Alpha-adrenergic receptor antagonists having the formula: ##STR1## which are useful to produce .alpha.-adrenoceptor antagonism, pharmaceutical compositions including these antagonists, and methods of using these antagonists to produce .alpha.-adrenoceptor antagonism in mammals.

This application is a 371 of PCT/US92/06538 filed Aug. 5, 1992. 
FIELD OF THE INVENTION 
This invention relates to novel substituted 
2,3,4,5-tetrahydro-1H-3-benzazepine compounds having .alpha.-adrenergic 
receptor antagonist activity. 
BACKGROUND OF THE INVENTION 
The autonomic nervous system is separated into the cholinergic and 
adrenergic nervous systems. Norepinephrine, the neurotransmitter of the 
adrenergic nervous system, exerts its activity by interaction with 
receptors (adrenoceptors) on the effector organs or on the nerve endings. 
The adrenoceptors are of two primary types: .alpha. and .beta.. Based upon 
selectivity of the receptors for a series of agonists and antagonists, the 
a adrenoceptors have been subdivided into .alpha..sub.1 and .alpha..sub.2 
subtypes. 
A large amount of experimental evidence now supports the view that the 
.alpha..sub.2 subtype is a heterogeneous adrenoceptor class. (For a 
general review see Timmermans and Van Zwieten, J. Med. Chem., 25, 1389 
(1982)). Experiments using 
6-chloro-9-(3-methyl-2-butenyloxy)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzaz 
epine (SK&F 104078) demonstrated that the classical adrenoceptors are 
heterogeneous and can be divided into SK&F 104078-insensitive and SK&F 
104078-sensitive .alpha..sub.2 adrenoceptors. The latter variously are 
referred to as postjunctional .alpha..sub.2 adrenoceptors or, preferably, 
.alpha..sub.3 adrenoceptors, U.S. Pat. No. 4,683,229, Jul. 28, 1987. 
As one of the primary regulators of peripheral vascular tone, .alpha. 
adrenoceptors long have been the targets of efforts to develop agents 
effective in changing vascular tone for use in treating diseases, such as 
hypertension, in which alterations in vascular resistance produce 
therapeutic benefits. Antihypertensive compounds presently in clinical use 
that function via interaction with a adrenoceptors include methyldopa, 
clonidine, and prazosin. Efforts to modulate sympathetic tone through 
interactions with a adrenoceptors have resulted in several compounds that 
interact somewhat selectively with .alpha..sub.1 or .alpha..sub.2 
adrenoceptors. Selective agonists include phenylephrine and methoxamine 
which preferentially activate .alpha..sub.1 receptors; and clonidine, 
.alpha.-methyl-norepinephrine, and tramazoline which preferentially 
activate .alpha..sub.2 adrenoceptors. Examples of selective 
.alpha.-adrenoceptor antagonists include prazosin which has high 
selectivity for .alpha..sub.1 adrenoceptors; and the .alpha..sub.2 
-selective blockers yohimbine and rauwolscine. 
U.S. Pat. No. 4,469,634, dated Sep. 4, 1984, describes allyloxy- and 
allythio-2,3,4,5-tetrahydro-1H-3-benzazepines useful as intermediates for 
preparing .alpha..sub.2 adrenoceptor affinity resins and as 
antihypertensive agents. 
U.S. Pat. No. 4,683,229 dated Jul. 28, 1987, describes 
6-halo-9-alkenyloxy-2,3,4,5-tetrahydro-1H-3-benzazepines having 
.alpha..sub.3 -selective antagonist activity. 
U.S. Pat. No. 4,265,890 dated May 5, 1981, describes mercapto 
substituted-2,3,4,5-tetrahydro-1H-3-benzazepines having dopamine receptor 
blocking activity. 
SUMMARY OF THE INVENTION 
The present invention resides in the discovery that certain 
substituted-2,3,4,5,-tetrahydro-1H-3-benzazepine compounds are 
.alpha.-adrenoceptor antagonists. Presently preferred compounds of the 
invention include: 
6-chloro-9-(3-furanylmethoxy)-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine, 
6-chloro-9-(4-chloro-1H-pyrazol-1-ylmethoxy)-2,3,4,5-tetrahydro-3-methyl-1H 
-3-benzazepine, 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-pyrazol-1-ylmethoxy)-1H-3-benzaz 
epine, 
6-chloro-9-(2-furanylmethoxy)-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine, 
6-chloro-9-[3-(2-furanyl)-2-propenyloxy]-2,3,4,5-tetrahydro-3-methyl-1H-3-b 
enzazepine, 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(2-thienylmethoxy)-1H-3-benzazepine, 
6-chloro-2,3,4,5-tetrahydro-3 methyl-9-(3 thienylmethoxy)-1H-3-benzazepine, 
6-chloro-2,3,4,5-tetrahydro-3 
methyl-9-[2-(1H-pyrazol-1-yl)ethoxy]-1H-3-benzazepine, 
6-chloro-2,3,4,5-tetrahydro-3-methyl 
-9-(1H-1,2,4-triazol-1-ylmethoxy)-1H-3-benzazepine, 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(4-pyridinylmethoxy)-1H-3-benzazepin 
e, 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-[2-(1H-1,2,4-triazol-1-yl)ethoxy]-1H 
-3-benzazepine, 
6-chloro-9-[(4-chloro-1H-pyrazol-1-ylmethoxy)-methyl]-2,3,4,5-tetrahydro-3- 
methyl-1H-3-benzazepine, 
6-chloro-9-[(4-chloro-1H-pyrazol-1-ylmethoxy)-carbonyl]-2,3,4,5-tetrahydro- 
3-methyl-1H-3-benzazepine, 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-pyrrol-1-yl)-1H-3-benzazepine, 
6-chloro-9-(2,5-dimethyl-1H-pyrrol-1-yl)-2,3,4,5-tetrahydro-3-methyl-1H-3-b 
enzazepine, 
6 
chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-pyrrol-1-ylmethyl)-1H-3-benzazepi 
ne, 
6-chloro-9-[5-(4-chloro-1H-pyrazol-1-yl)propyl]-2,3,4,5-tetrahydro-3-methyl 
-1H-3-benzazepine, and 
6-chloro-9-[5-(4-chloro-1H-pyrazol-1-yl)pentyl]-2,3,4,5-tetrahydro-3-methyl 
-1H-3-benzazepine; or a pharmaceutically acceptable salt thereof. 
