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Патент USA US3069430

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United States Patent O?ice
Patented Dec. 18, 19532
16¢,1'7a-‘(IYQLQCARBONATE ESTERS 0F 160:,17a
l6a-hydroxycortisone 16a,17u-carbonate,
l6a-hydroxycortisone 16a,17a-carbonate 21-acetate,
2ot-methyl- l 6a-hydroxyeortisone 16a,17ot-C?11‘bOna’[e,
9a-?uoro-l6a-hydroxycortisone 16a,l7a-carbonate,
Josef Fried, Princeton, Ni, assignor to @lin Mathieson
Chemical Corporation, New York, N.Y., a corporation
of Virginia
No Drawing. Filed July 17, 1961, Ser. No. 124,383
7 Claims. ((11. 269-43955)
12a-?uoro- l 6a-hydroxycortisone 16a, Hot-carbonate,
6a-methyl-1 6OL~i1ydfOXYCOIlIlSO116 16cc, 17OL-CEUE‘bODatG,
6a-chloro-16a-hydroxycortisone 16a,17a-carbonate,
6:1,9ot-di?l10f0-16ot-hYd1‘OXYCOItiSOI16 16a,17a-carbonate,
This invention relates to 16a,17a-cyclocarbonate esters
of 160:,170t-dii1Ydf0XY steroids of C-ring substituted preg
90:,21-di?uoro-A4-pregnene-16a, 17a.-diol-3 ,11,.20~trione
nenes, that is steroids having a pregnene, pregnadiene or
pregnatriene nucleus. More particularly, the invention
relates to compounds represented by the formula
16a-hydroxyprednisolone l6tt,l7u-carbonate,
9a-?uoro-1oa-hydroxyprednisolone 16a,17ot-carbonate,
lla-chloro-l6a-hydroxyprednisolone 16a,17a-carbonate,
éa-methyl-l6ot-hydroxyprednisolone IMAM-carbonate,
6ot~fluoro-l6ahydroxyprednisolone 16a, 17a-c arbonate,
6a.,9a-di?uoro-l6a~hydroxyprednisolone 1604,17»
9a,21sdi?uoro-alA-pregnadiene-1 lp,16cx,17a—triol-3,20
dione 16u,l7ot-carbonate.
loct-hydroxyprednisone 160:,170t-C31‘i30115t6,
loa-hydroxyprednisone 16m, Nit-carbonate 2.1~acetate,
9oc-?llO1'O- l 6m-hydroxyprednisone 1606,17Ct-C8Ib0l'1?i6,
i2a-?uoro-l6a-iiydroxyprednisone 16cc, 170t-C21fb0l13t6,
6a.-rnethyl- 1 ?a-hydroxyprednisone l6a,17v.-carbonate,
In Formula I, the 1,2- and/or 6,7—positions may be satu
rated or double bonded so that A4-, A1143 A‘LB- and AL“ 30
pregnanes are included within the scope of this invention.
6a-chloro~l6a-hydroxyprednisone l6cz,17ot-CarbOnate,
6a,9a-di?uoro-l6a-hydroxyprednisone 16ot,170t.-C21Ib0l'13i6.
The symbols in Formula I have the following meanings:
R represents hydrogen, R’ represnts fi-hydroxy or to
gether R and R’ are keto (C20); R" represents hydro
gen, halogen or lower alkyl; X and X’ each represents 35
hydrogen or halogen, but at least one of these two sym
bols represents hydrogen; Y represents hydrogen or lower
alkyl, preferably methyl; and Z represents hydrogen,
halogen, hydroxy or the acyloXy radical of a hydrocarbon
carboxylic acid of less than 10 carbon atoms.
The symbols R”, X, X" and Z represent all four halo
gens but chlorine and ?uorine are preferred in this group.
The same or different halogens may appear in a given
compound. Lower alkyl groups represented by Y and
R" include straight and branched chain saturated hydro
carbon radicals such as methyl, ethyl, propyl, isopropyl,
butyl, t~butyl, amyl and the like.
The compounds of this invention can be prepared by
Carboxylic acids from which the acyloxy radical Z may
reacting a compound of the formula
be derived to produce ZI-esters include, for example,
alkanoic acids, preferably lower alkanoic acids such as
acetic, propionic, butyric, heXanoic acids and the like, 50
lower alkenoic acids such as acrylic acid, monocyclic
aromatic carboxylic acids such as benzoic and o~, m- and
p-toluic acids, cycloalkanoic acids such as cyclohexanoic
acid, cycloalkenoic acids such as cyclohexenoic acid, and
monocyclic aryl-lower alkanoic acids such as phenylacetic 55
and B-phenylpropionic acids.
