4,5-dihydro-1H-benzazepine-3-carboxylic acid esters which are useful as anti-hypertensive agents

Compound of the formula ##STR1## wherein R.sub.3 is aryl and R.sub.1 is hydrogen or ##STR2## are disclosed. These compounds are useful as cardiovascular agents, and especially as anti-hypertensive agents.

SUMMARY OF THE INVENTION 
This invention relates to the novel 4,5-dihydro-1H-benzazepine-3-carboxylic 
acid esters of formula I and pharmaceutically acceptable salts thereof 
##STR3## 
R.sub.1 is hydrogen or 
##STR4## 
R.sub.2 is hydrogen, lower alkyl, --(CH.sub.2).sub.m --aryl, 
--(CH.sub.2).sub.m --cycloalkyl, --(CH.sub.2).sub.p --OH, 
--(CH.sub.2).sub.p --O--lower alkyl, --(CH.sub.2).sub.p 
--O--(CH.sub.2).sub.m --aryl, --(CH.sub.2).sub.p --SH, --(CH.sub.2).sub.p 
--S--lower alkyl, --(CH.sub.2).sub.p --S--(CH.sub.2).sub.m --aryl, 
##STR5## 
halo substituted lower alkyl, or a pharmaceutically acceptable salt 
forming ion; 
R.sub.3 is aryl; 
R.sub.4 and R.sub.5 are independently selected from the group consisting of 
hydrogen, lower alkyl, --(CH.sub.2).sub.m --aryl, 
##STR6## 
or R.sub.4 and R.sub.5 taken together with the N atom to which they are 
attached complete a heterocyclic ring of the formula 
##STR7## 
R.sub.6 is hydrogen, lower alkyl, --(CH.sub.2).sub.m --aryl, or a 
pharmaceutically acceptable salt forming ion; 
R.sub.7 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 
carbons, lower alkylthio of 1 to 4 carbons, halo, CF.sub.3 or hydroxy; 
R.sub.8 is hydrogen, lower alkyl of 1 to 4 carbons or (CH.sub.2).sub.m 
--aryl; 
R.sub.9 is hydrogen, lower alkoxy of 1 to 4 carbons, halo or CF.sub.3 ; 
m is zero or an integer from 1 to 6; 
n is an integer from 1 to 6; 
p is an integer from 2 to 6. 
DETAILED DESCRIPTION OF THE INVENTION 
This invention in its broadest aspects relates to the 
4,5-dihydro-1H-benzazepine-3-carboxylic acid esters of formula I above, to 
compositions and the method of using such compounds as cardiovascular 
agents. 
The term lower alkyl used in defining various symbols refers to straight or 
branched chain hydrocarbon radicals having up to eight carbons, preferably 
from one to five carbons. Similarly, the terms lower alkoxy and lower 
alkylthio refer to such lower alkyl groups attached to an oxygen or 
sulfur. 
The term lower alkenyl refers to straight or branched chain hydrocarbon 
radicals having from two to eight carbons and one double bond, preferably 
three to five carbons. The term lower alkynyl refers to straight or 
branched chain hydrocarbon radicals having from two to eight carbons and 
one triple bond, preferably three to five carbons. 
The term cycloalkyl refers to saturated rings of 4 to 7 carbon atoms with 
cyclopentyl and cyclohexyl being most preferred. 
The term halo refers to chloro, bromo and fluoro. 
The term halo substituted lower alkyl refers to such lower alkyl groups 
described above in which one or more hydrogens have been replaced by 
chloro, bromo or fluoro groups such as trifluoromethyl, which is 
preferred, pentafluoroethyl, 2,2,2-trichloroethyl, chloromethyl, 
bromomethyl etc. 
