WO2003062230A1 - Bibliotheque combinatoire de composes heterocycliques - Google Patents

Bibliotheque combinatoire de composes heterocycliques Download PDF

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Publication number
WO2003062230A1
WO2003062230A1 PCT/JP2002/000388 JP0200388W WO03062230A1 WO 2003062230 A1 WO2003062230 A1 WO 2003062230A1 JP 0200388 W JP0200388 W JP 0200388W WO 03062230 A1 WO03062230 A1 WO 03062230A1
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Prior art keywords
optionally substituted
compounds
library
formula
aryl
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PCT/JP2002/000388
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English (en)
Inventor
Naoki Kobayashi
Yasushi Okamoto
Kunizo Higurashi
Yumiko Kaku
Akira Ishibashi
Toshihiko Yamauchi
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Eisai Co., Ltd.
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Priority to PCT/JP2002/000388 priority Critical patent/WO2003062230A1/fr
Publication of WO2003062230A1 publication Critical patent/WO2003062230A1/fr

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    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/11—Compounds covalently bound to a solid support
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • This invention relates to a novel library containing a plurality of compounds, process for preparation thereof, and process for screening such a library for useful therapeutic compounds.
  • Certain pyrrole compounds of the present invention have demonstrated activity as RAR (retinoic acid receptor) a agonists. Other therapeutic activities are expected, depending on the substituents attached to the compounds.
  • combinatorial chemistry is the parallel, simultaneous preparation of multiple derivatives of a central, fixed moiety often referred to as the "scaffold,” “core” or “backbone”.
  • the number of compounds, which may be produced to establish a library is limited only by the number of reagents available to form the derivatives.
  • Combinatorial chemistry may be used to generate libraries, which are mixtures of individual compounds and complete identification of the individual compounds are postponed until after positive screening.
  • libraries which are mixtures of individual compounds and complete identification of the individual compounds are postponed until after positive screening.
  • parallel array synthesis whereby individual reaction products are simultaneously synthesized but each reaction is carried out in a separate vessel is generally preferred.
  • a compound library may be prepared, stored and assayed in standard microtiter plates such as the plates often used in the biological sciences.
  • the scaffold is typically attached to a solid support, e.g., a polymer, which is insoluble in the reaction solvent.
  • a solid support e.g., a polymer
  • the library compounds are detached from the support.
  • combinatorial libraries can be prepared in solution phase. It is also possible to tether the reactants to a support with the scaffold in solution. In all cases, the net effect is to produce a library of many derivatives of the scaffold each in its own small reaction vessel.
  • preparation of a combinatorial library by parallel synthesis appears to be logical and straightforward. However, in practice, efficient preparation of such libraries has demanded development of new techniques and new equipment.
  • HTS high throughput screening
  • the present invention provides the combinatorial library containing a plurality of compounds of the Formula (1):
  • X is 0, S, and NR 7 ;
  • R la , R l and R 7 are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted aryl;
  • Z is optionally substituted aryl, a 5 to 14 membered aromatic monocyclic or fused polycyclic moiety that includes from 1 to 4 heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen;
  • Y is optionally substituted arylene, a 5 to 14 membered aromatic monocyclic or fused polycyclic moiety that includes from 1 to 4 heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen; or a pharmaceutically acceptable salt there of.
  • the present invention also provides a process for preparing the combinatorial library containing a plurality of heterocyclic compounds, comprising using a solid-supported intermediate of Formula (2) :
  • R 6 is hydrogen, alkyl, aryl, alkenyl or alkynyl; f is optionally substituted arylene, a 5 to 14 membered aromatic monocyclic or fused polycyclic moiety that includes from 1 to 4 heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen; d is a single bond or optionally substituted alkylene;
  • R 2 is a stable moiety independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl or aryl;
  • R 3 is a stable moiety independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl or aryl;
  • R 5 is optionally substituted aryl, a 5 to 14 membered aromatic monocyclic or fused polycyclic moiety that includes from 1 to 4 heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen.
  • Alcohols include groups of the formula -OH.
  • Alkyl refers to a substituted or unsubstituted, straight, branched or cyclic hydrocarbon chain containing of from 1 to 20 carbon atoms.
  • Preferred alkyl groups are lower alkyl groups, i.e., alkyl groups containing from 1 to 6 carbon atoms.
  • Preferred cycloalkyls have from 3 tolO, preferably 3-6, carbon atoms in their ring structure.
  • Suitable examples of unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, iso-butyl, tert-butyl, sec- butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, and the like.
  • Alkylene is the two valences radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl group, and that groups may include one or more double or triple bonds.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone, and more preferably 20 or fewer and most preferred 10 or fewer.
  • preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure.
  • alkyl substituents include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, iso-butyl, tert-butyl, sec-butyl, cyclobutyl, pentyl, hexyl, cyclohexyl, etc.
  • "lower alkyl” as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure.
  • the aliphatic cyclic groups can be single or polycyclic containing between about 3 to 12 carbons per ring, but preferably between 3 and 9 carbons per ring.
  • alkenyl refers to a substituted or unsubstituted, straight, branched or cyclic, unsaturated hydrocarbon chain that contains at least one double bond and 2 to 20, preferably 2 to 6, carbon atoms.
  • cycloalkenyl groups contain having five to eight cabon atoms and at least one double bond.
  • Examples of cycloalkenyl groups include cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl, cyclooctatrienyl and the like.
  • Alkoxy refers to a substituted or unsubstituted, -0-alkyl group. Exemplary unsubstituted alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and the like .
  • Alkynyl refers to a substituted or unsubstituted, straight, branched or cyclic unsaturated hydrocarbon chain containing at least one triple bond and 2 to 20, preferably 2 to 6, carbon atoms .
