EP1165517A1 - N-benzimidazolylmethyl- et n-indolylmethyl-benzamides et leur application comme modulateurs de corticoliberine - Google Patents

N-benzimidazolylmethyl- et n-indolylmethyl-benzamides et leur application comme modulateurs de corticoliberine

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Publication number
EP1165517A1
EP1165517A1 EP00918516A EP00918516A EP1165517A1 EP 1165517 A1 EP1165517 A1 EP 1165517A1 EP 00918516 A EP00918516 A EP 00918516A EP 00918516 A EP00918516 A EP 00918516A EP 1165517 A1 EP1165517 A1 EP 1165517A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
methyl
compound according
carboxamide
methylethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00918516A
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German (de)
English (en)
Inventor
Raymond F. Horvath
Ping Ge
Taeyoung Yoon
Alan Hutchison
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Neurogen Corp
Original Assignee
Neurogen Corp
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Filing date
Publication date
Application filed by Neurogen Corp filed Critical Neurogen Corp
Publication of EP1165517A1 publication Critical patent/EP1165517A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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
    • A61P25/22—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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/72—Assays involving receptors, cell surface antigens or cell surface determinants for hormones
    • G01N2333/726—G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH

Definitions

  • This invention relates N-phenyl benzimidazolecarboxamides and N-phenyl indolecarboxamides . When appropriately substituted, such compounds act as selective modulators of CRF1 receptors.
  • This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treatment of psychiatric disorders and neurological diseases, including major depression, anxiety- related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders, as well as treatment of immunological , cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress. Additionally this invention relates to the use such compounds as probes for the localization of CRF1 receptors in cells and tissues.
  • Corticotropin releasing factor a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC) derived peptide secretion from the anterior pituitary gland.
  • POMC proopiomelanocortin
  • CRF Corticotropin releasing factor
  • CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders.
  • a role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system.
  • the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals.
  • CSF cerebral spinal fluid
  • the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF.
  • CRF adrenocorticotropin
  • the benzodiazepine receptor antagonist Ro 15-1788 which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose- dependent manner, while the benzodiazepine inverse agonist FG 7142 enhanced the actions of CRF.
  • CRF has also been implicated in the pathogeneisis of certain immunological, cardiovascular or heart-related diseases such as hypertension, tachycardia and congestive heart failure, stroke and osteoporosis, as well as in premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus and colonic hypersensitivity associated with psychopathological disturbance and stress.
  • the invention provides compounds of Formula I (shown below) , and pharmaceutical compositions comprising compounds of Formula I.
  • Such compounds bind to cell surface receptors, preferably G-coupled protein receptors, especially CRF receptors and most preferably CRF1 receptors .
  • Preferred compounds of the invention exhibit high affinity for CRF 1 receptors. Additionally, preferred compounds of the invention also exhibit high specificity for CRF1 receptors .
  • Preferred compounds of the present invention exhibit activity as corticotropin releasing factor receptor antagonists and appear to suppress the anxiogenic effects of CRF hypersecretion.
  • the invention also provides methods of using compounds of Formula I for the suppression of CRF hypersecretion and for the treatment of anxiogenic disorders.
  • the invention further comprises methods of treating patients suffering from certain disorders that are responsive to modulation of CRF1 receptors with an effective amount of a compound of the invention. These disorders include CNS disorders, particularly affective disorders, anxiety disorders, stress-related disorders, eating disorders and substance abuse. Treatment of human patients suffering from such disorders as well as other animals (domesticated companion animals (pets) or livestock animals in encompassed by the invention.
  • the invention provides pharmaceutical compositions comprising compounds of Formula I or the pharmaceutically acceptable salts or solvates thereof.
  • this invention relates to the use of the compounds of the invention (particularly labeled compounds of this invention) as probes for the localization of receptors in cells and tissues and as standards and reagents for use in determining the receptor-binding characteristics of test compounds.
  • Labelled compounds of the invention may be used in in vitro studies such as is autoradiography of tissue sections or for in vivo methods, e.g. PET or SPECT scanning.
