WO1997023498A1 - 18-methyl 16-methylene 19-nor pregnane derivatives as progestins, pharmaceutical compositions containing them and process for the preparation thereof - Google Patents

18-methyl 16-methylene 19-nor pregnane derivatives as progestins, pharmaceutical compositions containing them and process for the preparation thereof Download PDF

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Publication number
WO1997023498A1
WO1997023498A1 PCT/HU1996/000076 HU9600076W WO9723498A1 WO 1997023498 A1 WO1997023498 A1 WO 1997023498A1 HU 9600076 W HU9600076 W HU 9600076W WO 9723498 A1 WO9723498 A1 WO 9723498A1
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methyl
methylene
17α
formula
hydroxy
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PCT/HU1996/000076
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French (fr)
Inventor
Zoltán Tuba
Anna Dancsi
Csaba MOLNÁR
János CSÖRGEI
György Falkay
Clyde Wayne Bardin
Vilma DUKÁT
Erzsébet FRANCSICS
József SZUNYOG
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Richter Gedeon Vegyészeti Gyár Rt.
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J7/00Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/004Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
    • C07J7/005Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa substituted in position 16
    • C07J7/0055Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group

Abstract

The invention relates to novel 16-methylene-17α-acyloxy-18-methyl-19-norpregn-4-ene-3,20-dione derivatives to pharmaceutical compositions containing these compounds; to the intermediates useful for the preparation of these compounds as well as a process for the preparation of these compounds and compositions. The compounds exert a progestogenic effect.

Description

18-METHYL 16-METHYLENE 19-NOR PREGNANE DERIVATIVES AS PROGESTINS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESS FOR THE PREPARATION THEREOF

This invention relates to novel 16-methylene-17α-acyloxy-18-methyl-19-norpregn-4- ene-3,20-dione derivatives of formula (I),

Figure imgf000003_0001
wherein

R stands for CMO alkyl group as well as pharmaceutical compositions containing these compounds.

Furthermore, the invention relates to the intermediates of formulae ( V ), ( Va ) and

(π)

Figure imgf000003_0002

Figure imgf000003_0003
( Va )

Figure imgf000004_0001
used for the preparation of compounds of formula (I), as well as a process for the preparation ofthe above compounds and compositions

In addition, the invention includes a method of treatment, which compπses administering to a mammal including man in the need of such treatment one or more therapeutically effective dose(s) of compounds of formula (I) alone or in the form of a pharmaceutical composition to avoid an undesired pregnancy and/or to cure endometπosis and/or to substitute of estrogens absent from or present in an insufficient amount m the body

C O alkyl moieties as R may be straight or branched chain groups and include methyl, ethyl as well as vaπous straight and branched chain propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl groups, from which Ci-g alkyl groups from methyl up to octyl are favourable, CM alkyl moieties such as methyl, ethyl, n-propyl, isopropyl as well as the vaπous butyl groups being most preferred

In addition to the compounds of formula (I) accordmg to the invention, a number of intermediary products of the process such as the intermediates of formulae (LI), (Ilia), (TLTb), (IV), (V), (Va), (VI) and (VII),

Figure imgf000004_0002
Figure imgf000005_0001

Figure imgf000005_0002

Figure imgf000005_0003

Figure imgf000005_0004

are also new. The 16-methylene-17α-acyloxy-18-methyl-19-norprogesterone deπvatives of formula (I) exert a progestogenic effect Thus, they can be used alone or in combination with an estrogen as active components of contraceptive compositions

Furthermore, the compounds of formula (I) can be utilized also in the medication of endometnosis as well as in the estrogen-substitutive therapy as gestagenic comcomitants ofthe estrogenic component

The therapeutical importance of progestogenic substances is evidenced by the great number of literature data, patent applications and scientific publications

Based on the most recent literature ( Pharmacology of the Contraceptive Steroids, Raven Press New York, 199. 440-442 ) gestagens, being therapeutically employed or be g in an advanced peπod of biological investigations, are classified into four large groups as follows

1 ) Norethisterone group

Ethynodiol diacetate (3β,17β-dιhydroxy-19-norpregn-4-en-20-yne diacetate) ynestrenol ( 17β-hydroxy- 19-norpregn-4-en-20-yne) Norethisterone ( 17β-hydroxy- 19-norpregn-4-en-20-yn-3-one)

Norethisterone enanthate (17β-hydroxy-19-norpregn-4-en-20-yn-3-one enanthate) Norethisterone acetate (17β-hydroxy-19-norpregn-4-en-20-yn-3-one acetate) Norethynodrel ( 17β-hydroxy- 19-norpregn-5( 10)-en-20-yn-3-one)

2 ) Norgestrel group Desogestrel ( 11 -methylene- 17β-hydroxy- 18-methyl- 19-norpregn-4-en-20-yne) Gestodene ( 17β-hydroxy- 18-methyl- 9-norpregna-4, 15-dιen-20-yn-3-one) Levonorgestrel (17β-hydroxy- 18-methyl- 19-norpregn-4-en-20-yn-3-one) Norgestimate (3-hydroxιmιno- 17β-hydroxy- 18-methyl- 19-norpregn-4-en-20-yn 17-acetate) Etonogestrel ( 11 -methylene- 17β-hydroxy- 18-methyl- 19-norpregn-4-en-20-yn-3-one) 3 ) Progesterone group Progesterone 17α-Hydroxyprogesterone

17α-Hydroxyprogesterone caproate (17α-hydroxypregn-4-ene-3,20-dιone caproate) Medroxyprogesterone acetate (6α-methyl-17α-hydroxypregn-4-ene-3,20-dιone acetate Chlormadinone acetate (6-chloro-17α-hydroxypregna-4,6-dιene-3,20-dιone acetate) Megestrol acetate (6-methyl-17α-hydroxypregna-4,6-dιene-3,20-dιone acetate)

4 ) Gestagens under investigation

Nomegestrol acetate (6-methyl-17α-hydroxy-19-norpregna-4,6-dιene-3,20-dιone acetate)

Nestorone (ST- 1435, 16-methylene-17α-hydroxy-19-norpregn-4-ene-3,20-dιone acetate)

The norpregnene deπvatives of formula (I) according to the invention are members of a new structural class different from those known in the art, and surpπsingly, their efficacy supercedes the gestagenic activity of norgestrel or the compound of code No ST-1435, which are most effective (In our comparative biological investigations, the compounds thought to be most effective up to present were employed as reference substances )

According to the invention, the 16-methylene-17-acyloxy-l 8-methyl- 19-norpregn-4- en-3-one compounds of formula (I) are prepared by reacting 18-methyl- 19-norandrost-4-ene-3-17-dιone of formula (IX)

Figure imgf000007_0001

with tπmethyl orthoformate m a polar solvent m the presence of sulfuπc acid, then, reacting the obtained 3-methoxy-18-methyl-19-norandrosta-3,5,-dιen-17-one of formu¬ la (VIII)

Figure imgf000007_0002
( vπi ) first with dimethyl oxalate in a polar solvent in the presence of an alkaline metal alkanoate and subsequently, with formaldehyde in the presence of acetic acid and tπethylamine, then, reacting the obtained 3-methoxy-16-methylene-l 8-methyl- 19-norandrosta-3,5-dιen- 17- one of formula (VII) a) either with an ethoxyvmyl lithium deπvative preferably prepared in situ from an alkyl lithium and ethyl vinyl ether and hydrolyzing the obtained novel 3-methoxy-16- methylene- 17α-( 1 -ethoxyvmyl)- 17β-hydroxy- 18-methyl- 19-norandrosta-3, 5-dιene of formula (VI) by acidic treatment to give 16-methylene-17α-acetyl- 17 β-hydroxy-18-methyl- 19- norandrost-4-en-3-one of formula (IV), or, b) with lithium acety de preferably prepared in situ from butyl lithium and acetylene, then hydrating the thus formed novel 3-methoxy-16-methylene-17α-ethynyl-17β- hydroxy-18-methyl- 19-norandrosta-3,5-dιene of formula (V) in the presence of mercury (II) oxide, if desired, after hydrolyzing it to 16-methylene-17α-ethynyl-17β-hydroxy-18-methyl- 19-norandrost-4-ene-3-one of formula (Va) by hydrochloπc acid, thereafter reacting with phenylsulfenyl chloπde 16-methylene-17α-acetyl-17β-hydroxy-18- methyl-19-norandrost-4-en-3-one of formula (IV) obtained either m route a) or b) , boiling 16-phenylsulfinylmethylene-l 8-methyl- 19-norpregna-4,16-dιene obtained in the form of a mixture of isomers of formulae (Ilia) and (lllb), m methanol in the presence of thiophilic reagent and tπethylamine under atmospheπc pressure, and finally, reacting the thus formed 16-methylene-17 -hydroxy-l 8-methyl- 19-norpregn-4-en-3- one of formula (II) with an acid anhydride of formula

