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WO1998048811A1 - Procede de fixation de parfums dans des produits parfumes et autres - Google Patents

Procede de fixation de parfums dans des produits parfumes et autres Download PDF

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Publication number
WO1998048811A1
WO1998048811A1 PCT/US1998/008826 US9808826W WO9848811A1 WO 1998048811 A1 WO1998048811 A1 WO 1998048811A1 US 9808826 W US9808826 W US 9808826W WO 9848811 A1 WO9848811 A1 WO 9848811A1
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Prior art keywords
alpha
beta
group
pheromone
fragrance
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PCT/US1998/008826
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English (en)
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Clive Jennings-White
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Human Pheromone Sciences, Inc.
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Application filed by Human Pheromone Sciences, Inc. filed Critical Human Pheromone Sciences, Inc.
Priority to AU72738/98A priority Critical patent/AU7273898A/en
Publication of WO1998048811A1 publication Critical patent/WO1998048811A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q13/00—Formulations or additives for perfume preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/63—Steroids; Derivatives thereof

Definitions

  • This invention is generally related to the fields of personal care products, cosmetics and fragrances and to compositions of matter used in consumer products. More specifically, the invention pertains to a method of fixing fragrance in fragrance compositions and personal care products containing such fragrance compositions.
  • the present invention relates to cosmetics, particularly fragrances, and to compositions of matter which contain human pheromones and which are useful in the manufacture of consumer products .
  • Pheromones are chemicals produced by an animal or individual which elicits a specific physiological or behavioral response in another member of the same species .
  • the human pheromones referred to in this invention include certain 16-Androstene and/or Estrene steroids, some of which occur naturally in humans.
  • the steroid class of Androstenes are typified by testosterone, and are characterized by a 4 -ring steroid structure with methylations at the 13 -position and at the 10- position. 16-Androstenes are further characterized by a double bond at the 16- position. Some members of this group have been reported to act as pheromones in some mammalian species-for instance, 5 alpha -Androst-16-en-3 alpha -ol and 5 alpha -Androst-16-en-3-one in pigs (Melrose, D. R. , et al . , Br . vet. J. (1971) 127:497-502).
  • Androstenol (5 alpha -Androst-16-en-3 alpha -ol) has been claimed to exhibit a pheromone-like activity in a commercial men's cologne and women's perfume (Andron TM for Men and Andron TM for Women by Jovan) .
  • Japanese Kokai No. 2295916 refers to perfume compositions containing Androstenol and/or its analogue.
  • 5,16- Androstadien-3 beta -ol (and perhaps the 3 alpha -ol) has also been identified in human axillary secretion (Gower, et al., Supra at 57-60.
  • Estrene steroids are typified by 17 beta -Estradiol (1, 3 , 5 (10) -Estratrien-3 , 17 beta -diol) , and usually have a phenolic 1,3,5(10) A-ring and a hydroxy or hydroxy derivative, such as an ether or ester, at the 3- position.
  • the human pheromones described in this application have been referred to in applicant's U.S. Ser. No. 07/707,862, filed May 31, 1991, U.S. Ser. No. 07/708,936, filed May 5, 1991, both abandoned, P.C.T. application No. PCT/US92/00219, filed Jan. 7, 1991, and P.C.T. application No.
  • the subject invention is effective because it delivers a much larger amount of the active pheromone steroids to the skin than is normally present.
  • VNO vomeronasal organ
  • VNO receptor epithelium A pheromone-specific change in the electrical potential of VNO receptor epithelium can be measured as described by Monti-Bloch, L., et al . (J. Steroid Biochem. and Molec. Biol. (1991) 39:573). This receptor binding activity is an essential characteristic of an active pheromone.
  • compositions of many commercial perfumes and fragrances contain natural mammalian pheromones. Since pheromones are generally species specific, the natural mammalian pheromones found in commercial perfumes do not function as a pheromone, but instead provide a fixative note in the overall composition of the fragrance. Thus these perfumes, personal care products and cosmetics do not bind to pheromone receptors in the VNO and do not stimulate the vomeronasal nerve which communicates with the hypothalamus of the brain. Furthermore, in some cases the use of natural animal pheromones, or synthetics related to animal pheromones, may cause skin irritations or allergic responses in some individuals. Still further, since the source of animal pheromones used in fragrances are the anal glands of the contributing animal some individuals find it objectionable to use these substances .
