United States Patent {19]
`Bowler et al.
`
`[54] STEROID DERIVATIVES
`
`[75] Inventors: Jean Bowler, Sandbacli; Brian S.
`Tait, Maccles?eld, both of United
`Kingdom
`
`[11] Patent Number:
`[45] Date of Patent:
`
`4,659,516
`Apr. 21, 1987
`
`[73] Assignee: Imperial Chemical Industries PLC,
`London, England
`
`R30
`
`[21] Appl. No.1 656,466
`
`[22] Filed:
`
`Oct. 1, 1984
`
`Foreign Application Priority Data
`[30]
`Oct. 12, 1983 [GB] United Kingdom ............... .. 8327256
`
`[51] Int. Cl.4 ..................... .. C07J 00/00; A61K 31/56
`[52] US. Cl.
`................. .. 260/3975
`[58] Field of Search .................... .. 260/397.5; 514/182
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3,679,716 7/1972 Anner et al. ................... .. 260/3975
`4,011,314 3/1977 Petzoldt et al. ................ .. 260/3975
`
`Primary Examiner-Leonard Schenkman
`Assistant Examiner—Joseph A. Lipovsky
`Attorney, Agent, or Firm—Cushman, Darby & Cushman
`
`ABSTRACT
`[57]
`A steroid derivative of the formula:
`
`wherein the double bond(s) between carbon atoms 6
`and 7 and/or carbon atoms 8 and 9 are optional;
`wherein the aromatic ring A may optionally bear one or
`two halogen or alkyl substituents; wherein R3 is hydro
`gen, alkyl, or acyl; wherein R16 is hydrogen, alkyl or
`hydroxy; wherein either R17 is hydroxy or acyloxy and
`R27 is hydrogen, alkyl, alkenyl or alkynyl, or R17 and
`R27 together form 0x0 (:0); wherein R18 is alkyl;
`wherein A is alkylene, alkenylene or alkynylene option
`ally fluorinated and optionally interrupted by ——O—,
`——S—-, —SO—, —SO2—, —CO—, —NR—, —NR
`CO—, —CONR—, —COO—, ——OCO— or phenylene,
`wherein R is hydrogen or alkyl; wherein R1 is hydro
`gen, alkyl, alkenyl, cycloalkyl, halogenoalkyl, carboxy
`alkyl, alkoxycarbonylalkyl, aryl, arylalkyl, or dialkyl
`aminoalkyl, or R1 is joined to R2 as de?ned below; and
`wherein X is —CONR2—, —CSNR2-—, —NR12CO—,
`——NR12CS—, —NR12CONR2—,
`
`—SO2NR2~— or —CO——; or, when R1 is not hydrogen,
`is ——O—, —NR2—, —(NO)R2—, --(PO)R2——, —NRI'
`2COO—; —NR12SO2—, —S—, ——SO— or —SO2—;
`wherein R2 is hydrogen or alkyl or R1 and R2 together
`form alkylene or halogenoalkylene; wherein R12 is hy
`drogen or alkyl and wherein R22 is hydrogen, cyano or
`.nitro; or a salt thereof when appropriate.
`
`wherein ST is a 7a-linked steroid nucleus of the general
`formula:
`
`8 Claims, No Drawings
`
`MYLAN PHARMS. INC. EXHIBIT 1029 PAGE 1
`
`

`
`1
`
`STEROID DERIVATIVES
`
`4,659,516
`
`This invention relates to new steroid derivatives
`which possess antioestrogenic activity.
`Various oestradiol derivatives are known which bear
`a carboxyalkyl substituent at the 7a-position. These
`have been used, when bound via the carboxy group to
`polyacrylamide resin or to agarose, for the puri?cation
`of oestrogen receptors (Journal of Biological Chemis
`try, 1978, 253, 8221); and, when conjugated with bovine
`serum albumin, for the preparation of antigens (United
`Kingdom Speci?cation No. 1,478,356).
`We have now found that certain 7a-substituted deriv
`atives of oestradiol and related steroids possess potent
`antioestrogenic activity.
