4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine compounds for treating cardiovascular disorders

Novel 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine compounds are disclosed. The compounds have the property of inhibiting calcium induced contraction of the smooth muscle.

DESCRIPTION OF THE INVENTION 
The present invention is directed to novel compounds of the formula: 
##STR1## 
wherein the bond designation between the 10 and 11 positions indicates 
that the bond may be a saturated single bond or an unsaturated double 
bond, 
X is hydrogen, halogen, trifluoromethyl or lower alkoxy, 
R is selected from the group consisting of: 
(a) a substituted aralkyl group represented by the formula 
##STR2## 
wherein A is di(lower alkyl)amino or lower alkoxy; (b) an aralkenyl group 
represented by the formula: 
##STR3## 
wherein D is lower alkoxy; (c) a nitrogen containing alkyl group 
represented by the formula 
EQU --CH.sub.2 CH.sub.2 Y 
wherein Y is --CN, 
##STR4## 
or --CH.sub.2 NH.sub.2 ; (d) an acyl group represented by the formula: 
##STR5## 
wherein R' is lower alkyl, substituted lower alkyl, phenyl or substituted 
phenyl, styryl or substituted styryl; 
(e) an imido group represented by the formula: 
##STR6## 
(f) a formyl group represented by the formula: 
##STR7## 
wherein Z is oxygen or sulfur; (g) an alkylsulfonyl group represented by 
the formula: 
EQU --SO.sub.2 R" 
wherein R" is lower alkyl; 
(h) a heteroaryl group represented by the formula 
##STR8## 
wherein the dotted lines represent a residue of a heteroaromatic ring; 
and acid addition salts thereof. 
The expression "lower alkyl" and "lower alkoxy" hereinbefore employed is 
meant to refer to radicals having 1 to 6 carbon atoms, inclusive. The 
expression "substituted lower alkyl" is meant those lower alkyl groups 
which are substituted with halogen or .omega.-carboxy. The expression 
"substituted phenyl" is meant phenyl groups which are substituted with 
halogen and lower alkyl. By "halogen" is meant any of the halogens, i.e. 
fluorine, chlorine, bromine or iodine. By "heteroaryl" is meant a 
ring-nitrogen bearing aromatic group which includes condensed rings and 
which may be substituted such as with halogen. 
A preferred embodiment of the present invention is that in which the 
linkage between C.sub.10 and C.sub.11 is unsaturated so that the group is 
--CH.dbd.CH-- and when X is not hydrogen, it is in the 3-position as 
represented by the following formula: 
##STR9## 
The acid addition salts are those of non-toxic, pharmaceutically acceptable 
acids and include salts of inorganic acids such as hydrochloric, 
hydrobromic, hydroiodic, phosphoric, sulfuric, nitric and the like, and 
organic acids such as acetic, propionic, glycolic, pamoic, pyruvic, 
malonic, succinic, maleic, fumaric, malic, tartaric, citric, mandelic, 
benzoic, cinnamic, methanesulfonic, ethanesulfonic, salicylic, 
p-toluenesulfonic, cyclohexanesulfamic, and the like and include acids 
related to the pharmaceutically acceptable salts listed in Journal of 
Pharmaceutical Sciences, 66, 2 (1977) and incorporated herein by 
reference. 
In view of the non-planar configuration of the compounds of the present 
invention and in view of the presence of a chiral center when X is other 
than hydrogen, the compounds exist in several isomeric forms. 
The compounds useful in the compositions and methods of the present 
invention include the various isomeric forms including mixtures of isomers 
in various proportions and when the compound is named without designation 
as to a specific isomer or to a racemic mixture or to a specific mixture 
of isomers, it is intended to be a generic designation embracing all 
isomers and mixtures of isomers. 
Regarding the isomeric forms, it has been found that when X is hydrogen, 
and R is other than hydrogen, although there is no chiral center, the 
compound may be obtained in two isomeric forms as a result of restricted 
conformational mobility. Although conformational isomers are possible when 
R is hydrogen, it appears that one form is too unstable to be isolated 
using the present synthetic method. The two isomers may be represented by 
the following formulas: 
##STR10## 
(A) may be referred to as the equatorial form, then (B) may be designated 
the axial form. Whether the isomer is to be characterized as equatorial or 
axial depends on the choice of the reference group at the 5-position. In 
the present application, the hydrogen (proton) attached to the 5-position 
is selected as the reference group. When the hydrogen is in equatorial 
relationship to the four carbons of the dibenzocycloheptene ring system 
which are common to the cycloheptene and benzene rings, the isomer has 
been designated as the equatorial isomer. These isomers are obtained by 
employing different methods of synthesis as hereinafter described. It has 
been found further at (B) may be converted to (A) by heating but that the 
reverse conversion does not occur by the application of heat. 
