Note: Descriptions are shown in the official language in which they were submitted.
K548
~05B~
.
~ Hydroxy-3,20-diketopregnenes having a cyclic 16,17-
acetal or ketal group are well known and widely used anti-
inflammatory agents. Exemplary of this type of steroid are
halcinonide (21-chloro-9-fluoro-11~-hydroxy-2',2'-dimethyl-
pregn-4-eno[16~,17-d][1,3]dioxolane-3,20-dione) and triam-
cinolone acetonide (9-fluoro-11~,21-dihydroxy-2',2'-dimethyl-
pregna-1,4-dieno [i6a,17-d][1,3]dioxolane-3,20-dione). The
limited solubility of these pregnenes in slightly polar
solvents such as ether leads to problems in formulation
design.
In order to ease the problems of formulating 11~-
hydroxy-3,20-diketopregnenes having a 16,17-cyclic acetal
or ketal group (and in order to prepare new and useful anti-
inflammatory agents), the prior art has prepared ll-keto and
ll-acyloxy steroids. While these modifications do increase
the solubility of the steroids, they generally result in
steroids of lesser activity.
The prior art also shows that some steroids having 11-
acetal groups have been prepared. For example, Fukushima et
al., J. Org. Chem., 26, 520 (1961) disclose the formation
of ll~-(methoxymethyl)-17,20;20,21-bismethylenedioxypregn-
4-ene-3-one as a by-product during the reaction of hydro-
cortisone with formaldehvde. Gardi et al., J. Org. Chem.,
27, 668 (1962) and Tetrahedron, 21, 179 (1965), disclose
- steroids having 17,21-cyclic acetal groups as substituents
and in the ll-position a group of the formula
I O - alkyl
R- CH- O -
wherein R is alkyl or aryl. r~
K548
~S8~
It is an object of this invention to provide steroids
having topical and systemic anti-inflammatory activity.
It is an object of this invention to provide steroids
which can Be readily formulated in slightly polar solvents
such as castor oil or propylene carbonate.
These, and other o~jects that will be readily apparent
to a person of ordinary skill in the steroid art, are met
by the steroids of this invention.
The steroids of this invention are those having the
formula CH2-R
II OR
'~ --jl ~i ~oi R6
o
R7
and the 1,2~ and 6,7~defiydro deri~atives thereof; pregn~4~
enes and pregna-1,4~dienes are preferred. In formula II, and
throughout the specification, the symbols are as deflned
below.
Rl can be alkyl;
R2 can be hydrogen,~ alkyl, alkoxy, or halogen;
R3 can be hyd-rogen, acyloxy, halogen or hydroxy;
R4 can be hydrogen or halogen;
R5 can be hydrogen, alkyl, or aryl;
R6 can be a7kyl or aryl;
R7 can be hydrogen, fluorine, or methyl; and
R8 can be hydrogen, chlorine, or methyl.
K548
1~5~
The term "alkyL", as used throughout the specification,
refers to straight or branched chain alkyl groups having 1
to 8 carbon atoms. Alkyl groups having 1 to 3 carbon a toms
are preferred.
The term "halogen", as used throughout the specification,
refers to fluorine, chlorine, bromine, and iodine.
The term "acyloxy", as used throughout the specification,
refers to groups wherein the acyl portion is a physiologically
acceptable acid residue derived from an organic acid. Exemp-
lary monocarboxylic acids are those having the formula Y-COOH
wherein Y is alkyl, cycloalkyl of 3 to 6 carbon atoms, aryl-
alkyl or aryl; e.g., acetic, propionic, valeric, cyclohexane-
carboxylic, phenylacetic, benzoic, and toluic acids. Exemp~
lary polycarboxylic acids are malonic, succinic, glutaric,
adipic, pimelic and phthalic acids.
The term "aryl", as used throughout the specification,
refers to phenyl or phenyl substituted with 1 or 2 alkyl,
alkoxy, or halogen groups.
The term "alkoxy", as used throughout the specification,
refers to a group having the formula alkyl-O-, wherein alkyl
is as defined above.