`According to the invention there is provided a ste
`roid derivative of the formula:
`
`5
`
`10
`
`2
`have a total of l to 12 carbon atoms, and Y is —NR
`CO——, —CONR—, —COO——, —OCO- or pheny
`lene wherein R has the meaning stated above;
`wherein R1 is hydrogen, or alkyl, alkenyl, cycloalkyl,
`halogenoalkyl, carboxyalkyl, alkoxycarbonylalkyl,
`aryl or arylalkyl each of up to 10 carbon atoms, or
`dialkylaminoalkyl wherein each alkyl is of up to 6
`carbon atoms, or R1 is joined to R2 as de?ned below;
`and wherein X is —CONR2—, —CSNR2—-, —N
`
`wherein ST is a 7a-linked steroid nucleus of the general
`formula:
`
`R30
`
`wherein the dotted lines between carbon atoms 6 and 7,
`and carbon atoms 8 and 9, of the steroid nucleus
`indicate that there is an optional double bond be
`tween carbon atoms 6 and 7, or that there are two
`optional double bonds between carbon atoms 6 and 7
`and carbon atoms 8 and 9;
`wherein the aromatic ring A may optionally bear one or
`two halogen or alkyl substituents;
`wherein R3 is hydrogen or alkyl, alkanoyl, alkoxycar
`bonyl, carboxyalkanoyl or aroyl each of up to 10
`carbon atoms;
`wherein R16 is hydrogen, alkyl of up to 6 carbon atoms
`which is preferably in the B-con?guration, or hy
`droxy which is preferably in the a-con?guration;
`wherein either R17 (in the B-con?guration) is hydroxy
`or alkanoyloxy, carboxyalkanoyloxy or aroyloxy
`each of up to 10 carbon atoms; and R27 (in the a-con
`?guration) is hydrogen or alkyl, alkenyl or alkynyl
`each of up to 6 carbon atoms;
`or R17 and R27 together form 0x0 (:0);
`wherein R13 is alkyl of up to 6 carbon atoms;
`wherein A is straight- or branched-chain alkylene, alke
`nylene or alkynylene each of from 3 to 14 carbon
`atoms, which may have one or more hydrogen atoms
`replaced by ?uorine atoms, or has the formula
`
`45
`
`55
`
`20
`
`25
`
`30
`
`35
`
`wherein R2 is hydrogen or alkyl of up to 6 carbon
`atoms, or R1 and R2 together form alkylene or haloge
`noalkylene such that, with the adjacent nitrogen
`atom, they form a heterocyclic ring of 5 to 7 ring '
`atoms, one of which atoms may be a second heterocy
`clic atom selected from oxygen, sulphur and nitro
`gen;
`wherein R12 is hydrogen or alkyl of up to 6 carbon
`atoms;
`and wherein R22 is hydrogen, cyano or nitro;
`or a salt thereof when appropriate.
`A suitable value for the halogen or alkyl substituent
`in ring A is, for example, ?uoro, chloro, bromo, iodo,
`methyl or ethyl.
`A suitable value for R3 when it is alkyl, alkanoyl,
`alkoxycarbonyl, carboxyalkanoyl or aroyl is, for exam
`ple, methyl, ethyl, acetyl, propionyl, butyryl, pivalyl,
`decanoyl, isopropoxycarbonyl, succinyl or benzoyl. R3
`is preferably hydrogen or alkanoyl or alkoxycarbonyl
`each of up to 5 carbon atoms.
`~
`A suitable value for R16 when it is alkyl is, for exam
`ple, methyl or ethyl. R16 is preferably hydrogen.
`A suitable value for R17 when it is alkanoyloxy, car
`boxyalkanoyloxy or aroyloxy is, for example, acetoxy,
`propionyloxy, succinyloxy or benzoyloxy. R17 is prefer
`ably hydroxy.
`A suitable value for R27 when it is alkyl, alkenyl or
`alkynyl is, for example, ethyl vinyl or ethynyl. R27 is
`preferably hydrogen.
`A suitable value for R18 is methyl or ethyl, especially
`methyl.
`The group ST-— is preferably oestra-l,3,5(l0)-triene
`3,17,8-diol, 3-hydroxyoestra-l,3,5(l0)-trien-l7-one or
`l7a-ethynyloestra-1,3,5(l0)-triene-3,l7B-diol, all of
`which bear the —A—X----R1 substituent in the 7a-posi
`tion, or a S-alkanoyl ester thereof.
`One preferred value for the group —A- is a straight
`chain alkylene group of the formula
`
`wherein Al and A11 are each alkylene or alkenylene,
`optionally ?ourinated, having together a total of 2 to
`13 carbon atoms and Y is --O—, —S—, —SO-—,
`—SO;—, —CO- or —NR- wherein R is hydrogen
`or alkyl of up to 3 carbon atoms;
`or A1 is alkylene or alkenylene, optionally ?uorinated,
`and A“ is a direct link or alkylene or alkenylene,
`optionally fluorinated, such that A1 and All together
`
`65
`
`wherein n is an integer of from 3 to 14, especially from
`7 to 11, which may have one of the hydrogen atoms
`replaced by ?uorine, for example to provide the group
`—(CH2)3CHFCH2—. A may also be a branched-chain
`alkylene
`group,
`for
`example
`the
`group
`—(CH2)6CH(CH3)——, or a straight-chain alkenylene
`group, for example of the formula
`
`MYLAN PHARMS. INC. EXHIBIT 1029 PAGE 2
`
`

`
`4,659,516
`4
`wherein —A— is —(CH;),,—, wherein n is an integer
`from 3 to 14, especially from 7 to ll, or —A— is
`
`wherein m is an integer from 0 to 10, especially from 3
`to 7.
