IE42408B1 - Novel amidine compounds - Google Patents

Description

The present invention relates to novel amidine compounds and in particular to bis - pyrrolinyl derivatives of phenothiazines, phenoxazines or acridans.

The present invention provides a compound having the general Formula I γ (I) wherein X is a sulfur or oxygen atom, or a divalent methylene radical of the formula -C(Z^Z^)- wherein and Z^ are each independently a hydrogen atom or a straight chain lower alkyl group containing from 1 to 4 carbon atoms inclusive; Y is a hydrogen or halogen atom, a trifluoromethyl group, a lower alkyl group containing from 1 to 4 carbon atoms or a lower alkoxy group containing from 1 to 4 carbon atoms and R is a hydrogen atom or a straight chain lower alkyl group containing from 1 to 4 carbon atoms, inclusive; or a pharmaceutically acceptable acid addition salt thereof.

The compounds of Formula I are bis - pyrrolinyl derivatives belonging to the group of amidines consisting of bis - pyrrolinyl phenothiazines, bis - pyrrolinyl acridans and bis - pyrrolinyl phenoxazines. More particularly, in Formula X, when X is sulfur, - 2 42408 the resultant compounds are 10 ~ bis - pyrrolinyl phenothiazine derivatives; when X is oxygen, the compounds are bis - pyrrolinyl phenoxazine derivatives; and when X represents the divalent radical - (1(2^2,,)-, the compounds are bis - pyrrolinyl acridan derivatives.

The compounds of Formula I are useful as smooth muscle relaxants, inhibitors of platelet aggregation, and as diuretic agents, in mammals.

By the term halogen as used herein is meant all four halogens; i.e., chlorine, bromine, iodine and fluorine. By the terms lower alkyl and lower alkoxy as used herein are meant straight and branched chain carbon radicals containing from 1 to 4 carbon atoms inclusive. Exemplary of these carbon chain radicals are methyl, ethyl, propyl, isopropyl, 1 - butyl, 1 - methylpropyl, - methylpropyl, and tert. - butyl.

It will he apparent to those skilled in the art that the compounds of Formula T can exist as stereoisomeric modifications when an asymmetric center is present. For example, in the ease of a compound of Formula 1 wherein the bis - pyrrolinyl moiety* contains· an R - substituent other than hydrogen, such as 2 methoxy - 10 - [5 - methyl -1-(5- methyl - 1 - pyrrolin - 2 yl) - 2 - pyrrolin - 2 - ylJphenothiazine, two asymmetric centers arc present resulting in two racemic modifications. It is possible to separate tin· racemic modifications into individual (I) - pairs on the basis of physico-chemical differences such as solubility.

The (-) - pairs can be resolved according to conventional procedures by using appropriate optically active acids. It is to be understood that all stereoisomeric forms of the compounds of Formula £ are included within the scope of this invention.

The present invention further provides a method for producing said amidine compound of formula i or a pharmaceutically acceptable salt thereof which comprises reacting a compound of the Formula II (II) li XY H With a pyrrolidinone of the formula III I Lo (XXI) H wherein R, X and Y are as previously defined, in the presence of phosphorus oxychloride and in a reaction-inert solvent or reacting said compound of formula II with 2 - chloro -1-(1- pyrrolin 10 -2-yl)-2- pyrroline hydrochloride, in a reaction-inert solvent; and thereafter, if desired, converting the amidine free base reaction product to the corresponding pharmaceutically acceptable acid addition salt by methods known per se (e.g. by reaction with an inorganic or organic acid).

Illustrative of suitable phenothiazine reactants which may be employed are: phenothiazine, 2-chlorophenothiazine, 4-chlorophenothiazine, 2-bromophenothiazine, 2-fluorophenothiazine, 2-iodophenothiazine, 2-trifluoromethylphenothiazine, 4-trifluoromethylphenothiazine, 2-methoxyphenothiazine, 4-me thoxyphenothiazine, 2-ethoxyphenothiazine, - n - propoxyphenothiazine, - isopropoxyphenothiazine, 2 - n - butoxyphenothiazine, - isobutoxyphenothiazine, - see. - butoxyphenothiazine, - ij - butoxyphcnothiazinc, - mel.hyl phenothi az.im·, — me thy I plienoth i az i lie, 2 — i««propylphenothiazine, - methylphenothiazine, - n - butyiphenothiazine, - methylphenothiazine, - isopropylphenothiazine.

Suitable acridan reactants are: acridan, - methoxyacridan, - methoxyacridan, - chioroacridan, 4 - chioroacridan, - trifluoromethylacridan, - trifluoromethylacridan, 9,9 - di.methylaeridan, - chloro - 9,9 - dimethyiaericlan, 2 - trifluoromethyl - 9,9 - dimethylacridan, - methoxy - 9,9 - dimethylacrtdan, - methylacridan, - methylacridan, - n - butylacridan, 2 - trifluoromethyl - 9 - methylacridan, - ethyl - 9 - methylacridan, 9,9 - di - n - butylacridan.

Suitable phenoxazines are: phenoxazi ne, 2 - methoxyphenoxazine, -5 42408 - methoxyphenoxazine, - isopropoxyphenoxazine, - methylphenoxazine, - methylphenoxazine, 4 - n - butylphenoxazine, - chlorophenoxazine, - chlorophenoxazine, - chlorophenoxazine, - trifluoromethylphenoxazine.

Suitable pyrrolidinoncs are: - pyrrolidinone, - methyl - 2- pyrrolidinone, - ethyl - 2 - pyrrolidinone, - n - propyl - 2 - pyrrolidinone, - n - butyl --2 - pyrrolidinone.

The compounds of Formula I are basic, generally crystalline compounds which arc practically insoluble in water, but are 1 readily soluble in most organic solvents and in aqueous solutions of organic or inorganic acids.

The compounds of Formula I can be converted, if desired, to corresponding pharmaceutically acceptable acid addition salts by admixture of the free base with a selected acid in an inert organic solvent such ns ethanol, benzene, ethyl acetate, ether or haiogenated hydrocarbons. A preferred method of salt prepar25 ation is to treat the base with substantially one chemical equivalent of an acid such as hydrogen chloride in ethanol solution. The salt precipitates from the ethanolic solution upon chilling or the addition of ether. It is to be understood that both the free base and salt forms of the products of Formula I are useful for the purpose of the invention although salts are,in - 6 some instances, particularly preferred because of their increased water solubility.

By the term pharmaceutically acceptable acid addition salt, as used herein is meant the salt form of an amidine base of the present invention and an inorganic or organic acid which exhibits substantially no significant toxicity when administered at the effective dose for the purpose intended. Some examples of inorganic or organic acids which may be employed to provide a pharmaceutically acceptable acid addition salt of the compounds of Formula 1 are: sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, acetic, lactic, maleic, succinic, malic, fumaric, tartaric, citric, gluconic, glutaric, ascorbic, benzoic, cinnamic, iscthionic, and related acids.

