US3646010A - Spiroazetidine-ethanoanthracenes - Google Patents

Abstract

THIS DISCLOSURE TEACHES THAT A GROUP OF SPIROAZETIDINEETHANOANTHRACENES ARE USEFUL AS PHARMACEUTICAL AGENTS. THE DISCLOSURE ALSO TEACHES A METHOD FOR COMBATTING INFLAMMATION BY ADMINISTERING PHARMACEUTICAL FORMUALTIONS OF THE COMPOUNDS OF THIS INVENTION. REPRESENTATIVE COMPOUNDS OF THIS INVENTION INCLUDE COMPOUNDS SUCH AS 9'', 10''DIHYDROSPIRO(AZETIDINE-3,11''9,10-ETHANOANTHRACENE) AND DERIVATIVES THEREOF.

Description

3,646,010 SPIROAZETIDINE-ETHANOANTHRACENES Gilbert H. Berezin, West Chester, Pa., assignor to E. I. du Pont de Nemours and Company, Wilmington, Del. No Drawing. Continuation-impart of application Ser. No. 726,542, May 3, 1968. This application Apr. 2, 1969,

Ser. No. 812,846

Int. Cl. C07d 25/00, 99/04 US. Cl. 260-439 A Claims ABSTRACT OF THE DISCLOSURE This disclosure teaches that a group of spiroazetidineethanoanthracenes are useful as pharmaceutical agents. The disclosure also teaches a method for combatting inflammation by administering pharmaceutical formulations of the compounds of this invention. Representative compounds of this invention include compounds such as 9',l0- dihydrospiro [azetidine-3, 1 1-9, lO-ethanoanthracene] and derivatives thereof.

CROSS REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of my copending application Ser. No. 726,542, filed May 3, 1968, and now abandoned.

BACKGROUND OF THE INVENTION This invention relates to the discovery of novel 9',10' dihydrospiro [azetidine-3,1 1'-9,10-ethanoanthracene] and derivatives thereof which are useful as pharmaceutical agents. More particularly, the compounds of this invention are useful for reducing inflammation in warm blooded animals.

In general, inflammation is a disease process charac terized by redness, fever, swelling and pain. Inflammation occurs as a result of a chronic condition such as arthritis or can occur as the result of trauma or infection. Antiinflammatory drugs are often used to alleviate the condition thereby enabling the victim to regain more normal function of the affected area. The anti-inflammatory drugs in use today such as the adrenocortical steroids, aspirin, and indomethacin have troublesome side effects in some subjects. These side effects can range from irritation of the stomach and ulcers to more serious systemic effects. In addition, long term administration of a drug to combat a chronic inflammatory condition is often unsuccessful as individual cases of chronic inflammation, such as arthritis, are often refractory to any specific medication.

There is, therefore, a continuing need for additional anti-inflammatory agents which are effective, safe and different in their mode of action. It is to the continuing need for effective anti-inflammatory pharmaceutical agents that this invention is directed.

SUMMARY OF THE INVENTION This invention relates to novel 9',10'-dihydrospiro [azetidine-3,11-9,lO-ethanoanthracene] and selected derivatives thereof which are pharmaceutically active. More particularly the compounds of this invention are represented by the following formula:

United States Patent 3,646,010 Patented Feb. 29, 1972 wherein R is selected from the group consisting of hydrogen, chlorine, bromine, fluorine, alkylsulfonyl of one to four carbons, sulfamyl, trifluoromethyl, trifiuoromethylsulfonyl and alkoxy of one to four carbons;

R is selected from the group consisting of hydrogen, chlorine, bromine, fluorine, alkylsulfonyl of one to four carbons, sulfamyl, trifluoromethyl, trifluoromethylsulfony and alkoxy of one to four carbons;

R is selected from the group consisting of hydrogen and methyl;

R is selected from the group consisting of hydrogen and methyl;

R is selected from the group consisting of hydrogen, alkyl of one to six carbons, alkenyl of three to five carbon atoms, with the limitation that the double bond not be in the 1 position, Z-hydroxyethyl, 2-hydroxy-2-phenethyl, 2 hydroxypropyl, 3-hydroxypropyl, 2-(2-hydroxyethoxy)ethyl, furfuryl, tetrahydrofurfuryl, 2-acyloxyethyl, 2-acyloxypropyl, 3-acyloxypropyl, where the acyl group contains from 1 to 3 carbon atoms, 2-alkoxyethyl, Z-alkoxypropyl, 3-alkoxypropyl, where the alkyl contains one or two carbon atoms, alkyl of one to six carbons mono-substituted with a member of the group consisting of phenyl, halophenyl, methoxyphenyl, ethoxyphenyl, hydroxyphenyl, benzoyl, halobenzoyl, carboxamido or cyano;

and non-toxic pharmaceutically acceptable salts of the above.

Preferred compounds of this invention are those compounds of Formula 1 where R is hydrogen, chlorine or trifluoromethyl;

R is hydrogen, chlorine or trifluoromethyl;

R is hydrogen or methyl;

R is hydrogen or methyl; and

R is hydrogen, alkyl of one to three carbon atoms, allyl, Z-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropy1, 2 (2 hydroxyethoxy)ethyl, furfuryl, tetrahydrofurfuryl, Z-acryloxyethyl, 2-acyloxypropyl, 3-acloxypropyl where the acyl group contains from 1 to 3 carbon atoms, 2-alkoxyethyl, 2-alkoxypropyl, 3-alkoxypropyl Where alkyl contains one or two carbon atoms, monosubstituted alkyl of 1 to 3 carbon atoms where the mono-substituent is selected from the group consisting of phenyl, halophenyl, methoxyphenyl, ehtoxyphenyl, hydroxyphenyl, benzoyl, halobenzoyl, carboxamido or cyano;

and non-toxic pharmacetutically acceptable salts of the above.

Most preferred compounds of this invention are those compounds of Formula 1 where R is hydrogen, chlorine or trifluorornethyl; R is hydrogen, chlorine or trifiuoromethyl; R is hydrogen or methyl;

R is hydrogen or methyl;

R is hydrogen, methyl or allyl;

and the pharmaceutically acceptable salts of said compounds.

It will be understood that the method of producing anti-inflammatory effect on warm 'blooded animals which comprises administering an anti-inflammatory effective amount of the compound of Formula I is included within the scope of this invention.

It will be further understood that pharmaceutical formulations containing an effective amount of a compound of Formula 1 are included within the scope of this invention.

1 3 l-furfuryl-1-methy1sulfony1-9',10'-dihydrospiro [azetidine-3 ,11'9,10-ethanoanthracene] I-(Z-acetoxyethyl) -1'-methylsulfonyl-9,10'-dihydrospiro- [azetidine-3 ,11-9,10ethanoanthracene] 1-(2-methoxyethyl)-1'-methylsulfonyl-9',10'-dihydrospiro[azetidine-3,1 1'-9,10-ethanoanthracene] l-benzyl-1'-methylsulfonyl-9',lO'-dihydrospiro[azetidine-3,11'-9,10-ethanoanthracene] 1-flu0robenzyl1'-methylsulfonyl-9',10'-dihydrospir0 [azetidine-3,1 1-9, IO-ethanoanthracene] l-methoxybenzyl-1'-methylsulfonyl-9',10'-dihydrospiro- [azetodine-B ,11'-9,10-ethanoanthrecene] l-(a-ethylmethoxybenzyl)-1-methylsulfonyl-9',10'-

dihydrospiro [azetidine-3 ,11'-9,10-ethanoanthrecene] l-hydroxybenzyl-1'-methylsulfonyl-9" "-dihydrospiro- [acetidine-3,11'-9,10-ethanoanthracene] l-benzoylmethyl-1'-methylsulfonyl-9',10'-dihydrospiro- [azetidine-3,1 1'-9-,10-ethanoanthrecene] l-fluorobenzoylmethyl-l'-methylsulfonyl-9',10-dihydrospiro [azetidine-3 ,1 1'-9,10-ethanoanthracene] 1-carboxamidomethy1-1'-methylsulfonyl-9',10-dihydrospiro [azeidine-3,1 1'-9,10-ethanoanthracene] 1-(2-cyanoethyl) -1'-methylsulfonyl9,10'-dihydrospiro- [azetidine-3,11'-9,10-ethanoanthracene] 1-(2-hydroxyethyl)-1-sulfamyl-9,10-dihydrospiro [azetidine-3,11'-9,10-ethanoanthracene] l-[2-(2-hydroxyethoxy) ethyl] -1'-sulfamyl-9',10 '-dihydrospiro [azetidine-3,1 1'-9, 10-ethanoanthracene1 l-furfuryl-1'-sulfamyl-9",lO'-dihydrospiro [azetidine- 3 ,1 1'-9, I O-ethanOanthracene] 1-(2-acetoxyethyl) -1'-sulfarnyl-9',10'-dihydrospiro- [azetidine-3,1 1'-9,10-ethanoanthracene] 1-(2-methoxyethyl)-1'-sulfamyl-9',10'dihydrospiro- [azetidine-3 ,1 1'-9, 1 O-ethanoanthracene] 1-benzyl-1'-sulfamyl-9',1O-dihydrospiro [azetidine-3,1 1'- 9,10-ethanoanthracene] 1-fluorobenzyl-1'-sulfamyl-9',l0'-dihydrospiro [azetidine- 3 ,1 1-9,10-ethanoanthracene] 1-methoxybenzyl-1'-su1famyl-9,10'-dihydrospiro [azetidine-3,1 1-9,10-ethanoanthracene] 1-(a-ethylmethoxybenzyl)-1'-sulfamyl-9',10-dihydrospiro [azetidine-3,1 1'-9,10-ethanoanthracene] 1-hydroxybenzyl-1'-sulfamyl-9, 10'-dihydrospiro [azetidine-3 ,11'-9,10ethanoanthracene] l-benzoylmethyl- 1 -sulfamyl-9', 10'-dihydrospiro [azetidine-3,1 1'-9,10-ethanoanthracene] 1-fluor0benzoylmethyl-1'-sulfamyl-9',10'-dihydrospiro [azetidine-3 ,1 1'-9, 1 O-ethanoanthracene] 1-carboxamidomethyl-1-sulfamyl-9,10'-dihydrospiro- [azetidine-3,1 1'-9,1-0-ethanoanthracene] 1-(2-cyanoethyl)-1-sulfamyl-9,10-dihydrospiro [azetidine-3 ,1 1'-9,10-ethanoanthracene] 1-(2-hydroxyethy1) -1'-trifiuoromethylsulfonyl-9',10'