  • preferred compounds of the invention are useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF1 receptor.
  • A represents N or C-Y, where Y is hydrogen or (C ⁇ -Cg) alkyl
  • G represents hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitrile, (C ⁇ -Cg) alkyl, (C ⁇ -C ⁇ ) alkoxy, hydroxy, hydroxy (Cx-C ⁇ ) alkyl, (C ⁇ -C6) alkoxy (C ⁇ -Cg) alkyl, -
  • R. represents hydrogen, (C ⁇ -C ⁇ ) alkyl, or hydroxy (C ⁇ -Ce) alkyl
  • R 2 represents hydrogen or (Ci-C ⁇ ) alkyl, with the proviso that
  • R 2 is hydrogen when A is C-Y;
  • R 3 and R 4 are the same or different and represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitrile, (C ⁇
  • R 5 , R 6 , R 7 and R 8 are the same or different and represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitrile,.
  • the invention provides methods for treating and/or preventing the above-listed disorders, which methods comprise administration to a patient of an effective amount of a compound of Formula I.
  • the invention provides intermediates useful in the preparation of the compounds of Formula I .
  • Formula I include those compounds, or the pharmaceutically acceptable non-toxic salts thereof wherein:
  • A represents N or C-Y, where Y is hydrogen or (C ⁇ -Cg) alkyl;
  • G represents halogen, trifluoromethyl, trifluoromethoxy, nitrile, (C ⁇ -C6) alkyl, ( C__ - CQ ) alkoxy, hydroxy, hydroxy (C ⁇ C ⁇ ) alkyl, (Ci-C ⁇ ) alkoxy (C ⁇ -C6) alkyl, -SH, ⁇ C ⁇ - C6)alkylthio-, thio (Ci-C ⁇ ) alkyl or (C ⁇ -C ⁇ ) lkyl thio(C ⁇ - C6 ) alkyl ;
  • R_ represents hydrogen, (Cx-C ⁇ ) alkyl or hydroxy (C ⁇ -Cg) alkyl;
  • R 2 represents hydrogen or (C ⁇ -Cg) alkyl, with the proviso that R 2 is hydrogen when A is C-Y;
  • R 3 and R 4 are the same or different and represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitrile, (C ⁇ C6) alkyl, (C ⁇ -Cg) alkoxy, (C ⁇ -Cg) alkoxy (C ⁇ -C6) alkoxy, hydroxy (C ⁇ -C6) alkoxy, hydroxy, hydroxy (C ⁇ -C6) lkyl, (C ⁇ C6 ) alkoxy (C ⁇ -C6) alkyl, -SH, (C -C6) alkylthio, thio(C ⁇ - C ⁇ ) alkyl or (C ⁇ -C ⁇ ) alkyl thio (C ⁇ -Cg) alkyl, with the proviso that R 3 and R 4 cannot both be hydrogen simultaneously; and R 5 , R 6 , R 7 and R 8 are the same or different and represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitrile, (Ci-C ⁇ ) alkyl, (C ⁇
  • the compounds of the instant invention are represented by the general Formula I set forth above and include pharmaceutically acceptable non-toxic salts thereof.
  • Preferred compounds of Formula I are those where R. is a C 1 -C 4 group, more preferably a C 2 -C 4 group, and most preferably an isopropyl group.
  • Other preferred compounds of Formula I include those where R 2 is hydrogen or C ⁇ C j alkyl, preferably methyl . More preferred compounds of Formula I include those where R. is a C 2 -C 4 group, most preferably an isopropyl group, and R 2 is hydrogen or C_-C_ alkyl, preferably methyl.
  • Particularly preferred compounds of Formula I are those where G is methyl and R 7 and R 8 are in the 4- and 6-positions on the phenyl ring respectively and independently represent hydrogen, C 1 -C 2 alkoxy, alkyl, halogen, or trifluoromethyl .