The steroids of this invention are physiologically active
substances which possess glucocorticoid and anti-inflammatory
activity and hence can be used in lieu of known glucocorticoids
in the treatment of rheumatoid arthritis, for which purpose
they can be administered in the same manner as hydrocortisone,
for example, the dosage being adjusted for the relative potency
of the particular steroid. In addition, the steroids of this
invention can be used topically in lieu of known glucocorti-
coids in the treatment of skin conditions such as dermatitis,
~ K548
psoriasis, sunburn, neuro~ermatitis, eczema, and anogenitalpruritus.
When given orally, the compounds of this invention may be
used in a daily dosage range of 0.1 to 200 milligrams per 70
kilograms, preferably 0.3 to 100 milligrams per 70 kilograms.
If administered topically, the compounds of this invention may
be used in the range of 0.01 to 5.0% by weight, preferably 0.05
to 2.0% by weight, in a conventional cream or lotion.
The 3,20 diketopregnenes of formula II, wherein R2 is
ortho-alkyl, can be prepared ~y reacting an 11~-hydroxy-3,20-
diketopregnene, i.e., an ll~-hydroxy counterpart of the steroid
of Formula II with a l-alkoxybenzocyclobutene having the formula
III ~ OR
~ R'2
wherein R2 is hydrogen or an alkyl group having 1 to 7 carbon
atoms. The reaction, which is a novel one and constitutes a
part of this invention, can be run under neutral conditions in
an aprotic solvent, e.g. , a hydrocarbon such as benzene or
toluene. While reaction conditions are not critical, the re-
action will preferably be run at, or near, the reflux temperature
of the solvent. This reaction is useful not only in the pre-
paration of the steroids of this invention, but also in the
preparation of other steroids containing an ll~-hydroxy group
which must be protected during multi-step syntheses. The
blocking group can be readily removed by acid hydrolysis.
The 3,20 diketopregnenes of formula II can be prepared by
reacting an ll~-hydroxy-3,20-diketopregnene, i.e., an 11~-
hydroxy counterpart of the steroid of formula II with a benz-
aldehyde dialkyl acetal having the formula
K548
~ 6
IV
R2
OR
The reaction can be run in an aprotic solvent, e.~., a hydro-
carbon such as benzene or toluene. The reaction is run under
acid conditions (e.g., in the presence of an organic acid such
as p-toluenesulfonic acid) and can be run at, or near, the
reflux temperature of the solvent.
Many variations and modifications of this invention
will be apparent to a person of ordinary skill in the field of
steroid chemistry. If, for example, the ll~-hydroxv-3,20-diketo-
pregnene used to prepare the-steroids of this invention contains
additional hydroxyl groups, they should be protected before
proceeding with the above-described reactions.
The following examples are specific embodiments of
this invention.
--5--
~05~1~1 K548
Example 1
21-Chloro-11~-[ethoxy(2-meth lph~nyl)methoxy]-9-fluoro-2',2'-
dimethylpregn-4-eno[16a,17-d~1,3]d~loxolane-3,20-dione~ ~~~
A suspension of 21-chloro-9-fluoro-11~-hydroxy-2',2'-
dimethylpregn-4-eno[16a,17-dl[1,3]dioxolane-3,20-dione (684 mg)
in anhydrous toluene (17 ml) containing 1-ethoxy-1,2-dihydro-
benzocyclobutene (444 mg) is refluxed in a nitrogen atmosphere.
In a few minutes a homogeneous solution is obtained. After
about 6 hours, the solution is cooled and then absorbed on a
column of silica gel (20 g). Elution of the column with chloro-
form-hexane (1:4) yields unreacted 1-ethoxy-1,2-dihydrobenzo-
cyclobutene. Further eltuion of the column with chloroform-
hexane (1:4 and 1:1) gives the product as a foam (0.90 g). This
is dissolved in the minimum amount of ether, diluted with 10 ml
of hexane and maintained at a temperature of about 5C to yield
the solid (355 mg), melting point 171-180C. Recrystallization
of this material from ethyl acetate-hexane yields the title
compound (205 mg), melting point 182-185C.
Example 2
9-Fluoro-ll~-(methoxyphenylmethoxy)-2',2'-dimethy1pregna-1,4-
dieno[l6,17-d)[1,3]dioxolane-3,20-dione
A suspension of 9-fluoro-11~-hydroxy-2',2'-dimethyl-
pregna-1,4-dieno[16a,17-d]~1,3]dioxolane-3,20-dione (1.0 g) and
benzaldehyde dimethyl acetal (2.0 g) in benzene (130 mlj containing
~-toluenesulfonic acid (15 mg) is azeotropically distilled. After
about 25 minutes, the solution is cooled, washed with a dilute
sodium bicarbonate solution and water, dried and evaporated in
vacuo to yield a solid (1.3 g). Recrystallization of this
.:
material from ethyl acetate-hexane yields the title compound
(0.9 g), melting point 198-214C.
