WO1983004019A1

WO1983004019A1 - Cycloaliphatic pharmaceutical compounds

Info

Publication number: WO1983004019A1
Application number: PCT/US1983/000721
Authority: WO
Inventors: Walter J. Kasha
Original assignee: Cbd Corporation
Priority date: 1982-05-06
Filing date: 1983-05-06
Publication date: 1983-11-24
Also published as: AU546158B2; EP0107733A1; EP0107733B1; HUT37381A; JPH0227975B2; US4855322A; EP0107733A4; DK5384D0; NO840037L; JPS59500770A; DE3378265D1; NO159722B; ATE38028T1; DK172312B1; NO159722C; DK5384A; HK97991A; SG77891G; AU1703383A

Abstract

Novel cycloaliphatic anti-androgenic compounds which block androgen receptor sites, with both topical and systemic administration being provided. Pharmaceutical methods are also provided.

Description

CYCLOALIPHATIC PHARMACEUTICAL COMPOUNDS The present invention provides compounds of the formula

Q

(I)

Y-C-B

c ein B and B ' are both H or together form a single

Q is CO, CH-OR, or -COOR; each X is independently H or A; each Y and Y' is 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 together form the group CO;

^R3 is H, COOR, OR, CHR-OR or COR; c is an integer from zero to four; 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, or a pharmaceutically acceptable salt thereof. 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 group lower alkyl may be mentioned, for example, methyl, ethyl, 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 thereof.

In a preferred aspect, the compound (I) has the following parameters: Q is CO, CH-OH, CH-OCH₃ or CH-OCH₂CH₃; c is 3; and n is 1 to 4. A preferred group of compounds (I) has the formula

In this preferred group may be mentioned compounds, wherein A is defined by the group:

-CH₂-CH₂-CH₂-C (R⁴R⁵) R⁶ wherein R⁴ and R⁵ are independently H, methyl or ethyl;

R⁶ is COOH, CHO or C(R⁷R⁹)OR⁸; and

R ⁷ ' R⁸ and R⁹ are independently H, methyl or ethyl. As the group -C(R ⁴R⁵)R⁶ may be mentioned -CH₂COOH,

-CH₂CH₂OH, -CH₂CH(CH₃)OH,

-CH₂CH (CH₂CH₃) OCH₃ , -CH₂CHO,

-CH(CH₃)CH(CH₂CH₃)OH, or

-CH (CH₃) CH (CH₂CH₃) OCH₃. Particularly preferred are compounds which are 6-(5-substituted alkyl)-bicyclo-[3.3.0]octan-3-ones, including 6- (5-methoxyhept-l-yl)-bicycle-[3.3.0] octan-3-one, 6-(5-hydroxyhex-l-yl)-bicyclo-[3.3.0] octan-3-one, 6-(5-hydroxy-4-methylhept-l-yl)-bicyclo-[3.3.0]octan-3-one, and 6-(5-methoxy-4-methylhept-1-yl)-bicyclo-[3.3.0]octan-3-one.

Also provided is an anti-androgenic composition suitable for providing an anti-androgenic effect when administered to a patient which comprises a pharmaceutically effective amount of a compound (I) and a pharmaceutically inert carrier suitable for topical administration of said compound to said patient. As the pharmacetuically inert carrier may be mentioned an alcohol, salve, suspension, emulsion, ointment, cream, powder or spray. In a preferred embodiment, an alcohol such as ethanol and isopropanol are preferred as a pharmaceutically inert carrier.

In a further preferred embodiment, an anti-androgenic composition with the compound (I) is provided in a sustained release vehicle for trandermal application to the skin of a patient. The sustained release medium should be one which will maintain the compound (I) at the skin and permit release to the skin for a period of preferably at least about six to about 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).

A further embodiment provides a skin preparation suitable for topical administration to a patient to be exposed to ultraviolet light which includes both the Compound (I) and an anti-ultraviolet screening agent such as Paraaminobenzoic 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 incorporated therein the compound (I).

The invention provides a method of blocking androgen receptor sites in a patient which comprises introducing to said sites the compound (I), particularly via the topical route. The growth of some cancers is related to androgen, which is alleviated by blockage of androgen receptor sites by treatment with the compound (I). Male pattern baldness is also androgen linked and treated with the compound (I) to block androgen receptor sites. The compound (I) is also useful in the prevention of keloids, and wrinkling of the skin and related conditions. Extremely minute concentrations, even dilutions exceeding 100,000:1, have been effective for these conditions. Experiments generally following the methodology of Boote et al, Biochimica et Biophysicia Acta, 607, pp. 145-160 (1980), have shown that while control human fibroblast cells have copious collagen production, treatment with the compound (I) provides human fibroblast cells with suppressed collagen product and with an increase by 30% over control cells. Following the Salmon clonogenic assay. Cancer Treatment Reports, 65, p. 1 (1981), the compound (I) at a level of 10 mg/ml increases the chemosensitivity to standard anti-cancer drugs tested including mitomycin C, vinblastine, vincristine, cisplatinum, actinomycin D, adriamycin, hexamethylmelamine, methyl-GAG, 5-FU, melphalan and bleomycin.

