Title:
SUBSTITUTED LACTOSE AND LACTOSAMINE DERIVATIVES AS CELL ADHESION INHIBITORS
Document Type and Number:
WIPO Patent Application WO/1993/010796
Kind Code:
A1
Abstract:
Simple lactose or lactosamine related compounds which behave as ligands for the ELAM-1 and related receptors are described. These compounds are of formula (1) wherein each R1 is independently H or lower alkyl (1-4C); R2 is H, lower alkyl (1-4C), alkylaryl or one or more additional saccharide residues; R3 and R4 are each independently H, alkyl(1-6C), aryl or R3 and R4, taken together, form a five- or six-membered ring optionally containing a heteroatom selected from the group consisting of O, S, and NR1; wherein said five- or six-membered ring may further be substituted by one or more substituents selected from the group consisting of (CHOR1)mH wherein m is 1-4, OR1, OOCR1, NR12, NHCOR1, and SR1; Y is H, OR1, OOCR1, NR12, NCOR1 or SR1; and X is -CHR5(CHOR1)2CHR6OR1 wherein R5 and R6 are each independently H, lower alkyl(1-4C) optionally substituted with one or more F, or result in a five- or six-membered ring optionally containing a heteroatom selected from the group consisting of O, S, and NR1; said five- or six-membered ring optionally substituted with one substituent selected from the group consisting of R1, CH2OR1, OR1, OOCR1, NR12, NHCOR1, SR1 and F; or X is benzoyl or naphthoyl having 1-3 hydroxyl substituents, with the proviso that if X represents a hexose substituent R3 and R4, taken together, cannot provide a hexose substituent. These compounds are useful in the treatment of conditions characterized by excess inflammation.
Inventors:
NASHED MINA (US)
DASGUPTA FALGUNI (US)
ABBAS SAEED (US)
MUSSER JOHN (US)
ASA DARWIN (US)
DASGUPTA FALGUNI (US)
ABBAS SAEED (US)
MUSSER JOHN (US)
ASA DARWIN (US)
Application Number:
PCT/US1992/009870
Publication Date:
June 10, 1993
Filing Date:
November 13, 1992
Export Citation:
Assignee:
GLYCOMED INC (US)
International Classes:
A61K31/7008; A61K31/7024; A61K31/7028; A61K31/7034; A61K31/7042; C07H5/04; A61K31/715; A61P29/00; A61P37/06; A61P37/08; C07H3/06; C07H5/10; C07H13/04; C07H15/20; C07H17/00; (IPC1-7): A61K31/725; A61K39/385; A61K47/42; C07H5/06; C08B37/00
Other References:
Journal of Clinical Investigation, Vol. 74, issued December 1984, S. LADISCH et al., "Modulation of the Immune Response by Gangliosides", pages 2074-2081.
European Journal of Immunology, Vol. 16, issued 1986, J. CAVAILLON et al., "Inhibition of Lipopolysaccharide-induced Monocyte Interleukin 1 Secretion by Gangliosides", pages 1009-1012.
Carbohydrate Research, Vol. 136, issued 1985, D.P. KHARE et al., "The Synthesis of Monodeoxy Derivatives of Lacto-N-Biose 1 and N-Acetyl-Lactosamine to serve as Substrates for the Differentiation of alpha-L-Fucosyl Transferases", pages 285-308, entire document.
The Journal of Biological Chemistry, Vol. 264, No. 16, issued 05 June 1989, I. EGGENS et al., "Specific Interaction between Le x and Le x Determinants", pages 9476-9484, entire document.
Developmental Biology, Vol. 104, issued 1984, J.M. BIRD et al., "Oligosaccharides Containing Fucose Linked alpha (1-3) and alpha (1-4) to N-Acetylglucosamine Cause Decompaction of Mouse Morulae", pages 449-460, entire document.
Carbohydrate Research, Vol. 177, issued 1988, F. DASGUPTA et al., "Alkyl Sulfenyl Triflate as Activator in the Thioglycoside-mediated Formation of beta-Glycosidic Linkages During Oligosaccharide Synthesis", pages c13-c17, entire document.
The Journal of Experimental Medicine, Vol. 160, issued November 1984, B.A. FENDERSON et al., "A Multivalent Lacto-N-Fucopentaose III-Lysyllysine Conjugate Decompacts Preimplantation Mouse Embryos, While the Free Oligosaccharide is Ineffective", pages 1591-1596, entire document.