The term aryl refers to phenyl or mono substituted phenyl, wherein said 
substituent is lower alkyl of 1 to 4 carbons, lower alkylthio of 1 to 4 
carbons, lower alkoxy of 1 to 4 carbons, halo, cyano, hydroxy, amino, 
--NH--alkyl wherein alkyl is of 1 to 4 carbons, --N(alkyl).sub.2 wherein 
alkyl is of 1 to 4 carbons, CF.sub.3, OCHF.sub.2, 
##STR8## 
--O--CH.sub.2 --cycloalkyl, 
##STR9## 
or --S--CH.sub.2 --cycloalkyl, di- or tri-substituted phenyl wherein said 
substituents are selected from methyl, methoxy, methylthio, halo, 
CF.sub.3, hydroxy, amino, and OCHF.sub.2. 
The compounds of formula I can be prepared by first reacting a 
2-nitrotoluene having the formula 
##STR10## 
with a malonate having the formula 
##STR11## 
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 
##STR12## 
Reduction of a compound of formula IV yields the corresponding compound 
having the formula 
##STR13## 
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 
##STR14## 
Treatment of compound VI in a solvent such as tetrahydrofuran, with a 
reducing agent, such as lithium aluminum hydride, provides a compound 
having the formula 
##STR15## 
which can thereafter be treated with an acid, e.g. concentrated 
hydrochloric acid, in the presence of an alcoholic solvent, such as 
methanol, to yield 
##STR16## 
Compound VIII, in the presence of dimethylsulfoxide and triethylamine, can 
be treated with an oxidizing agent, e.g. pyridine-sulfur trioxide in 
dimethyl sulfoxide to provide 
##STR17## 
that is, the compounds of formula I wherein R.sub.1 is hydrogen. 
Treatment of the compound of formula IX in solvents, such as 
methylethylketone or dimethylformamide, with a base, such as potassium 
hydrogen carbonate or sodium hydride, followed by reaction with a compound 
having the formula 
##STR18## 
provides the compounds of formula I wherein R.sub.1 is 
##STR19## 
or salts thereof. 
Preferred compounds of this invention are those wherein 
R.sub.2 is straight or branched chain lower alkyl of 1 to 5 carbons, 
--(CH.sub.2).sub.p --O--lower alkyl wherein lower alkyl is straight or 
branched chain of 1 to 5 carbons, 
##STR20## 
p is 2, 3 or 4; 
R.sub.4 and R.sub.5 are independently selected from hydrogen, straight or 
branched chain lower alkyl of 1 to 5 carbons, and phenylethyl or 
substituted phenylethyl; 
R.sub.3 is phenyl, 2-, 3- or 4-mono substituted phenyl wherein said 
substituent is lower alkyl of 1 to 4 carbons lower alkoxy of 1 to 4 
carbons, lower alkylthio of 1 to 4 carbons, halo, CF.sub.3, or OCHF.sub.2, 
disubstituted phenyl, 2,3,4-trisubstituted phenyl or 3,4,5-trisubstituted 
phenyl wherein said phenyl substituents are selected from methyl, methoxy, 
methylthio, halo, CF.sub.3 and OCHF.sub.2 ; and, 
R.sub.9 is hydrogen, Cl or CF.sub.3. 
Most preferred are the above compounds wherein 
R.sub.1 is hydrogen or --(CH.sub.2).sub.2 --N(CH.sub.3).sub.2 ; 
R.sub.2 is lower alkyl; 
R.sub.3 is phenyl, 2-(trifluoromethyl)phenyl, 4-methylphenyl, 
4-methoxyphenyl or 2-chlorophenyl; and, 
R.sub.9 is CF.sub.3. 
The compounds of formula I form salts with a variety of inorganic and 
organic acids. The non-toxic pharmaceutically acceptable salts are 
preferred, although other salts may also be useful in isolating or 
purifying the product. Such pharmaceutically acceptable salts include 
those formed with hydrochloric acid, methanesulfonic acid, sulfuric acid, 
acetic acid, maleic acid, etc. The salts are obtained by reacting the 
product with an equivalent amount of the acid in a medium in which the 
salt precipitates. 
In addition, the compounds of formula I in which R.sub.2 is 
##STR21## 
or in which R.sub.2 is hydrogen include carboxylic acid salts, i.e. 
