Benzazepine derivatives useful, for example, as cardiovascular agents, are disclosed. These compounds have the general formula ##STR1## and pharmaceutically acceptable salts thereof.

FIELD OF THE INVENTION 
The present invention relates to benzazepine derivatives and more 
particularly concerns such compounds useful as cardiovascular agents. 
SUMMARY OF THE INVENTION 
In accordance with the present invention a novel class of benzazepine 
derivatives useful, for example, as cardiovascular agents, are disclosed. 
These compounds have the general formula 
##STR2## 
including pharmaceutically acceptable salts thereof, wherein 
##STR3## 
R.sub.2 and R.sub.3 are each independently hydrogen, alkyl, cycloalkyl or 
arylalkyl, or R.sub.2 and R.sub.3 together with the nitrogen atom to which 
they are attached are pyrrolidinyl, piperidinyl, or morpholinyl; 
R.sub.4, R.sub.5 and R.sub.6 are each independently hydrogen, halogen, 
alkyl, alkoxy, aryloxy, arylalkoxy, diarylalkoxy, arylalkyl, cyano, 
hydroxy, alkanoyloxy, 
##STR4## 
fluoro substituted alkoxy, fluoro substituted alkyl, (cycloalkyl)alkoxy, 
##STR5## 
and R.sub.5 and R.sub.6 can be present in the ortho, meta or para 
positions; 
R.sub.7 is acyl, alkyl, aryl, or arylalkyl; 
R.sub.8 and R.sub.9 are each independently hydrogen, alkyl, aryl, 
cycloalkyl or arylalkyl; 
n is 2 or 3; 
m is 0, 1 or 2; 
X.sub.1 and X.sub.2 are each independently hydrogen, alkyl, aryl or 
heteroaryl, or X.sub.1 and X.sub.2 together with the nitrogen atom to 
which they are attached are pyrrolidinyl, piperidinyl or morpholinyl; 
X.sub.3 and X.sub.4 are each independently hydrogen, alkyl, alkanoyl, 
arylcarbonyl, heteroarylcarbonyl, or 
##STR6## 
X.sub.5 is hydroxy, alkoxy, aryloxy, amino, alkylamino or dialkylamino; and 
X.sub.6 is alkyl, alkoxy or aryloxy; 
with the proviso that if R.sub.4 is a 7-alkyl group, it must have a 
tertiary carbon atom bonded to the ring. 
DETAILED DESCRIPTION OF THE INVENTION 
Listed below are definitions of various terms used to describe the 
benzazepines of this invention. These definitions apply to the terms as 
they are used throughout the specification (unless they are otherwise 
limited in specific instances) either individually or as part of a larger 
group. 
The terms "alkyl" and "alkoxy" refer to both straight and branched chain 
groups. Those groups having 1 to 10 carbon atoms are preferred. 
The term "alkenyl" refers to both straight and branched chain groups. Those 
groups having 2 to 10 carbon atoms are preferred. 
The term "aryl" refers to phenyl and substituted phenyl. Exemplary 
substituted phenyl groups are phenyl groups substituted with 1, 2 or 3 
amino (--NH.sub.2), alkylamino, dialkylamino, nitro, halogen, hydroxyl, 
trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon 
atoms), alkanoyloxy, carbamoyl, or carboxyl groups. 
The term "alkanoyl" refers to groups having the formula alkyl 
##STR7## 
Those alkanoyl groups having 2 to 11 carbon atoms are preferred. 
The term "heteroaryl" refers to an aromatic heterocyclic group having at 
least one heteroatom in the ring. Preferred groups are pyridinyl, 
pyrrolyl, imidazolyl, furyl, thienyl, or thiazolyl. 
The term "cycloalkyl" refers to groups having 3, 4, 5, 6 or 7 carbon atoms. 
The term "halogen" refers to fluorine, chlorine, bromine and iodine. 
The terms "fluoro substituted alkyl" and "fluoro substituted alkoxy" refer 
to alkyl and alkoxy groups (as described above) in which one or more 
hydrogens have been replaced by fluorine atoms. Exemplary groups are 
trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, fluoromethoxy, 
difluoromethoxy, etc. 
The compounds of formula I form acid-addition salts with inorganic and 
organic acids. These acid-addition salts frequently provide useful means 
for isolating the products from reaction mixtures by forming the salt in a 
medium in which it is insoluble. The free base may then be obtained by 
neutralization, e.g., with a base such as sodium hydroxide. Any other salt 
may then be formed from the free base and the appropriate inorganic or 
organic acid. Illustrative are the hydrohalides, especially the 
hydrochloride and hydrobromide, sulfate, nitrate, phosphate, borate, 
acetate, tartrate, maleate, fumarate, citrate, succinate, benzoate, 
ascorbate, salicylate, methanesulfonate, benzenesulfonate, 
toluenesulfonate and the like. 
The carbon atoms in the 3 and 4-positions of the benzazepine nucleus of the 
compound of formula I are asymmetric carbons. The compounds of formula I, 
therefore, exist in enantiomeric and diastereomeric forms and as racemic 
mixtures thereof. All are within the scope of this invention. It is 
believed that those compounds of formula I which have the 3R, 4R 
configuration are the most potent and are therefore preferred. 
The compounds of formula I can be prepared by first reacting a 
2-nitrotoluene having the formula 
##STR8## 
with a benzylidine malonate having the formula 
##STR9## 
wherein Y is alkyl. The reaction can be run in a polar nonprotic solvent 
(e.g., dimethylformamide), in the presence of a strong base such as sodium 
hydride, and yields a product having the formula 
##STR10## 
Reduction of a compound of formula IV yields the corresponding compound 
having the formula 
##STR11## 
The reduction can be accomplished by catalytic hydrogenation (using, for 
example, palladium on charcoal as a catalyst) or using a chemical reducing 
agent (e.g., ferrous sulfate or stannous chloride). 
