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WO1995006037A1 - Nouveaux derives d'imidazoles a activite agoniste ou antagoniste du recepteur h3 a l'histamine - Google Patents

Nouveaux derives d'imidazoles a activite agoniste ou antagoniste du recepteur h3 a l'histamine Download PDF

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Publication number
WO1995006037A1
WO1995006037A1 PCT/NL1994/000206 NL9400206W WO9506037A1 WO 1995006037 A1 WO1995006037 A1 WO 1995006037A1 NL 9400206 W NL9400206 W NL 9400206W WO 9506037 A1 WO9506037 A1 WO 9506037A1
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WO
WIPO (PCT)
Prior art keywords
formula
group
aryl
imidazole
alkyl
Prior art date
Application number
PCT/NL1994/000206
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English (en)
Inventor
Roelant Christiaan Vollinga
Wiro Michaël Petrus Bernardus MENGE
Hendrik Timmerman
Original Assignee
Vrije Universiteit
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 NL9302045A external-priority patent/NL9302045A/nl
Application filed by Vrije Universiteit filed Critical Vrije Universiteit
Priority to AU78238/94A priority Critical patent/AU7823894A/en
Publication of WO1995006037A1 publication Critical patent/WO1995006037A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

Definitions

  • the invention relates to novel imidazole derivatives having pharmacological activity.
  • the invention is in particular directed to novel imidazole derivatives having agonistic or antagonistic activity on the histamine H 3 receptor. More in particular the invention concerns 4- and 5-substituted aminoalkyl imidazoles and their derivatives.
  • the invention further relates to the synthesis of such compounds, pharmaceutical compositions comprising such compounds or pharmacological acceptable salts thereof, and the use of the compounds as agents having biological activity, as agents with agonistic or antagonistic activity on the histamine H 3 receptor or for preparing a pharmaceutical composition.
  • the histamine H 3 receptor is a presynaptic receptor, located in both the central and peripheral nervous system, the skin and in several organs such as the lung, the intestine and probably also in the spleen and the gastro ⁇ intestinal tract. Stimulation of the H 3 receptor leads to inhibition of the release of histamine (autoreceptor) , but also of other neurotransmitters (heteroreceptor) , such as e.g. acetylcholine and serotonine.
  • H 3 receptor can be regarded as a general regulatory system and as a potential target for new therapeutics (Tim erman, J. Med. Che . 33, p. 4-11 (1990) and Schwartz et al., Agents and Actions 30, 1/2, p. 13-23 (1990) ) .
  • Now a group of new imidazole derivatives showing agonistic or antagonistic activity on the H 3 receptor has been identified. These derivatives can be represented by the general formula: wherein the substituents are as defined in claim 1.
  • the imidazole derivatives of the present invention show either antagonistic or agonistic activity on the histamine H 3 -receptor and may therefore be used as the active ingredient of pharmaceutical compositions.
  • R 1 is hydrogen, methyl or ethyl and compounds of the formulas
  • R' is hydrogen, methyl, ethyl. are known to have (ant)agonistic activity on the H 3 -receptor.
  • the present invention comprises both linear and ringstructured compounds, all of which have the i idazole- part in common.
  • the linear compounds have for example one of the formulas
  • Compounds of formula I may be synthesized in general through a process that is analogous to the process as described in Vollinga et al., Reel. Trav. Chim. Pays-Bas, 112, p. 123-125 (1993) .
  • the process preferably comprises C5- lithiation of a 1,2-diprotected imidazole and subsequent treatment with a suitable electrophile.
  • the electrophile may be selected from the group consisting of halogen, aldehyde, keton, nitrile, epoxide or acylhalide. in general compounds of formula I (compounds with
  • R 4 is hydrogen excluded
  • compounds of formula I wherein R 4 represents hydrogen can be prepared from compounds of formula I wherein R 4 represents hydrogen.
  • compounds of formula III can be made from the compounds of formula II by simple addition or condensation reactions e.g. VUF 4613 can be made by the addition of methylisothiocyanate to VUF 4702.
  • 1- chloro-t ⁇ -iodoalkanes can be used as electrophiles.