A preferred embodiment is the provision of an antiacne treatment, where the patient afflicted with acne is treated with the compound (I), which reduces androgen to reach androgen receptor sites, thereby alleviating the acne problem.

While topical application of the compound (I) 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 compound (I) is 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 compound (I) is incorporated into vehicles conventionally used for lipid soluble compounds. By including at least one carboxy or carboxy ester group in the compound, a hydrophillic character may be obtained. Suppositories with the compound (I) are also contemplated, to provide a rectal suppository adminstration of the drug and which form takes advantage of the usual suppository ingredients.

The high potency of the compound (I) permits relatively low dosages both systemically via oral or suppository route or through topical (transdermal) application. A concentration of the compound (I) of from about 0.001 to 5 percent by weight of the composition, and generally from about 0.01 to about one percent. Topical application on an infrequent basis, including a sustained release delivery, may indicate a relatively higher amount of the compound (I), e.g., preferably in the range of from about 0.05 to about 3 percent by weight. A relatively lower concentration of the compound (I) 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 (I) is indicated for systemic delivery, oral, injection, suppository and sublingual forms may be used, preferably the compound (I) is administered as an oral dosage unit form, 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 (I), which is due to the high potency as an anti-androgenic of the compound (I). 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 0.0001 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 (I) necessarily means as a practical matter than a "normal" tablet size will have only a very small percentage of the compound (I), 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. The effectiveness of the compound (I) is determined in vitro in accordance with the method of Thomas et al, J. Clinical Endoocrinology and Medicine. 38, 19 (1974) .

added and the solution stirred via 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 for 4 hours. The solvent was removed and the residue chromatographically purified over silica gel, leaving the product (17 gm). Synthesis of 7,7 Dichloro-2-(5-methoxyhept-l-yl)-Mcyclo [3.3.0] Octan-7-one

The starting material 7,7 dichloro-2-(5-methoxyhept l-yl)-bicyclo [3.2.0] heptan-6-one (11 gm, .036 moles) 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-tolylsulfonylmethynitrosamide (21.5 gm) with KOH in ethanol. The CH₂N₂ was allowed to react for three hours, after which time oxalic 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 (10.3 gm) suitable for the next RXN, although some of the starting material was still present as evidenced by IR and gas chromotography. Synthesis of 6-(5-methoxyhept-l-yl) Bicyclo (3,3,0) Octan-3-one

To a single-neck 100ml, round-bottom flask equipped with a condenser was added 6,6 dichloro-2-(5-methoxylheptyl)-bicyclo [3.3.0] octan-7-one (45.9 gm, 149 moles). The solution was stirred via magnetic stirring and powdered zinc metal (5.2 gm, .079 moles) and glacial acetic acid

(10 ml, .17 moles) 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 NaHCO₃ and extracted with ether three times 50 ml. The etheral extracts were combined and dried over

Na₂SO₄. The resulting yellow oil was chromatographed with silica gel and eluted with 3:1 Hexane:Ether. The fractions were combined, yielding 6-(5-methoxyhept-l-yl)- 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 side chain. The ring and side chain precursors are combined and subjected to further reaction to generate the desired product.

The following examples illustrate the invention:

Example 1: Ring and Side Chain Combination:

Synthesis of 3-(5-methoxyhept-l-yl)-cyclopentene of 5-methoxyhept-l-yl Magnesium Chloride

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. The clear, colorless solution of 1-chloro-5-methoxyhept-l-yl (48.1 gm, 0.292 moles) was added and refluxed. The final third portion was added and allowed to stir for 12 hours. The dark yellow solution was cooled to-25°C, the condenser was removed and replaced with a dry ice addition funnel. The clear solution of 3-chloro cyclopentene (29.9 gm, 0.292 moles) was added over one hour. The viscous solution was poured into two liters of H₂O, extracted with ether, and dried over Na₂SO₄. Distillation yielded 3-(5-methoxyhept-l-yl-cyclopent-2-ene) (51.5 gm, 0.262 moles) as clear, colorless oil. BP. 54°C/0.1 mm.

Synthesis of 7,7 (dichloro-4-(5-methoxyhept-l-yl)-bicyclo (3,2,0) heptan-6-one

A 1,000 ml three-neck, round-bottom flask was equipped with a reflux condenser 3-(5-methoxyhept-l-yl)-cyclopentene (15.0 gm, .076 moles.) in 300 ml of hexane. Freshly distilled dichloroacetylchloride (35.1 gm, .240 moles) was bicyclo (3,3,0) octan-3-one (33 gm, .13 moles) as a clear, colorless oil.

