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WO2004058259A1 - Banque de composes contenant des derives de n-(aminocarbonyl)-piperidine-4-carboxamide, capables de se fixer aux recepteurs couples a la proteine g - Google Patents

Banque de composes contenant des derives de n-(aminocarbonyl)-piperidine-4-carboxamide, capables de se fixer aux recepteurs couples a la proteine g Download PDF

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Publication number
WO2004058259A1
WO2004058259A1 PCT/GB2003/005656 GB0305656W WO2004058259A1 WO 2004058259 A1 WO2004058259 A1 WO 2004058259A1 GB 0305656 W GB0305656 W GB 0305656W WO 2004058259 A1 WO2004058259 A1 WO 2004058259A1
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WIPO (PCT)
Prior art keywords
compounds
library
compound
receptors
piperidine
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PCT/GB2003/005656
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English (en)
Inventor
Terence Ward
Roger Crossley
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Biofocus Plc
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 Biofocus Plc filed Critical Biofocus Plc
Priority to AU2003290337A priority Critical patent/AU2003290337A1/en
Publication of WO2004058259A1 publication Critical patent/WO2004058259A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4747—Quinolines; Isoquinolines spiro-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic 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
    • C07D413/12—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 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
    • C07D471/04—Ortho-condensed systems
    • 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
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/08—Liquid phase synthesis, i.e. wherein all library building blocks are in liquid phase or in solution during library creation; Particular methods of cleavage from the liquid support

