CA1071195A - 10-imidoylacridans - Google Patents

Abstract

Abstract of the Disclosure Novel 10-imidoylacridans are prepared by reacting an acridan having optional substituents selected from the group consisting of trifluoromethyl, halogen, dihalogen, alkyl or alkoxy with an imidoyl halide prepared in situ from amides and lactams. Illustrative embodiments are 9,9-dimethyl-10-(5-methyl-l-pyrrolin-2-yl)acridan. The imidoylacridan products are generally useful as smooth muscle relaxants.

Description

107119~ ~

10-I~IDOYLACRIDANS

Background of the Invention This invention pertains to heterocyclic carbon compounds which have drug and bio-affecting properties. In particular, this invention relates to 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 inven-tion 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-imidoylacridans.

~ .
'.

. . . - : . .. ' :
- ' ' : . ' ' ~07119S

We have previously disclosed lO-imidoylphenothiazines in our United States patent No. 3,719,671, March 6, 1973 as being of interest for their intestinal relaxant and antithrombogenic activity.
We have now unexpectedly discovered that another class of amidines, namely 10-imidoylacridans and their salts, have smooth muscle relaxant activity and, in some instances, antithrombogenic activity.

Summary of the Invention This invention is broadly concerned with a group of amidines incorporating the acridan heterocycle ~ore particularly, the invention pertains to the preparation of 10-imidoylacridans of Formula I and non-toxic pharmaceutically acceptable acid addition salts thereof.
':

Y (I) The substances represented by Formula I are novel compo-sitions of matter and are useful as smooth muscle relaxants and, in some instances, as inhibitors of platelet aggregation in mammals.
In Formula I, X represents oxygen or a divalent methylene radical of the formula -C(ZlZ2)-. Substituents Zl and Z2 of the methylene radical are independently selected from hydrogen or straight chain lower alkyl of from 1 to 4 carbon atoms inclusive.

:

~ -- 2 ---107~19S

The substituent "Y" represents a member of the group con-sisting of hydrogen, trifluoromethyl, halogen, dihalogen, lower alkyl of 1 to 4 carbon atoms inclusive and lower alkoxy 1 to 4 carbon atoms inclusive.
S A is a substituent selected from the group consisting of an imidoyl moiety represented by -C-N-Rl -C - N
R2 and R3 (CH2) ~ 4 wherein n signifies an integer of 3 to 5, Rl represents a member of the group consisting of lower alkyl of 1 to 4 carbon atoms inclusive and cycloalkyl of 3 to 6 carbon atoms inclusive; R2 represents hydrogen or lower alkyl of 1 to 4 carbon atoms inclusive; R3 and R4 are members independently selected from the group consisting of hydrogen or lower alkyl of 1 to 4 carbon atoms inclusive. It is to be understood that by the terms "lower alkyl" and "lower alkoxy" as used herein, it is meant that the carbon chain which comprises these groups include both straight and branched carbon radicals of 1 to 4 carbon atoms inclusive. Exemplary of these carbon chain radicals are methyl, ethyl, propyl, isopropyl, l-butyl, l-methylpropyl, 2-methyl-propyl, and tert.-butyl. By the term "straight chain lower alkyl"
: as used herein it is meant that the carbon chain is a member of the group comprised of methyl9 ethyl, propyl, and n-butyl radicals. By the term "independently selected" as used herein, it is meant that the R3 and R4 substituents may or may not be identical. By the term "halogen" as used herein, it is meant to connote all members of that group, i.e., chlorine, bromine, fluorine, and iodine.

. . '~

The compounds of Formula I are basic and in some instances crystalline compounds, which are practically insoluble in water, but have substantial solubility in most organic solvents and in aqueous solutions of organic or inorganic acids. Conversion of the imidoylacridan bases of Formula I to corresponding non-toxic pharmaceutically acceptable acid addition sslt is accomplished by admixture of the base with a selected acid in an inert organic solvent such as ethanol, benzene, ethyl acetate, ether, halogenated hydrocarbons and the like. It is to be understood that, as used herein, the term "non-toxic pharmaceutically acceptable acid addition salt" refers to a combination of a compound of Formula I
with a relatively non-toxic inorganic or organic acid, the anion of which is pharmaceutically ineffective in the usual dosage.
Examples of inorganic or organic acids which may be employed to provide non-toxic pharmaceutically acceptable acid addition salts of the substances of Formula I are: sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, acetic, lactic, maleic, succinic, malic, fumaric, tartaric, citric, gluconic, glutaric, ascorbic, benzoic, cinnamic, methanesulfonic, para-toluenesulfonic, isethionic, and related acids.
A preferred method of salt preparation is to treat the Formula I base with substantially one chemical equivalent of hydrogen chloride in ethanol solution. The imidoylacridan salt precipitates from ethanolic solution upon the addition of anhydrous ether or chilling.
Both the free base and salt forms of the products of Formula I are useful for the purposes of the invention although salts are particularly preferred because of their general water solubility.

~07~195 It will be apparent to those skilled in the art that the amidines of Formula I can exist as stereoisomeric modifications when an asymmetric center is present. For example, in the case of a compound of Formula I wherein the "substituent A" is a pyrrolinyl moiety containing a R3 or R4 substituent other than hydrogen such as

2-chloro-10-(5-methyl-1-pyrrolin-2-yl)acridan, an asymmetric center is present resulting in a racemic modification. Resolution of a racemic modification may be carried out according to conventional procedures by using appropriate optically active acids. It is to be understood that all stereoisomeric forms of the compounds of Formula I
are considered to be within the purview of this invention.
The imidoyl acridans of the present invention characterized by Formula I are prepared by a process which comprises reacting an acridan having Formula II

~ N ~ Y (II) :
with a reactant selected from the group consisting of carboxamides of the formulas OaC-NH-Rl 0=C- NH
' and 3 ~ CH2)n 4 (III) (IV) in the presence of phosphorus oxychloride in a suitable inert organic solvent. The symbols "X" and "Y" in the heterocyclic reactant of Formula II and Rl , R2", "R3", "R4", and "n" in the carboxamide . .