  • Preferred groups m Formula I include 2-, 3-, or 4- (C j -C alkoxyphenyl, 4- (C- ⁇ C alkoxy-2- (C. -C 6 ) alkylphenyl, 2-, 3 - , or 4 - ( C ⁇ C g ) alkylphenyl , 2 - or 4 -halophenyl , hydroxyphenyl , and 4 - hydroxy- 2 - ( C x - C 6 ) alky lphenyl .
  • Particularly preferred groups in Formula I include (4 -methoxy-2 -methylphenyl) , 4-methoxyphenyl, 3- methoxyphenyl , 3 -methylphenyl, 2 -methoxyphenyl , 4-chloro-2- methylphenyl , 4 -methylphenyl , 2-chlorophenyl, 4 -fluorophenyl, 4-chlorophenyl, 4 -hydroxyphenyl, 2 , 4 -dimethylphenyl, 4- ethoxyphenyl , 4 -hydroxy-2-methylphenyl, 3-hydroxy-4- methoxyphenyl .
  • R 5 and R 6 are at the 5- and 6-positions of the benzimidazole or indole ring system and represent hydrogen, fluoro, chloro, bromo, C.-C 6 alkoxy, more preferably . methoxy or ethoxy, or C.-C 6 alkyl, more preferably methyl or ethyl .
  • Particularly preferred are compounds of Formula I where one of R 5 and R 6 is hydrogen and the other is hydrogen, fluoro, chloro, methoxy, ethoxy, methyl or ethyl .
  • R_ is as defined above for Formula I; Q is
  • G represents halogen, trifluoromethyl, trifluoromethoxy, nitrile, (C ⁇ -Cg) alkyl, (Cx-C ⁇ ) alkoxy, hydroxy, hydroxy (C ⁇ C ⁇ ) alkyl, (C ⁇ -C ⁇ ) alkoxy (C ⁇ -Cg) alkyl, -SH, (C ⁇ C6)alkylthio, thio (C -C6) alkyl or (C ⁇ -C ⁇ ) alkyl thio(C ⁇ - ⁇ ) alkyl;
  • R 2 represents hydrogen or (C ⁇ -Cg) alkyl
  • R 3 and R 4 are the same or different and represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitrile, (C ⁇ C ⁇ ) alkyl, (C ⁇ -Cg) alkoxy, hydroxy, hydroxy (C - C ⁇ ) alkyl , (Cx-C6 ) alkoxy (C ⁇ -C ⁇ ) alkyl, thiol, (C ⁇ -Cg) alkylthiol, thio (C ⁇ -C ⁇ ) alkyl or (C ⁇ -C ⁇ ) alkyl thio (C ⁇ -Cg) alkyl, with the proviso that R 3 and R 4 cannot both be hydrogen; and
  • R 5 , R 6 , R 7 and R 8 are the same or different and represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitrile, ( C - CQ ) alkyl, (C ⁇ -C6) alkoxy, hydroxy, hydroxy(C ⁇ C ⁇ ) alkyl, (C ⁇ -C6) alkoxy (C ⁇ -C ⁇ ) alkyl, thiol, (C ⁇ C6)alkylthiol, thio (C ⁇ -C6) alkyl or (C ⁇ -Cg) alkyl thio(C ⁇ - C 6 ) alkyl.
  • Other preferred compounds of Formula II are those where R 5 and R 6 independently represent hydrogen, halogen, more preferably chloro or fluoro, hydroxy, trifluoromethyl, nitrile,
  • C.-C 3 alkyl more preferably methyl, or C 1 -C 3 alkoxy, more preferably methoxy or ethoxy.
  • Still other preferred compounds of Formula II are those where G is C.-C 3 alkyl, C 1 -C 3 alkoxy, or halogen.
  • Still other preferred compounds of II include those where R 5 and R 6 are hydrogen and G is methyl, methoxy, or chloro. More preferred compounds of Formula II include those where R 5 and R 6 are hydrogen; G is methyl, methoxy, or chloro; and R 7 and R 8 are independently hydrogen, C--C 6 alkoxy, C.-C 6 alkyl, halogen, or trifluoromethyl .