R.sub.2 or R.sub.6 is a pharmaceutically acceptable salt forming ion. 
Preferred salt forming ions include alkali metal salt ions such as sodium, 
potassium and lithium, and alkaline earth metal salt ions such as calcium 
and magnesium. 
The compounds of formula I and the pharmaceutically acceptable salts 
thereof are useful as cardiovascular agents. These compounds act as 
calcium entry blocking vasodilators and are especially useful as 
antihypertensive agents. Thus, 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. 
A single dose, or preferably two to four divided daily doses, provided on 
a basis of about 0.1 to 100 mg per kilogram of body weight per day, 
preferably from about 1 to about 50 mg per kilogram per day, is 
appropriate to reduce blood pressure. 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 calcium entry blocking 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-ischemic agents, 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 a beta-adrenergic agent, or angiotensin converting enzyme 
inhibitor. Suitable diuretics include the thiazide diuretics such as 
hydrochlorothiazide and bendroflumethiazide, suitable beta-adrenergic 
agents include nadolol, and suitable angiotensin converting enzyme 
inhibitors include captopril. 
The compounds of formula I can be formulated for use in the reduction of 
blood pressure in compositions such as tablets, capsules or elixirs for 
oral administration, or in sterile solutions or suspensions for parenteral 
administration. About 10 to 500 mg of a compound of formula I is 
compounded with physiologically acceptable vehicle, carrier, excipient, 
binder, preservative, stabilizer, flavor, etc., in a unit dosage form as 
called for by accepted pharmaceutical practice. The amount of active 
substance in these compositions or preparations is such that a suitable 
dosage in the range indicated is obtained.

The present invention will be further described by reference to the 
following examples however, the invention should not be limited to the 
details therein. 
EXAMPLE 1 
1-[2-(Dimethylamino)ethyl]-4,5-dihydro-4-(4-methoxyphenyl)-7-(trifluorometh 
yl)-1H-1-benzazepine-3-carboxylic acid, methyl ester, fumarate (1:1) salt 
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 
2-methyl-4-trifluoromethylnitrobenzene (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. 
Analyst 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. 
[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, 59.29; H, 5.21; 
N, 3.29; F, 13.40; Found: C, 59.48; H, 5.26; N, 3.16; F, 13.43. 
C. 
7-(Trifluoromethyl)-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphe 
nyl)-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-hydroxymethyl-4-(4-methoxyphenyl) 
-2H-1-benzazepin-2-one 
To a suspension of lithium aluminum hydride (1.5 g, 0.04 mole) in dry 
tetrahydrofuran (50 ml) at -10.degree. C. under argon was added slowly a 
solution of the title C compound (8 g, 0.02 mole) in dry tetrahydrofuran 
(50 ml) and stirred for 30 minutes. It was then quenched slowly with (1:1) 
mixture of tetrahydrofuran/water (50 ml) and diluted with diethyl ether, 
filtered through Celite. The layers were separated and organic layer was 
washed with water (50 ml), dried and concentrated in vacuo. It was 
triturated with isopropyl ether to yield 5.9 g of the title D compound as 
a white solid, m.p. 189.degree.-190.5.degree. C. 
Analysis calc'd for C.sub.19 H.sub.18 F.sub.3 NO.sub.3 : C, 62.46; H, 4.97; 
N, 3.84; F, 15.59; Found: C, 62.35; H, 5.06; N, 3.84; F, 15.42. 
E. 
2-Amino-.alpha.-(hydroxymethyl)-.beta.-(4-methoxyphenyl)-5-(trifluoromethy 
l)benzenebutanoic acid, methyl ester 
To a solution of the title D compound (2.5 g, 6.8 mmole) in 20 ml of dry 
methanol was added 5 ml of concentrated sulfuric acid slowly and then 
heated under reflux under argon for 5 hours. It was then diluted with 
water (100 ml) and methanol was evaporated off in vacuo, aqueous layer was 
extracted 3 times with ethyl acetate (200 ml), and washed with saturated 
sodium bicarbonate (50 ml), water (50 ml), dried and concentrated in vacuo 
to yield 1.7 g of the title E compound. 