Treatment of an amine of formula V with an alkali metal alkoxide (e.g., 
sodium methoxide) and an alcohol (e.g., methanol) yields the corresponding 
benzazepine having the formula 
##STR12## 
Reaction of a compound of formula VI with a strong base (e.g., lithium 
diisopropylamide, potassium hexamethyldisilazide, or potassium t-amylate) 
in an etheral solvent, such as tetrahydrofuran, or a polar nonprotic 
solvent, e.g., dimethylformamide, at a low temperature in the presence of 
anhydrous oxygen gas and a reducing agent, e.g. triethyl phosphite, yields 
the corresponding compound having the formula 
##STR13## 
Alternatively, a compound of formula VII can be prepared by first cooling a 
compound of formula VI to a greatly reduced temperature (e.g., about 
-78.degree. C.) in a solvent such as tetrahydrofuran and treating it with 
a strong base (e.g., lithium diisopropylamide or potassium 
hexamethyldisilazide). Treatment of the compound with anhydrous oxygen gas 
in the presence of a reducing agent, such as triethyl phosphite, yields 
the desired compound of formula VII. 
Decarboxylation of a compound of formula VII can be accomplished by 
treating the compound with excess lithium iodide in hot pyridine which 
contains 1-2% water to obtain a mixture of isomers having the formulas 
##STR14## 
The preferred cis isomer is generally the predominant isomer formed during 
the above reaction. The isomers can be separated using art recognized 
techniques such as crystallization or chromatography. Alternatively, the 
reactions described hereinafter can be run using the diastereomeric 
mixture (mixture of compounds of formulas VIIIa and VIIIb). The isomeric 
mixture can be separated into its component isomers at any point during 
the reaction sequence. 
Treatment of a mixture of compounds VIIIa and VIIIb with 
p-toluenesulfonylchloride in the presence of a solvent such as pyridine 
provides a mixture of compounds having the formula 
##STR15## 
and the corresponding cis isomer 
##STR16## 
Thereafter, a mixture of compounds IXa and IXb in the presence of a 
solvent, e.g. dimethylsulfoxide, can be reacted with a compound of the 
formula 
EQU MSR.sub.7, X 
(wherein M is a metal, such as Li, Na or K) 
such as sodium thiomethoxide where R.sub.7 is methyl or potassium 
thioacetate thioacetate where R.sub.7 is acetyl, to yield a mixture of 
compounds having the formula 
##STR17## 
which can be separated using art recognized techniques such as 
crystallization and/or chromatography. 
Treatment of the compound of formula XIa with solvents, such as 
methylethylketone or dimethylformamide, and a base, such as potassium 
hydrogen carbonate or sodium hydride, followed by reaction with a compound 
having the formula 
EQU halogen--(CH.sub.2).sub.n --NR.sub.2 R.sub.3 XII 
provides a compound of the formula 
##STR18## 
Similar treatment of the compound of formula XIb with a compound of formula 
XII under similar conditions provides the compound of the formula 
##STR19## 
To prepare the compounds of formula I wherein R.sub.1 is N.sub.3, the trans 
isomer IXa in a solvent, e.g. dimethylformamide, can be reacted with 
sodium azide in the presence of an ammonium salt, such as 
tetra-n-butylammoniumhydrogen sulfate, to provide a diastereomeric mixture 
of the compounds having the formula 
##STR20## 
Treatment of compounds XIVa and XIVb with a base, such as potassium 
hydrogen carbonate, in a solvent, such as methylethylketone, followed by 
reaction with potassium iodide and a compound of formula XII, such as 
N,N-dimethyl-2-chloroethylamine, provides the compounds of formula I 
wherein R.sub.1 is N.sub.3 after separation of the isomers using art 
recognized techniques such as crystallization or chromatography. 
To prepare the compounds of formula I wherein R.sub.1 is --NH.sub.2, a 
diastereomeric mixture of compounds VIIIa and VIIIb can be used as the 
starting material to ultimately provide the diastereomeric azide of the 
formula 
##STR21## 
(i.e., the diastereomeric form of XIV) using the methodology outlined 
above. 
Reduction of the azide XV, for example, by treatment with 
palladium-on-carbon in trifluoroacetic acid, provides 
##STR22## 
Compound XVI can be treated with di-t-butyl dicarbonate in presence of 
organic solvents, such as methylene chloride, acetonitrile and 
tetrahydrofuran and an organic base, such as pyridine to provide a 
diastereomeric mixture of compounds having the formula 
##STR23## 
Compound XVII can be treated as Compounds XIVa and XIVb above to provide 
the compounds of formula I wherein R.sub.1 is 
##STR24## 
after separation of the diastereomers using art recognized techniques such 
as crystallization or chromatography. Compounds of formula I wherein 
R.sub.1 is 
##STR25## 
can be treated with trifluoroacetic acid in presence of anisole or 
thiophenol to provide the compounds of formula I wherein R.sub.1 is 
--NH.sub.2. 
To prepare the compounds of the present invention wherein R.sub.1 is 
--NHR.sub.7 the amine of formula XVI can be subjected to an acid anhydride 
(such as acetic anhydride in the case where R.sub.7 is acetyl) in the 
presence of organic solvents, such as methylene chloride and pyridine, to 
provide a diastereomeric mixture of compounds having the formula 
##STR26## 
Pure compound XVIIIa can be obtained from the mixture using art recognized 
separation techniques such as crystallization or chromatography. 
Compound XVIIIa can be treated as compounds XIVa and XIVb above to provide 
the compounds of formula I wherein R.sub.1 is --NHR.sub.7. 
To prepare compounds of formula I wherein R.sub.1 is 
##STR27## 
a compound of formula IXa or IXb is heated in a sealed tube at a 
temperature ranging from 100.degree.-150.degree. C. with an amine of the 
formula 
##STR28## 
to provide compounds of formula 
##STR29## 
The isomers can be separated using art recognized techniques such as 
crystallization or chromatography. The pure cis-isomer of Compound XIX can 
be treated as compounds XIVa and XIVb above to provide the compounds of 
formula I wherein R.sub.1 is 
##STR30## 
The resolved enantiomers of the compounds of this invention can be prepared 
by first hydrolyzing a compound of formula VI to obtain the corresponding 
carboxylic acid having the formula 
##STR31## 
The hydrolysis can be accomplished, for example, by treating a compound of 
formula VI with an alkali metal hydroxide in an alcohol (e.g., potassium 
hydroxide in methanol). 
