IE48369B1 - Thio etanic acid derivatives,their preparation and pharmaceutical use - Google Patents

Description

THIO ETIANIC ACID DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL USE This invention relates to novel· derivatives of thio etianic acid (i.e. androstane-17s-thiocarboxylic acid) which are active anti-inflammatory agents in mammals. The invention further relates to pharmaceutically active compositions comprising a compound of the invention, and to a process for the preparation of these novel compounds.

Certain 3-oxoandrost-4-ene-17B-carboxylic acids which are substituted at the 9 position with chlorine or fluorine and at the 11 position with keto or It hydroxy or chloro group are known. See for example U.S. 3,828,080 and 3,981,894 both to Phillipps et al.

It is also known that 3-oxoandrost-4-ene-17Bcarboxylic acids or esters thereof may be substituted at the 6a position with fluoro and optionally at the 9a position with a fluoro. See for example U.S. 3,636,010 and U.S. 4,093,721 to Phillipps.

It is also known from U.S. 3,989,686 to Phillipps - 3 et al of Glaxo that steroids of the formula wherein R1 is H or CH,; . J R is H or CH,; 3 2 R is H or, when R is H, C^_g alkoxy, C^_g alkyl, thiocyanato or halogen; R IS H or CH,; 3 R is C, λ alkyl optionally substituted by halo.or 6 7 δ 7 NR R , where R and R are the same or different C^_g alkyl or R6 and R7 together with N are morpholino, thiamorpholine or morpholino substituted with C-^_g alkyl; and the dotted line in the A ring represents an optional double bond at these positions; are useful as anesthetics·.

Methyl 36-acetoxyallothiolcholonate and methyl 36-acetoxy-etiothiochol-5-enate are also known. See, e.g., Jerger et al, Helv. Chem. Acta. 29, 684-92 (1947).

A heretofore unknown series of 3-oxoandrost-4-ene176-thiocarboxylates and derivatives thereof has been discovered and is disclosed herein. The 178-thiocarboxylates exhibit topical anti-inflammatory activity and few adverse side effects.

One aspect of this invention is a compound chosen from those represented by the formula wherein X1 is hydrogen, fluoro, or chloro; X is hydrogen, fluoro, chloro or bromo; OH ___PJ X is =C=O or =CCT.„ or may also be =C___IT when X is chloro; R is alkyl of 1 to 6 carbon atoms, or phenyl or benzyl optionally substituted with a substituent on the phenyl ring which is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halo; is hydrogen or alkanoyl of 2 to 6 carbon 2 atoms when R is hydrogen, a-methyl or β-methyl or 2 OR and R together are 16α,17o-isopropylidenedioxy; and the bond between C-1 and C-2 is a double or single bond.

Another aspect of this invention is a topical anti25 inflammatory pharmaceutical composition which comprises a suitable pharmaceutical excipient in combination with an effective amount of a suitable compound chosen from those represented by Formula (I), above, wherein each of the substituents are as defined. Particularly valuable compounds in this composition are set forth hereafter. Still another aspect of this invention is a compound of Formula I for use in treating an inflamed condition in mammals. Ί 8 3 (i a - 5 Still another aspect of this invention is a process for preparing a compound of this invention which process comprises treating an appropriate 17βcarboxylic acid or a corresponding reactive derivative thereof with a suitable base salt (preferably an alkali metal salt) of an appropriate alkyl, phenyl or benzyl sulfide (RSH).

One subgroup of the compounds represented by Formula (I) are those wherein R is alkyl of 1-6 carbon 2 atoms, phenyl or benzyl; R is hydrogen, α-methyl or β-methyl when R* is alkanoyl of 2-6 carbon atoms or OR1 1 and R together are 16a,i7a-isopropylidenedioxy; X is fluoro or hydrogen; X is fluoro, chloro or hydrogen; OH Cl 2 and X is or may also be when X is chloro. Of this subgroup the compounds wherein R2 is other than hydrogen, R is methyl or ethyl, X2 is hydrogen —«**0Η or fluoro and X is =C. „ are preferred. Particularly η ο preferred are those compounds wherein X and X are both fluoro. In each group or subgroup the compounds preferred are those with a double bond between C-l and C-2.

Representative examples of the compounds of this invention are set forth hereafter in the Examples.

In defining the compounds of this invention the term alkyl includes both straight chain and branched alkyl groups, thus alkyl of 1-6 carbons includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, isoarayl, n-hexyl and the like. The phenyl and benzyl substituents may be substituted on the phenyl ring at the 2, 3 or 4-positions with one substituent such as alkoxy (e.g. methoxy, ethoxy, n-propoxy, t-butoxy and the like), alkyl of 1-4 carbons (e.g. methyl, ethyl, isopropyl, n-propyl, t-butyl, n-butyl, etc.), or a halo such as fluoro, chloro, bromo or iodo.

Preferably the substitution is at the 2 or 4 positions.

The teem alkanoyl refers to a radical of the 4 V 4 formula R -C wherein R is alkyl of 1-5 carbon atoms and includes, e.g., acetyl, propionyl, butyryl, valeryl, caproyl and the like.

In naming the compounds of this invention the substi tuents present on the androstane ring shall be included alphabetically and the compounds shall be alkyl (or phenyl or benzyl) 17B-carboxylates. For example, if in 3 formula (I), above, X is fluoro, X is chloro, X is , R is methyl, R3- is acetoxy and R2 is a-methyl the name is methyl 17a-acetoxy-9a, llB-dichloro-6a30 fluoro-16a-methyl-3- oxoandrosta-l,4-diene-17S-thiocarcarboxylate. If on the other hand, R is hydrogen but X1, X2, X3, X4, R3 and R2 are the same, the compound is named 17a-acetoxy-9a,llB-dichloro-6a-fluoro-16a-methyl3-oxoandrosta-l,4-diene-17B-thiocarboxylic acid. -7Another aspect of this invention is the preparation of the compounds of the invention. This can be done by reacting an appropriate androsta-l,4-diene 170-carboxylic acid (or the corresponding 4-ene) or a reactive derivative , with an excess (e.g. about 1.1 to 5 molar equivalents based on the steroid) of alkali metal salt of a compound of the formula RSH where R is alkyl, benzyl or phenyl as defined hereinbefore. Representative alkali metal salts include, e.g., sodium methyl sulfide, sodium ethyl sulfide, sodium benzyl sulfide, sodium phenyl sulfide, potassium methyl sulfide, and the like. The alkali metal salt can be reacted directly with the reactive derivative of the 17(5-carboxylic acid, or the salt can be formed in situ by mixing an alkali metal hydride, such as sodium hydride or potassium hydride, with an alkyl, phenyl or benzyl sulfide. The thioesterification reaction readily takes place at temperatures of about 10° to 100eC (preferably at ambient temperatures of about 20°-25’C) in a suitable inert solvent such as dimethylformamide, diethylformamide, dimethyiacetamide, and the like. The reactive derivative of the 178-carboxylic acid may be an acid chloride, but is preferably a mixed anhydride, such as the dialkyl phosphate ester prepared by reacting a dialkyl (1-4 carbons) chlorophosphate (e.g. diethyl chlorophosphate) with the appropriate 178-carboxylic acid in an inert solvent such as tetrahydrofuran (THF) under an inert atmosphere (nitrogen).