`A second preferred value for the group A is a group
`of the formula
`
`5
`
`15
`
`20
`
`25
`
`wherein A1 is straight-chain alkylene or alkenylene each
`of 2 to 9 carbon atoms, especially alkylene of 4 to 6
`carbon atoms, —Y- is phenylene (ortho, meta- or,
`especially, para-) and AH is a direct link, ethylene or
`vinylene, especially ethylene.
`A suitable value for R1 when it is alkyl, alkenyl or
`cycloalkyl is, for example, methyl, ethyl, n-propyl, iso
`propyl, n-butyl, isobutyl, t-butyl, n-pentyl, t-pentyl,
`2,2-dimethylpropyl, l-methylbutyl, Z-methylbutyl, 3
`methylbutyl, n-hexyl, 1,1-dimethy1butyl, 1,3-dimethyl
`butyl, n-heptyl, n-nonyl, n-decyl, n-undecyl, allyl, cy
`clopentyl or cyclohexyl.
`A suitable value for R1 when it is aryl or arylalkyl is,
`for example, phenyl, 2-ethylphenyl, p-?uorophenyl,
`p-chlorophenyl, m-chlorophenyl, p-cyanophenyl, p
`methoxyphenyl, benzyl, a-methylbenzyl, p-chloroben
`zyl, p-?uorophenethyl or p-chlorophenethyl.
`A suitable value for R1 when it is halogenoalkyl,
`carboxyalkyl, alkoxycarbonylalkyl or dialkylaminoal
`kyl is, for example, 2-chloro-2,2-di?uoroethyl, 2,2,2-tri
`fluoroethyl, 2,2,3,3,3-penta?uoropropyl, 3-chloropro
`pyl, 2,2-di?uorobutyl, 4,4,4-tri?uorobutyl, lH,1H-hep
`ta?uorobutyl, 4,4,5,5,5-penta?uoropentyl, 4,4,5,5,6,6,6
`hepta?uorohexyl, 1H,lH-trideca?uoroheptyl, S-car
`boxypentyl, S-methoxycarbonylpentyl or 3-dime
`thylaminopropyl.
`A suitable value for the heterocyclic ring —NRlR2 is,
`for example, pyrrolidino,
`piperidino, 4-methyl
`piperidino, 4~ethylpiperidino, 3-methylpiperidino, 3,3
`dimethylpiperidino, 4-chloropiperidino, morpholino or
`4-methylpiperazino.
`A suitable value for R2 or R12 when it is alkyl is, for
`example, methyl, ethyl or n-butyl.
`One appropriate salt is an acid-addition salt of a ste
`roid derivative which possesses an amino function, for
`example a compound wherein Y is —NR—, X is
`—NR2—— or R1 is dialkylaminoalkyl. A suitable acid
`addition salt is, for example, a hydrochloride, hydrobro
`mide, acetate, citrate, oxalate or tartrate.
`Another appropriate salt is a base-addition salt of a
`steroid derivative which possesses a carboxy function,
`for example a compound wherein R1 is carboxyalkyl. A
`suitable base-addition salt is, for example, a sodium,
`potassium, ammonium or cyclohexylarnine salt.
`A preferred steroid derivative of the invention has
`the formula:
`
`35
`
`45
`
`55
`
`wherein R17 is hydroxy and R27 is hydrogen or ethynyl,
`or R17 and R2.7 together form 0x0;
`
`65
`
`wherein m is an integer from 2 to 9, especially from 4 to
`6, and p is 0 to 2, especially 0 or 2; wherein R1 is alkyl,
`fluoroalkyl or cycloalkyl each of up to 10 carbon
`atoms, or phenyl, chlorophenyl or benzyl, or is linked
`to R2 as stated below;
`wherein X is —CONR2—, ~—NR12CO—, —-S—,
`—SO— or —SO;-—, wherein R2 is hydrogen or alkyl
`of up to 3 carbon atoms or together with R1 forms
`alkylene of 5 or 6 carbon atoms, and wherein R12 is
`hydrogen or alkyl of up to 3 carbon atoms.
`A particularly preferred steroid derivative of the
`invention has the last-mentioned formula wherein the
`number of carbon atoms in the two groups A and R1
`adds up to between 12 and 16, inclusive, especially 14 if
`neither Rl nor A contains a phenyl or phenylene group,
`and 16 if there is a phenylene group in —A— or a
`phenyl group in R1.
`Speci?c steroid dervatives of the invention are here
`inafter described in the Examples. Of these, particularly
`preferred compounds are:
`N-n-butyl-N-methyl-, N-2,2,3,3,4,4,4-hepta?uorobutyl
`N-methyl- and N,N-(3-methylpentamethylene)-l1
`(3, 17B-dihydroxyoestra-1,3,5(l0)-trien-7a-yl)undeca
`mide;
`N-n-butyl- and N-2,2,3,3,4,4,4-hepta?uorobutyl-3-p-[4
`(3, 17B-dihydroxyoestra-l,3,5(l0)-trien-7a-yl)butyl]
`phenylpropionamide;
`7a-(lO-p-chlorophenylthiodecyl)-,
`7a-(10-p-chloro
`phenylsulphinyldecyl)-,
`7a-[9-(4,4,5,5,5-penta
`?uoropentylsulphinyl)nonyl]-,
`7a-[l0-(4,4,4-tri
`fluorobutylsulphinyl)—decyl]-
`and
`7ct-[l0-(p¢
`chlorobenzylsulphonyl)decyl]oestra-l,3,5(l0)-triene
`3,17B-diol; and
`7a-(9-n—heptylsulphinylnonyl)oestra-l,3,5(l0)-triene
`3,17B-diol.
