms that are substituted with a fused cycloalkyl
group:
##STR00011##
[0067] "Carboxy" or "carboxyl" refers interchangeably to the
groups
##STR00012##
--C(O)O, or --CO.sub.2.
[0068] "Halo" or "halogen" refers to fluoro, chloro, bromo, and
iodo.
[0069] "Haloalkyl" refers to substitution of an alkyl group with 1
to 3 halo groups (e.g., bifluoromethyl or trifluoromethyl).
[0070] "Haloalkoxy" refers to substitution of alkoxy groups with 1
to 5 (e.g. when the alkoxy group has at least 2 carbon atoms) or in
some embodiments 1 to 3 halo groups (e.g. trifluoromethoxy).
[0071] "Human Serum Protein Shift Assay" refers to an HIV assay
using a Luciferase Reporter to determine percent
inhibition--pIC.sub.50. The HIV assay makes use of a two-cell
co-culture system. In this assay, an infected cell line J4HxB2 and
an indicator cell line HOS (delta LTR+luciferase) are co-cultured
in the presence and absence of compound. The assay is designed to
find inhibitors that prevent the infection of HOS cells by the
J4HxB2 cell line. The assay can detect inhibitors of any stage of
the HIV infection cycle.
[0072] "Hydroxy" or "hydroxyl" refers to the group --OH.
[0073] "Heteroaryl" refers to an aromatic group of from 1 to 14
carbon atoms and 1 to 6 heteroatoms selected from oxygen, nitrogen,
and sulfur and includes single ring (e.g. imidazolyl) and multiple
ring systems (e.g. benzimidazol-2-yl and benzimidazol-6-yl). For
multiple ring systems, including fused, bridged, and spiro ring
systems having aromatic and non-aromatic rings, the term
"heteroaryl" applies if there is at least one ring heteroatom and
the point of attachment is at an atom of an aromatic ring (e.g.
1,2,3,4-tetrahydroquinolin-6-yl and
5,6,7,8-tetrahydroquinolin-3-yl). In some embodiments, the nitrogen
and/or the sulfur ring atom(s) of the heteroaryl group are
optionally oxidized to provide for the N-oxide (N.fwdarw.O),
sulfinyl, or sulfonyl moieties. More specifically the term
heteroaryl includes, but is not limited to, pyridyl, furanyl,
thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl,
imidazolinyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl,
pyrimidinyl, purinyl, phthalazyl, naphthylpryidyl, benzofuranyl,
tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl,
benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl,
indolizinyl, dihydroindolyl, indazolyl, indolinyl, benzoxazolyl,
quinolyl, isoquinolyl, quinolizyl, quianazolyl, quinoxalyl,
tetrahydroquinolinyl, isoquinolyl, quinazolinonyl, benzimidazolyl,
benzisoxazolyl, benzothienyl, benzopyridazinyl, pteridinyl,
carbazolyl, carbolinyl, phenanthridinyl, acridinyl,
phenanthrolinyl, phenazinyl, phenoxazinyl, phenothiazinyl, and
phthalimidyl.
[0074] "Heterocyclic" or "heterocycle" or "heterocycloalkyl" or
"heterocyclyl" refers to a saturated or partially saturated cyclic
group having from 1 to 14 carbon atoms and from 1 to 6 heteroatoms
selected from nitrogen, sulfur, phosphorus or oxygen and includes
single ring and multiple ring systems including fused, bridged, and
spiro ring systems. For multiple ring systems having aromatic
and/or non-aromatic rings, the terms "heterocyclic", "heterocycle",
"heterocycloalkyl", or "heterocyclyl" apply when there is at least
one ring heteroatom and the point of attachment is at an atom of a
non-aromatic ring (e.g. 1,2,3,4-tetrahydroquinoline-3-yl,
5,6,7,8-tetrahydroquinoline-6-yl, and decahydroquinolin-6-yl). In
one embodiment, the nitrogen, phosphorus and/or sulfur atom(s) of
the heterocyclic group are optionally oxidized to provide for the
N-oxide, phosphinane oxide, sulfinyl, sulfonyl moieties. More
specifically the heterocyclyl includes, but is not limited to,
tetrahydropyranyl, piperidinyl, piperazinyl, 3-pyrrolidinyl,
2-pyrrolidon-1-yl, morpholinyl, and pyrrolidinyl. A prefix
indicating the number of carbon atoms (e.g., C.sub.3-C.sub.10)
refers to the total number of carbon atoms in the portion of the
heterocyclyl group exclusive of the number of heteroatoms.
[0075] Examples of heterocycle and heteroaryl groups include, but
are not limited to, azetidine, pyrrole, imidazole, pyrazole,
pyridine, pyrazine, pyrimidine, pyridazine, pyridone, indolizine,
isoindole, indole, dihydroindole, indazole, purine, quinolizine,
isoquinoline, quinoline, phthalazine, naphthylpyridine,
quinoxaline, quinazoline, cinnoline, pteridine, carbazole,
carboline, phenanthridine, acridine, phenanthroline, isothiazole,
phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine,
imidazoline, piperidine, piperazine, indoline, phthalimide,
1,2,3,4-tetrahydroisoquinoline,
4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine,
thiophene, benzo[b]thiophene, morpholine, thiomorpholine (also
referred to as thiamorpholine), piperidine, pyrrolidine, and
tetrahydrofuranyl.
[0076] "Fused heterocyclic" or "fused heterocycle" refer to a 3 to
10 member cyclic substituent formed by the replacement of two
hydrogen atoms at different carbon atoms in a cycloalkyl ring
structure, as exemplified by the following structure wherein the
cycloalkyl group shown here contains bonds marked with wavy lines
which are bonded to carbon atoms that are substituted with a fused
heterocyclic group:
##STR00013##
[0077] "Compound", "compounds", "chemical entity", and "chemical
entities" as used herein refers to a compound encompassed by the
generic formulae disclosed herein, any subgenus of those generic
formulae, and any forms of the compounds within the generic and
subgeneric formulae, including the racemates, stereoisomers, and
tautomers of the compound or compounds.
[0078] The term "heteroatom" means nitrogen, oxygen, or sulfur and
includes any oxidized form of nitrogen, such as N(O)
{N.sup.+--O.sup.-} and sulfur such as S(O) and S(O).sub.2, and the
quaternized form of any basic nitrogen.
[0079] "Oxazolidinone" refers to a 5-membered heterocyclic ring
containing one nitrogen and one oxygen as heteroatoms and also
contains two carbons and is substituted at one of the two carbons
by a carbonyl group as exemplified by any of the following
structures, wherein the oxazolidinone groups shown here are bonded
to a parent molecule, which is indicated by a wavy line in the bond
to the parent molecule:
##STR00014##
[0080] "Oxo" refers to a (.dbd.O) group.
[0081] "Polymorphism" refers to when two or more clearly different
phenotypes exist in the same population of a species where the
occurrence of more than one form or morph. In order to be
classified as such, morphs must occupy the same habitat at the same
time and belong to a panmictic population (one with random
mating).
[0082] "Protein binding" refers to the binding of a drug to
proteins in blood plasma, tissue membranes, red blood cells and
other components of blood.
[0083] "Protein shift" refers to determining a binding shift by
comparing the EC.sub.50 values determined in the absence and
presence of human serum.
[0084] "QVT" refers to the amino acids at positions 369, 370, and
371, respectively in the Sp1 fragment of HIV-1 Gag.
[0085] "Racemates" refers to a mixture of enantiomers. In an
embodiment of the invention, the compounds of Formula I, or
pharmaceutically acceptable salts thereof, are enantiomerically
enriched with one enantiomer wherein all of the chiral carbons
referred to are in one configuration. In general, reference to an
enantiomerically enriched compound or salt, is meant to indicate
that the specified enantiomer will comprise more than 50% by weight
of the total weight of all enantiomers of the compound or salt.
[0086] "Solvate" or "solvates" of a compound refer to those
compounds, as defined above, which are bound to a stoichiometric or
non-stoichiometric amount of a solvent. Solvates of a compound
includes solvates of all forms of the compound. In certain
embodiments, solvents are volatile, non-toxic, and/or acceptable
for administration to humans in trace amounts. Suitable solvates
include water.
[0087] "Stereoisomer" or "stereoisomers" refer to compounds that
differ in the chirality of one or more stereocenters. Stereoisomers
include enantiomers and diastereomers.
[0088] "Tautomer" refer to alternate forms of a compound that
differ in the position of a proton, such as enol-keto and
imine-enamine tautomers, or the tautomeric forms of heteroaryl
groups containing a ring atom attached to both a ring --NH-- moiety
and a ring .dbd.N-- moiety such as pyrazoles, imidazoles,
benzimidazoles, triazoles, and tetrazoles.
[0089] The term `atropisomer` refers to a stereoisomer resulting
from an axis of asymmetry. This can result from restricted rotation
about a single bond where the rotational barrier is high enough to
allow differentiation of the isomeric species up to and including
complete isolation of stable non-interconverting diastereomer or
enantiomeric species. One skilled in the art will recognize that
upon installing a nonsymmetrical R.sup.x to core, the formation of
atropisomers is possible. In addition, once a second chiral center
is installed in a given molecule containing an atropisomer, the two
chiral elements taken together can create diastereomeric and
enantiomeric stereochemical species. Depending upon the
substitution about the Cx axis, interconversion between the
atropisomers may or may not be possible and may depend on
temperature. In some instances, the atropisomers may interconvert
rapidly at room temperature and not resolve under ambient
conditions. Other situations may allow for resolution and isolation
but interconversion can occur over a period of seconds to hours or
even days or months such that optical purity is degraded measurably
over time. Yet other species may be completely restricted from
interconversion under ambient and/or elevated temperatures such
that resolution and isolation is possible and yields stable
species. When known, the resolved atropisomers were named using the
helical nomenclature. For this designation, only the two ligands of
highest priority in front and behind the axis are considered. When
the turn priority from the front ligand 1 to the rear ligand 1 is
clockwise, the configuration is P, if counterclockwise it is M.
[0090] "Pharmaceutically acceptable salt" refers to
pharmaceutically acceptable salts derived from a variety of organic
and inorganic counter ions well known in the art and include, by
way of example only, sodium, potassium, calcium, magnesium,
ammonium, and tetraalkylammonium, and when the molecule contains a
basic functionality, salts of organic or inorganic acids, such as
hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate,
and oxalate. Suitable salts include those described in P. Heinrich
Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts
Properties, Selection, and Use; 2002.
[0091] "Patient" or "subject" refers to mammals and includes humans
and non-human mammals.
[0092] "Treating" or "treatment" of a disease in a patient refers
to 1) preventing the disease from occurring in a patient that is
predisposed or does not yet display symptoms of the disease; 2)
inhibiting the disease or arresting its development; or 3)
ameliorating or causing regression of the disease.
[0093] Wherever dashed lines occur adjacent to single bonds denoted
by solid lines, then the dashed line represents an optional double
bond at that position. Likewise, wherever dashed circles appear
within ring structures denoted by solid lines or solid circles,
then the dashed circles represent one to three optional double
bonds arranged according to their proper valence taking into
account whether the ring has any optional substitutions around the
ring as will be known by one of skill in the art. For example, the
dashed line in the structure below could either indicate a double
bond at that position or a single bond at that position:
##STR00015##
[0094] Similarly, ring A below could be a cyclohexyl ring without
any double bonds or it could also be a phenyl ring having three
double bonds arranged in any position that still depicts the proper
valence for a phenyl ring. Likewise, in ring B below, any of
X.sup.1-X.sup.5 could be selected from: C, CH, or CH.sub.2, N, or
NH, and the dashed circle means that ring B could be a cyclohexyl
or phenyl ring or a N-containing heterocycle with no double bonds
or a N-containing heteroaryl ring with one to three double bonds
arranged in any position that still depicts the proper valence:
##STR00016##
[0095] Where specific compounds or generic formulas are drawn that
have aromatic rings, such as aryl or heteroaryl rings, then it will
understood by one of still in the art that the particular aromatic
location of any double bonds are a blend of equivalent positions
even if they are drawn in different locations from compound to
compound or from formula to formula. For example, in the two
pyridine rings (A and B) below, the double bonds are drawn in
different locations, however, they are known to be the same
structure and compound:
##STR00017##
[0096] The present invention includes compounds as well as their
pharmaceutically acceptable salts. Accordingly, the word "or" in
the context of "a compound or a pharmaceutically acceptable salt
thereof" is understood to refer to either: 1) a compound alone or a
compound and a pharmaceutically acceptable salt thereof
(alternative), or 2) a compound and a pharmaceutically acceptable
salt thereof (in combination).
[0097] Unless indicated otherwise, the nomenclature of substituents
that are not explicitly defined herein are arrived at by naming the
terminal portion of the functionality followed by the adjacent
functionality toward the point of attachment. For example, the
substituent "arylalkyloxycarbonyl" refers to the group
(aryl)-(alkyl)-O--C(O)--. In a term such as "--C(R.sup.x).sub.2",
it should be understood that the two R.sup.x groups can be the
same, or they can be different if R.sup.x is defined as having more
than one possible identity. In addition, certain substituents are
drawn as --R.sup.xR.sup.y, where the "--" indicates a bond adjacent
to the parent molecule and R.sup.y being the terminal portion of
the functionality. Similarly, it is understood that the above
definitions are not intended to include impermissible substitution
patterns (e.g., methyl substituted with 5 fluoro groups). Such
impermissible substitution patterns are well known to the skilled
artisan.
[0098] As recited above, Bevirimat is a yet unapproved anti-HIV
drug derived from a betulinic acid-like compound, first isolated
from Syzygium claviflorum, a Chinese herb. It is believed to
inhibit HIV by a novel mechanism, so-called maturation inhibition.
Like protease inhibitors, Bevirimat and other maturation inhibitors
interfere with protease processing of newly translated HIV
polyprotein precursor, called gag. Gag is an essential structural
protein of the HIV virus. Gag undergoes a chain of interactions
both with itself and with other cellular and viral factors to
accomplish the assembly of infectious virus particles.
[0099] However, naturally occurring polymorphisms in HIV are
present in some infected individuals, thus lowering the anti-HIV
efficacy of some currently considered therapies. Indeed, studies
have shown that presence of a number of single nucleotide
polymorphisms in the Capsid/SP1 spacer protein (CA/SP1) cleavage
site has resulted in clinical resistance in HIV patients to
Bevirimat. Likewise, mutations in the glutamine-valine-threonine
(QVT) motif of the SP1 peptide are also known to cause Bevirimat
resistance in HIV infected patients. Mutations in the QVT motif of
the SP1 peptide are the primary predictors of failure to respond to
Bevirimat and the effect of these mutations has been repeatedly
demonstrated. These problems eventually led to the cessation of
clinical development of Bevirimat. See Knapp, D., et al., J. Clin.
Microbiol. 49(1): 201-208 (2011).
Bevirimat:
##STR00018##
[0100] Bevirimat's Clinical Problems:
[0101] Polymorphism issues & weak potency. [0102] MT4 antiviral
assay NL4-3 strain EC.sub.50=223 nM. [0103] MT4 antiviral assay
NL4-3 strain with V370A site directed mutant polymorphism
EC.sub.50=6062 nM. [0104] In assay fold shift with human serum 157
fold. See Table 6. [0105] C.sub.min target>20 .mu.g/mL*. [0106]
>40% of Glade B patients have QVT polymorphisms*. *See
McCallister, et al., XVII International Drug Resistance Workshop,
Jun. 10-14, 2008, Sitges, Spain. Conference poster "HIV-1 Gag
Polymorphisms Determine Treatment Response to Bevirimat
(PA-457)".
[0107] After the above HIV clinical problems with Bevirimat were
reported, several new HIV active maturation inhibitor compounds
were discovered. For example, certain maturation inhibitor
compounds (hereinafter, compounds "A", "B" and "C", as shown below)
have been described in PCT Published Application No. WO2011/100308
and PCT Application Serial No. PCT/CN2011/001302. In addition, the
present application also describes compounds 51 and 56, among
others, as detailed throughout. The present application describes
compounds that are novel over the compounds described in PCT
Published Application No. WO2011/100308 and PCT Application Serial
No. PCT/CN2011/001302. In addition, certain compounds described
herein show unexpectedly superior properties over the compounds
("A", "B", and "C") described in PCT Published Application No.
WO2011/100308 and PCT Application Serial No. PCT/CN2011/001302.
[0108] One difference between the compounds described in those two
references and the compounds of the present application is that
both of those references have compounds requiring a carbonyl group
at a position where, instead, the present application application
describes compounds that cannot have a carbonyl at the same
position. By way of example only, this carbonyl versus non-carbonyl
difference is highlighted by the arrows indicated directly below.
The generic structures of Formulas (I) and (II) bear this out
within the present application because when W is oxygen, there can
only be a single bond between the adjacent carbon and the W. In
sum, there can be no double bond between W and its adjacent carbon
so as to form a carbonyl in the Formulas of the present
application.
##STR00019##
[0109] Indeed, this structural difference has now been discovered
to unexpectedly improve many of the properties that are involved
with creating an efficacious drug for the prevention and/or
treatment of viral diseases, such as HIV. One or more of such
properties of certain compounds described within the present
application, include, but are not limited to, improving the HIV
virus polymorphism coverage, improving the in vitro potency
(EC.sub.50), reducing the projected clinical human AUC target,
potentially reducing any toxicity window by lowering the required
dosage to be efficacious, and reducing the impact of protein
binding and/or serum shift upon the projected clinical AUC
target.
[0110] Such improvements to the pharmacokinetics and projected
clinical use of certain compounds described herein are described in
more detail within Examples 84-89 below.
##STR00020##
[0111] In accordance with one embodiment of the present invention,
there is provided a compound having the structure of Formula I:
##STR00021##
or a pharmaceutically acceptable salt thereof, wherein:
[0112] A is
##STR00022##
[0113] L.sub.1 and L.sub.2 are independently selected from a bond
or [C(R.sup.6R.sup.6')].sub.q;
[0114] each instance of Q is independently selected from
--CH.sub.2-- or --C(.dbd.O)--;
[0115] W is selected from a bond or O;
[0116] R.sup.1 is selected from the group consisting of --H,
--C(O)R.sup.5, --CH.sub.2--O--(C.sub.1-C.sub.6)alkyl,
2-tetrahydro-2H-pyran, and
##STR00023##
[0117] R.sup.2 is selected from the group consisting of --H,
--(C.sub.1-C.sub.6)alkyl-OR.sup.4,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.5,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, and
--(CH.sub.2).sub.rN.sup.+(R.sup.4).sub.3, wherein when W is O,
R.sup.1 and R.sup.2 can optionally be taken together with the O and
N to which they are respectively joined to form a 4 to 8 membered
heterocyclyl ring, wherein the heterocyclyl ring may be optionally
substituted by one to two R.sup.11 groups;
[0118] R.sup.3 is selected from the group consisting of --H,
(C.sub.1-C.sub.12)alkyl, --NR.sup.1R.sup.2, --OR.sup.5,
##STR00024##
wherein: [0119] X is a monocyclic or bicyclic
(C.sub.5-C.sub.14)aryl, [0120] Y is selected from a monocyclic or
bicyclic (C.sub.2-C.sub.9)heterocyclyl or monocyclic or bicyclic
(C.sub.2-C.sub.9)heteroaryl, each having one to three heteroatoms
selected from S, N or O, and [0121] Z is a monocyclic or bicyclic
(C.sub.3-C.sub.8)cycloalkyl;
[0122] R.sup.2 and R.sup.3 can optionally be taken together with
the nitrogen and L.sub.2 to which they are respectively joined to
form a 4 to 8 membered heterocyclyl ring, wherein the heterocyclyl
ring may be optionally substituted by one to two R.sup.11
groups;
[0123] R.sup.4 is selected from the group consisting of --H and
(C.sub.1-C.sub.6)alkyl;
[0124] R.sup.5 is selected from the group consisting of --H,
(C.sub.1-C.sub.6)alkyl, --R.sup.3,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, and
--(CH.sub.2).sub.rOR.sup.7.
[0125] R.sup.6 and R.sup.6' are independently selected from the
group consisting of --H, (C.sub.1--C--.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, haloalkyl,
--Y, --(CH.sub.2).sub.rNR.sup.7R.sup.8, --C(O)OH, and
--C(O)NH.sub.2, wherein the R.sup.6 and R.sup.6' groups can
optionally be taken together with the carbon to which they are
joined to form a 3 to 8 membered cycloalkyl ring, and wherein the
cycloalkyl ring may be optionally substituted by one to three
R.sup.11 groups;
[0126] R.sup.7 and R.sup.8 are independently selected from the
group consisting of --H, (C.sub.1--C--.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, -Q-aryl-(R.sup.4).sub.n,
--NR.sup.14R.sup.15, --C(O)CH.sub.3, wherein R.sup.7 and R.sup.8
can optionally be taken together with the nitrogen to which they
are joined to form a 4 to 8 membered heterocyclyl or heteroaryl
ring containing one to three heteroatoms selected from
--NR.sup.5--, --O--, --S--, --S(O)--, or --SO.sub.2--, wherein the
heterocyclyl or heteroaryl ring may be optionally substituted by
one to three R.sup.11 groups;
[0127] R.sup.9 is halo;
[0128] R.sup.10 is --N(R.sup.16).sub.2;
[0129] R.sup.11, R.sup.12, and R.sup.13 are independently selected
from the group consisting of oxo, hydroxyl, halo,
(C.sub.1-C.sub.6)alkoxy, --R.sup.6(R.sup.9).sub.q,
--OR.sup.6(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.10, --R.sup.4YR.sup.6,
--CO(O)R.sup.4, and --CO(O)R.sup.6, wherein any two R.sup.11,
R.sup.12 or R.sup.13 groups can optionally join to form a 3 to 8
membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring, wherein
the heterocyclyl or heteroaryl ring may contain one to three
heteroatoms selected from --NR.sup.5--, --O--, --S--, --S(O)--, or
--SO.sub.2--, and wherein the cycloalkyl, aryl, heterocyclyl or
heteroaryl ring may be optionally substituted by one to three
R.sup.16 groups;
[0130] R.sup.14 and R.sup.15 are independently selected from the
group consisting of --H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy,
--[C(R.sup.6).sub.2].sub.r--, --O[C(R.sup.6).sub.2].sub.r--, oxo,
hydroxyl, halo, --C(O)R.sup.7, --R.sup.10, and --CO(O)R.sup.2,
wherein R.sup.14 and R.sup.15 can optionally be taken together with
the carbon to which they are joined to form a 3 to 8 membered
cycloalkyl ring or 4 to 8 membered heterocyclyl ring containing one
to three heteroatoms selected from --NR.sup.5--, --O--, --S--,
--S(O)--, or --SO.sub.2--, wherein the cycloalkyl ring or
heterocyclyl ring may be optionally substituted by one to three
R.sup.16 groups;
[0131] R.sup.16 is independently selected from the group consisting
of --H, halo, oxo, hydroxyl, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
--R.sup.6(R.sup.9).sub.q, --OR.sup.6(R.sup.9).sub.q,
--N(R.sup.4).sub.2, --(CH.sub.2).sub.r-heterocycle, --C(O)OH,
--C(O)NH.sub.2, --R.sup.5(R.sup.9).sub.q,
--OR.sup.5(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
--C(O)R.sup.10, and --CO(O)R.sup.4;
[0132] m and n in each instance are independently 0, 1, 2, 3, or
4;
[0133] p is independently 0, 1, 2, 3, or 4; and
[0134] r and q in each instance are independently 0, 1, 2, 3, or
4.
[0135] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I:
##STR00025##
or a pharmaceutically acceptable salt thereof, wherein:
[0136] A is
##STR00026##
[0137] L.sub.1 and L.sub.2 are [C(R.sup.6R.sup.6')].sub.q;
[0138] each Q is independently selected from --CH.sub.2-- or
--C(.dbd.O)--;
[0139] W is selected from a bond or O;
[0140] R.sup.1 is selected from the group consisting of --H,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.4, and
##STR00027##
[0141] R.sup.2 is selected from the group consisting of --H,
(C.sub.1-C.sub.6)alkyl, --(C.sub.1-C.sub.6)alkyl-OR.sup.4,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.5,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, and
--(CH.sub.2).sub.rN.sup.+(R.sup.4).sub.3;
[0142] R.sup.3 is selected from the group consisting of hydrogen,
(C.sub.1-C.sub.12)alkyl, --NR.sup.1R.sup.2, --OR.sup.5,
##STR00028##
wherein: [0143] X is a monocyclic or bicyclic
(C.sub.5-C.sub.14)aryl, [0144] Y is selected from a monocyclic or
bicyclic (C.sub.2-C.sub.9)heterocyclyl or monocyclic or bicyclic
(C.sub.2-C.sub.9)heteroaryl, each having one to three heteroatoms
selected from S, N or O, and [0145] Z is a monocyclic or bicyclic
(C.sub.3-C.sub.8)cycloalkyl;
[0146] R.sup.4 is selected from the group consisting of --H and
(C.sub.1-C.sub.6)alkyl;
[0147] R.sup.5 is selected from the group consisting of
(C.sub.1-C.sub.6)alkyl, --(CH.sub.2).sub.rNR.sup.7R.sup.8, and
--(CH.sub.2).sub.rOR.sup.7;
[0148] R.sup.6 and R.sup.6' are independently selected from the
group consisting of --H, (C.sub.1--C--.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, haloalkyl,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, --C(O)OH, and --C(O)NH.sub.2,
wherein the R.sup.6 and R.sup.6' groups can optionally be taken
together with the carbon to which they are joined to form a 3 to 8
membered cycloalkyl ring, and wherein the cycloalkyl ring may be
optionally substituted by one to three R.sup.11 groups;
[0149] R.sup.7 and R.sup.8 are independently selected from the
group consisting of --H, (C.sub.1--C--.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, --NR.sup.14R.sup.15, and
--C(O)CH.sub.3;
[0150] R.sup.9 is halo;
[0151] R.sup.10 is --N(R.sup.16).sub.2;
[0152] R.sup.11, R.sup.12, and R.sup.13 are independently selected
from the group consisting of oxo, hydroxyl, halo,
(C.sub.1-C.sub.6)alkoxy, --R.sup.6(R.sup.9).sub.q,
--OR.sup.6(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.10, --R.sup.4YR.sup.6,
--CO(O)R.sup.4, and --CO(O)R.sup.5;
[0153] R.sup.14 and R.sup.15 are independently selected from the
group consisting of --H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy,
--[C(R.sup.6).sub.2].sub.r--, --O[C(R.sup.6).sub.2].sub.r--, oxo,
hydroxyl, halo, --C(O)R.sup.7, --R.sup.10, and --CO(O)R.sup.2;
[0154] R.sup.16 is independently selected from the group consisting
of --H, oxo, halo, hydroxyl, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
--R.sup.6(R.sup.9).sub.q, --OR.sup.6(R.sup.9).sub.q,
--N(R.sup.4).sub.2, --(CH.sub.2).sub.r-heterocycle, --C(O)OH,
--C(O)NH.sub.2, --R.sup.5(R.sup.9).sub.q,
--OR.sup.5(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
--C(O)R.sup.10, and --CO(O)R.sup.4;
[0155] m and n in each instance are independently 0, 1, 2, 3, or
4;
[0156] p is independently 0, 1, 2, 3, or 4; and
[0157] r and q in each instance are independently 0, 1, 2, 3, or
4.
[0158] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I:
##STR00029##
or a pharmaceutically acceptable salt thereof, wherein:
[0159] A is
##STR00030##
[0160] L.sub.1 and L.sub.2 are both (--CH.sub.2--);
[0161] Q is --C(.dbd.O)--;
[0162] W is O;
[0163] R.sup.1 is --H;
[0164] R.sup.2 is selected from the group consisting of --H,
(C.sub.1-C.sub.6)alkyl, --(C.sub.1-C.sub.6)alkyl-OR.sup.4,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.5,
and --(CH.sub.2).sub.rNR.sup.7R.sup.8;
[0165] R.sup.3 is selected from the group consisting of
(C.sub.1-C.sub.12)alkyl, --NR.sup.1R.sup.2, --OR.sup.5,
##STR00031##
wherein: [0166] X is a monocyclic or bicyclic
(C.sub.5-C.sub.14)aryl, [0167] Y is selected from a monocyclic or
bicyclic (C.sub.2-C.sub.9)heterocyclyl or monocyclic or bicyclic
(C.sub.2-C.sub.9)heteroaryl, each having one to three heteroatoms
selected from S, N or O, and [0168] Z is a monocyclic or bicyclic
(C.sub.3-C.sub.8)cycloalkyl;
[0169] R.sup.4 is selected from the group consisting of --H and
(C.sub.1-C.sub.6)alkyl;
[0170] R.sup.5 is selected from the group consisting of
(C.sub.1-C.sub.6)alkyl, --(CH.sub.2).sub.rNR.sup.7R.sup.8, and
--(CH.sub.2).sub.rOR.sup.7;
[0171] R.sup.6 and R.sup.6' are independently selected from the
group consisting of --H, (C.sub.1--C--.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, haloalkyl,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, --C(O)OH, and
--C(O)NH.sub.2;
[0172] R.sup.7 and R.sup.8 are independently selected from the
group consisting of --H, (C.sub.1--C--.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, --NR.sup.14R.sup.15, and
--C(O)CH.sub.3;
[0173] R.sup.9 is halo;
[0174] R.sup.10 is --N(R.sup.16).sub.2;
[0175] R.sup.11, R.sup.12, and R.sup.13 are independently selected
from the group consisting of oxo, hydroxyl, halo,
(C.sub.1-C.sub.6)alkoxy, --R.sup.6(R.sup.9).sub.q,
--OR.sup.6(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.10, --R.sup.4YR.sup.6,
--CO(O)R.sup.4, and --CO(O)R.sup.5;
[0176] R.sup.14 and R.sup.15 are independently selected from the
group consisting of --H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy,
--[C(R.sup.6).sub.2].sub.r--, --O[C(R.sup.6).sub.2].sub.r--, oxo,
hydroxyl, halo, --C(O)R.sup.7, --R.sup.10, and --CO(O)R.sup.2;
[0177] R.sup.16 is independently selected from the group consisting
of --H, oxo, halo, hydroxyl, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
--R.sup.6(R.sup.9).sub.q, --OR.sup.6(R.sup.9).sub.q,
--N(R.sup.4).sub.2, --(CH.sub.2).sub.r-heterocyclyl, --C(O)OH,
--C(O)NH.sub.2, --R.sup.5(R.sup.9).sub.q,
--OR.sup.5(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
--C(O)R.sup.10, and --CO(O)R.sup.4;
[0178] m and n in each instance are independently 0, 1, or 2;
[0179] p is independently 0, 1, or 2; and
[0180] r and q in each instance are independently 0, 1, 2, or
3.
[0181] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I:
##STR00032##
or a pharmaceutically acceptable salt thereof, wherein:
[0182] A is
##STR00033##
[0183] L.sub.1 and L.sub.2 are both (--CH.sub.2--);
[0184] Q is --C(.dbd.O)--;
[0185] W is O;
[0186] R.sup.1 is --H;
[0187] R.sup.2 is selected from the group consisting of --H,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.5, and
--(CH.sub.2).sub.rNR.sup.7R.sup.8;
[0188] R.sup.3 is
##STR00034##
wherein X is a monocyclic or bicyclic (C.sub.5-C.sub.14)aryl;
[0189] R.sup.4 is selected from the group consisting of --H and
(C.sub.1-C.sub.6)alkyl;
[0190] R.sup.5 is selected from the group consisting of
(C.sub.1-C.sub.6)alkyl, --(CH.sub.2).sub.rNR.sup.7R.sup.8, and
--(CH.sub.2).sub.rOR.sup.7;
[0191] R.sup.6 is selected from the group consisting of --H,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.6)alkoxy, haloalkyl,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, --C(O)OH, and
--C(O)NH.sub.2;
[0192] R.sup.7 and R.sup.8 are independently selected from the
group consisting of --H, (C.sub.1--C--.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, --NR.sup.14R.sup.15, and
--C(O)CH.sub.3;
[0193] R.sup.9 is halo;
[0194] R.sup.10 is --N(R.sup.16).sub.2;
[0195] R.sup.11, R.sup.12, and R.sup.13 are independently selected
from the group consisting of oxo, hydroxyl, halo,
(C.sub.1-C.sub.6)alkoxy, --R.sup.6(R.sup.9).sub.q,
--OR.sup.6(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.10, --CO(O)R.sup.4, and
--CO(O)R.sup.5;
[0196] R.sup.14 and R.sup.15 are independently selected from the
group consisting of --H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy,
--[C(R.sup.6).sub.2].sub.r--, --O[C(R.sup.6).sub.2].sub.r--, oxo,
hydroxyl, halo, --C(O)R.sup.7, --R.sup.10, and --CO(O)R.sup.2;
[0197] R.sup.16 is independently selected from the group consisting
of --H, oxo, halo, hydroxyl, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
--R.sup.6(R.sup.9).sub.q, --OR.sup.6(R.sup.9).sub.q,
--N(R.sup.4).sub.2, --(CH.sub.2).sub.r-heterocyclyl, --C(O)OH,
--C(O)NH.sub.2, --R.sup.5(R.sup.9).sub.q,
--OR.sup.5(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
--C(O)R.sup.10, and --CO(O)R.sup.4;
[0198] m and n in each instance are independently 0, 1, or 2;
[0199] p is independently 0, 1, or 2; and
[0200] r and q in each instance are independently 0, 1, 2, or
3.
[0201] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I:
[0202] (I)
##STR00035##
or a pharmaceutically acceptable salt thereof, wherein:
[0203] A is
##STR00036##
[0204] L.sub.1 and L.sub.2 are both (--CH.sub.2--);
[0205] Q is --C(.dbd.O)--;
[0206] W is O;
[0207] R.sup.1 is --H;
[0208] R.sup.2 is --(CH.sub.2).sub.rNR.sup.7R.sup.8;
[0209] R.sup.3 is
##STR00037##
wherein X is phenyl;
[0210] R.sup.7 and R.sup.8 are independently selected from the
group consisting of --H and methyl;
[0211] R.sup.9 is selected from the group consisting of chloro,
bromo, and fluoro;
[0212] R.sup.11 is selected from the group consisting of chloro,
bromo, and fluoro;
[0213] m is 0, 1, or 2; and
[0214] r is 1, 2, or 3.
[0215] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula II:
##STR00038##
or a pharmaceutically acceptable salt thereof, wherein:
[0216] A is
##STR00039##
[0217] L.sub.1 and L.sub.2 are independently selected from a bond
or [C(R.sup.6R.sup.6')].sub.q;
[0218] each instance of Q is independently selected from
--CH.sub.2-- or --C(.dbd.O)--;
[0219] W is selected from a bond or O;
[0220] R.sup.1 is selected from the group consisting of --H,
(C.sub.1-C.sub.12)alkyl, --C(O)R.sup.5,
--CH.sub.2--O--(C.sub.1-C.sub.6)alkyl, 2-tetrahydro-2H-pyran,
and
##STR00040##
[0221] R.sup.2 is selected from the group consisting of --H,
(C.sub.1-C.sub.12)alkyl, --(C.sub.1-C.sub.6)alkyl-OR.sup.4,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.5,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, and
--(CH.sub.2).sub.rN.sup.+(R.sup.4).sub.3, wherein when W is O,
R.sup.1 and R.sup.2 can optionally be taken together with the O and
N to which they are respectively joined to form a 4 to 8 membered
heterocyclyl ring, wherein the heterocyclyl ring may be optionally
substituted by one to two R.sup.11 groups;
[0222] R.sup.3 is selected from the group consisting of hydrogen,
(C.sub.1-C.sub.12)alkyl, --NR.sup.1R.sup.2, --OR.sup.5,
##STR00041##
wherein: [0223] X is a monocyclic or bicyclic
(C.sub.5-C.sub.14)aryl, [0224] Y is selected from a monocyclic or
bicyclic (C.sub.2-C.sub.9)heterocyclyl or monocyclic or bicyclic
(C.sub.2-C.sub.9)heteroaryl, each having one to three heteroatoms
selected from S, N or O, and [0225] Z is a monocyclic or bicyclic
(C.sub.3-C.sub.8)cycloalkyl;
[0226] R.sup.2 and R.sup.3 can optionally be taken together with
the nitrogen and L.sub.2 to which they are respectively joined to
form a 4 to 8 membered heterocyclyl ring wherein the heterocyclyl
ring may be optionally substituted by one to two R.sup.11
groups;
[0227] R.sup.4 is selected from the group consisting of --H and
(C.sub.1-C.sub.6)alkyl;
[0228] R.sup.5 is selected from the group consisting of --H,
(C.sub.1-C.sub.6)alkyl, --R.sup.3,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, and
--(CH.sub.2).sub.rOR.sup.7.
[0229] R.sup.6 and R.sup.6' are independently selected from the
group consisting of --H, (C.sub.1--C--.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, haloalkyl,
--Y, --(CH.sub.2).sub.rNR.sup.7R.sup.8, --C(O)OH, and
--C(O)NH.sub.2, wherein the R.sup.6 and R.sup.6' groups can
optionally be taken together with the carbon to which they are
joined to form a 3 to 8 membered cycloalkyl ring, and wherein the
cycloalkyl ring may be optionally substituted by one to three
R.sup.11 groups;
[0230] R.sup.7 and R.sup.8 are independently selected from the
group consisting of --H, (C.sub.1--C--.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, -Q-aryl-(R.sup.4).sub.n,
--NR.sup.14R.sup.15, --C(O)CH.sub.3, wherein R.sup.7 and R.sup.8
can optionally be taken together with the nitrogen to which they
are joined to form a 4 to 8 membered heterocyclyl or heteroaryl
ring containing one to three heteroatoms selected from
--NR.sup.5--, --O--, --S--, --S(O)--, or --SO.sub.2--, wherein the
heterocyclyl or heteroaryl ring may be optionally substituted by
one to three R.sup.11 groups;
[0231] R.sup.9 is halo;
[0232] R.sup.10 is --N(R.sup.16).sub.2;
[0233] R.sup.11, R.sup.12, and R.sup.13 are independently selected
from the group consisting of oxo, hydroxyl, halo,
(C.sub.1-C.sub.6)alkoxy, --R.sup.6(R.sup.9).sub.q,
--OR.sup.6(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.10, --R.sup.4YR.sup.6,
--CO(O)R.sup.4, and --CO(O)R.sup.5, wherein any two R.sup.11,
R.sup.12 or R.sup.13 groups can optionally join to form a 3 to 8
membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring, wherein
the heterocyclyl or heteroaryl ring may contain one to three
heteroatoms selected from --NR.sup.5--, --O--, --S--, --S(O)--, or
--SO.sub.2--, and wherein the cycloalkyl, aryl, heterocyclyl or
heteroaryl ring may be optionally substituted by one to three
R.sup.16 groups;
[0234] R.sup.14 and R.sup.15 are independently selected from the
group consisting of --H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy,
--[C(R.sup.6).sub.2].sub.r--, --O[C(R.sup.6).sub.2].sub.r--, oxo,
hydroxyl, halo, --C(O)R.sup.7, --R.sup.10, and --CO(O)R.sup.2,
wherein R.sup.14 and R.sup.15 can optionally be taken together with
the carbon to which they are joined to form a 3 to 8 membered
cycloalkyl ring or 4 to 8 membered heterocyclyl ring containing one
to three heteroatoms selected from --NR.sup.5--, --O--, --S--,
--S(O)--, or --SO.sub.2--, wherein the cycloalkyl ring or
heterocyclyl ring may be optionally substituted by one to three
R.sup.16 groups;
[0235] R.sup.16 is independently selected from the group consisting
of --H, halo, oxo, hydroxyl, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
--R.sup.6(R.sup.9).sub.q, --OR.sup.6(R.sup.9).sub.q,
--N(R.sup.4).sub.2, --(CH.sub.2).sub.r-heterocycle, --C(O)OH,
--C(O)NH.sub.2, --R.sup.5(R.sup.9).sub.q,
--OR.sup.5(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
--C(O)R.sup.10, and --CO(O)R.sup.4;
[0236] m and n in each instance are independently 0, 1, 2, 3, or
4;
[0237] p is independently 0, 1, 2, 3, or 4; and
[0238] r and q in each instance are independently 0, 1, 2, 3, or
4.
[0239] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula II:
##STR00042##
or a pharmaceutically acceptable salt thereof, wherein:
[0240] A is
##STR00043##
[0241] L.sub.1 and L.sub.2 are [C(R.sup.6R.sup.6')].sub.q;
[0242] each Q is independently selected from--CH.sub.2-- or
--C(.dbd.O)--;
[0243] W is selected from a bond or O;
[0244] R.sup.1 is selected from the group consisting of --H,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.4, and
##STR00044##
[0245] R.sup.2 is selected from the group consisting of --H,
(C.sub.1-C.sub.6)alkyl, --(C.sub.1-C.sub.6)alkyl-OR.sup.4,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.5,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, and
--(CH.sub.2).sub.rN.sup.+(R.sup.4).sub.3;
[0246] R.sup.3 is selected from the group consisting of --H,
(C.sub.1-C.sub.12)alkyl, --NR.sup.1R.sup.2, --OR.sup.5,
##STR00045##
wherein: [0247] X is a monocyclic or bicyclic
(C.sub.5-C.sub.14)aryl, [0248] Y is selected from a monocyclic or
bicyclic (C.sub.2-C.sub.9)heterocyclyl or monocyclic or bicyclic
(C.sub.2-C.sub.9)heteroaryl, each having one to three heteroatoms
selected from S, N or O, and [0249] Z is a monocyclic or bicyclic
(C.sub.3-C.sub.8)cycloalkyl;
[0250] R.sup.4 is selected from the group consisting of --H and
(C.sub.1-C.sub.6)alkyl;
[0251] R.sup.5 is selected from the group consisting of
(C.sub.1-C.sub.6)alkyl, --(CH.sub.2).sub.rNR.sup.7R.sup.8, and
--(CH.sub.2).sub.rOR.sup.7;
[0252] R.sup.6 and R.sup.6' are independently selected from the
group consisting of --H, (C.sub.1--C--.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, haloalkyl,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, --C(O)OH, and --C(O)NH.sub.2,
wherein the R.sup.6 and R.sup.6' groups can optionally be taken
together with the carbon to which they are joined to form a 3 to 8
membered cycloalkyl ring, and wherein the cycloalkyl ring may be
optionally substituted by one to three R.sup.11 groups;
[0253] R.sup.7 and R.sup.8 are independently selected from the
group consisting of --H, (C.sub.1--C--.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, --NR.sup.14R.sup.15, and
--C(O)CH.sub.3;
[0254] R.sup.9 is halo;
[0255] R.sup.10 is --N(R.sup.16).sub.2;
[0256] R.sup.11, R.sup.12, and R.sup.13 are independently selected
from the group consisting of oxo, hydroxyl, halo,
(C.sub.1-C.sub.6)alkoxy, --R.sup.6(R.sup.9).sub.q,
--OR.sup.6(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.10, --R.sup.4YR.sup.6,
--CO(O)R.sup.4, and --CO(O)R.sup.5;
[0257] R.sup.14 and R.sup.15 are independently selected from the
group consisting of --H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy,
--[C(R.sup.6).sub.2].sub.r--, --O[C(R.sup.6).sub.2].sub.r--, oxo,
hydroxyl, halo, --C(O)R.sup.7, --R.sup.10, and --CO(O)R.sup.2;
[0258] R.sup.16 is independently selected from the group consisting
of --H, oxo, halo, hydroxyl, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
--R.sup.6(R.sup.9).sub.q, --OR.sup.6(R.sup.9).sub.q,
--N(R.sup.4).sub.2, --(CH.sub.2).sub.r-heterocycle, --C(O)OH,
--C(O)NH.sub.2, --R.sup.5(R.sup.9).sub.q,
--OR.sup.5(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
--C(O)R.sup.10, and --CO(O)R.sup.4;
[0259] m and n in each instance are independently 0, 1, 2, 3, or
4;
[0260] p is independently 0, 1, 2, 3, or 4; and
[0261] r and q in each instance are independently 0, 1, 2, 3, or
4.
[0262] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula II:
##STR00046##
or a pharmaceutically acceptable salt thereof, wherein:
[0263] A is
##STR00047##
[0264] L.sub.1 and L.sub.2 are both (--CH.sub.2--);
[0265] Q is --C(.dbd.O)--;
[0266] W is O;
[0267] R.sup.1 is --H;
[0268] R.sup.2 is selected from the group consisting of --H,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.5, and
--(CH.sub.2).sub.rNR.sup.7R.sup.8;
[0269] R.sup.3 is
##STR00048##
wherein X is a monocyclic or bicyclic (C.sub.5-C.sub.14)aryl;
[0270] R.sup.4 is selected from the group consisting of --H and
(C.sub.1-C.sub.6)alkyl;
[0271] R.sup.5 is selected from the group consisting of
(C.sub.1-C.sub.6)alkyl, --(CH.sub.2).sub.rNR.sup.7R.sup.8, and
--(CH.sub.2).sub.rOR.sup.7;
[0272] R.sup.6 is selected from the group consisting of --H,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.6)alkoxy, haloalkyl,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, --C(O)OH, and
--C(O)NH.sub.2;
[0273] R.sup.7 and R.sup.8 are independently selected from the
group consisting of --H, (C.sub.1--C--.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, --NR.sup.14R.sup.15, and
--C(O)CH.sub.3;
[0274] R.sup.9 is halo;
[0275] R.sup.10 is --N(R.sup.16).sub.2;
[0276] R.sup.11, R.sup.12, and R.sup.13 are independently selected
from the group consisting of oxo, hydroxyl, halo,
(C.sub.1-C.sub.6)alkoxy, --R.sup.6(R.sup.9).sub.q,
--OR.sup.6(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.10, --CO(O)R.sup.4, and
--CO(O)R.sup.5;
[0277] R.sup.14 and R.sup.15 are independently selected from the
group consisting of --H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy,
--[C(R.sup.6).sub.2].sub.r--, --O[C(R.sup.6).sub.2].sub.r--, oxo,
hydroxyl, halo, --C(O)R.sup.7, --R.sup.10, and --CO(O)R.sup.2;
[0278] R.sup.16 is independently selected from the group consisting
of --H, oxo, halo, hydroxyl, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
--R.sup.6(R.sup.9).sub.q, --OR.sup.6(R.sup.9).sub.q,
--N(R.sup.4).sub.2, --(CH.sub.2).sub.r-heterocycle, --C(O)OH,
--C(O)NH.sub.2, --R.sup.5(R.sup.9).sub.q,
--OR.sup.8(R.sup.6).sub.q, nitro, --SO.sub.2R.sup.6,
--C(O)R.sup.10, and --CO(O)R.sup.4;
[0279] m and n in each instance are independently 0, 1, or 2;
[0280] p is independently 0, 1, or 2; and
[0281] r and q in each instance are independently 0, 1, 2, or
3.
[0282] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula II:
##STR00049##
or a pharmaceutically acceptable salt thereof, wherein:
[0283] A is
##STR00050##
[0284] L.sub.1 and L.sub.2 are both (--CH.sub.2--);
[0285] Q is --C(.dbd.O)--;
[0286] W is O;
[0287] R.sup.1 is --H;
[0288] R.sup.2 is --(CH.sub.2).sub.rNR.sup.7R.sup.8;
[0289] R.sup.3 is
##STR00051##
wherein X is phenyl;
[0290] R.sup.7 and R.sup.8 are independently selected from the
group consisting of --H and methyl;
[0291] R.sup.9 is selected from the group consisting of chloro,
bromo, and fluoro;
[0292] R.sup.11 is selected from the group consisting of chloro,
bromo, and fluoro;
[0293] m is 0, 1, or 2; and
[0294] r is 1, 2, or 3.
[0295] In accordance with another embodiment of the present
invention, there is provided a compound of Formula II:
##STR00052##
or a pharmaceutically acceptable salt thereof, wherein:
[0296] A is
##STR00053##
[0297] L.sub.1 and L.sub.2 are independently selected from a bond
or [C(R.sup.6R.sup.6)].sub.q;
[0298] Q is selected from --CH.sub.2-- or --C(.dbd.O)--;
[0299] W is selected from a bond or oxygen;
[0300] R.sup.1 is selected from the group consisting of --H,
(C.sub.1-C.sub.12)alkyl, --C(O)R.sup.5,
--CH.sub.2--O--(C.sub.1-C.sub.6)alkyl, 2-tetrahydro-2H-pyran
and
##STR00054##
[0301] R.sup.2 is selected from the group consisting of --H,
(C.sub.1-C.sub.12)alkyl, --C.sub.1-6 alkyl-OH, --C.sub.1-6
alkyl-O--C.sub.1-6 alkyl, --C(O)R.sup.5, and
--(CH.sub.2).sub.rNR.sup.7R.sup.8, --C(O)R.sup.5, wherein when W is
oxygen, R.sup.1 and R.sup.2 can optionally be taken together with
the oxygen and nitrogen to which they are respectively joined to
form a 4 to 8 membered heterocyclyl ring wherein the heterocyclyl
ring may be optionally substituted by one to two R.sup.11
groups;
[0302] R.sup.3 is selected from the group consisting of hydrogen,
(C.sub.1-C.sub.12)alkyl, --NR.sup.1R.sup.2, --OR.sup.5,
##STR00055##
wherein: [0303] X is a monocyclic or bicyclic
(C.sub.5-C.sub.14)aryl, [0304] Y is selected from a monocyclic or
bicyclic (C.sub.2-C.sub.9)heterocyclyl or monocyclic or bicyclic
(C.sub.2-C.sub.9)heteroaryl, each having one to three heteroatoms
selected from S, N or O, and [0305] Z is a monocyclic or bicyclic
(C.sub.3-C.sub.8)cycloalkyl;
[0306] R.sup.2 and R.sup.3 can optionally be taken together with
the nitrogen and L.sub.2 to which they are respectively joined to
form a 4 to 8 membered heterocyclyl ring, wherein the heterocyclyl
ring may be optionally substituted by one to two R.sup.11
groups;
[0307] R.sup.4 is selected from --H and (C.sub.1-C.sub.6)alkyl;
[0308] R.sup.5 is selected from (C.sub.1-C.sub.6)alkyl, --R.sup.3,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, or
--(CH.sub.2).sub.rOR.sup.7;
[0309] R.sup.6 and R.sup.6' are independently --H,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.6)alkoxy, haloalkyl, --Y,
--(CH.sub.2).sub.rNR.sup.7R.sup.8, --C(O)OH, --C(O)NH.sub.2,
wherein the R.sup.6 and R.sup.6' groups can optionally be taken
together with the carbon to which they are joined to form a 3 to 8
membered cycloalkyl ring, wherein the cycloalkyl ring may be
optionally substituted by one to three R.sup.11 groups;
[0310] R.sup.7 and R.sup.8 are independently selected from the
group consisting of --H, (C.sub.1--C--.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, -Q-aryl-(R.sup.4).sub.n,
--NR.sup.14R.sup.15, --C(O)CH.sub.3, wherein R.sup.7 and R.sup.8
can optionally be taken together with the nitrogen to which they
are joined to form a 4 to 8 membered heterocyclyl or heteroaryl
ring containing one to three heteroatoms selected from
--NR.sup.5--, --O--, --S--, --S(O)--, or --SO.sub.2--, wherein the
heterocyclyl or heteroaryl ring may be optionally substituted by
one to three R.sup.11 groups;
[0311] R.sup.9 is halo;
[0312] R.sup.10 is --N(R.sup.16).sub.2;
[0313] R.sup.11, R.sup.12, and R.sup.13 are independently selected
from the group consisting of oxo, hydroxyl, halo,
(C.sub.1-C.sub.6)alkoxy, --R.sup.6(R.sup.9).sub.q,
--OR.sup.6(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.10, --R.sup.4YR.sup.6, and
--CO(O)R.sup.5, wherein any two R.sup.9, R.sup.10 or R.sup.11
groups can optionally join to form a 3 to 8 membered cycloalkyl,
aryl, heterocyclyl or heteroaryl ring, wherein the heterocyclyl or
heteroaryl ring may contain one to three heteroatoms selected from
--NR.sup.5--, --O--, --S--, --S(O)--, or --SO.sub.2--, and wherein
the cycloalkyl, aryl, heterocyclyl or heteroaryl ring may be
optionally substituted by one to three R.sup.16 groups;
[0314] R.sup.14 and R.sup.15 are independently selected from the
group consisting of --H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.6)alkoxy,
--[C(R.sup.6).sub.2].sub.r--, --O[C(R.sup.6).sub.2].sub.r--, oxo,
hydroxyl, halo, --C(O)R.sup.7, --R.sup.10, and --CO(O)R.sup.2,
wherein R.sup.14 and R.sup.15 can optionally be taken together with
the carbon to which they are joined to form a 3 to 8 membered
cycloalkyl ring or 4 to 8 membered heterocyclyl ring containing one
to three heteroatoms selected from --NR.sup.5--, --O--, --S--,
--S(O)--, or --SO.sub.2--, wherein the cycloalkyl ring or
heterocyclyl ring may be optionally substituted by one to three
R.sup.16 groups;
[0315] R.sup.16 is independently selected from the group consisting
of halo, oxo, hydroxyl, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
--R.sup.6(R.sup.9).sub.q, --OR.sup.6(R.sup.9).sub.q,
--N(R.sup.4).sub.2, --(CH.sub.2).sub.r-heterocyclyl, --C(O)OH,
--C(O)NH.sub.2, --R.sup.5(R.sup.9).sub.q,
--OR.sup.5(R.sup.9).sub.q, nitro, --SO.sub.2R.sup.6,
--C(O)R.sup.10, and --CO(O)R.sup.4;
[0316] m and n in each instance are independently 0, 1, 2, 3, or
4;
[0317] p is independently 0, 1, 2, 3, or 4; and
[0318] r and q in each instance are independently 0, 1, 2, 3, or
4.