The 178-carboxylic acid starting materials are prepared by eliminating the 21 carbon atom from a suitable 21-hydroxy-3,20-dioxopregn-4-ene or pregna1,4-diene. This is readily accomplished by any means known in the art such as using sodium hypobromite as taught in U.S. 2,769,822 or using sodium periodate to -8oxidize an appropriate 21-hydroxy pregnanes. Preferably, however, the elimination of the 21 carbon atom is carried out by using an alkali metal carbonate in alcohol and the presence of oxygen. In the latter case the reaction is carried out at room temperature and atmospheric pressure while the source of oxygen is preferably air. Generally the reaction will be completed within less than 24 hours with a. constant stream of air being bubbled into a stirred reaction mixture.

Suitable 21-hydroxy-3,20-dioxopregn-4-enes or -pregna-1,4-dienes include known compounds such as corticosterone, hydrocortisone, prednisolone, (3-methasone, dexamethasone, triamcinolone, paramethasone, fluo cinolonet triamcinolone acetonide, fluocinolone aceto15 nide, and the like. By following procedures generally known in the art steroids of a relatively simple structure can be converted to other structures as desired.

For example, the 6-fluoro starting steroids can be prepared from known steroids such as 17a-hydroxyproges2θ terone or hydrocortisone. The 6-fluoro group can be introduced by treating a 3-methoxy-pregna-3,5-diene (prepared by reacting a 3-keto-pregn-4-ene with triethyl orthoformate in methanol, with perchloryl fluoride in acetone-water 9:1.

Other 6-fluoro starting steroids employed in the present process to prepare the novel 17S-thiocarboxylic acid derivatives of this invention are -described in the literature and in United States and foreign patents.

For example, see U.S. Patents 2,983,737, 2,983,739, 3,053,838, 3,057,858, 3,124,251, 3,126,375, 3,201,391 and 3,248,389.

The 9a-fluoro, chloro or bromo group is introduced by treating a 98,116-oxido steroid with hydrogen fluoride, hydrogen chloride or hydrogen bromide respectively in an inert, nonaqueous, preferably anhydrous, solvent or mixture of such solvents. For example, see U.S. 3,211,758 to Tarkoey wherein a hydrogen fluoride/urea complex is employed. The 98,118-oxido steroid is prepared from the corresponding pregna-4,9(11)-diene (which is prepared by treating the corresponding 118-hydroxy steroid with methane sulfonyl chloride in dimethylformamide in the presence of pyridine and a catalytic amount of sulfur trioxide) by treating the pregna-4,9(11)-diene with N-bromoacetamide and perchloric acid in dioxane or tetrahydrofuran, and then refluxing the resulting 9-bromo-ll-hydroxy steroid with potassium acetate in acetone. The 9a,118-dichloro groups are introduced by treating the corresponding pregna-4,9(11)-diene with chlorine gas in chloroform.

A 16-methyl group is introduced by treating the corresponding 20-keto-pregn-16-ene with methyl magnesium bromide in the presence of cuprous chloride in an ether such as tetrahydrofuran. The 20-keto-pregn-16-ene is prepared by preparing the 3,20-bis-semicarbazone of a 20 3,20-diketo-17a-hydroxy steroid, treating the semicarbazone with glacial acetic acid and acetic anhydride and then allowing the resulting product to react with aqueous pyruvic acid.

The 17a-hydroxy group is introduced in conjunction with the 168-methyl group by first treating the corresponding 16-methyl-pregn-16-ene (which is prepared by treating the corresponding pregn-16-ene with diazomethane and then heating the resulting product to 180°C.) with hydrogen peroxide, in an aqueous basic media, then 82 permitting the resulting 16,17-oxido-16-methyl steroid to react with hydrogen bromide in glacial acetic acid. The resulting 16,17-bromohydrin is hydrogenated with the use of a palladium catalyst to afford the corresponding 168-methyl-17a-hydroxy derivative.

The 17a-hydroxy group is introduced in conjunction 8 3 6 ί) - 10 with the 1δα-methyl by methods known in the art, such as the method described by Edwards et al in the Journal of the American Chemical Society 82, 2318-22, 1960.

In this process an appropriate 21-substituted 16a5 methyl-pregn.a-1,4-diene-^20-di°ne is converted to 20enol acetate by refluxing with acetic anhydride and freshly distilled acetyl chloride. The 20-enol acetate is recovered and reacted with monoperphthalic acid in ether and benzene to form the 17,20-epoxide which in turn is treated with methanol and aqueous potassium hydroxide to give the l6a-methyl-17a-hydroxy steroid which is isolated by means known in the art.

Another aspect of this invention is a process Jt for preparing the compound of formula (I) wherein R is alkanoyl of 2 to 6 carbon atoms and X^ , X^, , R, R^ and the broken line between C-1 and C-2 are as defined in tbe broadest aspect of the invention. This process comprises esterifying the corresponding 17a-hydroxy compound. The esterification can be done by methods known in the art such as the methods set forth in U.S. Patent 3,828,080 issued August 6, 1974 to Phillips et al of Glaxo. Generally, the parent 17a-hydroxy compound is reacted with an appropriate carboxylic acid or a reactive derivative thereof such as an acid anhydride or acid chloride in the presence of a suitable acid catalyst and a solvent at temperatures of 20 to 100°C. Suitable carboxylic acids and reactive derivatives include, e.g. acetic acid, propionic acid, butyric acid etc., and the corresponding anhydrides and acid chlorides. Solvents include non-hydroxylic solvents such as methylene chloride, chloroform, benzene and the like, while suitable acid catalysts include p-toluene-sulfonic acid, sulfosalicylic acid, perchloride acid, strongly acidic cation exchange resins, and the like. - 11 The compounds of this invention are useful for the relief of inflamed conditions in mammals, and more specifically are useful for relieving inflammatory manifestations of corticosteroid responsive dermatoses.

