US20190016680A1 - Mast-cell modulators and uses thereof - Google Patents
Mast-cell modulators and uses thereof Download PDFInfo
- Publication number
- US20190016680A1 US20190016680A1 US16/069,961 US201716069961A US2019016680A1 US 20190016680 A1 US20190016680 A1 US 20190016680A1 US 201716069961 A US201716069961 A US 201716069961A US 2019016680 A1 US2019016680 A1 US 2019016680A1
- Authority
- US
- United States
- Prior art keywords
- compound
- pharmaceutically acceptable
- formula
- acceptable salt
- subject
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- UVKHUEWQHVXNGZ-UHFFFAOYSA-N CC.CC[Y]CC1=CN(CC2=CC=CC=C2)C2=CC=CC=C12 Chemical compound CC.CC[Y]CC1=CN(CC2=CC=CC=C2)C2=CC=CC=C12 UVKHUEWQHVXNGZ-UHFFFAOYSA-N 0.000 description 10
- 0 *NII*C1=N*(Cc2ccccc2)c2c1cccc2 Chemical compound *NII*C1=N*(Cc2ccccc2)c2c1cccc2 0.000 description 2
- RZIVDYDMOXVGPO-UHFFFAOYSA-N CC1=C(C(=O)NC2=NN(CC3=CC=C(Cl)C=C3Cl)C3=C2C=CC=C3)C=CN=C1 Chemical compound CC1=C(C(=O)NC2=NN(CC3=CC=C(Cl)C=C3Cl)C3=C2C=CC=C3)C=CN=C1 RZIVDYDMOXVGPO-UHFFFAOYSA-N 0.000 description 2
- HLUYSPXDJCETEX-UHFFFAOYSA-N CC1=C(NC(=O)C2=CN(CC3=CC=C(Cl)C=C3Cl)C3=CC=CC=C23)C(F)=CC=C1 Chemical compound CC1=C(NC(=O)C2=CN(CC3=CC=C(Cl)C=C3Cl)C3=CC=CC=C23)C(F)=CC=C1 HLUYSPXDJCETEX-UHFFFAOYSA-N 0.000 description 2
- QVYHPABDUURDHG-UHFFFAOYSA-N O=C(NC1=C(Cl)N=CC=C1)C1=CN(CC2=CC(F)=CC=C2)C2=CC=CC=C12.O=C(NC1=CC(F)=C(F)C=C1)C1=NN(CC2=C(Cl)C=CC=C2Cl)C2=CC=CC=C21 Chemical compound O=C(NC1=C(Cl)N=CC=C1)C1=CN(CC2=CC(F)=CC=C2)C2=CC=CC=C12.O=C(NC1=CC(F)=C(F)C=C1)C1=NN(CC2=C(Cl)C=CC=C2Cl)C2=CC=CC=C21 QVYHPABDUURDHG-UHFFFAOYSA-N 0.000 description 2
- FGQSLNATAGVVLS-UHFFFAOYSA-N O=C(NC1=C(F)C=CC=C1F)C1=NN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2 Chemical compound O=C(NC1=C(F)C=CC=C1F)C1=NN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2 FGQSLNATAGVVLS-UHFFFAOYSA-N 0.000 description 2
- BHPAIARYYGYBCC-UHFFFAOYSA-N O=C(NC1=C(F)C=NC=C1)C1=CN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2 Chemical compound O=C(NC1=C(F)C=NC=C1)C1=CN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2 BHPAIARYYGYBCC-UHFFFAOYSA-N 0.000 description 2
- UTPDKUZUERCNKP-UHFFFAOYSA-N O=C(NC1=CC=C(F)C=C1F)C1=CN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2 Chemical compound O=C(NC1=CC=C(F)C=C1F)C1=CN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2 UTPDKUZUERCNKP-UHFFFAOYSA-N 0.000 description 2
- AGMPFALDDKOUMU-UHFFFAOYSA-N O=C(NC1=CC=CC=C1F)C1=CN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2 Chemical compound O=C(NC1=CC=CC=C1F)C1=CN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2 AGMPFALDDKOUMU-UHFFFAOYSA-N 0.000 description 2
- WQUDTMIVGBBLQD-UHFFFAOYSA-N O=C(NC1=CN=NS1)C1=NN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2 Chemical compound O=C(NC1=CN=NS1)C1=NN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2 WQUDTMIVGBBLQD-UHFFFAOYSA-N 0.000 description 2
- UMFYKBOXEOOXKI-UHFFFAOYSA-N C.C.C.CC.CC.CC.CC.O=C(CC1=CC=CC=C1)C1=CN(CC2=CC=CC=C2)C2=CC=CC=C12.O=C(CC1=CC=NC=C1)C1=CN(CC2=CC=CC=C2)C2=CC=CC=C12 Chemical compound C.C.C.CC.CC.CC.CC.O=C(CC1=CC=CC=C1)C1=CN(CC2=CC=CC=C2)C2=CC=CC=C12.O=C(CC1=CC=NC=C1)C1=CN(CC2=CC=CC=C2)C2=CC=CC=C12 UMFYKBOXEOOXKI-UHFFFAOYSA-N 0.000 description 1
- XFUUDJMKIGULBK-UHFFFAOYSA-N C.C.C1=CC=C(CN2C=C(C[Y]C3=CC=CC=C3)C3=CC=CC=C32)C=C1.C1=CC=C(CN2C=C(C[Y]C3=CC=NC=C3)C3=CC=CC=C32)C=C1.CC.CC.CC.CC Chemical compound C.C.C1=CC=C(CN2C=C(C[Y]C3=CC=CC=C3)C3=CC=CC=C32)C=C1.C1=CC=C(CN2C=C(C[Y]C3=CC=NC=C3)C3=CC=CC=C32)C=C1.CC.CC.CC.CC XFUUDJMKIGULBK-UHFFFAOYSA-N 0.000 description 1
- QQMCVSUQPZVUAF-UHFFFAOYSA-N C1=CC=C(CN2C=C(C[Y]C3=CC=CC=C3)C3=CC=CC=C32)C=C1.C1=CC=C(CN2C=C(C[Y]C3=CC=NC=C3)C3=CC=CC=C32)C=C1.CC.CC.CC.CC Chemical compound C1=CC=C(CN2C=C(C[Y]C3=CC=CC=C3)C3=CC=CC=C32)C=C1.C1=CC=C(CN2C=C(C[Y]C3=CC=NC=C3)C3=CC=CC=C32)C=C1.CC.CC.CC.CC QQMCVSUQPZVUAF-UHFFFAOYSA-N 0.000 description 1
- DFKKTDVWCHXZIS-UHFFFAOYSA-N CC.CC.CC.CC.O=C(CC1=CC=CC=C1)C1=CN(CC2=CC=CC=C2)C2=CC=CC=C12.O=C(CC1=CC=NC=C1)C1=CN(CC2=CC=CC=C2)C2=CC=CC=C12 Chemical compound CC.CC.CC.CC.O=C(CC1=CC=CC=C1)C1=CN(CC2=CC=CC=C2)C2=CC=CC=C12.O=C(CC1=CC=NC=C1)C1=CN(CC2=CC=CC=C2)C2=CC=CC=C12 DFKKTDVWCHXZIS-UHFFFAOYSA-N 0.000 description 1
- WJUAJJNQBAOIMT-UHFFFAOYSA-N CC.CC.CCC(=O)NC1=CN(CC2=CC=CC=C2)C2=CC=CC=C12.CCClC=O.I.NC1=CN(CC2=CC=CC=C2)C2=CC=CC=C12 Chemical compound CC.CC.CCC(=O)NC1=CN(CC2=CC=CC=C2)C2=CC=CC=C12.CCClC=O.I.NC1=CN(CC2=CC=CC=C2)C2=CC=CC=C12 WJUAJJNQBAOIMT-UHFFFAOYSA-N 0.000 description 1
- YXYAALDJBJMCAN-UHFFFAOYSA-N CC.CC.CCCC(=O)C1=CN(CC2=CC=CC=C2)C2=CC=CC=C12.CCN.I.O=C(O)C1=CN(CC2=CC=CC=C2)C2=CC=CC=C12 Chemical compound CC.CC.CCCC(=O)C1=CN(CC2=CC=CC=C2)C2=CC=CC=C12.CCN.I.O=C(O)C1=CN(CC2=CC=CC=C2)C2=CC=CC=C12 YXYAALDJBJMCAN-UHFFFAOYSA-N 0.000 description 1
- GTGORTLSYHVCFB-UHFFFAOYSA-N CC.CC.ClCC1=CC=CC=C1.NC1=CN(CC2=CC=CC=C2)C2=CC=CC=C12.NC1=CNC2=CC=CC=C12 Chemical compound CC.CC.ClCC1=CC=CC=C1.NC1=CN(CC2=CC=CC=C2)C2=CC=CC=C12.NC1=CNC2=CC=CC=C12 GTGORTLSYHVCFB-UHFFFAOYSA-N 0.000 description 1
- DNQJWYLQCIFZDF-UHFFFAOYSA-N CC.CC.ClCC1=CC=CC=C1.O=C(O)C1=CN(CC2=CC=CC=C2)C2=CC=CC=C12.O=C(O)C1=CNC2=CC=CC=C21 Chemical compound CC.CC.ClCC1=CC=CC=C1.O=C(O)C1=CN(CC2=CC=CC=C2)C2=CC=CC=C12.O=C(O)C1=CNC2=CC=CC=C21 DNQJWYLQCIFZDF-UHFFFAOYSA-N 0.000 description 1
