WO2005023794A2 - Compound libraries of 4-carboxamidopiperidine derivatives - Google Patents

Compound libraries of 4-carboxamidopiperidine derivatives Download PDF

Info

Publication number
WO2005023794A2
WO2005023794A2 PCT/GB2004/003850 GB2004003850W WO2005023794A2 WO 2005023794 A2 WO2005023794 A2 WO 2005023794A2 GB 2004003850 W GB2004003850 W GB 2004003850W WO 2005023794 A2 WO2005023794 A2 WO 2005023794A2
Authority
WO
WIPO (PCT)
Prior art keywords
compounds
list
library
compound
arh
Prior art date
Application number
PCT/GB2004/003850
Other languages
French (fr)
Other versions
WO2005023794A3 (en
Inventor
Graham Peter Jones
Jacqueline Anne Macritchie
Martin John Slater
Original Assignee
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
Publication of WO2005023794A2 publication Critical patent/WO2005023794A2/en
Publication of WO2005023794A3 publication Critical patent/WO2005023794A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/622—Forming processes; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/626—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B
    • C04B35/63—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B using additives specially adapted for forming the products, e.g.. binder binders
    • C04B35/632—Organic additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • 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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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.
  • a library of compounds is 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, chole ⁇ ystokinin 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 that will enhance the probability of finding a small molecule that 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.
  • the present invention provides a novel focused library 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. Structural Novelty of Compounds of Library 11
  • Rl is a heterocycle from list 1 and R2 is a substituted phenyl or heterocycle from list 2.
  • Library 11 has been designed to target a group of receptors that recognise a central secondary amide moiety for example the melanocortins, vasopressin receptors and several .of the CC chemokines .
  • the invention provides a compound library comprising or consisting of a set of structurally related compounds of general formula II. (II) wherein;
  • Rl is derived from the list of nitriles given in List 1;
  • R2 is derived from the list of organo-metallic compounds given in List 2;
  • R3 is hydrogen or alkyl
  • R4 is an acyl, sulphonyl, carbamoyl or thiocarbamoyl group derived from Lists 3, 4, 5 and 6.
  • the amines (1) can be prepared by reacting the appropriate nitriles selected from List 1 with organo-metallic compounds selected from List 2.
  • the amines can then be coupled with a commercially available acid (2) in the presence of a suitable coupling reagent to give amides (3) .
  • the amides can then be alkylated with a suitable alkylating agent, where L is a leaving group (for example iodomethane) , in the presence of a strong base to give the N alkylated compounds (4) where R5 is methyl.
  • the tertiary butyloxycarbonyl group can then be removed from (3) and (4) to give the free piperidines (5) where R3 is hydrogen or alkyl .
  • the free piperidines can then be further derivatised by reaction at the secondary nitrogen which can include acylation by reaction with an acid chloride selected from List 3 , reaction with a sulphonyl chloride selected from List 4) , reaction with an isocyanate selected from List 5 or reaction with an isothiocyanate selected from List 6 to give compounds of formula II. These reactions are illustrated below. In each case Y is as defined by Lists 3,4,5 and 6.
  • the tert-butyloxycarbonyl protected piperidine acid (2) (3.43g) was dissolved in dry dichloromethane (25ml) and carbonyl di- imidazole was added. The reaction was stirred for 30 minutes and then a solution of C- (4-Fluoro-phenyl) -C-pridine-2-yl- methylamine (3.03g) in dichloromethane (5ml) was added. The reaction was stirred overnight .
  • the Gilson 215 was used as both auto-sampler and fraction collector.
  • the gradient used was 95% water / 5% acetonitrile (each containing 0.1% formic acid) for 1.5 min to 95% acetonitrile over 6 min then held at 95% acetonitrile for 3.0 min.
  • the solvent mixture was then returned to the initial conditions over 0.25 min.
  • the column was re-equilibrated over 2.5 minutes prior to the next injection.
  • the purification was controlled by Uhipoint software, triggering a threshold collection value monitoring at 240 nm. Collected fractions were analysed by LCMS. The fractions that contained the desired product were concentrated by vacuum centrifugation and the resultant residue dried by freeze- drying.

Abstract

The present invention provides a compound library targeted to receptors that recognise a central secondary amide moiety. The library is designed around an acetamide coupled to a piperidine moiety. A combination of specific motifs R1, R2, R3, and R4 are appended from the central scaffold and are designed to pick up different interactions at a receptor site. The library comprises or consists of a set of structurally related compounds of general formula (II).

