Adenosine, A3 receptor modulators

Details Adenosine, A3 receptor modulators Adenosine, A3 receptor modulators

2000-07-26

2002-03-19

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S251000

Reexamination Certificate

active

06358964

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to certain triazolo-quinazoline derivatives and their use in the practice of medicine as modulators of adenosine A
3
receptors.
BACKGROUND OF THE INVENTION
Three major classes of adenosine receptors, classified as A
1
, A
2
, and A
3
, have been characterized pharmacologically. A
1
receptors are coupled to the inhibition of adenylate cyclase through G
i
proteins and have also been shown to couple to other second messenger systems, including inhibition or stimulation of phosphoinositol turnover and activation of ion channels. A
2
receptors are further divided into two subtypes, A
2A
and A
2B
, at which adenosine agonists activate adenylate cyclase with high and low affinity, respectively. The A
3
receptor sequence was first identified in a rat testes CDNA library, and this sequence, later cloned by homology to other G-protein coupled receptors from a rat brain cDNA library, was shown to correspond to a novel, functional adenosine receptor.
The discovery of the A
3
receptor has opened new therapeutic vistas in the purine field. In particular, the A
3
receptor mediates processes of inflammation, hypotension, and mast cell degranulation. This receptor apparently also has a role in the central nervous system. The A
3
selective agonist IB-MECA induces behavioral depression and upon chronic administration protects against cerebral ischemia. A
3
selective agonists at high concentrations were also found to induce apoptosis in HL-60 human leukemia cells. These and other findings have made the A
3
receptor a promising therapeutic target. Selective antagonists for the A
3
receptor are sought as potential antiinflammatory or possibly antiischemic agents in the brain. Recently, A
3
antagonists have been under development as antiasthmatic, antidepressant, antiarrhythmic, renal protective, antiparkinson and cognitive enhancing drugs.
It would be desirable to have additional compounds and methods of preparation and use thereof, which are agonists, partial agonists, and/or antagonists of the adenosine A
3
receptor. The present invention provides such compositions and methods.
SUMMARY OF THE INVENTION
Compounds useful as potent modulators of the adenosine A
3
receptor, with activity as antagonists of this receptor, and methods of preparation and use thereof, are disclosed.
The compounds have the following general formula:
wherein:
R is —C(X)R
1
, —C(X)—N(R
1
)
2
, —C(X)OR
1
, —C(X)SR
1
, —SO
n
R
1
, —SO
n
OR
1
, —SO
n
SR
1
, or SO
n
—N(R
1
)
2
;
R
1
is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, heterocyclic, lower alkenyl, lower alkanoyl, or, if linked to a nitrogen atom, then taken together with the nitrogen atom, forms an azetidine ring or a 5-6 membered heterocyclic ring containing one or more heteroatoms such as N, O, S;
R
2
is hydrogen, halogen, preferably chloro, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl;
R
3
is furan, pyrrole, thiophene, benzofuran, benzypyrrole, benzothiophene, optionally substituted with one or more substituents as described herein for substituted heteroaryl rings;
X is O, S, or NR
1
;
n is 1 or 2;
radiolabeled analogues thereof, fluorescently labeled analogues thereof, and
pharmaceutically acceptable salts thereof, with the proviso that R
2
is not halogen when R is —C(X)R
1
. A preferred R group is —C(X)—N(R
1
)
2
, where X is O.
Preferably, R
1
is hydrogen; C
1-8
alkyl; C
2-7
alkenyl, C
2-7
alkynyl; C
3-7
cycloalkyl; C
1-5
alkyl substituted with one or more halogen atoms, hydroxy groups, C
1-4
alkoxy, C
3-7
cycloalkyl or groups of formula —NR
1
2
, —C(O)NR
1
2
; aryl, substituted aryl wherein the substitution is selected from the group consisting of C
1-4
alkoxy, C
1-4
alkyl, nitro, amino, cyano, C
1-4
haloalkyl, C
1-4
haloalkoxy, carboxy, carboxyamido; C
7-10
