U.S. patent application number 15/339883 was filed with the patent office on 2017-04-27 for low calcemic, highly antiproliferative, analogs of calcitriol.
The applicant listed for this patent is THE JOHNS HOPKINS UNIVERSITY. Invention is credited to Scott Borella, Douglas T. Genna, Lindsey C. Hess, Kimberly S. Petersen, Gary H. Posner.
Application Number | 20170114013 15/339883 |
Document ID | / |
Family ID | 39639271 |
Filed Date | 2017-04-27 |
United States Patent
Application |
20170114013 |
Kind Code |
A1 |
Posner; Gary H. ; et
al. |
April 27, 2017 |
LOW CALCEMIC, HIGHLY ANTIPROLIFERATIVE, ANALOGS OF CALCITRIOL
Abstract
The disclosure provides compounds, compositions and methods
using these compounds and compositions to stimulate the
differentiation of cells and inhibit excessive cell proliferation
of certain cells, including cancer cells and skin cells, which may
be useful in the treatment of diseases characterized by abnormal
cell proliferation and/or cell differentiation such as leukemia,
myelofibrosis and psoriasis without the well known effect on
calcium metabolism, which gives rise to hypercalcemia.
Inventors: |
Posner; Gary H.; (Baltimore,
MD) ; Petersen; Kimberly S.; (College Park, MD)
; Hess; Lindsey C.; (Baltimore, MD) ; Genna;
Douglas T.; (Timonium, MD) ; Borella; Scott;
(Charlotte, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
THE JOHNS HOPKINS UNIVERSITY |
Baltimore |
MD |
US |
|
|
Family ID: |
39639271 |
Appl. No.: |
15/339883 |
Filed: |
October 31, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12596252 |
Jan 28, 2010 |
9481646 |
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PCT/US2008/060885 |
Apr 18, 2008 |
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15339883 |
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60923998 |
Apr 18, 2007 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 307/42 20130101;
A61P 17/06 20180101; A61P 19/00 20180101; C07C 401/00 20130101;
A61P 17/00 20180101; C07C 2602/24 20170501; A61P 35/02 20180101;
C07C 2601/14 20170501; A61P 3/02 20180101; A61P 5/20 20180101; C07C
2601/16 20170501; A61P 35/00 20180101 |
International
Class: |
C07C 401/00 20060101
C07C401/00 |
Goverment Interests
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED
RESEARCH OR DEVELOPMENT
[0002] This study was supported in-part by the National Institute
of Health under CA 93547. The U.S. government may have certain
rights in the invention.
Claims
1. A compound having formula I: ##STR00077## or a pharmaceutically
acceptable salt or solvate thereof, wherein: is a single bond; X is
O; L.sub.1 is a direct bond; L.sub.2 is a direct bond; R.sup.1 is
an optionally substituted alkyl group; R.sup.2 is H, alkyl, or
perfluoroalkyl; R.sup.3 is independently H, F, Cl, Br, I, OH, CN,
NO.sub.2, substituted or unsubstituted alkyl, perfluoroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, --(CH.sub.2).sub.jOR.sup.4,
--(CH.sub.2).sub.jC(O)R.sup.4,
--(CH.sub.2).sub.jC(NR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(NNR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(O)OR.sup.4, --(CH.sub.2).sub.jNR.sup.5R.sup.6,
--(CH.sub.2).sub.jC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jOC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jNR.sup.7C(O)R.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)OR.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jS(O).sub.mR.sup.8,
--(CH.sub.2).sub.jNR.sup.7S(O).sub.2R.sup.8, or
--(CH.sub.2).sub.jS(O).sub.2NR.sup.5R.sup.6, wherein each j is
independently an integer from 0 to 6, wherein m is independently an
integer from 0 to 2, and wherein alkyl, cycloalkyl, alkenyl,
cycloalkenyl, alkynyl, aryl, arylalkyl, heteroaryl, and
heteroarylalkyl are each optionally independently substituted with
1 to 3 R.sup.9 groups; R.sup.4 is independently H, substituted or
unsubstituted alkyl, perfluoroalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heteroalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
heteroarylalkyl, wherein R.sup.4 is optionally independently
substituted with 1 to 3 R.sup.9 groups; R.sup.5, R.sup.6, R.sup.7
and R.sup.8 are each independently a direct bond, H, OH,
--(CH.sub.2).sub.jOR.sup.9, substituted or unsubstituted alkyl,
perfluoroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
heteroarylalkyl, wherein R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
each optionally independently substituted with 1 to 3 R.sup.9
groups, or R.sup.7 and R.sup.8 are as described above, and R.sup.5
and R.sup.6, together with the N atom to which they are attached,
form substituted or unsubstituted heterocycloalkyl, or substituted
or unsubstituted heteroaryl, wherein R.sup.5 and R.sup.6 are each
optionally independently substituted with 1 to 3 R.sup.9 groups;
and R.sup.9 is H, F, Cl, Br, I, OH, CN, NO.sub.2, alkyl,
perfluoroalkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl,
--(CH.sub.2).sub.jOR.sup.10, --(CH.sub.2).sub.jC(O)R.sup.10,
--(CH.sub.2).sub.jC(NR.sup.13)R.sup.4,
--(CH.sub.2).sub.jC(O)OR.sup.10,
--(CH.sub.2).sub.jNR.sup.11R.sup.12,
--(CH.sub.2).sub.jC(O)NR.sup.11R.sup.12,
--(CH.sub.2).sub.jOC(O)NR.sup.11R.sup.12,
--(CH.sub.2).sub.jNR.sup.13C(O)R.sup.14,
--(CH.sub.2).sub.jNR.sup.13C(O)OR.sup.10,
--(CH.sub.2).sub.jNR.sup.13C(O)NR.sup.11R.sup.12,
--(CH.sub.2).sub.jS(O).sub.mR.sup.15,
--(CH.sub.2).sub.jNR.sup.13S(O).sub.2R.sup.15, or
--(CH.sub.2).sub.jS(O).sub.2NR.sup.11R.sup.12; wherein each j is
independently an integer from 0 to 6, wherein m is independently an
integer from 0 to 2; and R.sup.10, R.sup.11, R.sup.12, R.sup.13,
R.sup.14 and R.sup.15 are each independently H, F, Cl, Br, I, OH,
CN, NO.sub.2, alkyl, perfluoroalkyl, cycloalkyl, alkenyl,
cycloalkenyl, alkynyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl.
2-9. (canceled)
10. A pharmaceutical composition, comprising an effective amount of
one or more of the compounds of formula I of claim 1, together with
one or more pharmaceutically acceptable carriers, optionally in
topical, oral or injectable form.
11. The compound of formula I of claim 1 or the pharmaceutical
composition of claim 10 for use in treating patients suffering from
disorders characterized by abnormal cell-proliferation and/or
cell-differentiation.
12. The compound of formula I of claim 1 or the pharmaceutical
composition of claim 10 for use in treating patients suffering from
secondary hyperparathyroidism.
13. A method of preparing the compound of formula I of claim 1,
comprising: ##STR00078## a) reacting the compound of formula XI
with base to form the corresponding anion; b) coupling the anion
with the compound of formula XII, wherein PG is a protecting group;
and c) removing the protecting groups to provide the compound of
formula I.
14. The method of claim 13, wherein the base is an alkali metal or
organolithium compound; and the protecting group is a silyl
protecting group.
15. The method of claim 14, wherein the alkali metal is sodium
hydride or lithium hydride; the organolithium compound is n-butyl
lithium, sec-butyl lithium or tert-butyl lithium, and the silyl
protecting group is tert-butyldimethylsilane.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 12/596,252, filed on Jan. 28, 2010, now pending, which is a 35
USC .sctn.371 National Stage application of International
Application No. PCT/US2008/060885 filed Apr. 18, 2008, now pending;
which claims the benefit under 35 USC .sctn.119(e) to U.S.
Application Ser. No. 60/923,998 filed Apr. 18, 2007, now abandoned.
The disclosure of each of the prior applications is considered part
of and is incorporated by reference in the disclosure of this
application.
BACKGROUND OF THE DISCLOSURE
[0003] Steroid hormones are necessary for good health in humans.
[Witzmann, R., Steroids: Keys to Life, Van Nostrand Reinhold Co.,
New York, N.Y., 1977; Hammes, S. R., Proc. Nat'l. Acad. Sci. 2003,
1009 21680-21700.] For example, these compounds are useful in the
treatment and/or prevention of cancer, dermatological disorders,
bone disorders, parathyroid disorders, immunological disorders,
wound healing and osteoporosis. Over the years, diverse oxa
steroids have been prepared to probe how the replacement of a
--CH.sub.2 group by an O-atom affects biological activity.
Significant and valuable biological benefits have been recorded for
some oxa steroids including: (1) 6-oxa steroids as GABA.sub.A
receptor modulators [Nicoletti, S. R. et al., Steroids 2000, 65,
349-356]; (2) 7-oxa steroids as potent and selective progesterone
receptor antagonists [Kang, F. A. et al.; Bioorg. Med Chem. Lett.
2007, 17, 907-910]; (3) 11-oxa steroids as progestational agents
[Engel, C. R. et al.; Steroids 1986, 47, 381-399; Cachoux, F.;
Tetrahedron Lett. 2000, 41, 1767-1769]; and (4) 15-oxa steroids as
estrogenic agents [Rosen, P. et al.; J. Med. Chem. 1980, 23,
329-330].
[0004] Some oxa analogs of the vitamin D seco-steroids have also
been reported [Calverley, M. J. et al.; Analogues, U.S. Pat. Nos.
5,378,695 and 5,401,732 (1995)]. The most noteworthy oxa analog of
the natural hormone 1.alpha.,25-dihydroxyvitamin D3 (calcitriol, A)
is the Chugai Pharmaceutical Company's maxacalcitol B [Kubodera,
N., Current Bioactive Compounds 2006, 2, 301-315]. This
22-oxa-25-OH analog is currently a clinically used drug for the
treatment of secondary hyperparathyroidism and is a drug candidate
for the topical treatment of psoriasis, an immune-mediated, chronic
skin disease. Other 23-oxa-25-hydroxy analogs of the natural
hormone A have been studied, but none surpasses or even matches
Chugai's drug 22-oxa-25-hydroxy B in terms of favorable separation
of antiproliferative and/or prodifferentiation activity from
unfavorable calcemic activity. [Steinmeyer, A., et al.; Curr.
Pharm. Des. 2000, 6, 767-789] For example, in a broad study of
structure-activity relationships (SAR) in 23-oxa-25-hydroxy analogs
of A, the Schering Corporation found that the potential therapeutic
window between desirably high antiproliferative or
prodifferentiation activity and desirably low calcemic activity was
small for 23-oxa calcitriol, 20-ene-23-oxa calcitriol, and
22-ene-25-oxa calcitriol [Steinmeyer, A., et al.; Curr. Pharm. Des.
2000, 6, 767-789], compared to a big therapeutic window for the
Chugai drug 22-oxa-25-hydroxy B. [Allewaert, K. et al.; Steroids
1994, 59, 686-690].
[0005] Thus, what is needed in the art are other analogs of the
vitamin D seco-steroids that selectively exhibit desirable
pharmacological activities but not exhibit hypercalcemic and other
undesirable activities.
SUMMARY OF THE DISCLOSURE
[0006] The disclosure provides biologically active analogs of the
natural hormone A that lack the conventional 25-0H group
[Sinishtaj, S. et al.; Bioorg. Med. Chem. 2006, 14, 6341-6348;
Agoston, E. S. et al.; Anti-Cancer Agents Med Chem. 2006, 6, 53-71;
Kahraman, M. et al.; Sinishtaj, S.; Dolan, P. M.; Kensler, T. W.;
Peleg, S.; Saha, U.; Chuang, S. S.; Bernstein, G.; Korczak, B.;
Posner, G. H. Potent, selective and low-calcemic inhibitors of
CYP24 Hydroxylase: 24-Sulfoximine analogues of the hormone
1.alpha.,25-dihydroxyvitamin D.sub.3. 2004, 47, 6854-6863]. In some
embodiments, the natural 25-OH group is removed and the natural
23-CH.sub.2 group is replaced by an oxygen atom. This overall
balanced removal of oxygen from position-25 and introduction of
oxygen at position-23 has produced several new vitamin D ether
analogs with high therapeutic potential. The disclosed series may
be easily synthesized using allylic, benzylic, and propargylic
ether analogs 1 in which an oxygen atom is located at position-23
on the C,D-ring side chain and, for the first time, in which the
standard side-chain terminal --OH group is absent. Despite the
absence of this terminal --OH group, thought to be essential for
effective binding to the vitamin D receptor (VDR) [Feldman, D. et
al.; Eds. Vitamin D. 2nd Ed., Elsevier, 2005], the disclosed
analogs have high antiproliferative activity in vitro and desirably
low calciuric activity in vivo.
##STR00001##
[0007] Thus, in one aspect the disclosure provides compounds having
formula I:
##STR00002##
or a pharmaceutically acceptable salt or solvate thereof,
wherein:
[0008] is a single or double bond;
[0009] X is independently O, NR.sup.2, S, S(O), or S(O).sub.2;
[0010] L.sub.1 is independently a direct bond, or substituted or
unsubstituted alkyl, wherein alkyl is optionally independently
substituted with 1 to 3 R.sup.9 groups;
[0011] L.sub.2 is independently a direct bond, or substituted or
unsubstituted alkyl, wherein alkyl is optionally independently
substituted with 1 to 3 R.sup.9 groups;
[0012] R.sup.1 is independently substituted or unsubstituted alkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
heteroarylalkyl, wherein R.sup.1 is optionally independently
substituted with 1 to 5 R.sup.3 groups;
[0013] R.sup.2 is H, alkyl, or perfluoroalkyl;
[0014] R.sup.3 is independently H, F, Cl, Br, I, OH, CN, NO.sub.2,
substituted or unsubstituted alkyl, perfluoroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted cycloalkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, --(CH.sub.2).sub.jOR.sup.4,
--(CH.sub.2).sub.jC(O)R.sup.4,
--(CH.sub.2).sub.jC(NR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(NNR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(O)OR.sup.4, --(CH.sub.2).sub.jNR.sup.5R.sup.6,
--(CH.sub.2).sub.jC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jOC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jNR.sup.7C(O)R.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)OR.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jS(O).sub.mR.sup.8,
--(CH.sub.2).sub.jNR.sup.7S(O).sub.2R.sup.8, or
--(CH.sub.2).sub.jS(O).sub.2NR.sup.5R.sup.6, wherein each j is
independently an integer from 0 to 6, wherein m is independently an
integer from 0 to 2, and wherein alkyl, cycloalkyl, alkenyl,
cycloalkenyl, alkynyl, aryl, arylalkyl, heteroaryl, and
heteroarylalkyl are each optionally independently substituted with
1 to 3 R.sup.9 groups;
[0015] R.sup.4 is independently H, substituted or unsubstituted
alkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
heteroarylalkyl, wherein R.sup.4 is optionally independently
substituted with 1 to 3 R.sup.9 groups;
[0016] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
a direct bond, H, OH, --(CH.sub.2).sub.jOR.sup.9, substituted or
unsubstituted alkyl, perfluoroalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heteroalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
heteroarylalkyl, wherein R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
each optionally independently substituted with 1 to 3 R.sup.9
groups, or
[0017] R.sup.7 and R.sup.8 are as described above, and R.sup.5 and
R.sup.6, together with the N atom to which they are attached, form
substituted or unsubstituted heterocycloalkyl, or substituted or
unsubstituted heteroaryl, wherein R.sup.5 and R.sup.6 are each
optionally independently substituted with 1 to 3 R.sup.9 groups;
and
[0018] R.sup.9 is H, F, Cl, Br, I, OH, CN, NO.sub.2, alkyl,
perfluoroalkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl,
--(CH.sub.2).sub.jOR.sup.10, --(CH.sub.2).sub.jC(O)R.sup.10,
--(CH.sub.2).sub.jC(NR.sup.13)R.sup.4,
--(CH.sub.2).sub.jC(O)OR.sup.10,
--(CH.sub.2).sub.jNR.sup.11R.sup.12,
--(CH.sub.2).sub.jC(O)NR.sup.11R.sup.12,
--(CH.sub.2).sub.jOC(O)NR.sup.11R.sup.12,
--(CH.sub.2).sub.jNR.sup.13C(O)R.sup.14,
--(CH.sub.2).sub.jNR.sup.13C(O)OR.sup.10,
--(CH.sub.2).sub.jNR.sup.13C(O)NR.sup.11R.sup.12,
--(CH.sub.2).sub.jS(O).sub.mR.sup.15,
--(CH.sub.2).sub.jNR.sup.13S(O).sup.2R.sup.15, or
--(CH.sub.2).sub.jS(O).sup.2NR.sup.11R.sup.12; wherein each j is
independently an integer from 0 to 6, wherein m is independently an
integer from 0 to 2; and
[0019] R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14 and
R.sup.15 are each independently H, F, Cl, Br, I, OH, CN, NO.sub.2,
alkyl, perfluoroalkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,
aryl, arylalkyl, heteroaryl, or heteroarylalkyl.
[0020] In other aspects the disclosure provides: pharmaceutical
compositions containing one or more of the compounds of formula I;
methods for treating disorders characterized by abnormal
cell-proliferation and/or cell-differentiation by administering a
compound of formula I or a pharmaceutical composition containing a
compound of formula I; methods for treating secondary
hyperparathyroidism by administering a compound of formula I or a
pharmaceutical composition containing a compound of formula I; and
methods for preparing a compound of formula I.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIG. 1 illustrates the in-vivo assay showing the effect of
the disclosed vitamin D.sub.3 analogs on calcium levels in rat
urine.
[0022] FIG. 2 illustrates the VDR binding assay results for
compound 1a.
[0023] FIG. 3 illustrates the VDR binding assay results for
compound 1b.
[0024] FIG. 4 illustrates the VDR binding assay results for
compound 1c.
[0025] FIG. 5 illustrates the VDR binding assay results for
compound 1 d.
