WO2006097766A1 - Ethers arylsulfonyle benzyle utilises en tant qu'antagonistes 5-ht2a - Google Patents

Ethers arylsulfonyle benzyle utilises en tant qu'antagonistes 5-ht2a Download PDF

Info

Publication number
WO2006097766A1
WO2006097766A1 PCT/GB2006/050048 GB2006050048W WO2006097766A1 WO 2006097766 A1 WO2006097766 A1 WO 2006097766A1 GB 2006050048 W GB2006050048 W GB 2006050048W WO 2006097766 A1 WO2006097766 A1 WO 2006097766A1
Authority
WO
WIPO (PCT)
Prior art keywords
mmol
formula
halogen
compound
pharmaceutically acceptable
Prior art date
Application number
PCT/GB2006/050048
Other languages
English (en)
Inventor
Mark Stuart Chambers
Myra Gilligan
Alexander Charles Humphries
Kevin John Merchant
Original Assignee
Merck Sharp & Dohme Limited
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 Merck Sharp & Dohme Limited filed Critical Merck Sharp & Dohme Limited
Priority to AU2006224336A priority Critical patent/AU2006224336A1/en
Priority to JP2008501425A priority patent/JP2008533119A/ja
Priority to EP06710166A priority patent/EP1861079A1/fr
Priority to CA002600508A priority patent/CA2600508A1/fr
Publication of WO2006097766A1 publication Critical patent/WO2006097766A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • 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
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • 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
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • 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
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/26—Radicals substituted by sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a class of sulphonyl derivatives which act on serotonin receptors (also known as 5-hydroxytryptamine or 5-HT receptors). More particularly, the invention concerns a class of arylsulphonylbenzyl ethers. These compounds are potent and selective antagonists of the human 5-HT 2A receptor and are therefore useful as pharmaceutical agents, especially in the treatment and/or prevention of adverse conditions of the central nervous system, including sleep disorders such as insomnia, psychotic disorders such as schizophrenia and psychiatric disorders such as anxiety.
  • Compounds of the invention typically display more effective binding to the human 5-HT 2A receptor than to other human receptors such as D 2 , 5HT 2C and DCr receptors. They can therefore be expected to manifest fewer side-effects than compounds which do not discriminate in their binding affinity between such receptors. In particular these compounds have lower effects on the DCr receptors and there is a separation of the desired effect from side effects such as cardiac effects.
  • the compounds of the present invention are effective in the treatment of neurological conditions including sleep disorders such as insomnia, psychotic disorders such as schizophrenia, and also depression, anxiety, panic disorder, obsessive-compulsive disorder, pain, eating disorders such as anorexia nervosa, and dependency or acute toxicity associated with narcotic agents such as LSD or MDMA; and moreover are beneficial in controlling the extrapyramidal symptoms associated with the administration of neuroleptic agents. They are also effective in the lowering of intraocular pressure and hence in treating glaucoma, and may also be effective in treating menopausal symptoms, in particular hot flushes (see Waldinger et al, Maturitas, 2000, 36, 165- 8).
  • the compounds according to the present invention are potent and selective 5-HT 2A receptor antagonists, suitably having a human 5-HT 2A receptor binding affinity (K 1 ) of 100 nM or less, typically of 50 nM or less and preferably of 10 nM or less.
  • the compounds of the invention may possess at least a 10- fold selective affinity, suitably at least a 20-fold selective affinity and preferably at least a 50-fold selective affinity, for the human 5-HT 2A receptor relative to the human dopamine D 2 receptor and/or the human DCr and/or 5-HT 2c receptors.
  • Preferred compounds show selectivities of at least 100-fold relative to the human 5-HT 2c receptor.
  • a pharmaceutical composition comprising, in a pharmaceutically acceptable carrier, a compound of formula I:
  • A represents CH or N
  • a 1 and A 2 each represent CH or N but do not both represent N:
  • E represents a chemical bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms, optionally incorporating an oxygen atom to form an ether linkage;
  • R a and R b independently represent H or a hydrocarbon group of up to 7 carbon atoms which is optionally substituted with up to 3 fluorine atoms and optionally with Cl, Br, CN, OH, Ci- 4 alkylthio, amino, or R a and R b , when linked through a nitrogen atom, together represent the residue of a heterocyclic ring of 4, 5 or 6 members, optionally bearing up to 3 substituents selected from halogen, CN, CF 3 , oxo, OH, and each R 1 independently represents halogen, CN, OH, Ci -4 alkoxy or hydroxymethyl; each R 2 independently represents halogen, CN, CONH 2 , or an R 2 group and the moiety -E-Z when attached to adjacent ring positions may complete a fused imidazole ring; and R 3 represents H, halogen, CN, CF 3
  • -E-Z does not combine with an adjacent R 2 group.
  • Compounds of formula I in which -E-Z is other than H are believed to be novel, and constitute a further aspect of the invention.
  • Compounds of formula I in which m is 1 or 2 and R 1 represents fluorine are believed to be novel, and constitute a further aspect of the invention.
  • variable occurs more than once in formula I or in a substituent group thereof, the individual occurrences of that variable are independent of each other, unless otherwise specified.
  • hydrocarbon group refers to groups consisting solely of carbon and hydrogen atoms. Such groups may comprise linear, branched or cyclic structures, singly or in any combination consistent with the indicated maximum number of carbon atoms, and may be saturated or unsaturated, including aromatic when the indicated maximum number of carbon atoms so permits unless otherwise indicated.
  • Ci -X alkyl where x is an integer greater than 1 refers to straight- chained and branched alkyl groups wherein the number of constituent carbon atoms is in the range 1 to x. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl. Derived expressions such as “C 2 - 6 alkenyl”, “hydroxyCi- 6 alkyl”, “heteroarylCi -6 alkyl”, “C 2 - 6 alkynyl” and “Ci -6 alkoxy” are to be construed in an analogous manner. Most suitably, the number of carbon atoms in such groups is not more than 6.