-107~95 reactant have the meanin~s hereinabove described for Formula I.
Suitable carboxamide reactants, by way of example, are:
N-alkylformamides such as:
N-methylformamlde, N-ethylformamide, N-n-propylformamide, N-isopropylformamide, N-n-butylformamide, N-tert.-butylforma;nide;
N-alkylcarboxamides such as:
N-methylacetamide, N-methyl-2-methylpropionamide, N-methylvaleramide, N-lsopropylacetamide;
N-cycloalkylformamides such as:
N-cyclopropylformamide, N-cyclobutylformamide, N-cyclopentylformamide, N-cyclohexyformamide;
N-cycloalkylcarboxamides such as:
N-cyclopropylacetamide, N-cyclohexylacetamide, - N-cyclopentyl-2-methylpropionamide.
In addition, cyclic carboxamides (lactams) can also be employed and include, for example:
2-pyrrolidinone, . 5-methyl-2-pyrrolidinone, 5,5-dlmethyl-2-pyrrolldinone, .

~7119S

3-methyl-2-pyrrolidinone,

4-methyl-2-pyrrolidinone,

5,5-di-n-butyl-2-pyrroliclinone, 2-oxohexamethyleneimine, 2-piperidone,

6-methyl-2-plperidone, 6,6-dimethyl-2-piperidone.
Suitable phenoxazines are:
phenoxazine, 2-(trlfluoro~ethyl)phenoxazine, 2-chlorophenoxazine, 3-chlorophenoxazine, 4-chlorophenoxazine, 2-bromophenoxazine, 2,3-dichlorophenoxazine, 3,4-dichlorophenoxazine, 2-methoxyphenoxa7ine, 4-methoxyphenoxazine, 4-isopropoxyphenoxazine, 2-methylphenoxazine, 4-methylphenoxazine.
Suitable acridans are:
- acridan, 2-chloroacridan, 4-chloroacridan, 2-methoxyacridan, 4-methoxyacridan, 2-(trifluoromethyl)acridan, : .- : . , ~, -.

