[go: up one dir, main page]

AP947A - Quaternary ammonium compounds as tachykinin antagonists. - Google Patents

Quaternary ammonium compounds as tachykinin antagonists. Download PDF

Info

Publication number
AP947A
AP947A APAP/P/1998/001262A AP9801262A AP947A AP 947 A AP947 A AP 947A AP 9801262 A AP9801262 A AP 9801262A AP 947 A AP947 A AP 947A
Authority
AP
ARIPO
Prior art keywords
alkyl
phenyl
alkoxy
fluoro
cycloalkyl
Prior art date
Application number
APAP/P/1998/001262A
Other versions
AP9801262A0 (en
Inventor
Sandra Marina Monaghan
David Alker
Christopher John Burns
Original Assignee
Pfizer
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 Pfizer filed Critical Pfizer
Publication of AP9801262A0 publication Critical patent/AP9801262A0/en
Application granted granted Critical
Publication of AP947A publication Critical patent/AP947A/en

Links

Classifications

    • 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
    • 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
    • A61P1/04—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
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • 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
    • 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
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P25/06—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
    • A61P25/18—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
    • A61P25/24—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
    • A61P25/28—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
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • 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
    • 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
    • C07D233/56—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • 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
    • 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
    • C07D405/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Pulmonology (AREA)
  • Virology (AREA)
  • Psychiatry (AREA)
  • Urology & Nephrology (AREA)
  • Pain & Pain Management (AREA)
  • Dermatology (AREA)
  • Immunology (AREA)
  • Hospice & Palliative Care (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Oncology (AREA)
  • Reproductive Health (AREA)
  • Endocrinology (AREA)
  • Communicable Diseases (AREA)
  • Otolaryngology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Molecular Biology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Ophthalmology & Optometry (AREA)

Abstract

The present invention provides a compound of the formula: wherein R is phenyl, C3-C7 cycloalkyl or heteroaryl, each of which being optionally benzo- or C3-C7 cycloalkyl-fused and optionally substituted, including in the benzo- or C3-C7 cycloalkyl-fused portion, by from 1 to 3 substituents each independently selected from C,-C4 alkyl, fluoro(C1-C4)alkyl, C,-C4 alkoxy, fluoro(C,-C4)alkoxy, phenoxy, C2-C4 alkanoyl, halo, C,-C4 alkoxycarbonyl, C3-C7 cycloalkyl, -S(O)m(CrC4 alkyl), cyano, -NR2R3, -S(O)mNR2R3, -NR4(C,-C4 alkanoyl) and -CONR2R3, or R is 2,3-dihydrobenzo[b]furanyl or chromanyl; R1 is H or C,-C6 alkyl; X is unbranched C2-C4 alkylene; Y is phenyl, naphthyl, benzyl, pyridyl, thienyl or C3-C7 cycloalkyl, each of which being optionally substituted by from 1 to 3 substituents each independently selected from C,-C4 alkyl, fluoro(CrC4)alkyl, C,-C4 alkoxy, fluoro(C,-C4)alkoxy, halo and cyano; Ar is phenyl, naphthyl, benzyl, thienyl, benzo[b]thienyl or indolyl, each of which being optionally substituted by from 1 to 3 substituents each independently selected from C,-C4 alkyl, fluorofCrC^alkyl, C,-C4 alkoxy, fluoro(C,-C4)alkoxy, halo and cyano, or Ar is 1,3-benzodioxolan-4 or 5-yl or 1,4-benzodioxan-5 or 6-yl; ZA is a pharmaceutically acceptable anion; with the proviso that when W is a direct link and R is optionally fused and optionally substituted heteroaryl, said heteroaryl is linked by a ring carbon atom to the carbonyl group. The compounds are tachykinin antagonists. W is a direct link, methylene or ethylene;