[0319] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein L.sub.1 and L.sub.2 are both
[C(R.sup.6R.sup.6')].sub.q.
[0320] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein L.sub.1 and L.sub.2 are both
--CH.sub.2--.
[0321] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein q is independently 1, 2, or
3.
[0322] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein q is 1.
[0323] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein W is O.
[0324] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein W is a bond.
[0325] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein when W is a bond, then
R.sup.1 is --H.
[0326] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein when W is O, then R.sup.1 is
--H.
[0327] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein Q.sub.m in the A group is
absent and Q, in the A group is --CH.sub.2-- and the Q in the
Formula I structure is --C(.dbd.O)--.
[0328] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein R.sup.1 is --H.
[0329] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein R.sup.2 is
--(CH.sub.2).sub.rNR.sup.7R.sup.8.
[0330] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein R.sup.2 is
(dimethylamino)ethyl.
[0331] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein r is independently 0, 1, 2,
or 3.
[0332] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein r is 2.
[0333] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein R.sup.3 is
##STR00056##
[0334] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein X is a monocyclic
(C.sub.5-C.sub.14)aryl.
[0335] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein X is phenyl.
[0336] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein R.sup.4 is --H.
[0337] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein m is 0 or 1.
[0338] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein m is 0.
[0339] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein m is 1.
[0340] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein n is 1.
[0341] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein R.sup.6 and R.sup.6' are
both --H.
[0342] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein R.sup.7 and R.sup.8 are both
(C.sub.1-C.sub.6)alkyl.
[0343] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein R.sup.7 is methyl.
[0344] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein R.sup.8 is methyl.
[0345] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein R.sup.7 and R.sup.8 are both
methyl.
[0346] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein R.sup.11 is halo.
[0347] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein R.sup.11 is selected from
chloro, bromo, or fluoro.
[0348] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein R.sup.11 is chloro.
[0349] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein R.sup.11 is absent.
[0350] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein R.sup.14 and R.sup.15 are
both (C.sub.1-C.sub.6)alkyl.
[0351] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein R.sup.14 and R.sup.15 are
both methyl.
[0352] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein A is
##STR00057##
[0353] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein A is
##STR00058##
[0354] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein A is
##STR00059##
[0355] In accordance with another embodiment of the present
invention, there is provided a compound having the structure of
Formula I or Formula II above, wherein A is
##STR00060##
[0356] In accordance with another embodiment of the present
invention, there is provided a compound having the structure:
##STR00061##
or a pharmaceutically acceptable salt thereof.
[0357] In accordance with another embodiment of the present
invention, there is provided a compound having the structure:
##STR00062##
or a pharmaceutically acceptable salt thereof.
[0358] In accordance with another embodiment of the present
invention, there is provided a compound having the structure:
##STR00063##
or a pharmaceutically acceptable salt thereof.
[0359] In accordance with another embodiment of the present
invention, there is provided a compound having the structure:
##STR00064##
or a pharmaceutically acceptable salt thereof.
[0360] In a further embodiment of the present invention, there is
provided a pharmaceutical composition comprising a compound of
Formula I or Formula II, or a pharmaceutically acceptable salt
thereof; and a pharmaceutically acceptable excipient.
[0361] In a further embodiment of the present invention, there is
provided a method of treating HIV comprising administering to a
patient suffering therefrom an effective amount of a compound of
Formula I or Formula II, or a pharmaceutically acceptable salt
thereof.
[0362] In a further embodiment of the present invention, there is
provided a pharmaceutical composition comprising a compound of
Formula I or Formula II, or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable excipient.
[0363] In a further embodiment of the present invention, there is
provided a pharmaceutical composition comprising a compound of
Formula I or Formula II, or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable excipient, wherein the
compound is present in an amorphous form.
[0364] In a further embodiment of the present invention, there is
provided a pharmaceutical composition comprising a compound of
Formula I or Formula II, or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable excipient, wherein the
composition is in a tablet form.
[0365] In a further embodiment of the present invention, there is
provided a pharmaceutical composition comprising a compound of
Formula I or Formula II, or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable excipient, wherein the
compound is present as a spray dried dispersion.
[0366] In a further embodiment of the present invention, there is
provided a method of treating an HIV infection in a subject
comprising administering to the subject a compound of Formula I or
Formula II, or a pharmaceutically acceptable salt thereof. In
certain embodiments, the subject is a mammal, and in other
embodiments, the subject is a human.
[0367] In a further embodiment of the present invention, there is
provided a method of treating an HIV infection in a subject
comprising administering to the subject a pharmaceutical
composition comprising a compound of Formula I or Formula II, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable excipient.
[0368] In a further embodiment of the present invention, there is
provided a method of preventing an HIV infection in a subject at
risk for developing an HIV infection, comprising administering to
the subject a compound of Formula I or Formula II, or a
pharmaceutically acceptable salt thereof.
[0369] In a further embodiment of the present invention, there is
provided a method of preventing an HIV infection in a subject at
risk for developing an HIV infection, comprising administering to
the subject a pharmaceutical composition comprising a compound of
Formula I or Formula II, or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable excipient.
[0370] In still other embodiments, the present invention also
provides the use of a compound or salt as defined in any of Formula
I or Formula II in the manufacture of a medicament for use in the
treatment of an HIV infection in a human.
[0371] Furthermore, the compounds of the invention can exist in
particular geometric or stereoisomeric forms. The invention
contemplates all such compounds, including cis- and trans-isomers,
(-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers,
(D)-isomers, (L)-isomers, the racemic mixtures thereof, and other
mixtures thereof, such as enantiomerically or diastereomerically
enriched mixtures, as falling within the scope of the invention.
Additional asymmetric carbon atoms can be present in a substituent
such as an alkyl group. All such isomers, as well as mixtures
thereof, are intended to be included in this invention.
[0372] Optically active (R)- and (S)-isomers and d and I isomers
can be prepared using chiral synthons or chiral reagents, or
resolved using conventional techniques. If, for instance, a
particular enantiomer of a compound of the present invention is
desired, it can be prepared by asymmetric synthesis, or by
derivatization with a chiral auxiliary, where the resulting
diastereomeric mixture is separated and the auxiliary group cleaved
to provide the pure desired enantiomers. Alternatively, where the
molecule contains a basic functional group, such as an amino group,
or an acidic functional group, such as a carboxyl group,
diastereomeric salts can be formed with an appropriate optically
active acid or base, followed by resolution of the diastereomers
thus formed by fractional crystallization or chromatographic means
known in the art, and subsequent recovery of the pure enantiomers.
In addition, separation of enantiomers and diastereomers is
frequently accomplished using chromatography employing chiral,
stationary phases, optionally in combination with chemical
derivatization (e.g., formation of carbamates from amines).
[0373] In another embodiment of the invention, there is provided a
compound of Formula I or Formula II, wherein the compound or salt
of the compound is used in the manufacture of a medicament for use
in the treatment of a viral infection in a human.
[0374] In another embodiment of the invention, there is provided a
pharmaceutical composition comprising a pharmaceutically acceptable
diluent and a therapeutically effective amount of a compound as
defined in Formula I.
[0375] In one embodiment, the pharmaceutical formulation containing
a compound of Formula I or Formula II or a salt thereof is a
formulation adapted for parenteral administration. In another
embodiment, the formulation is a long-acting parenteral
formulation. In a further embodiment, the formulation is a
nano-particle formulation.
[0376] The compounds of the present invention and their salts,
solvates, or other pharmaceutically acceptable derivatives thereof,
may be employed alone or in combination with other therapeutic
agents. Therefore, in other embodiments, the methods of treating
and/or preventing an HIV infection in a subject may in addition to
administration of a compound of Formula I or Formula II further
comprise administration of one or more additional pharmaceutical
agents active against HIV.
[0377] In such embodiments, the one or more additional agents
active against HIV is selected from the group consisting of
zidovudine, didanosine, lamivudine, zalcitabine, abacavir,
stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil,
emtricitabine, alovudine, amdoxovir, elvucitabine, nevirapine,
delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine,
lersivirine, GSK2248761, TMC-278, TMC-125, etravirine, saquinavir,
ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir,
brecanavir, darunavir, atazanavir, tipranavir, palinavir,
lasinavir, enfuvirtide, T-20, T-1249, PRO-542, PRO-140, TNX-355,
BMS-806, BMS-663068 and BMS-626529, 5-Helix, raltegravir,
elvitegravir, GSK1349572, GSK1265744, vicriviroc (Sch-C), Sch-D,
TAK779, maraviroc, TAK449, didanosine, tenofovir, lopinavir, and
darunavir.
[0378] As such, the compounds of the present invention and any
other pharmaceutically active agent(s) may be administered together
or separately and, when administered separately, administration may
occur simultaneously or sequentially, in any order. The amounts of
the compounds of the present invention and the other
pharmaceutically active agent(s) and the relative timings of
administration will be selected in order to achieve the desired
combined therapeutic effect. The administration in combination of a
compound of the present invention and salts, solvates, or other
pharmaceutically acceptable derivatives thereof with other
treatment agents may be in combination by administration
concomitantly in: (1) a unitary pharmaceutical composition
including both compounds; or (2) separate pharmaceutical
compositions each including one of the compounds. Alternatively,
the combination may be administered separately in a sequential
manner wherein one treatment agent is administered first and the
other second or vice versa. Such sequential administration may be
close in time or remote in time. The amounts of the compound(s) of
Formula I or Formula II or salts thereof and the other
pharmaceutically active agent(s) and the relative timings of
administration will be selected in order to achieve the desired
combined therapeutic effect.
[0379] In addition, the compounds of the present invention may be
used in combination with one or more other agents useful in the
prevention or treatment of HIV.
[0380] Examples of such agents include:
[0381] Nucleotide reverse transcriptase inhibitors such as
zidovudine, didanosine, lamivudine, zalcitabine, abacavir,
stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil,
emtricitabine, alovudine, amdoxovir, elvucitabine, and similar
agents;
[0382] Non-nucleotide reverse transcriptase inhibitors (including
an agent having anti-oxidation activity such as immunocal,
oltipraz, etc.) such as nevirapine, delavirdine, efavirenz,
loviride, immunocal, oltipraz, capravirine, lersivirine,
GSK2248761, TMC-278, TMC-125, etravirine, and similar agents;
[0383] Protease inhibitors such as saquinavir, ritonavir,
indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir,
darunavir, atazanavir, tipranavir, palinavir, lasinavir, and
similar agents;
[0384] Entry, attachment and fusion inhibitors such as enfuvirtide
(T-20), T-1249, PRO-542, PRO-140, TNX-355, BMS-806, BMS-663068 and
BMS-626529, 5-Helix and similar agents;
[0385] Integrase inhibitors such as raltegravir, elvitegravir,
GSK1349572, GSK1265744 and similar agents;
[0386] Maturation inhibitors such as PA-344 and PA-457, and similar
agents; and
[0387] CXCR4 and/or CCR5 inhibitors such as vicriviroc (Sch-C),
Sch-D, TAK779, maraviroc (UK 427,857), TAK449, as well as those
disclosed in WO 02/74769, PCT/US03/39644, PCT/US03/39975,
PCT/US03/39619, PCT/US03/39618, PCT/US03/39740, and PCT/US03/39732,
and similar agents.
[0388] Further examples where the compounds of the present
invention may be used in combination with one or more agents useful
in the prevention or treatment of HIV are found in Table 1.
TABLE-US-00001 TABLE 1 Brand FDA Approval Name Generic Name
Manufacturer Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
1987 Retrovir zidovudine, GlaxoSmithKline azidothymidine, AZT, ZDV
1991 Videx didanosine, Bristol-Myers dideoxyinosine, Squibb ddl
1992 Hivid zalcitabine, Roche dideoxycytidine, Pharmaceuticals ddC
1994 Zerit stavudine, d4T Bristol-Myers Squibb 1995 Epivir
lamivudine, 3TC GlaxoSmithKline 1997 Combivir lamivudine +
GlaxoSmithKline zidovudine 1998 Ziagen abacavir sulfate,
GlaxoSmithKline ABC 2000 Trizivir abacavir + GlaxoSmithKline
lamivudine + zidovudine 2000 Videx EC enteric coated Bristol-Myers
didanosine, ddl Squibb EC 2001 Viread tenofovir Gilead Sciences
disoproxil fumarate, TDF 2003 Emtriva emtricitabine, FTC Gilead
Sciences 2004 Epzicom abacavir + GlaxoSmithKline lamivudine 2004
Truvada emtricitabine + Gilead Sciences tenofovir disoproxil
fumarate Non-Nucleosides Reverse Transcriptase Inhibitors (NNRTIs)
1996 Viramune nevirapine, NVP Boehringer Ingelhelm 1997 Rescriptor
delavirdine, DLV Pfizer 1998 Sustiva efavirenz, EFV Bristol-Myers
Squibb 2008 Intelence etravirine Tibotec Therapeutics Protease
Inhibitors (PIs) 1995 Invirase saquinavir Roche mesylate, SQV
Pharmaceuticals 1996 Norvir ritonavir, RTV Abbott Laboratories 1996
Crixivan indinavir, IDV Merck 1997 Viracept nelfinavir Pfizer
mesylate, NFV 1997 Fortovase saquinavir (no Roche longer marketed)
Pharmaceuticals 1999 Agenerase amprenavir, APV GlaxoSmithKline 2000
Kaletra lopinavir + Abbott ritonavir, Laboratories LPV/RTV 2003
Reyataz atazanavir sulfate, Bristol-Myers ATV Squibb 2003 Lexiva
fosamprenavir GlaxoSmithKline calcium, FOS- APV 2005 Aptivus
tripranavir, TPV Boehringer Ingelhelm 2006 Prezista darunavir
Tibotec Therapeutics Fusion Inhibitors 2003 Fuzeon Enfuvirtide,
T-20 Roche Pharmaceuticals & Trimeris Entry Inhibitors 2007
Selzentry maraviroc Pfizer Integrase Inhibitors 2007 Isentress
raltegravir Merck
[0389] The scope of combinations of compounds of this invention
with HIV agents is not limited to those mentioned above, but
includes in principle any combination with any pharmaceutical
composition useful for the treatment of HIV. As noted, in such
combinations the compounds of the present invention and other HIV
agents may be administered separately or in conjunction. In
addition, one agent may be prior to, concurrent to, or subsequent
to the administration of other agent(s).
[0390] The present invention may be used in combination with one or
more agents useful as pharmacological enhancers as well as with or
without additional compounds for the prevention or treatment of
HIV. Examples of such pharmacological enhancers (or pharmakinetic
boosters) include, but are not limited to, ritonavir, GS-9350, and
SPI-452.
[0391] Ritonavir is
10-hydroxy-2-methyl-5-(1-methylethyl)-1-1[2-(1-methylethyl)-4-thiazolyl]--
3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic
acid, 5-thiazolylmethyl ester, [5S-(5S*,8R*,10R*,11R*)] and is
available from Abbott Laboratories of Abbott park, Ill., as Norvir.
Ritonavir is an HIV protease inhibitor indicated with other
antiretroviral agents for the treatment of HIV infection. Ritonavir
also inhibits P450 mediated drug metabolism as well as the
P-glycoprotein (Pgp) cell transport system, thereby resulting in
increased concentrations of active compound within the
organism.
[0392] GS-9350 is a compound being developed by Gilead Sciences of
Foster City, Ca. as a pharmacological enhancer.
[0393] SPI-452 is a compound being developed by Sequoia
Pharmaceuticals of Gaithersburg, Md., as a pharmacological
enhancer.
[0394] In one embodiment of the present invention, a compound of
Formula I or Formula II is used in combination with ritonavir. In
one embodiment, the combination is an oral fixed dose combination.
In another embodiment, the compound of Formula I or Formula II is
formulated as a long acting parenteral injection and ritonavir is
formulated as an oral composition. In one embodiment, is a kit
containing the compound of Formula I or Formula II formulated as a
long acting parenteral injection and ritonavir formulated as an
oral composition. In another embodiment, the compound of Formula I
or Formula II is formulated as a long acting parenteral injection
and ritonavir is formulated as an injectable composition. In one
embodiment, is a kit containing the compound of Formula I or
Formula II formulated as a long acting parenteral injection and
ritonavir formulated as an injectable composition.
[0395] In another embodiment of the present invention, a compound
of Formula I or Formula II is used in combination with GS-9350. In
one embodiment, the combination is an oral fixed dose combination.
In another embodiment, the compound of Formula I or Formula II is
formulated as a long acting parenteral injection and GS-9350 is
formulated as an oral composition. In one embodiment, there is
provided a kit containing the compound of Formula I or Formula II
formulated as a long acting parenteral injection and GS-9350
formulated as an oral composition. In another embodiment, the
compound of Formula I or Formula II is formulated as a long acting
parenteral injection and GS-9350 is formulated as an injectable
composition. In one embodiment, is a kit containing the compound of
Formula I or Formula II is formulated as a long acting parenteral
injection and GS-9350 formulated as an injectable composition.
[0396] In one embodiment of the present invention, a compound of
Formula I or Formula II is used in combination with SPI-452. In one
embodiment, the combination is an oral fixed dose combination. In
another embodiment, the compound of Formula I or Formula II is
formulated as a long acting parenteral injection and SPI-452 is
formulated as an oral composition. In one embodiment, there is
provided a kit containing the compound of Formula I or Formula II
formulated as a long acting parenteral injection and SPI-452
formulated as an oral composition. In another embodiment, the
compound of Formula I or Formula II is formulated as a long acting
parenteral injection and SPI-452 is formulated as an injectable
composition. In one embodiment, there is provided a kit containing
the compound of Formula I or Formula II formulated as a long acting
parenteral injection and SPI-452 formulated as an injectable
composition.
[0397] In one embodiment of the present invention, a compound of
Formula I or Formula II is used in combination with compounds which
are found in previously filed PCT/CN2011/0013021, which is herein
incorporated by reference.
[0398] The above other therapeutic agents, when employed in
combination with the chemical entities described herein, may be
used, for example, in those amounts indicated in the Physicians'
Desk Reference (PDR) or as otherwise determined by one of ordinary
skill in the art.
[0399] In another embodiment of the invention, there is provided a
method for treating a viral infection in a mammal mediated at least
in part by a virus in the retrovirus family of viruses which method
comprises administering to a mammal, that has been diagnosed with
said viral infection or is at risk of developing said viral
infection, a compound of Formula I or Formula II.
[0400] In another embodiment of the invention, there is provided a
method for treating a viral infection in a mammal mediated at least
in part by a virus in the retrovirus family of viruses which method
comprises administering to a mammal, that has been diagnosed with
said viral infection or is at risk of developing said viral
infection, a compound of Formula I or Formula II, wherein said
virus is an HIV virus. In some embodiments, the HIV virus is the
HIV-1 virus.
[0401] In another embodiment of the invention, there is provided a
method for treating a viral infection in a mammal mediated at least
in part by a virus in the retrovirus family of viruses which method
comprises administering to a mammal, that has been diagnosed with
said viral infection or is at risk of developing said viral
infection, a compound of Formula I or Formula II, further
comprising administration of a therapeutically effective amount of
one or more agents active against an HIV virus.
[0402] In another embodiment of the invention, there is provided a
method for treating a viral infection in a mammal mediated at least
in part by a virus in the retrovirus family of viruses which method
comprises administering to a mammal, that has been diagnosed with
said viral infection or is at risk of developing said viral
infection, a compound of Formula I or Formula II, further
comprising administration of a therapeutically effective amount of
one or more agents active against the HIV virus, wherein said agent
active against HIV virus is selected from Nucleotide reverse
transcriptase inhibitors; Non-nucleotide reverse transcriptase
inhibitors; Protease inhibitors; Entry, attachment and fusion
inhibitors; Integrase inhibitors; Maturation inhibitors; CXCR4
inhibitors; and CCR5 inhibitors.
[0403] In further embodiments, the compound of the present
invention, or a pharmaceutically acceptable salt thereof, is chosen
from the compounds set forth in Table 2.
TABLE-US-00002 TABLE 2 Example No. Parent Structure Chemical Name 1
##STR00065## 4-[(1R)-1- [(1R,2R,5R,10S,13R,14R, 17S,19R)-17-[(3-
carboxy-3,3- dimethylpropanoyl)oxy]- 1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-5-yl]-2-{[(4- chlorophenyl)methyl]
amino}ethoxy]-2,2- dimethyl- 4-oxobutanoic acid 2 ##STR00066##
4-[(1R)-1- [(1R,2R,5R,10S,13R,14R, 17S,19R)-17-[(3- carboxy-3,3-
dimethylpropanoyl)oxy]- 1,2,14,18,18- pentamethyl-7-oxo-8-
(propan-2- yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,
10}.0{circumflex over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-5-yl]-2-{[(4- chlorophenyl)methyl][2-
(dimethylamino)ethyl] amino}ethoxy]-2,2- dimethyl- 4-oxobutanoic
acid 3 ##STR00067## 4-[(1S)-1- [(1R,2R,5R,10S,13R,14R,
17S,19R)-17-[(3- carboxy-3,3- dimethylpropanoyl)oxy]- 1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-5-yl]-2-{[(4- chlorophenyl)methyl]
amino}ethoxy]-2,2- dimethyl- 4-oxobutanoic acid 4 ##STR00068##
4-[(1S)-1- [(1R,2R,5R,10S,13R,14R, 17S,19R)-17-[(3- carboxy-3,3-
dimethylpropanoyl)oxy]- 1,2,14,18,18- pentamethyl-7-oxo-8-
(propan-2- yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,
10}.0{circumflex over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-5-yl]-2-{[(4- chlorophenyl)methyl][2-
(dimethylamino)ethyl] amino}ethoxy]- 2,2-dimethyl- 4-oxobutanoic
acid 5 ##STR00069## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-(2-{[(4-
chlorophenyl)methyl] amino}ethyl)-1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 6 ##STR00070## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[2-
(benzylamino)ethyl]- 1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 7
##STR00071## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-(2-{[(3-
chlorophenyl)methyl] amino}ethyl)-1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 8 ##STR00072## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-(2-{[(3-
chloro-2- fluorophenyl)methyl] amino}ethyl)-1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 9 ##STR00073## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-(2-{[1-(4- chlorophenyl)cyclopropyl] amino}ethyl)-
1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 10
##STR00074## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-(2-{[(4-
chlorophenyl)methyl][2- (dimethylamino)ethyl]
amino}ethyl)-1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 11
##STR00075## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-(2-{[1-(4-
chlorophenyl)cyclopropyl] [2- (dimethylamino)ethyl]
amino}ethyl)-1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 12
##STR00076## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-(2-{[(4-
chlorophenyl)methyl] (methyl)amino}ethyl)- 1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 13 ##STR00077## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-(2-{N-[(4- chlorophenyl)methyl] acetamido}ethyl)-
1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 14
##STR00078## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1R)-2- {[(4-
chlorophenyl)methyl] amino}-1-hydroxyethyl]- 1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 15 ##STR00079## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-[(1S)-2- {[(4- chlorophenyl)methyl]
amino}-1-hydroxyethyl]- 1,2,14,18,18- pentamethyl-7-oxo-8-
(propan-2- yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,
10}.0{circumflex over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 16
##STR00080## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1S)-2- {[(4-
chlorophenyl)methyl] amino}-1-hydroxyethyl]- 1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 17 ##STR00081## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-[(1R)-1- (acetyloxy)-2-{[(4- chlorophenyl)methyl]
amino}ethyl]-1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 18
##STR00082## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1R)-2- {[(4-
chlorophenyl)methyl][2- (dimethylamino)ethyl]
amino}-1-hydroxyethyl]- 1,2,14,18,18- pentamethyl-7-oxo-8-
(propan-2- yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,
10}.0{circumflex over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 19
##STR00083## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1S)-2- {[(4-
chlorophenyl)methyl][2- (dimethylamino)ethyl]
amino}-1-hydroxyethyl]- 1,2,14,18,18- pentamethyl-7-oxo-8-
(propan-2- yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,
10}.0{circumflex over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 20
##STR00084## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1S)-1-
(acetyloxy)-2-{[(4- chlorophenyl)methyl][2- (dimethylamino)ethyl]
amino}ethyl]-1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 21
##STR00085## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1R)-1-
(acetyloxy)-2-{[(4- chlorophenyl)methyl][2- (dimethylamino)ethyl]
amino}ethyl]-1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 22
##STR00086## 5- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1R)-2- {[(4-
chlorophenyl)methyl][2- (dimethylamino)ethyl]
amino}-1-hydroxyethyl]- 1,2,14,18,18- pentamethyl-7-oxo-8-
(propan-2- yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,
10}.0{circumflex over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 3,3-dimethyl-5- oxopentanoic acid 23
##STR00087## 5- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1S)-2- {[(4-
chlorophenyl)methyl][2- (dimethylamino)ethyl]
amino}-1-hydroxyethyl]- 1,2,14,18,18- pentamethyl-7-oxo-8-
(propan-2- yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,
10}.0{circumflex over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 3,3-dimethyl-5- oxopentanoic acid 24
##STR00088## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1S)-2- {[(2-
chlorophenyl)methyl] amino}-1-hydroxyethyl]- 1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 25 ##STR00089## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-[(1R)-2- {[(2- chlorophenyl)methyl]
amino}-1-hydroxyethyl]- 1,2,14,18,18- pentamethyl-7-oxo-8-
(propan-2- yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,
10}.0{circumflex over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 26
##STR00090## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1S)-1-
(acetyloxy)-2-{[(4- fluorophenyl)methyl] amino}ethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 27 ##STR00091## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-[(1R)-1- (acetyloxy)-2-{[(4- fluorophenyl)methyl]
amino}ethyl]-1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 28
##STR00092## 4- (((3aR,5aR,5bR,7aR,9S, 11aR,11bR,13aS)-3a-
((S)-1-acetoxy-2-((4- fluorobenzyl)(methyl)
amino)ethyl)-1-isopropyl- 5a,5b,8,8,11a- pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11,11a,11b,12,13,13a-
octadecahydro-2H- cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-
oxobutanoic acid 29 ##STR00093## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-[(1S)-2- {[(4- chlorophenyl)methyl] (methyl)amino}-1-
hydroxyethyl]- 1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 30
##STR00094## 4- (((3aR,5aR,5bR,7aR,9S, 11aR,11bR,13aS)-3a-
((R)-1-Acetoxy-2-((4- chlorobenzyl)(methyl)
amino)ethyl)-1-isopropyl- 5a,5b,8,8,11a- penta methyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11,11a,11b,12,13,13a-
octadecahydro-2H- cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-
oxobutanoic acid 31 ##STR00095## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-[(1R)-2- {[(4- chlorophenyl)methyl] (methyl)amino}-1-
hydroxyethyl]- 1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 32
##STR00096## 4- (((3aR,5aR,5bR,7aR,9S, 11aR,11bR,13aS)-3a-
((S)-1-Acetoxy-2-(N-(4- chlorobenzyl)acetamido) ethyl)-1-isopropyl-
5a,5b,8,8,11a- pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,
10,11,11a,11b,12,13,13a- octadecahydro-2H- cyclopenta[a]chrysen-9-
yl)oxy)-2,2-dimethyl-4- oxobutanoic acid 32 ##STR00097## 4-
{[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1S)-2-{N- [(4-
chlorophenyl)methyl] acetamido}-1- hydroxyethyl]- 1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 33 ##STR00098## 4- (((3aR,5aR,5bR,7aR,9S, 11aR,11bR,13aS)-3a-
((S)-2-(N-(4- Chlorobenzyl)acetamido)- 1-hydroxyethyl)-1-
isopropyl-5a,5b,8,8,11a- pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11,11a,11b,12,13,13a-
octadecahydro-2H- cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-
oxobutanoic acid 34 ##STR00099## 4- (((3aR,5aR,5bR,7aR,9S,
11aR,11bR,13aS)-3a- ((R)-2-(N-(4- Chlorobenzyl)acetamido)-
1-hydroxyethyl)-1- isopropyl-5a,5b,8,8,11a- penta methyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11,11a,11b,12,13,13a-
octadecahydro-2H- cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-
oxobutanoic acid 35 ##STR00100## 4- (((3aR,5aR,5bR,7aR,9S,
11aR,11bR,13aS)-3a- ((S)-2-(N-(2- Chlorobenzyl)acetamido)-
1-hydroxyethyl)-1- isopropyl-5a,5b,8,8,11a- pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11,11a,11b,12,13,13a-
octadecahydro-2H- cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-
oxobutanoic acid 36 ##STR00101## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-[(1S)-1- (acetyloxy)-2-{[(2- chlorophenyl)methyl][2-
(dimethylamino)ethyl] amino}ethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 37 ##STR00102## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-[(1S)-2- {[(3- chlorophenyl)methyl]
amino}-1-hydroxyethyl]- 1,2,14,18,18- pentamethyl-7-oxo-8-
(propan-2- yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,
10}.0{circumflex over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 38
##STR00103## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1R)-2- {[(3-
chlorophenyl)methyl] amino}-1-hydroxyethyl]- 1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 37
##STR00104## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1S)-2- {[(3-
chlorophenyl)methyl][2- (dimethylamino)ethyl]
amino}-1-hydroxyethyl]- 1,2,14,18,18- pentamethyl-7-oxo-8-
(propan-2- yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,
10}.0{circumflex over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 38
##STR00105## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1R)-2- {[(3-
chlorophenyl)methyl][2- (dimethylamino)ethyl]
amino}-1-hydroxyethyl]- 1,2,14,18,18- pentamethyl-7-oxo-8-
(propan-2- yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,
10}.0{circumflex over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 39
##STR00106## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1S)-1-
(acetyloxy)-2-{[(3- chlorophenyl)methyl] amino}ethyl]-1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 40 ##STR00107## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-[(1R)-1- (acetyloxy)-2-{[(3- chlorophenyl)methyl]
amino}ethyl]-1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 41
##STR00108## 4- (((3aR,5aR,5bR,7aR,9S, 11aR,11bR,13aS)-3a-
((S)-1-acetoxy-2-((3- chlorobenzyl)(2- (dimethylamino)ethyl)
amino)ethyl)-1-isopropyl- 5a,5b,8,8,11a- pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11,11a,11b,12,13,13a-
octadecahydro-2H- cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-
oxobutanoic acid 42 ##STR00109## 4- (((3aR,5aR,5bR,7aR,9S,
11aR,11bR,13aS)-3a- ((R)-1-acetoxy-2-((3- chlorobenzyl)(2-
(dimethylamino)ethyl) amino)ethyl)-1-isopropyl- 5a,5b,8,8,11a-
pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,
10,11,11a,11b,12,13,13a- octadecahydro-2H- cyclopenta[a]chrysen-9-
yl)oxy)-2,2-dimethyl-4- oxobutanoic acid 43 ##STR00110## 4-
(((3aR,5aR,5bR,7aR,9S, 11aR,11bR,13aS)-3a- ((R)-2-((3-
chlorobenzyl)(ethyl) amino)-1-hydroxyethyl)-1-
isopropyl-5a,5b,8,8,11a- penta methyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11,11a,11b,12,13,13a-
octadecahydro-2H- cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-
oxobutanoic acid 44 ##STR00111## 4- (((3aR,5aR,5bR,7aR,9S,
11aR,11bR,13aS)-3a- ((S)-2-((3- Chlorobenzyl)(2-
(dimethylamino)ethyl) amino)-1-hydroxyethyl)-1-
isopropyl-5a,5b,8,8,11a- pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11,11a,11b,12,13,13a-
octadecahydro-2H- cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-
oxobutanoic acid 45 ##STR00112## 4- (((3aR,5aR,5bR,7aR,9S,
11aR,11bR,13aS)- 3a-((R)-2-((3- Chlorobenzyl)(2-
(dimethylamino)ethyl) amino)-1-hydroxyethyl)- 1-isopropyl-
5a,5b,8,8,11a- pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,
8,9,10,11,11a,11b,12, 13,13a- octadecahydro-2H-
cyclopenta[a]chrysen- 9-yl)oxy)-2,2-dimethyl- 4-oxobutanoic acid.
46 ##STR00113## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1R)-2-{N-
[(3- chlorophenyl)methyl] acetamido}-1- hydroxyethyl]-
1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 47
##STR00114## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1S)-2-{N-
[(3- chlorophenyl)methyl] acetamido}-1- hydroxyethyl]-
1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 48
##STR00115## 4- (((3aR,5aR,5bR,7aR,9S, 11aR,11bR,13aS)-3a-
((R)-1-acetoxy-2-((2- chlorobenzyl)(2- (dimethylamino)ethyl)
amino)ethyl)-1-isopropyl- 5a,5b,8,8,11a- pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11,11a,11b,12,13,13a-
octadecahydro-2H- cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-
oxobutanoic acid 49 ##STR00116## 4- (((3aR,5aR,5bR,7aR,9S,
11aR,11bR,13aS)-3a- ((R)-2-((2- chlorobenzyl)(ethyl) amino)-1-
hydroxyethyl)-1- isopropyl-5a,5b,8,8,11a- pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11,11a,11b,12,13,13a-
octadecahydro-2H- cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-
oxobutanoic acid 50 ##STR00117## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-[(1R)-2- {[(2- chlorophenyl)methyl][2-
(dimethylamino)ethyl] amino}-1-hydroxyethyl]- 1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 51 ##STR00118## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-[(1S)-2- {[(2- chlorophenyl)methyl][2-
(dimethylamino)ethyl] amino}-1-hydroxyethyl]- 1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 52 ##STR00119## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-[(1R)-1- (acetyloxy)-2- (benzylamino)ethyl]-
1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 53
##STR00120## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1S)-1-
(acetyloxy)-2- (benzylamino)ethyl]- 1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 54 ##STR00121## 4- (((3aR,5aR,5bR,7aR,9S, 11aR,11bR,13aS)-3a-
((R)-2-((3-Chloro-2- fluorobenzyl)amino)-1- hydroxyethyl)-1-
isopropyl-5a,5b,8,8,11a- pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11,11a,11b,12,13,13a-
octadecahydro-2H- cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-
oxobutanoic acid 55 ##STR00122## 4- (((3aR,5aR,5bR,7aR,9S,
11aR,11bR,13aS)-3a- ((S)-2-((3-chloro-2- fluorobenzyl)amino)-1-
hydroxyethyl)-1- isopropyl-5a,5b,8,8,11a- pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11,11a,11b,12,13,13a-
octadecahydro-2H- cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-
oxobutanoic acid 56 ##STR00123## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-[(1R)-2- {[(3-chloro-2- fluorophenyl)methyl][2-
(dimethylamino)ethyl] amino}-1-hydroxyethyl]- 1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 57 ##STR00124## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-[(1S)-2- {[(3-chloro-2- fluorophenyl)methyl][2-
(dimethylamino)ethyl] amino}-1-hydroxyethyl]- 1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 58 ##STR00125## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-[(1R)-1- hydroxy-2-[(propan-2- yl)amino]ethyl]-
1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 59
##STR00126## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1R)-2-
(cyclohexylamino)-1- hydroxyethyl]- 1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 53 ##STR00127## 4- {[(1R,2R,5S,10S,13R,14R, 17S,19R)-5-[1-
hydroxy-2-(4- methylpiperazin-1- yl)ethyl]-1,2,14,18,18-
pentamethyl-8-(propan- 2- yl)pentacyclo[11.8.0.0{circumflex over (
)}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 54 ##STR00128## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-(2-{[(4- chlorophenyl)methyl] amino}ethyl)-1,2,14,18,18-
pentamethyl-8-(propan- 2- yl)pentacyclo[11.8.0.0{circumflex over (
)}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 55 ##STR00129## 4- {[(1R,2R,5S,10S,13R,14R,
17S,19R)-5-[(1S)-2- {[(4- chlorophenyl)methyl]
amino}-1-hydroxyethyl]- 1,2,14,18,18- pentamethyl-8-(propan- 2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 56
##STR00130## 4- {[(1R,2R,5S,10S,13R,14R, 17S,19R)-5-[(1S)-2-
[(cyclohexylmethyl)amino]- 1-hydroxyethyl]- 1,2,14,18,18-
pentamethyl-8-(propan- 2- yl)pentacyclo[11.8.0.0{circumflex over (
)}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 57 ##STR00131## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-[(1S)-2- (cyclohexylamino)-1- hydroxyethyl]-
1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 58
##STR00132## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1R)-1-
hydroxy-2-(1,2,3,4- tetrahydroisoquinolin-2-
yl)ethyl]-1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 59
##STR00133## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1S)-1-
hydroxy-2-(1,2,3,4- tetrahydroisoquinolin-2-
yl)ethyl]-1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 60
##STR00134## 4- {[(1R,2R,10S,13R,14R, 17S,19R)-5-[(5S)-3-[1-(5-
chloropyrimidin-2- yl)cyclopropyl]-2-oxo-1,3- oxazolidin-5-yl]-
1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 61
##STR00135## 4- {[(1R,2R,10S,13R,14R, 17S,19R)-5-[(5R)-3-[1-(5-
chloropyrimidin-2- yl)cyclopropyl]-2-oxo-1,3- oxazolidin-5-yl]-
1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 62
##STR00136## 5- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1S)-2- {[(4-
chlorophenyl)methyl] amino}-1-hydroxyethyl]- 1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 3,3-dimethyl-5- oxopentanoic
acid 63 ##STR00137## 4- (((3aR,5aR,5bR,7aR,9S, 11aR,11bR,13aS)-3a-
((R)-2-(3,4- dihydroisoquinolin-2(1H)- yl)-1-hydroxyethyl)-1-
isopropyl-5a,5b,8,8,11a- pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11,11a,11b,12,13,13a-
octadecahydro-2H- cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-
oxobutanoic acid 64 ##STR00138## 4- (((3aR,5aR,5bR,7aR,9S,
11aR,11bR,13aS)-3a- ((S)-2-(3,4- dihydroisoquinolin-2(1H)-
yl)-1-hydroxyethyl)-1- isopropyl-5a,5b,8,8,11a- pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11,11a,11b,12,13,13a-
octadecahydro-2H- cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-
oxobutanoic acid 65 ##STR00139## 4- (((3aS,5aR,5bR,7aR,9S,
11aR,11bR,13aS)-3a- ((R)-1-hydroxy-2-(4- methylpiperazin-1-
yl)ethyl)-1-isopropyl- 5a,5b,8,8,11a- pentamethyl-
3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11,11a,11b,12,13,13a-
octadecahydro-2H- cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-
oxobutanoic acid 66 ##STR00140## 4- (((3aR,5aR,5bR,7aR,9S,
11aR,11bR,13aS)-3a-(2- ((4- chlorobenzyl)amino)ethyl)- 1-isopropyl-
5a,5b,8,8,11a- pentamethyl- 3,3a,4,5,5a,5b,6,7,7a,8,9,
10,11,11a,11b,12,13,13a- octadecahydro-2H- cyclopenta[a]chrysen-9-
yl)oxy)-2,2-dimethyl-4- oxobutanoic acid 67 ##STR00141## 4-
(((3aS,5aR,5bR,7aR,9S, 11aR,11bR,13aS)-3a- ((S)-2-
((cyclohexylmethyl)amino)- 1-hydroxyethyl)-1-
isopropyl-5a,5b,8,8,11a- pentamethyl- 3,3a,4,5,5a,5b,6,7,7a,8,9,
10,11,11a,11b,12,13,13a- octadecahydro-2H- cyclopenta[a]chrysen-9-
yl)oxy)-2,2-dimethyl-4- oxobutanoic acid 68 ##STR00142## 4-
(((3aR,5aR,5bR,7aR,9S, 11aR,11bR,13aS)-3a-
((S)-2-(cyclohexylamino)- 1-hydroxyethyl)-1-
isopropyl-5a,5b,8,8,11a- pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11,11a,11b,12,13,13a-
octadecahydro-2H- cyclopenta[a]chrysen-9- yl)oxy)-2,2-dimethyl-4-
oxobutanoic acid 69 ##STR00143## 4- (((3aR,5aR,5bR,7aR,9S,
11aR,11bR,13aS)-3a- ((S)-2-(benzyl(2- (dimethylamino)ethyl)
amino)-1-hydroxyethyl)-1- isopropyl-5a,5b,8,8,11a-
pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,
10,11,11a,11b,12,13,13a, octadecahydro-2H- cyclopenta[a]chrysen-9-
yl)oxy)-2,2-dimethyl-4- oxobutanoic acid 70 ##STR00144## 4-
{[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1S)-1- (acetyloxy)-2-{[2-
(dimethylamino)ethyl][(4- fluorophenyl)methyl]
amino}ethyl]-1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 71
##STR00145## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1R)-1-
(acetyloxy)-2-{[2- (dimethylamino)ethyl][(4- fluorophenyl)methyl]
amino}ethyl]-1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 72
##STR00146## 5- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1R)-2- {[(4-
chlorophenyl)methyl] amino}-1-hydroxyethyl]- 1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 3,3-dimethyl-5- oxopentanoic
acid 73 ##STR00147## 5- (((3aR,5aR,5bR,7aR,9S, 11aR,11bR,13aS)-3a-
((S)-2-((4- chlorobenzyl)amino)-1- hydroxyethyl)-1-
isopropyl-5a,5b,8,8,11a- pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11,11a,11b,12,13,13a-
octadecahydro-2H- cyclopenta[a]chrysen-9- yl)oxy)-3,3-dimethyl-5-
oxopentanoic acid 74 ##STR00148## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-[(1S)-2- {[(2,4- dichlorophenyl)methyl][2-
(dimethylamino)ethyl] amino}-1-hydroxyethyl]- 1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 75 ##STR00149## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-[(1R)-2- {benzyl[2- (dimethylamino)ethyl]
amino}-1-hydroxyethyl]- 1,2,14,18,18- pentamethyl-7-oxo-8-
(propan-2- yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,
10}.0{circumflex over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 76
##STR00150## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1R)-2- {[2-
(dimethylamino)ethyl][(4- fluorophenyl)methyl]
amino}-1-hydroxyethyl]- 1,2,14,18,18- pentamethyl-7-oxo-8-
(propan-2- yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,
10}.0{circumflex over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 77
##STR00151## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1R)-2- {[(4-
fluorophenyl)methyl] amino}-1-hydroxyethyl]- 1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 78 ##STR00152## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-[(1S)-2- {[2- (dimethylamino)ethyl][(4-
fluorophenyl)methyl] amino}-1-hydroxyethyl]- 1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 79 ##STR00153## 4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)-5-[(1S)-2- {[(4- fluorophenyl)methyl]
amino}-1-hydroxyethyl]- 1,2,14,18,18- pentamethyl-7-oxo-8-
(propan-2- yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,
10}.0{circumflex over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 80
##STR00154## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1R)-2-
{[(2,4- dichlorophenyl)methyl][2- (dimethylamino)ethyl]
amino}-1-hydroxyethyl]- 1,2,14,18,18- pentamethyl-7-oxo-8-
(propan-2- yl)pentacyclo[11.8.0.0{circumflex over ( )}{2,
10}.0{circumflex over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 81
##STR00155## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-[(1R)-2-[1-
(4-chlorophenyl)-N-[2- (dimethylamino)ethyl] formamido]-1-
hydroxyethyl]- 1,2,14,18,18- pentamethyl-7-oxo-8- (propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}]
henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic acid 82
##STR00156## 4- {[(1R,2R,5R,10S,13R,14R, 17S,19R)-5-(2-{[(2-
chlorophenyl)methyl] amino}ethyl)-1,2,14,18,18-
pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0{circumflex
over ( )}{2, 10}.0{circumflex over ( )}{5,9}.0{circumflex over (
)}{14,19}] henicos-8-en-17-yl]oxy}- 2,2-dimethyl-4- oxobutanoic
acid 83 ##STR00157## 2,2-dimethyl-4-oxo-4- {[(1R,2R,5R,10S,13R,14R,
17S,19R)- 1,2,14,18,18- pentamethyl-7-oxo-5-[2-
(phenylformamido)ethyl]- 8-(propan-2-
yl)pentacyclo[11.8.0.0{circumflex over ( )}{2, 10}.0{circumflex
over ( )}{5,9}.0{circumflex over ( )}{14,19}] henicos-8-en-17-
yl]oxy}butanoic acid
[0404] The compounds of Table 2 were synthesized according to the
Synthetic Methods, General Schemes, and the Examples described
below.
[0405] In certain embodiments, the compound(s) of the present
invention, or a pharmaceutically acceptable salt thereof, is chosen
from the compounds set forth in Table 2.
Synthetic Methods
[0406] The methods of synthesis for the provided chemical entities
employ readily available starting materials using the following
general methods and procedures. It will be appreciated that where
typical or preferred process conditions (i.e., reaction
temperatures, times, mole ratios of reactants, solvents, pressures,
etc.) are given; other process conditions can also be used unless
otherwise stated. Optimum reaction conditions may vary with the
particular reactants or solvent used, but such conditions can be
determined by one skilled in the art by routine optimization
procedures.
[0407] Additionally, the methods of this invention may employ
protecting groups which prevent certain functional groups from
undergoing undesired reactions. Suitable protecting groups for
various functional groups as well as suitable conditions for
protecting and deprotecting particular functional groups are well
known in the art. For example, numerous protecting groups are
described in T. W. Greene and G. M. Wuts, Protecting Groups in
Organic Synthesis, Third Edition, Wiley, N.Y., 1999, and references
cited therein.
[0408] Furthermore, the provided chemical entities may contain one
or more chiral centers and such compounds can be prepared or
isolated as pure stereoisomers, i.e., as individual enantiomers or
diastereomers, or as stereoisomer-enriched mixtures. All such
stereoisomers (and enriched mixtures) are included within the scope
of this specification, unless otherwise indicated. Pure
stereoisomers (or enriched mixtures) may be prepared using, for
example, optically active starting materials or stereoselective
reagents well-known in the art. Alternatively, racemic mixtures of
such compounds can be separated using, for example, chiral column
chromatography, chiral resolving agents and the like.
[0409] The starting materials for the following reactions are
generally known compounds or can be prepared by known procedures or
obvious modifications thereof. For example, many of the starting
materials are available from commercial suppliers such as Aldrich
Chemical Co. (Milwaukee, Wis., USA), Bachem (Torrance, Ca., USA),
Ernka-Chemce or Sigma (St. Louis, Mo., USA). Others may be prepared
by procedures, or obvious modifications thereof, described in
standard reference texts such as Fieser and Fieser's Reagents for
Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's
Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals
(Elsevier Science Publishers, 1989), Organic Reactions, Volumes
1-40 (John Wiley and Sons, 1991), March's Advanced Organic
Chemistry, (John Wiley and Sons, 4th Edition), and Larock's
Comprehensive Organic Transformations (VCH Publishers Inc.,
1989).
[0410] Unless specified to the contrary, the reactions described
herein take place at atmospheric pressure, generally within a
temperature range from -78.degree. C. to 200.degree. C. Further,
except as employed in the Examples or as otherwise specified,
reaction times and conditions are intended to be approximate, e.g.,
taking place at about atmospheric pressure within a temperature
range of about -78.degree. C. to about 110.degree. C. over a period
of about 1 to about 24 hours; reactions left to run overnight
average a period of about 16 hours.
[0411] The terms "solvent," "organic solvent," and "inert solvent"
each mean a solvent inert under the conditions of the reaction
being described in conjunction therewith, including, for example,
benzene, toluene, acetonitrile, tetrahydrofuranyl ("THF"),
dimethylformamide ("DMF"), chloroform, methylene chloride (or
dichloromethane), diethyl ether, methanol, N-methylpyrrolidone
("NMP"), pyridine and the like.
[0412] Isolation and purification of the chemical entities and
intermediates described herein can be effected, if desired, by any
suitable separation or purification procedure such as, for example,
filtration, extraction, crystallization, column chromatography,
thin-layer chromatography or thick-layer chromatography, or a
combination of these procedures. Specific illustrations of suitable
separation and isolation procedures can be had by reference to the
examples herein below. However, other equivalent separation or
isolation procedures can also be used.
[0413] When desired, the (R)- and (S)-isomers may be resolved by
methods known to those skilled in the art, for example by formation
of diastereoisomeric salts or complexes which may be separated, for
example, by crystallization; via formation of diastereoisomeric
derivatives which may be separated, for example, by
crystallization, gas-liquid or liquid chromatography; selective
reaction of one enantiomer with an enantiomer-specific reagent, for
example enzymatic oxidation or reduction, followed by separation of
the modified and unmodified enantiomers; or gas-liquid or liquid
chromatography in a chiral environment, for example on a chiral
support, such as silica with a bound chiral ligand or in the
presence of a chiral solvent. Alternatively, a specific enantiomer
may be synthesized by asymmetric synthesis using optically active
reagents, substrates, catalysts or solvents, or by converting one
enantiomer to the other by asymmetric transformation.
EXAMPLES
[0414] The following examples serve to more fully describe the
manner of making and using the above-described invention. It is
understood that these examples in no way serve to limit the true
scope of the invention, but rather are presented for illustrative
purposes. In the examples below and the synthetic schemes above,
the following abbreviations have the following meanings. If an
abbreviation is not defined, it has its generally accepted meaning.
[0415] aq.=aqueous [0416] .mu.L=microliters [0417] .mu.M=micromolar
[0418] NMR=nuclear magnetic resonance [0419]
boc=tert-butoxycarbonyl [0420] br=broad [0421]
Cbz=benzyloxycarbonyl [0422] d=doublet [0423] .delta.=chemical
shift [0424] .degree. C.=degrees celsius [0425] DCM=dichloromethane
[0426] dd=doublet of doublets [0427] DMEM=Dulbeco's Modified
Eagle's Medium [0428] DMF=N,N-dimethylformamide [0429]
DMSO=dimethylsulfoxide [0430] EtOAc=ethyl acetate [0431] g=gram
[0432] h or hr=hours [0433] HCV=hepatitis C virus [0434] HPLC=high
performance liquid chromatography [0435] Hz=hertz [0436]
IU=International Units [0437] IC.sub.50=inhibitory concentration at
50% inhibition [0438] J=coupling constant (given in Hz unless
otherwise indicated) [0439] m=multiplet [0440] M=molar [0441]
M+H.sup.+=parent mass spectrum peak plus H.sup.+ [0442]
mg=milligram [0443] min=minutes [0444] mL=milliliter [0445]
mM=millimolar [0446] mmol=millimole [0447] MS=mass spectrum [0448]
nm=nanomolar [0449] ppm=parts per million [0450] q.s.=sufficient
amount [0451] s=singlet [0452] RT=room temperature [0453]
sat.=saturated [0454] t=triplet [0455] TFA=trifluoroacetic acid
Equipment Description
[0456] .sup.1H NMR spectra were recorded on a Bruker Avance-III 400
spectrometer. Chemical shifts are expressed in parts per million
(ppm, 6 units). Coupling constants are in units of hertz (Hz).
Splitting patterns describe apparent multiplicities and are
designated as s (singlet), d (doublet), t (triplet), q (quartet),
quint (quintet), m (multiplet), br (broad).
[0457] The analytical low-resolution mass spectra (MS) were
recorded on Agilent 1200 HPLC/6110 or Agilent 1200 HPLC/6130 using
a SunFire C18, 4.6.times.50 mm, 3.5 .mu.m using a gradient elution
method.
[0458] Solvent A: 0.01% trifluoroacetic acid (TFA) in water;
[0459] Solvent B: 0.01% TFA in acetonitrile;
[0460] Constant A for 1.2 min followed by 5%-95% or 20%-95% B over
4 min.
Schemes and Experimental Procedures
[0461] The following schemes and procedures illustrate how
compounds of the present invention can be prepared. The specific
solvents and reaction conditions referred to are also illustrative
and are not intended to be limiting. Compounds not described are
either commercially available or are readily prepared by one
skilled in the art using available starting materials. The Examples
disclosed herein are for illustrative purposes only and are not
intended to limit the scope of the invention. All examples
exhibited LHIV IC.sub.50 values between 1 .mu.M and 1 nM using the
assay disclosed herein.
[0462] For several of the examples the stereochemistry of the C28
secondary alcohol when present was not definitively confirmed as to
its absolute configuration. Unless stated otherwise, the compounds
exemplified in the present application were isolated as optically
pure stereoisomers and initially assigned to a configuration as
drawn. There is the possibility that some of these may be listed as
the opposite stereochemistry at that single C28 position as shown.
This in no way is meant to limit the scope of the invention or
utility of the compounds of Formula I. Additional examples
contained within were determined to have the shown configuration by
spectroscopic methods well known to those skilled in the art
including, but not limited to, 1D and 2D NMR methods, vibrational
circular dichroism and X-ray crystallography. These examples and
the methods to make both diastereomers should serve to clearly
exemplify the pure stereoisomers of both R and S configuration at
the C28 position are readily obtained, separated and characterized
and any remaining undefined examples could be readily confirmed by
similar methods well known to one skilled in the art.
[0463] Synthesis of Aldehyde Intermediate 6.