When X is other than hydrogen, not only are there two isomeric forms as a 
result of restricted conformational mobility 
##STR11## 
but there are also enantiomers possible for each of the isomeric forms 
##STR12## 
Thus, (C) and (C') are mirror images and (D) and (D') are mirror images. 
The absolute configuration and conformation may be determined by X-ray 
diffraction methods. In addition to the foregoing isomers the occurrence 
of which are common to all the compounds, the compounds in which R is an 
aralkenyl group, can be as cis or trans isomers. The preferred 
configuration is the trans isomer. All the possible isomers and their 
preparation constitutes an aspect of the present invention. Hereinafter, 
when reference is made generically to the conformational isomers of 
Formula I, I.sub.eq is employed to refer to the equatorial isomer and 
I.sub.ax to refer to the axial isomer. 
The products of the present invention which are free bases are solids, 
soluble in most organic solvents and in acidic media. The products which 
are acid addition salts are crystalline solids. 
The compounds of the present invention have useful pharmacological 
properties rendering them useful for therapeutic applications in 
pharmaceutical compositions. The compounds have shown properties which 
would render them useful as calcium entry blockers thereby adaptable for 
application in the chemotherapeutic treament of cardiovascular disorders 
caused by high cellular concentration of Ca.sup.++. The compositions and 
methods constitute an aspect of the present invention. 
The compounds of Formula I may be prepared by reacting a 
4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine compound (II) of the 
formula: 
##STR13## 
with an R group introducing compound (III) by various methods depending on 
the nature of the substituent to be placed on the piperidine nitrogen. 
The reactant 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine compounds of 
Formula II are solids which may be prepared from the appropriate 
5H-dibenzo[a,d]-cyclohepten-5-one by reducing the ketone to the 
corresponding alcohol i.e. the hydroxy compound, then treating the hydroxy 
compound with thionyl chloride to produce a 5-chloro compound which then 
is reacted with a Grignard reagent of 1-methyl-4-chloropiperidine to 
produce the N-methyl compound which is demethylated with cyanogen bromide 
followed by acid hydrolysis to produce the desired starting material (II) 
according to the scheme below and as subsequently more fully described. 
##STR14## 
Reactant 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine compound of Formula 
II prepared in this manner is in the form of the more stable equatorial 
isomer and therefore are the ultimate compounds of the present invention. 
Preparation of the axial isomers are subsequently described. 
When the compounds of Formula I are those in which R is an aralkyl group 
and which may be represented by Formula Ia 
##STR15## 
they may be prepared by reductive alkylation or conventional alkylation. 
If the compounds are prepared by reductive alkylation, the piperidine 
compound (II) is reacted with an aldehyde reactant (IIIa) 
##STR16## 
in the presence of a reductant. The reaction may be carried out by 
intimately mixing piperidine compound (II), aldehyde reactant (IIIa), 
reductant and solvent. Suitable reductants include sodium 
cyanoborohydride, aluminum/mercuric chloride, and the like. Suitable 
solvents include methanol, ethanol, isopropanol and the like. The exact 
proportions of II and IIIa is not critical. Good results have been 
obtained employing substantially equimolar amounts of piperidine compound 
and aldehyde reactant. The reductant is employed in excess, from three to 
ten-fold molar excess. If the reductant is sodium cyanoborohydride, the 
amount is closer to threefold; if aluminum/mercuric chloride it is about 
ten-fold molar excess of aluminum with 0.05 percent mercuric chloride. 
Generally, stirring is carried out at ambient temperatures for from 
several hours to overnight. After completion of the reaction, the product 
is recovered from the reaction mixture by conventional procedures. If 
aluminum/mercuric chloride or other insoluble reductant is employed, the 
unreacted excess and salts are first filtered off, the reaction mixture of 
filtrate then is diluted with a water-immiscible solvent, washed with 
water and appropriate aqueous solutions such as aqueous bisulfite, aqueous 
base and brine, then dried, the organic solvent vaporized and the product 
recovered as residue. Further purification may be employed such as washing 
with solvent, recrystallization, treatment with adsorbent such as silica 
gel or charcoal, column-chromatography, Still or flash chromatography (J. 
