Pyridazino quinoline compounds

Details Pyridazino quinoline compounds Pyridazino quinoline compounds

1998-03-19

2001-05-15

Bernhardt, Emily (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S234000

Reexamination Certificate

active

06232313

ABSTRACT:

This invention relates to pyridazinedione compounds useful in the treatment of neurological disorders generally in mammals such as man. More specifically, the compounds are useful in the treatment of strokes and/or other neurodegenerative disorders such as hypoglycemia, cerebral palsy, transient cerebral ischemic attack, perinatal asphyxia, epilepsy, psychosis, Huntington's chorea, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Olivo-pontocerebellar atrophy, viral-induced neurodegeneration such as in acquired immunodeficiency syndrome and its associated dementia, anoxia such as from drowning, spinal cord and brain trauma, and chronic pain, for the prevention of drug and alcohol withdrawal symptoms, and for the inhibition of tolerance and dependence to opiate analgesics. The invention particularly relates to novel pyridazinedione compounds useful in reducing neurological degeneration such as can be induced by a stroke and the associated functional impairment which can result. Treatment using a compound of the invention can be remedial or therapeutic as by administering a compound following an ischemic event to mitigate the effects of that event. Treatment can also be prophylactic or prospective by administering a compound in anticipation that an ischemic event may occur, for example in a patient who is prone to stroke.
It is known that ischemic events can trigger a dramatic increase in extracellular concentrations of the excitatory amino acids glutamate and aspartate which can, in turn, cause prolonged neuronal excitation leading to a massive influx of calcium from extracellular to intracellular sites in brain neural cells. A calcium overload can thereby be created which leads to a cascade of events leading to cell catabolism and eventually resulting in cell death. The N-methyl-D-aspartate (NMDA) receptor complex is believed to play a significant role in the cascade of events leading to cell necrosis following an ischemic event.
The compounds provided by this invention may be useful in a variety of neurodegenerative disorders because they function as excitatory amino acid antagonists. They may do so indirectly, via allosteric modulation of the glutamate binding site, specifically by acting as antagonists of the strychnine-insensitive glycine receptor on the NMDA receptor complex. They may also do so directly, by binding to the glutamate site itself on the NMDA receptor complex.
According to the invention there is provided a compound and pharmaceutical compositions thereof suitable for the treatment of neurological disorders, comprising a compound of formula I or a pharmaceutically acceptable salt thereof (formula set out, together with other formulae referred to by Roman Numerals, on pages following the Examples) and tautomers thereof wherein
Z is selected from O, S or NH (or when the B-ring N tautomerizes or the B-ring is reduced, the Z group may be selected from H, OH, SH or NH
2
to form a compound of I′).
Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring selected from phenyl, pyridyl, furyl, pyrrolyl or thienyl either unsubstituted or multi-substituted at a ring carbon atom with R
4
wherein R
4
is independently selected from the group consisting of halo, (1-4C)alkyl, NO
2
, CN, (C1-3)perfluoroalkyl, OH, OCF
3
, (2-4C)alkenyl, (2-4C)alkynyl, O(1-4C)alkyl, NR′R″, SO
2
NR′R″, or SO
m
R′; a heterocyclic group, NR′COR″, COR″, NR′CO
2
R″, CO
2
R′, CONR′R″;
R
1
is selected from H or —(CH
2
)
n
L wherein L is M or W; M is
phenyl or benz derivatives thereof and is either unsubstituted or substituted with 1, 2, 3 or 4 groups chosen from —O—(1-4C)alkyl,—O—(2-4C)alkenyl, —O—(2-4C)alkynyl, —O(C0-C6alkyl)phenyl, —OH, —halo, —NO