##STR00158## ##STR00159##
Step A: Intermediate 2
((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-Acetoxy-5a,5b,8,8,11a-penta-
methyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-3a-yl)methyl
acetate
[0464] To a solution of the intermediate 1 (20 g, 45.2 mmol),
4-dimethylaminopyridine (DMAP, 1.66 g, 13.6 mmol), and Et.sub.3N
(63 mL, 136 mmol) in CH.sub.2Cl.sub.2 (DCM, 100 mL) at room
temperature was added acetic anhydride (Ac.sub.2O, 17.1 mL, 113
mmol). After it was heated at reflux overnight, and cooled down to
room temperature, the reaction was quenched with water (50 mL). The
organic phase was then washed with water (50 mL.times.2) and dried
over sodium sulfate. After removing most of the organic solvent
under reduced pressure, anhydrous ethanol (50 mL) was added and the
resulting precipitates were collected by filtration as a white
solid (intermediate 2, 20 g, 84%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 4.69 (1H, m), 4.59 (1H, m), 4.51-4.43 (1H,
m), 4.25 (1H, d, J=11.2 Hz), 3.85 (1H, d, J=10.8 Hz), 2.49-2.40
(1H, m), 2.07 (3H, s), 2.04 (3H, s), 1.98-0.77 (42H, m). LC/MS: m/z
calculated 526.4, found 527.7 (M+1)+.
Step B: Intermediate 3
((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-acetoxy-1-isopropyl-5a,5b,8,8,11a-p-
entamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-
-2H-cyclopenta[a]chrysen-3a-yl)methyl acetate
[0465] HBr in acetic acid (40 mL, 33%) was added to a suspension of
the intermediate 2 (20 g, 38 mmol) in toluene (40 mL), Ac.sub.2O
(40 mL), and acetic acid (AcOH, 40 mL) previously heated at
105.degree. C. The reaction mixture was stirred and heated at this
temperature for 1.5 h. After cooling down, sodium acetate (24 g)
was added and the resulting reaction mixture was evaporated to
dryness. The pale brownish residue was taken up in DCM (200 mL) and
the organic phase was washed with water (100 mL.times.3), dried
over sodium sulfate, and evaporated to dryness under reduced
pressure to provide a residue, which was then recrystallized from
ethanol (EtOH, 95%) and DCM, to afford the intermediate 3 (13.8 g,
69%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 4.50-4.46 (1H, m), 4.02 (1H, d, J=10.8 Hz), 3.98 (1H, d, J=10.8
Hz), 3.18-3.10 (1H, m), 2.43-2.40 (1H, m), 2.26-2.22 (2H, m), 2.04
(3H, s), 2.05 (3H, s), 2.00-1.95 (1H, m), 1.90-1.85 (1H, m),
1.77-0.83 (39H, m). LC/MS: m/z calculated 526.4, found 549.2
(M+Na)+.
Step C: Intermediate 4
((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-Acetoxy-1-isopropyl-5a,5b,8,8,11a-p-
entamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadec-
ahydro-2H-cyclopenta[a]chrysen-3a-yl)methyl acetate
[0466] A mixture of the intermediate 3 (7 g, 13.29 mmol), sodium
acetate (NaOAc, 6.21 g, 76 mmol) and sodium dichromate dihydrate
(4.75 g, 15.95 mmol) in anhydrous toluene (90 mL), AcOH (119 mL),
and Ac.sub.2O (29 mL) was stirred at 60.degree. C. overnight. After
cooling down, the reaction mixture was partitioned between water
(150 mL) and ethyl acetate (EtOAc, 250 mL). The organic phase was
washed successively with: water (100 mL), a saturated solution of
sodium carbonate (100 mL.times.2) and brine (100 mL.times.2), then
dried over sodium sulfate, and concentrated under reduced pressure
to afford a sticky oil. The sticky oil was triturated with MeOH
(250 mL) and the precipitates were collected to give the
intermediate 4 (6 g, 11.1 mmol, 83%) as a white solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 4.52-4.46 (1H, m), 4.33 (1H, d,
J=10.8 Hz), 4.06 (1H, d, J=11.2 Hz), 3.21-3.16 (1H, m), 2.86 (1H,
dd, J=12.8, 3.2 Hz), 2.42-2.36 (1H, m), 2.05 (3H, s), 2.00 (3H, s),
1.94-0.84 (40H, m). LC/MS: m/z calculated 540.4, found 563.3
(M+Na)+.
Step D: Intermediate 5
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(Hydroxymethyl)-1-isopropyl-5a,5b,8-
,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-
-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate
[0467] A mixture of the intermediate 4 (7 g, 12.94 mmol) and
potassium hydroxide (KOH, 0.872 g, 15.5 mmol) in EtOH (200 mL) and
toluene (200 mL) was stirred vigorously at room temperature for 1
h. The reaction mixture was neutralized with aqueous HCl (1N) to pH
7 and evaporated to dryness. The obtained residue was taken up in
water and a small amount of acetone. The precipitates were
collected and then washed with water and dried in vacuo to obtain
the intermediate 5 (6.0 g, 93%) as a white solid. LC/MS: m/z
calculated 498.4, found 499.3 (M+1)+.
Step E: Intermediate 6
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-Formyl-1-isopropyl-5a,5b,8,8,11a-pe-
ntamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadeca-
hydro-2H-cyclopenta[a]chrysen-9-yl acetate
[0468] To a solution of the intermediate 5 (5.1 g, 10.23 mmol) in
DCM (300 mL) at room temperature were added pyridinium
chlorochromate (PCC, 6.61 g, 30.7 mmol), and silica gel (6.6 g).
The reaction mixture was stirred at room temperature for 1 h. After
the reaction was quenched with water, the organic phase was washed
with saturated sodium bicarbonate solution (100 mL), dried over
sodium sulfate, and evaporated under reduced pressure to provide a
crude product, which was purified by column chromatography on
silica gel (EtOAc:PE=1:10 to 1:5) to provide the intermediate 6
(4.2 g, 83%) as a white solid. LC/MS: m/z calculated 496.4, found
497.2 (M+1)+.
[0469] Synthesis of the oxo-butanoate intermediate 10 was
accomplished according to the following procedures.
##STR00160##
Step A: Intermediate 8
4-Ethoxy-2,2-dimethyl-4-oxobutanoic acid
[0470] A solution of 3,3-dimethyl-dihydrofuran-2,5-dione 7 (25 g,
195 mmol) in anhydrous EtOH (150 mL) was stirred at 50.degree. C.
overnight. After cooling down to room temperature, the solvent was
removed under reduced pressure with a rotary evaporator and the
residue was triturated with hexane at -50.degree. C. to afford the
intermediate 8 (25 g, 133 mmol, 67.9%) as a white solid. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. ppm 4.13-4.18 (2H, q, J=7.2 Hz),
2.62 (2H, s), 1.28 (6H, s),1.32-1.25 (3H, t, J=7.6 Hz). LC/MS: m/z
calculated 174.1, found 173.1 (M-1)-.
Step B: Intermediate 9
1-Tert-butyl 4-ethyl 2,2-dimethylsuccinate
[0471] To a mixture of the intermediate 8 (20 g, 109 mmol),
magnesium sulfate (52.5 g, 436 mmol), and tert-butanol (60 mL) in
DCM (480 mL) was added to sulfuric acid (8.72 mL, 164 mmol). After
stirring at room temperature overnight, the reaction mixture was
poured into saturated sodium bicarbonate solution (300 mL) and
water (300 mL). DCM was added to extract the desired product, and
the organic phase was washed with brine, dried, and concentrated to
afford the intermediate 9 (19 g, 83 mmol, 80%) as a colorless oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 4.02-4.08 (2H, q,
J=7.2 Hz), 2.46 (2H, s), 1.07 (9H, s), 1.14-1.20 (9H, m). LC/MS:
m/z calculated 230.2, found 253.1 (M+Na)+.
Step C: Intermediate 10
4-(Tert-butoxy)-3,3-dimethyl-4-oxobutanoic acid
[0472] To a solution of the intermediate 9 (10 g, 41.3 mmol) in
EtOH (200 mL) was added to potassium hydroxide (12.86 g, 206 mmol)
in water (100 mL) at room temperature. The reaction mixture was
stirred at room temperature for 2 h. The pH of the reaction mixture
was adjusted to 3-4 by 1N HCl. The resulting solution was extracted
with ether (300 mL), and the ether phase was dried and concentrated
to afford a crude product, which was re-crystallized from hexane at
-10.degree. C. to afford the intermediate 10 (4 g, 19.78 mmol,
47.9%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 2.58 (2H, s), 1.43 (9H, s), 1.25 (6H, s). LC/MS: m/z calculated
202.1, found 201.1 (M-1).sup.-.
[0473] Synthesis of diastereomeric intermediates 18 and 19.
##STR00161## ##STR00162## ##STR00163##
Step A: Intermediate 11
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(1-Hydroxy-2-nitroethyl)-1-isopropy-
l-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,-
12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate
[0474] To a mixture of (3b)-21,28-dioxolup-18-en-3-yl acetate (6)
(25 g, 50.3 mmol)and nitromethane (150 ml, 2782 mmol) stirred at
room temp was added to triethylamine (75 ml, 538 mmol) in one
charge. The reaction mixture was stirred at rt overnight. The
reaction mixture was concentrated and washed with petroleum
ether/EtOAc (2:1, 100 mL) to give the product of (24 g, 43.0 mmol,
85% yield) as a white solid. LC/MS: m/z calculated 557.4, found
558.2 (M+1).sup.+.
Step B: Intermediate 12
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-Amino-1-hydroxyethyl)-1-isopropy-
l-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,-
12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate
[0475] To a solution of 11 (15.0 g, 26.9 mmol) in methanol (300 mL)
was added NiCl.sub.2.6H.sub.2O (9.59 g, 40.3 mmol) at -5.degree. C.
and was slowly added sodium borohydride (10.17 g, 269 mmol) at
5.about.10.degree. C. (internal temp). The reaction mixture was
stirred at -5.degree. C. (bath temp) for 30 min. The mixture was
then quenched with saturated NH.sub.4Cl (200 mL), diluted with
EtOAc (1500 mL), then stirred at rt overnight. And the organic
layer was washed with saturated NH.sub.4Cl (50 mL), water (800 mL),
brine (800 mL) and was dried over MgSO.sub.4, filtered and
concentrated to afford a solid, which was washed with petroleum
ether to give the 12 (14 g, 24.40 mmol, 91% yield) as a white
solid. LC/MS: m/z calculated 527.4, found 528.3 (M+1).sup.+.
Step C: Intermediate 13
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((Tert-butoxycarbonyl)(4-chlorob-
enzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3-
,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopen-
ta[a]chrysen-9-yl acetate
[0476] To a solution of 12 (8 g, 14.58 mmol), triethylamine (0.813
ml, 5.83 mmol) and MgSO.sub.4 (2.63 g, 21.87 mmol) in methanol (225
ml) stirred at rt was added 4-chlorobenzaldehyde (2.056 ml, 17.50
mmol). The reaction mixture was stirred at rt for 2 h, then cooled
to -5.degree. C. and NaBH.sub.4 was added in small portions during
10 min and stirred for 30 min. Following this, Boc.sub.2O (4.06 ml,
17.50 mmol) was added. The reaction was warmed to rt. and stirred
for 1 h. The reaction mixture was poured into ice water (300 ml)
and the solids were collected and dried to give 13 (7 g, 8.56 mmol,
58.7% yield) as a white foam. LC/MS: m/z calculated 751.5, found
774.3 (M+Na).sup.+.
Step D: Intermediate 14
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((Tert-butoxycarbonyl)(4-chlorob-
enzyl)amino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5-
a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chry-
sen-9-yl acetate
[0477] To a mixture of 13 (25 g, 29.9 mmol) in dichloromethane (200
mL), was added PCC (50 g, 232 mmol) and silica gel 50 g, This
mixture was stirred at rt overnight. The solids were removed by
filtration to obtain black solution, which was concentrated and
purified by silica gel column chromatography eluting with hex/EtOAc
(10:1) to afford the 14 (20 g, 23.99 mmol, 80% yield) as a white
solid. LC/MS: m/z calculated 749.4, found 772.2 (M+Na).sup.+.
Step E: Intermediate 15
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-Chlorobenzyl)amino)acetyl)-9-
-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,1-
0,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-2-one
[0478] To a solution of 14 in 1,4-dioxane (200 mL) and methanol
(200 mL) stirred at rt was added con HCl (100 mL) in one charge.
The reaction mixture was stirred overnight at 45.degree. C. The
reaction mixture was concentrated and washed with acetone to give
15 (12.5 g, 17.45 mmol, 87% yield) as a white foam. LC/MS: m/z
calculated 607.38, found 608.0 (M+1).sup.+.
Step F: Intermediate 16
Tert-butyl
4-chlorobenzyl(2-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-
-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,-
11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-oxoeth-
yl)carbamate
[0479] To a solution of 15 (6 g, 9.86 mmol) and Et.sub.3N (5.50 mL,
39.5 mmol) in dichloromethane (30 mL) stirred at rt was added
Boc.sub.2O (2.290 mL, 9.86 mmol) in one charge. The reaction
mixture was stirred at rt for 2 h. From TLC, the reaction was
finished. The solvent was removed in vacuo. The crude product 16 (6
g, 8.47 mmol, 86% yield) was used without further purification.
Step G: Intermediate 17
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((Tert-butoxycarbonyl)(4-chlo-
robenzyl)amino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,-
5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]c-
hrysen-9-yl)1-tert-butyl 2,2-dimethylsuccinate
[0480] To a solution of 10 (5.14 g, 25.4 mmol), DMAP (5.17 g, 42.3
mmol) and 16 (6 g, 8.47 mmol) in dichloromethane (50 mL) stirred at
rt was added EDC (8.12 g, 42.3 mmol). The reaction mixture was
stirred at rt until starting material disappeared as monitored by
TLC. After the reaction was finished, the mixture was diluted with
CH.sub.2Cl.sub.2, and washed with aq NH.sub.4Cl. The organic layer
was dried with Na.sub.2SO.sub.4 and the solvent was removed in
vacuo. The material was purified by silica gel chromatography
(hex:EtOAc, 12:1 to 5:1) to give 17 (5.4 g, 6.05 mmol, 71.4% yield)
as a light white solid. The proton NMR consists of a mixture of
rotomers. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.34-7.24 (m,
2H), 7.23-7.08 (m, 2H), 4.63-4.29 (m, 3H), 4.11-3.39 (m, 2H),
3.28-3.06 (m, 1H), 2.69-0.69 (m, 68H).
Step H: Intermediates 18 and 19
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(Tert-butoxycarbonyl)(4-c-
hlorobenzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-
-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cy-
clopenta[a]chrysen-9-yl)1-tert-butyl 2,2-dimethylsuccinate (18)
&
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((tert-butoxycarbonyl)(4-
-chlorobenzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl)1-tert-butyl 2,2-dimethylsuccinate
(19)
[0481] To a solution of and 17 (1.5 g, 1.680 mmol) in methanol (10
mL)and THF (10.00 mL) stirred at 0.degree. C. was added NaBH.sub.4
(0.127 g, 3.36 mmol). The reaction mixture was stirred at 0.degree.
C. until starting material disappeared (about 2 hours) as monitored
by TLC. Upon completion the mixture was diluted with water,
extracted with EtOAc and the organic layer was dried with
Na.sub.2SO.sub.4. The residue was purified by silica gel
chromatography (hex:EtOAc, 7:1 to 5:1) to give the diastereomer
with the S configuration
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((tert-butoxycarbonyl)(4-
-chlorobenzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl) 1-tert-butyl 2,2-dimethylsuccinate (18)
(700 mg, 0.782 mmol, 46.6% yield) and the diastereomer with the R
configuration
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((tert-butoxycarbonyl)(4-
-chlorobenzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl) 1-tert-butyl 2,2-dimethylsuccinate (19)
(500 mg, 0.559 mmol, 33.3% yield) both as a light white solids. For
18 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.40-7.24 (m, 2H),
7.18 (d, J=8.3 Hz, 2H), 4.87-4.57 (m, 1H), 4.51 (dd, J=5.3, 11.0
Hz, 1H), 4.42-4.13 (m, 2H), 3.43-3.05 (m, 3H), 2.97-2.78 (m, 1H),
2.62-2.47 (m, 2H), 2.47-2.29 (m, 1H), 2.01-0.70 (m, 64H); LC/MS:
m/z calculated 893.6, found 916.5 (M+Na).sup.+. For 19 .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 7.36-7.23 (m, 2H), 7.12 (d, J=8.3
Hz, 2H), 4.56-4.14 (m, 4H), 3.45-3.18 (m, 1H), 3.15-2.97 (m, 1H),
2.76-0.71 (m, 69H); LC/MS: m/z calculated 893.6, found 916.7
(M+Na).sup.+.
##STR00164## ##STR00165##
Example 1
Compound 21
4-((R)-1-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-((3-carboxy-3-methylbutano-
yl)oxy)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,-
8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-
-((4-chlorobenzyl)amino)ethoxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00166##
[0482] Step A: Intermediate 20
4-((R)-1-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9((4-(tert-butoxy)-3,3-dimet-
hyl-4-oxobutanoyl)oxy)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,-
5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]c-
hrysTn-3a-yl)-2-((tert-butoxycarbonyl)(4-chlorobenzyl)amino)ethyl)1-tert-b-
utyl 2,2-dimethylsuccinate
[0483] To a solution of 10 (543 mg, 2.68 mmol), DMAP (205 mg, 1.677
mmol) in dichloromethane (5 mL) stirred at rt was added EDC (514
mg, 2.68 mmol). The reaction mixture was stirred at rt for 1 h.
Then 19 (300 mg, 0.335 mmol) was added to the reaction mixture.
Upon completion, the mixture was washed with 2 M HCl, water and
brine. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated to give the crude product 20 (400 mg, 0.278 mmol, 83%
yield) as an oil. This material was used in the next step without
further purification.
Step B: Compound 21
4-((R)-1-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-((3-Carboxy-3-methylbutano-
yl)oxy)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,-
8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-
-((4-chlorobenzyl)amino)ethoxy)-2,2-dimethyl-4-oxobutanoic acid
[0484] To a solution of 20 (400 mg, 0.371 mmol) in dichloromethane
(5 mL) stirred at rt was added TFA (2 mL, 26.0 mmol). The reaction
mixture was stirred at rt for 1 h. The mixture was evaporated to
afford the the TFA salt of intermediate 21 (350 mg, 0.343 mmol, 93%
yield) as a light oil. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
7.33-7.12 (m, 4H), 5.76-5.60 (m, 1H), 4.48-4.32 (m, 1H), 4.26-3.98
(m, 2H), 3.18-2.89 (m, 2H), 2.89-2.68 (m, 2H), 2.69-0.60 (m, 58H);
LC/MS: m/z calculated 865.5, found 866.3 (M+1).sup.+.
Example 2
Compound 22
4-((R)-1-((3aR,5aR,5b
R,7aR,9S,11aR,11bR,13aS)-9-((3-Carboxy-3-methylbutanoyl)oxy)-1-isopropyl--
5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12-
,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-((4-chlorobenzyl)(2-
-(dimethylamino)ethyl)amino)ethoxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00167##
[0486] To a solution of 2-(dimethylamino)acetaldehyde,
hydrochloride (441 mg, 3.57 mmol) in methanol (12 mL) was added 21,
(as it's trifluoroacetic acid salt) (350 mg, 0.357 mmol). The
mixture's pH was adjusted to 7-8 with Et.sub.3N. The reaction
mixture was stirred at rt for 2 h then NaBH.sub.3CN (224 mg, 3.57
mmol) was added and mixture was stirred overnight. The reaction was
filtered and evaporated to afford a crude product. The residue was
purified by preparative-HPLC to obtain compound 22 as a TFA salt
(200 mg, 0.168 mmol, 47.2% yield) as a white solid. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 7.33 (d, J=8.3 Hz, 2H), 7.22 (d,
J=8.3 Hz, 2H), 5.83-5.67 (m, 1H), 4.54-4.42 (m, 1H), 3.88-3.75 (m,
1H), 3.65-3.49 (m, 1H), 3.04-0.60 (m, 71H); LC/MS: m/z calculated
936.6, found 937.4 (M+1).sup.+.
##STR00168## ##STR00169##
Example 3
Compound 25
4-((S)-1-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-((3-Carboxy-3-methylbutano-
yl)oxy)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,-
8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-
-((4-chlorobenzyl)(2-(dimethylamino)ethyl)amino)ethoxy)-2,2-dimethyl-4-oxo-
butanoic acid
##STR00170##
[0487] Step A: Intermediate 23
4-((S)-1-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-((4-(Tert-butoxy)-3,3-dime-
thyl-4-oxobutanoyl)oxy)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4-
,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]-
chrysen-3a-yl)-2-((tert-butoxycarbonyl)(4-chlorobenzyl)amino)ethyl)1-tert--
butyl 2,2-dimethylsuccinate
[0488] To a solution of 10 (203 mg, 1.006 mmol), DMAP (123 mg,
1.006 mmol) in dichloromethane (10 ml) stirred at rt was added EDC
(321 mg, 1.677 mmol). The reaction mixture was stirred at rt for 1
h, then 18 (300 mg, 0.335 mmol) was added to the reaction. Upon
completion, silica gel was added, the mixture was concentrated and
purified by chromatography (petroleum ether:EtOAc 6:1 to 3:1) to
give the 23 (344 mg, 0.319 mmol, 95% yield) as a light white
solid.
Step B: Compound 24
4-((S)-1-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-((4-(Tert-butoxy)-3,3-dime-
thyl-4-oxobutanoyl)oxy)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4-
,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]-
chrysen-3a-yl)-2-((tert-butoxycarbonyl)(4-chlorobenzyl)amino)ethyl)1-tert--
butyl 2,2-dimethylsuccinate
##STR00171##
[0490] To a solution of 23 (115 mg, 0.107 mmol) in DCM (5 mL) was
added TFA (2.5 mL, 0.107 mmol). The reaction mixture was stirred at
rt for 2 h and evaporated in vacuo to afford crude product. This
material was then washed with satd. sodium bicarbonate solution,
water and brine. The organics were filtered and concentrated to
give the 24 (89 mg, 0.023 mmol, 21.17% yield) as a white solid.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.40 (s, 4H), 5.97-5.65
(m, 1H), 4.93-3.75 (m, 3H), 3.59-3.27 (m, 1H), 3.27-2.92 (m, 3H),
2.83-2.11 (m, 5H), 1.98-0.59 (m, 52H) LC/MS: m/z calculated 865.5,
found 866.4 (M+1).sup.+.
Example 4
Compound 25
4-((S)-1-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-((3-Carboxy-3-methylbutano-
yl)oxy)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,-
8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-
-((4-chlorobenzyl)(2-(dimethylamino)ethyl)amino)ethoxy)-2,2-dimethyl-4-oxo-
butanoic acid
##STR00172##
[0492] To a solution of 2-(dimethylamino)acetaldehyde (325 mg, 2.63
mmol) in methanol (5 ml) and DCE (50 ml) was added 24 (228 mg,
0.263 mmol) and triethylamine (0.110 ml, 0.789 mmol). The reaction
mixture was stirred at rt for 3 h. The reaction was cooled to
0.degree. C., and sodium cyanoborohydride (24.80 mg, 0.395 mmol)
was added and resultant mixture was stirred overnight. The reaction
was filtered and the filter cake was washed with DCM. The filtrate
was concentrated under reduced pressure and the residue was
purified by preparative-HPLC to give the title compound 25 as a TFA
salt (76 mg, 0.065 mmol, 24.78% yield) as a white solid. .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. 7.38-7.30 (m, 2H), 7.30-7.19
(m, 2H), 5.82-5.69 (m, 1H), 4.53-4.44 (m, 1H), 4.05-3.89 (m, 1H),
3.70-3.54 (m, 1H), 3.41-2.51 (m, 15H), 2.45-2.12 (m, 2H), 1.97-0.65
(m, 54H); LC/MS: m/z calculated 936.6, found 937.4 (M+1).sup.+.
##STR00173## ##STR00174##
Example 5
Compound 32
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-Chlorobenzyl)amino)ethyl-
)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10-
,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2--
dimethyl-4-oxobutanoic acid
##STR00175##
[0493] Step A: Intermediate 26
1-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-Acetoxy-1-isopropyl-5a,5b,8,8,11a-
-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octad-
ecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-nitroethyl acetate
[0494] To a solution of 11 (20 g, 35.9 mmol) in acetic anhydride
(100 mL, 1065 mmol) was added 4-methylbenzenesulfonic acid (1.852
g, 10.76 mmol). The reaction mixture was stirred at rt overnight.
EtOAc (50 ml) and NaHCO.sub.3 aq. (100 ml) were added. The organic
layer was separated, washed with water, brine,and dried
(Na.sub.2SO.sub.4). Removal of the solvent resulted in the crude
product which was used directly in the next step. LC/MS: m/z
calculated 599.4, found 600.3 (M+1).sup.+.
Step B: Intermediate 27
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-Isopropyl-5a,5b,8,8,11a-pentamethyl--
3a-(2-nitroethyl)-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a--
octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate
[0495] To a solution of 26 (21 g, 35.0 mmol) in THF (30 mL) and
EtOH (80 mL) in an ice bath was added NaBH.sub.4 (5.30 g, 140
mmol). The mixture was then kept at rt for about 1 h, diluted with
ethyl acetate (200 mL) and extracted with aqueous 10% citric acid
solution (150 mL), saturated aqueous NaHCO.sub.3 (150 mL), and
brine (150 mL). The organic layer was dried (Na.sub.2SO.sub.4) and
evaporated to give the crude product 27 (19 g, 27.2 mmol, 78%
yield). This was used directly for the next step. LC/MS: m/z
calculated 541.4, found 542.3 (M+1).sup.+.
Step C: Intermediate 28
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-Isopropyl-5a,5b,8,8,11a-pentamethyl--
2-oxo-3a-(2-oxoethyl)-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-oc-
tadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate
[0496] To a stirred solution of 27 (10 g, 18.46 mmol) in acetone
(90.00 mL) and methanol (90 mL) at -5.degree. C. was added dropwise
a solution of KOH (1.036 g, 18.46 mmol) in 5 mL water, then
followed by KMnO4 (1.896 g, 12.00 mmol) and MgSO.sub.4 (1.666 g,
13.84 mmol) in 90 mL of water. The temperature was held below
0.degree. C. for 1 h and for another 1 h at room temperature. The
reaction mixture was diluted with DCM (100 mL), then filtered on
Celite.TM. and washed with DCM. The organic phase was concentrated,
then extracted with DCM, to give the crude product 28 (5 g, 8.12
mmol, 44.0% yield) which was used directly for the next step
without further purification. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 9.64 (s, 1H), 4.49 (dd, J=5.5, 11.0 Hz, 1H), 3.27-3.06 (m,
1H), 2.87-2.76 (m, 1H), 2.76-2.64 (m, 1H), 2.64-2.54 (m, 1H), 2.45
(d, J=18.8 Hz, 1H), 2.20 (d, J=18.8 Hz, 1H), 2.05 (s, 3H),
1.99-0.67 (m, 39H); LC/MS: m/z calculated 510.4, found 533.3
(M+Na).sup.+.
Step D: Intermediate 29
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((Tert-butoxycarbonyl)(4-chlorob-
enzyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a-
,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrys-
en-9-yl acetate
[0497] To a solution of 28 (1.5 g, 2.94 mmol), TEA (0.164 ml, 1.175
mmol) and MgSO.sub.4 (0.530 g, 4.41 mmol) in methanol (15 ml)
stirred at rt was added 4-chlorobenzylamine (0.487 ml, 4.11 mmol).
The reaction mixture was stirred at 20.degree. C. for 2 h, then
cooled to -5.degree. C. and NaBH.sub.4 (0.167 g, 4.41 mmol) was
added in small portions during 10 min and stirred for 30 min.
BOC.sub.2O (0.750 ml, 3.23 mmol) was then added. The reaction was
warmed to rt and stirred for 1 h. The reaction mixture was poured
into ice water (300 ml) and solids were collected and dried to give
29 (1.8 g, 2.106 mmol, 72%) as a white foam. This material was used
without further purification. LC/MS: m/z calculated 735.5, found
758.3 (M+Na).sup.+.
Step E: Intermediate 30
Tert-butyl
4-chlorobenzyl(2-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-
-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,-
11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)ethyl)car-
bamate
[0498] To a solution of 29 (1.6 g, 2.173 mmol) in methanol (6 mL)
and THF (6 mL), and water (6 mL) was added NaOH (5.21 g, 130 mmol).
The reaction mixture was stirred at rt for 1 h. Water and EtOAc
were added upon completion and the layers separated. The organic
layer was washed with water, brine, and dried (Na.sub.2SO.sub.4).
Removal of the solvent gave 30 (1.4 g, 1.590 mmol, 73%) as a white
solid. LC/MS: m/z calculated 693.5, found 716.3 (M+Na).sup.+.
Step F: Intermediate 31
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((Tert-butoxycarbonyl)(4-chlo-
robenzyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)1-tert-butyl 2,2-dimethylsuccinate
[0499] To a solution of DMAP (0.862 g, 7.06 mmol), EDC (1.932 g,
10.08 mmol) and 4-tert-butoxy-3,3-dimethyl-4-oxobutanoic acid (10)
(1.631 g, 8.06 mmol) in DCM (60 mL) stirred at 20.degree. C. for 30
min was added 30 (1.4 g, 2.016 mmol). The reaction mixture was
stirred at 20.degree. C. for 1 h. The mixture was washed with
saturated ammonium chloride, water, and saturated NaHCO.sub.3,
water, and lastly brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated to give the crude
product, which was purified by silica gel column eluting with
petrol ether/Ethyl acetate (4:1) to afford the product
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((tert-butoxycarbonyl)(4-chl-
orobenzyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,-
5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]c-
hrysen-9-yl) 1-tert-butyl 2,2-dimethylsuccinate (1.4 g, 0.986 mmol,
49%) as a yellow solid.
Step G: Compound 32
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-Chlorobenzyl)amino)ethyl-
)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10-
,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2--
dimethyl-4-oxobutanoic acid
[0500] To a solution of 31 (1.4 g, 1.593 mmol) in DCM (6 mL) was
added TFA (3 mL). The reaction mixture was stirred at 20.degree. C.
for 2 h and evaporated in vacuo to afford crude product which was
purified by preparative-HPLC to give the title compound
trifluoroacetic acid salt (1 g, 73%) as a white solid..sup.1H NMR
(400 MHz, METHANOL-d.sub.4) .delta.=7.57-7.42 (m, 4H), 4.51 (dd,
J=5.1, 11.2 Hz, 1H), 4.29-4.15 (m, 2H), 3.30-3.18 (m, 1H),
2.98-2.69 (m, 3H), 2.62 (q, J=16.0 Hz, 2H), 2.29 (d, J=19.1 Hz,
1H), 2.17-0.79 (m, 48H); LC/MS: m/z calculated 721.5, found 722.3
(M+1).sup.+.
Example 6
Compound 33
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(Benzylamino)ethyl)-1-isopro-
pyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11-
b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-
-oxobutanoic acid
##STR00176##
[0502] The title compound was made in a similar manner to example 5
as a TFA salt. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta.=7.48
(s, 5H), 4.51 (dd, J=5.1, 11.2 Hz, 1H), 4.30-4.17 (m, 2H),
3.31-3.19 (m, 1H), 2.96-2.71 (m, 3H), 2.62 (q, J=15.9 Hz, 2H), 2.29
(d, J=18.8 Hz, 1H), 2.21-0.78 (m, 48H); LC/MS: m/z calculated
687.5, found 688.4 (M+1).sup.+.
##STR00177## ##STR00178##
Example 7
Compound 39
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((3-Chlorobenzyl)amino)ethyl-
)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10-
,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2--
dimethyl-4-oxobutanoic acid
##STR00179##
[0503] Step A: Compound 34
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-Aminoethyl)-1-isopropyl-5a,5b,8,-
8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a--
octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate
[0504] To a solution of
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-3a-(2-nitroethyl)-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-
-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (27) (10 g,
18.46 mmol) and nickel(II) chloride (7.18 g, 55.4 mmol) in methanol
(100 ml) was added sodium borohydride (6.98 g, 185 mmol)
portionwise during 1 hour. The reaction mixture was stirred at
0.degree. C. for 1 h. The mixture was diluted with EtOAc (250 mL).
The organic phase was washed with sat. NH.sub.4Cl (50 mL) until the
organic layer change to colorless. The combined organic layers were
dried over anhydrous Na.sub.2SO.sub.4, and concentrated in vacuo to
get the crude product
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-aminoethyl)-1-isopropyl-5a,5b,8-
,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-
-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (34) (7 g,
12.63 mmol, 68.4% yield), which was used without further
purification. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.=9.15 (dd,
J=4.9, 11.4 Hz, 1H), 8.12 (br. s., 2H), 7.97-7.81 (m, 1H),
7.63-7.49 (m, 1H), 7.26-7.15 (m, 1H), 7.15-7.04 (m, 1H), 6.98 (d,
J=18.6 Hz, 1H), 6.81-5.38 (m, 47H); LC/MS: m/z calculated 511.4,
found 512.3 (M+1).sup.+.
Step B: Compound 35
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((Tert-butoxycarbonyl)amino)ethy-
l)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,1-
0,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl
acetate
[0505] To a solution of
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-aminoethyl)-1-isopropyl-5a,5b,8-
,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-
-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (34) (5.3 g,
10.36 mmol), TEA (2.165 mL, 15.53 mmol) and TEA (2.165 mL, 15.53
mmol) in dichloromethane (DCM) (100 mL) stirred at room temp was
added BOC.sub.2O (2.404 mL, 10.36 mmol). The reaction mixture was
stirred at 20.degree. C. for 2 h. The reaction mixture was poured
into ice water (300 ml) and the solids were collected and dried to
give
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((tert-butoxycarbonyl)amino)eth-
yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,-
10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl
acetate (35) (5.8 g, 8.34 mmol, 81% yield) as a white foam. This
was used crude in next reaction without further purification.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.=4.58-4.37 (m, 2H),
3.26-2.96 (m, 4H), 2.93-2.72 (m, 2H), 2.28 (d, J=18.8 Hz, 1H),
2.11-0.71 (m, 53H); LC/MS: m/z calculated 611.5, found 634.3
(M+Na).sup.+.
Step C: Compound 36
Tert-butyl(2-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a-
,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,1-
3,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)ethyl)carbamate
[0506] A solution of
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((tert-butoxycarbonyl)amino)eth-
yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,-
10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl
acetate (35) (5.8 g, 9.48 mmol), NaOH (11.37 g, 284 mmol) in
methanol (4 mL), THF (6 mL), and Water (2 mL) was stirred at room
temperature for 1 h. EtOAc was added and the reaction mixture was
washed with water. The organic layer was separated, washed with
water and brine,and dried (Na.sub.2SO.sub.4). Removal of the
solvent provide tert-butyl
(2-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,1-
1a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-oct-
adecahydro-2H-cyclopenta[a]chrysen-3a-yl)ethyl)carbamate (36) (5.4
g, 7.87 mmol, 83% yield) as a white solid. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta.=4.53-4.36 (m, 1H), 3.30-2.94 (m, 4H),
2.94-2.67 (m, 2H), 2.28 (d, J=18.8 Hz, 1H), 2.11-0.55 (m, 50H);
LC/MS: m/z calculated 569.4, found 592.3 (M+Na).sup.+.
Step D: Compound 37
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((Tert-butoxycarbonyl)amino)e-
thyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,-
9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)1-ter-
t-butyl 2,2-dimethylsuccinate
[0507] A solution of 4-tert-butoxy-3,3-dimethyl-4-oxobutanoic acid
(10) (4.79 g, 23.69 mmol), DMAP (3.47 g, 28.4 mmol) and tert-butyl
(2-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,1-
1a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-oct-
adecahydro-2H-cyclopenta[a]chrysen-3a-yl)ethyl)carbamate (36) (5.4
g, 9.48 mmol) EDC (9.08 g, 47.4 mmol) in dichloromethane (DCM) (25
mL) was stirred at rt overnight. NH.sub.4Cl was added and the
mixture was extracted with DCM, and purified by chromatography with
PE:EA (10:1) to give the
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((tert-butoxycarbon-
yl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl) 1-tert-butyl 2,2-dimethylsuccinate (37) (6.7 g, 8.75 mmol,
92% yield). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.=4.62-4.39
(m, 2H), 3.24-3.10 (m, 1H), 3.10-2.93 (m, 1H), 2.93-2.68 (m, 2H),
2.62-2.49 (m, 1H), 2.28 (d, J=18.8 Hz, 1H), 2.11-0.69 (m, 66H);
LC/MS: m/z calculated 753.6, found 776.5 (M+Na).sup.+.
Step E: Compound 38
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-Aminoethyl)-1-isopropyl-5a,5-
b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,-
13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobuta-
noic acid
[0508] To a solution of
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((tert-butoxycarbonyl)amino)-
ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8-
,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)
1-tert-butyl 2,2-dimethylsuccinate (37) (6.7 g, 8.88 mmol) in DCM
(20 mL) stirred at rt was added TFA (4 ml, 51.9 mmol). The reaction
mixture was stirred at rt for 2 h. The reaction mixture was washed
with sat. NaHCO.sub.3. A solid was formed and collected by
filtration to give
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-aminoethyl)-1-isopropyl-5a,-
5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13-
,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobut-
anoic acid (38) (4 g, 6.55 mmol, 73.7% yield) as a white
solid..sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.=4.44-4.28 (m,
1H), 3.20-3.05 (m, 1H), 2.87-2.75 (m, 1H), 2.46-2.16 (m, 6H),
1.97-0.66 (m, 47H); LC/MS: m/z calculated 597.4, found 598.3
(M+1).sup.+.
Step F: Compound 39
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((3-Chlorobenzyl)amino)ethyl-
)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10-
,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2--
dimethyl-4-oxobutanoic acid
[0509] To a solution of
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-aminoethyl)-1-isopropyl-5a,-
5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13-
,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobut-
anoic acid (38) (300 mg, 0.502 mmol), TEA (0.028 ml, 0.201 mmol)
and MgSO.sub.4 (91 mg, 0.753 mmol) in methanol (15 ml) stirred at
room temp was added 3-chlorobenzaldehyde (85 mg, 0.602 mmol). The
reaction mixture was stirred at 20.degree. C. for 2 h. The reaction
mixture was then cooled to 0.degree. C. and NaBH.sub.4 (1.541 g,
40.7 mmol) was added in portions within 30 min, after which the
solution was allowed to stirred for 1 h. The mixture was purified
by preparative-TLC eluting with DCM/MeOH (20:1) to give 39 (108 mg,
0.147 mmol, 29%). .sup.1H NMR (500 MHz, METHANOL-d.sub.4)
.delta.=7.41 (s, 1H), 7.38-7.24 (m, 3H), 4.48 (dd, J=5.7, 10.7 Hz,
1H), 3.89-3.67 (m, 2H), 3.26-3.11 (m, 1H), 2.84-2.73 (m, 1H),
2.66-2.47 (m, 2H), 2.46-2.34 (m, 1H), 2.34-2.21 (m, 2H), 2.08-0.77
(m, 48H).
Example 8
Compound 40
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((3-Chloro-2-fluorobenzyl)am-
ino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,-
7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)-
oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00180##
[0511] The title compound was made in a similar manner to Example
7, but as a TFA salt. .sup.1H NMR (500 MHz, METHANOL-d.sub.4)
.delta.=7.46-7.38 (m, 1H), 7.35 (t, J=6.6 Hz, 1H), 7.17 (t, J=7.7
Hz, 1H), 4.48 (dd, J=5.5, 10.6 Hz, 1H), 3.97-3.72 (m, 2H),
3.27-3.12 (m, 1H), 2.85-2.73 (m, 1H), 2.67-2.45 (m, 2H), 2.44-2.16
(m, 3H), 2.09-0.73 (m, 48H).
Example 9
Compound 41
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((1-(4-chlorophenyl)cyclopro-
pyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00181##
[0513] The title compound was made in a similar manner to Example
5, but as a TFA salt. The final step was performed according to the
following procedure. To a solution of
4-(tert-butoxy)-3,3-dimethyl-4-oxobutanoic acid (10) (0.988 g, 4.89
mmol), EDC (1.171 g, 6.11 mmol) and DMAP (0.522 g, 4.28 mmol) in
DCM (12 mL) stirred at room temp was added tert-butyl
(1-(4-chlorophenyl)cyclopropyl)(2-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9--
hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,-
8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)et-
hyl)carbamate (1.1 g, 1.221 mmol). The reaction mixture was stirred
at rt for 2 h. Next, TFA (6 mL) was added to the reaction mixture.
Then, the reaction solution was stirred at rt for another 1.5 h,
and the product was extracted with DCM (60 mL*3), and the combined
organic phase was washed with brine (100 ml), dried over
Na.sub.2SO.sub.4, concentrated and the residue was purified by
recrystallization from DCM and hexane (1:6) resulting in 800 mg of
the TFA salt of 41 as white solid. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta.=7.64-7.44 (m, 4H), 4.50 (dd, J=5.1, 11.2
Hz, 1H), 3.26-3.10 (m, 1H), 2.84-2.41 (m, 5H), 2.24-2.12 (m, 1H),
2.12-0.78 (m, 52H); LC/MS: m/z calculated 747.5, found 748.3
(M+1).sup.+.
##STR00182##
Example 10
Compound 42
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)(2-(dimethy-
lamino)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a-
,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[-
a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00183##
[0515] To a solution of 2-(dimethylamino)acetaldehyde (244 mg,
1.977 mmol) in methanol (100 ml) was added
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)amino)ethy-
l)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,1-
0,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-
-dimethyl-4-oxobutanoic acid, hydrochloride (32) (300 mg, 0.395
mmol). The reaction mixture was stirred at 40.degree. C. for 2 h.
The reaction was cooled to rt and sodium cyanoborohydride (24.84
mg, 0.395 mmol) was added and the resultant solution was stirred
overnight. The reaction was diluted with ammonium chloride (40 ml),
and extracted with DCM (60 ml.times.3). The combined organic layers
were washed with brine (20 ml), dried over sodium sulfate, filtered
and concentrated in vacuo. The residue was purified by
preparative-HPLC to afford 42 as a trifluoroacetic acid salt (200
mg, 49% yield) as a white solid. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta.=7.52-7.34 (m, 4H), 4.50 (dd, J=5.0, 11.0
Hz, 1H), 4.07-3.88 (m, 1H), 3.83-3.62 (m, 1H), 3.53-3.35 (m, 2H),
3.22-2.89 (m, 9H), 2.71-2.54 (m, 2H), 2.50-2.21 (m, 4H), 2.06-0.83
(m, 48H); LC/MS: m/z calculated 792.5, found 793.4 (M+1).sup.+.
Example 11
Compound 43
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((1-(4-Chlorophenyl)cyclopro-
pyl)(2-(dimethylamino)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentame-
thyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-
-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00184##
[0517] The title compound was made in a similar manner to Example
10, as a TFA salt. .sup.1H NMR (400 MHz, METHANOL-d.sub.4)
.delta.=7.35 (s, 4H), 4.51 (dd, J=5.1, 11.2 Hz, 1H), 3.31-3.17 (m,
2H), 3.12-2.73 (m, 9H), 2.73-2.51 (m, 2H), 2.44-2.17 (m, 3H),
2.14-0.77 (m, 53H); LC/MS: m/z calculated 818.4, found 819.4
(M+1).sup.+.
##STR00185##
Example 12
Compound 44
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-Chlorobenzyl)(methyl)ami-
no)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7-
a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)o-
xy)-2,2-dimethyl-4-oxobutanoic acid
##STR00186##
[0519] To a solution of 32 (150 mg, 0.208 mmol) in MeOH (6 mL) at
rt was added formaldehyde (33.7 mg, 0.415 mmol). The reaction
mixture was stirred at rt for 2 h. NaCNBH.sub.4 (104 mg, 1.661
mmol) was added portionwise and the mixture stirred for overnight.
The solvent was evaporated, and the mixture was purified by
preparative HPLC to provide the TFA salt of 44 (60 mg, 34%).
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta.=7.60-7.44 (m, 4H),
4.56-4.37 (m, 2H), 4.36-4.24 (m, 1H), 3.28-3.14 (m, 1H), 2.89 (m,
5H), 2.73-2.50 (m, 2H), 2.28 (d, J=19.1 Hz, 1H), 2.20-0.83 (m,
49H); LC/MS: m/z calculated 735.5, found 736.3 (M+1).sup.+.
##STR00187##
Example 13
Compound 45
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(N-(4-Chlorobenzyl)acetamido-
)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,-
8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy-
)-2,2-dimethyl-4-oxobutanoic acid
##STR00188##
[0521] A mixture of 32 (150 mg, 0.208 mmol), TEA (210 mg, 2.076
mmol) and DMAP (5 mg, 0.042 mmol) in DCM (5 ml) was stirred for 3
hours. Next, the mixture was quenched with water (50 ml). The
organics were then washed with water (2.times.50 ml), dried over
Na.sub.2SO.sub.4, and evaporated in vacuo to afford crude product.
This was then purified by preparative HPLC to give 45 (65 mg, 0.085
mmol, 41%) as a white solid. Mixture of rotomers. .sup.1H NMR (400
MHz, METHANOL-d.sub.4) .delta.=7.49-7.18 (m, 4H), 4.80-4.42 (m,
3H), 3.27-2.81 (m, 4H), 2.76-2.52 (m, 2H), 2.36-2.10 (m, 4H),
2.08-0.82 (m, 48H); LC/MS: m/z calculated 763.5, found 764.3
(M+1).sup.+.
##STR00189##
Example 14
Compound 46
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-Chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00190##
[0523] To a solution of
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((tert-butoxycarbonyl)(4-
-chlorobenzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl) 1-tert-butyl 2,2-dimethylsuccinate (19)
(300 mg, 0.335 mmol) in DCM (30 mL) stirred at rt was was added TFA
(15 mL, 195 mmol). The reaction mixture was stirred at rt until
LCMS and TLC indicated SM disappeared. The solvent was removed in
vacuo and the residue was purified by preparative HPLC to give
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-Chlorobenzyl)amino)-
-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (46) (100 mg, 0.135
mmol, 40.4% yield) as a TFA salt. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta.=7.38-7.18 (m, 4H), 4.54-4.42 (m, 1H),
4.28-4.14 (m, 1H), 3.93-3.70 (m, 2H), 3.19-3.00 (m, 1H), 2.75-0.69
(m, 52H); LC/MS: m/z calculated 737.4, found 738.2 (M+1).sup.+.
Example 15
Compound 47
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-Chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00191##
[0525] To a solution of
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((tert-butoxycarbonyl)(4-
-chlorobenzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl) 1-tert-butyl 2,2-dimethylsuccinate (18)
(130 mg, 0.145 mmol) in DCM (30 mL) stirred at rt was added TFA (15
mL, 195 mmol). The reaction mixture was stirred at rt until LCMS
and TLC indicated starting material disappeared. The solvent was
evaporated and then then CH.sub.3CN and H.sub.2O was added and the
material was lyophilized to give
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-Chlorobenzyl)amino)-
-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (47), trifluoroacetic
acid salt (120 mg, 0.139 mmol, 96% yield). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta.=10.30 (br. s., 1H), 8.08 (br. s., 1H), 7.38
(s, 4H), 4.73-4.33 (m, 2H), 4.28-4.07 (m, 2H), 3.34-3.06 (m, 2H),
2.99-2.74 (m, 2H), 2.73-2.50 (m, 2H), 2.48-2.29 (m, 1H), 2.05-0.64
(m, 47H); LC/MS: m/z calculated 737.4, found 738.3 (M+1).sup.+.
##STR00192##
Example 16
Compound 49
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-Acetoxy-2-((4-chlorobenz-
yl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00193##
[0526] Step A: Compound 48
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-acetoxy-2-((tert-butoxyca-
rbonyl)(4-chlorobenzyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl--
2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-c-
yclopenta[a]chrysen-9-yl) 1-tert-butyl 2,2-dimethylsuccinate
[0527] To a solution of 19 (500 mg, 0.559 mmol) in dichloromethane
(30 mL) stirred at rt was added Ac.sub.2O (0.158 mL, 1.677 mmol),
triethylamine (0.195 mL, 1.397 mmol) and DMAP (6.83 mg, 0.056
mmol). The reaction mixture was stirred at rt until TLC indicated
SM disappeared. The mixture was worked up and purified by silica
gel chromatography (PE:EA=5:1) to give 48 (510 mg, 0.517 mmol, 93%
yield). The product consisted of a mixture of rotomers. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta.=7.39-7.20 (m, 2H), 7.21-6.99 (m,
2H), 5.92-5.56 (m, 1H), 5.00-3.88 (m, 2H), 3.40-1.96 (m, 8H),
1.97-0.58 (m, 67H).
Step B: Compound 49
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-Acetoxy-2-((4-chlorobenz-
yl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
[0528] To a solution of 48 (500 mg, 0.534 mmol) in DCM (30 mL)
stirred at rt was added TFA (15 mL, 195 mmol). The reaction mixture
was stirred at rt until LCMS and TLC indicated SM had disappeared.
The solvent was evaporated and CH.sub.3CN and H.sub.2O were added
and mixture was lyophilized to give 49 as a trifluoroacetic acid
salt (400 mg, 0.439 mmol, 82% yield). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta.=7.46-7.19 (m, 4H), 5.94-5.70 (m, 1H),
4.58-4.36 (m, 1H), 4.25-3.88 (m, 2H), 3.25-3.02 (m, 1H), 3.01-2.41
(m, 5H), 2.08 (s, 3H), 2.00-0.64 (m, 47H); LC/MS: m/z calculated
779.5, found 780.4 (M+1).sup.+.
Example 17
Compound 50
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-Acetoxy-2-((4-chlorobenz-
yl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00194##
[0530] The title compound was made in a similar manner to Example
16 and isolated as a TFA salt. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta.=7.49-7.30 (m, 4H), 5.85-5.71 (m, 1H), 4.59-4.40 (m, 1H),
4.31-4.03 (m, 2H), 3.41-2.79 (m, 4H), 2.79-2.50 (m, 2H), 2.37 (d,
J=18.1 Hz, 2H), 2.02-0.63 (m, 49H); LC/MS: m/z calculated 779.5,
found 780.3 (M+1).sup.+.
##STR00195##
Example 18
Compound 51
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-Chlorobenzyl)(2-(dim-
ethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00196##
[0532] To a solution of 2-(dimethylamino)acetaldehyde,
hydrochloride (6.75 g, 54.6 mmol) in methanol (20 mL) was added
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)amino)-
-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid, Trifluoroacetic acid
salt (46) (9.5 g, 10.92 mmol). The pH was adjusted to 7-8 with
Et.sub.3N. The reaction mixture was stirred at rt for 2 h. Sodium
cyanoborohydride (0.686 g, 10.92 mmol) was then added and the
mixture was stirred at rt overnight. After the reaction was
complete, water (15 mL) and EtOAc (15 mL) were added, and then the
organic phase was removed and concentrated under reduced pressure.
The product was extracted with EtOAc (80 mL.times.3), the combined
organic phase was washed with brine, dried, and concentrated. The
product was purified by flash chromatography (DCM:EtOAc=2:1 to 1:1,
then DCM:MeOH=100:1 to 20:1) to give
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-(di-
methylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentame-
thyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-
-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
(51) (6 g, 7.41 mmol, 67.9% yield) as white solid. Multiple batches
of this material (were combined 95 g), dissolved in 600 mL of
dichloromethane and washed with NaHCO.sub.3 (400 mL*3) and the
organic phase was dried over Na.sub.2SO.sub.4, filtered and
concentrated. The solids were washed with a mixture of EtOAc:
petroleum ether (600 mL), and filtered followed by lyophilization
to provide the final title compound 62 g as a white solid. .sup.1H
NMR (400 MHz, METHANOL-d.sub.4) .delta.=7.47-7.29 (m, 4H), 4.48
(dd, J=5.8, 10.3 Hz, 1H), 4.15-4.04 (m, 1H), 3.80 (d, J=13.8 Hz,
1H), 3.57 (d, J=14.1 Hz, 1H), 3.21-2.82 (m, 5H), 2.72-2.41 (m, 9H),
2.37-2.05 (m, 4H), 2.05-0.74 (m, 45H); LC/MS: m/z calculated 808.5,
found 809.5 (M+1).sup.+.
##STR00197## ##STR00198##
Example 19
Compound 56
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-Chlorobenzyl)(2-(dim-
ethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00199##
[0533] Step A: Compound 52
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-Chlorobenzyl)(2-(dimethylami-
no)ethyl)amino)acetyl)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3-
a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta-
[a]chrysen-2-one
[0534] To a solution of 2-(dimethylamino)acetaldehyde (4.79 g, 38.8
mmol) in methanol (50 ml) and 1,2-dichloroethane (DCE) (25 ml) was
added
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(4-chlorobenzylamino)acetyl)-9--
hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3a,4,5,5a,6,7,7a,8,9,10,11,1-
1a,11b,12,13,13a-hexadecahydro-3H-cyclopenta[a]chrysen-2(5bH)-one
(15) (5 g, 7.75 mmol) at 0.degree. C. The pH was adjusted to 7 with
Et.sub.3N. The reaction mixture was stirred at rt for 1 h. Sodium
cyanoborohydride (0.487 g, 7.75 mmol) was added and the mixture was
stirred overnight. The reaction was diluted with water (40 ml), and
extracted with DCM (60 ml.times.3). The combined organic layer was
washed with brine (20 ml), dried over sodium sulfate and filtered
to afford crude product
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)(2-(dimethylam-
ino)ethyl)amino)acetyl)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3a-
,4,5,5a,6,7,7a,8,9,10,11,11a,11b,12,13,13a-hexadecahydro-3H-cyclopenta[a]c-
hrysen-2(5bH)-one (52) (5 g, 5.89 mmol, 76% yield) as a light
yellow solid, which was used in the next step. LC/MS: m/z
calculated 678.5, found 679.3 (M+1).sup.+.