4-(trifluoromethyl)acridan, 2-methylacridan, 4-n-butylacridan, 9,9-timethylacridan, 2-chloro-9,9-dlmethylacridan, 9,9-dlmethyl-2-(trifluoromethyl)acridan, 9,9-dimethyl-4-methoxyacridan, 9-methyl-2-(trifluoromethyl)acridan, 9-ethyl-9-methylacridan, 9,9-di-n-butylacridan.
In carrying out the process for the preparation of the substances of Formula I, approximate stoichiometric portions of the phenoxazine or scridan heterocycle and appropriate carboxamide and phosphorus oxychloride are mlxed together in an inert aprotic solvent. Solvents which are sultable include chloroform, carbon tetrachloride, l,l-dichloroethane, toluene, hexane, and preferably 1,2-dichloroethane. The mode of addition of the reactants is not critical in carrying out the process. For example, a solution or suspension of a phenoxazine or acridan and a carboxamide in 1,2-dichloroethane can be added to a solution of phosphorus oxychloride in 1,2-dichloroethane or the sequence of addition may be reversed and phosphorus oxychloride neat or dissolved ln 1,2-dichloroethane can be added to a solution of the carboxamide and the phenoxazine or acridan. Alternatively, phosphorus oxychloride csn be first added to the phenoxazine or acridan reactant and a carboxamide reactant then added. Another suitable adaptation of the process is the combination of phosphorus oxychloride with a carboxamide and the addition of this mixture to the heterocyclic phenoxazine or acridan reactant. Combination of the reactants provides an exothermic reaetion and external cooling can be employed to moderate the reactlon, slthouah, this is not necessary for the successful completion of the reaetlon. The reaction of the carboxamide with the heterocyclic phenoxazine or acridan reaetant takes plaee in a facile manner when the reaetants are combined and generally does not require prolonged heatlng for the formation of the substances of Formula I. Although the reaction may be earrled out at a temperature of about O-100C., it i8 generally preferred to slowly add the phosphorus oxychloride to the heteroeyclic phenoxazine or acridan reactant at a temperature in the range of from about 25-35C. with efficient ~tirring followed by a 15 hr. stirring period at room temperature before isolating the protuct.
- Illustrative of the preferred method for preparation of the eompounds of Formula I is addltion of phosphorus oxyehloride to a mixture of phenoxa~ine and 2-pyrrolidinone in 1,2-dichloroethane at 25C. employing equimolar amounts of reactants to provide after stlrring for 15 hr., 10-(1-pyrrolin-2-yl)phenoxazine.
The substances of Formula I are new ehemical substances and have utility as pharmacological agents. They are part~cularly useful for their smooth muscle relaxant effects exhibiting papaverine-like activity. Apart from smooth muscle relaxant activity, the amldines of Formula I have, in some instances, significant anti-thrombogenic properties as demonstrated by the ability to inhibit platelet ag~regation caused by the addition of adenosine diphosphate or eolla en to hu~an or rabbit plqtelet rich plasma.
Smooth muscle relaxant activity of the a~idines of Formula I
can be measured in standard and accepted in vitro and in vivo pharmacological tests. One such test is carried out essentially as 107~195 follows. A segment of the rabbit ileum is suspended in oxygenated Tyrode's solution and affixed to a tenslon transducer for electronic recordlng of isometric contractions. After control responses to a standard dose of a spasmogen such as barium chloride (0.25 mg./ml.) are established, the imldoylphenoxazine or lmidoylacrldan is added snt response to the spasmogen, in the presence of the heterocycllc amldine test agent, agaln determined. ~est compound effect is measured as a perc~ntage reduction in the response to the spasmogen in the presence of the test compounds, from the mean control response.
A mlnimum of three trlals is carried out at each of 2 to 5 different concentrations of test compound. The data obtained is expressed in log dose response curves and estimates therefrom of the EC~o or EC, 5 (concentration causing 50% or 75% reduction in the response of the tl6sue to the spasmogen).
The imidoylphenoxa7ines and lmidoylacrldans of the present inventlon have substantial activity ln this test. Wlth respect to potency, the substances of Formula I are equal to or have greater potency than papaverlne ln this test. As might be expected, certain of the compounds are more actlve than others. For example, 9,9-20 tlmethyl-10-(5-methyl-1-pyrrolln-2-yl)acridan hydrochloride has an antlspasmodic potency of 2 to 10 ~imes that of papaverine. Compounds such as:
10-C2~ pyrrolinyl)]acridan, 10-C2-(5-methyl-1-pyrrollnyl)~acridan, 10-C2-(5,5-dimethyl-1-pyrrollnyl)~acrldan, 10-C(3,4,5,6-tetrahydro-2-pyridyl)~acridan, 10-(isopropylimlnomethyl)acridan, 10-(5-metl-yl-1-pyrrolin-2-yl)phenoxazine, are equal in potency to papaverine in the foregoing in vitro test.
In the guinea pig isolated trachea smooth muscle preparation, 10-(5-methyl-1-pyrrolin-2-yl)phenoxazine was 2.8 S tlmes more potent than aminophylline, a well-known smooth muscle relaxant.
Apart from smooth muscle relaxant activity, some of the amidine heterocyclics of Formula I are antithrombogenic agents as demonstrated in such standard antithrombogenic tests as described by Born, ~ature, 194, 927 (1962) and O'Brien, J. Clin. Path., 15, 446 (1962).
The amidines of Formula I and non-toxic pharmaceutically acceptable salts thereof may be administered to ~ammals either singly or ln combination with other pharmacological active ingredients.
Routes of administration include parenteral as well as oral.
Pharmacological effects, particularly smooth muscle relaxant ac.ivity, -are obtained at non-toxic effective doses of the compounds of Formula I
ranglng from about 0.01 to 10 mg./kg. body weight. With respect to total daily dose, optimum smooth muscle relaxant effects are obtained at non-toxic effective doses of the compounds of Formula I ranging from about 0.05 to 100 mg./~g. body weight. It is to be understood that the term "non-toxic effective dose" as used herein refers to the quantlty of active ingredient necessary to produce the desired therapeutic effect wlthout causing any harmful or deleterious side effects. Whether singly or in combination, the subst~nces of Formula I may be used in the usual pharmaceutical forms.
Oral toxicity values (LD50) of the substances of Formula I
in mice range from about 00 to 1000 mg./kg. of body weight. For ~)71~95 instance, the LD50 value (mg.lkg. body weight) is 250-500 for 10-~2-(5-methyl-1-pyrrolinyl)]~cridan hydrochloride; 100 for 10-~2-(5,5-dimethyl-1-pyrrolinyl)~acridan hydrochloride; 200 for 10-(lsopropyliminomethyl)acridan and; 250-500 for 9,9-dimethyl-10-(5-methyl-1-pyrrolin-2-yl)acridan hydrochloride.
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, tablets, pills, capsules, powders, granules, emulsions, suspensions, and the like.
The solid preparations contain the active lngredient in admixture with non-toxic pharmaceutical excipients such as inert diluents, for example calclum 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 accacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by kno~n techniques so as to defy disintegration ant absorption in the gastrointestinal tract and thereby provide a euetained action over a longer period.
Liquld preparations suitable for parenteral administration lnclude solutions, suspensions, or emulsions of the compounds of Formula I. The aqueous suspensions of the pharmaceutical dosage forms of the compounds of Formula I contain the active ingredient in admixture with one or more non-toxic pharmaceutical excipients kno~ to be suitable in the manufacture of aqueous suspensions. Suitable excipients are, for example, suspending agents such as sodium carbox~ethylcellulose, methylcellulose, h~dro~ypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum accacia. Suitable dispersing or 107~95 wetting agênts are naturally occurring phosphatides, for example lecthin, polyoxyethylene stearate.
Non-aqueous suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive S oil, sesame oil or coconut oil, or in a mineral oil, for example liquid paraffin. The suspensions may contain a thickening agent such as bees wax, hard paraffin or cetyl alcohol. Sweetening and flavoring sgents generally used in pharmaceutical compositions may also be lncluded 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 further lllustrate the present invention ; and will enable others skilled in the art to understand it more completely.
lS It ls to be understood, however, that the invention is not llmited solely to the partlcular examples given belo~J.
In regard to "~IR" data, the following notations are employed:
æ ~ singlet, d = doublet, dd = doublet of doublets, t = trlplet, s-7 =
septet, m ~ multiplet, bs - broad singlet. The solvent and internal ; 20 reference peak, e.g., IMS (tetramethylsilane) is also given.

Exa~ple 1.- Phosphbrus oxychloride (3.8 g., 0.025 mole) is added ln 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 255. After stirring the reaction mixture for 15 hr., the reaction mixture is quenched in a mlxture of 30 ml. of 5~ sodium hydroxide and 30 g. of crushed ice. The organic layer is separated, extracted with 100 ml. of 1.5~ hydrochloric acid, made basic with sodium hydroxide and extracted with ether. After drying the ethereal extract over magnesium . .