dihydrospiro [azetidine-3 ,1 1-9, 1 O-ethanoanthracene] 1- [2- (2-hydroxyethoxy) ethyl] 1 '-trifluoromethylsulfonyl-9',10dihydrospiro [azetidine-3,1 1'-9,10-ethanoanthracene] 1-furfuryl-1 '-trifiuoromethylsu1fonyl-9", 1 O'-dihydrospiroazetidine-3,1 1-9,10-ethanoanthracene] 1-(2-acetoxyethyl)-1-trifiuorornethylsulfonyl-9', 10-

dihydrospiro [azetidine-3 ,11-9,10-ethanoanthracene] 1-(2-methoxyethyl) -1'-trifluoromethylsulfonyl-9,10-

dihydrospiro[aZetidine-3,11'-9,10-ethanoanthracene] 1-benzyl-1'-trifiuoromethylsulfonyl-9',10-dihydrospiro- [azetidine-3 ,11'-9,10-ethan0anthracene] l-fluorobenzyl-I'-trifiuoromethy1sulfonyl-9,10'-dihydrospiro[azetidine-3,11'-9,10-ethanoanthracene] l-methoxybenzyl-1'-trifiuoromethylsulfonyl-9',10-

dihydrospiro [azetidine-3,1 1'-9, IO-ethanoanthacene] 1- a-ethylmethoxybenzyl 1 '-trifiuoromethylsulfonyl- 9',10'-dihydrospiro[azetidine-3 ,1 1'-9,1()-ethanoanthracene] l-hydroxybenzyl-1-trifluoromethylsulfonyl-9',10'-dihydrospiro [azetidine-3 ,1 1-9,10-ethanoanthracene] l-benzoylmethyl-l'-trifluoromethylsulfonyl-9',1()-dihyspiro [azetidine-3,1 1-9, lO-ethanoanthracene] l-fluorobenzoylmethyl-l-trifluoromethylsulfonyl-9,10'- dihydrospiro[azetidine-3,1 1'-9,10ethanoanthracene] 1-carboxamidomethyl-1-trifluoromethylsulfonyl-9',10'-

dihydro [azetidine-3 ,1 1-9,10-ethanoanthracene] 1-(Z-cyanoethyl)-1'-trifluoromethylsulf0nyl-9',10- dihydrospiro [aZetidine-3,1 1-9, l O-ethanoanthracene] PREPARATION In general the compounds of this invention are prepared by treating anthracene or an appropriately substituted anthracene with acrolein at a temperature of about C. and at high pressure to give a 9,10-ethano- 9,10-dihydro-1l-formylanthracene or a 9,10-ethano9,10- dihydro-12-formylanthracene.

This product is then mixed with a caustic solution in ethanol and to the mixture is slowly added a solution of formaldehyde and ethanol. The temperature of the system is controlled at about 15 to 20 C. during the addition and is then allowed to rise to room temperature (approximately 23 C.) and is stirred for about 16 hours. The product is a 9,10-ethano-9,10-dihydro-11,11-bis(hydroxymethyl) anthracene.

The 9,10-ethano-9,10-dihydro-11,11-bis-(hydroxymethyl)-anthracene is treated with benzenesulfonyl chloride to give the corresponding bis-(benzenesulfonate) which in turn is reacted with an appropriate amine to give the desired 9,10-dihydrospiro[azetidine 3,11'-9,10 ethanoanthracene] It is postulated that the final reaction proceeds in a stepwise fashion and is represented by the following reaction in which A is a leaving group such as benzenesulfonyl and R is as defined above:

(1112A n CHQA.

N-R R2 H1 H2 5 H CHQA. N R c 5 R4 H2 /\N R5 R There are of course additional methods which can be employed in preparing various of the compounds of this invention.

Those compounds of this invention wherein R is hydrogen can be prepared according to one of the following alternate methods.

The preferred method comprises preparation of a compound of this invention wherein R is allyl and treating the l-allyl 9,10 dihydrospiro[azetidine-3,11',9,10-ethanoanthracene] with potassium tertiary butoxide and dimethyl sulfoxide under nitrogen for about 24 hours. The reaction mixture is then acidified with aqueous hydrochloric acid, refluxed for about 2 hours and cooled. The reaction mixture is then made strongly basic and extracted with solvent to give the desired 9',l0'-dihydrospiro [azetidine-3,1 l,9,10-ethanoanthracene] A compound of this invention where R is benzyl is prepared and the 1-benzyl-9',10'-dihydrospiro[azetidine 3,11',9,10-ethanoanthracene] is debenzylated by hydrogenolysis of the benzyl group using art recognized precedures to obtain the corresponding compound Where R is hydrogen.

A compound of Formula 1 is prepared where R is -COCF by reaction of an appropriate anthracene with l-trifluoroacetyl-3-methylazetidine. The resulting l-trifiuoroacetyl 9,10-dihydrospiro[azetidine-3,1l',9,l0-ethanoanthracene] is hydrolyzed with an aqueous or ethanolic base to give the corresponding compound of this invention where R is hydrogen. This method is preferred for preparing those compounds of the invention where R R R and/ or R are other than hydrogen. The compound produced using this method can optionally be treated as will be hereinafter described to obtain those compounds of this invention where R is other than hydrogen.

A compound of Formula 1 where R is an alkyl or aryl sulfonamide can be prepared by reacting a compound of the formula:

Rt 0112A OHZA a a a where R R R and R are as defined above and A is a leaving group such as a halide, alkyl sulfonate, substituted alkyl sulfonate, aryl sulfonate, substituted aryl sulfonate and the like, with an alkyl or aryl sulfonamide in the presence of a strong base such as sodium hydroxide followed by reduction with sodium in a high-boiling alcohol, ammonia, amine or sodium naphthalide in solvents such as tetrahydrofuran or ethylene glycol dimeth ylether (glyme) to give the corresponding compound of Formula 1 where R is hydrogen.

Those compounds of this invention Where R is other than hydrogen can be prepared starting with 9',l0-dihydrospiro[azetidine-3,ll'-9,10-ethanoanthracene] and adding the R group by well-known procedures such as those outlined below.

A compound of Formula 1 where R is methyl is prepared by treating the corresponding compound where R is hydrogen, with formaldehyde and formic acid.

A compound of Formula 1 in which R is hydrogen can be reacted with an alkylating agent containing a leaving group such as a halide, alkyl sulfonate or aryl sulforrate to give the corresponding N-substituted compound of this invention.

A compound of Formula 1 in which R is hydrogen can be acylated and then reduced according to well-known procedures to give the corresponding compound of Formula l where R is other than hydrogen. As will be recognized by those skilled in the art this procedure cannot be employed to produce the compounds of this invention Where R is alkyl substituted with COOH, CONH acyloxy or ketone.

A compound of Formula 1 in which R is alkyl or aryl ether can be reduced with LiAlH to give the corresponding compound where R is alkyl.

A compound of Formula 1 in which R is a carbamate or thiocaribamate can be prepared according to wellknown methods and this compound can be reduced with LiAll-L, to give the corresponding compound of the inveu= tion where R is methyl.

A compound of Formula 1 where R is an iminol can be prepared according to art known procedures from the corresponding compound where R is hydrogen and the product is reduced using a conventional hydrogenation catalyst at low pressure.

It will be understood that many of the above procedures are well known to the art. However, if further information concerning a described method is desired reference can be had to well-known texts in the field such as Organic Reactions published by John Wiley and Sons, especially vol. IV (1948).

The following examples are presented to further illustrate the invention. Parts and percentages are by weight unless otherwise indicated.

EXAMPLE 1 A mixture of 75 grams of lithium bromide, 1 grams of sodium carbonate and 50 grams of ll,l1-dibenzenesulfonoxymethyl-9,10-dihydro-9,lO-eth-anoanthracene in 200 ml. of diglyme is heated at ISO-200 C. for 20 hours. The reaction mixture is cooled and added to 1 liter of icewater. The solid is collected by filtration and is recrystallized fromethanol to yu'eld 27 grams of 11,11-dibromomethyl 9,10 dihydro 9,10 ethanoanthracene, M.P. -152 C.

A solution of 14 grams of sodium methylate in 200 ml. of diethylene glycol is added during an 8-hour period to a well stirred suspension of 35 grams of 11,11-dibromomethyl-9,10-dihydro-9,IO-ethanoanthracene and 22 grams of p-toluenesulfonamide in .250 ml. of diethylene glycol under a nitrogen atmosphere held at -175 C. The reaction mixture is stirred for an additional 40 hours at 170l75 C., cooled and added to 3 liters of water with vigorous stirring. The solid that separates is collected by filtration and recrystallized from 500 ml. of ethanol to yield 16 grams of white crystals, 'M.P. 187.5-188" C. The product is l-p-toluenesulfonyl-9',10'-dihydrospiro- [azetidine-3 ,1 l'-9,10-ethanoanthracene] Analysis.0alcd. for C H N O S (percent): C, 74.79; H, 5.78; N, 3.49; S, 7.99. Found (percent): C, 74.70; H, 5.89; N, 3.37; S, 8.07.

Twelve grams of 1-p-toluenesulfonyl-9',10'-dihydro- Spiro-[azetidine-3,l1-9,lO-ethanoanthracene] is 'added to 250 ml. of amyl alcohol. The mixture is refluxed under a nitrogen atmosphere while 15 one-gram pieces of sodium are added one at a time waiting for the dissolution of each piece before the next one is added. The mixture is cooled and the alcohol is removed under vacuum. The residue is dissolved in 1 liter of warm (SO-60 C.) 2 N sulfuric acid. Any insoluble material is removed by filtration. The filtrate is diluted with 1 liter of water and made strongly basic with potassium hydroxide. The precipitate is collected by filtration, dried and recrystallized from hexane to yield 7 grams of 9',l0'-dihydrospiro[azetidine- 3,11-9,10-ethanoanthracene] M.P. l59'--160 C.

It will be understood that substituted sulfonyls where the substituent is preferably an aryl group can be employed in place of the p-toluene sulfate in the above pro cedure.

