Substituted bicyclic derivatives for treating central...

Details Substituted bicyclic derivatives for treating central... Substituted bicyclic derivatives for treating central...

1999-04-27

2002-04-16

McKane, Joseph K. (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S321000, C544S359000, C544S376000, C544S377000, C546S196000, C546S197000

Reexamination Certificate

active

06372762

ABSTRACT:

BACKGROUND TO THE INVENTION
The present invention relates to novel substituted bicyclic derivatives that are dopamine receptor subtype ligands having a preference for the D4-dopamine receptor. These compounds exhibit central dopaminergic activity, as defined below, and are useful in the treatment and prevention of disorders of the dopamine system, including schizophrenic and schizo-affective disorders, akinesia, dementia, Parkinson's disease, nausea, bipolar disorders, emesis, tardive dyskinesia, extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, hyperprolactemia and amenorrhoea.
It is known that dopamine receptors are important for many functions in mammals. For example, altered functions of these receptors are thought to participate in the genesis of psychosis, drug addiction, compulsive disorders, bipolar disorders, vision, emesis, sleep, feeding, learning, memory, sexual behavior, regulation of immunological responses and blood pressure.
SUMMARY OF THE INVENTION
This invention relates to compounds of the formula 1
and to pharmaceutically acceptable salts and solvates thereof wherein:
each dashed line in the above formula represents an optional double bond, provided that both dashed lines do not simultaneously represent a double bond;
X
1
and X
2
are each independently selected from O and —(CH
2
)
j
— wherein j is 1 or 2, provided that no O is doubly-bonded to an adjacent atom;
X
3
is —CH(R
5
)N(R
8
)CH(R
6
)—, —CH(R
5
)C(R
8
)(R
9
)CH(R
6
)—, —C(R
5
)═C(R
8
)CH(R
6
)—, or —CH(R
5
)C(R
8
)═C(R
6
)—;
R
1
and R
2
are each independently H, hydroxy, or C
1
-C
6
alkyl;
or R
1
and R
2
are taken together as a bond;
each R
3
is independently selected from —S(O)
j
R
7
wherein j is an integer ranging from 0 to 2, —C(O)R
7
, —OR
7
, —NC(O)R
7
, —NR
7
R
12
, and the substituents provided in the definition of R other than H;
R
4
is absent where the dashed line in the above formula 1 represents a double bond or R
4
is selected from H and the substituents provided in the definition of R
3
;
or R
3
and R
4
are taken together with the carbon atom to which each is attached to form a 5-10 membered mono-cyclic or bicyclic group wherein said cyclic group may be carbocyclic or heterocyclic with 1 to 3 heteroatoms selected from O, S, and —N(R
11
)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said cyclic group is saturated or partially unsaturated; aromatic or non-aromatic; 1 or 2 of the carbon atoms in said cyclic group optionally may be replaced by an oxo —C(O)— moiety; and said cyclic group is optionally substituted by 1 to 3 R
10
groups;
R
5
and R
6
are each independently selected from H and C
1
-C
4
alkyl;
or R
5
and R
6
are taken together as —(CH
2
)
q
— wherein q is 2 or 3;
or R
5
or R
6
is taken together with R
8
as defined below;
each R
7
is independently selected from H, —(CH
2
)
t
(C
6
-C
10
aryl) and —(CH
2
)
t
(4-10 membered heterocyclic), wherein t is an integer ranging from 0 to 5; 1 or 2 of the carbon atoms of said heterocyclic group optionally may be replaced with an oxo —C(O)— group; said aryl and heterocyclic R
7
groups are optionally fused to a benzene ring, a C
5
-C
8
saturated cyclic group, or a 4-10 membered heterocyclic group; the —(CH
2
)
t
— moieties of the foregoing R
7
groups optionally include a carbon—carbon double or triple bond where t is an integer between 2 and 5; and the foregoing R
7
groups, except H, are optionally substituted by 1 to 5 R
10
groups;
R
8
is selected from the substituents provided in the definition of R
7
other than H;
R
9
is selected from the substituents provided in the definition of R
7
;
or R
8
and R
9
