EP1853269A2 - Amidderivate als ionenkanalliganden und pharmazeutische zusammensetzungen sowie verfahren damit - Google Patents

Amidderivate als ionenkanalliganden und pharmazeutische zusammensetzungen sowie verfahren damit

Info

Publication number
EP1853269A2
EP1853269A2 EP06736043A EP06736043A EP1853269A2 EP 1853269 A2 EP1853269 A2 EP 1853269A2 EP 06736043 A EP06736043 A EP 06736043A EP 06736043 A EP06736043 A EP 06736043A EP 1853269 A2 EP1853269 A2 EP 1853269A2
Authority
EP
European Patent Office
Prior art keywords
benzamide
trien
deca
methyl
ynyl
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.)
Withdrawn
Application number
EP06736043A
Other languages
English (en)
French (fr)
Other versions
EP1853269A4 (de
Inventor
Michael Kelly
John Kincaid
Matthew Duncton
Kiran Sahasrabudhe
Satyanarayana Janagani
Ravindra B. Upasani
Guoxian Wu
Yunfeng Fang
Zhi-Liang Wei
Carl Kaub
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.)
Evotec OAI AG
Original Assignee
Renovis Inc
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 Renovis Inc filed Critical Renovis Inc
Publication of EP1853269A2 publication Critical patent/EP1853269A2/de
Publication of EP1853269A4 publication Critical patent/EP1853269A4/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/50—Iso-indoles; Hydrogenated iso-indoles with oxygen and nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/28—Cinnolines
    • 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
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/16—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with only hydrogen or carbon atoms directly attached in positions 2 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with 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
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • 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
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/52—Radicals substituted by halogen atoms or nitro radicals
    • 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
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • This invention relates to novel compounds and to pharmaceutical compositions containing such compounds.
  • This invention also relates to methods for preventing and/or treating pain and inflammation-related conditions in mammals, such as (but not limited to) arthritis, Parkinson's disease, Alzheimer's disease, stroke, uveitis, asthma, myocardial infarction, the treatment and prophylaxis of pain syndromes (acute and chronic or neuropathic), traumatic brain injury, acute spinal cord injury, neurodegenerative disorders, alopecia (hair loss), inflammatory bowel disease, urinary incontinence, chronic obstructive pulmonary disease, irritable bowel disease, osteoarthritis, and autoimmune disorders, using the compounds and pharmaceutical compositions of the invention.
  • Ion channels are integral membrane proteins with two distinctive characteristics: they are gated (open and closed) by specific signals such as membrane voltage or the direct binding of chemical ligands and, once open, they conduct ions across the cell membrane at very high rates.
  • ion channels There are many types of ion channels. Based on their selectivity to ions, they can be divided into calcium channel, potassium channel, sodium channel, etc. The calcium channel is more permeable to calcium ions than other types of ions, the potassium channel selects potassium ions over other ions, and so forth. Ion channels may also be classified according to their gating mechanisms. In a voltage-gated ion channel, the opening probability depends on the membrane voltage, whereas in a ligand-gated ion channel, the opening probability is regulated by the binding of small molecules (the ligands). Since ligand-gated ion channels receive signals from the ligand, they may also be considered as "receptors" for ligands.
  • ligand-gated ion channels examples include nAChR (nicotinic acetylcholine receptor) channel,
  • GIuR glutamate receptor
  • TRP channel proteins constitute a large and diverse family of proteins that are expressed in many tissues and cell types. This family of channels mediates responses to nerve growth factors, pheromones, olfaction, tone of blood vessels and metabolic stress et al., and the channels are found in a variety of organisms, tissues and cell types including nonexcitable, smooth muscle and neuronal cells. Furthermore, TRP-related channel proteins are implicated in several diseases, such as several tumors and neurodegenerative disorders and the like. See, for example, Minke, et al., APStracts 9:0006P (2002).
  • Nociceptors are specialized primary afferent neurons and the first cells in a series of neurons that lead to the sensation of pain.
  • the receptors in these cells can be activated by different noxious chemical or physical stimuli.
  • the essential functions of nociceptors include the transduction of noxious stimuli into depolarizations that trigger action potentials, conduction of action potentials from primary sensory sites to synapses in the central nervous system, and conversion of action potentials into neurotransmitter release at presynaptic terminals, all of which depend on ion channels.
  • TRP channel protein of particular interest is the vanilloid receptor.
  • the vanilloid receptor is a non-selective cation channel which is activated or sensitized by a series of different stimuli including capsaicin, heat and acid stimulation and products of lipid bilayer metabolism (anandamide), and lipoxygenase metabolites. See, for example Smith, et al., Nature, 418:186-190 (2002).
  • VRl is especially important to VRl function, as extracellular Ca 2+ mediates desensitization, a process which enables a neuron to adapt to specific stimuli by diminishing its overall response to a particular chemical or physical signal.
  • VRl is highly expressed in primary sensory neurons in rats, mice and humans, and innervates many visceral organs including the dermis, bones, bladder, gastrointestinal tract and lungs. It is also expressed in other neuronal and non-neuronal tissues including the CNS, nuclei, kidney, stomach and T-cells.
  • the VRl channel is a member of the superfamily of ion channels with six membrane-spanning domains, with highest homology to the TRP family of ion channels.
  • VRl gene knockout mice have been shown to have reduced sensory sensitivity to thermal and acid stimuli. See, for example, Caterina, et al. Science, 14:306-313 (2000). This supports the concept that VRl contributes not only to generation of pain responses but also to the maintenance of basal activity of sensory nerves.
  • VRl agonists and antagonists have use as analgesics for the treatment of pain of various genesis or etiology, for example acute, inflammatory and neuropathic pain, dental pain and headache (such as migraine, cluster headache and tension headache).
  • Compounds, such as those of the present invention, which interact with the vanilloid receptor can thus play a role in treating or preventing or ameliorating these conditions.
  • Vanilloid compounds of different structures are known in the art, for example those disclosed in European Patent Application Numbers, EP 0 347 000 and EP 0 401 903, UK Patent Application Number GB 2226313 and International Patent Application, Publication Number WO 92/09285.
  • vanilloid compounds or vanilloid receptor modulators are capsaicin or trans 8-methyl-N-vanillyl-6- nonenamide which is isolated from the pepper plant, capsazepine (Tetrahedron, 53, 1997, 4791) and olvanil or- N- (4-hydroxy-3-methoxybenzyl)oleamide (J. Med. Chem., 36, 1993, 2595).
  • 02/16319 suggest that compounds having a high affinity for the vanilloid receptor are useful for treating stomach- duodenal ulcers.
  • Ureidopyrrolidines that are said to exhibit analgesic, central nervous system, and pyschopharmacologic activities. These patents specifically disclose the compounds l-(l-phenyl-3-pyrrolidinyl)-3-phenyl urea and l-(l-phenyl-3- ⁇ yrrolidinyl)-3-(4-methoxyphenyl) urea respectively.
  • WO 01/62737 and WO 00/69849 disclose a series of pyrazc 1 e derivatives which are stated to be useful in the treatment of discMeVs ahd ⁇ dks ⁇ SBbiMd ⁇ ffiftd ⁇ MPY receptor subtype Y5, such as obesity.
  • WO 01/62737 specifically discloses the compound S-amino-N-isoquinolin-S-yl-l-fS- ⁇ ifluorometliy ⁇ phenylJ-lH-pyrazole-S-carboxamide.
  • WO 00/69849 specifically discloses the compounds 5-methyl-N-quinolin-8-yl-l-[3-(trifluoromethyl)phenyl ]-lH- ⁇ yrazole-3-carboxamide, 5-methyl-N-quinolin-7-yl-l-[3-trifluoromethyl)phenyl]-lH- ⁇ yrazole-3-carboxamide, 5- methyl-N-quinolin-3-yl-l-[3-(trifluoromethyl) ⁇ henyl]-lH- ⁇ yrazole-3-carboxamide, N-isoquinolin-5-yl-5-methyl-l ⁇ [3-(trifluoromethyl)phenyl]-lH- ⁇ yrazole-3-carboxamide, 5-methyl-N-quinolin-5-yl-l-[3-(trifluoromethyl)phenyl]- lH-pyrazole-3-carboxamide, l-CS-chloropheny ⁇ -N-isoquinol
  • German Patent Application Number 2502588 describes a series of piperazine derivatives. This application specifically discloses the compound N-[3-[2-(diethylamino) ethyl]-l,2-dihydro-4-methyl-2-oxo-7- quinolinyl]-4-phenyl- 1 -piperazinecarboxamide.
  • the present compounds are capable of modifying mammalian ion channels such as the VRl cation channel. Accordingly, the present compounds are potent VRl antagonists with analgesic activity by systemic administration.
  • the compounds of the present invention may show less toxicity, good absorption, good half-life, good solubility, low protein binding affinity, less drug-drag interaction, a reduced inhibitory activity at HERG channel, reduced QT prolongation and good metabolic stability. This finding leads to novel compounds having therapeutic value.
  • compositions having the compounds of the present invention as active ingredients and to their use to treat, prevent or ameliorate a range of conditions in mammals such as but not limited to pain of various genesis or etiology, for example acute, chronic, inflammatory and neuropathic pain, dental pain and headache (such as migraine, cluster headache and tension headache).
  • pain of various genesis or etiology for example acute, chronic, inflammatory and neuropathic pain, dental pain and headache (such as migraine, cluster headache and tension headache).
  • each of W, Z, Y and X is independently N or CR 4 ;
  • R 1 is substituted or unsubstituted bicycloaryl or bicycloheteroaryl
  • R 3 is C 1 -C 6 alkyl, hydroxyl C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, heteroalkyl, aryl, cycloalkyl, cycloheteroalkyl, heteroaryl, aralkyl, or heteroaralkyl; 11 alkyl, hydroxyl C 1 -C 6 alkyl, C 2 -C 6 acyl, C 2 -C 6 acylamino, C r C 6 alkylamino, C 1 -C 6 alkylthio, CpC 6 alkoxy, C r C 6 alkoxycarbonyl, C 1 -C 6 alkylarylamino, aryl C 1 -C 6 alkyloxy, amino, aryl, aryl C 1 -C 6 alkyl, sulfoxide, sulfone, sulfanyl, aminosulfonyl, arylsulfonyl, sulfuric acid, sulfur
  • R 3 is as defined for compounds of formula I and R 5 and R ⁇ are independently selected from hydrogen, halo, C 1 -C 6 alkyl, hydroxyl C 1 -C 6 alkyl, hetero C 1 -C 6 alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl.
  • R 3 is selected from C 1 -C 6 alkyl, hydroxyl C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl; and each R 5 and R 6 are independently selected from hydrogen, halo and substituted and unsubstituted C 1 -C 6 alkyl; and 0-3 groups selected from W, Z, X and Y represent N.
  • R 5 and R 6 may, for example, independently represent hydrogen, halo, C 1 -C 6 alkyl or hydroxyl CpC 6 alkyl. Preferably R 5 and R 6 represent hydrogen.
  • R 3 -L represents the moiety R 3 C ⁇ C-.
  • R 1 may for example represent substituted or unsubstituted bicycloaryl or bicycloheteroaryl, e.g. substituted naphthyl, quinoline, isoquinoline or tetrahydroquinoline.
  • substituents include alkyl, alkyl(OH), -COOH, C(Me) 3 , CH(Me) 2 , halo, CF 3 , cyan' ⁇ t ⁇ dt ⁇ etlMyr 11 Mter ⁇ atityelyfR m rrf ⁇ y p represent substituted or unsubstituted tetrahydroisoquinoline or benzodioxane.
