CA1047507A - 4,5-seco steroids - Google Patents

Abstract

Abstract This invention describes novel 4,5-seco-steroids having the formula wherein A is -C=CH, -CH=CH2, -CH2CH3, or -?CH3; X1 is hydrogen, chlorine, bromine, or fluorine; R1 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 and a process for preparing these compounds which are useful as anti-inflammatory agents.

Description

~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 C=O

y___ ~ O _ C Q
IV

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~

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

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.

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 ~ ~__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.

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.

~r)35a 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.

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.

~53 5a 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 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.

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` ~
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1 0 ~ I ~ O O
~ I ~ ,1 ~I q) ~ ~1 ~ ~ ~ ~ a) ~ ~ c ,l ~ ~o u~ u u~ ~:
~ ~ c JJ ~S~ I I O
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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~
~ ~ ~ ~ ~

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 K535a 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.

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
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~ ~: O I o o :~ Q.l` S O `
~a o ~ U ~ ~ ~a ~I h U ` ~

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'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~
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c~ ~ ~ a~ aJ o ` I ~q~ I O O ~ t) ~ I I
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` ~ ~~I Ll O ~ O _~ U ~--I
N 'a N 1~ ~.) ` I

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~3 ~1 ,_1 ~ ,_ x K53Sa - 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 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.

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 R535a 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.

K535a 1047S0`7 ~, ~ X o, X
` ,` ~ ~ o t. .-- o ~
O
~ ~ o X , o o s o a~ o O
O ~ oX O

, o X~ ~o, ~, ~, r~ ~ o ~1 ~I Q) .C O
~ o H ~ 1 0 1 ~ ~ ~ ~r1 01 1 ~ ~1 ` ~ I ~
_~ ~1 ~ I IO ~ O~D a)~ a~ o O _I I 1` 0 C~ I ~ O ~1~~ ~ O I O a) O R~ O
1 ~ o ~a ` ` ~ o u o I ~ s~ o ~
_ V ~ O O ~a O ~ IO I ~
Q~ o ~ aJI 0 ~ o .~: 0 1`

O O
O I ~
0 0 ~1 _I
'~ ` O ~ I `
X ~ U I I ` U~
S-l 0 0 ~~ I ~ ~ I
.C I ~ ,I r~ I X ~ ~ I
~ o ~ ~ ~ o o `~ a~
H t~ U 8 ~ o o ~ ~
o ~ ~ ~ o o U
.C o ~1 U O 1 o u~
"~
~ ~l ~ o l l o u~
o o u `
~ t) 0 ~ ~ ~ ,l O ~ ~ X `O I ~:~ X a~
oI o aJ ~ ~ o . o ~
I ~ ` ~~ S~ ~~1 ~J~ U S~ O
`~ ~ S~ U~ ~-rl I ~ U

x ~ ~ ~ ~ ~
w ~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.

K535a 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

Claims (50)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound having the formula I

wherein A is -C=CH, -CH=CH2, -CH2CH3, or -?CH3; X1 is hy-drogen, chlorine, bromine, or fluorine; R1 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 comprises reacting a compound of the formula III

wherein X1, R1, P, Q, Y and Y' are defined as above with p-toluenesulfonylhydrazide in a mildly acidic medium to form a compound of the formula IV

wherein X1, R1, 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, hy-drating the compound of Formula IV in an aqueous acidic medium in the presence of mercuric sulfate.

2. The process according to claim 1 for preparing a compound of Formula I wherein R1 is hydrogen, chlorine or fluorine, X1 is hydrogen or fluorine and A is -C=CH
which comprises reacting a compound of Formula III where-in R1 is hydrogen, hydroxyl, -O?-R2, chlorine, bromine, fluorine or iodine, R2 is lower alkyl, and X1 is hydrogen, chlorine, bromine or fluorine with p-toluenesulfonyl-hydrazide.

3. The process according to claim 1 for preparing a compound of Formula I wherein R1 is hydrogen, chlorine or fluorine, X1 is hydrogen or fluorine and A is -?-CH3 which comprises reacting a compound of Formula III with p-toluenesulfonylhydrazide and hydrating the resultant product in an aqueous acidic medium in the presence of mercuricsulfate.

