US 3803133 A
Description (OCR text may contain errors)
United States Patent 3,803,133 ZI-SULFINYL STEROIDS B. Richard Vogt, North Brunswick, N.J., assignor to E. R. Squibb 8: Sons, Inc., Princeton, NJ. No Drawing. Filed Dec. 15, 1972, Ser. No. 315,701 Int. Cl. C07c 173/00 US. Cl. 260-23955 D 7 Claims ABSTRACT OF THE DISCLOSURE Novel 2l-sulfinyl steroids, having utility as anti-inflammatory agents, are disclosed.
SUMMARY OF THE INVENTION Novel 21-sulfinyl steroids having the following formula:
Alternatively, R and K, may together form a cyclized dioxolo group, i.e.
or a cyclized oxazole group, i.e.
N=CR| 3,803,133 Patented Apr. 9, 1974 (III) Throughout the specification, the symbol R represents lower alkyl, cycloalkyl, aryl, and aralkyl.
DETAILED DESCRIPTION OF THE INVENTION The compounds of Formula I are physiologically active substances which possess glucocorticoid and anti-inflammatory activity and hence can be used in lieu of known gucocorticoids 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 compounds of this invention can be used topically in leu of known glucocorticoids in the treatment of skin conditions such as dermatitis, sunburn, neurodermatitis, eczema, and anogenital pruritus.
When given orally, the compounds of this invention may be used in a dosage range of 0.1 to 200 milligrams,
preferably 0.3 to milligrams. If administered topically,
3 the compounds of this invention may be used in the range of .01 to 5.0% by weight, preferably .05 to 2.0% by weight, in a conventional cream or lotion.
The expression lower alkyl referes to those alkyl groups having from 1 to 6 carbon atoms, and includes both straight and branched chains, e.g., methyl, ethyl, propyl, isopropyl, t-butyl, etc.
The expression cycloalky refers to monovalent saturated hydrocarbon rings containing from 3 to 7 carbon atoms, e.g., cyclopropyl, cyclobutyl, etc.
The expression aryl refers to monocyclic carbocyclic aromatic groups that may either be unsubstituted or substituted with halogen, lower alkoxy (i.e. R wherein R is lower alkyl as defined above) or lower alkyl groups (as defined above) e.g. phenyl, ethoxyphenyl, propylphenyl, chlorophenyl, tolyl, etc.
The expression aralkyl refers to lower alkyl groups (as defined above) substituted with an aryl group (as defined above) e.g. benzyl, phenethyl, etc.
The term halogen refers to F, Cl, Br and I (Cl and Br are preferred).
The novel 21-sulfinyl steroids of Formula I are steroids of the A -pregnene series (including the pregnadiene, pregnatriene, and pregnatetraene series).
The starting materials for making the compounds of this invention are:
(VII) Steroids of this type are known (see, for example, US. Pat. No. 3,048,581 to Fried et al. and British Pat. No. 869,511).
The steroids of Formula I can be prepared by several different methods. One method of synthesis involves the selective oxidation of a ZI-substituted thio steroid with an appropriate selective oxidizing agent:
The oxidizing agent may be any compound capable of preferentially oxidizing a divalent sulfur atom of the type present in Formula II to the corresponding sulfoxide oxidation state in the presence of hydroxy groups, keto groups and/or carbon-carbon double bonds. Iodosobenzene diacetate, N-bromoand N-chloro-succinimide, iodobenzene dichloride and sodium metaperiodate are exemplary of suitable oxidizing agents. Sodium metaperiodate is preferred.
The oxidation reaction is carried out in a solvent which is essentially or completely inert to the reactants and provides some degree of solution for both the starting steroid and oxidizing agent. When sodium metaperiodate is used as the oxidizing agent, low molecular weight alcohols (e.g. methanol) are preferable solvents. Reaction of the 2l-substituted thio steroid with the oxidizing agent may be carried out at temperatures ranging from about 50 C. to about C. preferably within a temperature range of -15 C. to +40 C. for a period of time ranging from about 12 hours to 7 days, preferably from 1 to 4 days. Isolation of the 2l-sulfinyl steroid may be accomplished by pouring the reaction mixture into water (if a water miscible solvent is used), filtering oil the desired product and drying.
Preparation of the novel 21-substituted thio steroids of Formula II may be accomplished by reacting alkali metal salts of mercaptans (MSR wherein M is an alkali metal, preferably sodium or potassium) with steroids of Formula V:
An alternative method for preparing the ZI-substituted thio steroids of Formula II is to react an alkali metal salt of a mercaptan (MSR with steroids of Formula W:
Instead of iodine in the C-21 position, other halogens may be used; however, iodine is preferred.
The conversion of the steroids of either Formula V or Formula VI to the Zl-Substituted thio steroids of Formula II is carried out in a suitable nonreactive, polar solvent such as methanol, acetonitrile or dimethylformamide. The reaction takes from 12 hours to 7 days, preferably from 1 to 3 days at from 0 C. to C., preferably from 30 C. to 60 C. The starting steroid is reacted. with from 1 to 6, preferably 1 to 3 molar equivalents of the alkali metal salt derivative of the appropriate mercaptan (i.e., HSR Upon completion, the reaction is neutralized (if necessary), poured into water, and the ZI-substituted thio steroid of Formula II is. filmed otf and dried.
Another alternative for preparing -21 alkylthio steroids of Formula H involves the selective alkylation of the corresponding C-21 mercapto steroid of Formula III.
Base 0 alkylatlng agent The alkylating agent may be represented by the formula R X wherein X may be or a halogen. The 0-21 mercapto steroid of Formula III is reacted with a slight excess of a base such as sodium hydride in a non-reactive polar solvent such as 1,2- dimethoxyethane for about 15 minutes to 24 hours, preferably for 1 to 3 hours at from 0 C. to 5-1-80 0., preferably from +30 C. to +50 C. The reaction is then treated with a slight excess of the appropriate alkylating agent (R X for about 30 minutes to 48 hours, preferably 3 to 24 hours at from +50 C. to +100 0., preferably from +25 C. to +80 C. Evaporation of the solvent gives the 21-substituted thio steroid of Formula II.