The following 16a,17a-cyclocarb0nate esters of C-ring
substituted-16a,l7a-dihydroxypregnenes are compounds
of this invention. They and the working examples which
follow serve to illustrate the class of esters included.
l6a-hydroxyhydrocortisone 16a,17a-carbonate 21-acetate,
90c.—?tl0l‘0— l 6a-hydroxyhydrocortisone 16cc, 1 Wat-carbonate,
IZa-chloro-l 6a-hydroxyhydrocortisone 16ot,17ot—
6a.-methyl-16ot-hydroxyhydrocortisone 16c<,17a
6a-?uoro-16ot-hydroxyhydrocortisone 16a,17a-carbonate,
6a,9<x-di?uoro-16u-hydroxyhydrocortisone 16a, 1 70¢
|_ ..
__ ea
wherein the 1,2- and/0r 6,7-positions are saturated or
double bonded, R, R’, R", X, X’, and Y have the same
meaning as before and Z’ represents hydrogen, halogen
or the acyloxy radical of a hydrocarbon carboxylic acid
of less than 10 carbon atoms, with phosgene to produce
the cyclic carbonate. The reaction is carried out in the
presence of an organic nitrogen base such as pyridine, col
lidine, triethanolamine, quinoline or the like and the prod
uct is recovered from the solution by conventional pro
cedures. Preferably the compound of Formula II is dis
solved or suspended in the basic medium and then treated
with an equimolecular proportion or excess of the phos
hydroxyprednisolone, 6a,9a-di?uoro—l6a-hydroxypredni
gene at a temperature below about 0° C.
The starting materials of Formula I are known sub
The 2l-esters of l6a-hydroxyprednisones such as the
stances or are readily obtained from known compounds.
21-acetates of l6ot-hyo‘roxyprednisone, 9ot-fluoro-l6a-hy
Thus 16a,17u-dihydroxy compounds may be obtained
from their known 17or~hydroxy analogs by enzymatic hy
droxylation at the 16-positi0n by means of the micro
methyl-l6a hydroxyprednisone, 6a—chloro-16u-hydroxy
prednisone, 6e,9a-di?uoro-16tx-hydroxyprednisone.
droxyprednisone, 12a-?uoro-l6a-hydroxyprednisone, 6a
organism Streptomyces roseochromogenus according to
ll-hydroxy- or 1l-keto-At-pregnene-l6a,l7a»di0l~3,20~
the method described in US. Patent No. 2,855,343.
diones such as
Similarly, compounds saturated in the l,2~position may 10
be convered to the corresponding 1,2-unsaturated com
pound by the action of Bacterium cyclooxydans according
to the method described in Example 1 of US. Patent No.
Compounds of Formula 11 bearing l2a-halo and/or
6cx-rnethyl substituents may be produced as described in
my copending application Serial No. 677,205, ?led
August 9, 1957, now abandoned.
The 21-acyloxy-l6ot,17a-diol starting materials for the
compounds of this invention can be obtained by treating
the corresponding 16a,l7c¢,2l-triols with an acid anhy
dride in pyridine and separating the resulting mixture
by fractional crystallization. An alternate, more lengthy
but more general procedure involves the treatment of the
The compounds of this invention are physiologically ac
l6a,l7u,2l-triol with a ketone (e.g. acetone) or the alde<
tive substances which possess glucocorticoid and anti-in
hyde in the presence of an acid catalyst, (e.g. perchloric
?ammatory activities and hence can be used in lieu of
acid) to yield the corresponding 16L¥,17®-'l(€t21l or acctal
known glucocorticoids such as hydrocortisone and corti
which is then treated with an acyl chloride (e.g. acetyl
sone in the treatment of rheumatoid arthritis for which
chloride) or an acid anhydride (e.g. acetic anhydride)
purpose they can be administered in the same manner
in a basic organic medium (e.g. pyridine) to form the
as, for example, hydrocortisone, the dosage being adjusted
corresponding 2l-acyloxy-l6a,-17a-ketal or acetal. The
latter is converted by hydrolysis with aqueous formic
acid to the desired 2l-acyloxy-16a,l7ot-diol by the proce
dure described in my copending application Serial No.
