WO2006058600A1 - Thienopyrimidines as cooling agents - Google Patents
Thienopyrimidines as cooling agents Download PDFInfo
- Publication number
- WO2006058600A1 WO2006058600A1 PCT/EP2005/011972 EP2005011972W WO2006058600A1 WO 2006058600 A1 WO2006058600 A1 WO 2006058600A1 EP 2005011972 W EP2005011972 W EP 2005011972W WO 2006058600 A1 WO2006058600 A1 WO 2006058600A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkylene linkage
- alkyl group
- composition according
- formula
- together form
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- 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
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
- A61K2800/24—Thermal properties
- A61K2800/244—Endothermic; Cooling; Cooling sensation
Definitions
- the invention relates to tricyclic compounds which are capable of producing a refreshing or cooling sensation when they are brought into contact with the human body.
- Such compounds have applications in many fields, particularly in oral and personal hygiene products and foodstuffs.
- menthol 2- isopropyl-5-methyl-cyclohexanol
- the cooling effect of menthol is due to the action of menthol on the nerve endings of the human body which detect hot and cold stimuli.
- menthol is believed to activate cold receptors on nerve endings.
- the use of menthol is limited by its strong minty smell and relative volatility.
- cooling compounds which are menthol derivatives or analogues.
- Other cooling compounds have been based upon fundamentally different molecular species.
- a particularly well researched group of compounds comprises 1 ,4- disubstituted tetrahydropyrimidinone derivatives.
- R 1 is a C 4-6 alkylene linkage optionally substituted by a C- ⁇ alkyl group
- R 2 Js NH, -NH 2 Or -OH;
- R 3 is Ci- 5 alkyl optionally terminated by a hydroxy, phenyl or a 5- or 6- membered heterocyclic group such as furyl or N-imidazolyl and R 4 is H; or
- R 3 and R 4 together form a C 3 - 5 alkylene linkage; to produce a topical refreshing or cooling sensation in a mammal such as a human.
- R 1 is a C4-6 alkylene linkage optionally substituted by a Ci -4 alkyl group
- R 3 is C 1-5 alkyl optionally terminated by a hydroxy, phenyl or a 5- or 6- membered heterocyclic group such as fury! or N-imidazolyl and R 4 is H; or
- R 3 and R 4 together form a C 3 . 5 alkylene linkage; with the proviso that when R 1 is an unsubstituted C ⁇ O ⁇ C 5 akylene linkage and R 2 Js -NH 2 , then when R 4 is hydrogen, R 3 is other than an unsubstituted C 1-5 alkyl group
- R 3 and R 4 do not together form a C 3-5 alkylene linkage
- R 4 is hydrogen
- R 3 is other than -(CH 2 J 2 -CH 3 ,
- R 3 and R 4 do not together form a C 3 or a C 5 alkylene linkage
- R 1 is an unsubstituted C 4 alkylene linkage
- R 2 NH and R 4 is hydrogen
- R 3 is other than -CH 2 -Ph.
- R 1 is an unsubstituted C 5 alkylene linkage
- R 2 NH and R 4 is hydrogen
- R 3 is other than -(CH 2 J 3 -OH.
- a third aspect of the invention provides a composition comprising at least one compound of formula (I) as hereinbefore defined and at least one other - A -
- a fourth aspect of the present invention provides a method of imparting a topical refreshing or cooling sensation to a mammal such as human comprising applying topically to said human, at least one compound of formula (I) as hereinbefore defined.
- alkyl represents a linear or cyclic saturated hydrocarbon which may be straight-chain or branched, and preferably contains up to 20 carbon atoms.
- alkenyl represents a linear or cyclic, straight-chain or branched unsaturated hydrocarbon which preferably contains up to 20 carbon atoms.
- an alkyl group is linear, it preferably contains from 1 to 10, more preferably from 1 to 6 carbon atoms. Suitable examples include methyl, ethyl, propyl, butyl, pentyl and hexyl, and isomers thereof.
- a C 4 group can be present in the form of n-butyl, iso-butyl, sec-butyl or tert-butyl.
- an alkyl group is cyclic, it preferably contains from 5 to 10 carbon atoms, and may be, for example, cyclopentyl, cyclohexyl, cycloheptyl, decalin or adamantyl.
- R 1 is a C 4 or Cs alkylene linkage, preferably unsubstituted;
- R 3 is a C- 2 or C 3 straight chain alkyl group optionally terminated by a hydroxyl, phenyl, furyl or N-imidazolyl group, a C 3 or C 4 branched alkyl group and
- R 4 is hydrogen; or R 3 and R 4 together form a C 3-5 alkylene linkage.
- the compounds of formula (I) and compositions contain them produce a refreshing or cooling sensation upon topical application to the skin and/or mucosal membrane of a human or other mammalian body.
