United States Patent
`Schiilze et al.
`
`[19]
`
`[54] DEPOT STEROID ESTERS
`
`[75]
`
`Inventors: Paul-Eberhard Schiilze; Ulrich Speck;
`Dieter Bittler; Rudolf Wiechert;
`Bernard Acksteiner, all of Berlin,
`Fed. Rep. of Germany
`
`[73] Assigneel:
`
`Scliering, A.G., Fed. Rep. of
`Germany
`
`[211 Appl. No.: 748,411
`
`[22] Filed:
`
`Dec. 8, 1975
`
`Foreign Application Priority Data
`[30]
`Dec. 19, 1975 [DE]
`Fed. Rep. of Germany ..... .. 2558076
`
`Int. (31.2 ............................................ .. C07J 21/00
`[51]
`[52] U.S. c1.
`..... .;............... .. 260/239.55 C; 260/397.4;
`260/397.45; 260/397.5
`[58] Field of Search .............. 260/397.45, 397.4, 397.5
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3,629,245
`3,657,225
`3,856,956
`3,916,002
`
`....................... .. 424/241
`Bertin et al.
`12/1971
`424/241
`4/1972 Komeno
`
`.. 260/397.45
`12/1974 Oxley et al.
`.................... .. 424/241
`10/1975
`Taubert et al.
`
`Primary Exam1'ner—Elbert L. Roberts
`Attorney, Agent, or Firm—Millen & White
`
`ABSTRACT
`"
`[57]
`Steroid esters of the Formula I
`
`[11]
`
`[45]
`
`4,119,626
`
`Oct. 10, 1978
`
`~
`
`wherein the A, B, C, and D rings can be substituted in
`the usual manner,
`R10 is hydrogen or methyl;
`R” is alkyl of 1-3 carbon atoms;
`R17 is 17a-alkynyl or alkadiinyl of up to 4 carbon
`atoms or 17B—acetyl,
`Y—CO——-OH,
`is _
`X—0H,
`X—-O—CO—Y—CO—-OH, X—O—CO—-R, Y—-
`CO—OR,
`X—O—CO—Y—CO——OR,
`or
`
`Z
`
`X is a _straight-chain or branched alkylene of 1-6
`carbon atoms, optionally interrupted by O or S
`atoms, wherein the chain or branches can be substi-
`tutedby —OH, —O—CO—R, or —O—SO2——R;
`Y is a_ direct bond, a. straight-chain or branched car-
`bonchain of 1-3 atoms, optionally interrupted by
`an O_ or S atom if Y is linked to the steroid residue
`via -_-O—CO—; of 1-16 atoms if Y is linked to X
`via ———O———CO; or 1,4-phenylene, 1,4-cyclohexy-
`lene, or 1,3-cyclopentylene optionally substituted
`by; alkyl of 1-2 carbon atoms, or groups analo-
`gously l,2- and 1,3-disubstituted, respectively; and
`R is an optionally substituted alkyl of up to 22 carbon
`atoms, have longer acting activity than the corre-
`sponding unesterified steroids and higher activity
`than the corresponding long chain esters.
`
`37 Claims, No Drawings
`
`MYLAN PHARMS. INC. EXHIBIT 1040 PAGE 1
`
`

`
`
`
`rings can be substituted in
`wherein the A, B, C, and
`theusual manner and R10, R13, and R17 are as above.
`
`,DETAILED DESCRIPTION
`
`The."steroid molecule can befurther substituted by
`the usual substituents, examples of which include: "ether-
`ified or_..este’rified h_ydr_oxy in the ct-‘or B-configuration
`at the 1-, '2-, 3-,_4-, 7-, ll-, 15- and/or, 16-position; keto
`in’ the 3-, 6- and/or ll-position; saturated or unsaturated
`alkyl. of .1-5_ carbon atoms, preferably_methyl or ethyl,
`in ‘the 1-, 2-, 4-, 6-, 7- and/or 16-position; methylene in
`the 1,2-, 6,7- and/or 15,16-position; halogen, preferably
`fluorine or chlorine, in the 2-, 4-, 6-, 7-, 9-, ll- and/or
`16-position.
`'
`The A, B, C, and D rings can be saturated or unsatu-
`rated, that is, double bonds can be present, for example,
`in the 1(2)-, 3(4)-, .4(5)-, 5(lO)-,_5(6)-, 6(7)-, 9(10)-, 9(l1)-,
`1l(12)- and/or l5(16)-positions.
`"
`,
`R17 alkynyl includes ethynyl, chloreothynyl, propy-
`nyl, “and butadiynyl, of which ethynyl is preferred.
`X is straight-chain or branched alkylene of 1-6 car-
`bon atoms, optionally interrupted by O or S atoms. The
`branched ,groups as well as the end groups of X can be
`substituted by —OH, —.0-‘CO-R, or -O-S02-R. For
`example, X can be:
`
`..
`('33:
`-cH,—, —cH,—cH,-—, —cH—cH,—,
`CH —, —-
`CH —CH —CH -CH -,
`—cH,.—cn,—
`CH,
`ifi’
`I
`2 ‘ ?d3‘_
`2
`2
`-<|:—, —-CH,—cH—cH,—, —cH—CH,--cH,—,
`CH‘;
`ffia
`_
`—cH,—o—cH,—-, —cH,—s-cH,—, -cH,cH,cHcH,—,
`(III-I1
`N
`-cH,—<|:'—cH,—, —cH,—cHoH-cH,—, and
`CH,
`
`c|)so,cI-I,
`—cH,—cH-—cH, .