  • halogen as used herein includes fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred and fluorine particularly preferred.
  • C 3 - 6 cycloalkyl refers to nonaromatic monocyclic hydrocarbon ring systems comprising from 3 to 6 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexenyl.
  • the compounds of formula I may be in the form of pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of formula I or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, benzenesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable salt may be formed by neutralisation of said acidic moiety with a suitable base.
  • Examples of pharmaceutically acceptable salts thus formed include alkali metal salts such as sodium or potassium salts; ammonium salts; alkaline earth metal salts such as calcium or magnesium salts; and salts formed with suitable organic bases, such as amine salts (including pyridinium salts) and quaternary ammonium salts.
  • the compounds according to the invention may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
  • t is 1 or 2. In a preferred embodiment t is 2.
  • A represents CH or N. In a particular embodiment, A represents CH. When A represents N, the moiety S(O)t may be attached at any of the positions of the resulting pyridine ring in Formula I, but attachment at the 2- or 3- position relative to the ring N is preferred, and attachment at the 2-position particularly preferred.
  • a 1 and A 2 each represents CH or N; but do not both represent N. In a preferred embodiment A 1 and A 2 both represent CH. - A -
  • E represents a straight or branched alkylene chain
  • this may be, for example, methylene, ethylene, 1-methylethylene, propylene, 2-methylpropylene or butylene.
  • the alkylene chain E may optionally incorporate an oxygen atom, thereby forming an ether linkage such as -CH 2 O- or -CH 2 CH 2 CH 2 O-.
  • E may represent a chemical bond such that the moiety Z is attached directly to the relevant phenyl or pyridyl ring depicted in formula I above.
  • E represents a chemical bond or a methylene linkage.
  • E represents a chemical bond.
  • E represents a methylene linkage.
  • group Z represents an optionally substituted five-membered heteroaromatic ring
  • this is suitably an imidazole, pyrazole, thiazole, 1,2,3-triazole, 1,2,4-triazole or tetrazole ring, any of which optionally is substituted, typically by methyl.
  • Such rings may be attached via a carbon atom or a nitrogen atom.
  • Specific examples include pyrazol-3-yl, imidazol-2-yl, l,2,4-triazol-3-yl and thiazol-2-yl.
  • group Z represents an optionally substituted six-membered heteroaromatic ring
  • this is suitably a pyridine, pyrazine, pyrimidine, pyridazine or triazine ring, any of which optionally is substituted, typically by methyl or halogen.
  • a specific example is 2-pyridyl.
  • R a and R b independently represent H or an optionally substituted hydrocarbon group as defined previously, or when linked through a nitrogen atom they may complete an optionally-substituted heterocyclic ring as defined previously.
  • Hydrocarbon groups represented by R a or R b are preferably nonaromatic. Said hydrocarbon groups optionally bear up to 3 fluorine substituents and, in addition or as an alternative, optionally bear a substituent selected from Cl, Br, CN, OH, amino, and Preferred substituents include F, OH and CN.
  • R a and R b independently represent H; optionally substituted Ci -6 alkyl (such as methyl, ethyl, isopropyl, tert- butyl, 2,2,2-trifluoroethyl, 2-cyanoethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1- hydroxypropyl, 1 -hydroxy- 1-methylethyl and l-hydroxy-2,2,2-trifluoroethyl); optionally substituted C 3-6 cycloalkyl (such as cyclopropyl, cyclobutyl and 1-hydroxycyclobutyl); (such as cyclopropylmethyl); or, when linked through a nitrogen atom, together represent the residue of a heterocyclic ring of 4, 5 or 6 members optionally bearing up to 3 substituents as defined previously.
  • Ci -6 alkyl such as methyl, ethyl, isopropyl, tert- butyl, 2,2,2-trifluoroeth
  • Such rings typically comprise at most two heteroatoms selected from N, O and S, inclusive of the nitrogen atom connecting R a and R b , for example azetidine, pyrrolidine, piperidine, tetrahydropyridine, piperazine, morpholine and thiomorpholine.
  • Typical examples of cyclic groups represented by NR a R b include azetidin- IyI, 3,3-difluoroazetidin-l-yl, 3-hydroxyazetidin-l-yl, pyrrolidin-1-yl, 3-hydroxypyrrolidin-l-yl, 3- fluoropyrrolidin-1-yl, 2-trifluoromethylpyrrolidin-l-yl, piperidin-1-yl, 4-trifluoromethylpiperidin-l-yl, 3- trifluoromethylpiperidin-1-yl, 3-fluoropiperidin-l-yl, 3,3,-difluoropiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 4-trifluoromethyl-l,2,3,6-tetrahydropyridin-l-yl, 4-methylpiperazin-l-yl, 3-oxo-piperazin-l-yl, morpholin- 4-yl, 2,
  • Preferred identities for the moiety -E-Z include H, halogen, hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, 1-hydroxypropyl, 1 -hydroxy- 1-methylethyl, 1-hydroxycyclobutyl, CO 2 Me, CO 2 Et, CONH 2 , CONHMe, COCH 3 , NH 2 , NHMe, NMe 2 , NHSO 2 Me, SO 2 Me, CN, SO 2 NH 2 , pyrazol-3-yl, imidazol-2-yl and thiazol-3-yl.
  • n is O or 1 and hence not more than one R 2 group is present. Most preferably, n is O.
  • preferred identities for R 2 include halogen (especially F), (especially methyl) CN and CONH 2 .
  • the moiety -E-Z and an R 2 substituent are attached at adjacent ring positions and combine to complete a fused imidazole group.
  • the moiety -E-Z and R 2 may be attached at any available ring position, including a carbon atom represented by A.
  • m represents O, 1, 2 or 3, but preferably represents 1 or 2.
  • Each R 1 is preferably selected from halogen (preferably F or Cl, most preferably F), CN, hydroxymethyl, OH and (e.g. methoxy).
  • Specific embodiments of (R 1 J m include H, 2-fluoro, 3-fluoro, 4-fluoro, 2,4-difluoro, 3- cyano, 4-cyano, 2-chloro-4-fluoro, 4-fluoro-2-hydroxy, 4-chloro, 2-hydroxy, 2-cyano-4-fluoro, 4-fluoro-2- methoxy and 4-fluoro-2-hydroxymethyl.
  • (R 1 J m represents 2-fluoro, 4-fluoro or 2,4-difluoro substitution of the phenyl ring.
  • R 3 preferably represents H, halogen (such as Br or Cl), CN or CONH 2 . Most preferably, R 3 represents H.
  • the invention provides a compound of formula II:
