WO2004058264A1 - Compound libraries of 2h-spiro (isoquinoline-1, -piperidine derivatives and related compounds for targetting compounds capable of binding to the g-protein receptor - Google Patents

Compound libraries of 2h-spiro (isoquinoline-1, -piperidine derivatives and related compounds for targetting compounds capable of binding to the g-protein receptor Download PDF

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Publication number
WO2004058264A1
WO2004058264A1 PCT/GB2003/005637 GB0305637W WO2004058264A1 WO 2004058264 A1 WO2004058264 A1 WO 2004058264A1 GB 0305637 W GB0305637 W GB 0305637W WO 2004058264 A1 WO2004058264 A1 WO 2004058264A1
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give
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Terence Ward
Roger Crossley
Martin John Slater
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Biofocus Plc
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Priority to AU2003290323A priority patent/AU2003290323A1/en
Publication of WO2004058264A1 publication Critical patent/WO2004058264A1/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.
  • a library of compounds is provided for use in screening 10 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 15 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 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.
  • Library 3 is a library consisting of four scaffolds and is designed to pick up interactions with receptors for a subset of peptidic receptors, namely those with recognition sites for amide and acidic ligands centred on transmembrane helices (TM) 3 and TM6, although similar interactions are also found in lipid-type and ADP/ATP/UDP- types of receptors .
  • TM transmembrane helices
  • the general mode of interaction of peptide liganded receptors is considered to be a primary interaction with the extracellular loop regions followed by a secondary interaction brought about by the insertion of a C-terminal tail or a loop into a consensus binding region defined by the top halves of TM2-7. It is this secondary interaction which promotes signal transduction and which is the target for the vast majority of drugs which interact with this type of receptor. Accordingly, a subset of peptide liganded receptors contain a combination of residues which pick up C-terminal carboxylate interactions. In another group similar residues are able to interact with amide and urea functionalities on drugs.
  • the molecules in library 3 are designed to act as probes for both these type of interactions which are found in such receptors as angiotensin II, bombesin, some chemokines, growth hormone secretagogue receptor and melanocortin receptors.
  • the templates used in this library are designed to pick up extra interactions with areas recognising electron-rich rings and benzhydryl ⁇ rabbit ears' type of interactions .
  • the spatial arrangements between these functions have been captured in two ways .
  • One is illustrated in series of spiro-fused piperidines; examples are MK499 (K-channel blocker) , LU 28-179 (s2 ligand) and ibutamoren (growth hormone secretagogue) .
  • MK499 K-channel blocker
  • LU 28-179 s2 ligand
  • ibutamoren growth hormone secretagogue
  • the invention provides a compound library, library 3, comprising or consisting of a set of structurally related compounds based on scaffolds of general formulae PS203, PS204, PS205 and PS144.
  • n may be 1 or 2 and m may be 2 or 3 ; the permitted substituents for RI are derived from List 1; and the permitted substituents for R2 are derived from List 3 and List 4 in compounds of formula PS204, the permitted substituents for RI are derived from List 5; and the permitted substituents for R2 are derived from List 6 and List 7;
  • the permitted substituents for RI are derived from List 8; and the permitted substituents for R2 are derived from List 9 and 10;
  • the permitted substituents of RI are derived from List 11; the permitted substituents for R2 are derived from List
  • spiro compounds (7) An appropriately substituted tryptophol derivative (6) selected from List 5 is reacted with 4-piperidone monohydrate hydrochloride to give the spiro compounds (7) .
  • the benzhydryl amines (16) can be prepared from an appropriately substituted cyano heterocycle (15) (List 11) by reaction with an alkyl lithium or Grignard reagent (List 12) .
  • An amide (18) is formed from the reaction of an N-BOC protected amino acid (17) (List 13) and subsequent cyclisation provides the bicyclic heterocycle structure (19) .