Description

QUATERNARY AMMONIUM COMPOUNDS
This invention relates to quaternary ammonium compounds. More particularly, this invention relates to 1-(2-acylimidazol-1-ylalkyl)quinuclidinium salts and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such salts.
The present compounds are antagonists of tachykinins, including NKA (neurokinin A), NKB (neurokinin B) and Substance P, acting at the human neurokinin-1 (NK^, neurokinin-2 (NK2) and neurokinin-3 (NK3) receptors.
These compounds are particularly useful as dual NK·, and NK2 receptor antagonists and can therefore be used for treating an inflammatory disease such as arthritis, psoriasis, asthma or inflammatory bowel disease, a central nervous system (CNS) disorder such as anxiety, depression, dementia or psychosis, a gastro-intestinal (Gl) disorder such as functional bowel disease, irritable bowel syndrome, gastro-oesophageal reflux, faecal incontinence, colitis or Crohn’s disease, a disease caused by Helicobacter pylori or another ureasepositive Gram negative bacteria, a urogenital tract disorder such as incontinence, impotence, hyperreflexia or cystitis, a pulmonary disorder such as chronic obstructive airways disease, an allergy such as eczema, contact dermatitis, atopic dermatitis, urticaria, eczematoid dermatitis or rhinitis, a hypersensitivity disorder such as to poison ivy, a proliferative disorder such as a cancer or a disorder involving fibroblast proliferation, a vasospastic disease such as angiogenesis, angina or Reynaud’s disease, a fibrosing or collagen disease such as atherosclerosis, scleroderma or eosinophilic fascioliasis, reflux sympathetic dystrophy such as shoulder/hand syndrome, an addiction disorder such as alcoholism, a stress-related somatic disorder, a peripheral neuropathy such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, a burn, herpetic neuralgia or post-herpetic neuralgia, a neuropathological disorder such as Alzheimer’s disease or multiple sclerosis, a disorder related to immune enhancement or suppression such as systemic lupus erythematosis, a rheumatic disease such as fibrositis, emesis, cough, acute or chronic pain, migraine, an ophthalmic disease such as proliferative retinopathy, influenza or a cold. EP-A-680962 and EP-A-0739891 disclose heterocyclic compounds which are non-peptide antagonists of NKA and that are useful for the treatment of diseases such as asthma. EP-A-0591040 discloses quaternary compounds with tachykinin antagonist activity.
The present invention provides compounds of the formula:
-Z* (I) wherein R is phenyl, C3-C7 cycloalkyl or heteroaryi, each of which being optionally benzo- or C3-C7 cycloalkyl-fused and optionally substituted, including in the benzo- or C3-C7 cycloalkyl-fused portion, by from 1 to 3 substituents each independently selected from CrC4 alkyl, fluoro(C1-C4)alkyl, CrC4 alkoxy, fluoro(C1-C4)alkoxy, phenoxy, C2-C4 alkanoyl, halo, Ο·,-Ο4 alkoxycarbonyl, C3-C7 cycloalkyl, -5(0)^,(0^04 alkyl), cyano, -NR2R3, -S(O)mNR2R3, -NR4(CrC4 alkanoyl) and -CONR2R3, or R is 2,3-dihydrobenzo[b]furanyl or chromanyl; R1 is H or CrC6 alkyl;
R2 and R3 are either each independently selected from H and C.,-C6 alkyl, or when taken together, represent C4-C6 alkylene; R4 is H or CrC6 alkyl; W is a direct link, methylene or ethylene; X is unbranched C2-C4 alkylene; Y is phenyl, naphthyl, benzyl, pyridyl, thienyl or C3-C7 cycloalkyl, each of which being optionally substituted by from 1 to 3 substituents each independently selected from CrC4 alkyl, fluoro(C1-C4)alkyl, CrC4 alkoxy, fluoro(C.,-C4)alkoxy, halo and cyano;
