US20110082204A1 - N-alkylcarbonyl-amino acid ester and N-alkylcarbonyl-amino lactone compounds and their use - Google Patents
N-alkylcarbonyl-amino acid ester and N-alkylcarbonyl-amino lactone compounds and their use Download PDFInfo
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- US20110082204A1 US20110082204A1 US12/928,184 US92818410A US2011082204A1 US 20110082204 A1 US20110082204 A1 US 20110082204A1 US 92818410 A US92818410 A US 92818410A US 2011082204 A1 US2011082204 A1 US 2011082204A1
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- 0 [1*]C(C(=O)C[2*])N([H])C(=O)[C@@H]1C[C@H](C)CC[C@H]1C(C)C Chemical compound [1*]C(C(=O)C[2*])N([H])C(=O)[C@@H]1C[C@H](C)CC[C@H]1C(C)C 0.000 description 5
- XKZFMXOKCQATDH-FVCCEPFGSA-N [H]N(C(=O)[C@@H]1C[C@H](C)CC[C@H]1C(C)C)[C@H](C)C(=O)OC Chemical compound [H]N(C(=O)[C@@H]1C[C@H](C)CC[C@H]1C(C)C)[C@H](C)C(=O)OC XKZFMXOKCQATDH-FVCCEPFGSA-N 0.000 description 1
- VJKCLYOUWLDAPV-APIJFGDWSA-N [H]N(C(=O)[C@@H]1C[C@H](C)CC[C@H]1C(C)C)[C@H](C)C(=O)OC(C)C Chemical compound [H]N(C(=O)[C@@H]1C[C@H](C)CC[C@H]1C(C)C)[C@H](C)C(=O)OC(C)C VJKCLYOUWLDAPV-APIJFGDWSA-N 0.000 description 1
- KLOKSRAWLQVZFV-YIYPIFLZSA-N [H]N(C(=O)[C@@H]1C[C@H](C)CC[C@H]1C(C)C)[C@H](C)C(=O)OCC Chemical compound [H]N(C(=O)[C@@H]1C[C@H](C)CC[C@H]1C(C)C)[C@H](C)C(=O)OCC KLOKSRAWLQVZFV-YIYPIFLZSA-N 0.000 description 1
- WEHTUCYLMXHUMA-HZSPNIEDSA-N [H]N(CC(=O)OC(C)C)C(=O)[C@@H]1C[C@H](C)CC[C@H]1C(C)C Chemical compound [H]N(CC(=O)OC(C)C)C(=O)[C@@H]1C[C@H](C)CC[C@H]1C(C)C WEHTUCYLMXHUMA-HZSPNIEDSA-N 0.000 description 1
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Definitions
- This application is related to:
- the present invention generally relates to refreshing, soothing, and cooling compounds that affect sensory processes. More particularly, the present invention pertains to certain N-alkylcarbonyl-amino acid ester and N-alkylcarbonyl-amino lactone compounds; compositions and articles comprising such compounds; and methods of treatment, for example, methods of alleviating the discomforts of irritation, itch, and pain on the skin and on the ocular surface.
- Menthol and menthol-like compounds are used in toiletries, confectionery, comestibles, and over-the-counter medications as ingredients to refresh, cool, flavor, counter-irritate, and anesthetize the skin and mucous membranes of the mouth and upper airways.
- Menthol's utility in relief of sensory discomfort is, however, limited by its short duration of action and by its multimodal actions on sensory processes—including odor, harshness of taste, and irritation.
- the unpleasant effects of menthol can be easily experienced, for example, when menthol-containing ointments are brought near the eye surface. The menthol vapors hurt the eye and causes tearing.
- One aspect of the present invention pertains to certain N-alkylcarbonyl-amino acid ester compounds, as described herein.
- compositions comprising such a compound and a delivery vehicle (e.g., for delivering the compound to a human).
- a delivery vehicle e.g., for delivering the compound to a human.
- the delivery vehicle is a towelette.
- the compound is present in the composition in an amount of 0.02 to 0.2% wt/vol (0.2 to 2 mg/ml).
- Another aspect of the present invention pertains to use of such a compound in the manufacture of a medicament for use in a method of treatment.