`A preferred process for the manufacture of a steroid
`derivative of the invention wherein X has the formula
`-—-CONR2—, —CSNR2— or —SO2NR2— comprises
`the reaction of a compound of the formula
`ST1-~A—Z1, wherein A has the meaning stated above,
`wherein STl either has the same meaning as stated
`above for ST, or is an equivalent 7a-linked steroid nu
`cleus which bears one or more protecting groups for
`functional derivatives, and wherein Z1 is an activated
`group derived from a carboxylic, thiocarboxylic or
`sulphonic acid, with an amine of the formula HNR1RZ,
`wherein R1 and R2 have the meanings stated above,
`whereafter any protecting group in ST1 is removed by
`conventional means.
`A suitable activated group Z1 is, for example, a mixed
`anhydride, for example an anhydride formed by reac
`tion of the acid with a chloroformate such as isobutyl
`chloroformate.
`A suitable protecting group in ST1 is, for example, an
`alkyl or aralkyl ether, for example the methyl or benzyl
`ether, of the 3-hydroxy function, or a tetrahydropyra
`nyl ether of the l7B-hydroxy function.
`A preferred process for the manufacture of a steroid
`derivative of the invention wherein X has the formula
`
`MYLAN PHARMS. INC. EXHIBIT 1029 PAGE 3
`
`

`
`4,659,516
`5
`—CO— comprises the reaction of an acid of the for
`mula ST1——A—COOH, wherein ST1 and A have the
`meanings stated above, with an organometallic com
`pound of the formula R1—M, wherein R1 has the mean
`ing stated above and M is a metal group, for example the
`lithium group, whereafter any protecting group in ST1
`is removed by conventional means.
`A preferred process for the manufacture of a steroid
`derivative of the invention wherein X has the formula
`
`reaction of a compound of the formula ST1—A—Z2,
`wherein ST1 and A have the meanings stated above and
`wherein Zzis a displaceable group, with a compound of
`the formula RISH, RIOH, HNR1R2 or R1R2P—C6H5
`wherein R1 and R2 have the meanings stated above,
`whereafter any protecting group in ST1 is removed by
`conventional means, and whereafter a phosphonium salt
`is hydrolysed to the phosphinyl compound.
`A suitable value for Z2 is, for example, a halogen
`atom or a sulphonyloxy group, for example the me
`thanesulphonyloxy or toluene-p-sulphonyloxy group.
`A preferred process for the manufacture of a steroid
`derivative of the invention wherein X has the formula
`—NR12CO—, —-NR12CS—, —NR12C0NR2—,
`
`15
`
`20
`
`25
`
`6
`ing group; and converting the steroidal part of the mo
`lecular to the required structure by conventional reac
`tions. The intermediate product obtained, which has the
`formula:
`
`wherein ST1 has the meaning stated above, may be
`oxidised to the corresponding carboxylic acid of the
`formula ST‘—A2—COOH which provides the start
`ing material for the ?rst or second process of the‘
`invention described above;
`or it may be converted into a compound of the formula
`S.T1—A2-—CH2Z2 by reaction with a halogenating
`agent or a sulphonylating agent to provide the start
`ing material for the third process of the invention
`described above.
`The starting material for the fourth process of the
`invention described above may be obtained by using the
`third process of the invention described above except
`that an amine of the formula RIZNHZ is used in place of
`an amine of the formula HNR1R2.
`The intermediate of the formula ST1—A2—CH2OH
`may be oxidised to an aldehyde of the formula
`ST1—A2—CHO which may then be used, by reaction
`with an appropriately-substituted hydrocarbyltri
`phenylphosphonium salt or hydrocarbyltriethylphos
`phonate, to prepare a starting material wherein ——A— is
`alkenylene.
`'
`An alternative process for the manufacture of a ste
`roid derivative of the invention wherein —A-—- is alke
`nylene of the formula —A3—CH=CH—A4— com
`prises the reaction of a compound of the formula:
`
`—NR12COO— or —NR12SO2— comprises the reac
`30
`tion of a compound of the formula ST1—A—NHR12,
`wherein ST1, A and R12 have the meanings stated
`above, with an acylating agent derived from an acid of
`the formula RICOOH, R1CSOH, RIOCOOH or R'SO
`20H; or, for the manufacture of a urea, with an isocya
`nate of the formula RINCO; or, for the manufacture of
`a guanidine, with a cyanamide of the formula
`R1NR2—CN, whereafter any protecting group in ST1 is
`removed by conventional means.
