Fused ring system containing indole as M4 selective...

Details Fused ring system containing indole as M4 selective... Fused ring system containing indole as M4 selective...

2001-09-14

2002-12-31

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S053000, C546S050000

Reexamination Certificate

active

06500837

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to fused-ring compounds containing an indole. This invention further relates to compounds that selectively bind to the M
4
muscarinic receptor. In addition, this invention relates to a method of treating Parkinson's disease.
BACKGROUND OF THE INVENTION
Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by hypokinesia, tremor, and muscular rigidity. It results in a slowing of voluntary movements, a festinating gait, peculiar posture, and general weakness of muscles. There is progressive degeneration within the nuclear masses of the extrapyramidal system, and a characteristic loss of melanin-containing cells from the substantia nigra and a corresponding reduction in dopamine levels in the corpus striatum. The cause of PD is unknown, but it is widely believed that multifactorial genetic and environmental factors are contributors. While the disease can develop at any age, it is most common in adults, and typically afflicts people at about sixty years of age and older. Parkinson's disease is becoming a particularly serious disease given the aging population.
There are no known cures for PD. The most common treatment has been the administration of levodopa, the precursor to dopamine, whose concentration in the substantia nigra is known to diminish as the disease progresses. Levodopa often produces unpleasant complications, resulting in even more serious health problems that are untreatable.
There are a group of monomeric proteins called muscarinic receptors found throughout the body of animals, including humans. These muscarinic receptors are present in the central nervous system, the peripheral nervous system, and in peripheral organs. There have been five muscarinic receptor subtypes identified, and they are referred to as M
1
, M
2
, M
3
, M
4
, and M
5
receptors. The various receptors are present throughout the body, and the individual subtypes seem to be responsible for different actions. For example, in peripheral tissues, M
1
receptors amplify ganglionic neurotransmission. M
2
receptors are involved in contractility and heart rate, while M
3
receptors mediate contraction of smooth muscles. For muscarinic receptors in brain tissue, the M
1
receptors play a role in memory and learning, the M
2
receptors influence autonomic functions, and there is evidence that M
4
receptors control motor behavior.
Compounds that antagonize muscarinic receptors have been developed for treatment of neurodegenerative diseases such as PD. Because the various muscarinic receptor subtypes are expressed in numerous body tissues, and each subtype appears to control or effect a different bodily function, it would be useful to find compounds that are selective for a single subtype. The M
4
subtype is found in high levels in the striatum of the brain and is involved in motor function. Accordingly, compounds that selectively antagonize the M
4
receptor would be useful as treatments for PD, without adversely affecting other body functions controlled by the other muscarinic receptor subtypes.
SUMMARY OF THE INVENTION
The present invention provides compounds that are useful in a method of selectively antagonizing the M
4
muscarinic receptor, the method comprising the administration of an effective amount of such a compound to a subject, preferably mammalian, in need thereof.
The present invention is directed to fused-ring derivatives containing an indole and their use as antagonists of the M
4
muscarinic receptor. The compounds of the invention are those having the structure of Formula I:
wherein:
R
1
is hydrogen, lower alkyl or COOR
7
, or aryl, heteroaryl, arylalkyl or heteroarylalkyl optionally substituted with one, two, or three groups independently selected from hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, mono- or dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, sulfamoyl, trifluoromethyl, or alkylthio;
R
3
is hydrogen or lower alkyl;
R
2
, R
4
, R
5
, and R
6
independently represent hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, mono- or dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, sulfamoyl, trifluoromethyl, or alkylthio;
R
7
is hydrogen or lower alkyl;
—may or may not be a bond; and
R
8
is hydrogen or oxo.
The instant invention includes pharmaceutical compositions of compounds of Formula 1 and a method of treating PD, the method comprising administering to a patient having PD a therapeutically effective amount of a compound of Formula I.
Also provided is a method of selectively antagonizing the M
4
muscarinic receptor, the method comprising administering to a patient in need selectively antagonizing the M
4
muscarinic receptor an M
4
muscarinic receptor antagonizing amount of a compound of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds encompassed by the instant invention are those described by the general Formula I set forth above, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof
Preferred compounds of Formula I are those in which R
1
is COOR
7
; R
2
is lower alkyl or (un)substituted aryl or heteroaryl; R
3
is hydrogen; R
4
is hydrogen or halogen; R
5
is lower alkoxy, alkylthio, lower alkyl, or halogen; R
6
is hydrogen; R
7
is lower alkyl; and R
8
is hydrogen.
More preferred compounds of Formula I are those where R
2
are methyl, ethyl, n-propyl, or (un)substituted heteroaryl; R
4
is hydrogen or bromo; and R
5
is lower alkyl or alkylthio.
In addition to the compounds of Formula I, the invention encompasses compounds of Formula II:
wherein R
1
, R
2
, R
3
, R
4
, and R
5
are as defined above for Formula I.
Preferred compounds of Formula II are those where R
1
is COOR
7
; R
2
is lower alkyl or (un)substituted aryl or heteroaryl; R
3
is hydrogen; R
4
is hydrogen or halogen; R
5
is lower alkoxy, alkylthio, lower alkyl, or halogen; and R
7
is lower alkyl.
In addition, the invention encompasses compounds of Formula III:
wherein R
2
, R
3
, R
4
, R
5
, and R
6
are as defined above for Formula I.
Preferred compounds of Formula III are those where R
2
is lower alkyl or (un)substituted aryl or heteroaryl; R
3
is hydrogen; R
4
is hydrogen or halogen; R
5
is lower alkoxy, alkylthio, lower alkyl, or halogen; R
6
is hydrogen; and R
7
is lower alkyl.
In addition, the invention encompasses compounds of Formula IV:
Preferred compounds of Formula IV are those in which R
1
is COOR
7
; R
2
is lower alkyl or (un)substituted aryl or heteroaryl; R
4
is hydrogen or halogen; R
5
is lower alkoxy, alkylthio, lower alkyl, or halogen; R
6
is hydrogen; and R
7
is lower alkyl.
Except as expressly defined otherwise, the following definition of terms is employed throughout this specification.
The terms “alkyl,” “lower alkyl,” or “(C
1
-C
6
)-alkyl” mean a straight or branched hydrocarbon having from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. The alkyl group can also be substituted with one or more of the substituents listed below for aryl.
By “alkoxy,” “lower alkoxy,” or “(C
1
-C
6
)-alkoxy” in the present invention is meant straight or branched chain alkoxy groups having 1 to 6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
The term “halogen” includes chlorine, fluorine, bromine, and iodine, and their monovalent radicals.
The term “aryl” means an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), unsubstituted or substituted by 1 to 3 substituents selected from alkyl, O-alkyl and S-alkyl, OH, SH, —CN, halogen, 1,3-dioxolanyl, CF
3
, NO
2
, NH
2
, NHCH
3
, N(CH
3
)
2
, NHCO-alkyl, —(CH
2
)
m
CO
2
H, —(CH
2
)
m
CO
2
-alkyl, —(CH
2
)

Affiliated with

Also associated with

Rating

Fused ring system containing indole as M4 selective... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Fused ring system containing indole as M4 selective..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Fused ring system containing indole as M4 selective... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2997135