United States Patent [191
`Lehmann et al.
`
`[45] Reissued Jan. 20, 1976
`
`[54] 17 a-ETHINYL- 1 8-METHYL-19-NORTES
`TOSTERONE ESTERS
`[75] inventors: Hans-Giinter Lehmann; Heinz
`Gibian; Rudolf Wiechert;
`Friedmund Neumann, all of Berlin,
`Germany
`[73] Assignee: Schering Aktiengesellschaft, Berlin,
`Germany
`July 19, 1974
`[22] Filed:
`[21] Appl. No.: 490,022
`Related US. Patent Documents
`
`Reissue of:
`[64] Patent No.:
`issued:
`Appl. No.:
`Filed:
`
`3,514,514
`May 26, 1970
`547,438
`May 5, 1965
`
`[30]
`
`Foreign Application Priority Data
`May 5, 1965
`Germany .............................. .. 37001
`
`[52] U.S. Cl. ......... .. 424/238; 260/3975; 260/3974
`
`[51] Int. Cl.2 ........................................ .. A61K 31/56
`[58] Field of Search ....... .. 424/243, 238; 260/397.4,
`260/397.5
`
`[56]
`
`2,601,287
`2,798,879
`2,868,809
`3,006,933
`3,231,589
`
`References Cited
`UNITED STATES PATENTS
`6/1952
`Hey] et a].
`................ .. 260/3973
`7/1957 Donia et al. ..
`.......... .. 260/397.4
`1/1959
`Donia et a1. 4.
`...... .. 260/397.4
`10/1961
`Allen et al.
`260697.45
`1/1966 Greenspan et al ............. .. 260/397.4
`
`Primary Examiner—Elbert L. Roberts
`Attorney, Agent, or Firm—Michael S. Striker
`
`ABSTRACT
`[57]
`A therapeutic compound for inhibiting ovulation com
`prising a I7-ester of I70z-ethinyl-l8-methyI-l9-nor
`testosterone wherein the said l7-ester group isformed
`from an aliphatic carboxylic acid having from six to
`II carbon atoms in the ester residue.
`6 Claims, No Drawings
`
`MYLAN PHARMS. INC. EXHIBIT 1019 PAGE 1
`
`

`
`1
`
`Re. 28 ,690
`
`17a -ETHINYL-l8-METHYL-19-NORTESTOSTER
`ONE ESTERS
`
`Matter enclosed in heavy brackets [ ] appears in the
`original patent but forms no part of this reissue specifi
`cation; matter printed in italics indicates the additions
`made by reissue.
`
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`commonly used in tablet manufacture such as magne
`sium stearate, stearic acid, talc, corn starch, lactone or
`the like. If desired, these tablets may be coated with
`sugar or shellac preparations in accordance with the
`common practices in the tablet manufacturing art.
`In addition, the higher esters are characterized by an
`excellent and protracted activity.
`The active compounds can be prepared by the con
`ventional methods of steroid chemistry.
`The esteri?cation with the desired acid can be con
`ducted in an acid or an alkaline reaction medium. As a
`result, of the acid esteri?cation,-there is directly pro
`duced the l7-mono-ester. There must, however, be
`accepted a higher loss of desired product as simulta
`neously with the esterification an aromatization of the
`A-ring takes place. The undesired side reaction can be
`avoided through the intermediate protection of the
`3-keto group, for instance, by ketalization. This proce
`dure implies two steps in the formation of the 17-mono
`ester, i.e., ketal formation and ketal splitting.
`An alternate reaction is the alkaline esteri?cation
`effected in the presence of an organic nitrogen base, as
`for instance pyridine, quinoline, etc., whereby there is
`produced as the primary product a 3-enol-l7B-diacyl
`ester. The reaction mixture containing the primary
`product is further worked up, for example, by treat
`ment with neutral ice water or extraction, or through
`prolonged stirring in alkaline ice water and the result
`ing l7-mono-acyl-ester isolated.
