Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-29
2003-02-04
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S119000
Reexamination Certificate
active
06514989
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds of formula
wherein R
1
and R
2
are each selected from the group consisting of unsubstituted thiophenyl, unsubstituted phenyl, substituted thiophenyl and substituted phenyl. The compounds of formula I are adenosine receptor ligands useful in the treatment of diseases such as, e.g., Alzheimer's, Parkinson's and schizophrenia.
BACKGROUND
Adenosine modulates a wide range of physiological functions by interacting with specific cell surface receptors. The potential of adenosine receptors as drug targets was first reviewed in 1982. Adenosine is related both structurally and metabolically to several bioactive nucleotides. These bioactive nucleotides include adenosine triphosphate (ATP); adenosine diphosphate (ADP); adenosine monophosphate (AMP) and cyclic adenosine monophosphate (cAMP); the biochemical methylating agent S-adenosyl-L-methione (SAM); structurally to the coenzymes NAD, FAD and coenzyme A; and to RNA. Together adenosine and these related compounds are important in the regulation of many aspects of cellular metabolism and in the modulation of different central nervous system activities.
The receptors for adenosine have been classified as A
1
, A
2A
, A
2B
and A
3
receptors, belonging to the family of G protein-coupled receptors. Activation of adenosine receptors by adenosine initiates signal transduction mechanism. These mechanisms are dependent on the receptor associated G protein. Each of the adenosine receptor subtypes has been classically characterized by the adenylate cyclase effector system, which utilizes cAMP as a second messenger. The A
1
and A
3
receptors, coupled with G
i
proteins inhibit adenylate cyclase, leading to a decrease in cellular cAMP levels, while A
2A
and A
2B
receptors couple to G
S
proteins and activate adenylate cyclase, leading to an increase in cellular cAMP levels. It is known that the A
1
receptor system include the activation of phospholipase C and modulation of both potassium and calcium ion channels. The A
3
subtype, in addition to its association with adenylate cyclase, also stimulates phospholipase C and so activates calcium ion channels.
The A
1
receptor (326-328 amino acids) was cloned from various species (canine, human, rat, dog, chick, bovine, guinea-pig) with 90-95% sequence identify among the mammalian species. The A
2A
receptor (409-412 amino acids) was cloned from canine, rat, human, guinea pig and mouse. The A
2B
receptor (332 amino acids) was cloned from human and mouse with 45% homology of human A
2B
with human A
1
and A
2A
receptors. The A
3
receptor (317-320 amino acids) was cloned from human, rat, dog, rabbit and sheep.
The A
1
and A
2A
receptor subtypes are proposed to play complementary roles in adenosine's regulation of the energy supply. Adenosine, which is a metabolic product of ATP, diffuses from the cell and acts locally to activate adenosine receptors to decrease the oxygen demand (A
1
) or increase the oxygen supply (A
2A
) and so reinstate the balance of energy supply versus demand within the tissue. The actions of both subtypes is to increase the amount of available oxygen to tissue and to protect cells against damage caused by a short-term imbalance of oxygen. One of the important functions of endogenous adenosine is preventing damage during traumas such as hypoxia, ischaemia, hypotension and seizure activity.
Furthermore, it is known that the binding of the adenosine receptor agonist to mast cells expressing the rat A
3
receptor resulted in increased inositol triphosphate and intracellular calcium concentrations, which potentiated antigen induced secretion of inflammatory mediators. Therefore, the A
3
receptor plays a role in mediating asthmatic attacks and other allergic responses.
Adenosine is also a neuromodulator, possessing global importance in the modulation of molecular mechanisms underlying many aspects of physiological brain function by mediating central inhibitory effects. An increase in neurotransmitter release follows traumas such as hypoxia, ischaemia and seizures. These neurotransmitters are ultimately responsible for neural degeneration and neural death, which causes brain damage or death of the individual. The adenosine A
1
agonists which mimic the central inhibitory effects of adenosine may therefore be useful as neuroprotective agents. Adenosine has been proposed as an endogenous anticonvulsant agent, inhibiting glutamate release from excitatory neurons and inhibiting neuronal firing. Adenosine agonists therefore may be used as antiepileptic agents. Adenosine antagonists stimulate the activity of the CNS and have proven to be effective as cognition enhancers. Selective A
2a
-antagonists have therapeutic potential in the treatment of various forms of dementia, for example in Alzheimer's disease and are useful as neuroprotective agents. Adenosine A
2
-receptor antagonists inhibit the release of dopamine from central synaptic terminals and reduce locomotor activity and consequently improve Parkinsonian symptoms. The central activities of adenosine are also implicated in the molecular mechanism underlying sedation, hypnosis, schizophrenia, anxiety, pain, respiration, depression and substance abuse. Drugs acting at adenosine receptors therefore have also therapeutic potential as sedatives, muscle relaxants, antipsychotics, anxiolytics, analgesics, respiratory stimulants and antidepressants.
An important role for adenosine in the cardiovascular system is as a cardioprotective agent. Levels of endogenous adenosine increase in response to ischaemia and hypoxia, and protect cardiac tissue during and after trauma (preconditioning). Adenosine agonists thus have potential as cardioprotective agents.
Adenosine modulates many aspects of renal function, including renin release, glomerular filtration rate and renal blood flow. Compounds, which antagonize the renal affects of adenosine, have potential as renal protective agents. Furthermore, adenosine A
3
and/or A
2B
antagonists may be useful in the treatment of asthma and other allergic responses.
Numerous documents describe the current knowledge on adenosine receptors, for example the following publications:
Bioorganic & Medicinal Chemistry, 6, (1998), 619-641,
Bioorganic & Medicinal Chemistry, 6, (1998), 707-719,
J. Med. Chem., (1998), 41, 2835-2845,
J. Med. Chem., (1998), 41, 3186-3201,
J. Med. Chem., (1998), 41, 2126-2133,
J. Med. Chem., (1999), 42, 706-721,
J. Med. Chem., (1996), 39, 1164-1171,
Arch. Pharm. Med. Chem., (1999), 332, 39-41.
SUMMARY
The present invention is a compound of formula
or a pharmaceutically acceptable salt thereof, wherein
R
1
is selected from the group consisting of unsubstituted phenyl, unsubstituted thiophenyl and phenyl or thiophenyl substituted by one or two substituents selected from the group consisting of
halogen, trifluoromethyl, lower alkyl, lower alkoxy, acetlylamino, acetyl, lower alkenyl, —C(O)O-lower alkyl, and thio-lower alkyl; and
R
2
is selected from the group consisting of unsubstituted phenyl, unsubstituted thiophenyl and phenyl or thiophenyl substituted by one or two substitutents selected from the group consisting of
halogen , lower alkyl, halogen-lower alkyl and lower alkoxy.
It has surprisingly been found that the compounds of formula I are adenosine receptor ligands.
A compound of formula I, or a pharmaceutically acceptable salt thereof, is an object of the present invention. Another object of the invention is a pharmaceutical composition containing a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The manufacture of a compound of formula I and a pharmaceutical composition containing a compound of formula I is an object of the invention. Yet another object of the invention is a method of treatment for the control or prevention of illnesses based on the modulation of the adenosine system, such as Alzheimer's disease, Parkinson's disease, neuroprotection, schizophrenia, anxiety, pain, respiration deficits, depression, asthma,
Nettekoven Matthias Heinrich
Puellmann Bernd
Dawson Arthur D.
Dentz Bernard
Hoffmann-La Roche Inc.
Johnston George W.
Rocha-Tramaloni Patricia S.
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