Australia Patents Act 1990 ORIGINAL COMPLETE SPECIFICATION INNOVATION PATENT Name(s) of Applicant(s): BCS Business Consulting Services Pte Ltd. Title of Invention: 'Process for producing 6-(5-ethoxy-hpt 1-yl)bicyclo[3.3.0]octan-3-one and product thereof' The following is a full description of this invention, including the best method known to the Applicant(s) of performing the invention: PROCESS FOR PRODUCING 6-(5-ETHOXY-HEPT- 1 -YL)BICYCLO[3.3.0]OCTAN-3-ONE AND PRODUCT THEREOF TECHNICAL FIELD 5 100011 The invention relates generally to cosmetics, and more particularly to an improved process for producing the known cosmetic compound 6-(5-ethoxyhept-1 yl)bicyclo[3.3.0]octan-3-one (also known as "ethoxyheptyl bicyclooctanone"), and the compound produced by the process itself. .0 BACKGROUND [00021 Skin is comprised of two types of important skin fibers, collagen and elastin. Collagen fibers provide structure and resist stretching, while elastin fibers are generally considered responsible for the elasticity and resilience of the skin. Elastin fibers maintain the extensibility and elasticity of the skin when degraded and synthesized in a sustainable .5 manner. However, when the rate of degradation of elastin, for example by elastase, exceeds the rate of synthesis, due to aging or to other factors, the skin loses this resiliency. [00031 Although many factors contribute to mechanical properties of the skin, it has been found that when an androgen, a class of hormones found in both men and women, enters a skin cell it may inhibit the production of elastin causing increased laxity of the skin, among other 0 things. In a skin cell, androgens are converted to dihydrotestoterone ("DHT"). DHT binds to DHT receptors in the cell and signals the cell to reduce or discontinue elastin synthesis. [00041 Anti-androgens, such as the compound 6-(5-ethoxyhept- 1 yl)bicyclo[3.3.0]octan-3-one, comprise a group of hormone receptor antagonists that are able to prevent and/or inhibit the biological effects of androgens in normal tissue. These anti-androgens 25 may have an affinity for DHT receptors comparable to that of androgens. Anti-androgens, depending on the anti-androgen and cell type, may compete for androgen binding sites on the cells surface , in cytoplasm, or on the nuclear membrane and thereby competitively block the DHT receptor. The blocking of the DHT receptor with an anti-androgen prevents signaling and, when applied topically, allows the skin cell to continue producing elastin. 30 [00051 Skin synthesizes less elastin fibers as chronological age increases, which is known as "intrinsic aging." It has been discovered that modulation of the aging effects of hormones, such as androgens, may be of benefit in altering some aspects of the skin aging process. 2 [00061 In young skin, the ratio of DHT and DHT receptors to anti-androgens is balanced. However, at some point, usually between 25 and 30 years of age in humans, this equilibrium is changed. In particular, the number of DHT receptors increases, while the number of anti-androgens present in the skin cell decreases. This imbalance, at least partially, leads to 5 the age-related changes in the skin's mechanical properties, such as superficial skin laxity and fine wrinkling. More specifically, the decline in elastin production associated with a DHT/anti androgen imbalance may cause decreased extensibility and elasticity of the skin of a subject, which can be addressed with 6-(5-ethoxyhept-1-yl)bicyclo[3.3.0]octan-3-one. See, e.g., "New Nonsteriodal Antiandrogen Topical Benefits Aging Skin," Dermatology Times (Jan. 1996). 10 SUMMARY OF THE INVENTION [00071 The present invention generally provides an improved process for producing 6-(5-ethoxyhept- I -yl)bicyclo[3.3.0]octan-3-one from 6,6-dichloro-2-(5-ethoxyhept- 1 yl)bicyclo[3.2.0]heptan-7-one. The process to be improved is of the type wherein chlorine 15 atoms are removed from the from 6,6-dichloro-2-(5-ethoxyhept-1-yl)bicyclo[3.2.0]heptan-7 one, the resulting compound filtered, and the filtrate treated with a sodium bicarbonate solution, characterized in that, after filtration, the solvent is removed from the filtrate and the resulting product is added to the sodium bicarbonate solution to enhance recovery yield. In further embodiments, the resulting product may be thinned with diethyl ether and may be !0 added drop-wise to the sodium bicarbonate solution to also improve the resulting compound's purity. The invention also provides 6-(5-ethoxyhept-I-yl)bicyclo[3.3.0]octan-3-one produced