`For use in the esteri?cation, any of the acids suitable
`in steroid chemistry can be used. Illustrative of suitable
`acids are aliphatic carboxylic acids having 1 — l l, and
`most preferably 1 - 8, carbon atoms in the acid group,
`for example, acetic acid, propionic acid, caproic acid,
`onanthic acid, undecylic acid. The acids can be satu
`rated or unsaturated, branched or not, polybasic or
`substituted in the known manner such as trimethylace
`tic, t.butylacetic, phenylacetie, cyclopentyl-propionic,
`halogen-acetic, amino-acetic, oxypropionic, benzoic,
`succinic, adipic acids, etc. The esteri?cation is advan
`tageously carried out at elevated temperatures, prefer»
`ably at temperatures of from 130° - 200°C. The time
`required for the reaction is directly dependent on the
`reaction temperature. Thus the diester is produced
`after 6 hours with a reaction temperature of 160° C.,
`and in 5 hours with a reaction temperature of 170° C.
`The said diester, i.e., 3-enol-17B-diacyl ester is thereaf
`ter partially saponi?ed in the 3-position.
`The following examples are given in order to disclose
`more clearly the nature of the present invention. It
`should be understood, however, that the examples are
`not intended to be a limitation on the scope of the
`invention.
`
`This invention relates to 17 ,B-monoesters and
`3-enol-17B-diesters
`of
`17a-ethinyl-18-methyl-19
`nortestosterone esters. More particularly, this inven
`tion is concerned with an improved method for prepar
`ing and securing them.
`In accordance with the present invention, there are
`provided l7B-monoesters and 3-enol-l7B-diesters
`of l7a-ethinyl- 1 S-methyl- 1 q-nortestosterone constitut
`ing new therapeutic compounds having outstanding
`properties. These compounds possess progestive activ
`ity and are active when administered orally or subcuta
`neously. They are readily soluble in the conventional
`pharmaceutical carriers used for steroid hormones as,
`for example, vegetable oils such as sesame oil, castor
`oil, cotton seed oil, sun?ower oil, olive oil, and the like,
`as well as in synthetic solvents, for instance glycols,
`lactic acid esters, benzyl benzoate and the like. Be
`cause of their considerable solubility, it is possible to
`employ solutions of the esters of the invention as inject
`ibles and thereby also to utilize them as hormone de
`pots.
`The active compounds of the invention are prepared
`by reacting 17a-ethinyl-l S-methyl- l 9-nortestosterone
`with an organic carboxylic acid or reactive derivative
`thereof in the conventional manner to produce the
`ester. The 3-enol ester group of the primarily formed
`3-enol-l7B-diester is thereafter under regeneration of
`the 3-keto-A4-group partially saponified.
`The new esters demonstrate central inhibiting activ
`ity and are accordingly suitable as highly effective ovu
`lation inhibiting agents.
`The ovulation inhibiting activity was demonstrated in
`normal female rats (Sprague-Dawley) where following
`oral administration the conventional tube inspection
`tests were carried out and established for l'ia-ethinyl
`l8-methyl-19-nortestosterone-acetate a ED,o of only 3
`mg. in comparison, the free l7a-ethinyl-18-methyl-19
`nortestosterone had a ED“, of 10 mg. (the ED50 is that
`dosage which results in inhibition of ovulation in 50%
`of the experimental animals). Side effects such as
`weight gain, liver incompatibility or estrogen side reac
`tions were not observed.
`The new compounds accordingly are indicated as
`therapeutic agents for medical conditions where induc
`ing a quiet state in the ovaries is recommended.
`As further applications, the compounds can be used
`for example, in the treatment of dysmenorrhea, endo
`metriosis, cyclic disturbances, and functional sterility.
`The compounds of the invention are administered in
`the conventional dosage forms, such as capsules, gran
`ulates, solutions, drage'es, and tablets and are com
`pounded together with suitable pharmaceutical carri
`ers. When tablets are prepared they may be made in
`various sizes (total weight of 50 — 150 mg.) containing
`from about 0.1 - 0.5 mg. of the drug suitably in combi
`nation with another hormone component having estro
`genic activity as, for instance, 0.05 mg. ethinyl estra
`diol. The tablets are generally compounded with bind
`ing agents, lubricants and other substances which are
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`EXAMPLE 1
`A solution of 2 g. l7a-ethinyl-18-methyl-l9-nortes
`tosterone in 26 ml. pyridine was reacted with 13 ml.
`acetanhydride and the reaction mixture heated to 160°
`C. in a bomb tube. The reaction mixture was then
`cooled and the cooled mixture poured into ice water.
`The precipitate which was produced was filtered off,
`washed with water until neutral and following drying
`chromatographed using silica gel. There were recov
`ered 1.2 g crude l7a-ethinyl-lB-methyl-A’L’Lestradi
`ene-3, l7?-diol-diacetate, which following recrystalli
`zation from ether melted at I56" — 159° C. The yield
`amounted to 840 mg.
