JPH06192231A - 2,5-dihydro-2,5-dioxo-1h-benzazepines and their use - Google Patents

Abstract

PURPOSE: To provide a new compound useful for treating or preventing neuronal degeneration associated with isochemia, neurodegenerative pathophysiological conditions, convulsions, anxiety and chronic pains and for inducing anesthesia.

CONSTITUTION: A compound of formula is e.g. 6-nitro-7,8-dichlor-2,5-dihydro-2,5- dioxo-3-hydroxy-1H-benzazepine. In the formula, R₁ is H, halo, haloalkyl, alkyl, aryl, a heterocyclic ring group, heteroaryl, nitro, amino or azido; R₂-R₅ are each H, halo, haloalkyl, aryl, a heterocyclic ring group, heteroaryl, alkyl, nitro, amino or azido; R₆ is H, aryl, a heterocyclic ring group, heteroaryl, alkyl, amino, CH₂CONHAr, NHCONHAr, NHCOCH₂Ar, COCH₂Ar (Ar is aryl, a heterocyclic ring group, heteroaryl), OH, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy; R₄ is H.

COPYRIGHT: (C)1994,JPO

Description

Detailed Description of the Invention

This invention was made with US Government support. Accordingly, the United States Government has certain rights in this invention.

This invention is in the field of medicinal chemistry. In particular, the present invention provides novel substituted 2,5-dihydro-
Introducing 2,5-dioxo-1H-benzazepines and to treat or prevent neuronal degeneration associated with ischemia, pathophysiological conditions associated with neuronal degeneration, convulsions, anxiety and chronic pain, and anesthesia Regarding these uses for:

[0002]

Glutamate is believed to be the major stimulatory neurotransmitter in the brain. There are three major subtypes of glutamate receptors in the central nervous system. These are generally kainate, AMPA and N
-Methyl-D-aspartate (NMDA) receptor (Watkins and Olberman, Trends in Neurosci. 7: 265-272)
(1987). NMDA receptors are found on the membranes of virtually every neuron in the brain. NMDA
Receptors are ligand-gated cation channels that permeabilize Na ⁺ , K ⁺ and Ca ⁺⁺ when activated by glutamate or aspartate (non-selective endogenous agonist) or by NMDA (selective synthetic agonist). (ligznd-gated cation channels) (Wong and Kemp, Ann. Rev. Pharmacol. Toxicol.) 31 4
01-425 (1991).

Glutamate alone cannot activate the NMDA receptor. To activate with glutamate,
The NMDA receptor channel must first bind to glycine at a specific glycine high affinity binding site that is distinct from the glutamate / NMDA binding site of the receptor protein (Johnson and Usher, Nature). 325, 329-331 (1987).
Therefore, glycine is an essential co-agonist at the NMDA receptor / channel complex (Kemp;
J. A. Proceeding of National Academy of Science of the United. States of America (Proceeding of Nat
ional Academy of Science of the United
States of America, Vol. 85, pp. 6547-6550 (1
988)).

In addition to the glutamate / NMDA and glycine binding sites, the NMDA receptor has many other functionally important binding sites. These are Mg ⁺⁺ , Z
Contains binding sites for n ⁺⁺ , polyamines, arachidonic acid and phencyclidine (PCP) (Reynold and Miller, Adv. in Pharmacol. (Adv. in
Pharmacol. 21: 101-126 (1990); Miller, B.M. Et al., Nature 355 vol 722-7
25 (1992)). The PCP binding site is now commonly referred to as the PCP receptor and is located inside the pores of the ion permeable carrier of the NMDA receptor / channel complex (Wong, E .;
H. F et al., Proceeding of National Academy of Science of the United
States of America (Proceeding of Nationa
l Academy of Science of the United Stat
es of America 83: 7104-7108 (198)
6 years); Wittner and Bean, Proceeding ·
Of National Academy of Science of the United States of America (Pr
oceeding of National Academy of Science o
f the United States of America) Volume 85 130
7-1311 (1988); McDonald, J. et al. F.
Neurofidiol. (Neurophysiol.) 58: 251-266 (1987)). In order for PCP to access the PCP receptor, it must first open channels with glutamate and glycine. In the absence of glutamate and glycine, PCP becomes PC
I can't bind to the P receptor, but in some studies,
Small amounts of P, even in the absence of glutamate and glycine
Suggests that CP can bind (Silker and Zuckin, Brain Research 5)
56, 280-284 (1991)). Once PCP binds to the PCP receptor, it blocks the ion flow through the open channel. Therefore, PCP is an open channel blocker and a non-competitive glutamate antagonist at the NMDA receptor / channel complex.

One of the most potent and selective drugs that bind to the PCP receptor is the antispasmodic MK-801. This drug has a Kb at the PCP receptor of about 3 nM (Wong, E .;
H. F. , Proceeding of National Academy of Science of the United States of America (Proceeding of Natio
nal Academy of Science of the United St
ates America, 83, 7104-7108 (1986)
Year)). Both PCP and MK-801, as well as other PCP receptor ligands [eg dextromethorphan, ketamine and guanidine N, N 'disubstituted], have neuroprotective effects both in vitro and in vivo (Gill. , R. et al., J. Neurosai.
ci. 7: 3343-3349 (1987), Cana,
J. F. W. Et al. Proceeding of National
Academy of Science of the United States of America (Proceeding of Nat
ional Academy of Science of the United
States of America, Vol. 86, 5631-5635 (1
989); Steinberg, G .; K. Et al., Neuroscience Let. (Neuroscience Lett.) Volume 89 19
3-197 (1988); Church, J .; Et al .: Sigma and Phencyclidine-Like Compounds
as Molecular Probes in Biology), edited by Domino and Kamenka, Anne Arbor: 7 in NPP Books
47-756 (1988)) The very characteristic neuroprotective effects of these drugs are excessive due to excess glutamate released mainly in the state of cerebral ischemia (eg, stroke, cardiac arrest ischemia, etc.). By its ability to inhibit excess Ca ⁺⁺ flow into neurons through activated NMDA receptor channels (Collins, RC, Metabol Bull.
(Metabol. Br. Dis.) Vol. 1, pp. 231-240 (198)
6 years); Collins, R .; C. Anals Int. Med. (Annals Int. Med.) Volume 110 992-100
0 (1989)).

[0006] However, the therapeutic potential of these PCP receptor drugs as ischemic life-saving substances during stroke affects the strong PCP-like behavior that is thought to be due to the interaction between these drugs and PCP receptors. It is severely hampered by the fact that these drugs have side effects, the behavioral effects of psychotic effects (Trickle Bank, MD).
Et al., European Journal of Pharmacology, Vol. 167, 1
27-135 (1989); Cork, W .; , Journal of Pharmacology and Experimental Therapeutics (Jorunal of Pharmaco
logy and Experimental Therapeutics) Volume 245 9
69 (1989); Willets and Barster, Neuropharmacology 27: 1
249 (1988)). Due to these side effects on PCP-like behavior, MK801 seems to be discontinued from clinical development as an ischemic life-saving substance. Furthermore, these P
CP receptor ligands appear to have considerable potential for abuse, as shown by the propensity for abuse of PCP itself.

The effect of PCP receptor ligands on PCP-like behavior can be demonstrated in animal models: PCP
And correlating PCP receptor ligands have been described in rodents by behavioral excitement (hyperlocomotion) (Trickle Bank, MD et al., European Journal.
Of the European Journal of Pha
rmacology 167: 127-135 (1989)) and the characteristic catalepsy in pigeons (Cork, W. et al.
Et al., Journal of Pharmacology and Experimental Cerabotics (Jorunal o
f Pharmacology and Experimental Therapeutic
s) 245, 969 (1989); Willets and Barster, Neuropharmacol.
27: 1249 (1988)): Within the drug discrimination paradigm, there is a strong correlation between the PCP receptor affinity of these drugs and the strength that induces PCP-specific response behavior. (Zuckin, SR
Brain Research 294: 174 (1984); Brady, K. et al. T. Et al., Science 215: 178 (1982); Trickle Bank, M .; D. The European Journal
European Journal of Pha
rmacology 141, 497 (1987).

Drugs that act as competitive antagonists at the glutamate binding site of the NMDA receptor, eg CGS197
55 and LY274614, like PCP receptor ligands, also have neuroprotective effects by being able to protect against excess Ca ⁺⁺ flow through the NMDA receptor / channel during ischemia (Borst, CA et al., Brain Research
(Brain Research) 442, 345-348 (198)
8 years); Shoppe, D .; D. Et al., J. Neural, Transformer (J. Neural. Trans.) 8: 131-143 (19)
1991)). However, competing NMDA receptor antagonists also have side effects on PCP-like behavior in animal models (behavioral agitation, activity in PCP drug discrimination test) but are not as potent as MK-801 and PCP.
(Trickle Bank, MD et al., European Journal of Pharmacology
of Pharmacology 167: 127-135 (198)
9 years)).

Another method of inhibiting NMDA receptor channel activation is by using antagonists at the glycine binding site of the NMDA receptor. Glycine must bind to the glycine site in order for glutamate to open channels (Johnson and Usher, Nature 325: 329-331 (1
987); Kemp, J .; A. , Proceeding of National Academy of Science of the United States of America (Proc
eeding of National Academy of Science of
the United States of America) Volume 85 6547
-6550 (1988)), glycine antagonists are able to completely block ion flux through NMDA receptor channels even in the presence of high amounts of glutamate.

Recent in vivo microdialysis
s) studies have shown that glutamate release is greatly increased, but glycine release is not significantly increased in the ischemic brain region in a rat focal ischemia model (Grove, MYT. Et al., Journal of Neurochemistry, Vol. 57, 47.
0-478 (1991)). Therefore, theoretically, glycine antagonists should be very potent neuroprotectors. Because they can noncompetitively block the opening of NMDA channels by glutamate and, unlike competitive NMDA antagonists, do not need to overcome the high concentrations of endogenous glutamate released in the ischemic brain region. is there.

Furthermore, since glycine antagonists do not act to protect NMDA channel opening at either glutamate / NMDA or at the PCP binding site, these drugs are both PCP receptor ligands and competitive NMDA receptor antagonists. No observed side effects on PCP-like behavior will be induced (Trickle Bank, MD).
Et al., European Journal of Pharmacology, Vol. 167, 1
27-135 (1989); Cork, W .; , Journal of Pharmacology and Experimental Therapeutics (Jorunal of Pharmacolo
gy and Experimental Therapeutics) 245, 96
9 (1989); Willets and Barster, Neuropharmacology 27 (1).
249 (1988); Trickle Bank, M .; D. ,
European Journal of Pharmacology
(European Journal of Pharmacology) Volume 167 1
27-135 (1989); Zuckin, S .; R. Et al., Brain Research 294, 174
Page (1984); Bloody, K .; T. Et al, Science
(Science) 215, p. 178 (1982); Trickle Bank, M .; D. Et al., European Journal of Pharmacology
acology) 141, 497 (1987)). An available glycine antagonist was injected directly into the rodent brain,
This glycine antagonist has no side effects on PCP-like behavior, as shown by recent experiments that resulted in no PCP-like behavior (Trickle Bank, M. et al.
D. Et al., European Journal of Pharmacology 16
7: 127-135 (1989)).

[0012]

However, there are two major problems that prevent the development of glycine antagonists as clinically useful neuroprotective agents: A. The most available glycine antagonists, such as 7-Cl-kynurenic acid (Kemp; JA et al., Proceeding of
National Academy of Science of the United States of America (Proceedi
ng of National Academy of Science of the
United States of America) Volume 85 6547-
6550 page (1988)) 5,7-dichlorokynurenic acid
(MacNamara, D. et al., Neuroscience Let.
(Neuroscience Lett.) 120: 17-20 (19)
90)) and indole-2-carboxylic acid (Grey, NM et al., Journal of Medicinal Chemis.
34) 1283-1292 (1991))
Fail to cross the blood-brain barrier and therefore have no utility as therapeutic agents; B. The drug HA-966, which is the most widely available glycine antagonist that crosses the blood-brain barrier well (Fletcher and Lodge, European Journal of Pharmacolog
y) 151: 161-162 (1988) is a partial antagonist with micromolar affinity for the glycine binding site. The in vivo neuroprotective effect of HA-966 has not been shown due to its lack of in vivo bioavailability or with other available glycine antagonists.

Crosses the blood-brain barrier: PCP-like NMDA channel inhibitors, eg MK80
1, or a competitive NMDA receptor antagonist such as CGS
Lack of PCP-like behavioral side effects common to 19755; -Possess potent anti-ischemic effects due to the non-competitive properties of glutamate antagonists at NMDA receptors; -PCP-like NMDA channel inhibitors or competitive NMD
It has utility as a novel anticonvulsant with fewer side effects than A-antagonists; • A potent and selective glycine that helps define the functional importance of the glycine binding site of the NMDA receptor in vivo. The need for the presence of / NMDA antagonists continues.

[0014]

The present invention is directed to stroke, ischemia,
Treatment or prevention of central nervous system trauma, hypoglycemia and loss of neurons associated with surgical procedures, treatment, stimulation of neuronal degenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's syndrome Related to the treatment or protection of the adverse effects of hyperstimulation of sex amino acids and methods of anxiety, convulsions, chronic pain and induction anesthesia in animals in need of such treatment with formula (I):

[Chemical 19] [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl,
Aryl, heterocyclic group, heteroaryl group, nitro, amino, or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, haloalkyl, aryl, heterocyclic group, heteroaryl group, alkyl, nitro R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —NHC.
_{ONHAr, -NHCOCH 2 Ar, -COCH 2} Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy
(Wherein Ar is an aryl group, a heterocyclic group or a heteroaryl group); and R ₇ is hydrogen].

The present invention is directed to the treatment or prevention of neuronal loss associated with stroke, ischemia, central nervous system trauma, hypoglycemia and surgical procedures, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease. And methods for the treatment of neuronal degenerative diseases, including Down's syndrome, the treatment or protection of the adverse effects of hyperstimulation of stimulatory amino acids, and the treatment of anxiety, convulsions, chronic pain and induction anesthesia,
Animals in need of such treatment have formula (II):

[Chemical 20] [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl,
Aryl, heterocyclic group, heteroaryl group, nitro, amino, or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, haloalkyl, aryl, heterocyclic group, heteroaryl group, alkyl, nitro R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —NHC.
_{ONHAr, -NHCOCH 2 Ar, -COCH 2} Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy
(Wherein Ar is an aryl group, a heterocyclic group or a heteroaryl group); and R ₇ is hydrogen].

The present invention also relates to the novel 2,5-dihydro-2,
It also relates to 5-dioxo-1H-benzazepine substitutes and pharmaceutical compositions thereof. The present invention is the result of the discovery that 2,5-dihydro-2,5-dioxo-1H-benzazepine substitutes are highly bound to the glycine receptor. Further, certain 2,5-dihydro-2,5 of the present invention
The -dioxo-1H-benzazepine substitute readily crosses the blood-brain barrier, making it well suited for the treatment of neuronal degeneration in the central nervous system. Further, according to the invention 2,
Substituted 5-dihydro-2,5-dioxo-1H-benzazepines do not exhibit PCP-like behavioral side effects common to PCP-like NMDA channel inhibitors such as MK-801 and other NMDA antagonists such as CGS19755 . Therefore, the 2,5-dihydro-2,5-dioxo-1H-benzazepine substitution product of the present invention is
It has no significant side effects or toxicity and is beneficial in the treatment of pathophysiological conditions.

DESCRIPTION OF THE FIGURES FIG. 1 shows that 100 μM of 2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine
μM kainate (A) or 20 μM NMDA + 30
Membrane current induced by 0 μM glycine (B)
Fig. 7 depicts a graph showing inhibition at 50 mV and -80 mV. At these concentrations, DDHB completely inhibited the response to NMDA + glycine at both holding potentials. Inhibition of current induced by kainate is -80 m
V (5 experiments) up to 59 ± 3.6% of control, and +50 m
V (3 experiments) up to 55 ± 1.5% of control. This difference is not significant at p <0.05 (Student's t test). 100 μM 2,5-dihydro-2,5-dioxo-
Application of 3-hydroxy-1H-benzazepine alone had no effect at +50 or -80 mV (C).

FIG. 2A represents a graph showing control currents activated by 10 μM-10 mM kinate. Figure 2
B is 50 μM of 8-methyl-2,5-dihydro-2,5-
Shows a competitive antagonism of kainate currents activated with 40 μM-10 mM kainate by dioxo-3-hydroxy-1H-benzazepine, a control showing a graph showing the response to 10 mM kainate alone. Holding potential is -7
It is 0 mV.

FIG. 3 shows kynate alone (○) (1 in 4 cells)
3 times) or 8 μM 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine (▲) (13 times applied to 5 cells), 20 μM 8-methyl-2, 5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine (■) (applied 8 times to 50 cells),
Or 50 μM 8-methyl-2,5-dihydro-2,
5-dioxo-3-hydroxy-1H-benzazepine
Fig. 6 shows a graph showing the concentration-reactivity relationship in the presence of (●) (7 times applied to 3 cells). The point is the normalized current
rent) (I / Imax) mean ± standard error. The smooth curve is for all 4 concentrations of antagonist (0.8, 20 and 50 μ
M) is the best fit to eq.2 for all of the measured points, agonist EC ₅₀ = 120 μM (111-131 μM, 9
5% confidence interval), slope factor = 1.39 (1.29-1.4)
7) and the antagonist Kв = 6.4 μM (5.5-7.5 μM)
Is. The individual suitability of eq.1 is not significantly better than that achieved simultaneously with eq.2 at the 5% level (F ₅₁₉₇
= 0.17).

FIG. 4 shows that L-glutamate (Glu) -activated initial transient currents were detected by 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine. Fig. 6 shows a graph showing inhibition. Currents were activated by rapid application of 500 μM glutamate alone or with 8, 20 or 50 μM 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine. To apply each of the L-glutamates containing 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, the cells were first applied to the same concentration of 8-methyl-2,5 −
Dihydro-2,5-dioxo-3-hydroxy-1H-
Equilibrated in a control external solution containing benzazepine. MK-801 was contained at 1 μM in all solutions and
Inhibits DA receptor channels. Holding potential is -70 mV
Met.

FIG. 5 shows 8-methyl-2,5-dihydro-
FIG. 2 is a bar graph showing that 2,5-dioxo-3-hydroxy-1H-benzazepine inhibits the initial transient current activated by L-glutamate. value is,
(Current toward peak-steady current), and the control reaction (1
Expressed as a percentage of (peak current-steady current) with 00 μM L-glutamate alone. The rod is 8 μM
8-Me at 8 cells (20 times applied to 8 cells), 20 μM (23 times applied to 9 cells), and 50 μM (23 times applied to 10 cells)
-Mean ± standard error in DDHB.

FIG. 6 shows 8-methyl-2,5-dihydro-
FIG. 6 is a graph showing competitive antagonism of L-glutamate-activated constant current by 2,5-dioxo-3-hydroxy-1H-benzazepine. Currents were activated by applying 1 μM-1 mM glutamate (A). In another cell, currents were evoked with 4 μM-1 mM L-glutamate supplemented with 50 μM 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, the control being glutamate alone (B ). The holding potential is -70 mV. MK-801 is contained at 1 μM in total solution and inhibits NMDA receptor channel.

FIG. 7 shows glutamate alone ((◯) (10 cells) or 8 μM 8-methyl-2,5-dihydro-2,
5-dioxo-3-hydroxy-1H-benzazepine
(▲) (6 cells), 20 μM 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine (■) (6 cells), or 50 μM 8-methyl-2, Concentration in the presence of 5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine (●) (8 cells)
3 is a graph showing a relationship of reactivity. The point is the normalized current (I
/ Imax) mean ± standard error. The smooth curve shows that eq.2 is the best fit for all points of the measured values of all 4 concentrations of antagonist (0, 8, 20 and 50 μM), agonist EC ₅₀ = 17 μM (15-19 μM, 95 % Confidence interval), slope factor = 1.64 (1.74-1.80) and antagonist K в = 6.4 μM (7.8-11.8 μM).
The suitability of individual eq.1 is not significantly better than the suitability achieved simultaneously with eq.2 at the 5% level (F ₅₁₁₇ = 1.17).

FIG. 8 shows 8-methyl-2,5-dihydro-
Cainate (A) at non-NMDA receptors by 2,5-dioxo-3-hydroxy-1H-benzazepine
Fig. 6 shows a graph showing competitive antagonism of steady-state activation of glutamate (B). The points are eq. Apparent mid-highest concentration of agonist (E determined from individual suitability of 1
C ₅₀ '± 95% confidence limit) (see Examples) and kainate (A) and L-glutamate (B) as a function of antagonist K в + antagonist concentration (K в + [8-Me-DDHB])
It was plotted with. The straight line is the equation: EC ₅₀ '= (EC ₅₀ / K
в) · (Kв + [antagonist]) is the relationship assumed from a single competitive antagonism. The values of EC ₅₀ and Kв are
As in FIGS. 3 and 7, eq. It was determined from the compatibility of 2 (see Examples). For kainate, EC ₅₀ = 120 μM + 8−
KDD of MeDDHB vs. kynate = 6.4 μM. L
For glutamate, EC ₅₀ = 17 μM; 8-MeDDH
K v of B to glutamate = 9.6 μM.

FIG. 9 shows 8-methyl-2,5-dihydro-
FIG. 6 depicts a graph showing competitive antagonism of glycine synergy at the NMDA receptor by 2,5-dioxo-3-hydroxy-1H-benzazepine. Figure 9A shows 1 mM NMD
Whole cell currents induced by A and 6 concentrations of glycine are shown. In another cell, the current passed by NMDA and concentrations of glycine was 10 μM 8-methyl-2,5
-Dihydro-2,5-dioxo-3-hydroxy-1H
-Determined in the presence of benzazepine, control is antagonist (B)
Reactivity to NMDA + 50 μM glycine without. The holding potential was -70 mV.

FIG. 10 shows glycine alone (○) (1 in 5 cells).
5 times) or 2 μM 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine (▲) (8 times applied to 4 cells), 10 μM 8-methyl-2, 5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine (■) (9 times applied to 3 cells) or 50 μM 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy -1H-Benzazepine (●)
FIG. 6 shows a graph showing the concentration-reactivity relationship in the presence of (applied 13 times to 4 cells). The points are the average ± standard error of the normalized current (I / Imax). The smooth curve is the eq. 2 is the best match, agonist EC ₅₀
= 770 mM (690.850 mM, 95% confidence interval), slope factor = 1.29 (1.20-1.37) and antagonist Kx = 470 nM (410-540 nM). eq.
Individual suitability of 1 is at the 5% level, eq. 2 is not significantly better than the conformity achieved at the same time (F ₅₂₁₇ = 2.0)
3).