  • an t)-chloroalkane is introduced on the C5-position of the 1, 2-diprotected imidazole.
  • the chloro group can then be converted into an amino group and the protection groups removed.
  • Other compounds of formula I (excluding the compounds of formula II and III) have been made using aldehydes or ketones as electrophiles with subsequent removal, conversion or elimination of the formed hydroxyl group.
  • imidazole derivatives of the invention are examples of the imidazole derivatives of the invention.
  • VUF 4702 (4 (5) -(5-aminopentyl) -1 H-imidazole dioxalate) shows a particular advantageous antagonistic activity
  • VUF 4708 (4-[ (4 (5) -imidazolyl)methyl]piperidine) is a good agonist.
  • the following examples illustrate the synthesis of compounds of the present invention, but are never intended to limit the scope thereof.
  • VUF 4581 2 cyclohexyl 161.7 ox 252.1401 252.1409
  • VUF 4633 3 i-propyl 146.0 ox 226.127 1 226.1252
  • VUF 4634 3 cyclohexyl 102.2 ox 266.1 572 266. 1565
  • VUF 4687 4 phenylethyl 130.8- 132.2 ox 302.1560 302.1565
  • VUF 4613 5 methyl 1 1 1.0 ox 226.1251 226.1252
  • VUF 4620 5 phenylethyl 1 18.5- 1 19.5 ox 3 16.1716 3 16.1722
  • VUF 4764 4-(1-dimethylsulfamoyl-5-imidazolyl)piperid- 4-ol
  • VUF 4736 1.0 gram was dissolved in methanol, 0.1 gram Pd/C (10%) was added and this mixture was hygrogenated for 16 hours with 20 at . of H 2 in an autoclave. The reaction mixture was filtrated, concentrated and washed with absolute ethanol. The melting point was 260-263°C.
  • VUF 4582 (D 2 0) ⁇ S 2.94-3.03 (m, 2H, imidazole-CH 2 ) , 3.75-3.97 (m, 2H, CH 2 NH) , 7.11-7.57 (m, 6H, phenyl-H and imidazole-5(4)H) , 8.61 (s, 1H, imidazole-2H) ppm.
  • VUF 4584 (D,0) ⁇ 2.66-2.91 (m, 4H, imidazole-CH 2 and CH 2 -phenyl) , 3.32-3.80 (m, 4H, CH 2 NH and CH 2 CH 2 -phenyl) , 7.15 (s, IH, imidazole-5(4)H) , 7.10-7.34 (m, 5H, phenyl-H) , 8.47 (s, IH, imidazole-2H) ppm.
  • VUF 4616 (D ? 0) ⁇ 1.08 (s, 6H, CH 3 ) , 1.28 (m, 2H, (CH 2 CH 2 ) 2 CH 2 ) , 1.57 ( , 4H, (CH 2 CH 2 ) 2 CH 2 ) 2.65 (t, 2H, imidazole-CH 2 ) , 3.32 (m, 2H, CH 2 NH) , 4.00 (m, IH, CH) , 7.13 (s, IH, imidazole-5(4)H) , 8.47 (s, IH, imidazole-2H) ppm.
  • VUF 4636 (D 2 0) ⁇ 1.84 (m, 2H, CH 2 CH 2 NH) , 2.39-2.79 (m, 2H, imidazole-CH 2 ) , 3.30-3.57 (m, 2H, CH 2 NH) , 4.42-4.73 (m, 2H, CH 2 ⁇ phenyl) , 7.10 (s, IH, imidazole-5(4)H) , 7.29 ( , 5H, phenyl-H) , 8.47 (s, IH, imidazole-2H) ppm.
  • VUF 4684 (DMSO-d,) ⁇ 1.00-1.95 (m, 14H, CH 2 CH 2 + cyclohexyl-CH 2 ) , 2.64 ( , 2H, imidazole-CH 2 ) , 3.37 ( , 2H, CH 2 NH) , 3.93 (m, IH, CH 3 ) , 7.20 (s, IH, imidazole-5(4)H) , 7.28-7.62 (m, 4H, NH + C0 2 H) , 8.50 (s, IH, imidazole-2H) ppm.
  • VUF 4685 (D,0) ⁇ 1.59 (m, 4H, CH 2 CH 2 ) , 2.70 (t, 2H, imidazole-CH 2 ) , 3.49 ( , 2H, CH 2 NH) , 7.31 (m, 6H, imidazole-5 (4 ) H + phenyl-H) , 8.50 (s, IH, imidazole-2H) ppm.
  • VUF 4765 (D 2 0) ⁇ 1.98-2.31 (m, 4H, CH 2 CH 2 ⁇ H) , 2.52 (s, 6H, (CH 3 ) 2 N) , 3.16-3.42 (m, 5H, CH 2 CH 2 NH + CHOH) , 7.17 (s, IH, imidazole-5H) , 7.87 (s, IH, imidazole-2H) ppm.
  • the agonistic and antagonistic activities on the histamine H 3 receptor of the various compounds were determined with a test system, described in Vollinga et al., Meth. Find. Clin. Exp. Pharmacol., 14(10), p. 747-751 (1992) .
  • pD 2 is the negative value of the concentration of the test compound at which 50% agonistic activity was measured.
  • pA 2 is the negative logarithm of the concentration of the testcompound at which the concentration of the agonist had to be doubled to obtain the same effect as obtained when the antagonist was absent.
  • compositions comprising compounds of formula I as the active ingredient for therapeutically influencing the human and animal histaminergic system have the form of powders, suspensions, solutions, sprays, emulsions, unguents or creams and can be used for local application, intranasal, rectal, vaginal and also for oral or parenteral (intravenous, intradermal, intramuscular, intrathecal etc.) administration.
  • Such compositions can be prepared by combining (i.e.
  • the concentration of the active ingredient in a pharmaceutical composition can vary between 0.1% and 100%, depending on the nature of the influence and the method of administration.
  • the dose of the active ingredient that is administered can further be varied between 0.1 mg and 100 mg per kg bodyweight. Table 2. Antagonistic activity
  • VUF 4619 7.7 VUF 4620 . 7.5
  • VUF 4733 6.0
  • VUF 4734 6.0

