CA2734682C - Detection and use of low molecular-weight modulators of the cold-menthol receptor trpm8 - Google Patents

Detection and use of low molecular-weight modulators of the cold-menthol receptor trpm8 Download PDF

Info

Publication number
CA2734682C
CA2734682C CA2734682A CA2734682A CA2734682C CA 2734682 C CA2734682 C CA 2734682C CA 2734682 A CA2734682 A CA 2734682A CA 2734682 A CA2734682 A CA 2734682A CA 2734682 C CA2734682 C CA 2734682C
Authority
CA
Canada
Prior art keywords
compound
composition
modulator
trpm8
receptor
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.)
Active
Application number
CA2734682A
Other languages
French (fr)
Other versions
CA2734682A1 (en
Inventor
Thomas Subkowski
Claus Bollschweiler
Jens Wittenberg
Michael Krohn
Holger Zinke
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.)
BASF SE
Original Assignee
BASF SE
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 BASF SE filed Critical BASF SE
Priority to CA2937195A priority Critical patent/CA2937195C/en
Priority to CA2937196A priority patent/CA2937196C/en
Publication of CA2734682A1 publication Critical patent/CA2734682A1/en
Application granted granted Critical
Publication of CA2734682C publication Critical patent/CA2734682C/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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
    • C07D495/22—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 four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING OR TREATMENT THEREOF
    • A23C13/00—Cream; Cream preparations; Making thereof
    • A23C13/12—Cream preparations
    • A23C13/125—Cream preparations in powdered, granulated or solid form
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G9/00—Frozen sweets, e.g. ice confectionery, ice-cream; Mixtures therefor
    • A23G9/32—Frozen sweets, e.g. ice confectionery, ice-cream; Mixtures therefor characterised by the composition containing organic or inorganic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Preparation or treatment thereof
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A23L27/88—Taste or flavour enhancing agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/03—Organic compounds
    • A23L29/035—Organic compounds containing oxygen as heteroatom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/03—Organic compounds
    • A23L29/045—Organic compounds containing nitrogen as heteroatom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/03—Organic compounds
    • A23L29/055—Organic compounds containing sulfur as heteroatom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42—Amides
    • 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
    • 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
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • 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
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • 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
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4946—Imidazoles or their condensed derivatives, e.g. benzimidazoles
    • 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
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
    • 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
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • 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
    • A61K8/4986—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with sulfur as the only hetero atom
    • 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
    • A61K8/69—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing fluorine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/02—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings containing insect repellants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/004—Aftersun preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/02—Preparations for cleaning the hair
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/12—Preparations containing hair conditioners
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
    • C07D233/84—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
    • C07D317/64—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D495/12—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 three hetero rings
    • C07D495/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/16—Nitrogen-containing compounds
    • C08K5/20—Carboxylic acid amides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/16—Nitrogen-containing compounds
    • C08K5/34—Heterocyclic compounds having nitrogen in the ring
    • C08K5/3412—Heterocyclic compounds having nitrogen in the ring having one nitrogen atom in the ring
    • C08K5/3432—Six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/16—Nitrogen-containing compounds
    • C08K5/34—Heterocyclic compounds having nitrogen in the ring
    • C08K5/3442—Heterocyclic compounds having nitrogen in the ring having two nitrogen atoms in the ring
    • C08K5/3462—Six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/36—Sulfur-, selenium-, or tellurium-containing compounds
    • C08K5/45—Heterocyclic compounds having sulfur in the ring
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
    • D06M13/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment
    • D06M13/322—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing nitrogen
    • D06M13/35—Heterocyclic compounds
    • D06M13/355—Heterocyclic compounds having six-membered heterocyclic rings
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
    • D06M13/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment
    • D06M13/322—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing nitrogen
    • D06M13/402—Amides imides, sulfamic acids
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
    • D06M13/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment
    • D06M13/322—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing nitrogen
    • D06M13/402—Amides imides, sulfamic acids
    • D06M13/408—Acylated amines containing fluorine atoms; Amides of perfluoro carboxylic acids
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
    • D06M13/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment
    • D06M13/322—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing nitrogen
    • D06M13/402—Amides imides, sulfamic acids
    • D06M13/418—Cyclic amides, e.g. lactams; Amides of oxalic acid
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
    • D06M13/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment
    • D06M13/322—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing nitrogen
    • D06M13/402—Amides imides, sulfamic acids
    • D06M13/432—Urea, thiourea or derivatives thereof, e.g. biurets; Urea-inclusion compounds; Dicyanamides; Carbodiimides; Guanidines, e.g. dicyandiamides
    • D—TEXTILES; PAPER
    • D21—PAPER-MAKING; PRODUCTION OF CELLULOSE
    • D21H—PULP COMPOSITIONS; PREPARATION THEREOF NOT COVERED BY SUBCLASSES D21C OR D21D; IMPREGNATING OR COATING OF PAPER; TREATMENT OF FINISHED PAPER NOT COVERED BY CLASS B31 OR SUBCLASS D21G; PAPER NOT OTHERWISE PROVIDED FOR
    • D21H17/00—Non-fibrous material added to the pulp, characterised by its constitution; Paper-impregnating material characterised by its constitution
    • D21H17/03—Non-macromolecular organic compounds
    • D21H17/05—Non-macromolecular organic compounds containing elements other than carbon and hydrogen only
    • D21H17/07—Nitrogen-containing compounds
    • D—TEXTILES; PAPER
    • D21—PAPER-MAKING; PRODUCTION OF CELLULOSE
    • D21H—PULP COMPOSITIONS; PREPARATION THEREOF NOT COVERED BY SUBCLASSES D21C OR D21D; IMPREGNATING OR COATING OF PAPER; TREATMENT OF FINISHED PAPER NOT COVERED BY CLASS B31 OR SUBCLASS D21G; PAPER NOT OTHERWISE PROVIDED FOR
    • D21H17/00—Non-fibrous material added to the pulp, characterised by its constitution; Paper-impregnating material characterised by its constitution
    • D21H17/03—Non-macromolecular organic compounds
    • D21H17/05—Non-macromolecular organic compounds containing elements other than carbon and hydrogen only
    • D21H17/09—Sulfur-containing compounds
    • 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
    • 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
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/78—Enzyme modulators, e.g. Enzyme agonists