`
`MYLAN PHARMS. INC. EXHIBIT 1019 PAGE 2
`
`

`
`Re. 28,690
`
`3
`EXAMPLE 2
`400 mg. l7a-ethinyl-18-Ai“5-estradiene»3, 17B-diol
`liacetate were admixed with 400 mg. sodium bicarbon
`,te in 40 ml. methanol and 4 ml. water and the mixture
`tirred at room temperature for 6 hours. Thereafter,
`he reaction mixture was poured into ice water and
`leutralized with glacial acetic acid. The precipitate
`which formed was separated off by filtration, washed
`with water and dried. There were thereby produced
`50 mg. crude l7a-ethinyl-l8-methyl-l9-nortestoster
`me acetate having a melting point of 156° — 157° C.
`Tollowing recrystallization from ether, 260 mg. of the
`.cetate melting at 162° — 163° C. were obtained.
`
`EXAMPLE 3
`A solution of 400 mg. 17a-ethinyl-lS-methyLAM
`:stradiene-3, 17B-diol-diacetate in 40 ml. methanol
`ind 4 ml. water were re?uxed in the presence of4 ml.
`i7% HCl for 5 minutes. The reaction mixture was then
`)oured into water and worked up according to the
`)rocedure of Example 2. There were recovered 355
`ng. crude l7a-ethinyl-18-methyl-19-nortestosterone
`ieetate having a melting point of 157°C. After recrys
`allization from ether, there were obtained 256 mg.
`)ure 17B-acetate which had a melting point of 163° C.
`1nd is identical with the material of Example 2.
`
`EXAMPLE 4
`2 g. l'IB-ethinyl-lB-methyl-l9-nortestosterone in 26
`n1. pyridine and 27 g. caproic acid anhydride were
`ieated together under a nitrogen atmosphere for 7
`\OUI‘S at 160° C. Following cooling, the reaction mix
`vure which contained the primary formed 17a-ethinyl
`l8-methyl-l9-nortestosterone-3-enol-17?-dicapronate
`was poured into bicarbonate water and stirred for 30
`‘tours to saponify the excess caproic acid anhydride.
`Following filtration, there were obtained 2.1 g. of an
`)ily, crude product. The crude product was puri?ed
`
`chromatographically using silica gel and resulted in the
`recovery of 1.6 g. l7a-ethinyl-18-methyl-19-nortes
`tosterone-caproate having a melting point of 112° -
`1 13° C. After dissolution in pentane, there were recov
`ered 1.5 g. of the caproate having an unchanged melt
`ing point.
`In place of the nitrogen there can be used other inert
`protective gases as, for instance, argon.
`What is claimed is as follows:
`1. A therapeutic compound for inhibiting ovulation
`comprising [as active ingredient a compound selected
`from the group consisting of] a 17-ester of l7a-ethi
`nyl-l S-methyl-19-nortestosterone I and a l'la-ethinyl
`18-methyl-A="”-estradiene-3, 17?‘diol~3, I7B-diester]
`wherein the said 17-ester [and 3, l7B-diester groups
`are I group is formed from an aliphatic carboxylic
`I: acids] acid having from [1] six to 1 1 carbon
`atoms in the ester residue[; and a pharmaceutical
`carrier for said compound 1 .
`2. The compound of claim 1 which is the 173- [ace
`tate ] undecylale of the said nortestosterone.
`3. The compound of claim 1 which is the 17B-capro
`ate of the said nortestosterone.
`[4. The compound of claim 1 which is the 173
`diacetate of the said estradiene. ]
`[5. The compound of claim 1 which is the 173
`caproate of the said estradiene]
`6. A therapeutic composition for inhibiting ovulation
`comprising as active ingredient the l7a-ethinyl-l 8
`methyl-l9-nortestosterone ester de?ned in claim 1 in
`an amount of 0.1 to 0.5 mg. and in admixture with a
`pharmaceutical carrier.
`7. A therapeutic composition for inhibiting ovulation
`according to claim 6, wherein said ester is 17oz-ethinyl
`l8-methyl- l 9-nortestosterone- [ acetate 1 undecylate.
`8. A method of providing steroid therapy which com
`prises administering to a subject a therapeutic composi
`tion according to claim 6.
`it
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`‘It
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`MYLAN PHARMS. INC. EXHIBIT 1019 PAGE 3