- ~7~ 95 sulfate and concentratlng, the residue thus obtained is crystallized from n-heptane to provlde 4.2 g. of 10-(1-PYRROLIN-2-YL)PHENOXAZINE
free base, m.p. 110-113C. The free base taken up in ethanol, acidified with ethanolic hydrogen chloride and diluted with ether provides a 37% yield of 10-(1-PYRROLI~-2-YL)PHE~OXAZINE HYDROCHLORIDE as a monohydrate, m.p. 214-217C. (corr.).
Analvsis. Calcd. for C,6H,4N~O-HCl-H~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.
N~ delta (ppm) tD~SO-D6, rMS reference): 2.13m, 3.27t (7.2), 3.38s, 3.75t (7.0), 7.3m, 7.7m, 10.63bs.

Lxample 2.- Reaction of phenoxazine with 5-methyl-2-pyrrolidinone according to the procedure of Exampla 1 affords the free baqe 10-(5-METHYL-l-PYRROLIN-2-YL?PHE~OXAZI~E, m.p. 135-137C., from n-heptane. Conversion of the free base to the hydrochloride 8alt provides 10-(5-~THYL-l-PYRROLIN-2-YL)PHE~OXAZINE HYDROCHLORIDE, m.p. 229.5-236.0C. (dec.) (corr.), in a 57% overall yield.
Analysis. Calcd. for C~7H~6N2O-HCl (percent): C, 67.88;
H, 5.70; N, 9.32; Cl, 11.78. Found (percent): C, 67.79; H, 5.71;
~, 9.39; Cl, 11.75.
NMR delta (ppm)tcDcl3~ TMS reference): 1.57d t6.3), 2.22m, 3.27m, 4.54m, 7.2m, 7.8m, 11.65bs.

Example 3.- Reactlon of phenoxazine 5 5-dimethyl-2-.
pyrrolidinone and phosphorus oxychloride according to the procedure 25 of Example 1 provides the free base 10-(5,5-DI~THYL-l-PYRROLI~-2-YL)-PHE~O~YAZI~E, m.p. 148-150C. Conversion of the free base to the hydrochloride salt affords 10-(5,5-DI~ET13YL-l-PYRROLI~-2-YL)PHE~OXAZI~E

HYDROCHLORIDE, m.p. 239-242.5C. (corr.), in a 48~ overall yleld.

Analysls. Calcd. for CI~H~oN~O-HCl (percent): C, 68.67;
H, 6.08; N, 8.90; Cl, 11.27. Found (percent): C, 68.50; H, 6.21;
N, 8.75; Cl, 11.24.
NMR delta (ppm)(CDCl3, TMS reference): 1.69s, 2.05t t7.5), 3.26t (7.5), 7.2m, 7.8m, 11.80bs.

Exa~ple 4.- Reaction of 2-ttrifluoromethyl)phenoxazine, 2-pyrrolidinone and phosphorus oxychloride accordir.g to the procedure of Example 1 provides the free base 10~ PYPROLIN-2-YL)-2-(TRIFL~ORO-METHYL)PHE~OXAZINE as a distillable oil, b.p. 140-146C. at 0.1 mm Hg.
Converslon of the free base to the hydrochloride salt affords 10-(1-PYRROLIN-2-YL)-2-(TRIFLUORO~ETHYL)PHENO~AZINE HYDROCHLORIDE, m.p.
219.5-222.5C. (dec.)(corr.), in a 62% overall yield by triturating wlth war~ benzene.
Analysls. Calcd. for C~,HI~F9N20-HCl (percent): C, 57.55;
H, 3.98; N, 7.90; Cl, 9.99. Found (percent): C, 57.60; H, 4.14;
N, 7.63; Cl, 9.77.
NMR delta (ppm)(CDCl~, TMS reference): 2.27m, 3.31t (7.4), 4.11t (7.0), 7.2m, 7.9m.

Example 5.- Reaction of 2-(trifluoromethyl)phenoxazlne, 5-methyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 10-(5-~IETHYL-l-PYRROLIN-2-YL)-2-(TRIFLUORO`IETHYL)PHENOXAZINE as a distillable oil, b.p.
145-152C. at 0.03 mm H~. Conversion of the free base to the hydrochloride 6alt affords 10-(5-METHYL-l-PYRROLIN-2-YL)-2-(TRIFLUORO~ETHYL)PHENOXAZINE
~YDROCHLORIDE, m.p. 192.5-195.5C. (dec.) (corr.)., in a 45% overall yield.

~ 15 -." ' . '.

107~L195 Analysis. Calcd. for C,~H,,F3N,O-HCl (percen~): C, 58.62;
H, 4.37; N, 7.60; Cl, 9.61. Found (percent): C, 58.61; H, 4.42;
N, 7.41; Cl, 9.31.
NMR delta (ppm)(CDCl3, TMS reference): 1.57d (6.2), 1.97m, 3.26m, 4.54m, 7.3m, 8.0m.

Example 6.- Reaction of 2-(tr~fluoromethyl)phenoxazine, 5,5-dlmethyl-2-pyrrolldinone and phosphorus oxychloride according to ~he procedure of Example 1 provides the free base 10-(5,5-DIMETHYL-l-PYRROLIN-2-YL)-2-(TRIFL~'OROMETHYL)PHE.NOXAZI~E, m.p. 64-67C. Conversion of the free base to the hydrochloride salt affords 10-(5,5-DI`METHYL-l-PYRROLIN-2-YL)-2-(TRIFL~'OROMETHYL)PE~ENOXAZI~E HYDROCHLORIDE, m.p.
204.5-207.5C. (dec.) (corr.), in a 30~ overall yield.
AnalYsis. Calcd. for C,9Hl,F3N2O-HCl (percent): C, 59.61;
H, 4.74; N, 7.32; Cl, 9.26. Found (percent): C, 59.37; H, 4.78;
15 N, 7.12; Cl, 9.11.
NMR delta (ppm) (CDCl3, IMS reference): 1.70s, 2.10t (7.5), 3.27t t7.5), 7.4m, 12.00bs.