FIG. 11 is a graph showing competitive antagonism of 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine on glycine activation at the glycine allosteric site of the NMDA receptor. Represent The points correspond to individual eq. Apparent intermediate highest concentration of agonist (EC ₅₀ '± 9
5% confidence limit), and the antagonist K в + antagonist concentration (K
Plot as a function of ++ [8-Me-DDHB]).
The straight line is the relationship assumed in a single competitive antagonism, which is obtained by the equation EC ₅₀ '= (EC ₅₀ / K в) · (K в + [antagonist]). The values of EC ₅₀ and K × are eq. Determined from the suitability of 2. Glycine of EC ₅₀ = 770nM; 8
-Ke of Me-DDHB vs. glycine = 470 nM.

FIG. 12 represents a graph showing that increasing the concentration of NMDA lowers the EC ₅₀ of glycine at allosteric synergistic sites. Concentration-reactivity relationship is shown for glycine in the presence of 25 μM NMDA (○) (5 cells applied 9 times) or 1 mM NMDA (▲) (5 cells applied 15 times). . The points are the average ± standard error of the normalized current (I / Imax). The smooth curve is the eq. For all measured points for each concentration of NMDA. 1
Fits best. The EC ₅₀ for glycine at 25 μM NMDA was 308 nM (279-339 nM, 95% confidence interval; n = 1.4) compared to 1 mM NMD.
The EC _{50 for A} is 770 nM (690-850 nM; n = 1.
3). The dotted line is the scheme 2 of Benebeniste et al., Journal of Physiology (London) 428, 333-357 (1990).
Is a concentration-reactivity relationship of glycine predicted from the computer simulation of FIG. According to the simulation, when 5 μM NMDA was used, glycine E
C ₅₀ is 294 nM (n = 1.2), 25 μM NMD
In A, the EC ₅₀ is 586 nM (n = 1.1) and 1 mM NM
The EC _{50 for} DA was 853 nM (n = 1.2).

FIG. 13 is a graph showing antagonism of the NMDA recognition site by 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine. A: 1 mM-serine was added to saturate the glycine allosteric site to 1 μM-1 mM NM
Current induced by DA. B: another cell, 50 μM 8-
Controls are responsive to 1 mM NMDA without antagonist (all containing 1 mM D-serine), with current passed by 4 μM-1 mM NMDA in the presence of Me-DDHB. The holding potential is -70 mV.

FIG. 14 shows NMDA + 1 mM D-serine.
(○) (applied 17 times in 7 cells) and at 50 μM 8-methyl-2,5-dihydro-2,5-dioxo-3-
FIG. 6 shows a graph showing the concentration-reactivity relationship in the presence of hydroxy-1H-benzazepine (●) (9 applications in 3 cells). Points are the average ± standard error of the standardized current (I / Imax). The smooth curve is eq. For all 0 and 50 μM antagonist measured points. 2 was the best match, agonist EC ₅₀ = 13 μM (12-14 μM, 95% confidence interval), slope coefficient = 1.33 (1.25-1.42) and antagonist K в = 27 μM (23-32 μM) Is. eq.
Individual suitability for eq. 1 at the level of 5%. Was not significantly better than the conformity achieved simultaneously with 2 (F ₁₁₃₆ =
0.58).

FIG. 15 shows 2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 4-bromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, And 7-methyl-2,5
-Dihydro-2,5-dioxo-3-hydroxy-1H
-Represents a graph showing antagonism of kainate by benzazepine. Kainate alone (○) (applied 15 times to 5 cells) or 100 μM 2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine (●)
(6 times applied to 2 cells), 100 μM 4-bromo-2,5
-Dihydro-2,5-dioxo-3-hydroxy-1H
-Benzazepine (▲) (applied 11 times to 2 cells), or 1
00 μM 7-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine (■) (2
Concentration-reactivity relationship in the presence of (6 times applied to the cell). Points are the average ± standard error of the standardized current (I / Imax). The smooth curve is e for each concentration-reactivity relationship.
q. 1 was the best fit and the slope factors were such that all four curves were the same. If the fit is best, n = 1.
47. If the slopes are not equal, eq. Individual suitability of 1 is 5% level, not significantly worse
(F ₃₁₈₅ = 0.63). K × for each antagonist is eq. For the measurement results of the antagonist and the control. Determined from the best fit of 2, the slope factor was constant at the optimal values of all four curves (n = 1.47). Kynart alone, EC
₅₀ = 120 μM (112-129 μM, 95% confidence interval). For 2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, E
C ₅₀ '= 305 μM (279-333 μM) and Kв =
65 μM (53-80 μM). 4-bromo-2,5
-Dihydro-2,5-dioxo-3-hydroxy-1H
-For benzazepine, EC ₅₀ '= 310 μM (288-3
35 μM) and K × = 63 μM (53-74 μM). 7-methyl-2,5-dihydro-2,5-dioxo-
The 3-hydroxy -1H- benzazepine EC ₅₀ '=
566 μM (511-627 μM) and K × = 27 μM
(22-32 μM).

FIG. 16 shows 7-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 4-bromo-2,5-dihydro-2,5-dioxo-3-hydroxy. -1H-benzazepine and 2,
5-dihydro-2,5-dioxo-3-hydroxy-1
FIG. 6 is a graph showing antagonism at the glycine allosteric site of the NMDA receptor by H-benzazepine.
All currents were activated by various concentrations of glycine in the presence of 1 mM NMDA to saturate the NMDA recognition site. The concentration-reactivity relationship was either for glycine alone (○) (applied 23 times in 8 cells) or 100 μM 2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine (●) ( 9 times with 2 cells), 100 μM 4-
Bromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine (▲) (applied 10 times in 3 cells) or 100 μM 7-methyl-2,5-dihydro-2,5- In the presence of dioxo-3-hydroxy-1H-benzazepine (■) (4 cells applied 10 times). The points are the average ± standard error of the normalized current (I / Imax).
The smooth curve is eq. For each concentration-reactivity relationship.
1 was the best match and glycine alone had an EC ₅₀ = 66
5 μM (634-697 μM, 95% confidence interval) and n = 1.19. With 2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine,
EC ₅₀ '= 23 μM (22-24 μM) and n = 1.34
Met. For 4-bromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, E
C ₅₀ '= 3.3 μM (3.2-3.5 μM) and n = 1.46
Met. For 7-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, E
C ₅₀ '= 7.7 μM (7.4-8.4 μM) and n = 1.58
Met.

FIG. 17 shows 7-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 4-bromo-2,5-dihydro-2,5-dioxo-3-hydroxy. -1H-benzazepine and 2,
5-dihydro-2,5-dioxo-3-hydroxy-1
FIG. 6 is a graph showing antagonism at the agonist recognition site of the NMDA receptor by H-benzazepine. All currents were at various concentrations of NMD in the presence of 1 mM D-serine.
A-induced saturation of the glycine allosteric site. The concentration-reactivity relationship was either for NMDA alone (○) (17 applications in 7 cells) or 100 μM 7-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-. Benzazepine (●) (applied 11 times in 4 cells), 100 μM 4-bromo-2,5-dihydro-2,
5-dioxo-3-hydroxy-1H-benzazepine
(▲) (3 cells applied 10 times) or 100 μM 7-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine (■) (3 cells applied 10 times)
In the presence of. The points are the average ± standard error of the normalized current (I / Imax). A smooth curve shows that for each concentration-reactivity relationship, eq. 1 is the best match. NM
With DA alone, the EC ₅₀ = 13.2 μM (12.8-13.7).
μM, 95% confidence interval) and n = 1.31. For DDHB, EC ₅₀ '= 95 μM (92-99 μM
M) and n = 1.59. For 4-bromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, the EC ₅₀ ′ = 29 μM (28-30 μM) and n = 1.75. For 7-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, EC ₅₀ '= 25 μM (24-26 μM) and n
= 1.33.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention provides a novel 2,5-dihydro-2,5-dioxo, a highly selective and competitive antagonist of the glycine binding site of NMDA receptors and stimulatory amino acids. -1H-
It relates to a benzazepine substitute. The substituted 2,5-dihydro-2,5-dioxo-1H-benzazepine of the present invention has the following formula (I):

[Chemical 21] [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl, aryl, heterocyclic group, heteroaryl group, nitro, amino, or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, Haloalkyl, aryl, heterocyclic group, heteroaryl group, alkyl, nitro, amino or azide; R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —N
_{HCONHAr, -NHCOCH 2 Ar, -COCH 2} A
r, hydroxyl, alkoxy, aryloxy, aralkyloxy, cycloalkylaoxy or acyloxy (where Ar is an aryl group, a heterocyclic group or a heteroaryl group); and R ₇ is hydrogen] .
Other 2,5-dihydro-2,5-dioxo-1H-benzazepine substitutes have the formula (II):

[Chemical formula 22] [Wherein, R _{1 to} R ₇ are as defined above. ].

Within the scope of formula I, in preferred compounds, R ₂ is halo or nitro, R ₃ is hydrogen or halo,
R ₄ is halo or haloalkyl, and R ₅ is hydrogen. Typical C _6-14 aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups. Typical halo groups include fluorine, chlorine, bromine and iodine. Typical haloalkyl groups are C _1-4 alkyl groups substituted by one or more fluorine, chlorine, bromine or iodine atoms such as fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1- Contains difluoroethyl and trichloromethyl groups.

Typical heterocyclic groups include the tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolindinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl and pyrazolinyl groups. Typical heteroaryl groups are thienyl, benzo [b] thienyl, naphtho [2,3-
b] thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenaxanthinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indoridinyl, isoindolyl, 3H-indolyl, Indolyl, indazolyl, purinyl, 4H-quinolidinyl, isoquinolyl, quinolyl, phthaldinyl, naphthyridinyl, quinozalinyl, cinolinyl, pteridinyl, 5aH-carbazolyl, carbozolyl, β-carbazolyl, phenanthridinyl, acridinyl, perimidinyl, phenanthlorinyl,
Includes phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, flazanil and phenoxazinyl groups.

A particularly preferred 2,5-dihydro-2,5-dioxo-1H-benzazepine substitute of the present invention is 4-promo-2,5-dihydro-2,5-dioxo-
3-hydroxy-1H-benzazepine, 3-bromo-
2,5-dihydro-2,5-dioxo-4-hydroxy-
1H-benzazepine, 7-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-methyl-2,5-dihydro-2,5-dioxo-4-hydroxy-1H- Benzazepine, 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 8-methyl-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6,8-dichloro-2,5-dihydro-2,
5-dioxo-3-hydroxy-1H-benzazepine, 6,8-dichloro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7,8
-Dichloro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7,
8-dichloro-6-nitro-2,5-dihydro-2,5-
Dioxo-4-hydroxy-1H-benzazepine,
7,8-dichloro-6-bromo-2,5-dihydro-2,
5-dioxo-3-hydroxy-1H-benzazepine, 7,8-dichloro-6-bromo-2,5-dihydro-
2,5-Dioxo-4-hydroxy-1H-benzazepine, 7,8-dibromo-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7,8-dibromo- 6-Nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7,8-difluoro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy- 1H-benzazepine, 7,8-difluoro-6-nitro-2,5
-Dihydro-2,5-dioxo-4-hydroxy-1H
-Benzazepine, 7-chloro-8-bromo-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-chloro-8-bromo-
6-nitro-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 7-bromo-8-
Chloro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-bromo-8-chloro-6-nitro-2,5-dihydro-2,5
-Dioxo-4-hydroxy-1H-benzazepine,
7-Fluoro-8-chloro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-fluoro-8-chloro-6-nitro-
2,5-dihydro-2,5-dioxo-4-hydroxy-
1H-benzazepine, 8-fluoro-7-chloro-6
-Nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 8-fluoro-7-
Chloro-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-fluoro-8-bromo-6-nitro-2,5-dihydro-2,
5-dioxo-3-hydroxy-1H-benzazepine, 7-fluoro-8-bromo-6-nitro-2,5-
Dihydro-2,5-dioxo-4-hydroxy-1H-
Benzazepine, 8-fluoro-7-bromo-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 8-fluoro-7-bromo-6-nitro-2,5- Dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 6-chloro-8
-Trifluoromethyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-8-trifluoromethyl-2,5-dihydro-2,
5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-7-nitro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro- 7-nitro-8
-Trifluoromethyl-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-9-nitro-8-trifluoromethyl-2,5-
Dihydro-2,5-dioxo-3-hydroxy-1H-
Benzazepine, 6-chloro-9-nitro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 6,7,8-trichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6,7,8-trichloro-2,5-dihydro-2 , 5-Dioxo-4-hydroxy-1H-benzazepine, 6,7,8,9-tetrafluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6,7,8, 9-Tetrafluoro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-nitro-7,8-dibromo-2,5-dihydro-2,5-dioxo-3-hydroxy -1H-benzazepine, 6-nitro-7,8-
Dibromo-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-bromo-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H- Benzazepine, 6-bromo-8-trifluoromethyl-2,5-dihydro-2,5-
Dioxo-4-hydroxy-1H-benzazepine, 6
-Bromo-8-fluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-
Bromo-8-fluoro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy- 1H-benzazepine, 6-chloro-8-methyl-2,5-dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 7-chloro-8
-Methyl-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-chloro-8-methyl-6-nitro-2,5-dihydro-2,
5-dioxo-4-hydroxy-1H-benzazepine, 7-chloro-8-methyl-6-bromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-chloro-8- Methyl-6-bromo-
2,5-dihydro-2,5-dioxo-4-hydroxy-
1H-benzazepine, 7-bromo-8-methyl-6-
Nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-bromo-8-methyl-6-nitro-2,5-dihydro-2,5-dioxo-
4-hydroxy-1H-benzazepine, 7-fluoro-8-methyl-6-nitro-2,5-dihydro-2,5-
Dioxo-3-hydroxy-1H-benzazepine, 7
-Fluoro-8-methyl-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 8-methyl-6-trifluoromethyl-2,
5-dihydro-2,5-dioxo-3-hydroxy-1
H-benzazepine, 8-methyl-6-trifluoromethyl-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 8-methyl-7-nitro-6-trifluoromethyl-2, 5-dihydro-2,5-
Dioxo-3-hydroxy-1H-benzazepine, 8
-Methyl-7-nitro-6-trifluoromethyl-2,
5-dihydro-2,5-dioxo-4-hydroxy-1
H-benzazepine, 8-methyl-9-nitro-6-trifluoromethyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 8-methyl-9-nitro-6-trifluoro Methyl-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 8-methyl-6,7-dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H- Benzazepine, 8-methyl-6,7-dichloro-2,5-
Dihydro-2,5-dioxo-4-hydroxy-1H-
Benzazepine, 8-methyl-6,7,9-trifluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 8-methyl-6,7,9-trifluoro-2, 5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 8-methyl-6,7
-Dibromo-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 8-methyl-6,
7-dibromo-2,5-dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 8-methyl-7
-Bromo-6-trifluoromethyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 8-methyl-7-bromo-6-trifluoromethyl-2,5-dihydro-2 , 5-Dioxo-4-hydroxy-1H-benzazepine, 8-methyl-7-bromo-6-fluoro-2,5-dihydro-2,5-dioxo-
3-hydroxy-1H-benzazepine, and 8-methyl-7-bromo-6-fluoro-2,5-dihydro-
Including, but not limited to, 2,5-dioxo-4-hydroxy-1H-benzazepine.

Certain compounds of the present invention are expected to be potent anticonvulsant agents in animal models and may protect against ischemia-induced neuronal cell death after intraperitoneal administration in the gerbil systemic ischemia model. Ah 6-chloro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-8-trifluoromethyl-2,5-dihydro-2,5-
Dioxo-4-hydroxy-1H-benzazepine,
7,8-dichloro-6-nitro-2,5-dihydro-2,
5-Dioxo-3-hydroxy-1H-benzazepine and 7,8-dichloro-5-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine are expected to be particularly potent. It

The compounds of the present invention are effective in the treatment or protection of neuronal loss, neurodegenerative diseases, inertial pain, and as anticonvulsants and induction anesthesia. It is expected that certain compounds of the present invention will exhibit little or no non-selective binding to other receptors, especially the side effects caused by PCP and glutamate receptors associated with the NMDA receptor. Moreover, certain compounds inhibit the kainate, AMPA and quisqualate receptors, thus they are useful as broad spectrum stimulatory amino acid receptor antagonists.
Furthermore, the compounds of the invention occur, for example, in the NMDA receptor system. By counteracting the adverse effect of stimulatory amino acid overactivity, by inhibiting the glycine receptor and opening ligand-gated cation channels, allowing excess Ca ⁺⁺ current to enter neurons during ischemia, Effective in treating or defending. Neurodegenerative diseases that can be treated with the compounds of the invention include those selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's syndrome.

The compounds of the invention find particular utility in treating or preventing neuronal loss associated with multiple strokes that cause dementia. After a patient has been diagnosed with a stroke, the compounds of the invention can be administered to ameliorate immediate ischemia and prevent further neuronal damage that may result from recurrent stroke. In addition, the compounds of the present invention are capable of crossing the blood-brain barrier, which makes them particularly useful for treating or preventing pathologies involving the central nervous system. The compounds of the present invention find particular utility in treating or preventing the neurological adverse effects of surgical procedures. For example, coronary bypass surgery requires the use of a heart-lung mechanism that tends to cause air bubbles in the circulatory system within the brain. The presence of such bubbles deprives the neuronal tissue of oxygen, resulting in anoxia and ischemia. The dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine substitutes and 2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine substitutes of the present invention may be administered before or after surgical treatment. When administered, it will treat or prevent the resulting ischemia. In a preferred embodiment, the compounds of the invention are administered to patients undergoing cardiopulmonary bypass surgery or carotid endarterectomy surgery.

The compounds of the present invention also find utility in treating or preventing chronic pain. Such chronic pain is the result of surgical procedures, trauma, headaches, arthritis, or other degenerative diseases. The compounds of the present invention also find utility, inter alia, in the treatment of phantom pain that is the result of amputation. In addition to the treatment of pain, the compounds of the invention are also expected to be useful in the induction of general or local anesthesia, eg during surgical procedures.

The novel glycine and stimulatory amino acid antagonists were tested using a number of anticonvulsant drug tests in mice,
In vivo anticonvulsant activity after intraperitoneal injection can be tested (DBA-2 mouse audiogenic seizure model, mouse pentylenetetrazole-induced seizures, NMDA-induced death). The compounds can also be tested in a drug discrimination test in rats trained to discriminate PCP from saline. It is expected that most of the compounds of the invention will not generalize to PCP in any amount. further,
It is also expected that none of these compounds produce behavioral stimuli in the locomotor activity test in mice. These results indicate that the novel glycine, AMPA, kainate and quisqualate antagonists of the present invention have PCP-like behavior common to NMDA channel inhibitors such as MK-801 and PCP, or competing NMDA antagonists such as CGS19755. It is expected that it would suggest that there are no side effects on. Although the novel glycine and stimulatory amino acid antagonists are also expected to show potent activity in vivo after intracoelomic injection,
This suggests that these compounds can cross the blood-brain barrier.

The compounds of the invention were stimulated with 1 μM glycine in rat or guinea pig brain membrane homogenates.
By observing the inhibition of the binding of ^[3 H] -MK-801, can be tested for potential glycine antagonist activity ^[3 H] -MK-801 binding site (PCP receptor) is
[ ³ H] -MK-801 can barely bind in the presence of more potent glycine antagonists, as it is only accessible upon opening of ion channels by glutamate and glycine. (Fletcher, EL, et al., Glycine Neurotransmissio
n), Otterson, P. et al. (eds.), John Willey & Sons (1190); Johnson, J. et al. W. Et al., Nature 325: 529 (1987)).

The compounds of the present invention are described by Baychar and Res, Canadian Journal of Chemistry.
(Canadian Journal of Chemistry) Volume 52 610
Can be prepared by the general method taught by P. (1974), the entire contents of which are incorporated herein by reference.
Generally, this method involves reacting the appropriate 2-alkoxy-1,4-naphthoquinone substitution (III) with hydrazoic acid and gently alkaline hydrolysis to give the corresponding 2,5-dihydro-2,5-dioxo- 1H-1-benzazepine
This includes producing (IV) (see Scheme 1). For example, Schaffner Sabah, K .; , Journal of Medicinal Chemistry
6-chloro-2-alkoxy-1,4-naphthoquinone can be synthesized in accordance with "Emistry" Vol. 27, p. 990 (1984), which is treated with hydrazoic acid and
Dihydro-2,5-dioxo-1H-1-benzazepine can be obtained.

[Chemical formula 23]

Alternatively, the appropriate substituted 1,4-naphthoquinone (V) is treated with acetic anhydride and boron trifluoride in ether to give the corresponding 1,2,4-triacetoxynaphthylene.
(VI) can be obtained, which can be hydrolyzed in methanol in the presence of sodium methoxide and air to give the corresponding 2-hydroxy-1,4-naphthoquinone. This compound is F. Feeder, Journal ·
Of the American Chemical Society (Journa
l of American Chemical Society) Volume 70 316
P. 5 (1948) and Fishers Regent
(Fierser's Reagents) Vol. 1, p. 484, treated with azide ion and then the corresponding 2,5-dihydro-2,
5-Dioxo-3-hydroxy-1H-1-benzazepine (VII) is obtained. (See Scheme II)

[Chemical formula 24]

Further corresponding 1 or 2-octa-1,
By the method of oxidizing 2,3,4-tetrahydronaphthylene-substituted product (VIII) with molecular oxygen in the presence of potassium tertiary butoxide, the corresponding 2-hydroxy-1,4
Obtaining dioxo-1,4-dihydronaphthylene. Bailey and Thompson, Journal of American Society
Chemical Society) 70, 3165 (1948)
reference. The product of these reactions is the corresponding 2,5-dihydro-2,5-dioxo-3-hydroxy-according to Scheme I.
It may be continued until it becomes 1H-1-benzazepine.