- the treatment is the relief of (e.g., alleviation of) ocular irritation, itch, and/or pain (e.g., wherein the contacting delivers an amount of the compound that is therapeutically effective for alleviation of irritation, itch, and/or pain).
- the treatment is treatment to increase alertness, or to decrease sleepiness and fatigue (e.g., wherein the contacting delivers an amount of the compound that is effective to increase alertness, or to decrease sleepiness and fatigue).
- FIG. 1 is a bar graph showing duration of cooling (hours) for eight compounds (in order): D -Ala-OEt, D -Ala-OMe, D -Hsl, Sar-OEt, WS-5, WS-12, WS-3, and ( ⁇ )-menthol.
- a class of compounds that is suitable to be used as an active ingredient in (e.g., pharmaceutical) preparations for use on the skin of the eyelids and on the ocular surface has been found.
- These compounds are suitable, for example, for use as agents to reduce discomfort such as itch, a sense of dryness and irritation, and pain.
- the compound is selected from compounds of Formula (1):
- the menthyl group i.e., the 5-methyl-2-(1-methylethyl)cyclohex-1-yl group
- the ⁇ -carbon between the —NH— group and the —C( ⁇ O)OR 2 group, has the same stereochemistry as found in D -alanine. This is also known as the R-configuration, according to the Cahn-Ingold-Prelog nomenclature system. Except for glycine, all ⁇ -amino acids have a chiral center at the ⁇ -carbon. Although amino acids of the D -configuration are found in some antibiotics and in cell membranes of microorganisms, the amino acids of proteins are (almost) exclusively of the L (or S configuration).
- R 2 is independently methyl, ethyl, or isopropyl
- the isopropyl ester and the D -configuration have the effect of increasing potency and duration of action, and of producing a selective refreshing coolness near or on the ocular surface with the absence of tissue irritation.
- NACE compounds are “long-acting” NACE compounds that, when applied to the skin or mucous membranes, produce refreshing, soothing, and cooling sensations without skin irritation, with minimal eye irritation, and with a duration of action on skin that lasts more than about 1 hour when used at 0.20 to 2.0 mg/ml or less.
- the long-acting NACE compounds are distinguished from other N-alkylcarbonyl-amino acid esters (e.g., WS-5, see FIG. 1 ) and N-alkyl substituted carboxamides (e.g., WS-3, WS-12, WS-23; see FIG. 1 ) (WS-23 is N-2,3-trimethyl-2-isopropylbutanamide), which are known to have cooling properties and the two (WS-3 and WS-23) that are commercially used in comestibles, confectionery, and toiletries.
- N-alkylcarbonyl-amino acid esters e.g., WS-5, see FIG. 1
- N-alkyl substituted carboxamides e.g., WS-3, WS-12, WS-23; see FIG. 1
- WS-23 is N-2,3-trimethyl-2-isopropylbutanamide
- WS-3, WS-5, WS-12, WS-23 and WS-31 have a short duration of action (less than 1 hour) on the philtrum skin or slow onset (more than 5 minutes). Also, some of these compounds do not achieve significant cooling but rather produce skin sensations of tingling, burning, and irritation, effects similar to those observed with ( ⁇ )-menthol, a compound with multimodal actions of sensory processes.
- the preferred long-acting NACE compounds deliver a perfect cooling sensation, with rapid onset, long duration of action, and minimal skin or eye irritation that has not been previously recognized.
- the potency, duration, and selectivity (absence of irritation) of action are increased for the compounds of Formula 1, with R 1 ⁇ H, or C wherein the ⁇ -carbon is in the D -configuration, and R 2 is isopropyl.
- the compounds, compositions, and articles may be used to inhibit the perception of itch, pain, and discomfort from the skin and the mucous membranes of the eyelids and ocular surface.
- the compound is carried on a towelette adapted for, or of sufficient construction for, the delivery of a therapeutically effective dose.
- an effective amount pertains to that amount of an active compound, or a material, composition or dosage form comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
- Noxious stimuli from the skin are thought to be transmitted by unmyelinated C fibers and thinly myelinated A ⁇ fibers, together functionally called polymodal fibres.