The most preferred compound of the invention is 
6-chloro-9-(3-furanylmethoxy)-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine 
or a pharmaceutically acceptable salt thereof. 
In a further aspect of the invention there are provided methods of 
antagonizing a adrenoceptors in mammals, including humans, that comprise 
administering internally to a subject an effective amount of a substituted 
2,3,4,5-tetrahydro-1H-3-benzazepine compound. 
Included in the present invention are pharmaceutical compositions 
comprising compounds useful in the method of the invention and a suitable 
pharmaceutical carrier. Preferably, these compositions are used to produce 
a adrenoceptor antagonism and contain an effective amount of compounds 
useful in the methods of the invention. 
DETAILED DESCRIPTION OF THE INVENTION 
The presently invented compounds that are .alpha.-adrenoceptor antagonists 
or are useful in preparing .alpha.-adrenoceptor antagonists are 
represented by the following Formula (I): 
##STR2## 
in which: 
X is H, Cl , Br, F, I, CF.sub.3, C.sub.1-6 alkyl, COR.sup.1, CO2R.sup.2, 
CONR.sup.2 R.sup.2, CN, NO.sub.2, NR.sup.3 R.sup.4, OR.sup.3, SR.sup.1, 
SCF.sub.3, or any accessible combination thereof up to three substituents; 
R is H, C.sub.1-6 alkyl, or C.sub.3-5 alkenyl; 
A is --OCO(CH.sub.2).sub.1-4 --, --OCH.sub.2 CH.dbd.CH--, --CO.sub.2 
(CH.sub.2).sub.1-4 --, --(CH.sub.2).sub.0-6 --, or --(CH.sub.2).sub.n 
Z(CH.sub.2).sub.m --, wherein n is 0-4 and m is 1-5, with the proviso that 
m and n taken together are no greater than 5; 
Z is O or S; 
each R.sup.1 independently is C.sub.1-6 alkyl or (CH.sub.2).sub.0-6 phenyl; 
each R.sup.2 independently is H, C.sub.1-6 alkyl, or (CH.sub.2).sub.0-6 
phenyl; 
R.sup.3 is H, C.sub.1-6 alkyl, CHO, COR.sup.1, or SO.sub.2 R.sup.1 ; 
R.sup.4 is H or C.sub.1-6 alkyl; and 
Het is a heteroaryl group selected from thienyl, furanyl, pyrazolyl, 
imidazolyl, pyrrolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 
thiadiazolyl, pyridazolyl, pyrimidinyl, pyrazolyl, thiazolyl, pyridinyl, 
or tetrazolyl which are unsubstituted or substituted by C.sub.1-6 alkyl, 
C.sub.1-6 alkoxy, Cl, Br, F, I, NR.sup.3 R.sup.4, CO.sub.2 R.sup.2, 
CONR.sup.2 R.sup.2, CN, or NO.sub.2 ; 
or a pharmaceutically acceptable salt thereof, provided that when X is H, 
Cl, Br, F, CF.sub.3, CH.sub.3, OCH.sub.3, OH, or OC(O)C.sub.1-6 alkyl, 
A-Het is not --S(CH.sub.2).sub.0-1 -thienyl or -furanyl. 
As used herein C.sub.1-6 alkyl means straight or branched alkyl of one to 
six carbon atoms, C.sub.3-5 alkenyl means a straight or branched chain 
alkenyl having from 3 to 5 carbon atoms, and "any accessible combination 
thereof" means any combination of up to three substituents on the phenyl 
moiety that is available by chemical synthesis and is stable. 
Formula (Ia) includes presently preferred Formula (I) compounds: 
##STR3## 
in which: X is H, Cl, Br, F, I, CF.sub.3, C.sub.1-6 alkyl, COR.sup.1, 
CO.sub.2 R.sup.2, CONR.sup.2 R.sup.2, CN, NO.sub.2, NR.sup.3 R.sup.4, 
OR.sup.3, or SCF3; 
R is H, C.sub.1-6 alkyl, or C.sub.3-5 alkenyl; 
A is --OCO(CH.sub.2).sub.1-4 --, --OCH.sub.2 CH.dbd.CH--, --CO.sub.2 
(CH.sub.2).sub.1-4 --, --(CH.sub.2).sub.0-6 --, or --(CH.sub.2).sub.n 
Z(CH.sub.2).sub.m --, wherein n is 0-4 and m is 1-5, with the proviso that 
m and n taken together are no greater than 5; 
Z is O or S; 
each R.sup.1 independently is C.sub.1-6 alkyl or (CH.sub.2).sub.0-6 phenyl; 
each R.sup.2 independently is H, C.sub.1-6 alkyl, or (CH.sub.2).sub.0-6 
phenyl; 
R.sup.3 is H, C.sub.1-6 alkyl, CHO, COR.sup.1, or SO.sub.2 R.sup.1 ; 
R.sup.4 is H or C.sub.1-6 alkyl; and 
Het is a heteroaryl group selected from thienyl, furanyl, pyrazolyl, 
imidazolyl, pyrrolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, 
pyridinyl, or tetrazolyl, which are unsubstituted or substituted by 
C.sub.1-6, C.sub.1-6 alkoxy, Cl, Br, F, I, NR.sup.3 R.sup.4, CO.sub.2 
R.sup.2, CONR.sup.2 R.sup.2, CN, or NO.sub.2 ; 
or a pharmaceutically acceptable salt thereof, provided that when X is H, 
Cl, Br, F, CF.sub.3, CH.sub.3, OCH.sub.3, OH, or OC(O)C.sub.1-6 alkyl, 
A-Het is not --S(CH.sub.2).sub.0-1 -thienyl or -furanyl. 
Preferred compounds are represented by Formula (Ia) when: 
X is C1, Br, F, or I; 
R is CH.sub.3 ; and 
Het is pyrazolyl, furanyl, thienyl, triazolyl, pyridinyl, or pyrrolyl with 
each heteroaryl group being unsubstituted or substituted by Cl or 
CH.sub.3. 
