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WO1998035945A1 - Derives de 4-aminoalcoxy-1h-benzimidazole, leur preparation et leur utilisation comme agonistes des autorecepteurs de la dopamine (d2) - Google Patents

Derives de 4-aminoalcoxy-1h-benzimidazole, leur preparation et leur utilisation comme agonistes des autorecepteurs de la dopamine (d2) Download PDF

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Publication number
WO1998035945A1
WO1998035945A1 PCT/US1998/000613 US9800613W WO9835945A1 WO 1998035945 A1 WO1998035945 A1 WO 1998035945A1 US 9800613 W US9800613 W US 9800613W WO 9835945 A1 WO9835945 A1 WO 9835945A1
Authority
WO
WIPO (PCT)
Prior art keywords
ethyl
benzyl
yloxy
trifluoromethyl
pharmaceutically acceptable
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.)
Ceased
Application number
PCT/US1998/000613
Other languages
English (en)
Inventor
James Albert Nelson
Richard Eric Mewshaw
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.)
Wyeth LLC
Original Assignee
American Home Products Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by American Home Products Corp filed Critical American Home Products Corp
Priority to AU59153/98A priority Critical patent/AU746717B2/en
Priority to NZ336969A priority patent/NZ336969A/xx
Priority to JP53572798A priority patent/JP2001509814A/ja
Priority to CA002278700A priority patent/CA2278700A1/fr
Priority to HU0001302A priority patent/HUP0001302A3/hu
Priority to BR9807701-5A priority patent/BR9807701A/pt
Priority to EP98902513A priority patent/EP0973749A1/fr
Priority to IL13115898A priority patent/IL131158A0/xx
Publication of WO1998035945A1 publication Critical patent/WO1998035945A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • 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
    • A61P25/14—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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D235/10—Radicals substituted by halogen atoms or nitro radicals
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to 4-(aminoalkoxy)-lH-benzoimidazoles which have dopamine D 2 agonist activity and thus are useful in the treatment of schizophrenia, Parkinson's disease, Tourette's syndrome and drug or alcohol addiction.
  • Intrinsic activity is predicted using the ratio of the "low-affinity agonist" (LowAg) state of the receptor and the "high-affinity agonist” (HighAg) state of the receptor, i.e. LowAg HighAg. These ratios correlate with the agonist, partial agonist, and antagonist activities of a given compound, which activities characterize a compounds ability to elicit an antipsychotic effect.
  • the compounds of this invention are dopamine agonists various degrees of intrinsic activity some of which are selective autoreceptor agonists, and therefore partial agonist (i.e. activate only autoreceptors versus postsynaptic D 2 dopamine receptors). As such, they provide functional modulation of the dopamine systems of the brain without the excessive blockade of the postsynaptic dopamine receptors which have been observed to be responsible for the serious side effects frequently exhibited by agents found otherwise clinically effective for the treatment of schizophrenia.
  • the compounds of this invention were also found to have high intrinsic activity and therefore they can behave as the natural neurotransmitter i.e. as full agonists. As such, they are useful in the treatment of diseases having abnormal concentrations of dopamine could be used as dopamine surrogates possibly in the treatment of Parkinson's disease.
  • the compounds of this invention are essentially free from extrapyramidal side effects (EPS). DESCRIPTION OF THE PRIOR ART
  • JP 02306916A claims a class of benzazole compounds of the formula below, where
  • Ri includes -(O-A) m -NR 4 R 5 where A is lower alkylene, m is 0 or 1, R 4 and R 5 include hydrogen, phenyl(lower)alkyl, or NR 4 R 5 is a 5-6 membered saturated or unsaturated heterocycle and R 2 includes phenyl optionally substituted by 1-3 substituents selected from optionally halogenated lower alkoxy, lower alkyl, hydroxy, halogen or aminoalkoxy.
  • R 4 is methyl, cyano, carboxamido or aminomethyl
  • R 5 is H or alkyl
  • R 6 is alkyl or cycloalkyl or R 5 and R 6 completes a cyclohexane ring which are useful for the treatment of circulatory disorders and shock.
  • Rl is hydrogen, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, straight- chain or branched alkyl group having up to 6 carbons or benzyl optionally substituted by one to three substituents selected from halogen, amino, nitro, hydroxy, C ⁇ -C 6 alkoxy; R 2 is hydrogen or C ⁇ -C 6 alkyl.
  • the pharmaceutically acceptable acid addition salt having the utility of the free base are prepared by methods well known to the art with both inorganic or organic acids, including but not limited to fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicyclic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene-sulfonic, hydrochloric hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