The free base compounds of Formula I can be prepared by neutralization of the acid addition salt in aqueous base. In a convenient procedure, the salt is mixed with excess sodium hydroxide in aqueous solution, after which the free base can be separated by extraction with a chlorinated hydrocarbon or ether solvent. The solvent can be removed by conventional methods such as evaporation or distillation and the free base compound can be purified by methods such as recrystallization or short path distillation at reduced pressures.

In carrying out the process of tin· invention for (.he preparation of tin· bis — pyrrol iny I compounds of I’oriniila I I.he compound of Formula II is reacted with the compound ol Formula III and phosphorus oxychLorido in a reaction-inert aprotic solvent. Generally, ratios of from 1 to 2 moles of the pyrrolidinone reactant to 1 mole of phosphorus oxychloride and 1 mole of the compound of Formula II are employed. A preferred solvent for carrying .30 out the process is 1,2 - dichloroethane although other solvents are suitable such as benzene, chloroform, carbon tetrachloride, 1,1 - dichloroethane, hexane or xylene. The process may be - 7 43408 carried out at a temperature of about 0°C. to 150°C. However, room temperature in the range of about 25-35°C. is generallypreferred. Tn some instances, the reaction mixture is permitted to stand for several days but generally the reaction is essent5 ially complete in about 15 hr.

Whenever compounds characterized by Formula I wherein R is limited to hydrogen are prepared, an alternate aspect of the process of the present invention comprises reaction of the compound of formula II with the imidoyl chloride 2 — chloro -1-(110 pyrrolin - 2 - yl) - 2 - pyrroline hydrochloride” in a reactioninert solvent such as 1,2 - dichloroethane. Alkylation of the . compound of Formula XI with 2 - chloro - 1 - (l - pyrrolin - 2 yl)pyrroline hydrochloride is preferably carried out in 1,2 - dichloroethane at reflux temperature.

According to the foregoing process wherein a compound of Formula II is reacted with a pyrrolidinone and phosphorus oxychloride, in addition to the bis - pyrrolinyl compounds of Formula I, monomeric pyrrolinyl compounds described in United States Patent 3,719,671 are also obtained. For example, reaction of phenothiazine, 2 - pyrrolidinone, and phosphorus oxychloride in 1,2 - dichloroethane provides the bis - pyrrolinyl phenothiazine compounds of the present invention, ”10 - [1 - (l - pyrrolin - 2 yl) - 2 - pyrrolin - 2 - yl]phenothiazine” and the monomeric pyrrolinyl derivative ”10 - [2 - (l - pyrrolinyljphenothiazine” described in United States Patent 3,719j671. Separation of the bis - pyrrolinyl derivatives of the present invention from the monomeric pyrrolinyl by-products is generally effected by washing with a solvent, preferably acetone, wherein the bis - pyrrolinyl derivatives of the present invention are relatively less soluble than the monomeric pyrrolinyl by-products or by distillation. _ 8 _ The bis - pyrrolinyl compounds of the present invention are new chemical substances which have useful pharmacological properties. More particularly, they exert an intestinal relaxant effect similar to that obtained with papaverine. Aside from the intestinal relaxant activity, the his - pyrrolinyl compounds of Formula I have antithromhogenic properties as demonstrated by their ability to inhibit platelet aggregation caused by the addition of adenosine diphosphate to platelet rich plasma. intestinal relaxant activity of the bis - pyrrolinyl compounds of the present invention can be measured in standard and accepted in vitro and in vivo pharmacological tests. One such test is carried out essentially as follows. Λ segment of rabbit ileum is suspended in oxygenated Tyrode’s solution and affixed to a tension transducer for electronic recording of isometric contract15 ions. After control responses to a standard dose of a spasmogen such as barium chloride (0.25 mg./ml.) or acetyl-choline chloride (l.O meg./ml.) are established, the bis - pyrrolinyl compound is added and the response to the spasmogen, in the presence of the test compound, again determined. Test 2() compound effect is measured as the percentage reduction from the mean control response in the response to the spasmogen in tlie presence of the test compound. The data are expressed in log dose response curves obtained from a minimum of three trials at each of 2 to 5 different concentrations of the test compound.

Estimates are made therefrom of the EC^q or EC^^ (concentration causing 5θ% and 75% reduction, respectively, in the response of the tissue to the spasmogen).

In this test, papaverine, which is a well-known smooth muscle relaxant, has an EC^{) of 12.2 meg./ml. against barium 3() chloride spasms, in general, the bis - pyrrolinyl. substances of Formula I are more potent than papaverine. As might be - 9 42408 expected, certain of the compounds are more active than others.

In this respect, there can be mentioned by way of example 9,9 -dimethyl -10 [5 - methyl -1-(5- methyl - 1 - pyrrolin - 2 yl) - 2 - pyrrolin — 2 - yljacridan hydrochloride, 10 - [l - (l — pyrrolin - 2 - yl) - 2 - pyrrolin - 2 - yl]phenoxazine and 2 methoxy - 10 [5 - methyl -1-(5- methyl - 1 - pyrrolin - 2 yl) - 2 - pyrrolin - 2 — yl]-phenothiazine hydrochloride which are particularly preferred bis - pyrrolinyl compounds of the present invention and are respectively 7.6, 3.1 and 1.7 times as potent as papaverine. t Apart from intestinal relaxant activity, a bis - pyrrolinyl compound of this invention present in an effective amount in the mammalian circulatory system has the added benefit of providing a protective antithrombogenic effect. Measurement of the anti15 thrombogenic activity of the bis - pyrrolinyl compounds of Formula I can be carried out in a standard pharmacological test which essentially has been described by Born, Nature, 194, 927 (1902) and O'Brien, J. Clin. Path., 15, 44-6 (1962). This test is a nephelometric method in which the change Ln turbidity of a specimen of platelet rich blood plasma (generally human blood plasma) is measured on causation of platelet aggregation by addition of a thrombogenic inducing agent such as adenosine diphosphate or collagen. The compounds of the present invention are effective antithrombogenic agents according to this test at concentrations in the order of about 3 to 150 mcg./0.5 ml. human platelet rich plasma. The antithrombogenic effect is measured in the intact animal by applying the foregoing test to blood samples withdrawn prior to and after administration to the test animal of a bis pyrrolinyl compound of the present invention.