A carboxylic acid of formula XX can be resolved using a chiral amine. 
Reaction of the acid and amine in an appropriate solvent yields the 
diastereomeric salts which can be separated using conventional techniques 
such as crystallization. Regeneration of the carboxylic acid from the pure 
diastereomeric salt followed by esterification yields the desired 
nonracemic form of a compound of formula VI. Alternatively, compounds of 
formula VI can be generated directly from the diastereomeric salts by 
treatment with an alkyl halide in dimethylformamide in the presence of an 
inorganic base (e.g., potassium bicarbonate). This nonracemic compound can 
be converted to the corresponding nonracemic product of formula I via the 
nonracemic form of intermediates of formulas VII and VIII using the 
procedures described above. 
Alternatively, the resolved enantiomers of the compounds of this invention 
can be prepared by the reaction of the various forms of formula I, 
prepared above, with a chiral carboxylic acid in an appropriate solvent. 
The resulting diastereomeric salts can be separated by recrystallization. 
Preferred are those compounds of formula I wherein 
R.sub.1 is --SCH.sub.3, --S--acetyl and --N.sub.3 ; 
R.sub.2 and R.sub.3 are each methyl or R.sub.2 is hydrogen and R.sub.3 is 
methyl 
R.sub.4 is trifluoromethyl (especially 7-trifluoromethyl and 
6-trifluoromethyl); 
R.sub.5 is 4-methoxy; and, 
R.sub.6 is hydrogen. 
The compounds of formula I and the pharmaceutically acceptable salts 
thereof are useful as cardiovascular agents. These compounds act as 
vasodilators and are especially useful as anti-hypertensive agents. By the 
administration of a composition containing one (or a combination) of the 
compounds of this invention the blood pressure of a hypertensive mammalian 
(e.g, human) host is reduced. Daily doses of about 0.1 to 100 mg per 
kilogram of body weight per day, preferably about 1 to about 50 mg per 
kilogram per day, are appropriate to reduce blood pressure, and can be 
administered in single or divided doses. The substance is preferably 
administered orally, but parenteral routes such as the subcutaneous, 
intramuscular, or intravenous routes can also be employed. 
As a result of the vasodilating activity of the compounds of formula I, it 
is believed that such compounds in addition to being anti-hypertensives 
may also be useful as anti-arrhythmic agents, as anti-anginal agents, as 
anti-fibrillatory agents, as anti-asthmatic agents, and in limiting 
myocardial infarction. 
The compounds of this invention can also be formulated in combination with 
a diuretic or an angiotensin converting enzyme inhibitor. Suitable 
diuretics include the thiazide diuretics such as hydrochlorothiazide and 
bendroflumethiazide and suitable angiotensin converting enzyme inhibitors 
include captopril. 
The present invention will be further described by reference to the 
following examples, however, it is not meant to be limited by the details 
described therein.

EXAMPLE 1 
(trans)-1-[2-(Dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-3 
-(methylthio)-7-(trifluoromethyl)-2H-1-benzazeoin-2-one, monohydrochloride 
A. 
[2-(5-Trifluoromethyl-2-nitrophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic 
acid, dimethylester 
To a 2 liter three-neck flask (under nitrogen) was added 67 g (0.293 mol) 
of dimethyl-p-methoxybenzylidene malonate and 450 ml of dimethylformamide. 
The stirred solution was treated with a 50% sodium hydride dispersion 
(18.7 g, 0.39 mol). This mixture was treated dropwise with a solution of 
3-methyl-4-nitrobenzoic acid (60.5 g, 0.293 mol) in 50 ml of 
dimethylformamide over a period of 1 hour while maintaining a temperature 
at about 28.degree.-32.degree. C. This mixture was stirred for 4 hours at 
room temperature, cooled, treated portionwise with 25 ml of acetic acid 
and poured onto a 2.5 l of ice water. The mixture was extracted 3 times 
with 250 ml of methylene chloride. The organic phases were combined, 
washed 3 times with 500 ml of water, dried over anhydrous magnesium 
sulfate, filtered and the solvent evaporated to give 126 g of a pale brown 
semi-solid. The latter was dissolved in 270 ml of methanol, cooled and 
filtered to give 72.8 g of a pale yellow product, m.p. 
110.degree.-112.degree. C. A sample recrystallized from methanol, melted 
at 111.degree.-113.degree. C. 
Analysis calc'd for C.sub.21 H.sub.20 NF.sub.3 O.sub.7 : 
C, 55.39; H, 4.43; N, 3.08; F, 12.52; 
Found: C, 56.08; H, 4.70; N, 2.96; F, 12.09. 
B. 
[2-(5-Trifluoromethyl-2-aminophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic 
acid, dimethylester 
A suspension of the title A compound (25 g, 0.055 mol) in 200 ml of 
methanol was treated with a cold suspension of 2.5 g of 5% 
palladium-on-carbon in 50 ml of methanol (under nitrogen) and placed on 
the Parr apparatus at 58 psi of hydrogen. After 30 minutes, the mixture 
was heated at 50.degree.-55.degree. for 1 hour, cooled to room 
temperature, removed from the Parr apparatus and allowed to stand at room 
temperature overnight. The flask was heated to dissolve the crystallized 
product and the hot solution was filtered through Celite (under nitrogen) 
and washed with hot methanol. The colorless filtrate was concentrated on a 
rotary evaporator to give 22.2 g of a nearly colorless solid. The latter 
was triturated with 100 ml of hexane and then with 50 ml of hexane. The 
solvent was decanted and the entrained solvent removed on a rotary 
evaporator to give 21.3 g of product, m.p. 124.degree.-127.degree. C. A 
sample of this material, after crystallization from methanol, melted at 
125.degree.-127.degree. C. 
Analysis calc'd for C.sub.21 H.sub.22 NF.sub.3 O.sub.5 : 
C, 59.2; H, 5.2; N, 3.2; F, 13.40; 
Found: C, 59.48; H, 5.26; N, 3.16; F, 13.43. 