It will be further understood that in the above procedure reducing agents such as sodium napthalide in solvents such as tetra'hydrofunan, glyme and various other ethers or sodium in liquid ammonia, ethylamine and the like can be employed in place of the above procedure to obtain the '9',10' dihydrospirofiazetidine 3,11-9,10- ethanoanthracene] The hydrochloride of the free azetidine can be prepared by dissolving the free base in tetrahydrofuran and adding concentrated hydrochloric acid to the solution until precipitation is complete. The salt melts between 285286 C.

EXAMPLE 2 A mixture of 300 grams of benzyl amine, 250 grams of 11,11 dibenzenesulfoncxymethyl',1.0-dihydro=9,10=

ethanoanthracene and 100 grams of calcium oxide in 1500 ml. of diglyme is stirred at the reflux temperature for 7 days. The reaction mixture is added to 6 liters of water and the solid is collected by filtration. The solid is extracted with refluxing hexane to yield 114 g. of l-benzyl- 9',l0'-dihydrospiro[azetidine 3,11-9,10 ethanoanthracene], M.P. 141.5142 C. The hydrochloride melts between 256257 C.

Five grams of 1-benzyl-9,l0'-dihydrospiro[azetidine- 3,11'-9,10-ethanoanthracene] is dissolved in ml. of tetrahydrofuran and then diluted to 50 ml. with methanol. A suspension of 0.5 gram of 10% palladium on charcoal catalyst in 25 ml. of methanol is added to the benzylamino compound. The mixture is treated with hydrogen at 75 C. and 1500 pounds per square inch pressure for 8 hours. The catalyst and solvent are removed to yield a solid. The solid is recrystallized from hexane to yield 3 grams of 9',10'-dihydrospiro[azetidine-3,1l'-9,10-ethanoanthracene].

EXAMPLE 3 A mixture of 1300 grams of 11,11-dibenzenesulfonoxymethyl 9,10 dihydrospiro 9,10 ethanoanthracene, 930 grams of allylamine, 650 grams of calcium oxide and 6 liters of diethyl Carbitol is placed in a 12 liter stainless steel autoclave. The autoclave is purged with nitrogen, sealed and heated with stirring to 190 C. for 16 hours. The autoclave is then cooled and the solid material in the reaction mixture is filtered 01f. The filter cake is washed with 1500 ml. of ether. The combined filtrates are added to 10 liters of water and the resultant mixture is stirred vigorously for 30 minutes with an air motor. The ether layer is separated. The aqueous phase is extracted four more times with 1500-ml. portions of ether. The combined ether extracts are dried over anhydrous magnesium sulfate. The solvent is removed and the 503 grams of residue slowly crystallizes. Three recrystallizations from petro leum ether gives analytically pure 1-allyl-9',10-dihydrospiro[azetidine-3,11-9,10-ethanoanthracene], M.P. 61- 63 C. (as the hydrochloride M.P. 221222 C.).

An SO-gram quantity of potassium tertiary butoxide is added to a solution of 800 grams of crude 1-allyl-9,10'- dihydrospiro[azetidine-3,11-9,IO-ethanoanthracene] in 1 liter of dimethyl sulfoxide stirring in a nitrogen atmosphere. Stirring is continued for 24 hours. The reaction mixture is then added to a solution of 800 ml. of concentrated hydrochloric acid and 10 liters of water.

The aqueous mixture is refluxed for 2 hours, filtered and allowed to cool. The mixture is made strongly basic by the addition of 800 grams of sodium hydroxide.

The mixture is stirred for 3 hours and extracted with ether. The ether extract is dried and evaporated to yield 500 g. of ofi-white solid. Recrystallization from cyclohexane yields 400 g. of 9,10'-dihydrospiro[azetidine- 3,1 1G9,10-ethanoanthracene1 EXAMPLE 4 A 100-gram quantity of 9',10-dihydrospiro[azetidine- 3,1l'-9,l0-ethanoanthracene] is added to a solution of 100 grams of 37% formaldehyde in 300 grams of formic acid. The reaction mixture is heated to 95-100 C. for 8 hours, cooled and added to a 4 liter mixture of ice, water and 160 grams of sodium hydroxide. The mixture is stirred vigorously for 3 hours and filtered. The filtered solid is washed with water until the washings are neutral. The solid is recrystallized from aqueous methanol to give white crystals of 1-methyl-9,10'-dihydrospiro[azetidine- 3,11'-9,IO-ethanoanthracene], M.P. 125.5-127" C.

Analysis.Calcd. for C H N (percent): C, 87.31; H, 7.33; N, 5.36. Found (percent): C, 87.06; H, 7.51; N, 5.27.

If a salt of the free base is desired the azetidine is dissolved in tetrahydrofuran. To this solution is added concentrated hydrochloric acid until precipitation is complete to form 1 methyl-9,10'-dihydrospiro[azetidine- 3,l1'-9,l0-ethanoanthracene], M.P. 296-297 C.

18 EXAMPLE 5 To 0.10 mole of 9',10' dihydrospiro[azetidine-3,11'- 9,l0 ethanoanthracene], there is added ml. butyl formate. The resulting solution is heated at reflux for 24 hours. At the end of this period the solvent is removed at reduced pressure to give 1-formamido-9',10-dihydrospiro[azetidine-3,11'-9,IO-ethanoanthracene].

EXAMPLE 6 To a solution of 0.20 mole lithium aluminum hydride in 250 ml. tetrahydrofuran, there is added 0.10 mole l-formamido 9,10' dihydrospiro[azetidine-3,11'-9,10- ethanoanthracene] in 100 ml. tetrahydrofuran. The resulting suspension is heated at reflux for 16 hours. At the end of this period the excess lithium aluminum hydride is destroyed by the cautious addition of 20% sodium hydroxide solution until the inorganic salts precipitate. The tetrahydrofuran solution is decanted, dried over anhydrous potassium carbonate and filtered. Removal of the solvent at reduced pressure gives 1-methyl-9,10-dihydrospiro [azetidine-3,1 1'-9, 1 O-ethanoanthracene] EXAMPLE 7 To 1.00 g. of prereduced platinum oxide in 50 ml. of ethanol is added 0.1 mole 9',10'-dihydrospiro[azetidine-3,11'-9,10-ethanoanthracene] and 0.1 mole acetaldehyde. The solution is sealed in a Paar shaker apparatus and hydrogenated at 3 atmospheres hydrogen pressure until the hydrogen uptake ceases. The catalyst is filtered and the solvent is evaporated to give l-ethyl- 9,10'-dihydrospiro[azetidine 3,11 9,10 ethanoanthracene].

This reaction is representative of reductive alkylation of amines. Other means of reductive alkylation of amines is described in Organic Reactions vol. IV, pp. 174- 255 by John Wiley and Sons New York, N.Y. (1948) would be expected to give the alkylated product.

EXAMPLE 8 A mixture of 700 grams of 11,11-dibenzenesulfonoxymethyl 9,10 dihydro 9,10 ethanoanthracene, 350 grams of calcium oxide and 3600 ml. of diethyl Carbitol is placed in a 3-liter stainless steel autoclave. A 500-gram quantity of methyl amine is introduced into an autoclave. The autoclave is sealed and the contents are stirred and heated at 175 C. for 4.5 days. The reaction mixture is added to 6 gallons of water. The aqueous mixture is filtered and the filtered solid cake is dried. The dry solids are extracted with boiling heptane. The extracts are concentrated to yield 285 grams of 1-Inethyl-9,l0dihydrospiro[azetidine 3,11 9,10 ethanoanthracene], M.P. 125.5-127 C.

EXAMPLE 9 A mixture of 5 grams of 9,10'-dihydrospiro[azetidine- 3,1l'-9,IO-ethanoanthracene], 2 grams of gamma-chlorop-fluorobutyrophenone, 0.05 gram of potassium iodide and 150 ml. of toluene is refluxed for 24 hours. The mixture is cooled and the solid is removed by filtration. Anhydrous hydrogen chloride is passed into the toluene solution. The solid is removed by filtration and heated at reflux with 400 ml. of ethyl acetate. The solution is filtered and concentrated to 20 ml. The resultant solid is recrystallized from ethyl acetate to yield 1[4-p-fiuorophenyl) 4 oxobu-tyl]-9',10-dihydrospiro[azetidine-3, 11-9,10-ethanoanthracene]hydrochloride as a white solid, M.P. 2l1213 C.

EXAMPLE 10 A mixture of 65 grams of 11,11-dibenzenesulfonoxymethyl-9,10-dihydro-9,IO-ethanoanthracene, 33 grams of calcium oxide, 50 grams of ethanolamine and 400 ml. of diethyl Carbitol is stirred and heated under nitrogen in a pressure vessel at C. for 16 hours. The reaction mixture is cooled and the solids are removed by filtration.

19 The filtrate is diluted with 3 liters of water. The solid that separates is extracted into ether. The ether extract is washed with water and dried over potassium carbonate. Anhydrous hydrogen chloride is passed into the ether extract until precipitation is complete. The crude salt is recrystallized from an ether ethanol mixture to yield 1-(2- hydroxyethyl) 9',10' dihydrospiro[azetidine-3,11-9,10- ethanoanthracene]hydrochloride as a White solid, M.P. 244245 C.

EXAMPLE 11 A mixture of 65 grams of 11,11-dibenzenesulfonoxymethyl-9,10-dihydro-9,l-ethanoanthracene, 33 grams of calcium oxide, 65 grams of methoxyethylamine and 400 ml. of diethyl Carbitol is stirred and heated under nitrogen in a pressure vessel at 90 C. for 16 hours. The reaction mixture is cooled and the solids are removed by filtration. The filtrate is diluted With water. The water mixture is extracted with ether. The ether extract is Washed With water and dried over potassium carbonate. The ether solution is concentrated at first under mild heat and vacuum and finally at 150 C. and 0.1 mm. of mercury. The residue is again taken up in ether. Anhydrous hydrogen chloride is passed into the ether until precipitation is complete.

The product is recrystallized from an ethanol-ether solution to yield 15 grams of 1-(2-methoxyethy1)-9,10'-dihydrospiro[azetidine 3,11 9,10 ethanoanthracene] hydrochloride as a white solid, M.P. 206-208 C.

EXAMPLES 12-29 The procedure of Example ll is repeated substituting an equivalent amoung of the indicated Amine for the methoxyethylamine of Example 11 to obtain the indi cated Product.

20 V methoxyethylamine of Example 11 and a sufficient amount of the indicated Recrystallization Solvent for the ethanol/ether of Example 11 to obtain the indicated Product.