Example 2 :

Synthesis of 5-(5-methoxyhept-l-yl) Bicyclo (3,2,0) Heptan- 2-one

Zinc-copper catalyst (3 gm) was added to a stirred solution of 7,7-dichloro-4-(5-methoxyhept-l-yl) bicyclo

(3,2,0) heptan-2-one (2 gra, 6 moles) in ether

(100 ml) under a nitrogen atmosphere.

The solution was stirred at room temperature for one hour, then refluxed for 13 hours, after which time the mixture was filtered through a scintered 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, 5-(5-methoxyhept-l-yl) bicyclo (3,2,0) heptan- 2-one (1.2 gm), which, optionally, can be used to generate another compound of the invention by reaction with diazomethane to expand the ring and form the product of Example 2.

Analysis: IR 2933, 2857, 2821, 1806, 1490, 1460, 1410, 1378, 1301, 1273, 1265, 1240, 1155, 1115, 1093, 939, 935, 917, 796, 746, 726, 695, 683, 664.

Example 3: Synthesis of 6-(5-hydroxyhept-l-yl) Bicyclo (3,3,0) Octan-3-one

6-(5-methoxyhept-l-yl) bicyclo (3,3,0) octan-3-one (1 gm, 3.9 moles) (prepared as in Example 1) 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 triflouride etherate (7.0 ml) cooled to 0°C was added. The solution was stirred at 0°C for 25 hours, after which time the reaction was poured into ice water and stirred for two hours, followed by ether extraction (3x100 ml). The combined etheral extracts were washed with NaHCO₃ (3x100 ml), dried over Na₂SO₄, and the solvent removed under vacuum, leaving a yellow residue.

Chromatography on silica gel yielded 6-(5-hydroxyhept-l-yl) bicyclo (3,3,0) octan-3-one (0.18 gm), the hydroxy analog of the products of examples 1 and 2.

Analysis: IR 3395, 2935, 2855, 1748, 1465, 1267, 1245,

1160, 1120, 965, 920, 810, 785, 745.

Example 4 :

Synthesis of 6-and 7-bromo Bicyclo (3,3,0) Oct-2-en-7-one

HBr gas was bubbled into a solution of bicyclo (3,3,0) oct-2-en-7-one (1 gm, 8 mmoles) in 50 ml of methylene chloride. The solution was stirred at -10°C for three hours, then poured onto 250 gm of ice and extracted with ether. The etheral extract was washed with 10% NaOH solution (2 x 100 ml), dried over Na₂SO₄, and the solvent removed under vacuum leaving 1.4 gm of a dark yellow oil. Chromatography on silica gel yielded 6-bromobicyclo (3,3,0) octan-3-one and 7-bromo bicyclo (3,3,0) octan-3- one (1.2 gm).

Analysis: IR 2955, 2875, 1746, 1610, 1460, 1405, 785, 745. The two isomers can be separated for individual reaction with an appropriate side chain to form compounds of the invention, or a mixture of the isomers can be used for this reaction.

The keto-group substituted on the ring should be protected before reaction with the side chain and subsequently de-protected to restore the keto-group.

Thus in the protection step, the 1, 3-dioxolane derivative of the keto compound is first formed as follows. Synthesis of 6- and 7-bromospiro (bicyclo (3,3,0) Oct-2- ene-7,2(1,3) Dioxolane)

To a solution of benzene (100 ml) was added 6-bromobicyclo (3,3,0) octan-3-one and 7-bromobicyclo (3,3,0) octan-3-one (1 gm, 4.9 mmoles) and ethylene glycol (10 ml). A catalytic amount of p-toluenesulfonic acid was added to the stirring solution and then heated to reflux under a Dean Stark trap for 24 hours, after which time the solution was allowed to cool to room temperature, washed with NaHCO₃ (till neutral pH), and dried over Na₂SO₄. The solvent was removed under vacuum, leaving a yellow oil. Distillation yielded an isomeric mixture of 6- and 7- bromospiro (bicyclo (3,3,0) oct-2-ene-7,2 (1,3) dioxolane)

(0.7 gm). Bp (70-72°C/ 0.05 mm).

Example 5 : Side Chain Synthesis: Synthesis of n-5-methoxyheptyllithium

A solution of 82.3 gm of 1-chloro-5-methoxyheptane in 300 ml of petroleum ether was added slowly to 8.6 gm of lithium wire in a three-necked flask. The mixture was cooled to -10°C 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-methoxyhyeptyllithium (20 mmole in 50 ml of THF) was stirred at -60°C and Cul (10mmole) was added. After one hour the solution of 1-chloro-4-(2-tetra- hydropyranol) cyclooctaine (10 mmole in 50 ml of THF) added dropwise with stirring to the copper lithium over a period of three hours at a temperature of -50 °C. 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 combined and dried over powdered

Na₂SO₄, to yield the desired product 1-(5-methoxyheptyl)-4- (2-tetrahydropyranol) cyclooctane. Synthesis of 4-(5-methoxyheptyl)-cyclooctan-1-ol

A solution of 4-(5-methoxyheptyl)-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 minutes, then extracted two times with 50 ml portions of ether. The extracts were combined, distilled, and dried over powoered Na₂SO₄. The solvent was evaporated under vacuum, giving a 35% yield (1.6 gm) of the desired product 4-(5-methoxyheptyl)-cyclooctan-1-ol as an oil.