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Birds (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Food Science & Technology (AREA)
  • Nutrition Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Textile Engineering (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Emergency Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Cosmetics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)

Abstract

The invention relates to novel modulators of the cold-menthol receptor TRPM8, to a method for modulating the TRPM8 receptor using said modulators; to the use of the modulators for induction of cold sensation; and to the objects and means produced using said modulators.

Description

Detection and use of low molecular-weight modulators of the cold-menthol receptor TRPM8.
The invention relates to new types of modulators of the cold menthol receptor TRPM8, methods for modulating the TRPM8 receptor using these modulators; the use of the modulators for inducing a sensation of coldness; and also the articles and compositions produced using these modulators.
Background of the invention The cold menthol receptor TRPM8 (also referred to as Cold Membrane Receptor (CMR)1) belongs to the family of the "Transient Receptor Potential Ion Channels", is specifically expressed in a special group of neurons and, in the cell membrane, forms pores (in each case 4 units combine to give a tetramer), which selectively allow Ca2+
ions to pass. The protein has 6 transmembrane domains and a cytoplasmatic C
and N
terminus. Low temperatures (preferably 10-25 C) stimulate this receptor, resulting in a signal transduction which is interpreted by the nervous system as a sensation of coldness. The receptor was described for the first time in 2002 as cold receptor in a number of publications (Peier AM et al, .A TRP channel that senses cold stimuli and menthol.Cell. 2002 Mar 8;108(5):705-15; McKemy DD et al. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature.

Mar 7; 416 (6876): 52-8; Zuker CS. Neurobiology: a cool ion channel. Nature.

Mar 7; 416 (6876): 27-8).
Cooling compounds, such as e.g. menthol, have for a long time played an important role in the flavorings and fragrance industry in order to produce an association with freshness and cleanliness. For the compound menthol, it has been shown that it acts as a natural modulator of the receptor TRPM8 (McKemy D.D., Molecular Pain 1, 2005, 16; McKemy D.D., Nature 416, 2002, 52-58; Peier A.M., Cell 108, 2002, 705-715;
Dhaka A., Annu. Rev. Neurosci. 29, 2006, 135-161). By applying menthol, TRPM8 is activated, which brings about a Ca2+ influx into the cold-sensitive neurons.
The electrical signal produced as a result is ultimately perceived as a sensation of coldness.
Elevated menthol concentrations lead to irritation and an anesthetic effect.
Moreover, various publications have described menthol derivatives with a similar effect (British Patent 1971#1315761; Watson H.R., J. Soc. Cosmet. Chem. 29, 1978, 185-200;
Furrer S.M., Chem. Percept. 1, 2008, 119-126). There are also individual compounds, structurally unrelated to menthol, which bring about a significant TRPM8 modulation,
2 such as e.g. lcilin (Wei E.T., J. Pharm. Pharmacol 35, 1983, 110-112; WO
2004/026840), WS-23 or compounds listed in the patent application WO 2007/019719.
Further effects of substances which modulate the TRPM8 receptor and/or its insect analogs are a repellent effect on insects (WO 2002/015692; WO 2004/000023, US
2004/0028714), and also activity in antitumor therapy (e.g. an influencing of prostate tumors), activity in the treatment of inflammatory pain / hyperalgesia and an effect as TRPM8 antagonists in the treatment of bladder syndrome or overactive bladder (Beck B. Cell Calcium, 41, 2007, 285-294; Levine J.D.
Biochim. Biophys. Acta, Mol Basis Dis. 1772, 2007, 989-1003; Mukerji G., BMC
Urology 6, 2006, 6; US 2003/0207904; US 2005/6893626, Dissertation Behrendt H.J. 2004, Universitat Bochum; Lashinger E.S.R. Am. J. PhysioL Renal PhysioL Am J Physiol Renal Physiol. 2008 Jun 18. [Epub ahead of print]; PMID: 18562636).
However, many of the TRPM8 modulators found hitherto have deficiencies with regard to strength of effect, duration of effect, skin/mucosa irritation, odor, taste, solubility and/or volatility.
Summary of the invention It was therefore an object of the present invention to identify novel substances, which lead to a modulation of the TRPM8 receptor, which can be used as alternatives to the modulators known hitherto. Such compounds should in particular also be suitable for applications in the field of cosmetics (e.g. hair care, skin care, oral care), nutrition (feed/food), textiles, OTC products (e.g.
burn ointment), pharmaceuticals (e.g. tumor treatment, bladder weakness), packagings or as insecticide or repellent.
In one aspect, the invention relates to a method for in-vitro modulation of cold menthol receptor TRPM8 comprising contacting the receptor with a polynuclear organic compound, wherein in a cellular activity test, the compound is a modulator of the Ca2+ ion permeability of a cell that recombinantly expresses a human TRPM8 receptor, and wherein the modulator is a compound of formulae 1 to 19:

