Glutamate is thought to be the major excitatory neurotransmitter in the brain. There are three major subtypes of glummate receptors in the CNS. These are commonly referred to as kainate, AMPA and N-methyl-D-aspartate (NMDA) receptors (Watkins and Olverman, Trends in Neurosci. 7:265-272 (1987)). NMDA receptors are found in the membranes of virtually every neuron in the brain. NMDA receptors are ligand-gated cation channels that allow Na.sup.+, K.sup.+ and Ca.sup.++ to permeate when they are activated by glummate or aspartate (non-selective, endogenous agonists) or by NMDA (a selective, synthetic agonist) (Wong and Kemp, Ann. Rev. Pharmacol. Toxicol. 31:401-425 (1991)).
Glummate alone cannot activate the NMDA receptor. In order to become activated by glummate, the NMDA receptor channel must first bind glycine at a specific, high affinity glycine binding site which is separate from the glutamate/NMDA binding site on the receptor protein (Johnson and Ascher, Nature 325:329-331 (1987)). Glycine is therefore an obligatory co-agonist at the NMDA receptor/channel complex (Kemp, J. A., et al., i Proc. Natl. Acad. Sci. USA 85:6547-6550 (1988)).
Besides the binding sites for glutamate/NMDA and glycine, the NMDA receptor carries a number of other functionally important binding sites. These include binding sites for M.sup.++, Zn.sup.++, polyamines, arachidonic acid and phencyclidine (PCP) (Reynolds and Miller, Adv. in Pharmacol. 21:101-126 (1990); Miller, B., et al., Nature 355:722-725 (1992)). The PCP binding site--now commonly referred to as the PCP receptor--is located inside the pore of the ionophore of the NMDA receptor/channel complex (Wong, E. H. F., et al., Proc. Natl. Acad. Sci. USA 83:7104-7108 (1986); Huettner and Bean, i Proc. Natl. Acad. Sci. USA 85:1307-1311 (1988); MacDonald, J. F., et al., Neurophysiol. 58:251-266 (1987)). In order for PCP to gain access to the PCP receptor, the channel must first be opened by glummate and glycine. In the absence of glummate and glycine, PCP cannot bind to the PCP receptor although some studies have suggested that a small amount of PCP binding can occur even in the absence of glummate and glycine (Sircar and Zukin, Brain Res. 556:280-284 (1991)). Once PCP binds to the PCP receptor, it blocks ion flux through the open channel. Therefore, PCP is an open channel blocker and a non-competitive glummate antagonist at the NMDA receptor/channel complex.
One of the most potent and selective drugs that bind to the, PCP receptor is the anticonvulsant drug MK-801. This drug has a K.sub.d of approximately 3 nM at the PCP receptor (Wong, E. H. F., et al., Proc. Natl. Acad. Sci. USA 83:7104-7108 (1986)).
Both PCP and MK-801 as well as other PCP receptor ligands [e.g. dextromethorphan, ketamine and N,N,N'-trisubstituted guanidines] have neuroprotective efficacy both in vitro and in vivo (Gill, R., et al., J. Neurosci. 7:3343-3349 (1987); Keana, J. F. W., et al., Proc. Natl. Acad. Sci. USA 86:5631-5635 (1989); Steinberg, G. K., et al., Neuroscience Lett. 89:193-197 (1988); Church, J., et al., In: Sigma and Phencyclidine-Like Compounds as Molecular Probes in Biology, Domino and Kamenka, eds., Ann Arbor: NPP Books (1988), pp. 747-756). The well-characterized neuroprotective efficacy of these drugs is largely due to their capacity to block excessive Ca.sup.++ influx into neurons through NMDA receptor channels which become over activated by excessive glutamate release in conditions of brain ischemia (e.g. in stroke, cardiac arrest ischemia etc.) (Collins, R. C., Metabol. Br. Dis. 1:231-240 (1986); Collins, R. C., et al., i Annals Int. Med. 110:992-1000 (1989)).