`
`Y 'is"a direct carbon-carbon bond, a straight or
`branched carbon chain of 1-3 atoms, optionally inter-
`rupted by an O or S atom, for example --—CH2-, -CH2-
`CH2-,
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`In a compbsitionalflaspept,' this invention relates to a
`depot steroidal ester’ of"the cy‘c1opentanopolyhydro-
`phenanthrene series having at the:.13-position an alkyl of
`1-3 carbon atoms;_ at the 10-position H or methyl; and at
`the 17-position (a)’a 17a-alkynyliofalkadiinyl _of up to 4
`carbon atoms or (b) a _17,B-aqetyl and,’ in the opposition
`:
`*‘:'
`'
`(A.
`‘.
`. Ar,‘ y
`configuration,‘‘“_, A
`,,
`,
`_
`
`.
`
`‘
`
`{.
`
`,.
`
`~,
`..
`
`'
`
`. no
`VII‘-
`.‘_0Cz‘.
`
`'
`
`* wherein
`
`Z is alkenyl of up;,t_o 4_ carbon a,toms,.X-OH, Y-C0-
`OH, X-O-CO-Y-CO-‘OH, X-O-C0-R, Y-C0-OR,
`X-O-CO-Y-CO-Or, or X-O‘-S02-R, and X is a
`straight-chain or branched alkylene, oxalkylene or
`thiaalkylene of 1-6 carbon atoms, unsubstituted or
`substituted by an —OH, -50-CO-R, or —,O-SO2-
`R;
`~-
`-
`Y is a direct bond, a straight-chain or branched alkyl-
`ene, oxaalkylene or thiaalkylene, of 1-3 carbon
`atoms when'Y is linkedhat the 17-position of. the
`steroid residue via‘-O-CO-; alkylene, oxaalkylene
`or thiaalkylene of 1-16 carbon atoms, unsubstituted
`or substituted by an -OH, -OCOR, or -OSOZR
`when Y is linked to.X via -—-0-CO-; or l,4-pheny-
`lene, 1,4-cyclohexylene, or 1,3-cyclopentylene sub-
`stituted by up to two alkyl of 1-2 carbon atoms,
`and R is alkyl or oxaalkyl of up to 22 carbon atoms.
`In another compositional aspect, this inv‘enti_'on're-
`lates to a pharrnaceutical' c9m;po's_ition,, comprising a
`depot steroidal ester? as above, in admixture with a
`pharmaceutically acceptable carrier.
`'
`.
`This invention also relates to a process for the pro-
`duction of ‘the novel depot este‘rs,‘by conventionally
`esterifying steroid alcohols of the formula
`
`1
`
`‘
`
`' 4,119,626
`
`Dnporisrnnoin -ESEFERS
`
`e
`
`..
`
`f
`
`5
`
`15
`
`20
`
`_BACKGRpUND op l'NV‘vENT'IQN .
`is iknownthat protracted, effectiveness can be
`It
`achieved by esterifying biologically active steroid alco-
`hols with long-chain, branched, or cyclic fatty acids
`and/or by converting biologically active, lower esters of
`steroid alcohols into higher esters.
`The chain length or the branching of the fatty acid is 10
`the factor govemingthe desired protracting effect. It is
`possible, for example,fto obtain considerable protracting
`effect with an undecylateybut aconsiderable decrease in
`effectiveness must be tolerated ‘as a consequence of
`greatly diminished cleavage of the steroid ester liber-
`ated from the depot. Since saponification of “a tertiary
`ester takes place very gradually compared to metabo-
`lism or direct excretion of the ester, physiologically
`undesirably high doses of the long-chain ester must be
`administered to attain the‘ therapeutic effect of the alco-
`hol.
`.
`p
`,
`»
`_.
`.,_
`_
`It has now,be§n found that the depot steroi_d_.esters of
`this invention ,_are ‘either coriiplétely or almost com-
`pletely saponif1ed,. yielding correspondingly high levels
`of activity and that the saponiiication rate and thus the
`period of activity.can_be controlled bythe selection of
`X, Y and R of Foiirnulael, ,I_I, and"III.
`SUMMARY OF THE INVENTION
`
`ta
`‘.=“=
`—cH4cH,—‘, —c1-r,—cH—, —cH,4-cH,—cH,—,
`—cH,—o~—cH,—, or —cH,—s—cH,—.
`
`65
`
`l,4—cyclol1exylene, or
`Also, Y- can be 1,4-phenylenie,
`1,3-cyclopentylene group, optionally substituted by
`alkyl of 1-2 carbon atoms. If Y is linked to X by -O-CO-
`, Y can also be a carbon chain of 1-16 atoms, optionally
`interrupted by one or more 0 or S atoms.
`A
`
`MYLAN PHARMS. INC. EXHIBIT 1040 PAGE 2
`
`

`
`3
`R is an univalent hydrocarbon residue of the ali-
`phatic, cycloaliphatic, aromatic, aromatic-aliphatic, or
`heterocyclic series. The hydrocarbon residue can be
`saturated, unsaturated, and/or substituted, for example,
`by alkoxy, oxo, amino, and halogen atoms. R can be of
`up to 22 carbon atoms, preferably 4-18 carbon atoms.
