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 PDF

Info

Publication number
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
Authority
US
United States
Prior art keywords
isopropyl
ester
compounds
towelette
skin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12/928,184
Other languages
English (en)
Inventor
Edward T. Wei
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to CA2819466A priority Critical patent/CA2819466C/en
Priority to EP11715726.3A priority patent/EP2649046B1/de
Priority to KR1020187032672A priority patent/KR102027176B1/ko
Priority to CN201180066635.6A priority patent/CN103339103B/zh
Priority to JP2013542596A priority patent/JP5702864B2/ja
Priority to PCT/GB2011/000520 priority patent/WO2012076831A1/en
Priority to KR1020137017649A priority patent/KR101920050B1/ko
Priority to ES11715726.3T priority patent/ES2618560T3/es
Priority to SG2013043047A priority patent/SG190991A1/en
Priority to RU2013130166/04A priority patent/RU2598644C2/ru
Priority to AU2011340295A priority patent/AU2011340295B2/en
Publication of US20110082204A1 publication Critical patent/US20110082204A1/en
Priority to ZA2013/04896A priority patent/ZA201304896B/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C233/05—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/08—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/38—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/86—Hydrazides; Thio or imino analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

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).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Dermatology (AREA)
  • Addiction (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Otolaryngology (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Obesity (AREA)
  • Psychiatry (AREA)
  • Communicable Diseases (AREA)
  • Diabetes (AREA)
  • Hospice & Palliative Care (AREA)
  • Hematology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicinal Preparation (AREA)
  • Pyrane Compounds (AREA)
US12/928,184 2005-03-29 2010-12-06 N-alkylcarbonyl-amino acid ester and N-alkylcarbonyl-amino lactone compounds and their use Abandoned US20110082204A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
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
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
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
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
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
KR1020137017649A KR101920050B1 (ko) 2010-12-06 2011-04-04 〔（（1ｒ,2ｓ,5ｒ）―2―이소프로필―5―메틸―시클로헥산카르보닐）―아미노〕―아세트산 이소프로필 에스테르와 관련 화합물 및 요법에서 그의 용도
EP11715726.3A EP2649046B1 (de) 2010-12-06 2011-04-04 [((1r, 2s, 5r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino] -essigsäure-isopropylester und verwandte verbindungen sowie ihre therapeutische verwendung
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
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
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

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US66716605P 2005-03-29 2005-03-29
US68338405P 2005-05-20 2005-05-20
US70250505P 2005-07-25 2005-07-25
US20372805A 2005-08-13 2005-08-13
US77237406P 2006-02-09 2006-02-09
GBPCT/GB2006/001093 2006-03-23
PCT/GB2006/001093 WO2006103401A2 (en) 2005-03-29 2006-03-23 N-alkylcarbonyl-amino acid ester and n-alkylcarbonyl-amino lactone compounds and their use

Publications (1)

Publication Number Publication Date
US20110082204A1 true US20110082204A1 (en) 2011-04-07

Family

ID=36498694

Family Applications (2)

Application Number Title Priority Date Filing Date
US12/928,184 Abandoned US20110082204A1 (en) 2005-03-29 2010-12-06 N-alkylcarbonyl-amino acid ester and N-alkylcarbonyl-amino lactone compounds and their use
US12/930,794 Active 2029-03-04 US8853267B2 (en) 2005-03-29 2011-01-18 N-alkylcarbonyl-amino acid ester compounds and their use for skin irritation, itch, and pain

Family Applications After (1)

Application Number Title Priority Date Filing Date
US12/930,794 Active 2029-03-04 US8853267B2 (en) 2005-03-29 2011-01-18 N-alkylcarbonyl-amino acid ester compounds and their use for skin irritation, itch, and pain

Country Status (20)

