IE913815A1 - Diastereoisomers of bicyclo-substituted phenylacetonitrile¹derivatives - Google Patents

Abstract

A series of diastereoisomers of a compound of formula (I) which are useful as cardiovascular agents.

Description

The present invention provides novel compounds, novel compositions, methods of their use and methods of their manufacture, such compounds are generally pharmacologically useful as calcium channel-blocking cardiovascular agents and, particularly, as antihypertensive, anti-anginal, and antiarrhythmic agents. The aforementioned pharmacologic activities are useful in the treatment of mammals. More specifically, the compounds of the present invention are orally active calcium channel blockers that can be used in the treatment of hypertension with reduced deleterious effects on cardiac function, including heart rate. At the present time, there is a need in the area of cardiovascular therapy for such a calcium channel blocking agent. 0068C Calcium channel blocking agents are a class of pharmacologic agents that inhibit the entry of calcium ions into cells, or inhibit the mobilization of calcium from intracellular stores. The depolarization of excitable cells is mediated by two inwardly directed ionic currents. These are the so-called fast sodium channel and the slow calcium channel. In the presence of a calcium channel blocker, movement of calcium ions into cells is impeded, with resultant inhibition of excitation-contraction coupling. By inhibiting excitation-contraction coupling, calcium channel blockers act to prevent the contraction of arterial smooth muscle cells and therefore cause relaxation of arterial vascular beds. Calcium channel blockers also act to slow the rate of depolarization in the specialized cardiac cells that make up the sinoatrial and atrioventricular nodes. By inhibiting the rate of depolarization of these tissues, negative chronotropic, inotropic and dromotropic effects are exerted on the heart.

Three compounds are in popular use today as calcium channel blockers. They are nifedipine, diltiazem and racemic verapamil. Of the three, racemic verapamil has the greatest effects on atrioventricular conduction, myocardial 0068C contractility and sinoatrial automaticity. One drawback to the use of verapamil in the treatment of essential hypertension is that since it has the effects on myocardial conductivity discussed above, it can cause an unintended slowing of atrioventricular conduction that can lead to bradycardia and may also directly depress myocardial contractility. For this reason, anti-hypertensive therapy with verapamil is contraindicated in patients with disease of the sinoatrial node or atrioventricular conduction disturbances, or in the presence of beta-adrenergic blockade, or with significant left-side ventricular dysfunction (ejection.fraction of less than 30%). Beyond this group of patients, a certain percentage of patients will experience first or second degree atrioventricular nodal block as a side effect of therapy with verapamil. Atrioventricular nodal conduction disturbances may be worsened, particularly if paroxysmal atrial tachycardia with atrioventricular block is present.

Likewise, a certain percentage of patients whom a practitioner desires to have on beta-adrenergic blockade therapy will not be able to use verapamil, since the decrease in vascular resistance that the verapamil would induce would 0068C otherwise bring about a reflex increase in adrenergic tone as a compensatory mechanism; lacking this compensatory mechanism due to the presence of a beta-blocker, the intrinsic negative effects (both inotropic and dromotropic) of verapamil could lead to marked decrease in contractility and left ventricular function, which would be especially undesirable for patients having congestive heart failure.

Thus, there is a need in the area of cardiovascular therapeutics for a calcium channel blocking agent which can be used in the treatment of essential hypertension and that has minimal cardiac effects. The compounds of the present invention meet this need in the art by providing for therapeutic agents for the treatment of essential hypertension that have diminished effects on cardiac function.

The compounds made by the method of the present invention further have site-selective vasodilating activity useful in the treatment of renal ischemia and cerebral ischemia.

Brief Description of the Drawings 0068C Figure 1 is a graph showing per cent decrease of mean arterial pressure as a function of dosage, with the comparison being between verapamil, the racemate from which the diastereomers of the invention were resolved, and the individual diastereomers themselves.

Figure 2 is a graph showing per cent decrease in heart rate as a function of dosage, comparing the same six substances as Fig. 1.

Summary of the Invention The present invention relates to novel compounds which are diastereomers of the compound having the general structural Formula 1: CN CH3 O 0068C and the pharmaceutically acceptable salts thereof. The diastereomers of the present invention are as follows: / h3c namely, 3,4-dimethoxy-aR, aR*-(1-methylethyl)-a-[3-[methyl (1,2,3,4-tetrahydro-2S*-naphthalenyl)amino]propyl] benzeneacetonitrile, 2-hydroxy-l,2,3-propanetricarboxylate (1:1) ; / h3c 0068C namely, 3,4-dimethoxy-aS, aR*-(l-methylethyl)-a-[3[methyl(1,2,3,4-tetrahydro-2R*-naphthalenyl)amino]propyl] benzeneacetonitrile,2-hydroxy-l,2,3-propanetricarboxylate (1:1); ./ h3c namely, 3,4-dimethoxy-aS, aR*-(l-methylethyl)-a-[3[methyl(1,2,3,4-tetrahydro-2S*-naphthalenyl)amino]propyl] benzeneacetonitrile,2-hydroxy-l,2,3-propanetricarboxylate (1:1); and 0068C CN CH3 / h3c namely 3,4-dimethoxy-aR, aR*-(1-methylethyl)a-[3-[methyl (1,2,3,4-tetrahydro-2R*-naphthalenyl)amino] propyl]benzeneacetonitrile,2-hydroxy-1,2-,3propanetricarboxylate (1:1).

The 1,2,3-propanetricarboxylate salts recited above are the most preferred salts of this invention. Other salts encompassed within the term pharmaceutically acceptable salts refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.

Representative salts include the following salts: Acetate Benzenesulfonate Benzoate Bicarbonate Bisulfate Bitartrate Borate Lactobionate Laurate Malate Maleate Mandelate Mesylate Methylbromide 0068C Bromide Calcium Edetate Camsylate Carbonate Chloride Clavulanate Citrate Dihydrochloride Edetate Edisylate Estolate Esylate Fumarate Gluceptate Gluconate Glutamate Glycollylarsanilate Hexylresorcinate Hydrabamine Hydrobromide Hydrochloride Hydroxynaphthoate Iodide Isethionate Methylnitrate Methylsulfate Mucate Napsylate Nitrate Oleate Oxalate Pamoate (Embonate) Palmitate Pantothenate Phosphate/diphosphate Polygalacturonate Salicylate Stearate Subacetate Succinate Tannate Tartrate Teoclate Tosylate Triethiodide Valerate Lactate As used herein, the expression hypertension is defined as a persistently high arterial blood pressure which may have either no known underlying cause (primary, idiopathic or essential hypertension) or which may have a known cause (secondary hypertension) due to or associated with a variety of primary diseases, such as renal disorders, disorders of the central nervous system, endocrine diseases and vascular diseases. 0068C The term angina is defined as spasmodic, choking or suffocating pain, and especially as denoting angina pectoris, which is a paroxysmal thoracic pain due, most often, to anoxia of the myocardium.

The term congestive heart failure is defined to mean a syndrome in a mammal due to heart disease, characterized by breathlessness and abnormal sodium and water retention, resulting in edema and congestion, which congestion may occur in the lungs or the peripheral circulation, or in both, depending on whether the heart failure is right-sided, leftsided or general.

The term significant left ventricular dysfunction is defined to mean an ejection fraction of less than approximately thirty percent, or in the case of a mammal being treated with a beta-adrenergic blocking agent, an ejection fraction of less than approximately thirty-five percent.

The term significant atrioventricular conduction block shall mean second- or third-degree atrioventricular block (i.e., failure of the atrioventricular node to transmit every 0068C atrial impulse, or complete interruption of the atrioventricular nodal conduction, which causes the atria and ventricles to beat at independent rates.

The term cardiac arrhythmia is defined to mean any variation from the normal rhythm of the heartbeat, including, without limitation, sinus arrhythmia, premature heartbeat, heart block, fibrillation, flutter, pulsus alternans, tachycardia, paroxysmal tachycardia and premature ventricular contractions.

The term pharmacologically effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician.

The diastereoisomers of Formula I comprise substituted phenylacetonitrile derivatives wherein an alkylaminoalkylene chain is attached to the carbon atom bearing the cyano function and the amino group thereof is substituted by a hydrogenated bicyclic aromatic substituent; such compounds can be prepared readily according to the following reaction schemes or modifications thereof using readily available 0068C starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. 0068C SCHEME I 0068C SCHEME II VI 0068C SCHEME III 0068C SCHEME IV OH (S^L· hoch2// ch3 MsCI Ph3CCI ArCHgCOOH, LDA p-TsOH - VII ί. MsCI 2. NaBH/i CH3O, CHaO 0068C H2O2 disiamylborane SOCI2 0068C In the above schemes, various reagent symbols have the following meanings: Ph3CCI 4MsCl = methane sulfonyl chloride ArCH2COOH LDA = lithium diisopropylamine p-TsOH = p-toluene sulfonic acid -CH2OMs = mesylate 0068C pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. Likewise, they may also be administered in intravenous, intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. In general, the preferred form of administration is oral. An effective but non-toxic amount of the compound can be employed as an antihypertensive in the treatment of hypertension, renal ischemia, or cerebral ischemia, or as an antiarrhythmic in the treatment of mammalian cardiac arrhythmias, or as an anti-anginal agent in the treatment of angina.

Other methods of employing the compounds of the invention include treatment of vascular-related headaches including migraine and cluster headaches (either prophylactically or for acute therapy), congestive heart failure.

The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic 0068C condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

Dosages of the compounds of the present invention, when used for the indicated effects, will range between about 0.1 mg per kg of body weight per day (mg/kg/day) to about 1,000 mg/kg/day and preferably 1.0-100 mg/kg/day. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.

Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, 0068C the dosage administration will, of course, be continuous rather than intermittent, throughout the dosage regimen.

In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents excipients or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring 0068C agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can 0068C include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenyl, polyhydroxyethylaspartamide-phenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

The bicyclo-substituted phenylacetonitrile diastereoisomers were prepared according to the procedure of the above schemes, using appropriate materials and are further exemplified by the following specific examples. The preferred compounds of the invention are any or all of those specifically set forth in these examples. These compounds are not, however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds may itself form a genus. The following examples further illustrate details for the preparation of 0068C the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted. Unless otherwise noted, I.R. and NMR spectra were consistent with the assigned structure. 0068C EXAMPLE 1 Resolution of N-methyl-p-aminotetralin 2.63g of (S)(+)mandelic acid ([a]D=+142) was added to 30 mmole of thionyl chloride (2.2ml) at room temperature, which was then heated for one hour at 50 degrees. Excess SOC12 was removed under vacuum. 4 g of N-methyl-βaminotetralin and 2.8 g of potassium carbonate was heated to 50 degrees for two hours, cooled to room temperature and the organic material extracted with CHC13 (50ml x 3). Two spots were obtained from TLC (20:80-ethyl acetate:toluene) Rf 0.26, 0.25. The compound of Rf 0.26 was obtained as 2.6 g of one diastereomer, NMR (CDCl3) δ 1.2-1.9 (m, 2H), 2.3-2.8 (m, 4H) , 2.8, 2.87 (two sets of singlets, 3H), 3.48, 3.52 (two sets of singlets, 3H), 4.2-4.6(m), 4.85-5.0(4m) two sets of multiplets (1H), 6.9-7.5 (m, 9H). 0068C 2.1 g of the compound of Rf 0.25 was obtained, NMR (CDC13) , S 1.3-1.9 (m, 2H) 2.3-2.8 (m, 4H) 2.78, 2.87 (two sets of singlets, 3H), 3.45, 3.47 (two sets of singlets, 3H), 4.14.3 (m) 4.85-5.05 (m) , two sets of multiplets (1 H), 5..01, .05 (two sets of singlets, 1 H), 6.85-7.5 (d, 9H). From xray crystallography, the compound of Rf 0.25 was determined as (S)(S), that is, the (S) mandelic acid amide of (S) Nmethylaminotetralin.

One gram of the (S) mandelic acid amide of (S) Nmethylaminotetralin in 50 ml of ethyl ether was added to 2.2 g of potassium t-butoxide and 100 mg of water and was heated at 80-85 degrees for three hours. The solution was cooled to room temperature and the solvent was evaporated under vacuum. Approximately 20 ml of ice water and ice was added, and the organic material extracted with 20 ml of ethyl ether. The ethyl ether layer was separated and dried. HCI in ethyl ether was added to precipitate the amine salt to yield 0.3 g of (S)N-methyl-/?-aminotetralin V ([a]D-63.8) . 0068C Following the procedure of the above paragraph, one gram of (S) mandelic acid amide of (R) N-methyl-0-aminotetralin was hydrolyzed as above to yield 0.28g of product (R) N-methyl-p-aminotetralin(VI) ([a]D + 64.0). 0068C EXAMPLE 2 SYNTHESIS OF (S),(S) AND (R),(S) DlASTEREOISOMERS rw 0.3g of N-methyl-(S)-/3-aminotetralin hydrochloride (V) ([a]D-63.8, M.W. 197.5, 1.51 mmole) and 450mg (1.5 mmole) of α-3-chloropropyl)-3,4-dimethoxy-a-(1)-methylethyl)phenylacetonitrile were added to 12 ml of dimethylformamide. 0.8g K2CO3 and 50mg Nal was added with the mixture then being heated at 80 degrees overnight. Solvent was then removed under vacuum. Organic material was extracted with ethyl ether (20ml x 3) and was dried and separated by column chromatography using Merck silica neutral, and eluted with 0068C ethyl acetate:toluene:triethylamine. Rf 0.26 and 0.25. High pressure chromatography conditions: Column: resolve 5μπι; spherical silica (Waters) 150 x 3.9mm. Mobile phase-5:10:85 2-propanol:methylene chloride:1,1,2-trifluorochloroethane. Flow rate: 0.8ml/min. U.V. detector-240 nm. Diastereomer A (Rf 0.26) ret. 22 min. Diastereomer B (Rf 0.25) ret. HPLC time 24 min. 1HNMR(CDC13) , δ (PPM); 0.81 (d,J=3.2HZ,3H) , 1.18 (d,J=3.2HZ,3H), 1.1-1.3 (m,2H),1.4-1.71 (m,2H) ,1.8-2.2 (m,6H),2.21 (S,3H), 2.4-2.52 (m, 2H), 2.7-2.9 (m,5H), 3.81 (s,3H), 3.83 (s,3H), 6.78-7.4 (m ,7H). 13CNMR (CDC13) Diastereomer B, 59.2, 52.8, 30.9, 26.0. Diastereomer A (Rf 0.26) HPLC ret. time 22 min. 1HNMR (CDCL3), 6 (PPM); 0.81 (d,J=3.2HZ, 3H), 1.18 (d, J=3.2HZ,3H), 1.1-1.3 (m,2H), 1.4-1.71 (m,2H), 1.8-2.2 (m,6H), 2.21 (s,3H), 2.4-2.52 (m,2H), 2.7-2.9 (m,5H), 3.81 (s,3H) 3.83 (s,3H), 6.787.4(m,7H) 13CNMR (CDC13), 5 (PPM) 59.0, 53.0, 31.7, 25.2. 0068C In order that the absolute stereochemistry of diastereomer A and B can be unambiguously assigned, Compound VII of Scheme IV were prepared according to Nelson's procedure. [W. L. Nelson, J. Org. Chem., 52 . 1309-1315 (1987)]. Reaction of VII with (S) N-methyl-p-aminotetralin(V) as in Example 2 gave 3,4 dimethoxy-α(S)-(1-methylethyl)-a-[3-[methyl (1,2,3,4tetrahydro-2(S)-naphthalenyl)amino]propyl]benzene acetonitrile. Rf. 0.26 HPLC ret. time (example 2) ret. time 22 min. 13CNMR(CDC13), 59.0, 53.0, 31.7, 25.2 This compound is identical with diastereomer A in Example 2. Therefore, diastereomer A was assigned as VIII and similarly, diastereomer B was assigned as (IX). 0068C EXAMPLE 3 Following the procedure of Example 2, 450mg N-methyl-(R)-βaminotetralin HCI (VI) produced two products having Rf (50:1toluene:acetate:triethylamine), designated R-A (0.26) and R-B (0.25). Under HPLC conditions, the R-A diastereomer was found to have identical retention time as diastereomer A (VIII) of Example 2. Diastereomer R-B was shown to have the same retention time as diastereomer Β (IX) of Example 2. Diastereomer R-A 13CNMR (CDC13), .2 and this compound was assigned as (X). 0068C Diastereomer R-B, 13CNMR(CDC13) , 6(ppm); 59.2, 52.8, 30.9, 26.0 and this compound was assigned as (XI).

Details of the synthesis of the intermediate shown in Scheme IV, above, can be found in W. Nelson, et al., J. Organic Chemistry, 52 1309-1357, 1987.

The compounds of this invention exhibit antihypertensive activity comparable to that of prior art phenylacetonitrile compounds, while having decreased cardiodepressant activity compared to the prior art compounds.

The test procedures employed to measure this activity of the compound of the present invention are described below. 0068C EXAMPLE 4 The compounds in the present invention were tested in pentobarbital anesthetized male adult spontaneously hypertensive rats (SHR), with N=4/group, for effects on mean arterial pressure (MAP) and heart rate (HR). Racemic Verapamil was used as a standard. The compounds were dissolved in DMSO and injected intravenously accumulatively to 10 mg/kg. The injection volume of DMSO was 0.1 ml/kg. Injections were made every fifteen (15) minutes. Recordings were obtained ten to twelve minutes after injection. Data are expressed as percent changes from pre-treatment values.

A difference of a mean change from 0 was analyzed by a paired T-test; differences among mean percent changes were analyzed by analysis of variance and least significance tests.

All rats treated with verapamil died at the 10 mg/kg dose. All rats treated with the (S,S) diastereomer died at the 3 mg/kg dose. The (R,R), (S,R) and (R,S) diastereomers were not lethal up to 10 mg/kg. Comparative results of the 4-diastereomers of the invention compared to prior art compound verapamil are graphically illustrated as percent decrease in mean arterial pressure as a function 0068C of dosage of compound in Figure 1 and percent decrease in heart rate as a function of dosage in Figure 2.

Racemic verapamil and the S,R diastereomer decreased mean arterial pressure at 0.1 mg/kg (p = 0.0024 and 0.057, respectively). The R,R diastereomer and the S,S diastereomer decreased mean arterial pressure at 1 mg/kg (p = 0.036 and 0.008, respectively). The R,S diastereomer decreased mean arterial pressure at 3 mg/kg (p = 0.007). Verapamil, the S,S diastereomer, and the R,S diastereomer decreased heart rate at 0.1 mg/kg (p = 0.02, 0.01 and 0.06, respectively). The S,R diastereomer decreased heart rate at 0.3 mg/kg (p = 0.04). The R,R diastereomer decreased heart rate at 1 mg/kg (p = 0.04). At 3 mg/kg racemic verapamil decreased heart rate 42% but the decrease in heart rate with the R,R and S,R diastereomers was much less: 14% and 20%, respectively, p < 0.05. The results of these studies show that the S,R diastereomer is the most potent hypotensive compound of the invention with minimal effects on heart rate. Because the S,R and the R,R diastereomers have minimal effects on heart rate they are the preferred embodiments of 0068C the present invention for use in the treatment of hypertension and other cardiovascular diseases.

The preferred compounds of the invention are any or all of those specifically set forth in the above examples. These compounds are not, however, to be construed as forming the only genus that is considered as the invention and any combination of such compounds may itself form a genus.

While the invention has been described and illustrated in reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the preferred doses as set forth hereinabove may be applicable as a consequence of variations in the responsiveness of the mammal being treated for severity of hypertension. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results 0068C are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be limited only by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable. 0068C

Claims (20)

What is claimed is:

1. A compound of the structural formula or the pharmaceutically acceptable salt thereof.

2. A compound as claimed in Claim 1, namely 3,4-dimethoxyaR,aR*-(1-methylethyl)a-3-[methyl[1,2,3,4-tetrahydro2R*-naphthalenyl)amino]propyl] benzeneacetonitrile,2hydroxy-1,2,3-propanetricarboxylate (1:1).

3. A pharmaceutical composition useful in the treatment of hypertension comprising an effective amount of at least one compound according to Claim 1, together with one or more non-toxic pharmaceutically acceptable carrier. 0068C

4. A method of inducing vasodilation in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound of Claim 1.

5. A method of treating hypertension in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound of Claim 1.

6. A compound of the structural formula or the pharmaceutically acceptable salt thereof. 0068C

7. A compound as claimed in Claim 6, namely 3,4-dimethoxy-a S,aR*-(1-methylethyl)-a[3-[methyl(1,2,3,4-tetrahydro2R*-naphthalenyl)amino]propyl]benzeneaceto-nitrile,2hydroxy-l,2,3-propanetricarboxylate (1:1).

8. A pharmaceutical composition useful in the treatment of hypertension comprising an effective amount of at least one compound according to Claim 6, together with one or more non-toxic pharmaceutically acceptable carrier.

9. A method of inducing vasodilation in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound as claimed in Claim 6.

10. A method of treating hypertension in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound of Claim 6. 0068C

11. A compound of the structural formula or the pharmaceutically acceptable salt thereof.

12. A compound as claimed in Claim 11, namely 3,4-dimethoxyaS,aR*-(1 -methylethyl)-a-3-[methyl[1,2,3,4-tetrahydro2S*-naphthalenyl)amino]propylJbenzeneacetonitrile,2hydroxy-1,2,3-propanetricarboxylate (1:1).

13. A pharmaceutical composition useful in the treatment of hypertension comprising an effective amount of at least one compound according to Claim 11, together with one or more non-toxic pharmaceutically acceptable carrier.

14. A method of inducing vasodilation in a mammal in need thereof, comprising the step of administering to said 0068C mammal a pharmacologically effective amount of the compound as claimed in Claim 11.

15. A method of treating hypertension in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound as claimed in Claim 11.

16. A compound of the structural formula or the pharmaceutically acceptable salt thereof.

17. A compound as claimed in Claim 16, namely 3,4-dimethoxy a R, a R*-(1-methylethyl)-a-[3-[methyl(1,2,3,4tetrahydro-2S*-naphthalenyl)amino]propyl]benzeneacetonitrile , 2-hydroxy-1,2,3-propanetricarboxylate (1:1). 0068C

18. A pharmaceutical composition useful in the treatment of hypertension comprising an effective amount of at least one compound according to Claim 16, together with one or more non-toxic pharmaceutically acceptable carrier.

19. A method of inducing vasodilation in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound as claimed in Claim 16.

20. A method of treating hypertension in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound as claimed in Claim 16. 22. 22. 23. 23. 24. 24. A compound of the structural formula given in any one of Claims 1, 6, 11 or 16 or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described and exemplified. A pharmaceutical composition according to any one of Claims 3, 8, 13 or 18, substantially as hereinbefore described. A process for preparing a compound of the structural formula given in any one of Claims 1, 6, 11 or 16 or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described and exemplified. A compound of the structural formula given in any one of Claims 1, 6, 11 or 16 or a pharmaceutically acceptable salt thereof, whenever prepared by a process claimed in Claim 23.