Org. Chem. 43, 2923 (1978)) and the like. 
Alternatively, the compounds represented by Formula Ia may be prepared by 
conventional alkylation procedure wherein the piperidine compound (II) is 
reacted with an alkyl halide (IIIa') 
##STR17## 
in the presence of a base in a solvent medium. The hydrogen halide 
acceptor base may be a tertiary amine such as triethylamine, diisopropyl 
ethylamine, trimethylamine, pyridine, collidine and the like or may be an 
inorganic base. Suitable solvents include polar solvents such as ethanol, 
isopropanol, n-butanol and the like, or aqueous mixtures if an inorganic 
base is employed. Generally an excess of the alkyl halide is employed, and 
the reactants and the base are mixed together in the solvent and refluxed 
for time sufficient to complete the reaction with the formation of the 
desired cycloheptenylpiperidine compounds of Formula Ia. 
Compounds of the present invention in which R is an aralkenyl group and 
which may be represented by Formula Ib 
##STR18## 
may be prepared by employing an acylated piperidine compound Id in which 
R' is styryl or substituted styryl as subsequently described or by first 
reacting the piperidine compound II with an aralkenoyl halide (IIIbi) to 
produce an acylated piperidine compound (Ibi) which is then subjected to 
the action of a reducing agent as seen in the following reaction sequence: 
##STR19## 
The reaction may be carried out by adding the aralkenoyl halide to a 
stirred mixture of piperidine compound II, a tertiary-organic base and 
4-dimethylaminopyridine catalyst, and continuing the mixing for from about 
0.5 to several hours at room temperature to obtain an aralkenoyl 
piperidine compound in the reaction mixture. For the reaction, the 
piperidine compound II and aralkenoyl halide are employed in substantially 
equimolar proportions. The reaction is carried out in the presence of two- 
to fourfold molar excess of a tertiary amine to bind the hydrogen halide 
by-product which is formed. Suitable amines include triethylamine, 
trimethylamine, diisopropylethylamine, tripropylamine, pyridine, collidine 
and the like. There is also added to the reaction mixture 
4-dimethylaminopyridine as catalyst. A solvent is employed in the 
reaction. Suitable solvents include methylene chloride, chloroform, carbon 
tetrachloride and the like. The aralkenoyl piperidine intermediate (Ibi) 
may be recovered from the reaction mixture by diluting the mixture with an 
inert solvent such as ether, washing the ethereal solution with 
appropriate aqueous reagents such as dilute hydrochloric acid, bicarbonate 
and brine, drying, and then vaporizing the solvent. 
The intermediate aralkenoyl piperidine compound (Ibi) then is reacted with 
a reducing agent to obtain the desired product Ib. Lithium aluminum 
hydride is a convenient and suitable reagent although other reducing 
agents may be employed. When employing lithium aluminum hydride, the 
reaction is carried out in a solvent in an inert atmosphere. Suitable 
solvents are ethereal solvents, preferably tetrahydrofuran but also 
diethyl ether, diisopropyl ether, and the like. Argon or nitrogen 
atmosphere is provided. Generally from about 1.5 to 2.5 molar excess of 
the lithium aluminum hydride is employed. Lithium aluminum hydride in 
solid form may be added in small portions to a solution of the 
aralkenoylpiperidine intermediate in ethereal solution. Alternatively, a 
solution of the aralkenoylpiperidine may be contacted with a solution of 
the reducing agent. The addition is carried out at ambient temperature. 
After completion of the addition, the resulting mixture is stirred for 
time sufficient to complete the reaction. The entire operation may be 
carried out at ambient temperature or may be heated to the reflux 
temperature of the solution to complete the reaction. Usually the stirring 
is carried out for from several hours to conveniently overnight. After 
completion of the reaction. The mixture may be diluted with solvent and 
the reaction quenched employing the "n, n, 3n" method, and the product 
recovering employing conventional procedures. The product may be purified 
by conventional methods as previously described. 
The "n, n, 3n" method for quenching the reaction is described on page 584 
of Fieser and Fieser, "Reagent for Organic Synthesis" John Wiley and Sons, 
Inc., New York, 1967. Briefly, it entails treating the stirred reduction 
mixture from n grams of lithium aluminum hydride by successive dropwise 
addition of n milliliters of water n milliliters of 15 percent sodium 
hydroxide and 3n milliliters of water producing a granular precipitate 
which can be readily filtered and washed. 