  • R 3 may for example represent CR 6 'R 7 R 8 wherein R 6 ' represents hydrogen, halo, Ci-C ⁇ alkyl or hydroxyl C 1 -CO alkyl; each of R 7 and R 8 is independently halo, Cj-C 6 alkyl or hydroxyl C 1 -C 6 alkyl; or R 7 and R 8 together form a substituted or unsubstituted C 3 -C 8 cycloalkyl ring.
  • R 7 may represent lower alkyl (e.g. methyl).
  • R 8 may represent lower alkyl (e.g. methyl).
  • R 6 ' may represent hydrogen and R 7 and R 8 may represent methyl.
  • each of R 6 ', R 7 and R 8 may represent methyl.
  • each of R 6 ', R 7 and R 8 may represent fluoro.
  • R 6 ' may represent hydrogen and R 7 and R 8 together form a cyclopropyl ring.
  • R 3 may for example represent substituted or unsubstituted aryl or heteroaryl.
  • R 3 is CF 3 , n-propyl, or a group of the formula
  • R 2 is hydrogen or alkyl; and wherein two R 2 may join together to form a cycloalkyl or cycloheteroalkyl ring of 3-8 atoms; provided at least two of R 2 are alkyl.
  • R 1 may be substituted or unsubstituted naphthyl, or alternatively, substituted or unsubstituted tetrahydronaphthyl. Further, R 1 may also be substituted or unsubstituted bicycloheteroaryl, and in a particular embodiment, the bicycloheteroaryl may be selected from the group consisting of tetrahydroquinoline, tetrahydroisoquinoline, benzodioxane, benzopyran, indole and benzimidazole.
  • the bicycloheteroaryl may be quinoline, isoquinoline, benzodioxane, and benzoxazine.
  • the substitution on the bicycloheteroaryl is selected from the group consisting of hydrogen, alkyl, trifluoromethyl, halo, methoxy, trifluoromethoxy, amino and carboxy.
  • the substitution on bicycloheteroaryl is selected from the group consisting of tert-butyl, cyano, trifluoroalkyl, halo, nitro, methoxy, amino and carboxy.
  • R 1 may be substituted or unsubstituted isoquinolin-5-yl, quinolin-3-yl, benzodioxan-6-yl or benzoxazin-6-yl.
  • R 1 may be substituted or unsubstituted: wherein, when feasible, the ring N can further be substituted with H or alkyl.
  • R 1 may be substituted or unsubstituted:
  • the ring N can further be substituted with H or alkyl.
  • R 1 may be substituted or unsubstituted:
  • the ring N can further be substituted with H or alkyl.
  • R 3 may be substituted or unsubstituted cyclopropyl.
  • R 3 may be CF 3 .
  • the compounds of the invention are set forth and may be selected from a comprehensive listing of such compounds, set forth later on herein in Table 1.
  • Table 1 contains in excess of 200 compounds that have been or can be synthesized and have as a group, demonstrated activity in their capacity of modifying ion channels, in vivo, and thereby functioning in the therapeutic applications set forth herein in relation to capsaicin and the vanilloid receptor.
  • compounds are disclosed that are capable of modifying ion channels, in vivo, having a formula I-I: wherein: each of W, Z, Y and X is independently N or CR 4 ;
  • R 1 is substituted bicycloaryl or bicycloheteroaryl
  • R 3 is C r C 6 alkyl, hydroxyl Ci-C 1 ; alkyl, halo Ci-C 6 alkyl, heteroalkyl, aryl, cycloalkyl, cycloheteroalkyl, heteroaryl, aralkyl, or heteroaralkyl; each R 4 is independently hydrogen, C r C 6 alkyl, hydroxyl C]-C 6 alkyl, acylamino, alkylamino, allcylthio, alkoxy, alkoxycarbonyl, alkylarylamino, arylalkyloxy, amino, aryl, arylalkyl, sulfoxide, sulfone, sulfanyl, aminosulfonyl, arylsulfonyl, sulfuric acid, sulfuric acid ester, dihydroxyphosphoryl, aminohydroxyphosphoryl, azido, carboxy, carbamoyl, cyano, cycloheteroalkyl, dialkylamin
  • R 3 is as defined for compounds of formula I and R 5 and R 6 are independently selected from hydrogen, halo, C]-C 6 alkyl, hydroxyl Cj-C 6 alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl.
  • R 3 is selected from Cj-C 6 alkyl, hydroxyl Q-Cg alkyl, substituted or unsubstituted Ci-C 6 cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl; and each R 5 and R 6 are independently selected from hydrogen, halo and substituted and unsubstituted Q-C 6 alkyl; and 0-3 groups selected from W, Z, X and Y represent N.
  • R 5 and R 6 may, for example, independently represent hydrogen, halo, Cj-C 6 alkyl or hydroxyl Cj-C 6 alkyl. Preferably R 5 and R 6 represent hydrogen.
  • R 3 -L represents the moiety R 3 C ⁇ C-.
  • W, Z, X and Y may for example each represent CR 4 , especially CH.
  • X may represent N and W
  • Z and Y may each represent CR 4 .
  • W is N.
  • Y is N.
  • each of W, X and Z represents CR 4 especially CH and Y represents CR 4 .
  • R 4 may for example represent substituted alkyl, halo, sulfone, alkoxy, or amino. Particularly, R 4 may represent substituted alkyl or halo. More particularly,
  • R 4 may be methyl, chloro, trifluoromethyl or fluoro.
  • each of W and X represents
  • each R 4 may for example represent substituted alkyl, halo, alkoxy, or amino. Particularly, R 4 may represent substituted alkyl or halo. More particularly,
  • R 4 may be methyl, trifluoromethyl, chloro or fluoro.
  • L represents -C ⁇ C-.
  • R 1 may for example represent substituted bicycloaryl or bicycloheteroaryl, e.g. substituted benzopyranyl, benzoxazine, benzothiazine, indolyl, indazolyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, carbazolyl, naphthalene, tetrahydronaphthalene, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroquinolinyl, or dihydroisoquinolinyl.
  • substituted bicycloaryl or bicycloheteroaryl e.g. substituted benzopyranyl, benzoxazine, benzothiazine, indolyl, indazolyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, carbazolyl, naphthalene, tetrahydrona
  • R 1 may represent substituted or unsubstituted benzoxazine, dihydrobenzoxazine, benzodioxine or benzodioxane.
  • R 3 may for example represent CR 6 R 7 R 8 wherein R 6 ' represents hydrogen, halo, CpC 6 alkyl or hydroxyl C r C 6 alkyl; each of R 7 and R 8 is independently halo, C r C 6 alkyl or hydroxyl C 1 -C 5 alkyl; or R 7 and R 8 together form a substituted or unsubstituted C 3 -Cs cycloalkyl ring.
  • R 7 may represent lower alkyl (e.g. methyl).
  • R 8 may also represent lower alkyl (e.g. methyl).
  • R 6 may represent hydrogen and R 7 and R 8 may represent methyl.
  • each of R 6 , R 7 and R 8 may represent methyl.
  • each of R 6 , R 7 and R 8 may represent fluoro.
  • R 6 may represent hydrogen and R 7 and R 8 together form a cyclopropyl ring.
  • R 3 may for example represent substituted or unsubstituted aryl or heteroaryl.
  • R 3 is CF 3 , n-propyl, or a group of the formula
  • R 2 is hydrogen or alkyl; and wherein two R 2 s may join together to form a cycloalkyl or cycloheteroalkyl , ring of 3-8 atoms; provided at least two of R 2 are alkyl.
  • R 1 may be substituted naphthyl, or alternatively, substituted tetrahydronaphthyl. Further, R 1 may also be substituted bicycloheteroaryl, and in a particular embodiment, the bicycloheteroaryl may be selected from the group consisting of tetrahydroquinoline, tetrahydroisoquinoline, benzoxazine, dihydrobenzoxazine, benzodioxine, dihydrobenzodioxine, benzopyran, indole and benzimidazole.
  • the bicycloheteroaryl may be quinoline, isoquinoline, benzodioxine, and benzoxazine.
  • the substitution on the bicycloheteroaryl is selected from the group consisting of hydrogen, alkyl, trifluoromethyl, halo, methoxy, trifluoromethoxy, amino and carboxy.
  • suDSt ⁇ mti ⁇ Ott Dicycioheteroaryl is selected from the group consisting of substituted alkyl, cyano, trifluoroalkyl, halo, nitro, methoxy, amino and carboxy.
  • the substitution on bicycloheteroaryl is selected from alkyl substituted with hydroxyl or amino.
  • the substitution on bicycloheteroaryl is hydroxyalkyl, for example, hydroxymethyl, hydroxyethyl or hydroxypropyl.
  • R 1 may be substituted or unsubstituted:
  • each of A 1 , A 2 , A 3 , A 4 , B 1 and B 2 is independently CR 4' and N; and each of R 4 is independently H, substituted or unsubstituted lower alkyl, halo, hydroxyl, alkoxy, substituted alkoxy, amino, substituted amino, or hydroxyalkyl. More particularly, R 1 may be substituted or unsubstituted:
  • R may be substituted:
  • each of A 5 and A 8 is independently CR 4 R 4' , NR 4' , O, S, SO or SO 2 ; each of A 6 and A 7 is independently CR 4' , NR 4' , CR 4 R 4' or CO; each of B 3 and B 4 is independently CR 4' and N; when R 4 is attached to C, each of R 4 is independently H, C]-Cg alkyl, halo, or hydroxy Cj-Cg alkyl, and when R 4 is attached to N, each of R 4' is independently H or CpCg alkyl; and the dotted bond represents a single or a double bond. More particularly, R 1 may be substituted or unsubstituted:
  • R may be substituted or unsubstituted:
  • R 1 may be substituted or unsubstituted:
  • each of A 9 , A 10 and A 11 is independently CR 4' , CR 4 R 4' , CO, CS, N, NR 4' , O, S, SO or SO 2 ; each of B 5 and
  • B 6 is independently CR 4' and N; when R 4 is attached to C, each of R 4 is independently H, C r C 6 alkyl, halo, or hydroxy C]-C 6 alkyl, and when R 4 is attached to N, each of R 4' is independently H or C 1 -C 6 alkyl; and each of the dotted bonds independently represents a single or a double bond. More particularly, R 1 may be substituted or unsubstituted:
  • R 1 may be substituted or unsubstituted:
  • R 4' is substituted or unsubstituted lower alkyl. More particularly, R 4> is CpCe alkyl or hydroxy Ci-C 6 alkyl.
  • R 1 may be substituted
  • each of A 5 and A 8 is independently CH 2 , CHMe, NH, NMe 5 O, S, SO or SO 2 ; and R 4 is Cj-C 6 alkyl or hydroxy Ci-C 6 alkyl.
  • R 1 may be substituted
  • R 4 is substituted alkyl. More particularly, R 4 is Ci-C 6 alkyl or hydroxy CpC 6 alkyl.
  • R 1 may be substituted
  • R is substituted alkyl. More particularly, R is Ci-C 6 alkyl or hydroxy Ci-C 6 alkyl.
  • R 1 may be substituted
  • R 4 is substituted alkyl. More particularly, R 4 is CpC 6 alkyl or hydroxy C r C 6 alkyl.
  • R 1 may be substituted
  • R 4 is substituted alkyl. More particularly, R 4 is CpC 6 alkyl or hydroxy CpC 6 alkyl.
  • R 1 may be substituted
  • R may be substituted
  • R 4' is independently H, C 1 -C 6 alkyl, halo, or hydroxy C 1 -C 6 alkyl.
  • R 1 may be substituted dihydrobenzodioxin-6-yl or dihydrobenzoxazin-6-yl.
  • R 1 may be substituted or unsubstituted:
  • the ring N can further be substituted with H or C 1 -C 6 alkyl.
  • R 1 may be substituted or unsubstituted:
  • R 1 may be substituted or unsubstituted:
  • the ring N can further be substituted with H or alkyl.
  • R may be hydroxy Ci-C ⁇ alkyl.
  • R may be-(CH 2 ) n -OH; and n may be selected from 1-3.
  • R may be -CH 2 OH.
  • R 1 may be:
  • R 1 may be:
  • R 1 may be:
  • R 3 may be substituted or unsubstituted cycloalkyl. More particularly, R 3 may be substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 3 may be cyclopropyl.
  • R 3 may be CF 3 or CHF 2 . More particularly R 3 may be CF 3 .
  • R 3 may be t-Bu or isopropyl. More particularly R 3 may be t-Bu.
  • the present invention provides amide compounds according to formula
  • R 3 is t-Bu, CF 3 or cyclopropyl
  • Z and Y are independently C-H, C-F, C-Cl, C-Me, C-SO 2 Me or C-OMe
  • B 3 and B 4 are independently CR or N
  • each of A 5 and A 8 is independently CR 4 R 4 , NR 4 , O, S, SO or
  • each of A 6 and A 7 is independently CR 4' , NR 4' , CR 4 R 4' or CO; each of R 4' is independently H, substituted or unsubstituted alkyl or aryl; and the dotted bond represents a single or a double bond. In one particular embodiment, each R 4 is independently H, substituted or unsubstituted alkyl.
  • the present invention provides amide compounds according to formula
  • R 3 is t-Bu, CF 3 or cyclopropyl
  • Z and Y are independently C-H, C-F, C-Cl, C-Me, C-SO 2 Me or C-OMe
  • B 3 and B 4 are independently CR 4 or N
  • each of A 5 and A 8 is independently CR 4 R 4 , NR 4 , O, S, SO or SO 2
  • each of A 6 and A 7 is independently CR 4' , NR 4' , CR 4 R 4' or CO
  • each of R 4' is independently H, substituted or unsubs'tt ⁇ uted alKyl 'o"r Effyi
  • 1 andWuottelT bond represents a single or a double bond.
  • each of R 4 is independently H, substituted or unsubstituted alkyl.
