Quinoxalinedione derivatives, their preparation and use

Details Quinoxalinedione derivatives, their preparation and use Quinoxalinedione derivatives, their preparation and use

1995-05-18

2004-03-09

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S345000, C544S244000, C546S139000, C546S143000, C546S150000, C546S166000, C548S482000

Reexamination Certificate

active

06703391

ABSTRACT:

OBJECT OF THE INVENTION
It is an object of the present invention to provide novel quinoxaline dione compounds which are useful in the treatment of diseases in mammals, including a human, and especially in the treatment of diseases which can be treated by antagonizing an excitatory amino acid of such mammals.
Another object of the present invention is to provide a method of treating diseases in mammals, including a human, responsive to the blockade of glutamic and aspartic acid receptors which comprises administering to a mammal in need thereof a compound of the invention.
A third object of the present invention is to provide novel pharmaceutical compositions for the treatment of diseases in mammals, including a human, responsive to the blockade of glutamic and aspartic acid receptors.
BACKGROUND OF THE INVENTION
Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acids (EAA) glutamate and aspartate at the N-methyl-D-aspartate (NMDA), the &agr;-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, and the kainate receptor. This excitotoxic action is responsible for the loss of neurons in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma, as well as lathyrism, Alzheimer's, and Huntington's diseases.
The compounds of the present invention may also be useful in the treatment of schizophrenia, Parkinsonism, epilepsy, anxiety, pain, and drug addiction.
SUMMARY OF THE INVENTION
The invention then, inter alia, comprises the following, alone or in combination:
A compound having the formula
or a pharmaceutically acceptable salt thereof wherein
R is hydrogen or hydroxy;
R
1
is hydrogen,
alkyl,
arylalkyl,
(CH
2
)
n
OH, or
(CH
2
)
n
NR
7
R
8
;
R
5
and R
6
are each independently
hydrogen,
halogen,
NO
2
,
CN,
CF
3
,
SO
2
NR
7
R
8
,
PO
3
R
9
R
10
,
alkyl,
alkenyl,
alkynyl,
(CH
2
)
n
CONR
7
R
8
,
(CH
2
)
n
CO
2
R
10
,
NHCOR
11
,
wherein R
7
and R
8
are each independently hydrogen or alkyl or together R
7
and R
8
form a ring of from three to seven atoms,
R
9
is hydrogen or alkyl,
R
10
is hydrogen or alkyl,
R
11
is hydrogen or alkyl, and
n is an integer of from zero to four;
A is a ring of five to seven atoms fused with the benzo ring at the positions marked a and b, and formed by the following bivalent radicals:
a-NR
12
—CHR
13
—CHR
14
-b,
a-CHR
13
—CHR
14
—NR
12
-b,
a-CHR
13
—NR
12
—CHR
14
-b,
a-CHR
14
—CH
2
—NR
12
—CHR
13
-b,
a-CHR
13
—NR
12
—CH
2
—CHR
14
-b,
a-CH
2
—CH
2
—CHR
13
—NR
12
-b,
a-NR
12
—CHR
13
—CH
2
—CH
2
-b,
a-CH
2
—CH
2
—NR
12
—CH
2
—CH
2
-b,
a-CH
2
—CH
2
CH
2
—NR
12
—CH
2
-b,
a-CH
2
NR
12
—CH
2
—CH
2
—CH
2
-b,
a-CH
2
—CH
2
—CH
2
—CH
2
—NR
12
-b,
a-NR
12
—CH
2
—CH
2
—CH
2
—CH
2
-b,
wherein
R
12
is hydrogen, CH
2
CH
2
OH, or alkyl, and R
13
and R
14
are each independently hydrogen, CN, CONH
2
, CH
2
NH
2
, CH
2
OH, alkyl, arylalkyl, alkenyl, or CO
2
R
15
wherein R
15
is hydrogen or alkyl;
and a compound as above having the formula
wherein R, R
12
, R
5
, and R
6
have the meanings set forth above;
and a compound as above having the formula
wherein R, R
12
, R
5
, and R
6
have the meanings set forth above;
and a compound as above having the formula
wherein R, R
12
, R
5
, and R
6
have the meanings set forth above;
and a compound as above having the formula
wherein R, R
12
, R
5
, and R
6
have the meanings set forth above;
and a compound as above having the formula
wherein R, R
12
, R
5
, and R
6
have the meanings set forth above;
and further a compound as any above wherein R
5
and R
6
independently are
hydrogen,
halogen,
NO
2
,
CN,
SO
2
NR
7
R
8
wherein R
7
and R
8