[Chemical 25]

It is known that the naphthylene itself is oxidized to 1,4-naphthoquinone and the yield is 35%.
(See Broud and Faucet, Org. Synth. Col. IV, page 698). Using this method, chlorinated or 1,4-naphthylene nitrate can be synthesized and oxidized to the corresponding chlorinated and 1,4-naphthoquinone nitrate, which, as outlined in Scheme II, Nitric acid 2,5-dihydro-2,5-dioxo-3-hydroxy-
It may be continued until it becomes 1H-1-benzazepine. An electron withdrawing group on the benzene ring can be added by synthesis of the silyl derivative (IX) with a halotrialkylsilane, followed by an electron affinity substitution reaction. Silyl ether (IX) N
Expected to react with chlorosuccinimide to give the chlorine derivative (X) and react (IX) with nitrous acid to remove the silyl (eg with the fluoride anion) to give the nitro derivative (XI). (See Scheme IV).

[Chemical formula 26]

Compounds of formula XII (R ₆ ═CH ₂ CONHAr) can be synthesized by N-alkylating the corresponding hydroxyl protected anion with a reactive halide (see Scheme V). For example, 7,8-dichloro-6-nitro-2,
5-dihydro-2,5-dioxo-3-tertiary
Butyldimethylsiloxy-1H-1-benzazepine
Deprotonation of (XIII) with a base such as lithium diisopropylamide to give the corresponding anion
(XIV) is obtained. Alkylation with α-haloesters such as methyl-bromoacetate, followed by hydrolysis of the ester gives the corresponding acid (XV). Condensing the acid with an aryl alcohol in the presence of a dehydrating agent such as DCC,
The anilide (XII) is obtained. The silyl protecting group of (XII) can be removed with a fluoride anion.

[Chemical 27]

Compounds in which R = -NHCONHAr (XIX) are prepared by converting the aminated anion XVII to chloramine, mesitylenesulfonyloxyamine (Tamura, Y., et al., Synthesis 1, (1977)) or hydroxylamine-O. -Sulphonic acid (Warace, RG, Organic Preparations and Procedures International)
and Procedures International 14: 269 (1)
982)) and N-amino-
2,5-dihydro-2,5-dioxo-3-tert-butyldimethylsiloxy-1H-1-benzazepine intermediate XVIII is obtained. Alternatively, one of the amide nitrogen atoms is N-nitrosylated followed by reduction to give the N-amino-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-1-benzazepine intermediate. When a free amino group is acylated with, for example, phenylisocyanate,
Get XIX. In addition, R is —NHCOCH ₂ Ar (X
X), the intermediate I is acylated with phenylacetyl chloride to give XX (see Scheme VI).

[Chemical 28]

The corresponding 2,5-dihydro-2,5-dioxo-4-hydroxy-1H-1-benzazepine isomers are described by Mohr, H .; W. Et al. Let. (Tetr. Le
tt. ) 1243 (1960) and Reese, A .; H. ,
J. Chem. Sock. (J. Chem. Soc.) Page 3111 (1
959). Thus, the present invention provides 2,5-dihydro-2,5-dioxo-3-hydroxy, which has a high degree of binding to the glycine receptor and a low degree of binding to kainate and AMPA sites. −
The 1H-1-benzazepine substitute is indicated. Other compounds of the invention have a high degree of antagonism at kainate, AMPA and quisqualate receptors in addition to glycine receptors. According to the invention, 2,5-dihydro-2,5 having a high degree of binding to the glycine receptor
-Dioxo-3-hydroxy-1H-1-benzazepine substitution product and 2,5-dihydro-2,5-dioxo-4
The -hydroxy-1H-1-benzazepine substitute exhibits a glycine binding affinity (Ki) of about 10 μM or less in the glycine binding assay. (See Examples). 2,5-Dihydro-2,5-dioxo-3-hydroxy-1H-1-benzazepines of the present invention and 2,5-dihydro-2,5-dioxo-4-hydroxy-1H-1-
Benzazepines are preferred as they exhibit a Ki of 1 μM or less. Furthermore, the 2,5-dihydro-2,5-dioxo-3-hydroxy-1H-1-benzazepines and 2,5-dihydro-2,5-dioxo-4-hydroxy-1H-1-benzazepines of the present invention The kind is
It is preferred that Ki exhibit 0.1 μM or less.
A compound exhibits a high degree of binding to the kainate and AMPA sites when it exhibits a Ki in the kainate or AMPA binding assay of about 10 μM or less, especially 1 μM or less.

In vitro glycine antagonism is 1 μM
It can be determined using the glycine stimulated [ ³ H] -MK801 binding assay. This assay takes advantage of the fact that [ ³ H] -MK801 binding to the PCP receptor within the pore of the NMDA channel depends on the presence of both glutamate and glycine. In the absence of glycine but the presence of glutamate, [ ³ H] -MK801 cannot effectively bind to the PCP receptor. Because NMDA channels remain closed, and [ ³ H] -MK801's access to PCP receptors inside the closed channel pores is strictly limited.

The assay is performed using a rat brain membrane homogenate enriched in NMDA receptors. The membrane is prepared as follows. Frozen rat brain (obtained from Pelle Freeze, Loggers, Alkansas) is homogenized in 15 volumes (weight / volume) of ice-cold 0.32 M sucrose. 10 homogenates
Spin at 00 xg for 10 minutes. Collect the supernatant, 4400
Spin at 0xg for 20 minutes. The nodules are suspended in 15 volumes of water (relative to the original brain weight). Homogenate again 44
Spin at 000 xg for 20 minutes. The nodules are resuspended in 5 volumes of water and the suspension is freeze-thawed twice. After the last melt cycle, the suspension is made up to 15 volumes with water and 44000 × g
Resuspend the clumps spinning for 20 minutes at 5 volumes of ice-cold 10 mM HEPES, K containing 0.04% Triton X-100
Titrate with OH to pH 7.4. Membrane Triton / HEP
Incubate with ES buffer for 15 minutes at 37 ° C. Make 15 volumes with ice-cold 10 mM HEPES, pH 7.4 and spin / wash 3 times with 44000 × g spin between washes. The final obtained small mass is 50 mM HEPES, pH
Suspend in 3 volumes of 7.4 and determine protein concentration using a standard dye-binding protein assay (Bio-Rad, Richmond, CA). The suspension is stored at -80 ° C until needed. Use only HPLC grade water instead of all buffers and suspensions / washes. Sufficient washing is required to remove as much of the endogenous glycine from the membrane preparation as possible.

On the day of the assay, the pre-prepared membrane is melted and 5 mM Tris / HCl buffer, pH 7.4 is added to bring the final protein concentration to 0.156 mg / ml. For the binding assay, 0.8 ml of membrane was pipetted into a polypropylene tube followed by 15.1 μM 5,7-dichlorokynurenic acid.
(DCK) 0.033 ml, 30.3 μM glycine in buffer 0.033 ml (or buffer alone), 303 μM in buffer
Glutamate (or 1 mM PCP 0.1 ml instead of DCK / glycine / glutamate for control) 0.033
ml, glycine antagonist in buffer (or buffer alone) 0.
Transfer 033 ml and 0.1 ml of 200 000 com [ ³ H] -MK801 containing buffer. Non-specific binding is defined as the difference in binding that occurs in the absence or presence of PCP (final concentration: 100 μM). To determine the effect of 1 μM glycine on [ ³ H] -MK801 binding, 10 μM
The bound radioactivity when glutamate was present alone (final concentration) was determined by 10 μM glutamate and 1 μM glycine.
Subtract from bound radioactivity when both (final concentration) are present. 500 nM concentration (final) of 5,7-dichlorokynurenic acid
Add (DCK) to all test tubes. This concentration of the glycine antagonist DCK "buffers" most of the residual endogenous glycine that is not removed in the extensive washing steps that occur during the membrane preparation process. 500 nMDCK does not interfere with the stimulation of [ ³ H] -MK801 binding caused by the addition of 1 μM exogenous glycine.

After incubating the assay sample at room temperature for 120 minutes,
Membrane-bound activity is isolated from free radioactivity by vacuum filtration through Whatman glass fiber filters pretreated with 0.3% polyethyleneimine.
The filtration was performed using a Brandel 48-well cell harvester (Cell Harves
ter). The filtered membrane is washed 3 times with 3 ml of ice-cold buffer each. Transfer filter to scintillation vial and add 5 ml scintillation cocktail. The vial is shaken overnight and the radioactivity is counted by liquid scintillation spectroscopy. The assay is performed in triplicate and all experiments are performed at least three times.

The inhibitory dose-response curve is 5 nM-330 nM
Constructed with increasing concentrations of glycine antagonist. IC
₅₀ values were determined by computer-assisted plotting of inhibition curves and interpolation with 1 μM glycine stimulation [ ³ H] -MK8.
Determined with compounds active in inhibiting 01 binding. When the compounds were found to inhibit glycine stimulation ^[3 H] -MK801 binding, glycine stimulation ^[3 H] -MK801 binding to N
Experiments are carried out to determine if it is really mediated at the glycine binding site of the MDA receptor. In these experiments 1 μM glycine stimulated [ ³ H] -MK801
A fixed concentration of antagonist sufficient to inhibit binding by> 95% was used without additional glycine (1 μM or more) and an additional increasing concentration of glycine (2 μM-1 μM).
Incubate with membrane in the presence of M). Inhibition of [ ³ H] -MK801 binding by drugs in the presence of 1 μM glycine
Upon sufficient reversal by adding increasing concentrations of glycine, inhibition of [ ³ H] -MK801 binding then led to NMDA.
It is mediated by drugs that act as antagonists at the glycine binding site of the receptor. After constructing an inhibitory dose-response curve and determining the reversibility of glycine, the glycine antagonist Ki
Values are given as experimentally determined IC ₅₀ values, known concentration of glycine in the assay (1 μM) and known affinity of glycine for the glycine binding site of the NMDA receptor (100 μM).
Is calculated using the Cheng and Prusoff equations.

[0056] The same rat brain membrane homogenates as used in 1μM glycine-stimulated ^[3 H] -MK801 binding assay, ^[3
Used for H] -AMPA radioligand binding assay. On the day of assay, thaw the frozen membrane (prepared as described above) to 2.5 mM
Diluted with 30 mM Tris / HCl buffer containing 100 mM CaCl ₂ and 100 mM KSCN, pH 7.4, 1.25 mg /
Obtain the final membrane concentration of ml membrane protein. For the binding assay, 0.8 ml of membrane homogenate was added to a polypropylene tube, followed by 0.033 ml drug and 0.067 ml buffer (or 0.1 ml buffer alone for control) and 200,000 cpm [ ³ H]-.
Add 0.1 ml of buffer containing AMPA. The assay is incubated on ice for 30 minutes. Whatman glass fiber filter (0.
Pre-treatment with 3% polyethyleneimine)
The bound radioactivity is separated from the free radioactivity.

The filtered membrane is washed 3 times with 3 ml each of ice-cold buffer. Transfer filter to scintillation vial and add 5 ml scintillation cocktail. The vial is shaken overnight and the radioactivity is counted by liquid scintillation spectroscopy. Non-specific binding is determined as the radioactivity still bound to the membrane in the presence of 10 mM glutamate. Inhibitory dose-response curve is 10 nM-100 nM
Construct by adding increasing concentrations of drug.

The same membrane preparations used for the [ ³ H] AMPA binding assay can be used for the [ ³ H] -kainate radioligand binding assay. On the day of assay, frozen rat brain membranes are thawed and 5 mM Tris / hydrochloric acid, pH 7.4 is added to give a final concentration of 0.5 mg / ml membrane protein. For the binding assay, 0.8 ml of membrane homogenate was added to a polypropylene tube, followed by 0.033 ml drug and 0.067 ml buffer (or 0.1 ml buffer alone for controls) and 200,000 cpm.
0.1 ml of [ ³ H] -Kainate-containing buffer solution is obtained. The assay is incubated on ice for 2 hours. Bound radioactivity is separated from free radioactivity by filtration on Whatman glass fiber filters (pretreated with 0.3% polyethyleneimine) using a Brandel 48 well cell harvester. The filtered membrane is washed 3 times with 3 ml of ice-cold buffer each. Transfer filter to scintillation vial and add 5 ml scintillation cocktail. The vial is shaken overnight and the radioactivity is counted by liquid scintillation spectroscopy.
Non-specific binding is determined by radioactivity which is still membrane bound in the presence of 10 mM glutamate. Inhibitory dose response curves are constructed by the addition of increasing concentrations of drug from 250 nM to 330 μM.

2,5-Dihydro-2,5-dioxo-3-hydroxy-1H-1-benzazepine or 2,5-dihydro-2,5-dioxo-4-hydroxy-of the present invention
The anxiolytic activity of any particular substitution of 1H-1-benzazepine can be determined using any animal model that recognizes anxiety. The preferred model is Jones, B.A. J.
Et al., British Journal of Pharmacology, Vol. 93, pp. 985-993 (1988). This model involves administration of the compound under consideration to mice with high baseline anxiety. The test is based on the finding that such mice are uncomfortable when taken out of the dark, dark environment of a dark test room and placed in a place painted white and brightly illuminated. The test box has two rooms, one white and brightly illuminated and one black and unilluminated. The mouse approaches both rooms through the floor level openings in the two room partitions. Place the mouse in the center of a brightly lit place. After placing the opening in a dark place,
Mice move freely between the two rooms. Control mice tend to spend a longer time in a dark room. When administered with anxiolytics, mice have been shown to spend more time exploring newer, brightly lit rooms, with delayed latency to move to darker rooms. Furthermore, mice treated with anxiolytics show more behavior in the white room as measured by exploratory parenting and crossover. Since the mouse can get used to this test situation,
Naive mice should always be used for this test. Five parameters can be measured: latency to enter a dark room, time spent at each place, number of room moves,
The number of times the lines in each room are crossed, and the number of parenting in each room. 2,5-Dihydro-2,5-dioxo-3-of the present invention
Hydroxy-1H-1-benzazepine or 2,5-
Dihydro-2,5-dioxo-4-hydroxy-1H-
It is expected that administration of the 1-benzazepine substitute will result in mice having a longer and longer time in the large, brightly lit areas of the test box. In the light / dark exploration model, the estimated anxiolytic activity of the drug was found to increase the number of line crossings and parenting in bright rooms, and decrease the number of line crossings in dark rooms and parenting compared to control mice. Can be identified by

A second preferred animal model is Seans, B .; J. And the rat social interaction test reported above, which measures the time two mice spend in social interaction. The putative substance's anxiolytic effects can be identified by the increased time spent by male pairs in active social interactions (90% of behavior).
To actually study). Both test site habituation and brightness levels are operational. Unmedicated rats are shown to have a high level of social interaction when they are used to the test site and when they are dimly lit. If the location is unfamiliar to the rat or is brightly illuminated, social interaction is diminished. Anxiolytics prevent this decline. The overall level of locomotor activity can also be estimated to detect drug activity specific to social behavior.

The effect of glycine and stimulatory amino acid antagonists to inhibit glutamate neurotoxicity in rat brain cortical neuron cell culture system can be determined as follows. Developed by Choi (Choi, DWJ.
Vol. 7, 357, Neuroscience (J. Neuroscience)
(1987)) a modified model of stimulant toxicity can be used to test the anti-irritant toxic effects of novel glycine and stimulatory amino acid antagonists. Fetal embryos of rat 19 days are removed from time-mated pregnant rats. The brain is removed from the fetus and the brain cortex is dissected. Cells from the dissected cortex were analyzed using the Landon and Robins method (methods in enzymology).
(Methods in Enzymology) 124 412 (198
6 years) and combine mechanical shaking and enzymatic digestion for isolation. Separated cells were passed through an 80 micron Nitex screen to determine cell viability by trypan
It is evaluated by blue. The cells are placed on a plate coated with poly-D-lysine and incubated at 37 ° C. in the atmosphere containing 91% O ₂ /9% CO ₂ at a constant temperature. After 6 days, fluoro-d-uracil is added and the growth of non-neuronal cells is suppressed for 2 days. On day 12 of culture, the first neuronal culture is exposed to 100 μM glutamate for 5 minutes with or without increasing doses of glycine and stimulatory amino acid antagonists or other drugs. After 5 minutes, the culture is washed and incubated at 37 ° C. for 24 hours. Neuronal damage is quantified by measuring the lactate dehydrogenase (LDH) activity released into the culture medium. LDH activity is the method of Decker et al.
(Decker et al., J. Imnorno Methods)
l. Methods 15:16 (1988)).

The anticonvulsant activity of glycine and stimulatory amino acid antagonists can be evaluated in the audiogenic seizure model of DBA-2 mice as follows. DBA-2 mice are available from Jackson Laboratories, Bur Harbor, Maine. These mice were less than 27 days old and
When exposed to the sound of 14 kHz (sinus wave) at 10 dB, 5-1
He develops tonic convulsions within 0 seconds and dies (Lonsdale, D., Dev. Pharmacol. Sera. Vol. 4, p. 28 (1
(982)) Seizure protection is defined when an animal injected with a drug 30 minutes before exposure to sound does not develop seizures during 1 minute exposure to sound and does not die. 21 days old D
BA-2 mice are used for all experiments. Compounds are administered intraperitoneally in either saline, DMSO, or polyethylene glycol 400. Appropriate solvent controls are included in each experiment. Dose-response curve is 1 mg / kg-100 mg drug
It is prepared by giving an increasing dose of / kg. Each dose group
(Or solvent control) consisted of at least 6 animals.

The anticonvulsant effect of glycine receptor antagonists
It can be evaluated by the following pentylenetetrazole (PTZ) -induced seizure test. Swiss / Webster mice develop a minimal chronic seizure of approximately 5 seconds within 5-15 minutes after drug injection when injected with 50 mg / kg DTZ (intraperitoneal). The anticonvulsant effect of a glycine / stimulatory amino acid antagonist (or other) drug is that if the drug is administered 30 minutes before PTZ application and the seizure does not develop until 45 minutes after PTZ administration,
Defined as lack of seizure. The glycine / stimulatory amino acid antagonist or other drug is administered intraperitoneally in either saline, DMSO or polyethylene glycol-400. Appropriate solvent controls are included in each experiment. Dose response curves are generated by giving increasing doses of drug from 1 mg / kg to 100 mg / kg. Each dose group (or vehicle control) consists of at least 6 animals.

The glycine / stimulatory amino acid antagonist is N
The effect of protecting mice from MDA-induced mortality can be evaluated as follows. 200 mg / kg N-methyl-in mice
When D-aspartate (NMDA) is injected intraperitoneally,
Animals develop seizures and die within 5-10 minutes. Glycine / Stimulatory Amino Acid Antagonists
By intraperitoneal injection of the drug at 0 minutes, NMDA-
Test ability to protect against induced mortality. The glycine / stimulatory amino acid antagonist or other drug is administered intraperitoneally in either saline, DMSO or polyethyleneglycine-400. Appropriate solvent controls are included in each experiment. Dose response curves are generated by administering increasing doses of drug from 1 mg / kg-100 mg / kg. Each dose group (or vehicle control) consists of at least 6 animals.

A series of different assessments of the administration of the glycine / stimulatory amino acid antagonists of the present invention determined the physiological activity of the compounds in both normal gerbils and animals exposed to 5 minutes of bilateral carotid artery occlusion. Can be done to See Scheme VII.

[Chemical 29]

These studies are carried out on conscious animals which have not been administered with other pharmacological substances. The gerbils were pre-mechanized 48 hours before ischemia to completely eliminate the pentobarbital anesthesia used. When tested with drugs, animals are administered a glycine / stimulatory amino acid antagonist or vehicle by intraperitoneal injection. In the case of multiple injections, animals are given an intraperitoneal injection for 2 hours and the final injection is 3 during the ischemic period.
Animals are injected 0 minutes or, in the case of post-treatment administration, animals are injected 30 minutes, 2 hours, 4 hours and 6 hours post-ischemic reperfusion.

To assess the direct pharmacological or latent activity of glycine / stimulatory amino acid antagonists, naive gerbils are injected with saline or various doses of antagonist. Behavioral changes are evaluated using a photobeam locomotion activity chamber, which is a two-foot diameter circular mold with a photobeam detector. Animals are placed separately in a 2 foot diameter room. The room is housed in a closed cabinet and the noise is dampened using both a background white noise generator and a fan. For the 6-hour initial pharmacological evaluation, animals are placed in these rooms and total activity for each successive time is collected using a computer-controlled system.

Saline resulted in a higher initial rate of activity and control animals showed activity levels of approximately 1600 counts in the first hour. This control activity level is typical of gerbils under these experimental conditions. As the study progressed, the animals diminished exploratory activity,
The activity drops to about 250 counts / hour. The glycine / stimulatory amino acid antagonists of the invention are expected to have no significant effect on either the initial or terminal exploration rate.

In the next step in assessing glycine / stimulatory amino acid antagonists, gerbils are pretreated with various doses of antagonist and then exposed to bilateral carotid artery occlusion for 5 minutes.
Following the initiation of reperfusion, the animals were placed in a circular locomotion activity tester and the initial activity of the first hour after reperfusion was assessed.
Then monitor for 4 hours. Control animals that were not exposed to ischemia and were given saline prior to placement in the locomotor activity chamber were significantly higher in the first hour of locomotion activity than in all other hours, and at 4 hours were very high. It gradually decreases to a low value. It exhibits a characteristic type of activity. Control animals exposed to 5 minutes of cortical ischemia show a completely different locomotor type, whereas activity progressively diminishes during the 4 hour study period. At the first time, there was a marked decrease in activity followed by a gradual increase in activity, which at the fourth time was 10 times higher than that exhibited in animals not exposed to carotid occlusion. These results are typical and reliable results of the changes induced by a 5-minute bilateral carotid artery occlusion in gerbils.

Another group of gerbils was assigned 3 of carotid artery occlusion.
Pretreatment with glycine / stimulatory amino acid antagonists 0 minutes before, followed by 1 hour of perfusion followed by placement in locomotor activity chambers. Pretreatment of gerbils with the glycine / stimulatory amino acid antagonists of the invention is expected to protect against both decreased and increased post-ischemic activity. The decrease in activity after ischemia is expected to be near zero for the first hour after reperfusion. Pretreatment with the glycine / stimulatory amino acid antagonists of the invention is expected to reduce or prevent this initial behavioral depression. Furthermore, the glycine /
Stimulatory amino acid antagonists are expected to protect the behavioral post-ischemic stimulation.