  • Particularly preferred compounds of Formula II are those where Q is
  • G is C.-C 2 alkyl and R 7 and R 8 are independently hydrogen
  • Still other particularly preferred compounds of Formula II include those where R 5 and R 6 are hydrogen; G is methyl, methoxy, or chloro; and R 7 and R 8 are independently hydrogen, C--C 6 alkoxy, C.-C 6 alkyl, halogen, or trifluoromethyl .
  • Q is trimethylphenyl .
  • R. is G 2 -C 4 alkyl, more preferably isopropyl.
  • R 2 is hydrogen.
  • R 5 and R 6 are at the 5- and 6-positions of the benzimidazole or indole ring system and represent hydrogen, fluoro, chloro, bromo, C--C 6 alkoxy, more preferably methoxy or ethoxy, or C- L -C 8 alkyl, more preferably methyl or ethyl.
  • R 5 and R 6 are hydrogen and the other is hydrogen, fluoro, chloro, methoxy, ethoxy, methyl or ethyl.
  • Ri represents hydrogen or (C ⁇ -C ⁇ ) alkyl
  • R 3 and R 4 are the same or different and represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitrile, (C ⁇ C ⁇ ) alkyl, ( C ⁇ - CQ ) alkoxy, hydroxy, hydroxy (C ⁇ -C ⁇ ) alkyl, (Cx-C6) alkoxy (C ⁇ -C6) alkyl, thio, (C ⁇ -C ⁇ ) alkylthiol, thio (C ⁇ -C ⁇ ) alkyl or (C ⁇ -C6) alkyl thio (C ⁇ -C ⁇ ) alkyl, with the proviso that R 3 and R 4 cannot both be hydrogen simultaneously; and
  • R s , R 6 , R 7 and R 8 are the same or different and represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitrile, (C ⁇ -C6) alkyl, (C ⁇ -C ⁇ ) alkoxy, hydroxy, hydroxy (C ⁇ C ⁇ ) alkyl, (C ⁇ -C6) alkoxy (C ⁇ -C6) alkyl, -SH, (C ⁇ C ⁇ ) alkylthiol, thio (C ⁇ -C6) alkyl or (Cx-C ⁇ ) alkyl thio(C ⁇ - C ⁇ ) alkyl.
  • Preferred compounds of Formula III are those where R 5 and
  • R 6 independently represent hydrogen, halogen, more preferably chloro or fluoro, hydroxy, trifluoromethyl, nitrile, C.-C 3 alkyl, more preferably methyl, or C--C 3 alkoxy, more preferably methoxy or ethoxy.
  • Still other preferred compounds of Formula III are those where G is C ⁇ C.- alkyl, C.-C 3 alkoxy, or halogen. Still other preferred compounds of III include those where
  • R s and R 6 are hydrogen and G is methyl, methoxy, or chloro.
  • More preferred compounds of Formula III include those where R 5 and R s are hydrogen; G is methyl, methoxy, or chloro; and R 7 and R 8 are independently hydrogen, C--C 6 alkoxy, alkyl, halogen, or trifluoromethyl .
  • Particularly preferred compounds of Formula III are those where Q is
  • G is alkyl and R 7 and R 8 are independently hydrogen, C.-C 2 alkoxy, C ⁇ C, alkyl, halogen, or trifluoromethyl .
  • Still other particularly preferred compounds of Formula III include those where R 5 and R 6 are hydrogen; G is methyl, methoxy, or chloro; and R 7 and R 8 are independently hydrogen, C.-C 6 alkoxy, C_-C 6 alkyl, halogen, or trifluoromethyl .
  • Q is trimethylphenyl .
  • R x is C 2 -C 4 alkyl, more preferably isopropyl.
  • R 5 and R 6 are at the 5- and 6-positions of the benzimidazole or indole ring system and represent hydrogen, fluoro, chloro, bromo, C_-C 6 alkoxy, more preferably methoxy or ethoxy, or alkyl, more preferably methyl or ethyl.