2a o 1o N
s/s 0 N
0¨

/ H
N N
a 0 = o) N N
0 *

2b N+
6 $ 0 *0-=
N N
s HNO

HN

2c ,--N
S NN

\ NH

0 = \

13 0*
=

o Hr0, . CA 02734682 2015-10-28 . , =
, 2d p= , 15 NI,), 0 oz-zo N
\\\ F

16 _ \ -...õ \ F
\ N N--------/ \

N./
F

IN/ \ 1 NI ONCI
I
411( N

N,õ, \N/
*
or 2e In another aspect, the invention relates to a modulator for a TRPM8 receptor, wherein the modulator is a compound of formula 1 to 19:
o 1 o =N
\ 0 S S

N
0¨

/
1µ1 N
3 aN,0 =

2f (o N N

N +

N N

2g HN

/\
s NN vie *

NI
N\

0 11 0\
F/c) 10$

2h o o = \

S z 16 \ F
N N

N/
N Cl N

2i or In another aspect, the invention relates to a composition comprising the modulator defined herein, and an acceptable excipient, wherein the composition is a) a pharmaceutical composition, b) a food, c) a mouthcare composition, d) a skincare or haircare composition, or e) an insect repellent and insecticide.
In another aspect, the invention relates to a textile product comprising the modulator defined herein.

2j In another aspect, the invention relates to a packaging material comprising the modulator defined herein.
In another aspect, the invention relates to the use of one of the compound of formula 1 to 19, as defined herein, for the manufacture of a medicament useful for modulating the TRPM8 receptor.
In another aspect, the invention relates to the use of one of the compound of formula 1 to 19, as defined herein, for modulating the TRPM8 receptor.
In another aspect, the invention relates to the use of one of the compound of formula 1 to 19, as defined herein, for the manufacture of a medicament useful for inducing a sensation of coldness in a human or animal.
In another aspect, the invention relates to the use of one of the compound of formula 1 to 19, as defined herein, for inducing a sensation of coldness in a human or animal.
In another aspect, the invention relates to the use of one of the compound of formula 1 to 19, as defined herein, for the treatment of prostate carcinoma, bladder weakness or pain.
In another aspect, the invention relates to the use of one of the compound of formula 1 to 19, as defined herein, for the manufacture of a medicament for the treatment of prostate carcinoma, bladder weakness or pain.
Description of the figures:
Figure 1 shows the vector map of the plasmid pind_M8 coding with hTRPM8, which has been used for the transfection of HEK293 cells.

Detailed description of the invention:
1. Definition of general terms:
In the literature there are various synonyms for "TRPM8": TRPP8, LTRPC6, CMR1, MGC2849, transient receptor potential cation channel subfamily M member 8.
Within the context of the present invention, all names are encompassed. Also encompassed are all functional modifications of the receptor, such as, in particular, splice variants, isoforms, such as e.g. TRPM8 CRA_a, TRPM8 CRA_b and all analogous receptors from various organisms, such as human, mouse, rat. The nucleotide and amino acid sequences of the various receptors are known per se and listed in sequence databases. Thus, e.g. the sequence information for hTRPM8 is entered under the number NM_024080.
Within the context of the invention, a "modulator" is a compound which can act as agonist and/or antagonist of the TRPM8 receptor in vivo and/or in vitro.
Suitable modulators here can act either only as antagonist or agonist or both as antagonist and also as agonist. Here, in particular an agonistic or an antagonistic effect can be established depending on the particular modulator concentration selected.
Here, an "agonist" is a compound which mediates an activation of the TRPM8 receptor, thus induces a Ca2+ ingress into the cold-sensitive neurons and thereby mediates a sensation of coldness. By contrast, an "antagonist" is a compound which can counteract this activation of the TRPM8 receptor.
The mediators according to the invention can exert their effect by binding reversibly or irreversibly, specifically or nonspecifically to a TRPM8 receptor molecule.
Usually, the binding takes place noncovalently via ionic and/or nonionic, such as e.g.
hydrophobic, interactions with the receptor molecule. Here, "specific" encompasses both exclusive interaction with one or more different TRPM8 receptor molecules (such as e.g.

molecules of different origin or various isoforms). By contrast, "nonspecific"
is an interaction of the modulator with a plurality of various receptor molecules of different function and/or sequence but where, as a consequence, a desired agonistic and/or antagonistic modulation (as described above) of the TRPM8 receptor can be established.
4 2. Preferred embodiments The invention relates firstly to a method for the in-vitro or in-vivo modulation of the cold menthol receptor TRMP8, in particular of the human TRPM8 receptor, where the receptor is brought into contact with at least one compound which is selected from polynuclear organic compounds which, in a cellular activity test, in particular under standard conditions, using cells which recombinantly express the human TRPM8 receptor, modulate the permeability of these cells for Ca2+ ions.
In this connection, "standard conditions" is understood as meaning an activity test carried out with HEK293 cells which have been transformed with human TRPM8 and loaded with calcium-sensitive dye (such as e.g. Fluo-4AM, i.e. fluo-4-acetoxymethyl ester), subsequent addition of the test compound and detection of the color change, the experimental procedure taking place at 37 C; as described e.g. example 3 below, or in Behrendt et al. (2004) loc. cit.).
In particular, the modulating compound here comprises at least two 4- to 7-membered rings which, independently of one another, are carbocyclic or heterocyclic, monocyclic or polycyclic, and where at least two of these rings may be optionally condensed or spiro-linked. Other nonlimiting examples of suitable ring linkages comprise chemical single bonds between ring carbon atoms and/or ring heteroatoms, via 2 to 6-membered carbon bridging groups, where individual carbon atoms may be replaced by heteroatoms, such as N, 0 or S. Moreover, the ring groups and bridging groups may optionally carry substituents which are selected from keto groups, -OH, -SH, -CN, -NO2, -C1.6-alkyl, or C2.4-alkenyl, where, in the alkyl or alkenyl groups, one or more H atoms may be replaced by halogen, such as F, Cl, Br or I.
Carbocyclic rings comprise here 4, 5, 6 or 7 carbon atoms; besides the ring carbon atoms, heterocyclic rings comprise 1 to 3 identical or different ring heteroatoms, such as 0, N and S atoms. The rings here may be, independently of one another, saturated, mono- or polyunsaturated, such as e.g. aromatic rings.
The modulator used according to the invention have an agonistic or antagonistic effect here on the cellular Ca2+ ion permeability. In particular, the modulator is at least one compound selected from compounds of the following formulae 1 to 19 according to table 1 below.

