WO2000031037A1 - Derives de quinoline-4-carboxamide utilises comme antagonistes des recepteurs nk-3 et nk-2 - Google Patents

Derives de quinoline-4-carboxamide utilises comme antagonistes des recepteurs nk-3 et nk-2 Download PDF

Info

Publication number
WO2000031037A1
WO2000031037A1 PCT/EP1999/009115 EP9909115W WO0031037A1 WO 2000031037 A1 WO2000031037 A1 WO 2000031037A1 EP 9909115 W EP9909115 W EP 9909115W WO 0031037 A1 WO0031037 A1 WO 0031037A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
optionally substituted
alkyl
phenyl
Prior art date
Application number
PCT/EP1999/009115
Other languages
English (en)
Inventor
Carlo Farina
Giuseppe Giardina
Mario Grugni
Marcel Morvan
Guy Margueritte Marie Gérard NADLER
Luca Francesco Raveglia
Original Assignee
Smithkline Beecham S.P.A.
Smithkline Beecham Laboratoires Pharmaceutiques
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
Priority claimed from GBGB9825553.2A external-priority patent/GB9825553D0/en
Priority claimed from GBGB9825552.4A external-priority patent/GB9825552D0/en
Priority to AU17770/00A priority Critical patent/AU768708B2/en
Priority to NZ511777A priority patent/NZ511777A/en
Priority to BR9915475-7A priority patent/BR9915475A/pt
Priority to KR1020017006343A priority patent/KR20010075726A/ko
Priority to HU0104959A priority patent/HUP0104959A3/hu
Priority to EP99961001A priority patent/EP1131295A1/fr
Application filed by Smithkline Beecham S.P.A., Smithkline Beecham Laboratoires Pharmaceutiques filed Critical Smithkline Beecham S.P.A.
Priority to CA002351865A priority patent/CA2351865A1/fr
Priority to IL14313799A priority patent/IL143137A0/xx
Priority to MXPA01005095A priority patent/MXPA01005095A/es
Priority to JP2000583865A priority patent/JP2002530377A/ja
Publication of WO2000031037A1 publication Critical patent/WO2000031037A1/fr
Priority to NO20012473A priority patent/NO20012473L/no
Priority to HK02101024.6A priority patent/HK1041257A1/zh

