IL40220A - Anti-androgenic pharmaceutical compositions containing 2-(substituted methylene)cycloalkanones - Google Patents

Description

pharmaceutical compositions containing cycloalkanones LILLY COMPANY 2 This inventio relates to a method for inhibiting the action of androgens by administering an effective quantity of a substituted methylene More this invention relates to a method for inhibiting the action a of androgens which comprises administering subject exhibiting a superabundance of androgen action an effective quantity of a substituted methylene cycloalkanone having the formula in which Y is or Y is or each R independently is ethyl or Ar is or a or derivative of the substituents being selected from the group consisting of mono loweralkylamino nitro and is cyclohexyl or or cyclohexyl or and is and Retaken together is as herein and the ring A is optionally substituted by loweralkyl or loweralkoxy This invention also relates to an composition comprising an inert and an inhibiting proportion of a substituted methylene cycloalkanone of the above formulae in which R and Ar are as 5 compounds in this invention are alkanones containing at least one and optionally two substituted methylene which substituents are located at the carbons imiaediate ly to the carbonyl of the term as used when referring to alkoxy means a and ia illustrated for and referring to the refers to a such as and The term as herein refers to or Illustrative of compounds which can be used in this the 4 dibenzylidenecyclobutanone dibenzylidenecyclopentanone dibenzylidenecyc loheptanone cyclopentanone 2 eye lohexanone 2 od obe nzy ne cy c lohexa none eye lopentanone 2 t oxybe nzy lid e ne t ley c lope nt a none 2 obutylbenzy lldene hylcyc hexanone eye lopentanone lohexanone 2 t h roxybe nzy lide ne eye 2 opropy lbenzylidene eye lohexanone eye lopentanone lidene eye lohexanone cyclopentanone 4 lide ne eye d i urf ne t hy lcyc lohexa none 5 cyclohexanone cyclohexanone The above compounds are intended only to trate the variety of structures which can be used in the process of this and the foregoing listing is not to be construed as limiting the scope of the Particularly preferred compounds which are administered in accordance with the method of this invention are These are as having the formula 0 II in which is or R 6 hydrogen or and is a derivative of the being selected the group consisting of and The substituted methylene in this invention can be conveniently prepared by condensing the appropriate cyclic ketone with a suitable aryl heteroaryl aldehyde unde alkaline synthesis can be carried out using any of a variety of sets of reaction For the cyclic ketone and aryl or heteroaryl aldehyde can be dissolved together in a suitable solvent and base added to the In another reaction the cyclic ketone and base be placed in suitable solvent and the aryl or heteroaryl aldehyde added to the Depending upon the particula which are the substituted methylene cycloalkanone may be produced rapidly and at room temperature or or of the reaction mixture may be necessary in order to effect condensation of the determination of conditions is well within the skill of those skilled the If a is at least a molar ratio of aryl or heteroaryl aldehyde to cyclic ketone must be and the cyclic ketone must be free of substitution at the carbon atoms adjacent to the carbonyl In t e event that cycloalkanone is a 7 or a sligh excess of or eroaryl aldehyde is The cyclic ketone which is employed will be appropriately substituted with intended to be present in t e final and this will include appropriate substitution at one of the carbon atoms adjacent to the carbonyl function the If the final product is intended to be a eycloalkanone which remains unsubstltuted at one of the carbon atoms adjacent to the carbonyl in order to avoid preparation a mixture of and it will necessary to modify the cyclic ketone methylene so that aryl substitution will occur at only one of the carbons adjacent to the carbonyl can be for by first reacting the selected cyclic ketone with morpholine to produce an condensing the substituted morpholine wit the selected aryl or heteroaryl cleaving the produc under acidic conditions to obtain the desired eycloalkanone unsubstituted at one of the carbon atoms ad acent to the carbonyl The alkaline reagent which is employed in the condensation reaction need only be one which will assure a basic reaction and fo the sake of convenience and an alkali metal such for sodium