  • the moiety Z-E- is preferably attached at a ring position which is adjacent to the point of attachment of the -S(0) t - moiety or adjacent to the ring nitrogen, most preferably adjacent to the point of attachment of the -S(0) t - moiety.
  • the invention provides a compound of formula HI:
  • the moiety Z-E- is preferably attached at a ring position which is adjacent to the point of attachment of the -S(O) t - moiety and/or adjacent to the ring nitrogen.
  • the invention provides a compound of formula IV:
  • Specific compounds useful in this invention include those compounds exemplified hereinafter and their pharmaceutically acceptable salts.
  • the compounds of formula I have an activity as antagonists of the human 5-HT 2A receptor and hence find use in the treatment or prevention of disorders mediated by 5-HT 2A receptor activity.
  • compositions comprising one or more compounds of formula I and a pharmaceutically acceptable carrier.
  • these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, transdermal patches, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the principal active ingredient typically is mixed with a pharmaceutical carrier, e.g.
  • a tableting ingredient such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate and dicalcium phosphate, or gums, dispersing agents, suspending agents or surfactants such as sorbitan monooleate and polyethylene glycol, and other pharmaceutical diluents, e.g. water, to form a homogeneous preformulation composition containing a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient.
  • Tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • the liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, liquid- or gel-filled capsules, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil or coconut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, poly(ethylene glycol), poly(vinylpyrrolidone) or gelatin.
  • the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human body.
  • the treatment is for a condition mediated by 5-HT 2A receptor activity.
  • the present invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a condition mediated by 5-HT 2 A receptor activity.
  • Also disclosed is a method of treatment of a subject suffering from or prone to a condition mediated by 5-HT 2A receptor activity which comprises administering to that subject an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof.
  • the condition mediated by 5-HT 2A receptor activity is sleep disorder, in particular insomnia.
  • the condition mediated by 5-HT 2A receptor activity is selected from psychotic disorders (such as schizophrenia), depression, anxiety, panic disorder, obsessive-compulsive disorder, pain, glaucoma, eating disorders (such as anorexia nervosa), dependency or acute toxicity associated with narcotic agents such as LSD or MDMA, and hot flushes associated with the menopause.
  • a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day but preferably once per day, for example before going to bed.
  • the compounds according to this invention may be co-administered with another sleep inducing or anti-schizophrenic or anxiolytic medicament.
  • Such co-administration may be desirable where a patient is already established on sleep inducing or anti-schizophrenic or anxiolytic treatment regime involving other conventional medicaments.
  • the compounds of the invention may be co-administered with a GABA A receptor agonist such as gaboxadol, or with a short term and/or rapid-onset hypnotic such as Zolpidem, or a benzodiazepine, a barbiturate, a prokineticin modulator, an antihistamine, trazodone, or derivative of trazodone as disclosed in WO 03/068148.
  • GABA A receptor agonist such as gaboxadol
  • a short term and/or rapid-onset hypnotic such as Zolpidem, or a benzodiazepine
  • a barbiturate such as a prokineticin modulator
  • an antihistamine trazodone
  • derivative of trazodone as disclosed in WO 03/068148.
  • a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof for use in treatment or prevention of sleep disorders, schizophrenia or depression.
  • a method of treatment or prevention of sleep disorders, schizophrenia or depression comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof in combination with gaboxadol.
  • the expression "in combination with” requires that therapeutically effective amounts of both a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof and gaboxadol are administered to the subject, but places no restriction on the manner in which this is achieved.
  • the two species may be combined in a single dosage form for simultaneous administration to the subject, or may be provided in separate dosage forms for simultaneous or sequential administration to the subject. Sequential administration may be close in time or remote in time, e.g.
  • a pharmaceutical composition comprising, in a pharmaceutically acceptable carrier, a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof and gaboxadol.
  • the invention further provides the use, for the manufacture of a medicament for treatment or prevention of sleep disorders, schizophrenia or depression, of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof and gaboxadol.
  • the invention further provides a kit comprising a first medicament comprising a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof and a second medicament comprising gaboxadol together with instructions for administering said medicaments sequentially or simultaneously to a patient suffering from a sleep disorder, schizophrenia or depression.
  • gaboxadol is inclusive of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol in free base or zwitterionic form and also of pharmaceutically acceptable acid addition salts thereof such as the hydrochloride salt. Most suitably, gaboxadol is in the form of a crystalline monohydrate of the zwitterionic form.
  • Compounds of formula I may be prepared by reaction of a benzyl bromide of formula (Ia) with a phenol of formula (2): where m, n, t, A, A 1 , A 2 , Z, E, R 1 , R 2 and R 3 have the same meanings as before.
  • the reaction may be carried out at elevated temperature (e.g. about 100 0 C) in DMF in the presence of base (e.g. an inorganic base such as potassium carbonate).
  • Bromides (Ia) are available by treatment of alcohols (Ib) with a brominating agent such as phosphorus tribromide or a combination of carbon tetrabromide and triphenylphosphine.
  • a brominating agent such as phosphorus tribromide or a combination of carbon tetrabromide and triphenylphosphine.