- PRIPWZDZWWCPCG-UHFFFAOYSA-N CC1=C(C(=O)NC2=NN(CC3=CC=C(Cl)C=C3Cl)C3=C2C=CC=C3)SN=N1 Chemical compound CC1=C(C(=O)NC2=NN(CC3=CC=C(Cl)C=C3Cl)C3=C2C=CC=C3)SN=N1 PRIPWZDZWWCPCG-UHFFFAOYSA-N 0.000 description 1
- LOCFZXGICIVBGE-UHFFFAOYSA-N ClCC1=C(Cl)C=C(Cl)C=C1.O=C(O)C1=CN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C12.O=C(O)C1=CNC2=CC=CC=C21 Chemical compound ClCC1=C(Cl)C=C(Cl)C=C1.O=C(O)C1=CN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C12.O=C(O)C1=CNC2=CC=CC=C21 LOCFZXGICIVBGE-UHFFFAOYSA-N 0.000 description 1
- LGGCPKHEIXLDIP-UHFFFAOYSA-N NC1=C(F)C=CC=C1F.O=C(Cl)C1=CN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C12.O=C(Cl)C1OCl1.O=C(NC1=C(F)C=CC=C1F)C1=CN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C12.O=C(O)C1=CN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C12 Chemical compound NC1=C(F)C=CC=C1F.O=C(Cl)C1=CN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C12.O=C(Cl)C1OCl1.O=C(NC1=C(F)C=CC=C1F)C1=CN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C12.O=C(O)C1=CN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C12 LGGCPKHEIXLDIP-UHFFFAOYSA-N 0.000 description 1
- FAMRARGRNTZSJL-UHFFFAOYSA-N O=C(NC1=C(F)C=CC=C1Cl)C1=NN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2 Chemical compound O=C(NC1=C(F)C=CC=C1Cl)C1=NN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2 FAMRARGRNTZSJL-UHFFFAOYSA-N 0.000 description 1
- OOMZQKJXRMGHAI-UHFFFAOYSA-N O=C(NC1=C(F)C=CC=C1F)C1=CN(CC2=C(Cl)C=CC=C2Cl)C2=C1C=CC=C2 Chemical compound O=C(NC1=C(F)C=CC=C1F)C1=CN(CC2=C(Cl)C=CC=C2Cl)C2=C1C=CC=C2 OOMZQKJXRMGHAI-UHFFFAOYSA-N 0.000 description 1
- LACOQELXBRHMER-UHFFFAOYSA-N O=C(NC1=C(F)C=CC=C1F)C1=CN(CC2=CC=C(Cl)C=C2)C2=C1C=CC=C2 Chemical compound O=C(NC1=C(F)C=CC=C1F)C1=CN(CC2=CC=C(Cl)C=C2)C2=C1C=CC=C2 LACOQELXBRHMER-UHFFFAOYSA-N 0.000 description 1
- RLMAXVSWSXGFCX-UHFFFAOYSA-N O=C(NC1=C(F)C=CC=C1F)C1=CN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C12.O=C(NC1=C(F)C=CC=C1F)C1=NN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C21.O=C(NC1=C(F)C=NC=C1F)C1=NN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C21.O=C(NC1=CC=CC=C1F)C1=CN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C12.O=C(NC1=CC=CC=C1F)C1=NN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C21.O=C(NC1=NN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C21)C1=C(F)C=CC=C1F.O=C(NC1=NN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C21)C1=CC=CC=C1F.O=C(NC1=NN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C21)C1=CC=NC=C1F Chemical compound O=C(NC1=C(F)C=CC=C1F)C1=CN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C12.O=C(NC1=C(F)C=CC=C1F)C1=NN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C21.O=C(NC1=C(F)C=NC=C1F)C1=NN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C21.O=C(NC1=CC=CC=C1F)C1=CN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C12.O=C(NC1=CC=CC=C1F)C1=NN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C21.O=C(NC1=NN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C21)C1=C(F)C=CC=C1F.O=C(NC1=NN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C21)C1=CC=CC=C1F.O=C(NC1=NN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C21)C1=CC=NC=C1F RLMAXVSWSXGFCX-UHFFFAOYSA-N 0.000 description 1
- MXAIUTVCQSYQSH-UHFFFAOYSA-N O=C(NC1=C(F)C=CC=C1F)C1=CN(CC2=CC=CC=C2Cl)C2=C1C=CC=C2 Chemical compound O=C(NC1=C(F)C=CC=C1F)C1=CN(CC2=CC=CC=C2Cl)C2=C1C=CC=C2 MXAIUTVCQSYQSH-UHFFFAOYSA-N 0.000 description 1
- TUTFVELSLFOKME-UHFFFAOYSA-N O=C(NC1=C(F)C=CC=C1F)C1=CN(CC2=CC=CC=C2OC(F)(F)F)C2=C1C=CC=C2 Chemical compound O=C(NC1=C(F)C=CC=C1F)C1=CN(CC2=CC=CC=C2OC(F)(F)F)C2=C1C=CC=C2 TUTFVELSLFOKME-UHFFFAOYSA-N 0.000 description 1
- FUNLAMGXGVPTID-UHFFFAOYSA-N O=C(NC1=C(F)C=NC=C1F)C1=NN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2 Chemical compound O=C(NC1=C(F)C=NC=C1F)C1=NN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2 FUNLAMGXGVPTID-UHFFFAOYSA-N 0.000 description 1
- AVBVBZYJQRWPRE-UHFFFAOYSA-N O=C(NC1=CC=NC=C1F)C1=CN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C12.O=C(NC1=CC=NC=C1F)C1=NN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C21.O=C(NC1=NN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C21)C1=C(F)C=NC=C1F Chemical compound O=C(NC1=CC=NC=C1F)C1=CN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C12.O=C(NC1=CC=NC=C1F)C1=NN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C21.O=C(NC1=NN(CC2=CC=C(Cl)C=C2Cl)C2=CC=CC=C21)C1=C(F)C=NC=C1F AVBVBZYJQRWPRE-UHFFFAOYSA-N 0.000 description 1
- ZVIXCPOPOQVWKY-UHFFFAOYSA-N O=C(NC1=CN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2)C1=C(F)C=NC=C1 Chemical compound O=C(NC1=CN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2)C1=C(F)C=NC=C1 ZVIXCPOPOQVWKY-UHFFFAOYSA-N 0.000 description 1
- YKWGGEAZSNKVFD-UHFFFAOYSA-N O=C(NC1=NN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2)C1=C(F)C=CC=C1F Chemical compound O=C(NC1=NN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2)C1=C(F)C=CC=C1F YKWGGEAZSNKVFD-UHFFFAOYSA-N 0.000 description 1
- UIISXIZGODMRPJ-UHFFFAOYSA-N O=C(NC1=NN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2)C1=C(F)C=NC=C1F Chemical compound O=C(NC1=NN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2)C1=C(F)C=NC=C1F UIISXIZGODMRPJ-UHFFFAOYSA-N 0.000 description 1
- FBQQNHCKTFRLQR-UHFFFAOYSA-N O=C(NC1=NN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2)C1=CC=C(F)C=C1F Chemical compound O=C(NC1=NN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2)C1=CC=C(F)C=C1F FBQQNHCKTFRLQR-UHFFFAOYSA-N 0.000 description 1
