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"Sulfatation of Estrogen Mixtures"

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Patentamt Europaisches ||| || 1 1| || || || || || || || || || 1 1| (19) J European Patent Office Office europeen des brevets (1 1 ) EP0 875 515 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication:ation: (51) |nt. ci.6: C07J 31/00, A61 K 31/565 04.11.1998 Bulletin 1998/45 (21) Application number: 98201385.6 (22) Date of filing: 28.04.1998 (84) Designated Contracting States: (72) Inventors: AT BE CH CY DE DK ES Fl FR GB GR IE IT LI LU • Raijmakers, P. H. MC NL PT SE 5406 VD Uden (NL) Designated Extension States: • Hofstraat, R. G. AL LT LV MK RO SI 5346 JA OSS (NL) • Boom van den, H. P. A. J. M. (30) Priority: 02.05.1997 EP 97201333 5408 AA Volkel (NL) (71 ) Applicant: Akzo Nobel N.V. (74) Representative: Kraak, Hajo et al 6824 BM Arnhem (NL) N.V. Organon, Postbus 20 5340 BH OSS (NL) (54) "Sulfatation of estrogen mixtures" (57) The invention relates to a method for the prep- aration of a mixture of sulfated estrogens containing delta(8,9)-dehydro estrone [delta(8,9)DHE] or deriva- tives thereof. CM < LO LO LO co o Q_ LU Printed by Xerox (UK) Business Services 2.16.3/3.4 1 EP 0 875 51515 A2 2 Description according to the present invention has the advantage that in a single reaction mixture sulfated estrogens can The invention relates to a method for the prepara- be obtained in a specific ratio. It has surprisingly been tion of a mixture of sulfated estrogens, more particularly found that although the estrogens present in the natural to the sulfatation of a mixture containing 3-hydroxy- s conjugated estrogen preparations have different physi- estra-1 ,3,5(10),8(9)-tetra-en-1 7-one [delta(8,9)-dehy- cal properties, such as crystallization behavior and sol- dro estrone; delta(8,9)DHE; delta 8 estrone; 8,9 dehy- ubility, the ratio of sulfated products in the sulfatation dro estrone; CAS no. 61612-83-7]. reaction mixture reflects the amounts of the input com- The sodium sulfate of the delta(8,9) derivative of ponents. Therefore, a one pot reaction suffices to pre- estrone [delta(8,9)DHES] is present in minor amounts 10 pare the sulfated estrogen mixture. In addition, this of about 3-4% in natural conjugated estrogen composi- reaction can, when appropriate, be coupled directly to tions, for instance in the commercially available product the isomerization reaction by which delta(8,9)DHE is Premarin® which is being used in hormone replace- prepared, i.e. isomerization of equilin or a derivative ment therapy. thereof to said derivative. In this reaction equilin or a In addition to estrone sodium sulfate, several com- is derivative thereof is treated with a lithium salt of ethylen- ponents have been identified in natural conjugated ediamine or with lithium amide in dimethylsulfoxide. estrogen compositions a/o. the sodium sulfates of equi- Thus, the present invention offers the first easy and lin (in amounts of 22.5-30.5%), 17 alfa dihydro equilin inexpensive method of production of sulfated steroid (13.3-19.5%), 17 beta dihydro equilin (0.5-4.0%), 17 mixtures containing delta(8,9)DHE through sulfatation alfa estradiol (2.5-9.5%) 1 7 beta estradiol (< 4.5%) and 20 of an estrogen mixture containing delta(8,9)DHE or delta(8,9)-dehydro estrone (< 12.5%) (US Pharmaco- derivatives thereof which can be obtained by isomeriza- poeia, 1995, p. 627). tion of equilin or a derivative thereof. It has been suggested in SCRIP no. 2049 (1995), p. Accordingly mixtures of estrogens comprising a 15 that minor amounts of delta(8,9)DHES could have a compound according to the general formula I significant contribution to the effect of conjugated estro- 25 gens. It has further been suggested that delta(8,9)DHES, which has a relatively low affinity to the estrogen receptor, has a high functional activity, which may play a role in the reported LDL-cholesterol-reduc- ing properties and cardiovascular effects of conjugated 30 estrogens, in particular of Premarin®. Data reveal that delta(8,9)DHES contributes to about 18% of Premarin's circulating estrogens. It is therefore of importance to obtain an easy method of production of sulfated mix- tures of delta(8,9)DHE. 35 Apart from cumbersome total synthesis, J.C. Jac- quesy et al., Chem. Abstr. 