##STR4## 
The benzazepines of formula (1) are described in published references, such 
as J. Med. Chem., 27: 918-921 (1984), or can be obtained readily using 
known procedures. According to Scheme I, the starting compounds of formula 
(1) are added to a suitable base, such as an alkali metal hydride, for 
example, sodium hydride, in a suitable organic solvent, such as 
dimethylformamide. Thereafter, an appropriately substituted halide or 
sulfonate, such as 3-(bromomethyl)furan, 2-(3-chloro-1-propenyl)furan, or 
2-(1H-pyrazol-1-yl)ethyl 4-methylbenzenesulfonate, is reacted with the 
above-generated intermediate to produce Formula (I) compounds wherein A is 
--O(CH.sub.2).sub.m -- or --OCH.sub.2 CH.dbd.CH--. 
Alternately, Formula (I) compounds wherein A is --O(CH.sub.2).sub.2 -- are 
prepared by reacting the formula (1) benzazepine compounds with a suitable 
base, such as an alkali metal hydride, in a suitable solvent, such as 
dimethylformamide, followed by reaction with an ester of a haloacetate, 
such as ethyl bromoacetate. The resulting (benzazepinyl) oxy acetate ester 
is reduced to the corresponding alcohol using an appropriate reducing 
agent, such as lithium aluminum hydride, in an inert solvent, such as 
diethyl ether. Conversion of the alcohol to a suitable leaving group, such 
as a tosylate, or a mesylate, followed by displacement of the leaving 
group with an alkali metal salt of a heteroaryl group, such as 
1H-1,2,4-triazole sodium salt, in a suitable solvent, such as 
dimethylformamide, gives the Formula (I) compounds wherein A is 
--O(CH.sub.2).sub.2 --. 
##STR5## 
The benzazepines of formula (2) are known to the art (J. Med. Chem., 27: 
918-921 (1984)) or are synthesized by known procedures. According to 
Scheme II, the primary amine of formula (2) compounds is diazotized using, 
for example, sodium nitrite in acetic acid, water, and sulfuric acid. 
Conversion to the corresponding cyano compounds of formula (3) is 
accomplished by reacting the diazonium salt with cyanide, for example, 
potassium cyanide. The carboxylic acid compounds of formula (4) are 
prepared by reacting the cyano of the formula (3) compounds in the 
presence of barium hydroxide, in a suitable solvent, such as a mixture of 
ethanol and water. The resulting acids are reacted with a suitable base, 
such as an alkali metal hydride, such as sodium hydride, in an 
appropriate-solvent, such as dimethylformamide. Thereafter, reaction with 
an appropriately substituted halide, such as 
4-chloro-1-(chloromethyl)-1H-pyrazole, gives formula (5) compounds, which 
are Formula (I) compounds wherein A is --CO.sub.2 (CH.sub.2).sub.1-4 --. 
Formula (I) compounds wherein the heteroaryl group is directly attached to 
the phenyl portion of the benzazepine nucleus may be prepared from Formula 
(2) amine compounds. For example, the amine-substituted benzazepine 
compounds are reacted with 2,5-hexane-dione or 
2,5-dimethoxytetrahydrofuran in a suitable solvent, such as acetic acid or 
a mixture of acetic acid and toluene, at a temperature of about 80.degree. 
C. to about 120.degree. C., preferably at about 110.degree. C., to give 
pyrrole-substituted Formula (I) compounds. 
Additionally, Formula (I) compounds wherein A is a methylene group may be 
prepared from formula (3) cyano compounds. The cyano group of the formula 
(3) benzazepines is reduced, for example, using lithium aluminum hydride, 
in an inert solvent, such as tetrahydrofuran, at a temperature of about 
20.degree. C. to about 75.degree. C., preferably at about 70.degree. C. 
The resulting methylamine compounds are then reacted with 2,5-hexane-dione 
or 2,5-dimethoxytetrahydrofuran, as described hereinbefore, to give, for 
example, Formula (I) compounds wherein A is --CH.sub.2 -- and Het is a 
pyrrole moeity. 
##STR6## 
Scheme III illustrates the preparation of additional Formula (I) compounds. 
According to Scheme III, formula (3) cyano compounds are converted to the 
corresponding aldehyde derivatives of formula (6), for example using 
Raney.RTM. nickel in a suitable solvent, such as formic acid, at a 
temperature of about 35.degree. C. to about 100.degree. C., preferably at 
about 100.degree. C. The formula (7) hydroxymethyl benzazepines are 
prepared from the formula (6) aldehyde compounds by reductive methods, for 
example, using sodium borohydride in a suitable solvent, such as methanol, 
at a temperature from about 0.degree. C. to about 35.degree. C., 
preferably from about 5.degree. C. to about 24.degree. C. Formula (8) 
benzazepines, which are Formula (I) compounds, are prepared from formula 
(7) benzazepines, using the methods described in Scheme I. 
Scheme III also shows the preparation of Formula (I) compounds wherein A is 
--(CH.sub.2).sub.3-5 --. According to Scheme III, formula (6) aldehyde 
compounds are reacted with a phosphorus ylide, such as 
triphenylphosphoranylideneacetaldehyde, in a suitable solvent, such as 
toluene, at a temperature of about 80.degree. C. to about 110.degree. C., 
preferably at 110.degree. C., or with an alkylphosphonic ester, such as 
triethyl phosphonoacetate, which is converted to a phosphonate carbanion 
in reaction with a suitable base, such as sodium hydride, in a suitable 
solvent, such as tetrahydrofuran, to give the corresponding alkenyl 
derivatives, for example --CH.dbd.CH--CH.dbd.CH--CHO or 
--CH.dbd.CHCO.sub.2 ethyl, respectively. The vinyl intermediates thus 
generated are reduced to the corresponding saturated analogs, for example 
by hydrogenation in the presence of a suitable catalyst, such as platinum 
oxide, in a suitable solvent, such as ethanol. The terminal ester or 
formyl groups are reduced to the corresponding alcohol derivatives using 
standard reagents, for example, an ester-reducing agent, such as lithium 
aluminum hydride, or a formyl-reducing agent, such as sodium borohydride. 
The alcohols are reacted with a halogenating agent, such as thionyl 
chloride, to give --(CH.sub.2).sub.3-5 halo benzazepines. Displacement of 
the halide by an alkali metal salt of a heteroaryl group, such as 
1H-1,2,4-triazole sodium salt, gives Formula (I) compounds wherein A is 
--(CH.sub.2).sub.3-5 --. 