are taken together with the carbon to which each is attached to form a 5-10 membered mono-cyclic or bicyclic group wherein said cyclic group is carbocyclic or heterocyclic with 1 to 3 heteroatoms selected from O, S, and —N(R
11
)— with the proviso that two O atoms, two S atoms, or an 0 and S atom are not attached directly to each other; saturated or partially unsaturated; aromatic or non-aromatic; 1 or 2 of the carbon atoms in said cyclic group optionally may be replaced by an oxo —C(O)— moiety; and said cyclic group is optionally substituted by 1 to 3 R
10
groups;
or R
8
taken together with either R
5
or R
6
and the separate carbon atoms to which each is attached to form a fused 5-10 membered mono-cyclic or bicyclic group wherein said cyclic group may be carbocyclic or heterocyclic with 1 to 3 heteroatoms selected from O, S, and —N(R
11
)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; saturated or partially unsaturated; aromatic or non-aromatic; 1 or 2 of the carbon atoms in said cyclic group optionally may be replaced by an oxo —C(O)— moiety; and said cyclic group is optionally substituted by 1 to 3 R
10
groups;
each R
10
is independently selected from C
1
-C
10
alkyl, C
2
-C
10
, alkenyl, C
2
-C
10
alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR
11
, —C(O)R
11
, —C(O)O
R
11
, —NR
12
C(O)OR
11
, —OC(O)R
11
, —NR
12
SO
2
R
11
, —SO
2
NR
11
R
12
, —NR
12
C(O)R
11
, —C(O)NR
11
R
12
, —NR
11
R
12
, —S(O)
j
(C
1
-C
6
alkyl) wherein j is an integer ranging from 0 to 2, —(CH
2
)
m
(C
6
-C
10
aryl), —SO
2
(CH
2
)
j
(C
6
-C
10
aryl), —S(CH
2
)
m
(C
6
-C
10
aryl), —O(CH
2
)
m
(C
6
-C
10
aryl) and —(CH
2
)
m
(4-10 membered heterocyclic), wherein m is an integer ranging from 0 to 4; said C
1
-C
10
alkyl group optionally contains 1 or 2 hetero moieties selected from O, S and —N(R
12
)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic R
10
groups are optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, aryl and heterocyclic R
10
groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —NR
12
SO
2
R
11
, —SO
2
NR
11
R
12
, —C(O)R
11
, —C(O)OR
11
, —OC(O)R
11
, —NR
12
C(O)R
11
, —C(O)NR
11
R
12
, —NR
11
R
12
, C
1
-C
6
alkyl, —OR
11
and the substituents listed in the definition of R
11
;
each R
11
is independently selected from H, C
1
-C
10
alkyl, —(CH
2
)
m
(C
6
-C
10
aryl), and —(CH
2
)
m
(4-10 membered heterocyclic), wherein m is an integer ranging from 0 to 4; said alkyl group optionally includes 1 or 2 hetero moieties selected from O, S and —N(R
12
)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic R
11
groups are optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R
11
substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R
12
, —C(O)OR
12
, —CO(O)R
12
, —NR
12
C(O)R
13
, —C(O)NR
12
R
13
, —NR
12
R
13
, hydroxy, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy; and,
each R
12
and R
13
is independently H or C
1
-C
6
alkyl.
In an emobdiment of the invention, compounds of the invention of formula 1 have the following structure
wherein R
1
, R
2
, R
3
, R
4
, X
1
, X
2
, and X
3
are as defined above.
Other embodiments of the compounds of formula 1 include those wherein formula 1 has the following structure
wherein R
3
is —(CH
2
)
t
(C
6
-C
10
aryl) or —(CH
2
)
t
(4-10 membered heterocyclic), R
4
is H or hydroxy, and R
1
is —(CH
2
)
t
(C
6
-C
10
aryl) or —(CH
2
)
t
(4-10 membered heterocyclic), t is an integer ranging from 0 to 5, and the foregoing R
3
and R
8
heterocyclic groups are optionally fused to a 5 benzene ring, and said R
3
and R
8
groups are optionally substituted by 1 to 3 R
10
groups. More specific embodiments include those wherein R
8
and R
3
are each independently selected from phenyl and pyrimidyl, optionally substituted by 1 to 3 substituen

Affiliated with

Also associated with

Rating

Substituted bicyclic derivatives for treating central... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Substituted bicyclic derivatives for treating central..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted bicyclic derivatives for treating central... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2826501