  • inorganic or organic acids including but not limited to fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bis
  • the compounds of this invention are dopamine autoreceptor agonists, that is, they serve to modulate the synthesis and release of the neurotransmitter dopamine. They are thus useful for treatment of disorders of the dopaminergic system, such as schizophrenia, Parkinson's disease and Tourette's syndrome. Such agents are partial agonists at the postsynaptic dopamine D2 receptor and are thereby useful in the treatment of alcohol and drug addiction.
  • the compounds of this invention effect the synthesis of the neurotransmitter dopamine and thus are useful in the treatment of dopaminergic disorders such as schizophrenia, Parkinson's disease, Tourette's Syndrome, alcohol addiction, cocaine addiction, and addiction to analagous drugs.
  • Applicable solid carriers for pharmaceutical compositions containing the compounds of this invention can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintergrating agents or an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
  • the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g.
  • cellulose derivatives preferably sodium carboxymethyl cellulose solution
  • alcohols including monohydric alcohols and polyhydric alcohols e.g. glycols
  • oils e.g. fractionated coconut oil and arachis oil
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
  • the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
  • the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • the dosage to be used in the treatment of a specific psychosis must be subjectively determined by the attending physician.
  • the variables involved include the specific psychosis and the size, age and response pattern of the patient.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Addiction (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des composés dopaminergiques D2 de formule (I) dans laquelle R1 est hydrogène, trifluorométhyle, pentafluoroéthyle, heptafluoropropyle, un groupe alkyle à chaîne droite ou ramifié possédant jusqu'à 6 carbones, ou bien benzyle éventuellement substitué par un à trois substituants choisis parmi halogène, amino, nitro, hydroxy, alcoxy C¿1?-C6; R?2¿ est hydrogène ou alkyle C¿1?-C6. R?3¿ est hydrogène, un groupe alkyle à chaîne droite ou ramifié possédant jusqu'à 10 atomes de carbone, cyclohéxylméthyle, -(CH¿2?)mAr où Ar est phényle, thiényle, furanyle, ou bien pyridinyle, éventuellement substitués par un à deux substituants choisis parmi halogène, alcoxy C1-C6, trifluorométhyle ou alkyle C1-C6; ou bien NR?2R3¿ est 1,2,3,4-tétrahydroquinoléin-1-yle ou bien 1,2,3,4-tétrahydroisoquinoléin-2-yle; Y = halogène, alkyle inférieur, amino, et alcoxy inférieur; n = 1-5. L'invention concerne également un sel pharmaceutiquement acceptable de ces composés. Ces composés dopaminergiques D¿2? sont utiles dans le traitement de la schizophrénie, de la maladie de Parkinson, de la maladie de Gilles de La Tourette, et de la toxicomanie ou de l'alcoolisme.
PCT/US1998/000613 1997-02-18 1998-01-13 Derives de 4-aminoalcoxy-1h-benzimidazole, leur preparation et leur utilisation comme agonistes des autorecepteurs de la dopamine (d2) Ceased WO1998035945A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
AU59153/98A AU746717B2 (en) 1997-02-18 1998-01-13 4-aminoalkoxy-1H-benzimidazole derivatives, their preparation and their use as dopamine autoreceptor (D2) agonists
NZ336969A NZ336969A (en) 1997-02-18 1998-01-13 Substituted 4-aminoalkoxy-1H-benzimidazole derivatives useful as dopamine autoreceptor (D2) agonists
JP53572798A JP2001509814A (ja) 1997-02-18 1998-01-13 ４−アミノアルコキシ−１ｈ−ベンゾイミダゾール誘導体、それらの調製およびそれらのドパミン自己受容体（ｄ▲下２▼）作動薬としての使用
CA002278700A CA2278700A1 (fr) 1997-02-18 1998-01-13 Derives de 4-aminoalcoxy-1h-benzimidazole, leur preparation et leur utilisation comme agonistes des autorecepteurs de la dopamine (d2)
HU0001302A HUP0001302A3 (en) 1997-02-18 1998-01-13 4-aminoalkoxy-1h-benzimidazole derivatives, use of them for producing pharmaceutical compositions as dopamine autoreceptor (d2) agonists and pharmaceutical compositions containing them
BR9807701-5A BR9807701A (pt) 1997-02-18 1998-01-13 Derivados de 4-aminoalcóxi-1h-benzimidazol, seu preparo e seu uso como agonistas do auto-receptor (d2) de dopamina
EP98902513A EP0973749A1 (fr) 1997-02-18 1998-01-13 Derives de 4-aminoalcoxy-1h-benzimidazole, leur preparation et leur utilisation comme agonistes des autorecepteurs de la dopamine (d 2?)
IL13115898A IL131158A0 (en) 1997-02-18 1998-01-13 4-Aminoalkoxy-1h-benzimidazole derivatives their preparation and their use as dopamine autoreceptor (d2) agonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US80127697A 1997-02-18 1997-02-18
US08/801,276 1997-02-18