7-(Trifluoromethyl)-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphen 
yl)-2H-1-benzazepin-2-one 
A stirred solution of the title B compound (20 g, 0.047 mol) in 200 ml of 
methanol was treated with 13.3 ml of 25% sodium methoxide in methanol and 
heated to reflux (color lightened progressively from reddish to light 
yellow; also some solid separated during the heating). TLC (1:1 ethyl 
acetate/hexane) after 2.5 hours showed the reaction to be essentially 
complete. After a total of 2.75 hours of heating, the mixture was cooled 
in ice water and 70 ml of 1N hydrochloric acid was added to precipitate 
the partly gummy product. The latter became granular on rubbing and 
stirring in an ice water bath for 0.5 hours. The tan solid was filtered, 
washed with water and air dried to give 10.0 g of a pale yellow foam-like 
material. The latter was suspended in 30 ml of isopropyl alcohol, allowed 
to stand for 1 hour, filtered and washed with isopropyl alcohol and hexane 
to provide 13.64 g of the title C compound, m.p. 161.degree.-163.degree. 
C. 
Analysis calc'd for C.sub.20 H.sub.18 NF.sub.3 O.sub.4 : 
C, 61.07; H, 4.61; N, 3.56; F, 14.49; 
Found: C, 61.26; H, 4.62; N, 3.41; F, 14.21. 
D. 
7-(Trifluoromethyl)-1,3,4,5-tetrahydro-3-hydroxy-3-(methoxycarbonyl)-4-(4- 
methoxyphenyl)-2H-1-benzazepin-2-one 
A solution of the title C compound (7 g, 0.0178 mol) in 330 ml of dry 
tetrahydrofuran was cooled to -78.degree. C. and a 1.125M solution of 
potassium hexamethyldisilazide (64 ml, 0.072 mol) in tetrahydrofuran was 
added dropwise over 15 minutes. After stirring for 1 hour, 12.4 ml of 
triethylphosphite (0.0723 mol) was added and oxygen was bubbled rapidly 
through the resulting solution. The reaction temperature was then raised 
to 0.degree. C. and allowed to stir for 2 hours. Oxygenation was then 
discontinued and the reaction was quenched by addition of acetic acid. The 
reaction mixture was then concentrated and the residue was dissolved in 
ethyl acetate. The organic solution was washed successively with 1N 
hydrochloric acid, saturated sodium bicarbonate and brine and then dried 
over anhydrous sodium sulfate. Concentration of the organic extract, 
followed by trituration with 200 ml of hexane afforded 7 g of pale 
cream-colored solid; m.p. 196.degree.-198.degree. C. 
Analysis calc'd for C.sub.20 H.sub.18 F.sub.3 NO.sub.5 .multidot.H.sub.2 O: 
C, 56.20; H, 4.72; N, 3.28; 
Found: C, 56.39; H, 4.37; N, 3.13. 
E. 
7-(Trifluoromethyl)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-2H-1- 
benzazepin-2-one 
A solution of the title D compound (6.8 g, 0.0166 mol) and lithium iodide 
(5.8 g, 0.0433 mol) in 250 ml of pyridine was refluxed under argon for 2 
hours. The reaction was cooled to room temperature and concentrated in 
vacuo. The residue was dissolved in ethyl acetate and extracted with 1N 
hydrochloric acid, saturated sodium bicarbonate and sodium chloride. The 
solution was dried over anhydrous magnesium sulfate, filtered and 
concentrated to obtain 5.3 g of crude solid which was triturated with 120 
ml of ether at 0.degree. C. to obtain 4.45 g of colorless material, m.p. 
204.degree.-206.degree. C. TLC (1:1 ethyl acetate-hexane) showed an 
approximate 60:40 ratio of cis and trans-products. 
Analysis calc'd for C.sub.18 H.sub.16 F.sub.3 NO.sub.3 : 
C, 61.53; H, 4.59; N, 3.99; 
Found: C, 61.37; H, 4.57; N, 3.93. 
F. 
7-(Trifluoromethyl)-1,3,4,5-tetrahydro-3-(p-toluenesulfonyloxy)-4-(4-metho 
xyphenyl)-2H-1-benzazepin-2-one 
To a solution of the title E compound (12.53 g, 36 mmole) in pyridine (60 
ml) was added 99% pure p-toluenesulfonylchloride (8.98 g, 47.1 mmole) with 
stirring. After standing at room temperature for 24 hours, the mixture was 
diluted with ethyl acetate and washed thoroughly with saturated copper 
sulfate solution, followed by water. The organic extract was dried over 
anhydrous magnesium sulfate and concentrated. The oily residue was 
triturated with ether to obtain a white precipitate that was collected by 
suction-filtration, and washed with ether:hexane 1:3. After drying in 
vacuo 16.87 g of a 1:1 -cis:trans mixture of the title F compound was 
obtained as a white solid. 
G. 
(trans)-3-Thiomethyl-7-(trifluoromethyl)-1,3,4,5-tetrahydro-4-(4-methoxyph 
enyl)-2H-1-benzazepin-2-one and 
(cis)-3-Thiomethyl-7-(trifluoromethyl)-1,3,4,5-tetrahydro-4-(4-methoxyphen 
yl)-2H-1-benzazepin-2-one 
To a solution of the title F compound in dimethylsulfoxide (50 ml) was 
added solid sodium thiomethoxide (3.15 g, 45 mmole) with stirring under an 
argon atmosphere. The mixture was heated (bath temperature 
80.degree.-90.degree. C.) for 0.5 hour, cooled, diluted with ethyl acetate 
and washed thoroughly with 1N aqueous hydrochloric acid solution, followed 
by water. The ethyl acetate extract was dried over anhydrous magnesium 
sulfate and concentrated leaving a dark, oily residue. Ether trituration 
afforded a white crystalline material, which was collected by 
suction-filtration and washed with ether:hexane 1:3 to give 6.89 g of 1:1 
-cis:trans mixture of product. Recrystallization gave 1.27 g of pure trans 
of the title G compound; m.p. 232.degree.-233.5.degree. C. 
