Note: Descriptions are shown in the official language in which they were submitted.
~047SO~ K5 3 5a
This invention relates to novel 4,5-seco-steroids
which are useful as anti-inflammatory agents.
Compounds of the present invention have the formula
fH2-R
y~ C=O
~ 0~ C Q
A o
wherein A is -C-CH, -CH=CH2, -CH2CH3, or -CCH3; Xl iS
hydrogen, chlorine, bromine, or fluorine Rl is hydrogen,
hydroxyl, -OC-R2, chlorine, bromine, fluorine or iodine;
R2 ig lower alkyl; P is hydrogen, lower alkyl, or aryl; Q
is lower alkyl or aryl; Y is hydrogen and Y' is hydroxyl
or together Y and Y' are =0.
This invention also provides a process for preparing
a compound having the formula
fH2-Rl
y- ~C=O
y _ ~ -o C ~-Q
~'~
A O ~
wherein A is -C=CH, -CH=CH2, -CH2CH3~ or -~CH3; Xl iS
hydrogen, chlorine, bromine, or fluorine; Rl is hydrogen,
hydroxyl, -O~-R2, chlorine, bromine, fluorine or iodine;
R2 is lower alkyl; P is hydrogen, lower alkyl, or aryl; Q
is lower alkyl or aryl; Y is hydrogen and Y' is hydroxyl
or together Y and Y' are =O which comprise reacting a
compound of the formula
. .......................... ~
K535a
1047S0`7
2 Rl
~ ~ -O- C P III
wherein Xl, Rl, P, Q, Y and Y' are defined as above with
p-toluenesulfonylhydrazide in a mildly acidic medium to
form a compound of the formula
I H2Rl
y, C=O
y~ O--c--Q
IV
C o
wherein Xl, Rl, P, Q, Y and Y' are defined as above and,
where A is to be -CH=CH2, partially reducing the compound
of Formula IV or, where A is to be -CH2CH3, reducing the
compound of Formula IV or where A is to be -~-CH3~hydrating
the compound of Formula IV in an aqueus acidic medium in
the presence of mercuric sulfate.
The expression "lower alkyl" refers to both straight
and branched chain alkyl groups having 1 to 7 carbon atoms;
e.g., methyl, ethyl, propyl, isopropyl, t-butyl, heptyl, etc.
Alkyl groups having 1 to 3 carbon atoms are preferred.
The term "aryl" refers to a mono- or bi-carbocyclic
aromatic ring system having 6 or 10 carbon atoms7 e.g., phenyl
or naphthyl Phenyl or phenyl-substituted with halogen
~535a
~04750`7
(fluorine, chlorine, bromine or iodine), lower alkyl, or
lower alkoxy (having 1 to 7 carbon atoms) is preferred.
Phenyl is the most preferred aryl group.
The compounds of formula I are physiologically active
su~stances that posses anti-inflammatory activity, as
shown by the reversed passive Arthus skin reaction and the
mouse active Arthus reaction, and can be used in various
mammalian species such as domestic animals, e.g~, dogs and
cats. They can be used to decrease joint swelling, tender-
ness, pain and stiffness in conditions such as rheumatoid
arthritis. Surprisingly, in the 4,5-seco-steroids of this
invention hormonal side effects are greatly reduced or
eliminated in comparison to the 3-keto-~4-steroid starting
materials (see formulas II and VIII below).
A compound of formula I can be compounded according to
acceptable pharmaceutical practice in oral dosage forms such
as tablets, capsules, elixirs or powders, for administration
in an amount of about 100 mg/kg/day to 2 gm/kg/day, preferably
100 mg/kg/day to 1 gm/kg/day, in a single dose or in divided
doses.
Compounds of formula I, wherein Rl is hydrogen, chlorine,
or fluorine and Xl is hydrogen or fluorine, can be prepared
using as starting materials, steroids having the structure
fH2 -Rl
~=0
y ~ O C ~'Q II
0~
K535a
iO4750`7
wherein Rl is hydrogen, chlorine or fluorine and Xl is
hydrogen or fluorine.
Reaction of a steroid of formula II with hydrogen
peroxide in the presence of alkali, e.g., potassium hydroxide,
sodium hydroxide, etc., yields a 4,5-epoxy steroid having
the structure
fH2-R
C=O
~- ~ C ~'P
~ ~ III
O"~e~'
The reaction is run in a polar organic solvent, preferably
a lower alkanol such as methanol, at a temperature of
about 0C to 40C for 2 hours to 168 hours, preferably at
room temperature for 72 hours to 120 hours. The 4,5-epoxy
steroid of formula III is reacted with p-toluenesulfonyl-
hydrazide to yield a 4,5-seco-steroid of formula I wherein
Rl is hydrogen, chlorine, or fluorine, Xl is hydrogen or
fluorine, and A is -C-CH, i.e., compounds having the structure
1 2
C=O
y___ ~ O _ C Q
IV
111 0
HC
1047S07 K535a
The reaction is run in an organic solvent, or a muxture of organic
solvents, such as halogenated hydrocarbons at a temperature of fm m
0C to 40C for 2 hours to 24 hours, preferably at from 0~ to room
temperature for 4 hours to 16 hours.