Publications (1)

Publication Number Publication Date
WO1998035945A1 true WO1998035945A1 (fr) 1998-08-20

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ID=25180658

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/000613 Ceased WO1998035945A1 (fr) 1997-02-18 1998-01-13 Derives de 4-aminoalcoxy-1h-benzimidazole, leur preparation et leur utilisation comme agonistes des autorecepteurs de la dopamine (d2)

Country Status (14)

Country Link
EP (1) EP0973749A1 (fr)
JP (1) JP2001509814A (fr)
KR (1) KR20000071129A (fr)
CN (1) CN1252793A (fr)
AR (1) AR011136A1 (fr)
AU (1) AU746717B2 (fr)
BR (1) BR9807701A (fr)
CA (1) CA2278700A1 (fr)
HU (1) HUP0001302A3 (fr)
IL (1) IL131158A0 (fr)
NZ (1) NZ336969A (fr)
TW (1) TW513415B (fr)
WO (1) WO1998035945A1 (fr)
ZA (1) ZA981309B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003008419A1 (fr) * 2001-07-20 2003-01-30 Wyeth Derives de 2-(aminomethyl)-tetrahydro-9-oxa-1,3-diaza-cyclopenta[a]naphtalenyle a activite antipsychotique
WO2003075921A3 (fr) * 2002-03-05 2003-12-04 Transtech Pharma Inc Derives de l'azole et derives bicycliques fusionnes de l'azole, agents therapeutiques
US8580833B2 (en) 2009-09-30 2013-11-12 Transtech Pharma, Inc. Substituted imidazole derivatives and methods of use thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0237781A2 (fr) * 1986-02-13 1987-09-23 Warner-Lambert Company Composés phényl(ou hétérocycle)tétrahydropyridyl(ou pipérazinyl)alkoxy benzohétérocyclique utilisés comme antipsychotiques
EP0707007A1 (fr) * 1994-10-14 1996-04-17 MERCK PATENT GmbH Dérivés d'amino(thio)éther agissant sur le système nerveux central
WO1997023216A1 (fr) * 1995-12-22 1997-07-03 Warner-Lambert Company Analogues de piperidine a substitution en position 4 et utilisation de ces derniers en tant qu'antagonistes selectivement actifs contre les sous-types du recepteur de nmda
WO1998008817A1 (fr) * 1996-08-27 1998-03-05 American Home Products Corporation 4-aminoethoxy indoles utilises en tant qu'agonistes du recepteur d2 de la dopamine et en tant que ligands des recepteurs 5ht¿1a?

