Alpha-substituted pyridazino quinoline compounds

Details Alpha-substituted pyridazino quinoline compounds Alpha-substituted pyridazino quinoline compounds

1998-11-16

2004-05-18

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S230000, C544S234000

Reexamination Certificate

active

06737424

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 neuro-degenerative 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.
EPO publication number 0 516 297 A1 describes certain pyridazinediones. In addition, the compounds (1) thieno[2′,3′:5,6]pyrido[2,3-d]pyridazine-5,8,9(4H,6H,7H)-trione and (2) thieno[3′,2′:5,6]pyrido[2,3-d]pyrid-azine-4,5,8(6H,7H,9H)-trione are know, for example from J. Heterocyclic Chem., 28, 205, (1991).
Other pyridazinedione compounds are known from, for example, Beilstein's Handbuch der Organischen Chemie; Godard et. al., Bull. Soc. Chim. Fr., 1588, (1972); and Reid et. al., Chem. Ber., 85, 204, (1952).
Compounds of the present invention relate to novel 2-substituted pyridazinediones or tautomers thereof as shown in formulae I, Ia, Ib, Ic and Id, below, with the variables as recited hereinafter.
The compounds provided by this invention are 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, or by 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.
The present invention relates to a compound of formula I:
or pharmaceutically-acceptable salts thereof, wherein:
ring A is chosen from an ortho fused aromatic or hetero-aromatic five- or six-membered ring selected from phenyl, pyridyl, furyl, pyrrolyl or thienyl substituted at 0, 1, 2, 3 or 4 ring carbon atoms with R
1
;
R
1
at each occurrence is independently selected from halo, (C
1
-C
4
)alkyl, NO
2
, CN, perfluoro(C
1
-C
3
)alkyl, OH, O—CF
3
, (C
2
-C
4
)alkenyl, (C
2
-C
4
)alkynyl, O—(C
1
-C
4
)alkyl, NR′R″, SO
m
R′ where m is 0, 1 or 2, SO
m
NR′R″, a heterocyclic group, NR′COR″, COR″, NR′CO
2
R″, CO
2
R′ and CONR′R″;
R
2
is selected from a cycloalkyl moiety of 3-7 carbon atoms and —CHR
3
(CH
2
)
n
L where R
3
is selected from (C
1
-C
6
)alkyl, (C
0
-C
6
)alkylCF
3
and CO
2
(C
0
-C
6
)alkyl;
n is selected from 0-6;
L is selected from halo, OH, CF3, (C
3
-C
6
)cycloalkyl, O—(C
1
-C
4
)alkyl, O—(C
1
-C
4
)alkylaryl, (C
1
-C
4
)alkylCOOR′, O—COR′, SO
m
R′, SO
m
NR′R″, NR′COR″, NR′CO
2
R″, NRCONR′R″, CO
2
R′, CONRR′, NR′R″ and W; where
W is selected from phenyl or benz derivatives thereof substituted with 0, 1, 2, 3 or 4 groups selected from OH, halo, NO
2
, CN, CF
3
, (C
1
-C
4
)alkyl, O—(C
1
-C
4
)alkyl, O—(C
2
-C
4
)alkenyl, O—(C
2
-C
4
)alkynyl, O—(C
0
-C
6
)alkylphenyl, (C
1
-C
4
)alkylCF
3
, NH(CO)R′, NR′R″, CO
2
R′, CONR′R″, SO
m
R′, SO
2
NR′R″, O—(C
1
-C
6
)alkyloxy(C
1
-C
6
)alkyl, O—(C
1
-C
6
)alkylOH, O—(C
1
-C
6
)alkyl-O which forms a cyclic ring attached to a phenyl ring in an ortho manner, aryloxy(C
1
-C
4
)alkyloxy(C
1
-C
4
)alkyl, O—(C
1
-C
6
)alkyloxy(C
1
-C
6
