1-Phenoxy-3-[(3-indolyl)-tert.-butyl]amino-2-propanols and related 1-aryloxy compounds are antihypertensive agents having vasodilator and adrenergic .beta.-receptor blocking action. Preferred compounds bear an ortho-substituent in the phenoxy group, and most preferably the cyano group.

FIELD OF THE INVENTION 
The present invention is concerned with heterocyclic carbon compounds of 
the indole series having an amino substituent (Class 260/326.15), and with 
drug, bio-affecting and body-treating processes employing these compounds 
(Class 424/274). 
DESCRIPTION OF THE PRIOR ART 
I. A substantial body of prior art has developed during the last ten years 
involving compounds of the 3-aryloxy-2-hydroxypropylamine series which 
have .beta.-adrenergic receptor blocking activity and are useful in the 
treatment of cardiovascular diseases. These structures are typified by the 
substance 1-isopropylamino-3-(1-naphthoxy)-2-propanol which is currently 
in medical use under the non-proprietary name propranolol. Propranolol and 
a related group of naphthoxypropanolamines are the subject of U.S. Pat. 
No. 3,337,628 patented Aug. 22, 1967. A large number of patents have been 
granted since that time on carbocyclic ethers in which other aromatic 
rings replace the naphthoxy group of propranolol. Many of these compounds 
are in the phenoxy series and others are phenoxy compounds with a fused 
heterocyclic ring. 
II. The following patents and publications describe 3-indolylalkylamino 
compounds. 
Robinson, U.S. Pat. No. 2,908,691 patented Oct. 13, 1959 describes a group 
of 3-indolylalkylamines having an aralkyl substituent attached to the 
amino nitrogen atom. These substances have utility as hypnotic, 
anti-secretory, and anti-emetic agents. The product of Example 7 thereof 
has been referred to as SC10049 having bronchodilator and hyperglycemic 
action (Van Arman, J. Pharmacol. and Exptl. Therap. 133, 90-97 (1961)). 
Wasson, et al., U.S. Pat. No. 3,946,009 patented Mar. 23, 1976 discloses a 
group of pyrazinyloxpropanolamines among which the 3-indolyl-tert.-butyl 
group is mentioned as an amino substituent. Refer to column 22, line 15. 
These substances have adrenergic .beta.-receptor blocking properties. 
Jackman, G. B., et al., J. Pharm. Pharmacol., 1965 17, 742-746 entitled 
"Some Tryptamine Derivatives; 
1-Aryloxy-3-[(2-indol-3'-ylethyl)amino]propan-2-ols". 
3-Indolylethylaminopropanols were conceived of as central nervous system 
agents of the tranquilizer type. The only compound found to possess any 
activity had the structural formula shown below. It reflected only a 
fraction of the CNS activity of chlorpromazine hydrochloride in laboratory 
tests, and was considered not worthy of detailed biological study. 
##STR1## 
III. The following patent discloses various heterocyclic 
alkylaminopropanols but no indole compounds are disclosed. 
Augstein, et al. U.S. Pat. No. 3,852,291 patented Dec. 3, 1974. Pyrimidinyl 
alkylamino and imidazolinylalkylamino propanols are described which have 
adrenergic .beta.-receptor blocking action. 
IV. The following patents describe aryloxypropanolamino compounds in which 
the aryloxy group bears a heterocyclic substituent. 
McLoughlin, et al. U.S. Pat. No. 3,328,417 patented June 27, 1967 discloses 
phenoxypropanolamines in which the phenoxy substituent is further 
substituted by the 2-indolyl group (Column 2, line 12). 
Muchowski, et al. U.S. Pat. No. 3,940,407 patented Feb. 24, 1976 discloses 
a series of phenoxypropanolamine compounds in which the phenoxy 
substituent is further substituted by a 1,2,3-thiadiazole substituent. 
Seeman, U.S. Pat. No. 3,965,095 patented June 22, 1976 discloses a series 
of oxindole ethers in which the etherifying group is attached to the 
phenyl ring and has an esterified aminopropanol configuration. These 
substances are antiarrhythmic and .beta.-blocking agents. 
