Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-09-18
2004-02-17
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S228500, C514S233500, C544S061000, C544S127000, C546S119000, C546S120000
Reexamination Certificate
active
06693116
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel adenosine receptor ligands of formula
wherein
R
1
is hydrogen, halogen or lower alkoxy; and
R
2
is hydrogen; —C(O)-lower alkyl or —C(O)-phenyl, wherein the phenyl ring is unsubstituted or substituted by one or two substituents selected from the group consisting of halogen; lower alkyl; lower alkoxy or trifluoromethyl; or is —C(O)-furanyl or —C(O)-thiophenyl, wherein the rings are unsubstituted or substituted by halogen.
These compounds have useful pharmacological activities.
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 identified in 1982. Adenosine is both structurally and metabolically related to the bioactive nucleotides adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and cyclic adenosine monophosphate (cAMP); to the biochemical methylating agent S-adenosyl-L-methione (SAM); and structurally to the coenzymes NAD, FAD and coenzym 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, which belong 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 includes the activation of phospholipase C and modulation of both potassium and calcium ion channels. The A
3
receptor subtype, in addition to its association with adenylate cyclase, also stimulates phospholipase C and therefore 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 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 by the A
1
receptor or increase the oxygen supply by the A
2A
receptor so as to reinstate the balance of energy supply versus demand within the tissue. The actions of both subtypes are 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 to prevent 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 activated 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 that mimic the central inhibitory effects of adenosine therefore are useful as neuroprotective agents. Adenosine has been proposed as an endogenous anticonvulsant agent, inhibiting glutamate release from excitory neurons and inhibiting neuronal firing. Adenosine agonists therefore are 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 that modulate the adenosine receptors therefore also have therapeutic utility such 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, are useful as renal protective agents. Furthermore, adenosine A
3
and/or A
2B
antagonists are useful in the treatment of asthma and other allergic responses.
Numerous documents describe the current knowledge on adenosine receptors. These include 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; and Arch. Pharm. Med. Chem., (1999), 332, 39-41. The first two of these references disclose the agonist and antagonist functions of each of the receptor subtypes (A
1
, A
2A
, A
2B
, and A
3
) and their physiological effects. For example, adenosine receptor (AR) antagonists with selectivity for the A
1
-AR is useful for the treatment of senile dementia such as Alzheimer's disease and for the prevention of acute renal failure. A
2A
-selective antagonists are useful for the treatment of Parkinson's disease, hypotension and ischemias. A
2B
- and A
3
-selective antagonists are useful for the treatment of asthma and other allergic responses.
SUMMARY OF THE INVENTION
An aspect of the present invention is directed to the compounds of formula
wherein
R
1
is hydrogen, halogen or lower alkoxy; and R
2
is hydrogen; —C(O)-lower alkyl or —C(O)-phenyl, wherein the phenyl ring is unsubstituted or substituted by one or two substituents selected from the group consisting of halogen; lower alkyl; lower alkoxy or trifluoromethyl;
or is —C(O)-furanyl or —C(O)-thiophenyl, wherein the rings are unsubstituted or substituted by halogen;
and their pharmaceutically acceptable salts. Other embodiments of the invention are directed to methods of manufacture of compounds of formula I, pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof, as well as a method of controlling or preventing of illnesses base
Nettekoven Matthias Heinrich
Schmitt Sebastien
Hoffmann-La Roche Inc.
Huang Evelyn Mei
Johnson George W.
Lau Bernard
Rocha-tramaloni Patricia S.
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