Table 1: Modulators according to the invention o 1 o =N
s/ \s 0 ON
0¨

/
N

,1023 4 o>
5 (N N

N/ >
6 imoo .0 _ N/\N/\./\./\
7 N\ZZ
8 N).H
9 F 140 11 NIN 40, =0 , CA 02734682 2011-02-17 o *

N----'"

:0 441 \
15 0 NI) //

N
\ \ F F

S z 16 ____\
\
,-/ \

F-i N/ \ 1 /
WN
I

\ N7 Si = CA 02734682 2011-02-17 where the compound may be present in chemically pure or enriched form, as individual stereoisomer or in the form of stereoisomer mixtures. Furthermore, the compounds can be present uncharged or in the form of their salts, such as e.g. as acid addition salt.
Functional groups may optionally be replaced by equivalent chemical groups;
fluorine atoms may thus be replaced e.g. by other halogen atoms, such as Cl, Br or I;
oxygen atoms (such as e.g. ether groups) may be replaced by corresponding sulfur groups, and vice versa; keto groups may be replaced by corresponding thionyl groups.
The compounds specified above are chemical substances known per se which are either commercially available or are obtainable using customary organic synthesis methods.
Thus, the following are known for example:
Compound 1 under CAS number: 99602-94-5 (3R-cis form) Compound 2 under CAS number: 165753-08-2 Compound 3 under CAS number: 338771-57-6 Compound 4 under CAS number: 878942-21-3 Compound 5 under CAS number: 748783-13-3 The modified forms or derivatives are also referred to as functional analogs or functionally equivalent compounds, if they furthermore exhibit the desired biological activity (receptor TRPM8 modulation).
Furthermore, particularly derivatives which permit a coupling of the specifically disclosed substances to solid carriers are also encompassed within the context of the invention; a large selection of corresponding linker/spacer groups is known to the person skilled in the art. The derivatization can take place here prior to the coupling to a solid phase or only as a result of the coupling.
The invention further relates to the use of a modulator, in particular agonists, for the TRPM8 receptor, where the modulator is as defined above, for inducing a sensation of coldness, in particular topically, i.e. cutaneously or orally, in humans and/or animals.
An "induction of a sensation of coldness" is present when the compound in the cellular = CA 02734682 2011-02-17 activity test described above exhibits an agonistic effect on hTRPM8.
The invention further relates to the use of a modulator for the TRPM8 receptor, where the modulator is as defined above, as active constituent of a pharmaceutical composition.
The invention further relates to the use of a modulator for the TRPM8 receptor, where the modulator is as defined above, for the treatment of prostate carcinomas, for the treatment of bladder weakness or in pain therapy.
The invention further relates to the use of a modulator for the TRPM8 receptor, where the modulator is as defined above, as insect repellent or insecticide.
The invention further relates to the use of a modulator for the TRPM8 receptor, where the modulator is as defined above, for inducing a sensation of coldness in packaging s (e.g. made of paper or plastic) in a very wide variety of processing forms (such as e.g.
fibers, fabrics, moldings), where the sensation of coldness becomes noticeable in particular upon contact with the packaging material. In this connection, the substances can be associated in very diverse ways with the packaging material: e.g. by spin-coating, imprinting, in the form of microencapsulation, direct incorporation into the packaging material (e.g. extruding), covalent coupling of suitable derivatives of the modulators (via suitable spacer/linker groups, with the help of which the molecule is reversibly or irreversibly bonded to the packaging material). Suitable methods are known to the person skilled in the art.
The invention further relates to the use of a modulator for the TRPM8 receptor, where the modulator is as defined above, for inducing a sensation of coldness in textiles. In this connection, the substances can be associated in very diverse ways with the textile:
e.g. by spin-coating, imprinting, in the form of microencapsulation, direct incorporation into the textile material (e.g. extruding), covalent coupling of suitable derivatives of the modulators (via suitable spacer/linker groups, with the help of which the molecule is reversibly or irreversibly bonded to the packaging material). Suitable methods are known to the person skilled in the art.
The invention further relates to substances per se according to the above definition for use as mediator, in particular agonists and/or antagonists, of the TRMP8 receptor.
The invention further relates to compositions comprising at least one compound according to the above definition. In particular, such compositons are selected from a) pharmaceutical compositions, such as antitumor compositions, compositions for the treatment of diseases of the bladder, painkillers;
b) foods, such as ice cream, mousse, cream, beverages, confectionery, 5 c) mouthcare compositions, such as toothpaste, mouthwash, chewing gum, breath freshene rs d) skincare or haircare compositions, such as suncream, sunburn cream, lotions, shampoos, plasters, mouthwash, lotions, shaving cream, conditioners, face cleansers, soaps, bath oils and bath foams, antiperspirants, deodorants,
10 e) insect repellents, insecticides.
Besides constituents customary in each case for the particular composition, such compositions comprise an effective amount of at least one modulator according to the invention. In this connection, "effective" means a concentration of the modulator which suffices to bring about the desired effect, such as e.g. pharmacological effect, or sensory effect, such as the olfactory effect of coldness, upon application of the composition (e.g. application to the skin).
Optionally, the compounds according to the invention can be combined with further known active ingredients, in particular also those with a comparable effect.
For example, these can be combined with known cooling compounds, such as e.g.
menthol, menthone, N-ethyl-p-menthanecarboxamide (WS-3), N-2,3-trimethy1-2-isopropylbutanamide (WS-23), menthyl lactate (Frescolat ML), menthone glycerol acetal (Frescolat MGA), monomenthyl succinate (Physcool 0), monomenthyl glutarate, 0-menthylglycerol, menthyl N,N-dimethylsuccinamate.
The invention furthermore relates to textile products, such as e.g. shirts, trousers, socks, towels, finished (in particular on the surface) with at least one compound according to the above definition.
The invention furthermore relates to packaging materials which are associated with at least one compound according to the above definition.
The invention will now be described with reference to the following nonlimiting working examples.