  • Aprotic solvent refers to polar solvents of moderately high dielectric constant which do not contain an acidic hydrogen.
  • Examples of common aprotic solvents are dimethyl sulfoxide (DMSO) , dimethylformamide (DMF) , sulfolane, tetrahydrofuran (THF), diethyl ether (Et20) , methyl t-butyl ether or 1,2- dimethoxyethane .
  • DMSO dimethyl sulfoxide
  • DMF dimethylformamide
  • Et20 diethyl ether
  • Aryl refers to any 5 to 14 membered monovalent aromatic monocyclic or fused polycyclic moieties . Preferred aryl groups include phenyl and naphthyl.
  • the aryl group can be substituted at one or more positions with halo, alkyl, alkoxy, alkoxy carbonyl, haloalkyl, cyano, amino sulfonyl, aryl, sulfonyl, aminocarbonyl, carboxy, acylamino, alkyl sulfonyl, amino and substituted or unsubstituted substituents.
  • Assay kit refers to an assemblage of at least two cooperative elements, namely (1) a well plate apparatus and (2) biological assay materials.
  • Biological assay materials are materials necessary to conduct a biological evaluation of the efficacy of any library compound in a screen relevant to a selected disease state.
  • "Diverse library” means a library where the substituents on the combinatorial library scaffold are highly variable in constituent atoms, molecular weight, and structure and the library, considered in its entirety, is not a collection of closely related homologues or analogues (compare to "directed library”) .
  • Heterocyclic refers to a stable, saturated, partially unsaturated, or aromatic group containing 5 to 14, preferably 5 or 6, ring atoms.
  • the ring can be substituted 1 or more times with a substituent.
  • the ring can be mono-, bi- or polycyclic.
  • the heterocyclic group consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • heterocyclic groups include acridinyl, benzothiazolidinyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, carbazolyl, cinnolinyl, furanyl, imidazolyl, lH-indazolyl, indolyl, isoindolyl, isoquinolinyl, isothiazolyl, morpholinyl, oxazolyl, 1,2,3- oxadiazolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, piperazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrole, quinazolinyl, quinolinyl, quinoxalinyl, thiazo
  • Inert atmosphere refers to reaction conditions in which the mixture is covered with a layer of inert gas such as nitrogen or argon .
  • “Library” or “Combinatorial library” means a large number of chemical derivatives preferably used in screening for biological activity or other activity.
  • “Library compound” is an individual reaction product (usually a single compound) in a combinatorial library.
  • “Lead compound” means a compound in a selected combinatorial library for which the assay kit has revealed significant activity relevant to a selected disease state.
  • “Nitriles” (or cyano) include groups of the formula -CN.
  • Organic solvent includes solvents containing carbon, such as halogenated hydrocarbons, ether, toluene, xylene, benzene, and tetrahydrofuran.
  • “Pharmaceutically acceptable salt” and “salts thereof” means organic or inorganic salts of the pharmaceutically important molecule.
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an ammonium ion, a sodium ion, an acetate ion, a succinate ion or other counterion.
  • the counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a pharmaceutically important organic molecule may have more than one charged atom in its structure.
  • the molecule of a pharmaceutically acceptable salt may contain one or more than one charged atoms and may also contain, one or more than one counterion.
  • the desired charge distribution is determined according to methods of drug administration. Examples of pharmaceutically acceptable salts are well known in the art but, without limiting the scope of the present invention, exemplary presentations can be found in the Physician's Desk Reference, The Merck Index, The Pharmacopoeia and Goodman & Gilman' s The Pharmacological Basis of Therapeutics.
  • Protecting group means a group used to protect a heteroatom such as oxygen, nitrogen, sulfur or phosphorus from chemical reaction.
  • a heteroatom such as oxygen, nitrogen, sulfur or phosphorus from chemical reaction.
  • an O-protecting group is used to protect an oxygen heteroatom, such as in a hydroxy group, from reaction.
  • O-protecting groups include t-butoxycarbonyl (Boc) , t-butyl ether, benzyl ethers, and the like.
  • N-protecting groups examples include acetyl (Ac) , 1-adamantanesulfonyl (AdS0 2 ) , 1-adamantaneacetyl (AdAc) , benzoyl (Bz) , t-butoxycarbonyl (Boc) , carbobenzoxy (Cbz) , 2-carboxybenzoyl (2-Cbz) , dansyl (DNS) , isovaleryl (Iva) , fluorenylmethoxycarbonyl (Fmoc) , methoxysuccinyl (MeOSuc) , nitropiperonyl, pyrenylethoxycarbonyl, nitroveratryl (NV) , nitrobenzyl, succinyl (Sue), tosyl (Ts) , and such aminoprotecting groups which are functionally equivalent thereto.
  • Protecting groups are well known in the art, see for example Protective Groups in Organic Synthesis, Peter G. M. Wuts (Editor), Theodora W. Greene, 3 rd ed. (April 1999), Vch Pub; Protective groups in Organic Synthesis, Theodora W. Greene, Peter G. Wuts (Contributor), 2 nd ed., (March 1991) John Wiley & Sons.
  • Preferred protecting groups include, but are not limited to, the "Boc" protecting group, trialkyl silyl groups such as TBS (tert-butyldimethylsilyl, Si (CH 3 ) 2 C (CH 3 ) 3 ) , MEM (2- methoxyethoxymethyl) , MOM (methoxymethyl) , SEM (2- (trimethylsily) ethoxymethyl) , and THP (tetrahydropyranyl) .
  • TBS tert-butyldimethylsilyl
  • Si CH 3 ) 2 C (CH 3 ) 3 )
  • MEM 2- methoxyethoxymethyl
  • MOM methoxymethyl
  • SEM trimethylsily
  • THP tetrahydropyranyl
  • Protic solvent refers to a solvent containing hydrogen that is attached to oxygen, and hence is appreciably acidic. Common protic solvents include such solvents as water, methanol (MeOH) , ethanol (EtOH) , 2-propanol (PrOH) , and 1-butanol (n-BuOH) .
