US3707471A

US3707471A - Fluoranthene bis-basic ethers and thioethers

Info

Publication number: US3707471A
Application number: US32456A
Authority: US
Inventors: William L Albrecht; Robert W Fleming
Original assignee: Richardson Merrell Inc
Current assignee: Richardson Vicks Inc
Priority date: 1970-04-27
Filing date: 1970-04-27
Publication date: 1972-12-26
Anticipated expiration: 1989-12-26
Also published as: CA960218A

Abstract

THE NOVEL BIS-BASIC ETHERS AND THIOETHERS OF FLUORANTHENE OF THE PRESENT INVENTION HAVE USEFUL ANTIVIRAL ACTIVITY. THESE NEW COMPOUNDS ARE REPRESENTED BY THE FOLLOWING FORMULA:

R2-N<(-(CH2)M-(CH2)3-)(-(CH2)N-)

BIS(X-Y-)FLUORANTHENE

WHEREIN EACH Y IS OXYGEN OR DIVALENT SULFUR; AND EACH X IS (A) THE GROUP

-A-N(-R)-R1

WHEREIN EACH A IS A STRAIGHT OR BRANCHED ALKYLENE CHAIN HAVING FROM 2 TO 8 CARBON ATOMS; R AND R1 ARE INDIVIDUALLY HYDROGEN, (LOWER)ALKYL HAVING FROM 1 TO 6 CARBON ATOMS, CYCLOALKYL OF FROM 3 TO 6 CARBON ATOMS, ALKENYL OF FROM 3 TO 6 CARBON ATOMS AND HAVING THE VINYL UNSATURATION IN OTHER THAN THE 1-POSITION OF THE ALKENYL GROUP; OR EACH SET OF R AND R1 TAKEN TOGETHER WITH THE NITROGEN ATOM TO WHICH THEY ARE ATTACHED IS A SATURATED MONOCYCLIC HETEROCYCLIC GROUP SUCH AS PYRROLIDINO, PIPERIDINO, MORPHOLINO OR N-(LOWER)ALKYLPIPERAZINO; OR (B) THE GROUP R2-N<(-CH2-CH2-CH(-(CH2)N-)-(CH2)M-) WHEREIN N IS A WHOLE INTEGER FROM 0 TO 2, M IS 1 TO 2, AND R2 IS HYDROGEN (LOWER)ALKYL OF FROM 1 TO 6 CARBON ATOMS, OR ALKENYL OF FROM 3 TO 6 CARBON ATOMS AND HAVING THE VINYL UNSATURATION IN OTHER THAN THE 1-POSITION OF THE ALKENYL GROUP. THIS INVENTION ALSO INCLUDES PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS OF THE BASES REPRESENTED BY FORMULA I. THESE NEW COMPOUNDS MAY BE PREPARED BY SEVERAL DIFFERENT METHODS WHICH ARE DESCRIBED.

Description

United States Patent 3,707,471 FLUORANTHENE BIS-BASIC ETHERS AND THIOETHERS William L. Albrecht and Robert W. Fleming, Cincinnati, Ohio, assignors to Richardson-Merton, Inc., New York,

NI) brawing. Filed Apr. 27, 1970, Ser. No. 32,456 Int. (:1. 007a 29/28 us. or. 260293.62 Claims ABSTRACT OF THE DISCLOSURE The novel bis-basic ethers and thioethers of fiuoranthene of the present invention have useful antiviral activity. These new compounds are represented by the following formula:

Formula wherein each Y is oxygen or divalent sulfur; and each X is (A) the group wherein each A is a straight or branched alkylene chain having from 2 to 8 carbon atoms; R and R are individually hydrogen, (lower)alkyl having from 1 to 6 carbon atoms, cycloalkyl of from 3 to 6 carbon atoms, alkenyl of from 3 to 6 carbon atoms and having the vinyl unsaturation in other than the 1-position of the alkenyl group; or each set of R and R taken together with the nitrogen atom to which they are attached is a saturated monocyclic heterocyclic group such as pyrrolidino, piperidino, morpholino or N-(lower)alky1- piperazino; or

(B) the group This invention relates to novel fiuoranthene bis-basic ethers and thioethers, their method of preparation and use as antiviral agents. The compounds of this invention include both the base form and pharmaceutically accept- Patented Dec. 26, 1972 able acid addition salts of the base wherein the base form is represented by the general formula Formula I wherein each Y is oxygen or divalent sulfur; and each X is (A) the group (B) the group wherein n is a whole integer of from 0 to 2, m is 1 or 2, and R is hydrogen, (lower)alkyl having from 1 to 6 carbon atoms, or alkenyl of from 3 to 6 carbon atoms and having the vinyl unsaturation in other than the 1- position of the alkenyl group.