While compounds of Formula I generally exhibit significant antithrombogenic activity, compounds which reduce the thrombogonic: capacity of collagen or adenosine diphosphate induced platelet aggregation by 50% or more at concentrations of less than 15 meg./ 0.5 ml. of platelet rich plasma are preferred and by way of example there can be mentioned: 9,9 - dimethyl - 10 - [1 - (l-pyrrolin - 2 - yl) - 2 - pyrrol!n 2 - ylj. aeridan; 9,9 - dimethyl - 10 - [5 - methyl -1-(5- methyl - 1 pyrrol in - 2- yl)-2 - pyrrolin - 2 - yl]aeridan; - [5 - methyl - 1 - (5 - methyl - 1 - pyrrolin- 2-yl) 2 - pyrrolin - 2 - yljphenothiazine; 2 - methoxy - 10 - [5 - methyl -1-(5- methyl - 1 - pyrrolin -2-yl)-2- pyrrolin - 2 - yljphenothiazine; - [1 - (1 - pyrrolin - 2 - yl) - 2 - pyrrolin - 2 - yl]phenoxazine. in addition to having intestinal relaxant and antithrombogenic properties, compounds of formula I are effective diuretic agents as demonstrated by the method of W.L, Lipsehitz, et al., ·). I’harinaeol. txpt. 'fherap., 79. 97 (1943). In this method, groups of 8 rats are fasted IS hours prior to the experiment. A control group is hydrated orally with 25 ml. per kilogram of body weight of isotonic saline solution which is also the vehicle used for dosing the test compound. One control group received a dose of 960 mg./kg. of body weight of urea. Animals of other groups are treated with various doses of the test compound. Immediately after treatment, the animals are placed in metabolism cages (two rats of the same group per cage) and maintained without food or water for 5 hrs.

The volume of uri.ru: excreted by each pair is determined after this period and the pooled urine is analyzed for sodium, potassium, and chloride ions. The results for the test compounds are expressed as ratios of the volume of urine or total quantities of electrolytes (i.e. sodium, potassium, and chloride) excreted during tho experimental period compared to the saline and/or urea control group. The test compounds are orally administered in doses ranging from 2.7 to 25 mg./kg. of body weight. in this test, ΕΙ\οο values (dose providing a 100% increase in volume) for 9,9 - dimethyl - 10 - [5 - methyl - 1 - (5 - methyl - 1 5 pyrrolin -2-yl)-2- pyrrolin — 2 - yl] — acridan and 10 [5 - methyl -1-(5- methyl - 1 - pyrrolin - 2 - yl) - 2 pyrrolin - 2 - yl] - 2 - (trifluoromethyl)phenothiazine are respectively 3.58 and 6.63 mg./kg. body weight.

The present invention further provides a method for producing a diuretic, antithrombogenic or intestinal smooth muscle relaxant effect in a mammal other than a human being which comprises parenterally or orally administering to said mammal an effective amount, to produce said effect of a compound of the general formula I or a pharmaceutically acceptable acid addition salt thereof.

Pharmacological activity including diuretic antithrombogenic, and intestinal relaxant effects are obtained at doses of the compounds of Formula I or pharmaceutically acceptable acid addition salts thereof ranging from about 0.01 to 30 mg./kg. body weight, based on the free base. With respect to total daily dose, 2θ optimum intestinal relaxant and antithrombogenic effects are obtained by oral administration of the bis - pyrrolinyl compounds of Formula Γ or pharmaceutically acceptable acid addition salts thereof in a dose based on the free base ranging from about 0.05 to 100 mg/kg, body weight. It is to be understood that the term «an effective amount as used herein refers to the quantity of active ingredient necessary to produce the desired therapeutic effect without causing any substantial, significant, harmful or deleterious side effects.

Oral toxicity values (ALD^q) of the substances of Formula I in mice range from about 125 to greater than 1000 milligrams per 3408 kilogram of body weight. For instance, the ADLjQ for 10 [1-(1- pyrrolin - 2 - yl) - 2 - pyrrolin - 2 - yl]phenoxazine hydrochloride is 250-500 mg./kg. body weight.

The compounds of. the present invention can be formulated according to conventional pharmaceutical practice to provide pharmaceutical compositions of unit dosage form which may include, for example, tabLcts, pills, capsules, powders, granules, emulsions or suspensions. The solid preparations contain the active ingredient in admixture with pharmaceutically acceptable excipients such as inert diluents, for .example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating 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 delay disintegration and absorption in the gastrointestinal, tract and 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 1. The aqueous suspensions of the pharmaceutical dosage forms of the compounds of Formula I contain the active ingredient in admixture wi th one. or more pharmaceutically acceptable excipients known to be suitable in the manufacture of aqueous suspensions. Suitable excipients are, for example, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia. Suitable dispersing or wetting agents are naturally occurring phosphatides, for example lecithin and polyoxyethylene stearate. 43408 Not» - aqueous suspensions may be formulated by suspending the aotive ingredient in a vegetable oil, for example arachis oil, 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 beeswaz, 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 additional absorbing agents, stabilizing agents, weighing agents and buffers.

The following examples are intended to further illustrate the present invention and to enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited solely to the particular examples given below.

In regard to NMR data the following notations are employed; s»singlet, d»doublet, dd=doublet of doublets, t=triplet, q=quintet, m=mulbiplet=, nm=narrow multiplet, bs=broad. singlet.

Example 1 Phosphorus oxychloride (38,3 g.j 0.25 mole) in 50 ml. of 1,2dichloroethane is added in one portion to a stirred mixture of phenothiazine (49.8 g., 0.25 mole) and 2 - pyrrolidinone (42.6 g., 0.5 mole) in 250 ml. of 1,2 - dichloroethane. The mixture is stirred for 4 hr. at room temperature, permitted to stand for a period of 15 hr, and then poured into a mixture of 200 ml. of 5N sodium hydroxide and 100 g. of crushed ice. The 1,2 - dichloroethane layer is separated and the aqueous layer extracted with 100 ml. of additional 1,2 - dichloroethane. The combined 1,2 - dichloroethane fractions are sequentially extracted with 300 ml. of 1.5N hydrochloric acid and 200 ml. of water. The combined acid-water extracts are washed with ether, made basic with 5N sodium hydroxide - 14 42408 and extracted repeatedly with chloroform. After drying over magnesium sulfate, the chloroform solution is concentrated and the residual material thus obtained is stirred with 200 ml. of acetone to remove the acetone soluble 10-[2-(l- pyrrolinyl)jphenothiaz5 i.ne by-product and filtered. The filter cake is washed with additional acetone and dried to provide 14.1 g. (17% yield) of 10- [1 - (1 - PYRROLIN - 2 - YL) - 2 - PYRROLIN - 2 - YL] PHENOTHIAZINE as the free hase, m.p. 199-21O°C. The bis - pyrrolInyl phenothiazine free base suspended in 60 ml. of absolute ethanol, acidified with an equivalent of ethanolic hydrogen chloride, treated with decolorizing charcoal, filtered, and diluted with 200250 ml, of anlylrous ether provides the hydrochloride salt. Crystallization of the hydrochloride salt from absolute ethanol-anhydrous other affords analytically pure 10 -[1- (l - PYRROLIN - 2 - YL) 15 2 - PYRROLIN - 2 - YL - ΡΙΙΕΝΟΤΗΓΑΖΙΝΕ]HYDROCHLORIDE solvated with l/5 mole of ethanol as an off white solid, m.p. 237“239°C. (corr.).