`Examples of R and contemplated equivalents include,
`but are not limited to: alkyl, and substituted alkyl, e.g.,
`methyl, diethylaminomethyl, chloromethyl, ethyl, pro-
`pyl, isopropyl, butyl, isobutyl, tert.-butyl. pentyl, iso-
`pentyl, tert.-pentyl, 2-methylbutyl, hexyl, heptyl, octyl,
`nonyl, decyl, dodecyl, pentadecyl, hexadecyl, and octa-
`decyl; cycloalkyl, e.g., cyclopentyl, cyclohexyl. and
`cyclopentylmethyl;
`aryl,
`e.g., phenyl, benzyl,
`2-
`phenethyl, tolyl, cinnamyl, a- and B-naphthyl; hetero-
`cyclic groups, e.g., pyridyl, piperidyl, pyrrolidinyl,
`furanyl, piperidinomethyl, and morpholinomethyl; and
`hydrocarbon groups interrupted by oxygen, e.g., 3,6,9-
`trioxaisoundecane.
`_
`Preferred depot steroid esters are compounds of For-
`mula II
`
`
`
`wherein R” and Z are as in Formula I; the dashed lines
`are optional, double carbon-carbon bonds;
`
`35
`
`4,119,626
`
`5
`
`10
`
`20
`
`25
`
`30
`
`4
`Preferred lower alkanoyl R3 are acetyl, propionyl,
`and butyryl. Alkyl or alkyl in alkylsulfonyl are likewise
`of 1-4 carbon atoms, for example, methyl, ethyl, propyl,
`isopropyl, butyl, isobutyl, and tert.-butyl. Cycloalkyl
`are of 3-8 carbon atoms, of which cyclopentyl is pre-
`ferred.
`Other preferred depot steroid esters are compounds
`of Formula III
`'
`
`CH,
`l
`
`ICI)
`=0
`"' O—C—Z
`
`111
`
`
`
`wherein R10. R13, and Z are as in Formula I,
`R, and R2 each are hydrogen or collectively are meth-
`ylene or a further carbon-carbon bond between the
`C, and C2 carbon atoms.
`R4 is hydrogen or chlorine,
`R5 is hydrogen, chlorine or methyl, and
`6'—"7 is a single or double bond between the C6 and
`C7 carbon atoms.
`Included within the compounds of the invention are
`compounds of Formula I, wherein:
`(a) R” is 17a-alkynyl;
`(b) R” is 17B-acetyl;
`(c) Z is alkenyl of up to 4 carbon atoms, including
`(a)-(b);
`(d) Z is CHZOH, or CHZOCOR, including (a)-(b);
`(e) Z is CHZCHZOH or CH2CH;OCOR, including
`(a)-(b);
`(I) Z is CHZCOOH, or Cl-I;COOR, including (a)-(b);
`(g) Z is COOI-I or COOR, including (a)-(b);
`(h) Z is
`
`45
`
`50
`
`55
`
`CHOH or cuocon,
`I
`I
`c1-1,
`cu,
`
`including (a)-(b);
`(i) Z is
`
`cH,ocoOcwR.
`
`including (a)-(b);
`(j) Z is
`
`cH,oco
`
`COOR,
`
`. R30
`
`.
`
`R10 is hydrogen or methyl;
`R3 is hydrogen, lower alkanoyl, alkylsulfonyl, alkyl,
`or cycloalkyl;
`W IS H2, 0, 01' H,0R3;
`
`‘
`
`is a double bond in the 4,5-, 5,6-, or 5,10- position; and
`R1, and R1,», each are hydrogen or collectively are 65 including (a)-(b);
`(k) Z is CHZOSOZR, including (a)-(b);
`methylene in the a- or B-position or an additional
`(1) Z is CH2CH2CH2OC0R, including (a)-(b);
`carbon-carbon bond between the C15 and Cm car-
`bon atoms.
`(m)
`
`MYLAN PHARMS. INC. EXHIBIT 1040 PAGE 3
`
`

`
`4,119,626
`
`as
`‘re
`Z is C-—OH or C-OCOR,
`I
`I
`CH,
`CH,
`
`including (a)i(b)_;
`(n) R is oxaalkyl of up to 22 carbon atoms including
`(a)*(m);
`'
`,
`(o) R is alkyl of up to 22 carbon including (a)—(m).
`Also, within the compounds of this invention are l7oL-
`or 17B-thioesters, e.g., 17-carbomethoxy-thioacetoxy
`and methoxycarbonyl-methylthioacetoxy steroids.
`The depot steroid esters of this invention have higher
`levels of effectiveness. than steroid esters known hereto-
`fore. The increase in effectiveness is up to 800%. The
`novel steroid esters have the same pharmacological
`properties as conventional, corresponding steroid alco-
`hols from which they are produced, but have particu-
`larly strong estrogenic and/or progestational activities.
`Whereas usually, following esterification of the ter-
`tiary 17-hydroxy group during in vitro experiments,
`there is no longer a receptor linking to the steroid, a
`receptor linkage is present in the l7-hydroxy esters (Z is
`X-OH) of this invention, e.g., in case of the 17-glyco-
`lates, which is diminished in receptor linking merely by
`a factor of 34 with respect to the steroid alcohol. Thus,
`the desired therapeutic effect is even enhanced, because
`pharmacologically effective compounds are already
`present even before cleavage of the hydroxy esters.