Step B: Compound 53
1-Tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)(2-(dimethy-
lamino)ethyl)amino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3-
a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta-
[a]chrysen-9-yl) 2,2-dimethylsuccinate
[0535] To a solution of 4-(tert-butoxy)-3,3-dimethyl-4-oxobutanoic
acid (11.91 g, 58.9 mmol), N,N-dimethylpyridin-4-amine (4.50 g,
36.8 mmol) in DCM (20 mL) was added EDC (11.29 g, 58.9 mmol). The
reaction mixture was stirred at rt for 1 h. Then,
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)(2-(dimethylam-
ino)ethyl)amino)acetyl)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,-
3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopent-
a[a]chrysen-2-one (52) (5 g, 7.36 mmol) was add. Upon completion,
the mixture was washed with 2 M HCl, water and brine. The organic
layer was dried over Na.sub.2SO.sub.4, filtered and concentrated to
give the crude product. The product was purified by a silica gel
column using dichloromethane/methanol (20:1) to afford 1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)(2-(dimethy-
lamino)ethyl)amino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3-
a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta-
[a]chrysen-9-yl) 2,2-dimethylsuccinate (53) (1.8 g, 1.917 mmol,
26.1 yield) as an oil. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta.=7.27 (s, 4H), 4.60-4.39 (m, 1H), 3.82 (d, J=13.8 Hz, 1H),
3.59 (d, J=13.8 Hz, 1H), 3.50-3.05 (m, 3H), 2.82-2.63 (m, 2H),
2.63-0.53 (m, 67H).
Step C: Compounds 54 and 55
1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-(dim-
ethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (54) and
1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chlorobenzyl)(2-(dim-
ethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (55)
[0536] To a solution of 1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)(2-(dimethy-
lamino)ethyl)amino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3-
a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta-
[a]chrysen-9-yl) 2,2-dimethylsuccinate (53) (1.5 g, 1.737 mmol) in
methanol (10 mL) was added NaBH.sub.4 (0.131 g, 3.47 mmol). The
reaction mixture was stirred at rt for 1 h. The mixture then was
extracted with DCM, washed with water and brine. The organic layer
was dried over Na.sub.2SO.sub.4, and concentrated to give the crude
product. This was purified by preparative-HPLC then purified by SFC
to get 54 (230 mg, 15%) and 55 (360 mg 23%). For 54: .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta.=7.45-7.18 (m, 4H), 4.49 (dd, J=5.6,
10.7 Hz, 1H), 4.04 (d, J=9.8 Hz, 1H), 3.92-3.47 (m, 3H), 3.46-0.45
(m, 72H); LC/MS: m/z calculated 864.6, found 865.4 (M+1).sup.+. For
55: .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.=7.37-7.19 (m, 4H),
4.50 (dd, J=5.5, 10.5 Hz, 1H), 4.18-3.98 (m, 1H), 3.75 (d, J=13.3
Hz, 1H), 3.55 (d, J=13.3 Hz, 1H), 3.29-3.10 (m, 1H), 3.10-2.97 (m,
1H), 2.81-0.63 (m, 70H); LC/MS: m/z calculated 864.6, found 865.9
(M+1).sup.+.
Step D: Compound 56
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-Chlorobenzyl)(2-(dim-
ethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
[0537] To a solution of 55 (360 mg, 0.416 mmol) in DCM (5 mL)
stirred at rt was added TFA (2 mL, 26.0 mmol). The reaction mixture
was stirred at rt for 1 h. The mixture was evaporated to afford the
crude product. This material was purified by preparative-HPLC to
provide the title compound 56 as a TFA salt (300 mg, 0.285 mmol,
68.6% yield) as a white solid. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta.=7.58-7.34 (m, 4H), 4.50 (dd, J=5.0, 11.0
Hz, 1H), 4.23-4.10 (m, 1H), 4.09-3.74 (m, 2H), 3.58-3.12 (m, 3H),
3.12-2.37 (m, 10H), 2.12-0.67 (m, 50H); LC/MS: m/z calculated
808.5, found 809.3 (M+1).sup.+.
##STR00200##
Example 20
Compound 57
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-Acetoxy-2-((4-chlorobenz-
yl)(2-(dimethylamino)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00201##
[0539] To a solution of 2-(dimethylamino)acetaldehyde,
hydrochloride (238 mg, 1.922 mmol) in methanol (12 mL) was added
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-((4-chloroben-
zyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (50) (150 mg, 0.192
mmol). The reaction mixture was stirred at rt for 2 h then sodium
cyanoborohydride (121 mg, 1.922 mmol) was added and the mixture was
stirred overnight. Upon completion, the mixture was purified
preparative-HPLC to provide the title compound (50 mg, 24%).
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.=7.35-7.12 (m, 4H), 5.65
(d, J=9.3 Hz, 1H), 4.49 (dd, J=5.8, 10.0 Hz, 1H), 3.83 (d, J=13.6
Hz, 1H), 3.55 (d, J=13.6 Hz, 1H), 3.25-2.91 (m, 7H), 2.91-2.73 (m,
7H), 2.73-2.52 (m, 3H), 2.33 (d, J=18.1 Hz, 1H), 1.99-0.72 (m,
48H); LC/MS: m/z calculated 850.5, found 851.4 (M+1).sup.+.
Example 21
Compound 58
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-Acetoxy-2-((4-chlorobenz-
yl)(2-(dimethylamino)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00202##
[0541] The title compound was made in a similar manner to example
20. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.=7.40-7.10 (m, 4H),
5.68 (d, J=9.8 Hz, 1H), 4.55-4.39 (m, 1H), 3.81 (d, J=13.8 Hz, 1H),
3.57 (d, J=13.8 Hz, 1H), 3.29-2.74 (m, 11H), 2.74-2.27 (m, 6H),
2.14 (s, 3H), 2.09-0.68 (m, 46H); LC/MS: m/z calculated 850.5,
found 851.4 (M+1).sup.+.
##STR00203##
Example 22 and 23
Compound 62 and 63
5-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-Chlorobenzyl)(2-(dim-
ethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid
(62) and
5-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-Chlorobenzyl)(2-
-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pen-
tamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecah-
ydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic
acid (63)
##STR00204##
[0542] Step A: Compound 59
5-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((Tert-butoxycarbonyl)(4-chl-
orobenzyl)amino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4-
,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]-
chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid
[0543] To a solution of tert-butyl
4-chlorobenzyl(2-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isoprop-
yl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b-
,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-oxoethyl)carbama-
te (15) (1 g, 1.412 mmol), DMAP (0.517 g, 4.23 mmol) in pyridine (2
ml) stirred at rt was added 4,4-dimethyl-dihydro-3H-pyran-2,6-dione
(1.003 g, 7.06 mmol). The reaction mixture was stirred at
50.degree. C. for 5 h. The mixture was diluted with EtOAc and
washed with water. The resultant extract was purified by silica gel
column to provide 59 (800 mg, 60%). .sup.1H NMR (500 MHz,
CHLOROFORM-d) .delta.=8.67 (br. s., 1H), 7.98-7.36 (m, 1H),
7.33-7.27 (m, 2H), 7.21-7.09 (m, 2H), 4.62-4.26 (m, 3H), 4.07-3.42
(m, 2H), 3.30-3.05 (m, 1H), 2.66-0.66 (m, 61H).
Step B: Compound 60
5-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-Chlorobenzyl)amino)acety-
l)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,1-
0,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-
-dimethyl-5-oxopentanoic acid
[0544] To a solution of
5-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((tert-butoxycarbonyl)(4-ch-
lorobenzyl)amino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,-
4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a-
]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid (59) (800 mg,
0.941 mmol) in dichloromethane (6 mL) stirred at rt was added
trifluoroacetic acid (2 mL, 0.941 mmol). The reaction mixture was
stirred at rt for 1 h. The mixture was evaporated to provide the
target compound (600 mg, 81%) which was used without further
purification. LC/MS: m/z calculated 749.4, found 750.1
(M+1).sup.+.
Step C: Compound 61
5-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-Chlorobenzyl)(2-(dimethy-
lamino)ethyl)amino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3-
a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta-
[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid
[0545] To a solution of
5-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)amino)acet-
yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,-
10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-3,-
3-dimethyl-5-oxopentanoic acid, trifluoroacetic acid salt (60) (700
mg, 0.810 mmol) in methanol (30 ml) was added
2-(dimethylamino)acetaldehyde (353 mg, 4.05 mmol) at 0.degree. C.
The pH was adjusted to 7 with Et.sub.3N. The reaction mixture was
stirred at rt for 1 h and sodium cyanoborohydride (50.9 mg, 0.810
mmol) was added and the resultant mixture was stirred overnight.
The reaction was diluted with water (40 ml) and extracted with DCM
(60 ml.times.3). The combined organic layer was washed with brine
(20 ml), dried over sodium sulfate and filtered to afford crude
product
5-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)(2-(dimeth-
ylamino)ethyl)amino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,-
3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopent-
a[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid,
trifluoroacetic acid salt (61) (200 mg, 23% yield) as a light
yellow solid. .sup.1H NMR (500 MHz, METHANOL-d.sub.4) .delta.=7.39
(s, 4H), 4.49 (dd, J=5.7, 10.7 Hz, 1H), 3.95 (d, J=13.6 Hz, 1H),
3.57 (d, J=13.2 Hz, 1H), 3.40-3.29 (m, 1H), 3.27-3.16 (m, 2H), 3.05
(s, 6H), 3.00-2.88 (m, 2H), 2.57-2.26 (m, 6H), 2.09 (d, J=19.5 Hz,
1H), 2.04-0.75 (m, 47H); LC/MS: m/z calculated 820.5, found 821.3
(M+1).sup.+.
Step D: Compounds 62 and 63
5-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((4-Chlorobenzyl)(isopen-
tyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3-
a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta-
[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid (62) and
5-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chlorobenzyl)(isope-
ntyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,-
3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopent-
a[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid (63)
[0546] To a solution of
5-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)(2-(dimeth-
ylamino)ethyl)amino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,-
3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopent-
a[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid,
trifluoroacetic acid salt (61) (140 mg, 0.133 mmol) in methanol (10
mL) stirred at 0.degree. C. was added NaBH.sub.4 (10.09 mg, 0.267
mmol). The reaction mixture was stirred at 0.degree. C. for 1 h,
then more NaBH.sub.4 (10.09 mg, 0.267 mmol) was added. After an
additional 1 h at 0.degree. C., the mixture was warmed to rt
stirred for another 1 h. LCMS indicated the reaction was complete.
EtOAc was added and the mixture was washed with water. The organic
phase was evaporated to give the crude which was purified by
preparative-HPL to give two diastereomers. 5 mg of isomer A (62)
was isolated (3.5% yield) and 10 mg of isomer B (63) was isolated
(7%). The stereochemistry of the newly formed stereocenter in each
isomer was assigned by spectral similarity to compounds 51
(analogous to 62) and 56 (analogous to 63). For isomer A (62);
.sup.1H NMR (500 MHz, METHANOL-d.sub.4) .delta.=7.48-7.30 (m, 4H),
4.57-4.43 (m, 1H), 4.14 (d, J=10.1 Hz, 1H), 3.91-3.74 (m, 1H), 3.67
(d, J=13.9 Hz, 1H), 3.26-3.10 (m, 2H), 3.10-2.93 (m, 2H), 2.93-2.81
(m, 6H), 2.68-2.10 (m, 9H), 2.06-0.65 (m, 46H); LC/MS: m/z
calculated 822.5, found 823.5 (M+1).sup.+. For isomer B
(63);.sup.1H NMR (500 MHz, METHANOL-d.sub.4) .delta.=7.43 (br. s.,
4H), 4.51 (dd, J=5.8, 9.9 Hz, 1H), 4.16 (d, J=10.1 Hz, 1H),
3.98-3.75 (m, 2H), 3.52-3.37 (m, 1H), 3.31-3.02 (m, 3H), 3.02-2.71
(m, 9H), 2.64-2.34 (m, 6H), 2.19-0.69 (m, 46H); LC/MS: m/z
calculated 822.5, found 823.4 (M+1).sup.+.
Example 24
Compound 64
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((2-Chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00205##
[0548] The title compound was made in a similar manner to example
14. Stereochemistry was tentatively assigned as drawn but not fully
confirmed spectroscopically. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta.=7.73-7.38 (m, 4H), 4.65-4.37 (m, 4H),
3.44 (d, J=12.3 Hz, 1H), 3.39-3.22 (m, 1H), 3.11-2.96 (m, 2H), 2.62
(q, J=16.0 Hz, 2H), 2.48 (d, J=18.3 Hz, 1H), 2.21-0.77 (m, 46H);
LC/MS: m/z calculated 737.4, found 738.3 (M+1).sup.+.
Example 25
Compound 65
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00206##
[0550] The title compound was made in a similar manner to example
14. Stereochemistry was tentatively assigned as drawn but not fully
confirmed 6spectroscopically. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta.=7.63-7.37 (m, 4H), 4.55-4.31 (m, 4H),
3.26-3.11 (m, 1H), 3.01-2.46 (m, 6H), 2.36-2.16 (m, 1H), 2.15-0.79
(m, 45H); LC/MS: m/z calculated 737.4, found 738.0 (M+1).sup.+.
Example 26
Compound 66
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-Acetoxy-2-((4-fluorobenz-
yl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00207##
[0552] The title compound was made as a TFA salt in a similar
manner to example 16. Stereochemistry was tentatively assigned as
drawn but not fully confirmed spectroscopically. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta.=10.54-8.79 (m, 1H), 7.50-7.34 (m, 2H),
7.19-6.99 (m, 2H), 5.81 (d, J=9.8 Hz, 1H), 4.49 (dd, J=5.8, 10.3
Hz, 1H), 4.31-3.93 (m, 2H), 3.26 (d, J=12.5 Hz, 1H), 3.20-3.05 (m,
1H), 3.05-2.82 (m, 2H), 2.80-2.47 (m, 2H), 2.36 (d, J=18.1 Hz, 1H),
2.05-0.57 (m, 49H); LC/MS: m/z calculated 763.5, found 764.3
(M+1).sup.+.
Example 27
Compound 67
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-acetoxy-2-((4-fluorobenz-
yl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00208##
[0554] The title compound was made as a TFA salt in a similar
manner to example 16. Stereochemistry was tentatively assigned as
drawn but not fully confirmed spectroscopically. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta.=9.65 (br. s., 1H), 7.46-7.28 (m, 2H),
7.03 (t, J=8.2 Hz, 2H), 5.86 (br. s., 1H), 4.50 (dd, J=5.5, 10.3
Hz, 1H), 4.29-4.06 (m, 1H), 4.06-3.85 (m, 1H), 3.19-2.99 (m, 1H),
2.81-2.39 (m, 6H), 2.21-0.62 (m, 49H); LC/MS: m/z calculated 763.5,
found 764.3 (M+1).sup.+.
##STR00209##
Example 28
Compound 68
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-((4-fluorobenz-
yl)(methyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4-
,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]-
chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00210##
[0556] To a solution of
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-((4-chloroben-
zyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (50) (150 mg, 0.192
mmol) in MeOH (6 mL) stirred in air at rt was added formaldehyde
(31.2 mg, 0.384 mmol). The reaction mixture was stirred at rt for 2
h. Then it was added NaCNBH.sub.3 (85 mg, 1.345 mmol) portionwise
and stirred for overnight. The solvent was evaporated and the the
residue diluted with DCM and washed with water and brine. The dried
organics were filtered and concentrated to give
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-((4-chloroben-
zyl)(methyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,-
4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a-
]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (68) (120 mg,
65% yield) as a white solid. This material was used without further
purification. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.=7.31-7.26
(m, 2H), 7.24-7.16 (m, 2H), 5.65 (d, J=8.5 Hz, 1H), 4.50 (br. s.,
1H), 3.66-3.51 (m, 1H), 3.49-3.36 (m, 1H), 3.27-3.06 (m, 2H),
2.73-2.32 (m, 5H), 2.26 (s, 3H), 2.08-0.73 (m, 49H); LC/MS: m/z
calculated 793.5, found 794.3 (M+1).sup.+.
Example 29
Compound 69
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-Chlorobenzyl)(methyl-
)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4-
,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]-
chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00211##
[0558] To a solution of
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-((4-chloroben-
zyl)(methyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,-
4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a-
]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (68) (120 mg,
0.151 mmol) in ethanol (2 mL) and toluene (2 mL) was added
potassium hydroxide (15.25 mg, 0.272 mmol). The reaction mixture
was stirred at rt for 30 min. The reaction mixture was neutralized
with aqueous 1N HCl to pH=7 and evaporated to obtain the residue.
This was extracted with DCM, washed with water and dried to yield
the crude product which was purified by preparative-HPLC to afford
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chlorobenzyl)(methy-
l)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,-
4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a-
]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid as a
trifluoroacetate salt (95 mg, 72% yield) as a white solid..sup.1H
NMR (400 MHz, METHANOL-d.sub.4) .delta.=7.55 (s, 4H), 4.60-4.12 (m,
3H), 3.32-3.19 (m, 1H), 3.18-2.84 (m, 5H), 2.71-2.52 (m, 2H),
2.11-0.78 (m, 49H); LC/MS: m/z calculated 751.5, found 752.4
(M+1).sup.+.
Example 30
Compound 70
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-Acetoxy-2-((4-chlorobenz-
yl)(methyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4-
,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]-
chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00212##
[0560] The title compound was made in similar manner to example 28.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.=7.31-7.23 (m, 2H),
7.22-7.13 (m, 2H), 5.66 (dd, J=2.4, 8.7 Hz, 1H), 4.55-4.43 (m, 1H),
3.51-3.35 (m, 2H), 3.19-3.05 (m, 1H), 2.74-2.42 (m, 5H), 2.42-0.66
(m, 53H); LC/MS: m/z calculated 793.5, found 794.5 (M+1).sup.+.
Example 31
Compound 71
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((4-Chlorobenzyl)(methyl-
)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4-
,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]-
chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00213##
[0562] The title compound was made in similar manner to example 29.
.sup.1H NMR (500 MHz, METHANOL-d.sub.4) .delta.=7.63-7.38 (m, 4H),
4.56-4.25 (m, 4H), 3.25-3.14 (m, 1H), 2.99 (s, 3H), 2.82-2.52 (m,
4H), 2.52-2.32 (m, 2H), 2.24 (d, J=12.9 Hz, 1H), 2.09-0.77 (m,
45H); LC/MS: m/z calculated 751.5, found 752.3 (M+1).sup.+.
##STR00214##
Example 32
Compound 72
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-Acetoxy-2-(N-(4-chlorobe-
nzyl)acetamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00215##
[0564] A mixture of
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-((4-chloroben-
zyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (50) (200 mg, 0.256
mmol), TEA (0.332 mL, 2.56 mmol), DMAP (6.3 mg, 0.05 mmol) and in
DCM (5 ml) was stirred for 3 h. The mixture was quenched with water
(50 ml), washed with water (2.times.50 ml), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-(N-(4-chlorob-
enzyl)acetamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,-
5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]c-
hrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (72) (160 mg,
0.182 mmol, 71.0% yield) as a white solid. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta.=7.42-7.24 (m, 2H), 7.24-6.90 (m, 2H),
5.98-5.68 (m, 1H), 5.15-4.56 (m, 1H), 4.56-4.45 (m, 1H), 4.40-3.98
(m, 2H), 2.29-0.68 (m, 66H), 3.48-0.58 (m, 58H); LC/MS: m/z
calculated 821.5, found 822.3 (M+1).sup.+.
Example 33
Compound 73
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(N-(4-Chlorobenzyl)aceta-
mido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00216##
[0566] To a solution of
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-(N-(4-chlorob-
enzyl)acetamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,-
5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]c-
hrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (72) (150 mg,
0.182 mmol) in ethanol (2 mL) and toluene (2 mL) was added
potassium hydroxide (40.9 mg, 0.729 mmol). The reaction mixture was
stirred at rt for 30 min. The reaction mixture was neutralized with
aqueous 1 N HCl to pH=7 and concentrated to obtain a residue. The
residue was extracted with DCM, washed with water and dried to
yield the crude product which was purified by preparative-HPLC to
afford
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(N-(4-chlorobenzyl)acet-
amido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,-
5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]c-
hrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (73) (40 mg, 28%)
as a white solid. Compound exists as a mixture of rotomers; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.=12.18 (br. s., 1H), 7.52-7.14
(m, 4H), 5.03-3.77 (m, 5H), 3.39-2.80 (m, 3H), 2.62-2.54 (m, 1H),
2.27 (t, J=17.2 Hz, 1H), 2.20-0.58 (m, 51H); LC/MS: m/z calculated
779.5, found 802.3 (M+Na).sup.+.
##STR00217##
Example 34
Compound 74
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-(4-Chlorobenzyl)aceta-
mido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00218##
[0568] A mixture of
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-acetoxy-2-((4-chloroben-
zyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (49) (150 mg, 0.192
mmol), Na.sub.2CO.sub.3 (20.37 mg, 0.192 mmol), in methanol (3 mL)
was stirred for 3 h, then purified by preparative-HPLC to afford
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-(4-chlorobenzyl)acet-
amido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,-
5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]c-
hrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (74) (45 mg, 30%)
as a white solid. Compound exists as a mixture of rotomers; .sup.1H
NMR (500 MHz, METHANOL-d.sub.4) .delta.=7.43-7.27 (m, 2H),
7.28-7.11 (m, 2H), 5.30-4.09 (m, 6H), 3.55-2.09 (m, 11H), 2.09-0.78
(m, 44H); LC/MS: m/z calculated 779.5, found 780.4 (M+1).sup.+.
##STR00219##
Example 35
Compound 76
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(N-(2-Chlorobenzyl)aceta-
mido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00220##
[0570] To a solution of
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-((tert-butoxyc-
arbonyl)(2-chlorobenzyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl) 1-tert-butyl 2,2-dimethylsuccinate (75,
made in a similar manner to compound 48) (100 mg, 0.107 mmol) in
DCM (30 mL) stirred at rt was added TFA (15 mL, 195 mmol). The
reaction mixture was stirred at rt until LCMS and TLC indicated SM
disappeared. The solvent was removed to give the crude product
purified by preparative HPLC to give
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(N-(2-chlorobenzyl-
)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,-
3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopent-
a[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (40 mg, 48%).
Stereochemistry was tentatively assigned as drawn, but not fully
confirmed spectroscopically. The compound exists as a mixture of
rotomers. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta.=7.55-7.14
(m, 4H), 5.10-4.72 (m, 2H), 4.72-3.97 (m, 3H), 3.54-3.39 (m, 1H),
3.30-3.21 (m, 1H), 3.13-2.97 (m, 1H), 2.84-0.69 (m, 53H); LC/MS:
m/z calculated 779.5, found 780.3 (M+1).sup.+.
Example 36
Compound 77
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-Acetoxy-2-((2-chlorobenz-
yl)(2-(dimethylamino)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00221##
[0572] The title compound was made in a similar manner to Example
20. Stereochemistry was tentatively assigned as drawn but not fully
confirmed spectroscopically. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta.=7.64-7.06 (m, 4H), 5.61 (d, J=8.8 Hz, 1H), 4.50 (dd, J=5.4,
10.7 Hz, 1H), 3.82 (d, J=13.8 Hz, 1H), 3.65 (d, J=13.6 Hz, 1H),
3.26-2.92 (m, 7H), 2.89-2.74 (m, 7H), 2.74-2.53 (m, 3H), 2.26 (d,
J=18.3 Hz, 1H), 1.93-0.67 (m, 48H); LC/MS: m/z calculated 850.5,
found 851.4 (M+1).sup.+.
Example 37
Compound 78
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((3-Chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00222##
[0574] The title compound was made in a similar manner to example
20 as a TFA salt. Stereochemistry was tentatively assigned as drawn
but not fully confirmed spectroscopically. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta.=7.61 (s, 1H), 7.56-7.43 (m, 3H),
4.57-4.44 (m, 2H), 4.35-4.21 (m, 2H), 3.38 (dd, J=2.5, 12.5 Hz,
1H), 3.31-3.23 (m, 1H), 3.09-3.01 (m, 1H), 2.96 (t, J=11.8 Hz, 1H),
2.71-2.51 (m, 1H), 2.46 (d, J=18.3 Hz, 1H), 2.15-0.79 (m, 48H);
LC/MS: m/z calculated 737.4, found 738.3 (M+1).sup.+.
Example 38
Compound 79
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((3-Chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00223##
[0576] The title compound was made in a similar manner to example
20 as a TFA salt. Stereochemistry was tentatively assigned as drawn
but not fully confirmed spectroscopically. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta.=7.77-7.28 (m, 4H), 4.68-4.15 (m, 4H),
3.27-3.11 (m, 1H), 2.73-2.48 (m, 5H), 2.38-2.17 (m, 1H), 2.16-0.71
(m, 4H); LC/MS: m/z calculated 737.4, found 738.4 (M+1).sup.+.
Example 39
Compound 80
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-Acetoxy-2-((3-chlorobenz-
yl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00224##
[0578] The title compound was made in a similar manner to example
16 as a TFA salt. Stereochemistry was tentatively assigned as
drawn, but not fully confirmed spectroscopically. .sup.1H NMR (500
MHz, CHLOROFORM-d) .delta.=7.43 (s, 1H), 7.42-7.32 (m, 3H), 5.81
(d, J=10.1 Hz, 1H), 4.49 (dd, J=5.5, 10.2 Hz, 1H), 4.24 (d, J=13.2
Hz, 1H), 4.13-3.96 (m, 1H), 3.34-3.04 (m, 2H), 3.05-2.82 (m, 2H),
2.75-2.62 (m, 1H), 2.62-2.52 (m, 1H), 2.37 (d, J=18.0 Hz, 1H), 1.93
(s, 3H), 1.90-0.65 (m, 47H); LC/MS: m/z calculated 779.5, found
780.3 (M+1).sup.+.
Example 40
Compound 81
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-Acetoxy-2-((3-chlorobenz-
yl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00225##
[0580] The title compound was made in a similar manner to Example
16 as a TFA salt. Stereochemistry was tentatively assigned as drawn
but not fully confirmed spectroscopically. .sup.1H NMR (500 MHz,
CHLOROFORM-d) .delta.=9.77 (br. s., 1H), 7.50-7.09 (m, 4H), 5.87
(br. s., 1H), 4.57-4.44 (m, 1H), 4.12 (d, J=1.6 Hz, 1H), 3.96 (d,
J=13.2 Hz, 1H), 3.23-3.00 (m, 1H), 2.86-2.37 (m, 5H), 2.20-0.66 (m,
50H); LC/MS: m/z calculated 779.5, found 780.2 (M+1).sup.+.
Example 41
Compound 82
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-((3-chlorobenz-
yl)(2-(dimethylamino)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00226##
[0582] The title compound was made in a similar manner to Example
18 as a TFA salt. To a solution of 2-(dimethylamino)acetaldehyde
(553 mg, 4.47 mmol) in methanol (10 ml), was added
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-((3-chloroben-
zyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid, trifluoroacetic acid
salt (80) (400 mg, 0.447 mmol). The reaction mixture was stirred at
40.degree. C. for 2 h. The reaction was cooled to rt and
NaBH.sub.3CN (281 mg, 4.47 mmol) was added. The mixture and stirred
overnight. Then concentrated in vacuo and purified by
preparative-HPLC to afford
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-((3-chloroben-
zyl)(2-(dimethylamino)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentame-
thyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-
-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
(82) (80 mg, 20%) as a light yellow solid. Stereochemistry was
tentatively assigned as drawn but not fully confirmed
spectroscopically. LC/MS: m/z calculated 850.5, found 851.5
(M+1).sup.+.
##STR00227##
Example 42 and 43
Compound 83 and 84
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-acetoxy-2-((3-chlorobenz-
yl)(2-(dimethylamino)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
(83) and
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((3-chlorobenzyl)(ethyl-
)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4-
,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]-
chrysen-9-yl) oxy)-2,2-dimethyl-4-oxobutanoic acid (84)
##STR00228##
[0584] To a solution of 2-(dimethylamino)acetaldehyde,
hydrochloride (553 mg, 4.47 mmol) in methanol (10 ml) was added
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(4-chlorobenzylamino)acetyl)-9--
hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3a,4,5,5a,6,7,7a,8,9,10,11,1-
1a,11b,12,13,13a-hexadecahydro-3H-cyclopenta[a]chrysen-2(5bH)-one
(81) (15 g, 24.66 mmol). The reaction mixture was stirred at
40.degree. C. for 2 h. The reaction was cooled to rt and sodium
cyanoborohydride (7.75 g, 123 mmol) was added and the resultant
mixture was stirred overnight. The reaction was diluted with
ammonium chloride solution (40 ml), and extracted with DCM (60
ml.times.3). The combined organic layer was washed with brine (20
ml), dried over sodium sulfate, filtered and concentrated in vacuo
to afford crude product which was purified by preparative-HPLC to
give
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-acetoxy-2-((3-c-
hlorobenzyl)(2-(dimethylamino)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-
-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octad-
ecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid (83) (80 mg, 20%) and
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((3-chlorobenzyl)(ethyl-
)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4-
,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]-
chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (84) (14 mg, 3%)
as their respective TFA salts. Stereochemistry was tentatively
assigned as drawn but not fully confirmed spectroscopically. For
83; .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta.=7.25-7.10 (m, 3H),
7.04 (d, J=3.8 Hz, 1H), 5.57 (d, J=9.1 Hz, 1H), 4.42 (dd, J=5.0,
10.7 Hz, 1H), 3.72 (d, J=13.9 Hz, 1H), 3.42 (d, J=14.2 Hz, 1H),
3.16-2.90 (m, 6H), 2.90-2.79 (m, 1H), 2.79-2.65 (m, 7H), 2.65-2.41
(m, 3H), 2.22 (d, J=18.3 Hz, 1H), 1.89 (s, 3H), 1.84-0.62 (m, 45H);
LC/MS: m/z calculated 850.5, found 851.4 (M+1).sup.+. For 84;
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .quadrature.=7.65 (s, 1H),
7.62-7.46 (m, 3H), 4.58-4.28 (m, 4H), 3.49-3.38 (m, 1H), 3.31-3.23
(m, 2H), 3.13-2.91 (m, 2H), 2.62 (q, J=15.9 Hz, 2H), 2.10-0.76 (m,
51H); LC/MS: m/z calculated 765.5, found 766.5 (M+1).sup.+.
Example 44
Compound 85
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((3-Chlorobenzyl)(2-(dim-
ethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00229##
[0586] The title compound was made in a similar manner to Example
33. Stereochemistry was tentatively assigned as drawn but not fully
confirmed spectroscopically. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta.=7.57-7.31 (m, 4H), 4.50 (dd, J=5.0, 11.0
Hz, 1H), 4.28 (br. s., 1H), 4.02-3.69 (m, 2H), 3.53-3.36 (m, 1H),
3.32-3.07 (m, 4H), 3.08-2.85 (m, 2H), 2.78 (s, 6H), 2.73-2.51 (m,
3H), 2.45 (d, J=18.3 Hz, 1H), 2.13-0.75 (m, 46H); LC/MS: m/z
calculated 808.5, found 809.5 (M+1).sup.+.
Example 45
Compound 86
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((3-Chlorobenzyl)(2-(dim-
ethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00230##
[0588] The title compound was made in a similar manner to example
33. Stereochemistry was tentatively assigned as drawn but not fully
confirmed spectroscopically. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta.=7.46-7.23 (m, 4H), 4.49 (dd, J=5.1, 10.9
Hz, 1H), 4.19 (d, J=10.0 Hz, 1H), 3.95-3.78 (m, 1H), 3.78-3.66 (m,
1H), 3.41-3.33 (m, 1H), 3.27-3.00 (m, 3H), 2.87 (s, 6H), 2.70-2.50
(m, 3H), 2.37 (br. s., 1H), 2.34-2.16 (m, 3H), 2.08-0.82 (m, 46H);
LC/MS: m/z calculated 808.5, found 809.5 (M+1).sup.+.
Example 46
Compound 87
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-(3-chlorobenzyl)aceta-
mido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00231##
[0590] The title compound was made in a similar manner to example
33 from compound 81. Stereochemistry was tentatively assigned as
drawn but not fully confirmed spectroscopically. The compound
exists as a mixture of rotomers. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta.=7.42-7.04 (m, 4H), 5.42-3.97 (m, 3H),
3.55-3.00 (m, 3H), 2.82-0.79 (m, 53H); LC/MS: m/z calculated 779.5,
found 780.3 (M+1).sup.+.
Example 47
Compound 88
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(N-(3-chlorobenzyl)aceta-
mido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00232##
[0592] The title compound was made in a similar manner to example
33 from compound 80. Stereochemistry was tentatively assigned as
drawn but not fully confirmed spectroscopically. .sup.1H NMR (400
MHz, METHANOL-d.sub.4) .delta.=7.36-6.99 (m, 4H), 4.89-3.88 (m,
4H), 3.39-2.83 (m, 3H), 2.73-0.66 (m, 53H); LC/MS: m/z calculated
779.5, found 780.3 (M+1).sup.+.
Example 48 and 49
Compounds 89 and 90
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-acetoxy-2-((2-chlorobenz-
yl)(2-(dimethylamino)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
(89) and
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-chlorobenzyl)(ethyl-
)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4-
,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]-
chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (90)
##STR00233##
[0594] The title compounds were made in a similar manner to
examples 42 and 43. Stereochemistry was tentatively assigned as
drawn but not fully confirmed spectroscopically. For 89; .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta.=7.42-7.18 (m, 4H), 5.70-5.56
(m, 1H), 4.57-4.42 (m, 1H), 3.83-3.51 (m, 2H), 3.21-2.85 (m, 3H),
2.79 (s, 6H), 2.74-2.54 (m, 3H), 2.54-2.23 (m, 4H), 2.15-0.65 (m,
50H); LC/MS: m/z calculated 850.5, found 851.4 (M+1).sup.+. For 90;
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta.=7.77-7.43 (m, 4H),
4.69-4.27 (m, 4H), 3.62-3.37 (m, 2H), 3.26-3.10 (m, 1H), 2.97-2.82
(m, 1H), 2.61 (q, J=16.0 Hz, 2H), 2.27-2.10 (m, 1H), 2.10-0.77 (m,
51H); LC/MS: m/z calculated 765.5, found 766.3 (M+1).sup.+.
Example 50
Compound 91
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-chlorobenzyl)(2-(dim-
ethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00234##
[0596] The title compound was made in a similar manner to Example
33. Stereochemistry was tentatively assigned as drawn but not fully
confirmed spectroscopically. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta.=7.55-7.42 (m, 2H), 7.42-7.32 (m, 2H),
4.49 (dd, J=5.5, 11.0 Hz, 1H), 4.43-4.30 (m, 1H), 4.00-3.89 (m,
1H), 3.87-3.76 (m, 1H), 3.42-3.34 (m, 1H), 3.24-2.91 (m, 3H),
2.91-2.51 (m, 10H), 2.52-2.17 (m, 4H), 2.11-1.84 (m, 2H), 1.84-0.78
(m, 44H); LC/MS: m/z calculated 808.5, found 809.4 (M+1).sup.+.
Example 51
Compound 92
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((2-chlorobenzyl)(2-(dim-
ethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00235##
[0598] The title compound was made in a similar manner to Example
33. Stereochemistry was tentatively assigned as drawn but not fully
confirmed spectroscopically. .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) .delta.=7.57-7.45 (m, 2H), 7.39 (dd, J=3.6, 5.6
Hz, 2H), 4.56-4.40 (m, 2H), 4.02 (d, J=12.8 Hz, 1H), 3.81 (d,
J=12.8 Hz, 1H), 3.46-3.23 (m, 2H), 3.13-2.89 (m, 4H), 2.81-2.41 (m,
10H), 2.15-1.91 (m, 3H), 1.89-0.82 (m, 44H); LC/MS: m/z calculated
808.5, found 809.5 (M+1).sup.+.
Example 52
Compound 93
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-Acetoxy-2-(benzylamino)e-
thyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,-
9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)--
2,2-dimethyl-4-oxobutanoic acid
##STR00236##
[0600] The title compound was made as a TFA salt in a similar
manner to Example 16. Stereochemistry was tentatively assigned as
drawn but not fully confirmed spectroscopically. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta.=12.17 (br. s., 1H), 9.49 (br. s., 1H),
9.19 (br. s., 1H), 7.66-7.28 (m, 5H), 5.86-5.53 (m, 1H), 4.49-3.97
(m, 3H), 3.16-2.84 (m, 2H), 2.68-2.55 (m, 1H), 2.55-2.47 (m, 2H),
2.41 (d, J=19.5 Hz, 1H), 2.11 (s, 3H), 2.04-0.67 (m, 47H); LC/MS:
m/z calculated 745.5, found 746.5 (M+1).sup.+.
Example 53
Compound 94
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-Acetoxy-2-(benzylamino)e-
thyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,-
9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)--
2,2-dimethyl-4-oxobutanoic acid
##STR00237##
[0602] The title compound was made as a TFA salt in a similar
manner to Example 16. Stereochemistry was tentatively assigned as
drawn but not fully confirmed spectroscopically. .sup.1H NMR (500
MHz, CHLOROFORM-d) .delta.=7.41 (br. s., 5H), 5.81 (d, J=10.1 Hz,
1H), 4.48 (dd, J=5.5, 10.2 Hz, 1H), 4.25 (d, J=13.2 Hz, 1H), 4.06
(d, J=13.2 Hz, 1H), 3.27 (d, J=12.3 Hz, 1H), 3.14 (dt, J=6.8, 13.6
Hz, 1H), 3.08-2.85 (m, 2H), 2.74-2.62 (m, 1H), 2.62-2.54 (m, 1H),
2.36 (d, J=18.0 Hz, 1H), 1.99-0.63 (m, 49H); LC/MS: m/z calculated
745.5, found 746.5 (M+1).sup.+.
Example 54
Compound 95
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((3-Chloro-2-fluorobenzy-
l)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,-
4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a-
]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00238##
[0604] The title compound was made as a TFA salt in a similar
manner to Example 14. Stereochemistry was tentatively assigned as
drawn but not fully confirmed spectroscopically. LC/MS: m/z
calculated 755.4, found 756.3 (M+1).sup.+.
Example 55
Compound 96
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((3-chloro-2-fluorobenzy-
l)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,-
4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a-
]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00239##
[0606] The title compound was made as a TFA salt in a similar
manner to Example 14. Stereochemistry was tentatively assigned as
drawn but not fully confirmed spectroscopically. LC/MS: m/z
calculated 755.4, found 756.2 (M+1).sup.+.
Example 56
Compound 97
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((3-Chloro-2-fluorobenzy-
l)(2-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-
-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octad-
ecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00240##
[0608] The title compound was made as a TFA salt in a similar
manner to Example 18. Stereochemistry was tentatively assigned as
drawn but not fully confirmed spectroscopically. .sup.1H NMR (500
MHz, CHLOROFORM-d) .delta.=7.49-7.35 (m, 2H), 7.15 (t, J=7.7 Hz,
1H), 4.46 (dd, J=6.1, 9.9 Hz, 1H), 4.22 (d, J=10.4 Hz, 1H), 4.05
(d, J=13.9 Hz, 1H), 3.90 (d, J=13.6 Hz, 1H), 3.48 (br. s., 1H),
3.32-3.02 (m, 4H), 2.85 (br. s., 6H), 2.74-2.40 (m, 4H), 2.40-2.15
(m, 3H), 1.99-0.58 (m, 43H); LC/MS: m/z calculated 826.5, found
827.3 (M+1).sup.+.
Example 57
Compound 98
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((3-Chloro-2-fluorobenzy-
l)(2-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-
-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octad-
ecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00241##
[0610] The title compound was made as a TFA salt in a similar
manner to Example 18. Stereochemistry was tentatively assigned as
drawn but not fully confirmed spectroscopically. .sup.1H NMR (500
MHz, CHLOROFORM-d) .delta.=7.56-7.32 (m, 2H), 7.16 (t, J=7.7 Hz,
1H), 4.53-4.38 (m, 1H), 4.28 (d, J=9.1 Hz, 1H), 4.13-3.87 (m, 2H),
3.44 (br. s., 1H), 3.33-2.91 (m, 5H), 2.93-2.21 (m, 11H), 2.09-1.95
(m, 1H), 1.95-0.65 (m, 45H); LC/MS: m/z calculated 826.5, found
827.3 (M+1).sup.+.
Example 58
Compound 99
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-Hydroxy-2-(isopropylamin-
o)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a-
,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)ox-
y)-2,2-dimethyl-4-oxobutanoic acid
##STR00242##
[0612] The title compound was made as a TFA salt in a similar
manner to Example 18. Stereochemistry was tentatively assigned as
drawn but not fully confirmed spectroscopically. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta.=10.30 (br. s., 1H), 4.71-4.26 (m, 2H),
3.49-2.98 (m, 2H), 2.87-2.42 (m, 6H), 2.42-2.21 (m, 1H), 2.07-0.68
(m, 53H); LC/MS: m/z calculated 655.5, found 656.5 (M+1).sup.+.
Example 59
Compound 100
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(cyclohexylamino)-1-hydr-
oxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7-
a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)o-
xy)-2,2-dimethyl-4-oxobutanoic acid
##STR00243##
[0614] The title compound was made as a TFA salt in a similar
manner to Example 18. Stereochemistry was tentatively assigned as
drawn but not fully confirmed spectroscopically. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta.=10.25 (br. s., 1H), 7.12 (br. s., 1H),
4.67-4.34 (m, 2H), 3.29-3.03 (m, 1H), 2.92 (br. s., 1H), 2.83-2.42
(m, 6H), 2.42-2.26 (m, 1H), 2.11-0.72 (m, 55H); LC/MS: m/z
calculated 695.5, found 696.4 (M+1).sup.+.
##STR00244## ##STR00245##
Example 60 and 61
Compound 111 and 112
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-3-(1-(5-chloropyrimidin-2--
yl)cyclopropyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethy-
l-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-
-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
(111) and
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-3-(1-(5-chloropyrimidin-2-
-yl)cyclopropyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentameth-
yl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2-
H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
(112)
##STR00246##
[0615] Step A: Intermediate 101
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((1,3-Dithian-2-yl)-9-hydroxy-1-iso-
propyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,1-
2,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-2-one
[0616] To a solution of 1,3-dithiane (5.7 g, 47.4 mmol) in
anhydrous tetrahydrofuran (THF, 60 mL) under an atmosphere of
nitrogen at -40.degree. C. was slowly added a solution of n-BuLi
(27 mL, 67.5 mmol). After the reaction mixture was stirred at
-20.degree. C. for another 2 h, a solution of the intermediate 6
(4.2 g, 8.46 mmol) in anhydrous THF (40 mL) was slowly added under
an atmosphere of nitrogen at -70.degree. C. The reaction was then
stirred at -78.degree. C. for 1 h before it was quenched with a
saturated solution of NaHCO.sub.3. Extraction was conducted with
EtOAc and the organic phase was washed with water (50 mL),
saturated brine (50 mL), dried over sodium sulfate, and evaporated
under reduced pressure to provide a crude product, which was
purified by column chromatography on silica gel (PE:EtOAc=8:1 to
4:1) to afford the intermediate 101 (3.0 g, 5.22 mmol, 61.7%).
LC/MS: m/z calculated 574.4, found 575.0 (M+1).sup.+.
Step B: Intermediate 102
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(Acetoxy(1,3-dithian-2-yl)methyl)-1-
-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11-
,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl
acetate
[0617] To a solution of the intermediate 101 (3.5 g, 6.09 mmol),
Et.sub.3N (2.55 mL, 18.26 mmol), and DMAP (0.149 g, 1.218 mmol) in
DCM (40 mL) was added Ac.sub.2O (3.45 mL, 36.5 mmol) at room
temperature. After stirring at 50.degree. C. for 2 h, the reaction
mixture was quenched with water. The organic phase was washed with
water (100 mL), dried over sodium sulfate, and evaporated under
reduced pressure to provide the intermediate 102 (3.41 g, 85%).
LC/MS: m/z calculated 658.4, found 659.1 (M+1).sup.+.
Step C: Intermediate 103
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((1,3-Dithian-2-yl)-1-isopropyl-5a,-
5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13-
,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate
[0618] A solution of 102 (6.7 g, 10.17 mmol) and potassium
hydroxide (1.141 g, 20.33 mmol) in a mixture 1:1 of toluene and
ethanol (100 ml) was stirred vigorously at rt for 1 hr. The
reaction mixture was neutralized with aqueous 1N HCl to pH 7 and
reduced to dryness. The residue was purified on a silica gel using
Petroleum ether/EtOAc (5:1) to yield
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((1,3-dithian-2-yl)(hydroxy)-
methyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,-
8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl
acetate (103) (3.4 g, 5.01 mmol, 49%) as a light yellow compound.
LC/MS: m/z calculated 616.4, found 617.3 (M+1).sup.+.
Step D: Intermediate 104
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(1-hydroxy-2-oxoethyl)-1-isopropyl--
5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12-
,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate
[0619] To a solution of 103 (1.2 g, 1.945 mmol) in acetonitrile (20
ml) and water (5.00 ml) stirred in air at rt was added NBS (1.385
g, 7.78 mmol) in one charge. The reaction mixture was stirred at rt
for 0.5 h, then quenched with Na.sub.2SO.sub.3 (solid),
concentrated and the residue was extracted with EtOAc. The organic
phase was washed with water and saturated brine, dried over sodium
sulphate and concentrated in vacuo to give
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(1-hydroxy-2-oxoethyl)-1-isop-
ropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,-
11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate
(104) (1.09 g, 1.083 mmol, 55.7% yield) as a light yellow solid
which was used without further purification.
Step E: Intermediate 106
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((1-(5-Chloropyrimidin-2-yl)cycl-
opropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-
-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclop-
enta[a]chrysen-9-yl acetate
[0620] To a solution of
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(1-hydroxy-2-oxoethyl)-1-isopropyl-
-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,1-
2,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (104)
(545 mg, 1.035 mmol) and
1-(5-chloropyrimidin-2-yl)cyclopropanamine, hydrochloride (105)
(213 mg, 1.035 mmol) in methanol (5 ml) and 1,2-dichloroethane (5
ml) was added zinc chloride (141 mg, 1.035 mmol). The reaction
mixture was stirred at room temperature overnight. and then sodium
cyanoborohydride (65.0 mg, 1.035 mmol) was added. The reaction
mixture was allowed to stir for 1 h, then silica gel was added to
the mixture and the solvents removed in vacuo to give the
residue-silica gel powder which was purified on a silica gel column
using petroleum ether/EtOAc (5:1 to 3:1) to afford
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((1-(5-chloropyrimidin-2-yl)cyc-
lopropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-ox-
o-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclo-
penta[a]chrysen-9-yl acetate (105) as a mixture of diastereomers
(200 mg, 0.166 mmol, 16.04% yield) as a yellow foam. LC/MS: m/z
calculated 679.4, found 680.3 (M+1).sup.+.
Step F: Intermediate 107
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(3-(1-(5-Chloropyrimidin-2-yl)cyclo-
propyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo--
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclope-
nta[a]chrysen-9-yl acetate
[0621] To a solution of
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((1-(5-chloropyrimidin-2-yl)cyc-
lopropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-ox-
o-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclo-
penta[a]chrysen-9-yl acetate (106) (400 mg, 0.588 mmol) in
dichloromethane (15 ml) stirred at rt was added BOC.sub.2O (1.365
ml, 5.88 mmol). The reaction mixture was stirred at rt overnight
then evaporated under reduced pressure and the residue was
subjected to a silica gel chromatography with petroleum ether/EtOAc
(6:1 to 3:1) to give
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(3-(1-(5-chloropyrimidin-2-yl)cycl-
opropyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-
-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclop-
enta[a]chrysen-9-yl acetate (107) (350 mg, 0.496 mmol, 84% yield)
as a white solid.
Step G: Intermediate 108
3-(1-(5-Chloropyrimidin-2-yl)cyclopropyl)-5-((3aR,5aR,5bR,7aR,9S,11aR,11bR-
,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-3a-yl)oxazolidin-2-one
[0622] To a solution of
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(3-(1-(5-chloropyrimidin-2-yl)cycl-
opropyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-
-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclop-
enta[a]chrysen-9-yl acetate (107) (350 mg, 0.496 mmol) in
1,4-dioxane (10 mL) and methanol (5 mL) was added hydrochloric acid
(5 mL, 165 mmol). The reaction mixture was stirred at 40.degree. C.
overnight. The solvents were removed under reduced pressure and
taken up in DCM (100 ml), washed with sat. NaHCO.sub.3 (20 ml),
water (20 ml) and brine (20 ml), dried over sodium sulfate,
filtered and concentrated to give residue, which was subjected to a
silica gel column eluting with petroleum ether/EtOAc (6:1 to 3:1)
to give
3-(1-(5-chloropyrimidin-2-yl)cyclopropyl)-5-((3aR,5aR,5bR,7aR,9S,11aR,11b-
R,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,-
5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chryse-
n-3a-yl)oxazolidin-2-one (130 mg, 0.087 mmol, 17%) as a white
solid. LC/MS: m/z calculated 663.4, found 664.3 (M+1).sup.+.
Step H: Intermediates 109 and 110
1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-3-(1-(5-chloropyrimidin-2--
yl)cyclopropyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethy-
l-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-
-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (109) and
1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-3-(1-(5-chloropyrimidin-2--
yl)cyclopropyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethy-
l-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-
-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (110)
[0623] A mixture of 4-tert-butoxy-3,3-dimethyl-4-oxobutanoic acid
10 (119 mg, 0.587 mmol),
3-(1-(5-chloropyrimidin-2-yl)cyclopropyl)-5-((3aR,5aR,5bR,7aR,9S,11aR,11b-
R,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,-
5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chryse-
n-3a-yl)oxazolidin-2-one (108) (130 mg, 0.196 mmol), EDC (188 mg,
0.978 mmol) and DMAP (71.7 mg, 0.587 mmol) in DCM (5 mL) was
stirred at rt overnight. After the reaction finished, the mixture
was diluted with DCM (25 ml), washed with water (2.times.15 ml) and
brine (20 ml), dried over sodium sulfate, filtered and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography using petroleum ether/EtOAc (6:1 to 3:1) as eluent
to give the two diastereomeric products 1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-3-(1-(5-chloropyrimidin-2--
yl)cyclopropyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethy-
l-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-
-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (109) and
1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-3-(1-(5-chloropyrimidin-2--
yl)cyclopropyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethy-
l-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-
-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (110) in the
amounts of (80 mg, 45%) and (50 mg, 22%) as white solids. The
stereochemical assignments for each diastereomer were not made.
Compound A (tentatively designated as 109): LC/MS: m/z calculated
847.5, found 848.3 (M+1).sup.+. Compound B (tentatively designated
as 110): LC/MS: m/z calculated 847.5, found 848 (M+1).sup.+.
Step I: Compound 111
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-3-(1-(5-chloropyrimidin-2--
yl)cyclopropyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethy-
l-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-
-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
[0624] To a solution of 1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-3-(1-(5-chloropyrimidin-2--
yl)cyclopropyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethy-
l-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-
-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (109) (80 mg,
0.094 mmol) in DCM (10 mL) was added TFA (1 mL, 0.094 mmol). The
reaction mixture was stirred at rt overnight, then diluted with DCM
(20 ml) and washed with water (2.times.15 ml), saturated sodium
bicarbonate solution (20 ml) and brine (20 ml), dried over sodium
sulfate, filtered and concentrated to get a residue. The residue
was purified on silica gel using petroleum ether/EtOAc (4:1 to 1:1)
as eluent to give the product
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-3-(1-(5-chloropyrimidin-2-
-yl)cyclopropyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentameth-
yl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2-
H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
(111) (50 mg, 67%) as a white solid. This material was lyophilized
to give a white powder. Stereochemistry was tentatively assigned as
drawn but not fully confirmed spectroscopically. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta.=8.58 (s, 2H), 5.04 (t, J=8.5 Hz, 1H),
4.51 (dd, J=4.6, 10.9 Hz, 1H), 3.41-3.04 (m, 4H), 2.75-2.44 (m,
3H), 2.36 (d, J=13.3 Hz, 1H), 2.12-0.72 (m, 49H); LC/MS: m/z
calculated 791.4, found 792.3 (M+1).sup.+.
Step J: Compound 112
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-3-(1-(5-chloropyrimidin-2--
yl)cyclopropyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethy-
l-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-
-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
[0625] The title compound was made in a similar manner to that
described for compound 111. Stereochemistry was tentatively
assigned as drawn but not fully confirmed spectroscopically.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.=8.59 (s, 2H), 5.10 (t,
J=8.8 Hz, 1H), 4.52 (dd, J=5.3, 10.8 Hz, 1H), 3.70-3.54 (m, 2H),
3.28-3.10 (m, 2H), 3.08-2.92 (m, 2H), 2.77-2.53 (m, 2H), 2.14-0.58
(m, 49H); LC/MS: m/z calculated 791.4, found 792.3 (M+1).sup.+.
