IE832063L - 1-pyridyloxy-3-indolyalkylamino-2-propanols - Google Patents

Abstract

1-(Pyridinyloxy)-3-(indolylalkylamino)- 2-propanols, novel cardiovascular agents having vasodilator activity and a range of adrenergic beta-receptor blocking action, are prepared by any one of three routes that comprise a novel general process. The general process comprises coupling a hydroxyl- or halogen- substituted pyridine with a suitable halogen- or hydroxyl-substituted propanol or incipient propanol intermediate; and the products of these couplings are also novel. In the preferred of the three coupling routes, product 1-(pyridinyloxy)-3-(indolyl- alkylamino)-2-propanols are formed directly; in the other two coupling routes further processing of the coupling products is required to form the 1-(pyridinyloxy)-3-(indolylalkylamino)- 2-propanols. Preferred compounds bear an amide or cyano substituent in the 3-position of the pyridine ring. [GB2126230A]

Description

; i H a \> t The present invention is concerned with heterocyclic carbon compounds of the indol® series having an amino substituent, and with drug bio-affecting and body-treating processes employing these compounds. 5 A rather large body of prior art exists relating to compounds of 3-(aryloxy)-2-hydroxypropylamine series which have beta-adrenergic receptor blocking activity and/or vasodilating properties and are useful in treatment of cardiovascular diseases. Much of this prior 10 art concerns the beta-adrenergic blocking agent class of these series of compounds. The prototype for these structures is propranolol; chemically, l-(isopropylamino)-3-(l-naphthyloxy)-2-propanol. Propranolol and some related naphthyloxy propanolamines are the subject of U.S. Patent 15 No. 3,337,628 issued August 22, 1967. numerous subsequent patents have been granted covering carbocyclic ethers in which other aromatic rings or heterocyclic systems replaced the naphthyloxy group of propranolol.

A series o£ patents has been granted to J. J. Baldwin disclosing the employment of the pyridinyloxy group in this fashion. These compounds and their salts are disclosed and claimed as useful antihypertensive agents. These patents, which are listed below, generally disclose the following generic structure (1) (Q}-O^Y^hr » OR1 (1) 0 1 " wherein R is alkyl, phenalkyl, phenoxyalkyl; R is H, OL, with L 0 being alkyl or aryl; R2 is H, CN, CFj, OH, C-L, CI, NO^ F, pyrrolyl, oxadiazolyl.

The series of Baldwin patents, assigned to Merck & Co., Inc. comprise the following: A,000,282, December 28, 1976; 4,060,601, November 29, 1977; 4,091,104, May 23, 1978; 4,092,419, May 30, 1978; 4,144,343, March 13, 1979; 4,145,425, March 20, 1979; 4,151,284, April 24, 1979; 4,210,653, July 1, 1980; 4,259,327, March 31, 1981; 4,263,307, April 21, 1981; 4,279,913, July 21, 1981; and 4,329,351, May 11, 1982.

A preferred compound of this series, 2-[3-(tert.-butylamino) 2-hydroxypropoxy]-3-cyanopyridine, also known as MK-761, has undergone considerable further study as described in: Sweet, et al., The Journal of Pharmacology and Experimental Therapeutics, 211/1, 195-296 (1979); Sweet, et al., Clinical and Experimental Hypertension. 1(4), 449-471 (1979); and Vickers, et al., Drug Metabolism and Disposition, 8/3, 163-167 (1980). Acute studies in nan were terminated, however, when MK-761 was found to be teratogenic in rabbits after chronic •i 15 administration at high doses (ef: Journal of Medicinal Chemistry. 22/11, 1284-1290 (1979)).

CN MK-761 n'^^O^Y^SvJ!HC(CH3) -HC1 OH A series of indol-3-yl-tert.butylaminopropanols (2,3) with antihypertensive properties was described in: Kreighbaum, et al., U.S. Patent No. 4,234,595 patented November 18, 1980; U.S. Patent No. 4,314,943 patented February 9, 1982; and Journal of Medicinal Chemistry, 23:3, 285-289 (1980).

-Xiry^o-A r3 fAVl il S T O-Ar-Xn R1 .r2 OH (2) io R3 3 Vn 0-Ar-He t ■M' ^R2 0H R1 (3) A preferred compound of the series represented by structure (2) is designated MJ 13105, also knovm as bucindolol, and is currently undergoing evaluation clinically as an antihypertensive agent.

CN J OH MJ 13105 This Invention concerns a series of vasodilating agents having e range of beta-adrenergic blocking potency end possessing the general formula X and the pharmaceuticals acceptable acid addition salts thereof.

B (1) Xn the foregoing structural formula, X Is CHO, CH^OH, CM, CF^, CONRaR^ or COjR0 with 8a and being independently chosen from hydrogen or Rc, and Rc being lower alkyl, aryl, or arylalkyl; Y is H, QM, halogen, acylax^, alkoxy, aralkylasy, arylcrey, or 000(C1 6alkyl) I" R is hydrogen or I C-L | with L being selected from alkyl, aryl, 1 ? substituted aryl, or arylalkyl; 3 , R*, A and B are independently selected from hydrogen or alkyl; end C Is . halogen, hydrogen, hydroxy, alkyl or alkoxy. hs will be eppsecifeted isom th® representation of its bonding in Formula X, the indolyl aystam shown therein is attached (i.e. attached to the remainder of the molecule) at its 2- or 3- position.

These compounds have X in the 3- position of the pyridine ring and the indolylalkylaminopropoxy side chain in the 2- or 4- position o£ the pyridine ring. Preferred, compounds have th® indolylalkylaminopropoxy side chain in the 2- position. Preferred compounds also include those wherein: 31 is cyano or amido; Y is hydrogen; R is hydrogen; H' and are lower alkyl; A and 3 asr® hydrogen; C being halogen, hydrogen, hydroxy, alkyl or alkoxy.

Th® word "lower", in all occurrences in the present description wherein it indicates a carbon-chain length, sneans "C-j to Cfl".

G The invention includes compounds having the foregoing structural foraula (X) and the acid addition salts thereof. As stated, X in Formula (I) is -CHO, -CN, =CF3, ~COHRaRb, -COjR0 or CHjOH; Ra and Rb are independently 5 chosen from hydrogen or Rc which is lower alkyl (C^ to C^); aryl; or arylalkyl. Tha aryl, however, is preferably phenyl. It is also preferred that X ba attached to the 3- position in the pyridine ring system. Y represents a second aubstituant on the pyridine ring being H, OH, 10 halogen, acyloxy, alkoxy, arelkyloxy, aryloxy or COO(Cl g-- alkyl). Preferably, the pyridinyl group ie coupled to the indolylalkvl-aminopropoxy raid® chain at the pyridine 2- or 0 II 4- position. R is hydrogen or C-L with L being selected from alkyl, aryl, substituted aryl or arylalkyl. 1 2 15 R , R , A, and B are independently chosen from hydrogen or alkyl. C represents a substituent in the benzo ring of indole and is selected from hydrogen, halogen, alkyl, alkoxy, or hydroxy. The indole moiety itself is preferably coupled to the main side chain through its 3-20 position.

For Medicinal usa, the pharmaceutical^ acceptable acid addition salts, those salts in which the anion does not contribute significantly to toxicity or pharmacological activity of the organic cation, are preferred. The 25 acid addition salts are obtained either by reaction of an organic base of structure X with an organic or inorganic acid, preferably by contact in solution, or by any of the standard methods detailed in the literature and available to any practitioner skilled in the art. Example of useful 30 organic acids are carboxylic acids such as, for example, malaic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, pamoic acid, cyclamic acid and pivalic acid; useful inorganic acids are, for example, hydrohalid® acids such as HC1, KBr, HI; 35 sulfuric acid and phosphoric acid.

It is also to be understood that the compounds of the prasent invention include all the optical isomer forms, that is, mixtures of anantiosaers, e.g., ir&casic modifications as well as the individual enantiomcrs. These individual enantiomcrs are commonly designated according to the optical rotation they effect, by (+) and (-)> (1) and (d), or combinations of these symbols. The symbols (1) and (D) and the symbols (S) and (R), which stand for sinister and 5 rectus respectively, designate an absolute spatial configuration of the enantiomer. Where no isomer designation is given for a compound, the compound is the racemic modification* Biological testing of the subject compounds of Formula I in aniamls demonstrates that they possess potent vasodilating properties 10 along with varying degrees of adrenergic betareceptor blocking properties and intrinsic sympathomimetic activity. Preferred members have a particularly desirable combination of the foregoing actions, and ancillary pharmacological effects, or a lack thereof, which particularly suits their, for specific cardiovascular indications, e.g. 15 use as antihypertensives. The utility of the compounds of Formula I can be demonstrated in various animal models including antagonism of isoproterenol in the anesthetized dog treated intravenously (adrenergic betareceptor action), the spontaneous hypertensive and DOCA salt hypertensive rat (antihypertensive action), angiotensin-maintained 20 ganglion-blocked rat model (vasodilator action), and in various other animal and laboratory models (cf: Deitchman, et al., Journal Pharmacological Methods, 3, 311321, (1980)). No evidence of teratogenicity or mutagenicity has been found to be associated with the compounds of formula I. 25 For use as antihypertensives, vasodilators, and/or beta- adrenergic blocking agents, therapeutic agents of this invention may be utilised in therapeutic procedures which oanprise systemic administration, by both oral and parenteral routes, of an effective, nontoxic amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof. An effective amount is construed to mean a dose which exerts the desired pharmacological activity, such as those stated hereinabove, without undue 5 toxic side effects when administered to a mammal in need of such treatment. Dosage will vary* according to the subject and route of administration selected, with an expected range of about 0.1 meg to 100 mg/kg body weight of a compound of Formula I or a pharmaceutical^ acceptable acid addition salt thereof generally providing the desired 10 therapeutic effect. convenient general process. This process involves the coupling of a Z-substituted pyridine (IV) with a suitable W-substituted propanol or incipient propanol intermediate (II).

The compounds of the present invention can be prepared by a 15 General Process Hydrolysis (I) (IV) (IIB) \ (IIC) In the foregoing general process, D is hydrogen, or preferably, phenyl; G is the radical •K1 R2A ^0 ; Z is hydroxyl or halogen, preferably B chloride; Wis halogen, preferably chloride, when Z is hydroxyl and is hydroxyl when Z is halogen. Generally, the hydroxyl-bearing reactant 5 is initially converted to the oxide anion with a strong base prior to reaction with the halogen-bearing intermediate.

This process employs methods known in the prior art for the preparation of l-(substituted amino)-3-(hetaryloxy)-2-propanols as represented by the patents and publications cited in "Background of 10 the Invention". The process involves reaction of the appropriately substituted pyridine with either 1) a [3-(indolylalkyl)oxazolidin-5-yl]methanol (or methyl halide) of Formula IIA, or 2) an indolylalkyl-aminopropanediol (or halopropanol) of Formula TIB, or 3) glycidol of Formula IIC. 13 The intermediate from reaction of IV and Ila is Converted to the product I by hydrolysis under acidic conditions. This hydrolysis nay bG accomplished with dilute mineral acid of from 0.1N to IN concentration at temperatures of from about 20-100°C. The product of Formula I can be recovered as the free base by neutralization of the 20 hydrolysis mixture and collecting the precipitate. Acid addition salts may be obtained by evaporating the hydrolysis mixture or by reaction of the free base with acid. Purification is accomplished by conventional means such as recrystallization.

The conversion of the epoxide intermediate resulting from 2b the reaction of IV with IIC into the product of Formula I is carried out simply by heating the epoxy ether either neat or in the presence of a reaction inert organic solvent with an amine of the formula as shown. 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 5 but are not limited to, for example, benzene, tetrahydrofuran, di-butylether, butanol, hexanol, methanol, dimethoxyethane and ethylene glycol. Suitable reaction temperatures are fran about 60-200°C The single step process pathway involves the reaction of IV with ITB and this is the preferred pathway for synthesis of the 10 products of this invention.

This process is illustrated by the following specific reaction equation which shows the preferred synthetic method of the above as Reaction 1.

Reaction 1 (IV) (HE) (I) 1 2 15 In the foregoing scheme, X, If, R, R , R , A, B, and C are as defined in Formula 1. Essentially this process involves heating the selected substituted halopyridine with the appropriate indolylalkylamirvo-propanol intermediate (IIB) in the presence of a base, all in an inert organic liquid under mild conditions. Standard strong bases 20 such as potassium t-butoxide, potassium hydroxide, or sodium hydride may be employed but the sodium hydride is preferred. Similarly, any of a number of inert organic liquids may be chosen as the reaction medium or the cyanopyridine and indolylalkylaminopropanol may be reacted neat in the presence of the base. Suitable solvents include but are not limited to, for example, benzene, toluene, tetrahydrofuran, dibutylether and dimethoxyethane. Suitable reaction temperatures are 5 frcm about 20-80°C. Addition of a suitable crown ether, such as 18-crown-6 ether, aids the reaction process.

Formula 1 products in which Y and/or C are hydroxy, are prepared by cleavage of the corresponding roethoxy precursor as shown in Reaction 2: 10 Reaction 2 OH B Other synthetic methods resulting in conversion to hydroxylated products, e.g. such as hydrogenolysis of benzyloxy precursors, are well known to the chemical practitioner and may also be applied in these cases. 15 Requisite halopyridines are available commercially or may be prepared using standard methods for their preparation reported in the literature. Preparation of related trisubstituted pyridines is disclosed in U.S. 4,329,351, issued May 11, 1982 to Baldwin, et al.. Reference to U.S. 4,329,351 is particularly recommended. 20 The intermediate indolylalkylaminopropanols (IIB; R ■ H), preferred synthetic intermediates, are conveniently prepared by reacting an appropriately substituted indolylalkylamine (III) with 3-chloro-l,2-propanediol In refluxing alcohol containing sodium carbonate. This process Is illustrated by reaction equation 3.

Reaction 3 r1 r2 A C * B (HI) (TIB) 1 2 In reaction scheme 3, R , R , A, B, and C are as defined in Formula t. b Formula I products of the present invention wherein R is other than hydrogen are conveniently prepared by treating the corresponding Formula I product wherein R is hydrogen with an appropriate acylating agent such as, for exanple, an acyl halide, e.g. undecanoyl chloride, pivaloyl chloride, benzoyl chloride, para-methoxybanzoyl chloride, or 10 anhydride, e.g. acetic anhydride. The reaction is illustrated by the following equation shown below as Reaction 4: Reaction 4 The indolylalkylamines (III) are described In the aforementioned Kreighbaum, et al. patents and Journal of Medicinal Chemistry "J article, consultation of these texts being reccsmtended, as also certain references cited therein. Although these referenced procedures are applicable to the preparation of other indolylalkylamine intermediates not specifically disclosed therein but which are required as inter-5 mediates for the present invention, representative syntheses of Formula III compounds are given hereinbelow for further exemplification.

The compounds of the present invention can be formulated according to conventional pharmaceutical practice to provide pharmaceutical compositions of unit dosage form comprising, for example, 10 tablets, capsules, powders, granules, emulsions and suspensions.

The solid preparations contain the active ingredient in admixture with non-toxic pharmaceutical excipients such as inert diluents, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating 15 agents, for example, maize, starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques so as to defy disintegration and absorption in the gastrointestinal tract and 20 thereby provide a sustained action over a longer period.

Liquid preparations suitable for parenteral administration include solutions, suspensions, or emulsions of the compounds of Formula I. The aqueous suspensions of the pharmaceutical dosage forms of the compounds of Formula I contain the active ingredient in 25 admixture with one or more non-toxic pharmaceutical excipients known to be suitable in manufacture of aqueous suspensions. Suitable excipients are, for example, suspending agents such as sodium carboxy-methyl cellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragecanth, and gum acacia. Suitable disbursing or wetting agents are naturally occuring phosphatides, for example, lecithin, polyoxyethylene stearate.

Non-aqueous suspensions may be formulated by suspending the active ingredient in a 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 beeswax, hard paraffin, or cetyl alcohol. Sweetening and flavoring agents generally used in pharmaceutical compositions may also be included such as saccharin, sodium cyclamate, sugar and caramel to provide a palatable oral 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 a consideration of the following examples and appended claims which are given for the purpose of illustration only and are not to be construed as limiting the invention In sphere or scope. In the following examples used to illustrate the foregoing synthetic processes, temperatures are expressed in degrees Celsius (°) and melting points are uncorrected. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (6 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 corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shifts as to multiplicity is reported as broad singlet (bs), singlet (s), multiplet (m), or doublet (d).

Abbreviations employed are DMSO-d, (d^uterodimethylsulfoxide)» CDC3 o J (deuterochloroforro) and are otherwise conventional. The infrared (IR) spectral descriptions include only absorption wave numbers (cm "*) having functional group identification value. The IR determinations were employed using potassium bromide (KBr) as diluent. The elemental analyses are reported as percent by weight.

Synthesis of Intermediates A. Intermediates of Formula III EXAMPLE 1 3- (2-Amino-'2-roethylpropyl)-6-methoxyindole (R1 = R= Me, A and B « H, C « 6-MeO) To 15.2 mL of a chilled 25% aqueous solution of dimethyl-amine the following were added sequentially with stirring and continued cooling: 16.9 mL of acetic acid, 7.2 mL of 37% formaldehyde, 27 mL of 95% ethanol. The resulting stirred solution was kept at 0° to -5° with a cooling bath while 6-methoxyindole (10,0 g, 0.07 mole) was added in portions. This mixture was stirred and gradually warmed to 30° over a period of one-half hour and then held at 30° with stirring for 3 hrs. The reaction mixture was then chilled to 10-15° and acidified with 170 mL of 2N HC1. This acidic mixture was decolorized (Darco*G-60), filtered and the filtrate made basic using 245 mL of 20% NaOH while being cooled and stirred. A resulting brown oily precipitate was ether extracted, and the extracts were water-washed, dried (MgSO^) and concentrated to a brown oily residue (14 g). The residue was recrystallized from isopropylether and hexane to yield 9 g (65?0 of 6-methoxygramine as a tan solid, m.p. 88-90°.

*Trade Mark A mixture comprised of the 6-methoxygramine (7.7 g, 0.04 mole), 2-nitropropane (26.5 g, 0.3 mole), and NaOH (1.7 g pellets, 0.04 mole) was refluxed under a nitrogen atmosphere for 3-5 hrs. The reaction mixture was cooled to room temperature, acidified with 10% 5 act'tic acid and extracted with ether. The ether extracts were water-washed, dried (MgSO^), and concentrated in vacuo to a residue. Recrystallization of the residue from isopropyl alcohol-water gave 7.6 g (80Z) of 3-(2-methyl-2-nitropropyl)-6-methoxyindole as a tan solid, m.p. 98-100°. 10 The nitropropylindole compound and activated Raney nicVel (4.2 g) were combined in 80 mL 95% ethanol and heated to reflux.

I Heating was halted as a solution comprised of 85% hydrazine hydrate (7.8 g) in 8 mL 95% ethanol was added dropwise. The reaction mixture was then heated at reflux for 2 hrs, cooled to room temperature and 15 filtered. The filtrate was concentrated to a residual oil which slovjy solidified and was recrystallized from ethyl acetate-isopropyl ether to give 4.2 g of product, m.p. 125-128°.

EXAMPLE 2 2-(2-Amino-2-methyIpropyl)indole 20 (R ° R = Me, A, B, and C = H) A solution comprising indole-2-carboxylic acid (10.0 g, 0.06 mole) and thionyl chloride (20.0 g, 0.17 mole) in 130 mL of dry Et^O was stirred for 12-18 hrs at room temperature under a nitrogen atmosphere. The reaction mixture was filtered and the filtrate was 25 concentrated to an oily residue which was taken up in 150 mL of dry Et20. This ether solution was treated with 80 mL of dimethylamine in 90 mL of Et^O. The ethereal reaction mixture was concentrated to dryness and the Residue crystallized in isopropyl alcohol. The solid was isolated by filtration to give 4.0 g (34%) of the 2-indolylamide product, m.p. 181-183°.

The amide was dissolved in 100 mL THF and this solution was added dropwise to a stirred suspension comprised of 3.g lithium aluminum hydride in 50 mL of THF under a nitrogen atmosphere. After heat at reflux for 2 hr, the reaction mixture was cooled and decomposed with a small amount of water and dilute NaOH solution. This mixture was filtered and the filtrate concentrated to a residual oil which was taken up in absolute ethanol and treated with a slight excess of dimethyl sulfate. The resulting alcoholic solution was stirred at roofli temperature for 4 hrs and then concentrated in vacuo to dryness giving as residue the trimethy1amine quaternary salt.

The crude quaternary salt product (3.0 g, 0.01 mole) was combined with NaOH (2.0 g pellets, 0.05 mole) and 2-nitropropane (15 mL) and the mixture was heated at reflux under a nitrogen atmosphere for 1 hr. The resultant dark thick mixture was cooled, diluted with water, acidified with acetic acid to a pH of approximately 6 and then extracted with Et^O. These Et^O extracts were combined, washed with water, dried (MgSO^) and concentrated to a dark residue which was chromatographed on a silica column and diluted with methylene chloride. Removal of the methylene chloride and recrystallization of the crude material from isopropyl alcohol-water gave 0.4 g of 2-(2-roethyl-2-nitropropyl)indole as a cream colored solid, m.p. 102-103°.

Reduction of this nitro product with Rancy nickel and hydrazine according to the procedure used in Example 1 above yields the desired indolalkylamine as a white solid, m.p. 130-133°.

Additional examples of indolealkylamines are displayed in Tabic 1.

Ex at 3 A 5 6 7 8 9 10 11 12 : a Table 1 Indolealkylamlnes h2N B (III) Me Me Me Me H H tt Me Me Me H Me Me Me Me Me Me Me H H 3-H 2-Me 2-H 2-H 2-H 2-Me 3-Me 2-H 2-Et 2-H Me H H H H Me Me H H H H H 5-Br 5-OMc H 5-OPr 5-Br 6-OMe 4-C1 7-OMe B. Intermediates of Formula II EXAMPLE 13 3-[[2-(3-Indolyl)-l,1-dimethylethyl] aminoT-I,2-propanediol Hydrate (IIB) A mixture of a,a-diniethyl-f5-(3-lndolyl)ethanainlne (10.0 g, 0.05 mole), Na2C03 (11.3 g, 0.11 mole), 3-chloro-l,2-propanediol (7.0 g, 0.06 mole) and EtOH (250 mL) was stirred overnight at reflux. After cooling, the mixture was filtered and concentrated in vacuo. The residue was dissolved in EtOAc, decolorized (Darco G-60), and evaporated to a volume of 100 mL. The solution deposited a white solid which was recrystallized from EtOAc to give 7.7 g (55%), m.p. 112-114°C. The material crystallized with one-fifth mole of water.

Using other intermediates of Formula III in this or a similar procedure readily gives a variety of Formula IIB intermediates.

Synthesis of Products EXAMPLE 14 2-[ 2-Hydroxy-3-[ [ 2- (lH-indol-3-yl)-l ,1-dimetViyl ethyl]amino]propoxy]-3-pyridinecarbonitrile Hydrochloride (Y - H, X = CN, R =■ H, R and R ° Me, A, B, and C - H) 3—[(2-(3-Indolyl)-l,1-dimethylethyl]amino]-l,2-propanediol (47.3 g, 0.18 mole) and sodium hydride (7.6 g of 57% dispersion in oil, 0.18 mole) were stirred in 2.5 liters of toluene and heated at 70° for 3 hrs under a nitrogen atmosphere. The mixture was then allowed to cool to room temperature while being stirred and 18-crown-6 ether (0.5 g), anhyd. powdered ^CO^ (62.1 g of powder, 0.45 mole) and 2-chloro-3-cyanopyridine (25.0 g, 0.18 mole) were added sequentially to the stirring mixture and then the whole was stirred for an additional 42 hrs. Concentration to dryness gave a residue which was partitioned between hot H^O and EtOAc. After cooling to room temperature, the :0 aqueous layer was separated, washed with additional EtOAc and this wash combined with the original EtOAc layer. The EtOAc was dried (MgSO^) and concentrated hot to about half volume. Upon cooling, a solid precipitated and was isolated by filtration to give approximately 5 Al g (62%) of the crude product base.

Conversion of the base into the hydrochloride salt is accomplished by treating an isopropyl alcohol solution of the base with ethanolic HC1. Recrystallization of the crude hydrochloride salt from absolute ethanol gives a white solid, m.p. 181-183°. 10 Anal. Calcd. for C^H^N^O^HCl: C, 62.92; H, 6.29; N, 13.98. Found: C, 62.85; H, 6.29; N, 1A.04.

NMR (DMSO-d6): 1.30 (6, s); 3.20 (4, m); 3.99 (3, ro); 6.02 (1, d [4.0 Hz]); 7.30 (6. m); 8.31 (1, dd [2.0, 7.6 Hz]); 8.51 (1, dd [2.0, 5.6 Hz]); 8.82 (1, bs); 9.32 (l,bs); 11.27 (l,bs). 15 IR (Kbr): 750, 1110, 1310, 1440, 1460, 1580, 1588, 2230, 2790, 2980, and 3400 cm"1.

Preparation of the Cyclamate Salt The cyclamate salt may be prepared by treating the crude base synthesized above (2 g crude base) with cyclamic acid (1 g) in 20 50 mL methanol. The methanol solution was warmed, filtered and the filtrate concentrated in. vacuo to give a residue which was crystallized in 10 mL acetonitrlle. Recrystallization of the crude salt from methanol-acetonitrile gave 2.0 g of white solid, m.p. 172-174°.

Anal. Calcd. for C21H2AN402®C6H13N03S: C, 59.65; H, 6.87; 25 N, 12.89. Found: C, 59.74; H, 6.77; N, 12.82.

EXAMPLE 15 4-1 2-Hydroxy-3-1[2-(lH-indol-3-yl)-l,1- dimethylethyl]amino]propoxy]-3-pyridinecarbonitrile Using the procedure of Example 14 and utilizing 3—{[2—(3— indolyl)-l,1-dimethylethyl]amino]-l,2-propanediol (10.4 g, 0.04 mole); sodium hydride (1.7 g, 0.04 mole), 550 mL toluene, 4-chloro-3-cyanopyridine (5.5 g, 0.04 mole), Cf: Wieland and Biener, Chem.

Borichte-, 96, pages 268-274 (1963)); 18-crown-6 ether (0.11 g) and anhydrous powdered (13.7 g, 0.1 mole), a gummy material (15 g) wus obtained. The gum was chromatographed on a silica column eluting with methylene chloride (90 parts), methanol (10 parts) and ammonium hydroxide (1 part) to give 2 fractions. The second fraction to be eluted gave 6.8 g of gum which was crystallized in ethyl acetate to give 5 g of solid, m.p. 124-126°. Recrystallization of this material from ethyl acetate gave 4.2 g of white solid, m.p. 126-128°.

Anal. Calcd. for C,.,H_. N, 0„: C, 69.21; H, 6.64; N, 15.38. 21 24 4 2 Found: C, 69.42; H, 6.75; N, 15.65.

NMR (DMS0-d6): 1.00 (6, s); 1.55 (l.bs); 2.75 (4, m); 3.90 (1, m); 4.27 (2, m); 5.10 (l,bs); 7.25 (6, m); 8.64 (1, d [6.0 Hz]); 8.78 (1, s); 10.82 (l,bs).

IR (KBr): 745, 1010. 1190, 1290, 1315, 1455, 1495, 1520, 1590, 2225, 2970, and 3400 cm"1.

EXAMPLE 16 2-[ 2-Hydroxy-3-[ [2-(lH-indol-3-yl)-l,l-dimcthy] ethyl ]amino ]propoxv1-3-pyridinecarboxamide Using a procedure similar to that outlined in Example 4 5 above, 3~[(2-(3-indolyl)-l,1-dimethylethyl]amino]-l,2-propanediol (10.5 g, 0.04 mole), sodium hydride (1.7 g, 0.04 mole), 400 mL toluene, 2-chloronicotinamide (5.6 g, 0.04 mole), 18-crown-6 ether (0.11 g) and anhydrous powdered K^CO^ (13.8 g, 0.1 mole) were reacted to give 17 g of residual gum. The gum was chromatographed on a 10 silica column eluting with methylene chloride (90 parts), methanol (10 parts) and ammonium hydroxide (1 part). The product-containing fractions were combined and concentrated to a residue which was crystallized in ethyl acetate to give 5.2 g of material, m.p. 68-72°.

Recrystallization from ethyl acetate and drying in a vacuum oven 15 afforded 4 g of white solid, m.p. 131-133°.

Anal. Calcd. for C.,H,,N.O,: C, 65.95; H, 6.86; N, 14.65. 21 2b 4 3 Found: C, 65.80; H, 6.85; N, 14.31.

NMR (DMSO-d,): 1.03 (6, s); 2.77 (4, m); 3.95 (1, m); b 4.46 (2, ffl); 7.20 (6, m); 7.81 (2, bs); 8.30 (2, d [6.1 Hz]); 2C 10.85 (l,bs).

IR (KBr): 740, 780, 1100, 1235, 1430, 1460, 1585, 1670, 2970, 3330, and 3470 cm"1.

EXAMPLE 17 Conversion of Methoxy Products to 25 Hydroxy Products - General Procedure Dissolve the methoxy product in methylene chloride and stir under a nitrogen atmosphere while keeping chilled with an ice bath.

Add dropwise 3 equivalents of boron tribromide in methylene chloride solution. Following addition, remove the ice bath and allow the reaction mixture to stir at room temperature for 6-8 hrs. Again, chill the reaction mixture with an ice bath and decompose excess reagent by adding excess H^O dropwise, causing a gummy material to precipitate. The supernatant is decanted from the gummy material 5 which is rinsed with two portions of water. The gum is dissolved in hot water, treated with activated charcoal (Darco), filtered, the filtrate chilled and made basic with ammonium hydroxide to a pH of approximately 8. The resultant precipitate is filtered, washed with water, dried and further purified by column chromatography on silica 10 gel, eluting with CRCl^ (90 parts) - methanol (10 parts) - NH OH (1 port). Concentration of product-containing fractions gives a residue which is recrystallized from ethanol-water to give pure hydroxy product.

Starting with the appropriate pyridine and indolylalkyl-15 amine, additional examples of Formula I products may be synthesized using substantially the same procedures as outlined hereinabove.

Some additional products of Formula I which may be synthesized are shown in Table 2, G in the formulae represents the group as determined by the intermediate III selected 20 (cf: examples 1-12).

Table 2 Formula Example Formula CN OCCH, NG 3 0 0 'VCf HQ ^CN NG OH .CONH- NG OH CHO NG OCCH, ii J ^P°2Et ° n^O/>Y^ng OH cr.

-N/>vO^'vVj/>^NG OCPh 25 26 27 28 29 30 0 CNMe, N 0' y ^ NG OH F v ^CN 'N' ^O' | NG OH CI ^ CN N "0^ Y ^ NG OCCH _ II J H0v(^Sy.C01'H2 ° Ul Oil CHO NC OH CCyie NC OC.Et Biological Evaluation These biological tests were used to gauge the cardiovascular profile of a number of the compounds of Formula I as vasodilators with a range of beta-adrenergic blocking activity. 5 EXAMPLE 31 The efficacy of antihypertensive agents other than adrenergic beta-receptor blocking agents is commonly estimated in the spontaneous hypertensive rat. Blood pressure values are determined for test animals prior to and 2U hours after oral doses of 50 rag/kg of test 10 compounds; the observed percentage change in heart^rate is noted as well. A fall in blood pressure in the range of 19-24 mmHg is considered "questionable". "Active" and "inactive" designations are decreases greater and less than that range.

EXAMPLE 32 15 The angiotensin-maintained ganglion-blocked rat model is utilized as a screening test for estimation of the vasodilator component of activity. Percentage changes in blood pressure in anesthetized rats 30 minutes after intravenous dosing are determined. The intravenous dosing is done with test compound at 3 mg/kg. 20 Borderline activity is defined as a 15-202 decrease in blood pressure measured 30 minutes after dosing. "Active" and "inactive" designations are increases greater and less than that range.

EXAMPLE 33 Diastolic blood pressure and heart rate responses to a fixed 25 challenge dose of isoproterenol are obtained before and 15-minutes after graded doses of test compound administered intravenously over a 3-min interval to anesthetized dogs. A branch of a femoral artery and vein are cannulated to record blood pressure and to administer the drugs which are dissolved in saline. The vagi were sectioned bilaterally in the mid-cervical region of the neck and the dogs are ventilated mechanically (Harvard respirator) with room air at a rate of 20/minute and a stroke volume of 20 mL/kg. Heart rate is monitored with a cardiotachometer triggered by the pressure pulse. All measurements an- recorded on a Beckman*R-6l2 recorder. The drug effect is expressed in terms of a cumulative dose (microgram/kg) causing 502 inhibition of isoproterenol response.

The following abbreviations used herein have the following meanings: Ph stands for a phenyl group, Pr stands for a propyl group, Me stands for methyl group, and Et stands for an ethyl group.

Additionally, an accepted convention in modern organic chemistry has been used throughout. For alkyl structures, in a shorthand form, joined line sigments substitute for explicit notation of C and H groups. Thus, for example, formula I can also be written: i 2 R\ ^-R TJ 'A . CH, CH C 0/ 2-S. / 2^ -S.

° CH N CH.- I H OR In connection with the intermediates referred to earlier in the present description, reference should be made to our Divisional Patent Specification No. SGJ02 _ ■ Trade Mark

Claims (25)

CLAIMS:

1. A compound having the formula or an acid addition salt thereof, wherein X is selected from -CHO, -CN, CH2OH, 5 "CONR3^, or "C02^C ^ an(* ^ being independently c C;chosen from hydrogen or R and wherein R is lower alkyl, aryl, or arylalkyl;;Y represents a second substituent on the pyridine ring and is hydrogen, halogen, acyloxy, alkoxy, aralkyloxy,;10 aryloxy, CH or COO (alky!) wherein alkyl is Cj-Cgalkyl;;the* indolylalkylaminopropoxy side chain is coupled at the pyridine 2- or It- position; ^ II R is hydrogen or -C-L with L being selected from C^ to C10 alkyl, aryl, substituted aryl, or arylalkyl; 1 2 15 R ,R ,A and B are independently chosen from hydrogen or alkyl; C represents a substituent in the benzo ring of indole and is selected from hydrogen, halogen, alkyl, lower alkoxy, or hydroxy; and the indolyl system is attached by its 2- or 3- position; "lower" 20 meaning "C^ to C^". : a

2. A compound of claim 1 wherein the indolylalkylaminopropoxy side chain is coupled to the pyridine 2-position.

3. A compound of claim 1 wherein the indolyl ring is attached at its 3-position. 5 A. A compound of claim 2 or claim 3 wherein X is cyano 1 2 or amido; Y is hydrogen; R is hydrogen; R and R are lower alkyl;

4. A and B are hydrogen; and C is halogen, hydrogen, hydroxy, alkyl, or alkoxy.

5. A compound of claim 1, which is 2-[2-hydroxy-3- 10 [(2-(lH-indol-3-y1)-1,1-dimethylethyl]amino]oropoxv1-3-pyridine- carbonitrile or a pharmaceutically acceptable acid addition salt thereof.

6. The cyclamic acid addition salt of the compound of claim 5. 15

7. The HC1 acid addition salt of the compound of Claim 5.

8. - A compound of claim 1,"which is 4-[2-hydroxy-3-[[2-(lH-indol-3-yl)1,1-dimethylethyl]amino]propoxy]-3-pvridinecarbo-nitrile or a pharmaceutically acceptable acid addition salt thereof.

9. A compound of claim 1, which is 2-[2-hydroxy-3-[[2-20 (lH-indol-3-yl)-1,1-dimethylethyl]amino]propoxy ]— 3-pyridinecarbox- aSiide jois pharmaceutically acceptable acid addition salt thereof.

10. A compound (or salt) as claimed in any of claims 1 to 9, wherein X is attached at the 3- position of the pyridine ring.

11. A ocmpound (or salt) as claimed in any of claims 1 to 10, wherein 25 the indolylalkylaminoprcpoxy side chain is attached at the 2- or 4- position of the pyridine ring.

12. A non-toxic effective vasodilating dose of a compound as claimed in claim 1, for use in a method of exerting a vasodilating effect in a mammalian host having a condition in which therapeutic benefit is derived from vasodilatation.

13. A non-toxic antihypertensive effective dose of a compound as claimed in claim 1, for use in a method of treating hypertension in a mammalian host having hypertension.

14. A pharmaceutical composition in dosage unit form suitable for systemic administration to a mammalian host, said composition comprising a pharmaceutical carrier and an amount of a Formula I compound according to claim 1 to provide an effective non-toxic dose of from 0,1 meg to lOOmg/kg body weight of said host.

15. a pharmaceutical composition of claim 14 wherein the Formula X compound is 2-[2-hydroxy-3-[[2-(lH-indol-3-yl)-l,1-dimethylethyl]aniino]propoxy]-3-pyridinecarbonitrile or a pharmaceutically acceptable acid addition salt thereof.

16. a pharmaceutical composition of claim 14 wherein the Formula I compound is 4-[ 2-hydroxy-3~r [ 2-(lH-indol-3-yl)-l, 1-dimcthylethyl]amino]propoxy]-3-pyridint'carbonitrile or a pharmaceutically acceptable acid addition salt thereof.

17. A pharmaceutical composition of claim 14 wherein the Formula 1 compound is 2-[2-hydroxy-3-[[2-(lH-indol-3-yl)-l,l-dimethylcthyl]amino]propoxy]-3-pyridinecarboxamide or a pharmaceutically acceptable acid addition salt thereof.

18. A process for preparing a compound having the formula OR i and the acid addition salts thereof, wherein X is selected from CH2OH, -CHO, -CN -CF3, -CONRaRb, or -C02Rc, with Ra and Rb being independently chosen from hydrogen or R and wherein Rc is lower alkyl, aryl, or arylalkyl; Y represents a second substitutent on the pyridine ring and is hydrogen, halogen, acyloxy, alkoxy, aralkyloxy, aryloxy, OH or COO(alkyl) wherein alkyl is C1-Cg alkyl; R is hydrogen or -C-L with L being selected from alkyl, aryl, substituted aryl, or arylalkyl; 1 2 R , R , A and B are independently chosen from hydrogen or alkyl; C represents a substituent in the benzo ring of indole and is selected from hydrogen, halogen,, alkyl, alkoxy, or hydroxy; and the indolyl system is attached by its 2- or 3- position, said process comprising: (a) coupling a S-substituted pyridine of formula IV (IV) wherein X and V are as defined above and wherein 8 is hydroxyl or halogen, with a W-substituted propanol or incipient propanol intermediate II selected from IIA, HE, and IIC: Y N-G IIA OR N-G IIB » <} IIC wherein D is hydrogen or phenyl and preferably phenyl; wherein G is the radical ,1 -2 1 2 wherein R , R , A, B, and C are as defined above; wherein W is halogen and preferably chloride when 8 is hydroxyl and wherein W is hydroxyl when B is halogen; and (b) i) when compound IIA is reacted with compound IV, then converting the product thereof by hydrolysis under acidic conditions to said compound I; ii) when compound IIC is reacted with compound IV, an epoxy ether is formed and including a further step of heating said epoxy ether either neat or in the presence of a reaction inert organic solvent with an amine of the formula HjNG, wherein G is as defined above, so as to form said compound I "lower" meaning "C^ to C4".

19. A process according to Claim 18, wherein said compound IIB is used, wherein W is hydroxyl, wherein S is halogen, and said coupling in step (a) comprises heating compound IV with compound IIB in the presence of a base, all in an inert organic 5 liquid under mild conditions.

20. a process according to Claim 18, wherein said hydrolysis under acidic conditions employs dilute mineral acid of from 0.1N to IN concentration and temperatures within the range from about 20-100°C and including also the step of 10 recovering either (a) the product of Formula I as the free base of neutralization of the hydrolysis mixture and collecting the precipitate or (b) the acid addition salts thereof by evaporating the hydrolysis mixture or by reacting the free base with acid.

21. A process according to Claim 18, wherein said Y 15 and/or C in said Formula I products are/is hydroxy, said process comprising the process according to Claim 18 wherein said compound IIB is used and including also the step of cleaving the corresponding methoxy precursor by the reaction as shown in Reaction 2: Reaction 2

22. A process as claimed in claim 18, substantially as indicated in respcct of any of Examples 14-16 and 18-30.

23. A compound of the formula "(I)" specified in claim 18, prepared by a process as clained in any of claims 18 to 22.

24. A method of exerting a vasodilating effect in a non-human mammalian host, wherein said method comprises administering to a non-human martrail having a condition in which therapeutic benefit is derived from vasodilatation, a non-toxic effective vasodilating dose of a compound as claimed In claim 1.

25. A method of treating hypertension, said method comprising administering to a non-human mammalian host having hypertension, a non-toxic antihypertensive effective dose of a compound claimed in claim 1. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.