Synthesis of 4-(5-methoxyheptyl)-cyclooctan-l-one

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-methoxybeptyl)-cyclooctan-1-ol (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, yielding 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 Vigreux column giving a 79% yield (3.7 gm) of the desired product 4- (5-methoxyheptyl) cyclooctan-1-one .

Example 6 :

Side Chain Formation and Combination With Ring: Synthesis of 1-acetyloxy-5- (5-methoxyheptylere) cyclooctane A solution of triphenylphosphine ( 55 gm in 45 ml of dry benzene) was added to a pressure bottle . The bottle was cooled wi th ice, and alkcylbromide ( 28 gm) added. The bottle was sealed and allowed to stand at room temperature for two days, after which time the Dottle was reopened. The white solid was collected with 500 ml of hot benzene and dried in a vacuum oven at 100 °C over phosphorous pentoxide giving a 98% yield. (M .p. 232ºC, literature m.p. 232-233 ºC. )

An etheral solution of n-butylli thium (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 triphenylmethyl-phosphonium bromide carefully added over five minutes , after which time the mixture was stirred at room temperature for four hours.

Freshly distilled 1-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 with 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 1-acetoxy-5- ( 5-methoxyheptylidene) cyclooctane. Synthesis of 5-(5-methoxyheptilidene)-cyclooctanol

To a stirred solution of 5-(5-methoxyheptylidene)- cyclooctanol acetate (2 mmoles) was addeα NaOH (8 mmoles, in 15 ml of 95% ethanol). The solution was stirred at room temperature for 1 hour, after which time dilute H₂SO₄ was added and the solvent removed under vacuum. The residue was extracted with ether (3x50 ml), dried over Na₂SO₄, and thesolvent removed under vacuum leaving the crude product. Chromatography on silica gel yielded 5-methoxyheptylidene cyclooctanol (0.4gm). Synthesis of 5-(5-methoxyheptyl)-Cyclooctanone

A solution of 5-(5-methoxyheptylidene) cyclooctane (4.8 gm in 95% ethanol) was reduced to the alkane with a barium sulfate supported platinum catalyst. The barium sulfate was suspended in a 20% solution of chloroplatinic acid and warmed at 40-50°C for ten hours. A sodium carbonate solution was then added to neutralize the acidity. The platinum was reduced with NaOH, filtered, washed with hot water, and dried in a vacuum. dessicator. A solution of 5-(5-methoxyheptyiene)-cyclooctan-1-ol was vigorously mixed with the platinum catalyst (0.02 gm of reduced platinum) under two atmospheres of hydrogen gas at 25°C for 10 minutes. The 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-methoxyheptyl)-cyclooctane.

Synthesis of 5-(5-methoxyheptyl) Cyclooctanone

A solution of the alcohol (20 mmole) was oxidized to the ketone with pyridinium chlorochromate by the aforementioned procedure. EXAMPLES 7-25 :

7. 4-(5-methoxyhept-1-yl) cyclooctanone

2965, 2853, 2835, 1702, 1465, 1440, 1415, 1360, 1335, 1260, 1205, 1170, 1130, 1095, 965, 925, 860, 735

8. 5-(5-methoxyheptylldene)-cyclooctoneacetate 3065, 2935, 2860, 1738, 1660, 1645, 1365, 1350, 1270, 1248, 1125, 1095 9. 5-(5-methoxyhept-1-yl) cyclooctanol

3420, 2935, 2855, 1460, 1445, 1420, 1376, 1270, 1095, 1027, 985, 920, 730

10.5-(5-methoxyhept-1-yl) cyclooctanone 3027, 2060, 2855, 2830, 1705, 1460, 1445, 1425,

1355, 1268, 1195, 1170, 1125, 1095, 965, 920, 910, 855, 820, 735

11. 6-hydroxy-6-(5-hydroxypent-1-yl) bicyclo [3,3,0] octan-3-one

3445, 2935, 2865, 1745, 1660, 1460, 1445, 1370, 1355, 1305, 1260, 1245, 1190, 1175, 1045, 1025, 960, 835, 820, 735