##STR00247## ##STR00248##
Example 62
Compound 124
4-(((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-Chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7-
a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)o-
xy)-2,2-dimethyl-4-oxobutanoic acid
##STR00249##
[0626] Step A: Intermediate 113
(3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(Hydroxymethyl)-1-isopropyl-5a,5b,8-
,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octad-
ecahydro-2H-cyclopenta[a]chrysen-9-yl acetate
[0627] To a solution of the intermediate 3 (5 g, 7.59 mmol) in EtOH
(100 mL) and toluene (100 mL) was added KOH (0.51 g, 9.11 mmol).
After stirring at room temperature for 4 h, the reaction mixture
was then partitioned between water (500 mL) and EtOAc (500 mL). The
organic phase was washed with water (200 mL.times.3), brine (100
mL), and dried over sodium sulfate. Removal of the solvent provided
a residue, which was purified by column chromatography on silica
gel (Hex:EtOAc=6:1 to 4:1) to afford the intermediate 113 (2.5 g,
67.9%) as a white solid. .sup.1H NMR (400 Hz, CDCl.sub.3) .delta.
ppm 4.50-4.67 (1H, m), 3.68 (1H, d, J=10.4 Hz), 3.32 (1H, d, J=10.4
Hz), 3.23-3.15 (1H, m), 2.42-2.28 (3H, m), 2.05 (3H, s), 2.02-1.89
(2H, m), 1.77-0.83 (40H, m).
Step B: Intermediate 114
(3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-Formyl-1-isopropyl-5a,5b,8,8,11a-pe-
ntamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl acetate
[0628] To a solution of the intermediate 113 (3 g, 6.19 mmol) in
DCM (75 mL) at room temperature were added PCC (4 g, 18.57 mmol)
and silica gel (3.0 g). After stirring at room temperature for 2 h,
the reaction was quenched with water (100 mL). The organic phase
was separated, washed with saturated sodium bicarbonate (50 mL),
dried over sodium sulfate and concentrated in vacuo to provide a
residue, which was purified by column chromatography on silica gel
(Hex:EtOAc=10:1) to afford the intermediate 114 (3 g, 100%) as a
white solid. .sup.1H NMR (400 Hz, CDCl.sub.3) .delta. ppm 9.43 (1H,
s), 4.50-4.46 (1H, m), 3.25-3.21 (1H, m), 2.43-2.02 (5H, m), 2.04
(3H, m), 2.00-1.93 (1H, m), 1.75-0.81 (38H, m).
Step C: Intermediate 115
(3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(1-Hydroxy-2-nitroethyl)-1-isopropy-
l-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,-
13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate
[0629] To a solution of the intermediate 114 (5 g, 10.36 mmol) in
MeNO.sub.2 (128 mL, 2382 mmol) was added Et.sub.3N (10.11 mL, 72.5
mmol). After it was stirred at 60.degree. C. overnight, the
reaction mixture was partitioned between water and EtOAc (100 mL
each). The organic phase was washed with water (20 mL.times.3),
brine (20 mL), and dried over sodium sulfate. Removal of the
solvent provided a residue, which was purified by column
chromatography on silica gel (Hex:EtOAc=10:1 to 6:1) to afford the
intermediate 115 (2.8 g, 49.7%) as a white powder. LC/MS: m/z
calculated 543.4, found 566.3 (M+Na.sup.+)+.
Step D: Intermediate 116
(3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-Amino-1-hydroxyethyl)-1-isopropy-
l-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,-
13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate
[0630] To a solution of the intermediate 115 (2.8 g, 5.15 mmol) in
MeOH (166 mL) were added nickel(II) chloride (1.67 g, 12.87 mmol)
and sodium borohydride (4.87 g, 129 mmol) at 0.degree. C. After
stirring at 0.degree. C. for 10 min, the reaction mixture was
partitioned between water and EtOAc (200 mL each), and the organic
phase was washed with water (100 mL.times.3), brine (50 mL), and
dried over sodium sulfate. Removal of the solvent provided the
intermediate 116 (2.65 g, 100%) as a solid. LC/MS: m/z calculated
513.4, found 514.3 (M+1)+.
Step E: Intermediate 118
(3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((tert-Butoxycarbonyl)(4-chlorob-
enzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,-
5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]c-
hrysen-9-yl acetate
[0631] To a solution of the intermediate 116 (350 mg, 0.613 mmol)
and 4-chlorobenzaldehyde (86 mg, 0.613 mmol) in MeOH (15 mL) and
dichloroethane (DCE, 15 mL) was added zinc chloride (50.1 mg, 0.368
mmol). After the reaction mixture was stirred at 80.degree. C. for
1 h and cooled down to room temperature, sodium cyanoborohydride
(57.8 mg, 0.92 mmol) was added. The resulting mixture was stirred
at room temperature for another 1 h to provide the intermediate
117.
[0632] To the reaction mixture obtained above were added Et.sub.3N
(0.18 mL, 1.38 mmol) and di-tert-butyl dicarbonate (0.157 mL, 0.674
mmol). After stirring at room temperature for 30 min, the reaction
mixture was partitioned between water (20 mL) and EtOAc (100 mL).
The organic phase was washed with water (30 mL.times.3), brine (20
mL), and dried over sodium sulfate. Removal of the solvent provided
a residue, which was purified by column chromatography on silica
gel (Hex:EtOAc=15:1) to afford the intermediate 118 (125 mg, 27.6%)
as a white solid.
Step F: Intermediate 119
(3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((tert-Butoxycarbonyl)(4-chlorob-
enzyl)amino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6-
,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9--
yl acetate
[0633] To a solution of the intermediate 118 (120 mg, 0.162 mmol)
in DCM (10 mL) were added PCC (35 mg, 0.162 mmol) and silica gel
(100 mg). After stirring at room temperature for 2 h, the insoluble
material was removed by filtration and the filtrate was
concentrated to afford the intermediate 119 (110 mg, 92%) as a
white solid.
Step G: Intermediate 120
tert-butyl
4-Chlorobenzyl(2-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-
-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a-
,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-oxoethyl)car-
bamate
[0634] To a solution of NaOH (597 mg, 14.94 mmol) in MeOH (1 mL),
THF (1 mL), and water (0.5 mL) was added the intermediate 119 (110
mg, 0.149 mmol). After stirring at room temperature for 1 h, the
reaction was diluted with water (20 mL), and extracted with EtOAc
(50 mL). The organic phase was washed with brine (20 mL), dried
over sodium sulfate, and evaporated in vacuo to afford the
intermediate 120 (100 mg, 96%) as a white solid.
Step H: Intermediate 121
4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((tert-butoxycarbonyl)(4-chlo-
robenzyl)amino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)1-tert-butyl 2,2-dimethylsuccinate
[0635] To a solution of 4-tert-butoxy-3,3-dimethyl-4-oxobutanoic
acid 10 (1.648 g, 8.15 mmol), DMAP (0.995 g, 8.15 mmol) in DCM (15
ml) stirred at rt was added EDCI (2.60 g, 13.58 mmol). The reaction
mixture was stirred at rt. for 2 h. Then tert-butyl
4-chlorobenzyl(2-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isoprop-
yl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13-
,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-oxoethyl)carbamate
120 (1.886 g, 2.72 mmol) was added to the reaction. The reaction
mixture was stirred at rt overnight. Upon completion, the mixture
was washed with water (25 mL.times.2) and brine, dried over sodium
sulfate filtered through a short silica gel column and evaporated
in vacuo to give the crude product which was further purified on a
silica gel column using petroleum ether/EtOAc (50:1 to 10:1) to
give intermediate 121 (2.37 g, 99%) as white foam.
Step I: Intermediates 122 and 123
4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((tert-Butoxycarbonyl)(4--
chlorobenzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl--
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclope-
nta[a]chrysen-9-yl) 1-tert-butyl 2,2-dimethylsuccinate (122) and
4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((tert-butoxycarbonyl)(4-
-chlorobenzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclop-
enta[a]chrysen-9-yl) 1-tert-butyl 2,2-dimethylsuccinate (123)
[0636] To a solution of and
4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((tert-butoxycarbonyl)(4-chl-
orobenzyl)amino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,-
5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chryse-
n-9-yl) 1-tert-butyl 2,2-dimethylsuccinate (121) (791 mg, 0.90
mmol) in MeOH (10 mL) and THF (10.00 mL) stirred at 0.degree. C.
was added NaBH.sub.4 (170 mg, 4.50 mmol). The reaction mixture was
stirred at rt for 2 h until starting material had disappeared. Upon
completion, silica gel was added and the mixture evaporated to
dryness and purified by silica gel chromatography (petroleum
ether/EtOAc, 40:1 to 10:1) to give the two diastereomeric products:
4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((tert-butoxycarbonyl)(4-
-chlorobenzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclop-
enta[a]chrysen-9-yl) 1-tert-butyl 2,2-dimethylsuccinate and
4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((tert-butoxycarbonyl)(4-
-chlorobenzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclop-
enta[a]chrysen-9-yl) 1-tert-butyl 2,2-dimethylsuccinate.
Stereochemistry was not confirmed but the diastereomers were
produced in the amount of (410 mg, 52%, tentatively assigned as
compound 122) and (77 mg, 10%, tentatively assigned as compound
123) as white foams.
Step J: Compound 124
4-(((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7-
a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)o-
xy)-2,2-dimethyl-4-oxobutanoic acid
[0637] To a solution of 122 (410 mg, 0.466 mmol) in DCM (10 mL) was
added TFA (2 mL, 26.0 mmol). The reaction mixture was stirred at rt
for 2 h. The reaction mixture was concentrated to dryness and
purified by preparative-HPLC to afford
4-(((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chlorobenzyl)amino)-
-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,-
7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)-
oxy)-2,2-dimethyl-4-oxobutanoic acid, trifluoroacetic acid salt
(124) (185 mg, 0.221 mmol, 47.4% yield) as white solid. .sup.1H NMR
(500 MHz, CHLOROFORM-d) .delta.=7.36 (q, J=8.5 Hz, 4H), 4.58-4.41
(m, 1H), 4.41-4.31 (m, 1H), 4.20-3.97 (m, 2H), 3.23-3.05 (m, 2H),
2.85-2.66 (m, 2H), 2.56 (d, J=16.1 Hz, 1H), 2.51-2.38 (m, 1H),
2.34-2.19 (m, 2H), 1.93-1.82 (m, 1H), 1.83-0.67 (m, 46H); LC/MS:
m/z calculated 723.5, found 724.3 (M+1).sup.+.
##STR00250##
Example 63
Compound 132
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(3,4-dihydroisoquinolin--
2(1H)-yl)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a-
,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[-
a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00251##
[0638] Step A: Intermediate 125
(3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamethyl--
2-oxo-3a-vinyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecah-
ydro-2H-cyclopenta[a]chrysen-9-yl acetate
[0639] To a cold (-78.degree. C.) solution of
methyltriphenylphosphonium bromide (8.63 g, 24.16 mmol) in THF (30
mL) was added lithium bis(trimethylsilyl)amide (4.4 g, 24.1 mmol)
in THF dropwise. The reaction was stirred at -78.degree. C. for 1
h, then 6 (10.0 g, 20.1 mmol) in THF (60 ml) was added. The mixture
was allowed to warm to rt and stirred for 1 h. TLC indicated the
reaction was complete. 2N HCl was added to the mixture and it was
extracted with ethyl acetate and washed with water and brine. The
organic phase was dried with Na.sub.2SO.sub.4 followed by
filtration and concentration followed by precipitation of the
desired product (10 g of 85% purity, 85% chemical yield) with 5%
EtOAc/petroleum ether.
Step B: Intermediate 126
(3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pe-
ntamethyl-3a-vinyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octad-
ecahydro-2H-cyclopenta[a]chrysen-2-one
[0640] To a solution of 125 (16 g, 32.3 mmol) in 1,4-dioxane (300
mL) and MeOH (30 ml) stirred at rt was added HCl (37%) (150 mL,
32.3 mmol). The reaction mixture was stirred at 60.degree. C. for 3
h. TLC and LCMS indicated the starting material was consumed
completely. Water was added and the volatiles were concentrated, a
resultant precipitate was filtered and washed with water. The cake
was dried to give 126 (14 g, 81%).
Step C: Intermediate 127
1-tert-butyl
4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-vinyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octad-
ecahydro-2H-cyclopenta[a]chrysen-9-yl)2,2-dimethylsuccinate
[0641] To a solution of 10 (14.52 g, 71.8 mmol), DMAP (10.52 g, 86
mmol) and 126 (13 g, 28.7 mmol) in dichloromethane (150 mL) was
added EDC (27.5 g, 144 mmol). The mixture was stirred at rt for 2
h, at which time TLC indicated the reaction was complete. The
reaction was washed with 2N HCl, and brine. The organics were dried
with Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by silica gel chromatography to give 127 (9.5 g, 49%)
alogn with an additional 4 g impure product requiring
repurification prior to further use.
Step D: Intermediates 128 and 129
1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-3a-((S)-oxiran-2-yl)-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,-
13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)
2,2-dimethylsuccinate (128) and 1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-((3a-((R)-oxiran-2-yl)-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,1-
2,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)
2,2-dimethylsuccinate (129)
[0642] To a solution of 127 (8.5 g, 13.34 mmol) in DCM (90 mL) at
rt was added m-CPBA (5.42 g, 26.7 mmol). The reaction mixture was
stirred at rt overnight. The mixture was further diluted with DCM
150 ml then washed with saturated NaHCO.sub.3, water and brine
(note for safety reasons this the excess peroxide should be
neutralized but was not in this specific procedure). The organic
phase was concentrated and purified by silica gel chromatography
(EtOAc/PE 5% to 15%) to give 128 (2.0 g, 21%) and 129 (800 mg, 8%)
along with 2.4 g of recovered starting material. For 128: .sup.1H
NMR (500 MHz, CHLOROFORM-d) .quadrature.=4.51 (dd, J=5.4, 11.3 Hz,
1H), 3.26-3.12 (m, 3H), 2.66 (t, J=4.4 Hz, 1H), 2.54 (s, 2H), 2.35
(dd, J=2.7, 4.6 Hz, 1H), 2.18 (d, J=18.3 Hz, 1H), 2.12-1.93 (m,
3H), 1.91-0.74 (m, 52H); LC/MS: m/z calculated 652.5, found 653.3
(M+1).sup.+. For 129: .sup.1H NMR (500 MHz, CHLOROFORM-d)
.delta.=4.51 (dd, J=5.0, 11.3 Hz, 1H), 3.26-3.07 (m, 2H), 3.00 (dd,
J=3.2, 12.6 Hz, 1H), 2.69 (t, J=4.3 Hz, 1H), 2.59-2.41 (m, 3H),
2.21-0.76 (m, 56H); LC/MS: m/z calculated 652.5, found 653.3
(M+1).sup.+.
Step E: Intermediate 131
1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(3,4-dihydroisoquinolin--
2(1H)-yl)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a-
,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[-
a]chrysen-9-yl) 2,2-dimethylsuccinate
[0643] To a solution of 1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-3a-((R)-oxiran-2-yl)-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,-
13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)
2,2-dimethylsuccinate (0.2 g, 0.306 mmol) in tert-butanol (3 mL)
was added 1,2,3,4-tetrahydroisoquinoline (0.408 g, 3.06 mmol). The
reaction mixture was stirred at 100.degree. C. for 5 h. Upon
completion and cooling, EtOAc was added and the mixture was washed
with 4N HCl, and brine, then dried with Na.sub.2SO.sub.4, filtered
and concentrated to give 132 (200 mg, 66%) which was used without
further purification. LC/MS: m/z calculated 785.6, found 786.5
(M+1).sup.+.
Step F: Compound 132
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(3,4-dihydroisoquinolin--
2(1H)-yl)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a-
,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[-
a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
[0644] To a solution of 131 (0.2 g, 0.254 mmol) in DCM (2 mL) was
added TFA (1 mL, 12.98 mmol). The reaction mixture was stirred at
rt for 1 h then concentrated. The residue was purified by
preparative-HPLC to give the title compound (106 mg, 48%) as a TFA
salt as white solid. .sup.1H NMR (500 MHz, METHANOL-d.sub.4)
.delta.=7.43-7.15 (m, 4H), 4.66-4.41 (m, 4H), 3.28-3.05 (m, 3H),
3.05-2.83 (m, 2H), 2.73-2.52 (m, 3H), 2.30 (d, J=13.9 Hz, 1H),
2.16-2.03 (m, 1H), 2.00-0.72 (m, 48H); LC/MS: m/z calculated 729.5,
found 730.5 (M+1).sup.+.
[0645] The Examples below were made in a similar manner to the
above examples or via combinations or re-ordering of the methods
described and/or usage of other methods well known to those skilled
in the art.
Example 64
Compound 133
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(3,4-dihydroisoquinolin--
2(1H)-yl)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a-
,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[-
a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00252##
[0647] Stereochemistry was tentatively assigned as drawn but not
fully confirmed spectroscopically. LC/MS: m/z calculated 729.5,
found 730.5 (M+1).sup.+.
Example 65
Compound 134
4-(((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(4-methylpiper-
azin-1-yl)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,-
7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)-
oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00253##
[0649] Isolated as a mixture of diastereomers. LC/MS: m/z
calculated 682.53, found 683.5 (M+1).sup.+.
Example 66
Compound 135
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)amino)ethyl-
)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11-
a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimeth-
yl-4-oxobutanoic acid
##STR00254##
[0651] LC/MS: m/z calculated 707.5, found 708.3 (M+1).sup.+.
Example 67
Compound 136
4-(((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((cyclohexylmethyl)amino-
)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7-
,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl-
)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00255##
[0653] Stereochemistry was tentatively assigned as drawn but not
fully confirmed spectroscopically. LC/MS: m/z calculated 695.6,
found 696.5 (M+1).sup.+.
Example 68
Compound 137
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(cyclohexylamino)-1-hydr-
oxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7-
a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)o-
xy)-2,2-dimethyl-4-oxobutanoic acid
##STR00256##
[0655] Stereochemistry was tentatively assigned as drawn but not
fully confirmed spectroscopically. LC/MS: m/z calculated 695.5,
found 696.5 (M+1).sup.+.
Example 69
Compound 138
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((S)-2-(benzyl(2-(dimethylamino-
)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo--
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclope-
nta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00257##
[0657] Stereochemistry was tentatively assigned as drawn but not
fully confirmed spectroscopically. LC/MS: m/z calculated 774.6,
found 775.5 (M+1).sup.+.
Example 70
Compound 139
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-((2-(dimethyla-
mino)ethyl)(4-fluorobenzyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00258##
[0659] Stereochemistry was tentatively assigned as drawn but not
fully confirmed spectroscopically. LC/MS: m/z calculated 834.6,
found 835 (M+1).sup.+.
Example 71
Compound 140
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-acetoxy-2-((2-(dimethyla-
mino)ethyl)(4-fluorobenzyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00259##
[0661] Stereochemistry was tentatively assigned as drawn but not
fully confirmed spectroscopically. LC/MS: m/z calculated 834.6,
found 835 (M+1).sup.+.
Example 72
Compound 141
5-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid
##STR00260##
[0663] Stereochemistry was tentatively assigned as drawn but not
fully confirmed spectroscopically. LC/MS: m/z calculated 751.5,
found 752.3 (M+1).sup.+.
Example 73
Compound 142
5-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid
##STR00261##
[0665] Stereochemistry was tentatively assigned as drawn but not
fully confirmed spectroscopically. LC/MS: m/z calculated 751.5,
found 752.3 (M+1).sup.+.
Example 74
Compound 143
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((2,4-dichlorobenzyl)(2--
(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pent-
amethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahy-
dro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00262##
[0667] Stereochemistry was tentatively assigned as drawn but not
fully confirmed spectroscopically. LC/MS: m/z calculated 842.5,
found 843.3 (M+1).sup.+.
Example 75
Compound 144
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(benzyl(2-(dimethylamino-
)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo--
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclope-
nta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00263##
[0669] Stereochemistry was tentatively assigned as drawn but not
fully confirmed spectroscopically. LC/MS: m/z calculated 774.6,
found 775.4 (M+1).sup.+.
Example 76
Compound 145
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)ethyl-
)(4-fluorobenzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00264##
[0671] Stereochemistry was tentatively assigned as drawn but not
fully confirmed spectroscopically. LC/MS: m/z calculated 792.5,
found 793.5 (M+1).sup.+.
Example 77
Compound 146
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-fluorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00265##
[0673] Stereochemistry was tentatively assigned as drawn but not
fully confirmed spectroscopically. LC/MS: m/z calculated 721.5,
found 722.3 (M+1).sup.+.
Example 78
Compound 147
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2((2-(dimethylamino)ethyl)-
(4-fluorobenzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentameth-
yl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2-
H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00266##
[0675] Stereochemistry was tentatively assigned as drawn but not
fully confirmed spectroscopically. LC/MS: m/z calculated 792.5,
found 793.5 (M+1).sup.+.
Example 79
Compound 148
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-fluorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00267##
[0677] Stereochemistry was tentatively assigned as drawn but not
fully confirmed spectroscopically. LC/MS: m/z calculated 721.5,
found 722.3 (M+1).sup.+.
Example 80
Compound 149
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2,4-dichlorobenzyl)(2--
(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pent-
amethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahy-
dro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00268##
[0679] Stereochemistry was tentatively assigned as drawn but not
fully confirmed spectroscopically. LC/MS: m/z calculated 842.5,
found 843.5 (M+1).sup.+.
Example 81
Compound 150
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(4-chloro-N-(2-(dimethyl-
amino)ethyl)benzamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentameth-
yl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2-
H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00269##
[0681] Stereochemistry was tentatively assigned as drawn but not
fully confirmed spectroscopically. LC/MS: m/z calculated 822.5,
found 823.4 (M+1).sup.+.
Example 82
Compound 151
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((2-chlorobenzyl)amino)ethyl-
)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10-
,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2--
dimethyl-4-oxobutanoic acid
##STR00270##
[0683] LC/MS: m/z calculated 721.5, found 722.3 (M+1).sup.+.
Example 83
Compound 152
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-benzamidoethyl)-1-isopropyl--
5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12-
,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxo-
butanoic acid
##STR00271##
[0685] LC/MS: m/z calculated 701.5, found 702.5 (M+1).sup.+.
Example 84
Compound 153
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((((R)-1-(4-Chlorophenyl)ethyl)-
amino)methyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6-
,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9--
yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00272##
[0687] LC/MS: m/z calculated 721.5, found 722.3 (M+1).sup.+.
Example 85
Compound 154
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((N-(4-chlorobenzyl)acetamido)m-
ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8-
,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-
-2,2-dimethyl-4-oxobutanoic acid
##STR00273##
[0689] LC/MS: m/z calculated 749.4, found 750.3 (M+1).sup.+.
Example 86
Compound 155
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(((4-chlorobenzyl)amino)methyl)-
-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,-
11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-d-
imethyl-4-oxobutanoic acid
##STR00274##
[0691] LC/MS: m/z calculated 707.4, found 708.3 (M+1).sup.+.
Example 87
Compound 156
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((N-(4-chlorophenethyl)acetamid-
o)methyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7-
a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)o-
xy)-2,2-dimethyl-4-oxobutanoic acid
##STR00275##
[0693] LC/MS: m/z calculated 763.5, found 764.3 (M+1).sup.+.
Example 88
Compound 157
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(((4-chlorophenethyl)amino)meth-
yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,-
10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,-
2-dimethyl-4-oxobutanoic acid
##STR00276##
[0695] LC/MS: m/z calculated 721.5, found 722.3 (M+1).sup.+
Example 89
Compound 158
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(3-meth-
oxypropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-o-
xo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cycl-
openta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00277##
[0697] LC/MS: m/z calculated 809.50, found 810.7 (M+1).sup.+
Example 90
Compound 159
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chlorobenzyl)(3-meth-
oxypropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-o-
xo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cycl-
openta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00278##
[0699] LC/MS: m/z calculated 809.5, found 810.4 (M+1).sup.+
Example 91
Compound 160
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-meth-
oxyethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-ox-
o-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclo-
penta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00279##
[0701] LC/MS: m/z calculated 795.5, found 796.3 (M+1).sup.+
Example 92
Compound 161
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chlorobenzyl)(2-meth-
oxyethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-ox-
o-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclo-
penta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00280##
[0703] LC/MS: m/z calculated 795.5, found 796.3 (M+1).sup.+
Example 93
Compound 162
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(4-chloro-N-(2-(dimethyl-
amino)ethyl)benzamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentameth-
yl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2-
H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00281##
[0705] LC/MS: m/z calculated 822.5, found 823.5 (M+1).sup.+
Example 94
Compound 163
4-(((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-(dim-
ethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyc-
lopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00282##
[0707] LC/MS: m/z calculated 794.5, found 795.5 (M+1).sup.+
Example 95
Compound 164
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)((R)-py-
rrolidin-2-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-penta-
methyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahyd-
ro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00283##
[0709] LC/MS: m/z calculated 820.5, found 821.5 (M+1).sup.+
Example 96
Compound 165
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chlorobenzyl)((R)-py-
rrolidin-2-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-penta-
methyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahyd-
ro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00284##
[0711] LC/MS: m/z calculated 820.5, found 821.5 (M+1).sup.+
Example 97
Compound 166
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-hydr-
oxyethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-ox-
o-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclo-
penta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00285##
[0713] LC/MS: m/z calculated 781.5, found 782.5 (M+1).sup.+
Example 98
Compound 167
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-4-(4-chlorobenzyl)-5,6-dio-
xomorpholin-2-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,-
5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chryse-
n-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00286##
[0715] LC/MS: m/z calculated 791.4, found 792.5 (M+1).sup.+
Example 99
Compound 168
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(((5-chloropyridin-2-yl)-
methyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo--
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclope-
nta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00287##
[0717] LC/MS: m/z calculated 738.4, found 739.5 (M+1).sup.+
Example 100
Compound 169
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-4-(4-chlorobenzyl)-5-oxomo-
rpholin-2-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6-
,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9--
yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00288##
[0719] LC/MS: m/z calculated 777.4, found 778.6 (M+1).sup.+
Example 101
Compound 170
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-4-(4-chlorobenzyl)-6-oxomo-
rpholin-2-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6-
,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9--
yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00289##
[0721] LC/MS: m/z calculated 777.4, found 777.9 (M+1).sup.+
Example 102
Compound 171
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-4-(4-chlorobenzyl)-5-oxomo-
rpholin-2-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6-
,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9--
yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00290##
[0723] LC/MS: m/z calculated 777.4, found 777.9 (M+1).sup.+
Example 103
Compound 172
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(((5-chloropyridin-2-yl)-
methyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo--
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclope-
nta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00291##
[0725] LC/MS: m/z calculated 737.4, found 739.4 (M+1).sup.+
Example 104
Compound 173
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chlorobenzyl)(2-hydr-
oxyethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-ox-
o-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclo-
penta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00292##
[0727] LC/MS: m/z calculated 781.5, found 782.3 (M+1).sup.+
Example 105
Compound 174
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-(((4-chlorobenzyl)(2-(dimethyla-
mino)ethyl)amino)methyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,-
4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a-
]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00293##
[0729] LC/MS: m/z calculated 778.5, found 779.5 (M+1).sup.+
Example 106
Compound 175
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(((4-chlorophenethyl)(2-(dimeth-
ylamino)ethyl)amino)methyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,-
3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopent-
a[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00294##
[0731] LC/MS: m/z calculated 792.5, found 793.5 (M+1).sup.+
Example 107
Compound 176
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((S)-2-(N-(4-chlorobenzyl)-2-(d-
imethylamino)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00295##
[0733] LC/MS: m/z calculated 822.5, found 823.5 (M+1).sup.+
Example 108
Compound 177
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-(4-chlorobenzyl)-2-(d-
imethylamino)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00296##
[0735] LC/MS: m/z calculated 822.5, found 823.5 (M+1).sup.+
Example 109
Compound 178
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-(pyr-
rolidin-1-yl)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentam-
ethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydr-
o-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00297##
[0737] LC/MS: m/z calculated 834.5, found 835.5 (M+1).sup.+
Example 110
Compound 179
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chlorobenzyl)(2-(pyr-
rolidin-1-yl)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentam-
ethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydr-
o-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00298##
[0739] LC/MS: m/z calculated 834.5, found 835.5 (M+1).sup.+
Example 111
Compound 180
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-(met-
hylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethy-
l-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-
-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00299##
[0741] LC/MS: m/z calculated 794.5, found 795.4 (M+1).sup.+
Example 112
Compound 181
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((2-aminoethyl)(4-chloro-
benzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo--
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclope-
nta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00300##
[0743] LC/MS: m/z calculated 780.5, found 781.4 (M+1).sup.+
Example 113
Compound 182
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-aminoethyl)(4-chloro-
benzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo--
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclope-
nta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00301##
[0745] LC/MS: m/z calculated 780.5, found 781.4 (M+1).sup.+
Example 114
Compound 183
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chlorobenzyl)(2-(met-
hylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethy-
l-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-
-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00302##
[0747] LC/MS: m/z calculated 794.5, found 795.5 (M+1).sup.+
Example 115
Compound 184
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-(N-m-
ethylacetamido)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pent-
amethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahy-
dro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00303##
[0749] LC/MS: m/z calculated 836.5, found 837.5 (M+1).sup.+
Example 116
Compound 185
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chlorobenzyl)(2-(N-m-
ethylacetamido)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pent-
amethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahy-
dro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00304##
[0751] LC/MS: m/z calculated 836.5, found 837.5 (M+1).sup.+
Example 117
Compound 186
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((S)-2-(((S)-1-(5-chloropyridin-
-2-yl)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-
-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cy-
clopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00305##
[0753] LC/MS: m/z calculated 752.5, found 753.4 (M+1).sup.+
Example 118
Compound 187
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(((S)-1-(5-chloropyridin-
-2-yl)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-
-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cy-
clopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00306##
[0755] LC/MS: m/z calculated 752.5, found 753.4 (M+1).sup.+
Example 119
Compound 188
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)ethyl-
)(phenethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-
-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cy-
clopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00307##
[0757] LC/MS: m/z calculated 788.6, found 789.5 (M+1).sup.+
Example 120
Compound 189
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(cyclohexyl(2-(dimethyla-
mino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2--
oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyc-
lopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00308##
[0759] LC/MS: m/z calculated 766.6, found 767.6 (M+1).sup.+
Example 121
Compound 190
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(cyclohexyl(2-(dimethyla-
mino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2--
oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyc-
lopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00309##
[0761] LC/MS: m/z calculated 766.6, found 767.6 (M+1).sup.+
Example 122
Compound 191
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(((5-chloropyridin-2-yl)-
methyl)(2-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,-
8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a--
octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00310##
[0763] LC/MS: m/z calculated 809.5, found 810.5 (M+1).sup.+
Example 123
Compound 192
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(N-(4-chlorobenzyl)-2-(dimet-
hylamino)acetamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a-
,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[-
a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00311##
[0765] LC/MS: m/z calculated 806.5, found 807.4 (M+1).sup.+
Example 124
Compound 193
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(2-amino-N-(4-chlorobenzyl)a-
cetamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00312##
[0767] LC/MS: m/z calculated 778.5, found 779.4 (M+1).sup.+
Example 125
Compound 194
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(N-(4-chlorobenzyl)-2-(methy-
lamino)acetamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4-
,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]-
chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00313##
[0769] LC/MS: m/z calculated 792.5, found 793.4 (M+1).sup.+
Example 126
Compound 195
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(((S)-2-(dimethylamino)--
1-phenylethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00314##
[0771] LC/MS: m/z calculated 760.5, found 761.5 (M+1).sup.+
Example 127
Compound 196
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(((R)-2-(dimethylamino)--
1-phenylethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00315##
[0773] LC/MS: m/z calculated 760.5, found 761.5 (M+1).sup.+
Example 128
Compound 197
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(((R)-2-(dimethylamino)--
1-phenylethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00316##
[0775] LC/MS: m/z calculated 760.5, found 761.5 (M+1).sup.+
Example 129
Compound 198
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(3-(dim-
ethylamino)propyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentame-
thyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-
-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00317##
[0777] LC/MS: m/z calculated 822.5, found 823.5 (M+1).sup.+
Example 130
Compound 199
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chlorobenzyl)(3-(dim-
ethylamino)propyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentame-
thyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-
-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00318##
[0779] LC/MS: m/z calculated 822.5, found 823.5 (M+1).sup.+
Example 131
Compound 200
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-(2-(phenethylamino)ethyl)-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a-
,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethy-
l-4-oxobutanoic acid
##STR00319##
[0781] LC/MS: m/z calculated 701.5, found 702.5 (M+1).sup.+
Example 132
Compound 201
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)ethyl-
)(isopropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-
-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cy-
clopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00320##
[0783] LC/MS: m/z calculated 726.5, found 727.5 (M+1).sup.+
Example 133
Compound 202
2-(((R)-2-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-((3-carboxy-3-methylbutan-
oyl)oxy)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a-
,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)--
2-hydroxyethyl)(4-chlorobenzyl)amino)-N,N,N-trimethylethanaminium
trifluoroacetate.
##STR00321##
[0785] LC/MS: m/z calculated 823.5, found 823.5 (M).sup.+
Example 134
Compound 203
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-4-(4-chlorobenzyl)-6-oxomo-
rpholin-2-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6-
,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9--
yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00322##
[0787] LC/MS: m/z calculated 777.4, found 778.4 (M+1).sup.+
Example 135
Compound 204
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(((S)-2-(dimethylamino)--
1-phenylethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00323##
[0789] LC/MS: m/z calculated 760.5, found 761.4 (M+1).sup.+
Example 136
Compound 205
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((2-(dimethylamino)ethyl-
)(isopropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-
-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cy-
clopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00324##
[0791] LC/MS: m/z calculated 726.6, found 727.5 (M+1).sup.+
Example 137
Compound 206
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(((5-chloropyridin-2-yl)-
methyl)(2-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,-
8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a--
octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00325##
[0793] LC/MS: m/z calculated 809.5, found 810.5 (M+1).sup.+
Example 138
Compound 207
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-(isopropylamin-
o)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a-
,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)ox-
y)-2,2-dimethyl-4-oxobutanoic acid
##STR00326##
[0795] LC/MS: m/z calculated 655.5, found 656.4 (M+1).sup.+
Example 139
Compound 208
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(((R)-2-(dimethylamino)-1-ph-
enylethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,-
5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]c-
hrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00327##
[0797] LC/MS: m/z calculated 744.5, found 745.5 (M+1).sup.+
Example 140
Compound 209
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(((S)-2-(dimethylamino)-1-ph-
enylethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,-
5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]c-
hrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00328##
[0799] LC/MS: m/z calculated 744.5, found 745.5 (M+1).sup.+
Example 141
Compound 210
2-(((S)-2-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-((3-carboxy-3-methylbutan-
oyl)oxy)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a-
,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)--
2-hydroxyethyl)(4-chlorobenzyl)amino)-N,N,N-trimethylethanaminium
trifluoroacetate.
##STR00329##
[0801] LC/MS: m/z calculated 823.5, found 823.5 (M).sup.+
Example 142
Compound 211
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-4-(4-chlorobenzyl)-6-oxopi-
perazin-2-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6-
,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9--
yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00330##
[0803] LC/MS: m/z calculated 776.5, found 777.4 (M+1).sup.+
Example 143
Compound 212
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((S)-4-(4-chlorobenzyl)-1-methy-
l-6-oxopiperazin-2-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,-
5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]c-
hrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00331##
[0805] LC/MS: m/z calculated 790.5, found 791.4 (M+1).sup.+
Example 144
Compound 213
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-(dim-
ethylamino)ethyl)amino)-1-methoxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00332##
[0807] LC/MS: m/z calculated 822.5, found 823.5 (M+1).sup.+
Example 145
Compound 214
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-(piperidin-1-y-
l)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a-
,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)ox-
y)-2,2-dimethyl-4-oxobutanoic acid
##STR00333##
[0809] LC/MS: m/z calculated 681.5, found 682.5 (M+1).sup.+
Example 146
Compound 215
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(piperidin-1-y-
l)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a-
,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)ox-
y)-2,2-dimethyl-4-oxobutanoic acid
##STR00334##
[0811] LC/MS: m/z calculated 681.5, found 682.5 (M+1).sup.+
Example 147
Compound 216
4-(((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7-
a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)o-
xy)-2,2-dimethyl-4-oxobutanoic acid
##STR00335##
[0813] LC/MS: m/z calculated 723.5, found 724.4 (M+1).sup.+
Example 148
Compound 217
4-(((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7-
a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)o-
xy)-2,2-dimethyl-4-oxobutanoic acid
##STR00336##
[0815] LC/MS: m/z calculated 653.5, found 654.4 (M+1).sup.+
Example 149
Compound 218
4-(((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7-
a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)o-
xy)-2,2-dimethyl-4-oxobutanoic acid
##STR00337##
[0817] LC/MS: m/z calculated 653.5, found 654.4 (M+1).sup.+
Example 150
Compound 219
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chlorobenzyl)(2-(dim-
ethylamino)ethyl)amino)-1-methoxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00338##
[0819] LC/MS: m/z calculated 822.5, found 823.5 (M+1).sup.+
Example 151
Compound 220
5-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(benzylamino)-1-hydroxye-
thyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,-
9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)--
3,3-dimethyl-5-oxopentanoic acid
##STR00339##
[0821] LC/MS: m/z calculated 717.5, found 718.5 (M+1).sup.+
Example 152
Compound 221
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)amino)--
1-methoxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00340##
[0823] LC/MS: m/z calculated 751.5, found 752.5 (M+1).sup.+
Example 153
Compound 222
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chlorobenzyl)amino)--
1-methoxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00341##
[0825] LC/MS: m/z calculated 751.5, found 752.5 (M+1).sup.+
Example 154
Compound 223
5-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(2-(dimethylamino)-N-(4--
fluorobenzyl)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic
acid
##STR00342##
[0827] LC/MS: m/z calculated 820.5, found 821.5 (M+1).sup.+
Example 155
Compound 224
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((cyclohexylmethyl)amino-
)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,-
5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chryse-
n-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00343##
[0829] LC/MS: m/z calculated 709.5, found 710.6 (M+1).sup.+
Example 156
Compound 225
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((S)-4-(4-chlorobenzyl)-1-methy-
l-5-oxopiperazin-2-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,-
5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]c-
hrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00344##
[0831] LC/MS: m/z calculated 790.5, found 791.5 (M+1).sup.+
Example 157
Compound 226
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((cyclohexylmethyl)(2-(d-
imethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentam-
ethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydr-
o-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00345##
[0833] LC/MS: m/z calculated 780.6, found 781.5 (M+1).sup.+
Example 158
Compound 227
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((cyclopropylmethyl)(2-(-
dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-penta-
methyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahyd-
ro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00346##
[0835] LC/MS: m/z calculated 738.6, found 739.8 (M+1).sup.+
Example 159
Compound 228
2-(2-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(benzylamino)-1-hydro-
xyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a-
,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)ox-
y)-2-oxoethoxy)acetic acid
##STR00347##
[0837] LC/MS: m/z calculated 691.4, found 692.5 (M+1).sup.+
Example 160
Compound 229
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chloro-2-((dimethylamino-
)methyl)benzyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,-
3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopent-
a[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00348##
[0839] LC/MS: m/z calculated 778.5, found 779.5 (M+1).sup.+
Example 161
Compound 230
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(N-(4-chloro-2-((dimethylami-
no)methyl)benzyl)acetamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2--
oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyc-
lopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00349##
[0841] LC/MS: m/z calculated 820.5, found 821.7 (M+1).sup.+
Example 162
Compound 231
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(N-(4-chloro-2-((dimethylami-
no)methyl)benzyl)acetamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2--
oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyc-
lopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00350##
[0843] LC/MS: m/z calculated 717.5, found 718.5 (M+1).sup.+
Example 163
Compound 232
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-benzamido-1-hydroxyethyl-
)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10-
,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2--
dimethyl-4-oxobutanoic acid
##STR00351##
[0845] LC/MS: m/z calculated 717.5, found 718.5 (M+1).sup.+
Example 164
Compound 233
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(N-methylbenza-
mido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7-
,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl-
)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00352##
[0847] LC/MS: m/z calculated 731.5, found 732.3 (M+1).sup.+
Example 165
Compound 234
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-(N-methylbenza-
mido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7-
,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl-
)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00353##
[0849] LC/MS: m/z calculated 731.5, found 732.5 (M+1).sup.+
Example 166
Compound 235
4-(((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chlorobenzyl)(2-(dim-
ethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyc-
lopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00354##
[0851] LC/MS: m/z calculated 794.5, found 795.7 (M+1).sup.+
Example 167
Compound 236
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-(2-(dimethylamino)-N-(py-
ridin-2-ylmethyl)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pent-
amethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahy-
dro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00355##
[0853] LC/MS: m/z calculated 789.5, found 790.5 (M+1).sup.+
Example 168
Compound 237
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(2-(methylamin-
o)-N-(pyridin-2-ylmethyl)acetamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentam-
ethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydr-
o-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00356##
[0855] LC/MS: m/z calculated 775.5, found 776.5 (M+1).sup.+
Example 169
Compound 238
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chloro-2-((dimethylamino-
)methyl)benzyl)(methyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl--
2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-c-
yclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00357##
[0857] LC/MS: m/z calculated 792.5, found 793.5 (M+1).sup.+
Example 170
Compound 239
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-acetoxy-2-((2-chlorobenz-
yl)(2-(dimethylamino)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00358##
[0859] LC/MS: m/z calculated 850.5, found 851.5 (M+1).sup.+
Example 171
Compound 240
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(2-amino-N-benzylacetami-
do)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5-
a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chry-
sen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00359##
[0861] LC/MS: m/z calculated 760.5, found 761.5 (M+1).sup.+
Example 172
Compound 241
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-benzyl-2-(methylamino-
)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,-
3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopent-
a[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00360##
[0863] LC/MS: m/z calculated 774.5, found 775.5 (M+1).sup.+
Example 173
Compound 242
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-(N-benzyl-2-(dimethylami-
no)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo--
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclope-
nta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00361##
[0865] LC/MS: m/z calculated 788.5, found 789.5 (M+1).sup.+
Example 174
Compound 243
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-(2-amino-N-(pyridin-2-yl-
methyl)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2--
oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyc-
lopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00362##
[0867] LC/MS: m/z calculated 761.5, found 762.5 (M+1).sup.+
Example 175
Compound 244
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(((R)-1-(5-chloropyridin-
-2-yl)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-
-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cy-
clopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00363##
[0869] LC/MS: m/z calculated 752.5, found 753.5 (M+1).sup.+
Example 176
Compound 245
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-(((R)-1-(5-chloropyridin-
-2-yl)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-
-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cy-
clopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00364##
[0871] LC/MS: m/z calculated 752.5, found 753.4 (M+1).sup.+
Example 177
Compound 246
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N--((R)-1-(5-chloropyri-
din-2-yl)ethyl)-2-(dimethylamino)acetamido)-1-hydroxyethyl)-1-isopropyl-5a-
,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,1-
3,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobu-
tanoic acid
##STR00365##
[0873] LC/MS: m/z calculated 837.5, found 838.5 (M+1).sup.+
Example 178
Compound 247
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((2-(dimethylamino)ethyl-
)(phenethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-
-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cy-
clopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00366##
[0875] LC/MS: m/z calculated 788.6, found 789.5 (M+1).sup.+
Example 179
Compound 248
5-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-benzyl-2-(dimethylami-
no)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo--
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclope-
nta[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid
##STR00367##
[0877] LC/MS: m/z calculated 802.6, found 803.5 (M+1).sup.+
Example 180
Compound 249
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-(2-(dimethylamino)eth-
yl)cyclohexanecarboxamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-penta-
methyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahyd-
ro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00368##
[0879] LC/MS: m/z calculated 794.6, found 795.5 (M+1).sup.+
Example 181
Compound 250
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(cyclohexanecarboxamido)-
-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00369##
[0881] LC/MS: m/z calculated 723.5, found 724.5 (M+1).sup.+
Example 182
Compound 251
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(2-amino-N--((S)-1-(5-ch-
loropyridin-2-yl)ethyl)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11-
a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octa-
decahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00370##
[0883] LC/MS: m/z calculated 809.5, found 810.4 (M+1).sup.+
Example 183
Compound 252
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-(N--((S)-1-(5-chloropyri-
din-2-yl)ethyl)-2-(methylamino)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5-
b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,-
13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobuta-
noic acid
##STR00371##
[0885] LC/MS: m/z calculated 823.5, found 824.5 (M+1).sup.+
Example 184
Compound 253
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N--((S)-1-(5-chloropyri-
din-2-yl)ethyl)-2-(dimethylamino)acetamido)-1-hydroxyethyl)-1-isopropyl-5a-
,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,1-
3,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobu-
tanoic acid
##STR00372##
[0887] LC/MS: m/z calculated 837.5, found 838.5 (M+1).sup.+
Example 185
Compound 254
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((2-aminoethyl)(benzyl)a-
mino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00373##
[0889] LC/MS: m/z calculated 746.5, found 747.5 (M+1).sup.+
Example 186
Compound 255
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((cyclobutylmethyl)amino-
)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,-
5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chryse-
n-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00374##
[0891] LC/MS: m/z calculated 681.5, found 682.5 (M+1).sup.+
Example 187
Compound 256
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-acetoxy-2-(benzyl(2-(dim-
ethylamino)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo--
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclope-
nta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00375##
[0893] LC/MS: m/z calculated 816.6, found 817.5 (M+1).sup.+
Example 188
Compound 257
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-(benzyl(2-(dim-
ethylamino)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo--
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclope-
nta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00376##
[0895] LC/MS: m/z calculated 816.6, found 817.5 (M+1).sup.+
Example 189
Compound 258
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(cyclohexanecarboxamido)-
-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00377##
[0897] LC/MS: m/z calculated 723.5, found 724.5 (M+1).sup.+
Example 190
Compound 259
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((cyclobutylmethyl)amino-
)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,-
5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chryse-
n-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00378##
[0899] LC/MS: m/z calculated 681.5, found 682.5 (M+1).sup.+
Example 191
Compound 260
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(N-(2-(dimethylamino)eth-
yl)cyclohexanecarboxamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-penta-
methyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahyd-
ro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00379##
[0901] LC/MS: m/z calculated 794.6, found 795.6 (M+1).sup.+
Example 192
Compound 261
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((cyclobutylmethyl)(2-(d-
imethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentam-
ethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydr-
o-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00380##
[0903] LC/MS: m/z calculated 752.6, found 753.6 (M+1).sup.+
Example 193
Compound 262
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(((1H-pyrazol-3-yl)methy-
l)(2-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-
-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octad-
ecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00381##
[0905] LC/MS: m/z calculated 764.6, found 765.5 (M+1).sup.+
Example 194
Compound 263
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((cyclopropylmethyl)amin-
o)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a-
,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrys-
en-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00382##
[0907] LC/MS: m/z calculated 667.5, found 668.5 (M+1).sup.+
Example 195
Compound 264
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((1S)-1-hydroxy-2-((2-hydroxy-2-
-phenylethyl)(methyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2--
oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyc-
lopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00383##
[0909] LC/MS: m/z calculated 747.5, found 748.5 (M+1).sup.+
Example 196
Compound 265
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-((2-(pyridin-3-
-yl)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,-
5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]c-
hrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00384##
[0911] LC/MS: m/z calculated 718.5, found 719.5 (M+1).sup.+
Example 197
Compound 266
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-((R)-3-hydroxy-
piperidin-1-yl)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00385##
[0913] LC/MS: m/z calculated 697.5, found 698.5 (M+1).sup.+
Example 198
Compound 267
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-((3-(2-oxopyrr-
olidin-1-yl)propyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-ox-
o-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclo-
penta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00386##
[0915] LC/MS: m/z calculated 738.5, found 739.5 (M+1).sup.+
Example 199
Compound 268
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-((2-phenoxyeth-
yl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00387##
[0917] LC/MS: m/z calculated 733.5, found 734.5 (M+1).sup.+
Example 200
Compound 269
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-(4-(2-hydroxye-
thyl)piperazin-1-yl)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3-
a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta-
[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00388##
[0919] LC/MS: m/z calculated 726.5, found 727.5 (M+1).sup.+
Example 201
Compound 270
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((1S)-2-(2,6-dimethylmorpholino-
)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,-
5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chryse-
n-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00389##
[0921] LC/MS: m/z calculated 711.5, found 712.5 (M+1).sup.+
Example 202
Compound 271
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-thiomorpholino-
ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8-
,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-
-2,2-dimethyl-4-oxobutanoic acid
##STR00390##
[0923] LC/MS: m/z calculated 699.5, found 700.4 (M+1).sup.+
Example 203
Compound 272
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-((3-morpholino-
propyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5-
a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chry-
sen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00391##
[0925] LC/MS: m/z calculated 740.5, found 741.5 (M+1).sup.+
Example 204
Compound 273
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((3-(1H-imidazol-1-yl)pr-
opyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,-
3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopent-
a[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00392##
[0927] LC/MS: m/z calculated 721.5, found 722.5 (M+1).sup.+
Example 205
Compound 274
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-((4-hydroxyphe-
nethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5-
a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chry-
sen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00393##
[0929] LC/MS: m/z calculated 733.5, found 734.5 (M+1).sup.+
Example 206
Compound 275
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(cyclopentylamino)-1-hyd-
roxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,-
7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)-
oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00394##
[0931] LC/MS: m/z calculated 681.5, found 682.5 (M+1).sup.+
Example 207
Compound 276
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((S)-2-((cyclohexylmethyl)amino-
)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,-
5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chryse-
n-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00395##
[0933] LC/MS: m/z calculated 709.5, found 710.5 (M+1).sup.+
Example 208
Compound 277
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((cyclobutylmethyl)(2-(d-
imethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentam-
ethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydr-
o-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00396##
[0935] LC/MS: m/z calculated 752.6, found 753.6 (M+1).sup.+
Example 209
Compound 278
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(((1H-pyrazol-4-yl)methy-
l)(2-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-
-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octad-
ecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00397##
[0937] LC/MS: m/z calculated 764.6, found 765.5 (M+1).sup.+
Example 210
Compound 279
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((cyclopropylmethyl)amin-
o)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a-
,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrys-
en-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00398##
[0939] LC/MS: m/z calculated 667.5, found 668.5 (M+1).sup.+
Example 211
Compound 280
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(cyclobutylamino)-1-hydr-
oxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7-
a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)o-
xy)-2,2-dimethyl-4-oxobutanoic acid
##STR00399##
[0941] LC/MS: m/z calculated 667.5, found 668.5 (M+1).sup.+
Example 212
Compound 281
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(cyclobutylamino)-1-hydr-
oxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7-
a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)o-
xy)-2,2-dimethyl-4-oxobutanoic acid
##STR00400##
[0943] LC/MS: m/z calculated 667.5, found 668.5 (M+1).sup.+
Example 213
Compound 282
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-((3-(pyrrolidi-
n-1-yl)propyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3-
a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta-
[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00401##
[0945] LC/MS: m/z calculated 724.5, found 725.5 (M+1).sup.+
Example 214
Compound 283
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-(4-(pyridin-2--
yl)piperazin-1-yl)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,-
4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a-
]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00402##
[0947] LC/MS: m/z calculated 759.5, found 760.5 (M+1).sup.+
Example 215
Compound 284
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-(4-methyl-1,4--
diazepan-1-yl)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,-
5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chr-
ysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00403##
[0949] LC/MS: m/z calculated 710.5, found 711.5 (M+1).sup.+
Example 216
Compound 285
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-((4-sulfamoylp-
henethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00404##
[0951] LC/MS: m/z calculated 796.5, found 797.5 (M+1).sup.+
Example 217
Compound 286
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(4-carbamoylpiperidin-1--
yl)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5-
a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chry-
sen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00405##
[0953] LC/MS: m/z calculated 724.5, found 725.5 (M+1).sup.+
Example 218
Compound 287
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-(4-(2-methoxye-
thyl)piperazin-1-yl)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3-
a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta-
[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00406##
[0955] LC/MS: m/z calculated 740.5, found 741.5 (M+1).sup.+
Example 219
Compound 288
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-(((R)-2-hydrox-
y-1-phenylethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3-
,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopen-
ta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00407##
[0957] LC/MS: m/z calculated 733.5, found 734.5 (M+1).sup.+
Example 220
Compound 289
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((1S)-1-hydroxy-2-(octahydroiso-
quinolin-2(1H)-yl)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,-
4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a-
]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00408##
[0959] LC/MS: m/z calculated 735.5, found 736.5 (M+1).sup.+
Example 221
Compound 290
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-((3-(piperidin-
-1-yl)propyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a-
,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[-
a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00409##
[0961] LC/MS: m/z calculated 738.5, found 739.5 (M+1).sup.+
Example 222
Compound 291
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(2-(dimethylamino)-N--((-
S-1-(pyridin-2-yl)ethyl)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,1-
1a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-oct-
adecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00410##
[0963] LC/MS: m/z calculated 803.5, found 804.5 (M+1).sup.+
Example 223
Compound 292
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(cyclopentylamino)-1-hyd-
roxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,-
7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)-
oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00411##
[0965] LC/MS: m/z calculated 681.5, found 682.5 (M+1).sup.+
Example 224
Compound 293
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(benzo[d][1,3]dioxol-5-y-
lamino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4-
,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]-
chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00412##
[0967] LC/MS: m/z calculated 733.5, found 734.5 (M+1).sup.+
Example 225
Compound 294
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-((2-(thiophen--
2-yl)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4-
,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]-
chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00413##
[0969] LC/MS: m/z calculated 723.5, found 724.4 (M+1).sup.+
Example 226
Compound 295
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-(4-(4-methylbe-
nzyl)piperazin-1-yl)
ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,-
8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy-
)-2,2-dimethyl-4-oxobutanoic acid
##STR00414##
[0971] LC/MS: m/z calculated 786.5, found 787.5 (M+1).sup.+
Example 227
Compound 296
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((S)-2-(bis(2-methoxyethyl)amin-
o)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a-
,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrys-
en-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00415##
[0973] LC/MS: m/z calculated 729.5, found 730.5 (M+1).sup.+
Example 228
Compound 297
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(((1S)-1-hydroxy-2-((2-methylcy-
clohexyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00416##
[0975] LC/MS: m/z calculated 709.5, found 710.5 (M+1).sup.+
Example 229
Compound 298
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(((1S)-1-hydroxy-2-((2-(1-methy-
lpyrrolidin-2-yl)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl--
2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-c-
yclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00417##
[0977] LC/MS: m/z calculated 724.5, found 725.5 (M+1).sup.+
Example 230
Compound 299
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-(((1r,4S)-4-hy-
droxycyclohexyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3-
,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopen-
ta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00418##
[0979] LC/MS: m/z calculated 711.5, found 712.4 (M+1).sup.+
Example 231
Compound 300
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((S)-2-(4-ethylpiperazin-1-yl)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00419##
[0981] LC/MS: m/z calculated 710.5, found 711.5 (M+1).sup.+
Example 232
Compound 301
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-(((S)-2-hydrox-
ypropyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,-
5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chr-
ysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00420##
[0983] LC/MS: m/z calculated 671.5, found 672.4 (M+1).sup.+
Example 233
Compound 302
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chlorophenyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00421##
[0985] LC/MS: m/z calculated 723.4, found 724.4 (M+1).sup.+
Example 234
Compound 303
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-(isoindolin-2--
yl)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7-
a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)o-
xy)-2,2-dimethyl-4-oxobutanoic acid
##STR00422##
[0987] LC/MS: m/z calculated 715.5, found 716.5 (M+1).sup.+
Example 235
Compound 304
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(((S)-1-(5-chloropyridin-
-2-yl)ethyl)(2-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,-
5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13-
,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobut-
anoic acid
##STR00423##
[0989] LC/MS: m/z calculated 823.5, found 824.5 (M+1).sup.+
Example 236
Compound 305
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((S)-2-(((S)-1-(5-chloropyridin-
-2-yl)ethyl)(2-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,-
5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13-
,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobut-
anoic acid
##STR00424##
[0991] LC/MS: m/z calculated 823.5, found 824.5 (M+1).sup.+
Example 237
Compound 306
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(isoindolin-2--
yl)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7-
a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)o-
xy)-2,2-dimethyl-4-oxobutanoic acid
##STR00425##
[0993] LC/MS: m/z calculated 715.5, found 716.5 (M+1).sup.+
Example 238
Compound 307
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((2-(5-chloropyridin-2-y-
l)propan-2-yl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00426##
[0995] LC/MS: m/z calculated 766.5, found 767.5 (M+1).sup.+
Example 239
Compound 308
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-(5-chloropyridin-2-y-
l)propan-2-yl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00427##
[0997] LC/MS: m/z calculated 766.5, found 767.6 (M+1).sup.+
Example 240
Compound 309
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(((S)-1-(pyrid-
in-2-yl)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3-
a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta-
[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00428##
[0999] LC/MS: m/z calculated 718.5, found 719.5 (M+1).sup.+
Example 241
Compound 310
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-((pyridin-2-yl-
methyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5-
a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chry-
sen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00429##
[1001] LC/MS: m/z calculated 704.5, found 705.5 (M+1).sup.+
Example 242
Compound 311
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((pyridin-2-yl-
methyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5-
a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chry-
sen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00430##
[1003] LC/MS: m/z calculated 704.5, found 705.5 (M+1).sup.+
Example 243
Compound 312
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)ethyl-
)(pyridin-2-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pent-
amethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahy-
dro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00431##
[1005] LC/MS: m/z calculated 775.5, found 776.5 (M+1).sup.+
Example 244
Compound 313
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-(phenylamino)e-
thyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,-
9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)--
2,2-dimethyl-4-oxobutanoic acid
##STR00432##
[1007] LC/MS: m/z calculated 689.5, found 690.5 (M+1).sup.+
Example 245
Compound 314
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-((4-methoxyphe-
nyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00433##
[1009] LC/MS: m/z calculated 719.5, found 720.5 (M+1).sup.+
Example 246
Compound 315
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-((S)-2-(hydrox-
ymethyl)pyrrolidin-1-yl)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-
-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclop-
enta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00434##
[1011] LC/MS: m/z calculated 697.5, found 698.5 (M+1).sup.+
Example 247
Compound 316
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((R)-3-(ethoxycarbonyl)p-
iperidin-1-yl)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-
-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclop-
enta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00435##
[1013] LC/MS: m/z calculated 753.5, found 754.5 (M+1).sup.+
Example 248
Compound 317
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(4-formylpiperazin-1-yl)-
-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00436##
[1015] LC/MS: m/z calculated 710.5, found 711.5 (M+1).sup.+
Example 249
Compound 318
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(4-benzylpiperidin-1-yl)-
-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00437##
[1017] LC/MS: m/z calculated 771.5, found 772.5 (M+1).sup.+
Example 250
Compound 319
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(4-acetylpiperazin-1-yl)-
-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00438##
[1019] LC/MS: m/z calculated 724.5, found 725.5 (M+1).sup.+
Example 251
Compound 320
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-(4-(2-morpholi-
noethyl)piperazin-1-yl)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo--
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclope-
nta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00439##
[1021] LC/MS: m/z calculated 795.6, found 796.5 (M+1).sup.+
Example 252
Compound 321
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(benzyl(carboxymethyl)am-
ino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,-
5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chr-
ysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00440##
[1023] LC/MS: m/z calculated 761.5, found 762.5 (M+1).sup.+
Example 253
Compound 322
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-(((S)-1-(pyrid-
in-2-yl)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3-
a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta-
[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00441##
[1025] LC/MS: m/z calculated 718.5, found 719.5 (M+1).sup.+
Example 254
Compound 323
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(2-(dimethylamino)-N--((-
R)-1-(pyridin-2-yl)ethyl)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,-
11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-oc-
tadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00442##
[1027] LC/MS: m/z calculated 803.5, found 804.5 (M+1).sup.+
Example 255
Compound 324
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((2-(methylami-
no)ethyl)(pyridin-2-ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentam-
ethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydr-
o-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00443##
[1029] LC/MS: m/z calculated 761.5, found 762.5 (M+1).sup.+
Example 256
Compound 325
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(bis(4-chlorobenzyl)amino-
)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,-
5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chryse-
n-9-yl) 1-tert-butyl 2,2-dimethylsuccinate
##STR00444##
[1031] LC/MS: m/z calculated 917.5, found 918.5 (M+1).sup.+
Example 257
Compound 326
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(bis(4-chlorobenzyl)amin-
o)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a-
,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrys-
en-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00445##
[1033] LC/MS: m/z calculated 861.4, found 862.4 (M+1).sup.+
Example 258
Compound 327
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((2-(pyridin-3-
-yl)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,-
5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]c-
hrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00446##
[1035] LC/MS: m/z calculated 718.5, found 719.5 (M+1).sup.+
Example 259
Compound 328
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((R)-3-hydroxy-
piperidin-1-yl)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00447##
[1037] LC/MS: m/z calculated 697.5, found 698.5 (M+1).sup.+
Example 260
Compound 329
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((4-hydroxyphe-
nethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5-
a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chry-
sen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00448##
[1039] LC/MS: m/z calculated 733.5, found 734.4 (M+1).sup.+
Example 261
Compound 330
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(4-(2-hydroxye-
thyl)piperazin-1-yl)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3-
a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta-
[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00449##
[1041] LC/MS: m/z calculated 726.5, found 727.5 (M+1).sup.+
Example 262
Compound 331
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-thiomorpholino-
ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8-
,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-
-2,2-dimethyl-4-oxobutanoic acid
##STR00450##
[1043] LC/MS: m/z calculated 699.4, found 700.4 (M+1).sup.+
Example 263
Compound 332
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(4-(pyridin-2--
yl)piperazin-1-yl)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,-
4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a-
]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00451##
[1045] LC/MS: m/z calculated 759.5, found 760.5 (M+1).sup.+
Example 264
Compound 333
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(4-methyl-1,4--
diazepan-1-yl)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,-
5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chr-
ysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00452##
[1047] LC/MS: m/z calculated 710.5, found 711.5 (M+1).sup.+
Example 265
Compound 334
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(4-carbamoylpiperidin-1--
yl)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5-
a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chry-
sen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00453##
[1049] LC/MS: m/z calculated 724.5, found 725.5 (M+1).sup.+
Example 266
Compound 335
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(4-(2-methoxye-
thyl)piperazin-1-yl)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3-
a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta-
[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00454##
[1051] LC/MS: m/z calculated 740.5, found 741.5 (M+1).sup.+
Example 267
Compound 336
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(((R)-2-hydrox-
y-1-phenylethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3-
,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopen-
ta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00455##
[1053] LC/MS: m/z calculated 733.5, found 734.5 (M+1).sup.+
Example 268
Compound 337
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-((pyrimidin-2--
ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00456##
[1055] LC/MS: m/z calculated 705.5, found 706.4 (M+1).sup.+
Example 269
Compound 338
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((pyrimidin-2--
ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00457##
[1057] LC/MS: m/z calculated 705.5, found 706.4 (M+1).sup.+
Example 270
Compound 339
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-benzyl-2-(dimethylami-
no)-2-oxoacetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl--
2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-c-
yclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00458##
[1059] LC/MS: m/z calculated 802.5, found 803.5 (M+1).sup.+
Example 271
Compound 340
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chloro-2-((dimethyla-
mino)methyl)benzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentam-
ethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydr-
o-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00459##
[1061] LC/MS: m/z calculated 794.5, found 795.5 (M+1).sup.+
Example 272
Compound 341
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chloro-2-((dimethyla-
mino)methyl)benzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentam-
ethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydr-
o-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00460##
[1063] LC/MS: m/z calculated 794.5, found 795.5 (M+1).sup.+
Example 273
Compound 342
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chloro-2-((dimethyla-
mino)methyl)benzyl)(methyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11-
a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octa-
decahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00461##
[1065] LC/MS: m/z calculated 808.5, found 809.5 (M+1).sup.+
Example 274
Compound 343
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-(4-chloro-2-((dimethy-
lamino)methyl)benzyl)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a--
pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octade-
cahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00462##
[1067] LC/MS: m/z calculated 836.5, found 837.5 (M+1).sup.+
Example 275
Compound 344
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chloro-2-((dimethyla-
mino)methyl)benzyl)(methyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11-
a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octa-
decahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00463##
[1069] LC/MS: m/z calculated 808.5, found 809.5 (M+1).sup.+
Example 276
Compound 345
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-(cyclopropylmethyl)-2-
-(dimethylamino)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-penta-
methyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahyd-
ro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00464##
[1071] LC/MS: m/z calculated 752.5, found 753.5 (M+1).sup.+
Example 277
Compound 346
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(benzyl(2-(methylamino)e-
thyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,-
3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopent-
a[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00465##
[1073] LC/MS: m/z calculated 760.5, found 761.5 (M+1).sup.+
Example 278
Compound 347
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((cyclopropylmethyl)(2-(-
dimethylamino)-2-oxoethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-
-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octad-
ecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00466##
[1075] LC/MS: m/z calculated 752.5, found 753.5 (M+1).sup.+
Example 279
Compound 348
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-acetamidoethyl)(cycl-
opropylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00467##
[1077] LC/MS: m/z calculated 752.5, found 753.5 (M+1).sup.+
Example 280
Compound 349
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((cyclopropylmethyl)(2-(-
N-methylacetamido)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-p-
entamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadec-
ahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00468##
[1079] LC/MS: m/z calculated 766.5, found 767.5 (M+1).sup.+
Example 281
Compound 350
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-amino-2-oxoethyl)(be-
nzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,-
3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopent-
a[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00469##
[1081] LC/MS: m/z calculated 760.5, found 761.5 (M+1).sup.+
Example 282
Compound 351
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-(benzyl(2-(dimethylamino-
)-2-oxoethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl--
2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-c-
yclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00470##
[1083] LC/MS: m/z calculated 788.5, found 789.5 (M+1).sup.+
Example 283
Compound 352
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-(isobutylamino-
)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,-
8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy-
)-2,2-dimethyl-4-oxobutanoic acid
##STR00471##
[1085] LC/MS: m/z calculated 669.5, found 670.5 (M+1).sup.+
Example 284
Compound 353
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-(2-amino-N-(pyridin-3-yl-
methyl)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2--
oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyc-
lopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00472##
[1087] LC/MS: m/z calculated 761.5, found 762.5 (M+1).sup.+
Example 285
Compound 354
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(2-(dimethylamino)-N-(py-
ridin-3-ylmethyl)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pent-
amethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahy-
dro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00473##
[1089] LC/MS: m/z calculated 789.5, found 790.5 (M+1).sup.+
Example 286
Compound 355
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(2-(methylamin-
o)-N-(pyridin-3-ylmethyl)acetamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentam-
ethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydr-
o-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00474##
[1091] LC/MS: m/z calculated 775.5, found 776.5 (M+1).sup.+
Example 287
Compound 356
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((3-(trifluoro-
methyl)benzyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3-
a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta-
[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00475##
[1093] LC/MS: m/z calculated 771.5, found 772.4 (M+1).sup.+
Example 288
Compound 357
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((pyridin-4-yl-
methyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5-
a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chry-
sen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00476##
[1095] LC/MS: m/z calculated 704.5, found 705.5 (M+1).sup.+
Example 289
Compound 358
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(((1R)-1-hydroxy-2-(((tetrahydr-
ofuran-2-yl)methyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-ox-
o-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclo-
penta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00477##
[1097] LC/MS: m/z calculated 697.5, found 698.5 (M+1).sup.+
Example 290
Compound 359
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(cyclohexyl(methyl)
amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4-
,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]-
chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00478##
[1099] LC/MS: m/z calculated 709.5, found 710.5 (M+1).sup.+
Example 291
Compound 360
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(((S)-1-hydrox-
y-4-methylpentan-2-yl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-
-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cy-
clopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00479##
[1101] LC/MS: m/z calculated 713.5, found 714.5 (M+1).sup.+
Example 292
Compound 361
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((1-methylpipe-
ridin-4-yl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4-
,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]-
chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00480##
[1103] LC/MS: m/z calculated 710.5, found 711.5 (M+1).sup.+
Example 293
Compound 362
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-benzyl-1-carboxyforma-
mido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00481##
[1105] LC/MS: m/z calculated 775.5, found 776.5 (M+1).sup.+
Example 294
Compound 363
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(2-amino-N-benzyl-2-oxoa-
cetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a-
,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[-
a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00482##
[1107] LC/MS: m/z calculated 774.5, found 775.5 (M+1).sup.+
Example 295
Compound 364
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(isobutylamino-
)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,-
8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy-
)-2,2-dimethyl-4-oxobutanoic acid
##STR00483##
[1109] LC/MS: m/z calculated 669.5, found 670.5 (M+1).sup.+
Example 296
Compound 365
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(phenethylamin-
o)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a-
,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)ox-
y)-2,2-dimethyl-4-oxobutanoic acid
##STR00484##
[1111] LC/MS: m/z calculated 717.5, found 718.5 (M+1).sup.+
Example 297
Compound 366
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)ethyl-
)(pyridin-3-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pent-
amethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahy-
dro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00485##
[1113] LC/MS: m/z calculated 775.5, found 776.5 (M+1).sup.+
Example 298
Compound 367
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-aminoethyl)(pyridin--
3-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2--
oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyc-
lopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00486##
[1115] LC/MS: m/z calculated 747.5, found 748.5 (M+1).sup.+
Example 299
Compound 368
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((1-(5-chloropyrimidin-2-
-yl)cyclopropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentameth-
yl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2-
H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00487##
[1117] LC/MS: m/z calculated 765.5, found 766.5 (M+1).sup.+
Example 300
Compound 369
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(2-amino-N-(pyridin-4-yl-
methyl)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2--
oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyc-
lopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00488##
[1119] LC/MS: m/z calculated 761.5, found 762.5 (M+1).sup.+
Example 301
Compound 370
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(2-(methylamin-
o)-N-(pyridin-4-ylmethyl)acetamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentam-
ethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydr-
o-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00489##
[1121] LC/MS: m/z calculated 775.5, found 776.5 (M+1).sup.+
Example 302
Compound 371
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(2-(dimethylamino)-N-(py-
ridin-4-ylmethyl)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pent-
amethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahy-
dro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00490##
[1123] LC/MS: m/z calculated 789.5, found 790.5 (M+1).sup.+
Example 303
Compound 372
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)ethyl-
)(pyridin-4-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pent-
amethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahy-
dro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00491##
[1125] LC/MS: m/z calculated 775.5, found 776.5 (M+1).sup.+
Example 304
Compound 373
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((2-(methylami-
no)ethyl)(pyridin-4-ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentam-
ethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydr-
o-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00492##
[1127] LC/MS: m/z calculated 761.5, found 762.5 (M+1).sup.+
Example 305
Compound 374
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-(2-(cyclohexanecarboxamido)ethy-
l)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,1-
0,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-
-dimethyl-4-oxobutanoic acid
##STR00493##
[1129] LC/MS: m/z calculated 707.5, found 708.5 (M+1).sup.+
Example 306
Compound 375
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-aminoethyl)(pyridin--
4-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2--
oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyc-
lopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00494##
[1131] LC/MS: m/z calculated 747.5, found 748.5 (M+1).sup.+
Example 307
Compound 376
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-aminoethyl)(pyridin--
2-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2--
oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyc-
lopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00495##
[1133] LC/MS: m/z calculated 747.5, found 748.5 (M+1).sup.+
Example 308
Compound 377
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((2-(N-methyla-
cetamido)ethyl)(pyridin-2-ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a--
pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octade-
cahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00496##
[1135] LC/MS: m/z calculated 803.5, found 804.5 (M+1).sup.+
Example 309
Compound 378
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((1-(5-chloropyrimidin-2-
-yl)cyclopropyl)(2-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-
-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,1-
2,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-ox-
obutanoic acid
##STR00497##
[1137] LC/MS: m/z calculated 836.5, found 837.5 (M+1).sup.+
Example 310
Compound 379
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(benzyl(2-(methylamino)--
2-oxoethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2--
oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyc-
lopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00498##
[1139] LC/MS: m/z calculated 774.5, found 775.5 (M+1).sup.+
Example 311
Compound 380
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)-2-ox-
oethyl)(pyridin-2-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11-
a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octa-
decahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00499##
[1141] LC/MS: m/z calculated 789.5, found 790.5 (M+1).sup.+
Example 312
Compound 381
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(benzyl(2-(N-methylaceta-
mido)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2--
oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyc-
lopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00500##
[1143] LC/MS: m/z calculated 802.5, found 803.5 (M+1).sup.+
Example 313
Compound 382
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(benzyl(2-(2-oxopyrrolid-
in-1-yl)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00501##
[1145] LC/MS: m/z calculated 814.5, found 815.5 (M+1).sup.+
Example 314
Compound 383
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(((1H-benzo[d]imidazol-2-
-yl)methyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2--
oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyc-
lopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00502##
[1147] LC/MS: m/z calculated 743.5, found 744.5 (M+1).sup.+
Example 315
Compound 384
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(2-(aminomethyl)-1H-benz-
o[d]imidazol-1-yl)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-
-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cy-
clopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00503##
[1149] LC/MS: m/z calculated 743.5, found 744.5 (M+1).sup.+
Example 316
Compound 385
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((1-(4-chlorophenyl)cycl-
opropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-
-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclop-
enta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00504##
[1151] LC/MS: m/z calculated 763.5, found 764.5 (M+1).sup.+
Example 317
Compound 386
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((1-(4-chlorophenyl)cycl-
opropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-
-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclop-
enta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00505##
[1153] LC/MS: m/z calculated 763.5, found 764.5 (M+1).sup.+
Example 318
Compound 387
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((2-morpholino-
ethyl)(pyridin-2-ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentameth-
yl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2-
H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00506##
[1155] LC/MS: m/z calculated 817.6, found 818.5 (M+1).sup.+
Example 319
Compound 388
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((2-(2-oxopyrr-
olidin-1-yl)ethyl)(pyridin-2-ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,1-
1a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-oct-
adecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00507##
[1157] LC/MS: m/z calculated 815.5, found 816.5 (M+1).sup.+
Example 320
Compound 389
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-(phenethylamin-
o)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a-
,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)ox-
y)-2,2-dimethyl-4-oxobutanoic acid
##STR00508##
[1159] LC/MS: m/z calculated 717.5, found 718.5 (M+1).sup.+
Example 321
Compound 390
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((thiazol-5-yl-
methyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5-
a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chry-
sen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00509##
[1161] LC/MS: m/z calculated 710.4, found 711.4 (M+1).sup.+
Example 322
Compound 391
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(cyclopentylamino)ethyl)-1-i-
sopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,1-
1a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimet-
hyl-4-oxobutanoic acid
##STR00510##
[1163] LC/MS: m/z calculated 665.5, found 666.5 (M+1).sup.+
Example 323
Compound 392
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)-2-ox-
oethyl)(pyridin-4-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11-
a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octa-
decahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00511##
[1165] LC/MS: m/z calculated 789.5, found 790.5 (M+1).sup.+
Example 324
Compound 393
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-amino-2-oxoethyl)(py-
ridin-2-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00512##
[1167] LC/MS: m/z calculated 761.5, found 762.5 (M+1).sup.+
Example 325
Compound 394
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((2-((2-hydrox-
yethyl)amino)ethyl)(pyridin-2-ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,-
11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-oc-
tadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00513##
[1169] LC/MS: m/z calculated 791.5, found 792.5 (M+1).sup.+
Example 326
Compound 395
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((2-((2-methox-
yethyl)amino)ethyl)(pyridin-2-ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,-
11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-oc-
tadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00514##
[1171] LC/MS: m/z calculated 805.6, found 806.5 (M+1).sup.+
Example 327
Compound 396
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-((tert-butoxycarbony-
l)amino)ethyl)(cyclopropylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,-
8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13-
a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutano-
ic acid
##STR00515##
[1173] LC/MS: m/z calculated 810.6, found 811.5 (M+1).sup.+
Example 328
Compound 397
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-((tert-butoxycarbony-
l)(methyl)amino)ethyl)(cyclopropylmethyl)amino)-1-hydroxyethyl)-1-isopropy-
l-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,-
12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-o-
xobutanoic acid
##STR00516##
[1175] LC/MS: m/z calculated 824.6, found 825.5 (M+1).sup.+
Example 329
Compound 398
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(N-benzyl-1-carboxyformamido-
)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,-
8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy-
)-2,2-dimethyl-4-oxobutanoic acid
##STR00517##
[1177] LC/MS: m/z calculated 759.5, found 760.5 (M+1).sup.+
Example 330
Compound 399
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((2-aminoethyl)(cyclopro-
pylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-o-
xo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cycl-
openta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00518##
[1179] LC/MS: m/z calculated 710.5, found 711.5 (M+1).sup.+
Example 331
Compound 400
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-acetamidoethyl)(pyri-
din-3-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethy-
l-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-
-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00519##
[1181] LC/MS: m/z calculated 789.5, found 790.5 (M+1).sup.+
Example 332
Compound 401
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((thiazol-4-yl-
methyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5-
a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chry-
sen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00520##
[1183] LC/MS: m/z calculated 710.4, found 711.4 (M+1).sup.+
Example 333
Compound 402
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((thiazol-2-yl-
methyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5-
a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chry-
sen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00521##
[1185] LC/MS: m/z calculated 710.4, found 711.4 (M+1).sup.+
Example 334
Compound 403
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)ethyl-
)(thiazol-4-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pent-
amethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahy-
dro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00522##
[1187] LC/MS: m/z calculated 781.5, found 782.5 (M+1).sup.+
Example 335
Compound 404
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(benzyl(carboxymethyl)amino)-
ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8-
,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-
-2,2-dimethyl-4-oxobutanoic acid
##STR00523##
[1189] LC/MS: m/z calculated 745.5, found 746.5 (M+1).sup.+
Example 336
Compound 405
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-3a-(2-(N-methylbenzamido)ethyl)-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,-
11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dime-
thyl-4-oxobutanoic acid
##STR00524##
[1191] LC/MS: m/z calculated 715.5, found 716.5 (M+1).sup.+
Example 337
Compound 406
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(N-benzyl-2-(dimethylamino)--
2-oxoacetamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00525##
[1193] LC/MS: m/z calculated 786.5, found 787.5 (M+1).sup.+
Example 338
Compound 407
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((2-acetamidoethyl)(benz-
yl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a-
,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[-
a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00526##
[1195] LC/MS: m/z calculated 788.5, found 789.5 (M+1).sup.+
Example 339
Compound 408
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(2-amino-N-benzyl-2-oxoaceta-
mido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7-
,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl-
)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00527##
[1197] LC/MS: m/z calculated 758.5, found 759.5 (M+1).sup.+
Example 340
Compound 409
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((2-acetamidoethyl)(pyri-
din-2-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethy-
l-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-
-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00528##
[1199] LC/MS: m/z calculated 789.5, found 790.5 (M+1).sup.+
Example 341
Compound 410
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)ethyl-
)(thiazol-5-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pent-
amethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahy-
dro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00529##
[1201] LC/MS: m/z calculated 781.5, found 782.5 (M+1).sup.+
Example 342
Compound 411
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)ethyl-
)(thiazol-2-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pent-
amethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahy-
dro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00530##
[1203] LC/MS: m/z calculated 781.5, found 782.5 (M+1).sup.+
Example 343
Compound 412
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((cyclopropylmethyl)(2-(-
methylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentame-
thyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-
-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00531##
[1205] LC/MS: m/z calculated 724.5, found 725.5 (M+1).sup.+
Example 344
Compound 413
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((2-acetamidoethyl)(pyri-
din-4-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethy-
l-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-
-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00532##
[1207] LC/MS: m/z calculated 789.5, found 790.5 (M+1).sup.+
Example 345
Compound 414
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((2-acetamidoethyl)(cycl-
opropylmethyl)amino)-1-acetoxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00533##
[1209] LC/MS: m/z calculated 794.5, found 795.5 (M+1).sup.+
Example 346
Compound 415
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-acetoxy-2-((cyclopropylm-
ethyl)(2-(N-methylacetamido)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-p-
entamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadec-
ahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00534##
[1211] LC/MS: m/z calculated 808.6, found 809.5 (M+1).sup.+
Example 347
Compound 416
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((5-chloropyrimidin-2-yl-
)methyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-
-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclop-
enta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00535##
[1213] LC/MS: m/z calculated 739.4, found 740.4 (M+1).sup.+
Example 348
Compound 417
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)ethyl-
)(pyrimidin-2-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pe-
ntamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadeca-
hydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00536##
[1215] LC/MS: m/z calculated 776.5, found 777.5 (M+1).sup.+
Example 349
Compound 418
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(((5-chloropyrimidin-2-y-
l)methyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-ox-
o-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclo-
penta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00537##
[1217] LC/MS: m/z calculated 739.4, found 740.4 (M+1).sup.+
Example 350
Compound 419
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((2-(methylami-
no)ethyl)(pyridin-3-ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentam-
ethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydr-
o-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00538##
[1219] LC/MS: m/z calculated 761.5, found 762.5 (M+1).sup.+
Example 351
Compound 420
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-((R)-2-oxo-3-(pyridin-2-ylmethyl)oxazolidin-5-yl)-3,3a,4,5,5a-
,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrys-
en-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00539##
[1221] LC/MS: m/z calculated 730.5, found 731.4 (M+1).sup.+
Example 352
Compound 421
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((1-(5-chloropyrimidin-2-
-yl)cyclopropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentameth-
yl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2-
H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00540##
[1223] LC/MS: m/z calculated 765.4, found 766.4 (M+1).sup.+
Example 353
Compound 422
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2,11-dimethyl-3,10-dioxo-5-
-(pyridin-3-ylmethyl)-8-oxa-2,5,11-triazadodecan-7-yl)-1-isopropyl-5a,5b,8-
,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-
-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoi-
c acid
##STR00541##
[1225] LC/MS: m/z calculated 874.6, found 875.6 (M+1).sup.+
Example 354
Compound 423
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((2-(methylami-
no)-2-oxoethyl)(pyridin-2-ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a--
pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octade-
cahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00542##
[1227] LC/MS: m/z calculated 775.5, found 776.5 (M+1).sup.+
Example 355
Compound 424
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)-2-ox-
oethyl)(pyridin-3-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11-
a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octa-
decahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00543##
[1229] LC/MS: m/z calculated 789.5, found 790.5 (M+1).sup.+
Example 356
Compound 425
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-(2-(dimethylamino)-N-(py-
rimidin-2-ylmethyl)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pe-
ntamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadeca-
hydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00544##
[1231] LC/MS: m/z calculated 790.5, found 791.5 (M+1).sup.+
Example 357
Compound 426
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-(2-(picolinamido)ethyl)-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,1-
1b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl--
4-oxobutanoic acid
##STR00545##
[1233] LC/MS: m/z calculated 702.5, found 703.4 (M+1).sup.+
Example 358
Compound 427
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-(1H-imidazol-1-yl)et-
hyl)(benzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-
-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cy-
clopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00546##
[1235] LC/MS: m/z calculated 797.5, found 798.5 (M+1).sup.+
Example 359
Compound 428
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((3-(1H-imidazol-1-yl)pr-
opyl)(benzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl--
2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-c-
yclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00547##
[1237] LC/MS: m/z calculated 811.5, found 812.5 (M+1).sup.+
Example 360
Compound 429
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((3-(1H-imidazol-1-yl)pr-
opyl)(benzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl--
2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-c-
yclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00548##
[1239] LC/MS: m/z calculated 811.5, found 812.5 (M+1).sup.+
Example 361
Compound 430
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(N-benzyl-2-(dimethylamino)a-
cetamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00549##
[1241] LC/MS: m/z calculated 772.5, found 773.5 (M+1).sup.+
Example 362
Compound 431
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-(2-(dimethylamino)-N-iso-
propylacetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-o-
xo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cycl-
openta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00550##
[1243] LC/MS: m/z calculated 740.5, found 741.5 (M+1).sup.+
Example 363
Compound 432
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(N-isopropyl-2-
-(methylamino)acetamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-
-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclop-
enta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00551##
[1245] LC/MS: m/z calculated 726.5, found 727.5 (M+1).sup.+
Example 364
Compound 433
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(2-amino-N-isopropylacet-
amido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,-
5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]c-
hrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00552##
[1247] LC/MS: m/z calculated 712.5, found 713.5 (M+1).sup.+
Example 365
Compound 434
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)ethyl-
)(3-(trifluoromethoxy)benzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,-
11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-oc-
tadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00553##
[1249] LC/MS: m/z calculated 858.5, found 859.5 (M+1).sup.+
Example 366
Compound 435
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)ethyl-
)(4-(trifluoromethoxy)benzyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,-
11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-oc-
tadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00554##
[1251] LC/MS: m/z calculated 858.5, found 859.5 (M+1).sup.+
Example 367
Compound 436
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(2-(dimethylamino)-N-(pyridi-
n-2-ylmethyl)acetamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo--
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclope-
nta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00555##
[1253] LC/MS: m/z calculated 773.5, found 774.5 (M+1).sup.+
Example 368
Compound 437
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((2-aminoethyl)(isopropy-
l)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,-
4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a-
]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00556##
[1255] LC/MS: m/z calculated 698.5, found 699.5 (M+1).sup.+
Example 369
Compound 438
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-acetamidoethyl)(isop-
ropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3-
,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopen-
ta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00557##
[1257] LC/MS: m/z calculated 740.5, found 741.5 (M+1).sup.+
Example 370
Compound 439
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)-2-ox-
oethyl)(thiazol-2-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11-
a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octa-
decahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00558##
[1259] LC/MS: m/z calculated 795.5, found 796.4 (M+1).sup.+
Example 371
Compound 440
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-3a-((R)-2-methyl-5-(pyridin-2-ylmethyl)-8,11-dioxa-2,5-diazadodecan-7--
yl)-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00559##
[1261] LC/MS: m/z calculated 833.6, found 834.5 (M+1).sup.+
Example 372
Compound 441
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((S)--N-benzyl-3,4-dihyd-
roxybutanamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-ox-
o-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclo-
penta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00560##
[1263] LC/MS: m/z calculated 805.5, found 806.5 (M+1).sup.+
Example 373
Compound 442
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((2-amino-2-oxoethyl)(is-
opropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-
-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclop-
enta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00561##
[1265] LC/MS: m/z calculated 712.5, found 713.5 (M+1).sup.+
Example 374
Compound 443
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)-2-ox-
oethyl)(isopropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentame-
thyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-
-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00562##
[1267] LC/MS: m/z calculated 740.5, found 741.5 (M+1).sup.+
Example 375
Compound 444
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(isopropyl(2-(-
methylamino)-2-oxoethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00563##
[1269] LC/MS: m/z calculated 726.5, found 727.5 (M+1).sup.+
Example 376
Compound 445
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((S)-3,4-dihydroxy-N-(py-
ridin-2-ylmethyl)butanamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pen-
tamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecah-
ydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00564##
[1271] LC/MS: m/z calculated 806.5, found 807.5 (M+1).sup.+
Example 377
Compound 446
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-(ethylamino)-2-oxoet-
hyl)(isopropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethy-
l-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-
-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00565##
[1273] LC/MS: m/z calculated 740.5, found 741.5 (M+1).sup.+
Example 378
Compound 447
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((carboxymethyl)(isoprop-
yl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a-
,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[-
a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00566##
[1275] LC/MS: m/z calculated 713.5, found 714.5 (M+1).sup.+
Example 379
Compound 448
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-(cyclopropylamino)-2-
-oxoethyl)(isopropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pent-
amethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahy-
dro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00567##
[1277] LC/MS: m/z calculated 752.5, found 753.5 (M+1).sup.+
Example 380
Compound 449
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-(((5-chloropyrimidin-2-y-
l)methyl)(2-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,-
8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13-
a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutano-
ic acid
##STR00568##
[1279] LC/MS: m/z calculated 810.5, found 811.5 (M+1).sup.+
Example 381
Compound 450
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-(cyclopropylmethyl)ac-
etamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,-
4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a-
]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00569##
[1281] LC/MS: m/z calculated 709.5, found 710.5 (M+1).sup.+
Example 382
Compound 451
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-(2-((pyridin-2-ylmethyl)amino)ethyl)-3,3a,4,5,5a,5b,6,7,7a,8,-
9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)--
2,2-dimethyl-4-oxobutanoic acid
##STR00570##
[1283] LC/MS: m/z calculated 688.5, found 689.5 (M+1).sup.+
Example 383
Compound 452
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((cyclopropylmethyl)(met-
hyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3-
a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta-
[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00571##
[1285] LC/MS: m/z calculated 681.5, found 682.5 (M+1).sup.+
Example 384
Compound 453
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-(cyclopropylmethyl)-2-
-(methylamino)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentame-
thyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-
-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00572##
[1287] LC/MS: m/z calculated 738.5, found 739.5 (M+1).sup.+
Example 385
Compound 454
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-benzylisobutyramido)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00573##
[1289] LC/MS: m/z calculated 773.5, found 774.5 (M+1).sup.+
Example 386
Compound 455
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-(N-benzyl-3-methylbutana-
mido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00574##
[1291] LC/MS: m/z calculated 787.5, found 788.5 (M+1).sup.+
Example 387
Compound 456
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-benzylpropionamido)-1-
-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,-
6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-
-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00575##
[1293] LC/MS: m/z calculated 759.5, found 760.5 (M+1).sup.+
Example 388
Compound 457
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-(2-((pyridin-3-ylmethyl)amino)ethyl)-3,3a,4,5,5a,5b,6,7,7a,8,-
9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)--
2,2-dimethyl-4-oxobutanoic acid
##STR00576##
[1295] LC/MS: m/z calculated 688.5, found 689.5 (M+1).sup.+
Example 389
Compound 458
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-(2-((pyridin-4-ylmethyl)amino)ethyl)-3,3a,4,5,5a,5b,6,7,7a,8,-
9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)--
2,2-dimethyl-4-oxobutanoic acid
##STR00577##
[1297] LC/MS: m/z calculated 688.5, found 689.5 (M+1).sup.+
Example 390
Compound 459
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((cyclopropylmethyl)(2-(-
pyrrolidin-1-yl)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pen-
tamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecah-
ydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00578##
[1299] LC/MS: m/z calculated 764.6, found 765.5 (M+1).sup.+
Example 391
Compound 460
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-benzylacetamido)-1-hy-
droxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7-
,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl-
)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00579##
[1301] LC/MS: m/z calculated 745.5, found 746.5 (M+1).sup.+
Example 392
Compound 461
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(benzyl(2-morpholinoethy-
l)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,-
4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a-
]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00580##
[1303] LC/MS: m/z calculated 816.6, found 817.5 (M+1).sup.+
Example 393
Compound 462
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N,
3-dimethylbutanamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentameth-
yl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2-
H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00581##
[1305] LC/MS: m/z calculated 711.5, found 712.5 (M+1).sup.+
Example 394
Compound 463
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-(cyclopropylmethyl)-2-
-(2-oxopyrrolidin-1-yl)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11-
a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octa-
decahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00582##
[1307] LC/MS: m/z calculated 792.5, found 793.5 (M+1).sup.+
Example 395
Compound 464
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-(isobutyryloxy)-2-(methy-
lamino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6-
,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9--
yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00583##
[1309] LC/MS: m/z calculated 697.5, found 698.5 (M+1).sup.+
Example 396
Compound 465
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((cyclobutylmethyl)amino)eth-
yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,-
10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,-
2-dimethyl-4-oxobutanoic acid
##STR00584##
[1311] LC/MS: m/z calculated 665.5, found 666.5 (M+1).sup.+
Example 397
Compound 466
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((cyclopropylmethyl)amino)et-
hyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9-
,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2-
,2-dimethyl-4-oxobutanoic acid
##STR00585##
[1313] LC/MS: m/z calculated 651.5, found 652.5 (M+1).sup.+
Example 398
Compound 467
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-(cyclobutylmethyl)-2--
(dimethylamino)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentam-
ethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydr-
o-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00586##
[1315] LC/MS: m/z calculated 766.5, found 767.5 (M+1).sup.+
Example 399
Compound 468
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((cyclobutylmethyl)(2-(dimet-
hylamino)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,-
3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopent-
a[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00587##
[1317] LC/MS: m/z calculated 736.6, found 737.5 (M+1).sup.+
Example 400
Compound 469
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((pyrimidin-4--
ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00588##
[1319] LC/MS: m/z calculated 705.5, found 706.5 (M+1).sup.+
Example 401
Compound 470
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-(cyclobutylmethyl)ace-
tamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4-
,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]-
chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00589##
[1321] LC/MS: m/z calculated 723.5, found 724.5 (M+1).sup.+
Example 402
Compound 471
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-((4-chlorobenzoyl)oxy)-2-
-(methylamino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,-
5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chr-
ysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00590##
[1323] LC/MS: m/z calculated 765.4, found 766.4 (M+1).sup.+
Example 403
Compound 472
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-(benzoyloxy)-2-((2-hydro-
xyethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,-
5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chr-
ysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00591##
[1325] LC/MS: m/z calculated 761.5, found 762.4 (M+1).sup.+
Example 404
Compound 473
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-3a-((R)-2-(methylamino)-1-(2-phenylacetoxy)ethyl)-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00592##
[1327] LC/MS: m/z calculated 745.5, found 746.5 (M+1).sup.+
Example 405
Compound 474
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(N-methylaceta-
mido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7-
,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl-
)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00593##
[1329] LC/MS: m/z calculated 669.5, found 670.4 (M+1).sup.+
Example 406
Compound 475
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(4-chloro-N-methylbenzam-
ido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,-
5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chr-
ysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00594##
[1331] LC/MS: m/z calculated 765.4, found 766.4 (M+1).sup.+
Example 407
Compound 476
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(N-methyl-2-ph-
enylacetamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,-
5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chr-
ysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00595##
[1333] LC/MS: m/z calculated 745.5, found 746.5 (M+1).sup.+
Example 408
Compound 477
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(N-(2-hydroxye-
thyl)benzamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00596##
[1335] LC/MS: m/z calculated 761.5, found 762.4 (M+1).sup.+
Example 409
Compound 478
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((pyrimidin-5--
ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00597##
[1337] LC/MS: m/z calculated 705.5, found 706.5 (M+1).sup.+
Example 410
Compound 479
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-((cyclobutylmethyl)a-
mino)-2-oxoethyl) (isopropyl)
amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4-
,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]-
chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00598##
[1339] LC/MS: m/z calculated 780.6, found 781.6 (M+1).sup.+
Example 411
Compound 480
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(N-methylisobu-
tyramido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00599##
[1341] LC/MS: m/z calculated 697.5, found 698.5 (M+1).sup.+
Example 412
Compound 481
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(N-methylcyclo-
pentanecarboxamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a-
,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[-
a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00600##
[1343] LC/MS: m/z calculated 723.5, found 724.5 (M+1).sup.+
Example 413
Compound 482
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(N-methylcyclo-
hexanecarboxamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,-
4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a-
]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00601##
[1345] LC/MS: m/z calculated 737.5, found 738.5 (M+1).sup.+
Example 414
Compound 483
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((cyclopropylmethyl)(2-(dime-
thylamino)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3-
,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopen-
ta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00602##
[1347] LC/MS: m/z calculated 722.6, found 723.6 (M+1).sup.+
Example 415
Compound 484
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(cyclopentyl(2-(dimethylamin-
o)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,-
5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chr-
ysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00603##
[1349] LC/MS: m/z calculated 736.6, found 737.5 (M+1).sup.+
Example 416
Compound 485
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)ethyl-
)(pyrimidin-4-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pe-
ntamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadeca-
hydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00604##
[1351] LC/MS: m/z calculated 776.5, found 777.5 (M+1).sup.+
Example 417
Compound 486
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((S)-2-(benzyl(2-(2-oxopyrrolid-
in-1-yl)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00605##
[1353] LC/MS: m/z calculated 814.5, found 815.5 (M+1).sup.+
Example 418
Compound 487
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(N-methylpicol-
inamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,-
6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-
-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00606##
[1355] LC/MS: m/z calculated 732.5, found 733.5 (M+1).sup.+
Example 419
Compound 488
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-(N-(4-chlorobenzyl)-2-hy-
droxyacetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-ox-
o-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclo-
penta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00607##
[1357] LC/MS: m/z calculated 795.4, found 796.3 (M+1).sup.+
Example 420
Compound 489
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(N-methylisoni-
cotinamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,-
5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chryse-
n-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00608##
[1359] LC/MS: m/z calculated 732.5, found 733.5 (M+1).sup.+
Example 421
Compound 490
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(N-methylnicot-
inamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,-
6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-
-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00609##
[1361] LC/MS: m/z calculated 732.5, found 733.4 (M+1).sup.+
Example 422
Compound 491
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-(4-chlorobenzyl)-2-me-
thoxyacetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-ox-
o-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclo-
penta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00610##
[1363] LC/MS: m/z calculated 809.5, found 810.3 (M+1).sup.+
Example 423
Compound 492
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-(4-chlorobenzyl)isobu-
tyramido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a-
,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[-
a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00611##
[1365] LC/MS: m/z calculated 807.5, found 808.5 (M+1).sup.+
Example 424
Compound 493
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-(N-(2-(dimethylamino)eth-
yl)-5-methyl-1,3,4-oxadiazole-2-carboxamido)-1-hydroxyethyl)-1-isopropyl-5-
a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,-
13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxob-
utanoic acid
##STR00612##
[1367] LC/MS: m/z calculated 794.5, found 795.5 (M+1).sup.+
Example 425
Compound 494
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-(2-((pyrimidin-2-ylmethyl)amino)ethyl)-3,3a,4,5,5a,5b,6,7,7a,-
8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy-
)-2,2-dimethyl-4-oxobutanoic acid
##STR00613##
[1369] LC/MS: m/z calculated 689.5, found 690.4 (M+1).sup.+
Example 427
Compound 496
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)amino)--
1-sulfoethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6-
,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9--
yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00614##
[1371] LC/MS: m/z calculated 801.4, found 802.2 (M+1).sup.+
Example 428
Compound 497
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-(2-((pyrimidin-4-ylmethyl)amino)ethyl)-3,3a,4,5,5a,5b,6,7,7a,-
8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy-
)-2,2-dimethyl-4-oxobutanoic acid
##STR00615##
[1373] LC/MS: m/z calculated 689.5, found 690.4 (M+1).sup.+
Example 429
Compound 498
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((2-(dimethylamino)-2-oxoeth-
yl)(pyridin-3-ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl--
2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-c-
yclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00616##
[1375] LC/MS: m/z calculated 773.5, found 774.5 (M+1).sup.+
Example 430
Compound 499
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((2-(dimethylamino)-2-oxoeth-
yl)(pyridin-2-ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl--
2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-c-
yclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00617##
[1377] LC/MS: m/z calculated 773.5, found 774.5 (M+1).sup.+
Example 431
Compound 500
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)ethyl-
)(pyrimidin-5-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pe-
ntamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadeca-
hydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00618##
[1379] LC/MS: m/z calculated 776.5, found 777.4 (M+1).sup.+
Example 433
Compound 502
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-(2-(((R)-1-(pyridin-2-3/1)ethyl)amino)ethyl)-3,3a,4,5,5a,5b,6-
,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9--
yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00619##
[1381] LC/MS: m/z calculated 702.5, found 703.3 (M+1).sup.+
Example 434
Compound 503
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-(N-(cyclobutylmethyl)-2--
(2-oxopyrrolidin-1-yl)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-
-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octad-
ecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00620##
[1383] LC/MS: m/z calculated 806.5, found 806.9 (M+1).sup.+
Example 435
Compound 504
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((cyclobutylmethyl)(2-(m-
ethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00621##
[1385] LC/MS: m/z calculated 738.5, found 739.5 (M+1).sup.+
Example 436
Compound 505
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)ethyl-
)(oxazol-2-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-penta-
methyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahyd-
ro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00622##
[1387] LC/MS: m/z calculated 765.5, found 765.9 (M+1).sup.+
Example 437
Compound 506
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(1-oxoisoindol-
in-2-yl)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,-
6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-
-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00623##
[1389] LC/MS: m/z calculated 729.5, found 729.9 (M+1).sup.+
Example 438
Compound 507
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(cyclobutylamino)ethyl)-1-is-
opropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11-
a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimeth-
yl-4-oxobutanoic acid
##STR00624##
[1391] LC/MS: m/z calculated 651.5, found 652.0 (M+1).sup.+
Example 439
Compound 508
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(cyclobutyl(2-(dimethylamino-
)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5-
a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chry-
sen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00625##
[1393] LC/MS: m/z calculated 722.6, found 723.0 (M+1).sup.+
Example 440
Compound 509
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((2-acetamidoethyl)(cycl-
obutylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl--
2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-c-
yclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00626##
[1395] LC/MS: m/z calculated 766.5, found 766.9 (M+1).sup.+
Example 441
Compound 510
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(2-(dimethylamino)-N-(pyridi-
n-3-ylmethyl)acetamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo--
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclope-
nta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00627##
[1397] LC/MS: m/z calculated 773.5, found 774.5 (M+1).sup.+
Example 442
Compound 511
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((2-(dimethylamino)ethyl)(py-
ridin-2-ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo--
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclope-
nta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00628##
[1399] LC/MS: m/z calculated 759.6, found 760.5 (M+1).sup.+
Example 443
Compound 512
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((cyclobutylmethyl)(2-(d-
imethylamino)-2-oxoethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a--
pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octade-
cahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00629##
[1401] LC/MS: m/z calculated 766.5, found 767.5 (M+1).sup.+
Example 444
Compound 513
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((2-(dimethylamino)ethyl)(py-
ridin-3-ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo--
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclope-
nta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00630##
[1403] LC/MS: m/z calculated 759.6, found 760.5 (M+1).sup.+
Example 445
Compound 514
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((2-(dimethylamino)ethyl)(py-
ridin-4-ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo--
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclope-
nta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00631##
[1405] LC/MS: m/z calculated 759.6, found 760.5 (M+1).sup.+
Example 446
Compound 515
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(2-(dimethylamino)-N-(pyridi-
n-4-ylmethyl)acetamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo--
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclope-
nta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00632##
[1407] LC/MS: m/z calculated 773.5, found 774.5 (M+1).sup.+
Example 447
Compound 516
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((cyclobutylmethyl)(2-(N-
-methylacetamido)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pe-
ntamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadeca-
hydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00633##
[1409] LC/MS: m/z calculated 780.6, found 781.4 (M+1).sup.+
Example 448
Compound 517
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(((R)-1-(pyrim-
idin-4-3/1)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo--
3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclope-
nta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00634##
[1411] LC/MS: m/z calculated 719.5, found 720.4 (M+1).sup.+
Example 449
Compound 518
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((azetidin-3-ylmethyl)amino)-
ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8-
,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-
-2,2-dimethyl-4-oxobutanoic acid
##STR00635##
[1413] LC/MS: m/z calculated 666.5, found 667.4 (M+1).sup.+
Example 450
Compound 519
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-(cyclopropylmethyl)-2-
-(pyrrolidin-1-yl)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pen-
tamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecah-
ydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00636##
[1415] LC/MS: m/z calculated 778.5, found 779.5 (M+1).sup.+
Example 451
Compound 520
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-(2-(((R)-1-(pyridin-4-yl)ethyl)amino)ethyl)-3,3a,4,5,5a,5b,6,-
7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-y-
l)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00637##
[1417] LC/MS: m/z calculated 702.5, found 703.5 (M+1).sup.+
Example 452
Compound 521
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((azetidin-3-ylmethyl)(2-(di-
methylamino)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-
-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclop-
enta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00638##
[1419] LC/MS: m/z calculated 737.6, found 738.7 (M+1).sup.+
Example 454
Compound 523
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((2-morpholino-
ethyl)(pyridin-3-ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentameth-
yl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2-
H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00639##
[1421] LC/MS: m/z calculated 817.6, found 818.5 (M+1).sup.+
Example 455
Compound 524
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((2-(dimethylamino)ethyl)((R-
)-1-(pyridin-2-yl)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00640##
[1423] LC/MS: m/z calculated 773.6, found 774.5 (M+1).sup.+
Example 456
Compound 525
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)ethyl-
)((5-methyl-1,3,4-oxadiazol-2-yl)methyl)amino)-1-hydroxyethyl)-1-isopropyl-
-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,1-
2,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-ox-
obutanoic acid
##STR00641##
[1425] LC/MS: m/z calculated 780.6, found 781.5 (M+1).sup.+
Example 457
Compound 526
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-(2-(((R)-1-(pyridin-3-3/1)ethyl)amino)ethyl)-3,3a,4,5,5a,5b,6-
,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9--
yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00642##
[1427] LC/MS: m/z calculated 702.5, found 703.5 (M+1).sup.+
Example 458
Compound 527
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((1-acetylazetidin-3-yl)meth-
yl)(2-(dimethylamino)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00643##
[1429] LC/MS: m/z calculated 779.6, found 780.7 (M+1).sup.+
Example 459
Compound 528
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((2-(dimethylamino)ethyl)(py-
rimidin-2-ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-ox-
o-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclo-
penta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00644##
[1431] LC/MS: m/z calculated 760.5, found 761.7 (M+1).sup.+
Example 460
Compound 529
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(((S)-1-(pyrim-
idin-5-yl)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3-
,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopen-
ta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00645##
[1433] LC/MS: m/z calculated 719.5, found 720.5 (M+1).sup.+
Example 461
Compound 530
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((2-morpholino-
-2-oxoethyl)(pyridin-2-ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pen-
tamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecah-
ydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00646##
[1435] LC/MS: m/z calculated 831.5, found 832.7 (M+1).sup.+
Example 462
Compound 531
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((2-(dimethylamino)ethyl)((R-
)-1-(pyridin-4-yl)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00647##
[1437] LC/MS: m/z calculated 773.6, found 774.7 (M+1).sup.+
Example 463
Compound 532
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(benzyl(2-morpholino-2-o-
xoethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-
-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclop-
enta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00648##
[1439] LC/MS: m/z calculated 830.5, found 831.5 (M+1).sup.+
Example 464
Compound 533
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((cyclopentylmethyl)amino)et-
hyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9-
,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2-
,2-dimethyl-4-oxobutanoic acid
##STR00649##
[1441] LC/MS: m/z calculated 679.5, found 680.7 (M+1).sup.+
Example 465
Compound 534
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(((1-acetylazetidin-3-yl)met-
hyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00650##
[1443] LC/MS: m/z calculated 708.5, found 709.7 (M+1).sup.+
Example 466
Compound 535
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-((2-((2-methox-
yethyl)(methyl)amino)ethyl)(pyridin-2-ylmethyl)amino)ethyl)-1-isopropyl-5a-
,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,1-
3,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobu-
tanoic acid
##STR00651##
[1445] LC/MS: m/z calculated 819.6, found 820.5 (M+1).sup.+
Example 467
Compound 536
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(N-(2-(dimethylamino)ethyl)b-
enzamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00652##
[1447] LC/MS: m/z calculated 772.5, found 773.5 (M+1).sup.+
Example 468
Compound 537
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(((S)-1-(pyrim-
idin-4-yl)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3-
,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopen-
ta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00653##
[1449] LC/MS: m/z calculated 719.5, found 720.5 (M+1).sup.+
Example 469
Compound 538
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-(2-((1-(pyridin-2-yl)cyclopropyl)amino)ethyl)-3,3a,4,5,5a,5b,-
6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-
-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00654##
[1451] LC/MS: m/z calculated 714.5, found 715.5 (M+1).sup.+
Example 471
Compound 540
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-(2-(piperidin-1-yl)ethyl)-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a-
,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethy-
l-4-oxobutanoic acid
##STR00655##
[1453] LC/MS: m/z calculated 665.5, found 666.5 (M+1).sup.+
Example 472
Compound 541
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-(2-(((S)-1-(pyridin-3-yl)ethyl)amino)ethyl)-3,3a,4,5,5a,5b,6,-
7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-y-
l)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00656##
[1455] LC/MS: m/z calculated 702.5, found 703.4 (M+1).sup.+
Example 473
Compound 542
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((2-(dimethylamino)ethyl)((S-
)-1-(pyridin-3-yl)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00657##
[1457] LC/MS: m/z calculated 773.6, found 774.7 (M+1).sup.+
Example 474
Compound 543
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((2-(dimethylamino)ethyl)((R-
)-1-(pyridin-3-yl)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00658##
[1459] LC/MS: m/z calculated 773.6, found 774.7 (M+1).sup.+
Example 475
Compound 544
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-(((R)-1-(pyrim-
idin-5-yl)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3-
,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopen-
ta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00659##
[1461] LC/MS: m/z calculated 719.5, found 719.8 (M+1).sup.+
Example 476
Compound 545
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-(2-chlorobenzyl)aceta-
mido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5-
,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]ch-
rysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00660##
[1463] LC/MS: m/z calculated 779.4, found 780.3 (M+1).sup.+
Example 477
Compound 546
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-(2-o-
xopyrrolidin-1-yl)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-p-
entamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadec-
ahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00661##
[1465] LC/MS: m/z calculated 848.5, found 849.5 (M+1).sup.+
Example 478
Compound 547
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-3a-(2-((oxetan-3-ylmethyl)amino)ethyl)-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9-
,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2-
,2-dimethyl-4-oxobutanoic acid
##STR00662##
[1467] LC/MS: m/z calculated 667.5, found 668.4 (M+1).sup.+
Example 479
Compound 548
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-(2-((8)-1-(pyridin-2-yl)ethyl)amino)ethyl)-3,3a,4,5,5a,5b,6,7-
,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl-
)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00663##
[1469] LC/MS: m/z calculated 702.5, found 703.5 (M+1).sup.+
Example 480
Compound 549
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-(2-((8)-1-(pyridin-4-yl)ethyl)amino)ethyl)-3,3a,4,5,5a,5b,6,7-
,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl-
)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00664##
[1471] LC/MS: m/z calculated 702.5, found 703.4 (M+1).sup.+
Example 481
Compound 550
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)ethyl-
)((R)-1-(pyrimidin-4-yl)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8-
,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-o-
ctadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00665##
[1473] LC/MS: m/z calculated 790.6, found 791.5 (M+1).sup.+
Example 482
Compound 551
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((2-(dimethylamino)ethyl)(1--
(pyridin-2-yl)cyclopropyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentameth-
yl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2-
H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00666##
[1475] LC/MS: m/z calculated 785.6, found 786.5 (M+1).sup.+
Example 483
Compound 552
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-(2-((2-(pyridin-2-3/1)
propan-2-yl)amino)ethyl)-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13-
a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutano-
ic acid
##STR00667##
[1477] LC/MS: m/z calculated 716.5, found 717.5 (M+1).sup.+
Example 484
Compound 553
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((2-(dimethylamino)ethyl)(ox-
etan-3-ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3-
,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopen-
ta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00668##
[1479] LC/MS: m/z calculated 738.5, found 739.5 (M+1).sup.+
Example 485
Compound 554
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((2-(dimethylamino)ethyl)((S-
)-1-(pyridin-2-yl)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00669##
[1481] LC/MS: m/z calculated 773.6, found 774.5 (M+1).sup.+
Example 486
Compound 555
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((2-(dimethylamino)ethyl)((S-
)-1-(pyridin-4-yl)ethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-
-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H--
cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00670##
[1483] LC/MS: m/z calculated 773.6, found 774.5 (M+1).sup.+
Example 487
Compound 556
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-(2-((1-(pyrimidin-2-yl)cyclopropyl)amino)ethyl)-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00671##
[1485] LC/MS: m/z calculated 715.5, found 716.5 (M+1).sup.+
Example 488
Compound 557
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((2-(dimethylamino)ethyl)(1--
(pyrimidin-2-yl)cyclopropyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentame-
thyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-
-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00672##
[1487] LC/MS: m/z calculated 786.6, found 787.5 (M+1).sup.+
Example 489
Compound 558
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-(N-(2-(dimethylamino)ethyl)p-
icolinamido)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a-
,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrys-
en-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00673##
[1489] LC/MS: m/z calculated 773.5, found 774.5 (M+1).sup.+
Example 490
Compound 559
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-(2-((2-(pyridin-3-yl)propan-2-yl)amino)ethyl)-3,3a,4,5,5a,5b,-
6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-
-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00674##
[1491] LC/MS: m/z calculated 716.5, found 717.5 (M+1).sup.+
Example 491
Compound 560
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3a-(2-((2-(pyridin-4-yl)propan-2-yl)amino)ethyl)-3,3a,4,5,5a,5b,-
6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-
-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00675##
[1493] LC/MS: m/z calculated 716.5, found 717.5 (M+1).sup.+
Example 492
Compound 561
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-(benzyl(2-(4-methylpiper-
azin-1-yl)-2-oxoethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pen-
tamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecah-
ydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00676##
[1495] LC/MS: m/z calculated 843.6, found 844.5 (M+1).sup.+
Example 493
Compound 562
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)ethyl-
)(oxazol-4-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-penta-
methyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahyd-
ro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00677##
[1497] LC/MS: m/z calculated 765.5, found 766.5 (M+1).sup.+
Example 494
Compound 563
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((2-(dimethylamino)ethyl)(2--
(pyridin-2-yl)propan-2-yl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentameth-
yl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2-
H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00678##
[1499] LC/MS: m/z calculated 787.6, found 788.5 (M+1).sup.+
Example 495
Compound 564
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((2-(dimethylamino)-2-oxoeth-
yl)(pyridin-4-ylmethyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl--
2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-c-
yclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
##STR00679##
[1501] LC/MS: m/z calculated 773.6, found 774.5 (M+1).sup.+
Example 496
Compound 565
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)ethyl-
)(oxazol-5-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-penta-
methyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahyd-
ro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00680##
[1503] LC/MS: m/z calculated 765.5, found 766.5 (M+1).sup.+
Example 497
Compound 46
##STR00681## ##STR00682##
[1504] Step A: Intermediate 566
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pe-
ntamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadeca-
hydro-2H-cyclopenta[a]chrysene-3a-carbaldehyde.