`A suitable acylating agent is, for example, an acyl
`chloride or acyl anhydride.
`The starting materials for use in all the abovemen
`tioned processes may be obtained by reacting a steroid
`derivative of the formula
`
`35
`
`40
`
`45
`
`wherein R16 and R18 have the meanings stated above
`and wherein R3’7 is an acyl group, for example the acetyl
`group, with a compound of the formula
`
`55
`
`wherein ST1 and A3 have the meanings stated above,
`with a triphenylphosphonium salt of the fonnula:
`
`wherein R1, X and A4 have the meanings stated above
`and wherein Q- is an anion, for example the bromide
`ion.
`The reaction may be carried out in solution in di
`methyl sulphoxide in the presence of dimsyl sodium.
`The steroidal aldehyde starting material when
`—A3— is -—A2—— as de?ned above may be obtained by
`oxidation of the corresponding alcohol as described
`above. The steroidal aldehyde starting material wherein
`—A3— is a direct link may be obtained from the 3-keto
`A4’6-inital steroidal starting material described above by
`reaction with cyanide to give the 3-keto-A4-7a-cyano
`compound, aromatisation, suitable protection and then
`reduction of the cyano group to the formyl group.
`The phosphonium starting material may be obtained
`by reaction of triphenylphosphine with a bromide of the
`formula
`
`wherein A2 either has the same meaning as stated above
`for A, or wherein --A2—CH2—- has the same meaning
`as stated above for A; separating the isomers at the
`7-position of the steroid nucleus to provide the 7a-iso
`mer; hydrolysing off the dimethyl-t-butylsilyl protect
`
`65
`
`A steroid derivative of the invention wherein ST is a
`l7B-hydroxy-steroid derivative may be converted by
`conventional reactions into the corresponding l7-keto
`steroid derivative, and thence to the corresponding
`17B-hydroxy-l7a-hydrocarbyl steroid derivative (that
`is, a steroid derivative of the invention wherein R27 is
`alkyl, alkenyl or alkynyl). Similarly, a steroid derivative
`
`MYLAN PHARMS. INC. EXHIBIT 1029 PAGE 4
`
`

`
`4,659,516
`
`7
`of the invention wherein R3 and/or R17 are other than
`hydrogen may be obtained from the corresponding
`compounds wherein R3 and/or R17 are hydrogen by
`conventional etheri?cation or esteri?cation processes,
`and these may also be used in reverse to prepare the
`corresponding hydroxy compounds.
`A steroid derivative of the invention wherein A is
`alkenylene may be hydrogenated to provide the corre
`sponding compound wherein A is alkylene.
`A steroid derivative of the invention wherein —X
`is —CI-l2NR2-— or —NR2CH2— may be obtained by
`the reduction, for example with borane, of the corre
`sponding compound wherein —X-— is —CONR2— or
`—NR2CO—.
`A steroid derivative of the invention wherein —-X—
`is -—CSNH-- or —NHCS- may be obtained by the
`reaction of the corresponding compound wherein X is
`—CONH- or —NHCO- with 2,4-bis-(4-methoxy
`phenyl)-l,3—dithia-Z,4-diphosphetane-2,4-disulphide.
`A steroid derivative of the invention wherein X is
`—(NO)R2, —SO-— or —SO;— may be obtained by'the
`oxidation of the corresponding compound wherein X is
`—NR2— or —S-—.‘ The conditions for the oxidation
`will be chosen to provide the desired product; for exam
`ple-aqueous sodium metaperiodate will oxidise the sul
`phur group to sulphinyl, and m-chloroperbenzoic acid
`in chloroform solution will oxidise the sulphur group to
`sulphonyl or the amine to its oxide.
`As stated above, a steroid derivative of the invention
`possesses antioestrogenic activity. This may be demon
`strated by its effect in antagonising the increase in
`weight of the uterus of an immature female rat pro
`duced by administering oestradiol benzoate to said rat.
`Thus, when a steroid derivative of the invention and
`oestradiol benzoate are co-administered for 3 days to
`such a rat, a smaller increase in uterine weight is pro
`duced than the substantial increase which would be
`produced by the administration of oestradiol benzoate
`without the steroid derivative of the invention.
`In particular, a preferred steroid derivative of the
`invention produces an antioestrogenic effect at a dose
`which produces no partial agonist effect, unlike the
`known antioestrogens tamoxifen and clomiphene.
`When a preferred steroid is coadministered with oes
`tradiol benzoate to a rat as described above, no increase
`in uterine weight whatsoever is observed at a suitable
`dose.
`A compound with the above pharmacological prop
`erties is of value in the treatment of the same conditions
`in which tamoxifen is bene?cial, in particular, in the
`treatment of anovulatory infertility and in the treatment
`of breast tumors. It is also of value in the treatment of
`menstrual disorders.