- YKQLSTQPJFOHJR-UHFFFAOYSA-N O=C(NC1=NN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2)C1=CC=CC=C1F Chemical compound O=C(NC1=NN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2)C1=CC=CC=C1F YKQLSTQPJFOHJR-UHFFFAOYSA-N 0.000 description 1
- RIBFVYACOKUSST-UHFFFAOYSA-N O=C(NC1=NN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2)C1=CC=NC=C1F Chemical compound O=C(NC1=NN(CC2=CC=C(Cl)C=C2Cl)C2=C1C=CC=C2)C1=CC=NC=C1F RIBFVYACOKUSST-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/36—Oxygen atoms in position 3, e.g. adrenochrome
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present disclosure relates to mast cell (MC) modulators, processes for their preparation, pharmaceutical compositions containing these modulators, and their use in the treatment of diseases associated with mast cells.
- MC mast cell
- mast cells have been known for their role in allergic and anaphylactic reactions, as well as their involvement in acquired and innate immunity, bacterial infections, and autoimmunity. See e.g., Respitory Medicine, Volume 106, Issue 1, pp. 9-14 (January 2012); Proc. Natl Acad. Sci. USA 102 (2005) 1578-1583; Nat. Immunol. 6 (2005) 135-142; Nature 432 (2004) 512-516; Eur. J. Immunol. 40 (2010) 1843-1851; Nat. Rev. Immunol. 10 (2010) 440-452; Autoimmun. Rev. 4 (2005) 21-27; and Nat. Immunol. 11 (2010) 471-476.
- SFN small fiber neuropathy
- DPN diabetic peripheral neuropathy
- mast cell stabilizers Given the involvement of mast cells in a wide variety of therapeutic pathways and targets, it is therefore desirable to prepare compounds that modulate mast cells (e.g., mast cell stabilizers) and hence have utility for treating one or more conditions associated with mast cells.
- FIG. 1 illustrates the effects on would healing in diabetic mice from treatment of a compound described herein.
- FIG. 2 illustrates the effects on the M1/M2 ratio in intact skin of diabetic mice from treatment with a compound described herein.
- FIG. 3 shows dose-dependent inhibition by compound 12 of ⁇ -hex release from activated mast cells. Released ⁇ -Hex in cell culture supernatant were measured and compared with total ⁇ -Hex in cell lyses (reported as %).
- FIG. 4 shows dose-dependent inhibition by compound 12 of nuclear translocation of NFAT in activated mast cells.
- the present disclosure provides a compound of Formula I:
- Z is CH or N
- X is CO and Y is NH, or X is NH and Y is CO;
- Cy is phenyl or pyridyl
- R 1 and R 2 are each halo
- p and s are each independently 1, 2, or 3; provided the compound is not
- halo and “halogen” as used herein refer to an atom selected from fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br), and iodine (iodo, —I).
- the terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
- the subject is a human in need of treatment.
- the compounds of the herein may be present in the form of pharmaceutically acceptable salts.
- the salts of the compounds of the invention refer to non-toxic “pharmaceutically acceptable salts.”
- Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
- Pharmaceutically acceptable acidic/anionic salts include, but are not limited to the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, carbonate, citrate, dihydrochloride, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, malate, maleate, malonate, mesylate, nitrate, salicylate, stearate, succinate, sulfate, tartrate, and tosylate.
- the present disclosure provides a compound of Formula I:
- the present disclosure provides a compound of Formula I or a pharmaceutically acceptable salt thereof.
- the compound of Formula I is of the Formula II or III:
- the compound of Formula I is of the Formula IV or V:
- p in Formula I, II, III, IV, and V is 2, wherein the remaining variables are as described above for Formula I and the second or third embodiment.
- s in Formula I, II, III, IV, and V is 1 or 2, wherein the remaining variables are as described above for Formula I and the second, third, or fourth embodiment.
- R 2 in Formula I, II, III, IV, and V is fluoro, wherein the remaining variables are as described above for Formula I and the second, third, fourth, or fifth embodiment.
- R 1 in Formula I, II, III, IV, and V is chloro, wherein the remaining variables are as described above for Formula I and the second, third, fourth, or fifth embodiment.
- the compound of Formula I is selected from
- a provided compound is one or more compounds selected from those exemplified in the EXEMPLIFICATION section below, or a pharmaceutically acceptable salt thereof. That is, pharmaceutically acceptable salts as well as the neutral forms of these compounds are included herein.
- the present disclosure provides a method of treating a subject (e.g., a human) with a condition associated with mast cells comprising the step of administering to the patient an effective amount of a compound of the Formula I, II, III, IV, and V, or a pharmaceutically acceptable salt or composition thereof.
- Conditions associated with mast cells include, but are not limited to, bacterial infections, allergic reactions, inflammatory diseases, fibrosis, cancers, central nervous system disorders, and metabolic disorders.
