CA1217496A - L-phenoxy-3-hydroxyindolylalkylamino-3-propanols and preparation - Google Patents

Abstract

Abstract of the Disclosure 1-(2-Cyanophenyloxy)-3-(hydroxyindolylalkylamino)-2-propanols are cardiovascular agents having promise as antihypertensive agents by virtue of their vasodilating and adrenergic receptor blocking actions. Preferred compounds contain the 3-indolyl-tertiary-butylamino moiety.

Description

rIJ-582 ~l'7~3~

l-PHENOXY-3-HYDROXYINDOLYL-The present invention is concerned with heterocyclic carbon compounds of the iDdole serles having an ami~o substituent, and with drug b~o-affecting and body treating proce6ses employing these compounds.

A large body ~f prior art exists for msny aeries of compounds classified as 3-tarYloxY)-2-hYdroxyProPylamines. ~o~t of these series clai~ utility as useful agents in treatmen~ of cardiovascular diseases, particularly beta-adrenergic recep~or blocking act~vity.
Many compounds in this general class also possess a degree of vaso-dilating effectiveness due, in some instances, to inherent alph~-adrenergic receptor blo~ing activity. ~arious other cardiovasoular dru~ effects, or ~heir lack, combine to make s~me of these c~mpounds ~:
appear to be us~ful as antihypertensive agents. Most prior art, ho~ever, concerns the beta-adrenergic blocking agent proper~y for "

3~

~hese series of compounds. The prototype or structures of this kind is propranolol; chemically, l-(isopropylamino)-3-(1-naphthyloxy)-2-propanol. Propranolol and some related naphthyloxy propanolamines are the sub~ect of U.S. Patent No. 3,337,628 issued August 22, 1967.
Numerous subsequent patents have been granted coverlng series of compounds representing structurally modified 3-~aryloxy)-2-hydro~y-propylamines.
A series of indol-3-yl-tert.-butylaminopropanols (1,2) ~ith antihypertensive properties was described in: Kreighbaum, et alO, U.S. Patent No. 4,234,595 patented November 18, 1980; U.S. Pat&nt No.
4,314,943 patented February 9, 1982; and Journal of Medicinal Chemistr~, 23:3, 285-289 (1980~.

X3 ~ J ~ 03 tl) R3 ~ ~XN~ O-Ar-Het ~N R2 OH
Rl

(2) In these foregoing structural for~ulas, the symbol R c~n be hy~rogen, halogen, lower alkyl or alkoxy but not hydroxyl.
A preferred compound of the ~tructural For~ula ~1) series is deslgnated MJ 13105, also known by the ~nited States Adopted ~ame 85 bucindolol, and is currently undergoing evaluation cllnically as an antlhypertensive ~gent.
CN

D -It is of lnterest in regsrd to the instant co~pounds that a ~aior metabolic pathway for ~J 13105 involves 6-hydroxylation of the indole ring. This was confirmed by comparison nf ~etabolic ~solates with the synthetically ~vailable correspondin~ 6-hydroxyindolyl compound of the insta~t invention.
Attention is also called to applicsnt~s pending Canadian Appli-cation Serial No. 435,880, filed September 19 1983, ~hich discloses a series of vasodilating agents hav$ng a ran~e of beta-adrenerglc blocking potency 2nd possessing structural for~ula ~3).

A l 2 R ~
C ~ ~Y

B

~3 7~

While in the foregoing structural formula (3), C can be hydroxyl, among other ~ubstituents, the series in general is dis~inguishable from tha lrlstant invention in that compGunds of structure (3) are pyridinyloxypropanolamines.

The present invention ~ncludes the compounds of Formula I
and the acid addition salts of these substances.

HO ~ ~ ~ r ~ RS

(I) In th~ fore~olng structural formul~ the symbols R -~5 have the follo~ing meanings. One of Rl and R2 is hydrogen and the other is hydro~en or Cl 4 alkyl, R3 and R4 are independently selected from hydrogen or Cl 4 alkyl, and R5 can be halogen, hydrogen, hydroxy, or Cl 4 alkyl. For prefesred csmpounds Rl is H, R2 is 2-H, R3 and R are methyl, and R5 is hydrogen or 5-fluoro. The compounds of ~he present inventlon are useful as antlhypertenslve agents due in part to a combination of their adrenergic receptor-blockin~ and vasodilator activi~ies.

7~6 The invention includes compounds having the foregoing structural formula (I) and the acid addition salts thereof. In structural formula I, Rl, R2, R3, and R4 can be hydrogen or alkyl having 1 to 4 carbon atoms. One of Rl and R2 will always be hydrogen whereas R and R4 are independently selected and can both be slkyl.
R can be halogen, preferably fluoro or chloro; hydrogen; hydroxyl;
or lower alkyl. The lndolyl syste~ is attached to the side ch~in at either the 2- or 3- position and the hydroxyl substituent occupies either the 4-, 5-, 6-, or 7- ring position of indole. F~r preferred compounds, Rl is hydrogen; R2 is 2-hydrogen (the indole moiety being coupled to the main side chain through its 3-position); R3 and R4 are methyl; and R5 is hydrogen or 5-fluoro.
For medicinal use, the pharmaceutically acceptable acid addition salts, those salts in which the anion does not contribute significantly to toxicity or pharmacological activity of their organic eation, are preferred. The acid addition salts are obtained either by react~on of an organic base of structure I with an organic or inorganic acid, preferably by contact in solution, or by any of the standard methods detailed ln the llterature and available to any practitioner skilled in the art. Examples of useful organic acids are carboxyllc acids such as maleic acid, acetic acid, tartaric acid, proplonic scid, fumaric acid, isethionic acid, succinic acid, pamoi~
~cld, cycl~mic acid, pavalic acid, and the like; useful inorgan$c acid are hydrohalid~ acids such as HCl, ~Br, HI; sulfuric ~cid;
phosphoric acid; and the like.