Definitions

  • the present invention relates to compounds capable of binding to G-protein coupled receptors.
  • libraries of compounds are provided for use in screening programmes against GPCR targets as well as the individual compounds for use in hit to lead and lead optimisation projects and similar stages in the drug discovery process .
  • the method also provides methods for making compounds and libraries.
  • Screening libraries are commonly collections of compounds from several sources. As a result, they typically contain compounds synthesised as a part of previous projects in the history of a company. With regard to drug discovery, these collections will be drug-like but are likely to be limited in scope and will be directed to certain areas of a particular project. It has been the common practice of many pharmaceutical companies in recent times to augment the collections by purchasing either single compounds from vendors or by contracting the synthesis of combinatorial libraries of compounds. The singly purchased compounds may have been selected to fill in areas of compound space poorly represented in the compound collections .
  • Combinatorial libraries are typically synthesised around well- performing chemistries with some design based on producing 'diversity' in compound space.
  • a complementary approach, and one that is increasingly preferred, is to screen focused libraries against the target of choice. Focused libraries are becoming of increasing importance in their ability to generate hits capable of rapid expansion in many areas including GPCRs . Such libraries are slightly more expensive to prepare but have attributes of reliability, reproducibility and provide a considerably higher hit rate: typically 10-100 fold and above compared with random screening. They are, however, very difficult to design and their efficiency relates directly to the amount of effort that has gone into the design. Using focused libraries, it is usually possible to get a number of hits in the low micromolar and below range. As there is a defined set of compounds there is the potential to observe indications of SAR in a chemical series and progress the chemistry efficiently.
  • GPCRs G-protein-coupled receptors
  • the rhodopsin receptor is somewhat unusual in its interactions with its ligand and is not used as a drug target. Nevertheless, the overall three dimensional arrangement can be deduced from the X-ray and is in accordance with previous work based upon bacteriorhodopsin receptor which is not G-protein-coupled.
  • GPCRs are most often characterised by sequence homology as being comprised of several sub-families. Most attention currently is directed towards Family A receptors as being the most tractable class historically and also the one with the most potential targets .
  • Family A comprises about 300 receptors that are potential drug targets, approximately half of which have known ligands and the rest, the so-called orphan receptors.
  • the group of druggable receptors is composed essentially of two types: those whose natural ligand interacts wholly within the transmembrane domain, such as the aminergic, nucleotide-like, prostaglandin receptors, etc. and those peptide liganded receptors, which have a large part of their interactions in the extracellular region and which may insert a peptide loop or tail into the transmembrane region to effect signal transduction. Examples of this class are angiotensin, cholecystokinin and opioid receptors .
  • the focused library provided herein is designed to interact with a range of the family A receptors.
  • Each library is a defined set of compounds which will enhance the probability of finding a small molecule which will interact with one or more type of GPCR receptor.
  • focused libraries can be provided having compounds which will interact with aminergic GPCRs, and peptidic GPCRs requiring an obligatory positive charge in ligands, or other types or groups of GPCRs .
  • Focused libraries according to this invention can provide hit rates of 1-13% or more for the requisite predicted GPCRs from both amine- and peptide-liganded classes and with agonists and antagonists .
  • library means a group of compounds which are structurally related by virtue of a core chemical structure (or “scaffold”) but which differ from each other by virtue of permutation of specific substituent groups attached to the scaffold.
  • such a library will consist of or comprise a number of compounds, e.g. as many as about 100, 1000,2000, 3000 or indeed 10,000 compounds.
  • the number of compounds should be sufficient to provide an adequate diversity of related compounds without being so large as to be unduly complex/expensive to produce.
  • the substituent may appear in the compound exactly as shown (i.e. simply covalently bonded to the scaffold) or may be a derivative of the shown chemical formula of the substituent by virtue of use of a reactive group to couple the substituent to the scaffold.
  • the total number of permutations created by the permitted substituents may be a very large number, far greater in magnitude than the actual number of compounds in an actual library.
  • the number of possible compounds for any "virtual" library may well greatly exceed the number of synthesised compounds making up an embodiment of the "real" library.
  • the invention is intended to encompass libraries having all, and a number, which is less than all, of the permitted substitutions represented by compounds therein. It will be appreciated that some specific combinations of permitted substituents may be more or less difficult to synthesise and/or use in a focused library of the invention. This does not detract from the generality of applicability of the invention as described herein. It is to be expected that real libraries will be synthesised from a selected group of permutations/combinations of permitted substituents, taking into consideration factors affecting the intended purpose of the library and its cost and complexity of synthesis.
  • the present invention provides novel focused libraries of compounds .
  • Most of the compounds defined by the permitted substitutions on the scaffolds are also novel compounds per se and the invention is intended to encompass each individual novel compound.
  • Any known compound having a structural formula identical to any one of the compounds covered by the formulae of scaffolds and permitted substitutions described herein is hereby explicitly disclaimed per se.
  • SFGOl Library 1
  • SFGOl is a broad-spectrum library targeted largely at receptors with a requirement for a positively charged amine in their structure activity relationships but also has features that make it a particularly good all round library. It is designed to produce both agonists and antagonists and so is expected to be especially useful in producing ligands for orphan receptors .
  • the central design of the library revolves around an acylurea coupled to a piperidine moiety.
  • a combination of specific motifs R2 and Rl are appended from the central scaffold and are designed to pick up different interactions at a receptor site.
  • the invention provides a compound library comprising or consisting of a set of structurally related compounds of general formula (I) :
  • Rl and R2 are independently hydrogen, optionally substituted alkyl, aryl, heteroaryl or heterocyclyl .
  • R2 & R1 H, Alkyl, aryl, hetero aryl or heterocyclyl
  • the resultant intermediate compound (2) can then be reacted with the intermediate urea compound (3) to form the desired compounds of formula I .
  • the core chemical scaffold is formed at the final stage of this reaction scheme by the reaction of the two intermediate compounds, which have already had the permitted substituents Rl and R2 added to each intermediate compound respectively.
  • the -OH groups may be modified to form leaving groups .
  • aqueous solution was basified with NaHC0 3 and extracted with DCM (3 x 30 ml) , dried (MgS0 4 ) and concentrated under reduced pressure to give a brown liquid (l.OOg, 91%); ⁇ H (270 MHz; CDC1 3 ; Me 4 Si) , 1.69-2.03 (6 H, m) , 2.23-2.32 (4H, m) , 2.78- 2 . 83 (2H, m) , 3 . 68 (3 H, s) ; m/z (APCI ) 158 ( 100% [M+H] + ) , 126 (33 , C 7 H 12 ON) .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Structural Engineering (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne une banque de composés ciblant des récepteurs afin de rechercher une amine à charge positive dans leurs rapports d'activité structurels. Cette banque est conçue pour produire à la fois des agonistes et des antagonistes et s'avère particulièrement utile pour produire des ligands de récepteurs orphelins. Elle est conçue sur la base d'une acylurée couplée à une fraction pipéridine. Une combinaison de motifs spécifiques R2 et R1 est annexée au squelette central et conçue pour recueillir différentes interactions au niveau d'un site récepteur. Cette banque comprend ou consiste en un ensemble de composés à structure apparentée représentés par la formule générale (I).
PCT/GB2003/005656 2002-12-24 2003-12-24 Banque de composes contenant des derives de n-(aminocarbonyl)-piperidine-4-carboxamide, capables de se fixer aux recepteurs couples a la proteine g WO2004058259A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003290337A AU2003290337A1 (en) 2002-12-24 2003-12-24 Compound libraries of n-(aminocarbonyl)-piperidine-4-carboxamide derivatives capable of binding to g-protein coupled receptors

