Adenosine A2a receptor antagonists

Details Adenosine A2a receptor antagonists Adenosine A2a receptor antagonists

2002-10-11

2003-11-25

Shah, Mukund J. (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

06653315

ABSTRACT:

BACKGROUND
The present invention relates to substituted 5-amino-imidazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine adenosine A
2a
receptor antagonists, the use of said compounds in the treatment of central nervous system diseases, in particular Parkinson's disease, and to pharmaceutical compositions comprising said compounds.
Adenosine is known to be an endogenous modulator of a number of physiological functions. At the cardiovascular system level, adenosine is a strong vasodilator and a cardiac depressor. On the central nervous system, adenosine induces sedative, anxiolytic and antiepileptic effects. On the respiratory system, adenosine induces bronchoconstriction. At the kidney level, it exerts a biphasic action, inducing vasoconstriction at low concentrations and vasodilation at high doses. Adenosine acts as a lipolysis inhibitor on fat cells and as an antiaggregant on platelets.
Adenosine action is mediated by the interaction with different membrane specific receptors which belong to the family of receptors coupled with G proteins. Biochemical and pharmacological studies, together with advances in molecular biology, have allowed the identification of at least four subtypes of adenosine receptors: A
1
, A
2a
, A
2b
and A
3
. A
1
and A
3
are high-affinity, inhibiting the activity of the enzyme adenylate cyclase, and A
2a
and A
2b
are low-affinity, stimulating the activity of the same enzyme. Analogs of adenosine able to interact as antagonists with the A
1
, A
2
, A
2b
and A
3
receptors have also been identified.
Selective antagonists for the A
2a
receptor are of pharmacological interest because of their reduced level of side affects. In the central nervous system, A
2a
antagonists can have antidepressant properties and stimulate cognitive functions. Moreover, data has shown that A
2a
receptors are present in high density in the basal ganglia, known to be important in the control of movement. Hence, A
2a
antagonists can improve motor impairment due to neurodegenerative diseases such as Parkinson's disease, senile dementia as in Alzheimer's disease, and psychoses of organic origin.
Some xanthine-related compounds have been found to be A
1
receptor selective antagonists, and xanthine and non-xanthine compounds have been found to have high A
2a
affinity with varying degrees of A
2a
vs. A
1
selectivity. Triazolo-pyrimidine adenosine A
2a
receptor antagonists with different substitution at the 7-position have been disclosed previously, for example in WO 95/01356; U.S. Pat. No. 5,565,460; WO 97/05138; WO 98/52568 and US Provisional Application 60/334,342. Pyrazolo-substituted triazolo-pyrimidine adenosine A
2a
receptor antagonists are disclosed in WO 01/92264.
SUMMARY OF THE INVENTION
The present invention relates to a compound represented by the structural formula I
or a pharmaceutically acceptable salt thereof, wherein
R is R
1
-heteroaryl, R
10
-phenyl, C
4
-C
6
cycloalkenyl, —C(═CH
2
)CH
3
, —C≡C—CH
3
, —C≡C—CH
2
—OR
2
, —CH═C(CH
3
)
2
,
X is C
1
-C
6
alkylene, —C(O)CH
2
— or —C(O)N(R
2
)CH
2
—;
Y is —N(R
2
)CH
2
CH
2
N(R
3
)—, —OCH
2
CH
2
N(R
2
)—, —O—, —S—, —CH
2
S—, —(CH
2
)
2-3
N(R
2
)—, R
5
-divalent heteroaryl,
and Z is R
5
-phenyl, R
5
-phenyl(C
1
-C
6
)alkyl, R
5
-heteroaryl, R
5
-bicyclic heteroaryl, R
5
-benzofused heteroaryl, diphenylmethyl or R
6
—C(O)—;
or when Y is
Z is also R
1
—SO
2
—, R
7
—N(R
8
)—C(O)—, R
7
—N(R
8
)—C(S)— or R
6
OC(O)—;
or when Q is
Z is also phenylamino or pyridylamino;
or Z and Y together are
or Y and Z together form a piperidinyl or pyrrolidinyl ring fused to a monocyclic or bicyclic aryl or a monocyclic or bicyclic heteroaryl ring wherein X is attached to the N atom of the piperidinyl or pyrrolidinyl ring;
R
1
is 1 to 3 substituents independently selected from hydrogen, C
1
-C
6
-alkyl, —CF
3
, halogen, —NO
2
, —NR
12
R
13
, C
1
