CH704562A2 - A method for producing 6- (5-Ethoxyhept-1-yl) -bicyclo [3.3.0] octan-3-one. - Google Patents

Abstract

Described are improved processes for preparing 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one from 6,6-dichloro-2- (5-ethoxyhept-1-yl) bicyclo [3.2 .0] heptan-7-one and 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one prepared by the described methods.

Description

FIELD OF THE INVENTION

The invention relates generally to cosmetics and more particularly to an improved process for preparing the known cosmetic compound 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one (also known as "ethoxyheptylbicyclooctanone") and the product produced by the process.

STATE OF THE ART

Skin includes two types of important skin fibers, namely collagen and elastin. Collagen fibers give structure and inhibit expansion, while elastin fibers are generally considered to be responsible for the elasticity and resilience of the skin. Elastin fibers retain the stretch and elasticity of the skin when degraded and formed in a sustainable manner. However, when the breakdown of elastin, for example by elastase, due to aging or other reasons, is faster than its formation, the skin loses its elasticity.

Although many factors contribute to the skin's mechanical properties, it has been found that when an androgen, a class of hormones found in both men and women, invades a skin cell, it inhibits the production of elastin can, which causes, among other things, an increased slackness of the skin. In skin cells, androgens are converted into dihydrotestosterone ("DHT"). DHT binds to DHT receptors in the cell and signals the cell to decrease or discontinue elastin synthesis.

Anti-androgens, such as the compound 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one, comprise a group of Honnon receptor antagonists that are capable of prevent and / or inhibit the biological effects of androgens in normal tissue. These anti-androgens may have an affinity to DHT receptors similar to those of androgens. Depending on the type of anti-androgen and cell type, anti-androgens can compete for androgen binding sites on the cell surface, in the cytoplasm or on the nuclear membrane and thus competitively block the DHT receptor. Blocking the DHT receptor with an anti-androgen prevents signaling and, when applied topically, allows skin cells to continue to produce elastin.

With increasing age, the skin synthesizes less elastin fibers, which is known as "intrinsic skin aging". It has been discovered that modulating the aging effects of hormones, such as androgens, can be beneficial in altering various aspects of the skin aging process.

In young skin, the ratio of DHT and DHT receptors to antiandrogens is balanced. But at some point, usually between the age of 25 and 30, this balance changes in humans. In particular, the number of DHT receptors increases while the number of anti-androgens present in the skin cell decreases. This imbalance leads, at least in part, to the age-related changes in the mechanical properties of the skin, such as superficial flaccidity of the skin and wrinkles. Specifically, the decline in elastin production associated with DHT / anti-androgen imbalance can cause diminished elasticity and elasticity of the skin of an individual, which is met with 6- (5-ethoxyhept-1-yl) bicyclo [3.30] octane. 3-on can be treated. See, for example, B. "New Nonsteroidal Antiandrogen Topical Benefits Aging Skin" Dermatology Times (Jan. 1966).

SUMMARY OF THE INVENTION

An improved process for preparing 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one from 6,6-dichloro-6- (5-ethoxyhept-1-yl ) bicyclo [3.3.0] octan-3-one. The method to be improved is that chlorine atoms are removed from 6,6-dichloro-6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one, the resulting compound is filtered and the filtrate with a sodium bicarbonate solution is treated, characterized in that after the filtration, the solvent is removed from the filtrate and the product obtained is added to the sodium bicarbonate solution to increase the yield. In further embodiments, the resulting product may be diluted with diethyl ether and added dropwise to a sodium bicarbonate solution to improve the purity and yield of the resulting compound. Application of these steps improves the yield of the process according to the invention by about twice compared with the prior art. The invention includes 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one prepared by the above method.

DETAILED DESCRIPTION

[0008] Embodiments described herein include an active ingredient consisting of at least one compound and / or methods of making the at least one compound, wherein the compound is 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octane 3-one prepared by any of the foregoing methods and cosmetically acceptable salts thereof. The salts may include alkali salts, alkaline earth salts and ammonium salts. The compound comprises a racemic mixture of isomers of 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one.