(R-CO)2O or with an acyl chloπde of formula

(R-CO-C1), wherein R is the same as defined above, in the presence of a strong mineral acid

The method of preparation of 3-methoxy-l 8-methyl- 19-norandrosta-3,5-dιen-17-one of formula (VIII) from 18-methyl- 19-norandrostene-dιone of formula (IX) used as starting substance for the process according to the invention is in se known from the literature [Chem Ber .71 .1766 (1938)] According to the invention, the compound of formula (IX) is preferably reacted with tπmethyl orthoformate in a polar solvent in the presence of sulfuπc acid It is suitable to use tetrahydrofuran as polar solvent An 1 4 to 1 8, preferably 1 5-fold molar excess of tπmethyl orthoformate whereas 0 006-fold molar excess of sulfuπc acid are employed advantageously in tetrahydrofuran solution The reaction is earned out at a temperature range between 10 °C and 40 °C, preferably between 20 °C and 25 °C, suitably under nitrogen After termination of the reaction the mixture is neutralized by pyπdine, evaporated under reduced pressure and, after addition of an ether/petroleum ether mixture, the compound of formula (Vffl) is isolated in the form of a crystalline precipitate

A number of methods are known from the literature for prepaπng deπvatives containing the methylene ketone structural moiety in πng D of steroids According to two publications [J Chem Soc 1572, (1962), J Med Chem < 178 (1963)] these deπvatives are obtained through aminomethyl compounds, whereas methylene-ketosteroids are achieved through ethoxalyl compounds on the basis of other publications [ J Chem Soc 4312 (1963), and J Org Chem 32 . 3434 (1967)] According to the invention, it is advantageous to react a tetrahydrofuran solution of the compound of formula (VIII) produced in the preceding step first with dimethyl oxalate in the presence of sodium methoxide and subsequently, with aqueous formaldehyde solution m the presence of tnethylamine and acetic acid It is suitable to use an 1 7-fold molar amount of dimethyl oxalate, 2 4-fold molar amount of sodium methoxide, 0, 6-fold molar amount of acetic acid, 1,35-fold molar amount of tnethylamine and 1 4-fold molar amount of 35% aqueous formaldehyde solution The reaction is suitably earned out at a temperature from 20 °C to 25 °C The thus formed product of formula (VII) is separated by precipitation with an aqueous solution of sodium chlonde and sodium hydrogen carbonate

According to the invention, 16-methylene-17α-acetyl-17β-hydroxy-l 8-methyl- 19- norandrost-4-en-3-one of formula (IV) can be prepared from 3 -methoxy- 16-methylene- 18- methyl-19-norandrosta-3,5-dιen-17-one of formula (VII) in two ways Based on one of these methods the compound of formula (VII) is preferably reacted first with an ethoxyvmyl lithium compound prepared in situ from an alkyl lithium and vinyl ethyl ether then, the thus obtained 3-methoxy- 16-methylene- 17α-( 1 -ethoxyvmyl)- 17β-hydroxy- 18-methyl- 19-norandrosta-3, 5- diene of formula (VI) is hydrolyzed to 16-methylene-17α-acetyl-17β-hydroxy-l 8-methyl- 19- norandrost-4-en-3-one of formula (IV) in acidic medium The task ofthe first step is to form an (to introduce an) α-acetyl and β-hydroxyl group in position 17 of compound of formula (VII) In the chemical practice, the mtoduction of acetyl group is achieved by intervention of acetyl cation, e g in esteπfication and amidation reactions earned out by using acyl chloπdes or anhydπdes Vaπous Lewis acid catalysts, e g aluminium chloπde (Fπedel - Crafts type reactions), boron tπfluoπde, zinc chloride and like similarly result in the formation of acyl cations Such reactions are widely known

However, the formation of acyl anions and organic chemical reactions leading through such moieties are less known This is due thereto that the acyl group is easily formed as a cation as a consequence of its ground-state electron distπbution Its occurrence as anion cannot directly be achieved Only "hidden" acyl anions are known in the literature Actually, these are anions equivalent to acyl anions [ J A C S 96. 7125 (1974), as well as literature references 1 to 11 listed there] Synthesis of enol ether lithium deπvatives equivalent to acyl anions and reactions thereof with carbonyl compounds are descπbed in this paper In the course of such reactions, the respective enol ether lithium deπvative reacts through its unsaturated carbon atom connected to the ether oxygen with the carbon atom of the carbonyl moiety At this point, the 2-hydroxy-oxo- compound has been formed out, the oxo group only appears in an enol ether form The acidic hydrolysis thereof results in the free oxo-alcohol Inter aha, such reaction of the 17-oxo group of estrone methyl ether is discussed in the reference cited

According to the invention, after dissolving tertiary butyl lithium in tetrahydrofuran at a temperature of about -70 °C and adding ethyl vinyl ether thereto, the reaction mixture is heated to 0 °C to develop the lithium compound of ethyl vinyl ether Then, it is again cooled down to about - 70 °C and 3-methoxy-16-methylene-18-methyl-19-norandrosta-3,5-dιen-17- one of formula (VII) is added Under the conditions defined above the reaction proceeds at a rate suitable to the manufacture on industrial scale and results in good yield The thus formed 3-methoxy- 16-methylene-l 7α-(ethoxyvmyl)- 17β-hydroxy- 18-methyl- 19-norandrosta-3 ,5- diene of formula (VI) is isolated after decomposition of excess reagent or, the enol ether groups in positions 3 and 20 are directly hydrolyzed without isolation to obtain 16-methylene- 17α-acetyl- 17β-hydroxy- 18-methyl- 19-norandrost-4-en-3-one of formula (IV)

According to a prefeπed embodiment of the process of invention 8 moles of ethyl vinyl ether are added to a solution of 5 moles of tertiary butyl lithium dissolved in a mixture of n- hexane and tetrahydrofuran at - 60 °C , then the temperature ofthe reaction mixture is elevated to 0 °C to foπn the ethoxyvmyl lithium reagent Subsequently, the reaction mixture is again cooled down to - 60 °C and the tetrahydrofuran solution of 3-methoxy-16-methylene-18- methyl-19-norandrosta-3,5-dιen-17-one of formula (VII) is portionwise added

Tetrahydrofuran used in the reaction plays not only the role of solvent but it is simultaneously an important factor for the activation of tertiary butyl lithium dunng the formation of ethoxyvmyl lithium The reaction is earned out in an inert atmosphere, e g under argon, nitrogen or the like to exclude both air and humidity

After portionwise adding the tetrahydrofuran solution of the steroid to the reaction mixture suitably dunng 30 minutes, the reaction takes place within about 30 minutes Thereafter, the reaction is stopped by adding aqueous ammonium chlonde solution and ethyl acetate is added to the reaction mixture After separation and washing with water of the ethyl acetate phase 3 -methoxy- 16-methylene- 17α-( 1 -ethoxyvmyl)- 17β-hydroxy- 18-methyl- 19- norandrosta-3,5-dιene of formula (VI) can be isolated

The reaction could not be expected in the cases of 16-methylene-17-oxo-steroιd denvatives On the one part, a significant steπc hindrance is induced both by the 16-methylene as well as the 13-ethyl groups making difficult or delaying, respectively the entry of ethyl vinyl ether anion, and on the other hand, the exocyc c double bond incorporated by the 16- methylene moiety is conjugated with the 17-oxo group whereby the anionic attackabihty of the 17-oxo group is significantly diminished In an extreme case, this attack could have occuned (instead of 17-carbon atom) on the relatively positive methylene carbon taking place on the 16-carbon atom