76 (1972), 154000f disclosed isomerization of equilin in hyperacidic media. Conver- wherein R1 is H, sion to delta(8,9)DHE was achieved by using hydrogen R2 is H and R3 is O-acyl; or fluoride or hydrogen fluoride/antimony fluoride at -30 40 R3 is H and R2 is O-acyl; or °C. It is evident that such dangerous reaction conditions R2 and R3 together represent O can be sulfated in are completely unsuitable and unacceptable for large admixture with one or more compounds taken from scale production of delta(8,9)DHE. Moreover, in US pat- the group of compounds of general formula II ent 5,395,831, wherein the method of Jacquesy is applied, it has been disclosed that said hydrogen fluo- 45 ride method does not provide pure delta(8,9)DHE, but in addition thereto 10 % of the unwanted delta(9,11)-iso- mer. Methods of production which are commercially acceptable, whether or not through isomerization of equilin, thus have not been disclosed. so Synthesis of sulfated esters of steroids has been described in the literature. As summarized by Jenkins and Sandberg (Methods in Enzymology, 15, 351-358, 1969) one of the methods involves the sulfatation of mono- and dihydroxy C-18 and C-19 steroid com- ss wherein R1 , R2 and R3 have the previously defined pounds utilizing pyridine sulfuric acid complexes. This meanings and the dotted line at position 7-8 repre- process, however, has been applied to individual, i.e. sents an optional double bond. free from other, steroid compounds. The process 2 3 EP 0 875 515 A2 4 In a preferred embodiment of the invention R2 and when (co)solvents are added. Lithium amide in dimeth- R3 in formula I and/or II represent O. More preferably, ylsulfoxide (DMSO) also provides mixtures of delta 8,9 estrone is sulfated in admixture with equilin. delta(8,9)DHE and equilin or derivatives thereof, which According to another embodiment of the invention can be converted according to the present invention into compounds of general formula II are one or more of the s their sodium sulfates, to be used in the manufacture of precursors of the minor components as present in natu- pharmaceutical compositions containing conjugated ral conjugated estrogen mixtures such as sulfate esters estrogens. of 1 7 alfa dihydro equilin, 1 7 beta dihydro equilin, 1 7 alfa Preferably, the C3 position is occupied by a tetrahy- estradiol and 17 beta estradiol. dropyranyl ether because such an ether can easily be The ratio of the compounds in the reaction mixture to prepared on an aromatic group, is stable under the is not critical but for economical reasons the preferred isomerization conditions, and, after isomerization, can ratio is the ratio as present in natural mixtures. easily be removed to prepare a hydroxyl group for sulfa- The compounds of general formula I can be pre- tation. pared by isomerization of equilin and said derivatives If R1 in formula III is silyl(alkyl)3, the isomerization is which are indicated in Formula III: ts preferably performed at a temperature of between about 0 and 90 °C, and with more preference at about 30 °C if equilin or a derivative thereof is treated with a lithium salt of ethylenediamine or about 65 °C if equilin or a derivative thereof is treated with lithium amide in 20 dimethylsulfoxide. If on the other hand, R-| is tetrahydro- pyranyl a mixture of the substrate and an aforemen- tioned solvent is treated with a lithium salt of ethylenediamine at a temperature of between about -78 °C and 50 °C, preferably between approximately 0 °C 25 and -20 °C using THF as the cosolvent. If the isomerization reaction is performed only par- tially a mixture of compounds of general formula III and delta 8,9 derivatives is formed which can be further wherein R-| is silyl(alkyl)3 or O-tetrahydropyranyl, processed to obtain sulfate conjugated estrogens mix- R2 and R3 together represent O; or 30 tures. Optionally also derivatives of general formula II R2 and R3 together represent acetal or cyclic can be added and in a single reaction all compounds acetal. can be sulfated simultaneously. Preferred compounds to be isomerized and sulfated according to the present The term alkyl, as used in the definition of the for- invention are those wherein R2 and R3 in the formulas mulas, means a branched or unbranched alkyl group 35 represent O. having preferably 1-7 carbon atoms, like hexyl, isobutyl, If in the compound of formula 1 1 1 , Ri is silyl(alkyl)3 or tertiary butyl, propyl, isopropyl, ethyl, and methyl. Pref- tetrahydropyranyl, the derivatives can be isomerized erably, silyl(alkyl)3 is Si(Me)2tert.butyl. The term acyl and subsequently hydrolyzed resulting in compounds means an acyl group derived from an alkylcarboxylic according to formula I or a mixture of compounds acid, the alkyl moiety having the meaning given previ- 40 according to formulas I and III wherein R-| is H by treat- ously, or derived from formic acid. Acetals are derived ment with mild acid such as dilute (< 0.2 N) hydrochloric from alcohols having preferably 1-6 carbon atoms. acid, 50 % acetic acid with cosolvents like THF, ace- With the term tetrahydropyranyl also equivalent tone, methylene chloride, ethanol or by treatment of the mixed acetals or mixed hemithioacetals are meant such derivatives under neutral conditions like trimethylsilyl as e.g.
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