2
, —CN, —CF
3
, —(1-4C)alkylCF
3
, —NH(CO)R′, —(1-4C)alkyl, —NR′R″, —CO
2
R′, —CONR′R″, —SO
m
R′, —SO
2
NR′R″, (C1-C6)alkyloxy(C1-C6)alkyloxy-, hydroxy(C1-C6)alkyloxy-, oxy(1-6C)alkyloxy which may form a cyclic ring attached to the phenyl ring in an ortho manner, aryloxy(1-4C)alkyloxy(1-4C)alkyl, (C1-C6)alkyloxy(C1-C6)alkyloxy(C1-C6)alkyloxy-, hydroxy(C1-C6)alkyloxy(C1-C6)alkyloxy-, —O(C1-C6alkyl)NR′R″, —NR′(C1-C6alkyl)NR′R″, —(C1-C6alkyl)NR′R″, —O—(1-4C)perfluroalkyl, —(1-4Cperfluroalkyl, —NR′(C1-C6alkyloxy), —NR′(C1-C6alkylhydroxy), —(C1-4alkyl)oxy(C1-4alkyl), —O(C1-4alkyl)COOR′, —(CH
2
)
n
NR′R″COOR′, wherein n is 1-4, —(C1-4alkyl)NR′R″, —(C1-4alkyl)OR′, —NR′(CH
2
)
n
COOR′, —S(O)
m
(C1-4alkyl)oxy(C1-4alkyl), —S(O)
m
(C1-4alkyl)oxy(C1-4alkyl)oxy(C1-4alkyl), —NR′(C1-4alkyl)oxy(C1-4alkyl), —NR′(C1-4alkyl)oxy(C1-4alkyl)oxy(C1-4alkyl);
heterocycle wherein heterocycle is selected from a five- and/or six- and/or seven-membered heterocyclic ring containing 1,2, or 3 heteroatoms chosen from O, N, or S, or aryl or heteroaryl benz derivatives thereof, wherein the N on the heterocycle is optionally substituted with R′ and a carbon or nitrogen atom on the heterocycle may be substituted with R or R′ or a carbon atom may be disubstituted to form a C5-C7 spiral group or a carbon atom or sulfur atom may be substituted with 0 to form a carbonyl group or sulfonyl group (S(O)
m
) with the proviso that a heterocyclic nitrogen may not be attached to a nitrogen or the tricyclic ring system of formula I:
heteroaryl wherein heteroaryl is selected from unsubstituted or substituted aromatic species and benz derivatives thereof including pyridyl, thienyl, furanyl, or those groups containing two heteroatoms selected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole, thiazole or isothiazole (and oxidized versions thereof selected from S(O)
m
wherein m is 0-2), pyridazine, pyrimidine, pyrazine or those groups containing three heteroatoms chosen from N, O or S such as triazole or oxadiazole or triazine, or those groups containing four heteroatoms such as tetrazole, wherein the N on the heteroaryl group is optionally substituted with R and the substituted aromatic substituents include typical aromatic substituents selected from hydroxy, alkoxy, halo or cyano and the heteroaryl group is attached to —(CH
2
)
n
via a carbon atom or a heteroatom on the heteroaryl group;
W is selected from OH, OR′, CF
3
OCOR′, S(O)
m
R′, S(O)
m
NR′R″, halo, NR′R″ with the proviso that NR′R″ is not equal to NH
2
, COR′, NR′COR″, OCONR′, NR
40
CO
2
R″, (C3-6)cycloalkyl, NRCONR′R″, CO
2
R′, or CONRR′ with the proviso that n is greater than zero and;
n is chosen from 0-6;
R
2
is selected from H or —(CH
2
)
n
L wherein L is M or W and
M is:
phenyl or benz derivatives thereof and is either unsubstituted or substituted with 1, 2 or 3 groups chosen from —O—(1-4C)alkyl, —OH, —halo, —NO
2
, —CN, —CF
3
, —NH(CO)R′, —(1-4C)alkyl, —NR′R″, —CO
2
R′, —CONR′R″, —SO
m
R′, —SO
2
NR′R″, (C1-C6)alkyloxy(C1-C6)alkyloxy-, hydroxy(C1-C6)alkyloxy-, (C1-C6)alkyloxy(C1-C6)alkyloxy(C1-C6)alkyloxy-, hydroxy(C1-C6)alkyloxy(C1-C6)alkyloxy-, —O(C1-C6alkyl)NR′R″, —NR′(C1-C6alkyl)NR′R″, —(C1-C6alkyl)NR′R″, —OCF
3
, —NR′(C1-C6alkyloxy), —NR′(C1-C6alkylhydroxy);
heterocycle wherein heterocycle is selected from a five- and/or six- and/or seven-membered heterocyclic ring containing 1,2,or 3 heteroatoms chosen from O, N, or S, or aryl or heteroaryl benz derivatives thereof, wherein the N on the heterocycle is optionally substituted with R′ and a carbon or nitrogen atom on the heterocycle may be substituted with R or R′ or a carbon atom may be disubstituted to form a C5-C7 spiral group or a carbon atom or sulfur atom may be substituted with 0 to form a carbonyl group or sulfonyl group (S(O)
m
);
heteroaryl wherein heteroaryl is selected from unsubstituted or sub

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