IES85914Y1 - Process for producing 6-(5-ethoxy-hept-1-yl)bicyclo[3.3.0]octan-3-one - Google Patents

Abstract

ABSTRACT Described are improved processes for producing 6-(5-ethoxyhepb 1 - yl)bicyc1o[3.3.0]octan-3 -one from 6,6-dichloro-2-(5-ethoxyhept-1- y1)bicyc10[3 .2.0]heptan-7-one and 6-(5-exthoxyhept-1-y1)bicyc1o[3.3.0]octan-3-one produced by the described processes.

Description

TITLE OF THE INVENTION PROCESS FOR PRODUCING 6-(5—ETHOXY-HEPT-1—YL)B|CYCLO[3.3.0]OCTANONE TECHNICAL FIELD

[0001] The invention relates generally to cosmetics. and more particularly to an improved process for producing the known cosmetic compound 6—(5-ethoxyheptyl)bicyclo[3_3.0]octan—3—one (also known as "ethoxyheptyl bicyclooctanone"). and the compound produced by the process itself.

BACKGROUND

[0002] 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 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. : 3[0B03] 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 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.

[0004] Anti-androgens, such as the compound 6—(5—ethoxyheptyl)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 have an affinity for DHT receptors comparable to that of androgens. Typically, anti—androgens compete for binding sites on the cells‘ surface thereby competitively blocking 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.

[0005] 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‘.

[0006] in young skin, the ratio of DHT and DHT receptors to anti—androgens is balanced.

However, at some point, usually about 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 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- y|)bicyclo[3.3.0]octan—3-one.

Skin,” Dermatology Times (Jan. 1996).

See, eg., “New Nonsteriodal Antiandrogen Topical Benefits Aging SUMMARY OF THE INVENTION

[0007] Described is an improved process for producing 6-(5-ethoxyhept-‘I-y|)bicyclo[3.3.0]octan- 3-one from 6,6-dichloro(5-ethoxyheptyl)bicyclo[3.2.0]heptanone. The process to be improved is of the type wherein chlorine atoms are removed from the from 6,6-dichloro(5- ethoxyheptyl)bicyclo[3.2.0]heptanone, 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 added drop-wise to the sodium bicarbonate solution to also improve the resulting compound’s purity.

The invention includes 6-(5-ethoxyheptyl)bicyclo[3.3.0]octanone produced by the foregoing process.

DETAILED DESCRIPTION

[0008] 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-I-yl)bicyclo[3.3.0]octanone 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 isomers of 6-(5-ethoxyhept yl)bicyclo[3.3.0]octanone.

[0009] The 6-(5-ethoxyheptyI)bicyclo[3.3.0]octanone 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 6-(5- ethoxyheptyl)bicyclo[3.3.0]octan—3-one is also known as ethoxyheptyl bicyclooctanone or 2-(5- ethoxyheptyl)bicycIo{3.3.0]octan-7one (available as ETHOCYN® from BCS Pharma Corp., Beverley Hills, CA, US).

[0010] All percentages and ratios used herein are by weight of the total composition unless otherwise indicated.

[0011] 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 like. A "cosmetically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and othenivise 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 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.

[0012] 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 objective or subjective parameter such as abatement, remission, or diminishing of symptoms or the condition.

[0013] 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 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.

[0014] After the compound is made as described herein, a cosmetic composition (e.g., 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., 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.

[0015] A lower concentration of the active ingredients is indicated if the composition 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 1 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.

[0016] 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 The cosmetically acceptable excipient may contain at least one filler, for example, a clermatologically cosmetically acceptable excipient may act as a diluent, dispersant, solvent or the like. acceptable solid, semi-solid, or liquid filler. The cosmetically acceptable excipient may be inert (lie. 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, or efficacy of the composition.

[0017] The cosmetically acceptable excipient may comprise hydrophilic diluents such as water, lower monovalent alcohols (C1~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—iri—oil emulsion, oil—in—water emulsion, and water-in silicone emulsion. Such emulsions may contain a lipid or oil from animals, plants, or petroleum, 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.

[0018] Optional ingredients may also be included in the composition described herein.

Optional components include aesthetic agents and other active agents. For example, the compositions may include absorbents, abrasives, anti-caklng 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 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 hydroxy acids, and natural extracts. Such other materials are known in the art. Nonexclusive examples of such materials are described herein.