The 0-21 sulfonates of Formula V can be prepared by reacting the corresponding 0-21 hydroxy steroid of Formula VII with about 1 molar equivalent of a sulfonyl halide, i.e.
O Rr Y where Y is chlorine or bromine.
The reaction is carried out in an inert anhydrous solvent containing an appropriate hydrogen acceptor (e.g. a' tertiary amine such as triethylamine or a basic heterocyclic amine such as pyridine).
An explained above, reaction of the 0-21 hydroxy steroid of Formula VII with the sulfonyl halide may be run in an inert anhydrous solvent. Alternatively, the reaction can be run in a liquid tertiary amine or basic heterocyclic amine hydrogen acceptor. The reaction time can be from a few hours to several days, preferably from 12 to 24 hours, while the reaction temperature can be from C. to +40 0., preferably between 50 C. and 10 0. Upon completion the reaction is poured into could water and the steroid of Formula V is filtered off and dried.
} The 0-21 iodo steroids of Formula VI can be obtained using well known procedures (see I Am. Chem. Soc., 80, 250 (1958) and 81, 439 (1959); J. Org. Chem., 25, 1966 (1960) One general procedure for the preparation of a 0-21 iodo steroid of Formula VI involves starting with an appropriate steroid of the following formula (i.e. a steroid unsubstituted in the 0-21 position);
(VIII) The steroid of Formula VIII is reacted with a mixture of calcium oxide, iodine, and a free radical initiator, preferably a,a-azabisisobutyronitrile, in a suitable solvent system such as tetrahydrofurammethanol.
Is, 0110 free radical After a period of time of from about 30 minutes to 24 hours, preferably from 1 to 4 hours at from 30 C. to +50 C., preferably +10 C. to +30 C., the reaction is diluted with a suitable organic solvent, such as methylene chloride, washed with an aqueous solution of a compound capable of removing excess iodine, such as sodium thiosulfate, and the organic solvent evaporated to 'give the C-21 iodo steroid of Formula VI.
Another procedure for the preparation of C-21 iodo steroid of Formula VI involves reacting a -21 sulfonate steriod of Formula V with an alkali metal iodide salt, preferably sodium or potassium, in a polar, non-reactive solvent such as acetone or a lower molecular weight alcohol.
The reaction time is from about 1 hour to 5 days, preferably 6 hours to 2 days at from -10 C. to +80 C., preferably from +20 C. to +50 C. Upon completion, the reaction is treated with a low molecular weight carboXylic acid (e.g. acetic acid) equivalent to the amount of base used, and poured into water. The product is filtered off and dried.
An alternative method for the preparation of the 21- mercapto steroids of Formula III involves the reaction of a C-21 substituted steroid of Formula V or Formula VI (or Formula VI with a halogen other than iodine in the C-21 position) with an alkali metal (preferably sodium or potassium) salt of hydrogen sulfide (i.e. MSH) in a polar solvent such as dimethyl formamide or a lower molecular weight alcohol such as ethanol.
alkali metal iodide 25 ---b salt The reaction time may be from about 30 minutes to 48 hours, preferably from 1 to 24 hours at from 20 C. to +100 C. preferably from +10 C. to 80 C. The solvent is then evaporated, the residue stirred with water and the 0-21 iodo steroid is filtered off and dried.
Several methods are available for the preparation of ZI-mercapto steroids of Formula III. One method involves the reaction of a C-21 acylthio steroid of Formula IV with about 1 to 5, preferably 1.1 to 3, molecular equivalents of an alkali metal (preferably sodium or potassium) salt of a lower molecular weight alcohol (e.g. sodium methoxide) or an alkali metal carbonate (e.g. potassium carbonate) in a wet, non-reactive polar solvent such as the corresponding alcohol (e.g. methanol) or dimethyl sulfoxide.
In the second equation, other halogens may be substituted for iodine in the steroid of Formula VI. The reaction time is from about 15 minutes to 4 days, preferably 30 minutes to 2 days, at from +25 C. to +200 C., preferably from C. to +150 C. Upon completion, the reaction is concentrated to a small volume, cooled, neutralized with one equivalent of a strong acid (e.g. hydrochloric acid), poured into five volumes of water, and the C-21 mercapto steroid of Formula III is filtered off and dried.
The 21-acylthio steroids of Formula IV can be prepared by reacting a steroid of Formula V or Formula VI (or Formula VI with a halogen other than iodine in the C-21 position) with about 1 to 5, preefrably l to 3, molecular equivalents of an alkali metal (preferably potassium) salt of a thio carboxylic acid of formula (III) in a non-reactive polar solvent such as acetone or dimethylformamide.
In the second equation, other halogens may be substituted for iodine in the steroid of Formula VI. The reaction time is from about 1 hour to 4 days, preferably from 3 hours to 2 days, at from C. to +100 C., preferably from C. to +70 C. The solvent is evaporated, the residue stirred with water, and the product filtered off and dried.
10 The diagram below is a summary of the above described processes for producing the novel compounds of this invention. In the diagram, the symbol K represents:
In the following examples all reactions are run under an inert atmosphere (e.g. argon), at room temperature, using anhydrous solvents unless otherwise indicated; in addition, reactions which are heated are subsequently cooled to room temperature for work-up. Steroids named as 9-halo refer to the 9a-halo.
