WO2004058263A1 - 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 - Google Patents

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 Download PDF

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WO2004058263A1
WO2004058263A1 PCT/GB2003/005642 GB0305642W WO2004058263A1 WO 2004058263 A1 WO2004058263 A1 WO 2004058263A1 GB 0305642 W GB0305642 W GB 0305642W WO 2004058263 A1 WO2004058263 A1 WO 2004058263A1
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list
compounds
contd
compound
library
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Terence Ward
Roger Crossley
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Biofocus Plc
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Priority to AU2003290326A priority patent/AU2003290326A1/en
Publication of WO2004058263A1 publication Critical patent/WO2004058263A1/en

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    • 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
    • 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
    • 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.
  • SFG02 The design philosophy behind Library 2 (SFG02) revolves around two of the most common recognition features present in GPCRs, that of the interplay of electron-rich rings and basic amines.
  • the spatial arrangements between these functions can be captured in two ways.
  • One is captured in series of spiro-fused piperidines which show propensities to interact with all- helical environments, examples are MK499 (K-channel blocker) , LU 28-179 (s2 ligand) and ibutamoren (growth hormone secretagogue) , and the other is present in a more folded back isoquinoline type arrangement.
  • the library is also designed to extend this recognition site for a subset of compounds to recruit antagonist recognition sites around TM7.
  • the invention provides a compound library comprising or consisting of a set of structurally related compounds of general formulae A, B and C:
  • the spiro compounds are then alkylated on the piperidine nitrogen with an appropriate alkylating agent (R2-#) selected from List 3 wherein # is a leaving group (e.g. halogen or sulphonate) to give compounds of formula A where R is hydrogen.
  • R2-# alkylating agent
  • # is a leaving group (e.g. halogen or sulphonate)
  • Phosphoric acid 85 wt.% in H 2 0, 70.00g was added dropwise to phosphorus pentoxide (70.00g) with constant stirring. After the addition of the acid, the reaction mixture was heated to 200 °C until a clear viscous solution was obtained. The solution was then cooled to room temperature with constant stirring. To this solution was added 2-phenyl acetamide (6.00g, 44.39 mmol) and 1-benzyl-4-piperidone (lO.OOg, 52.84 mmol). The mixture was heated at 105°C for 26hrs. Water was added to the reaction mixture and the acidic solution was neutralized to pH 7 with sodium hydroxide solution.

Abstract

The present invention provides a compound library designed to target the interplay of electron-rich rings and basic amines. The spatial arrangements between these functions can be captured in two ways, one is captured in series of spiro-fused piperidines which show a propensity to interact with all-helical environments, and the other is present in a more folded back isoquinoline type arrangement. In GPCRs the basic function is commonly found to interact with TM3 aspartates and the electron-rich ring often is stabilised by Phe or Tyr and Ser or Thr on TM4 and TM5. The library is also designed to extend this recognition site for a subset of compounds to recruit antagonist recognition sites around TM7. The library comprises or consists of a set of structurally related compounds of general formulae A, B and C.

Description

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
Introduction
Background
The present invention relates to compounds capable of binding to G-protein coupled receptors. In particular, 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.
As part of the process of discovering drugs or agrochemicals it is customary to screen libraries of compounds against biological targets to discover λHits' which are then further developed into Leads' 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 modeling 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, cholecystokinin 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 which will enhance the probability of finding a small molecule which 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 which 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 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. DESCRIPTION OF THE INVENTION
The design philosophy behind Library 2 (SFG02) revolves around two of the most common recognition features present in GPCRs, that of the interplay of electron-rich rings and basic amines. The spatial arrangements between these functions can be captured in two ways. One is captured in series of spiro-fused piperidines which show propensities to interact with all- helical environments, examples are MK499 (K-channel blocker) , LU 28-179 (s2 ligand) and ibutamoren (growth hormone secretagogue) , and the other is present in a more folded back isoquinoline type arrangement.