Analysis. Calcd. for CgQH^gN^S.HCl l/5 C^H^OH (percent: C, 64. 63; H, 5.64; Cl, 9.35; N, 11.08. Found (percent): C, 64.68; II, 5.61; Cl, 9.41; N, 11.18.

NMR delta, (ppm) (D^O, HDO reference): 1.75'», 2,96m, 3.41m, 4.23m, 5.88mn, 7-θ1*· Example 2 A solution of 4 - chlorophenothiazine (32.3 g., 0.134 mole) and 2 - pyrroli.dinone (23 g., 0.27 mole) in 125 ml. of 1,2 25 diehloroethane is added dropwise to a solution of phosphorus oxychloride (2Ο.5 g., 0.134 mole) in 50 ml. of 1,2 - diehloroethane in about 35 min. Isolation of the product from the reaction mixture according to the procedure of Example 1 provided 7.5 g. , (17.1% yield) of 4 - CHLORO - 10 - [l - (l - PYRROLIN - 2 - YL) 30 2 - PYRROLIN - 2 - YLjPHENOTHXAZINE free base, m.p. 195-197°C.

Analytically pure 4 - CHLORO - 10 - [1 - (1 - PYRROLIN - 2 - YL) 15 42408 - PYRROLIN - 2 - YL]PHENOTHIAZINE HYDROCHLORIDE obtained by crystallization from ethanol - ether has a melting point of 232-234°C. (corr.).

Analysis: Calcd. for CgQH^^ClN^S.HCl (percent): C, 59.41; H, 4.74; N, 10.39; Cl, 17.53. Found (percent): C, 59.20j H, 4.74; N, 10.59; Cl, 17.46.

NMR delta (ppm) (D20), HDO reference): 1.77®, 2.97®, 3.43m, 4.14m, 5.91nm, 6.9m.

Example 3 Reaction of 2 - methoxyphenothiazine, 2 - pyrrolidinone and phosphorus oxychloride in 1,2 - diehloroethane according to the procedure of Example 1 affords 2 - METHOXY -10-[l-(lPYRROLIN - 2 - Yl.) - 2 - PYRROLIN - 2 - YLjPIIENOTHIAZINE free base m.p. 151-153°C. (corr.), from isopropyl alcohol.

Analysis: Calcd. for C^I^N^OS (percent): C, 69.39; H, 5-83; N, 11.56. Found (percent: C, 69.35; H, 5.«7; N, 11.76.

NMR delta (ppm) (CDCl^, 'IMS reference ): 1.78q (7.0), 2.77®, 3.56t (7.1), 3.71s, 4.19dd (8.0, 9.8), 5.20t (2.8), 6.5®, 6.9m.

Example 4 A mixture of 5 - methyl - 2 - pyrrolidinone (6.0 g., 0.06 mole), phosphorus oxychloride (9.2 g., 0.06 mole) in 60 ml. of I, 2 - diehloroethane is refluxed for 10 min. . A solution of phenothiazine (6.0 g., 0.03 mole) in 20 ml. of 1,2 - diehloroethane is added at the end of the reflux period and the reaction mixture stirred and refluxed for 20 hr., and then poured onto 20 ml. of 5N potassium hydroxide and 20 g. of crushed ice. The 1,2 diehloroethane layer is separated and extracted with 30 mi. of 1.5 N hydrochloric acid and 30 ml. of water removing water soluble by-product 10 - [2 - (5 - methyl - 1 - pyrrolinyl)] - phenothiazine hydrochloride. After drying the 1,2 - diehloroethane solution - 16 424 over magnesium sulf .ate, the 1,2 - dichloroethane solution is concentrated and the solid thus obtained stirred with 40 ml. of acetone and filtered. Crystallization of the filtercake from ethanol - ether provides analytically pure 10 - [5 - METHYL - I 5 (5 - METHYL -1 - PYRROLIN - 2 - YL) - 2 - PYRROLIN - 2 YL]PHENOTHIAZINE HYDROCHLORIDE in a yield of 17%, m.p. 257264°O. (corr.).

Analysis. Calcd. for C22H29^9SHil (percent): C, 66.4θ; H, 6.08; N, 10.56; Cl, 8.91. Found (percent): C, 06.51; H, 6.14; N, 10.52; Cl, 8.99.

NMR delta (ppm) (CDCl^, TMS reference): 1.41d (6.4), 1.57H (6.2), 1.7-3.5m, 4.05m, 5.62m, 5.86t (2.9), 7-0m, 11.75bs.

Example 5 Reaction of 5 - methyl - 2 - pyrrolidinone, 2 - methoxyphenJ5 othiazine and phosphorus oxychloride in 1,2 - dichIoroethane according Lo l.lu· procedure ol' Example 4 affords 2 - METHOXY - (0 [ 5 - METHYL -1-(5- METHYL - 1 - PYRROLIN - 2 - YL) - 2 PYRROLIN - 2 - YLjPHENOTHIAZJNE HYDROCHLORIDE (3.6% yield), m.p. 236.5-238.5°C (corr.), from ethanol - ether.

Analysis. Calcd. for C^^H^jN^OS, HCl (percent): C, 64.54; H, 6.12; N, 9.82; Cl, 8.29. Found (percent): C, 64.50; H, 6.15; N, 9.88; Cl, 8.33.

NMR delta (ppm) (CDCl^, TMS reference): 1.48d (6.3), 1.54d (6.4), 1.56d (6.4), 1.6-3.3m, 3.70s, 4.10m, 5.57m, 5.8lt (3.0), 6.8m, 11.93bs.

Example 6 A mixture of 5 - methyl - 2 - pyrrolidinone (2.0 g. , 0,02 mole) and phosphorus oxychloride (3.0 g., 0.02 mole) in 15 ml. of I, 2 - dichloroethane after standing 15 hr. at room temperature i.s combined witli 9,9 - dimethyl-acridan (2.1 g., 0.01 mole). 43408 After a 48 hr. period, the resultant mixture is added to 30 ml. of 5N potassium hydroxide and 30 g. of crushed tee. The 1,2 dichloroethane fraction is separated, extracted with 50 ml. of 1.5N hydrochloric acid and 50 ml. of water and dried over magnesium sulfate. Concentration of the 1,2 - dichloroethane solution provides a residue which is stirred with 100 ml. of ether and filtered. The filter cake containing crude hydrochloride salt of the product is stirred with sodium hydroxide solution affording l.he free base. Crystallization from n - heptane provides 1.3 g. (35% yield) of 9,9 - DIMETHYL - 10 [5 - METHYL - 1 (5 - methyl - 1- pyrrolin - 2 - yl) - 2 - pyrrolin - 2 - YL]ACRIDAN, m.p, 135-139°C. from which the hydrochloride salt is prepared according to the procedure of Example 1. Analytically pure 9,9 - DIMETHYL - 10 - [5 - METHYL - 1 - (5 - METHYL - 1 15 PYRROLIN - 2 - YL) - 2 - PYRROLIN - 2- YL]ACRIDAN HYDROCHLORIDE, from acetone - ether, has a melting point of 247·5-248.0°C. (corr.).