The hydrolysis of the obtained 3-methoxy- 16-methylene-l 7α-(l -ethoxyvmyl)- 17β- hydroxy-18-methyl- 19-norandrosta-3,5-dιene of formula (VI) is preferably earned out in an acidic aqueous medium by using methanol, ethyl acetate or acetone as solvent After dissolving the compound of formula (VI) preferably in methanol, e g p-toluene-sulfonic acid and water are added to the reaction mixture The reaction takes place at 20 to 25 °C within a few minutes Subsequently, the reaction mixture is mixed with ethyl acetate, the ethyl acetate phase is washed with water and then with sodium chloπde solution until neutral and 16-methylene- 17α-acetyl-17β-hydroxy-l 8-methyl- 19-norandrost-4-en-3-one of formula (IV) is isolated from the solution - 10-

Accordmg to an alternative embodiment, the compound of formula (VI) is directly hydrolyzed without separating it from the ethyl acetate solution obtained in the course of preparation In this case , after adding an aqueous hydrochloric acid solution to the ethyl acetate solution of compound of formula (VI), the hydrolysis is performed at 20 to 25 °C temperature for 9 hours Further on, the compound of formula (IV) is isolated as descπbed above

An other known method of introduction of the 17α-acetyl group consists of introducing and then hydrat g the 17α-ethynyl group The ethynylation of keto steroids is published in a number of literature references Thus, accordmg to European patent specification No 0,104,054 the ethynyl deπvatives are prepared by reacting 16-methylene-17- oxoandrostane derivatives with lithium acetyhde formed from butyl lithium and acetylene

Compound of formula (V) can be prepared from compound of formula (VII) in a good yield by using this process at a lower temperature, namely at - 60 °C because of the enhanced sensitivity which is cheractenstic of 19-nor compounds The product obtained can be isolated by a simple precipitation with water and used in the next reaction without puπfication

According to a favourable embodiment of our invention the ethynylation reaction is carried out by reacting 3-methoxy-16-methylene-l 8-methyl- 19-norandrosta-3,5-dιen-17-one of formula (VII) in tetrahydrofuran solution with lithium acetyhde prepared from butyl lithium and acetylene. Suitably, 7 moles of butyl lithium are used for 1 mole of steroid The reaction is carried out at a temperature between - 40 °C and - 70 °C, preferably at - 60 °C dunng 2 5 hours The 3-methoxy- 16-methylene- 17α-ethynyl- 17β-hydroxy- 18-methyl- 19-norandrosta- 3,5-dιene of formula (V) formed in the reaction is separeted by precipitation with water

The reaction mixture of ethynylation may be worked up also in such a way that the 3- enol ether group is hydrolyzed by methanolic hydrogen chloride without isolation of the compound of formula (V), and then 16-methylene-17α-ethynyl-17β-hydroxy-l 8-methyl- 19- norandrost-4-ene-3-one of formula (Va) is isolated

The hydratation of the thus obtained compounds of formulae (V) and (Va) is achieved by a process known in se from the literature [ Helv Chim Acta 26^ 680 (1943)] for analogous compounds According to the invention the compound of formula (V) or (Va), respectively is reacted in a polar solvent with the aqueous sulfuric acid solution of mercury (II) oxide In the process of the invention ethanol, methanol, preferably acetone are used as polar solvents An aqueous sulfuπc acid solution of mercury (II) oxide is prepared by dissolving 0 5-fold molar amount of mercury (II) oxide in an aqueous solution containing 2-fold molar amount of sulfuric acid In addition to hydratation of the ethynyl group, the hydrolysis of 3-enol ether group simultaneously occurs in the reaction According to the invention, the process of hydratation is earned out at a temperature range between 40 °C and 60 °C, preferably between 50 °C and 55 °C The reaction mixture is worked up in such a way that, after clarification with a 0 5-fold weight of celite, acetone is distilled off under reduced pressure After addition of water the crude product is filtered, exemphted from mercury by zinc powder in methylene chloπde solution in the presence of acetic acid and finally, by changing methylene chloπde for acetone dunng distillation, the compound of formula (IV) is obtained in a crystalline form

The next step of the synthesis comprises isomenzation of 17-carbon atom of the compound of formula (IV) obtained m the above reaction routes with the other parts of the molecule left intact The 16-methylene group and 17-hydroxyl group of the compound of formula (IV) represent an allyl alcohol type bond system

On the basis of literature, several authors have been engaged in the rearrengement of arylsulfe c acid esters (arylsulfenates) of allyl alcohol type systems [J A C S 4870 (1968), ibidem 2100 (1970), ibidem 4956 (1971), ibidem 3672 (1972), ibidem 6774 (1974)] In a publication [ ibidem 4956 (1971)], the reversible transformation of arylsulfemc acid esters denved from allyl alcohol systems and of the rearranged allyl sulfoxides formed therefrom were discussed It is desenbed in an other publication [ ibidem 3672 (1972)] that an arylsulfemc acid ester of an allyl alcohol having a given spatial structure can be transformed to the respective allyl sulfoxide which can be balanced by a reverse-rearranged arylsulfemc acid ester possessing two kinds of spatial positions By the reaction of these with a thiophilic reagent, the onginal starting allyl alcohol or an isomer thereof, respectively of inverse spatial position were obtained The ratio of isomers formed depends upon the stability of the product, solvents, or nature ofthe thiophilic reagent

The preparation of several 16-methylene 17α-hydroxypregnane denvatives on the basis of these pnnciples is desenbed in the published European patent application No 0, 104,054 and the conformal United States patent specification No 4,567,001 which possesses a more restricted scope of protection and is not related to 19-norsteroιds The essence of the process disclosed in the patent specification compnses reacting a 16-methylene-17β-hydroxysteroιd with an arylsulfemc acid halide to obtain the unsaturated isomers of 16-phenylsulfinylmethylene derivative, wherem the double bond takes place in endo or exo, respectively position in relation to the πng D The isomers thus obtained are transformed to the respective 16-methylene-17α- hydroxy-pregnane denvatives in the presence of a thiophilic reagent in a solvent medium, preferebly by heating under pressure

The above literature data can be evaluated only in a limited degree No yield is given in the Examples concerning descπption of preparation of the arylsulfoxide denvative By considenng that (as mentioned above) in principle in course of the reaπangement in question hydroxy deπvatives are obtained, the configuration of which is identical with or opposite to that of allyl alcohol used as starting substance, no teaching is given concerning the proportion of the desired pregnane denvative and recovery of the starting isopregnane compound It is mentioned in the descnption that the 16-arylsulfinylmethylene denvative being formed through the respective sulfenic acid ester can be a mixture of two isomers, from which the characteristics ofthe endo isomer are only descπbed

However, when according to the above patent specification the respective 16-aryl- sulfinylmethylene denvative was tned to prepare by starting from 16-methylene-17 -acetyl- 17β-hydroxy-l 8-methyl- 19-norandrost-4-en-3-one of formula (IV) (by carrying out the reaction at - 20 °C in methylene chlonde by using a 2-fold molar excess of phenylsulfenyl chloπde), it was found that the reaction is multidirectional and, in addition to the desired 16- phenylsulfiny Imethyl ene derivatives of formulae (Ilia) and (lllb) a significant amount of start¬ ing substance remains in the reaction mixture and the reaction stops after one hour