  • Protic acid refers to an acid having acidic hydrogen. Preferred protic acids include acetic acid, hydrochloric acid (HC1), formic acid, perchloric acid, sulfuric acid (H 2 S0 4 ) , and phosphoric acid (H 3 P0 4 ) in an aqueous medium. The most preferred protic acids are hydrochloric acid, sulfuric acid, and formic acid.
  • “Scaffold” as used in accordance with the present invention refers to the invariable region of the compounds that are members of the combinatorial library. That is, “scaffold” means a common chemical structure found within a library of organic compounds. Similarly, within a combinatorial chemical library the scaffold forms the basis for a diverse series of chemical derivatization, additions and subtractions. Importantly, regardless of the extent of the chemical derivatization performed on the scaffold, the product is within the scope of the combinatorial library.
  • Solid support broadly refers to any structure which is capable of supporting the chemical compound and is substantially inert to the chemical reactions conducted on the surface.
  • Exemplary solid supports include, but are not limited to, metals, resins, polymers, gels, glass beads, silica gels, ceramic supports and other solid and semi-solid compositions.
  • substantially pure is intended to mean at least about 90 mole percent, more preferably at least about 95 mole percent, and most preferably at least about 98 mole percent of the desired enantiomer of stereoisomer is present compared to other possible configurations.
  • “Substituted” means that the moiety contains at least one, preferably 1-3 substituent (s) .
  • -Amino acids can be mono- substituted at the backbone nitrogen atom, substituted at the ⁇ -carbon (to form a a , -disubstituted -carbon) or substituted 1-3 times at one or more side chain atoms.
  • Suitable substituents include hydrogen (H) and hydroxyl (-OH) , amino (-NR 2 ) , oxy (-0-), carbonyl (-CO-), thiol, alkyl, alkenyl, alkynyl, alkoxy, halo, nitrile, nitro, aryl and heterocyclic groups. These substituents can optionally be further substituted with 1-3 substituents.
  • substituted substituents include carboxamide, alkylmercapto, alkylsulphonyl, alkylamino, dialkylamino, carboxylate, alkoxycarbonyl, alkylaryl, aralkyl, alkylheterocyclic, (Cl- C4) fluoroalkyl groups (such as trifluoromethyl or 2,2,2- trifluoroethyl) and the like.
  • “Thiols” include compounds of the formula -SH or -SR where R is a substituent, preferably alkyl.
  • Exemplary thiols include methanthiol, ethanethiol, propanethiol, and the like. All other acronyms and abbreviations have the corresponding meaning as published in journals relative to the art of chemistry.
  • Leaving group means halo, oxo, thioxo radicals and activated alcohols such as a p-toluenesulfonyl activated alcohols and other groups that are susceptible to displacement and replacement by a nucleophile under selected conditions of temperature, solvent and time.
  • TFA trifluoroacetic acid
  • HC1 hydrochloric acid
  • THF tetrahydrofuran
  • DMF dimethyl ormamide
  • TAA triethylamine
  • Chemical derivatized means the chemical manipulation such as addition to, oxidation of, substitution for, reduction of, or cyclization of the selected R group or R groups of the intermediate. Chemical derivatization also means the manipulation of two or more groups of the intermediate such that additional aryl or alkyl rings are formed and that rings may be fused or unfused to the intermediate ring, and that new ring may be substituted with further chemically derivatizable substituents .
  • the present invention provides the combinatorial library containing a plurality of compounds of Formula (1):
  • X is 0, S, and NR 7 ;
  • R la , R l and R 7 are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted aryl;
  • Z is optionally substituted aryl, a 5 to 14 membered aromatic monocyclic or fused polycyclic moiety that includes from 1 to 4 heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen;
  • Y is optionally substituted arylene, a 5 to 14 membered aromatic monocyclic or fused polycyclic moiety that includes from 1 to 4 heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen; or a pharmaceutically acceptable salt there of.
  • the above library preferably contains compounds comprising from 2 to 1000000 compounds, and more preferably from 20 to 1000 compounds, of Formula (1) .
  • Z is preferably optionally substituted 9-, 10- or 13- membered fused bicyclic or tricyclic aromatic heterocyclic group having 1 or 2 heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen;
  • Y is preferably optionally substituted phenyl, optionally substituted naphthyl, optionally substituted 5- or 6- membered aromatic heterocyclic ring having 1 or 2 heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen, or optionally substituted 9- or 10- membered fused bicyclic aromatic heterocyclic group having 1 or 2 heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen.
  • the library mentioned above is useful for screening the biological activity of the said compounds.
  • optically active isomers and diastereomers of the compounds of Formula (1) are also considered part of this invention.
  • Such optically active isomers may be prepared from their respective optically active precursors, or by resolving the racemic mixtures. This resolution can be carried out by derivatization with a chiral reagent followed by chromatography or by repeated crystallization. Removal of the chiral auxiliary by standard methods affords substantially optically pure isomers of the compounds of the present invention or their precursors . Further details regarding resolutions can be obtained in Jacques, et al . , Enantiomers, Racemates, and Resolutions, John Wiley & Sons, 1981.
  • X is preferably NH.
  • the above library preferably contains compounds comprising from 2 to 1000000 pyrrole compounds, and more preferably from 20 to 1000 pyrrole compounds, of Formula (1) .
  • This library is particularly useful for screening the retinoic acid receptor agonizing activity of said compounds.