[0026] FIG. 6 illustrates the VDR binding assay results for
compound 1f.
[0027] FIG. 7 illustrates the VDR binding assay results for
compound 1g.
[0028] FIG. 8 illustrates the VDR binding assay results for
compound 1h.
[0029] FIG. 9 illustrates the VDR binding assay results for
compound 1i.
DETAILED DESCRIPTION OF THE DISCLOSURE
General
[0030] Abbreviations used herein have their conventional meaning
within the chemical and biological arts.
[0031] Where substituent groups are specified by their conventional
chemical formulae, written from left to right, they equally
encompass the chemically identical substituents that would result
from writing the structure from right to left, e.g., --CH.sub.2O--
is equivalent to --OCH.sub.2--.
[0032] The term "alkyl," by itself or as part of another
substituent, means, unless otherwise stated, a straight (i.e.
unbranched) or branched chain, or cyclic hydrocarbon group, or
combination thereof, which may be fully saturated, mono- or
polyunsaturated and can include di- and multivalent groups, having
the number of carbon atoms designated (i.e. C.sub.1-C.sub.10 means
one to ten carbons). Examples of saturated hydrocarbon groups
include, but are not limited to, groups such as methyl, ethyl,
n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl,
cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and
isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and
the like. An unsaturated alkyl group is one having one or more
double bonds or triple bonds. Examples of unsaturated alkyl groups
include, but are not limited to, vinyl, 2-propenyl, crotyl,
2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,
3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the
higher homologs and isomers. Alkyl groups which are limited to
hydrocarbon groups are termed "homoalkyl".
[0033] The term "alkylene" by itself or as part of another
substituent means a divalent group derived from an alkyl, as
exemplified, but not limited, by
CH.sub.2CH.sub.2CH.sub.2CH.sub.2--. Typically, an alkyl (or
alkylene) group will have from 1 to 24 carbon atoms, with those
groups having 10 or fewer carbon atoms being preferred in the
present disclosure. A "lower alkyl" or "lower alkylene" is a
shorter chain alkyl or alkylene group, generally having eight or
fewer carbon atoms.
[0034] The term "heteroalkyl," by itself or in combination with
another term, means, unless otherwise stated, a stable straight or
branched chain, or cyclic hydrocarbon group, or combinations
thereof, consisting of at least one carbon atoms and at least one
heteroatom selected from the group consisting of O, N, P, Si and S,
and wherein the nitrogen and sulfur atoms may optionally be
oxidized and the nitrogen heteroatom may optionally be quaternized.
The heteroatom(s) O, N, P and S and Si may be placed at any
interior position of the heteroalkyl group or at the position at
which alkyl group is attached to the remainder of the molecule.
Examples include, but are not limited to,
--CH.sub.2--CH.sub.2--O--CH.sub.3,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--S--CH.sub.2--CH.sub.3, --CH.sub.2--CH.sub.2,
--S(O)--CH.sub.3, --CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3,
--CH.dbd.CH--O--CH.sub.3, --Si(CH.sub.3).sub.3,
--CH.sub.2--CH.dbd.N--OCH.sub.3, CH.dbd.CH--N(CH.sub.3)--CH.sub.3,
O--CH.sub.3, --O--CH.sub.2--CH.sub.3, and CN. Up to two heteroatoms
may be consecutive, such as, for example, --CH.sub.2--NH--OCH.sub.3
and CH.sub.2--O--Si(CH.sub.3).sub.3.
[0035] Similarly, the term "heteroalkylene" by itself or as part of
another substituent means a divalent group derived from
heteroalkyl, as exemplified, but not limited by,
--CH.sub.2--CH.sub.2--S--CH.sub.2--CH.sub.2-- and
CH.sub.2--S--CH.sub.2--CH.sub.2--NH--CH.sub.2--. For heteroalkylene
groups, heteroatoms can also occupy either or both of the chain
termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino,
alkylenediamino, and the like). Still further, for alkylene and
heteroalkylene linking groups, no orientation of the linking group
is implied by the direction in which the formula of the linking
group is written. For example, the formula C(O)OR'-- represents
both C(O)OR'-- and R'OC(O)--.
[0036] As described above, heteroalkyl groups, as used herein,
include those groups that are attached to the remainder of the
molecule through a heteroatom, such as --C(O)R', --C(O)NR',
--NR'R'', --OR', --SR', and/or --SO.sub.2R'. Where "heteroalkyl" is
recited, followed by recitations of specific heteroalkyl groups,
such as --NR'R'' or the like, it will be understood that the terms
heteroalkyl and --NR'R'' are not redundant or mutually exclusive.
Rather, the specific heteroalkyl groups are recited to add clarity.
Thus, the term "heteroalkyl" should not be interpreted herein as
excluding specific heteroalkyl groups, such as --NR'R'' or the
like.
[0037] The terms "cycloalkyl" and "heterocycloalkyl", by themselves
or in combination with other terms, represent, unless otherwise
stated, cyclic versions of "alkyl" and "heteroalkyl", respectively.
Additionally, for heterocycloalkyl, a heteroatom can occupy the
position at which the heterocycle is attached to the remainder of
the molecule. Examples of cycloalkyl include, but are not limited
to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl,
cycloheptyl, and the like. Examples of heterocycloalkyl include,
but are not limited to, 1 (1,2,5,6-tetrahydropyridyl),
1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl,
3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,
tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 piperazinyl,
2-piperazinyl, and the like. The terms "cycloalkylene" and
"heterocycloalkylene" refer to the divalent derivatives of
cycloalkyl and heterocycloalkyl, respectively.
[0038] The term "cycloalkyl" or "cycloalkylalkyl" also refers to a
3 to 7 membered cycloalkyl group attached to the remainder of the
molecule via an unsubstituted alkylene group. Recitation of a
specific number of carbon atoms (e.g. C.sub.1-C.sub.10
cycloalkylalkyl) refers to the number of carbon atoms in the
alkylene group.
[0039] The term "heterocycloalkyl" or "heterocycloalkylalkyl" also
refers to a 3 to 7 membered heterocycloalkyl group attached to the
remainder of the molecule via an unsubstituted alkylene group.
Recitation of a specific number of carbon atoms (e.g.
C.sub.1-C.sub.10 hetero-cycloalkylalkyl) refers to the number of
carbon atoms in the alkylene group.
[0040] The terms "halo" or "halogen," by themselves or as part of
another substituent, mean, unless otherwise stated, a fluorine,
chlorine, bromine, or iodine atom. Additionally, terms such as
"haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl.
For example, the term "halo(C.sub.1-C.sub.4)alkyl" is mean to
include, but not be limited to, trifluoromethyl,
2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the
like.
[0041] The term "aryl" means, unless otherwise stated, an aromatic,
hydrocarbon substituent which may be a single ring or multiple
rings (preferably from 1 to 3 rings) which are fused together or
linked covalently. The term "heteroaryl" refers to aryl groups (or
rings) that contain from one to four heteroatoms selected from N,
O, and S, wherein the nitrogen and sulfur atoms are optionally
oxidized, and the nitrogen atom(s) are optionally quaternized. A
heteroaryl group may be attached to the remainder of the molecule
through a carbon or heteroatom. Non-limiting examples of aryl and
heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl,
4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,
2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,
2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,
5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl,
3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl,
2-benzimidazolyl, 5-indolyl, 1-isoquinolinyl, 5-isoquinolinyl,
2-quinoxalinyl, 5-quinoxalinyl, 3-quinolinyl, and 6-quinolinyl.
Substituents for each of above noted aryl and heteroaryl ring
systems are selected from the group of acceptable substituents
described below. The terms "arylene" and "heteroarylene" refer to
the divalent derivatives of aryl and heteroaryl, respectively.
[0042] For brevity, the term "aryl" when used in combination with
other terms (e.g., aryloxo, arylthioxo, arylalkyl) includes both
aryl and heteroaryl rings as defined above. Thus, the term
"arylalkyl" is meant to include those groups in which an aryl group
is attached to an alkyl group (e.g., benzyl, phenethyl,
pyridylmethyl and the like) including those alkyl groups in which a
carbon atom (e.g., a methylene group) has been replaced by, for
example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl,
3-(1-naphthyloxy)propyl, and the like).
[0043] The term "oxo" as used herein means an oxygen that is double
bonded to a carbon atom.
[0044] Each of above terms (e.g., "alkyl," "heteroalkyl,"
"cycloalkyl, and "heterocycloalkyl", "aryl," "heteroaryl" as well
as their divalent derivatives) are meant to include both
substituted and unsubstituted forms of the indicated group.
Preferred substituents for each type of group are provided
below.
[0045] Substituents for alkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl monovalent and divalent derivative groups
(including those groups often referred to as alkylene, alkenyl,
heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) may be one
or more of a variety of groups selected from, but not limited to:
--OR', .dbd.O, .dbd.NR', .dbd.N--OR', --NR'R'', --SR', -halogen,
--SiR'R''R''', --OC(O)R', --C(O)R', --CO.sub.2R', --C(O)NR'R'',
--OC(O)NR'R'', --NR''C(O)R', --NR'--C(O)NR''R''', --NR''C(O)OR',
--NR--C(NR'R'').dbd.NR''', --S(O)R', --S(O).sub.2R',
--S(O).sub.2NR'R'', --NRSO.sub.2R', --CN and NO.sub.2 in a number
ranging from zero to (2m'+1), where m' is the total number of
carbon atoms in such group. R', R'', R''' and R'''' each preferably
independently refer to hydrogen, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl (e.g., aryl substituted with 1-3 halogens), substituted or
unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl
groups. When a compound of the disclosure includes more than one R
group, for example, each of the R groups is independently selected
as are each R', R'', R''' and R'''' groups when more than one of
these groups is present. When R' and R'' are attached to the same
nitrogen atom, they may be combined with the nitrogen atom to form
a 4-, 5-, 6-, or 7-membered ring. For example, --NR'R'' is meant to
include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl.
From above discussion of substituents, one of skill in art will
understand that the term "alkyl" is meant to include groups
including carbon atoms bound to groups other than hydrogen groups,
such as haloalkyl (e.g., --CF.sub.3 and CH.sub.2CF.sub.3) and acyl
(e.g., --C(O)CH.sub.3, --C(O)CF.sub.3, --C(O)CH.sub.2OCH.sub.3, and
the like).
[0046] Similar to the substituents described for alkyl groups
above, exemplary substituents for aryl and heteroaryl groups (as
well as their divalent derivatives) are varied and are selected
from, for example: halogen, --OR', --NR'R'', --SR', -halogen,
--SiR'R''R''', --OC(O)R', --C(O)R', --CO.sub.2R', --C(O)NR'R'',
--OC(O)NR'R'', --NR''C(O)R', --NR'--C(O)NR''R''', --NR''C(O)OR',
--NR--C(NR'R''R''').dbd.NR'''', --NR--C(NR'R'').dbd.NR''',
--S(O)R', --S(O).sub.2R', --S(O).sub.2NR'R'', --NRSO.sub.2R', --CN
and NO.sub.2, --R', --N.sub.3, --CH(Ph).sub.2,
fluoro(C.sub.1-C.sub.4)alkoxo, and fluoro(C.sub.1-C.sub.4)alkyl, in
a number ranging from zero to the total number of open valences on
aromatic ring system; and where R', R'', R''' and R'''' are
preferably independently selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl
and substituted or unsubstituted heteroaryl. When a compound of the
disclosure includes more than one R group, for example, each of the
R groups is independently selected as are each R', R'', R''' and
R'''' groups when more than one of these groups is present.
[0047] Two of the substituents on adjacent atoms of aryl or
heteroaryl ring may optionally form a ring of the formula
-T-C(O)--(CRR').sub.q--U--, wherein T and U are independently NR--,
--O--, --CRR'-- or a single bond, and q is an integer of from 0 to
3. Alternatively, two of the substituents on adjacent atoms of aryl
or heteroaryl ring may optionally be replaced with a substituent of
the formula -A-(CH.sub.2).sub.r--B--, wherein A and B are
independently CRR'--, --O--, --NR--, --S--, --S(O)--,
--S(O).sub.2--, --S(O).sub.2NR'-- or a single bond, and r is an
integer of from 1 to 4. One of the single bonds of the new ring so
formed may optionally be replaced with a double bond.
Alternatively, two of the substituents on adjacent atoms of aryl or
heteroaryl ring may optionally be replaced with a substituent of
the formula --(CRR').sub.s--X'--(C''R''').sub.d--, where s and d
are independently integers of from 0 to 3, and X' is O--, --NR'--,
--S--, --S(O)--, --S(O).sub.2--, or S(O).sub.2NR'--. The
substituents R, R', R'' and R''' are preferably independently
selected from hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0048] As used herein, the term "heteroatom" or "ring heteroatom"
is meant to include oxygen (O), nitrogen (N), sulfur (S),
phosphorus (P), and silicon (Si).
[0049] The compounds of the present disclosure may exist as salts.
The present disclosure includes such salts. Examples of applicable
salt forms include hydrochlorides, hydrobromides, sulfates,
methanesulfonates, nitrates, maleates, acetates, citrates,
fumarates, tartrates (eg (+)-tartrates, (-)-tartrates or mixtures
thereof including racemic mixtures, succinates, benzoates and salts
with amino acids such as glutamic acid. These salts may be prepared
by methods known to those skilled in art. Also included are base
addition salts such as sodium, potassium, calcium, ammonium,
organic amino, or magnesium salt, or a similar salt. When compounds
of the present disclosure contain relatively basic functionalities,
acid addition salts may be obtained by contacting the neutral form
of such compounds with a sufficient amount of the desired acid,
either neat or in a suitable inert solvent. Examples of acceptable
acid addition salts include those derived from inorganic acids like
hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic,
phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
as well as the salts derived organic acids like acetic, propionic,
isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric,
lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic,
citric, tartaric, methanesulfonic, and the like. Also included are
salts of amino acids such as arginate and the like, and salts of
organic acids like glucuronic or galactunoric acids and the like.
Certain specific compounds of the present disclosure contain both
basic and acidic functionalities that allow the compounds to be
converted into either base or acid addition salts.
[0050] The neutral forms of the compounds are preferably
regenerated by contacting the salt with a base or acid and
isolating the parent compound in the conventional manner. The
parent form of the compound differs from the various salt forms in
certain physical properties, such as solubility in polar
solvents.
[0051] Certain compounds of the present disclosure can exist in
unsolvated forms as well as solvated forms, including hydrated
forms. In general, the solvated forms are equivalent to unsolvated
forms and are encompassed within the scope of the present
disclosure. Certain compounds of the present disclosure may exist
in multiple crystalline or amorphous forms. In general, all
physical forms are equivalent for the uses contemplated by the
present disclosure and are intended to be within the scope of the
present disclosure.
[0052] Certain compounds of the present disclosure possess
asymmetric carbon atoms (optical centers) or double bonds; the
enantiomers, racemates, diastereomers, tautomers, geometric
isomers, stereoisometric forms that may be defined, in terms of
absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for
amino acids, and individual isomers are encompassed within the
scope of the present disclosure. The compounds of the present
disclosure do not include those which are known in art to be too
unstable to synthesize and/or isolate. The present disclosure is
meant to include compounds in racemic and optically pure forms.
Optically active (R)- and (S)-, or (D)- and (L)-isomers may be
prepared using chiral synthons or chiral reagents, or resolved
using conventional techniques. When the compounds described herein
contain olefinic bonds or other centers of geometric asymmetry, and
unless specified otherwise, it is intended that the compounds
include both E and Z geometric isomers.
[0053] The term "tautomer," as used herein, refers to one of two or
more structural isomers which exist in equilibrium and which are
readily converted from one isomeric form to another.
[0054] It will be apparent to one skilled in the art that certain
compounds of this disclosure may exist in tautomeric forms, all
such tautomeric forms of the compounds being within the scope of
the disclosure.
[0055] Unless otherwise stated, structures depicted herein are also
meant to include all stereochemical forms of the structure; i.e.,
the R and S configurations for each asymmetric center. Therefore,
single stereochemical isomers as well as enantiomeric and
diastereomeric mixtures of the present compounds are within the
scope of the disclosure.
[0056] Unless otherwise stated, structures depicted herein are also
meant to include compounds which differ only in the presence of one
or more isotopically enriched atoms. For example, compounds having
the present structures except for the replacement of a hydrogen by
a deuterium or tritium, or the replacement of a carbon by .sup.13C-
or .sup.14C-enriched carbon are within the scope of this
disclosure.
[0057] The compounds of the present disclosure may also contain
unnatural proportions of atomic isotopes at one or more of atoms
that constitute such compounds. For example, the compounds may be
radiolabeled with radioactive isotopes, such as for example tritium
(.sup.3H), iodine-125 (.sup.125I) or carbon-14 (.sup.14C). All
isotopic variations of the compounds of the present disclosure,
whether radioactive or not, are encompassed within the scope of the
present disclosure.
[0058] The term "pharmaceutically acceptable salts" is meant to
include salts of active compounds which are prepared with
relatively nontoxic acids or bases, depending on the particular
substituent moieties found on the compounds described herein. When
compounds of the present disclosure contain relatively acidic
functionalities, base addition salts may be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired base, either neat or in a suitable inert solvent. Examples
of pharmaceutically acceptable base addition salts include sodium,
potassium, calcium, ammonium, organic amino, or magnesium salt, or
a similar salt. When compounds of the present disclosure contain
relatively basic functionalities, acid addition salts may be
obtained by contacting the neutral form of such compounds with a
sufficient amount of the desired acid, either neat or in a suitable
inert solvent. Examples of pharmaceutically acceptable acid
addition salts include those derived from inorganic acids like
hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic,
phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
as well as the salts derived from relatively nontoxic organic acids
like acetic, propionic, isobutyric, maleic, malonic, benzoic,
succinic, suberic, fumaric, lactic, mandelic, phthalic,
benzenesulfonic, p-tolylsulfonic, citric, tartaric,
methanesulfonic, and the like. Also included are salts of amino
acids such as arginate and the like, and salts of organic acids
like glucuronic or galactunoric acids and the like (see, for
example, Berge et al., "Pharmaceutical Salts", Journal of
Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds
of the present disclosure contain both basic and acidic
functionalities that allow the compounds to be converted into
either base or acid addition salts.