Following completion of the single dose pretreatment evaluation, gerbils will also be evaluated with multiple injections of the glycine / stimulatory amino acid antagonists of the invention. Administration is performed intraperitoneally 6 hours, 4 hours, 2 hours and 30 minutes before the start of ischemia for 5 minutes. At 24 hours, all animals are evaluated for loitering differences using an 8-foam radial maze. In this method, an animal is placed in the center of the labyrinth's departure chamber, the barrier is removed, and the time and number of times the animal makes an error is recorded before all eight arms of the maze have been explored. Error is defined as the animal revisiting the arm by entering the full length, which does not include the tail. If the animal persists or fails to leave the arm for more than 5 minutes, the test ends. The animals in the control group were previously unexperienced (naive), but the number of errors and maze exploration is approximately 6 times. This is the average of N = 28 gerbils. When tested at 24 hours after 5 minutes of bilateral carotid occlusion, the mean number of gerbil errors was 21 and pretreatment of animals with the glycine / stimulatory amino acid antagonists of the invention significantly increased the number of errors made. Expected to decline. It is also expected that the behavioral changes induced during the implementation of the radial arm maze will be significantly reduced.

It is also expected that post-treatment of the glycine / stimulatory amino acid antagonists of the present invention will reduce short term memory deterioration 24 hours after ischemia / reperfusion. 5
The effect of minute bilateral carotid artery occlusion on neuronal cell death in the dorsal hippocampus can be evaluated in animals 7 days after ischemia-reperfusion surgery. Previous studies have shown that neuronal degeneration begins to occur around 3 days after cerebral ischemia. By 7 days, these affected neurons undergo cytolysis and either completely degenerate or appear as dark nuclei, with nuclei with eosinophilic cytoplasm replacing dark nuclei. The 5-minute ischemic injury is essentially localized to the CA1 area of the dorsal hippocampal body within the hippocampal body. The outer cingulate in the middle of the horn is unaffected and shows no pathological condition in the dentate gyrus and / or CA3. Gerbils after ischemia 7
Anesthetize with 60 mg / kg pentobarbital daily. Brains were buffered with ice-cold saline followed by buffered paraformaldehyde (1
Perfuse through the heart at 0%). The brain is removed, embedded and cut pieces are made. Sections are stained with hematoxylin-eosin and the number of Neuron cells is determined by the number of neurons' nuclei / 100 micrometers. Normal control animals (without ischemia-reperfusion surgery) show no significant changes in normal density nuclei in this area. A 5-minute bilateral carotid artery occlusion results in a significant reduction in the number of nuclei present in the CA1 segment. Generally, this injury results in patchy necrosis instead of the confluent necrosis seen with 10 minutes of ischemia. Pretreatment with the glycine receptor antagonists of the invention is expected to significantly protect the degeneration of hippocampal neurons.

The NMDA receptor is known to dangerously develop persistent pain after nerve and tissue injury. For example, tissue injury induced by a small subcutaneous injection of formalin into the hindlimb of test animals has been shown to produce a rapid increase in glutamate and aspartate in the spinal cord (Skilling, SR et al., J. Neuro. Sai (J. Neurosci.) 10: 1309-1318
(1990)). Administration of NMDA receptor inhibitors reduces reactivity of dorsal horn neurons of the spinal cord after injection of formalin (Dickenson and Eider, Neuroscience Lett. 1)
21: 263-266 (1991); Harley, J. et al.
E. Et al. Brain Research 51
8: 218-226) (1990)). These dorsal horn neurons are crucial for the transport of pain signals from the spinal cord to the brain, and the reduced reactivity of these neurons is associated with pain experienced by test animals pained by subcutaneous injection of formalin. Is shown to decrease.

It was observed that NMDA receptor antagonists can inhibit dorsal horn neuronal reactivity caused by subcutaneous injection of formalin, so that NMDA receptor antagonists can cause chronic pain, eg, surgical treatment, Or disconnect
It may treat pain caused by (fantasy pain), or other sore pain (wound pain). However, the use of conventional NMDA antagonists such as MK801 or CGS19755 in the protection or treatment of chronic pain is severely limited by the undesirable side effects of PCP-like behavior caused by these drugs. It is expected that the glycine receptor antagonists that are the subject of the present invention will be very effective in protecting against chronic pain in mice induced by subcutaneous injection of formalin into the hind limbs of animals. PCP- is a glycine / stimulatory amino acid antagonist of the present invention.
It is expected that these drugs will not cause side effects.
It is very useful in protecting or treating chronic pain without causing P-like undesirable, behavioral side effects.

The effect of the glycine receptor antagonist of the present invention on chronic pain is evaluated as follows. Five male Swiss / Weber mice, weighing 25-35 g, were housed in cages with free access to food and water.
Maintain a light cycle of time (lights turn on at 8:00). Glycine receptor antagonists are 1-40 and 5 respectively.
Dissolve in DMSO at a concentration of -40 mg / ml. DMSO is used as a vehicle control. All drugs are injected intrathecally (1 μl / g). The formalin test is performed as reported (Duvidson and Dennis, Pain Volume 4: H
161-174 (1977)). The mouse is 25 cm in diameter,
Observe in a 30 cm high Plexiglas cylinder.
20 μl of 5% formalin is injected subcutaneously on the lower surface of one paw. The degree of pain is determined by measuring the time spent licking (licking) the paw injected with the animal formalin at the following time intervals: 0-5 '(early phase): 5'-
10 ', 10'-15' and 15'-50 '(late phase). To test whether glycine / stimulatory amino acid antagonists protect against chronic pain in test animals, a vehicle (DMSO)
Alternatively, the drug dissolved in vehicle at a dose of 1 mg / kg-40 mg / kg is injected intraperitoneally 30 minutes before formalin injection. At least 6 for each dose of drug or vehicle control
Use one animal.

Intraperitoneal injection of a glycine receptor antagonist 30 minutes prior to injection into the hind limb of formalin, compared to vehicle controls, caused formalin-induced chronic pain to be glycine /
It is expected to significantly inhibit in a dose-dependent manner as defined by the reduced time spent licking hindlimb formalin-injected mice induced by increasing doses of stimulatory amino acid antagonists.

Compositions within the scope of the invention are
5-dihydro-2,5-dioxo-3-hydroxy-1
H-1-benzazepine or 2,5-dihydro-2,5
All compositions containing -dioxo-4-hydroxy-1H-1-benzazepine substitutes in an amount effective to achieve the intended purpose are included. Those skilled in the art will determine the optimum range of the effective amount of each component, although the individual needs are different. Typically, the compound is administered orally to a mammal, eg, a human, per day for anxiety disorders such as generalized anxiety disorders, fear disorders, threatening disorders, panic disorders and post-traumatic stress disorders. Weight 0.0025-5
0 mg / kg, or an equivalent amount of a pharmaceutically acceptable salt thereof, can be administered. It is preferred that about 0.01 to about 10 mg / kg be administered orally to treat or prevent such disorders. For intramuscular injection, the dose will generally be about 1/2 of the oral dose. For example, to treat or prevent anxiety, a suitable intramuscular dose is about 0.0
025 to about 15 mg / kg, and most preferably about 0.01 to about 10 mg / kg.

Treatment or protection of neuronal loss in ischemia, brain and spinal cord trauma, hypoxia, hypoglycemia and surgical procedures, and treatment of Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's syndrome. In a method, or in the treatment of a disease in which the pathophysiology of the disorder comprises hyperreactivity of stimulatory amino acids or NMDA receptor ion channels associated with neurotoxicity, the pharmaceutical composition of the invention comprises -Dihydro-2,5-dioxo-3-hydroxy-1H-1-benzazepine or 2,5-dihydro-2,5-dioxo-4-hydroxy-1H-1-benzazepine substitute at a unit dose level of about 0 0.01-about 50 mg / kg body weight, or equivalent amount of a pharmaceutically acceptable salt thereof, followed by a regimen of 1-4 times per day. It can be administered. When used to treat chronic pain or induce anesthesia, the compounds of the invention may be administered at a unit dose level of about 0.01 to about 50 mg / kg body weight, or equivalent amounts of these pharmaceutically acceptable salts per day. 1-4
Can be administered with a regimen of times. The exact level of treatment will, of course, depend on the medical history of the animal being treated, eg human. The precise treatment level can be determined by one of ordinary skill in the art without undue experimentation. Oral dosage unit is about 0.0
1 to about 50 mg, preferably about 0.1 to about 10 mg of the compound can be contained. This dosage unit is about 0.1-about 1 each
0, conveniently as one or more tablets containing about 0.25-50 mg of the compound or solvates thereof,
It can be administered once a day or more.

In addition to administering the compounds as source chemicals, the compounds of the present invention include suitable excipients and adjuvants that facilitate the processing of the compounds into pharmaceutically acceptable formulations. It can be administered as part of a pharmaceutical formulation containing a pharmaceutically acceptable carrier. Preferably formulations, especially those which can be administered orally and which can be used in preferred dosage forms, such as tablets, dragees and capsules, also those which can be administered rectally, such as suppositories, and solutions suitable for injection or oral administration Is 0.01-99%, preferably 0.25-75% of active compound (s) with excipients.
contains.

2,5-Dihydro-2,5-dioxo-3-hydroxy-1H-1-benzazepine or 2,5-dihydro-2,5-dioxo-4-hydroxy-of the present invention
Non-toxic acceptable salts of 1H-1-benzazepine substitutes are also included within the scope of this invention. The acid addition salt is the 2,5-dihydro-2,5-dioxo-3- of the present invention.
Hydroxy-1H-1-benzazepine or 2,5-
Dihydro-2,5-dioxo-4-hydroxy-1H-
A solution of the 1-benzazepine substitution product is treated with a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid,
It is formed by mixing with succinic acid, acetic acid, citric acid, tartaric acid, carboxylic acid, phosphoric acid, oxalic acid and the like. The basic salts are 2,5-dihydro-2,5-dioxo-3-hydroxy-1H-1-benzazepine or 2,5-dihydro-2,5-dioxo-4-hydroxy-1H-1 of the present invention. -Forming benzazepine substitutes in admixture with pharmaceutically acceptable non-toxic bases such as sodium hydroxide, sodium carbonate and the like.

The pharmaceutical composition of the invention may be administered to any animal that may experience the beneficial effects of the compounds of the invention. Human beings are the most prominent of these animals,
It is not intended to be so limiting of the invention. The pharmaceutical compositions of the present invention can be administered by any means that achieve their intended purpose. For example, parenteral, subcutaneous, intravenous,
It can be administered by intramuscular, intraperitoneal, transdermal or buccal routes. Alternatively or simultaneously, it can be administered orally.
The dosage will depend on the age, health, and weight of the recipient, the type of concurrent treatment, number of treatments, if any, and the nature of the effect desired.

In addition to the pharmacologically active compound, the new pharmaceutical preparations contain suitable pharmaceutical agents which contain excipients and auxiliaries which facilitate the processing of the active compound into pharmaceutically usable preparations. A pharmaceutically acceptable carrier can be included. Preferably formulations, especially those which can be administered orally and which can be used in preferred dosage forms, such as tablets, dragees and capsules, and those which can be administered rectally, such as suppositories, and suitable for injection or oral administration Solutions are present at concentrations of about 0.01-99% with excipients.

The pharmaceutical preparations according to the invention are prepared in a manner known per se, for example by the usual mixing, granulating, sugar-coating, dissolving or freeze-drying steps. Thus, oral pharmaceutical formulations may be combined with solid excipients to give tablets or dragee coatings, if desired or necessary, after addition of suitable adjuvants, and optionally resulting in It can be obtained by pulverizing the mixture produced in step 1 and processing the granular mixture.

Suitable excipients include, among others, fillers such as sugars, such as lactose or sucrose, mannitol or sorbitol, cellulose preparations and / or
Or with calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate, and with, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone There is a binder such as starch paste. If desired, disintegrating agents may be added, such as the starches and carboxymethylated starches mentioned above, crosslinked polyvinylpyrrolidone, agar, or alginic acid or salts thereof, such as sodium alginate. Adjuvants include, among others, flow regulators and lubricants such as silica, talc, stearic acid or salts thereof,
Examples are magnesium stearate or calcium stearate and / or polyethylene glycol. Sugar coatings are provided with suitable coatings that resist gastric juices if desired. For this purpose, concentrated sugar solutions can be used, which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. it can. To make coatings that resist gastric juices, solutions of suitable cellulose preparations are used, such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate. Dyeing materials or pigments may be added to the tablets or dragee coatings for identification or to characterize the formulation of active compound doses.

Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules can contain the active compounds in the form of granules, which can be mixed with fillers such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. . In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils or liquid paraffin. In addition, stabilizers can be added. Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of one or more active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. It is also possible to use gelatin rectal capsules which consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example water-soluble salts and alkaline solutions. In addition, suspensions of the active compounds can be administered as appropriate oily injection suspensions. Suitable lipophilic solvents or excipients include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides or polyethylene glycol-400 (the compound is soluble in PEG-400). Aqueous injection suspensions may contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethyl cellulose, sorbitol and / or dextran. Optionally, the suspension may also contain stabilizers.

Characterization of the glycine binding site in vitro has been difficult due to the lack of selective drug ligands. Thus, the glycine ligands of the invention can be used to characterize glycine binding sites. A particularly preferred invention of the present invention which can be used for this purpose,
5-dihydro-2,5-dioxo-3-hydroxy-1
H-benzazepine or 2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine substitutes are radioisotopically labeled derivatives such as one or more atoms of ³ H, ¹¹ C, ¹⁴ Substituted with C, ¹⁵ N or ¹⁸ F.

The following examples are illustrative, but do not limit the scope of the methods and compositions of this invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the invention. Examples Example 1 Antagonism of binding by substituted 1-H-benzazepine-2,5-diones Compound L-glutamate, glycine, kainate, N
MDA and D-serine were obtained from Sigma and were (+)-
Kiscarato was purchased from Research Biochemicals. Parent compound 2,4-dihydro-2,5-dioxy-
3-hydroxy-1H-benzazepine (DDHB),
8-Me-DDHB, and 7-Me-DDHB are substituted with 2-methoxy-1,4-naphthoquinones, which are appropriately substituted, to Virtual (Birchall) and Leeds (Ree).
(Birchall, GR and Rees, AH, Canadian Journal of Chemistry (Can.J.Che).
m.), 52, 610-615 (1974)). The (Virtual (Birchal
l), GR and Rees, AH, Canadian Journal of Chemistry, Volume 52:
Pp. 610-615 (1974)), DDHB
3-acetyl ester and 3-methyl ether of D
Synthesized from DHB. (Virtual (Birchal
l), GR and Rees, AH, Canadian Journal of Chemistry (Can.
J. Chem., 52, 610-615, (197).
4))), 4-Br-DDHB
Was prepared by bromination of DDHB.

Benzazepine was dissolved in standard external solution by sonication at 40 ° C. The absence of visible precipitate after centrifugation for 5 minutes at 3000 rpm was considered as evidence of complete lysis. The maximum solubility of 8-Me-DDHB is about 5
0 micromole, slightly higher than that of the other benzazepines. The parent molecule, DDHB, has been previously described to undergo an intramolecular rearrangement to kynurenic acid in the presence of aqueous base (Birchall, GR.
And Rees, A.H., Canadian Journal of Chemistry (Cad.J.Che.
m.) 52, 610-615 (1974)). The concentration of kynurenic acid in all solutions used in electrophysiological experiments was determined as described above (Swarts et al., Analytical Biochemistry (Anal. Bioch.
em.) 185, pp. 363-376 (1990)).
And found to be <0.1% on a molar basis.

Cell culture and electrophysiology. PO after birth 5
Nerve cells in the visible cortex of the Long Evans mouse of the day were described in (Huettner, JE.
And Bowman, RW, Journal of Neuroscience (J. Neurosci.)
6, 3044-3060 (1986)) and separated with papain (Worthington Biochemical Co.). Cells were plated either directly on the glia monolayer or on cover slips coated with Cell-Tac (Biopolymers). Closed whole cell recordings were obtained from cells that were in culture medium for 6-14 days. Pipettes drawn from a 100 micron liter Volarex micropipette (Rochester Scientific) were covered with Sylgard (Dow Corning) and burned. The resistance of the pipette is internal solution, 140 mM CsCH ₃ SO ₃ ,
5 mM CsCl, 10 mM HEPES, pH 7.4
2 to 6 MΩ (adjusted with CsOH). The external drug solution is 160 mM NaCl, 2 mM C
Consists of aCl ₂ , 1 micromolar tetrodotoxin (Sigma), and 10 mM HEPES, pH 7.4. Dizocilpine (MK-801, donated by Merck Sharp & Dome, Inc.) was added to an external solution for experiments with L-glutamate to block the current through the channel gated by the NMDA receptor. Added at 1 micron mole.

The drug solution was applied by topical spray from a line of 8 microcapillaries (2-micron mole Drummond Microcaps, 64 mm length). The solution flow was often driven by gravity. For rapid application of L-glutamate, the solution was drained by a peristaltic pump and the flow to the microcapillary gated by a set of three-way valves (Vicklicky).
, Journal of Physiology (J. Phys
iol.) (London) 428, 313-331 (1990)). The bath was filled with Tyrode's solution (150 mM NaCl, 4 mM KCl, 2 mM CaCl ₂ , 2 m).
M MgCl ₂ , 10 mM glucose, 10 mM H
Perfusion with EPES, pH 7.4) at 1-5 ml / min.
The membrane potential was corrected to a junction potential of 10 mV between the inner solution and the Tyrode solution with a seal in the solution. Dagan 3
The whole cell current recorded in the 900 amplifier was set to 1 kHz (3d
B, 8 pole vessel) and filtered at 5 kHz.
For storage and analysis, data were compressed with an average current of 3 msec at 0.1-0.5 sec intervals.

Experimental design and data analysis. Concentration response curves were generated by applying 5 to 7 agonist concentrations. In most experiments, each concentration was 10-15
Applied for seconds. Steady-state current was measured as the average current during the last to third of each application. In many cells, all steps of application were repeated several times. Absolute current levels vary from cell to cell, so values were normalized to the maximum current (I _max ) produced by saturating concentrations of agonist. This control dose of agonist was included in all application steps. The current evoked by the combination of agonist and antibody was normalized to a control (saturating) dose of agonist alone.

Non-Linear Regression (Sigma Plot 4.1, Marquardt-Lehenberg Algorithm, Jandel
Scientific) was used to enter the concentration response data into the logistic equation (Equation 1).

[Equation 1] Where EC ₅₀ is the agonist concentration that produces half maximal activation and n is the tilt factor. In several cases, the control dose-response relationship for agonist alone, along with 1 to 3 agonist dose-response curves obtained in the presence of the antagonist antibody, was calculated at the same time as Equation 2 (Waud, DR, Methos Pharma. Kology (MethodsPharma)
col.) 3: 471-506 (1975)) and was fitted with the model of simple antagonistic effect (Clark, AJ, Journal of Physiology (J. Physiol.). (London) Volume 61, 5
Pp. 47-556 (1926) Gadam
m), JH, Journal of Physiology (J. Physiol.) (London), 61, 141-
150 pages (1926), Arun
lakshana), O., and Schild (Schill
d), HO, British Journal of Pharmacology (Br.J. Pharmacol.) 14
Vol. 48-58 (1959)).

[0094]

[Equation 2] Where the parameters EC ₅₀ (half maximal dose of agonist alone), K _B (titration antibody separation constant), and n (slope factor) were adjusted simultaneously to best fit all curves. Equation 2 are parallel all concentration-response curves are forced to move from the control curve by a factor (1 + [Kit antibody] / K _B). These coercions are exactly -1 sild slopes (Arunlakshana and Schild, British Journal of Pharmacology (Br. J. Pharmacol.).
Volume 14, pages 48-58 (1959)). The main advantage of simultaneous inclusion in Equation 2 compared to standard Schild analysis is that the control concentration-response relationship (agonist only) is given the same weight relative to the relationship obtained in the presence of the antagonist antibody. There is (Waud),
D.R., Methos Pharmacology (Methods)
Pharmacol.) 3, 471-506 (19)
1975), Stone, M. and Angus, JA, Journal of Pharmacology and Experimental Therapeutics (J. Pharmacol. Exp. Ther.
p.), 207, 705-718 (1978).
Year)). Furthermore, Equation 2 provides greater certainty in the value of K _B. Because it is obtained from regression of theoretical dose ratios more directly from the direct insertion of experimental data.
The plot of concentration-response relationship shown in the figures shows I / I _max as the average value ± standard error of each agonist concentration. However, Equations 1 and 2 were fitted to all of each data point to ensure proper weighing.

To test for statistically significant changes from the simple antagonistic model, the proportion of residual dispersion was calculated according to Equation 3 (Waud, DR, Methos.
Pharmacology (Methods Pharmaco
l.) 3, 471-506 (1975) Stone, M. and Angus,
JA, Journal of Pharmacology and Experimental Therapeutics (JA Ph)
armacol.Exp.Therp.), Volume 207, 7
05-718 (1978) De Lean (De Le
an) et al., Molecular Pharmacology (Mol.
Pharmacol., 21: 5-16 (198).
2 years)).

[Equation 3] [Where SS ₂ is the sum of the squared deviations simultaneously fitted to Equation 2 and SS ₁ is the sum of the squared deviations obtained when Equation 1 is fitted to each concentration-response curve, df ₁ and df ₂ individually fit equation 1 and simultaneously fit equation 2, degrees of freedom (number of data points-number of parameters). In this specification, the F value is F (df ₁ −d
f ₂ ), df ₁ ). Since EC ₅₀ and K _B are expected to show a lognormal distribution (De Lean (De
Lean) et al., Molecular Pharmacology (M
ol. Pharmacol., 21: 5-16 (1
982)), and confidence intervals were obtained using the permutations described below in Equations 1 and 2. EC ₅₀ = 10 ^−pE , where pE =
_{-LogEC 50], K B = 10} -pK B, [ wherein, pK _B = -
confidence intervals for log K _B] 95% of pE and pK _B, was calculated as the product obtained by multiplying the appropriate value from the t distribution the standard deviation of each parameter (obtained from suppliers particulars). The confidence limits shown herein were converted to EC ₅₀ and K _B. ]

[0096]

SUMMARY OF THE INVENTION In preliminary experiments, DDHB was found to cause a voltage-independent disturbance of current produced by half-maximal concentrations of L-glutamate, (+)-quisqualate, kainate, and NMDA. FIG. 1 shows inhibition of kinate and NMDA gated currents by DDHB with voltages of +50 mV and -80 mV. 1
At 00 μM, DDHB blocks 40-45% of the current caused by 100 μM kinate, and 20 μM NMD.
The current generated by A plus 300 nM glycine was completely blocked. The onset of blockage and recovery from blockade were completely within seconds. Due to the initial blockade of the effective derivative of DDHB, 8-Me-DDHB is the most potent antagonist antibody, and 4-Br-DDHB and 7-Me-DDHB are also effective, but the 3-acetyl ester of DDHB and It was found that 3-methyl ether hardly blocks the current gated by any agonist. 8-Me
-DDHB was selected for detailed analysis.

