WO2010082912A1 - Dérivés de composés aromatiques à noyaux multiples et utilisations comme agents anti-tumoraux - Google Patents

Dérivés de composés aromatiques à noyaux multiples et utilisations comme agents anti-tumoraux Download PDF

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WO2010082912A1
WO2010082912A1 PCT/US2009/000257 US2009000257W WO2010082912A1 WO 2010082912 A1 WO2010082912 A1 WO 2010082912A1 US 2009000257 W US2009000257 W US 2009000257W WO 2010082912 A1 WO2010082912 A1 WO 2010082912A1
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cancer
compound
mammal
colon
colorectal
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PCT/US2009/000257
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English (en)
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Wieslaw M. Cholody
Yi Zang
Karina Zuck
Jeffrey W. H. Watthey
Zoe Ohler
Jeffrey Strovel
Norman E. Ohler
Sheela Chellappan
Janak Padia
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Avalon Pharmaceuticals
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems 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 carbon atoms of the ring system
    • C07D219/08—Nitrogen atoms

Definitions

  • Provisional Application 60/928,592 filed 10 May 2007 and U.S. Provisional
  • the present invention relates to the field of novel compounds useful for the treatment of cancer and methods of use thereof.
  • the Wnt/beta-catenin signaling pathway is recognized as one of the key signaling pathways in cancer and as a valid target for therapeutic intervention in many tumor types, especially colon tumors.
  • the cells of multicellular organisms have the ability to recognize and signal each other, sometimes from fair distances. Such signaling may be accomplished by production of signaling molecules produced by one cell and which subsequently bind to a specific receptor on a different cell. Such signaling pathways have been implicated in various disease processes, including cancer. Wnt signaling, via receptor binding and subsequent increase in intracellular ⁇ -catenin, is referred to as the canonical pathway. Wnt proteins form a family of highly conserved secreted signaling molecules that regulate cell-to-cell interactions and have been implicated in cancer pathogenesis. Wnt proteins bind to receptors of the Frizzled and LRP families on the cell surface. Through several cytoplasmic relay components, the signal is transduced to ⁇ - catenin, which then enters the nucleus and forms a complex with TCF to activate transcription of Wnt target genes.
  • Wnt polypeptides is either present on the surface of a signaling cell or released by that cell and eventually contact a specific cell- surface receptor of another cell.
  • GSK-3/APC/Axin GSK-3/APC/Axin
  • APC Adenomatous Polyposis CoIi
  • mutations that promote constitutive activation of the Wnt signaling pathway can lead to cancer, [for a review, see Logan and Nusse, "The Wnt Signaling Pathway in Development and Disease," in Ann. Rev. Cell Dev. Biol., 20:781 -810 (2004)]
  • mutations in Axin2 may predispose an individual to colon cancer (Lammi et a)., Am. J. Hum. Genet., 74:1043-50 (2004)).
  • familial adenomatous polyposis an inherited disease characterized by numerous polyps in the colon and rectum, is often caused by truncation of APC (another Wnt signaling- pathway protein), which promotes aberrant activation of the Wnt pathway, [see: Kinzler et al., Science, 253:661 -665 (1991 )] Mutations in APC and ⁇ - catenin have also be detected in colon cancer and other tumor types (for a review see Giles et al., Biochim. Biophys. Acta, 1653:1-24 (2003)).
  • APC another Wnt signaling- pathway protein
  • the present invention provides such agents in the form of disulfonamide derivatives of fluorene, anthracene, xanthene, dibenzosuberone and acridine that reduce levels of beta-catenin in tumor cells.
  • Structurally related fluorene and anthracene derivatives with the sulfonamide groups substituted with aromatic amines are known in the art (see, for example, US 2004/0019042) as inhibitors of P2X3 and P2X2/3 containing receptors and have been found useful in the treatment and prevention of disorders such as bladder overactivity, urinary incontinence or pain.
  • novel structurally related compounds can be prepared and used as modulators of the Wnt/ ⁇ -catenin pathway. It is known that ⁇ -catenin is a regulator of the Wnt signally pathway, (see Willed and Nusse, Current Opinion in Genetics and Development, 8:95-102 (1998).
  • the invention provides novel compounds useful for the treatment of cancer that interfere with the Wnt signaling pathway and reduce levels of beta-catenin in cancer cells, and methods for their synthesis.
  • these compounds include disulfonamide derivatives of fluorene, anthracene, xanthene, dibenzosuberone and acridine that reduce levels of beta-catenin in tumor cells.
  • Ri, R2, R3, and R 4 are each independently selected from H, alkyl, heteroalkyl, cycloalkyl, arylcycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and each of said NRiR 2 and NR 3 R 4 can independently combine to form a heterocycloalkyl
  • R 5 and R 6 are each independently selected from H, OH, SH, alkoxy, thioalkoxy, alkyl, halogen, CN, CF 3 , NO 2 , COOR D , CONRDRE, NR D R E , NR D COR EI NR D SO 2 R E> and NR F CONR D R E ; wherein R 0 , RE and RF are independently H, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl;
  • NR 1 Ra and NR 3 R 4 are not identical then R 1 and R 3 are each independently selected from H and lower alkyl, and wherein R 2 and R 4 are each independently selected from lower alkoxy(loweralkyl), di(lower)alkylamino(lower)alkyl, halobenzyl, morpholino(lower)alkyl, or NR 1 R2 and NR 3 R 4 are independently piperidino, morpholino, piperazino, N- phenylpiperazino, ethylamino, or substituted glycine
  • NR 1 R2 and NR 3 R 4 are not identical and R 1 , R 2 , R 3 , and R 4 are each independently selected from C 1 -Cs alkyl, C 1 O alkyl, C1 6 alkyl, C 17 alkyl, phenyl, benzyl, naphthalenyl, piperizino, pyridinyl, pyrazolyl, benzimidazolyl, triazolyl; or NR 1 R 2 and NR 3 R 4 are independently piperidino, morpholino, or piperazino.