The pharmaceutically acceptable, nontoxic, acid addition salts having the 
utility of the free bases of Formula (I), are formed with inorganic or 
organic acids, by methods well known in the art. Representative examples 
of suitable acids are maleic, fumaric, benzoic, ascorbic, pamoic, 
succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, 
acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, 
stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, 
benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, 
phosphoric and nitric acids. 
Because the compounds of Formula (I) are .alpha.-adrenoceptor antagonists 
they are useful in treating cardiovascular diseases in which changes in 
vascular resistance are desirable, including hypertension, pulmonary 
hypertension, congestive heart failure, myocardial ischemia, and angina 
pectoris. Formula (I) compounds also are useful in treating peripheral 
vascular disease, benign prostatic hypertrophy, diabetes, glaucoma, ocular 
hypertension, obesity, disorders of gastrointestinal motility, including 
colonic spasm, irritable bowel syndrome, and constipation, impotence, and 
central nervous system disorders such as depression and senile dementia. 
Additionally, the invented compounds are useful in treating diseases 
resulting from inappropriate platelet aggregation. 
The .alpha.-adrenoceptor activity of certain compounds of the present 
invention was determined using the following in vitro systems. 
Alpha.sub.1 adrenoceptor antagonist activity was determined using the 
rabbit aorta. Male New Zealand White rabbits (2-4 Kg) were euthanized by 
cervical concussion. A 4 cm portion of the thoracic aorta was removed and 
placed in a dish of cold (10.degree. C.) Krebs-Hensleit solution. The 
tissue was cleaned of fat and connective tissue and cut into segments of 
approximately 3 mm in length. These segments were suspended in 10 ml 
tissue baths via hangers constructed of 0.25 mm tungsten wire. One hanger 
was fixed to a support in the bath and the other was attached via silk 
thread to a force-displacement transducer. 
Tissue segments were equilibrated for 2 hours prior to drug testing, during 
which time basal tension was maintained at 2 gm. Tissues were washed at 30 
minute intervals during this equilibration period. The Krebs-Hensleit 
solution contained cocaine (6 mM) to block neuronal uptake and propranolol 
(1 mM) to block beta-adrenoceptors. Tissues were usually challenged once 
with norepinephrine (0.1 mM) during the equilibration period to check for 
viability. 
A cumulative concentration-response curve to norepinephrine was obtained in 
each aortic segment. Following washout of norepinephrine, the a 
adrenoceptor antagonist to be tested was added to the bath. After the 
tissue had been in contact with the antagonist for 30-60 minutes, the 
norepinephrine concentration response-curve was repeated in the presence 
of antagonist. The tissue was then washed again, and a tenfold higher 
concentration of antagonist added. Following equilibration (30-60 
minutes), a third norepinephrine concentration-response curve was 
determined in the presence of the antagonist. 
The receptor dissociation constant (K.sub..beta.) for the antagonist was 
determined using the relationship 
##EQU1## 
(Furchgott, R. F., Handbook of Experimental Pharmacology, eds. Eichler, et 
al., pp. 283-335 (Springer 1972)). The K.sub..beta. value obtained at 
each antagonist concentration was averaged to obtain a mean K.sub..beta. 
for each experiment. 
Alpha.sub.2 adrenoceptor antagonist activity of the compounds was 
determined using the isolated, superfused guinea pig left atrium. Briefly, 
the heart is removed from a pentobarbital-anesthetized male guinea pig. 
The left atrium is separated, dissected free of extraneous tissue and 
mounted in a 2 ml superfusion chamber. The tissue is paced at 30 
pulse/minute and the sympathetic nerves excited at 6 minute intervals by 
field stimulation. The response to nerve stimulation is measured as the 
difference in contractile force between the basal contraction and peak 
contraction following a nerve stimulation. A concentration-response curve 
for B-HT 920 (a known .alpha..sub.2 agonist) is prepared by administering 
increasing concentrations of B-HT 920 following each successive 
stimulation. The tissue then is superfused for thirty minutes with the 
.alpha.-adrenoceptor antagonist to be tested and the B-HT 920 
concentration-effect curve is repeated in the presence of antagonist. Data 
are reported as K.sub.B, defined above. Additional details of this test 
system are found in Hieble, J. P. and R. G. Pendleton, Arch. Pharmacol., 
309: 217-224 (1979). 
Alpha.sub.3 adrenoceptor antagonist receptor activity was determined using 
the dog saphenous vein (DSV) as the test system. This test system has been 
shown a suitable preparation in which to characterize postsynaptic 
.alpha..sub.2 (.alpha..sub.3) adrenoceptors, Sullivan, A. T. and G. M. 
Drew, Arch. Pharmacol., 314: 249-58 (1980). This test system is prepared 
by removing the lateral saphenous vein from an anesthetized dog and 
cutting the vein into segments of 4 mm in length. Segments are mounted as 
described for the isolated rabbit aorta. 
The .alpha..sub.3 adrenoceptor antagonist activity of the compounds of 
interest is determined by measuring shifts in the dose-response curve of a 
specific agonist induced by the tested compounds. The .alpha..sub.2, 
.alpha..sub.3 agonist, B-HT 920, was used in testing the compounds listed 
in Table I. 
Representative Formula (I) compounds which were tested using the above 
described in vitro test systems are listed in Table I. Each of the 
compounds tested was found to have antagonist activity at one or more of 
the .alpha.-adrenoceptor subtypes. 