Ccmpounds of formula I wherein Rlis hydrogen, chlorine, or fluo-
rine, Xl is hydrogen or fluorine, and A is ~ 3, i.e., compounds having
the structure lH2 R
y~ C=O
Y~ o~ c~ Q V
~\ ~
~ 1 Q~
O CH3
can be prepared by hydratLng a oompound of formula rv in the presence of
mercuric sulfabe. The reaction is carried out in an acidic aqueous med-
ium, e.g., a mu`xture of formic or a oe tic acid and a lower alkanol such
as methanol, at a temperature of from 0C to 80C for 1/2 hour to 24 hours,
preferably at 50C to 70C for 1/2 hour to 2 hours.
Reduction of a compound of formLla IV yields a oonpcund of formLla
I wherein Rl is hydrogen, chlorine, or fluorine, Xl is hydrogen or fluo-
rine, and A is -CH2CH3, i.e., a oompound having the structure
Cl H2-Rl
y _ ~ ~ = ~ 0- C ' Q
VI
~ xlJ
CIH2 ~
CH3 o
K535a
~047507
Reduction can be carried out at atmospheric pressure using
gaseous hydrogen and a catalyst such as palladium or platinum
oxicle.
Partial reduction of a compound of formula IV yields a
compound of formula I wherein Rl is hydrogen, chlorine, or
fluorine, Xl is hydrogen or fluorine and A is -CH=CH2, i.e.,
a compound having the structure
y~ C=O
~ o~C Q VII
1/\ ~
CH
1
CH2
The reduction can be carried out at atmospheric pressure using
a small amount (i.e., about 0.1-5.0% weight) of a poisoned
hydrogenation catalyst, e.g., palladium poisoned with synthetic
quinoline.
Compounds of formula I wherein Rl is hydroxyl, -OC-R2,
chlorine, bromine, or iodine and Xl is hydrogen or fluorine,
can be prepared using steroids having the structure
fH2-OH
C=O
_ O P
¦ VIII
o-J~J .
The 21-hydroxyl group in the steroid of formula VIII is
first blocked using a protecting group such as tetrahydro-
pyranyl. Reaction of a steroid of formula VIII and
1047507 K535a
dihydropyran can be carried out neat, or in an organic
solvent such as benzene, at a temperature of from 0C to
101)C. The reaction takes from about 1 hour to 24 hours
in the presence of an acid catalyst.
The steroid with the 21-hydroxyl group protected is
reacted with hydrogen peroxide in the presence of alkali,
as described above, to obtain a 4,5-epoxy steroid. The
4,5-epoxy steroid is then cleared with an acid to yield
a 21-hydroxy-4,5-epoxy steroid which can be treated as
described above to obtain compounds of formula I wherein
Rl is hydroxyl and Xl is hydrogen or fluorine.
Reaction of a compound of formula I, wherein Rl is
hydroxyl and Xl is hydrogen or fluorine, with an anhydride
having the formula (R2C0)2O yields the corresponding 21-
lower alkanoyloxy compound. The reaction can be carried
out in an organic solvent such as pyridine at a temperature
of from 0C to 40C for 1 hour to 24 hours, preferably 0C
to 30C for 1 hour to 4 hours.
Reaction of a compound of formula I, wherein Rl is
hydroxyl and Xl is hydrogen or fluorine, with a lower alkyl
(or aryl) sulfonyl chloride (e.g., methanesulfonyl chloride
or p-tolylsulfonyl chloride) yields the corresponding 21-
sulfonate. the reaction can be carried out in the presence
of an organic base such as pyridine, at a temperature of
from about 0-C to 20C under anhydrous conditions. Reaction
of the 21-sulfonate with an inorganic hallde (e.g., sodium
iodide, lithium chloride, lithium bromide, potassium fluoride,
etc.) yields the corresponding 21-iodo, 21-chloro, 21-bromo,
and 21-1uoro compounds of formula I. The reaction is con-
ducted in a polar organic solvent (e.g., dimethylformamide,
acetone, etc.) under reflux conditions for about 1 hour to 12
hours, preferably about 2 hours to 4 hours.
K535a
~04750`7
Compounds of formula I wherein Xl is bromine can be
prepared from the corresponding compound of formula I
wherein Xl is hydrogen, Y is hydrogen, and Y' is hydroxyl,
i.e., a compound having the structure
ICH2Rl
C=O
OH
-- O_ ,-P IX
I o C Q
A o
Reaction of a compound of formula IX, when Rl is other
than hydroxyl, with lower alkylsulfonyl chloride in a polar
organic solvent, e.g., dimethylforamide, in the presence
of an organic base, e.g., pyridine, yields a ~9 )-compound
having the structure
ICH2 Rl
C=O
~ ~ ~ `- C ~ X
A O
wherein Rl is other than hydroyl. The reaction can be run
at room temperature for about 4 hours to 24 hours, preferably
for about 4 hours to 12 hours.