Links

Classifications

    • 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
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61P1/14—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
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • 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
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/22—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
    • A61P25/28—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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C07D215/52—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4 with aryl radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • the present invention relates to novel compounds, in particular to novel quinoline derivatives, to processes for the preparation of such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds in medicine.
  • the mammalian peptide Neurokinin B belongs to the Tachykinin (TK) peptide family which also include Substance P (SP) and Neurokinin A (NKA).
  • TK Tachykinin
  • SP Substance P
  • NKA Neurokinin A
  • Pharmacological and molecular biological evidence has shown the existence of three subtypes of TK receptor (NK j , N -2 and NK3) and NKB binds preferentially to the NK3 receptor although it also recognises the other two receptors with lower affinity (Maggi et al, 1993, J Auton. Pharmacol., 13, 23-93).
  • NK3 receptor antagonists are known (Drapeau, 1990 Regul. Pept., 31, 125-135), and findings with peptidic NK3 receptor agonists suggest that NKB, by activating the NK3 receptor, has a key role in the modulation of neural input in airways, skin, spinal cord and nigro-striatal pathways (Myers and Undem, 1993, J.Physiol, 470, 665-679; Counture et al., 1993, Regul. Peptides, 46, 426-429; Mccarson and Krause, 1994, J Neurosci., 14 (2), 712-720; Arenas et al. 1991, J.Neurosci., 11, 2332-8).
  • the peptide-like nature of the known antagonists makes them likely to be too labile from a metabolic point of view to serve as practical therapeutic agents.
  • Copending International Patent Application number PCT/EP98/03014 discloses certain compounds stated to be non-peptide NK-3 antagonists and also to have NK-2 antagonist activity. These compounds are therefore considered to be of potential use in the prevention and treatment of a wide variety of clinical conditions which are characterized by overstimulation of the tachykinin receptors, in particular NK-3 and NK- 2.
  • NK-3 antagonists which are far more stable from a metabolic point of view than the known peptidic NK-3 receptor antagonists and are of potential therapeutic utility. These compounds also have NK-2 antagonist activity and are therefore considered to be of potential use in the prevention and treatment of a wide variety of clinical conditions which are characterized by overstimulation of the tachykinin receptors, in particular NK-3 and NK-2.
  • respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, airway hyperreactivity, cough; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis and inflammatory pain; neurogenic inflammation or peripheral neuropathy, allergies such as eczema and rhinitis; ophthalmic diseases such as ocular inflammation, conjunctivitis, vernal conjuctivitis and the like; cutaneous diseases, skin disorders and itch, such as cutaneous wheal and flare, contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systhemic lupus erythematosis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative COPD
  • Certain of these compounds also show CNS activity and hence are considered to be of particular use in the treatment of disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as AIDS related dementia, senile dementia of the Alzheimer type, Alzheimer's disease, Down's syndrome, Huntington's disease, Parkinson's disease, movement disorders and convulsive disorders (for example epilepsy); demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as diabetic neuropathy, AIDS related neuropathy, chemotherapy-induced neuropathy and neuralgia; addiction disorders such as alcoholism; stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; eating disorders (such as food intake disease); fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of the blood flow caused by vasodilation and vasospastic diseases such as angina, migraine and Reynaud'
  • the compounds of formula (I) are also considered to be useful as diagnostic tools for assessing the degree to which neurokinin-3 and neurokinin-2 receptor activity (normal, overactivity or underactivity) is implicated in a patient's symptoms.
  • Ar is an optionally substituted aryl or a C 5.7 cycloalkdienyl group, or an optionally substituted C5.7 cycloalkyl group, , or an optionally substituted single or fused ring aromatic heterocyclic group;
  • R is hydrogen, linear or branched ⁇ . alkyl, C3-.7 cycloalkyl, C3.7 cycloalkylalkyl;
  • R ⁇ represents hydrogen or up to three optional substituents selected from the list consisting of: C1 _g alkyl, C1.5 alkenyl, aryl, C ⁇ _6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulphonamido, C ⁇ . alkoxycarbonyl, trifluoromethyl, acyloxy, amino or mono- and di-C ⁇ . alkylamino;
  • R2 represents a moiety -(CH2) n -NY ⁇ Y2 wherein n is an integer in the range of from 1 to 9, Yi and Y2 are independently selected from C ⁇ _6-alkyl; C ⁇ .g alkyl substituted with hydroxy, alkoxy, C ⁇ . alkylamino or bis C ⁇ . alkyl) amino; C3-6 cycloalkyl; C4-6 azacycloalkyl; C1 _6-alkenyl; aryl or aryl-C g-alkyl or Y ⁇ and Y2 together with the nitrogen atom to which they are attached represent an optionally substituted N-linked single or fused ring heterocyclic group;
  • R3 is branched or linear C ⁇ . alkyl, C3.7 cycloalkyl, C4.7 cycloalkylalkyl, optionally substituted aryl, or an optionally substituted single or fused ring aromatic heterocyclic group;
  • R4 represents hydrogen or C ⁇ . alkyl.
  • Rs represents hydrogen or halogen.
  • R 5 represents hydrogen.
  • R5 is chloro or bromo.
  • Ar represents optionally substituted phenyl,unsubstituted phenyl or cyclohexyl.
  • Ar represents cyclohexyl
  • Ar is phenyl or cyclohexyl.
  • R represents C ⁇ -6 alkyl, for example methyl or ethyl or iso-propyl.
  • R is ethyl. In another preferred aspect, R is methyl or isopropyl.
  • R ⁇ represents hydrogen, C ⁇ . alkoxy, for example methoxy, or hydroxy.
  • R ⁇ represents hydrogen.
  • Rl is methoxy or hydroxy.
  • NY1 Y2 represents an optionally substituted N-linked single or fused ring heterocyclic group.
  • Suitable N-linked single or fused heterocyclic groups include groups in which any single or fused ring is saturated or unsaturated and consists of 5- or 6- ring atoms, said ring atoms optionally comprising 1 or 2 additional heteroatoms selected from O or N and wherein one or two ring atoms are optionally substituted with one or two oxo groups or one or two of hydroxy, carboxy, carboxy Cl-6 alkyl, C ⁇ . ⁇ alkoxycarbonyl, aminocarbonyl, Cl-6 alkylcarbonyl optionally substituted with an aromatic heterocyclic group, arylcarbonyl, aryl Cl-6 alkylcarbonyl, carboxy Cl-6 alklycarbonyl, carboxyarylcarbonyl, amino, Cl-6 alkylcarbonylamino, C ⁇ _6 alkyl, C ⁇ . ⁇ hydroxyalkyl, aryl, aryl, Cl-6
  • the additional heteroatom is N.
  • Favoured optional substituents for the N-linked single or fused heterocyclic groups are selected from carboxy Cl-6 alkyl, aminocarbonyl, Cl-6 alkylcarbonyl optionally substituted with an aromatic heterocyclic group, arylcarbonyl, aryl Cl-6 alkylcarbonyl, carboxy Cl-6 alklycarbonyl, carboxyarylcarbonyl, amino, Cl-6 alkylcarbonylamino, C ⁇ . alkyl, C ⁇ .
  • Preferred optional substituents for the N-linked single or fused heterocyclic groups include isopropylcarbonyl, hydroxyethyl, cyclohexyl, phenyl, benzyl, isopropyl, phenethyl, 1-piperidinyl, hydroxyethoxyethyl, (4-hydroxy)-l-piperidinyl, 4- piperidinyl, ( 1 -methyl)-4-piperidinyl, dimethylaminomethylcarbonyl, diethylaminoethylcarbonyl, (4-methy 1)- 1 -piperazinylmethylcarbony 1, 4- morpholinylethylcarbonyl, amino, (4-methyl)-l-piperazinyl, 1-piperazinyl, N-methyl-N'- cyanocarboxamidine, 2-thiazolinyl, pyrrolidinyl-N-cyanomethyleneimine, pyrrolidinyl- N-methylmethy leneimine
  • oxo substituents are preferably alpha to the point of linkage of the N-linked single or fused heterocyclic group.
  • preferred substituents are selected from C . alkyl, hydroxy Cl-6 alkyl for example hydroxyethyl, C3.7 cycloalkyl, C3.7 cycloalkylalkyl, aryl and arylalkyl, for example methyl, ethyl, isopropyl, phenyl,phenethyl, or benzyl, optionally substituted C4- 7 azacycloalkyl for example 4-piperidinyl or (l-methyl)-4-piperidinyl, dialkylaminoalkylcarbonyl for example dimethylaminomethylcarbonyl or diethylaminoethylcarbonyl, hydroxy Cl-6 alkoxy Cl-6 alkyl for example hydroxyethoxyethyl, optionally substituted C4-7 diazacycloalkyl Cl-6 alkylcarbonyl or C4-7 oxaazacycloalkyl Cl-6
  • Fused heterocyclic groups include groups having one or more rings which share one or more atoms, such as spiro fused rings, or one or more bonds.
  • a suitable N-linked single ring heterocyclic group comprising a 5- membered saturated heterocyclic ring is a pyrrolidin -1- yl group.
  • a suitable N-linked single ring heterocyclic group comprising a 6- membered saturated heterocyclic ring is an optionally substituted piperidin-1-yl group, for example a 4-(piperidin-l-yl)piperidin-l-yl group or 4-aminopiperidin-l-yl group.
  • a suitable N-linked single ring 6- membered saturated heterocyclic group comprising an additional heteroatom is an optionally substituted piperazin-lyl group, for example an optionally substituted 4-alkylpiperazin-l-yl group.
  • a suitable N-linked fused ring heterocyclic group includes a 5 -or 6- membered saturated or unsaturated heterocyclic ring fused to a benzene ring.
  • a suitable N-linked fused ring heterocyclic group comprising a 6- membered saturated heterocyclic ring fused to a benzene ring is a 2-(l, 2 ,3 ,4- tetrahydro)isoquinolinyl group.
  • Suitable, N-linked fused heterocyclic groups include spiro fused groups, for example l,4-dioxa-8-azaspiro[4.5]dec-8-yl group or 3-oxo-2,8-diazaspiro[4.5]dec-8-yl or 2,4-dioxo-l,3,8-triazaspiro[4.5]dec-8-yl or 2,7-diazaspiro[4.4]non-2-yl or 2,3-dioxa-l,8- diazaspiro[4.5]dec-8-yl.
  • -NYi Y2 is a piperazin-1-yl group, especially a 4- hydroxyalkylpiperazin-1-yl, or 4-(dialkylaminoalkylcarbonyl)piperazin-l-yl, or 4- (azacycloalkyl)piperazin-l-yl, which piperazinyl group may be substituted or unsubstituted
  • a particularly preferred value of -NY1 Y2 is a group of formula (a), (b) (c) or (d):
  • Tj represents isopropylcarbonyl, hydroxyethyl, cyclohexyl, phenyl, benzyl, isopropyl, phenethyl, 1 -piperidinyl, hydroxyethoxyethyl, (4-hydroxy)-l-piperidinyl, 4- piperidinyl, ( 1 -methyl)-4-piperidinyl, dimethylaminomethylcarbonyl, diethylaminoethylcarbonyl, (4-methy 1)- 1 -piperazinylmethylcarbony 1, 4- morpholinylethylcarbonyl, amino, (4-methyl)-l-piperazinyl, l-piperazinyl, N-methyl-N'- cyanocarboxamidine, 2-thiazolinyl, pyrrolidinyl-N-cyanomethyleneimine, pyrrolidinyl- N-methylmethyleneimine, 1 -pyrrolidiny
  • Ti represents one of the following groups:
  • Re represents H or a lower alkyl, preferably H or methyl
  • m is an integer from 1 to 5
  • R 7 and R 8 represent a lower alkyl, preferably methyl or ethyl or together form an heterocycle, for example a piperidine, mo ⁇ holine or optionally substituted piperazine.
  • Qi represents 2-phthalic acid, a saturated or unsaturated Cl-6 carboxylic acid or an heterocycle for example 2-imidazolyl or thiazolyl.
  • Ti represents also an heterocycle for example imidazolyl, thiazolyl, pyridyl, pyrimidyl, tetrazolyl or Ti represents an optionally substituted carboxamidine or a corresponding quaternary carboxamidine derivative.
  • suitable Ti represents also one of the chemical entities below: wherein R 9 and R ⁇ 0 represent hydrogen, alkyl or together form a 5 to 7 membered ring with the N atom to which they are attached, preferably a pyrrolidin or piperidin ring and R[ i represents C ⁇ -6 linear or branched alkyl or optionally substituted aryl wherein Q 2 is hydrogen, alkyl, aralkyl, aryl, cyano.
  • suitable TI represents also a sulphonamide of formula:
  • R ⁇ 2 and Rj 3 are independently selected from hydrogen; C ⁇ -6 alkyl; optionally substituted aryl or R ⁇ 2 and R [3 together with the nitrogen atom to which they are attached represent an optionally substituted N-linked single or fused ring heterocyclic group.
  • -NYi Y2 is a moiety of formula (a). In one particular aspect -NYj Y2 is a moiety of formula (b). In one particular aspect -NYj Y2 is a moiety of formula (c). In one particular aspect -NY1 Y2 is a moiety of formula (d).
  • R3 is optionally substituted aryl, preferably an unsubstituted aryl group such as a phenyl group.
  • R4 is hydrogen
  • n is an integer from 1 to 6, favourably 1 to 4 and most preferably 1 , 2 or 3.
  • n' 1
  • n' represents 2.
  • n' represents 3.
  • Preferred compounds of formula (I) are those wherein: Ar is phenyl or cyclohexyl, R is methyl, ethyl, or isopropyl, R ⁇ is hydrogen or methoxy or hydroxy, R2 is a moiety (CH2)n wherein n is 1, 2, 3 or 4, R3 is phenyl and R4 is hydrogen and NYj Y2 1S :
  • the compounds of formula (I) may have at least one asymmetric centre - for example the carbon atom labelled with an asterisk (*) in the compound of formula (I) - and therefore may exist in more than one stereoisomeric form.
  • the invention extends to all such stereoisomeric forms and to mixtures thereof, including racemates.
  • the invention includes compounds wherein the asterisked carbon atom in formula (I) has the stereochemistry shown in formula (la):
  • the compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form.
  • pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • a substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula (I) or its salt or solvate.
  • One preferred pharmaceutically acceptable form is the crystalline form, including such form in pharmaceutical composition.
  • the additional ionic and solvent moieties must also be non-toxic.
  • Suitable salts are pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts include the acid addition salts with the conventional pharmaceutical acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
  • Suitable pharmaceutically acceptable salts include salts of acidic moieties of the compounds of formula (I) when they are present, for example salts of carboxy groups or phenolic hydroxy groups.
  • Suitable salts of acidic moieties include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl- ⁇ -phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline.