- Specific conditions include e.g., allograft rejection, diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, osteoarthritis, rheumatoid arthritis, synovial pannus invasion in arthritis, multiple sclerosis, myasthenia gravis, diabetes mellitus, diabetic angiopathy, diabetic neuropathy, infantile hemangiomas, non-small cell lung, bladder and head and neck cancers, prostate cancer, breast cancer, ovarian cancer, gastric and pancreatic cancer, psoriasis, fibrosis, rheumatoid arthritis, atherosclerosis, restenosis, allergy, respiratory diseases, asthma, transplantation rejection, thrombosis, retinal vessel proliferation, inflammatory bowel disease, Crohn's disease, ulcerative colitis, bone diseases, transplant or bone marrow transplant rejection, lupus, chronic pancreatitis, cachexia, septic shock, fibropro
- the present disclosure provides a method of delaying the onset of, reversing, or reducing the risk of acquiring peripheral neuropathy (PN) in a subject (e.g., a human) having diabetes, comprising administering to the subject an effective amount of a compound of the Formula I, II, III, IV, and V, or a pharmaceutically acceptable salt or composition thereof.
- PN peripheral neuropathy
- the present disclosure provides a method of delaying the onset of, reversing, or reducing the risk of acquiring peripheral diabetic neuropathy (PN) in a subject (e.g., a human) in need thereof, comprising administering to the subject an effective amount of a compound of the Formula I, II, III, IV, and V, or a pharmaceutically acceptable salt or composition thereof.
- PN peripheral diabetic neuropathy
- the present disclosure provides a method of delaying the onset of, reducing the risk of developing, or accelerating the healing of a wound in a subject (e.g., a human) having diabetes, comprising administering to the subject an effective amount of a compound of the Formula I, II, III, IV, and V, or a pharmaceutically acceptable salt or composition thereof.
- the present disclosure provides a method for altering the M1/M2 macrophage ratio in a wound on a subject (e.g., a human) having diabetes, comprising administering to the subject an effective amount of a compound of the Formula I, II, III, IV, and V, or a pharmaceutically acceptable salt or composition thereof.
- a subject e.g., a human having diabetes
- the present disclosure provides a method of preventing the increase of matrix metallopeptidase 9 (MMP-9), in a subject (e.g., a human) having diabetes, comprising administering to the subject an effective amount of a compound of the Formula I, II, III, IV, and V, or a pharmaceutically acceptable salt or composition thereof.
- a subject e.g., a human having diabetes
- the present disclosure provides a method of treating a subject (e.g., a human) with a condition associated with mast cells using a composition comprising a compound of the Formula I, II, III, IV, and V, or a pharmaceutically acceptable salt or composition thereof; and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
- a subject e.g., a human
- a composition comprising a compound of the Formula I, II, III, IV, and V, or a pharmaceutically acceptable salt or composition thereof; and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
- disorders associated with mast cells are described above e.g., in paragraph [0022].
- the present disclosure provides a method of delaying the onset of, reversing, or reducing the risk of acquiring peripheral neuropathy (PN) in a subject (e.g., a human) having diabetes, using a composition comprising a compound of the Formula I, II, III, IV, and V, or a pharmaceutically acceptable salt or composition thereof; and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
- PN peripheral neuropathy
- the present disclosure provides a method of delaying the onset of, reversing, or reducing the risk of acquiring peripheral diabetic neuropathy (PN) in a subject (e.g., a human) in need thereof, using a composition comprising a compound of the Formula I, II, III, IV, and V, or a pharmaceutically acceptable salt or composition thereof; and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
- PN peripheral diabetic neuropathy
- the present disclosure provides a method of delaying the onset of, reducing the risk of developing, or accelerating the healing of a wound in a subject (e.g., a human) having diabetes, using a composition comprising a compound of the Formula I, II, III, IV, and V, or a pharmaceutically acceptable salt or composition thereof; and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
- a composition comprising a compound of the Formula I, II, III, IV, and V, or a pharmaceutically acceptable salt or composition thereof; and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
- the present disclosure provides a method for altering the M1/M2 macrophage ratio in a wound on a subject (e.g., a human) having diabetes, using a composition comprising a compound of the Formula I, II, III, IV, and V, or a pharmaceutically acceptable salt or composition thereof; and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
- a composition comprising a compound of the Formula I, II, III, IV, and V, or a pharmaceutically acceptable salt or composition thereof; and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
- the present disclosure provides a method of preventing the increase of matrix metallopeptidase 9 (MMP-9), in a subject (e.g., a human) having diabetes, using a composition comprising a compound of the Formula I, II, III, IV, and V, or a pharmaceutically acceptable salt or composition thereof; and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
- MMP-9 matrix metallopeptidase 9
- delaying the onset of, reversing, or reducing the risk of acquiring, or reducing the risk of developing a condition recited herein means decreasing the amount of mast cell degranulation in subjects who have elevated mast cell degranulation levels due to a condition/disease, such as e.g., diabetes. It has been found that subject having diabetes have an increase in mast cell degranulation. See e.g., U.S. Provisional Application No. 62/162,972.
- accelerating the healing of wound means that the compound of Formula I, II, III, IV, and V, or a pharmaceutically acceptable salt or composition thereof elicits a cellular environment that accelerates or promotes healing of the wound.
- the he compound of Formula I, II, III, IV, and V, or a pharmaceutically acceptable salt or composition thereof may elicit the release of cytokines such as CXCL8, CCL2 and CXCL7, each of which are necessary for the first phase of wound healing, thereby promoting healing of a wound.
- the first phase of wound healing is the inflammatory phase that lasts for approximately three days and it is followed by the proliferative phase that lasts two to three weeks.
- the amount of compound of the Formula I, II, III, IV, and V in a provided composition is such that it is effective as a mast cell stabilizer (such as a mast cell degranulation inhibitor) in a biological sample or in a subject.
- a provided composition is formulated for administration to a subject in need of such composition.
- a provided composition is formulated for oral administration to a subject.
- a provided composition is formulated for topical administration to a subject.
- compositions of this disclosure refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
- Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block
- compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
- carriers commonly used include lactose and corn starch.
- Lubricating agents such as magnesium stearate, are also typically added.
- useful diluents include lactose and dried cornstarch.
- aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
- compositions described herein may also be prepared in injectable form.
- injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil can be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid are used in the preparation of injectables.
- compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
- compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the inhibitor, such as e.g., 0.1-100 mg/kg body weight/day, can be administered to a patient receiving these compositions.
- a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
- the amount of a compound described herein in the composition will also depend upon the particular compound in the composition.
- treatment refers to therapeutic treatment.
- Modulation of mast cells means that a change or alternation in the activity of mast cells has occurred from the administration of one or more of the compounds described herein. Modulation may be an upregulation (increase) or a downregulation (decrease) in the magnitude of the activity or function of mast cells. Exemplary activities and functions include e.g., binding characteristics, enzymatic activity, cell receptor activation, transcriptional activity, and signal transduction. In one aspect, the compounds described herein stabilize mast cells. In further aspects, the compounds described herein act as mast cell degranulation inhibitors.
- compound of Formula I where X is CO and Y is NH can be prepared by reacting a compound of Formula 100 with a compound of Formula 110 in an organic solvent (e.g., DMF) in the presence of base (e.g., NaH) to form a compound of Formula 120. See e.g., Scheme 1.
- organic solvent e.g., DMF
- base e.g., NaH
- the compound of Formula I can then be formed by converting the carboxylic acid portion of the compound of Formula 120 to an activated group (such as an acid chloride via treatment with DMF and (COCl) 2 in DCM) followed by treatment with a compound of Formula 130 in the presence of base (e.g., TEA).
