CA1246604A - Cycloaliphatic pharmaceutical compounds - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Novel pharmaceutical compounds, useful in anti-?
genic compositions, have the formulae:
(I) (II) In these formulae:
B and B' are both H or together form a single bond;
M1 and M2 are H, Cl, Br or I
Q is CO, CH-OR, or CR-OH;
each X is independently H or A;
Y and Y' are independently H, halo. or A;
A is -CRR-(CR1R2)nR3 n is an integer of from one to eight;
R is H or lower alkyl;
each R1 and R2 is independently R, OR, COOH, CHO, or CR1R2 together form the group CO;
R3 is H, COOR, OR, CHR-OR or COR;
c is an integer from zero to four; and d is three or four; and p is zero or one provided that at least one A group is present and each A
group contains at least one of COOR, CHO, CO, OR and COR, and not more than one of COOH, CO or COR, and wherein up to two ethylenic bonds may be present in the ring shown above.
Pharmaceutically-acceptable salts of these compounds also are provided.

Description

ii6~
-1- 18775-Canada CYCLOALIPHATIC PHARMACEUTICAL COMPOUNDS
_ The present invention provides compounds of the formulas Q (I) - ~ or MlM2C - Q (II) MlM2C (CH2) ¦ -Hl ¦H CH - CH
11 1 \ /
X -CH /C-X (CH-X)d (CH2) C

In these formulas, M and M are H, Cl, Br or I
Q is C0, CH-OR, or CR-OH;
one of X and Xl is H and the other is A;
A is -CRR-(CR R )~R
n is an integer of from one to eight;
R is H or lower alkyl;
each R1 and R2 is independently R, OR, COOH, CHO, or CR R2 together form the group C0;
: R is ~, COOR, OR, CHR-OR or COR;
c is one or two;
d is three or four; and p is zero or one;
:provided that the A group contains a group COOR, CHO, CO, OR, COR or CHR OR or a pharmaceutically acceptable salt thereo~.
In Formula (II) only one X group is A; the remainder ; being H.
~:As the pharmaceutically acceptable salts may be mentioned, for example, alkali metal salts, alkaline earth salts and ammoniacal salts. As specific salts may be mentioned sodium, magnesium and ammonium salts.~ As the ~ ~ .

~'b ~
;

-2- l8775-Cana~a lower alkyl group may be mentioned, for example, methyl, ethyl, straight chain or branched propyl and butyl.
Compounds where the B and B' groups form a single bond are a preferred embodiment, and the cis form of such compounds constitutes a preferred aspect th~reof.
In a preferred aspect, the compound ~I~ has the fol-lowing parameters:
Q is CO, CH-OH, CH-OCH3 or CH-OCH2CH3;
c is l; and n is l to 4.
A preferred group of compounds (I~ has the formula ~`

CH Ia 2 ~ /
~2 In this preferred group may be mentioned compounds, wherein A is defined by the group:
-CH~-CH~-CEI2-C(R R5)R6 wherein R4 and R are independently H, methyl or ethyl;
R5 is COOH, CHO or C(R7R9)oR8; and R7' R8 and R9 are independently H, methyl or ethyl.
As the group -C(R4R51R6 may be mentioned -CH2COOH, -CH2C~2~H, -CH2CH(C~3)OH, -cH2cH(cH2cH3)~cH3~ -CH2cHO~
-C(O~)(cH3~c2H5~ -CH~CH3)CH(C~2CH3)OHI or -CH(CH3~C~(CH2CH3)OCH3. Particularly preferred are com-pounds which are 2-(5-substituted alkyl)bicyclo E 3.3.0]octan-7-ones, including 2-(5-methoxyhept-l-yl)bi cyclo[3.3.0]octan-7-one" 2-(5-hydroxyhept-l-yl)bicyclo [3.3.01octan-7-one, 2-(5-hydroxy-4-m~thylhept-l-yl) hicyclo[3.3.Q]octan-7-one, and 2-(5-methoxy-4-methylhept-l-yl~bicyclo~3.3.0]octan-7-one.
It has also been found ~hat compounds of Formula I
above in which the oxygenated group Q is a member of a fused cyclobutane ring, are of great value. In a preferred

-3- 18775-Canada embodiment, integer d is three, thus establishing a bicyclo [3.2.0] heptan-7-one ring structure.
In certain preferred compounds a single nuclear A-substituent of the type described above is present and a cis bridge. Especially preferred are the compounds with a 2-A substitutent of the formula M M ~ Q
CH ~H

~H/
In this preferred group there are especially preferxed co~pounds with a cis bridge and a group Q being carbonyl Ml M2 and A being defined as ahove. Also preferred are A
substituents in the 2-position of the formula (CH~)m-CH(OE)G, where E and G are H, methyl or ethyl, m is desirably four.
Also provided is an anti-androgenic composition suit-able or providing an anti-androgenic effect when adminis-~ tered to a patient which comprises a pharmaceutically ; effective amount of a compound (I) or (II) and a pharmaceutically inert carrier suitable for topical administration of said compound to said patient. As the pharmaceutically inert carrier may be mentioned an alcohol, salve, suspension, emulsion, ointment, cream, powder or spray. In a preferred am~odiment, alcohols such as ethanol and isopropanol are preferred as a pharmaceutically inert ca:rrler .
In a further preferred embodiment, an anti-androgenic composition with the compounds (I~ and (II) is provided in a sustained release vehicle for transdermal application to the skin of a patient. The sustained release medium should be one which will maintain the compQund (I~ or ~II) at the skin and permit release to the skin for a period of ,~ :

:, ~ :

-4- 18775~Canada preferably at least about six to abou~ eight hours. As an example of a sustained release medium may be mentioned polyvinylalcohol having a degree of hydrolysis of about 88%
and having a molecular weight of at least about 8,000. For example, a polyvinylalcohol having a molecular weight of about 20,000 is suitable for the the compound [I) or (II).
A further embodiment provides a skin preparation suitable for topical administration to a patient to be exposed to ultraviolet light which includes both the Com-pound (I) in which p is one and an anti ultraviolet screening agent such as paraminobenzoic acid or cocoa butter.
A shampoo is advantageously provided for sufferers of skin problems and particularly male pattern baldness, which comprises conventional shampoo ingredients having incor-porated therein the compound (I) or (II).
The invention provides a method of blocking androgen receptor sites in a patient which comprises introducing to said sites the compounds ~I) or ~II), particularly via the topical route. The growth of some cancers is alleviated by treatment with the compound of this invention. Male pattern baldness, which is androgen linked and can be treated with these compounds to block androgen receptor sites.
Compounds of ~ype ~I) in which p is one are also useful in the prevention of keloids, and wrinkling of the skin and related conditions. Extremely minute concentra-tions, even dilutions exceeding 100,000:1, have been effec-tive for these conditions. Experiments generally following the methodology of Boote et al, Biochimica et Biophys~ca Acta, 607, pp. 145-160 11980), have shown that while con-trol human fibroblast cells have copious collagen produc-tion, treatment with the compounds of the invention provides human fibroblast cells with suppressed collagen product and with an increase by 30% over control cel 15.
Following the Salmon clonogenic assay, Cancer Treatment ~E~ 65, p. 1 ~1981), the compounds at a level of 10 ".L

