Phthalazines with angiogenesis inhibiting activity

• US 6,258,812 B1
• Filed: 10/20/1999
• Issued: 07/10/2001
• Est. Priority Date: 02/13/1997
• Status: Expired due to Term

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Stover, David Raymond, Mett, Helmut, Traxler, Peter, Bold, Guido, Wood, Jeanette Marjorie, Altmann, Karl-Heinz, Frei, Jörg
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): Patel, Sudhaker B.
• Application Number:
  US09/367,273
• Time in Patent Office: 629 Days
• Field of Search: 514/252.03, 544/238, 544/237
• US Class Current: 514/252.03
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The invention relates to compounds of formula I,

wherein r is 0 to 2, n is 0 to 2; m is 0 to 4; R₁ and R₂ (i) are in each case a lower alkyl, or (ii) together form a bridge in subformula I*

(I*) or (iii) together form a bridge in subformula I**

(I**), wherein one or two of the ring members T₁, T₂, T₃, and T₄ are nitrogen, and the remainder are in each case CH; A, B, D, and E are N or CH, wherein not more than 2 of these radicals are N; G is lower alkylene, acyloxy- or hydroxy-lower alkylene, —CH₂—O—, —CH₂—S—, —CH₂—NH—, oxa, thia, or imino; Q is methyl; c is H or lower alkyl; X is imino, oxa, or thia; Y is aryl, pyridyl, or (un)substituted cycloalkyl; and Z is mono- or disubstited 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, phenylsulfinyl, phenyl-lower alkylsulfinyl, alkylphenylsulfinyl, phenylsulfonyl, phenyl-lower alkylsulfonyl, or alkylphenylsulfony; and wherein the bonds characterized by a wavy line are either single or double bonds; or an N-oxide of said compound with the stipulation that, if Y is pyridyl or unsubstituted cycloalkyl, X is imino, and the remaining radicals are a s defined, then G is selected from the group comprising lower alkylene, —CH₂—O—, CH₂—S—, oxa and thia; or a salt thereof. The compounds inhibit angiogenesis.

Claims

1. A compound of formula IA

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.

2. A compound according to claim 1, wherein

r is 0;

n is 0,

m is 0;

A, B, D, and E are in each case CH,

G is lower alkylene,

R is H,

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; and

the bonds characterized by a wavy line are double bonds or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1, wherein

r is 0;

n is 0,

m is 0;

A, B, D, and E are in each case CH,

G is methylene,

R is H,

X is imino,

Y is phenyl, 2-, 3- or 4-aminophenyl, 2-, 3- or 4-acetylaminophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2,3-, 2,4-, 2,5- or 3,4-dichlorophenyl, chlorofluorphenyl, 2,-3- or 4-methylphenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4-hydroxyphenyl, 2-, 3- or 4-methoxycarbonyl, methoxychlorophenyl, 2-, 3- or 4-benzyloxyphenyl, or 2-, 3- or 4-cyanophenyl; and

the bonds characterized by a wavy line are double bonds;

or a salt thereof.

4. A compound according to claim 1, selected from the group consisting of

1-(4-Methylanilino)-4-(4-pyridylmethyl)phthalazine;

1-(3-Chloroanilino)-4-(4-pyridylmethyl)phthalazine;

1-Anilino-4-(4-pyridylmethyl)phthalazine;

1-(4-Methoxyanilino)-4-(4-pyridylmethyl)phthalazine;

1-(3-Benzyloxyanilino)-4-(4-pyridylmethyl)phthalazine;

1-(3-Methoxyanilino)-4-(4-pyridylmethyl)phthalazine;

1-(2-Methoxyanilino)-4-(4-pyridylmethyl)phthalazine;

1-(4-Trifluoromethylanilino)-4-(4-pyridylmethyl)phthalazine;

1-(4-Fluoroanilino)-4-(4-pyridylmethyl)phthalazine;

1-(3-Hydroxyanilino)-4-(4-pyridylmethyl)phthalazine;

1-(4-Hydroxyanilino)-4-(4-pyridylmethyl)phthalazine;

1-(3-Aminoanilino)-4-(4-pyridylmethyl)phthalazine;

1-(3,4-Dichloroanilino)-4-(4-pyridylmethy)phthalazine;

1-(4-Bromoanilino)-,-(4-pyridylmethyl)phthalazine;

1-(3-Chloro-4-methoxyanilino)-4-(4-pyridylmethyl)phthalazine;

1-(4-Cyanoanilino)-4-(4-pyridylmethyl)phthalazine;

1-(3-Chloro-4-fluoroanilino)-4-(4-pyridylmethyl)phthalazine; and

1-(3-Methylaniino)-4-(4-pyridylmethyl)phthalazine;

or a pharmaceutically acceptable salt thereof.

6. A process for the preparation of a compound of formula IA according to claim 1, or a pharmaceutically acceptable salt thereof, characterized by reacting

a) a compound of formula IIA,

wherein A, B, D, E, Q, G, Z, m and n, as well as bonds characterized by wavy lines, are as defined for a compound of formula IA and L is a nucleofugal leaving group, with a compound of formula III

wherein n, R, X, and Y are as defined for a compound of formula IA, the functional groups in the compounds of formula IIA and formula III which do not participate in the reaction being present in protected form where necessary, and removing any protective groups present, or reacting

b) a compound of formula IVA,

wherein A, B, D, E, G, Q, Z, m and r, as well as bonds characterized by wavy lines, are as defined for a compound of formula IA, with a compound of formula II, as illustrated in process a), in the presence of a dehydrating agent and a tertiary amine, the functional groups in the compounds of formula IVA and formula liI which do not participate in the reaction being present in protected form where necessary, and removing any protective groups present, or

c) for the preparation of a compound of formula IA, wherein G is —

CH₂—

, —

CH₂—

O—

, —

CH₂—

S—

or —

CH₂—

NH—

, or also oxa, thia, or imino, and the other symbols are as described for a compound of formula IA, reacting a compound of formula VA,

wherein Z, X, Y, R, m and n, as well as bonds characterized by wavy lines, are as defined for a compound of formula I and L* is a nucleofugal leaving group, with a compound of formula VI

wherein G is —

CH₂—

O—

, —

CH₂—

S—

or —

CH₂—

NH—

, or also oxa, thia or imino and A, B, D, E, Q, and r are as defined for compounds of formula IA, or (for the preparation of a compound of formula IA, wherein G is the bivalent radical —

CH₂—

) with the corresponding metallate of a compound of formula VI, wherein G-H is the radical —

CH₂—

Me, where Me is a metal, the functional groups in the compounds of formula VA and formula VI, or their metallate, which do not participate in the reaction being present in protected form where necessary, and removing any protective groups present, or

d) for preparation of a compound of formula IA, wherein G is —

CH₂—

O—

, —

CH₂—

S—

, —

CH₂—

NH—

, oxa, thia or imino, and the other symbols are as described for a compound of formula IA, reacting a compound of formula VIIA,

wherein X, Y, Z, R, and n, as well as bonds characterized by wavy lines, are as defined for compounds of formula IA, and wherein K is amino, hydroxy, or mercapto, or a tautomer thereof, with a compound of formula VIII,

wherein M is —

CH₂—

L** or —

L**, where L** is a nucleofugal leaving group; and

the other symbols are as described for a compound of formula IA, the functional groups in the compounds of formula VIIA and formula VIII which do not participate in the reaction being present in protected form where necessary, and removing any protective groups present, or

e) for the preparation of a compound of formula IA, wherein G is lower alkylene substituted by acyloxy, and the other radicals are as under formula IA, reacting a compound of formula

wherein Ac is acyl, as defined under formula I for lower alkylene G substituted by acyloxy, R₁ and R₂ together form a bridge of subformula I*

and X, Y, R₁, Z, m and n, as well as bonds characterized by wavy lines, are as defined for a compound of formula IA, with an aldehyde of formula XVI,

wherein A, B, D, E, Q, and r are as described for a compound of formula IA, in the presence of a strong base, the functional groups in the compounds of formula XV and formula XVI which do not participate in the reaction being present in protected form where necessary, and removing any protective groups present, whereas the starting compounds defined in a) to e) may also be present in the form of salts, provided a salt-forming group is present and the reaction in salt form is possible; and

, if so desired, converting an obtainable compound of formula IA or an N-oxide thereof into another compound of formula IA or an N-oxide thereof, converting a free compound of formula IA or an N-oxide thereof into a salt, converting an obtainable salt of a compound of formula IA or an N-oxide thereof into the free compound or another salt, and/or separating a mixture of isomeric compounds of formula IA or N-oxides thereof into the individual isomers.

7. The compound of claim 1 which is 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine, or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

9. A composition according to claim 8 wherein the compound is 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine, or a pharmaceutically acceptable salt thereof.

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

wherein Y is

and a compound of said formula wherein Y is

or a pharmaceutically acceptable salt thereof.

10. A method of treating a disease associated with deregulated angiogenesis comprising administering to a warm-blooded animal a therapeutically effective amount of a compound of formula I

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*

the binding being achieved via the two terminal carbon atoms, or

(iii) together form a bridge in subformula I**

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 proviso 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 thereof, wherein 1 or more N atoms carry an oxygen atom;

with the proviso that, if Y is pyridyl or unsubstituted cycloalkyl, X is imino, and the remaining radicals are as defined, G is selected form the group comprising lower alkylene, —

CH₂—

O—

, —

CH₂—

S—

, oxa and thia;

or a pharmaceutically acceptable salt thereof.

11. A method according to claim 10 comprising administering a therapeutically effective amount of a compound of formula IA

wherein

r is 0 to 2,

n is 0 to 2,

m is 0 to 4,

A, B, D, and E are, independently of one another, N or CH, with the proviso 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 thereof, wherein 1 or more N atoms carry an oxygen atom;

with the proviso 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.

12. A method according to claim 10 comprising administering a therapeutically effective amount of a compound of formula I wherein

r is 0 to 2,

n is 0 or 1,

m is 0 or 1,

R₁ and R₂ (i) are lower alkyl or

(ii) together form a bridge in subformula I*

the binding being achieved via the two terminal carbon atoms, or

(iii) together form a bridge in subformula I**

wherein one of the ring members T₁, T₂, T₃, and T₄ is nitrogen, and the others are in each case CH, and the binding is achieved via T₁ and T₄;

A, B, D, and E are in each case CH, or A, D, and E are each CH and B is N;

G is lower alkylene, —

CH₂—

NH—

, —

CH₂—

O—

, hydroxymethylene, or benzoyloxymethylene;

Q is methyl, which is bound to A, to D, or to A and D;

R is H or lower alkyl;

X is imino, oxa, or thia;

Y is phenyl, which is unsubstituted or substituted by one or two substituents independently selected from the group consisting of amino, lower alkanoylamino, halogen, lower alkyl, halogen-lower alkyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, cyano, benzyloxy, lower alkenyl, C₈-C₁₂alkoxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, lower alkanoyl, phenyloxy, halogen-lower alkyloxy, lower alkylmercapto, halogen-lower alkylmercapto, hydroxy-lower alkyl, lower alkylsulfonyl, halogen-lower alkylsulfonyl, phenylsulfonyl, dihydroxybora, 2-methylpyrimidin-4-yl, oxazol-5-yl, 2-methyl-1,3-dioxolan-2-yl, 1H-pyrazol-3-yl, 1-methylpyrazol-3-yl, and lower alkylenedioxy bound to two adjacent C atoms;

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 selected from benzoylamino and phenyl-lower alkoxycarbonylamino, wherein the phenyl radical in each case is unsubstituted or substituted by nitro, amino, halogen, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl or carbamoyl; and

wherein the bonds characterized, if present, by a wavy line are either single or double bonds;

or a pharmaceutically acceptable salt thereof.

13. A method according to claim 10 comprising administering a therapeutically effective amount of a compound of formula i wherein n is O;

or a pharmaceutically acceptable salt thereof.

14. A method according to claim 11 comprising administering a therapeutically effective amount of a compound of formula IA wherein n is O;

or a pharmaceutically acceptable salt thereof.

15. A method according to claim 12 comprising administering a therapeutically effective amount of a compound of formula I wherein n is O;

or a pharmaceutically acceptable salt thereof.

16. A method according to claim 10 wherein the compound administered is 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine, or a pharmaceutically acceptable salt thereof.

17. A method of treating a disease responsive to the inhibition of VEGF-receptor tyrosine kinase comprising administering to a warm-blooded animal a therapeutically effective amount of a compound of formula I

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*

the binding being achieved via the two terminal carbon atoms, or

(iii) together form a bridge in subformula I**

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 proviso 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 thereof, wherein 1 or more N atoms carry an oxygen atom;

with the proviso that, if Y is pyridyl or unsubstituted cycloalkyl, X is imino, and the remaining radicals are as defined, G is selected form the group comprising lower alkylene, —

CH₂—

O—

, —

CH₂—

S—

, oxa and thia;

or a pharmaceutically acceptable salt thereof.

18. A method according to claim 17 comprising administering a therapeutically effective amount of a compound of formula IA

wherein

r is 0 to 2,

n is 0 to 2,

m is 0 to 4,

A, B, D, and E are, independently of one another, N or CH, with the proviso 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 thereof, wherein 1 or more N atoms carry an oxygen atom;

with the proviso 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.

19. A method according to claim 17 comprising administering a therapeutically effective amount of a compound of formula I wherein

r is 0 to 2,

n is 0 or 1,

m is 0 or 1,

R₁ and R₂ (i) are lower alkyl or

(ii) together form a bridge in subformula I*

the binding being achieved via the two terminal carbon atoms, or

(iii) together form a bridge in subformula I**

wherein one of the ring members T₁, T₂, T₃, and T₄ is nitrogen, and the others are in each case CH, and the binding is achieved via T₁ and T₄;

A, B, D, and E are in each case CH, or A, D, and E are each CH and B is N;

G is lower alkylene, —

CH₂—

NH—

, —

CH₂—

O—

, hydroxymethylene, or benzoyloxymethylene;

Q is methyl, which is bound to A, to D, or to A and D;

R is H or lower alkyl;

X is imino, oxa, or thia;

Y is phenyl, which is unsubstituted or substituted by one or two substituents independently selected from the group consisting of amino, lower alkanoylamino, halogen, lower alkyl, halogen-lower alkyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, cyano, benzyloxy, lower alkenyl, C₈-C₁₂alkoxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, lower alkanoyl, phenyloxy, halogen-lower alkyloxy, lower alkylmercapto, halogen-lower alkylmercapto, hydroxy-lower alkyl, lower alkylsulfonyl, halogen-lower alkylsulfonyl, phenylsulfonyl, dihydroxybora, 2-methylpyrimidin-4-yl, oxazol-5-yl, 2-methyl-1,3-dioxolan-2-yl, 1H-pyrazol-3-yl, 1-methylpyrazol-3-yl, and lower alkylenedioxy bound to two adjacent C atoms;

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 selected from benzoylamino and phenyl-lower alkoxycarbonylamino, wherein the phenyl radical in each case is unsubstituted or substituted by nitro, amino, halogen, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl or carbamoyl; and

wherein the bonds characterized, if present, by a wavy line are either single or double bonds;

or a pharmaceutically acceptable salt thereof.

20. A method according to claim 17 comprising administering a therapeutically effective amount of a compound of formula I wherein n is O;

or a pharmaceutically acceptable salt thereof.

21. A method according to claim 18 comprising administering a therapeutically effective amount of a compound of formula IA wherein n is O;

or a pharmaceutically acceptable salt thereof.

22. A method according to claim 19 comprising administering a therapeutically effective amount of a compound of formula I wherein n is O;

or a pharmaceutically acceptable salt thereof.

23. A method according to claim 17 wherein the compound administered is 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine, or a pharmaceutically acceptable salt thereof.

24. A method of treating tumors comprising administering to a warm-blooded animal a therapeutically effective amount of a compound of formula I

wherein r 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*

the binding being achieved via the two terminal carbon atoms, or

(iii) together form a bridge in subformula I**

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 proviso 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 thereof, wherein 1 or more N atoms carry an oxygen atom;

with the proviso that, if Y is pyridyl or unsubstituted cycloalkyl, X is imino, and the remaining radicals are as defined, G is selected form the group comprising lower alkylene, —

CH₂—

O—

, —

CH₂—

S—

, oxa and thia;

or a pharmaceutically acceptable salt thereof.

25. A method according to claim 24 comprising administering a therapeutically effective amount of a compound of formula IA

wherein

r is 0 to 2,

n is 0 to 2,

m is 0 to 4,

A, B, D, and E are, independently of one another, N or CH, with the proviso 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 beingthe 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 thereof, wherein 1 or more N atoms carry an oxygen atom;

with the proviso 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.

26. A method according to claim 24 comprising administering a therapeutically effective amount of a compound of formula I wherein

r is 0 to 2,

n is 0 or 1,

m is 0 or 1,

R₁ and R₂ (i) are lower alkyl or

(ii) together form a bridge in subformula I*

the binding being achieved via the two terminal carbon atoms, or

(iii) together form a bridge in subformula I**

wherein one of the ring members T₁, T₂, T₃, and T₄ is nitrogen, and the others are in each case CH, and the binding is achieved via T₁ and T₄;

A, B, D, and E are in each case CH, or A, D, and E are each CH and B is N;

G is lower alkylene, —

CH₂—

NH—

, —

CH₂—

O—

, hydroxymethylene, or benzoyloxymethylene;

Q is methyl, which is bound to A, to D, or to A and D;

R is H or lower alkyl;

X is imino, oxa, or thia;

Y is phenyl, which is unsubstituted or substituted by one or two substituents independently selected from the group consisting of amino, lower alkanoylamino, halogen, lower alkyl, halogen-lower alkyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, cyano, benzyloxy, lower alkenyl, C₈-C₁₂alkoxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, lower alkanoyl, phenyloxy, halogen-lower alkyloxy, lower alkylmercapto, halogen-lower alkylmercapto, hydroxy-lower alkyl, lower alkylsulfonyl, halogen-lower alkylsulfonyl, phenylsulfonyl, dihydroxybora, 2-methylpyrimidin-4-yl, oxazol-5-yl, 2-methyl-1,3-dioxolan-2-yl, 1H-pyrazol-3-yl, 1-methylpyrazol-3-yl, and lower alkylenedioxy bound to two adjacent C atoms;

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 selected from benzoylamino and phenyl-lower alkoxycarbonylamino, wherein the phenyl radical in each case is unsubstituted or substituted by nitro, amino, halogen, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl or carbamoyl; and

wherein the bonds characterized, if present, by a wavy line are either single or double bonds;

or a pharmaceutically acceptable salt thereof.

27. A method according to claim 24 comprising administering a therapeutically effective amount of a compound of formula I wherein n is O;

or a pharmaceutically acceptable salt thereof.

28. A method according to claim 25 comprising administering a therapeutically effective amount of a compound of formula IA wherein n is O;

or a pharmaceutically acceptable salt thereof.

29. A method according to claim 26 comprising administering a therapeutically effective amount of a compound of formula I wherein n is O;

or a pharmaceutically acceptable salt thereof.

30. A method according to claim 24 wherein the compound administered is 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine, or a pharmaceutically acceptable salt thereof.