Description

COMPOUND LIBRARIES
Introduction
Background
The present invention relates to compounds capable of binding to G-protein coupled receptors. In particular, a library of compounds is 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 .
As part of the process of discovering drugs or agrochemicals it is customary to screen libraries of compounds against biological targets to discover 'Hits' which are then further developed into λLeads' and subsequently drugs or agrochemicals by using the techniques of medicinal chemistry. Accordingly the success or not of a drug or agrochemical discovery project is critically dependent on the quality of the hit and this in turn is dictated by the quality of the screening library.
Technological advances have enabled screening on a very large scale and the screening of hundreds of thousands of compounds at the start of a discovery program is routine. This, however, does entail a significant cost . The hits obtained from such screening efforts are not all of the best quality and often take a large amount of subsequent time and effort in order to get a good lead. It has been estimated that only about 25% of projects actually get to the lead optimisation stage and part of the reason for this is the intractability of hits from high throughput screening.
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.
G-protein-coupled receptors (GPCRs) are very important in the regulation of numerous body processes and a significant proportion of all drugs work by interaction with these receptors. There are several hundred known, many of which are orphans - those receptors that have no established ligands. They fall into a class of 7-transmembrane receptors and there is only one X-ray structure known that of the bovine rhodopsin receptor, and this is at a resolution of 2.8 Angstroms and is thus not suitable for accurate modelling work. In addition, 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, choleσystokinin and opioid receptors . Irrespective of the mode of action of the natural ligand or the GPCR family, the vast majority of drug molecules interact in the all-helical domain of the transmembrane region with exceptions being those mimics of glutamate at the metabotropic glutamate receptor and some peptide therapeutics administered parenterally. In looking for lead molecules for an unexplored or orphan GPCR it therefore makes sense to concentrate on interactions in the transmembrane domain.
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 that will enhance the probability of finding a small molecule that will interact with one or more type of GPCR receptor.
For example, 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 .
Summary of Invention
We provide herein a "focused" library of compounds which will provide "leads" for ligands which bind to Family A G-Protein coupled receptors . In the context of the present invention, "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.
Generally speaking 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.
In the context of the present invention the terms "permitted substituents" and analogous terms are used to refer to defined chemical groups that may be attached to a "scaffold" to provide permutations of the chemical structure of related compounds .
Where the chemical formulae of permitted substituents are shown in this description and claims, 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.
It will be appreciated that 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. In other words, 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.
Even if theoretically permitted, it is currently considered unlikely that any compound would be prepared for inclusion in a focused library if it had either or both of the following properties
(1) molecular weight >700 (2) log p <-3 or >9 (an index of lipophilicity as calculated using commercially available "Chemenlighten 2.8" and "Biobyte" software for the log p calculation) .
The present invention provides a novel focused library 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. Structural Novelty of Compounds of Library 11