According to our examinations the phenylsulfenyl chlonde reagent is decomposed when the above reaction conditions are maintained dunng the reaction This is the direct reason for the stop of reaction In addition, a significant amount of by-product is formed, from these, 16α-chloro- 16 β-phenylthiomethylene- 17α-acetyl- 17β-hydroxy- 18-methyl- 19- norandrost-4-en-3-one (formed in the addition reaction of the exocyc c methylene group) as well as the 17β-ρhenylsulfenyl-16-methylene derivative (formed by the undesired rearrangement of 17-sulfenιc acid ester intermediate) were isolated It has surpπsmgly been found that the denvative of formula (II) can be prepared from the compound of formula (IV) as starting substance under industπally applicable, simple reaction conditions in a good yield by reacting 16-methylene- 17α-acetyl- 17β-hydroxy- 18-methyl-l 9-norandrost-4-en-3- one of formula (IV) with an at least 2-fold molar excess of phenylsulfenyl chloπde in a mixture of carcon tetrachloπde and methylene chlonde containing 15 to 25 % by weight of carbon tetrachloride, at a temperature between - 50 °C and 0 °C, in the presence of 3-5-fold molar excess of tnethylamine, and subsequently boiling 16-phenylsulfinylmethylene-l 8-methyl- 19-norpregna-4, 16-dιene, obtained as a mixture of the isomers of formulae (Ilia) and (lllb), in methanol in the presence of a thiophilic reagent and tπethylamine under atmospheπc pressure

According to a preferred embodiment of the sulfenylation reaction the compound of formula (IV) is reacted with phenylsulfenyl chloπde at a temperature between - 50 °C and - 40 °C It is suitable to introduce a carbon tetrachloπde solution of phenylsulfenyl chlonde to a methylene chloπde solution of the steroid and to select suitable concentration conditions to provide the presence of 15 to 25 % by weight of carbon tetrachloπde in the reaction mixture on introducing the required reagent The decomposition of the reagent can be prevented by this solving and therefore, the reagent will be present in each moment in a suitable concentration for the complete reaction ofthe steroid If the sulfenylation reaction is earned out as desenbed above, a mixture of 7 3 ratio of diastereomers of formulae (Ilia) and (lllb) is obtained These two modifications are different from each other in the sequence of groups on the sulfoxide sulfur chiral centre Thus, the isomeπsm of the novel compounds of formulae (Ilia) and (lllb) not desenbed till now in the literature is a new example of the stereoisomeπsm of sulfoxide deπvatives in the class of steroids The course of reaction leading to compound of formula (II) is not affected by the presence of both isomers

On the basis of the literature it could not be expected and it is considered to be a surpnsmg recognition that, under the given reaction conditions, carbon tetrachlonde exerts a stabilizing effect on phenylsulfenyl chloπde, prevents its self-decompositin and simultaneously, it provides a very good yield in the desired reaction The mixture of compounds of formulae (Ilia) and (lllb) resulted from the sulfenylation reaction are recovered from the rection mixture in such a way that, after termination of the reaction, the excess of phenylsulfenyl chloride is decomposed by adding water and/or methanol, the reaction mixture is washed with aqueous hydrochlonc acid solution and water until neutral and after drying, the solvent is removed under reduced pressure The mixture of the compounds of formulae (Ilia) and (lllb) is obtained by adding n-hexane to the distillation residue

Subsequently the obtained mixture compnsing the compounds of formulae (Ilia) and (lllb) is reacted with a thiophilic reagent in methanol solution in the presence of tπehtylamme It is preferable to use tnmethyl phosphite as thiophilic reagent and to carry out the reaction suitably at 60 to 66 °C temperature under atmospheric pressure Preferably the mixture of compounds of formulae (Ilia) and (lllb) is reacted with a 0 6-fold molar amount of tπethylamine and 4-fold molar excess of tπmethyl phosphite

The 16-methylene-17α-hydroxy-l 8-methyl- 19-norpregn-4-ene-3,20-dιone of formula (II) prepared according to the invention is obtained from the reaction mixture by pounng it into an aqueous solution containing 10 % of sodium chloπde, and then isolating crystalline product

In the final step of these synthesis, 16-methylene-17α-hydroxy-l 8-methyl- 19-norpregn- 4-ene-3,20-dιone of formula (II) is acylated in a manner known in se [P F G Praill Acylation Reactions (1963), Pergamon Press ], e g in a mixture of acetic acid and acetic anhydπde in the presence of perchloric acid at a temperature between 15 °C and 25 °C in order to prepare a compound of formula (I) containing methyl group as R Thus, the compound of formula (II) is preferably suspended m a 5-fold volume of acetic acid and reacted with a 8-fold molar amount of acetic anhydπde in the presence of 1 5 molar amount of 70 % perchloπc acid This reaction is advantageously earned out at a temperature between 20 °C and 25 °C

The 16-methylene- 17α-acyloxy-l 8-methyl- 19-norpregn-4-ene-3 ,20-dιone derivatives of formula (I) prepared according to the invention are isolated after pounng the reaction mixture onto water

The biological activity of the novel 16-methylene-17α-acyloxy-l 8-methyl- 19- norpregn-4-ene-3,20-dιone derivatives of formula (I) according to the invention was studied as follows 1 ) CLAUBERG TEST

The Clauberg test is bioassay used to measure the progestagenic activity of compounds by administering the test progestin to immature female rabbits pπmed with 17β- estradiol [Contraception 36^ 181-192 (1987)] The test progestin will induce a change in the endometnum from the proliferative to the secretory stage The extent of the change of the endometnum is measured by McPhail Index [J Physiol 81, 141 (1934)] In this assay estradiol is administered initially to pπme the uterus, followed by varying doses of progestins Progesterone and levonorgestrel, known progestins, are used as positive control for companson of potency Estradiol-pnmed rabbits treated with corn oil are used as negative controls The aim of the study is to determine the doses of formula (I) (progestm) having half maximum progestagenic activity (ED50 value) and compare its potency to that of Nestorone, levonorgestrel and progesterone

Immature female New Zealand rabbits (700-800 g) were obtained from Mareland

Farms (Hewitt, NJ) All steroids were dissolved in ethanol and made up to the appropnate concentrations with corn oil 17β-estradιol (Sigma no E4260) was prepared at a concentration of 5μg / 0 2 ml in corn oil The suspension was stirred for 2 h at room temperature on a magnetic stirrer

The compounds tested were

1 Compound of formula (I) 16-methylene- 17α-acetoxy- 18-methyl- 19-norpregn-4- ene-3,20-dιone

2 Nestorone progestin (ST 1435, 16-methylene-17α-acetoxy-19-norpregn-4-ene-

3,20-dιone)

3 Levonorgestrel ( 17 β-hydroxy-18-methyl- 19-norpregn-4-en-20-yne-3 ,20-dιone)

4 Progesterone (pregn-4-ene-3,20-dιone)

Nestorone and levonorgestrel solutions were prepared at the following concentrations 100, 30, 10, 3, 1 and 0 3 μg in 0 2 mL of corn oil The concentration of the compound No 1 was expanded to include 10, 5, 3, 0 5, 0 3 μg in 0 2 mL of corn oil

Progesterone solutions were prepared in the following concentrations 1 mg, 500μg, 300μg, 150μg, 1 OOμg and 50μg in 0 2 mL of corn oil

Bourn's solution (Sigma, St Louis, MO) was used as the tissue fixative On the first day of the expenment, all rabbits were weighed and their body weights recorded For six consecutive days, each rabbit was injected subcutaneously with 5 μg/day of estradiol to pπme the uterus The injection site was the hindquarters or the back of the neck Subsequently, the estradiol-pnmed rabbits were divided into groups of five or six rabbits each Animals in each group were injected subcutaneously with progestin for five consecutive days The negative control group animals were injected with 200μl of corn oil

On the 12th day, the animals were killed by asphyxiation with CO2 The body weights were recorded and the uterus excised Excess fat was removed and the utenne weights recorded Each uterus was fixed in Bourn's solution The tissues were embedded in paraffin, sectioned and stained with hematoxylin and eosin Three sections of each utenne horn were prepared The slides were examined for determination of the McPhail Index of endometnal growth

The body and utenne weights and McPhail indices for the control and treated rabbits are shown m Table I

Table I. Progestagenic Activity of the compounds tested in the Rabbit (Clauberg Test)

Compound Dose n Mean body Utenne wt Utenne McPhail

(μg Rabbit/ wt gain (g) cross-sect Index * day) (g) diameter

(mm)