Initial approximation of anti-inflammatory activity is done by the following procedure of McKenzie, S.W. and Stoughton, R.B., Method for Comparing Percutaneous Absorption of Steroids Arch Dermat, 86, 608 (1962) or modifications thereof.

Generally, the inflammatory manifestation in mammals, particularly humans, is combatted by treating the afflicted mammal with a therapeutically effective amount of the novel steroids of this invention, that is an amount which results in improvement of the inflamed con15 ditions.

Preferably the steroids are first formulated to prepare a suitable pharmaceutical formulation, as discussed hereinafter, which is then placed in contact with the afflicted area. An effective amount will depend upon the particular condition and the animal receiving the treatment but will vary between 0.001% to 10% by weight of the pharmaceutical composition and preferably - 12 will be between 0.02 and 1% by weight of the formulation. Using these levels in the formulation, a therapeutically effective and non-side effect producing amount, i.e. enough to effect an anti-inflammatory response, but not enough to adversely effect the recipient, is applied to the inflamed area.

The compounds of this invention not only have antiinflammatory activity but also exhibit a low level of systemic activity, as measured by recognized laboratory 10 assays. This allows for the application of an effective amount of the anti-inflammatory compounds with little adverse effect on the rest of the animal's system.

The novel steroids of this invention may be formulated with suitable pharmaceutical excipients known in the art to form particularly effective anti-inflammatory compositions which may be administered orally, nasally, rectally or, preferably, topically. Generally an effective amount of the steroid is about 0.001%w to about 10%w of the total formulated composition. The rest of 20 the formulated composition will be about 90%w to about 99.999%w of suitable excipients which may include a pharmaceutically acceptable solvent and other pharmaceutically acceptable additives to form an effective pharmaceutical formulation. The composition is prepared 25 by dissolving the active ingredient in the desired solvent and mixing with the Other excipients as required A pharmaceutically acceptable solvent is one which is substantially non-toxic and non-irritating under the conditions used and may be readily formulated into any 30 of the classical drug formulations such as powders, creams, ointments, lotions, gels, foams, suppositories, aerosols, solutions or the like. Particularly suitable solvents include water, glycerine, propylene carbonate, and a glycol such as 1,2-propylene diol (i.e. propylene 35 glycol), 1,3-propylene diol, polyethylene glycol having - 13 a molecular weight of from 100 to 10,000, dipropylene glycol, etc.; and mixtures of the aforementioned with each other.

A topical cream may be prepared as a semi-solid emulsion of oil in water or water in oil. A cream base formulation by definition is an emulsion which is a twophase system with one liguid (for example fats or oils) being dispersed as small globules in another substance (e.g., a glycol-water solvent phase) which may be employed as the primary solvent for the novel steroids therein, the cream formulation may contain fatty alcohols, surfactants, mineral oil or petrolatum and other typical pharmaceutical adjuvants such as antioxidants, antiseptics, or compatible adjuvants. A typical cream base formulation is given in the following table; Water/glycol mixture (15% or more glycol) - 99 parts by weight Fatty alcohol 1-20 Non-ionic Surfactant 0-10 Mineral oil 0-10 Typical pharmaceutical 0-5 adjuvants Active Ingredients 0.001 - 10 The fatty alcohol, non-ionic surfactant, and other adjuvants are discussed in O.S. 3,934,013 to Poulsen which is incorporated herein by reference.

The novel steroids of this invention may also be formulated as ointments. A classical” ointment is a semisolid anhydrous composition which may contain mineral oil, white petrolatum, a suitable solvent such as a glycol and may include propylene carbonate and other pharmaceutically suitable additives such as surfactants, for example Span and Tween, or wool fat (lanolin), along with stabilizers such as antioxidants - 14 4 8 3 Γ. 9 and other adjuvants as mentioned before. Following is an example of a typical classical ointment base: White petrolatum Mineral Oil Glycol solvent Surfactant Stabilizer Active Ingredients - 94 parts by weight 5-20 1-15 0-10 0-10 0.001 - 10.0 Other suitable ointment base formulations which employ propylene carbonate are described in U.S. patent 4,017,615 issued April 12, 1977 by Shastri et al entitled Propylene Carbonate Ointment Vehicle and U.S. 3,924,004 issued December 2, 1975 by Chang et al entitled Fatty Alcohol-Propylene Carbonate-Glycol Solvent Cream Vehicle. As much of those applications as is pertinent is incorporated herein by reference. Following is a typical ointment base formulation con20 taining propylene carbonate: Active Ingredients 0.001 - 10 Propylene Carbonate 1 - 10 Solvent 1 - 10 Surfactant 1 - 10 White Petrolatum 70 - 97 Surfactants, stabilizers, etc. are discussed in U.S. 3,934,013 and such discussion is incorporated herein by reference.

A suitable non-classical anhydrous, water washable ointment type base is described in U.S. Patent No. 3,952,930 to Katz and Neiman, and that patent is incorporated herein by reference. A representative composition of this invention utilizing such a base is as follows: Glycol solvent 50 - 35 parts by weight Fatty alcohol 15 - 45 Compatible plasticizer 0-15 Compatible coupling - 15 - Agent 0-15 Penetrant 0-20 Active Ingredients 0.001 - 10.0 Preparation 1 A process is set forth for preparing 16a-methyl-3oxoandrosta-l,4~diene-178-carboxylic acids substituted at the 9a-position with hydrogen, fluoro, chloro or bromo; at the 6a-position with hydrogen, fluoro or chloro; and at the HB-position with hydroxy or chloro when 9a is chloro substituted.

