Pyridyl alkane acid amides as cytostatics and...

Details Pyridyl alkane acid amides as cytostatics and... Pyridyl alkane acid amides as cytostatics and...

1998-12-18

2002-09-03

Rotman, Alan L. (Department: 1612)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S207000, C514S318000, C514S317000

Reexamination Certificate

active

06444823

ABSTRACT:

The invention relates to new pyridine compounds, methods for their production, medicaments containing these compounds as well as their use, especially in the treatment of tumor conditions and/or as cytostatic agents or as immunosuppressive agents.
A strong need exists for the enrichment of cytostatic therapy to provide pharmaceuticals and/or medicaments which not only possess a strong activity, but also exert diminished side effects in comparison to many classical cancerostatic agents, whereby treatment of a broad as possible spectrum of tumors should be made accessible. Furthermore, effective cytostatic agents for an efficient therapy should be made available. Active ingredients of this type should also be exceptionally suitable in the mentioned indications for a combination therapy, be it in connection with other cytostatic agents or with radiation (for example X-rays, radioactive elements, such as cobalt, or linear accelerator, etc.), with operative procedures, heat treatment, etc.
In this connection, a strong need also exists to enrich tumor therapy with new compounds for overcoming or preventing resistances for example.
This object was successfully solved in a completely suprising manner by raking available the pyridyl alkane acid amide derivatives defined below.
It was known that various pyridine compounds substituted in a specific manner have pharmacologically useful properties which lie however in completely different indication areas.
Thus, &ohgr;-pyridyl alkane and/or alkene amides with anti-allergic activity are described in EP 0 210 782 which are referred to as having a 5-lipoxygenase-inhibiting and anti-histamine action, wherein the amide components of these compounds contain a piperizine or homopiperizine ring and the pyridine ring can be linked together in the 2-, 3- or 4-position. JP 63,179,869 describes further pyridyl amides, &ohgr;n-pyridyl alkane and alkene amides as anti-allergic effective substances containing a substituted piperidine ring in the amine component. Such compounds with the same properties are mentioned in Chem. Pharm. Bull 37, 100-105 (1989) and in J. Med. Chem. 1989, 583-593.
Pyridyl ureas, pyridyl thioureas and pyridyl carbonamides, wherein the amide portion is bound over an aryl substituted alkyl chain with a piperidine ring or piprazine ring, are described for example in EP-A-0 428 434 or in EP-A-0 512 902 as antagonists of the neurokinin receptor and subtance P. Furthermore, pyridyl(alkyl)carbonamides, pyridyl(alkyl)sulfonamides and analogous ureas, wherein the amide portion is bound over an alkyl chain with a piperidine ring are disclosed in EP-A-0 479 601 as active ingredients with anti-arrhythmic properties.
In WO 91/15 485, the production of pyridine-3,5-dicarboxylic acid esters and amides as well as their use for the treatment of tumor conditions is described. These compounds differ from the compounds according to the invention described below in very important structural features, for example by the dicarboxyl grouping on the pyridine ring or the absence of the hydrocarbon chain between the pyridine ring and the amide grouping. The compounds disclosed in WO 89/07 443 in the form of optically pure R(−)-Ni-guldipine and further analogous dihydropyridines with cytotoxic activity have larger structural differences. However, the compounds according to the invention unexpectedly possess a better activity and a wider spectrum of action despite the large structural differences.
Structurally closely related compounds are represented by the antagonists of the histimine-H
1
-receptor generally described in EP-A-0 343 307 which constitute substituted piperidine derivatives. However, no particular 3-pyridyl substitutions derivatives are concretely described in this publication.
