US2645594A - Antiseptic acridane compounds - Google Patents

Description

Patented July 14, 1953 ANTISEPTIC ACRIDANE COMPOUNDS,

Donalee L. Tabern, Lake Bluff, Ill., assignor to Abbott Laboratories, North Chicago, Ill., a corporation of Illinois N Drawing. Application October 19, 1948,

Serial No. 55,424

This invention relates in general to acridine compounds and more specifically to substituted acridine compounds of thefollowing structure, which are more properly called acridanes:

wherein R is an alkyl group containing from one to fourteen carbon atoms inclusive; X is a monovalent radical selected from class comprising hydrogen, halogen, alkyl and alkoxy groups; Y is a hydrocarbon group containing from one to ten carbon atoms inclusive and Z is a mineral acid anion. Other useful compounds of the present invention have also been prepared in which Z is an alkoxy group (the alkyl group of which contains from one to four carbon atoms inclusive), or a hydroxyl group.

The OR group in the above formula may be in any position: ortho, meta or para. For ease in preparation the para compound is often preferred.

It has long been known that various of the acridines have served as antiseptics and germicides. Among the most important of these are proflavine and acrifiavine.

The acridines are characterized by a heterocyclic central ring containing one nitrogen atom as indicated in the structural formula below:

28 Claims. ((1167-65) the Q-carbon, compounds are obtained, which, when converted to suitable salts, such as the halide or sulfate, have unique physiological prope erties. These compounds are usually light yellow to orange in color. They are soluble in Water or in the usual tincture menstra at pH ranges of 3 to 7. These solutions are stable to light and air; remaining unchanged for many months. In the concentrations required for sterilization of the skin or mucous surfaces, they cause little irritation. These compounds penetrate the skin facilitate the isolation and purification of the reaction products.

-The' water-soluble acridane salts are active against a wide variety of organisms both gram positive and gram negative and even against certain pathogenic fungi. Their antiseptic activity persists to a great extent even in the presence of such organic matter as gelatine, sputum and sera. As little as 1 milligram of the compounds of this invention per cc. of saliva acts as an antacid in the mouth which is so important in the prevention of tooth decay. Moreover, most of these compounds are only moderately bitter, and in view of the above stated properties are valuable in treating infections of the throat and mouth.

An increase in the size of the alkyl group of the alkoxy-phenyl substituent from methoxy to n-hexoxy increases the antiseptic power many fold even when in dilutions of 1 to 5,000,000 for the latter compounds. Investigations also indicate that as the size of this chain is increased, the surface tension of the aqueous solutions decreases, giving increased drug penetration. The alkoxy group may be on any position of the phenyl ring: ortho, meta or para. From the standpoint of ease of preparation, the p-alkoxy phenyl compounds are preferred.

The hydrocarbon group Y may be an alkyl, aryl or aralkyl group containing one to ten carbon atoms inclusive. For ease of manufacture 3 and economy, the groups are preferably methyl, ethyl, phenyl, or benzyl. The compounds of the invention may be further substituted in the acridine rings. Also one of these rings may be saturated or heterocyclic.

The processes of synthesizing the substituted anthranilic acids and simple acridones used as intermediates are in general those of the literature. Acridones are characterized by the following structure:

7 ing bomb at 130-140 C. for four hours.

product N-hexyl acridone is isolated as in Exam- For example, acridone may be prepared from phenylanthranilic acid by ring closure with sulfuric acid or with phosphorous pentichloride plus aluminum chloride.

For the preparation of substituted N-alkyl, or aralkyl acridones the processes of the prior art have been found less saisfactory than those that I have discovered. These latter processes are described below:

Process (A) 'O ample below:

EXAMPLE IA About 10 gms. of acridone and gms. of sodium hydroxide are dissolved in alcohol with stirring and heating. Most of the solvent is then distilled off and replaced by a hydrocarbon solvent such as xylene and preferably a solvent boiling between 100 and 150 C. To this solution is added 10 to 15 "gms. of dimethyl sulfate dissolved in dry acetone and the mixture warmed. On cooling the resulting methyl acridone precipitates. The precipitate is then filtered and purified. by crystallization. The yield from this process is from 85-90% of the theoretical.

An alternative process for the preparation of N-alkyl acridones reacts an alkali-metal alcoholate with the acridone to form the alkali-metal salt of the acridone. This product is reacted with an alkyl halide to form the N-alkyl acridone.

This reaction may be illustrated by the following illustration:

+ VROM N/ i l 0 V o l t (I RlX N N it 1's 4 wherein M is an alkali metal, R is an alkyl group, R is an alkyl or aralkyl group and X may be chlorine, bromine or iodine. A specific example to illustrate this process is given below.

