Treatment of platelet derived growth factor related disorders such as cancers
First Claim
1. 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.
1 Assignment
0 Petitions
Accused Products
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.
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Citations
15 Claims
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1. A method of evaluating the susceptibility of a cancer to growth inhibition by a compound comprising the steps of:
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(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;
whereinR1, 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;
whereinR4 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;
whereinR7, 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;
whereinR10 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;
whereinR26 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;
whereinR30 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;
whereinR33 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. - View Dependent Claims (2, 3, 4, 5, 6, 7)
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8. A method of evaluating the susceptibility of a cancer to growth inhibition by a compound comprising the steps of:
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(a) culturing cells of said disorder in medium containing PDGF;
(b) culturing cells of said disorder 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;
whereinR1, R2, R′
2, 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;
whereinR4 and R5 are independently selected from the group consisting 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;
whereinR7, R′
7 and R8 are independently selected from the group consisting halogen, OH, hydrogen, alkoxy, SH, NH2 and C(CH3)3; and
R9 is aryl or hydrogen;
(iv) a compound of Formula IV;
whereinR10 is selected from the group consisting of ═
S, ═
O, SH, OH, and NH2;
R3, is selected from the group consisting of SH, OH, NH2, ═
C(CN)2 and aryl;
or R9 andR11, 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;
whereinR13, R′
14, R15, R16, R17 and R18 are independently selected from the group consisting hydrogen, halogen, alkoxy, OH, amino, alkylamino, and SH;
(vi) a compound of Formula VI;
whereinR19 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 independndtly 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, NO2, alkoxy, alkyl, 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 optionaly has a substituent selected from the group consisting hydrogen, alkyl, alkyleneamino, alkyleneaminoalkyl, and alkylenecyano;
(viii) a compound of Formula VIII;
whereinR26 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;
whereinR30 is selected from the group consisting of alkyl, alkenyl, and alkynyl;
R31 is aryl; and
R32 is either O or S;
(x) a compound of Formula X;
whereinR33 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. - View Dependent Claims (9, 10, 11, 12, 13, 14, 15)
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Specification