  • the invention provides a method for fixing fragrance in non- herapeutic, fragrance compositions containing a perfumery odorant, by adding a human pheromone which serves as a fixative.
  • the fixatives include steroidal compounds having human pheromone activity such as Androsta-4, 16-dien-3-one, Androsta-4 , 16-dien-3 alpha -ol, Androsta-4 , 16-dien-3 beta -ol, 19-nor-4,16- Androstadien-3-one, 19-nor-10-OH-4 , 16-Androstadien -3one, 19-OH- , 16-Androstadien-3-one 1,3,5(10) ,16- Estratetraen-3-ol methyl ether, 1, 3 , 5 (10) , 16-Estratetraen -3-yl acetate, 1, 3 , 5 (10) , 16-Estratetraen-3-yl propionate, 1, 3 , 5 (10) , 16-Estratetraen-3-ol, and any combinations thereof .
  • steroidal compounds having human pheromone activity such as Androsta-4, 16-dien-3-one, Andros
  • FIG. 1 schematically illustrates the synthesis of 10 -hydroxy-4 , 16-estradien-3-one .
  • FIG. 2 schematically illustrates the synthesis of Androsta- , 16-dien-3-one, Androsta-4 , 16-dien-3 alpha -ol, and Androsta-4 , 16-dien-3 beta -ol.
  • FIG. 3 schematically illustrates the synthesis of 19-nor 4 , 16-Androstadien-3-one .
  • FIG. 4 schematically illustrates syntheses of 19-OH-Androst- 4 , 16-dien-3-one .
  • FIG. 5 schematically illustrates an alternate synthesis of 19-OH-Androsta-4 , 16-dien-3 -one .
  • FIG. 6 schematically illustrates synthesis of 1, 3, 5 (10) , 16-Estratetraen-3-ol.
  • FIG. 7 schematically illustrates an alternate synthesis of Androsta- , 16-dien-3-one .
  • an "environmental fragrance” is a fragrance or odor which is used to odorize a volume of air rather than an individual or object.
  • the source of the environmental fragrance may be an object, for example an object composed to gradually release a fragrance into the adjacent air.
  • odor is any scent or smell, whether pleasant or offensive. An odor is consciously perceived by an individual when odorant molecules bind to the olfactory epithelium of the nasal passage.
  • a "perfumery odorant” is an odorant used for the principal purpose of providing a odor.
  • a “scent” is the odor left behind by an animal or individual. People use perfumes to augment their natural scent .
  • perfumes are mixtures of a variety of substances, and may include natural materials of vegetable or animal origin, wholly or partly artificial compounds, or mixtures thereof. Dissolved in alcohol, these mixtures of various volatile fragrant substances release their scents into the air at normal temperatures. The tinct-the mixture which contains the highest proportion of fragrance concentrate and the least possible alcohol-is called perfume. Mixtures of lower concentration include eau de perfume, after shave, eau de toilette, eau de sport, splash cologne, eau de cologne, cologne, eau fraiche, and the like.
  • fragrance solutions which are diluted with alcohol
  • compact and cream perfumes are produced by mixing up to 25% fragrance oil with solids such as paraffin or other waxes.
  • fragrance oil solids such as paraffin or other waxes.
  • a "pheromone” is a chemical secretion which elicits a specific physiological or behavioral response in another member of the same species.
  • pheromones can be identified by their species specific binding to receptors in the vomeronasal organ (VNO) .
  • VNO vomeronasal organ
  • Human pheromones induce a change of at least about - 5 millivolts in human neuroepithelial tissue of the appropriate sex (The binding of pheromones is generally gender specific) .
  • Naturally occurring human pheromones induce gender specific changes in receptor binding potential in vivo in the human VNO.
  • Naturally occurring human pheromones can be extracted and purified from human skin and they can also be synthesized, as described herein.
  • “Human pheromones” are pheromones which are effective as a specifically binding ligand in human VNO tissue, regardless of how the pheromone was obtained. Thus, both a synthesized and purified substance may be considered a human pheromone.