In GPCRs the basic function is commonly found to interact with TM3 aspartates and the electron-rich ring often is stabilised by Phe or Tyr and Ser or Thr on TM4 and TM5 although such microenvironments are also present in other areas. The library is also designed to extend this recognition site for a subset of compounds to recruit antagonist recognition sites around TM7. The invention provides a compound library comprising or consisting of a set of structurally related compounds of general formulae A, B and C:
Figure imgf000008_0001
A B Structural Novelty of Compounds of Library 2
General Formula A (when nl = n2 = 2)
The following substituents are known for R2 where # = point of attachment but are not permitted in Library 2.
Figure imgf000009_0001
Substitution of the following groups at R2 are known, where # point of attachment, but are not permitted in Library 2:
Figure imgf000009_0002
General Formula A (when nl = 1, n2 = 3)
The following substituents are known for R2 where # = point of attachment, but are not permitted in Library 2.
Figure imgf000009_0003
General Formula A (when nl = 1, n2 = 2)
The following substituents are known for R2 where # = point of attachment, but are not permitted in Library 2.
Figure imgf000010_0001
General Formula B
The compound below is known but not permitted in Library 2 :
Figure imgf000010_0002
General Formula C
The following substituents are known for R6 where # = point of attachment but are not permitted in Library 2.
Figure imgf000010_0003
Methods for Synthesising Scaffolds of Library 2
Compounds of Formula A can be made according to Scheme 1:
Figure imgf000011_0001
A
R2
Figure imgf000011_0002
Scheme 1
(A: R = C(=0)R3)
An appropriately substituted tryptamine derivative (1) selected from List 1 is reacted with an appropriately substituted nitrogen heterocycle (2) selected from List 2 (wherein n = 1, 2 or 3) to give spiro compounds (3) . The spiro compounds are then alkylated on the piperidine nitrogen with an appropriate alkylating agent (R2-#) selected from List 3 wherein # is a leaving group (e.g. halogen or sulphonate) to give compounds of formula A where R is hydrogen. These compounds can then be acylated to give compounds A where R is an acetyl or formyl group.
Compounds of Formula B can be made according to Scheme 2
Figure imgf000012_0001
Figure imgf000012_0002
Scheme 2
An appropriately substituted tryptophol derivative (4) selected from List 4 is reacted with 4-piperidone monohydrate hydrochloride to give the spiro compounds (5) . The spiro compounds are then alkylated on the piperidine nitrogen with an appropriate alkylating agent (R2-#) selected from List 5 where # is a leaving group (e.g. halogen or sulphonate) to give compounds of formula B.
Compounds of Formula C can be made according to Scheme 3
Figure imgf000014_0001
Scheme 3
An appropriately substituted phenylacetonitrile (6) selected from List 6 was reacted with an N protected 4-piperidone (7) . The resultant spiropiperidine structure was deprotected and then alkylated with a reagent from List 7, wherein # is a leaving group, to give compounds of formula C.
It will be apparent to the man skilled in the art that a compound library as herein described may be made from a mixture of compounds of formulae A, B & C, which have been produced according to the methods of Schemes 1, 2, & 3 respectively.