8-Me-DDHB at non-NMDA receptors
Antagonism by non-NMDA or kainate / AM
The PA receptor conjugation channel can be activated by L-glutamate, quisqualate, kainate, and AMPA (Mayer et al., Progress of.
Neurobiology (Prog. Neurobio
l.) 28: 197-276 (1987), Dingledine, R. et al., Critical Review of Neurobiology (Cr).
It. Rev. Neurobiol.) 4: 1-96 (1988)). To quantitatively assess the affinity of 8-Me-DDHB for non-NMDA receptors, we measured the concentration-response relationship of kainate and L-glutamate in the presence of 0, 8, 20 and 50 μM of the antagonist antibody. . As shown in Figures 2 and 3, it caused a concentration-dependent block of the current induced by kainate. 8-
The inhibition caused by Me-DDHB was completely overcome by increasing the concentration of kainate, a property that predicts an antagonistic mechanism of antagonism. Baud's Method (Waud, D.R., Methods Pharmacol., Vol. 3, 47)
1-506 (1975)), the model of simple antagonism represented by Equation 2 fits all four concentration-response curves shown in FIG. 3 simultaneously. Equation 2 uses a logistic curve (Equation 1) to describe the shape of the concentration-response relationship. This method results in the addition of kit antibody, factor (1 + [Kit antibody] / K _B) [wherein, K _B is the kicker antibody degradation constant. ] Introduces a major feature of simple antagonism, as it results in a translation of the control curve obtained only with the agonist by [Gaddum (Gaddum
m), JH, Journal of Physiology (J. Physiol.) (London), 61, 141-
150 pages (1926), Arun
Lakshana), O., et al., British Journal of Pharmacology (Br.J.Pharma).
col.), 14: 48-58 (1959)).

As shown in FIG. 3, the smooth curve defined by Equation 2 agrees well with the experimental data (see FIG. 8). The ratio of residual variances shows that the deviation from the simple antagonist model was not statistically significant at the 5% level (F ₅ , ₁₉₇ = 0.71). Consistent with previous studies (Huetner,
J., Neuron, Volume 5, 255-3
66 pages (1990), Birdon (Verdoor)
n), TA, et al., Molecular of Pharmacology 34, 298-3.
07 (1988), Patnea
u), DK, et al., Journal of Neuroscience (J. Neurosci.), Vol. 10, 238-239.
9 (1990)), only kinate underwent semi-maximal activity at a concentration of 120 μM (111-113 μM, 95% confidence interval of EC ₅₀ fitted to Equation 2). 8-Me
-DDHB blocked the current gated by the kinate with a K _B of 6.4 μM (5.5-7.5 μM).

Activation of non-NMDA receptors by L-glutamate was also blocked by 8-Me-DDHB.
L-Glutamate is applied to the central nervous system sufficiently quickly (onset, <30-50 msec) to cause Kiskin (Kis).
kin), NI, et al., Neuro Scientific
Letters (Neurosci. Lett.), Volume 63, 2
25-230 (1986)), causing both transient and persistent currents. As shown in FIGS. 4 and 5,
Increasing concentrations of 8-Me-DDHB gradually blocked the fast transient current produced by the rapid application of 500 μM L-glutamate. For all experiments with glutamate, 1 μM MK-801 was added to the external solution to completely block the current through the NMDA receptor channel. 8-Me as a non-NMDA receptor antagonist
-The capacity of DDHB was evaluated quantitatively only for interruption of the continuous current. Knock antibody affinity was not measured for the transient component of the current because the zero method used in Eq. 2 requires equilibrium binding between the agonist and the antibody (Colquhou
n), D., Handbook of Experimental Pharmacology (Handb.Exp.Pharma)
col.) 59, pages 59-113 (1986)).
This is not the case at the peak of the transient current caused by L-glutamate. FIG. 7 shows L-glutamate alone and 8, 20, and 50 μM 8-Me-DDH.
4 represents accumulated steady state concentration response data applied in the presence of B. Kainate, glycine and NMD
In contrast to the experiment with A, considerable intercellular variability was observed in the EC ₅₀ values obtained for the application of L-glutamate both in the absence and in the presence of 8-Me-DDHB. For this reason, a large number of cells were tested with L-glutamate rather than with other agonists. The cause of this variability is unclear, but is probably due to the different degree of desensitization of one cell with another. In order to compensate for the fact that different applications are made for each cell, in the present invention, the average normalized current produced by each concentration of agonist was first calculated for each cell. The average mean and standard deviation of these individual cells were then calculated for each agonist concentration across all cells tested. Using this method, FIG. 7 shows a control EC of L-glutamate only.
₅₀ is a 17μM (15-19μM, 95% confidence space), K _B of 8-Me-DDHB measured from the optimum value of the formula 2 was 9.6μM (7.8-11.8μM). Control EC of the action of steady-state current by this L-glutamate
_{The 50} is in agreement with what has been previously reported by other inventions (Verdorn, TA et al., Molecular Pharmacology.
col.) 34, 298-307 (1988),
Patneau, DK, et al., Journal of Neuroscience (J. Neurosci.)
10: 2385-2399 (1990), O'dell, TJ, et al., Journal of Neurophysiology (J. Neurophysio).
l.), 61, 162-172 (1989)).

The two plots shown in FIG. 8 represent the extent to which the concentration-response relationship for kainate and L-glutamate differs from the equation for antagonism. Each point represents the control agonist EC ₅₀ along with the agonist concentration required to produce half-maximal activity (EC ₅₀ ) in the presence of the antagonist antibody concentration, obtained from each fit to the logistic equation (Equation 1).
Is shown. These values, with the K _B given by the simultaneous adaptation of equation 2, the sum (K _B + [Kit Antibodies)
Can be pointed against. The straight line in FIG. 8 is EC ₅₀ '=
_{(EC 50 / K B) ·} (K B + [ Kit antibody]) represents the antagonistic relationship defined by. Kainat and L-
The point is well documented by theory for both glutamate. This display method is similar to the Clark plot developed by Stone and Angus (Stone, M. et al., Journal of Pharmacology and Expersive Therapeutics (J. Pharmacol. Exp. Ther.),
207, 705-718 (1978), Stone, M., Journal of Pharmacy and Pharmacology (J. Pharm.
Pharmacol.) 32: 81-86 (19).
80 years))). That is, these results are non-NMDA
Consistent with the action of 8-Me-DDHB as simple antagonist of an agonist recognition site on the receptor, channel Kainato (K _B = 6.4μM) or L- glutamate (K _B = 9.6μM) by activity True if

Antagonism at the glycine allosteric site by 8-Me-DDHB. In preliminary experiments, benzazepine was found to block the current elicited by submaximal concentrations of NMDA and glycine. Further studies also revealed antagonism occurring at both the glycine allosteric site and the transmitter binding site recognized by NMDA (see below). To selectively test the glycine site antagonism, the glycine concentration-response relationship was measured using the saturation level of NMDA (1 mM, see Figures 13 and 14). A few cells in culture medium expressed strychnine-sensitive glycine receptors that activate chloride-selective currents. But,
Cells showing this current due to this high concentration of glycine are
Excluded from analysis. As seen in FIG. 9, 2, 10 and 50 μM 8-Me-DDHB shifted the glycine dose response relationship to higher concentrations. The magnitude of migration shows a K _{B of} 470 nM (410-540 nM) relative to 8-Me-DDHB at the glycine site. FIG. 10 (F ₅ , ₂₁₇
= 2.03, not effective at 5%), the effect of the drug is entirely consistent with the mechanism of simple antagonism, as shown by the translation of the glycine dose-response relationship and the plot in FIG.

In the absence of antibody, glycine is 770
The response to NMDA was increased with an EC ₅₀ of nM (690-850 nM). This value was reported previously, 9
Somewhat higher than EC ₅₀ values in the range of 0 to 700 nM (Kleckner, NW et al., Science (Washington, D.C.) 241:
Pp. 835-837 (1988), Whitner (Hu
ettner), JE, Science (Science)
e) (Washington, DC) 243, 1611-16.
Page 13 (1989), Henderson
on), G. et al., Journal of Physiology (J. Physiol.) (London) 430, 189.
-212) (1990) Kleckner
ner), N.W., et al., Mol. Pharmacol. 36, 430-4.
36 pages (1989), Vyklick
y), L. Jr. et al., Journal of Physiology (J. Physiol.) (London) 428, 313.
Pp. 331 (1990), McBain (McBai)
n), CJ, et al., Molecular Pharmacology (M
ol. Pharmacol. 36: 556-565 (1989)). Mayer and colleagues (Vyklicky, L., Jr., et al., Journal of Physiology (J. Physiol.)
(London), Volume 428, pp. 313-331 (1990)
Year), Benveniste, M.
, Journal of Physiology (J. Phys
iol.) London, 428, 333-
357 (1990)) recently proposed a model of NMDA receptor desensitization in which binding of NMDA to a transmitter recognition site reduces the affinity of the allosteric enhancing site for glycine. Therefore, the present invention considered whether the unusually low affinity for glycine obtained in FIG. 10 was due to the high concentration of NMDA (1 mM) used in this experiment. As shown in FIG. 12, the EC ₅₀ for the steady-state current-enhancing effect of glycine was sensitive to the concentration of NMDA. Glycine is
Approximately 800 nM E when 1 mM NMDA was used
Compared to the C _50, it increased the current caused by 25 μM NMDA with an EC ₅₀ of 310 nM. These results, obtained from the sister medium after 7 days in vitro, are in fairly close agreement with the model of Meyer and colleagues. The dotted line shown in FIG. 12 is the Benvenist.
5 μM, 25 μM predicted by Scheme 2 of e) et al.
And the concentration-response relationship of glycine with 1 mM NMDA (Benveniste,
M. et al., Journal of Physiology (J. Phy
siol. (London) 428, 333-357 (1990)). 853 nM glycine EC predicted by their model in the presence of 1 mM NMDA
₅₀ is the EC ₅₀ (690-850 nM) of the experiments of this invention
Is just outside the 95% confidence interval of. Previous reports (Huettner, JE, Science, Washington, DC) 24
Volume 3, 1611-1613 (1989), Kleckner, NW, et al., Molecular.
Pharmacology (Mol. Pharmacol.) 36
Volume 430-436 (1989), Vyklicky, L. Jr. et al., Journal of Physiology (J. Physiol.) (London).
428, 313-331 (1990), McBain, CJ, et al., Molecular Pharmacol. 36, 5
56-565 (1989), Benbnist (Ben
veniste), M. et al., Journal of Physiology (J. Physiol.), London 428.
Consistent with Vol. 333-357 (1990)), the present invention has obtained a significantly higher affinity for the glycine-enhancing effect of currents gated by 25 μM NMDA. However, in the experiment of the present invention, 308 nM (279-3
The EC ₅₀ for glycine at 39 nM is 25 μM NMD
At a value of 586 nM estimated for A, the model of Benvenist et al. (Benveniste, M. et al., Journal of Physiology. (L. London), vol. : 333-357 pages (199
Closer to the EC ₅₀ foretold by Year 0)). The deviation between their model and the result of this invention is the Bembunist (Be
0.2 mM (Benvenist in a modeled experiment by Nveniste et al.
e), M. et al., Journal of Physiology (J.
Physiol.) London, Volume 428, 333-35
This may be due to the fact that the external solution of this invention contains 2 mM calcium, as compared to page 7 (1990)). Calcium is known to influence the rate and extent of desensitization of the NMDA receptor (Mayer.
er), ML et al., Journal of Physiology (J. Physiol.) (London) 361, 65-.
Page 90 (1985), Vyklick
y), L. Jr. et al., Journal of Physiology (J. Physiol.) (London) 428, 313.
-331 (1990)). Age (Fetus 16-18
Differences can also be due to the results of day to postnatal period 0-5 days), species (mouse vs rat), or cell type (hippocampus of the brain vs cortex). Benvenist
Their model is microscopically reversible (Benvist
eniste) M. et al., Journal of Physiology (J. Physiol.) (London), vol. 428, 3
33-357 (1990)), it is interesting that glycine binding is required to cause a decrease in the affinity of NMDA. However, such a decrease has not been observed to our knowledge. (Kleckner, NW, et al., Science (Washington, D.C.) Volume 241;
Pp. 835-837 (1988), Whitner (Hu
ettner), JE, Science (Science)
e) (Washington, DC) Volume 243: 1611-16
Page 13 (1989).

Antagonism at the NMDA recognition site by 8-Me-DDHB. In addition to acting at the glycine allosteric site, 8-Me-DDHB also blocks receptor activation by NMDA. As seen in FIG. 14, NMD
The potency of the antagonist antibody at the A recognition site is about 60 times lower than at the glycine allosteric site. The inhibition caused by 50 μM 8-Me-DDHB is completely overcome by increasing the concentration of NMDA. 50 μM 8-M based on the assumption that the interaction is antagonistic.
NM from 13 to 28 μM after addition of e-DDHB
The change in DA EC ₅₀ is 27 μM (23-32 μ
The K _B of M) is shown. Control EC _{50 for} NMDA (13 μM)
Findings so far (Huettner (Huettne
r), J.E., Science (Washington, D.C.), 243, 1611-1613 (1)
989), Verdorn, TA.
, Molecular Pharmacology (Mol.Pha
rmcol.), 34, 298-307 (198).
8 years), Patneau, DK, et al., Journal of Neuroscience (J. Neuro)
sci) 10: 2385-2399 (1990)
Year))). D-serine (1 mM) (Kleckner), NW, et al., Science (Washington, D.C.) 241, 835-837 (198).
8 years), Snell, LD, et al., European Journal of Pharmacology (Eur.J.
Pharmacol.) 156, 105-110 (1988)), in order to avoid activation of chloride channels by the strychnine-sensitive glycine receptor.
Glycine was used in place of glycine in the experiments shown in Figures 13 and 14. Preliminary experiments with 1 mM glycine revealed similar changes in the EC ₅₀ of NMDA in cells lacking strychnine-sensitive glycine receptors. The fact that the inhibition produced by 50 μM of 8-Me-DDHB was completely overcome by the high concentration of NMDA shows the appreciable binding of 8-Me-DDHB to the glycine allosteric site in the presence of 1 mM D-serine. It shows that there was not.

Structural analogue of 8-Me-DDHB DDH
B, 4-Br-DDHB, and 7-Me-DDHB were each tested against kainate, glycine, and NMDA at a concentration of 100 μM. As seen in FIG. 15, the three compounds changed the dose-response relationship of kainate to higher concentrations. 7-Me-DDHB is 4-
63 μM of Br-DDHB (53-74 μM) and D
27 μM against 65 μM (53-80 μM) of DHB
Maximal migration occurred with a K _{B of} (22-32 μM). All three compounds are 6.4 for kynate
less potent than 8-Me-DDHB showing the K _B of [mu] M (FIG. 3 and 8). The four smooth curves fitted to the data in Figure 15 were constrained to be parallel according to the simple antagonist model. This inhibition did not diminish the goodness of fit, as measured by the residual dispersity percentage (F ₃ , ₁₈₅ = 0.63).

FIG. 16 shows 100 μM DDHB, 4- at the glycine allosteric site on the NMDA receptor.
4 shows the antagonism produced by Br-DDHB and 7-Me-DDHB. All three compounds reduced the apparent affinity for glycine and in each case the inhibition was overcome by adding a sufficiently high concentration of glycine (400 μM). The four concentration-response relationships in FIG. 16 must be parallel in order to be fully consistent with the simple antagonistic mechanism of inhibition. However, the slight difference in the slopes of the four curves caused a significant deviation from parallelism. When the fits obtained from the parallel curves and the individual fits for each dose-response relationship were compared to the logistic equation (Equation 1), the residual variance was F ₃ , ₂₇₁ = 4.64 (at the 1% level Was significant). The four smooth curves seen in Figure 16 represent the individual fits of Equation 1 to the control data and each data point of the three antagonists. Although the curves are not parallel, K _B values were calculated for the three antagonistic antibodies to compare their potency with that of 8-Me-DDHB. From changes in the EC ₅₀ for glycine, a K _B of DDHB, the 7-Me-DDHB 9.5μM
And 3.0 compared to 25 μM of 4-Br-DDHB
Estimated to be μM. All of these values are 8-Me-DDHB
Significantly higher than the 470 nM K _B obtained for (FIG. 11).

At the NMDA recognition site, the antagonism by DDHB was found to be slightly more potent than that produced by 8-Me-DDHB. FIG. 17 shows NM
100 μM DDHB, 4-B in the concentration-response relationship of DA
The changes produced by r-DDHB and 7-Me-DDHB are shown. All four curves are 1 mM D
Made to saturate glycine synergistic sites in the presence of serine. At 1 mM, NMDA completely overcomes the inhibition produced by each of the three antagonistic antibodies. The smooth curve seen in FIG. 17 is an individual fit of Equation 1. Four
When the two curves were forced to have the same slope, the residual dispersion was significant at the 1% level (R ₃ , ₂₂₉ = 6.19), which is why the data are well represented by the four curves. Has not shown. In any case, D
DHB, 4-Br-DDHB, and 7-Me-DDH
The value of K _B for _B was calculated using the assumption of antagonism for comparison with 8-Me-DDHB. Figure 1
K _B calculated for DDHB from 7 data is 16
μM, which is below the K _B value of 27 μM obtained for 8-Me-DDHB (FIG. 14). 7-Me-DDHB is 1
Shows the K _B of 08μM, 4-Br-DDHB is the K _B 81
μM.

[Table 1]

Discussion This study revealed that substituted benzazepines comprise a novel class of broadly stimulating amino acid antagonist antibodies.
Table 1 shows four compounds, DDHB, 7-Me-DDH.
The structure-activity relationships for B, 8-Me-DDHB, and 4-Br-DDHB are summarized. All four compounds
8-Me-DDHB the most powerful derivatives (K _B = 47
0 nM vs. glycine), showing high potency as an antagonist of the glycine allosteric site on the NMDA receptor. 8-Me-DDHB is approximately 14 times as a non-NMDA receptor antagonist (K _B = 6.4 for kynate).
μM) and the ability to block the NMDA recognition site was approximately 60-fold (K _B = 2 for NMDA).
7 μM). The parent compound, DDHB, showed a slightly higher affinity for the NMDA recognition site than the 8-methyl derivative (K
_B = 16 μM), but DDHB was less potent than 8-Me-DDHB against glycine and kainate (DDHB K _B = 3 and 65 μM, respectively).

Antagonism. Two lines of evidence suggest that benzazepines inhibit stimulatory amino acid receptor activation by antagonism. First, the inhibition caused by all derivatives could be completely overcome by increasing the agonist concentration. Release of such blockade by saturating doses of agonist is associated with steady-state activation of non-NMDA by kinate or glutamate and NMD.
It was seen in the activation of the NMDA receptor by both A and glycine. Second, 8-M tested at three different concentrations
In the case of e-DDHB, the changes that occurred in the concentration-response relationship of kainate, glutamate and glycine were well explained by a simple antagonistic inhibition model (Clark (Cla (Cla
rk), A.J., Journal of Physiology (J. Physiol.), London, 61, 547.
-556 (1926), Gaddum,
JH, Journal of Physiology (JPh
ysiol. (London) 61, 141-150 (1926), Arnlaks.
Hana), O., et al., British Journal of Pharmacology (Br.J.Pharmaco).
l.) 14, 48-58 (1959)). For all three agonists, the dose-response relationship in the presence of 8-Me-DDHB was the factor (1+ [8-Me-DDH
The _B] / K B), was well suited parallel curve that varies in correlation with the control dose-response relationship. Each fit of the logistic equation to each dose-response relationship was not significantly better than the simultaneous fit with parallel curves fitted to a simple antagonistic relationship at the 5% confidence level.

The logistic equations have been used to provide an empirical description of concentration-response relationships (Verdorn, TA et al., Mol. Pharmaco).
34, 298-307 (1988), Patneau, DK, et al., Journal of Neuroscience (J. Neurosci) 10.
Vol. 2385-2399 (1990), Werman, R., Comparative Biochemistry and Physiology (Comp.Bio).
Chem. Physiol.) Volume 30, 997-1017
Page (1969)). This equation does not correspond to a specific reaction equation for channel activation (except in the special case of integral gradient factors) (Werman),
R., Competitive Biochemistry and
Physiology (Comp.Biochem.Physi
ol.) 30: 997-1017 (1969)),
This has the advantage that the half-maximum of the relationship is one of the fitting parameters and the two parameters, EC ₅₀ and n, are not interdependent. Using a mathematical formula, a gradient factor value greater than 1 indicates that the receptor must bind one or more agonist molecules before the channel can be effectively opened. In the experiments of this invention, the slope factor of the various agonists was about 1.3 to 1.7. Similar results were obtained from physiological experiments in several other laboratories (Verdorn, T.A.
, Molecular Pharmacology (Mol.Pha
rmcol.) 34, 298-307 (1988).
Year), Patneau, DK, et al., Journal of Neuroscience (J. Neuros).
ci.) 10, pp. 238-239 (1990),
O'Dell, TJ, et al., Journal of Neurophysiology (J. Neurophys)
61, 162-172 (1989).
Year)). A simple antagonistic model of the antagonist antibody was developed with the assumption of a single agonist binding site, but Colquhoun, D., Drug Receptors (HP Lang (R.
ang) ed) in "The relation bitween"
Classical and Cooperative Models for Drag Action (The Relation
Between Classic and Co
operating Models For Drug
Action ”, Macmillan (Macmilla
n), London (1973) 149
-182 and Thron (Thron
ron), C.D., Molecular Pharmacology (also l. Pharmacol.), vol. 9, pages 1-9 (19).
1973)) showed that it also applies to many receptor mechanisms involving the binding of one or more agonist molecules. Colquhoun (Colquhoun, D., Handbook of Excitemental Pharmacology (Hand)
b. Exp. Pharmacol.) Volume 59, 59-11
3 (1986)) further elaborated on the predicted inhibition at receptors with two unequal sites that could in some cases deviate from the simple antagonistic relationship.

