Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-03-25
2000-04-25
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514443, 540552, 549 12, 549 26, 549 43, 549 88, 549 90, A01N 4302, A01N 4312, C07D26702, C07D33712
Patent
active
060544740
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to novel polycyclic opioid receptor agonists having analgesic activity and pharmaceutical acceptable compositions thereof. In another aspect, the invention relates to methods and uses relating to the novel agonists and compositions.
BACKGROUND OF THE INVENTION
Narcotic opiate analgesics remain the mainstay of presently available drug regimens used to alleviate moderate to severe pain. Opiate analgesics produce a characteristic antinociceptive response in various animal species (including homo sapiens) through activation of specific receptors in the central nervous system. It is well established that activation of one or more of these receptors produces antinociceptive effects in relevant animal models of pain assessment.
Multiple types of opioid receptors have been shown to co-exist in higher animals, of which at least three distinct classes have been characterized, with evidence for additional classes or subclasses: mu (.mu.), kappa (K) and delta (.delta.). For example, see W. Martin et al., J. Pharmacol. Exp. Ther., 197, p. 517(1975); and J. Lord et al., Nature (London), 257, p. 495 (1977). The .mu. receptor is located in the brain and appears to be involved in the analgesic effect of morphine-like drugs. .kappa.-Receptor activation in the brain and spinal cord appears capable of producing analgesia, particularly at the spinal level. The .delta.-receptor is found in some peripheral tissues in addition to the brain and spinal cord, and shows a differentiating affinity for endogenous opioid peptides known as enkephalins. Finally, although it is doubtful that .sigma.-receptors are strictly "opioid" in character as they are activated by non-opioid compounds, the majority of psychotomimetic effects of opioid drugs, such as dysphoria and hallucinations, appear to be mediated by this class of receptors.
SUMMARY Of THE INVENTION
The present invention provides for compounds having analgesic activity which are novel polycyclic opioid receptor agonists having the general structure represented by formula I. ##STR2## wherein R.sub.1 is H, C.sub.1-6 alkyl, or C.sub.6-12 aryl optionally substituted with polar groups; --C(NH)--NH.sub.2, a positively charged group or C.sub.7-13 aralkyl optionally substituted with NH.sub.2, OH, C.sub.1-6 alkyl, or halogen; or R.sub.2 and R.sub.3 together form a 5 to 6 member ring optionally incorporating a heteroatom; wherein each R.sub.6 is independently H, C.sub.1-3 alkyl, or halogen; independently H, C.sub.1-6 alkyl, or C.sub.7-13 aralkyl optionally interrupted with one or more heteroatom;
In another aspect of the present invention, there is provided a method of agonizing opioid receptors in a mammal comprising administering to said mammal an opioid receptor agonizing amount of a compound according to formula (I).
In a further aspect there is provide a method of inducing analgesia in a mammal comprising administering to said mammal a pharmaceutically effective amount of a compound according to formula (I).
It will be appreciated by those skilled in the art that the compounds of formula (I), depending on the substituents, may contain one or more chiral centers and thus exist in the form of many different isomers, optical isomers (i.e. enantiomers) and mixtures thereof including racemic mixtures. All such isomers, enantiomers and mixtures thereof including racemic mixtures are included within the scope of the invention.
The invention also provides for pharmaceutically acceptable compositions comprising compounds of formula (I), for use in the management of pain.
The invention also provides for pharmaceutically acceptable compositions comprising compounds of formula (I), for use as diagnostic aids and/or research tools such as radioligands, radiotracers with Positron Emission Tomography or paramagnetic agents for use with Magnetic Resonance Imaging for opiate receptor mediated processes.
The invention further provides the use of a compound of Formula (I) for the manufacture of therapeutic agents for the management of pain.
The in
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DiMaio John
Dixit Dilip M.
Biochem Pharma Inc.
Shah Mukund J.
Truong Tamthom N.
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