Substituted triazolopyridine compounds

Details Substituted triazolopyridine compounds Substituted triazolopyridine compounds

2002-10-07

2004-02-10

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, C546S120000, C546S119000

Reexamination Certificate

active

06689790

ABSTRACT:

FIELD OF INVENTION
The present invention relates to a compound of the formula
This compound is an adenosine receptor ligand useful in the control or prevention of illnesses modulated by the adenosine system, such as, for example, Alzheimer's disease and Parkinson's disease.
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 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 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, 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 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 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
wherein
R
1
is —NR′R″, wherein R′ and R″ are independently selected from the group consisting of lower alkyl, —(CH
2
)
n
—C(O)NR
a
R
b
, —(CH
2
)
n
-heteroaryl, —(CH
2
)
n
-aryl, —(CH
2
)
n
—CN, —(CH
2
)
n
—O-lower alkyl or —(CH
2
)
n
-cycloalkyl, or R′ and R″ form together with the N-atom a five or six-membered non-aromatic ring, containing no or one additional heteroatom selected from the group O and S, said ring being unsubstituted or substituted by one or two substituents, selected from the group consisting of lower alkyl, —C(O)NR
a
R
b
or —(CH
2
)
n
—O-lower alkyl and R
a
R
b
are independently from each other hydrogen or lower alkyl;
R
2
is aryl or heteroaryl, unsubstituted or substituted by lower alkyl or halogen; and
n is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
It has surprisingly been found that the compounds of formula I are adenosine receptor ligands.
Compounds of the present invention of formula I and their pharmaceutically acceptable salts are pharmaceutically active substances. The present invention includes a process for the manufacture of compounds of formula I and pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of formula I and an excipient. The present invention is also directed to a method of controlling or preventing 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, allergic responses, hypoxia, ischaemia, seizure and subst

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