Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
1999-07-28
2001-01-30
Fan, Jane (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
active
06180786
ABSTRACT:
The present invention is directed to a new class of excitatory amino acid antagonists and intermediates thereof. These new antagonists, heterocycle substituted propenoic acid derivatives, are useful as NMDA (N-methyl-D-aspartate) antagonists. They preferentially bind to the strychnine-insensitive glycine binding site on the NMDA receptor complex associated with the treatment of a number of disease states. Another aspect of the invention is directed to their use in treatment of a number of diseases as well as to pharmaceutical compositions containing these excitatory amino acid antagonists.
In accordance with the present invention, a new class of NMDA antagonists has been discovered which can be described by the formula:
wherein
Z is hydrogen or —CH
3
;
X is represented by —OH, a physiologically acceptable ester, or a physiologically acceptable amide;
Y is represented by —OH, a physiologically acceptable ester, or a physiologically acceptable amide;
R
1
is represented by from 1 to 3 substituents independently chosen from the group: hydrogen, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halogen, —CF
3
, or —OCF
3
;
G is a radical chosen from the group
wherein
R
2
is represented by from 1 to 2 substituents independently chosen from the group: hydrogen or C
1
-C
4
alkyl;
R
3
is represented by from 1 to 2 substituents independently chosen from the group: hydrogen, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, or halogen;
and pharmaceutically acceptable addition salts thereof.
As used in this application:
a) the term “C
1
-C
4
alkyl” refers to a branched or straight chained alkyl radical containing from 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and the like;
b) the term “C
1
-C
4
alkoxy” refers to a branched or straight chained alkoxy radical containing from 1-4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and the like;
c) the term “halogen” refers to a fluorine atom, a chlorine atom, a bromine atom, or a iodine atom;
d) the term “physiologically acceptable ester” refers to any non-toxic ester or any prodrug that allows the compounds of this application to function as NMDA antagonists: these physiologically acceptable esters may be chosen from but are not limited to compounds wherein X and Y may each independently be represented by —OR
4
, —OCH
2
OR
4
or —O—(CH
2
)
p
—NR
5
R
6
; wherein R
4
is represented by C
1
-C
4
alkyl, phenyl, substituted phenyl, or an phenylalkyl substituent, such as benzyl, in which the phenyl ring may be optionally substituted; p is 2 or 3; and R
5
and R
6
are each independently represented by a C
1
-C
4
alkyl or together with the adjacent nitrogen atom to form a ring —CH
2
—CH
2
—Z—CH
2
—CH
2
— wherein Z is a bond, O, S, or NR
7
in which R
7
is hydrogen or C
1
-C
4
alkyl; such rings include but are not limited to piperidino, morpholino, thiomorpholino, piperazino, N-methylpiperazino, or pyrrolidino; and the pharmaceutically acceptable addition salts thereof;
e) the term “physiologically acceptable amide” refers to any non-toxic amide or any prodrug that allows the compounds of this application to function as NMDA antagonists: these physiologically acceptable amides may be chosen from, but are not limited to, compounds wherein X and Y may each independently be represented by —NR
8
R
9
; wherein R
8
and R
9
are each independently represented by hydrogen, phenyl, substituted phenyl, phenylalkyl, or a C
1
-C
4
alkyl; or R
8
and R
9
are taken together with the adjacent nitrogen atom to form a ring —CH
2
—CH
2
—Z—CH
2
—CH
2
— wherein Z is a bond, O, S, or NR
7
in which R
7
is hydrogen or C
1
-C
4
alkyl; such rings include but are not limited to piperidino, morpholino, thiomorpholino, piperazino, N-methylpiperazino, or pyrrolidino and the pharmaceutically acceptable addition salts thereof;
f) the designation
refers to a thienyl or thiophene and it is understood that the radical is attached at either the 2-position or 3-position, it is further understood that when the radical is attached at the 2-position the substituent or substituents represented by R can be attached in any of the 3, 4, or 5 positions, and that when the radical is attached at the 3-position the substituent or substituents represented by R can be attached in any of the 2, 4, or 5 positions;
g) the designation
refers to a furyl, furanyl, or furan and it is understood that the radical is attached at either the 2-position or the 3-position, it is further understood that when the radical is attached at the 2-position the substituent or substituents represented by R can be attached in any of the 3, 4, or 5 positions, and that when the radical is attached at the 3-position the substituent or substituents represented by R can be attached in any of the 2, 4, or 5 positions;
h) the designation “C(O)” refers to a carbonyl group of the formula:
i) the designation
refers to a pyridine, pyridinyl, or pyridyl and it is understood that the radical can be attached at either the 2-position, 3-position, or 4-position, it is further understood that when the radical is attached at the 2-position the substituent or substituents represented by R can be attached in any of the 3, 4, 5, or 6 positions, that when the radical is attached at the 3-position the substituent or substituents represented by R can be attached in any of the 2, 4, 5, or 6 positions, and that when the radical is attached at the 4-position the substituent or substituents represented by R can be attached in any of the 2, 3, 5, or 6 positions;
j) the designation “
”
refers to a bond for which the stereochemistry is not designated;
k) the term “pharmaceutically acceptable addition salts” refers to either an acid addition salt or a basic addition salt.
The expression “pharmaceutically acceptable acid addition salts” is intended to apply to any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula (I) or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di-, and tricarboxylic acids. Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, and sulfonic acids such as p-toluenesulfonic acid, methane sulfonic acid and 2-hydroxyethane sulfonic acid. Such salts can exist in either a hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and which in comparison to their free base forms, generally demonstrate higher melting points.
The expression “pharmaceutically acceptable basic addition salts” is intended to apply to any non-toxic organic or inorganic basic addition salts of the compounds represented by the Formula (I) or any of its intermediates. Illustrative bases which form suitable salts include alkali metals or alkaline-earth metals hydroxides such as, sodium, potassium, calcium, magnesium, or barium hydroxides; ammonia and aliphatic, cyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine,and picoline.
The compounds of Formula (I) exist as geometric isomers. Any reference in this application to one of the compounds of Formula (I) is meant to encompass either a specific geometrical isomer or a mixture of isomers. The specific isomers can be separated and recovered by techniques known in the art such as chromatography, and selective crystallization.
Illustrative examples of compounds encompassed by the present invention include:
(E)-2-Bromo-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoic acid, t-butyl ester;
(Z)-2-Bromo-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoic acid, t-butyl
Fan Jane
Ferrell Michael W.
Hoechst Marion Roussel Inc.
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