Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-11-05
2003-09-16
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S058200, C544S121000, C544S130000, C544S131000, C544S364000, C546S193000, C546S270100
Reexamination Certificate
active
06620811
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention generally relates to benzothiazole compounds useful as adenosine receptor ligands. Specifically, the present invention relates to compounds having good affinity to the A
2A
-receptor and a high selectivity to the A
1
- and A
3
receptors.
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 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 receptores 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 subtyps has been classically characterised by the adenylate cyclase effector system, which utilises 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: demand within the tissue. The actions of both subtyps 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 a neuromodulator, able to modulate many aspects of physiological brain function. Endogenous adenosine, a central link between energy metabolism and neuronal activity, varies according to behavioural state and (patho)physiological conditions. Under conditions of increased demand and decreased availability of energy (such as hypoxia, hypoglycemia, and/or excessive neuronial activity), adenosine provides a powerful protective fedback mechanism. Interacting with adenosine receptors represents a promising target for therapeutic intervention in a number of neurological and psychiatric diseases such as epilepsy, sleep, movement disorders (Parkinson or Huntington's disease), Alzheimer's disease, depression, schizophrenia, or addiction. 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 excitory 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 of neurodegenerative disorders, e.g. stroke. Adenosine A
2b
receptor antagonists modulate the activity of striatal GABAergic neurons and regulate smooth and well-coordinated movements, thus offering a potential therapy for Parkinsonian symptoms. Adenosine is also implicated in a number of physiological processes involved in sedation, hypnosis, schizophrenia, anxiety, pain, respiration, depression, and drug addiction (amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids). Drugs acting, at adenosine receptors therefore have therapeutic potential as sedatives, muscle relaxants, antipsychotics, anxiolytics, analgesics, respiratory stimulants, antidepressants, and to treat drug abuse. They may also be used in the treatment of ADHD (attention deficit hyper-activity disorder).
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). By acting at the A
1
receptor, adenosine A
1
agonists may protect against the injury caused by myocardial ischemia and reperfusion. The modulating, influence of A
2a
receptors on adrenergic function may have implications for a variety of disorders such as coronary artery disease and heart failure. A
2a
antagonists may be of therapeutic benefit in situations in which an enhanced antiadrenergic response is desirable, such as during acute myocardial ischemia. Selective antagonists at A
2a
receptors may also enhance the effectiveness of adenosine in terminating supraventricula arrhytmias.
Adenosine modulates many aspects of renal function, including renin release, glomerular filtration rate and renal blood flow. Compounds which antagonise 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 or and in the treament of diabetes mellitus and obesity.
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., 332, 39-41, (1999),
Am. J. Physiol., 276, H1113-1116, (1999) or
Naunyn Schmied, Arch. Pharmacol. 362, 375-381, (2000).
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
wherein R
1
, A and R are as defined herewithin.
The present invention generally relates to compounds of formula IA and IB per se, the use of compounds of formula IA and IB and their pha
Flohr Alexander
Jakob-Roetne Roland
Norcross Roger David
Riemer Claus
Hoffmann-La Roche Inc.
Johnston George W.
Ramsuer Robert W.
Rocha-Tramaloni Patricia S.
Smith Lyman H.
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