Abstract

The present invention provides a compound library, designed to pick up interactions with receptors for a subset of peptidic receptors, with recognition sites for amide and acidic ligands centred on transmembrane helices TM3 and TM6, although similar interactions are also found in lipid-type and ADP/ATP/UDP-types of receptors. The library comprises or consists of a set of structurally related compounds based on scaffolds of general formulae PS203, PS204, PS205 and PS144.

Description

COMPOUND LIBRARIES OF 2H-SPIRO (ISOQUINOLINE-1 , 4 -PIPERIDINE) DERIVATIVES AND RELATED COMPOUNDS FOR TARGETTING COMPOUNDS CAPABLE OF BINDING TO THE G-PROTEIN
RECEPTOR
Introduction
5 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 10 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 15 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'
20 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
25 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 30 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, 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 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.
Library 3
Library 3 is a library consisting of four scaffolds and is designed to pick up interactions with receptors for a subset of peptidic receptors, namely those with recognition sites for amide and acidic ligands centred on transmembrane helices (TM) 3 and TM6, although similar interactions are also found in lipid-type and ADP/ATP/UDP- types of receptors .
The general mode of interaction of peptide liganded receptors is considered to be a primary interaction with the extracellular loop regions followed by a secondary interaction brought about by the insertion of a C-terminal tail or a loop into a consensus binding region defined by the top halves of TM2-7. It is this secondary interaction which promotes signal transduction and which is the target for the vast majority of drugs which interact with this type of receptor. Accordingly, a subset of peptide liganded receptors contain a combination of residues which pick up C-terminal carboxylate interactions. In another group similar residues are able to interact with amide and urea functionalities on drugs. The molecules in library 3 are designed to act as probes for both these type of interactions which are found in such receptors as angiotensin II, bombesin, some chemokines, growth hormone secretagogue receptor and melanocortin receptors.
In addition to the acid-amide interactions described above, the templates used in this library are designed to pick up extra interactions with areas recognising electron-rich rings and benzhydryl ^rabbit ears' type of interactions . The spatial arrangements between these functions have been captured in two ways . One is illustrated in series of spiro-fused piperidines; examples are MK499 (K-channel blocker) , LU 28-179 (s2 ligand) and ibutamoren (growth hormone secretagogue) . The other is found in such ligands as devazepide and sertindole amongst others
The invention provides a compound library, library 3, comprising or consisting of a set of structurally related compounds based on scaffolds of general formulae PS203, PS204, PS205 and PS144.
Figure imgf000010_0001
PS144 wherein in compounds of formula PS203 n may be 1 or 2 and m may be 2 or 3 ; the permitted substituents for RI are derived from List 1; and the permitted substituents for R2 are derived from List 3 and List 4 in compounds of formula PS204, the permitted substituents for RI are derived from List 5; and the permitted substituents for R2 are derived from List 6 and List 7;
in compounds of formula PS205, the permitted substituents for RI are derived from List 8; and the permitted substituents for R2 are derived from List 9 and 10;
in compounds of formula PS144, the permitted substituents of RI are derived from List 11; the permitted substituents for R2 are derived from List
12 ; and the permitted substituents for R3 are derived from List 14 and List 15; and Y may be C or N.
Novelty of Compounds of Library 3
PS203
Figure imgf000011_0001
Substitution of the following groups at X is known where * = point of attachment.
Figure imgf000012_0001
PS204
There are no known compounds .
PS205
Figure imgf000012_0002
Substitution of the following group at Y is known where * = point of attachment .
Figure imgf000012_0003
PS144
There are no known compounds ,
Methods for Preparing Compounds of Library 3
Compounds of Library 3 (SFG03) can be produced according to the following reaction schemes :
Method of Preparing Compounds of Formula PS203
PS 203
Figure imgf000014_0001
(CH2)n (CH2)m
Figure imgf000014_0002
An appropriately substituted tryptamine derivative (1) selected from List 1 is reacted with an appropriately substituted nitrogen heterocycle (2) selected from List 2 (n = 1 or 2 and m = 2 or 3) to give spiro compounds (3) . The spiro compounds are then acylated by reacting (3) with cylic anhydrides selected from List 3 to give PS203 compounds (4) with R2 = -(C)nCOOH (where n = 2 or 3) or by reacting with isocyanates selected from List 4 to give PS203 compounds (5) with R2 = optionally substituted alkyl, aryl or heteroaryl.