List 1
Figure imgf000016_0002
Figure imgf000016_0001
Figure imgf000016_0003
List 2
Figure imgf000017_0001
Figure imgf000017_0002
List 3
Figure imgf000017_0003
List 3 (Contd)
Figure imgf000018_0001
List 3 (Contd)
Figure imgf000019_0002
Figure imgf000019_0003
Figure imgf000019_0001
Figure imgf000019_0004
Figure imgf000019_0005
List 3 (Contd)
Figure imgf000020_0001
Figure imgf000020_0003
Figure imgf000020_0002
Figure imgf000020_0004
N- -#
*^Λ>
Figure imgf000020_0005
List 3 (Contd)
Figure imgf000021_0001
Figure imgf000021_0002
List 3 (Contd)
Figure imgf000022_0001
Figure imgf000022_0002
Figure imgf000022_0003
List 3 (Contd)
Figure imgf000023_0001
List 4
Figure imgf000023_0002
List 5
Figure imgf000024_0001
Figure imgf000024_0002
List 5 (Contd)
Figure imgf000025_0001
Figure imgf000025_0002
Figure imgf000026_0001
List 5 (Contd)
Figure imgf000027_0001
List 6
Figure imgf000028_0001
Figure imgf000028_0002
Figure imgf000028_0004
Figure imgf000028_0003
List 7
Figure imgf000029_0001
List 7 (Contd)
Figure imgf000030_0001
Figure imgf000030_0002
Figure imgf000030_0003
Figure imgf000030_0004
List 7 (Contd)
Figure imgf000031_0001
List 7 (Contd)
Figure imgf000032_0001
Figure imgf000032_0002
Figure imgf000032_0003
List 7 (Contd)
Figure imgf000033_0001
Figure imgf000033_0002
Specific examples of compounds of formula A
Synthesis of 5-chloro-2/ 3, 4, 5-tefcrahydrospiro/'jS-carJ oline-2, 4 ' ■ piper i dine]
Figure imgf000033_0003
A solution of 5-chlorotryptamine hydrochloride (9.24g, 40.0mmol) and 4-piperidinone monohydrate hydrochloride (6.78g, 44.0mmol) in acetic acid (100ml) was stirred at 100°C for 16hrs . The solution was concentrated under reduced pressure. Dichloromethane (150ml) was added and the suspension filtered, the solid was washed several times with dichloromethane. The solid was dried under reduced pressure to afford 6-chloro- 2,3,4, 9-tetrahydrospiro [β-carboline-1, 1 -piperidine] (14.26g, 99%) as a white solid. HPLC (100%) ; XH NMR (D20) : δH 7.57 (s, 1H, ArH) , 7.42 (d, 1H, J 7.8 Hz, ArH) , 7.23 (d, 1H, J 8.0 Hz, ArH) , 3.74-3.70 ( , 4H, 2x CH2N) , 3.51 (brt, 2H, J 12.5 Hz, CH2) , 3.14-3.11 (m, 2H, CH2N) and 2.73-2.47 (m, 4H, 2x CH2) ; MS (AP; [M+H]+) m/z: 275.9.
Synthesis of 6-chloro-l' - [3-(l-naphthyloxy)propyl] -2,3 ,4,9 tetrahydrospiro [ β-carboline-1,4 ' -piperidine]
Figure imgf000034_0001
To a solution of 6-chloro-2, 3 ,4, 9-tetrahydrospiro [/S-carboline- 1, 4 ' -piperidine] (55.0mg, 0.2mmol) and triethylamine (60mg, 0.6mmol) in isopropanol (0.9ml) and water (0.1ml) was added a solution of methanesulfonic acid 3- (naphthalen-1-yloxy) -propyl ester (56.0mg, 0.2mmol) in dichloromethane (0.5ml). Aqueous IM potassium carbonate solution (0.6ml) was added and the reaction was heated at 80°C for 18hrs. The reaction was evaporated under reduced pressure. The crude product was then dissolved in DMSO (1ml) and purified by preparative HPLC to give 6-chloro-l '- [3- (1-naphthyloxy) propyl] -2,3,4,9 tetrahydrospiro [/3-carboline- 1,4' -piperidine] (21.9mg, 24%) as a colorless solid; HPLC (100%); 1H NMR (CDC13) : δH 8.56 (s, 1H, NH) , 8.26-8.23 (m, 1H, ArH), 7.82-7.76 (m, 1H, ArH), 7.51-7.32 (m, 5H, ArH), 7.18 (d, 1H, J 8.5Hz, ArH), 7.04 (dd, 1H, J 1.9 & 8.5 Hz, ArH), 6.76 (dd, 1H, J 1-1 & 7.2 Hz, ArH), 4.15 (t, 2H, J 6.0 Hz, ArOCH2) , 3.11 (t, 2H, J 5.6 Hz), 2.86-2.44 (m, 8H) , 2.19-2.02 (m, 4H) and 1.78 (d, 2H, J 12.7Hz); 13C NMR (CDC13) : δc 154.5, 141.4, 134.4, 133.8, 128.4, 127.4, 126.4, 125.8, 125.5, 125.1, 124.8, 121.8, 121.6, 120.1, 117.6, 111.7, 108.4, 104.5, 66.2, 55.6, 50.5, 48.8, 38.9, 36.0, 26.8 and 22.9; MS (AP; [M+H] +) m/z: 460.