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0237781A2 (fr) * 1986-02-13 1987-09-23 Warner-Lambert Company Composés phényl(ou hétérocycle)tétrahydropyridyl(ou pipérazinyl)alkoxy benzohétérocyclique utilisés comme antipsychotiques
EP0707007A1 (fr) * 1994-10-14 1996-04-17 MERCK PATENT GmbH Dérivés d'amino(thio)éther agissant sur le système nerveux central
WO1997023216A1 (fr) * 1995-12-22 1997-07-03 Warner-Lambert Company Analogues de piperidine a substitution en position 4 et utilisation de ces derniers en tant qu'antagonistes selectivement actifs contre les sous-types du recepteur de nmda
WO1998008817A1 (fr) * 1996-08-27 1998-03-05 American Home Products Corporation 4-aminoethoxy indoles utilises en tant qu'agonistes du recepteur d2 de la dopamine et en tant que ligands des recepteurs 5ht¿1a?

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JAEN J.C. ET AL.: "Dopamine autoreceptor agonists as potential antipsychotics. 1. (Aminoalkoxy)anilines", JOURNAL OF MEDICINAL CHEMISTRY, vol. 31, no. 8, August 1988 (1988-08-01), pages 1621 - 1625, XP000674393 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003008419A1 (fr) * 2001-07-20 2003-01-30 Wyeth Derives de 2-(aminomethyl)-tetrahydro-9-oxa-1,3-diaza-cyclopenta[a]naphtalenyle a activite antipsychotique
US6541502B1 (en) 2001-07-20 2003-04-01 Wyeth 2-(aminomethyl)-tetrahydro-9-oxa-1,3-diaza-cyclopenta[a]-naphthalenyl derivatives with antipsychotic activity
WO2003075921A3 (fr) * 2002-03-05 2003-12-04 Transtech Pharma Inc Derives de l'azole et derives bicycliques fusionnes de l'azole, agents therapeutiques
US7361678B2 (en) 2002-03-05 2008-04-22 Transtech Pharma, Inc. Azole derivatives and fused bicyclic azole derivatives as therapeutic agents
US7714013B2 (en) 2002-03-05 2010-05-11 Transtech Pharma, Inc. Azole derivatives and fused bicyclic azole derivatives as therapeutic agents
US7737285B2 (en) 2002-03-05 2010-06-15 Transtech Pharma, Inc. Azole derivatives and fused bicyclic azole derivatives as therapeutic agents
US8580833B2 (en) 2009-09-30 2013-11-12 Transtech Pharma, Inc. Substituted imidazole derivatives and methods of use thereof
US9598375B2 (en) 2009-09-30 2017-03-21 Vtv Therapeutics Llc Substituted imidazole derivatives and methods of use thereof
US10363241B2 (en) 2009-09-30 2019-07-30 Vtv Therapeutics Llc Substituted imidazole derivatives and methods of use thereof

Also Published As

Publication number Publication date
BR9807701A (pt) 2000-05-02
CA2278700A1 (fr) 1998-08-20
IL131158A0 (en) 2001-01-28
TW513415B (en) 2002-12-11
AU5915398A (en) 1998-09-08
ZA981309B (en) 1999-08-17
HUP0001302A3 (en) 2001-07-30
AU746717B2 (en) 2002-05-02
EP0973749A1 (fr) 2000-01-26
NZ336969A (en) 2001-03-30
HUP0001302A2 (hu) 2001-05-28
AR011136A1 (es) 2000-08-02
KR20000071129A (ko) 2000-11-25
CN1252793A (zh) 2000-05-10
JP2001509814A (ja) 2001-07-24

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