. .
..
11 Experimental section:
Example 1 - Cloning of human TRPM8 The starting point for the cloning of the human TRPM8 receptor is an LnCaP
cDNA library. This is, for example, commercially available (e.g. BioChain, Hayward, USA) or can be produced from the androgen-sensitive human prostate adenocarcinoma cell line LnCaP (e.g.
ATCC, CRL1740 or ECACC, 89110211) using standard kits.
The coding TRPM8 sequence (SEQ ID NO: 1) can be PCR-amplified and cloned using standard methods. The human TRPM8 gene isolated in this way was used for producing the plasmid pind_M8, the construction of which is illustrated by the plasmid map according to figure 1.
Alternatively to this, the TRPM8 gene can also be produced synthetically.
Example 2 - Generation of the HEK293 test cells As test cell system, HEK293 cell line stably transfected with the human TRPM8 DNA (cf. above plasmid pind-M8) are produced. Preference here is given to HEK293 which offers the option, via the introduced plasmid, of inducing the TRPM8 expression by means of tetracycline.
Methods for producing suitable test cell systems are known to the person skilled in the art. For example, the details of the preparation of the cells used according to the invention can be found in Behrendt H.J. et al., Br. J. Pharmacol. 141, 2004, 737-745 or the dissertation by Behrendt "Comparative functional investigations of the heat capsaicin receptor (TRPV1) and of the cold menthol receptor (TRPM8) in recombinant and native cell systems".
Example 3- Assay on TRPM8 modulators A test comparable with the test already described in the literature by Behrendt H.J. et
12 al., Br. J. Pharmacol. 141, 2004, 737-745 is carried out. The agonization or antagonization of the receptor can be quantified by means of a Ca2+-sensitive dye (e.g.
FURA, Fluo-4 etc.). On their own, agonists bring about an increase in the Ca2+
signal;
antagonists bring about, in the presence of e.g. menthol, a reduction in the Ca2+ signal (in each case detected via the dye Fluo-4, which has different fluorescent properties as the result of Ca2+).
a) Test procedure:
Firstly, a fresh culture of transformed HEK cells is prepared in a manner known per se in cell culture flasks. The test cells HEK293-TRPM8 are detached from the cell culture flasks by means of trypsin and 40 000 cells/well are sown out with 100 pl of medium in 96-well plates (Greiner # 655948 poly-D-lysine-coated). To induce the receptor TRPM8, tetracycline is added to the growth medium (DMEM/HG, 10% FCS
tetracycline-free, 4 mM L-glutamine, 15 pg/ml blasticidin, 100 pg/ml hygromycin B, 1 pg/ml tetracycline). On the following day, the cells are loaded with Fluo-4AM dye and the test is carried out. For this, the procedu re is as follows:
- addition of in each case 100 pl/well of dye solution Ca-4 kit (RB
141, Molecular Devices) to in each case 100 pl of medium (DMEM/HG, 10% FCS tetracycline-free, 4 mM L-glutamine, 15 pg/ml blasticidin, 100 pg/ml hygromycin B, 1 pg/ml tetracycline) - incubation in the hatching cabinet, 30 minutes / 37 C / 5% CO2, 30 minutes /
RT
-preparation of the test substances (various concentrations in 200 pi of HBSS
buffer), and also of positive controls (various concentrations of menthol, icilin and ionomycin in 200 pl of HBSS buffer) and negative controls (only 200 pl of HBSS buffer) - addition of the test substances in amounts of 50 pl/well and measurement of the change in fluorescence (e.g. in the assay instrument FLIPR, Molecular Devices or NovoStar, BMG) at 485 nm excitation, 520 nm emission, and evaluation of the effectiveness of the various substances/concentrations and determination of the EC50 values.
The test substances are used in the assay in triplicate in concentrations of 0.1 -200 uM. Normally, the compounds are kept ready in DMSO solutions and are diluted down to a maximum DMSO concentration of 2% for the assay.
b) Test result
13 The EC50 values determined for modulators according to the invention are summarized in table 2 below Table 2: Activity of test substances on the human receptor TRPM8 Activity 1 0.4 4 2.5 5 2.5 6 3.5
14 20 The evaluation surprisingly reveals that, according to the invention, it was possible for the first time to prepare agonists of TRPM8 which differ significantly in structural terms 10 from agonists known hitherto, such as (-) menthol, icilin and other modulators described by Behrendt H.J. et al., in Br. J. Pharmacol. 141, 2004, 737-745 (cf. table 1 therein), and, moreover, in some cases exhibit better acitivities than (-) menthol, or are as comparably effective as icilin.

.CA 02734682 2015-10-28 , , .
,.

Example 4 - Preparation of mouthwash A mouthwash of the following composition is prepared:
Ethanol 95% 177m1 Sorbitol 70% 250 g TRPM8 agonist according to tab. 2 as 1% solution in the ethanol 50 ml Peppermint oil 0.30 g Methyl salicylate 0.64 g Eucalyptol 0.922 g Thymol 0.639 g Benzoic acid 1.50 g Pluronic F127 nonionic surfactant 5.00 g Sodium saccharin 0.60 g Sodium citrate 0.30 g Citric acid 0.10 g Water q.s. 1 liter To prepare a mouthwash, the above-described components are mixed together in the stated amounts.