Figure imgf000008_0001
0)
Optionally substituted compounds of general formula I are unknown in the literature where Rl is a heterocycle from list 1 and R2 is a substituted phenyl or heterocycle from list 2.
Description of the Invention
Library 11 has been designed to target a group of receptors that recognise a central secondary amide moiety for example the melanocortins, vasopressin receptors and several .of the CC chemokines .
The invention provides a compound library comprising or consisting of a set of structurally related compounds of general formula II.
Figure imgf000009_0001
(II) wherein;
Rl is derived from the list of nitriles given in List 1;
R2 is derived from the list of organo-metallic compounds given in List 2;
R3 is hydrogen or alkyl; and
R4 is an acyl, sulphonyl, carbamoyl or thiocarbamoyl group derived from Lists 3, 4, 5 and 6.
Methods for Synthesising Scaffolds of Library 11
Compounds of formula II can be made according to the following general scheme (Scheme 1) :
CN . MMπgRBrr NaBH R ^R2 R2' (1) NH,
Figure imgf000010_0001
(5) (ID Scheme 1 The amines (1) can be prepared by reacting the appropriate nitriles selected from List 1 with organo-metallic compounds selected from List 2. The amines can then be coupled with a commercially available acid (2) in the presence of a suitable coupling reagent to give amides (3) . The amides can then be alkylated with a suitable alkylating agent, where L is a leaving group (for example iodomethane) , in the presence of a strong base to give the N alkylated compounds (4) where R5 is methyl.
The tertiary butyloxycarbonyl group can then be removed from (3) and (4) to give the free piperidines (5) where R3 is hydrogen or alkyl . The free piperidines can then be further derivatised by reaction at the secondary nitrogen which can include acylation by reaction with an acid chloride selected from List 3 , reaction with a sulphonyl chloride selected from List 4) , reaction with an isocyanate selected from List 5 or reaction with an isothiocyanate selected from List 6 to give compounds of formula II. These reactions are illustrated below. In each case Y is as defined by Lists 3,4,5 and 6.
Figure imgf000012_0001
Figure imgf000012_0002
Other methods for the synthesis of the intermediates will be apparent to the chemist skilled in the art as will be the methods for preparing starting materials and intermediates . The isolated novel compounds were confirmed by IH N.M.R and/or other appropriate methods .
Figure imgf000014_0001
Figure imgf000014_0002
Listl (R1CN)
Figure imgf000015_0001
List 2 (R2MgBr)
Figure imgf000016_0001
Figure imgf000017_0001
List 3 (cont'd)
Figure imgf000018_0001
List 3 (cont'd)
Figure imgf000019_0001
Figure imgf000019_0002
Figure imgf000019_0003
List 3 (Cont'd)
Figure imgf000020_0001
Figure imgf000020_0002
Figure imgf000021_0001
Figure imgf000022_0001
List 4 (Cont'd)
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000023_0003
Figure imgf000024_0001
Figure imgf000024_0002
Figure imgf000024_0003
List 5 (Cont'd)
Figure imgf000025_0001
Figure imgf000025_0002
List 6
Specific examples of compounds of Library 11
Synthesis of C- (5-methyl-pyridin-2-yl) -C-phenyl-methylamine
Figure imgf000026_0001
4-methyl-pyridine-2-carbonitrile (10. g) was dissolved in dry Toluene (300ml) and cooled to 0-5°C. Phenyl-magnesium chloride (55ml of 2M in tetrahydrofuran) was added dropwise over 30 minutes to give a thick creamy precipitate. The reaction was stirred for a further 30 minutes at 5°C then iso butanol (120ml) was added dropwise keeping the temperature below 5°C to give a clear brown solution. The reaction was then treated with sodium borohydride (5.3g) portionwise and the reaction was stirred at room temperature overnight . The reaction was quenched with methanol/water and concentrated in vacuo to remove the toluene . The mixture was extracted with dichloromethane and the organic phase was dried over magnesium sulphate before concentrating in vacuo . Purification was carried out by flash column chromatography on silica eluted with ethyl acetate/triethylamine to give (13.6g; 69% overall yield) of C- (4-methyl-pyridin-2-yl) -C-phenyl methylamine as a brown oil; XΗ NMR (CDC13) : δ = 2.1 (bs, 3H, NH3Cl) , 2.3 (s, 3H, CH3) , 5.2 (s, IH, CH) , 6.9-7.5 (m, 7H, ArH) , 8.4 (nα, IH, ArH) .