  • the present invention provides amide compounds according to formula
  • R 3 is t-Bu, CF 3 or cyclopropyl
  • Z and Y are independently C-H, C-F, C-Cl, C-Me, C-SO 2 Me or C-OMe
  • B 3 and B 4 are independently CR 4' or N
  • a 5 and A 8 are independently O or NH.
  • R 3 may be t-Bu. In another particular embodiment, with respect to the compounds of formula IV, R 3 may be CF 3 . In another particular embodiment, with respect to the compounds of formula IV, R 3 may be cyclopropyl.
  • Y is C-H and Z is C-F or C-
  • Y is C-H and Z is C-F.
  • Y is C-H and Z is C-Cl.
  • Y is C-Me or C-OMe.
  • Y and Z both may be C-F.
  • Y and Z both may be C-Cl.
  • Y and Z both may be C-Me.
  • a 5 and A s both may be O. In one particular embodiment, with respect to the compounds of formula IV, A 5 and A 8 both may be NH. In one particular embodiment, with respect to the compounds of formula IV, A 5 may be O and A may be NH. In one particular embodiment, with respect to the compounds of formula IV, A 5 may be NH and A 8 may be O.
  • the present invention provides amide compounds according to formula
  • R 3 is t-Bu, CF 3 or cyclopropyl
  • Z and Y are independently C-H, C-F, C-Cl, C-Me, C-SO 2 Me or C-OMe
  • B 3 and B 4 are independently CR 4 or N
  • a 5 and A 8 are independently O or NH.
  • R 3 may be t-Bu. In another particular embodiment, with respect to the compounds of formula V, R 3 may be CF 3 . In another particular embodiment, with respect to the compounds of formula V, R 3 may be cyclopropyl.
  • Y and Z both may be C-H.
  • Y is C-H and Z is C-F or C-Cl. In another particular embodiment, with respect to compounds of formula V, Y is C-H and Z is C-F. In a further particular embodiment, with respect to the compounds of formula V, Y is C-H and Z is C-Cl. In another particular embodiment, with respect to compounds of formula V, Y is C-H and Z is C-Me or C-OMe. [0084J ' In a particular embodiment, with respect to the compounds of formula V, Y and Z both may be C-
  • Y and Z both may be C-Cl. In yet another particular embodiment, with respect to the compounds of formula IV, Y and Z both may be C-Me. [0085] In one particular embodiment, with respect to the compounds of formula V, A 5 and A 8 both may be
  • a 5 and A 8 both may be NH. In one particular embodiment, with respect to the compounds of formula V, A 5 may be O and A 8 may be NH. In one particular embodiment, with respect to the compounds of formula V, A 5 may be NH and A 8 may be O. [0086] In a further aspect, the present invention provides compounds according to formula (VI):
  • R 3 is CR 6 R 7 R 8 wherein R 6 ' is hydrogen, halo,
  • Ci-C 6 alkyl or hydroxyl CpC 6 alkyl; each of R 7 and R 8 is independently halo or substituted or unsubstituted CpC 6 alkyl; or R 7 and R 8 together form a substituted or unsubstituted C 3 -C 8 cycloalkyl ring.
  • R 7 may represent lower alkyl (e.g. methyl).
  • R s may also represent lower alkyl (e.g. methyl).
  • R 6> may represent hydrogen and R 7 and R 8 may represent methyl.
  • each of R 6 , R 7 and R 8 may represent methyl.
  • each of R 6 , R 7 and R 8 may represent fluoro.
  • R 6 may represent hydrogen and R 7 and R 8 together may form a cyclopropyl ring.
  • R 3 is selected from the group consisting of CF 3 , t-Bu and cycloalkyl. In particular embodiments, R 3 is CF 3 . In particular embodiments, R is £-Bu. In particular embodiments, R 3 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In particular embodiments, R 3 is cyclopropyl.
  • R 5 and R 6 may, for example, independently represent hydrogen, halo, CpC 6 alkyl or hydroxyl CpC 6 alkyl.
  • R 5 and R 6 represent hydrogen.
  • L represents -CsC-.
  • each of B 7 , B 8 and B 9 is N or CR 4 wherein R 4 is selected from the group consisting of substituted alkyl, halo, alkoxy, or amino.
  • each of B , B and B 9 is CR .
  • R 4 is independently H, CH 3 , CF 3 , Cl, or F.
  • each of B 7 , B 8 and B 9 is N or CR 4 wherein R 4 is selected from the group consisting of substituted alkyl, halo, alkoxy, or amino.
  • each of B , B and B 9 is CR .
  • R 4 is independently H, CH 3 , CF 3 , Cl, or F.
  • each of B 7 , B 8 and B 9 is N or CR 4 wherein R 4 is selected from the group consisting of substituted alkyl, halo, alkoxy, or amino.
  • each of B , B and B 9 is CR .
  • R 4 is independently H, CH 3 , CF 3 , Cl, or
  • R 4 is H.
  • W, Z, X and Y may for example each represent CR 4 , especially
  • X may represent N and W, Z and Y may each represent CR 4 .
  • each of X, Y and Z represents CR 4 , especially CH.
  • W is N.
  • Y is N.
  • each of W, X and Z represents CR 4 especially CH and Y represents CR 4 .
  • R 4 may for example represent substituted alkyl, halo, alkoxy, or amino. Particularly, R 4 may represent substituted alkyl or halo. More particularly, R 4 may be methyl, chloro or fluoro.
  • each of W and X represents CR especially CH and each of Y and Z represent CR 4 .
  • each R 4 may for example represent substituted alkyl, halo, alkoxy, or amino.
  • R 4" may represent substituted alkyl or halo, and more particularly, methyl, chloro or fluoro.
  • each of W and X is N or CR 4
  • each of Y and Z is N or CR and each R 4 is independently selected from hydrogen, alkyl, trihaloalkyl and halo.
  • each of R is independently H, CH 3 , CF 3 , Cl, or F.
  • each R 4 is H.
  • each of W, X, and Z is N or CH
  • Y is C-
  • R is hydroxyl substituted alkyl.
  • R 4 is -(CH 2 ) n -OH wherein n is selected from 1-6.
  • R 4' is CH 2 OH.
  • the compounds of the invention are set forth and may be selected from a comprehensive listing of such compounds, set forth later on herein in Table 1.
  • the Table contains in excess of 200 compounds that have been or can be synthesized and have as a group, demonstrated activity in then- capacity of modifying ion channels, in vivo, and thereby functioning in the therapeutic applications set forth herein in relation to capsaicin and the vanilloid receptor.
  • [UUl(JUJ Th ' e ' compounds of the present invention are useful for the treatment of inflammatory pain and associated hyperalgesia and allodynia. They are also useful for the treatment of neuropathic pain and associated hyperalgesis and allodynia (e.g.
  • the compounds of the present invention are also useful as anti-inflammatory agents for the treatment of arthritis, and as agents to treat Parkinson's Disease, Alzheimer's Disease, stroke, uveitis, asthma, myocardial infarction, traumatic brain injury, spinal cord injury, neurodegenerative disorders, alopecia (hair loss), inflammatory bowel disease and autoimmune disorders, renal disorders, obesity, eating disorders, cancer, schizophrenia, epilepsy, sleeping disorders, cognition, depression, anxiety, blood pressure, lipid disorders, and atherosclerosis.
  • this invention provides compounds which are capable of modifying ion channels, in vivo.
  • Representative ion channels so modified include voltage-gated channels and ligand-gated channels, including cation channels such as vanilloid channels.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent.
  • the pharmaceutical composition can comprise one or more of the compounds described herein.
  • a method for treating mammals, including humans, as well as lower mammalian species, susceptible to or afflicted with a condition from among those listed herein, and particularly, such condition as may be associated with e.g. arthritis, uveitis, asthma, myocardial infarction, traumatic brain injury, acute spinal cord injury, alopecia (hair loss), inflammatory bowel disease and autoimmune disorders, which method comprises administering an effective amount of one or more of the pharmaceutical compositions just described.
  • this invention provides a method of treating a mammal susceptible to or afflicted with a condition that gives rise to pain responses or that relates to imbalances in the maintenance of basal activity of sensory nerves.
  • Compounds have use as analgesics for the treatment of pain of various geneses or etiology, for example acute, inflammatory pain (such as pain associated with osteoarthritis and rheumatoid arthritis); various neuropathic pain syndromes (such as post-herpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, Guillian Barre syndrome, fibromyalgia, phantom limb pain, post- masectomy pain, peripheral neuropathy, HIV neuropathy, and chemotherapy-induced and other iatrogenic neuropathies); visceral pain, (such as that associated with gastroesophageal reflex disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, and various gy
  • this invention provides methods of treating a mammal susceptible to or afflicted with neurodegenerative diseases and disorders such as, for example Parkinson's disease, Alzheimer's disease and multiple sclerosis; diseases and disorders which are mediated by or result in neuroinflammation such as, for example traumatic brain injury, stroke, and encephalitis; centrally-mediated neuropsychiatric diseases and disorders such as, for example depression mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction such as, for example urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; irritable bowel syndrome, over active bladder, respiratory and airway disease and disorders such as, for example, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders which are ir ⁇ iated by or result in
  • Figure 1 Graph depicts significant inhibition of the Capsaicin induced intracellular calcium response, under described experimental conditions, by 3 tiM of Compound 225.
  • Figure 2 Graph depicts significant inhibition of the Capsaicin induced intracellular calcium response, under described experimental conditions, by 3 nM of Compound 187.
  • Figure 3 Graph depicts significant inhibition of the Capsaicin induced intracellular calcium response, under described experimental conditions, by 3 nM of Compound 96.
  • Figure 4 Graph depicts significant inhibition of the Capsaicin induced intracellular calcium response, under described experimental conditions, by 3 nM of Compound 45.
  • Figure 5 Graph depicts significant inhibition of the Capsaicin induced intracellular calcium response, under described experimental conditions, by 3 nM of Compound 233.
  • Figure 6 Graph depicts significant inhibition of the Capsaicin induced intracellular calcium response, under described experimental conditions, by 3 nM of Compound 167.
  • halo such as fluoro, chloro, bromo
  • -CN -CF 3 , -OH, -OCF 3
  • C 2 -C 6 alkenyl C 3 -C 6 alkynyl, C 1 -C 6 alkoxy, aryl and di- C 1 -C 6 alkylamino.
  • Acyl refers to a radical -C(O)R, where R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl as defined herein.
  • Acylamino refers to a radical -NR 5 C(O)R, where R' is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl and R is hydrogen, alkyl, alkoxy, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl or heteroarylalkyl, as defined herein.
  • Acyloxy refers to the group -OC(O)R where R is hydrogen, alkyl, aryl or cycloalkyl.
  • Substituted alkenyl includes those groups recited in the definition of "substituted” herein, and particularly refers to an alkenyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, subEirilit'ed''alkox ⁇ , ⁇ lcox ⁇ c ⁇ rb ⁇ yl7allcdx ⁇ c ⁇ bonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, m ' tro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, al
  • Alkoxy refers to the group -OR where R is alkyl. Particular alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2- dimethylbutoxy, and the like.
  • Substituted alkoxy includes those groups recited in the definition of "substituted” herein, and particularly refers to an alkoxy group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-
  • aryl-S(O)- alkyl-S(O) 2 - and aryl-S(O) 2 -.
  • Alkoxycarbonylamino refers to the group -NRC(O)OR' where R is hydrogen, alkyl, aryl or cycloalkyl, and R' is alkyl or cycloalkyl.
  • Aliphatics refers to hydrocarbyl organic compounds or groups characterized by a straight, branched or cyclic arrangement of the constituent carbon atoms and an absence of aromatic unsaturation. Aliphatics include, without limitation, alkyl, alkylene, alkenyl, alkenylene, alkynyl and alkynylene. Aliphatic groups typically have from 1 or 2 to about 12 carbon atoms.