EXAMPLE IB About 15 gms. of potassium metal is dissolved in an excess of methyl alcohol. To this solution is added about 50 gms. of acridone and the excess alcohol is removed by distilling with xylene. Hexyl 'chloride'irithe amount of 125 gms. is added to the mixture and the whole heated in a rock- The ple IA and purified by recrystallization from alcohol.

' EXAMPLE IC Iiia manner similar to that of Example IB, N benzyl acridone may be prepared by reacting 'gm's. of the potassium salt of acridone with 2 moles ofbenzyl chloride at -140" C. for nine hours to give 9 gms. of product melting at 181 C.

N-aryl acridones are best prepared from the appropriate triphenylamine carboxylic acids by ring closure.

By the use of the above procedures the N-substituted acridones used as intermediates may be prepared.

Neither do the processes reported in the literature for the preparation of compounds similar to the acridanes of the invention work well. These processes teachusing the Grignard reagent and the result of the process is the formation of an insoluble Grignard complex which will not react further. I have discovered anew process for making 9-a1koxy-phenyl-10-hydrocarbon substituted acridine derivatives which may be outlined as follows: A halo (such as iodo)-aryl-alkoxy compound (I) is reacted with an alkali metal such as lithium in an inert solvent such as ether to form the lithium derivative (II). The lithium derivative reacts rapidly with the N-substituted acridone (III) (see Examples IA, IE, 10) to give the essentially pure acridol (IV) in practically quantitative yields. The reaction product remains'dissolved in the solvent. Addition of gaseous hydrogen halides gives the ether insoluble halide (V) or halo-hydrochloride (VI) which are lemon yellow powders which may be removed by filtration. When the halo-hydrohalide is dissolved in an inert solvent such as chloroform and a neutralizing agent such as dry calcium carbonate is added, which removes the excess acid, a neutral halide acridane (VII) is obtained which is very soluble in water and alcohol. This latter product may also be obtained'by drying the'halohydrohalide with heat.

Some of the mineral-acid anion acridones are diflicult to purify. Therefore, for purification or characterization it maybe convenient to isolate the crude acridols (IV and VIII) by addition of excess alkali to the solution of the halide (V) in water. These acridols upon warming with an alkanol such as methanol give colorless and usually crystalline methoxyl derivatives (IX). The addition of an excess of hydrogen halide will reconvert the methyl ether to the halide (V). Sulfuric acid may be used in this synthesis in place of the hydrogen halide to form the bisulfate. This process may be illustrated by the following reactions with the compounds numbered to conform to the description above:

OR OR I g a L1 I v I a I (1) Li (H) Y (III) OR OR O 20 HZ X y I X N E: III X (IV) Y (V) OR OR zz (I 11 CaCOg alkali X orheat AK f H Y 2 (VI) Y (VII) OR OR OH 00113 I/ I/ C C CHZlOH t Y (VIII) Y (IX) wherein R is an alkyl group containing from one to fourteen carbon atoms inclusive; X is a monovalent radical selected from the class comprising hydrogen, halogen, alkyl and alkoxy groups; Y is a hydrocarbon group containing one to ten carbon atom inclusive; Z is a mineral acid anion such as chlorine, bromine, iodine and sulfate.

In the formulae above it is understood that the aromatic rings may be suitably substituted.

It is possible to write several tautomeric formulae for the products which are the subject of this invention. The ethers are, as has been stated, colorless and possess the structure:

6' By analogy the halide and sulfate derivatives would possess the structure:

These derivatives, on the other hand, are deeply colored. It was shown many years ago [Journal American Chemical Society 48, 1345 (1926)] that in the case of certain related compounds, these derivatives may form by a simultaneous tautomerization to a quinonoid form, expressable in this case as On the other hand, by convention, proflavine i written as containing a pentavalent nitrogen and by analogy these compounds could be represented by Quite obviously, the exact mode of expressing the structure here under discussion is immaterial and for purposes of generalization the formulation Many of these compounds possess quite unexpected physica1 properties. For instance, the

EXAMPLE II 9- (p-n-hexoxyphenyll -10-methyl acridane chloride CsH2a To approximately 1.4 gms. of lithium suspended in 100 cc. of anhydrous ether is added drop-wise about gms. of p-(n-hexoxy) -phenyl iodide at such a rate that the surface of the metal remains bright. When the reaction ceases, as evidenced by the solution of the lithium metal, an amount of from. 19 to 21 gms. of powdered, dry N-methyl acridone is added gradually. This reaction mixture is refluxed for 2 or 3 hours following which ice wateriis added alongwith sufficientzdiethyl ether. to: dissolve theorganic matter present. The ether solution is separated, washed with water, dried and treated with gaseous hydrogen chloride. The insoluble chloride hydrochloride is thus formed which is separated by filtration and recrystallized from toluene. The chloride hydrochloride may be converted to the chloride either by drying the compound with heatorby dissolving the chloride hydrochloride in'*'chloroform and treating this solution with dried calcium carbonate. If the latter procedure is used the excess calcium carbonate and calcium stains the skin to a clear yellow color which color is readily. removed by washing with soap and water.

