3-(4'-dimethylaminobenzylidenyl)-2-indolinone and analogues thereof for the treatment of disease

A compound having the formula:

• ##STR12## or a pharmaceutically acceptable salt thereof, wherein:
• R.sub.1 is H or alkyl;
• R.sub.2 is O or S;
• R.sub.3 is hydrogen;
• R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• R.sub.2 ', R.sub.3 ', R.sub.5 ', and R6' are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• n is 0-3;
• R is H, alkyl or aryl;
• R' is H, alkyl or aryl;
• and
• Ra and Rb are each independently selected from the group consisting of H, alkyl and C(O)R, or NRaRb taken together are a heterocyclic ring of from 3 to 8 atoms optionally substituted at one or more positions with hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• with the provisos that:
• (i) when Ra and Rb are both H, at least one of R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.2 ', R.sub.3 ', R.sub.5 ' or R6' must be other than hydrogen provided that R.sub.2 ' is not alkyl;
• (ii) when R.sub.1 is methyl and one of Ra and Rb is methyl and the other is isooctyl, at least one of R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.3 ' or R.sub.5 ' must be other than hydrogen;
• (iii) if one of Ra and Rb is H or lower alkyl, the other of Ra and Rb is not lower alkyl;
• and
• (iv) if one of Ra or Rb is C(O)R, the other of Ra or Rb is not H.

A compound having the formula:

• ##STR13## or a pharmaceutically acceptable salt thereof, wherein:
• R.sub.1 is H or alkyl;
• R.sub.2 is O or S;
• R.sub.3 is hydrogen;
• R.sub.4, R.sub.6, and R.sub.7 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• R.sub.5 is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• R.sub.2 ' is selected from the group consisting of hydrogen, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• R.sub.3 ', R.sub.5 ', and R.sub.6 ' are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• n is 0-3;
• R is H, alkyl or aryl;
• R' is H, alkyl or aryl;
• and
• Ra and Rb are each independently selected from the group consisting of H, alkyl and C(O)R, or NRaRb taken together are a heterocyclic ring of from 3 to 8 atoms optionally substituted at one or more positions with hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO2NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• with the provisos that:
• (i) when Ra and Rb are both H, at least one of R.sub.4, R.sub.5, R.sub.6,R.sub.7, R.sub.2 ', R.sub.3 ', R.sub.5 ' or R6' must be other than hydrogen;
• and
• (ii) when R.sub.1 is methyl and one of Ra and Rb is methyl and the other is isooctyl, at least one of R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.3 ' or R.sub.5 ' must be other than hydrogen,
• (iii) if one of Ra and Rb is H or lower alkyl the other of Ra and Rb is not lower alkyl;
• and
• (iv) if one of Ra or Rb is C(O)R, the other of Ra or Rb is not H.

A compound having the formula:

• ##STR14## or a pharmaceutically acceptable salt thereof, wherein:
• R.sub.1 is H or alkyl;
• R.sub.2 is O or S;
• R.sub.3 is hydrogen;
• R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• R.sub.2 ', R.sub.3 ', R.sub.5 ', and R.sub.6 ' are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• n is 0-3;
• R is H, alkyl or aryl;
• R' is H, alkyl or aryl;
• and
• NRaRb taken together are a heterocyclic ring of from 3 to 8 atoms optionally substituted at one or more positions with hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR'.

A pharmaceutical composition comprising a compound having the formula:

• ##STR15## or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient, wherein:
• R.sub.1 is H or alkyl;
• R.sub.2 is O or S;
• R.sub.3 is hydrogen;
• R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• R.sub.2 ', R.sub.3 ', R.sub.5 ', and R.sub.6 ' are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• Ra and Rb are each independently selected from the group consisting of H, alkyl and C(O)R, or NRaRb taken together are a heterocyclic ring of from 3 to 8 atoms optionally substituted at one or more positions with hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R or CONRR';
• n is 0-3;
• R is H, alkyl or aryl;
• and
• R'is H, alkyl or aryl;
• with the proviso that when the pharmaceutically acceptable carrier or excipient is selected from the group consisting of anise oil, carboxymethylcellulose and peanut oil, the compound is not 3-(4-dimethylaminobenzylidene)-2-indolinone.