12. 6-(5-hydroxyheρtylidene) bicyclo [3,3,0] octan-3-one

3400, 2935, 2860, 1745, 1660, 1465, 1410, 1170, 1165, 1085, 1040, 935, 850, 735

13; 5-(5-hydrόxyhept-1-yl) cycloctanol

3380, 2935, 2865, 1460, 1450, 1365, 1350, 1325, 1270, 1115, 1080, 985, 735

14. 5-(5-hydroxypent-1-yl) cycloheptanone

3400, 2938, 2860, 2840, 1705, 1460, 1440, 1365, 1265, 1110, 1075, 970, 935, 730

15. 4-(5-hydroxypent-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, 700

17. 5-(5-hydroxypent-1-yl) bicyclo [3,3,0] octan-3-one

2935, 2865, 1742, 1465, 1420, 1265, 1230, 1175, 1155, 1050, 945, 735 18.5-(4-carboxylbut-1-yl)-bicyclo [3,3,0] octan-3-one

3150, 2935, 2865, 1745, 1710, 1665, 1460, 1265, 1235, 1190, 1165, 1150, 1050, 938, 725

19. 5-(5-carboxylpent-1-yl)-bicyclo [3,3,0] octan-3-one

3100, 2935, 2860, 2835, 1743, 1705, 1660, 1465, 1260, 1225, 1170, 1155, 1045, 935

20. 5-(6-carboxylhex-1-yl)-bicyclo [3,3,0] octan-3-one

3380, 2935, 2860, 1743, 1465, 1420, 1260, 1235, 1140, 1055, 935

21.5-(3-oxopent-1-yl) bicyclo [3,3,0]octan-3-one

2938, 2865, 2820, 1745, 1708, 1460, 1435, 1415,

1275, 1255, 1230, 1120, 1070, 940, 745 22. 5-(3-hydroxypent-1-yl) bicyclo [3,3,0] octan-3-one]

3400, 2935, 2865, 1743, 1465, 1435, 1420, 1260,

1225, 1125, 1065, 935, 735 23. (5-hydroxypent-1-yl) cycloheptanone

3420, 2945, 2855, 1700, 1465, 1420, 1255, 1230,

1100, 1075, 945, 735

24.5-(5-methoxyhept-1-yl) bicyclo [3,3,0] octan-3-ol

3420, 2935, 2860, 2835, 1465, 1425, 1380, 1365, 1245, 1195, 1155, 1095, 1070, 930

25. 4-(butanoic acid) cyclohexanone

3100, 2940, 2865, 2830, 1703, 1625, 1465, 1360, 1330, 1265, 1225, 1195, 1170, 1105, 1065, 1030, 980, 935, 745 Example 26: Synthesis of 3-(Methylheptyl) cyclohexanone

4-Hydroxycyclohexanone is subjected to 1,2-ketone transposition to yield 3-hydroxycyclohexanone.

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 1-bromo-5-methoxyheptane 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 benzene and dried in a vacuum oven at 100°C over phosphorous pentoxide. . An etheral solution of n-butyllithium (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 temperautre 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 combined etheral extracts are extracted with 100 ml portions of H₂O until neutral, and dried over Na₂SO₄. Distillation of the desired product 3-(5-methoxyheptylidene) cyclohexanol. Synthesis of 5-(5-methoxyheptyl)-cyclohexanol

A solution of 5-(5-methoxyheptylidene) cyclooctand (4.8 gm in 95% ethanol) was reduced to the alkane with a barium sulfate supported platinum catalyst. The barium sulfate was suspended in a 20% solution of chloroplatinic acid and warmed at 40-50°C for ten hours. A sodium carbonate solution was then added to neutralize the acidity. The platinum was reducted with NaOH, filtered, washed with hot water, and dried in a vacuum, dessicator. A solution of 5-(5-methoxyheptylene)-cyclohexanone was vigorously mixed with the platinum catalyst under two atmospheres of hydrogen gas at 25°C 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-methoxyheptyl)-cyclohexanol. Synthesis of 3-(5-methoxyheptyl) cyclohexanone

A solution of 3-(5-methoxyheptyl) cyclohexanol (8.5 mmoles) in 25 ml of acetone was cooled to 0°C. 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 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 Na₂SO. and the solvent removed under vacuum, yielding 3-(5-methoxyheptyl) cyclohexanone. Example 27: Synthesis of Methyl 5-methoxyheptanoate

To a stirred solution of methanol (1580 ml), trimethylorthoformate (1533 gm, 14.4 moles), and H₂SO₄ (63 ml) was added 5-hydroxyheptanoic acid (158 gm, 1.25 moles). The mixture was stirred at room temperature for three days, 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 (122oc/ 21mm).

Example 28 : Synthesis of 5-methoxyneptanol

To a stirred solution of ether (1500 ml) was added LiAlH₄ (48 gm, 1.25 moles). The gray mixture was cooled to 0°C and methyl 5-methoxyheptanoate (128 gm, 0.74 moles) was added over 10 minutes, after which time the solution was stirred at room temperature for 16 hours. The excess LiAlH₄ was destroyed by adding dropwise water (48 ml), 15% NaOH 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 oil.