To a solution of (3) (0.12mmol) in DMF (0.7ml, 0.16M) with triethylamine (6eq. , 0.1ml) was added a solution of anhydride or isocyanate (0.24mmol) in DMF (0.5ml, 0.48M) and the suspension shaken at room temperature for 16h. The reactions were quenched by addition of DMF:H20, 1:1 (0.5ml) and the crude products purified by prep HPLC.
Examples of Compounds having- Formula PS203
3,3-Dimethyl-5-oxo-5- (1' ,4' ,5' ,6' -tetrahydro-lH- spiro[2,3,4, 9-tetrahydro-lH-beta-carboline] -1,4 ' - piperidine) pentanoic acid.
Figure imgf000015_0001
Yield; 54.3mg, HPLC; RT 2.10 mins (100%); MS (AP; [M+H] +) m/z: 384.3.
N- (3-methoxyphenyl) -l'^'fS'-β1 -tetrahydro-lH- spiro [2,3,4, 9-tetrahydro-lH-beta-carboline-l,4 ' - piperidine] -1-carboxamide.
Figure imgf000016_0001
Yield; 54.1mg, HPLC; RT 3.20 mins (100%) ; MS (AP; [M+H] m/z: 391.3.
Method for Preparing Compounds of Formula PS204
PS 204
Figure imgf000016_0002
An appropriately substituted tryptophol derivative (6) selected from List 5 is reacted with 4-piperidone monohydrate hydrochloride to give the spiro compounds (7) . The spiro compounds are then acylated by reacting with a cylic anhydride selected from list 6 to give PS204 compounds (9) with R = -(C)nCOOH (where n = 2 or 3) or by reacting with isocyanates selected from list 7 to give PS204 compounds (8) with R = optionally substituted alkyl, aryl or heteroaryl .
To a solution of (7) (0.12mmol) in DMSO (0.75ml, 0.16M) with triethylamine (3eq., 0.05ml) was added a solution of anhydride or isocyanate (0.24mmol) in DMSO (0.5ml, 0.48M) and the suspension shaken at room temperature for 16h. The reactions were quenched by addition of DMSO:H0, 1:1 (0.5ml) and the crude products purified by prep HPLC.
Examples of Compounds of Formula PS204
N- (2,3-dihydro-l,4-benzodioxin-6-yl) - ' , 5 ' -dihydro-lH, l'H- spiro [6-methoxy-l,3,4, 9-tetrahydropyrano{3,4-b}indole- 1,4 ' -piperidine] -1-carboxamide.
Figure imgf000017_0001
Yield; 56.0mg HPLC; RT 3.34 mins (100%); MS (AP; [M+H] +) m/z: 450.4. 2- (41 ,5' -dihydro-lH,l'H-spiro[6-methoxy-l,3,4,9- tetrahydropyrano{3,4 b}indole-l, 4' -piperidine] -1- ylcarbonyl) cyclobutanecarboxylic acid.
Figure imgf000018_0001
Yield; 53.3mg, HPLC; RT 2.10 mins (100%); MS (AP; [M+H] +) m/z: 399.4.
Method of Preparing Compounds of Formula PS205 PS 205
Figure imgf000019_0001
(14) (13) An appropriately substituted phenylacetonitrile (10) selected from List 8 was reacted with an N protected 4- piperidone. The resultant spiropiperidine structure (11) was deprotected to give the amines (12) . These spiro compounds are then acylated by reacting with a cylic anhydride selected from list 9 to give PS204 compounds (13) with R2 = -(C)nCOOH (where n = 2 or 3) or by reacting with isocyanates selected from list 10 to give PS205 compounds (14) with R2 = optionally substituted alkyl, aryl or heteroaryl.