The 9a-bromo-compound of formula I is prepared by re-
acting the intermediate of formula X with an N-bromoamide
tincluding imide) of a carboxylic acid (including derivatives),
inter alia,N-bromoacetamide (or N-bromo-amide of other
lower fatty acid), N-bromoswcinimide and dibromodimethylhydantoin.
--8--
R535a
:104'7507
Preferably this conversion is effected in the presence of
perchloric acid or other relatively strong acid (e.g.,
E~toluenesulfonic acid or trichloracetic acid) not forming
an ester with the ll~-hydroxy compound.
Compounds of formula I wherein Rl is hydroxyl and X
is bromine are prepared as described above, except that
two additional steps are required. Before reacting the
compound of formula IX with lower alkylsulfonyl chloride to
obtain a ~9(11)-compound, the 21-hydroxyl group must be
protected (e.g., by reaction of the compound with acetic
anhydride). After the 9~-bromo-compound is formed, the
protecting group is removed by reaction with a base.
Compounds of Formula I wherein Xl is chlorine bromine
iodine or fluorine may also be prepared by reacting a
compound of the formula
CIH2Rl
C80
~ ~__O- C Q
with a hydrogen halide, preferably in an alcohol-free solvent
to form a compound of the formula
fH2Rl
f~=O
HO ~ -~ C Q
~~
0~
10~75~7 K535a
wherein Xl is chlorine, bromine, iodine or fluorine and
reacting this compound as described above with respect
to Formula II to produce a compound of Formula I.
Compounds of formula I wherein P and Q are both methyl
are preferred.
Compounds of formula I wherein X is hydrogen or
fluorine are preferred, and those wherein Xl is fluorine
are particularly preferred.
Compounds of formula I wherein Y is hydrogen and Y'
is hydroxyl are preferred.
Compounds of formula I wherein Rl is halogen are
preferred and those wherein Rl is chlorine are particularly
preferred.
The following examples are specific embodiments of
the above described invention.
--10--
K535a
104'~507
Example 1
21-Chloro-9-fluoro-ll,B,16,17-trihydroxy-4,5~
secopregn-3-yn-5,20-dione, 16,17-acetonide
a) 21-Chloro-4,5-epoxy-9-fluoro~ ,16~,17-trihydroxy-
5~-pregnane-3,20-dione, 16,17-acetonide
A solution of 1.0 g of 21-chloro-9-fluoro-11~,16a,
17-trihydroxypregn-4-ene-3,20-dione, 16,17-acetonide in
100 ml of methanol is prepared at 0C,and 6.2 ml of 30~
hydrogen peroxide and 4.1 ml of 4N sodium hydroxide are
added. After 150 minutes the slurry is allowed to warm
to room temperature and stirred overnight. The slurry
is diluted to 2 liters with water and filtered. The re-
sulting solid (978 mg) is plate chromatographed on two l mm
silica gel plates with 5:1 chloroform-ethyl acetate as the
developing solvent. The iodine-absorbing band which
appears above that of the residual starting material is
excised and eluted with 9:1 ethyl acetate-methanol to give
560 mg of solid. Recrystallization from ethanol-water
gives 409 mg of the title compound, melting point 254-256C.
This is combined with 406 mg of the title compound, melting
point 254-256C (prepared in a separate batch), to give
the analytical sample.
Anal. Calcd for C24H36ClFO6: C, 61.21; H, 6-85;
Cl, 7.53; F, 4.03.
Found: C, 61.48; H, 6.75;
Cl, 7.30; F, 3.91.
K535a
104750`7
b) 21-Chloro-9-fluoro~ ,16~ ! 17-trihydroxy-4,5-
secopregn-3-yn-5~2o-dio-e~ 16,17-acetonide
To a solution o~ 1.413 g of 21-chloro-4,5-epoxy-9-
fluoro~ ,16a,17-trihydroxy-5~-pregnane-3,20-dione,
16,17-acetonide in 36.9 ml of 1:1 dichloromethane-acetic
acid that is cooled to 0C is added dropwise a solution
of 564.9 mg of p-toluenesulfonylhydrazide in 36.9 ml of
1:1 dichloromethane-acetic acid. The reaction mixture is
stirred at 0C for 2 hours, at room temperature overnight,
and then poured into ice water and extracted several times
with ether. The combined ether extracts are washed with
10~ sodium carbonate solution, water, and dried over sodium
sulfate. The solvent is evaporated ln vacuo to give 1.36 g
of yellowish crude material which is chromatographed through
a column of 20 g of silica gel HF with 6:1 hexane-ethyl
acetate as the eluant. The first 450 ml of eluate is
evaporated in vacuo to give 1.16 g of TLC (thin layer
chromatography) homogeneous material. Recrystallization
rom ethyl acetate-hexane gives 793.4 mg of the title com-
pound, melting point 201-203C.