TABLE I 
______________________________________ 
6-chloro-9-(4-chloro-1H-pyrazol-1-ylmethoxy)- 
2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine; 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-pyrazol- 
1-ylmethoxy)-1H-3-benzazepine; 
6-chloro-9-(2-furanylmethoxy)-2,3,4,5-tetrahydro-3- 
methyl-1H-3-benzazepine; 
6-chloro-9-(3-furanylmethoxy)-2,3,4,5-tetrahydro-3- 
methyl-1H-3-benzazepine; 
6-chloro-9-[3-(2-furanyl)-2-propenyloxy]-2,3,4,5- 
tetrahydro-3-methyl-1H-3-benzazepine; 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(2- 
thienylmethoxy)-1H-3-benzazepine; 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(3- 
thienylmethoxy)-1H-3-benzazepine; 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-[2-(1H- 
pyrazol-1-yl)ethoxy]-1H-3-benzazepine 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-1,2,4- 
triazol-1-ylmethoxy)-1H-3-benzazepine; 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(4- 
pyridinylmethoxy)-1H-3-benzazepine; 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-[2-(1H-1,2,4- 
triazol-1-yl)ethoxy]-1H-3-benzazepine; 
6-chloro-9-[(4-chloro-1H-pyrazol-1-ylmethoxy)- 
methyl]-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine; 
6-chloro-9-[(4-chloro-1H-pyrazol-1-ylmethoxy)- 
carbonyl]-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine; 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-pyrrol-1- 
yl)-1H-3-benzazepine; 
6-chloro-9-(2,5-dimethyl-1H-pyrrol-1-yl)-2,3,4,5- 
tetrahydro-3-methyl-1H-3-benzazepine; 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-pyrrol-1- 
ylmethyl)-1H-3-benzazepine; 
6-chloro-9-[3-(4-chloro-1H-pyrazol-1-yl)propyl]- 
2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine; and 
6-chloro-9-[5-(4-chloro-1H-pyrazol-1-yl)pentyl]- 
2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine; or a 
pharmaceutically acceptable salt thereof. 
______________________________________ 
The antihypertensive activity of certain compounds of the present invention 
was determined using the spontaneously hypertensive rat model. The details 
of this in vivo test are found in Roesler, J. M., et al., J. Pharmacol. 
Exp. Ther., 236: 1-7 (1986). 
Novel pharmaceutical compositions are obtained when the compounds are 
incorporated with pharmaceutical carriers into convenient dosage forms 
such as capsules, tablets, or injectable preparations. Solid or liquid 
pharmaceutical carriers can be employed. Solid carriers include, starch, 
lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, 
agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid 
carriers include syrup, peanut oil, olive oil, saline, and water. 
Similarly, the carrier or diluent may include any prolonged release 
material, such as glyceryl monostearate or glyceryl distearate, alone or 
with a wax. The amount of solid carrier varies widely but, preferably, 
will be from about 25 mg to about 1 g per dosage unit. When a liquid 
carrier is used, the preparation will be in the form of a syrup, elixir, 
emulsion, soft gelatin capsule, sterile injectable liquid, or an aqueous 
or nonaqueous liquid suspension or solution. 
The pharmaceutical preparations are made following conventional techniques 
of a pharmaceutical chemist involving mixing, granulating and compressing, 
when necessary, for tablet forms, or mixing,, filling, and dissolving the 
ingredients, as appropriate, to give the desired oral or parenteral 
products. 
Doses of the present compounds in pharmaceutical dosage units will be an 
efficacious, nontoxic quantity selected from the range of 0.01-100 mg/kg 
of active compound, preferably 0.1-50 mg/kg. The selected dose is 
administered to a human patient in need of treatment from 1-6 times daily, 
orally, rectally, topically, by inhalation, or injection, or continuously 
by infusion. Oral administration, however, is preferred because it is more 
convenient for the patient.

The following examples are illustrative of preparation of Formula (I) 
compounds. The examples are not intended to limit the scope of the 
invention as defined hereinabove and as claimed below. 
EXAMPLE 1 
6-Chloro-9-(4-chloro-1H-pyrazol-1-ylmethoxy)-2,3,4,5-tetrahydro-3-methyl-1H 
-3-benzazepine 
A solution of 9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-ol, 
(633 mg, 3 mmol, J. Med. Chem., 27, 918 (1984)) in dry dimethylformamide 
(10 ml) was treated with sodium hydride (50% dispersion in mineral oil, 
3.9 mmol), stirred for 10 minutes and treated with a solution of 
4-chloro-1-(chloromethyl)-1-pyrazole (485 mg, 3.1 mmol) in 
dimethylformamide (5 ml). The mixture was heated to 50.degree. C. for 30 
minutes, poured into ice water, basified with 10% sodium hydroxide and 
extracted with ethyl acetate. The organic phase was washed with brine, 
dried with magnesium sulfate and concentrated. The residue was treated 
with hydrogen chloride in ethanol-ethyl ether to give 275 mg (26%) of 
6-chloro-9-(4-chloro-1H-pyrazol-1-ylmethoxy)-2,3,4,5-tetrahydro-3-methyl-1 
H-3-benzazepine hydrochloride (acetone); mp 174.degree.-175.degree. C. 
EXAMPLE 2 
6-Chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-pyrazol-1-ylmethoxy)-1H-3-benzaz 
epine 
Using the general procedure of Example 1, replacing 
4-chloro-1-(chloromethyl)-1H-pyrazole with 1-(chloro-methyl)-1-pyrazole 
gave, after chromatography on silica gel eluted with a methanol-methylene 
chloride gradient, 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-pyrazol-1-ylmethoxy)-1H-3-benza 
zepine; mp 69.degree.-71.5.degree. C. 
EXAMPLES 3-10 
6-Chloro-9-(2-furanylmethoxy)-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine 
6-Chloro-9-(3-furanylmethoxy)-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine 
6-Chloro-9-[3-(2-furanyl)-2-propenyloxy]-2,3,4,5-tetrahydro-3-methyl-1H-3-b 
enzazepine 
6-Chloro-2,3,4,5-tetrahydro-3-methyl-9-(2-thienylmethoxy)-1H-3-benzazepine 
6-Chloro-2,3,4,5-tetrahydro-3-methyl-9-(3-thienylmethoxy)-1H-3-benzazepine 
6-Chloro-2,3,4,5-tetrahydro-3-methyl-9-[2-(1H-pyrazol-1-yl) 
ethoxy]-1H-3-benzazepine 
6-Chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-1,2,4-triazol-1-ylmethoxy)-1H-3- 
benzazepine 
6-Chloro-2,3,4,5-tetrahydro-3-methyl-9-(4-pyridinylmethoxy)-1H-3-benzazepin 
Using the general procedure of Example 2, replacing 
1-(chloromethyl)-1H-pyrazole with 2-(chloromethyl)furan, 3-(bromomethyl) 
furan, 2-(3-chloro-1-propenyl)furan, 2-(bromomethyl)thiophene, 
3-(bromomethyl)thiophene, 2-(1H-pyrazol-1-yl)ethyl 
4-methylbenzenesulfonate, 1-(chloro-methyl)-1H-1,2,4-triazole, and 
4-(chloromethyl)pyridine hydrochloride gave: 
6-chloro-9-(2-furanylmethoxy)-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine 
maleate; mp 168.degree.-173.5.degree. C., 
6-chloro-9-(3-furanylmethoxy)-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine 
maleate; mp 181.degree.-183.degree. C., 
6-chloro-9-[3-(2-furanyl)-2-propenyloxy]-2,3,4,5-tetrahydro-3-methyl-1H-3-b 
enzazepine maleate; mp 149.degree.-153.5.degree. C., 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(2-thienyl-methoxy)-1H-3-benzazepine 
maleate; 196.5.degree.-199.5.degree. C., 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(3-thienyl-methoxy)-1H-3-benzazepine 
maleate; mp 195.5.degree.-198.5.degree. C., 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-[2-(1H-pyrazol-1-yl)ethoxy]-1H-3-ben 
zazepine hydrochloride; mp 98.degree.-180.degree. C., 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-1,2,4-triazol-1-ylmethoxy)-1H-3- 
benzazepine hydrochloride; mp 82.degree.-92.5.degree. C., and 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(4-pyridinyl-methoxy)-1H-3-benzazepi 
ne dihydrochloride (ethanolethyl acetate); mp 222.degree. C. (dec). 