hydroxide or potassium will be 8 As previously this invention is directed to compositions for inhibiting androgen action and to a method s for combating such action in animals than The action of an androgen is evidenced by development of secondary male sex Although important to no as previously androgens can and do stimulate the development of undesirable such as acne and prostatic An which can inhibit but not extinguish androgen action is highly Such an agent administered in appropriate dose either prophylactically or is the basis of the teaching of this a suitable dose level will be from about milligram to about 50 milligrams of the arylidene cyclanone per kilogram body weight of the recipient per dosage level will be about milligram to about 30 grams per kilogram body weight per more from about 1 milligram to about per kilogram body per 9 used in accordance with The substituted methylene cycloalkanones invention are highly attractive not only due to their activity in inhibiting the actio of androgens but also because of their exceptionall low levels of They are in large dosages without development of serious detrimental side The substituted methylene cycloalkanones used in accordance with the of this invention can be administered in any suitable form and Administration can be by any of usual for and The can be administered alone in combination with an appropriate inert diluent such as corn oil or an saline the defined by this invention can be prepared for oral administration using any of the customary for chewing and medicinal Preparations suitable for topical tion may likewise be These include tions in liquid form for are also suitable preparative forms The a also may be present in bination with therapeutic for appropriate The following examples illustrate this tion with respect both to the preparation and activity of the EXAMPLE PREPARATION 2 7 ENE C YC LOHE ONE About grams of cycloheptanone and grams of benzaldehyde were dissolved in a mixture of 300 milliliters of methanol and 100 liters of To this solution 120 milliliters of 10 percent aqueous potassium hydroxide were added dropwise during which time the solution turned light The mixture was stirred three the last hour of which it was heated to re and then permitted to stand A precipitate and the mixture was the precipitate recrystallized from dilute acetic acid to afford grams of yellow needles of EXA PIE PREPARATION OP CYCLOHEXANONE About grams of hexanone and grams of were dissolved in 350 milliliters of To this stirred solution 100 milliliters of 10 percent aqueous potassium hydroxide were added A yellow precipitate formed after about 4 minutes and stirring was continued for an additional 6 The mixture was and the yellow cake was recrystallized from to afford 4 grams of canary yellow needles of EXAMPIE PR PARATION OF PENTANONE About grams of cyclopentanone and grams of were solved in a mixture of 300 milliliters of methanol and 100 milliliters of The resulting solution was cooled to about with and 90 milliliters of 10 percent aqueous potassium hydroxide were added a Within ten minutes a heavy yellow precipitate The reaction mixture was stirred an additional six hours during which time it was allowed to warm to room The mixture was and the solid recrystallized from glacial acetic acid taining About 63 grams of as bright canary yellow having a of were BIS EXAMPLE 4 PREPARATION OP THOX YBE ZYLIDE E About grams of cyclopentanone and grams aldehyde were dissolved 300 milliliters of The resulting solution was cooled to with and 100 milliliters of 10 percent aqueous potassium hydroxide were added over a period Almost immediately a precipitate and stirring of the reaction mixture was ued without cooling while the mixture warmed to room temperature The mixture was and the solid crystallized from a mixture of glacial acetic a cid and dimethylformamlde About grams of benzylidene cyc as canary yellow ing a of were collected BIS EXAMPLE PREPARATION OF CYCLOPENTANONE About grams of cyclopentanone and grams of were dissolved in 300 milliliters of The sulting solution was cooled to about with and 90 milliliters of 10 percent aqueous potassium droxide were added A heavy yellow precipitate formed after about ten minute s The reaction mixture was and the solid recrystallized from a mixture glacial acetic acid and ormamide About bis grams of as a canary yellow having a of were collected V EXAMPLE PREPARATION OF CYC LOPENTA NONE About grams of eye lope ntanone and grams mole