Anal. Calc'd for C24H32O5FCl:
C, 63.36: H, 7.09; F, 4.18; Cl, 7.79.
- Found: C, 63.23; H, 7.35; F, 4.01, Cl, 7.76.
-
K535a
1047S~7
Example 2
21-Chloro-9-fluoro~ ,16~,17-trihydroxy-4,5-
secopre~nane-3,5,20-trione,_16,17-acetonicle
A solution of 659.2 mg of 21-chloro-9-fluoro-11~,
16a,17-trihydroxy-4,5-secopregn-3-yn-5,20-dione, 16,17-
acetonide (prepared as described in Example 1) in a mixture
of 8.3 ml of 85% formic acid and 8.3 ml of 80~ aqueous methanol
is added to a solution of mercuric sulfate (prepared from 50
mg of mercuric oxide, 0.08 ml of sulfuric acid and 1.9 ml of
water). After 30 minutes at 60C, the solution is cooled
to 0C, maintained at that temperature overnight, and
then extracted with ether. The ether solution is washed
with 2~ sodium carbonate solution, 8~ sodium chloride
solution, and dried. Solvent removal in vacuo yields
670 mg of crude product which is combined with 225 mg of
crude product prepared in a separate batch. The combined
material i5 plate chromatographed on silica gel plates.
After development with 2:1 hexane-ethyl acetate, the major
iodine-absorbing band is excised and eluted with 9:1 ethyl
acetate-methanol. Solvent removal ln vacuo gives a resi-
due which is recrystallized from ethyl acetate-hexane to
give 464 mg of solid which is filtered through a column
of silica gel with 4:1 ethyl acetate-hexane. The eluate
; is evaporated in vacuo, and the residue is recrystallized
from hexane-ethyl acetate to give 320 mg of the title
compound, melting point 235-236C, dec., homogeneous on
TLC.
Anal. Calcd for C24H34ClFO6:
C, 60.94; H, 7.25; Cl, 7.50; F, 4.02.
Found: C, 61.15; H, 7.44; Cl, 7.71; F, 4.24.
-13-
~r)35a
1047507
Example 3
21-Chloro-9-f luoro~ 16a,17-trih~droxy-4,5-
secoprec~llane-5,20-dione, 16,17-acetonide
. . _
A solution of 682.5 mg of 21-chloro-9-fluoro-11~,16~,
17-trihydroxy-4,5-secopregn-3-yn-5,20-dione, 16,17-acetonide
(prepared as described in Example 1) in 15 ml of ethyl acetate
is hydrogenated over 205 mg of 10% palladium on charcoal at
atmospheric pressure. After 1 hour, hydrogen uptake (63 ml)
- ceases. After 2 hours the catalyst is filtered and the fil-
trate is evaporated ln vacuo to give 630.9 mg of crude product.
Crystallization from ethyl acetate-hexane gives 377.5 mg
of analytical sample, melting point 219-220.5C
Anal. Calcd for C24H36ClFO5:
C, 62.80; H, 7.91; Cl, 7.72; F, 4.14.
Found: C, 63.06; H, 7.97; Cl, 7.70; F, 4.03.
-14-
104 7S0`7 1~ 535a
Examples 4 - 8
Following the procedure of Example lj but sub-
stituting the steroid listed in column I for 21-chloro-
9-fluoro-llB,16~,17-trihydroxypregn-4-ene-3,20--dione,
16,17-acetonide, the compound listed in column II is
obtained.
-15-
~53 5a
1047507
o
i. ~ o ~ `
x a) ~ I I U aJ ,
o ~
~ o U) ~~, ~ ~ o ~,
s, ~ X ~ ~,
~1 0 ~ ~ ~ O O I `~
h~ I ` ` I ~ ~o
I U~ X ~ ~ ~ U ~ ` ~ ~ ~
I` I OO ~1 0 1~ ~ ~1 1 0 O
H ~ ` h I ~ ~1 ~1 ~
1 o ~ I U) O O O
~ ~
E ~ ~ N I
~ ` ~ ` O v~ ~ ` ~rl ~ U~ I~
O .-1 0 O I I O U~ ` ~D ~ O ~ L~
O O O ` I ~ ~ I O O ~ 0 ~1 1
O O I ~ ~ X ~ O ~ I ~I X
o I o I ~ o~ ~ o ~
~ ' ~ ` ~ ~ ~ ~ ~ ~ ~
~ I ~ ` 1:
X r-- I ~rl I a) ~ I
~1 ` I O ~ 0
~1 o O--I ~ ~ a
I O X ~
O ~ I I
~1 ~ ~1 ~D` O ~rl O O O ~)
~ ~ ~ ~ o a~ o
GU H `~ ~ ~O I ~rl `O ~ I t~
I ~ O
1 0 ~ o
e
:~ ~ ~ O I ~ a) o h
_~ O I ~ `O ~ ~ U O `~ h
O h d' ~ h ~ ~rl O ~
C.) O I ~ ~ X I O 1 1~ ~ X O
o ~ ~ I o r- ~ a) o ~ o
J ` I~1 h r~ ~ U h O
h t) ~1 ~ D I I O ~1 ~ h
E ~ ~ ~ r~ co
x
--16--
K53Sa
~0~750`7
Examples 9-13
Following the procedure of Example 2, but sub-
stituting the compound listed in column I (prepared as
described in Examples 4-8 respectively) for 21-chloro-
9-fluoro-llB,16,17-trihydroxy-4,5-secopregn-3-yn-5,20-
dione, 16,17-acetonide, the compound listèd in column II
is obtained.