- Noxious stimuli produce sensory discomforts on the skin and in the mucous membranes, discomforts which are ameliorated by cooling (vide infra). Cooling of the facial skin and mucous membranes is detected by a subset of primary sensory afferents that have receptors on nerve endings. These sensory fibers exhibit a rhythmic, ongoing discharge at neutral temperatures that increases in response to skin temperature cooling (step reductions from 33 to 23° C.) and are suppressed by warming.
- the dynamic information is propagated along axons in spike trains, at about 20 to 40 impulses/sec, to central neurons, leading to cooling sensations. This type of sensation is mimicked by facial exposure to air or water temperatures of 15 to 22° C.
- the primary afferents from facial skin terminate in the superficial layer of the caudal trigeminal nucleus where they represent over 95% of the thermoceptive input (see, e.g., Hutchinson et al., J. Neurophysiol., 77:3252-3266, 1997).
- Sensations can be “confusing” when a chemical affects more than one sensory modality. This is especially true for ( ⁇ )-menthol (also known as L -menthol, (1 R)-menthol, and (1 R,2S,5R)-menthol).
- ( ⁇ )-Menthol is widely used as a cooling agent but it has multimodal action on sensory processes. For example, in the upper airways and oral cavity, ( ⁇ )-menthol can elicit cooling, irritation, tingling, minty flavor, and bitter taste. Especially around the eyes, menthol is an irritant and elicits sensations of burning, stinging, and pain.
- the peripheral ( ⁇ )-menthol coolness receptor is thought to be a protein called TRP-M8.
- TRP-M8 The peripheral ( ⁇ )-menthol coolness receptor is thought to be a protein called TRP-M8.
- TRP-M8 the potency of compounds that activate TRP-M8 is not correlated to cooling actions (see, e.g., A. K. Vogt-Eisele, D. Bura, H. Hatt, and E. T. Wei. N-Alkylcarboxamide Cooling Agents: Activities on Skin and Cells with TRPM8 and TRPA1 Receptors. 3rd Annual Workshop on the Study of Itch, Sep. 25 to 27, 2005 in Heidelberg, Germany. Acta Dermato-Venereological 85: pg.468, 2005).
- TRP-M8 is activated by mustard oil, an agent that produces the pungent sensations of wasabi.
- the compounds of the present invention should not be viewed as solely acting via TRP-M8 receptors.
- menthol preparations such as confectionery
- menthol compositions cannot be applied to facial skin in effective concentrations to arouse because it causes eye irritation (stinging, smarting, tearing, and pain).
- eye irritation stinging, smarting, tearing, and pain.
- identification of an agent that does not irritate the eye surfaces, but which can be applied to facial skin to refresh and to reduce skin irritation, itch and pain would have utility.
- a compound to treat skin and eye discomfort, a compound must act for at least one hour and preferably longer, otherwise the patient would have to repeatedly apply the drug to obtain relief.
- the ideal agent should have rapid onset of action, soothing effects, and the ability to relieve discomfort for an extended duration, for example, for several hours.
- the long-acting NACE compounds described herein activate the transmission of cool neurons so that the brain perceives the ambient temperature at about 15 to 18° C. Activation of these neurons is like turning on a robust air-conditioner within a hot environment. This sensory band in normal individuals is felt as alerting, refreshing, and cool. This is referred to herein as the “perfect cool.”
- the presence of the NACE compounds and the perfect cool, in pathological conditions, gates the passage of noxious signals into the spinal cord and/or brain. Hence, a soothing anti-nociceptive (anti-irritant, anti-pruritic and antinociceptive) effect is achieved with therapeutic benefit.
- the inventor has identified molecules with potent and prolonged activation of the perfect cool. These molecules are qualitatively and quantitatively unlike ( ⁇ )-menthol and WS-3 which act for less than 20 minutes.
- the long-acting NACE compounds are active at single doses per eye of 1 to 50 ⁇ g or at concentrations of 10 mg/mL or less when applied topically to the facial skin including the eyelids.
- the long-acting NACE compounds also have a rapid onset of action (from about 0.5 to about 3 minutes). The onset and offset of action of these compounds was first revealed by testing on the philtrum skin of subjects and then subsequently by applying them onto the skin near the eyes or on the closed eyelids with a towelette.
- Receptor assays based on cells transfected with the genes for proteins associated with thermosensation (e.g., TRP-M8, TRP-A1, TRP-V1) may be used as a model of sensory processes.