and cosmetically acceptable salts thereof, produced by the foregoing process. DETAILED DESCRIPTION 25 [00081 Embodiments described herein comprise an active ingredient consisting of at least one compound and/or processes of making the at least one compound, wherein the compound is 6-(5-ethoxyhept-1-yl)bicyclo[3.3.0]octan-3-one produced by one of the foregoing process and cosmetically acceptable salts thereof. The salts may include alkali metal salts, alkaline earth salts, and ammonium salts. The compound comprises a racemic mixture of 30 isomers of 6-(5-ethoxyhept- 1 -yl)bicyclo[3.3.0]octan-3-one. [00091 The 6-(5-ethoxyhept-1-yl)bicyclo[3.3.0]octan-3-one is produced by one of the foregoing process, which is modified from the methods described in U.S. Patent 4,689,345 to Kasha et al., U.S. Patent 4,689,349 to Kasha et al., and U.S. Patent 4,855,322 to Kasha et al., the disclosures of each of which are incorporated herein by this reference in their entireties. The 6 3 (5-ethoxyhept-1-yl)bicyclo[3.3.0]octan-3-one is also known as ethoxyheptyl bicyclooctanone or 2-(5-ethoxyhept-1-yl)bicyclo[3.3.0]octan-7one (available as ETHOCYN* from BCS Pharma Corp., Beverley Hills, CA, US). 100101 All percentages and ratios used herein are by weight of the total composition 5 unless otherwise indicated. [00111 The term "cosmetically acceptable excipient" refers to and includes any suitable cosmetic excipient, including but not limited to, water, saline, phosphate buffered saline, Hank's solution, Ringer's solution, dextrose/saline, glucose, lactose, or sucrose solutions, magnesium stearate, sodium stearate, glycerol monostearate, glycerol, propylene glycol, and the [0 like. A "cosmetically acceptable excipient" refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluents to facilitate administration of an inventive agent and that is compatible therewith. Further examples of excipients include calcium carbonate, calcium phosphate, various sugars [5 and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. The excipient may be solid, semi-solid, or liquid. Further, the excipient may possess dermatological benefits of its own. [00121 The term "treating" means and includes to any indicia of success in cosmetic treatment or amelioration of a condition or symptom (e.g., skin inflammation), including any !0 objective or subjective parameter such as abatement, remission, or diminishing of symptoms or the condition. [00131 The compounds and compositions disclosed herein are useful for regulating signs of aging of the skin. The compositions enhance skin condition, including the subject skin's appearance and texture. Regulating the condition of the skin of a subject includes 25 prophylactically delaying, minimizing, and preventing visible or tangible discontinuities in skin texture. It also includes cosmetically ameliorating, diminishing, or eliminating discontinuities of the skin. Therefore, regulating the condition of the skin leads to improved skin appearance and feel. 100141 After the compound is made as described herein, a cosmetic composition (e.g., 30 solution or drops for topical application) is formed with the compound. The composition may take any suitable form, for example, a solid, a soluble agent such as a lotion, an emulsified agent such as a cream, ointment, gel, foam, dispersant, mousse, solution, aerosol, liquid, oil, tablet, or capsule. Further, the compound described herein may be incorporated into a wide variety of cosmetic products, including but not limited to solid, semi-solid, and liquid make-up (e.g., 4 foundations, eye makeup, and lip treatments), make-up remover, deodorants and antiperspirants, soaps, bath products (e.g, oils or salts), hair care products, sunscreen, shaving lotions, and baby products. 100151 A lower concentration of the active ingredients is indicated if the composition 5 is to be applied to a large surface area of the skin of a subject. A concentration of from about 0.01 weight percent to about 10 weight percent (of the total) of each of the bicycloalkane should be provided in a composition that will be administered over larger surface areas of the skin of a subject. In particular embodiments, a concentration of between about 0.025 weight percent and about 5 weight percent may be provided in a composition for topical application. 