~5- 18775-Canada mcg/ml cause selective destruction of cancer cells. They also increase the chemosensitivity to standard anti-cancer drugs tested including mitomycin C, vinblastine, vincristine, cis-platinum, actinomycin D, adriamycin, hexamethylmelamine, methyl-GAG, 5-FU, melphalan and bleomycin.
A preferred embodiment is the provi~;ion of an anti-acne tr~atment, where the patient afflicted with acne is treated with the compound ~I), which reduces androgen reaching androgen receptor sites, ~hereby alleviating the acne problem.
Both th~ compounds of Structure (I~ and (II) have a desirable effect in that , on topical administration, they increase elastin and decrease collagen. In this respect, the effect resembles that of estrogen, but the estrogenic hormonal actions are avoided.
While topical application of the compounds (I) and (II) constitutes one embodiment of the invention, other routes for pharmaceutical administration are also contemplated, particularly the oral and suppository routes.
Oral dosage unit formulations include tablets, capsules and other conventional oral forms. As a tablet the compounds are typically present in an amount of from about 1 to about 50% by weight, with the inert carrier constituting the remainder of the tablet. Tablets are compressed in a conventional manner, with typically one percent magnesium stearate being included in the mixture to be tabletted~
Liquid oral dosage unit formulations may also be used in which the compounds are incorporated into vehicles conventionally used for lipid soluble compounds. By including at least one carboxy or carboxy ester group in the compound, a hydrophilic character may be obtained.
Suppositories wi~h the compounds ~I) and (II~- are also con*emplated, to provide a rectal suppository administration of the dru~ and which form takes advantage of the usual suppositoFy ingredients-:~

"

-6- 18775-Canada The high potency of the compounds permits relatively low dosages both systemically via oral or suppository route or through topical (transdermal) application. A
concentration of the compounds of from about OoOO1 to 5 percent by weight of the composition, and generally from about 0.01 to about one percent is useful. Topical application on an infrequent basis, including a sustained release delivery, may indicate a relatively higher amount of the compounds, preferably in the range of from about 0.05 to about 3 percent by weight. A relatively lower concentration of the compounds is indicated where a relatively larger surface area is treated, such as the back, chest, etc., e.g., a concentration of from about 0.01 to one percent by weight.
Where the compound is indicated for systemic delivery, oral, injection, suppository and sublingual forms may be used, preferably the compound is administered as an oral dosage unit foxm, such as a tablet, capsule, powder or other traditional dosage unit form. In a preferred embodiment, the oral dosage unit form is a tablet which contains a relatively small amount of the compound, which is due to the high potency as an anti-androgenic. A single oral dosage unit formulation, when administered as one oral dosage unit formulation several times per day, generally up to about four times per day, will for a normal adult male comprise an amount of about O.OOOI to about 40 mg per oral dosage unit form, and preferably from about 0.01 to about 2 mg per oral dosage unit form.
It is to be understood that the extremely small amount of the compound necessary means as a practical matter that a "normal" tablet size will have only a very small percentage of the compound, with the remainder comprising pharmaceutically inert ingredients such as talcum, maize starch, polyvinyl pyrrolidone and lactose, together with a small amount of a tabletting agent such as magnesium stearate.

,~.Z'~
-7- 18775-Canada Use of bicyclo [3.2.0] heptan-7-ones of formula (II~
is described herein for the preparation of intermediates in the production of bicyclooctanes of Formula (I) above.
This ring enlargement can utilize diazomethane, alkyl diazoalkanoates such as ethyl diazoacetate or equivalent reagents.
In addition, however, compounds of Formula (II~ are also of a high degree of biological acti~ity, displaying especially excellent utility in their capacity to selectively destroy cancer cells, as demonstrated in the Salmon clonogenic assay. They are also especially active topically in treatment of male pattern baldness.
The general scheme for preparing the novel compounds comprises two phases. In one phase the ring structure is prepared, in the other the side chain in the form of a precursor of the desired chain. The ring and side chain precursors are combined and subjected to further r~action to generate the desired product.
Thus a dihalide of Formula I, in which Ml and M2 are halogen is dehalogenated to the compound in which Ml and M2 are hydrogen. This dehalogenation reaction can be carried out in conventional manner using a metallic catalyst such as zinc or a zinc copper alloy. Acid solutions are preferred using mineral acids or organic acids.
Preparation of compounds of type II can be conveniently carried out by subjecting a cycloalkene of the formula Fl 2-Xjd to a ketene reaction. For example a cyclopentene with an A-substituent in the 3- position can be heated with a ~; dihaloacetyl halide. Other reagents include ketene or a dihaloketene.

~ ~ :
:

-8- 18775-Canada The following examples illustrates the invention:
Exam~le 1.
Ring and Side Chain Combination:
3-(5-Methoxyhe~t-l-yl)cyclopentene Magnesium metal turnings (7.2 gm, 0.299 moles) were added to a three-neck, round-bottom flask equipped with a Friedrich condenser and kept under N2 gas. Tetrahydrofuran (300 ml~ was transferred to the flask and the contents allowed to stir. A clear t colorless solution of 1 chloro-5-methoxyheptane (48.1 gm, 0.292 rnoles~ was added portionwisè and refluxed. The final third portion was added and the mixture allowed to stir for 3 hours. 'rhe dark yellow solution was cooled to -25C, the condenser was removed and replaced with a dry ice addition funnel. A
clear solution oE 3-chlorocyclopentene (29.9 gm, 0.292 moles) was added over one hour. The viscous solution was poured into two liters of El2O, extracted with ether, and dried over Na2SO4. Distillation yielded 3-(5-methoxyhept-1-yl)cyclopentene (51.5 gm, 0.2S2 moles~
as clear, colorless oil boiling at about 90C at 0.3 mm.
and 54C at 0.1 mm.
6,6-Dichloro-2-~5-methox~hept-1-yl~bicyclo[3.2.0]
heptan-7-one To a 1,000 ml three-neck, round-bottom flask, equipped with a reflux condenser containing 3-(5-methoxyhept-1-yl) cyclopentene (15.0 gm, .076 moles) in 300 ml of hexane, freshly distilled dichloroacetyl chloride (35.1 gm, .240 moles~ was added and the solution stirred by a mechanical stirrer and heated to reflux. Triethylamine ~25.2 gm, 0.249 moles), dissolved in 200 ml hexane, was added dropwise and the refluxing solution allowed to stir or 4 hours. The solvent was removed and then the residue distilled and chromatographically purified over silica gel, leaving the product ~17 gm.~. Analysis, IR 2963, 2932, 2864, 2857, 2820, 1803, 1461, 1378, 1223, 1197, 1157, 10~3, 1030, 968, 914, 842,821, 802, 778, 740, 673.