`When used to produce an anti-oestrogenic effect in
`warm-blooded animals, a typical daily dose is from 0.1
`to 25 mg/kg. administered orally or by injection. In
`man this is equivalent to an oral dose of from 5 to 1250
`mg./day. A steroid derivative of the invention is most
`conveniently administered to man in the form of a phar
`maceutical composition.
`According to a further feature of the invention, there
`is provided a pharmaceutical composition comprising a
`steroid derivative of the invention together with a phar
`maceutically acceptable diluent or carrier.
`The composition may be in a form suitable for oral or
`parenteral administration. A tablet or capsule is a partic
`ularly convenient form for oral administration and such
`a composition may be made by conventional methods
`
`20
`
`25
`
`45
`
`55
`
`8
`and contain conventional excipients. Thus a tablet could
`contain diluents, for example mannitol or maize starch,
`disintegrating agents, for example alginic acid, binding
`agents, for example methyl-cellulose, and lubricating
`agents, for example magnesium stearate.
`The composition may contain, in addition to the ste
`roid derivative of the invention, one or more antiandro
`genic agents or antiprogestational agents.
`A composition for oral administration may conve
`niently contain from 5 to 500 mg. of a steroid derivative
`of the invention.
`The invention is illustrated but not limited by the
`following Examples:_
`EXAMPLE 1
`N-Methylmorpholine (0.24 ml.) and isobutyl chloro
`formate (0.288 ml.) were successively added to a stirred
`solution
`of
`l l-(l7B—acetoxy-3-benzoyloxyoestra
`1,3,5(l0)-trien-7a-yl)undecanoic acid (1.0 g.) in methy
`lene chloride (17 ml.) which was cooled to -—l0° C.,
`and after 30 minutes n-butylamine (0.29 ml.) was added
`and the mixture was stirred at laboratory temperature
`for 15 minutes. Saturated aqueous sodium bicarbonate
`solution (20 ml.) was added and the mixture was ex
`tracted four times with methylene chloride (50 ml. each
`time). The combined extracts were washed with water
`(10 ml.), dried and evaporated to dryness. There was
`thus obtained as residue 1l-(l7B-acetoxy-3-benzoyloxy
`N-n-butyloestra-l,3,5(l0)-trien-7a-yl)undecanamide as
`an oil.
`Aqueous N-sodium hydroxide solution (8 ml.) was
`added to a stirred solution of the above amide (1.06 g.)
`in a mixture of methanol (16 ml.) and tetrahydrofuran (8
`ml.) and the mixture was stirred at laboratory tempera
`ture for 18 hours, neutralised with aqueous N-hydro
`chloric acid and the organic solvents were removed by
`evaporation. Water (40 ml.) was added and the mixture
`was extracted four times with methylene chloride (60
`ml. each time). The combined extracts were washed
`with water (10 ml.), dried and evaporated to dryness
`and the residue was puri?ed by chromatography on a
`silica gel (Merck Kieselgel 60) column using a 13:7 v/v
`mixture of ethyl acetate and toluene as eluant. There
`was thus obtained N-n-butyl-ll-(3,17B-dihydroxyoes
`tra-l,3,5(l0)trien-7a-yl)undecanamide as an oil which
`was characterised by the following data:
`
`Proton magnetic resonance spectrum (in CDCl3)
`Shift (6) Type of peak No of protons
`Assignment
`7. l6
`multiplet
`l
`aromatic
`6.65
`"
`2
`protons at
`positions
`1, 2 and 4
`position 17
`—CH2- adjacent
`to —CO—
`—CH3 in
`n-butyl
`position 18
`
`3.7
`3.28
`
`quartet
`
`triplet
`
`singlet
`
`0.90
`
`0.78
`
`1
`2
`
`3
`
`3
`
`65
`
`Mass Spectrum
`M+ =511.4039 (C33H5303N requires 511.4024).
`M—H2O=493.
`M—-(CH2CONHC4H9) = 397.
`
`MYLAN PHARMS. INC. EXHIBIT 1029 PAGE 5
`
`

`
`4,659,516
`
`15
`
`20
`
`25
`
`30
`
`9
`Thin layer chromatography (silica gel plates using a 7.3
`v/ v mixture of ethyl acetate and toluene)
`RF: 0.3.
`The l l-(l7B-acetoxy-3-benzoyloxyoestra-1,3,5(l0)
`trien-7a-yl)-undecanoic acid used as starting material
`was obtained as follows:
`A solution of dimethyl-t-butylsilyl chloride (37.3 g.)
`in tetrahydrofuran (40 ml.) was added to a solution of
`ll-bromoundecanol (50.18 g.) and imidazole (28.95 g.)
`in tetrahydrofuran (120 ml.) and the mixture was kept at
`laboratory temperature for 1.75 hours, diluted with
`diethyl ether (300 ml.) and filtered. The ?ltrate was
`evaporated to dryness and the residue puri?ed by chro
`matography on silica gel using a 4:1 v/v mixture of
`petroleum ether (b.p. 60°-80° C.) and toluene as eluant.