F. 
4,5-Dihydro-4-(4-methoxyphenyl)-7-trifluoromethyl-1H-1-benzazepine-3-carbo 
xylic acid, methyl ester 
To a solution of the title E compound (1.7 g, 4.2 mmole) in dry dimethyl 
sulfoxide (5 ml) was added triethyl amine (1.1 g, 10 mmole) and then a 
solution of pyridine-sulfur trioxide (2.4 g, 16.6 mmole) in dimethyl 
sulfoxide (5 ml) at room temperature and allowed to stir overnight. It was 
then diluted with diethyl ether and 10% hydrochloric acid. Aqueous layer 
was separated and extracted twice with diethyl ether (50 ml). Combined 
organic layer was washed twice with water (50 ml), dried over anhydrous 
magnesium sulfate and concentrated in vacuo. It was purified by flash 
chromatography eluting with (1:1) hexane/ethyl acetate mixture to yield 
0.4 g of the title F compound as an oil. 
G. 
1-[2-(Dimethylamino)ethyl]-4,5-dihydro-4-(4-methoxyphenyl)-7-(trifluoromet 
hyl)-1H-1-benzazepine-3-carboxylic acid, methyl ester, fumarate (1:1) salt 
To a suspension of sodium hydride (0.08 g, 1.6 mmole) in anhydrous dimethyl 
sulfoxide (5 ml) was added a solution of the title F compound (0.6 g, 1.6 
mmole) in anhydrous dimethyl sulfoxide (2 ml) and stirred for 45 minutes 
at room temperature. A solution of dimethylaminoethyl chloride (1.1 ml of 
2.2M solution in toluene, 2.4 mmole) was added and stirred for 1 hour and 
then heated at 65.degree. for 2 hours. It was then poured into water (50 
ml) and extracted 3 times with ethyl acetate (150 ml). Organic layer was 
then washed 3 times with water (50 ml), dried over anhydrous magnesium 
sulfate and concentrated in vacuo. It was purified by flash chromatography 
eluting with methylene chloride/methanol (9:1) mixture to give 0.6 g of 
the free amine. To a solution of this amine (0.6 g, 1.34 mmole) in 
methanol (5 ml) was added a solution of fumaric acid (0.16 g, 1.4 mmole) 
in hot methanol (2 ml) and stirred for 5 minutes. It was then concentrated 
in vacuo to a small amount of methanol and diluted with diethyl ether and 
filtered to give 0.42 g of the title compound, m.p. 
198.degree.-199.degree. C. 
Analysis calc'd for C.sub.28 H.sub.31 F.sub.3 N.sub.2 O.sub.7.0.24H.sub.2 
O: C, 59.11; H, 5.57; N, 4.92; Found: C, 59.11; H, 5.54; N, 4.89. 
EXAMPLE 2 
1-[2-Dimethylamino)ethyl]-4,5-dihydro-4-(4-methoxyphenyl)-6-(trifluoromethy 
l)-1H-benzazepine-3-carboxylic acid, methyl ester oxalate (1:1) salt 
A. 
[2-(6-Trifluoromethyl-2-nitrophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic 
acid, dimethyl ester 
To a dry 3-neck flask (2 l) equipped with a stirrer, thermometer, condenser 
and dropping funnel was added dimethyl-p-methoxybenzylidene malonate (52.7 
g, 0.21 ml) and dimethylformamide (350 ml). This solution was stirred 
(under nitrogen), treated with 60% sodium hydride (11 g, 0.27 mole) 
dispersion and this slurry was treated dropwise with a solution of 
2-methyl-3-trifluoromethylnitrobenzene (43 g, 0.21 mol) in 
dimethylformamide (50 ml) over a period of 30 minutes while maintaining 
temperature at 28.degree.-30.degree.. The pale brown mixture was stirred 
at room temperature for 6 hours, allowed to stand overnight at room 
temperature, cooled and treated portionwise with acetic acid (20 ml). The 
pale yellow slurry was poured onto ice water (2 l) and extracted with 
methylene chloride (500 ml). The aqueous layer was extracted once with 250 
ml of methylene chloride and then two more times with 100 ml of methylene 
chloride. The organic phases were combined, extracted three times with 
water (500 ml), dried over anhydrous magnesium sulfoxide, filtered and the 
solvent evaporated to give a pale brown granular solid (99.1 g). The 
latter was digested with hot methanol (150 ml). The suspension was allowed 
to cool to room temperature, cooled overnight, filtered, washed with cold 
methanol and dried to give 78.3 g of the title A compound as a colorless 
solid, m.p. 117.degree.-119.degree.. 