  • Alcohols (Ib) are available by reduction of aldehydes (3):
  • n, A, A 1 , A 2 , Z, E, R 1 , and R 3 have the same meanings as before, followed by oxidation of the thioether group.
  • the reduction is suitably carried out using sodium borohydride, e.g. in a methanol - THF mixture at ambient temperature.
  • Suitable oxidants include Oxone® and peroxyacids such as m-chloroperoxybenzoic acid.
  • a preferred oxidant for use in preparing the sulphones is hydrogen peroxide in acetic acid in the presence of sodium tungstate.
  • Compounds (3) are available by reaction of thiols (4a) with halobenzaldehydes (5):
  • Y SO 2 -Na +
  • Hal represents halide (eg. Cl, F) and n, A, A 1 , A 2 , Z, E, R 1 , and R 3 have the same meanings as before.
  • the reaction takes place at elevated temperature (e.g. 12O 0 C) in the presence of base (preferably an inorganic base such as potassium carbonate) in DMSO.
  • base preferably an inorganic base such as potassium carbonate
  • An alternative route to alcohols (Ib) in which t is 2 comprises reaction of fluorobenzaldehydes (5) with sulphinate salts (4b), followed by reduction of the aldehyde group as before. The reaction takes place in DMSO solution at elevated temperature (e.g. about 100 - 13O 0 C) (Ulman et al, J.Org.Chem. (1989), 54(19), 4691-2).
  • An alternative route to compounds of formula I in which t is 2 and A 1 and A 2 are both CH comprises reaction of a sulphura rattee s ! alt of formula (6a) with an aryl bromide or iodide of formula (7):
  • the sulphurate salts (6a) are available by treatment of the corresponding thioanisoles (6b) sequentially with an oxidising agent (e.g. m-chloroperoxybenzoic acid), sodium acetate in acetic anhydride, magnesium peroxyphthalate, and sodium hydroxide.
  • an oxidising agent e.g. m-chloroperoxybenzoic acid
  • Thioanisoles (6b) are obtainable by coupling of a phenol (2) with the appropriate A- (hydroxymethyl)thioanisole under standard Mitsonobu conditions (e.g. using diisopropylazodicarboxylate and Ph 3 P in THF at O 0 C).
  • An alternative route to sulphurate salts (6a) comprises coupling of the bromo-derivative (6c) with methyl 3-mercaptopropionate, oxidation of the resulting thioether to the corresponding sulphone, and treatment of the resulting arylsulphonylpropionate methyl ester with sodium methoxide to generate the sulphurate salt. Suitable conditions for this process are described in the examples section herein.
  • the starting materials and reagents described above may be obtained from commercially available precursors by means of well known synthetic procedures and/or the methods disclosed in the Examples section herein.
  • any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further desired compound of formula I using techniques known from the art.
  • a bromo substituent represented by Z-E-, R 1 , R 2 or R 3 may be replaced by cyano by treatment with copper(I) cyanide in the presence of l-methyl-2-pyrrolidinone (NMP), or with zinc cyanide in the presence of tetrakis(triphenylphosphine)palladium(0).
  • NMP l-methyl-2-pyrrolidinone
  • the cyano group thereby obtained may in turn be converted into carboxamido by heating in mineral acid, e.g.
  • a fluoro substituent represented by Z-E- or R 3 may be replaced by NR a R b or an optionally substituted N-linked heteroaryl moiety, e.g. imidazol-1-yl, pyrazol-1-yl, 1,2,3-triazol-l-yl or 1,2,4-triazol-l-yl, by treatment with HNR a R b orthe appropriate optionally substituted N-containing heteroaryl compound, typically with heating in DMSO.
  • a bromo substituent represented by Z-E- may be replaced by an optionally substituted C-linked five- membered heteroaromatic ring, e.g. 2-methyltetrazol-5-yl or 1 -methyl- l,2,4-triazol-5-yl, by reaction with a tributylstannyl derivative of the appropriate heteroaromatic compound, e.g.
  • a cyano substituent represented by Z-E- may be converted to CHO by diisobutylaluminium hydride (DIBAL-H) reduction and hydrolysis.
  • DIBAL-H diisobutylaluminium hydride
  • a CHO substituent represented by Z- E- may be converted to CH 2 NR a R b by treatment with HNR a R b and sodium triacetoxyborohydride or sodium cyanoborohydride.
  • a substituent COR a represented by Z-E- may be converted to CH(0H)R a by reduction (e.g. using sodium borohydride) or to CR a (0H)R b by treatment with R 1 TVIgHaI where Hal is Cl, Br or I.
  • Compounds in which Z-E- take the form Z-(CH 2 ) y -O- where y is 1, 2, 3, or 4 may be formed by treating the corresponding compounds in which Z-E- is F with Z-(CH 2 ) y OH in the presence of strong base.
  • Such processes may also be used to prepare appropriately-substituted precursors of the compounds of Formula I and/or to manipulate the identity of R 3 .
  • a preferred route to compounds (7) wherein A represents N, Hal is in the 2-position and Z-E- represents 1-hydroxyalkyl or 1-hydroxycycloalkyl attached to the 3-position comprises treatment of 2-bromopyridine with lithium diisopropylamide followed by the appropriate ketone.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
  • it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T. W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • Step 3 ( ⁇ 4-r(2,4-Difluorophenoxy)methyl1phenyl ⁇ sulfonyl)methyl acetate
  • the reaction was allowed to warm to room temperature and stirred for 16 h.
  • the reaction was quenched by adding saturated NaHCO 3 (300 mL) and water (300 mL) and then diluting with EtOAc.
  • the organic extract was washed with NaHCO 3 and water, dried and evaporated.
  • the residue was purified by flash column chromatography on silica, eluting with 20-35% ethyl acetate/isohexane to give the title compound as a solid (7.65g, 42%).
  • Step 4 Sodium 4-r(2,4-difluorophenoxy)methyl1benzenesulfinate
  • Step 2 methyl 3-( ⁇ 4-r(2,4-difluorophenoxy)methyl1phenyl ⁇ thio)propanoate
  • l-[(4-bromobenzyl)oxy]-2,4-difluorobenzene 9.8 g, 32.6 mmol
  • diisopropylethylamine 11.4 mL, 65.3 mmol
  • methyl 3-mercaptopropionate 3.9 mL, 35.9 mmol
  • tris(dibenzylideneacetone) dipalladium 745 mg, 0.82 mmol
  • 9,9-dimethyl-4,5-bis(diphenylphosphino) xanthene 945 mg, 1.63 mmol.
  • the reaction was heated to 110 0 C for 18 h. On cooling, the reaction was partitioned between EtOAc and water, the organics were washed water and brine successively; dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 25% ethyl acetate/isohexane, to yield a yellow solid (11.1 g, 98%).
  • Step 3 methyl 3-( ⁇ 4-r(2,4-difluorophenoxy)methyl1phenyl ⁇ sulfonyl)propanoate