A. Preparation of 6a,9a-di£luoro-llB, 17a-dihydroxy16a-methyl-3-oxoandrosta-l,4-diene-178-carboxylic acid.

Thirty-five grams of flumethasone is mixed with 550 ml of methanol and 35 g of anhydrous potassium carbonate and stirred at room temperature and atmospheric pressure while a current of air is slowly bubbled through the solution for 22 hours. Methanol is added at intervals to maintain a constant volume. The reaction mixture is diluted with water to 1.5 1, then concentrated hydrochloric acid is added slowly to the mixture under magnetic stirring until a final pH of 2 is obtained. Methanol is eliminated under reduced pressure, and the resulting crystalline precipitate is collected by filtration, washed with water, and air dried to give 6a,9a-difluoro-116,17a-dihydroxy-16amethyl-3-oxoandrosta-l,4-diene-176-carboxylic acid, melting point (m.p.) 289.5-290eC.

B. By following the procedure set forth in part A of this example but substituting other appropriate starting materials the following compounds of this invention can be prepared: 9a,118-dichloro-6a-fluoro-17a-hydroxy-16amethyl-3-oxoandrosta-l,4-diene-17B-carboxylic acid; 9 - 16 35 9a-bromo-6a-fluoro-ΙΙβ,17a-dihydroxy-16amethyl-3-oxo-androsta-1,4-diene-178-carboxylic acid; 9a,118-dichloro-17a-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-178-carboxylic acid; 118,17a-dihydroxy-16a-methyl-3-oxo-androstal,4-diene-178-carboxylic acid; 9a-chloro-118,17a-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-178-carboxylic acid; 9a-bromo-118,17a-d ihydroxy-16a-methyl-3-oxoandrosta-l,4-diene-178-carboxylic acid; 9a-fluoro-118,17a-dihydroxy-16a-methyl-3-oxoandrosta-l,4-diene-178-carboxylic acid; 6a-fluoro-118,17a-dihydroxy-16a-methyl-3-oxoandrosta-l,4-diene-178-carboxylic acid; 6a,9a-dichloro-118,17a-dihydroxy-16o-methyl-3oxo-androsta-1,4-diene-178-carboxylic acid; 6a-chloro-9a-fluoro-118,17ct-dihydroxy-16a-methyl3-oxo-androsta-l,4-diene-178-carboxylic acid; 9a-bromo-6a-chloro-llB,17a-dihydroxy-16a-methyl3-oxo-androsta-1,4-diene-176-carboxylic acid; 6a-chlor0-118,17a-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene -178-carboxylic acid; and 6α,9a-d ichlorο-11β,17a-dihydroxy-16a-methyl-3-oxoandrosta-l,4-diene-178-carboxylic acid.

C. By following in principle the process of Part A but substituting other appropriate starting materials having a 178-methyl group or being unsubstituted at 17 (e.g.B-methasone or hydrocortisone), other 178-methyl or 17-unsubstituted starting materials are prepared.

D. Ten g of a compound prepared according to Parts A-C of this preparation is dissolved in 100 ml methanol. Fifty ml of anhydrous pyridine and 25 ml of propionic anhydride are added.and the resulting mixture stirred until TLC shows the reaction is complete. The solution is cooled in an ice-water bath and slowly - 17 diluted with water up to 2 1. The resulting crystalline precipitate is collected by filtration and air dried to give the 17a-propionate. Other alkanoates are obtained by substituting other anhydrides for propionic anhydride.

Preparation 2 A process is set forth for preparing 16a,17a-isopropylidenedioxy-3-oxoandrosta-l,4-diene-176-carboxylic acid substituted at 9a with hydrogen, fluoro, chloro or bromo; at 6a with hydrogen, fluoro or chloro; and at 116 with hydroxy or chloro when there is a 9a-chloro.

A. By following in principle the process of Preparation 1, Part A but substituting fluocinolone acetonide for flumethasone, one obtains 6a,9a-difluoro116-hydroxy-16a,17a-isopropylidenedioxy-3-oxoandrostal,4-diene-176-carboxylic acid, m.p. 297-300°C (with decomposition).

B. By following in principle the process of Part A of this preparation but substituting other 16α,17αisopropylidenedioxypregna-l,4-diene-3,20-diones for fluocinolone acetonide, other 176-carboxylic acids are obtained, for example 9a,116-dichloro-6a-fluoro~16a,17a-isopropylidenedioxy-3-oxoandrosta-l,4-diene-176-carboxylic acid; 9a-chloro-6a-fluoro-116-hydroxy-16a,17a-isopropylidenedioxy-3-oxoandrosta-1.4-diene-176-carboxylic acid; 6α,9α,116-tr ichloro-16a,17a-isopropylidenedioxy3-oxoandrosta-l,4-diene-176-carboxylic acid; and the like.

Specific embodiments of the process of this invention are found in the following Examples which are given by way of illustration only and are not to be interpreted as limiting the scope of the claims appended hereto. 8 3θ 9 - 18 Example 1 A process is set forth for preparing alkyl, benzyl or phenyl 17a-alkanoyloxy-16a-methyl-3-oxoandrosta1,4-diene-178-thiocarboxylates of this invention which are substituted with hydrogen, fluoro or chloro at the 6a-position; with fluoro, chloro, bromo or hydrogen at the 9a-position; and 118-hydroxy or 118-chloro when there is a chloro at 9a.

A. Preparation of methyl 6a,9a-difluoro-11810 hydroxy-l6a-methyl-3-oxo-17“-propionyloxyandrosta-l,4diene -178-thiocarboxylate.

Six hundred (600) mg of 6a,9a-difluoro-ll(5-hydroxyl6a-methyl-3-oxo-17a-propionyloxyandrosta-l,4-diene178-carboxylic acid, prepared in the manner set forth in Preparation 1,A, are mixed with 8 ml THP and 0.2 ml triethylamine (TEA) in a suitable reaction vessel and stirred at room temperature under Ng. Thereafter, .24 g of diethyl chlorophosphate (DCP; CgHjOJgPfOJCl) in 8 ml THF is added over 13 minutes. Stirring is continued for about 6 hours (pH 6). Then, 0.04 ml TEA is added followed by .05 gm DCP in 3 ml THF. Stirring is continued for another 17.5 hours. The resulting precipitate is filtered, washed with 10 ml THF and the filtrates are combined. To the filtrate are then added 2.05 ml of a solution prepared previously which consists of 20 ml dimethylformamide (DMF), 0.758 g 75% sodium hydride and 0.86 g (1 ml) methylsulfide. The resulting reaction mixture of the filtrates and the DMF solution is stirred for about 5.5 hours whereupon an additional 1 30 ml of the DMF solution is added and stirring is continued for another 1.5 hours.