Analysis calc'd for C.sub.21 H.sub.20 NH.sub.3 O.sub.7 : C, 55.39; H, 4.43; 
N, 3.08; F, 12.52; Found: C, 55,33; H, 4.38; N, 3.02; F, 12.43. 
B. 
[2-(6-Trifluoromethyl-2-aminophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic 
acid, dimethyl ester 
The reduction of the title A compound was carried out as described for the 
title B compound in Example 1. The product was crystallized from methanol 
to yield the title B compound, m.p. 112.degree.-114.degree. C. 
Analysis calc'd for C.sub.21 H.sub.22 NF.sub.3 O.sub.5 : C, 59.29; H, 5.21; 
N, 3.29; F, 13.40; Found: C, 59.04; H, 5.41; N, 3.27; F, 13.17. 
C. 
6-(Trifluoromethyl)-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphe 
nyl)-2H-1-benzazepin-2-one 
To a dry 3-neck flask (2 l) was added the title B compound (34.5 g, 0.081 
mol) and methanol (350 ml). The suspension was heated to 45.degree. and 
the resulting solution was cooled to 30.degree. and treated with 25% 
solution of sodium methoxide in methanol (23 ml). This mixture was heated 
and refluxed for 1 hour. The slurry was cooled to 15.degree. and treated 
with a solution of 6N hydrochloric acid in water (350 ml). After stirring 
in an ice bath for 2 hours, the pale gray solid was filtered and dried to 
give 30.8 g of the title C compound, m.p. 214.degree.-216.degree.. 
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, 61.02; H, 4.56; N, 3.53; F, 14.30. 
D. 
6-(Trifluoromethyl)-1,3,4,5-tetrahydro-3-hydroxymethyl-4-(4-methoxyphenyl) 
-2H-1-benzazepine-2-one 
To a suspension of lithium aluminum hydride (2.9 g, 0.076 mole) in dry 
tetrahydrofuran (100 ml) at -10.degree. C. under argon was added slowly a 
solution of the title C compound (15 g, 0.038 mole) in dry tetrahydrofuran 
(100 ml) and stirred for 30 minutes. It was then quenched slowly with 
(1:1) mixture of tetrahydrofuran/water (100 ml) and diluted with diethyl 
ether, filtered through Celite. The layers were separated and organic 
layer was washed with water (50 ml), dried and concentrated in vacuo. It 
was triturated with isopropyl ether to yield 11.8 g of the title D 
compound as a white solid, m.p. 189.degree.-190.5.degree. C. 
Analysis calc'd for C.sub.19 H.sub.18 F.sub.3 NO.sub.3 : C, 62.46; H, 4.97; 
N, 3.84; F, 15.59; Found: C, 62.66; H, 5.11; N, 3.73; F, 15.77. 
E. 
2-Amino-.alpha.-(hydroxymethyl)-.beta.-(4-methoxyphenyl)-6-(trifluoromethy 
l) benzenebutanoic acid, methyl ester 
To a solution of the title D compound (4 g, 10.9 mmole) in dry methanol (60 
ml) was added concentrated sulfuric acid (12 ml) slowly and then heated 
under reflux under argon for 5 hours. It was then diluted with water (100 
ml) and methanol was evaporated off in vacuo, aqueous layer was extracted 
with ethyl acetate (3.times.200 ml), and washed with saturated sodium 
bicarbonate (50 ml), water (50 ml), dried and concentrated in vacuo and 
purified by flash chromatography eluting with (1:1) hexane/ethyl acetate 
mixture to yield 3.2 g of the title E compound as an oil. 