Synthesis of 4-{ [ (4-fluoro-phenyl) -pyridin- -yl-methyl] - carbamoyl}-piperidine-l-carboxyliσ acid tert-butyl ester
Figure imgf000027_0001
The tert-butyloxycarbonyl protected piperidine acid (2) (3.43g) was dissolved in dry dichloromethane (25ml) and carbonyl di- imidazole was added. The reaction was stirred for 30 minutes and then a solution of C- (4-Fluoro-phenyl) -C-pridine-2-yl- methylamine (3.03g) in dichloromethane (5ml) was added. The reaction was stirred overnight . The solution was washed with water, dried over magnesium sulphate and concentrated in vacuo to give (6.2g; 100% overall yield) of 4- { [ (4-flouro-phenyl) - pyridin-2-yl-methyl] -carbamoyl}-piperidine-l-carboxylic acid tert-butyl ester as a cream solid; 41 NMR (CDC13) : δ = 1.4 (s, 9H, Bufc) , 1.7 (bm, 2H, 2xCH) , 1.9 (bm, 2H, 2xCH) , 2.4 (bm, IH, CH) , 2.8 (bm, 2H, 2xCH) , 4.1 (bm, 2H, 2xCH) , 6.1 (m, IH, CHNH) , 6.9 ( , IH, ArH) 7.2-7.3 (m, 3H, 3xArH) , 7.6-7.8 (m, 2h, 3xArH) 8.6 (m, IH, NH) . Synthesis of 4-{methyl- [ (3-methyl-ρyridin-2-yl) -o-tolyl- ethyl] -carbamoyl}-piperidine-l-carboxylic acid tert-butyl ester
Figure imgf000028_0001
4-{ [ (3-Methyl-pyridin-2-yl) -o-tolyl-methyl] -carbamoyl}- piperidine-1-carboxylic acid tert-butyl ester (9.1g) was dissolved in dimethylformamide (100ml) at room temperature under nitrogen and sodium hydride (0.87g of 60% in oil) was added portionwise. Stirred for 20 minutes. Iodomethane (3g) was added in one portion and the resulting solution was stirred at room temperature for 4 hours . The reaction was treated with water and extracted with ether. The ether was dried over magnesium sulphate and evaporated in vacuo to give an orange oil which was purified by flash chroma ography to give (9.3g; 98% overall yield) of 4__{Methyl- [ (3 -methyl-pyridin-2-yl) -o- tolyl-methyl] -carbamoyl} -piperidine-1-carboxylic acid tert- butyl ester; 4. NMR (CDC13) : δ= 1.46 (s, 9H, Bufc) , 1.74 (bm, 3H, 3xCH) , 2.08 (s, 3H, CH3) , 2.3 (s, 3H, CH3 ), 2.78 (bm, 3H, 3xCH) , 2.99 (s, 3H, CH3) , 4.12 (bm, 2H, 2xCH) , 6.58 (d, IH, J = 8Hz, NCH) , 6.98 (t, IH, J = 6.4Hz, ArH), 7.02 (s, IH, ArH), 7.08 (m, IH, ArH), 7.2 (m, 2H, ArH), 7.35 (d, IH, J = 9.6Hz, ArH)', 8.38 (s, IH, ArH) Synthesis of piperidine-4-carboxylic acid [ (4-fluoro-phenyl) (3-methyl-pyridin-2-yl) -methyl] -amide
Figure imgf000029_0001
4-{ t (4-Fluoro-phenyl) - (3 -methyl-pyridin-2-yl) -methyl] - carbamoyl} -piperidine-1-carboxylic acid tert butyl ester (11.6g) was dissolved in dichloromethane (100ml) and trifluoroacetic acid (25ml) was added. The solution was stirred for 4 hours and then concentrated in vacuo. Water (100ml) was added and the mixture was basified with sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts were dried over magnesium sulphate and evaporated in vacuo to give (llg; >100% overall yield by weight) of piperidine-4-carboxylic acid [ (4-fluoro-phenyl) - (3- methy-pyridin-2-yl) -methyl] -amide as a colourless glass which was used without further purification; Η NMR (DMS0) : δ = 1.68 (m, 2H, 2xCH) , 1.8 (m, 2H, 2xCH) , 2.3 (s, 3H, CH3) , 2.65 (m, IH, CH) , 2.83 (m, 2H, 2xCH) , 3.25 (m, 2H, 2xCH) , 6.3 (d, IH, J = 4.8Hz, CHN) , 7.1 (t, 2H, J = 12.8Hz, 2xArH) , 7.26 (m, IH, ArH), 7.3 (m, 2H, 2 ArH) , 7.6 (d, IH, J = 9 . 6Hz , ArH), 8.4 (s, IH, Ar) , 8.8 (d, IH, J = 9.6Hz, C0NH) . Synthesis of 1- (3-phenyl-propionyl) -piperidine-4-carboxylic acid (pyridin-2-yl-thiophen-2-yl-methyl) -amide
Figure imgf000030_0001