Example 7.- Reaction of 2-chlorophenoxazine, 2-pyrrolidinone, ' and phosphorus oxychloride according to the procedure of Example 1 provites the free base 2-CHLORO-10-(1-P~'RROLIN-2-YL)PHENOXAZINE as a distillable oil, b.p. 150-165C. at 0.1 mm Hg. Conversion of the free base to the hydrochloride salt affords 2-CHLORO-10-(1-PYRROLIN-2-YL)-PHENO.YAZINE HYDROCHLORIDE, m.p. 209.5-213.5C. (corr.), in a 40 overall yield.
Anal~sis. Calcd. for C,6H~3ClN2O-HCl (percent): C, 59.82;
H, 4.39; N, 8.72; Cl, 22.09. Found (percent): C, 59.71; H, 4.44;
N, 8.50; Cl, 21.97.

' 1o7ll9s NMR delta (ppm)(DMSO-d6, TMS reference): 2.13m, 3.27t (7.5), 3.75t (7.0), 7.3m, 7.7m, 10.67bq.

. Example 8.- Reaction of 2-chlorophenoxazine, 5-methyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of S Example 1 provides the free base 2-CHLORO-10-(5-METHYL-l-PYRROLIN-2-YL)-PHENOXAZINE as a distillable oil, b.p. 150-170C. at 0.1 mm Hg.
Conversion of the free base to the hydrochloride salt affords 2-CHLORO-10-(5-~1ETHYL-l-PYRROLIN-2-YL)PHENOXAZI~IE HYDROCHLORIDE, m.p. 213.5-215.5C., as a crystalline solid in a 34~ overall yield by refluxing with benzene.
Analysis. Calcd. for C "H~ClN2O-HCl (percent): C, 60.90;
X, 4.81; N, 8.36; Cl, 21.16. Found (percent): C, 60.79; H, 5.01;
N, 8.28; Cl, 20.78.
NMR delta (ppm)(CDCl3, TMS reference): 1.58d (6.2), 2.23m, 3.34m, 4.58m, 7.2m, 7.8m, 12.03bs.

.
Example 9.- Reaction of 2-chlorophenoxazine, 5,5-dimethyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provid~s 2-CHLORO-10-(5,5-DIMETXXL-l-PYRROLIN-2-YL)-PHENOXAZINE, m.p. 118-120C., from ethanol.

Analysis. Calcd. for C~AH~,ClN2O tpercent): C, 69.11;.

H, 5.48; N, 8.96; Cl, 11.34. Found ~percent): C, 68.89; H, 5.41;

~, 8.85; Cl, 11.01.

NMR delta (ppm)(CDCl3, TMS reference): 1.28s, 1.78t (7.5), 2.81t (7.5), 6.9m, 7.25m, 7.53dd (1.8, 0.53.

~ .- Reaction of 4-chlorophenoxazine, 5-methyl 2-pyrrolldinone and phosphorus oxychloride according to the procedure of Example 1 provldes the free base 4-CHLORO-10-(5-METHYL-l-PYRROLIN-2-YL)PHE~OXAZINE, m.p. 120-122C., from ethanol. Conversion of the 10'7~95 free base to the hydrochloride salt affords 4-CHLORO-10-(5-~HYL-l-PYRROLIN-2-YL)PHENO~AZI~iE HYDROCHLORIDE, m.p. 228-230C., (dec.) (corr.), by trituration with hot benzene.
Analysis. Calcd. for Cl7H "ClN2O-HCl (percent): C, 60.90;
H, 4.81; N, 8.36; Cl, 21.16. Found (percent): C, 60.85; H, 4.90;
N, 8.22; Cl, 20.94.
~ ~ delta (ppm)(CDCl3, TMS reference): 1.57d (6.4), 2.17m, 3.30m, 4.60m, 7.3m, 7.9m, il.70bs.

Example 11.- Reaction of 2-methoxyphenoxazine, 5-methyl-2-pyrrolidir.one and phosphorus oxychloride according to the procedure - of Example 1 provides the free base 2-~THOXY-10-(5-METHYL-l-PYRROLIX-2-YL)PHEN0XAZINE as an oll. Conversion of the free base to the hydrochlor$de salt affords 2-METHOXY-10-(5-~THYL-l-PYRROLIN-2-YL)-PHENOXA2INE HYDROCHLORIDE, m.p. 223.5-224.5C. (dec.)(corr.), as the hemihydrate by trituration with acetone.
Analysis. Calcd. for C~8Hl3N2o2~HCl-l/2 H20 (percent):
C, 63.62; H, 5.92; N, 8.25; Cl, 10.42. Found (percent): C, 63.96;
H, 6.40; N, 7.99; Cl, 10.05.
NMR delta (ppm)(D2O, HDO reference): 1.18d (6.1), 2.18m, 2.77m, 3.81s, 3.95m, 7.1m.

Example 12.- Reaction of phenoxazine, 2-piperidone, and phosphorus oxychloride accortin~ to the procedure of Example 1 provides 10-(3,4j5,6-TETRAHYDRO-2-PYRIDYL)PP.ENOXAZIXE 8YDROCHLORIDE, m.p.
218.5-221~C. (corr.), in a 27% overall yield from absolute ethanol.
Analysis. Calcd. for C,7H,6N20-HCl (percent): C, 67.88;
8, 5.70; N, 9.30; Cl, 11.78. Found (percent): C, 67.51; H, 5.68;
N, 9.19; Cl, 11.69.

NMR delta (ppm)(CDCl~, TMS reference): 1.87m, 2.84m, 3.83m,

7.2m, 7.7m, 10.77bs.