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups particularly having up to about 11 carbon atoms, more particularly as a lower alkyl, from 1 to 8 carbon atoms and still more particularly, from
  • the hydrocarbon chain may be either straight-chained or branched. This term is exemplified by groups such as methyl, ethyl, r ⁇ -propyl, isopropyl, «-butyl, wo-butyl, tert-butyl, w-hexyl, «-octyl, tert-octyl and the like.
  • the term “lower alkyl” refers to alkyl groups having 1 to 6 carbon atoms.
  • alkyl also includes
  • Substituted alkyl includes those groups recited in the definition of "substituted” herein, and particularly refers to an alkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, heteroaryl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-
  • aryl-S(O)- alkyl-S(O) 2 -, and aryl-S(O) 2 -.
  • Alkylene refers to divalent saturated aliphatic hydrocarbyl groups particularly having up to about 11 carbon atoms and more particularly 1 to 6 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), the propylene isomers (e.g., -
  • Substituted alkylene includes those groups recited in the definition of "substituted” herein, and particularly refers to an alkylene group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, arylox azido, carboxyl, cyano, halogen, hydroxyl, keto, nitro, thioSMwtyi 1 s ⁇ bstit ⁇ Sd'Tlh ⁇ dialkd ⁇ riMo'a ⁇ Xy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 -
  • alkenyl refers to monovalent olef ⁇ nically unsaturated hydrocarbyl groups preferably having up to about 11 carbon atoms, particularly, from 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olef ⁇ nic unsaturation.
  • Alkynyl refers to acetylenically unsaturated hydrocarbyl groups particularly having up to about
  • alkynyl groups include acetylenic, ethynyl (-C ⁇ CH), propargyl (-CH 2 CsCH), and the like.
  • Substituted alkynyl includes those groups recited in the definition of "substituted” herein, and particularly refers to an alkynyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl— S(O)-, alkyl
  • alkanoyl or “acyl” as used herein refers to the group R-C(O)-, where R is hydrogen or alkyl as defined above.
  • Aryl refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, ⁇ s-indace ⁇ e, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, ple
  • Substituted Aryl includes those groups recited in the definition of "substituted” herein, and particularly refers to an aryl group that may optionally be substituted with 1 or more substituents, for instance from 1 to 5 substituents, particularly 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkoxycarbonyl, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thiol, alkyl-
  • fused Aryl refers to an aryl having two of its ring carbon in common with a second aryl ring or with an aliphatic ring.
  • Alkaryl refers to an aryl group, as defined above, substituted with one or more alkyl groups, as defined above.
  • alkyl or "arylalkyl” refers to an alkyl group, as defined above, substituted with one or more aryl groups, as defined above.
  • Aryloxy refers to -O-aryl groups wherein “aryl” is as defined above.
  • Alkylamino refers to the group alkyl-NR'R", wherein each of R' and R" are independently selected from hydrogen and alkyl.
  • Arylamino refers to the group aryl- NR'R", wherein each of R' and R" are independently selected from hydrogen, aryl and heteroaryl.
  • Alkoxyamino refers to a radical -N(H)OR where R represents an alkyl or cycloalkyl group as defined herein.
  • Alkoxycarbonyl refers to a radical -C(O)-alkoxy where alkoxy is as defined herein.
  • Alkylarylamino refers to a radical -NRR' where R represents an alkyl or cycloalkyl group and
  • R' is an aryl as defined herein.
  • Alkylsulfonyl refers to a radical -S(O) 2 R where R is an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and the like.
  • Alkylsulfinyl refers to a radical -S(O)R where R is an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl and the like.
  • Alkylthio refers to a radical -SR where R is an alkyl or cycloalkyl group as defined herein that may be optionally substituted as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, and the like.
  • Amino refers to the radical -NH 2 .
  • Substituted amino includes those groups recited in the definition of "substituted” herein, and particularly refers to the group -N(R) 2 where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, and where both R groups are joined to form an alkylene group.
  • both R groups are hydrogen
  • -N(R) 2 is an amino group.
  • Aminocarbonyl refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, aryl and cycloalkyl, or where the R groups are joined to form an alkylene group.
  • Aminocarbonylamino refers to the group -NRC(O)NRR where each R is independently hydrogen, alkyl, aryl or cycloalkyl, or where two R groups are joined to form an alkylene group.
  • Aminocarbonyloxy refers to the group -OC(O)NRR where each R is independently hydrogen, alkyl, aryl or cycloalky, or where the R groups are joined to form an alkylene group.
  • Arylalkyloxy refers to an -O-arylalkyl radical where arylalkyl is as defined herein.
  • Arylamino means a radical -NHR where R represents an aryl group as defined herein.
  • Aryloxycarbonyl refers to a radical -C(O)-O-aryl where aryl is as defined herein.
  • Arylsulfonyl refers to a radical -S(O) 2 R where R is an aryl or heteroaryl group as defined herein.
  • Azido refers to the radical -N 3 .
  • aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent bicycloaromatic ring system.
  • Typical bicycloaryl groups include, but are not limited to, groups derived from indane, indene, naphthalene, tetrahydronaphthalene, and the like. Particularly, an aryl group comprises from 8 to 11 carbon atoms.
  • Bicycloheteroaryl refers to a monovalent bicycloheteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent bicycloheteroaromatic ring system.
  • Typical bicycloheteroaryl groups include, but are not limited to, groups derived from benzofuran, benzimidazole, benzindazole, benzdioxane, chromene, chromane, cinnoline, phthalazine, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, benzothiazole, benzoxazole, naphthyridine, benzoxadiazole, pteridine, purine, benzopyran, benzpyrazine, pyridopyrimidine, quinazoline, quinoline, quinolizine, quinoxaline, benzomorphan, tetrahydroisoquinoline, tetrahydroquinoline, and the like.
  • the bicycloheteroaryl group is between 9-11 membered bicycloheteroaryl, with 5-10 membered heteroaryl being particularly preferred.
  • Particlar bicycloheteroaryl groups are those derived from benzothiophene, benzofuran, benzotliiazole, indole, quinoline, isoquinoline, benzimidazole, benzoxazole and benzdioxane.
  • Carbamoyl refers to the radical -C(O)N(R) 2 where each R group is independently hydrogen, alkyl, cycloalkyl or aryl, as defined herein, which may be optionally substituted as defined herein.
  • Carboxy refers to the radical -C(O)OH.
  • Carboxyamino refers to the radical -N(H)C(O)OH.
  • Cycloalkyl refers to cyclic hydrocarbyl groups having from 3 to about 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems, which optionally can be substituted with from 1 to 3 alkyl groups.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclo ⁇ entyl, 2- methylcyclooctyl, and the like, and multiple ring structures such as adamantanyl, and the like.
  • Substituted cycloalkyl includes those groups recited in the definition of "substituted” herein, and particularly refers to a cycloalkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl- S(O)-,
  • Cycloalkoxy refers to the group -OR where R is cycloalkyl. Such cycloalkoxy groups include, by way of example, cyclopentoxy, cyclohexoxy and the like.
  • Cycloalkenyl refers to cyclic hydrocarbyl groups having from 3 to 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems and having at least one and particularly from 1 to 2 sites of olef ⁇ nic unsaturation.
  • Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.
  • Substituted cycloalkenyl includes those groups recited in the definition of “substituted” herein, and particularly refers to a cycloalkenyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, lialdfee ⁇ rh ⁇ dfoxK'K ⁇ 'i'ftltt'o, M ⁇ W ⁇ xy ⁇ ' ⁇ 'bstituted thioalkoxy, thioaryloxy, thioketo,
  • Fused Cycloalkenyl refers to a cycloalkenyl having two of its ring carbon atoms in common with a second aliphatic or aromatic ring and having its olef ⁇ nic unsaturation located to impart aromaticity to the cycloalkenyl ring.
  • Cyclone refers to the radical -OCN.
  • Dialkylamino means a radical -NRR' where R and R' independently represent an alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, or substituted heteroaryl group as defined herein.
  • Ethylene refers to substituted or unsubstituted -(C-C)-.
  • Ethynyl refers to -(C ⁇ C)-.
  • Halo or “halogen” refers to fluoro, chloro, bromo and iodo. Preferred halo groups are either fluoro or chloro.
  • Halo or “Halo” refers to the radical -OH.
  • Niro refers to the radical -NO 2 .
  • Substituted refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • R 6 and R 7 may be hydrogen and at least one of R 6 and R 7 is each independently selected from alkyl, alkenyl, alkynyl, cycloheteroalkyl, alkanoyl, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 10 COR 11 , NR 10 SOR 1 ⁇ NR 10 SO 2 R 14 , COOalkyl, COOaryl, CONR 10 R 11 , CONR 10 OR 11 , NR 10 R 11 , SO 2 NR 10 R 11 , S-alkyl, S-alkyl, SOalkyl, SO 2 alkyl, Saryl, SOaryl, S0 2 aryl; or R 6' and R 7' may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O or S.
  • R 6' and R 7'
  • R 10 , R 11 . and R 12 are independently hydrogen, alkyl, alkenyl, alkyftyl ⁇ effluorb ⁇ lk ⁇ Irfc ⁇ OlOali ⁇ l ⁇ fi ⁇ cloftfetetoalkyU aryl, substituted aryl, heteroaryl, substituted or hetero alkyl or the like.
  • Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. cycloheteroalkyl, aryl, e.g. heteroaryl, cycloalkenyl, cycloheteroalkenyl, and the like having from 1 to 5, and especially from 1 to 3 heteroatoms.
  • Heteroaryl refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system.
  • Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,
  • the heteroaryl group is between 5-20 membered heteroaryl, with 5-10 membered heteroaryl being particularly preferred.
  • Particlar heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.
  • Examples of representative heteroaryls include the following:
  • each Y is selected from carbonyl, N, NR 4 , O, and S.
  • each X is selected from CR 4 , NR 4 , O and S; and each Y is selected from carbonyl, N, NR 4 , O and S.
  • Examples of representative aryl having hetero atoms containing substitution include the following:
  • Hetero substituent refers to a halo, O, S or N atom-containing functionality that may be present as an R 4 in a R 4 C group present as substituents directly on A 5 B, W, X, Y or Z of the compounds of this invention or may be present as a substituent in the "substituted" aryl and aliphatic groups present in the compounds.
  • hetero substituents examples include:
  • each R is independently an aryl or aliphatic, optionally with substitution.
  • hetero substituents containing R groups preference is given to those materials having aryl and alkyl R groups as defined herein. Preferred hetero substituents are those listed above.
  • cycloheteroalkyl refers to a stable heterocyclic non-aromatic ring and fused rings containing one or more heteroatoms independently selected from N, O and S.
  • a fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring.
  • heterocyclic rings include, but are not limited to, piperazinyl, homopiperazinyl, piperidinyl and morpholinyl, and are shown in the following illustrative examples: optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-
  • Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives.