`The novel tertiary depot esters are produced by ester-
`ification with a short-chain hydroxy- or carboxycar-
`boxylic acid, HO-X-COOH or HOOC-Y-COOH, re-
`spectively, and optionally further esterification of an
`initially obtained hydroxy- or carboxy- carboxylic acid
`ester with another carboxylic acid (R-COOI-I), dicar-
`boxylic acid (HOOC-Y-COOH),
`sulfonic acid (R-
`SOZOH) and/or an alcohol (R-OH), or by esterification
`with the desired acylated hydroxycarboxylic acid and-
`/or or mono-esterified carboxycarboxylic acid. In this
`way, compounds having one,
`two, or three esters
`groupsiare obtained.
`The length and structure, especially of the second
`' and optionally third ester group, determine the duration
`of activity. By esterification with hydroxy- and carbox-
`ycarboxylic acids, — fat solubility of the steroid is in-
`creased and, in many cases, the melting point is simulta-
`neously raised. Consequently, several of the novel
`depotiesters can be administered intramuscularly in an
`oily solution as well as in an aqueous microcrystal sus-
`pension.
`Esterification of the 17a.-hydroxy is carried out by
`methods generally known to those skilled in the art.
`The steroid alcohol can be dissolved in an inert solvent
`and reacted with the desired acid anhydride or halide in
`the presence of an acidic’ or alkaline catalyst at tempera-
`tures of O"—150° C.
`--
`A steroid alcohol can be reacted with a free hydrox
`ycarboxylic acid or a hydroxycarboxylic acid esterified
`on the hydroxy group, or with a free or mono-esterified
`dicarboxylic acid by treatment with trifluoroacetic an-
`hydride in an inert solvent, optionally with addition of
`an acidic catalyst, at temperatures between about 0° C.
`and 40° C.
`'
`
`Examples of acidic catalysts are p-toluenesulfonic
`acid, perchloric acid and sulfuric acid. Basic catalysts,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`S0
`
`55
`
`60
`
`65
`
`6
`which can also serve as the solvent, are, for example,
`triethylamine, pyridine, and collidine.
`Any inert solvent can serve as reaction medium, but
`benzene or aromatic solvents, such as toluene or chloro-
`benzene, are preferred, along with ethers, such as di-
`ethyl ether, dioxane or tetrahydrofuran; hydrocarbons,
`such as hexane; halogenated hydrocarbons, such as
`methylene chloride, ethylene chloride or chloroform;
`and polar solvents; e.g., acetonitrile and dimethyl sulf-
`oxide.
`.
`A hydroxy ester (X-OH) obtained from a hydroxy
`fatty acid can be esterifled on the free hydroxy group in
`the customary manner. Esterification agents are prefer-
`ably acid anhydrides or halides, in the presence of a
`basic catalyst. Reaction temperatures are about O°—100°
`C. The hydroxy fatty acids can contain 1-3 hydroxy
`groups, preferably lhydroxy group.
`An acyloxy fatty acid ester (Z is X-O-CO-R) ob-
`tained from an acyloxy fatty acid can be saponified with
`a catalytic amount of an solution of an alkali metal or
`alkaline earth metal hydroxide in alcohol at tempera-
`tures between about 0° and 50° C. and reactions times of
`1 minutes to 3 hours.
`The reaction mixture can also contain inert solvents
`and diluents, such as methylene chloride, diethyl ether,
`and tetrahydrofuran. If desired, esterification can be
`carried out in a second step after saponification with the
`desired carboxylic or sulfonic acid (R-COOH or R-
`SOZOH) or dicarboxylic acid (HOOC-Y-COOH).
`The optional esterification of a free carboxy group of
`an initially formed mono-ester (Y-CO-OH) takes place
`likewise according to conventional methods. Thus, a
`mono-ester can be reacted, for example, with diazo-
`methane or diazoethane, to obtain the corresponding
`methyl or. ethyl ester. A generally applicable method is
`reaction of a mono-ester with an alcohol in the presence
`of carbonyl diimidazole, dicyclohexylcarbodiimide, or
`trifluoroacetic anhydride. It is also possible to convert
`an acid to a silver salt and react the latter with a R-
`halogenide. A further method is in conversion of a
`mono-ester with a free carboxyl group to the corre-
`sponding alkyl ester by an intermediate corresponding
`dimethylformamide alkyl acetal.
`‘A mono-ester can be reacted in the presence of a
`strongly acidic catalyst, such as hydrogen chloride,
`sulfuric acid, perchloric acid, trimethylsulfonic acid, or
`p-toluenesulfonic acidwith an alcohol or a lower al-
`kanecarboxylic acid ester of an alcohol. The carboxy of
`a mono-ester can be converted to an acid chloride or
`anhydride and then reacted with an alcohol in the pres-
`ence of a basic catalyst.
`It is frequently advantageous first to prepare, in a
`single step, a hydroxy or carboxy ester, respectively,
`esterified with a lower fatty acid or with a lower alco-
`hol; to saponify this product to a free hydroxy or car-
`boxy ester; and, as a final step, carry out esterification
`with an acid or an alcohol of the desired chain length.
`The 17-glycolic acid esters can be prepared as fol-
`lows:
`
`(1) A 17-crotonic acid ester is prepared using cro-
`tonic acid in the presence of trifluoroacetic anhy-
`dride.