Claims (18)

Claims
1. A method for in-vitro modulation of cold menthol receptor TRPM8 comprising contacting the receptor with a polynuclear organic compound, wherein in a cellular activity test, the compound is a modulator of the Ca2+ ion permeability of a cell that recombinantly expresses a human TRPM8 receptor, and wherein the modulator is a compound of formula:
2. The method of claim 1, wherein the compound is of formula 1.
3. The method of claim 1, wherein the compound is of formula 2.
4. A modulator for a TRPM8 receptor, wherein the modulator is a compound as defined in any one of claims 1 to 3.
5. A composition comprising the modulator of claim 4, and an acceptable excipient, wherein the composition is a) a pharmaceutical composition, b) a food, c) a mouthcare composition, d) a skincare or haircare composition, or e) an insect repellent and insecticide.
6. The composition of claim 5, wherein the composition is a pharmaceutical composition.
7. The composition of claim 5, wherein the food is an ice cream, a mousse, a cream, a beverage or a confection.
8. The composition of claim 5, wherein the mouthcare composition is a toothpaste, a mouthwash or a chewing gum.
9. The composition of claim 5, wherein the skincare or haircare composition is a suncream, a sunburn cream, a lotion, a shampoo or a plaster.
10. A textile product comprising the modulator of claim 4.
11. The textile product of claim 10, wherein the textile product is a shirt, a trouser, a sock or a towel.
12. A packaging material comprising the modulator of claim 4.
13. Use of one of the compound as defined in any one of claims 1 to 3, for the manufacture of a medicament useful for modulating the TRPM8 receptor.
14. Use of one of the compound as defined in any one of claims 1 to 3, for modulating the TRPM8 receptor.
15. Use of one of the compound as defined in any one of claims 1 to 3, for the manufacture of a medicament useful for inducing a sensation of coldness in a human or animal.
16. Use of one of the compound as defined in any one of claims 1 to 3, for inducing a sensation of coldness in a human or animal.
17. Use of one of the compound as defined in any one of claims 1 to 3, for the manufacture of a medicament for the treatment of prostate carcinoma, bladder weakness or pain.
18. Use of one of the compound as defined in any one of claims 1 to 3, for the treatment of prostate carcinoma, bladder weakness or pain.
CA2734682A 2008-08-26 2009-08-26 Detection and use of low molecular-weight modulators of the cold-menthol receptor trpm8 Active CA2734682C (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CA2937195A CA2937195C (en) 2008-08-26 2009-08-26 Detection and use of compounds containing a benzodioxol group as modulators of the cold-menthol receptor
CA2937196A CA2937196C (en) 2008-08-26 2009-08-26 Detection and use of aromatic compounds as modulators of the cold-menthol receptor

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP08162997.4 2008-08-26
EP08162997 2008-08-26
PCT/EP2009/061019 WO2010026094A1 (en) 2008-08-26 2009-08-26 Detection and use of low molecular-weight modulators of the cold-menthol receptor trpm8

Related Child Applications (2)

Application Number Title Priority Date Filing Date
CA2937195A Division CA2937195C (en) 2008-08-26 2009-08-26 Detection and use of compounds containing a benzodioxol group as modulators of the cold-menthol receptor
CA2937196A Division CA2937196C (en) 2008-08-26 2009-08-26 Detection and use of aromatic compounds as modulators of the cold-menthol receptor

Publications (2)

Publication Number Publication Date
CA2734682A1 CA2734682A1 (en) 2010-03-11
CA2734682C true CA2734682C (en) 2017-09-26

Family

ID=41119517

Family Applications (4)

Application Number Title Priority Date Filing Date
CA2937195A Active CA2937195C (en) 2008-08-26 2009-08-26 Detection and use of compounds containing a benzodioxol group as modulators of the cold-menthol receptor
CA2734682A Active CA2734682C (en) 2008-08-26 2009-08-26 Detection and use of low molecular-weight modulators of the cold-menthol receptor trpm8
CA3044178A Active CA3044178C (en) 2008-08-26 2009-08-26 Detection and use of aromatic compounds as modulators of the cold-menthol receptor
CA2937196A Active CA2937196C (en) 2008-08-26 2009-08-26 Detection and use of aromatic compounds as modulators of the cold-menthol receptor

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CA2937195A Active CA2937195C (en) 2008-08-26 2009-08-26 Detection and use of compounds containing a benzodioxol group as modulators of the cold-menthol receptor

Family Applications After (2)

Application Number Title Priority Date Filing Date
CA3044178A Active CA3044178C (en) 2008-08-26 2009-08-26 Detection and use of aromatic compounds as modulators of the cold-menthol receptor
CA2937196A Active CA2937196C (en) 2008-08-26 2009-08-26 Detection and use of aromatic compounds as modulators of the cold-menthol receptor

Country Status (7)

Country Link
US (2) US8710096B2 (en)
EP (4) EP3103447B1 (en)
JP (3) JP5591238B2 (en)
CN (4) CN107375284B (en)
CA (4) CA2937195C (en)
ES (3) ES2659421T3 (en)
WO (1) WO2010026094A1 (en)