EXAMPLE III 9- (p-n-hexoatyphenyl) -10-methyl acridome bisulfate To approximately 1.5 grams of lithium metal The compound is readily ni -200 cc. of anhydrous ether which has been heated to reflux is added 25.7 grams of p-bromophenyl-n-hexyl ether, with stirring over a period of about one hour. After further stirring and refluxing, the mixture is cooled somewhat and 20.9 grams of N-methyl acridone is added over a period of about 10 minutes. After a short period of further stirring and refluxing, the solution is cooled, filtered and poured into 250 cc. of ice and water.- The ether solution and the water solution separate into two phases. The aqueous phase is-extracted with cc. of ether. This ether extract is combined with the ether phase, washed twice with water and dried over anhydrous magnesium sulfate. The light orange colored solution is filtered, treated with adsorbing charcoal and refiltered. The filtrate is orangeyellow in color. The ethereal solution contains 9- (p-n-hexoxyphenyl) -10-methyl-9-acridol.

One half of the above solution containing the carbinol is diluted into 150 cc. with anhydrous ether. To this solution is added dropwise a solution of 5.16 grams of sulfuric acid dissolved in 50 cc. of ether until the precipitation of the orange-yellow bisulfate is complete. This requires about one half of the ethereal sulfuric acid solution. This precipitate is removed by filtration, washed twice with ether and twice with nhexane and dried in vacuum at 50 C.

The crude bisulfate form is purified as follows:

About 7.0 grams of crude sulfate obtained above is dissolved in about cc. of toluene and about 10 cc. of absolute ethanol, at the boiling point of the solvent. The solution is concentrated by distilling off most of the alcohol. Toluene is added and most of the remainder of the ethanol distilled off. On seeding with the crude bisulfate, the pure product begins to crystallize from the solution. After the solution has been cooled the bisulfate is filtered, washed with toluene and dried at 50 C. in vacuum. The yellowish-orange platelets of 9 (p n hexoxyphenyl) 10 methyl acridane bisulfate melt at 229-230.5 C. with decomposition. The product analyzes for the bisulfate rather than the sulfate.

EXAMPLE IV 9- (p-n-beroxyphenyl) -1 O-mefhyl acrzdanebromide To one half of the ether solution of the 9-(pn hexoxyphenyl) -l0methyl-9-acridol prepared according to Example III, is added enough anhydrous ether to dilute the solution to cc.

To this solution is added dropwise a solution of i 4.5 grams of hydrogen bromide gas dissolved in 50 cc. of anhydrous ether until precipitation of the yellowish-orange product is complete. Ap-

proximately one half of the above ethereal hydrogen bromide is needed. The crude bromide 9. form is filtered, washed three times with n-hexane and dried in vacuum at 50 C.

About 7.0 grams of the crude bromide is dissolved in 100 cc. of boiling toluene. The solution is concentrated until the product begins to crystallize from the boiling solution. The solution is cooled, the solid removed by filtration, washed with toluene and dried at 50 C. in vacuum. This procedure is repeated and a further purification accomplished by a third recrystallization from toluene which contains slightly over 1% absolute ethanol. The crystals are filtered, washed with toluene and dried at 50 C. in vacuum. The yellow plates of Q-(p-n-hexoxyphenyl) -10-methyl acridane bromide melts at 178-178.5 C. with decomposiiton.

EXAMPLE V 9- (p-methoxyphenyl) -1 O-phenyl acridane chloride In the same manner as in Example III, pbromoanisole and lithium are reacted to give plithium anisole. The p-lithium anisole is reacted With N-methyl acridone to produce the lithium-salt of Q-(p-methoxyphenyl)-10-pheny1-9-acridol.

This compound may be converted directly into the compound 9-(p methoxyphenyl) -l-phenyl acridane chloride by filtering the dried ethereal solution of the lithium salt of the acridol and precipitating with ethereal hydrogen chloride. The crude product is filtered, Washed with nhexane aand dried at 50 C. in vacuum. The crude product is purified by dissolving in ethyl acetate containing a small amount of absolute ethanol, treating with adsorbing charcoal, filtered, concentrated and cooled. The orange crystals formed are filtered, washed with ethyl acetate and dried at 50 C. in vacuum. The orange, finely crystalline Q-(p-methoxyphenyD- -phenyl acridane 'chloride melts at 172.5- l'74.5 C. a

EXAMPLE VI 9-(o-methoxyphenyl) -10-jmethyl acridane chloride 1 In a manner analogous to that of Example V but using o-bromo anisole to prepare the o-lithium anisole and reacting this with N-methyl acridone the crude compound 9-(o-methoxyphenyl) IO-methyl acridane chloride may be prepared. The crude product may be purified as in Example IV by recrystallizing from toluene containing a small amount of absolute ethanol. After repeating the crystallization several times in toluene containing the small amount of absolute ethanol, the product is recrystallized from ethyl acetate containing a trace of ethanol. The compound Q-(o-methoxy-phenyl) 10 methyl acridane chloride is in the form of small, dense yellow crystals having a melting point of 208.5 to 209 C. with decomposition.