  • Step 4 Sodium 4-r(2,4-difluorophenoxy)methyl1benzenesulfinate
  • Step 1 l-(bromomethyl)-4-(phenylsulfonyl)benzene 4-(Phenylsulfonyl)benzaldehyde (prepared according to the method of Ulman et ah, J. Org. Chent. (1989), 54(19), 4691-2; 12.3 g, 50 mmol) was dissolved in THF and MeOH was added, followed by careful addition of sodium borohydride (2.0 g, 52.9 mmol). The reaction was stirred for 1 h before pouring into water and extracting with EtOAc. The organic layer was dried over MgSO 4 and evaporated in vacuo to give [4-(phenylsulfonyl)phenyl]methanol.
  • Step 2 l-fluoro-2- ⁇ r4-(phenylsulfonyl)benzyl1oxy ⁇ benzene l-(Bromomethyl)-4-(phenylsulfonyl)benzene (Step 1, 78 mg, 0.25 mmol), 2-fluorophenol (0.05 mL, 0.6 mmol), potassium carbonate (69 mg, 0.50 mmol) and DMF (1 mL) were combined and the mixture stirred at 100 0 C for 18 h. On cooling, water (4 mL) and aqueous sodium hydroxide (4N, 1 mL) were added sequentially to the vigorously stirred mixture causing precipitation.
  • Examples 2-7 were prepared as for Example 1, using the appropriate phenol in Step 2.
  • Step 2 ⁇ 4-r(2-bromophenyl)sulfonyl1phenyl ⁇ methanol
  • Diisobutylaluminium hydride (1.5M in toluene, 0.13 mL, 0.195 mmol) was added dropwise to a solution of 2-( ⁇ 4-[(2,4-difluorophenoxy)methyl]phenyl ⁇ sulfonyl)benzonitrile (Example 9, 72 mg, 0.187 mmol) in dichloromethane (1 mL) and toluene (0.6 mL) at -78 0 C.
  • the reaction was allowed to warm to 0 0 C and stirred for 30 min, then quenched with MeOH (1 drop), 2M HCl (2 mL) and DCM (2 mL) and stirred vigorously. The mixture was partitioned between DCM and water.
  • Step 2 ⁇ 2-( ⁇ 4-r(2,4-difluorophenoxy)methyl1phenyl ⁇ sulfonvDphenylimethanol Sodium borohydride (10 mg, 0.26 mmol) was added to a solution of 2-( ⁇ 4-[(2,4- difluorophenoxy)methyl]phenyl ⁇ sulfonyl)benzaldehyde (Step 1, 17 mg, 0.04 mmol) in MeOH (2 mL) and dichloromethane (0.5 mL). The reaction was stirred for 1 h. The solvent was removed in vacuo and the residue partitioned between DCM and water. The organic layer was dried over MgSO 4 and concentrated in vacuo.
  • Step 1 2-( ⁇ 4-r(2,4-difluorophenoxy)metfayl1phenyl ⁇ sulfonvDnicotinaldehyde 2-Bromonicotinaldehyde (1 g, 5.41 mmol), sodium 4-[(2,4-difluorophenoxy)methyl]benzenesulfinate (Intermediate 1; 1.65 g, 5.41 mmol) and copper iodide (3.23 g, 16.22 mmol) were suspended in DMSO (10 mL) and heated to 130 0 C for 1 h. The cooled reaction mixture was diluted with EtOAc, poured into saturated ammonium chloride solution and filtered through Hyflo ® .
  • Step 2 2-( ⁇ 4-r(2,4-difluorophenoxy)methyl1phenyl ⁇ sulfonyl)nicotinamide 2-( ⁇ 4-[(2,4-Difluorophenoxy)methyl]phenyl ⁇ sulfonyl)nicotinaldehyde (Step 1, 200 mg, 0.51 mmol) was dissolved in ammonium hydroxide (3 mL) and THF (5 mL) and iodine (0.14 g, 0.57 mmol) was added. The reaction was stirred for 16 h at room temperature. Hydrogen peroxide (35%, 2 mL) was added and the reaction was stirred for one hour before pouring into water and extracting with ethyl acetate.
  • Step 3 2-r2-( ⁇ 4-r(2,4-difluorophenoxy)methyl1phenyl ⁇ sulfonyl)phenyl1-l,3-thiazole
  • the title compound was prepared from 2-(2-bromophenyl)-l,3-thiazole (Step 2) and sodium 4-[(2,4- difluorophenoxy)methyl]benzenesulfinate (Intermediate 1) according to the method of Example 15, Step 1.
  • Step 1 2-(2-bromopyridin-3-yl)propan-2-ol Lithium diisopropylamide (2 M in tetrahydrofuran, 12.5 mL, 25 mmol) was dissolved in THF (40 mL) and cooled to -78 0 C. 2-Bromopyridine (3.9 g, 25 mmol) was added dropwise and the reaction was stirred for 3 h before adding acetone (1 mL, dried over freshly activated molecular sieves) and allowed to warm to room temperature. The reaction was quenched with saturated ammonium chloride and extracted with EtOAc. The organic layer was dried over MgSO 4 and evaporated.
  • Step 2 2-[2-( ⁇ 4-r(2,4-difluorophenoxy)methyl1phenyl ⁇ sulfonyl)pyridin-3-yl1propan-2-ol
  • the title compound was prepared from 2-(2-bromopyridin-3-yl)propan-2-ol (Step 1) and sodium 4-[(2,4- difluorophenoxy)methyl]benzenesulf ⁇ nate (Intermediate 1) according to the method of Example 15, Step 1.
  • Step 2 3-[2-( ⁇ 4-r(2,4-difluorophenoxy)methvHphenyl ⁇ sulfonvDphenylMH- 1 ,2,4-triazole Ethylchloroformate (3.9 mL, 0.05 mol) and 2-iodo-N'-4H-l,2,4-triazol-4-ylbenzenecarboximidamide (Step 1, 15.6 g, 0.05 mol) were combined in acetonitrile (75 mL) under nitrogen and heated to reflux overnight.
  • Step 2 2-( ⁇ 4-r(2,4-difluorophenoxy)methyl1phenyl ⁇ sulfonyl)-3-(lH-imidazol-2-yl)pyridine
  • the title compound was prepared from sodium 4-[(2,4-difluorophenoxy)methyl]benzenesulfinate (Intermediate 1) and l-(2-bromopyridin-3-yl)cyclobutanol (prepared as described in Example 18, Step 1, using cyclobutanone in place of acetone) to give the title compound as a white solid.
  • the title compound was prepared from sodium 4-[(4-fluorophenoxy)methyl]benzenesulf ⁇ nate (prepared as described in Intermediate 1, Method 2, using 4-fluorophenol in Step 1) and l-(2-bromopyridin-3- yl)cyclobutanol (prepared as described in Example 22), to give the title compound as a white solid.
  • Step 4 4-( ⁇ 4-r(2,4-difluorophenoxy)methyl1phenyl ⁇ sulfonyl)- lH-benzimidazole
  • the title compound was prepared from sodium 4-[(2,4-difluorophenoxy)methyl]benzenesulfinate (Intermediate 1, Method 2, Step 4) and 4-iodo-lH-benzimidazole to give the title compound as a white solid.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Ophthalmology & Optometry (AREA)
  • Psychiatry (AREA)
  • Addiction (AREA)
  • Nutrition Science (AREA)
  • Anesthesiology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des composés de formule (I) Z-E R3 (R1)m S(O)t O 1 2 AA A (R2)n I 10 qui sont des antagonistes puissants et sélectifs du récepteur 5-HT2A et qui sont utilisés dans le traitement de nombreux troubles du système nerveux central.
PCT/GB2006/050048 2005-03-17 2006-03-08 Ethers arylsulfonyle benzyle utilises en tant qu'antagonistes 5-ht2a WO2006097766A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU2006224336A AU2006224336A1 (en) 2005-03-17 2006-03-08 Arylsulfonyl benzyl ethers as 5-HT2A antagonists
JP2008501425A JP2008533119A (ja) 2005-03-17 2006-03-08 ５−ｈｔ２ａ拮抗薬としてのアリールスルホニルベンジルエーテル
EP06710166A EP1861079A1 (fr) 2005-03-17 2006-03-08 Ethers arylsulfonyle benzyle utilises en tant qu'antagonistes 5-ht2a
CA002600508A CA2600508A1 (fr) 2005-03-17 2006-03-08 Ethers arylsulfonyle benzyle utilises en tant qu'antagonistes 5-ht2a