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3103447B1 (en) 2008-08-26 2020-08-05 Basf Se Detection and use of low molecular weight modulators of the cold menthol receptor trpm8
DE102010002558A1 (en) 2009-11-20 2011-06-01 Symrise Ag Use of physiological cooling agents and agents containing such agents
DE202011111014U1 (en) 2010-11-05 2018-05-02 Senomyx, Inc. Compounds useful as modulators of TRPM8
EP2497458A1 (en) 2011-03-08 2012-09-12 B.R.A.I.N. Biotechnology Research And Information Network AG Small molecule modulators of the cold and menthol receptor TRPM8
WO2013041621A1 (en) 2011-09-20 2013-03-28 Basf Se Low molecular weight modulators of the cold-menthol receptor trpm8 and use thereof
US20130251647A1 (en) * 2011-09-20 2013-09-26 Basf Se Low molecular weight modulators of the cold menthol receptor trpm8 and use thereof
JP2013155141A (en) * 2012-01-31 2013-08-15 Mikimoto Pharmaceut Co Ltd Cosmetic
US20130273619A1 (en) 2012-04-16 2013-10-17 Basf Se Process for the Preparation of (3E, 7E)-Homofarnesol
JP6882144B6 (en) * 2012-12-12 2021-06-23 シムライズ アーゲー Compositions and cosmetic compositions
CN105025870B (en) * 2012-12-12 2018-02-02 西姆莱斯股份公司 Composition
US20180296497A1 (en) * 2014-10-31 2018-10-18 Avent, Inc. Method and Articles for Inhibiting Bladder Contractions
KR101624339B1 (en) 2014-12-16 2016-05-25 남우현 shampoo for protect from loose hair for excellenting activate transient receptor potential melastatin-8
EP3297676A2 (en) 2015-05-22 2018-03-28 Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Combination of trpm8-agonist and nachr-agonist for treatment of obesity and related disorders and for weight reduction
CN108473484B (en) * 2015-10-01 2021-06-29 弗门尼舍公司 Compounds useful as modulators of TRPM8
EP3589276B9 (en) 2017-07-26 2024-01-17 TGX Soft Chew, LLC Starch-free soft chew for veterinary applications
WO2019043164A1 (en) * 2017-08-31 2019-03-07 Basf Se Use of physiological cooling active ingredients, and compositions comprising such active ingredients
US20220313629A1 (en) * 2019-02-01 2022-10-06 Marshall University Research Corporation Transient potential melastatin 8 (trpm8) antagonists and related methods
WO2022105986A1 (en) 2020-11-17 2022-05-27 Symrise Ag Novel cooling agents and preparations containing same
WO2023143741A1 (en) 2022-01-28 2023-08-03 Symrise Ag New coolants, and preparations containing same
WO2025026525A1 (en) 2023-07-28 2025-02-06 Symrise Ag Heterocyclic compounds as physiological coolants
CN119354938A (en) * 2024-11-21 2025-01-24 广州市华代生物科技有限公司 A method for screening cooling substances using a TRPM8 stably transfected cell line and the construction of its cell model