In view of this art, the finding that the compounds according to the general formula (I) defined below have activities which make them particularly suitable in an excellent manner for the therapy of tumor illnesses was completely unexpected. Equally unexpected was the pharmacological finding that the compounds according to the invention also possess immunosuppressive properties besides cytostatic activity.
Pharmacological test results as well as the concrete tumor indications and combination possibilities are detailed and illustrated in the last part of the description.
Therefore, subject-matter of the invention relates to compounds of formula (I)
wherein
R
1
is hydrogen, halogen, cyano, trifluoromethyl, hydroxy, benzyloxy, aminocarbonyl, carboxy, phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio, alkyl, especially C
1
-C
6
-alkyl, alkenyl, especially C
3
-C
6
-alkenyl, alkinyl, especially C
3
-C
6
-alkinyl, hydroxyalkyl, especially C
1
-C
6
-hydroxyalkyl, alkoxy, especially C
1
-C
6
-alkoxy, alkenyloxy, especially C
3
-C
6
-alkenyloxy, alkinyloxy, especially C
3
-C
6
-alkinyloxy, alkanoyloxy, especially C
1
-C
7
-alkanoyloxy, alkoxycarbonyloxy, especially C
2
-C
7
-alkoxycarbonyloxy, alkylthio, especially C
1
-C
6
-alkylthio, alkenylthio, especially C
3
-C
6
-alkenylthio, alkinylthio, especially C
3
-C
6
-alkinylthio, cycloalkyl, especially C
3
-C
8
-cycloalkyl, cycloalkyloxy, especially C
3
-C
8
-cycloalkyloxy, cycloalklylthio, especially C
3
-C
8
-cycloalkylthio, alkoxycarbonyl, especially C
2
-C
7
-alkoxycarbonyl, alkylaminocarbonyl, especially C
2
-C
7
-alkylaminocarbonyl, dialkylaminocarbonyl, especially C
3
-C
13
-dialkylaminocarbonyl, or NR
5
R
6
, wherein
R
5
and
R
6
are selected independently of each other from hydrogen, alkyl, especially C
1
-C
6
-alkyl, alkenyl, especially C
3
-C
6
-alkenyl and alkinyl, especially C
3
-C
6
-alkinyl,
R
2
is hydrogen, halogen, cyano, hydroxy, trifluoromethyl, benzyloxy, alkyl, especially C
1
-C
6
-alkyl, alkoxy, especially C
1
-C
6
-alkoxy or alkanoyloxy, especially C
1
-C
7
-alkanoyloxy,
wherein R
1
and R
2
, if they are adjacent, optionally form a bridge which is selected from —(CH
2
)
4
—, —(CH═CH)
2
— and —CH
2
O—CR
7
R
8
—O—, wherein
R
7
and
R
8
are, independently of each other, hydrogen or alkyl, especially C
1
-C
6
-alkyl,
R
3
is hydrogen, halogen, alkyl, especially C
1
-C
6
-alkyl, trifluoromethyl or hydroxyalkyl, especially C
1
-C
6
-hydrohyalkyl and
R
4
is hydrogen, hydroxy, benzyloxy, alkyl, especially C
1
-C
6
-alkyl, alkenyl, especially C
3
-C
6
-alkenyl, alkinyl, especially C
3
-C
6
-alkinyl, cycloalkyl, especially C
3
-C
6
-cycloalkyl or alkoxy, especially C
1
-C
6
-alkoxy,
k is 0 or 1,
A is alkylene, especially C
1
-C
6
-alkylene, which is optionally substituted once to three-fold by alkyl, especially C
1
-C
3
-alkyl, hydroxy, alkoxy, especially C
1
-C
3
-alkoxy, fluorine or phenyl, or
1,2-cyclopropylene or
alkylene with at least two C-atoms, especially C
1
-C
6
-alkylene in which a methylene unit can be isosterically replaced by O, S, NR
9
, CO, SO or SO
2
, wherein the isosteric substitution, with the exception of ═CO, cannot be adjacent to the amide group and wherein
R
9
is selected from hydrogen, alkyl, especially C
1
-C
6
-alkyl, alkenyl, especially C
3
-C
6
-alkenyl, alkinyl, especially C
3
-C
6
-alkinyl, acyl, especially C
1
-C
6
-acyl or alkylsulfonyl, especially C
1
-C
6
-alkylsulfonyl,
D is selected from alkylene, especially C
1
-C
10
-alkylene, optionally substituted once or twice by alkyl, especially C
1
-C
6
-alkyl, hydroxy, or alkoxy, especially C
1
-C
6
-alkoxy,
alkenylene with at least two C-atoms, especially C
2
-C
10
-alkenylene, which is optionally substituted once or twice by alkyl, especially C
1
-C
6
-alkyl, hydroxy, or alkoxy, especially C
1
-C
6
-alkoxy, wherein the double bond can also be to ring E,
alkinylene with at least three C-atoms, especially C
3
-C
10
-alkinylene, optionally substituted once or twice by alkyl, especially C
1
-C
6
-alkyl, hydroxy or alkoxy, especially C
1
-C
6
-alkoxy, and
alkylene, especially C
1
-C
10
-alkylene, alkenylene with at least two C-atoms, especially C
2
-C
10
-alkenylene or alkinylene with at least three C-atoms, especially C
3
-C
10
-alkinylene, whereby one to three methylene units are each isosterically replaced by O,

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