Analysis. Calcd. for C25H29N3‘HC1 (percent): C, 73.60; H, 7.41; N, 10.30; Cl, 8.69· Found (percent): C, 73.98; H, 7.40; N, 10.22; Cl, 8.67.

NMR delta (ppm) (CDCl^, TMS reference): 1.40d (6.2), I. 45d (6.2), 1.6ls, 1.70d (6.2), 1.72s, 1.8-3.2m, 4.l6m, 5.69m, .82t (2.9), 6.7 m, 7.3m» 11.82bs.

Example 7 A mixture of acridan (3.6 g., 0.02 mole) and 2 - chloro - 1 (l - pyrrolin - 2 - yl) -2- pyrroline hydrochloride (5.1 g., 0.025 mole), obtained according to the method of H. Brederick, et al., Chem. Ber., 94, 2292 (1961), in 50 ml. of 1,2 - dichloroethane is refluxed for a period of 15 hr. The mixture is sequentia30 lly extracted with 50 ml. of 1.5 N hydrochloric acid and three 50 - 18 42408 ml. portions of water. The combined acid-water extracts are basified with 5N potassium hydroxide, extracted with ether and the ethereal extract concentrated. Crystallization of the residue thus obtained from ethanol affords the free base 10 - [1 (2 - PYRROLIN - 2 - YL) - 2 - PYRROLIN - 2 - YL]ACRIDAN, m.p. 179-l8l°C. which is converted according to the procedure of Example I to 10 - [1 - (2 - PYRROLIN - 2 - YL) - 2 - PYRROLIN 2 - YLjACRLDAN HYDROCHLORIDE, m.p. 212.5-216.5°C. (dec.) (corr), from ethanol - ether.

Analysis. Calc-d. for ^21^21^2’^^ (percent): C, 71.68; H, 6.30; Ν, 11.94; Cl, 10.08. Found (percent): C, 71.43; II, 6.24; N, 11.90; Cl, 9.85.

NMR delta (ppm) (Ι^θ’ reference): 1.60m, 2.33m, 2.80m, 3.36m, 3.69s, 4.11m, 5.49em, 6.9m.

Example 8 Reaction of 9,9 - dimethylacridan, and 2 - chloro -1-(1pyrrolin -2-yl) - 2 - pyrroline hydrochloride according to the procedure of Example 7 affords a 21% yield of the free base, 9,9 DIMETHYL - 10 - fl - (1 - PYRROLIN - 2 - YL) - 2 - PYRROLIN - 2 YL]ACRIDAN, m.p. 166-168°C. Acidification of the free base with ethanolic hydrogen chloride according to the procedure of Example 1 provides 9,9 - DIMETHYL - 10 - [1 - (1 - PYRROLIN 2 - YL) - 2 - PYRROLIN - 2 - YL]ACRIDAN 1YDR0CHL0RIDE, m.p. 256.5-258°C. (dec.) (corr.), from benzene - ether.

Analysis. Calcd. for CzyHg^Nj.HCl (percent): C, 72.71; H, 6.90; N, 11.06; Cl, 9.33. Found (percent): C, 72,46; H, 6.32: N, 10.88; Cl, 9.04.

NMR delta (ppm) (CDCl^, TMS reference): 1.6ls 1.73s, 1.90m, 2.29m, 3.07m, 3.72t (7.0), 4.80dd (8.0, 8.5), 5.88t (3.0), 6.7m, 7.3m.

Example 9 Reaction of phenaxazine with 2 - chloro -1-(1pyrrolin - 2 - yl)pyrroline hydrochloride according to the procedure of Example 7 affords 10 -Q - (l - PYRROLIN - 2 - YL) 2- PYRROLIN - 2 - YL] PHENOXAZINE HYDROCHLORIDE, m.p. 257-5203°C. (corr.) from ethanol - ether.

Analysis. Calcd. for ^θΗ^Ν^Ο. HCl (percent): C, 67·88;Η, 5·7Ο Ν, 11.88; Cl, 10.02. Found (percent): C,67·52; Η ,5·82; N, 11.83; ci, 9.85.

NMR delta (ppm) (CDCl^, TMS reference): 2.08m, 2.95 m, 3.72t (7.1), 4-65dd (8.0, 8.5), 5.86t (2.9), 6.4m, 6,8m.

Example 10 Reaction of 2 - chlorophenoxazine with 2 - chloro - (1 pyrrolin - 2 - yl)pyrroline hydrochloride according to the procedure of Example 7 affords .2 - CHLORO -10-(1-(1PYRROLIN - 2 - YL) - 2 - PYRROLIN - 2 - ΥΪ] PHENOXAZINE HYDROCHLORIDE, m.p. 262.5-264.5°C. (dec.) (corr.) from ethanol ether.

Analysis. Calcd. for C^H^CIN^O. HCl (percent); C, 61.86; II, 4,93; N, 10.82; Cl, 18.27. Found (percent): C, 61.65; II, 4-97; N, 10.79; Cl, 18.16.

NMR delta (ppm) (CDCl^, IMS reference): 2.17m, 2.98m, 3.74t (7.0), 4.68dd (8.0, 9-0), 5-88t (3-0), 6.4m, 6.8m, 12.0bs.

Example 11 Reaction of 2 - trifluoromethylphenoxazine with 2 - chloro 1-(1- pyrrolin - 2 - yl) — pyrroline hydrochloride according to the procedure of Example 7 affords the free base, 2 TRIFLUOROMETHYL - 10 -fl - (l - PYRROLIN - 2 - yl) - 2 - PYRROLIN 2 - YlI PHENOXAZINE, m.p. 14O-142°C., from n-hexane. Conversion of the free base affords 2 - TRIFLUOROMETHYL - 10 -jj - (ΙΣΟ 42403 PYRROLIN - 2 - YL) - 2 - PYRROLIN - 2 - YLjPHENOXAZINE HYDROCHLORIDE HYDRATE, m.p. 222.5-229°C. (doc.) (corr.).

Analysis: Calcd. for Cj^Hi^FgNg.HCl. 1^0 (percent): C, 57.35; H, 4.81; N, 9.55; Cl, 8.06. Found (percent): C, 57.42; H, 4.7«; N, 9.43; Cl, 8.32.