  • M is CR 7 , NR 2 , O, or S;
  • Q is O, NR 2 or S.
  • R 7 and R 8 are independently selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-
  • Dihydroxyphosphoryl refers to the radical -PO(OH) 2 .
  • Substituted dihydroxyphosphoryl includes those groups recited in the definition of "substituted” herein, and particularly refers to a dihydroxyphosphoryl radical wherein one or both of the hydroxyl groups are substituted. Suitable substituents are described in detail below.
  • Aminohydroxyphosphoryl refers to the radical -PO(OH)NH 2 .
  • substituted herein, and particularly refers to an aminohydroxyphosphoryl wherein the amino group is substituted with one or two substituents. Suitable substituents are described in detail below. In certain embodiments, the hydroxyl group can also be substituted.
  • Thioalkoxy refers to the group -SR where R is alkyl.
  • Substituted thioalkoxy includes those groups recited in the definition of "substituted” herein, and particularly refers to a thioalkoxy group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-
  • R is any substituent described herein.
  • Sulfonyl refers to the divalent radical -S(O 2 )-.
  • Substituted sulfonyl refers to a radical such as
  • R-(O 2 )S- wherein R is any substituent described herein.
  • Aminosulfonyl or “Sulfonamide” refers to the radical H 2 NCOIJ)S-" aiid ⁇ fettHstiMWaiftih ⁇ Ultbiiyr ⁇ substituted sulfonamide” refers to a radical such as R 2 N(O 2 )S- wherein each R is independently any substituent described herein.
  • Sulfone refers to the group -SO 2 R.
  • R is selected from H, lower alkyl, alkyl, aryl and heteroaryl.
  • Thioaryloxy refers to the group -SR where R is aryl.
  • Thiol refers to the group -SH.
  • heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
  • “Pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid,
  • 3-phenylpropionic acid trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-rnethylglucamine and the like.
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-rnethylglucamine and the like.
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • pharmaceutically acceptable cation refers to a non toxic, acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
  • “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • Preventing refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).
  • Prodrugs refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or tinder physiological conditions the compounds of the invention which ' ⁇ re plidniMeiftMf-y 1 active 'bf Wo! 1
  • Silbh examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Solvate refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction.
  • solvents include water, ethanol, acetic acid and the like.
  • the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non- stoichiometric solvates.
  • Subject includes humans.
  • the terms “human,” “patient” and “subject” are used interchangeably herein.
  • “Therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • Treating" or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder ⁇ i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically,
  • treating refers to delaying the onset of the disease or disorder.
  • Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or
  • ((alkoxycarbonyl)oxy)alkylesters Preferred are the C 1 to C 8 alkyl, C 2 -C 8 alkenyl, aryl, C 7 -Ci 2 substituted aryl, and
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a "racemic mixture”.
  • [002 ⁇ 2] " " ⁇ 4 Tatit'6Meifs"" ⁇ » ⁇ 'donipbunds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons.
  • two structures may be in equilibrium through the movement of ⁇ electrons and an atom (usually H).
  • enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base.
  • Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Representative enol — keto structures and equilibrium are illustrated below:
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.
  • the compounds of the present invention are useful for preventing and/or treating a broad range of conditions, among them, arthritis, Parkinson's disease, Alzheimer's disease, stroke, uveitis, asthma, myocardial infarction, the treatment and prophylaxis of pain syndromes (acute and chronic or neuropathic), traumatic brain injury, acute spinal cord injury, neurodegenerative disorders, alopecia (hair loss), inflammatory bowel disease and autoimmune disorders or conditions in mammals.
  • invention provides prodrugs and derivatives of the compounds according to the formulae above.
  • Prodrugs are derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo.
  • Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
  • Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Preferred are the Ci to C 8 allcyl, C 2 -C 8 alkenyl, aryl, C 7 -Ci 2 substituted aryl, and C 7 -Ci 2 arylalkyl esters of the compounds of the invention.
  • CCI Model Chronic Constriction Injury Model
  • mice Male Sprague-Dawley rats (270-300 g; B.W., Charles River, Tsukuba, Japan) are used.
  • the chronic constriction injury (CCI) operation is performed according to the method described by Bennett and Xie (Bennett, GJ. and Xie, Y.K. Pain, 33:87-107, 1988). Briefly, animals are anesthetized with sodium pentobarbital (64.8 mg/kg, i. ⁇ .) and the left common sciatic nerve is exposed at the level of the middle of the thigh by blunt dissection through the biceps femoris.
  • sodium pentobarbital (64.8 mg/kg, i. ⁇ .
  • VFHs von Frey hairs
  • Caco-2 permeability is measured according to the method described in Shiyin Yee, Pharmaceutical
  • Caco-2 cells are grown on filter supports (Falcon HTS multiwell insert system) for 14 days.
  • Culture medium is removed from both the apical and basolateral compartments and the monolayers are preincubated with pre-warmed 0.3 ml apical buffer and 1.0 ml basolateral buffer for 0.75 hour at 37 0 C in a shaker water bath at 50 cycles/min.
  • the apical buffer consists of Hanks Balanced Salt Solution, 25 n ⁇ VI D-glucose monohydrate, 20 mM MES Biological Buffer, 1.25 mM CaCl 2 and 0.5 mM MgCl 2 (pH 6.5).
  • the basolateral buffer consists of Hanks Balanced Salt Solution, 25 mM D-glucose monohydrate, 20 mM HEPES Biological Buffer, 1.25 mM CaCl 2 and 0.5 mM MgC12 (pH 7.4).
  • test compound solution (lO ⁇ M) in buffer is added to the apical compartment.
  • the inserts are moved to wells containing fresh basolateral buffer and incubated for 1 hr. Drug concentration in the buffer is measured by LC/MS analysis.
  • Cell paste of HEK-293 cells expressing the HERG product can be suspended in 10-fold volume of
  • the cells are homogenized using a Polytron homogenizer (at the maximum power for 20 seconds) and centrifuged at 48,00Og for 20 minutes at 4°C. The pellet is resuspended, homogenized and centrifuged once more in the same manner. The resultant supernatant is discarded and the final pellet is resuspended (10-fold volume of 50 mM Tris buffer) and homogenized at the maximum power for 20 seconds.
  • the membrane homogenate is aliquoted and stored at -8O 0 C until use.
  • compounds are diluted in 96 well polypropylene plates as 4-point dilutions in semi-log format. All dilutions are performed in DMSO first and then transferred into 50 mM Tris buffer (pH 7.5 at 25°C) containing 1 mM MgCl 2 , 10 mM KCl so that the final DMSO concentration became equal to 1%.
  • Compounds are dispensed in triplicate in assay plates (4 ⁇ l). Total binding and nonspecific binding wells are set up in 6 wells as vehicle and 10 ⁇ M dofetilide at final concentration, respectively.
  • the radioligand is prepared at 5.6x final concentration and this solution is added to each well (36 ⁇ l).
  • the assay is initiated by addition of YSi poly-L- lysine Scintillation Proximity Assay (SPA) beads (50 ⁇ l, 1 mg/well) and membranes (110 ⁇ l, 20 ⁇ g/well). Incubation is continued for 60 min at room temperature. Plates are incubated for a further 3 hours at room temperature for beads to settle. Receptor-bound radioactivity is quantified by counting Wallac MicroBeta plate counter.
  • SPA YSi poly-L- lysine Scintillation Proximity Assay
  • HEK 293 cells which stably express the HERG potassium channel are used for electrophysiological study.
  • the methodology for stable transfection of this channel in HEK cells can be found elsewhere (Z.Zhou et al., 1998, Biophysical Journal, 74, pp230-241).
  • MEM Minimum Essential Medium
  • FCS Fetal Calf Serum
  • HERG currents are studied using standard patch clamp techniques in the whole-cell mode.
  • the cells are superfused with a standard external solution of the following composition (mM); NaCl, 13(f 1 K 1 GU, HEPES, 5; pH 7.4 with NaOH.
  • Whole-cell recordings are made using a patch clamp amplifier and patch pipettes which have a resistance of l-3M0hm when filled with the standard internal solution of the following composition (niM); KCl, 130; MgATP, 5; MgCl 2 , 1.0; HEPES, 10; EGTA 5, pH 7.2 with KOH. Only those cells with access resistances below 15M ⁇ and seal resistances >1G ⁇ is accepted for further experimentation.
  • Series resistance compensation is applied up to a maximum of 80%. No leak subtraction was done. However, acceptable access resistance depended on the size of the recorded currents and the level of series resistance compensation that can safely be used.
  • a standard voltage protocol was applied to the cell to evoke membrane currents. The voltage protocol is as follows. The membrane was depolarized from a holding potential of -8OmV to +4OmV for 1000ms. This is followed by a descending voltage ramp (rate 0.5mV msec-1) back to the holding potential. The voltage protocol is applied to a cell continuously throughout the experiment every 4 seconds (0.25Hz).
  • the amplitude of the peak current elicited around -4OmV during the ramp is measured.
  • vehicle (0.5% DMSO in the standard external solution) is applied for 10-20 min by a peristalic pump.
  • the test compound of either 0.3, 1, 3, 1OmM is applied for a 10 min period.
  • the 10 min period included the time which supplying solution is passing through the tube from solution reservoir to the recording chamber via the pump. Exposure time of cells to the compound solution is more than 5 min after the drug concentration in the chamber well reaches the intended concentration. There is a subsequent wash period of a 10-20 min to assess reversibility. Finally, the cells are exposed to high dose of dofetilide (5mM), a specific IKr blocker, to evaluate the insensitive endogenous current.
  • dofetilide 5mM
  • IKr blocker a specific IKr blocker
  • Test compounds (1 ⁇ M) were incubated with 3.3 mM MgCl 2 and 0.78 mg/niL HLM (HLlOl) in
  • MIA Mono-Iodoacetate
  • Rats are trained to measure the WB once a week until 20 days post MIA-injection. Analgesic effects of compounds are measured at 21 days after the MIA injection. Before the compound administration, the "pre value" of WB deficit is measured. After the administration of compounds, attenuation of WB deficits is determined as analgesic effects.
  • CFA Complete Freund's adjuvant
  • Tuberculosis H37RA (Difco, MI) in 100 ⁇ L of liquid paraffin (Wako, Osaka, Japan)) is injected into the plantar surface of a hind paw of the rats.
  • thermal hyperalgesia is determined by method described previously (Hargreaves et al., 1988) using the plantar test apparatus (Ugo-Basil, Varese, Italy). Rats are adapted to the testing environment for at least 15 minutes prior to any stimulation. Radiant heat is applied to the plantar surface of a hind paw and paw withdrawal latencies (PWL, seconds) are determined. The intensity of radiant heat is adjusted to produce the stable PWL of 10 to 15 seconds.
  • the test compound is administered in a volume of 0.5 mL per 100 g body weight. PWL are measured after 1, 3 or 5 hours after drug administration. Mechanical hyperalgesia
  • MI in 100 ⁇ L of liquid paraffin (Wako, Osaka, Japan)) is injected into the plantar surface of a hind paw of the rats.