  • “Gender specific” refers to a difference in the effect of, or response to, a compound or composition between males and females of the same species.
  • tissue paper is a soft, fibrous, absorbent paper such as the type commonly used as a disposable handkerchief or as toilet paper.
  • the "vomeronasal organ” is a cul-de-sac which opens to the nasal passage in humans and contains specialized receptor cells for pheromones.
  • a “fixative” or fixing agent is an agent which prolongs the odor of a fragrance when placed on a substrate, such as skin, paper and the like.
  • a perfumer will typically have numerous oils, isolates, and tinctures from a variety of natural sources within each category. The perfumer will also have a vast array of artificial odorants and synthetics of naturally occurring compounds.
  • the art of perfumery involves the mixing of these various materials to produce a finished fragrance . While there are many subjective approaches to the formulation of a perfume, most seem to incorporate the notion of top notes, middle notes and base notes. Top notes are very volatile and lack tenacity, or staying power. Middle notes are somewhat lower in volatility and are used as modifiers of the top notes. Base notes are still lower in volatility and are long-lasting in odorous effect. Base notes are also referred to as fixatives of the fragrance. Notes of animal origin, or artificials which mimic animal notes, are usually base notes.
  • ambergris-a regurgitated or excreted material obtained from sperm whales The first three are pheromones for the species of origin, but since pheromones are species specific, they do not induce any pheromone-related behavior in humans.
  • Animal notes are used as a fixative for the perfume fragrance . As a concentrate the odor of animal notes may not be pleasing, but when diluted, they contribute to the fragrance of the final product.
  • human pheromones or analogs thereof are used instead of, or in addition to animal pheromones, or their derivatives or homologues .
  • human pheromones have several advantages .
  • Perfumed products that do not contain human pheromones do not stimulate VNO receptors since an odorant which is not a pheromone for humans stimulates only the olfactory receptors of the nose.
  • Fragrance compositions which are both pleasant smelling and also contain human pheromones will stimulate both olfactory receptors, and pheromone receptors in the VNO of individuals.
  • Such a fragrance composition provides a broader olfactory stimulation than previously possible.
  • pheromones may or may not have a detectable odor. Since they bind to receptors which are physically and functionally distinct from olfactory receptors, they may or may not carry their own smell. However, some of the pheromones described herein do in fact have an odor. As a concentrate, the odor of these pheromones may not necessarily be pleasant. Thus, when diluted in a perfume the practical upper concentration limit is determined by the pleasantness of the resulting fragrance.
  • human pheromones are present in the fragrance composition as a fixative of the subject invention at a concentration of no more than about 200 mu g/ml, more commonly no more than about 100 mu g/ml, preferably no more than about 50 mu g/ml, and more preferably no more than about 25 mu g/ml.
  • human pheromones are present in the fragrance composition of the subject invention at a concentration of at least about 50 ng/ml , but it will depend upon the concentration of fragrant substances present. There is a direct effect on prolonged smell related to the pheromone concentration, because the more fixative used, in general, the longer the fragrance persists .
  • Perfumes are commonly used per se as a personal care product. However, odours can be used in a variety of personal care products, household products and industrial products. The use of human pheromones per se, or perfumes containing human pheromones in these other products falls within the scope of the subject application. 1. Personal Care Products
  • Fragrances containing human pheromones can be used in the preparation of cosmetics, make-up preparations, toilet and beauty preparations, bath and beauty soaps, bath oils, face and body creams and oils, underarm deodorants and the like.
  • the preparations of these personal care products are known to those skilled in the art. These products frequently contain a fragrance.
  • a human pheromone or a fragrance containing human pheromones is added to these products in the same way that fragrance per se may be added.
  • Pheromones or fragrances containing human pheromones may also be used as environmental odorants as in air fresheners and the like.
  • the fragrance and pheromone can be dispensed into the air by use of an aerosol dispenser, or by preparations of liquid, gel or solid compositions containing fragrance and pheromone which slowly release the pheromone, or fragrance and pheromone, into the air by exposure of the composition to the atmosphere .
  • the active ingredient is preferably supplied in a liquid or finely divided form along with a surfactant and a propellant.
