Tetrahydropyridothiophenes for use in the treatment of cancer

The invention relates to heteroarylamido-substituted tetrahydropyridothiophene derivatives, which can be used in the pharmaceutical industry for the production of pharmaceutical compositions.

The invention further relates to the contribution made to the art by the finding, that said tetrahydropyridothiophene derivatives display cell-cycle dependent, anti-proliferative and apoptosis inducing activity.

The invention also relates to the use of these compounds for the therapy of hyperproliferative diseases, in particular human cancer.

Cancer chemotherapy was established with the alkylating agent Cyclophosphamide (Endoxan®), an oxazaphosphorin pro-drug activated preferentially in the tumor. The target of alkylating agents like Cyclophosphamide is DNA and the concept, that cancer cells with uncontrolled proliferation and a high mitotic index are killed preferentially, proved to be very successful. Standard cancer chemotherapeutic drugs finally kill cancer cells upon induction of programmed cell death (“apoptosis”) by targeting basic cellular processes and molecules. These baste cellular processes and molecules include RNA/DNA (alkylating and carbamylating agents, platin analogs and topoisomerase inhibitors), metabolism (drugs of this class are named anti-metabolites and examples are folic acid, purin and pyrimidine antagonist) as well as the mitotic spindle apparatus with αβ-tubulin heterodimers as the essential component (drugs are categorized into stabilizing and destabilizing tubulin inhibitors; examples are Taxol/Paclitaxel®, Docetaxel/Taxotere® and vinca alkaloids).

A subgroup of proapoptotic anticancer agents target cells preferentially in mitosis. In general these agents do not induce apoptosis in non-dividing cells, arrested in the G0, G1 or G2 phase of the cell division cycle. In contrast, dividing cells going through mitosis (M-phase of the cell division cycle), are killed efficiently by induction of apoptosis by this subgroup agents. Therefore, this subgroup or class of anti-cancer agents is described as cell-cycle specific or cell-cycle dependent. Tubulin inhibitors, with Taxol (Paclitaxel®) as a prominent example, belong to this class of cell-cycle specific, apoptosis inducing anti-cancer agents.

The international application WO2004/024065 mentions, inter alia, arylamido-substituted tetrahydropyridothiophene derivatives as glucagon antagonists for the treatment of diabetes. The international application WO2004/024066 mentions, inter alia, arylamido-substituted tetrahydrobenzothiophene derivatives as glucagon antagonists for the treatment of diabetes.

The german document DE4039734 describes, inter alia, N-alkylated tetrahydropyridothiophene derivatives as components of herbicidal agents.

The german document DD272078 describes, inter alia, N-alkylated tetrahydropyridothiophene derivatives with antianaphylactic and antihistaminergic properties.

The international application WO02/092076 is directed to substituted coumarins and quinolines as caspase activators.

The U.S. Pat. No. 4,963,559 relates to 5-(2-chlorobenzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine as an agent for treating cancer and preventing cancer metastasis.

It has now been found that the heteroarylamido-substituted tetrahydropyridothiophene derivatives, which are described in greater details below, differ from prior art compounds by creative structural alterations and have surprising and particularly advantageous properties.

In more detail, it has been unexpectedly and unanticipatedly found that the tetrahydropyridothiophene derivatives, which are described in greater details below, are potent and highly efficacious cell-cycle specific inducers of apoptosis in cancer cells. Therefore, yet unanticipatedly, these tetrahydropyridothiophene derivatives are useful for treating (hyper)proliferative diseases and/or disorders responsive to the induction of apoptosis, in particular cancer. By having a cell-cycle specific mode of action, these tetrahydropyridothiophene derivates should have a higher therapeutic index compared to standard chemotherapeutic drugs targeting basic cellular processes like DNA replication or interfering with basic cellular molecules like DNA

Thus, for example, the compounds according to this invention are expected to be useful in targeted cancer therapy.

The invention thus relates in a first aspect (aspect 1) to compounds of formula I

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