of hylamlnobenzaldehyde we re dissolved in 0 milliliters of The sulting solution was and 100 milliliters of 10 percent aqueous potassium hydroxide was added at room temperature over a period An orange cipitate and stirring was continued for five after which time the reaction mixture was allowed to stand overnight The mixture was and the solid was re cryst llized from dimethylf ormamide About bis grams as a deep orange crystalline having a of were collected BIS EXAMPLE PREPARATION CYCLOPE NTANONE About grams of eye lope ntanone was dissolved in a mixture of 75 milliliters of methanol and 15 milliliters of 2N sodium and the sulting solution cooled an ice To this solution 25 grams of dissolved in 125 milliliters of a mixture of tetrahydrof uran and methanol were added dropwise with continuous stirring of the mixture The mixture turned dark and stirring was continued for about eight hours after completion of the dropwise The mixture was allowed to stand and a solid which precipitated was filtered off The solid was recrystalllzed from a mixture pf grams of as golden having a of EXAMPLE PREPARATION OF PENTANONE About grams of cyclopentanone and grams of ophene were dissolved 100 milliliters of About milliliters of 10 percent aqueous potassium hydroxide were added to the mixture during which time a precipitate The mixture was stirred for an additional four after which time the solid was collected by tration and re crys allized from acetic About grams of as golden brown having a of were BIS EXAMPLE PREPARATION CYC HEXANONE About grams of cyclohexanone and grams of were dissolved in 200 milliliters of About 100 milliliters of percent aqueous potassium hydroxide were added dropwise to the stirred A yellow cipitate formed upon completion of addition of the sium Stirring was continued for about six after which time the solid was removed by tion and re crystallized from a mixture ethanol and Ms glacial acetic About grams of t ny lid yclohexan as having a of were BIS EXAMPLES PRE PARATION LO PE NTA NONE About 21 grams mole of cyclopentanone and grams mole of were dissolved 300 milliliters of About 90 milliliters of 10 percent aqueous potassium hydroxide were added over a f ive period A heavy yellow precipitate formed and the reaction mixture was ted to stand after which time the solid was removed by The solid upon recrystallization from a mixture of glac ial acetic acid and dime hy amide afforded about grams ldene as yellow flakes having a of EXAMPLE PREPARATION OP 2 Z NE ME CYCLOHEXANONE About grams mole thylcyc hexanone and 53 grams of benzaldehyde were dissolved in 350 milliliters of met About 110 milliliters of 10 percent aqueous potassium hydroxide were added dropwise to the stirred The mixture was allowed to s tand overnight during which time a clpitate formed The precipitate was removed by tion and recrystallized from a mixture of ethanol and water to produce about grams of having a of EXAMPLE 12 PREPARATION OP About 84 grams of cyclopentanone and grams mole of morphollne were diss olved for eight hours and a water trap was used to remove any water which formed during the Benzene and morpholine were removed from the reaction mixture in vacuo on a steam bath and the residue was distilled to produce 110 grams of N b To 100 milliliters of benzene was added grams mole benzaldehyde and grams of N The resulting yellow solution was refluxed for twelve hours using a water trap to collect water formed during the ly milliliters of water were collected in the trap ing the reflux period The reaction mixture was then cooled to room and a solution of 60 liters of concentrated hydrochloric acid and 60 liters of water was added with Benzene milliliters was added to the and stirring was continued for one The aqueous layer was then rated from the benzene and extracted with additional zene which was combined with the benzene reaction mixture Benzene was removed in vacuo to give a dark brown residue which crystallized on The residue was then distilled to produce grams of cyclopentanone having a boiling point of This substance crystallized on cooling to a light yellow solid having EXAMPLE 13 PREPARATION OP 2 E CYC LOHEXA About grams mole of morpholine in the manner described in were dissolved in milliliters of dry benzene The resulting s olution was refluxed hours us ing a water trap to collect water f ormed during the The reaction mixture was then cooled to room temperature and a mixture of about 70 milliliters concentrated chloric acid