Analysis calc'd for C.sub.19 H.sub.18 NFhd 3O.sub.2 S: 
C, 59.83; H, 4.76; N, 3.67; F, 14.94; 
S, 8.41; 
Found: C, 60.17; H, 4.80; N, 3.66; F, 14.75; 
S, 8.82. 
Purification of the mother liquor by chromatography on a silica-gel column 
with 1:1 ethyl acetate:hexane as eluent afforded 620 mg cis-adduct. 
H. 
(trans)-1-[2-(Dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)- 
3-(methylthio)-7-(trifluoromethyl)-2H-1-benzazepin-2-one, monohydrochloride 
To a homogeneous solution of the title G trans compound (1.29 g, 3.38 
mmole) in hot methylethyl- ketone (16 ml) and dimethylformamide (3 ml) 
under argon was added potassium hydrogen carbonate (1.35 g; 13.5 mmole; 4 
eq). After stirring for 15 minutes, a 2.15M toluene solution of 
N,N-dimethyl-2-chloroethylamine (3.1 ml, 6.8 mmole, 2 eq) was added, and 
heating was continued for 4 hours. The mixture was cooled, diluted with 
ethyl acetate, washed consecutively with water, 1N sodium hydrogen 
carbonate, and saturated sodium chloride, and dried over anhydrous 
magnesium sulfate. The ethyl acetate solution was then treated with 
saturated hydrochloric acid/ethyl ether and concentrated. The off-white 
solid was triturated and vacuum-dried leaving 1.34 g of the title compound 
as a white solid; m.p. 230.degree.-231.degree. C. 
Analysis calc'd for 2.sub.23 H.sub.28 N.sub.2 ClF.sub.3 O.sub.2 
S.multidot.0.07H.sub.2 O: 
C, 56.36; H, 5.78; N, 5.72; Cl, 7.23 
F, 11.62; S, 6.54; 
Found: C, 56.08; H, 5.78; N, 5.74; Cl, 7.20; 
F, 11.92; S, 6.74. 
EXAMPLE 2 
(cis)-1-[2-(Dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-3-( 
methylthio)-7-trifluoromethyl)-2H-1-benzazepin-2-one, monohydrochloride 
To a homogeneous solution of Example 1, Part G cis-compound (0.62 g, 1.51 
mmol) in methylethylketone (8 ml) and dry dimethylformamide (4 ml) was 
added potassium hydrogen carbonate (0.60 g, 6.0 mmol; 4 eq). After 
stirring for 15 minutes at 90.degree. , a 2.15M toluene solution of 
N,N-dimethyl-2-chloroethylamine (1.4 ml, 3.0 mmol; 2 eq) was added and 
heating was continued for 5.75 hours. The solution was cooled, diluted 
with ethyl acetate and washed with water. The organic extract was dried 
over anhydrous magnesium sulfate, filtered and concentrated. The free 
amine was purified by preparative plate chromatography (silica gel, 
eluting solvent 5% methanol in methylene chloride), dissolved in warm 
ether and treated with etheral hydrochloric acid solution to obtain 350 mg 
of a white solid, m.p. 160.degree.-164.degree. C. 
Analysis calc' for C.sub.23 H.sub.28 N.sub.2 ClF.sub.3 O.sub.2 
S.multidot.0.58H.sub.2 O: 
C, 55.31; H, 5.89; N, 5.61; Cl, 7.10; 
F, 11.41; S, 6.42; 
Found: C, 55.28; H, 5.74; N, 5.64; Cl, 7.01; 
F, 11.56; S, 6.41. 
EXAMPLE 3 
(cis)-3-(Acetylthio)-1-[2-(dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4-met 
hoxyphenyl)-7-(trifluoromethyl)-2H-1-benzazepin-2-one, monohydrochloride 
A. 
(cis)-3-(Acetylthio)-7-(trifluoromethyl)-1,3,4,5-tetrahydro-4-(4-methoxyph 
enyl)-2H-benzazepin-2-one 
To a solution of the epimeric mixture of the tosylate of Part F of Example 
1 (1.06 g, 2 mmole) in 10 ml dimethylsulfoxide was added with stirring 
potassium thioacetate (570 mg, 5 mmole) under an argon atmosphere. The 
reaction mixture was heated to 90.degree. C. and left at that temperature 
for 1 hour. The reaction was cooled, diluted with ethyl acetate and washed 
thoroughly with water. The ethyl acetate, extract was dried over anhydrous 
magnesium sulfate and concentrated under reduced pressure to obtain a 
yellow residue. Trituration with ether gave almost pure cis-thioacetate 
(215 mg) as a white crystalline solid. A combination of flash 
chromatography and recrystallization gave analytically pure product; m.p. 
215.degree.-215.5.degree. C. 
Analysis calc'd for C.sub.20 H.sub.18 NF.sub.3 O.sub.3 S.0.25H.sub.2 O: C, 
58.03; H, 4.51; N, 3.38; S, 7.75; F, 13.76; Found: C, 58.06; H, 4.30; N, 
3.35; S, 8.09; F, 13.94. 
B. 
cis-3-(Acetylthio)-1-[2-(dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4-meth 
oxyphenyl)-7-(trifluoromethyl)-2H-1-benzazepin-2-one, monohydrochloride 
The reaction was run as described in Example 1, Part H except that the 
compound from Part B of Example 3 (740 mg, 1.81 mmole) was substituted for 
the compound of part G of Example 1. The crude free amine was purified by 
preparative plate chromatography (silica gel, eluting solvent 10% methanol 
in methylene chloride) and then treated with etheral hydrochloric acid 
solution to obtain 500 mg of a white solid; m.p. 
147.5.degree.-150.5.degree. C. 
Analysis calc'd for C.sub.24 H.sub.27 N.sub.2 F.sub.3 O.sub.3 
S.HCl.0.69H.sub.2 O: C, 54.45; H, 5.59; N, 5.29; Cl, 6.70; S, 6.06; Found: 
C, 54.45; H, 5.46; N, 5.42; Cl, 6.94; S, 6.28. 