84,989, ?led January 26, 1961.
The 21-halo~16ot,17wdiol starting materials for the
compounds of this invention are prepared by converting
for the relative potency of the particular steroid. They
may be administered orally, for example, in the form
of tablets or capsules by incorporating a therapeutic
35 dosage with a carrier according to conventional practice.
The following examples are presented to more fully
illustrate the present invention (all temperatures being ex
pressed in degrees centigrade).
the corresponding 16u,17u,21-triol to its 16a,17u-ketal or
acetal as described above, treating the latter with an
organic sulfonyl chloride (e.g. tosyl chloride or rnesyl 40
chloride) to prepare the 2l-sulfonyloxy derivative which
is then 2l-halogenated by treatment with an alkali metal
A solution of 500 mg. of triamcinolone and .195 ml.
halide (e.g. potassium bi?uoride, lithium chloride, lithium
(1.6 moles) of acetic anhydride in 8 ml. of pyridine is
bromide and sodium iodide). The latter is converted to
the desired 2l-halO-l6oz,l7oc-dl0l compound by hydrolyz
Triamcinolone Z 604,17ot-Cdl‘b0?dt8 21-Acetate
45 allowed to stand at room temperature for 20 hours. After
removal of the reagents in vacuo, the residue is triturated
ing oil‘ tie 16a,l7ot-acetal or ketal grouping with formic
When a 6,7~saturated steroid is used as the starting
material and a 6-dehydro ?nal product is desired, the
washed with chloroform. The crystalline precipitate after
in ethyl acetate and acetic acid.
Among the starting materials of Formula II which may
be used to produce the products of Formula I are the
5.75, 5.82, 6.04, 6.20 and 625a
Analysis.—Calc’d for C23H29OqF (436.46): C, 63.29;
with chloroform, the resulting crystals ?ltered, and
recrystallization from acetone furnishes about 130 mg.
latter may be obtained by treating the 6,7-saturated 50 of pure triamcinolone 21-monoacetate having the follow
ing properties: M.P. 2l8~220° and 227~229°;
l6u,l7a-cyclic esters of this invention with a dehydro
[a]D23—|-57° (c. .37 in acetone);
genating agent capable of selectively dehydrogenating this
postiion. A suitable dehydrogenating agent is chloranil
Hit}. 238 mu (E=13,600); Milli?‘ 2.88 (shoulder), 2.98,
H, 6.69. Found: C, 63.21; H, 6.81.
The 21-esters of l6u-hydroxyhydrocortisones, such as
the 2l-acetates of 16u-hydroxyhydrocortisone, Zea-methyl
16a-hydroxyhydrocortisone, 9ct—?ll01"0—l6oz-hYClI'0XYhYdI'O
cortisone, 12a-chloro - 16a - hydroxyhydrocortisone, 6a -
To a solution of 200 mg. of triamcinolone 2l-mono
methyl- 1 6a-hydroxyhydrocortisone, 6a-?1lO1'O-16ot-hyClI‘OX
yhydrocortisone, and 6a,9a-di?uoro-l6a-hydroxyhydro
acetate in 6, ml. of anhydrous pyridine is added with
tisone, 9ot-iluoro-l6ot-hydroxycortisone, 120L-?llOI'0-16ot
water, dilute sodium bicarbonate solution and again with
stirring at 0°, 2.5 ml. of a 10% solution of phosgene
in toluene. The reaction is allowed to proceed at 0° for
20 minutes after which timeice and water are added.
The ill-esters of hydroxycortisones such as the 21-ace~
The mixture is extracted with chloroform. The chloro
tates of 16a-hydroxycortisone, 2a-methyl-16oz-hydroxycor
form extract is washed with water, dilute sulfuric acid,
hydroxycortisone, Got-methyl - 160a - hydroxycortisone, 6a
chloro-l6whydroxycortisone, 6ot~?uoro-l6a-hydroxycorti
sone, and éa-?a-di?uoro-l6ot-hydroxycortisone.
