Pharmaceutical compounds

Details Pharmaceutical compounds Pharmaceutical compounds

2000-12-19

2002-05-28

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S331000, C514S428000, C514S637000, C544S159000, C544S165000, C546S234000, C548S569000, C564S245000

Reexamination Certificate

active

06395735

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel indane-like compounds and to formulations containing such indane-like compounds as an active ingredient for pharmaceutical or veterinary use.
BACKGROUND OF THE INVENTION
Currently there are many drugs available for the treatment of disorders of the central nervous system. Amongst these drugs is a category known as antipsychotics for treating serious mental conditions such as psychosis, including but not limited to schizophrenia and schizophreniform illnesses. The skilled artisan will recognize that these psychotic conditions are characterized by hallucinations, delusions, or grossly disorganized behavior which indicate that the patient suffers from gross impairment in reality testing. Drugs having said antipsychotic activity can be useful for treating a variety of important psychotic disorders. The drugs commercially available for such conditions are often associated with undesirable side effects. There is a need for additional therapeutic choices to control or eliminate the symptoms in the safest and most effective way.
Furthermore, patients often do not respond or only partially respond to present drug treatment. and estimates of such partial- or non-responders has varied between 40% and 80% of those treated.
Ever since antipsychotics were introduced it has been observed that patients are liable to suffer from drug-induced extrapyramidal symptoms which include and tardive dystonia. The Simpson Angus Scale, Barnes Akathisia Rating Scale and Abnormal Involuntary Movement Scale (AIMS) are well known scales for assessing extrapyramidal symptoms. The great majority of drugs available for treatment of schizophrenia are prone to produce these extrapyramidal side effects when used at dosages that yield a beneficial effect on the symptoms of the disease. The severity of adverse events and/or lack of efficacy in a considerable number of patients frequently results in poor compliance or termination of treatment.
Many of the drugs are associated with a sedative effect and may also have an undesirable influence on the affective symptoms of the disease, causing depression. In some instances long term use of the drug leads to irreversible conditions, such as the tardive dyskinesia and tardive dystonia referred to supra.
A widely-used antipsychotic, haloperidol, is one such drug, which has been reported as causing a high incidence of extrapyramidal symptoms and may also cause tardive dyskinesia. More recently, clozapine, one of a large group of heterocyclic antipsychotics, has been introduced with the claim that it is free from extrapyramidal effects. However, the compound was found to cause agranulocytosis in some patients, a condition resulting in a lowered white blood cell count which can be life-threatening, and it may now only be employed under very strict medical observation and supervision.
The cholinergic deficits observed in Alzheimer's disease have given rise to the cholingeric hypothesis of dementia and spawned many efforts to develop therapies based on enhancement of central cholinergic transmission. The greatest efforts have focused on the use of acetylcholinesterase inhibitors and directly acting cholinomimetic drugs, but the results of clinical trials have been generally disappointing, potentially because the side effects seen with these agents prevent therapeutic doses from being employed. These intolerable side effects might be avoided by developing drugs that are functionally selective for muscarinic receptor subtypes.
Four pharmacologically distinct muscarinic receptor subtypes have been identified and designated M
1
-M
4
. Five genetically distinct human muscarinic receptors designated m
1
-m
5