A pharmaceutical composition comprising a compound having the formula:

• ##STR16## or a pharmaceutically acceptable salt thereof, in combination with a pharmacuticaly acceptable carrier or excipient, wherein:
• R.sub.1 is H or alkyl;
• R.sub.2 is O or S;
• R3iS hydrogen;
• R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• R.sub.2 ', R.sub.3 ', R.sub.5 ', and R.sub.6 ' are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR',
• n is 0-3;
• R is H, alkyl or aryl;
• R' is H, alkyl or aryl;
• and
• Ra and Rb are each independently selected from the group consisting of H, alkyl and C(O)R, or NRakb taken together are a heterocyclic ring of from 3 to 8 atoms optionally substituted at one or more positions with hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkayloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• with the provisos that:
• (i) when the pharmaceutically acceptable carrier or excipient is selected from the group consisting of anise oil, carboxymethylcellulose and peanut oil, the compound is not 3-(4dimethylaminobenzylidene)-2-indolinone;
• and
• (ii) when Ra and Rb are both methyl, R.sub.5 is not halogen.

A pharmaceutical composition comprising a compound having the formula:

• ##STR17## or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient, wherein:
• R, is H or alkyl;
• R.sub.2 is O or S;
• R.sub.3 is hydrogen;
• R.sub.4, R.sub.6, and R7 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• R.sub.5 is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• R.sub.2 ', R.sub.3 ', R.sub.5', and R.sub.6 ' are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• n is 0-3;
• R is H, alkyl or aryl;
• R' is H, alkyl or aryl;
• and
• Ra and Rb are each independently selected from the group consisting of H, alkyl and C(O)R, or NRaRb taken together are a heterocyclic ring of from 3 to 8 atoms optionally substituted at one or more positions with hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• with the provisos that when the pharmaceutically acceptable carrier or excipient is selected from the group consisting of anise oil, carboxymethylcellulose and peanut oil, the compound is not 3-(4-dimethylaminobenzylidene)-2-indolinone.

A pharmaceutical composition comprising a compound having the formula:

• ##STR18## or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient, wherein:
• R.sub.1 is H or alkyl;
• R.sub.2 is O or S;
• R.sub.3 is hydrogen;
• R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• R.sub.2 ', R.sub.3 ', R.sub.5 ', and R.sub.6 ' are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR, SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• n is 0-3;
• R is H, alkyl or aryl;
• R' is H, alkyl or aryl;
• and
• NRaRb taken together are a heterocyclic ring of from 3 to 8 atoms optionally substituted at one or more positions with hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR'.

A method for treating diseases related to tyrosine kinase signal transduction, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound having the formula:

• ##STR19## and pharmaceutically acceptable salts thereof, wherein:
• R.sub.1 is H or alkyl;
• R.sub.2 is O or S;
• R.sub.3 is hydrogen;
• R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• R.sub.2 ', R.sub.3 ', R.sub.5 ', and R.sub.6 ' are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• n is 0-3;
• R is H, alyl or aryl;
• R' is H, alkyl or aryl;
• and
• Ra and Rb are each independently selected from the group consisting of H, alkyl and C(O)R, or NRaRb taken together are a heterocyclic ring of from 3 to 8 atoms optionally substituted at one or more positions with hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NPR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R or CONRR'.

A method for regulating, modulating or inhibiting tyrosine kinase signal transduction comprising administering to a subject a therapeutically effective amount of a compound having the formula:

• ##STR20## and pharmaceutically acceptable salts thereof, wherein;
• R.sub.1 is H or alkyl;
• R.sub.2 is O or S;
• R.sub.3 is hydrogen;
• R.sub.4, R.sub.5, R.sub.6 and R7 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRRW, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• R.sub.2 ', R.sub.3 ', R.sub.5 ', and R.sub.6 ' are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO2NRR', SO.sub.3 R, SP, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
• n is 0-3;
• R is H, alkyl or aryl;
• R' is H, alkyl or aryl;
• and
• Ra and Rb are each independently selected from the group consisting of H, alkyl and C(O)R, or NRaRb taken together are a heterocyclic ring of from 3 to 8 atoms optionally substituted at one or more positions with hydrogen, allyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, tribalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R or CONRR'.