EXAMPLE 34 A mixture of 65 grams of 11,11-dibenzenesulfonoxymethyl-9,10-dihydro-9,IO-ethanoanthracene, 33 grams of calcium oxide, 50 grams of Z-aminomethyltetrahydrofur-an and 400 ml. of diethyl Carbitol is stirred and heated under nitrogen in a pressure vessel at 190 C. for 16 hours. The reaction mixture is cooled and the solids are removed by filtration. The filtrate is concentrated on a rotary evaporator at 100 C. and under a vacuum of 0.1 mm. of mercury. The residue is taken up in ethanol. A solution of maleic acid in ethanol is added to the dissolved residue until precipitation is complete. The solid is collected by filtration and recrystallized from ethanol to yield 13 grams of I-(tetrahydrofurfuryl)-9,10'-dihydrospiro[azetidine-3,1l-9,10-ethano anthracene], maleic acid salt as a White solid, M.P. 202204 C.

Analysis.Calcd. for C H N O (percent): C, 72.46; H, 6.53; N, 3.13. Found (percent): C, 72.46; H, 6.49; N, 3.12.

EXAMPLE One gram of propionyl chloride in ml. of ether is added dropwise to a mixture of 2.9 grams of 1-(2-hydroxyethyl) 9',10' dihydrospiro[azetidine 3,11-9,10- ethanoanthracene], 1.5 grams of triethyl amine and 75 ml. of ether and the reaction mixture is refluxed for 18 hours. The reaction mixture is then added to a mixture of ether and water. The ether solution is separated and dried over magnesium sulfate. The solid is removed by Example Amine Product 12 3-methoxypropylamine 1-(3methoxypropyl)-9,l0-dihydrospiro[azetidine-3,1l-9,IU-ethanoanthraeenelhydrochloride,

M P. 210211 C.

13 Ethylamine I-et-h LQZCIW-dihydrospirol'azetidineEJl9,l0ethanoanthracenelhydrochloride, M.P. 279- 280 14 2-hydroxypropylamine l-ta-li ydggoxgprgryl)-9,l0-dihydrospiro[azetidine-3,11 9,10-ethanoanthracenelhydrochloride,

l 7- 88 15 l-methoxy-2-aminopropane 1-(2-111ethoxy-l-methylethyl)-9,10-dihydrospiroIazetidine-El,119,10-

ethanoanthracene]hydrochloride, M.P. HS-219 C. 16 Phenethylamine 1-filillenetlglg-c,lO-dihydrospiro[azetidine-3,11-9,10-ethanoanthracenelhydrochloride,

. 266- 17 2-(p-methoxyphenethynamme 1-[2(p-nrethoxyphenyl)ethy119,lfl dihydrospiro[azetidine-3,113,10-

ethanoanthraeentflhydrochloride, M.P. 243.5-?A4.5 C. 18 l-hydroxyphenethylamine Alpha-t),10-dihydrospiro[azetidine-B,ll-9,wethanoanthracene-1-yl]methyl-benzyl alcohol hydrochloride M.P. 266268 C. 19 dethoxyethylamine l-gfielghoxyethyllc- ',10'-dihydrospiro[azetidine-3,11"-9,10-ethanoanthracenflhydrochloridc,

. 202-204 20 2-(2-aminoethoxy)ethanol I-[Z-tZ-hydroxyethoxy)ethylI-Q,10-dihydr0spir0[azetidine-3,11{),l0-

etnandanthraeene1hydrochloride. M.P. 226-227" G. 21 Propylamine l-propyl-Q'.l0-dihydrospirolazetidine-i,,11-9,10-ethanoanthracene]hydrochloride. 22.- Isopropylamine l-isopropyl-Q,10-dihydrospiro[azetidine3,11-9.ltlethanoanthracene]hydrochloride. 23 -aMethylbenzylamine l-fi-giethylbgnzgD-Q',10-dihydrospirolazetidine-B,1l'-9,ill-ethanoanthracene1hydroehioride,

. 269-27 24 p-Fluorobenzyiamine- 1-ga-tlluorcbeizyg-9510'-dihydr0spiro[azetidined,1l'-9,l0-ethanoanthracene]hydrochloride,

. ee. 25 a-hydroxypropylamine Hfihgdggggpggpgl)-9,lo'dihydrospirolazetidinee,l1-9,10-ethauoanthracene1hydrochloride,

. 1 26 3-(p-chlorophenyl)propylamine l-lg-tggchlqciropienyl)propyl1-9',10-dihydrospirolazetidinet},1l'-9.l0-ethanoanthraeene] y 00 on e. 27 3-(p-methoxyphenyl)propyiamine Hg-ggrmgtieoxgphenyl(propylj-9,10'dihydrospiro{azetidine-3,11'-9,10-ethanoanthraceue] y roe on e. 28 p-Ethoxybenzylamine l-tp-ethoxybenzyl)-9.10-dihydrospiro[aZetidine-3.11-910ethanoanthraeene]hydrochloride.

29 p-Hydroxybenzylamine l-(p-hydroxybenzyD)-9,l0'-dihydrospiro[azetidine-3,l1-9,10ethanoanthracene]hydrochloride.

EXAMPLES 30-33 The procedure of Example 11 is repeated substituting filtration. Ethanolic HCl is added to the filtrate until the filtrate is acidic. The precipitate is collected by filtraan equivalent amount of the indicated Amine for the tion and the solid is recrystallized from ethanol-ether to Recrystallization Example Amine solvent Product 30 Furiurylamine Tetrahydroiuran l-iizr li uggyg ilcilW-dihydrospirolazetidine-3,119,lo-ethanoanthracenelhydrochloride, mp. 31 2'(p-ehlorophenyl)ethyl- Water/ethanol I-IQ-(pehIordphenyl)ethylJ-Q, l0'-dihydrospiro[aZetidjne-3,11'-9,10-ethanoanthracene] amine. hydrochloride, M.P. 256-2565 0. 32 8-phenyl-1-propylamine. Aeetonitrile 1-(3-phenylpropyl)-9,10-dihydrospiro[azetidine-a,11-9,IO-ethanoanthraeene]hydrochloride, M.P. 223-225 C. 33 Alpha-methyl-phenethyll-(alpha-methyl-alpha-phenethyl)-tl,10-dii1ydrospirolaeetidineil,l1-9,l0-ethanoamine. V anthraoene]hydroehioiide.

21 yield 1.5 grams of [9',10-dihydro-1-(2-hydroxyethyl)- spiro(azetidine 3,11-9,10 ethanoanthracene)]propionate hydrochloride, M.P. 220222 C.

EXAMPLE 36 A IO-gram quantity of 9',10'-dihydrospiro[azetidine- 3,11'-9,10-ethanoanthracene] is slowly added to 22 grams of acrylonitrile. Four drops of a 40% methanolic solution of benzyltrimethylammonium hydroxide is cautiously added to the acrylonitrile solution. The mixture is refluxed for 2 hours after the initial reaction subsides. The solvent is removed under vacuum. The residue is shaken with a mixture of dichloromethane and water. The dichloromethane is separated and dried over anhydrous magnesium sulfate. Anhydrous hydrogen chloride is passed into the dichloromethane extract until it is acidic. The acidified solution is heated to boiling until a precipitate forms. The precipitate is 9',10' dihydrospiro[azetidine 3,11-9,10- ethanoanthracene] -l-propionitrile hydrochloride.

A solution of 8.0 grams of 9',l0-dihydrospiro[azetidine-3,11'-9,10-ethanoanthracene] 1 propionitrile hydrochloride, 50 ml. of water, 50 ml. of glacial acetic acid and 50ml. of concentrated hydrochloric acid is refluxed for 6 hours. The solution is concentrated to dryness. The residue is 9',10'-dihydrospiro[azetidine-3,ll'9,10-ethanoanthracene1-1-propionic acid hydrochloride, M.P. 230- 231 C.

EXAMPLE 37 A mixture of grams of 9,10'-dihydrospiro[azetidine- 3,11-9,10-ethanoanthracene], 50 ml. of DMF, 4 grams of calcium oxide and 1.8 grams of 2-chloroacetamide is heated at 80 C. for one and one-half hours. The mixture is poured into 300 ml. of water and extracted with dichloromethane, the extract is washed with water and dried over magnesium sulfate. The solvent is stripped off and the residue is taken up in ether. Anhydrous HCl is passed into the solution until precipitation is complete. The solid is collected and dissolved in a minimum of hot ethanol and allowed to cool yielding 9',10 dihydrospiro[azetidine-3,11-9,10-ethanoanthracene]-1-yl-acetamide hydrochloride, M.P. 218-219 C.

EXAMPLE 3 8 The procedure of Example 37 is repeated but substituting an equivalent amount of chloroacetonitrile for the 2-chloroacetamide of Example 37 to obtain 9',10'- dihydrospiro[azetidine 3,11-9,10 ethanoanthracene]- l-yl-acetonitrile hydrochloride, =M.P. 217218.5 C.

EXAMPLE 39 The procedure of Example 37 is repeated but substituting an equivalent amount of p-chlorophenacyl bromide for the 2-chloroacetamide of Example 37 to obtain l-(pchlorobenzoylmethyl) 9',10 dihydrospiro[azetidine- 3, 1 1'-9, 1 O-ethanoanthracene] hydrochloride.

EXAMPLE 40 A .05 mole quantity of methyl lithium in ether solution is added dropwise to a solution of 15 grams of 9,10'- dihydrospiro[azetidine 3,11-9,10 ethanoanthracene]- l-propionitrile in 200 ml. of ether. After the addition is complete, the reaction mixture is refluxed for 6 hours. The mixture is then shaken with 1 N ammonium chloride solution. The ether layer is separated and dried over magnesium sulfate. Anhydrous hydrogen chloride is passed into the ether until precipitation is complete. The hydrochloride salt is dissolved in hot ethanol, then ether is added to the hot ethanol until a faint cloudiness appears. The mixture is cooled and the solid, 1-(3-ox0- butyl)-9',l0'-dihydrospiro[azetidine 3,11'-9,10 ethanoanthraceneJhydrochloride, is collected by filtration.