NMR delta (ppm) (CDCl^, l'MS reference): 2.13m, 2.89m, 3.75t (7.0), 4.6?dd (9.0, 8.0), 5.90t (3.0), 6.5m, 6.8m 11.63bs. Example 12 Reaction of 3 - chlorophenoxazine with 2 - chloro -(110 pyrrolin - 2 - yl)pyrrolin hydrochloride according to the procedure of Example 7 affords 3 - CHLORO - 10 - [1 - (l - PYRROLIN - 2 - YL) 2 - PYRROLIN - 2 - YL]PHENOXAZINE HYDROCHLORIDE, m.p. 262.5-27O°C. (dec.) (corr.), from ethanol - ether.

Analysis. Calcd. for C^yH^^ClN^O.HCl (percent): C, 61.86; II, 4.93; N, 10.82; Cl, 18.27. Found (percent); C, 61.82; II, 4.99; N, 10.74; Cl, 18.03.

NMR delta (ppm)(CDCl^, TMS reference): 2.12m, 2.97m, 3.73t (7.0), 4.67dd (9.0, 8.0), 5.87t (3.0), 6.4m, 6.8m.

Example 13 Reaction of 4 - chlorophenoxazine with 2 - chloro -(1pyrrolin - 2- yl)pyrroline hydrochloride according to the procedure of Example 7 affords 4 - CHLORO - 10 - [1 - (1 - PYRROLIN - 2 YL) - 2 - PYRROLIN - 2 - YL]PHENOXAZINE HYDROCHLORIDE, m.p. 278-282°C. (dec.), from ethanol - ether.

Analysis. Calcd. for C^^H^jjClN^O.HCl (percent): C, 61.86; H, 4.93; N, 10.82; Cl, 18.27. Found (percent): C, 61.87; H, 4.99; N, 10.82; Cl, 18.16.

NMR delta (ppm) (CDCl^, TMS reference): 2.11m,2.97m, 3-74t (7.0), 4.67dd (9.0, 8.0), 5.87t (3-0), 6.4 m, 6.8m.

Example 14 Reaction of the phenoxazines: - methoxyphenoxazine, 4- methoxyphenoxazine, - isopropoxyphenoxazine, - methylphenoxazine, - methylphenoxazine, - 0. - hutylphenoxazine with 2 - chloro - 1 - (1 - pyrrolin - 2 - yl)pyrroline hydrochloride according to the procedure of Example 7 provides the respective bis - pyrrolinyl phenoxazines: - METHOXY - 10 - [1 - (1- PYRROLIN - 2 - YL) - 2 - PYRROLIN - 2 - YLjPHENOXAZINE HYDROCHLORIDE, m.p. 201.5-206.5°C. (dec.) (corr.). Analysis. Calcd. for ^^21^302 (Percent): C, 65.70; H, 5.78; N, 10.95; Cl, 9.24. Found (percent): C, 64.98; H, 5.71; N, 11.04; Cl, 9.23. NMR delta (ppm) (CDC13, TMS reference): 2.10m, 3.01m, 3.72L (7.1), 3.71s, 4.63t (7.5), 5.9-6.9m.

- METHOXY - 10 -[1(1- PYRROLIN - 2 - YL) - 2 - PYRROLIN 2 - YLjPHENOXAZINE, - ISOPROPOXY _ 10 - [1 - (1 - PYRROLIN - 2 - YL) ;- 2 PYRROLIN - 2 - YLjPHENOXAZINE, - METHYL -10-(1-(1- PYRROLIN - 2 - YL) - 2 PYRROLIN - 2 - YLjPHENOXAZINE, - METHYL -10-(1- (1 - PYRROLIN - 2 -YL )-2PYRROLIN - 2 - YL] PHENOXAZINE, 4-n - BUTYL -10-(1- (1 - PYRROLIN - 2 - YL) - 2 PYRROLIN - 2 - YLjPHENOXAZINE.

Example 15 Reaction of phenoxazine with 5 - methyl - 2 - pyrrolidinone or 5 - n - butyl - 2 - pyrrolidinone according to the procedure of Example 4 provides the bis - pyrrolinyl phenoxazines: - 22 4340 ~ fs - METHYL -1-(5- METHYL - 1 - PYRROLIN - 2 - YL) · 2 - PYRROLIN - 2 - YL]PHENOXAZINE, - | 5 - n - BUTYL - 1 - (5 - n - BUTYL - 1 - PYRROLIN - 2 YL) _ 2 - PYRROLIN - 2 - YL]PHENOXAZINE.

Reaction of 4 - chlorophenoxazine with 5 - methyl - 2 pyrrolidinone according to the procedure of Example 4 provides - CHLORO - 10 - [5 - METHYL -1-(5- METHYL - 1 PYRROLIN - 2 - YL) - 2 - PYRROLIN - 2 - YL]PHENOXAZINE.

Example 16 Reaction of the phenothiazines: - trifluorophenothiazine, - chlorophenothiazine, - chlorophenothiazine, - isopropoxyphenothiazine, - methylphenothiazine, - n - butyiphenothiazine, - methylphenothiazine, - isopropylphenothiazine with 2 - chloro - 1 - (l - pyrrol.in - 2 - yl) - pyrroline hydrochloride according to the procedure of Example 7 provides the respective bis - pyrrolinyl phenothiazines: - TfilFLUOROMETHYL - 10 - [1 - (l - PYRROLIN - 2 - YL) 2 - PYRROLIN - 2 - YL]PHENOTHIAZINE, - CHLORO - 10 - [1 - (1 - PYRROLIN - 2 - YL) - 2 - PYRROLIN 2 - YL]PHENOTHIAZ1NE, - CHLORO - 10 - [1 - (1 - PYRROLIN - 2 - YL) - 2 - PYRROLIN 2 - YL]PHENOTHIAZINE - ISOPROPOXY -10-(1-(1- PYRROLIN - 2 - YL) - 2 PYRROLIN - 2 - YLJPHENOTHIAZINE, - METHYL -10(1-(1- PYRROLIN _ 2 - YL) - 2 - PYRROLIN 2 - YL]PHENOTHIAZINE, - n - BUTYL -10-(1-(1- PYRROLIN - 2 - YL) - 2 ,PYRROLIN - 2 - YL]PHENOTHIAZINE, - 23 42408 - METHYL - 10 [J - (l - PYRROLIN - 2 - YL) - 2 - PYRROLIN 2 - YLj PHENOTHIAZINE, - ISOPROPYL - 10 [1 - (i - PYRROLIN - 2 - YL) - 2 - PYRROLIN - 2 - YL]PHENOTHIAZINE.

Example 17 Reaction of phenothiazine with 5 - n - butyl - 2 - pyrrolidinone according to the procedure of Example 4 provides 10 [5 - n - BUTYL - 1 - (5 - n - BUTYL - 1 - PYRROLIN - 2 - YL) - 2 PYRROLIN - 2- YL]PHENOTHIAZINE.