The 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one is prepared by one of the foregoing methods, in comparison to 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. and their disclosures, each of which is incorporated herein by reference, is modified. The 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one is also known as ethoxyheptylbicyclooctanone or 2- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-7-one (known as ETHOCYN® available from BCS Pharma Corp, Beverly Hills, CA).

All percentages and ratios used herein are by weight of the total composition unless otherwise specified.

The term "cosmetically-acceptable excipient" refers to and includes all suitable cosmetic adjuncts, 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, biocompatible and otherwise biologically suitable for administration to an individual, such as an inert substance added to a pharmacological composition or otherwise used as a vehicle, carrier or diluent facilitate the administration of an agent of the invention and which is compatible therewith. Other examples of excipients are calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. The adjuvant may be solid, semi-solid or liquid. Furthermore, the excipient itself may have dermatological benefits.

The term "treat" means and includes any sign of success in the cosmetic treatment or alleviation of a condition or symptom (e.g., dermatitis), including any objective or subjective parameters such as diminution, disappearance or reduction of symptoms or condition.

The compounds and compositions disclosed herein are useful for regulating signs of skin aging. The compositions improve the condition of the skin, including the appearance and texture of the individual's skin. Regulating the condition of an individual's skin includes prophylactically delaying, minimizing, and preventing visual or tactile discontinuities in skin texture. It also includes cosmetically improving, reducing or eliminating discontinuities of the skin. Therefore, regulating the condition of the skin results in improved appearance and skin feel.

After the compound has been prepared as described herein, a cosmetic composition (e.g., solution or drop 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, an ointment, a gel, a foam, a dispersant, a mousse, a solution, an aerosol, a liquid, an oil, a tablet or a capsule. Furthermore, the compound described herein may be included in a variety of cosmetic products including, but not limited to, solid, semi-solid and liquid make-up (e.g., foundation, eye make-up and lip treatments), make-up removal, deodorant and Antiperspirants, soaps, bath additives (eg oils or salts), hair care products, sunscreen, shaving lotions and baby products.

A lower concentration of the active ingredients is indicated when the composition is to be applied to a large area of skin of an individual. In a composition applied to a large skin area of an individual, the concentration should be about 0.01% to about 10% by weight (in total) of each bicycloalkane. In particular embodiments, in a composition for topical application, the concentration may be about 0.025% to about 5% by weight.

The compositions described herein may further be admixed and include a cosmetically acceptable excipient or carrier. The cosmetically acceptable excipient allows the compound and other optional ingredients to be provided to the individual 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, such as a dermatologically acceptable solid, semi-solid or liquid filler. The cosmetically acceptable excipient may be inert (i.e., an inactive agent) or may provide additional benefits relating to the condition of an individual's skin. Suitable carriers include known cosmetic carriers. The cosmetically-acceptable excipient should be compatible with the bicycloalkane and any optional ingredients so as not to interfere with the stability, appearance, feel, penetration of the dermis of the skin, or efficacy of the agent. In embodiments, a formulation of a dose and an adjuvant may be developed such that upon local anti-androgenic action, but before general systemic absorption, complete decomposition to an inert non-anti-androgen occurs. Without wishing to be bound by theory, the compound can interact locally with local androgen receptors and be subsequently completely degraded to have no systemic effect.

The cosmetically acceptable excipient may include hydrophilic diluents such as, for example, water, lower monohydric alcohols (C1-C4), low molecular weight glycols and polyols, sorbitol esters, alcohols and oxylated ethers. In some embodiments, the cosmetically-acceptable excipient may comprise a water-in-oil emulsion, an oil-in-water emulsion, or a water-in-silicone emulsion. Such emulsions may contain a lipid or an oil from animals, plants or petroleum and may be natural or synthetic. The emulsions, if present, may also contain humectants, such as glycerol. The emulsions may further comprise at least one nonionic, anionic or cationic emulsifier.