Synthesis of 6-chloro-2-acetyl -l ' - [3 - (l ~naphthyloxy) propyl] - 2,3, 4,9-tetrahydrospiro[β-carboline-l, 4 ' -piperidine]
Figure imgf000035_0001
To a solution of 6-chloro-l '- [3- (1-naphthyloxy) propyl] -2,3 ,4, 9- tetrahydrospiro [(5-carboline-l, 4 ' -piperidine] (2) (92.0mg,
0.2mmol), in dichloromethane (2ml) was added acetic anhydride (102mg, Immol) , and triethyl amine (lOlmg, Immol) . The mixture was heated at 50°C for 16hrs. The mixture was filtered and evaporated under reduced vacuum. The crude product was then dissolved in dimethyl sulfoxide (1ml) and purified by preparative HPLC to give 6-chloro-2-acetyl-l ' - [3- (1- naphthyloxy) propyl] -2 ,3,4, 9-tetrahydrospiro [/3-carboline-l, 4 ' - piperidine] (lOmg, 10%) as a colorless solid. HPLC (100%) ; MS (AP; [M+H]+) m/z: 502. Specific examples of compounds of formula B
Synthesis of 6 -Fluoro- 1,3, , 9- tetrahydrospiro [pyranol 3, 4 - b] indol-1 -yl) -1 ,4 ' -piperidine]
Figure imgf000036_0001
To a solution of 5-fluorotryptophol (5.8g, 32mmol) in tetrahydrofuran (100ml) was added 4-piperidone monohydrate hydrochloride (4.9g, 32mmol) followed by boron trifluoride diethyl etherate (8ml) . The mixture was stirred for 16 hrs at room temperature under nitrogen. The reaction mixture was stirred at reflux for 4 hrs . The reaction mixture was poured into a mixture of IM sodium hydroxide solution (100ml) and crushed ice (150ml) . The mixture was saturated with sodium chloride and extracted with ether (150ml) , dichloromethane (150ml) and finally ethyl acetate (150ml) . The combined organic phases were concentrated to give 6-chloro-2-acetyl-l ' - [3- (1-naphthyloxy) propyl] -2,3,4, 9-tetrahydrospiro [J-carboline- 1, 4 ' -piperidine] as a brown solid. Purified by triturating with ether (100ml) to give the desired compound (6.2 g,- 74 %) ; HPLC (100 %) ; 1H NMR (CD3OD) : δH 2.06-2.20 (m, 4H, 2 X CH2) , 2.84 (t, J = 5.4 Hz, 2H, CH2) , 3.15-3.36 (m, 4H, 2x CH3) , 6.91- 6.98 (m, 1H, Ar) , 7.16-7.20 (m, 1H, Ar) , 7.34-7.39 (m, 1H, CH2) . MS (APCI (M+H)+) m/e = 261, 302 (M+CH3CN) .
