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United States Patent (19) 11) Patent Number: 4,544,555 Gastaud 45 Date of Patent: Oct

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United States Patent (19) 11) Patent Number: 4,544,555 Gastaud 45 Date of Patent: Oct United States Patent (19) 11) Patent Number: 4,544,555 Gastaud 45 Date of Patent: Oct. 1, 1985 54 320-DIKETO, 6-METHYL, 1515284 6/1978 United Kingdom ............. 260/.397.4 17ALPHA-HYDROXY 19-NORPREGNA 4,6-DIENE, ITS ESTERS AND THE USES OTHER PUBLICATIONS THEREOF Chem. Abstracts, vol. 84 (1976), Par. 122,148(). 76) Inventor: Jean M. Gastaud, 3 avenue Prince Primary Examiner-Elbert L. Roberts Pierre, Monte Carlo, Monaco Attorney, Agent, or Firm-Gifford, VanOphem, 21 Appl. No.: 424,350 Sheridan, Sprinkle & Nabozny 22) Filed: Sep. 27, 1982 57 ABSTRACT A novel 3,20-diketo, 6-methyl, 17-alpha hydroxy 19 Related U.S. Application Data norpregna-4,6-diene is disclosed, along with a method 63) Continuation of Ser. No. 144,064, Apr. 28, 1980, aban for its production from 17-alpha-hydroxy 19-nor-prog doned, and a continuation-in-part of Ser. No. 577,009, esterone acetate. The 17-alpha acetic ester, and the May 13, 1975. 17-alpha saturated or unsaturated aliphatic carboxylic 51 Int, Cl* ............................. CO7J 5/00; CO7J 7/00 acid esters (having up to 11 carbon atoms) of the com 52) as a a was a 88 w 260/.3974 pound, are also disclosed. The compound and its deriva 58 Field of Search ...................................... 260/.397.4 tives are useful in the treatment of luteal deficiency, hyperestrogenic or hyperandrogenic conditions, and 56) References Cited seborrhea, either simple or complicated with acne. FOREIGN PATENT DOCUMENTS 2522533 12/1975 Fed. Rep. of Germany ... 260/3974 18 Claims, No Drawings 4,544,555 1. 2 and its 17-alpha esters, such as the 17-alpha-acetoxy 320-DIKETO, 6-METHYL, 17-ALPHA-HYDROXY ("Compound II' hereafter) and 17-alpha hexanoyloxy 19-NORPREGNA 4,6-DIENE, ITS ESTERS AND ("compound III' hereafter) esters. THE USES THEREOF The new compound of the invention can be prepared starting from 3,20-diketo, 17-alpha-acetoxy, 19-nor CROSS REFERENCE TO RELATED pregna 4,6-diene in the following sequence: APPLICATION A-The starting material is methoxylated by ethyl orthoformate in acid conditions into the 3-methoxy This application is a continuation of copending Ser. derivative. No. 144,064, filed Apr. 28, 1980, now abandoned; and a 10 B-Said 3-methoxy derivative is formylated using continuation-in-part of Ser. No. 577,009, filed May 13, Vilmeier's reagent (POCl3-dimethyl formamide) into 1975, now abandoned. the 3-methoxy, 6-formyl derivative. FIELD OF THE INVENTION agent. C-This product is reduced (C1) by sodium borohy dride to a non isolated intermediary, which, in acid SUMMARY OF THE PRESENT INVENTION 5 conditions, leads (C2) to 6-methylene, 17-alpha-acetox This invention relates to a new steroid of the series of y, 19-nor-progesterone which is isomerised in the pres compounds derived from 17-alpha-hydroxy, 19-nor ence of palladium charcoal, to 3,20-diketo, 6-methyl, pregna 4,6-diene 3,20-dione, and its use in human thera 17-alpha-acetoxy, 19-nor-pregna-4,6-diene, which is an peutics by the oral, perlingual, transcutaneous, rectal or ester of the compound (I) of the invention and therefore parenteral route, as a progestational, anti-estrogen, anti 20 comprised within the invention. androgen and pituitary-suppressing agent. D-This ester is hydrolyzed by methanolic potassium According to the invention, this new compound is to compound I, and can be further esterified, more 3,20-diketo, 6-methyl, 17-alpha hydroxy, 19-nor-pregna specifically, to the 17-alpha-hexanoyloxy derivative, 4,6-diene, having the formula (I) which is also comprised within the invention. 25 This sequence can be illustrated by the following CH3 (I) scheme: CH3 CE CH3 are oac -A se CHO CH2OH 4,544,555 3 4. 17-alpha-hydroxy 19-nor-progesterone acetate used as starting material in this process, has been described by EXAMPLE NO. 3 C. Djerassi et al. (J. Am. Chem. Soc. 1954,76,6210). Preparation of 6-methylene, 17-alpha-acetoxy, 19-nor According to another embodiment modification of progesterone (step C) this process an enol ether is used which must be for 5 1 g sodium borohydride was added during a period of mylated in position 6 according to the method (B) using 15 minutes at room temperature to 9 g of the product of the reagent formed from the action of phosphorus oxy step B, in a solution of 90 ml methanol. After extraction chloride (POCl3) on dimethylformamide (D.M.F.) with chloroform, the crude product was directly added (Belgian Pat. No. 610054). After reduction and dehy to 100 ml methanol to which 