EXAMPLE 4 
(cis)-3-Azido-7-chloro-1-[2-(dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4-m 
ethoxyphenyl)-2H-1-benzazepin-2-one, monohydrochloride 
A. [2-(5-Chloro-2-nitrophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, 
dimethylester 
To a stirred mixture of dimethyl p-methoxybenzylidene malonate (40 g, 0.16 
mole) and 60% dispersion of sodium hydride (9.6 g, 0.24 mole) in 350 ml of 
dry dimethylformamide, was added dropwise over 2 hours a solution of 
5-chloro-2-nitrotoluene (30 g, 0.176 mole) in 30 ml of dimethylformamide. 
The reaction was stirred at room temperature for 6 hours, then quenched 
with glacial acetic acid (15.4 ml, 0.26 mole). The solvent was removed in 
vacuo and the residue was triturated with water. The yellow solids were 
filtered and triturated with methanol to yield 50.3 g of a white solid, 
melting point 128.5.degree.-130.5.degree. C. 
B. [2-(2-Amino-5-chlorophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, 
dimethylester 
To a refluxing mixture of 
[2-(5-chloro-2-nitrophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, 
dimethyl ester (40 g, 95 mmole) and hydrated ferrous sulfate (184.5 g, 
0.663 mole) in a 1:10 solution of methanol:water (1.2 L) was added 
concentrated ammonium hydroxide (142.5 ml) over a 30 minute period. The 
reaction was stirred at reflux for 20 minutes then cooled to room 
temperature. Ethyl acetate and Celite were added and the mixture was 
filtered through Celite. The filtrate was partitioned between ethyl 
acetate and water. The organic phase was dried over magnesium sulfate and 
concentrated in vacuo. The product was recrystallized from isopropyl 
alcohol to yield 28.22 g of the title compound, melting point 
114.degree.-116.degree. C. 
C. 
7-Chloro-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-1-b 
enzazepin-2-one 
To a solution of 
[2-(2-amino-5-chlorophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, 
dimethyl ester (23.2 g, 59.2 mmole) in methanol (200 ml) was added a 25% 
solution of sodium methoxide in methanol (16 ml, 69.97 mmole). The 
solution was refluxed for 3 hours under argon. The reaction was cooled to 
room temperature and treated with 200 ml of 1N hydrochloric acid. The 
white precipitate was filtered and washed with water, methanol, and dried 
in vacuo to yield 19.5 g of the title compound, melting point 
189.degree.-190.5.degree. C. 
D. 
7-Chloro-1,3,4,5-tetrahydro-3-hydroxy-3-(methoxycarbonyl)-4-(4-methoxyphen 
yl)-2H-1-benzazepin-2-one 
A solution of 
7-chloro-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-1-b 
enzazepin-2-one (15 g, 41.7 mmole) in 780 ml of tetrahydrofuran was cooled 
to -78.degree. C. and 147 ml (167 mmole in tetrahydrofuran) of potassium 
hexamethyldisilazide solution was added. After stirring for 1 hour, 28.7 
ml of triethyl phosphite (166.7 mmole) was added and anhydrous oxygen gas 
was rapidly bubbled through the resulting solution. The reaction 
temperature was then raised to 0.degree. C. and allowed to stir for an 
additional hour. Oxygenation was then discontinued and the reaction was 
quenched by the addition of 50 ml of acetic acid. The reaction mixture was 
then concentrated and the residue dissolved in ethyl acetate. The organic 
solution was washed successively with 1N hydrochloric acid, saturated 
sodium bicarbonate, and brine and then dried over anhydrous sodium 
sulfate. Concentration of the dried organic solution afforded a solid 
which, upon trituration in hexane, gave 14.8 g of the title compound. 
E. 
(trans)-7-Chloro-1,3,4,5,-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-2H-1-be 
nzazepin-2-one 
A solution of lithium iodide (1.42 g, 10.6 mmole; 4 eq) in pyridine (27 ml) 
and benzene (27 ml) were distilled under argon until pyridine started to 
distill over. Title D compound (1 g, 2.66 mmole) was added and the 
reaction mixture was refluxed for 8 hours to maximize the yield of the 
trans product. The reaction mixture was cooled to room temperature, 
diluted with ethyl acetate and washed with 1N hydrochloric acid solution. 
The aqueous layer was extracted twice with ethyl acetate. Combined organic 
extract was washed with saturated sodium bicarbonate solution, dried over 
anhydrous sodium sulfate, filtered and concentrated to obtain 890 mg of a 
tan solid. TLC indicated a trans/cis ratio of 75:25. Purification by 
chromatography on a silica-gel column and elution with 25-75% ethyl 
acetate in hexane furnished 420 mg of a sticky yellow solid which on 
trituration with ether and etyl acetate gave 180 mg of a white solid, m.p. 
161.5.degree.-162.5.degree. C. 
Analysis calc'd for C.sub.17 H.sub.16 ClNO.sub.3.0.14H.sub.2 O: C, 63.74; 
H, 5.12; N, 4.37; Cl, 11.07; Found: C, 63.80; H, 5.12; N, 4.35; Cl, 11.12. 
F. 
(trans)-7-Chloro-1,3,4,5-tetrahydro-3-(p-toluenesulfonyloxy)-4-(4-methoxyp 
henyl)-2H-1-benzazepin-2-one 
Tosyl chloride (204 mg, 1.07 mmole; 2 eq) and pyridine (2 ml) were added to 
the title E compound (160 mg, 0.503 mmole) and stirred at room temperature 
for 3 hours. The mixture was diluted with ethyl acetate, washed with 
saturated copper sulfate followed by water and dried over anhydrous 
magnesium sulfate, filtered and concentrated. The concentrated crude 
product was purified by flash chromatography giving 250 mg of the title F 
compound as a white solid product. 
G. 
(cis)-3-Azido-7-chloro-1,3,4,5,-tetrahydro-4-(4-methoxyphenyl)-2H-1-benzaz 
epin-2-one 
Sodium azide (120 mg, 1.54% mmole, 5 eq) and tetra-n-butyl ammonium 
hydrogen sulfate (54 mg) were added to a solution of the title F compound 
(150 mg, 0.31 mmole) in dimethylformamide (2 ml). The mixture was stirred 
at 80.degree. C. for 8 hours. The cooled solution was diluted with ethyl 
acetate, washed with water, dried over anhydrous magnesium sulfate and 
concentrated. The crude residue was triturated with ethyl acetate giving 
46 mg of clean title C compound. The material in the mother liquor was 
purified by flash chromatography yielding an additional 15 mg of the title 
G compound and 50 mg of recovered starting material. 
