IE57682B1 - 1-phenoxy-3-hydroxyindolyl-alkylamino-2-propanols and preparation - Google Patents

Abstract

1-(2-Cyanophenyloxy)-3-(hydroxyindolylalkylamino)-2-propanols and their salts 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. The compounds have the formula wherein one of R<1> and R<2> is hydrogen and the other is hydrogen or C1-4 alkyl; R<3> and R<4> are independently selected from hydrogen or C1-4 alkyl; R<5> is halogen, hydrogen, hydroxy, or C1-4 alkyl;o

Description

The present invention is concerned with heterocyclic carbon compounds of the indole series having an amino substituent, and with medication utilizing these conpouncls. A large body of prior art exists for many series of compounds5 classified as 3-(aryloxy)-2-hydroxypropylamines. Most of these series claim utility as useful agents in treatment of cardiovascular diseases, particularly beta-adrenergic receptor blocking activity.

Many compounds in this general class also possess a degree of vaso-dilating effectiveness due, in some instances, to inherent alpha- lO adrenergic receptor blocking activity. Various other cardiovascular drug effects, or their lack, combine to make some of these compoundsappear to be useful as antihypertensive agents. Most prior art,however, concerns the beta-adrenergic blocking agent property for these series of compounds. The prototype for structures of this kindis propranolol; chemically, l-(isopropylamino)-3-(l~naphthylo3ty)-2-propanol. Propranolol and some related naphthyloxy propanolaminesare the subject of U.S. Patent So. 3,33/,628 issued August 22, 1967. 5 Numerous subsequent patents have been granted covering series ofcompounds representing structurally modified 3~(aryloxy)-2-hydroxy"propylamines. A series of lndol-3-yl-tert.-butvlaminopropanols Cl,2) withantihypertensive properties was described in: Kreighbaua, et al., 10 U.S. Patent No. 4,234,595 patented November 18, 1980; U.S. Patent No.4,314,943 patented February 9, 1982; end Journal of MedicinalChemistry, 23:3, 285-289 (1980). (1) 0-Ar-Het (2) In these foregoing structural formulae, the symbol R canbe hydrogen, halogen, lower alkyl or alkoxy but not hydroxyl. A preferred compound of the structural Formula (1) seriesis designated MJ 13105» also known by the United States Adopted Name 5 as bucindolol, and is currently undergoing evaluation clinically as an antihypertensive agent.

It is of interest in regard to the present compounds that amajor metabolic pathway for MJ 13105 involves 6-hydroxylation of the 10 indole ring. This was confirmed by comparison of metabolic isolateswith the synthetically available corresponding 6-hydroxyindolylcompound of the present invention.

Attention is also called to applicant's pending U.S. Appli-cation Serial No. 414,748. filed September 3, 1982, which discloses a J 5 series of vasodilating agents having a range of beta-adrenergicblocking potency and possessing structural formula (3). (3) While in the foregoing structural formula (3), C can behydroxyl., among other substituents, the series in general isdistinguishable from the present invention in that compounds ofstructure (3) are pyridinvloxypropanolamines.

The present invention includes the compounds of Formula Ϊ and the acid addition salts of these substances. 1 5 In the foregoing structural formula the symbols R -R1 2 have the following meanings. One of R and R is hydrogen and the3 4 10 other is hydrogen or C . alkyls R and R are independently selected from hydrogen or alkyl, and R^ can be halogen, hydrogen, hydroxy, i ? 3 or alkyl. For preterred compounds R is H, R" is 2-H, R and R^ are methyl, and R^ is hydrogen or 5-fluoro. The compounds of thepresent invention are useful as antihypertensive agents due in part 15 to a combination of their adrenergic receptor-blocking and vasodilator activities.

The invention includes compounds having the foregoing structural formula (I) and the acid addition salts thereof. Inτ 2 3 A structural formula I, 3''s κ „ R . and R can be hydrogen or alkyl1 2 having 1 to 4 carbon atoms. One ox R" and R will always be hydrogen3 Λ whereas R and R’ are independently selected and can both be alkyl. r5 can be halogen, preferably fluoro or chloro; hydrogen; hydroxyl; or lower alkyl. The indolyl system is attached to the side chain at either the 2- or 3- position and the hydroxyl substituent occupies either the 4-, 5-, 6-, or 7- ring position of indole. For preferred1 2 compounds. R" is hydrogen; R" is 2-hydrogen (the indole moiety being3 4 coupled to the main side chain through its 3-position); R and R aremethyl; and is hydrogen or 5-fluoro.

For medicinal use, the pharmaceutically acceptable acid addition salts, those salts in which the anion does not contributesignificantly to toxicity or pharmacological activity of theirorganic cation, are preferred. The acid addition salts are obtainedeither by reaction of an organic base of structure I with an organicor inorganic acid, preferably by contact in solution, or by any ofthe standard methods detailed in the literature and available to anypractitioner skilled in the art. Examples of useful organic acidsare carboxylic acids such as, for example, maleic acid, acetic acid,tartaric acid, propionic acid, fumaric acid, isethionic acid, succinicacid, panoic acid, cydantic acid and pavalic acid; useful inorganicacids are, for exanple, hydrohalide acids such as 1IC1, IEr, III;sulfuric acid and phosphoric acid.

It is also to be understood that the compounds of the present invention include all the optical isomer forms,, that is, mixtures of enantiomers, e.g., racemic modifications as well as theindividual enantiomers. These individual enantiomers are commonlydesignated according to the optical rotation they effect, by (-r) and(-), (1) end (d), or combinations of these symbols. The symbols (L)and (D) and the symbols (S) and (R), which stand for sinister andrectus, respectively, designate an absolute spatial configuration ofthe enantiomer. Where no isomer designation is given for a compound,the compound is the racemic modification.

The individual optical isomers of the aryloxypropanolamineclass of compounds, of which the present compounds are members, havemost generally been obtained by one of four basic methods. Theseare: 1) the fractional recrystallisation of chiral acid salt derivatives; 2) derivatizalion with a chiral organic reagent, resolution and regeneration of the original compound in optically active form; 3) synthesis of the single optical isomer using chiral intermediates;and A) column chromatography utilizing chiral stationary phases.Applications of these various methods are well known to practitioners in the art.

Biological testing of representative subject compounds ofFormula 1 in animals demonstrates that they possess biologicalproperties which would make them useful as antihypertensive agents.

In addition to antihypertensive activity demonstrable in animaltesting, the instant compounds also possess vasodilating properties along with varying degrees of adrenergic alpha- and beta-receptor blocking properties and intrinsic sympathomimetic activity. A more detailed description of the specific pharmacological tests employedand the criteria used to judge the pertinent biological activity is contained in the Description of Specific Embodiments section under the subheading Biological Evaluation. Preferred representativemembers have a particularly desirable combination of the foregoingactions, 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 ofFormula I can be demonstrated in these various animal models, as referred to above, which include antagonism of isoproterenol in theanesthetized dog treated intravenously (adrenergic beta-receptoraction), the spontaneous hypertensive and DOCA salt hypertensive rat(antihypertensive action),, angiotensin-maintained ganglion-blockedrat model (vasodilator action), and an anesthetized rat model (alpha-adrenergic blockade), and in various ocher animal laboratory models(cf: Deitchman, et al., Journal Pharmacological Methods, 3, 311-321 (1980)).

As examples, two of the representative compounds ofFormula I’ 2-[2-hydroxy~3-[[2~(6-hydroxy-lH-indol-3-yl)-l,1-dimethvl-ethy1]amino J propoxy]benzonitrile and 2-[2-hydroxv-3-[(2-(5-hydroxy-1H-indo1-3-yl)-1,1-dimethylethyl]amino]propoxyIbenzonitrile causedgreater than 20 mmHg mean drop in systolic blood pressure of ratsin one or both of the antihypertensive tests when given at ® doselevel of 30 mg/kg p.o. A3 mg/kg intravenous dose of these compoundsresulted in over a 202 drop in mean arterial blood pressure (taken30 minutes after dosing) in the vasodilation test.

For use as antihypertensives, vasodilators, and/oradrenergic blocking agents, therapeutic processes of this inventioncomprise systemic administration, by both oral and parenteral routes,of an effective, non-toxic amount of a compound of Formula I or a 5 pharmaceutically acceptable acid addition salt thereof. An effectiveamount is construed to mean a dose which exerts the desired pharma-cological activity, such as those stated hereinabove, without undue toxic side effects when administered to a mammal in need of such treatment. Dosage will vary, according to the subject and route of10 administration selected, with an expected range of about 0,1 meg to 100 mg/kg body weight of a compound of Formula 1 or a pharmaceuticallyacceptable acid addition salt thereof generally providing the desiredtherapeutic effect. A preferred range for an effective dose wouldbe about 0.1 to 0.5 mg/kg when given intravenously and about 0.5 to 15 5 mg/kg when given orally.

The compounds of the present invention can be prepared by a convenient general process. This process is outlined below in Scheme 1.

Throughout this application, Me stands for a methyl group and Ac stands for the acetate ion, · Scheme 1 R^-r5 are as defined above.

This process involves the coupling of a suitable methoxylated indolalkylamine (III) with an R^-substituted phenoxyepoxide intermediate (IV). Synthetic methodology required to reachthis point in the preparation of Formula I products is analogous to a synthetic process used to prepare bucindolol. Reference is madeto the pertaining Kreighbaum, et al. patents U.S. 4,234,595 and Li.S. 4,314,943, and J.. Med. Chem., 23:3, 285-289 (1980) article. An additional step, however, is required as the resulting methoxylatedindole analog (II) is converted to the desired (I) product bycleavage of the methoxy group with boron tribromide in methylene 5 chloride solution. Other synthetic methods resulting in conversionto hydroxylated products, e.g. such as hydrogenolysis of benzyloxyprecursors, are well known to the chemical practitioner and may alsobe adapted for use in a modified process.

The coupling of the epoxy ether intermediate (IV) with the 10 indolylalkylamine (III) to give intermediate (II) is carried out simply by heating the epoxy ether either neat or in the presence of areaction inert organic solvent with an appropriate indolylalkylamineas shown. No catalyst or condensation agent is usually required.

Suitable solvents include 95% ethanol but other reaction-inert Γ) organic liquids in which the reactants are soluble may be employed.

These may include but are not limited to benzene, tetrahydrofuran,dibutyl ether, butanol, hexanol, methanol, dimethoxyethane, ethyleneglycol, etc. Suitable reaction temperatures are from about 60-200°C.

The required reaction intermediates. III and IV, may be 20 obtained by several methods and are not limited to the following.

The phenoxy epoxide intermediates (IV) can be obtained by alkylationof the appropriate R^-substituted cyanophenol (V) with epichlorohydrin asin Scheme 2; or in recalcitrant cases by using epibromohydrin, K2C°3and dimethylfonnamide.

Schssne 2 While many cyanophenols (V) are commercially available, they may alsobe conveniently prepared from readily available phenols via thesynthesis outlined as Scheme 3.

Scheme 3 Ac This sequence essentially involves formylation of an R -substitutedphenol according to Reimer-Tiemann conditions to afford the salicyl- 10 aldehyde derivative which is converted via the oxime intermediate to the desired salicylonitrile (V). It should be noted that when5 Formula I products in which R is hydroxyl are desired, the IV I 3' intermediate in which κ is methoxy is to be used in Scheme 1.

Cleavage by BBr^ to the hydroxyl group is effected in the last stepof the synthesis.

For the intermediate indolylalkylamines of structure III,typical synthetic procedures for their preparation are available inthe Kreighbaum, et al., patents and the J. Med. Chem. article citedhereinabove. Aithoucjh these referenced procedures are applicable to the preparation of other indolylalkylamine intermediates which may bedesired but are not specifically disclosed therein, representativesyntheses of Formula III compounds will be given hereinbelow forfurther exemplification of intermediates which may be required for the present invention.

Finally, it is of interest that a 6-hydroxyindolylcompound of Formula 1 (2-[2-hydroxy-3-[[2-(6-hydroxy-lH-indol-3-yl)- 1,1-dimethylethyl]amino]propoxy]benzonitrile) which structurally X 2 S 3 Λ corresponds to bucindolol (R , R , Ά are hydrogen and R » R aremethyl) was used to confirm the identity of a major metabolite ofbucindolol. It is known that 6-hydroxylation is perhaps more importantthan 5-hydroxylation in the metabolism of tryptamine derivatives (cf:Jepson, et al., Bjochim. Biophys. Acta,. 62, 91 (1962); Jaccarini andJepson, Biochim. Bjophvs. Acta.„ 156, 347 (1968)). This knowledgesuggested the possibility that 6-hydroxylation of bucindolol might bean important metabolic pathway. This has been confirmed by demonstrationthat this 6-hydroxyindolyl compound of the instant invention agreesin mass spectrum and gas chromatographic retention time with acorresponding major hydroxy metabolite of bucindolol. In this regard, another aspect of the present invention comprises 2- [ 2-hydroxy- 3-Π 2- (6-hydroxy-ln^-indol-3-y 1)-1,1-dimethylethyl ] amino]propoxy ]-benzonitrile in purified pharmaceutically acceptable form.

The compounds of the present invention can be formulatedaccording to conventional pharmaceutical practice to provide pharma-ceutical compositions of unit dosage fora comprising, for example,tablets, capsules, powders, granules, emulsions ^nd susrxxis ions. 'i'lic solid preparations contain the active ingredient in admixture with non-toxic pharmaceutical excipients such as inertdiluents, for example, calcium carbonate, sodium carbonate, lactose,calcium phosphate or sodium phosphate; granulating and disintegratingagents, for example, maite, starch, or slginic acid; binding agents, for example, starch, gelatin ox acacia; and lubricating agents, forexample, magnesium stearate, stearic acid or talc. The tablets maybe uncoated or they may be coated bv known techniques so as co retarddisintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. Liquidpreparations suitable for parenteral administration include solutions,suspensions, or emulsions of the compounds of Formula I. The aqueoussuspensions of the pharmaceutical dosage forms of the compounds ofFormula I contain the active ingredient in admixture with one or more non-toxic pharmaceutical excipients known to be suitable in themanufacture of aqueous suspensions. Suitable excipients are, forexample, suspending agents such as sodium carboxymethylcellulose,methylcellulose, hydroxypropyl methylcellulose, sodium alginate,polyvinylpyrrolidone, gum tragecanth and gum acacia. Suitabledisbursing or wetting agents are naturally occuring phosphatidas, forexample, lecithin, polyoxyethylene stearate.

Non-aqueous suspensions may be formulated by suspending theactive ingredient in vegetable oil, for example, olive oil, sesameoil, or coconut oil, or in a mineral oil, for example, liquid paraffin.The suspensions may contain a thickening agent such as beeswax, hardparaffin, or cetyl alcohol. Sweetening and flavoring agents generallyused in pharmaceutical compositions may also be included such assaccharin, sodium cyclamate, sugar and caramel to provide a palatablepreparation. The compositions may also contain other absorbingagents, stabilizing agents, wetting agents, and buffers.

The compounds which constitute this invention, theirmethods of preparation and their biologic actions will appear morefully from consideration of the following examples, which are givenfor the purpose of illustration only and are not to be construed aslimiting the invention in sphere or scope, and the appended claims.

In the following examples, used to illustrate the foregoing syntheticprocesses, temperatures are expressed in degrees Celsius and meltingpoints are uncorrected. The nuclear magnetic resonances (NMR)spectral characteristics refer to chemical shifts (6) expressed asparts per million (ppm) versus tetramethylsilane (TMS) as referencestandard. The relative area reported for the various shifts in theH NMR spectral data corresponds to the number of hydrogen atoms of aparticular functional type in the molecule. The nature of the shiftsas to multiplicity Is reported as broad singlet (hs), singlet (s),multiplet (m) , or doublet (d). Abbreviations employed are DMSO-d,(deuterodimethylsulfoxide), CDCl^ (deuterochloroform), and are jli δ otherwise conventional. The infrared (XR) spectral descriptions-1 include only absorption wave numbers (cm ) having functional groupidentification value. The 1R determinations were employed usingpotassium bromide (KBr) as diluent. The elemental analyses are reported as percent by weight.

Synthesis of Intermediates A. Intermediates of Formula Ill; General Procedures EXAMPLE 1 Methoxyindol-3-yl-ter t. -butylamineTo 15.2 mL of a chilled 252 aqueous solution of dimethyl- amine the following are added sequentially with stirring and continuedcooling: 16.9 mL of acetic acid, 7.2 mL of 372 formaldehyde, 27 mLof 952 ethanol. The resulting stirred solution is kept at 0° to -5°with a cooling bath while the appropriate methoxyindole (10.0 g, 0.07mole) is added in portions. This mixture is stirred and graduallywarmed 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 acidified with 170 mL of 2N HCl. This acidic mixture can be decolorized (Darco*G-60), filtered and the filtrate made basic using245 mL of 202 NaOH while being cooled and stirred. A resulting brownoily precipitate is ether extracted, and the extracts are water-washed, dried (MgSO^) and concentrated to a brown oily residue (14 g).The residue is recrystallized, e.g. from isopropyl ether and hexaneto yield the desired methoxygramine, usually as a tan solid. A mixture comprised of the appropriate methoxygramine (7.7 g„ 0.04 mole), 2-nitropropane (26.5 g, 0.3 mole), and NaOH (1.7 g pellets, 0.04 mole) is refluxed under a nitrogen atmosphere*Trade Mark for 3-5 hours. The reaction mixture is then cooled to room temperatures acidified with 10% acetic acid and extracted with ether.

The ether extracts are water-washed, dried (MgSO ), and concentratedin vacuo to a residue. Recrystallisation of the residue, e.g. fromisopropyl alcohol-water gives a 3-(2-methyl-2-nitropropyl)methoxyindole.

This nitropropylindole compound and activated Raney Nickel(4.2 g) are combined in 30 mL 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 reactionmixture is then heated at reflux for 2 hours, cooled to room temperatureand filtered. The filtrate is concentrated to an oily residue whichcan be recrystallized,, e.g. from ethyl acetate-isopropyl ether togive the desired methoxyindol-3-yl-v-butylamine product. EXAMPLE la 6-Methoxvindol-3-yl-tert.-butylamine A mixture of 6-methoxy gramine (0.9 g, 0.004 mole;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 NaOHpellets was stirred at reflux in an oil bath under a nitrogen atmos-phere for 2 hours, as dimethylamine escaped through the condenser.

The resulting mixture was cooled to 25°, treated with a solution of0.47 mL of glacial acetic acid in 4.1 mL of water and extracted withether. The ether extract was washed with three portions of water,dried (MgSO^) and evaporated to dryness. The residual brown oilcrystallized upon rubbing and cooling in a small amount of isopropylether. The solid was isolated by filtration, washed with coldisopropyl ether and dried in air to give 0.6 g of tan solid which was 1 8 recrystallized from isopropyl alcohol-water to give 0.52 g (462)of 3-(2-methyl-2-nitropropyl)-6-raethoxyindoles m.p. 98-99°C. A slurry of 8,0 g (0.32 mole) of the nitro compound asprepared above,, 80 mL of 952 ethanol and 4.2 g of Raney ISickel(washed with water and 952 ethanol) was heated to reflux with paddlestirring. Exterior heating was halted and a solution of 7.8 g of 852hydrazine hydrate in 8 mL of 952 ethanol was added dropwise at asufficient rate to maintain a gentle reflux. After the addition,, the mixture was reheated at reflux for two hours and then cooled to 25°C.

Filtering and concentrating the filtrate to dryness gave a crudesyrup which was chromatographed on silica gel columns eluting withCHjClj^CH^OH-concentrated NH^OH (90:10:1). The tan solid thusobtained (2.9 g, m.p, 125-128°C) was recrystallized from ethylacetate-isopropyl ether to afford 1.27 g (182) of o-methoxyindol-3-yl-tert.-butylamine, m.p. 125-128°. EXAMPLE 2 Methoxyindol-2-yl-tert-butylamine(R1, R2 ° H, R3, R4 - Me) In this general procedure a solution comprising theappropriate methoxyindole-2-carhoxylic acid (0.06 mole) and thionylchloride (2.0 g, 0.17 mole) in 130 mL of dry ether is stirred for 12-18 hours at room temperature under a nitrogen atmosphere. The reaction mixture is filtered and the filtrate is concentrated to an oily residue which is taken up in 150 mL of dry ether. This ethersolution is treated with 80 mL of dimethylamine in 90 mL of ether.

The ethereal reaction mixture is concentrated to dryness and the 1 9 residue crystallized in isopropyl alcohol» The solid is Isolated byfiltration to give a 30-40% yield of the methoxyindole-2-carboxamideproduct.

The methoxyindol-2-yl carboxamide is dissolved in 100 mLof THF and this solution is added dropwise to a stirred suspensioncomprised of 3 g of lithium aluminum hydride in 50 mL of THF under anitrogen atmosphere. After heating at reflux for 2 hours, thereaction mixture is cooled and decomposed with a small amount 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 treated with a slight excess of dimethyl sulfate.The resulting alcoholic solution is stirred at room temperature forfour hours and then concentrated in vacuo to dryness giving asresidue a trimethylamine quaternary salt.

The crude quaternary salt product (0.01 mole) is combinedwith NaOH (2.0 g pellets, 0.05 mole) and 2-nitropropane (15 mL) andthe mixture is heated at reflux under a nitrogen atmosphere for 1 hour. The resultant dark thick mixture is cooled, diluted withwater9 acidified with acetic acid to a pH of approximately 6 and thenextracted with ether. These ether extracts are combined, washed withwater, dried (MgSO^) and concentrated to a dark residue which ischromatographed on a silica column and diluted with methylene chlorideRemoval of the methylene chloride solvent and recrystallization ofthe crude material from isopropyl alcohol-water gives a methoxyindolesubstituted in the 2-position vzith a 2-methy1-2-nitropropyl moiety.

Reduction of this nitro product with Raney Nickel andhydrazine according to the procedure used in Example 1 above will yield the desired methoxyindol-2-yl-tert.-butylamine. 2 0 EXAMPLE 3 1-Methylation of Methoxyindolylalkylamines: 3-(2-Amino-2~aethylpropyl)-l-methy1-methoxyindole (r\ Λ R4 » Me, R2 « H) 5 In this general process 7 g (0.11 mole) of 85Z XOH is ground in a mortar and quickly transferred to a nitrogen-flushed25-mL Erlenmeyer flask. DMSO (55 mL) is added and the mixture isstirred for 5 minutes. Additions of methoxyindolyl-tert.-butylamine (0.27 mole) and iodomethane (3.78 g„ 0.03 mole or any other suitable10 alkylating agent) are each followed by 45 minutes of stirring after which the suspension is quenched in 300 mL of water. Extraction ofthe mixture with ethyl acetate, followed by washing of the extractswith water and brine affords a clear solution which is dried (MgSO^)and evaporated in vacuo to an oily product. This free base may be 15 used as a intermediate without further purification. Characterizationis usually made by converting the oily base to the hydrochloride saltin order to obtain a crystalline product. EXAMPLE 4 Methoxyindol-2-ylethylafflina 20 In this procedure which is essentially that of 3hat and Siddappa, J~. Chem. Soc. (C)s 1971, 178-81; various methoxyindol-2-carboxylate esters (commercially available or prepared by literaturemethods) is reduced to the corresponding 2-hydroxymethyllndolederivative by reduction with lithium aluminum hydride in ether. 25 Conversion to the indol-2-carbaldehyde is accomplished by dissolvinga 2-hydroxywethyl-methoxyindole (4 g) in dichloromethane (250 mL) andadding activated manganese dioxide (10 g) followed by stirring of thereaction mixture at room temperature for 20-30 hours. The reaction 2 1 is followed by TLC, soon!coring the disappearance of the starting2-hvdroxymethylindole spot. If necessary, fresh quantities ofmanganese dioxide (2-3 g) can be added. The reaction mixtureis filtered and the residual manganese dioxide washed repeatedly witha little fresh dichloromethane. The combined filtrate is evaporatedto dryness to give the crude methoxyindol-2-carbaIdehyde as a paleyellow solid which is then recrystallized.

The methoxyindol-2-carbaldehyde (5 g) , nitromethane (8 mL) ,and ammonium acetate (1 g) are heated under reflux for 1/2 hour.

The reaction mixture is cooled and the dark red crystals that separateare collected, washed thoroughly with water, dried and crystallizedfrom ethanol. The nitrovinylmethoxyindole thus prepared is thenreduced to the desired methoxyindol-2-ylethylamine by treatment withlithium aluminum hydride in dry ether. The reduction mixture isgently heated under reflux for 10 hours following which the excess lithium aluminum hydride is decomposed. Following filtration, thefiltrate is concentrated in vacuo to give a residue which Is crystallized from a suitable solvent to give the desired methoxy-indol-2-ylethylamine. EXAMPLE 5 Methoxyi ndol-2-vlpropylamine Modifying the procedure of Example A, an appropriatemethoxyindol-2-carbaldehyde (1 g) in nitroethane (0.5 mL) is treatedwith four drops of benzylamine; following which the mixture is heatedat reflux for one hour. The cool reaction mixture on standing deposits dark red crystals which may he collected, washed with a little ether, dried, and crystallized from ethanol. These nitro-propenyl indoles thus prepared are reduced with lithium aluminum hydride as described above in Example k. Solid products are crystallized and the liquids are characterized as benzoyl derivatives. EXAMPLE 6 Methoxyindol-3~ylethylamine Cf: Young5 Cheai. Soc. „ 1958, 3493-96; This synthesisstarts with methoxyindol-3-aldehydes which are either available commercially or prepared from literature methods. Using the pro-cedure outlined in Example 4 above, an appropriate methoxyindol-3"carbaldehyde is condensed with a nitromethane using ammonium acetate as a catalyst. On standing, the cooled solution gradually depositsdark red crystals which can be recrystallized from benzene or methanolto give the 3-nitrovinyl-methoxyindole which is reduced with lithiumaluminum hydride, as above to yield the desired methoxyindol-2-ylethylamine. EXAMPLE 7 Methoxyindol-3-ylpropylamine A selected raethoxyindol-3-carbaldehyde (5 g), nitroethane(10 mL) 9 and ammonium acetate (1 g) are heated on a steam bath withoccasional shaking for 1/2 hour. On cooling, the crystals arecollected, washed with hot water (2 x 50 mL) and crystallized frommethanol. The resulting 3-(2-nitropropenyl)"methoxyindole is reducedto the desired 3-(2-aminopropyl)-methoxyindole by treatment withlithium aluminum hydride as detailed in the above procedures. B.

Intermediates of Formula IV EXAMPLE 8 2-((2,3-Epoxy)propoxy]benzonitrileA solution of 2-cyanophenol (25.0 g, 0.21 mole), epichloro- hydrin (117 g, 0.26 mole), and piperidine (10 drops) was stirred andheated at 115-120° in an oil bath for 2 hours. The reaction mixturewas then concentrated (90°/30 Torr.) to remove unreacted epichlorohydrin.The residue was diluted with toluene and concentrated to drynesstwice to help remove the last traces of volatile material. Theresidual oil was dissolved in 263 mL of tetrahydrofuran and this solution was stirred at 40-50° for one hour with 263 mL of IN NaOH.

The organic layer was separated and concentrated to give an oil whichwas combined with the aqueous phase. The mixture was extracted(CH„Cl,,)s and the extract dried (MgSO.) and concentrated to give36.6 g (100%) of oil which slowly crystallized to a waxy solid. Thisintermediate product may be used without further purification in thepreparation of Formula I products. EXAMPLE 9 2-((2,3-Epoxv)propoxy]-4-methoxybenzonitrileThe requisite 5-methoxysalicylaldehyde can be obtained from 4-methoxyphenol by the Reimer-Tiemann procedure which is well described in the literature, e.g. Ci: Kappa, et al., Arch. Pharm., 308/5, 339 (1975). A solution comprising 0.005 mole of the startingsalicylaldehyde in 6 mL of pyridine and 6 mL of absolute ethanol istreated with 0.4 g (0.02 mole) of hydroxylamine hydrochloride and heated at reflux for 4 hours. The mixture is concentrated in vacuoto a gray syrup which is stirred with 50 mL of H^O and the suspension 2 4 decanted. Addition of 10 saL of to the residual glassy materialfollowed by chilling at 5° affords^ upon filtration,, approximately1.2 g of crude solid which is taken up in 25 mL of 502 ethyl ether-isopropyl ether. The ether solution is filtered, dried (MgSO^),treated with Darco G-60 and Celitef filtered and concentrated invacuo to a waxy solid. Recrvstallization from ethyl ether-Skellv 3gives the corresponding benzaldehyde oxime. A mixture of 0.002 mole of the oxime and 1.02 g (0.01 mole)of acetic anhydride is heated at reflux for 30 minutes and thencooled to 25°. Water (50 mL) was added, followed by dropvise additionof 202 WaOH to pH 10. The resulting suspension was stirred at 25°for 20 hours (to hydrolyze any acetate ester of the desired phenolderivative. The pH is adjusted to about 2 using 6N HCl and theresulting mixture is extracted with 40 mL of ethyl acetate to give anorganic layer which is separated, dried (MgSO^) and evaporated at65°/70 Torr. to give a tan syrup which still consists mainly of theacetate ester. Further hydrolysis of the syrup in a mixture of 7 mLof methanol J 7 mL of water and 0.1 g of NaOH pellets at 25° for3 hours is followed by removal of the methanol at 60°/70 torr.

Dilution of the aqueous residue with 0.5N HCl affords a precipitatewhich can be recrystallized from 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 g (0.03 mole) of finely powdered anhydrous potassium carbonate and 140 mL of DMF was stirred at 50° for 15 minutes.

Epibromohydrin (2.8 g or 0.02 mole) was added in one portion and stirring was continued for 3 days. The reaction mixture was*T.rade Mark poured into 1 liter of brine end the resulting suspension stirred for 3 hours at 0-5°. Filtering the mixture and washing the filter cake with water gave upon drying in air the crude intermediate compound which could be used without further purification, Similarly, using other substituted 2-cyanophenoIs in modifications of the above procedures will provide the other inter-mediate compounds of Formula IV to be used in synthesis of thevarious Formula I compounds of this invention.

Synthesis of Products EXAMPLE 10 General Procedure: 2-[2-Hydroxy-3-[(hydroxy-indolyl)alkvlamino]propoxy]benzonitrile A selected wethoxyindolylalkylamine (Ill) is mixed with anequimolar or slight excess amount of a selected epoxy propoxy benzo-nitrile (IV) and the coupling is accomplished by either refluxing asolution of the reactants for approximately 18 to 24 hours or heatinga neat mixture at a temperature of about 120-130° for about 1/2 to 2 hours. Ethanol and toluene are the usual solvents chosen for the reaction medium for coupling via refluxing a solution of III and IV.In some instances, it is advantageous to follow the course of thereaction by TLC, adding additional IV epoxide until all indolylamineIII has disappeared. Following reaction the mixture is concentratedto dryness and the residue is either washed and used crude in thenext step or the intermediate methoxy product may be purified bycrystallization-recrystallization either as the base or a suitable acid addition salt. 26 A solution of the methoxvindolyl product (II) dissolvedin methylene chloride and stirred under a nitrogen atmosphere at0-10° while a several-fold excess of IN boron tribromide in methylenechloride is added dropwise. Following addition„ the reaction mixtureis stirred at room temperature for about 6-8 hours» The excess borontribromide is decomposed by chilling the reaction mixture and dropwise addition of excess water» The crude hydrobromide salt of the Formula Iproduct may be worked up in a number of conventional ways such asrecrystallizations conversion to the base and purification, conversionto the base followed by conversion to a different acid addition salt, and so forth» The modifications necessary to adapt this procedure for thepreparation of specific compounds of Formula I are wall within theskill of any ordinary practitioner in the chemical arts, EXAMPLE 11 2-[2-Hydroxy-3-[(2-(6-methoxy-lH-indol-3-yl)-1,1-dimethylethyl]amino]propoxy[benzonitrile A solution of 6-wethoxyindol-3-yl-_t-butyl amine (2.6 gp0.012 mole; prepared in Example la) „ 2-[(2,3-epoxy)propoxy]benzo-nitrile (2.1 g, 0.012 mole; prepared in Example 8) „ and 100 mL ofabsolute ethanol was stirred at reflux for 20 hours. Additional epoxide (0.21 g) was added and reflux was continued for 4 hours,after which the mixture was concentrated to dryness and the residuetriturated in isopropyl alcohol to induce crystallization. Theproduct was collected by filtration, washed with cold isopropylalcohol and dried in air to give 4,0 g (85%) of the methoxy product (II), m.p. 145-146°, which was used directly in the next step. 2? A solution of the metboxyindole product prepared above(1.5 g, 0.004 mole) in 225 mL of methylene chloride was stirred undera nitrogen atmosphere at 5-10°C while 15.3 mL (0.015 mole) of 1Mboron tribromide in methylene chloride was added dropwise. Followingthe addition,, the ice bath was removed and the reaction mixture wasstirred at 25° for 6 hours before refrigeration to 5-10° and dropwiseaddition of 47.5 mL of H^O. The resulting mixture was decanted andthe residual gummy solid rinsed with 2 portions of H^O. Dissolvingthis crude hydrobromide salt in 50 mL of hot H^O followed by treatmentwith Darco G-60, filtering., cooling (25°) and basifying (pH 8) withcone. WH.OH gave 1.2 g of tan morphous solid which was chromatographed(silica gel 60, 230-400 mesh. EM Reagents) on a medium pressuresystem with chloroform-methanol-conc. NH OH (90:10:1). The productobtained in this manner crystallized from a small amount of 95%ethanol to afford, by gradual addition of H^O, 1.03 g (71%) of thedesired 6-methoxyindole product (I) as a tan solid, m„p. 90-94°.

Anal. Calcd. for C22H25N3°3’'1/3H2°: C, 68.56; H, 6.67; N, 10.90; HO, 1.54. Found: C, 68.69; H, 6.68; W, 10.68; ^0, 1.80. NMR (DMSO-d,): 0.98 (6,s); 2.70 (4.m); 3.30 (2,bs); o 3.83 (l,m); 4.11 (2,d [5.8Hz]); 5.00 (l,bs); 6.65 (3,m); 7.20 (3,m);7.60 (2.m); 8.71 (l,bs); 10.35 (l,bs). IR (KBr): 760, 800, 1260, 1290, 1450, 1495, 1600, 1630,2230, and 3300 cm-1. 28 EXAMPLE 12 2-[2-Hydroxy~3-[[2~(5-hydroxy-lH-indol-3-yl)~ 1,1-diroethylethyl]amino]propoxyjbenzonitrile A solution of 5-methoxyindol-3-yl«_t-bucylamine (2.7 g, 0.0125 mole; prepared from 5-methoxyindole utilizing the proceduregiven in Example 1), 2-[(2,3-epoxy)propoxy]benzonitriie (2.2 g, 0.0125 mole), and 20 mL of acetone was refluxed for 1/2 hour. Theacetone solvent was then allowed to boil off and the oilyresidue heated neat at 100° for 2 hours. Isopropyl alcohol (20 mL)was added and the reaction solution refluxed for 4 hours following which it was cooled to room temperature, diluted with 50 mL ofether and a stirring rod was used to rub out a white powder, 4.7 g(96X), m.p. 119-124°; TLC (9:1 CHCl^-methanol) exhibits a singlespot, R^ 0.25. This crude methoxy product may be used directly inthe next step or be purified via conversion to the HCl salt. Con-version to the HCl salt by treatment of an acetonitrile solution withethanolic HCl gives a crude product which is recrystallized inbutanone-957. ethanol (20:1) to off-white powder, m.p. 164-166°.

Anal. Calcd. for C._H»-N-O-«HCl: C, 64.25", H, 6.56; - 23 27 3 3 N, 9.77. Found: C, 64.14; H, 6.54; N, 9.68.

Using the procedure given above in Example 11 for borontribromide cleavage of the methoxy group, but employing the 5-methoxy-indole intermediate product (II) prepared above, the desired 5-hydroxy indole product (I) in the form of Its hydrobromide salt maybe obtained. The pure hydrobromide salt is a beige powder, m.p. 219-221°.

Anal. Calcd. for c22H25W3°3*HBr: c> 57.40; H, 5.70; N, 9.13. Found: C, 56.90; H, 5.67; K, 9.45. NMR (DMSO-dJ: 2.32 (6,s); 3.08 (2,m); 3.36 (2,m); 4.30 t> (3,m); 5.90 (l,bs); 7.10 (6,m); 7.71 (2,m); 8.55 (3,bs); 10.95 (l,bs)IR (KBr): 750, 800, 1265, 1290, 1455, 1495, 1580, 1600, 2230, and 3300 cm \ 5 Starting with appropriate methoxyindolalkylamines (Ill) and epoxypropoxybenzonitriles (IV), additional examples of formula Iproducts may be synthesized using substantially the same proceduresas outlined hereinabove with only slight modifications which would bewell within the skill of a practitioner in the chemical arts. Some 10 additional products of Formula I which may be synthesized by these means are shown in Table 1.

Example -OH H1 R2 R3 4 R R5 13 4- H 2-H Me Me H b τ.4 7- H 2-H Me Me H 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 Me Me H ΙΟ 19 4- Me 3-H H Me H 20 5- Me 3-H H Me 5-F 21 6- Me 3-H H Me b-J 22 7- Me 3-H H H 4-Me 23 4- H 2-Me H Me H .15 2U 5- H 2-Me H H H 25 6" H 2-Me Me Me H 26 7- H 2-Me Me Me H 27 4- H 3-Me H H 5-OH 28 5- H 3-Me H Me 5-F 20 29 6- H 3-Me H Me H 30 7- H 3-Me H H 5-3r 31 4- H 2-H H Me 5-Me 32 5- H 2-H H Me 4-C1 33 6- H 2-H H Me H 2b 34 7- H 2-H H Me 4-OH 3λ X Biological Evaluation These biological tests were used to gauge the antihyper-tensive profile of selected compounds of Formula I. EXAMPLE 35 The efficacy of antihypertensive agents other than adrenergicbeta-receptor blocking agents is commonly estimated in the spontaneouslyhypertensive rat. Blood pressure values are determined for testanimals prior to and 2 and k hours after oral doses of 30-100 sag/kgof test compounds. Heart rate is determined with each pressuremeasurement as well. A fall in blood pressure at 2 or 4 hours afterthe single dose in the range of 15-20 mmHg is considered "questionable"."Active" and "inactive" designations are decreases greater and lessthan that range, respectively. EXAMPLE 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 rats of the Sprague-Dawley strain weighing approximately 90 g are individually caged withfree access to food and water for a 5-day pretreatment period, afterwhich, the drinking water is replaced with 1% saline solution.

During a 3-week treatment period, the rats are given a total of 10subcutaneous injections containing 10 mg of DOCA (deoxycorticosteroneacetate) in 0.2 mL suspending vehicle (0.25% Tween^eO and 0.125% CMCin normal saline solution). After the final injection, the 1% salineis replaced by distilled water and the animals are available for use one week later. * Trade ffcirk The test is made by selecting non-fasted animals withelevated systolic blood pressures (>160 asnHg). Blood pressure valuesare determined for these test animals prior to and four hours afteroral doses of 30-100 mg/kg of test compounds. During the test periodthe animals are housed in metabolism cages without feed or water andurine is collected for A hours. Heart rate and body weight are bothdetermined with each pressure measurement as well. A fall in bloodpressure Λ hours after dosing which lies in the range of 15-20 mmHgis considered "questionable". "Active" and "inactive" designationsare decreases greater and less than that range. EXAMPLE 37 The angiotensin Il-supported ganglion-blocked rat model isutilized as a screening test for estimation of the direct vasodilator component of activity. Percentage changes in blood pressure in anesthetized rats 30 minutes after intravenous dosjng are determined.The intravenous dosing is done with test compounds at 3 mg/kg.Borderline activity is defined as approximately a 10% decrease inblood pressure measured 30 minutes after dosing. "Active" and"inactive" designations are increases greater and less than that. EXAMPLE 38 Diastolic blood pressure and heart rate responses to afixed challenge dose of isoproterenol are obtained before and 15minutes after graded doses of test compound administered intravenouslyover a 3 minute interval to anesthetized dogs. A branch of a femoralartery and vein are cannulated to record blood pressure and toadminister the drugs which are dissolved in saline. The vagi weresectioned bilaterally in the mid-cervical region of the neck and the 3 3 dogs are ventilated mechanically (Harvard respiratory) with room airat a rate of 20/minute and a stroke volume of 20 mL/kg. Heart rateis monitored with a cardiotachometer triggered by the pressure pulse.All measurements are recorded on a Beckman*R-612 recorder. The drugeffect is expressed in terms of a cumulative dose (wicrograw/kg)causing 50% inhibition of isoproterenol response. EXAMPLE 39 Rats (male Wistar) are anesthetized with a combination of urethane and chloralase intraperitoneally. Following induction of anesthesias chlorisondamine is injected into the peritoneal cavity toproduce ganglion blockage. A femoral artery was cannulated tomonitor blood pressure and heart rate and two femoral veins were cannulated to administer compounds, The trachea was intubated and rats were allowed to breath spontaneously. Animals were challenged before and 15 minutes after intravenous administration of test compound with graded doses of phenylephrine and the changes in bloodpressure recorded. Data were plotted to obtain dose-response curvesand the dose of phenylephrine required to elicit a 50 mmHg (Εϋ^θ)increase in blood pressure was interpolated from the curves. Doseshifts are calculated by dividing the Εϋ^θ after drug by the Εϋ^θbefore drug. * Trade Mark

Claims (23)

1. 3 4 dlAI-MS:

1. A compound having the formula < img-format="tif" img-content="drawing" /> , >r .in acid addition salt thereof wherein one of 1 2 R and R is hydrogen and the other is hydrogen or alkyl; 3 A R and R are independently selected from hydrogen or alkyl; is halogen, hydrogen, hydroxy, or alkyl; 10 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.

2. A compound according to claim. 1, wherein the indolyl ring is attached at its 3- position to the phenoxypropanolaminoalkyl side15 chain. , i . 2 3. A compound according to claim 1 or 2, wherein R anu R are hydrogen. 4. A compound according l.o c l a.i in 1 or 2, wherein , ,-,4 and R are in Ί Jiy 1. 5. A compound according to claim b 2 or 4, wherein 5 . R is hydrogen or 5-fluoro.

3. 6. A compound according to claim 3, wherein R^ and R^ are methyl. 3 5

4. 7. A compound according to claim 6, wherein is hydrogen or 5-fluoro.

5. 8. A compound according to any one of claims L-7, wherein the 110substituent occupies the 6- ring position of indole. 5 9. 2 — [ 2 — Hydroxy — 3—[[2 — (6 — hydroxy - lH-indol-3-yl)-ls1-diroethylethyl]amino]propoxy]benzonitxlle. 10. 2 - [ 2 - Hydroxy - 3 - [ [ 2 - ( 5 - hydroxy - lH-indol-3-yl)-lB1-dimethylethyl]amino]propoxy]benzonitrile.

6. 11. ,Medication comprising a non-toxic antihypertensive cffcct-.10 i.vc dose of a compound claimed in claim 1, for use in a method of treating a mammal for hypertension.

7. 12. Medication as claimed in claim 11 wherein the said compound is 2-[2-hydroxy-3- [ [2-(b-hydroxy-lH-indol-S- yl)-! ,1-dimethylethyl]amino]propoxy]benzonitrile.»

8. 13. A pharmaceutical composition in unit dosage form suitable for systemic administration to a mammalian host comprising a[iiarmaceutically acceptable carrier and an amount of a Formula I compound asclaimed in claim 1 to provide an effective antihypertensive but non-toxic dose offrom o.l meg to 100 mg of said compound of Formula I per kg body weight of said host

9. 14. A pharmaceutical composition according to claim 13, wherein theFormula I compound is 2-[2-hydroxy-3-[[2-(6-hydroxy-lH-indol-3-yl)-1,1-dimethylethyl]amino]propoxy]benzonitrile.

10. 15. A pharmaceutical composition according to claim 13, wherein theFormula I compound is 2-[2-hydroxy-3-[[2-(5-hydroxv-111-indol-3-yl)-1,1-dimethyl-ethyl] amino]propoxy]benzonitrile. 25 3 8

11. 16. A process for preparing a ccrrpomd having the formula < img-format="tif" img-content="drawing" /> or an acid addition salt thereof wherein one of 1 2 '> R and R is hydrogen and the other is hydrogen or C, , alkyl; 3 4 R and R are independently selected from hydrogen or alkyl; R^ is halogen. hydrogen. hydroxy, or C. . alkyl; l~-4 the phenoxypropanolaminoalkyl side chain is attached to the indole ring10 at either the 2- or 3-position; and the hydroxyl substituent group occupies either the 4-, 5-. or 7- ring position of indole,, said process comprising: a) coupling a methoxylated indolalkylamine III < img-format="tif" img-content="drawing" /> (III) T 2 3 A 5 1 ) wherein R„ R , R , and R are as defined hereinbefore, with an (R -substituted phcnoxy epoxide) IV < img-format="tif" img-content="drawing" /> (IV) wherein r\ R^p r\ and R^ are as defined hereinbefore, by heating III andIV together either neat or in the presence of a reaction inert organic solvent,, 20 so as to produce an intermediate II 37 < img-format="tif" img-content="drawing" /> 12 3 4 5 wherein R , R t, R , R , and R are as defined hereinbefore; then b) reacting intermediate II under suitable conditions so as to cleave theMethoxy group to a hydro^eyl group and so as thus to form the compound of 5 formula I; and then c) optionally, if a pharmaceutically acceptable acid addition salt of formulaI is desired,, then converting the product in step (b) to said salt by standardtechniques,

12. 17. A process according to claim 15, wherein step (b) comprises 1(1 reacting intermediate II with boron tribromide in methylene chloride solutionunder reaction conditions so as to form the compound of formula I.

13. 18. Medication comprising a non-toxic vasodilating effective dose of a compound of claim 1, for use in a method of treating a mammalhaving need of vasodilating treatment. )'j i9. Indication conprising a non-toxic adrenergic-block i.ng effect- ive dose of

14. 20. A pharmaceutical composition according to claim 13, 14, or 15,wherein said dose of said formula I compound is to be administered intravenously 20 to said nairmal and provides 0.1 to 0.5 ng of said formula I compound per kgbody weight of said mammal.

15. 21. A pharmaceutical composition according to claim 13, 14, or 15,wherein said dose of said formula I compound is to be administered orally tosaid mammal and provides 0.5 to 5.0 ng of said formula I compound per kg body -1’ weight of said mammal

16. 22. A compound having the formula I given and defined in Claim 1 or an acid addition salt thereof,which is any one of those specifically hereinbefore mentioned.

17. 23. A pharmaceutical composition according toClaim 13, substantially as hereinbefore described.

18. 24. A process for preparing a compound havingthe formula I given and defined in Claim 1 or an acidaddition salt thereof, substantially as hereinbeforedescribed with particular reference to the accompanyingExamples.

19. 25. A compound having the formula I given anddefined in Claim 1 or an acid addition salt thereof,whenever prepared by a process claimed in a preceding c 1 ci 1 m.

20. 26. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the formula (1) as claimed in claim 25 or an acid addition salt thereof-

21. 27. An antihypertensive method which comprisesadministering to a non-human mammalian host having- hyper-tension a non-toxic antihypertensive effective dose of acompound claimed in claim 1. 3 9

22. 28. A vasodilating method comprising administ-ering Lo a non-human mammalian host having need of LreaL-ment a non-toxic vasodilating effective dose of a compoundof claim 1.

23. 29. An adrenergic-blocking method comprising administering to a non-human mammalian host having needof treatment a non-toxic adrenergic-blocking effectivedose of a compound of claim 1. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS. liaraai