US 6,331,555 B1 · Treatment of platelet derived growth factor related disorders such as cancers

Treatment of platelet derived growth factor related disorders such as cancers

AssigneesUniversity of California, Yissum Research Development Company of the Hebrew University of Jerusalem, Biosignal Limited, Sugen, Inc., Max-Planck-Gesellschaft zur Forderung der Wissenschaften e.V.

InventorsKlaus P. Hirth, Elaina Mann, Laura K. Shawyer, Axel Ullrich, Istvan Szekely, Tamas Bajor, Janis Haimichael, Laszlo Orfi, Alex Levitzki, Aviv Gazit, Peng Cho Tang, Reiner Lammers

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Abstract

The present invention concerns compounds which can inhibit platelet derived growth factor receptor (PDGF-R) activity, preferably such compounds also inhibit the activity other members of the PDGF-R super family and are selective for members of the PDGF-R super family. The PDGF-R super family includes PDGF-R and PDGF-R related kinases Flt, and KDR. The featured compounds are active on cell cultures to reduce the activity of the PDGF-R and preferably one or more PDGF-R related kinases. An example of a featured compound, A10 (see FIG. 1a), and its ability to inhibit growth of tumor cells in vivo is described below. Using the present application as guide other compounds able to inhibit PDGF-R and preferably Flt and/or KDR can be obtained. Such compounds are preferably used to treat patients suffering from cell proliferative disorders characterized by inappropriate PDGF-R activity.

A method of evaluating the susceptibility of a cancer to growth inhibition by a compound comprising the steps of:

(a) culturing cells of said cancer in medium containing PDGF;
(b) culturing cells of said cancer in medium containing PDGF and said compound;
and
(c) measuring and comparing the growth of said cells in (a) and (b), wherein said compound is selected from the group consisting of:
i) a compound of Formula I:
wherein
R1, R2, R′2, R″2, and R″2 are independently selected from the group consisting of hydrogen, halogen, trihalomethyl, and NO2;
and
R3 is selected from the group consisting of hydrogen, carboxy, alkoxy, and carbalkoxy;
ii) a compound of Formula II:
wherein
R4 and R5 are independently selected from the group consisting of halogen, hydrogen, trihalomethyl, and NO2;
and
R6 is selected from the group consisting of aryl, alkyl, alkenyl and alkynyl;
iii) a compound of Formula III:
wherein
R7, R′7, and R8 are independently selected from the group consisting of halogen, OH, hydrogen, alkoxy, SH, NH2, and C(CH3)3;
and
R9 is aryl or hydrogen;
iv) a compound of Formula IV:
wherein
R10 is selected from the group consisting of ═S, ═O, SH, OH, and NH2;
R11 is selected from the group consisting of SH, OH, NH2, ═C(CN)2 and aryl;
or R10 and R11 taken together are aryl;
and
R12 is selected from the group consisting of hydrogen, aryl, alkyl, alkenyl, and alkynyl;
v) a compound of Formula V:
wherein R13, R14, R15, R16, R17, and R18 are independently selected from the group consisting of hydrogen, halogen, alkoxy, OH, amino, alkylamino, and SH;
vi) a compound of Formula VI:
wherein R19 is selected from the group consisting of aryl, alkyl, alkenyl and alkynyl;
and R20 is alkyl;
or R19 and R20 are together aryl;
vii) a compound of Formula VII:
wherein b is an optional pi bond;
Y and Z are independently carbon or nitrogen;
R21 and R22 are independently selected from the group consisting of hydrogen, halogen, OH, SH, NH2, NO2, alkyl, alkenyl, alkynyl, alkoxy, benzoyl, COOH, and carbalkoxy;
or R21 and R22 are together aryl;
R23 is selected from the group consisting of hydrogen, halogen, ═O, OH, SH, NH2, alkoxy, COOH, and aryl;
R24 is H or aryl;
and
R25 is selected from the group consisting of hydrogen, halogen, ═S, or ═O, wherein if R25 is ═O or ═S then b is present as a bond;
provided that if b is not a bond, the adjacent nitrogen optionally has a substituent selected from the group consisting of hydrogen, alkyl, alkyleneamino, alkyleneaminoalkly, and alkylenecyano;
viii) a compound of Formula VIII:
wherein
R26 and R28 are independently selected from the group consisting of alkyl, aryl, alkenyl, and alkynyl;
and
R27 is aryl;
ix) a compound of Formula IX:
wherein
R30 is selected from the group consisting of alkyl, alkenyl, and
R31 is aryl;
and
R32 is either O or S;
x) a compound of Formula X:
wherein
R33 is alkyl or aryl;
R34, R35, and R36 are independently selected from the group consisting of halogen, OH, hydrogen, alkoxy, SH, NH2, and C(CH3)3;
and
xi) a compound of any one Formula XI(a)-Formula XI(o):
or a pharmaceutically acceptable salt of said compound.

57 more elements

Facts

Application

09/363,237Filed 27 Jul 1999 · continuation

Priority

1 Jun 1995

Granted

18 Dec 2001

Term ends

Not estimatedThe source records don’t support an estimate.

Classification6 codes

A61K 31/135
Amines: having aromatic rings , e.g. ketamine, nortriptyline
A61K 31/12
Medicinal preparations containing organic active ingredients: ketones
A61K 31/13
Medicinal preparations containing organic active ingredients: amines
A61K 31/415
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2-Diazoles

Abstract

Claims15