Adenosine receptor ligands and their use in the treatment of...

Details Adenosine receptor ligands and their use in the treatment of... Adenosine receptor ligands and their use in the treatment of...

2001-02-20

2003-07-01

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...

C514S258100, C514S266100, C514S299000, C514S307000, C514S311000, C514S326000, C514S329000, C544S253000, C544S298000, C544S319000, C544S320000, C544S321000, C546S112000, C546S139000, C546S152000, C546S212000, C546S215000, C546S216000, C546S223000

Reexamination Certificate

active

06586441

ABSTRACT:

FIELD OF THE INVENTION
The present invention is generally related to compounds useful as adenosine receptor ligand and more particularly to compounds showing activity as modulators of the andenosine receptor system.
BACKGROUND OF THE INVENTION
Several compounds related to general formula I have been reported.
The present invention relates to the use of compounds of the general formula
wherein
A is a bond, —S—, —N(R)—, —(CH
2
)
2
—, —CH═CH—, —C≡C— or —O—;
X/Y are independently from each other —N═ or ═N—, —CH═ or ═CH—, —C(cyano)═ or ═C(cyano)—, or —C[C(S)—NH
2
]═ or ═—C[C(S)—NH
2
]—, wherein at least one of X or Y is nitrogen;
R
1
is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, halogen, cyano, cycloalkyl or the following groups
—(CH
2
)
n
—C(O)O-lower alkyl,
—(CH
2
)
n
—C(O)O-lower alkyl-phenyl,
—(CH
2
)
n
—NH—C(O)O-lower alkyl-phenyl,
—(CH
2
)
n
—O-lower alkyl,
—(CH
2
)
n
—O-phenyl,
—(CH
2
)
n
—NH-phenyl,
—(CH
2
)
n
-phenyl, optionally substituted by 1 or 2 substituents, selected from hydroxy, lower alkoxy, lower alkyl, CF
3
-lower alkenyl, halogen, CF
3
, OCF
3
, amino,
—(CH
2
)
n
—N-di-lower alkyl, —C(O)NH-lower alkyl or —S(O)
2
-lower alkyl, or is —(CH
2
)
n
-morpholinyl,
—(CH
2
)
n
-amino, optionally substituted by lower alkyl or benzyl,
—(CH
2
)
n
-piperidin-1-yl or —(CH
2
)
n
-piperidin-3-yl, which are optionally substituted by lower alkyl,
—(CH
2
)
n
-pyridin-2-yl, —(CH
2
)
n
-pyridin-3-yl or —(CH
2
)
n
-pyridin-4-yl, which are optionally substituted by 1 or 2 substituents, selected from lower alkyl, hydroxy, nitro, cyano, halogen, CF
3
or —OC(O)N(R)
2
, or is
—(CH
2
)
n
—NH-pyridin-2-yl, optionally substituted by lower alkyl or halogen,
—(CH
2
)
n
-piperazin-4-yl, optionally substituted by lower alkyl, phenyl or carbonyl-phenyl,
—(CH
2
)
n
-phenyl—OC(O)-phenyl, optionally substituted by halogen, or the group
—(CH
2
)
n
—S-phenyl or —(CH
2
)
n
—S(O)
2
-phenyl,
—(CH
2
)
n
—S-lower alkyl,
—(CH
2
)
n
(CH═CH)
m
-phenyl,
—(CH
2
)
n
(CH≡CH)
m
-phenyl,
—(CH
2
)
n
—NH-cycloalkyl,
—(CH
2
)
n
—NH-phenyl, optionally substituted by amino or nitro,
—(CH
2
)
n
-tetrahydro-pyran-4-yl,
—(CH
2
)
n
-quinolin-2-yl,
—(CH
2
)
n
-naphthyl or —(CH
2
)
n
—NH-naphthyl,
—(CH
2
)
n
-3,4-dihydro-1H-isoquinolin-2-yl,
—(CH
2
)
n
—benzo[1,3]dioxolyl,
—(CH
2
)
n
—NH—S(O)
2
-phenyl, optionally substituted by halogen,
—(CH
2
)
n
-1,2,3,4-tetrahydro-quinolin-2-yl, optionally substituted by lower alkyl or
—(CH
2
)
n
-furanyl;
R
2
is hydrogen, halogen, cyano, nitro, lower alkyl, lower alkenyl, —C(O)-lower alkyl, —C(O)O-lower alkyl, —C(O)O-lower alkyl-phenyl, lower alkynyl-phenyl, lower alkenyl-C(O)O-lower alkyl, lower alkenyl-cyano or phenyl, optionally substituted by halogen;
R
3
is lower alkyl, or
phenyl, which is optionally substituted by lower alkyl, lower alkoxy, or halogen, or is thien-2-yl or fur-2-yl, which is optionally substituted by lower alkyl,
S-lower alkyl, halogen, lower alkoxy, —C(O)O-lower alkyl, —C(═CH
2
)-O-lower alkyl,
—(CH
2
)
n
-halogen, —(CH
2
).-OH, —(CH
2
)
n
-lower alkoxy, cyano, CHF
2
, or CH
2
F, or is 2,3-dihydro-benzo[1.4]dioxin-6-yl,
benzo[1.3]dioxol-5-yl,
isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl,
—C(═CH
2
)O-lower alkyl,
4,5-dihydrofuran-2-yl,
5,6-dihydro-4H-pyran-2-yl,
oxazol-2-yl,
benzofuranyl,
pyrazin-2-yl,
—O—(CH
2
)
n
phenyl,
—O—(CH
2
)
n
-pyridyl, optionally substituted by lower alkyl,
—S—(CH
2
)
n
-pyridyl,
or pyrazol-1-yl, optionally substituted by lower alkyl or halogen;
R
4
/R
5
are independently from each other hydrogen, —CO—(CH
2
)
n
-phenyl, optionally substituted by halogen or —CH
2
N(R)(CH
2
)
n
-lower alkyl, or is phenyl, optionally substituted by lower alkoxy, or —C(O)-phenyl;
R is hydrogen or lower alkyl; or
A and R
2
may be together with the two carbon atoms
and
n is 0, 1, 2, 3, or 4;
m is 1 or 2;
and to their pharmaceutically acceptable salts.
A number of compounds of formula I are known, and are described in the following documents:
Tetrahedron Let., (1969), 247-250, used as intermediates;
Journal fuar prakt. Chemieg 320, (1978), 576-584, synthesis;
Synthesis, (1983), 402-404, used as intermediates;
Journ. of Heterocycl. Chem, 24, (1987), 1305-1307, synthesis;
Heterocycles, 36, (1993), 2281-2290, used for the treatment of AIDS;
EP 806418, used for the treatment of rotaviral diseases and acute gastroentritis;
JP 08134044, uses as antiviral agent; or
DE 24 59 629, used as hypotensive and analgesic agents.
It has now surprisingly been found that the compounds of general formula I are adenosine receptor ligands, and these compounds are therefore useful in the treatment of diseases, based on the modulation of the adenosine system.
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 subtypes 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. proteins inhibit adenylate cyclase, leading to a decrease in cellular cAMP levels, while A2A and A2B 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) has been cloned from various species (canine, human, rat, dog, chick, bovine, guinea-pig) with 90-95% sequence identity among the mammalian species. The A
2A
receptor (409-412 amino acids) has been cloned from canine, rat, human, guinea pig and mouse. The A
2B
receptor (332 amino acids) has been 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) has been 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

Affiliated with

Also associated with

Rating

Adenosine receptor ligands and their use in the treatment of... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Adenosine receptor ligands and their use in the treatment of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Adenosine receptor ligands and their use in the treatment of... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3015429