However, the therapeutic potential of these PCP receptor drugs as ischemia rescue agents in stroke has been severely hampered by the fact that these drugs have strong PCP-like behavioral side effects (psychotomimetic behavioral effects) which appear to be due to the interaction of these drugs with the PCP receptor (Tricklebank, M. D., et al., Eur. J. Pharmacol. 167:127-135 (1989); Koek, W., et al., J. Pharmacol. Exp. Ther. 245:969 (1989); Willets and Balster, Neuropharmacology 27:1249 (1988)). These PCP-like behavioral side effects appear to have caused the withdrawal of MK-801 from clinical development as an ischemia rescue agent. Furthermore, these PCP receptor ligands appear to have considerable abuse potential as demonstrated by the abuse liability of PCP itself.
The PCP-like behavioral effects of the PCP receptor ligands can be demonstrated in animal models: PCP and related PCP receptor ligands cause a behavioral excitation (hyperlocomotion) in rodents Tricklebank, M. D., et al., Eur. J. Pharmacol. 167:127-135 (1989)) and a characteristic katalepsy in pigeons (Koek, W., et al., J. Pharmacol. Exp. Ther. 245:969 (1989); Willets and Balster, Neuropharmacology 27:1249 (1988)); in drug discrimination paradigms, there is a strong correlation between the PCP receptor affinity of these drugs and their potency to induce a PCP-appropriate response behavior (Zukin, S. R., et al., Brain Res. 294:174 (1984); Brady, K. T., et al., Science 215:178 (1982); Tricklebank, M. D., et al., Eur. J. Pharmacol. 141:497 (1987)).
Drugs acting as competitive antagonists at the glutamate binding site of the NMDA receptor such as CGS 19755 and LY274614 also have neuroprotective efficacy because these drugs--like the PCP receptor ligands--can prevent excessive Ca.sup.++ flux through NMDA receptor/channels in ischemia (Boast, C. A., et al., Brain Res. 442:345-348 (1988); Schoepp, D. D., et al., J. Neural. Trans. 85:131-143 (1991)). However, competitive NMDA receptor antagonists also have PCP-like behavioral side-effects in animal models (behavioral excitation, activity in PCP drug discrimination tests) although not as potently as MK-801 and PCP (Tricklebank, M. D., et al., Eur. J. Pharmacol. 167:127-135 (1989)).
An alternate way of inhibiting NMDA receptor channel activation is by using antagonists at the glycine binding site of the NMDA receptor. Since glycine must bind to the glycine site in order for glummate to effect channel opening (Johnson and Ascher, Nature 325:329-331 (1987); Kemp, J. A., et at., Proc. Natl. Acad. Sci. USA 85:6547-6550 (1988)), a glycine antagonist can completely prevent ion flux through the NMDA receptor channel--even in the presence of a large amount of glutamate.
Recent in vivo microdialysis studies have demonstrated that in the rat focal ischemia model, there is a large increase in glummate release in the ischemic brain region with no significant increase in glycine release (Globus, M. Y. T., et al., J. Neurochem. 57:470-478 (1991)). Thus, theoretically, glycine antagonists should be very powerful neuroprotective agents, because they can prevent the opening of NMDA channels by glummate non-competitively and therefore--unlike competitive NMDA antagonists--do not have to overcome the large concentrations of endogenous glummate that are released in the ischemic brain region.
Furthermore, because glycine antagonists act at neither the glutamate/-NMDA nor the PCP binding sites to prevent NMDA channel opening, these drugs might not cause the PCP-like behavioral side effect seen with both PCP receptor ligands and competitive NMDA receptor antagonists (Tricklebank, M. D., et al., i Eur. J. Pharmacol. 167:127-135 (1989); Koek, W., et al., i J. Pharmacol. Exp. Ther. 245:969 (1989); Willets and Balster, Neuropharmacology 27:1249 (1988); Tricklebank, M. D., et at., Eur. J. Pharmacol. 167:127-135 (1989); Zukin, S. R., et al., Brain Res. 294:174 (1984); Brady, K. T., et at., Science 215:178 (1982); Tricklebank, M. D., et al., Eur. J. Pharmacol. 141:497 (1987)). That glycine antagonists may indeed be devoid of PCP-like behavioral side effects has been suggested by recent studies in which available glycine antagonists were injected directly into the brains of rodents without resulting in PCP-like behaviors (Tricklebank, M. D., et al., Eur. J. Pharmacol. 167:127-135 (1989)).