22 EXAMPLE 41 A mixture of 10 g. of 1-(3-hydroxypropyl)-9',10'-dihydrospiroLazetidine 3,11'-9,1O ethanoanthracene] and ml. of 98100% formic acid is refluxed for four hours. The excess acid is removed by distillation; the last portion of acid being removed under vacuum to yield l-(3-formyloxypropyl) 9',10' dihydrospiro[azetidine- 3,11-9,l0-ethanoanthracene].

EXAMPLE 42 The procedure of Example 11 is repeated but substituting an equivalent amount of p-(a-methoxymethoxy) phenylpropylamine for the methoxyethylamine of Example 11 to obtain 1 [p (a methoxymethoxy)phenylpropyl]-9,10'-dihydrospiro[azetidine 3,11-9,10-ethanoanthracene]. The product hydrolyzed with dilute hydrochloric acid to give 1-(p-hydroxyphenylpropyl)-9',10'-dihydrospiro[azetidine 3,11'-9,10 ethanoanthracene]hydrochloride.

The p-(a-methoxymethoxy)phenylpropylamine is obtained by converting p-hydroxyphenylpropionarnide to 0:- methoxymethoxyphenylpropionamide according to the method taught by F. B. LaForge, Am. Soc. vol. 55, pp. 30-40 (1933). The product is reduced with LiAlH to give p-(a-methoxymethoxy)phenylpropylamine.

EXAMPLE 43 Nine grams of p-toluenesulfonylchloride are added to 15.2 grams of 1-(3-hydroxypropyl)-9,l0'-dihydrospiro [azetidine-3,11'-9,10-ethanoanthracene] in 100 ml. of dichloromethane and 10 ml. of pyridine at 0 C. The mixture is allowed to stir at room temperature for 18 hours, the solvent is stripped off under vacuum and the residue is taken up in 300 ml. of dimethylsulfoxide. To the solution is added 8 g. of sodium cyanide and the mixture is heated at 100 C. for 24 hours under nitrogen. The mixture is poured into one liter of Water and the organic phase is extracted into dichloromethane. The solvent is stripped oiT, the residue is taken up in ether and anhydrous HCl is passed into the ether solution until precipitation is complete. The crude product is recrystallized from ethanol ether to yield 9,10-dihydr0spiro[azetidine- 3,11 9,10 ethanoanthracene] 1 yl butyronitrile hydrochloride.

EXAMPLE 44 A solution of 8.0 grams of 9,10'-dihydrospiro[azetidine-3,11 9,10 ethanoanthracene] 1 butyronitrile hydrochloride, 50 ml. of water, 50 ml. of glacial acetic acid and 50 ml. of concentrated hydrochloric acid are refluxed for six hours. The solution is concentrated to dryness. The residue is 9,10'-dihydrospiro[azetidine-3,11'9, l0-ethanoanthracene]-1-butyric acid hydrochloride.

Five grams of the 9,10'-dihydro[azetidine-3,11'-9,10- ethanoanthracene]-1-butyric acid hydrochloride, 75 ml. of ethanol and 0.1 g. of p-toluene sulfonic acid are refluxed for 8 hours. The solvent is removed under vacuum and the residue is taken up in ether and washed with 2% sodium bicarbonate solution. The ether is removed under vacuum. The residue is heated to to 16 hours in 18% ammonium hydroxide solution. The liquid is removed under vacuum. The residue is 9",10'-dihydrospiro[azetidine- 3,11-9,10-ethanoanthracene]-1-butyramide.

EXAMPLE 45 To 0.1 mole l-anthracenecarboxylic acid dissolved in 300 ml. methylene chloride in a Hastelloy bomb, there is added 0.5 mole of HF and 2.0 moles of sulfur tetrafluoride. The bomb is sealed and the reaction is shaken at 20-22 C. for 80 hours. At the end of this period the solution is decanted, washed with two 200 ml. portions of water, two 200 ml. portions of 5% sodium hydroxide and finally two 200 ml. portions of sodium chloride solution. The solution is dried over anhydrous magnesium sulfate,

23 filtered and evaporated at reduced pressure. The residual material is chromatographed through Activity I alumina to give 1-trifiuoromethylanthracene.

EXAMPLE 46 The procedure of Example 45 is repeated but substituting an equivalent amount of 1,S-anthracenedicarboxylic acid for the l-anthracenecarboxylic acid of Example 45 to obtain 1,S-ditrifiuoromethylanthracene.

EXAMPLE 47 A mixture of 21.0 grams of Z-anthracenethiol, 25 grams of potassium carbonate, 20 grams of methyl iodide and 200 ml. of dimethylformamide is stirred and heated on a steam bath for two hours. The mixture is poured into one liter of water and the resultant sulfide is extracted into 400 ml. of carbon tetrachloride.

The extract is dried over anhydrous magnesium sulfate. The drying agent is removed by filtration. Chlorine gas is passed into the carbon tetrachloride solution until 10.5 grams is taken up. The temperature of the carbon tetrachloride solution is maintained at 25-35 C. during the chlorination. After the addition of chlorine is complete, the solution is stirred for a period of about one hour at room temperature. The temperature of the solution is raised to 70 C. and the solution is stirred for an additional period of 30 minutes. The solvent is removed from the system at reduced pressure and the material remaining is crude Z-anthracenyl trichloromethyl sulfide.

A mixture of 30 grams of Z-anthracenyl trichloromethyl sulfide and 20 grams of anhydrous hydrogen chloride is charged into a Hastelloy B bomb. The bomb is heated to 100 C. for 1 hour, cooled in a Dry Ice bath, and the hydrogen chloride slowly bled from the bomb. After the pressure is released, the contents of the bomb are transferred to a polyethylene bottle, and the bomb washed out with dichloromethane and this combined with the contents of the bottle. This is stirred with a Teflon coated stirring bar on a magnetic stirrer. Powdered calcium carbonate is added slowly to prevent excessive foaming. When all of the hydrogen fluoride and hydrogen chloride have been neutralized, the liquid is filtered. The solvent is removed at reduced pressure. The residue is crude 2- anthracentyltrifiuoromethylsulfide.

A ZO-gram quantity of 2-anthracenyltrifiuoromethylsulfide in 30 grams of glacial acetic acid is stirred while it is heated to 80 C. on a steam bath and 26.5 grams of 40% peracetic acid is added slowly. The temperature is maintained between 5090 C. throughout the addition. After all of the peracetic acid is added, the temperature is held at 90 C. for 1 /2 hours. The mixture is cooled to room temperature, poured into one liter of ice and water and is then extracted with dichloromethane. The dichloromethane extract is back washed with a saturated solution of sodium bicarbonate until neutral, dried over magnesium sulfate, and concentrated. The residue is crude Z-anthracenyltrifiuoromethylsulfone.

EXAMPLE 48 A mixture of 20 grams of Z-anthracenyltrifiuoromethylsulfone, 10 grams of acrolein and 100 ml. of diglyme is heated in a bomb at 150 C. for 2 hours. The bomb is allowed to cool over a six hour period. The excess acrolein is removed under vacuum. The residue is poured into 1 liter of water, and the product is extracted with a methylene chloride. The solution is treated with charcoal. The charcoal and solvent are removed. The residue is a mixture of crude 9,10-ethano-2trifluoromethylsulfonyl-9,10'- dihydro-ll-formylanthracene and 9,10-ethano-3-trifluoromethylsulfonyl-9, 1 U-dihydro-l l-formylanthracene.

A solution of 10 grams of sodium hydroxide in 160 ml. of ethanol is added to a well stirred mixture of 25 grams of crude reaction product containing 9,10-ethano-2-trifluoromethylsulfonyl-9,IO-dihydro-l1-formylanthracene and 9, l-ethano-3-trifluoromethylsulfonyl-9,10 dihydro llformylanthracene, 31 grams of 37% formaldehyde solu tion and 10 ml. of ethanol during a /2 hour period. The temperature is maintained between 15 and 20 C. At the end of this time, the solution is allowed to stir at room temperature for 16 hours. The solution is poured into 500 ml. of water and the mixture is stirred vigorously. The product is filtered with suction and washed with water until the washings are neutral to pH paper. The product is a mixture of 9,10-ethano-9, IO-dihydro-l 1,1 l-bis('hydroxyme thyl -2- trifiuoromethylsulfonylanthracene and 9,10-ethano 9,10- dihydro-l1,1l-bis(hydroxymethyl)-3 trifiuoromethylsulfonylanthracene. The two isomers may be separated if desired by fractional crystallization or by chromotography.

EXAMPLE 49 A 22 gram quantity of benezenesulfonyl chloride is add ed dropwise to 20 grams of 9,10-ethano-9,10-dihydro-11, ll-bis(hydroxymethyl) -2 trifluoromethylsulfonylanthraride is added at a rate that maintains the temperature at cene in 60 ml. of dry pyridine. The benzenesulfonyl chlo- 30. The mixture is stirred overnight at room temperature. The reaction mixture is poured into a beaker containing ml. of methanol, 93 m1. of water and 73 ml. of concentrated hydrochloric acid. The mixture is cooled and the solid is collected by filtration and washed with water to yield crude 9,10-ethano-Z-trifluoromethylsulfonyl-9,10-dihydro-11,11-bis(hydroxymethyl)anthracene bis(benzenesulfonate).

A mixture of 21 grams of 9,10-ethano-Z-trifluoromethylsulfony1-9,10-dihydro 11,11 bis(hydroxymethyl)anthracene-bis(benzenesulfonate), 11 grams of calcium oxide, 20 grams of phenethylamine and 150 ml. of diethylcarbitol is stirred and heated under nitrogen in a pressure vessel at C. for 16 hours. The reaction mixture is cooled and the solids are removed by filtration. The filtrate is diluted with water and the water mixture is extracted with dichloromethane. The dichloromethane extract is dried over magnesium sulfate. The solvent is removed at first under reduced pressure and mild heat and finally at 150 C. and 0.1 mm. of mercury. The residue is taken up in a solvent such as butanol and anhydrous hydrogen chloride is passed into the solution until it is acid. The butanol is removed under reduced pressure until the product, 2-trifiuoromethylsulfonyl-9 ,10'-dihydro-l-phenethylspiro [azetidine- 3 ,1 1-9,10-ethanoanthracene hydrochloride separates.

When the other isomer, 9,10-ethano-9,10 dihydro-11,11- bis(hydroxymethyl) 3 trifiuoromethylsulfonylanthracene, is carried through the last steps of this example, 3'- trifiuoromethylsulfonyl-9,10'-dihydro 1 phenethylspiro [azetidine-3,1l-9,1O ethanoanthracene]hydrochloride is the resultant product.

