Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2002-11-15
2004-03-09
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S252120, C514S315000, C514S357000, C514S394000, C514S438000, C514S459000, C514S471000, C514S601000, C544S401000, C544S398000, C546S246000, C546S338000, C548S340100, C548S335100, C549S075000, C549S426000, C549S495000
Reexamination Certificate
active
06703425
ABSTRACT:
In the mammalian central nervous system (CNS), the transmission of nerve impulses is controlled by the interaction between a neurotransmitter, that is released by a sending neuron, and a surface receptor on a receiving neuron, which causes excitation of this receiving neuron. L-Glutamate, which is the most abundant neurotransmitter in the CNS, mediates the major excitatory pathway in mammals, and is referred to as an excitatory amino acid (EAA). The receptors that respond to glutamate are called excitatory amino acid receptors (EAA receptors). See Watkins & Evans,
Ann. Rev. Pharmacol. Toxicol
., 21, 165 (1981); Monaghan, Bridges, and Cotman,
Ann. Rev. Pharmacol. Toxicol
., 29, 365 (1989); Watkins, Krogsgaard-Larsen, and Honore,
Trans. Pharm. Sci
., 11, 25 (1990). The excitatory amino acids are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.
Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed “ionotropic”. This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5methylisoxazole4-propionic acid (AMPA), and kainic acid (KA). The second general type of receptor is the G-protein or second messenger-linked “metabotropic” excitatory amino acid receptor. This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in c-AMP formation, and changes in ion channel function. Schoepp and Conn,
Trends in Pharmacol. Sci
., 14, 13 (1993). Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek,
Trends in Pharmacol. Sci
., 11, 508 (1990); McDonald and Johnson,
Brain Research Reviews
, 15, 41 (1990).
AMPA receptors are assembled from four protein sub-units known as GluR1 to GluR4, while kainic acid receptors are assembled from the sub-units GluR5 to GluR7, and KA-1 and KA-2. Wong and Mayer,
Molecular Pharmacology
44:505-510, 1993. It is not yet known how these sub-units are combined in the natural state. However, the structures of certain human variants of each sub-unit have been elucidated, and cell lines expressing individual sub-unit variants have been cloned and incorporated into test systems designed to identify compounds which bind to or interact with them, and hence which may modulate their function. Thus, European patent application, publication number EP-A2-0574257 discloses the human sub-unit variants GluR1B, GluR2B, GluR3A and GluR3B. European patent application, publication number EP-A1-0583917 discloses the human sub-unit variant GluR4B.
One distinctive property of AMPA and kainic acid receptors is their rapid deactivation and desensitization to glutamate. Yamada and Tang,
The Journal of Neuroscience
, September 1993, 13(9):3904-3915 and Kathryn M. Partin,
J. Neuroscience
, Nov. 1, 1996, 16(21):6634-6647.
It is known that the rapid desensitization and deactivation of AMPA and/or kainic acid receptors to glutamate may be inhibited using certain compounds. This action of these compounds is often referred to in the alternative as “potentiation” of the receptors. One such compound, which selectively potentiates AMPA receptor function, is cyclothiazide. Partin et al.,
Neuron. Vol
. 11, 1069-1082, 1993.
International Patent Application Publication WO 98/33496 published Aug. 6, 1998 discloses certain sulfonamide derivatives which are useful, for example, for treating psychiatric and neurological disorders, for example cognitive disorders; neuro-degenerative disorders such as Alzheimer's disease; age-related dementias; age-induced memory impairment; movement disorders such as tardive dyskinesia, Huntington's chorea, myoclonus, and Parkinson's disease; reversal of drug-induced states (such as cocaine, amphetamines, alcohol-induced states); depression; attention deficit disorder; attention deficit hyperactivity disorder, psychosis; cognitive deficits associated with psychosis, and drug-induced psychosis.
The present invention provides compounds of formula I:
wherein A represents
R represents hydrogen or (1-4C)alkyl;
R
1
represents (1-6C)alkyl, (2-6C)alkenyl, or NR
9
R
10
;
R
2
and R
3
each independently represent hydrogen, (1-4C)alkyl, F, or —OR
11
;
R
4a
and R
4b
each independently represent hydrogen, (1-4C) alkyl, (1-4C)alkoxy, I, Br, Cl, or F;
R
5
and R
6
each independently represent hydrogen, (1-4C)alkyl, F, or —OR
11
;
R
7
represents hydrogen, or (1-4C)alkyl;
R
8
represents (1-6C)alkyl, unsubstituted or substituted aromatic group, unsubstituted or substituted heteroaromatic group, cycloalkyl, or alkylcycloalkyl;
n is zero or an integer 1, 2, 3, 4, or 5;
m is zero or an integer 1, 2, 3, 4, or 5;
p is an integer 1 or 2;
R
9
and R
10
each independently represent hydrogen or (1-4C)alkyl; and
R
11
represents hydrogen or (1-4C)alkyl;
or a pharmaceutically acceptable salt thereof.
The present invention further provides compounds of formula Ia:
wherein
R
1
represents (1-6C)alkyl, (2-6C)alkenyl, or NR
9
R
10
;
R
2
and R
3
each independently represent hydrogen, (1-4C)alkyl, F, or —OR
11
;
R
4a
and R
4b
each independently represent hydrogen, (1-4C) alkyl, (1-4C)alkoxy, I, Br, Cl, or F;
R
5
and R
6
each independently represent hydrogen, (1-4C)alkyl, F, or —OR
11
;
R
7
represents hydrogen, or (1-4C)alkyl;
R
8
represents (1-6C)alkyl, unsubstituted or substituted aromatic group, unsubstituted or substituted heteroaromatic group, cycloalkyl, or alkylcycloalkyl;
n is zero or an integer 1, 2, 3, 4, or 5;
m is zero or an integer 1, 2, 3, 4, or 5;
p is an integer 1 or 2;
R
9
and R
10
each independently represent hydrogen or (1-4C)alkyl; and
R
11
represents hydrogen or (1-4C)alkyl;
or a pharmaceutically acceptable salt thereof.
The present invention further provides a method of potentiating glutamate receptor function in a patient, which comprises administering to said patient an effective amount of a compound of formula I.
The present invention provides a method of treating cognitive disorders in a patient, which comprises administering to said patient an effective amount of a compound of formula I.
In addition, the present invention further provides a method of treating cognitive deficits associated with psychosis in a patient, which comprises administering to said patient an effective amount of a compound of formula I.
According to another aspect, the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for potentiating glutamate receptor function.
In addition, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for potentiating glutamate receptor function.
The invention further provides pharmaceutical compositions comprising, a compound of formula I and a pharmaceutically acceptable diluent or carrier.
This invention also encompasses novel intermediates, and processes for the synthesis of the compounds of formula I.
In this specification, the term “potentiating glutamate receptor function” refers to any increased responsiveness of glutamate receptors, for example AMPA receptors, to glutamate or an agonist, and includes but is not limited to inhibition of rapid desensitization or deactivation of AMPA receptors to glutamate.
A wide variety of conditions may be treated or prevented by the compounds of formula I and their pharmaceutically acceptable salts through their action as potentiators of glutamate receptor function. Such cond
Knobelsdorf James Allen
Shepherd Timothy Alan
Tromiczak Eric George
Zarrinmayeh Hamideh
Zimmerman Dennis Michael
Cleveland, Jr. John A.
Eli Lilly and Company
Lentz Nelsen L.
O'Sullivan Peter
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