However, there have been two major problems which have prevented the development of glycine antagonists as clinically useful neuroprotective agents:
A. Most available glycine antagonists with relatively high receptor binding affinity in vitro such as 7-Cl-kynurenic acid (Kemp, J. A., et al., i Proc. Natl. Acad. Sci. USA 85:6547-6550 (1988)), 5,7-dichlorokynurenic acid (DCK) (McNamara, D., et al., Neuroscience Lett. 120:17-20 (1990)) and indole-2-carboxylic acid (Gray, N. M., et al., J. Med. Chem. 34:1283-1292 (1991)) cannot penetrate the blood/brain barrier and therefore have no utility as therapeutic agents; PA1 B. The only widely available glycine antagonist that sufficiently penetrates the blood/brain barrier--the drug HA-966 (Fletcher and Lodge, Eur. J. Pharmacol. 151:161-162 (1988))--is a partial agonist with micromolar affinity for the glycine binding site. A neuroprotective efficacy for HA-966 in vivo has not been demonstrated nor has it been demonstrated for the other available glycine antagonists because they lack bioavailability in vivo. PA1 lack the PCP-like behavioral side effects common to the PCP-like NMDA channel blockers such as MK-801 or to the competitive NMDA receptor antagonists such as CGS 19755; PA1 show potent anti-ischemic efficacy because of the non-competitive nature of their glutamate antagonism at the NMDA receptor; PA1 have utility as novel anticonvulsants with fewer side-effects than the PCP-like NMDA channel blockers or the competitive NMDA antagonists; PA1 help in defining the functional significance of the glycine binding site of the NMDA receptor in vivo. PA1 R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol; PA1 R.sub.6 is hydrogen, aryl, a heterocyclic group, a heteroaryl group, alkyl, amino, --CH.sub.2 CONHAr, --NHCONHAr, --NHCOCH.sub.2 Ar, --COCH.sub.2 Ar, hydroxy, alkoxy, aryloxy, aralkyloxy, cycloalkylalkoxy or acyloxy, wherein Ar is an aryl group or a heteroaryl group; and PA1 R.sub.7 is hydrogen, acyl or alkyl; PA1 R.sup.5 is selected from hydrogen and alkyl; PA1 R.sup.6 and R.sup.7 are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and CH.sub.2 Y wherein Y is selected from (CHOH).sub.n CH.sub.2 OH and (CH.sub.2).sub.m R.sup.c wherein m is 0 to 5, n is 1 to 5 and R.sup.c is selected from hydroxy, alkoxy, alkoxycarbonyl, carboxy, cycloalkyl, and NR.sup.d R.sup.e in which R.sup.d and R.sup.e are independently selected from hydrogen and alkyl or R.sup.d and R.sup.e, together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered heterocyclic ring which optionally contains one additional heteroatom selected from nitrogen, oxygen and sulfur; or PA1 R.sup.6 or R.sup.7, together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered heterocyclic ring which is bonded to said compound through said nitrogen atom, said heterocyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen and sulfur; PA1 R.sup.8 is selected from hydrogen, halo, alkyl which may optionally bear a substituent selected from amino, acylamino, carboxy and carboxamido, arylalkyl and heteroarylalkyl; and wherein each aryl or heteroaryl moiety may be optionally substituted; and pharmaceutically acceptable salt thereof, are useful in treating neurological disorders. PA1 X is carbon or nitrogen; PA1 Y is carbon or nitrogen; and PA1 Z is carbon, nitrogen, oxygen or sulfur; PA1 the bond between X and Y is single; PA1 R.sub.1 -R.sub.6 are hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, alkylthiol, trialkylsilyloxy, or phenyldialkylsilyloxy; or R.sub.1 and R.sub.2 or R.sub.5 and R.sub.6 are an unshared electron pair where W and Z, respectively, are oxygen or sulfur; or one of R.sub.1 and R.sub.2, or R.sub.3, or R.sub.4, or one of R.sub.5 and R.sub.6 is an unshared electron pair when W, X, Y or Z respectively is nitrogen; or where R.sub.1 and R.sub.6 together are a C.sub.1-4 alkylene bridge, a substituted C.sub.1-4 alkylene bridge, an oxygen bridge, or an amine bridge, wherein the substituent is a halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, acyl, nitro, amino, cyano, acylamido, alkoxy, carboxy, carbonylamido