A solution of Piperidine-4-carboxylic acid (pyridin-2-yl- thiophen-2-yl-methyl) -amide (60mg) in pyridine (0.625ml) was placed in a screw-capped tube and a solution of 3-phenyl- propionyl chloride in dichloromethane (3.5ml) was added in one portion. The tube was capped and shaken for 4 hours. Allowed to stand overnight. Water (4ml) was added and the organic phase was separated, the aqueous phase was extracted with a further 2ml of dichloromethane . The combined organic phases were concentrated in vacuo and the residue was purified by reverse phase chromatography (See appendix 1) to give (59.3mg; 68%overall yield) of 1- (3 -Phenyl-propionyl) -piperidine-4- carboxylic acid(pyridin-2-yl-thiophene-2-yl-methyl) -amide; HPLC (95.4% Rτ = 1.57 minutes); 4ϊ MR (DMS0) : δ=1.6 (bm, 2H, 2xCH) , 1.92 (bm, 2H, 2xCH) , 2.8 (bm, 4H, 4xCH) , 2.98 (t, 2H, J = 8Hz, CH2) , 3.17 (m, IH, CH) , 4.08 (bm, IH, IH) , 4.6 (bm, IH, CH) , 6.56 (d, IH, J = 8.47Hz, CHNH) , 7.01 (s, IH, ArH), 7.15 (m, IH, ArH), 7.32 (m, IH, ArH), 7.45 (m, 4H, 4xAr) , 7.54 (m, IH, ArH), 7.62 (d, IH, J = 5.01Hz, ArH), 7.71 (d, IH, J = 7.87Hz, ArH), 8 . 05 (m, IH , ArH) , 8 . 74 (m, IH , ArH) , 9 . 06 ( d, IH, J = 8 . 5Hz , CONH) .
Synthesis of l-meth.anesulfonyl-piperidine-4-carboxylic acid (pyridin-2-yl-thiophen-2-yl-methyl) -amide
Figure imgf000031_0001
A solution of methane sulphonyl chloride (22.8mg) in dichloromethane (3.5ml) was reacted with Piperidine-4- carboxylic acid (pyridin-2-yl-thiophen-2-yl-methyl) -amide (60mg) in pyridine (0.625ml) as described above to give (44.64mg;
59%overall yield) of l-methanesulphonyl-piperidine-4-carboxylic acid(pyridin-2-yl-thiophen-2-yl-methyl) -amide; HPLC (86.3% Rτ = 1.11 minutes); 4ϊ NMR (DMSO) : δ = 1.81 (m, 2H, 2xCH) , 2.06 (m,
2H, 2xCH) , 2.72 (m, IH, CH) , 2.89 (m, 2H, 2xCH) , 3.04 (s, 3H,
CH3) , 3.82 (m, 2H, 2xCH) , 6.58 (d, IH, J = 8.35Hz, NHCH) , 7.04 (s, IH, ArH), 7.18 (m, IH, ArH), 7.53 ( , IH, ArH), 7.62 (d,
IH, J = 5.07Hz, ArH), 7.7 (m, IH, ArH), 8.03 (t, IH, J = 7.7Hz, ArH), 8.78 (s, IH, ArH), 9.12 (d, IH, J = 11.0Hz, CONH) . Synthesis of piperidine-l,4-diσarboxylic acid 1-phenylamide 4' [ (phenyl-pyridin-2-yl-methyl) -amide]
Figure imgf000032_0001
A solution of phenyl isocyanate (23.8mg) in dichloromethane (3.5ml) was reacted with Piperidine-4-carboxylic acid(phenyl-l- pyridin-2-yl-methyl) -amide (59mg) in pyridine (0.5ml) as described above to give (51mg; 62% overall yield) of piperidine-l,4-dicarboxylic acid l-phenylamide-4- [ (phenyl- pyridin-2-yl-methyl) -amide] ; HPLC (100% Rτ = 1.36 minutes); XH NMR (DMS0) : δ=1.72 (q, 2H, J = 12.61Hz, CH2) , 1.95 (s, 2H, CH2) , 2.86 (m, IH CH) , 3.01 ( , 2H, CH2) , 4.36 (d, 2H, J = 12.13, CH2) , 6.34 (d, IH, J = 8.56Hz, CHNH) , 7.11 (t, IH, J = 8.6Hz, ArH), 7.37-7.58 (m, 8H, 8xArH) , 7.68 (m, 2H, 2xArH) , 7.98 (m, IH, ArH), 8.64 (s, IH, ArH), 8.75 (d, IH, J = 5Hz, ArH), 9.0 (d, IH, J = 8.66Hz, CONH) .
Appendix 1
Analytical HPLC Conditions
Conditions Detection
Column: Column Phenomenex LUNA UV detection - diode Ci8(2); 5μm; 30x4.6mm with 5mm guard. array range 210-350 Gradient: (percent acetonitrile in nm. water) : 20-100 over 2.5 minutes then Electrospray 100 for 1 minute followed by 20 for one ionisation: minute. Formic acid was present at 0.1% Cone voltage: 30 V. throughout . Cone temperature: 20 Flow rate: 2 ml/min at 400-bar °C. pressure. Source temperature Temperature : 30 °C . 150 °C. Injection volume: 5 μL partial loop. RF lens voltage : 0.0 V. Ion energy: 0.5 eV. Multiplier: 650 V.
Preparative HPLC Conditions
All compounds were purified by reverse phase HPLC using a Gilson preparative HPLC system (321 pump, diode array detector, 215 liquid handler) and a Luna lOμm Cm 100 x 21mm column. A flow rate of 25 mL/min was used.
The Gilson 215 was used as both auto-sampler and fraction collector.
The gradient used was 95% water / 5% acetonitrile (each containing 0.1% formic acid) for 1.5 min to 95% acetonitrile over 6 min then held at 95% acetonitrile for 3.0 min. The solvent mixture was then returned to the initial conditions over 0.25 min. The column was re-equilibrated over 2.5 minutes prior to the next injection.
The purification was controlled by Uhipoint software, triggering a threshold collection value monitoring at 240 nm. Collected fractions were analysed by LCMS. The fractions that contained the desired product were concentrated by vacuum centrifugation and the resultant residue dried by freeze- drying.