aralkyl in which the aryl moiety can be substituted with one or more of the substituents indicated above for the aryl group; a group of formula —(CH
2
)m—Het, wherein Het is a 5-6 membered aromatic or non aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of N, O, and S and m is an integer from 1 to 5;
Preferred C
1-8
alkyl groups are methyl, ethyl, propyl, butyl and isopentyl. Examples of C
3-7
cycloalkyl groups include cyclopropyl, cyclopentyl, and cyclohexyl. Examples of C
1-5
alkyl groups substituted with C
3-7
cycloalkyl groups include cyclohexylmethyl, cyclopentylmethyl, and 2-cyclopentylethyl. Examples of substituted C
1-5
alkyl groups include 2-hydroxyethyl, 2-methoxyethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 3-aminopropyl, 2-(4methyl-1-piperazine)ethyl, 2-(4-morpholinyl)ethyl, 2-aminocarbonylethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl. Aryl is preferably phenyl, optionally substituted with Cl, F, methoxy, nitro, cyano, methyl, trifluoromethyl, difluoromethoxy groups. Examples of 5 to 6 membered ring heterocyclic groups containing N, O and/or S include piperazinyl, morpholinyl, thiazolyl, pyrazolyl, pyridyl, furyl, thienyl, pyrrolyl, triazolyl, tetrazolyl. Examples of C
7-10
aralkyl groups comprise benzyl or phenethyl optionally substituted by one or more substituents selected from Cl, F, methoxy, nitro, cyano, methyl, trifluoromethyl, and difluoromethoxy. Preferably, R
1
is hydrogen, C
1-8
alkyl, aryl or C
7-10
aralkyl, optionally substituted, preferably with halogen atoms. Preferably, X is O, R
2
is chloro, C
2-3
alkyl or substituted alkyl and R
3
is furan.
Particularly preferred compounds are those in which R is a phenethyl group in which the phenyl ring is substituted with one or more substituents selected from the group consisting of chlorine, fluorine atoms, methoxy, nitro, cyano, methyl, trifluoromethyl, and difluoromethoxy groups.
The compounds can be used in a method for modulating adenosine A
3
receptors in a mammal, including a human. The methods involve administering an effective amount of a compound of Formula I sufficient to moderate adenosine A
3
receptors in the mammal. Uses for the compounds include:
treating hypertension;
treating inflammatory disorders such as rheumatoid arthritis and psoriasis;
treating allergic disorders such as hay fever and allergic rhinitis;
mast cell degranulation;
antitumor agents;
treating cardiac hypoxia; and
protection against cerebral ischemia;
diagnostic uses, for example to determine the presence of one or more of the above described medical conditions, or in a screening assay to determine the effectiveness of other compounds for binding to the A
3
Ado receptor (i.e., through competitive inhibition as determined by various binding assays), as described in Jacobson and Van Rhee,
Purinergic approaches to experimental therapy
, Jacobson and Jarvis, ed., Wiley, New York, 1997, pp. 101-128; Mathot et al.,
Brit. J. Pharmacol
., 116:1957-1964 (1995); van der Wenden et al.,
J. Med. Chem
., 38:4000-4006 (1995); and van Calenbergh,
J. Med. Chem
., 40:3765-3772 (1997), the contents of which are hereby incorporated by reference.
The compounds can also be used in a method for fully or partially inhibiting adenylate cyclase (A
3
) in a mammal, including a human. The methods involve administering an effective amount of a compound of Formula I sufficient to fully or partially inhibit adenylate cyclase in the mammal. The compounds can also be labeled and used to detect the presence of tumor cells containing adenosine A
3
ligands in a patient or in a cell sample, by contacting the cells with the labeled compound, allowing the compound to bind to the A
3
receptors, and detecting the presence of the label.
The compounds can be used in a pharmaceutical formulation that includes a compound of Formula I and one or more excipients. Various chemical intermediates can be used to prepare the compounds.
DETAILED DESCRIPTION OF THE INVENTION
The present application discloses compounds useful as potent modulators of adenosine rece

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