or alkylthiol group; and R.sub.7 is alkyl, alkanoyl, trialkylsilyl, phenyldialkylsilyl or tetrahydropyranyl; PA1 by the Diels-Alder reaction of an compound having the Formula (II): ##STR14## where R.sub.1 -R.sub.6 are defined above and, in addition, R.sub.1 and R.sub.6 may be an oxygen bridge, a sulfur bridge, an amino bridge (N--R.sub.8, where R.sub.8 is alkyl, or acyl), a methamino bridge or a substituted methamino bridge where the substituent is a halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, nitro, amino, cyano, acylamido, alkoxy, carboxy, carbonylamido or alkylthio group; and where the compound having Formula II may exist as a mixture of cis and trans isomers; PA1 with a dienophile having the Formula (III): ##STR15## wherein at least one of A and B is hydrogen and the other of A and B is hydrogen, alkoxy, chloro, bromo, iodo, tosyl or mesityl; and PA1 R.sub.7 is alkyl, alkanoyl, trialkylsilyl, phenyldialkylsilyl or tetrahydropyranyl; to give a compound having the Formula (IV): ##STR16## PA1 (a) the Diels-Alder reaction of the compound having Formula VII with the quinone having Formula III to give the compound having Formula VIII PA1 (b) enolization to the corresponding hydroquinone; PA1 (c) halogenation; hydroboration/oxidation; nitration; nitration, reduction of the nitro group to an amine followed by acylation of the amine; epoxidation; or epoxidation, ring opening with an amino compound, and acylation; respectively, to give a compound having the formula: ##STR26## (d) oxidation to give the corresponding quinone; and (e) reaction with azide in acidic solution to give said azepine. PA1 (a) the Diels-Alder reaction of the compound having Formula VII with a quinone having the Formula: ##STR28## where A', B' and R.sub.7 are defined above, to give a compound of the Formula: ##STR29## (b) halogenation; hydroboration/oxidation; nitration; nitration, reduction of the nitro group to an amine followed by acylation of the amine; epoxidation; or epoxidation, ring opening with an amino compound, and acylation; respectively, to give a compound having formula: ##STR30## and (c) reaction with azide in acidic solution to give said azepine. PA1 W is carbon, nitrogen, oxygen or sulfur; PA1 X is carbon or nitrogen; PA1 Y is carbon or nitrogen; and PA1 Z is carbon, nitrogen, oxygen or sulfur; PA1 the bond between X and Y is single; PA1 R.sub.1 -R.sub.6 are hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, alkylthiol, trialkylsilyloxy, phenyldialkylsilyloxy; or R.sub.1 and R.sub.2 or R.sub.5 and R.sub.6 are an unshared electron pair where W and Z, respectively, are oxygen or sulfur; or one of R.sub.1 and R.sub.2, or R.sub.3, or R.sub.4, or one of R.sub.5 and R.sub.6 is an unshared electron pair when W, X, Y or Z respectively is nitrogen; or where R.sub.1 and R.sub.6 together are a C.sub.1-4 alkylene bridge, a substituted C.sub.1-4 alkylene bridge, an oxygen bridge or an amino bridge; and R.sub.7 is alkyl, alkanoyl, trialkylsilyl, phenyldialkylsilyl or tetrahydropyranyl; PA1 by the Diels-Alder reaction of a compound having the Formula H: ##STR81## where R.sub.1 -R.sub.6 are described above and wherein the diene may exist as a mixture of cis and trans isomers, with a quinone having the Formula III: ##STR82## where A, B and R.sub.7 are described above (R.sub.7 .noteq.H); to give a compound having the Formula IV: ##STR83## PA1 by the Diels-Alder reaction of a diene having Formula VII: ##STR87## wherein R.sub.1, R.sub.3, R.sub.4 and R.sub.6 are defined above, and wherein R.sub.1 and R.sub.6 may additionally be an oxygen bridge, a sulfur bridge, an amino bridge (N--R.sup.9, where R.sup.9 is alkyl, aryl, acyl or carbalkoxy), a methanimine bridge or a substituted methanimine bridge, wherein such substituent is a halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, nitro, amino, cyano, acylamido, alkoxy, carboxy, carbonylamido or alkylthiol group; PA1 and wherein the diene having Formula VII may exist as a mixture of cis and trans isomers; PA1 with the quinone