[1505]
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-Formyl-1-isopropyl-5a,5b,8,8-
,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-o-
ctadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (50 g) placed in
a round bottomed flask with methanol (500 ml, 10 vol) and DCM
("dichloromethane"--200 ml, 4 vol) and stirred at ambient temp
while adding solid ZrCl.sub.4 (23.4 g, 1 equiv.) in portions.
[1506] The reaction was warmed to approximately 60.degree. C. and
maintained for a total of 16 hours. The reaction was monitored for
completion on HPLC (starting material and product formed an acetal
derivative during the reaction). Once complete, the reaction was
treated with water (5 equiv.) and maintained at 60 degrees for
approximately 30 minutes.
[1507] Next, the reaction was cooled and evaporated under vacuum at
a bath temp of approximately 40.degree. C. to 200 ml (4 volumes).
Ethyl acetate (500 ml, 10 vol) was added and reaction was then
treated with 1N HCl (250 ml, 5 vol). The reaction was then mixed
thoroughly and the layers were allowed to separate. The lower
aqueous layer was drained off and back-washed with fresh ethyl
acetate (100 ml, 2 vol).
[1508] The combined organic layer was washed with 1N HCl (250 ml, 5
vol) and evaporated under vacuum at a bath temp of 40.degree. C. to
200 ml (4 vol) and then treated with acetonitrile (500 ml, 10 vol).
The reaction was then evaporated to a final volume of approximately
150 ml (3 vol). Acetonitrile (500 ml, 10 vol) was then added and
the reaction was warmed to a 60.degree. C. forming solution. Next,
was slowly added 3N HCl (100 ml, 2 vol), which resulted in
precipitate formation. (see note 2). The reaction was then allowed
to cool to ambient temperature and then it was filtered. The
filtrated solid was next rinsed with acetonitrile (2 vol) and dried
in vacuo to give a weight of 33.0 g, 72% yield of
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-p-
entamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadec-
ahydro-2H-cyclopenta[a]chrysene-3a-carbaldehyde.
[1509] Note 1: The isolated solids were contaminated with a small
amount of dimethyl acetal of product, which required reslurry in
hot acetonitrile/3N HCl to complete the hydrolysis and resulted in
loss of product (27 g recovered on re-treatment). It was determined
that in process monitoring of reaction slurries during final
hydrolysis require filtration of reaction aliquot in order to
observe remaining dimethyl acetal. Dissolution of crude
acetonitrile/aqueous HCl reaction solution for HPLC monitoring
results in artificially low observed levels of dimethyl acetal due
to hydrolysis in sample prep.
[1510] Note 2: Preferred procedure would be to add a portion of the
3N HCl (0.5 vol) and maintain reaction in solution at approximately
60.degree. C. until dimethyl acetal hydrolysis is complete followed
by addition of remainder (1.5 vol) of the 3N HCl and cooling to
ambient temperature for filtration. Expected yield is 72%.
Step B: Intermediate 567
1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-formyl-1-isopropyl-5a,5b,8,8,11-
a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octa-
decahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate
[1511]
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-Hydroxy-1-isopropyl-5a,5b,8,8-
,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-o-
ctadecahydro-2H-cyclopenta[a]chrysene-3a-carbaldehyde (26.9 g, 1
equiv), 4-(tert-butoxy)-3,3-dimethyl-4-oxobutanoic acid (14.96 g,
1.25 equiv) and THF (538 ml, 20 vol) were charged to a flask.
Benzoyl chloride (10.4 g, 1.25 equiv) was added followed by slow
addition of triethylamine (14.97 g, 2.5 equiv) forming a thick
slurry. DMAP (0.1.81 g, 0.25 equiv) was added and the reaction was
allowed to stir at ambient temperature for approximately 18 hours
until complete by HPLC. Reaction was then charged with ethyl
acetate (538 mL, 20 vol) and water (269 ml, 10 vol), stirred well
and allowed to settle. Aqueous phase was removed and the organic
phase washed with saturated sodium bicarbonate solution (2.times.10
vol) followed by water (269 mL, 10 vol). The reaction solution
evaporated under vacuum to approximately 4 volumes to produce
solids. Additional hexanes (269 ml, 10 vol) was added and reaction
heated back to reflux to nearly form solution and slowly cooled to
ambient temperature (seeding with desired product) and let stir for
15 minutes then cooled to 0.degree. C. for approximately two hours
and filtered solid. Washed solid with hexanes (2.times.10 vol) and
dried at 50.degree. C. under vacuum to a weight of 32.15 g, 85%
yield of 1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-formyl-1-isopropyl-5a,5b,8,8,11-
a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octa-
decahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate.
Step C: Intermediate 569
1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-nitroethyl)-1--
isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,-
11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)2,2-dimethyls-
uccinate
[1512] The reaction was charged with 1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-formyl-1-isopropyl-5a,5b,8,8,11-
a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octa-
decahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate
(15.75 g, 1 equiv), tert-butanol (157 ml, 10 vol) and toluene (47
ml, 3 vol) and stirred at ambient temperature. The ligand
(N1,N2-bis(1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)ethane-1,2-diamine,
derived from (S)-camphor, 0.492 g, 0.06 equiv) and copper (II)
acetate mono hydrate (0.246 g, 0.05 equiv) were added in a single
portion and reaction allowed to stir at ambient temperature for at
least 2.5 hours (see note 1). The reaction is charged with
nitromethane (7.52 g, 5 equiv) and Hunig's base
("N,N-diisopropylethylamine"--3.82 g, 1.2 equiv) and allowed to
stir at ambient temperature for approximately 5 days. (See note 2).
Reaction concentrated under vacuum at bath temp of no more than
35.degree. C. to approximately 2 vols. (See note 3). Reaction
charged with toluene (236 ml, 15 vols) and concentrated under
vacuum again to approx 3 vols. Additional toluene (95 ml, 3 vol)
was added to achieve a final reaction volume of approx 6 vols.
Heptane (158 ml, 10 vols) was added slowly of to solution. Product
began to crystallize out of solution upon seeding. Reaction was
allowed to stir at ambient temperature for one to two hours and
solids collected by filtration and washed with 10 vols of heptane.
Solids were dried to a weight of 14.3 g (83% yield). Purity of
isolated solid is typically 90-95% with a 98/2 diastereomeric ratio
favoring 1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-nitroethyl)-1--
isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,-
11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)
2,2-dimethylsuccinate as the major diastereomer.
Step D: Intermediate 570
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-amino-1-hydroxyethyl)-1-i-
sopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,1-
1a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)
1-tert-butyl 2,2-dimethylsuccinate
[1513] 1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-nitroethyl)-1--
isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,-
11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)
2,2-dimethylsuccinate (12.9 g, 18.4 mmol) was placed in 1-L retreat
curve impeller reactor and then added 22 vol of 90% THF-HOAc and
stirred to dissolve at ambient temp. The reactor was purged
3.times. with nitrogen and then a slurry of water was added and
then washed (pH 8-9) RaNi catalyst (50% water, added 2.6 ml
catalyst slurry, 1.3 g RaNi calculated) and then placed under
hydrogen at 0.3 bar pressure for 3 hours and then raised the
pressure to 2 bar and allowed to stir for 18 hours. Reaction was
approximately 20% complete at this time. The temperature was raised
to 35 deg C. and then the reaction was stirred for another 7 hours
and sampled. The reaction was approximately 31% complete at this
time. Reaction pressure was increased to 4 bar hydrogen and was
allow to continue stirring at 35 deg for 20 hours. Reaction is 75%
complete at this time and no change in impurity profile. Added
another 0.15 wt of RaNi (3.0 ml of 50% slurry) to bring total RaNi
loading up to 25 wt % and the reaction was allowed to stir at 35
deg under 4 bar Hydrogen for another 24 hours. The reaction was
then determined to be complete by HPLC.
[1514] The reaction was then filtered through a 4 micron in-line
filter, rinsing with THF (50 ml). Evaporated to approximately 3 vol
and added ethyl acetate (195 ml, 15 vol) and washed with 1N NaOH
solution (3.times.10 vol) and verified final wash to be basic pH.
(Note: addition of 0.5 vol saturated NaCl solution was required on
second and third washes to obtain efficient separation). Washed
with saturated sodium chloride solution (5 vol) and evaporated to a
solid foam that was azeotroped with 2.times.5 vol dichloromethane
in order to obtain a solid foam. Dried on high vacuum pump to
weight of 11.1 g (90% yield).
[1515] Recrystallized above sample (10.5 g) by dissolving in
methanol (147 ml, 14 volumes) at reflux and then cooling with
seeding to ambient temperature and allowed to stir 30 minutes).
Mixture was further cooled to 15 degrees and filtered. Solids
collected by filtration and washed with methanol (1 volume) and
dried at 50 degrees in vacuo to a weight of 7.5 g (71% yield on
recrystallization) of
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-amino-1-hydroxyethyl)-1--
isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,-
11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)
1-tert-butyl 2,2-dimethylsuccinate.
Step E and F: Compound 46
1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl) 2,2-dimethylsuccinate
[1516]
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-Amino-1-hydroxyeth-
yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,-
10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)
1-tert-butyl 2,2-dimethylsuccinate and p-Cl-benzaldehyde (1.1
equiv) were placed in a round bottomed flask with EtOH (10 vol) and
added Na.sub.2CO.sub.3 powder (2.5 equiv) and allowed to stir
overnight (16 hrs). The next day, the reaction slurry was cooled to
approximately 10 degrees and added NaBH.sub.4 to the reaction in a
single portion and allowed reaction to stir while slowly warming to
ambient temperature. Obtained HPLC after 45 minutes showing
essentially complete conversion to desired product. p-Cl-benzyl
alcohol present as well (using 220 nm wavelength). The reaction was
then diluted with methylene chloride (30 ml, 10 vol) and water (30
ml, 10 vol) and the layers were allowed to separate. The DCM layer
was then washed with additional water (10 vol) and evaporated to
minimum volume on rotovap and added back DCM (10 vol) and treated
with trifluoroacetic acid (6 ml, 2 vol) and the reaction was
allowed to stir at ambient temperature. The reaction was almost
complete after one hour, but it was left to stir overnight. After
18 hours reaction complete by HPLC and was evaporated to an
oil.
[1517] Dissolved with warming to approximately 45 degrees in ethyl
acetate (60 ml, 20 vol) and washed with NaHCO.sub.3 solution
(2.times.10 vol) to remove residual TFA. Then, washed with ethyl
acetate and with half-saturated NaCl solution and evaporated to
dryness and azeotroped dry with isopropanol (2.times.5 vol).
Dissolved in isopropanol (5 vol) and diluted with acetonitrile to
cloud point (10 vol) and then allowed to crystallize overnight.
Cloudy mixture, but no filterable solids present. Meanwhile the
test crystallization from ethyl acetate-heptane of the original
isolated TFA salt solution had produced nice solids.
[1518] The entire reaction was then evaporated to dryness and
azeotroped several portions of ethyl acetate on rotovap (3.times.10
vol) to remove all isopropanol and acetonitrile. Reaction dissolved
with warming to reflux in ethyl acetate (30 ml, 10 vol). Added one
equivalent trifluoroacetic acid (0.51 g) and slowly diluted with
heptane to cloud point (15 ml, 3 volumes). Seeded with test
crystallization seeds from above. Nice solids resulted almost
immediately. Stirred with cooling to ambient temperature. Filtered
solids and washed with heptane (15 ml, 3 vol). Dried on funnel to
weight of 2.55 g, 67% yield of
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)amino)-
-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
Alternative Procedure
[1519]
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-Amino-1-hydroxyeth-
yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,-
10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)
1-tert-butyl 2,2-dimethylsuccinate (7 g, 1 equiv.) was placed in a
round bottom flask and added MgSO.sub.4 powder (2.5 equiv) and
Et.sub.3N (0.8 equiv) and p-Chlorobenzaldehyde and added MeOH (10
vol) and allowed to stir overnight (16 hrs). After this time an
aliquot (0.5 ml) of the white slurry was removed and treated with
approximately 25 mg NaBH.sub.4 and allowed to stir for 5 minutes.
Obtained HPLC of this aliquot indicating complete consumption of
the amine starting material. The reaction mixture was cooled to 0
degrees on ice-brine bath and treated with solid NaBH.sub.4 in a
single portion (475 mg, 1.2 equiv) and allowed to stir at 0 degrees
for approximately 45 minutes. HPLC after this time shows reaction
is complete. The reaction was warmed to ambient temperature briefly
and filtered through a celite bed. The solid was rinsed with
additional methanol (35 ml, 5 vol) and then dichloromethane (70 ml,
10 vol). The filtrate/rinse was then treated with water (70 ml, 10
vol) and shaken in separatory funnel. The upper aqueous was washed
well with additional dichloromethane (3.times.5 vol) and then the
combined organic layers were washed with brine (10 vol). The
organic phase was evaporated to a solid foam and azeotroped with
dichloromethane. Dissolved in dichloromethane (70 ml, 10 vol) and
treated with trifluoroacetic acid (14 ml, 2 vol) and allowed to
stir at ambient temperature. The reaction almost complete in
approximately 2 hours.
[1520] The reaction was allowed to sit over a weekend at which
point the reaction was complete. The reaction was allowed to
evaporate to a minimum volume and then ethyl acetate (10 vol) was
added and evaporated to a minimum volume again. Repeated this
evaporating to minimum volume and then dissolved in total of 10
volume ethyl acetate. Heated to near reflux and diluted with
heptane (5 vol) and stirred while cooling to ambient temperature
while solids were formed. Stirred for 30 minutes and filtered.
Rinsed with heptane (3 vol) and dried to a weight of 4.85 g, 63%
yield of
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)amino)-
-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid over two steps.
Example 498
Compound 51
##STR00683## ##STR00684##
[1521] Step A: Intermediate 566
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pe-
ntamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadeca-
hydro-2H-cyclopenta[a]chrysene-3a-carbaldehyde
[1522] The compound
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-formyl-1-isopropyl-5a,5b,8,8,11a-p-
entamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadec-
ahydro-2H-cyclopenta[a]chrysen-9-yl acetate (400 g, 0.81 mol) was
placed in a flask with methanol (4 L) and DCM (1.6 L) and stirred
at ambient temp while adding solid ZrCl.sub.4 (225.2 g, 0.97 mol)
in portions. The reaction was warmed to approximately 45-55.degree.
C. and maintained for a total of 30-36 hours. The reaction was
monitored for completion by HPLC.
[1523] Once complete, the reaction was then treated with water (120
mL) and maintained at 45-55.degree. C. for approximately 30-60
minutes. The reaction was then cooled and evaporated under vacuum
(at bath temp approximately 40.degree. C.) to 1200 mL.
Dichloromethane (4 L) was added and reaction was treated with 1N
HCl (2 L), mixed thoroughly and the layers were allowed to
separate. Afterwards, the upper aqueous layer was washed with fresh
dichloromethane (800 mL). Next, the combined organic layer was
washed with 1N HCl (2 L) and evaporated under vacuum (at bath temp
of 40.degree. C.) to 800 mL and treated with acetonitrile (4
L).
[1524] The reaction was then evaporated (at bath temp of 40.degree.
C.) to a final volume of approximately 800 mL. Acetonitrile (3.2 L)
was added and the reaction was warmed to 50-60.degree. C., thus
forming a solution. Next was slowly added, 3N HCl (100 mL), which
resulted in precipitate formation and which was maintained as a
reaction in solution at approximately 50-60.degree. C. until
dimethyl acetal hydrolysis was complete followed by addition of
water (4.8 L).
[1525] The reaction was allowed to cool to 0-10.degree. C. and then
the mixture was filtered and the resultant solid was rinsed with
acetonitrile/water (1/1,800 mL). The solid was then slurried in 10
volumes of heptane at 85-100.degree. C. for 1-3 hours. The slurry
was then cooled to ambient temperature and filtered. Washed the
cake with 800 mL heptane then dried in vacuo at 40-50.degree. C. to
the
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-formyl-1-isopropyl-5a,5b,8,8,11-
a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octa-
decahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate 286
g. Yield is 72.6% corrected by assay.
[1526] .sup.1H NMR (400 MHz, CDCl3) .delta.=9.33 (s, 1H), 3.20-3.28
(m, 2H), 2.57 (d, J=1H), 2.36-2.42 (m, 2H), 2.04-2.08 (m, 2H),
1.86-1.90 (m, 2H), 1.75-1.78 (m, 1H), 1.23-1.66 (m, 35H); LC/MS:
m/z calculated 454.3, found 455.4 (M+1).sup.+
Step B: Intermediate 567
1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-formyl-1-isopropyl-5a,5b,8,8,11-
a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octa-
decahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate
[1527] The starting material
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-p-
entamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadec-
ahydro-2H-cyclopenta[a]chrysene-3a-carbaldehyde (32.4 g, 71 mmol),
4-(tert-butoxy)-3,3-dimethyl-4-oxobutanoic acid (18 g, 89 mmol) and
THF (648 mL) were charged to a flask. Benzoyl chloride (12.5 g, 89
mmol) was added followed by slow addition of triethyl amine (18 g,
178 mmol) forming a thick slurry. DMAP (2.17 g, 18 mmol) was added
and the reaction was allowed to stir at ambient temperature for
approximately 24-30 hours until complete by HPLC. The reaction was
then charged with ethyl acetate (648 mL) and water (324 mL),
stirred well and allowed to settle. The aqueous phase was removed
and the organic phase washed with saturated sodium bicarbonate
solution (2.times.324 mL) followed by water (324 mL).
[1528] The reaction solution was then evaporated under vacuum to
approximately 129 mL in order to produce solids. Additional heptane
(324 mL) was added and the reaction heated back to reflux to a
nearly formed solution and slowly cooled to ambient temperature and
was stirred for 15 minutes then cooled to 0.degree. C. for
approximately two hours and the solids were filtered. The solids
were then washed with heptane (2.times.324 mL) and dried at
50.degree. C. under vacuum to give the desired compound as an
off-white solid 1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-formyl-1-isopropyl-5a,5b,8,8,11-
a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octa-
decahydro-2H-cyclopenta[a]chrysen-9-yl)2,2-dimethylsuccinate 36.8
g. yield is 80%. 1H NMR (400 MHz, CDCl3) .delta.=9.24 (s, 1H),
4.41-4.45 (m, 1H), 3.19-3.20 (m, 1H), 2.33-2.48 (m, 5H), 0.96-1.60
(m, 37H), 0.77-0.87 (m, 17H); LC/MS: m/z calculated 638.4, found
639.4 (M+1).sup.+.
Step C: Intermediate 569
1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-nitroethyl)-1--
isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,-
11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)2,2-dimethyls-
uccinate
[1529] The reaction was charged with of
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-formyl-1-isopropyl-5a,5b,8,8,11-
a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octa-
decahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (50
g, 78 mmol), tert-butanol (500 mL) and toluene (150 mL) and the
temperature was adjusted to 20-25.degree. C. The ligand
(N1,N2-bis(1,7,7-trimethylbicyclo [2.2.1]
heptan-2-yl)ethane-1,2-diamine (1.56 g, 4.7 mmol) and Copper(I)
acetate (0.48 g, 3.9 mmol) were added in a single portion and the
reaction was then stirred at 20-25.degree. C. for 3-5 hrs.
[1530] The reaction was next allowed to cool to 7-13.degree. C. The
reaction was then charged with nitromethane (33 g, 0.55 mmol) and
N,N-diisopropyl ethylamine (12.1 g, 94 mmol) and allowed to stir at
7-13.degree. C. for approximately 30 hrs. The reaction was again
charged with nitromethane (17 g, 0.3 mmol) and allowed to stir at
7-13.degree. C. for approximately 40 hrs. The reaction was yet
again charged with nitromethane (17 g, 0.3 mmol) and allowed to
stir at 7-13.degree. C. for approximately 20 hrs.
[1531] Next, the reaction was charged with MTBE (750 mL) and a 15%
ammonium chloride solution (300 mL), allowed to stir for 30 min,
and then separated into two phases. The organic phase was washed
with water (250 mL) followed by brine (200 mL). The organic phase
was then concentrated to 100 mL and MTBE (25 mL) was added. Next,
n-heptane (500 mL) was slowly added and then stirred at
10-20.degree. C. for 2 hrs. The reaction was then filtered and
washed with n-heptane, and then dried under vacuum at 50-55.degree.
C. to give
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-nitroethyl)-1--
isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,-
11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)
2,2-dimethylsuccinate as off-white solid 41.6 g. Yield is
75.9%,.sup.1H NMR (400 MHz, CDCl3) .delta.=4.85 (bd, 1H), 4.51-4.55
(dd, 1H), 4.08-4.20 (m, 2H), 3.15-3.22 (m, 1H), 2.35-2.83 (m, 6H),
0.80-2.03 (m, 54H); LC/MS: m/z calculated 699.4, found 700.4
(M+1).sup.+.
Step D: Intermediate 570
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-amino-1-hydroxyethyl)-1-i-
sopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,1-
1a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)1-tert-butyl
2,2-dimethylsuccinate
[1532] To
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-nitro-
ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8-
,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)
2,2-dimethylsuccinate (30 g, 42.6 mmol) in THF (600 mL) and AcOH
(30 mL) was added Raney Ni (30 g, 5%) under N.sub.2 at room
temperature. The reaction was stirred at 45-55.degree. C. under
hydrogen gas (0.30-0.40 MPa) for 10-12 hours. The reaction mixture
was filtered through a filter aid, washing with THF [2.times.90 mL]
and the filtrate was adjusted to a pH of 7-8 with 5%
K.sub.2CO.sub.3 aqueous.
[1533] Next, ethyl acetate (450 mL) was added to the reaction
mixture and the two phases were separated. The aqueous layer was
extracted with ethyl acetate (150 mL). The combined organic phase
was washed two times with 7.5% NaCl aqueous (300 mL) and then
washed with 17% NaCl aqueous (300 mL). The organic phase was
concentrated under vacuum to give 25.7 g of
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-amino-1-hydroxyethyl)-1--
isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,-
11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)
1-tert-butyl 2,2-dimethylsuccinate. Yield is 92%. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.=4.40-4.44 (dd, 1H), 3.79-3.80 (bd, 1H),
3.59-3.62 (M, 2H), 3.12-3.17 (m, 2H), 2.60-2.75 (m, 1H), 2.22-2.34
(m, 2H), 2.19-2.22 (m, 2H), 1.37-1.84 (m, 25H), 1.08-1.11 (m, 17H),
0.81-0.91 (m, 13H); LC/MS: m/z calculated 669.5, found 670.4
(M+1).sup.+
Step E: Intermediate 571
1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)2,2-dimethylsuccinate
[1534] To a solution of
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-amino-1-hydroxyethyl)-1--
isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,-
11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)
1-tert-butyl 2,2-dimethylsuccinate in THF (5 g, 7.6 mmol in 100 mL
THF) was added 4-chlorobenzaldehyde (0.96 g, 6.84 mmol) and then
stirred at -2-2.degree. C. for 0.5 hours. Next, NaHB(OAc).sub.3
(3.53 g, 16.7 mmol) was added to the reaction and stirred at
-2-2.degree. C. for 0.5 hours. The reaction was then warmed to
3-7.degree. C. and again stirred at 3-7.degree. C. for 10-15 hours
and then stirred at 8-12.degree. C. for 5-8 hours.
[1535] The reaction was quenched by saturated NI-1.sub.4Cl
(aqueous) (50 mL) and water (20 mL) and then stirred at
10-20.degree. C. for 0.5 hours. The reaction was then extracted
with MTBE (75 mL) and the aqueous layer was extracted with MTBE (25
mL). The combined organic phase was washed with water (25 mL) and
the pH adjusted to 7-8 with 5% K.sub.2CO.sub.3 aqueous. The organic
phase was separated and washed two times with 7.5% NaCl aqueous (50
mL) and then washed with 20% NaCl aqueous (50 mL). The organic
phase was concentrated under vacuum again to approx 20 mL.
Additional DCM (60 mL) was added and concentrated under vacuum to
approx 20 mL. Additional DCM (60 mL) was again added and
concentrated under vacuum to approx 20 mL. Additional DCM (60 mL)
was again added and concentrated under vacuum to approx 20 mL.
Then, 50 mL MeOH was charged and concentrated under vacuum again to
approx 20 mL. An additional 50 mL MeOH was charged to give a
solution of
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl) 2,2-dimethylsuccinate in MeOH. This mixture was used in the
next step directly. 1HNMR (400 MHz, DMSO-d6)
.delta.=0.81-1.78(m,49H),1.91(s,6H), 2.18-2.20(m,2H) 2.32-2.37
(m,3H), 3.02-3.08 (M, 2H?] 3.56-3.62(m,4H) 4.00-4.04 (d,1H)
4.12-4.15(d,1H) 4.27-4.40 (m,1H) 4.39-4.43(m,1H), 7.43-7.45 (d,
2H),7.52-7.54 (d,2H); LC/MS: m/z calculated 793.5, found 794.4
(M+1).sup.+.
Step F: Intermediate 54
1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-(dim-
ethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)2,2-dimethylsuccinate
[1536] Added a solution of
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl) 2,2-dimethylsuccinate (55 g, 69.3 mmol) dissolved in methanol
(825 mL), dimethyl amino acetaldehyde hydrogen sulfite sodium salt
(66.8 g, 0.35 mol) and Et.sub.3N(38.7 g, 0.38 mol) into a reactor.
The reaction was stirred for 2-3 hrs at 30-40.degree. C. under
nitrogen protection. NaBH.sub.3CN (8.8 g, 0.14 mol) was added and
stirred at 30-40.degree. C. under nitrogen protection for 13-15
hrs. Next, the reaction temperature was adjusted to 50-60.degree.
C. and stirred for 3-5 hrs. The reaction mixture was then
concentrated to 275 mL and then DCM (550 mL) was added, followed by
water (440 mL). The two phases were separated and the water phase
was extracted with DCM (twice with 385 mLs each time). The organic
phase was washed with water (twice with 358 mLs each time). Next,
the organic phase was concentrated to give 1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-(dim-
ethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate 43 g oil. Yield
is 71%. 1HNMR (400 MHz, CDCl3) .delta.=7.27-7.29 (m, 4H),4.46-4.50
(m,1H), 4.08-4.13 (m,2H), 4.00-4.02 (m, 1H), 3.59-3.60 (m, 1H),
3.09 (m, 1H), 2.03-2.67 (m, 14H), 0.62-1.42 (m, 57H); LC/MS: m/z
calculated 864.5, found 865.6 (M+1).sup.+.
Step G: Compound 51
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-(dim-
ethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
[1537] From the last step, dissolved the 1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-(dim-
ethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (0.8 g, 0.92
mmol) in 3.2 mL DCM, then charged 1.6 mL TFA into the solution.
[1538] The reaction mixture was then stirred at 15-25.degree. C.
for 1-3 hrs. Next, the reaction was charged with 4 mL DCM and 4 mL
water, stirred well and then allowed to settle. The aqueous phase
was then removed and the organic phase washed two times with water
(4 mLs each). The aqueous phase was then extracted with DCM (1.6
mL). The combined organic phase was then washed with saturated
sodium bicarbonate until the pH was between 7-8, followed by two
more washes with water (4 mLs each).
[1539] Next, the organic phase was evaporated under vacuum to give
0.69 g crude product. The crude product was then dissolved in 4.8
mL isopropanol and heated to reflux to dissolve all material.
Acetonitrile (19 mL) was added and brought to a gentle reflux and
allowed to start cooling while seeded with 2 mg seed material at
45.degree. C. The mixture was then stirred at 45.degree. C. for 2
hours. Solids began form and they were cooled to 10-20.degree. C.
and stirred for 3 hours. The solution solids were filtered and then
rinsed twice with 1 g acetonitrile each time.
[1540] The solids were then dried in a vacuum oven at 45 deg C. for
18 hours to give the desired product:
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-(di-
methylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentame-
thyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-
-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
(0.59 g, yield was 78%).
Example 499
Compound 51
##STR00685## ##STR00686##
[1542] Procedures for steps A and D below are not included and are
similar to those reported in previous examples and will be
understood by one skilled in the art.
Step B: Intermediate 567
1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-formyl-1-isopropyl-5a,5b,8,8,11-
a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octa-
decahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate
[1543] The starting material
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-p-
entamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadec-
ahydro-2H-cyclopenta[a]chrysene-3a-carbaldehyde (5 g, 11 mmol),
4-(tert-butoxy)-3,3-dimethyl-4-oxobutanoic acid (3.4 g, 16.5 mmol),
THF ("tetrahydrofuran"--100 mL) and triethylamine (3.4 g, 33 mmol)
were charged to a flask.
[1544] The mixture was then stirred for 20-30 mins at 0-5.degree.
C. Then, 4-methoxybenzoyl chloride (2.8 g, 16.5 mmol) was added
through a dropping funnel while the reaction temperature was
maintained at 0-5.degree. C. The reaction was then stirred for an
additional 1 hour, then DMAP ("dimethylaminopyridine"--0.2 g, 1.65
mmol) was added and the reaction allowed to stir at ambient
temperature for approximately 24-30 hours until complete by
HPLC.
[1545] Next, the reaction was charged with ethyl acetate (100 mL)
and water (50 mL), stirred well and allowed to settle. The aqueous
phase was removed and the organic phase washed with saturated
sodium bicarbonate solution (2.times.50 mL) followed by water (50
mL). The reaction solution was evaporated under vacuum to
approximately 5-10 mL to produce solids. An additional amount of
heptane (50 mL) was added and the reaction heated back to reflux to
nearly form solution and slowly cooled to ambient temperature and
let stir for 15 minutes then cooled to 0.degree. C. for
approximately two hours and the solids were filtered out. Next, the
solids were washed with heptane (2.times.50 mL) and dried at
50.degree. C. under vacuum to give the desired compound as
off-white solid 1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-formyl-1-isopropyl-5a,5b,8,8,11-
a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octa-
decahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate. (4.7
g, yield is 67%).
Step C: Intermediate 569
1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-nitroethyl)-1--
isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,-
11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)
2,2-dimethylsuccinate
[1546] A reaction was charged with
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-formyl-1-isopropyl-5a,5b,8,8,11-
a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octa-
decahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (6 g,
9.4 mmol), tert-butanol (60 mL) and toluene (18 mL) and temperature
was adjusted to 20-25.degree. C. The ligand
(N1,N2-bis(1,7,7-trimethylbicyclo [2.2.1]
heptan-2-yl)ethane-1,2-diamine (0.2 g, 0.57 mmol)) and Copper(I)
acetate (0.06 g, 0.47 mmol) were added in a single portion and the
reaction allowed to stir at 20-25.degree. C. for 3-5 hrs.
[1547] The reaction was then cooled to a temperature of
7-13.degree. C. Afterwards, the reaction was charged with
nitromethane (3.9 g, 63 mmol) and allowed to stir at 7-13.degree.
C. for approximately 30 hrs. The reaction was charged with
additional nitromethane (2.2 g, 35.7 mmol) and allowed to stir at
7-13.degree. C. for approximately 40 hrs. The reaction was charged
again with additional nitromethane (2.2 g, 35.7 mmol) and allowed
to stir at 7-13.degree. C. for approximately 20 hrs.
[1548] Next, the reaction was charged with MTBE ("methyl tertiary
butyl ether"--90 mL) and a 15% ammonium chloride solution (36 mL),
and allowed to stir for 30 min and then allowed to separate out
into two phases. The organic phase was washed with water (30 mL)
followed by brine (24 mL). The organic phase was then concentrated
to 12 mL and MTBE (3 mL) was added. Next, n-heptane (60 mL) was
slowly added and then stirred at 10-20.degree. C. for 2 hrs. The
solution was then filtered and washed with n-heptane, the cake was
then dried under vacuum at 50-55.degree. C. to give
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-hydroxy-2-nitroe-
thyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,-
9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)
2,2-dimethylsuccinate as off-white solid 4.27 g. (65% yield)
Step E: Intermediate 571
1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl) 2,2-dimethylsuccinate
[1549]
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-amino-1-hydroxyeth-
yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,-
10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)
1-tert-butyl 2,2-dimethylsuccinate (15 g, 22.4 mmol) was placed in
a round bottomed flask and then the following were also added:
MgSO.sub.4 powder (8.1 g, 56 mmol) and Et.sub.3N (3.6 g,35.8 mmol)
and p-Chlorobenzaldehyde (5.05 g, 29.1 mmol) and added MeOH (300
mL). The reaction was then allowed to stir for 2 hrs.
[1550] The reaction mixture was then cooled to 0 degrees C. on
ice-brine bath and treated with solid NaBH.sub.4 (1.61 g, 42.56
mmol) under 10 degrees C. and allowed to stir at 20 degrees for
approximately 45 minutes. HPLC after this time showed the reaction
was complete. The reaction was then filtered through a Celite.TM.
bed. The solids were rinsed with additional methanol (75 mL) and
then dichloromethane (150 mL). The filtrate/rinse was treated with
water (150 mL) and shaken in a separation funnel. The organic
layers were then washed with water (150 mL). Next, the organic
phase was evaporated to give 15 g of 1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl) 2,2-dimethylsuccinate as a foamy solid, 84% yield. The crude
product was used for the next step directly.
Step F: Compound 46
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid, 2,2,2-trifluoroacetic
acid salt (1:1)
[1551] Dissolved 1-tert-butyl
4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)amino)--
1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl) 2,2-dimethylsuccinate (15 g, 18.9 mmol) in dichloromethane
(150 mL) and treated with trifluoroacetic acid (30 mL) and allowed
to stir at ambient temperature. The reaction was complete in
approximately 10 hours. Next, the reaction washed with water
(2.times.150 mL) and the organic phase was evaporated to a minimum
volume and ethyl acetate (150 mL vol) was added and then evaporated
again to a minimum volume. Evaporated again to a minimum volume and
then dissolved in a total of 150 mL volume ethyl acetate.
[1552] Next, the resultant solution was heated to near reflux and
then diluted with heptane (90 mL) and stirred while cooling to
ambient temperature, at which point, solids were formed. The
solution was then stirred for 30 minutes and filtered. The filtered
solids were rinsed with heptane (30 mL) and dried to give 13 g
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)amino)-
-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5-
b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-
-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid, 2,2,2-trifluoroacetic
acid salt (1:1), 81% yield. 1HNMR (400 MHz, DMSO-d6)
.delta.=0.60-1.89(m, 46H) 2.16-2.19(d,1H) 2.32-2.68 (m, 4H)
3.02-3.11 (m,1H) 4.10-4.26 (m, 3H), 4.38-4.42(dd,1H) 5.93(s,1H)
7.51(s,4H), 8.80-8.98(d, 2H); LC-MS: m/z calculated (free base)
737.4, found 738.1 (M+1)+.
Step G: Compound 51
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-(dim-
ethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamet-
hyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro--
2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
[1553] From Step F above, the
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)amino)-
-1-hydroxyethyl)-1isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b-
,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen--
9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid trifluoroacetic acid salt
(9.0 g, 10.56 mmol) was placed in a round bottomed flask and added
dimethylamino acetaldehyde hydrogen sulfite salt (5.05 g, 26.4
mmol) and CH.sub.3COONa (3.46 g, 42.23 mmol) and added MeOH (180
mL) and allowed to stir for 1 hour.
[1554] To the reaction mixture was added NaBH.sub.3CN (2.65 g,
42.23 mmol) and allowed to stir at 25 degrees C. for approximately
36 hrs. HPLC after this time showed reaction was complete. Next,
the reaction was filtered through a Celite.TM. bed. The solids were
then rinsed with additional methanol (45 mL) and then
dichloromethane (90 mL). The filtrate/rinse was treated with water
(45 mL) and shaken in separatory funnel. The organic layers were
then washed with NaHCO.sub.3 (4 times--45 mL each) and water (two
times--45 mL each).
[1555] The organic phase was then evaporated to a minimum volume
and i-PrOH (36 mL) was added and heated to 75 degrees C. for 2
hours. The resulting solution was then diluted with CH.sub.3CN (45
mL) at 75 degrees C. The solution was then cooled to 5 degrees C.
over 4 hours. The solution was then stirred at 5 degrees C. for 2
hours and filtered. The filtrate was then rinsed with CH.sub.3CN (9
mL) and dried to give crude
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-(di-
methylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentame-
thyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-
-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
(5.6 g, 65% yield).
Re-Crystallization
[1556] From Step G above, the crude
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-(di-
methylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentame-
thyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-
-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid
(5.6 g) was placed in a round bottomed flask and added i-PrOH (36
mL) and heated to 75 degrees C. for 2 hours. Next, the reaction was
diluted with CH.sub.3CN (45 mL) at 75 degrees C. The reaction was
then cooled to 5 degrees C. over 4 hours.
[1557] The reaction was then stirred at 5 degrees C. for 2 hours
and filtered. The filtrate was then rinsed with CH.sub.3CN (9 mL)
and dried to give 4.8 g
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2-(di-
methylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentame-
thyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-
-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid,
84% yield. 1HNMR (400 MHz, DMSO-d6) .delta.=0.80-0.29
(m,14H),0.97-1.17 (m, 21H),1.32-1.91 (m, 13), 2.08-2.23 (m,12H)
2.27-2.38 (m, 3H) 2.40-2.46 (m, 1H) 2.51-2.20 (m,1H) 2.66-2.70
(m,1H) 3.00-3.04 (m,1.0H) 3.71-3.78(m, 1H) 3.89-3.91(d, 1H)
4.37-4.41(dd, 1H), 7.31-7.37 (m,4H); LC-MS: m/z calculated 808.5,
found 809.1 (M+1)+.
Synthesis of Intermediate 11S
##STR00687##
[1558]
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-nitroethyl)-
-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,-
11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl
acetate
[1559]
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-formyl-1-isopropyl-5a,5b,8,8-
,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-o-
ctadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (2.0 g, 4.03
mmol) was placed in a flask with n-BuOH (10 ml) and diamine
catalyst derived from (R)-camphor
(N1,N2-bis(1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)ethane-1,2-diamine,
0.08 g, 0.242 mmol) diamine catalyst and Cu(OAc).sub.2 (0.037 g,
0.201 mmol) and stirred approximately 16 hours at ambient
temperature.
[1560] The reaction was then cooled to approximately 0.degree. C.
and treated with nitromethane (1.23 g, 20.1 mmol) and Hunig's base
(("N,N-diisopropylethylamine"--0.053 g, 0.40 mmol) and allowed to
held at 5.degree. C. for 24 hours. Additional BuOH (25 ml) and
Hunig's base ("N,N-diisopropylethylamine") were added and the
reaction held at -10.degree. C. for 24 hours and then at ambient
temperature for 24 hours. Solids present in the reaction were
filtered to provide the title compound as an off white solid (1.1
g, 49% as .about.95:5 mixture of diastereomers). .sup.1H NMR (500
MHz, CDCl3) .delta.=4.89 (bd, 1H), 4.57 (d, 1H), 4.49 (dd, 1H),
4.34 (dd, 1H), 3.21 (m, 1H) 2.94 (dd, 1H) 2.38 (m, 2H) 2.08 to 0.8
(m, 54H) *Note: Integration of the 2.4 to 0.8 region of the
spectrum is higher due to the presence of impurities in the
sample.
Synthesis of Intermediate 12S
##STR00688##
[1562]
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-amino-1-hydroxyethyl)-
-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,-
11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl
acetate
[1563] To a flask containing
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-hydroxy-2-nitroethyl)-1-iso-
propyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a-
,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate
(.about.95% single diastereomer from the previous Intermediate 11S
stage, 0.5 g, 0.89 mmol) in methanol and cooled to -5.degree. C.
was added NiCl.sub.2 (0.232 g, 1.79 mmol). The contents were
stirred and treated with NaBH.sub.4 (0.475 g, 12.5 mmol), which was
added slowly in portions over a 30 minute period while maintaining
at approximately -5.degree. C.
[1564] An extremely exothermic reaction resulted in some material
loss. The reaction was warmed to ambient temperature slowly over a
30 minute period and allowed to stir for approximately 2 hours. The
reaction was then quenched with NH.sub.4Cl soln and diluted with
methylene chloride. The liquid layers were separated and the
organic layer was washed several times with NH.sub.4Cl soln. Next,
the organic layer was evaporated to dryness and the residue was
chromatographed on silica gel column and eluted with 10%
methanol-dichloromethane. The product containing fractions were
evaporated to give title compound as grey solid (250 mg, 53%
yield). Sample was carried on to next stage without further
characterization.
Synthesis of Intermediate 13S
##STR00689##
[1565]
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-chlorobenzyl)amin-
o)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a-
,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrys-
en-9-yl acetate
[1566] To a flask containing
(3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-amino-1-hydroxyethyl)-1-iso-
propyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a-
,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate
(200 mg, 379 mmol) and methanol (15 ml) was added triethylamine (15
mg, 0.152 mmol), magnesium sulfate (68 mg, 0.168 mmol) and
4-chlorobenzaldehyde (64 mg, 0.455 mmol). The contents were allowed
to stir at ambient temperature for approximately 2 hours. To the
resulting mixture was added sodium borohydride (17 mg, 455 mmol) in
a single portion and the reaction was allowed to stir at ambient
temperature for two and a half days. The reaction was then charged
with an additional 20% excess of the p-Cl-benzaldehyde and sodium
borohydride and allowed to stir an additional 2 hours. Finally, the
reaction was quenched with water, allowed to stir 15 minutes and
solids filtered to provide title compound contaminated with
impurities. LC/MS: m/z calculated 651.4, found 652 (M+1).sup.+.
Synthesis of (S) Camphor Derived Chiral Diamine Ligand 568
##STR00690##
[1567] Step A: N,N'-bis(isobornyl)ethylenediimine (573)
[1568] Titanium (IV) isopropoxide (235.4 g, 830 mmol, 1.04 eq) was
added to a flask containing (1S)-(-)-camphor (121.43 g, 798 mmol, 1
eq) at ambient temperature. The reaction was then heated to
.about.50.degree. C. Next, ethylenediamine (31.2 g, 518 mmol, 0.65
eq) was charged to the reaction. The temperature was then kept
above 45.degree. C. during the addition. The reaction was then
heated to .about.91.degree. C. for 17 hours. Next, the reaction was
cooled to 20-25.degree. C. and heptane (1.2 L) was added. Water
(29.9 g, 1659 mmol, 2.08 eq) was added over at least 15 minutes.
The slurry was then stirred for 20 minutes at ambient temperature,
cooled to .about.0.degree. C., and stirred for 30 minutes at
.about.0.degree. C. The slurry was then filtered and the solids
washed with heptane (607 mL). The diimine solution was stored
.about.5.degree. C. overnight. The solution was then warmed to
ambient temperature and filtered to remove additional salts. Next,
the solution was partially concentrated and filtered through
Celite.TM.. Finally, the solution was concentrated to .about.608 mL
and used as is in the next reaction.
Step B: N,N'-bis(isobornyl)ethylenediamine ligand (568).
[1569] To a 1 L Jacketed Lab Reactor (JLR) was added the above
diimine solution followed by 5% Pt/C (Johnson-Matthey, B501018-5,
6.6 g). The reaction was hydrogenated for .about.15 hours at 4 par
at ambient temperature. The reaction was filtered and washed with
heptane (300 mL). The solution was concentrated to provide a white
solid (115.07 g). This two step procedure was repeated. Both
batches were combined. Attempts to crystallize the material from
i-PrOH and water failed. The product was extracted with heptane.
The heptane layer was then washed with water, brine, dried over
sodium sulfate, filtered and concentrated on rotovapor and then
high vacuum. The product 568 (222.18 g) was obtained as a white
solid and used as is in the asymmetric Henry reaction during the
camphor ligand addition step. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 2.69-2.61 (m, 1H), 2.53-2.47 (m, 2H), 1.71-1.63 (m, 2H),
1.6-1.43 (m, 3H), 1.1-1.01 (m, 2H), 1.01-0.98 (m, 3H), 0.89-0.83
(m, 3H), 0.81-0.78 (m, 3H)
Synthesis of (R) Camphor Derived Chiral Diamine Ligand 572
##STR00691##
[1571] This material was prepared with modifications to methods
shown in Tetrahedron: Asymmetry 14 (2003) 1451-1454.
Step A: N,N'-bis(isobornyl)ethylenediimine (574).
[1572] Titanium isopropoxide (100 mL, 341 mmol, 1.04 eq) was
charged to a roundbottom flask containing (1R)-(+)-camphor (50 g,
328 mmol) at 20-25.degree. C. The reaction mixture was then heated
to 50.degree. C., at which time ethylenediamine (14.3 mL, 213 mmol,
0.65 eq) was charged to the reaction. Note: The ethylenediamine
addition was exothermic, but it is important to conduct the charge
above 45.degree. C. to prevent solidification of the reaction
mixture as titanium/ethylenediamine complexes are formed. The
solution was then heated to reflux (.about.90-92.degree. C.) for
20-24 hours. At that time, the reaction is cooled to 20-25.degree.
C. and diluted with heptane (500 mL), followed by slow addition of
H.sub.2O (12.3 mL, 2.08 eq) over .about.15 minutes to initiate the
formation (and subsequent precipitation) of TiO.sub.2 from the
reaction. The slurry was stirred for 20 minutes at 20-25.degree.
C., cooled to 0.degree. C., and stirred for 20 minutes at 0.degree.
C. Finally, the precipitate was filtered and washed with heptane
(250 mL) to obtain a solution of diimine (573) in heptane, which
was concentrated to 250 mL of heptane (.about.4.6 vol) prior to use
in the subsequent hydrogenation stage.
Step B: N,N'-bis(isobornyl)ethylenediamine ligand (572)
[1573] Johnson-Matthey Yellow Kit #28 [5% Pt/C, B501018-5] catalyst
(2.7 g, 5 wt % wrt 6) was charged to a Parr vessel, followed by a
solution of diimine (6) in heptane (.about.54 g in 250 mL heptane).
The reaction was hydrogenated for 15 h at 100 psi H.sub.2,
20.degree. C., at which time the only product was observed by LCMS.