-17-
K53 5a
1(~47507
o ~ ,~
~- a) o I N
X 1 ~ 1` 1`U) C
O O ~ ~ ~ O
) ` h`~r h ~ ~
` I` ~ x ~ ~ Q~ ~a
~1 0 e1~ OO I `
h ~ I ` 11 ~ h O
I In X o ~D
I~ ` O r~ ~ ~ O~ ~ I ~ ~
H ,1 ~ h ~ ` h ~'~ ~ ~
a) ~ 1 ~1 0 ~ I U' o o I
~D ~ a) ~ o~1 ~ Id 1` ` a) ~ o 1`
` O U~ I~ ` I ~r~ ~ U~ `
h I ~1
O ~1 a) o ~ `o ~ ~ O ~ u~
O O O ` ~ 'a ~ I O tJ~ t.) h I
O ~ C ~5 X a) O h I --1 X C
~ I c o I o ~ ` .c o o
_I I ~ ` tJ~ IJ ~I h O --1 0 ~
tLt ~1 ~ t h I ~ ~ ~
t-l Qt ~ ~ O`t U~
~)
~ ` O I ` ~
x a) o I I ~ a) I ~I
O ~
~1 0 U~ 1 1 0er O ~ I O
~t~ m D I ~ '1 ~ h 1` ~
~1 o ~r ~ ~ Oo
~` I O O ~1 a
>., ~ ~n Qll` ~ ` ~ Qt~
1 0 ~ I ~ O O
~ I ~ ,1 ~I q) ~ ~1 ~ ~ ~ ~ a)
~ ~ c ,l ~ ~o u~ u u~ ~:
~ ~ c JJ ~S~ I I O
C ~ aJ O I Io ~ ~ ~ ~ o a~
~ I Q~ t O ~ U o el~
_, o o o ~u I O O ~ ~
o s~ o ~ o
'J O ~ I ~t. I t: ~ X ~ O Sl I ~I
O I O I:~ Q~ l` ~ O
O~-I O ~
aJ
~ O~ O ~ ~ r~
~ ~ ~ ~ ~
--18--
K535a
~C~47S07
Example 14
9-Fluoro-11~, 16a, 17-trihydroxy 4,5-secopregnane
5.2Q-dione,16,17-acetonide
A) 9-Fluo~o-4-,5-epoxy-11~16~, 17-trih~r~xy-pregnane
3,20-diope, 16,17-acetonide
A solution of 9.7 g of 9-fluoro-11~,16a,17-trihydroxy-
pregn-4-ene-3,20-dione, 16,17-acetonide in 500 ml of methanol
was stirred with 30 ml of 30% hydrogen peroxide and 20 ml of
4 N sodium hydroxide solution for 4 days and then diluted with
ice-water. The resulting solid was filtered, dissolved in
chloroform, dried, and evaporated in vacuo. This residue was
dissolved in 200 ml of 1:1 dichloromethane-hexane and chromato-
graphed on a 150 g-silica gel column. Elution with dichloro-
methane and then 3:1 dichloromethane-ethyl acetate gave 7.0 g
of TLC pure epoxide. m.p. 258-260. -
B) 9-Fluoro~ ,16a,17 tri-hydroxY-4,5-secopregn-3yn-
5,20-dione,~16,17-aee~0nide---
A solution of 2.44 of p-toluenesulfonyl hydrazine in 300 ml
of 1:1 dichloromethane-acetic acid was added dropwise at 0 to
a solution of 7.0 g (0.016 mole) of the above epoxide in 300 ml
of the same solvent. After stirring overnight at room temperature
the solution was diluted with dichloromethane, washed with 4x lQ
of 5~ sodium bicarbonate solution, dried and evaporated in vacuo.
The residue was chromatographed on a 60 g-silica gel column.
Elution with dichloromethane gave 4.7 g of pure acetylene,
m.p. 215-217.