`A solution of the ll-(dimethyl-t-butylsilyloxy)unde
`cyl bromide thus obtained (73.1 g.) in tetrahydrofuran
`(200 ml.) was added during 2 hours to a stirred suspen
`sion of magnesium turnings (4.8 g.) in tetrahydrofuran
`(20 ml.) under normal conditions for preparation of a
`Grignard reagent, and the mixture was heated under
`re?ux for 2 hours, diluted with tetrahydrofuran (100
`ml.) and cooled to —30° C. Cuprous iodide (19.05 g.,
`dried at 100° C. immediately before use) was added, the
`mixture was vigorously stirred for 10 minutes and a
`solution of 6-dehydro-l9-nortestosterone acetate (15.48
`g.) in tetrahydrofuran (50 ml.) was added. The mixture
`was stirred for 40 minutes, acetic acid (12 ml.) was
`added. and the mixture was evaporated to dryness.
`Water (150 ml.) was added to the residue, and the mix
`ture was extracted four times with diethyl ether (300 ml.
`each time). The combined extracts were washed with
`water (50 ml.), dried and evaporated to dryness, and the
`residue was puri?ed by chromatography on a silica gel
`column using a 24:1 v/v mixture of toluene and ethyl
`acetate as eluant.
`A mixture of 17B-acetoxy-7a-[1l-(dimethyl-t-butyl
`silyloxy)undecyl]oestr-4-ene-3-one thus obtained (11.2
`g.), acetic acid (62 ml.), water (31 ml.) and tetrahydrofu
`40
`ran (56 ml.) was stirred at 50° C. for 2.75 hours and was
`then evaporated to dryness. A solution of the residue in
`pyridine (56 ml.) and acetic anhydride (28 ml.) was kept
`at laboratory temperature for 18 hours, cooled to 0° C.,
`water (10 ml.) was added and the mixture was stirred
`45
`for 45 minutes and then evaporated to dryness. The
`residue was dissolved in diethyl ether (400 ml.) and the
`solution was washed with saturated aqueous sodium
`bicarbonate solution (20 ml.) and then with water (20
`ml.), dried and evaporated to dryness.
`A solution of the 17B-acetoxy-7a-(l l-acetoxyun
`decyl)oestr-4-ene-3-one thus obtained (8.98 g.) in aceto
`nitrile (50 ml.) was added rapidly to a vigorously stirred
`suspension of cupric bromide (7.75 g.) and lithium bro
`mide (1.52 g.) in acetonitrile (120 ml.) which was heated
`under re?ux under an atmosphere of argon, and the
`mixture was stirred and heated for 30 minutes and then
`cooled. Saturated aqueous sodium bicarbonate solution
`(200 ml.) was added and the mixture was extracted four
`times with ethyl acetate (200 ml. each time). The com
`bined extracts were washed with water (50 ml.), dried
`and evaporated to dryness, and the residue was puri?ed
`by chromatography on a silica gel column using a 9:1
`v/v mixture of toluene and ethyl acetate as eluant.
`Aqueous N-sodium hydroxide solution (8 ml.) was
`added to a stirred solution of the 17B-acetoxy-7a-(l l
`acetoxyundecyl)oestra-l,3,5(l0)-trien-3-ol
`thus ob
`tained (2.8 g.) in methanol (54 ml.) and the mixture was
`
`10
`stirred at laboratory temperature for 70 minutes, neu
`tralised with aqueous N-hydrochloric acid and the
`methanol was removed by evaporation. The residue
`was extracted four times with ethyl acetate (60 ml. each
`time) and the combined extracts were washed with
`water (20 ml.), dried and evaporated to dryness. The
`residue was puri?ed by chromatography on a silica gel
`column using a 7:3 v/v mixture of toluene and ethyl
`acetate as eluant.
`Aqueous N-sodium hydroxide solution (6 ml.) and '
`benzoyl chloride (0.93 ml.) were added to a stirred
`solution of the l7B-acetoxy-7a-(11-hydroxy-undecyl)o- ,
`estra-l,3,5(l0)-trien-3-ol thus obtained (1.94 g.) in ace
`tone (20 ml.) which was cooled to 0° C., and the mixture
`was stirred for 20 minutes and then poured into a mix
`ture of ice-water (200 ml.) and saturated aqueous so
`dium bicarbonate solution (50 ml.). The mixture was
`extracted four times with diethyl ether (120 ml. each
`time) and the combined extracts were washed twice
`with saturated aqueous sodium bicarbonate solution (15
`ml. each time) and then with water (20 ml.), dried and
`evaporated to dryness. The residue was puri?ed by
`chromatography on a silica gel column using a 7:3 v/v
`mixture of toluene and ethyl acetate as eluant.
`Jones’s reagent (8N-chromic acid solution, 2.3 ml.)