The compounds of the present invention in which R is Y--CH.sub.2 --CH.sub.2 
-- and which may be represented by the formula: 
##STR20## 
are preferably prepared by specific methods wherein one may be an 
intermediate in the preparation of the other. 
Those compounds in which Y is CN and represented by the formula 
##STR21## 
may be prepared by reacting the piperidine compound II with acrylonitrile. 
The reaction is conveniently carried out by intimately mixing piperidine 
compound II, acrylonitrile and solvent for time sufficient to complete the 
reaction with the formation of the nitrile compound (Ic'). Suitable 
solvents for the reaction include benzene, toluene, xylenes, and the like. 
The acrylonitrile reactant is employed in excess, suitably about a 
two-fold molar excess. The reaction is preferably carried out at elevated 
temperatures, conveniently at the reflux temperature of the solution. The 
reaction is usually substantially complete in several hours, the actual 
time can be determined readily by thin layer chromatographic (TLC) 
analysis of the reaction mixture to determine extent of consumption of the 
starting material. After completion of the reaction, the product is 
recovered as residue by vaporizing the solvent and unreacted 
acrylonitrile. The residue then may be purified by conventional 
procedures. 
Those compounds in which Y is 
##STR22## 
and represented by the formula 
##STR23## 
may be prepared by a controlled hydrolysis of the nitrile (Ic') but is 
best prepared by an addition reaction between the piperidine compound II 
and acrylamide (IIIc"). The reaction is conveniently carried out by 
intimately mixing piperidine compound II, acrylamide and tertiary amine 
catalyst in a solvent for time sufficient to complete the reaction with 
the formation of the amide compound (Ic"). 
The conditions for carrying out the reaction are similar to that employed 
in the addition of acrylonitrile. Thus, molar excess of the acrylamide is 
employed and the reaction is carried out in an inert environment protected 
from atmospheric moisture at moderately elevated temperatures, preferably 
reflux temperature of the solution. Suitable solvents for the reaction 
include isopropanol, n-propanol, ethanol and the like. Suitable catalysts 
are tertiary amines such as triethylamine, dimethylethylamine, 
trimethylamine, pyridine, collidine, 4-dimethylaminopyridine, and the 
like. 
The reaction is usually substantially complete in several hours, the actual 
time being readily determinable by TLC analysis of the reaction mixture. 
After completion of the reaction, the unreacted acrylamide and solvent are 
vaporized, the amide compound (Ic") recovered as residue and thereafter 
purified by conventional procedures. 
Those compounds in which Y is --(CH.sub.2).sub.3 NH.sub.2 and represented 
by the formula (Ic'") 
##STR24## 
may be prepared by reduction of an amide (Ic") in which Y is 
##STR25## 
The reduction may be carried out by contacting the amide and the reducing 
agent in solution in an inert atmosphere at ambient temperature and the 
resulting mixture stirred for time sufficient to complete the reduction. 
Various reducing agents may be employed. Lithium aluminum hydride is a 
preferred agent. When it is the reducing agent employed, the conditions 
for carrying out the reaction are similar to that previously described for 
reduction of an amide during the preparation of compounds in which R is an 
aralkenyl group. Thus, with lithium aluminum hydride, the reaction may be 
carried out by adding the lithium aluminum hydride portionwise as solid or 
in solution, in an inert atmosphere to the amide compound in an ethereal 
solvent and intimately contacting the components at ambient or reflux 
temperature of the solution for time sufficient to complete the reaction. 
The product then may be recovered in a conventional manner after quenching 
the reaction as previously described. 
The compounds of the present invention in which R is an acyl group and 
which may be represented by Formula Id 
##STR26## 
may be prepared by the reaction of the piperidine compound II with an acyl 
chloride or anhydride (IIId) in the presence of a catalyst and an acid 
binding agent to bind the by-product hydrogen halide or other acid formed 
in the reaction. From equimolar to about two-fold molar excess of acid 
chloride is employed. Suitable catalysts include 4-dimethylaminopyridine 
and the like. Suitable acid binding agents are preferably tertiary amines 
such as those described previously in connection with alkylation. At least 
a two-fold molar excess of the tertiary amine is employed; a four- to 
fivefold molar excess may be employed. The reaction is carried out in a 
solution under anhydrous conditions. Suitable solvents for reaction medium 
include methylene chloride, carbon tetrachloride and the like. 