Claims

1. A compound library comprising or consisting of a set of structurally related compounds of general formula II :
Figure imgf000035_0001
(II) wherein; the permitted substituents for Rl are derived form the nitriles of List 1; the permitted substituents for R2 are derived from the organo-metallic compounds of List 2; the permitted substituents for R3 are hydrogen or alkyl; and the permitted substituents for R4 are acyl, sulphonyl, carbamoyl or thiocarbamoyl groups derived from Lists 3 , 4 , 5 and 6.
Figure imgf000036_0001
Figure imgf000036_0002
Listl (R1CN)
Figure imgf000037_0001
List 2 (R2MgBr)
Figure imgf000038_0001
Figure imgf000039_0001
List 3 (cont'd)
Figure imgf000040_0001
List 3 (cont'd)
Figure imgf000041_0001
Figure imgf000041_0002
List 3 (Cont'd)
Figure imgf000042_0001
.oγc,
Figure imgf000042_0002
Figure imgf000042_0004
Figure imgf000042_0003
Figure imgf000042_0005
Figure imgf000043_0001
Figure imgf000043_0003
Figure imgf000043_0002
Figure imgf000043_0005
Figure imgf000043_0004
Figure imgf000044_0002
Figure imgf000044_0003
Figure imgf000044_0004
Figure imgf000044_0001
List 4 (Cont'd)
Figure imgf000045_0001
Figure imgf000045_0002
Figure imgf000045_0003
Figure imgf000045_0004
Figure imgf000045_0005
Figure imgf000045_0006
Figure imgf000046_0001
Figure imgf000046_0002
Figure imgf000046_0003
Figure imgf000046_0004
Figure imgf000046_0005
Figure imgf000046_0006
List 5 (Cont'd)
Figure imgf000047_0001
Figure imgf000047_0002
List 6
2. A library according to the claim 1 wherein said library has all or substantially all of the compounds represented therein.
3. A library according to claim 1 or 2 wherein said library has about 100, 1000, 2000, 3000, or 10000 of the compounds represented therein.
4. A method for making a compound library according to claim 1, which method comprises the step of synthesising compounds of formula II according to the following reaction scheme: NaBH4 R1. .R2 R1 R2^ (1) NHn
Figure imgf000048_0001
(5) (ID Scheme 1 wherein Rl, R2, R3 and R4 are as defined in claim 1; R5 is methyl; and L is a leaving group.
5. A method for making a compound library according to claim 4, which method comprises the step of synthesising compounds of formula II according to the following reaction scheme:
Figure imgf000049_0001
(5) wherein Rl, R2, R3 and are as defined in claim 1; and Y is as defined by List 3.
6. A method for making a compound library according to claim 4, which method comprises the step of synthesising compounds of formula II according to the following reaction scheme:
Figure imgf000050_0001
wherein Rl, R2, R3 and R4 are as defined in claim 1; and Y is as defined by Lists 4.
7. A method for making a compound library according to claim 4, which method comprises the step of synthesising compounds of formula II according to the following reaction scheme:
Figure imgf000050_0002
wherein Rl, R2, R3 and R4 are as defined in claim 1; and Y is as defined by List 5.
A method for making a compound library according to claim 4, which method comprises the step of synthesising compounds of formula II according to the following reaction scheme:
Figure imgf000051_0001
wherein Rl, R2, R3 and R4 are as defined in claim 1; and Y is as defined by List 6.
9. Intermediate compounds of formulae (1) to (5), as defined in claim 4, for use in a method according to any of claims 4 to 8 for making a compound library according to any of claims 1 to 3.
10. A compound capable of binding to a G-protein coupled receptor, which compound is selected from compounds represented within a library according to claim 1.
11. A method of making a compound according to claim 10, which method is according to the methods of claims 4 to 8.
12. A compound library comprising or consisting of a set of structurally related compounds, substantially as herein described.
13. A compound capable of binding to a G-protein coupled receptor, substantially as herein described.
PCT/GB2004/003850 2003-09-08 2004-09-08 Compound libraries of 4-carboxamidopiperidine derivatives WO2005023794A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0320983A GB0320983D0 (en) 2003-09-08 2003-09-08 Compound libraries
GB0320983.0 2003-09-08