[0059] In addition to salt forms, the present disclosure relates to
compounds, which are in a prodrug form. Prodrugs of the compounds
described herein are those compounds that readily undergo chemical
changes under physiological conditions to provide the compounds of
the present disclosure. Additionally, prodrugs may be converted to
the compounds of the present disclosure by chemical or biochemical
methods in an ex vivo environment. For example, prodrugs may be
slowly converted to the compounds of the present disclosure when
placed in a transdermal patch reservoir with a suitable enzyme or
chemical reagent.
[0060] The terms "a," "an," or "a(n)", when used in reference to a
group of substituents herein, mean at least one. For example, where
a compound is substituted with "an" alkyl or aryl, the compound is
optionally substituted with at least one alkyl and/or at least one
aryl. Moreover, where a moiety is substituted with an R
substituent, the group may be referred to as "R-substituted." Where
a moiety is R-substituted, the moiety is substituted with at least
one R substituent and each R substituent is optionally
different.
[0061] Description of compounds of the present disclosure are
limited by principles of chemical bonding known to those skilled in
the art. Accordingly, where a group may be substituted by one or
more of a number of substituents, such substitutions are selected
so as to comply with principles of chemical bonding and to give
compounds which are not inherently unstable and/or would be known
to one of ordinary skill in the art as likely to be unstable under
ambient conditions, such as aqueous, neutral, physiological
conditions.
[0062] The terms "treating" or "treatment" in reference to a
particular disease includes prevention of the disease.
[0063] The structure:
##STR00003##
signifies the point of attachment of a moiety "R" to the remainder
of the molecule.
[0064] The structure:
##STR00004##
signifies mixtures of .alpha.- and .beta.-isomers.
Analogs of Calcitriol
[0065] The disclosure provides compounds, compositions and methods
using these compounds and compositions to stimulate the
differentiation of cells and inhibit excessive cell proliferation
of certain cells, including cancer cells and skin cells. The
disclosed compounds, compositions and methods may be useful in the
treatment of diseases characterized by abnormal cell proliferation
and/or cell differentiation such as leukemia, myelofibrosis and
psoriasis without the well known effect on calcium metabolism,
which gives rise to hypercalcemia. The disclosure further provides
these compounds and compositions, along with dosage units of such
preparations, which are useful in methods for treating diseases
characterized by abnormal cell differentiation and/or cell
proliferation.
[0066] Thus, in one aspect the disclosure provides compounds having
formula I:
##STR00005##
or a pharmaceutically acceptable salt or solvate thereof,
wherein:
[0067] is a single or double bond;
[0068] X is independently O, NR.sup.2, S, S(O), or S(O).sub.2;
[0069] L.sub.1 is independently a direct bond, or substituted or
unsubstituted alkyl, wherein alkyl is optionally independently
substituted with 1 to 3 R.sup.9 groups;
[0070] L.sub.2 is independently a direct bond, or substituted or
unsubstituted alkyl, wherein alkyl is optionally independently
substituted with 1 to 3 R.sup.9 groups;
[0071] R.sup.1 is independently substituted or unsubstituted alkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
heteroarylalkyl, wherein R.sup.1 is optionally independently
substituted with 1 to 5 R.sup.3 groups;
[0072] R.sup.2 is H, alkyl, or perfluoroalkyl;
[0073] R.sup.3 is independently H, F, Cl, Br, I, OH, CN, NO.sub.2,
substituted or unsubstituted alkyl, perfluoroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted cycloalkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, --(CH.sub.2).sub.jOR.sup.4,
--(CH.sub.2).sub.jC(O)R.sup.4,
--(CH.sub.2).sub.jC(NR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(NNR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(O)OR.sup.4, --(CH.sub.2).sub.jNR.sup.5R.sup.6,
--(CH.sub.2).sub.jC(O)NR.sup.5R.sup.6,
(CH.sub.2).sub.jOC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jNR.sup.7C(O)R.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)OR.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jS(O).sub.mR.sup.8,
--(CH.sub.2).sub.jNR.sup.7S(O).sub.2R.sup.8, or
--(CH.sub.2).sub.jS(O).sub.2NR.sup.5R.sup.6, wherein each j is
independently an integer from 0 to 6, wherein m is independently an
integer from 0 to 2, and wherein alkyl, cycloalkyl, alkenyl,
cycloalkenyl, alkynyl, aryl, arylalkyl, heteroaryl, and
heteroarylalkyl are each optionally independently substituted with
1 to 3 R.sup.9 groups;
[0074] R.sup.4 is independently H, substituted or unsubstituted
alkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
heteroarylalkyl, wherein R.sup.4 is optionally independently
substituted with 1 to 3 R.sup.9 groups;
[0075] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each independently
a direct bond, H, OH, --(CH.sub.2).sub.jOR.sup.9, substituted or
unsubstituted alkyl, perfluoroalkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heteroalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
heteroarylalkyl, wherein R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
each optionally independently substituted with 1 to 3 R.sup.9
groups, or
[0076] R.sup.7 and R.sup.8 are as described above, and R.sup.5 and
R.sup.6, together with the N atom to which they are attached, form
substituted or unsubstituted heterocycloalkyl, or substituted or
unsubstituted heteroaryl, wherein R.sup.5 and R.sup.6 are each
optionally independently substituted with 1 to 3 R.sup.9 groups;
and
[0077] R.sup.9 is H, F, Cl, Br, I, OH, CN, NO.sub.2, alkyl,
perfluoroalkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl,
--(CH.sub.2).sub.jOR.sup.10, --(CH.sub.2).sub.jC(O)R.sup.10,
--(CH.sub.2).sub.jC(NR.sup.13)R.sup.4;
--(CH.sub.2).sub.jC(O)OR.sup.10,
--(CH.sub.2).sub.jNR.sup.11R.sup.12,
--(CH.sub.2).sub.jC(O)NR.sup.11R.sup.12,
--(CH.sub.2).sub.jOC(O)NR.sup.11R.sup.12,
--(CH.sub.2).sub.jNR.sup.13C(O)R.sup.14,
--(CH.sub.2).sub.jNR.sup.13C(O)OR.sup.10,
--(CH.sub.2).sub.jNR.sup.13C(O)NR.sup.11R.sup.12,
--(CH.sub.2).sub.jS(O).sub.mR.sup.15,
--(CH.sub.2).sub.jNR.sup.13S(O).sub.2R.sup.15, or
--(CH.sub.2).sub.jS(O).sub.2NR.sup.11R.sup.12; wherein each j is
independently an integer from 0 to 6, wherein m is independently an
integer from 0 to 2; and
[0078] R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14 and
R.sup.15 are each independently H, F, Cl, Br, I, OH, CN, NO.sub.2,
alkyl, perfluoroalkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,
aryl, arylalkyl, heteroaryl, or heteroarylalkyl.
[0079] In another aspect the disclosure provides compounds of
formula I, wherein:
[0080] X is independently O;
[0081] L.sub.1 is independently a direct bond, or
(C.sub.1-C.sub.6)alkyl;
[0082] L.sub.2 is independently a direct bond, or
(C.sub.1-C.sub.6)alkyl;
[0083] R.sup.1 is independently substituted or unsubstituted alkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl,
or substituted or unsubstituted alkynyl; and
[0084] R.sup.3 is independently H, F, Cl, Br, I, OH, CN, NO.sub.2,
substituted or unsubstituted alkyl, perfluoroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted cycloalkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, --(CH.sub.2).sub.jOR.sup.4,
--(CH.sub.2).sub.jC(O)R.sup.4,
--(CH.sub.2).sub.jC(NR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(NNR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(O)OR.sup.4, --(CH.sub.2).sub.jNR.sup.5R.sup.6,
--(CH.sub.2).sub.jC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jOC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jNR.sup.7C(O)R.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)OR.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jS(O).sub.mR.sup.8,
--(CH.sub.2).sub.jNR.sup.7S(O).sub.2R.sup.8, or
--(CH.sub.2).sub.jS(O).sub.2NR.sup.5R.sup.6.
[0085] In another aspect the disclosure provides compounds of
formula I, wherein:
[0086] R.sup.1 is independently substituted or unsubstituted
(C.sub.1-C.sub.12)alkyl, substituted or unsubstituted
(C.sub.3-C.sub.32)cycloalkyl, substituted or unsubstituted
(C.sub.2-C.sub.12)alkenyl, substituted or unsubstituted
(C.sub.4-C.sub.12)cycloalkenyl, or substituted or unsubstituted
(C.sub.2-C.sub.12)alkynyl, wherein R.sup.1 is optionally
independently substituted with 1 to 3 R.sup.3 groups; and
[0087] R.sup.3 is independently F, Cl, Br, I, OH, CN, NO.sub.2,
alkyl, perfluoroalkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl,
--(CH.sub.2).sub.jOR.sup.4, --(CH.sub.2).sub.jC(O)R.sup.4,
--(CH.sub.2).sub.jC(NR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(NNR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(O)OR.sup.4, --(CH.sub.2).sub.jNR.sup.5R.sup.6,
--(CH.sub.2).sub.jC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jOC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jNR.sup.7C(O)R.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)OR.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jS(O).sub.mR.sup.8,
--(CH.sub.2).sub.jNR.sup.7S(O).sub.2R.sup.8, or
--(CH.sub.2).sub.jS(O).sub.2NR.sup.5R.sup.6.
[0088] In another aspect the disclosure provides compounds of
formula I, wherein:
[0089] L.sub.1 is independently a direct bond,
##STR00006##
[0090] L.sub.1 is independently a direct bond or CH.sub.2; and
[0091] R.sup.1 is independently:
##STR00007## ##STR00008## ##STR00009## ##STR00010##
##STR00011##
wherein n is independently an integer from 0 to 2.
[0092] In another aspect the disclosure provides compounds of
formula I, wherein:
[0093] L.sub.1 is independently a direct bond,
##STR00012##
[0094] L.sub.1 is independently a direct bond or CH.sub.2; and
[0095] R.sup.1 is independently:
##STR00013## ##STR00014## ##STR00015##
[0096] In another aspect the disclosure provides compounds of
formula I, having formula II or formula III:
##STR00016##
wherein:
[0097] L.sub.1 is independently a direct bond,
##STR00017##
[0098] L.sub.1 is independently a direct bond or CH.sub.2; and
[0099] R.sup.1 is independently:
##STR00018## ##STR00019## ##STR00020##
[0100] In another aspect the disclosure provides compounds of
formula I, wherein:
[0101] X is independently O;
[0102] L.sub.1 is independently a direct bond, or
(C.sub.1-C.sub.6)alkyl;
[0103] L.sub.2 is independently a direct bond, or
(C.sub.1-C.sub.6)alkyl;
[0104] R.sup.1 is independently substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
heteroarylalkyl; and
[0105] R.sup.3 is independently H, F, Cl, Br, I, OH, CN, NO.sub.2,
substituted or unsubstituted alkyl, perfluoroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted cycloalkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, --(CH.sub.2).sub.jOR.sup.4,
--(CH.sub.2).sub.jC(O)R.sup.4,
--(CH.sub.2).sub.jC(NR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(NNR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(O)OR.sup.4, --(CH.sub.2).sub.jNR.sup.5R.sup.6,
--(CH.sub.2).sub.jC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jOC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jNR.sup.7C(O)R.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)OR.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jS(O).sub.mR.sup.8,
--(CH.sub.2).sub.jNR.sup.7S(O).sub.2R.sup.8, or
--(CH.sub.2).sub.jS(O).sub.2NR.sup.5R.sup.6.
[0106] In another aspect the disclosure provides compounds of
formula I, wherein:
[0107] R.sup.1 is independently substituted or unsubstituted
phenyl, substituted or unsubstituted naphthyl, substituted or
unsubstituted furanyl, substituted or unsubstituted pyrrolyl,
substituted or unsubstituted thiofuranyl, substituted or
unsubstituted oxazolyl, substituted or unsubstituted isooxazolyl,
substituted or unsubstituted pyrazolyl, substituted or
unsubstituted imidazolyl, substituted or unsubstituted pyridinyl,
substituted or unsubstituted pyridazinyl, substituted or
unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl,
wherein R.sup.1 is optionally independently substituted with 1 to 3
R.sup.3 groups; and
[0108] R.sup.3 is independently F, Cl, Br, I, OH, CN, NO.sub.2,
alkyl, perfluoroalkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl,
--(CH.sub.2).sub.jOR.sup.4, --(CH.sub.2).sub.jC(O)R.sup.4,
--(CH.sub.2).sub.jC(NR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(NNR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(O)OR.sup.4, --(CH.sub.2).sub.jNR.sup.5R.sup.6,
--(CH.sub.2).sub.jC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jOC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jNR.sup.7C(O)R.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)OR.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jS(O).sub.mR.sup.8,
--(CH.sub.2).sub.jNR.sup.7S(O).sub.2R.sup.8, or
--(CH.sub.2).sub.jS(O).sub.2NR.sup.5R.sup.6.
[0109] In another aspect the disclosure provides compounds of
formula I, wherein:
[0110] L.sub.1 is independently a direct bond,
##STR00021##
[0111] L.sub.1 is independently a direct bond or CH.sub.2; and
[0112] R.sup.1 is independently:
##STR00022##
[0113] In another aspect the disclosure provides compounds of
formula I, having formula II or formula III:
##STR00023##
wherein:
[0114] L.sub.1 is independently a direct bond,
##STR00024##
[0115] L.sub.1 is independently a direct bond or CH.sub.2; and
[0116] R.sup.1 is independently:
##STR00025##
[0117] In another aspect the disclosure provides compounds of
formula I, wherein the compound of formula I has formula IV:
##STR00026##
wherein:
[0118] q is independently an integer from 0 to 2;
[0119] R.sup.1 is independently substituted or unsubstituted alkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl,
or substituted or unsubstituted alkynyl; and
[0120] R.sup.3 is independently H, F, Cl, Br, I, OH, CN, NO.sub.2,
substituted or unsubstituted alkyl, perfluoroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted cycloalkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, --(CH.sub.2).sub.jOR.sup.4,
--(CH.sub.2).sub.jC(O)R.sup.4,
--(CH.sub.2).sub.jC(NR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(NNR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(O)OR.sup.4, --(CH.sub.2).sub.jNR.sup.5R.sup.6,
--(CH.sub.2).sub.jC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jOC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jNR.sup.7C(O)R.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)OR.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jS(O).sub.mR.sup.8,
--(CH.sub.2).sub.jNR.sup.7S(O).sub.2R.sup.8, or
--(CH.sub.2).sub.jS(O).sub.2NR.sup.5R.sup.6.
[0121] In another aspect the disclosure provides compounds of
formula IV, wherein:
[0122] R.sup.1 is independently substituted or unsubstituted
(C.sub.1-C.sub.12)alkyl, substituted or unsubstituted
(C.sub.3-C.sub.12)cycloalkyl, substituted or unsubstituted
(C.sub.2-C.sub.12)alkenyl, substituted or unsubstituted
(C.sub.4-C.sub.12)cycloalkenyl, or substituted or unsubstituted
(C.sub.2-C.sub.12)alkynyl, wherein R.sup.1 is optionally
independently substituted with 1 to 3 R.sup.3 groups; and
[0123] R.sup.3 is independently F, Cl, Br, I, OH, CN, NO.sub.2,
alkyl, perfluoroalkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl,
--(CH.sub.2).sub.jOR.sup.4, --(CH.sub.2).sub.jC(O)R.sup.4,
--(CH.sub.2).sub.jC(NR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(NNR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(O)OR.sup.4, --(CH.sub.2).sub.jNR.sup.5R.sup.6,
--(CH.sub.2).sub.jC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jOC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jNR.sup.7C(O)R.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)OR.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jS(O).sub.mR.sup.8,
--(CH.sub.2).sub.jNR.sup.7S(O).sub.2R.sup.8, or
--(CH.sub.2).sub.jS(O).sub.2NR.sup.5R.sup.6.
[0124] In another aspect the disclosure provides compounds of
formula. IV, wherein:
[0125] R.sup.1 is independently:
##STR00027## ##STR00028## ##STR00029## ##STR00030##
##STR00031##
wherein n is independently an integer from 0 to 2.
[0126] In another aspect the disclosure provides compounds of
formula IV, wherein R.sup.1 is independently:
##STR00032## ##STR00033## ##STR00034##
[0127] In another aspect the disclosure provides compounds of
formula IV, having formula V or formula VI:
##STR00035##
wherein:
[0128] R.sup.1 is independently:
##STR00036## ##STR00037## ##STR00038##
[0129] In another aspect the disclosure provides compounds of
formula IV, wherein:
[0130] R.sup.1 is independently substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
heteroarylalkyl; and
[0131] R.sup.3 is independently H, F, Cl, Br, I, OH, CN, NO.sub.2,
substituted or unsubstituted alkyl, perfluoroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted cycloalkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, --(CH.sub.2).sub.jOR.sup.4,
--(CH.sub.2).sub.jC(O)R.sup.4,
--(CH.sub.2).sub.jC(NR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(NNR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(O)OR.sup.4, --(CH.sub.2).sub.jNR.sup.5R.sup.6,
--(CH.sub.2).sub.jC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jOC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jNR.sup.7C(O)R.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)OR.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jS(O).sub.mR.sup.8,
--(CH.sub.2).sub.jNR.sup.7S(O).sub.2R.sup.8, or
--(CH.sub.2).sub.jS(O).sub.2NR.sup.5R.sup.6.