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Nouveaux dérivés d'imidazoles répondant à la formule (I) et présentant une activité agoniste ou antagoniste du récepteur H3 à l'histamine. Plus particulièrement, il s'agit d'imidazoles d'aminoalkyle substitués en position 4 ou 5, et de leurs dérivés. On a également prévu la synthèse de ces composés, des compositions pharmaceutiques comportant lesdits composés ou leurs sels pharmacologiques, et l'utilisation des composés comme agents à activité biologique dirigée sur le récepteur H3 à l'histamine, ou leur application à la préparation d'une composition pharmaceutique.
PCT/NL1994/000206 1993-08-27 1994-08-29 Nouveaux derives d'imidazoles a activite agoniste ou antagoniste du recepteur h3 a l'histamine WO1995006037A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU78238/94A AU7823894A (en) 1993-08-27 1994-08-29 New imidazole derivatives having agonistic or antagonistic activity on the histamine h3 receptor

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP93202528.1 1993-08-27
EP93202528 1993-08-27
NL9302045A NL9302045A (nl) 1993-08-27 1993-11-25 Nieuwe imidazoolafgeleide met agonistische of antagonistische activiteit op de histamine H3-receptor.
NL9302045 1993-11-25

Publications (1)

Publication Number Publication Date
WO1995006037A1 true WO1995006037A1 (fr) 1995-03-02

