Use of pyridyl alkane, pyridyl alkene and/or pyridyl alkine...

Details Use of pyridyl alkane, pyridyl alkene and/or pyridyl alkine... Use of pyridyl alkane, pyridyl alkene and/or pyridyl alkine...

1998-12-18

2002-09-17

Rotman, Alan L. (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S317000, C546S196000, C546S197000, C546S198000, C546S207000, C546S208000

Reexamination Certificate

active

06451816

ABSTRACT:

The invention relates to the use of pyridyl aklane, pyridyl alkene and/or pyridyl alkine acid amides, especially in the treatment of tumor conditions and/or as cytostatic agents or as immunosuppressive agents as well as medicaments with an amount of these compounds in combination with other cytostatic agents or immunosuppresive 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. As a consequence, further subject-matter of the invention relates to new medicaments in the form of combinations of the compounds defined below and used according to the invention together with other compounds or immunosuppressive agents customary in the therapy of tumors.
In this connection, a strong need also exists in tumor therapy to open up new possibilities which were not usable up to now in these indications, for example for overcoming or preventing resistances.
This object was successfully solved in a completely suprising manner by making available the specially structured pyridyl 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;-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 substance 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.
Further structurally closely related compounds are represented by the antagonists of the histimine-H
1
-receptor described in EP-A-0 343 307 which discloses a series of substituted piperidine derivatives without naming concrete examples for special 3-pyridyl substitutions.
EP-A-0 330 026 also discloses substituted piperidine derivatives with possible, generic pyridyl substitutions for which, however, merely a single concrete example is disclosed, namely (E)-3-(3-pyridyl)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-propenamide hydrochloride. These compounds are distinguished by an anti-cholinesterase activity, an anti-amnesia activity as well as activities directed against hyperkinesia, senile demensia, mania and Alzheimer's disease.
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.
Considering the above-mentioned completely different known medical indications of known piperidine derivatives, such as neurokinin receptor antagonism, hyperkineses, amnesias, allergies, or rhythm disorders, the activity of the compounds used according to the invention with the structural modifications as they are defined below with respect to the present general formula, and the combinations according to the invention in the form of the detected excellent cytostatic or immunomodulatory activity with advantageous therapeutic properties was completely surprising for the person skilled in the art.
Pharmacological test results from which this conclusion must be drawn, 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 the use of one or more 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, cycloalkylthio, 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
-hydroxyalkyl 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 thre

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