10 ml of 1 NHCl were dration to a 6-methylene derivative (C2), the compound 10 added. obtained is isomerised to a 6-methyl derivative (D), The mixture was shaken for 30 minutes at room tem according to a method that has already been reported perature and poured into 1 liter of water; the crystalline precipitate (5.5 g) was then dried. M.P. 195 C. Centesi (U.S. Pat. Nos. 3,117,966; 3,705,181; N.L. 6,911,649). mal analysis: C23H3004. According to a still further embodiment of the pres 15 ent invention, the intermediary 6-methylene derivative EXAMPLE NO. 4 can also be prepared by the action of N,N-dimethylfor Preparation of 3,20-diketo,6-methyl, 17-alpha-acetox maldimmonium trifluoroacetate (J. Am. Chem. Soc. y, 19-nor-pregna-4,6-diene (step D) 1968, 90,5622) on 3-methoxy, 17-alpha-acetoxy,20-keto, 600 mg sodium acetate and 1.2 g palladium charcoal 19-norpregna-3,5-diene (Upjohn, Belgian Pat. BE No. 20 were added to 1.2 g of the product of step C, in 240 ml 759,143). ethanol. The solution was refluxed for 1 hour and 30 The 6-methyl, 17-alpha-hydroxy, 3,20-diketo, 19-nor minutes. After extraction and crystallisation in metha pregna-4,6-diene derivative of the invention (I) is ob nol, crystals were obtained (60% yield). M.P. 178 C. tained by hydrolysis of the acetoxy derivative in the Centesimal analysis: C23H3004. presence of methanolic potassium. There can be pre 25 pared this compound (I) esters, comprised within the EXAMPLE NO. 5 invention, by action of an acid anhydride in the pres Preparation of 3,20-diketo,6-methyl, 17-alpha-hydrox ence of perchloric acid in a solvent such as chloroform. y, 19-nor-pregna-4,6-diene (Compound I) An acid chloride can also be used in pyridine or in a 1 g of the product of step D was dissolved in 40 ml solvent such as chloroform in the presence of triethyl 30 ethanol containing 20% water and 0.5 g potassium. amine or dimethylamino-4-pyridine. After one hour at 60 C., the reaction mixture was ex DETAILED DESCRIPTION OF THE tracted. The product obtained crystallised in methanol. PREFERRED EMBODIMENTS OF THE M.P. 204-205 C. Centesimal analysis: C2H28O3. PRESENT INVENTION 35 This process will be illustrated by the following non N.M.R. spectrum (60 megacycles/sec.; CDCl3; T.M.S. 8 = 0) CH3 at C20) singlet at 136 Hz limitative examples: CH3 at Co6) large singlet at 1 Hz EXAMPLE NO. 1 CH3 at C(3) singlet at 56 H2 Preparation of 3-methoxy, 17-alpha-acetoxy,20 keto, 19-nor-pregna-3,5-diene (step A) EXAMPLE NO. 6 17 ml ethyl orthoformate and 1 g p-toluenesulphonic acid were added to a suspension of 16.5 g of 17-alpha Preparation of 3,20-diketo,6-methyl, 17-alpha-hex acetoxy, 19-nor-progesterone in 250 ml dioxane. After 45 anoyloxy, 19-nor-pregna-4,6-diene (ester of Compound I) shaking for 3 hours at room temperature, 6 ml pyridine 1 g of Compound I was dissolved in 25 cc chloro were added; the reaction mixture was then shaken for a form; a solution of 3 cc hexanoic anhydride and 200 mg further 2 hours and slowly poured into 2 liters of water. p-toluenesulphonic acid were added. The reaction mix The precipitate was dried, washed and dried. ture was heated to its reflux temperature under a nitro After crystallisation in methanol containing 1% pyri gen atmosphere for 3 hours. Half of the solvent was dine, crystals (M.P. 212-214 C.) of a compound corre then distilled, and 15 cc ethanol and 0.2 cc concentrated sponding to a centesimal analysis of C23H32O4 were hydrochloric acid were added. This mixture was re obtained. fluxed for 1 hour under nitrogen. This was done with EXAMPLE NO. 2 55 the aim of hydrolysing the enol ester formed at position C3). The reaction mixture was then diluted with ice Preparation of 6-formyl, 3-methoxy, 17-alpha-acetox water and brought to pH 8 with sodium hydroxide. y,20-keto, 19-nor-pregna-3,5-diene (step B) After extraction, 3 g oil were obtained which crystal A mixture of 6.5 ml phosphorus oxychloride and 55 lised from hexane after purification by silica column ml dimethylformamide was slowly added to a solution 6 chromatography. Melting point: 132 C. of 9 g of the product obtained in step A in 100 ml of This substance is characterized by an infra-red spec anhydrous dimethylformamide. trun having absorption bands at After stirring for 1 hour and 30 minutes, the reaction 1735,1715, 1655, 1620, 1575 cm-1. mixture was poured into 1.5 liters of a saturated aqueous Solution of sodium bicarbonate. After extraction with 65 CLINICAL RESULTS chloroform, 11 g of the crude product were obtained Compound (I) is new; its progestational properties, which were used as such for the remaining part of the which are potential, are revealed by esterification of the synthesis.
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