[0132] In another aspect the disclosure provides compounds of
formula IV, wherein:
[0133] R.sup.1 is independently substituted or unsubstituted
phenyl, substituted or unsubstituted naphthyl, substituted or
unsubstituted furanyl, substituted or unsubstituted pyrrolyl,
substituted or unsubstituted thiofuranyl, substituted or
unsubstituted oxazolyl, substituted or unsubstituted isooxazolyl,
substituted or unsubstituted pyrazolyl, substituted or
unsubstituted imidazolyl, substituted or unsubstituted pyridinyl,
substituted or unsubstituted pyridazinyl, substituted or
unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl,
wherein R.sup.1 is optionally independently substituted with 1 to 3
R.sup.3 groups; and
[0134] R.sup.3 is independently F, Cl, Br, I, OH, CN, NO.sub.2,
alkyl, perfluoroalkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl,
--(CH.sub.2).sub.jOR.sup.4, --(CH.sub.2).sub.jC(O)R.sup.4,
--(CH.sub.2).sub.jC(NR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(NNR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(O)OR.sup.4, --(CH.sub.2).sub.jNR.sup.5R.sup.6,
--(CH.sub.2).sub.jC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jNR.sup.7C(O)R.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)OR.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jS(O).sub.mR.sup.8,
--(CH.sub.2).sub.jNR.sup.7S(O).sub.2R.sup.8, or
--(CH.sub.2).sub.jS(O).sub.2NR.sup.5R.sup.6.
[0135] In another aspect the disclosure provides compounds of
formula IV, wherein:
[0136] R.sup.1 is independently:
##STR00039##
[0137] In another aspect the disclosure provides compounds of
formula IV, having formula V or formula VI:
##STR00040##
wherein:
[0138] R.sup.1 is independently:
##STR00041##
[0139] In another aspect the disclosure provides compounds having
formula I, wherein the compound of formula I has formula VII:
##STR00042##
wherein:
[0140] R.sup.1 is independently substituted or unsubstituted alkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl,
or substituted or unsubstituted alkynyl; and
[0141] R.sup.3 is independently H, F, Cl, Br, I, OH, CN, NO.sub.2,
substituted or unsubstituted alkyl, perfluoroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted cycloalkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, --(CH.sub.2).sub.jOR.sup.4,
--(CH.sub.2).sub.jC(O)R.sup.4,
--(CH.sub.2).sub.jC(NR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(NNR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(O)OR.sup.4, --(CH.sub.2).sub.jNR.sup.5R.sup.6,
--(CH.sub.2).sub.jC(O)NR.sup.5R.sup.6,
(CH.sub.2).sub.jOC(O).sub.jNR.sup.5R.sup.6,
--(CH.sub.2).sub.jNR.sup.7C(O)R.sup.4--(CH.sub.2).sub.jNR.sup.7C(O)OR.sup-
.4, --(CH.sub.2).sub.jNR.sup.7C(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jS(O).sub.mR.sup.8,
--(CH.sub.2).sub.jNR.sup.7S(O).sub.2R.sup.8, or
--(CH.sub.2).sub.jS(O).sub.2NR.sup.5R.sup.6.
[0142] In another aspect the disclosure provides compounds of
formula VII, wherein:
[0143] R.sup.1 is independently substituted or unsubstituted
(C.sub.1-C.sub.12)alkyl, substituted or unsubstituted
(C.sub.3-C.sub.12)cycloalkyl, substituted or unsubstituted
(C.sub.2-C.sub.12)alkenyl, substituted or unsubstituted
(C.sub.4-C.sub.12)cycloalkenyl, or substituted or unsubstituted
(C.sub.2-C.sub.12)alkynyl, wherein R.sup.1 is optionally
independently substituted with 1 to 3 R.sup.3 groups; and
[0144] R.sup.3 is independently F, Cl, Br, I, OH, CN, NO.sub.2,
alkyl, perfluoroalkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl,
--(CH.sub.2).sub.jOR.sup.4, --(CH.sub.2).sub.jC(O)R.sup.4,
--(CH.sub.2).sub.jC(NR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(NNR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(O)OR.sup.4, --(CH.sub.2).sub.jNR.sup.5R.sup.6,
--(CH.sub.2).sub.jC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jOC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jNR.sup.7C(O)R.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)OR.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jS(O).sub.mR.sup.8,
--(CH.sub.2).sub.jNR.sup.7S(O).sub.2R.sup.8, or
--(CH.sub.2).sub.jS(O).sub.2NR.sup.5R.sup.6.
[0145] In another aspect the disclosure provides compounds of
formula VII, wherein:
[0146] R.sup.1 is independently:
##STR00043## ##STR00044## ##STR00045## ##STR00046##
##STR00047##
wherein n is independently an integer from 0 to 2.
[0147] In another aspect the disclosure provides compounds of
formula VII, wherein R.sup.1 is independently:
##STR00048## ##STR00049## ##STR00050##
[0148] In another aspect the disclosure provides compounds of
formula VII, having formula VIII or formula IX:
##STR00051##
wherein:
[0149] R.sup.1 is independently:
##STR00052## ##STR00053## ##STR00054##
[0150] In another aspect the disclosure provides compounds of
formula VII, wherein:
[0151] R.sup.1 is independently substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
heteroarylalkyl; and
[0152] R.sup.3 is independently H, F, Cl, Br, I, OH, CN, NO.sub.2,
substituted or unsubstituted alkyl, perfluoroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted cycloalkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, --(CH.sub.2).sub.jOR.sup.4,
--(CH.sub.2).sub.jC(O)R.sup.4,
--(CH.sub.2).sub.jC(NR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(NNR.sup.7)R.sup.4--(CH.sub.2).sub.jC(O)OR.sup.4,
--(CH.sub.2).sub.jNR.sup.5R.sup.6,
--(CH.sub.2).sub.jC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jOC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jNR.sup.7C(O)R.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)OR.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jS(O).sub.mR.sup.8,
--(CH.sub.2).sub.jNR.sup.7S(O).sub.2R.sup.8, or
--(CH.sub.2).sub.jS(O).sub.2NR.sup.5R.sup.6.
[0153] In another aspect the disclosure provides compounds of
formula VII, wherein:
[0154] R.sup.1 is independently substituted or unsubstituted
phenyl, substituted or unsubstituted naphthyl, substituted or
unsubstituted furanyl, substituted or unsubstituted pyrrolyl,
substituted or unsubstituted thiofuranyl, substituted or
unsubstituted oxazolyl, substituted or unsubstituted isooxazolyl,
substituted or unsubstituted pyrazolyl, substituted or
unsubstituted imidazolyl, substituted or unsubstituted pyridinyl,
substituted or unsubstituted pyridazinyl, substituted or
unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl,
wherein R.sup.1 is optionally independently substituted with 1 to 3
R.sup.3 groups; and
[0155] R.sup.3 is independently F, Cl, Br, I, OH, CN, NO.sub.2,
alkyl, perfluoroalkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl,
--(CH.sub.2).sub.jOR.sup.4, --(CH.sub.2).sub.jC(O)R.sup.4,
--(CH.sub.2).sub.jC(NR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(NNR.sup.7)R.sup.4,
--(CH.sub.2).sub.jC(O)OR.sup.4, --(CH.sub.2).sub.jNR.sup.5R.sup.6,
--(CH.sub.2).sub.jC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jOC(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jNR.sup.7C(O)R.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)OR.sup.4,
--(CH.sub.2).sub.jNR.sup.7C(O)NR.sup.5R.sup.6,
--(CH.sub.2).sub.jS(O).sub.mR.sup.8,
--(CH.sub.2).sub.jNR.sup.7S(O).sub.2R.sup.8, or
--(CH.sub.2).sub.jS(O).sub.2NR.sup.5R.sup.6.
[0156] In another aspect the disclosure provides compounds of
formula VII, wherein:
[0157] R.sup.1 is independently:
##STR00055##
[0158] In another aspect the disclosure provides compounds of
formula VII, having formula VIII or formula IX:
##STR00056##
wherein:
[0159] R.sup.1 is independently:
##STR00057##
[0160] In another aspect the disclosure provides compounds having
formula:
##STR00058## ##STR00059## ##STR00060## ##STR00061##
##STR00062##
or a pharmaceutically acceptable salt of solvate thereof.
[0161] In another aspect the disclosure provides pharmaceutical
compositions containing an effective amount of one or more of the
compounds of formula I, together with one or more pharmaceutically
acceptable carriers.
[0162] In another aspect the disclosure provides pharmaceutical
compositions containing an effective amount of one or more of the
compounds of formula I, together with one or more pharmaceutically
acceptable carriers, wherein the pharmaceutical composition is in
topical form.
[0163] In another aspect the disclosure provides pharmaceutical
compositions containing an effective amount of one or more of the
compounds of formula I, together with one or more pharmaceutically
acceptable carriers, wherein the pharmaceutical composition is in
topical, oral or injectable form.
[0164] In another aspect the disclosure provides methods for
treating patients suffering from disorders characterized by
abnormal cell-proliferation and/or cell-differentiation, by
administering an effective amount of a compound of formula I, or a
pharmaceutical composition containing a compound of formula I, to
the patient in need of such treatment.
[0165] In another aspect the disclosure provides methods for
treating patients suffering from disorders characterized by
abnormal cell-proliferation and/or cell-differentiation, comprising
administering an effective amount of a compound of formula I, or a
pharmaceutical composition containing a compound of formula I, to
the patient in need of such treatment, wherein the abnormal cell
proliferation and/or cell-differentiation is psoriasis.
[0166] In another aspect the disclosure provides methods for
treating patients suffering from secondary hyperparathyroidism, by
administering an effective amount of a compound of formula I, or a
pharmaceutical composition containing a compound of formula I, to
the patient in need of such treatment.
[0167] In another aspect the disclosure provides methods for
treating patients suffering from secondary hyperparathyroidism, by
administering an effective amount of a compound of formula I, or a
pharmaceutical composition containing a compound of formula I, to
the patient in need of such treatment, wherein the patient is
suffering from chronic kidney disease (CKD).
[0168] In another aspect the disclosure provides methods for
preparing a compound of formula I, comprising:
[0169] a) reacting the compound of formula XI with base to form the
corresponding anion; and
[0170] b) coupling the anion with the compound of formula XII:
##STR00063##
wherein PG is a protecting group; and
[0171] c) removing the protecting groups to provide the compound of
formula I.
[0172] In another aspect the disclosure provides methods for
preparing a compound of formula I, comprising:
[0173] a) reacting the compound of formula XI with base to form the
corresponding anion, wherein the base is an alkali metal or
organolithium compound; and
[0174] b) coupling the anion with the compound of formula XII,
wherein the protecting group is a silyl protecting group; and
[0175] c) removing the protecting groups to provide the compound of
formula I.
[0176] In another aspect the disclosure provides methods for
preparing a compound of formula I, comprising:
[0177] a) reacting the compound of formula XI with base to form the
corresponding anion, wherein the base is an alkali metal or
organolithium compound, wherein the alkali metal is sodium hydride
or lithium hydride, and the organolithium compound is n-butyl
lithium, sec-butyl lithium or tert-butyl lithium; and
[0178] b) coupling the anion with the compound of formula XII,
wherein the protecting group is tert-butydimethylsilane; and
[0179] c) removing the protecting groups to provide the compound of
formula I.
[0180] In another aspect the disclosure provides the compound of
formula I, prepared by any of the methods disclosed herein.
Secondary Hyperparathyroidism and Chronic Kidney Disease (CKD)
[0181] Secondary hyperparathyroidism (SHPT) is a disorder which
develops primarily because of Vitamin D deficiency. It is
characterized by abnormally elevated blood levels of parathyroid
hormone (PTH) and, in the absence of early detection and treatment;
it becomes associated with parathyroid gland hyperplasia and a
constellation of metabolic bone diseases. It is a common
complication of chronic kidney disease (CKD), with rising incidence
as CKD progresses. Secondary hyperparathyroidism can also develop
in individuals with healthy kidneys, due to environmental, cultural
or dietary factors which prevent adequate Vitamin D supply.
[0182] Bone and joint pain are common, as are limb deformities in
secondary hyperparathyroidism. The elevated PTH has also
pleiotropic effects on blood, immune system and neurological
system.
[0183] The compounds of formula I may be useful for treating the
suppression of parathyroid hormone (PTH) levels in patients who
have secondary hyperparathyroidism. The compounds of formula I may
be able to bind with high affinity to vitamin D receptors (VDRs)
not only in the parathyroid glands, but also in cells throughout
the body. For example, recent data has shown that pulsatile,
intravenous vitamin D treatment (calcitriol or paricalcitol)
confers a survival advantage in the dialysis population through VDR
activation. The compounds of formula I may also effect VDR
activation, particularly in the predialysis stages of CKD where
high mortality rates from cardiovascular disease have recently been
documented. Previous underutilization of calcitriol treatment to
control PTH levels in Stages 3 and 4 CKD was often due to concerns
about its potential for accelerating the progression of CKD as a
consequence of hypercalcemia, hypercalciuria, or hyperphosphatemia.
The compounds of formula I, however, may show more selective VDR
activity and therefore, have greater potential for preventing
parathyroid hyperplasia and bone loss in early CKD without
adversely affecting kidney function. Further, the compounds of
formula I may also reduce cardiovascular morbidity and mortality in
early CKD.
Preparation of the Compounds of Formula I
[0184] The disclosed compounds may be readily prepared from
inexpensive vitamin D.sub.2. It has been shown that vitamin D.sub.2
may be fragmented and converted into C,D-ring building block
23-alcohol 2. [Posner, G. H. et al.; J. Org. Chem. 1997, 62,
3299-3314] Starting with the C,D-ring 23-alcohol 2, Williamson
ether coupling and C-8 desilyation produced the 23-oxa ethers 4a-d,
g-i, f in 30-85% yields (Scheme I).
##STR00064##
[0185] Analog 1i was made in an umpolung manner starting with
CD-ring C-22 iodide [Mascarenas, J. L. et al.; J. Org. Chem. 1986,
51, 1269-1272] and furfuryl alcohol. Oxidation of 4a-d, g-i, f with
PDC (pyridinium dichromate) produced C-8 ketones 5 a-d, g-i, f in
>75% yields. Coupling of C-8 ketones with the known [Daniewski,
A. R. et al.; J Org. Chem. 2002, 67, 1580-1587] A-ring
lithiophosphine oxide 6, and then desilylation afforded the desired
23 oxa ether analogs KSP-23-oxa-25-CH.sub.2-26 TB (1a),
KSP-23-oxa-25-ene-26-TB (1b), KSP-23-oxa-25-C(CH.sub.2)-McCyclohex
(1c), KSP-23-oxa-CH.sub.2Me.sub.2cyclohexene (1d),
KSP-23-oxa-25-C(CH.sub.2)-Ph (1g), KSP-23-oxa-24-CH.sub.2Ph (1h),
KSP-23-oxa-furfuryl (1i), and KSP-23-oxa-25yne-TB (1f) in 10-65%
yields.
[0186] The convergent nature of synthetic Scheme I and the
relatively small number of chemical steps between starting
materials and target analog suggest that large scale manufacture of
a lead drug candidate should be feasible and economically
favorable. All of these 23-oxa analogs (without the natural 25-OH
group) except furan analog Hare more lipophilic (higher log P) than
the natural hormone A (Table I).
[0187] Other examples of the disclosed compounds of formula I
include analogs 1a-1o as shown below in Scheme II.
##STR00065## ##STR00066##
[0188] Also disclosed are compounds of formula I as shown in Scheme
III.
##STR00067## ##STR00068##
[0189] A standard in vitro protocol [Posner, G. H. et al.; J. Org.
Chem. 1997, 62, 3299-3314] for determining antiproliferative
activity of new analogs 1a-d, g-i, f in murine keratinocytes
produced the data shown in Table I. Noteworthy is the exceptionally
high antiproliferative potency of allylic ether analogs 1a and 1d
and especially of propargylic ether analog 1f (Table I).
Propargylic ether analog 1f, with an IC.sub.50 of 2 nM, is
approximately 40 times more antiproliferative than the natural
hormone A (IC.sub.50=80 nM). [Peleg, S. et al.; J. Med. Chem. 2006,
49, 7513-7517].
TABLE-US-00001 TABLE I Competitive Calciuria Antipro-
Transcriptional VDR Activity liferative Activity Binding Compared
Analog IC.sub.50.sup.a (nM) ED.sub.50 (nM) IC.sub.50 (nM) to 1 Log
P A 80 1.5 0.8 1 3.6 1a 20 6 85 <0.02 4.7 1b 400 --.sup.a
--.sup.a --.sup.a 4.9 1c 100 350 198 <0.02 5.3 1d 50 52 300
<0.02 4.9 1f 2 40 47 <0.02 4.6 1g 400 --.sup.a --.sup.a
--.sup.a 5.1 1h 180 410 63 <0.02 4.4 1i 600 --.sup.a --.sup.a
--.sup.a 3.3
[0190] Log P values were calculated using ChemAxon's Marvin and
calculator plugin demo. The purity of analogs 1a-d, g-i, f was
judged to be .gtoreq.96% based on HPLC analysis.
Biology of the Compounds of Formula I
[0191] A standard in vitro protocol [Posner, G. H. et al.; J. Org.
Chem. 1997, 62, 3299-3314] for determining antiproliferative
activity of new analogs 1a-d, g-i, fin murine keratinocytes
produced the data shown in Table I. Noteworthy is the exceptionally
high antiproliferative potency of allylic ether analogs 1a and 1d
and especially of propargylic ether analog 1f (Table I).
Propargylic ether analog 1f, with an IC.sub.50 of 2 nM, is
approximately 40 times more antiproliferative than the natural
hormone A (IC.sub.50=80 nM).
[0192] A standard protocol [Liu, Y. Y. et al.; J. Biol. Chem. 1997,
272, 3336-3345] using a recombinant human VDR and a reporter gene
containing a vitamin D response element (VDRE) gave the
transcriptional potencies of 23-oxa analog 1a-d, g-i, f as shown in
Table I. Noteworthy is the very high transcriptional potency of
allylic ether 1a (ED.sub.50=6 nM), approaching that of A
(ED.sub.50=1.5 nM).