and 70 milliliters water was added with ring continued for about one The aqueous layer was separated the benzene layer and extracted with more benzene which was combined with the benzene reaction ture The benzene was and residue was distilled to produce a straw colored oil which crystallized on Recrystalllzation from hexene provided about 15 grams of having a of EXAMPLE 14 PREPARATION OP ZYLIDENE CYC LO NTA NONE About grams mole of as described in Example 12 and about grams mole of were diss olved in 150 milliliters of dry benzene The resulting solution was refluxed for eighteen hours using a water trap to collect water produced during the The reaction mixture was cooled to room and a mixture of about milliliters concentrated hydrochloric acid and milliliters water was added along with milliliters of benzene The benzene layer was separated from the aqueous and the benzene evaporated to a dark residue which s olidified on Recrystalllzation from hexane gave about grams of i crystals haying a of EXAMPLE PREPARATION OP CYCLOHEXANONE About grams mole of cyclohexanone and grams mole of benzaldehyde were dissolved in 75 milliliters of To this stirred milliliters of 10 percent aqueous potassium hydroxide were added dropwise The solution turned pale yellow and turbid during addition of the tassium and the resulting mixture was f luxed with stirring f or five hours It was then ed to s tand or three days during which time a tate formed which was f iltered from the mixture The collected solid was recrystallized from methanol taining a minor amount of ethanol and water t o give grams of as white crystals having of EXAMPLE 16 PREPARATION OP About grams 1 mole of and grams of benzaldehyde were dissolved in 300 milliliters of To this stirred mixture was added dropwise 90 milliliters of 10 percent aqueous tassium hydroxide over a period Upon addition of approximately of the potassium droxide a white precipitate formed Upon completion of the addition of the potassium hydroxide the reaction ture was stirred at room temperature for hours after which the white s olid was collected by The white solid was crystallized from an ethanolt water 7 19 as a white crystalline material having a EXAMPLE PREPARATION OP 2 NE ME THOX About grams of in 100 milliliters of 10 percent aqueous tassium hydroxide was stirred at room temperature during which time grams of benzaldehyde in 300 milliliters of methanol were added dropwise The ring was continued for four hours during which time no precipitate formed The reaction mixture was ed overnight during which time a precipitate formed The precipitate was collected and re from a ture of ethanol and water to produce about 3 grams of having a melting of representative compounds include the 2 t r oxybe nzy lid e c cyc eye 20 2 lide ne t hy i nnamy lid e ne ey e lope nt a none hylene eye cyclohexaT lidene lohexy lcyc lohexanone methyl The activity of substituted ined by this invention can be demonstrated by a customary assay conducted in accords ance with the following scheme using immature male These when days were castrated and separated into at least two a testosterone stimulated group comprising twelve rats and one or more experimental each comprising six Beginning the day of the testosterone stimulated group received milligram of testosterone per day for twelve consecutive The experimental group group for each compound and dose level received an injection of milligram of testosterone well as a suboutaneous injection of the amount of the experimental 21 compound each day twelve consecutive On the thirteenth all of the each being days sacrificed and the following endocrine glands being removed and seminal vesicles ventral prostate levator ani preputial glands The organ weights of each experimental group were compared with those of the testosterone stimulated group and the differences calculated and expressed as percent The effect of the administered substituted methylene eycloalkanone on the testosterone is evidenced by the failure of the weighed endocrine glands to grow at the rate indicated for the rats which did not receive any of the substituted methylene Table I following demonstrates the inhibiting activity of substituted methylene Table I methy Activity 0 Compound a Dose Ar Y S Phenyl Phenyl S Phenyl s Phenyl s Phenyl CHg s Phenyl s Phenyl s Phenyl Activity 0 Compound a Dose Ar S Phenyl S Phenyl S Phenyl S S Table I ted methy Activity Cyolano 0 Compound a Dose Ar Y S S yl S t hoxyphe nyl S 3 4 t oxy n 