EXAMPLE 1 9-fluoro 115,16d,17,21 tetrahydroxypregna-l,4-diene-3, 20-dione, 21-p-toluenesulfonate, cyclic 16,17-acetal with acetone To 2.9 g. of 9-fiuoro-115,16a,17,2l-tetrahydroxypregna- 1,4diene-3,20dione, cyclic 16,17-acetal with acetone dissolved in 30 ml. of dry pyridine at 56 C. is added a 0 C. solution of 1.8 g. of p-toluenesulfonyl chloride in 18 ml. dry methylene chloride. The reaction is stirred at 30 C. for 2 hours and then at -5 C. for 96 hours. The reaction is poured into chloroform and washed consecutively with water, dilute hydrochloric acid, dilute aqueous sodium carbonate and water. The chloroform solution is dried with sodium sulfate and the solvent 5 evaporated to give the crude title compound. After stirring with water, the product is filtered off, dried and re crystallized from a mixture of acetone-hexane, M.P. is
EXAMPLES 21 8 Following the procedure of Example 1 but substituting the steroids in Column I below for 9-fluoro-1 l B,16a,17,21- tetrahydroxypregna-1,4-diene 3,20 dione, cyclic 16,17- acetal with acetone in Example -1, the corresponding 5 steroid tosylates indicated in Column II are obtained:
8 9-iiuoro-11fl,17,21-trihydroxy- 16a,-methylpregna-l,4- diene3,20-dione.
17,21-trihydroxypregna- 1,4-dlene-3,20-dione, cyclic 16,17acetal with acetone.
13... 11fl,16a,17,21-tetrahydroxypregna-1,4'diene-3,20 dione, cyclic 16,17-amta1 with acetone.
14".-- 115,17 21-trlhydi'oXy-16 met ylenepregna-1,4-dlene- 3,20-dione.
16..... 9-fluoro-l1fl,17,21-trihydr0xy- 16-methylenepregna-1,4- diene-3,20-dione.
ione. 18"... 9-fluoro-1lfl,l6a,17,21-tetrahydroxypregna-L-tdiene- 3, 20-dione, Iii-acetate.
16a,-methylpregna-1,4-diene 3,20-dione, 21-p-toluenesulionate. 6a,9 iifluoro-11fl,l7a,21-trihydmxy-16a,-methylpregna- 1,4-diene-3,20dione, 2l-ptoluenesulionate. 6a,9-difluoro-11B,16a,l7,2i-
tetrahydroxypregna-M diene-3,20-dione, 21-ptoluenesulionate, cyclic 16,17- aeetal with acetone. 6a-fluoro-11B,2l-dihydroxy-16e:-
methyipregna-1,4 dime-3,20- dione, 21-ptoluenesulionate. 9,l1fi-dicl1loro-6B-fluoro-l6a,l7,21-
trlhydroxypregna-Li-diene- 3,20-dione, 2l-p-toluene sulfonate, cyclic 16,17-acetal with acetone. 11B,16a,i7,21-tetrahydroxypregna-IA'dieneSJO-dione, 2bp-toluenm1lfonate, cyclic 16, i7-acetal with acetone. 1lfl,17,21-trihydroXy-16- methylene-pregna-htdlene' 3,20-dione, 21-p-tcluene- EXAMPLES 19 AND 20 fonyl chloride in Example 1, sulfonates indicated in Column II are obtained.
the corresponding steroid Column I Methanesulionyl bromide dr0Xypregna-1,4-diene-3,20-
gyclic 16,17-acetal with aceone.
EXAMPLE 21 9-fluoro-1 1B,16a,17-trihydroxy-21- (methylthio) -pregna-l, 4-diene-3,20-dione, cyclic 16,17-acetal with acetone 5.0 g. of 9-fluoro-115,160,17,21-tetrahydroxy-pregna- 1,4-diene-3,20-dione, 21-p-t0luenesulfonate, cyclic 16,17- acetal with acetone and 2.1 g. of sodium methyl mercaptide in ml. of dry methanol are refluxed under argon at room temperature for 60 hours. The reaction is acidified with 3.0 ml. of glacial acetic acid, diluted with 75 ml. water and the aqueous solution concentrated to a minimal volume. The crude product precipitated out, is filtered off, washed with water and dried. After recrystallization from an acetone-petroleum ether mixture, the product has EXAMPLES 22-38 Ex. Column I Column II 22---. 9-fluoro11fl, 17, 21- 9-fluoro-118. 16o: 17-trihydroxytetrahydroxy-pregnaA-ene- 21 (methylthio3 pregnai-ene- 3,20-dione-2l-p-toluenesulionate, cyclic 16, 17-acetal with acetone.
23..... 9-fluoro11fi, 16a, 17, 21-
tetrah droxypregna-1,4- diene ,ZtHiione, 21-ptoluenesultonate, cyclic 16,17-acetal with acetophenone (B-methyl).
24.--- 9-fluoro-11p,16,l7,21-tetrahydroxypregno-Ltdlenc- 3,20-dione, 21-p-toluenesulinnate, cyclic 16,17-acetal with acetaidehyde (tr methyl).
25- 9fluoro-1lfl,16a,17,2I-tetrahydroxypregna-1,4-diene 3,20dione, 2l-p-toluenesultonate, c 0110 16,17'ocetal with eye ohexanone.
l7,2l-trihydroxypregna-l,4- dieneSJO-dione, 21-p toiuenesuifonate, cyclic 16,17-acetal with acetone.
33- 11fl,16a,17,21-tetrahydroxypregna-1,4diene-3,20-dione, 2l-p-toluenesuli'onate, cyclic 16,17-acetal with acetone.
34.--- 1lB,17,2l-trihydroxy-16- methylenepregna-l,4-diene- 3,20-dione, 2l-p-to1uenesulionate.
3,20diene, cyclic 16,l7-acetal with acetone.
9-fluoro-11B, 16a. 17-trlhydroxy- 21 (methylthios pregna-l,4- diene i,20-dione, c clic 16,17- acetal with acetop enone (B-methyl).
9-fluoro11fl,16a,17-trihydroxy- 21(methylthio)pregna-l,4- dicne-3,20-dione, cyclic 16,17- acetal with cyclohexanone.
11B,17dihydroxy-6,16-dimethyi- 21(methylthio)-l,4,6,l5- pregnatetraene-3,20-dione.
