Use of CXCR4 Antagonists
AssigneesGenzyme Corporation, University of Washington Center for Commercialization
InventorsDavid C. Dale, Gary J. Bridger, Frank J. Hsu
Life of this patent
Estimating the term…
Abstract
Presently disclosed are methods and compositions for treating or preventing WHIM syndrome and certain other disorders or conditions with a certain CXCR4 antagonist.
Claims81
A method for treating or preventing WHIM syndrome in a human in need thereof comprising administering to said human a CXCR4 antagonist in an amount effective to treat or prevent the WHIM syndrome, wherein the CXCR4 antagonist is a compound of formula I:
- Z-linker-Z′ (I)
- or a pharmaceutically acceptable salt or metal complex thereof, wherein Z is a cyclic polyamine containing 9-32 ring members of which 2-8 are nitrogen atoms, said nitrogen atoms being separated from each other by at least 2 carbon atoms, and wherein said heterocycle may optionally contain additional heteroatoms besides nitrogen and/or may be fused to an additional ring system;
- Z′ is either Z or of the formula
- —N(R)—(CR2)n—X
- wherein each R is independently H or straight, branched or cyclic alkyl (1-6C), n is 1 or 2, and X is an aromatic ring, including heteroaromatic rings, or is a mercaptan,
- or Z′ is of the formula
- —Ar(Y)j
- wherein Ar is an aromatic or heteroaromatic moiety, and each Y is independently a noninterfering substituent and j is 0-3;
- and
- “linker” represents a bond, alkylene (1-6C) or may comprise aryl, fused aryl, oxygen atoms contained in an alkylene chain, or may contain keto groups or nitrogen or sulfur atoms.
A pharmaceutical composition for treating or preventing WHIM syndrome or a disease or condition associated with WHIM syndrome in a human in need thereof comprising:
- a compound of formula I:
- Z-linker-Z′ (I)
- or a pharmaceutically acceptable salt or metal complex thereof, wherein Z is a cyclic polyamine containing 9-32 ring members of which 2-8 are nitrogen atoms, said nitrogen atoms being separated from each other by at least 2 carbon atoms, and wherein said heterocycle may optionally contain additional heteroatoms besides nitrogen and/or may be fused to an additional ring system;
- Z′ is either Z or of the formula
- —N(R)—(CR2)n—X
- wherein each R is independently H or straight, branched or cyclic alkyl (1-6C), n is 1 or 2, and X is an aromatic ring, including heteroaromatic rings, or is a mercaptan,
- or Z′ is of the formula
- —Ar(Y)j
- wherein Ar is an aromatic or heteroaromatic moiety, and each Y is independently a noninterfering substituent and j is 0-3;
- and
- “linker” represents a bond, alkylene (1-6C) or may comprise aryl, fused aryl, oxygen atoms contained in an alkylene chain, or may contain keto groups or nitrogen or sulfur atoms;
- and
- a pharmaceutically acceptable diluent or carrier.
A method for treating or preventing a disorder or condition independently selected from hypogammaglobulinemia, myelokathexis, neutropenia, leukopenia, lymphopenia, abnormalities attributed to improper trafficking of leukocytes, SCID's, diphtheria, bacterial infections, viral infections, or reduced immune function in a human in need thereof comprising administering to said human a CXCR4 antagonist in an amount effective to treat or prevent the disorder or condition, wherein the CXCR4 antagonist is a compound of formula I:
- Z-linker-Z′ (I)
- or a pharmaceutically acceptable salt or metal complex thereof, wherein Z is a cyclic polyamine containing 9-32 ring members of which 2-8 are nitrogen atoms, said nitrogen atoms being separated from each other by at least 2 carbon atoms, and wherein said heterocycle may optionally contain additional heteroatoms besides nitrogen and/or may be fused to an additional ring system;
- Z′ is either Z or of the formula
- —N(R)—(CR2)n—X
- wherein each R is independently H or straight, branched or cyclic alkyl (1-6C), n is 1 or 2, and X is an aromatic ring, including heteroaromatic rings, or is a mercaptan,
- or Z′ is of the formula
- —Ar(Y)j
- wherein Ar is an aromatic or heteroaromatic moiety, and each Y is independently a noninterfering substituent and j is 0-3;
- and
- “linker” represents a bond, alkylene (1-6C) or may comprise aryl, fused aryl, oxygen atoms contained in an alkylene chain, or may contain keto groups or nitrogen or sulfur atoms.