Country Link
US (2) US20110082204A1 (de)
EP (2) EP1871738B1 (de)
JP (2) JP2008538115A (de)
KR (1) KR20070116133A (de)
CN (1) CN101184725B (de)
AU (1) AU2006228280B2 (de)
BR (1) BRPI0609784C1 (de)
CA (1) CA2602075C (de)
CY (1) CY1109420T1 (de)
DE (1) DE602006007831D1 (de)
DK (1) DK1871738T3 (de)
ES (1) ES2328847T3 (de)
HK (1) HK1106761A1 (de)
IL (1) IL186297A0 (de)
MX (1) MX2007011831A (de)
PL (1) PL1871738T3 (de)
PT (1) PT1871738E (de)
SI (1) SI1871738T1 (de)
WO (1) WO2006103401A2 (de)
ZA (1) ZA200709252B (de)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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
WO2014052389A2 (en) 2012-09-28 2014-04-03 The Gillette Company A skin engaging shaving aid member comprising at least one thermally resilient sensate
WO2014052390A2 (en) 2012-09-28 2014-04-03 The Gillette Company A skin engaging member comprising at least one thermally resilient sensate
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
US9265458B2 (en) 2012-12-04 2016-02-23 Sync-Think, Inc. Application of smooth pursuit cognitive testing paradigms to clinical drug development
AU2012321090B2 (en) * 2011-12-21 2016-05-05 Wm. Wrigley Jr. Company Chewing gum products containing [ (2 - isopropyl - 5-methyl-cyclohexanecarbon yl) - amino] - acetic acid isopropyl ester
US9380976B2 (en) 2013-03-11 2016-07-05 Sync-Think, Inc. Optical neuroinformatics
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