- the receptor assays yield quantitative data but give no information on onset and offset of action, or on the quality of human sensations evoked by the chemicals.
- potency as measured by the median effective concentrations (EC 60 ) in the receptor assays may not be correlated to anti-nociceptive or cooling actions.
- the best information on the pharmacological properties of chemicals is derived from direct tests on humans.
- Watson et al. (U.S. Pat. No. 4,178,459) tested the properties of N-substituted p-menthane carboxamides.
- the branched chain alkylesters such as the isopropyl analogs described here in the Gly and D -Ala configuration of Formula 1 were never synthesized by Watson et al.
- Bioactivity of the Watson et at compounds were tested by putting filter paper (1 ⁇ 1 cm), impregnated with a known amount of compound, onto the dorsal surface of the tongue of the volunteer test subject. After 30 seconds, the subject was required to report presence or absence of a cooling effect.
- Theshold, 82 g refer to the threshold amount of the test substance that produces cooling sensations upon application onto the tongue of a panel of human volunteers.
- the average threshold of ( ⁇ )-menthol for 6 subjects was 0.25 ⁇ g, but there was a 100-fold variation in individual sensitivity.
- the potencies of coolness signals detected from the dorsal surface of the tongue are not correlated to skin sensations of coolness may be confounded by gustatory, olfactory, and other variables, as well as by dilution from saliva.
- the intensity of the subjective skin sensation is rated as 0, 1, 2 or 3 with: 0 as no change; 1 as slight coolness, cold, or tingling; 2 as clear-cut signal of coolness, cold, or tingling; and 3 as robust cooling or cold.
- the intervals for recording sensations are 5 to 10 minutes, until two successive zeroes are obtained.
- the results (shown in FIG. 1 ) are averaged values of 4 to 6 separate trials in the same individual. The data are plotted using SigmaPlot® (Systat Software, Point Richmond Calif.) and a smoothing function with a negative exponential was used for analysis and statistical fit of the results. Confirmatory trials of cooling action of the long-acting NACE compounds were obtained in 2 to 4 individuals but not quantified for some because of the large number of chemicals that were evaluated
- the onset of drug action is taken as the time to reach 2 units of coolness intensity, and offset of drug action is the time when coolness intensity drops below 2, after previously surpassing 2 units.
- the duration of cooling action is defined as the offset time minus the onset time.
- An inactive compound is defined as one that does not exceed 2 units of cooling for 5 minutes after application.
- the quality of the sensation is noted, for example, as pure refreshing coolness, or if the sensation is accompanied by irritation (stinging or burning). The quality of the sensation is not rated for intensity.
- the ointment was also applied to the periorbital skin (upper and lower eyelids and on skin adjacent to the lateral canthus) for tests of irritancy near the eyes, and the subject is asked if irritation is present or absent. The intensity of the eye sensation is not rated.
- a second method of testing was to take a towelette saturated with a test solution of the cooling agent and to wipe the towelette over the dosed eyelids. The presence or absence of cooling (or irritanty, if applicable) sensations was then recorded at 10 minute intervals until the cessation of coolness in two successive intervals.
- the long-acting NACE compounds described herein are useful as a topical agent for the relief of skin discomfort, and mimic the effects of running cold water on injured skin.
- the “nominal” ambient skin surface temperature to mimic with a cooling agent is in the range of 15 to 22° C.
- the effect can also be simulated by putting a towel wet with cold water onto the face. The coolness of a wet towel will rapidly dissipate, an effect called adaptation, even when the cooling stimulus is still there.
- the stimulus is more constantly present.
- the exact physiological sensation to replicate with the inventive compounds is that of refreshing, soothing coolness, with minimal or no sensations of irritation or sting, and the absence of excessive cold.
- one or more long-acting NACE compounds is topically applied to therapeutically relieve the irritation, itch, and/or pain of inflamed surfaces.
- Other contemplated uses include refreshment of the facial skin and to increase alertness and vigilance.
- Therapeutic uses for topical formulations of one or more long-acting NACE compounds are contemplated in a towelette for conjunctivitis, ocular surface irritation, pain from corneal abrasions, and pain from eye surgery.
- the long-acting NACE compound may also be applied onto the skin using a towelette that is of a construction sufficient or adapted to deliver the NACE compound to the skin.