EXAMPLE 50 To a mixture of 45 grams of 2-anthracenylmethylsulfide, 100 ml. glacial acetic acid and 200 ml. acetic anhydride, cooled to 0 C., is added dropwise during a period of 20 minutes, 55 grams of 30% hydrogen peroxide. The mixture is allowed to stir for 24 hours at room temperature. The excess hydrogen peroxide is destroyed by addition of a trace of magnanese dioxide. The solvents are removed and the residue is recrystallized to yield pure Z-methylsulfonylanthracene.

EXAMPLE 5i Substitution of Z-methylsulfonylanthracene for 2 trifluorornethylsulfonylanthracene in Example 48 yields a mixture which can be separated to give 9,10-ethano-9,10- dihydro-ll,11-bis(hydroxymethyl) 2 methylsulfonylanthracene and 9,10-ethano9,10-dihydro-11,11 bis(hydroxymethyl)-3-methylsulfonylanthracene.

EXAMPLES 52-62 The procedure of Example 48 is repeated substituting an equivalent amount of the indicated Anthracene for the Z-trifiuoromethylsulfonylanthracene of Example 48 to obtain the indicated Product.

Example Anthracene Product 52 l-flumnthmne --{3;i it ifi i fififilgg fil3538 ?ilt tliEfilggiigfiifigZQEEZEZEZ:

9 l-et an09 -dihy ro-l1,11-bis hydroxymet yl -1-s amy ant racene. 53 l-sulfamylanthracene. ethano glodih e ydro11 ll-bis(hydroxymethyl)4-sulfamylanth1aeene. 54 methoxyanthmcene {g,lgegiano-g,iggigygro-gjfi-gisgygroxymezgyg g-meglfioxyantgracene. -e 2110-, 1 y rois y roxyme y -me oxyan racene. 55 1 m a thr c {Lehloro-QJOethane-9,10-dihydro-11,11-bis(hydroxymethyl)anthracene. on) n a 4-chl0ro-9,10-ethano-9,10dihydro-11,11-bis(hydr0xymethyl)anthracene. 56 1-5diehloroanthracene {1,5gich50r0-9,l%ettfiano-%l%-diilfiy%ro-ll,ll-gisgygroxymetgygantzgracene. 18 ie ore-91 -e ano- 1 i y 1'o-1111- is y roxyme y an racene. 57 1-8-d1chloroanthraeene 45mch1om9m ethano g'mdih ydro-ll,11-bis-(hydroxymethyl)anthraoene. 58 2 bmmoanthmcene {g-gromo-alg-eggandg,lg-gigygrdfi,fi-gisggygroxymetgygantlfiracene. r0m0-9,1 -e ano- .1 i y rois y roxyme y an racene.

9,10-ethano-9 lfl-dihydro-ll 1l-bis(hydroxymethyl)-9-methylanthracene. 59 g'methylanthmcem "iQJO-ethano-0I10-dihydro-11:11-bis(hydroxymethyl)10-methylanthraeene. 60 9,l0-dimethylanthracene 9,10ethano-9,101i1hydro-l1,11-bis(hydroxymethyl)-9,10-dimethy1anthracene. 61 1-trifluoromethylanthracene. 9,lOethanO-Q,IO-dihyrdo-ll,11-bis(hydroxymethyl)-1-trifluoromethylanthracene. 62 1,5-ditrifluoromethy1anthracene 1,fi-ditrifluoromethyl-Q,10-ethano-9,10-dihydro-11,11-bis(hydroxymethyl)anthracene.

EXAMPLES 63-74 The procedure of Example 49 is repeated substituting the indicated Anthracene for the 9,10-ethano-9,l0-dihydro-11,1l-bis(hydroxymethyl) 2 trifluoromethylsulfonylanthracene of Example 49 and the indicated Amine for the phenethylamine of Example 49 to obtain the indicated Product.

furan solution is decanted, dried over anhydrous potassium carbonate and filtered. The solvent is reduced at reduced pressure to give 1-propyl-9',10'-dihydrospiro[azetidine-3,11-9,10-ethanoanthracene].

It will be understood that diborane or other suitable metal hydrides can be substituted for the lithium aluminum hydride of the above example.

Example Anthracene Amine Product 63 9,10-ethano-1-fiuoro-9,l0-dihydro-11,11-bis Ethanolamine 1-(2-hydroxymethyl)-1-fluoro-9,10-dihydrospiro[azetidi (hydroxymethyl) anthracene. 3,11-9,10-ethanoanthracenelhydrochloride.

64 9,10ethano-9J0nihydro-11,11-bis-(hyd1'oxy- Methylamme l-methyl-Q,l0'-dihydro3-methy1sulfony1spim[azetidinemethyl)-3-methylsulfonylanthracene. 3,11-9,IO-ethanoanthracene]dihydrochloride.

65 9.IO-ethano-Q,10-dihydro-11,11-bis-(hydroxy- -d0 l-methyl-Q',10-dihydro-4-sulfamylspiro[azet1dine-3,11-

methyl)Asulfamylanthracene. 9,IO-ethauoanthracene1hydrochloride.

66 9,10-ethano-9,IO-dihydro-ll,ll-bis-(hydroxy- Diphenylethylamlne 1-(2-dihpenylethyl)-9,10-dihydro-2-methoxyspiromethyl) -2methoxyanthracene. [azetidine-3,11-9,IO-ethanoanthracene]hydrochloride.

67 1-chl0ro-9,l0ethan0-9,10-dihydro-11,11-bis- 2-(2-aminoethoxy)ethanoL 1-ehloro-1-[2-(2-hydroxyethoxy)ethyl]-9,10-dihyd.rospiro- (hydroxymethybanthraeene. [azetidine-3,1l-9,lO-ethanoanthracene]]hydr0chl0ride.

68 1,5-dich1oro-9,10ethano-9,10-dihydro-11,l1-bis- 2-(p-ehlorophenyl)ethy1- 1,5 dichloro-1-[2-(p-chlorophenyDethyl -9,10-dihydro- (hydroxymethybauthraeene. amine. sphifdagetidine-li,11-9,loethanoanthracenqhydroe on e.

69 4,541ich10r0-9,10ethano9,10-dihydro-11,11-bis- Methylamine 4,5dichloro-Lmeth LQ,10kd m g (hydroxymethyl) anthracene. ethanoanthracene1hydroeh loride.

70 3bromo-9,methane-9,IO-dihydro-lLll-bis- Furfurylamine 3-br0In0-1-furfuryl-9,10-dihydr psi [az tidin .3 11' 9 10- (hydroxymethybanthracene. ethanoanthraeene1hydroehloride.

71 9,10-ethan0-9,10-dihydr0-11,ll-bis-(hydrOXy- Ethylamine 1ethy19,10-dihydro-10-methylspiro[aeetidlne-3,11-9,10-

methyl)-10-methylanthracene. ethanoanthracene]hydr0chloride.

72 9,l0-ethano-9,l0-dihydro-11,ll-bis-(hydroxy- 2-hydroxypropy1am1ne 1-(2-hydroxypropyl)-9,lO-dihydro-Q,10-dimethylspir0- methyl)9,10-dimethylanthracene. [azetidine-S,11-9,10-ethanoanthraeene1hydroehloride.

73 9,ioethano-mo-dihydro-ll,li-bisthydroxy- Methylamme l-methyl-Y-trifluoromethyl-l-methyl-Q 10-dihydrospimmethyl)-1-trifluoromethylanthracene. [azetidine-3,11-9,IO-ethanoanthraeenelhydroehloride.

74 1,5-ditrifluoromethy1 9,methane-9,10-dihydr0- .d0 l,5-ditrifiuoromethyl-l-methyl-Q,10-dihydrospriol1,ll-bis-(hydroxymethybanthracene.

[azetidine-3,11-9,IOethanoanthracene1hydroehloride.

EXAMPLE 75 To 0.1 mole of 9'.-10'-dihydrospiro[azetidine-B,11'- 9,l0-ethanoanthracene] dissolved in 200 ml. methylene chloride is added 0.11 mole pyridine and 0.11 mole propionyl chloride at 0-5 C. The solution is allowed to come to room temperature and is stirred for an additional 16 hours. At the end of this period, the methylene chloride solution is washed successively with ice cold 5% hydrochloric acid solution, 5% sodium hydroxide and saturated sodium chloride solution. The methylene chloride solution is dried with anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to give a thick oil. Chromatography of the oil through activity I alumina gives 1-propionyl-9',10-dihydrospiro [azetidine-3,l 1'9,10- ethanoanthracene], M.P. 100-402 C.

Analysis.-Calcd. for C H NO (percent): C, 83.13; H, 6.98; N, 4.62. Found (percent): C, 82.77; H, 6.82; N, 4.37.

To 0.2 mole of lithium aluminum hydride suspended in 250 ml. of tetrahydrofuran there is added 0.1 mole of 1- propionyl-9',10-dihydrospiro[azetidine 3,11 9,10-ethanoanthracene] in 100 ml. of tetrahydrofuran at 0-10". The solution is allowed to come to room temperature and then heated at reflux for 16 hours. The solution is cooled and the excess lithium aluminum hydride is decomposed with 20% sodium hydroxide solution. The tetrahydro- EXAMPLE 76 To 0.1 mole of 9,10'-dihydrospiro[azetidine-3,l1'-9,10- ethanoanthracene] dissolved in 250 ml. of dry benzene is added 0.11 mole of 15% butyl lithium in hexane at 05 in a nitrogen atmosphere. The resulting suspension is stirred for 15 minutes. To this suspension is added 0.11 mole of methyl iodide. The mixture is stirred at room temperature for 8 hours. At the end of this period 50 m1. of water is added. The benzene solution is separated and extracted with 2-100 ml. portions of water. The benzene solution is dried with anhydrous magnesium sulfate, filtered and evaporated to give 1-methyl-9',10'-dihydrospiro- [azetidine3,1 1-9,10-ethanoanthracene] EXAMPLE 77 To 0.1 mole 9 ,10'-dihydrospiro[azetidine-3,11'-9,10- ethanoanthracene] dissolved in 200 ml. of tetrahydrofuran there is added 0.2 mole triethylamine and 0.1 mole allyl bromide. The solution is stirred for 6 hours. At the end of this period the solution is added to two liters of water and extracted with ether. The ether is dried with anhydrous potassium carbonate, filtered and evaporated at reduced pressure. The residual oil is chromatographed through activity I alumina to give 1-allyl-9',10-dihyd rospiro [azetidine-3,1 1-9,10ethanoanthracene] It will be understood that the procedure of Examples 27 76 and 77 can be generally employed to replace the hydrogen on the azetidine nitrogen with one of the other groups within the definition of R of Formula 1.. It will be further understood that the allylbromide and methyliodide are illustrative only and that a compound containing another suitable leaving group such as alkylor arylsulfonate could be employed in the reactions.