The mixture was then filtered through a celite pad and washed with
heptane (130 mL). The filtrate solvent was swapped from heptanes to
isopropanol (270 mL, 5 vol), after which water (86 mL, 1.5 vol) was
charged and the reaction was heated to reflux to dissolve all
material. Slow cooling of the solution to 20.degree. C. resulted in
crystallization of the product. Additional water (200 mL, 3.7 vol)
was charged over 15 minutes and the reaction was held for an
additional 20 minutes. The slurry was then cooled to 0.degree. C.
and held for 30 minutes, at which time the product was filtered and
washed with a 0.degree. C. mixture of 1:1 water/isopropanol (130
mL) to yield 46.05 g (572) (84.3%) after drying overnight.
[1574] The above intermediates 11S, 12S, and 13S serve to
demonstrate application of the asymmetric Henry reaction in the
camphor ligand step to produce the S alcohol on a useful
intermediate in consistent yield and selectivity with the earlier
examples that provide the R diastereomeric alcohol. It will be
apparent to one skilled in the art that this methodology can be
employed in combination with the appropriate triterpene derived
scaffolds to give either the R or S diastereomer upon choosing the
appropriate camphor derived diamine chiral ligand under the
conditions outlined herein. Furthermore, it is shown that the above
nitroalcohol intermediates, whether a mixture of diastereomeric
alcohols or in optically enriched form, are useful to provide
compounds of Formula I or Formula II.
Example 500
Compound 575
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(((5-chloropyrimidin-2-y-
l)methyl)(2-(2-oxopyrrolidin-1-yl)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-
-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,1-
2,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-ox-
obutanoic acid
##STR00692##
[1576] LC/MS: m/z calculated 850.5, found 851.5 (M+1).sup.+
Example 501
Compound 576
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(((5-chloropyrimidin-2-y-
l)methyl)(2-(dimethylamino)-2-oxoethyl)amino)-1-hydroxyethyl)-1-isopropyl--
5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12-
,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxo-
butanoic acid
##STR00693##
[1578] LC/MS: m/z calculated 824.5, found 825.5 (M+1).sup.+
Example 502
Compound 577
(R)-4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((cyclopropylmethyl)-
(2-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-p-
entamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadec-
ahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2-methyl-4-oxobutanoic
acid
##STR00694##
[1580] LC/MS: m/z calculated 724.5, found 725.5 (M+1).sup.+
Example 503
Compound 578
(R)-4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2--
(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pent-
amethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahy-
dro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2-methyl-4-oxobutanoic
acid
##STR00695##
[1582] LC/MS: m/z calculated 794.5, found 795.5 (M+1).sup.+
Example 504
Compound 579
4-(((3aR,5aR,5bR,7aR,8S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)ethyl-
)(pyridazin-3-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pe-
ntamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadeca-
hydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00696##
[1584] LC/MS: m/z calculated 776.5, found 777.6 (M+1).sup.+
Example 505
Compound 580
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((cyclobutylmethyl)(2-(2-
-oxopyrrolidin-1-yl)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-
-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octad-
ecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00697##
[1586] LC/MS: m/z calculated 792.6, found 793.6 (M+1).sup.+
Example 506
Compound 581
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(((S)-1-(5-chloropyrimid-
in-2-yl)ethyl)(2-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5-
a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,-
13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxob-
utanoic acid
##STR00698##
[1588] LC/MS: m/z calculated 824.5, found 825.5 (M+1).sup.+
Example 507
Compound 582
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(((R)-1-(5-chloropyrimid-
in-2-yl)ethyl)(2-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5-
a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,-
13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxob-
utanoic acid
##STR00699##
[1590] LC/MS: m/z calculated 824.5, found 825.5 (M+1).sup.+
Example 508
Compound 583
(R)-4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((2-(dimethylamino)e-
thyl)(isopropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentameth-
yl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2-
H-cyclopenta[a]chrysen-9-yl)oxy)-2-methyl-4-oxobutanoic acid
##STR00700##
[1592] LC/MS: m/z calculated 712.5, found 713.7 (M+1).sup.+
Example 509
Compound 584
4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((cyclopropylmethyl)(2-(-
2-oxopyrrolidin-1-yl)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11-
a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octa-
decahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic
acid
##STR00701##
[1594] LC/MS: m/z calculated 778.6, found 779.6 (M+1).sup.+
Example 510
Compound 585
(S)-4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((4-chlorobenzyl)(2--
(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pent-
amethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahy-
dro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2-methyl-4-oxobutanoic
acid
##STR00702##
[1596] LC/MS: m/z calculated 794.5, found 795.5 (M+1).sup.+
[1597] After the above description of synthesis procedures for the
compounds described herein, there is provided in accordance with
other embodiments of the present invention, a process for preparing
a compound of Formula (I) having the structure:
##STR00703##
comprising the steps of: [1598] (1) saponifying a compound having
the structure:
##STR00704##
[1598] in the presence of a first metal catalyst, in order to
provide a compound having the structure:
##STR00705## [1599] (2) reacting the compound product of Step (1),
with a compound having the structure:
##STR00706##
[1599] , in the presence of an acid chloride and a tertiary amine
in order to provide a compound having the structure:
##STR00707## [1600] (3) reacting nitromethane with the compound
product of Step (2) in the presence of a chiral ligand, an optional
base, and a second metal catalyst in order to provide a compound
having the structure:
[1600] ##STR00708## [1601] (4) reducing the compound product of
Step (3), in the presence of a third metal catalyst and hydrogen
gas in order to provide a compound having the structure:
[1601] ##STR00709## [1602] (5) reacting p-chlorobenzaldehyde with
the compound product of Step (4), in the presence of a metal
hydride, to provide a compound having the structure:
[1602] ##STR00710## [1603] (6) acidifying the compound product of
Step (5), in the presence of an acid in order to provide the
compound having the structure:
[1603] ##STR00711## [1604] (7) reacting the compound product of
Step (6) with a compound having the structure according to Formula
III:
##STR00712##
[1604] wherein A.sup.1 is either optionally absent or is selected
from the group consisting --H, methyl, and ethyl; and A.sup.2 is
selected from the group consisting of --H, methoxy, ethoxy,
hydroxyl, and --SO.sub.3.sup.-Na.sup.+; while in the presence of a
metal hydride in order to provide the compound having the
structure:
##STR00713##
[1605] As will be known to one of skill in the art after reading
the synthetic procedures described here and the process steps
described above and below, several suitable chemical components can
be used to carry out the process steps. Such suitable chemical
components can be used interchangeably with any process step
description described herein according to knowledge in the art.
[1606] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein one or more of Steps (1)-(7) are conducted in
the presence of a solvent.
[1607] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein one or more of Steps (1)-(7) are conducted in
the presence of an organic solvent.
[1608] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein one or more of Steps (1)-(7) are conducted in
the presence of a solvent that is selected from the group
consisting of water, dichloromethyl, methanol, tetrahydrofuran,
tetrahydrofuran acetate, ethanol, ethyl acetate, heptane,
isopropanol, tert-butanol, toluene, acetonitrile, and tert-butyl
methyl ether.
[1609] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the first metal catalyst of Step (1) is a
metal halide.
[1610] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the first metal catalyst of Step (1) is
zirconium tetrachloride.
[1611] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the acid chloride of Step (2) is selected from
the group consisting of benzoyl chloride and methoxybenzoyl
chloride.
[1612] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the acid chloride of Step (2) is
methoxybenzoyl chloride.
[1613] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the tertiary amine of Step (2) is a tertiary
amine coupling agent.
[1614] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the tertiary amine of Step (2) is selected
from the group consisting of triethylamine,
N,N-diisopropylethylamine, and
1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride.
[1615] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the tertiary amine of Step (2) is
1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride.
[1616] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the tertiary amine of Step (2) is
triethylamine.
[1617] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the second metal catalyst of Step (3) is a
compound comprising a metal selected from the group consisting of
Zn, Co, Cu, Mg, and Cr.
[1618] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the second metal catalyst of Step (3) is a
compound comprising a metal selected from the group consisting of
Cu(I) and Cu(II).
[1619] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the second metal catalyst of Step (3) is a
compound comprising Cu(I).
[1620] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the second metal catalyst of Step (3) is
selected from the group consisting of Copper(I) acetate and Cu(II)
acetate.
[1621] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the second metal catalyst of Step (3) is
Copper(I) acetate.
[1622] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the second metal catalyst of Step (3) is
Copper(II) acetate.
[1623] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the optional base of Step (3) is selected from
the group consisting of alkali metal hydroxides, alkoxides,
carbonates, fluoride anions, and nonionic organic amine bases.
[1624] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the optional base of Step (3) is
.sup.iPr.sub.2Net.
[1625] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the chiral ligand of Step (3) is a derivative
of S-Camphor.
[1626] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the chiral ligand of Step (3) is a compound
having the structure:
##STR00714##
[1627] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the third metal catalyst of Step (4) is
selected from the group consisting of Raney Nickel, nickel, nickel
chloride, aluminum, palladium, copper, zinc, chromium, iridium,
rhodium, platinum, and combinations thereof.
[1628] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the third metal catalyst of Step (4) is Raney
Nickel.
[1629] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the hydrogen of Step (4) is hydrogen gas.
[1630] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the metal hydride of Step (5) is a
borohydride.
[1631] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the metal hydride of Step (5) is selected from
the group consisting of NaBH.sub.4 and NaBH(OAc).sub.3.
[1632] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the metal hydride of Step (5) is
NaBH.sub.4.
[1633] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the metal hydride of Step (5) is
NaBH(OAc).sub.3.
[1634] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the acid of Step (6) is selected from the
group consisting of trifluoroacetic acid, HCl, and trichloroacetic
acid,
[1635] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the acid of Step (6) is trifluoroacetic
acid.
[1636] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the A.sup.2 of Step (7) is --SO.sub.3Na.
[1637] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the A.sup.2 of Step (7) is --H.
[1638] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the A.sup.1 of Step (7) is absent.
[1639] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the A.sup.1 of Step (7) is --H.
[1640] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the compound of Formula III of Step (7) has
the following structure:
##STR00715##
[1641] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the compound of Formula III of Step (7) has
the following structure:
##STR00716##
[1642] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the compound of Formula III of Step (7) has
the following structure:
##STR00717##
[1643] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the compound of Formula III of Step (7) has
the following structure:
##STR00718##
[1644] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the compound of Formula III of Step (7) has
the following structure:
##STR00719##
[1645] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the metal hydride of Step (7) is a
borohydride.
[1646] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the metal hydride of Step (7) is
NaBH.sub.3CN.
[1647] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I) having the structure:
##STR00720##
comprising the steps of: [1648] (1) saponifying a compound having
the structure:
##STR00721##
[1648] in the presence of a first metal catalyst, in order to
provide a compound having the structure:
##STR00722## [1649] (2) reacting the compound product of Step (1),
with a compound having the structure:
##STR00723##
[1649] in the presence of an acid chloride and a tertiary amine in
order to provide a compound having the structure:
##STR00724## [1650] (3) reacting nitromethane with the compound
product of Step (2) in the presence of a chiral ligand and a base
and a second metal catalyst in order to provide a compound having
the structure:
[1650] ##STR00725## [1651] (4) reducing the compound product of
Step (3), in the presence of a third metal catalyst and hydrogen
gas in order to provide a compound having the structure:
[1651] ##STR00726## [1652] (5) reacting p-chlorobenzaldehyde with
the compound product of Step (4), in the presence of a metal
hydride and a tertiary amine, to provide a compound having the
structure:
[1652] ##STR00727## [1653] (6) reacting the compound product of
Step (5) with a compound having the structure according to Formula
III:
##STR00728##
[1653] wherein A.sup.1 is either optionally absent or is selected
from the group consisting --H, methyl, and ethyl; and A.sup.2 is
selected from the group consisting of --H, methoxy, ethoxy,
hydroxyl, and --SO.sub.3.sup.-Na.sup.+; while in the presence of a
metal hydride in order to provide the compound having the
structure:
##STR00729## [1654] (7) acidifying the compound product of Step
(6), in the presence of an acid in order to provide the compound
having the structure:
##STR00730##
[1655] With regards to the synthesis procedures herein, and in
accordance with other embodiments of the present invention, there
is also provided a process for preparing a compound of Formula (I),
wherein one or more of Steps (1)-(7) are conducted in the presence
of a solvent.
[1656] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein one or more of Steps (1)-(7) are conducted in
the presence of an organic solvent.
[1657] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein one or more of Steps (1)-(7) are conducted in
the presence of a solvent that is selected from the group
consisting of water, dichloromethyl, methanol, tetrahydrofuran,
tetrahydrofuran acetate, ethanol, ethyl acetate, heptane,
isopropanol, tert-butanol, toluene, acetonitrile, and tert-butyl
methyl ether.
[1658] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the base of Step (3) is selected from the
group consisting of alkali metal hydroxides, alkoxides, carbonates,
fluoride anions, and nonionic organic amine bases.
[1659] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the base of Step (3) is .sup.iPr.sub.2Net.
[1660] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the tertiary amine of Step (5) is selected
from the group consisting of triethylamine and
1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride.
[1661] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the tertiary amine of Step (5) is
triethylamine.
[1662] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the metal hydride of Step (5) is a
borohydride.
[1663] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the metal hydride of Step (5) is selected from
the group consisting of NaBH.sub.4 and NaBH(OAc).sub.3.
[1664] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the metal hydride of Step (5) is
NaBH.sub.4.
[1665] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), wherein the tertiary amine of Step (6) is
triethylamine.
[1666] In accordance with other embodiments of the present
invention, there is provided a process for preparing a compound of
Formula (I), having the structure:
##STR00731##
comprising the steps of: [1667] (1) reacting a compound having the
structure:
[1667] ##STR00732## with a compound having the structure according
to Formula III:
##STR00733##
wherein A.sup.1 is either optionally absent or is selected from the
group consisting --H, methyl, and ethyl; and A.sup.2 is selected
from the group consisting of --H, methoxy, ethoxy, hydroxyl, and
--SO.sub.3.sup.-Na.sup.+; while in the presence of a metal hydride
in order to provide the compound having the structure:
##STR00734##
[1668] In accordance with other embodiments of the present
invention and the suitable process step components recited above,
there is provided a process for preparing a compound of Formula
(I), having the structure:
##STR00735##
comprising the steps of: [1669] (1) acidifying a compound having
the structure:
##STR00736##
[1669] in the presence of an acid in order to provide the compound
having the structure:
##STR00737##
[1670] In accordance with other embodiments of the present
invention and the suitable process step components recited above,
there is provided a process for preparing a compound of Formula
(I), having the structure:
##STR00738##
[1671] comprising the steps of: [1672] (1) reacting
p-chlorobenzaldehyde with a compound having the structure:
##STR00739##
[1672] in the presence of a metal hydride to provide the compound
having the structure:
##STR00740##
[1673] In accordance with other embodiments of the present
invention and the suitable process step components recited above,
there is provided a process for preparing a compound of Formula
(I), having the structure:
##STR00741##
[1674] comprising the steps of: [1675] (1) reducing a compound
having the structure:
##STR00742##
[1675] in the presence of a metal catalyst and hydrogen gas in
order to provide the compound having the structure:
##STR00743##
[1676] In accordance with other embodiments of the present
invention and the suitable process step components recited above,
there is provided a process for preparing a compound of Formula
(I), having the structure:
##STR00744##
comprising the steps of: [1677] (1) reacting nitromethane with a
compound having the structure:
##STR00745##
[1677] in the presence of a chiral ligand and a metal catalyst in
order to provide a compound having the structure:
##STR00746##
[1678] In accordance with other embodiments of the present
invention and the suitable process step components recited above,
there is provided a process for preparing a compound of Formula
(I), having the structure:
##STR00747##
comprising the steps of: [1679] (1) reacting a compound having the
structure:
##STR00748##
[1679] with a compound having the structure:
##STR00749##
in the presence of an acid chloride and a tertiary amine in order
to provide the compound having the structure:
##STR00750##
[1680] In accordance with other embodiments of the present
invention and the suitable process step components recited above,
there is provided a process for preparing a compound of Formula
(I), having the structure:
##STR00751##
comprising the steps of: [1681] (1) saponifying a compound having
the structure:
##STR00752##
[1681] in the presence of a metal catalyst, in order to provide the
compound having the structure:
##STR00753##
[1682] In accordance with other embodiments of the present
invention and the suitable process step components recited above,
there is provided a process for preparing a compound of Formula
(I), having the structure:
##STR00754##
comprising the steps according to the following synthesis scheme.
As will be known to one of skill in the art, the above reagents
recited in still other synthesis schemes may be substituted within
the synthesis scheme below as described above.
##STR00755## ##STR00756## ##STR00757##
Administration and Formulation
[1683] In another embodiment, there is provided a pharmaceutical
composition comprising a pharmaceutically acceptable diluent and a
therapeutically effective amount of a compound of Formula I or
Formula II or a pharmaceutically acceptable salt thereof.
[1684] The compounds of the present invention can be supplied in
the form of a pharmaceutically acceptable salt. The terms
"pharmaceutically acceptable salt" refer to salts prepared from
pharmaceutically acceptable inorganic and organic acids and bases.
Accordingly, the word "or" in the context of "a compound or a
pharmaceutically acceptable salt thereof" is understood to refer to
either a compound or a pharmaceutically acceptable salt thereof
(alternative), or a compound and a pharmaceutically acceptable salt
thereof (in combination).
[1685] As used herein, the term "pharmaceutically acceptable"
refers to those compounds, materials, compositions, and dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, or other problem or
complication. The skilled artisan will appreciate that
pharmaceutically acceptable salts of compounds according to Formula
I or Formula II may be prepared. These pharmaceutically acceptable
salts may be prepared in situ during the final isolation and
purification of the compound, or by separately reacting the
purified compound in its free acid or free base form with a
suitable base or acid, respectively.
[1686] Illustrative pharmaceutically acceptable acid salts of the
compounds of the present invention can be prepared from the
following acids, including, without limitation formic, acetic,
propionic, benzoic, succinic, glycolic, gluconic, lactic, maleic,
malic, tartaric, citric, nitric, ascorbic, glucuronic, maleic,
fumaric, pyruvic, aspartic, glutamic, benzoic, hydrochloric,
hydrobromic, hydroiodic, isocitric, trifluoroacetic, pamoic,
propionic, anthranilic, mesylic, oxalacetic, oleic, stearic,
salicylic, p-hydroxybenzoic, nicotinic, phenylacetic, mandelic,
embonic (pamoic), methanesulfonic, phosphoric, phosphonic,
ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic,
2-hydroxyethanesulfonic, sulfanilic, sulfuric, salicylic,
cyclohexylaminosulfonic, algenic, .beta.-hydroxybutyric, galactaric
and galacturonic acids. Preferred pharmaceutically acceptable salts
include the salts of hydrochloric acid and trifluoroacetic
acid.
[1687] Illustrative pharmaceutically acceptable inorganic base
salts of the compounds of the present invention include metallic
ions. More preferred metallic ions include, but are not limited to,
appropriate alkali metal salts, alkaline earth metal salts and
other physiological acceptable metal ions. Salts derived from
inorganic bases include aluminum, ammonium, calcium, copper,
ferric, ferrous, lithium, magnesium, manganic salts, manganous,
potassium, sodium, zinc, and the like and in their usual valences.
Exemplary base salts include aluminum, calcium, lithium, magnesium,
potassium, sodium and zinc. Other exemplary base salts include the
ammonium, calcium, magnesium, potassium, and sodium salts. Still
other exemplary base salts include, for example, hydroxides,
carbonates, hydrides, and alkoxides including NaOH, KOH,
Na.sub.2CO.sub.3, K.sub.2CO.sub.3, NaH, and
potassium-t-butoxide.
[1688] Salts derived from pharmaceutically acceptable organic
non-toxic bases include salts of primary, secondary, and tertiary
amines, including in part, trimethylamine, diethylamine,
N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and
procaine; substituted amines including naturally occurring
substituted amines; cyclic amines; quaternary ammonium cations; and
basic ion exchange resins, such as arginine, betaine, caffeine,
choline, N,N-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine
resins, procaine, purines, theobromine, triethylamine,
trimethylamine, tripropylamine, tromethamine and the like.
[1689] All of the above salts can be prepared by those skilled in
the art by conventional means from the corresponding compound of
the present invention. For example, the pharmaceutically acceptable
salts of the present invention can be synthesized from the parent
compound which contains a basic or acidic moiety by conventional
chemical methods. Generally, such salts can be prepared by reacting
the free acid or base forms of these compounds with a
stoichiometric amount of the appropriate base or acid in water or
in an organic solvent, or in a mixture of the two; generally,
nonaqueous media like ether, ethyl acetate, ethanol, isopropanol,
or acetonitrile are preferred. The salt may precipitate from
solution and be collected by filtration or may be recovered by
evaporation of the solvent. The degree of ionisation in the salt
may vary from completely ionised to almost non-ionised. Lists of
suitable salts are found in Remington's Pharmaceutical Sciences,
17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the
disclosure of which is hereby incorporated by reference only with
regards to the lists of suitable salts.
[1690] The compounds of the invention may exist in both unsolvated
and solvated forms. The term `solvate` is used herein to describe a
molecular complex comprising the compound of the invention and one
or more pharmaceutically acceptable solvent molecules, for example,
ethanol. The term `hydrate` is employed when said solvent is water.
Pharmaceutically acceptable solvates include hydrates and other
solvates wherein the solvent of crystallization may be isotopically
substituted, e.g. D.sub.2O, d.sub.6-acetone, d6-DMSO.
[1691] Compounds of Formula I or Formula II containing one or more
asymmetric carbon atoms can exist as two or more stereoisomers.
Where a compound of Formula I or Formula II contains an alkenyl or
alkenylene group or a cycloalkyl group, geometric cis/trans (or
Z/E) isomers are possible. Where the compound contains, for
example, a keto or oxime group or an aromatic moiety, tautomeric
isomerism (`tautomerism`) can occur. It follows that a single
compound may exhibit more than one type of isomerism.
[1692] Included within the scope of the claimed compounds present
invention are all stereoisomers, geometric isomers and tautomeric
forms of the compounds of Formula I or Formula II, including
compounds exhibiting more than one type of isomerism, and mixtures
of one or more thereof. Also included are acid addition or base
salts wherein the counterion is optically active, for example,
D-lactate or L-lysine, or racemic, for example, DL-tartrate or
DL-arginine.
[1693] Cis/trans isomers may be separated by conventional
techniques well known to those skilled in the art, for example,
chromatography and fractional crystallisation.
[1694] Conventional techniques for the preparation/isolation of
individual enantiomers include chiral synthesis from a suitable
optically pure precursor or resolution of the racemate (or the
racemate of a salt or derivative) using, for example, chiral high
pressure liquid chromatography (HPLC).
[1695] Alternatively, the racemate (or a racemic precursor) may be
reacted with a suitable optically active compound, for example, an
alcohol, or, in the case where the compound of Formula I or Formula
II contains an acidic or basic moiety, an acid or base such as
tartaric acid or 1-phenylethylamine. The resulting diastereomeric
mixture may be separated by chromatography and/or fractional
crystallization and one or both of the diastereoisomers converted
to the corresponding pure enantiomer(s) by means well known to a
skilled person.
[1696] Chiral compounds of the invention (and chiral precursors
thereof) may be obtained in enantiomerically-enriched form using
chromatography, typically HPLC, on a resin with an asymmetric
stationary phase and with a mobile phase consisting of a
hydrocarbon, typically heptane or hexane, containing from 0 to 50%
isopropanol, typically from 2 to 20%, and from 0 to 5% of an
alkylamine, typically 0.1% diethylamine. Concentration of the
eluate affords the enriched mixture.
[1697] Mixtures of stereoisomers may be separated by conventional
techniques known to those skilled in the art. [see, for example,
"Stereochemistry of Organic Compounds" by E L Eliel (Wiley, N.Y.,
1994).]
[1698] The present invention includes all pharmaceutically
acceptable isotopically-labelled compounds of Formula I or Formula
II wherein one or more atoms are replaced by atoms having the same
atomic number, but an atomic mass or mass number different from the
atomic mass or mass number usually found in nature.
[1699] Examples of isotopes suitable for inclusion in the compounds
of the invention include isotopes of hydrogen, such as .sup.2H and
.sup.3H, carbon, such as .sup.11C, .sup.13C and .sup.14C, chlorine,
such as .sup.36Cl, fluorine, such as .sup.18F, iodine, such as
.sup.123I and .sup.125I, nitrogen, such as .sup.13N and .sup.15N,
oxygen, such as .sup.15O, .sup.17O and .sup.18O, phosphorus, such
as .sup.32P, and sulphur, such as .sup.35S.
[1700] Certain isotopically-labelled compounds of Formula I or
Formula II, for example, those incorporating a radioactive isotope,
are useful in drug and/or substrate tissue distribution studies.
The radioactive isotopes tritium, i.e. .sup.3H, and carbon-14, i.e.
.sup.14C, are particularly useful for this purpose in view of their
ease of incorporation and ready means of detection.
[1701] Substitution with heavier isotopes such as deuterium, i.e.
.sup.2H, may afford certain therapeutic advantages resulting from
greater metabolic stability, for example, increased in vivo
half-life or reduced dosage requirements, and hence may be
preferred in some circumstances.
[1702] Isotopically-labelled compounds of Formula I or Formula II
can generally be prepared by conventional techniques known to those
skilled in the art or by processes analogous to those described in
the accompanying Examples and Preparations using an appropriate
isotopically-labelled reagents in place of the non-labelled reagent
previously employed.
[1703] The compounds of the present invention may be administered
as prodrugs. Thus, certain derivatives of compounds of Formula I or
Formula II, which may have little or no pharmacological activity
themselves can, when administered into or onto the body, be
converted into compounds of Formula I or Formula II as
`prodrugs`.
[1704] Administration of the chemical entities described herein can
be via any of the accepted modes of administration for agents that
serve similar utilities including, but not limited to, orally,
sublingually, subcutaneously, intravenously, intranasally,
topically, transdermally, intraperitoneally, intramuscularly,
intrapulmonarilly, vaginally, rectally, or intraocularly. In some
embodiments, oral or parenteral administration is used.
[1705] Pharmaceutical compositions or formulations include solid,
semi-solid, liquid and aerosol dosage forms, such as, e.g.,
tablets, capsules, powders, liquids, suspensions, suppositories,
aerosols or the like. The chemical entities can also be
administered in sustained or controlled release dosage forms,
including depot injections, osmotic pumps, pills, transdermal
(including electrotransport) patches, and the like, for prolonged
and/or timed, pulsed administration at a predetermined rate. In
certain embodiments, the compositions are provided in unit dosage
forms suitable for single administration of a precise dose.
[1706] The chemical entities described herein can be administered
either alone or more typically in combination with a conventional
pharmaceutical carrier, excipient or the like (e.g., mannitol,
lactose, starch, magnesium stearate, sodium saccharine, talcum,
cellulose, sodium crosscarmellose, glucose, gelatin, sucrose,
magnesium carbonate, and the like). If desired, the pharmaceutical
composition can also contain minor amounts of nontoxic auxiliary
substances such as wetting agents, emulsifying agents, solubilizing
agents, pH buffering agents and the like (e.g., sodium acetate,
sodium citrate, cyclodextrine derivatives, sorbitan monolaurate,
triethanolamine acetate, triethanolamine oleate, and the like).
Generally, depending on the intended mode of administration, the
pharmaceutical composition will contain about 0.005% to 95%; in
certain embodiments, about 0.5% to 50% by weight of a chemical
entity. Actual methods of preparing such dosage forms are known, or
will be apparent, to those skilled in this art; for example, see
Remington's Pharmaceutical Sciences, Mack Publishing Company,
Easton, Pa.
[1707] In certain embodiments, the compositions will take the form
of a pill or tablet and thus the composition will contain, along
with the active ingredient, a diluent such as lactose, sucrose,
dicalcium phosphate, or the like; a lubricant such as magnesium
stearate or the like; and a binder such as starch, gum acacia,
polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or
the like. In another solid dosage form, a powder, marume, solution
or suspension (e.g., in propylene carbonate, vegetable oils or
triglycerides) is encapsulated in a gelatin capsule.
[1708] Liquid pharmaceutically administrable compositions can, for
example, be prepared by dissolving, dispersing, etc. at least one
chemical entity and optional pharmaceutical adjuvants in a carrier
(e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol
or the like) to form a solution or suspension. Injectables can be
prepared in conventional forms, either as liquid solutions or
suspensions, as emulsions, or in solid forms suitable for
dissolution or suspension in liquid prior to injection. The
percentage of chemical entities contained in such parenteral
compositions is highly dependent on the specific nature thereof, as
well as the activity of the chemical entities and the needs of the
subject. However, percentages of active ingredient of 0.01% to 10%
in solution are employable, and will be higher if the composition
is a solid which will be subsequently diluted to the above
percentages. In certain embodiments, the composition will comprise
from about 0.2 to 2% of the active agent in solution.
[1709] Pharmaceutical compositions of the chemical entities
described herein may also be administered to the respiratory tract
as an aerosol or solution for a nebulizer, or as a microfine powder
for insufflation, alone or in combination with an inert carrier
such as lactose. In such a case, the particles of the
pharmaceutical composition have diameters of less than 50 microns,
in certain embodiments, less than 10 microns.
[1710] In general, the chemical entities provided will be
administered in a therapeutically effective amount by any of the
accepted modes of administration for agents that serve similar
utilities. The actual amount of the chemical entity, i.e., the
active ingredient, will depend upon numerous factors such as the
severity of the disease to be treated, the age and relative health
of the subject, the potency of the chemical entity used the route
and form of administration, and other factors. The drug can be
administered more than once a day, such as once or twice a day.
[1711] Therapeutically effective amounts of the chemical entities
described herein may range from approximately 0.01 to 200 mg per
kilogram body weight of the recipient per day; such as about
0.01-100 mg/kg/day, for example, from about 0.1 to 50 mg/kg/day.
Thus, for administration to a 70 kg person, the dosage range may be
about 7-3500 mg per day.
[1712] In general, the chemical entities will be administered as
pharmaceutical compositions by any one of the following routes:
oral, systemic (e.g., transdermal, intranasal or by suppository),
or parenteral (e.g., intramuscular, intravenous or subcutaneous)
administration. In certain embodiments, oral administration with a
convenient daily dosage regimen that can be adjusted according to
the degree of affliction may be used. Compositions can take the
form of tablets, pills, capsules, semisolids, powders, sustained
release formulations, solutions, suspensions, elixirs, aerosols, or
any other appropriate compositions. Another manner for
administering the provided chemical entities is inhalation.
[1713] The choice of formulation depends on various factors such as
the mode of drug administration and bioavailability of the drug
substance. For delivery via inhalation the chemical entity can be
formulated as liquid solution, suspensions, aerosol propellants or
dry powder and loaded into a suitable dispenser for administration.
There are several types of pharmaceutical inhalation
devices-nebulizer inhalers, metered dose inhalers (MDI) and dry
powder inhalers (DPI). Nebulizer devices produce a stream of high
velocity air that causes the therapeutic agents (which are
formulated in a liquid form) to spray as a mist that is carried
into the patient's respiratory tract. MDIs typically are
formulation packaged with a compressed gas. Upon actuation, the
device discharges a measured amount of therapeutic agent by
compressed gas, thus affording a reliable method of administering a
set amount of agent. DPI dispenses therapeutic agents in the form
of a free flowing powder that can be dispersed in the patient's
inspiratory air-stream during breathing by the device. In order to
achieve a free flowing powder, the therapeutic agent is formulated
with an excipient such as lactose. A measured amount of the
therapeutic agent is stored in a capsule form and is dispensed with
each actuation.
[1714] Recently, pharmaceutical compositions have been developed
for drugs that show poor bioavailability based upon the principle
that bioavailability can be increased by increasing the surface
area i.e., decreasing particle size. For example, U.S. Pat. No.
4,107,288 describes a pharmaceutical formulation having particles
in the size range from 10 to 1,000 nm in which the active material
is supported on a cross-linked matrix of macromolecules. U.S. Pat.
No. 5,145,684 describes the production of a pharmaceutical
formulation in which the drug substance is pulverized to
nanoparticles (average particle size of 400 nm) in the presence of
a surface modifier and then dispersed in a liquid medium to give a
pharmaceutical formulation that exhibits remarkably high
bioavailability.
[1715] The compositions are comprised of, in general, at least one
chemical entity described herein in combination with at least one
pharmaceutically acceptable excipient. Acceptable excipients are
non-toxic, aid administration, and do not adversely affect the
therapeutic benefit of the at least one chemical entity described
herein. Such excipient may be any solid, liquid, semi-solid or, in
the case of an aerosol composition, gaseous excipient that is
generally available to one of skill in the art.
[1716] Solid pharmaceutical excipients include starch, cellulose,
talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,
silica gel, magnesium stearate, sodium stearate, glycerol
monostearate, sodium chloride, dried skim milk and the like. Liquid
and semisolid excipients may be selected from glycerol, propylene
glycol, water, ethanol and various oils, including those of
petroleum, animal, vegetable or synthetic origin, e.g., peanut oil,
soybean oil, mineral oil, sesame oil, etc. Liquid carriers, for
injectable solutions, include water, saline, aqueous dextrose, and
glycols.
[1717] Compressed gases may be used to disperse a chemical entity
described herein in aerosol form. Inert gases suitable for this
purpose are nitrogen, carbon dioxide, etc. Other suitable
pharmaceutical excipients and their formulations are described in
Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack
Publishing Company, 18th ed., 1990).
[1718] The amount of the chemical entity in a composition can vary
within the full range employed by those skilled in the art.
Typically, the composition will contain, on a weight percent (wt %)
basis, from about 0.01-99.99 wt % of at least one chemical entity
described herein based on the total composition, with the balance
being one or more suitable pharmaceutical excipients. In certain
embodiments, the at least one chemical entity described herein is
present at a level of about 1-80 wt %.
Example 84
MT4 Cell Antiviral Assay
[1719] Experimental Procedure:
[1720] Antiviral HIV activity and compound-induced cytotoxicity
were measured in parallel by means of a propidium iodide based
procedure in the human T-cell lymphotropic virus transformed cell
line MT4. Aliquots of the test compounds were serially diluted in
medium (RPMI 1640, 10% fetal calf serum (FCS), and gentamycin) in
96-well plates (Costar 3598) using a Cetus Pro/Pette. Exponentially
growing MT4 cells were harvested and centrifuged at 1000 rpm for 10
min in a Jouan centrifuge (model CR 4 12). Cell pellets were
resuspended in fresh medium (RPMI 1640, 20% FCS, 20% IL-2, and
gentamycin) to a density of 5.times.105 cells/ml. Cell aliquots
were infected by the addition of HIV-1 (strain IIIB) diluted to
give a viral multiplicity of infection of 100.times.TCID50. A
similar cell aliquot was diluted with medium to provide a
mock-infected control. Cell infection was allowed to proceed for 1
hr at 37.degree. C. in a tissue culture incubator with humidified
5% CO.sub.2 atmosphere. After the 1 hr incubation the virus/cell
suspensions were diluted 6-fold with fresh medium, and 125 .mu.l of
the cell suspension was added to each well of the plate containing
pre-diluted compound. Plates were then placed in a tissue culture
incubator with humidified 5% CO.sub.2 for 5 days. At the end of the
incubation period, cell number and hence HIV-induced cytopathy was
estimated by either (A) propidium iodide staining, or by an (B) MTS
tetrazolium staining method.
[1721] For propidium iodide readout, 27 .mu.l of 5% Nonidet-40 was
added to each well of the incubation plate. After thorough mixing
with a Costar multitip pipetter, 60 .mu.l of the mixture was
transferred to filter-bottomed 96-well plates. The plates were
analyzed in an automated assay instrument (Screen Machine,
Idem(Laboratories). The control and standard used was
3'-azido-3'-deoxythymidine tested over a concentration range of
0.01 to 1 .mu.M in every assay. The expected range of IC.sub.50
values for 3'-azido-3'-deoxythymidine is 0.04 to 0.12 .mu.M. The
assay makes use of a propidium iodide dye to estimate the DNA
content of each well.
[1722] For MTS readout, 20 .mu.l CellTiter 96 AQ One Solution
reagent (Promega #G3582) was added to each well. At 75 minutes
following the addition of MTS reagent, absorbance was read at 492
nM using a Tecan Sunrise 96-well plate reader.
[1723] Analysis:
[1724] The antiviral effect of a test compound is reported as an
EC.sub.50, i.e. the inhibitory concentration that would produce a
50% decrease in the HIV-induced cytopathic effect. This effect is
measured by the amount of test compound required to restore 50% of
the cell growth of HIV-infected MT4 cells, compared to uninfected
MT4 cell controls. IC.sub.50 was calculated by RoboSage, Automated
Curve Fitting Program, version 5.00, 10 Jul. 1995.
[1725] For each assay plate, the results (relative fluorescence
units, rfU, or OD values) of wells containing uninfected cells or
infected cells with no compound were averaged, respectively. For
measurements of compound-induced cytotoxicity, results from wells
containing various compound concentrations and uninfected cells
were compared to the average of uninfected cells without compound
treatment. Percent of cells remaining is determined by the
following formula:
Percent of cells remaining=(compound-treated uninfected cells, rfU,
or OD values/untreated uninfected cells).times.100.
[1726] A level of percent of cells remaining of 79% or less
indicates a significant level of direct compound-induced
cytotoxicity for the compound at that concentration. When this
condition occurs the results from the compound-treated infected
wells at this concentration are not included in the calculation of
EC.sub.50.
[1727] For measurements of compound antiviral activity, results
from wells containing various compound concentrations and infected
cells are compared to the average of uninfected and infected cells
without compound treatment. Percent inhibition of virus is
determined by the following formula:
Percent inhibition of virus=(1-((ave. untreated uninfected
cells-treated infected cells)/(ave. untreated uninfected cells-ave.
untreated infected cells))).times.100.
[1728] Results:
[1729] Compounds of the present invention have anti-HIV activity in
the range EC.sub.50=1-1000 nM.
Table 3
[1730] Table 3 shows EC.sub.5o values for representative compounds
of Table 2 after the HIV MT4 Antiviral Cell Assay of Example
84.
TABLE-US-00003 Example number EC.sub.50 NL4-3 wt (nM) EC.sub.50
V370A (nM) 1 41.1 34.6 2 5.2 4.7 3 61.7 242.7 4 10.1 9.3 5 2.6 3.2
6 0.5 3.8 7 6.1 23.1 8 5.9 14.3 9 12.3 13.5 10 2.3 2.4 11 6.3 6.7
12 4.5 5.1 13 1.6 2.1 14 2.1 3.6 15 6.9 31.1 16 11.0 7.6 17 8.7
29.2 18 0.8 0.7 19 3.9 4.1 20 2.3 4.1 21 76.5 103.5 22 3.3 3.5 23
4.9 11.7 24 40.4 1528.0 25 14.7 27.8 26 4.9 545.0 27 8.2 8.9 29
17.5 28.6 31 5.4 22.5 33 5.3 ND 34 7.1 21.1 35 4.2 124.0 36 4.0 9.4
37 26.9 556.6 38 5.2 20.9 39 6.6 217.1 40 11.1 18.9 44 1.8 2.6 45
1.9 2.5 46 11.1 64.8 47 7.7 72.9 49 21.8 192.3 50 1.1 1.4 51 3.5
6.3 52 4.6 7.0 53 6.2 494.3 56 3.4 3.4 57 4.2 8.0 58 31.5 379.0 59
5.3 17.2 60 60.2 8409.0 61 129.7 10000.0 62 103.6 213.2 63 3.2 5.0
64 7.2 120.2 65 83.8 3077.0 66 9.2 16.1 67 135.5 411.1 68 10.5
110.2 69 1.0 4.1 70 1.6 2.1 71 31.2 35.3 72 5.1 10.8 73 31.8 62.3
74 2.9 4.8 75 0.6 1.0 76 0.7 0.9 77 4.7 5.0 78 2.1 2.7 79 14.7 76.1
80 2.4 2.7 81 3.0 5.4 82 8.9 70.5 83 7.3 143.5
Example 86
[1731] This example shows the EC.sub.50 potencies of Bevirimat,
compound 51, compound A, and compound B against wild type HIV, site
directed HIV mutants, and clinical HIV isolates. As can be seen in
Table 5, compound 51 demonstrates higher potency than the other
compounds when measured against HIV among wildtype, certain site
directed mutants, and against several clinical HIV isolates.
Surprisingly, compound 51 continues to have excellent potency
against HIV relative to the other compounds, when protein binding
is taken into account as can be seen in Table 6.
[1732] The results in Tables 5 and 6 for compound 51 demonstrate an
unexpected result taken in light of Bevirimat and compounds A and
B. The results in the above tables are indicative of the
unpredictability in developing anti-HIV compounds where a subtle
change in the chemical structure can have a large impact on the
clinical result. Where compounds A and B show alternating efficacy
in their both their EC.sub.50 values for polymorphism and protein
binding, compound 51 shows none of this variability and is therefor
unexpectedly superior when viewed in terms of potential clinical
applicability. A direct comparison between compound 51 and
compounds A and B, demonstrate how subtle chemical substitutions
can have a dramatic effect on the in vitro efficacy of a putative
anti-HIV compound.
[1733] A similar advantage for compound 51 can be seen in Table 6
where protein binding and serum shift for the above compounds are
compared. This table shows both a significant decrease in the
EC.sub.50 and a reduced serum effect for compound 51 relative to
the other compounds tested.
TABLE-US-00004 TABLE 5 Wild-type, Polymorphisms, &
PBLs--EC.sub.50 (nM) HIV-1 B HIV-1 B HIV-1 C MT4 NL. MT4 NL. CC1/85
ASJM108 972A009 wt* V370A (V370A) (V370A+) (V370A+) Bevirimat 223
6062 >10000 >10000 13435 Compound A 14 16 5 51 1159 CompoundB
8 8 13 6 2000 Compound51 0.8 0.7 1.2 1.0 4 *Consensus Clade B Sp1
Genotype.
TABLE-US-00005 TABLE 6 Protein Binding Effects on Potency LHIV Fold
shift LHIV IC.sub.50 (nM) with 40% IC.sub.50 (nM) with 40% HuS HuS
Bevirimat 42 6600 157 Compound A 9.3 73 7.9 CompoundB 3.2 43 13.4
Compound51 1.9 10.6 5.5.sup.a .sup.aDefinitive protein shift value
determined in PBL's by titration at SRI is 1X
Example 87
[1734] It is suspected that many anti-HIV compounds might
potentially be less effective in the treatment of patients who have
failed a previous protease inhibitor-containing regimen and whose
viruses have developed drug resistance mutations within the
protease gene.
[1735] A major obstacle to their long-term efficacy of anti-HIV
therapies has been the emergence of resistance to current
antiretroviral drugs. One method for comparing the effectiveness of
anti-HIV compounds is the characterization of such compounds'
polymorphism at drug resistant sites.
[1736] A comparison of compound 51 versus Bevirimet ("BVM") against
a broad panel of HIV isolates is shown in FIG. 1. From FIG. 1, it
can be seen that compound 51 shows superior polymorphism coverage
across this panel of HIV isolates to Bevirimat. Likewise, compound
51 shows superior polymorphism coverage as compared to compound C
as shown in FIG. 2.
[1737] This example was performed as follows. Crude human primary
blood mononuclear cells (PBMCs) were collected from healthy donors
via leukapheresis and determined to be negative for HIV exposure,
among a variety of additional infectious diseases. PBMCs were
isolated via Ficoll-Hypaque density gradient separation followed by
aspiration of the banded leukocytes from the gradient. Purified
PBMCs from 10 individual donors were combined and cryopreserved in
liquid nitrogen as a PBMC pool. Various PBMC pools were
utilized.
[1738] Various HIV-1 isolates were obtained from different sources.
A stock of the virus was generated in a pool of CD4+ PBMCs and
frozen. Viral replication for each virus stock was measured on
PHA-blasted PBMC pools to determine the appropriate virus input for
anti-viral assays. HIV gag sequences were determined for each
isolate by the Sanger di-deoxy sequencing method.
[1739] Cryo-preserved PBMC pools were thawed and stimulated with 2
.mu.g/mL PHA in media (RPM11640, 20% FBS, 10% T cell growth factor,
antibiotics) for 3 days. Blasts were then washed, counted, and
cultured in media at 2.times.10.sup.6 cells/mL in media with 10U/mL
recombinant IL-2 for an additional 24 hours. Stimulated PBMCs were
counted for trypan blue exclusion viability and seeded in 96-well
round bottom plates at a final density of 1.times.10.sup.6
cells/well. A volume of the drug dose titration was added to the
cells followed by a pre-determined amount of virus. The plates were
incubated for 7 days at 37.degree. C., 5% CO.sub.2. to allow for
viral replication and inhibition by compound to assess anti-viral
potency.
[1740] In order to determine anti-viral potency, HIV reverse
transcriptase activity in cell culture supernatants was measured as
a measure of viral replication in the presence or absence of
compound. At the end of the incubation period, fifty (50) .mu.L of
PBMC culture supernatants were transferred to a new 96-well plate;
10 .mu.L of RT extraction buffer was added followed by the addition
of 40 .mu.L of RT assay buffer. The RT plates were thoroughly mixed
and placed in a humidified incubator at 37.degree. C., 5% CO.sub.2
for 2 h. DE-81 96-well plates were placed on a vacuum manifold and
100 uL of the RT reaction transferred to the ion-exchange
chromatography plates. After applying the solution phase of the RT
reaction to the DE-81 plate, the plate was then washed once with
prepared 5% Na.sub.2HPO.sub.4, followed by a wash of dH.sub.20.
Plates were then allowed to dry overnight at room temperature. The
plates were sealed and 50 .mu.L scintillation fluid added prior to
reading on a Topcount (Packard) luminometer at 10s/well.
[1741] Below are the particular HIV-1 isolates tested as shown in
FIG. 1: [1742] 1--HIV-1 A_UG275 [1743] 2--HIV-1 AE_42368 [1744]
3--HIV-1 C_97/ZA/009 [1745] 4--HIV-1 C_ETH2220 [1746] 5--HIV-1
C_ZAM18 [1747] 6--HIV-1 C_I-2516 [1748] 7--HIV-1 B_CC1/85 [1749]
8--HIV-1 B_ASJM108 [1750] 9--HIV-1 B_SF162 [1751] 10--HIV-1
B_92US657 [1752] 11--HIV-1 B_BR92030 [1753] 12--HIV-1 B_ASM42
[1754] 13--HIV-1 B_BR92023 [1755] 14--HIV-1 B_ASM44 [1756]
15--HIV-1 B_92US660 [1757] 16--HIV-1 B_THA92014 [1758] 17--HIV-1
B_IIIB [1759] 18--HIV-1 B_301596 [1760] 19--HIV-1 B_ASM34 [1761]
20--HIV-1 B_BK132 [1762] 21--HIV-1 B_ASM57 [1763] 22--HIV-1 B_ASM54
[1764] 23--HIV-1 B_92HT599 [1765] 24--HIV-1 B_CM237 [1766]
25--HIV-1 B_92HT593 [1767] 26--HIV-1 B_BZ167 [1768] 27--HIV-1
B_92US723
[1769] Below are the particular HIV isolates tested as shown in
FIG. 2: [1770] 1--HIV-1 A_UG275 [1771] 2--HIV-1 AE_42368 [1772]
3--HIV-1 B_301596 [1773] 4--HIV-1 B_92HT593 [1774] 5--HIV-1
B_92HT599 [1775] 6--HIV-1 B_92US657 [1776] 7--HIV-1 B_92US660
[1777] 8--HIV-1 B_92US723 [1778] 9--HIV-1 B_ASJM108 [1779]
10--HIV-1 B_ASM34 [1780] 11--HIV-1 B_ASM42 [1781] 12--HIV-1 B_ASM44
[1782] 13--HIV-1 B_ASM54 [1783] 14--HIV-1 B_BK132 [1784] 15--HIV-1
B_BZ167 [1785] 16--HIV-1 B_CC1/85 [1786] 17--HIV-1 B_CM237 [1787]
18--HIV-1 B_IIIB [1788] 19--HIV-1 B_SF162 [1789] 20--HIV-1
C_97/ZA/009 [1790] 21--HIV-1 C_ETH2220 [1791] 22--HIV-1 C_ZAM18
Example 88
[1792] This example shows in Table 7 a direct comparison between
compound 51, compound 56, and compound C. Intrinsic HIV wild type
potency for compound 51 relative to compound C is about 10.times.
better (0.8 nM vs. 6 nM). In the HIV polymorphic strain, V370, the
potency for compound 51 relative to compound C is even more
dramatic (0.7 nM vs. 19 nM). In terms of human protein shift listed
as human serum (HS) in this example, is another factor of 10 fold
better for compound 51 relative to compound C (5.5 fold shift vs. a
48.9 fold shift).
[1793] All taken together, as can be seen in Table 7 there is a
factor of 238 fold improvement for compound 51 over compound C for
the C.sub.trough target, which is the PAEC.sub.50 (or PAEC.sub.90
which is the same factor just higher for each by a factor of 3-4
fold). In fact, the reported 5.5 fold shift in Table 7 for 40%
human serum in a multicell HIV full life cycle reporter based
assay.
[1794] Table 7 also depicts the protein adjusted EC.sub.50 for the
V370A polymorphic virus (which represents up to 40% of patients in
Glade B and maybe more outside Glade B) you can see that compound
51 potency is unexpectedly greater at 3.9 nM, while compound C
potency is lower at 929 nM.
TABLE-US-00006 TABLE 7 HIV w/t V370A Human Serum V370A Compound
Identity .sup.MT4EC.sub.50 .sup.MT4EC.sub.50 Fold Shift**
PAEC.sub.50*** Compound 51 ('232) 0.8 nM 0.7 nM 5.5X 3.9 nM
Compound 56 ('233) 4 nM 4 nM 16.2X 65 nM Compound C ('163) 6 nM 19
nM 48.9X 929 nM **Human Serum fold shift values determined using
40% human serum in a HIV multicell full life cycle assay. ***V370A
PAEC.sub.50 is determined by the product of V370A .sup.MT4EC.sub.50
and human serum fold shift.
Example 89
[1795] The PBL assay in this example was performed as follows in
order to study the effect of human serum on the HIV antiviral
activity of certain compounds. In particular, the effect of the
presence of human serum on the antiviral activity of compound 51
and Bevirimat ("BVM") was evaluated in a modified PMBC assay.
[1796] In the standard assay, PHA/IL-2 stimulated PBMCs
(5.times.10.sup.4 cells/well) were incubated with virus and
compound 51 or BVM (both compounds tested at range of 0.06 nM to 25
mM) for 7 days.
[1797] In the modified PBMC assay, PHA/IL-2 stimulated PBMCs were
pre-incubated with HIV-1 strain JR-CSF prior to addition of
compound 51 or BVM and human serum. In this assay, 8.times.10.sup.6
cells from pooled donors were incubated with virus for 1 hour,
followed by centrifugation for 1 hour. Cells were then gently
re-suspended and incubated an additional 2 hours. During this
second incubation period, 2.5.times.10.sup.4 uninfected PBMCs from
pooled donors were added to the interior 60 wells of a 96 well
plate, followed by the addition of compound 51 or BVM (both
compounds tested at range of 0.06 nM to 25 mM) and human serum
(10%, 20%, 30% and 40%) to the appropriate wells. At the end of the
second incubation period, infected cells were diluted in media
(5.times.10.sup.5 cells/mL) (without washout of virus) and 50 mL
(2.5.times.10.sup.4 cells) were added to each well of the plate and
incubated for 7 days.
[1798] Following incubation in both the standard and modified
assays, supernatants were assayed for reverse transcriptase (RT)
activity and p24 antigen content by ELISA and spectrophotometric
analysis at 450 nM.
[1799] Compound 51 maintained antiviral activity in the presence of
human serum at all serum concentrations tested, with no apparent
shift in IC.sub.50 values (range: 0.52 to 3.07 nM) compared to the
IC.sub.50 value (0.69 nM) in the standard assay (0% serum). These
results indicate that the inhibitory activity of compound 51 is
minimally or not at all impacted by serum proteins. Extrapolating
from the normalized IC.sub.50 values observed in the presence of
the various human serum concentrations gave an estimated IC.sub.50
value of 0.33 nM for 100% human serum (assuming a linear
relationship). BVM also maintained antiviral activity in the
presence of human serum at all concentrations, however, there was a
large increase in the IC.sub.50 values (range: 1.38 mM to 13 mM)
associated with increasing human serum concentrations compared to
the standard assay (9.76 nM). Extrapolating from the normalized
IC.sub.50 values observed in the presence of the various
concentrations of human serum there is a 2,310-fold change in the
IC.sub.50 value in the presence of 100% serum (compared to the
control experiment, suggesting that BVM is highly bound by serum
proteins).
[1800] The effect of human serum on antiviral activity of compound
51 and BVM was also evaluated in the LHIV assay. Using the same
format as the standard LHIV assay, the addition of 40% human serum
caused a 5.6-fold shift in the IC.sub.50 value (10.6 nM) for
compound 51 and a 174.9-fold shift in IC.sub.50 value (3.88 mM) for
BVM.
[1801] However, when determined in a PBL assay containing a
titration between 0 and 40% human serum the extrapolated value is 1
fold or less. Therefore, the improvement of compound 51 over
compound C, in terms of potency while in the presence of human
serum, is likely >1300 fold better when a more typical baseline
is taken into account. See FIGS. 3, 4, and 5.
* * * * *