  • metal salts such as for example aluminium, alkali metal salts such as lithium, sodium
  • Suitable solvates are pharmaceutically acceptable solvates.
  • Suitable pharmaceutically acceptable solvates include hydrates.
  • 'alkyl' when used alone or when forming part of other groups (such as the 'alkoxy' group) includes straight- or branched-chain alkyl groups containing 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms, examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group.
  • 'carbocylic' refers to cycloalkyl and aryl rings.
  • 'cycloalkyl' includes groups having 3 to 12, suitably 4 to 6 ring carbon atoms.
  • 'aryl' includes phenyl and naphthyl, preferably phenyl which unless specified to the contrary optionally comprise up to five, preferably up to three substituents selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxyalkyl, hydroxy, amino, nitro, cyano, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups.
  • 'aromatic heterocyclic group' includes groups comprising aromatic heterocyclic rings containing from 5 to 12 ring atoms, suitably 5 or 6, and comprising up to four hetero-atoms in the or each ring selected from S, O or N.
  • suitable substituents for any heterocyclic group includes up to 4 substituents selected from the group consisting of: alkyl, alkoxy, aryl and halogen or any two substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, may form an aryl group, preferably a benzene ring, and wherein the carbon atoms of the aryl group represented by the said two substituents may themselves be substituted or unsubstituted.
  • halogen refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine or bromine.
  • acyl includes residues of acids, in particular a residue of a carboxylic acid such as an alkyl- or aryl- carbonyl group.
  • the invention also provides a process for the preparation of a compound of formula (I), or a salt thereof and/or a solvate thereof, which process comprises reacting a compound of formula (II) or an active derivative thereof:
  • R'j, R'2, R'3 and R'5 are R ⁇ , R2, R3 and R5 respectively as defined in relation to formula (I) or a group convertible to R ⁇ , R2, R3 and R5 respectively; with a compound of formula (III):
  • R', R4' and Ar' are R, R4 and Ar as defined for formula (I) or a group or atom convertible to R, R4 and Ar respectively; to form a compound of formula (lb):
  • Suitable groups convertible into other groups include protected forms of said groups.
  • Ar', R', R' j , R' , R'3, R'4 or R' 5 each represents Ar, R, Ri , R 2 , R3, R4 or R5 respectively or a protected form thereof.
  • a suitable active derivative of a compound of formula (II) is a transient activated form of the compound of formula (II) or a derivative wherein the carboxy group of the compound of formula (II) has been replaced by a different group or atom, for example by an acyl halide, preferably a chloride, or an acylazide or a carboxylic acid anhydride.
  • Suitable active derivatives include: a mixed anhydride formed between the carboxyl moiety of the compound of formula (II) and an alkyl chloro formate; an activated ester, such as a cyanomethyl ester, thiophenyl ester, p-nitrophenyl ester, p- nitrothiophenyl ester, 2,4,6-trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxy-phtalimido ester, N-hydroxypiperidine ester, N- hydroxysuccinimide ester, N-hydroxy benzotriazole ester; alternatively, the carboxy group of the compound of formula (II) may be activated using a carbodiimide or N,N'- carbonyldiimidazole.
  • an activated ester such as a cyanomethyl ester, thiophenyl ester, p-nitrophenyl ester, p
  • reaction between the compound of formula (II) or the active derivative thereof and the compound of formula (III) is carried out under the appropriate conventional conditions for the particular compounds chosen.
  • the reaction is carried out using the same solvent and conditions as used to prepare the active derivative, preferably the active derivative is prepared in situ prior to forming the compound of formula (lb) and thereafter the compound of formula (I) or a salt thereof and/or a solvate thereof is prepared.
  • reaction between an active derivative of the compound of formula (II) and the compound of formula (III) may be carried out:
  • a suitable condensing agent such as for example N,N'-carbonyl diimidazole (CDI) or a carbodiimide such as dicyclohexylcarbodiimide (DCC) or N- dimethylaminopropyl-N'-ethylcarbodiimide, preferably in the presence of N- hydroxybenzotriazole (HOBT) to maximise yields and avoid racemization processes (see Synthesis, 453, 1972), or O-benzotriazol-l-yl-N,N,N',N'- tetramethyluroniumhexafluorophosphate (HBTU), in an aprotic solvent, such as a mixture of acetonitrile (MeCN) and tetrahydrofuran (THF), for example a mixture in a volume ratio of from 1:9 to 7:3 (MeCN:THF), at
  • a compound of formula (lb) may be converted to a compound of formula (I), or one compound of formula (I) may be converted to another compound of formula (I) by interconversion of suitable substituents.
  • certain compounds of formula (I) and (lb) are useful intermediates in forming other compounds of the present invention.
  • the invention provides a process for preparing a compound of formula (I), or a salt thereof and/or a solvate thereof, which process comprises converting a compound of the above defined formula (lb) wherein at least one of Ar', R', R , R' 2 , R' , R' 4 or R' 5 is not Ar, R, R ⁇ , R2 , R3, R4 or R 5 respectively, thereby to provide a compound of formula (I); and thereafter, as required, carrying out one or more of the following optional steps: (i) converting a compound of formula (I) into another compound of formula (I); and (ii) preparing a salt of the compound of formula (I) and/or a solvate thereof.
  • the variables Ar', R', R'j, R'2, R'3, R'4 and R'5 are Ar, R, Rj, R2, R3, R4 or R5 respectively or they are protected forms thereof.
  • a compound of formula (II) or the corresponding alkyl (such as methyl or ethyl) ester wherein n is an integer 1 is prepared by reacting a compound of formula (IV) or the corresponding alkyl (such as methyl or ethyl) ester:
  • R' ⁇ , R'3 and R'5 are as defined above and ⁇ represents a halogen atom such as a bromine atom, with a compound of formula (V):
  • Y' ⁇ and Y * 2 are Y and Y .
  • reaction between the compounds of formulae (IV) or the corresponding alkyl (such as methyl or ethyl) ester and (V) is carried out under conventional animation conditions, for example when Li is a bromine atom then the reaction is conveniently carried out in an aprotic solvent, such as tetrahydrofuran or dimethylformamide at any temperature providing a suitable rate of formation of the required product, usually at ambient temperature; preferably the reaction is carried out in the presence of triethylamine (TEA) or K 2 CO 3 .
  • TAA triethylamine
  • a compound of formula (IV) or the corresponding alkyl (such as methyl or ethyl) ester is prepared by appropriate halogenation of a compound of formula (VI) or the corresponding alkyl (such as methyl or ethyl) ester: wherein R' ⁇ , R'3 and R'5 are as defined above in relation to formula (II).
  • Suitable halogenation reagents are conventional reagents depending upon the nature of the halogen atom required, for example when L ⁇ is bromine a preferred halogenation reagent is N-bromosuccinimide (NBS).
  • NBS N-bromosuccinimide
  • halogenation of the compound of formula (VI) or the corresponding alkyl (such as methyl or ethyl) ester is carried out under conventional conditions, for example bromination is carried out by treatment with NBS in an inert solvent, such as 1,2- dichloroethane or CH 3 CN, at any temperature providing a suitable rate of formation of the required product, suitably at an elevated temperature such as a temperature in the range of 60°C to 100°C, for example 80°C; preferably the reaction is carried out in the presence of a catalytic amount on benzoyl peroxide.
  • an inert solvent such as 1,2- dichloroethane or CH 3 CN
  • R'3 is as defined in relation to formula (II)
  • T5 is a group - ⁇ Y1Y2 as defined in relation to formula (I) or a protected form thereof or a group convertible thereto
  • p is an integer in the range of 2 to 9; and thereafter as required removing any protecting group and/or converting any group T5 to NY j Y2.
  • the reaction between the compounds of formula (VII) and (VIII) is conveniently carried out using Pfitzinger reaction conditions (see for example J. Prakt. Chem. 33, 100 (1886), J. Prakt. Chem. 38, 582 (1888), J. Chem. Soc. 106 (1948) and Chem. Rev.
  • Groups convertible to -NYj Y2 include groups dictated by conventional chemical practice to be required and to be appropriate, depending upon the specific nature of the - NY1 Y2 consideration.
  • Suitable deprotection methods for deprotecting protected forms of NYi Y2 and conversion methods for converting T5 to NY1Y2 will be those used conventionally in the art depending upon the particular groups under consideration with reference to standard texts such as Greene, T.W. and Wuts, P.G.M. Protective Groups in Organic Synthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.) or in Kocienski, P.J. Protecting groups. George Thieme Verlag, New York, 1994 and Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; or Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992.
  • a compound of formula (VIII) is prepared from a compound of formula (IX):
  • T5 is a group -NY[ Y2
  • a compound capable of forming a group T5 is a compound of the above defined formula (V).
  • halogenation of the compound of formula (IX) is suitably carried out using a conventional halogenation reagent.
  • Mesylation is conveniently carried out using mesyl chloride in an inert solvent such as methylene dichloride, at a temperature below room temperature, such as 0°C, preferably in the presence of triethylamine.
  • reaction conditions between the compound of formula (IX) and the compound capable of forming a group T5 will be those conventional conditions dictated by the specific nature of the reactants, for example when the T5 required is a group NYj Y2 and the required compound capable of forming a group T5 is a compound of the above defined formula (V), then the reaction between the halogenation or mesylation product of the compound of formula (IX) and the compound of formula (V) is carried out under analogous conditions to those described for the reaction between the compounds of formulae (IV) and (V).
  • T5 Other compounds capable of forming a group T5 will depend upon the particular nature of T5, but will be those appropriate compounds dictated by conventional chemical practice with reference to standard texts such asChemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; and Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992.
  • a compound of formula (IX) may be prepared by reacting a compound of formula (IX)
  • reaction between the compounds of formulae (X) and (XI) can be carried out in an aprotic solvent, such as diethyl-ether at any temperature providing a suitable rate of formation of the required product, usually at a low temperature such as in the range of - 10°C to -30°C, for example -20°C.
  • aprotic solvent such as diethyl-ether
  • the compounds of formula (III) are known commercially available compounds or they can be prepared from known compounds by known methods, or methods analogous to those used to prepare known compounds, for example the methods described in Liebigs Ann. der Chemie, (1936), 523, 199.
  • the compounds of formula (V) are known, commercially available compounds or they can be prepared using methods analogous to those used to prepare known compounds; for example the methods described in the Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992 ; J. Heterocyclic Chem. (1990), 27, 1559; Synthesis (1975), 135, Bioorg. Med. Chem. Lett. (1997), 7, 555, or Protective Groups in Organic Synthesis (second edition), Wiley Interscience, (1991) or other methods mentioned herein.
  • 4-amino substituted piperidines are generally prepared by reductive amination of 4-oxo-piperidine, or a 4-oxo-piperidine N-substituted with an appropriated protecting group, with an appropriate amine. Typical examples can be found in J. Org. Chem. (1990), 55 (8), 2552-4 or ibid. (1995), 60 (15), 4928-9.
  • the compounds of formula (VII) are known compounds or they are prepared according to methods used to prepare known compounds for example those disclosed in J. Org. Chem. 21, 171 (1955); J. Org. Chem. 21, 169 (1955).
  • the compounds of formula (X) and (XI) are known compounds or they are prepared according to methods used to prepare known compounds for example those disclosed by Krow G. R. in Organic Reactions, Vol 43, page 251, John Wiley & Sons Inc.1994 (for the compounds of formula (X)) and Organometallics in Synthesis, Schlosser M.(Ed), John Wiley & Sons Inc.1994 (for the compounds of formula (XI)).
  • L 2 and L' 2 represent leaving groups such as -SAlkyl or -OAlkyl, preferably -SCH 3 and -OButyl and Ri 1 is as defined above.
  • R[ 2 represents lower alkyl, optionally substituted aryl or aralkyl, followed by the substitution of the group -SCH3, which takes place of the leaving group L 2 , with a compound of formula
  • (XVI) are prepared by reacting a compound of formula (XII) with the benzotriazole derivative of formula (XVII).
  • (CH 2 )n-NY!Y 2 and -NY ⁇ Y 2 is a piperazinyl group of formula (a) wherein TI represents carboxy, alkoxycarbonyl, optionally substituted alkyl, optionally substituted aryl, aralkyl, cycloalkyl, can suitably be prepared by reacting a compound of formula XII with a compound of formula
  • Ti represents one of the radicals defined as above and L3 a leaving group for example halogen or sulfonate, preferably chlorine, bromine or mesylate.
  • Compounds of formula (XII) are prepared by removing the protective group of a compound of formula (XIX) wherein Ar', R', R' ⁇ , R'2, R'3, R'4 and R'5 are as defined above and P is an amine protective group, for example fmoc or benzyl, preferably fmoc.
  • the protective group is removed by standard methods described in the literature, for example the fmoc residue is splitted by action of piperidine at room temperature in a solvent like acetonitrile.
  • the compounds of formula (I) may exist in more than one stereoisomeric form - and the process of the invention may produce racemates as well as enantiomerically pure forms.