- a "refreshing or cooling sensation" as used throughout is thus intended to mean any sensation of freshness and/or coolness which is perceived by human or animal body.
- Such a sensation is analogous to the sensation produced by compounds such as menthol, and/or the sensation elicited when cold-sensitive receptors, such as those identified in McKemy et al, Nature, Vol. 416, 2002, 52-58, are stimulated.
- a refreshing or cooling sensation is desirable in many different applications.
- the compounds and compositions of the invention have applications in a number of personal hygiene, oral hygiene and food product compositions.
- Personal hygiene applications include lotions, shaving cream, post shaving preparations, shampoos, hair conditioners, facial cleansers, soaps, bath oils and foams, antiperspirants, deodorants.
- Oral hygiene applications include toothpastes, mouthwashes, dental floss, chewing gum and breath fresheners.
- Foodstuff applications include beverages, spreads, ice-creams and confectionery.
- Possible other applications where a cooling sensation may be desirable include pharmaceutical products for oral conditions (for example chewable pharmaceutical products, oral creams, gels or ointments or throat lozenges), pharmaceutical products for application to the skin (for example skin creams, ointments or lotions, especially any for alleviation or treatment of itch, inflammation or other irritation or dry skin), tobacco products, insect repellents and cosmetics.
- the compounds may be used alone, or in a composition in combination with another substance or substances such as a carrier. The nature of these additional substances, and the relative proportions of components of the composition will depend on a number of factors, such as the specific use for which the composition is employed.
- the compositions may be used in a variety of applications, such as those discussed above. Particularly preferred uses include personal hygiene products such as deodorant, shower gel and skin cream; oral hygiene products such as toothpastes and mouthwashes; and foodstuffs, such as beverages, ice-creams, confectionery and spreads.
- Compounds of formula (I) and compositions containing them may also be used, for example, in applications such as personal hygiene products such as deodorant, shower gel and skin cream; oral hygiene products such as mouthwash and toothpaste; and food products.
- the compounds may have particularly useful applications in foodstuffs such as beverages, spreads, confectionery and ice-cream.
- Such applications may include the fields of personal hygiene products (including lotions, shaving cream, post shaving preparations, shampoos, conditioners, facial cleansers, soaps, bath oils and foams, antiperspirants and deodorants); oral hygiene products (including toothpastes, mouthwashes, dental floss, chewing gum and breath fresheners); food products (including beverages, spreads, ice-creams and confectionery); and other applications where a cooling sensation may be desirable (including pharmaceutical products such as chewable pharmaceutical products or throat lozenges, tobacco products, insect repellents and cosmetics).
- compositions for use as toothpastes, mouthwashes and food products such as confectionery, beverages, spreads and ice-cream.
- the specific nature of the composition e.g. the nature of the additional components, the relative proportions of the components and the physical nature of the composition will depend on the particular application.
- the compound or compounds of formula (I) are preferably included in any composition in an amount of from 0.00001% to 3%, eg from 0.001% to 3% by weight, based on the total weight of the composition.
- An especially preferred range is from 0.0001 % to 0.3% by weight.
- the compound may present in an amount of from 0.0003% to 0.1% or from 0.003% to 0.1%.
- R 1 , R 3 and R 4 have the same meanings as in formula (I);
- scheme 1 the temperatures shown are exemplary and scheme 1 is not limited to use of these temperatures.
- Compounds of formula (I) or formula (II) may also be prepared by methods as, or analogous to, those described in Chowdhury A.Z.M.S., J. Bangladesh Acad. Sci., 1999, 23, 59-67, in Hozein, Z.A. et al, Pharmazie, 1997, 52 (10), 753-758, or in Potacek et al, Studies in Organic Chemistry (Amsterdam) (1989) 35, (Chem. Heterocycl. Compd.), 484-6.
- a heterologous expression system in which HEK cells stably expressing the human TRPM8 channel, was used to set up a screening system in order to search for compounds that elicit a cooling sensation.
- the open reading frame of human cDNA TRPM8 from position 41- 3355bp was amplified from a human prostate cDNA library (Stratagene) using primers TATAGTTAACGCCGCCACCATGTCCTTTCGGGCAGCCAGGCTCAG and TATATCTAGATTATTTGATTTTATTAGCAATCTCTTTC as previously described previously (Tsavalier et al., 2001 ).
- HEK 293 cells were transfected with human TRPM8 cDNA that was cloned into a pcDNA4 vector, using a standard calcium phosphate method (Wigler et al., 1977). The transfected cells were placed under selective pressure by growth in 100 ⁇ g/ml_ zeocin (Invitrogen) and cells stably expressing the human TRPM8 were generated.
