Phthalazines with angiogenesis inhibiting activity

A compound of the formula I

• 181
• wherein
• r is 0 to 2,
• n is 0
• m is 0 to 4,
• R1 and R2 (i) are lower alkyl or
• (ii) together form a bridge in subformula I*
• 182
• the binding being achieved via the two terminal carbon atoms, or
• (iii) together form a bridge in subformula I**
• 183
• wherein one or two of the ring members T1, T2, T3 and T4 are nitrogen, and the others are in each case CH, and the binding is achieved via T1 and T4
• A, B, D, and E are, independently of one another, N or CH, with the stipulation that not more than 2 of these radicals are N;
• G is lower alkylene, lower alkylene substituted by acyloxy or hydroxy, —CH2—O—, —CH2—S—, —CH2—NH—, oxa (—O—), thia (—S—), or imino (—NH—);
• Q is lower alkyl;
• R is H or lower alkyl;
• X is imino, oxa, or thia;
• Y is aryl, pyridyl, or unsubstituted or substituted cycloalkyl;
• and
• Z is amino, mono- or disubstituted amino, halogen, alkyl, substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amidino, guanidino, mercapto, sulfo, phenylthio, phenyl-lower alkylthio, alkylphenylthio, phenylsulfonyl, phenyl-lower alkylsulfinyl or alkylphenylsulfinyl, substituents Z being the same or different from one another if more than 1 radical Z is present;
• and wherein the bonds characterized, if present, by a wavy line are either single or double bonds;
• or an N-oxide of the defined compound, wherein 1 or more N atoms carry an oxygen atom;
• with the stipulation that, if Y is pyridyl or unsubstituted cycloalkyl, X is imino, and the remaining radicals are as defined, G is selected from the group comprising lower alkylene, —CH2—O—, —CH2—S—, oxa and thia;
• or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of the human or animal body.

A compound, or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of the human or animal body, wherein the compound is of formula IA,

• 184
• wherein
• r is 0 to 2,
• n is 0
• m is 0 to 4,
• A, B, D, and E are, independently of one another, N or CH, with the stipulation that not more than 2 of these radicals are N;
• G is lower alkylene, —CH2—O—, —CH2—S—, —CH2—NH—, oxa, thia, or imino;
• Q is methyl;
• R is H or lower alkyl;
• X is imino, oxa, or thia;
• Y is aryl, pyridyl, or unsubstituted or substituted cycloalkyl;
• and
• Z is amino, mono- or disubstituted amino, halogen, alkyl, substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amidino, guanidino, mercapto, sulfo, phenylthio, phenyl-lower alkylthio, alkylphenylthio, phenylsulfonyl, phenyl-lower alkylsulfinyl or alkylphenylsulfinyl, substituents Z being the same or different from one another if more than 1 radical Z is present;
• and wherein the bonds characterized by a wavy line are either single or double bonds;
• or an N-oxide of the defined compound, wherein 1 or more N atoms carry an oxygen atom;
• with the stipulation that, if Y is pyridyl or unsubstituted cycloalkyl, X is imino, and the remaining radicals are as defined, G is selected from the group comprising lower alkylene, —CH2—O—, —CH2—S—, oxa and thia.

A compound of formula IA

• 187
• wherein
• r is 0 to 2,
• n is 0,
• m is 0 or 1,
• A, B, D, and E are in each case CH,
• G is lower alkylene, especially methylene,
• Q is methyl, which is bound to A, to D, or to A and D;
• R is H or lower alkyl,
• X is imino,
• Y is phenyl, which is unsubstituted or substituted by one or two substituents independently of one another from the group comprising amino;
• lower alkanoylamino;
• halogen;
• lower alkyl;
• halogen-lower alkyl;
• hydroxy;
• lower alkoxy;
• phenyl-lower alkoxy;
• and cyano, or is pyridyl;
• Z is amino;
• N-lower alkylamino;
• hydroxy-lower alkylamino;
• phenyl-lower alkylamino;
• N,N-di-lower alkylamino;
• n-phenyl-lower alkyl-N-lower alkylamino;
• N,N-di-lower alkylphenylamino;
• lower alkanoylamino;
• or a substituent from the group comprising benzoylamino or phenyl-lower alkoxycarbonylamino, wherein the phenyl radical in each case is unsubstituted or especially substituted by nitro or amino, or by halogen, amino, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl or carbamoyl;
• or is halogen;
• and,
• the bonds characterized by a wavy line are in each case a double bond or in each case a single bond;
• or a salt thereof.

A compound selected from the group consisting of 1-Benzylamino-4-(4-pyridylmethyl)phthalazine, a compound of the formula

• 188
• wherein Y is
• 189
• and a compound of said formula wherein Y is
• 190
• or a pharmaceutically acceptable salt thereof.

A method for the treatment of a disease which responds to an inhibition of VEGF-receptor tyrosine kinase or an inhibition of angiogenesis, which comprises administering a compound of formula I,

• 191
• wherein
• r is 0 to 2,
• n is 0 to 2,
• m is 0 to 4,
• R1 and R2 (i) are lower alkyl or
• (ii) together form a bridge in subformula I*
• 192
• the binding being achieved via the two terminal carbon atoms, or
• (iii) together form a bridge in subformula I**
• 193
• wherein one or two of the ring members T1, T2, T3 and T4 are nitrogen, and the others are in each case CH, and the binding is achieved via T1 and T4
• A, B, D, and E are, independently of one another, N or CH, with the stipulation that not more than 2 of these radicals are N;
• G is lower alkylene, lower alkylene substituted by acyloxy or hydroxy, —CH2—O—, —CH2—S—, —CH2—NH—, oxa (—O—), thia (—S—), or imino (—NH—);
• Q is lower alkyl;
• R is H or lower alkyl;
• X is imino, oxa, or thia;
• Y is aryl, pyridyl, or unsubstituted or substituted cycloalkyl;
• and
• Z is amino, mono- or disubstituted amino, halogen, alkyl, substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amidino, guanidino, mercapto, sulfo, phenylthio, phenyl-lower alkylthio, alkylphenylthio, phenylsulfonyl, phenyl-lower alkylsulfinyl or alkylphenylsulfinyl, substituents Z being the same or different from one another if more than 1 radical Z is present;
• and wherein the bonds characterized, if present, by a wavy line are either single or double bonds;
• or an N-oxide of the defined compound, wherein 1 or more N atoms carry an oxygen atom;
• with the stipulation that, if Y is pyridyl or unsubstituted cycloalkyl, X is imino, and the remaining radicals are as defined, G is selected from the group comprising lower alkylene, —CH2—O—, —CH2—S—, oxa and thia;
• or a pharmaceutically acceptable salt thereof, in a quantity effective against said diseases, to a warm-blooded animal requiring such treatment in a quantity suitable for the treatment of said disease.