`
`(2) After blocking any keto groups which are present,
`for example, in the 3- or 3,20-positions, preferably
`by ketalization, an oxidation is conducted with
`potassium permanganate in the presence of formic
`acid at temperatures around the freezing point, to
`obtain a 2,3-dihydroxybutyric acid ester.
`
`MYLAN PHARMS. INC. EXHIBIT 1040 PAGE 4
`
`

`
`4,119,626
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`7
`(3) By oxidative cleavage with periodate at tempera-
`tures between about 0° and 50° C., a 17-glyoxylic
`acid ester, which is converted into the desired gly-
`colic acid ester during the reduction, is obtained.
`Oxidation with permanganate and oxidative splitting
`with periodate are conducted in aqueous, inert solvent,
`such as, for example, acetone,
`tetrahydrofuma, and
`dioxane. The reduction can be effected in the usual
`manner with alkali metal boranate or lithium tri-tert.-
`butoxyalanate. Depending on the final product desired,
`any blocked keto groups present are liberated directly
`or after first esterifying a hydroxy groupof the glycolic
`acid ester.
`The invention also concerns pharmaceutical prepara-
`tions, especially depot preparations, of the steroid esters
`of Formula I.
`The progestationally and/or estrogenically active
`steroid esters are suitable, for example, for fertility con-
`trol in humans and animals or for the treatment of cli-
`macteric complaints in women. Also combinations of,
`for example, progestational and estrogenic, or estro-
`genic and androgenic steroid esters are possible.
`The effective dose depends on the purpose of the
`treatment, on the type of active agent, and on the de-
`sired duration of effectiveness. The effective dose of,
`for
`example,
`l7a-ethyny1-18-methyl-17B-(O-
`undecanoylglyco1oyoxy)-4-estren-3-one
`for
`fertility
`control in the human female is approximately 10-50 mg.
`for three months. The amount of other, progestationally
`active, steroid esters administered is equal to that corre-
`sponding to 10-50 mg. of l7a-ethynyl-l8-methyl-17B-
`(O-undecanoylglycoloyloxy)-4-estren-3-one each three
`months.
`The preparations are injected intramuscularly in an
`oily solution or in an aqueous crystalline suspension.
`The injection volume is about 1-4 ml., preferably 1-2
`ml.
`To produce the oily solution, the steroid esters are
`dissolved in an oily sovlent or solvent mixture suitable
`for the injection, filtered under sterile conditions, and
`charged into ampoules under aseptic conditions.
`Examples of preferred oily solvents are sesame oil
`and castor oil. To increase the solubility of the active
`agent, it is possible to add solubilizers, for example,
`benzyl benzoate or benzyl alcohol, to the oily solvents.
`Other vegetable oils which can be utilized include,
`e.g, linseed oil, cottonseed oil, sunflower oil, peanut oil,
`olive oil, and wheat-germ oil.
`Synthetic oils, such as polyethylene glycol, triglycer-
`ides of higher saturated fatty acids and mono-esters of
`higher fatty acids are also useable.
`A mixture of castor oil/benzyl benzoate in a ratio of
`6:4 is a preferred solvent mixture.
`Without further elaboration, it is believed that one
`skilled in the art can, using the preceding description,
`utilize the present invention to its fullest extent. The
`following preferred specific embodiments are,
`there-
`fore, to be construed as merely illustrative and not limi-
`tative of the remainder of the disclosure in any way
`whatsoever. The temperature in the following examples 60
`is indicated in degrees Celsius.
`EXAMPLE 1
`
`8
`at room temperature. The reaction solution is diluted
`with ether, washed with water and sodium bicarbonate
`solution, dried, and evaporated. The residue is taken up
`in 1.3 1. of methanol for enol ester cleavage, combined
`with 130 ml. of 8 vol.-% sulfuric acid, and heated under
`reflux for 2 hours. After precipitation in ice water, the
`precipitate is filtered off, washed with water, taken up
`in methylene chloride, and dried. The residue obtained
`after evaporation is recrystallized from diisopropyl
`ether-acetone, thus obtaining 43.3 g. of l7a-ethynyl-
`17,8-crotonoyloxy-18-methyl-4-estren-3-one,
`m.p.
`l87°—l88°.
`UV! 62“ = 18,700; E233 =
`45 g. of 17a-ethynyl-l7B-crotonoyloxy-l8-methyl-4-
`estren-3-one is combined in 450 ml. of methylene chlo-
`ride with 90 ml. of triethyl orthoforrnate, 112 g. of 2,2-
`dimethyl-1,3-propanediol, and 450 mg. of p-toluenesul-
`fonic acid and agitated for 60 minutes at a bath tempera-
`ture of 50°. The mixture is then diluted with ether,
`washed with sodium bicarbonate solution and water,
`dried, and evaporated. The residue is chromatographed
`on silica gel, thus producing 39.5 g. of l7a-ethynyl-17/3-
`crotonoyloxy-3,3-(2,2-dimethyltrimethylenedioxy)- l8-
`methyl-5- and -5(lO)-estrene in the form of an oil.