'7~ 6 It is also to be understood that ~he compounds of the present invention include all the optical isomer forms, that is, mi~tures of enantiomers, e.g., r~cemlc modifications as well as the individual enantiomers. These individual enantiomers are commonly desi~nated according to the optlcal rotation they effect, by (+) and (-), (1) and (d), or combinations of these symbols. The symbols (L) and (D) and the symbols (S) and (R), which stand for sinister and rectus, respectively, designate an absolute spatial conf~guration of the enantiomer. Whese no isomer designation ls given fo~ a compound, the compound is the racemic modification.
The individual optical isomers of the aryloxypropanolamlne class of compounds, of which the instant compounds are members~ have most generally been obtained by one of four basic methods. These are: 1) the fractional recrystalli~ation of chiral acid salt derivatives;
2) derivatization wi~h a chiral organic reagent, resolution and regene~at~on of the ori~inal compound ln optically active form

3) synthesis of the single op~ical isomer usin~ ch~ral in~ermediates;
and 4) column chromatography utilizing chiral statio~sry phases.
Applications of these various methods are well known to practitioners in the art.
Biological testing of representative subject compounds of Formula I in animals demonstrates that they possess biological propertiPs which ~ould make them useful as antihypertensive agents.
In addition to antihypertensive activi~y demonstrable in animal ~esting, the instant compounds also possess vasodilating properties along ~ith varying degrees of adrenergic alpha- a~d bet~-receptor blocking properties and intrinsic sympathomimetic activ~ty. h more detailed description of the specific pharmacological tests employed and the criteria used to judge the pertinent biological activity is contained in the Description of Specific Embodiments section under the subheading Biological Evaluation. Preferred representative members have a particularly desirable combination of the foregoing actions, and ancillary pharmacological effects, or lack thereof, which particularly suits them for specific cardiovascular indications, e.g. use as antihypertensives. The utility of the compounds of Formula I can be demonstrated in these various animal models, as referred to above, which include antagonism of isoproterenol in the anesthetized dog treated intravenously (adrenergic beta-receptor action), the spontaneous hypertensive and DOCA salt hypertensive rat (antihypertensive action), antiotensin-maintained ganglion-blocked rat model (vasodilator action), and an anesthetized rat model (alpha-andrenergic blockade), and in various other animal laboratory models (cf: Deitchman, et al., Journal Pharmacological Methods, 3, 311-321 (1980)).
As examples, two of the representative compounds of Formula I; 2-[2-hydroxy-3-[[2-(6-hydroxy-1H-indol-3-y1)-1,1-dimethyl-ethyl]amino]propoxy]benzonitrile and 2-[2-hydroxy-3-[[2-(5-hydroxy-1H-indol-3-y1)-1,1-dimethylethyl]amino]propoxy]bennzonitrile caused greater than 20 mmHg mean drop in systolic blood pressure of rats in one or both of the antihypertensive tests when given at a dose level of 30 mg/kg p.o. A 3 mg/kg intravenous dose of these compounds resulted in over a 20% drop in mean arterial blood pressure (taken 30 minutes after dosing) in the vasodilation test.

For use as antihypertensives, ~asodllators, ~nd¦or adrenergic blocking agents, the apeu~:Lc proc~sses ~f this inven~ion comprise sgstemic admin~st.a~ion, by both oral ard parenteral L~o~ tes~
of an ~ffective9 non-toxic amount of a compound of Formula I or a pharmaceutically acceptable acid additlon salt thereof. An effective amount is construed to mean a dose which exerts the desired phar~a-cological actlvity, such as those stated hereinabove, without undue toxic side effects when administered to a mammal in need of such treatment. Dosage will Yary, according to the subject and route of administration selected, with an expected range of 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 ~he desired therapeutic effect. A preferred range for an effective dose would be about 0.1 to 0.5 mg/kg when gi~en intravenously and about 0.5 to 5 mg/kg when gi~en orally.
The compounds of t~e present in~ention can be prepared by a ~onvenient general yrocess. This process is outlined below in Scheme ~.

~ hroughout this application, r~ stand~ for a methyl grou~? and ~c sta~ds for the acet~ta ion, C2H302 .

5cheme 1 ~~ ' (IV) (III) B ~ R5 ~ ~ ~ OM

(II) R R R
H~--o~R5 . (I) Rl-R5 are as defined above.
This process ln~olves the coupling of a suitable methoxylated indolalkylamine (III~ with an R~ substi~uted pheno~y epoxide iDtermediate (IV). Synthetic methodology required ~o reach this pD$nt iD the preparation of Formula I products is analo~ous to a syDthetic process used to prepare bucindololiin the per~aining Krei~hb~um, et ~1. patents U.S. 4,234,595 ~nd U.S. 4,314,943, ~nd ~79~6 J. Med. Chem., 23:3, 2B5-2B9 (198~) artlcle. An additional ~tep, however, is required as ~he resulting ~ethoxylated indole analog (II) is converted to the desired (I) product by cleavage of the methoxy group with boron tribromide in methylene chloride aolution. Other synthetic methods resulting in CDnVersion to hydroxylated products, e.g. such as hydrogenolysis of benzyloxy precursors, are well known to the chemical practitioner and may also be adapted for use in a modified process.
The coupling of the epoxy ether int~nmediate (IV) with the indolylalkylamine (III) to give in ermediate (II) is carried out si~ply by heat:ing the epoxy ether eieher neat or ln the presence of a reactioD iner~ organic sol~ent with an appropriate indolylalkylamine as shown. No catalyst or condensation a~ent is usually requlred.
Suitable solvents include 95Z ethanol but other reaction-inert organic liquids in which the reactants are soluble may be employed~
These may inçlude but are not limited to be~ene, tetrahydrofuran, dibutyl ether, butanol, hexanol, methanol, dimethoxyethane, ethylene glycol, etc. Suitable reaction temperatures are from about 6Q 200C.
The requi~ed reaction in~ermedlates, Ill and IV, ~ay be obtained by se~eral methods and are not lImlted to the follo~ing.
The phenoxy epDxide in~ermediates (IV3 can be obtained by alkylation of the appropriate R5-substituted cyanophenol (V~ with epichlorohydrin as ln Scheme 2; or in recalcitrant cases by usin~ epibromohydrin, R2C03 and dim~thylformamide.

.. ~ . . . . .