EXAMPLE VII Q-(p-n-butoxyphenyl) -10-methyl acridane chloride In a manner analogous to that of Example IV reacting lithium metal with p-bromophenyl-nbutyl ether to form the p-lithium compound and reacting this compound with N-methyl acridone, the above mentioned compound may be prepared. After recrystallizing from toluene containing a small amount of absolute ethanol, the compound 9-(p-n-butoxyphenyl) -10-methyl acridane chloride is obtained in the form of small brownishyellow plates which have a melting point of 186.5- 187 C.

EXAMPLE VIII 9- (p-hexomyphenyl) -10-ethyl acridane chloride In a manner analogous to that of Example II but using n-ethyl acridane with p-lithium phenyln-hexyl ether, the above mentioned compound may be prepared. After recrystallization from toluene containing a small amount of absolute ethanol, the compound 9-(p-hexoxyphenyl) -10- ethylacridane chloride thus prepared is in, a form of a light yellow powder having a melting point of 197.5'199.C. withdecomposition.

EXAMPLE IX 9- (p-n-hexoxyphenyl) -1 O-benzyl acridane chloride ({laHra In a manner analogous to Example II but using N-benzyl acridone with p-lithium phenyl-n-hexyl ether, the above mentioned compound may be prepared. After recrystallization from toluene containing absolute ethanol the compound 9-(pn-hexoxyphenyl)-10-benzy1 acridane chloride is obtained in the form of orange-yellow crystals having a melting point of 91-98 C. The compound is hygroscopic and difficult to obtain in pure form.

EXAMPLE X 9-(0ctoxyphenyl) -10-methyl acridane chloride CsH11n composition.

EXAMPLE XI 9- (p-Z-ethylbutoncyphenyl) -10--methyl acridane chloride (|JH1(I]HCzH c2115 (lib In a manner analogous to that of Example II but using p-lithium phenyl-Z-ethylbutyl ether with N-methyl acridone, the above mentioned compound may be prepared. After crystallization from toluene, the compound 9-(p-2-ethylbutoxyphenyl) --methy1 acridane chlor de is, O

12 tained in the form of yellow needles with a melting point of 157158 C. with decomposition.

EXAMPLE XII 9-(p-rL-decyl0xyphenyl) -10-meihyl acridane chloride Giu a- (iii) In a manner analogous to that of Example II but using p-lithium phenyl-n-decyl ether and N-methyl acridene the above mentioned compound may be prepared. After crystallization from toluene the compound Q-(p-n-decyloxyphenyl) -10-methyl acridane chloride is obtained in the form of golden yellow needles having a melting point of 161-164 C. with decomposition.

EXAMPLE XIII Z-methoxy-Q- (p-n-hezcoxyphenyl) -1 O-methyl acridane chloride SJsHxs- O I G 1 @OCEH i CH In a manner analogous to that of Example II but using p-lithium phenyl-n-hexyl ether and 2-methoxy-10-methyl acridone, the above mentioned compound may be prepared. After crystallization from toluene containing a small amount of absolute ethanol the compound 2- methoxy-9- (p-n-hexoxyphenyl) -10-methyl acridane chloride is obtained in the form of bright orange crystals having a melting point of 196.5- 197C. with decomposition.

EXAMPLE XIV 1-chZor0-9- (p-n-hexoxyphenyl) -4,1 O-dimethyl acridane chloride (|JaH1sn CH3 CH3 In a manner analogous to that of Example II but using p-lithium phenyl-n-hexyl ether with 1-chloro-4,10-dimethyl acridone, the above mentioned compound may be prepared. After crystallization from ethyl acetate containing a small amount of absolute ethanol a compound 1- chloro 9 (p n-hexoxyphenyl) -4,10-dimethyl acridane chloride is obtained as brilliant orangered platelets having a melting point of 98-102 C. with decomposition. q

. In a manner analogous to that of Example II the above mentioned compound may be prepared by reacting p-lithium phenyl-n-tetradecylether and N-methyl acridone. The compound may be purified in the previous examples.