`40
`g. of
`l7a-ethynyl-17,B-crotonoyloxy-3,3-(2,2-
`dimethyltrimethylenedioxy)-l8-methyl-5- and -5(lO)-
`estrene is dissolved in 1.5 1. of acetone, cooled in an ice
`bath, and then 11.2 ml. of 100% formic acid is added to
`the reaction mixture. Within 2 hours, a solution of 23.7
`g. of potassium permanganate in 395 ml. of water and
`3.3 l. of acetone is also added to the mixture, whereafter
`the latter is agitated for 30 minutes at 0°. One liter of
`methylene chloride is added, and the mixture is filtered
`off from the thus-separated manganese dioxide. The
`filtrate is extensively concentrated under vacuum; the
`residue is taken up in ether, washed with water, dried,
`and evaporated. After chromatography on silica gel,
`the product is, in addition to 12 g. of unreacted starting
`material, 30.2 g. of 17cz-ethynyl-17B-(2,2-dihydrox-
`ybutyryloxy)-3,3-(2,2-dimethyltrimethy1enedioxy)-18-
`methyl-5- and -5(lO)-estrene as an oil.
`30 g. of l7a—ethynyl-17,3-(2,2-dihydroxybutyryloxy)-
`3,3-(2,2-demethyltrimethylenedioxy)-18-methyl-5- and
`-5(lO)-estrene is combined in 1.5 1. of dioxane with 89.6
`g. of sodium periodate in 450 ml. of water; the mixture
`is then stirred for 1 hour at room temperature, stirred
`into ice water, extracted with methylene chloride,
`washed with water, and dried. After evaporation, the
`product is 28.5 g. of crude 17a-ethynyl-3,3-(2,2-dime-
`thyltrimethylenedioxy)-17B-glyoxoyloxy- 1 8-methyl-5-
`and -5(lO)-estrene.
`32.5 g. of crude 17a-ethynyl-3,3-(2,2-dimethyltrime-
`thylenedioxy)-17fi-glyoxoyloxy-18—methy1—5-
`and
`-5(lO)-estrene is combined in 995 ml. of methanol and
`142.5 ml. of water under ice cooling with incremental
`portions of 6.5 g. of sodium boranate. The mixture is
`then agitated for 10 minutes at the ice bath temperature
`and stirred into ice water. The precipitate—containing
`phase, acidified with 2N sulfuric acid, is extracted with
`ether, washed with water, and dried. The residue ob-
`tained after evaporation is chromatographed on silica
`gel,_ thus obtaining 30.5 g. of 17a-ethynyl-3,3-(2,2-dime-
`thyltrimethylenedioxy)-17B-glycoloyloxy-18-methyl-5-
`and -5(lO)-estrene. A sample recrystallized from diiso-
`propyl ether melts at 2l5.5°—219°.
`200 mg.
`of
`17a-ethynyl-3,3-(2,2-dimethyltrime-
`thylenedioxy)-17B-glycoloyloxy-18-methyl-5-
`and
`-5(lO)-estrene is allowed to stand in 2 ml. of pyridine
`
`45
`
`50
`
`55
`
`30.9 g. of crotonic acid is combined in 800 ml. of
`benzene with 48.1 ml. of trifluoroacetic anhydride and
`stirred for 30 minutes at room temperature. Then, 50 g.
`of
`l7a-ethynyl—l7B-hydroxy-18-methyl-4-estren-3-one
`is added thereto and the mixture agitated for 30 minutes
`
`65
`
`MYLAN PHARMS. INC. EXHIBIT 1040 PAGE 5
`
`

`
`4,119,626
`.
`9
`with 1 ml. of propionic anhydride for 3 hours at room
`temperature. The mixture is then stirred into ice water.
`The precipitate is filtered off,'taken up in ether, washed
`with water and sodium bicarbonate solution, and dried.
`After evaporation, 240 -mg. of crude~l7a-ethynyl-3,3-
`(2,2-dimethyltrimethylenedioxy} 1 8-methyl- l 7B-(O-
`-
`I
`propionylglycoloyloxy)-S- and -5('l_0)-estrene is ob-
`tained.
`t
`'
`T
`‘
`'
`;>
`‘
`'
`240 mg. of crude 17a-ethynyl-3,3-(2,2-dimethyltrime-
`thylenedioxy)- l8-methyl->17B-(O-propionyl-
`glycoloyloxy)-5-‘ and -5(10)-estrene» is ‘heated under
`reflux ‘in 6 ml. of methanol and l.2iir1l..of water with 120
`mg. of oxalic acid for one hour. The mixture is then
`diluted with ether, washed withjwater, and dried. After
`evaporation, the residue is'__ehromatographed on silica
`gel, thus obtaining after recrystallization from diisopro-
`pyl ether 100 mg. of l7B-ethynyl-18-methyl-17B-(O-.
`propionylglycoloyloxy)-4-estren-3-one, m.p. 125°—126°.
`UV: em = 17,500.
`"
`'
`_
`
`10
`ml: of 8 vol.-% sulfuric acid for 3 hours at room temper-
`ature. The mixture is then diluted with ether, washed
`with water, and dried. After evaporation, the residue is
`chromatographed on silica gel,
`thus obtaining after
`recrystallization from diisopropyl ether 620 mg. of 17a-
`ethynyl- 17,8-glycoloyloxy-1 8-methyl-4-estren-3-one,
`m.p. 158.5°—l59.5°.
`UV! E240 = 17,600.
