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Description  |
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BACKGROUND OF THE INVENTION
This invention relates to steroidal glycosides and methods of using the
same, particularly as hypocholesterolemic agents and antiatherosclerosis
agents, in mammals.
Many known products possessing hypocholesterolemic activity are
cross-linked synthetic polymer derivatives, for example of polystyrene.
For example, cross-linked, water-insoluble, bile-acid-binding
polystyrene-based resins, e.g., Cholestyramine.RTM. agents, have a gritty
"mouth-feel", and thus have poor palatability. In addition, these resin
beads typically have a low in vivo efficiency. Thus, the effective
hypocholesterolemic dose of these materials is excessive, typically 18-24
grams of formulated product per day. Other known polymers having
hypocholesterolemic activity include the natural product chitosan and
chitosan derivatives as described in European Application pub. no.
0212145. However, the effective hypocholesterolemic dose of these
materials is also high.
Other known hypercholesterolemia controlling agents include plant extracts
such as "alfalfa saponins". However, these plant extracts are of variable
composition and contain significant amounts of nonuseful chemical
substances. Due to the variations in composition, it is difficult to set a
standard dosage or predict the impurities present. Thus, such extracts are
not well suited for use by humans. Furthermore purification of these
extracts would be expensive. As an alternative certain synthetically
produced, pure "sapogenin-derived" compounds e.g., substances compounded
from spirostane, spirostene or sterol-derived compounds depress
cholesterol absorption more effectively than alfalfa extracts on a weight
basis and thus can be administered in reasonable sized doses. Because the
chemical compositions of these substances are known and because they can
be synthesized at a high degree of purity, they are suitable for use by
any warm-blooded animal, including humans.
However, unless administered in massive mounts, pure sapogenins do not
significantly inhibit cholesterol's absorption. It is only when compounded
with another moiety that sapogenins have the desired effect. Examples of
such sapogenin compounds are compounds of tigogenin and diosgenin,
particularly glycosides thereof. P. K. Kintia, Iu. K. Vasilenko, G. M.
Godanu, V. A. Bobeiko, I. V. Suetina, N. E. Mashchenko, Kim. Pharm. Zh.,
1981, 15(9), 55 discloses 3-O-(.beta.-D-galactopyranosyl)hecogenin and its
use as a hypocholesterolemic agent. U.S. Pat. Nos. 4,602,003 and 4,602,005
disclose certain steroidal glycosides, in particular
3-O-(.beta.-D-glucopyranosyl)tigogenin and
3-O-(.beta.-D-cellobiosyl)tigogenin and their use for the control of
hypercholesterolemia. 3-O-(.beta.-D-cellobiosyl)tigogenin has superior
hypocholesterolemic activity when compared to, for example,
cholestyramine.
In addition, certain other steroidal glycosides described below have been
published, however these publications do not address hypocholesterolemic
activity. "Structural Features of the Antioxidant and fungicidal Activity
of Steroid Glycosides", Dimoglo, A. S.; Choban I. N.; Bersuker, I. B.;
Kintya, P. K.; Balashova, N. N.; Bioorg. Khim, 11 (3), 408-413, 1985
discloses rockogenin .beta.-D-galactopyranoside and tigogenin
.beta.-D-lactoside. "Preparation and Properties of Some New Steroid
.beta.-D-Glucopyranosides, .beta.-D-Glucopyranosiduronic Acids, and
Derivatives", Schneider, J. J.; Carb. Research, 17, 199-207, 1971
discloses tigogenin .beta.-D-glucopyranuronoside. "Sterol Glycoside with
Activity as Prostaglandin Synthetase Inhibitor", Pegel, K. H. Walker, H.;
U.S. Pat. No. 4,260,603, Apr. 7, 1981 discloses hecogenin
.beta.-D-glucopyranoside. "Hemolytic Properties of Synthetic Glycosides",
Segal, R.; Shud, F.; Milo-Goldzweig, I.; J. Pharm. Sci. , 67 (11)
1589-1592, 1978 discloses tigogenin .beta.-D-maltosside, tigogenin
.beta.-L-fucopyranoside smilagenin .beta.-maltoside and tigogenin
.alpha.-L-rhamnoside. "Steroid Glycosides from the Roots of Capsicum
annuum II: The Structure of the Capsicosides", Gutsu, E. V.; Kintya, P.