EXAMPLE XVI 9- (p-n-methoxyphenyl) -1 O-n-decyl acridane chloride 7 In accordance with the process of Example II the above mentioned compound may be prepared by reacting p-lithium phenyl-methyl ether with N-n-decyl acridane. The compound may be purifled in the same manner as in the previous examples. v

The alkyl groups of the Q-alkoxyphenyl substituent may be in cyclic form. For example, by starting with a p-cyclohexyloxyphenyl halide and reacting the lithium salt with N-methyl acridone, the compound produced is Q-(p-cyclohxyloxyphenyD-lO-methyl acridane chloride. In. addition to having the alkoxy group in the para and ortho positions the group may'be'in the meta position. For example, by starting with the lithium phenyl-m-methyl ether and reacting this with N-methyl acridone, the compound produced.

is Q-(m-methoxyphenyl) 7 .methyl acridane chloride.

The above compounds are unique in that their solutions have a low surface tension and other favorabl properties with in agar disc plates give wide zones of bacterial inhibition.

At times it is difficult to purify the above mentioned acridane-mineral acid salts of the invention. Frequently repeated recrystallization results in no improvement of purity since it only accomplishes further decomposition. It has been found to be exceedingly advantageous to produce the corresponding 9-alkoxy acridane as an interr absolute methanol.

14 mediate for purification. These compound are easily purified and are an excellent source for obtaining pure acridane-mineral acid anion salts. The 9-alkoxy acridane derivative may be prepared as indicated above by adding an excess of alkali to a solution of the acridane-mineral acid anion salt to produce the acridolw By simply warming the acridol formed with an alcohol, the corresponding 9-alkoxy acridane is obtained. Investigation shows that the methoxyl derivative obtained by refluxing with methyl alcohol are the most desirable 9 -alkoxy acridane compounds. The following examples-illustrate the preparation of the 9-aoridols and 9-alkoxy acridanes.

EXAMPLE XVII 9- (p-hemoxyphenyl) -9-methoxy-1 O-methyl acridane An aqueous solution of 9-(p-hexoxyphenyD- IO-methyl acridane chloride (see Example II) or the bisulphate (see Example III) or a bromide (see Example IV) is covered with ether and treated with a dilute solution of alkali. The ether layer is separated, washed free of alkali and dried over anhydrous magnesium sulphate and adsorbing charcoal. The solution is filtered and concentrated to a residue. The residue is dissolved in n-hexane, the solution evaporated to a small volume. On cooling, the compound 9-(p-hexoxyphenyl)-10-methyl 9acridol crystallizes from the solution having a melting point of C.

The above mentioned acridol is refluxed in On cooling, the compound 9- (p-hexoxyphenyl) -9-methoxy-1 0-methyl aeridane crystallizes out, is filtered, washed with methanol and dried in vacuum at 50 C. This compound has a melting point of '77-'78" C.

EXAMPLE XVIII 9- (p-methoxyphenyl) -9-methoa:y-10-phenyl acridane" Treatment of the above mentioned acridol with methanol yields the compound Q-(p-methoxyphenyl)-9-methoxy-10-phenyl acridane, having a melting point of 1585-1605 C.

, IEXAMPLEIUX 9- (o-methox-yphenyl) -9-methorry-10methyl acridane Following the procedure of Example XVII but using 9- (o-methoxyphenyl) 10-methyl-acridane chloride, (see Example VI), the compound 9-(0- methoxyphenyl) -l0-methyl-9-acridol is obtained upon alkali treatment. This compound has a melting point of 132-135" C.

The treatment of the above acridol with methanol yields 9-(o-methoxyphenyl) -9-methoxy-l0- methyl acridane, having a melting point of 162- 163 C. with decomposition.

EXAMPLE XX 9- (p-n-butomyphenyl) -9-methowy-10-methyl acridane EXAMPLE XXI 9- (p-n-hewowyphenyl) -9-methomy-10-ethyl acridane (I)CeH1a O CH:

By following the procedure of Example XVII starting with the compound Q-(p-n-hexoxyphenyl)-10-ethyl acridane chloride (see Example VIII), the compound Q-(p-n-hexoxyphenyl) -10 ethy1-9-acrid01 is prepared upon treatment with alkali. The refluxing of this acridol compound with methanol produces the compound 9-(p-nhexoxyphenyl) -9-methoxy-10-ethyl acridane.

EXAMPLE XXII 9- (p-n-hexozcyphenyl) -9-methoxy-10-benzyl acridane OOH;

By following the procedure of Example XVII but starting with 9-(p-n-hexoxyphenyl)-l0-benzyl acridane chloride (see Example IX), the compound Q-(p-n-hexoxyphenyl) -10-benzyl-9-acri dol is prepared upon treatment with alkali. This compound has a melting point of 126.5128.5 C. Refluxing of this-acridol compound with methanol produces the compound Q-(p-n-hexoxyphenyl) -9-methoxy-10benzyl acridane, having a melting point of 1l8.5-'l20.5 0.