The reaction mixture is then poured into 200 ml of ethyl acetate (EtOAc) which, in turn, is washed twice with 200 ml portions of water, washed with brine, dried 35 for about 15 hours over sodium sulfate and filtered. - 19 The solvents are then removed under reduced pressure using a rotary evaporator to give 235 mg of residue which is recrystallized from aeetone/hexane to give 54.3 mg of methyl 6a,9a-difluoro-118-hydroxy-16a-methyl5 17a-propionyloxyandrosta-l,4-diene-176-thiocarboxylate, m.p. 305-308°C (with decomposition).

B. By following in principle the procedure of Part A of this example but substituting other sulfides such as ethyl sulfide, isopropyl sulfide, n-butyl 1® sulfide, phenyl sulfide, or benzyl sulfide for methyl sulfide other compounds of this invention are prepared, namely ethyl 6tt,9a-difluoro-118-hydroxy-16o-methyl3-oxo-17a-propionyloxyandrosta-l,4-diene-178-thiocarbox15 ylate, m.p. 300°C (with decomposition); isopropyl 6a,9a-difluoro-118-hydroxy-16a-methyl3-oxo-17a-propionyloxyandrosta-1,4-diene-17 (5-thiocarboxylate, m.p. 286e-289eC; n-butyl 6a,9a-difluoro-118-hydroxy-16a-methyl20 3-oxo-17a-propionyloxyandrosta-l,4-diene-178-thiocarboxylate, m.p. 247°-250eC; phenyl 6a,9a-di£luoro-ll(5-hydroxy-16a-methyl-3-oxo17a-propionyloxyandrosta-1,4-diene -178-thiocarboxylate, m.p. 281e-283eC. (with decomposition); benzyl 6a,9a-difluoro-118-hydroxy-16a-raethyl3-oxo-17a-propionyloxyandrosta-1,4-diene-178-thiocarboxylate, m.p. 246°-248eC.

C. By following in principle the process of Part A of this example, but substituting other appropriate 30 steroids for 6a,9a-difluoro-il8-hydroxy-16a-methyl3-oxo-17-propionyloxyandrosta-l,4-diene-178-carboxylic acid and other appropriate alkyl, phenyl or benzyl sulfides for methyl sulfide, other compounds of this invention are obtained such as methyl 6a,9ct-di£luoro-16a-methyl-3-oxo~17a-valeryl35 8 3 6 9 - 20 androsta-l,4-diene-176-thiocarboxylate, m.p. 267-268°C(d) ; methyl 17a-butyryloxy 6a,9a-difluoro-118-hydroxy16a-methyl-3-oxo-17a-propionyloxyandrosta-l,4-diene-17β5 thiocarboxylate, m.p. 276-280°C(d); ethyl 17a-acetoxy-6a,9a-difluoro-118-hydroxy-16amethyl-3-oxoandrosta-l,4-diene-178-thiocarboxylate, m.p. 285-290°C(d) -, methyl 17a-acetoxy-6a,9a-difluoro-16a-methyl-310 oxoandrosta-1,4-diene-178-thiocarboxylate, m.p. +300°C; methyl 118-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-l,4-diene-17β-thiocarboxylate; isopropyl 17a-acetoxy-9a-chloro-118-hydroxy-16amethyl-3-oxrendrosta-1,4-disie-17p--thiocarboxylatE, m. p. 123-126°C; methyl-17a-butyryloxy-9a-fluoro-118-hydroxy-16amethyl-3-oxoandrosta-l,4-diene-178-thiocarboxylate; methyl 6a-fluoro-118-hydroxy-16a-methyl-3-oxo17a-propionyloxyandrosta-l,4-diene*178-thiocarboxylate; methyl 6a-chloro,9a-fluoro-118-hydroxy-16a-methyl20 3-oxo-17a-propionyloxyandrosta-l,4-diene-178-thiocarboxylate.

Example 2 A process is set forth for preparing alkyl, benzyl 25 or phenyl 17a-hydroxy-16a-methyl-3-oxoandrosta-l,4diene-178-thiocarboxylates of this invention which are substituted at the 6a-position with fluoro, chloro or hydrogen; at the 9a-position with hydrogen, fluoro, chloro or bromo; and at the 118-position with hydroxy or 30 also chloro when there is a 9a-chloro.

A. Preparation of ethyl 6a,9a-difluoro-118,17adihydroxy-16a-methyl-3-oxoandrosta-l,4-diene-178-thiocarboxylate.

One hundred five (105) mg of 6a,9a-difluoro35 11β,17a-dihydroxy-16a-methyl-3-oxoandrosta-l,4-diene178-carboxylic acid are dissolved in 7 ml DMF and cooled - 21 to -10°C. Eighty (80) mg carbonyl diimidazole (CDI) are dissolved in 30 ml DMF, and this solution is added to the DMF/acid solution under a nitrogen blanket. The resulting mixture i-s stirred for about 18 hours at -5°C, and about 0.2 ml ethyl sulfide (EtSH) is added thereto. The reaction is stirred at -5°C for an additional 16 hours. The reaction mixture is stored in the freezer for 2 weeks, the solvents removed under reduced pressure.

The residue is applied to a 1 meter X 0.75 TLC plate and developed twice with a mixture of 10% acetone/90% benzene. After recovery, the material is recrystallized from acetone/hexane to give 47 mg of ethyl 6α,9αdifluoro-116,17a-dihydroxy-16a-methyl-3-oxoandrosta-l,4diene-176-thiocarboxylate, m.p. 235-239°C (with decomposition) .

B. Similarly, by following in principle the process of Part A of this example but substituting other alkyl, phenyl or benzyl sulfides for ethyl sulfide, other compounds of this invention such as methyl 6a,9a-difluoro-118,17a-dihydroxy-16a-methyl3-oxoandrosta-1,4-diaie-17P-thiocar'bcKy3Hte, m.p. 272-275°C; n-hexyl 6a,9a-difluoro-118,17a-dihydroxy-16amethyl-3-oxoandrosta-1,4-d ίene-176-th iocarboxylate; phenyl 6a,9a-difluoro-118,17a-dihydroxy-16amethyl-3-oxoandrosta-l,4-diene-176-thiocarboxylate; benzyl 6a,9a-difluoro-118,17a-dihydroxy-16amethyl-3-oxoandrosta-l,4-diene -176-thiocarboxylate; are obtained.