  • NR 1 R 2 and NR 3 R 4 are not identical, and wherein R 1 , R 2 , R 3 , and R 4 are each independently selected from methyl, ethyl, hydroxy-C- ⁇ -C 3 -alkyl, SH,
  • NR 1 R 2 and NR 3 R 4 are unsubstituted piperidino, N-methylpiperazino or N- methylhomopiperazino,
  • the compounds of the invention include those of Tables 2 to 9 and said compounds make up the invention either individually or in any combination.
  • the present invention also provides therapeutic compositions of any of the compounds of the invention, such as the compounds of Tables 1 to 9 and 11.
  • the present invention also relates to a method for ameliorating cancer or tumor metastasis in a mammal comprising administering to said mammal an effective amount of a compound of the invention.
  • a method for ameliorating cancer or tumor metastasis in a mammal comprising administering to said mammal an effective amount of a compound of the invention.
  • Especially contemplated are uses of the compounds of Tables 1 to 9 and 11.
  • Preferred acyl groups include acetyl, formyl, and propionyl, with acetyl being most preferred.
  • Alkyl means a saturated hydrocarbon radical having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 5 carbon atoms, most preferably 1 to 3 carbon atoms, that may be branched or unbranched.
  • alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like, wherein methyl, ethyl, n-propyl, and isopropyl represent specifically preferred examples.
  • alkenyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon radical having one or more carbon-carbon double-bonds and having 2 to 15 carbon atoms, preferably 2 to 10, more preferably 2 to 5 carbon atoms, more preferably two to about eighteen carbons.
  • alkenyl radicals include ethenyl, propenyl, butenyl, 1 ,3-butadienyl and the like.
  • alkynyl refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon radical having one or more carbon-carbon triple-bonds and having 2 to 15 carbon atoms, preferably 2 to 10, more preferably 2 to 5 carbon atoms, more preferably from two to about twelve carbon atoms, from two to about six carbon atoms as well as those having from two to about four carbon atoms.
  • alkynyl radicals include ethynyl, 2-propynyl, 2- butynyl, 1 ,3-butadiynyl and the like.
  • Preferred branched alkyl, alkenyl and alkynyl chains have one or two branches, preferably one branch, and each may be unsubstituted or substituted with from 1 to 4 substituents, preferably up to 3 substituents, more preferably 2 substituents and most preferably one substituent.
  • Preferred substituents are hydrocarbon, halo (preferably F, Cl 1 Br and I), hydroxy, aryloxy (e.g., phenoxy), heteroaryloxy, acyloxy (e.g., acetoxy), carboxy, aryl (e.g., phenyl), heteroaryl, cycloalkyl, heteroalkyl, heterocycloalkyl, spirocycle, amino, amido, acylamino, keto, thioketo, cyano, or any combination thereof.
  • Preferred hydrocarbons are methyl, ethyl, propyl, isopropyl, butyl, vinyl, allyl, butenyl, and exomethylenyl.
  • a “lower alkyl” is a shorter alkyl, e.g., one containing from one to about six carbon atoms.
  • a “lower” alkyl, alkenyl or alkynyl moiety is a chain comprised of 1 to 10, preferably from 1 to 8, carbon atoms in the case of alkyl and 2 to 10, preferably 2 to 8, carbon atoms in the case of alkene and alkyne.
  • Alkoxy means an oxygen radical having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl or alkenyl (i.e., -O-alkyl or -O-alkenyl).
  • alkoxy radicals include methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, allyloxy and the like.
  • Aryl is an aromatic hydrocarbon ring. Aryl rings are monocyclic or fused bicyclic ring systems. Monocyclic aryl rings contain 6 carbon atoms in the ring. Monocyclic aryl rings are also referred to as phenyl rings. Bicyclic aryl rings contain from 8 to 17 carbon atoms, preferably 9 to 12 carbon atoms, in the ring.
  • Bicyclic aryl rings include ring systems wherein one ring is aryl and the other ring is aryl, cycloalkyl, or heterocycloakyl.
  • Preferred bicyclic aryl rings comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7- membered rings.
  • Aryl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring.
  • Aryl may be substituted with halo, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, aryloxy, alkoxy, heteroalkyloxy, carbamyl, haloalkyl, methylenedioxy, heteroaryloxy, or any combination thereof.
  • Preferred aryl rings include naphthyl, tolyl, xylyl, and phenyl. The most preferred aryl ring radical is phenyl.
  • Aryloxy is an oxygen radical having an aryl substituent (i.e., -O-aryl).
  • Preferred aryloxy groups include, for example, phenoxy, napthyloxy, methoxyphenoxy, and methylenedioxyphenoxy.
  • Cycloalkyl refers to a saturated hydrocarbon ring that is not aromatic. Cycloalkyl rings are monocyclic, or are fused, spiro, or bridged bicyclic or polycyclic ring systems. Monocyclic cycloalkyl rings contain from about 3 to about 12 carbon atoms, preferably from 3 to 7 carbon atoms, in the ring. Bicyclic cycloalkyl rings contain from 7 to 17 carbon atoms, preferably from 7 to 12 carbon atoms, in the ring. Preferred bicyclic cycloalkyl rings comprise 4-, 5- 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings.
  • Cycloalkyl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Cycloalkyl may be substituted with halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy, or any combination thereof. Preferred cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl rings.
  • lower alkenyl or “lower alkynyl” refers to an alkenyl or alkynyl radical, respectively, having from two to about six carbons in the carbon chain and not including substituents.
  • Halo or "halogen” is fluoro, chloro, bromo or iodo. Preferred halo are fluoro, chloro and bromo; more preferred typically are chloro and fluoro, especially fluoro.
  • Heteroatom is a nitrogen, sulfur, or oxygen atom. Groups containing more than one heteroatom may contain different heteroatoms.