`was added to a solution of the 17 B-acetoxy-3-ben
`zoyloxy-7a-(l 1-hydroxyundecyl)oestra-1,3,5(l0)-triene
`thus obtained (2.17 g.) in acetone (37 ml.) which was
`cooled to 0° C. After 15 minutes isopropanol (0.5 ml.)
`was added and the mixture was evaporated to dryness.
`Water (40 ml.) was added and the mixture was extracted
`three times with methylene chloride (60 ml. each time).
`The combined extracts were washed twice with water
`(10 ml. each time), dried and evaporated to dryness, and
`the residue was puri?ed by chromatography on a silica
`gel column using a 7:3 v/v mixture of toluene and ethyl
`acetate as eluant. There was thus obtained ll-(17B
`acetoxy-3-benzoyloxyoestra-l,3,5(10)-trien-7a-yl)un
`decanoic acid;
`
`EXAMPLE 2
`The process described in Example 1 was repeated
`using the appropriate amine in place of n-butylamine.
`There were thus obtained the compounds described in
`the following table, all of which were oils the structures
`of which were con?rmed by proton magnetic reso
`nance and mass spectroscopy:
`
`ethyl
`n-propyl
`isopropyl
`isobutyl
`t-butyl
`S-methylbutyl
`l-methylbutyl
`Z-methylbuty]
`2,2-dimethylpropyl
`n-hexyl
`
`mmmmmmmmmmu:
`
`++++
`
`50
`
`55
`
`65
`
`MYLAN PHARMS. INC. EXHIBIT 1029 PAGE 6
`
`

`
`4,659,516
`12
`was then oxidised to the corresponding undecanoic acid
`as described in the 9th paragraph of Example 1, and this
`product was puri?ed by chromatography on a silica gel
`column using a 19:1 v/v mixture of methylene chloride
`and methanol as eluant. The undecanoic acid was
`aromatised as described in the 6th paragraph of Exam
`ple 1, except that the pH of the reaction mixture was
`adjusted to 3 before extraction into ethyl acetate. The
`product was puri?ed by chromatography on a silica gel
`column using a 3:1 v/v mixture of diethyl ether and
`petroleum ether (b.p. 60°-80° C.) as eluant. There was
`thus obtained, as an oil, ll-(l7B-acetoxy-3-hydroxyoes
`tra- l,3,5(l0)-trien-7a-yl)undecanoic acid.
`
`EXAMPLE 3
`The process described in Example 1 was repeated
`except that the appropriate (l7B-acetoxy-3-hydroxy
`oestra-1,3,5-(10)trien-7a-yl)alkenoic acid and the appro
`priate amine were used as starting materials. There were
`thus obtained the compounds described in the following
`table, all of which were oils the structures of which
`were con?rmed by proton magnetic resonance and
`mass spectroscopy:
`
`15
`
`20
`
`25
`
`OH
`
`+
`
`+
`
`+
`
`"‘
`
`11
`-continued
`
`OH
`
`H
`
`HO
`
`" (cnmocomzlnl
`
`R2
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`H
`methyl
`methyl
`methyl
`methyl
`methyl
`methyl
`methyl
`methyl
`methyl
`ethyl
`n-butyl
`n-butyl
`
`R 1
`l,1-dimethylbutyl
`1,3-dimethylbutyl
`cyclohexyl
`2,2,2-triiluoroethyl
`2,2,3,3,4,4,4-hepta?uorobutyl
`2.2-diiluorobutyl
`3-chloropropyl
`phenyl
`4-methoxyphenyl
`4-chlorophenyl
`4~cyanophenyl
`Z-ethylphenyl
`benzyl
`l-phenylethyl
`S-carboxypentyl
`B-dimethylaminopropyl
`n-butyl
`2,2-dimethylpropyl
`Z-methylbutyl
`n-hexyl
`2,2,3,3,3-penta?uoropropyl
`2,2-di?uorobutyl
`4,4,4-triiluorobutyl
`2,2,3,3,4,4,4-hepta?uorobutyl
`benzyl
`n-butyl
`n-butyl
`2,2,2-tri?uoroethyl
`'-(CH2)5
`
`'-(CH2)2-I“1'-(CH2)2
`
`CH3
`
`CH3
`
`+
`
`30
`
`35
`
`45
`
`50
`
`H0
`
`in
`3
`3
`3
`5
`v 5
`8
`8
`10
`
`H
`
`R!
`n-butyl
`n-heptyl
`n-heptyl
`n-butyl
`n-pentyl
`ethyl
`n-butyl
`methyl
`
`R1
`H
`H
`methyl
`H
`H
`H
`H
`methyl
`
`The initial compounds obtained are (l7B-acetoxy-3
`isobutyloxycarbonyloestra- l , 3,5( l0)-trien-7a-yl)alkena
`mides, the hydroxy group at the 3-position being con
`verted into the carbonate during the ?rst stage of the
`amide-forming reaction by the isobutyl chloroformate.