Synthesis of 6- Fluoro - 1 ' ~ (4~tr if luoromethoxy benzyl) -1,3, 4, 9- tetrahydrospiro [pyrano[3 , 4 -b]indol -1 -yl ) -l,4 ' -piperidine]
Figure imgf000037_0001
To a solution of 6-fluoro-l, 3 ,4, 9-tetrahydrospiro [pyrano [3,4- b] indol-1-yl) -1,4 ' -piperidine] (52.0mg, 0.2mmol) and triethylamine (60mg, 0.6mmol) in isopropanol (0.9ml) and water (0.1ml) was added a solution of 4- (trifluoromethoxy) benzyl bromide (51.0mg, 0.2mmol) in dichloromethane (0.5ml). Aqueous IM potassium carbonate solution (0.6ml) was added and the reaction was heated at 80°C for 18hrs. The reaction was evaporated under reduced pressure. The crude product was then dissolved in dimethyl sulfoxide (1ml) and purified by preparative HPLC to give 6-Fluoro-l' - (4-trifluoromethoxy benzyl) -1,3,4, 9-tetrahydrospiro [pyrano [3, 4-b] indol-1-yl) -1,4 ' - piperidine] (28.8mg, 33%) as a colorless solid. HPLC (100%); MS (AP; [M+HD m/z: 435.
Specific examples of compounds of formula C
Synthesis of 1 ' -Benzyl -4H- spiro [ isoquinoline-1, 4 ' -piperidin] -3- one.
Figure imgf000038_0001
Phosphoric acid (85 wt.% in H20, 70.00g) was added dropwise to phosphorus pentoxide (70.00g) with constant stirring. After the addition of the acid, the reaction mixture was heated to 200 °C until a clear viscous solution was obtained. The solution was then cooled to room temperature with constant stirring. To this solution was added 2-phenyl acetamide (6.00g, 44.39 mmol) and 1-benzyl-4-piperidone (lO.OOg, 52.84 mmol). The mixture was heated at 105°C for 26hrs. Water was added to the reaction mixture and the acidic solution was neutralized to pH 7 with sodium hydroxide solution. The mixture was extracted with dichloromethane and the combined extracts were dried with magnesium sulfate and filtered. The solution was concentrated under reduced pressure and the resulting residue was purified by silica chromatography (5% methanol in ethyl acetate) to give 1 ' -Benzyl-4H-spiro [isoquinoline-1, 4 ' -piperidin] -3 -one (10.31g, 76%) as a pale yellow solid. HPLC (98%) ; XH nmr (CDCl3) : δH 7.40-7.25 (m, 8H, ArH), 7.17 (m, 1H, ArH), 6.46 (brs, 1H, NH) , 3.64 (s, 2H, -CH2C0) , 3.60 (s, 2H, -CH2Ph) , 2.95-2.90 (m, 2H) , 2.36-2.19 (m, 4H) , 1.78 (d, 2H, J 11.23 Hz); MS (AP+; [M+H] +) m/z: 307.25.
Synthesis of 4H-Spiro[ isoquinoline-1, 4 ' -piperidin] -3 -one .
Figure imgf000039_0001
To a solution of 1 ' -benzyl-4H-spiro [isoquinoline-1, 4' - piperidin] -3 -one (6) (5.80g, 19 mmol), in methanol (285ml) was added ammonium formate (3.60g, 57.1 mmol) and 5% palladium on activated carbon (1.16g) . The mixture was heated at reflux for 2hrs. The mixture was cooled to room temperature and filtered through a pad of celite. The solution was evaporated under reduced pressure to give 1' -Benzyl-4H-spiro [isoquinoline-1, 4 ' - piperidin] -3 -one (3.82g, 93%) as a colourless solid; HPLC (97%); XH n r (CDC13) : δH 7.39 (d, 1H, J 7.08 Hz, ArH), 7.33- 7.23 (m, 2H, ArH), 7.15 (dd, 1H, J 2.08 & 6.23 Hz, ArH), 6.96 (brs, 1H, NH) , 3.65 (s, 2H, -CH2CO) , 3.12-2.95 (m, 4H) , 2.12 (td, 2H, J 5.21 & 12.94 Hz), 1.98 (brs, 1H, NH) , 1.79 (dd, 2H, J 2.32 & 13.79 Hz); MS (AP+; [M+H] +) m/z: 217.08.