EXAMPLE XXIII 9- (p-n-octylowyphenyl) -9-methoacy-1 O-methyl acridane OC BH17I1 1 I CH5 By following the procedure of Example XVII but starting with 9-(p-n-octyloxyphenyl) -l0- methyl acridane chloride (see Example X), the compound 9-(p-n-octyloxyphenyl) -l0-methyl-9- acridol is obtained on treatment with alkali. This acridol upon refluxing with methanol is converted to the compound Q-(p-n-octyloxyphenyl) Q-methcxy-lO-methyl acridane, which has a melting point of 7275 0.

EXAMPLE XIHV 9- (ZJ-Z-ethyZbutOxyphenyZ) -9-methoacy-10- methyl acridane C] CzH fiy proceeding" according to Example XVII. but starting with 9-(2eethylbutoxyphenyl) -10- methyl acridane chloride (see Example XI), the compound 9-(2-ethylbutoxyphenyl) -10 methyl 9- acridol is prepared upon treatment with alkali. Upon refluxing this acridol with methanol, the compound 9- (p-2-ethylbutoxyphenyl) -9-methoxy-lO-methyl acridane is prepared.

EXAMPLE XXV 2,9 methoxy 9 (p n hexoxyphenyl) 10- methyl acridane O-CoHn- By following the processv of Example XVII but starting with 2-methoxy-9-(p-n-hexoxyphenyl) IO-methyl acridane chloride (see Example XIII), the compound 2 methoxy 9 -.(p n hexoxyphenyl) -10-methyl-9-acridol is obtained upon treatment with alkali. Upon refluxing this acridol with methanol the compound 2,9-methoxy-9- (p-n-hexoxyphenyl) -10-methyl acridane is formed.

EXAMPLE XXVI 1 chloro 9 memory-9-(p-n-hemomyphenyl)- 4,10-dimethyl acridane ?CoHuperature.

EXAMPLE XXVII 9 (p n decyloxyphenyl) 9- methoazy 10- methyl acridane (!)--Cm-H211 By following the procedure of Example XVII but starting with 9-(p-n-decyloxypheny1)-l0e methyl acridane chloride (see Example XII), the compound 9- (p-n-decyloxyphenyl) -.lO-methyl-9- acridol is obtained. Upon refluxing this acridol with methanol the compound Q-(p-n-decyloxyphenyl) 9 methoxy 10 methyl acridane is formed.

The N -alkyl acridones may be prepared as indicated in Examples IA, IB and IC, for example, the N-methyl-Z-methoxy-acridone may be prepared by reacting Z-methoxy acridine with dimethyl sulfate. 4,10-dimethyl-l-chloro-acridone may be prepared by reacting l-chlorol-methyl acridine with dimethyl sulphate.

As examples of other Q-acridol compounds and 9-methoxy derivatives which may be prepared are 9-(p-n-hexoxyphenyl)-10-n-decyl-9-acridol, 9 (p methoxyphenyl)-9-methoxy-l0-n-decyl acridane, 9 (p n tetradecyloxyphenyl) 10- methyl 9 acridol and 9 (p n tetradecyloxyphenyl) -9-methoxy-10-methyl acridane.

Also, by replacing the methanol used for converting the acridols to the corresponding 9-alkoxy derivatives with other alcohols, ethers of other alkyl groups may be prepared. For example by refluxing Q-(p-n-hexoxyphenyl) 10 methyl- Q-acridol with ethanol, 9-(p-n-hexoxyphenyl) 9-ethoxy-10-methyl acridane; with I n-butanol, 9 (p-n-hexoxyphenyl)-9-n-butoxy l0 methyl acridane.

To emphasize the totally unexpected antiseptic properties exhibited by representative compounds of this invention, the following table of compara tive values is given: a

g fig figs Bacteriostatic Acrifiavin 1 1, 000 1:33, 000 Rivanol (2cthoxy-6,9-dia1nino acridane 1:5, 000 9-(p-n-Butoiwphenyl)-l0-methyl acridane chloride. 1:50, 000 1:1, 500, 000 Q-(p-n-Hexoxyphenyl)-10-methy1 ac- 'ridane chloride 1:100, 000 1:5, 000, 000 9(p-n-Hexoxypheny1)-l0-benzyl acridane chloride 1:100, 000 1 4, 000, 000 Q-(p-n-Hexoxyphenyl)-lO-ethyl acridane chloride 1:50, 000 1:10, 000, 000 9 (p-n-2-Ethylbutoxyphenyl) 10 methyl acridane chloride; 1:50, 000 1:6, 000, 000 Q-(p-n-Octoxyphenyl) -lO-methyl acridane chloride I 1: 100, 000 1:4, 000, 000 9 (p-n-DecyloxyphenyD-lflmethyl acridanc chloride 1; 100, 000 1:10, O00, O00 Q-(p-n-Hexoxyphenyl) 10 thyl acridane bisulfate 1:10, 000, 000

The term bactericidal refers to the maximum dilution which will kill a culture of Staphylococcus aureus in five minutes. Bacteriostatici refers to the maximum dilution which will prevent the growth of the abovementioned organism.