  • Typical percentages of active ingredients are 0.001 to 2% by weight, preferably 0.004 to 0.10%.
  • Surfactants must, of course, be nontoxic, and preferably soluble in the propellant.
  • Representative of such agents are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, olestearic and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride such as, for example, ethylene glycol, glycerol, erythritol, arabitol, mannitol, sorbitol, and hexitol anhydrides derived from sorbitol (the sorbitan esters sold under the trademark "Spans”) and the polyoxyethylene and polyoxypropylene derivatives of these esters.
  • an aliphatic polyhydric alcohol or its cyclic anhydride such as, for example, ethylene glycol, glycerol, erythritol, arab
  • the preferred surface-active agents are the oleates or sorbitan, e.g., those sold under the trademarks "Arlacel C” (sorbitan sesquioleate) , "Span 80” (sorbitan monoleate) and “Span 85” (sorbitan trioleate) .
  • the surfactant may constitute 0.1-20% by weight of the composition, preferably 0.25-5%.
  • the balance of the composition is ordinarily propellant. Liquefied propellants are typically gases at ambient conditions, and are condensed under pressure.
  • suitable liquefied propellants are the lower alkanes containing up to five carbons, such as butane and propane; fluorinated or fluorochlorinated alkanes, such as are sold under the trademark "Freon” . Mixtures of the above may also be employed.
  • a container equipped with a suitable valve is filled with the appropriate propellant, containing the finely divided active ingredient and surfactant .
  • the ingredients are thus maintained at an elevated pressure until released by action of the valve.
  • An alternative means of releasing fragrance and pheromone into a designated air space is by means of gradual evaporation and release into the atmosphere from a liquid, semi-solid or solid composition containing or a fragrance and pheromone.
  • a fragrance containing a human pheromone may be incorporated into the composition in a variety of ways depending on the nature of the composition.
  • the composition is a liquid, gel, cream or ointment, and the pheromone ingredient is soluble in the composition it can simply be dissolved in the composition. If the pheromone ingredient is slightly soluble or insoluble in the composition, a suspension can be prepared by addition and mixing. In some cases such as room odorants, car odorants and the like, the composition containing pheromone is applied in a liquid state and remains liquid during evaporation. In other cases, such as paints and the like, the composition containing pheromone is applied as a liquid and then solidifies, leaving the pheromone to slowly evaporate from the solid.
  • the pheromone ingredient can be added by first melting the solid up to a maximum temperature of 100 degrees C, preferably 75 degrees C, more preferably 50 degrees C, adding the pheromone ingredient and then allowing the mixture to cool and solidify. This approach may be used with wax or resin for example.
  • the pheromone ingredient may first be mixed in a volatile solvent such as ethanol, dimethyl sulfoxide or the like, and then mixed with an absorbent solid composition such as tissue paper, cloth and the like. The solvent then evaporates leaving the pheromone residue in the solid composition, from which the pheromone slowly evaporates into the atmosphere .
  • a volatile solvent such as ethanol, dimethyl sulfoxide or the like
  • an absorbent solid composition such as tissue paper, cloth and the like.
  • the solvent then evaporates leaving the pheromone residue in the solid composition, from which the pheromone slowly evaporates into the atmosphere .
  • This mixture includes other products such as fibrous materials which will absorb pheromones with fragrances. For instance, cloth, papers (including tissue papers) , clothing, paper towels, stationery and the like.
  • human pheromones generate a change in receptor potential in the VNO of human subjects .
  • 16-Androstene steroids are aliphatic polycyclic hydrocarbons characterized by a four-ring steroidal structure with a methylation at the 13- position, and a double bond between the 16- and 17- positions.
  • Androstene steroid is commonly understood to mean that the compound has at least two methylations, at the 13-position and the 10- position, thereby creating 18- position and 19- position carbons respectively. Unless a compound is explicitly described as "19-nor” it is understood that the compound does have a 19- carbon group. However; it is intended that 19-nor-16-Androstenes are generally regarded as 16 -Androstene steroids for the purpose of the present invention.