In the composition described herein, optional ingredients may also be included. Optional ingredients include esthetic agents and other agents. For example, the compositions may include absorbents, abrasives, flow aids, antifoaming agents, antimicrobial agents, binders, biological additives, buffering agents, fillers, chemical additives, cosmetic biocides, denaturants, cosmetic astringents, pharmaceutical astringents, external analgesics, film formers, opacifiers, essentials Oils, skin feel improving agents, emollients, skin soothing agents, skin healing agents, emollients, preservatives, preservative enhancers, propellants, reducing agents, additional skin conditioning agents, skin penetration enhancing agents, skin protection agents, solvents, suspending agents, emulsifying agents, thickening agents, solubilizers, sunscreens, Sunblock, ultraviolet light absorber or scattering agent, self-tanning agent, chelating agent, sequestering agent, depilatory, peeling agent, organic hydroxy acid n and contain natural extracts. Other such materials are known in the art. Non-exclusive examples of such materials are described herein.

In some embodiments, the additional optional ingredients may include nicotinic acids such as nicotinic acid, nicotinamide and benzyl nicotinate, vitamin A compounds such as retinol, retinoyl acetate and vitamin A oils, vitamin B2 compounds such as riboflavin, riboflavin acetate and flavin adenine dinucleotide, vitamin B6 compounds such as pyridoxine hydrochloride and pyridoxine dioctanoate, pantothenic acid such as calcium pantothenate, dexpanthenol ethyl ether, D-dexpanthenol and acetylpantothenylethyl ether, vitamin D compounds such as cholecalciferol and ergocalciferol, and various vitamins.

The additional ingredients may also include amino acids such as glycine, 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 succinotriethanolamine, Pyrrolidonecarboxylic acid and its salts, amino acid derivatives such as polyoxyethylenated hardened castor oil monopyroglutamate monoisostearate diester and coconut 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, paraffin oil, squalane, carnauba wax , Isostearyl alcohol, isostearyl palmitate and glyceryl tri-2-ethylhexanoate, polyhydric alcohols such as glycerin, sorbi t, mannitol and 1,3-butylene glycol, polyhydric alcohol ethers such as polyethylene glycol, mucic acid polysaccharides such as collagen, sodium hyaluronate, chondroitin sulfate sodium and dextran sulfate sodium, antioxidants such as p-hydroxyanisole and sodium erythorbate.

In further embodiments, the composition may include cellulose derivatives such as carboxyvinyl polymer, carboxymethyl cellulose and hydroxypropylmethyl cellulose, surfactants such as sodium stearyl sulfate, diethanolamine cetyl sulfate, cetyltrimethylammonium saccharin, isostearyl polyethylene glycol, diglyceryl isostearate and phospholipids, preservatives such as ethylparaben, propylparaben and butylparaben, antiinflammatory agents such as Hinokitiol, salicylic acid derivatives, glycyrrhizic acid derivatives, glycyrrhetinic acid derivatives, allantoin and zinc oxide, various pH regulators, buffers, perfumes and dyes.

After preparation, the compound and the composition obtained therefrom are preferably used in methods for improving, treating and / or preventing damage to the skin of the individual. The methods comprise employing a composition containing alkyl-substituted bicycloalkane prepared as described herein on the skin surface of an individual, for example, by applying the composition to the skin surface in the form of a cream, lotion or ointment. For example, the composition may be included in a cosmetic, such as makeup or moisturizer, and applied directly to the skin. For example, a composition containing from about 0.001% to about 5% by weight of ethoxyheptylbicyclooctanone may be applied to the skin. In embodiments, the compound and / or composition may be left at the site of use for about 10 minutes to 1 hour until the area is cleaned.

In embodiments, the composition may be applied daily for about 45 to about 60 days. In certain embodiments, the composition may reduce wrinkles and improve skin texture within 10 minutes after application. Such immediate effects may be due to proven moisturizers and skin softeners routinely used in cosmetic formulations.

In other embodiments, the composition may be incorporated into a matrix system (e.g., a "patch" to provide a compound) that is applied to the skin surface for controlled release of the composition into the skin. The matrix may comprise a single layer or multiple layers of adhesive in which the composition is incorporated. Alternatively, the matrix may comprise a reservoir in which the composition is in release and a separate adhesive layer. In further embodiments, the matrix system may comprise a semi-solid suspension of the composition surrounded by an adhesive layer. For example, a composition comprising from about 0.01% to about 1% by weight of ethoxyheptylbicyclooctanone may be incorporated into a matrix and applied to the skin of an individual in need thereof. The methods include topical application to the skin, e.g. B. Adherence of a matrix, including the composition, to the skin of an individual. The invention is illustrated by the following illustrative examples.