0 [00161 The compositions described herein may be admixed with and further comprise a cosmetically acceptable excipient or carrier. The cosmetically acceptable excipient enables the compound and other optional ingredients to be delivered to the subject in an effective amount. The cosmetically acceptable excipient may act as a diluent, dispersant, solvent or the like. The cosmetically acceptable excipient may contain at least one filler, for example, a dermatologically .5 acceptable solid, semi-solid, or liquid filler. The cosmetically acceptable excipient may be inert (i.e. an inactive agent) or may provide additional benefits to the condition of the skin of a subject. Suitable carriers include known cosmetic carriers. The cosmetically acceptable excipient should be compatible with the bicycloalkane and any optional ingredients, so as to not impair the stability, appearance, feel, penetration of skin dermis, or efficacy of the composition. !0 In embodiments, a dose and excipient formulation may be designed such that decomposition to an inert non-anti-androgen is complete after local anti-androgen effect but prior to general systemic absorption. While not intending to be bound by any particular theory, the compound may be absorbed locally to interact with local androgen receptors and may then be completely metabolized thereafter so as not to have any systemic effect. 25 100171 The cosmetically acceptable excipient may comprise hydrophilic diluents such as water, lower monovalent alcohols (Cl-C4), low molecular weight glycols and polyols, sorbitol esters, alcohols, and oxylated ethers. In some embodiments, the cosmetically acceptable excipient may comprise one of a water-in-oil emulsion, oil-in-water emulsion, and water-in silicone emulsion. Such emulsions may contain a lipid or oil from animals, plants, or petroleum, 30 and may be natural or synthetic. The emulsions, when present, may also contain humectants, such as glycerin. The emulsions may further contain at least one nonionic, anionic, or cationic emulsifier. 100181 Optional ingredients may also be included in the composition described herein. Optional components include aesthetic agents and other active agents. For example, the 5 compositions may include absorbents, abrasives, anti-caking agents, antifoaming agents, antimicrobial agents, binders, biological additives, buffering agents, bulking agents, chemical additives, cosmetic biocides, denaturants, cosmetic astringents, drug astringents, external analgesics, film formers, opacifying agents, essential oils, skin sensates, emollients, skin 5 soothing agents, skin healing agents, plasticizers, preservatives, preservative enhancers, propellants, reducing agents, additional skin-conditioning agents, skin penetration enhancing agents, skin protectants, solvents, suspending agents, emulsifiers, thickening agents, solubilizing agents, sunscreens, sun blocks, ultraviolet light absorbers or scattering agents, sunless tanning agents, chelating agents, sequestrants, depilation agents, desquamation agents/exfoliants, organic 0 hydroxy acids, and natural extracts. Such other materials are known in the art. Nonexclusive examples of such materials are described herein. [00191 In some embodiments, the additional optional ingredients may include nicotinic acids, such as nicotinic acid, nicotinamide and benzyl nicotinate, vitamin As, such as retinol, retinoyl acetate and vitamin A oils, vitamin B2s, such as riboflavin, riboflavin acetate 5 and flavin adenine dinucleotide, vitamin B6s, such as pyridoxine hydrochloride and pyridoxine dioctanoate, pantothenic acids, such as calcium pantothenate, pantothenyl ethyl ether, D pantothenyl alcohol and acetylpantothenyl ethyl ether, vitamin Ds, such as cholecalciferol, and ergocalciferol, and miscellaneous vitamins. [00201 The additional ingredients may also include amino acids, such as glycine, !0 alanine, phenylalanine, valine, leucine, isoleucine, serine, threonine, asparagine, aspartic acid, aspartates, glutamine, glutamic acid, glutamates, lysine, methionine, cysteine, cystine, arginine, histidine, tryptophan, proline and hydroxyproline, N-acylated acidic amino acid salts, such as sodium N-coconut oil fatty acid-L-glutamate and diethyl N-palmitoyl-L-aspartate, acylated neutral amino acid salts, such as sodium lauroylmethyl-(3-alanine and coconut oil fatty acid 25 succinotriethanolamine, pyrrolidonecarboxylic acid and its salts, amino acid derivatives, such as polyoxyethylenated hardened castor oil monopyroglutamate monoisostearate diester and coconut oil fatty acid -L-arginine ethyl ester-DL-pyrrolidonecarboxylate, oils, such as rice bran oil, peanut oil, palm oil, beef tallow, avocado fat, jojoba oil, lanolin, liquid paraffin, squalane, carnauba wax, isostearyl alcohol, isostearyl palmitate and glyceryl tri-2-ethylhexanoate, 30 polyhydric alcohols, such as glycerol, sorbitol, mannitol and 1,3-butylene glycol, polyhydric alcohol ethers, such as polyethylene glycol, mucic polysaccharides, such as collagen, sodium hyalauronate, sodium chondroitin sulfate and sodium dextran sulfate, antioxidants, such as p hydroxyanisole and sodium erythorbate. 