The 2l-esters of l6u-hydroxyprednisolones such as the
ZI-acetates of 1éa-hydroxyprednisolone, 9a-?uoro-16u
Water, died over sodium sulfate and the solvent removed
in vacuo. The crystalline residue (about 224 mg.) is
recrystallized from 95% alcohol (with the aid of car
bon) and has the following properties: M.P. 267—278°;
[11]];23 +69° (c. .47 in chlf.);
hydroxyprednisolone, 12a-chloro ~ 16oz - hydroxypredniso
lone, 6a-methyl-16a-hydroxyprednisolone, 6a-?uoro-16u 75
A333?‘ 2.95, 5.50, 5.72, 5.75, 6.03, 6.18, and 6.23;;
Analysis.—Calc’d for CHI-127081? (462.45): C, 62.33;
H, 5.88. Found: C, 62.60; H, 5.16.
triol-3,20-dione 16,17-acetonide which melts at about
310° after recrystallization from acetone-ethanol.
By further processing the above product as described in
Triamcinolone 1 601,1 7a-Carb0nate
Example 4, 21 - chloro - 9a - ?uoro - A1,‘! - pregnadiene
1l?,l6ot,l70c-tfiOl-3,20-Cli0l1€ IMAM-carbonate is ob
To a solution of 100 mg. of triamcinolone 16a,l7¢x
carbonate 21-acetate in 10 ml. of methanol is added
under nitrogen 1 ml. of a 10% solution potassium car
1 6 “,1 7 tit-Carbonate 21~Pr0pi0nate
bonate in water. The mixture is allowed to stand at 10
room temperature for 1/2 hour after which the mixture is
acidi?ed with 0.1 ml. of glacial acetic acid, 2 ml. Water
are added and the methanol removed in vacuo.
resulting crystalline precipitate is ?ltered off, washed with ,
water and dried to yield the product triamcinolone
A solution of 200 mg. of 6a-?uorotriamcinolone ace
tonide in 1 ml. of pyridine and 0.5 ml. of propionic an
hydride is allowed to remain at room temperature for
twenty hours. After removal of the reagents in vacuo
the residue l60t,170¢~aC€tOIllde of 6a-?uorotriamcinolone
2l-propionate is deacetonated with 60% formic acid at
100° according to the procedure described in Example
A solution of 250 mg. of the product of Example 113 20 .4, thereby yielding 6ot~?uorotriamcinolone 2l-propionate.
and 1.250 g. of recrystallized chloranil in 15 ml. of tert.
butanol is heated under re?ux for three hours. The mix
ture is cooled, ?ltered, the ?ltrate poured into water and
the layers separated. After an additional extraction of
To a solution of 1 g. of the product of part A in 30
the aqueous layer with ethyl acetate, the ethyl acetate
ml. of pyridine is added, with stirring, at 0°, 10 ml. of
extract is washed with a 1 N sodium hydroxide solution
a 10% solution of phosgene in toluene. The reaction
until the aqueous layer becomes colorless. The washed
mixture is treated as in Example 18 to yield the product
6-Dehydrotriamcinolone 16a,17a-Carb0nate 21-Acetate
6ot-?uorotriamcinolone IMAM-carbonate ZI-propionate.
extract is dried over sodium sulfate and evaporated to
dryness in vacuo leaving as residue the product 6-dchy 30
drotriamcinolone 16a,17ot-carbonate 21-acetate.
2-Methyltriamciiz0lone 1 6a,] 7ot—Carb0naz‘e 21 -Acetate
200 mg. of Za-methyl-triamcinolone 2l-acetate (pre
pared by sequentially acetonating, acctylating and
deacetonating 2tx-methyl triamcinolone in accordance
with the procedure of Example 6A) is dissolved in 3 ml.
of pyridine and treated at 0° with stirring with 2.5 ml.
To a solution of 1 g. of triamcinolone acetonide in 10
ml. of anhydrous pyridine is added at 0° 1 ml. of meth
anesulfonyl chloride. After two hours at 0° ice Water
of a 10% solution of phosgene in toluene in accordance
is added and the precipitated mesylate is removed by ?l 40 with the procedure of Example 113 thereby ielding the
tration. The precipitate is washed thoroughly with Wa
product 2 ~ methyltriamcinolone - l6CL,17OL ~ carbonate~2l
ter and dried in vacuo, then recrystallized from acetone
hexane. The triamcinolone acetonide 21-mesylate melts
at about 248—250° (dec.) or 286-287° (dec.) (poly
morphic forms).