Applications Claiming Priority (2)

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GB0230195.0 2002-12-24
GB0230195A GB0230195D0 (en) 2002-12-24 2002-12-24 Compound Libraries

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WO2004058259A1 true WO2004058259A1 (fr) 2004-07-15

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GB (1) GB0230195D0 (fr)
WO (1) WO2004058259A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005023794A3 (fr) * 2003-09-08 2005-06-02 Biofocus Plc Banques de composes
WO2011038776A1 (fr) * 2009-10-02 2011-04-07 L'oreal Utilisation d'un dérivé d'ester de pipéridine en tant que solvant dans des compositions cosmétiques et compositions cosmétiques comprenant celui-ci

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Publication number Priority date Publication date Assignee Title
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WO1999009024A1 (fr) * 1997-08-14 1999-02-25 Smithkline Beecham Plc Derives de phenyluree et de phenylthiouree utilises en tant qu'antagonistes de hfgan72
EP1083172A1 (fr) * 1998-05-26 2001-03-14 Rimma Iliinichna Ashkinazi Derives n-substitues d'acide 5-oxyiminobarbiturique
WO2001064036A1 (fr) * 2000-02-28 2001-09-07 Uniroyal Chemical Company, Inc. Augmentation du rendement de semences/fruits/fruits a coque de plantes a fleurs
WO2001068604A2 (fr) * 2000-03-14 2001-09-20 Sepracor, Inc. Piperidines 3-substituees comprenant un groupement uree et procedes d'utilisation de ces dernieres
WO2001070182A1 (fr) * 2000-03-22 2001-09-27 Wella Aktiengesellschaft Agent et procede pour la coloration de fibres keratiniques
WO2001098270A2 (fr) * 2000-06-21 2001-12-27 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines utiles comme modulateurs de l'activite du recepteur de chimiokine
WO2002076953A1 (fr) * 2001-03-21 2002-10-03 Warner-Lambert Company Llc Nouveaux derives spirotricycliques et utilisation de ces derives en tant qu'inhibiteurs de la phosphodiesterase-7

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US3684803A (en) * 1967-08-11 1972-08-15 Ciba Geigy Corp 1,4,4-substituted piperidine derivatives
WO1999009024A1 (fr) * 1997-08-14 1999-02-25 Smithkline Beecham Plc Derives de phenyluree et de phenylthiouree utilises en tant qu'antagonistes de hfgan72
EP1083172A1 (fr) * 1998-05-26 2001-03-14 Rimma Iliinichna Ashkinazi Derives n-substitues d'acide 5-oxyiminobarbiturique
WO2001064036A1 (fr) * 2000-02-28 2001-09-07 Uniroyal Chemical Company, Inc. Augmentation du rendement de semences/fruits/fruits a coque de plantes a fleurs
WO2001068604A2 (fr) * 2000-03-14 2001-09-20 Sepracor, Inc. Piperidines 3-substituees comprenant un groupement uree et procedes d'utilisation de ces dernieres
WO2001070182A1 (fr) * 2000-03-22 2001-09-27 Wella Aktiengesellschaft Agent et procede pour la coloration de fibres keratiniques
WO2001098270A2 (fr) * 2000-06-21 2001-12-27 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines utiles comme modulateurs de l'activite du recepteur de chimiokine
WO2002076953A1 (fr) * 2001-03-21 2002-10-03 Warner-Lambert Company Llc Nouveaux derives spirotricycliques et utilisation de ces derives en tant qu'inhibiteurs de la phosphodiesterase-7

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005023794A3 (fr) * 2003-09-08 2005-06-02 Biofocus Plc Banques de composes
WO2011038776A1 (fr) * 2009-10-02 2011-04-07 L'oreal Utilisation d'un dérivé d'ester de pipéridine en tant que solvant dans des compositions cosmétiques et compositions cosmétiques comprenant celui-ci

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AU2003290337A1 (en) 2004-07-22

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