`EXAMPLE 5
`
`100 mg. of l7a-ethynyl-17B-glycoloyloxy-18-methyl-
`4-estren-3-one is dissolved in 1 ml. of pyridine, and 160
`mg.‘ of 3-cyclopentylpropionyl chloride is added
`thereto under cooling. The mixture is allowed to stand
`for 24 hours at room temperature, stirred into ice water,
`taken up in ether, washed neutral, and, after drying and
`concentration, chromatographed on silica ‘gel, thus ob-
`taining ll0 mg. of l7a-ethyn‘yl-17B-[O-(3-cyclopentyl-
`propionyl)-glycoloyloxyl-18-methyl-4-estren-3-one.
`Analogously to Example 5, the following compounds
`are prepared:
`,
`‘
`17a-ethynyl-17B-(O-tridecanoylglycoloyloxy)-4-
`estren-3-one
`"
`A
`l7a-ethynyl-17B-(O-hexadecanoylglycoloy1oxy)-4-
`estren-3-one
`‘
`"
`
`17a-ethynyl-17B-(0-octadecanoylglycoloyloxy)-4-
`estren-3-one
`‘
`
`17/3-ethynyl- 1 7B-(O-tridecanoylg1ycoloyloxy)- 1 8-
`methyl-4-estren-3-one
`g 17a-ethynyl-17B-(O-tridecanoylglyco1oyloxy)-18-
`methyl-4, 15-estradien-3-one..
`EXAMPLE 6
`
`500 mg. of 17a-ethynyl-17B-hydroxy-18-methyl-4-
`estren-3-one is dissolved in 5 ml. of collidine (freshly
`distilled). With ice cooling, 180 mg. of 4-dimethylpyri-
`dine and 1.25 g.» of 2-nonanoyloxypropionyl chloride
`are added to the reaction mixture. The latter is then
`heated under nitrogen for 24 hours to-110°. The reac-
`tion mixture is taken up in ether and washed neutral
`with aqueous oxalic acid solution and water. After the
`ether has been dried and the mixture concentrated
`under vacuum,
`the product
`is chromatographed on
`silica
`gel,
`thus
`obtaining
`_l7d-ethynyl-17B-(2-
`nonanoyloxypropionyloxy)-18-methyl-4-estren-3-one.
`
`EXAMPLE 7
`(a) One gram of 3-acetoxypropionic acid is stirred in
`21 ml. of benzene with 1.05 ml. of trifluoroacetic anhy-
`dride for 51 hour at room temperature. Under cooling
`and an N; atmosphere, 0.99 g. of 17a-ethynyl-17/3-
`hydroxy-18-methyl-4-estren-3—one is added thereto and
`the mixture agitated for 24 hours.
`.
`The reaction solution is decomposed with methanol/-
`water and washed neutral with water, sodium bicarbon-
`ate solution and once again water. The benzene solution
`is dried with sodium sulfate and concentrated under
`vacuum. The oily residue is chromatographed on silica
`gel,
`thus obtaining 650 mg. of 17[3(3-acetoxypro-
`pionyloxy)-l7a-ethyny1-18-methyl-4-estren-3-one.
`UV: 6240 = 17,2“).
`'
`(b) 250 mg. of 17/3-(3-acetoxypropionyloxy)-17a-
`ethynyl-18-methyl-4-estren-3-one is dissolved in 2 ml. of
`methylene chloride and 2 ml. of methanol and, under
`nitrogen, ethanolic KOH solution is added thereto at 5°.
`After 2 hours, the mixture is neutralized with glacial
`acetic‘ acid and stirred into ice water. The thus-
`precipitated product is vacuumfiltered and dried. Chro-
`
`10
`
`.
`15
`
`20
`
`EXAMPLE 2
`
`i,
`
`’ 17a-ethynyl-3,3-(2,2-di1nethyltrime-
`of‘
`’
`g.
`4.0
`thylenedioxy)-17B-glycoloyloxy-1%-methyl-5 '
`and
`-5(10)-estreneis ‘allowed’ to‘ stand for~20 hours at room
`temperature in 12-inl. of pyridine and 8 ml. of enanthic
`anhydride. The mixture is thendistilled ‘with steam, the
`residue is taken up‘ in methylenerchloride, and dried.
`After evaporation, the mixture is chromatographed on
`silica gel, thus obtaining 3.8 g. of 1'7‘a.-ethynyl-3,3-(2,2-
`dimethyltrimethylenedioxy)-,17B-(O-heptanoyl-
`glycoloyloxy)-18-methyl-5- and -5'(10)-estrene.
`3.8
`g. of
`1‘7a-ethy'riyl—3,'3-(2,2-dimethy1trime-
`thylenedioxy)-ll 7B-(O-heptanoylglycoloyloxy)- 1 8-
`methyl-5- and -5(10)—estren‘e is heated under reflux in 95
`ml. of methanol and 19 ml. of water with 1.9 g. of oxalic
`acid for 90 minutes. The mixture is then stirred into ‘ice
`water. The precipitate is "filtered off, taken up in ether,
`washed‘ with water, and dried.‘ After evaporation, the
`product is ‘chromatographedon silica gel, thus obtain-
`ing
`2.0
`g. ’
`' of ‘ 1':7‘a.-ethynyl-17B-(O -heptanoy1-
`glycoloyloxy)-18-methyl-4-estreri-3-one,_ m.p. 90°-9 1°.
`UV: e,.,,,»= 17,000.
`v
`‘
`’
`"
`‘
`-
`"EXAMPLE 3'
`
`17a-etliynyl-3,3-(2,2-dimethyltrime-
`of'
`4.0 ’ g.