Example l8 Reaction of the acridanss - chloroacridan, - methoxyacridan, - isopropoxyacridan, - trifluoromethylacridan, - methylacridan, - methylacridan, - n - butylacridan, - trifluoromethyl - 9,9 - dimethylacridan, - trifluoromethyl - 9 - methylacridan, - chloro - 9,9 - dimethylacridan, - ethyl - 9 - methylacridan, 9,9 - di - n - butylacridan with 2 - chloro - 1 - (l - pyrrolin - 2 - yl)pyrroline hydrochloride according to the procedure of Example 7 provides the respective bis - pyrrolinyl acridans: - CHLORO -10-[l-(l- PYRROLIN - 2 - YL) - 2- PYRROLIN 2 - YLjACRIDAN, - METHOXY - 10 - [1 - (l - PYRROLIN - 2 - YL) - 2 PYRROLIN - 2 - YLJACRIDAN, - ISOPROPOXY -10-[l-(l- PYRROLIN - 2 - YL) - 2 PYRROLIN - 2 - YL]ACRIDAN, - TRIFLUOROMETHYL - 10 - [l -(l - PYRROLIN - 2 - YL) 2 - PYRROLIN - 2 - YLjACRIDAN, - METHYL _ 10 - fl - (1 - PYRROLIN - 2 YL) - 2 - PYRROLIN 2 - YLJACRIDAN, - METHYL - 10 - [1 - (1 - PYRROLIN - 2 - YL) - 2 - PYRROLIN 2 - YL]ACRIDAN, 4 - n - BUTYL - 10 - [1 - (1 - PYRROLIN - 2- YL) - 2 PYRROLIN - 2- YL]ACRIDAN, - TR1FLU0R0METHYL - 9,9 - DIMETHYL - 10 - [1 - (1 PYRROLIN - 2 - YL) - 2 - PYRROLIN - 2- YLjACRIDAN, - TRIFLUOROMETHYL - 9 - METHYL - 10 - fl - (l - PYRROLIN 10 2 - YL) - 2 - PYRROLIN - 2 - YLjACRIDAN, - CHLORO - 9,9 - DIMETHYL - 10 - fl - (l - PYRROLIN - 2 YL)- 2 - PYRROLIN - 2 - YLjACRIDAN, _ ETHYL - 9 - METHYL _ 10 - fl - (1 - PYRROLIN - 2 - YL) 2 - PYRROLIN - 2 - YLjACRIDAN, 9,9 _ DI- n - BUTYL - 10 - fl - (1 - PYRROLIN - 2 - YL) - 2 PYRROLIN - 2 - YLjACRIDAN.

Example 19 Reaction of acridan and 2 - chloroacridan with 5 - methyl 2 - pyrrolidinone and 5 - _n - butyl - 2 - pyrrolidinone respect20 ively according to the procedure of Example 4 respectively provides: - CHLORO - 10 - | 5 - METHYL - I - (5 - METIIYI. - I PYRROLIN - 2 - YL) - 2 - PYRROLIN -2-YL] ACRIDAN, - f5 - n - BUTYL - 1 - (5 - n - BUTYL - 1 - PYRROLIN - 2 25 YL) - 2 - PYRROLIN - 2 - YLjACRIDAN.

Example 20 A solution of 5 - methyl - 2 - pyrrolidinone (19.8 g., 0.2 mole) in 25 ml. of xylene is added drop-wise to a mixture of 2 - trifluoromethylphenothiazine (26.7 g., 0.1 mole) and 3° phosphorus oxychloride (15.3 g., 0.1 mole) in 125 ml. of refluxing xylene over a two hour period. When the addition is - 25 42408 complete, refluxing is continued for an additional 1.5 hr., the. reaction mixture is poured into 75 ml. of 5N sodium hydroxide and 75 g. of crushed ice, and, after mixing well, the xylene fraction; r, is separated. The xylene fraction is sequentially extracted with 100 ml. of 1.5 HCl followed by 100 ml. of water and then made basic by stirring with 5N sodium hydroxide solution. The basified xylene fraction is separated, dried over magnesium sulfate and concentrated under reduced pressure·. The resultant residue is taken up in JO. ml. of benzene and the benzene solution is concentrated. An addition10 al 100 ml. portion of benzene is added to the residue thus obtained and the solution partially concentrated until crystals begin to form. After cooling and standing, the mixture is filtered to remove recovered 2 - trifluoromethylphenothiazine starting material. Concentration of the filtrate affords a residual material which is taken up in ether, extracted with 1.5 N hydrochloric acid and then with 50 ml. of water. The combined acidaqueous extracts are made basic with sodium hydroxide and the mixture is extracted with ether. The ethereal extract is dried over magnesium sulfate, filtered and concentrated. Distillation of the residual oil through a 6 cm. column provides 10-(5methy.1 - 1 - (5 - methyl - 1 - pyrrolin - 2- yl )-2 - pyrrolin 2-yl] - 2 - (trifluoromethyl)phenothiazine free base, b.p. 175-l85OC./0,15 mm. Hg. The bis- pyrrolinyl phenothiazine free base is taken up in ethanol and acidified with ethanolic hydrogen. chloride. Addition of ether provides the hydrochloride salt which when crystallized from ethanol affords analytically pure 10 - [5 METHYL -1-(5- METHYL - 1 - PYRROLIN - 2 - YL) - 2 - PYRROLIN -..

- YLJ - 2 - (TRIFLUOROMETHYL) - PHENOTHIAZINE HYDROCHLORIDE, m.p. 25O-253°C. (dec.) (corr.).

Analysis. Calcd. for C23H22F3N3S·HC1: C, 59.28; H, 4.98; N, 9.02; Cl. 7.61. Found: C, 59.18; H, 5.14; N, 9.05; Cl, 7.39. - 26 4340 NMR. delta (ppm) (CDCl^, TMS reference): 1.49d (6.5), 1.55d (6.5) 2.37 m, 3.12m, 4.03m, 5-50m, 5.94m, 7.05m, ll.Sbs.

Example 21 Pharmaceutical Compositions The bis - pyrrolinyl compounds of the present invention characterized by Formula I are compounded with pharmacologically acceptable carriers to provide compositions useful in the present invent Lon. Typical of the pharmaceutical compositions arc the following: Ιθ A. Tablets The bis - pyrrolinyl compounds of Formula I are compounded into tablets according to the following example: Materials Amount 9,9 - Dimethyl - 10 - [5 - methyl -1-(5- methyl - 1 - pyrrolin 15 2 - yl) - 2 - pyrrolin - 2 - yl]acridan hydrochloride Magnesium stearate Corn starch Corn starch, prcgelatinized Lactose 2H The foregoing materials are blended in a twin-shell blender and then granulated and pressed into tablets employing 250 mg. each. Each tablet contains about 50 mg. of active ingredient.