Ar is phenyl, naphthyl, benzyl, thienyl, benzo[b]thienyl or indolyl, each of which being optionally substituted by from 1 to 3 substituents each independently selected from CrC4 alkyl, fluoro(C1-C4)alkyl, CrC4 alkoxy, fluoro(C.,-C4)alkoxy, halo and cyano, or Ar is 1,3-benzodioxolan-4 or 5-yl or 1,4-benzodioxan-5 or 6-yl; m is 0, 1 or 2; ZA is a pharmaceutically acceptable anion; and “heteroaryl”, used in the definition of R, means thienyl or a 5- or 6-membered ring heteroaryl group containing either from 1 to 4 nitrogen heteroatoms, or 1 or 2 nitrogen heteroatom(s) and 1 oxygen or sulphur heteroatom, with the proviso that when W is a direct link and R is optionally fused and optionally substituted heteroaryl, said heteroaryl is linked by a ring carbon atom to the carbonyl group.
In the above definitions, “halo” means fluoro, chloro, bromo or iodo and alkyl and alkoxy groups having three or more carbon atoms, alkanoyl groups having four carbon atoms and alkylene groups having two or more carbon atoms (except where stated) may be unbranched- or branched-chain. ZA is a pharmaceutically acceptable anion such as chloride, bromide, nitrate, methanesulphonate, para-toluenesulphonate, benzenesulphonate, hydrogen sulphate or sulphate.
Preferably, ZA is chloride or methanesulphonate.
Most preferably, ZA is methanesulphonate. A compound of the formula (I) contains one or more asymmetric carbon atoms and therefore exists in two or more stereoisomeric forms. The present invention includes the individual stereoisomers of the compounds of the formula (I) and mixtures thereof.
Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid.
Preferably, R is phenyl which is optionally benzo- or C3-C7 cycloalkyl-fused and optionally substituted, including in the benzo- or C3-C7 cycloalkyl-fused portion, by 1, 2 or 3 substituents each independently selected from CrC4 alkyl, fluoro(C1-C4)alkyl, CrC4 alkoxy, fluoro(C1-C4)alkoxy, phenoxy and halo, or R is 2,3-dihydrobenzo[b]furanyl.
More preferably, R is phenyl which is optionally benzo- or C3-C7 cycloalkyl-fused and optionally substituted, including in the benzo- or C3-C7 cycloalkyl-fused portion, by 1, 2 or 3 substituents each independently selected from methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy, phenoxy, fluoro and chloro, or R is 2,3-dihydrobenzo[b]furanyl.
Yet more preferably, R is phenyl, naphthyl or tetrahydronaphthyl, each of which being optionally substituted by 1, 2 or 3 substituents each independently selected from methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy, phenoxy, fluoro and chloro, or R is 2,3-dihydrobenzo[b]furanyl.
Yet further preferably, R is phenyl, 3,5-dimethylphenyl, 2,3-dimethylphenyl, 2-trifluoromethoxyphenyl, 2-methoxy-3-methylphenyl, 2,3-dihydrobenzo[b]furan-7-yl, naphth-2-yt, 4-fluoro-3-trifluoromethylphenyl, 1,2,3,4-tetrahydronaphth-5-yl, 1,2,3,4-tetrahydronaphth-6-yl, 5-chloro-2-methoxyphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 2-isopropoxyphenyl, 2-ethylphenyl, 2-phenoxyphenyl or 3,5-bis(trifluoromethyl)phenyl.
Most preferably, R is 2,3-dimethylphenyl, naphth-2-yl, 1,2,3,4-tetrahydronaphth-5-yl or 2-methoxyphenyl.
Preferably, R1 is H.
Preferably, W is a direct link or methylene.
Most preferably, W is a direct link.
Preferably, X is 1,2-ethylene.
Preferably, Y is phenyl, naphthyl or cyclohexyl, each of which being optionally substituted by 1, 2 or 3 CrC4 alkyl substituents.
More preferably, Y is phenyl, 3,5-dimethylphenyl, cyclohexyl or naphthoyl-
Most preferably, Y is phenyl. c
Preferably, Ar is phenyl optionally substituted by 1, 2 or 3 halo 4 substituents. *