EXAMPLE 78 To 0.1 mole 9',10'-dihydrospiro[azetidine-3,1l'-9,10- ethanoanthracene] dissolved in 200 ml. tetrahydrofuran is added 0.1 mole butyl lithium solution at 0-5 in a nitrogen atmosphere. To this solution is added 0.1 mole chloromethyl ether. The reaction is stirred at room temperature for 6 hours. At the end of this period 0.1 mole of lithium aluminum hydride is added and the solution is heated at reflux for 16 hours. At the end of this period the solution is cooled. To the solution at 0-5 is added 20% sodium hydroxide solution until the salts precipitate. The tetrahydrofuran solution is decanted, dried over anhydrous potassium carbonate, and filtered. The solvent is removed to give l-methyl-Q',10'-dihydrospiro [azetidine-3,1 1'-9',10-ethanoanthracene] EXAMPLE 79 Using the procedure of Example 78 except replacing chloromethyl ether with methyl chloroformate, there is obtained l-methyl 9',10 dihydrospiro[azetidine-3,l 1'-9, IO-ethanoanthracene] EXAMPLE 80 Using the procedure of Example 78 except replacing chloromethyl ether with methyl thiochloroformate, there is obtained 1-methyl-9,10-dihydrospiro[azetidine-S,11'- 9,10-ethanothracene] EXAMPLE 81 To 2.14 mols of trifluoroacetic anhydride dissolved in 500 ml. of methylene chloride there is added 1.75 moles of 9',10'-dihydrospiro[azetidine-3,11'-9,10-ethanoanthracene] dissolved in 1200 ml. of methylene chloride in a nitrogen atmosphere at 10 C. The solution is stirred anthracene and other solids by distillation into the second trap cooled by Dry Ice-acetone. The contents of the second trap are dissolved in ether and recrystallized from ether at -30 C. to give l-trifluoroacetyl-3-methylene azetidine, M.P. -51 C.

EXAMPLE 82 A mixture of 2 g. of 9,10-dimethylanthracene, 10 ml. of benzene and 3 g. of l-tri-fluoroacetyl-3-methylene azetidine is heated in a sealed glass tube at 200 C. for 12 hours. The benzene is removed under vacuum and the residue chromatographed on silicic acid using chloroform as eluent. The desired 9',l0-dihydro-9',l0'-dimethyll-trifiuoroacetyl[azetidine 3,11'-9,10 ethanothracene] is crystallized in the central fractions and the chloroform is stripped oif. The resulting material is added to a mixture of 25 ml. of ethanol, 2 g. of potassium hydroxide and 5 ml. of water. The mixture is refluxed for 20 minutes and poured into water. The resultant solid is extracted into ether and is dried over solid potassium hydroxide. The ether is decanted and anhydrous hydrogen chloride is passed into the ether until precipitation is complete. The solid is collected by filtration to yield 9,l0'-dihydro- 9',10-dimethyl[azetidine 3,1l-9,l0 ethanoanthracene] hydrochloride. The material, recrystallized from ethanol ether, melts with decomposition at 291 C.

AnaZysis.--Calcd. for C H ClN (percent): C, 77.05; H, 7.06; N, 4.49. Found (percent): C, 77.36; H, 7.21; N, 4.51.

EXAMPLE 83 A mixture of 0.10 mole of 1-methyl-9',10'-dihydrospiro[azetidine 3,11 9,10 ethanoanthracene] and 0.10 mole of 48% hydrobromic acid is concentrated in vacuo at C. The resulting salt, 1-methyl-9',10-dihydrospiro- [azetidine-3,1l'-9,IO-ethanoanthracenelhydrobromide, is dried in vacuo at 60, M.P. 285280 C.

EXAMPLES 84-99 Example 83 is repeated substituting the indicated acid for the hydrobromic acid of Example 83 to obtain the indicated product.

Example Acid (0.10 mole) Product 84 85% phosphoric acid..... l-methyl-9',10

.. Mnndelic acid- Pamoic acid...

phosphate. ydrogen sulfate.

tartrate M.P. 119-l20 C.

citrate. M.P. -117 C 94 I Isethionic acid 1-methyl-9,10' Methylsulfonic acid 1-methyl-9',10 Nitric acid 1rnethyl-9,10' I Hydroiodlc acidl-mgt hgl-Q'JO ydroiodide, M.P. 247- 24 98 Gluconic acid l-methyl-Q',l0-dihydrospiro[azetidinc-3,11-9,10ethanoanthraeenelgluconate.

99 Malic acid l-methyl-Q,10-dihydrospirolazetidine-s,11'-9.10-ethanoanthraeene1hydroxysuccinate.

and allowed to come to room temperature over a 1- hour period. At the end of this period, the solution is treated with 50 ml. of ethanol. The methylene chloride is removed and the residual solid is recrystallized from ethanol to give 1-trifluoroacetyl-9',10'-dihydrospiro[azetidine-3,11'-9,IO-ethanoanthracene], M.P. 206-2075".

Analysis.-Calcd. for C H NOF (percent): C, 69.96; H, 4.70; N, 4.08; F, 16.60. Found (percent): C, 70.03; H, 4.58; N, 4.28; F, 16.41.

To a 300 ml. pyrolysis flask is added 0.20 mole of 1- trifluoroacetyl 9',10' dihydrospiro[azetidine-3,l1'-9,10- ethanoanthracene]. The flask is immersed in the Woods metal bath and the heater on the discharge arm of the column is heated at 250 C. under nitrogen. The pyrolysate is collected in the first nncooled trap. Pyrolysis is continued for 1 hour. At the end of this period, the pyrolysis flask is disconnected from the rest of the train and the system is sealed. A vacuum 1 mm.) is placed on the system and the crude pyrolysate is separated from USE As mentioned above, it has been discovered that the compounds of this invention are useful as pharmaceutical agents. They are particularly useful as anti-inflammatory agents although certain of the compounds exhibited are also active as central nervous system depressants. It can therefore be recognized that the discovery of the compounds of this invention is another step forward in the worthwhile search for new and effective pharmaceutical agents.

Inflammation is a disease process characterized by redness, fever, swelling and pain. As stated above, arthritis is perhaps the most common and therefore the most economically significant inflammatory afliiction.

It will be understood that the compounds of this invention can be administered to combat inflammation by any means that effectively delivers an effective amount of the compound administered to the site of the inflammation. In many applications this means that the parenteral route of administration will be the route of choice. For example, an effective amount of a compound of this invention can be injected directly into the affected area. In other instances, subcutaneous or intramuscular application may to male, 100-gram, Carworth Farms CFE rats by oral intubation in volume of 1 ml. of formulation per 100 grams of body weight of the rat. The formulations administered are prepared as solutions in a PVA-acacia mebe preferred. Alternatively or concurrently, the comdium containing polyvinyl alcohol 1%, acacia 5% and pounds of this invention can also be administered orally methylparaben 0.1%. Uniform hydration of each rat is or applied topically. However, in most instances, oral adassured by administering a volume of water equal to 2 ml. ministration is the preferred route. per 100 grams of body weight. The formulations are pre- It will be understood that the dosage administered will pared at the dose levels indicated in Table I below. be dependent on the age, health and weight of the recipi- One hour after the drug is administered to the test subent; the severity of the condition being treated; the kind ject, 0.05 ml. of 1% carrageenin solution is injected into of concurrent treatment if any; the frequency of treatment the plantar region of the right hind paw of each rat. The and the nature of the effect desired. Generally, a daily volume of the foot is measured immediately after injecdosage of active ingredient compound will be from about tion and again three hours later. The difference between 0.3 to 100 milligrams per kilogram of body weight per the two volumes is the volume of induced edema. Foot day, although lower or higher amounts can be used. A volume is measured by immersion in mercury to an ink preferred range is from about 1.0 to about 50.0 milligrams mark on the lateral malleolus. The mercury column is conper kilogram per day in one or more doses with from about nected via hydraulic system to a strain gauge. The out ut 2.0 to about 25.0 milligrams per kilogram per day being of the transducer is led to a Sanborn transducer amplifier, most preferred. which is calibrated in terms of mercury displacement.

The compounds of this invention produced marked anti- Results are stated in Table 1 as percent inhibition of inflammatory effects in warm-blooded animals. edema at a particular dose level.