9,iifl-dichloro-GBJiuoro-IMJI- dihydroxy-21-(methylthio)- pregna-l,4diene3,20-dione, cyclic 16.17-acetal with acetone.
11fl,16cr,17-ti'ihydr0!y-21- (methylthio)-pregna-l,4- diene-Zi,20-dione, cyclic 16,17- acetal with acetone.
11B,l7-dihydroxy-l6-methylene- ZI-(methylthio) pregna-l ,4- diene-3,20-dione.
EXAMPLES 39-45 Followingthe procedures of Example 21, but substituting the mercaptides in Column I below for sodium methyl mercaptide in Example 21, the corresponding 21-substituted thio steroids indicated in Column H are obtained.
42-... Sodium thiophenolate 1,4-d1ene'3,20-dione,cyclic 16, l7-acetal with acetone. 44.... Potassium-p-methoxy- Qa-fluoro-llfi, l6a.17-trihydroxythlphenolate. 21-(p-methoxypl1enylthio) pregna-1,4-diene3,2 -dione,
cyclic 16,17-eoetal with acetone 9a-fluoro-11 ,lfia, 17-trlhydroxy- 2l-(p-met ylphenylthio) pregna-1,4 ilene-3,20-d.ione, cyclic 16,17-acetal with acetone.
45 Sodium p-methylthlophenolate.
EXAMPLES 46 AND 47 9fluoro- 1 15,1601, l7-trihydroxy-21- (methylthio) -pregnal,4-diene-3,20-dione, cyclic 16,17-acetal with acetone Following the procedure of Example 21 but substituting the 2l-sulfonyl steroids in Column I below for 9-fluoro- 11 B,16a,17 ,21-tetrahydroxypregna 1,4 diene-3,20-dione, 2l-p-toluenesulfonate, cyclic 16,17-acetal with acetone in Example 21, gives the title compound.
Example: Column ii 46 9-fluoro 11,6,l6a,17,21 tetrahydroxypregna 1,4 diene- 3,20-dione, 21 methanesulfonate, cyclic 16,17 acetal with acetone. 47 9 fluoro llfl,l6a,l7,2l-tetrahydroxypregna 1,4 diene 3,20 dione, 21-cyclopentylsulfonate, cyclic 16,17-acetal with acetone.
EXAMPLE 48 9-fluoro- 1 15,16, 17-trihydroxy-21-(methylthio) -pregnal,4diene-3,20-dione, cyclic 16,17-acetal with acetone Following the procedure of Example 21 but substituting 9-fiuoro-1lfl,l6a,l7-trihydroxy 21 iodopregna-l,4- diene-3,20-dione, cyclic 16,17-acetal with acetone for 9- fluoro-l1B,l6a,17,21-tetrahydroxypregna 1,4-diene-3,20- dione, 21-p-toluenesulfonate, cyclic 16,17-acetal with acetone in Example 21 gives 9-fluoro-llB,l6a,17-trihydroxy- 21- (methylthio)pregna-l,4-diene-3,20-dione, cyclic 16,17- acetal with acetone.
EXAMPLE 49 9 fluoro 11B,16a,17 trihydroxy-Zl-(methylsulfinyl)- pregna 1,4 diene 3,20 dione, cyclic 16,17-acetal with acetone Method A: 2.0 g. of 9-fluoro-1lp,16a,17-trihydroxy- 2l-(methylthio)pregna-1,4-diene-3,20-dione, cyclic 16,17- acetal with acetone and 0.92 g. of sodium metaperiodate in 400 ml. of methanol is stirred at 5 C. for five days. An additional 0.92 g. of sodium metaperiodate is added at the end of the first and fourth day. The solvent is then evaporated. The crude product is dissolved in 400 ml. chloroform, washed with water, dried and chromatographed on a 20 g. Florisil column. 300 ml. of chloroform eluant is discarded. The column is then eluted with 500 ml. ethyl acetate followed by 400 ml. acetone. These fractions are combined and the solvents evaporated to give the product. After recrystallization from methylene chloride-petroleum ether, the product has a M.P.'=234- 236 C.
Method B: To 4.64 g. of 9-fiuoro-llt9,l6a,l7-trihydroxy-2l-(methylthio) pregna 1,4 diene-3,20-dione, cyclic 16,17-acetal with acetone in 800 ml. of methanol at 5 (ice water-salt bath cooling) is added, portionwise, 1.33 g. of N-chlorosuccinimide at such a rate that the inernal temperature of the reaction does not exceed 10 C. After stirring at 5 for two days, the solvent is evaporated. The residue is dissolved in chloroform and washed successively with cooled, dilute aqueous sodium hydroxide and then water.
The Organic phase is then dried, filtered and the solvent evaporated to give the title compound.
Method C: 4.64 g. of 9-fluoro-1 lB,16a,17-trihydroxy- 21-(methylthio)-pregna-1,4-diene-3,20-dione, cyclic 16,17- acetal with acetone and 3.22 g. of iodosobenzene diacetate in ml. glacial acetic acid are refluxed for 4 hours. After standing for 16 hours at room temperature, the re action is filtered, heated to near its boiling point and diluted with 450 ml. hot water. After standing at room temperature overnight, the reaction is concentrated to ca. 200 ml., cooled to room temperature and the title compound filtered oif.
Method D: To 4.64 g. of 9fluoro-11p,16a,17-trihydroxy-21-(methylthio) pregna 1,4 diene-3,20-dione, cyclic 16,17-acetal with acetone in 200 ml. of 10% (V/ V) aqueous pyridine at 20 C., is added, dropwise, with stirring, 2.75 g. of iodobenzene dichloride in anhydrous pyridine. Direct sunlight is avoided. After ten hours, the reaction is diluted with chloroform and washed successively with dilute aqueous sulfuric acid and then water. After drying, the organic phase is evaporated to give the title compound.
EXAMPLES 50-66 Column II aeetal with acetone. acetal with acetone.