To a solution of (12) (0.12mmol) in DMSO (0.75ml, 0.16M) with triethylamine (3eq., 0.05ml) was added a solution of anhydride or isocyanate (0.24mmol) in DMSO (0.5ml, 0.48M) and the suspension shaken at room temperature for 16h. The reaction was quenched by addition of DMSO:H20, 1:1 (0.5ml) and the crude product purified by prep HPLC.
Examples of Compounds of Formula PS205
6,7-Dimethoxy-3-oxo-3 ,4-dihydro-2H-spiro [isoquinoline-
1,4 ' -piperidine] -1' -carboxylic acid (2,5-dimethoxy- phenyl) -amide.
Figure imgf000020_0001
Yield; 33.0mg, HPLC; RT 2.98 mins (91%); MS (AP; [M+H]+) m/z: 456.5.
[2-oxo-2-(3-oxo-3,4-dihydro-l'H,2H-spiro[3,4- dihydrobenzo [f] isoquinolin-2 (IH) -one-1, ' -piperidin] -1' - yl) ethoxy] acetic acid.
Figure imgf000021_0001
Yield; 32.9mg, HPLC; RT 1.95 mins (100%); MS (AP; [M+H] m/z: 383.3.
Method of Preparing Compounds of Formula PS144 PS 144
Figure imgf000022_0001
(20)
Figure imgf000023_0001
(22) (21) v '
The benzhydryl amines (16) can be prepared from an appropriately substituted cyano heterocycle (15) (List 11) by reaction with an alkyl lithium or Grignard reagent (List 12) . An amide (18) is formed from the reaction of an N-BOC protected amino acid (17) (List 13) and subsequent cyclisation provides the bicyclic heterocycle structure (19) . Removal of the protecting group to give (20) allows subsequent derivitisation to be carried out by acylating with a cylic anhydride selected from list 15 to give PS144 compounds (22) with R3 = -(C)nCOOH (where n = 1 or 2) or by reacting with isocyanates selected from list 14 to give PS144 compounds (21) with R3 = optionally substituted alkyl , aryl or heteroaryl .
To a solution of (20) (0.12mmol) in DMF (0.75ml), 0.16M) with triethylamine (3eq., 0.05ml) was added a solution of anhydride or isocyanate (0.24mmol) in DMF (0.5ml), 0.48M) and the suspension shaken at room temperature for 16h. The reactions were quenched by addition of DMF:H20, 1:1 (0.5ml)) and the crude products purified by prep HPLC.
Examples of Compounds of Formula PS144
2- [1- ( -Fluoro- henyl) -imidazo [l,5-a]pyridin-3-yl] - pyrrolidine-1-carboxylic acid (4-trifluoromethoxy-phenyl) - amide.
Figure imgf000024_0001
Yield; 62.5mg, HPLC; RT 4.15 mins (100%); MS (AP; [M+H] +) m/z: 485.3.
2,3,4,5-Tetrachloro-6-{4- [1- (4-fluoro-phenyl) -imidazo [1, 5- a]pyridin-3-yl] -piperidine-l-carbonyl}-benzoic acid.
Figure imgf000024_0002
Yield; 49.8mg, HPLC; RT 2.95 mins (100%) ; MS (AP; [M+H] +) m/z: 582.2. 3,3-Dimethyl-5-oxo-5- [2- (1-phenyl-imidazo [l,5-a]pyridin-3- yl) -pyrrolidin-1-yl] -pentanoic acid.
Figure imgf000025_0001
Yield; 49.7mg, HPLC; RT 2.51 mins (100%); MS (AP; [M+H]+) m/z: 406.3.
4- [1- (4-Fluoro-phenyl) -imidazo [l,5-a]pyridin-3-yl] - piperidine-1-carboxylic acid (4-trifluoromethoxy-phenyl) - amide.
Figure imgf000025_0002
Yield; 49.8mg, HPLC; RT 4.16 mins (100%); MS (AP; [M+H]+) m/z: 498.8.