  • R 5 and R 6 are hydrogen and the other is hydrogen, fluoro, chloro, methoxy, ethoxy, methyl or ethyl.
  • Compounds of the invention are useful in treating a variety of conditions including affective disorders, anxiety disorders, stress disorders, eating disorders, and drug addiction.
  • Affective disorders include all types of depression, bipolar disorder, cyclothymia, and dysthymia.
  • Anxiety disorders include generalized anxiety disorder, panic, phobias and obsessive-compulsive disorder.
  • Stress-related disorders include post-traumatic stress disorder, hemorrhagic stress, stress-induced psychotic episodes, psychosocial dwarfism, stress headaches, stress- induced immune systems disorders such as stress-induced fever, and stress-related sleep disorders.
  • Eating disorders include anorexia nervosa, bulimia nervosa, and obesity.
  • Modulators of the CRF receptors may also be useful in the treatment of a variety of neurological disorders including supranuclear palsy, AIDS related dementias, multiinfarct dementia, neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, head trauma, spinal cord trauma, ischemic neuronal damage, amyotrophic lateral sclerosis, disorders of pain perception such as fibromyalgia and epilepsy.
  • neurological disorders including supranuclear palsy, AIDS related dementias, multiinfarct dementia, neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, head trauma, spinal cord trauma, ischemic neuronal damage, amyotrophic lateral sclerosis, disorders of pain perception such as fibromyalgia and epilepsy.
  • compounds of Formula I are useful as modulators of the CRF receptor in the treatment of a number of gastrointestes inal, cardiovascular, hormonal, autoimmune and inflammatory conditions. Such conditions include irritable bowel syndrome, ulcers, Crohn ' s disease, spastic colon, diarrhea, post operative ilius and colonic hypersensitivity associated with psychopathological disturbances or stress, hypertension, tachycardia, congestive heart failure, infertility, euthyroid sick syndrome, inflammatory conditions effected by rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies. Compounds of Formula I are also useful as modulators of the CRF- L receptor in the treatment of animal disorders associated with aberrant CRF levels.
  • porcine stress syndrome bovine shipping fever
  • equine paroxysmal fibrillation and dysfunctions induced by confinement in chickens
  • sheering stress in sheep or human- animal interaction related stress in dogs psychosocial dwarfism and hypoglycemia .
  • alkyl straight or branched chain alkyl groups or cycloalkyl groups having 1-6 carbon atoms, such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3 -methylpentyl , cyclopropyl, and cyclopropylmethyl .
  • alkoxy straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3- hexoxy, and 3-methylpentoxy.
  • halogen in the present invention is meant fluorine, bromine, chlorine, and iodine.
  • the compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms.
  • These compounds can be, for example, racemates or optically active forms.
  • the single enantiomers, i.e., optically active forms can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
  • Representative compounds of the present invention include, but are not limited to the compounds described in the Examples and their pharmaceutically acceptable acid addition salts.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds .
  • Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC- (CH 2 )n-COOH where n is 0-4, and the like.
  • acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC- (CH 2 )n-COOH where n is 0-4, and the like.
  • Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
  • the present invention also encompasses
  • the invention encompasses all possible tautomers and rotamers of the compounds represented by Formula I .
  • the compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles .
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier.
  • One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
  • compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol , or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propyiene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1, 3-butanediol .
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides .
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of general Formula I may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols .
  • Compounds of general Formula I may be administered parenterally in a sterile medium.
  • the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
  • Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day) .
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient . Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most CNS disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of stress and depression a dosage regimen of 1 or 2 times daily is particularly preferred.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability, low toxicity, low serum protein binding and desirable in vitro and in vivo half-lifes. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat periphereal disorders are often preferred.
  • Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers . Toxicity to cultured hepatocyctes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously.
  • Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcova, et al . (Journal of Chromatography B (1996) volume 677, pages 1-27) .
  • Compound half-life is inversely proportional to the frequency of dosage of a compound.
