Pyridine derivatives inhibiting angiogenesis and/or VEGF...

Details Pyridine derivatives inhibiting angiogenesis and/or VEGF... Pyridine derivatives inhibiting angiogenesis and/or VEGF...

2002-10-11

2004-03-16

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S332000, C546S148000, C546S255000

Reexamination Certificate

active

06706731

ABSTRACT:

The invention relates to new pyridine derivatives, processes for the preparation thereof, the application thereof in a process for the treatment of the human or animal body, the use thereof—alone or in combination with one or more other pharmaceutically active compounds—for the treatment of a disease, especially a proliferative disease, such as a tumour disease, a method for the treatment of such disease in mammals, especially in humans, and the use of such a compound—alone or in combination with one or more other pharmaceutically active compounds—for manufacture of a pharmaceutical preparation (medicament) for the treatment especially of a proliferative disease, such as a tumour.
Surprisingly, it has now been found that pyridine derivatives of formula I, described below, have advantageous pharmacological properties and inhibit, for example, the activity of the VEGF receptor tyrosine kinase and the VEGF-dependent cell proliferation.
The compounds of formula I permit, for example, an unexpected new therapeutic approach, especially for diseases in the treatment of which, and also for the prevention of which, an inhibition of angiogenesis and/or of the VEGF receptor tyrosine kinase shows beneficial effects.
The invention relates to compounds of formula I:
wherein
A, D and T, independently of one another, are each N, CH or CR
4
, with the proviso that at least one of A and D is CR
4
when T is N;
R
4
is lower alkyl, lower alkenyl, lower alkylthio, mercapto, free, etherified or esterified hydroxy, unsubstituted, mono- or disubstituted amino or halogen;
B and E, independently of one another, are each N or CH;
G is C
1
-C
6
-alkylene, C
2
-C
6
-alkenylene, acyloxy- or hydroxy-substituted C
1
-C
6
-alkylene or C
3
-C
6
-alkenylene, C
1
-C
2
-alkyleneoxy, C
1
-C
2
-alkylenethio, C
1
-C
2
-alkyleneimino, —CH
2
—O—CH
2
—, —CH
2
—S—CH
2
—, —CH
2
—NH—CH
2
—, oxa, thia or imino;
n is 0 to 2;
Q is lower alkyl, whereby A, D and T are not substituted by Q if they represent CR
4
;
r is 0 to 5;
R
1
und R
1′
independently of one another are each hydrogen or lower alkyl;
R
2
and R
3
a) independently of one another, are each lower alkyl; or
b) together form a bridge of the part formula I*:
wherein the ring members T
1
, T
2
, T
3
and T
4
, independently of one another, are each nitrogen or CH, and binding is achieved via the atoms T
1
and T
4
, the bonds characterised by a wavy line, independently of one another, are each either single or double bonds, m is 0 to 4 and Z is a substituent of one or more carbon atoms, whereby Z is unsubstituted, mono- or disubstituted amino, halogen, unsubstituted or substituted alkyl, free, etherified or esterified hydroxy, nitro, cyano, free or esterified carboxy, alkanoyl, unsubstituted, 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 alkylphenylsulfonyl, whereby if more than 1 radical Z is present (m≧2), the substituents Z are identical or different;
W is hydrogen, unsubstituted, mono- or disubstituted amino, halogen, unsubstituted or substituted alkyl, free, etherified or esterified hydroxy, nitro, cyano, free or esterified carboxy, alkanoyl, unsubstituted, 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 alkylphenylsulfonyl;
X is —N(R
5
)—, oxa, or thia; and
R
5
is H or lower alkyl;
and Y is hydrogen, aryl, heterocyclyl or unsubstituted or substituted cycloalkyl;
or a tautomer of the said compound;
or an N-oxide of the said compound or tautomers thereof, whereby one or more N atoms carry an oxygen atom;
or a salt of the said compounds.
The general terms used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, unless otherwise indicated:
The prefix “lower” denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4 carbon atoms, the radicals in question being either unbranched or branched with single or multiple branching.
Where compounds of formula I are mentioned, this is taken to mean also the tautomers of the compounds of formula I.
Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.
Asymmetric carbon atoms of a compound of formula I that are optionally present may exist in the (R), (S) or (R,S) configuration, preferably in the (R) or (S) configuration. Substituents at a double bond or a ring may be present in cis-(=Z-) or trans(=E-) form. The compounds may thus be present as mixtures of isomers or as pure isomers, preferably as enantiomer-pure diastereomers.
Of the ring members A, B, D, E and T in formula I, one ring member is preferably N, while the others are CH or CR
4
. In particular, A, D or T is preferably N. If T is N, at least one of the ring members A or D is CR
4
.
R
4
is preferably lower alkyl, especially methyl or ethyl; lower alkenyl, such as ethenyl or propenyl; lower alkylthio, such as methylthio or ethylthio; free etherified or esterified hydroxy as defined below; unsubstituted, mono- or disubstituted amino as defined below; or halogen, such as fluorine, chlorine, bromine or iodine. R
4
is most preferably methyl, hydroxy, methoxy or halogen.
If G is a bivalent group C
1
-C
2
-alkyleneoxy, C
1
-C
2
-alkylenethio or C
1
-C
2
-alkyleneimino, the alkylene group is bonded to the ring with the ring members A, B, D, E and T, while the hetero atom (O, S or NH) is bonded to the ring with the substituents R
2
, R
3
, W and X in formula I.
C
1
-C
6
-alkylene and C
2
-C
6
-alkenylene as G may be branched or preferably unbranched, and are in particular C
1
-C
4
-alkylene or C
2
-C
4
-alkenylene, primarily methylene (—CH
3
—), ethylene (—CH
2
—CH
2
—), ethenylene (—CH═CH—), propylene (—CH
2
—CH
2
—CH
2
—), propenylene (—CH═CH—CH
2
—) or tetramethylene (—CH
2
—CH
2
—CH
2
—CH
2
—) and most preferably methylene, ethylene or ethenylene. In the definition of G, C
1
-C
2
-alkyleneoxy is —CH
2
—O— or —CH
2
—CH
2
—O—, C
1
-C
2
-alkylenethio is —CH
2
—S— or —CH
2
—CH
2
—S— and C
1
-C
2
-alkyleneimino is —CH
2
—NH— or —CH
2
—CH
2
—NH—. G is most preferably methylene, ethylene or ethenylene. In C
2
-C
6
-alkenylene for G, the substituents are present on the double bond preferably in the E-(=trans-) form.
Acyloxy in acyloxy-substituted C
1
-C
6
-alkylene or C
3
-C
6
-alkenylene is preferably lower alkanoyloxy.
Hydroxy-substituted C
1
-C
6
-alkylene is preferably hydroxyethylene. Hydroxy-substituted C
3
-C
6
-alkenylene is preferably hydroxypropenylene.
The index n is preferably 0 or 1.
Lower alkyl is in particular C
1
-C
4
-alkyl, e.g. n-butyl, sec.-butyl, tert.-butyl, n-propyl, isopropyl or primarily methyl or also ethyl.
The index r is preferably 0 or 1.
Preferably, R
2
and R
3
together form a bridge of the part formula I*. Here, the index m is preferably 0, 1 or 2. In particular, m is preferably 0.
Preferably 0 or 1 of the ring members T
1
, T
2
, T
3
and T
4
is nitrogen and the remaining ring members are CH. Most preferably all of the ring members T
1
, T
2
, T
3
and T
4
are CH or T
4
is nitrogen and the remaining ring members T
1
, T
2
and T
3
are CH.
Z and W, independently of one another, are preferably unsubstituted or substituted alkyl, as defined below; amino; hydroxy-lower alkylamino such as 2-hydroxyethylamino; lower alkanoylamino such as acetylamino; or halogen such as bromine; preferably only one substituent is present (m=1), especially one of the latter substituents, particularly halogen. A compound of formula I*, wherein Z is absent (m=0), is quite especially preferred. W stands especially preferred for hydrogen or lower alkyl, most preferably for hydrogen.
Mono- or disubstituted amino is especially amino substituted by one

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