A mixture containing 1 g. of triamcinolone acetonide
21-mesylate, 1 g. of potassium ?uoride and 25 ml. of
Zoe-Methy l~16a-Hydr0xyhydrocortisone 1 6 [1,] 706
Carbonat'e 21 -A aerate
2ot-methyl-l6ot—hydroxyhydrocortisone ZI-acetate (pre
pared by sequentially acetonating, acylating and deace
ethylene glycol is re?uxed (180°) for 19 hours. The
dark solution is poured into ice water and extracted with
tonating 2ct-methyl-1éot-hydroxyhydrocortisone in ac
chloroform. The chloroform extract is washed with wa 50 cordance with the procedure in Example 6A) is treated
ter, dried over sodium sulfate and evaporated to dryness
in a solution of pyridine with phosgene as described in
in vacuo. The residue, 16a,l7a-isopropylidene-9a,2l-di
Example 1B thereby yielding the product 2ut-rnethyl-16tt
hydroxyhydrocortisone léocl'lu-carbonate ZI-acetate.
?uoro-AlA-pregnadiene-11,6-16u,17a-triol - 3,20 - dione, is
recrystallized from acetone with the aid of charcoal and
melts at about 310°.
The above product is deacetonated by treatment with
formic acid by the procedure of Example 7 of my co
pending application Serial No. 84,989, ?led January 26,
9,21 - di?uoro - A114 - pregnadiene
Treatment of the above products with phosgene in
pyridine at 0° for 20 minutes in accordance with the
16a,l7a-Carb0nate 21 -A cetate
The product of the preceding example is treated with
recrystallized chloranil in accordance with the procedure
60 of Example 3 yielding the product 2ot-rnethyl-6-dehydro
l6a-hydroxyhydrocortisone 160:,17u-C2l1‘b0112l't6 21~acetate.
12a-Chl0ro-1 6 OL-Hydroxycortisone-I 6a,] hit-Carbonate
procedure of Example 1B yields the ?nal product 904,21
di?uoro-AlA-pregnadiene-1l/3,16a,17a-triol - 3,20 - dione
Sid-Dione 16a,17ot-Carb0nate
2oc-Methyl-6-D ehydro-I doc-Hydroxyhydromrtisone
21 -A cetale
Substitution of 1 g. of 12a-chloro~l6u-hydroxycor
tisone-Zl-acetate (prepared by sequentially treating 12a
chloro-l6a-hydroxycortisone with acetone and perchloric
acid, acetic anhydride and pyridine and 60% formic acid
A solution of 200 mg. of triamcinolone acetonide 21 70 in accordance with the procedure of Example 6A) is
meeylate and 900 mg. of lithium chloride in 25 ml. of
treated with phosgene in accordance with the procedure
dimethylformamide is kept at 100° for 24 hours. The
mixture is poured on ice, extracted with chloroform and
of Example 13 thereby yielding the product IZwChlOI‘O
l6a-hydroxycortisone 16a,17ot-carbouate ZI-acetate.
the chloroform extract washed with Water and dried over
This invention may be variously otherwise embodied
sodium sulfate. Evaporation of the solvent in vacuo 75 within the scope of the appended claims.
What is claimed is:
wherein the acyloxy group is the acyloxy radical of a hy
1. A compound selected from the group consisting of
steroids of the formula
drocarbon carboxylic acid of less than ten carbon atoms
and the halo group is a member of the group consisting
of chlorine and ?uorine.
3. A compound of the formula
and the 1,2- and 6,7-unsaturates thereof, wherein R rep
resents hydrogen, R’ represents B-hydroxy and together
R and R’ are keto; R" represents a member of the group
consisting of hydrogen, chlorine, ?uorine and lower alkyl;
X and X’ each represents a member of the group consist 20 wherein the acyloxy group is the acyloxy radical of a hy
drocarbon carboxylic acid of less than ten carbon atoms
ing of hydrogen chlorine and ?uorine, at least one rep
and the halo group is a member of the group consisting
resenting hydrogen; Y represents a member of the group
of chlorine and fluorine‘
consisting of hydrogen and lower alkyl; and Z represents
4. Triarncinolone 1606,1704-C3fb01’13te 21-acetate.
a member of the group consisting of hydrogen, chlorine,
5. 9a-?u01‘O-l6o: - hydroxyhydrocortisone 1604,1706 - car
?uorine, hydroxy and the acyloxy radical of a hydrocar 25
bonate 21—acetate.
bon carboxylic acid of less than 10 carbon atoms.
2. A compound of the formula
7. 6ot-?uorotriarncinolone - 16%1711 - carbonate 21-pro
References Qited in the file of this patent
Noller Chemistry of Organic Compounds, W. B. Saun
ders Co., Philadelphia, Pa. (1957) , p. 741.
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