  • the pyrrole compounds of Formula (1) are useful whenever retinoic acid receptor agonis is efficacious, for example, as preventive and therapeutic agents for various cornification anomalies and skin diseases such as xeroderma pigmentosum, psoriasis, arthropathia psoriatica, acne or leukoplakia; various alopeciae such as alopeica areata, seborrheic alopecia or cachectic alopecia; various osteoporoses and osteopeniae such as postmenopausal osteoporosis, senile osteoporosis, steroidal osteoporosis, idiopathic osteoporosis, diabetic osteopenia, rheumatoid osteopenia or renal osteomalacia; diseases of bone and joint such as ectopic hyperostosis, osteoarthritis or shoulder periarthritis; automimmune diseases such as chronic rheumatoid arthritis, multiple sclerosis, systemic l
  • the library of compounds of Formula (1) according to the present invention may be screened for biological activity.
  • the library to be screened is exposed to a biological substance, usually a protein such as a receptor, enzyme, membrane binding protein or antibody; and the presence or absence of an interaction between the heterocycle derivative and the biological substance is determined.
  • a biological substance usually a protein such as a receptor, enzyme, membrane binding protein or antibody; and the presence or absence of an interaction between the heterocycle derivative and the biological substance is determined.
  • a biological substance usually a protein such as a receptor, enzyme, membrane binding protein or antibody; and the presence or absence of an interaction between the heterocycle derivative and the biological substance is determined.
  • this will comprise determining whether the biological substance is bound to one or more of the members of the library.
  • binding may be determined by attaching a label to the biological substance.
  • Commonly used labels include fluorescent labels. Other methods of labeling may be used, such as radioactive labels.
  • certain compounds of Formula (1) may exist in, and be isolated in, isomeric forms, including tautomeric forms or cis- or trans-iso ers, as well as optically active, racemic or diastereomeric forms.
  • the present invention encompasses library containing a plurality of compounds of Formula ( 1 ) in any of the tautomeric forms or as a mixture thereof .
  • the present invention encompasses library of compounds of Formula (1) as a mixture of diastereomers, as well as in the form of an individual diastereomer, and that the present invention encompasses library of compounds of Formula (1) as a mixture of enantiomers, as well as in the form of an individual enantiomer, any of which mixtures or form possesses agonism for retinoic acid receptors, it being well known in the art how to prepare or isolate particular forms and how to determine agonism for retinoic acid receptors by standard tests.
  • compounds of Formula (1) may exhibit polymorphism or may form a solvate with water or an organic solvent.
  • the present invention also encompasses any such polymorphic form, any solvate or any mixture thereof.
  • a pyrrole compound of Formula (1) is useful whenever retinoic acid receptor agonism is usuful, for example, as preventive and therapeutic agents for various cornification anomalies and skin diseases such as xeroderma pigmentosum, psoriasis, arthropathia psoriatica, acne or leukoplakia; various alopeciae such as alopeica areata, seborrheic alopecia or cachectic alopecia; various osteoporoses and osteopeniae such as postmenopausal osteoporosis, senile osteoporosis, steroidal osteoporosis, idiopathic osteoporosis, diabetic osteopenia, rheumatoid osteopenia or renal osteomalacia; diseases of bone and joint such as ectopic hyperostosis, osteoarthritis or shoulder periarthritis; automimmune diseases such as chronic rheumatoid arthritis, multiple sclerosis, systemic lup
  • the pyrrole compounds of Formula (1) are lowly toxic and highly safe, being useful also in this respect.
  • the route of administration may suitably be selected. Specifically, they may be orally administered as preventive or therapeutic agents in the form of tablets, powders, granules, capsules, syrups or the like, or may be parenterally administered in the form of suppositories, injections, external preparations or drops.
  • the dosage of the compound remarkably depends on the kind of diseases, the extent of symptom, the interval from sedation to the first administration, the age, sex and sensitivity of patient or the like, the compound may be administered generally in a dosage of about 0. 03 to 1000 mg, preferably 0.1 to 500 mg, still preferably of 0.1 to 100 mg per adult a day in several portions.
  • the dosage of the compound is generally about 0.001 to 3 mg/kg, preferably about 3 to 1000 mg/kg.
  • Those pyrrole compounds may be isolated in the form of a salt.
  • a salt of the compounds of formula (1) formed with a base or an acid such as one of those mentioned above are useful as a pharmaceutically acceptable salt for administration of the retinoic acid receptor agonistic agent and for preparation of a formulation of the agent.
  • Other base addition salts or acid addition salts may be prepared and used in the isolation and purification of the compound.
  • the process for preparing the library of compounds of the Formula (1) of the invention may be carried out in any reaction vessel capable of holding the liquid reaction medium and having, preferably, inlet and outlet means.
  • the present invention also provides a process for preparing the library of compounds of Formula (1) , by using a solid-supported intermediate of Formula (2) .
  • g is a solid-support
  • b is a single bond, -0-, -0C(O)-, -NR 6 -, -S-, -S0 2 NHC(0)-, -NC(0)R 6 - or -NS(0) 2 R 6 - where R 6 is hydrogen, alkyl, aryl, alkenyl or alkynyl;
  • f is optionally substituted arylene, a 5 to 14 membered aromatic monocyclic or fused polycyclic moiety that includes from 1 to 4 heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen;
  • d is a single bond or optionally substituted alkylene;
  • R 2 is a stable moiety independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl or aryl
  • R 3 is a stable moiety independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl or aryl
  • R 5 is optionally substituted aryl, a 5 to 14 membered aromatic monocyclic or fused polycyclic moiety that includes from 1 to 4 heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen.
  • solid-supported intermediate of Formula (2) is prepared by reacting a solid-supported enone with aldehyde.
  • solid supported-enone means a solid support that at least has one enone moiety chemically attached thereto.