Example 29:

Synthesis of 1-chloro-5-methoxyheptane

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 -10°C and redistilled thionyl chloride (140 gm, 1.19 moles) was added dropwise to the mixture 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 ( 2x 100 ml), and water again (2 x 100 ml). 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

(96° C/17 mm).

Example 30:

In vitro experiments were conducted in a procedure modified 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, 1 and 8, whihc were assayed using blandeded scalp samples: Specific preferred compounds include the following:

Example 31:

Following the procedure of Example 30, compounds of Formulae 9 and 10 were tested to determine their percent inhibition of labeled androgen binding to the skin, the test utilizing caesarean section skin from hirsuite patients:

In skin samples from hirsuite 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) affinity for the receptor site. Furthermore, there is evidence that 5 alpha reductase enzymes converts testosterone to DHT in vivo, 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 dihydrotesto sterone (DHT) vs. the anti-androgen compounds afore herein recited.

The results with compounds 9 and 10 are shown in Table below.

% inhibition of Binding ³H DHT to Androgen Receptor '

Again, the nonhirsuite patient (having less androgenic sites available for interaction) displayed the preferred uptake for the natural androgen over any of the new family of anti-androgens. This data supports the concept of higher K_d for these compounds compared with that of the natural androgen:

Competitive inhibition experiments were periormed 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 in 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 glands. In vitro inhibition of the Androgen r eceptor-DHT interaction by Compound 9 and Compound 10.

*Corrected for non-specific binding In vitro inhibition of the Androgen receptor-testosterone interaction by Compound 9 and Compound 10.

*Corrected for non-specific binding Example 32 ; In vitro studies utilizing ³H steroids and anti-androgen compound to demonstrate that the subject anti-androgen( s) do not displace any of the natural occuring hormone away from SHBG ( Sex Hormone Binding Globulin) .

Example 33:

Inhibition of the androgen receptor and DHT in six representative patient samples are noted below:

Example 35: Wrinkling of the skin involves the decreased formation of elastin and the increased formation of collagen by supporting cells, predominantly the fibroblasts. Experiments show taht the control (non-treated) cells had only trace elastin production but copious collagen production. The cells 'treated with the compound of Formula 10 had approximately 30% elastin production with a resultant decrease in collagen production.

Example 36: 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 elatin. 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 beneficial result

Example 37:

The following results were observed at concentrations of anti-androgen of formula 10 to DHT of 1000 :1

These quantitative experiments demonstrate the importance of the anti-androgen and its theraputic use in the topical application for alterning collagen: elastin formation, thus decreasing wrinkles; but more importantly, its systemic applications would include its use in decreasing the rate of athlerscerosis by decreasing the rate of collagen formation.

Example 38;

The anti-cancer activity of the Compound (I) was 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) was shown to have a significant anti-tumor activity against the three selected tumors when used at a level of 10mcg/ml with the compound of the Formula 10, based upon observations of a cytologist. The Compound (I) compares favorably in tests against mitomycin C, vinblastine, vincristine, melamine, methyl-GAG, 5-FU, melphalan, and bleomycin. The relationship of the androgen blockage to the anticancer applicability of the Compound (I) is seen by the more pronounced effects that were observed on prostatic cancers, as it the prostate has a greater number of androgen receptor sites than the other tested 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 adnrogen receptors at 1:1000 DHT to the Compound (I), and no significant deleterious effects were noticed in the estrogen and progesterone receptors.

Example 39: The compound of Formula 10 was found to block 59-80% of androgen binding sites in a melanoma at concentrations of 1:1000 of dihydrotestosterone to the tested compound, with no significant effect on either the estrogen or progesterone receptors in the tissue.

Example 40: The compound of Formula 8 was tested on tumor cells in the absence of steroid, with squamous skin cancer cells being employed for assays on this compound. The test results showed that there was no effect obsered on cell counts or viability and that there is a concentration-dependent decrease in ³H thymidine update. The tests which were conducted show that Compound (I) has activity agaisnt cancer cells, even those with non-hormone receptors, suggesting the use of the Compound (I) for therapy for numerous forms of cancer, singularly, and/or in conjuction with present standard chemotherapies.