- a towelette that is of a construction sufficient or adapted to deliver the NACE compound to the skin.
- the desired NACE compound is suspended, dissolved, and/or dispersed so as to be in contact with the towelette.
- Suitable towelettes include a pad that may be of woven or nonwoven material usually in a unit dispenser. The wiping of the towelette or pad across skin results in delivery to the skin of dermatologically active ingredient(s), meaning that the skin is substantially medicated.
- Other drugs, cosmeceuticals, herbal medicines, traditional medicines, and active cosmetic ingredients suitable for topical human use may also be incorporated into the towelette.
- a long-acting NACE compound is carried by a towelette, which, for example, when applied to the face, will be especially valuable in counter-acting fatigue and to produce alertness and increased vigilance; for example, to combat tiredness from long car journeys or work in a hot environment.
- Cooling Cooling “perfect” Acts for on on skin cooling Eye >1 hour at Chemical Class tongue of face experience Irritancy 1 mg/ml Long-acting yes yes no yes NACE non-NACE yes variable no yes no carboxamides ( ⁇ )-menthol yes yes no yes no SD alcohol no yes yes yes no
- substituted amino acid esters may be obtained from commercial sources such Sigma-Aldrich Corp., St. Louis, Mo., USA.
- sarcosine ethyl ester, ⁇ -alanine ethyl ester, R- or S-amino butyrolactone, and L - or D -alanine methyl ester are listed in the 2003-2004 Aldrich Catalog.
- the precursor, D -alanine ethyl ester is available from Indofine Chemicals, Co., Hillsborough, N.J.
- the precursor, D -alanine isopropyl ester is not available from commercial sources and was custom synthesized (Phoenix Pharmaceuticals, Burlingame, Calif.).
- the acid chloride is reacted with the appropriate amino acid ester to form the NACE compound.
- D -Ala methyl ester hydrochloride was obtained from Aldrich Chemical Co., 1.0 g was dissolved in 28 mL diethyether and 1 mL double-distilled water and cooled to 0° C. A pinch of the catalyst diaminopyrimidine was added. 1.62 mL of p-menthoyl chloride was then added dropwise, followed by 2 mL of triethylamine. Clumps of white precipitates appeared in the mixture, which was stirred overnight at room temperature. The precipitate was dissolved with ethyl acetate, washed with double-distilled water, and dried over sodium sulfate. The organic phase was then evaporated under reduced pressure to yield the final product (2 g), which crystallized at room temperature. The expected molecular mass was then confirmed by mass spectroscopy and the absorption spectrum by nuclear magnetic resonance.
- the intensity of the subjective skin sensation was rated as 0, 1, 2 or 3 with: 0 as no change; 1 as slight coolness, cold, or tingling; 2 as clear signal of coolness, cold, or tingling; and 3 as robust cooling or cold.
- the intervals for recording sensations were 5 to 10 minutes, until two successive zeroes were obtained.
- the results (shown in FIG. 1 ) are averaged values of 4 to 6 separate trials in the same individual.
- the data are plotted using SigmaPlot® (Systat Software, Point Richmond, Calif., USA) and a smoothing function with a negative exponential was used for analysis and statistical fit of the results.
- the onset of drug action was taken as the time to reach 2 units of coolness intensity, and offset of drug action was the time when coolness intensity drops below 2, after previously surpassing 2 units.
- the duration of cooling action was defined as the offset time minus the onset time.
- An inactive compound is defined as one that did not exceed 2 units of cooling after application.
- the quality of the sensation was also noted: such as pure refreshing coolness, or if the sensation was accompanied by irritation (stinging or burning). The quality of the sensation was not rated for intensity.
- the dose delivered to both eyes is a total of ⁇ 40 to 42 ⁇ g, or ⁇ 20 ⁇ g per eye.
- This method allows a reliable delivery of test substances because the dissolved or suspended particles in solution are evenly dispersed on the cotton pad in an excess volume of liquid.
- the presence or absence of cooling sensations was noted as being present or absent at 5 to 10 min intervals until no coolness was noticeable in two successive test intervals. Only the duration of cooling on the ocular surface was recorded, without an attempt to quantify the intensity of the sensation.
