Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-01-23
2004-02-17
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, C514S274000, C514S331000, C514S347000, C514S428000, C514S524000, C514S542000, C514S546000, C544S311000, C544S410000, C546S233000, C546S293000, C548S568000, C558S413000, C560S013000, C560S252000, C564S099000
Reexamination Certificate
active
06693137
ABSTRACT:
The present invention relates to the potentiation of glutamate receptor function using certain sulphonamide derivatives. It also relates to novel sulphonamide 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 unknown.
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.
It has now been found that cyclothiazide and certain sulphonamide derivatives potentiate agonist-induced excitability of human GluR4B receptor expressed in HEK 293 cells. Since cyclothiazide is known to potentiate glutamate receptor function in vivo, it is believed that this finding portends that the sulphonamide derivatives will also potentiate glutamate receptor function in vivo, and hence that the compounds will exhibit ampakine-like behavior.
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.
Accordingly, the present invention provides a compound of the formula:
wherein:
L
a
represents (1-4C)alkylene;
L
b
represents (1-4C)alkylene;
L
c
represents (1-4C)alkylene;
r is zero or 1;
m is zero or 1;
n is zero or 1;
q is 1 or 2;
X
1
represents O, S, NR
9
, C(═O), OCO, COO, NHCO
2
, O
2
CNH, CONH, NHCO, SO or SO
2
;
X
2
represents O, S, NR
10
, C(═O), OCO, COO, NHCO
2
, O
2
CNH, CONH, NHCO, SO or SO
2
;
X
3
represents O, S, NR
11
, C(═O), NHCO
2
, O
2
CNH, CONH, NHCO, SO or SO
2
;
R
1
represents a hydrogen atom, a (1-4C)alkyl group, a (3-8C)cycloalkyl group, an optionally substituted aromatic group, an optionally substituted heteroaromatic group, or a saturated 4 to 7 membered heterocyclic ring containing the group NR
10
and a group X as the only hetero ring members, wherein X represents —CH
2
—, CO, O, S or NR
12
and R
12
represents hydrogen or (1-4C);
R
9
is hydrogen or (1-4C)alkyl;
R
10
is hydrogen or (1-4C)alkyl, or
R
1
and R
10
together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, 4-di(1-4C)alkylaminopiperidinyl, morpholino, piperazinyl or N-(1-4C)alkylpiperazinyl group;
R
11
is hydrogen or (1-4C)alkyl;
R
2
represents (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)fluoroalkyl, (1-6C)chloroalkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or a group of formula R
3
R
4
N in which R
3
and R
4
each independently represents (1-4C)alkyl or, together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; and
either one of R
5
, R
6
, R
7
and R
8
represents hydrogen; (1-6C)alkyl; aryl(1-6C)alkyl; (2-6C)alkenyl; aryl(2-6C)alkenyl or aryl, or two of R
5
, R
6
, R
7
and R
8
together with the carbon atom or carbon atoms to which they are attached form a (3-8C) carbocyclic ring; and the remainder of R
5
, R
6
, R
7
and R
8
represent hydrogen; or a pharmaceutically acceptable salt thereof,
provided that (1) if m represents zero, then X
1
represents C(═O), CONH, or SO
2
, X
2
represents NR
10
and R
1
and R
10
together with the nitrogen atom to which they are attached form an azetidinyl, piperidinyl, 4-di(1-4C)alkylaminopiperidinyl, piperazinyl or N-(1-4C)alkylpiperazinyl group, and (2) if the group
—X
2
—(L
a
)
m
—(X
3
L
c
)
r
—X
1
—(L
b
)
n
—
represents —OCH
2
CONH—, then R
1
does not represent an optionally substituted aromatic group or an optionally substituted heteroaromatic group.
According to another aspect, the present invention provides a method of potentiating
Arnold Macklin Brian
Bender David Michael
Cantrell Buddy Eugene
Jones Winton Dennis
Ornstein Paul Leslie
Cleveland, Jr. John A.
Eli Lilly and Company
Lentz Nelsen L.
O'Sullivan Peter
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