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AU (1) AU7823894A (fr)
WO (1) WO1995006037A1 (fr)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2732017A1 (fr) * 1995-03-21 1996-09-27 Inst Nat Sante Rech Med Nouveaux derives de l'imidazole antagonistes et/ou agonistes du recepteur h3 de l'histamine, leur preparation et leurs applications therapeutiques
WO1997029092A1 (fr) * 1996-02-09 1997-08-14 James Black Foundation Limited Ligands du recepteur de l'histamine h¿3?
WO1999005115A1 (fr) * 1997-07-25 1999-02-04 James Black Foundation Limited Derives substitues de l'imizadole et leur utilisation comme ligands du recepteur h3 de l'histamine
WO1999005141A1 (fr) * 1997-07-25 1999-02-04 James Black Foundation Limited Ligands du recepteur h3 de l'histamine
WO1999024421A1 (fr) * 1997-11-07 1999-05-20 Schering Corporation Imidazoylalkyle substitue par un noyau heterocyclique a cinq, six ou sept chainons contenant un atome d'azote
US5990147A (en) * 1997-11-07 1999-11-23 Schering Corporation H3 receptor ligands of the phenyl-alkyl-imidazoles type
US6034251A (en) * 1997-11-07 2000-03-07 Schering Corporation Phenyl-alkyl-imidazoles
US6100279A (en) * 1998-11-05 2000-08-08 Schering Corporation Imidazoylalkyl substituted with a five, six or seven membered heterocyclic ring containing one nitrogen atom
US6417218B1 (en) 1999-01-18 2002-07-09 Novo Nordisk A/S Substituted imidazoles, their preparation and use
US6437147B1 (en) 2000-03-17 2002-08-20 Novo Nordisk Imidazole compounds
FR2827863A1 (fr) * 2001-07-27 2003-01-31 Sanofi Synthelabo Derives d'aminoalkylimidazole, leur preparation et leur utilisation en therapeutique
EP1311477A1 (fr) * 2000-08-21 2003-05-21 Pacific Corporation Nouveaux derives d'acide thiocarbamique et compositions pharmaceutiques contenant lesdits derives
US6610721B2 (en) 2000-03-17 2003-08-26 Novo Nordisk A/S Imidazo heterocyclic compounds
EP1477487A1 (fr) * 2002-02-21 2004-11-17 Azwell Inc. Amelioration apportee a la production de derives d'imidazole et de nouveaux intermediaires de ces derives
US6908926B1 (en) 1999-04-16 2005-06-21 Novo Nordisk A/S Substituted imidazoles, their preparation and use
US8017646B2 (en) 2005-04-29 2011-09-13 Bioprojet Histamine H3-receptor ligands and their therapeutic application
US8044052B2 (en) 2006-10-18 2011-10-25 Pfizer Inc. Biaryl ether urea compounds
US8076329B2 (en) 2005-04-29 2011-12-13 Bioprojet Histamine H3-receptor ligands and their therapeutic applications
JP2012508249A (ja) * 2008-11-06 2012-04-05 ムスク ファウンデーション フォー リサーチ デベロップメント 酸性セラミダーゼのリソソーム親和性阻害剤
US8431575B2 (en) 2010-02-18 2013-04-30 Transtech Pharma, Inc. Phenyl-heteroaryl derivatives and methods of use thereof
US8486947B2 (en) 2005-04-01 2013-07-16 Bioprojet Treatment of Parkinson's disease, obstructive sleep apnea, dementia with Lewy bodies, vascular dementia with non-imidazole alkylamines histamine H3-receptor ligands
WO2013151982A1 (fr) 2012-04-03 2013-10-10 Arena Pharmaceuticals, Inc. Méthodes et composés utiles pour traiter le prurit, et procédés d'identification desdits composés
US10633336B2 (en) 2014-12-19 2020-04-28 The Broad Institute, Inc. Dopamine D2 receptor ligands
US10752588B2 (en) 2014-12-19 2020-08-25 The Broad Institute, Inc. Dopamine D2 receptor ligands