0 3 6 477±99 1 95±0 381 3 2±0 26 4 6

0 5 5 366±144 1 96±0 491 3 3±0 451 4 0

1 5 48U86 3 84±1 443 4 l±O 653 5 6

3 6 447±107 5 22±1 073 4 8±0 423 7 5

10 6 521±55 6 42±1 313 5 4±0 383 8 6

2 0 3 6 490±43 1 52=0 37 2 66±0 26 2 0

2 1 6 465±28 2 95±0 463 3 50±0 453 6 2

2 3 12 417±74 4 34±0 813 4 58±0 363 8 8

2 10 40 402±139 5 OO±O 973 4 98±0 643 8 8

2 30 6 417±81 4 03±0 483 4 50±0 323 10 0

2 100 6 389±37 4 60±1 213 4 92±0 803 10 5 3 3 6 360±80 1 58±0 32 2 83±0 26 3 2

3 10 6 314±143 2 16±0 902 3 33±0 412 5 2

3 30 6 336±116 3 24±0 563 4 OO±O3 8 0

3 100 33 420±74 3 97±0 563 4 39±0 433 7 6

4 50 5 436±30 1 96±1 16 3 3±0 76 3 3

4 100 5 378±187 2 12±0 662 3 6±0 42 ' 4 5

4 150 5 411±135 2 36±0 773 3 9±0 551 5 6

4 300 12 332±52 3 05±1 IO3 3 δ±O.51 5 4

4 500 12 382±34 3 46±0 623 4 O±O 332 6 3

4 1 mg 12 369±81 4 27±0 853 4 6±0 292 7 4

Controll 0 34 408±145 1 38±0 50 2 81±0 49 2 2

* McPhail Index, uterine estrogenic / progestagenic activity n number of rabbits

0 P<0 05

C) P<0 01

0 P<0 001

The minimum effective doses required to the increase of utenne weight are as follows Compound 1 0 3 μg/rabbit/day

Compound 2 1 0 μg/rabbit/day Compound 3 10 0 μg/rabbit/day

Compound 4 100 0 μg/rabbit/day

A dose-response mcrease in utenne weights was determined by administeπng

Nestorone at doses ranging from 0 3 to 10 μg/rabbit/day, denvative 1 from 0 3 μg to lOμg/rabbit/day, levonorgestrel from 3 to 100 μg/rabbit/day and with progesterone at doses from 50 μg to 1 mg Based on the plot of uterine weights, the approximate doses that elicited half maximal response (ED5o) were determined

Compound 1 1 0 μg/rabbit/day

Compound 2 1 0 μg/rabbit/day

Compound 3 20 0 μg/rabbit/day Compound 4 200 0 μg/rabbit/day

The minimum effective dose to induce an increase in the McPhail index were

Compound 1 0 3 μg/rabbit/day

Compound 2 1 0 μg/rabbit/day Compound 3 30 0 μg/rabbit/day

Compound 4 50 0 μg/rabbit/day

The McPhail index reached a near maximal level (8 8) with Nestorone at a dose of 10 μg/rabbit/day At higher doses of 30 and 100 μg/rabbit/day a slight increase occured ( 10 0 and 10 5, respectively) Maximal response in the McPhail Index was obtained with levonorgestrel (8 0) at a dose of 30 μg/rabbit/day, with Compound 1 (8 6) at 10 μg and with progesterone (74) at 1 mg/rabbit/day The doses (ED50) inducing half maximal response with

Compound 1 1 0 μg/rabbit/day,

Compound 2 1 0 μg/rabbit/day, Compound 3 10 0 μg/rabbit/day and

Compound 4 were estimated as 100 0 μg/rabbit/day, respectively These estimates are approximates as the dose response curves do not have the same slope The body weights of all progestin treated animals remained unchanged

Progestagenic activities were determined using the Clauberg test The lowest effective doses showing progestagenic activity determined by the Clauberg test (uterine weights and McPhail index) were

0 3 μg/rabbit/day for Compound 1,

1 0 μg/rabbit/day for Compound 2,

3 0 μg/rabbit/day for Compound 3 and 100 0 μg/rabbit/day for Compound 4

Based on the minimum effective doses, Compound 1 is more potent than Nestorone, and Nestorone is about three times and 100 times more potent than levonorgestrel and progesterone, respectively

Based on the ED50 values, Nestorone and Compound 1 have equivalent potency and are about 10-20 times and 100-200 times more potent than levonorgestrel and progesterone, respectively The ED50 data of the Clauberg test show that the order of decreasing progestagenic potencies ofthe compounds tested is as follows

Compound 1 = Nestorone > levonorgestrel > progesterone

2 ) MAINTENANCE OF PREGNANCY IN RATS

Progestogen is required to maintain the pregnancy in rats After removal of the ovary of pregnant rats the pregnancy can be maintained by introducing progestogen into the body. In this biological test, the ovaπes of pregnant rats are removed on the 8th day following the embedding ofthe fertilized zygote The progestogen is daily administered together with estrone from the 8th to the 21th day in order to maintain the pregnancy The presence of embryo is examined in the uterus on the 22nd day [Proc Soc Exp Biol Med 99,. 500-504 (1958), and Intemat J Fert & 15-20 (1961)]

The aim of this experiment is to determine the minimum effective doses of the gestagens tested, which are required to maintain the embryo developing in the pregnant rat Young adult female Sprague Dawley rats (approx 200-250 g) were purchased from

Charles River (Wilmington, MA) The following concentrations of Nestorone were prepared 3, 1, 0 3, 0 1, 0 03 and 0 01 mg in 0 2 mL of corn oil Estrone suspension (Sigma no E-9750) was prepared in a concentration of 1 μg/0 lmL in corn oil

The compounds tested were identical to those investigated in the Clauberg test Female rats were placed each with a male breeder in a suspended cage in the morning

The next morning the lining paper underneath the cages was examined for vaginal plugs The presence of vaginal plug was recorded as day 1 of pregnancy The pregnant rats were separated from the males and their ovaπes were removed on the 8th day of pregnancy From the day of surgical intervention up to the 21th day of pregnancy each animal received daily 1 μg of estrone and vaπous doses of the gestagens tested in subcutaneous injection The rats of negative control group received 1 μg of estrone in corn oil without gestagen On the 22nd day the animals were killed by asphyxiation with CO2 from dry ice The number of embryos found in the oviduct was registered

The result of tretment of pregnant rats with increasing doses of gestagens from 8th to 21st day are shown in Table II A The enhancement of pregnancy-maintaining effect was expressed as percentage of treated rats in relation to the control group Table ELA Maintaince of pregnancy in ovariectomized rats by various gestagens and estrone

Compound No Dose n Number of Number of Pregnancy

(mg/rat/day) pregnant rats embryos(mean) maintained (%)

1. 0 01 5 4 10 5±3 9 80

1. 0 03 6 6 13 2±2 5 100

1. 0 1 5 4 9 0±3 4 80

1. 0 3 5 5 15 4±3 5 100

2. 0 01 5 0 0

2. 0 03 5 2 11 5±3 5 40

2. 0 1 6 3 12 3±1 5 50

2. 0 3 19 19 1 1 4±3 5 100

2. 1 5 5 12 0±2 0 100

2. 3 4 4 12 7±2 1 100

3. 0 3 5 5 13 8±3 1 100

3. 0 5 6 6 14 0±2 5 100

4. 0 3 5 0 0 0

4. 1 5 2 10±7 1 40

4. 3 5 3 8 0±1 0 60

4. 5 6 6 12 2±4 3 100

4. 8 6 6 1 6±1 9 100

4. 10 5 5 14 8±2 3 100 Control 0 19 0 0 0 n number o "rats in separate g roup s

The minimum effective daily doses of the tested gestagens, which are required to maintain the pregnancy in 100% of treated animals, are as follows Compound 1 0 03 mg/rat/day

Compound 2 0 3 mg/rat/day

Compound 3 0 3 mg/rat day Compound 4 5 0 mg/rat/day

It has been published in 1994 that estrone is not required to this examination [R A Edgren Issues in Animal Pharmacology, Golzieher and Fotherby, eds , In Pharmacology of the Contraceptive Steroids, Raven Press, NY ,(1994),Chap , pp 86-89] Therefore , the progestogens were studied in the pregnancy maintaince test without estrone, too Nestorone and Compound 1 are in the tested doses equally effective without or with estrone However, progesterone and levonorgestrel were in the tested doses without estrone less effective than m the presence of estrone It was concluded therefore that the presence of estrone is required in this test The result obtained are shown in Table ILB

