Cyclopentyl sulfonamide derivatives

Details Cyclopentyl sulfonamide derivatives Cyclopentyl sulfonamide derivatives

2002-05-14

2003-10-28

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S079000

Reexamination Certificate

active

06639107

ABSTRACT:

The present invention relates to the potentiation of glutamate receptor function using certain cyclopentyl sulfonamide derivatives. It also relates to cyclopentyl sulfonamide novel derivatives, to processes for their preparation and to pharmaceutical compositions containing them.
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-5-methylisoxazole-4-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. The physiological implications of rapid desensitization, and deactivation if any, are not fully understood.
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. Compounds which potentiate AMPA receptors, like cyclothiazide, are often referred to as ampakines.
International Patent Application Publication Number WO 9625926 discloses a group of phenylthioalkylsulphonamides, S-oxides and homologs which are said to potentiate membrane currents induced by kainic acid and AMPA.
Ampakines have been shown to improve memory in a variety of animal tests. Staubli et al.,
Proc. Natl. Acad. Sci
., Vol. 91, pp 777-781, 1994
, Neurobiology
, and Arai et al.,
The Journal of Pharmacology and Experimental Therapeutics
, 278: 627-638, 1996.
In addition, certain sulfonamide derivatives which potentiate glutamate receptor function in a mammal have been disclosed in International Patent Application Publication WO 98/33496 published Aug. 6, 1998 and International Patent Application Publication WO 99/43285 published Sep. 2, 1999.
It has now been found that cyclopentyl derivatives of the present invention are surprisingly potent potentiators of glutamate receptor function.
The present invention provides compounds of formula I:
wherein
R
1
, R
2
, and R
3
each independently represent hydrogen, halogen, CF
3
, OCF
3
, CN, NO
2
, NH
2
, (1-6C)alkyl, (1-6C)alkoxy, —(CH
2
)
n
NHSO
2
R
5
, —(CH
2
)
n
NNHC(═O)R
5
, —SO
2
R
5
, —C(═O)R
6
, —CH═CHCO
2
R
7
, heterocycle, or phenyl which is unsubstituted or substituted by one, two, or three substituents selected from the group consisting of halogen, CF
3
, OCF
3
, CN, NO
2
, NH
2
, (1-6C)alkyl, (1-6C)alkoxy, —(CH
2
)
n
NHSO
2
R
5
, —(CH
2
)
n
NHC(═O)R
5
, —SO
2
R
5
, —C(═O)R
6
, —C(═O)NR
10
R
11
, —SO
2
NR
10
R
11
, or —CH═CHCO
2
R
7
;
R
4
represents (1-6C)alkyl, (2-6C)alkenyl, or NR
8
R
9
;
R
5
represents (1-6C)alkyl, CF
3
, or phenyl which is unsubstituted or substituted by one, two, or three substituents selected from the group consisting of halogen, CF
3
, CN, NO
2
, NH
2
, (1-6C)alkyl, or (1-6C)alkoxy;
R
6
represents (1-4C)alkyl or phenyl;
R
7
represents hydrogen or (1-4C)alkyl;
R
8
and R
9
each independently represent hydrogen or (1-4C)alkyl;
R
10
and R
11
each independently represent hydrogen or (1-4C)alkyl; and
n is 0, 1, 2, 3, or 4;
or a pharmaceutically acceptable salt thereof.
The present invention further provides a method of potentiating glutamate receptor function in a patient requiring such treatment, which comprises administering to said patient an effective amount of a compound of formula I.
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.
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.
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.
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

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