  • mechanical hyperalgesia is tested by measuring paw withdrawal threshold (PWT, grams) to pressure using the analgesy-Meter (Ugo-Basil, Varese, Italy). The animals are gently restrained, and steadily increasing pressure is applied to the dorsal surface of a hind paw via a plastic tip. The pressure required to elicit paw withdrawal is determined.
  • the test compound is administered in a volume of 0.5 mL per 100 g body weight. PWT are measured after 1, 3 or 5 hours after drug administration.
  • the amide compounds of this invention are typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • the compounds of this invention are administered in a pharmaceutically effective amount.
  • the amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • compositions of this invention can be administered by a variety of routes including by way of non limiting example, oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal.
  • the compounds of this invention are preferably fo ⁇ ulted"aS ' e ⁇ tH'e'f 'Mj'e'c'tarj'le 6f ⁇ ral'tbrhpOsitions or as salves, as lotions or as patches all for transdermal administration.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the furansulfonic acid compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such as sucrose or saccharin
  • Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art.
  • the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the active ingredients When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in- water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
  • transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • the compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • a description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences. [00245J
  • the following formulation examples illustrate representative pharmaceutical compositions of this invention. The present invention, however, is not limited to the following pharmaceutical compositions.
  • a compound of formula I is admixed as a dry powder with a dry gelatin binder in an approximate
  • a compound of fo ⁇ nula I is admixed as a dry powder with a starch diluent in an approximate 1 : 1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active compound per capsule).
  • a compound of formula I (125 mg), sucrose (1.75 g) and xanthan gum (4 mg) are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water.
  • Sodium benzoate (10 mg) flavor, and color are diluted with water and added with stirring. Sufficient water is then added to produce a total volume of 5 niL.
  • the compound of formula I is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active compound) in a tablet press.
  • the compound of fo ⁇ nula I is dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 nig/ml.
  • the present compounds are used as therapeutic agents for the treatment of conditions in mammals.
  • the compounds and pharmaceutical compositions of this invention find use as therapeutics for preventing and/or treating neurodegenerative, autoimmune and inflammatory conditions in mammals including humans.
  • this invention provides a method of treating a mammal susceptible to or afflicted with a condition associated with arthritis, uveitis, asthma, myocardial infarction, traumatic brain injury, acute spinal cord injury, alopecia (hair loss), inflammatory bowel disease and autoimmune disorders, which method comprises administering an effective amount of one or more of the pharmaceutical compositions just described.
  • this invention provides a method of treating a mammal susceptible to or afflicted with a condition that gives rise to pain responses or that relates to imbalances in the maintenance of basal activity of sensory nerves.
  • Compounds have use as analgesics for the treatment of pain of various geneses or etiology, for example acute, inflammatory pain (such as pain associated with osteoarthritis and rheumatoid arthritis); various neuropathic pain syndromes (such as post-herpetic neuralgia, trigeminal neuralgia, reflex MftWiliifO'patib.y, Guillian Barre syndrome, fibromyalgia, phantom limb pain, post- masectomy pain, peripheral neuropathy, HIV neuropathy, and chemotherapy-induced and other iatrogenic neuropathies); visceral pain, (such as that associated with gastroesophageal reflex disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, and
  • this invention provides methods of treating a mammal susceptible to or afflicted with neurodegenerative diseases and disorders such as, for example Parkinson's disease, Alzheimer's disease and multiple sclerosis; diseases and disorders which are mediated by or result in neuroinflammation such as, for example traumatic brain injury, stroke, and encephalitis; centrally-mediated neuropsychiatric diseases and disorders such as, for example depression mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction such as, for example urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; respiratory and airway disease and disorders such as, for example, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders which are mediated by or result in inflammation such as, for example rheumatoid arthritis and
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
  • each dose provides from about 0.01 to about 20 mg/kg of the compound or its derivative, with preferred doses each providing from about 0.1 to about 10 mg/kg and especially about 1 to about 5 mg/kg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • the compounds or thier derivatives of this invention When used to prevent the onset of a neurodegenerative, autoimmune or inflammatory condition, the compounds or thier derivatives of this invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • the compounds of this invention can be administered as the sole active agent or they can be administered in combination with other agents, including other active derivatives.
  • a VRl antagonist may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of pain.
  • a VRl antagonist particularly a compound of forrii ⁇ UHl)" dr or solvate thereof, as defined above, may be administered simultaneously, sequentially or separately in combination with one or more agents selected from:
  • an opioid analgesic e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;
  • NSAID nonsteroidal antiinflammatory drug
  • NSAID nonsteroidal antiinflammatory drug
  • diclofenac diflusinal, etodolac
  • fenbufen fenoprofen
  • flufenisal flurbiprofen
  • ibuprofen indomethacin
  • ketoprofen ketorolac
  • meclofenamic acid mefenamic acid
  • meloxicam nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac
  • NSAID nonsteroidal antiinflammatory drug
  • a barbiturate sedative e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal or thiopental;
  • a benzodiazepine having a sedative action e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;
  • an Hl antagonist having a sedative action e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;
  • a skeletal muscle relaxant e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;
  • an NMDA receptor antagonist e.g. dextromethorphan ((+)-3-hydroxy-N-methylmo ⁇ liinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4- (phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®, a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g.
  • an alpha-adrenergic e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafmil, or 4-amino- 6,7-dimethoxy-2-(5-methane-sulfonamido-l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline;
  • a tricyclic antidepressant e.g. desipramine, imipramine, amitriptyline or nortriptyline;
  • an anticonvulsant e.g. carbamazepine, lamotrigine, topiratmate or valproate;
  • a tachykinin (NK) antagonist particularly an NK-3, NK-2 or NK-I antagonist, e.g. (aR,9R)-7-[3,5- bis(trifluoromethyl)benzyl]-8,9,10,ll-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[l,4]diazocino[2,l-g][l,7]- naphthyridine-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4- fluorophenyl)-4-moipholinyl]-methyl]-l,2-dihydro-3H-l,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]
  • a muscarinic antagonist e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;
  • COX-2 selective inhibitor e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;
  • a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, soriepifsfaz'ol'e, ⁇ feil' ⁇ 'ge ⁇ n j lloperM'oneJ ' pef ⁇ spirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan;
  • a beta-adrenergic such as propranolol
  • a corticosteroid such as dexamethasone
  • a 5-HT receptor agonist or antagonist particularly a 5-HT1B/1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;
  • a 5-HT2A receptor antagonist such as R(+)-al ⁇ ha-(2,3-dimethoxy-phenyl)-l-[2-(4-fluoro ⁇ henylethyl)]-4- piperidinemethanol (MDL-100907);
  • a cholinergic (nicotinic) analgesic such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-l-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;
  • a PDEV inhibitor such as 5-[2-ethoxy-5-(4-methyl-l-piperazinyl-sul ⁇ honyl)phenyl]-l-methyl-3-n-propyl-l,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-r ⁇ ethyl-6-(3,4- methylenedioxyphenyl)-pyrazino[2',r:6,l]-pyrido[3,4-b]indole-l,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4- ethyl-piperazin-l-yl-l-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,l-fj[l,2,4]triazin-4-
  • an alpha-2-delta ligand such as gabapentin, pregabalin, 3-methylgaba ⁇ entin, (la,3a,5a)(3-amino-methyl- bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3_aminomethyl-5_jnethyl-heptanoic acid, (3S,5R)-3_ amino- 5_methyl-heptanoic acid, (3S,5R)-3_amino-5_methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)- 4-(3-fluorobenzyl)-proline, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l-aminomethyl- cyclohexylmethyl)-4H-[l,2,4]oxadiazol-5-one, C
  • a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericla ⁇ ne and trazodone;
  • a noradrenaline (norepinephrine) reuptake inhibitor such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine (Vivalan®), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S 5 S)- reboxetine; • a cfuaI'' ⁇ W6t ⁇ nin-ri6ra'drenaline' ⁇ e ⁇ t'ake' ⁇ n ⁇ i ⁇ bitor, such as venlafaxine, venlafaxine metabolite O- desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine;
  • an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(l-iminoethyl)amino]ethyl]-L-homocysteine, S- [2-[(l-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(l-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(l-iminoethyl)amino]-5-heptenoic acid, 2-[[(lR,3S)-3-amino-4- hydroxy-l-(5- thiazolyl)-butyl]thio]-5-chloro-3- ⁇ yridinecarbonitrile; 2-[[(lR,3S)-3-amino-4-hydroxy-l-(5-
  • an acetylcholinesterase inhibitor such as donepezil
  • a prostaglandin E2 subtype 4 (EP4) antagonist such as N-[( ⁇ 2-[4-(2-ethyl-4,6-dimethyl-lH-imidazo[4,5-c]pyridin- 1 -yl)phenyl] ethyl ⁇ amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[( 1 S)- 1 -( ⁇ [5-chloro-2-(3- fluorophenoxy)pyridin-3-yl]carbonyl ⁇ amino)ethyl]benzoic acid;
  • a leukotriene B4 antagonist such as l-(3-bi ⁇ henyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E- hexenyl]oxyphenoxy] -valeric acid (ONO- 4057) or DPC-11870,
  • a 5-lipoxygenase inhibitor such as zileuton, 6-[(3-fluoro-5-[4-inethoxy-3,4,5,6-tetrahydro-2H-pyran-4- yl])phenoxy-methyl]- 1 -methyl-2-quinolone (ZD-2138), or 2,3 ,5-trimethyl-6-(3-pyridylmethyl),l ,4-benzoquinone (CV-6504);
  • a sodium channel blocker such as lidocaine
  • a 5-HT3 antagonist such as ondansetron
  • pharmaceutically acceptable salts and solvates thereof • a 5-HT3 antagonist, such as ondansetron; and the pharmaceutically acceptable salts and solvates thereof.
  • the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • the grey powder was dissolved in acetone (10 mL) and Jone's Reagent was added (10 mL). The solvent was evaporated and the residue was dissolved in diethyl ether and washed with brine and water, dried (MgSO 4 ), filtered and concentrated under vacuum to give a white solid.
  • the white solid (730 mg) was re-suspended in anhydrous THF.