independently are hydrogen or C
1-3
-alkyl which may be straight or branched or cyclic, and wherein R
12
is C
1-3
-alkyl which may be straight or branched or cyclic;
and a compound having the formula
wherein R
12
is hydrogen, methyl, or ethyl and R
6
is
NO
2
, SO
2
NMe
2
,
 or
and a compound having the formula
wherein R
12
is hydrogen, methyl, or ethyl and R
6
is
NO
2
, SO
2
NMe
2
,
 or
and further method of treating disorders of a mammal, including a human, responsive to the blockade of glutamic and aspartic acid receptors, which comprises administering to a patient in need thereof an effective amount of a compound as any above in unit dosage form;
and a method as above wherein cerebrovascular disorders are treated;
and further a pharmaceutical composition comprising a therapeutically effective amount of a compound as any above together with a pharmaceutically acceptable carrier.
Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts such as the hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate, oxalate, and the acetate.
Halogen is fluorine, chlorine, bromine, or iodine; fluorine, chlorine, and bromine are preferred groups.
Alkyl means a straight chained or branched chain of from one to six carbon atoms or cyclic alkyl of from three to seven carbon atoms including, but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
Alkenyl means a straight chained or branched chain alkenyl group of two to six carbon atoms or a cyclic alkenyl group of three to seven carbon atoms, for example, but not limited to ethylene, 1,2- or 2,3-propylene, 1,2-, 2,3-, or 3,4-butylene, cyclopentene, or cyclohexene.
Alkynyl means a straight chained or branched chain alkynyl group of two to six carbon atoms, for example, but not limited to ethynyl, 2,3-propynyl, 2,3- or 3,4-butynyl.
Aryl means a monocyclic or bicyclic carbocyclic aromatic ring system, for example, but not limited to phenyl, 2-naphthyl, or 1-naphthyl.
Arylalkyl means aryl as defined above and alkyl as defined above, for example, but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl; a preferred group is benzyl.
Also included in the instant invention is a process for preparing a compound of formula (see Scheme I).
The process comprises
(1) reacting a compound of Formula I (Scheme I) with a brominating agent, for example, bromine in trifluoroacetic acid, bromine in acetic acid or mixtures thereof, or reacting a compound of Formula I with a chlorinating agent, for example, sodium hypochlorite in hydrochloric acid to give a compound of Formula II
 wherein X is bromine or chlorine;
(2) treating a compound of Formula II above with fuming nitric acid in a solvent such as trifluoroacetic acid, acetic acid, or with mixtures thereof to give a compound of Formula III
(3) deprotecting a compound of Formula III with under acidic or basic conditions to provide a compound of Formula IV
(4) hydrogenating a compound of Formula IV in a solvent to give a compound of Formula V
 wherein X may be hydrogen, bromine, or chlorine;
(5) reacting a compound of Formula V with oxalic acid in a solvent such as aqueous HCl or aqueous methanesulfonic acid or with diethyl oxylate to give a compound of Formula VI
(6) reacting a compound of Formula VI wherein X is hydrogen sequentially with chlorosulfonic acid neat or in a solvent followed by treatment with a primary or secondary amine to give a compound of Formula VII
 wherein R
7
and R
8
are as previously defined.
Also included in the invention is a process for the preparation of formula
which comprises;
(1) reacting 3-nitrophthalic acid with a 1,3-dialkyl urea, neat or in a solvent to provide a compound of the formula
(2) hydrogenating a compound of the above formula in a solvent to give a compound of the formula
(3) reacting a compound of the above formula with a hydride reducing agent, for example, lithium aluminum hydride or the like in a solvent to gi

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