[0193] A standard assay for competitive binding to the human VDR
generated the IC.sub.50 values shown in Table I. Noteworthy is that
allylic ether 1a binds to the human VDR only about 1% as well as
natural hormone A but nevertheless is almost as transcriptionally
potent and is more antiproliferative than A. Noteworthy also is
that propargylic ether 1f binds to the human VDR only twice as well
as allylic ether 1a but is approximately ten times more
antiproliferative than 1a. [Peleg, C. et al.; Mol. Endocrinol.
1998, 12, 524-535]
[0194] A standard in vivo [Posner, G. H. et al.; J Med. Chem. 1998,
41, 3008-3014] assay probed the calciuric activity of these new
23-oxa analogs. Remarkably, 23-oxa allylic ethers 1a and 1d and
23-oxa propargylic ether 1f are at least 50 times less calciuric
than A (FIG. 1). Thus, the 23-oxa allylic ether 1a lacking a 25-OH
group has a substantial therapeutic window, and the 23-oxa
propargylic ether 1f also lacking a 25-OH group has an even better
therapeutic window, comparing favorably to that of the Chugai drug
[Kubodera, N., Current Bioactive Compounds 2006, 2, 301-315;
Allewaert, K. et al.; Steroids 1994, 59, 686-690] 22-oxa-25-hydroxy
B.
[0195] It is expected that in vivo catabolism (hydroxylation)
[Jones, G. et al.; Physiological Reviews 1998, 4, 1193-1231] of
this series of 23-oxa analogs by cytochrome P-450 enzymes will
occur mainly at C-24 due to the radical-stabilizing effect of the
23-oxygen atom and to the radical-stabilizing effect also of the
adjacent olefinic or acetylenic multiple bond. Since such allylic
or propargylic radical intermediates would be stabilized by
resonance delocalization, they are expected to be formed more
easily than in saturated 23-oxa side-chain analogs. Thus, the in
vivo half-life of 23-oxa allylic ethers 1a and 1d and of
propargylic ether 1f is expected to be shorter than that of the
natural hormone A, leading in all three cases to side-chain
fragmentation and formation of the same 22-CH.sub.2--OH alcohol
that is only weakly antiproliferative (data not shown). An analog's
having a relatively short half-life in vivo may represent a
therapeutic advantage in minimizing any undesirable calciuric
activity, as is the case for the topically used antipsoriasis drug
calcipotriol. [Masuda, S. et al.; J. Bio. Chem. 1994, 269,
4794-4803]
[0196] Three of these new lipophilic analogs of A possess a very
desirable therapeutic profile of high antiproliferative activity
and desirably low calcemic activity. Of these three, 23-oxa allylic
ether 1a and especially 23-oxa propargylic ether 1f feature the
best combination of structural features leading to high
antiproliferative activity and low calcemic activity. Based on
these promising results, further evaluation of the pharmacological
properties and the medical potential of these easily and
convergently synthesized 23-oxa vitamin D new chemical entities is
appropriate and timely.
Protecting Groups
[0197] The compounds of the present disclosure may be synthesized
using one or more protecting groups generally known in the art of
chemical synthesis. The term "protecting group" refers to chemical
moieties that block some or all reactive moieties of a compound and
prevent such moieties from participating in chemical reactions
until the protective group is removed, for example, those moieties
listed and described in Greene, et al., Protective Groups in
Organic Synthesis, 3rd ed. John Wiley & Sons (1999). It may be
advantageous, where different protecting groups are employed, that
each (different) protective group be removable by a different
means. Protective groups that are cleaved under totally disparate
reaction conditions allow differential removal of such protecting
groups. For example, protective groups may be removed by acid,
base, and hydrogenolysis. Groups such as trityl, dimethoxytrityl,
acetal and t-butyldimethylsilyl are acid labile and may be used to
protect carboxy and hydroxy reactive moieties in the presence of
amino groups protected with Cbz groups, which are removable by
hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic
acid and hydroxy reactive moieties may be blocked with base labile
groups such as, without limitation, methyl, ethyl, and acetyl in
the presence of amines blocked with acid labile groups such as
t-butyl carbamate or with carbamates that are both acid and base
stable but hydrolytically removable.
[0198] Carboxylic acid and hydroxy reactive moieties may also be
blocked with hydrolytically removable protective groups such as the
benzyl group, while amine groups capable of hydrogen bonding with
acids may be blocked with base labile groups such as Fmoc.
Carboxylic acid reactive moieties may be blocked with
oxidatively-removable protective groups such as
2,4-dimethoxybenzyl, while co-existing amino groups may be blocked
with fluoride labile silyl carbamates.
[0199] Allyl blocking groups are useful in the presence of acid-
and base-protecting groups since the former are stable and may be
subsequently removed by metal or pi-acid catalysts. For example, an
allyl-blocked carboxylic acid may be deprotected with a
palladium(0)-catalyzed reaction in the presence of acid labile
t-butyl carbamate or base-labile acetate amine protecting groups.
Yet another form of protecting group is a resin to which a compound
or intermediate may be attached. As long as the residue is attached
to the resin, that functional group is blocked and cannot react.
Once released from the resin, the functional group is available to
react.
[0200] Silyl ethers are a group of chemical compounds that contain
a silicon atom covalently bonded to an alkoxy group and are
commonly used as protecting groups for alcohols. The general
structure may be represented as R.sup.1R.sup.2R.sup.3Si--O--R.sup.4
where R.sup.4 is an alkyl group or an aryl group. Since
R.sup.1R.sup.2R.sup.3 may be combinations of differing groups that
may be varied in order to provide a number of silyl ethers, this
protecting group provides a wide spectrum of selectivity for
protecting group chemistry. Common silyl ethers include but are not
limited to trimethylsilyl (TMS), triethylsilyl (TES),
tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl
(TBS/TBDMS) and triisopropylsilyl (TIPS). They are particularly
useful because they may be installed and removed very selectively
under mild conditions
[0201] Typical blocking or protecting groups include, for
example:
##STR00069##
Pharmaceutical Compositions and Administration
[0202] In another aspect, the present disclosure provides
pharmaceutical compositions including one or more compounds of
formula I in admixture with one or more pharmaceutically acceptable
excipients. One of skill in the art will recognize that the
pharmaceutical compositions include the pharmaceutically acceptable
salts of the compound of formula I as described above.
[0203] The disclosed compounds of formula I are intended for use in
pharmaceutical compositions which are useful in the treatment of
human and veterinary disorders which, as mentioned above, are
characterized by abnormal cell-proliferation and/or
differentiation. In therapeutic and/or diagnostic applications, the
compounds of the disclosure may be formulated for a variety of
modes of administration, including systemic and topical or
localized administration. Techniques and formulations generally may
be found in Remington: The Science and Practice of Pharmacy
(20.sup.th ed.) Lippincott, Williams & Wilkins (2000).
[0204] The disclosed compounds of formula I may be effective over a
wide dosage range. For example, in the treatment of adult humans,
dosages from 0.001 to 1000 mg per day may be applicable. In other
embodiments, the dosages may range from 0.5 to 100 mg; from 1 to 50
mg per day, and/or from 5 to 40 mg per day may be used. A
preferable dosage is 1 to 30 mg per day, however, the exact dosage
will depend upon the route of administration, the form in which the
compound is administered, the subject to be treated, the body
weight of the subject to be treated, and the preference and
experience of the attending physician.
[0205] The disclosed compounds may be administered by the
parenteral, enteral or topical routes. They are well absorbed when
given enterally and this is the preferred form of administration in
the treatment of systemic disorders. In the treatment of
dermatological disorders like psoriasis, topical forms like
ointments, creams or lotions are preferred. In the treatment of
systemic disorders, a compound of formula I may be administered in
daily doses ranging from 0.001-1000 mg, with 1-50 mg doses being
preferred. In the topical treatment of dermatological disorders,
ointments, creams or lotions containing from 0.001-1000 mg/g, and
preferably from 1-50 mg, of a compound of formula I may be
administered. The oral compositions may be formulated as tablets,
capsules, or drops, containing from 0.001-1000 mg, preferably from
1-50 mg, of a compound of formula I, per dosage unit. While it is
possible for an active ingredient to be administered alone as the
raw chemical, it is preferable to present it as a pharmaceutical
formulation.
[0206] The term "dosage unit" is meant a unitary, i.e. a single
dose which is capable of being administered to a patient, and which
may be readily handled and packed, remaining as a physically and
chemically stable unit dose comprising either the active material
as such or a mixture of it with solid or liquid pharmaceutical
diluents or carriers.
[0207] The formulations, both for veterinary and for human medical
use, of the present disclosure comprise an active ingredient in
association with a pharmaceutically acceptable carrier, and
optionally other therapeutic ingredient(s). The carrier(s) must be
"acceptable" in the sense of being compatible with the other
ingredients of the formulations and not deleterious to the
recipient thereof.
[0208] The formulations include e.g. those in a form suitable for
oral, rectal, parenteral (including subcutaneous, intramuscular and
intravenous), and topical administration.
[0209] The formulations may conveniently be presented in dosage
unit form and may be prepared by any of the methods well known in
the art of pharmacy. All methods include the step of bringing the
active ingredient into association with the carrier which
constitutes one or more accessory ingredients. In general, the
formulations are prepared by uniformly and intimately bringing the
active ingredient into association with a liquid carrier or a
finely divided solid carrier or both, and then, if necessary,
shaping the product into the desired formulation.
[0210] Formulations of the present disclosure suitable for oral
administration may be in the form of discrete units as capsules,
sachets, tablets or lozenges, each containing a predetermined
amount of the active ingredient; in the form of a powder or
granules; in the form of a solution or a suspension in an aqueous
liquid or non-aqueous liquid; or in the form of an oil-in-water
emulsion or a water-in-oil emulsion. The active ingredient may also
be administered in the form of a bolus, electuary or paste.
[0211] A tablet may be made by compressing or moulding the active
ingredient optionally with one or more accessory ingredients.
Compressed tablets may be prepared by compressing, in a suitable
machine, the active ingredient in a free-flowing form such as a
powder or granules, optionally mixed with a binder, lubricant,
inert diluent, surface active or dispersing agent. Moulded tablets
may be made by moulding, in a suitable machine, a mixture of the
powdered active ingredient and a suitable carrier moistened with an
inert liquid diluent.
[0212] Formulations for rectal administration may be in the form of
a suppository incorporating the active ingredient and a carrier
such as cocoa butter, or in the form of an enema.
[0213] Formulations suitable for parenteral administration
conveniently comprise a sterile oily or aqueous preparation of the
active ingredient which is preferably isotonic with the blood of
the recipient.
[0214] Formulations suitable for topical administration include
liquid or semi-liquid preparations such as liniments, lotions,
applications; oil-in-water or water-in-oil emulsions such as
creams, ointments or pastes; or solutions or suspensions such as
drops.
[0215] In addition to the aforementioned ingredients, the
formulations of the disclosure may include one or more additional
ingredients such as diluents, buffers, flavoring agents, binders,
surface active agents, thickeners, lubricants, preservatives, e.g.
methyl hydroxybenzoate (including anti-oxidants), emulsifying
agents and the like.
[0216] Pharmaceutically acceptable salts are generally well known
to those of ordinary skill in the art, and may include, by way of
example but not limitation, acetate, benzenesulfonate, besylate,
benzoate, bicarbonate, bitartrate, bromide, calcium edetate,
camsylate, carbonate, citrate, edetate, edisylate, estolate,
esylate, fumarate, gluceptate, gluconate, glutamate,
glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,
hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,
lactobionate, malate, maleate, mandelate, mesylate, mucate,
napsylate, nitrate, pamoate (embonate), pantothenate,
phosphate/diphosphate, polygalacturonate, salicylate, stearate,
subacetate, succinate, sulfate, tannate, tartrate, or teoclate.
Other pharmaceutically acceptable salts may be found in, for
example, Remington: The Science and Practice of Pharmacy (20.sup.th
ed.) Lippincott, Williams & Wilkins (2000). Preferred
pharmaceutically acceptable salts include, for example, acetate,
benzoate, bromide, carbonate, citrate, gluconate, hydrobromide,
hydrochloride, maleate, mesylate, napsylate, pamoate (embonate),
phosphate, salicylate, succinate, sulfate, or tartrate.
[0217] Depending on the specific conditions being treated, such
agents may be formulated into liquid or solid dosage forms and
administered systemically or locally. The agents may be delivered,
for example, in a timed- or sustained-low release form as is known
to those skilled in the art. Techniques for formulation and
administration may be found in Remington: The Science and Practice
of Pharmacy (20.sup.th ed.) Lippincott, Williams & Wilkins
(2000). Suitable routes may include oral, buccal, by inhalation
spray, sublingual, rectal, transdermal, vaginal, transmucosal,
nasal or intestinal administration; parenteral delivery, including
intramuscular, subcutaneous, intramedullary injections, as well as
intrathecal, direct intraventricular, intravenous, intra-articular,
intra-sternal, intra-synovial, intra-hepatic, intralesional,
intracranial, intraperitoneal, intranasal, or intraocular
injections or other modes of delivery.
[0218] For injection, the agents of the disclosure may be
formulated and diluted in aqueous solutions, such as in
physiologically compatible buffers such as Hank's solution,
Ringer's solution, or physiological saline buffer. For such
transmucosal administration, penetrants appropriate to the barrier
to be permeated are used in the formulation. Such penetrants are
generally known in the art.
[0219] Use of pharmaceutically acceptable inert carriers to
formulate the compounds herein disclosed for the practice of the
disclosure into dosages suitable for systemic administration is
within the scope of the disclosure. With proper choice of carrier
and suitable manufacturing practice, the compositions of the
present disclosure, in particular, those formulated as solutions,
may be administered parenterally, such as by intravenous injection.
The compounds may be formulated readily using pharmaceutically
acceptable carriers well known in the art into dosages suitable for
oral administration. Such carriers enable the compounds of the
disclosure to be formulated as tablets, pills, capsules, liquids,
gels, syrups, slurries, suspensions and the like, for oral
ingestion by a patient to be treated.
[0220] For nasal or inhalation delivery, the agents of the
disclosure may also be formulated by methods known to those of
skill in the art, and may include, for example, but not limited to,
examples of solubilizing, diluting, or dispersing substances such
as, saline, preservatives, such as benzyl alcohol, absorption
promoters, and fluorocarbons.
[0221] Pharmaceutical compositions suitable for use in the present
disclosure include compositions wherein the active ingredients are
contained in an effective amount to achieve its intended purpose.
Determination of the effective amounts is well within the
capability of those skilled in the art, especially in light of the
detailed disclosure provided herein.
[0222] In addition to the active ingredients, these pharmaceutical
compositions may contain suitable pharmaceutically acceptable
carriers comprising excipients and auxiliaries which facilitate
processing of the active compounds into preparations which may be
used pharmaceutically. The preparations formulated for oral
administration may be in the form of tablets, dragees, capsules, or
solutions.
[0223] Pharmaceutical preparations for oral use may be obtained by
combining the active compounds with solid excipients, optionally
grinding a resulting mixture, and processing the mixture of
granules, after adding suitable auxiliaries, if desired, to obtain
tablets or dragee cores. Suitable excipients are, in particular,
fillers such as sugars, including lactose, sucrose, mannitol, or
sorbitol; cellulose preparations, for example, maize starch, wheat
starch, rice starch, potato starch, gelatin, gum tragacanth, methyl
cellulose, hydroxypropylmethyl-cellulose, sodium
carboxymethyl-cellulose (CMC), and/or polyvinylpyrrolidone (PVP:
povidone). If desired, disintegrating agents may be added, such as
the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a
salt thereof such as sodium alginate.
[0224] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may be used, which may
optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol
gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
Dye-stuffs or pigments may be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0225] Pharmaceutical preparations that may be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin, and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds may
be dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols (PEGs). In
addition, stabilizers may be added.
[0226] The disclosed compositions may further contain other
therapeutically active compounds usually applied in the treatment
of the above mentioned pathological conditions. Depending upon the
particular condition, or disease state, to be treated or prevented,
additional therapeutic agents, which are normally administered to
treat or prevent that condition, may be administered together with
the inhibitors of this disclosure. For example, chemotherapeutic
agents or other anti-proliferative agents may be combined with the
inhibitors of this disclosure to treat proliferative diseases and
cancer. Examples of known chemotherapeutic agents include, but are
not limited to, adriamycin, dexamethasone, vincristine,
cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and
platinum derivatives.
[0227] Other examples of agents the inhibitors of this disclosure
may also be combined with include, without limitation,
anti-inflammatory agents such as corticosteroids, TNF blockers,
IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;
immunomodulatory and immunosuppressive agents such as cyclosporin,
tacrolimus, rapamycin, mycophenolate mofetil, interferons,
corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;
neurotrophic factors such as acetylcholinesterase inhibitors, MAO
inhibitors, interferons, anti-convulsants, ion channel blockers,
riluzole, and anti-Parkinsonian agents; agents for treating
cardiovascular disease such as beta-blockers, ACE inhibitors,
diuretics, nitrates, calcium channel blockers, and statins; agents
for treating liver disease such as corticosteroids, cholestyramine,
interferons, and anti-viral agents; agents for treating blood
disorders such as corticosteroids, anti-leukemic agents, and growth
factors; agents for treating diabetes such as insulin, insulin
analogues, alpha glucosidase inhibitors, biguanides, and insulin
sensitizers; and agents for treating immunodeficiency disorders
such as gamma globulin.
[0228] These additional agents may be administered separately, as
part of a multiple dosage regimen, from the inhibitor-containing
composition. Alternatively, these agents may be part of a single
dosage form, mixed together with the inhibitor in a single
composition.
[0229] The compounds described above may be provided as
pharmaceutically acceptable formulations using formulation methods
known to those of ordinary skill in the art. These formulations may
be administered by standard routes. In general, the combinations
may be administered by the topical, transdermal, oral, rectal or
parenteral (e.g., intravenous, subcutaneous or intramuscular)
route. In addition, the combinations may be incorporated into
biodegradable polymers allowing for sustained release of the
compound, the polymers being implanted in the vicinity of where
drug delivery is desired.