  • methylmagnesium bromide(3.3 mL, 10 mmol, 3.0 M solution in diethyl ether) The reaction mixture was warmed to room temperature and stirred for 2 hours. The solution was acidified with 50% sulfuric acid in water and the THF was removed under vacuum.
  • the vessel was sealed and the mixture was heated at 80 ° C for 24 hrs.
  • the solvents were evaporated to dryness and 2OmL of tetrahydrofuran and 2OmL of ION NaOH was added.
  • the mixture was stirred at room temperature for 30 minutes and the solvent was evaporated.
  • the basic layer was acidified with concentrated HCl and extracted three times with EtOAc.
  • the organic layers were washed with brine and dried over Na 2 SO ⁇ filtered and evaporated to give the desired product as a brown powder (210 mg; 28%).
  • m/z 203 (M+l).
  • triphenylstannane derivative was prepared using a modified procedure of Brisdon (Chem.
  • 1,1,1,3,3-pentafluoropro ⁇ ane (2.0 g, 14.9 inmol) was condensed into a 500 mL three neck round bottom flask containing ether (2OmL) cooled to -15 0 C. The mixture was maintained below -10 ° C while n-BuLi (2.5 M in hexanes, 16.08 mL, 40.2 mmol) was added. After the reaction was stirred for 10 minutes at -10 ° C, triphenyl tin chloride (5 g, 13.4 mmol) was added as a solution in ether, maintaining -10 C. The mixture was slowly warmed to room temperature and allowed to stir for an additional 4 hours.
  • Ethyl 4-bromo-3-(cyclopropylmethoxy)benzoate (0.77g, 2.57 mmol), ethynylcyclopropane (0.45 mL of a 70% w/v solution in toluene, 3.86 mmol), co ⁇ per(I) iodide (49 mg, 0.26 mmol) and bis(tri ⁇ henyl ⁇ hos ⁇ hine) ⁇ alladium(II) chloride (0.36 g, 0.51 mmol) were placed in 50 mL triethylamine and stirred in a sealed tube at room temperature for 20 h. The reaction was diluted with MeOH and Filtered through Celite®., then the filtrate was concentrated to an oil.
  • MS 4A (powder, 16 g) was added to a 1 M solution of TBAF in THF (20 mL, 20 mmol), and the mixture was stirred at room-temperature overnight under an argon atmosphere. To the mixture were added a solution of methyl 4-formyl-2-methoxybenzoate (420 mg, 0.0022 mol) and 2,2,2-trifluoroethyldi ⁇ henylphosphine oxide (1.23 g, 0.00432 mol) in THF (20 mL). After the mixture was stirred for 2 h, MS 4A was removed by filtration. The filtrate was concentrated and water (120 mL) was added. The mixture was extracted with AcOEt.
  • This compound was prepared using the same method as for 4-(3,3-dimethylbut-l-ynyl)-2- methylbenzoic acid, with the exception that cyclopopylacetylene was used as the alkyne coupling partner.
  • Molecular sieves 4A (powder, 24 g) was added to a 1 M solution of TBAF in THF (30 mL, 30 mmol), and the mixture was stirred at room-temperature overnight under an argon atmosphere. To the mixture were added a solution of tert-butyl 2-fluoro-4-formylbenzoate (750 mg, 0.0033 mol) and 2,2,2- trifluoroethyldiphenylphosphine oxide (1.9 g, 0.0067 mol) in THF (30 mL). After the mixture was stirred for 2 h it was filtered. The filtrate was concentrated under vacuum and water (120 mL) was added.
  • 6-Ammo-2#-benzo[b][l,4]oxazin-3(4.ff)-one (590 mg, 3.6 mmol) was added to a THF solution of borane tetrahydrofuran complex (9 mL, IM solution) and the reaction mixture was refluxed for 2.5 h.
  • EtOH (2 mL) was added and stirred at 70 0 C for 1 h before 1 mL HCl (cone.) was added.
  • the mixture was stirred at 80 0 C overnight then the volatiles were removed under vacuum to leave a crude reside. The residue was dissolved in water,
  • H 2 SO 4 (35 mL) was treated with a solution of fuming HNO 3 (10 mL) and potassium nitrate (4.0 g, 0.040 mol) in cone. H 2 SO 4 (35 mL) at 0-5 0 C. The mixture was stirred at 0 0 C for a further 90 min, and then poured into ice. The precipitate was collected, washed and dried to give the product as a yellow solid. LC-MS: 3.68 min, 209.2 & 211.1 (M + 1). l-Chloroisoquinolin-5-amine.
  • Method A A Representative Synthesis Of Benzamides Using An Automated Parallel Synthesis Method [00396]
  • the appropriate benzoic acid (2 mmol) is dissolved or suspended in 15ml of chloroform and treated with 20 mmol of thionyl chloride.
  • the reaction mixture is refluxed for fifteen minutes and the solvents are removed under vacuum.
  • the residue is dissolved in 4ml of anhydrous chloroform and 60 ⁇ l (30 ⁇ mole) of this solution is added to each well of the 96 well glass plates.
  • Appropriate amine is then added to the corresponding well (60 ⁇ mole), followed by n,n-diisopropylethylamine (120 ⁇ mole).
  • the plate is then heated at 65 ° c for 15 minutes.
  • DIPEA (0.92 mmol) was added to the solution of appropriate acid (0.46 mmol), appropriate amine
  • DIPEA (0.92 mmol) was added to the solution of appropriate acid (4.0 mmol), appropriate amine
  • the chromatographic method employed was 10-100% gradient of acetonitrile to water over 8 minutes at a flow rate of 6 ml per minute.
  • the column used was a 10X50mm YMC C18 and the compounds were collected using a Gilson 204 fraction collector.
  • Functional activity of compounds against the VRl receptor was determined by measuring changes in intracellular calcium in HEK 293 cells expressing hVRl . Compounds were examined for their ability to inhibit agonist-induced calcium influx. Dual wavelength ratiometric dye, Fura2, was used as an indicator of relative levels of [Ca 2+ ] in a 96-well format using a Flex Station ® , Molecular Devices.
  • hVRl was cloned into a pcDNA5/TO vector from Invitrogen and stably transformed into T-REx
  • HEK 293 cell line from Invitrogen HEK 293 cells expressing hVRl were grown to confluency (24 hour culture) on PDL-coated, plastic 96-well black-walled plates, in the presence of DMEM medium containing 5% PenStrep, 5% Glutamax, 200 ⁇ g/mL Hygromycin, 5 ⁇ g/mL Blasticidin and 10% heat inactivated FBS. Twenty-four hours prior to assay, cells were transferred to DMEM media containing 1 ⁇ g/mL doxycycline.
  • the agonist EC 50 was determined at the start of the assay and compound IC 50 experiments were run using an agonist concentration equal to its EC 50 as stimulus.
  • the assay consists of two stages: a pre-treatment phase followed by a treatment phase. 50 ⁇ l of a compound solution was added to the cells (Pre-treatme"t ⁇ In some instances, following pre-treatment, 50 ⁇ l of the test compound i ⁇ -a M ⁇ rifeifetDl ⁇ tran ktopSf Sri!, was added (Treatment). Compounds were tested as follows: For the pre-treatment phase, 50 ⁇ L of 3x concentration of test compound in saline is added to cells containing 100 ⁇ L of saline to achieve a final concentration of x. For the treatment phase, at a determined time after pre-treatment, 50 ⁇ L of test compound plus agonist solution is added to cells at the relevant concentrations.
  • the precipitated protein was spun down in a centrifuge (2000 rpm, 15 min).
  • the compound concentration in supernatant was measured by LC/MS/MS system.
  • the results of the tests and corresponding Ty 2 values are set forth in Table 3, below.
  • compounds were dissolved (0.25 to 1 mg/niL) in a mixture of 3% dimethyl sulfoxide, 40% PEG 400 and the rest percentage of 40% Captisol in water (w/v).
  • compounds of this invention are dissolved (2 mg/mL) in a mixture of 5% of 10% Tween 80 in water (v/v) and 95% of 0.5 % methyl cellulose in water (w/v). The animals are weighed before dosing. The determined body weight is used to calculate the dose volume for each animal.
  • Dose volume (mL/kg) 1 mg/kg/formulation concentration (mg/niL).
  • the dosing volume is about 2 mL/kg
  • PO rats are typically dosed through oral gavage at 2.5 mL/kg to achieve a dose level of 5 mg/kg.
  • blood samples are collected (using a pre-heparinized syringe) via the jugular vein catheter at 2, 5, 15, 30, 60, 120, 180, 300, 480, and 1440 minutes post dosing.
  • blood samples are collected (using a pre-heparinized syringe) via the jugular vein catheter before dosing and at 5, 15, 30, 60, 120, 180, 300, 480, and 1440 minutes post dosing. About 250 uL of blood is obtained at each time point from the animal. Equal volumes of 0.9% normal saline are replaced to prevent dehydration. The whole blood samples are maintained on ice until centrifugation. Blood samples are then centrifuged at 14,000 rpm for 10 minutes at 4 0 C and the upper plasma layer transferred into a clean vial and stored at -80 0 C. The resulting plasma samples are then analyzed by liquid chromatography-tandem mass spectrometry.
  • Plasma concentration-time curve is plotted. Plasma exposure is calculated as the area under the concentration-time curve extrapolated to time infinite (AUC j nf ). The AUQ nf is averaged and the oral bioavailability (%F) for individual animal is calculated as:
  • the %F is reported as the mean %F of all oral dosed animals.
  • VRl protein is a heat-gated cation channel that exchanges approximately ten calcium ions for every sodium ion resulting in neuronal membrane depolarization and elevated intracellular calcium levels. Therefore the functional activity of compounds at the VRl receptor may be determined by measuring changes in intracellular calcium levels in neurons such as the dorsal root ganglion.
  • DRG neurons were grown on PDL coated 96-well black-walled plates, in the presence of DMEM medium containing 5% Penstrep, 5% Glutamax, 200 ⁇ g/ml hygromycin, 5 ⁇ g/ml blasticide and 10% heat inactivated FBS. Prior to assay, cells were loaded with 5 ⁇ g/ml Fura2 in normal saline solution at 37 C for 40 minutes. Cells were then washed with normal saline to remove dye before commencement of the experiment.
  • the plated neurons were transferred into a chamber on the stage of a Nikon eclipse TE300 microscope after which neurons were allowed to attain a stable fluorescence for about 10 minutes before beginning the experiment.
  • the assay consists of two stages, a pretreatment phase followed by a treatment phase. First, a solution of the test compound was added from a multivalve perfusion system to the cells for 1 minute (pretreatment). Immediately following, capsaicin (250 nM) was added in the presence of the test compound (treatment) for a specific period between 20 and 60 seconds.
  • Fura2 was excited at 340 and 380 nm to indicate relative calcium ion concentration. Changes in wavelength measurements were made throughout the course of the experiment. The fluorescence ratio was calculated by dividing fluorescence measured at 340 nm by that at 380 nm. Data were collected using Intelligent Imaging's Slidebook software. All compounds that inhibited capsaicin induced calcium influx greater than 75% were considered positives. [00438] Table 4 provides the data obtained. Figure 1 demonstrates results obtained when compound 225 is administered with capsaicin. Fluorescence reflecting calcium ion influx is reduced. [00439] Table 4
  • DRG neurons Dorsal root ganglion (DRG) neurons were recovered from either neonatal or adult rats and plated onto poly-D-lysine coated glass coverslips. The plated neurons were transferred into a chamber to allow drug solutions to be added to the cells using a computer-controlled solenoid- valve based perfusion system. The cells were imaged using standard DIC optics. Cells were patched using finely-pulled glass electrodes. Voltage-clamp electrophysiology experiments were carried out using an Axon Instruments Multiclamp amplified controlled by pCLAMP ⁇ software. [00442] The cells were placed into a whole-cell voltage clamp and held at a voltage of — 8OmV while monitoring the membrane current in gap-free recording mode.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Urology & Nephrology (AREA)
  • Reproductive Health (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Virology (AREA)
  • Hospice & Palliative Care (AREA)
  • Dermatology (AREA)
  • Pregnancy & Childbirth (AREA)
  • Vascular Medicine (AREA)
  • Rheumatology (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Orthopedic Medicine & Surgery (AREA)
EP06736043A 2005-02-28 2006-02-24 Amidderivate als ionenkanalliganden und pharmazeutische zusammensetzungen sowie verfahren damit Withdrawn EP1853269A4 (de)

