Benzothiazole derivatives with activity as adenosine...

Details Benzothiazole derivatives with activity as adenosine... Benzothiazole derivatives with activity as adenosine...

2001-06-14

2003-02-18

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C546S193000, C546S198000, C548S163000, C544S361000

Reexamination Certificate

active

06521754

ABSTRACT:

FIELD OF INVENTION
The present invention is related to benzothiazole compounds, and more particularly to benzothiazole dervitives showing activity as adenosine receptor ligands.
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 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, 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 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
2a
—receptor antagonists inhibit the release of dopamine from central synaptic terminals and stimulate 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 therapeutic potential as sedatives, muscle relaxants, antipsychotics, anxiolytics, analgesics, respiratory stimulants and antidepressants, and they may 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). 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 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 responsesor 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).
SUMMARY
The present invention is a method of treatment of a person having a disease state treatable by modulation of the adenosine A
2a
receptor by administering to a person in need of such treatment an effective amount of a compound of the formula
wherein
R
1
is hydrogen, lower alkyl, lower alkoxy, benzyloxy, cycloalkyloxy, halogen, hydroxy or trifluoromethylloxy;
R
2
, R
3
are independently from each other hydrogen, halogen, lower alkyl or lower alkyloxy;
R
4
is hydrogen, lower alkyl, lower alkenyl, halogen, —C(O)OH, —C(O)-lower alkyl, —C(O)-halogen-lower alkyl, —CH(OH)-halogen-lower alkyl, —C(O)O-lower alkyl, —NHC(O)-lower alkyl, —(CH
2
)
n
—OH, or is phenyl, which is optionally attached to the benzo group via the linker —(O)
m
—(CH
2
)
n
—and is unsubstituted or substituted by N(R
5
)(R
6
), halogen, alkoxy or nitro, or is 2,3-dihydro-1H-indolyl, azepan-1-yl, [1,4]oxazepan-4-yl, or is a five or six membered aromatic or non aromatic heterocycle, which may be attached to the benzo group via the linker —(O)
m
—(CH
2
)
n
or —N=C(CH
3
)—and is unsubstituted or substituted by one or two group(s) R
7
, wherein R
7
is defined below;
R is
(a) phenyl, unsubstituted or substituted by lower alkyl, halogen-lower alkyl, lower alkoxy, cyano, nitro, —C(O)H, —C(O)OH or by the following groups
—(CH
2
)
n
—C(O)—N(R
5
)—(CH
2
)
o
-lower alkoxy,
—(CH
2
)
n
O-halogen-lower alkyl,
—(CH
2
)
n
O—(CH
2
)
n+1
—O-lower alkyl,
—S(O)
2
—N(R
5
)—(CH
2
)
n
—O-lower alkyl,
—(CH
2
)
n
—OR
5
,
—(CH
2
)
n
N(R
5
)—(CH
2
)
o
-lower alkoxy,
—(CH
2
)
n
N[(CH
2
)
o
-lower alkoxy]
2
,
—(CH
2
)
n
N(R
5
)(R
6
),
—(CH
2
)
n
N[S(

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