~o7~95 Example 13.- Reaction of acridan, 2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 10-C2-(l-PYRROLINYL)~ACRIDAN, m.p. 130-132C., from n-heptane. Conversion of the free base to the hydrochloride salt affords 10-[2-(1-PYRROLINYL)]ACRIDAN HYDROCHLORIDE as the hemihydrate, m.p. 251-252C. (dec.).(corr.), from ethanol-ether in a 42% overall yield.
al~sis. Calcd. for C "Hl~N2-HCl-l/2 H20 (percent): C, 69.50;
- H, 6.18; N, 9.53; Cl, 12.07. Found (percent): C, 69.74; H, 6.29;
- 10 N, 9.50; Cl, 12.17.
NMR delta (ppm)(D20, HDO reference): 2.25m, 3.05m, 3.57s, 3.86t (7.0), 7.4m.

Example 14.- Reaction of acridan, 5-methyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 15 provides the free base 100[2-(5-METHYL-l-PYRROLINYL)~ACRIDAN, m.p.
107-109C. Conversion of the free base to the hydrochloride salt afford4 1O-C2-(5-~THYL-1-PYRROLI.~L)]ACRIDAN' HYDROCHLORIDE, m.p.
203.5-206C. (dec.) (corr.), by trituration with hot benzene in a 33~ overall yield.
AnalYsis. Calcd. for Cl~H:8N2-HCl (percent): C, 72.35;
H, 6.41; N, 9.38; Cl, 11.86. Found (percent): C, 72.38; H, 6.46;
N, 9.37; Cl, 11.67.
NMR delta (ppm)(D20, HDO reference): 1.26d (6.3), 2.01m, 2.93m, 3.68s, 4.14m, 7.3m.

Example 15.- Reaction of acridan, 5,5-di~ethyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 10-C2-(5,5-DI`ETHYL-l-P~RROLINYL)]-.

107~195 ACRID~N, m.p. 84-86C. Conver~ion of the free base to the hydrochloride salt affords 10-[2-(5,5-DI~THYL-l-PYRROLI~YL)~ACRID~N HYDROCHLORIDE, m.p. 266.5-267C. (dec.) (corr.), by triturating first with acetone and then crystalllzing from ethanol-ether in a 31~ overall yield.
AnalYsis. Calcd. for Cl9H~oN2~HCl tpercent): C, 72.94;
H, 6.77; N, 8.96; Cl, 11.33. Found (percent): C, 73.14; H, 6.64;
~, 8.81; Cl, 11.31.
NMR delta (ppm)(D20, HDO reference): 1.39s, 2.01t (7.5), 3.07m, 3.72s, 7.4m.

Exampl~ 16.- Reaction of acridan, 2-piperidone and phosphorus oxychloride accordin~ to the procedure of Example 1 provides the free base 10-(3,4,5,6-TETRAHYDRO-2-PYRIDYL)ACRIDA~ as a distillable oll, b.p. 145-150C. at 0.15 m~ Hg. Conversion of the free base to the hydrochloride salt affords 10-(3,4,5,5-TETR~HYDRO-2-PYRIDYL)ACRIDAI~
HYDROCHLORIDE as the hemihydrate, m.p. 190.5-192.5C. (corr.) by trituratlon with hot benzene in a 19% overall yield.
Analysis. Calcd. for C~oHlsN2-HCl-l/2 H20 (percent): C, 70.23;
H, 6.55; N, 9.10; Cl, 11.52. Found (percent): C, 70.12; H, 6.15; N, 9.16;
Cl, 11.56.
NMR delta (ppm)~D20, HDO reference): 1.73m, 2.72m, 3.38m, 3.71s, 7.3m.

Example 17.- Reaction of acridan, isopropylformamide and phosphorus oxychloride according to the procedure of Example 1 provides the free base 10-[(ISOPROPYLI~ITNO)`ETHYL]ACRIDAN, m.p. 149.5-150.5C. (corr.), from n-hexane.
Analysis. Calcd. for Cl,HI~N2 (percent): C, 81.56; H, 7.25;
N, 11.19. Found (percent): C, 81.86; H, 7.23; N, 11.18.

.

- ~071195 NMR delta (ppm)(CDCl3, TMS reference): 1.23d (6.3), 3.48s_7 (6.3), 3.82s, 7.2m, 7.8m, 8.30s.

Example 18.- Reaction of 9,g-dimethylacridan, 5-methyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provldes the free base 9,9-DI~THYL-10-(5-~ETHYL-l-PYRROLIN-2-YL)ACRIDA~ as a distillable oil, b.p. 160-180C. at 0.15 ~m Hg. in 11~ yield. Conversion of the free base to the hydrochloride 8alt affords 9,9-DIMETHYL-10-(5-~THYL-l-PYRROLIN-2-YL)~CRID~
HYDROCHLORIDE, m.p. 232.5-234.5C. (dec.) (corr.), by trituration with hot benzene.
Analysis. Calcd. for C20H22N2-HCl (percent): C, 73.49;
H, 7.09; N, 8.57; Cl, 10.85. Found (perce~t): C, 73.39; H, 7.04;
N, 8.-74; Cl, 10.63.
NMR delta (ppm)(DMSO-d6, TMS referencej: 1.35d (6.4), 1.59s~ 1.75m, 3.32m, 4.36m, 7.6m, 10.63bs.

Example 19.- Reaction of the enumerated phenoxazines and carboxamides in the presence of phosphorus oxychlorlde according to the procedure of Example 1 provides the following amidine products of Formula I:
~a) 3-chloro-10-(5-methyl-1-pyrrolin-2-yl)phenoxazine from 3-chlorophenoxazine and 5-methyl-2-pyrrolidinone;
; (b) 2,3-dichloro-10-(5-methyl-1-pyrrolin-2-yl)phenoxazine from 2,3-dichlorophenoxazine and 5-methyl-2-pyrrolidinone;
(c) 3,4-dichloro-10-(5-methyl-1-pyrrolin-2-yl)phenoxazine from 3,4-dichlorophenoxa7ir.e and 5-methyl-2-pyrrolidinone;
(d) 4-methoxy-10-(1-pyrrolin-2-yl)phenoxazine from 4-methoxy-phenoxazine and 2-pyrrolidinonc;

, .