Families Citing this family (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2618560T3 (es) * 2005-03-29 2017-06-21 Axalbion Sa Éster isopropílico del ácido [((1R,2S,5R)-2-isopropil-5-metil-ciclohexanocarbonil)-amino]-acético y compuestos relacionados y su uso en terapia
DE102006047162A1 (de) * 2006-09-29 2008-04-03 Beiersdorf Ag Kosmetische oder dermatologische Zubereitungen mit Kombinationen aus (R)-2-[((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-propionsäure methyl ester und einer oder mehreren Lichtschutzfiltersubstanzen
DE102006047164A1 (de) * 2006-09-29 2008-04-03 Beiersdorf Ag Kosmetische oder dermatologische Zubereitungen mit einem Gehalt an 2-Isopropyl-5-Methyl-Cyclohexancarbonyl-D-Alaninmethylester und einem oder mehreren Hautbefeuchtungsmitteln
EP1913976A1 (de) * 2006-10-18 2008-04-23 Symrise GmbH & Co. KG N-alpha-(Menthancarbonyl)aminosäureamide und deren Verwendung als physiologische Kühlwirkstoffe
ATE481379T1 (de) * 2006-11-08 2010-10-15 Edward T Wei N-alkylcarbonyl-d- aminohydroxyalkylesterverbindungen und ihre verwendung
EP2014333A1 (de) * 2007-07-12 2009-01-14 Hakiman Shargh Research Company Verwendung von Kühlmitteln zur Behandlung oder Verhinderung von Tränenfluss oder Augenbrennen
GB2451503B (en) * 2007-08-01 2011-10-12 Lrc Products Stimulating gel comprising a cyclic carboxamide coolant
WO2009081107A1 (en) * 2007-12-21 2009-07-02 Paget, Hugh, Charles, Edward P-menthawe-3-carboxylic acid esters to treat airways diseases
DE102008015424A1 (de) * 2008-03-20 2009-09-24 Beiersdorf Ag Kühlende kosmetische oder dermatologische Zubereitungen mit einem Gehalt an (1R,2S,5R)-2-Isopropyl-5-methyl-N-(2-(pyridyn-2-yl)ethyl-cyclohexancarboxamid und/oder (1R,2S,5R)-N-(4-(Cyanomethyl)-phenyl)-2-isopropyl-5- methylcyclohexancarboxamid mit Menthoxypropandiol
DE102008015426A1 (de) * 2008-03-20 2009-09-24 Beiersdorf Ag Kühlende kosmetische oder dermatologische Zubereitungen mit einem Gehalt an (1R,2S,5R)-2-Isopropyl-5-methyl-N-(2-(pyridyn-2-yl)ethyl-cyclohexancarboxamid und/oder (1R,2S,5R)-N-(4-(Cyanomethyl)-phenyl)-2-isopropyl-5-methylcyclohexancarboxamid zu Reduktion von Hautrötungen
AU2009282004A1 (en) 2008-08-15 2010-02-18 The Procter & Gamble Company Solution of menthane carboxamides for use in consumer products
ES2538789T3 (es) 2008-08-15 2015-06-24 The Procter & Gamble Company Síntesis de derivados de ciclohexano útiles como compuestos refrescantes en productos de consumo
WO2010059289A1 (en) 2008-11-20 2010-05-27 The Procter & Gamble Company Personal care compositions providing enhanced cooling sensation
RU2538696C2 (ru) * 2009-06-05 2015-01-10 Эдвард Так ВЭЙ Лечение дискомфорта глаз путем местного применения охлаждающего агента на наружной поверхности века
US9446267B2 (en) 2009-10-06 2016-09-20 Symrise Ag Products comprising a flavoring agent composition
EP2364689B1 (de) 2009-10-06 2019-12-11 Symrise AG Mentholhaltige Zahnputz-Zusammensetzung mit reduzierter Bitterwahrnehmung
BR112013001142A2 (pt) 2010-07-19 2016-05-17 Procter & Gamble composições que compreendem derivados de compostos do óleo essencial e uso em produtos para cuidados pessoais
PL2621462T3 (pl) 2010-10-01 2020-07-27 The Procter & Gamble Company Kompozycje do higieny jamy ustnej o ulepszonym aromacie
WO2012098342A1 (en) 2011-01-18 2012-07-26 Paget, Hugh, Charles, Edward (r)-1,2-propanediol for use as a solvent in therapeutic cooling agent compositions
US8426463B2 (en) * 2011-04-04 2013-04-23 Edward T. Wei [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester and related compounds and their use in therapy
US20130042482A1 (en) 2011-08-16 2013-02-21 Valerie Jean Bradford Skin Engaging Member Comprising An Anti-Irritation Agent
US8956593B2 (en) 2011-09-01 2015-02-17 The Procter & Gamble Co. Oral care compositions with improved rheology
US20130315843A1 (en) 2012-05-25 2013-11-28 The Procter & Gamble Company Composition for reduction of trpa1 and trpv1 sensations
US9884130B2 (en) 2013-11-13 2018-02-06 The Procter & Gamble Company Compositions for delivery of oral comfort sensations
MX2016011170A (es) 2014-02-27 2016-12-16 Procter & Gamble Composiciones para el cuidado bucal con una percepcion reducida de sabor amargo.
WO2016025414A1 (en) 2014-08-15 2016-02-18 The Procter & Gamble Company Oral care compositions and regimens
RU2017103002A (ru) 2014-08-15 2018-09-18 Дзе Проктер Энд Гэмбл Компани Композиции для ухода за полостью рта, создающие улучшенное ощущение
EP3180092A1 (de) 2014-08-15 2017-06-21 The Procter and Gamble Company Zahnpasta mit inkrementaler chemischen eigenschaften
US10682778B2 (en) 2014-11-26 2020-06-16 The Gillette Company Llc Skin engaging member comprising ethylene vinyl acetate
US9951295B2 (en) 2015-02-19 2018-04-24 The Procter & Gamble Company Compositions for deposition on biological surfaces
CN107438424A (zh) 2015-04-09 2017-12-05 宝洁公司 通过减少trpa1受体、tprv1受体或上述两者的cpc活化减少cpc味觉厌恶
MX2017017169A (es) * 2015-06-30 2018-03-09 Wrigley W M Jun Co Formulaciones refrigerantes de larga duracion.
US20170057911A1 (en) * 2015-10-22 2017-03-02 The Procter & Gamble Company Synthesis of aryl cyclohexane carboxamide derivatives useful as sensates in consumer products
CN108135812A (zh) * 2015-10-22 2018-06-08 宝洁公司 色谱分离的方法
BR112018012071A2 (pt) 2015-12-18 2018-11-27 Procter & Gamble síntese de derivados de éster de ciclo-hexano úteis como elementos sensoriais nos produtos destinados ao consumidor
US10765610B2 (en) 2016-04-01 2020-09-08 The Procter & Gamble Company Oral care compositions containing potassium nitrate and peroxide
CN109069361B (zh) 2016-04-01 2023-04-28 宝洁公司 包含凝胶网络相和硝酸钾的口腔护理组合物
US10219988B2 (en) 2016-04-01 2019-03-05 The Procter & Gamble Company Oral care compositions containing gel networks and potassium nitrate
MX2018011991A (es) 2016-04-01 2019-02-13 Procter & Gamble Composiciones para el cuidado bucal con una exhibicion de saborizante eficaz.
CN108883033A (zh) 2016-04-01 2018-11-23 宝洁公司 含有凝胶网络相的口腔护理组合物
US20170334082A1 (en) 2016-05-18 2017-11-23 The Gillette Company Llc Skin Engaging Member Comprising Ethylene Vinyl Acetate
US11198972B2 (en) 2016-10-25 2021-12-14 The Procter & Gamble Company Fibrous structures
CA3177722A1 (en) 2016-10-25 2018-05-03 The Procter & Gamble Company Differential pillow height fibrous structures
EP3535028A1 (de) 2016-11-03 2019-09-11 The Gillette Company LLC Hautkontaktelement mit ethylenvinylacetat
BR112019009754B1 (pt) 2016-11-17 2022-11-22 The Gillette Company Llc Membro de contato com a pele compreendendo etileno-acetato de vinila e uma fragrância
WO2018144678A1 (en) * 2017-02-03 2018-08-09 The Johns Hopkins University Mini-cancers utilization for personalized cancer drug regimens
KR102132713B1 (ko) 2018-12-04 2020-07-13 주식회사 오스테온 모발 또는 두피 상태 개선용 조성물
GB201908219D0 (en) * 2019-06-10 2019-07-24 Axalbion Sa Therapeutic use of a compound
CA3190969A1 (en) 2020-09-28 2022-03-31 The Procter & Gamble Company Oral care composition comprising hops and flavor
MX2023012062A (es) 2021-05-11 2023-10-23 Procter & Gamble Composiciones para el cuidado bucal que comprenden copolimero de bloque.