  • this compound may be represented by the Formula (3) :
  • g is a solid-support, such as defined above; b is a single bond, -0-, -0C(0)-, -NR 6 -, -S-, -S0 2 NHC(0)-, -NC(0)R 6 - or -NS(0) 2 R 6 - where R 6 is hydrogen, alkyl, aryl, alkenyl or alkynyl; f is optionally substituted arylene, a 5 to 14 membered aromatic monocyclic or fused polycyclic moiety that includes from 1 to 4 heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen; d is a single bond or optionally substituted alkylene;
  • R 2 is a stable moiety independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl or aryl;
  • R 3 is a stable moiety independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl or aryl.
  • reaction is comprising of, (a) reacting a compound of Formula (5) :
  • f is optionally substituted arylene, a 5 to 14 membered aromatic monocyclic or fused polycyclic moiety that includes from 1 to 4 heteroatoms which are the same or different and which are selected from sulfur, oxygen and nitrogen;
  • R 2 is a stable moiety independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl or aryl;
  • R 3 is a stable moiety independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl or aryl) ;
  • the solid-supported intermediate of Formula (2) is prepared by reacting a solid-supported aldehyde with enone.
  • solid supported-aldehyde means a solid support that at least has one aldehyde moiety chemically attached thereto.
  • this compound may be represented by the Formula (4) :
  • g is a solid-support, such as defined above; b is a single bond, -0-, -OC(O)-, -NR"-, -S-, -S0 2 NHC(0)-, -NC(0)R 6 - or -NS(0) 2 R 6 - where R 6 is hydrogen, alkyl, aryl, alkenyl or alkynyl; f is optionally substituted arylene; d is a single bond or optionally substituted alkylene;
  • f may be substituted one to three times with a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, halo, hydroxy, alkoxy, alkylthio, carbonyl, amino, sulfonyl, aryl and where the substituents of the moieties substituted can themselves be substituted with one to three further substituents, if desired.
  • reaction is comprising of, (a) reacting a compound of Formula (9) :
  • reaction of preparing for formula (1) is as below;
  • the temperature for the coupling procedure may be between about 50°C and 100°C but is preferably between about 60°C and 80°C and is most preferably at about 65°C.
  • the solvents suitable for the coupling procedure include protic or aprotic solvents.
  • a preferred solvent is DMF.
  • the thiazolium salts suitable for the coupling procedure include 5- (2-hydroxyethyl) -4-methylthiazonium halide that has alkyl or arylalkyl substituents at 3 position.
  • a preferred thiazolium salt is 3-benzyl-5- (2-hydroxyethyl) -4- ethylthiazolium chloride.
  • the amount of the thiazolium salt suitable for the coupling procedure may vary, but is between about 0.1 equivalent to 10 equivalent but is preferably btween about 1 equivalent to 3 equivalent and most preferably is 2 equivalent.
  • the bases suitable for the coupling procedure include organic or inorganic bases.
  • a preferred base is triethylamine.
  • the amount of triethylamine is between about 0.3 equivalent to 5 equivalent but is preferably between about 1 equivalent to 3 equivalent and most preferably is 2 equivalent.
  • the time for the coupling reaction may vary, but generally is about 10 minutes and 3 days but preferably between about 2 hours and 18 hours .
  • the process for making libraries of compounds of the Formula (1) of the invention may be carried out in any reaction vessel capable of holding the liquid reaction medium and having, preferably, inlet and outlet means.
  • the process of the invention is preferably carried out in containers adapted for parallel array synthesis. With parallel array synthesis, individual reaction products are prepared in each of multiple reaction zones. The reaction zones are physically separated from one another in a reaction vessel.
  • a preferred parallel synthesis embodiment of the present invention is a diverse compound library in the form of a plurality of wellplates, each wellplate having wells containing a separate reaction product (library compound) .
  • the library compounds are conveniently identified by their wellplate number and "x" column and "y” row coordinates.
  • the process of making the library of phenyl ether compounds may be conveniently carried out in a conventional wellplate apparatus . It is particularly advantageous to carry out the method of the invention in a standard wellplate apparatus such as a plastic 96 well microtiter plate, or FLEXCHEM TM 96 well Synthesis Assembly available from Robbins Scientific.
  • the wellplate apparatus is in the form of a rigid or semi- rigid plate.
  • the plate has a common surface containing openings of a plurality of reservoirs arranged in rows and columns.
  • a standard form of wellplate apparatus is a rectangular plastic plate having 8 rows and 12 columns (total 96) of liquid retaining depressions, or reservoirs, on its surface.
  • a wellplate apparatus may optionally have other elements or structure such as a top or cover (e.g., plastic or foil) , a bottom in a form such as a plate or reservoir, clamping means to secure the wellplate and prevent loss of its contained compounds .
  • the amount of solid bound compound introduced into such reaction zone will depend on the desired amount of each library compound that is needed for conducting biological assays, archival storage and other related needs. Typically desired amount of individual reaction product is from 1 microgram to 50 milligrams .
  • the amount of solid bound compound in each reaction zone is represented by the symbol "(n)", where (n) represents the equivalents of compound.
  • (n) represents the equivalents of compound.
  • diverse coupling reagents are employed serially to synthesize a library of compound.
  • Combinatorial techniques are preferably very robust to work well for highly diverse groups of reactants.
  • the reactant is used in excess.
  • the method of the invention contemplates solution phase reactions where a stoichiometric excess of the coupling reactant is used.
  • the amount of coupling reactant used to ensure an excess is defined as at least 1.1 (n) and preferably a larger excess in the range of from 1.25 (n) to 5 (n) , where the variable (n) is as previously defined.
  • the 1.1 multiplier is used to ensure at least a 10 % stoichiometric excess of coupling agent is present to drive the reaction to completion.
  • the reaction zone is maintained at a temperature and for a time sufficient to permit reaction of solid bound compound with the coupling reactant, that is, to complete consumption of the solid bound compound and form an amount of compound necessary to conduct biological assays to determine the efficacy of the prepared library compounds.