~c ' ~2~

Schema 2 R5 ~ Cl ~ ~ R

(V3 (IV) While many cyanophenols (V) are commercially available, they may also be conveniently prepared from readily availsble phenDls via the synthesis outlined as Scheme 3.
Scheme 3 R5 ~ CHCl~ R5 ~ H2NOH 5 ~ CH=~O~
OH NaO~ OH OH

IAC~O

CN

OH
(V) Thls sequence ~ssentially invol~es formylation of an R5-substi~uted phenol accordiDg to Reimer-Tiemann conditions to afford the salicyl-aldehyde deriva~ive which is converted via ebe oxime in~er~ediate to the desired salicylonitrile (V). It s~ould be noted that when Formula I products in which R5 is hydroxyl are desired, the IV

intermedi~te in ~hich R5 is methoxy is to b~ used in Scheme 1.
Cleavage by BBr3 to the hydroxyl group is effected ln the last step of ehe synehesis.
For the intermediate indolylalkylamines of structure III, typical synthe~ic procedures for eheir preparation are ~vailable in the Rreighbaum, et 81 ., patents and ehe J. Med. Chem. artiele c~ted hereinabove. Although these refereneed procedures are applicable to the preparation of o~her indolylalkylamine i~termediates which may be desired but are not specifically disclosed there~n, representative syntheses of ~ormula III compcunds will be given hereinbelow for further ~xemplification of intermediates whlch may be required for the present invention.
Finally, it is of interest that a 6-hydroxyindolyl compound of Formula I (2-~2-hydroxy-3-[~2-(6-hydroxy-I~-indol-3-yl)-l,l-dimethylethyl]amino~propoxy]benzonitrile) which structurally corresponds to bucindolol ~Rl~ R , R5 are hydrogen and R3, R ~re methyl) was used to confirm ~he identi~y of a ma~or ~etabol~te of bucindolol. It ~s k~own that 6-hydroxylation is pPrhaps more import~nt than 5-hydroxylation $n the metabol$sm of tryptamine derivatlves (cf:
Jepson, et al., Biochi~. Bio~ys. Acta., 62, 91 (1962); Jaccarini a~d Jepson, Biochi~. Bioph~s. Acta., 156, 347 (1968)). This knowledge suggested the possibility that 6-hydroxylation of bueindolol might be sn important metabolic pathway. This has been confirmed by demonstr~tion that this 6-hydroxyindolyl compound of the instant invention a~rees in mass spectrum ant gas chromatographlc retention ti~e wieh a corresponding major hydroxy ~etsboli~e of bucindolol. In this regard, .
,,, , ~
, .

ano~her aspect of the instant lnvention comprises 2-~2-hydroxy-3-[~2-(6-hydroxy-lH-lndol~3-yl~-1,1-dimethylethyl]amino]propoxy]-benzonitrile in purified phar~aceutically scceptable for~.
The compounds of the present invention can be for~ulated according ts conventional pharmaceutical practice to provide pharma-ceutical compositions of unit dosage fsrm comprising, for example, tablets9 capsules, powder~, granules, emulfiions, suspensions, and the like. The solid preparations contain the actiYe lngredie.lt in ad~ix~ure ~ith non-toxic pharmaceutical excipient6 such as lnert diluents, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and ~isintegra~ing a~ent~, for exa~ple9 maize, starch, or alginic ac$d; binding agents, for exampl~, starch, gelatin or acacia; and lubricating agents, for exa~ple, magnesium stearate, stearic acid sr talc. The tablets ~8y be uncosted or ehey may be coated by known techniques so as to ret rd disintegration and absorptioD in the gastrointestinal tract snd thereby provide a sustained action over a longer period. Llquid preparations suitable ~or parenteral administration include solutions, suspensions, or emul~ions of the compounds of Formul~ I. The aqueo~s ~uspenslons of the pharmaceut$cal dosage for~s of the compounds of Formula I contain the activ~ lngredient in admixture with one or more non-toxic phar~aceutical excipients known to be suitable in the manufacture of aqueous ~uspensions. Suitable exclpients are, for example~ suspending agents such as sodium carbsxymethylcellulose, 2~ ~ethylcellulose, hydroxypropyl methylcellulose, sodium al~inate, polyvinylpyrrolidone, gum tragecanth and gum acacia. Suitable disbursing or wetting agents are naturally oc~urin~ phosphatides, for example, lecithin, polyoxyethylen~ stearate.

. .

12 ~916 Non-aqueous suspensions may be formulated by suspending the active ingredient in vegetable oil, for example, olive oil, sesame oil, or coconut oil, or in a mineral oil, for example, liquid paraffin.
The suspensions may contain a thickening agent such as beeswsx, hard paraffin, or cetyl alcohol. Sweetening and flavoring agent~ generally used in pharmaceutical compositions may also be included such as saccharin9 sodium cycla~ate, sugar and caramel to provide a palatable preparation. The compositions may also contain other absorbing agents, stabilizing agents, wetting agents, and buffers.

The compounds which constitute this invention, their methods of preparation and their biologic actions will appear more fully from consideration of the following examples, which are given for the purpose of illustration only and are not to be co~strued as limiting the invention in sphere or scope, and the appended claims.
In the following examples, used to ~llustrate the foregoing syntheeic processes, temperatures are expressed in degrees Celsius and melting points are uncorrected. The nuclear magnetic resonances (MMR) spectral characteristics refer to chemical shifts (~) expressed as parts per million (ppm) versus tetramethylsilane (TMS) as reference standard. The relative area reported for the various shifts in the H NMR spectral data rorresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shift~
as to mul~iplicity is reported as broad sin~let (bs), singlet (s), multiplet (m), or doublet (d). Abbreviations employed are DMS0-d6 (deuterodimethylsulfoxide), CDC13 (deuter~chloroform), and are otherwise conventional. The infrared (IR) spectral descriptlons include only absorption wave numbers (cm ) having functional group identificatlon value. The IR determinations were e~ployed using potassium bromide (KBr) as diluent. The elemen~al analyses are j reported as pPrcent by ~eight.

Synthesis of Intermediates A. Intermedl~tes of Formula III: General Procedures Methoxyindol-3-vl-tert.-butylamine To 15.2 ~L of a chilled 25% aqueous solution of dimethyl-amine the followin~ are added sequentially with stirring snd contlnued cooling: 16D9 ~L of ~c~tic acidg 7.2 mL of 37% for~aldehyde, 27 ~L
of 95% ethanol. The resulting stirred solution is kept at 0~ to -5 with a c~oling bath while the appropriate methoxyindole tlO.O g, 0.~7 mole) is added in portions. This mixture is stirred and gradually warmed to 30 over a period of one-half hour and then held at 30~
with stirring for 3 hours. The reaction mixture is then chilled to 10-15 and acldified ~ith 17~ mL of 2N HCl. This acidic mixeure can be decolorized ~Darco G-60), filtered and the filtrate made basic using 20 245 mL of 20% NaO~ ~hile being cooled and stirred. A resul~ing brown oily precipitate is ether extracted, and the extracts are water-washed, dried (MgS04) snd concentrated to a brown oily residue (14 g).
The residue is recrystallized, e.g. from isopropyl ether and hexane to yield the desired methoxygramine, usually as a tan solid.
A mixture comprised of the appropriate methoxygramine (7.7 g, 0.04 mole), 2-nitropropane (2~.5 g, 0.3 mole), and NaOH
(1.7 g pellets, 0.04 mole) is refluxed under a nitrogen atmosphere ..
, for 3-5 hours. The reaction mixture is then cooled to room tempera,ure, acidified with lOX acetic acid and extracted with ether.
The ether ~xtracts ~re water-washed, dried (~gSO~), and concentrated in vacuo to a residue. Recrystallization of the residue, e.g. from isopropyl alcohol-water gives a 3-(2-meehyl-2-nitropropyl)methoxyindole.
This nitropropylindole compound and activsted Raney Nickel (4.2 g) are combined in 80 ~L 95~ ethanol and heated to reflux.
Heating is halted as a solution comprised of 85% hydrazine hydrate (7.8 g) in 8 mL of 95% ethanol is added dropwise. The reaction mixture is then heated at reflux for 2 hours, cooled to room temperature and filtered. The filtrate is concentrated to an oily residuç which can be recrystalli7ed, e.g. from ethyl acetate-isopropyl ether to give the desired ~ethoxyindol-3-yl-t-hutylamine product.
EXAMPLE la 6-MethoxYindol-3-yl-tert.-butylamine A mixture of 6-methoxy gramine (0.9 g, 0.004 ~ol~, prepared from 6-methoxyindole by the procedure of Example 1), 3.0 g (0.034 mole) of 2-nitropropane and 0.19 g (0.005 mole) of ~aO~
pell~ts was stirred a~ reflux in an oil ba~h under a nitrogen atmos-phere for 2 hours, as dimethylamine escaped through the condenser.The resulting mixtus~ was cooled to 25, treated with a solution of 0.47 mL of glacial acetic acid ln 4.1 mL of ~ater and extracted with ether. The ether ~tract was washed with three portionæ of water, dried (M~SO~ and evaporated to dryness. The residual brown oil crystallized upon rubbing and coolir.g in a small amount of isopropyl ether. The solid was isolated by filtration, washed with cold isopropyl ether and drled in air to give 0.6 g of tan solid which was , 3~

recrystalli~ed from isopropyl alcohol-water to give 0.52 g (46X) of 3-~2-m2thyl-2 nitropropyl)~ etho~yindole, m.p. 9B-99 DC.
A slurry of 8.0 & ~0.32 ~ole) of the nltro compound as prepared above, 80 mL of 95% ethanol and 4.2 g of Raney Nickel ~washed with water and 95% ethanol) was heated to reflux ~ith paddle stirring. Exterior heatlng was halted and a solution of 7.8 g of 85%
hydrazine hydrate in 8 mL of 95% ethanol was added dropwise at a sufficient rate to maintain a gentle reflux. After the addition, the mixture was reheated at reflux for two hours and then cooled to 25C.
Filtering and concentrating the filtrate to dryness gave a crude syrup ~hich was chromatographed on silica gel column, eluting with CH2C12-CH30H-concentrated NH40H (90:10:1). The tan solid th~s obtained ~2.9 g, m.p. 125-128~C) was recrystallized from ethyl acetate-isopropyl ether to afford 1.27 g (18~) of 6~methoxylndol-3-yl-tert.-butylamine, m.p. 125-128.

- Methoxyindol-~-yl-ter~-butylamine (~1 R2 = ~, R3. R4 ~ Me) _ In this ~eneral procedure a solution comprising the appropriate m2thoxyindole-2-carboxylic acid (0.06 mole) and thionyl chloride (2.0 g, 0.17 mole) in 130 mL of dry ether is stlrred for 12-18 hours at room temperature under a nitrogen atmosphere. The reaction mixture is flltered and the filtrate is concentrated to an oily residue which i~ taken up ln 150 mL of dry ether. This ether solution is ~reated uith 80 mL of dimethylamine in 90 mL of ether.
The ethereal reactlon mixture is concentrated to dryness aDd the residue crystallized in i~opropyl alcohol~ The solid i8 isolated by filtratioIl to give a ~0-40X y~elt of the metiIvxyiTldole-2-carboxamide product.
The methoxyindol-2-yl carboxamide is dissolved in lOO mL
of THF and this solution is add~d dropwise to a stirred suspension comprised of 3 g of lithium aluminum hydride in 50 mL of I~IF under a nitrogen atmosphere. After heating at reflux for 2 hours, the reaction mixture is cooled and decomposed with a ~mall a~ount of water and dilute NaOH solution. This mixture is filtered and the filtrate is concentrated to a residual oil which is taken up in absolute ethanol and tre2ted with a slight excess of dimethyl sulf~te.
The resulting alcoholic solution is stirred at room temperature for four hours and then concentrated in vacuo to dryness giving as residue a tr$methylam$ne quaternary salt.
l~ The crude quaternary salt product (0.01 mole) is combined with NaOH ~2.0 g pellets, 0.05 mole) and 2-nitropropane (15 mL) and the mixture is heated at reflux under a nitrogen atmosphere for 1 hour. The resultant dark thick mixture is cooled, diluted ~ith water, acidified with acetic acid to a pH of approx$mately 6 and then extracted with ether. These ether extracts are combined, washed with water, dried (MgS04) and concentrated to a dark residue which is chromatographed on a silica column and diluted with methylene chloride.
Removal of the methylene chloride ~olvent and recrystallization of the crude material from isopropyl alcohol-water gives a methoxyi~dole substituted in the 2-position with a 2-methyl-2-nitropropyl moiety.
R~duction of this n$tro product ~i~h Raney Nickel and hydrazine according to the procedure used in Example 1 above will yield the desired methoxy~ndol-2-yl-tert.-butylEmine.

, l-~ethylation of Methoxyindolylalkylamines:
3-(2-A~ino-2-methylpropyl~ methyl-methoxyindole (Rl R3 R4 - Me, R2 ~ H) In this general proc~ss 7 g (0.11 mole) of ~5% ~OH ls ground in a mortar and quickly transferred to a nitrogen-flushed 25-mL Erlenmeyer flask. DMSO (55 mL) is added and the mixture is stirred fDr 5 mlnutes. Additions of methoxyindolyl-tert.-butylamine (0.27 mole) and iodomethane (3.78 g, 0.03 mole or any other s~itable alkylating agent~ are each followed by 45 minutes of stirring after which the suspension is quenched in 300 ~L o water. Extraction of the mix~ure with ethyl acetate9 followed by washing of the extracts ~ith water and brine affords a clear solution which is dried (MgSO4) and evaporated in vacuo to an olly product. This free base ~ay be used as a ineermediate without further purification. Chsracteriza~ion is usually made by converting the oily base to the hydrochloride salt in order to obtain a crystalline product.
EXAMPL~ 4 Methox~indol-2-ylethylamine In this pro~edure whlch iB essentially that of Bhat and Siddappa, J. Chem. Soc. (C), 1971, 178-81; va~ious methoxyindol-2-carboxylate esters (commercially available or prepared by literature methods) is reduced to the corresponding 2-hydroxymethylindole derivative by reduction with lithium aluminum hydride in ether.
Conversion to the indol-2-carbaldehyde ls accomplish~d by dissolving a 2-hydroxymethyl-methoxyindole (4 g~ in dichloromethane (2~0 mL) and adding activated manganese dioxide (10 g~ followet by stirring of the reaction mixture at room temperature for 20-30 hours. The reaction is followed by TLC, monitoring the di~appearance of the starting 2-hydroxymethyl~ndDle spot. If neces~ary, fresh quantities of manganese dioxide ~2-3 g) can be ~dded. l'he reaction mix~ure is filtered and the residual manganese dioxide washed repeatedly with ~ little fresh dichloromethsne. The combined filtrate i8 ev~porated ~o dryness to give the crude methoxyindol 2-carbaldehyde ~s a pale yellow solid which is then r~crystsllized.
The me~hoxyindol-2~carbaldehyde (5 g), nitromethane (B mL), and ammonium acetate (1 g) are h ated under reflux for 1/2 hour.
The reaction mixture is cooled and the dark red crystals that separate are collected, washed thoroughly with water, dried and crystallized from ethanol. The nitrovinylmethoxyindole thus prepared is then reduced to the desired methoxyindol-~~ylethylamine by treatment with lithium aluminum hydride in dry ether. The reduction mixtu~e is gently heated under reflux for lo hours following which the excess lithium aluminum hydride is deco~posed. Follo~in~ filtsation, the -filtrate is concentrated in vacuo to give a residu~ which is crystallized from a suitable solvent to give ~he desired ~ethoxy-indol-2~ylethylamine.

MethoxYindol~2~y~prop~1am$ne Modifying the procedure of Exa~ple 4, an appropriate methoxyindol~2~carbaldehyde tl g) in nitroethane (O.S mL~ is treated with four drops of benzylamine; following which the mixture is heated at reflux for one hour. The cool reaction mixture on standin~
deposits d~rk red crystals which may be collected, washed with a little ether, dried, and crystallized from ethanol. ~hese nitro-propenyl indoles thus prepared are reduced with lithium alu~inum hydride ns described above In Ex~ple 4. Solid products are crystallized and the liquids are characterized as benzoyl derivatives.

Methoxyindol-3-ylethyl~mine Cf: Young, J. Chem. Soc., 1958, 3493-96; This synthesis starts with methoxylndol-3-aldehydes which are either available commercially or prepared from literature methods. Using the pro-cedure outlined in Ex2mple 4 abo~e, an appropriate methoxyindol-3-carbaldehyde is condensed with a nitromethane using ~mmonium acetate as a catalyst~ On standing, the cooled solution grsdually deposits dark red crystals which can be recrystallized from benzene or methanol to give the 3-nitrovinyl-methoxyindole which is reduced wi~h lithium aluminum hydride, as ~bove to yield the desired methoxyindol-2-ylethylamine.

Methoxvindol-3-ylpropylamiDe A selected methoxyindol-3-carbaldehyde (5 g), nitroethane (10 ~L)~ snd ammonium acetate ~l ~) are heated on a ~team bath with occasional shaking for 1/2 hour. On cooling, the crystals are collected, washed with hot ~ater (2 x 50 mL) and crystallized from methanol. The resulting 3-(2-nitropropenyl)-methoxy~ndole is reduced to the desired 3-(2-aminopropyl)-methoxyindole by treatment with lithium al~minum hydride as detailed in the above procedures.

- 2~ -B. Inter~ediates of Formula IV

2-[(2,3-Epoxy)propoxy~benzonitrile A solution of 2-cyanophenol (25.0 g, 0.21 mole), epichloro-S hydrin (117 g, 0.26 mole)~ and piperidine (10 drops) was stirred and - heated at 115-120 in an oil bath for 2 hours. The reaction mixture was then concentrated (90~30 Torr.) to remo~e unreacted epichlorohydrin.
The residue was diluted with toluene and concen~rated to dryness twice to help remove the last traces of volatile material. The residual oil ~as dissolved in 263 mL of tetrahydrofuran and this solution was stirred at 40-50~ for one hour ~ith 263 mL of lN NaOH.
The organic layer was s&parated and concentrated to give an oil which ~as combined with the aqueous phase. The mixture was extracted (CH2C12), and the extract dried (MgS04) and concentrated to ~ive 36.6 g (100~ of oil which slowly csystalli~ed to a waxy solid. This intermediate product may be used without further purlfication in the preparation of Formula I products.

2-~(2,3-Epoxy)propox~1-4-methoxybenzonitrile The requisite 5-methoxysalicylaldehyde can be obtained from

4-methoxyphenol by the Reimer-Tiemann procedure which is well described in the l~erature~ e.g. CE: Rappe, et al., Arch. Pharm., 308/5, 339 (1975). A solution comprising O.OOS mole o~ the starting salicylaldehyde in 6 mL of pyridine and 6 mL ~f absolote ethanol is trea~ed with 0.4 g (0.02 mole) of hydroxylamine hydrochloride and heated at reflux for 4 hours. The mixture is concentrated in vacuo to a gray syrup ~h~ch is stirred with 50 mL of H20 and the suspension ~;23L~7~4~6 decanted. Addition ~f 10 ~L of ~0 to the residual glassy material followed by chilllng at 5 affords, upon filtration, approximately 1.2 g of crude solid which is taken up in 25 mL of 50~ ethyl e~her-isopropyl ether. The ether solution ic filtered, dried ~MgS04), ereated with Darco G-60 and Celite, filtered ant concentrated in vacuo to a waxy solid. Recrystallization from ethyl ether~Skelly B
gives the corresponding ben~aldehyde oxime.
A m~xture of 0.002 mole of the oxime and 1.02 g ~0.01 mole) of acetic anhydride is heated at reflux for 30 ~inutes and then cooled to 25. Wa~er (50 mL) was added~ followed by dropwise addit~on of 20% ~aO~ ~o p~ 10. The resulting suspension was ~tirred at 253 fos 20 hours (to hydrolyze any acetate ester of the desired phenol derivative. The pH is adjusted to about 2 using ~_ HCl and the resulting mixture i6 extracted with 40 mL of ethyl acetate to give an organic layer which is separated, dried (MgS04) end evaporated at 65/70 Torr. to give a tan syrup which sti:Ll consists mainly of the acetate ester. Further hydrolysis of the syrup in a mixture of 7 mL
of methanvl, 7 mL of water ~nd D.l g of ~a~H pellets at 25 for 3 hourc ~s followed by remo~al of the methaDol at 6~7~ torr.
Dilution of the aqueous residue with 0.5~ HCl affords a precipitate which can be recrystallized ~rom isopropyl ether and dried to give the desired benzonitrile intermediate.
A mixture of 0.015 mole of the 2-hydroxy-5-methoxybenzo-nitrile, 4.2 ~ (0.03 mole) of finely powdered anhydroue potassium 25 carbonate and 140 mL of D~F was stirred at 50 for 15 minuteæ.
Epibromohydrin (2.8 g or 0.02 mole) was added in one portioD ~nd stirring was continued for 3 days. The reaction mixture was '3~i poured into 1 liter of brine and the resulting suspension stirred for 3 hours at 0-5~. Filtering the mixture and washing the ftlter cake with water gave upon drying in air the crude lntermediate compound which could be used without further purification.
Similarly, using other substituted 2-cyanophenol~ in modifications of the above procedures will provide the other inter-mediate compounds of Formula IV to be used in synthesis of the vsrious Formula I compounds of this invention~

Synthesis of Products General Procedure: 2-~2-Hydroxy-3-[(hydroxy-indolYl)alk~lamino]propoxy]benzonitrile A selected methoxyindolylalkylamine (III~ is mixed with an equimolar or slight excess amount of a selected epoxy propoxy benzo-nitrile (IV) and the coupling is accomplished by either refluxing a solution of the ~eactants for apprDximately 18 to 24 hours or heating -a neat mixture at a temperatu~e of about 120L13~ for abQut lJ2 t~
2 hours. Ethanol and tol~ene are the usual solvents chosen for the reaction ~edium for coupling via refluxing a solution of III and IV.
In some instances, it is advantageous to follow the course of the reaction by TLC, adding addltional IV epoxide un~il all indolylamine III has disappeared. FO11DWing reaction the ~ixture is concentrated to dryness and the residue is either washed and used crude in the next step or the intermediate methoxy product may be pur$fied by crystallization-recrystallization either as the base or a suitable acid addition salt.

A jolution of the methoxyindolyl product ~II) dissolved in ~ethylene ehloride ~nd stirred under a nitrogen at~ofiphere at 0-10 ~hile a several-fold excess of lN boron tribromide ln me~hylene chloride i6 added dropwise. Following ~dditlon, the resction mlxture is stirred a~ room ~e~p~rature for about 6-8 hours. The excess boron tribromide is decomposed by chilling the reaction mixtu~e And dropwlse addition of excess waeer. The crude hydrobromlde salt of the Formula I
product may be worked up in a number of GonventioDal ways ~uch as recrystallization, conversion to the base and purification, co~verslon to the base followed by conversion to a tifferent acid addition salt, and 60 forth.
The modific~eions necessary to ~dapt thi6 procedure for the preparatlon of speclfic compounds of Formula I are well wiehin the skill of any ordinary practitloner in ehe chemichl arts.
E~AMPLE 11 2-[2-Hydroxy-3-[[2-(6-hydroxy-lH-indol-3-yl)- --1.l-dimeth~lethyl~amino~proPoxy]benzonitr~le A solution of 6-methoxyindol-3-yl-t-butylamine ~2.S g, 0.012 mole; prepared ~n Exa~ple la), 2 ~(2,3-epoxy)propoxy~benzo-20 ni~ril2 (2.1 g, 0.012 mole; prep~red in Example 8)~ and 100 mL of absolute ethanol was stirred ae reflux for 20 hours. Additional epoxide ~0.21 g) was added aDd reflux was continued for 4 hours, after which the mixture ~as concentrated to dryne~s s~d the r~sidue trituratPd in isopropyl alcohol to induce crystallization. The produc~ ~as collected by filtration, washed with cold isopropyl ~lcohol and dried in ~ir to give 4.0 g (85~) of the me hoxy pr~duct (II), m.p. 145-146~, which was used directly in the next step.

- 25 ~

, ~ . ~ ., 2 .:. ' 7~3~i A ~olutlon o ehe methoxyindole product prepared ~bove ~1.5 g, 0.004 mole) in 225 mL o~ methylene ~hlo~lde W~6 6tirr~d under ~ nitrogen atmospherP ac 5-lD~C wh~le 15.3 mL (0.015 ~ole) of lM
boron t~ibrom~de in methylene chlorite was added dropwlse. F~lluwing ~he addi~lon, the ice b~th ~as removed and the re~ction mixtuse was stir~ed it 25~ for 6 hours b~fore refrigeratlon to 5~10~ and dropwlse ~ddition of 47.5 ~L of H20. The result$ng ml~ture was decanted ~nd the residual ~ummy solid rinsed wlth 2 portions of ~0. Dissolving ~his crude hydrobromide salt ln 50 mL of hot H20 followed by treatment with Darco G-60, fil~eri~g, cool~ng (25) aDd basifying ~p~ B) with conc. N~40H gave 1.2 g of tan morphous sol~d wh~ch was chromatographed (silica gel 609 230-400 mesh, ~M Reagenes) o~ ~ medium pre~sure syste~ with chloroform-methanol-conc. N~40~ (90:10:1). The prDduct ob~ain~d in this manner crystallized from a small amount of 95Z
ethanol to afford, by gradual add~tion of H20, 1.~3 g ~71%) of the desired ~hydro~yindole protuct (I) as a t~n ~olid, m.p. 90-94.
Anal. Calcd- for C22~25N33-1/3~ C~ 68-56; ~ 6-67;
N, 10.90; ~2~ 1054. Found: C, 6~.69; ~ 6.68; ~, 10.68; ~2~ l.B0.
NMR (DMS0-d6): 0.98 t6.s); 2.70 (4,m); 3.30 ~2~s);
3.83 (l~m); 4.11 (2,d [5.8 Hz)); 5.00 (l,bs); S.65 ~3,m), 7.20 (3,m);
7.60 (2,m); 8.71 (l,bs); 10.35 ~l,bs).
IR (K~r): 760, 800, 1260l 1290, 1450, 1495, 1600, 1630, 2230. and 3300 c~ 1.

*Trademark - 2~ -t ............................. .. . . . .

2-[2-Hydroxy-3-[[2~(5-hydroxy-lH indol-3~yl)-1 =~l~oxy]ben:ollitrile A solution of 5-methoxyindol-3-yl-t-butylamine (2.7 g, 0.0125 mole; prepared from 5-methoxyindole utilizing the procedure g1ven in Example 1), 2-1(2,3-epoxy)propoxy]ben~onltrile (2.2 g, 0.0125 mole)9 and 20 mL of acetone was refluxed for 1/2 hour. The acetone solvent was then allowed to boil off and the oily residueheated neat at 100 for 2 hours. Isopropyl alcohol (20 mL) was added and the reaction solution refluxed for 4 hours following wh~ch it was cooled to room temperature, diluted with 50 ~L of ether and a stirring rod was used to rub out a white powder, 4.7 g (96~), m.p. 119~124; TLC (9:1 CHC13-methanol) cxhibits a single spot, Rf 0.25. This crude methoxy product ~ay be used direotly in the next seep or be purified via conversion to the RCl salt. Con-version to the ~Cl salt by treatment of an ~cetonitrile solution with ethanvlic HCl gives a crude product which is recrystallized ln butanone-95~ ethanol ~20:1) to off-~hite powder, m.p. 164-166.

Anal. Calcd. for C23~27N303-HCl: C, 64.~5; ~, ~.56;
20 N, 9.77. Found: C, 64.14; H, 6.54; N, 9.68.
Using the procedure given above in Example 11 for boron tribromide cleavage of the methoxy group, bu~ employing the 5-methoxy-indole intermediate product (II) prepared above, the d~sired

5-hydroxy indole product (I) in the form of its hydrDbrGmide salt may be obtained. The pure hydrobromide salt is a beige powder, m.p.
219-221 .
Anal. Calcd. for C22H25N303oHBr: C, 57.40; H, 5.70;

N, 9.13. Found: C, 56.90; H, 5~67; N, 9.45.

~'7~3~i N~R (DMSO-d6):- 1.32 t6,s~; 3.08 (2,m); 3.36 (2,m); 4.30 (3,m); 5.90 (l,bs); 7.10 (6,m); 7071 (2,m); 'Q.55 {3,bs); 10.95 (l,bs).
IR (~Br): 750, 800~ 1265, 1290, 1455, lb95, 1580, 1600, 7230, and 3300 cm 1.
5tartin~ with appropriate methoxyindolalkylamines (III) and epoxypropoxybenzonitriles (IV), additional examples of Formula I
products may be synthesized using substantially the same procedures as outlined hereinabove with only slight mod$fications which would be well within the skill of a practitioner in the chemical arts. Some additional products of Formula I which may be synthesized by these means are shown in Table 1.

'9~

Table 1 HO ~ O ~ R5 (I) CN

Example -OH R R2 R3 R R5 13 4- H 2-H Me Me H
14 7- ~ 2-H Me Me 5 . 15 4- Me 2-H Me Me H
16 5- Me 2-H Me Me 5-F
17 6- Me 2-H Me Me 5-OH
18 7- Me 2-H ~e Me H
19 4- Me 3-H H Me H
5- Me 3-H H Me 5-F
21 6- Me 3-H H Me H
22 7- Me 3-H H H 4-Me 23 4- H 2-Me H Me 24 5- M 2-Me H ~ H

6- H 2-Me Me Me H
26 7- H 2-Me Me Me 27 4- H 3-Me. H H 5-OH
28 5- H 3-Me H Me 5-F
29 6- H 3-Me H Me H

7- H 3-Me H H 5-Br 31 4- H 2-H H Me 5-Me 32 5- H 2-H H Me 4-Cl 33 6- H 2-H H Me 34 7- H 2-H B Me 4-OH

'7~

Biolo~icsl E~aluation These biologica~ tests were used to gauge the antihyper-tensive profile of selected co~pounds of Formuls I.

EXA~PLE 35 The efficacy of antihypertensive agents other than adrener~c beta-receptor blocking agent~ is commonly estimated in the spontaneously hypertensive rat. Blood pr~ssure vslues are determined for test animals prior to and 2 and 4 hours after oral doses of 30-10~ mg/k~
of test compounds. Heart rate is dete D ined w~th each pressure measure~ent as well. A fall in blood pressure at 2 or 4 hours after the single dose in the range of 15-2~ mm~g is considered "questionable"O
"Active" and "inactive" designations are decreases greater and less than ~hat range, respectively.
EXA~LE 36 Another test useful in determining efficacy of antihyper-tensive agents utilizes DOCA-salt hypertensive rats. These hyper-tensive rats are prepared as follows: male rst6 of ~he Sprague-Dawley strain weighing approximately 90 g are iDdividually c~ged ~ith ~ree access ~o foDd and ~ater for a 5-day pretreatment period, afeer which, the drinking water is replaced with 1~ saline solution.
During a 3-week ~reatment period, ~he rats are given a total of 10 subcutaneous injections containing 10 ~g of DOCA (deoxycortico6terone acetate) in 0.2 mL suspending vehicle (0.25% Tween B0 and 0.125~ CMC
in normal saline solution). After the final injection, the 1~ saline i6 replaced by distilled water and the animals are available for use one week later.

*Trademark The test i6 made by selecting non-fasted animals with elevated systol~c blood pressures ~>160 mmHg). Blood pressure values are dete~mined for these test animals prior to and fsur hours after oral do~es of 30-100 mg/kg of test compounds. During the test period 5 the animals are housed in metabolism cages without feed or water and urine is collected for 4 hours. Heart rate and body weight are both determined with each pressure measurement as ~ell. A all in blood pressure 4 hours after dosing ~hich lies in the range of 15-20 mmHg is considered "q~estionable"O "Active" and "inactive" designations 10 are decreases greatel and less than that range.

The angiotensin II-~upported ganglion-blocked rat model is utilized as a screening test for estimation of the direct vasodilator component of activity. Percentage changes in blood pressure in 15 anesthetized rats 30 minutes after intravenous dosing are determined.
~ne intravenous dosing is done with test compounds at 3 mg/kg Borderllne activiey is defined as appr~x~mately a 10% tecrease in blood pressure measured 30 ~inutes after dosing. "Active" and "inactive" desigDations are increases greater and less than that.

Dias~olic blood pressure and heart rate responses to a fixed challenge dose of isoproterenol are obtained before and 15 minutes after graded doses of ~est compound administered intravenously over a 3 minute interval to ~nesthetized dogs. A branch of a femoral 25 artery and vein are cannulated to record blood pressure and t~
administer the drugs which are dissolved in saline. The ~agi were sectioned bilaterally in the mid-cervical region of the neck and the 1~ 36 dogs are ventilated mechanically (~arvard respiratory) with room air at a rate of 20/minute and a stroke volu~e of 20 nI,/kg. Heart rate is monitored with a cardiotachometer triggered by the pressure pulse.
All measurements are recorded on a Beck~an R 612 recorder. The drug effect is expressed in terms of a cumulative dose (microgram/kg) causing 50% inhibition of isoproterenol response.
EXAMPL~ 39 Rats (male Wistar) are anesthetized with ~ co~bination of urethane and chlcralase intraperitoneally. Following induction of anes~hesia, chlorisondamine ls in~ected into the peritoneal c~vity to produce ganglion blockage. A femoral artery was cannulsted to ~oni~or blood pressure and heart rate and two femoral veins were cannulated to administer compounds. The trachea was intubated and rats were allowed ~o breath spontaneously. Animals were challenged before and 15 minutes after intravenous administration of test compound with graded doses of phenylephrine and the changes in blood pressure recorded. Data were plotted to obtain dose-response curves and the dose of phenylephrine required to elicit a 50 ~mHg (ED5~) inerease in blood pressure was interpolated fro~ the curv~s. Dose shifts are calculated by divid~ng the ED50 after drug by the ED50 before drug.

Claims (22)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound having the formula (I) and the acid addition salts thereof wherein one of R1 and R2 is hydrogen and the other is hydrogen or C1-4 alkyl;
R3 and R4 are independently selected from hydrogen or C1-4 alkyl;
R5 is halogen, hydrogen, hydroxy, or C1-4 alkyl;
the phenoxypropanolaminoalkyl side chain is attached to the indole ring at either the 2- or 3-position; and the hydroxyl substituent group occupies either the 4-, 5-, 6-, or 7- ring position of indole, said process comprising:
a) coupling a methoxylated indolalkylamine III

(III) wherein R1, R2, R3, and R4 are as defined hereinbefore, with an (R5-substituted phenoxy epoxide) IV

(IV) wherein R1, R2, R3, and R4 are as defined hereinbefore, by heating III and IV together either neat or in the presence of a reaction inert organic solvent, so as to produce an intermediate II

(II) wherein R1, R2, R3, R4, and R5 are as defined hereinbefore; then b) cleaving the methoxy group of the reacting intermediate II
to a hydroxyl group so as to form the compound of formula I;
and then c) optionally, if a pharmaceutically acceptable acid addition salt of formula I is desired, then converting the product in step (b) to said salt by standard techniques.

2. A process according to claim 1, wherein step (b) comprises reacting intermediate II with boran tribromide in methylene chloride solution under reaction conditions so as to form the compound of formula I.

3. A process according to claim 1, wherein the indolyl ring is attached at its 3-position to the phenoxypropanolaminoalkyl side chain.

4. A process according to claim 1, wherein R1 and R2 are hydrogen.

5. A process according to claim 1, wherein R3 and R4 are methyl.

6. A process according to claim 1, wherein R5 is hydrogen or 5-fluoro.

7. A process according to claim 3, wherein R3 and R4 are methyl.

8. A process according to claim 6 wherein R5 is hydrogen or 5-fluoro.

9. A process according to claim 1, wherein the hydroxyl substituent occupies the 6-ring position of indole.

10. A process for preparing 2-[2-hydroxy-3[[2-(6-hydroxy-1H-indole-3-yl)-1,1-dimethylethyl]amino]propoxy]benzonitrile, said process comprising:
a) reacting 5-methoxyindol-3-yl-t-butylamine with 2-[(2,3-epoxy)propoxy]benzonitrile in the presence of a suitable refluxing organic medium so as to produce a methoxylated indole intermediate product;
b) cleaving the methoxy group of the intermediate to an hydroxyl group.

11. A process for preparing 2-[2-hydroxy-3-[[2-(5-hydroxy-1H-indol - 3-yl)-1,1-dimethyl ethyl]amino]propoxy]benzonitrile, said process comprising:
a) reacting 5-methoxyindol- 3-yl-t-butylamine with 2-[(2,3-epoxy)propoxy]benzonitrile in the presence of a reaction inert organic solvent;
b) refluxing the resultant mixture in a suitable organic medium so as to produce a methoxylated indole intermediate product;
c) cleaving the methoxy group of the intermediate to an hydroxyl group.

12. A compound having the formula (I) and the acid addition salts thereof wherein one of R1 and R2 is hydrogen and the other is hydrogen or C1-4 alkyl;
R3 and R4 are independently selected from hydrogen or C1-4 alkyl;

R5 is halogen, hydrogen, hydroxy, or C1-4 alkyl; the phenoxypropanolaminoalkyl side chain is attached to the indole ring at either the 2- or 3-position; and the hydroxyl substituent group occupies either the 4-, 5-, 6-, or 7- ring position of indole, whenever prepared by the process of claim 1.

13. A compound of claim 12, whenever prepared by the process of claim 2.

14. A compound of claim 12 wherein the indolyl ring is attached at its 3- position to the phenoxypropanolaminoalkyl side chain, whenever prepared by the process of claim 3.

15. A compound of claim 12 wherein R1 and R2 are hydrogen, whenever prepared by the process of claim 4.

16. A compound of claim 12 wherein R3 and R4 are methyl, whenever prepared by the process of claim 5.

17. A compound of claim 12 wherein R5 is hydrogen or 5-fluoro, whenever prepared by the process of claim 6.

18. A compound of claim 12, wherein R1 and R2 are hydrogen and R3 and R4 are methyl, whenever prepared by the process of claim 7.

19. A compound of claim 12, wherein R1 and R2 are hydrogen, R3 and R4 are methyl and R5 is hydrogen or 5-fluoro, whenever prepared by the process of claim 8.

20. A compound of claim 12 wherein the hydroxyl substituent occupies the 6- ring position of indole, whenever prepared by the process of claim 9.

21. A compound of claim 1 which is 2-[2-hydroxy-3-[[2-(6-hydroxy-1H-indol 3-yl)-1,1-dimethylethyl]amino]propoxy]benzonitrile, whenever prepared by the process of claim 10.

22. A compound of claim 1 which is 2-[2-hydroxy-3-[[2-(5-hydroxy-1H-indol-3-yl)-1,1-dimethylethyl]amino]propoxy]benzonitrile, whenever prepared by the process of claim 11.