More preferably, Ar is phenyl substituted by 1 or 2 chloro substituents. < Most preferably, Ar is 3,4-dichlorophenyl. ( <
Preferred examples of compounds of the formula (I) are compounds of ( the formula: ί
I
.ZA (IA) wherein 1) R-W- is 3,5-dimethylphenyl, Y is phenyl and ZA is CH3SO3‘; 2) R-W- is 2,3-dimethylphenyl, Y is phenyl and ZA is CH3SO3';
3) R-W- is 2-trifluoromethoxyphenyl, Y is phenyl and ZA is CH3SO3'; 4) R-W- is 2-methoxy-3-methylphenyl, Y is phenyl and ZA is CH3SO3'; 5) R-W- is 2,3-dihydrobenzo[b]furan-7-yl, Y is phenyl and ZA is CH3SO3"; 6) R-W- is naphth-2-yl, Y is phenyl and ZA is CH3SO3'; 7) R-W- is 4-fluoro-3-trifluoromethylphenyl, Y is phenyl and ZA is CH3SO3'; 8) R-W- is 1,2,3,4-tetrahydronaphth-5-yl, Y is phenyl and ZA is CH3SO3'; 9) R-W- is 1,2,3,4-tetrahydronaphth-6-yl, Y is phenyl and ZA is CH3SO3'; 10) R-W- is 5-chloro-2-methoxyphenyl, Y is phenyl and ZA is CH3SO3'; 11) R-W- is 2-methoxyphenyl, Y is phenyl and ZA is CH3SO3'; 12) R-W- is 2-trifluoromethylphenyl, Y is phenyl and ZA is CH3SO3'; 13) R-W- is 2-isopropoxyphenyl, Y is phenyl and ZA is CH3SO3'; 14) R-W- is 2-ethylphenyl, Y is phenyl and ZA is CH3SO3"; 15) R-W- is 2-phenoxyphenyl, Y is phenyl and ZA is CH3SO3'; 16) R-W- is benzyl, Y is phenyl and ZA is CH3SO3'; 17) R-W- is 3,5-bis(trifluoromethyl)phenyl, Y is phenyl and ZA is Cl'; 18) R-W- is 2-methoxyphenyl, Y is cyclohexyl and ZA is CH3SO3'; 19) R-W- is 4-fluoro-3-trifluoromethylphenyl, Y is cyclohexyl and ZA is CH3SO3'; 20) R-W- is 2-methoxyphenyl, Y is 3,5-dimethylphenyl and ZA is CH3SO3'; or 21) R-W- is 2-methoxyphenyl, Y is naphth-2-yl and ZA is CH3SO3': or an alternative pharmaceutically acceptable salt of any thereof (re ZA).
Particularly preferred examples of the compounds of the formula (I) are 4-phenyl-1-(3(S)-[3,4-dichlorophenyl]-4-[2-(1,2,3,4-tetrahydro-5-naphthoyl)-imidazol-1-yl]butyl)quinuclidinium methanesulphonate and 4-phenyl-1-(3(R)-[3,4-dichlorophenyl]-4-[2-(1,2,3,4-tetrahydro-5-naphthoyl)imidazol-1-yl]butyl)quinuclidinium methanesulphonate.
All the compounds of the formula (I) can be prepared by reaction of a compound of the formula;
(II) wherein R, R1, Ar, W and X are as previously defined for a compound of the formula (I), Z is a suitable leaving group capable of forming a pharmaceutically acceptable anion (ZA) and Z1 is a suitable leaving group, with a compound of the formula:
(III) wherein Y is as previously defined for a compound of the formula (I), said process being followed by either (a), where Z1 is a suitable leaving group, exchange for a pharmaceutically acceptable anion (ZA), or (b), optionally, where ZA is a pharmaceutically acceptable anion, exchange for another pharmaceutically acceptable anion.
Preferred examples of Z are alkanesulphonyloxy, benzenesulphonyloxy, para-toluenesulphonyloxy, chloro, bromo and iodo.
An example of Z1 is trifluoromethanesulphonyloxy.
Preferably, the leaving group in the compound of the formula (II) forms a pharmaceutically acceptable anion (Z/ZA), e.g. methanesulphonyloxy/ methanesulphonate, and therefore anion exchange at the end of the process is unnecessary.
It is possible to exchange pharmaceutically acceptable anions (ie ZA) in the work-up procedure, e.g. methanesulphonate may be exchanged to chloride by treatment of the isolated compound or the crude mixture with aqueous hydrochloric acid solution.
The reaction of the compounds (II) and (III) is generally carried out in a suitable solvent, e.g. acetonitrile, at elevated temperatures, preferably at the reflux temperature thereof.
The starting materials of the formula (II) can be prepared as shown in Scheme 1.
Scheme 1

Claims (1)

  1. Original document published without claims.
APAP/P/1998/001262A 1997-06-18 1998-06-11 Quaternary ammonium compounds as tachykinin antagonists. AP947A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GBGB9712882.1A GB9712882D0 (en) 1997-06-18 1997-06-18 Quaternary ammonium compounds

Publications (2)

Publication Number Publication Date
AP9801262A0 AP9801262A0 (en) 1998-06-30
AP947A true AP947A (en) 2001-03-08

Family

ID=10814535

Family Applications (1)

Application Number Title Priority Date Filing Date
APAP/P/1998/001262A AP947A (en) 1997-06-18 1998-06-11 Quaternary ammonium compounds as tachykinin antagonists.

Country Status (43)

Country Link
US (2) US6207678B1 (en)
EP (1) EP0994876B1 (en)
JP (1) JP3280993B2 (en)
KR (1) KR100345389B1 (en)
CN (1) CN1199971C (en)
AP (1) AP947A (en)
AR (1) AR012249A1 (en)
AT (1) ATE275564T1 (en)
AU (1) AU726027B2 (en)
BG (1) BG63341B1 (en)
BR (1) BR9810619A (en)
CA (1) CA2291975C (en)
CO (1) CO4940478A1 (en)
DE (1) DE69826129T2 (en)
DZ (1) DZ2524A1 (en)
EA (1) EA002424B1 (en)
ES (1) ES2227856T3 (en)
GB (1) GB9712882D0 (en)
HN (1) HN1998000087A (en)
HR (1) HRP980337B1 (en)
HU (1) HUP0003962A3 (en)
ID (1) ID23410A (en)
IL (2) IL155621A0 (en)
IS (1) IS5269A (en)
MA (1) MA26509A1 (en)
MY (1) MY136376A (en)
NO (1) NO995782L (en)
NZ (1) NZ501286A (en)
OA (1) OA11235A (en)
PA (1) PA8452501A1 (en)
PE (1) PE80099A1 (en)
PL (1) PL189557B1 (en)
PT (1) PT994876E (en)
SI (1) SI0994876T1 (en)
SK (1) SK283346B6 (en)
TN (1) TNSN98089A1 (en)
TR (1) TR199903135T2 (en)
TW (1) TW479055B (en)
UA (1) UA62966C2 (en)
UY (1) UY25045A1 (en)
WO (1) WO1998057972A1 (en)
YU (1) YU64699A (en)
ZA (1) ZA985239B (en)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6919372B1 (en) * 1997-12-26 2005-07-19 Yamanouchi Pharmaceutical Co., Ltd. Sustained release pharmaceutical compositions
JP4546589B2 (en) * 1998-04-23 2010-09-15 武田薬品工業株式会社 Naphthalene derivatives
CA2412355A1 (en) * 2000-06-12 2001-12-20 University Of Rochester Method of treating symptoms of hormonal variation, including hot flashes, using tachykinin receptor antagonist
US6656953B2 (en) * 2000-12-06 2003-12-02 Sepracor Inc. 4,4-Disubstituted piperidines, and methods of use thereof
WO2003101459A1 (en) * 2002-05-29 2003-12-11 The Regents Of The University Of California Antagonizing nk1 receptors inhibits consumption of substances of abuse
WO2004091597A2 (en) * 2003-04-15 2004-10-28 Pharmacia & Upjohn Company Llc Method of treating irritable bowel syndrome (ibs)
EP1747203A4 (en) * 2004-05-07 2009-04-22 Janssen Pharmaceutica Nv Scalable synthesis of imidazole derivatives
JP2010516731A (en) 2007-01-24 2010-05-20 グラクソ グループ リミテッド Pharmaceutical composition comprising 2-methoxy-5- (5-trifluoromethyl-tetrazol-1-yl) -benzyl]-(2S-phenyl-piperidin-3S-yl) -amine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0591040A1 (en) * 1992-09-30 1994-04-06 Sanofi Quaternary basic amides as tachykinines antagonists

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3991201A (en) * 1974-06-27 1976-11-09 Janssen Pharmaceutica N.V. 1-(β-Aryl-β-R-ethyl)imidazoles as antimicrobial agents
US5583134A (en) * 1992-09-30 1996-12-10 Sanofi 1-azoniabicyclo[2.2.2] octanes and pharmaceutical compositions in which they are present

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0591040A1 (en) * 1992-09-30 1994-04-06 Sanofi Quaternary basic amides as tachykinines antagonists

Also Published As

Publication number Publication date
JP3280993B2 (en) 2002-05-13
JP2000513030A (en) 2000-10-03
ZA985239B (en) 1999-12-17
PL189557B1 (en) 2005-08-31
DE69826129D1 (en) 2004-10-14
WO1998057972A1 (en) 1998-12-23
IL133079A0 (en) 2001-03-19
HUP0003962A3 (en) 2001-12-28
TNSN98089A1 (en) 2005-03-15
CA2291975A1 (en) 1998-12-23
MA26509A1 (en) 2004-12-20
UY25045A1 (en) 2000-09-29
EP0994876A1 (en) 2000-04-26
IL133079A (en) 2004-06-01
EP0994876B1 (en) 2004-09-08
PL337713A1 (en) 2000-08-28
CO4940478A1 (en) 2000-07-24
EA002424B1 (en) 2002-04-25
PE80099A1 (en) 1999-08-25
AU8215398A (en) 1999-01-04
KR100345389B1 (en) 2002-07-24
NZ501286A (en) 2000-07-28
ES2227856T3 (en) 2005-04-01
PA8452501A1 (en) 2000-05-24
BG63341B1 (en) 2001-10-31
SK174499A3 (en) 2001-05-10
ID23410A (en) 2000-04-20
BG103919A (en) 2001-07-31
UA62966C2 (en) 2004-01-15
IL155621A0 (en) 2003-11-23
IS5269A (en) 1999-11-23
US6380396B1 (en) 2002-04-30
HRP980337B1 (en) 2003-02-28
CN1199971C (en) 2005-05-04
NO995782D0 (en) 1999-11-25
CN1260795A (en) 2000-07-19
NO995782L (en) 2000-02-16
EA199900986A1 (en) 2000-06-26
KR20010013909A (en) 2001-02-26
TR199903135T2 (en) 2000-04-21
DZ2524A1 (en) 2003-02-01
AP9801262A0 (en) 1998-06-30
GB9712882D0 (en) 1997-08-20
SK283346B6 (en) 2003-06-03
HUP0003962A2 (en) 2001-04-28
OA11235A (en) 2003-07-09
HRP980337A2 (en) 1999-02-28
AU726027B2 (en) 2000-10-26
HN1998000087A (en) 1998-10-22
MY136376A (en) 2008-09-30
US6207678B1 (en) 2001-03-27
TW479055B (en) 2002-03-11
ATE275564T1 (en) 2004-09-15
AR012249A1 (en) 2000-09-27
BR9810619A (en) 2000-09-12
CA2291975C (en) 2004-02-10
SI0994876T1 (en) 2005-02-28
PT994876E (en) 2005-01-31
DE69826129T2 (en) 2005-09-22
YU64699A (en) 2002-06-19

Similar Documents

Publication Publication Date Title
US6159982A (en) 2,4-diaminopyrimidine derivates as dopamine D4 receptor antagonist
CN1165532C (en) Substituted 3-cyanoquinolines as protein tyrosine kinase inhibitors
CN1720225B (en) N-arylsulfonyl-3-substituted indole with 5-hydroxytryptamine receptor affinity, its preparation method and pharmaceutical composition containing it
AP947A (en) Quaternary ammonium compounds as tachykinin antagonists.
US9073911B2 (en) Pyrazole derivatives
KR101518660B1 (en) Heterocyclic amine derivatives
AP1110A (en) Azetidinylpropylpiperidine derivatives and use as tachykinin antagonist.
JP2009524616A (en) Use of 4-imidazole derivatives for CNS disease
CN101374516A (en) Use of 2-imidazole derivatives of substituted imidazolines
CN1198741A (en) Imidazole derivatives having affinity for alpha 2 receptors activity
CN1067655A (en) Fluoroalkoxybenzylamino derivatives of nitrogen containing heterocycles
US4369184A (en) 1-(Cyclohexyl)-4-aryl-4-piperidinecarboxylic acid derivatives
CZ362092A3 (en) Piperazinyl cyclohexanol and piperidinyl cyclohexanol derivative, process of its preparation and a pharmaceutical preparation containing thereof
IL124309A (en) Azetidinylalkyl derivatives of n-containing heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them for antagonizing tachykinin
Romanelli et al. Structure− affinity relationships of a unique nicotinic ligand: N-dimethyl-N4-phenylpiperazinium iodide (DMPP)
US5286735A (en) Derivatives of 4-aminomethylpiperidine, their preparation and their use as therapeutics
CA2240964C (en) Piperidone tachykinin antagonists
US5846965A (en) 3-aza and 3-oxa piperidone tachykinin antagonists
Karataş et al. Synthesis and potent in vitro activity of novel 1H‐benzimidazoles as anti‐mrsa agents
JP2004525184A (en) 3-Substituted quinoline-4-carboxamide derivatives as NK-3 and NK-2 receptor antagonists
US9957261B2 (en) 6-amino-5,6,7,8-tetrahydronaphthalen-2-yl or 3-aminochroman-7-yl derivatives
EP0962457B1 (en) Piperidones as tachykinin antagonists
TW201425308A (en) Pyrazolecarhamamine derivative
US6022971A (en) Azetidines
JP2020518555A (en) Heterocyclic P2X7 antagonist