  • Estrene steroids are aliphatic polycyclic hydrocarbons with a four-ring steroidal structure, usually an aromatic 1,3,5(10) A-ring, a methylation at the 13 -position and a hydroxyl at the 3 -position. In describing the location of groups and substituents of 16-Androstene and Estrene steroids, the following numbering system will be employed.
  • the invention is directed to fragrance compositions containing a human pheromone which may be included in a group known as Androstene steroids of which testosterone (17-hydroxy-4-androstene-3-one) is an example, and to combinations of Androstene and Estrene steroids. Specifically included are those steroids disclosed in the U.S. patent application Ser. No. 07/903,604 filed Jun. 24, 1992, the entirety of which is incorporated by notice. 16 -Androstenes are further characterized by a double bond at position 16-.
  • the 16 -Androstenes of this invention have the formula : I
  • Rl is selected from the group consisting of oxo, alpha -( beta -)hydroxy, alpha -( beta -) acetoxy, alpha -( beta -) propionoxy, alpha -( beta -)methoxy, alpha -( beta -) lower acyloxy, alpha -( beta -) lower alkyloxy, and alpha -( beta -) benzoyloxy;
  • R2 is selected from the group consisting of hydrogen, hydroxy, acyl, acyloxy, alkoxy, methyl, hydroxymethyl , acylmethyl, acyloxymethyl, alkoxymethyl, lower alkyl, hydroxyalkyl, acylalkyl, acyloxyalkyl, and alkoxylalkyl ; and "a" and "b" are alternative sites for an optional double bond.
  • Estrenes Useful in Conjunction with the Invention is additionally directed to fragrance compositions containing a human pheromone which may be included in a group of Estrene Steroids, or to combinations of Estrene and 16 -Androstene steroids.
  • Estrenes are structurally similar to
  • Estradiol also referred to as 1 , 3 , 5 (10) -Estratriene-3 , 17 beta -diol
  • Estradiol are distinguished from Estradiol by the double bond at the 16 -position.
  • R4 is selected from the group consisting of hydrogen, and alkyl
  • R6 is selected from the group consisting of hydrogen, lower alkyl, lower acyl, benzoyl, cypionyl, acetyl, glucuronide, propionyl, and sulfate
  • "c" is an optional double bond
  • Estrenes can be distinguished from each other by variations at the 3 -position, variations at the 17-position and variations at the 16-position, with an optional double bond at the 16 -position.
  • Preferred embodiments include 1, 3 , 5 (10) , 16-Estratetraen-3-ol, available from Research Plus, Inc. and from Steraloids, Inc .
  • the compounds used in the methods of the present invention are 16 -Androstene steroids substituted at the 3-, 5-, and 19-positions .
  • Many of the 3- and 5- substituted steroids are known compounds which may be derived from 17-hydroxy-and 17-oxosteroids (commercially available e.g. from Aldrich Chemical Co) by elimination or reduction to the DELTA 16 homologue. The syntheses of most of these compounds are described by Ohloff (supra) .
  • Alkoxy derivatives are prepared from their corresponding hydroxy steroids by reaction with an alkylating agent such as trimethyloxonium fluoroborate, triethyloxonium fluoroborate or methylfluorosulfonate in an inert chlorocarbon solvent such as methylene chloride .
  • alkylating agents such as alkyl halides, alkyl tosylates, alkyl mesylates and dialkylsulfate may be used with a base such as silver oxide or barium oxide in polar, aprotic solvents as for example, DMF, DMSO and hexamethylphosphoramide .
  • EXAMPLE 1 Estra-4, 16-dien-10j ⁇ -ol-3-one, 4
  • DME 2-dimethoxyethane
  • MCPBA 189.8 MG, 1.100 mmol
  • Androsta-4 , 16-dien-3-one This synthesis is depicted in FIG. 2.
  • Several methods are known for the conversion of testosterone into Androsta-4 , 16-dien-3-one (Brooksbank et al . , Biochem. J. (1950) 47:36).
  • thermolysis (460o) of the methyl carbonate of testosterone gives Androsta-4 , 16- dien-3-one in 90% yield.
  • 17 beta -Methoxycarbonyloxy- androst-4-en-3-one (IV) was prepared from testosterone (III. Fluka) with methyl chloroformate/pyridine (a) in 76% yield (after recrystallization from MeOH) . M.p.
