Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-11-08
2004-11-02
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S089000
Reexamination Certificate
active
06812228
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to treatment of movement disorders such as Parkinson's disease using certain benzoxazine compounds.
BACKGROUND OF THE INVENTION
Movement disorders are progressive neurodegenerative diseases characterized by hypokinesia, tremor, and muscular rigidity. One of the most common movement disorders is Parkinson's disease (PD). 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 movement disorders such as 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 now been five muscarinic receptor subtypes identified, and they are referred to as M
1
, M
2
, M
3
, M
4
, and M
5
receptors. These 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 cause reduced contractility and heart rate, while M
3
receptors cause contraction of smooth muscles. For muscarinic receptors in brain tissue, the M
1
receptors are responsible for memory and learning, the M
2
receptors are responsible for control of autonomic functions, and the M
4
receptors control motor behavior.
Compounds that antagonize muscarinic receptors have been developed for treatment of neurodegenerative diseases and movement disorders 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 responsible for motor function. Accordingly, compounds that selectively antagonize the M
4
receptor would be useful as treatments for movement disorders such as PD, without adversely affecting other body functions controlled by the other muscarinic receptor subtypes.
Augelli-Szafram et al., describe a series of benzoxazines that are said to be M4 selective muscarinic antagonists (
Bioorg. Med. Chem. Lett.
8,1998;1991-1996). The compounds permit only hydrogen and methyl at the 2-position. We have now found a group of benzoxazine compounds having longer chain alkyl groups at the 2-position that are surprisingly potent and selective antagonists at the M
4
receptor. An object of this invention is to provide the compounds as new chemical entities, and a method for treating movement disorders utilizing such compounds.
SUMMARY OF THE INVENTION
This invention provides certain benzoxazine compounds, pharmaceutical compositions comprising them, and a method for treating movement disorders by administering them. More particularly, the invention is a benzoxazine of Formula I
or a pharmaceutically acceptable salt thereof, wherein:
R
1
is C
1
-C
6
allyl, C
2
-C
6
alkenyl, or (CH2)
n
phenyl;
R
2
is C
3
-C
6
alkyl;
R
3
is hydrogen, halo, hydroxy, O—C
1
-C
6
alkyl, or S—C
1
-C
6
alkyl;
R
4
is hydrogen, C
1
-C
6
alkyl, or (CH
2
)
n
phenyl; and
n is an integer from 0 to 3.
Preferred compounds have Formula I wherein R
2
is n-propyl.
Also preferred are compounds of Formula I wherein R
1
is ethyl.
The most preferred compounds have Formula I wherein R
1
is ethyl, R
2
is n-propyl, R
4
is hydrogen or methyl, and R
3
is OCH
3
or SCH
3
.
Another embodiment of the invention is a pharmaceutical composition comprising a compound of Formula I together with a pharmaceutically acceptable diluent, excipient, or carrier therefor.
Another embodiment is a method for treating movement disorders such as Parkinson's disease comprising administering to a patient in need of treatment a compound of Formula I.
REFERENCES:
Augelli-Szafran et al., “Identification and Characterization of m 4 Selective Muscarinic Antagonists”,Bioorg Med Chem Lett B, 1998, pp. 1991-1996.
Augelli-Szafran Corinne Elizabeth
Boehme Thomas
Schwarz Roy Douville
Raymond Richard L.
Scully Scott Murphy & Presser
Warner-Lambert & Company
LandOfFree
Benzoxazines for use in the treatment of parkinson's... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Benzoxazines for use in the treatment of parkinson's..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Benzoxazines for use in the treatment of parkinson's... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3311602