Applications Claiming Priority (15)

Application Number Priority Date Filing Date Title
US65698405P 2005-02-28 2005-02-28
US71044505P 2005-08-23 2005-08-23
US77593006P 2006-02-23 2006-02-23
US77610606P 2006-02-23 2006-02-23
US77594506P 2006-02-23 2006-02-23
US77605606P 2006-02-23 2006-02-23
US77605706P 2006-02-23 2006-02-23
US77594906P 2006-02-23 2006-02-23
US77610506P 2006-02-23 2006-02-23
US77606406P 2006-02-23 2006-02-23
US77605806P 2006-02-23 2006-02-23
US77603306P 2006-02-23 2006-02-23
PCT/US2006/006615 WO2006093832A2 (en) 2005-02-28 2006-02-24 Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
US83990306P 2006-08-24 2006-08-24
US83999406P 2006-08-24 2006-08-24

Publications (2)

Publication Number Publication Date
EP1853269A2 true EP1853269A2 (de) 2007-11-14
EP1853269A4 EP1853269A4 (de) 2011-09-07

Family

ID=39773016

Family Applications (2)

Application Number Title Priority Date Filing Date
EP06736043A Withdrawn EP1853269A4 (de) 2005-02-28 2006-02-24 Amidderivate als ionenkanalliganden und pharmazeutische zusammensetzungen sowie verfahren damit
EP07751654A Withdrawn EP1954132A4 (de) 2005-02-28 2007-02-22 Amidderivate als ion-kanalliganden und pharmazeutische zusammensetzungen und verwendungsverfahren dafür

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP07751654A Withdrawn EP1954132A4 (de) 2005-02-28 2007-02-22 Amidderivate als ion-kanalliganden und pharmazeutische zusammensetzungen und verwendungsverfahren dafür

Country Status (8)

Country Link
EP (2) EP1853269A4 (de)
JP (1) JP2008531690A (de)
KR (1) KR20070119655A (de)
AP (1) AP2007004119A0 (de)
AU (2) AU2006218824A1 (de)
CA (1) CA2600933A1 (de)
NO (1) NO20074739L (de)
WO (2) WO2006093832A2 (de)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2600933A1 (en) * 2005-02-28 2006-09-08 Renovis, Inc. Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
WO2008109179A1 (en) 2007-03-07 2008-09-12 Alantos Pharmaceuticals Holding, Inc. Metalloprotease inhibitors containing a squaramide moiety
AU2008259776A1 (en) * 2007-06-03 2008-12-11 Vanderbilt University Benzamide mGluR5 positive allosteric modulators and methods of making and using same
US8853392B2 (en) 2007-06-03 2014-10-07 Vanderbilt University Benzamide mGluR5 positive allosteric modulators and methods of making and using same
ES2372655T3 (es) * 2007-11-13 2012-01-25 Evotec Ag Derivados amídicos como ligandos de canales iónicos y composiciones farmacéuticas y métodos de uso de los mismos.
EP2220075A4 (de) * 2007-11-16 2012-02-29 Neuraxon Inc Indolverbindungen und verfahren zur behandlung von viszeralen schmerzen
FR2933977B1 (fr) * 2008-07-18 2013-04-26 Centre Nat Rech Scient Derives heterocycliques utiles dans le traitement des maladies neurodegeneratives
US8809380B2 (en) 2009-08-04 2014-08-19 Raqualia Pharma Inc. Picolinamide derivatives as TTX-S blockers
BR112013028895A2 (pt) 2011-05-10 2016-08-09 Bayer Ip Gmbh (tio)carbonilamidinas bicíclicas
RU2616608C2 (ru) * 2011-09-29 2017-04-18 Мицуи Кемикалз Агро, Инк. Способ получения производных 4,4-дифтор-3,4-дигидроизохинолина
CN105566219B (zh) * 2011-09-29 2019-03-01 三井化学Agro株式会社 3，4－二氢异喹啉衍生物的制造方法及其制造中间体
JP2014533747A (ja) 2011-11-30 2014-12-15 アクテリオン ファーマシューティカルズ リミテッドＡｃｔｅｌｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｌｔｄ ３，７−二置換オクタヒドロ−２Ｈ−ピリド［４，３−ｅ］［１，３］オキサジン−２−オン抗生物質
US9562002B2 (en) 2013-01-15 2017-02-07 Board Of Regents, The University Of Texas System STAT3 inhibitor

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004096784A1 (en) * 2003-04-28 2004-11-11 Astrazeneca Ab New heterocyclic amides exhibiting an inhibitory activity at the vanilloid receptor 1 (vr1).
WO2005046683A1 (en) * 2003-10-07 2005-05-26 Renovis, Inc. Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2092729T3 (es) * 1992-07-01 1996-12-01 Hoechst Ag Benzoilguanidinas 3,4,5-sustituidas, procedimiento para su preparacion, su empleo como medicamento o agente de diagnostico, asi como medicamento que las contiene.
WO1999018105A1 (en) * 1997-10-07 1999-04-15 Ortho-Mcneil Pharmaceutical, Inc. Dipyridoimidazolderivatives useful in treating central nervous system disorders
EP1775283A4 (de) * 2004-07-14 2008-12-10 Japan Tobacco Inc 3-aminobenzamid-verbindung und hemmer der aktivität des vanilloid-rezeptors 1 (vr1)
CA2600933A1 (en) * 2005-02-28 2006-09-08 Renovis, Inc. Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004096784A1 (en) * 2003-04-28 2004-11-11 Astrazeneca Ab New heterocyclic amides exhibiting an inhibitory activity at the vanilloid receptor 1 (vr1).
WO2005046683A1 (en) * 2003-10-07 2005-05-26 Renovis, Inc. Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2006093832A2 *

Also Published As

Publication number Publication date
EP1954132A4 (de) 2009-11-04
WO2007100758A3 (en) 2007-11-29
EP1853269A4 (de) 2011-09-07
AP2007004119A0 (en) 2007-08-31
NO20074739L (no) 2007-11-15
WO2007100758A2 (en) 2007-09-07
WO2006093832A3 (en) 2007-03-22
JP2008531690A (ja) 2008-08-14
CA2600933A1 (en) 2006-09-08
KR20070119655A (ko) 2007-12-20
AU2007221118A1 (en) 2007-09-07
AU2006218824A1 (en) 2006-09-08
WO2006093832A2 (en) 2006-09-08
EP1954132A2 (de) 2008-08-13

Similar Documents

Publication Publication Date Title
US7576099B2 (en) Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
WO2006093832A2 (en) Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
US20120088746A1 (en) Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
EP2215054B1 (de) Amidderivate als ionenkanalliganden sowie pharmazeutische zusammensetzungen und verwendungsverfahren dafür
WO2006129164A1 (en) Substituted aryloxy-n-bicyclomethyl acetamide compounds as vr1 antagonists
US7312233B2 (en) Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
EP1824837A1 (de) Substituierte n-sulfonylaminobenzyl-2-phenoxyacetamidverbindungen
EP2240467B1 (de) Amidderivate als ionenkanalliganden sowie pharmazeutische zusammensetzungen und verwendungsverfahren dafür
US20080300243A1 (en) Amide Derivatives as Ion-Channel Ligands and Pharmaceutical Compositions and Methods of Using the Same
US20100004222A1 (en) Amide Derivatives as Ion-Channel Ligands and Pharmaceutical Compositions and Methods of Using the Same
MX2008010365A (en) Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
CN101171015A (zh) 作为离子通道配体的酰胺衍生物、药物组合物及其使用方法
BRPI0710080A2 (pt) composto, composição farmacêutica, métodos para prevenir, tratar, melhorar ou controlar uma doença ou condição, para preparar um composto e para o tratamento de um mamìfero, uso de um composto ou de um sal, solvato ou composição farmaceuticamente acetável do mesmo, e, combinação

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20070713

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK YU

RIN1 Information on inventor provided before grant (corrected)

Inventor name: KAUB, CARL

Inventor name: WEI, ZHI-LIANG

Inventor name: FANG, YUNFENG

Inventor name: WU, GUOXIAN

Inventor name: UPASANI, RAVINDRA, B.

Inventor name: JANAGANI, SATYANARAYANA

Inventor name: SAHASRABUDHE, KIRAN

Inventor name: DUNCTON, MATTHEW

Inventor name: KINCAID, JOHN

Inventor name: KELLY, MICHAEL

RIN1 Information on inventor provided before grant (corrected)

Inventor name: KAUB, CARL

Inventor name: WEI, ZHI-LIANG

Inventor name: FANG, YUNFENG

Inventor name: WU, GUOXIAN

Inventor name: UPASANI, RAVINDRA, B.

Inventor name: JANAGANI, SATYANARAYANA

Inventor name: SAHASRABUDHE, KIRAN

Inventor name: DUNCTON, MATTHEW

Inventor name: KINCAID, JOHN

Inventor name: KELLY, MICHAEL

A4 Supplementary search report drawn up and despatched

Effective date: 20110809

RIC1 Information provided on ipc code assigned before grant

Ipc: C07D 413/02 20060101ALI20110803BHEP

Ipc: C07D 405/14 20060101ALI20110803BHEP

Ipc: A61K 31/4709 20060101ALI20110803BHEP

Ipc: A61K 31/538 20060101AFI20110803BHEP

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: EVOTEC AG

17Q First examination report despatched

Effective date: 20120613

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20121228