- Cells stably expressing the human TRPM8 were seeded in a 96 well plate (coated with polylysine) at a density of 10 5 cells /well in 200 ⁇ l of media. The next day the cell medium was removed and the cells were incubated a DMEM solution (supplemented with 0.001 %BSA w/w, 0.01 % FCS v/v, 0.02% plurinoc acid, 1 mM probenicide) that contained the calcium sensitive fluorescent dye fluo-4 ( ⁇ 3 ⁇ M, Molecular Probes) at 37 0 C for 1 hr.
- DMEM solution supplied with 0.001 %BSA w/w, 0.01 % FCS v/v, 0.02% plurinoc acid, 1 mM probenicide
- the dye was then removed and the cells were incubated in a Tyrodes buffer (containing 1 mM probenicide, pH 7.4) pre-equilibrated at a certain temperature (i.e 37°C) and the intracellular calcium levels were monitored at the same temperature, using the Novostar plate reader.
- the cells in each well were illuminated at 480 nm, and the fluorescent light emitted at 510 nm was measured.
- the fluorescence was determined before (basal fluorescence) and after the addition of increasing concentrations of a test compound.
- the maximal increase in fluorescence (DFmax) caused by a compound was measured as the peak fluorescence induced by that compound minus the basal fluorescence.
- the potency of a compound is expressed as the EC 5O and it is the concentration of the compound that produces one-half of the maximal response (DFmax).
- Example 1 In the above assay, the compound of Example 1 was found to have an EC 50 of 6.5 ⁇ M.
- the following example compounds were either sourced commercially or made by the route of Reaction Scheme 1 and were found to have the EC 50 values quoted.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Birds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cosmetics (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Plural Heterocyclic Compounds (AREA)
- Saccharide Compounds (AREA)
- Confectionery (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2005800408768A CN101065100B (en) | 2004-11-30 | 2005-11-07 | Thienopyrimidines as cooling agents |
EP05803655A EP1817000B8 (en) | 2004-11-30 | 2005-11-07 | Thienopyrimidines as cooling agents |
US11/791,268 US7615560B2 (en) | 2004-11-30 | 2005-11-07 | Thienopyrimidines as cooling agents |
JP2007541748A JP4938680B2 (en) | 2004-11-30 | 2005-11-07 | Thienopyrimidine as a coolant |
DE602005012144T DE602005012144D1 (en) | 2004-11-30 | 2005-11-07 | THIENOPYRIMIDINE AS A COOLANT |
BRPI0518683-8A BRPI0518683B1 (en) | 2004-11-30 | 2005-11-07 | USE OF A COMPOUND, COMPOUND, AND, COMPOSITION |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0426266.3 | 2004-11-30 | ||
GBGB0426266.3A GB0426266D0 (en) | 2004-11-30 | 2004-11-30 | Compounds and their uses |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2006058600A1 true WO2006058600A1 (en) | 2006-06-08 |
Family
ID=33561587
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2005/011972 WO2006058600A1 (en) | 2004-11-30 | 2005-11-07 | Thienopyrimidines as cooling agents |
Country Status (10)
Country | Link |
---|---|
US (1) | US7615560B2 (en) |
EP (1) | EP1817000B8 (en) |
JP (1) | JP4938680B2 (en) |
CN (1) | CN101065100B (en) |
AT (1) | ATE418962T1 (en) |
BR (1) | BRPI0518683B1 (en) |
DE (1) | DE602005012144D1 (en) |
ES (1) | ES2318564T3 (en) |
GB (1) | GB0426266D0 (en) |
WO (1) | WO2006058600A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2934778A1 (en) * | 2008-08-11 | 2010-02-12 | Natura Cosmeticos Sa | ANTI-TRANSPARENT COMPOSITIONS AND METHODS FOR REDUCING TRANSPIRATION IN HUMANS |
EP2642287A2 (en) | 2012-03-21 | 2013-09-25 | Takasago International Corporation | Method for evaluating sensory stimulus component |
WO2018131575A1 (en) | 2017-01-10 | 2018-07-19 | 高砂香料工業株式会社 | Methylmenthol derivative and cool-sensation imparter composition containing same |
WO2019078185A1 (en) | 2017-10-16 | 2019-04-25 | 高砂香料工業株式会社 | Cool-sensation imparter composition containing 2,2,6-trimethylcyclohexanecarboxylic acid derivative |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5539623B2 (en) | 2008-03-27 | 2014-07-02 | 日清紡ホールディングス株式会社 | Carbodiimide compound, carbodiimide composition, and aqueous coating composition |