Publications (2)

Publication Number Publication Date
WO2005023794A2 true WO2005023794A2 (en) 2005-03-17
WO2005023794A3 WO2005023794A3 (en) 2005-06-02

Family

ID=29226682

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2004/003850 WO2005023794A2 (en) 2003-09-08 2004-09-08 Compound libraries of 4-carboxamidopiperidine derivatives

Country Status (2)

Country Link
GB (1) GB0320983D0 (en)
WO (1) WO2005023794A2 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8710043B2 (en) 2011-06-24 2014-04-29 Amgen Inc. TRPM8 antagonists and their use in treatments
US8778941B2 (en) 2011-06-24 2014-07-15 Amgen Inc. TRPM8 antagonists and their use in treatments
US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors
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

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2415063A1 (en) * 1974-03-28 1975-10-16 Bayer Ag Pyridyl alkyl-amidine derivs - hypoglycemics which influence flat metabolism for use in diabetes, hyperlipemia and adiposis
US5516783A (en) * 1992-02-11 1996-05-14 British Biotech Pharmaceuticals Limited 4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonamide derivatives as antagonist of PAF
WO1999003832A1 (en) * 1997-07-14 1999-01-28 Phytera Symbion Aps Piperidine oligomers and combinatorial libraries thereof
WO2000001375A2 (en) * 1998-06-30 2000-01-13 Neuromed Technologies, Inc. Calcium channel blockers
WO2001064632A1 (en) * 2000-03-03 2001-09-07 Aventis Pharma S.A. Azetidine derivatives, preparation thereof and pharmaceutical compositions containing same
WO2002022572A2 (en) * 2000-09-11 2002-03-21 Sepracor, Inc. Ligands for monoamine receptors and transporters, and methods of use thereof (neurotransmission)
WO2002083624A1 (en) * 2001-04-16 2002-10-24 Schering Corporation 3,4-di-substituted cyclobutene-1,2-diones as cxc-chemokine receptor ligands
WO2004058755A2 (en) * 2002-12-24 2004-07-15 Biofocus Plc Compound libraries of imidazo[1,5-a]pyridin-3-yl derivatives and related heterobicycles for targetting compounds capable of binding to g-protein coupled receptors
WO2004058259A1 (en) * 2002-12-24 2004-07-15 Biofocus Plc Compound libraries of n-(aminocarbonyl)-piperidine-4-carboxamide derivatives capable of binding to g-protein coupled receptors

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2415063A1 (en) * 1974-03-28 1975-10-16 Bayer Ag Pyridyl alkyl-amidine derivs - hypoglycemics which influence flat metabolism for use in diabetes, hyperlipemia and adiposis
US5516783A (en) * 1992-02-11 1996-05-14 British Biotech Pharmaceuticals Limited 4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonamide derivatives as antagonist of PAF
WO1999003832A1 (en) * 1997-07-14 1999-01-28 Phytera Symbion Aps Piperidine oligomers and combinatorial libraries thereof
WO2000001375A2 (en) * 1998-06-30 2000-01-13 Neuromed Technologies, Inc. Calcium channel blockers
WO2001064632A1 (en) * 2000-03-03 2001-09-07 Aventis Pharma S.A. Azetidine derivatives, preparation thereof and pharmaceutical compositions containing same
WO2002022572A2 (en) * 2000-09-11 2002-03-21 Sepracor, Inc. Ligands for monoamine receptors and transporters, and methods of use thereof (neurotransmission)
WO2002083624A1 (en) * 2001-04-16 2002-10-24 Schering Corporation 3,4-di-substituted cyclobutene-1,2-diones as cxc-chemokine receptor ligands
WO2004058755A2 (en) * 2002-12-24 2004-07-15 Biofocus Plc Compound libraries of imidazo[1,5-a]pyridin-3-yl derivatives and related heterobicycles for targetting compounds capable of binding to g-protein coupled receptors
WO2004058259A1 (en) * 2002-12-24 2004-07-15 Biofocus Plc Compound libraries of n-(aminocarbonyl)-piperidine-4-carboxamide derivatives capable of binding to g-protein coupled receptors