~LZ~6~
-9- 18775-Canada For the production of C14- labelled 6,6~dichloro-2-(5-methoxyhept-1-yl~bicyclo[3~2.0]heptan~7-one, C14-labelled dichloroacetyl chloride was employed.
6,6-Dichloro-2-(5-methoxvhept-1-yl)bicyclo~3.3.0]
octan-7-one The starting material, 6,6-dichloro-2-(5-methoxyhept-l-yl)bicyclo[3.2.0}heptan-7-one (5 gm,), was dissolved in 100 ml of ether and transferred to a 500 ml, round-bottom glass. Excess diazomethane was generated in situ by reacting p-tolylsulfonylmethylnitrosamide (60 gm) with KO~
in ethanol. The CH2N2 was allowed to react for 50 minutes, after which time acetic acid was added to destroy any remaining diazomethane. The solution was extracted with ether and dried over Na2SO4, yielding the crude product as an orange oil suitable for the nex~ preparation.
2-~5-Met~yhept-l-yl)bicyclol3.3.0]octan-7-one To a single-neck lOOml, round-bottom flask equipped with a condenser was added ~,6-dichloro-2-(5-methoxy hept-l-yl)bicyclo(3.3.0)octan-7-one (45 9 gm). The solution was stirred by magnetic stirring and powdered zinc metal (92 gm) and glacial acetic acid ~312 ml~ was added and the solution allowed to reflux for six hours, during which time white ZnCl2 precipitates out of solution. The solution was filtered, washed with Na~CO3 and extracted three times with ether. The ether extracts were combined and dried over Na2SO~. The resul~ing yellcw oil was chromatographed with silica gel and eluted with 3:1 hexane:ether~ The fractions were combi~ed, yielding 2-(5-methoxyhept-l-yl)bicyclo[3.3.0~octan-7-one as a clear, colorless oil.
IR 2928, 2853j 2828, 1740, 1460, 1402, 1735, 1158, 1122, 1093, 1050, 1035, 960, 740.
Example 2:
2-(5-Methoxyhept-l-~l)bicyclo~3.2.0]he~tan-7-one Zinc-copper catalyst (3 gm) was added to a stirred solution of 6,6-dichloro-2-(S-methoxyhept-l-yl)bicyclo :

-10- 18775-Canada L3.2.0]heptan-7-one (2 ~m, 6 moles~ in acetic acid (100 ml) under a nitrogen atmosphere~
The solution was stirred at room temperature for one hour, then refluxed for 1 hour, after which time the mixture was filtered through a sintered glass funnel and the etheral solution dried over Na2SO4. The solvent was removed under vacuum, leaving the crude product.
Chromatography on silica gel yields the compound of the invention, 2-~5-methoxyhept-1-yl)bicyclo~3O2.0]
heptan-7-one (1.2 gm~, (which, optionally, can be used to generate another compound of the invention by reaction with dia~omethane to expand the ring and form the product of the preceding example~.
Analysis: IR 2959, 2933, 285g, 2820, 1778, 1461, 1~06, 1386/ 1316, 1303, 1260, 1236, llg7, 1154, 1091, 1024, 921, ~62, al9.
Example 3:
2-(~ydrox he t-l- l)bic clo[3.3.0]octan-7-one Y _ P Y _. Y , _ _ 2-(5-methoxyhept-1-yl)bicyclo[3.3.0]octan -7-one (1 gm, 3.9 moles) (prepared as in Example 2) in ether (5 ml) was added to a solution of acetic anhydride (40 ml). The stirring mixture was cooled to OC and freshly distilled boron trifluoride etherate (7.0 ml) cooled to 0C was added. The solution was sti~red at 0C for 25 hours, after which time the reaction mixture was poured into ice water and stirred for two hours, followed by e~her extr~ction (3xlO0 ml). The combined ether extracts were washed with NaHCO3 (3xlO0 ml), dried over Na2SO4, and the solvent removed under vacuum, leaving a yellow residue.
Chromatography on silica gel yielded 2-(5-hydroxyhept-1-yl) bicyclo[3.3.0]octan-7-one l0.18 gm).
Analy~is: IR 3395, 2935, 2855, 1748, 1465, 1267, 1245, 1160, 1120, ~65, 920, 810, 785, 745.
~This compound can bè prepared more conveniently by the ;following method. To a solution of 1 gm. of 2~~5-methoxyhept-1-yl)bicyclo[3.3.0]octan~7-one in 20 ml of acetonitrile under nitrogen was added 3 gm of sodium -11- 18775-Canada iodide. The red solution was stirred at room temperature and 2.5 ml of methyl silyl chloride was added at once.
After 7.5 hours, water was added, followed by a saturated aqueous sodium sulfate solution. The solvent was removed under vacuum, leaving a light yellow oil. Chromatography on silica gel left pl~re 2-(5-hydroxyhept-1-yl)bicyclo [3.3.0~octan-7-one.
Example 4 6,6-Dichloro-2(5-hy~rox~ptyl)bicyclo[3.3.0]octan-7-one Using the demethoxylation procedure of the immediately preceding example on 6,6-dichloro-2(5-methoxyhept-1-yl) bicyclo[3.3.0]octan-7-one there was obtained the

5-hydroxyheptyl derivative.
Analysls: IR 341~, 2955, 2868, 2856, 1801, 1462, 1131, 1118, 1029, 987, 967, 7~1, 675.
Subjecting 6,6-dichloro-2-(5-methoxyhept-1-yl)bicyclo [3.2.0]heptan-7-one to this same demethoxylation procedure produces 6,6-dichloro-2-(5-hydroxyhept-1-yl)bicyclo[3.~.0]
heptan-7-one.
The coxresponding 2-(5-ethoxyhept-1-yl) homologs are prepared by substituting an equivalent amount of 1-chloro-5-ethoxyheptane in the Grignard reaction of Example 1 in place of the 5-methoxy homolog and using the reaction sequence shown above to prepare irst the 3-(5-ethoxyhept-1-yl)cyclopentene, which is then converted to the 6,6-dichloro-2-~5-ethoxyhept-1-yl)bicyclo[3.2.0]
heptan-7-one of this invention. The diazomethane reaction described for the methoxy homolog produces the

6,6 dichloro-2-15-ethoxyhept-1-yl)bicyclo[3.3.0]
octan-7-one.
The two chlorine atoms ~an be removed from the aforementioned 6,~-dichloro derivatives by the above described method of ~reatment with zinc-copper catalyst in ether under nitrogen atmosphere to produce the 2-l5-ethoxyhept-l-yl)bicyclo[3.2.0]heptan-7-one and the 2-(5-ethoxyhept-1-yl~bicyclo[3.3.0]octan-7-one respectively.

6~1~
-12- 18775-Canada Exam~
2-(5-Methox he t-l- 1)-7-meth 1-bicyclo[3.3.0]octan-7-ol Y P Y _ _ Y _ .
6 gm 6,6-dichloro-2-(5-methoxyhept-1-yl)bicyclo [3.2.0]heptan-7-one were added to 400 ml ether solution of dlazomethane, generated from 45gm of p-tolylsulfonylmethylnitrosamide. The reaction i5 allowed to proceed for 5 hours after which glacial acetic acid is added dropwise to neutralize the excess diazomethane. The ether solution is washed with sodium bicarbonate and dried over sodium sulphate. The solvent is removed under vacuum, leaving an orange oil. Chromatography on silica gel yields the pure product as a clear liquid (2.2 gm).
Analysis: IR 3430, 2931, 2856, 1658, 1461, 1379, 1362, 1328, 1325, 1316, 1244, 1195, 1173, 1162, 1093, 1027, g84, 950, 923.
Treatment of 6,6-dichloro-2-(5-methoxyhept-1-yl)-

7-methylbicyclo[3.3.0]octan-7-ol with zinc-copper catalyst in ether as described above yielcls 2-(5-methoxyhept-1-yl)-7-methylbicyclo[3.300]octan-7-ol.
Example 6 6,6-Dichloro-2~(5-methoxyhept~l)bicyclo[3.2.0]he~tan-7-ol To a solution of 50 ml of ethanol, 30 ml of water, and

8 gm of sodium hydroxide, there i5 added in pellet form 0.2 gm of sodium borohydride in a single portion. 6,6 dichloro-2-(5-methoxyheptyl)bicyclo[3.2.0]heptan~7-one (1 gm~ is added and the reaction mixture is heated at 45C for 10 hours. The so}ution is then cooled in an ice bath and concentrated hydrochloric acid is added dropwise until the solution has reached a pH of 1. The reaction mixture is then extracted 3 times with 75 ml ether. The combined ether extracts are washed with sodium bicarbonate and dried over sodium sulphate. The solvent is removed under vacuum, leaving 0.4 gm of a clear yellow product.
Treatment of the product with zinc-copper catalyst as described above yields 2-(5-methoxyhept-1-yl)bicyclo[3.2.0]heptan-7-ol.

6~'~
-13- 18775-Canada The reactions of this example can also be conducted using an equivalent amount of 6,6-dichloro-2-(5-methoxyhept-1-yl)bicyclo[3.3.0]
octan-7-one to prepare first 6,6-dichloro-2-(5-methoxyhept-1-yl)bicyclo[3.3.0]octan-7-ol which is then treated by the ~inc-copper catalyst reaction in ether to produce 2-t5-methoxyhept-1-yl)bicyclo(3.3.0)octan-7-ol.
Analysis: IR: 3501, 2960, 2932, 2856, 2822r 2736, 1657, 1638, 1635, 1461, 1374, 1303, 1261, 1248, 1246, 1239, 1161, 1132, 1093, 1037, 99~, 963, 943, 920l 750, 724, 690.

Example 7-Side Chain Synthesis:
Synthesi 5 0 f 5-Methoxyhept~llithium A solution of 82.3 gm of 1-chloro-5-methoxyheptane in 300 ml. of petroleum ether was added slowly to 8.6 ~m of lithium wire in a three-necked 1ask. The mixture was cooled to -10C until all of the lithium dissolved (about one hour). Additional ether was added and the distillation repeated to remove any unreacted halide. The solution was transferred to a well-stoppered flask under nitrogen.
Ring and Side Chain Combination Synthesis of 1-(5-Methoxyheptyl)-4-(2-tetrahydropyranol) cyclooctane A solution of 5-methoxyheptyllithium (20 mmole in 50 ml of THF) was stirred at -60C and CuI (lOmmole) was added. After one hour, a solution of l-chloro-4-~2-tetrahydropyranol) cyclooctane (10 mmole in 50 ml of THF) was added dropwise with stirring to the alkyl copper lithium solution over a period of three hours at a temperature of -50C. The mixture was stirred for an additional three hours, after which time the mixture was poured into a saturated solution of NH4Cl and stirred for 30 minutes, after which ether extraction took place. The extracts were combined and dried over powdered Na2SO~, to 6~'~
-14- 18775-Canada yield the desired product 1~15~methoxyheptyl)-4-(2-tetrahydropyranol~ cyclooctane.
Synthesis of 4-(5-Methoxyheptyl)cyclooctanol A solution of 4-(5-methoxylheptyl)cyclooctyl-2-tetrahydropyran (20 mmole in 50 ml of ether) was shaken with 25 ml of 2N HCl for two minutes, until the solution was effected. The reaction was allowed to stand at room temperature for 15 mintes, then extracted two times with 50 ml portions of ether. The extracts were combined, distilled, and dried over powdered Na2SO4. The solvent was evaporated under vacuum, giving a 35% yield (1.6 gm) of the desired product 4-(5-methoxyheptyl)cyclooctanol as an oil.

Synthesis of 4-(5-Methoxyheptyl)cyclooctanone A solution of pyridinium chlorochromate (30 mmole in 150 ml of CH2Cl2) added to a 500 ml, round-bottom flask. A
solution of 4-(5-methoxyheptyl)cyclooctanol (20 mmole in 20 ml of CH2Cl2) was added all at once to the stirring mixture. After 90 minutes, 200 ml of dry ether was added and the supernatant was decanted, leaving a black solid gum. The residue was washed three times with 50 ml portions of anhydrous ether, yielaing a black granular solid. The extracts were combined, passed through a shortpad of Florisil and the solvent removed by distillation. The residual oil was distilled through a short Vigreaux column giving a 79~ yield l3.7 gm) of the desired product 4-~5-methoxyheptyl)cyclooctanone.
Examp~e 8:
Side Chain Formation and Combination With Ring:
S nthesis of 1-Acetvloxv-5-(5-methoxvhe~tYlene)cyclooctane Y .. ~ ~
A solution of triphenylphosphine ~55 gm in 45 ml of dry benzene3 was added to a pressure bottle The bottle was cooled with ice, and 5-methoxyheptyl bromide (28 gm~
added. The bottle was sealed and allowed to stand a~ room temperature for two days, after which time the bottle was reopened. The white solid was collected wi~h 500 ml of hot ~,.

-15- 18775-Canada benzene and dried in a vacuum oven at 100C over phosphorous pentoxide giving a 98~ yield of triphenyl-5-methoxyheptylphosphonium bromideO (M.p. 232C, literature m.p. 232-233C.) An ether solution o n-butyllithium (6.4 gm in 100 ml of ether) and 200 ml of dry ether was added to a three-necked round bottom flask under nitrogen. The solution was stirred and 3.5 gm of triphenyl-5 methoxheptyl-phosphonium bromide carefully added over five minutes, after which time the mixture was stirred at room temperature for four hours.
Freshly distilled l-hydroxy-9-oxabicyclo(3.3.1) nonane (1.56 gm in 50 ml of ether~ was added dropwise to the flask forming a white precipitate. The solution was heated under reflux overnight, after which time the mixture was cooled and the precipitate extracted three times w~th 50 ml of ether. The combined etheral extracts were extracted with 100 ml portions of H2O until neutral, and dried over Na2SO4. Distillation followed by fractionation yielded 35-42% (0.5-0.65 gm) of the desired product l-acPtoxy-5-(5-methoxyheptylidene)cyclooctane.
Svnthesis of 5-(5-Methoxvhe~tvlidene)cyclooctanol To a stirred solution of 5-(5-methoxyheptylidene~
cyclooctanol acetate (2 mmoles) was added NaOH (8 mmoles, in 15 ml of 95% ethanol). The solution was stirred at room temperature for 1 hour, after which time dilute H2S04 was added and the solvent removed under vacuum. The residue was extracted with ether (3x50 ml), dried over Na2SO4, and the solvent removed under vacuum leaving the crude product.
Chromatography on silica gel yielded 5-methoxyheptylidene cyclooctanol (0.4gm).
Synthesis of 5-(5-Methoxyheptyl)cyclooctanol A solution of 5-(5-methoxyheptylidene) c~clooctane (4.8 gm in 95~ ethanol~ was reduced to the alkane with a barium sulfate supported platinum catalyst containing 0.02 gm of reduced platinum with vigorous stirring under two atmospheres of hydrogen gas at 25C for 10 minutesO The ~66S3~
-16- 18775-Canada mixture was then filtered, washed two times with 50 ml of ether, distilled, and dried over powdered Na2SO4 to give a 98% (4.6 gm) of the desired product 5-(5-methoxyhep~yl)-cyclooctanol.
Synthesis of 5-(5-Methoxyh~ptyl)cyclooctano~e A solution of 5-(5-methoxyhepthyl)cyclooctanol t20 mmole) was oxidized to the ketone with pyridinium chlorochromate by the procedure of Example 7.
Examples_9-25:
Using the procedures described above, the following futher compounds according to the invention were prepared and characterized by the spectral data given.