C~ 9-Fluoro-11~,16~,17-trihydroxY-4~5-secopregnan-
5,20-~ione~ 7sacetonide ~
A solution of 4.7 g (0.011 mole) of the above acetylene in
300 ml of ethyl acetate was stirred with 500 mg of 5% Pd/C in an
-19-
K535a
1047507
atmosphere of hydrogen. After 90 minutes hydrogen uptake
had practically ceased (520 ml, 0.0235 mole). After 210
minutes the catalyst was filtered and the residue crystallized
twice from methanol-chloroform to give 3.5 g, m.p. 193-195.
Anal. Calc'd. for C H FO5: C, 68.06 H, 8.57; F, 4.50
_ 24 37
Found: C, 68.30; H, 8.65; F, 4.66
Examples 15-18
Following the procedure of Example 3, but substituting
the compound listed in column I ~prepared as described in
Examples 4-8 respectively) for 21-chloro-9-fluoro-11~,16~,
17-trihydroxy-4,5-secopregn-3-yn-5,20-dione, 16,17-acetonide,
the compound listed in column II is obtained.
-20-
K53 5a
1047S0`~
a
, o U~
a) ~1 N
u~ I h ` 'J' ~ ~
U~ ~ I I ~ O 1~ 1
X ` ~ 1 ~ o ~ ~ ~_1
H ~ O c~ ~D
_1 ~ 1 0 ~ I ~ O O
/ u u 1~ u
~ ~ O O U~
:~ J ~ I I O
I ` O U) ~ O a~
o ,~
C~ ~ I ~ a) o
I ~O ~U ~ I I
o ~ o
~ X `O S~ I ~ X ~
~ ~: O I o o :~ Q.l` S O `
~a o ~ U ~ ~ ~a
~I h U ` ~
~1
L'I ~ ~ ~ ~ a
`~ I` I .~ X ~ ~ I O
'J' ~ ~7 0 0 1 `
o ~ ~ l
o o ~ a) ~ .c: ~ I
` h I ~ I O
20 ,_, ~ _1 oQ',I ~ U~ o o
s o ~1 u ~ ~ I a) ~ u
U~
I I O U~ ` D ~ O O~ U~ rl
O
c~ ~ ~ a~ aJ o
` I ~q~ I O O ~ t) ~ I I
o :~ o
'a X ~ 0 ~ ~ ~ X
` ~ ~~I Ll O ~ O _~ U ~--I
N 'a N 1~ ~.) ` I
a~
Q Ul ~O I` CO
~3 ~1 ,_1 ~ ,_
x
K53Sa
1047S07
- Example 19
9-Fluoro~ ,16a,17,21-tetrahydroxy-4,5-secopregn-
3-Yn-5,20-dione, 16,17-acetonidc
a) 21-(TetrahydroEyran-2-~loxy)-9-fluoro-11~,16a,17-
trihydroxypregn-4-ene-3,20-dione, 16,17-acetonide
A suspension of 1 g of 9-fluoro-11~,16a,17,21-tetra-
hydroxypregn-4-ene-3,20-dione, 16,17-acetonide in 20 ml
of dihydropyran is treated with 0.5 ml of an anhydrous
solution of hydrochloric acid in ether. The resulting
mixture is stirred for 4 hours, diluted with water, and
filtered to give the title compound.
b) 21-(Tetrahydropyran-2-yloxy)-9-fluoro-4,5-epoxy-
llB~16a~17-trihydroxy-5~-pregnane-3!20-dione~
16,17-acetonide
A solution of 1.0 g of 21-(tetrahydropyran-2-yloxy)-
9-fluoro-11~,16a,17-trihydroxypregn-4-ene-3,20-dione,
16,17-acetonide in 100 ml of methanol is prepared at 0C,
and 6.2 ml of 30% hydrogen peroxide and 4.1 ml of 4N
sodium hydroxide are added. After 150 minutes the slurry
is allowed to warm to room temperature and stirred over-
night. The slurry is diluted to 2 liters with water and
filtered to give the title compound.
c) 9-Fluoro-4,5-epoxy-11~,16a,17,21-tetrahydroxy-5~-
pregnane-3,20-dione, 16,17-acetonide
A solution of 1 g of 21-(tetrahydropyran-2-yloxy)-
9-fluoro-4~5-epoxy-11~16a~17-trihydroxy-5~-pregnane-
3,20-dione, 16,17-acetonide in 50 ml of 1:1 acetic acid-
water is stirred for 6 hours, diluted with water, and the
solid filtered to give the title compound
- -22-
K535a
~04'~507
d) 9-Fluoro~ 16~,17~21-tetrahydroxy-4~5-s~copre~n
3-yn-5,20-dione, 16,17-acetonide_
To a solution of 1.0 g of 9-fluoro-4,5-epoxy-
llB,16a,17,21-tetrahydroxy-5~-pregnane-3,20-dione, 16,17-
acetonide in 30 ml of 1:1 dichloromethane-acetic acid that
is cooled to 0C is added dropwise a solution of 500 mg
of p-toluenesulfonylhydrazide in 30 ml of 1:1 dichloro-
methane-acetic acid. The reaction mixture is stirred at
0C for 2 hours, at room temperature overnight, and then
poured into ice water and extracted with ether. The
ether extract is washed with 10% sodium carbonate solution,
water, and dried over sodium sulfate. The solvent is
evaporated in vacuo to give the title compound.
