Smooth muscle relaxant process employing 10-imidoylphenoxazines

#This invention pertains to heterocyclic carbon compounds which have drug and bio-affecting properties. In particular, this invention relates to 10-imidoylphenoxazines and 10-imidoylacridans effective as smooth muscle relaxants. The term "smooth muscle relaxant" has a definite meaning in pharmacology and medicine. It generally refers to agents known to relax smooth muscle in blood vessels, in the bronchial tree and in the gastrointestinal, biliary, urinary and uterine tracts. Two types of smooth muscle relaxants are known; namely, those that produce their effect by direct action on smooth muscle (e.g., papaverine or aminophylline) and those that produce their action primarily via the autonomic nerve supply (e.g., isoproterenol and atropine). The compounds of the instant invention are thought to be direct acting. Another feature of the invention is a therapeutic process for producing smooth muscle relaxant effects in mammals by administration of the 10-imidoylphenoxazines and 10-imidoylacridans.

#We have previously disclosed 10-imidoylphenothiazines in our co-pending U.S. Pat. application Ser. No. 147,667, filed May 27, 1971, now U.S. Pat. No. 3,719,671, as being of interest for their intestinal relaxant and antithrombogenic activity. We have now unexpectedly discovered that another class of amidines, namely 10-imidoylphenoxazines and 10-imidoylacridans and their salts, have smooth muscle relaxant activity and, in some instances, antithrombogenic activity.

#This invention is broadly concerned with a group of amidines incorporating phenoxazine and acridan heterocycles. More particularly, the invention pertains to 10-imidoylphenoxaines and 10-imidoylacridans of Formula I and non-toxic pharmaceutically acceptable acid addition salts thereof. ##STR1##

#Phosphorus oxychloride (3.8 g., 0.025 mole) is added in one portion to a mixture of phenoxazine (4.6 g., 0.025 mole) and 2-pyrrolidinone (2.1 g., 0.025 mole) in 50 ml. of 1,2-dichloroethane at 25.degree. C. After stirring the reaction mixture for 15 hr., the reaction mixture is quenched in a mixture of 30 ml. of 5N sodium hydroxide and 30 g. of crushed ice. The organic layer is separated, extracted with 100 ml. of 1.5N hydrochloric acid, made basic with sodium hydroxide and extracted with ether. After drying the ethereal extract over magnesium sulfate and concentrating, the residue thus obtained is crystallized from n-heptane to provide 4.2 g. of 10-(1-PYRROLIN-2-YL)PHENOXAZINE free base, m.p. 110.degree.-113.degree. C. The free base taken up in ethanol, acidified with ethanolic hydrogen chloride and diluted with ether provides a 37% yield of 10-(1-PYRROLIN-2-YL)PHENOXAZINE HYDROCHLORIDE as a monohydrate, m.p. 214.degree.-217.degree. C. (corr.).

#Analysis. Calcd. for C.sub.16 H.sub.14 N.sub.2 O.HCl.H.sub.2 O (percent): C, 63.05; H, 5.62; N, 9.19; Cl, 11.64. Found (percent): C, 62.92; H, 5.66; N, 9.35; Cl, 11.34.

#NMR delta (ppm) (DMSO-D.sub.6, TMS reference): 2.13m, 3.27t (7.2), 3.38s, 3.75t (7.0), 7.3m, 7.7m, 10.63bs.