Both tests are made by the oflicial methods of ing powders, tooth pastes, etc.

Due to the highly antiseptic properties and low toxicities of the compounds described, these preparation have many and varied applications in preventing and .duringbacterial infections.

As illustrative examples of the preparations referred to above are the following:

EXAMPLE XXVIII The water soluble salts of the invention form,

Stable aqueous solutions and :arei'efiective as germicides even in very dilute solutions,=while by practicing further dilution these solutions retain bacteriostatic action. As usedin' this. specifica- .tionzthe term antiseptic refers to a substance which. prevents or arrests the" growth of microorganisms either by inhibiting theirzactivitymr destroying them. The word germicide.;.refers to. an agent which destroys microorganisms.

EXAMPLE ")QKIX ..I have determinedafter a thorough investigation that aqueous solutionsin 1: 1,000 concentration are very desirablefor practical use. "Such a solution may be prepared by dissolving 1 unit by weight of the acridane antiseptic in 1,000 units of distilled water.

-,A-suitable tincture using: one of thesehalides may beprepa-red asfollows:

0.1 gm. Q-(p-n-hexoxyphenyl)- methyl acridane chloride 54.0 cc. ethyl alcohol denatured 5.0 cc. acetone 41 cc. distilled water "Other acridane halides may be used in place. of

the acridane compound used here.

EXAMPLE XXXI The antiseptic compounds disclosed .herein may be made up for use in tooth pastes'or powder form byembodying about 0.1% of the active ingredient ina conventional tooth paste or powder base.

EXAMPLEXXXII A dusting powder maytbej prepared by incorporating about 1% of the antiseptic compounds of theinvention into a therapeutically inert .fine

powder.

application is continuation-.finepartzof my --earlier'-application, Serial Number 781,758, filed October 23, 1947, now abandoned.

The present application; isdi-rectedito' applicants novel antiseptic. mineral-anion acridane compounds. Applicants copending application -Serial.No. 191,088 of October'l9,1950;-which?'is a division of the present application, is directed to applicants novel 9+alkoxyracridane :compounds. These compounds .are intermediates for and derivatives of the compounds of. the present application. Applicants novel acridol -:.compounds are the subject matter. of..applicants.copending. application. Serial No. 250,185 ,1 filedl'Ootober 6, 1951, which is a divisional application .of the present application.

Others may readily 'adaptzthe invention: for use under various conditionsoflservice, byxemploying one or moreof vthenovel features -disclosed herein, .or equivalents thereof. iAS :at present advised with respect ;.to the apparent scope of my invention, .I:desire1to;claim:the following subject'matter.

.Iclaim:

,1. An *acridane compound characterized -by the presence of an .alkoxyephenyl;groupaati the 9-.position' and axhydrocarbon group.;.at thexlO- position, the alkylygroup .of said .alkoxyrgroup containing from oneto fourteen carbon atoms and the hydrocarbon group at' the 10-position containing from one -toten carbon atoms.

.-.2.ZSub'stituted :acridane compounds :1 retire sented by theifollowingformula:

' ethylacridanechloride'.

'6; The-compound 9'(o'ctoxyph'enyl) -'10=methyl acridane chloride.

The compound 9-"(p'=n=dec'yloxyphenyl) =10- methyracridane chloride.

1 8. The processbf preparing" an" acridane'compound of claim 1,"which-'"comprises' reacting'an acridone compound with the lithium metal' derivatives of alkoxybenzene.

' 9..'.'The processeofupreparingn compound-represented by theformula:

WhereinR is an alkyl group containing from one toyfourteen' carbon atoms'inclu'sive'fX 'is' a monovalent radicals elected" from the class consisting of 'hydrogen," halogen, alkyl and alkoxyfgroups; Y.is a hydrocarbon'group containing frompne to ten "carbon atoms'inclusiverand'iz is a mineral acid -anion, "which 'comprisesrreacting the lithium -metal derivativeiof alkoxy benzene "with ,"a "Y N subs'tituted iacridone; and then treating the resulting acrid'ol "with mineral acid. 10."The processbf preparing a "compound represented-by the formula:

Von

is a hydrocarbon group, containingfroinone to ten carbon atoms inclusive, and Z is a mineral acid anion, which comprises: reacting the ,9,a lkoxy derivative with a mineral acid.

11. The process of preparing a compound represented by the formula:

wherein R is an alkyl group containing from one to fourteen carbon atoms inclusive, X is a monovalent radical selected from the class consisting of hydrogen, halogen, alkyl and alkoxy groups; Y is a hydrocarbon group containing from one to ten carbon atoms inclusive, and Z is a halide, which comprises: reacting the 9-alkoxy derivative with gaseous hydrogen halide. E

12. The process of preparing a compound represented by the formula:

groups; Y is a hydrocarbon group containing from one to ten carbon atoms inclusive, which comprises: reacting the Q-alkoxy derivative with gaseous hydrogen chloride.