  • 19-Nortestosterone (XIX) is commercially available, e.g. from Chemical Dynamics Corp. It provides the starting material for 19-Nor-16-androsten derivatives.
  • 19-Nor- testosterone (XIX) (Chemical Dynamics Corp.) was converted into the known acetate (Hartman, J. A. et al . , J. Am. Chem. Soc. (1956) 78:5662) with acetanhydride and pyridine (a) .
  • Androsta-4 , 16-dien-19-ol-3-one , 19 Refer to Figure 5.
  • Anh. Amonia (ca. 75 mL) was distilled through a KOH tower into a 250 mL flame-dried 3 -neck flask fitted with an inlet adapter, a magnetic stirring bar, a dry ice/acetone condenser, and a stopper.
  • the intermediate ketal proved remarkably unreactive, but was finally hydrolyzed by refluxing 18 h in 5 L of chloroform and 2.5 mL of 4 N hydrochloric acid.
  • ethyl acetate 50 mL was added and the layers were separated.
  • the organic phase was washed with 25 mL of saturated sodium bicarbonate + 25 mL of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 mL of ethyl acetate and the combined filtrates were concentrated under reduced pressure.
  • Residue was taken up in 10 L of hot benzene and the cooled suspension was filtered. The filtrate was concentrated under reduced pressure and then flash chromatographed (40% ethyl acetate/hexanes on silica gel) to give an opaque resin (0.69 g, 1.6 mmol, 87%).
  • Androsta-5 , 16-dien-3ff, 19-diol, 3 Refer to Figure 6.
  • Tetrahydrofuran (THF, 35 mL) was cooled in an ice/acetone bath under argon and n-butyllithium (2.6 M in hexanes, 3.7 mL, 9.3 mmol) was added dropwise, with stirring, over the period of 1 min.
  • the reaction mixture was stirred 4 days, during which time it was allowed to gradually warm to room temperature.
  • the reaction was then poured into 50 mL of ice-saturated ammonium chloride and the layers were separated. The aqueous layer was extracted twice with 25 mL portions of ethyl acetate. The combined organic phases were washed with 25 mL of saturated sodium bicarbonate + 25 L of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 mL of ethyl acetate and the combined filtrates were concentrated under reduced pressure.
  • the residual yellow resin was flash chromatographed (50-55-60% ethyl acetate/hexanes on silica gel) and crystallized from methyl t-butyl ether/benzene to give fluffy white crystals (92.5 mg, 0.361 mmol, 24%), m.p. 169-171°C.
  • EXAMPLE 7 Alternate synthesis of Androsta-4 , 16-dien-3-one (25) The following method of synthesis is depicted in FIG. 7: Dehydroepiandrosterone p-Toluenesulfonylhydrazone (23)
  • Dehydroepiandrosterone (VII) (14.4 g, 50.0 m mole) and p-toluenesulfonylhydrazide (12.75 g, 68.5 m mole) in dry methanol (300 ml) were heated under reflux for 20 hours. The mixture was transferred to a conical flask and allowed to cool. The crystalline product was filtered off under suction and washed with methanol (50 ml) . Further crops of product were obtained by sequentially evaporating the filtrate to 75 ml and 20 ml, and allowing to crystallize each time. Total yield was 21.6 g (95%) .
  • EXAMPLE 8 Synthesis of Estra-1, 3 , 5 (10) , 16-tetraen-3-ol (28) The following method of synthesis is depicted in FIG. 6:
  • Estrone p-Toluenesulfonylhydrazone Estrone (26) (270 g, 1.00 mole) and p-toluenesulfonylhydrazide (232.8 g, 1.25 mole) in dry methanol (2.5 liters) were heated under reflux for 20 hours. The mixture was transferred to a conical flask and allowed to cool. The crystalline product was filtered off under suction and washed with methanol (300 ml) . Further crops of product were obtained by sequentially evaporating the filtrate to 2000 ml, 800 ml and 400 ml, and allowing to crystallize each time. Total yield was 433.5 g (99%) .