4-{3- [1- (4-Fluoro-phenyl) -imidazo [l,5-a]pyridin-3-yl] iperidin-1-yl} -4-oxo-2,3-diphenyl-but-2-enoic acid.
Figure imgf000026_0001
Yield; 51.7mg, HPLC; RT 2.96 mins (100%); MS (AP; [M+H] +) m/z: 546.4.
3- (1-Phenyl-imidazo [l,5-a]pyridin-3-yl) -piperidine-1- carboxylic acid (1-phenyl-ethyl) -amide.
Figure imgf000026_0002
Yield; 54.0mg, HPLC; RT 3.91 mins (100%); MS (AP; [M+H] m/z: 425.
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
The permitted substituents for compounds of Library 3 (SFG03) can be derived from the following lists:
List 1
Figure imgf000028_0001
List 2
Figure imgf000029_0001
List 3
Figure imgf000029_0002
Figure imgf000029_0004
Figure imgf000029_0003
List 3 (Continued)
Figure imgf000030_0001
List 4
Figure imgf000031_0001
Figure imgf000031_0002
Figure imgf000031_0003
List 4 (Continued)
Figure imgf000032_0001
List 4 (Continued)
Figure imgf000033_0001
List 4 (Continued)
Figure imgf000034_0001
Figure imgf000034_0002
List 4 (Continued)
Figure imgf000035_0001
Figure imgf000035_0002
List 6
Figure imgf000036_0001
List 6 (Continued)
Figure imgf000037_0001
List 7
Figure imgf000038_0001
List 7 (Continued)
Figure imgf000039_0001
List 7 (Continued)
Figure imgf000040_0001
List 7 (Continued)
Figure imgf000041_0001
List 7 (Continued)
Figure imgf000042_0001
List 8
Figure imgf000042_0002
List 9
Figure imgf000043_0001
List 9 (Continued)
Figure imgf000044_0001
List 10
Figure imgf000045_0001
List 10 (Continued)
Figure imgf000046_0001
Figure imgf000046_0003
Figure imgf000046_0002
Figure imgf000046_0004
List 10 (Continued)
Figure imgf000047_0001
Figure imgf000047_0002
Figure imgf000047_0003
List 10 (Continued)
Figure imgf000048_0001
List 10 (Continued)
Figure imgf000049_0001
Figure imgf000049_0002
List 10 (Continued)
Figure imgf000050_0001
List 11
Figure imgf000050_0002
List 12
Figure imgf000051_0001
Figure imgf000051_0002
List 13
Figure imgf000052_0001
List 14
Figure imgf000052_0002
List 14 (Continued)
Figure imgf000053_0001
List 14 (Continued)
Figure imgf000054_0001
List 15
Figure imgf000054_0002
Figure imgf000055_0001
Figure imgf000055_0002
Figure imgf000055_0003
Figure imgf000055_0004
Figure imgf000055_0005
Figure imgf000055_0006

Claims

Claims
1. A compound library copmrising or consisiting of a set of structurally related compounds having core chemical structures (scaffolds) of general formulae PS203, PS204, PS205 and PS144 :
Figure imgf000056_0001
wherein in compounds of formula PS203 (above) n may be 1 or 2 and m may be 2 or 3 ; the permitted substituents for RI are derived from List 1; and the permitted substituents for R2 are derived from List 3 and List 4 :
Figure imgf000056_0002
wherein in compounds of formula PS204 (above) , the permitted substituents for RI are derived from List 5; and the permitted substituents for R2 are derived from List 6 and List 7 :
Figure imgf000056_0003
wherein in compounds of formula PS205 (above) , the permitted substituents for RI are derived from List 8; and the permitted substituents for R2 are derived from List 9 and 10:
Figure imgf000057_0001
wherein in compounds of formula PS144 (above) , the permitted substituents of RI are derived from List 11; the permitted substituents for R2 are derived from List 12; and the permitted substituents for R3 are derived from List 14 and List 15; and Y may be C or N.