6 100211 In still further embodiments the composition may include cellulose derivatives, such as carboxyvinyl polymer, carboxymethylcellulose and hydroxypropyl methylcellulose, surfactants, such as sodium stearyl sulfate, diethanolamine cetyl sulfate, cetyl trimethylammonium saccharin, isostearyl polyethylene glycol, diglyceryl isostearate and 5 phospholipids, preservatives, such as ethylparaben, propylparaben and butyl-paraben, anti inflammatory agents, such as hinokitiol, salicylic acid derivatives, glycyrrhizinic acid derivatives, glycyrrhetic acid derivatives, allantoin and zinc oxide, miscellaneous pH regulating agents, buffers, perfumes and coloring agents. [00221 After being made, the compound and resulting composition is preferably used 0 in methods of enhancing, treating, and/or preventing damage to the skin of the subject. The methods include applying a composition comprising alkyl- substituted bicycloalkane, produced as described herein, to the surface of the skin of a subject, e.g., by spreading the composition over the skin surface in the form of a cream, lotion, or ointment. For example, the composition may be incorporated into a cosmetic such as make-up or moisturizer and applied directly to the 5 skin. For example, a composition comprising from about 0.001 weight percent to about 5 weight percent of ethoxyheptyl bicyclooctanone may be applied to the skin. In embodiments, the compound and/or composition may be left on the site of application for about 10 minutes to about 1 hour before cleansing the area. 100231 In embodiments, the composition may be applied daily for about 45 to about 60 !0 days. In certain embodiments, the composition may reduce wrinkles and skin texture within 10 minutes of application. Such immediate effects may result from proven moisturizers, skin softeners, routine to cosmetic formulations. [00241 In other embodiments, the composition may be integrated with a matrix system (e.g., a compound delivery "patch") that is adhered to the surface of the skin for controlled 25 release of the composition into the skin. The matrix may comprise a single layer or multiple layers of adhesive into which the composition is integrated. Alternatively, the matrix may comprise a reservoir where the composition is maintained until delivery and a separate adhesive layer. In still further embodiments the matrix system may comprise a semisolid suspension of the composition surrounded by an adhesive layer. For example, a composition comprising from 30 about 0.01 weight percent to about 1 weight percent of ethoxyheptyl bicyclooctanone may be integrated with a matrix and applied to the skin of a subject in need thereof. The methods include topical application to the skin, e.g., adhering a matrix, including the composition, to the skin of a subject. The invention is further explained by the following illustrative Examples. 7 EXAMPLE I 100251 The following process is modified from the disclosures of U.S. Patent 4,689,345 to Kasha et al., U.S. Patent 4,689,349 to Kasha et al., and U.S. Patent 4,855,322 to Kasha et al., the entirety of each of which are incorporate herein. 5 100261 A three-neck, round-bottomed flask containing magnesium metal turnings (0.299 moles), is equipped with a Friedrich condenser and kept under a nitrogen atmosphere. Tetrahydrofuran (300 ml) is added, and the contents are allowed to stir. A solution of 1-chloro 5-ethoxyheptane (0.292 moles) is added in small portions and refluxed. The mixture is stirred for 3 hours. The resultant dark yellow solution is cooled to -25* C, and the condenser is t0 removed and replaced with a dry ice addition funnel. A solution of 3-chlorocyclopentene (0.292 moles) is added over a period of one hour. The viscous solution is poured into two liters of saturated ammonium chloride, extracted with ether, and dried over anhydrous sodium sulfate. By distillation, a yield of 3-(5-ethoxyhept-1-yl)cyclopentene {3-(5-ethoxyheptyl)cyclopentene} (0.262 moles) is obtained as a clear, colorless oil boiling at about 900 C at 0.3 mm and 540 C and 15 at 0.1 mm. [00271 A 1,000 ml three-neck, round-bottomed flask, containing 3-(5-ethoxyhept-1 yl)cyclopentene (0.076 moles) in 300 ml of hexane, is equipped with a reflux condenser. Freshly distilled dichloroacetyl chloride (0.240 moles) is added and the solution stirred and heated to reflux. Triethylamine (0.249 moles) in 200 ml hexane, is added drop-wise to the refluxing 20 solution and the solution is stirred for 4 hours. The solvent is removed and the residue distilled and is chromatographically purified with silica gel, leaving the product (6,6-dichloro-2-(5 ethoxyhept-lyl)biclyo[3.2.0]heptan-7-one) (17 g). [00281 Diazomethane is generated in situ from N-methyl-N-nitroso-p-toluene sulfonamide (Diazald) using a macro diazald kit (Aldrich). 