having Formula III (A and B=H in this example, but one of A and B may be other than hydrogen whereby the quinone is obtained directly), to give a compound having Formula VIII: ##STR88## PA1 (a) the Diels-Alder reaction of the compound having Formula VII with the quinone having Formula III to give the compound having Formula VIII PA1 (b) enolization to the corresponding hydroquinone; PA1 (c) halogenation; hydroboration/oxidation; nitration; nitration, reduction of the nitro group to an amine followed by acylation of the amine; epoxidation; or epoxidation, ring opening with an amino compound, and acylation; respectively, to give a compound having the formula: ##STR95## (d) oxidation to give the corresponding quinone; and (e) reaction with azide in acidic solution to give said azepine. PA1 (a) the Diels-Alder reaction of the compound having Formula VII with a quinone having the Formula: ##STR97## where A', B' and R.sub.7 are defined above, to give a compound of the Formula: ##STR98## (b) halogenation; hydroboration/oxidation; nitration; nitration, reduction of the nitro group to an amine followed by acylation of the amine; epoxidation; or epoxidation, ring opening with an amino compound, and acylation; respectively, to give a compound having formula: ##STR99## and (c) reaction with azide in acidic solution to give said azepine. PA1 by the Diels Alder reaction of the compound having Formula XIV with the quinone having Formula III (A and B are hydrogen in this example) to give the intermediates having Formulas XV and XVI. Ring opening of the cyclic ether and elimination of water gives a compound having Formula XXII: ##STR112## and its isomer having Formula XXIII: ##STR113## PA1 with the quinone having Formula III to give the intermediate having Formula XXVII: ##STR117## and its isomer having Formula XXVIII: ##STR118## PA1 by the Diels-Alder reaction of the diene having Formula XXXIII: ##STR123## with the quinone having Formula III (A and B are hydrogen in this example, but one of A and B may be other than hydrogen) to give a compound having Formula XXXIV: ##STR124## or its isomer having Formula XXXV: ##STR125## PA1 (1) Placing a substituent (methyl) at position R.sub.6 (i.e., position 9) of compounds of formula VI (see, compounds 43-45, Table IV) results in loss of activity. This is probably due to steric interference with the important N-H group in position 1. Therefore, preferred compounds of the invention should not have any substituent other than hydrogen in this position. PA1 (2) Placing a lone substituent at position R.sub.3 (i.e., position 7) of compounds of formula VI (see, compounds 11-15, Table II) results in greatly reduced to no activity. Therefore, preferred compounds should not be monosubstituted at R.sub.3. PA1 (3) Placing a substituent at R.sub.4 (i.e., position 8) of compounds of formula VI (see, compounds 3, 5, 6, 7 (Table I) and 16) yields enhanced activity. Therefore, preferred compounds are mono-substituted at position R.sub.4. PA1 (4) Placing a substituent at R.sub.3 and R.sub.4 (i.e., positions 7 and 8) of compounds of formula VI (see, compound 46, Table IV) yields compounds of similar activity as the unsubstituted benzazepine. Therefore, these are not preferred compounds. On the other hand, placing substituents at R.sub.1, R.sub.3 and R.sub.4 of compounds of Formula IX (see, dichloro compound described above) results in enhanced activity. Therefore, for compounds of Formula IX, substituents at R.sub.1, R.sub.3 and R.sub.4 are preferred compounds. PA1 (5) Preferred compounds have a hydrogen at R.sub.7 (i.e., OH at position 3) or a pharmaceutically acceptable salt thereof. Also, substituents that may be readily cleaved to OH by intracellular enzymes, e.g. alkyl and alkanoyl groups such as acetate, are preferred.
One recent success in identifying orally active glycine receptor antagonists was reported by Kulagowski et at., J. Med. Chem. 37:1402-1405 (1994), who disclose that 3-substituted 4-hydroxyquinoline-2(1H)-ones are selective glycine antagonists possessing potent in vivo activity.