Example 20
9-Fluoro-11~,16~,17,21-tetrahydroxy-4,5-seco-
pregnane-3,5,20-trione, 16,17-acetonide
A solution of 660 mg of 9-fluoro-11~,16~,17,21-
tetrahydroxy-4,5-secopregn-3-yn-5,20-dione, 16,17-acetonide
(prepared as described in Example 19) in a mixture of 8~3
ml of 85% formic acid and 8.3 ml of 80% aqueous methanol
is added to a solution of mercuric sulfate (prepared from
50 mg of mercuric oxide, 0.08 ml of sulfuric acid and 1.9
ml of water). After 30 minutes at 60C, the solution is
cooled to 0C, maintained at that temperature overnight,
and then extracted with ether. The ether solution is
washed with 2% sodium carbonate solution, 8% sodium
chloride solution, and dried. Solvent removal in vacuo
yields the title compound.
K535a
10~7~0`7
Example 21
9-Fluoro-11~16a,17,21-tetrahYdroxy, 4,5-secopregnane-
5,20-dione, 16,17-acetonide
A) 9-Fluoro-11~,16a~17-trihydroxY-21-[(tetrahyd~Eyran-2-
yl)oxy]pregn-4-ene-3,20-dione, 16,17-acetonide
A slurry of 16 g of 9-fluoro-11~,16a,17,21-tetrahydroxy-
pregn-4-ene-3,20-dione, 16,17-acetonide, 240 ml of dioxane
and 32 ml of tetrahydropyran was stirred at ambient tempera-
ture with 500 mg of p-toluenesulfonic acid for 2 hours. Excess
5% sodium bicarbonate solution was added and the mixture di-
luted with water and extracted with dichloromethane to give
a crude oil. This was dissolved in dichloromethane and chro-
matographed on a 100 g-silica gel column. Elution with the
same solvent gave 17.8 g of the title compound. Crystalliza-
tion of another small sample from acetone-hexane gave material
with m.p. 218-220.
B) 4~,5-Epoxy-9-flu ~ hydroxy-2l-[(tetrahydr
pyran-2-yl~oxy ]pregnane-3,20-dione, 16-17-acetonide
A solution of 18.32 g of 9-fluoro-11~,16a,17-trihydroxy-21-
~(tetrahydropyran-2-yl)oxy]pregn-4-ene-3,20-dione, 16,17-ace-
tonide in 1.8Q of methanol was stirred with 50 ml of 30% hydro-
gen peroxide and 40 ml of 4 N sodium hydroxide solution for 4
days. The solution was diluted with water and filtered to give
11.8 g of solid; extraction of the filtrate with chloroform gave
3.0 g of similar material. These were combined, dissolved in
1:1 hexanedichloromethane, and chromatographecl on a 100 g-silica
gel column. Elution with the same solvent gave 7.0 g of the
title compound.
- 24 -
K535a
~047S07
C) 4~.5-ly~L-9-fluoro~ 16a!17~21-tetrahydroxy~regnane
3,20-dione,16,17-acetonide
A solution of 7.0 g of 4~,5-epoxy-9-fluoro~ ,16a,17-
trihydroxy-21-~(tetrahydropyran-2-yl)oxy]pregnane-~20-dione~16~17
acetonide in 500 ml of 1:1 acetic acid-water was stirred
for 5 hours, diluted with water and extracted with chloroform.
The chloroform solution wa~ washed withaqueous sodium bicarbonate,
dried, and evaporated to give 5.9 g of the title compound.
D) 9-Fluoro-11~,16a,17,21-tetrahydroxy-4.5-secopregn-3-yn-
5,20-dione, 16,17-acetonide
. .
A solution of 5.9 g of 4~,5-epoxy-9-fluoro-11~,16a,17,21-
tetrahydroxy-pregnane-3,20-dionel6,17-acetonide in 300 ml of
1:1 acetic acid-dichloromethane was stirred at 0 as a solution
of 2.5 g of p-toluenesulfonyl hydrazine in 300 ml of the same
solvent was added dropwise. The resulting solution was stirred
overnight at ambient temperature, diluted with dichloromethane
and washed with water, aqueous sodium bicarbonate, and dried.
The crude product was chromatographed on a 60 g-silica gel column.
Elution with dichloromethane gave 3.86 g of the title compound.
E) 9-Fluoro-11~,16a,17~21-tetrahydroxy-4~5-secopregnane-5~2
dione, 16,17-acetonide
A solution of 3.86 g of 9-fluoro-ll~8~l6a~l7~2l-tetrahydr
4.5-seco~pregnane-5,20-dione,16,17-acetonide in 500 ml of ethyl
acetate was stirred in an atmosphere of hydrogen with 500 mg
of 5~ Pd/C for 315 minutes (590 ml of hydrogen were used). The
catalyst was filtered and the filtrate evaporated in vacuo.