  • Heteroalkyl is a saturated or unsaturated chain containing carbon and at least one heteroatom, wherein no two heteroatoms are adjacent. Heteroalkyl chains contain from 2 to 15 member atoms (carbon and heteroatoms) in the chain, preferably 2 to 10, more preferably 2 to 5. For example, alkoxy (i.e., -O-alkyl or -O-heteroalkyl) radicals are included in heteroalkyl. Heteroalkyl chains may be straight or branched. Preferred branched heteroalkyl have one or two branches, preferably one branch. Preferred heteroalkyl are saturated. Unsaturated heteroalkyl have one or more carbon-carbon double bonds and/or one or more carbon-carbon triple bonds.
  • Preferred unsaturated heteroalkyls have one or two double bonds or one triple bond, more preferably one double bond.
  • Heteroalkyl chains may be unsubstituted or substituted with from 1 to 4 substituents.
  • Preferred substituted heteroalkyl are mono-, di-, or tri-substituted.
  • Heteroalkyl may be substituted with lower alkyl, haloalkyl, halo, hydroxy, acyloxy, carboxy, amino, acylamino, amido, keto, thioketo, cyano, or any combination thereof.
  • an alkyl derivative such as "- ethylpyridine” the dash "-" indicates the point of attachment of the substituent.
  • ethylpyridine means attachment of ethylpyridine via the ethyl portion of the group whereas "ethylpyridine-" means attachment via the pyridine ring.
  • Heteroaryl is an aromatic ring containing carbon atoms and from 1 to about 6 heteroatoms in the ring. Heteroaryl rings are monocyclic or fused bicyclic ring systems. Monocyclic heteroaryl rings contain from about 5 to about 9 member atoms (carbon and heteroatoms), preferably 5 or 6 member atoms, in the ring. Bicyclic heteroaryl rings contain from 8 to 17 member atoms, preferably 8 to 12 member atoms, in the ring. Bicyclic heteroaryl rings include ring systems wherein one ring is heteroaryl and the other ring is aryl, heteroaryl, cycloalkyl, or heteroalkyl, heterocycloalkyl.
  • Preferred bicyclic heteroaryl ring systems comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings.
  • Heteroaryl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring.
  • Heteroaryl may be substituted with halo, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy, heteroaryloxy, or any combination thereof.
  • Preferred heteroaryl rings include, but are not limited to, the following:
  • a fused heteroaryl radical may contain from two to four fused rings and where the ring of attachment is a heteroaromatic ring, the other individual rings within the fused ring system may be aromatic, heteroaromatic, alicyclic or heterocyclic.
  • heteroaryl also includes mono-heteroaryls or fused heteroaryls having from five to about twelve skeletal ring atoms, as well as those having from five to about ten skeletal ring atoms.
  • the term "lower heteroaryl” refers to a heteroaryl having five to about ten skeletal ring atoms, e.g., pyridyl, thienyl, pyrimidyl, pyrazinyl, pyrrolyl, or furanyl.
  • Heteroaryloxy is an oxygen radical having a heteroaryl substituent (i.e., -O-heteroaryl).
  • Preferred heteroaryloxy groups include (for example) pyridyloxy, furanyloxy, (thiophene)oxy, (oxazole)oxy, (thiazole)oxy, (isoxazole)oxy, pyrmidinyloxy, pyrazinyloxy, and benzothiazolyloxy.
  • Heterocycloalkyl is a saturated or unsaturated ring containing carbon atoms and from 1 to 4 (preferably 1 to 3) heteroatoms in the ring. Heterocycloalkyl rings are not aromatic.
  • Heterocycloalkyl rings are monocyclic, or are fused, bridged, or spiro bicyclic ring systems.
  • Monocyclic heterocycloalkyl rings contain from about 3 to about 9 member atoms (including both carbons and heteroatoms), preferably from 5 to 7 member atoms, in the ring.
  • Bicyclic heterocycloalkyl rings contain from 7 to 17 member atoms, preferably 7 to 12 member atoms, in the ring.
  • Bicyclic heterocycloalkyl rings contain from about 7 to about 17 ring atoms, preferably from 7 to 12 ring atoms.
  • Bicyclic heterocycloalkyl rings may be fused, spiro, or bridged ring systems.
  • Preferred bicyclic heterocycloalkyl rings comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings.
  • Heterocycloalkyl rings may be unsubstituted (i.e., contain hydrogens as substituents of the ring atoms) or substituted (on either carbons or heteroatoms or both) with from 1 to 4 substituents selected from methyl, cyano, hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido, alkyl, heteroalkyl, phenyl, alkoxy, aryloxy or any combination thereof.
  • Preferred substituents on heterocycloalkyl include methyl, ethoxyl, and halo.
  • a heterocycloalkyl ring may be attached as a substituent of a larger structure by any chemically feasible atom of said heterocycloalkyl ring.
  • Preferred heterocycloalkyl rings include, but are not limited
  • membered ring can embrace any cyclic structure, including aromatic, heteroaromatic, alicyclic, heterocyclic and polycyclic fused ring systems as described below.
  • membered is meant to denote the number of skeletal atoms that constitute the ring.
  • pyridine, pyran, and pyrimidine are six-membered rings and pyrrole, tetrahydrofuran, and thiophene are five-membered rings.
  • alkylaryl refers to an aryl radical as defined above in which one H atom is replaced by an alkyl radical as defined above, such as, for example, tolyl, xylyl and the like.
  • arylalkyl or “aralkyl,” alone or in combination, refers to an alkyl radical as defined above in which one H atom is replaced by an aryl radical as defined above, such as, for example, benzyl, 2-phenylethyl and the like.
  • heteroarylalkyl refers to an alkyl radical as defined above in which one H atom is replaced by a heteroaryl radical as defined above, each of which may be optionally substituted but wherein the aryl group is attached to a larger core structure with the alkyl group being the terminal moiety.
  • alkylheteroaryl refers to an alkyl radical as defined above in which one H atom is replaced by a heteroaryl radical as defined above, each of which may be optionally substituted but wherein the alkyl group is attached to a larger core structure with the heteroaryl group being the terminal moiety.
  • alkylthio alone or in combination, refers to an alkylthio radical, alkyl-S--, wherein the term alkyl is as defined above.
  • arylthio alone or in combination, refers to an arylthio radical, aryl-S--, wherein the term aryl is as defined above.
  • heteroarylthio refers to the group heteroaryl-S-, wherein the term heteroaryl is as defined above.
  • acyloxy refers to the ester group -OC(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl, or heteroarylalkyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl or heteroarylalkyl may be optionally substituted.
  • carboxy esters refers to -C(O)OR where R is alkyl, aryl or arylalkyl, wherein the alkyl, aryl and arylalkyl groups may be optionally substituted.
  • carboxy refers to the structure_-C(O)NRR' where nitrogen is attached to the carbonyl carbon and each of R and R' are independently selected from the group consisting of H, alkyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl and heteroarylalkyl, wherein the alkyl, aryl, heteroaryl, alicyclic, heterocyclic, or arylalkyl groups may be optionally substituted.
  • alkylamino refers to the group -NHR' where R is independently selected from alkyl.
  • dialkylamino refers to the group -NRR' where R and R 1 are alkyls.
  • sulfuride refers to a sulfur atom covalently linked to two atoms; the formal oxidation state of said sulfur is (II).
  • thioether may be used interchangeably with the term “sulfide.”
  • sulfoxide refers to a sulfur atom covalently linked to three atoms, at least one of which is an oxygen atom; the formal oxidation state of said sulfur atom is (IV).
  • sulfone refers to a sulfur atom covalently linked to four atoms, at least two of which are oxygen atoms; the formal oxidation state of said sulfur atom is (Vl).
  • aryl optionally mono- or di- substituted with an alkyl means that the alkyl may but need not be present, or either one alkyl or two may be present, and the description includes situations where the aryl is substituted with one or two alkyls and situations where the aryl is not substituted with an alkyl.
  • Optionally substituted groups may be substituted or unsubstituted.
  • substituents of an "optionally substituted" group may include, without limitation, one or more substituents independently selected from the following groups or designated subsets thereof: lower alkyl, lower alkenyl, lower alkynyl, lower aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl, heteroarylalkyl, lower alkoxy, lower aryloxy, amino, alkylamino, dialkylamino, diarylalkylamino, alkylthio, arylthio, heteroarylthio, oxo, oxa, carbonyl (--C(O)), carboxyesters (-- C(O)OR), carboxamido (--C(O)NH 2 ), carboxy, acyloxy, --H, halo, -CN, --NO 2 , - -N 3 , --SH, --OH, --C(O)CH 3 , perhaloalkyl, perhaloalkoxy, perhaloacyl
  • An optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., --CF 2 CF 3 ), monosubstituted (e.g., -- CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., --CH 2 CF 3 ).
  • Independently selected groups are groups present in the same structure that need not all represent the same substitution. For example, where two substituents are represented as R and each R is said to be independently selected from H, methyl, ethyl, etc., this means that where one R is methyl, the other R may be methyl but could be H or ethyl (or any other recited substitution). Typical embodiments appear in the tables.
  • Some of the compounds of the present invention may contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms.
  • the scope of the present invention is intended to cover all isomers per se, as well as mixtures of cis and trans isomers, mixtures of diastereomers and racemic mixtures of enantiomers (optical isomers) as well. Further, it is possible using well known techniques to separate the various forms, and some embodiments of the invention may feature purified or enriched species of a given enantiomer or diastereomer.
  • a “pharmacological composition” refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, with other chemical components, such as pharmaceutically acceptable carriers and/or excipients.
  • the purpose of a pharmacological composition is to facilitate administration of a compound to an organism.
  • pharmaceutically acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1 ) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum
  • excipient refers to an inert substance added to a pharmacological composition to further facilitate administration of a compound.
  • excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • the term "therapeutic effect” includes, but is not limited to, the inhibition, in whole or in part, of the growth of cells characteristic of a proliferative disorder, e.g., colon cancer.
  • a therapeutic effect may also include amelioration of one or more of the symptoms of the disease, other than cell growth or size of the cell mass, and may include 1) a reduction in the number of cells; 2) a reduction in cell size; 3) inhibition (i.e., slowing, preferably stopping) of cell infiltration (i.e., metastasis) into peripheral organs; 3) inhibition or slowing of cell growth; and/or 4) relieving one or more symptoms associated with the disease, such as cancer. Any amount or dose of a compound disclosed herein that results in such a therapeutic effect is deemed to be a "therapeutically effective dose” or a "therapeutically effective amount” of said compound.
  • the phrase "effective amount” means an amount sufficient to effect a desired response, or to ameliorate a symptom or sign, with respect to metastasis or primary tumor progression, size, or growth.
  • Typical mammalian treatment recipients include mice, rats, cats, dogs, and primates, including humans.
  • An effective amount for a particular patient may vary depending on factors such as the condition being treated, the overall health of the patient, the method, route, and dose of administration and the severity of side affects.
  • the effect will result in a change in quantitation of at least about 10%, preferably at least 20%, 30%, 50%, 70%, or even 90% or more.
  • an effective amount is in ratio to a combination of components and the effect is not limited to individual components alone.
  • a “solvate” is a complex formed by the combination of a solute (e.g., a metalloprotease inhibitor) and a solvent (e.g., water). See J. Honig et al., The Van Nostrand Chemist's Dictionary, p. 650 (1953).
  • optical isomer e.g., a cis and/or trans isomer
  • stereoisomer e.g., a cis and/or trans isomer
  • diastereomer e.g., a cis and/or trans isomer
  • optical isomer e.g., a cis and/or trans isomer
  • stereoisomer e.g., a cis and/or trans isomer
  • diastereomer e.g., a cis and/or trans isomer
  • the illustration of specific protected forms and other derivatives of the compounds of the instant invention is not intended to be limiting.
  • the application of other useful protecting groups, salt forms, prodrugs etc. is within the ability of the skilled artisan.
  • a prodrug is a form of a drug that must undergo chemical conversion by metabolic processes before becoming an active, or fully active, pharmacological agent.
  • a prodrug is not active, or is less active, in its ingested or absorbed or otherwise administered form.
  • a prodrug may be broken down by bacteria in the digestive system into products, at least one of which will become active as a drug. Alternatively, it may be administered systemically, such as by intravenous injection, and subsequently be metabolized into one or more active molecules.
  • the term “IC 50 " refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response.
  • the "IC 50 " value of a compound of the invention can be greater for normal cells than for cells exhibiting a proliferative disorder, e.g., breast cancer cells. The value depends on the assay used.
  • a "standard” is meant a positive or negative control.
  • a negative control in the present case refers to a normal as opposed to a cancerous cell, e.g., a sample possessing Wnt/ ⁇ -catenin pathway activity that correlates with a normal cell.
  • a negative control may also include a sample that contains no such pathway.
  • a positive control does contain such pathway, preferably of an amount that correlates with overexpression as found in proliferative disorders, e.g., breast cancers.
  • the controls may be from cell or tissue samples, or else contain purified ligand (or absent ligand), immobilized or otherwise. In some embodiments, one or more of the controls may be in the form of a diagnostic "dipstick.”
  • selective targeting is meant affecting one type of cell to a greater extent than another, e.g., in the case of cancerous cells versus noncancerous cells.
  • the present invention provides a compound having the structure of Formula I
  • Ri, R 2 , R 3 , and R 4 are each independently selected from H, alkyl, heteroalkyl, cycloalkyl, arylcycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and each of said NRiR 2 and NR 3 R 4 can independently combine to form a heterocycloalkyl,
  • R 5 and RQ are each independently selected from H, OH, SH, alkoxy, thioalkoxy, alkyl, halogen, CN, CF 3 , NO 2 , COOR D , CONR D R E , NR D R E , NR D COR E , NR D SO 2 R E , and NR F CONR D RE; wherein RD, RE and RF are independently H, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl;
  • Ri and R 3 are each independently selected from H and lower alkyl, and wherein R 2 and R 4 are each independently selected from lower alkoxy(loweralkyl), di(lower)alkylamino(lower)alkyl, halobenzyl, morpholino(lower)alkyl, or
  • NR1R 2 and NRsR 4 are not identical and Ri, R2, R3, and R 4 are each independently selected from C1-C 5 alkyl, C10 alkyl, C1 6 alkyl, C 17 alkyl, phenyl, benzyl, naphthalenyl, piperizino, pyridinyl, pyrazolyl, benzimidazolyl, triazolyl; or NRiR 2 and NR 3 R 4 are independently piperidino, morpholino, or piperazino.
  • NRiR 2 and NR 3 R 4 are not identical, and wherein R 1 , R 2 , R 3 , and R 4 are each independently selected from methyl, ethyl, hydroxy-C ⁇ Cs-alkyl, SH, RO, COOH, SO, NH 2 , and phenyl or wherein one or both of non-identical NR1R2 and NR 3 R 4 is unsubstituted piperidino, N-methylpiperazino or N- methylhomopiperazino,
  • R 3 or R 4 is not H or alkyl
  • the compound of Formula I is a structure wherein Y is O, or wherein Y is NRi or wherein Y is NORi and wherein Ri is as defined elsewhere herein.
  • Y is O 1
  • a compound of Formula I has the structure of Formula II, Formula or has the structure of Formula Formula or has the structure of Formula IV,
  • the compounds of the invention are derivatives of one of the following ring systems, especially disulfonamide derivatives thereof:
  • Such compounds may be suitably substituted with any of the substitutents described for Formula I 1 preferably any of the substitutents described in Tables 1 , 2, 3, 4, 5, 6, 7, 8 and/or 9.
  • the present invention also relates to compositions of compounds, including those in Tables 1-9, and having structures of Formula I in a therapeutically effective amount in pharmaceutically acceptable carrier
  • Ri ⁇ R2, R 3 , and R 4 are each independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, arylcycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and each of said NRiR 2 and NR3R 4 can independently form heterocycloalkyl
  • R 5 and R 6 are selected from hydrogen, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF 3 , NO 2 ,
  • R 0 , RE and RF are independently hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
  • the compounds of said compositions may also contain a multi-ring cycloalkyl or heterocycloalkyl bridge structure (as shown in the tables) containing a total of up to 12 atoms an up to 4 heteroatoms selected from N and O.
  • the present invention also provides therapeutic compositions of any of the compounds of the invention, such as the compounds of Tables 1 to 9.
  • the compounds of the invention may be in the form of pharmaceutically acceptable salts, esters, amides, stereoisomers, geometric isomers, solvates or prodrugs thereof.
  • a compound of the invention is a stereoisomer, the latter may be an enantiomer or a diastereomer.
  • the form of the compound used for pharmaceutical purposes may include either enantiomer or the racemate, although one of said enentiomers may be preferred, such as where it is the active form or is more active than the other enentiomer.
  • said compound of the invention is a geometric isomer (e.g., contains a carbon pair with substituents attached in cis- or trans- configuration)
  • either the cis- form, or the trans- form may be preferred for pharmaceutical use, although mixtures of the cis- and transforms may be used in the methods of the invention to the extent they have the desired pharmaceutical effect.
  • a “pharmaceutically-acceptable salt” is a cationic salt formed at any acidic (e.g., carboxylic acid) group, or an anionic salt formed at any basic (e.g., amino) group. Many such salts are known in the art, as described in WO 87/05297 (Johnston et al., published September 11 , 1987 incorporated by reference herein).
  • Suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydriodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, oxalate; palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,
  • Preferred cationic salts include the alkali metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and calcium) and organic salts.
  • Preferred anionic salts include the halides (such as chloride salts), sulfonates, carboxylates, phosphates, and the like.
  • compositions of the present invention that contain one or more acidic functional groups are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Illustrative examples of some of the bases that can be used include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (Ci -4 alkyl) 4 , and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. This invention also envisions the quatemization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quatemization.
  • Such salts are well understood by the skilled artisan, and the skilled artisan is able to prepare any number of salts given the knowledge in the art. Furthermore, it is recognized that the skilled artisan may prefer one salt over another for reasons of solubility, stability, formulation ease and the like. Determination and optimization of such salts is within the purview of the skilled artisan's practice.
  • the present invention relates to compositions of any of the compounds of the invention, preferably wherein such compound is present in a pharmaceutically acceptable carrier and in a therapeutically effective amount.
  • Such compositions will generally comprise an amount of such compound that is not toxic (i.e., an amount that is safe for therapeutic uses).
  • the present invention also contemplates metabolites of any of the novel compounds of the invention, such metabolites representing second compound formed by one or more in vivo metabolic reactions on a first compound following administration of the latter to a mammal wherein the first compound is a novel compound of the invention.
  • said first compound is any of the compounds disclosed herein as having a structure as defined for Formulas I to IX, with the substituents disclosed for those formulas, and even more preferably any compound of Tables 2, 3, 4, 5, 6, 7, 8, and/or 9 including all pharmaceutically acceptable salts thereof.
  • Selected examples of compounds of the invention include, but are not limited to, any or all of the compounds of Tables 2 through 9, including all pharmaceutically acceptable salts thereof as well has metabolites of any said compounds produced by normal mammalian, especially human, metabolism of said compounds after administration to said mammal as a therapeutic agent.
  • Such compounds are also specifically claimed individually or in any combination to the extent that they are novel. Any and all such compounds are specifically claimed individually or in their entirety or in any subcombination for their use in any and all of the methods of the invention.
  • the ligand is attached via the atom marked with an asterisk (*).
  • the sulfur atoms of the indicated formula i.e., the "core structure”
  • the indicated R group at the asterisked nitrogen of the R column of the table; similarly for the other tables.
  • the present invention is drawn to a method of preventing, treating or ameliorating cancer or tumor metastasis in a mammal comprising administering to said mammal an effective amount of a compound that modulates expression of one or more genes of Table 10.
  • a compound that modulates expression of one or more genes of Table 10. such compounds have the structure of Formula I 1 II, III, IV, V,
  • the present invention is directed to use of the compounds of the invention as active ingredients for medicaments, in particular for medicaments useful for the treatment of tumors.
  • the compounds of the invention will thus be present in pharmaceutical compositions containing compounds of Formulas I, II, III, IV, V, Vl, VII, VIII and/or IX (with the substituents disclosed herein for those formulas) and even more preferably any compound of Tables 1 , 2, 3, 4, 5, 6, 7, 8, and/or 9, including all pharmaceutically acceptable salts thereof, as active ingredients, in admixture with pharmaceutically acceptable vehicles and excipients, which includes any pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.
  • Pharmaceutically acceptable carriers include, but are not limited to, liquids such as water, saline, glycerol and ethanol, and the like, including carriers useful in forming sprays for nasal and other respiratory tract delivery or for delivery to the ophthalmic system.
  • the present invention relates to a method for preventing or treating a disease associated with a change in levels of expression of particular sets of genes in a mammal comprising administering to said mammal an effective amount of a compound of the invention.
  • Compounds according to the present invention will have the effect of reducing size and number of tumors, especially primary tumors, in a mammal, especially a human, in need of such treatment.
  • a statistically significant change in the numbers of primary tumor or metastasizing cells will typically be at least about 10%, preferably 20%, 30%, 50%, 70%, 90%, or more.
  • the agents described herein may be combined with other treatments of the medical conditions described herein, such as other chemotherapies, radiation treatments, immunotherapy, surgical treatments, and the like.
  • the compounds of the invention may also be administered in combination with such other agents as painkillers, diuretics, antidiuretics, antivirals, antibiotics, nutritional supplements, anemia therapeutics, blood clotting therapeutics, bone therapeutics, and psychiatric and psychological therapeutics.
  • Determination of the appropriate treatment dose is made by the clinician, e.g., using parameters or factors known in the art to affect treatment or predicted to affect treatment. Generally, the dose begins with an amount somewhat less than the optimum dose and it is increased by small increments thereafter until the desired or optimum effect is achieved relative to any negative side effects.
  • a typical daily dose (administered in single or divided doses) will contain a dosage level of from about 0.01 mg/kg to about 50-100 mg/kg of body weight of an active compound of the invention.
  • Preferred daily doses generally will be from about 0.05 mg/kg to about 25 mg/kg and ideally from about 0.1 mg/kg to about 10 mg/kg.
  • Factors such as clearance rate, half-life and maximum tolerated dose (MTD), while not specifically recited herein, may be readily determined by one of ordinary skill in the art using standard procedures.
  • An effective amount of a therapeutic will modulate the symptoms typically by at least about 10%; usually by at least about 20%; preferably at least about 30%; or more preferably at least about 50%.
  • modulation of migration will mean that the migration or trafficking of various cancer cell types is affected. Such will result in, e.g., statistically significant and quantifiable changes in the numbers of cells being affected. This may be a decrease in the numbers of target cells being attracted within a time period or target area. Rate of primary tumor progression, size, or growth may also be monitored.
  • the present invention relates to a method for preventing or treating a disorder modulated by altered gene expression, wherein the disorder is selected from the group consisting of cancer, cardiovascular disorders, arthritis, osteoporosis, inflammation, periodontal disease and skin disorders, comprising administering to a mammal in need of such treatment or prevention a therapeutically effective amount of a compound of the invention.
  • the present invention relates to a method of preventing, treating or ameliorating cancer or tumor metastasis in a mammal comprising administering to said mammal an effective a compound of the invention, preferably where said mammal is a human.
  • the compounds of the invention will commonly exert a therapeutic effect by modulation of one or more genes found in a cell, especially a mammalian cell, such as a cancer cell, preferably colon cancer and most preferably adenocarcinoma.
  • a compound, or compounds, of the invention can be used to determine or demarcate a set of genes by determining modulation of such set of genes by one or more compounds of the invention.
  • a set of genes can be determined by their common property of being modulated (based on a change in expression of the genes, such as a change in rate or amount of RNA transcribed or the amount of polypeptide produced by said expression) by contacting such genes, or a cell containing such genes, with one or more of the compounds of the invention.
  • modulation may, of course, be related to the amount of said compound, or compounds, used in the contacting.
  • Such modulation may include the increased expression of all the determined genes (i.e., the genes of the set), the decreased expression of all genes of the set, or the increase in expression of some of the genes of the set and decreased expression of others.
  • a gene not modulated by the test compound is not considered a member of the set.
  • the present invention relates to a gene set wherein expression of each member of said gene set is modulated as a result of contacting said gene set with a compound of the invention.
  • expression of each member of said gene set is increased as a result of said contacting or is decreased as a result of said contacting.
  • the gene set is present in a cell.
  • Such a gene set will commonly be related to a specific disease process, such as a set of genes all of which are modulated by a compound of the invention wherein such compound has a specific therapeutic effect, such as being an anti-neoplastic agent.
  • the present invention also relates to a method for ameliorating cancer or tumor metastasis in a mammal comprising administering to said mammal an effective amount of a compound of the invention.
  • a compound of the invention Especially contemplated are uses of the compounds of Table 1.
  • said cancer is a sarcoma or said cancer is a carcinoma.
  • Specific cancers contemplated by the methods of the invention include, but are not limited to, one or more of colon cancer, adenocarcinoma, rectal cancer, colorectal cancer, breast cancer, lung cancer, ovarian cancer, adenomatous polyposis, and hepatocellular carcinoma.
  • the invention also provides convenient methods for the synthesis of compound of Formula I 1 according to the general synthetic pathway presented in Scheme 1.
  • the starting sulfonyl chlorides 1 can be obtained by direct chlorosulfonylation of the corresponding aromatic ring system or by chlorination of an appropriate sulfonic acid derivative.
  • Compounds 1 are reacted with 6 or 7-membered cyclic amines to give secondary sulfonamides 2.
  • Compounds 2 can be additionally transformed into derivatives 3 which in some cases serve as prodrugs with modified physico-chemical and pharmacological properties such as solubility in water, modified protein binding properties, stability in plasma, toxicity, and others.
  • Anthraquinone-2,7-disulfonylchloride (1215 mg, 3 mmole) was dissolved in 100 mL DCM. The solution was cooled to -5O 0 C. To this solution was added 1 mL (8 mmole) of heptamethyleneimine, followed by 1 mL of diisopropylethylamine. The reaction mixture was stirred at room temperature for 4 hrs. Solvent was evaporated and the residue was treated with 1 N HCI, filtered off, washed with water and dried. Crude material was crystallized from chloroform-hexane to give 1.014 g (91 %) of yellow compound 1-27.
  • Reaction mixture was then condensed, cooled down to room temperature and poured carefully on 500 g of ice.
  • the yellow precipitate of product was collected by filtration, washed with water and dried to provide 8.1 g of the title compound. This material was used for next step without purification.
  • Anthraquinone-2,7-disulfonylchloride (10 g, 24.7 mmol)) was dissolved in 200 ml_ DCM. The solution was cooled to -5O 0 C. To this solution was added 4-te/t-butylcyclohexanamine (8.43 g, 54 mmol), followed by triethyl amine (8.6 ml, 61.7 mmol). The reaction mixture was stirred at room temperature for 4 hrs. Solvent was evaporated and the residue was treated with MeOH, filtered off, and dried to obtain 15 g (95%) of the product (1-36) as yellow powder.
  • the APH (acid phosphatase) assay which is based on quantification of cytosolic acid phosphatase activity, was utilized for determining cell viability in cell lines (Connolly et al., 1986; Friedrich et al., 2007; Martin & Clynes, 1993).
  • Intracellular acid phosphatases in viable cells hydrolyze p-nitrophenyl phosphate to p-nitrophenol. Its absorption at 405 nm is directly proportional to the cell number in the range of 10 3 -10 5 monolayer cells .
  • HT-29 cells were grown in standard flat-bottom 96-well microtiter plates and allowed to adhere for 24 hours prior to drug treatment.
  • the cells were washed with PBS and 100 ⁇ l of the assay buffer (0.1 M sodium acetate, 0.1 % Triton X-100, supplemented with ImmunoPure p-nitrophenyl phosphate, Pierce Biotech. Inc., Rockford, IL USA) were added per well and incubated for 90 min at 37°C. Following incubation, 10 ⁇ l of 1 N NaOH were supplemented to each well and absorption at 405 nm was measured within 10 minutes on a Fusion Universal Microplate Analyzer (Packard, Meriden, CT, USA).
  • the assay buffer 0.1 M sodium acetate, 0.1 % Triton X-100, supplemented with ImmunoPure p-nitrophenyl phosphate, Pierce Biotech. Inc., Rockford, IL USA

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Abstract

L'invention porte sur des agents chimiques, tels que des dérivés disulfonamide du fluorène, de l'anthracène, du xanthène du dibenzosuberone et de l'acridine, et des structures à noyaux hétérocycliques similaires, y compris des sels de ceux-ci, qui jouent le rôle d'agents anticancéreux et anti-tumoraux, et sur des procédés pour préparer de tels agents ainsi que sur des compositions pharmaceutiques contenant de tels agents comme ingrédients actifs et sur des procédés d'utilisation de ceux-ci comme agents thérapeutiques.
PCT/US2009/000257 2009-01-15 2009-01-15 Dérivés de composés aromatiques à noyaux multiples et utilisations comme agents anti-tumoraux WO2010082912A1 (fr)

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WO2017058716A1 (fr) * 2015-09-28 2017-04-06 Vivace Therapeutics, Inc. Composés tricycliques
US9884815B2 (en) 2011-10-14 2018-02-06 Emory University PGAM1 inhibitors and methods related thereto
WO2018118711A1 (fr) * 2016-12-19 2018-06-28 The Trustees Of Columbia University In The City Of New York Inducteurs de ferroptose à petites molécules
CN109640970A (zh) * 2016-06-23 2019-04-16 马里兰大学巴尔的摩分校 具有内皮稳定化活性和抗炎活性的非催化底物选择性p38α特异性MAPK抑制剂及其使用方法
WO2019241730A2 (fr) 2018-06-15 2019-12-19 Flagship Pioneering Innovations V, Inc. Augmentation de l'activité immunitaire par modulation de facteurs de signalisation post-cellulaires
WO2021127217A1 (fr) 2019-12-17 2021-06-24 Flagship Pioneering Innovations V, Inc. Polythérapies anticancéreuses ayant des inducteurs de désassemblage cellulaire dépendant du fer
WO2021208559A1 (fr) * 2020-04-16 2021-10-21 苏州大学 Composé du plomb ciblant l'interaction entre les nœuds immuns pd-1 et shp-2 et application associée
US11286260B2 (en) 2020-05-18 2022-03-29 Gen1E Lifesciences Inc. P38α mitogen-activated protein kinase inhibitors
US11390581B2 (en) 2020-10-29 2022-07-19 Gen1E Lifesciences Inc. Crystalline 5-(dimethylamino)-n-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide di-hydrochloride di-hydrate
US11555020B2 (en) 2021-03-23 2023-01-17 Gen1E Lifesciences Inc. Substituted naphthyl p38α mitogen-activated protein kinase inhibitors
US11718595B2 (en) 2018-12-07 2023-08-08 University Of Maryland, Baltimore Non-ATP/catalytic site p38 Mitogen Activated Protein Kinase inhibitors
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CN106106481B (zh) * 2016-06-16 2019-06-28 湖北工业大学 一种棉铃虫甾醇载体蛋白2抑制剂及其虚拟筛选方法
CN106106481A (zh) * 2016-06-16 2016-11-16 湖北工业大学 一种棉铃虫甾醇载体蛋白2抑制剂及其虚拟筛选方法
JP7013453B2 (ja) 2016-06-23 2022-01-31 ユニバーシティ・オブ・メリーランド・ボルティモア 内皮安定化及び抗炎症活性を有する非触媒基質選択的ｐ３８α特異的ＭＡＰＫ阻害剤、及びその使用方法
US11911393B2 (en) 2016-06-23 2024-02-27 University Of Maryland, Baltimore Non-catalytic substrate-selective p38alpha-specific MAPK inhibitors with endothelial-stabilizing and anti-inflammatory activity, and methods of use thereof
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CN109640970B (zh) * 2016-06-23 2023-05-23 马里兰大学巴尔的摩分校 选择性p38α特异性MAPK抑制剂
JP7372993B2 (ja) 2016-06-23 2023-11-01 ユニバーシティ・オブ・メリーランド・ボルティモア 内皮安定化及び抗炎症活性を有する非触媒基質選択的ｐ３８α特異的ＭＡＰＫ阻害剤、及びその使用方法
JP2019527239A (ja) * 2016-06-23 2019-09-26 ユニバーシティ・オブ・メリーランド・ボルティモアＵｎｉｖｅｒｓｉｔｙ Ｏｆ Ｍａｒｙｌａｎｄ， Ｂａｌｔｉｍｏｒｅ 内皮安定化及び抗炎症活性を有する非触媒基質選択的ｐ３８α特異的ＭＡＰＫ阻害剤、及びその使用方法
US11911392B2 (en) 2016-06-23 2024-02-27 University Of Maryland, Baltimore Non-catalytic substrate-selective p38α-specific MAPK inhibitors with endothelial-stabilizing and anti-inflammatory activity, and methods of use thereof
US11357781B2 (en) 2016-06-23 2022-06-14 University Of Maryland, Baltimore Non-catalytic substrate-selective, p38α-specific MAPK inhibitors with endothelial-stabilizing and anti-inflammatory activity, and methods of use thereof
US10947188B2 (en) 2016-12-19 2021-03-16 The Trustees Of Columbia University In The City Of New York Small molecule ferroptosis inducers
WO2018118711A1 (fr) * 2016-12-19 2018-06-28 The Trustees Of Columbia University In The City Of New York Inducteurs de ferroptose à petites molécules
WO2019241730A2 (fr) 2018-06-15 2019-12-19 Flagship Pioneering Innovations V, Inc. Augmentation de l'activité immunitaire par modulation de facteurs de signalisation post-cellulaires
US11718595B2 (en) 2018-12-07 2023-08-08 University Of Maryland, Baltimore Non-ATP/catalytic site p38 Mitogen Activated Protein Kinase inhibitors
WO2021127217A1 (fr) 2019-12-17 2021-06-24 Flagship Pioneering Innovations V, Inc. Polythérapies anticancéreuses ayant des inducteurs de désassemblage cellulaire dépendant du fer
WO2021208559A1 (fr) * 2020-04-16 2021-10-21 苏州大学 Composé du plomb ciblant l'interaction entre les nœuds immuns pd-1 et shp-2 et application associée
US11440918B2 (en) 2020-05-18 2022-09-13 Gen1E Lifesciences Inc. p38α mitogen-activated protein kinase inhibitors
US11286260B2 (en) 2020-05-18 2022-03-29 Gen1E Lifesciences Inc. P38α mitogen-activated protein kinase inhibitors
US11926635B2 (en) 2020-05-18 2024-03-12 Gen1E Lifesciences Inc. P38α mitogen-activated protein kinase inhibitors
US11390581B2 (en) 2020-10-29 2022-07-19 Gen1E Lifesciences Inc. Crystalline 5-(dimethylamino)-n-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide di-hydrochloride di-hydrate
US11555020B2 (en) 2021-03-23 2023-01-17 Gen1E Lifesciences Inc. Substituted naphthyl p38α mitogen-activated protein kinase inhibitors
US11976049B2 (en) 2021-03-23 2024-05-07 Gen1E Lifesciences Inc. Substituted naphthyl p38alpha mitogen-activated protein kinase inhibitors
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