' 107~195 (e) 4-lsopropoxy-10-(1-pyrrolin-2-yl)phenoxazine from 4-isopropoxyphenoxazine and 2-pyrrolidinone;
tf) 2-methyl-10-(1-pyrrolin-2-yl)phenoxazine from 2-methyl-phenoxazine and 2-pyrrolidinone;
(g) 4-methyl-10-(1-pyrrolin-2-yl)phenoxazine from 4-methyl-phenoxazine and 2-pyrrolidinone;
(h) 4-n-butyl-10-(1-pyrrolin-2-yl)phenoxazine from 4-n-butyl-phenoxazine and 2-pyrrolidinone;
(1) 2-bromo-10-(1-pyrrolin-2-yl)phenoxazine from 2-bromo-phenoxazlne and 2-pyrrolidinone;
(~) 10-(4-methyl-1-pyrrolin-2-yl)phenoxazine from phenoxazine and 4-methyl-2-pyrrolidinone;
(k) 10-(5,5-di-n-butyl-1-pyrrolin-2-yl)phenoxazine from phenoxazine and 5,5-di-n-butyl-2-pyrrolidinone;
(1) 10-C(methylimino)methyl~pheDoxazine from phenoxazine and ~-methylformamide;
~m) 10-C(cyclopropylimino)methyl]yhenoxazine from phenoxazine and N-cyclopropylformamide;
(n~ 10-C(cycloyen~ylimino)methyl]phenoxazine from phenoxazine snd N-cyclopentylformamide;
(o) 10-C(cyclohexylimino)methyl]phenoxazine from phenoxazine ant N-cyclohexylformamide;
(p) 10-Cl-(l-cyclohexylimino)ethyl]phenoxazine from phenoxazine and N-cyclohexylacetamlde;
(q) 10-Cl-(methylimino)ethyl]phenoxazine from phenoxazine and N-methylace~amide;
(r) 4-chloro-10-Cl-(methylimino)-2-methylpropyl]phenoxazine from 4-chlorophenoxazine and N-me~hyl-2-methylpropionamide;

,~

~o7~95

(8) 10-[1-tmethylimino)-n-pentyl]phenoxazine from phenoxazine and n-methylvaleramide;
(t) 10-(6-methyl-3,4,5-trihydro-2-pyridyl)phenoxazine from phenoxazine and 6-methyl-2-piperidone;
tu) 10-(6,6-dimethyl-3,4,5-trihydro-2-pyridyl)phenoxazine from phenoxazine ant 6,6-dimethyl-2-plperidone;
(v) 10-C7-(3,4,5,6-tetrahydro-2H-azepinyl)]-2-(trifluoromethyl)-phenoxazine from 2-(trifluoromethyl)phenoxazine and 2-oxohexamethyleneimine.
.
Example 20.- Reaction of the enumerated acridan and carboxamide in the presence of phosphor.us oxychloride according to the procedure of Example 1 provides the follo~ing amidine products - of Formula I:
ta) 2-methoxy-10-(1-pyrrolin-2-yl)acridan from 2-methoxy-acridan and 2-pyrrolidinone;
lS (b) 4-methoxy-10-C(methylimino)methyl~acridan from 4-methoxyacridan and N-methylformamide;
(c) 2-chloro-lo-cl-(methylimino)ethyllacridan from 2-chloro-scridan and N-methylacetamide;
(d) 4-chloro-10-C(cyclopropylimino)methyl~acridan from 4-chloroacrldan and N-cyclopropylacetamide;
(e) 10-C(cyclohexylimino)methyl }2-(trifluoromethyl)acridan from 2-ttrlfluoromethyl)acridan and N-cyclohexylormamide;
(f) 10-~(isopropylimino)methyl }4-(trifluoromethyl)acridan from 4-(trlfluoromethyl)acrldan and N-isopropylformamide;
(g) 2-chloro-9,9-dimethyl-10-(5,5-dimethyl-1-pyrrolin-2-yl)-acridan from 2-chloro-9 t 9-dimethylacridan and 5,5-dimethyl-2-pyrrolidinone;

10'7~95 (h) 9,9-dimethyl-10-(4-methyl-1-pyrrolin-2-yl)-2-(trifluoro-methyl)acridan from 9,9-dimethyl-2-(trifluoromethyl)acridan ant 4-methyl-2-pyrrolidinone;
(i) 9,9-dimethyl-4-methoxy-10-(3,4,5,6-tetrahydro~2-pyridyl)-aeridan from 9,9-dimethyl-4-methoxyacridan and 2-piperidone;
~ ) 2-methyl-10-(6-methyl-3,4,5-trihydro-2-pyridyl)acridan from 2-methylacridan and 6-methyl-2-piperidone;
(k) 4-methyl-10-(6,6-dimethyl-3,4,5-trihydro-2-pyridyl)acridan from 4-methylacridan and 6,6-dimethyl-2-piperidone;
(1) 4-n-butyl-10-[7-(3,4,5,6-tetrahydro-2H-azepinyl)~acridan from 4-n-butylacridan and 2-o~ohexamethyleneimine;
(m) 9-methyl-10-(1-pyrrolin-2-yl)-2-(trifluoromethyl)acridan from 9-methyl-2-(trifluoromethyl)acridan and 2-pyrrolidinone;
tn) 9-ethyl-9-methyl-10-(1-pyrrolin-2-yl)acridan from

9-ethyl-9-methylacridan and 2-pyrrolidinone;
(o) 9,9-di-n-butyl-10-(1-pyrrolin-2-yl)acridan from 9,9-ti-n-butylacridan and 2-pyrrolidinone.
While specific embodiments are disclosed in the foregoing speeifleation, it will be appreciated that other modifications may be made without departing from the spirit and scope of the appended elaims.