9. 4-~5'-methoxyhept-1-yl~ cyclooctanone I.R. 2965, 2853, 2835, 1702, 1465, 1440, 1415, 1360, 1335, 1260, 1205, 1170, 1130, 1095, 965, 925, 860,

10. 5-(5'-methoxyhept-1-yl) cyclooctanol 3420, 2g35, 2855, 1460, 1445, 1420, 1376, 1270, 1095, 1027, 985, 920, 730 lOa 5-(5'-methox he~t-l-vl) c~clooctanone Y . ..
3027, 2060, 2855, 2830, 1705, 1460, 1445, 1425, 1355, 1268, 1195, 1170, 1125, 1095, ~65, 920, 91~, 855, 820, 735

11. 2-hydroxy-2-(5~-hydroxypent-l-yl) bicyclo [3.3,0]
octan-?-one 3445, 2935, 2865, 1745, 1660, 1460, 1445, 1370, 1355, 1305, 1260,1245, 1190, 1175, 1045, 1~25, 960, 835, 820, 735

12. 2-(5'-hydroxyh~tylidene) bicyclo [3,3.0] octan-7 one 3400, 2935, 2860, 17~5, 1660, 1465, 1~10, 1170, 1165, 10~5, 1040, 935, 850, 735

13. 5-(5'-hydroxyhe~t-l-yl) cycloctanol 3380, 2g35, 28~5, 1460, 1450, 1365, 1350, 1325, ; 127~, 1115, 1080,' 985, 735

14. ~
3400, 2938, 2860, 284~, 1705, 1460, 1440, 1365, 1265, 1110, 1075, 970, 935, 730 ~jr,l~

~2~6~
-17- 18775-Canada

15. 4-(5'-hydro~y~ent-1-yl)cyclohexanone 3420, 2945, 2860, 2835, 1700, 1620, 1465, 1360, 1325, 1265, 1220, 1195, 1165, 1135, 1065, 935

16. 3-~5'-hydroxypent-1-yl~cyclopentanone 3455, 2955, 2938, 2842, 2815, 1747, 1620, 1457, 1435, 1379, 1360, 1238, 1195, 1151, 1144, 1110, 1089, 905, 7~0

17. 2-(5'-h~dr~ypent-l-yl)bicyclo[3.3.o]octan-7-one 2935, 2865, 1742, 1465, 14~0, 1265, 1230, 1175, 1155, 1050, 945, 735

18. 2-(4-carboxybut-1-yl)bicyclo[3.3.0]octan-7-one 3150, 2935, 2865, 1745, 1710, 1665, 1460, 1265, 1235, ll90, 1165, 1150, 1050, 938, 725

19. 2-(5'-carboxypent-1-yl)blcyclo[3~3~0}octan-7-one 3100, 2935, 2860, 2835, 1743, 1705, 1660, 1465, 1260, 1225, 1170, 1155, 1045, 935

20. 2-(5'-carboxyhex-1-yl)bicyclo[3.3.0]octan-7-one 3380, 2935, 2860, 1743, 1465, 1420, 1260, 1235, 1140, 1055, 935

21. 2-(3'~oxopent-1-yl)bicyclo[3.3.0~octan-7-cne 293~, 2865, 2820, 1745, 1708, 1460, 1435, 1415, 1275, 1255, 1230, 1120, 1070, 940, 745

22. 2-(3'-hydro~ypent-1-~L~ cyclo[3 3.0]octan-7-one : 3400, 2935, 2865, 1743, 14~5, 1435, 1420, 1260, 1225, 1125, 1065, 935, 735

23. 5-(5'-hydroxypent-l-yl)cycloheptanone 3420, 2945, 2855, 1700, 1~65, 1420, 1255l 1~30, 1100, 1075, 945, 735 : 24. 2-l5'-methoxyhept-l-yl)blcyclo[3.3.0]octan-7-ol 3420, 2935, 2860, 2835, 1465, 1425, 1380, 1365, ~ 1245, 1195, 1155, 1095, 1070, 930 : ~ 25. : ~
: 3100, 2940, 2865, 2830, 1703, 1625, 1465, 1360, 1330, 1~65, 1225, 1195, 1170, 1105, 1065, 1030, ~: ~; 980, 935, 745 :: ~ Example 26:
3-(Meth~heptyl)cyclohexanone -18- 18775-Canada A solution of triphenylphosphine (55 gm in 45 ml of dry benzene) is added to a pressure bottle. The bottle is cooled with ice, and 5-bromomethoxyheptane added. The bottle is sealed and allowed to stand at room temperature for two days, after which time the bottle :is reopened. The white solid was collected with 500 ml of hot ben~ene and dried in a vacuum oven at 100C over phosphorous pentoxide.
An etheral solution of n-bu~yllithium (6.4 gm in 100 ml of ether) and 200 ml of dry ether is added to a three-necked round bottom flask under nitrogen. The solution is stirred and 3.5 gm of triphenyl-5-methoxyheptyl-phosphonium bromide carefully added over five minutes, after which time the mixture is stirred at room temperature for four hours.
Freshly distilled 3-hydroxycyclohexanone is added dropwise to the flask forming a white precipitate. The solution is heated under reflux overnight, after which time the mixture is cooled and the precipitate extracted three times with 50 ml of ether. The combine~ etheral extracts are extracted with 100 ml portions of ~2 until neutral, and dried over Na2SO4. Distillation of the desired product yields 3 (5-methoxyheptylidene)cyclo-hexanol.
Synthesis of 5-(5-Methox ~
A solution of 5-(5-methoxyheptylidene)cyclohexarlol (4 8 gm in 95~ ethanol) was reduced to the alkane with a barium sulfate supported platinum catalyst. A solution of 5~~5-methoxyheptylidenelcyclohexanone was vigorously mixed with the platinum catalyst under two atmospheres of hydrogen gas at 25C for 10 minutes. The mixture was then filtered, washed two times with 50 ml of ether, distilled, and dried over powdered Na2SO4 to give the desired product 5-(5-mathoxyheptyl)cyclohexarlol.
Sy~thesis of 3-(5-Methoxyhept~l)cyclohexanone ;~ A solution of 3-(5-methoxyheptyl)cyclohexanol ~8.5 mmoles) in 25 ml of acetone was cooled to 0C. A chromic acid solution ~1.5 gm CrO3 in 9 ml~H2SO4) was added and the reaction stirred for one hour, after which time water was ~,~