  • Estrone p-toluenesulfonylhydrazone (219.0 g, 500 m mole) in dry tetrahydrofuran (8.0 liters) was cooled in a sodium chloride/ice bath. The mixture was mechanically stirred while n-butyl lithium (800 ml of a 2.5M solution in hexane, 2.00 mole) was added via double-ended needle. The mixture was stirred at room temperature for 3 days. Ice (250 g) was added, followed by saturated ammonium chloride solution (500 ml) . The phases were mixed by stirring and then allowed to settle.
  • n-butyl lithium 800 ml of a 2.5M solution in hexane, 2.00 mole
  • the aqueous phase was removed via aspiration with teflon tube and extracted with ether (500 ml) .
  • the two organic phases were sequentially washed with the same batch of saturated sodium bicarbonate solution (500 ml) followed by saturated sodium chloride solution (500 ml) .
  • the organic layers were dried (MgS04) and evaporated in vacuo to give crude product. This was subjected to flash filtration on 500 g silica gel 60, 230-400 mesh, eluting with ethyl acetate/hexane (25:75, 2.5 liters). The filtrate was evaporated in vacuo to give crystalline material.
  • FIXATIVE EFFECT OF ESTRATETRAENOL Three 10% solutions of cineole in ethanol were prepared, containing, respectively, 0.1%, 1.0% and 10.0% by weight of estra-1 3 , 5 (10) , 16-tetraen-3-ol . Each sample was placed on a perfurmer's smelling strip and allowed to evaporate. The time required to fall below olfactory threshold was measured;
  • EXAMPLE 10 FIXATIVE EFFECT OF ANDROSTADIENONE
  • Four solutions were prepared containing the same level of fragrances as the product RealmTM.
  • the samples contained respectively, 8 ⁇ g/ml, 12 ⁇ g/ml, 16 ⁇ g/ml and 0 (control) of androsta-4 , 16-dien-3-one .
  • the samples were placed on human skin and testers were asked to estimate the length of time the fragrances could be detected by smell.
  • the sample containing 16 ⁇ g/ml of the androstadienone lasted the longest according to all testers.

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Abstract

L'invention porte sur un fixateur de parfums et autres substances odoriférantes isolées dans des produits parfumés et autres produits d'hygiène et de beauté. Ces fixateurs prolongent la présence du parfum sur la peau. Il existe une proportionnalité entre la persistance et la concentration de fixateur dans une quantité donnée de composants parfumés.
PCT/US1998/008826 1997-04-30 1998-04-30 Procede de fixation de parfums dans des produits parfumes et autres WO1998048811A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007139782A3 (fr) * 2006-05-23 2008-01-24 Philip Y Braginsky Composition d'enrobage contenant un composant à base de phéromone humaine
JP2008156467A (ja) * 2006-12-22 2008-07-10 Lion Corp 対男性好感度向上剤
WO2008138651A3 (fr) * 2007-05-14 2009-06-11 Henkel Ag & Co Kgaa Agents cosmétiques contenant des phéromones
US9642850B2 (en) 1997-02-24 2017-05-09 Purdue Pharma L.P. Method of providing sustained analgesia with buprenorphine

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US5272134A (en) * 1992-03-24 1993-12-21 Erox Corporation Fragrance compositions and other compositions which contain human pheromones
US5278141A (en) * 1992-03-24 1994-01-11 Erox Corporation Fragrance compositions containing human pheromones

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
US5272134A (en) * 1992-03-24 1993-12-21 Erox Corporation Fragrance compositions and other compositions which contain human pheromones
US5278141A (en) * 1992-03-24 1994-01-11 Erox Corporation Fragrance compositions containing human pheromones

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9642850B2 (en) 1997-02-24 2017-05-09 Purdue Pharma L.P. Method of providing sustained analgesia with buprenorphine
WO2007139782A3 (fr) * 2006-05-23 2008-01-24 Philip Y Braginsky Composition d'enrobage contenant un composant à base de phéromone humaine
JP2008156467A (ja) * 2006-12-22 2008-07-10 Lion Corp 対男性好感度向上剤
WO2008138651A3 (fr) * 2007-05-14 2009-06-11 Henkel Ag & Co Kgaa Agents cosmétiques contenant des phéromones

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