In carrying out the reaction, the components are mixed in an inert 
atmosphere protected from atmospheric moisture. Depending on the activity 
of the acid chloride or anhydride, it may be desirable to add the acid 
chloride portionwise to the reaction mixture. The reaction is usually 
rapid and is complete in from about one-half hour to several hours. The 
time for completion of the reaction may be determined by TLC analysis of 
the reaction mixture. 
After completion of the reaction, the mixture is admixed with ice and 
stirred with warming to ambient temperature to decompose unreacted 
starting acid halide or anhydride. The organic solution is separated from 
the aqueous solution, washed successively with aqueous hydrochloric acid, 
bicarbonate, and brine, then dried and the N-acyl piperidine product (Id) 
then is recovered by conventional procedures. Thereafter, the product may 
be purified using any one or a combination of conventional procedures. 
The compounds of the present invention in which R is a 
##STR27## 
group and which is represented by the formula 
##STR28## 
may be prepared by intimately mixing the piperidine reactant (II) 
preferably as the hydrohalide salt with cyanamide. 
The hydrohalide salt of the piperidine compound II may be prepared as first 
step employing conventional procedures. In the reaction of the salt with 
cyanamide, the cyanamide is employed in excess, from about 1.5 to 2.5 
molar excess. The reaction is carried out in the presence of a solvent at 
temperatures above about 90.degree. C. for from 8 to 12 days. Suitable 
solvents include alcohol solvents such as n-butanol, n-propanol, 
isopropanol and the like. 
In carrying out the reaction, the piperidine compound II hydrohalide, 
cyanamide and solvent are heated together at reflux temperature for time 
sufficient to complete the reaction with the formation of Compound Ie in 
the reaction mixture usually as a solid. The solid may be recovered by 
conventional procedures and crystallized or recrystallized from suitable 
solvents, generally lower alkanols. 
The compounds of the present invention which may be represented by the 
formula 
##STR29## 
may be prepared by reacting a piperidine compound II with a 
dimethylformamide compound (IIIf). When Z is oxygen (If'), the reactant 
dimethylformamide compound would be dimethylformamide itself (IIIf'). When 
Z is sulfur (If"), the reactant is dimethylthioformamide (IIIf"). An 
excess of the dimethylformamide compound is employed. When the reactant is 
dimethyl thioformamide, generally from about 1.5 to 2.5 molar excess is 
employed in a solvent as reaction medium. Suitable solvents include 
toluene, the xylenes, benzene and the like. When dimethylformamide is the 
reactant, a large excess of dimethylformamide is employed with the 
dimethylformamide itself serving as a solvent. 
In carrying out the reaction, the components are stirred together 
conveniently at the reflux temperature of the solution for time sufficient 
to complete the reaction with the formation of the Compound If. The actual 
time for substantial completion of the formation of the Compound If may be 
determined by TLC analysis. At the temperatures employed, for the thioacyl 
compound, it has been found that the reaction may require several days. 
After completion of the reaction, the product may be recovered as residue 
by diluting with solvent, washing with water, drying and vaporizing the 
solvent. The product residue may be purified by conventional procedures. 
It has been found that at the reflux temperature of dimethylformamide, the 
N-formyl compound may be produced even when N-arylation is intended. Thus, 
in attempted preparation of N-phenyl compounds from iodobenzene and copper 
in dimethylformamide as solvent, the N-formyl compound was produced. 
Compounds of the present invention which may be represented by formula (Ig) 
##STR30## 
may be prepared by the reaction of piperidine compound II with a sulfonyl 
halide R"SO.sub.2 Cl (IIIg) in solvent medium in the presence of a 
tertiary amine to bind the acid halide by-product. The sulfonyl halide is 
employed in excess; generally, from about 1.5 to 2 molar excess is 
suitable. Suitable tertiary amines include those previously enumerated as 
acid binding agents. Suitable solvents are methylene chloride, carbon 
tetrachloride, chloroform, and the like. The reaction is preferably 
carried out by adding neat sulfonyl chloride dropwise to a solution 
containing the piperidine compound II and the tertiary amine acid binding 
agent. The reaction is exothermic and substantially instantaneous. After 
completion of the addition, the reaction mixture may be stirred for from 
one-half to several hours to assure completion of the reaction. At the end 
of this time, the product may be recovered and purified employing 
conventional techniques. 