A need continues to exist for potent and selective glycine/NMDA antagonists which can penetrate the blood/brain barrier and which:
International Application No. PCT/US93/09288 discloses that compounds having the formula: ##STR1## or a tautomer thereof; ps wherein: R.sub.1 is hydrogen, halo, haloalkyl, alkyl, aryl, a heterocyclic group, a heteroaryl group, nitro, amino, hydroxy, alkoxy or azido;
are useful for treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia and surgery, as well as treating neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's syndrome, treating or preventing the adverse consequences of the overstimulation of the excitatory amino acids, as well as treating anxiety, convulsions, chronic pain and inducing anesthesia.
International Application Publication No. WO93/25534 discloses that compounds having the Formula: ##STR2## wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently selected from hydrogen, perfluoroalkyl, halo, nitro and cyano;
Swartz et al. report that 3-hydroxy-1H-1-benzazepine-2,5-dione (1, Table I), its 7-methyl (2) and 8-methyl (3) derivatives, act as antagonists at the strychnine insensitive glycine site associated with the NMDA receptor complex (Swartz et al., Molecular Pharmacol. 41:1130-1141 (1992)). In addition, U.S. Pat. No. 5,254,683 describes the synthesis and biological activities of a series of halo-substituted analogs of 1, i.e. 4-10.
TABLE I ______________________________________ Published Aromatic Ring Substituted Derivatives of 3-hydroxy-1H-1-benzazepine-2,5-dione ##STR3## Compound # R.sub.1 R.sub.2 R.sub.3 IC.sub.50 (.mu.M) ______________________________________ 1 H H H 7.8.sup.a 2 H CH.sub.3 H See Footnote.sup.4 3 H H CH.sub.3 3.4.sup.a 4 H Cl H No Data.sup.e 5 H H F 1.7.sup.a 6 H H Cl 2.5.sup.a /0.030.sup.b /0.11.sup.c 7 H H Br 1.3.sup.a /0.097.sup.b /1.0.sup.c 8 F H F No Data.sup.e 9 Cl H Cl No Data.sup.e 10 Br H Br No Data.sup.e 46 H CH.sub.3 CH.sub.3 7.3.sup.a,f ______________________________________ .sup.a Experiments described herein utilizing rat brain homogenates and a [.sup.3 H]-MK801 binding assay. .sup.b U.S. Pat. No. 5,254,683, utilizing rat brain homogenates and a [.sup.3 H]-glycine binding assay. .sup.c U.S. Pat. No. 5,254,683, utilizing a guinea pig ileum contraction method. .sup.d Swartz et al., Mol. Pharmacol. 41:1130-1141 (1992) lists a K.sub.B of 9.5 .mu.M versus a value of 3.0 .mu.M for compound 1 and 0.47 .mu.M fo compound 3. .sup.e Compound described in U.S. Pat. No. 5,254,683. .sup.f Compound described in Birchell et al., Can. J. Chem. 52:610-615 (1974).
Recently, efforts have been initiated to confirm the above mentioned findings and, more importantly, to improve the desired pharmacological properties of this class of compounds. To this end, compound 1 and a series of analogs were prepared and tested for biological activity (compounds 5-7, compounds 11-15, Table II and compound 16 (8-trifluoromethyl). The IC.sub.50 for 16 was determined to be 3.4 .mu.M utilizing rat brain homogenates and a [.sup.3 H]-MK-801 binding assay.) Compounds 11 and 15, which possess a substituent at position 7, were readily prepared via direct electrophilic nitration or bromination of the methyl ether of 1 (formed in situ by the ring expansion of 2-methoxynaphthalene-l,4-dione) followed by demethylation. Compounds 12 through 14 were the result of performing standard chemistry on the nitro group of the methyl ether of compound 11 (reduction with subsequent derivatization of the resulting amine) followed by demethylation. Unfortunately, all of these 7-substituted compounds, though readily prepared, proved to be ineffective glycine receptor antagonists.