  • a pure enantiomer of a compound of formula (I) is obtained by reacting a compound of the above defined formula (II) with an appropriate enantiomerically pure primary amine of formula (Ilia) or (IIIc):
  • R4 represents hydrogen
  • An alternative method for separating optical isomers is to use conventional, fractional separation methods in particular fractional crystallization methods.
  • a pure enantiomer of a compound of formula (I) is obtained by fractional crystallisation of a diastereomeric salt formed by reaction of the racemic compound of formula (I) with an optically active strong acid resolving agent, such as camphosulphonic acid, in an appropriate alcoholic solvent, such as ethanol or methanol, or in a ketonic solvent, such as acetone.
  • the salt formation process should be conducted at a temperature between 20°C and 80°C, preferably at 50°C.
  • a suitable conversion of one compound of formula (I) into a further compound of formula (I) involves converting one group R2 into another group R2 by for example: (i) converting a ketal into a ketone, by such as mild acidic hydrolysis, using for example dilute hydrochloric acid;
  • any group Ar', R, R'j R'2, R'3, R'4 and R'5 into Ar, R, R ⁇ , R2, R3, R4 or R5 which as stated above are usually protected forms of Ar, R, Rj, R2, R3, R4 or R5 may be carried out using appropriate conventional conditions such as the appropriate deprotection procedure.
  • any reactive group in the substrate molecule may be protected and deprotected according to conventional chemical practice, for example as described by Greene-, T.W. and Wuts, P.G.M. Protective Groups in Organic Synthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.) or in Kocienski, P.J. Protecting groups. George Thieme Verlag, New York, 1994.
  • Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art.
  • suitable hydroxyl protecting groups include benzyl or trialkylsilyl groups.
  • benzyloxy group may be prepared by treatment of the appropriate compound with a benzyl halide, such as benzyl bromide, and thereafter, if required, the benzyl group may be conveniently removed using catalytic hydrogenation or a mild ether cleavage reagent such as trimethylsilyl iodide or boron tribromide.
  • a benzyl halide such as benzyl bromide
  • the compounds of formula (I) have useful pharmaceutical properties.
  • the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance.
  • the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the treatment or prophylaxis of the Primary and Secondary Conditions.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of the Primary and Secondary Conditions.
  • the Primary conditions include respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma, airway hyperreactivity, cough; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis and inflammatory pain; neurogenic inflammation or peripheral neuropathy, allergies such as eczema and rhinitis; ophthalmic diseases such as ocular inflammation, conjunctivitis, vernal conjuctivitis and the like; cutaneous diseases, skin disorders and itch, such as cutaneous wheal and flare, contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systhemic lupus erythematosis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of vis
  • COPD
  • the Secondary conditions include disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as AIDS related dementia, senile dementia of the Alzheimer type, Alzheimer's disease, Down's syndrome, Huntington's disease, Parkinson's disease, movement disorders and convulsive disorders (for example epilepsy); demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as diabetic neuropathy, AIDS related neuropathy, chemotherapy-induced neuropathy and neuralgia; addiction disorders such as alcoholism; stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; eating disorders (such as food intake disease); fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of the blood flow caused by vasodilation and vasospastic diseases such as angina, migraine and Reynaud's disease and pain or nociception, for example,
  • Such a medicament, and a composition of this invention may be prepared by admixture of a compound of the invention with an appropriate carrier. It may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
  • a pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields.
  • preparations may be in a pack form accompanied by written or printed instructions for use as an agent in the treatment of the conditions.
  • the suitable dosage range for the compounds of the invention depends on the compound to be employed and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration.
  • the compound or composition of the invention may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage.
  • the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may be designed to give slow release of the active ingredient.
  • Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
  • compositions may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinyl-pyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium stearate
  • disintegrants for example starch, polyvinyl-pyrrolidone
  • Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
  • any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • the composition may also be in the form of an ingestible capsule, for example of gelatin containing the compound, if desired with a carrier or other excipients.
  • compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colour
  • compositions may be formulated, for example for rectal administration as a suppository. They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
  • a pharmaceutically acceptable liquid e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
  • the liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives.
  • Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi- dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an injectable formulation.
  • the compounds of this invention may also be administered by inhalation, via the nasal or oral routes.
  • administration can be carried out with a spray formulation comprising a compound of the invention and a suitable carrier, optionally suspended in, for example, a hydrocarbon propellant.
  • Preferred spray formulations comprise micronised compound particles in combination with a surfactant, solvent or a dispersing agent to prevent the sedimentation of suspended particles.
  • the compound particle size is from about 2 to 10 microns.
  • a further mode of administration of the compounds of the invention comprises transdermal delivery utilising a skin-patch formulation.
  • a preferred formulation comprises a compound of the invention dispersed in a pressure sensitive adhesive which adheres to the skin, thereby permitting the compound to diffuse from the adhesive through the skin for delivery to the patient.
  • pressure sensitive adhesives known in the art such as natural rubber or silicone can be used.
  • the effective dose of compound depends on the particular compound employed, the condition of the patient and on the frequency and route of administration.
  • a unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.
  • the composition may be administered once or more times a day for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg.
  • the unit dose will contain from 2 to 20 mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose.
  • the present invention also provides a method for the treatment and/or prophylaxis of the Primary and Secondary Conditions in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective, non-toxic pharmaceutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • NK3 ligands The activity of the compounds of the present invention, as NK3 ligands, is determined by their ability to inhibit the binding of the radiolabelled NK3 ligands, [ 125 I]- [Me-Phe 7 ]-NKB or [ 3 H]-Senktide, to guinea-pig and human NK3 receptors (Renzetti et al, 1991, Neuropeptide, 18, 104-114; Buell et al, 1992, FEBS, 299(1), 90-95; Chung et al, 1994, Biochem. Biophys. Res. Commun., 198(3), 967-972).
  • the binding assays utilized allow the determination of the concentration of the individual compound required to reduce by 50% the [125 _[] v f e _p e ' ' 7 ]-NKB and [ 3 H]- Senktide specific binding to NK3 receptor in equilibrium conditions (IC50).
  • Binding assays provide for each compound tested a mean IC50 value of 2-5 separate experiments performed in duplicate or triplicate.
  • the most potent compounds of the present invention show IC50 values in the range 0.1-1000 nM.
  • the NK3 -antagonist activity of the compounds of the present invention is determined by their ability to inhibit senktide-induced contraction of the guinea-pig ileum (Maggi et al, 1990, Br. J. Pharmacol., 101, 996-1000) and rabbit isolated iris sphincter muscle (Hall et al., 1991, Eur. J. Pharmacol., 199, 9-14) and human NK3 receptors-mediated Ca " " mobilization (Mochizuki et al, 1994, J.
  • Guinea-pig and rabbit in-vitro functional assays provide for each compound tested a mean Kg value of 3-8 separate experiments, where Kg is the concentration of the individual compound required to produce a 2-fold rightward shift in the concentration-response curve of senktide.
  • Human receptor functional assay allows the determination of the concentration of the individual compound required to reduce by 50% (IC50 values) the Ca ""1" mobilization induced by the agonist NKB. In this assay, the compounds of the present invention behave as antagonists.
  • NK-2 ligands The activity of the compounds of the present invention, as NK-2 ligands, is determined by their ability to inhibit the binding of the radiolabelled NK-2 ligands, [ 125 I]-NKA or [ 3 H]-NKA, to human NK-2 receptors (Aharony et al, 1992, Neuropeptide, 23, 121-130).
  • the binding assays utilized allow the determination of the concentration of the individual compound required to reduce by 50% the [125jj_js KA and [ 3 H]-NKA specific binding to NK2 receptor in equilibrium conditions (IC50).
  • Binding assays provide for each compound tested a mean IC50 value of 2-5 separate experiments performed in duplicate or triplicate.
  • the most potent compounds of the present invention show IC50 values in the range 0.5-1000 nM, such as 1-1000 nM.
  • the NK-2-antagonist activity of the compounds of the present invention is determined by their ability to inhibit human NK-2 receptor-mediated Ca " ⁇ mobilization (Mochizuki et al, 1994, J. Biol. Chem., 269, 9651-9658).
  • Human receptor functional assay allows the determination of the concentration of the individual compound required to reduce by 50% (IC50 values) the Ca " " " mobilization induced by the agonist NKA. In this assay, the compounds of the present invention behave as antagonists.
  • the therapeutic potential of the compounds of the present invention in treating the conditions can be assessed using rodent disease models.
  • the compounds of formula (I) are also considered to be useful as diagnostic tool.
  • the invention includes a compound of formula (I) for use as diagnostic tools for assessing the degree to which neurokinin-3 and neurokinin-2 receptor activity (normal, overactivity or underactivity) is implicated in a patient's symptoms.
  • Such use comprises the use of a compound of formula (I) as an antagonist of said activity, for example including but not restricted to tachykinin agonist-induced inositol phosphate turnover or electrophysiological activation, of a cell sample obtained from a patient. Comparison of such activity in the presence or absence of a compound of formula (I), will disclose the degree of NK-3 and NK-2 receptor involvement in the mediation of agonist effects in that tissue.
  • DESCRIPTION 15 3-[4-(l-Cyanoimino-l-methylsulfanyl-methyI)-piperazin-l- ylmethyI]-2-phenyI-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)-amide
  • DESCRIPTION 16 3-[4-(l-Methanesulfonylimino-l-methylsulfanyl-methyl)- piperazin-l-ylmethyl]-2-phenyl-quinoline-4-carboxylic acid ((S)-l-cyclohexyl-ethyl)- a ide
  • DESCRIPTION 17 4-[4-((S)-l-Cyclohexyl-ethylcarbamoyl)-2-phenyl-quinolin-3- ylmethyl]-N-methyl-piperazine-l-carboximidothioic acid methyl ester
  • DESCRIPTION 18 3-(4-Oxo-piperidin-l-ylmethyl)-2-phenyl-quinoline-4-carboxyIic acid ((S)-l-phenyl-propyI)-amide
  • the aqueous phase was basified with 1 N NaOH and extracted with EtOAc.
  • the organic phase was dried over Na 2 SO 4 and evaporated to dryness to yield a crude material which was purified by flash column chromatography on 230-400 mesh silica gel, utilising a mixture of EtOAc/hexane 3:7 as eluent. After evaporation of the solvent, 3.0 g of the title compound as a yellow solid were obtained.
  • Table 1 summarizes all the compounds of the Examples 1-95 and their analytical data
  • Table 2 describes NMR spectroscopic data of Examples 1-95
  • Table 3 illustrates chemical names of compounds of Examples 1-95.
  • EXAMPLE 53 ( ⁇ 4-[4-((S)-l-Cyclohexyl-ethylcarbamoyI)-2-phenyI-quinolin-3- ylmethyl]-piperazin-l-yl ⁇ -dimethylamino-methylene)-dimethyl-ammonium hexafluorophosphate 50 mg (0.11 mmol) of the piperazine of Example 34 were reacted with 62 mg (0.16 mmol) of HBTU and 18 mg (0.17 mmol) of triethylamine in a mixture of 1.2 ml of anhydrous THF and 1 ml of CH 2 C1 2 .
  • EXAMPLE 66 S-ll ⁇ 'lBipiperidinyl-l'-ylmethyl-S-bromo-T-methoxy-Z-phenyl- quinoline-4-carboxylic acid ((S)-l-phenyl-propyl)-amide
  • the catalyst was filtered off, the solvent was evaporated in vacuo to dryness and the residue was purified by gradient flash column chromatography on 230-400 mesh silica gel, utilising EtOAc containing 0.05 % NH 4 OH (28%) as starting eluent, and a mixture of EtOAc/MeOH 95:5 containing 0.05 % N UOH (28%) as final eluent.
  • the residue was dissolved in acetone and acidified with HCl/Et 2 O; the precipitate so formed was recovered by suction filtration to yield 0.1 g of the title compound as a pale yellow solid.
  • EXAMPLE 72 3-[4-(3,4-Dioxo-2-pyrroIidin-l-yl-cyclobut-l-enyI)-piperazin-l- ylmethyl]-2-phenyl-quinoline-4-carboxy lie acid ((S)-l-cyclohexyl-ethyl)-amide
  • the white solid was purified by two successive flash chromatographies on silicagel, eluting first with CH 2 Cl 2 /MeOH : 90/10, then with CH 2 Cl 2 /MeOH/NH 4 OH : 90/10/1. Concentration of the desired fractions gave a solid which was triturated with diethyl ether to afford 0.225 g of the title compound as a salt ofp-toluenesulfonic acid. Analysis of the NMR spectra suggested the occurrence of 1.6 equivalent of acid for one molecule of parent compound (in Table 2, the NMR refers to the parent compound).