EXAMPLE I

The following procedure is different from the disclosures 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., which is incorporated herein by reference in its entirety.

A three-neck round bottom flask with magnesium turnings (0.299 mol) is equipped with a Friedrich condenser and kept under a nitrogen atmosphere. Tetrahydrofuran (300 ml) is added and the contents of the column are stirred. A solution of 1-chloro-5-ethoxyheptane (0.292 mol) is added in small portions and heated to reflux. The mixture is stirred for 3 hours. The resulting dark yellow solution is cooled to -25 ° C and the reflux condenser is removed and replaced with a dry ice dropping funnel. A solution of 3-chlorocyclopentene (0.292 mol) 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, 3- (5-ethoxyhept-1-yl) cyclopentene (3- (5-ethoxyheptyl) cyclopentene) (0.262 mol) is obtained as a clear, colorless oil which is 0.3 mm at about 90 ° C and at 0, 1 mm at 54 ° C, obtained.

A 1,000 ml three-necked round bottom flask of 3- (5-ethoxyhept-1-yl) cyclopentene (0.076 mol) in 300 ml of hexane is fitted with a reflux condenser. Freshly distilled dichloroacetyl chloride (0.240 mol) is added and the solution is stirred and heated to reflux. Triethylamine (0.249 mol) in 200 ml of hexane is added dropwise to the boiling solution and the solution is stirred for 4 hours. The solvent is removed and the residue is distilled and purified by chromatography on silica gel to give the product (6,6-dichloro-2- (5-ethoxyheptyl) bicylo [3.2.0] heptan-7-one) (17 g).

Diazomethane is generated in situ from N-methyl-N-nitroso-p-toluenesulfonamide (Diazald) with a macro Diazald kit (Aldrich). 6,6-Dichloro-2- (5-ethoxyhept-1-yl) bicyclo [3.2.0] heptan-7-one (7,7-dichloro-4- (5-ethoxyheptyl) bicyclo [3.2.0] heptane 6-one) and isomers (0.113 mol) are treated with a diazomethane ethereal solution (100 ml) followed by methanol (4 ml). After 50 minutes, the excess diazomethane is neutralized by the addition of acetic acid (10 ml). The solvent is removed in vacuo to give a clear, yellow liquid.

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

EXAMPLE II

The solvent of the filtrate of EXAMPLE I is stripped off with a rotary evaporator and the crude product is diluted (diethyl ether) with diethyl ether (dropwise addition). The diluted product is added dropwise to a vigorously stirred solution of sodium bicarbonate. After the addition of the diluted product, the solution consisting of ether and sodium bicarbonate is stirred for a further 20 minutes. The ether phase is separated and dried over anhydrous sodium sulfate.

Any remaining solvent is removed in vacuo to give a clear, yellow oil. The crude 2- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-7-one (also known as 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one ) (Hexahydro-4- (5-methoxyheptyl) -2 (1H) pentalenone) is chromatographed on silica gel and then distilled in a Kugelrohr oven in vacuo to give the product as a clear, colorless oil (0.089 mol).

EXAMPLE III

The ethoxyheptylbicyclooctanone prepared in EXAMPLE III is incorporated into a composition in an amount (total weight of the composition) of from about 0.001% to about 10% by weight. The composition (eg, a lotion) is formulated for application to a human's skin and can then be applied to the skin to improve the appearance of the skin, for example, by reducing the appearance of wrinkles.

Claims (2)

A process for producing 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one comprising: Removal of Chloro atoms from 6,6-dichloro-6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one to give 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0 ] octan-3-one. Adding ether to the 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one to form a solution, Filtering the solution to form a filtrate, Removing the solvent from the filtrate to form a residue of 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one, Dilute the residue with ether, Treating the diluted residue with a sodium bicarbonate solution, separating the ether layer thereof, and removing the solvent from the ether layer; thus recovering 6- (5-ethoxyhept-1-yl) bicyclo [3.3.0] octan-3-one therefrom. 2. The method of claim 1, wherein treating the diluted residue with a sodium bicarbonate solution comprises dropwise adding the diluted residue to the sodium bicarbonate solution.