TABLE II ______________________________________ 7-Substituted Derivatives of 3-hydroxy-1H-1-benzazepine-2,5- dione Derived from Electrophilic Substitution Reactions ##STR4## Compound # R.sub.2 R.sub.3 IC.sub.50 (.mu.M) ______________________________________ 11 NO.sub.2 H 300 12 AcNH H 92.5 13 TFAcNH H Inactive 14 N.sub.3 H Inactive 15 Br H Inactive 16 H CF.sub.3 3.4 ______________________________________ ##STR5## ##STR6## Since the direct electrophilic substitution of these benzazepines resulted in relatively inactive 7-substituted derivatives, it was desirable to prepare benzazepines with substitution at the other three available aromatic positions or at a combination of some or all of the available aromatic positions. To accomplish this required the availability of appropriately substituted 2-methoxynaphthalene-1,4-diones. Subjecting such quinones to ring expansion conditions followed by demethylation generally yield the desired benzazepines (Birchall et al., Can. J. Chem 52:610-615 (1974)). ##STR7## ##STR8## Substituted 2-methoxynaphthalene-1,4-diones are generally prepared by the methylation of the corresponding 2-hydroxy compounds (Fieset, L. J., J. Am. Chem. Soc. 48:2922-2937 (1926)). These enols may be obtained, for example, by the oxidation of appropriately substituted 1- or 2-tetralones, (Baillie et al., J. Chem. Soc. (C):2184-2186 (1966)) by the hydrolysis of 2-anilinonaphthalene-1,4-diones (Lyons et al., J. Chem. Soc. 2910-2915 (1953)) or by the hydrolysis and oxidation of 1,2,4-triacetoxynaphthalenes (Thiele et al., Ann. Chem. 311:341-352 (1900)). Another general method to 2-methoxynaphthalene-1,4-diones involves a 6 step synthesis starting from 3,4-diisopropoxy-3-cyclobutene-1 ,2-dione incorporating an appropriately substituted aryl lithium compound (U.S. Pat. No. 5,254,683). These various methods are outlined in Scheme
All of these methods have inherent disadvantages. The cyclobutenedione method involves six steps (four from a common intermediate) and involves the use of various highly reactive lithium reagents. The anilinonaphthoquinone and triacetoxynaphthalene methods require substituted naphthalene-1,4-diones as precursors. These, like substituted 2-methoxynaphthalene-1,4-diones, are not readily available. In addition, the oxidation reaction of 7-halo or 7-perfluoroalkyl-1-tetralones processed in only moderate yield (25-40%). Oxidations of 1-tetralones possessing nitrogen substituents, such as nitro, amino, acetamido or azido, failed to yield any desired product. Attempted oxidations of 5-halo-l-tetralones failed in our hands. Also, the preparation of substituted tetralones is, in general, laborious. Direct electrophilic substitution of 1-tetralone gives an isomeric mixture, which must be separated chromatographically. Other methods of synthesizing 1-tetralones generally involve the cyclization of substituted 4-phenylbutyric acids. Such butyric acids may be prepared by the succinylation of substituted benzenes followed by the reduction of the resulting .gamma.-ketopropionic acid (Blair, A. H., Organic Syntheses, John Wiley & Sons, Inc., New York, Collect. Vol. 2, pp 81 and 499 (1943)) or via multistep syntheses such as those starting from substituted benzaldehydes (Beugelmans et al., J. Org. Chem. 50:4933-4938 (1985) or aryltributylstannanes (Owton et al., Synth. Commun. 21:981-987 (1991)). Some of these cumbersome methods have been used by us for the preparation of a variety 8-substituted 3-hydroxy-1H-1-benzazepine-2,5-diones (5, 6, 7 and 16, see Scheme II).
Finally, the cyclobutenedione method involves the use of highly reactive lithium reagents which cannot be used to prepare analogs of 3-hydroxy-1H-1-benzazepine-2,5-diones having one or more nitrogens in the benzene ring. This method requires the reaction of a substituted ortho-bromopyridine with n-butyllithium. The reaction between halo-pyridines and n-butyllithium is known to proceed by either the addition of n-butane to the 4-position or metalation at the 3-position, but not metalation at the 2-position (Gubble and Saulnier, Tet. Lett. 21:4137 (1980); Foulgner and Wakefield, J. Organ. Met. Chem. 69:161 (1974)). These metalation reactions are not specific and usually give a variety of products. ##STR9##