A3 adenosine receptor antagonists

Details A3 adenosine receptor antagonists A3 adenosine receptor antagonists

2001-04-02

2002-04-23

Aulakh, C. S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S322000, C546S321000, C546S318000

Reexamination Certificate

active

06376521

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The present invention relates to certain novel A
3
adenosine receptor antagonists, pharmaceutical compositions, and methods of selectively blocking A
3
adenosine receptors in a mammal. The present invention also relates to methods of preventing or treating various medical disorders or conditions with the adenosine receptor antagonists.
BACKGROUND OF THE INVENTION
The use of caffeine and other alkylxanthines as physiological stimulants is well known. The principle mechanism by which caffeine and other alkylxanthines act as physiological stimulants is by blocking the effects of the ubiquitous neuromodulator adenosine. Daly, “Mechanism of Action of Caffeine”, in
Caffeine, Coffee and Health,
(S. Garattini, Ed.), Chapter 4, pp. 97-150 (1993). Adenosine is produced locally in response to increased activity or stress to the system. This feedback mechanism allows the organ to compensate for the stress by decreasing energy demand (depressant activity) and increasing oxygen supply (e.g., by vasodilation). Bruns,
Nucleosides
&
Nucleotides,
10, 931-944 (1991).
Adenosine plays several key physiological roles. In addition to its role in intermediary metabolism, adenosine displays a number of receptor-mediated physiological actions, including dilation of coronary vessels, inhibition of platelet aggregation, and inhibition of lipolysis. Bruns et al.,
Proc. Nat. Acad. Sci. U.S.A.,
77, 5547-5551 (1980). Adenosine receptors, A
1
, A
2
, and A
3
, belong to the G protein-coupled superfamily characterized by seven transmembrane helical domains. Several antagonists have been reported for these receptors in the literature. See, for example, Jacobson et al., “Development Of Selective Purinoceptor Agonists And Antagonists”, in
Purinergic Approaches In Experimental Therapeutics,
K. A. Jacobson and M. F. Jarvis, Ed, Wiley, Ch. 6, pp. 101-128 (1997). The pharmacology of the A
3
receptor is unique within the class of adenosine receptors. Zhou et al.,
Proc. Natl. Acad. Sci. USA,
89, 7432-7436 (1992).
The distribution of the A
3
receptor is found primarily in the central nervous system (CNS), brain, testes, and immune system, where it appears to be involved in the modulation of release from mast cells of mediators of the immediate hypersensitivity reaction. Ramkumar et al.,
J. Biol. Chem.,
268, 16887-16890 (1993). It is believed that A
3
-selective compounds will have utility in the therapeutic and/or prophylactic treatment of cardiac disease, infertility, kidney disease, and CNS disorders. Activation of the A
3
receptor has been linked to several second messenger systems such as stimulation of phospholipidases C and D and inhibition of adenylyl cyclase. Ali et al.,
J. Pharmacol. Exp. Therap.,
276, 837-845 (1996).
Antagonists for the A
3
receptor are sought as potential anti-inflammatory, antiasthmatic, and antiischemic agents. von Lubitz et al.,
Eur. J. Pharmacol.,
263, 59-67 (1994);
Soc. For Neurosciences,
Abstr. 745.16, 23, 1924 (1997). Some promising leads for A
3
adenosine receptor antagonists have been identified in certain 1,4-dihydropyridines, triazoloquinazolines, flavonoids, a triazolonaphthyridine, and a thiazolopyrimidine. Van Rhee et al.,
J. Med. Chem.,
39, 2980-2989 (1996); Jiang et al.,
J. Med. Chem.,
39, 4667-4675 (1996); Jiang et al.,
J. Med. Chem.,
40, 2596-2608 (1997); Kim et al.,
J. Med. Chem.,
39, 4142-4148 (1996); Karton et al.,
J. Med. Chem.,
39, 2293-2301 (1996); Jacobson et al.,
Drug Devel. Res.,
37, 131 (1996). WO 97/27177 discloses certain dihydropyrdines, pyridines, flavonoids, and triazoloquinazolines as possible A
3
adenosine receptor antagonists. Li et al.,
J. Med. Chem.,
41, 3186-3201 (1998) discloses certain pyridine derivatives as possible A
3
adenosine receptor antagonists.
Thus, there remains a need for antagonists for A
3
adenosine receptors. The present invention seeks to provide such compounds, as well as methods of using these compounds to selectively block adenosine receptors in mammals, and pharmaceutical compositions comprising such compounds. These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
SUMMARY OF THE INVENTION
The present invention provides compounds of formula (I)
wherein R
2
is selected from the group consisting of C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, and C
1
-C
6
alkoxy C
1
-C
6
alkyl; R
3
is selected from the group consisting of C
1
-C
6
alkoxy, C
1
-C
6
alkylsulfanyl, hydroxy, C
1
-C
6
alkoxy C
1
-C
6
alkylsulfanyl, hydroxy C
1
-C
6
alkylsulfanyl, and halo C
1
-C
6
alkylsulfanyl, or R
3
together with R
4
forms a 3-7 membered heterocyclic ring containing O, N, or S; R
4
is selected from the group consisting of C
1
-C
6
alkyl, halo C
1
-C
6
alkyl, hydroxy C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
alkylsulfanyl, C
1
-C
6
alkylamino, C
1
-C
6
alkylcarbonyl sulfanyl C
1
-C
6
alkyl, aryl C
2
-C
6
alkenyl, aryl C
2
-C
6
alkynyl, formyl, and acetal; R
5
is selected from the group consisting of C
1
-C
6
alkyl, aryl C
1
-C
6
alkyl, hydroxy C
1
-C
6
alkyl, and halo C
1
-C
6
alkyl; and R
6
is selected from the group consisting of aryl, C
3
-C
7
cycloalkyl, and haloaryl; wherein the aryl is a phenyl or naphthyl; or a pharmaceutically acceptable salt thereof.
The present invention further provides compounds of formula (II)
wherein R
2
is a C
1
-C
6
alkyl; R
3
is selected from the group consisting of C
1
-C
6
alkoxy, C
1
-C
6
alkoxy C
1
-C
6
alkylsulfanyl, and C
1
-C
6
alkylsulfanyl; R
4
is selected from the group consisting of C
1
-C
6
alkyl, acetal, formyl, aryl C
2
-C
6
alkenyl, and aryl C
2
-C
6
alkynyl; R
5
is selected from the group consisting of C
1
-C
6
alkyl and aryl C
1
-C
6
alkyl; and R
6
is selected from the group consisting of aryl and C
3
-C
6
cycloalkyl; wherein said aryl is a phenyl or naphthyl; or a pharmaceutically acceptable salt thereof.
The present invention further provides pharmaceutical compositions comprising any of the aforesaid compounds and a method of treating a mammal comprising selectively blocking one or more of the adenosine receptors, particularly the A
3
adenosine receptors, of the mammal by administering to the mammal at least one compound of formulas I and II.
The present invention further provides a method of characterizing an adenosine receptor, particularly an A
3
receptor, in a substrate comprising contacting said substrate with a compound of the present invention and evaluating the interaction of the compound with the adenosine receptor.
The present invention further provides a method of inhibiting the binding of a ligand to an adenosine receptor, particularly an A
3
receptor, of a substrate comprising contacting the substrate with a compound of the present invention so that the compound binds to the adenosine receptor and inhibits the ligand from binding to the adenosine receptor.


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Beach et al.,A

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