Table HB. Maintaince of pregnancy in ovariectomized rats by various gestagens without estrone

Compound Dose n Number of Number of Pregnancy

No (mg/rat/day) pregnant rats embryos (mean) maintained

(%)

1. 0 1 6 6 15 3±1 2 100

1. 0 3 5 5 14 2±1 5 100

2. 0 3 6 6 13 O±l 8 100

3. 0 3 6 5 12 8±2 3 83

3. 0 5 5 5 13 4±3 5 100

4. 1 5 0 0 0

4. 3 5 1 l±O 20

Control 0 5 0 0 0 n number of rats in the separate groups

Compound 1 proved to be effective and progesterone was least effective The effect of Nestorone was equal to that of levonorgestrel Compound 1 was found to be 10 times as effective as Nestorone or levonorgestrel

Estrone is also required as adjuvant to the examination Nestorone and compound 1 exert identical effect with or without estrone, however, progesterone and levonorgestrel are in the tested doses less active without estrone than in the presence thereof Based on the pregnancy-maintaining activity, the following order of the tested progestogens can be stated

Compound 1 > Nestorone = levonorgestrel > progesterone The summary of results of both tests is illustrated in Table III Table m.

Comparison of activities of various gestagens in the separate tests

Test Order of activities and doses of tested gestagens

Cauberg (rabbit) Compound 1 > Nestorone > levonorgestrel >progesterone 0 3 μg / l O μg / 3 μg / 100 μg

Maintaince of Compound 1 > Nestorone > levonorgestrel > progesterone pregnancy (rat) 0 03 mg / 0 3 mg / 0 3 mg / 1 0 mg

Table III shows the mimmum effective doses, which are not identical to the doses required develop the total effect By summanzmg the results of Clauberg test and maintaince of pregnancy it can be stated that compound 1 according to the invention proved to be most effective when investigated by either of both methods

The novel compounds of formula (I) are employed alone or m the form of their salts, suitably in formulations commonly used in the therapeutics These formulations (medicaments) are solid, liquid or semi-solid, filling, diluting, stabilizing (preserving) agents, substances influencing the pH value and osmotic pressure, savouπng and flavouring agents as well as additives and auxihanes facilitating or making possible the formulation, which are commonly employed in the preparation of such compositions, may be used for their preparation

The solid pharmaceutical compositions may be e g tablets, dragees, capsules, wafered powder compositions or powder-ampouled compositions for the preparation of injections

Liquid compositions are the injectable and infusion compositions, liquid medicines, compact compositions and drops Semi-liquid compositions are the ointments, balsams, cremes, shaking mixtures and suppositones

The pharmaceutical composition in administered to the patient in such amount, which contains the dose of the active compound (component) required to achieve the desired effect

This dosage depends on the degree of disorder, seventy of the clinical picture desired to mfluence, body weight of patient, sensibility of the patient against the active compound and number of the daily treatments The dose to be used can with safety be determined by the attending physician skilled in the art m knowledge ofthe patient to be treated

For the sake of simple administration the pharmaceutical compositions are suitably dosage units containing tha active compound in an amount of a single dose or a low-number multiple thereof , or a half, third or fourth part thereof Such dosage units are e g tablets, which can be provided with a groove facilitating the halving or quarteπng ofthe tablet in order to obtain the required amount of active compound

The tablets can be coated with an acid-insoluble layer to make them entenc-coated to assure that the tablets release their active compound content after leaving the stomach A similar effect can be achieved by encaptulating the active compound

The pharmaceutical compositions containing an active compound according to the invention usually contain 0 01 to 100 μg of active compound in each dosage unit It is also possible of course that the amount of active compound exceeds m some compositions the lower or upper limit given above

The invention is illustrated in more detail by the following non-limiting Examples

Example 1 3 -Methoxy- 18-methyl- 19-norandrosta-3 , 5-dιen- 17-one

To a solution prepared from 100 g (0 35 mol) of 18-methyl- 19-norandrost-4-ene-3, 17- dione with a mixture of 500 ml of tetrahydrofuran and 60 ml (0 55 mol) of tπmethyl orthoformate, the solution of 0 12 ml of concentrated sulfunc acid in 11 ml of tetrahydrofuran is added at a temperature of 20-25 °C then, while bubbling nitrogen through, the mixture is stirred for 2 hours Subsequently, after adding 37 ml of pyndine to the reaction mixture, the mixture is evaporated to a volume of 260 ml under reduced pressure Then, 75 ml of a mixture containing petroleum ether and diethyl ether in 2 1 ratio are added to the evaporation residue The crystal suspension formed is cooled down to a temperature between 0 °C and -5 °C, the precipitate is filtered, washed with a mixture of petroleum ether and diethyl ether of the above ratio and dπed at 50 °C to obtain 94,4 g (90% yield) ofthe title product, m p 157-160 °C Example 2 -24-

3-Methoxy- 16-methylene- 18-methyl- 19-norandrosta-3 , 5-dιen- 17-one To a solution containing 75 g (0 25 mol) of 3-methoxy-18-methyl-19-norandrosta-3,5- dιen-17-one in 950 ml of tetrahydrofuran, 55 5 ml (0 47 mol) of dimethyl oxalate and 117 ml of 28 % sodium methoxide solution (0 6 mol) are added under nitrogen flow After stirπng at 20-25 °C temperature for 30 minutes, 9 ml of glacial acetic acid, 47 ml of tnethylamine, 180 ml of methanol and 30 ml of 35% aqueous formaldehyde solution (0 35 mol) are added The thus obtained suspension is stirred at 20-25 °C for 5 hours and then allowed to stand for 1 to 2 hours Subsequently, the reaction mixture is added to 19 litres of a solution containing sodium chlonde and sodium hydrogen carbonate and stirred for 1 hour The precipitated product is filtered, washed with water until neutral and dned at 50 °C temperature to give 74 8 g (95 9%) of title product, mp 175-180 °C Example 3

16-Methylene- 17α-acetyl- 17β-hydroxy- 18-methyl- 19-norandrost-4-en-3-one A mixture consisting of 160 ml of n-hexane and 400 ml of tetrahydrofuran is cooled to -60 °C under flowing nitrogen, then 400 ml of tertiary butyl lithium solution of 1 7 mol/litre concentration (0 68 mol) are dropwise added during 30 minutes, and after 5 mmutes 104 ml (1 08 mol) of ethyl vinyl ether are added at -60 °C Thereafter, the reaction mixture is heated to 0 °C, stined at 0 °C for 10 minutes, and cooled again to -60 °C While maintaining the temperature below -60 °C, 40 g (0 128 mol) of 3-methoxy-16-rnethylene-l 8-methyl- 19- norandrosta-3,5-dιen-17-one dissolved in 800 ml of tetrahydrofuran are added within 30 mmutes After stirnng for 30 minutes, 40 g of ammonium chlonde dissolved in 400 ml of water are dropped to the reaction mixture After separation ofthe phases the aqueous layer is washed with 200 ml of ethyl acetate To the combined organic phase 15 ml of concentrated hydrochlonc acid diluted with 400 ml of water are added and the mixture is stined at 20 to 25 °C temperature for 1 hour, then allowed to stand for 8 hours After separation the aqueous phase is extracted with 200 ml of ethyl acetate The combined organic phase is washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to a volume of 80 ml under reduced pressure After addition of 60 ml of hexane the residue is cooled down to 0 °C and stined at the same temperature for 1 hour After filteπng, the crystalline precipitate is dned at 50 °C to result in 31 6 g (72%) of title compound, m p 125- 130 °C Example 4

3-Methoxy- 16-methylene- 17α-ethynyl- 17β-hydroxy- 18-methyl- 19-norandrosta- 3,5- diene