[0019] In some embodiments, the additional optional ingredients may include nicotinic acids, such as nicotinic acid, nicotinamide and benzyl nicotinate, vitamin As, such as retinol, retinoyi acetate and vitamin A oils, vitamin B2s, such as riboflavin, riboflavin acetate and flavin adenine dinucleotide, vitamin B63, such as pyridoxine hydrochloride and pyridoxine dioctanoate, pantothenic acids, such as calcium pantothenate, pantothenyl ethyl ether, D-pantothenyl alcohol and acetyipantothenyl ethyl ether, vitamin Ds, such as cholecalciferol, and ergocalciferol, and miscellaneous vitamins.

[0020] The additional ingredients may also include amino acids, such as glycine, alanine, phenylalanine, valine, leucine, isoieucine, 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, acyiated neutral amino acid salts, such as sodium lauroylmethyl-(3—ala_nine and coconut oil fatty acid 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 tailow, avocado fat, jojoba oil, lanolin, liquid paraffin, squalane, carnauba wax, isostearyl alcohol, isostearyl palmitate and glyceryl tri-2—ethylhexanoate, 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.

[0021] 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 phosphoiipids, preservatives, such as ethylparaben, propylparaben and butyl—paraben, anti-inflammatory agents, such as hinokitiol, salicylic acid derivatives, glycyrrhizinic acid derivatives, giycyrrhetic acid derivatives, aliantoin and zinc oxide, miscellaneous pH regulating agents, buffers, perfumes and coloring agents.

[0022] After being made, the compound and resulting composition is preferably used in methods of enhancing, treating, andlor 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 soap and applied directly to the 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.

[0023] 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 controtled release of the composition into the skin. T-he 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 In still further embodiments the matrix system may comprise a semisolid suspension of the composition the composition is maintained until .delivery and a separate adhesive layer. surrounded ‘by an adhesive layer. For example, a composition comprising from 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.

EXAMPLE!

[0024] 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.

[0025] 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-chloroethoxyheptane (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 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 yl)cyclopentene {3-(5—ethoxyheptyl)cyc|opentene} (0.262 moles) is obtained as a clear, colorless oil boiling at about 90° C at 0.3 mm and 54° C and at 0.1 mm.

[0026] A 1,000 ml yl)cyclopentene (0.076 moles) in 300 ml of hexane, is equipped with a reflux condenser. Freshly three-neck, round-bottomed flask, containing 3-(5-ethoxyhept distilled dichloroacetyl chloride (0.240 motes) 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 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- 1y|)bic|yo[3.2.0]heptanone) (17 g).

[0027] Diazomethane is generated in situ from N-methyl-N-nitroso-p-toluene sulfonamide (Diazald) using a macro diazald kit (Aldrich). 6,6-Dichloro(5-ethoxyheptyl)bicyc|o[3.2.0]heptan- 7-one {7,7-dichloro(5-ethoxyheptyl)bicyc|o[3.2.0]heptanone} and isomers (0.113 moles) is After 50 minutes, the excess diazomethane is neutralized with the addition of acetic acid (10 ml). The solvent treated with an etheral diazomethane solution (100 ml) followed by methanol (4 ml). is removed, under vacuum, and leaves a clear, yellow liquid.

[0028] The crude product is then diluted with acetic acid (240 ml) and stirred while zinc powder (1.10 moles) is slowly added. The reaction is heated in a 70° C water bath for 1 hour, after which time ether (500 ml) is added and the solution filtered.

EXAMPLE Il

[0029] 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 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.

[0030] Any remaining %olvent is removed, under vacuum, leaving a clear, yellow oil. The (also 6—(5-ethoxyhept {hexahydro—4-(5-methoxyheptyl)-2(1 H)-pentalenone} is crude 2-(5-ethoxyhept-1—yl)bicyc|o[3.3.0]octan-Tone known as yI)bicyclo[3.3.0]octan-3one) chromatographed on silica gel and is subsequently “kugelrohred” under vacuum leaving the product as a clear, colorless oil (0.045 moles).

EXAMPLE Ill

[0031] The ethoxyheptyl bicyclooctanone produced by EXAMPLE Ill is incorporated into a composition in an amount (total weight of composition) of from about 0.001 weight percent to about 5 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 after several days of daily application.

Claims (2)

1. A process for producing 6-(5-ethoxyhepty|)bicyclo[3.3.0]octanone from 6,6-dich|oro- 2-(5-ethoxyheptyl)bicyclo[3.2.0]heptanone through removal of chlorine atoms from 6,6-dichloro- 2-(5-ethoxyhepty|)bicyclo[3.2.0]heptanone. filtration of the resulting compound, and treatment of the filtrate 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.

2. The process according to claim 1, wherein the resulting product is thinned with ether before being added drop wise to the sodium bicarbonate solution.