The major feature of the simple antagonist antibody model is that the antagonistic inhibitor exhibits the same K _B regardless of whether the agonist is used to activate the receptor. This property provides one of the main medicinal means for defining receptor subtypes (Colquh).
OU), D., Handbook of Expeditional Pharmacology (Handb.Exp.Phar)
macol. 59, p. 59-113 (1986),
Corquhoun, D., Drug Receptors
"The Relation Bitween Classical and Co-operative Models for Drag Action (The) in (H.P. Rang)
Relation Between Classic
al and Cooperative Models
For Drug Action "Macmillan (M
acmillan), London (1973) 149-
182). The results of this invention of the steady-state antagonism of kainate and glutamate demonstrate that these two agonists activate the same number of receptors (Boulter, J. et al., Science (Sci. Science) (Washington, DC) 249
Vol. 1033-1037 (1990), Keinanen, K. et al., Science (Scie).
No.) (Washington, DC) Volume 249, 556-5
It is in good agreement with page 60 (1990)). 8-Me
-DDHB is 6.4 μM K _B (5.5-7.5 μM, 95
Inhibits kynate current at (% confidence interval) 9.6 μM
K _B (7.8-11.8 μM, 95% confidence interval) blocked the steady-state response to glutamate. Although the difference between these values reached statistical significance (Student's t-test), the two K _B values are about the same.
K _B for Kainato Since large variability in the concentration-response relationship of glutamate were observed, are considered to be more reliable indicators of the affinity of the antagonist of non-NMDA receptors. The reason for this variability is unclear. maybe,
This may be due to the strong desensitization produced by glutamate or due to the heterogeneity in the expression of non-NMDA receptor subunits (Boulter (B
, J. et al., Science (Science)
e) (Washington, DC) Volume 249, 1033-10
Page 37 (1990), Keinanen
n), K. et al., Science (Washington, D.C.) 249, 556-560 (1990).
Year)).

Structure-activity relationships. The glutamate receptor antibody shows promise as a neuroprotective agent (Meldrum, B. et al., Trends Phrmological Sciences).
acol.Sci.) 11: 379-387 (199)
(0 years)), and accelerates efforts to develop another antibody and to elucidate the structural determinants of affinity of the antibody. To this end, many compounds have recently been synthesized and tested for antagonistic antibody activity at the binding sites of glycine, NMDA, and kainate or AMPA [Leeson, PD, et al., Journal of・ Medicine and Chemistry (J. Med. Chem.) Volume 34, 1243-1252
Page (1991), Harrison,
BL et al., Journal of Medicine and Chemistry (J. Med. Chem.), Vol. 33, 3130.
-3132 (1990), Salitu
ro), FG, et al., Journal of Medicine and Chemistry (J. Med. Chem.) Vol. 33,
2944-2946 (1990)). DDHB and its derivatives are these parent compounds, kynurenic acid, indole-2-carboxylic acid, and quinoxaline-2,3-
It shares many structural features with Zion. Although direct comparisons of the potency of the four parent compounds are difficult, the data available represent the major compounds for which DDHB is attractive due to the variety of methods that have been used to assess avidity of avid antibodies. It shows that it is doing. DDHB has a clear dissociation constant of 3, 16 and 65 μM, respectively,
Glycine modulation site, NMDA recognition site, and non-NMD
It acted on the A receptor (Table 1). About Kynurenic Acid (Birch, PJ et al., European Journal of Pharmacology (Eur. J. Pharm)
acol.) 154, pp. 85-87 (1988),
Kemp, JA, et al., Proceeding of National Academy of Science of United States of America (Pro
c. Natl. Acad. Sci. USA) Volume 85, 654
7-6550 (1988), Kessler
er), M. et al., Journal of Neurochemistry (J. Neurochem.) 52, 1319-1.
328 (1989), Leeson,
PD et al., Journal of Medicinal Chemistry (J. Med. Chem.) Vol. 34, 1243-12.
52 (1991)), 15-41 against glycine
μM, 154-325 μM for NMDA, 82-132 for kainate, quisqualate or AMPA
The inhibition constant of μM has been measured. Unsubstituted quinoxaline-2,3-diones show the following potency (Kesler (Ke
Ssler), M. et al., Journal of Neurochemistry (J. Neurochem.) 52, 131.
Pages 9-1328 (1989), Leeson (Leeso)
n), PD et al., Journal of Medicinal Chemistry (J. Med. Chem.) Vol. 34, 1243.
-1252 (1991)), ie, 26-39 μM for glycine, 52 μM for NMDA, 120 μM for kainate, kiss carat, or AMPA.
Is. Indole-2-carboxylic acid has a K of about 25 μM
It is bound to the glycine site by _B (Huettner, JE, Science (Scie)
(Washington, DC) 243, 1611-
1613 (1989) is, with a very low affinity for the other two sites (K _B> 0.5-1 mm). Together, these values indicate that DDHB's antagonism is kynurenic acid, quinoxaline-2,3-dione and indole-.
It is shown to be equal to or greater than the 2-carboxylic acid.

The results of this invention for the substituted derivatives of DDHB show that Leesson (Lee) on the efficacy of kynurenic acid.
exactly in agreement with the observations made by Son et al. (Leeson, PD et al., Journal.
Of Medicinal Chemistry (J.Med.Che
m.), 34, 1243-1252 (1991).
Year)). They found that methylation at the 7-position of kynurenic acid, which corresponds to the 8-position of DDHB, significantly enhanced its affinity for the glycine modulation site. On the other hand, addition of a 6-methyl group to kynurenic acid (7-Me-
Corresponding to DDHB decreased the ability to antagonize glycine but increased affinity for non-NMDA receptors (Leeson, PD, et al., Journal of Medicinal Chemistry (J. Med). .C
hem.), 34, 1243-1252 (1991).
Year)). Table 1 shows that 8-Me-DDHB is about 6 times more potent than DDHB against glycine and 7-Me-DDHB is less potent than the parent compound at both the glycine and NMDA recognition sites, but activated by kinate. It is shown to be approximately twice as effective as DDHB against the applied current.

Halogen substitution of the benzene ring increases the affinity of kynurenic acid (Kemp, JA, et al., Proceeding of National Academy of Sciences of United States of America).
America (Proc. Natl. Acad. Sci. US
A), 85, 6547-6550 (1988),
Baron, BM, et al., Mol. Pharmacol., 38.
Volume, 554-561 (1990), Leeson (Le
Eson), PD et al., Journal of Medicinal Chemistry (J. Med. Chem.), Volume 34,
1243-1252 (1991), Kleckner, N.W., et al., Mol. Pharmacol., 36.
430-436 (1989)), indole-2- for glycine modulation sites and non-NMDA receptors.
Carboxylic acid (Huettner, J.
E., Science (Washington, D.)
C.), 243, 1611-1613 (1989).
, Salituro, FG, et al., Journal of Medicinal Chemistry (J. Me.
d. Chem., 33, 2944-2946 (19)
90)), and quinoxaline-2,3-dione (Kleckner, N.W. et al., Mol. Pharmaco.
l.), 36, 430-436 (1989)). 4-Br-substituted on the heterocycle
DDHB, in efficacy against kainate,
B was unchanged, but glycine and NMD
The potency against both A was somewhat reduced. Compounds such as 6,8-dichloro-DDHB include dichlorokynurenic acid (Baron, BM et al., Mol. Pharmacol., 38.
Volume, 554-561 (1990), Leeson (Le
Eson) PD et al., Journal of Medicinal Chemistry (J. Med. Chem.), 34, 1
243-1252 (1991)) and 4,6-dichloroindole-2-carboxylic acid (Sarituro (Sal
ITU), FG et al., Journal of Medicinal Chemistry (J. Med. Chem.)), and is particularly effective as a glycine site-binding antibody. Leeson et al. (Leeson,
PD et al., Journal of Medicinal Chemistry (J. Med. Chem.), 34, 1243-1.
252 (1991)) emphasized the importance of hydrophobic interactions in potentiating potency with substituents on the benzene ring, but electronegativity of substituents also plays an important role in measuring affinity of the antibody. It can be achieved. Energy calculation (Harrison, BL et al., Journal of Medicinal Chemistry (J. Med. C.
hem.), 33, 3130-3132 (1991).
)) And spectroscopic data (Leeson, PD, et al., Journal of Medicinal Chemistry (J. Med. Chem.) 34, 1243.
-1252 page (1991), L Ezabe (EL-E
Zaby), MS, et al., Indian Journal of Chemistry (Indian J. Chem.), 1
1, 1142-1145 (1973), Pileni, MP, et al., Photochemistry and Photobiology (Photochem.Ph).
autobiol.), Volume 30, pp. 251-256 (19)
1979)) both propose that the 4-keto tautomeric isomer of kynurenic acid is predominant in aqueous solution and is the type most likely to interact with receptor sites (Huettner (Huettner).
ner), J.E., Biochemical Pharmacology., 41, 9
-16 (1991)). The contribution of the hydrogen bond by the 1-NH group is (Leeson,
PD et al., Journal of Medicinal Chemistry (J. Med. Chem.), 34, 1243-1.
252 (1991)), appears to be essential for receptor binding by all of these antagonistic antibodies.

3-acetyl ester and 3-of DDB
The lack of antagonism by methyl ether (Table 1) was
It suggests that the 3-hydroxyl group of DHB is required for receptor binding. In DDHB, quinoxaline-
Like the 2,3-dione, the oxygens at the 2 and 3 positions show partial anionic character (Leeson, P. et al.
D. et al., Journal of Medicinal Chemistry (J. Med. Chem.), 34, 1243-12.
52 (1991), Huettner
r), JE, Biochemical Pharmacology (B
iochem.Pharmacol.), Volume 41, 9-1
6 (1991)), therefore it seems possible to replace kynurenic acid, indole-2-carboxylic acid, and various amino acid agonists. Finally, the oxygen at the 5-position of DDHB is the 4-keto group (Leeson) of kynurenic acid.
(Leason), PD, et al., Journal of Medicinal Chemistry (J. Med. Chem.), 34.
Vol. 1243-1252 (1991)), various C-3 derivatives of indole-2-carboxylic acid (Gray).
(Gray), N. et al., Journal Medicinal Chemistry (J. Med. Chem.), 34, 1283.
-1292 (1991)) and several small agonist compounds (McBain, CJ.
, Molecular Pharmacology (Mol.Pha
rmcol.), 36, 556-565 (198).
9))) and may undergo hydrogen bonding upon binding to the glycine modulation site.

Biochemical Efficacy Excessive activation of glutamate receptors damages nerves and results in cell death (Choi, DW, Neurons (Neu).
ron), pp. 623-634 (1988)). The neurotoxic effects of these L-glutamates and other endogenous stimulatory amino acids have also probably been put into pathological conditions including local anemia, epilepsy, and Huntington's disease (Choi, D.W. ., Neuron (Ne
Uron, Vol. 1, pp. 623-634 (1988), Meldrum, B., et al., Trends Pharological Science (Trends Phar).
Macol. Sci., 11: 379-387 (19)
90 years)). Studies on animal model systems suggest that glutamate receptor antagonist antibodies may protect nerves from the deleterious effects of hyperstimulation. Such neuroprotection has been found with selective antagonistic antibodies at both NMDA and non-NMDA receptors (Meldrum (Meld).
rum), B. et al., Trends Pharmacol. Sc.
i.) 11: 379-387 (1990), Sheardown, MJ, et al., Science (Washington, DC) 247,
Pp. 571-574 (1990). However, to be therapeutically useful, the antagonizing antibody must enter the CNS, usually through the blood-brain barrier from the periphery and into the periphery. Most antagonistic antibodies have groups that are ionized at physiological pH and, therefore, rarely penetrate the blood-brain barrier. In contrast, DDHB and its derivatives are uncharged and have a neutral pH.
Although highly lipophilic at, this suggests that they can enter the brain much more easily than many antagonistic antibodies.

In the case of the NMDA receptor, hydrophobic non-competitive antagonist antibodies such as phencyclidine and dizocilpine, which act by blocking the ion channels gated by NMDA, are of interest due to their need to penetrate into the CNS. It has been. Although these compounds are neuroprotective, they include potentiation of self-administration and potential direct adverse effects (Ollney JW et al., Science (S.
Science) (Washington, DC) 244, 13
60-1362 (1989)), with side effects (Willets J. et al., Trends Pharm Science).
acol.Sci.) 11: 423-428 (199)
0 years). Recent research (Research by Willets et al., Trends Pharmacol. Sci.) 11
Vol. 423-428 (1990)) suggest that NMDA antagonistic antibodies exhibit different modes of activity with little unwanted hallucinogenic effects characteristic of phencyclidine and related compounds.

As mentioned above, recent research has been described by Meldrum, B. et al., Trends Pharmaco.
11 Sci., pp. 379-387 (1990).
Year), Sheardown, MJ et al.,
Science (Washington, DC)
247, 571-574 (1990)) is NM
It has been shown that DA and non-NMDA receptor antagonist antibodies can separately contribute to neuroprotection. Four unsubstituted parent compounds, kynurenic acid, indole-2-carboxylic acid, quinoxaline-2,3-dione and 2,5-dihydro-2,
5-Dioxo-3-hydroxy-1H-benzazepine (DDHB), DDHB, has the most prominent affinity at glycine allosteric sites, NMDA recognition sites, and non-NMDA receptors. NMDA (glycine) and non-N
Antibodies with dual functions at the MDA receptor are prone to neurological decline but they may be particularly valuable in combating the heterogeneity of pathological mechanisms that occur during local anemia. all right. Preliminary experiments of this invention indicate that DDHB is neuroprotective in both in vitro and in vivo assays. Although the invention has been fully described herein, those skilled in the art will appreciate that the same can be done within a wide range of conditions, formulations, and other parameters,
It will be understood that it is not intended to limit the scope of this invention or embodiments thereof. All patents and publications cited in this specification are incorporated herein by reference in their entirety.

[Brief description of drawings]

FIG. 1: 2,5-Dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine induced kainate (A) or MDA + glycine (B) -induced membrane currents at holding potentials of +50 mV and -80 mV. It is a graph which shows inhibiting.

FIG. 2 represents a graph showing control currents activated by kainate. FIG. 2B shows 8-methyl-2,5-
Dihydro-2,5-dioxo-3-hydroxy-1H-
FIG. 6 is a graph showing competitive antagonism of kainate-activated kainate currents by benzazepine.

FIG. 3: Kainate alone (○) or 8-methyl-2,
5-dihydro-2,5-dioxo-3-hydroxy-1
H-benzazepine (▲), 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine (■), or 8-methyl-2,5-dihydro-2,5-dioxo 3 is a graph showing the concentration-reactivity relationship in the presence of 3-hydroxy-1H-benzazepine (●).

FIG. 4 shows that 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine inhibits early transient currents activated by L-glutamate. It is a graph.

FIG. 5: 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine
FIG. 6 is a bar graph showing inhibition of glutamate-activated early transient currents.

FIG. 6: With 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine,
FIG. 6 is a graph showing competitive antagonism of L-glutamate-activated constant current.

FIG. 7: Glutamate alone ((○) or 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine (▲), 20 μM 8-methyl-
2,5-dihydro-2,5-dioxo-3-hydroxy-
1 is a graph showing the concentration-reactivity relationship in the presence of 1H-benzazepine (■) or 50 μM 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine (●). is there.

FIG. 8: With 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine,
FIG. 6 is a graph showing competitive antagonism of kinate (A) and glutamate (B) steady-state activation at non-NMDA receptors.

FIG. 9: With 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine,
FIG. 6 is a graph showing glycine synergistic competitive antagonism at the NMDA receptor.

FIG. 10: Glycine alone (○) or 8-methyl-2,
5-dihydro-2,5-dioxo-3-hydroxy-1
H-benzazepine (▲), 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine (■) or 8-methyl-2,5-dihydro-
2 is a graph showing the concentration-reactivity relationship in the presence of 2,5-dioxo-3-hydroxy-1H-benzazepine (●).

FIG. 11 is a graph showing competitive antagonism of glycine activation at the glycine allosteric site of the NMDA receptor by 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine.

FIG. 12 is a graph showing that increasing the concentration of NMDA decreases the EC ₅₀ of glycine at the site of allosteric synergism.

FIG. 13 is a graph showing antagonism of the NMDA recognition site by 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine.

FIG. 14: NMDA + 1 mM D-serine (O) and 50 μM 8-methyl-2,5-dihydro-
2 is a graph showing a concentration-reactivity relationship in the presence of 2,5-dioxo-3-hydroxy-1H-benzazepine (●).

FIG. 15: 2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 4-bromo-2,
5-dihydro-2,5-dioxo-3-hydroxy-1
FIG. 6 is a graph showing antagonism of kainate by H-benzazepine and 7-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine.

FIG. 16: 7-Methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 4-
Glycine allosteric site of the NMDA receptor by bromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine and 2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine 2 is a graph showing antagonism in FIG.

FIG. 17: 7-Methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 4-
Agonist recognition site of NMDA receptor by bromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine and 2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine 2 is a graph showing antagonism in FIG.

 ─────────────────────────────────────────────────── ─── Continued Front Page (71) Applicant 592246831 Kenton J. Schwartz Kenton J. SWARTZ United States 02144 15th Street, High Street, Smerville, Mass. (71) Applicant 592246842 Walter J. Corochets Walter J. KOROSHETZ United States 02186 Gerald Road 140, Milton, Mass. (71) Applicant 592246853 Alan H. Lees Alun H. REES Canada, Ontario K.O.L.2 Ethio, Lakefield, P.O. Box 1204 (Route No. 3) (71) Applicant 592246864 James E. Hütner James E. HUETTNER USA 93122 Brownell Avenue, Missouri 931 Browner Avenue 931 (72) Inventor Eckard Weber USA 92651 Del Mar Avenue, Laguna Beach, CA 1560 (72) Inventor John F. W. Kena USA 97405 Onyx Street, Eugene, Oregon 3854 (72) Inventor Kenton Jay Schwartz United States 02144 Smeerville, Massachusetts High Street 15 (72) Inventor Walter Jay Corochets United States 02186 Milton, Massachusetts Gerald Road No. 140 (72) Inventor Alan H. Leeds Canada Canada Ontario L2 Ethiop, Lakefield, P.O. Box 1204 (Route No. 3) (72) Inventor James E. Hutner 931, Brownell Avenue, Glendale, Missouri, USA 9312

Claims (61)