  • In vitro half-lifes of compounds may be predicted from assays of microsomal half- life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127) .
  • the present invention also pertains to packaged pharmaceutical compositions for treating disorders responsive to C5a receptor modulation, e.g., eating disorders, depression or stress.
  • the packaged pharmaceutical compositions include a container holding a therapeutically effective amount of at least one CRF1 receptor modulator as described supra and instructions for using the treating disorder responsive to CRF1 receptor modulation in the patient .
  • Compounds of the invention can be prepared using the reactions depicted in Schemes I to III. In Schemes I-III, the groups G, R., R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and Y are as defined in general Formula I .
  • Diarylamines were prepared according to literature procedure [J.J. Kulagowski and C.W. Rees, Synthesis, 215
  • N-Phenyl indolecarboxylic acids are prepared according to literature procedures [P.C. Unangst et al . , J “ . Heterocyclic Chem. , 24, 811 (1987)].
  • N- (4- methoxy) phenylindole-2 -carboxylic acid (2g, 7.48 mmol) in N,N- dimethylformamide (15 ml) is added triethylamine (1.25 ml, 9 mmol) followed by diethyl cyanophosphonate (DECP) (1.52 ml, 9 mmol) at 0 °C.
  • DECP diethyl cyanophosphonate
  • the resulting yellow solution is refluxed for 24 hours and then cooled to room temperature, diluted with Et 2 0 and quenched by adding water at 0 °C until formation of a gel.
  • the Et 2 0 layer is separated and the gel is extracted with more Et 2 0.
  • the combined Et 2 0 extract is washed with water, washed with brine and dried.
  • Solvent is removed in vacuo to give a yellow oil residue that is stirred in IN HC1 (5 ml) and Et 2 0 (10 ml) .
  • the white precipitate is separated, washed with water, rinsed with Et 2 0 and dried to give the product as its hydrochloride (430 mg, 48%) .
  • Example 5 Assay for CRF Receptor Binding Activity The following two assays for human CRF1 receptor activity are standard assays of CRF binding that may be used to determine the affinity of CRF for the CRF receptor.
  • CRF receptor binding is performed using a modified version of the assay described by Grigoriadis and De Souza (Methods in Neuro ⁇ ciences, Vol. 5, 1991).
  • Membrane pellets containing CRF receptors are re-suspended in 50mM Tris buffer pH 7.7 containing 10 mM MgCl2 and 2 mM EDTA and centrifuged for 10 minutes at 48000g. Membranes are washed again and brought to a final concentration of 1500mg/ml in binding buffer (Tris buffer above with 0.1 % BSA, 15 mM bacitracin and 0.01 mg/mL aprotinin.).
  • binding buffer Tris buffer above with 0.1 % BSA, 15 mM bacitracin and 0.01 mg/mL aprotinin.
  • 100 mL of the membrane preparation is added to 96 well microtube plates containing
  • IC50 values are calculated with the non-linear curve fitting program RS/1 (BBN Software Products Corp., Cambridge, MA) .
  • the binding affinity for the compounds of Formula I expressed as IC50 value generally ranges from about 0.5 nanomolar to about 10 micromolar.
  • Preferred Arylpyrimidines of the invention exhibit good activity in standard in vitro receptor binding assays, specifically the assay as specified in Example 44, which follows and is defined below.
  • Particularly preferred arylpyrimidines of the invention have an IC S0 of about 10 micromolar or less, still more preferably and IC 50 of about 100 nanomolar or less even more preferably an IC 50 of about 10 nanomolar or less or even 1 nanomolare or less in such a defined standard in vitro CRF receptor binding assay.
  • the binding activity of the compounds of formula I to the human ORF ⁇ receptor can be measured as follows : Assay for Human CRF Receptor Binding Activity in IMR32 cells
  • IMR-32 human neuroblastoma cells are grown to 80% confluence in EMEM containing Earle's Balanced Salts and 2 mM 1-glutamine with 10% FBS, 25 mM HEPES, 1 mM Sodium Pyruvate, and nonessential amino acids. At this time, flasks of cells are treated with 2.5 uM 5-bromo-2' -deoxyuridine (Br-dU) for 10 days. Media is changed every 3-4 days across the 10-day period. Cells are harvested using No-Zyme (JRH Biosciences) and rinsed with PBS.