List 1
Figure imgf000058_0001
List 2
Figure imgf000059_0001
List 3
Figure imgf000059_0002
Figure imgf000059_0004
Figure imgf000059_0003
List 3 (Continued)
Figure imgf000060_0001
List 4
Figure imgf000061_0001
Figure imgf000061_0002
Figure imgf000061_0003
List 4 (Continued)
Figure imgf000062_0001
List 4 (Continued)
Figure imgf000063_0001
List 4 (Continued)
Figure imgf000064_0001
Figure imgf000064_0002
List 4 (Continued)
Figure imgf000065_0001
Figure imgf000065_0002
List 6
Figure imgf000066_0001
List 6 (Continued)
Figure imgf000067_0001
List 7
Figure imgf000068_0001
List 7 (Continued)
Figure imgf000069_0001
List 7 (Continued)
Figure imgf000070_0001
List 7 (Continued)
Figure imgf000071_0001
List 7 (Continued)
Figure imgf000072_0001
List 8
Figure imgf000072_0002
List 9
Figure imgf000073_0001
List 9 (Continued)
Figure imgf000074_0001
List 10
Figure imgf000075_0001
List 10 (Continued)
Figure imgf000076_0001
Figure imgf000076_0002
Figure imgf000076_0003
List 10 (Continued)
Figure imgf000077_0001
Figure imgf000077_0002
Figure imgf000077_0004
Figure imgf000077_0003
Figure imgf000077_0005
List 10 (Continued)
Figure imgf000078_0001
List 10 (Continued)
Figure imgf000079_0001
Figure imgf000079_0002
List 10 (Continued)
Figure imgf000080_0001
List 11
Figure imgf000080_0002
List 12
Figure imgf000081_0001
Figure imgf000081_0002
List 13
Figure imgf000082_0001
List 14
Figure imgf000082_0002
List 14 (Continued)
Figure imgf000083_0001
List 14 (Continued)
Figure imgf000084_0001
List 15
Figure imgf000084_0002
Figure imgf000085_0001
Figure imgf000085_0002
Figure imgf000085_0003
Figure imgf000085_0004
Figure imgf000085_0005
Figure imgf000085_0006
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 PS203 according to the following reaction scheme:
PS 203
Figure imgf000086_0001
(CH2)n (CH2)m
Figure imgf000086_0002
wherein RI and R2, and n and m are as defined in claim 1. '"■' v f
86
5. A method for making a compound library according to claim 1, which method is according to claim 4 and wherein an appropriately substituted tryptamine derivative (1) selected from List 1 is reacted with an appropriately substituted nitrogen heterocycle (2) selected from List 2 (n = 1 or 2 and m = 2 or 3) to give spiro compounds (3) ,- the resultant spiro compounds are acylated by reaction with cylic anhydrides selected from List 3 to give PS203 compounds (4) (R2 = -(C)nCOOH, where n = 2 or 3) ; or reacted with isocyanates selected from list 4 to give PS203 compounds (5) (R2 = optionally substituted alkyl, aryl or heteroaryl) .
6. A method for making a compound library according to claim 1, which method comprises the step of synthesising compounds of formula PS204 according to the following reaction scheme:
PS 204
Figure imgf000088_0001
wherein RI and R2 are as defined in claim 1.
7. A method for making a compound library according to claim 1, which method is according to claim 6, and wherein an appropriately substituted tryptophol derivative (6) selected from List 5 is reacted with 4-piperidone monohydrate hydrochloride; the resultant spiro compounds (7) are acylated by reaction with a cylic anhydride selected from list 6 to give PS204 compounds (9) (R2 = -(C)nCOOH, where n = 2 or 3); or reacted with isocyanates selected from list 7 to give PS204 compounds (8) (R2 = optionally substituted alkyl, aryl or heteroaryl) .
8. A method for making a compound library according to claim 1, which method comprises the step of synthesising compounds of formula PS 205 according to the following reaction scheme:
PS 205
Figure imgf000090_0001
(14) (13) wherein RI and R2 are as defined in claim 1.