51-.-- B-fluoro-llfl,l6a,l7trlhydroxy- Q-fluoro-llB,16a,17-trihydroxy- 2l-(methylthlo)-pregna-1,4- 2l-(methylsulfinyl)pregna-1,4 dlene-3,20-dione, cyclic diene-3,20-dione, cyclic 16,17- 16,l7-acetal with acetophe acetal with acetophenone (13- none (Q-methyl). methyl) diene4i,20-dione, cyclic diene-3,20-dlone, cyclic 16,17- 16,17-acetalw1th acetalde acetal with acetaldehyde (w hyde (ct-methyl).
diene-3,2odlone, cyclic diene-3,2(Hiione, cyclic 16,17- llgggacggal with cycloacetal with cyclohexanone.
17 sium thioacetate in Example 74, the corresponding 21- acylthio steroids indicated in Column 11 are obtained.
Ex. Column I Column II 92.--. Sodium thlohexanoate Q-fluoro-llfl,16a,17-trihydroxy- 21-mercapt0pregna-1,-diene- 3,20-dione, 2l-hexanoate, cyclic 16,17-acetal with acetone.
9-fluoro-11B,16a,17-trihydroxy- 2Lmcrcaptopregna-1,4dicne- 3,20-dine, 2l-benzoate, cyclic 16,17-acetal with acetone.
Q-fiuarc-115,160;,17-trihydroxy- .Zl-mercaptopregna-lA-diene- 3,20-dione, 21-(p-chlorobenzoate), cyclic 16,17-acetal with acetone.
Q-fluorodlfldfia,17-trihydroxy- 21-mercapt0pregna-1,tdiene- 3,2041ione, 2l-(p-methoxybenzoate), cyclic 16,17-acetal with acetone.
9-fiuoro-11fl,16a,17-trihydroxy- 21-mercaptopregna-1,4-diene- 3,20-dione, 21-(p-methylbenzoate), cyclic 16,17-acetal with acetone.
EXAMPLE 97 EXAMPLE 98 9-fluoro- 1 15,164, 17-trihydroxy-2 I-mercaptopregna-l ,4- diene-3,20-dione, cyclic 16,17-acetal with acetone Method A: 4.0 g. of 9-fluoro-1lB,16a,17-trihydroxy-21- mercaptopregna-1,4diene-3,20-dione, 21 acetate, cyclic 16,17-acetal with acetone and 0.62 g. of sodium methoxide in 115 ml. dry methanol are stirred for four days at room temperature. After acidifying with 3.3 ml. glacial acetic acid, the product is filtered off, washed with cold water and dried. Several recrystallizations from a mixture of di methyl formamide and methanol give a product with a M.P. of 315316 C.
Method B through F: Following the procedure of Method A, but substituting the bases in Column 1 below and the sol-"vents in Column II below for sodium methoxide and for methanol, respectively, in Method A the title compound is obtained.
93.... Thiobenzoic acid, potassium salt.
94.-.. p-Chloro-thiobenzoic acid, potassium salt.
95--.. p-Methoxythiohenzolc acid, potassium salt.
Method Column 1 Column II B Sodium ethoxide Ethanol.
. Potamium ethoxide- Do Potassium i-propoxide. I Isopropanol. Potassium bicarbonate 5% aqueous methanol.
Potassium carbonate Do.
EXAMPLES 99-115 Following the procedure of Example 98 but substituting the 2l-acetylthio steroids in Column 1 below for 9u-fluoro-11fi,16a,17-trihydroxy 21 mercaptopregna- 1,4-diene-3,20-dione, ZI-acetate, cyclic 16,17-acetal with acetone in Example 98, the corresponding 21-mercapt0 steroids indicated in Column 11 are obtained.
cyclic 16,17-acetal with acewith acetophenone (Li-methyl). tophenone i-methyl) 2l-mercapto pregna-1,4- 21-mercapto pregna-1,4-diene diene-3, 20'di0ne, ZI-acetate, 3,20dione, cyclic 16 17-aeetal cyclic 16,17-acetal with with acetaldehyde (at-methyl). eceta1dehyde(a-methyl).
TABLE- Continued Ex. Column I Column II 102. Q-fluoro-l1fi,16a,17-trihydroxy- 9-fluoro-11B,16a,17-trlhydroxy- ZI-mercapto pregna-1,4- 21-mercapto pregna-1,4diene diene-3,20dione,2l-acetate, 3,20dione,cyclic 16,17-acetal cyclic 16,17-acetal with cywith cyclohexanone. clohexanone.
103... 116,17-dihydroxy-21-mercapto- 1119,17-dihydroxy-21-mercapto- 6,16-dimethyl-1,4,6,15- 6,16-dimethyl-1 1,6,15-pregnapregnatetraene-iiflo dione, tetraene-3,20-d10ne. 21-acetate.
104....9-iluoro- B,17-dihydroxy-21- 9-fluoro-1lB-17-dlhydroxy-21- mercapto-ltifl-methyl mercapto-lGfi-methyl pregnapregna-1,4-d.iene-3,20-dione, 1,4-diene3,20-dlone. 21-acetatc.
9-fiuoro-11l3,17-dihydroxy-21- 9-fiuoro-1lBJ7-dihydroxy-2lmercapto-ltia-methyl mercapto-lGa-methyl pregnapregua-LkdienetflO-dione, 1,4-diene-3,20-d1one. 21-acetate.
106- 6a,94iifluoro-11fl,17a 6a,9-difluoro-1lBJ7a-dihydroxyhydroxy-21-mercapto-l6w 21-mercapto-16a-methy1 methyl pregua-lA'diene-Ii, pregna-LkdienetSiO-dione. 20-d1one, 21-acetate.
107--- 6a,9-difluoro-115,16a,17-trl- 6a,9-difll10r0-11B,16a,17-tri hydroxy-21-mercapto hydroxy-21-mercapto pet-gnapregna-1,4-diene-3,20-dione, 1,441ieue-3,20'dlone, cyclic 16, 16,17-acetal with acetone. 17acetal with acetone.