F. 
4,5-Dihydro-4-(4-methoxyphenyl)-6-trifluoromethyl-1H-1-benzazepine-3-carbo 
xylic acid, methyl ester 
To a solution of the title E compound (3.2 g, 7.8 mmole) in dry dimethyl 
sulfoxide (20 ml) was added triethyl amine (1.1 g, 10 mmole) and then a 
solution of pyridine-sulfur trioxide (2.4 g, 16.6 mmole) in dimethyl 
sulfoxide (10 ml) at room temperature and allowed to stir overnight. It 
was then diluted with diethyl ether and 10% hydrochloric acid. Aqueous 
layer was separated and extracted with diethyl ether (2.times.50 ml). 
Combined orgaic layers were washed with water (2.times.50 ml), dried over 
anhydrous magnesium sulfate and concentrated in vacuo. It was purified by 
flash chromatography eluting with (1:1) hexane/ethyl acetate mixture to 
yield 0.6 g of the title F compound as an oil. 
G. 
1-[2-(Dimethylamino)ethyl]-4,5-dihydro-4-(4-methoxyphenyl)-6-(trifluoromet 
hyl)-1H-benzazepine-3-carboxylic acid, methyl ester oxalate (1:1) salt 
To a suspension of sodium hydride (0.166 g, 3.4 mmole) in anhydrous 
dimethyl sulfoxide (5 ml) was added a solution of the title F compound 
(1.3 g, 3.4 mmole) in anhydrous dimethyl sulfoxide (5 ml) and stirred for 
45 minutes at room temperature. A solution of dimethylaminoethyl chloride 
(4 ml of 2.2M solution, 8.6 mmole) was added and stirred for 24 hours at 
room temperature. It was then poured into water (50 ml) and extracted 3 
times with ethyl acetate (150 ml). Organic layer was then washed 3 times 
with water (50 ml), dried over anhydrous magnesium sulfate and 
concentrated in vacuo. It was purified by flash chromatography eluting 
with hexane/ethyl acetate (1:1), methylene chloride/methanol (95:5) to 
give 1 g of the free amine. To a solution of this amine (0.7 g, 1.56 
mmole) in isopropanol (5 ml) was added a solution of oxalic acid (0.144 g, 
1.56 mmole) in hot isopropanol (2 ml) and stirred for 5 minutes. It was 
then concentrated in vacuo and triturated with diethyl ether and filtered 
to give 0.6 g of the title compound, m.p. 115.degree.-117.degree. C. 
Analysis calc'd for C.sub.24 H.sub.27 F.sub.3 N.sub.2 O.sub.3.C.sub.2 
H.sub.2 O.sub.4 : C, 57.99; H, 5.43; N, 5.20; F, 10.58; Found: C, 57.65; 
H, 5.31; N, 5.10; F, 10.66. 
EXAMPLE 3 
4-(2-Chlorophenyl)-4,5-dihydro-7-(trifluoromethyl)-1H-1-benzazepine-3-carbo 
xylic acid, ethyl ester 
A. [(2-Chlorophenyl)methylene]propanedioic acid, diethyl ester 
A mixture of 97% chlorobenzaldehyde (51.5 g, 41.3 ml, 0.35 mole), diethyl 
malonate (57 g, 54 ml, 0.35 mole), acetic acid (1 ml) and piperdine (2 ml) 
in benzene (150 ml) was heated under reflux with azeotropic removal of 
water overnight. Benzene was removed by distillation, the residue was 
diluted with ethyl acetate (200 ml), washed with 10% hydrochloric acid, 
saturated potassium bicarbonate, brine and dried over anhydrous magnesium 
sulfate and concentrated in vacuo to yield 100 g of the title A compound 
as an oil. 