- FIG. 1 A number of compounds were synthesized and tested with the results are shown in FIG. 1 .
- the test compounds were singly applied to the skin above the upper lips at a 40 to 70 mg dose of a 1% wt/vol (10 mg/ml) ointment.
- the test dose on the philtrum was reduced to a 0.5% wt/vol (5 mg/ml) ointment.
- the reason for choosing a lower dose was to increase the number of trials per individual and to have a reduced chance of substances accumulating in the skin.
- the duration of cooling effects of some known agents e.g., (-menthol, WS-3 and WS-5 are 0.3, 0.3, and 0.5 hour, respectively, is relatively short compared to the NACE compounds, specifically, D -Hsl, D -Ala-OMe and D -Ala-OEt analogs with 1.3, 1.9, and 2.4 hours of cooling, respectively.
- test results of substances applied to the philtrum skin in an ointment vehicle and to the eylids with a towelette were 5 mg/ml in Aquaphor ® ointment and the concentrations for the eye wipes was 1 mg/ml in 5%-95% v/v ethanol-distilled water. The duration of cooling is recorded as (minutes).
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CA2819466A CA2819466C (en) | 2010-12-06 | 2011-04-04 | [((1r,2s,5r)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester and related compounds and their use in therapy |
ES11715726.3T ES2618560T3 (es) | 2005-03-29 | 2011-04-04 | Éster isopropílico del ácido [((1R,2S,5R)-2-isopropil-5-metil-ciclohexanocarbonil)-amino]-acético y compuestos relacionados y su uso en terapia |
CN201180066635.6A CN103339103B (zh) | 2010-12-06 | 2011-04-04 | [((1r,2s,5r)-2-异丙基-5-甲基-环己烷羰基)-氨基]乙酸异丙酯和相关化合物及它们在治疗中的应用 |
JP2013542596A JP5702864B2 (ja) | 2010-12-06 | 2011-04-04 | [((1r,2s,5r)−2−イソプロピル−5−メチル−シクロヘキサンカルボニル)−アミノ]−酢酸イソプロピルエステル及び関連化合物並びにそれらの療法における使用 |
KR1020187032672A KR102027176B1 (ko) | 2005-03-29 | 2011-04-04 | 〔((1r,2s,5r)―2―이소프로필―5―메틸―시클로헥산카르보닐)―아미노〕―아세트산 이소프로필 에스테르와 관련 화합물 및 요법에서 그의 용도 |
AU2011340295A AU2011340295B2 (en) | 2010-12-06 | 2011-04-04 | [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester and related compounds and their use in therapy |
EP11715726.3A EP2649046B1 (en) | 2010-12-06 | 2011-04-04 | [((1r,2s,5r)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester and related compounds and their use in therapy |
PCT/GB2011/000520 WO2012076831A1 (en) | 2010-12-06 | 2011-04-04 | [((1r,2s,5r)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester and related compounds and their use in therapy |
SG2013043047A SG190991A1 (en) | 2010-12-06 | 2011-04-04 | [((1r,2s,5r)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester and related compounds and their use in therapy |
RU2013130166/04A RU2598644C2 (ru) | 2010-12-06 | 2011-04-04 | Изопропиловый эфир [(1r,2s,5r)-2-изопропил-5-метилциклогексанкарбонил)-амино]-уксусной кислоты, родственные соединения и их применение в терапии |
ZA2013/04896A ZA201304896B (en) | 2010-12-06 | 2013-07-01 | [((1r,2s,5r)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester and related compounds and their use in therapy |
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- 2006-03-23 AU AU2006228280A patent/AU2006228280B2/en active Active
- 2006-03-23 CN CN2006800189445A patent/CN101184725B/zh active Active
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- 2006-03-23 CA CA2602075A patent/CA2602075C/en active Active
- 2006-03-23 JP JP2008503573A patent/JP2008538115A/ja active Pending
- 2006-03-23 EP EP09165292A patent/EP2161252A1/en not_active Withdrawn
- 2006-03-23 KR KR1020077024165A patent/KR20070116133A/ko not_active Application Discontinuation