  • cells are homogenized in wash buffer (50 mM Tris HC1, 10 mM MgCl 2 , 2 mM EGTA, pH 7.4) and centrifuged at 48,000 x g for 10 minutes at 4°C. Pellets are resuspended, homogenized and centrifuged two additional times.
  • wash buffer 50 mM Tris HC1, 10 mM MgCl 2 , 2 mM EGTA, pH 7.4
  • the receptor binding assay is performed using assay buffer (50 mM Tris HC1, 10 mM MgCl 2 , 2 mM EGTA, pH 7.4, 0.1% BSA, 0.1 mM bacitracin (22.0mg/100 mL) ) , 150 ug protein/tube, and [ 125 1] Sauvagine (NEN; 100 pM for competition analysis and 10 pM-1 nM for saturation analysis) to yield a final volume of 200 uL.
  • Nonspecific binding is defined using 2 uM r/h CRF or 9-41 alpha-helical CRF. Cells are incubated for 2 hours at room temperature .
  • the assay is terminated by rapid vacuum filtration (Tomtec: Deepwell 3) through GFC filters presoaked in 1% PEI using ice-cold 50 mM Tris Hcl and dry thoroughly by air.
  • Specific Binding 70-80%; Kd (nM) : 0.30 nM; Bmax (fmole/mg protein) : 40-50.
  • IC50 values are calculated with the non-linear curve fitting program RS/1 (BBN Software Products Corp., Cambridge, MA).
  • the binding affinities for the compounds of Formula I expressed as IC50 value are less than 10 micromolar.
  • the compounds of the invention are prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope.
  • the radioisotope is preferably selected from of at least one of carbon (preferably 1 C) , hydrogen (preferably 3 H) , sulfur
  • radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds.
  • a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds.
  • suppliers include Amersham Corporation, Arlington Heights, IL; Cambridge Isotope Laboratories, Inc. Andover, MA; SRI International, Menlo Park, CA; Wizard Laboratories, West Sacramento, CA; ChemSyn Laboratories, Lexena, KS; American Radiolabeled Chemicals, Inc., St. Louis, MO; and Moravek Biochemicals Inc., Brea, CA.
  • Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph using the compound of the invention as substrate. In addition, certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate.
  • Receptor autoradiography (receptor mapping) is carried out in vitro as described by Kuhar in sections 8.1.1 to

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Abstract

L'invention concerne des composés de formule (I) (ou leurs sels non toxiques pharmaceutiquement acceptables) dans laquelle A désigne N ou CH; R1 et R2 désignent un hydrogène ou un alkyle inférieur; G, R3, R4, R5, R6, R7 et R8 désignent des variables définies dans le descriptif. Ces composés sont des modulateurs des récepteurs de la corticolibérine et sont utiles pour le traitement de troubles affectifs, de l'anxiété, de la dépression, de troubles alimentaires et de troubles de stress chez les êtres humains et les animaux. Font aussi l'objet de cette invention des traitements de ces troubles et des compositions pharmaceutiques emballées. Les composés de cette invention sont également utiles comme sondes servant à localiser les récepteurs de la corticolibérine et comme normes dans les tests de liaison des récepteurs de la corticolibérine. Font aussi l'objet de cette invention les composés analysés dans les études de localisation des récepteurs.
EP00918516A 1999-04-02 2000-03-31 N-benzimidazolylmethyl- et n-indolylmethyl-benzamides et leur application comme modulateurs de corticoliberine Withdrawn EP1165517A1 (fr)

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KR101020350B1 (ko) * 2003-03-13 2011-03-08 이데미쓰 고산 가부시키가이샤 신규한 질소 함유 헤테로환 유도체 및 이를 이용한 유기 전기발광 소자
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