EXAMPLE 11 
6-Chloro-2,3,4,5-tetrahydro-3-methyl-9-[2-(1H-1,2,4-triazol-1-yl)ethoxy]-1H 
-3-benzazepine 
A 35% dispersion of potassium hydride in mineral oil (2.6 g, 23 mmol) in 
dimethylformamide (40 ml) was stirred and treated with 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-ol (4.0 g, 19 
mmol), stirred for 20 minutes, treated with ethyl bromoacetate (3.8 g, 23 
mmol) and stirred for 72 hours. The mixture was concentrated, partitioned 
between water and methylene chloride and the organic phase was washed, 
dried with magnesium sulfate and concentrated. The residue was 
chromatographed on silica gel eluted with methanol-methylene chloride 
(8:92) to give 4.3 g of ethyl 
[(9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-yl)oxy]acetate. 
Lithium aluminum hydride (1.53 g, 40 mmol) in ethyl ether (80 ml) was 
stirred, heated to reflux and treated with a solution of ethyl 
[(9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-yl)oxy]acetate 
(4.0 g, 13.5 mmol) in ethyl ether (60 ml). The mixture was stirred at 
reflux for 3.5 hours, cooled, and carefully treated with water (1.5 ml), 
10% sodium hydroxide (4.5 ml) and water (1.5 ml). The mixture was filtered 
and the filtrate dried with magnesium sulfate and concentrated to give 3,2 
g (91%) of 
[(9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-yl)oxy]ethanol. 
A solution of 
[(9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-yl)oxy]ethanol 
(0.375 g, 1.5 mmol) in pyridine (5 ml) was stirred at 5.degree. C., 
treated with 4-methylbenzenesulfonyl chloride (0.56 g, 3 mmol) and stored 
in a freezer for 16 hours. The mixture was poured into water and extracted 
with ethyl ether. The organic phase was washed and concentrated under high 
vacuum to give 0.5 g of 
[(9-chloro-2,3,4,5-tetrahydro-3-methyl-1-3-benzazepin-6-yl) oxy]ethanol 
4-methylbenzenesulfonate. 
Following the general procedure of Example 2, 
[(9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-yl) oxy]ethanol 
4-methylbenzenesulfonate was heated with one equivalent of 
1H-1,2,4-triazole sodium salt (prepared from 1H-1,2,4-triazole and sodium 
hydride in dimethylformamide) at 65.degree. C. for 30 minutes to give 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-[2-(1H-1,2,4-triazol-1-yl)ethoxy]-1 
H-3-benzazepine hydrochloride; mp 204.degree.-211.degree. C. 
EXAMPLE 12 
6-Chloro-9-[(4-chloro-1H-pyrazol-1-ylmethoxy)methyl]-2,3,4,5-tetrahydro-3-m 
ethyl-1H-3-benzazepine 
A solution of 9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-amine, 
(10 g, 47.5 mmol) in acetic acid (34 ml) and water (20 ml) was stirred, 
treated with sulfuric acid (7.5 ml), cooled to 5.degree. C. and treated 
with a solution of sodium nitrite (3.65 g, 53 mmol) in water (7.5 ml) 
added below the surface over 20 minutes. The mixture was added dropwise 
under the surface of a stirred mixture prepared from cupric sulfate 
pentahydrate (14.2 g, 57 mmol) in water (35 ml), potassium cyanide (15.4 
g, 240 mmol), ice (24 g), sodium bicarbonate (31.8 g, 380 mmol) in water 
(36 ml) and toluene (35 ml) at 50.degree.-55.degree. C. The mixture was 
stirred for 15 minutes at 50.degree. C. and for 1 hour at 25.degree. C., 
treated with a solution of sodium bicarbonate (70 g) in water (700 ml) to 
pH 8 and then with 10% sodium hydroxide (300 ml). The mixture was 
extracted with ethyl acetate and the organic phase was washed with aqueous 
sodium hydroxide and brine, dried with magnesium sulfate and concentrated. 
The residual oil was treated with ethereal hydrogen chloride to give 8.3 g 
(68%) of 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-carbonitrile; mp 
288.degree.-290.degree. C. 
A solution of 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-carbonitrile (3.1 
g, 14 mmol) in 90% formic acid (40 ml) was treated with Raney.RTM. nickel 
(3.1 g), stirred and heated to reflux for 3 hours. Additional Raney.RTM. 
nickel (17 g) and 90% formic acid (85 ml) were added over the next 12 
hours and the mixture was stirred for an additional 3 hours. The mixture 
was cooled, filtered and the filter cake washed with 45% formic acid. The 
filtrate was concentrated, basified with 10% sodium hydroxide, extracted 
with ethyl acetate and the organic phase was washed, dried and 
concentrated to give 3 g of 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-carboxaldehyde. 
A solution of 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-carboxaldehyde 
(3.07 g, 13.8 mmol) in methanol (35 ml) was cooled to 5.degree. C. and 
treated with sodium borohydride (3.07 g, 81 mmol). The mixture was stirred 
for 15 minutes at 5.degree. C. and for 45 minutes at 25.degree. C. The 
mixture was cooled and carefully treated with dilute hydrochloric acid. 