:
.

Claims (24)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing 10-imidoylacridans having the formula (I) wherein X represents a divalent methylene radical of the formula -C(Z1Z2)- in which Z1 and Z2 are independently selected from hydrogen or straight chain lower alkyl of from 1 to 4 carbon atoms inclusive;
Y represents hydrogen, trifluoromethyl, halogen, dihalogen, lower alkyl of 1 to 4 carbon atoms inclusive, lower alkoxy of 1 to 4 carbon atoms inclusive; and A is selected from the group consisting of and wherein R1 is lower alkyl of 1 to 4 carbon atoms inclusvie or cycloalkyl of 3 to 6 carbon atoms inclusive;
R2 is hydrogen or lower alkyl of 1 to 4 carbon atoms inclusive;

R3 and R4 are independent members selected from the group consisting of hydrogen or lower alkyl of 1 to 4 carbon atoms inclusive;
n is an integer of 3 to 5;
which comprises reacting in the presence of phosphorus oxychloride in a suitable inert organic solvent an acridan having the formula (II) with a carboxamide of the formula or (III) (IV) wherein X, Y, R1, R2, R3, R4 and n are as stated above; and when a salt is desired, reacting the product of Formula (I) with an acid.

2. 10-Imidoylacridans having the formula (I) wherein X represents a divalent methylene radical of the formula -C(Z1Z2)- in which Z1 and Z2 are independently selected from hydrogen or straight chain lower alkyl of from 1 to 4 carbon atoms inclusive;
Y represents hydrogen, trifluoromethyl, halogen, dihalogen lower alkyl of 1 to 4 carbon atoms inclusive, lower alkoxy of 1 to 4 carbon atoms inclusive; and A is selected from the group consisting of and wherein R1 is lower alkyl of 1 to 4 carbon atoms inclusive or cycloalkyl of 3 to 6 carbon atoms inclusive;
R2 is hydrogen or lower alkyl of 1 to 4 carbon atoms inclusive;
R3 and R4 are independent members selected from the group consisting of hydrogen or lower alkyl of 1 to 4 carbon atoms inclusive;
n is an integer of 3 to 5, when prepared by the process of Claim 1.

3. A process as claimed in Claim 1 which comprises reacting acridan and 2-pyrrolidinone.

4. 10-[2(1-Pyrrolinyl)]acridan when prepared by the process of Claim 3 or an obvious chemical equivalent thereof.

5. A process as claimed in claim 1 which comprises reacting the product of acridan and 2-pyrrolidinone with hydrochloric acid to form the hydrochloride salt thereof.

6. 10-[2-(1-Pyrrolinyl)]acridan hydrochloride when prepared by the process of Claim 5 or an obvious chemical equivalent thereof.

7. A process as claimed in Claim 1 which comprises reacting acridan and 5-methyl-2-pyrrolidinone.

8. 10-[2-(5-Methyl-l-pyrrolinyl)]acridan when prepared by the process of Claim 7 or an obvious chemical equivalent thereof.

9. A process as claimed in Claim 1 which comprises reacting the product of acridan and 5-methyl-2-pyrrolidinone with hydrochloric acid to form the hydrochloride salt thereof.

10. 10-[2-(5-Methyl-1-pyrrolinyl)]acridan hydrochloride when prepared by the process of Claim 9 or an obvious chemical equivalent thereof.

11. A process as claimed in Claim 1 which comprises reacting acridan and 5,5-dimethyl-2-pyrrolidinone.

12. 10-[2-(5,5-Dimethyl-l-pyrrolinyl)]acridan when prepared by the process of Claim 11 or an obvious chemical equivalent thereof.

13. A process as claimed in Claim 1 which comprises reacting the product of acridan and 5,5-dimethyl-2-pyrrolidinone with hydro-chloric acid to form the hydrochloride salt thereof,

14. 10-[2-(5,5-Dimethyl-l-pyrrolinyl)]acridan hydrochloride when prepared by the process of Claim 13 or an obvious chemical equivalent thereof.

15. A process as calimed in Claim 1 which comprises reacting acridan and 2-piperidone.

16. 10-(3,4,5,6-Tetrahydro-2-pyridyl)acridan when prepared by the process of Claim 15 or an obvious chemical equivalent thereof.

17. A process as claimed in Claim 1 which comprises reacting the product of acridan and 2-piperidone with hydrochloric acid to form the hydrochloride salt thereof.

18. 10-(3,4,5,6-Tetrahydro-2-pyridyl)acridan hydrochloride when prepared by the process of Claim 17 or an obvious chemical equivalent thereof.

19. A process as claimed in Claim 1 which comprises reacting acridan and isopropylformamide.

20. 10-[(Isopropylimino)methyl]acridan when prepared by the process of Claim 19 or an obvious chemical equivalent thereof.

21. A process as claimed in Claim 1 which comprises reacting 9,9-dimethylacridan and 5-methyl-2-pyrrolidinone.

22. 9,9-Dimethyl-10-(5-methyl-1-pyrrolin-2-yl)acridan when prepared by the process of Claim 21 or an obvious chemical equivalent thereof.

23. A process as claimed in Claim 1 which comprises reacting the product of 9,9-dimethylacridan and 5-methyl-2-pyrrolidinone with hydrochloric acid to form the hydrochloride salt thereof.

24. 9,9-Dimethyl-10-(5-methyl-1-pyrrolin-2-yl)acridan hydrochloride when prepared by the process of Claim 23 or an obvious chemical equivalent thereof.