Carbohydrate Research, Vol. 155, issued 1986, S. SATO et al., "An Efficient Approach to O-Glycosides Through CuBrs-Bu4NBr Mediated Activation of Glycosides", pages c6-c10, entire document.
Nature, Vol. 292, issued 09 July 1981, H.C. GOOI et al., "Stage-Specific Embryonic nitrogen Involves alpha1-3 Fucosylated Type 2 Blood Group Chains", pages 156-158, entire document.
Developmental Biology, Vol. 122, issued 1987, B.A. FENDERSON et al., "Glycolipid Core Structure Switching from Globo- to Lacto- and Ganglio- Series during Retinoic Acid-Induced Differentiation of TERA-2 Derived Human Embryonal Carcinoma Cells", pages 21-34, entire document.
Differentiation, Vol. 38, issued 1988, B.A. FENDERSON et al., "The Blood Group I Antigen Defined by Monoclonal Antibody C6 is a Marker of Early Mesoderm During Murine Embryogenesis", pages 124-133, entire document.
The Journal of Biological Chemistry, Vol. 264, No. 34, issued 06 December 1989, N. KOJIMA et al., "Specific Interaction between Gangliotriaosylceramide (Gg3) and Sialosyllactosylceramide (GM3) as a Basis for Specific Cellular Recognition Between Lymphoma and Melanoma Cells", pages 20159-20162.
See also references of EP 0614367A4
European Journal of Immunology, Vol. 16, issued 1986, J. CAVAILLON et al., "Inhibition of Lipopolysaccharide-induced Monocyte Interleukin 1 Secretion by Gangliosides", pages 1009-1012.
Carbohydrate Research, Vol. 136, issued 1985, D.P. KHARE et al., "The Synthesis of Monodeoxy Derivatives of Lacto-N-Biose 1 and N-Acetyl-Lactosamine to serve as Substrates for the Differentiation of alpha-L-Fucosyl Transferases", pages 285-308, entire document.
The Journal of Biological Chemistry, Vol. 264, No. 16, issued 05 June 1989, I. EGGENS et al., "Specific Interaction between Le x and Le x Determinants", pages 9476-9484, entire document.
Developmental Biology, Vol. 104, issued 1984, J.M. BIRD et al., "Oligosaccharides Containing Fucose Linked alpha (1-3) and alpha (1-4) to N-Acetylglucosamine Cause Decompaction of Mouse Morulae", pages 449-460, entire document.
Carbohydrate Research, Vol. 177, issued 1988, F. DASGUPTA et al., "Alkyl Sulfenyl Triflate as Activator in the Thioglycoside-mediated Formation of beta-Glycosidic Linkages During Oligosaccharide Synthesis", pages c13-c17, entire document.
The Journal of Experimental Medicine, Vol. 160, issued November 1984, B.A. FENDERSON et al., "A Multivalent Lacto-N-Fucopentaose III-Lysyllysine Conjugate Decompacts Preimplantation Mouse Embryos, While the Free Oligosaccharide is Ineffective", pages 1591-1596, entire document.
Carbohydrate Research, Vol. 155, issued 1986, S. SATO et al., "An Efficient Approach to O-Glycosides Through CuBrs-Bu4NBr Mediated Activation of Glycosides", pages c6-c10, entire document.
Nature, Vol. 292, issued 09 July 1981, H.C. GOOI et al., "Stage-Specific Embryonic nitrogen Involves alpha1-3 Fucosylated Type 2 Blood Group Chains", pages 156-158, entire document.
Developmental Biology, Vol. 122, issued 1987, B.A. FENDERSON et al., "Glycolipid Core Structure Switching from Globo- to Lacto- and Ganglio- Series during Retinoic Acid-Induced Differentiation of TERA-2 Derived Human Embryonal Carcinoma Cells", pages 21-34, entire document.
Differentiation, Vol. 38, issued 1988, B.A. FENDERSON et al., "The Blood Group I Antigen Defined by Monoclonal Antibody C6 is a Marker of Early Mesoderm During Murine Embryogenesis", pages 124-133, entire document.
The Journal of Biological Chemistry, Vol. 264, No. 34, issued 06 December 1989, N. KOJIMA et al., "Specific Interaction between Gangliotriaosylceramide (Gg3) and Sialosyllactosylceramide (GM3) as a Basis for Specific Cellular Recognition Between Lymphoma and Melanoma Cells", pages 20159-20162.
See also references of EP 0614367A4
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