Under streaming nitrogen 200 ml of 15% solution of butyl lithium in hexane (0 47 mol) are added to 800 ml of tetrahydrofuran cooled to -10 °C about dunng 10 minutes To the solution obtained gaseous acetylene is introduced at -10 °C for 1 hour Subsequently, the reaction mixture is cooled to -60 °C and the solution of 20 g (0 064 mol) of 3-methoxy-16- methylene-18-methyl- 19-norandrosta-3,5-dιen-17-one in 200 ml of tetrahydrofuran is added After stirπng under nitrogen stream at -60 °C for 2 5 hours, the reaction mixture is poured onto 2 litres of water and extracted 3 times with 500 ml of ethyl acetate each The combined ethyl acetate solution is washed with water and saturated sodium chlonde solution, dned over anhydrous sodium sulfate, evaporated to a volume of 50 ml under reduced pressure and cooled to 0 °C After filtration the product is dried at 50 °C to give 15 g of title compound, m p 150- 152 °C Example 5

16-Methylene- 17α-ethynyl- 17β-hydroxy- 18-methyl- 19-norandrost-4-en-3-one The process desenbed in Example 4 is followed, except that for working up a mixture of 20 ml of hydrochlonc acid solution and 140 ml of methanol is added In this way 14 5 g of title compound are obtained, m p 170-174 °C Example 6

16-Methylene- 17α-acetyl- 17β-hydroxy- 18-methyl- 19-norandrost-4-en-3 -one

A solution of 9 9 ml (0 185 mol) of concentrated sulfunc acid and 2 g of yellow mercury(II) oxide in 60 ml of water is added to the solution containing 60 g (0 185 mol) of 3- methoxy-16-methylene-17α-ethynyl-17β-hydroxy-l 8-methyl- 19-norandrosta-3,5-dιene in 300 ml of acetone The reaction mixture is heated to 50-55 °C and stirred at this temperature for 1 hour After adding 30 g of celite and additional stirπng for 30 minutes, the reaction mixture is filtered, poured onto 2 4 litres of water and stiπed for 15 minutes After filtration the crystalline precipitate is washed with 300 ml of water until neutral and dned at 60 °C Thus, 59 g of crude product are obtained, which is dissolved in 590 ml of methylene chlonde containing 3 ml of acetic acid, then stirred with 0 6 g of zinc powder for 30 minutes Subsequently, 20 g of celite are added, the reaction mixture is filtered, the filtrate is clanfied by activated charcoal and evaporated under reduced pressure until it becomes solvent free After crystallization ofthe evaporation residue from acetone 48 5 g (80%) of title compound are obtained, m p 125-130 °C

Example 7 16-Phenylsulfinylmethylene- 18-methyl- 19-norpregna-4, 16-dιene-3,20-dιone

A solution containing 32 8 g (0 1 mol) of 16-methylene-17α-acetyl-17β-hydroxy-18- methyl-19-norandrost-4-en-3-one and 55 7 ml of tnethylamine in 328 ml of methylene chlonde

*ιs cooled to -50 °C and 28 8 g (0 2 mol) of phenylsulfenyl chlonde dissolved in 82 ml of carbon tetrachloπde are added at the same temperature about dunng 20 minutes The reaction mixture is stirred at this temperature for 4 hours and the process of reaction is observed by thin layer chromatography After completion of the reaction 65 ml of methanol and 130 ml of hydrochlonc acid solution of 2 mol/litre concentration are added to the reaction mixture which is warmed to 20-25 °C Then, the methylene chloπde phase is separated, washed with 300 ml of water, dned over anhydrous sodium sulfate and evaporated under reduced pressure until solvent free The evaporation residue is recrystallized from a mixture of acetone and diisopropyl ether, the crystal suspension is cooled to a temperature between 0 °C and -5 °C and filtered After drying the product at 60 °C 30 g (68 8%) of title substance are obtained [as a mixture of isomers of formulae (Ilia) and (lllb)], m p 146-150 °C

Example 8 16-Methylene- 17α-hydroxy- 18-methyl- 19-norpregn-4-ene-3 , 20-dιone

30 g (0 069 mol) of 16-phenylsulfinylmethylene-l 8-methyl- 19-norpregna-4, 16-dιene- 3,20-dιone [e g the mixture of isomers of formulae (Ilia) and (lllb) obtained according to the preceding Example] are suspended at 20-25 °C in methanol, then 5 8 ml (0 041 mol) of tnethylamine and 32 6 ml (0 276 mol) of tnmethyl phosphite are added and it is stirred at a temperature between 60 °C and 66 °C for 8 hours The course of the reaction is followed by thin layer chromatography When the reaction becomes complete, the reaction mixture is cooled to 20 °C and added to 3 litres of 10% sodium chlonde solution The crystalline product is filtered, washed with water until neutral and dried at 60 °C to give 20 5 g (90 5%) of title compound, m p 222-226 °C Example 9

16-Methylene- 17α-hydroxy- 18-methyl- 19-norpregn-4-ene-3,20-dιone 17-acetate After dissolving 41 g (0 12 mol) of 16-methylene-17α-hydroxy-l 8-methyl- 19- norpregn-4-ene-3,20-dιone in 200 ml of acetic acid at 20-25 °C, 16 ml (0 18 mol) of 70% perchloπc acid are added While keeping the temperature of the reaction mixture at 20 °C, 64 ml (0 66 mol) of acetic anhydπde are dropwise added and then stined at 15-20 °C for 10 minutes Subsequently 400 ml of water are added to the reaction mixture, the crystalline precipitate is filtered, washed with water until neutral and dned at 60 °C After recrystallization ofthe crude product from a mixture of acetone and n-hexane 36 8 g (80%) of title compound are obtained, m p 154- 155 °C Example 10 16-Methylene-17α-hydroxy-l 8-methyl- 19-norpregn-4-ene-3,20-dιone 17- propionate

To a solution containing 10 3 g (0 03 mol) of 16-methylene-17α-hydroxy-18-methyl- 19-norpregn-4-ene-3,20-dιone in 100 ml of methylene chloride 1 5 g (0 01 mol) of zinc chloride, 24 ml of methylene chloπde containing 0 6% of hydrogen chlonde as well as 6 24 g (0 048 mol) of propionic anhydnde are added while keeping the temperature of the reaction mixture at 20-25 °C by external cooling After stirπng the reaction mixture at 20-25 °C for 4 hours 10 ml of water are added and it is stirred for additional 30 minutes The methylene chloπde phase is separated, successively washed with water, 5% sodium hydroxide solution, 5% hydrochloπc acid and again water until neutral The solution dned over anhydrous sodium sulfate is evaporated under reduced pressure The thus obtained oil is dissolved in 120 ml of n- hexane while boiling, clarified and then concentrated to a thick crystal pulp under reduced pressure The crystalline product is filtered and dned at a temperature lower than 50 °C to give 10 37 g (90%) of the title compound, m p 132-135 °C Example 11

16-Methylene-l 7α-hydroxy-l 8-methyl-19-norpregn-4-ene-3,20-dιone 17- butyrate 10 3 g (0 03 mol) of 16-methylene-17α-hydroxy-l 8-methyl- 19-norpregn-4-ene-3, 20- dione are reacted with 7 58 g (0 048 mol) of butync anhydnde according to Example 10 to obtain 10 98 g (92%) of title compound, m p 128-131 °C Example 12 16-Methylene- 17α-hydroxy- 18-methyl- 19-norpregn-4-ene-3 ,20-dιone 17- valerate 10.3 g (0.03 mol) of 16-methylene-17α-hydroxy-l 8-methyl- 19-norpregn-4-ene-3, 20- dione are reacted with 8.93 g (0.048 mol) of valeric anhydride according to Example 10 to obtain 11.3 g (91.5%) of title compound, m.p.: 157-160 °C.

Example 13 16-Methylene- 17α-hydroxy- 18-methyl- 19-norpregn-4-ene-3 ,20-dιone 17- caproate

10.3 g (0.03 mol) of 16-methylene-17α-hydroxy-l 8-methyl- 19-norpregn-4-ene-3, 20- dione are reacted with 10.27 g (0.048 mol) of caproic anhydride according to Example 10 to give 11.4 g (89.3%) of title compound, m.p.: 84-88 °C.