108. da-fluoro-ll/S-hydroxy-Zl- 6a-fluoro-11B-hydroxy-21- mercapto-lfia-methylmercapto-ma-methylpregnapregna-1,4-diene-3,20dione, 1,4'diene-3,?x)dione. zl-acetate.
109..- 9,11 oichlaro-fiflhuoro-ma, 9,11B-dichloro6B-iluoro 16 17- 17-dihydroxy-21-mercapto dihydroxy-Zl-mercapto pregna-lA'diene-il, "one, pregna-1,4-diene-3,20-dione, 2l-acetate, cyclic 16,17- cyclic 16,17-acetal with acetal with acetone. acetone.
110--- 11B,16a,17-trihydroxy-21- 115,16a,17-trihydroxy-21-mermercapto pregua-1,4-dienecapto pregna-1,4-diene-3,20- 3,20-dione,21acetate, cyclic dione, cyclic 16,17-acetal with 16, 17-acetal with acetone. acetone.
111--- 116,17-dihydroxy-21-mer- 115,17-dihydroxy-21-mercaptw capto-lG-methylene pregnalit-methylene pregna-1,4 lA-iigge-SflO-dione, 21- diene-3,20-dione. ace a 112... 9-fluoroF11B-hydroxy-21-mer- 9-fluoro1118-hydroxy-21-mercapcapto-16a,17- dimethyl to-16a-17-dimethy1 magma-1,4- pregna-l,diene-3,2Udione, diene-3,20-dione. 21-acetate.
113. 9-tluoro-115,17-dihydroxy-21- 9-fluoro-11B,17-dihydroxy-Zlmercapto-lo-methyleue mercapto-16-methylenepregnapregna-lA-dieneBflO-dione- 1,4-diene-3,2D-dione. 2l-acetate.
114. 9-iluoro-11B-hydroxy-21-mer- 9fluoro 11Bhydroxy-21-mercapto-2'-methyl]pregna-l,4- capto-2'methyl regna-1,4 dieno[17a,16-d oxazolet", dieno[17a,16a-dYoxaz0le-3,20- 3,20-dione,21-acetate. dione.
115-.- 9-fiuoro-11B,16a,17-trihydroxy- 9-fluoro-11B,16a,17-trihydroxy- 21-mercapto pregna-IA- zl-mereapto pregna-lA diene diene-3,20-dione, 3,20-dioue. 21-acetate.
EXAMPLES 116-120 Following the procedure of Example 98 but substituting the acylthio steroids indicated below for 9a-flouro- 11p,16a,17-trihydroxy 21 cyclic 16,17-aceta1 with acetone in 3,20-dione, ZI-acetate,
mercaptopregna-l,4-diene- Example 98 gives the title compound.
Example: Column I 116 9-fluoro 11B,16a,17 trihydroxy-21- mercaptopregna 1,4-diene 3,20-
dione 21 hexanoate,
acetal with acetone. 117 9-fluoro 11p,16u,17 trihydroxy-Zlmercaptoprcgna-1,4 diene 3,20-
acetal with acetone.
trihydroxy 21- mercaptopregna-1,4 diene 3,20- dione, 2l-(p chlorobcnzoate), cyclic 16,17-acetal with acetone.
119 9-fl1l0tO-11fl,16a,17 trihydroxy 21- mercaptopregna-1,4 diene 3,20- dione, 21-(p-methoxybenzoate), cycyic 16,17-acetal with acetone.
120 9-fluoro-11fl,16a,17 trihydroxy 21- mercaptopregna 1,4 diene 3,20- dione, ZI-(p-methylbcnzoate), cyclic 16,17-acetal with acetone.
19 EXAMPLE 121 9-fiuoro-1 15, 160:, 17 trihydroxy-Z1-(methyithio)-pregna- 1,4-diene-3,20-dione, cyclic 16,17-acetal with acetone 4.5 g. of 9-fluoro-1118,160,17-trihydroxy-21-mercapto pregna-1,4-diene-3,20-dione, cyclic 16,17-acetal with acetone and 0.25 g. of sodium hydride in 300 ml. of 1,2- dimethoxyethane is stirred for two hours at 50. To the reaction is then added, in a dropwise manner, 1.56 g. of methyl iodide in 25 ml. 1,2-dimethoxyethane. Stirring is continued at 50 C. for 2 days. The solvent is evapo rated to give the crude product which is recrystallized from an acetone-petroleum ether mixture.
EXAMPLES 122-13 8 Following the procedure of Example 121 but substituting the 21-mercapto steroids in Column I below for 9a-fluoro-11f3,16a,17-trihydroxy-2l-mercaptopregnal,4-diene-3,20-dione, cyclic 16,17-acetal with acetone in Example 121, the corresponding Zl-methylthio steroids indicated in Column II are obtained.
Column I1 Ex. Column I 3,20-dione, cyclic 16,17- 3,20-dione,cyclic 16,17'acetal acetai with acetone. with acetone.
123... 9-fluoro-l1fl,16a,17-trihydroxy- 9-fluoro-11B,l6a,l7-trihydroxy- 21-mercaptopregna-L4 2l-(methylthio)pregna-1,4 diene-3,20-dione, cyclic diene-3,20-dione, cyclic 16,17- 16,17-acetai with acetoacetal with acetophenone (B- phenone (IS-methyl).
124.... 9 fiuorol1 3,16a,l7-trlhydroxy- 21-mercaptopregna-1,4- diene-3,20-dione, cyclic 16,17-acetal with acetaldehyde (wmethyl).
125 9-iluoro-1lB,l6a,l7-trihydroxy- 2l-mercaptopregna-L4- diene-3,20-dione, cyclic 16,17-acetal with cyelohexanone.
127. 9-fiuoro-11B,17-dihydroxy-2lmercapto-ltiB-methyl pregna-1,4-diene3,20-dione.