K.; Lazurevskii, G. V.; Khim. Prir. Soedin., (2), 242-246, 1987 discloses
tigogenin .alpha.-D-arabanopyranoside and tigogenin
.beta.-D-galactopyranoside. "Molluscicidal Saponins from Cornus Florida
L.", Hostettmann, K.; Hostettmann- Kaldas, M.; Nakanishi, K.; Helv. Chim.
Acta, 61, 1990-1995, 1978 discloses smilagenin .beta.-D-galactopyranoside.
"Steroidal Saponins from Several Species of Liliifiorae Plants", Yang, C.;
Li, K.; Ding, Y.; Yunnan Zhiwu Yanjiu Zengkan, Suppl. 3, 13-23, 1990
discloses (25S)-hecogenin cellobioside. "Determination of the Absolute
Configuration of a Secondary Hydroxy Group in a Chiral Secondary Alcohol
Using Glycosidation shifts in Carbon-13 NMR Spectroscopy", Seo, S.;
Tomita, Y.; Tori, K.; Yoshimura, Y.; J. Am. Chem. Soc. , 100(11),
3331-3339, 1978 discloses smilagenin .beta.-glucoside and smilagenin
.alpha.-glucoside. "Steroid Glycosides from Asparagus officinalis",
Lazurevskii, G. V.; Goryanu, G. M.; Kintya, P. K.; Dokl. Akad. Nauk. SSSR,
231(6), 1479-81, 1976 discloses sarsasapogenin .beta.-glucoside.
Although the hypocholesterolemic compounds described above make a
significant contribution to the art there is a continuing search in this
field of art for improved hypocholesterolemic pharmaceuticals.
SUMMARY OF THE INVENTION
This invention is directed to steroidal glycosides, particularly
spirostanyl glycosides, that are useful as hypocholesterolemic agents and
antiatherosclerosis agents. The compounds of this invention have the
formula
##STR1##
wherein either (A):
##STR2##
Q.sup.4 and Q.sup.5 are both methylene; and wherein
R.sup.1 is
.beta.-D-glucopyranosyl,
.beta.-D-glucopyranuronosyl,
.beta.-D-2-acetamido-2-deoxy-glucopyranosyl,
.beta.-D-galactopyranosyl,
.beta.-D-fucopyranosyl,
.beta.-L-fucopyranosyl,
.beta.-D-xylopyranosyl,
.beta.-L-xylopyranosyl,
.alpha.-D-arabanopyranosyl,
.alpha.-L-arabanopyranosyl,
.alpha.-D-cellobiosyl,
.beta.-D-cellobiosyl,
.beta.-D-lactosyl,
.beta.-D-maltosyl,
.beta.-D-gentiobiosyl,
3-O-.alpha.-D-galactopyranosyl-.alpha.-D-arabanopyranosyl or
.beta.-D-maltotriosyl;
or (B):
Q.sup.1, Q.sup.4 and Q.sup.5 are all methylene;
##STR3##
and wherein R.sup.1 is
.beta.-D-glucopyranosyl,
.beta.-D-glucopyranuronosyl,
.beta.-D-2-acetamido-2-deoxy-glucopyranosyl,
.beta.-D-fucopyranosyl,
.beta.-L-fucopyranosyl,
.beta.-D-xylopyranosyl,
.beta.-L-xylopyranosyl,
.alpha.-D-arabanopyranosyl,
.alpha.-L-arabanopyranosyl,
.beta.-D-cellobiosyl,
.beta.-D-lactosyl,
.beta.-D-maltosyl,
.beta.-D-gentiobiosyl,
3-O-.beta.-D-galactopyranosyl-.alpha.-D-arabanopyranosyl or
.beta.-D-maltotriosyl;
or (C):