- 2006-03-23 ZA ZA200709252A patent/ZA200709252B/xx unknown
- 2006-03-23 BR BRPI0609784A patent/BRPI0609784C1/pt active IP Right Grant
- 2006-03-23 WO PCT/GB2006/001093 patent/WO2006103401A2/en active Application Filing
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WO2012076831A1 (en) * | 2010-12-06 | 2012-06-14 | Paget, Hugh, Charles, Edward | [((1r,2s,5r)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester and related compounds and their use in therapy |
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EP2793877B1 (en) | 2011-12-21 | 2018-08-15 | WM. Wrigley Jr. Company | Chewing gum products containing [(2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester |
RU2627839C2 (ru) * | 2011-12-21 | 2017-08-14 | Вм. Ригли Дж. Компани | Жевательная резинка и её композиция (варианты) |
WO2013096405A1 (en) | 2011-12-21 | 2013-06-27 | Wm. Wrigley Jr. Company | Chewing gum products containing [(2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester |
US10478388B2 (en) | 2012-09-28 | 2019-11-19 | The Gillette Company Llc | Skin engaging shaving aid member comprising at least one thermally resilient sensate |
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US9380976B2 (en) | 2013-03-11 | 2016-07-05 | Sync-Think, Inc. | Optical neuroinformatics |
WO2015059432A1 (en) | 2013-10-22 | 2015-04-30 | Edward Tak Wei | Di-isopropyl-phosphinoyl-alkane (dapa) compounds as topical agents for the treatment of sensory discomfort |
WO2015059433A1 (en) | 2013-10-22 | 2015-04-30 | Edward Tak Wei | 1-di(sec-butyl)-phosphinoyl-pentane (dapa-2-5) as a topical agent for the treatment of discomfort from non-keratinized stratified epithelial (nkse) tissue |
WO2015148309A1 (en) | 2014-03-26 | 2015-10-01 | The Gillette Company | Razor comprising a molded shaving aid composition comprising a thermally resilient sensate |
WO2015148308A1 (en) | 2014-03-26 | 2015-10-01 | The Gillette Company | Skin engaging shavng aid comprising a thermally resilient sensate and a trpa1 receptor inhibitor |
US9974761B2 (en) | 2014-04-23 | 2018-05-22 | The Procter & Gamble Company | Medications for deposition on biological surfaces |
US10871363B2 (en) | 2018-05-28 | 2020-12-22 | The Procter & Gamble Company | Oral care composition with improved deposition efficacy of a cooling sensate agent in the oral cavity |
Also Published As
Publication number | Publication date |
---|---|
BRPI0609784B1 (pt) | 2020-07-07 |
US8853267B2 (en) | 2014-10-07 |
BRPI0609784A2 (pt) | 2010-04-27 |
CA2602075A1 (en) | 2006-10-05 |
AU2006228280A1 (en) | 2006-10-05 |
JP2008538115A (ja) | 2008-10-09 |
EP2161252A1 (en) | 2010-03-10 |
KR20070116133A (ko) | 2007-12-06 |
DE602006007831D1 (de) | 2009-08-27 |
EP1871738A2 (en) | 2008-01-02 |
BRPI0609784A8 (pt) | 2017-07-11 |
AU2006228280B2 (en) | 2012-08-30 |
PT1871738E (pt) | 2009-09-11 |
PL1871738T3 (pl) | 2009-12-31 |
CY1109420T1 (el) | 2014-08-13 |
EP1871738B1 (en) | 2009-07-15 |
CN101184725B (zh) | 2012-03-21 |
WO2006103401A2 (en) | 2006-10-05 |
SI1871738T1 (sl) | 2009-12-31 |
CN101184725A (zh) | 2008-05-21 |
US20110152366A1 (en) | 2011-06-23 |
WO2006103401A3 (en) | 2007-03-08 |
BRPI0609784C1 (pt) | 2021-05-25 |
CA2602075C (en) | 2014-04-29 |
ES2328847T3 (es) | 2009-11-18 |
IL186297A0 (en) | 2008-01-20 |
DK1871738T3 (da) | 2009-09-21 |
BRPI0609784B8 (pt) | 2020-07-21 |
ZA200709252B (en) | 2009-04-29 |
MX2007011831A (es) | 2007-11-21 |
HK1106761A1 (en) | 2008-03-20 |
JP2011068656A (ja) | 2011-04-07 |
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