13. A composition of 'mouor xorois og action antagonistic to microorganisms and comprising as an active ingredient a 9-alkoxy-phenyl-10- hydrocarbon substituted acridane mineral acid anion salt; said ingredient being present in combination with a pharmaceutical carrier.

14. An antiseptic dusting powder comprising a therapeutically inert powder in combination with a compound according to claim 2. v

15. An antiseptic composition of matter comprising a solution containing as an active ingredient a compound according to claim 2.

16. A composition according'to claim 15 in the form of a tincture. 1

1'7. The process of preparing the compound represented by the formula: v v

wherein R is an alkyl group containing from one to'fourteen carbon atoms inclusive; X is a monovalent radical selected from the class consisting of hydrogen, halogen, alkyl, and alkoxy groups; Y is a hydrocarbon group containing from one to ten carbon atoms inclusive, and Z is a mineral acid anion, which comprises; reacting an acridol compound of the formulazl OH I/ C with a mineral acid.

18. The process of preparing a compound represented by the formula wherein R is an alkyl group containing from one to fourteen carbon atoms inclusive, X is a monovalent radical selected from the class consisting of hydrogen, halogen, alkyl, andalkoxy groups;

Y is a hydrocarbon group containing fromone to ten carbon atoms inclusive, and Z is an ion selected from the class consisting of chlorine,

bromine, and iodine, which comprisesyresicting an acridol compound of the formula:

r ,with a gaseous hydrogen halide.

wherein R is an alkyl group containing from one to fourteen carbon atoms inclusive, X is a monovalent radical selected from the class consisting of hydrogen, halogen, alkyl, and alkoxy groups; Y is a hydrocarbon group containing from one to ten carbon atoms inclusive, which comprises;

reactina'ri acri'dol: compound: of the following f formula-i with gaseous hydrogen chloride.

20. The process of preparing a compound represented by the formula:

1 a i Y Z wherein R is an alkyl group containing from one to fourteen carbon atoms inclusive, X is a monovalent radical selected from the class consisting of hydrogen, halogen, alkyl and alkoxy groups; Y is a hydrocarbon group containing from one toten carbon-atoms inclusive, and Z isa mineral acid-anion, which comprises: reacting the "lith ium'rme'talderivative of an alkoxy benzene with a Y-N-substituted acridone; warming-the product I in whichziisamineral'acidanion from the 'group consistingor monoland-polyvalentanions.

232*"A communa -representedb the formula in which Z is a mineral acid anion from the group consisting of -mono and polyvalent anions.

241* A compound represented by: the formula N V LE3 in which R is an alkyl group containing from one to 14 carbon atoms inclusive.

Within an alkan'ol and-- treating the l resulting compound with'amineral acid.

21 Theprocessof preparing. a compound rep-rresentedby the-formula:

wherein R is an alkyl groupcontaining from one to fourteen carbon atoms inclusive, X is a monovalent radical selected from the class consisting;

of-hydrogen; halogen; alkyl and alkoxy groups;

Y is a hydrocarbon group containing .from' one-to 25. A compound represented by the formula in whichRis-analkyl group'containingfrom 'one' in which R is an alkyl group containing'frombne J to"14*carhoxratomsinclusive:

27. A compound representedbythefoririula O-CaH13 25 in which Y is a hydrocarbon group containing from one to ten carbon atoms inclusive.

28. An antiseptic composition comprising an aqueous solution of a 9-alkoxy phenyl-lO-hydrocarbon substituted acridane mineral acid salt.

DONALEE L. TABERN.

to 1945 (J. W. Edwards; Ann Arbor, Michigan; 10

1946.) volume II, part I, page 585.

Beilstein: Handbuch der organischen'Chemie (4th edition, 1935), pages 335 and 336, volume 21.

Luttringhaus: Berichte, volume 67, pages 1602 to 1603 (1934).

Wittig et a1.: Berichte, volume 68, pages 924 to 927 (1935).

Frankel: Die Arzneimittel-Synthese, 16th edition, Berlin, J. Springer, pages 640 to 644.

Claims (1)

1. AN ACRIDANE COMPOUND CHARACTERIZED BY THE PRESENCE OF AN ALKOXY-PHENYL GROUP AT THE 9-POSITION AND A HYDROCARBON GROUP AT THE 10POSITION, THE ALKYL GROUP OF SAID ALKOXY GROUP CONTAINING FROM ONE TO FOURTEEN CARBON ATOMS AND THE HYDROCARBON GROUP AT THE 10-POSITION CONTAINING FROM ONE TO TEN CARBON ATOMS.