The table t may be scored and quartered so that a unit dose of 12.5 mg. of active ingredient may be conveniently obtained. β. Capsules The biff - pyrrolinyl compounds of Formula I are compounded into capsules according to the following example: Materials Amount Active ingredient 125.0 ng. 3θ Lactose 146.0 mg.

Magnesium stearate 4.0 g. 54.9 g. 1.3 g. 12.4 g. 1.3 g. 181.0 g. - 27 The foregoing materials are blended in a twin-shell blender and then filled into No. 1 hard gelatin capsules. Each capsule contains 125 g. of active ingredient.

C. Solution for oral or parenteral administration A sterile aqueous solution having a concentration of 40 mg. per ml. of 9,9 - dimethyl - 10 [5 - methyl - 1 - (5 - methyl - 1 pyrrolin - 2 - yl) - 2 r pyrrolin - 2 - yljacridan hydrochloride is prepared by dissolving 400 g. of the substance in 9 litres of water for injection, U.S.P., adjusting the pH to 5.5 with dilute 1° aqueous sodium hydroxide and dilution to 10 litres. This solution is then filtered sparkling clear and filled into 2 ml. glass ampoules and sealed.

Claims (30)

1. A compound having the general formula Γ r / Formula I wherein X is a sulfur or oxygen atom or a divalent methylene radical having the formula -CiZ^Zg)-, wherein Z^ and are each independently a hydrogen atom or a straight chain lower alkyl group containing from 1 to 4 carbon atoms inclusive; Y is a hydrogen or halogen atom, a trifluoromethyl group, lower alkyl group containing from 1 to 4 carbon atoms inclusive; and R is a hydrogen atom or a straight chain lower alkyl group containing from 1 to 4 carbon atoms inclusive.

2. 10 — |1 — (1 — Pyrrolin - 2 - yl) - 2 - pyrrolin - 2 - yljphenothiazine.

3. - 4 - Chloro - 10 - [1 - (1 - pyrrolin -2-yl)-2- pyrrolin 2 - ylJphenothiazine.

4. 2 - Methoxy -10-(1- (l - pyrrolin - 2 - yl) - 2 - pyrrolin 2 - ylJphenothiazine.

5. 10 - [5 - Methyl - 1 - (5 - methyl - 1 - pyrrolin - 2 - yl) 2 - pyrrolin - 2 - yljphenothiazine.

6. 2 - Methoxy - 10 - [5 - methyl - 1 - (5 - methyl - 1 - pyrrolin 2 - yl) - 2 - pyrrolin - 2 - yljphenothiazine.

7. 10 - [1 - (2 - Pyrrolin - 2 - yl) - 2 - pyrrolin - 2 - yljacridan.

8. 9,9 - Dimethyl -10-(1-(1- pyrrolin -2-yl)-2pyrrolin - 2 - yljacridan.

9. · 9,9 - Dimethyl - 10-(5- methyl -1-(5- methyl - 1 - pyrrolin - 2 - yl) - 2 - pyrrolin - 2 - yljacridan.

10. 10 - [1 - (l - Pyrrolin - 2 - yl) - 2 - pyrrolin - 2 - yl]phenoxazine.

11. 2 - Chloro - 10 - [1 - (l - pyrrolin - 2 - yl) - 2 - pyrrolin 2 - yl]phenoxazine.

12. 3 - Chloro - 10 - [1 - (l - pyrrolin - 2 - yl) - 2 - pyrrolin 2 - yl]phenoxazine.

13. 4 - Chloro - 10 - [1 - (1 - pyrrolin - 2 - yl) - 2 - pyrrolin 2 - yl]phenoxazine.

14. 2 - Trifluoromethyl - 10 - [1 - (1 - pyrrolin - 2 - yl) - 2 pyrrolin - 2 - yl]phenoxazine.

15. 2 - Methoxy -10-[l-(l- pyrrolin - 2 - yl) - 2 - pyrrolin 2 - yl]phenoxazine.

16. 10 - [5 - Methyl -1-(5- methyl - 1 - pyrrolin - 2 - yl) 2 - pyrrolin - 2 - yl] - 2 - (trifluoromethyl)phenothiazine.

17. A pharmaceutically acceptable acid addition salt of a compound as claimed in any one of claims 1 to 16.

18. A method for producing an amidine compound as claimed in claim 1, or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting a compound of fche Formula IX H (II) wherein X and Y are as defined in claim 1 with a pyrrolidinone of the Formula III wherein R is as defined in claim 1, in the presence of phosphorus oxychloride and in a reaction-inert solvent; or reacting said compound of formula II with 2 - chloro -1-(1- pyrrolin - 2 yl) - 2 - pyrroline hydrochloride in a reaction-inert solvent; and when the acid addition salt is desired, converting the amidine free 43408 base reaction product to the corresponding pharmaceutically acceptable aei.d addition salt by methods known in the art.

19. Λ method as claimed in claim 18 wherein the compound of formula 111, (.lie phosphorus oxychloride anti the compound of 5 formula II arc respectively reacted in a molar ratio of 1 to 2:1:1.

20. A method as claimed in claim 18 or claim 19 wherein the reaction is carried out at a temperature of from about 0°C. to 150°C.

21. A method as claimed in claim 20 wherein the reaction is carried out. at a temperature of from 25°C to 35°C. 10

22. A method as claimed in any one of claims l8 to 21 wherein the reaction-inert solvent is 1,2 - dichloroethane, benzene, chloroform, carbon tetrachloride, 1,1 - dichloroethane, hexane or xylene

23. A method as claimed in any one of claims 18 to 22 which included the step of separating Lhe reaction product from monomeric 15 pyrrolinyl byproduct by solvent extraction or distillation.

24. A method ns claimed in claim 18 substantially as hereinbefore described with reference to any one of the foregoing Examples.

25. A compound of Formula I as claimed in Claim 1 whenever produced by a process as claimed in any one. of claims 18 to 24. 20

26. A pharmaceutical composition which comprises a compound as claimed in any one of claims 1 to 16, or claim 25, or a salt as cLaimed in claim 17, together with a pharmaceutically acceptable diluent or carrier.

27. A pharmaceutical composition as claimed in claim 26 which is 25 in unit dosage form,

28. A pharmaceutical composition as claimed in claim 26 or claim 27 substantially as hereinbefore described.

29. A method for producing a diuretic, anti-thrombogenic or intestinal smooth muscle relaxant effect in a mammal other than 30. A human being which comprises parenterally or orally administering to said mammal an amount effective to produce said effect of a 31. 48408 compound claimed in claim 1 or a pharmaceutically acceptable acid addition salt thereof.

30. A method as claimed in claim 29 wherein the compound or salt thereof is administered to the mammal in a dose, based on 5 the free base, or from about 0.01 to 30 mg./kg. of body weight of the mammal.