4. The process according to claim 1 for preparing compounds of Formula I wherein R1 is hydrogen, chlorine or fluorine, X1 is hydrogen or fluorine and A is -CH=CH2 which comprises reacting a compound of Formula III with p-toluenesulfonylhydrazide and partially reducing the resultant product.

5. The process according to claim 1 for preparing a compound of Formula I wherein R1 is hydroxyl and X1 is hydrogen or fluorine which comprises reacting a com-pound of Formula III wherein R1 is hydrogen, hydroxyl, -OC-R2, chlorine, bromine, fluorine or iodine, R2 is lower alkyl and X1 is hydrogen, chlorine, bromine or fluorine with p-toluenesulfonylhydrazide.

6. The process according to claim 1 for preparing a compound of Formula I wherein R1 is -O-?-R2, R2 is lower alkyl and X1 is hydrogen or fluorine which comprises reacting a compound of Formula III wherein R1 is hydroxyl and X1 is hydrogen, chlorine, bromine or fluorine with p-toluenesulfonylhydrazide and reacting the resultant product with an anhydride of the formula (R2CO)2O.

7. The process according to claim 1 for preparing a compound of Formula I where R1 is iodine, chlorine, bro-mine or fluorine and X1 is hydrogen or fluorine which com-prises reacting a compound of Formula III wherein R1 is hydroxyl and X1 is hydrogen, chlorine, bromine or fluo-rine with p-toluenesulfonylhydrazide and reacting the resultant product with a lower alkyl or aryl sulfonyl chloride followed by reaction with an inorganic halide to form a compound of Formula I wherein R1 is iodine, chlorine, bromine, or fluorine.

8. The process according to claim 1 for preparing a compound of Formula I wherein X1 is bromine which com-prises reacting a compound of Formula I wherein X1 is hydro-gen, Y is hydrogen and Y' is hydroxyl with lower alkyl sulfonyl chloride and reacting the resultant product with an N-bromoamine of a carboxylic acid.

9. The process of claim 1 for preparing a compound of Formula I wherein X1 is chlorine, bromine, iodine or fluorine which comprises reacting a compound of the formula wherein R1, P and Q are defined as in claim 1 with a hy-drogen halide to form a compound of the formula wherein X1 is chlorine, bromine, iodine or fluorine and reacting this compound with hydrogen peroxide in the pre-sence of an alkali to form the epoxide of Formula III.

10. A process according to claim 1 wherein A is -C=CH.

11. A process according to claim 1 wherein A is -CH=CH2.

12. A process according to claim 1 wherein A is -CH2CH3.

13. A process according to claim 1 wherein A is -?CH3.

14. A process according to claim 1 wherein X1 is fluorine.

15. A process according to claim 1 wherein R1 is hydrogen.

16. A process according to claim 1, wherein R1 is hydroxyl.

17. A process according to claim 1 wherein R1 is -O?-R2 .

18. A process according to claim 1 wherein R1 is chlorine, bromine, fluorine or iodine.

19. A process according to claim 19 wherein R1 is chlorine.

20. A process according to claim 1 wherein P and Q
are both methyl.

21. A process according to claim 1 wherein Y is hydro-gen and Y' is hydroxyl.

22. A process according to claim 1 wherein together Y and Y' are = O.

23. A process according to claim 1 wherein A is -C?CH, X1 is fluorine, R1 is chlorine, P and Q are methyl, Y is hydrogen, and Y' is hydroxyl.

24. A process according to claim 1 wherein A is -?CH3, X1 is fluorine, R1 is chlorine, P and Q are both methyl, Y is hydrogen and Y' is hydroxyl.

25. A process according to claim 1 wherein A is -CH2CH3, X1 is fluorine, R1 is chlorine, P and Q are both methyl, Y is hydrogen and Y' is hydroxyl.

26. A process according to claim 1, wherein A is -CH=CH2, X1 is fluorine, R1 is chlorine, P and Q are both methyl, Y is hydrogen and Y' is hydroxyl.