`thylenediox'y)- 17B-glycoloyloxy-l8-methyl-5-
`and
`-5(l0) -estrene is combined in 12 ml.’ of pyridine at ice
`bath temperaturewith 4 ml.’of undecanoic acid chloride
`and allowed to stand for 20 hours at room temperature.
`After the reaction mixture has ' been worked up and
`purified analogously to Example 2, the product is 3.9 g.
`of 17B-ethynyl-3,3-(2,2-dimethyltrimethylenedioxy)-18-
`methyl-17B-(O-undecanoylglycoloyloxy)-5- and -5(l0)-
`estrene. 3.9 g.‘ of l7d-ethynyl-3,3-(2,2-dimethyltrime-
`thylenedioxy)-18-methyl-'1TB-(O-undecanoyb
`-
`glycoloyloxy)-5- and -5(10)-estrene is heated under
`reflux in 95 ml. of methanol and 19.5 ml. of water with
`1.95 g. of oxalic acid f_or"90 minutes. After the mixture
`has been worked up and purified analogously to Exam-
`ple 2, the product is 2.0 g. of 17a-ethynyl-18 -methyl-
`17/3-(O-undecanoylglycoloyloxy)-4-estren-3-one in the
`form of an oil..
`_
`‘
`.
`UV: 5240 = 17,000,‘
`,
`EXAMi>LE~4uy
`17a-ethynyl-3,3-(2,2-dimethyltrime-
`of
`g.
`1.3
`thylenedioxy)- 1-7B-gly'coloyl_ox‘y-‘ 1- 8-methyl-5-
`and
`-5(l'0)-estrene"is stirred in**39 ml. of methanol with 3.9
`
`25
`
`‘30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`MYLAN PHARMS. INC. EXHIBIT 1040 PAGE 6
`
`

`
`4,119,626
`
`12
`
`EXAMPLE 12
`
`11
`matography on silica gel and recrystallization from
`diisopropyl ether yeilds 200 mg. of l7a-ethynyl-l7B-(3.-
`hydroxypropionyloxy)-18-methyl-4-estren-3-one, m.p.
`159°-160°.
`UV: 5240 = 16,4“).
`EXAMPLE 8
`
`(a) One gram of monoethyl malonate is stirred in 20
`ml. of dry benzene with 1 ml. of trifluoroacetic anhy-
`dride for one hour at room temperature under a nitro-
`gen atmosphere. The mixture is then combined with
`0.93
`g.
`of
`l7a—ethynyl-17B-hydroxy‘-18-methyl-4—
`estren-3-one and allowed to stand for 36 hours at room
`
`10
`
`temperature. After adding methanol and ether, the mix-
`ture is washed neutral and concentrated. Chromatogra-
`phy on silica gel yields 550 mg. of l7a-ethynyl-l7[3-
`(ethoxyma1onyloxy)- 18-methyl’-4-—estren-3-one,
`m.p.
`75°-95°. The substance which crystallizes spontane-
`ously is tritrated with hexane and dried under a high
`vacuum).
`'
`UV: 6240 -'= 17,300.
`(b) 100 mg. of 17a.-ethynyl-17B-(ethoxymalonyloxy)—
`18-methyl-4-estren-3-one is dissolved in 1 g. of dodecyl
`alcohol and 5 ml. of benzene at 40° and, under nitrogen,
`5 mg. of potassium tert.-butylate is added thereto. After
`one hour, excess alcohol is removed under a high vac-
`uum; the residue is neutralizedwith acetic acid and
`chromatographed on silica gel, thus obtaining 120 mg.
`of l7a-ethynyl- l7/3-(dodecyloxymalonyloxy)- 1 8-meth-
`yl-4-estren-3-one.
`UV: (240 = 16,100.
`EXAMPLE 9
`
`l7a-ethynyl-l7B-hydroxy—4-estren-
`One gram of
`3-one is dissolved in 10 ml. of collidine. The solution is
`cooled to 0° and, under a nitrogen atmosphere, 1.3 ml.
`of ethoxyoxalyl chloride is added thereto. The mixture
`is allowed to stand‘ for one hour at room temperature
`and then stirred into aqueous oxalic acid solution. The
`thus-precipitated product is vacuum-filtered, washed
`with water, and dried. After chromatography on silica
`gel, 770 mg. of 17a—ethynyl-17B-(ethoxyoxalyloxy)-4-
`estren-3-one is obtained, rn.p. 89°—90°.
`UV! 6240 = 17M.
`EXAMPLE 10
`
`100 mg. of 17a-ethynyl-17B-(ethoxyoxalyloxy)-4-
`estren-3-one is dissolved in 10 ml. of benzene, and 500
`mg. of butanol is added thereto. At room temperature,
`5 mg. of potassium tert.-butylate is added, and the mix-
`ture is agitated. The benzene is removed after adding
`acetic acid, and the residue is chromatographed on
`silica gel, thus producing 120 mg. of 17a-ethynyl-l7B-
`(butoxyoxaly1oxy)—4-estren-3-one.
`EXAMPLE 1 1
`
`50 mg. of l7a.-ethynyl-17B-glycoloy1oxy-4-estren-
`3-one is dissolved in 0.5 ml. of dry pyridine. Under ice
`cooling, 0.11 g. of 3,6,9—trioxaisodecanoyl chloride is
`added thereto. The mixture is allowed to stand at room
`temperature f