Heteroary1 derivatives and their use as medicaments

Details Heteroary1 derivatives and their use as medicaments Heteroary1 derivatives and their use as medicaments

2001-07-20

2003-10-28

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252180, C514S253030, C514S253060, C514S253090, C514S253100, C514S253110, C514S253130, C544S295000, C544S357000, C544S361000, C544S364000, C544S365000

Reexamination Certificate

active

06638935

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to novel heteroaryl derivatives to their preparation and to their use as medicaments, in particular for treating tumors.
DESCRIPTION OF INVENTION
According to one aspect of the present invention, novel pyridine derivatives are provided of formula 1
wherein
R, R
1
, R
2
, R
3
can be attached to any of the pyridine carbon atoms C
2-6
, and are the same or different and independently of one another are hydrogen, hydroxyl straight-chain or branched C
1-8
alkyl, C
3-7
cycloalkyl, straight-chain or branched C
1-8
alkylcarbonyl, suitably acetyl, straight-chain or branched C
1-8
alkoxy, halogen, aryl-C
1-8
alkoxy, suitably benzyloxy or phenylethyloxy, nitro, amino, mono-C
1-4
alkylamino, di-C
1-4
alkylamino, C
1-8
alkoxycarbonylamino, C
1-6
alkoxycarbonylamino-C
1-8
alkyl, cyano, straight-chain or branched cyano-C
1-6
alkyl, carboxyl, C
1-8
alkoxycarbonyl, C
1-4
alkyl which is substituted by one or more fluorine atoms, suitably the trifluoromethyl group, carboxy-C
1-8
alkyl or C
1-8
alkoxycarbonyl-C
1-6
alkyl C
2-6
alkenyl, suitably allyl, C
2-6
alkynyl, suitably ethynyl or propargyl, straight-chain or branched cyano-C
1-6
alkyl, suitably cyanomethyl, aryl, where the aryl radical may be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of halogen, straight-chain or branched C
1-8
alkyl, C
3-7
cycloalkyl, carboxyl, straight-chain or branched C
1-8
alkoxycarbonyl, suitably tert-butoxycarbonyl, by trifluoromethyl, hydroxyl, straight-chain or branched C
1-8
alkoxy, suitably methoxy or ethoxy, benzyloxy, nitro, amino, mono-C
1-4
alkylamino, di-C
1-4
alkylamino, cyano, straight-chain or branched cyano-C
1-6
alkyl, where additionally R and R
1
and/or R
2
and R
3
may form a fused aromatic 6-membered ring with the pyridine ring forming a quinoline or acridine ring which can be substituted at any C atom ring position by the radicals R, R
1
, R
2
and R
3
having the meanings mentioned above;
Z is oxygen or sulfur, where the radical
 substituted on the pyridine heterocycle can be attached to C atoms C
2
-C
6
of the pyridine ring;
P, Q are independently of one another oxygen or in each case two hydrogen atoms as in —CH
2
—;
X is nitrogen or C-R
5
, where R
5
is hydrogen or C
1-6
alkyl;
n,m are independently of one another a cardinal number between 0 and 3, with the proviso that in the case when n is 0, X is a CR
5
R
6
group where R
5
and R
6
are independently of one another hydrogen or C
1-6
alkyl and that the nitrogen atom adjacent to the C═Z group is substituted by a hydrogen atom or a C
1-6
alkyl group;
R
4
a straight-chain or branched C
1-20
alkyl radical which can be saturated or unsaturated, with one to three double and/or triple bonds, and which can be unsubstituted or can be substituted at the same or different C atoms by one, two or more aryl, heteroaryl, halogen, C
1-6
alkoxy, amino, mono-C
1-4
alkylamino, cyano, —C═NH (NH
2
), or di-C
1-4
alkylamino; a C
6-14
aryl radical, carboxy, C
1-4
alkoxycarbonyl, C
6-14
aryl-C
1-4
alkyl radical or a C
2-10
heteroaryl or C
2-10
heteroaryl-C
1-4
alkyl radical which contains one or more heteroatoms of N, O or S, where the C
1-4
alkyl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of C
1-6
alkyl, halogen or oxo (═O),, and where the C
6-14
aryl or C
2-10
heteroaryl radical can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of straight-chain or branched C
1-8
alkyl, C
3-7
cycloalkyl, halogen, cyano, C
1-6
alkoxycarbonylamino, C
1-4
alkoxy, carboxyl, C
1-8
alkoxycarbonyl, straight-chain or branched C
1-4
alkyl which is substituted by one or more fluorine atoms, suitably trifluoromethyl, hydroxyl, straight-chain or branched C