have been cloned and characterized. The relationship between the two classifications are: M
1
=m
1
, M
2
=m
2
, M
3
=m
3
, and M
4
=m
4
. These muscarinic receptor subtypes are differentially located in the brain with high levels of the m
1
-m
3
receptors being located in the cortex and hippocampus, areas of the brain normally associated with cognition and learning.
Therefore, new compounds having antipsychotic activity as well as compounds which are agonists for the muscarinic receptors are highly desired.
SUMMARY OF THE INVENTION
The present invention provides a compound of the Formula I:
R
1
is selected from the group consisting of hydrogen, —OR
4
, —SR
5
, C
1
-C
3
alkyl, C
2
-C
3
alkenyl, halo, —CN, S(O)
m2
, —COR
4b′
, and —OC(O)—R
15
;
m2 is from 0 to 2;
R
2
is selected from the group consisting of C
1
-C
10
alkyl, substituted C
1
-C
10
alkyl, C
2
-C
10
alkenyl, substituted C
2
-C
10
alkenyl, C
3
-C
8
cycloalkyl, substituted C
3
-C
8
cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic;
R
4
is hydrogen, C
1
-C
3
alkyl;
R
5
is hydrogen, C
1
-C
3
alkyl;
R
10
is selected from the group consisting of hydrogen, carbonyl, halo, and C
1
-C
3
alkyl;
R
11
is selected from the group consisting of hydrogen and C
1
-C
3
alkyl;
R
12
is independently selected from the group consisting of hydrogen, C
1
-C
10
alkyl, and aryl;
R
13
is independently selected from the group consisting of hydrogen, C
1
-C
10
alkyl, and aryl; or
R
12
and R
13
together with the nitrogen to which they are attached form a group of the formula II:
 II′ wherein the II′ group is a group of Formula II which is unsaturated; or
R
11
and R
12
together with the nitrogen and carbon to which they are bound can join to form a three to six membered ring;
R
14
is selected from the group consisting of H, halo, C
1
-C
3
alkyl, S(O)
m3
and —OR
16
;
R
15
is C
1
-C
3
alkyl or aryl;
R
16
is C
1
-C
3
alkyl;
R
17
is independently selected from the group consisting of hydrogen, —OR
4′
, —SR
5′
, C
1
-C
3
alkyl, C
2
-C
3
alkenyl, halo, —CN, S(O)
m2′
, —COR
4b
, and —OC(O)—R
15′
;
R
4b
and R
4b′
are each independently selected from hydrogen and C
1
-C
3
alkyl;
R
15′
is C
1
-C
3
alkyl or aryl;
m2′ is 0 to 2;
R
4′
is hydrogen, C
1
-C
3
alkyl;
R
5′
is hydrogen, C
1
-C
3
alkyl;
m2is 0 to 2;
X is selected from the group consisting of CH
2
, O, S, NH, carbonyl, and a bond;
n′ is 0 to 2;
m′ is 0 to 2;
m3 is 0 to 2;
n is 0 to 3; or
a pharmaceutically acceptable salt or solvate thereof.
Further, the invention provides a method for treating psychosis comprising administering a compound of Formula I to a mammal in need of such treatment.
Additionally, the present invention provides a method for interacting with a muscarinic receptor comprising administering a compound of Formula I. Finally, the invention provides a formulation containing a compound of Formula I as an active ingredient.
Further this invention provides compounds of the Formula III
R
1
is selected from the group consisting of hydrogen, —OR
4
, —SR
5
, C
1
-C
3
alkyl, C
2
-C
3
alkenyl, halo, —CN, S(O)
m2
, —COR
4b′
, and —OC(O)—R
15
;
m2 is from 0 to 2;
R
2
is selected from the group consisting of C
1
-C
10
alkyl, substituted C
1
-C
10
alkyl, C
2
-C
10
alkenyl, substituted C
2
-C
10
alkenyl, C
3
-C
8
cycloalkyl, substituted C
3
-C
8
cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic;
R
4
is hydrogen, C
1
-C
3
alkyl;
R
5
is hydrogen, C
1
-C
3
alkyl;
R
10
is selected from the group consisting of hydrogen, carbonyl, halo, and C
1
-C
3
alkyl;
R
11
is selected from the group consisting of hydrogen and C
1
-C
3
alkyl;
R
12
is independently selected from the group consisting of hydrogen, C
1
-C
10
alkyl, and aryl;
R
13
is independently selected from the group consisting of hydrogen, C
1
-C
10
alkyl, and aryl; or
R
12
and R
13
together with the nitrogen to which they are attached form a group of the formula II:
 II′ wherein the II′ group is a group of Formula II which is unsaturated; or
R
11
and R
12
together with the nitrogen and carbon to which they are bound can join to form a three to s

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