Alkylsulfonylphenoxypropanolamine derivatives

#This invention pertains to carbon compounds having drug and bio-affecting properties and in particular to alkylsulfonylphenoxypropylamine .beta.-adrenergic blocking agents.

#According to present belief, there are at least two sub-groups of .beta.-adrenergic receptors. .beta..sub.1 -Receptors are through to mediate cardiac stimulation and .beta..sub.2 -receptors are supposed to mediate relaxation of smooth muscle responsible for vasodilating and bronchodilating effects; refer to C. G. Dollery, et al., Clinical Pharmacology and Therapeutics, 10(6), 765- 799 (1969); D. Jack, The Pharmaceutical Journal, 237-240 (Aug. 29, 1970). Various derivatives of phenoxypropanolamines reportedly have .beta.-adrenergic blocking properties and there can be mentioned as representative of the state of the art, Netherlands Pat. No. 69,07700 (Derwent Basic No. 41,107) and Belgian Pat. No. 762629 (Derwent Basic No. 55533S-B). The Netherlands patent, while generically disclosing pharmaceutical preparations containing a variety of substituted (including alkylsulfonyl) phenoxypropanolamines, does not specifically disclose the class of alkylsulfonylphenoxypropanolamines of the present invention. The Belgian Pat. No. 762629 describes a group of alkylsulfonylalkylphenoxypropanolamine derivatives.

#This invention relates generally to novel alkylsulfonylphenoxypropylamines which possess cardioselective .beta..sub.1 -adrenergic blocking and antiarrhythmic properties. More particularly, the present invention provides compounds characterized by general structural Formula I and non-toxic pharmaceutically acceptable acid addition salts thereof. ##STR1##

#a. A mixture of 4-(methylsulfonyl)-m-cresol (18.6 g., 0.1 mole), epichlorohydrin (60 g., 0.65 mole) and 0.6 g. of pyrrolidine is heated on steam bath for 12 hr. Excess epichlorohydrin is removed under reduced pressure, the resulting chlorohydrin derivative taken up in 50 ml. of absolute ethanol and filtered through diatomaceous earth. Isopropylamine (50 g., 0.85 mole) and 0.1 g. of potassium iodide are added to the ethanol filtrate of the epichlorohydrin derivative and the mixture is refluxed for 18 hr. and filtered. Concentration of the filtrate under reduced pressure affords a residue which is taken up in 70 ml. of 1N hydrochloric acid and 300 ml. of absolute ethanol. Distillables are removed under reduced pressure and the resulting residue stirred with ether to provide solid crude product. Crystallization of the crude product from butanone-methanol and again from 95% ethanol-ether, affords 1-(ISOPROPYLAMINO)-3-[4-(METHYLSULFONYL)-m-TOLYLOXY]-2-PROPANOL HYDROCHLORIDE, m.p. 177.0.degree.-179.0.degree. C. (corr.) in a 62% overall yield. A sample, m.p. 176.0.degree.-178.0.degree. C. (corr), analyzed as follows.

#Analysis. Calcd. for C.sub.14 H.sub.23 NO.sub.4.HCl: C, 49.77; H, 7.16; N, 4.15. Found: C, 49.72; H, 7.16; N, 4.08.

#Nuclear Magnetic Resonance, DMSO-d.sub.6, .delta.(ppm): 1.28 [d, 6.5 Hz, 6H]; 2.58 [s, 3H]; 3.11 [s, 3H]; 3.13 [m, 3H]; 4.11 [m, 3H]; 7.01 [m, 2H]; 7.77 [d, 9.2 Hz, 1H]; 8.9 [bs, 2H].