- an activated group such as an acid chloride via treatment with DMF and (COCl) 2 in DCM
- a compound of Formula 130 in the presence of base e.g., TEA
- compounds of Formula I, where X is NH and Y is CO can be prepared by reacting a compound of Formula 140 with a compound of the Formula 110 in an organic solve′nt (e.g., DMF) in the presence of base (e.g., KOH) to form a compound of 150.
- organic solve′nt e.g., DMF
- base e.g., KOH
- the compound of Formula I can then be formed by reacting amine 150 with a compound of the Formula 160 in the present an organic solvent (e.g., dichloromethane). See e.g., Scheme 4.
- an organic solvent e.g., dichloromethane
- Reagents and solvents were purchased from commercially available sources and used without further purification. All reactions were carried out according to the indicated procedures and conditions. Reactions were monitored by LC/MS analysis and/or thin-layer chromatography (TLC) on silica-coated glass plates (EMD silica gel 60 F254) with the indicated eluent. The compounds were visualized by UV light (254 nm). LC/MS analysis was performed on an Agilent 1200 HPLC/UV (220 nm and/or 254 nm wavelength) system coupled with a mass spectroscopic (Applied Biosystems, MDS SCIEX, Q TRAP LC/MS/MS) detector.
- the title compound can be prepared following the procedures set forth above.
- RBL-2H3 cells (ATCC) were seeded in 96-well plate at 4 ⁇ 10 4 cells per well in DMEM-supplemented with 2% FBS and allowed to adhere overnight. Culture medium was then replaced with 50 ⁇ l of Ca 2+ -free Tyrode solution to load Ca 2+ -probe Fluo-4NW (Molecular Probe, Thermo Fisher, MA, USA) at 1:1 to the cells. New compound at indicated concentration was supplied during the probe loading from the beginning. Cells were incubated in the presence or absence of new compound for 60 minutes in the Ca 2+ -free medium at 37° C.
- [Ca 2+ ] ER in RBL2H3 cells were depleted by Tg in the same manner in the presence of the CRAC channel blockers as for [Ca 2+ ] i measurement but without loading the cells with Fluo-4NW. Then 200 ⁇ l of DMEM-3% FBS (containing 3 mM Ca 2+ ) was supplemented back in the presence of the corresponding concentration of CRAC channel blockers. Thirty minutes after Ca 2+ -add back culture supernatant was collected for degranulation measurement. Degranulation was measured as secreted ⁇ -hexosaminidase according to the protocol of the assay kit (Sigma-Aldrich, MO, USA).
- Nuclear fraction was prepared from the cells for NFAT by using a subcellular protein fractionation kit (NE-PERTM Nuclear and Cytoplasmic Extraction Reagents, Pierce Biotechnology, Thermo Fisher Scientific, MA, USA). Nuclear NFAT-c1 was measured with an ELISA kit (Active Motif, CA, USA). At this time point TNF ⁇ was measured as pre-stored release with ELISA kits (R&D Systems, MN, USA). In a part after Ca 2+ add back incubation was prolonged for 4 h to measure de novo production of the cytokine TNF ⁇ .
- NE-PERTM Nuclear and Cytoplasmic Extraction Reagents Pierce Biotechnology, Thermo Fisher Scientific, MA, USA.
- Nuclear NFAT-c1 was measured with an ELISA kit (Active Motif, CA, USA). At this time point TNF ⁇ was measured as pre-stored release with ELISA kits (R&D Systems, MN, USA). In a part after Ca 2+ add back incubation was prolonged
- Toxicity was tested in RBL-2H3 cells.
- Cells were seeded in 96-well plate at 4 ⁇ 10 4 cells per well in DMEM-supplemented with 2% FBS and allowed to adhere overnight. Cells were then exposed to MCS compound at indicated concentrations for 4 h. Cell viability was determined by using counting assay (CCK8 cell counting kit, Dojindo Molecular Technologies, MD, USA).
- IC 50 and EC 50 were calculated by nonlinear regression using Prims Graphpad software. Statistical analysis was performed by one-way ANOVA and post-hoc test (Tukey's test).
- Inhibitory activity of calcium influx by the described compounds was determined using the RBL-2H3 rodent MC cell line as the primary in vitro assay.
- RBL-2H3 cells are known to express functional CRAC channel.
- Thapsigargin (Tg) is a sarco/endoplasmic reticulum (ER) Ca 2+ -ATPase (SERCA) inhibitor that selectively activates the CRAC channels by depleting Ca 2+ in the ER store ([Ca 2+ ] ER )
- Fluo-4NW was used as the molecular sensor to detect the concentration of intracellular calcium ([Ca 2+ ],). Under these assay conditions, approximately 3.5-fold higher [Ca 2+ ] i was consistently observed in RBL cells treated with Tg (1 ⁇ M) than that in untreated resting MCs. IC 50 results are shown in Table 1.
- Compound 12 was used to determine the inhibition of MC degranulation by measuring the release of pre-stored ⁇ -hexosaminidase ( ⁇ -hex) upon MC activation.
- ⁇ -hex ⁇ -hexosaminidase
- RBL-2H3 cells were activated with the treatment of 1 ⁇ M thapsigargin in Ca 2+ free culture. 30 Minutes after assay media were replenished with extracellular Ca 2+ , supernatants and cell lysates were analyzed for ⁇ -hex concentrations by ELISA.
- the inhibition of nuclear translocation of the nuclear factor of activated T-cells (NFAT) by compound 12 in activated MCs was determined.
- the nuclear factor NFAT is a master regulator of numerous cytokines including TNF ⁇ . Cytosolic NFAT is dephosphorylated by the phosphatase calcineurin, which leads to the nuclear translocation of NFAT and subsequent gene activations for the expression of the corresponding cytokines.
- RBL cells were first treated with 1 ⁇ M thapsigargin in Ca 2+ free culture in the absence or presence of various concentrations of compound 12, which was followed by replenishing with extracellular Ca 2+ for 30 minutes. Nuclear fraction was prepared from the cells by subcellular protein fractionation, and the nuclear NFAT-c1 content was measured by ELISA.
- TNF ⁇ protein secretions Certain compounds were selected and demonstrated dose-dependent inhibition of the production of TNF ⁇ protein by activated MCs.
- Mast cells can secrete pre-stored TNF ⁇ immediately upon activation, as well as de novo synthesized TNF ⁇ that takes a few hours to produce.
- RBL cells were activated similarly as described above, in the presence of various concentrations of a CRAC channel blocker. 4 Hours after RBL cells were re-exposed to Ca 2+ , secreted TNF ⁇ (which accounted for the combined protein from pre-stored and de novo synthesized TNF ⁇ ) in the supernatants were measured by ELISA.
- Compounds showed dose-dependent inhibition of TNF ⁇ protein secretions (Table 2).
- C57B16 mice were made diabetic (DM) using Streptozotocin (STZ) and rabbits were made DM using alloxan.
- a 10-day wound-healing period was chosen since at least 80% wounds in non-DM mice and rabbits heal by that time-point.