C. Similarly, by following in principle the process of Part A or Part B but substituting other appropriate 176-carboxylic acid prepared in the manner set forth in Preparation 1 for 6a,9a-difluoro-116,17adihydroxy-16a-methyl-3-oxoandrosta-l,4-diene176-carboxylic acid, other compounds of this invention are obtained such as 8 3 6 9 -22methyl 6a-fluoro-ΙΙβ,17a-dihydroxy-16a-methyl3-oxoandrosta-l,4-diene-17B-thiocarboxylate; methyl 9a-fluoro-ΙΙβ,17a-dihydroxy-16a-methyl3-oxoandrosta-l,4-diene-17B-thiocarboxylate; methyl 6a-fluoro-9a,llB-dichloro-17a-hydroxy16a-methyl-3-oxoandrosta-l,4-diene-17β-thiocarboxylate; and the like.

Example 3 1° By following in principle the procedures set forth in Examples 1-2 but substituting the corresponding 16(3methyl steroid starting material for the 16a-methyl steroid starting material, the corresponding 16(3-methyl steroids of this invention are obtained such as 33 methyl 17a-caproyloxy-9a-fluoro-ll(3-hydroxy-16(3methyl-3-oxoandrosta-l,4-diene- 17B-thiocarhoxylate, m.p. 139-141°C; hexyl 17a-acetoxy-9a-fluoro-llB-hydroxy-16B-methyl3-oxoandrosta-l,4-diene-17(3-thiocarboxylate, m.p. 176-179°C; methyl 17a-acetoxy-9a,ll(3-dichloro-6a-fluoro-16f3raethyl-3-oxoandrosta-l,4-diene-17B-thiocarboxylate; and other corresponding 17a-alkanoyloxy derivatives along with other alkyl, phenyl or benzyl 17B-thiocarbox25 ylates.

Example 4 By following in principle the procedures set forth in Example 1 but substituting the corresponding 30 16-unsubstituted steroid starting material for the 16a-methyl steroid starting material, the corresponding 16-unsubstituted steroids of this invention are obtained, such as methyl 6α,9a-difluoro-ΙΙβ,17a-dihydroxy-3-oxo33 androsta-1,4-diene-17B-thiocarboxylate; 483C9 - 23 methyl 6a-fluoro-118-hydroxy-3-oxo-17a-propionyloxyandrosta-l,4-diene“178-thiocarboxyiate; hexyl 6a,9a-difluoro-118-hydroxy-3-oxo~17a-propion yloxy-androsta-1,4- 178-thiocarboxylate; benzyl 6a,9a-difluoro-118-hydroxy-3-oxo-17a-propionyloxy-androsta-1,4-diene-178-thiocarboxylate; and and other corresponding alkyl, phenyl or benzyl 178-thiocarboxylates as well as the 17-a-alkanoyloxy derivatives.

EXAMPLE 5 A process is set forth for preparing alkyl, benzyl or phenyl 16a, 17a-isopropylidenedioxy-3-oxo-androsta1.4- diene-176-thiocarboxylates of this invention which are substituted with hydrogen, fluoro or chloro at the 6a-position; with hydrogen, fluoro, chloro or bromo at the 9a-position; and with hydroxy at the 118-position or also chloro at the 118-position when there is a chloro at the 9a position.

A. Preparation of methyl 6a, 9a-difluoro-118hydroxy-16a, 17a-isopropylidenedioxy-3-oxo-androsta1.4- diene-178-thiocarboxylate.

Six hundred ¢600) mg of 6a, 9a-difluoro-118~ hydroxy-16a, 17a, isopropylidenedioxy-3-oxoandrosta1.4- diene-178-carboxylic acid (prepared in the manner described in Preparation 2, Part A) are mixed with 8 ml/THF and 0.21 ml TEA and stirred under nitrogen at room temperature. Three-tenths (0.3) of a ml of DCP in 11 ml THF is added to the steroid mixture over 6 minutes and the mixture is stirred at room temperature for about 17 hours, at which point, 5 drops of neat DCP are added. Stirring is continued for another 3.5 hours after which the precipitate in the reaction mixture is filtered and washed with 10 ml of THF. The filtrates are combined, and 3.15 ml of the solution of the methyl 8 3 6 9 - 24 sulfide, sodium hydride, DMF as prepared in Example 1 is added thereto. The resulting mixture is stirred at room temperature under nitrogen for about 3.5 hours then poured into 300 ml of EtOAc which is then washed twice with 250 ml portions of water. The aqueous washes are extracted with 150 ml EtOAc, and the EtOAc solutions are combined, washed with brine and dried over sodium sulfate for about 15 hours in a refrigerator. The solvents are removed under reduced pressure by rotary evaporator 12 to yield 546 mg of material which is recrystallized from acetone to give 309 mg of methyl 6a, 9a-difluoro-ll£5hydroxy-16a, 17a-isopropylidenedioxy-3-oxoandrosta-l,4diene-176-thiocarboxylate, mp 299-301°C (with decomposition) .

B. Similarly, by substituting other alkyl, phenyl or benzyl sulfides for methyl sulfide, and following in principle the process of Part A of this example, other compounds of this invention are prepared, such as ethyl 6a,9a-difluoro-118-hydroxy-16a, 17a-iso2° propylidenedioxy-3-oxoandrosta-l,4<-diene-176-thiocarboxylate, m.p. +300°C(d); isopropyl 6a,9a-difluoro-116-hydroxy-16a, 17a-isopropylidenedioxy-3-oxoandrosta-l,4-diene-17£5-thiocarboxylate; n-butyl 6a,9a-difluoro-110-hydroxy-16a,17a-isopropylidenedioxy-3-oxoandrosta-l,4-diene-17f3-thiocarboxylate; n-hexyl 6α,9a-di fluoro-116-hydroxy-16a,17a-isopropylidenedioxy-3-oxoandrosta-l,4-diene-176-thiocarbox30 ylate; phenyl 6a,9a-difluoro-116-hydroxy-16a,17a-isopropylidenedioxy-3-oxoandrosta-l,4-diene-170-thiocarboxylate; benzyl 6a,9a-difluoro-llB-hydroxy-16a,17a-isopro33 pylidenedioxy-3-oxoandrosta-l,4-diene-176-thiocarbox48369 - 25 ylate; and the like.