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0505437.4 2005-03-17
GBGB0505437.4A GB0505437D0 (en) 2005-03-17 2005-03-17 Therapeutic agents

Publications (1)

Publication Number Publication Date
WO2006097766A1 true WO2006097766A1 (fr) 2006-09-21

Family

ID=34509190

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2006/050048 WO2006097766A1 (fr) 2005-03-17 2006-03-08 Ethers arylsulfonyle benzyle utilises en tant qu'antagonistes 5-ht2a

Country Status (6)

Country Link
EP (1) EP1861079A1 (fr)
JP (1) JP2008533119A (fr)
AU (1) AU2006224336A1 (fr)
CA (1) CA2600508A1 (fr)
GB (1) GB0505437D0 (fr)
WO (1) WO2006097766A1 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010056938A1 (fr) * 2008-11-14 2010-05-20 Theravance, Inc. Procédé de préparation de composés à base de 4-[2-(2-fluorophénoxy­méthyl)phényl]pipéridine
JP2010150200A (ja) * 2008-12-25 2010-07-08 Tosoh Corp イミダゾール化合物およびその製造方法
US8148417B2 (en) 2006-05-18 2012-04-03 Arena Pharmaceuticals, Inc. Primary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US8148418B2 (en) 2006-05-18 2012-04-03 Arena Pharmaceuticals, Inc. Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
WO2012136724A1 (fr) 2011-04-06 2012-10-11 Basf Se Composés pyrimidinium substitués utilisables dans le cadre de la lutte contre les animaux nuisibles
US8481535B2 (en) 2006-05-18 2013-07-09 Arena Pharmaceuticals, Inc. Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulators of the 5-HT2A serotonin receptor
US8785441B2 (en) 2004-11-19 2014-07-22 Arena Pharmaceuticals, Inc. 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US8871797B2 (en) 2003-07-22 2014-10-28 Arena Pharmaceuticals, Inc. Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto
US8980891B2 (en) 2009-12-18 2015-03-17 Arena Pharmaceuticals, Inc. Crystalline forms of certain 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9034911B2 (en) 2008-10-28 2015-05-19 Arena Pharmaceuticals, Inc. Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto
US9126946B2 (en) 2008-10-28 2015-09-08 Arena Pharmaceuticals, Inc. Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)urea and crystalline forms related thereto
US9434692B2 (en) 2006-10-03 2016-09-06 Arena Pharmaceuticals, Inc. Pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9556149B2 (en) 2008-04-02 2017-01-31 Arena Pharmaceuticals, Inc. Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor
US9567327B2 (en) 2007-08-15 2017-02-14 Arena Pharmaceuticals, Inc. Imidazo[1,2-a]pyridine derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US10022355B2 (en) 2015-06-12 2018-07-17 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of REM sleep behavior disorder
US10034859B2 (en) 2015-07-15 2018-07-31 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003099786A2 (fr) * 2002-05-29 2003-12-04 Glaxo Group Limited Composes
WO2005086661A2 (fr) * 2004-02-27 2005-09-22 Amgen Inc. Composes, compositions pharmaceutiques et procedes d'utilisation dans le traitement de troubles metaboliques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003099786A2 (fr) * 2002-05-29 2003-12-04 Glaxo Group Limited Composes
WO2005086661A2 (fr) * 2004-02-27 2005-09-22 Amgen Inc. Composes, compositions pharmaceutiques et procedes d'utilisation dans le traitement de troubles metaboliques