  • the time, temperature, and pressure of the combinatorial reaction zones used for the creation of library compounds are not critical aspects of the invention. Reaction times for a single step of the reaction are generally from about 0.1 seconds to about 24 hours.
  • the temperature of the reaction may be any temperature between the freezing point and the boiling point of the liquid reaction medium, but is generally between about -10°C and about 80°C, with 10°C to 40°C being preferred and ambient temperatures (about 20°C-30°C) being most preferred.
  • the reactions may be conducted at subatmospheric pressure or superatmospheric pressure, but ambient atmospheric pressure (about 101325 Pa) is most often used.
  • Attaching the compounds to the solid support, cleaving the compounds from the solid support, and cyclization may be monitored by a number of conventional techniques, including, but not limited to, chromatography (preferably, thin layer chromatography) . Oxidation and coupling is described above.
  • the library intermediate dissolved in the solvent phase of the cleavage reaction may be used for the next reaction after drying without purification.
  • the purification of the library compound dissolved in the solvent phase of the reaction may be done by any conventional chemical or physical method.
  • the last purification step of the process may optionally be supplemented by a solvent removal step in which the solute library compound is removed from its solvent by conventional processes known in the art; such as solvent evaporation, distillation, salting out, solvent extraction, and etc.
  • the libraries of compounds of Formula (1) according to the present invention may be screened for biological activity.
  • the library to be screened is exposed to a biological substance, usually a protein such as a receptor, enzyme, membrane binding protein or antibodies wherein the presence or absence of an interaction between the heterocycle derivative and the biological substance is determined.
  • a biological substance usually a protein such as a receptor, enzyme, membrane binding protein or antibodies wherein the presence or absence of an interaction between the heterocycle derivative and the biological substance is determined.
  • a biological substance usually a protein such as a receptor, enzyme, membrane binding protein or antibodies wherein the presence or absence of an interaction between the heterocycle derivative and the biological substance is determined.
  • this will comprise determining whether the biological substance is bound to one or more of the members of the library.
  • binding may be determined by attaching a label to the biological substance.
  • Commonly used labels include fluorescent labels. Other methods of labeling may be used, such as radio active labels.
  • the degree of binding affinity may be determined by quantitating the amount or intensity of the bound label.
  • Illustrative additional assays include, but are not limited to, in vitro assays such as enzymatic inhibition, receptor - ligand binding, protein - protein interaction, and protein - DNA interaction; cell based, functional assays such as transcriptional regulation, signal transduction / second messenger, and viral infectivity; add, incubate & read assays such as scintillation proximity assays (SPA) , fluorescence polarization assay, fluorescence correlation spectroscopy, colorimetric biosensors, cellular reporter assays using reporter genes such as luciferase, green fluorescent protein, 0 -lactamase, and the like; and electrical cell impedance sensor assays .
  • in vitro assays such as enzymatic inhibition, receptor - ligand binding, protein - protein interaction, and protein - DNA interaction
  • cell based, functional assays such as transcriptional regulation, signal transduction / second messenger, and viral infectivity
  • ATRA all trans retinoic acid
  • CH 2 C1 2 dichloromethane
  • DIC diisopropylcarbodiimide
  • Relative IC 50 IC 50 /ATRA IC 50 .
  • c - not detectable (relative IC 50 > 1000) .
  • the resin (307 mg) was then suspended in DMF (16 ml) followed by addition of Dess-Martin reagent (330 mg, 0.778 mmol) . After standing for 3.5 h at r.t., the resin was rinsed with 5 x 20 ml of DMF and 5 x 20 ml of CH 2 C1 2 . The resin was dried in vacuum overnight.
  • the resin (100 mg) was then suspended in DMF (4 ml) followed by addition of 4, 5, 7-trimethylbenzofuran-2- carboxaldehyde (36 mg, 0.19 mmol), 3-benzyl-5- (2- hydroxyethyl) -4-methylthiazolium chloride (34 mg, 0.13 mmol), and Et 3 N (0.017 ml, 0.12 mmol). After standing for 3 h at 65 °C, the reaction vessel was allowed to cool to r.t. And the resin was rinsed with 3 x 6 ml of DMF and 3 x 6 ml of CH 2 C1 2 . The resin was then suspended in 50% TFA/CH 2 C1 2 (3 ml) for 2 h.
  • p-benzyloxybenzyl alcohol polystyrene (Wang) resin 75mg, 0.63 mmol/g, 0.047 mmol was rinsed with 1.5 ml of DMF and filtered. To the resin was added DMF (0.5ml) and 3-bromo-4-formylbenzoic acid (0.5 ml, 0.28 M in DMF, 0.14 mmol), DIC (0.5 ml, 0.28 M in DMF, 0.14 mmol), and DMAP (0.5 l, 0.28 Min DMF, 0.14 mmol).
  • the resin was rinsed with 3 x 1.5 ml of DMF and 2 x 1.5 ml of CH 2 C1 2 .
  • the resin was dried by nitrogen stream.
  • the resin was rinsed with 2 x 1 ml of DMF, followed by addition of 3-benzyl-5- (2- hydroxyethyl) -4-methylthiazolium chloride (1ml, 0.093 Min DMF, 0.093 mmol), Et 3 N (0.1 ml, 0.94 M in DMF, 0.094 mmol), and 4, 7-dimethylbenzofuran-2-yl vinyl ketone (0.5ml, 0.28MinDMF, 0.14 mmol) . After mixing for 4 h at 65 °C on ACT496 at 500 r.p.m.s, the reaction vessel was allowed to cool to r.t.
  • a pyrrole compound of the present invention to be an effective retinoic acid receptor agonist is evaluated in the following assay.