-C
6
alkoxy, C
1
-C
6
alkylthio, C
1
-C
6
alkylsulfinyl, C
1
-C
6
, alkylsulfonyl, —COOR
7
or —C(O)NR
2
R
3
;
R
2
and R
3
are independently selected from the group consisting of hydrogen and C
1
-C
6
alkyl;
m and n are independently 2-3;
p and q are independently 0-2;
Q and Q
1
are independently selected from the group consisting of
provided that at least one of Q and Q
1
is
R
4
is 1-2 substituents independently selected from the group consisting of hydrogen, C
1
-C
6
alkyl, R
1
-aryl and R
1
-heteroaryl, or two R
4
substituents on the same carbon can form ═O;
R
5
is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C
1
-C
6
alkyl, hydroxy, C
1
-C
6
alkoxy, —CN, di—((C
1
-C
6
)alkyl)amino, —CF
3
, —OCF
3
, acetyl, —NO
2
, hydroxy(C
1
-C
6
)alkoxy, (C
1
-C
6
)-alkoxy(C
1
-C
6
)alkoxy, di—((C
1
-C
6
)-alkoxy)(C
1
-C
6
)alkoxy, (C
1
-C
6
)-alkoxy(C
1
-C
6
)alkoxy—(C
1
-C
6
)-alkoxy, carboxy(C
1
-C
6
)-alkoxy, (C
1
-C
6
)-alkoxycarbonyl(C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkoxy, di—((C
1
-C
6
)alkyl)amino(C
1
-C
6
)alkoxy, morpholinyl, (C
1
-C
6
)alkyl—SO
2
—, (C
1
-C
6
)alkyl—SO
2
-(C
1
-C
6
)alkoxy, tetrahydropyranyloxy, (C
1
-C
6
)alkylcarbonyl(C
1
-C
6
)-alkoxy, (C
1
-C
6
)-alkoxycarbonyl, (C
1
-C
6
)alkylcarbonyloxy(C
1
-C
6
)-alkoxy, —SO
2
NH
2
, phenoxy,
(R
2
O)
2
—P(O)—CH
2
—O— and (R
2
O)
2
—P(O)—; or adjacent R
5
substituents together are —O—CH
2
—O—, —O—CH
2
CH
2
—O—, —O—CF
2
—O— or —O—CF
2
CF
2
—O— and form a ring with the carbon atoms to which they are attached;
R
6
is (C
1
-C
6
)alkyl, R
5
-phenyl, R
5
-phenyl(C
1
-C
6
)alkyl, thienyl, pyridyl, (C
3
-C
6
)—cycloalkyl, (C
1
-C
6
)alkyl—OC(O)—NH—(C
1
-C
6
)alkyl—, di—((C
1
-C
6
)alkyl)aminomethyl, or
R
7
is (C
1
-C
6
)alkyl, R
5
-phenyl or R
5
-phenyl(C
1
-C
6
)alkyl;
R
8
is hydrogen or C
1
-C
6
alkyl; or R
7
and R
8
together are —(CH
2
)
p
—A—(CH
2
)
q
, wherein p and q are independently 2 or 3 and A is a bond, —CH
2
—, —S—or —O—, and form a ring with the nitrogen to which they are attached;
R
9
is 1-2 substituents independently selected from the group consisting of hydrogen, C
1
-C
6
alkyl, hydroxy, C
1
-C
6
alkoxy, halogen, —CF
3
and (C
1
-C
6
)alkoxy-(C
1
-C
6
)alkoxy;
R
10
is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C
1
-C
6
alkyl, hydroxy, C
1
-C
6
alkoxy, —CN, —NH
2
, C
1
-C
6
alkylamino, di—((C
1
-C
6
)alkyl)amino, —CF
3
, —OCF
3
, —S(O)
0-2
(C
1
-C
6
)alkyl and —CH
2
—SO
2
-phenyl;
R
11
is H, C
1
-C
6
alkyl, phenyl, benzyl, C
2
-C
6
alkenyl, C
1
-C
6
alkoxy(C
1
-C
6
)alkyl, di-((C
1
-C
6
)alkyl)amino(C
1
-C
6
)alkyl, pyrrolidinyl(C
1
-C
6
)alkyl or piperidino(C
1
-C
6
)alkyl;
R
12
is H or C
1
-C
6
alkyl;
R
13
is H, (C
1
-C
6
)alkyl—C(O)— or (C
1
-C
6
)alkyl—SO
2
—;
R
14
is H, halogen, C
1
-C
6
alkyl, hydroxy(C
1
-C
6
)alkyl, C
1
-C
6
alkoxy(C
1
-C
6
)alkyl, thio(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylthio(C
1
-C
6
)alkyl or NR
2
R
3
—(C
1
-C
6
)alkyl; and
R
15
is H, halogen, C
1
-C
6
alkyl or C
1
-C
6
alkoxy.
Another aspect of the invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I in a pharmaceutically acceptable carrier.
Yet another aspect of the invention is a method of treating central nervous system diseases such as depression, cognitive diseases and neurodegenerative diseases such as Parkinson's disease, senile dementia or psychoses of organic origin, or stroke, comprising administering a compound of formula I to a mammal in need of such treatment. In particular, the invention is drawn to the method of treating Parkinson's disease comprising administering a compound of formula I to a mammal in need of such treatment.
Still another aspect of the invention is a method of treating Parkinson's disease with a combination of a compound of formula I and one or more agents useful in the treatment of Parkinson's disease, for example dopamine; a dopaminergic agonist; an inhibitor of monoamine oxidase, type B (MAO-B); a DOPA decarboxylase inhibitor (DCI); or a catechol-O-methyltransferase (COMT) inhibitor. Also claimed is a pharmaceutical co

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