B. 
[1-(2-Chlorophenyl)-2-[2-nitro-5-(trifluoromethyl)-phenyl)ethyl]propanedio 
ic acid, diethyl ester 
To a solution of the title A compound (80 g, 0.29 mole) in 
dimethylformamide (200 ml) was slowly added sodium hydride (13.8 g, 0.29 
mole) at room temperature and stirred for 10 minutes. A solution of 
2-methyl-4-trifluoromethylnitrobenzene (58.7 g, 0.29 mole) in 
dimethylformamide (20 ml) was added slowly under argon and allowed to stir 
at room temperature for 2 hours. It was then quenched with 30% acetic acid 
(10 ml) and extracted 3 times with ethyl acetate (150 ml). The organic 
layer was washed 3 times with water (100 ml), saturated sodium 
bicarbonate, brine, dried over anhydrous magnesium sulfate and 
concentrated in vacuo. It was purified by flash chromatography eluting 
with hexane (1 l), hexane/acetone (9:1) (2 l) to yield 72 g of the title B 
compound as an oil. 
C. 
[2-[amino-5-(trifluoromethyl)phenyl]-1-(2-chlorophenyl)ethyl]propanedioic 
acid, diethyl ester 
To a solution of stannous chloride hydrate (57.9 g, 0.26 mole) in a mixture 
of methanol and concentrated hydrochloric acid (540/50 ml) was added a 
solution of the title B compound (25 g, 0.05 mole) in 20 ml of methanol 
and stirred mechanically under nitrogen for 16 hours. Celite (50 g) was 
added followed by the addition of ethyl acetate (200 ml) and solid 
potassium carbonate (50 g). The reaction was stirred for .about.30 
minutes, filtered through celite and concentrated in vacuo. It was diluted 
with ethyl acetate (300 ml) and washed twice with water (100 ml), dried 
over anhydrous magnesium sulfate and concentrated in vacuo to give 20 g of 
the crude product which was crystallized from isopropyl ether and hexane 
to give 15 g of the title C compound, m.p. 74.degree.-76.degree. C. 
D. 
4-(2-Chlorophenyl)-2,3,4,5-tetrahydro-2-oxo-7-(trifluoromethyl)-1H-1-benza 
zepine-3-carboxylic acid, methyl ester 
To a solution of the title C compound (5 g, 10.9 mmole) in 100 ml methanol 
was a solution of sodium methoxide 4.37M (6.3 ml, 27.4 mmole) in methanol 
and the reaction was heated at reflux for 4 hours under argon. It was then 
cooled down and quenched with a mixture of water/acetic acid/methanol 
(70/20/10) and then water (200 ml) was added and cooled in ice, 
precipitates were filtered off and dried to give 2.7 g of the title D 
compound, m.p. 183.degree.-184.degree. C. 
E. 
[4-(2-Chlorophenyl)-1,3,4,5-tetrahydro-3-hydroxymethyl)-7-(trifluoromethyl 
)-2H-1-benzazepin-2-one 
To a suspension of lithium aluminum hydride (2.1 g, 0.058 mole) in dry 
tetrahydrofuran (100 ml) at -10.degree. under argon was added a solution 
of the title D compound (11 g, 0.20 mole) in 20 ml of dry tetrahydrofuran 
slowly (.about.30 minutes) and stirred for .about.30 minutes. It was then 
quenched with a mixture of tetrahydrofuran/water (1:1) (50 ml) and diluted 
with ethyl acetate (200 ml), filtered through celite, aqueous layer was 
separated and organic layer was washed with water (100 ml), dried over 
anhydrous magnesium sulfate and concentrated in vacuo to give 4 g of the 
title E compound, m.p. 153.degree.-157.degree.. 
F. 