Example 14 16-Methylene- 17α-hydroxy- 18-methyl- 19-norpregn-4-ene-3 ,20-dione 17-heptanoate

10.3 g (0.03 mol) of 16-methylene-17α-hydroxy-l 8-methyl- 19-norpregn-4-ene-3, 20- dione are reacted with 11.6 g (0.048 mol) of heptanoic anhydride according to Example 10 to obtain 11.55 g (87.5%) of title compound, m.p.: 99-101 °C.

Claims

Claims:
1 Novel 16-Methylene- 17-acyloxy- 18-methyl- 19-norpregn-4-ene-3,20-dιone derivatives of formula (I),
Figure imgf000031_0001
wherein
R stands for CMO alkyl group
2 16-Methylene- 17 -hydroxy- 18-methyl- 19-norpregn-4-ene-3 ,20-dιone 17-acetate 3 16-Methylene-17α-hydroxy-18-methyl-19-norpregn-4-ene-3,20-dιone 17-propιonate
4 16-Methylene- 17α-hydroxy- 18-methyl- 19-norpregn-4-ene-3 ,20-dιone 17-butyrate
5 16-Methylene- 17α-hydroxy- 18-methyl- 19-norpregn-4-ene-3,20-dιone 17-valerate
6 16-Methylene- 17α-hydroxy- 18-methyl- 19-norpregn-4-ene-3 ,20-dιone 17-caproate
7 16-Methylene- 17α-hydroxy- 18-methyl- 19-norpregn-4-ene-3 ,20-dιone 17-heptanoate 8 Pharmaceutical composition with progestogenic effect, which c o m p r i s e s as active in¬ gredient (a) therapeutically effective dose(s) of one or more novel 16-methylene-17- acyloxy-18-methyl-19-norpregn-4-ene-3,20-dιone deπvatιve(s) of formula (I), wherein R stands for C O alkyl group, in an admixture with filling, stabilizing, diluting agents and other additives commonly used in the preparation of such compositions 9 The novel 3-methoxy-16-methylene-17α-ethynyl-17β-hydroxy-l 8-methyl- 19-norandrosta- 3,5-dιene of formula (V)
Figure imgf000032_0001
10. 16-Methylene- 17α-ethynyl- 17β-hydroxy- 18-methyl- 19-norandrost-4-ene of formula (Va).
Figure imgf000032_0002
11. 16-Methylene- 17α-hydroxy- 18-methyl- 19-norpregn-4-en-3-one of formula (JJ) .
Figure imgf000032_0003
12. Process for the preparation of novel 16-methylene-17-acyloxy-l 8-methyl- 19-norpregn-4- ene-3,20-dione derivatives of formula (I),
Figure imgf000033_0001
wherein
R stands for CMO alkyl group, which comprises reacting 18-methyl- 19-norandrost-4-ene-3,17-dione of formula (IX)
Figure imgf000033_0002
with trimethyl orthoformate in a polar solvent in the presence of sulfuric acid; reacting the obtained 3 -methoxy- 18-methyl- 19-norandrosta-3,5-dιen-17-one of for¬ mula (VIII)
Figure imgf000033_0003
(Vffl) first with dimethyl oxalate in a polar solvent in the presence of an alkaline metal alkanoate and subsequently, with formaldehyde in the presence of acetic acid and tπethylamine, reacting the thus formed 3-methoxy-16-methylene-18-methyl-19-norandrosta-3,5-dιen- 17-one of formula (VII)
Figure imgf000034_0001
a ) either preferably with an ethoxyvmyl lithium denvative prepared from an alkyl lith¬ ium and ethylvinyl ether in situ and hydrolyzing by treatment with an acid the ob¬ tained novel 3-methoxy- 16-methylene- 17α-( 1 -ethoxyvmyl)- 17β-hydroxy- 18- methyl-19-norandrosta-3,5-dιene of formula (VI)
Figure imgf000034_0002
to 16-methylene-17α-acetyl-17β-hydroxy-18-methyl-19-norandrost-4-en-3-one of formula (IV),
Figure imgf000035_0001
b ) or preferably with lithium acetyhde prepared from butyl lithium with acetylene in situ and hydratating the thus formed novel 3-methoxy-16-methylene-17α-ethynyl- 17β-hydroxy-l 8-methyl- 19-norandrosta-3,5-dιene of formula (V) - if desired, after hydrolyzing it by means of hydrochloπc acid to 16-methylene-17α-ethynyl-17β- hydroxy-18-methyl- 19-norandrost-4-ene of formula (Va) - in the presence of mer- cury(II) oxide, then, reacting 16-methylene- 17α-acetyl- 17β-hydroxy- 18-methyl- 19-norandrost-4-en-3-one of formula (IV) obtained either in reaction route a ) or b ) with phenylsulfenyl chloπde, boiling in methanol 16-phenylsulfinylmethylene-l 8-methyl- 19-norpregna-4,16-dιene obtained as a mixture ofthe isomers of formulae (Ilia) and (lllb)
Figure imgf000035_0002
Figure imgf000036_0001
in the presence of a thiophilic reagent and tnethylamine under atmosphenc pressure, and finally, reacting the thus obtained 16-methylene-17α-hydroxy-l 8-methyl- 19-norpregn-4-en-3- one of formula (II) with an acid anhydπde of formula (R-CO)2O or with an acyl chloride of formula R-CO-Cl, wherein R is the same as defined above, in the presence of a strong mineral
13 A process according to claim 9 for the preparation of 16-methylene-17α-acetoxy-18- methyl-19-norpregn-4-ene-3,20-dιone, which comprises carrying out the reaction of
16-methylene-17α-hydroxy-l 8-methyl- 19-norpregn-4-en-3-one with acetic anhydπde in acetic acid medium in the presence of a strong inorganic acid
14 A process according to claim 9, which comprises carrying out the reaction of 16- methylene- 17α-hydroxy- 18-methyl- 19-norpregn-4-en-3-one with an acid anhydπde of for¬ mula (R-CO)2O, wherein R is the same as defined above, in the presence of a Lewis acid catalyst and strong inorganic acid
15 Process for the preparation of a pharmaceutical composition with progestogenic effect which comprises mixing (a) therapeutically effective dose(s) of one or more novel 16- methylene- 17α-acyloxy-l 8-methyl- 19-norpregn-4-ene-3,20-dιone deπvatιve(s), wherein R stands for CMO alkyl group, with filling, diluting, stabilizing agents and other additives commonly used in the preparation of such compositions, and formulating them to a phar¬ maceutical composition
16 Method of treatment characterized by administering a therapeutically effective dose of one or more novel 16-methylene-17α-acyloxy-l 8-methyl- 19-norpregn-4-ene-3,20-dιone denvatιve(s) of formula (I), wherein R stands for CMO alkyl group, alone or in the form of a pharmaceutical composition into the body of a mammal in the need of such treatment
PCT/HU1996/000076 1995-12-22 1996-12-13 18-methyl 16-methylene 19-nor pregnane derivatives as progestins, pharmaceutical compositions containing them and process for the preparation thereof WO1997023498A1 (en)

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HU9503738A HU216828B (en) 1995-12-22 1995-12-22 Steroids, process for producing them, pharmaceutical compositions containing them and their intermediates

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WO2004101594A1 (en) * 2003-05-14 2004-11-25 Richter Gedeon Vegyészeti Gyár Rt. New mono-and bismethylene-steroid derivatives and process for their synthesis
WO2013092668A1 (en) 2011-12-23 2013-06-27 Crystal Pharma, S.A.U. Process for alkynylating 16-substituted-17-keto steroids

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WO2004101594A1 (en) * 2003-05-14 2004-11-25 Richter Gedeon Vegyészeti Gyár Rt. New mono-and bismethylene-steroid derivatives and process for their synthesis
WO2013092668A1 (en) 2011-12-23 2013-06-27 Crystal Pharma, S.A.U. Process for alkynylating 16-substituted-17-keto steroids
JP2015500857A (en) * 2011-12-23 2015-01-08 クリスタル ファルマ、エセ、ア、ウCrystal Pharma,S.A.U. Method alkynyl of the 16-substituted-17-keto steroids
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