C. Similarly by following in principle the procedure of Parts A and B of this example, but substituting other 176-carboxylic acids prepared in the manner set forth in Preparation 2 for 6a,9a-difluoro-118-hydroxy16a,17a-isopropylidenedioxy-3-oxoandrosta-l,4-diene175-carboxylic acid, other compounds of this invention are prepared, such as methyl 6a-fluoro-118-hydroxy-16a, 17a-isopropylidenedioxy-3-oxoandrosta-l,4-diene-178-thiocarboxylate, m.p. +300°C; methyl 118-hydroxy-16a, 17a-isopropylidenedioxy-3oxoandrosta-1,4-diene-178-thiocarboxylate, m.p. +300°C(d); methyl 9a-fluoro-118-hydroxy-16a, 17a-isopropylidenedioxy-3-oxoandrosta-l,4-diene-178-thiocarboxylate; methyl 9a-chloro-6a-fluoro-118-hydroxy-16a,17aisopropylidenedioxy-3-oxoandrosta-l,4-diene-178-thiocarboxylate; methyl 9a-bromo-6a-fluoro-110-hydroxy-16a,17aisopropylidenedioxy-3-oxoandrosta-l,4-diene- 178-thiocarboxylate; methyl 9a,118-dichloro-6a-fluoro-16a,17a-isopropylidenedioxy-3-oxoandrosta~l,4-diene-178-thiocarboxylate; n-butyl 9a,Ιΐβ-dichloro-6a-fluoro-16a,17a-isopropylidenedioxy-3-oxoandrosta-l,4-diene-178-thiocarboxylate; phenyl 9a,118-dlchloro-6a-fluoro-16a,l-7a-isopro~ pylidenedioxy-3-oxoandrosta-l,4-diene-178-thiocarboxylate; benzyl 9a,118-dichloro-6a-fluoro-16a,17a-isopropylidenedioxy-3-oxoandrosta-1,4-diene-178-thiocarboxylate; and the like. - 26 Example 6 This example sets forth a process for preparing an 11-keto compound of this invention by oxidizing any of the 116-hydroxy steroids set forth in Preparations 1-2 and converting the so-obtained compound to the 176-thiocarboxylate according to the process of Examples 1-5.

One g of 6a,9a-difluoro-116,17a-dihydroxy-16amethyl-3-oxoandrosta-l,4-diene-178-carboxylic acid is dissolved in 50 ml of acetone and treated at room temperature with Jones reagent (chromic anhydride in dilute sulfuric acid) dropwise until TLC indicates the absence of starting material. The mixture is treated with five drops of isopropyl alcohol to destroy any excess of reagent, then diluted with 50 ml of water and the mixture concentrated under vacuum under reduced pressure to give a crystalline material, namely 6α,9αdifluoro-17a-hydroxy-16a-methyl-3,11-dioxoandrosta-l, 4diene-178-carboxylic acid. This compound, in turn, is reacted according to the process of Example 2 to give 20 methyl 6a,9a-difluoro-17a-hydroxy-ll-keto-16a-methyl3-oxoandrosta-1,4-diene-176-thiocarboxylate.

Example 7 This example sets forth a process for converting an 25 androsta-l,4-diene of this invention to the corresponding androst-4-ene.

To a solution of 25 mg of tris-(triphenylphosphine) chlororhodium in 7 ml of benzene and 15 ml of ethanol, 244 mg methyl 6a,9a-difluoro-118,17a-dihydroxy59 16a-methyl-3-oxoandrosta-l,4-diene-17e-thiocarboxylate are added and the resulting solution is stirred under hydrogen at room temperature at atmospheric pressure. After hydrogen uptake is complete the solution is evaporated to dryness and,the residue is taken up in a raix35 ture of petroleum ether and methylene chloride. The - η pure product is isolated by column chromatography on silica gel to give methyl 6α,9a-difluoro-118,17adihydroxy-16a-methy1-3-oxoandrost-4-ene-178-thiocarboxylate. Similarly, by substituting other androsta-1,4dienes of this invention made according to examples 1-6 for the compound used above in this example, Other corresponding androst -4-enes of the invention are prepared such as methyl 6a-fluoro-118-hydroxy 17apropionyloxyandrost-4-ene -178-thiocarboxylate, m.p. 210-212°C.

EXAMPLE 8 - LD5Q Six Swiss-Webster mice (Simonsen) each weighing about 25 grams, were injected subcutaneiously with a solution of methyl 6a,9a-difluoro-118-hydroxy16a-methyl-3-oxo-17a-propionyloxyandrosta-l,4-diene178-thiocarboxyate in carbomethoxycellulose having a concentration of 10 ml/kg. The dosage was 25 mg/kg or about .625 mg/mouse. The mice were observed daily for mortality for 21 days. No mice died. The LD^q is, therefore, more than 25 mg/kg.

The same procedure was employed to find the LD^gOf methyl 6α,9a-difluoro-118-hydr oxy-16a,17a-isopropyledinedioxy-3-oxoandrost-l,4-diene~176 -thiocarboxylate. The^D^5, 50 / compound was found to be more than 25 mg/kg as well.

EXAMPLE 9 - Biological Activity This example sets forth data comparing the topical anti-inflammatory and thymolytic activities of compounds of this invention versus compounds known in the art.

The topical anti-inflammatory activity potential for each compound was assayed using a modified Stoughton/ McKenzie vaso-constriction assay in humans, as described by V. A. Place, J. G. Balasquez and Κ. H. Burdick in Arch. Derrnat. 101, 531-537 (1970).

Eight normal adult human subjects were treated on 48363 -28four sites on each forearm by topical administration with alcoholic solutions containing 1 X 10 3 and 1 X 10 g/ml of each of the compounds to provide 64 total test sites for each compound in a series (32 for each 5 concentration). Areas of the subjects' forearms were outlined by a rubber stamp grid coated with silicone grease, and 10 microliters of each solution were applied per 7x7 mm. square site. After the preparations dried, the areas on each forearm are covered with Saran wrap and the margins sealed with tape. The occlusive wrap is removed after 18 hours. Twenty-four hours after application, the presence or absence of vasoconstriction is noted by visual examination by two independent observers, and expressed as the number of sites responding (vasoconstriction) and is calculated as a percentage of the total number of sites. Also, the intensity of the vasoconstriction is scored on a 0, 1, 2 scale, 2 being the most intense reaction. Both scores are used in the constructing dose-response graphs according to methods set forth in an article by V. A.