  • Mouse splenocyte proliferation assay induced by E. coli lipopolysaccharide (LPS) is performed according to the method previously reported with slight modifications. See C. Apfel, F. Bauer, M. Crettaz, L. Forni, M. Kamber, F. Kaufmann, P. LeMotte, W. Pirson, andM. A. Klaus, Proc. Natl. Acad. Sci. U.S.A.
  • BALB/c spleen cell suspensions are placed at 1.2 x 10 5 cells/180 ⁇ L/well in 96-well culture plates, in RPMI-1640 medium containing antibiotics, 50 ⁇ M 2- mercaptoethanol, 10% FBS and 5 ⁇ g/mL LPS. Then 20 ⁇ L of each compound serially diluted is added to the wells and the plates are incubated for 3 days at 37 °C, 5% C0 2 . Splenocytes are pulsed with 20 ⁇ L of 0.5 ⁇ Ci of [ 3 H] thymidine for further 6h.
  • IC 50 50% inhibitory concentration
  • Suitable conditions for this reaction include having a suitable solvent mixture with a base and a thiazolium salt, a suitable temperature and reacting for a suitable period of time.
  • a suitable solvent mixture is preferably of basic pH.
  • the base is organic base, more preferably base is TEA or sodium acetate and most preferably the base is TEA.
  • a suitable solvent is either protic or aprotic and preferably the solvent is DMF.
  • a suitable thiazolium salt is 5- (2-hydroxyethyl) -4- methylthiazoniu halide that has alkyl or arylalkyl substituents at 3 position, preferably the thiazolium salt is 3-benzyl-5- (2-hydroxyethyl) -4-methyl-l, 3-thiazolium chloride or 3-ethyl-5- (2-hydroxyrthyl) -4-methyl-l, 3- thiazolium bromide and most preferably the thiazolium salt is 3-benzyl-5- (2-hydroxyethyl) -4-methyl-l, 3-thiazolium chloride .
  • the reaction temperature is preferably between about 50°C and 100°C but more preferably between about 60°C and 80°C and most preferably at about 65°C.
  • the reaction time is preferably between about 10 minutes and 3 days, more preferably between about 2 hours and 18 hours.
  • the compounds (3) and (8), alternatively, compounds (4) and (10) react forming an intermediate (2) wherein g, b, f, d, R 2 , R 3 and R 5 are as defined above .
  • This intermediate (2) is optionally chemically derivatized prior to the displacement and cyclization procedure to form corresponding intermediate (2'):
  • f' , R 2 ', R 3 ' and R 5 ' substituents are each independently the same as substituents f, R 2 , R 3 and R 5 respectively if not derivatized or are each independently the chemically derivatized substituents respectively.
  • Examples of chemical derivatizationreactions include, but are not limited to, the following general derivatizations procedures .
  • f' , R 2 ' , R 3 ' andR 5 ' substituents are each independently the same as substituents f, R 2 , R 3 and R 5 respectively if not derivatized or are each independently the chemically derivatized substituents respectively.
  • each of f' , R 2 ', R 3 ' and R 5 ' may be correspondingly the same as f, R 2 , R 3 and R 5 or may represent the result of the optional chemical derivatization of the corresponding substituent, prior to displacement . It is understood from the synthetic routes that either R 2 ' or R 3 ' is hydrogen or that both of R 2 ' and R 3 ' are hydrogen.
  • the temperature for the displacement procedure may be between about 0°C and 60°C and is preferably at about 20°C.
  • the solvents suitable for the displacement procedure include protic and aprotic solvent mixtures, aqueous and anhydrous solvent mixtures.
  • a preferred solvent is TFA
  • a more preferred solvent mixture is TFA:CH 2 C1 2
  • the most preferred solvent mixture is about 50 % mixture of TFA and CH 2 C1 2 .
  • the time for the displacement reaction may vary, but generally is between about 5 minutes and 2 days but preferably between about 1 hour and 4 hours .
  • R 7 is hydrogen, alkyl, alkenyl, alkynyl, carbonyl or aryl; to form the product (13) :
  • the f' , R 2 ', R 3 ' andR 5 ' are each independently the same as substituents f, R 2 , R 3 and R 5 respectively if not derivatized or are each independently the chemically derivatized substituents respectively.
  • each of f' , R ' , R 3 ' and R 5 ' may be correspondingly the same as f, R 2 , R 3 and R 5 or may represent the result of the optional chemical derivatization of the corresponding substituent, prior to displacement and cyclization. It is understood from the synthetic routes that either R 2 or R 3 is hydrogen or that both of R 2 and R 3 are hydrogen.
  • the temperature for the cyclization procedure may be between about 60°C and 100°C and is preferably at about 65°C.
  • the solvents suitable for the cyclization procedure include protic and aprotic solvent mixtures, aqueous and anhydrous solvent mixtures.
  • a preferred solvent is alcohol, a more preferred solvent is methanol or ethanol, the most preferred solvent is methanol.
  • the time for the displacement reaction may vary, but generally is between about 10 minutes and 4 days but preferably between about 10 hour and 40 hours.
  • the intermediate (2) can be derivatized before the displacement and cyclization procedure to thereby provide further options for the groups in the final product.
  • the preferred, yet optional, derivatizations of the intermediate compound (2), and preferred conditions whereby optional derivatizations occur are as described above.
  • the solid supported mediated method of the invention may be carried out by way of parallel synthesis in any reaction vessel capable of holding the liquid reaction medium and having, preferably, inlet and outlet means.
  • the solid support mediated method of the invention is preferably carried out in containers adaptable to parallel array syntheses.
  • parallel array synthesis individual reaction products are prepared in each of multiple reaction zones.
  • the reaction zones are physically separated from one another in a reaction vessel.
  • Compounds can be added to the reaction vessel by multiple delivery apparatus, automated or robotic apparatus, any of that may be either manually or computer controlled.