2-Amino-.beta.-(2-chlorophenyl)-.alpha.-(hydroxymethyl)-5-(trifluoromethyl 
)benzenebutanoic acid, ethyl ester 
The solution of the title E compound (4 g, 10.8 mmol) in 100 ml of ethanol 
was treated with concentrated sulfuric acid (10 ml) at room temperature 
and heated at 65.degree. C. for 16 hours. It was then concentrated in 
vacuo and purified on silica gel, eluting with 1:1 mixture of hexane and 
ethyl acetate to give 1.2 g of the title F compound as an oil. 
G. 
4-(2-Chlorophenyl)-4,5-dihydro-7-(trifluoromethyl)-1H-1-benzazepine-3-carb 
oxylic acid, ethyl ester 
To a solution of the title F compound (2 g, 4.8 mmol) in dry dimethyl 
sulfoxide (2 ml) was added triethyl amine (1.2 g, 12.0 mmole) at room 
temperature and then a solution of pyridine-sulfur trioxide in dry 
dimethyl sulfoxide (3 ml) and allowed to stir at room temperature for 16 
hours. It was then diluted with ethyl acetate (50 ml) and water (50 ml); 
water layer was extracted twice with ethyl acetate (100 ml) and combined 
ethyl acetate layers was washed twice with water (100 ml). The solution 
was dried over anhydrous magnesium sulfate and concentrated in vacuo. 
Different batches of this material were combined and purified on silica 
gel, eluting with a mixture of hexane/ethyl acetate (9:1) to give 0.188 g 
of the title compound, which was recrystallized from isopropyl 
ether-hexane to give 0.12 g of the title compound, m.p. 
190.degree.-192.degree. C. 
Analysis calc'd for C.sub.20 H.sub.17 ClF.sub.3 NO.sub.2 : C, 60.68; H, 
4.33; N, 3.54; Found: C, 60.72; H, 4.30; N, 3.53. 
EXAMPLES 4-29 
Using the procedures outlined above and in Examples 1-3, the following 
additional compounds of formula I within the scope of the present 
invention can be made. 
__________________________________________________________________________ 
##STR22## 
Ex. No. 
R.sub.1 R.sub.9 
R.sub.2 R.sub.3 
__________________________________________________________________________ 
4 H Cl (6-position) 
CH.sub.3 
##STR23## 
5 H Br (7-position) 
C.sub.2 H.sub.5 
##STR24## 
6 H OCH.sub.3 (6-position) 
CH.sub.3 
##STR25## 
7 H CF.sub.3 (7-position) 
CH.sub.3 
##STR26## 
8 H H CH.sub.3 
##STR27## 
9 H H 
##STR28## 
##STR29## 
10 H H 
##STR30## 
##STR31## 
11 H H C.sub.2 H.sub.5 
##STR32## 
12 H Cl (6-position) 
CH.sub.2CH(CH.sub.3).sub.2 
##STR33## 
13 H H CH.sub.3 
##STR34## 
14 H H (CH.sub.2).sub.2SCH.sub.3 
##STR35## 
15 H H 
##STR36## 
##STR37## 
16 H H (CH.sub.2).sub.2N(CH.sub.3).sub.2 
##STR38## 
17 H H 
##STR39## 
##STR40## 
18 H H CH.sub.3 
##STR41## 
19 H H C.sub.2 H.sub.5 
##STR42## 
20 H H CH.sub.3 
##STR43## 
21 H H CH.sub.3 
##STR44## 
22 H H CH.sub.3 
##STR45## 
23 
##STR46## CF.sub.3 (7-position) 
CH.sub.3 
##STR47## 
24 
##STR48## CF.sub.3 (6-position) 
CH.sub.3 
##STR49## 
25 
##STR50## Cl (6-position) 
CH.sub.3 
##STR51## 
26 (CH.sub.2).sub.2N(C.sub.2 H.sub.5).sub.2 
H CH.sub.3 
##STR52## 
27 
##STR53## Cl (6-position) 
CH.sub.3 
##STR54## 
28 
##STR55## H C.sub.2 H.sub.5 
##STR56## 
29 
##STR57## CF.sub.3 (7-position) 
CH.sub.3 
##STR58## 
__________________________________________________________________________