H. 
(cis)-3-Azido-7-chloro-1-[2-(dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4- 
methoxyphenyl)-2H-1-benzazepin-2-one, monohydrochloride 
To the title G compound (0.85 g, 2.48 mmole), potassium hydrogen carbonate 
(0.50 g, 4.96 mmole) and potassium iodide (0.10 g, 0.62 mmole) suspended 
in methylethylketone (20 ml), was added 1.86 ml (3.16 mmole) of 1.7N 
solution of 2-dimethylaminoethylchloride in toluene with stirring. The 
mixture was refluxed (85.degree. C.) for 12 hours. The cooled solution was 
evaporated almost to dryness, diluted with ethyl acetate and washed twice 
with water, saturated sodium chloride and dried over anhydrous magnesium 
sulfate. The concentrated residue was flash chromatographed giving an oily 
residue. This material was co-evaporated with ether which produced a 
fluffy white solid. The free amine product was dissolved into ether and 
treated with ethereal hydrogen chloride to give 0.64 g of the title 
compound as an hygroscopic white solid; m.p. 183.degree.-193.degree. C. 
(decomp). 
Analysis calc'd for C.sub.21 H.sub.24 N.sub.5 ClO.sub.2.0.8H.sub.2 O: C, 
54.30; H, 5.77; N, 14.84; Cl, 15.27; Found: C, 54.30; H, 5.47; N, 15.08; 
Cl, 15.23. 
EXAMPLE 5 
(cis)-3-Azido-1-[2-(dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4-methoxyphe 
nyl)-7-(trifluoromethyl)-2H-1-benzazepin-2-one, monohydrochloride 
A. 
(trans)-7-(Trifluoromethyl)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxypheny 
l)-2H-1-benzazepin-2-one 
The Example 1, Part E alcohol (6.6 g, 60:40 cis:trans) was purified on a 
silica gel column with 1:9 ethyl acetate:hexane as eluent to obtain 1.77 g 
pure title A trans-alcohol. 
B. 
(trans)-7-(Trifluoromethyl)-1,3,4,5-tetrahydro-3-(p-toluenesulfonyloxy)-4- 
(4-methoxyphenyl)-2H-1-benzazepin-2-one 
To the Example 5, Part A alcohol (1.77 g, 5.04 mmole) in pyridine (15 ml) 
was added p-toluene- sulfonyl chloride (1.92 g, 10.08 mmole; 2 eq). The 
reaction mixture was stirred at room temperature overnight, diluted with 
ethyl acetate, and washed with saturated cooper sulfate solution (2X), 
water and saturated salt solution. The organic extract was dried over 
anhydrous magnesium sulfate, filtered and concentrated to obtain 2.88 g of 
a pink solid. Purification by chromatography on a silica gel column and 
elution with 25-50% ethyl acetate in hexane followed by ethyl acetate and 
1% acetone in ethyl acetate afforded 2.22 g of a white solid. 
C. 
3-Azido-7-(trifluoromethyl)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-2H-1-be 
nzazepin-2-one 
Sodium azide (1.68 g, 25.86 mmole, 6 eq) was added to a solution of title A 
compound (2.22 g, 4.3 mmole) and tetra-n-butyl ammonium hydrogen-sulfate 
(0.73 g, 2.15 mmole, 0.5 eq). After heating at 80.degree. C. overnight, 
the mixture was partitioned between ethyl acetate and water. The aqueous 
layer was extracted with ethyl acetate and combined extracts were dried 
over anhydrous magnesium sulfate, filtered and concentrated to obtain 3.83 
g of a viscous yellow oil which was purified on a silica gel column to 
obtain 1.14 g of a solid. TLC indicated it to be a 1:1 mixture of cis and 
trans compound. 
D. 
cis-3-Azido-1-[2-(dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4-methoxyphen 
yl)-7-(trifluoromethyl)-2H-1-benzazepin-2-one, monohydrochloride 
Title C compound (430 mg, 1.14 mmole) in methylene chloride (10 ml) and 
water (1.5 ml) was treated with pulverized barium hydroxide octahydrate 
(0.75 g, 2.39 mmole) and benzyltrimethylammonium chloride (catalytic). 
2-dimethylamino ethyl bromide (0.60 g, 2.57 mmole) in water (2 ml) was 
added with vigorous stirring. After stirring at room temperature 
overnight, the reaction mixture was partitioned between methylene chloride 
and water. The organic layer was washed successively with water, 1N 
hydrochloric acid, saturated sodium hydroxide and saturated salt solution. 
The organic layer was dried over anhydrous magnesium sulfate, filtered and 
concentrated. The free amine was purified on a silica gel column. The pure 
cis-amine was dissolved in ether and treated with etheral hydrogen 
chloride to obtain 540 mg of a white solid; m.p. 195.degree.-197.degree. 
C. 
Analysis calc'd for C.sub.22 H.sub.25 F.sub.3 N.sub.5 O.sub.2 
Cl.0.62H.sub.2 O: C, 53.36; H, 5.34; N, 14.14; Cl, 7.16; F, 11.51; Found: 
C, 53.36; H, 5.26; N, 13.72; Cl, 7.10; F, 11.29. 
EXAMPLE 6 
(cis)-3-(Acetylamino)-1-[2-(dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4-me 
thoxyphenyl)-7-(trifluoromethyl)-2H-1-benzazepin-2-one, monohydrochloride 
A. 
7-(Trifluoromethyl)-1,3,4,5-tetrahydro-3-amino-4-(4-methoxyphenyl)-2H-1-be 
nzazepin-2-one 
The azide of part B of Example 5 (870 mg, 2.31 mmole) was catalytically 
reduced with 10% palladium-on-carbon (163 mg) in trifluoroacetic acid (40 
ml). After 2 hours, the mixture was filtered through a pad of celite. The 
solid residue was rinsed with ethyl acetate and the combined filtrate was 
concentrated. The residue was dissolved in ethyl acetate and washed twice 
with 1N sodium hydrogen carbonate, followed by saturated sodium chloride, 
dried over anhydrous magnesium sulfate, and concentrated to give 800 mg of 
an off-white solid which was triturated with ether and vacuum-dried to 
obtain 660 mg of the title A compound. 