27. A process according to claim 1 wherein A is -CH2CH3, X1 is fluorine, R1 is hydrogen, P and Q are both methyl, Y is hydrogen and Y' is hydroxyl.

28. A process according to claim 1 wherein A is -CH2CH3, X1 is fluorine, R1 is hydroxyl, P and Q are both methyl, Y is hydrogen and Y' is hydroxyl.

29. A process according to claim 1 wherein A is -CH2CH3, X1 is hydrogen, R1 is chlorine, P and Q are both mehtyl, Y is hydrogen and Y' is hydroxyl.

30. A compound having the formula wherein A is -C?CH, -CH=CH2, -CH2CH3, or -?CH3; X1 is hydrogen, chlorine, bromine, or fluorine; R1 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, whenever prepared by the pro-cess of claim 1.

31. A compound in accordance with claim 30 wherein A is -C?CH, whenever prepared by the process of claim 10.

32. A compound in accordance with claim 30 wherein A is -CH=CH2, whenever prepared by the process of claim 11.

33. A compound in accordance with claim 30 wherein A is -CH2CH3, whenever prepared by the process of claim 12.

34. A compound in accordance with claim 30 wherein A is -?CH3, whenever prepared by the process of claim 13.

35. A compound in accordance with claim 30 wherein X1 is fluorine, whenever prepared by the process of claim 14.

36. A compound in accordance with claim 30 wherein R1 is hydrogen, whenever prepared by the process of claim

37. A compound in accordance with claim 30 wherein R1 is hydroxyl, whenever prepared by the process of claim 16.

38. A compound in accordance with claim 30 wherein R1 is -O?-R2, whenever prepared by the process of claim 17.

39. A compound in accordance with claim 30 wherein R1 is chlorine, bromine, fluorine or iodine, whenever prepared by the process of claim 18.

40. A compound in accordance with claim 30 wherein R1 is chlorine, whenever prepared by the process of claim 19.

41. A compound in accordance with claim 30 wherein P and Q are both methyl, whenever prepared by the process of claim 20.

42. A compound in accordance with claim 30 wherein Y is hydrogen and Y' is hydroxyl, whenever prepared by the process of claim 21.

43. A compound in accordance with claim 30 wherein together Y and Y' are =O, whenever prepared by the process of claim 22.

44. The compound in accordance with claim 30 having the name 21-chloro-9-fluoro-11.beta.,16.alpha.,17-trihydroxy-4,5-secopregn-3-yn-5,20-dione, 16,17-acetonide, whenever prepared by the process of claim 23.

45. The compound in accordance with claim 30 having the name 21-chloro-9-fluoro-11.beta.,16.alpha.,17-trihydroxy-4,5-secopregnane-3,5,20-trione, 16,17-acetonide, whenever prepared by the process of claim 24.

46. The compound in accordance with claim 30 having the name 21-chloro-9-fluoro-11.beta.,16.alpha.,17-trihydroxy-4,5-secopregnane-5,20-dione, 16,17-acetonide, whenever pre-pared by the process of claim 25.

47. The compound in accordance with claim 30 having the name 21-chloro-9-fluoro-11.beta.,16.alpha.,17-trihydroxy-4,5-secopregn-3-ene-5,20-dione, 16,17-acetonide, whenever prepared by the process of claim 26.

48. The compound in accordance with claim 30 having the name 9-fluoro-11.beta.,16.alpha.,17-trihydroxy-4,5-secopregnane-5,20-dione, 16,17-acetonide, whenever prepared by the pro-cess of claim 27.

49. The compound in accordance with claim 30 having the name 9-fluoro-11.beta.,16.alpha.,17,21-tetrahydroxy-4,5-secopreg-nane-5,20-dione, 16,17-acetonide, whenever prepared by the process of claim 28.

50. The compound in accordance with claim 30 having the name 21-chloro-11.beta.,16.alpha.,17-trihydroxy-4,5-secopregnane-5,20-dione, 16,17-acetonide, whenever prepared by the pro-cess of claim 29.