[Claims] 1. An animal in need of treatment has the formula: [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl, aryl, heterocyclic group, heteroaryl group, nitro, amino or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, haloalkyl, aryl , Heterocyclic group, heteroaryl group, alkyl, nitro, amino or azido; R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —NHCONHAr, —N
HCOCH ₂ Ar, —COCH ₂ Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy (wherein Ar is an aryl group, a heterocyclic group or a heteroaryl group) and;
R ₇ is hydrogen]. A method of treating or preventing nerve damage associated with stroke, ischemia, CNS trauma, hypoglycemia or surgery, comprising administering an effective amount of a compound represented by the formula: 2. The method of claim 1 wherein R ₂ is halo or nitro, R ₃ is hydrogen or halo, R ₄ is halo or haloalkyl and R ₁ and R ₅ -R ₇ are hydrogen. 3. The compound is 6-nitro-7,8-dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-nitro-7,8-.
Dibromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H- Benzazepine, 6-bromo-7,8-dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-7-nitro-8-trifluoromethyl-2,5- Dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-9-nitro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 6,7,8-trichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-7,8-difluoro-2,5-dihydro- 2,5-dioxo-3-hydroxy-1H-benzazepine, 6-bromo-7,8
-Difluoro-2,5-dihydro-2,5-dioxo-3
-Hydroxy-1H-benzazepine, 6,7,8,9-
Tetrafluoro-2,5-dihydro-2,5-dioxo-
3-hydroxy-1H-benzazepine, 6-chloro-
8-fluoro-2,5-dihydro-2,5-dioxo-3
-Hydroxy-1H-benzazepine, 6,8-dibromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-bromo-8-trifluoromethyl-2,5-dihydro-2 , 5-dioxo-3-
Hydroxy-1H-benzazepine, 6-bromo-8-
Fluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7,8-dibromo-
6-nitro-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 7,8-difluoro-6-nitro-2,5-dihydro-2,5-dioxo-
3-hydroxy-1H-benzazepine, 7-chloro-
8-Bromo-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-
Bromo-8-chloro-6-nitro-2,5-dihydro-
2,5-dioxo-3-hydroxy-1H-benzazepine, 7-fluoro-8-chloro-6-nitro-2,5
-Dihydro-2,5-dioxo-3-hydroxy-1H
-Benzazepine, 8-fluoro-7-chloro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-fluoro-8-bromo-6-nitro-2,5 -Dihydro-2,5-dioxo-
3-hydroxy-1H-benzazepine and 8-fluoro-7-bromo-6-nitro-2,5-dihydro-2,
The method of claim 1 selected from the group consisting of 5-dioxo-3-hydroxy-1H-benzazepine. 4. The above compound is 2,5-dihydro-2,5.
-Dioxo-3-hydroxy-1H-benzazepine,
4-Bromo-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 7-methyl-2,
5-dihydro-2,5-dioxo-3-hydroxy-1
H-benzazepine, 8-methyl-2,5-dihydro-
2,5-Dioxo-3-hydroxy-1H-benzazepine and 6,8-dichloro-2,5-dihydro-2,5
The method of claim 1, wherein the method is selected from the group consisting of -dioxo-3-hydroxy-1H-benzazepine. 5. An animal in need of treatment has the formula: [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl, aryl, heterocyclic group, heteroaryl group, nitro, amino or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, haloalkyl, aryl , Heterocyclic group, heteroaryl group, alkyl, nitro, amino or azido; R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —NHCONHAr, —N
HCOCH ₂ Ar, —COCH ₂ Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy (wherein Ar is an aryl group, a heterocyclic group or a heteroaryl group) and;
R ₇ is hydrogen]. A method of treating or preventing nerve damage associated with stroke, ischemia, CNS trauma, hypoglycemia or surgery, comprising administering an effective amount of a compound represented by the formula: 6. The compound as described above is 6-nitro-7,8-dichloro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-nitro-7,8-.
Dibromo-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-4-hydroxy-1H- Benzazepine, 6-bromo-7,8-dichloro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-7-nitro-8-trifluoromethyl-2,5- Dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-9-nitro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 6,7,8-trichloro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-7,8-difluoro-2,5-dihydro- 2,5-dioxo-4-hydroxy-1H-benzazepine, 6-bromo-7,8
-Difluoro-2,5-dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 6,7,8,9-
Tetrafluoro-2,5-dihydro-2,5-dioxo-
4-hydroxy-1H-benzazepine, 6-chloro-
8-fluoro-2,5-dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 6,8-dibromo-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-bromo-8-trifluoromethyl-2,5-dihydro-2 , 5-dioxo-4-
Hydroxy-1H-benzazepine, 6-bromo-8-
Fluoro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7,8-dibromo-
6-nitro-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 7,8-difluoro-6-nitro-2,5-dihydro-2,5-dioxo-
4-hydroxy-1H-benzazepine, 7-chloro-
8-Bromo-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-
Bromo-8-chloro-6-nitro-2,5-dihydro-
2,5-dioxo-4-hydroxy-1H-benzazepine, 7-fluoro-8-chloro-6-nitro-2,5
-Dihydro-2,5-dioxo-4-hydroxy-1H
-Benzazepine, 8-fluoro-7-chloro-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-fluoro-8-bromo-6-nitro-2,5 -Dihydro-2,5-dioxo-
4-hydroxy-1H-benzazepine and 8-fluoro-7-bromo-6-nitro-2,5-dihydro-2,
The method of claim 5, wherein the method is selected from the group consisting of 5-dioxo-4-hydroxy-1H-benzazepine. 7. A method according to claim 1 or 5, wherein the nerve damage is the result of air bubbles occurring during or immediately after surgery. 8. The method of claim 1 or 5, wherein the nerve injury is a result of cardiopulmonary bypass surgery. 9. The method of claim 1 or 5, wherein the nerve injury is a result of carotid endarterectomy surgery. 10. The method of claim 1 or 5, wherein the nerve damage is the result of multiple strokes leading to dementia. 11. An animal in need of treatment has the formula: [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl, aryl, heterocyclic group, heteroaryl group, nitro, amino or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, haloalkyl, aryl , Heterocyclic group, heteroaryl group, alkyl, nitro, amino or azido; R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —NHCONHAr, —N
HCOCH ₂ Ar, —COCH ₂ Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy (wherein Ar is an aryl group, a heterocyclic group or a heteroaryl group) and;
R ₇ is hydrogen], and a method for treating and preventing a neurodegenerative disease selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's syndrome. 12. The method of claim 11, wherein R ₂ is halo or nitro, R ₃ is hydrogen or halo, R ₄ is halo or haloalkyl, and R ₁ and R ₅ -R ₇ are hydrogen. 13. The compound is 6-nitro-7,8-
Dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-nitro-7,8
-Dibromo-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 6-chloro-8-
Trifluoromethyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-bromo-7,8-dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy- 1H-benzazepine, 6-chloro-7-nitro-8-trifluoromethyl-2,5-
Dihydro-2,5-dioxo-3-hydroxy-1H-
Benzazepine, 6-chloro-9-nitro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-3
-Hydroxy-1H-benzazepine, 6,7,8-trichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-7,8-
Difluoro-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 6-bromo-7,
8-difluoro-2,5-dihydro-2,5-dioxo-
3-hydroxy-1H-benzazepine, 6,7,8,9
-Tetrafluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-8-fluoro-2,5-dihydro-2,5-dioxo-
3-Hydroxy-1H-benzazepine, 6,8-dibromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-bromo-8-trifluoromethyl-2,5-dihydro- 2,5-dioxo-3
-Hydroxy-1H-benzazepine, 6-bromo-8
-Fluoro-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 7,8-dibromo-6-nitro-2,5-dihydro-2,5-dioxo-3
-Hydroxy-1H-benzazepine, 7,8-difluoro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-chloro-8-bromo-6-nitro-2 , 5-dihydro-2,5-
Dioxo-3-hydroxy-1H-benzazepine, 7
-Bromo-8-chloro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-fluoro-8-chloro-6-nitro-2,
5-dihydro-2,5-dioxo-3-hydroxy-1
H-benzazepine, 8-fluoro-7-chloro-6-
Nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-fluoro-8-bromo-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy- 1H-benzazepine and 8-fluoro-7-bromo-6-nitro-2,5-dihydro-
12. The method of claim 11, selected from the group consisting of 2,5-dioxo-3-hydroxy-1H-benzazepine. 14. The compound is 2,5-dihydro-2,
5-dioxo-3-hydroxy-1H-benzazepine, 4-bromo-2,5-dihydro-2,5-dioxo-
3-hydroxy-1H-benzazepine, 7-methyl-
2,5-dihydro-2,5-dioxo-3-hydroxy-
1H-benzazepine, 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine and 6,8-dichloro-2,5-dihydro-2,
12. The method of claim 11, selected from the group consisting of 5-dioxo-3-hydroxy-1H-benzazepine. 15. An animal in need of treatment has the formula: [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl, aryl, heterocyclic group, heteroaryl group, nitro, amino or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, haloalkyl, aryl , Heterocyclic group, heteroaryl group, alkyl, nitro, amino or azido; R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —NHCONHAr, —N
HCOCH ₂ Ar, —COCH ₂ Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy (wherein Ar is an aryl group, a heterocyclic group or a heteroaryl group) and;
R ₇ is hydrogen], and a method for treating and preventing a neurodegenerative disease selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's syndrome. 16. The compound is 6-nitro-7,8-
Dichloro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-nitro-7,8
-Dibromo-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 6-chloro-8-
Trifluoromethyl-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-bromo-7,8-dichloro-2,5-dihydro-2,5-dioxo-4-hydroxy- 1H-benzazepine, 6-chloro-7-nitro-8-trifluoromethyl-2,5-
Dihydro-2,5-dioxo-4-hydroxy-1H-
Benzazepine, 6-chloro-9-nitro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 6,7,8-trichloro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-7,8-
Difluoro-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 6-bromo-7,
8-difluoro-2,5-dihydro-2,5-dioxo-
4-hydroxy-1H-benzazepine, 6,7,8,9
-Tetrafluoro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-8-fluoro-2,5-dihydro-2,5-dioxo-
4-hydroxy-1H-benzazepine, 6,8-dibromo-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-bromo-8-trifluoromethyl-2,5-dihydro- 2,5-dioxo-4
-Hydroxy-1H-benzazepine, 6-bromo-8
-Fluoro-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 7,8-dibromo-6-nitro-2,5-dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 7,8-difluoro-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-chloro-8-bromo-6-nitro-2 , 5-dihydro-2,5-
Dioxo-4-hydroxy-1H-benzazepine, 7
-Bromo-8-chloro-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-fluoro-8-chloro-6-nitro-2,
5-dihydro-2,5-dioxo-4-hydroxy-1
H-benzazepine, 8-fluoro-7-chloro-6-
Nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-fluoro-8-bromo-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy- 1H-benzazepine and 8-fluoro-7-bromo-6-nitro-2,5-dihydro-
16. The method of claim 15, selected from the group consisting of 2,5-dioxo-4-hydroxy-1H-benzazepine. 17. An animal in need of treatment has the formula: [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl, aryl, heterocyclic group, heteroaryl group, nitro, amino or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, haloalkyl, aryl , Heterocyclic group, heteroaryl group, alkyl, nitro, amino or azido; R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —NHCONHAr, —N
HCOCH ₂ Ar, —COCH ₂ Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy (wherein Ar is an aryl group, a heterocyclic group or a heteroaryl group) and;
R ₇ is hydrogen]. A method of treatment and prophylaxis of the adverse consequences of the high activity of stimulatory amino acids, which comprises administering an effective amount of a compound of the formula 18. The method of claim 17, wherein R ₂ is halo or nitro, R ₃ is hydrogen or halo, R ₄ is halo or haloalkyl, and R ₁ and R ₅ -R ₇ are hydrogen. 19. The compound is 6-nitro-7,8-
Dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-nitro-7,8
-Dibromo-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 6-chloro-8-
Trifluoromethyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-bromo-7,8-dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy- 1H-benzazepine, 6-chloro-7-nitro-8-trifluoromethyl-2,5-
Dihydro-2,5-dioxo-3-hydroxy-1H-
Benzazepine, 6-chloro-9-nitro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-3
-Hydroxy-1H-benzazepine, 6,7,8-trichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-7,8-
Difluoro-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 6-bromo-7,
8-difluoro-2,5-dihydro-2,5-dioxo-
3-hydroxy-1H-benzazepine, 6,7,8,9
-Tetrafluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-8-fluoro-2,5-dihydro-2,5-dioxo-
3-Hydroxy-1H-benzazepine, 6,8-dibromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-bromo-8-trifluoromethyl-2,5-dihydro- 2,5-dioxo-3
-Hydroxy-1H-benzazepine, 6-bromo-8
-Fluoro-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 7,8-dibromo-6-nitro-2,5-dihydro-2,5-dioxo-3
-Hydroxy-1H-benzazepine, 7,8-difluoro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-chloro-8-bromo-6-nitro-2 , 5-dihydro-2,5-
Dioxo-3-hydroxy-1H-benzazepine, 7
-Bromo-8-chloro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-fluoro-8-chloro-6-nitro-2,
5-dihydro-2,5-dioxo-3-hydroxy-1
H-benzazepine, 8-fluoro-7-chloro-6-
Nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-fluoro-8-bromo-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy- 1H-benzazepine and 8-fluoro-7-bromo-6-nitro-2,5-dihydro-
18. The method of claim 17, selected from the group consisting of 2,5-dioxo-3-hydroxy-1H-benzazepine. 20. The compound is 2,5-dihydro-2,
5-dioxo-3-hydroxy-1H-benzazepine, 4-bromo-2,5-dihydro-2,5-dioxo-
3-hydroxy-1H-benzazepine, 7-methyl-
2,5-dihydro-2,5-dioxo-3-hydroxy-
1H-benzazepine, 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine and 6,8-dichloro-2,5-dihydro-2,
19. The method of claim 18, selected from the group consisting of 5-dioxo-3-hydroxy-1H-benzazepine. 21. In an animal in need of treatment, the formula: [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl, aryl, heterocyclic group, heteroaryl group, nitro, amino or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, haloalkyl, aryl , Heterocyclic group, heteroaryl group, alkyl, nitro, amino or azido; R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —NHCONHAr, —N
HCOCH ₂ Ar, —COCH ₂ Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy (wherein Ar is an aryl group, a heterocyclic group or a heteroaryl group) and;
R ₇ is hydrogen]. A method of treatment and prophylaxis of the adverse consequences of the high activity of stimulatory amino acids, which comprises administering an effective amount of a compound of the formula 22. The compound is 6-nitro-7,8-
Dichloro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-nitro-7,8
-Dibromo-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 6-chloro-8-
Trifluoromethyl-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-bromo-7,8-dichloro-2,5-dihydro-2,5-dioxo-4-hydroxy- 1H-benzazepine, 6-chloro-7-nitro-8-trifluoromethyl-2,5-
Dihydro-2,5-dioxo-4-hydroxy-1H-
Benzazepine, 6-chloro-9-nitro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 6,7,8-trichloro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-7,8-
Difluoro-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 6-bromo-7,
8-difluoro-2,5-dihydro-2,5-dioxo-
4-hydroxy-1H-benzazepine, 6,7,8,9
-Tetrafluoro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-8-fluoro-2,5-dihydro-2,5-dioxo-
4-hydroxy-1H-benzazepine, 6,8-dibromo-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-bromo-8-trifluoromethyl-2,5-dihydro- 2,5-dioxo-4
-Hydroxy-1H-benzazepine, 6-bromo-8
-Fluoro-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 7,8-dibromo-6-nitro-2,5-dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 7,8-difluoro-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-chloro-8-bromo-6-nitro-2 , 5-dihydro-2,5-
Dioxo-4-hydroxy-1H-benzazepine, 7
-Bromo-8-chloro-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-fluoro-8-chloro-6-nitro-2,
5-dihydro-2,5-dioxo-4-hydroxy-1
H-benzazepine, 8-fluoro-7-chloro-6-
Nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-fluoro-8-bromo-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy- 1H-benzazepine and 8-fluoro-7-bromo-6-nitro-2,5-dihydro-
22. The method of claim 21, selected from the group consisting of 2,5-dioxo-4-hydroxy-1H-benzazepine. 23. In an animal in need of treatment, the formula: [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl, aryl, heterocyclic group, heteroaryl group, nitro, amino or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, haloalkyl, aryl , Heterocyclic group, heteroaryl group, alkyl, nitro, amino or azido; R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —NHCONHAr, —N
HCOCH ₂ Ar, —COCH ₂ Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy (wherein Ar is an aryl group, a heterocyclic group or a heteroaryl group) and;
R ₇ is hydrogen]. A method of treatment and prophylaxis of the adverse consequences of the high activity of the NMDA receptor, which comprises administering an effective amount of a compound of formula 24. The method of claim 23, wherein R ₂ is halo or nitro, R ₃ is hydrogen or halo, R ₄ is halo or haloalkyl, and R ₁ and R ₅ -R ₇ are hydrogen. 25. The compound is 6-nitro-7,8-
Dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-nitro-7,8
-Dibromo-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 6-chloro-8-
Trifluoromethyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-bromo-7,8-dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy- 1H-benzazepine, 6-chloro-7-nitro-8-trifluoromethyl-2,5-
Dihydro-2,5-dioxo-3-hydroxy-1H-
Benzazepine, 6-chloro-9-nitro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-3
-Hydroxy-1H-benzazepine, 6,7,8-trichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-7,8-
Difluoro-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 6-bromo-7,
8-difluoro-2,5-dihydro-2,5-dioxo-
3-hydroxy-1H-benzazepine, 6,7,8,9
-Tetrafluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-8-fluoro-2,5-dihydro-2,5-dioxo-
3-Hydroxy-1H-benzazepine, 6,8-dibromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-bromo-8-trifluoromethyl-2,5-dihydro- 2,5-dioxo-3
-Hydroxy-1H-benzazepine, 6-bromo-8
-Fluoro-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 7,8-dibromo-6-nitro-2,5-dihydro-2,5-dioxo-3
-Hydroxy-1H-benzazepine, 7,8-difluoro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-chloro-8-bromo-6-nitro-2 , 5-dihydro-2,5-
Dioxo-3-hydroxy-1H-benzazepine, 7
-Bromo-8-chloro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-fluoro-8-chloro-6-nitro-2,
5-dihydro-2,5-dioxo-3-hydroxy-1
H-benzazepine, 8-fluoro-7-chloro-6-
Nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-fluoro-8-bromo-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy- 1H-benzazepine and 8-fluoro-7-bromo-6-nitro-2,5-dihydro-
24. The method of claim 23, selected from the group consisting of 2,5-dioxo-3-hydroxy-1H-benzazepine. 26. The compound is 2,5-dihydro-2,
5-dioxo-3-hydroxy-1H-benzazepine, 4-bromo-2,5-dihydro-2,5-dioxo-
3-hydroxy-1H-benzazepine, 7-methyl-
2,5-dihydro-2,5-dioxo-3-hydroxy-
1H-benzazepine, 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine and 6,8-dichloro-2,5-dihydro-2,
25. The method of claim 24, selected from the group consisting of 5-dioxo-3-hydroxy-1H-benzazepine. 27. An animal in need of treatment has the formula: [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl, aryl, heterocyclic group, heteroaryl group, nitro, amino or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, haloalkyl, aryl , Heterocyclic group, heteroaryl group, alkyl, nitro, amino or azido; R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —NHCONHAr, —N
HCOCH ₂ Ar, —COCH ₂ Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy (wherein Ar is an aryl group, a heterocyclic group or a heteroaryl group) and;
R ₇ is hydrogen]. A method of treatment and prophylaxis of the adverse consequences of the high activity of the NMDA receptor, which comprises administering an effective amount of a compound of formula 28. The compound is 6-nitro-7,8-
Dichloro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-nitro-7,8
-Dibromo-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 6-chloro-8-
Trifluoromethyl-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-7-nitro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo- 4-Hydroxy-1H-benzazepine, 6-chloro-9-nitro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 6,7,8-trichloro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-7,8-difluoro-2,5-dihydro- 2,5-dioxo-4-hydroxy-1H-benzazepine, 6-bromo-7,8
-Difluoro-2,5-dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 6,7,8,9-
Tetrafluoro-2,5-dihydro-2,5-dioxo-
4-hydroxy-1H-benzazepine, 6-chloro-
8-fluoro-2,5-dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 6,8-dibromo-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-bromo-8-trifluoromethyl-2,5-dihydro-2 , 5-dioxo-4-
Hydroxy-1H-benzazepine, 6-bromo-8-
Fluoro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7,8-dibromo-
6-nitro-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 7,8-difluoro-6-nitro-2,5-dihydro-2,5-dioxo-
4-hydroxy-1H-benzazepine, 7-chloro-
8-Bromo-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-
Bromo-8-chloro-6-nitro-2,5-dihydro-
2,5-dioxo-4-hydroxy-1H-benzazepine, 7-fluoro-8-chloro-6-nitro-2,5
-Dihydro-2,5-dioxo-4-hydroxy-1H
-Benzazepine, 8-fluoro-7-chloro-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-fluoro-8-bromo-6-nitro-2,5 -Dihydro-2,5-dioxo-
4-hydroxy-1H-benzazepine and 8-fluoro-7-bromo-6-nitro-2,5-dihydro-2,
28. The method of claim 27, selected from the group consisting of 5-dioxo-4-hydroxy-1H-benzazepine. 29. In an animal in need of treatment, the formula: [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl, aryl, heterocyclic group, heteroaryl group, nitro, amino or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, haloalkyl, aryl , Heterocyclic group, heteroaryl group, alkyl, nitro, amino or azido; R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —NHCONHAr, —N
HCOCH ₂ Ar, —COCH ₂ Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy (wherein Ar is an aryl group, a heterocyclic group or a heteroaryl group) and;
R ₇ is hydrogen], and a method for treating and preventing chronic pain, which comprises administering an effective amount of a compound represented by the formula: 30. The method of claim 29, wherein R ₂ is halo or nitro, R ₃ is hydrogen or halo, R ₄ is halo or haloalkyl, and R ₁ and R ₅ -R ₇ are hydrogen. 31. The compound is 6-nitro-7,8-
Dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-nitro-7,8
-Dibromo-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 6-chloro-8-
Trifluoromethyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-bromo-7,8-dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy- 1H-benzazepine, 6-chloro-7-nitro-8-trifluoromethyl-2,5-
Dihydro-2,5-dioxo-3-hydroxy-1H-
Benzazepine, 6-chloro-9-nitro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-3
-Hydroxy-1H-benzazepine, 6,7,8-trichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-7,8-
Difluoro-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 6-bromo-7,
8-difluoro-2,5-dihydro-2,5-dioxo-
3-hydroxy-1H-benzazepine, 6,7,8,9
-Tetrafluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-8-fluoro-2,5-dihydro-2,5-dioxo-
3-Hydroxy-1H-benzazepine, 6,8-dibromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-bromo-8-trifluoromethyl-2,5-dihydro- 2,5-dioxo-3
-Hydroxy-1H-benzazepine, 6-bromo-8
-Fluoro-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 7,8-dibromo-6-nitro-2,5-dihydro-2,5-dioxo-3
-Hydroxy-1H-benzazepine, 7,8-difluoro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-chloro-8-bromo-6-nitro-2 , 5-dihydro-2,5-
Dioxo-3-hydroxy-1H-benzazepine, 7
-Bromo-8-chloro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-fluoro-8-chloro-6-nitro-2,
5-dihydro-2,5-dioxo-3-hydroxy-1
H-benzazepine, 8-fluoro-7-chloro-6-
Nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-fluoro-8-bromo-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy- 1H-benzazepine and 8-fluoro-7-bromo-6-nitro-2,5-dihydro-