128- 9-iluoro-1lfi,17-dihydroxy-Zlmercapto-16a-methyl pregna-1,4-diene4i,2(}dione.
129 6a,9-diiluoro-l1fi,17a-diliydroxy-2l-rnercapto-16amethyl pregna-1,4diene- 3.20-dione.
130--- 60:,9-diil11010-1lB,16a,l7-tl'iilydroxy-21-n1ercapto pregna- 1,4diene3,20dione, cyclic 16,17-acetal with acetone.
131 6a-ilnoro1lB-hydroxy-21 mercapto-lfia-methylpregnal,4diene-3,20-dione.
133 116,16a-17-trihydroxy-2l-mercapto pregna-l,4-diene-3,20- dione, cyclic 16,17-acetal with acetone.
134.-. 115,17-dihydroxy-21-mercap to-lG-methylene pregna-1,4- diene-3,204iione.
135 9-iluoro-11B-hydroxy-2l-mercepto-16a,17-dimethylpregna-1,4 diene-3,20-diore.
136 9-tluoro-11B,17-dihydroxy-21- mercaptolfi-methylenepregna-lA-diene-Bfltldione.
138 9-fiuoro-11B,16a,l7-trihydroxy- ZI-mereapto pregna-1,4. diene-3,20 iione.
methyl). 9-fiuoro-11B,16a,17-trlhydroxy- 2l-(methylthio)pregna-1,4- diene'3,20-dione, cyclic 16,17- acetal with acetaldehyde (amethyl).
9-fiuoro-115J6a 17-trihydroxy- 21-(methylthio)pregna-1,4- diene-3,2 O-dione, cyclic 16,17- acetal with cyclohexanone.
tone. 1m,16 x,17-trihydroxy-2l- (methylthio)pregna-1,4diene 3,2(Hiione, cyclic 16,17-acetal with acetone. 11B,17-dihydroxy-16-methylene- 2l-(methy1thio)pregna-l,4 diene-3,20-dione. 9-iiuoro-11B-hydroxy-16a,17- dimethyl-21-(rncthylthie) pregna-lA-diene-iizwlione. 9-fiuoro-11B,17-dihydroxy-16- methylene-Zl-(methylthio) pregna-lkdieneiiJO-dlone. Q-fiuoro-HB-hydroxy-Zl- (methylthio)-2-methylpregna-1,4'dieno[17a,16a-d]-oxazole-3,20-dione. 9-fiuoro-11B,16u,17-trihydroxy 21-(methylthio)pregna-1,4- diene-3,20 1ione.
EXAMPLE 139 9-tluoro-l 1B, 16m,l7-trihydroxy-2l-iodopregna-4-ene-3 ,20- dione, cyclic 16,17-acetal with acetone To a rapidly stirred mixture of 7.45 g. of 9-fiuoro-llfl, 16u,17-trihydr0xypregna-l,4-diene-3,20 dione, cyclic l6, l7-acetal with acetone, 9.90 g. of calcium oxide and 0.33 g. a,a'-azabisisobutyronitrile in 200 ml. tetrahydrQ l a 20 methanol (1:1), is added dropwise a solution of 6.6 g. iodine in 33 ml. tetrahydrofuran and 19 ml. methanol. The reaction is stirred for three hours, poured into methylene chloride and filtered. The filtrate is washed with 3% aqueous sodium thiosulfate, water and solvent evaporated at below 40 C. to give the title compound.
EXAMPLE 140 9-flu0ro-l 1B,l6a,17-trihydroxy-2l-iodopregna-1,4-diene-3 20-dione, cyclic 16,17-acetal with acetone To 3.21 g. of 9-fiuoro-l15,160,17,2l-tetrahydroxypregna-l,4-diene-3,20dione, 2-p-toluenesulfonate, cyclic 16,17-acetal with acetone in 35 ml. acetone is added 2.88 g. of sodium iodide in 25 ml. acetone. The reaction is refluxed for eight hours, evaporated to a volume of ca. 8 ml. and cooled. 10 ml. of 0.1 N sodium thiosulfate is added and the reaction is cooled to 0 C. The title compound is filtered oif and dried.
EXAMPLES 141-157 Following the procedure of Example 140 but substituting the steroid tosylates in Column I below for 9-fiuoro- 11,8,l6u,17,2l-tetrahydroxypregna-1,4-diene 3,20 dione, 2l-p-toluenesulfonate, cyclic 16,17-aceta1 with acetone in Example 140, the corresponding 21-iodo steroids in Column II are obtained:
Ex. Column I Column II 141.- 9-iluoro-11B, 16a, 17, 21- 9-fiuoro-11fl, 16a, 17-trihydr0xytetrahydroxy-pregnai-ene 21-iodopregna-4-ene-3 20- ionate.
6a,9-diflu0r0-11B,16a,17,21- tetrahydroxypregna-L4- dlene-3,20-dione, 21-ptoluenesulionate, cyclic 16,17-acetal with acetone.
9,11fl-dichloro-6B-fluorm 16a,17,21,trihydroxypregna- 1,4diene-3,20-dione, 21-ptoluenesulfonate cyclic 16,
17-acetal with acetone.
11B,16a,17,21-tetrahydroxypregna-1,4-diene3,20-dione 21-p-to1uenesulionate, cyclic 16,17-acetal with acetone.
3... 11B,17,21-trihydroxy-16- methylenepregna-lA-daene- 3,20'dlone, 21-p-toluenesulionate.
154 9-fluoro-1lB,21-dihydroxy- 16a,17-dimethylpregna-1,4- diene-3,20-dione, 21-ptoluenesulionate.
155 9-fluoro-113,17,21-trihydroxyl6-methylenepregna-1,4- diene43,20-dione, 21-ptoluenesulionate,
dioue, cyclic-16,17-acetal with with acetone.
21-iodopregna-1,4-diene-3, dione, cyclic 16,17-acetal with ecetophenonc i-methyl).
9-fluoro-1lB,l6a, 17-trihydroxy- 21-iodopregna-L4 dime-3,20- dlone, cyclic 16,17-acetal with acetal-dehyde (amethyl).
21-iodopregna-1,4 diene-3,20- dione, cyclic 16,17-acetal with cyclohexanone.
trihydroxy-2lodopregna-1,4- diene-3,20-dione, cyclic 16,17- acetal with acetone.
17-dihydroxy-2i'iodopregna- 1,4-diene'3,20-dione, cyclic 16,17-acetal with acetone.
11fl,16a,17-trihydroxy-21- iodopregna-1,4-d1cne-3,2D- dionc, cyclic 16,17-acetal with acetone.
EXAMPLE 158 9-fluoro-1 1B,l6a,17-trihydroxy-2-mercaptopregna-l ,4- diene-'3,20-dione, cyclic 16,17-acetal with acetone Method A: A solution containing 5.9 g. of sodium ethoxide in 100 ml. of dimethylformamide is saturated with dry hydrogen sulfide. To this solution is added 14.7 g. of 9-fluoro-l15,16u,17,2l-tetrahyrdoxypyregna-l,4-diene-3,20-dione, 21-p-toluenesulf0nate, cyclic 11,17-acetul with acetone in 50 ml. of dimethylformamide. After heating for 12 hours at 100, the reaction is concentrated to a volume of ca. 30 ml., cooled, treated with 7.25 ml. concentrated hydrochloric acid and poured into 90 ml. of water. The title compound is filtered off and dried.
Method B: Following the procedure of Method A, but substituting 9-fluoro-l1p,16a,17-trihydroxy 21 iodopregna-l,4-diene-3,20-dione, cyclic 16,17-acetal with acetone for 9-fluoro-115,160,17,ZI-tertahydroxypregna-IA diene-3,20-dione, 21-p toluenesulfonate, cyclic 16,17- acetal with acetone in Method A, gives the title compound.
What is claimed is:
1. A compound having the structure wherein R is lower alkyl of 1 to 6 carbon atoms, cyclm alkyl of 3 to 7 carbon atoms, monocarbocyclic aryl, or monocarbocyclic aralkyl; R is hydrogen, lower alkyl of 1 to 6 carbon atoms, or hydroxy; R is hydrogen, lower alkyl of 1 to 6 carbon atoms, methylene, or hydroxy; or R and R may together form a cyclized dioxolo group of the structure R; or a cyclized oxazole group of the structure N=CRo 22 3. A method of preparing a compound having the structure:
wherein R is lower alkyl of l to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, monocarbocyclic aryl, or monocarbocyclic aralkyl; R is hydrogen, lower alkyl of 1 to 6 carbon atoms, or hydroxy; R is hydrogen, lower alkyl of 1 to 6 carbon atoms, methylene, or hydroxy; or R and R may together form a cyclized dioxolo group of the structure --0 R5 or a cyclized oxazole group of the structure N=C--Rt wherein R and R are the same or difierent and are hydrogen, lower alkyl of 1 to 6 carbon atoms or monocarbocyclic aryl or R and R together form a cycloalkyl group of 3 to 7 carbon atoms and wherein R is lower alkyl of 1 t0 6 carbon atoms; X, is hydroxy or halogen; X is hydrogen or halogen; and X is hydrogen, lower alkyl of 1 to 6 carbon atoms or halogen, which comprises reacting a compound having the structure:
according to claim 4 wherein the halo 1 wherein the preg' References Cited UNITED STATES PATENTS 3,681,407 8/1972 Los 260-3974 HENRY A. FRENCH, Primary Examiner US. Cl. X.R.
Dated April 9, 1974 Inventor(s) B. Richard Vogt It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
Column Column Column 14,
line 28, the word "leu" should he: lieu formula II, lines 21 through 34 and formula II, lines 45 through 58, that portion of the formula reading:
" l Iv S--R should be: .R 3 R line 23, delete the word "could" and insert the word: cold should be:
line 55, the word "procedurde" should be:
- procedure line 40, Example 81, Column I, insert a hyphen after the word "methylpregna".
line-54, Example 69, Column II, the word "dlene" should be: diene Patent NO. I
Inventor(s) Dated April 9, 1974 B. Richard Vogt It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
Column Column Column Column Column Column Column Column Column Column Column Column Example 85, Column I, that portion reading:
should be: cyclic l6,l7-
line 63, Example 89, Column II, that portion reading: "ercapto" should be: mercapto Example 90, Column I, that portion-reading:
should be: l,4dieneline 65, "l,4dione-" Column I, after the words:
line l9,Example 107,
-- 2l-acetate, cyclic "3,20-dione" insert:
line 18, Example 107, Column II, the word reading: "pergna-" should be: pregnaline 6, "0.25 9]" should be: 0.24 g
line 59, Example ;l3 5, Column I, the word "diore" should be: dione line 53, Example 148, Column II, the word "methylprenga-" should be: methylpregna Column 1, that portion reading:
l,4diene line 60, Example 150, "l4,diene-" should be:
line 70, Example 154, Column II, delete the colon (z) and insert in its place a hyphen line 18, tetrahyrdoxypyregnashould be:
-- tetrahydroxypregna line 19, "ll,l7-acetal" should be: l6,l7acetal mg? UNITED STATES PA'l'tLLi'l' Ur'ilbb CERTIFICATE OF CORRECTION 3, 803,133- Dated April 9, 1974 Patent Flo lnvcntor( Rlchard Vogt;
It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
' '1 Column 21, Claim 1, that portion of the structure, lines 39 to 43, reading:
S AT 3 should be:
Column 21, Claim 1, line 65, the word "cabon" should be:
carbon Column 21, Claim 1, line 68, delete the comma at the end of the line.
Signed and sealed this 17th day of September 1974.
(SEAL) Attest: McCOY M. GIBSON JR. C. MARSHALL DANN Attesting Officer Commissioner of Patents