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
COLEMAN, MICHAEL D. ET AL: "Preliminary evaluation of the toxicity and efficacy of novel 2,4-diamino-5-benzylpyrimidine-sulfone derivatives using rat and human tissues in vitro", ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY , 2(4), 389-395 CODEN: ETOPFR; ISSN: 1382-6689, 1996, XP002393315 *
DATABASE REGISTRY [online] Chemical Abstract Service, COPYRIGHT (C) 2006 American Chemical Society (ACS); 18 June 2004 (2004-06-18), XP002393322, retrieved from STN *
DATABASE REGISTRY [online] Chemical Abstract Service, COPYRIGHT (C) 2006 American Chemical Society (ACS); 18 June 2004 (2004-06-18), XP002393323, retrieved from STN *
DATABASE REGISTRY [online] Chemical Abstract Service, COPYRIGHT (C) 2006 American Chemical Society (ACS); 18 June 2004 (2004-06-18), XP002393324, retrieved from STN *
FLETCHER S R ET AL: "4-(Phenylsulfonyl)piperidines: Novel, Selective, and Bioavailable 5-HT2A Receptor antagonists", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 45, no. 2, 2002, pages 492 - 503, XP002290071, ISSN: 0022-2623 *
HOWARD H.R.: "ANTIPSYCHOTIC DRUGS: RECENT DEVELOPMENTS AND NOVEL AGENTS", EXPERT OPINION ON THERAPEUTIC PATENTS, vol. 7, no. 4, April 1997 (1997-04-01), pages 353 - 369, XP002393317, ISSN: 1354-3776 *
MARTYN D WOOD, DAVID R THOMAS, JEANNETTE M WATSON,: "Therapeutic potential of serotonin antagonists in depressive disorders", EXPERT OPINION ON INVESTIGATIONAL DRUGS, vol. 11, no. 4, April 2002 (2002-04-01), pages 457 - 467, XP002393316, ISSN: 1357-3784 *
SCHOP H ET AL: "Partial resistance of E. coli mutants against 2,4-diamino-5-benzylpyrimidines by interactions with bacterial membrane lipopolysaccharides. Derivation of quantitative structure-binding relationships", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 35, no. 6, June 2000 (2000-06-01), pages 619 - 634, XP004330453, ISSN: 0223-5234 *