Synthesis of 1' - (4 -Fluoro- benzyl ) -4H- spiro [isoquinoline-1 , 4 ' ■ piperidin] -3 -one .
Figure imgf000039_0002
To a solution of 4H-spiro [isoquinoline-1, 4 ' -piperidin] -3 -one
(7) (43.2mg, 0.2mmol) in isopropanol (1ml) was added a solution 4-fluoro benzyl bromide (37.8mg, 0.2mmol) in dichloromethane
(0.5ml) and IM aqueous sodium carbonate (0.6ml) . The mixture was heated at 80°C for 6hrs . The mixture was then evaporated under reduced pressure and the crude product was dissolved in dimethyl sulfoxide (1ml) . The product was purified by preparative HPLC to give 1' - (4-Fluoro-benzyl) -4H- spiro [isoquinoline-1, 4 ' -piperidin] -3 -one (41.6mg, 43%) as a colourless solid. HPLC (100%); 1H nmr (CDCl3) : δH 7.40-7.23 (m, 5H, ArH), 7.16 (m, IH, ArH), 7.02 (t, 2H, J 8.79 Hz, ArH), 6.44
(brs, IH, NH) , 3.64 (s, 2H, -CH2C0) , 3.55 (s, 2H, -CH2Ph) , 2.92- 2.87 (m, 2H) , 2.34-2.17 (m, 4H) , 1.80-1.70 (m, 2H) ; MS (AP+;
[M+H]+) m/z: 325.23.
Analytical HPLC conditions
Mobile phase.
0.2% TFA/water, ACN
Flow rate 25 ml/min.
Gradient : 85/15 H20 + 0 .2% for 1.5 min.
TFA / ACN 5/95 in 9 . 5 min . for 1.5 min. 85/15 in 0 . 5 min .
Detector: ELS. (approx. 1.5ml/min flow split to Sedex 55 ELSD) Gas (Nitrogen) 2.0 bar
Nebulizer 40°C Column: Waters SymmetryPrep ™ 19mm x
150m x 7mm C18

Claims

Claims
1. A compound library comprising or consisting of a set of structurally related compounds having core chemical structures (scaffolds) of general formulae A, B and C:
Figure imgf000041_0001
Figure imgf000041_0002
wherein the permitted combinations of nl and n2 are; nl =2 and n2 = 2; nl = 2 and n2 = 1; nl = 3 and n2 =
1; the permitted substituents for R are H, acetyl or formyl; the permitted substituents for Rl are derived from
List 1; the permitted substituents for R2 are derived from
List 2; the permitted substituents for R3 are derived from
List 4; the permitted substituents for R4 are derived from
List 5; the permitted substituents for R5 are derived from
List 6; the permitted substituents for R6 are taken from
List 7; and
# = point of attachment where applicable.
List 1
Figure imgf000042_0001
List 1 (Contd)
Figure imgf000043_0001
List 3
Figure imgf000043_0002
List 3 (Contd)
Figure imgf000044_0001
List 3 (Contd)
Figure imgf000045_0002
Figure imgf000045_0003
Figure imgf000045_0001
Figure imgf000045_0004
Figure imgf000045_0005
List 3 (Contd)
Figure imgf000046_0001
Figure imgf000046_0003
Figure imgf000046_0002
Figure imgf000046_0004
#
^^ύ N- -
Figure imgf000046_0005
List 3 (Contd)
Figure imgf000047_0001
Figure imgf000047_0002
List 3 (Contd)
Figure imgf000048_0001
Figure imgf000048_0002
Figure imgf000048_0003
List 3 (Contd)
Figure imgf000049_0001
List 4
Figure imgf000049_0002
List 5
Figure imgf000050_0001
Figure imgf000050_0002
List 5 (Contd)
Figure imgf000051_0001
Figure imgf000051_0002
Figure imgf000052_0001
List 5 (Contd)
Figure imgf000053_0001
List 6
Figure imgf000054_0001
Figure imgf000054_0002
Figure imgf000054_0004
Figure imgf000054_0003
List 7
Figure imgf000055_0001
List 7 (Contd)
Figure imgf000056_0001
List 7 (Contd)
Figure imgf000057_0001
List 7 (Contd)
Figure imgf000058_0001
Figure imgf000058_0002
Figure imgf000058_0003
List 7 (Contd)
Figure imgf000059_0001
Figure imgf000059_0002
A compound library according to the claim 1 wherein said library has all or substantially all of the compounds represented therein.