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Urology & Nephrology (AREA)
  • Psychiatry (AREA)
  • Dermatology (AREA)
  • Psychology (AREA)
  • Rheumatology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Vascular Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Ophthalmology & Optometry (AREA)
  • Transplantation (AREA)
  • Otolaryngology (AREA)
  • Hospice & Palliative Care (AREA)
  • Nutrition Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Cette invention se rapporte à un composé, ou un solvate ou sel de ce composé, représenté par la formule (I), où Ar représente un aryle éventuellement substitué ou un groupe cycloalkdiényle C5-7, ou un groupe cycloalkyle C5-7 éventuellement substitué, ou un groupe hétérocyclique aromatique à anneaux simples ou condensés éventuellement substitué; R représente hydrogène, alkyle C1-6 linéaire ou ramifié, cycloalkyle C3-7, cycloalkylalkyle C3-7; R1 représente hydrogène ou jusqu'à 3 substituants optionnels choisis dans la liste des radicaux suivants: alkyle C1-6, alcényle C1-6, aryle, alcoxy C1-6, hydroxy, halogène, nitro, cyano, carboxy, carboxamido, sulfonamido, alcoxycarbonyle C1-6, trifluorométhyle, acyloxy, amino ou mono et di-alkylamino C1-6; R2 représente une fraction (CH2)n-NY1Y2, où n est égal à un nombre entier compris entre 1 et 9, Y1 et Y2 sont choisis séparément parmi alkyle C1-6, alkyle C1-6 substitué par hydroxy, alcoxy, alkylamino C1-6 ou bis (alkyle C1-6)amino, cycloalkyle C3-6; azacycloalkyle C4-6, alcényle C1-6; aryle ou aryle-alkyle C1-6, où Y1 et Y2 forment avec l'atome d'azote auquel ils sont liés un groupe hétérocyclique à anneaux simples ou condensés liés par N éventuellement substitué; R3 représente alkyle C1-6 linéaire ou ramifié, cycloalkyle C3-7, cycloalkylalkyle C4-7, aryle éventuellement substitué ou un groupe hétérocyclique aromatique à anneaux simples ou condensés éventuellement substitué; et R4 représente hydrogène ou alkyle C1-6; R5 représente hydrogène ou halogène. Cette invention se rapporte en outre à un procédé de préparation de ces composés, à une composition pharmaceutique comprenant ces composés et à l'utilisation de ces composés et de cette composition en médecine.
PCT/EP1999/009115 1998-11-20 1999-11-19 Derives de quinoline-4-carboxamide utilises comme antagonistes des recepteurs nk-3 et nk-2 WO2000031037A1 (fr)