30. The method of claim 29, selected from the group consisting of 2,5-dioxo-3-hydroxy-1H-benzazepine. 32. The compound is 2,5-dihydro-2,
5-dioxo-3-hydroxy-1H-benzazepine, 4-bromo-2,5-dihydro-2,5-dioxo-
3-hydroxy-1H-benzazepine, 7-methyl-
2,5-dihydro-2,5-dioxo-3-hydroxy-
1H-benzazepine, 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine and 6,8-dichloro-2,5-dihydro-2,
31. The method of claim 30, selected from the group consisting of 5-dioxo-3-hydroxy-1H-benzazepine. 33. In an animal in need of treatment, the formula: [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl, aryl, heterocyclic group, heteroaryl group, nitro, amino or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, haloalkyl, aryl , Heterocyclic group, heteroaryl group, alkyl, nitro, amino or azido; R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —NHCONHAr, —N
HCOCH ₂ Ar, —COCH ₂ Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy (wherein Ar is an aryl group, a heterocyclic group or a heteroaryl group) and;
R ₇ is hydrogen], and a method for treating and preventing chronic pain, which comprises administering an effective amount of a compound represented by the formula: 34. The compound is 6-nitro-7,8-
Dichloro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-nitro-7,8
-Dibromo-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 6-chloro-8-
Trifluoromethyl-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-bromo-7,8-dichloro-2,5-dihydro-2,5-dioxo-4-hydroxy- 1H-benzazepine, 6-chloro-7-nitro-8-trifluoromethyl-2,5-
Dihydro-2,5-dioxo-4-hydroxy-1H-
Benzazepine, 6-chloro-9-nitro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 6,7,8-trichloro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-7,8-
Difluoro-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 6-bromo-7,
8-difluoro-2,5-dihydro-2,5-dioxo-
4-hydroxy-1H-benzazepine, 6,7,8,9
-Tetrafluoro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-8-fluoro-2,5-dihydro-2,5-dioxo-
4-hydroxy-1H-benzazepine, 6,8-dibromo-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-bromo-8-trifluoromethyl-2,5-dihydro- 2,5-dioxo-4
-Hydroxy-1H-benzazepine, 6-bromo-8
-Fluoro-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 7,8-dibromo-6-nitro-2,5-dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 7,8-difluoro-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-chloro-8-bromo-6-nitro-2 , 5-dihydro-2,5-
Dioxo-4-hydroxy-1H-benzazepine, 7
-Bromo-8-chloro-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-fluoro-8-chloro-6-nitro-2,
5-dihydro-2,5-dioxo-4-hydroxy-1
H-benzazepine, 8-fluoro-7-chloro-6-
Nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-fluoro-8-bromo-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy- 1H-benzazepine and 8-fluoro-7-bromo-6-nitro-2,5-dihydro-
34. The method of claim 33, selected from the group consisting of 2,5-dioxo-4-hydroxy-1H-benzazepine. 35. The method of claim 29 or 33, wherein the chronic pain is the result of surgery on the animal. 36. In an animal in need of treatment, the formula: [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl, aryl, heterocyclic group, heteroaryl group, nitro, amino or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, haloalkyl, aryl , Heterocyclic group, heteroaryl group, alkyl, nitro, amino or azido; R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —NHCONHAr, —N
HCOCH ₂ Ar, —COCH ₂ Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy (wherein Ar is an aryl group, a heterocyclic group or a heteroaryl group) and;
R ₇ is hydrogen], and a method for treating and preventing anxiety, which comprises administering an effective amount of a compound represented by the formula. 37. The method of claim 36, wherein R ₂ is halo or nitro, R ₃ is hydrogen or halo, R ₄ is halo or haloalkyl, and R ₁ and R ₅ -R ₇ are hydrogen. 38. The above compound is 6-nitro-7,8-
Dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-nitro-7,8
-Dibromo-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 6-chloro-8-
Trifluoromethyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-bromo-7,8-dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy- 1H-benzazepine, 6-chloro-7-nitro-8-trifluoromethyl-2,5-
Dihydro-2,5-dioxo-3-hydroxy-1H-
Benzazepine, 6-chloro-9-nitro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-3
-Hydroxy-1H-benzazepine, 6,7,8-trichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-7,8-
Difluoro-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 6-bromo-7,
8-difluoro-2,5-dihydro-2,5-dioxo-
3-hydroxy-1H-benzazepine, 6,7,8,9
-Tetrafluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-8-fluoro-2,5-dihydro-2,5-dioxo-
3-Hydroxy-1H-benzazepine, 6,8-dibromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-bromo-8-trifluoromethyl-2,5-dihydro- 2,5-dioxo-3
-Hydroxy-1H-benzazepine, 6-bromo-8
-Fluoro-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 7,8-dibromo-6-nitro-2,5-dihydro-2,5-dioxo-3
-Hydroxy-1H-benzazepine, 7,8-difluoro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-chloro-8-bromo-6-nitro-2 , 5-dihydro-2,5-
Dioxo-3-hydroxy-1H-benzazepine, 7
-Bromo-8-chloro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-fluoro-8-chloro-6-nitro-2,
5-dihydro-2,5-dioxo-3-hydroxy-1
H-benzazepine, 8-fluoro-7-chloro-6-
Nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-fluoro-8-bromo-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy- 1H-benzazepine and 8-fluoro-7-bromo-6-nitro-2,5-dihydro-
37. The method of claim 36, selected from the group consisting of 2,5-dioxo-3-hydroxy-1H-benzazepine. 39. The compound is 2,5-dihydro-2,
5-dioxo-3-hydroxy-1H-benzazepine, 4-bromo-2,5-dihydro-2,5-dioxo-
3-hydroxy-1H-benzazepine, 7-methyl-
2,5-dihydro-2,5-dioxo-3-hydroxy-
1H-benzazepine, 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine and 6,8-dichloro-2,5-dihydro-2,
39. The method of claim 38, selected from the group consisting of 5-dioxo-3-hydroxy-1H-benzazepine. 40. In an animal in need of treatment, the formula: [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl, aryl, heterocyclic group, heteroaryl group, nitro, amino or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, haloalkyl, aryl , Heterocyclic group, heteroaryl group, alkyl, nitro, amino or azido; R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —NHCONHAr, —N
HCOCH ₂ Ar, —COCH ₂ Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy (wherein Ar is an aryl group, a heterocyclic group or a heteroaryl group) and;
R ₇ is hydrogen], a method for treating or preventing anxiety, which comprises administering an effective amount of a compound represented by 41. The above compound is 6-nitro-7,8-
Dichloro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-nitro-7,8
-Dibromo-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 6-chloro-8-
Trifluoromethyl-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-bromo-7,8-dichloro-2,5-dihydro-2,5-dioxo-4-hydroxy- 1H-benzazepine, 6-chloro-7-nitro-8-trifluoromethyl-2,5-
Dihydro-2,5-dioxo-4-hydroxy-1H-
Benzazepine, 6-chloro-9-nitro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 6,7,8-trichloro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-7,8-
Difluoro-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 6-bromo-7,
8-difluoro-2,5-dihydro-2,5-dioxo-
4-hydroxy-1H-benzazepine, 6,7,8,9
-Tetrafluoro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-8-fluoro-2,5-dihydro-2,5-dioxo-
4-hydroxy-1H-benzazepine, 6,8-dibromo-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-bromo-8-trifluoromethyl-2,5-dihydro- 2,5-dioxo-4
-Hydroxy-1H-benzazepine, 6-bromo-8
-Fluoro-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 7,8-dibromo-6-nitro-2,5-dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 7,8-difluoro-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-chloro-8-bromo-6-nitro-2 , 5-dihydro-2,5-
Dioxo-4-hydroxy-1H-benzazepine, 7
-Bromo-8-chloro-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-fluoro-8-chloro-6-nitro-2,
5-dihydro-2,5-dioxo-4-hydroxy-1
H-benzazepine, 8-fluoro-7-chloro-6-
Nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-fluoro-8-bromo-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy- 1H-benzazepine and 8-fluoro-7-bromo-6-nitro-2,5-dihydro-
41. The method of claim 40, selected from the group consisting of 2,5-dioxo-4-hydroxy-1H-benzazepine. 42. In an animal in need of treatment, the formula: [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl, aryl, heterocyclic group, heteroaryl group, nitro, amino or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, haloalkyl, aryl , Heterocyclic group, heteroaryl group, alkyl, nitro, amino or azido; R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —NHCONHAr, —N
HCOCH ₂ Ar, —COCH ₂ Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy (wherein Ar is an aryl group, a heterocyclic group or a heteroaryl group) and;
R ₇ is hydrogen]. 43. The method of claim 42, wherein R ₂ is halo or nitro, R ₃ is hydrogen or halo, R ₄ is halo or haloalkyl, and R ₁ and R ₅ -R ₇ are hydrogen. 44. The compound is 6-nitro-7,8-
Dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-nitro-7,8
-Dibromo-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 6-chloro-8-
Trifluoromethyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-bromo-7,8-dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy- 1H-benzazepine, 6-chloro-7-nitro-8-trifluoromethyl-2,5-
Dihydro-2,5-dioxo-3-hydroxy-1H-
Benzazepine, 6-chloro-9-nitro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-3
-Hydroxy-1H-benzazepine, 6,7,8-trichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-7,8-
Difluoro-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 6-bromo-7,
8-difluoro-2,5-dihydro-2,5-dioxo-
3-hydroxy-1H-benzazepine, 6,7,8,9
-Tetrafluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-8-fluoro-2,5-dihydro-2,5-dioxo-
3-Hydroxy-1H-benzazepine, 6,8-dibromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-bromo-8-trifluoromethyl-2,5-dihydro- 2,5-dioxo-3
-Hydroxy-1H-benzazepine, 6-bromo-8
-Fluoro-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 7,8-dibromo-6-nitro-2,5-dihydro-2,5-dioxo-3
-Hydroxy-1H-benzazepine, 7,8-difluoro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-chloro-8-bromo-6-nitro-2 , 5-dihydro-2,5-
Dioxo-3-hydroxy-1H-benzazepine, 7
-Bromo-8-chloro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-fluoro-8-chloro-6-nitro-2,
5-dihydro-2,5-dioxo-3-hydroxy-1
H-benzazepine, 8-fluoro-7-chloro-6-
Nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-fluoro-8-bromo-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy- 1H-benzazepine and 8-fluoro-7-bromo-6-nitro-2,5-dihydro-
43. The method of claim 42, selected from the group consisting of 2,5-dioxo-3-hydroxy-1H-benzazepine. 45. The compound is 2,5-dihydro-2,
5-dioxo-3-hydroxy-1H-benzazepine, 4-bromo-2,5-dihydro-2,5-dioxo-
3-hydroxy-1H-benzazepine, 7-methyl-
2,5-dihydro-2,5-dioxo-3-hydroxy-
1H-benzazepine, 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine and 6,8-dichloro-2,5-dihydro-2,
44. The method of claim 43, selected from the group consisting of 5-dioxo-3-hydroxy-1H-benzazepine. 46. In an animal in need of treatment, the formula: [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl, aryl, heterocyclic group, heteroaryl group, nitro, amino or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, haloalkyl, aryl , Heterocyclic group, heteroaryl group, alkyl, nitro, amino or azido; R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —NHCONHAr, —N
HCOCH ₂ Ar, —COCH ₂ Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy (wherein Ar is an aryl group, a heterocyclic group or a heteroaryl group) and;
R ₇ is hydrogen]. 47. The compound is 6-nitro-7,8-
Dichloro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-nitro-7,8
-Dibromo-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 6-chloro-8-
Trifluoromethyl-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-bromo-7,8-dichloro-2,5-dihydro-2,5-dioxo-4-hydroxy- 1H-benzazepine, 6-chloro-7-nitro-8-trifluoromethyl-2,5-
Dihydro-2,5-dioxo-4-hydroxy-1H-
Benzazepine, 6-chloro-9-nitro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 6,7,8-trichloro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-7,8-
Difluoro-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 6-bromo-7,
8-difluoro-2,5-dihydro-2,5-dioxo-
4-hydroxy-1H-benzazepine, 6,7,8,9
-Tetrafluoro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-8-fluoro-2,5-dihydro-2,5-dioxo-
4-hydroxy-1H-benzazepine, 6,8-dibromo-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-bromo-8-trifluoromethyl-2,5-dihydro- 2,5-dioxo-4
-Hydroxy-1H-benzazepine, 6-bromo-8
-Fluoro-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 7,8-dibromo-6-nitro-2,5-dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 7,8-difluoro-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-chloro-8-bromo-6-nitro-2 , 5-dihydro-2,5-
Dioxo-4-hydroxy-1H-benzazepine, 7
-Bromo-8-chloro-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-fluoro-8-chloro-6-nitro-2,
5-dihydro-2,5-dioxo-4-hydroxy-1
H-benzazepine, 8-fluoro-7-chloro-6-
Nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-fluoro-8-bromo-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy- 1H-benzazepine and 8-fluoro-7-bromo-6-nitro-2,5-dihydro-
47. The method of claim 46, selected from the group consisting of 2,5-dioxo-4-hydroxy-1H-benzazepine. 48. In an animal in need of treatment, the formula: [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl, aryl, heterocyclic group, heteroaryl group, nitro, amino or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, haloalkyl, aryl , Heterocyclic group, heteroaryl group, alkyl, nitro, amino or azido; R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —NHCONHAr, —N
HCOCH ₂ Ar, —COCH ₂ Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy (wherein Ar is an aryl group, a heterocyclic group or a heteroaryl group) and;
R ₇ is hydrogen], and a method of inducing anesthesia, comprising administering an effective amount of a compound represented by the formula: 49. The method of claim 48, wherein R ₂ is halo or nitro, R ₃ is hydrogen or halo, R ₄ is halo or haloalkyl, and R ₁ and R ₅ -R ₇ are hydrogen. 50. The above compound is 6-nitro-7,8-
Dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-nitro-7,8
-Dibromo-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 6-chloro-8-
Trifluoromethyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-bromo-7,8-dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy- 1H-benzazepine, 6-chloro-7-nitro-8-trifluoromethyl-2,5-
Dihydro-2,5-dioxo-3-hydroxy-1H-
Benzazepine, 6-chloro-9-nitro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-3
-Hydroxy-1H-benzazepine, 6,7,8-trichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-7,8-
Difluoro-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 6-bromo-7,
8-difluoro-2,5-dihydro-2,5-dioxo-
3-hydroxy-1H-benzazepine, 6,7,8,9
-Tetrafluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-8-fluoro-2,5-dihydro-2,5-dioxo-
3-Hydroxy-1H-benzazepine, 6,8-dibromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-bromo-8-trifluoromethyl-2,5-dihydro- 2,5-dioxo-3
-Hydroxy-1H-benzazepine, 6-bromo-8
-Fluoro-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 7,8-dibromo-6-nitro-2,5-dihydro-2,5-dioxo-3
-Hydroxy-1H-benzazepine, 7,8-difluoro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-chloro-8-bromo-6-nitro-2 , 5-dihydro-2,5-
Dioxo-3-hydroxy-1H-benzazepine, 7
-Bromo-8-chloro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-fluoro-8-chloro-6-nitro-2,
5-dihydro-2,5-dioxo-3-hydroxy-1
H-benzazepine, 8-fluoro-7-chloro-6-
Nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-fluoro-8-bromo-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy- 1H-benzazepine and 8-fluoro-7-bromo-6-nitro-2,5-dihydro-
49. The method of claim 48, selected from the group consisting of 2,5-dioxo-3-hydroxy-1H-benzazepine. 51. The above compound is 2,5-dihydro-2,
5-dioxo-3-hydroxy-1H-benzazepine, 4-bromo-2,5-dihydro-2,5-dioxo-
3-hydroxy-1H-benzazepine, 7-methyl-
2,5-dihydro-2,5-dioxo-3-hydroxy-
1H-benzazepine, 8-methyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine and 6,8-dichloro-2,5-dihydro-2,
50. The method of claim 49, selected from the group consisting of 5-dioxo-3-hydroxy-1H-benzazepine. 52. In an animal in need of treatment, the formula: [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl, aryl, heterocyclic group, heteroaryl group, nitro, amino or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, haloalkyl, aryl , Heterocyclic group, heteroaryl group, alkyl, nitro, amino or azido; R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —NHCONHAr, —N
HCOCH ₂ Ar, —COCH ₂ Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy (wherein Ar is an aryl group, a heterocyclic group or a heteroaryl group) and;
R ₇ is hydrogen], and a method of inducing anesthesia, comprising administering an effective amount of a compound represented by the formula: 53. The above compound is 6-nitro-7,8-
Dichloro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-nitro-7,8
-Dibromo-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 6-chloro-8-
Trifluoromethyl-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-bromo-7,8-dichloro-2,5-dihydro-2,5-dioxo-4-hydroxy- 1H-benzazepine, 6-chloro-7-nitro-8-trifluoromethyl-2,5-
Dihydro-2,5-dioxo-4-hydroxy-1H-
Benzazepine, 6-chloro-9-nitro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 6,7,8-trichloro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-7,8-
Difluoro-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 6-bromo-7,
8-difluoro-2,5-dihydro-2,5-dioxo-
4-hydroxy-1H-benzazepine, 6,7,8,9
-Tetrafluoro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-8-fluoro-2,5-dihydro-2,5-dioxo-
4-hydroxy-1H-benzazepine, 6,8-dibromo-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-bromo-8-trifluoromethyl-2,5-dihydro- 2,5-dioxo-4
-Hydroxy-1H-benzazepine, 6-bromo-8
-Fluoro-2,5-dihydro-2,5-dioxo-4-
Hydroxy-1H-benzazepine, 7,8-dibromo-6-nitro-2,5-dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 7,8-difluoro-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-chloro-8-bromo-6-nitro-2 , 5-dihydro-2,5-
Dioxo-4-hydroxy-1H-benzazepine, 7
-Bromo-8-chloro-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-fluoro-8-chloro-6-nitro-2,
5-dihydro-2,5-dioxo-4-hydroxy-1
H-benzazepine, 8-fluoro-7-chloro-6-
Nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-fluoro-8-bromo-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy- 1H-benzazepine and 8-fluoro-7-bromo-6-nitro-2,5-dihydro-
53. The method of claim 52, selected from the group consisting of 2,5-dioxo-4-hydroxy-1H-benzazepine. 54. Claims 1, 5, 11, 15, 17, 21, 23, 27, 29, wherein said compound is administered as part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
53. The method according to any one of 33, 36, 40, 42, 46, 48 and 52. 55. The formula: [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl, aryl, heterocyclic group, heteroaryl group, nitro, amino or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, haloalkyl, aryl , Heterocyclic group, heteroaryl group, alkyl, nitro, amino or azido; R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —NHCONHAr, —N
HCOCH ₂ Ar, —COCH ₂ Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy (wherein Ar is an aryl group, a heterocyclic group or a heteroaryl group) and;
R ₇ is hydrogen, provided that at least one of R ₂ , R ₃ , R ₄ and R ₅ is a halo, haloalkyl, aryl, nitro, amino or azido group, or R ₆ is other than hydrogen. ] The compound shown by these. 56. The compound according to claim 55, wherein R ₂ is halo or nitro, R ₃ is hydrogen or halo, R ₄ is halo or haloalkyl, and R ₁ and R ₅ -R ₇ are hydrogen. 57. The above compound is 6-nitro-7,8-
Dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-nitro-7,8
-Dibromo-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 6-chloro-8-
Trifluoromethyl-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-bromo-7,8-dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy- 1H-benzazepine, 6-chloro-7-nitro-8-trifluoromethyl-2,5-
Dihydro-2,5-dioxo-3-hydroxy-1H-
Benzazepine, 6-chloro-9-nitro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-3
-Hydroxy-1H-benzazepine, 6,7,8-trichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-7,8-
Difluoro-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 6-bromo-7,
8-difluoro-2,5-dihydro-2,5-dioxo-
3-hydroxy-1H-benzazepine, 6,7,8,9
-Tetrafluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-chloro-8-fluoro-2,5-dihydro-2,5-dioxo-
3-Hydroxy-1H-benzazepine, 6,8-dibromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 6-bromo-8-trifluoromethyl-2,5-dihydro- 2,5-dioxo-3
-Hydroxy-1H-benzazepine, 6-bromo-8
-Fluoro-2,5-dihydro-2,5-dioxo-3-
Hydroxy-1H-benzazepine, 7,8-dibromo-6-nitro-2,5-dihydro-2,5-dioxo-3
-Hydroxy-1H-benzazepine, 7,8-difluoro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-chloro-8-bromo-6-nitro-2 , 5-dihydro-2,5-
Dioxo-3-hydroxy-1H-benzazepine, 7
-Bromo-8-chloro-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-fluoro-8-chloro-6-nitro-2,
5-dihydro-2,5-dioxo-3-hydroxy-1
H-benzazepine, 8-fluoro-7-chloro-6-
Nitro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine, 7-fluoro-8-bromo-6-nitro-2,5-dihydro-2,5-dioxo-3-hydroxy- 1H-benzazepine and 8-fluoro-7-bromo-6-nitro-2,5-dihydro-
56. The compound of claim 55, selected from the group consisting of 2,5-dioxo-3-hydroxy-1H-benzazepine. 58. 7-Methyl-2,5-dihydro-2,5
-Dioxo-3-hydroxy-1H-benzazepine,
8-methyl-2,5-dihydro-2,5-dioxo-3-
A compound selected from the group consisting of hydroxy-1H-benzazepine and 6,8-dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzazepine. 59. The formula: [Wherein R ₁ is hydrogen, halo, haloalkyl, alkyl, aryl, heterocyclic group, heteroaryl group, nitro, amino or azido; R ₂ , R ₃ , R ₄ and R ₅ are hydrogen, halo, haloalkyl, aryl , Heterocyclic group, heteroaryl group, alkyl, nitro, amino or azido; R ₆ is hydrogen, aryl, heterocyclic group, heteroaryl group, alkyl, amino, —CH ₂ CONHAr, —NHCONHAr, —N
HCOCH ₂ Ar, —COCH ₂ Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy (wherein Ar is an aryl group, a heterocyclic group or a heteroaryl group) and;
R ₇ is hydrogen, provided that at least one of R ₂ , R ₃ , R ₄ and R ₅ is a halo, haloalkyl, aryl, nitro, amino or azido group, or R ₆ is other than hydrogen. ] The compound shown by these. 60. 6-Nitro-7,8-dichloro-2,5
-Dihydro-2,5-dioxo-4-hydroxy-1H
-Benzazepine, 6-nitro-7,8-dibromo-2,
5-dihydro-2,5-dioxo-4-hydroxy-1
H-benzazepine, 6-chloro-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-4-hydroxy-1 H-benzazepine, 6-bromo-7,8-dichloro-2,5-dihydro- 2,5-Dioxo-4-hydroxy-1H-benzazepine, 6-chloro-7-nitro-8-trifluoromethyl-2,5-dihydro-2,5
-Dioxo-4-hydroxy-1H-benzazepine,
6-chloro-9-nitro-8-trifluoromethyl-
2,5-dihydro-2,5-dioxo-4-hydroxy-
1H-benzazepine, 6,7,8-trichloro-2,5
-Dihydro-2,5-dioxo-4-hydroxy-1H
-Benzazepine, 6-chloro-7,8-difluoro-
2,5-dihydro-2,5-dioxo-4-hydroxy-
1H-benzazepine, 6-bromo-7,8-difluoro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6,7,8,9-tetrafluoro-2,5-dihydro -2,5-dioxo-4-hydroxy-1H-benzazepine, 6-chloro-8-fluoro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6,8-dibromo-2 , 5-
Dihydro-2,5-dioxo-4-hydroxy-1H-
Benzazepine, 6-bromo-8-trifluoromethyl-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 6-bromo-8-fluoro-
2,5-dihydro-2,5-dioxo-4-hydroxy-
1H-benzazepine, 7,8-dibromo-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7,8-difluoro-6-nitro-2,5-dihydro- 2,5-Dioxo-4-hydroxy-1H-benzazepine, 7-chloro-8-bromo-6-nitro-2,5-dihydro-2,5-dioxo-4
-Hydroxy-1H-benzazepine, 7-bromo-8
-Chloro-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine, 7-fluoro-8-chloro-6-nitro-2,5-dihydro-
2,5-dioxo-4-hydroxy-1H-benzazepine, 8-fluoro-7-chloro-6-nitro-2,5
-Dihydro-2,5-dioxo-4-hydroxy-1H
-Benzazepine, 7-fluoro-8-bromo-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine and 8-fluoro-7-
A compound selected from the group consisting of bromo-6-nitro-2,5-dihydro-2,5-dioxo-4-hydroxy-1H-benzazepine. 61. A pharmaceutical composition comprising a compound according to any one of claims 55-60 and a pharmaceutically acceptable carrier.