Family Cites Families (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3699323A (en) 1970-12-23 1972-10-17 Ibm Error detecting and correcting system and method
SU636236A1 (en) 1976-05-25 1978-12-05 Институт Биоорганической Химии Ан Белорусской Сср 8-aza-16-oxagonane derivatives possessing anti-inflammatory effect and method of obtaining same
RU704083C (en) 1978-07-05 1993-10-30 Институт биоорганической химии АН БССР Derivatives d-номо-8-azagonane possessing antiinflammatory, membranostabilizing and anticoagulating activity
SU704082A1 (en) 1978-07-05 1989-10-23 Институт биоорганической химии АН БССР Derivative of 8,16-diazagonane possessing antiinflammation activity and membrane-protecting effect
SU776048A1 (en) * 1979-06-05 1983-09-23 Институт Бисорганической Химии Ан Бсср Derivatives of 8-aza-16-oxagon-17-ones having antiinflammatory, membrane-stabilizing effect and process for preparing the same
CH651445A5 (en) 1982-07-28 1985-09-30 Ciba Geigy Ag Composition and method for the selective control of weeds in transplanted rice or rice which is sown in water
EP0436729A4 (en) * 1989-08-01 1991-09-11 Kanebo, Ltd. Microcapsule, treatment liquid containing microcapsules, and textile structure having microcapsules stuck thereto
JP3394596B2 (en) * 1994-05-23 2003-04-07 日本テトラパック株式会社 Packaging container
WO1998058905A1 (en) * 1997-06-25 1998-12-30 Yamanouchi Pharmaceutical Co., Ltd. Novel amidrazone derivatives having antifungal activity
NO306533B1 (en) 1998-04-21 1999-11-22 Gunnar Volden insecticide
JP2000302760A (en) * 1999-02-17 2000-10-31 Hokuriku Seiyaku Co Ltd 2-mercaptoquinoline derivative
EP1301458B1 (en) 2000-06-23 2015-09-09 California Institute Of Technology Synthesis of functionalized and unfunctionalized olefins via cross and ring-closing metathesis
MXPA03001271A (en) * 2000-08-24 2003-06-30 Givaudan Sa Composition having insect repellent characteristics.
US6919348B2 (en) 2002-05-02 2005-07-19 Edward T. Wei Therapeutic 1,2,3,6-tetrahydropyrimidine-2-one compositions and methods therewith
GB0214342D0 (en) 2002-06-21 2002-07-31 Givaudan Sa Insect repellents
US7247741B2 (en) * 2005-01-21 2007-07-24 Ptc Therapeutics, Inc. Acetylamino benzoic acid compounds and their use for nonsense suppression and the treatment of disease
DE10234876A1 (en) * 2002-07-25 2004-02-05 Bayer Cropscience Gmbh 4-trifluoromethylpyrazolyl substituted pyridines and pyrimidines
GB0221697D0 (en) * 2002-09-18 2002-10-30 Unilever Plc Novel compouds and their uses
DE10259619A1 (en) * 2002-12-18 2004-07-08 Metagen Pharmaceuticals Gmbh Use of a TRPM8 activating substance for tumor treatment
US6893626B2 (en) 2003-02-18 2005-05-17 Edward T. Wei Compositions for TRP-M8 binding and radioreceptor methods therewith
US7169377B2 (en) * 2003-10-15 2007-01-30 Wei Edward T Radioligands for the TRP-M8 receptor and methods therewith
JP2007527913A (en) * 2004-03-08 2007-10-04 ワイス Ion channel modulator
CN1964988A (en) * 2004-04-08 2007-05-16 詹森药业有限公司 Canine cold- and menthol-sensitive receptor 1
ATE485824T1 (en) 2004-04-13 2010-11-15 Icagen Inc POLYCYCLIC PYRIMIDINES AS POTASSIUM ION CHANNEL MODULATORS
US20050250836A1 (en) * 2004-05-03 2005-11-10 Pfizer Inc Inhibitors of checkpoint kinases (Wee1 and Chk1)
EP1802600A1 (en) 2004-10-13 2007-07-04 Bayer HealthCare AG Substituted 4-benzyloxy-phenylmethylamide derivatives as cold menthol receptor-1 (cmr-1) antagonits for the treatment of urological disorders
WO2006097337A2 (en) * 2005-03-18 2006-09-21 Onepharm Gmbh 11β-HYDROXYSTEROID DEHYDROGENASES
WO2007017093A1 (en) * 2005-08-04 2007-02-15 Bayer Healthcare Ag Substituted 2-benzyloxy-benzoic acid amide derivatives
ES2668361T3 (en) 2005-08-15 2018-05-17 Givaudan Sa Refrigerant compounds
EP1940791B1 (en) 2005-10-25 2009-09-16 Givaudan SA Organic compounds
WO2007080109A1 (en) * 2006-01-16 2007-07-19 Bayer Healthcare Ag Substituded benzyloxy-phenylmethylurea derivatives
RU2509079C2 (en) * 2006-02-15 2014-03-10 Дендреон Корпорейшн LOW-MOLECULAR WEIGHT Trp-p8 ACTIVITY MODULATORS
GB0615136D0 (en) * 2006-07-29 2006-09-06 Univ Edinburgh Induction of analgesia in neuropathic pain
EP1913976A1 (en) 2006-10-18 2008-04-23 Symrise GmbH & Co. KG N-alpha-(menthane carbonyl) amino acid amides and their use as physiological coolants
EP1958627A3 (en) 2007-01-04 2010-09-01 Symrise GmbH & Co. KG Use of certain menthyl-3-oxocarbonic acid esters as physiological cooling agents
EP2033688B1 (en) 2007-08-20 2012-10-17 Symrise AG Oxalic acid derivatives and their use as physiological cooling agents
WO2009064388A2 (en) * 2007-11-09 2009-05-22 Liu Jun O Inhibitors of human methionine aminopeptidase 1 and methods of treating disorders
WO2010010435A2 (en) 2008-07-22 2010-01-28 Glenmark Pharmaceutical S.A. Fused oxazole and thiazole derivatives as trpms modulators
EP3103447B1 (en) 2008-08-26 2020-08-05 Basf Se Detection and use of low molecular weight modulators of the cold menthol receptor trpm8

Also Published As

Publication number Publication date
ES2659421T3 (en) 2018-03-15
CN102137660B (en) 2014-08-13
CA3044178C (en) 2022-03-15
EP3115045A2 (en) 2017-01-11
JP2014218508A (en) 2014-11-20
EP3103447A1 (en) 2016-12-14
WO2010026094A1 (en) 2010-03-11
CA2937196A1 (en) 2010-03-11
JP2016029042A (en) 2016-03-03
CN111803478A (en) 2020-10-23
US8710096B2 (en) 2014-04-29
CN102137660A (en) 2011-07-27
CA2937195C (en) 2019-07-09
EP2349239A1 (en) 2011-08-03
ES2828975T3 (en) 2021-05-28
US9346823B2 (en) 2016-05-24
JP5591238B2 (en) 2014-09-17
JP5956036B2 (en) 2016-07-20
EP3698779A1 (en) 2020-08-26
CN104147016B (en) 2017-07-11
EP3103447B1 (en) 2020-08-05
CN107375284B (en) 2020-08-07
EP3115045B1 (en) 2020-08-12
CN104147016A (en) 2014-11-19
US20140194433A1 (en) 2014-07-10
EP3115045A3 (en) 2017-05-17
CA3044178A1 (en) 2010-03-11
CN111803478B (en) 2023-12-05
CA2937196C (en) 2019-07-09
EP2349239B1 (en) 2017-11-15
JP5795107B2 (en) 2015-10-14
CA2734682A1 (en) 2010-03-11
US20110145970A1 (en) 2011-06-23
ES2828974T3 (en) 2021-05-28
JP2012500828A (en) 2012-01-12
CA2937195A1 (en) 2010-03-11
CN107375284A (en) 2017-11-24

Similar Documents

Publication Publication Date Title
CA2734682C (en) Detection and use of low molecular-weight modulators of the cold-menthol receptor trpm8
JP6124939B2 (en) Use of physiologically cool active ingredients and medicaments containing such active ingredients
US20060106217A1 (en) Novel compounds and their uses
JP2024505595A (en) Organic compounds as TRPM8 activators
EP2683352B1 (en) Small molecule modulators of the cold and menthol receptor trpm8
FR2654101A1 (en) NOVEL INTERNAL SALTS OF DIAMINO-2,4-ALCOXY-6 SULFOOXY-3 PYRIMIDINIUM HYDROXIDES AND THEIR USE FOR THE TREATMENT AND PREVENTION OF FALL OF HAIR.

Legal Events

Date Code Title Description
EEER Examination request

Effective date: 20140822