Place, infra, et al. The compounds of the invention (A and C) were compared directly with the compound of the art (B and D), respectively.

The compounds to be tested for thymolytic activity, including a hydrocortisone standard, were prepared in three or more concentrations by suspension in a sodium carboxymethyl-cellulose vehicle. Animals received the test materials by subcutaneous injection of 0.5 ml of the suspension on each of three successive days. Four ° hours following the final injection, the rats were sacrificed and the thymus gland of each animal removed and weighed. These weights are then employed to establish dose-response graphs by methods known in the art. Of the compounds tested only one pair showed - 29 measurable activity; the remaining compounds showed no activity in the dose range of hydrocortisone (the standard) and are therefore labelled inactive (less than 2 x hydrocortisone in potency).

In the data analysis shown (Table 1), each compound of this invention (A and C) bearing a thiomethyl ester function was. compared directly with the closest oxygen analogue (B and D). Overall, the compounds show excellent topical potency with little or no systemic activity and distinct therapeutic advantage of the sulfur bearing compounds over the oxygen ester analogue is apparent. This superiority is surprising and unexpected.

Table 3 Rat VasoconThymus striction Therapeutic (T) (V)Advantage A. Methyl 6a,9a-difluoro- 1 116-hydroxy-3-oxo~16amethyl-17a-propionyloxyandrosta -1,4-diene176-thiocarboxylate B. Methyl 6a,9a-difluoro- 40 116-hydroxy-3-oxo-16amethyl-17a-propionyloxyandrosta -1,4-diene176-carboxylate C. Methyl 6a,9a-difluoro- Inactive 110-hydroxy-3-oxo16a,17a-isopropylidenedioxyandrosta1,4-diene -176-thiocarboxylate >0.8 >32 >10 >10 D. Methyl 6a,9a-difluoro- Inactive llji-hydroxy-3-oxo16a,17a-isopropylidenedioxyandrosta-1,4diene-176-carboxylate 8 3 6 9 - 30 In the case of Compound A vs Compound B, the therapeutic advantage of the compound of the invention was calculated according to the following equation: 3 V (Comp A) V (Comp B) _ >0,8 . 1 _ T (Comp A) ‘ T (Comp B) 170- ' 40“ Because compound C is inactive in the rat thymus (T) test, the therapeutic advantage is given as >10. 1° Example 10 In this example a formulation is prepared of the following composition % w/w Methyl 6a,9a-difluoro-118-hydroxy-16a-methyl- 0.025 3-oxo-17a-propionyloxyandrosta-l,4-diene 17£3-thiocar boxylate Stearyl Alcohol 30.0 PEG 6000 5.0 1,2,6-Hexanetriol 2.5 Citric Acid Anhydrous, OSP 0.02 Propylene Glycol, USP, q.s. 100.0 The steroid is dissolved in 624.8 grams of propylene glycol at 90-95°C. The latter is then mixed with the other ingredients at 80-85°C to give the desired formulation.

Claims (14)

CLAIMS:

1. A compound chosen from those represented by the formula wherein X 1 is hydrogen, fluoro, or chloro; X is hydrogen, fluoro, chloro or bromo; 3 OH «-’'Cl X is =C=O or =C^^ H or may also be =C.,jj when X 2 is chloro; R is alkyl of 1 to 6 carbon atoms, or phenyl or benzyl optionally substituted with a substituent on the phenyl ring which is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halo; R is hydrogen or alkanoyl of 2 to 6 carbon 2 atoms when R is hydrogen,a-methyl or 8-methyl or i 2 OR and R together are 16a,17a-isopropylidenedioxy; and the solid and broken lines between C-l and C-2 represent a double or single bond. 2. A compound of Claim 1 wherein R is alkyl of one to six carbon atoms, phenyl or benzyl; R^ is alkanoyl of two to six carbon atoms when

2 . 12 R is hydrogen, α-methyl or 8-methyl or OR and R - 32 483C9 together are 16α, 17a-isopropylidenedioxy; X 3 is fluoro or hydrogen; X is fluoro, chloro or hydrogen; and X 3 is = CTTgH may also be =C^g 3 when X 2 is chloro.

3. A compound of Claim 2 wherein R is methyl or ethyl; R 3 is alkanoyl of two to six carbon atoms when 2 12 R is α-methyl or β-methyl or OR and R together are is is is fluoro or hydrogen; fluoro or hydrogen; and _^0H and X and A compound of Claim 3 wherein R is a-methyl 2 X are both fluoro. Ί f p

4. 5. The Δ v -compound of Claim 4 wherein R is methyl and R 3 is propionyl, namely methyl 6a,9a-difluoro118-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandr os ta-1,4-diene-178-th iocarboxylate.

5. 6. The compound of Claim 1 wherein 1 2 OR and R together are 16a,17a-isopropylidenedioxy.

6. 7. An anti-inflammatory pharmaceutical composition which comprises a therapeutically effective amount of the compound of Claim 1 in combination with at least one suitable pharmaceutical excipient. 33

7. 8. A composition according to claim 7 suitable for topical application.

8. 9. A process for treating an inflamed condition in a non-human mammal, which comprises administering a therapeutically effective amount of a confound of claim 1 to said mammal.

9. 10. A process for preparing a compound of claim 1 which comprises a) treating a compound of the formula v1 v2 n1 2 between wherein X , X/ - , X , R , R and the solid and broken lineSyC-1 and c-2 are as defined in claim 1 or a corresponding reactive derivative thereof with a suitable base salt of a comDound represented by RSH wherein R is as defined in claim 1; or ή b) esterifying a compound of claim 1 in which R is hydrogen to produce the corresponding compound in which R is alkanoyl of 2 to 6 carbon atoms.

10. 11. A compound according to claim 1, substantially as exemplified herein.

11. 12. A process for preparing a compound of claim 1, substantially as described herein.

12. 13. A compound of claim 1 whenever prepared by a process according to claim 10 or claim 12.

13.

14. A pharmaceutical composition according to claim 7 substantially as described herein.