Q.sup.1, Q.sup.4 and Q.sup.5 are all methylene;
Q.sup.2 is carbonyl;
##STR4##
C.sub.25 is (R); and wherein
R.sup.1 is
.beta.-D-glucopyranuronosyl,
.beta.-D-2-acetarnido-2-deoxy-glucopyranosyl,
.beta.-D-fucopyranosyl,
.beta.-L-fucopyranosyl,
.beta.-D-xylopyranosyl,
.beta.-L-xylopyranosyl,
.alpha.-D-arabanopyranosyl,
.alpha.-L-arabanopyranosyl,
.beta.-D-cellobiosyl,
.beta.-D-lactosyl,
.beta.-D-maltosyl,
.beta.-D-gentiobiosyl,
3-O-.beta.-D-galactopyranosyl-.alpha.-D-arabanopyranosyl or
.beta.-D-maltotriosyl;
or (D):
Q.sup.1, Q.sup.2, Q.sup.4 and Q.sup.5 are each methylene;
##STR5##
and wherein R.sup.1 is
.beta.-D-2-acetamido-2-deoxy-glucopyranosyl,
.beta.-D-fucopyranosyl,
.beta.-D-xylopyranosyl,
.beta.-L-xylopyranosyl,
.alpha.-L-arabanopyranosyl,
.beta.-D-cellobiosyl,
.beta.-D-gentiobiosyl,
3-O-.beta.-D-galactopyranosyl-.alpha.-D-arabanopyranosyl, or
.beta.-maltotriosyl;
or (E):
Q.sup.1, Q.sup.2, and Q.sup.5 are each methylene;
##STR6##
C.sub.5 is alpha; C.sub.25 is (R); and wherein
R.sup.1 is
.beta.-D-galactopyranosyl,
.beta.-D-cellobiosyl,
.beta.-D-lactosyl,
.beta.-D-maltosyl or
.beta.-D-maltotriosyl;
or (F):
Q.sup.1, Q.sup.2, and Q.sup.4 are each methylene;
##STR7##
C.sub.5 is alpha; C.sub.25 is (R); and wherein
R.sup.1 is
.beta.-D-galactopyranosyl,
.beta.-D-cellobiosyl,
.beta.-D-lactosyl,
.beta.-D-maltosyl or
.beta.-D-maltotriosyl;
with the proviso that
(3.beta.,5.alpha.,25R)-3-[(.beta.-D-cellobiosyl)oxy]spirostane is not
included.
A first group of preferred compounds of Formula IA consists of these
compounds wherein Q.sup.1 is carbonyl,
##STR8##
Q.sup.2 is methylene, Q.sup.3 is
##STR9##
Q.sup.4 is methylene, Q.sup.5 is methylene, the C.sub.5 hydrogen is alpha
and C.sub.25 has the R configuration. Especially preferred within this
group are compounds wherein Q.sup.1 is carbonyl and R.sup.1 is
.beta.-D-cellobiosyl, .alpha.-D-cellobiosyl, .beta.-D-glucopyranosyl,
.beta.-D-galactopyranosyl, .beta.-D-lactosyl, .beta.-D-maltosyl or
.beta.-D-maltotriosyl. Also, especially preferred within this group is a
compound wherein Q.sup.1 is
##STR10##
and R.sup.1 is .beta.-D-cellobiosyl. Another especially preferred compound
within this group is a compound wherein Q.sup.1 is
##STR11##
and R.sup.1 is .beta.-D-cellobiosyl.
A second group of preferred compounds of Formula IA are compounds wherein
Q.sup.1 is methylene, Q.sup.2 is
##STR12##
Q.sup.4 is methylene, Q.sup.5 is methylene, the C.sub.5 hydrogen is alpha
and C.sub.25 is (R). Especially preferred within this second group is a
compound wherein Q.sup.2 is
##STR13##
and R.sup.1 is .beta.-D-cellobiosyl.