1-8
alkoxy, suitably methoxy or ethoxy, where adjacent oxygen atoms can also be linked by C
1-2
alkylene groups, suitably by a methylene group, benzyloxy, nitro, amino, mono-C
1-4
alkylamino, di-C
1-4
alkylamino, aryl, which for its part can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of straight-chain or branched C
1-8
alkyl, C
3-7
cycloalkyl, carboxyl, straight-chain or branched C
1-8
alkoxycarbonyl, trifluoromethyl, hydroxyl, straight-chain or branched C
1-8
alkoxy, suitably methoxy or ethoxy, benzyloxy, nitro, amino, mono-C
1-4
alkylamino, di-C
1-4
alkylamino, cyano, straight-chain or branched cyano-C
1-6
alkyl;
and their structural isomers and stereoisomers, particularly tautomers, diastereomers and enantiomers, and their pharmaceutically acceptable salts, particularly acid addition salts, are provided.
Thus, for example, the compounds of formula (1) according to the present invention which have one or more centers of chirality and which are present as racemates can be separated by methods known per se into their optical isomers, i.e. enantiomers or diastereomers. The separation can be carried out by column separation on chiral phases or by recrystallization from an optically active solvent or using an optically active acid or base or by derivatization with an optically active reagent, such as, for example, an optically active alcohol, and subsequent removal of the radical.
Furthermore, the pyridine derivatives of formula (1) of the present invention can be converted into their salts with inorganic or organic acids, in particular, for pharmaceutical use, into their pharmaceutically acceptable salts. Acids which are suitable for this purpose include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, acetic acid, tartaric acid, malic acid, embonic acid, malonic acid, trifluoroacetic acid or maleic acid.
Moreover, the compounds of formula (1) of the present invention can, if they contain a sufficiently acidic group, such as a carboxyl group, be converted into their salts with inorganic or organic bases, particularly for pharmaceutical use, into their pharmaceutically acceptable salts. Bases which are suitable for this purpose include sodium hydroxide, potassium hydroxide, calcium hydroxide, lysine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
According to a suitable embodiment, pyridine derivatives of formula 1 are provided in which R, R1, R2, R3, X, Z, P, Q, n and m have the meanings given above
Y is a substituent group of the same or different substituents of C
1-6
alkyl, halogen, nitro, amino, mono-C
1-6
alkylamino, di-C
1-6
alkylamino, hydroxyl, C
1-6
alkoxy, benzyloxy, carboxyl, C
1-6
alkoxycarbonyl, C
1-6
alkoxycarbonylamino, C
1-6
alkyl mono- or polysubstituted with fluorine, suitably trifluoromethyl, C
6-10
aryl, and C
6-10
aryl-C
1-6
alkyl, and
R
4
is a straight-chain or branched C
1-20
alkyl radical which can be saturated or unsaturated, with one to three double and/or triple bonds, and which can be unsubstituted or substituted on the same or different C atoms by one, two or more aryl, heteroaryl, halogen, C
1-6
alkoxy, amino, mono-C
1-4
alkylamino or di-C
1-4
alkylamino;
a phenyl ring or a naphthyl ring, each of which can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of straight-chain or branched C
1-8
alkyl, C
3-7
cycloalkyl, halogen, cyano, C
1-6
alkoxycarbonylamino, C
1-6
alkoxy, carboxyl, C
1-8
alkoxycarbonyl, straight-chain or branched C
1-6
alkyl which is substituted by one or more fluorine atoms, suitably trifluoromethyl, hydroxyl, straight-chain or branched C
1-8
alkoxy, suitably methoxy or ethoxy, where adjacent oxygen atoms can also be linked by C
1-2
alkylene groups, suitably a methylene group, benzyloxy, nitro, amino, mono-C
1-4
alkylamino, di-C
1-4
alkylamino, aryl, which can be unsubstituted or mono- or polysubstituted by the same or different substituents from the group of straight-chain or branched C
1-8
alkyl, C
3-7
cycloalkyl, carboxyl, straight-chain or branched C
1-8
alkoxycarbonyl,

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