[0230] The present disclosure is not to be limited in scope by the
exemplified embodiments, which are intended as illustrations of
single aspects of the disclosure. Indeed, various modifications of
the disclosure in addition to those described herein will become
apparent to those having skill in the art from the foregoing
description. Such modifications are intended to fall within the
scope of the disclosure. Moreover, any one or more features of any
embodiment of the disclosure may be combined with any one or more
other features of any other embodiment of the disclosure, without
departing from the scope of the disclosure. References cited
throughout this application are examples of the level of skill in
the art and are hereby incorporated by reference herein in their
entirety for all purposes, whether previously specifically
incorporated or not.
[0231] The disclosure will now be further described in the
following non-limiting examples.
Examples
[0232] The following examples are offered to illustrate, but not to
limit the claimed invention.
Example 1: Preparation of Analogs 1a-1i
##STR00070##
[0233] Compounds 1a-1i (except 1e) were made as previously
described..sup.2
Ketone 5e
[0234] To an ice-cooled solution of 2.sup.3 (45 mg, 0.14 mmol) in
DMF (2 mL), NaH (11 mg of a 60% suspension in mineral oil, 0.28
mmol) was added. The mixture was stirred at room temperature for 1
h until a light yellow color developed. After cooling the mixture
to 0.degree. C., 4-fluorobenzyl bromide (34 pt, 0.28 mmol) was
added to the reaction flask and the mixture was stirred at room
temperature for 14 h. The reaction was quenched by addition of
water and extracted with CH.sub.2Cl.sub.2 (dichloromethane)
(3.times.5 mL). The combined organic extracts were dried over
MgSO.sub.4, filtered, concentrated, and purified by column
chromatography (5% ethyl acetate in hexanes) to afford 56 mg of
crude TES protected alcohol. The crude TES protected alcohol was
dissolved in CH.sub.3CN (3 mL) and HF (160 .mu.L, 3.86 mmol) was
added. The solution was stirred 2 h before being quenched with a
solution of saturated NaHCO.sub.3. The mixture was extracted with
ethyl acetate (3.times.5 mL), washed with brine, dried over
MgSO.sub.4, and concentrated in vacuo. Column chromatography (20%
ethyl acetate in hexanes) afforded 17 mg of the alcohol 4e as a
colorless oil in 40% yield for the 2 steps. [.alpha.].sub.D.sup.29
+42.3 (c 0.20, CHCl.sub.3); IR (neat, cm.sup.-1) 3457 (brs), 2933
(m), 2866 (m), 1604 (w), 1509 (m), 1456 (w), 1222 (m), 1091 (m) 944
(w), 823 (w), 772 (w); .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
7.29 (m, 2H), 7.02 (m, 2H), 4.43 (q, 2H, J=14.4 Hz), 4.08 (m, 1H)
3.41 (dd, 1H, J=9.2, 3.6 Hz), 3.18 (dd, 1H, J=8.8, 7.2 Hz), 1.99
(m, 1H), 1.87-1.14 (m, 13H), 1.04 (d, 3H, J=6.8 Hz), 0.95 (s, 3H);
.sup.13C NMR (CDCl.sub.3, 100 MHz) .delta. 162.22 (d, J=243 Hz),
149.60 (d, J=4 Hz), 129.18 (d, J=8 Hz), 115.11 (d, J=21 Hz), 75.54,
72.35, 69.28, 53.48, 52.37, 41.95, 40.24, 36.35, 33.63, 26.71,
22.60, 17.45, 17.41, 13.57; .sup.19F NMR (282 MHz, CDCl.sub.3)
.delta. -115.86 (septet, J=2.82 Hz).
[0235] A solution of the alcohol 4e (12 mg, 0.04 mmol) in
CH.sub.2Cl.sub.2 (2 mL) was cannulated into a reaction vessel
equipped with PDC (42 mg, 0.11 mmol) and oven dried Celite.RTM. (45
mg). After stirring overnight the mixture was filtered,
concentrated in vacuo, and purified by column chromatography (20%
ethyl acetate in hexanes) to afford 12 mg of ketone 5e as a
colorless oil in 96% yield. [.alpha.].sub.D.sup.29 +2.8 (c 0.20,
CHCl.sub.3); IR (neat, cm.sup.-1) 2957 (m), 2874 (m), 1713 (s),
1509 (m), 1456 (w), 1359 (w), 1221 (w), 1091 (w); .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 7.29 (m, 2H), 7.02 (m, 2H), 4.44 (q,
2H, J=211.6 Hz), 3.41 (dd, 1H, J=8.8, 3.2 Hz), 3.22 (dd, 1H, J=8.8,
6.8 Hz), 2.44 (m, 1H), 2.24 (m, 2H), 2.11 (m, 1H), 1.83-1.51 (m,
9H), 1.09 (d, 3H, J=6.4 Hz), 0.64 (s, 3H); .sup.13C NMR
(CDCl.sub.3, 100 MHz) .delta. 211.73, 162.24 (d, J=244 Hz), 134.44
(d, J=3 Hz), 129.19 (d, J=32 Hz), 115.15 (d, J=21 Hz), 75.27,
72.42, 61.67, 53.47, 49.89, 40.94, 38.82, 36.52, 27.03, 24.01,
19.16, 17.65, 12.50; .sup.19F NMR (282 MHz, CDCl.sub.3) .delta.
-115.68 (septet, J=5.64 Hz); HRMS: calcd for
C.sub.20H.sub.27FO.sub.2 [MH.sup.+]: 319.2073, found 319.2076.
Analog 1e
[0236] Enantiomerically pure phosphine oxide (-)-6.sup.3 and
CD-ring ketone 5e, were separately azeotropically dried with
anhydrous benzene (3.times.5 mL) on a rotary evaporator and held
under vacuum (ca. 0.1 mm Hg) for at least 48 hours prior to
use.
[0237] A flame-dried 10 mL recovery flask equipped with a magnetic
stir bar and an Ar balloon was charged with phosphine oxide (-)-6
(33 mg, 0.06 mmol). The reagent was dissolved in 2.0 mL freshly
distilled THF (tetrahydrofuran) and cooled to -78.degree. C. To
this solution n-BuLi (35 .mu.L, 0.06 mmol, 1.60 M solution in
hexanes) was added drop-wise over several minutes during which time
a deep red color developed and persisted. This mixture was allowed
to stir at -78.degree. C. for an additional 30 min. Meanwhile, a
flame-dried 10 mL flask containing CD-ring ketone 5e (7 mg, 0.021
mmol) was dissolved in 0.75 mL of freshly distilled THF and cooled
to -78.degree. C. The solution of CD-ring ketone 5e was transferred
drop-wise into the flask containing the phosphine oxide anion at
-78.degree. C. via cannula over several minutes. After the addition
was complete, the deep red color persisted and the mixture was
allowed to stir at -78.degree. C. for 4 h. Upon observation of a
light yellow color, the reaction was quenched with 5 mL of pH 7
buffer and allowed to warm to room temperature. The mixture was
extracted with ethyl acetate (3.times.15 mL). The combined organic
extracts were washed with water and brine, dried over MgSO.sub.4,
and filtered. The filtrate was concentrated in vacuo to give crude
a product that was purified by column chromatography (5% ethyl
acetate in hexanes with 1% NEt.sub.3) affording 12 mg of the
protected product. The protected analog was dissolved in THF (2 mL)
and tetra-n-butylammonium fluoride (TBAF) (1.0 M in THF, 180 .mu.L,
0.18 mmol) was added. After stirring overnight the reaction was
quenched with H.sub.2O and extracted with CH.sub.2Cl.sub.2
(3.times.5 mL), dried over MgSO.sub.4, and filtered. The filtrate
was concentrated in vacuo to give the crude product that was
purified by column chromatography (50-75% ethyl acetate in hexanes
with 1% NEt.sub.3) to afford 6 mg of analog 1e as an oil (53% yield
for 2 steps). [.alpha.].sub.D.sup.25 +24.9 (c 0.30, CHCl.sub.3); IR
(neat, cm.sup.-1) 3355 (brs), 2943 (m), 2872 (m), 1604 (w), 1509
(m), 1222 (m), 1056 (w), 824 (w), 756 (w); .sup.1H NMR (CDCl.sub.3,
400 MHz) .delta. 7.28 (m, 2H), 7.02 (m, 2H), 6.38 (d, 1H, J=11.2
Hz), 6.02 (d, 1H, J=11.2 Hz), 5.32 (s, 1H), 5.00 (s, 1H), 4.45 (m,
3H), 4.23 (m, 1H), 3.43 (dd, 1H, J=8.8, 3.2 Hz), 3.18 (dd, 1H,
J=8.8, 7.2 Hz), 2.83 (m, 1H), 2.60 (m 1H) 2.31 (dd, 1H, J=13.2, 6.4
Hz), 2.08-1.16 (m, 16H), 1.07 (d, 3H, J=6.8 Hz), 0.56 (s, 3H);
.sup.13C NMR (CDCl.sub.3, 100 MHz) .delta. 162.22 (d, J=244 Hz),
147.66, 142.99, 134.57 (d, J=3 Hz), 132.99, 129.20 (d, J=8 Hz),
124.95, 117.09, 115.13 (d, J=21 Hz), 111.76, 75.58, 72.36, 70.84,
66.86, 56.06, 53.34, 46.00, 45.28, 42.89, 40.32, 37.16, 29.07,
27.18, 23.55, 22.36, 17.70, 12.04; .sup.19F NMR (282 MHz,
CDCl.sub.3) .delta. -115.83 (septet, J=8.46 Hz); HRMS: calcd for
C.sub.29H.sub.39FO.sub.3 [M.sup.+]: 454.2883, found 454.2875; UV
(MeOH) .lamda..sub.max 263 nm (.epsilon. 14,702).
Example 2: Preparation of Analogs 1i-1k
##STR00071##
[0238] Compound 1j was made as previously reported..sup.5
Analog 1k
[0239] Enantiomerically pure phosphine oxide (-)-6 and CD-ring
ketone 9,.sup.5 were separately azeotropically dried with anhydrous
benzene (4.times.5 mL) on a rotary evaporator and held under vacuum
(ca. 0.1 mm Hg) for at least 48 hours prior to use.
[0240] A flame-dried 10 mL recovery flask equipped with a magnetic
stir bar and an Ar balloon was charged with phosphine oxide (-)-6
(28 mg, 0.048 mmol). The reagent was dissolved in 2.0 mL freshly
distilled THF and cooled to 78.degree. C. To this solution n-BuLi
(32 .mu.L, 0.06 mmol, 1.50 M solution in hexanes) was added
drop-wise over several minutes during which time a deep red color
developed and persisted. This mixture was allowed to stir at
78.degree. C. for an additional 10 min. Meanwhile, a flame-dried 10
mL flask containing CD-ring ketone 9 (7 mg, 0.024 mmol) was
dissolved in 0.75 mL of freshly distilled THF and cooled to
78.degree. C. The solution of CD-ring ketone 9 was transferred
drop-wise into the flask containing the phosphine oxide anion at
78.degree. C. via cannula over several minutes. After the addition
was complete, the deep red color persisted and the mixture was
allowed to stir at 78.degree. C. for 3 h. Upon observation of a
light yellow color, the reaction was quenched with 5 mL of pH 7
buffer and allowed to warm to room temperature. The mixture was
extracted with ethyl acetate (3.times.15 mL). The combined organic
extracts were washed with water and brine, dried over MgSO.sub.4,
and filtered. The filtrate was concentrated in vacuo to give crude
product that was purified by column chromatography (5% ethyl
acetate in hexanes with 1% NEt.sub.3) affording 4.3 mg of 10 in a
27% yield. Compound 10 was dissolved in anhydrous pyridine (3 mL)
and hydroxyl amine hydrochloride (8 mg, 0.12 mmol) was added. The
mixture was stirred under Ar for 15 h. The reaction mixture was
purified by directly using silica gel column chromatography (10%
ethyl acetate in hexanes with 1% NEt.sub.3). The protected oxime
analog was dissolved in Tiff (2 mL) and TBAF (1.0 M in THF, 200
.mu.L), along with one drop NEt.sub.3 was added. After stirring
overnight the reaction was quenched with H.sub.2O and extracted
with CH.sub.2Cl.sub.2 (3.times.5 mL), dried over MgSO.sub.4, and
filtered. The filtrate was concentrated in vacuo to give the crude
product that was purified by column chromatography (75% ethyl
acetate in hexanes with 1% NEt.sub.3) to afford 1.7 mg of analog 1k
as an oil (63% yield for 2 steps). [.alpha.].sup.23 +28.5 (c 0.085,
CHCl.sub.3); IR (neat, cm.sup.-1) 3328 (brs), 2925 (m), 2853 (m),
2363 (s), 2334 (s), 1464 (w), 1111 (w), 951 (w); .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 6.38 (d, 1H, J=11.2 Hz), 6.02 (d, 1H,
J=11.2 Hz), 5.33 (t, 1H, J=2.0 Hz), 5.00 (m, 1H), 4.43 (m, 1H),
4.24 (m, 3H), 3.93 (m, 2H), 3.45 (dd, 1H, J=8.8, 3.2 Hz), 3.20 (dd,
1H, J=8.8, 7.6 Hz), 2.83 (dd, 1H, J=12.0, 4.0 Hz), 2.60 (dd, 1H,
J=13.2, 3.6 Hz), 2.31 (dd, 1H, J=13.2, 6.4 Hz), 2.08-1.14 (m, 23H),
1.04 (d, 3H, J=6.8 Hz), 0.86 (m, 3H), 0.56 (s, 3H); .sup.13C NMR
(CDCl.sub.3, 100 MHz) .delta. 163.69, 147.63, 142.99, 132.95,
124.97, 117.08, 111.78, 70.84, 66.86, 62.81, 56.05, 53.27, 45.99,
45.26, 42.86, 4032, 37.03, 36.92, 29.06, 27.93, 27.19, 23.54,
22.35, 17.62, 14.11, 12.05; HRMS: calcd for
C.sub.28H.sub.46NO.sub.4 [MNa+]: 482.3241, found 482.3227; UV
(MeOH) .lamda..sub.max 264 nm (.epsilon. 21,634).
Example 3: Preparation of Analog 1l
##STR00072## ##STR00073##
[0241] Analog 1l
[0242] KH (30%, 0.15 g, 1.1 mmol, 5 equiv.) was washed with hexanes
and dried under vacuum for 2 hours in a 25 mL round-bottom flask.
In a separate 10 mL round-bottom flask TES protected alcohol 2
(0.07 g, 0.215 mmol, 1 equiv.) was dissolved in dry THF (1.5 mL)
and cannulated into the KH. The solution was allowed to stir for
2-3 hours until an orange/yellow color persisted. At this time
1,2-epoxy-3,3-dimethylbutane was added and the reaction was allowed
to stir overnight at room temperature. TLC analysis had indicated
the reaction had gone to completion, and it was quenched with water
and extracted with CH.sub.2Cl.sub.2 (3.times.). The combined
organic layers were dried over anhydrous MgSO.sub.4 and
concentrated in vacuo. The crude alcohol was used in the next step
without further purification. The alcohol was dissolved in
CH.sub.2Cl.sub.2, and PDC (0.62 g. 1.6 mmol, 1.5 equiv.) and
Celite.RTM. (0.24 g) was added. The reaction mixture was allowed to
stir overnight. TLC analysis had indicated the reaction had gone to
completion. The reaction mixture was filtered over Celite.RTM. and
purified via column chromatography using 25% ethyl acetate in
hexanes to yield the desired ketone 11 (0.055 g, 0.13 mmol) in 60%
chemical yield. .sup.1H NMR data matched that of the known
compound..sup.5
[0243] To a 10 mL round-bottom flask was added 11 (0.04 g, 0.1
mmol, 1 equiv.) and O-allyl hydroxylamine (0.06 g, 0.05 mmol, 5
equiv.) in anhydrous pyridine (2 mL) The reaction was allowed to
stir at room temperature until TLC analysis indicated complete
consumption of the starting material. The reaction was quenched
with water (10 mL) and extracted with CH.sub.2Cl.sub.2 (3.times.),
dried over MgSO.sub.4, and purified via column chromatography to
yield the desired TES protected oxime (0.03 g, 0.08 mmol) in 80%
yield. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 5.95 (m, 1H); 5.18
(m, 3H); 4.55 (d, 2H, J=6 Hz); 4.22 (m, 3H); 3.40 (dd, 1H, J=8.7,
3.0 Hz); 3.15 (t, 1H, J=8.7 Hz); 2.0 (m, 1H); 1.85 (m, 3H); 1.7-0.8
(m, 26H). To a 10 mL round-bottom flask charged with the oxime
(0.05 g, 0.1 mmol, 1 equiv.) in anhydrous THF (2 mL) was added 0.3
mL of a 1M solution of TBAF in THF at -78.degree. C. The reaction
was allowed to slowly wane to room temperature and stir overnight.
TLC analysis indicated complete consumption of starting material.
The reaction was then quenched with water and extracted with
CH.sub.2Cl.sub.2 (3.times.), dried over anhydrous MgSO.sub.4, and
purified via column chromatography to yield the desired alcohol
(0.015 g, 0.1 mmol) in 42% yield. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 5.95 (m, 1H); 5.18 (m, 3H); 4.55 (d, 2H, J=6.1 Hz); 4.22
(m, 3H); 3.40 (dd, 1H, J=8.6, 3.0 Hz); 3.17 (t, 1H, J=8.6 Hz); 2.0
(m, 1H); 1.85 (m, 3H); 1.7-0.8 (m, 26H). To a 10 mL round-bottom
flask was added the alcohol (0.015 g, 0.041 mmol, 1 equiv.), PDC
(0.045, 0.12 mmol, 2.9 equiv.) and Celite.RTM. (0.05 g) in
anhydrous CH.sub.2Cl.sub.2 (2 mL). The reaction mixture was allowed
to stir overnight at room temperature. TLC analysis indicated
complete consumption of the starting material. The reaction was
then filtered over Celite.RTM., and purified via column
chromatography to yield the desired ketone 12 (0.011 g, 0.036 mmol)
in 76% yield. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 5.96 (m,
1H); 5.29 (m, 2H); 4.55 (m, 2H); 4.13 (q, 2H, J=21.3 Hz); 3.38 (m,
1H); 3.22 (m, 1H); 2.41 (m, 1H); 2.28 (m, 2H); 2.15-0.81 (25H).