6,6-Dichloro-2-(5-ethoxyhept-1 25 yl)bicyclo[3.2.0]heptan-7-one {7,7-dichloro-4-(5-ethoxyheptyl)bicyclo[3.2.0]heptan-6-one} and isomers (0.113 moles) is treated with an etheral diazomethane solution (100 ml) followed by methanol (4 ml). After 50 minutes, the excess diazomethane is neutralized with the addition of acetic acid (10 ml). The solvent is removed, under vacuum, and leaves a clear, yellow liquid. 100291 The crude product is then diluted with acetic acid (240 ml) and stirred while zinc 30 powder (1.10 moles) is slowly added. The reaction is heated in a 700 C water bath for 1 hour, after which time ether (500 ml) is added and the solution filtered. 8 EXAMPLE II [0030] The filtrate resulting from EXAMPLE I has the solvent removed with a rotary evaporator and the raw product is diluted (thinned drop by drop) with diethyl ether. The thinned product is added drop by drop to a strongly agitated solution of sodium bicarbonate. After the 5 addition of the thinned product, the ether and sodium bicarbonate solution is stirred for an additional 20 minutes. The ether layer is separated and dried over anhydrous sodium sulfate. [0031] Any remaining solvent is removed, under vacuum, leaving a clear, yellow oil. The crude 2-(5-ethoxyhept-1-yl)bicyclo[3.3.0]octan-7one (also known as 6-(5-ethoxyhept-1 yl)bicyclo[3.3.0]octan-3one) { hexahydro-4-(5-methoxyheptyl)-2(1 H)-pentalenone } is 10 chromatographed on silica gel and is subsequently "kugelrohred" under vacuum leaving the product as a clear, colorless oil (0.045 moles). EXAMPLE III [0032] The ethoxyheptyl bicyclooctanone produced by EXAMPLE III is incorporated [5 into a composition in an amount (total weight of composition) of from about 0.001 weight percent to about 10 weight percent. The composition (e.g., a lotion) is formulated for application to a human's skin, and may then be applied to the skin to improve skin appearance, for example, by reducing the appearance of wrinkles. 0 INTERPRETATION OF THIS SPECIFICATION [00331 It will therefore be understood that the invention could take many forms and be put to many different uses. All such forms and uses are embodied within the spirit and scope of the invention, which is to be understood as not being limited to the particular details 25 of the embodiments or the examples discussed previously, but which extends to each novel feature and combination of features disclosed in or evident from this specification (including in the accompanying claims and abstract). All of these different combinations constitute various alternative aspects of the invention. 100341 Throughout this specification, unless the context requires otherwise, the word 30 "comprise" is (and variants, variations or other forms of that word, such as "comprises" or "comprising" are) to be understood as implying the inclusion of a stated element, feature or integer or group of elements, features or integers, but not the exclusion of any other element, feature or integer or group of elements, features or integers. Further, wherever used in this 9 specification, the term "includes" is not a term of limitation, and is not be taken as excluding the presence of other any element, feature or integer or group of elements, features or integers. [0035] It is further to be understood that any discussion in this specification of background or prior art documents, devices, acts, information, knowledge or use 5 ('Background Information') is included solely to explain the context of the invention. Any discussions of such Background Information is not be taken as an admission in any jurisdiction that any such Background Information constitutes prior art, part of the prior art base or the common general knowledge in the field of the invention on or before the priority date of the appended claims or any amended claims later introduced into this specification. 10 10