,~ , -19- 18775-Canada added dropwise and the solution extracted with hexane (3x75 ml). The organic phase was washed with water (3x100 ml) followed by saturated NaHCO3 (3x100 ml). The solution was dried over Na2SO4 and the solvent removecl under vacuum, yielding 3-(5-methoxyheptyl)cyclohexanone.
Example 27:
Synthesis of Methyl_5-metho~yheptanoate To a stirred solution of methanol (1580 ml), trimethyl orthoformate (1533 gm, 14.4 moles~, and perchloric acid (63 ml) was added 5-hydroxyheptanoic acid (158 gm, 1.25 moles).
The mixture was stirred at room temperature for three hours, after which time the solution was washed with NaHCO3 (until neutral pH) and extracted with ether (3x 700 ml).
The combined etheral extracts were washed with brine solution (300 ml) and dried over Na2SO4. The solvent was removed under vacuum, leaving a yellow oil. Distillation yielded pure methyl 5-methoxyheptanoate (129 gm) as a clear, colorless oil. Bp (122/ 21mm).
Ethyl 5-ethoxyheptanoate is obtained using this procedure, except that equivalent amounts of triethyl orthoformate and ethanol are used.
Exam~e 28:
Synthesis of 5-Methoxyheptanol To a stirred solution of ether (1500 ml) was added LiAlH4 (48 gm, 1.25 moles). The gray mixture was cooled to 0C and methyl 5-methoxyheptanoate (128 gm, 0.74 moles) was added over 10 minutes, aiter which time the solution was stirred at room temperature for 16 hours. The excess LiA1~4 was destroyed by adding dropwise water (48 ml), 15%
NaO~ solution (48 ml), and water (48 ml). The precipitate was removed by filtration and the etheral solution dried over Na2SO4. The solvent was removed under vacuum, leaving 5 methoxyheptanol ~108 gm) as a clear, colorless oi~.
5-Ethoxyheptanoa~e is obtained by substituting 0.74 ~; moles of ethyl 5-ethoxyheptanoate for methyl 5-methoxyheptanoate.
:

:

6~
-20- 18775-Canada Example 29:
S nthesis of l-chloro-5~methoxYhePtane Y
To a mechanically stirred solution of 5-methoxyheptanol (128 gm, 1~25 moles) dissolved in ether (100 ml), was added pyridine (98 gm, 1.25 moles). The solution was cooled to -10C and redistilled thionyl chloride ~140 gm, 1.19 moles~ was added dropwise to the mixtur~ over four hours. The reaction was stirred at room temperature for an additional three hours and then heated to reflux for one hour, after which time the solution was allowed to cool to room temperature. The upper layer was removed and washed with water (100 ml), 5% NaOH 12x 100 ml), again and water (2 x 100 mll. The etheral solution was dried over Na2SO4 and removed under vacuum, leaving the crude product. Distillation yielded pure 1-chloro-5 methoxyheptane (76.4 gm) as a clear, colorless oil. Bp (96C/17 mm). An analogous procedure yields 1-chloro-5-ethoxyheptane from 5-ethoxyheptanol.
Specific preferred bicyclooctanone compounds referred to in the following experimental data by number are the 2-(5-oxygenated alkyl~bicyclo[3.3.0]octan-7-ones of the formula:

/\
~H2 lH2 CH ~ - -CH

\2 / H -(CH2)~-~; CH2 :

~2~6~
-21- 18775-Canada In this formula, Y is hydrogen, Z being COOH in compound 6, CH2OH in compound 7, CH(OH~-CH3 in compound 8, CH(OH)-C2H5 in compound 9, and CH(OCH3)-C2H5 in compound 10 and CHO in compound 13.
In the formula Y is methyl, Z being -CH(OH)-C2H5 in compound 11 and -CH(OCH3)-C2H5 in compound 12-In vitro experiments were conducted in a proceduremodified from that disclosed by Thomas and Oake, "Androgen Metabolism in the Skin of Hirsute Women, J.C.E. and M., 38, 19 ~1974). While compounds 9 and 10 are preferred, positive test results are shown in the table below for compounds of Formula 6, 13, 7 and 8, which were assayed using blended scalp samples:
; ' .
Percent Receptor Blocking Patient Ratio of 3H DHT to Compound Compound Number ~ 10 _ 1 20 1:100 1:1000 6 1 0 0 0 0 12%
; : " 2 ~ 0 0 0 32~
~: " 3 o 0 0 16~ :
; 13 1 . 0 0 0 0 15~
" 2 0 0 0 0 30%
" 3 o 0 0 10%
7 1 0 0 : 1~ 30 36%
2 0 ~0 24 35 : 42 . 3 0 3 ~ 33 44 51%
8~; ~ l; 0 0 17: 33 37%
" : 2 0 0 22 38 41 : `" 3 0 0 34 49 52 , :: ~

.~

,~

66qP~
-22- 18775-Canada Example 31:
Following the procedure of Example 30, compounds 9 and 10 were tested to determine their percent inhibition of labeled androgen binding to the skin, the test utilizing caesarean section skin from hirsute patients:
Ratio of compound ~ inhibition of 3H Androgen to androgen binding to skin Compound 9Compound 10 10 : 1 ~5% 32%
100 : 1 51% 55%
1000 1 75% 80~
lO000 : 1 83% 86%
In skin samples from hirsute patients the compounds in this invention blocked the binding of 3H DHT to the androgen receptor site. DHT was selected for use in the assay because it is a more potent androgen than testosterone and exhibits a greater (stronger) afinity for the receptor site. Furthermore, there is evidence that 5 alpha reductase enzyme converts testosterone to DHT ln lvo, and it is DHT which is the active steroid on the in vivo receptor sites.
In order to substantiate the effects of the derived anti-androgen compounds on actual balded scalp specimens, skin was obtained from volunteers undergoing hair transplantation. The bald skin was used for androgen receptors using the second technique described above. The androgen used was dihydrotestosterone ~DHT) vs. the anti-androgen compounds afore herein reci~ed.
The results with compounds 9 and 10 are shown in Table below Inhibition of Binding 3H DHT to Androgen Receptor ~2~
-23- 18775-Canada PATIENT rat_o of compound 9:_ H DHT
# 10:1 20:1 100:1 _ 200:11000:1 #1 25% 30~ 35~ 39~ 42~
#2 40~ 47% 69~ 72% 75%
~3 0% 0% 13% 15~ 22 #4 14% 43% 45% 47~ 50 #5 17% 46% 4~% 48% 50~
#6 15% 36% 37% 39% 43%

PATIENT ratio of compound 10:3H DHT _ _ # _ 10:1 20~ 100:1 __200:11000:
#1 S0% 60~ 67~ 68% 70%
#2 43~ 59% 74% 76% 77%
#3 0% 0~ 17% 18% 25%
N4 19% 47% 47% 48% 50 ; #5 23% 51% 51% 52% 54 #6` 18~ ~1% 42% ~5% S0~
Again, the nonhirsute patient (having less androgenic sites available for interactionl displayed the preferred uptake for the natural androgen over any ~; of the new family of anti-androgens. This data supports the concept of a higher Kd for these anti-androgen ~ compounds compared with that of the natural androgen:

:
::

, ~

; :

~2'~6~
-~4- 18775-Canada % Inhihition_of_Bindin~ 3H DHT to Androgen Receptor Ratio of Compound to H DHT
Com~ound 10:1 100:1 1000:1 10000:1 40 ~7 56 65 Competitive inhibition experiments were performed using compound 9 in the second technique described above. The results are presented in the tables below.
As noted below, the test compound inhibited the androgen receptor site at 10 molecules of compound 9 or of compound 10 for one molecule of testosterone. The degree of inhibition increased as the ratio of compound/androgen increased.
The ln vitro interaction of compounds 9 and 10 with dihydrotestosterone are recorded below.
The ratio of 10 or 20 to 1 is readily exceeded by topical therapy, as the ratio of compound 9 to androgen applied topically in the small therapeutic trial was in excess of 10,000 to 1. This lipophilic molecule would be concentrated in the pilosebaceous gland~.
In vitro inhibition of the androgen r~ceptor-DHT inter-action by Compound 9 and Compound 10.