--6--
K548
~"os~6~
Example 3
21-(Acetyloxy)-9~fluoro~ (methox henylmethoxy)-2',2'-
d;methylpregna-1,4-dieno~16a,17-dJ ~,31dioxolane-3,20-dione
A suspension of triamcinolone acetonide, 21-acetate
(1.0 g~ in benzene (150 ml) containing benzaldehyde dimethyl
acetal t2.0 g) and ~-toluenesulfonic acid (25 mg) i5 distilled
removing the benzene. After about 30 minutes, the solution is
cooled, washed with a dilute sodium bicarbonate solution and
water, dried using magnesium sulfate and evaporated to a solid
which is absorbed on a column of silica gel (40 g). Elution
of the column with chloroform-hexane (1:4) removes non-steroidal
impurities. Further elution with chloroform-hexane (3:7 and
1:1) yields 0.96 mg of material which is recrystallized from
ethyl acetate-hexane to yield the title compound (0~5 g),
- melting point 196-198C.
Example 4
21-(Acetyloxv)-ll~-[ethoxy(2-methylphenYl)methoxy]-9-fluoro-
2',2'-dimethylpregna-1,4-dieno[r6a,17-d~[1,3]dioxolane-3,20-dione
Triamcinolone acetonide, 21-acetate (1.0 g) is dissolved
in anhydrous xylenes (37 ml) in an oil bath maintained at about
125C in a nitrogen atmosphere. l-Ethoxybenzocyclobutene (1.11 g)
is added and after 18 hours the reaction is incomplete. The
following additional amounts of l-ethoxybenzocyclobutene are
added at the indicated time intervals:
0.3ml (21 hours)
0.3ml (24 hours)
0.3ml (28 hours)
0.3ml (46 hours)
and 0.3ml (48 hours)
The solution is evaporated and the residue is dissolved in chloro-
form and chromatographed on a silica gel column (25 mg). Elution
of the column with chloroform-hexane (1:4 to 1:1) removes non-
K548
l~)S~
steroidal impurities. Further elution with chloroform-hexane
(4:1) and chloroform yield the desired material (0.8 g). The
solid is dried to yield the title compound, melting point 105-
11 0 C .
Exam~les 5-8
Following the procedure of Example 1, but substituting
the steroid listed in column I for 21-chloro-9-fluoro-11~-hydroxy-
2',2'-dimethylpregn-4-eno~16a,17-d][1,3]dioxolane-3,20-dione
and the compound listed in column II for l-ethoxy-1,2-dihydro-
ben7.ocyclobutene, yields the steroid listed in column III.
l()S81~1 K5 4 8
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105~16~ K548
xamples 9-11
Following the procedure of Example 2, but substituting
the steroid listed in column I for 9-fluoro-11~-hydroxy-2',2'-
dimethylpregna-1,4-dieno[16a,17-d][1,3]dioxolane-3,20-dione and
the compound listed in column II for benzaldehyde dimethyl acetal,
yields the steroid listed in column III.
--10--
h:~4ff
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r-l Ei N ~ ~ X ~ O
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I ' ~ O I ~ O
C~ N ~ C ~ ~ '~J ''~ '~
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Sl O ~ ~1 `~21 ~ `~
O rC I _I ~ ¦ ~J _ _
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a~ o ~ ~ o ~ ~ ~D
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. X548
~058161
Example 12
(methoxyphen lmethox )-2',2'-dimeth 1-
re~na-1,4-di ~
A suspension of 21-(acetyloxy)-9-fluoro-11~-(methoxy-
phenylmethoxy)-2',2'-dimethylpregna-1,4-dieno[16a,17-dl[1,3]-
dioxolane-3,20-dione (0.7 g, prepared as described in Example 3)
in 7s ml of methanol is cooled to OC and 7 ml of 10% potassium
carbonate solution is added. After lS minutes, 20 mI of 20%
aqueous acetic acid is added followed by water, and the
resulting solid is filtered and dried in vacuo.to yield the
title compound.