The mixture was diluted with brine, basified with 10% sodium hydroxide and 
extracted with ethyl acetate. The organic phase was dried, concentrated 
and the residue chromatographed on silica gel eluted with a gradient of 
methanol-methylene chloride (5:95-9:91) to give 1.45 g (47%) of 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-methanol; mp 
136.5.degree.-140.degree. C. 
Using the general procedure of Example 1, replacing 
9-chloro-2,3,4,5-tetrahydro-1H-3-benzazepin-6-ol with 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-methanol gave, 
after chromatography on silica gel eluted with methanol-methylene chloride 
(4:96), 0.3 g (40%) of 
6-chloro-9-[(4-chloro-1H-pyrazol-1-ylmethoxy)methyl]-2,3,4,5-tetrahydro-3- 
methyl-1H-3-benzazepine hydrochloride; mp 168.degree.-171.degree. C. 
EXAMPLE 13 
6-Chloro-9-[(4-chloro-1H-pyrazol-1-ylmethoxy)carbonyl]-2,3,4,5-tetrahydro-3 
-methyl-1H-3-benzazepine 
A solution of 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-carbonitrile, 
prepared as in Example 12, (1.5 g, 6.8 mmol) in ethanol (25 ml) was 
treated with barium hydroxide octahydrate (2.6 g, 8.1 mmol) and water (25 
ml) and heated to reflux for 94 hours. The mixture was cooled, diluted 
with water, ethanol and methanol, saturated with carbon dioxide and 
filtered. The filtrate was treated with Dry Ice to pH 5-6 and filtered. 
The filtrate was concentrated and extracted with ethyl acetate-ethyl ether 
and ethyl ether. The aqueous phase was treated with toluene, concentrated 
and the residue triturated with ethyl ether to give 
9-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine-6-carboxylic acid. 
Using the general procedure of Example 1, replacing 
9-chloro-2,3,4,5-tetrahydro-1H-3-benzazepin-6-ol with 
9-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine-6-carboxylic acid gave, after 
chromatography on silica gel eluted with methanol-methylene chloride 
(3:97), 94 mg (10%) of 
6-chloro-9-[(4-chloro-1H-pyrazol-1-ylmethoxy)carbonyl]-2,3,4,5-tetrahydro- 
3-methyl-1H-3-benzazepine maleate; mp 144.degree.-149.degree. C. 
EXAMPLE 14 
6-Chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-pyrrol-1-yl)-1H-3-benzazepine 
A solution of 9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-amine 
(633 mg, 3 mmol) in acetic acid (6 ml) was treated with 
2,5-dimethoxytetrahydrofuran (396 mg, 3 mmol) and stirred at 110.degree. 
C. for 1.5 hours. The mixture was poured into ice, basified with 10% 
sodium hydroxide and extracted with ethyl acetate. The organic phase was 
dried, concentrated and treated with hydrogen chloride to give 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-pyrrol-1-yl)-1H-3-benzazepine 
hydrochloride (methanol-acetonitrile); mp 262.degree.-264.degree. C. 
EXAMPLE 15 
6-Chloro-9-(2,5-dimethyl-1-pyrrol-1-2,3,4,5-tetrahydro-3-methyl-1H-3-benzaz 
epine 
Using the general procedure of Example 40, 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-amine (420 mg, 2.7 
mmol) in acetic acid (6 ml) and toluene (6 ml) was treated with 
2,5-hexanedione (300 mg, 2.7 mmol) and heated to reflux for 1 hour to give 
6-chloro-9-(2,5-dimethyl-1H-pyrrol-1-yl)-2,3,4,5-tetrahydro-3-methyl-1-3-b 
enzazepine (acetonitrile); mp 268.degree.-270.degree. C. 
EXAMPLE 16 
6-Chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-pyrrol-1-ylmethyl)-1H-3-benzazep 
ine 
A suspension of lithium aluminum hydride (1.14 g, 30 mmol) in 
tetrahydrofuran (20 ml) was stirred and treated with a solution of 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-carbonitrile, 
prepared as in Example 12, (1.5 g, 6.8 mmol) in tetrahydrofuran (20 ml) 
and heated to reflux for 3 hours. The mixture was cooled and treated with 
water (1.14 ml), 10% sodium hydroxide (1.14 ml) and water (1.14 ml), 
diluted with tetrahydrofuran (100 ml), stirred for 1 hour, filtered and 
concentrated to give 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1-3-benzazepine-6-methanamine. 
A solution of 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-methanamine (0.75 
g, 3.4 mmol) in acetic acid (6.5 ml) was treated with 
2,5-dimethoxy-tetrahydrofuran (0.44 ml, 3.4 mmol) and heated to 
115.degree. C. for 1 hour. The mixture was quenched with ice water, 
basified with 20% sodium hydroxide and extracted with ethyl acetate. The 
organic phase was washed, dried and concentrated. The residue was 
triturated with ethyl ether and the residue chromatographed on silica gel 
eluted with methanol-methylene chloride (3:97) to give 
6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-pyrrol-1-ylmethyl)-1H-3-benzaze 
pine hydrochloride; mp 219.degree.-223.degree. C. 
EXAMPLE 17 
6-Chloro-9-[3-(4-chloro-1H-pyrazol-1-yl)propyl]-2,3,4,5-tetrahydro-3-methyl 
-1H-3-benzazepine 
A solution of triethyl phosphonoacetate (1.9 g, 8.6 mmol) in 
tetrahydrofuran (200 ml) was stirred and treated with a 50% dispersion of 
sodium hydride in mineral oil (0.45 g, 9.4 mmol), stirred for 15 minutes 
and treated with a solution of 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-carboxaldehyde, 
prepared as in Example 12, (2.2 g, 9.0 mmol) in tetrahydrofuran (270 ml). 
The mixture was stirred for 16 hours, concentrated, dissolved in ethyl 
ether and washed with water and brine. The organic phase was dried with 
magnesium sulfate and concentrated to give 2.6 g of ethyl 
(E)-3-(9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-yl)-2-propen 
oate. 
