Title:
PRODRUGS OF PROTEIN TYROSINE KINASE INHIBITORS
Document Type and Number:
WIPO Patent Application WO1995002420
Kind Code:
A3
Abstract:
PCT No. PCT/GB94/01532 Sec. 371 Date Jul. 1, 1996 Sec. 102(e) Date Jul. 1, 1996 PCT Filed Jul. 15, 1994 PCT Pub. No. WO95/02420 PCT Pub. Date Jan. 26, 1995A compound which comprises a prodrug of a protein tyrosine kinase inhibitor (PTKi) linked to a protecting group which is capable of being cleaved from the compound to release the PTKi, said PTKi prodrugs including tyrphostins, of formula (I), N->O, n is 1 to 3; each group R1, which may be the same or different is H, OH, mercapto, carboxy, formyl, C1-4 alkyl, C2-4 alkenyl, C1-4 alkoxy, C1-4 alkylthio, carboxyC1-4 alkyl, carboxyC2-4 alkenyl, C1-4 alkylsulphoxy, halo, nitro, amino, C1-4 alkylamino, or C1-4 dialkylamino, or when n is 2 or 3 two R1 groups may together form a methylenedioxy or ethylenedioxy group; R2 is H, OH, C1-4 alkyl or together with position 2 of the ring to which the group(s) R1 is (are) attached forms a 5 or 6 membered aliphatic or heterocyclic ring, optionally containing a ketone group; and R3 is cyano, carboxy, carbamoyl, thiocarbamoyl, C(O)HNCH2CN, C(NH2)=C(CN2), an alpha keto C(O)R4 where R4 is 3,4-dihydroxyphenyl or 2-thiophene or an alpha amido C(O)NHR5 where R5 is benzyl, phenyl, or 2,4-dimethoxyphenyl; provided that at least one of R1 and R2 is mercapto, hydroxy or amino.
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Inventors:
SPRINGER CAROLINE JOY (GB)
MARAIS RICHARD (GB)
MARAIS RICHARD (GB)
Application Number:
PCT/GB1994/001532
Publication Date:
March 16, 1995
Filing Date:
July 15, 1994
Export Citation:
Assignee:
SPRINGER CAROLINE JOY (GB)
MARAIS RICHARD (GB)
MARAIS RICHARD (GB)
International Classes:
C12N9/99; A61K31/195; A61K31/27; A61K31/275; A61K31/70; A61K35/76; A61K38/00; A61K38/46; A61K45/00; A61K47/48; A61K48/00; A61P35/00; A61P43/00; (IPC1-7): A61K47/48; A61K31/275
Domestic Patent References:
| WO1991016892A1 | 1991-11-14 |
Foreign References:
| EP0211363A2 | 1987-02-25 |
Other References:
SAPERSTEIN R. ET AL: "Design of a selective insulin receptor tyrosine kinase inhibitor and its effect on glucose uptake and metabolism in intact cells", BIOCHEMISTRY (USA), 1989, VOL. 28, NO. 13, PAGE(S) 5694-5701,
DONG Z. ET AL: "Activation of tumoricidal properties in macrophages by lipopolysaccharide requires protein-tyrosine kinase activity", J. LEUKOCYTE BIOL. (USA), 1993, VOL. 53, NO. 1, PAGE(S) 53-60,
DATABASE WPI Section Ch Week 9315, Derwent World Patents Index; Class B02, AN 93-121272
ENNIS B.W. ET AL: "The EGF receptor system as a target for antitumor therapy", CANCER INVEST. (USA), 1991, VOL. 9, NO. 5, PAGE(S) 553-562,
DATABASE WPI Section Ch Week 9149, Derwent World Patents Index; Class B05, AN 91-354341
MITCHELL A G ET AL: "Prodrugs of phosphonoformate: the effect of para-substituents on the products, kinetics and mechanism of hydrolysis of dibenzyl methoxycarbonylphosphonate", J. CHEM. SOC., PERKIN TRANS. 2; 1992; NO. 7; PAGE(S) 1145-50
GETZ J J ET AL: "Mechanism of hydrolysis of benzamidomethyl derivatives of phenols and its implications for prodrug design", J. ORG. CHEM.; 1992; VOL.57, NO. 6; PAGE(S) 1702-6
HAIMOVITZ-FRIEDMAN A. ET AL: "Protein kinase C mediates basic fibroblast growth factor protection of endothelial cells against radiation-induced apoptosis", CANCER RES. (US), 15-05-1994, VOL. 54, NO. 10, PAGE(S) 2591-2597,
DONG Z. ET AL: "Activation of tumoricidal properties in macrophages by lipopolysaccharide requires protein-tyrosine kinase activity", J. LEUKOCYTE BIOL. (USA), 1993, VOL. 53, NO. 1, PAGE(S) 53-60,
DATABASE WPI Section Ch Week 9315, Derwent World Patents Index; Class B02, AN 93-121272
ENNIS B.W. ET AL: "The EGF receptor system as a target for antitumor therapy", CANCER INVEST. (USA), 1991, VOL. 9, NO. 5, PAGE(S) 553-562,
DATABASE WPI Section Ch Week 9149, Derwent World Patents Index; Class B05, AN 91-354341
MITCHELL A G ET AL: "Prodrugs of phosphonoformate: the effect of para-substituents on the products, kinetics and mechanism of hydrolysis of dibenzyl methoxycarbonylphosphonate", J. CHEM. SOC., PERKIN TRANS. 2; 1992; NO. 7; PAGE(S) 1145-50
GETZ J J ET AL: "Mechanism of hydrolysis of benzamidomethyl derivatives of phenols and its implications for prodrug design", J. ORG. CHEM.; 1992; VOL.57, NO. 6; PAGE(S) 1702-6
HAIMOVITZ-FRIEDMAN A. ET AL: "Protein kinase C mediates basic fibroblast growth factor protection of endothelial cells against radiation-induced apoptosis", CANCER RES. (US), 15-05-1994, VOL. 54, NO. 10, PAGE(S) 2591-2597,
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