Priority Applications (12)

Application Number Priority Date Filing Date Title
MXPA01005095A MXPA01005095A (es) 1998-11-20 1999-11-19 Derivados de quinolin-4-carboxamida como antagonistas de receptor de neurocinina-3 y neurocinina-2.
JP2000583865A JP2002530377A (ja) 1998-11-20 1999-11-19 Ｎｋ−３およびｎｋ−２受容体アンタゴニストとしてのキノリン−４−カルボキシアミド誘導体
CA002351865A CA2351865A1 (fr) 1998-11-20 1999-11-19 Derives de quinoline-4-carboxamide utilises comme antagonistes des recepteurs nk-3 et nk-2
BR9915475-7A BR9915475A (pt) 1998-11-20 1999-11-19 Derivados da quinolina-4-carboxamida comoantagonistas dos receptores de nk-3 e nk-2
KR1020017006343A KR20010075726A (ko) 1998-11-20 1999-11-19 Ｎｋ-3 및 ｎｋ-2 수용체 길항제로서의퀴놀린-4-카르복스아미드 유도체
HU0104959A HUP0104959A3 (en) 1998-11-20 1999-11-19 Quinoline-4-carboxamide derivatives their preparation, their use as nk-3 and nk-2 receptor antagonists and medicaments containing them
EP99961001A EP1131295A1 (fr) 1998-11-20 1999-11-19 Derives de quinoline-4-carboxamide utilises comme antagonistes des recepteurs nk-3 et nk-2
AU17770/00A AU768708B2 (en) 1998-11-20 1999-11-19 Quinoline-4-carboxamide derivatives as NK-3 and NK-2 receptor antagonists
NZ511777A NZ511777A (en) 1998-11-20 1999-11-19 Quinoline-4-carboxamide derivatives as NK-3 and NK-2 receptor antagonists
IL14313799A IL143137A0 (en) 1998-11-20 1999-11-19 Quinoline-4-carboxamide derivatives as nk-3 and nk-2 receptor antagonists
NO20012473A NO20012473L (no) 1998-11-20 2001-05-18 Kinolin-4-karboksamidderivater som NK-3 og NK-2 reseptorantagonister
HK02101024.6A HK1041257A1 (zh) 1998-11-20 2002-02-08 作為nk-3受體拮抗劑的喹啉-4-酰胺衍生物

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GBGB9825553.2A GB9825553D0 (en) 1998-11-20 1998-11-20 Novel Compounds
GB9825552.4 1998-11-20
GB9825553.2 1998-11-20
GBGB9825552.4A GB9825552D0 (en) 1998-11-20 1998-11-20 Novel compounds

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US09856085 A-371-Of-International 2001-09-04
US15921802A Continuation 1998-11-20 2002-05-31

Publications (1)

Publication Number Publication Date
WO2000031037A1 true WO2000031037A1 (fr) 2000-06-02

Family

ID=26314705

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/009115 WO2000031037A1 (fr) 1998-11-20 1999-11-19 Derives de quinoline-4-carboxamide utilises comme antagonistes des recepteurs nk-3 et nk-2

Country Status (18)

Country Link
EP (1) EP1131295A1 (fr)
JP (1) JP2002530377A (fr)
KR (1) KR20010075726A (fr)
CN (1) CN1406225A (fr)
AR (2) AR021355A1 (fr)
AU (1) AU768708B2 (fr)
BR (1) BR9915475A (fr)
CA (1) CA2351865A1 (fr)
CO (1) CO5150149A1 (fr)
HK (1) HK1041257A1 (fr)
HU (1) HUP0104959A3 (fr)
IL (1) IL143137A0 (fr)
MX (1) MXPA01005095A (fr)
NO (1) NO20012473L (fr)
NZ (1) NZ511777A (fr)
PL (1) PL347721A1 (fr)
TR (1) TR200101412T2 (fr)
WO (1) WO2000031037A1 (fr)

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002038548A1 (fr) * 2000-11-13 2002-05-16 Glaxosmithkline S.P.A. Derives de quinoline-4-carboxamide utilises comme antagonistes de recepteurs de nk-3 et nk-2
WO2002038547A1 (fr) * 2000-11-13 2002-05-16 Glaxosmithkline Spa Derives de la quinoline en tant qu'antagonistes de nk-3 et nk-2
WO2002044165A1 (fr) * 2000-11-28 2002-06-06 Glaxosmithkline Spa Derives de quinoline utilises comme antagonistes de nk-3
WO2002044154A1 (fr) * 2000-11-28 2002-06-06 Glaxosmithkline Spa Nouveaux composés
WO2002043734A1 (fr) * 2000-11-28 2002-06-06 Glaxosmithkline Spa Composes
WO2002083663A1 (fr) * 2001-04-11 2002-10-24 Glaxosmithkline S.P.A. Derives de quinoline-4-carboxamide comme antagonistes de recepteurs de nk-3 et nk-4
WO2002083645A1 (fr) * 2001-04-11 2002-10-24 Glaxosmithkline S.P.A. Nouveaux composes
WO2004002484A1 (fr) * 2002-06-26 2004-01-08 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de phosphodiesterase
EP1387687A2 (fr) * 2001-05-18 2004-02-11 Smithkline Beecham Corporation Nouvelle utilisation
US6777421B2 (en) 2001-04-10 2004-08-17 Ortho-Mcneil Pharmaceutical, Inc. 1,3,8-Triazaspiro[4.5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders
WO2004072045A1 (fr) * 2003-02-11 2004-08-26 Merck Sharp & Dohme Limited Hydrazides d'acide carboxylique de 4-quinoleine substitues en tant que ligands du recepteur de nk-2/nk-3
EP1635834A2 (fr) * 2003-06-25 2006-03-22 Smithkline Beecham Corporation Nouveaux composes
US7037922B1 (en) 2000-03-10 2006-05-02 Neurogen Corporation Aryl fused 2,4-disubstituted pyridines: NK3 receptor ligands
WO2006050992A1 (fr) * 2004-11-12 2006-05-18 Smithkline Beecham Corporation Composés ayant une activité au niveau du récepteur nk3 et utilisations de ceux-ci en médecine
WO2006120478A2 (fr) * 2005-05-10 2006-11-16 Merck Sharp & Dohme Limited Derives de quinoline utilises comme antagonistes du recepteur de la neurokinine
WO2006130080A2 (fr) * 2005-06-03 2006-12-07 Astrazeneca Ab Derives de quinoline utilises comme antagonistes de nk3
WO2007012900A1 (fr) 2005-07-29 2007-02-01 Merck Sharp & Dohme Limited Dérivés de la quinoline en tant qu’antagonistes des récepteurs de la neurokinine
WO2007039123A2 (fr) * 2005-09-22 2007-04-12 Smithkline Beecham Corporation Traitement combine
US7217740B2 (en) 2004-08-27 2007-05-15 Merck Sharp And Dohme Diarylsulfones as 5-HT2A antagonists
WO2007069977A1 (fr) * 2005-12-12 2007-06-21 Astrazeneca Ab Quinoléines alkylsulfonamidiques
WO2008016006A1 (fr) * 2006-07-31 2008-02-07 Ono Pharmaceutical Co., Ltd. Composé auquel un groupe cyclique est lié par une liaison spiro et son utilisation
WO2008097976A1 (fr) * 2007-02-09 2008-08-14 Kalypsys, Inc. Modulateurs hétérocycliques de tgr5 pour le traitement des maladies
US7964733B2 (en) 2005-09-21 2011-06-21 Astrazeneca Ab Alkyl sulfoxide quinolines as NK-3 receptor ligands
US8703948B2 (en) 2006-11-28 2014-04-22 Janssen Pharmaceutica Nv Salts of 3-(3-amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one
US8741916B2 (en) 2007-04-09 2014-06-03 Janssen Pharmaceutica Nv 1,3,8-trisubstituted-1,3,8-triaza-spiro[4.5]decan-4-one derivatives as ligands of the ORL-1 receptor
US8778956B2 (en) 2002-09-09 2014-07-15 Janssen Pharmaceutica Nv Hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders
US9475773B2 (en) 2013-04-19 2016-10-25 Astrazeneca Ab NK3 receptor antagonist compound (NK3RA) for use in a method for the treatment of polycystic ovary syndrome (PCOS)
WO2017072629A1 (fr) 2015-10-29 2017-05-04 Cadila Healthcare Limited Combinaison pharmaceutique d'antagoniste du récepteur nk3 et de biguanides

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2549872B1 (fr) * 2010-03-23 2015-11-25 GlaxoSmithKline LLC Antagonistes de trpv4

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995032948A1 (fr) * 1994-05-27 1995-12-07 Smithkline Beecham Farmaceutici S.P.A. Derives de quinoline utilises comme antagonistes du recepteur nk3 de la tachykinine
WO1997019926A1 (fr) * 1995-11-24 1997-06-05 Smithkline Beecham S.P.A. Nouveaux derives de quinoline-4-carboxamide, leur preparation et leur utilisation en tant qu'antagonistes des recepteurs des neurokinines 3 (nk-3) et des neurokinines 2 (nk-2)
WO1998052942A1 (fr) * 1997-05-23 1998-11-26 Smithkline Beecham S.P.A. Nouveaux composes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995032948A1 (fr) * 1994-05-27 1995-12-07 Smithkline Beecham Farmaceutici S.P.A. Derives de quinoline utilises comme antagonistes du recepteur nk3 de la tachykinine
WO1997019926A1 (fr) * 1995-11-24 1997-06-05 Smithkline Beecham S.P.A. Nouveaux derives de quinoline-4-carboxamide, leur preparation et leur utilisation en tant qu'antagonistes des recepteurs des neurokinines 3 (nk-3) et des neurokinines 2 (nk-2)
WO1998052942A1 (fr) * 1997-05-23 1998-11-26 Smithkline Beecham S.P.A. Nouveaux composes

Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7037922B1 (en) 2000-03-10 2006-05-02 Neurogen Corporation Aryl fused 2,4-disubstituted pyridines: NK3 receptor ligands
WO2002038548A1 (fr) * 2000-11-13 2002-05-16 Glaxosmithkline S.P.A. Derives de quinoline-4-carboxamide utilises comme antagonistes de recepteurs de nk-3 et nk-2
WO2002038547A1 (fr) * 2000-11-13 2002-05-16 Glaxosmithkline Spa Derives de la quinoline en tant qu'antagonistes de nk-3 et nk-2
WO2002043734A1 (fr) * 2000-11-28 2002-06-06 Glaxosmithkline Spa Composes
WO2002044154A1 (fr) * 2000-11-28 2002-06-06 Glaxosmithkline Spa Nouveaux composés
WO2002044165A1 (fr) * 2000-11-28 2002-06-06 Glaxosmithkline Spa Derives de quinoline utilises comme antagonistes de nk-3
US7053101B2 (en) 2001-04-10 2006-05-30 Alfonzo Jordan 1,3,8-triazaspiro[4,5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders
US6777421B2 (en) 2001-04-10 2004-08-17 Ortho-Mcneil Pharmaceutical, Inc. 1,3,8-Triazaspiro[4.5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders
WO2002083663A1 (fr) * 2001-04-11 2002-10-24 Glaxosmithkline S.P.A. Derives de quinoline-4-carboxamide comme antagonistes de recepteurs de nk-3 et nk-4
WO2002083664A1 (fr) * 2001-04-11 2002-10-24 Glaxosmithkline S.P.A. Derives de 3-substitue quinoline-4-carboxamide utilises comme antagonistes du recepteur nk3 et du recepteur nk2
WO2002083645A1 (fr) * 2001-04-11 2002-10-24 Glaxosmithkline S.P.A. Nouveaux composes
EP1659120A1 (fr) * 2001-04-11 2006-05-24 GlaxoSmithKline S.p.A. Derives de 3-substitue quinoline-4-carboxamide utilises comme antagonistes du recepteur NK3 et du recepteur NK2
EP1387687A2 (fr) * 2001-05-18 2004-02-11 Smithkline Beecham Corporation Nouvelle utilisation
EP1387687A4 (fr) * 2001-05-18 2006-07-05 Smithkline Beecham Corp Nouvelle utilisation
WO2004002484A1 (fr) * 2002-06-26 2004-01-08 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de phosphodiesterase
US8778956B2 (en) 2002-09-09 2014-07-15 Janssen Pharmaceutica Nv Hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders
US7482457B2 (en) 2003-02-11 2009-01-27 Merck Sharp & Dohme Substituted quinoline-4-carboxylic hydrazides as NK-2/NK-3 receptor ligands
WO2004072045A1 (fr) * 2003-02-11 2004-08-26 Merck Sharp & Dohme Limited Hydrazides d'acide carboxylique de 4-quinoleine substitues en tant que ligands du recepteur de nk-2/nk-3
EP1635834A4 (fr) * 2003-06-25 2009-12-02 Smithkline Beecham Corp Nouveaux composes
EP1635834A2 (fr) * 2003-06-25 2006-03-22 Smithkline Beecham Corporation Nouveaux composes
US7468393B2 (en) 2004-08-27 2008-12-23 Merck Sharp & Dohme Ltd. Diarylsulfones as 5-HT2A antagonists
US7217740B2 (en) 2004-08-27 2007-05-15 Merck Sharp And Dohme Diarylsulfones as 5-HT2A antagonists
WO2006050992A1 (fr) * 2004-11-12 2006-05-18 Smithkline Beecham Corporation Composés ayant une activité au niveau du récepteur nk3 et utilisations de ceux-ci en médecine
WO2006120478A2 (fr) * 2005-05-10 2006-11-16 Merck Sharp & Dohme Limited Derives de quinoline utilises comme antagonistes du recepteur de la neurokinine
WO2006120478A3 (fr) * 2005-05-10 2007-03-29 Merck Sharp & Dohme Derives de quinoline utilises comme antagonistes du recepteur de la neurokinine
WO2006130080A2 (fr) * 2005-06-03 2006-12-07 Astrazeneca Ab Derives de quinoline utilises comme antagonistes de nk3
WO2006130080A3 (fr) * 2005-06-03 2007-01-25 Astrazeneca Ab Derives de quinoline utilises comme antagonistes de nk3
WO2007012900A1 (fr) 2005-07-29 2007-02-01 Merck Sharp & Dohme Limited Dérivés de la quinoline en tant qu’antagonistes des récepteurs de la neurokinine
US7964733B2 (en) 2005-09-21 2011-06-21 Astrazeneca Ab Alkyl sulfoxide quinolines as NK-3 receptor ligands
WO2007039123A2 (fr) * 2005-09-22 2007-04-12 Smithkline Beecham Corporation Traitement combine
WO2007039123A3 (fr) * 2005-09-22 2007-06-21 Smithkline Beecham Corp Traitement combine
US7608628B2 (en) 2005-12-12 2009-10-27 Astrazeneca Ab Alkylsulphonamide quinolines
US8071621B2 (en) 2005-12-12 2011-12-06 Astrazeneca Ab Alkylsulphonamide quinolines
WO2007069977A1 (fr) * 2005-12-12 2007-06-21 Astrazeneca Ab Quinoléines alkylsulfonamidiques
WO2008016006A1 (fr) * 2006-07-31 2008-02-07 Ono Pharmaceutical Co., Ltd. Composé auquel un groupe cyclique est lié par une liaison spiro et son utilisation
JPWO2008016006A1 (ja) * 2006-07-31 2009-12-24 小野薬品工業株式会社 スピロ結合した環状基を含有する化合物およびその用途
JP5245827B2 (ja) * 2006-07-31 2013-07-24 小野薬品工業株式会社 スピロ結合した環状基を含有する化合物およびその用途
US8703948B2 (en) 2006-11-28 2014-04-22 Janssen Pharmaceutica Nv Salts of 3-(3-amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one
WO2008097976A1 (fr) * 2007-02-09 2008-08-14 Kalypsys, Inc. Modulateurs hétérocycliques de tgr5 pour le traitement des maladies
US8741916B2 (en) 2007-04-09 2014-06-03 Janssen Pharmaceutica Nv 1,3,8-trisubstituted-1,3,8-triaza-spiro[4.5]decan-4-one derivatives as ligands of the ORL-1 receptor
US9475773B2 (en) 2013-04-19 2016-10-25 Astrazeneca Ab NK3 receptor antagonist compound (NK3RA) for use in a method for the treatment of polycystic ovary syndrome (PCOS)
WO2017072629A1 (fr) 2015-10-29 2017-05-04 Cadila Healthcare Limited Combinaison pharmaceutique d'antagoniste du récepteur nk3 et de biguanides

Also Published As

Publication number Publication date
EP1131295A1 (fr) 2001-09-12
AU768708B2 (en) 2004-01-08
JP2002530377A (ja) 2002-09-17
AR021354A1 (es) 2002-07-17
PL347721A1 (en) 2002-04-22
NZ511777A (en) 2003-12-19
CA2351865A1 (fr) 2000-06-02
MXPA01005095A (es) 2002-04-24
AU1777000A (en) 2000-06-13
NO20012473D0 (no) 2001-05-18
HUP0104959A3 (en) 2003-01-28
HK1041257A1 (zh) 2002-07-05
KR20010075726A (ko) 2001-08-09
TR200101412T2 (tr) 2001-10-22
IL143137A0 (en) 2002-04-21
AR021355A1 (es) 2002-07-17
NO20012473L (no) 2001-07-18
CO5150149A1 (es) 2002-04-29
HUP0104959A2 (hu) 2002-04-29
BR9915475A (pt) 2001-12-18
CN1406225A (zh) 2003-03-26

Similar Documents

Publication Publication Date Title
WO2000031037A1 (fr) Derives de quinoline-4-carboxamide utilises comme antagonistes des recepteurs nk-3 et nk-2
US20050176762A1 (en) Quinoline-4-carboxamide derivatives as NK-3 and NK-2 receptor antagonists
EP1019377A1 (fr) Nouveaux derives de quinoline-4-carboxamide, leur preparation et leur utilisation en tant qu'antagonistes des recepteurs des neurokinines 3 (nk-3) et des neurokinines 2 (nk-2)
EP1377555B1 (fr) Un derive de dioxino[2,3-g]quinoline-9-acide carboxylique en tant qu'antagoniste du recepteur nk3
EP0983262B1 (fr) Derives de quinoline-4-carboxamide comme antagonistes des recepteurs nk-2 et nk-3
US6613770B1 (en) Quinoline derivatives as NK-2 and NK-3 receptor ligands
US20060161004A1 (en) Novel compounds
EP1334088A1 (fr) Derives de quinoline-4-carboxamide utilises comme antagonistes de recepteurs de nk-3 et nk-2
US20040082589A1 (en) Quinoline derivatives as nk-3 and nk-2 antagonists
WO2002044165A1 (fr) Derives de quinoline utilises comme antagonistes de nk-3
US6780875B2 (en) Quinoline-4-carboxamide derivatives as NK-3 and NK-2 receptor antagonists
WO2002043734A1 (fr) Composes
US20060205735A1 (en) Quinoline-4-carboxamide as NK-2 and NK-3 receptor antagonists

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 99815753.8

Country of ref document: CN

ENP Entry into the national phase

Ref document number: 2000 17770

Country of ref document: AU

Kind code of ref document: A

AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

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: 143137

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 17770/00

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: PV2001-1743

Country of ref document: CZ

Ref document number: 511777

Country of ref document: NZ

ENP Entry into the national phase

Ref document number: 2351865

Country of ref document: CA

Ref document number: 2351865

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2001/04071

Country of ref document: ZA

Ref document number: 200104071

Country of ref document: ZA

Ref document number: IN/PCT/2001/00419/DE

Country of ref document: IN

Ref document number: 2001/01412

Country of ref document: TR

WWE Wipo information: entry into national phase

Ref document number: 1020017006343

Country of ref document: KR

ENP Entry into the national phase

Ref document number: 2000 583865

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PA/a/2001/005095

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 1999961001

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1020017006343

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 09856085

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 1999961001

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: PV2001-1743

Country of ref document: CZ

WWG Wipo information: grant in national office

Ref document number: 17770/00

Country of ref document: AU

WWW Wipo information: withdrawn in national office

Ref document number: 1020017006343

Country of ref document: KR

WWR Wipo information: refused in national office

Ref document number: PV2001-1743

Country of ref document: CZ