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Laborchemikalien und analytische Reagenzien" 1999, FLUKA RIEDEL-DE HAEN , XP002304990 page 235; compound 15518 *
A.K. DUTTA ET AL.: "Structure-Activity Relationship Studies of 4-[2-(Diphenylmethoxy)ethylÜ-1-benzylpiper idine Derivatives and Their N-Analogues: Evaluation of Behavioral Activity of O- and N-Analogues and Their Binding to Monoamine Transporters" J. MED. CHEM., vol. 44, no. 6, 2001, page 937-948, XP002304988 *
E.M. ROBERTS: "Naphthylalkyl Lactamimides as Inhibitos of Blood Platelet Aggregation" J. MED. CHEM., vol. 15, no. 12, 1972, pages 1270-1273, XP002304989 *
K. SHIMADA ET AL.: "Synthesis and Gastric Antisecretory Activity of N-Cyano-N'-(phenyl-pyridinylmethyl)guanidi ne Derivatives" CHEM. PHARM. BULL., vol. 32, no. 12, 1984, pages 4893-4906, XP001203593 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8710043B2 (en) 2011-06-24 2014-04-29 Amgen Inc. TRPM8 antagonists and their use in treatments
US8778941B2 (en) 2011-06-24 2014-07-15 Amgen Inc. TRPM8 antagonists and their use in treatments
US9096527B2 (en) 2011-06-24 2015-08-04 Amgen Inc. TRPM8 antagonists and their use in treatments
US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors
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

Also Published As

Publication number Publication date
WO2005023794A3 (en) 2005-06-02
GB0320983D0 (en) 2003-10-08

Similar Documents

Publication Publication Date Title
AU2004206856B9 (en) Capture compounds, collections thereof and methods for analyzing the proteome and complex compositions
EP0734398B1 (en) Compounds and methods
US6218551B1 (en) Combinatorial hydroxy-amino acid amide libraries
WO2005023794A2 (en) Compound libraries of 4-carboxamidopiperidine derivatives
WO2004058265A1 (en) Compound libraries of 2,3-substituted pyrazine derivatives capable of binding to g-protein coupled receptors
WO2004111056A2 (en) Compound libraries of spiro-benzodioxine-piperidines
EP1192136B1 (en) Oligomers and polymers of cyclic imino carboxylic acids
WO2004058755A2 (en) Compound libraries of imidazo[1,5-a]pyridin-3-yl derivatives and related heterobicycles for targetting compounds capable of binding to g-protein coupled receptors
WO2004058264A1 (en) Compound libraries of 2h-spiro (isoquinoline-1, -piperidine derivatives and related compounds for targetting compounds capable of binding to the g-protein receptor
US6710186B2 (en) Oligomers and polymers of di-substituted cyclic imino carboxylic acids
Ali et al. Imidomethylation of C-nucleophiles using O-phthalimidomethyl trichloroacetimidate and catalytic amounts of TMSOTf
US20040077019A1 (en) Tagging compounds and process for use in aida libraries
WO2004058259A1 (en) Compound libraries of n-(aminocarbonyl)-piperidine-4-carboxamide derivatives capable of binding to g-protein coupled receptors
US5773512A (en) Compounds and methods
Davis et al. Solid‐phase synthesis of a library of functionalized aminodiol scaffolds
AU736264B2 (en) Convergent synthesis of combinatorial library
Shey et al. Liquid phase combinatorial synthesis of benzylpiperazines
Shey et al. Soluble polymer-supported synthesis of N, N-di (Boc)-protected guanidines
Chaturvedi et al. Carbon-carbon bond formation via the Mitsunobu reaction on solid supports
AU2006249219B2 (en) Capture compounds, collections thereof and methods for analyzing the proteome and complex compositions
WO2004058263A1 (en) Compound libraries of 2, 3, 4, 9-tetrahydrospiro (beta-carboline-1, 4 -piperidine) derivatives and related compounds for targetting compounds capable of binding to the g-protein receptor
US20100210474A1 (en) Heterocyclic scaffolds useful for preparation of combinatorial libraries, libraries and methods for preparation thereof
Karskela Solid-Phase Organic Synthesis: Bicyclic Peptides and Purine-Derived Small Molecules
US7038054B1 (en) Diazabicyclononane scaffold for combinatorial synthesis
Mirk et al. Rapid evaluation of suitable substrates with high affinity to artificial caffeine receptors by MS based techniques

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

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

AL Designated countries for regional patents

Kind code of ref document: A2

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

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase