GB2044251A

GB2044251A - Phenoxypropanolamine derivatives

Info

Publication number: GB2044251A
Application number: GB7941385A
Authority: GB
Original assignee: Bristol Myers Co
Current assignee: Bristol Myers Co
Priority date: 1978-12-01
Filing date: 1979-11-30
Publication date: 1980-10-15
Also published as: GB2044251B

Abstract

Substituted phenoxypropanolamines of the formula <IMAGE> and salts thereof wherein R is 3,4-methylenedioxy, meta or para alkyl of 1 to 8 carbon atoms inclusive, meta or para alkoxy of 1 to 8 carbon atoms inclusive, meta or para fluoro, or meta-chloro; R1 is alkyl of 5 to 11 carbon atoms inclusive; have vasodilating and antispasmodic activity, inhibit blood platelet aggregation and are substantially free of beta-adrenergic blocking effects.

Description

SPECIFICATION Phenoxypropanolamine derivatives Numerous phenoxypropanolamine modifications have been described and studied in the field of adrenergic agents with particular emphasis on optimizing beta-adrenergic blocking activity and selectivity. Compounds having beta-adrenergic blocking properties are generally considered useful in treating certain forms of hypertension, angina pectoris, heart arrhythmia, and pheochromocytoma.

The following patents and publications describe phenoxypropanolamines with structural features similar in some respects to the compounds of the instant invention.

Crowther, et al., U.S. 3,501,769 patented March 17, 1970 generically discloses compounds of the type

wherein, inter alia, R1 is halogen, alkyl (up to 10 C) or alkoxy (up to 10 C); and R2 is alkyl (up to 20 C).

Compounds specifically disclosed by Crowther, et al., are the following.

R1 RZ p-methyl isopropyl p-isopropyl isopropyl p-methoxy isopropyl p-n-butoxy isopropyl p-chloro isopropyl m-methyl isopropyl m-chloro isopropyl m-fluoro isopropyl Koppe, et al., U.S. 3,872,147 patented March 18, 1975 generically discloses phenoxypropanolamines illustrated by the formula

wherein R' is alkyl (C1-C5), halogen, alkoxy (C1 -C5), etc., and R2 is alkyl (C5-C6) containing at least one quaternary carbon attached directly through an alkylene chain (C,-C4) to the amino nitrogen atom.

These compounds are reportedly useful as beta- adrenolytics and hypotensives in warm-blooded animals. Specifically described phenoxypropanolamines include the following compounds.

R1 R2 o-bromo -C(CH3)2C2Hs m-methyl -C(CH3)2C4Hg Kukalenko, et al., Chem. Abstracts, Vol. 78, (page 428) 71621z (1973) describe phenoxypropanolamines having herbicidal and fungicidal activity, e.g., the compound

Broadly described, the present invention is directed to novel phenoxypropanolamines of the formula

wherein R is 3, 4-methylenedioxy, meta orpara alkyl of 1 to 8 carbon atoms inclusive, meta orpara alkoxy of 1 to 8 carbon atoms inclusive, meta orpara fluoro ormeta-chloro; R1 is alkyl of 5 to 11 carbon atoms inclusive; and acid addition salts thereof.

This invention is also concerned with pharmaceutical compositions containing the instant compounds and further contemplates methods for both producing as well as employing the compounds and compositions therapeutically for treatment of peripheral vascular disease as well as degenerate conditions of the vascular systems such as atherosclerosis and otherthrombogenic conditions.

The phenoxypropanolamines provided by this invention are illustrated by a compound of formula I

or a pharmaceutically acceptable acid addition salt thereof wherein R is 3,4-methylenedioxy, meta orpara alkyl of 1 to 8 carbon atoms inclusive, alkoxy of 1 to 8 carbon atoms inclusive, fluoro ormeta-chloro; and R, is alkyl of 5 to 11 carbon atoms inclusive.

Contemplated subclasses within the ambit of Formula I which further characterize the phenoxypropanolamines of the invention are compounds of Formula I wherein (la) R is fluoro and R, isn-octyl; (Ib) R ispara-fluoro and R, is (Cs-C1,) alkyl; (Ic) R ispara-(C,-Ca) alkyl and R1 is (C5-C11) alkyl; (Id) R ispara-(C,-C8) alkyl and R, isn-octyl; (le) R ispara-isopropyl and R, is (C5-C")alkyl; (If) R ispara-tert.-butyl and R, is (C5-C11) alkyl; (lg) R ispara-(C,-C8) alkoxy and R, is (Cs-C") alkyl; (Ih) R ispara-methoxy and R, is (Cs-C,,) alkyl; (li) R is fluoro and R, is (Cs-C") alkyl;; (Ij) R is (C,-Ca) alkyl and R, is (Cs-C") alkyl; (Ik) R is (C,-C8) alkoxy and R, is (Cs-C") alkyl; (II) R is 3, 4-methylenedioxy and R, is (Cs-C" )alkyl; (Im) R Fl ismeta-chloro and R, is (Cs-C1,) alkyl; (In) R is 3, 4-methylenedioxy, meta orpara alkyl of 1 to 8 carbon atoms, meta orpara alkoxy of 1 to 8 carbon atoms, meta orpara fluoro, ormeta-chloro and R, is straight chain alkyl of 5 to 11 carbon atoms.

As used herein, the terms "alkyl" and "alkoxy" refer to straight or branched chain carbon radicals with the number of carbon atoms comprising the particular alkyl or alkoxy radical specifically designated or referred to by notations such as (C,-C8) and (C5-C11).

As used herein, the term "pharmaceutically acceptable acid addition salt" refers to a salt of a formula I compound formed with a variety of inorganic and organic acids, the anions of which are relatively non-toxic. Such acid addition salts are considered pharmacologically equivalent to the bases characterized by structural formula I. Examples of useful salt forming acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzenesulfonic, p-toluenesulfonic, and related acids.Acid addition salts of this invention are prepared and isolated by conventional means; for instance, by treating a solution or suspension of the free base in a reaction inert solvent with the desired acid and recovering the salts which form by concentration under reduced pressure or by crystallization techniques or other standard chemical manipulations. Acid addition salts which are somewhat toxic and therefore do not meet the foregoing criteria for pharmaceutical acceptability are sometimes useful as intermediates for isolation and purification of the bases of formula I orforotherchemical purposes such as separation of optical isomers. Such salts are also considered part of the invention.

According to a feature of the present invention, there is provided a process for preparing phenoxyp ropanolamines of formula I which comprises reacting a phenol derivative of formula II

wherein R is 3, 4-methylenedioxy,metaorpara alkyl of 1 to 8 carbon atoms inclusive, meta orpara alkoxy of 1 to 8 carbon atoms inclusive, meta orpara fluoro, ormeta-chloro with an epihalohydrin of formula Ill

wherein X signifies halogen, preferably chlorine or bromine, and condensing the epihalohydrin reaction product with an amine of formula IV H2N-CH2-R, (lav) wherein R1 is alkyl of 5 to 11 carbon atoms inclusive; whereafter, if desired, the formula I product in free base form is reacted with an acid to form an acid addition salt thereof.

Inasmuch as an epihalohydrin molecule of formula lil has two reactive positions, reaction with a phenol of formula 11may yield a mixture of formulas V and VI reaction products wherein R, and X are as defined above.

During the further course of the process, however, the two possible intermediates of formula V and formula VI on condensation with a formula IV amine yield the same final phenoxypropanolamine product. Consequently, it is not necessary to effect a separation of any mixtures of intermediates of formulas V and VI which may result from interaction of a formula II phenol with a formula III epihalohydrin.

Underthe reaction conditions employed in the instant process, the epoxides of formula VI are preferentially formed.

If desired, the epihalohydrin reaction product may be taken up in an inert solvent such as chloroform and shaken with excess concentrated hydrochloric acid to convert epoxides of formula VI into the corresponding formula V phenoxy-halohydrin. Conversely, if desired, the halohydrins of formula V may be converted to the corresponding formula VI intermediates by a conventional method, e.g., by treatment with base according to the procedure of O.

Stephenson, J. Chem. Soc., 1574 (1954).

The interaction of formula II phenols with formula Ill epihalohydrins is carried out in the presence of a sufficient amount of a dilute aqueous alkaline metal hydroxide such as sodium hydroxide to neutralize the acidic phenolic group at temperatures in the range of 0-100 and preferably at 25-35 according to the procedure of Y. M. Beasley, et al., J. Pharm.

Pharmacol., 10,47-59(1958).

Alternatively, the interaction of formula II phenols with formula Ill epihalohydrins can also be effected with catalysts such as N-benzylisopropylamine hydrochloride, pyrrolidine, pyridine, piperidine, piperidine acetate, piperidine hydrochloride, and the like with an excess of epihalohydrin. The condensation of the epihalohydrin reaction product of formula V or VI amine is carried out preferably in organic solvent inert under the reaction conditions. Suitable solvents include methanol, ethanol, butanol, hexanol, isopropanol, toluene, dioxane, tetrahydrofuran, dibutylether, dimethoxyethane, ethylene glycol.

The condensation can also be effected in the absence of a reaction solvent with equimolar amounts of the reactants.

An alternate method for producing compounds of formula I comprises reacting a formula II phenol with a compound of formula VII in alkaline medium

to provide a compound of formula VIII

wherein R and R1 have the same meaning as in formula I and R2 stands for hydrogenolysable radical such as benzyl or benzhydryl; and converting said compound of formula VIII to a phenoxypropanolamine of formula I. Removal of the hydrogenolysable blocking group may be effected by catalytic hydrogenation, for example, by hydrogenation in the presence of palladium-in-charcoal catalyst, in an inert solvent, e.g., ethanol or aqueous ethanol.

The compounds of formula VII may be obtained according to known methods. For example, 1 -[(N benzyl)-n-octylaminoa - 2,3 - epoxypropane is obtained by reaction of N-benzyl-n-octylamine and epichlorohydrin in alkaline medium (e.g. aqueous potassium hydroxide) according to the method described by L. Villa, et al., Farmaco. Ed. Sci.,24(3), 349-357 (1969).

As stated hereinabove, the phenoxypropanolamines of the present invention increase peripheral blood flow, relax vascular smooth muscle, and inhibit platelet aggregation. The compounds are substantially free of beta-adrenergic blocking effects which inhibit peripheral vasodilating activity ofbeta-adrenergic stimulatory endogenous amines.

Standard in vivo and in vitro pharmacological test methods can be employed in assessing the activity of compounds characterized by formula I. Among such tests considered useful are the perfused dog hind limb preparation (vasodilator action), the spasmogen-challenged rabbit aortic strip (antispasmodic activity) and inhibition of adenosine diphosphate and collagen-induced platelet aggregration in human platelet-rich plasma (antithrombogenic action). The isopropterenol challenged guinea pig trachea test, which is standard in the art, is suitable for measuring beta-adrenergic blocking action.

Another aspect of the instant invention concerns a therapeutic process of treating vascular disease which comprises systemically administering to a mammal vasodilation an effective vasodilating amount of a compound of formula I or a phar maceuticallyacceptable acid addition salt thereof.

As used herein, the term "effective vasodilating amount" is constructed to means a dose which exerts a vasodilator effect in the effected mammal without untoward side effects.

By systematic administeration, it is intended to include both oral and parenteral routes. Examples of parenteral administration are intramuscular, intravenous, intraperitoneal, rectal, and subcutaneous administration. In rectal administration, both ointments and suppositories may be employed.

While the dosage will vary to some extent with the mode of administration and the particular compound chosen, from about 0.5 mg. per kg. body weight to 25 mg. per kg. body weight of a compound characterized by formula I or non-toxic pharmaceutically acceptable salts thereof administered in effective single or multiple dosage units generally provides the desired vasodilating effect.

In carrying out the therapeutic process of the instant invention, the formula I compounds are generally administered for vasodilating purposes in the form of a pharmaceutical preparation containing either a formula I free base or a pharmaceutically acceptable non-toxic acid addition salt thereof as the active component in combination with a pharmaceutically acceptable carrier. The carrier may be solid, semi-solid, a liquid diluent or a capsule.

Accordingly, a further feature of the instant inven- tion is directed to pharmaceutical compositions containing the compounds of formula I or non-toxic pharmacuetically acceptable acid addition salts thereof in combination with a pharmaceutically acceptable carrier.

Another aspect of the instant invention concerns a pharmaceutical composition in dosage unit form comprising a pharmaceutical carrier and an effective vasodilating amount of a compound of formula 1.

For the preparation of pharmaceutical compositions containing the compounds of formula I in the form of dosage units for oral administration, the compound is mixed with a solid, pulverulent carrier, (e.g. lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin) as well as with an anti-friction agent (e.g. magnesium stearate, calcium stearate, polyethylene glycol waxes or the like) and pressed into tablets. The tablets may be used uncoated or coated by conventional techniques to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over a longer time period. If coated tablets are wanted, the above prepared core may be coated with concentrated solution of sugar, which solution may contain e.g. gum arabic, gelatin, talc, titanium dioxide, or the like.

Furthermore, tablets may be coated with a lacquer dissolved in an easily volatile organic solvent or mixture of solvents. If desired, dye may be added to this coating.

In preparation of soft gelatin capsules or in the preparation of similar closed capsules, the active compound is mixed with a vegetable oil. Hard gelatin capsules may contain granules of the active ingredient in combination with a solid, pulverulent carrier such as lactose, sucrose, sorbitol, starch, 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 active substance of formula I in mixture with a neutral fat base, or they may be prepared in the form of gelatin-rectal capsules containing the active substance in a mixture with a vegetable oil or paraffin oil.

Liquid preparations for oral administration may be present in the form of elixirs, syrups or suspensions containing from about 0.2% by weight to about 20% by weight of the active ingredient. Such liquid preparations may contain coloring agents, flavoring agents, sweetening agents, and carboxymethylcellulose as a thickening agent.

Suitable solutions for parenteral administration by injection may be prepared as an aqueous solution of a water-soluble pharmaceutically acceptable salt of the compounds of formula I adjusted to a physiologically acceptable pH. These solutions may also contain stabilizing agents.

Pharmaceutical tablets for oral use are prepared by conventional methods involving mixing the therapeutic compound of formula I and necessary auxillary agents.

Preferred compounds having pronounced antispasmodic activity with insignificantbeta-adrenergic blocking action include 1 -[3,4-(methylenedioxy) phenoxyi -3- (octylamino) - 2 - propanol and 1 - (4 - fluorophenoxy) - 3 - (octylamino) - 2 - propanol.

The following examples illustrate but do not limit the scope of the invention. All temperatures expressed herein are in degrees centrigade.

EXAMPLE 1 General Method for Preparing Phenoxypropanolamines of formula I A. Epichlorohydrinlntermediate.-Asolution of 0.04 mole of the appropriate phenol and 2.4 g (0.06 moles) of sodium hydroxide in 50 ml of water is treated with 7.4 g (0.08 mole) of 1 - chloro - 2,3 - epoxypropane. The resulting mixture is first stirred at 30 35 for 24 hr and then extracted with chloroform.

After washing the chloroform extract with water and drying over magnesium sulfate, distillables are removed under reduced pressure to provide the nearly pure epichlorohydrin intermediate according to NMR analysis.

The epichlorohydrin intermediate is also obtained by an alternate procedure as follows: A mixture of 0.07 mole of the appropriate phenol and 0.35 mole of 1 - chloro - 2,3 - epoxypropane is treated with 10 drops of piperidine and heated at 115 for 3 hr. The mixture is first concentrated under reduced pressure, and the residue then dissolved in toluene and reconcentrated under reduced pressure three times.

The final residue is dissolved in 150 ml of tetrahydrofuran and 150 ml of aqueous IN sodium hydroxide solution, warmed at 40450 for 30 minutes and left at 27 for a 19 hr. period. The layers are separated and the aqueous phase extracted with methylene chloride. The tetrahydrofuran layer is concentrated under reduced pressure to an oil which is combined with the methylene chloride extract, washed with water and brine, and dried over magnesium sulfate.

Concentration under reduced pressure generally affords the epichlorohydrin intermediate as a pure product in nearly quantative yield.

B. Reaction of Epichloroh ydrin Intermediate with Amine. A solution of 0.03 mole of the appropriate epichlorohydrin intermediate in 30 ml of 95% ethanol is treated with 0.03 to 0.05 mole of the desired amine, and the resulting solution refluxed for 4 hrs. The solvent and excess amine (if any) are removed by distil lation under reduced pressure to provide the free base which is crystallized at this point or converted to the hydrochloride salt for purification.

The reaction of the epichlorohydrin intermediate with amine can also be carried out by heating a neat equimolar mixture of the reactants on a steam bath for 16 to 24 hrs. The resulting free base product of Formula I is purified by crystaliization or converted to the hydrochloride salt which is then generally purified by crystallization.

EXAMPLE 2 1- (4 - Fluorophenoxy) - 3 - (octylamino) - prop- anol Hydrochloride

The epichlorohydrin derivative of 4-fluorophenol (7.689., 0.08 mole) is reacted withn-octylamine (15 g., 0.12 mole) according to the procedure of Example 1.

Conversion of the free base to the hydrochloride and crystallation from ethanol affords a 45% yield of analytically pure 1 - (4 - fluorophenoxy) - 3 (octylamino) - 2 - propanol hydrochloride, m.p.

179-181" (corr.) Anal. Calcd.forC17H28FNO2 HCI: C,61.16; H,8.75; N, 4.20. Found: C,61.54; H, 9.13; N, 4.28.

EXAMPLE 3 1 -[4- (1 -Methylethyl)phenoxy] -3- (octylamino) - 2 - propanol

Reaction of the epichlorohydrin derivative of 4-isopropylphenol (13.6 g., 0.1 mole) with n-octylamine (13.7 g., 0.106 mole) according to the procedure of Example 1 and crystallization of the crude product from petroleum solvent b.p. 60-68 affords a 19% analytical yield of 1 -[4 - (1 methylethyl) phenoxy] - 3 - (octylamino) - 2 - propanol, m.p. 71.5-72.5" (corr.).

Anal. Calcd.forC20H3sNO2: C,74.72; H, 10.97; N, 4.36. Found: C,75.04; H,11.14; N,4.27.

EXAMPLE 4 1 - [4 -(1,1 -Dimethylethyl)phenoxy] - 3 - (octylamino) - 2- propanol Hydrochloride

The epichlorohydrin derivative (9.07 g.) of 4tert.-butylphenol is reacted with 15 ml. of n-octylamine in 40 ml. of 95% ethanol according to the procedure of Example 1. Conversion of the free base to the hydrochloride and crystallization from ethanol affords a 44% yield of analytically pure 1 -[ - (1,1 - dimethylethyl) - phenoxyli - 3 - (octylamino) - 2 - propanol hydrochloride. This material melts slowly over a rangeoffrom 172.0-201.5 .

Anal. Calcd.forC2,H3TNO2 HCl: C,67.81; H,10.30; N, 3.77. Found: C,67.52; H, 10.26; N, 3.83.

EXAMPLES 1- (4 - Methoxyphenoxy) - 3 - foctylamino) - prop- anol

The epichlorohydrin derivative (9.0 g., 0.05 mole) of 4-methoxyphenol is reacted with 8.5 ml. of n-octylamine (6.65 g., 0.052 mole) according to the procedure of Example 1. After cooling the reaction, the produce is crystallized from petroleum soivant, b.p. 60-68" and dissolved in ethyl acetate. The ethyl acetate solution is first dried over magnesium sulfate (with decoloring charcoal) and then filtered.

Concentration of the filtrate provides 5.4 g. (35% yield) of the free base product which is crystallized from methanol to afford analytically pure 1 (4-methoxyphenoxy) - 3 - (octylamino) - 2 - propanol, m.p. 86.5-87.5" (corr.).

Anal. Calcd. for C18H31 NO3: C,69.85;H,10.10; N, 4.35. Found: C, 70.16; H, 10.12; N, 4.41 EXAMPLE 6 1- [3,4- (Methylenedioxy)phenoxy] -3 (octylamino) - 2- propanol Hydrochloride

The epichlorohydrin derivative (9.7 g., 0.05 mole) of 3,4-methylenedioxyphenol is reacted with 8.3 ml. of n-octylamine (6.5 g., 0.05 mole) according to the procedure of Example 1. Conversion of the free base to the hydrochloride and crystallization from absolute ethanol affords analytically pure 1 -[3,4 (methylenedioxy) phenoxy] - 3 - (octylamino) - 2 propanol hydrochloride, m.p, 185.5-186.5" (corr.).

Anal. Calcd.forC18H29NO4 HCl: C,60.07; H,8.40; N, 3.89. Found: C, 60.11; H, 8.60; N, 3.75.

EXAMPLE 7 - (3- Chlorophenoxy) - 3- (octylamino) - 2 - propanol Hydrochloride

The epichlorohydrin derivative (29.5 g., 0.16 mole) of 3 - chlorophenol is reacted with 21.6 ml. of n-octylamine (16.9 g., 0.13 mole) according to the procedure of Example 1. Conversion of the free base to the hydrochloride and crystallization from isopropanol affords analytically pure 1 - (3 chlorophenoxy) - 3 - (octylamino) -2 - propanol hydrochloride, m.p. 176177" (corr.).

Anal. Calcd. for C'7H28CINO2 HCl: C, 58.28; H, 8.34; N, 4.00. Found: C, 58.00; H, 8.50; N, 3.89.

EXAMPLE 8 Tablets The following ingredients are blended into 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 - (4 fluorophenoxy) - 3 - (octylamino) - 2- propanol hyd rochloride to provide tablets containing 10, 20,40, 80, 160 and 320 mg. of active ingredient and compressed in a conventional tablet press.

EXAMPLE 9 Dry-Fllle d 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 - (4 - fluorophenoxy) - 3 - (octylamino) 2 - propanol hydrochloride is added 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.

Claims

1. Acompound oftheformula

or a pharmaceutically acceptable salt thereof wherein R is3,4-methylenedioxy,meta orpara alkyl of 1 to 8 carbon atoms inclusive, meta orpara alkoxy of 1 to 8 carbon atoms inclusive, meta orpara fluoro, or meta-chloro; and R1 is alkyl of 5 to 11 carbon atoms inclusive.

2. The compound of Claim 1 wherein R is fluoro.

3. The compound of Claim 1 which is 1 - (4fluorophenoxy) - 3 - (octylamino) - 2 - propanol hydrochloride or a pharmaceutically acceptable acid addition salt thereof.

4. The compound of Claim 1 wherein R is alkyl of 1 to 8 carbon atoms.

5. The compound of Claim 1 which is 1 -[4 - (1,1 dimethylethyl) phenoxy] - 3 - (octylamino) - 2 - propanol hydrochloride or a pharmaceutically acceptable acid addition salt thereof.

6. The compound of Claim 1 which is 1 -[4 - (1 methyl ethyl) - phenoxy] - 3 - (octylamino) - 2 - propanol or a pharmaceutically acceptable acid addition salt therof.

7. The compound of Claim 1 wherein R is alkoxy of 1 to 8 carbon atoms.

8. The compound of Claim 1 which is 1 - (4 methoxyphenoxy) - 3 - (octylamino) - 2 - propanol or a pharmaceutically acceptable acid addition salt thereof.

9. The compound of Claim 1 wherein R is 3,4 methylenedioxy.

10. The compound of Claim 1 which is 1 -[3,4 (methylenedioxy) phenoxy] - 3 - (octylamino) - 2 propanol hydrochloride or a pharmaceutically acceptable acid addition salt thereof.

11. The compound of Claim 1 wherein R is meta-chloro.

12. The compound of Claim 1 which is 1 - (3 chlorophenoxy) - 3 - (octylamino) - 2 - propanol or a pharmaceutically acceptable acid addition salt thereof.

13. The compound of Claim 1 wherein R1 is straight chain alkyl.

14. The therapeutic process of treating vascular disease which comprises administering to a mam mal requiring vasodilation an effective vasodilating amount of a compound of Claim 1.

15. A pharmaceutical composition in dosage unit form comprising a pharmaceutical carrier and an effective vasodilating amount of a compound of Claim 1.

16. Acompound in accordance with Claim 1 sub stantially as hereinbefore described in any one of the Examples.

17. A compound in accordance with Claim 1 specifically as hereinbefore mentioned.

18. A pharmaceutical component comprising a pharmaceutical carrier and an effective vasodilating amount of a compound in accordance with any one of Claims 1 to 13 or Claim 16, or Claim 17.

19. A pharmaceutical composition substantially as hereinbefore described in Example 8 or Example 9.