)alkyloxy(C
1
-C
6
)alkyl, O—(C
1
-C
6
)alkyloxy(C
1
-C
6
)alkyl-OH, O—(C
1
-C
6
)alkylNR′R″, NR′(C
1
-C
6
)alkylNR′R″, (C
1
-C
6
)alkylNR′R″, O-perfluoro(C
1
-C
4
)alkyl, perfluoro(C
1
-C
4
)alkyl, NR′(C
1
-C
6
)alkyloxy, NR′(C
1
-C
6
)alkylhydroxy, (C
1
-C
4
)alkyloxy(C
1
-C
4
)alkyl, O—(C
1
-C
4
)alkylCOOR′, (C
1
-C
4
)alkyl)NR′R″, (C
1
-C
4
)alkylOR′, NR′(CH
2
)
q
COOR′ wherein q is 1-4, S(O)
m
(C
1
-C
4
)alkyloxy(C
1
-C
4
)alkyl, S(O)
m
(C
1
-C
4
)alkyloxy(C
1
-C
4
)alkyloxy(C
1
-C
4
)alkyl, NR′(C
1
-C
4
)alkyloxy(C
1
-C
4
)alkyl and NR′(C
1
-C
4
)alkyloxy(C
1
-C
4
)alkyloxy(C
1
-C
4
)alkyl; or
W is a heterocycle selected from a five-, six-, 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 said heterocycle is substituted at a carbon or nitrogen atom with 0 or 1 R or R′ moieties, or a carbon atom on said heterocycle is disubstituted to form a C
5
-C
7
spiral group, or a carbon atom or sulfur atom on said heterocycle is substituted with 0 or 1 oxygen moieties to form a carbonyl group or SO
m
group respectively; wherein said heterocycle may be selected from, 2-pyrrolidinone, piperazine, oxazolidone, 2,5-oxazolidinedione, 2,4-imidazolidinedione, 2,4-thiazolidinedione, succinimide or aryl or benz or heteroarylbenz derivatives thereof selected from 3,4-pyridinedicarboximide, -1-pthalimido, isatoic anhydride, orthobenzoic-sulfimide substituted with 0, 1, 2 or 3 alkyl or aromatic substituents selected from halo, OH, phenyl, CF
3
, CF
3
, NO
2
, CN, NH
2
, SO
m
R′, NH(C
1
-C
4
)alkyl, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy and N(C
1
-C
4
)alkyl
2
; with the proviso that a heterocyclic nitrogen may not be attached to a nitrogen of the tricyclic ring system of formula I; or
W is a heteroaryl selected from aromatic species and benz derivatives thereof selected from pyridyl, thienyl, furanyl, heteroaryl groups containing two heteroatoms selected from N, O and S, pyrazole, imidazole, isoxazole, oxazole, thiazole, isothiazole, oxidized versions thereof selected from SO
m
, pyridazine, pyrimidine, pyrazine, heteroaryl groups containing three heteroatoms chosen from N, O or S, triazole, oxadiazole, triazine, heteroaryl groups containing four heteroatoms chosen from N, O or S, and tetrazole, wherein said heteroaryl is substituted at 0 or 1 nitrogen atoms with substituents are selected from OH, (C
1
-C
6
)alkoxy, halo, CN and R, where said heteroaryl group is attached to —(CH
2
)
n
via a carbon atom or a heteroatom of the heteroaryl group; wherein
R is selected from H or (C
1
-C
4
)alkyl;
R′ and R″ are independently selected at each occurrence from H, (C
1
-C
6
)alkyl, (C
2
-C
4
)alkenyl, (C
2
-C
4
)alkynyl, cyclo(C
3
-C
6
)alkyl, (C
0
-C
4
)alkylphenyl, (C
0
-C
4
)alkylaryl, (C
0
-C
4
)alkylheterocycle and (C
0
-C
4
)alkylheteroaryl wherein phenyl, heterocycle and heteroaryl are as defined a

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