[0244] To a round-bottom flask charged with phosphine oxide 6
(0.063 g, 0.11 mmol, 2.9 equiv.) in anhydrous THF (2 mL) was added
0.065 mL of a 1M solution of n-BuLi in THF dropwise at -78.degree.
C. At this time the reaction mixture turned bright reddish-orange
and was allowed to stir for 20 min at -78.degree. C. A pre-cooled
solution of ketone 12 (0.012 g, 0.037 mmol, 1 equiv.) in THF (1 mL)
was added to the lithiated solution via cannula. The reaction was
then allowed to stir at -78.degree. C. for 7 hours, after which it
was quenched with pH 7 buffer, diluted with water, extracted with
CH.sub.2Cl.sub.2 (3.times.), dried over anhydrous MgSO.sub.4, and
purified via column chromatography to yield the desired TES
protected deltanoid (0.025 g, 0.035 mmol) in 95% yield. .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 6.25 (m, 1H); 6.03 (m, 2H); 5.25 (m,
3H); 4.86 (s, 1H); 4.55 (s, 2H); 4.35 (s, 1H); 4.16 (m, 5H); 3.4
(m. 1H); 3.15 (m, 1H); 2.85 (m, 1H); 2.25 (m, 1H); 1.95-0.8 (m,
20H), 0.15 (30H)
[0245] To a 10 mL amber glass round-bottom flask charged with the
protected analog (0.025 g, 0.035 mmol, 1 equiv.) in anhydrous THF
(2 mL) was added a 1M solution of TBAF in THF (0.185 mL, 5 equiv.).
The reaction mixture was allowed to stir overnight at room
temperature TLC analysis indicated complete consumption of the
starting material, and the reaction was quenched with water,
extracted with CH.sub.2Cl.sub.2 (3.times.), dried over anhydrous
MgSO.sub.4 and purified via column chromatography to yield the
desired deltanoid 1l (0.0077 g, 0.015 mmol) in 43% yield.
[.alpha.].sup.21.1.sub.D 13.5 (c 0.19, CHCl.sub.3); IR (CHCl.sub.3,
cm.sup.-1) 3327, 2924, 2869, 2360, 1647, 1457, 1393, 1363, 1044,
916; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.39 (d, 1H, J=8.7
Hz), 5.98 (m, 2H), 5.33 (m, 3H), 4.99 (s, 1H), 4.54 (s, 2H), 4.43
(s, 1H), 4.26 (m, 4H), 3.41 (m, 1H), 3.15 (m, 1H), 2.82 (d, 1H,
J=9.9 Hz), 2.58 (d, 1H, J=12 Hz), 2.36 (m, 1H), 2.05 (m, 6H), 1.86
(m, 3H), 1.7-1.4 (m, 7H), 1.4-1.1 (m, 4H), 1.04 (d, 5H, J=5.1 Hz),
0.89 (m, 4H), 0.55 (s, 4H); .sup.13C NMR (100 MHz, CDCl.sub.3)
.delta. 165.0, 162.0, 148.0, 145.0, 134.5, 132.9, 124.9, 117.6,
116.7, 111.8, 74.5, 70.8, 66.8, 62.8, 56.1, 53.3, 45.9, 45.2, 42.7,
40.3, 37.0, 29.7, 29.1, 28.1, 27.2, 23.6, 22.3, 17.7, 12.0; UV
(MeOH) .lamda.max 265 nm (.epsilon. 7612). HRMS: calcd. for
C.sub.31H.sub.29NO.sub.4Na.sup.+=522.3544; found=522.3547.
Example 4: Preparation of Analog 1m
##STR00074##
[0246] 16-ene-24-alcohol 14
[0247] A flame-dried 100 mL round-bottomed flask equipped with a
magnetic stir bar and an Ar balloon was charged with aldehyde
13.sup.6 (0.146 g, 0.434 mmol), 15 mL of dry CH.sub.2Cl.sub.2 and
cooled to -78 0.degree. C. DIBAL-H (1.5 mL of a 1.0 M solution in
CH.sub.2Cl.sub.2, 1.5 mmol) was syringed into the flask and allowed
to stir for 45 minutes. When consumption of the starting material
was seen via TLC analysis the reaction was quenched with dilute HCl
(0.1 N, 15 mL). The solution was extracted with CH.sub.2Cl.sub.2,
washed with saturated aqueous sodium bicarbonate (10 mL), dried
over anhydrous MgSO.sub.4 (magnesium sulfate), filtered and
purified by column chromatography (1.5:1, hexanes:ethyl acetate) to
yield alcohol 14 as a colorless oil (143 mg, 98%).
[.alpha.].sub.D.sup.25=+38.8 (c=7.1, CHCl.sub.3); .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 9.63 (t, J=2.4 Hz, 1H), 5.30 (t, J=1.6 Hz,
1H), 4.11 (m, 1H), 2.75-2.66 (m, 1H), 2.58 (dd, J=8.0, 2.8 Hz, 1H),
2.41 (dd, J=7.4, 2.0 Hz, 1H), 2.24 (tt, J=13.2, 1.2 Hz, 1H),
1.92-1.83 (m, 2H), 1.77-1.61 (m, 3H), 1.53-1.44 (m, 2H), 1.43-1.35
(m, 1H), 1.06 (d, 3H), 1.03 (s, 3H), 0.94 (t, J=8.0 Hz, 9H), 0.55
(q, J=8.0 Hz, 6H); .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.
203.09, 158.68, 121.78, 6839, 54.94, 49.93, 46.89, 35.90, 34.80,
30.75, 26.59, 22.00, 18.98, 18.02, 6.91, 4.88.
16-ene-24-oxa-26-yne-TB 15
[0248] Dry hexanes washed KH (16 mg, 9.0 eq., 0.40 mmol) was added
to a 25 mL receiving flask. A solution of alcohol 14 (15 mg, 0.044
mmol) in 2.5 mL of THF was added to the KH and allowed to stir for
45 minutes at room temperature. Propargyltosylate.sup.7 (61 mg,
0.23 mmol) was added and the reaction was allowed to stir at room
temperature overnight. The reaction was quenched with water,
extracted with ethyl acetate, dried over anhydrous MgSO.sub.4,
filtered, and concentrated in vacuo. The crude TES-protected
alcohol was dissolved in 2.5 mL of THF and TBAF (0.13 mL, 0.13 mL
of a 1 M solution in THF) was added to the solution. The mixture
was allowed to stir overnight, quenched with water, extracted with
ethyl acetate, dried over anhydrous MgSO.sub.4, filtered and
purified by column chromatography to yield deprotected alcohol 15
in 62% yield for two steps. [.alpha.].sub.D.sup.25=+27.3 (c 0.75,
CHCl.sub.3); IR (neat, cm-1) 3466 (br), 2966 (s), 2933 (s), 2700
(m), 2242 (w), 1658 (w), 1475 (w), 1450 (w), 1367 (w), 1259 (w),
1209 (w), 1092 (m), 992 (w), 942 (w); .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 4.09 (m, 3H), 3.45 (dd, 1H, J) 8.8, 3.2 Hz), 3.24 (dd,
1H, J) 8.8, 6.8 Hz), 1.99 (m, 1H), 1.92-1.03 (m, 22H), 1.02 (d, 3H,
J) 6.8 Hz), 0.95 (s, 3H); .sup.13C NMR (CDCl.sub.3, 100 MHz)
.delta. 94.84, 74.80, 74.68, 69.32, 58.62, 53.35, 52.37, 41.88,
40.18, 36.07, 33.61, 30.98, 27.42, 26.63, 22.56, 17.45, 17.41,
13.56; HRMS (FAB) calcd for C.sub.20H.sub.32O.sub.2 [M-H+],
317.2481; found, 317.2459.
16-ene-24-oxa-26-yne-TB ketone 16
[0249] Alcohol 15 (20 mg, 1.0 eq., 0.07 mmol), NMO (13 mg, 1.5 eq.,
0.11 mmol), and 4 .ANG. molecular sieves were dissolved in 2 mL of
CH.sub.2Cl.sub.2 in 50 mL receiving flask. After stirring for 10
minutes, TPAP (tetrapropylammonium perruthenate) (1.5 mg, 0.05 eq.,
0.004 mmol) was added and the reaction was followed by TLC. After 3
hours the reaction was quenched with water, filtered, extracted
with CH.sub.2Cl.sub.2, dried over anhydrous MgSO.sub.4, and
purified by column chromatography to yield ketone 16 in 50% yield.
[.alpha.].sub.D.sup.25=+1.22 (c 0.50, CHCl.sub.3); IR (neat,
cm.sup.-1) 2968 (s), 2929 (s), 2849 (m), 1714 (s), 1476 (w), 1456
(m), 1381 (m), 1358 (m), 1306 (w), 1264 (m), 1239 (w), 1096 (s),
1010 (w), 942 (w), 834 (w); .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 4.09 (m, 2H), 3.43 (dd, 1H, J=8.8, 2.8 Hz), 3.29 (dd, 1H,
J=8.8, 6.4 Hz), 2.45 (dd, 1H, J=11.6, 7.6 Hz), 2.28-1.28 (m, 11H),
1.22 (s, 9H), 1.07 (d, 3H, J=6.4 Hz), 0.64 (s, 3H); .sup.13C NMR
(CDCl.sub.3, 100 MHz) .delta. 211.88, 94.98, 74.62, 74.36, 61.68,
58.66, 53.30, 49.85, 40.94, 38.75, 36.24, 30.94, 29.67, 26.94,
24.02, 19.09, 17.65, 12.47; HRMS (FAB) calcd for
C.sub.20H.sub.30O.sub.2 [MH+], 317.2481; found, 317.2478.
Analog 1m
[0250] Enantiomerically pure phosphine oxide 6 and CD-ring ketone
16, were separately azeotropically dried with anhydrous benzene
(3.times.2 mL) on a rotary evaporator and held under vacuum for 120
hours prior to use. A flame-dried 10 mL round-bottom flask equipped
with a magnetic stir bar and an Ar balloon was charged with
phosphine oxide 6 (35 mg, 0.060 mmol), dissolved in 1 mL of freshly
distilled THF, and cooled to -78.degree. C. To this solution,
n-BuLi (33 .mu.L, 0.054 mmol, 1.6 Min hexanes) was added drop-wise
over 5 minutes during which time a deep red color developed and
persisted. This mixture was allowed to stir at -78.degree. C. for
an additional 25 minutes. Meanwhile, a flame-dried 10 mL
round-bottomed flask containing CD-ring ketone 16 (9 mg, 0.028
mmol) was dissolved in 1 mL of THF and cooled to -78.degree. C.
This solution was transferred drop-wise into the flask containing
phosphine oxide anion at -78.degree. C. via cannula over 5 minutes.
After the addition was complete, the deep red color persisted and
the reaction was allowed to stir at -78.degree. C. for 4 hours.
Upon observation of a light yellow color, the reaction was quenched
with 3 mL of pH=7 buffer and allowed to warm to room temperature.
The mixture was extracted with ethyl acetate (1.times.5 mL) and
methylene chloride (2.times.5 mL). The combined organic extracts
were dried over MgSO.sub.4 and filtered. The filtrate was
concentrated in vacuo to give crude product that was purified by
column chromatography (10% ethyl acetate in hexanes with 1%
NEt.sub.3), affording the protected analog. The protected analog
was dissolved in 2 mL of THF and tetrabutyl-ammonium fluoride
(TBAF) (100 .mu.L, 1.6 M solution in THF) was added and the mixture
was allowed to stir overnight. The reaction was quenched with
water, extracted with ethyl acetate (1.times.5 mL) and methylene
chloride (2.times.5 mL). The combined organic extracts were dried
over MgSO.sub.4 and filtered. The filtrate was concentrated in
vacuo, and the crude product was purified by column chromatography
(70% ethyl acetate in hexanes with 1% NEt.sub.3) to afford 1m (2.3
mg, 0.005 mmol, 58%) as a colorless oil.
[.alpha.].sub.D.sup.25=+22.7 (c=0.35, CHCl.sub.3); IR (thin film)
3300, 2960, 2873, 1651, 1487, 1375, 932, 870 cm.sup.-1; .sup.1H NMR
(400 MHz, CDCl.sub.3) 6.25 (d, J=11.2 Hz, 1H), 6.09 (d, J=11.2 Hz,
1H), 5.32 (t, J=1.6 Hz, 1H), 5.30 (m, 1H), 5.00 (m, 1H), 4.42-4.44
(m, 1H), 4.20-4.4.26 (m, 1H), 3.80 (bs, 1H), 2.78-2.83 (m, 1H),
2.40-2.61 (m, 3H), 2.29-2.38 (m, 2H), 2.13-2.24 (m, 2H), 1.90-1.93
(m, 2H), 1.60-1.89 (m, 6H), 1.45-1.54 (m, 1H), 1.35 (s, 3H), 1.34
(s, 3H), 1.04 (d, J=6.8 Hz, 3H), 0.66 (s, 3H); .sup.13C NMR (100
MHz, CDCl.sub.3) .delta. 158.60, 151.55, 147.65, 143.10, 132.91,
124.98, 117.04, 111.76, 94.88, 74.78, 70.84, 66.85, 58.61, 56.07,
53.23, 45.95, 45.27, 42.87, 40.26, 36.86, 31.92, 29.69, 29.07,
27.11, 25.50, 23.55, 18.76, 11.26; HRMS (FAB) calcd 452.3292 for
C.sub.30H.sub.44O.sub.3 [(M+H)+], found 452.3290; UV (MeOH)
.lamda..sub.max 263 nm (.epsilon. 10790).
Example 5: Preparation of Analog 1n
##STR00075##
[0251] Alcohol 18
[0252] To a suspension of paraformaldehyde (272 mg, 9.1 mmol) in 50
mL of CH.sub.2Cl.sub.2 was added 13.5 mL (13.5 mmol) of 1 M
dimethylaluminum chloride solution in hexanes at -78.degree. C.
After 30 min, a solution of (+)-17.sup.6 (503 mg, 2.8 mmol) in 5 mL
of CH.sub.2Cl.sub.2 was added into the mixture at -78.degree. C.,
and then the reaction mixture was warmed to -40.degree. C. After
being stirred for 16 h at -40.degree. C., it was quenched with 10%
K.sub.2HPO.sub.4 at -40.degree. C. and then warmed to room
temperature. The reaction mixture was extracted with ethyl acetate
(2.times.100 mL), washed with 10% HCl, saturated aqueous
NaHCO.sub.3 solution, and brine, dried, concentrated in vacuo, and
then purified by chromatography (50% ethyl acetate/hexanes) to give
400 mg (68%) of (+)-18 as an oil. [.alpha.].sub.D.sup.25
+1.63.degree. (c 3.2, CHCl.sub.3); IR (CHCl.sub.3, cm.sup.-1) 3579,
2937, 1727; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.40 (t,
J=1.6 Hz, 1H), 5.21 (m, 1H), 3.57 (m, 2H), 2.34 (m, 1H), 2.10 (m,
2H), 2.04 (s, 3H), 1.81 (m, 4H), 1.57 (m, 3H), 1.41 (m, 1H), 1.01
(d, J=6.8 Hz, 3H), 1.00 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3)
.delta. 156.97, 121.66, 70.56, 66.57, 52.85, 46.52, 34.82, 34.60,
30.65, 21.34, 18.41, 17.90, 12.35; HRMS m/z calcd for
C.sub.13H.sub.21O 193.1593, found 193.1596.
Alcohol 19
[0253] Dry hexanes washed KH (16 mg, 9.0 eq., 0.40 mmol) was added
to a 25 mL receiving flask. A solution of alcohol 18 (15 mg, 0.044
mmol) in 2.5 mL of THF was added to the KH and allowed to stir for
45 minutes at room temperature. Propargyltosylate (61 mg, 0.23
mmol) was added and the reaction was allowed to stir at room
temperature overnight. The reaction was quenched with water,
extracted with ethyl acetate, dried over anhydrous MgSO.sub.4,
filtered, and concentrated in vacuo. The crude TES-protected
alcohol was dissolved in 2.5 mL of THF and TBAF (0.13 mL, 0.13 mL
of a 1 M solution in THF) was added to the solution. The mixture
was allowed to stir overnight, quenched with water, extracted with
ethyl acetate, dried over anhydrous MgSO.sub.4, filtered and
purified by column chromatography to yield 19 in 65% yield (20 mg)
for two steps as a colorless oil. [.alpha.].sub.D.sup.25=+14.8 (c
0.75, CHCl.sub.3); IR (neat, cm.sup.-1) 3466 (br), 2966 (s), 2933
(s), 2700 (m), 2242 (w), 1658 (w), 1475 (w), 1450 (w), 1367 (w),
1259 (w), 1209 (w), 1092 (m), 992 (w), 942 (w); .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 4.09 (m, 3H), 3.45 (dd, 1H, J=8.8,
3.2 Hz), 3.24 (dd, 1H, J=8.8, 6.8 Hz), 1.99 (m, 1H), 1.92-1.03 (m,
22H), 1.02 (d, 3H, J=6.8 Hz), 0.95 (s, 3H); .sup.13C NMR
(CDCl.sub.3, 100 MHz) .delta. 156.97, 121.66, 94.84, 74.80, 74.68,
69.32, 58.62, 53.35, 52.37, 41.88, 40.18, 36.07, 33.61, 30.98,
27.42, 26.63, 22.56, 17.45, 17.41, 13.56; HRMS (FAB) calcd for
C.sub.20H.sub.32O.sub.2, 304.24036; found, 304.2401.
Ketone 20
[0254] Alcohol 19 (20 mg, 1.0 eq., 0.07 mmol), NMO
(N-morpholine-N-oxide) (13 mg, 1.5 eq., 0.11 mmol), and 4 .ANG.
molecular sieves were dissolved in 2 mL of CH.sub.2Cl.sub.2 in 50
mL receiving flask. After stirring for 10 minutes, TPAP (1.5 mg,
0.05 eq., 0.004 mmol) was added and the reaction was followed by
TLC. After 3 hours the reaction was quenched with water, filtered,
extracted with CH.sub.2Cl.sub.2, dried over anhydrous MgSO.sub.4,
and purified by column chromatography to yield ketone 20 in 50%
yield. [.alpha.].sub.D.sup.25=+1.22 (c 0.50, CHCl.sub.3); IR (neat,
cm.sup.-1) 2968, 2929, 2849, 1714, 1476, 1456, 1381 (m), 1358,
1306, 1264, 1239, 1096, 1010, 942, 834; .sup.1H NMR (CDCl.sub.3,
400 MHz) .delta. 4.09 (m, 2H), 3.43 (dd, 1H, J=8.8, 2.8 Hz), 3.29
(dd, 1H, J=8.8, 6.4 Hz), 2.45 (dd, 1H, J=11.6, 7.6 Hz), 2.28-1.28
(m, 11H), 1.22 (s, 9H), 1.07 (d, 3H, J=6.4 Hz), 0.64 (s, 3H);
.sup.13C NMR (CDCl.sub.3, 100 MHz) .delta. 211.88, 156.97, 121.66,
94.98, 74.62, 74.36, 61.68, 58.66, 53.30, 49.85, 40.94, 38.75,
36.24, 30.94, 29.67, 26.94, 24.02, 19.09, 17.65, 12.47; FIRMS (FAB)
calcd for C.sub.20H.sub.30O.sub.2, 302.2247; found, 302.2250.
Analog 1n
[0255] Enantiomerically pure phosphine oxide 6 and CD-ring ketone
20, were separately azeotropically dried with anhydrous benzene
(3.times.2 mL) on a rotary evaporator and held under vacuum for 120
hours prior to use. A flame-dried 10 mL round-bottom flask equipped
with a magnetic stir bar and an Ar balloon was charged with
phosphine oxide 6 (35 mg, 0.060 mmol), dissolved in 1 mL of freshly
distilled THF, and cooled to -78.degree. C. To this solution,
n-BuLi (33 pit, 0.054 mmol, 1.6 Min hexanes) was added drop-wise
over 5 minutes during which time a deep red color developed and
persisted. This mixture was allowed to stir at -78.degree. C. for
an additional 25 minutes. Meanwhile, a flame-dried 10 mL
round-bottomed flask containing CD-ring ketone 20 (10 mg, 0.028
mmol) was dissolved in 1 mL of THF and cooled to -78.degree. C.
This solution was transferred drop-wise into the flask containing
phosphine oxide anion at -78.degree. C. via cannula over 5 minutes.
After the addition was complete, the deep red color persisted and
the reaction was allowed to stir at -78.degree. C. for 4 hours.
Upon observation of a light yellow color, the reaction was quenched
with 3 mL of pH=7 buffer and allowed to warm to room temperature.
The mixture was extracted with ethyl acetate (1.times.5 mL) and
methylene chloride (2.times.5 mL). The combined organic extracts
were dried over MgSO.sub.4 and filtered. The filtrate was
concentrated in vacuo to give crude product that was purified by
column chromatography (10% ethyl acetate in hexanes with 1%
NEt.sub.3), affording the protected analog. The protected analog
was dissolved in 2 mL of THF and TBAF (100 pit, 1.6 M solution in
THF) was added and the mixture was allowed to stir overnight. The
reaction was quenched with water, extracted with ethyl acetate
(1.times.5 mL) and methylene chloride (2.times.5 mL). The combined
organic extracts were dried over MgSO.sub.4 and filtered. The
filtrate was concentrated in vacuo, and the crude product was
purified by column chromatography (70% ethyl acetate in hexanes
with 1% NEt.sub.3) to afford in (2.3 mg, 0.005 mmol, 51%) as a
colorless oil. [.alpha.].sub.D25=+14.6 (c=0.35, CHCl.sub.3); IR
(thin film) 3300, 2960, 2873, 1651, 1487, 1375, 932, 870 cm.sup.-1;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.25 (d, J=11.2 Hz, 1H),
6.09 (d, J=11.2 Hz, 1H), 5.32 (t, J=1.6 Hz, 1H), 5.30 (m, 1H), 5.00
(m, 1H), 4.42-4.44 (m, 1H), 4.20-4.4.26 (m, 1H), 3.80 (bs, 1H),
2.78-2.83 (m, 1H), 2.40-2.61 (m, 3H), 2.29-2.38 (m, 2H), 2.13-2.24
(m, 2H), 1.90-1.93 (m, 2H), 1.60-1.89 (m, 6H), 1.45-1.54 (m, 1H),
1.35 (s, 3H), 1.34 (s, 3H), 1.04 (d, J=6.8 Hz, 3H), 0.66 (s, 3H);
.sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 158.60, 151.55, 147.65,
143.10, 132.91, 124.98, 117.04, 111.76, 94.88, 74.78, 70.84, 66.85,
58.61, 56.07, 53.23, 45.95, 45.27, 42.87, 40.26, 36.86, 31.92,
29.69, 27.11, 25.50, 23.55, 18.76, 11.26; HRMS (FAB) calcd 438.3156
for C.sub.29H.sub.42O.sub.3, found 438.3156; UV (MeOH)
.lamda..sub.max 260 nm (.epsilon. 10800).
Example 6: Preparation of Analog 1o
##STR00076##
[0256] Alcohol 22
[0257] A flame dried 10 mL round bottom flask equipped with a
magnetic stir bar and an Ar balloon was charged with 21.sup.8 (48
mg, 0.17 mmol) in 2 mL of freshly distilled THF and cooled to
0.degree. C. To this solution, n-butyl lithium (0.11 mL, 0.17 mmol,
1.6 M in hexane) was added drop wise over 5 min and this mixture
was allowed to stir at 0.degree. C. for 20 min, then was warmed to
room temperature and stirred 16 h. When consumption of the starting
material was seen via TLC analysis, the reaction was quenched with
a H.sub.2O (5 mL). The aqueous layer was extracted with diethyl
ether (3.times.5 mL), and the organics were washed with a saturated
solution of brine (10 mL), dried over MgSO.sub.4 and filtered. The
filtrate was concentrated in vacuo, and the crude product was
purified by column chromatography (0-10% diethyl ether in hexanes)
to afford the intermediate ether. A flame dried 10 mL round bottom
flask equipped with a magnetic stirbar and an Ar balloon was
charged with the intermediate ether (21 mg, 0.056 mmol) in 2 mL of
freshly distilled THF. To this solution, tetrabutyl ammonium
fluoride (0.28 mL, 0.28 mmol, 1.0 M in THF) was added dropwise and
this mixture was allowed to stir for 16 h. When consumption of the
starting material was seen via TLC analysis, the reaction was
quenched with H.sub.2O (3 mL). The aqueous layer was extracted with
CH.sub.2Cl.sub.2 (3.times.5 mL). The organics were washed with a
saturated solution of brine (10 mL), dried over MgSO.sub.4 and
filtered. The filtrate was concentrated in vacuo, and the crude
product was purified by column chromatography (10% ethyl acetate in
hexane) to afford 22 as a clear oil (13 mg, 0.051 mmol, 30% yield
over 2 steps). [.alpha.].sub.D23=+7.2 (c=0.67, CHCl.sub.3); IR
(thin film) 3477, 2966, 2927, 2864, 1454, 1361, 1263, 1086, 989,
962, 893, 720 cm.sup.-1; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
4.13 (s, 2H), 4.04 (d, 1H, J=2.8 Hz), 3.47 (t, 1H, J=8 Hz),
2.06-1.71 (m, 5H), 1.54-1.24 (m, 7H), 1.21 (s, 9H), 1.01 s, 3H;
.sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 94.5, 87.8, 74.5, 69.2,
57.8, 471, 41.9, 38.2, 33.7, 30.9, 27.4, 26.9, 21.7, 17.1, 13.1;
HRMS (FAB) calc 265.2168 for C.sub.17H.sub.29O.sub.2 [(M+H).sup.+],
found 265.2159.
Ketone 23
[0258] A flame dried 10 mL round bottom flask equipped with a
magnetic stir bar and an Ar balloon was charged with the alcohol 22
(13 mg, 0.049 mmol) in 2.0 mL of methylene chloride To this
solution, PDC (55 mg, 0.15 mmol) and Celite.RTM. (60 mg) were added
and the reaction stirred for 18 hr. When consumption of the
starting material was seen via TLC analysis, the reaction was
charged directly to a column and purified by column chromatography
(0-15% ethyl acetate in hexanes) to afford 23 (11 mg, 0.043 mmol,
86%) as a colorless oil. [.alpha.].sub.D.sup.25=-7.3 (c=0.57,
CHCl.sub.3); IR (thin film) 2967, 2868, 1715, 1454, 1361, 1263,
1226, 1102, 483 cm.sup.-1; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 4.14 (q, 2H, J=13 Hz), 3.79 (t, 1H, J=8 Hz), 2.42-1.86 (m,
8H), 1.58-1.5 (m, 3H), 1.22 (s, 9H), 0.72 (s, 3H); .sup.13C NMR
(100 MHz, CDCl.sub.3) .delta. 209.4, 94.8, 87.1, 74.9, 57.8, 57.6,
49.3, 40.9, 36.7, 30.9, 27.4, 26.9, 23.7, 18.2, 12.0.
Analog 1o
[0259] Enantiomerically pure phosphine oxide 6 and C,D-ring ketone
23, were separately azeotropically dried with anhydrous benzene
(3.times.2 mL) on a rotary evaporator and held under vacuum for 120
hr prior to use.
[0260] A flame dried 10 mL pear shaped flask equipped with a
magnetic stir bar and an Ar balloon was charged with phosphine
oxide 6 (45 mg, 0.077 mmol), dissolved in 1 mL of freshly distilled
THF and cooled to -78.degree. C. To this solution, n-BuLi (52 pt,
0.077 mmol, 1.6 M in hexanes) was added drop-wise over 5 min during
which time a deep red color developed and persisted. This mixture
was allowed to stir at -78.degree. C. for an additional 25 min.
Meanwhile, a flame-dried 10 mL round bottom flask containing
C,D-ring ketone 23 (8 mg, 0.031 mmol) was dissolved in 1 mL of THF
and cooled to -78.degree. C. This solution was transferred
drop-wise into the flask containing the phosphine oxide anion at
-78.degree. C. via cannula over 5 min. After the addition was
complete, the deep red color persisted and the mixture was allowed
to stir at -78.degree. C. for 6 hr. Upon observation of a light
yellow color, the reaction was quenched with 3 mL of pH=7 buffer
and allowed to warm to room temperature. The mixture was extracted
with ethyl acetate (1.times.5 mL) and methylene chloride (2.times.5
mL). The combined organic extracts were dried over MgSO.sub.4 and
filtered. The filtrate was concentrated in vacuo to give crude
product that was purified by column chromatography (0-15% ethyl
acetate in hexanes with 1% NEt.sub.3), affording the protected
analog along with a major side product (4.7 mg, 0.0075 mmol, 10%).
The protected analog was dissolved in acetonitrile (2 mL) and
tetrabutyl ammonium fluoride (100 .mu.L, 0.1 mmol, 1.0 M in THF)
was added. After stirring for 24 hr, the reaction was quenched with
H.sub.2O (5 mL) and allowed to stir until gas ceased to evolve. The
aqueous layer was extracted with ethyl acetate (3.times.5 mL),
dried over MgSO.sub.4 and filtered. The filtrate was concentrated
in vacuo, and the crude product was purified by column
chromatography (60% ethyl acetate in hexanes with 1% NEt.sub.3) to
afford 1o (1 mg, 0.0024 mmol, 38%) as a colorless oil. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 6.37 (d, 1H, J=12 Hz), 6.01 (d, 1H,
J=1 Hz), 5.35 (s, 1H), 5.01 (s, 1H), 4.44 (m, 1H), 4.22 (m, 1H),
4.14 (d, 2H, J=6 Hz), 3.69 (t, 1H, J=8 Hz), 2.84 (m, 1H), 2.58 (m,
1H), 2.34-0.58 (m, 27H with s at 1.17 and 0.58); FIRMS (FAB) calc
421.2721 for C.sub.26H.sub.38O.sub.3Na.sup.+ [(M.sup.+Na).sup.+],
found 421.2708.
Example 7: Preparation of Dermatological Creams
[0261] Any of the disclosed compounds of formula I may be dissolved
in 1 g of almond oil. To this solution may be added 40 g of mineral
oil and 20 g of self-emulsifying beeswax. The mixture may be heated
to liquefy. After the addition of 40 ml hot water, the mixture may
be mixed well, wherein the resulting cream contains approximately
10 .mu.g of the compound of formula I per gram of cream.
Example 8: Preparation of Capsules
[0262] Any of the disclosed compounds of formula I may be dissolved
in a triglyceride of a medium chain fatty acid to a final
concentration of 50 .mu.g/ml oil. 10 parts by weight of gelatin, 5
parts by weight glycerine, 0.08 parts by weight potassium sorbate,
and 14 parts by weight of distilled water may be mixed together
with heating and formed into soft gelatin capsules. These capsules
may be filled each with 100 .mu.l of the oil solution, such that
each capsule contained 5 .mu.g of the compound of formula I.
Example 9: VDR Binding Experiment
[0263] A competitive binding assay was performed according to Jones
et al. (1980) and Fujishima et al. (2001), with some
modifications.sup.9,10. Briefly, human recombinant VDR (1
pmol/reaction; Biomol, Plymouth Meeting, Pa., USA, Cat# SE-140)
prepared in binding buffer (50 mM Tris-HCl pH 7.4, 1.5 mM EDTA, 300
mM KCl, 5 mg/ml gelatin and 10 mM DTT) was pre-incubated with
1.alpha.,25(OH).sub.2D.sub.3 (10.sup.-8-10.sup.-10 M) or compound
(10.sup.-6-10.sup.-10 M) for 1 h at room temperature. Then, 0.25 nM
of [.sup.3H]1.alpha.,25(OH).sub.2D.sub.3 (20,000 cpm; Perkin Elmer,
Boston, Mass., USA, Cat# NET626) was added to the solution, mixed
thoroughly and incubated for 1 h at room temperature. Unbound
radioactive ligand was removed by incubation on ice for 30 min with
charcoal-dextran, and then pelleted by centrifugation at 2000 rpm
at 4.degree. C. for 10 min. The radioactivity in 100 .mu.l of the
supernatant was measured using a scintillation counter. The control
reactions contained either no VDR protein (background) or no
competing ligand (maximum binding). The VDR binding assay results
for compounds 1a, 1b, 1c, 1d, 1f, 1g, 1h, and 1i are shown in FIGS.
2-9, respectively.
Example 10: CYP24 Induction
Assay.sup.11,12
Cell Culture, Stimulation & Plating
[0264] HPK1a-ras cells were propagated in DMEM+10% FBS (Invitrogen)
to a level of 80% confluence. Cells were pelleted by centrifugation
and resuspended to a concentration of 100.times.10.sup.3 cells per
1 ml media. To each well of a 24-well plate, 1 ml of cell
suspension was added and incubated overnight at 37.degree. C.+5%
CO.sub.2.
Cell Treatment & TRIzol Addition
[0265] The cells were washed with PBS and then 1 ml DMEM+1% BSA
media was added per well. To each well, 1 .mu.l of the working
solutions of 1, 10, and 100 nM of each compound was added. As a
control, 1 .mu.l of isopropanol was added to untreated cells, in
duplicate. The cells were incubated at 37.degree. C.+5% CO.sub.2
for 8 hours, lysed in TRIzol reagent (Invitrogen, Cat #15596-018)
and stored at -80.degree. C. Each treatment was done in
duplicate.
RNA Isolation and cDNA Synthesis
[0266] RNA was isolated from cell lysates in TRIzol through phase
separation, RNA precipitation, and RNA wash as per the
manufacturer's instructions (Invitrogen). The concentration of RNA
was determined using a Spectrophotmeter to measure the optical
density of each sample, at a wavelength of 260 nm. The
ThermoScript.TM. RT-PCR System kit (Invitrogen, Cat #11146-016) was
used to create cDNA from 1 .mu.g of RNA, as per manufacturer's
instructions.
CYP24/GAPDH TaqMan.RTM. Real Time PCR
[0267] The commercial TaqMan.RTM. probes, from Applied Biosystems
Inc. (ABI--Foster City, Calif.), for human CYP24 and GAPDH were
used to determine to the amount of mRNA of CYP24 and GAPDH present
in each sample, respectively. Both genes were detected in the same
20 .mu.l reaction, carried out in an ABI PRISM 96-well optical
reaction plate. The reaction was setup as per manufacturer's
instructions, performed in triplicate and cycled 50 times using an
ABI Prism 7000 Sequence Detection System.RTM..
[0268] The relative fold induction of CYP24 by 100 nM for some of
the disclosed compounds is provided below in Table II:
TABLE-US-00002 TABLE II Relative Fold Induction of CYP24 by Analog
100 nM of Compound (%) 1a 89.8 1b 9.8 1c 1.4 1d 73.8 1g 5.8 1h 2.3
1i 18.3 1f 0.3 Calcitriol 100.0
REFERENCES
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[0281] Those with ordinary skill in the art will recognize methods
for substitution of the positions of the core structures described
herein that may be made while maintaining anti proliferative
activity. It is understood that the examples and embodiments
described herein are for illustrative purposes only and that
various modifications or changes in light thereof will be suggested
to persons skilled in the art and are to be included within the
spirit and purview of this application and scope of the appended
claims. All publications, patents, and patent applications cited
herein are hereby incorporated by reference in their entirety for
all purposes.
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