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3889804A (en) * 1973-03-14 1975-06-17 Gorham Int Inc Disposable towel
US4226988A (en) * 1971-02-04 1980-10-07 Wilkinson Sword Limited N-substituted paramenthane carboxamides

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1351761A (en) * 1971-02-04 1974-05-01 Wilkinson Sword Ltd Substituted p-menthane carboxamides and compositions containing them
US4150052A (en) * 1971-02-04 1979-04-17 Wilkinson Sword Limited N-substituted paramenthane carboxamides
US4178459A (en) * 1971-02-04 1979-12-11 Wilkinson Sword Limited N-Substituted paramenthane carboxamides
US4136163A (en) * 1971-02-04 1979-01-23 Wilkinson Sword Limited P-menthane carboxamides having a physiological cooling effect
JP2978043B2 (ja) * 1993-09-16 1999-11-15 高砂香料工業株式会社 （２ｓ）−３−｛（１ｒ，２ｓ，５ｒ）−［ ５−メチル−２−（１−メチルエチル）シクロヘキシル ］オキシ｝−１，２−プロパンジオール，その製造方法および用途
US7189760B2 (en) * 2004-04-02 2007-03-13 Millennium Specialty Chemicals Physiological cooling compositions containing highly purified ethyl ester of N-[[5-methyl-2-(1-methylethyl) cyclohexyl] carbonyl]glycine
US20080227857A1 (en) * 2005-03-29 2008-09-18 Edward Tak Wei N-Alkylcarbonyl-Amino Acid Ester and N-Alkylcarbonyl-Amino Lactone Compounds and Their Use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4226988A (en) * 1971-02-04 1980-10-07 Wilkinson Sword Limited N-substituted paramenthane carboxamides
US3889804A (en) * 1973-03-14 1975-06-17 Gorham Int Inc Disposable towel