B. 
(cis)-(3-Acetylamino)-7-(trifluoromethyl)-1,3,4,5-tetrahydro-4-(4-methoxyp 
henyl)-2H-1-benzazepin-2-one 
Acetic anhydride (2 ml) was added to the amine of the title A compound (100 
mg, 0.285 mmole) in methylene chloride (3 ml) and pyridine (3 ml). 
Stirring was continued for about 5 hours. The mixture was diluted with 
methylene chloride and washed three times with 1N hydrochloric acid, dried 
over anhydrous magnesium sulfate, and concentrated. The oily residue was 
placed under high vacuum overnight to obtain 100 mg of a white solid which 
was flash chromatographed to give 50 mg of the title B pure cis-compound 
as a white solid. 
C. 
(cis)-3-(Acetylamino)-1-[2-(dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4-m 
ethoxyphenyl)-7-(trifluoromethyl)-2H-1-benzazepin-2-one, monohydrochloride 
Potassium hydrogen carbonate (300 mg, 2.96 mmole), the title B compound 
(580 mg, 1.48 mmole), and potassium iodide were suspended in 
methylethylketone (25 ml). A 2.15M toluene solution of 
N,N-dimethylaminoethyl chloride (1 ml, 2.22 mmole) was added with 
stirring, and the mixture was refluxed for 4 hours. Another 1 ml of 
N,N-dimethylaminoethyl chloride solution was added, and reflux was 
continued for an additional 3 hours. The solvent was evaporated and the 
residue was dissolved in ethyl acetate, washed with water, dried over 
anhydrous magnesium sulfate, and concentrated giving 0.56 g of a tan 
semisolid. This crude material was flash chromatographed to give 400 mg of 
free amine which was dissolved in ether, and treated with saturated 
ethereal hydrochloric acid. The off-white solid was collected by suction 
filtration and then triturated with ether (X2) to yield 340 mg of the 
title compound; m.p. 192.degree.-196.degree. C. 
Analysis calc'd for C.sub.24 H.sub.29 F.sub.3 N.sub.3 O.sub.3 
Cl.1.25H.sub.2 O: C, 55.17; H, 6.07; N, 8.04; Cl, 6.79; F, 10.9; Found: C, 
55.17; H, 5.77; N, 7.84; Cl, 6.66; F, 10.5. 
EXAMPLES 7 TO 30 
Following the procedures described above and as outlined in Examples 1-6, 
the following additional compounds within the scope of the present 
invention can be made. 
__________________________________________________________________________ 
##STR32## 
Ex. No. 
R.sub.1 R.sub.2 
R.sub.3 
R.sub.4 
R.sub.5 R.sub.6 
n 
__________________________________________________________________________ 
7 SC.sub.2 H.sub.5 
CH.sub.3 
CH.sub.3 
7-CF.sub.3 
4-OCH.sub.3 
H 2 
8 
##STR33## CH.sub.3 
CH.sub.3 
7-CF.sub.3 
4-OCH.sub.3 
H 3 
9 
##STR34## CH.sub.3 
CH.sub.3 
6-CF.sub.3 
4-OCH.sub.3 
H 2 
10 
##STR35## CH.sub.3 
CH.sub.3 
7-CF.sub.3 
4-OCH.sub.3 
H 2 
11 SC.sub.3 H.sub.7 
CH.sub.3 
CH.sub.3 
7-CF.sub.3 
4-OCH.sub.3 
H 2 
12 SCH.sub.3 
##STR36## 
7-CF.sub.3 
4-OCH.sub.3 
H 2 
13 NNN 
##STR37## 
7-CF.sub.3 
4-OCH.sub.3 
H 3 
14 
##STR38## 
##STR39## 
7-CF.sub.3 
4-OCH.sub.3 
H 2 
15 NH.sub.2 CH.sub.3 
CH.sub.3 
7-CF.sub.3 
4-OCH.sub.3 
H 2 
16 
##STR40## CH.sub.3 
CH.sub.3 
7-CF.sub.3 
4-OCH.sub.3 
H 2 
17 
##STR41## CH.sub.3 
CH.sub.3 
7-CF.sub.3 
4-OCH.sub.3 
H 2 
18 NHCH.sub.3 CH.sub.3 
CH.sub.3 
7-CF.sub.3 
4-OCH.sub.3 
H 2 
19 
##STR42## CH.sub.3 
CH.sub.3 
7-Cl 
3-CN 4-OCH.sub.3 
2 
20 
##STR43## CH.sub.3 
CH.sub.3 
6-CF.sub.3 
4-Br H 3 
21 SCH.sub.3 CH.sub.3 
CH.sub.3 
6-NO.sub.2 
##STR44## 
3-CH.sub.3 
2 
22 
##STR45## CH.sub.3 
CH.sub.3 
7-NO.sub.2 
4-SO.sub.2 CH.sub.3 
H 3 
23 
##STR46## H CH.sub.3 
7-CF.sub.3 
4-OCH.sub.3 
H 2 
24 SC.sub.2 H.sub.5 
H CH.sub.3 
6-Cl 
4-OCH.sub.3 
H 2 
25 SCH.sub.3 H CH.sub.3 
6-CF.sub.3 
4-OCH.sub.3 
H 3 
26 NNN H CH.sub.3 
7-CF.sub.3 
4-OCH.sub.3 
H 2 
27 
##STR47## H CH.sub.3 
7-CF.sub.3 
4-OCH.sub.3 
H 3 
28 NH.sub.2 H CH.sub.3 
6-CF.sub.3 
4-OCH.sub.3 
H 2 
29 
##STR48## H CH.sub.3 
7-CF.sub.3 
4-OCH.sub.3 
H 3 
30 SCH.sub.3 H CH.sub.3 
7-Cl 
4-OCH.sub.3 
H 2 
__________________________________________________________________________