Troxler, Canadian Pat. No. 834,751 issued Feb. 17, 1970 discloses a series 
of indole derivatives having a 3-(N-substituted amino)-2-propanoloxy 
substituent in the 4-position of the indole ring. The compounds are useful 
in the therapy of coronary disease, angina, cardiac arrhythmia, and 
hypertension. 
Jaeggi, et al., U.S. Pat. No. 3,984,436 patented Oct. 5, 1976 discloses a 
series of phenoxypropanolamines in which the phenoxy substituent is 
further substituted by the 1-pyrrolyl group. These compounds are blockers 
of adrenergic .beta.-receptors. 
SUMMARY OF THE INVENTION 
The present invention includes the compounds of Formula I and the acid 
addition salts of these substances 
##STR2## 
In the foregoing structural formula the symbols R.sup.1, R.sup.2, R.sup.3, 
Ar, X, and n have the following meanings. One of 
R.sup.1 and R.sup.2 is hydrogen and the other is hydrogen or alkyl having 1 
to 4 carbon atoms, 
R.sup.3 is hydrogen, halogen, alkyl having 1 to 4 carbon atoms, or alkoxy 
having 1 to 4 carbon atoms located in the 4-, 5-, 6-, or 7- positions of 
the indole ring, 
Ar is selected from the group consisting of phenyl and naphthyl, 
X refers to 1 or 2 optional Ar-attached substituents which are located in 
any of the available ring positions and are independently selected from 
the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, 
alkynoxy, alkoxyalkyl, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, 
alkylsulfonyl, alkylsulfinyl, alkylthio, alkanoylamino, alkenoylamino, 
alkoxycarbonyl, alkenoxycarbonyl, alkoxycarbonylamino, 
alkoxycarbonylaminoalkyl, cycloalkyl having 3 to 6 ring members and 1 to 3 
optional alkyl substituents, cycloalkenyl having 4 to 6 ring members and 
up to 3 optional alkyl substituents, cycloalkylalkyl having 3 to 6 ring 
members and up to 3 optional alkyl substituents, cycloalkenylalkyl having 
4 to 6 ring members and up to 3 optional alkyl substituents with the 
additional proviso that each of the foregoing Ar-attached substituents has 
up to 8 carbon atoms, trifluoromethyl, nitro, amino, hydroxyl, halogen, 
aminocarbonyl, cyano, cyanoalkyl having from 2 to 4 carbon atoms, 
aminocarbonylalkyl having 2 to 4 carbon atoms, 
n is the integer 0, 1, or 2 signifying the number of X groups, or 
Ar-X.sub.n as a unit refers to 4-indenyl, 
6,7-dihydroxy-5,6,7,8-tetrahydro-1-naphthyl, or 
5-oxo-5,6,7,8-tetrahydro-1-naphthyl. 
When R.sup.3 or X is halogen, it is intended to include fluorine, chlorine, 
bromine, and iodine. Also, when n is 2 and the X substituents are 
adjacent, those which are sterically incompatible, that is incapable of 
occupying adjacent positions such as adjacent tertiary alkyl groups, are 
not intended by the formula. 
The compounds of the present invention are unique as antihypertensive 
agents in that they combine adrenergic .beta.-blocking and vasodilator 
activity. They also have utility as anti-anginal agents, anti-stress 
agents, antiarrhythmic agents, antithrombogenic agents and in the 
treatment of conditions where it is desirable to reduce the oxygen demand 
of the heart such as post-myocardial infarct management. Preferred members 
have a particularly desirable combination of the foregoing actions, and 
ancillary pharmacological effects, or a lack thereof, which particularly 
suits them for specific indications from among those listed. Those of 
Formula I wherein Ar is phenyl, n=1, and X is located in the ortho 
position are preferred for antihypertensive use. The utility of the 
compounds of Formula I can be demonstrated in various animal models 
including antagonism of isoproterenol in the conscious rat treated orally 
(adrenergic .beta.-receptor blocking action), the spontaneous hypertensive 
rat (antihypertensive action), the dog hind limb preparation (vasodilator 
action), angiotensin-maintained ganglion blocked rat model (vasodilator 
action), ouabain-induced ventricular tachycardia in the dog 
(antiarrhythmic action), in the coronary artery occluded dog 
(antiarrhythmic action), in vitro by measuring platelet aggregation in 
platelet-rich plasma photometrically following challenge with a 
thrombogenic agent such as adenosine diphosphate or collagen 
(antithrombogenic action), and in various other animal and laboratory 
models. 