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
AU2011340295B2 (en) * 2010-12-06 2016-11-03 Axalbion Sa [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester and related compounds and their use in therapy
EP2793877A4 (de) * 2011-12-21 2015-10-28 Wrigley W M Jun Co Kaugummiprodukte mit [(2-isopropyl-5-methyl-cyclohexancarbonyl-)amino-]essigsäure-isopropylester
AU2012321090B2 (en) * 2011-12-21 2016-05-05 Wm. Wrigley Jr. Company Chewing gum products containing [ (2 - isopropyl - 5-methyl-cyclohexanecarbon yl) - amino] - acetic acid isopropyl ester
EP2793877B1 (de) 2011-12-21 2018-08-15 WM. Wrigley Jr. Company Kaugummiprodukte mit [(2-isopropyl-5-methyl-cyclohexancarbonyl-)amino-]essigsäure-isopropylester
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
WO2014052389A2 (en) 2012-09-28 2014-04-03 The Gillette Company A skin engaging shaving aid member comprising at least one thermally resilient sensate
WO2014052390A2 (en) 2012-09-28 2014-04-03 The Gillette Company A skin engaging member comprising at least one thermally resilient sensate
US9265458B2 (en) 2012-12-04 2016-02-23 Sync-Think, Inc. Application of smooth pursuit cognitive testing paradigms to clinical drug development
US9380976B2 (en) 2013-03-11 2016-07-05 Sync-Think, Inc. Optical neuroinformatics
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
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
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
WO2015148309A1 (en) 2014-03-26 2015-10-01 The Gillette Company Razor comprising a molded shaving aid composition comprising a thermally resilient sensate
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
JP2011068656A (ja) 2011-04-07
SI1871738T1 (sl) 2009-12-31
EP1871738A2 (de) 2008-01-02
BRPI0609784A2 (pt) 2010-04-27
CA2602075A1 (en) 2006-10-05
BRPI0609784B1 (pt) 2020-07-07
WO2006103401A3 (en) 2007-03-08
EP2161252A1 (de) 2010-03-10
US20110152366A1 (en) 2011-06-23
WO2006103401A2 (en) 2006-10-05
BRPI0609784A8 (pt) 2017-07-11
JP2008538115A (ja) 2008-10-09
CA2602075C (en) 2014-04-29
KR20070116133A (ko) 2007-12-06
PT1871738E (pt) 2009-09-11
BRPI0609784B8 (pt) 2020-07-21
ES2328847T3 (es) 2009-11-18
PL1871738T3 (pl) 2009-12-31
CN101184725B (zh) 2012-03-21
AU2006228280B2 (en) 2012-08-30
DK1871738T3 (da) 2009-09-21
CN101184725A (zh) 2008-05-21
US8853267B2 (en) 2014-10-07
HK1106761A1 (en) 2008-03-20
IL186297A0 (en) 2008-01-20
BRPI0609784C1 (pt) 2021-05-25
CY1109420T1 (el) 2014-08-13
ZA200709252B (en) 2009-04-29
EP1871738B1 (de) 2009-07-15
DE602006007831D1 (de) 2009-08-27
AU2006228280A1 (en) 2006-10-05
MX2007011831A (es) 2007-11-21

Similar Documents

Publication Publication Date Title
US20110082204A1 (en) N-alkylcarbonyl-amino acid ester and N-alkylcarbonyl-amino lactone compounds and their use
US20080227857A1 (en) N-Alkylcarbonyl-Amino Acid Ester and N-Alkylcarbonyl-Amino Lactone Compounds and Their Use
ES2261234T5 (es) Metabolitos de bupropion y metodos de sintesis y uso.
US8529915B2 (en) (R)-(-)-1,2-propanediol compositions and methods
US20150105349A1 (en) (R)-(-)-1,2-propanediol compositions and methods
JP2014508740A (ja) 治療用冷却剤組成物における溶媒としての使用のための（ｒ）−１，２−プロパンジオール
ES2350618T3 (es) Compuestos de éster n-alquilcarbonil-d-aminohidroxialquílico y su uso.
CA2819466C (en) [((1r,2s,5r)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester and related compounds and their use in therapy
RU2417218C2 (ru) Эфиры n-алкилкарбониламинокислот и n-алкилкарбониламинолактоны и их применение
US8258320B2 (en) N alkylcarbonyl amino lactone compounds and their use
US8476317B2 (en) N-alkylcarbonyl-amino acid ester compounds and their use for cough and pharyngitis
CN118787623A (zh) 用于皮肤炎症和气道粘液过度分泌的药剂
KR20140037045A (ko) 치료적 쿨링제 조성물에서 용매로서 사용하기 위한 (r)-1,2-프로판디올
AU2011356169A1 (en) (R)-1,2-propanediol for use as a solvent in therapeutic cooling agent compositions

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION