Claims
- 1. A compound of formula I whereinr is from 0 to 2; n is from 0 to 2; m is from 0 to 4; A, B, D and E are each independently of the others N or CH, with the proviso that not more than two of those radicals are N; G is lower alkylene, —CH2—O—, —CH2—S—, —CH2—NH—, oxa (—O—), thia (—S—) or imino (—NH—), or is lower alkylene substituted by acyloxy or by hydroxy; Q is lower alkyl; R is H or lower alkyl; X is imino, oxa or thia; Y is lower alkyl, aryl, heteroaryl or unsubstituted or substituted cycloalkyl; and Z is amino, mono- or di-substituted amino, halogen, alkyl, substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, carbamoyl, N-mono- or N,N-di-substituted carbamoyl, amidino, guanidino, mercapto, sulfo, phenylthio, phenyl-lower alkythio, alkylphenylthio, phenylsulfinyl, phenyl-lower alkylsulfinyl, alkyiphenylsulfinyl, phenylsulfonyl, phenyl-lower alkanesulfonyl or alkylphenylsulfonyl, and where, if more than one radical Z is present (m≧2), the substituents Z are identical or different; and wherein the bonds indicated by a wavy line are either single bonds or double bonds;or an N-oxide of the mentioned compound, wherein one or more N atoms carry an oxygen atom;or a salt thereof.
- 2. A compound of formula I according to claim 1, whereinr is from 0 to 2; n is from 0 to 2; m is from 0 to 4; A, B, D and E are each independently of the others N or CH, with the proviso that not more than two of those radicals are N; G is lower alkylene, lower alkylene substituted by acyloxy or by 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, heteroaryl or unsubstituted or substituted cycloalkyl; and Z is amino, mono- or di-substituted amino, halogen, alkyl, substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, carbamoyl, N-mono- or N,N-di-substituted carbamoyl, amidino, guanidino, mercapto, sulfo, phenylthio, phenyl-lower alkylthio, alkylphenylthio, phenylsulfinyl, phenyl-lower alkylsulfinyl, alkylphenylsulfinyl, phenylsulfonyl, phenyl-lower alkanesulfonyl or alkylphenylsulfonyl, and where, if more than one radical Z is present (m≧2), the substituents Z are identical or different; and wherein the bonds indicated by a wavy line are either single bonds or double bonds;or an N-oxide of the mentioned compound, wherein one or more N atoms carry an oxygen atom;or a salt thereof.
- 3. A compound of formula I according to claim 1, whereinr is from 0 to 2; n is 0 or 1; m is 0, or is 1; A, B, D and E are each CH, or A, D and E are each CH and B is N; G is lower alkylene, —CH2—NH—, —CH2—O—, hydroxymethylene or benzoyloxy-methylene; Q is methyl which is bonded to A, to D or to A and D; R is H or lower alkyl; X is imino, oxa or thia; Y is phenyl that is unsubstituted or substituted by one or two identical or different substituents selected from the group consisting of amino; lower alkanoylamino, halogen, lower alkyl, halo-lower alkyl, lower alkoxy, phenyl-lower alkoxy, cyano, lower alkenyl, C8-C12alkoxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, lower alkanoyl, phenyloxy, halo-lower alkyloxy, lower alkoxycarbonyl, lower alkylmercapto, halo-lower alkylmercapto, hydroxy-lower alkyl, lower alkanesulfonyl, halo-lower alkanesulfonyl, phenylsulfonyl, dihydroxybora, 2-methyl-pyrimidin-4-yl, oxazol-5-yl, 2-methyl-1,3-dioxolan-2-yl, 1H-pyrazol-3-yl, 1-methyl-pyrazol-3-yl, and lower alkylenedioxy bonded to two adjacent carbon atoms; 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 substitutent selected from the group consisting of benzoylamino and phenyl-lower alkoxycarbonylamino, wherein the phenyl radical in each case is unsubstituted or substituted by nitro, halogen, amino, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl or by carbamoyl; or Z is halogen; and the bonds indicated by a wavy line are both a double bond, or are both a single bond;or a salt thereof.
- 4. A compound of formula I according to claim 1, whereinr is 0; n is 0; m is 0; A, B, D and E are each CH; G is lower alkylene; X is imino; Y is phenyl that is unsubstituted or substituted by one or two identical or different substituents selected from the group consisting of halogen; lower alkyl; and halo-lower alkyl; and the bonds indicated by a wavy line are double bonds;or a salt thereof.
- 5. A compound of formula I according to claim 1, whereinr is 0; n is from 0 to 2; m is 0; A, B, D and E are each CH; G is methylene; R is H; X is imino; and Y is phenyl that is unsubstituted or substituted by halogen or by lower alkoxy; naphthyl; cyclohexyl that is unsubstituted or substituted by lower alkyl; or indolyl that is unsubstituted or substituted by halogen; especially 6-fluoroindol-3-yl; or is lower alkyl; or a salt thereof where a salt-forming group is present.
- 6. A compound according to claim 1 which is 1-(3,5-dimethylanilino)-4-(pyridin-4ylmethyl)-isoquinoline, or a pharmaceutically acceptable salt thereof.
- 7. A compound according to claim 1 of the formula which falls within the scope of formula I, selected from the group of compounds of that formula wherein Y is one of the radicals shown below: or in each case a salt thereof.
- 8. A method of treating a disease responsive to inhibition of VEGF receptor tyrosine kinase or to inhibition of angiogenesis, wherein a compound of formula I or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, according to claim 1 is administered in an amount that is effective against the mentioned disease to a warm-blooded animal requiring such treatment.
- 9. A pharmaceutical composition which is suitable for administration to a warm-blooded animal suffering from a disease responsive to inhibition of angiogenesis or of VEGF receptor tyrosine kinase, comprising a compound of formula I or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, according to claim 1 in an amount that is effective in inhibiting angiogenesis or VEGF receptor tyrosine kinase, together with at least one pharmaceutically acceptable carrier.
- 10. A compound according to claim 1 which is 1-(4-t-butylanilino)-4-(pyridin-4ylmethyl)-isoquinoline, or a pharmaceutically acceptable salt thereof.
- 11. A compound according to claim 1 which is (1-(4-isopropyl-3-methylanilino)-4-(pyridin-4ylmethyl)-isoquinoline, or a pharmaceutically acceptable salt thereof.
- 12. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof.
Priority Claims (1)
Number |
Date |
Country |
Kind |
1654/98 |
Aug 1998 |
CH |
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Parent Case Info
This is a continuation of International Application No. PCT/EP99/05781, filed Aug. 9, 1999, the contents of which are incorporated herein by reference.
US Referenced Citations (1)
Number |
Name |
Date |
Kind |
4943581 |
Hidaka et al. |
Jul 1990 |
A |
Foreign Referenced Citations (3)
Number |
Date |
Country |
WO 9730035 |
Aug 1997 |
WO |
WO 9734876 |
Sep 1997 |
WO |
WO 9835958 |
Aug 1998 |
WO |
Continuations (1)
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Number |
Date |
Country |
Parent |
PCT/EP99/05781 |
Aug 1999 |
US |
Child |
09/781036 |
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US |