Example 41: Lou Gehrig's disease, amyotrophic laterial sclerosis. Is advantageously treated with the Compound (I), based upon tests with surgical specimens of neurotissues with this disease. The compound of Formula 10 blocked 79% of the androgen receptors in these tissues of both benign and malignant tissues at ratios of DHT to the tested compound of 1:1000. 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 estrogen and progesterone receptor 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 42; 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 ccomprises topically applying to a patient an anti- androgenic agent to the skin of said patient, whereby androgen receptor sites are blocked, thereby retarding the formation of keloids. Tests conducted with 6-(5-methoxyhept-1-yl)-bicycle-[3.3.0] octan-3-one have shown the suppression of keloid formation. Surgical exci sion of keloids was performed from clinic and private patient populations. 6-(5-methoxyhept-1-yl)-bicyclo- [3.3.0]octan-3-one was incubated in ratios of 1:0 to 1:10000 steroid hormone to this 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 gytosal- protein ±101 femtamoles/mg. The following results were obtained:

Treatment for prevention of interabdominal and other post surgical systemic adhesions were also evaluated. Skin fibroblast collagen suppresion was also considered using surgical explants. At ratios of DHT:6-(5-methoxyhept-1-yl)-bicyclo-[3.3.0]octan-3-one of 1:1000, in more than 400 experiments, the 6-(5-methoxyhept-1-yl)-bicyclo- [3.3.0]octan-3-one blocked between 22% and 94% of the androgen receptors without significant interference with either the estrogen or progeserone receptors. Tissue from keloid showed androgen receptor inhibition of 41 to 72% and no measurable estrogen or progesterone receptor inhibition. Scalp samples showed from 22 to 89% androgen inhibition and zero to 7% progesterone inhibition. Forearm sample showed 22% androgen receptor inhibition and 4% progesterone receptor inhibition. In none of the tests was there any measurable estrogen receptor inhibition.

"Hard fibrous band" formation was retarded around breast implants after augmentation surgery. Blockage of 34% to 79% of androgen receptor sites was measured for 6-(5-methoxyhept-1-yl)-bicyclo-[3.3.0]octan-3-one without any significant effects on either estrogen or progesterone binding sites. The amount protein (in mg) per gram of gross tissue was meaured for four breast capsule group numbers which showed:

In a further embodiment there are provided compounds of the formula:

wherein each X is independently H or A; each M is independently H, Cl, Br or I;

A is -CRR-(CR¹R²)_nR₃ n is an integer of from one to eight;

R is H or lower alkyl;

R¹ and R² are independently R, OR, COOH, CHO, or together form the group CO;

R₃ is H, COOR, OR, CHR-OR or COR; c is three or four; 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, or a pharmaceutically acceptable salt thereof. Preferably c is three, thus providing a bicyclo[3,2,0] heptan-6-one ring structure, and in a preferred embodiment there is only one X substituent which is at the 2 or 4 position of the alkyl-bicyclo[3,2,0]heptan-6-one ring. The A group is preferably -CH₂-CH₂-CH₂-C(R⁴R⁵)R⁶ wherein R⁴ and R⁵ are independently H, methyl or ethyl; and R is COOH, CHO or C(R⁷R⁹)OR⁸; and

R ⁷, R⁸ and R⁹ are independently H, methyl or ethyl.

The compound preferably contains a cis bridge. The group -C(R ⁴R⁵)R⁶ is preferably -CH₂COOH, -CH₂CH₂OH,

-CH₂CH (CH₃) OH, -CH₂CH (CH₂CH₃) OCH₃ ,

-CH₂CHO, -CH(CH₃)CH(CH₂CH₃)OH, or

-CH(CH₃) CH (CH₂CH₃) OCH₃. The compounds (II) have the same utility as the compounds (I) and in some cases the compounds (II) serve as intermediates for the production of the compounds (I). For example, the compound 7,7-dichloro-4-(5-methoxyhept-1-yl)-bicyclo[3,2,0]heptan-6-one is both an intermediate for producing a compound of the formula (I) and is also itself an anti-androgenic agent sharing the utilities of the compound (I). Representative compounds (II) include:

7 ,7-dichloro-4-(5-hydroxyhept-l-yl)-bicyclo[3,2,0]heptan-6-one

4-(5-methoxyhept-1-yl)-bicyclo[3,2,0]heptan-6-one

7-chloro-4-(5-methoxyhept-l-yl)-bicyclo[3,2,0]heptan-6-one

7,7-dichloro-4-(5-methoxyhept-1-yl)-bicyclo[3,2,0]heptan-6-one 7-chloro-4-(5-methoxyhept-l-yl)-bicyclo-[3.2.0]heptan-6-one

7-chloro-2- (5-hydroxyhex-l-yl) -bicyclo- [3.2.0] heptan- 6-one 7,7-dibromo-4-(5-hydroxyhept-l-yl)-bicyclo[3,2,0]heptan-6-one

The compounds (II) are useful in anti-androgenic composition suitable for providing an anti-androgenic effect when administered to a patient in the same manner as for compound (I). A skin preparation is provided which is suitable for topical administration to a patient to be exposed to ultraviolet light which includes an antiultraviolet screening agent.