A solution of ethyl 
(E)-3-(9-chloro-2,3,4,5-tetrahydro-3-methyl-1-3-benzazepin-6-yl)-2-propeno 
ate (2.6 g, 8.9 mmol) in ethanol (150 ml) was treated with concentrated 
hydrochloric acid (18 drops) and platinum oxide (0.11 g) and shaken under 
hydrogen (40 psi) for 2 hours, filtered and concentrated. The residue was 
partitioned between cooled ethyl acetate-ethyl ether (3:1) (300 ml) and 5% 
sodium bicarbonate. The organic phase was washed with water and brine, 
dried with magnesium sulfate and concentrated to give 2.5 g (96%) of ethyl 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-propenoate. 
A suspension of lithium aluminum hydride (0.55 g, 14.6 mmol) in 
tetrahydrofuran (20 ml) was stirred, heated to reflux and treated with a 
solution of ethyl 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-propenoate (2.1 g, 
7 mmol) in tetrahydrofuran (25 ml). The mixture was stirred at reflux for 
3 hours, cooled and carefully treated with water (1.65 ml) and 10% sodium 
hydroxide (0.55 ml). The mixture was stirred at 25.degree. C., filtered 
and the filtrate was concentrated. The residue was dissolved in ethyl 
acetate-ethyl ether (4:1) (160 ml) and washed with water, 5% sodium 
hydroxide and water, filtered, dried with magnesium sulfate and 
concentrated. The residue was partitioned between ethyl acetate-ethyl 
ether (2:1) and 3N hydrochloric acid. The aqueous phase was washed with 
ethyl ether, basified with aqueous sodium hydroxide and extracted with 
ethyl acetate-ethyl ether (2:1). The organic phase was washed with water 
and brine, dried with magnesium sulfate and concentrated. The residue was 
dissolved in ethyl ether and treated with ethereal hydrogen chloride to 
give 9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-propanol 
hydrochloride; mp 218.5.degree.-223.5.degree. C. 
A solution of 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-propanol (0.8 g, 3 
mmol) in methylene chloride (30 ml) was stirred at 5.degree. C. and 
treated with thionyl chloride (40 ml). The mixture was stirred for 10 
minutes at 5.degree. C., 15 minutes at 25.degree. C., 3 hours at 
55.degree. C. and 16 hours at 25.degree. C. The mixture was concentrated 
to give 0.96 g of 
6-chloro-9-(3-chloropropyl)-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine 
hydrochloride. 
Using the general procedure of Example 11, replacing 
[(9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-yl)oxy]ethanol 
4-methylbenzenesulfonate with 
6-chloro-9-(3-chloropropyl)-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine 
and 1H-1,2,4-triazole sodium salt with 4-chloro-1H-pyrazole gave 0.33 g 
(60%) of 
6-chloro-9-[3-(4-chloro-1H-pyrazol-1-yl)propyl]-2,3,4,5-tetrahydro-3-methy 
l-1H-3-benzazepine hydrochloride; mp 142.5.degree.-145.degree. C. 
EXAMPLE 18 
6-Chloro-9-[5-(4-chloro-1H-pyrazol-1-yl)pentyl]-2,3,4,5-tetrahydro-3-methyl 
-1H-3-benzazepine 
A solution of 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-carboxaldehyde, 
prepared as in Example 12, (2.2 g, 10 mmol) in toluene (15 ml) was treated 
with triphenylphosphoranylideneacetaldehyde (4.4 g, 14 mmol) and stirred 
at 100.degree. C. for 24 hours. The mixture was concentrated and the 
residue was triturated with ethyl ether-petroleum ether (4:1) and the 
supernatant concentrated to give 3 g of 
5-(9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-yl)-2,4-pentadie 
nal. 
A solution of 
5-(9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-yl)-2,4-pentadie 
nal (3 g) in ethanol (100 ml) and platinum oxide was shaken under hydrogen 
(50 psi) for 2 hours, filtered, concentrated and the residue 
chromatographed on silica gel eluted with a gradient of methanol-methylene 
chloride (3:97.degree.-7:93) to give 0.5 g of 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-pentanal. 
Using the general procedure of Example 12, replacing 
9-chloro-3-methyl-2,3,4,5-tetrahydro-1-3-benzazepine-6-carboxaldehyde with 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-pentanol gave 0.33 
g (64%) of 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-pentanol. 
Using the general procedure of Example 43, replacing 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-propanol with 
9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-pentanol gave 
6-chloro-9-(5-chloropentyl)-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine 
hydrochloride. 
Using the general procedure of Example 43, replacing 
6-chloro-9-(3-chloropropyl)-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine 
with 
6-chloro-9-(5-chloropentyl)-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine 
gave 52 mg (13%) of 
6-chloro-9-[5-(4-chloro-1H-pyrazol-1-yl)pentyl]-2,3,4,5-tetrahydro-3-methy 
l-1H-3-benzazepine hydrochloride; mp 158.degree.-161.degree. C. 
EXAMPLE 19 
An oral dosage form for administering the presently invented compounds is 
produced by screening, mixing, and filling into a hard gelatin capsule 
ingredients in the proportions shown in Table II, below. 
TABLE II 
______________________________________ 
Ingredients Amounts 
______________________________________ 
6-chloro-9-(3-furanylmethoxy)- 
50 mg 
2,3,4,5-tetrahydro-3-methyl-1H-3- 
benzazepine 
magnesium stearate 5 mg 
lactose 75 mg 
______________________________________ 
EXAMPLE 20 
The sucrose, calcium sulfate dihydrate and Formula (I) compound shown in 
Table III below, are mixed and granulated with a 10% gelatin solution. The 
wet granules are screened, dried, mixed with the starch, talc and stearic 
acid, screened and compressed into a tablet. 
TABLE III 
______________________________________ 
Ingredients Amounts 
______________________________________ 
6-chloro-2,3,4,5,-tetrahydro-3- 
100 mg 
methyl-9-(1H-pyrazol-1-ylmethoxy)- 
1H-3-benzazepine 
calcium sulfate dehydrate 
150 mg 
sucrose 20 mg 
starch 10 mg 
talc 5 mg 
stearic acid 3 mg 
______________________________________ 
EXAMPLE 21 
6-Chloro-9-(3-furanylmethoxy)2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine 
75 mg, is dispersed in 25 ml of normal saline to prepare an 
injectable-preparation. 
While the preferred embodiments of the invention are illustrated by the 
above, the invention is not limited to the precise instructions herein 
disclosed and that the right to all modifications coming within the scope 
of the following claims is reserved.