;

:
-"~`rJ

~'~46~

-25- 18775-Canada Ratio of CompoundFemtamoles of DHT % of Androgen To Androgenbound/mg protein* receptor inhibition Compound 9 0:1 78 0 10:1 58 25.6 100:1 46 41.0 Compound 10 0:1 78 0 10:1 44 43.6 100:1 38 51.3 *Corrected for non-specific binding In vitro inhibition of the Androgen receptor-testosterone interaction by Compound 9 and Compound 10.

Ratio of CompoundFemtamoles of %of Androgen To Androgen testosterone receptor _ _ bound/mg protein* inhibition Compound 9 0:1 3.6 0 :20:1 2.0 43~7 Compound lO 0:1 3.6 0 20:1 1.9 47.0 :*Corrected for non-specific binding :~ Example 32:
:
~ :Inhibiti~n of the androgen receptor and D~T in six ~: :
~ representative:patient samples are noted below:
:

~: ~ :: : :

-26- 18775-Canada R~TIO OF COMPOUND 11 to DHT

Patient 10x 20x 1~0x 200x lOOOx % INHIBITIQN 1 25 30 3539 42 o~ 2 40 47 6972 75 5 17 ~6 4649 50 MEAN %
INHIBITION 18.5 33.7 40.8 43.5 47.0 S.D. 13.3 17.7 18.2 18.5 17.1 Bxample 33:
Inhibition c~ the androgen receptor and DHT in six representative patient samples are noted below or Compound 12:
RATIO OF COMPOUND 12 to DHT
_ _ _ _ _ Patient 10 20 100 200 % INHIBITION 1 50 60 67 68 70 of 2 43 59 7~ 76 77 4 1~ 47 47 ~8 5 MEAM %
: INHIBITION 25.543.0 49.1 Sl.2 54.3 S.D. I8.2 22.3 20.1 20.2 18.2 . ~
:
Wrinkling of the skin involves the decreased formaklon of elastin and the increased formation of ':
' ~4~6~
-27- 18775-Canada collagen by supporting cells, predominantly the fibroblasts. Experiments sh~w that the control ~non-treated) cells had only trace elastin production but copious collagen production. The cel:Ls treated with the compound of Formula 10 had approximately 30% elastin production with a resultant decrease in collagen production.
Example_35-Collagen formation has been found to be decreased in experiments with compounds of Formulas 6 through 13 inclusive, whilst showing a massive observable increase in the formation of elastin. It is to be recognized that peripheral effects, such as the arteris and dermis, when affected without altering more basic hormonal essential functions of the androgens, provides a bene-ficial result.
Example 36:
The following results were observed at concentrations of anti androgen of formula 10 to DHT of 1000:1 Patient~ of Collagen Fold Elastic increase synthesized compared to Control 1 23 1.4 2 23 4.7 ll 39 3 Thsse quanti~ative experiments demonstrate the importance of the anti-androgen and its therapeutic use ;

,~

-28- 18775-Canada in the topical application for altering collagen:elastin formation, thus decreasing wrinkles; but more importantly, its systemic applications would include its use in decreasing the rate of atherosclerosis by decreasing the rate of collagen formation.
Example 37:
The anti-cancer activity of the compounds of this invPntion were tested on tumors which had been obtained after surgery which were placed in an appropriate testing media. Samples of cancers from the prostate, ovary and breast were tested, with a recognition that these cell lines have a high level of androgen binding.
The in vitro clonogenic assay of Salmon et al, New England Journal of Medicine, 298 1321 (1978) was used.
The Compound ~I) of Formula 10 was shown to have a significant anti-tumor activity against the three selected tumors when used at a level of lOmcgtml based upon observations o a cytologist.
This compound compares favorably in tests against mitomycin C, vinblastine, vincris~ine, melamine, methyl-GAG, 5-FU, melphalan, and bleomycin. The relationship of the androgen blockage to the anticancer applicability of Compound (I) was suggested by the more pronounced effects that were observed on prostatic cancers, as i~ the prostate has a greater number of androgen receptor si~es than the other ~ested cancers.
Three prostatic cancers and six specimens of benign prostatic hypertrophy were used for experiments, with androgen receptors being found in all. The compound of the Formula 10 blocked between 35 to 87% of the hormonal androgen receptors at 1:1000 DHT to the Compound ~10), and no significant deleterious effects were noticed in the estrogen and progesterone receptors.
Further experiments were conducted to determine the effect on various types of cancer cells using doses of 0.1 and la mcg/ml. of 6,6-dichloro-2-~5-methoxyhept-1-yl)bicyclo[3.2.0Jheptan--7~one 12~6~'~
29- 18775-Canada of the formula:

C1 7 C ~ = O
Cl ~H CH
~CH (CH2)~H (OCH3)--C2H5 The clonogenic chemosensitivity test reports showed that the compound produced a highly potent effect comparable to the most potent est~blished anti-cancer reagent in various assays on human specimens from cancers of the breast, kidney, and ovary. Such effect is seen even in the absence of androgenic receptors, indicating another mechanism of action.

In order to further investigate the action of the compounds on nuclei, human lymphocytes were placed in a short term culture, colchicine was added and a chromosomal smear was made. The smear was incubated with C14-labelled 6,6-dichloro-2-(5-methoxyhept-1-yl)bicyclo[3.2.01heptan -7-one. The material was sub,ected to autoradiography and developed. Staining of the slides with giemsa stain caused a chromosomal region to light up, putatively identified a~ the aging gene.
; In another experiment, malignant and non-malignant tissue cultures were treated with C14-labelled 6,6-dichloro-2-(5-methoxyhept-1-yl~bicyclo[3.2.0]heptan~
7-one. Colchicine was then added. Treatment as above showed the same chromosomal region to light up on staining in the case of normal,~ non-malignant tissue.
Cancer cells were rapidly destroyed, but cells which were stained before death were caused to light up in a different region.