  • a preferred parallel synthesis embodiment of the present invention is a diverse heterocycle compound library in the form of a plurality of wellplates, each wellplate having wells containing a separate reaction product (library compound) .
  • the wellplate apparatus is in the form of a rigid or semi-rigid plate, the plate having a common surface containing openings of a plurality of reservoirs arranged in rows and columns.
  • a standard form of wellplate apparatus is a rectangular plastic plate having 8 rows and 12 columns (total 96) of liquid retaining depressions, or reservoirs, on its surface.
  • a wellplate apparatus may optionally have other elements of structure such as a top or cover (e.g., plastic or foil) , a bottom in a form such as a plate or reservoir, clamping means to secure the wellplate and prevent loss of its contained compounds .
  • heterocycle library of compounds formed using the solid support mediated method aspects of the invention can be used to screen compounds for biological or other activity.
  • Myriad biological assays are know in the art and can be used to screen the heterocycle library of compounds.
  • the libraries of plurality of compounds according to the solid support mediated method of the present invention may be screened for biological activity.
  • a biological substance usually a protein such as a receptor, enzyme, membrane binding protein or antibody, and the presence or absence of an interaction between the heterocycle derivative and the biological substance is determined.
  • this will comprise determining whether the biological substance is bound to one or more of the members of the library.
  • binding may be determined by attaching a label to the biological substance.
  • Commonly used labels include fluorescent labels. Other methods of labeling may be used, such as radioactive labels.
  • the degree of binding affinity may be determined by quantitating the amount or intensity of the bound label.
  • various biologically active compounds may be selected by identifying that compounds bind the particular biological substance most effectively.
  • additional assays include but are not limited to in vitro assays such as enzymatic inhibition, receptor - ligand binding, protein - protein interaction, and protein - DNA interaction; cell based, functional assays such as transcriptional regulation, signal transduction / second messenger, and viral infectivity; add, incubate and read assays such as scintillation proximity assays (SPA) , fluorescence polarization assay, fluorescence correlation spectroscopy, colorimetric biosensors, cellular reporter assays using reporter genes such as luciferase, green fluorescent protein, b-lactamase, and the like; and electrical cell impedance sensor assays. All of the above assays are known in the art to be predictive of success for an associated disease state.
  • SPA scintillation proximity assays
  • fluorescence polarization assay fluorescence correlation spectroscopy

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Abstract

L'invention concerne une bibliothèque combinatoire de composés du pyrrole et un procédé de préparation de la bibliothèque. Celle-ci est utile pour le balayage de l'activité biologique des composés du pyrrole.
PCT/JP2002/000388 2002-01-21 2002-01-21 Bibliotheque combinatoire de composes heterocycliques WO2003062230A1 (fr)

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WO2013052647A3 (fr) * 2011-10-04 2013-07-11 Quretino Therapeutics, Inc. Formulations et utilisations d'agonistes sélectifs du récepteur de l'acide rétinoïque
WO2016097004A1 (fr) * 2014-12-17 2016-06-23 King's College London Composés de type acide bicyclohétéroaryl-hétéroaryl-benzoïque utilisés comme agonistes de récepteurs bêta de l'acide rétinoïque (rarβ)
US10870644B2 (en) 2016-06-22 2020-12-22 King's College London Crystalline forms of 4-(5-(4,7-dimethylbenzofuran-2-yl)-l,2,4-oxadiazol-3-yl)benzoic acid and processes for their preparation

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013052647A3 (fr) * 2011-10-04 2013-07-11 Quretino Therapeutics, Inc. Formulations et utilisations d'agonistes sélectifs du récepteur de l'acide rétinoïque
US8772273B2 (en) 2011-10-04 2014-07-08 Quretino Therapeutics, Inc. Formulations and uses of retinoic acid receptor selective agonists
WO2016097004A1 (fr) * 2014-12-17 2016-06-23 King's College London Composés de type acide bicyclohétéroaryl-hétéroaryl-benzoïque utilisés comme agonistes de récepteurs bêta de l'acide rétinoïque (rarβ)
JP2017537967A (ja) * 2014-12-17 2017-12-21 キングス カレッジ ロンドン レチノイン酸受容体ベータ（ＲＡＲβ）アゴニストとしてのビシクロヘテロアリール−ヘテロアリール−安息香酸化合物
US9994559B2 (en) 2014-12-17 2018-06-12 King's College London Bicycloheteroaryl-heteroaryl-benzoic acid compounds as retinoic acid receptor beta (RARβ) agonists
US10385044B2 (en) 2014-12-17 2019-08-20 King's College London Bicycloheteroaryl-heteroaryl-benzoic acid compounds as retinoic acid receptor beta (RARβ) agonists
AU2015367531B2 (en) * 2014-12-17 2020-04-30 King's College London Bicycloheteroaryl-heteroaryl-benzoic acid compounds as retinoic acid receptor beta (RARbeta) agonists
US10752616B2 (en) 2014-12-17 2020-08-25 King's College London Bicycloheteroaryl-heteroaryl-benzoic acid compounds as retinoic acid receptor beta (RARβ) agonists
US11401265B2 (en) 2014-12-17 2022-08-02 King's College London Bicycloheteroaryl-heteroaryl-benzoic acid compounds as retinoic acid receptor beta (RARβ) agonists
US10870644B2 (en) 2016-06-22 2020-12-22 King's College London Crystalline forms of 4-(5-(4,7-dimethylbenzofuran-2-yl)-l,2,4-oxadiazol-3-yl)benzoic acid and processes for their preparation
US11584741B2 (en) 2016-06-22 2023-02-21 King's College London Crystalline forms of 4-(5-(4,7-dimethylbenzofuran-2-yl)-1,2,4-oxadiazol-3-yl)benzoic acid and processes for their preparation

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