9. A method for making a compound library according to claim 1, which method is according to claim 8, and wherein an appropriately substituted phenylacetonitrile (10) selected from List 8 is reacted with an N protected 4- piperidone; the resultant spiropiperidine structure (11) is deprotected to give the amines (12) ; these spiro compounds are then acylated by reaction with a cyclic anhydride selected from list 9 to give PS204 compounds (13) (R2 = -(C)nC00H, where n = 2 or 3); or by reaction with isocyanates selected from list 10 to give PS205 compounds (14) (R2 = optionally substituted alkyl, aryl or heteroaryl) .
10. A method for making a compound library according to claim 1, which method comprises the step of synthesising compounds of formula PS144 according to the following reaction scheme:
PS 144
Figure imgf000092_0001
(20)
Figure imgf000093_0001
(22)
(21)
wherein Y, RI, R2, R3 , and n and m are as defined in claim 1.
11. A method for making a compound library according to claim 1, which method is according to claim 10, and wherein the benzhydryl amines (16) are prepared from an appropriately substituted cyano heterocycle (15) (List 11) by reaction with an alkyl lithium or Grignard reagent (List 12) ,- the amide (18) is formed by the reaction of an N-BOC protected amino acid (17) and subsequent cyclisation provides the bicyclic heterocycle structure (19) ; removing the protecting group gives (20) allowing subsequent derivitisation to be carried out by acylating with a cylic anhydride selected from list 15 to give PS114 compounds (22) (R3 = -(C)nC00H, where n = 1 or 2) ; or reaction with isocyanates selected from list 14 to give PS144 compounds (21) (R3 = optionally substituted alkyl, aryl or heteroaryl) .
12. A method for making a compound library according to any or all of the steps of claims 4-11.
13. Intermediate compounds of formula (3) for use in a method according to claim 4 or 5 or 12 wherein (3) is as defined in claim 4.
14. Intermediate compounds of formula (7) for use in a method according to claim 6 or 7 or 12 wherein (7) is as defined in claim 6.
15. Intermediate compounds of formulae (11) and (12) for use in a method according to claim 8 or 9 or 12 wherein
(11) and (12) are as defined in claim 8.
16. Intermediate compounds of formulae (16), (17), (18), (19) and (20) for use in a method according to claim 10 or 11 or 12 wherein (16) , (17) , (18) , (19) and (20) are as defined in claim 10.
17. 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 the following general formula:
Figure imgf000095_0001
wherein X is one on the following groups
Figure imgf000095_0002
and * = point of attachment
compounds of the following general formula;
Figure imgf000095_0003
wherein Y is one of the follwing groups :
Figure imgf000096_0001
and * = point of attachment .
18. Methods for making a compound according to claim 17 which method is according to the methods of claims 4-12.
19. A compound library comprising or consisting of a set of structurally related compounds, substantially as herein described.