CN109081824A (en) * | 2018-10-08 | 2018-12-25 | 浙江工业大学上虞研究院有限公司 | The preparation method of 2- aminothiophene class compound |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004072074A1 (en) * | 2003-02-12 | 2004-08-26 | Boehringer Ingelheim International Gmbh | Pyrrolidinohydrochinazolines |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
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AU462733B2 (en) | 1970-08-21 | 1975-07-03 | International Flavors & Fragrances Inc | Pyrimidine containing flavoring compositions |
BR9101256A (en) | 1990-03-30 | 1991-11-05 | Dowelanco | COMPOUND, FUNGICIDE COMPOSITION, FUNGICIDE PROCESS, INSECTICIDE OR ACARICIDE COMPOSITION AND INSECTICIDE OR ACARICIDE PROCESS |
AU2003239947A1 (en) * | 2002-05-31 | 2003-12-19 | Sloan-Kettering Institute For Cancer Research | Heterologous stimulus-gated ion channels and methods of using same |
US6897195B2 (en) | 2002-07-24 | 2005-05-24 | Nanjing Zhongshi Chemical Co. | Composition of menthol and menthyl lactate, its preparation method and its applications as a cooling agent |
GB0229811D0 (en) * | 2002-12-20 | 2003-01-29 | Unilever Plc | Compound delivery systems |
-
2004
- 2004-11-30 GB GBGB0426266.3A patent/GB0426266D0/en not_active Ceased
-
2005
- 2005-11-07 BR BRPI0518683-8A patent/BRPI0518683B1/en not_active IP Right Cessation
- 2005-11-07 DE DE602005012144T patent/DE602005012144D1/en active Active
- 2005-11-07 ES ES05803655T patent/ES2318564T3/en active Active
- 2005-11-07 JP JP2007541748A patent/JP4938680B2/en not_active Expired - Fee Related
- 2005-11-07 EP EP05803655A patent/EP1817000B8/en not_active Not-in-force
- 2005-11-07 AT AT05803655T patent/ATE418962T1/en not_active IP Right Cessation
- 2005-11-07 US US11/791,268 patent/US7615560B2/en not_active Expired - Fee Related
- 2005-11-07 CN CN2005800408768A patent/CN101065100B/en not_active Expired - Fee Related
- 2005-11-07 WO PCT/EP2005/011972 patent/WO2006058600A1/en active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004072074A1 (en) * | 2003-02-12 | 2004-08-26 | Boehringer Ingelheim International Gmbh | Pyrrolidinohydrochinazolines |
Non-Patent Citations (3)
Title |
---|
DATABASE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften; XP002365034, retrieved from STN Database accession no. 7761696,7762833,7764466 * |
R. ANDERSKEWITZ ET AL.: "Pyrrolidinohydroquinazolines - a novel class of CCR3 modulators", BIOORG. MED. CHEM. LETT., vol. 15, no. 3, 9 December 2004 (2004-12-09), pages 669 - 673, XP002364991 * |
Z. A. HOZIEN ET AL.: "Synthesis of some biologically active agents derived from thieno[2,3-d]pyrimidine derivatives", PHARMAZIE, vol. 52, no. 10, 1997, pages 753 - 758 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2934778A1 (en) * | 2008-08-11 | 2010-02-12 | Natura Cosmeticos Sa | ANTI-TRANSPARENT COMPOSITIONS AND METHODS FOR REDUCING TRANSPIRATION IN HUMANS |
WO2010017609A2 (en) * | 2008-08-11 | 2010-02-18 | Natural Cosmeticos S.A. | Antiperspirant compositions and methods for reducing perspiration in humans |
WO2010017609A3 (en) * | 2008-08-11 | 2010-04-08 | Natural Cosmeticos S.A. | Antiperspirant compositions and methods for reducing perspiration in humans |
EP2642287A2 (en) | 2012-03-21 | 2013-09-25 | Takasago International Corporation | Method for evaluating sensory stimulus component |
WO2018131575A1 (en) | 2017-01-10 | 2018-07-19 | 高砂香料工業株式会社 | Methylmenthol derivative and cool-sensation imparter composition containing same |
WO2019078185A1 (en) | 2017-10-16 | 2019-04-25 | 高砂香料工業株式会社 | Cool-sensation imparter composition containing 2,2,6-trimethylcyclohexanecarboxylic acid derivative |
Also Published As
Publication number | Publication date |
---|---|
ATE418962T1 (en) | 2009-01-15 |
DE602005012144D1 (en) | 2009-02-12 |
BRPI0518683B1 (en) | 2014-10-14 |
EP1817000B1 (en) | 2008-12-31 |
US20080170999A1 (en) | 2008-07-17 |
CN101065100A (en) | 2007-10-31 |
BRPI0518683A2 (en) | 2008-12-02 |
CN101065100B (en) | 2011-04-20 |
EP1817000B8 (en) | 2009-04-15 |
JP2008521758A (en) | 2008-06-26 |
EP1817000A1 (en) | 2007-08-15 |
US7615560B2 (en) | 2009-11-10 |
JP4938680B2 (en) | 2012-05-23 |
GB0426266D0 (en) | 2004-12-29 |
ES2318564T3 (en) | 2009-05-01 |
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