A pharmaceutical composition for treating or preventing a disorder or condition independently selected from hypogammaglobulinemia, myelokathexis, neutropenia, leukopenia, lymphopenia, abnormalities attributed to improper trafficking of leukocytes, SCID's, diphtheria, bacterial infections, viral infections, or reduced immune function in a human in need thereof comprising:
- a compound of formula I:
- Z-linker-Z′ (I)
- or a pharmaceutically acceptable salt or metal complex thereof, wherein Z is a cyclic polyamine containing 9-32 ring members of which 2-8 are nitrogen atoms, said nitrogen atoms being separated from each other by at least 2 carbon atoms, and wherein said heterocycle may optionally contain additional heteroatoms besides nitrogen and/or may be fused to an additional ring system;
- Z′ is either Z or of the formula
- —N(R)—(CR2)n—X
- wherein each R is independently H or straight, branched or cyclic alkyl (1-6C), n is 1 or 2, and X is an aromatic ring, including heteroaromatic rings, or is a mercaptan,
- or Z′ is of the formula
- —Ar(Y)j
- wherein Ar is an aromatic or heteroaromatic moiety, and each Y is independently a noninterfering substituent and j is 0-3;
- and
- “linker” represents a bond, alkylene (1-6C) or may comprise aryl, fused aryl, oxygen atoms contained in an alkylene chain, or may contain keto groups or nitrogen or sulfur atoms;
- and
- a pharmaceutically acceptable diluent or carrier.
A method for treating or preventing a disorder or condition independently selected from WHIM syndrome, hypogammaglobulinemia, myelokathexis, neutropenia, leukopenia, lymphopenia, abnormalities attributed to improper trafficking of leukocytes, SCID's, diphtheria, bacterial infections, viral infections, or reduced immune function in a human in need thereof comprising
- testing for the presence of a CXCR4 mutation in a human having one of the disorders or conditions;
- selecting a human having the CXCR4 mutation;
- administering to the selected human a CXCR4 antagonist in an amount effective to treat or prevent the disorder or condition, wherein the CXCR4 antagonist is a compound of formula I:
- Z-linker-Z′ (I)
- or a pharmaceutically acceptable salt or metal complex thereof, wherein Z is a cyclic polyamine containing 9-32 ring members of which 2-8 are nitrogen atoms, said nitrogen atoms being separated from each other by at least 2 carbon atoms, and wherein said heterocycle may optionally contain additional heteroatoms besides nitrogen and/or may be fused to an additional ring system;
- Z′ is either Z or of the formula
- —N(R)—(CR2)n—X
- wherein each R is independently H or straight, branched or cyclic alkyl (1-6C), n is 1 or 2, and X is an aromatic ring, including heteroaromatic rings, or is a mercaptan,
- or Z′ is of the formula
- —Ar(Y)j
- wherein Ar is an aromatic or heteroaromatic moiety, and each Y is independently a noninterfering substituent and j is 0-3;
- and
- “linker” represents a bond, alkylene (1-6C) or may comprise aryl, fused aryl, oxygen atoms contained in an alkylene chain, or may contain keto groups or nitrogen or sulfur atoms.
A method for correcting neutropenia and/or lymphocytopenia in a human patient with myelokathexis or WHIM syndrome comprising administering to the human a CXCR4 antagonist in an amount effective to correct the neutropenia and/or lymphocytopenia, wherein the CXCR4 antagonist is a compound of formula I:
- Z-linker-Z′ (I)
- or a pharmaceutically acceptable salt or metal complex thereof, wherein Z is a cyclic polyamine containing 9-32 ring members of which 2-8 are nitrogen atoms, said nitrogen atoms being separated from each other by at least 2 carbon atoms, and wherein said heterocycle may optionally contain additional heteroatoms besides nitrogen and/or may be fused to an additional ring system;
- Z′ is either Z or of the formula
- —N(R)—(CR2)n—X
- wherein each R is independently H or straight, branched or cyclic alkyl (1-6C), n is 1 or 2, and X is an aromatic ring, including heteroaromatic rings, or is a mercaptan,
- or Z′ is of the formula
- —Ar(Y)j
- wherein Ar is an aromatic or heteroaromatic moiety, and each Y is independently a noninterfering substituent and j is 0-3;
- and
- “linker” represents a bond, alkylene (1-6C) or may comprise aryl, fused aryl, oxygen atoms contained in an alkylene chain, or may contain keto groups or nitrogen or sulfur atoms.
Dependencies are inferred from the claim text.