A third group of preferred compounds of Formula IA are compounds wherein
Q.sup.1 is carbonyl,
##STR14##
Q.sup.2 is carbonyl,
##STR15##
Q.sup.4 is methylene, Q.sup.5 is methylene, the C.sub.5 hydrogen is alpha
and C.sub.25 is (R). Especially preferred within this group is a compound
wherein Q.sup.1 is carbonyl, Q.sup.2 is carbonyl and R.sup.1 is
.beta.-D-cellobiosyl. Another especially preferred compound within this
group is a compound wherein Q.sup.1 is carbonyl, Q.sup.2 is
##STR16##
and R.sup.1 is .beta.-D-cellobiosyl. Another especially preferred compound
within this group is a compound wherein Q.sup.1 is carbonyl, Q.sup.2 is
##STR17##
and R.sup.1 is .beta.-D-lactosyl. Another especially preferred compound
within this group is a compound wherein Q.sup.1 is
##STR18##
Q.sup.2 is carbonyl and R.sup.1 is .beta.-D-cellobiosyl. Another
especially preferred compound within this group is a compound wherein
Q.sup.1 is
##STR19##
Q.sup.2 is carbonyl and R.sup.1 is .beta.-D-cellobiosyl.
A fourth group of preferred compounds of Formula IA are compounds wherein
Q.sup.1 is methylene, Q.sup.2 is carbonyl, Q.sup.3 is
##STR20##
Q.sup.4 is methylene, Q.sup.5 is methylene, the C.sub.5 hydrogen is alpha
and C.sub.25 is (R). Especially preferred within this fourth group are
compounds wherein R.sup.1 is .beta.-D-lactosyl or .beta.-D-cellobiosyl.
A fifth group of preferred compounds of Formula IA are compounds wherein
Q.sup.1 and Q.sup.2 are each methylene, Q.sup.3 is
##STR21##
Q.sup.4 and Q.sup.5 are each methylene and C.sub.25 is (R). Especially
preferred within this fifth group is a compound wherein the C.sub.5
hydrogen is alpha and R.sup.1 is .beta.-D-gentiobiosyl. Another especially
preferred compound within this group is a compound wherein the C.sub.5
hydrogen is beta and R.sup.1 is .beta.-D-cellobiosyl.
A sixth group of preferred compounds of Formula IA are compounds wherein
Q.sup.1, Q.sup.2 and Q.sup.5 are each methylene, Q.sup.3 is
##STR22##
Q.sup.4 is carbonyl, the C.sub.5 hydrogen is alpha and C.sub.25 is (R).
Especially preferred within this group is a compound wherein R.sup.1 is
.beta.-D-cellobiosyl.
A seventh group of preferred compounds of Formula IA are compounds wherein
Q.sup.1, Q.sup.2 and Q.sup.4 are each methylene, Q.sup.3 is
##STR23##
Q.sup.5 is carbonyl, the C.sub.5 hydrogen is alpha and C.sub.25 is (R).
Especially preferred within this group is a compound wherein R.sup.1 is
.beta.-D-cellobiosyl.
Yet another aspect of this invention is directed to a method for
controlling hypercholesterolemia or atherosclerosis in a mammal by
administering to a mammal suffering from hypercholesterolemia or
atherosclerosis a hypercholesterolemia or atherosclerosis controlling
amount of a Formula I spirostanyl glycoside
##STR24##
wherein either (A):
##STR25##
Q.sup.4 and Q.sup.5 are both methylene; and wherein
R.sup.1 is
.beta.-D-glucopyranosyl,
.beta.-D-glucopyranuronosyl,
.beta.-D-2-acetamido-2-deoxy-glucopyranosyl,
.beta.-D-galactopyranosyl,
.beta.-D-fucopyranosyl,
.beta.-L-fucopyranosyl,
.beta.-D-xylopyranosyl,
.beta.-L-xylopyranosyl,
.alpha.-D-arabanopyranosyl,
.alpha.-L-arabanopyranosyl,
.alpha.-D-cellobiosyl,
.beta.-D-cellobiosyl,
.beta.-D-lactosyl,
.beta.-D-maltosyl,
.beta.-D-gentiobiosyl,
3-O-.beta.-D-galactopyranosyl-.alpha.-D-arabanopyranosyl, or
.beta.-maltotriosyl;
or (B):
Q.sup.1, Q.sup.2, and Q.sup.5 are each methylene;
##STR26##
C.sub.5 is alpha; C.sub.25 is (R);
and wherein
R.sup.1 is
.beta.-D-galactopyranosyl,
.beta.-D-cellobiosyl,
.beta.-D-lactosyl,
.beta.-D-maltosyl or
.beta.-D-maltotdosyl;
or (C):
Q.sup.1, Q.sup.2 and Q.sup.4 are each methylene;
##STR27##
C.sub.5 is alpha; C.sub.25 is (R);
and wherein;
R.sup.1 is
.beta.-D-galactopyranosyl,
.beta.-D-cellobiosyl,
.beta.-D-lactosyl,
.beta.-D-maltosyl or
.beta.-D-maltotriosyl;
with the proviso that
(3.beta.,5.alpha.,25R)-3-[(.alpha.-D-cellobiosyl)oxy]spirostane,
(3.beta.,5.alpha.,25R)-3-[(.beta.-D-glucopyranosyl)oxy]spirostane,
(3.beta.,5.alpha.,25R)-3-[(.beta.-D-cellobiosyl)oxy]spirostane or
(3.beta.,5.alpha.,25R)-3-[(.beta.-D-galactopyranosyl)oxy]spirostan-12-one
are not included.
A first group of preferred compounds of Formula I are compounds wherein
Q.sup.1, Q.sup.2, Q.sup.4 and Q.sup.5 are methylene, C.sub.25 is (R) and
Q.sup.3 is
##STR28##
Especially preferred within this group are compounds wherein the C.sub.5
hydrogen is alpha and R.sup.1 is .beta.-D-glucopyranuronosyl,
.beta.-D-maltosyl, .beta.-D-lactosyl, .beta.-D-gentiobiosyl or
.beta.-D-galactopyranosyl. Another especially preferred compound within
this group is a compound wherein the C.sub.5 hydrogen is beta and R.sup.1
is .beta.-D-cellobiosyl.
A second group of preferred compounds of Formula I are compounds wherein
Q.sup.1 is carbonyl,
##STR29##
Q.sup.2 is methylene, Q.sup.3 is
##STR30##
Q.sup.4 and Q.sup.5 are each methylene, C.sub.25 is (R) and the C.sub.5
hydrogen is alpha. Especially preferred within this second group are
compounds wherein Q.sup.1 is carbonyl and R.sup.1 is .beta.-D-cellobiosyl,
.alpha.-D-cellobiosyl, .beta.-D-glucopyranosyl, .beta.-D-galactopyranosyl,
.beta.-D-lactosyl, .beta.-D-maltosyl or .beta.-D-maltotdosyl. Another
especially preferred compound within this second group is a compound
wherein Q.sup.1 is
##STR31##
and R.sup.1 is .beta.-D-cellobiosyl. Another especially preferred compound
within this second group is a compound wherein Q.sup.1 is
##STR32##
and R.sup.1 is .beta.-D-cellobiosyl.
A third group of preferred compounds of Formula I are compounds wherein
Q.sup.1 is methylene, Q.sup.2 is carbonyl,
##STR33##
Q.sup.4 and Q.sup.5 are each methylene, C.sub.25 is (R) and the C.sub.5
hydrogen is alpha. Especially preferred within this third group are
compounds wherein Q.sup.2 is carbonyl and R.sup.1 is .beta.-D-cellobiosyl
or .beta.-D-lactosyl. Other especially preferred compounds within this
third group are compounds wherein Q.sup.2 is
##STR34##
and R.sup.1 is .beta.-D-cellobiosyl or .beta.-D-galactopyranosyl.
A fourth group of preferred compounds of Formula I are compounds wherein
Q.sup.1 is carbonyl,
##STR35##
Q.sup.2 is carbonyl,
##STR36##
Q.sup.4 and Q.sup.5 are each methylene, the C.sub.5 hydrogen is alpha and
C.sub.25 is (R). Especially preferred within this fourth group is a
compound wherein Q.sup.1 is carbonyl, Q.sup.2 is carbonyl and R.sup.1 is
.beta.-D-celiobiosyl. Especially preferred within this fourth group are
compounds wherein Q.sup.1 is carbonyl, Q.sup.2 is
##STR37##
and R.sup.1 is .beta.-D-cellobiosyl or .beta.-D-lactosyl. Another
especially preferred compound within this group is a compound wherein
Q.sup.1 is
##STR38##
Q.sup.2 is carbonyl, and R.sup.1 is .beta.-D-cellobiosyl. Another
especially preferred compound within this group is a compound wherein
Q.sup.1 is
##STR39##
Q.sup.2 is carbonyl and R.sup.1 is .beta.-D-cellobiosyl.
A fifth group of preferred compounds of Formula I are compounds wherein
Q.sup.1, Q.sup.2 and Q.sup.5 are each methylene, Q.sup.3 is
##STR40##
Q.sup.4 is carbonyl, the C.sub.5 hydrogen is alpha and C.sub.25 is (R).
Especially preferred within this group is a compound wherein R.sup.1 is
.beta.-D-cellobiosyl.
A sixth group of preferred compounds of Formula I are compounds wherein
Q.sup.1, Q.sup.2 and Q.sup.4 are each methylene, Q.sup.3 is
##STR41##
Q.sup.5 is carbonyl, the C.sub.5 hydrogen is alpha and C.sub.25 is (R).
Especially preferred within this group is a compound wherein R.sup.1 is
.beta.-D-cellobiosyl.
This invention is also directed to pharmaceutical compositions for the
control of hypercholesterolemia or atherosclerosis in mammals which
comprise a compound of the Formula IA and a pharmaceutically acceptable
carrier.
Yet another aspect of this invention is directed to a composition
comprising a hydrate of a compound of the Formula 1A,
The compounds of Formulas IA and I are herein defined as the single
enantiomer having the absolute stereochemistry depicted in Formulas IA and
I respectively.
Other features and advantages will be apparent from the specification and
claims which describe the invention.
DETAILED DESCRIPTION OF THE INVENTION
##STR42##
The Formula IA compounds are a subset of the Formula I compounds. Thus, in
the following detailed descriptions of the invention (e.g., how to make
the invention, how to use the invention) reference to the Formula I group
of compounds, inherently encompasses the Formula IA compounds.
The following description of reaction Schemes I, II & III describe how to
make the Formula I compounds wherein Q.sup.4 and Q.sup.5 are both
methylene.
According to reaction Scheme I, the desired Formula I compounds wherein
Q.sup.1, Q.sup.2 and Q.sup.3 are as defined above may be prepared by
deacetylating the appropriate alpha peracetylated Formula III compound or
beta peracetylated Formula IV compound wherein Q.sup.1 and Q.sup.2 are as
defined above and X is either a bond or alkylene--O--.
Typically the deacetylation is accomplished by combining the Formula III or
IV compound with a nucleophilic base such as sodium methoxide or potassium
cyanide in a solvent such as methanol, tetrahydrofuran, n-propanol or
mixtures thereof at elevated temperatures of about 40.degree. C. to about
100.degree. C. (typically at reflux) and pressures of 0.5 psi to about 50
psi (typically ambient) for about 0.25 hour to about 2 hours. In addition,
for Formula I compounds when the sugar is glucopyranuronosyl, the
resultant deacetylated compound is further hydrolyzed by, for example,
exposure to sodium hydroxide. Also, where appropriate, those compounds
wherein either Q.sup.1 or Q.sup.2 are carbonyl may be reduced to yield the
corresponding alcohols in an alternative process to performing the
reduction prior to coupling (described in Reaction Scheme IV and the
accompanying text). In an analogous manner, where appropriate, those
compounds wherein either Q.sup.1 or Q.sup.2 are hydroxy may be oxidized to
yield the corresponding carbonyl in an alternative process to performing
the oxidation prior to coupling.
The desired Formula III compound wherein Q.sup.1 and Q.sup.2 are as defined
above may be prepared by anomedzing the appropriate Formula IV compound
wherein Q.sup.1 and Q.sup.2 are as defined above. The stereochemical terms
alpha and beta refer to the configuration of the attachment carbon of the
sugar.
Typically the anomedzation is performed by treatment with a mineral acid
such as hydrobromic acid in an anhydrous aprotic solvent such as methylene
chloride at temperatures of 20.degree. C. to about 40.degree. C.
(typically ambient) for at least 24 hours, typically to several days.
However, for arabanopyranosyl derivatives the alpha anomer is obtained
directly from the saccharide-steroid coupling described below and the beta
anomer from the above process (i.e., the nomenclature reverses).
According to Reaction Scheme II the desired Formula IV compounds wherein
Q.sup.1 and Q.sup.2 are as defined above may be prepared by coupling the
appropriate acetylated sugar halide (e.g., bromide) and steroid. More
specifically, for those Formula IV compounds where the sugar is other than
.beta.-D-maltosyl, .beta.-D-gentiobiosyl or
.beta.-D-2-acetamido-2-deoxy-glucopyranosyl, a zinc fluoride promoted
coupling of the appropriate Formula V compound (wherein Q.sup.1 and
Q.sup.2 are as defined above and X is either a bond or alkylene--O--) and
peracetylated sugar halide is used and for those Formula IV compounds
where the sugar is .beta.-D-maltosyl, .beta.-D-gentiobiosyl or
.beta.-D-2-acetamido-2-deoxy-glucopyranosyl, a mercuric bromide and
mercuric cyanide promoted coupling of the appropriate Formula VI compound
(e.g., trimethyl silyl ether of the Formula V compound wherein Q.sup.1 and
Q.sup.2 are as defined above and X is either a bond or alkylene--O--) and
peracetylated sugar halide is used.
Generally, the zinc fluoride promoted coupling of the Formula V compound
and the peracetylated sugar bromide occurs in a non-protic, anhydrous
reaction-inert solvent (e.g., acetonitrile) at a temperature of about
20.degree. C. to about 100.degree. C. for about 0.5 to about 12 hours.
Typically about 0.5 to about 4 equivalents (based on Formula V compound)
zinc fluoride is used and about 0.5 to about 3 equivalents acetylated
sugar bromide is used. Preferably the coupling is acid catalyzed and it is
especially preferred that hydrohalic acid generated during the reaction is
used as the acid catalyst. The desired compounds may be prepared at
pressures of 0.5 to 50 psi, although typically ambient pressures are used.
In a preferred isolation technique the glycosides may be precipitated from
the crude filtered reaction mixture (e.g., acetonitrile product solution)
by the addition of about 25% to 75% water and the remainder alcohol (e.g.,
methanol). Precipitation of the product from aqueous methanol/acetonitrile
requires less processing than an extractive isolation, and provides a
product of greater purity.
Generally, the mercuric bromide and mercuric cyanide promoted coupling of
the Formula VI compound and the acetylated sugar bromide is performed in
an aprotic, anhydrous solvent such as methylene chloride at a temperature
of about 20.degree. C. to about 100.degree. C. for about 0.5 to about 6
hours. Typically about 0.5 to about 4 equivalents (based on Formula IV
compound) mercuric bromide and mercuric cyanide is used and about 0.5 to
about 3 equivalents peracetylated sugar bromide (e.g., .beta.-D-maltosyl,
.beta.-D-gentiobiosyl or .beta.-D-2-acetamido-2-deoxy-glucopyranosyl) is
used. The desired compounds may be prepared at pressures of 0.5 to 50 psi,
although typically ambient pressures are used. Preferably they are
isolated as described for the zinc fluoride promoted coupling of the
Formula V compound above.
The desired Formula VI compounds wherein Q.sup. and Q.sup.2 are as defined
above and X is either a bond or alkylene--O--may be prepared by silylating
the appropriate Formula V compound wherein Q.sup.1 and Q.sup.2 are as
defined above and X is either a bond or alkylene--O--.
Generally the Formula V compound, a base such as triethylamine and an
activated trialkylsilyl compound (e.g., trimethylsilyl trifluoromethane
sulfonate or trimethylsilyl chloride) are reacted in an aprotic, anhydrous
solvent such as methylene chloride at a temperature less than about
10.degree. C. for about 0.5 hour to about 2 hours.
According to Reaction Scheme III the desired Formula V compounds wherein
Q.sup.1 and Q.sup.2 are as defined above and X is alkylene--O--may be
prepared by reducing the appropriate Formula VII compound wherein Q.sup.1
and Q.sup.2 are as defined above.