DETAILED DESCRIPTION OF THE INVENTION 
The invention includes compounds having the foregoing structural formula 
and the acid addition salts thereof. For medical use, the pharmaceutically 
acceptable acid addition salts are preferred. The pharmaceutically 
acceptable acid addition salts are those salts in which the anion does not 
contribute significantly to the toxicity or pharmacological activity of 
the salt, and as such, they are the pharmacological equivalents of the 
bases having the foregoing structural formulas. In some instances, the 
salts have physical properties which make them more desirable for 
pharmaceutical formulation purposes such as solubility, lack of 
hygroscopicity, compressibility with respect to tablet formation and 
compatibility with other ingredients with which the substances may be used 
for pharmaceutical purposes. Acid addition salts which do not meet the 
foregoing criteria for pharmaceutical acceptability, for instance as to 
toxicity, are sometimes useful as intermediates for isolation and 
purification of the present substances or for other chemical synthetic 
purposes such as separation of optical isomers. Such salts are also part 
of the invention. 
The acid addition salts are made by reaction of a base of the foregoing 
structural formula with the acid preferably by contact in solution. They 
may also be made by metathesis or treatment with an anion exchange resin 
whereby the anion of one salt of the substance is replaced by another 
anion under conditions which allows for separation of the undesired 
species such as by precipitation from solution or extraction into a 
solvent or elution from or retention on an anion exchange resin. 
Pharmaceutically acceptable acids for the purposes of salt formation 
include hydrochloric, hydrobromic, hydroiodic, citric, acetic, benzoic, 
phosphoric, nitric, mucic, isethionic, methanesulfonic, p-toluenesulfonic, 
glucosaccharic, palmitic, heptanoic, oxalic, cyclamic, succinic, malic, 
fumaric, mandelic, malonic, and others. 
The compounds of the present invention shown by the foregoing structural 
formula contain an asymmetric carbon atom in the propanolamine side chain 
and occur as optically active isomers as well as racemic mixtures thereof. 
The present invention is intended to include each of the optically active 
and racemic forms. Some of the substances of the present invention contain 
an asymmetric carbon atom in the X substituent, and diastereoisomeric 
pairs of racemates exist. These forms are also included. 
Resolution of racemic mixtures to provide the optically active isomers of 
the foregoing compounds is carried out, for example, by forming a salt 
with an optically active acid many of which are known to those skilled in 
the art such as optically active tartaric, mandelic, cholic, 
O,O-di-p-toluoyl tartaric, and O,O-dibenzoyl tartaric acids, or other 
acids conventionally employed for this purpose. The claims, therefore, 
will be understood to embrace the products in the form of the several 
racemic mixtures as well as in the form of the optically active isomers 
where appropriate. 
The therapeutic processes of this invention comprise systemic 
administration of an effective, non-toxic amount of a compound of Formula 
I or a pharmaceutically acceptable acid addition salt thereof to a mammal 
having a disease state resulting from excessive stimulation of the 
adrenergic .beta.-receptors, or to a mammal requiring vasodilation, or to 
a mammal having hypertension. An effective amount is construed to mean a 
dose which exerts an adrenergic .beta.-receptor blocking action, a 
vasodilator effect, or antihypertensive action in the affected animal 
without undue toxic side effects. By systemic administration, it is 
intended to include both oral and parenteral routes. Examples of 
parenteral administration are intravenous injection or infusion, and 
intraperitoneal, intramuscular or subcutaneous injection. Rectal 
administration by ointment or suppository may be employed. Dosage will 
vary according to the route of administration with from about 0.1 mcg to 
100 mg/kg body weight of a compound of Formula I or a pharmaceutically 
acceptable acid addition salt thereof generally providing the desired 
therapeutic effect. Acute toxicities measured in the mouse treated orally 
are within the range of about ALD.sub.50 125 mg/kg to &gt;2000 mg/kg of body 
weight, with non-lethal signs of drug effect such as central nervous 
system stimulation or depression, mydriasis, or lacrimation appearing at 
from 1/2 to 1/10 that dose. 
The combination of pharmacological properties of the compounds of Procedure 
10, 
1-[[2-(3-indolyl)-1,1-dimethylethyl]-amino]-3-(2-methylphenoxy)-2-propanol 
hydrochloride, and Procedure 26, 
2-[2-hydroxy-3-[[2-(3-indolyl)-1,1-dimethylethyl]amino]propoxy]-benzonitri 
le hydrochloride, indicates that they are particularly desirable for 
antihypertensive use. They have five-fold the adrenergic .beta.-receptor 
blocking potency of propranolol shown by oral administration to rats 
followed by challenge of the animals with isoproterenol administered 
intravenously (Test Method 349F). The latter is a well known adrenergic 
.beta.-receptor stimulant which causes an increase in heart rate and a 
decrease in blood pressure. These effects of isoproterenol are antagonized 
by adrenergic .beta.-receptor blocking agents, and the relative potency 
values given above were prepared by regression analysis of log 
dose-response data for the compounds. For therapeutic use, dosage size and 
frequency will vary with the subject and the route of administration, with 
from about 0.2 mg. for intravenous administration up to about 100 mg 
orally being suitable for man. 
The substances of Procedures 10 and 26 are distinguished from other 
adrenergic .beta.-receptor blocking drugs in that they are effective in 
lowering the blood pressure in the spontaneously hypertensive rat (Test 
Method 410C). Although adrenergic .beta.-receptor blocking agents have 
come into widespread use in human medicine for the treatment of 
hypertension, their mechanism of action is unknown and their 
antihypertensive activity cannot be detected by this animal test in most 
instances. With the present substances in the spontaneously hypertensive 
rat, a reduction of blood pressure, respectively, of 25 mm. and 44 mm. of 
Hg occurs at doses of 100 mg/kg of body weight orally with only a minimal 
reduction in heart rate. This is thought to be indicative of utility in 
hypertensive indications where other adrenergic .beta.-receptor blocking 
drugs are inoperative or less desirable. 
The substances of Procedures 10 and 26 also cause a reduction in blood 
pressure when administered intravenously to the anesthetized dog in a dose 
of 3.33 mg/kg of body weight. They are further distinguished in that they 
do not depress heart rate or right ventricular contractile force as is the 
case with many prior adrenergic .beta.-receptor blocking agents. Both a 
positive inotropic and a positive chronotropic effect are exhibited by the 
substances, and these effects are apparent even when the animal is first 
treated with an adrenergic .beta.-receptor blocking agent such as sotalol. 
Pulmonary artery pressure remains substantially unchanged, while aortic 
blood flow and total peripheral resistance are decreased, all of the 
foregoing in the anesthetized dog. 
The compounds of Procedures 10 and 26 possess vasodilator activity which 
may account, in part, for their unique anti-hypertensive action. In the 
anesthetized ganglion blocked (chlorisondamine chloride) angiotension 
supported rat (Test Method 432), direct acting vasodilators such as 
diazoxide exert a reduction in blood pressure. The substances of 
Procedures 10 and 26 are at least equivalent in potency to diazoxide in 
this test. The vasodilator action thereof can also be shown in the 
pump-perfused hind limb of the dog in doses of from 0.03 to 1.0 mg/min. 
urine volume and a decrease in sodium ion excretion occurs which is 
typical of vasodilator compounds. 
The antithrombogenic action of the substance of Procedure 10 is reflected 
by its ability to reduce platelet aggregation in vitro in platelet-rich 
plasma following challange with ADP or collagen. It is comparable in in 
vitro activity to suloctidil or to papaverine. 
A hazard exists in the use of a preponderance of adrenergic .beta.-receptor 
blocking agents in patients suffering from non-allergic bronchospasm in 
view of the tendency of these agents to provoke an asthmatic attack or to 
render the subject refractory to treatment with adrenergic .beta.-receptor 
stimulants such as isoproterenol which are used in the treatment of acute 
attacks. The substances of Procedures 10 and 26 lack bronchospastic 
liability as is demonstrated by the fact that they do not reduce pulmonary 
ventilatory pressure, and evoke only moderate enhancement of the response 
of sensitized rats to immunologically induced broncho-constriction at a 
dose of 0.5 mg/kg of body weight intravenously. In contrast, propranolol 
at a dose of 0.5 mg/kg of body weight intravenously reduces pulmonary 
ventilatory pressure and precipitates an acute bronchospastic response in 
sensitized rats to immunologically-induced broncho-constriction. 
For the preparation of pharmaceutical compositions containing the compounds 
of Formula I in the form of dosage units for oral administration, the 
compound is mixed with a solid, pulverulent carrier such as lactose, 
sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, 
cellulose derivatives, or gelatin, as well as with glidents such as 
magnesium stearate, calcium stearate, polyethylene glycol waxes or the 
like and pressed into tablets. The tablets may be used uncoated or coated 
by known techniques to delay disintegration and absorption in the 
gastrointestinal tract and thereby provide a sustained action over a 
longer period. When coated tablets were wanted, the above prepared core 
may be coated with a concentrated solution of sugar, which solution may 
contain e.g. gum arabic, gelatin, talc, titanium dioxide or the like. 
Furthermore, the tablets may be coated with a lacquer dissolved in an 
easily volatile organic solvent or mixture of solvents and if desired, dye 
may be added to this coating. 
In the preparation of soft gelatin capsules consisting of gelatin and e.g. 
glycerine and the like, the active ingredient is mixed with a vegetable 
oil and encapsulated in conventional manner. Hard gelatin capsules may 
contain granules of the active ingredient in combination with a solid, 
pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, 
starch (such as e.g. potato starch, corn starch, or amylopectin), 
cellulose derivatives or gelatin. 
Dose units for rectal administration may be prepared in the form of 
suppositories containing the compound in a mixture with a neutral fat 
base, or in the form of a gelatin-rectal capsule with a mixture of 
vegetable oil or paraffin oil. 
Liquid preparations suitable for oral administration are suspensions, 
syrups and elixirs containing from about 0.2% by weight to about 20% by 
weight of the active ingredient. 
A suitable injectible composition comprises an aqueous solution of a water 
soluble pharmaceutically acceptable acid addition salt adjusted to 
physiologically acceptable pH. 
The compounds of Formula I are prepared by application of known processes 
to the appropriate starting materials. Representative know methods for the 
preparation of aryloxypropanolamine compounds are disclosed in the 
foregoing patents and publications cited above under Description of the 
Prior Art of which the Troxler Canadian Pat. No. 834,751 and the Jaeggi, 
et al., U.S. Pat. No. 3,984,436 are illustrative. More specifically, the 
present invention provides a process for the preparation of the compounds 
of Formula I according to the following reaction scheme. 
##STR3## 
In the foregoing reaction scheme, the symbol Ar' represents the groups Ar, 
X, and n as they are defined in Formula I, R.sup.1, R.sup.2, and R.sup.3 
have the same meaning as in Formula I, and the symbol B is defined by 
Formulas III and IV in which R is a lower alkyl group of 4 or fewer carbon 
atoms. The preferred method is according to reactions (1) and (2) in which 
step (1) involves reacting the appropriately substituted phenolic compound 
Ar'--OH with epichlorohydrin in the presence of a catalytic quantity of an 
amine followed by treating with aqueous alkali metal hydroxide, or 
conducting the reaction in the first instance in an aqueous alkali metal 
hydroxide reaction medium whence the amine catalyst is not required. There 
is produced in step (1) an Ar' epoxypropyl ether which is caused to react 
in step (2) with 2-(R.sup.1,R.sup.2,R.sup.3 
-3-indolyl)-1,1-dimethylethylamine to yield a product of Formula I. Each 
of reaction steps (1) and (2) takes place facilely in ordinary laboratory 
or plant equipment under convenient operating conditions. 
Heating of epichlorohydrin in substantial molecular excess amount with a 
phenol Ar'OH containing a drop or two of piperidine as catalyst on a steam 
bath overnight results in the condensation shown in step (1). Some of the 
corresponding halohydrin intermediate is also produced and is converted 
without isolation to the oxirane shown by treatment of the mixture with 
aqueous alkali metal hydroxide. Alternatively, the Ar'OH phenol and 
epichlorohydrin can be caused to react in the presence of a sufficient 
amount of a dilute aqueous alkali metal hydroxide to neutralize the acidic 
Ar'OH group at room temperature with formation of the desired intermediate 
##STR4## 
Step (2) is carried out simply by heating the oxirane intermediate 
produced in step (1) with 2-(R.sup.1,R.sup.2,R.sup.3 
-3-indolyl)-1,1-dimethylethylamine either neat or in the presence of a 
reaction inert organic solvent. No catalyst or condensation agent is 
required. Suitable solvents include 95% ethanol but other reaction inert 
organic liquids in which the reactants are soluble may be employed. These 
include but are not limited to benzene, toluene, tetrahydrofuran, dibutyl 
ether, butanol, hexanol, methanol, dimethoxyethane, ethylene glycol, etc. 
Suitable reaction temperatures are from about 60.degree.-200.degree. C. 
An alternate variation of the process for the preparation of compounds of 
Formula I involves reaction of the Ar'OH starting material as defined 
above with a reactant of the formula 
##STR5## 
according to reaction (3) of the scheme to yield an intermediate which is 
transformed to the final product by hydrolysis or hydrogenolysis. The 
substituent B in the reactant used in step (3) is a group such as shown by 
III or IV which is reactive with the phenolic hydroxyl group Ar'OH to 
incorporate into the product an incipient propanolamine side chain. 
The reactants for step (3) wherein B has Formula III are prepared by 
forming the N-benzyl derivative of 2-(R.sup.1,R.sup.2,R.sup.3 
-3-indolyl)-1,1-dimethylethylamine and reacting the latter with 
epichlorohydrin by adaptation of the method of L. Villa et al., II. 
Farmaco. Sci., Ed., 24, (3) 349 (1969). 
Those reactants wherein B has Formula IV are prepared by reductive 
alkylation of 2-(R.sup.1,R.sup.2,R.sup.3 
-3-indolyl)-1,1-dimethylethylamine with glyceraldehyde according to known 
methods, for instance, employing 5% palladium-on-carbon catalyst in an 
atmosphere of hydrogen with methanol or other suitable non-reactive liquid 
as solvent. When using an optically active form of glyceraldehyde, an 
optically active end product of Formula I is obtained. The amino 
propanediol resulting from the foregoing reductive alkylation reaction is 
then converted to the desired 2-(R.sup.1,R.sup.2,R.sup.3 
-3-indolyl)-1,1-dimethylethyloxazolidinone reactant wherein B has Formula 
IV by reaction with formaldehyde employing 37% aqueous formaldehyde in 
refluxing benzene with continued removal of the water by distillation. 
Esterification with an alkanesulfonyl chloride of the formula RSO.sub.2 Cl 
in which R is a lower alkyl group of 1 to 4 carbon atoms introduces the 
necessary group which is reactive with Ar'OH. 
The intermediate produced by step (3) wherein the B has Formula III is 
converted in step (4) to a product of Formula I by debenzylation by known 
means such as catalytic hydrogenation or reaction with sodium in liquid 
ammonia. The intermediates produced in step (3) wherein B has formula IV 
are converted to the products of Formula I in step (4) by mild acid 
hydrolysis. In this instance, care must be taken to avoid decomposition of 
the reactant since certain R.sup.1,R.sup.2,R.sup.3 -3-indolyl substituents 
are known to be acid sensitive. Aqueous mineral acids of from 0.1 N to 1 N 
concentration at temperatures of from 20.degree.-100.degree. C. are 
suitable. The product is recovered as the free base from the hydrolysis 
mixture by neutralization thereof and collecting the precipitate.