1 S 3 th oxy nyl S 3 t hox henyl s 4 hoxyphe nyl s hoxyphe nyl s 3 4 hoxyphe nyl Table I Substituted methy A Activity 0 S hoxyphe S 3 4 hoxy phenyl 0 S S phenyl S 3 t hoxy phenyl S 3 t phenyl S 3 t h phenyl Table I Subs AAccttllyyllttyy O Compound a Dose 10 Ar Y O S 3 1 phenyl S 3 t phenyl S 3 phenyl S 3 3 phenyl S 20 S 4 ophe ny 1 I methy Activity Compound s s s p enyl s s 20 s s 0 II s s s s 2 s s s 2 1 s 2 1 s Table I methylene Activity A 0 Compound Dose mg Ar Y s s s s s s s s s 3 Thienyl Table I Substmtuted methylene Activity 0 Compound Dose 10 Y mg R2 I o H Phenyl H Phenyl Cyc Phenyl H H Phenyl H Phenyl Cyc H 1 20 Ή Table I Substituted met Ant Activity 0 Compound Dose 10 Ar Y ditto Phenyl Phenyl ditto Phenyl t r a S refers to and taken together being the radical b Testosterone dosage was instead of the prescribed mg c SV Seminal Vesicle VP Ventral Prostate LA Levator Ani PP Preputial glands The action of the substituted methylene nones of this invention can also be by the inhibiting effect they have on the uptake of testosterone by an As with the previously described test immature male rats each 21 days were used These rats were kept were separated into four groups arbitrarily designated as cycloalkanone Groups and The substituted used in this test was Group was administered a single dose of of the above cycloalkanone and t hirty minutes later re ceived trltiated testosterone Group B was istered milligrams of the above cycloalkanone daily for three consecutive days and 2k hours later received the Group C was administered 3 milligrams of the above cycloalkanone daily for twelve consecutive days and hours after the last administration received the Group D received nothing but the single is tration of the i All rats were aut t hirty minutes s ubsequent to the administration of the and the ventral prostate of each was removed As Table II following demonstrates the presence of radioactive 33 testosterone was markedly reduced in the ventral prostate glands of those rats which were first administered the above when compared with those which received only the radioactive Table INHIBITION OP UPTAKE OP TESTOSTERONE Percent Inhibition Test Group Days of Uptake of A 1 23 3 C 12 61 The above results give clear indication of the ability of the compounds of this invention to inhibit the uptake testosterone by glands and thereby to inhibit the action of androgens by precluding their retention in such glands 34 insufficientOCRQuality

Claims (3)

1. A process for inhibiting the action of androgens in non-htunan animals which comprises administering to a non-human subject exhibiting a superabundance of androgen action an effective quantity of a substituted methylene cycloalkanone having the formula in which Y ±s -CHR, -CHR-CHR- , -CHR-CHR-CHR- , xn -CHR-CHR-CHR— CHR-; Y' is -CHR- or -CHR-CHR- ; each R independently is hydrogen, methyl, ethyl or propyl, Ar is phenyl, furyl, thienyl, styryl, naphthyl, or a mono- or dt-substituted derivative of each, the substituents being selected from the group consisting of hydroxy, loweralkoxy, loweralkyl, methylenedioxy , amino, mono loweralkylamino , diloweralkylamino , nitro and halo; R^ is hydrogen, cyclohexyl or phenyl, or loweralkyl-substituted cyclohexyl or phenyl, and R2 is hydrogen; R^ and taken together is =CH-Ar as herein defined; and the ring A is optionally substituted by . loweralkyl or loweralkoxy groups .

2, The process of Claim 1, which comprises administerin from about 0,1 to about 50 milligrams of the substituted methylene cycloalkanone per kilogram body weight of the non-human subject per day.

3. The process of Claim 1 or 2, which comprises - 35 - 40220/2 in which Y is -CH2-, -CH2-CH2-t or CH2-CHR-CH2-, . R is hydrogen or methyl; and Ar is phenyl, furyl, thienyl, styryl, naphthyl, or a mono- or di-substituted derivative of each, the substituents hydroxy being selected from the group consisting of/loweralkoxy , lower-alkyl, meth lenedioxy,. -di-loweralkyl-amino, nitro and halo. 4· The process of any one of Claims 1 - 3 which comprises administering a compound selected from 2,5-his(3,4-dimethoxybenzylidene)cyclopentanone, 2,6-dibenzylidene-4-methyIcyclohexanone, 2,6-his.(3-methoxy-4-hydroxybenz lidene) cyclohexanone . 5· An anti-androgenic composition comprising an inert diluent, and an androgen-inhibiting proportion of a substituted methylene cycloalkanone having the formula I or II in Claim 1, wherein Y, Y', Rlf R2 and R have the same meaning as in Claim 1. For DR. B y