Compounds of the present invention which may be represented by the formula 
(Ih) 
##STR31## 
wherein the dotted line represents a residue of a heteroaromatic ring 
which may be mononuclear or polynuclear and which may contain other 
heterocyclic atoms and/or other substituents may be prepared by the 
reaction of the piperidine compound (II) and a halo-heteroaromatic 
compound (IIIh) in the presence of an acid binding agent and a catalyst. 
The acid binding agents are tertiary amines previously described. The 
catalyst preferably is 4-dimethylaminopyridine. The reaction is carried 
out in a solvent such as butanol, propanol, ethanol and the like. 
Approximately equimolar amounts of the reactants are employed. The 
reaction is conveniently carried out at reflux temperature for time 
sufficient for completion of the reaction. Thereafter the product may be 
recovered employing conventional procedures, and purified, if desired, 
also employing conventional procedures. 
The axial isomers are not obtained by the foregoing procedures. In fact, 
none of the compounds are obtained as axial isomers by any currently known 
methods. The compounds of Formula Ia and Ib may be obtained as axial 
isomers by employing an appropriately substituted Grignard reagent in the 
following sequence of reactions: 
##STR32## 
In the foregoing formulas Q represents; 
##STR33## 
thus the formula represents compounds of Formula Ia and Ib in the axial 
form. 
When the axial isomer is to be prepared, the preparation of the hydroxy 
compound from the ketone is a conventional Grignard synthesis. Thus, an 
appropriate 5H-dibenzo[a,d]cyclohepten-5-one (IV) is caused to react with 
the Grignard reagent of 1-aralkyl-4-chloropiperidine or 
1-aralkenyl-4-chloropiperidine initially in a cooled ethereal solution and 
thereafter at ambient temperature to obtain the magnesium halide salt of a 
5H-dibenzo-[a,d]cyclohepten-5-ol which is hydrolyzed under acid conditions 
to obtain the hydroxy compound. The hydroxy compound may be recovered by 
conventional procedures. The reductive cleavage of the hydroxy group of 
the compounds of Formula V may be carried out by mixing the hydroxy 
compound with a molar excess of triethylsilane in a water-immiscible 
organic solvent, cooling the mixture to -40.degree. to 0.degree. C. and 
bubbling in boron trifluoride for time sufficient to saturate the reaction 
mixture, thereafter bringing the reaction mixture gradually to ambient 
temperature to complete the reduction. The reaction may be quenched by 
adding first solid potassium carbonate, then water, and thereafter 
recovering the product from the organic solution employing conventional 
procedures. 
All of the compounds of Formula I may be obtained as acid addition salts. 
Some of the products of the present invention are preferably isolated as 
acid addition salts. In other cases, they may be isolated as bases and 
converted into salts as desired. When salts are desired, the base product 
may be dissolved in a solvent such as alkanol and the appropriate acid 
added thereto. Usually the crystalline salt will start to form immediately 
and precipitate in the reaction mixture. The reaction mixture may be 
cooled to facilitate and/or complete the reaction. 
The compounds of the present invention possess pharmacological properties 
adaptable for therapeutic uses. One of the properties demonstrated by the 
compounds is inhibition of calcium induced contraction of tracheal smooth 
muscle or vascular tissue. The property may be observed in a test in which 
segments of vascular smooth muscle obtained from male Sprague-Dawley rats 
are suspended in physiological salt solution in a tissue bath instrumented 
for recording contractions. After the tissue has been equilibrated, washed 
in calcium-free physiological salt solution and depolarized, 0.1 mM 
calcium chloride is re-added to induce contraction. After the contraction 
has reached a plateau, tissues are washed and a test compound or vehicle 
is added to determine the effect on a second contraction achieved by the 
above cyclic protocol. From measuring the initial contraction as well as 
the second contraction in the presence of the first compound, the extent 
of inhibition may be calculated. 