~z~
-30- 18775-Canada Example 39~
The compound of Formula 10 was found to block 59~80% of androgen binding sites in a melanoma at concentratlons of 1:1000 of dihydrotestosterone to the tested compound, with no significant efEect on ei-ther the estrogen or progesterone receptors in the tissue.
Example 40:
Amyotrophic lateral sclero~is is advantageously treated with these compounds, based upon tests with surgical specimens of neurotissues with this disease.
Thus, compound of Formula 10 blocked 79~ of the androgen receptors in these tiss~es of both benign and malignant tissues at ratios of DHT to the tested compound of l:1000. There was no measurable estrogen receptor inhibition in this test, and there was only 3%
progesterone receptor inhibition.
Astrocytoma tissue was similarly tested with 21%
androgen site blockage and the same results for estroyen and progesterone receptox inhibition. Gliablastoma tissue showed 39~ androgen receptor inhibition, no estrogen receptor inhibition, and 2% progesterone inhibition. Meningioma tissue showed 64~ androgen receptor inhibition, no estrogen receptor inhibition, and 5% progesterone receptor inhibition.
Example 41-Keloid formation is suppressed by blocking androgen receptor sites. In its generic aspect, the invention comprises a method of suppressing the formation of keloids which comprises topically applying to a patient an anti-androgenic agent to the skin of said patient, whereby androgen receptor sites are blocked, thereby retarding the forma~ion of keloids. Tests conducted with 2-t5-methoxyhept-1-yl)bicyclo[3.3.0~octan-i-one have shown the suppression of keloid formation.
Surgical excision of keloids was performed from clinic and private patient populations. 2-(5-methoxyhept-6~`~
-31- 18775-Canada l-yl)bicyclo[3.3.0]octan-7-one was incubated in ratios of 1 to 1:10000 steroid hormone to thls compound.
Non-specific binding was determined with a 200-fold excess of unlabeled ligand at each concentration of 3H-ligand use. Male patients showed neither detectable estrogen or progesterone binding. Mean DHT binding was 867 femtamoles/mg cytosol-protein +101 femtamoles/mg.
The following results were obtained:

kocation B ~ ing ~inding Bindin~
of of of of Pt Sex Race Age Keloid DHT % slOck Estrogen Progesterone 1 F Blk 37 Suprapubic 703 43 9 7 2 F Blk 21 Chest 816 244 Non-detectable 3 M Cauc 23 Neck 795 57Non Non-detectable detectable 4 M Blk 26 Inguinal 938 86 Non- Non-groin det~ble detectable Treatment for prevention of interabdominal and other post surgical systemic adhesions were also evaluated. Skin fibroblast collagen suppression was also considered using surgical explants. At ratios of DHT:2-(5-methoxyhept-1-yl)bicyclo-[3.3.0]octan-7-one of 1:1000, in more than 400 experiments, the 2-(5-methoxy hept-l-yl)bicyclo[3.3.0]octan-7-one blocked between 22%
and 94~ of the androgen receptors without significant interference with either the estrogen or progesterone receptors. Tissue from keloid showed androgen receptor inhibition of ~1 to 72% and no measurable estrogen or progeterone receptor inhibition. Scalp samples showed from 22 to 89% androgen inhibition and æero to 7%
progesterone inhibition. Forearm sample showed 22~
androgen receptor inhibition and 4% progesterone re-ceptor inhibition. In none of the tests was there any ~ ~ measurable estrogen receptor inhibition.
'1 ~

-32- 18775-Canada "Hard fibrous band" formation was retarded around breast implants after augmentation surgery. Blockage of 34~ to 79~ of androgen receptor sites was measured for 2-(5-methoxyhept-1-yl)bicyclo[3.3.0]octan-7-one without any significant effects on either estrogen or progesterone binding sites~ The amount protein (in mg) per gram of gross tissue was measured for four breast capsule group numbers which showedo Mean % Androgen 9inding Mean % Androgen Inh bition 10.7 17 31.0 49 99.9 70 109.8 74 :

`: :
~, ;:

Claims (17)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. Process for preparing a compound of the formula wherein:
M1 and M2 are hydrogen;
Q is CO, CH-OR, or CR(OH);
one of X and X1 is H and the other is A;
A is -CRR-(CR1R2)n R3;
R is hydrogen or lower alkyl;
R1 and R2 are R, OR, COOH, CHO or CR1R2 together form the group C?;
R3 is H, COOR, OR, CHR-OR or COR;
n is one to eight:
c is one or two;
p is zero or one;
provided that the group A contains one group COOR, CHO, CO, OR, COR or CHR-OR, or a pharmaceutically acceptable salt thereof which comprises dehalogenating a dihalide of formula I in which M1 and M2 are halogen, all other symbols being defined as above.

2. A process of claim 1 wherein A is a hydroxyalkyl, methoxyalkyl or ethoxyalkyl and oxoalkyl wherein the alkyl portion has 2-8 carbon atoms.

3. The process of claim 1 in which zinc is used as a dehalogenation catalyst in an acid medium.

4. Process of claim 1,wherein Q is CO, CH-OH, CH-OCH3 or CH-OCH2CH3;
C i 9 3; and n is 1 to 4.

5. A process of claim 1, wherein said prepared compound has the formula

6. A process of claim 5, wherein the compound produced contains a cis bridge.

7. A process of claim 2, wherein Q is CO, X1 is H and A is methoxyhept-1-yl, c is one and p is one to prepare the compound 2-(5-methoxyhept-1-yl)bicyclo[3.3.0] octan-7-one.

8. A process of claim 2, wherein Q is CO, X1 is H and A
is ethoxyhept-1-yl, c is one and p is one to prepare the compound 2-(5-ethoxyhept-1-yl)bicyclo[3.3.0]octan-7-one.

9. A process of claim 2 wherein Q is CO, X1 is H and A is hydroxyhept-1-yl, c is one and p is one to prepare the compound 2-(5-hydroxyhept-1-yl)bicyclo[3.3.0]octan-7-one.

10. A compound of the formula:

wherein:
M1 and M2 are hydrogen;
Q is CO, CH-OR, or CR(OH);
one of X and X1 is H and the other is A;
A is -CRR-(CR1R2)n R3;
R is hydrogen or lower alkyl;
R1 and R2 are R, OR, COOH, CHO or CR1R2 together form the group CO;
R3 is H, COOR, OR, CHR-OR or COR;

n is one to eight;
c is one or two;
p is zero or one;
provided that the group A contains one group COOR, CHO, CO, OR, COR, or CHR-OR, or a pharmaceutically acceptable salt thereof.

11. A compound of claim 10 wherein A is a hydroxyalkyl, methoxyalkyl or ethoxyalkyl and oxoalkyl.

12. A compound of claim 10 wherein:
Q is CO, CH-OH, CH-OCH3 or CH-OCH2CH3;
c is 3; and n is 1 to 4.

13. A compound of the formula:
wherein:
A is CRR-(CR1R2)nR3;
R is hydrogen or lower alkyl;
R1 and R2 are hydrogen and lower alkyl;
R3 is COOR, OR, CHR-OR or COR; and n is one to eight.

14. A compound of claim 13 wherein the compound contains a cis bridge.

15. The compound 2-(5-methoxyhept-1-yl)bicyclo[3.3.0]-octan-7-one.

16. The compound 2-(5-ethoxyhept-1-yl)bicyclo[3.3.0]-octan-7-one.

17. The compound, 2-(5-hydroxyhept-1-yl)bicyclo[3.3.0]
octan-7-one.