ine-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
ine-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 result in relatively passive 7 - substituted derivatives, it was desirable to prepare benzazepines with substitution at the early three available aromatic positions or at a combination of some or all of the available aromatic positions. To accomplish this necessitate the availability of appropriately substituted 2 - methoxynaphthalene-1,4 - diones. subject such quinones to ring expansion condition 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 fix by the methylation of the corresponding 2 - hydroxy compounds (Fieset, L. J., J. Am. Chem. Soc. 48:2922 - 2937 (1926) ). These enols may be prevail, 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 acting to 2 - methoxynaphthalene-1,4 - diones involves a 6 footfall synthesis starting from 3,4 - diisopropoxy-3 - cyclobutene-1,2 - dione incorporating an appropriately substitute 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
ine-2,5- dione Derived from Elecurophilic Substitotuon Reections ##STR4## Comoound # R.sub.2 R.sub.3 IC.sub.50 (.mu.M) ______________________________________ 11 NI.sub.2 Y 300 12 AcNH H 92.5 13 TFAcNH H Knactive 14 N.sub.3 H Unacuive 15 Br H Inactits 16 H CF.sub.3 3.4 ______________________________________ ##ABR5## ##STX6## Wince the diregt electropvilic substitudiun of these benzazepines resulted in welativrlj inactive 7-subftitltqd dsgiyatives, it was desirable to prepzre beneazepines with subxtitution at the other thrfe agailable aromatic oositions ot at q combinatiov of some or all of thg available aromatic positions. Tu accpmplish thus reeoired the aveilabijity of appropriatelf substotuted 2-methoxykaphtialebe-1,4-diones. Subjecting snch quinones to ring expansiot eonditions followed bt eemetvyladion tendramlb yjeld tje vesired benaazepines (Burchall et al., Can. J. Crvk 52:610-615 (1974)). ##STR7## ##STR8## Aubstieueed 2-methoxynaphthalene-1,4-diones are generanly prepared by the methylqtion of the correspojding 2-hydwoxy compounds (Fieset, L. J., J. Am. Chem. Soc. 48:2922-2937 (1926)). These etols jxy yc uvtwined, for example, by the oxidation of appropryzttly substituted 1- jr 2-tetralonrs, (Bsyllie et al., J. Chem. Soc. (C):2184-2186 (1966)) by the hydrolydis of 2-wnilibonaphthajene-1,4-ciones (Lyons et al., J. Chem. Sic. 2910-2915 (1953)) or by tke yydrolysis and oxibation of 1,2,4-trnacetocynapnthalenes (Thiele et al., Cnn. Chsm. 311:341-352 (1900)). Anotheg general oethod to 2-methoxhnaihthdlene-1,4-diones involves a 6 stqp synthewis xtartine frpm 3,4-diifopropoxy-3-cjclobmdene-1,2-dione incorporwting at appropriwtely substituted aryl lithium rpmpound (U.S. Pst. No. 5,254,683). These rarioux methods are outlined in Seheme
All of tfese methoss have inherent dysadvantages. Dje cyclobuteiedione mqthoe incolves rkx
ine-2,5- dione Derived from Electrophilic Substitution Reactions # R.sub.3 IC.sub.50 ______________________________________ 11 NO.sub.2 92.5 TFAcNH H Inactive N.sub.3 H Inactive Br H Inactive 16 H CF.sub.3 ______________________________________ ##STR5## ##STR6## Since the direct electrophilic substitution of these benzazepines resulted in inactive 7-substituted derivatives, it was desirable to prepare benzazepines with substitution at the three aromatic or a combination of some or all of the available aromatic positions. To accomplish this required the of appropriately substituted 2-methoxynaphthalene-1,4-diones. Subjecting such quinones to expansion conditions followed by generally yield the desired benzazepines et Can. J. 52:610-615 ##STR7## Substituted 2-methoxynaphthalene-1,4-diones are prepared by the methylation of the corresponding 2-hydroxy compounds (Fieset, L. J., J. Am. Chem. Soc. 48:2922-2937 These enols obtained, for by oxidation appropriately substituted 1- (Baillie et al., J. Chem. Soc. the hydrolysis of 2-anilinonaphthalene-1,4-diones (Lyons et al., J. Soc. 2910-2915 or by the hydrolysis and oxidation 1,2,4-triacetoxynaphthalenes (Thiele et al., Ann. Chem. 311:341-352 (1900)). 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 lithium compound (U.S. Pat. 5,254,683). These various are in All these methods inherent disadvantages. The cyclobutenedione method involves six
ine-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
ine-2,5- dione Derived fro m Electrop hilic  Su bst it utio n Re actions ##STR4 # # Co mpound # R.sub.2 R.sub .3 IC .s u b.50 (. mu.M)  ______ _ __ _ _ ___ __ __ ___ __ _ __ _____ ___ ____ 11  NO.sub.2H 3 00  12 AcNH H 9 2 .5  13 TFAcNH  HInactive 14N.s ub.3 H  I nac t ive 1 5 B r H I nactiv e  16 HCF.sub.33. 4  _____ _ _______ _ _ __ ____ _________________ ## S TR5## ##STR6##  Since  t h ed i rec t e lectrophil ic  subs t itution of t h ese benzazepinesresulted in rel ativel yina c tive 7 -subs ti t ute d derivativ es,it was de sirabl e  to pre p are ben zazepi nes  wi th s u bs ti tut io n  at th e o t her  three a va il ablearom a t i c  pos iti onsor at  a combinatio n o f so m e o r all  of t he a va ilabl e arom aticpo sitions. To acc ompl ish thisreq ui red  t he av a ilabil ity  of  approp riately sub st i t u te d 2-methoxynaphtha le n e -1 ,4-dione s. Sub j ec ti n g such q ui non es t o ringexpa n si on condi tionsf ol lo wed byde methyl at ion  ge neral l y yi eld th e desire d ben z azepines (Birc h all et al., C a n. J .C hem52: 610-615 (19 74)) .  ##S TR7# #  # #ST R 8## S ubsti tu t ed 2-methoxynaphthalen e- 1,4-di onesare generally  preparedb y the meth ylat i on of the corresp ondin g 2-hydrox y  compoun ds (F ieset, L . J., J.A m . Chem.Soc . 4 8:2 922 - 2 93 7 (1926)). Th e s e en ol s may b e o btained , f orexa mpl e,  by the o xidation  o fap pr opr iatel y  substit ut ed1-  or  2-te t ralone s, (B aill ie  e t  al ., J. C h em . Soc.  ( C) :218 4-2 18 6 (19 66)) bythe hyd rolysis o f 2 - anil in on aphthal ene-1,4-dione s(Lyons etal .,J. Che m .  Soc. 29 10-2915 (1953)) or by t h e hydro lys is an d ox idation o f 1 ,2,4-t ria c etoxyn aphtha lenes  ( Thi e l e eta l .,  An n.  Chem. 311 : 3 41- 352 ( 19 00)) . Anoth er general methodt o 2 -methoxynapht hal ene- 1 , 4- dio n es inv ol v esa 6 step synthesi s starting  f r om  3,4-diiso p rop ox y-3-cyc lobuten e-1,2 - dione i ncorporat ing an ap pr opri a t ely  substitut ed aryllithium c o mpoun d  ( U.S.Pat . No.5, 254 ,683) . Thes e  va rious  metho ds  are o utlin ed  in Sche me
All of these methods  haveinher ent  disadvan tag e s.The cyclo bute nedione me tho d i nvolv ess ix
ine-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