Substituted 5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine-2-yl compounds and 5,6,7,8-tetrahydro-quinazoline-2-yl compounds

This application is a division of co-pending application Ser. No. 11/588,238, filed Oct. 27, 2006, now U.S. Pat. No. ______, which in turn is a continuation of International patent application Serial No. PCT/EP2005/004489 filed Apr. 27, 2005 designating the United States of America, and published in German on Nov. 10, 2005 as WO 2005/105759, which claims benefit of Federal Republic of Germany patent application no. DE 10 2004 020 908.1, filed Apr. 28, 2004, the entire disclosures of which are incorporated herein in their entirety.

The present invention relates to substituted 5,6,7,8-tetrahydro-pyrido[4,3-d]-pyrimidin-2-yl and 5,6,7,8-tetrahydroquinazolin-2-yl compounds, processes for the production thereof, pharmaceutical formulation containing these compounds, methods of producing such pharmaceutical formulation, and related methods of treating or inhibiting certain conditions or disorders, including pain.

Pain is one of the basic clinical symptoms. There is a worldwide need for effective pain treatments. The urgency of the requirement for therapeutic methods for providing tailored and targeted treatment of chronic and non-chronic pain, this being taken to mean pain treatment which is effective and satisfactory from the patient\'s standpoint, is also evident from the large number of scientific papers relating to applied analgesia and to basic nociception research which have appeared in recent times.

Conventional opioids, such as for example morphine, are effective in the treatment of severe to very severe pain, but they often lead to unwanted accompanying symptoms, such as for example respiratory depression, vomiting, sedation, constipation or the development of tolerance. Moreover, they are frequently insufficiently effective in the case of neuropathic pain, suffered in particular by tumor patients.

One object of the present invention was accordingly to provide novel compounds which are suitable in particular as pharmaceutical active ingredients in pharmaceutical preparations, preferably in pharmaceutical preparations for the prevention and/or treatment of pain, in particular acute pain, chronic pain, neuropathic or visceral pain.

It has now surprisingly been found that the substituted 5,6,7,8-tetrahydro-pyrido-[4,3-d]pyrimidin-2-yl and 5,6,7,8-tetrahydro-quinazolin-2-yl compounds of the general formula I stated hereinafter are suitable for noradrenalin receptor regulation, in particular for inhibiting noradrenalin reuptake (noradrenalin uptake), for 5-HT receptor regulation, in particular for inhibiting 5-hydroxy tryptophan reuptake (5-HT uptake), for mGluR5 receptor regulation and/or for batrachotoxin (BTX) receptor regulation and may therefore be used in particular as pharmaceutical active ingredients in pharmaceutical preparations for preventing and/or treating disorders or diseases associated with these receptors or processes.

The present invention accordingly provides substituted 5,6,7,8-tetrahydro-pyrido-[4,3-d]pyrimidin-2-yl and 5,6,7,8-tetrahydroquinazolin-2-yl compounds of the general formula I,

in which

X denotes a C(H)(NHR²) group or an NR^2a group,

R¹ denotes a —C(═O)—R³ group or a —C(═O)—O—R⁴ group,

R², R^2a, mutually independently, in each case denote a —C(═O)—R⁵ group or an —S(═O)₂—R⁶ group,

R³ denotes a linear or branched, unsubstituted or at least monosubstituted, saturated or unsaturated aliphatic residue, optionally comprising at least one heteroatom as a chain link, an unsubstituted or at least monosubstituted, saturated or unsaturated cycloaliphatic residue, optionally comprising at least one heteroatom as a ring member, which residue may be attached via a linear or branched, unsubstituted or at least monosubstituted alkylene group, optionally comprising at least one heteroatom as a chain link, or an unsubstituted or at least monosubstituted aryl or heteroaryl residue, which may be attached via a linear or branched, unsubstituted or at least monosubstituted alkylene group,

R⁴ denotes an unsubstituted or at least monosubstituted aryl or heteroaryl residue, which may be attached via a linear or branched, unsubstituted or at least monosubstituted alkylene group,