Crystallization from methanol gave 2.0 g, m.p. 205-207.
Anal- Calc d- for C24H37F6 C~ 65-43; H~ 8-47; F~ 4.31
Found: C, 65.19; H, 8.35; F, 4.03
-25-
R535a
1047S07
Example 22
.
21-Chloro-9-fluoro~ ,16a,17-trihydroxy-4,5-secopregn-
3-ene-5,20-dione,16,17-acetonide
A solution of 3.0 g of 21-chloro-9-fluoro-11~,16a,17-
trihydroxy-4,5-secopregn-3-yn-5,20-dione, 16,17-acetonide
(prepared as described in Example 1) in 250 ml of ethyl
acetate containing 60 mg of synthetic quinoline and 30:mg
of 5~ Pd/BaSO4 catalyst is stirred at room temperature under
1.0 atmosphere of hydrogen for 15 hours.
The catalyst is removed by filtration, the filt~ate
i~ evaporated and the residue (3.0 g) is dissolved in chloro-
form-hexane (1:1) and absorbed on a column of silica gel
(60 g). Elution of the column with chloroform-hexane (1:1)
gives a mixture of starting materiaI and the title compound.
Further elution with chloroform-hexane and then chloroform
yields a solid (1.8 g). This is crystallized once from ethyl
acetate-hexane to yield the title compound, melting point
229-230C.
Anal. Calc'd for C24H34ClFO5:
C, 63.01; H, 7.50; Cl, 7.75; F, 4.16.
Found: C, 62.92; H, 7.40; Cl, 7.81s F, 4.39
Examples 23-27
Following the procedure of Example 22, but substituting
the compound listed in column I (prepared as described in
Examples 4-8 respectively) for 21-chloro-9-fluoro-11~,16~,17-
trihydroxy-4,5-seccpregn-3-yn-5,20-dione, 16,17_acetonide,
the compound listed in column II is obtained.
-26-
K535a
1047S0`7
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r~ ~ o ~1 ~I Q) .C O
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H t~ U 8 ~ o o ~ ~
o ~ ~ ~ o o U
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O ~ ~ X `O I ~:~ X a~
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w
--27--
~047S0`7
Example 28
21-Chloro-llp~16~17-trihydroxy-4~5- ecopregnane-
3,20-dione, 16,17-acetonide
.
A) 21--Chloro-4,5-epoxy-11~,16,17-trihy-droxy-pregnane,
3,20-dione,16,17-acetonide
A solution of 10 g of 21-chloro-11~,16,17-trihydroxypregn-
4-ene-3,20-dione, 16,17-acetonide in 1 liter of methanol was
stirred with 31 2 ml of 30% hydrogen peroxide and 20.6 ml of
4 N sodium hydroxide at 0 for 1 hour, at room temperature for
3 hours, and the resulting mixture poured into 3 liters of ice
water. The resulting solid was filtered, dissolved in chloro-
form and the solution washed with 5% hydrochloric acid and 5%
sodium bicarbonate solution, dried, and evaporated in vacuo.
The residue was dissolved in dichloromethane and chromatographed
on a 100 g-silica gel column. Elution with dichloromethane
gave 7.7 g of a mixture of thea and~-epoxides.
B) 21-Chloro-11~16a,17-trihydroxy-4,5-seco-pregn-3-yn-5,20-
dione, 16,17-acetonide
A solution of 2.55 g Of P~toluenesulfonvl hydrazine in 250 ml
of 1:1 dichloromethaneacetic acid was added drcpwise at oC to
a SG~ utior of 7.7 g (0.017 mole) of the above epoxide mixture in
250 ml of the same sclvent. After 1 hour at 0C the mixture was
stirred for 3 hours at room temperature, diluted with lQ of 5%
sodium bicarbonate solution, and dried, The residue obtained on
solvent removal was chromatographed on a 50 g-silica gel column.
Elution with chloroform gave 5.7 g of material in fractions 3-6
which crystallized from methanol-chloroform to give 5.1 g of the
title compound.
-28-
K535a
104750 7
C) 21-Chloro-ll~B-160l,17-trihydro~y-4r5-secopregnane
5,20-dione, 16,17-acetonide
.
A solution of 5.1 g (0.0117 mole) of the above acetylene
in 510 ml of ethyl acetate was stirred with 510 mg of 5~
of Pd/C under an atmosphere of hydrogen. After 30 minutes,
hydrogen uptake t590 ml, 0.026 mole) ceased. After
2.5 hours the catalyst was filtered and the solvent evaporated
in vacuo. The residue was recrystallized from acetone-hexane
to give 4.91 g, m.p. 153-155.
Anal. Calc'd. for C24H37C105: C, 65.50; H, 8.48; Cl, 8.06
Found: C, 65.51; H, 8.59; Cl, 8.26
-29-