20. A compound capable of binding to a G-protein coupled receptor, substantially as herein described .
PCT/GB2003/005637 2002-12-24 2003-12-24 Compound libraries of 2h-spiro (isoquinoline-1, -piperidine derivatives and related compounds for targetting compounds capable of binding to the g-protein receptor WO2004058264A1 (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005080390A1 (en) * 2004-02-18 2005-09-01 Biofocus Discovery Ltd Imidazopyridine derivatives as bsr-3 antagonists
WO2007062175A2 (en) * 2005-11-21 2007-05-31 Amgen Inc. Spiro-substituted tricyclic heterocycles cxcr3 antagonists
WO2008022060A2 (en) * 2006-08-14 2008-02-21 Novartis Ag Imidazo-pyridine derivatives for modulating protein kinase activity
US8138168B1 (en) 2007-09-26 2012-03-20 Takeda Pharmaceutical Company Limited Renin inhibitors
CN112898376A (en) * 2019-12-02 2021-06-04 首都医科大学 Dioxane-modified tetrahydrocarboline-3-formyl-The-HGK, preparation thereof, antitumor activity thereof and application thereof
CN112979667A (en) * 2019-12-02 2021-06-18 首都医科大学 Dioxahexacyclic modified tetrahydrocarboline-3-formyl-The, synthesis, activity and application thereof
CN113754675A (en) * 2020-06-04 2021-12-07 首都医科大学 Synthesis, biological activity and application of dimethyldioxane-tetrahydro-beta-carboline-3-carboxylic acid
US11814367B2 (en) 2021-03-15 2023-11-14 Maze Therapeutics, Inc. Inhibitors of glycogen synthase 1 (GYS1) and methods of use thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001013917A1 (en) * 1999-08-26 2001-03-01 Bristol-Myers Squibb Company Npy antagonists: spiroisoquinolinone derivatives
WO2001014376A1 (en) * 1999-08-20 2001-03-01 Banyu Pharmaceutical Co., Ltd. Novel spiro compounds
WO2001025200A1 (en) * 1999-10-01 2001-04-12 Takeda Chemical Industries, Ltd. Cyclic amine compounds as ccr5 antagonists
US20020016337A1 (en) * 2000-05-25 2002-02-07 Cuny Gregory D. Heterocyclic analgesic compounds and methods of use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001014376A1 (en) * 1999-08-20 2001-03-01 Banyu Pharmaceutical Co., Ltd. Novel spiro compounds
WO2001013917A1 (en) * 1999-08-26 2001-03-01 Bristol-Myers Squibb Company Npy antagonists: spiroisoquinolinone derivatives
WO2001025200A1 (en) * 1999-10-01 2001-04-12 Takeda Chemical Industries, Ltd. Cyclic amine compounds as ccr5 antagonists
US20020016337A1 (en) * 2000-05-25 2002-02-07 Cuny Gregory D. Heterocyclic analgesic compounds and methods of use thereof

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ABSTRACTS OF PAPERS, 227TH ACS NATIONAL MEETING, ANAHEIM, CA, UNITED STATES, MARCH 28-APRIL 1, 2004 (2004), ORGN-337 PUBLISHER: AMERICAN CHEMICAL SOCIETY, WASHINGTON, D. C. *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; NIETO, MARCELO J. ET AL: "Solution-phase parallel synthesis of spirohydantoins derivatives", XP002276327, retrieved from STN Database accession no. 2004:227207 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; WEINER, D. M. ET AL: "5-Hydroxytryptamine2A receptor inverse agonists as antipsychotics", XP002276328, retrieved from STN Database accession no. 136:112520 *
GOODFELLOW V S ET AL: "RATIONALLY DESIGNED NON-PEPTIDES: VARIOUSLY SUBSTITUTED PIPERAZINE LIBRARIES FOR THE DISCOVERY OF BRADYKININ ANTAGONISTS AND OTHER G-PROTEIN-COUPLED RECEPTOR LIGANDS", MOLECULAR DIVERSITY, ESCOM SCIENCE PUBLISHERS, LEIDEN, NL, vol. 2, 1996, pages 97 - 102, XP002919939, ISSN: 1381-1991 *
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS (2001), 299(1), 268-276 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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WO2007062175A2 (en) * 2005-11-21 2007-05-31 Amgen Inc. Spiro-substituted tricyclic heterocycles cxcr3 antagonists
WO2007062175A3 (en) * 2005-11-21 2007-07-26 Amgen Inc Spiro-substituted tricyclic heterocycles cxcr3 antagonists
WO2008022060A2 (en) * 2006-08-14 2008-02-21 Novartis Ag Imidazo-pyridine derivatives for modulating protein kinase activity
WO2008022060A3 (en) * 2006-08-14 2008-12-31 Novartis Ag Imidazo-pyridine derivatives for modulating protein kinase activity
US8138168B1 (en) 2007-09-26 2012-03-20 Takeda Pharmaceutical Company Limited Renin inhibitors
CN112898376A (en) * 2019-12-02 2021-06-04 首都医科大学 Dioxane-modified tetrahydrocarboline-3-formyl-The-HGK, preparation thereof, antitumor activity thereof and application thereof
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