Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-16
2003-07-15
Raymond, Richard L (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S231500, C544S124000, C546S193000
Reexamination Certificate
active
06593344
ABSTRACT:
The invention relates to new piperidinyl-substituted pyridyl-alkane, alkene and alkine carboxamides with a saturated or one or several-fold unsaturated hydrocarbon residue in the carboxylic acid portion, methods for the synthesis of these compounds, medicaments containing these and their production as well as their therapeutic use especially as cytostatic agents and immunosuppresive agents, for example, in the treatment or prevention of various types of tumors and control of immune reactions, for example of autoimmune diseases.
A pressing need exists for new pharmaceuticals and/or medicaments for cytostatic and immunosuppressive therapy which not only possess a strong activity, but also exert diminished side effects in comparison to many classical cancerostatic agents. At the same time 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.
Additionally, from another point of view, there exists a strong need in the field of tumor therapy for new compounds, for example for overcoming or avoiding resistances, which enrich the pallet of cancerostatics based on new modes of action in the ideal case.
This object was successfully solved by the creation of the piperidinyl-substituted pyridylalkane, alkene and alkine carboxamide derivatives as defined in detail in the claims and medicaments containing these as well as the use of these compounds, optionally in combination with other suitable active ingredients and adjuvants, for cytostatic and immunosuppressive therapy or prevention.
It is known that various pyridine compounds or substituted in a specific manner have pharmacologically useful properties; however, in contrast to the actions of the compounds according to the invention, these lie in completely different fields of indication.
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;-pyridylalkane and alkene amides as anti-allergic effective substances containing a substituted piperidine ring in the amine component. However, corresponding overlapping compound groups are excluded from the present claimed scope of protection according to the invention. Similarly compounds with the same properties are mentioned in Chem. Pharm. Bull 37, 100-105 (1989) and in J. Med. Chem. 1989, 583-593 whereby corresponding known substitutions are also excluded from the present scope of protection.
Pyridyl ureas, pyridyl thioureas and pyridyl carbonamides, wherein the amide portion is bound over an aryl-substituted alkyl chain with a piperidine ring or piperidine ring or piperazine 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 pyridine ring is bound directly or over a methylene bridge with the amide group are disclosed in EP-A-0 479 601 as active ingredients with anti-arrhythmic properties.
Other structurally closely related compounds are represented by the piperidine compounds described in EP-A-0 330 026. These known compounds are distinguished by an anti-cholinesterase activity, an anti-amnesia activity as well as activities directed against hyperkinesia, senile dementia, mania and Alzheimer's disease.
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(−)-niguldipin and further analogous dihydropyridines with cytotoxic activity have larger structural differences. However, as compared to these known compounds, the compounds according to the invention possess a higher activity and a wider spectrum of action despite the large structural differences.
In the international PCT patent applications WO 96/31477 or for example WO 96/31478 tricyclic anellated compounds are described which possess an anti-proliferative activity. All of these compounds described therein are distinguished in that they must imperatively possess a tricyclic anellated ring system with at least one nitrogen atom, for example 6, 11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridinyl ring system as a pharmaphoric group. The molecule portion at the other end of this tricyclic anellated system is uncommonly variable such that the pyridyl substitution given therein among numerous substitution possibilities merely represents one of many variation possibilities. A further meaningful difference in the substitution of these molecules in comparison to the compounds according to the invention is to be seen in the lack of the present structural element D (i.e. the inserted, optionally unsaturated hydrocarbon chain between the two essential terminal and/or opposite heterocycles); expressed in other words, the known compounds have a direct bond between the carboxy group and the piperidine ring.
A further essential difference of the compounds according to the invention in comparison to these known tricyclic anellated compounds is to be recognized in the presence of the terminal 3-pyridyl-substitution which must be present. The presence of this heterocyclic ring required according to the invention as well as this particular bond site in the substituted compounds according to the invention in comparison to the above mentioned anti-proliferative compounds of the state of the art with a tricyclic ring system is to be understood as a meaningful indication that, in a completely surprising manner, the pyridyl group is responsible for the anti-tumor action according to the invention.
In fact, the compounds according to the invention cover a different tumor spectrum from those named in the PCT/WO publications with this necessarily present tricyclic anellated ring system. In the mentioned PCT/WO publications of the state of the art, a treatment possibility in tumors is merely mentioned which is made in connection with a potential inhibition of the farnesyl protein transferase, whereby this mechanism relates to the expression of the activated rasoncogene. In contrast to this, the presently claimed new compounds with the 3-pyridyl-substitution required according to the invention are not limited to the therapy of tumor cells of this type with abnormal production of the ras-oncogene; rather, the therapy possibilities with the new compounds according to the invention extend to the combat of numerous other types of tumors with different causal mechanisms as well as immunosuppressive treatment possibilities such as autoimmune diseases.
In view of this art, the finding demonstrated in the pharmacological experimental section below according to which the compounds according to the general formula (I) with the particular substitutions defined below have superior pharmacological activities which make them particularly suitable in an excellent manner for the therapy of tumor illnesses over a broad anti-proliferative spectrum, was completely unexpected. The pharmacological finding that, aside from the cytostatic effectiveness,
Biedermann Elfi
Hasmann Max
Löser Roland
Rattel Benno
Reiter Friedemann
Fitch Even Tabin & Flannery
Klinge Pharma GmbH
Raymond Richard L
Truong Tamthom N.
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