Generally the reduction is performed by reaction of the Formula VII
compound with lithium aluminum hydride in an anhydrous solvent such as
tetrahydrofuran at temperatures of less than about 10.degree. C. for about
0.5 hour to about 3 hours.
The desired Formula VII compounds wherein Q.sup.1 and Q.sup.2 are as
defined above may be prepared by coupling the appropriate Formula VIII
compound where Q.sup.1 and Q.sup.2 are as defined above with ethyl
diazoacetate in the presence of rhodium acetate dimer. Thus, the Formula
VIII compound and ethyl diazoacetate are reacted in an aprotic solvent
such as methylene chloride in the presence of rhodium acetate dimer at
ambient temperature for about 0.5 hour to about 3 hours.
The starting materials for the above described reaction schemes (e.g.,
ethyl diazoacetate, peracetylated sugar halides) are readily available or
can be easily synthesized by those skilled in the art using conventional
methods of organic synthesis.
In addition, as an aid to the preparation of the above steroids, the
following paragraphs describe the preparation of the various Formula VIII
compounds. Literature references for the preparation of Formula VIII
steroid compounds (wherein Q.sup.1 is methylene and Q.sup.2 and the
stereochemistry of the C.sub.5 hydrogen and C.sub.25 carbon are as defined
below) are described in Table I.
TABLE I
__________________________________________________________________________
Formula VIII Compounds Where Q.sup.1 is Methylene and
the C.sub.3 Hydroxy Group is Beta
C.sub.5
hydrogen
C.sub.25
Q.sup.2
Reference
__________________________________________________________________________
.alpha.
R CH.sub.2
R. E. Marker et. al., J. Am.
Chem. Soc.(1943) 65 1199.
.alpha.
R C.dbd.O
Marker et. al., J. Am. Chem. Soc. (1947) 69, 2167.
.alpha.
S CH.sub.2
Goodson & Noller J. Am. Chem. Soc.
(1939) 61, 2420.
.alpha.
S C.dbd.O
Callow & James J. Chem. Soc. (1955) 1671.
.beta.
R CH.sub.2
Marker et. al., J. Am. Chem. Soc. (1943) 65, 1199.
.beta.
R C.dbd.O
Marker et. al., J. Am. Chem. Soc. (1947) 69, 2167.
.beta.
S CH.sub.2
Marker et. al., J. Am. Chem. Soc. (1943) 65, 1199.
.beta.
S C.dbd.O
Kenney & Wall J. Org. Chem. (1957) 22, 468.
__________________________________________________________________________
The following paragraphs describe and/or give literature references for the
preparation of the various steroids used as starting materials (i.e., the
alternative stereochemistry at the C.sub.3 position and the oxygenation
and different epimers at C.sub.11 and C.sub.12) from the above Formula
VIII compounds described in Table I. In general the preparation of the
different oxygenated steroids is independent of the stereochemistry at the
C.sub.3, C.sub.5 and C.sub.25 positions. Thus, once the appropriate
stereochemistry at the C.sub.3, C.sub.5 and C.sub.25 positions are
achieved where Q.sup.1 and Q.sup.2 are each methylene or where Q.sup.1 is
methylene and Q.sup.2 is carbonyl, the various oxygenated compounds at
Q.sup.1 and Q.sup.2 may be prepared therefrom.
Some of the preparation methods described herein will require protection of
remote functionality (i.e., Q.sup.1, Q.sup.2 and Q.sup.3). The need for
these protecting groups will vary depending on the nature of the remote
functionality and the conditions of the preparation methods. This need is
readily determined by one skilled in the art. For a general description of
protecting groups and their use, see T. W. Greene, Protective Groups in
Organic Synthesis, John Wiley & Sons, New York, 1981.
The Formula VIII compounds wherein Q.sup.1 is methylene, Q.sup.2 is either
methylene or carbonyl and the C.sub.3 hydroxy is beta may be converted to
the corresponding Formula VIII compounds where the C.sub.3 hydroxy is
alpha by the following two procedures. These preparative methods may be
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