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GB1305548A (fr) * 1969-10-29 1973-02-07
EP0197840A1 (fr) * 1985-03-26 1986-10-15 Institut National De La Sante Et De La Recherche Medicale (Inserm) (Imidazolyl-4) piperidines, leur préparation et leur application en thérapeutique
WO1993012107A1 (fr) * 1991-12-18 1993-06-24 Schering Corporation Imidazoylalkyle substitue par un cycle heterocyclique contenant de l'azote a six elements

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GB1305548A (fr) * 1969-10-29 1973-02-07
DE2131625A1 (de) * 1970-06-25 1971-12-30 Smith Kline French Lab Thioharnstoffderivate,Verfahren zu ihrer Herstellung und Arzneipraeparate
EP0197840A1 (fr) * 1985-03-26 1986-10-15 Institut National De La Sante Et De La Recherche Medicale (Inserm) (Imidazolyl-4) piperidines, leur préparation et leur application en thérapeutique
WO1993012107A1 (fr) * 1991-12-18 1993-06-24 Schering Corporation Imidazoylalkyle substitue par un cycle heterocyclique contenant de l'azote a six elements

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F. BORDI ET AL: "Synthesis and binding assays of H3-receptor ligands", FARMACO, vol. 47, no. 11, 1992, PAVIA IT, pages 1343 - 1365 *

Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996029315A3 (fr) * 1995-03-21 1996-10-24 Inst Nat Sante Rech Med Derives d'imidazole (ant)agonistes du recepteur h3 de l'histamine
FR2732017A1 (fr) * 1995-03-21 1996-09-27 Inst Nat Sante Rech Med Nouveaux derives de l'imidazole antagonistes et/ou agonistes du recepteur h3 de l'histamine, leur preparation et leurs applications therapeutiques
US6080871A (en) * 1996-02-09 2000-06-27 James Black Foundation Limited Sulfonamides and sulfamides as H3 receptor antagonists
WO1997029092A1 (fr) * 1996-02-09 1997-08-14 James Black Foundation Limited Ligands du recepteur de l'histamine h¿3?
US6407132B1 (en) 1997-07-25 2002-06-18 James Black Foundation Limited Substituted imidazole derivatives and their use as histamine H3 receptor ligands
GB2341861B (en) * 1997-07-25 2001-08-15 Black James Foundation Substituted imidazole derivatives and their use as histamine H3 receptor ligands
WO1999005115A1 (fr) * 1997-07-25 1999-02-04 James Black Foundation Limited Derives substitues de l'imizadole et leur utilisation comme ligands du recepteur h3 de l'histamine
GB2341862B (en) * 1997-07-25 2001-08-22 Black James Foundation Histamine H3 receptor ligands
GB2341862A (en) * 1997-07-25 2000-03-29 Black James Foundation Histamine H3 receptor ligands
GB2341861A (en) * 1997-07-25 2000-03-29 Black James Foundation Substituted imidazole derivatives and their use as histamine H 3 receptor ligands
WO1999005141A1 (fr) * 1997-07-25 1999-02-04 James Black Foundation Limited Ligands du recepteur h3 de l'histamine
US6159994A (en) * 1997-07-25 2000-12-12 James Black Foundation Histamine H3 receptor ligands
WO1999024421A1 (fr) * 1997-11-07 1999-05-20 Schering Corporation Imidazoylalkyle substitue par un noyau heterocyclique a cinq, six ou sept chainons contenant un atome d'azote
US6034251A (en) * 1997-11-07 2000-03-07 Schering Corporation Phenyl-alkyl-imidazoles
US5990147A (en) * 1997-11-07 1999-11-23 Schering Corporation H3 receptor ligands of the phenyl-alkyl-imidazoles type
US6100279A (en) * 1998-11-05 2000-08-08 Schering Corporation Imidazoylalkyl substituted with a five, six or seven membered heterocyclic ring containing one nitrogen atom
US6417218B1 (en) 1999-01-18 2002-07-09 Novo Nordisk A/S Substituted imidazoles, their preparation and use
US6908926B1 (en) 1999-04-16 2005-06-21 Novo Nordisk A/S Substituted imidazoles, their preparation and use
US6610721B2 (en) 2000-03-17 2003-08-26 Novo Nordisk A/S Imidazo heterocyclic compounds
US6437147B1 (en) 2000-03-17 2002-08-20 Novo Nordisk Imidazole compounds
US6756384B2 (en) 2000-03-17 2004-06-29 Novo Nordisk A/S Imidazole compounds
EP1311477A1 (fr) * 2000-08-21 2003-05-21 Pacific Corporation Nouveaux derives d'acide thiocarbamique et compositions pharmaceutiques contenant lesdits derives
EP1311477A4 (fr) * 2000-08-21 2005-01-12 Pacific Corp Nouveaux derives d'acide thiocarbamique et compositions pharmaceutiques contenant lesdits derives
WO2003011856A1 (fr) * 2001-07-27 2003-02-13 Sanofi-Synthelabo Derives d'aminoalkylimidazole, leur preparation et leur utilisation en therapeutique
FR2827863A1 (fr) * 2001-07-27 2003-01-31 Sanofi Synthelabo Derives d'aminoalkylimidazole, leur preparation et leur utilisation en therapeutique
EP1477487A1 (fr) * 2002-02-21 2004-11-17 Azwell Inc. Amelioration apportee a la production de derives d'imidazole et de nouveaux intermediaires de ces derives
US6951944B2 (en) 2002-02-21 2005-10-04 Azwell Inc. Production of imidazole derivatives and novel intermediates of the derivatives
EP1477487A4 (fr) * 2002-02-21 2006-05-03 Azwell Inc Amelioration apportee a la production de derives d'imidazole et de nouveaux intermediaires de ces derives
US8486947B2 (en) 2005-04-01 2013-07-16 Bioprojet Treatment of Parkinson's disease, obstructive sleep apnea, dementia with Lewy bodies, vascular dementia with non-imidazole alkylamines histamine H3-receptor ligands
US8076329B2 (en) 2005-04-29 2011-12-13 Bioprojet Histamine H3-receptor ligands and their therapeutic applications
US8017646B2 (en) 2005-04-29 2011-09-13 Bioprojet Histamine H3-receptor ligands and their therapeutic application
US8044052B2 (en) 2006-10-18 2011-10-25 Pfizer Inc. Biaryl ether urea compounds
JP2012508249A (ja) * 2008-11-06 2012-04-05 ムスク ファウンデーション フォー リサーチ デベロップメント 酸性セラミダーゼのリソソーム親和性阻害剤
US8431575B2 (en) 2010-02-18 2013-04-30 Transtech Pharma, Inc. Phenyl-heteroaryl derivatives and methods of use thereof
US8741900B2 (en) 2010-02-18 2014-06-03 Transtech Pharma, Llc Phenyl-heteroaryl derivatives and methods of use thereof
US9045461B2 (en) 2010-02-18 2015-06-02 Transtech Pharma, Llc Phenyl-heteroaryl derivatives and methods of use thereof
WO2013151982A1 (fr) 2012-04-03 2013-10-10 Arena Pharmaceuticals, Inc. Méthodes et composés utiles pour traiter le prurit, et procédés d'identification desdits composés
US10633336B2 (en) 2014-12-19 2020-04-28 The Broad Institute, Inc. Dopamine D2 receptor ligands
US10752588B2 (en) 2014-12-19 2020-08-25 The Broad Institute, Inc. Dopamine D2 receptor ligands
US11498896B2 (en) 2014-12-19 2022-11-15 The Broad Institute, Inc. Dopamine D2 receptor ligands

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