Claims

WHAT IS CLAIMED IS:

1. A compound of the formula

wherein B and B' are both H or together form a single bond;

Q is CO, CH-OR, or -COOR; each X is independently H or A;

Y and Y' are each 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; R¹ and R² are independently R, OR, COOH, CHO, or together form the group CO; R₃ is H, COOR, OR, CHR-OR or COR; c is an integer from zero to four; 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, or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1, wherein

Q is CO, CH-OH, CH-OCH₃ or CH-OCH₂CH₃; c is 3; and n is 1 to 4.

3. A compound of claim 1, wherein said compound has the formula

4. A composition of claim 3, wherein A has the formula

-CH₂-CH--CH₂-C(R⁴R⁵)R⁶ wherein and R⁵ are independently H, methyl or ethyl;

R⁶ is COOH, CHO or C(R⁷R⁹)OR⁸; and R⁷, R ⁸ and R⁹ are independently H, methyl or ethyl, and the compound contains a cis bridge.

5. A composition of claim 4, wherein -C(R⁴R⁵)R⁶ is

-CH₂COOH, -CH₂CH₂OH, -CH₂CH (CH₃) OH, -CH₂CH(CH₂CH₃) OCH₃,

-CH₂CHO, -CH(CH₃)CH(CH₂CH₃)OH, or -CH(CH₃)CH(CH₂CH₃) OCH₃.

6. A compound of claim 1 which is 6-(5-methoxyhept-1-yl)-bicyclo-[3.3.0]octan-3-one.

7. A compound of claim 1 which is 6-(5-hydroxyhex-1-yl)-bicyclo-[3.3.0]octan-3-one.

8. A compound of claim 1 which is 6-(5-hydroxy-4-methylhept-1-yl)-bicyclo-[3.3.0]octan-3-one.

9. A compound of claim 1 which is 6-(5-methoxy-4-methylhept-1-yl)-bicyclo-[3.3.0]octan-3-one.

10. An anti-androgenic composition suitable for providing an anti-androgenic effect when administered to a patient which comprises a pharmaceutically effective amount of a compound of any of claims 1-9 and a pharmaceutically inert carrier suitable for topical administration of said compound to said patient.

11. An anti-androgenic composition of claim 10, wherein said pharmacetuically inert carrier includes an alcohol, salve, suspension, emulsion, ointment, cream, powder or spray.

12. An anti-androgenic composition of claim 10, wherein said pharmaceutically inert carrier includes an alcohol.

13. An anti-androgenic composition of claim 10 which is contained in a sustained release medium, whereby upon application of said sustained release medium the anti- androgenically active composition is released to the skin over a prolonged period of time.

14. An anti-androgenic composition of claim 10 in the form of a suppository for rectal administration.

15. A skin preparation of claim 10 which is suitable for topical administration to a patient to be exposed to ultraviolet light which includes an anti-ultraviolet screening agent.

16. A shampoo which includes the anti-androgenic composition of claim 10.

17. A method of blocking androgen receptor sites in a patient which comprises introducing to said sites a compound of any of claims 1 through 9.

18. A method of claim 17, wherein said compound is topically applied.

19. A method of claim 18, wherein said patient is afflicted with acne which is alleviated by reducing androgen to reach androgen receptor sites.

20. A method of claim 18, wherein said patient is afflicted with a cancer, the growth of which is retarded through blockage of androgen receptor sites.

21. A method of claim 18, wherein said patient is afflicted with male pattern baldness, which is treated by blockage of androgen receptor sites.

22. A compound of the formula

wherein each X is independently H or A; each M is independently H, Cl, Br, or I;

A is -CRR-(CR¹R²)_nR₃. n is an integer of from one to eight; is H or lower alkyl;

R¹ and R² are independently R, OR, COOH, CHO, or together form the group CO;

R₃ is H, COOR, OR, CHR-OR or COR; c is three or four; 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, or a pharmaceutically acceptable salt thereof.

23. A compound of claim 22, wherein c is three, thus constituting a bicyclo[3,2,0]heptan-6-one ring structure.

24. A compound of claim 23, which contains one X substituent which is at the 2 or 4 position of the alkyl-bicyclo[3,2,0]heptan-6-one ring.

25. A compound of claim 24 wherein A is

R⁶ is COOH, CHO or C(R⁷R⁹)OR⁸; and

R^7, R⁸ and R⁹ are independently H, methyl or ethyl, and the compound contains a cis bridge.

26. A compound of claim 25, wherein -C(R⁴R⁵)R⁶ is -CH₂COOH, -CH₂CH₂OH, -CH₂CH(CH₃)OH, -CH₂CH (CH₂CH₃) OCH₃ , -CH₂CHO, -CH (CH₃) CH (CH₂CH₃) OH, or -CH(CH₃)CH(CH₂CH₃)OCH .

27. A compound of claim 22 which is 7,7-dichloro-4- (5-methoxyhept-l-yl)-bicyclo[3,2,0]heptan-6-one.

28. 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 formation of keloids.