TABLE I Percent Dose, edema Compound tested mgJkg. inhibition 86 9,l0-dihydrospiro[azetidine3,11-9,IO-ethanoanthracene1hydrochloride 74 85 30 62 1methy1-9,10-dihydrospiro [azetidine-3,11-9,10-ethanoanthracenelhydrochloride 188 74 3 Toxic 30 1-[4-(p-f1uorophenyl) -4-oxabutyl]-9,lO-dihydrospiro[azetidine-3,l1-9,lOethanoanthracenelhydrochloride gg 48 e5 30 43 1-(2-hydroxyethyl) -9, IOdihydrospiro[azetidine-3,11-9,10-ethanoanthracene1hydrochlo1ide 95 30 26 1-(2-methoxyethyl)-9,10-dihyd.rospiro[azetidine-3,1l-9,10-ethanoanthracene1hydrochloride 30 19 I-(S-methoxypropyl)-9',10dihydrospiro[azetidine-ii,11'-9,lO-ethanoanthracene1hydroehloride $88 if) 30 28 1-ethyl-9',10-dihydrosplro[azetidlne-(S,l1-9,l0ethaneanthracenelhydrochloride $88 21 so 29 1-(2-methoxy-l-methylethyl) -9,l0-dihydrospiro[azetidine-3, ll-9,l0-ethanoanthracene]hydrochloride 7i 8 30 18 1-(2-hydroxypropy1)-9,10-dihydrospiro[azetidine-3,1l-9,l0ethanoanthracene1hydrochloride zligg g 30 a0 1(2-phenethyl)-9,10-dihydrospiro[azetidine-3,11-9,10-ethanoanthraceneIhydrochloride 1:83 30 0 1-[2-(methoxyphenyi)ethyl]-9,10-dihydrospiro[azetidine-3,1l-9,10cthanoanthracene1hydrochloride 30 5 Hurturyl-Q,10-dihydrospiro[azetidine-3,11-9,lO-ethanoanthracene1hydrochloride $88 5% 30 21 Alpha-9',l0-dihydrospiro[azetidine-3,11-9,10-etl1anoanthracene-l-ylhnethyl-benzyl alcohol hydrochloride. 30 2s 9,10-dihydrospiro[azetidine-3,1l'-9,l0-ethanoanthracene]-l-hexanol hydrochloride .1588 30 2a 1-(2ethoxyethyl) -9l0-dihydrospiro[azetidine-3,11-9,lO-ethanoanthracene1hydrochloride 30 26 2-(9,10-dihydrospiro)[azetidine-3,li-9,lO-ethanoanthracene]-1-butanol hydrochloride 538 I 30 14 1-(2-ethoxyethyl) -9,10-dihydrospiro[azetidine-3,11'-9,loathan0anthracene1hydrochlo1ide 58g 2g 30 0 l-[2-(p-chlorophenyl) ethyl]9,10-dihydrospiro[azetidine3,l1-9,IO-ethanoanthraeenelhydrochloride FORMULATION A test on laboratory animals used to demonstrate the anti-inflammatory activity of the compounds of this invention is based on the inhibition of carregeenin-induced edema in the rat paw as described by Winter (Winter, C. A., Risley, E. A. and Nuss, G. A., Proc. Soc. Exp. Biol. and Med., 111, 544 (1962)).

As specific examples of anti-inflammatory activity, the compounds shown in Table I below are each administered tions for parenteral use, and in certain cases, suspensions for parenteral use. In such compositions, the active ingredient will ordinarily always be present in an amount of at least 0.01% by weight based on the total weight of the composition and not more than 90% by weight.

Besides the active ingredient of this invention the composition will contain a solid or liquid non-toxic pharmaceutical carrier for the active ingredient.

In one embodiment of a pharmaceutical composition of this invention, the solid carrier is a capsule which can be of the ordinary gelatin type. The capsule will be from about 0.1% to 75% by weight of a compound of this invention and about 99.925% of a carrier. In another embodiment, the active ingredient is tableted with or without adjuvants. In yet another embodiment, the active ingredient is put into powder packets and employed. These capsules, tablets, and powders will generally constitute from about 0.5% to about 95% and preferably from 1% to 50% by weight of active ingredient. These dosage forms preferably contain from about 10 to about 500 milligrams of active ingredient, with from about 25 milligrams to about 250 milligrams most preferred.

The pharmaceutical carrier can, as previously indicated, be a sterile liquid such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, for example peanut oil, soybean oil, mineral oil, sesame oil, and the like. In general, water, saline, aqueous dextrose (glucose) and related sugar solution and glycols such as propylene glycol or polyethylene glycols are preferred liquid carriers, particularly for injectable solutions. Sterile injectable solutions such as saline will ordinarily contain from about 0.5 to 25%, and preferably about 1% to 5% by weight of the active ingredient.

As mentioned above, oral administration can be in a suitable suspension, syrup or elixir in which the active ingredient ordinarily will constitute from about 0.5 to 15% and preferably about 1% to by weight. The pharmaceutical carrier in such composition can be an aqueous vehicle such as an aromatic water, a syrup or a pharmaceutical mucilage.

Suitable pharmaceutical carriers are described in Remingtons Pharmaceutical Sciences by E. W. Martin, a well-known reference text in this field.

In addition to the examplary illustrations above, the following examples further explain one aspects of the present invention.

EXAMPLE 100 A large number of unit capsules are prepared for oral administration by filling standard two-piece No. 3 hard gelatin capsules with a homogenous mixture of 25 milligrams of powdered 1-rneth'yl-9',10-dihydrospiro[azetidine-3,11'-9,IO-ethanoanthracene}hydrochloride, 145 milligrams of lactose, l milligram of finely divided pyrogenic siica, and 3.5 milligrams of magnesum stearate.

EwAM PLE l 01 A large number of tablets are prepared by conventional procedures so that the dosage unit contains 50 mg. of 1 methyl 9',l0' dihydrospiroliazetidine-B,ll'9,l0-ethanoanthracene]hydrochloride, 75.3 mg. of mannitol, mg. of corn starch, 4.5 mg. of magnesium stearate, 0.2 mg. of finely divided pyrogenic silica, and 6 mg. of gelatin. By applying appropriate materials, enteric-coated or filmcoated tablets may be obtained.

In other tablet formulations, binders such as ethylcellulose, starch or polyethylene 4000 may be used in place of gelatin. From 1 to 7% of the total weight can be comprised of lubricants or glidants such as talc, calcium stearrate, or stearic acid in place of magnesium stearate. Tablet fillers such as lactose, microcrystalline cellulose or anhydrous lactose may also be used.

EXAMPLE 102 A parenteral composition suitable for administration by injection is prepared by dissolving 1.0% by weight of 32 1 methyl 9,10' dihydrospiro[azetidine-3,ll-9,l0-ethanoanthracene]hydrochloride in water for iniection, adding the appropriate agents for adjusting isotonicity and pH, and sterilizing the solution.

EXAMPLE 103 EXAMPLE 104 An elixir may be prepared by dissolving 1% by Weight of the 1-(2-ethoxyethyl) 9,10' dihydrospiro[azetidine- 3,1l'-9,l0-ethanoanthracene]hydrochloride in 30% aqueous alcohol containing sweeteners such as glycerin, sucrose, sorbitol, saacharin or the cyclamates. Flavors and color additives can also be added.

A large variety of compositions according to this invention can thus readily be made by substituting other compounds for this invention, and including specifically but not limited to compounds for this invention that have specifically been named hereinbefore. The compounds will be used in the amounts indicated in accordance with procedures well known and described in the Martin text mentioned above.

Since many different embodiments of the invention can be made without departing from the spirit and scope thereof, it is to be understood that the invention is not limited by the specific illustrations except to the extent defined in the following claims.

What is claimed is 1. A compound of the formula:

is N

where R; is selected from the group consisting of hydrogen, chlorine, bromine, fluorine, alkylsulfon'yl of one to four carbons, sulfamyl, trifluoromethyl, tritlluoromethylsulfonyl and alkoxy of one to four carbons;

R is selected from the group consisting of hydrogen, chlorine, bromine, fluorine, alkylsulfonyl of one to four carbons, sulfamyl, trifluoromethyl, trifluoromethylsulfonyl and alkoxy of one to four carbons;

R is selected from the group consisting of hydrogen and methyl;

R is selected from the group consisting of hydrogen and methyl; 1

R is selected from the group consisting of hydrogen, alkyl of one to six carbons, alkenyl of three to five carbon atoms, with the limitation that'the double bond not be in the 1 position, Z-hydroxyethyl, 2-hydroxy-2-phenethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-(2-hydroxyethoxy)ethyl, furfuryl, tetrahydrofurfuryl, 2-alkanoyloxyethyl, 2-alkanoyloxypro- Py 3-alkanoyloxypropyl, where the alkanoyl group contains from 1 to 3 carbon atoms, 2alkoxyethyl, 2-alkoxypropyl, 3-alkoxypro-pyl, where the alkyl con tains from one to two carbon atoms, alkyl of one to six carbons mono-substituted with a member of the group consistong of I phenyl, halophenyl, methoxyphenyl, ethoxyphenyl,

hydroxyphenyl, benzoyl, halobenzoyl, carboxamido or cyano; and a non-toxic pharmaceutically acceptable salts of said compound.

2. A compound of claim 1 where R is selected from the group consisting of hydrogen,

chlorine or trifluoromethyl;

R is selected from the group consisting of hydrogen,

chlorine or trifluoromethyl;

R is selected from the group consisting of hydrogen or methyl;

R is selected from the group consisting of hydrogen or methyl;

R is hydrogen, alkyl of one to three carbon atoms,

allyl, Z-hydroxyethyl, Z-hydroxypropyl, 3-hydroxypropyl, 2-(2-hydroxyethoxy)ethyl, furfuryl, tetrahydrofurfuryl, 2-alkanoyl0xyethyl, 2-alkanoyloxypropyl, 3-alkanoyloxypropyl, where the alkanoyl group contains from 1 to 3 carbon atoms, Z-alkox'yethyl, 2-alkoxypropyl, 3-alkoxypropyl where alkyl contains one or two carbon atoms, the mono-substituted alkyl of l to 3 carbon atoms where the mono-substituted is selected from the group consisting of phenyl, halophenyl, methoxyphenyl, ethoxyphenyl,

hydroxyphenyl, benzoyl, halobenzoyl, carboxamido or cyano;

and non-toxic pharmaceutically acceptable salts of the above.

3. A compound of claim 2 where R is selected from the group consisting of hydrogen, methyl or allyl and a pharmaceutically acceptable salt of said compound.

4. The compound of claim 1 which is 9',10'-dihydrospiro[azetidine-3,1 1-9,lO-ethanoanthracene].

5. A non-toxic pharmaceutically acceptable salt of the compound of claim 4.

6. The compound of claim 1 which is 1-methyl-9,l0'- dihydrospiro [azetidine-3,l l'-9, l O-ethanoanthracene].

7. A non-toxic pharmaceutically acceptable salt of the compound of claim 6.

8. The compound of claim 1 which is l-allyl-9',lO-dihydrospiro [azetidine-3 ,l 1-'9, l O-ethanoanthracene].

9. The non-toxic pharmaceutically acceptable salt of the compound of claim 8.

10. The compound l-trifluoroacetyl-9,10-dihydrospiro [azetidine-3,l 1'-9, lO-ethanoanthracene] References Cited UNITED STATES PATENTS 2,931,805 4/1960 Weinstouk 260326.5 3,257,456 6/1966 Smith 2/60326.5 3,310,469 3/ 1967 P'awlshock et a1. 260326.5

ALTON D. ROLLINS, Primary Examiner U.S. Cl. X.R.

260347.2, 347.7, 456 R, 456 P, 556 B, 607 A, 609 R, 613 R, 618 D, 618 F, 651 R; 424244, 285