Cited By (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9273035B2 (en) 2003-07-22 2016-03-01 Arena Pharmaceuticals, Inc. Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto
US8871797B2 (en) 2003-07-22 2014-10-28 Arena Pharmaceuticals, Inc. Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto
US9775829B2 (en) 2003-07-22 2017-10-03 Arena Pharmaceuticals, Inc. Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto
US8785441B2 (en) 2004-11-19 2014-07-22 Arena Pharmaceuticals, Inc. 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US10781180B2 (en) 2004-11-19 2020-09-22 Arena Pharmaceuticals, Inc. 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US8680119B2 (en) 2006-05-18 2014-03-25 Arena Pharmaceuticals, Inc. Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US8148417B2 (en) 2006-05-18 2012-04-03 Arena Pharmaceuticals, Inc. Primary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9783502B2 (en) 2006-05-18 2017-10-10 Arena Pharmaceuticals, Inc. Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulators of the 5-HT2A serotonin receptor
US8481535B2 (en) 2006-05-18 2013-07-09 Arena Pharmaceuticals, Inc. Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulators of the 5-HT2A serotonin receptor
US8664258B2 (en) 2006-05-18 2014-03-04 Arena Pharmaceuticals, Inc. Primary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9199940B2 (en) 2006-05-18 2015-12-01 Arena Pharmaceuticals, Inc. Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulators of the 5-HT2A serotonin receptor
US8148418B2 (en) 2006-05-18 2012-04-03 Arena Pharmaceuticals, Inc. Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9987252B2 (en) 2006-05-18 2018-06-05 Arena Pharmaceuticals, Inc. Primary amines and derivitves thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
USRE45337E1 (en) 2006-05-18 2015-01-13 Arena Pharmaceuticals, Inc. Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
USRE45336E1 (en) 2006-05-18 2015-01-13 Arena Pharmaceuticals, Inc. Primary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9732039B2 (en) 2006-10-03 2017-08-15 Arena Pharmeceuticals, Inc. Pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9434692B2 (en) 2006-10-03 2016-09-06 Arena Pharmaceuticals, Inc. Pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US10351531B2 (en) 2006-10-03 2019-07-16 Arena Pharmaceuticals, Inc. Pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US10058549B2 (en) 2007-08-15 2018-08-28 Arena Pharmaceuticals, Inc. Imidazo[1,2-α]pyridine derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9567327B2 (en) 2007-08-15 2017-02-14 Arena Pharmaceuticals, Inc. Imidazo[1,2-a]pyridine derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9556149B2 (en) 2008-04-02 2017-01-31 Arena Pharmaceuticals, Inc. Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor
US10787437B2 (en) 2008-04-02 2020-09-29 Arena Pharmaceuticals, Inc. Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor
US9801856B2 (en) 2008-10-28 2017-10-31 Arena Pharmaceuticals, Inc. Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto
US9126946B2 (en) 2008-10-28 2015-09-08 Arena Pharmaceuticals, Inc. Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)urea and crystalline forms related thereto
US9353064B2 (en) 2008-10-28 2016-05-31 Arena Pharmaceuticals, Inc. Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto
US9034911B2 (en) 2008-10-28 2015-05-19 Arena Pharmaceuticals, Inc. Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto
US10583122B2 (en) 2008-10-28 2020-03-10 Arena Pharmaceuticals, Inc. Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto
US10543193B2 (en) 2008-10-28 2020-01-28 Arena Pharmaceuticals, Inc. Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto
US10117851B2 (en) 2008-10-28 2018-11-06 Arena Pharmaceuticals, Inc. Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto
US10071075B2 (en) 2008-10-28 2018-09-11 Arena Pharmaceuticals, Inc. Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto
US9745270B2 (en) 2008-10-28 2017-08-29 Arena Pharmaceuticals, Inc. Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto
CN102209712A (zh) * 2008-11-14 2011-10-05 施万制药 制备4-[2-(2-氟苯氧基甲基)苯基]哌啶化合物的方法
WO2010056938A1 (fr) * 2008-11-14 2010-05-20 Theravance, Inc. Procédé de préparation de composés à base de 4-[2-(2-fluorophénoxy­méthyl)phényl]pipéridine
US8802857B2 (en) 2008-11-14 2014-08-12 Theravance Biopharma R&D Ip, Llc Process for preparing 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compounds
US8247433B2 (en) 2008-11-14 2012-08-21 Theravance, Inc. Process for preparing 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compounds
US11723900B2 (en) 2008-11-14 2023-08-15 Theravance Biopharma R&D Ip, Llc 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compounds
US11596624B2 (en) 2008-11-14 2023-03-07 Theravance Biopharma R&D Ip, Llc Crystalline form of a 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compound
US9187423B2 (en) 2008-11-14 2015-11-17 Theravance Biopharma R&D Ip, Llc Process for preparing 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compounds
AU2009313948B2 (en) * 2008-11-14 2015-03-12 Theravance Biopharma R&D Ip, Llc Process for preparing 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compounds
US10946006B2 (en) 2008-11-14 2021-03-16 Theravance Biopharma R&D Ip, Llc Crystalline form of a 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compound
KR20110082197A (ko) * 2008-11-14 2011-07-18 세라밴스 인코포레이티드 4­［2­（2­플루오로페녹시메틸）페닐］피페리딘 화합물의 결정형
US10441579B2 (en) 2008-11-14 2019-10-15 Theravance Biopharma R&D Ip, Llc 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compounds
US10946007B2 (en) 2008-11-14 2021-03-16 Theravance Biopharma R&D Ip, Llc 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compounds
US10576073B2 (en) 2008-11-14 2020-03-03 Theravance Biopharma R&D Ip, Llc Crystalline form of a 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compound
KR101656338B1 (ko) 2008-11-14 2016-09-09 세라밴스 바이오파마 알앤디 아이피, 엘엘씨 4­［2­（2­플루오로페녹시메틸）페닐］피페리딘 화합물의 결정형
US10722504B2 (en) 2008-11-14 2020-07-28 Theravance Biopharma R&D Ip, Llc 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compounds
CN102209712B (zh) * 2008-11-14 2016-04-06 施万生物制药研发Ip有限责任公司 制备4-[2-(2-氟苯氧基甲基)苯基]哌啶化合物的方法
JP2010150200A (ja) * 2008-12-25 2010-07-08 Tosoh Corp イミダゾール化合物およびその製造方法
US8980891B2 (en) 2009-12-18 2015-03-17 Arena Pharmaceuticals, Inc. Crystalline forms of certain 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
WO2012136724A1 (fr) 2011-04-06 2012-10-11 Basf Se Composés pyrimidinium substitués utilisables dans le cadre de la lutte contre les animaux nuisibles
US10022355B2 (en) 2015-06-12 2018-07-17 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of REM sleep behavior disorder
US11304932B2 (en) 2015-07-15 2022-04-19 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease
US10034859B2 (en) 2015-07-15 2018-07-31 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease

Also Published As

Publication number Publication date
JP2008533119A (ja) 2008-08-21
GB0505437D0 (en) 2005-04-20
AU2006224336A1 (en) 2006-09-21
CA2600508A1 (fr) 2006-09-21
EP1861079A1 (fr) 2007-12-05

Similar Documents

Publication Publication Date Title
EP1861079A1 (fr) Ethers arylsulfonyle benzyle utilises en tant qu'antagonistes 5-ht2a
EP1858852B1 (fr) Heteroarylsulfonylstilbenes en tant qu'antagonistes de 5-ht2a
EP1824817B1 (fr) Derives de l'arylsulfonylnaphtalene utilises en tant qu'antagonistes de 5ht2a
US20090012134A1 (en) Arylsulfonyl Benzofused Heterocycles as 5-Ht2a Antagonists
EP1786768A1 (fr) Derives d'arylsulfonylstilbene destines au traitement de l'insomnie et de conditions apparentees
EP0040696B1 (fr) Aminothiadiazoles comme inhibiteurs de la sécrétion gastrique
EP0548934A1 (fr) Dérivés du benzamide
EP0190015A1 (fr) Nouvelles 4H-1-benzopyranones-4 et leurs analogues contenant du soufre
HU220062B (hu) Helyettesített alkil-tio-piridinil-metil-tio-benzimidazol és -imidazo[4,5-b]piridin-származékok és felhasználásuk gyógyszerkészítmények előállítására
JP2008517907A (ja) 新規な使用
NO851220L (no) Tiatriazinderivater

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2006224336

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2600508

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2006710166

Country of ref document: EP

Ref document number: 2008501425

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2006224336

Country of ref document: AU

Date of ref document: 20060308

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2006224336

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 7777/DELNP/2007

Country of ref document: IN

NENP Non-entry into the national phase

Ref country code: RU

WWW Wipo information: withdrawn in national office

Ref document number: RU

WWP Wipo information: published in national office

Ref document number: 2006710166

Country of ref document: EP