The most effective compounds for inhibiting calcium induced contraction of 
tracheal smooth muscle or vascular tissue were rated to be those in which 
the carbon of the R group attached to the piperidine nitrogen at the point 
of attachment is in the reduced form, e.g. a methylene group, so that the 
group may be represented as 
EQU --CH.sub.2 G 
wherein G represents the remainder of the substituent. The most active 
compounds were those in which the carbon of G attached to the reduced 
carbon was part of an unsaturated grouping. Thus, the most active 
compounds, included these in which R was cinnamyl, 
3,4,5-trimethoxycinnamyl and 4-dimethylaminobenzyl. The compounds having 
the foregoing groups demonstrated high level of activity at low level of 
concentrations of 10.sup.-7 M in the above described test. Thus, in the 
test, 
4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-(4-dimethylaminobenzyl)piperidine 
showed 69 percent inhibition, 
4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-cinnamylpiperidine showed 70 percent 
and 
4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-(3,4,5-trimethoxycinnamyl)piperdine 
showed 68 percent inhibition at 10.sup.-7 M. 
The compounds which were intermediate in activity were those in which the 
atom attached to the piperidine nitrogen was part of an acyl group. The 
groups were those which may be represented as 
##STR34## 
wherein L,L' and L" represents the remainder of the substituent. Compounds 
having these groups showed moderate to low activity at 10.sup.-7 M 
indicating the desirability of employing higher concentrations of these 
compounds. Certain of the compounds are additionally useful as 
intermediates in the preparation of the highly active aralkenyl compounds. 
The compounds least active were the heteroaryl substituted compounds 
indicating higher concentration requirement. 
For use in the treatment of cardiovascular diseases caused by high cellular 
concentration of Ca.sup.++, a therapeutically effect amount of the 
4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperdine compound of Formula I or a 
pharmaceutically acceptable acid addition salt thereof, or compositions 
containing said compounds are administered to subjects with such diasease. 
The administration may be made orally, parenterally, by inhalation, or by 
suppository, and in any suitable dosage form. For oral administration, the 
compounds may be offered in the form of tablets or capsules with suitable 
dispersants and carrier materials or dispersed in a liquid carrier for 
administration as solution or aqueous dispersion or emulsion; for 
parenteral administration, the compounds may be dispersed in an 
appropriate liquid carrier with or without dispersing agents depending on 
whether a solution, emulsion or other dispersion is intended; for aerosol 
administration the compound may be dispersed formulated with a suitable 
dispersant and propellant; and for use as suppository the compounds may be 
dispersed in a suitable carrier. Suitable carriers and dispersants are 
hereinafter described. 
The ratio of the compound of the present invention to carrier varies with 
the particular compound, purpose and the mode of administration and 
whether or not it is intended to be employed without dilution or 
modification. The dosage level of the compounds may be varied from about 
0.3 mg to about 40.0 mg per kilogram of body weight per day. Daily doses 
in the range of 1 to 12 mg/kg are preferred. 
The compounds may be administered in pharmaceutically acceptable acid 
addition salt form. Such acid addition salt forms exhibit the same order 
of activity as the free base forms and may be prepared from the free base 
as previously described or other conventional procedures. 
The free base or salt may be formulated with a pharmaceutical carrier or 
diluent. 
To prepare the pharmaceutical compositions of this invention, compound of 
Formula (I) or acid addition salt thereof, as the active ingredient, is 
intimately admixed with a pharmaceutically acceptable carrier according to 
conventional pharmaceutical compounding techniques, which carrier may take 
a wide variety of forms depending on the form of preparation desired for 
administration, e.g., oral or parenteral. In preparing the compositions in 
oral dosage form, any of the usual pharmaceutical media may be employed. 
Thus, for liquid oral preparations, such as, for example, suspensions, 
elixirs and solutions, suitable carriers and additives include water, 
glycols, oils, alcohols, flavoring agents, preservatives, coloring agents 
and the like; for solid oral preparations such as, for example, powders, 
capsules and tablets, suitable carriers and additives include starches, 
sugars, diluents, granulating agents, lubricants, binders, disintegrating 
agents and the like. Because of their ease in administration, tablets and 
capsules represent the most advantageous oral dosage unit form, in which 
case solid pharmaceutical carriers are obviously employed. If desired, 
tablets may be sugar coated or enteric coated by standard techniques. For 
parenterals, the carrier will usually comprise sterile water, although 
other ingredients may be included for purposes such as, for example, for 
aiding solubility or for preservation. Injectable suspensions also may be 
prepared, in which case appropriate liquid carriers, suspending agents and 
the like may be employed. The pharmaceutical compositions herein will 
contain, per dosage unit, e.g., tablet, capsule, powder, injection, 
teaspoonful and the like, from about 0.075 to about 10.0 mg of the active 
ingredient, and, preferably, from about 0.3 to about 4.0 mg. 
The following examples illustrate the invention but are not to be construed 
as limiting.