- a dressing based on an alginate bandage for topical sustained release of Compound 1 was generated following the methods described in WO 2014/169250, and was then applied the shaved dorsum of DM mice either before (pre-wound) or after wounds (post-wound) were introduced.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16/069,961 US20190016680A1 (en) | 2016-01-14 | 2017-01-13 | Mast-cell modulators and uses thereof |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662278722P | 2016-01-14 | 2016-01-14 | |
US16/069,961 US20190016680A1 (en) | 2016-01-14 | 2017-01-13 | Mast-cell modulators and uses thereof |
PCT/US2017/013279 WO2017123826A1 (en) | 2016-01-14 | 2017-01-13 | Mast-cell modulators and uses thereof |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2017/013279 A-371-Of-International WO2017123826A1 (en) | 2016-01-14 | 2017-01-13 | Mast-cell modulators and uses thereof |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/738,371 Division US11084789B2 (en) | 2016-01-14 | 2020-01-09 | Mast-cell modulators and uses thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
US20190016680A1 true US20190016680A1 (en) | 2019-01-17 |
Family
ID=57966103
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/069,961 Abandoned US20190016680A1 (en) | 2016-01-14 | 2017-01-13 | Mast-cell modulators and uses thereof |
US16/738,371 Active US11084789B2 (en) | 2016-01-14 | 2020-01-09 | Mast-cell modulators and uses thereof |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/738,371 Active US11084789B2 (en) | 2016-01-14 | 2020-01-09 | Mast-cell modulators and uses thereof |
Country Status (5)
Country | Link |
---|---|
US (2) | US20190016680A1 (de) |
EP (1) | EP3402780A1 (de) |
CN (1) | CN108602775B (de) |
CA (1) | CA3010615C (de) |
WO (1) | WO2017123826A1 (de) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11084789B2 (en) | 2016-01-14 | 2021-08-10 | Beth Israel Deaconess Medical Center, Inc. | Mast-cell modulators and uses thereof |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110437235B (zh) * | 2019-08-27 | 2021-04-09 | 北京诺康达医药科技股份有限公司 | 3-酰胺氮杂吲哚类化合物作为肥大细胞调节剂及其制备方法和用途 |
CN110885308A (zh) * | 2019-09-30 | 2020-03-17 | 北京诺康达医药科技股份有限公司 | 甲酰胺晶体 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1180468A (en) * | 1913-09-11 | 1916-04-25 | George Miller Bartlett | Universal joint. |
WO2006015263A2 (en) * | 2004-07-29 | 2006-02-09 | Threshold Pharmaceuticals, Inc. | Lonidamine analogs |
Family Cites Families (86)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE9103397D0 (sv) | 1991-11-18 | 1991-11-18 | Kabi Pharmacia Ab | Nya substituerade salicylsyror |
JPH11503445A (ja) | 1995-04-10 | 1999-03-26 | 藤沢薬品工業株式会社 | cGMP−PDE阻害剤としてのインドール誘導体 |
WO1999023070A1 (en) | 1997-11-04 | 1999-05-14 | St. Elizabeth's Medical Center Of Boston, Inc. | N-acetylserotonin derivatives and uses thereof |
CA2316172C (en) | 1997-12-24 | 2010-02-02 | Aventis Pharma Deutschland Gmbh | Indole derivatives as inhibitors of factor xa |
US6500853B1 (en) | 1998-02-28 | 2002-12-31 | Genetics Institute, Llc | Inhibitors of phospholipase enzymes |
ES2262072T3 (es) | 1998-04-28 | 2006-11-16 | Elbion Ag | Derivados de indol y su utilizacion como inhibidores de la fosfodiesterasa 4. |
WO2000012045A2 (en) | 1998-08-26 | 2000-03-09 | St. Elizabeth's Medical Center Of Boston, Inc. | Method for treating neurodegenerative disorders |
AU3540101A (en) | 2000-01-07 | 2001-07-16 | Universitaire Instelling Antwerpen | Purine derivatives, process for their preparation and use thereof |
GB0002666D0 (en) | 2000-02-04 | 2000-03-29 | Univ London | Blockade of voltage dependent sodium channels |
WO2001058869A2 (en) | 2000-02-11 | 2001-08-16 | Bristol-Myers Squibb Company | Cannabinoid receptor modulators, their processes of preparation, and use of cannabinoid receptor modulators in treating respiratory and non-respiratory diseases |
WO2002060426A2 (en) | 2001-01-03 | 2002-08-08 | President And Fellows Of Harvard College | Compounds regulating cell proliferation and differentiation |
JP4399253B2 (ja) | 2001-06-20 | 2010-01-13 | ワイス | プラスミノゲンアクチベーターインヒビター−1(pai−1)のインヒビターとしての、置換されたインドール酸誘導体 |
WO2003035005A2 (en) | 2001-10-26 | 2003-05-01 | University Of Connecticut | Heteroindanes: a new class of potent cannabimimetic ligands |
US7528165B2 (en) | 2001-12-13 | 2009-05-05 | National Health Research Institutes | Indole compounds |
US7632955B2 (en) | 2001-12-13 | 2009-12-15 | National Health Research Institutes | Indole compounds |
TWI317634B (en) | 2001-12-13 | 2009-12-01 | Nat Health Research Institutes | Aroyl indoles compounds |
US20040038958A1 (en) | 2002-07-11 | 2004-02-26 | Chris Rundfeldt | Topical treatment of skin diseases |
US7196082B2 (en) | 2002-11-08 | 2007-03-27 | Merck & Co. Inc. | Ophthalmic compositions for treating ocular hypertension |
DE10253426B4 (de) | 2002-11-15 | 2005-09-22 | Elbion Ag | Neue Hydroxyindole, deren Verwendung als Inhibitoren der Phosphodiesterase 4 und Verfahren zu deren Herstellung |
EP2239012A3 (de) | 2003-04-11 | 2011-06-15 | High Point Pharmaceuticals, LLC | Substituierte amide Derivate und deren pharmazeutische Verwendungen |
EP1615667A2 (de) | 2003-04-11 | 2006-01-18 | Novo Nordisk A/S | Kombinationspräparate welche einen 11-beta-hydroxysteroid-dehydrogenas typ-3 hemmer und einen glucocorticoid rezeptor agonist enthalten |
JP2006522750A (ja) | 2003-04-11 | 2006-10-05 | ノボ ノルディスク アクティーゼルスカブ | 代謝性症候群ならびに関連の疾患および障害を治療するために、11β−ヒドロキシステロイドデヒドロゲナーゼ1型阻害剤および抗高血圧剤を使用する併用療法 |
EP1532980A1 (de) | 2003-11-24 | 2005-05-25 | Novo Nordisk A/S | N-Heteroaryl Indol-Carboxamide und deren analoga zur Vewendung als glucokinase Aktivatoren zur Behandlung von Diabetes |
AU2005265270B2 (en) | 2004-06-22 | 2011-09-22 | Vertex Pharmaceuticals Incorporated | Heterocyclic derivatives for modulation of calcium channels |
NZ580387A (en) | 2004-07-12 | 2011-06-30 | Cadila Healthcare Ltd | Tricyclic pyrazole derivatives as cannabinoid receptor modulators |
ES2341559T3 (es) | 2004-07-23 | 2010-06-22 | The Medicines Company (Leipzig) Gmbh | Pirido(3',2':4,5)tieno(3,2-d)pirimidinas y pirido(3',2':4,5)furo(3,2-d)pirimidinas sustituidas para su utilizacion como inhibidores de la liberacion de pda-4 y/o tnf-alfa. |
US20070015771A1 (en) * | 2004-07-29 | 2007-01-18 | Threshold Pharmaceuticals, Inc. | Lonidamine analogs |
WO2006015283A2 (en) | 2004-07-29 | 2006-02-09 | Threshold Pharmaceuticals, Inc. | Treatment of benign prostatic hyperplasia |
FR2875230A1 (fr) | 2004-09-13 | 2006-03-17 | Sanofi Aventis Sa | Derives de pyrazole condense, leur preparation et leur application en therapeutique |
DE102004054666A1 (de) | 2004-11-12 | 2006-05-18 | Bayer Cropscience Gmbh | Substituierte Pyrazol-3-carboxamide, Verfahren zur Herstellung und Verwendung als Herbizide und Pflanzenwachstumsregulatoren |
JP2008521831A (ja) | 2004-11-30 | 2008-06-26 | プレキシコン,インコーポレーテッド | Ppar活性化合物 |
CA2613678A1 (en) | 2005-06-02 | 2006-12-07 | Glenmark Pharmaceuticals S.A. | Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation |
EP2526942B1 (de) | 2005-06-08 | 2017-08-09 | The University of North Carolina At Chapel Hill | Verfahren zur Ermöglichung des Überlebens von Nervenzellen anhand nicht-peptidischer und peptidscher BDNF-Neurotrophin-Mimetika |
WO2007025613A2 (en) | 2005-07-15 | 2007-03-08 | Laboratorios Del Dr. Esteve, S.A. | Use of compounds binding to the sigma receptor for the treatment of diabetes-associated pain |
WO2007011647A2 (en) | 2005-07-15 | 2007-01-25 | Kalypsys, Inc. | Inhibitors of mitotic kinesin ksp |
CN101263115A (zh) | 2005-08-17 | 2008-09-10 | 惠氏公司 | 经取代吲哚和其用途 |
RU2448703C2 (ru) | 2005-11-23 | 2012-04-27 | Дзе Борд Оф Риджентс Оф Дзе Юниверсити Оф Техас Систем | Онкогенное ras-специфичное цитотоксическое соединение и способы его применения |
CN101460458A (zh) | 2006-02-15 | 2009-06-17 | 阿勒根公司 | 具有1-磷酸-鞘氨醇(s1p)受体拮抗剂生物活性的带芳基或者杂芳基基团的吲哚-3-羧酸的酰胺、酯、硫代酰胺和硫羟酸酯化合物 |
AU2007214434B2 (en) | 2006-02-15 | 2012-06-14 | Allergan, Inc. | Indole-3-carboxylic acid amide, ester, thioamide and thiol ester compounds bearing aryl or heteroaryl groups having sphingosine-1-phosphate (S1P) receptor antagonist biological activity |
WO2007109362A2 (en) * | 2006-03-20 | 2007-09-27 | Synta Pharmaceuticals Corp. | Benzoimidazolyl-parazine compounds for inflammation and immune-related uses |
US8097644B2 (en) | 2006-03-28 | 2012-01-17 | Allergan, Inc. | Indole compounds having sphingosine-1-phosphate (S1P) receptor antagonist |
DE102006033109A1 (de) | 2006-07-18 | 2008-01-31 | Grünenthal GmbH | Substituierte Heteroaryl-Derivate |
US8445437B2 (en) | 2006-07-27 | 2013-05-21 | The Brigham And Women's Hospital, Inc. | Treatment and prevention of cardiovascular disease using mast cell stabilizers |
NZ596024A (en) | 2006-08-07 | 2013-07-26 | Ironwood Pharmaceuticals Inc | Indole compounds |
WO2008027340A2 (en) | 2006-08-30 | 2008-03-06 | Merck & Co., Inc. | Topical ophthalmic formulations |
WO2008027341A2 (en) | 2006-08-30 | 2008-03-06 | Merck & Co., Inc. | Topical ophthalmic formulations |
WO2008036967A2 (en) | 2006-09-22 | 2008-03-27 | Reddy Us Therapeutics, Inc. | Novel heterocyclic compounds as lasy activators |
US7960569B2 (en) | 2006-10-17 | 2011-06-14 | Bristol-Myers Squibb Company | Indole antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions |
US7858645B2 (en) | 2006-11-01 | 2010-12-28 | Hoffmann-La Roche Inc. | Indazole derivatives |
WO2008071451A1 (en) | 2006-12-14 | 2008-06-19 | Bayer Schering Pharma Aktiengesellschaft | Dihydropyridine derivatives useful as protein kinase inhibitors |
CN101668741A (zh) | 2007-01-11 | 2010-03-10 | 阿勒根公司 | 具有鞘氨醇-1-磷酸(s1p)受体拮抗剂生物学活性的6-取代吲哚-3-羧酸酰胺化合物 |
US20090047246A1 (en) | 2007-02-12 | 2009-02-19 | Intermune, Inc. | Novel inhibitors of hepatitis c virus replication |
US8563594B2 (en) | 2007-05-08 | 2013-10-22 | Allergan, Inc. | S1P3 receptor inhibitors for treating pain |
US20090118503A1 (en) | 2007-06-20 | 2009-05-07 | Kevin Sprott | Faah inhibitors |
KR20100066422A (ko) | 2007-08-10 | 2010-06-17 | 하. 룬트벡 아크티에 셀스카브 | 헤테로아릴 아미드 유사체 |
US9149463B2 (en) | 2007-09-18 | 2015-10-06 | The Board Of Trustees Of The Leland Standford Junior University | Methods and compositions of treating a Flaviviridae family viral infection |
EP2205243A4 (de) | 2007-09-28 | 2012-06-13 | Brigham & Womens Hospital | Mastzellstabilisatoren für die behandlung von adipositas |
WO2009108551A2 (en) | 2008-02-25 | 2009-09-03 | H. Lundbeck A/S | Heteroaryl amide analogues |
WO2009106980A2 (en) | 2008-02-29 | 2009-09-03 | Pfizer Inc. | Indazole derivatives |
MX2010009462A (es) | 2008-02-29 | 2010-09-24 | Pfizer | Derivados de indazol. |
WO2009117335A2 (en) | 2008-03-17 | 2009-09-24 | Allergan, Inc. | S1p3 receptor inhibitors for treating inflammation |
US20110098483A1 (en) | 2008-03-27 | 2011-04-28 | University Of Southern California | Substituted Nitrogen Heterocycles and Synthesis and Uses Thereof |
JP2011516442A (ja) | 2008-04-04 | 2011-05-26 | ビオマリン アイジーエー リミテッド | 筋ジストロフィーを治療するための化合物 |
US8822513B2 (en) | 2010-03-01 | 2014-09-02 | Gtx, Inc. | Compounds for treatment of cancer |
US9447049B2 (en) | 2010-03-01 | 2016-09-20 | University Of Tennessee Research Foundation | Compounds for treatment of cancer |
EP2427189A1 (de) | 2009-05-05 | 2012-03-14 | Allergan, Inc. | S1p3-rezeptor-inhibitoren zur behandlung von augenerkrankungen |
US8575089B2 (en) | 2009-08-17 | 2013-11-05 | University-Industry Cooperation Group Of Kyung Hee | Composition for preventing or treating inflammation |
EP2491033A4 (de) | 2009-10-20 | 2013-03-13 | Eiger Biopharmaceuticals Inc | Azaindazole zur behandlung von flaviviridae-virusinfektionen |
MX336731B (es) | 2010-01-28 | 2016-01-28 | Harvard College | Composiciones y metodos para potenciar la actividad de proteasoma. |
WO2011109059A1 (en) | 2010-03-01 | 2011-09-09 | Gtx, Inc. | Compounds for treatment of cancer |
TWI429628B (zh) | 2010-03-29 | 2014-03-11 | Univ Taipei Medical | 吲哚基或吲哚啉基羥肟酸化合物 |
CN103380112A (zh) * | 2010-11-24 | 2013-10-30 | 阿勒根公司 | 作为s1p受体调节剂的吲哚衍生物 |
JP2014522570A (ja) | 2011-05-31 | 2014-09-04 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | 電解質配合物 |
EP2849733B1 (de) | 2011-12-19 | 2020-04-08 | Mahmut Bilgic | Brauseformulierung enthaltend pregabalin und vitamin b12 |
KR20150016377A (ko) | 2012-06-01 | 2015-02-11 | 노그라 파마 리미티드 | T-세포 반응을 조절할 수 있는 비시클릭 헤테로사이클 및 그의 사용 방법 |
ITRM20120335A1 (it) | 2012-07-13 | 2014-01-14 | Aboca Spa Societa Agricola | Nuove composizioni per il trattamento del dolore neuropatico. |
WO2014031732A2 (en) | 2012-08-22 | 2014-02-27 | Cornell University | Methods for inhibiting fascin |
JP6412503B2 (ja) * | 2012-11-21 | 2018-10-24 | ピーティーシー セラピューティクス, インコーポレイテッド | 置換逆ピリミジンBmi−1阻害剤 |
US9580400B2 (en) | 2013-02-26 | 2017-02-28 | Northeastern University | Cannabinergic nitrate esters and related analogs |
WO2014167530A1 (en) | 2013-04-11 | 2014-10-16 | Bowden Matthew James | Cannabinoid compounds |
WO2014169250A1 (en) | 2013-04-11 | 2014-10-16 | President And Fellows Of Harvard College | Prefabricated alginate-drug bandages |
CA2910473C (en) | 2013-04-26 | 2021-06-22 | Hofstra University | Nuclear magnetic resonance implemented synthetic indole and indazole cannabinoid detection, identification, and quantification |
US9357781B2 (en) | 2013-05-03 | 2016-06-07 | Inscent, Inc. | Honeybee repellents and uses thereof |
US8663663B1 (en) | 2013-06-10 | 2014-03-04 | JCDS Holdings, LLC | Topical compositions to treat circulatory disorders |
US20180161388A1 (en) | 2015-05-18 | 2018-06-14 | Beth Israel Deaconess Medical Center, Inc. | Substance p, mast cell degranulation inhibitors, and peripheral neuropathy |
EP3402780A1 (de) | 2016-01-14 | 2018-11-21 | Beth Israel Deaconess Medical Center, Inc. | Mastzellenmodulatoren und verwendungen davon |
-
2017
- 2017-01-13 EP EP17703502.9A patent/EP3402780A1/de not_active Withdrawn
- 2017-01-13 US US16/069,961 patent/US20190016680A1/en not_active Abandoned
- 2017-01-13 CN CN201780006583.0A patent/CN108602775B/zh active Active
- 2017-01-13 CA CA3010615A patent/CA3010615C/en active Active
- 2017-01-13 WO PCT/US2017/013279 patent/WO2017123826A1/en active Application Filing
-
2020
- 2020-01-09 US US16/738,371 patent/US11084789B2/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1180468A (en) * | 1913-09-11 | 1916-04-25 | George Miller Bartlett | Universal joint. |
WO2006015263A2 (en) * | 2004-07-29 | 2006-02-09 | Threshold Pharmaceuticals, Inc. | Lonidamine analogs |
Non-Patent Citations (5)
Title |
---|
Aboul-Einein Y hassan et al , scavenging of reactive oxygen species bt N-substitued indole-2 and 3-carboxamides. (Year: 2004) * |
S. Olgen et al. Syntheses and biological evaluation of indole-2 and 3-carboxamides: New selective cyclooxygenase-2 inhibitors. (Year: 2002) * |
Scavenging of reactive oxygen species by N-substitued indole-2 and 3-carboxamides . Hassan Y. Aboul-Enein et al (Year: 2004) * |
Sureyya Olgen et al , Synthesis and evaluation of novel H-H and N-substitued indole-2- and 3-carboxamide derivatives as antioxidants agents. (Year: 2007) * |
Syntheses and biological evaluation of indole-2 and 3-carboxamides: new selective cyclooxygenase-2 inhibitors. Olgen S. et al. (Year: 2002) * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11084789B2 (en) | 2016-01-14 | 2021-08-10 | Beth Israel Deaconess Medical Center, Inc. | Mast-cell modulators and uses thereof |
Also Published As
Publication number | Publication date |
---|---|
CN108602775A (zh) | 2018-09-28 |
US20200148638A1 (en) | 2020-05-14 |
CA3010615A1 (en) | 2017-07-20 |
CA3010615C (en) | 2024-02-20 |
EP3402780A1 (de) | 2018-11-21 |
US11084789B2 (en) | 2021-08-10 |
WO2017123826A1 (en) | 2017-07-20 |
CN108602775B (zh) | 2022-04-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11045476B2 (en) | Compounds and methods for inducing chondrogenesis | |
US11084789B2 (en) | Mast-cell modulators and uses thereof | |
US7799812B2 (en) | Reverse isoxazoles | |
US11976056B2 (en) | Substituted alkoxypyridinyl indolsulfonamides | |
JP6337109B2 (ja) | ナトリウムチャネルの調節剤としてのスルホンアミド | |
CN102958925B (zh) | 吡唑衍生物钙释放激活钙通道调节剂及非小细胞肺癌的治疗方法 | |
JP2022504949A (ja) | アンドロゲン受容体モジュレーター及びその使用方法 | |
US20120238588A1 (en) | 1H-Pyrrolo[2,3-B]Pyridines | |
US11046660B2 (en) | Compounds and their use as PDE4 activators | |
JP2000510164A (ja) | 選択的神経ペプチドy受容体アンタゴニストとしてのアミド誘導体 | |
JP2004522710A (ja) | 性機能障害の治療 | |
WO2019052557A1 (zh) | μ-阿片受体激动剂及其制备方法和在医药领域的应用 | |
US20210032231A1 (en) | Compounds and Their Use as PDE4 Activators | |
KR101905295B1 (ko) | 나프티리딘디온 유도체 | |
EP3373931A1 (de) | Heterocyclische verbindungen zur behandlung von erkrankungen | |
JP2020524660A (ja) | Ror−ガンマモジュレーターとして有用な2,3−ジヒドロイソインドール−1−カルボキサミド | |
TW201922700A (zh) | 醯胺苯衍生物及其醫藥用途 | |
US11465998B2 (en) | Therapeutic compounds and methods of use thereof | |
WO2024028654A2 (en) | Histone deacetylase inhibitors and use of the same | |
WO2017152570A1 (zh) | 新型gvs系列化合物及其用途 | |
EA041031B1 (ru) | Дейтерированные пиридонамиды и их пролекарства в качестве модуляторов натриевых каналов | |
US20170088545A1 (en) | Carboxamide inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF Free format text: CONFIRMATORY LICENSE;ASSIGNOR:BETH ISRAEL DEACONESS MEDICAL CENTER;REEL/FRAME:046718/0522 Effective date: 20180716 |
|
AS | Assignment |
Owner name: BETH ISRAEL DEACONESS MEDICAL CENTER, INC., MASSAC Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SUN, LIJUN;VEVES, ARISTIDIS;SIGNING DATES FROM 20180722 TO 20180727;REEL/FRAME:046594/0527 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |