NZ187763A - 3-aryloxy-1-(2-(indol-3-yl)-1,1-dimethylethyl)amino-propan-2-ols - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 87763 41 1 877 Priority Datc{s): . X?; ."V.7.7.........

Complete Specification Filed: <3'.7;7& C.c~t02-cA ; coTOitoS- colC"**'*>\Coio M-n Class: ft'F....

Publication Date: .. si. .mm.

P.O. Journal, /2fcO I N.Z. PATENT OFFICE 3-JUL 1978 NEW ZEALAND £ , RECEIVED PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION "3-INDOLYL-TERTIARY BUTYLAMINOPROPANOLS" Jd/Vfe, BRISTOL-MYERS COMPANY, a Delaware Corporation with offices at 345 Park Avenue, New York 10022, United States of America hereby declare the invention for whichjjl / we pray that a patent may be granted tojggs/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - 1 " (followed by page la) 1 87763 3-INDOLYL-TERTIARY BUTYLAMINOPROPANOLS The present invention is concerned with heterocyclic carbon compounds of the indole series having an amino substituent and with drug, bio-affecting and body-treating processes employing these compounds.

Tha present invention includes tha compounds of Formula I and Formula II and the acid addition salts of these substances OH C-NKCH jCHCH 3 -0-Ar-:< CH3 OH i i CH2-C-NHCHJCHCHJ-0-Ar-HeC t ch3 Formula I Formula II P- Q> \° & s. .2° In the foregoing structural formulas the symbols Ar, X, n, and Ket have the following meanings.

Ar is selected from the group consisting of phenyl and naphthyl, X refers to optional Ar-attac'ned substituents which ace independently selected from tha group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkylsulfinyl, alkylthio, alkanoamido, cyeloalkyl having 3 to 6 ring members and 1 to 3 optional alkyl substituents, cycloalkylalkyl having 3 to ^ ring ■members and 1 to 3 optional alkyl Substicuents^wherein each of the foregoing groups has up to 3 carbon atoms, phenyl, crifluoromathy1, nitro, amino, hydroxyl, halogen, carboxamido, eyano, and cyanoalkyl having from 2 to 4 carbon atoms, - la 187763 n is the integer 0, 1, or 2 signifying the number cf X groups, and Het is a nitrogen heterocycle, preferably a 5-member ring with four carbon atoms and one nitrogen atom, having 5 or 6 ring members and up to 1 additional heter'o atom selected from the group' consisting of oxygen, sulfur, and nitrogen wherein said heterocycle bears from 0 to 2 ring substituents selected from the group consisting of alkyl, N-lower alkyl carboxamido, N,N-dilow2r alkyl carboxamido, carbalkoxy, wherein each of the foregoing ring substituent groups contains up to 8 carbon atoms, oxo, and carboxamido.

The compounds of the present invention are unique as antihypertensive agents in that they combine adrenergic 3-blocking and vasodilator activity. They also have utility as anti-anginal agents, anti-stress agents, antiarrhythmic agents, antit'nrombogenic agents and in the treatment of conditions where it is desirable to reduce the oxygen demand of the heart such as post-myocardial infarct management. Preferred members have a particularly desirable combination of the foregoing actions, and ancillary pharmacological" effects, or a lack thereof, which particularly suits them for specific indications from among those listed. Those of Formula I wherein Ar is phenyl, n = 1, and X is located in the ortho position are preferred for antihypertensive use. The utility cf the compounds of Formulas I and II can be demonstrated in various animal models including antagonist: of isoproterenol in the conscious rat treated orally (adrenergic p-receptor blocking action), the spontaneo.tts—-s.- 187763 hypertensive rat (antihypertensive action), the dog hind limb preparation (vasodilator action), ouabain-induced ventricular tachycardia in the dog (antiarrhythmic action), in the coronary artery occluded dog (antiarrhythmic action), in vitro by measuring platelet aggregation in platelet-rich plasma photometrically following challenge with a throiubogenic agent such as adenosine diphosphate or collagen (anti-thrombogenic action), and in various other animal and laboratory, models.

The invention includes compounds having the foregoing structural formulas and the acid addition salts thereof. For medical use, the pharmaceutical^' acceptable acid addition salts are preferred. The pharmaceutically acceptable acid addition salts are those salts in which the anion does not contribute significantly to the toxicity or pharmacological activity of the salt, and as such, they are the pharmacological equivalents of tha bases having the foregoing structural formulas. In some instances, the salts have physical properties which make them aore desirable for pharmaceutical formulation purposes such as solubility, lack, of hygroscopicity, compressibility with respect to tablet formation and compatibility with other ingredients with which the substances may be used for pharmaceutical purposes. Acid addition salts which do not meet the foregoing criteria for pharmaceutical acceptability, for instance as to toxicity, are sometimes useful as intermediates for isolation and purification of the present substances or for other chemical synthetic purposes such as separation of optical isomers. Such salts are also part of the invention. 1 877 The acid addition salts are made by reaction of a base of the foregoing structural formula with the acid preferably by contact in solution. They may also be made by metathesis or treatment with an anion exchange resin whereby the anion of one salt of the substance is replaced by another anion under conditions which allows for separation of the undesired species such as by precipitation from solution or extraction into a solvent or elution from or retention on an anion exchange resin. Pharmaceutically acceptable acids for the purposes of salt formation include hydrochloric, hydrobromic, hydroiodic, citric, acetic, benzoic, phosphoric, nitric, mucic, isethionic, methanesulfonic, £-toluenesulfonic, glucosaccharic, palmitic, heptanoic, oxalic, cyclamic, and others.

The compounds of the present invention shown by the foregoing structural formula contain an asymmetric carbon atom in the propanolamine side chain and occur as optically active isomers as well as racemic mixtures thereof. The present invention is intended to include each of the optically active and racemic forms. Some of the substances of the present invention contain an asymmetric carbon atom in the X or Het substituent, and diastereoisomeric pairs of racemates exist. These forms are also included.

Resolution of racemic mixtures to provide the optically active isomers of the foregoing compounds is carried out, for example, by forming a salt with an optically active acid many of which are known to those skilled in the. art such as optically activc tartaric, mandelic, cholic, 0,0-di-£-toluoyl tartaric, and 0,0-difcenzoyl tartaric acids, or other acids conventionally employed for this purpose. The claims, therefore, will be understood to embrace the products in the form of the several racemic 1 877 mixtures as well as in the form of the optically active isomers where appropriate.

The therapeutic processes of this invention comprise systemic administration of an effective, non-toxic amount of a compound of Formula I or Formula II or a pharmaceutically acceptable acid addition salt of either to a mammal having a disease state resulting from excessive stimulation of the adrenergic 0-receptors, or to a mammal requiring vasodilation, or to a mammal having hypertension. An effective amount is construed to mean a dose which exerts an adrenergic 3-receptor blocking action, a vasodilator effect, or antihypertensive action in the affected animal without-undue toxic side effects. By systemic administration, it is intended to include both oral and parenteral routes. Examples of parenteral administration are intravenous injection or infusion, and intraperitoneal, intramuscular or subcutaneous injection. Rectal administration by ointment or suppository may be employed. Dosage will vary according to the route of administration with from about 0.1 meg to 100 mg/kg body weight of a compound of Formula I or Formula II or a pharmaceutically acceptable acid addition salt thereof generally providing the desired therapeutic effect. Acute toxicities measured in the mouse treated orally are within the range of about ALD30 250 mg/kg to >2000 mg/kg of body weight, with non-lethal signs of drug effect such as central nervous system stimulation or depression, mydriasis, or lacrimation appearing at from 1/2 to 1/10 that dose.

The combination of pharmacological properties of the compound of Procedure 10, 1-Cl2-(3-indolyl)-1,i-diraethylethyljamino^-3-(2-methylphenoxy)-2-propanol hydrochloride, indicates that it is 1 877 particularly desirable for antihypertensive use. It has five-fold the adrenergic (3-receptor blocking potency of propranolol shown by oral administration to rats followed by challenge of the animals with isoproterenol administered intravenously. The latter is a well known adrenergic |3-receptor stimulant which causes an increase in heart rate and a decrease in blood pressure. These effects of isoproterenol are antagonized by adrenergic 3-receptor blocking agents, and the relative potency values given above were prepared by regression analysis of log dose-response data for the two compounds. For therapeutic use, dosage size and frequency will vary with the subject and the route of administration, with from about 0.2 rag. for intravenous administration up to about 100 mg orally being suitable for man.

The substance of Procedure 10 is distinguished from other adrenergic fj-receptor blocking drugs in that it is effective in lowering the blood pressure in the spontaneously hypertensive rat. Although adrenergic p-receptor blocking agents have come into vjidespread use in human medicine for the treatment of hypertension, their mechanism of action is unknown and their antihypertensive activit cannot be detected by this animal test in most instances. With the present substance in the spontaneously hypertensive rat, a reduction of blood pressure of 25 mm. of Hg occurs at a dose of 100 mg/kg of body weight orally wich only a minimal reduction in heart rate.

This is thought to be indicative of utility in hypertensive indications where other adrenergic 3-receptor blocking drugs are inoperative or less desirable.

The substance of Procedure 10 also causes a reduction in blood pressure when administered intravenously to the anesthetized 1 877 dog in a dose of 3.33 mg/kg of body weight. It is further distinguished in that it does not depress heart rate or right ventricular contractile force as is the case with many prior adrenergic g-receptor blocking agents. Both a positive, inotropic and a positive chronotropic effect are exhibited by the substance, and these effects are apparent even when the animal is first treated with an adrenergic g-recptor blocking agent such as sotalol. Pulmonary artery pressure remains substantially unchanged, while aortic blood flow and total peripheral resistance are decreased, all of the foregoing in the anesthetized dog.

The compound of Procedure 10 possesses vasodilator activity which may account, in part, for its unique anti-hypertensive action. In the anesthetized ganglion blocked (chlorisondamine chloride) angiotension supported rat, direct acting vasodilators such as diazoxide exert a reduction in blood pressure. The substance of Procedure 10 is equivalent in potency to diazoxide in this test. The vasodilator action thereof can also be shown in the pump-perfused hind limb of the dog in doses of from 0.03 to 1.0 mg/min. of perfusion. Following oral administration to rats a decrease in urine volume and a decrease in sodium ion. excretion occurs which is typical of vasodilator compounds.

The antithrombogenic action of the substance of Procedure 10 is reflected by its ability to reduce platelet aggregation in vitro in platelet-rich plasma following challenge with ADP or collagen.

It is comparable in iri vitro activity to suloctidil or to papaverine.

A hazard exists in the use of a preponderance of adrenergic receptor blocking agents in patients suffering from non-allergic 1877 bronchospasm in view of the tendency of these agents to provoke an asthmatic attack or to render the subject refractory to treatment with adrenergic JJ-receptor stimulants such as isoproterenol which are used in the treatment of acute attacks. The substance of Procedure 10 lacks bronchospastic liability as is demonstrated by the fact that it does not reduce pulmonary ventriculatory prssure, and evokes only moderate enhancement of the response of sensitized rats to immunologically induced broncho-constriction at a dose of 0.5 mg/kg of body weight intravenously. In contrast, propranolol at a dose of 0.5 mg/kg of body weight intravenously reduces pulmonary ventilatory pressure and precipitates an acute bronchospastic response in sensitized rats tc immunologically-induced broncho-constriction.

For the preparation of pharmaceutical compositions containing the compounds of Formula I or Formula II in the form of dosage units for oral administration, the compound is mixed with a solid, pulverulent carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin, as well as with glidents such as magnesium stearate, calcium stearate, polyethylene glycol waxes or the like and pressed into tablets. The tablets may be used uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. When coated tablets are wanted, the above prepared core may be coated with a concentrated solution of sugai", which solution may contain e.g. guai arabic, gelatin, talc, titanium dioxide or the like. Furthermore, the tablets may be coated with a 187763 lacquer dissolved in an easily volatile organic solvent or mixture of solvents and if desired, dye may be added to this coating.

In the preparation of soft gelatin capsules consisting of gelatin and e.g. glycerine and the like, the active ingredient is mixed with a vegetable oil and encapsulated in conventional manner. ' Hard gelatin capsules may contain granules of the active ingredient in combination with a solid, pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, starch (such as e.g. potato starch, corn starch, or amylopectin), cellulose derivatives or gelatin.

Dose units for rectal administration may be prepared in the form of suppositories containing the compound in a mixture with a neutral fat base, or in the form of a gelatin-rectal capsule with a mixture of vegetable oil or paraffin oil.

Liquid preparations suitable for oral administration are suspensions, syrups and elixirs containing from about 0.2% by weight to about 20% by weight of the active ingredient.

A suitable injectible composition comprises an aqueous solution of a water soluble pharmaceutically acceptable acid addition salt adjusted to physiologically acceptable pH.

The compounds of Formula I and Formula II are prepared by application of known processes to the appropriate starting materials. Representative known methods for the preparation of aryloxypropanol-amine compounds are disclosed in New Zealand Patent Specification No. 173519. More specifically, the present invention provides a process for the preparation of the compounds of Formulas I and II according to the following reaction scheme.

- Q - 187763 (i) Ar'-OH 0 /\ Ar -O-CH2CHCH2 ch3 t 3-Indolyl-CH2C-B (2) CH, 3-Indolyl-CH2C-NH2 1 ch3 Formulas I and II CH, CH2C6HS I /°\ -n-ch2chch2 III —N -ch20s02r IV In the foregoing reaction scheme, tha symbol Ar' represents the groups ArX^ and ArHet as they are defined in Formula I and Formula II, and the symbol B is defined by Formulas III and IV in which R is a lower alkyl group of 4 or fewer carbon atoms. The preferred method is according to reactions (1) and (2) in which step (1) involves reacting the appropriately substituted phenolic compound Ar'-OH with epichlorohydsin in the presence of a catalytic quantity of an amine followed by treatment with aqueous alkali metal hydroxide, or conducting the reaction in an aqueous alkali metal hydroxide reaction medium whence the amine catalyst is not required. There is produced in step (1) an Ar' epoxypropyl ether which is caused to react in step (2) with 2-(3-indolyl)-l,1-dimethylethylamine to yield a product of Formula I or Formula II depending upon the nature of the Ar'OH starting material employed. Each of reaction steps (1) and (2) takes place facilely in ordinary laboratory or plant equipment under convenient operating conditions. 187763 Heating of epichlorohydrin in substantial molecular excess amount with a phenol Ar'OH containing a drop or two of piperidine as catalyst on a steam bath overnight results in the condensation shown in step (1). Some of the corresponding halohydrin intermediaue is also produced and is converted without isolation to the cxirane shown by treatment of the mixture with aqueous alkali metal hydroxide. Alternatively, the Ar'OH phenol and epichlorohydrin can be caused to react in the presence of a sufficient amount of a dilute aqueous alkali metal hydroxide to neutralize the acidic Ar'OH group at room temperature with formation of the desired intermediate 0 Ar'0CH2C!HCH2. Step (2) is carried out simply by heating the oxirane intermediate produced in step (1) with 2-(3-indolyl)-l,1-dimethylethylamine either neat or in the presence of a reaction inert organic solvent. No catalyst or condensation agent is required. Suitable solvents include 95% ethanol but other reaction inert organic liquids in which the reactants are soluble may be employed. These include but are not limited to benzene, tetrahydrofuran, dibutyl ether, butanol, hexanol. methanol,^dimethoxyethane, ethylene glycol, etc. Suitable reaction temperatures are from about 60-200°C.

An alternate variation of the process for the preparation of compounds of Formulas I and II involves reaction of the Ar'OH starting material as defined above with a reactant of the formula fH3 3-Indolyl-CH2C-E according to reaction (3) of the scheme to yield an CH3 intermediate which is transformed to the final product by hydrolysis or hydrogenolysis. The substituent B in the reactant used in step (3) is a group such as shown by III or IV which is reactive with the phenolic hydroxyl group Ar'OH to incorporate into the product an incipient propanolamine side chain. 1 877 The reactants for step (3) wherein B has Formula III are prepared by forming the N-benzyl derivative of 2- (3-indolyl)-L, 1-dimethylethylamine and reacting the latter with epichlorohydrin by adaptation of the method of L. Villa et al., II. Farmaco. Sci., Ed., 24, (3) 349 (1969). .

Those reactants wherein B has Formula IV are prepared by reductive alkylation of 2-(3-indolyl)-i,1-dimethylethylamine with glyceraldehyde according to known methods, for instance, employing 5% palladium-on-carbon catalyst in an atmosphere of hydrogen with methanol or other suitable non-reactive liquid as solvent. When using an optically active form of glyceraldehyde, an optically active end product of Formula I or Formula II is obtained. The amino propanediol resulting from the foregoing reductive alkylation reaction is then converted to the desired 2-(3-indolyl)-l,1-dimethyl-ethyloxazolidinone reactant wherein B has Formula IV by reaction with formaldehyde employing 37% aqueous formaldehyde in refluxing benzene wi continued removal of the water by distillation. Esterification with an alkanesulfonyl chloride of the formula RS02C1 in which R is a lower alkyl group of 1 to 4 carbon atoms introduces the necessary group which is reactive with Ar'OH.

The intermediate produced by step (3) wherein the B has Formula III is converted in step (4) to a product of Formula I or Formula II by debenzylation by known means such as catalytic hydro-gcnation or reaction with sodium in liquid ammonia. The intermediates produced in step (3) wherein B has foimula IV are converted to the products of formulas I and II in step (4) by mild acid hydrolysis. In this instance, care must be taken to avoid decomposition of the 187763 reactant since the 3-indolyl substituent is acid sensitive. Aqueous mineral acids of from 0.1 N to IN concentration at temperatures of from 20-100°C. are suitable. The product is recovered as the free base from the hydrolysis mixture by neutralization thereof and collecting the precipitate. ?• s- The 2-(3-indolyl)-l,1-dimethylethylamine employed is prepared by the method of H. R. Snyder, et al., J. Am. Chem. Soc., 69, 3140 (1947) from 3-indolylmethyldimethylamine and 2-nitro-propane followed by reduction of the resulting 2-(3-indolyl)-l,1-dimethylnitroethane.

In the following procedures temperatures are expressed in degrees centigrade (°). Melting points are corrected values according to the U.S.P. method where indicated (corr.). The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shift (6) expressed as parts per million (ppm) versus tetramethylsilane (TMS) as reference standard. The relative area reported for the various shifts corresponds to the number of hydrogen atoms of the particular functional type in the molecule, and the nature of the shift as to multiplicity is reported as broad singlet (bs), singlet (s), , multiplet (in), doublet (d) . triplet (t), or quadruplet (q) with coupling constants (J) reported where appropriate. The format is NMR (solvent): £(relative area, multiplicity, J value). Abbreviations employed are MeOH (methanol), DMS0-d6 (deuterodimethylsulfoxide), i-PrOH (isopropanol), abs.EtOH (absolute ethanol), EtOAc (ethyl acetate), EtOU (95% ethanol), (i.3opropctnJl)\ i-PrOAc (isopropyl ar.**' vp..-v 1 877 acetate), i-Pr20 (di-isopropyl ether), d (decomposition). Other abbreviations have conventional established meanings. The infrared (IR) spectral descriptions include only absorption wave numbers (cm *) having functional group identification value. KBr was employed as diluent for all IR spectral determinations. TMS was used as internal reference for the NMR spectral determination. The elemental analyses are reported as percent by weight.

Procedure 1. 4-(Methylsulfonyl)-m-to.lyloxymethyl Qxirane.-To a mixture of 3-methyl-4-methylsulfonylphenol, 8.1 g. (0.0435 mole), and 20.0 g. (0.216 mole) of epichlorohydrin, there are added two drops of piperldine to serve as condensation catalyst and the mixture is heated at 105-108° for 18 hrs. The excess epichlor-hydrin is then removed by distillation using toluene as a chaser. A solution of 2.1 g. of sodium hydroxide in 50 ml. of water and u- _ 70 ml. of ,'dimethoxyethane is then added and the mixture is stirred for 2 hrs. with occasional warming on the steam bath to convert any phenoxychlorohydrin compound to the oxirane. The. solvent is then removed by distillation in vacuo and the residue is dissolved in a 1: (V/V) mixture of ether and benzene. The solution is dried over anhydrous sodium carbonate and examined by thin layer chromatography for purity of the desired oxirane using a 9:1 mixture of chloroform and a methanol for development (R^ = 0.8). The solvent is then removed by distillation to yield 10.7 g. of a residue constituting the desired oxirane. Measurement of the infrared absorption spectrum is employed to confirm the substantial absence of hydroxyl containing contaminants. This material is suitable for further reaction in Procedure 3 without further purification. 1 877 Procedure 2. 2-Chlorophenoxymethyl Oxirane.- A solution of 12.9 g. of 2-chlorophenol (0.1 mole) in 125 ml. of water containing 6.5 g. (0.162 mole) of sodium hydroxide, and 18.5 g. (0.2 mole) of epichlorohydrin are stirred together at 25° for 20 hrs. The mixture is then extracted twice with 70 ml. portions of methylene chloride. The extract is dried over anhydrous sodium carbonate and the solvent removed by distillation in_ vacuo. The residue constitutes the desired oxirane and is suitable for further transformation as is described in Procedure 4.

Procedure 3. 1-CC2-(3-Indolyl)-l,1-dimethylethvljaminol-3-r4-(methylsulfonyl)-m-tolyloxyl-2-propanol.- The oxirane of Procedure 1, 1C.7 g.,was dissolved in 150 ml. of toluene, 8.2 g. (0.044 mole) of 2-(3-indolyl)-l,1-dimethylethylamine was added and the mixture was refluxed for 18 hrs. The toluene was removed by distillation _in vacuo and a portion of the residue was converted to tha acetate salt, m.p. 142-147°C. The structure was confirmed by examination of the infrared absorption and nuclear magnetic resonance spectra. The remainder of the sample was converted to the hydrochloride salt by treatment of an acetonitrile solution thereof with 8 N ethanolic HC1. After recrystallisation from CH3CN/MeOH 12.5 g. of product was obtained, m.p. 174.0-177.0° (corr.). t Anal. Found: C, 59.40; H, 6.90: N, 5.87.

NMR (DMSO-cU): 1.29 (6, s); 2.52 (3, s); 3.12 (3, s); 3.16 (4, m); 4.13 (3, m); 5.95 (1, bs); 7.10 (8, m); 9.00 (2, bs); and 11.12 (1, bs).

IR: 740, 765. 1120, 1290, 1450, 1590, and 3270. 1 877 Procedure 4. l-(2-Chlorophenoxy)-3~Cll2-(3-indolyl)-l,1-dimethylethylHaminon-2-propanol.- A portion of the oxirane produced in Procedure 2, 7 g. (0.033 mole), was refluxed in solution with 6.3 g. (0.033 mole) of 2-(3-indolyl)-l,1-dimethylethylamine in 70 ml. of ethanol. After 24 hrs. the solvent was removed by distillation in vacuo and the viscous liquid residue was dissolved in 200 ml. of ether, acidified with 8 ethanolic HC1 and the solvents again removed by distillation. Crystallization was induced by adding acetonitrile and rubbing with a glass rod. Eecystallized from acetonitrile and di-isopropyl ether to yield 4.8 g. of product, m.p. 150.5-153.5°C. (corr.).

Anal. Found: C, 61.54; H, 6.41; N, 6.94.

NMR (DMS0-ds): 1.28 (6, s); 3.22 (4, m); 4.25 (3, m); 5.96 (1, bs); 7.23 (9, m); 8.84 (2, bs); and 11.12 (1, bs).

IR: 745, 1250, 1455, 1480, 1590, and 2780.

By adaptation of the foregoing procedures, the products listed in the following table were prepared.

PRODUCTS OF FORMULAS I AND II PROCEDURES 5-14 Procedure Recryst. Elemental No. ArXn or ArHet m.p." (corr.) Solvent Analysis 1-naphthyl 232.0-233.0 MeOH/CH3CH C, 70.47 hydrochloride H, 7.07 N, 6.47 3-methylphenyl 165.0-167.0 hydrochloride MeOH/i-PrOH C, 67.76 H, 7.62 N, 7.05 A 7 3-chlorophenyl 197.0T198.0 MeOH/abs.EtOll C, 61.34 hydrochloride H, 6.36 N, 6.75 CI , 17.14 nhr(dms0-d6) ir ]. 28 6, s) 750, 775, 800 3. 24 4,m) 1110, 1270, 1400 4. 28 3,m) 1460, 1580, 2780 6. 01 l,d, 4 .4 z) 7. 39 12 ,m) 8. 90 2,bs) 11. 00 l.bs) 1. 6,s) 745, 770, 1160 O L. » 28 3,s) 1260, 1450, 1490 3. 18 4 ,m) 1580, 1600, 2780 4. 13 3 ,m) . 93 l.bs) 7. 9,rn) 8. 72 1 ,bs) 9. 12 1 ,bs) 11. 00 l.bs) 1. 6,s) 750, 770, 1110, 3. 4,m) 1230, 1275, 1475, 4. 17 3 ,u) 1580, 1590, 2800, 6. 03 l,d, 3340 .0 Hz) 7. 9,in) 8. 86 l.bs) 9. l.bs) CO -vj •^1 CN Osl Procedure Recryst.

No. ArXn or Arllet m.p.0 (corr.) Solvent 8 2-ethoxyphenyl 173.0-175.0 MeOH/ji-PrOH hydrochloride 9 2-acetylphenyl 161.0-163.0 CH3CN hydrochloride * 2-methylphenyl 173.0-174.5 hydrochloride MeOH/EtOAc • • Elemental Analysis NMR(DMS0--d6) IR c, 65. 86 1. 6,s) 74C, 755, 1130, H, 7. 51 1. 32 3,t, 1215, 1260, 1510, N, 6. 63 7.0 Hz) 1580, 1590, 2800 3. 29 4,m) 4. 11 ,m) . 99 1, bs) 7. 22 9,m) 8. 90 1 ,bs) 9. 31 l.bs) C, 65. 73 1. 6. s) 745, 755, 1240, c, 65. 59 2. 65 3,s) 1450, 1485, 1590, II, 7. 3. 4,m) 1665, 2780 H, 6. 94 4. 3.m) N, 7. 05 6. 04 l.bs) N, 7. 03 7. 41 9,m) 8. 86 l,bs) c, 68. 09 1. 6, s) 750, 1170, 1250, H, 7. 77 2. 3,s) 1460, 1500, 2800, N, 7. 16 3. 28 4 ,m) 3300 4. 3,m) 6. 02 l,d, 4.2 Hz) 7. 22 9,m) 9. 2,bs) 11. 1 ,bs) NJ as 04 Procedure No. ArXn or ArHet ir..p.° (corr.) 11 2-(IH-pyrrol-l-yl)- 124,0-126.0 phenyl base 12 (4-methylsulfonyl)- phenyl 217.0-220.0 hydrochloride 13 CONH, 224.5-227.5 hydrochloride hemihydrate Recryst. Solvent Elemen t r.l Analysis NMR(DMSO-de) IR EtOAc/jL-PrOAc c, 74.40 1 6,s) 740, 1100, 1230, H, 7.32 T 33 l.bs) 1450, 1510, 1590 N, .38 2 80 4,m) 3160, 3400 3 96 3,m) ■ 92 1 ,bs) 6 33 2, m) 7 19 11,m) 8 l,bs) MeOH/abs.EtOH n 58.32 1 6,s) 760, 780, 1155, H, 6.62 3 16 3,s) 1300, 1510, 1600, N, 6.90 3 4,m) 2800 4 26 3 ,m) 6 07 1 ,bs) 7 0-8 0 (9,m) 8 85 l,bs) 9 1 ,bs) abs.EtOH/ c, 61.41 1 6, s) 760, 1430, 1510, EtOAc c, 61.24 2 55 2,m) 1600, 1680, 3400 H, 6.90 3 -t .25 H, 6.59 (10 m) N, .81 6 05 1 ,bs) N, .72 7 11,m) CI ,7.34 8 90 l,bs) 9 31 1 ,bs) OD Ox Procedure No. 14 ArXn or ArHet (2-methylsulfonyl)-phenyl m.-p.° (corr.) 175.0-179.0 hydrochloride hemihydrate Recryst. Solvent MeOH/i-Pr20 Elemental Analysis C, 57.23 C, 57.37 H, 6.91 H, 6.61 N, 5.90 N, 5.94 miR(DMS0-d6) 1.39 (6,s) 3.60 (3,s) 3.62 (4,in) 4.42 (3,m) 6.22 (1,m) 7.42 9.00 IR 750, 1300, 1590, (9 ,ro) (l,bs) 1130, 1150, 1450, 1485, 1625 9.51 (l,bs) *Procedure 10 involved reaction of the 2-(3-indolyl)-l,1-dimethylethylamine and the oxirane ^ intermediate at 140° for \ hr. with no solvent or diluent. \ \ 00 V4 OJ 187763 Procedure 15. Tablets.- The following ingredients are blended in the proportion by weight indicated according to conventional pharmaceutical techniques to provide a tablet base.

Ingredient Amount Lactose ' 79 Corn starch 10 Talcum 6 Tragancanth 4 Magnesium stearate 1 This tablet base is blended with sufficient 1-CC2-(3-indolyl)-l, l-dimethylethyl]]amino j-3-(2-methylphenoxy)-2-propanol hydrochloride (Procedure 10) to provide tablets containing 10, 20, 40, 80, 160 and 320 mg. of active ingredient, and compressed in a conventional tablet press.

Procedure 16. Dry Filled Capsules.- The following ingredients are blended in a conventional manner in the proportion by weight indicated.

Ingredient Amount Lactose, U.S.P. 50 Starch 5 Magnesium stearate 2 Sufficient 1-EC2-(3-indolyl)-l,l-diaiethylethylHaminc^-3-(2-methylphenoxy)-2-prcpanol hydrochloride (Procedure 10) is addsd to the blend to provide capsules containing 10, 20, 40, 80, 160 and 320 mg. of active ingredient which is filled into hard gelatin capsules; of a suitable size. 1 8776 Procedure 17. Solution.- A solution of 1-CC2-(3-indolyl)-1 ,l-dimethylethyllamino!]-3-(2-methylphenoxy)-2-propanol hydrochloride (Procedure 10) is prepared from the following ingredients.

Amount g. 400 g. 100 g. 20 g.

Ingredient Active ingredient Sucrose, U.S.P.

Sorbitol, U.S.P.

Bentonite Flavors, q.s.

Water, q.s. to make 1 liter Each milliliter of the solution contains approximately 20 mg. of the active ingredient.

By application of the methods of Procedures 1 or 2 to the appropriate phenol, or by other conventional methods, the following oxiranes are prepared and then converted to products of Formula I or II by reaction with 2-(3-indolyl)-l,1-dimethylethylamine according to Procedures 3 or 4.

C===CH 0 HCH2 V Proc. 18 -0-CH2CCH VCH2CH=CH2 Proc. 19 0 / \.

CH3CH=CHC—0CHaCHCH:2 ocHzdncHj CH3S0 Proc. 20 Proc. 21 22 - 1 877 63 v 0 /\ .OCHjCHCHz 0 /\ -och2chch.

S-CH, Proc. 22 Proc. 23 0 <• ^ v^ 'NHCOCHa Proc. 24 -OCHaCH^Hj Vs CONH, Proc. 25 och2</hch X/ XN Proc. 26 ' OCH^Hfri, 0ch2ch=cha Proc. 27 0 /\ och2chch2 CI CI Proc. 28 Proc. 29 0 / \ OCHjCHCHs 0 / I \/0ch2chch2 Br Proc.. 30 A/ 0 /\ och2chch ' conhch3 Proc. 31 - 2 3- t 877 0 /\ och2chcha A ■c0n(ch3); Proc. 32 / ^ ch 0 / \ 0ch2chch2 A Proc. 33 CH3 1 0 0ch2chch Proc. 34 0 / \ -0ch2chch2 cha ^ ch3 Proc. 35 0 ,0ch2ch^h2 conh2 conh2 ch3O/\^ 0 /\ och2chch2 Proc. 36 Proc. 37 •yv 0 !\ o-ch2chch2 0 c02c2h= A D// \ / Proc. 38 Proc. 39 24 - J 87763 "\ 7 0 /\ och,chch2 Proc. 40 0 /\ 0ch2chch2 -^0 Proc. 41 AV o /\ 0ch2chch2 co 2/x/XCH2CN Proc. 42 0 /\ ^\,0CH2CHCH2 x/ xch2ch(ch3) : Proc. 43 <0ch2chch2 ■S Proc. 44 0 / \ ^/\-0CH2CHCH2 v xc2hs Proc. 45 0 M och2ciich2 XA" S02CH3 Proc. 46 0 / \ 0ch2chch2 VAc, Proc. 47 1 877 och2chch2 lX/AsN0 och2^hch2 nh, Proc. 48 Proc. 49 \A A 0ch2CHCHj oh Proc. 50 Proc. 51 0 /\ 0ch2chch2 och2chch2 h Proc. 52 Proc. 53 Physical properties were determined as follows: - 26,-

Claims (7)

f 877 Procedure 19.- 1-Ll2-(3-indolyl)-l,1-dimethylethyljamino]-3-C2-(2-properiyl)phenoxy3-2-prcpanol hydrochloride, m.p. 163.0-168.6° (corr.), recrystallized from Me0H/i-Pr20. Anal. Found: C, 69.22; H, 7.56; N, 6.70. NMR (DMS0-d6): 1.30 (6,s); 3.32 (6,m); 4.20 (3,in); 5.03 (2,m); 6.00 (2,m); 7.25 (9,m); 8.90 (l,bs); 9.60 (l,bs); and 11.40 (l,bs). IR: 752, 1120, 1245, 1455, 1490, 1590, 1600, 2790, 2980, and 3350. Procedure 43. 1-QH2-(3-Indolyl)-l,l-dimethylethyl]amino]-3-C2-(2-methyl-l-propyl)phenoxy]-2-propanol hydrochloride, m.p. 163.0-166.0° (corr.), recrystallized from MeOH/CH3CN. Anal. Found: C, 69.34; H, 8.19; N, 6.49. NMR (DMS0-d6): 0.81 (3,t, 7.0 Hz); 1.17 (3,d, 7.0 Hz); 1.32 (6,s); 1.39 (2,m); 3.2S (5,m); 4.22 (3,m); 6.04 (l,bs); 7.22 (9,m); 9.00 (l,bs); 9.60 (l,bs); 11.20 (l,bs). IR: 750, 1100, 1240, 1450, 1490, 1582, 1600, 2780, 2960, and 3320. Procedure 45.- 3-(2-Ethylphenoxy)-l-CC2-(3-indolyl)-l,1-dimethylethyl]]aminoI]-2-propanol hydrochloride, m.p. 170.0-171.5° (Corr.) recrystallized from EtOH. Anal. Found: C, 68.36; H, 7.95; N, 6.85. NMR: (DMSO-ds): 1.21 (3,5, 7.0 Hz); 1.33 (6.s); 2.64 (2,m); 3.24 (4,m); 4.21 (3,m); 6.00 (l,bs); 7.25 (9,m); 9.00 (l,bs); and 9.55 (l,bs). IR: 750, 1130, 1240, 1460, 1495, 1590, 1605, 2800, 2970, and 3350. - 27 - 187763 WHAT/tfWE CLAIM IS? WHAT 13 CLAlMli.ll lb:

1. A compound selected from the group consisting of CH 3 OH CH_-C-NHCH_CHCHo-0-Ar-X 2 , 2 I n CH „ (Formula I), and CH. OH ' i H -CH2-C-NHCH2CHCH2-0-Ar-Het CH„ (Formula II) and the acid addition salts thereof wherein Ar is selected from the group consisting of phenyl and naphthyl, X refers to optional Ar-attached substituents which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, alkylsulf.onyl, alkylsulfinyl, alkylthio, alkanoamido, cycloalkyl having 3 to 6 ring members and 1 to 3 optional alkyl substituents, cycloalkylalkyl having 3 to 6 ring members and 1 to 3 optional alkyl substituents, wherein each of the foregoing groups has up to 8 carbon atoms, phenyl, trifluoromethyl, nitre, amino, hydroxyl, halogen, carboxamido, cyano, and cyanoalkyl having from 2 to 4 carbon atoms, - 28 - 187763 n is the integer 0, 1, or 2 signifying the number of X groups, and » Het is a nitrogen heterocycle having 5 or 6 ring members and up to 1 additional hetero atom selected from the group consisting of oxygen, sulfur, and nitrogen wherein said heterocycle bears from 0 to 2 ring substituents selected from the group consisting of alkyl, N-lower alkyl carboxamido, N,N-dilower alkyl carboxamido, carbalkoxy, wherein each of the foregoing ring substituent groups contains up to 8 carbon atoms, oxo, and carboxamido. I

2. The compound of Claim 1 having Formula i wherein Ar is phenyl, X is in the ortho-position, and n is the intege'r 1.

3. The compound of Claim 1 having Formula I wherein Ar is phenyl, X is alkyl having up to 8 carbon atoms, and n is the integer 1.

A. The compound of Claim 3 wherein X is methyl,

5. The compound of Claim 3, 1-CC2-(3-indolyl)-1,1- *;dimethylethyl3amino3-3-(2-methylphenoxy)-2-propanol.;

6. The compound of Claim 3, 1-CC2-(3-indolyl)-l,1-dimethylethyl^aminoJ-3-(2-methylphenoxy)-2-propanol hydrochloride.;187763;

7. The compound of Claim 1 having Formula I wherein Ar is phenyl, X is cyano, and n is the integer 1.;8, A process for preparing a compound selected from the group consisting of;CH. i J;OH;CH_-C-NHCH_CHCH,-0-Ar-X 2 , 2. 2 n;CH.;(Formula 1), and;H;CH, t J;OH;-CH2-C-NHCH2CHCH2-0-Ar-Het (Formula II) CH.;and the acid addition salts thereof wherein;Ar is selected from the group consisting of- phenyl and naphthyl,;X refers" to optional Ar-attached substituents which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkylsulfinyl, alkylthio, alkanoatnlJo, cycloalkyl having 3 to 6 ring members and 1 to 3 optional alkyl substituents, cycloalkylalkyl having 3 to 6 ring members and 1 to 3 optional alkyl substituents, wherein each of the foregoing groups has up to 8 carbon atoms, phenyl, trifluoromethyl, nitro, amino, hydroxy1, halogen, carboxamido, cyano, and cyanoalkyl having from 2 to 4 carbon atoms,;- 30 -;187763;n is the integer 0, 1, or 2 signifying the number of X groups, and;Het is a nitrogen heterocycle having 5 or 6 ring members and up to 1 additional hetero atom selected from the group consisting of oxygen, sulfur, and nitrogen wherein said heterocycle bears from O.to 2 ring substituents selected from the group consisting of alkyl, N-lower alkyl carboxamido, N,N-dilower alkyl carboxamido, carbalkoxy, wherein each of the said foregoing ring substituent groups contains up to 8 carbon atoms, oxo, and carboxamido by (a) reacting 2-(3-indolyl)-1,1-dimethylethylaniine;CH.,;» 3;J;"CH0-C-NH,;2 I;N' CH3;H;with an Ar' epoxypropyl ether of the formula;O /\;Ar'-0-CH2CHCH2;wherein Ar' represents the group Ar-J^or Ar-Het (wherein Ar, X, n and Het are as defined above); or (b) reacting an indolyl compound of the formula;CH.;Oct;I 3;CH0-C-B;2 »;CH3;CH2C6H£;A;wherein B represents the group -N-CH CHCHj (III);I;or the group f 1 CH-OSC^R (IV);-□;(wherein R is alkyl having from 1 to 4 carbon atoms),;with a phenolic compound of the formula Ar1-OH;When Ar1 is as defined above, and subjecting either the product btained when B represents the group (III) to debenzylation or the product obtained when B represents the group (IV) to mild acid hydrolysis.;- 31 -;/ £■ v ^;9. A pharmaceutical composition which comprises a compound having Formula I or Formula II as defined in Claim 1, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier or diluent therefor.;10. A pharmaceutical composition as claimed in Claim 9 wherein the compound is as defined in any one of Claims 2 to 7.;11. A pharmaceutical composition as claimed in Claim 9, substantially as hereinbefore described with particular reference to any one of Procedures 15 to 17.;12. The method of inhibiting p-adrenergic activity in a non-human mammalian host having a disease state resulting from excessive activation of the 3-adrenergic receptors which comprises administering to said host a non-toxic effective adrenergic g-receptor inhibiting dose of a compound as claimed in Claim 1.;13. The method of exerting a vasodilator effect in a non-human mammalian host which comprises administering to a mammal in need of vasodilatation a non-toxic vasodilator effective dose of a compound as claimed in Claim 1.;14. The antihypertensive process which comprises administering to a non-human mammalian host having hypertension a non-toxic antihypertensive effective dose of a compound claimed in Claim 1.;15. The antihypertensive process which comprises administering to a non-human mammalian host having hypertension a non-toxic antihypertensive effective dose of a compound claimed in Claim 2.;16. The antihypertensive process which comprises administering to a non-human mammalian host having hypertension a non-toxic antihypertensive effective dose of the compound claimed in Claim 7.;A. J. PARK & SON;PE.-l //• S. W*' AGENTS FOR THE APPLICANTS