A compound library according to claim 1 or 2 wherein said library has about 100, 1000, 2000, 3000, or 10000 of the compounds represented therein.
A method for making a compound library according to claim 1, which method comprises the step of synthesising compounds of formula A according to scheme 1:
Figure imgf000060_0001
M
R2
Figure imgf000060_0002
Scheme 1
(A: R = C(=Q)R3)
wherein the permitted substituents for R, Rl,and R2 are as defined in claim 1, and # = a leaving group. A method for making a compound library according to claim 1, which method comprises the step of synthesising compounds of formula B according to scheme 2 :
Figure imgf000061_0001
(5)
R4'
Figure imgf000061_0002
Scheme 2
wherein the permitted substituents for R3 and R4 are as defined in claim 1, and # = a leaving group.
A method for making a compound library according to claim 1, which method comprises the step of synthesising compounds of formula C according to scheme 3 :
Figure imgf000062_0001
wherein the permitted substituents are for R5 and R6 as defined in the claim 1, and # = a leaving group.
A method for making a compound library according to any or all of the steps of claims 4-6.
Compounds of formulae (1) , (2) and (3) , as defined in claim 4, for use in a method according to claim 4 or 7 for making a compound library according to any of claims 1-3.
Compounds of formulae (4) and (5) as defined in claim 5, for use in a method according to claim 5 or 7 for making a compound library according to any of claims 1-3.
10 Compounds of formulae (6) , (7) and (8) and (9) as defined in claim 4, for use in a method according to claim 6 or 7 for making a compound library according to any of claims 1-3.
11. 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 but not including:
compounds of formula A (nl =2 and n2=2) where R2 is represented by any of the following groups :
Figure imgf000063_0001
Figure imgf000064_0001
and # = point of attachment
compounds of Formula A (nl = 1, n2 = 3)where R2 is represented by any of the following groups :
Figure imgf000064_0002
and # = point of attachment
compounds of Formula A (nl = 1, n2 = 2) where R2 is represented by any of the following groups :
Figure imgf000064_0003
and # = point of attachment
a compound of Formula B having the following structure:
Figure imgf000065_0001
compounds of Formula C where R6 is represented by any of the following groups :
Figure imgf000065_0002
and # = point of attachment
12. Methods for making a compound according to claim 11 which method is according to the methods of claim 4,5 or 6.
13. A compound library comprising or consisting of a set of structurally related compounds, substantially as herein described.
14. A compound capable of binding to a G-protein coupled receptor, substantially as herein described.
PCT/GB2003/005642 2002-12-24 2003-12-24 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 WO2004058263A1 (en)

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WO2007062175A3 (en) * 2005-11-21 2007-07-26 Amgen Inc Spiro-substituted tricyclic heterocycles cxcr3 antagonists
CN105315324A (en) * 2014-06-10 2016-02-10 首都医科大学 1-(ethyl amino acid benzyl ester)-[beta]-carboline-3-carboxylic acid benzyl ester, preparation, activity, nano structure and application
CN105218624A (en) * 2014-06-13 2016-01-06 首都医科大学 1-(ethylamino acid benzyl ester)-β-carboline-3-benzyl carboxylate, preparation, nanostructure, active and application

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