As can be seen from the above Formula I one of the side chains, that is, -YX, is on the naphthalene portion of the fiuoranthene ring whereas the other is on the benzene portion of the fiuoranthene ring. Thus, one of the basic groups can be linked to the fiuoranthene ring by replacement of one of the hydrogen atoms in positions 1 through 6, and the other replaces one of the hydrogen atoms in positions 7 through 10 of the fiuoranthene ring. Preferably, the side chains are in the 3- and 8-positions or the 3- and 9-positions of the fiuoranthene ring.

Although one of the two X groups on a compound of the above general Formula I can be and the other can be the group it is preferred that both X groups are the same as more fully shown by the following general Formulas H and III:

; Formula III In the above general Formulas II and III, the various groups Y, A, R, -R R n and m have the same meanings given hereinbefore.

Each of the symbols A in the above Formula II is an alkylene group having from 2 to 8 carbon atoms which can be straight chained, or branched chained, and which separates Y, that is, the ether oxygen or thioether sulfur, from the amino nitrogen by an alkylene chain of at least 2 carbon atoms. Each of the alkylene groups represented by A can be the same or different, although preferably both of these groups are the same. Illustrative of alkylene groups represented by A there can be mentioned for example: 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5- pentylene, 1,6-hexylene, 2-methyl-1,4-butylene, Z-ethyl- 1,4-butylene, 3-methyl-1,5-pentylene and the like. Preferably A is an alkylene group having from 2 to '6 carbon atoms.

In the compounds of Formula H each amino group,

that is,

groups is a tertiary amino group.

The term (lower)alkyl as used herein relates to straight or branched alkyls having from 1 to 6 carbon atoms. Illustrative of (lower)a1ky1s which can be represented -by each R or R in the compounds of Formula H, or R in the compounds of Formula IH there can be mentioned straight or branched chain alkyls, such as, for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, n-pentyl, isoamyl, n-hexyl and the like.

The heterocyclic groups which can be represented by each group of Formula II are saturated monocyclic heterocyclic groups. These heterocyclic groups, in addition to the one nitrogen atom, can contain a second hetero atom, such as, for example, oxygen or nitrogen in the ring and 4 or 5 ring carbon atoms. The ring can be substituted with a (lower)alkyl group, particularly, with an alkyl group having from 1 to 3 carbon atoms. As examples of suitable heterocyclic groups which are represented by R and R taken together with the nitrogen atom to which they are attached there can be mentioned for example, pyrrolidino, piperidino, morpholino, N-(lower)alkylpiperazino, such as, N-methyl or N-ethylpiperazine and the like.

Each R, R or R group can be the same or different in each of the basic ether or thioether groups attached to the fluoranthene ring system. Preferably, however, both of the R groups, R groups or R groups in each compound are the same. Preferred substituents for the R, R and R groups are alkyl radicals having from 1 to 6 carbon atoms.

Each of the saturated hetherocyclic groups of the compounds of Formula III can be attached to Y through an alkylene linkage of l or 2 carbon atoms, for example, methylene or 1,2-ethylene, or each saturated heterocyclic group can be attached to Y through a ring carbon atom of the heterocyclic group when n is zero. The saturated heterocyclic group is attached to either the alkylene group or Y through a carbon atom of the ring by replacement of one of the hydrogen atoms of the ring. The heterocyclic groups in the compounds represented by Formula III can be 5- or 6-membered rings, that is, m is 1 or 2. As examples of various groups represented by in the compounds of the present invention there can be mentioned for example: N-methyl-4-piperidyl, N-methyl- 3-p1per1dyl, N-ethyl-3-pyrro1idyl, (N-methyl-4-piperidyl) methyl, (N-methyl-3-piperidyl)methyl, 2-(2-piperidyl) ethyl and the like.

Illustrative of base compounds of this invention as represented by general Formula II there can be mentioned for example:

3,9-bis (4-aminobutoxy fiuoranthene,

3 ,9-bis [Z-(diethylamino) ethylthio1fiuoranthene,

3,9-bis [2- (diethylamino) ethoxy] fiuoranthene, 3,8-bis[2-(diethylamino)ethoxy1fiuoranthene,

3,9-bis [3-(diethylamino)propoxyl1fluoranthene,

3 ,9-bis [2- diisopropylamino)ethoxy]fiuoranthene, 3,9-bis [5- (dipropylamino) pentoxy1fiuoranthene, 3,9-bis [2-(diethylamino) -1-methylethoxy] fluoranthene, 3 ,9-bis[ 3- (dimethylamino -2-methylpropoxy] floranthene, 3,8-bis [3- (dimethylamino) propoxy] fiuoranthene and the like.

Illustrative of base compounds of this invention as represented by general Formula III there can be mentioned for example: 3,9-bis [2-(N methyl 4 piperidyl) ethoxy]fluoranthene, 3,9-bis [2- (N-methyl 4 piperidyl)- ethylthio]fluoranthene, 3,9-bis(N-methyl-4-piperidyloxy) fluoranthene, 3,8-bis[2-(N-methyl 4 piperidyl)ethoxy] fluorantheue and the like.

The pharmaceutically acceptable acid addition salts of the base compounds of this invention are those of any suitable inorganic or organic acids. Monoor bis-acid addition salts can be formed, although in practice, the bis-salts are usually isolated. Also, the salts can be hydrated, for example, monohydrate, or substantially anhydrous. Suitable inorganic acids for preparing the salt form are, for example, mineral acids, such as, hydrochloric, hydrobromic, sulfuric or phosphoric acids and the like. Suitable organic acids are, for example, citric acid, malic acid, glycolic acid, lactic acid, tartaric acid, malonic acid, succinic acid, maleic acid, fumaric acid and the like.

Hal-A-YO Y-A-Hal The compounds of the present invention can be administered to prevent or inhibit infections of picornaviruses, for example, encephalomyocarditis; myxoviruses, for example, Influenza A (Jap/ 305 arboviruses, for example, Semliki Forest; herpesvirus group, for example, herpes simplex; and pox-viruses, for example, Vaccinia IHD. When administered prior to infection, that is, prophylactically, it is preferred that the administration be within 0 to 96 hours prior to infection of the animal with pathogenic virus. When administered therapeutically to inhibit an infection, it is preferred that the administration be Within about a day or two after infection with pathogenic virus.

The dosage administered will be dependent upon the virus for which treatment or prophylaxis is desired, the type of animal involved, its age, health, weight, extent of infection, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. Illustratively, dosage levels of the administered active ingredients can be: intravenously, 0.1 to about 10 mg./kg.; intraperitoneal, 0.1 to about mg./kg.; subcutaneous, 0.1 to about 250 mg./kg.; orally, 0.1 to about 500 mk./kg. and preferably about 1 to 250 mg./kg.; intranasal instillation, 0.1 to about 10 mg./kg.; and aerosol, 0.1 to about 10 mg./ kg. of animal body weight.

The compounds may be administered, dissolved or suspended, in any conventional non-toxic pharmaceutical carrier of the type that may be taken orally, applied topically, buccally or parenterally.

The compounds of the present invention may be prepared by various methods such as, for example, according to the methods described below in the several schemes illustrated by the equations and in the specific examples.

Scheme 1 ill Base (2 equivs.)

(2 equls.)

(1 equv lent) Formula II Scheme 2 (1 equiv.)

(4 equivs.)

Scheme 3 Formula III In the above reaction schemes, Y, RR N--, A, R m, and n have the same meanings specified hereinbefore, and each Hal is either Cl, Br or 1.

Typical haloalkylamines, 2, useful in Scheme 1, are for example, N,N-diethyl-Z-chloroethylamine, N-(2-chloroethyl)piperidine and the like. Typical dihaloalkanes, 3, useful in Scheme 2 are for example, l-bromo-Z-chloroethane, 1,6-dibromohexane and the like. Amines, 5, useful in Scheme 2 are primary amines such as, for example, ethylamine, or secondary amines, such as, for example, dimethylamine, or tertiary amines, such as, for example, hexamethylenetetramine and the like. Typical of the halogen substituted heterocyclic nitrogen compounds, 6, useful in Scheme 3 are for example, 3-chlorometl1yl-1- methyl-piperidine and the like.

In the above reaction schemes, the base used may be for example, sodium methoxide, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide and the like. Solvents used as the reaction medium may vary over a wide range of solvent types and include aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated aromatics, such as chlorobenzene and the like; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and the like; alcohols such as ethanol, isopropanol and the like; ketones such as acetone, butanone and the like; ethers such as tetrahydrofuran, dioxane and the like; Water; or mixtures of solvents.

*In the method of synthesis where either sodium methoxide, sodium amide or sodium hydride, for example, is used as the base, the reaction is carried out in an anhydrous medium, such as anhydrous toluene, chlorobenzene and the like. About 2.5 equivalents of the base is added to a suspension of, for example, 1 equivalent of compound 1 where Y is oxygen in the anhydrous solvent, and the mixture heated to form the diphenoxide. In the case where sodium methoxide is used, the methanol formed may be removed advantageously by azeotropic distillation. About 2.5 equivalents of the halide, 2, 3 or 6 is then added and the mixture heated to reflux for a period which may vary from about 4 to 24 hours. The products, that is, compounds of Formula II or III and compound 4 are then isolated by customary procedures. Compounds of Formula II and III are usually isolated as bis-acid addition salts.

In the method where an alkali hydroxide, such as potassium hydroxide, for example, is used as the base, two difierent procedures may be used. In the one procedure a 25 to 50 percent aqueous solution of the alkali hydroxide (about 2.5 equivalents) is added to a suspension of, for example, 1 equivalent of compound 1 wherein Y is oxygen in a suitable aromatic solvent, such as, for example, xylene. This mixture is then heated to boiling, stirring being optional, and the water removed by azeotropic distillation, a convenient method being to collect the water in a device such as the Dean-Stark distilling receiver. The reaction mixture, now being essentially anhydrous, is treated with about 2.5 equivalents of the halide, compound 2, 3 or 6, as described above. In the other procedure the reaction is carried out in a heterogeneous medium of water and an aromatic hydrocarbon, such as, for example, toluene, xylene and the like. For example, 1 equivalent of compound 1 where Y is oxygen is suspended in the aromatic hydrocarbon. Then in Schemes 1 and 3, a solution of about 2.5 equivalents of a hydrohalide salt of the amino halide, that is, a hydrohalide salt of 2 or 6, in the minimum volume of water is added and with efficient stirring, a 25 to 50 percent solution of the alkali hydroxide (about 5 equivalents) is added. The mixture is heated to reflux for a period of about 6 to 24 hours, and the product isolated from the hydrocarbon layer. In Scheme 2, when the aqueous/ aromatic hydrocarbon medium is used to prepare compounds of type 4, which contain no amine functions, the amount of alkali hydroxide used is only in slight excess of 2.0 equivalents per 1 equivalent of diphenol or dithiol, that is, compound 1 wherein Y is equal to oxygen or divalent sulfur.

In Scheme 2, the reaction between the bis( w-'haloalkyl) ether or thioether, 4, and the amine, 5, may be carried out under a variety of conditions. For example, the compound 4 may be heated together with a large excess of the amine, 5, the excess amine serving as both the reaction medium and the hydrohalide acceptor. This method is particularly suitable for readily available amines, the excess of which can be easily removed from the reaction mixture by, for example, distillation at reduced pressure or by steam distillation. Or, 1 equivalent of the biS(whaloalkyl)ether or thioether, 4, and 4 equivalents of the amine, 5, may be heated together in one of a number of different types of solvents, for example, in aromatic solvents, such as, benzene, toluene, xylene, chlorobenzene and the like; or lower molecular weight alcohols, such as, methanol, ethanol, isopropyl alcohol and the like; or lower molecular weight ketones, such as, acetone, methyl ethyl ketone and the like. The reaction between the halo compound and the amine is usually promoted by the addition of either sodium or potassium iodide, the iodide being used in either catalytic or stoichiometric amounts. In some cases, it may be advantageous to use only two equivalents of the amine, 5, for each equivalent of the bisM-haloalkyl) ether or thioether, 4, an excess of either powdered sodium or potassium carbonate being used as the acceptor for the hydrohalide generated. In the case of volatile amines, this reaction may be best carried out under pressure in a suitable bomb or autoclave.

Formula II (A=A CH2) In this scheme of synthesis, R, R A and Y have the same meanings specified hereinbefore, and A is an alkylene chain having one less methylene, CH group in a straight chain than does A, that is, A=A +CH The intermediate nitriles, 7a, and amides, 7b, may be prepared by the method illustrated, for example, in Scheme 1 above, in which the appropriate w-haloalkyl nitriles and amides are substituted for the w-hfllOZllkYl amines, 2.

According to the method of preparation illustrated in Scheme 4, compounds of Formula II, in which both R and R are hydrogen, may be prepared from either the nitriles, 7a, or the unsubstituted amides, 717, wherein R=R =H. Secondary amines, that is, compounds of Formula II wherein R=H and R is not H, can also often be prepared by this method from the corresponding secondary amides, 7b, wherein R=H and R is not H.

Scheme N Alk l ation N-A-Y Y-A-N Rl 1 Formula II (R=H) R\ K /R NA--Y I Y-A-N Formula II (R is not H) In this scheme of synthesis, R A and Y have the same meanings specified hereinbefore, and with the exceptions noted in the two formulas above, R has the same meaning specified hereinbefore.

Alkylation of the primary amines, that is, compounds of Formula II wherein R=R =H, by the method illustrated in Scheme 5 may be used to prepare either the secondary amines, that is, compounds of Formula II wherein R=H and R is not H, or the symmetrically substituted tertiary amines, that is, compounds of Formula II wherein R==R but neither is H.

One method for preparing the secondary amines, that is, compounds of Formula II wherein R==H and R is not H, is the reaction of the primary amines, that is, compounds of Formula II wherein R=R =H with the stoichiornetric quantities of the appropriate aldehydes or ketones to yield the corresponding Schiffs bases, which may then be reduced with either a borohydride or molecular hydrogen in the presence of a catalyst, such as platinum or Raney nickel, for example. Another method for preparing the secondary amines is acylation of the primary amines with the appropriate acyl halides or anhydrides, followed by reduction of the N-acyl with lithium aluminum hydride.

Reductive alkylation of the primary amines with an excess of the appropriate aldehydes or ketones in the presence of molecular hydrogen and a catalyst, such as platinum or Raney nickel, for example, will yield the symmetrically substituted tertiary amines, that is, compounds of Formula II wherein R=R but neither is H.

Alkylation of the primary amines with a large excess of the appropriate halides yields the symmetrically substituted tertiary amines, that is, compounds of Formula II wherein R=R but neither is H. Alkylation of the primary amines with formaldehyde and formic acid by the Eschweiler-Clarke procedure yields the tertiary amines of Formula II in which R=R =CH Alkylation of the secondary amines, that is, compounds of Formula II wherein R=H and R is not H by the method illustrated in Scheme 5 may be used to prepare either the symmetrically substituted tertiary amines, that is, compounds of Formula II wherein R=R but neither is H or the unsymmetrically substituted tertiary amines, that is, compounds of Formula II wherein R and R are difierent and neither is H.

Reaction of the secondary amines with the appropriate halides is one method for eifecting N-alkylation. Another useful method is the reductive alkylation of the secondary amines with the appropriate aldehydes or ketones in the presence of molecular hydrogen and a catalyst, such as platinum or Raney nickel, for example. Another useful alkylation method is the two-tsep method whereby the secondary amines are acylated with the appropriate acyl halides or anhydrides and the resulting N-acyl amines are reduced with lithium aluminum hydride to the corresponding tertiary amines. Alkylation of the secondary amines with formaldehyde and formic acid by the Esch- Weiler-Clarke procedure is a method for preparing the tertiary amines of Formula II in which R=CH Another useful method for preparing the bis-basic ethers and thioethers represented by Formulas II and III is illustrated in Scheme 6.

Scheme 6 o o R l H Base CH3-CY Y-C-CH; N-A-Hal.

(2 equi- R valents) 8 2 l (1 equivalent) (2 equivalents) Y-A-N Rt R,

Formula II This method is equally applicable to the preparation of bis-basic ethers and thioethers represented by Formula III, in which case haloalkylamines of type 6 are substituted for the type 2 haloalkylamines shown in the above illustration.

By the method of Scheme 6, the bis-basic ethers and thioethers can be prepared directly from the diacetates of fluoranthene-diols and -dithiols, that is, compound 8 wherein Y is equal to oxygen or divalent sulfur, which in some cases are more conveniently isolated than are the diols and dithiols, that is, compound l'wherein Y is equal to oxygen or divalent sulfur, particularly, when the latter are relatively unstable or diflicult to purify.

In this procedure, it is often advantageous to use the hydrochloride salt of the haloalkylamine, 2 or 6, in place of the base form, in which case, the amount of base is doubled. Conveniently, the base used can be an alkali alkoxide, such as sodium methoxide, sodium ethoxide and the like. Solvents used in this procedure include aromatic hydrocarbons, such as benzene and toluene, and halogenated aromatics, such as chlorobenzene and the like. Reaction conditions can vary over a wide range with respect to the reaction period and temperature; however, the reaction is generally effected at the reflux temperature of the solvent for a period of 6 to 72 hours. The preferred method is to heat a mixture of compound 8, the hydrochloride salt of compound 2 or 6, and four equivalents of sodium methoxide in refluxing chlorobenzene for 24 hours.

The intermediate fluoranthene diols, that is, compound 1 wherein Y is oxygen, may be synthesized in the following manner. Two general methods avilable for the preparation of 3,9-dihydroxyfluoranthene [N. Campbell and N. H. Kier, J. Chem. Soc., 1233 (1955)] are the alkali fusion of fluoranthene-3,9-disulfonic acid obtained by the disulfonation of fluoroanthene and the Baeyer-Villiger oxidation of 3,9-diacetylfluoranthene followed by hydrolysis. Hydrolysis of the bis-diazonium sulfate of 3,8-diaminofluoranthene, prepared by the method disclosed by Th. Holbro and N. Campbell, J. Chem. Soc., 2652 (1957) will yield 3,8-dihydroxyfiuoranthene. The corresponding fluoranthene dithiols, that is, compound 1 wherein Y is equal to divalent sulfur, can be prepared by the thermal rearrangement of the bis-thiocarbamate of the above diols followed by alkaline hydrolysis, according to the procedure as disclosed by M. S. Newman and H. A. Karnes, J. Org. Chem. 31, 3980 (1966) for the conversion of phenols to thiophenols.

The diacetates, 8, can be obtained by acetylation of the above described diols and dithiols.

Representative compounds of the present invention and several of the methods of preparing them, mentioned above, are illustrated in the following specific examples.

EXAMPLE 1 3,9-bis(3-piperidinopropoxy)fluoranthene max.

EXAMPLE 2 3,9-bis[3-(diethylamino)propoxy]fluoranthene dihydrochloride When 3-(diethylamino)propyl chloride was used in place of 3-piperidinopropyl chloride hydrochloride and the procedure of Example 1 was followed, the product obtained as the free base was subsequently converted to the dihydrochloride salt with ethereal hydrogen chloride and crystallized from methanol-butanone. M.P. 235- 236.5 C.,

12 EXAMPLE 3 3,9-bis[3 -(dibutylamino)propoxy]fluoranthene dihydrochloride When 3-(dibutylamino)propyl chloride was used in place of 3-(diethylamino)propyl chloride and the procedure of Example 2 was followed, the desired product was obtained. M.P. 170-172 C.,

A532 298, Elt... 623

EXAMPLE 4 3,9-bis [2- (diethylamino) ethoxy]fluoranthene dihydrochloride When 2- (diethylamino)ethyl chloride hydrochloride was used in place of 3-(diethylamino)propyl chloride and the procedure of Example 2 was followed, the desired product was obtained. M.P. 220-222 C.,

max.

EXAMPLE 5 3,9-bis(Z-morpholinoethoxy)fiuoranthene dihydrochloride A53; 241, Etta. 783

EXAMPLE 6 3,9-bis [2-(dimethylamino)-1-methylethoxy] fluoranthene When 2-(dimethylamino)-l-rnethylethyl chloride was used in place of N-(Z-chloroethyl)morpholine and the procedure of Example 5 was followed, the product was obtained as a yellow viscous oil after subsequent chromatography of the free base on alumina, using chloroform to elute the product.

x533 243, 1060 EXAMPLE 7 3,9-bis(2-piperidinoethoxy)fluoranthene When Z-piperidinoethyl chloride was used in place of 2-(dimethylamino)-1-methylethyl chloride and the procedure of Example 6 was followed, the desired product was obtained which was recrystallized from chloroformpentane. M.P. 122-123.5 C.,

EXAMPLE 8 3,9-bis [Z-(diethylamino) -l-methylethoxy]fluoranthene When 2-(diethylamino)-l-methylethyl chloride was used in place of 2-(dimethylamino)-1-methylethyl chloride and the procedure of Example 6 was followed, the desired product was obtained as viscous oil.

EES. lf... 946

EXAMPLE 9 3,9-bis[3-(dimethylamino)propoxy]fiuoranthene When 3-(dimethylamino)propyl chloride was used in place of 2-(dimethylamino)l-methylethyl chloride and the procedure of Example 6 was followed, the desired product was obtained after crystallization from methylene chloride-pentane. M.P. 82 C.,

13 EXAMPLE Following the procedure of Example 1, only substituting for 3,9-dihydroxyfluoranthene, the appropriate molar equivalent amounts of 3,8-dihydroxyfiuoranthene or fluoranthene-3,9-dithiol the following compounds are prepared: 3,8-bis(3-piperidinopropoxy)fluoranthene 3,9-bis(3-piperidinopropylthio)fluoranthene.

EXAMPLE 1 1 3,9-bis [2- (dihexylamino ethoxy] fluoranthene When Z-(dihexylamino) ethyl chloride hydrochloride is used in place of 3-piperidinopropyl chloride hydrochloride and the procedure of Example 1 is followed, the desired product is obtained.

EXAMPLE 12 3,9-bis[2-(ethylamino)ethoxy] fluoranthene dihydrochloride (A) To a stirred mixture of 0.1 mole of 3,9-dihydroxyfluoranthene and 0.3 mole of l-bromo-2-chloroethane in 400 ml. of water is added dropwise, over a period of 30 minutes, 80 ml. of 10% aqueous sodium hydroxide. After complete addition of the alkali, the mixture is refluxed with stirring for eighteen hours. Upon cooling, the supernatant water layer is decanted and the residue taken up in ethanol. The solid which separates is filtered and crystallized from ethanol-chloroform to yield 3,9bis(2-chlo roethoxy)fluoranthene.

(B) A mixture of 0.1 mole of 3,9-bis(2-chloroethoxy) fluoranthene, 1.0 mole of ethylamine, 2.0 g. of potassium iodide and 100 ml. of tetrahydrofuran is heated with stirring at 110 C. for 24 hours in a Parr pressure reactor. The solvent and excess amine are removed in vacuo, and the resulting residue is treated with dilute sodium hydroxide and ether. The ether layer is washed twice with water, dried over magnesium sulfate and acidified with ethereal hydrogen chloride to give the desired product which can be crystallized from methanol-ethyl acetate.

EXAMPLE 13 3,9-bis(2-aminoethoxy)fluoranthene dihydrochloride When hexamine is used in place of ethylamine and the procedure of Example 12(B) is followed, the desired product is obtained after subsequent decomposition of the intermediate quaternary ammonium complex with dilute acid.

EXAMPLE 14 3,9-bis[6-(diethylamino)hexyloxy] fluoranthene dihydrochloride Following the procedure of Example 12(A), only substituting for 1-bromo-2-chloroethane, l-bromo-6-chlorohexane, the intermediate 3,9-bis(6-chlorohexyloxy)fluoranthene is prepared. When an excess of diethylamine is allowed to react with 3,9-bis(6-chlorohexyloxy)fluoranthene by the procedure of Example 12(B), the desired product is obtained.

EXAMPLE l5 3,9-bis[l-metliyl-3-piperidyl)methoxy] fluoranthene dihydrochloride Following the procedure of Example 5, only substituting for N-(2-chloroethyl)morpholine, the appropriate molar equivalent amounts of 3-chloromethyl-1-methylpiperidine, the desired product is obtained.

EXAMPLE 16 3,8-bis-[ 1-methyl-3-piperidyl) ethoxy] fluoranthene dihydrochloride Following the procedure of Example 1 only substituting respectively for 3,9-dihydroxyfluoranthene and piperidinopropyl chloride the appropriate molar equivalent amounts 14 of 3,8-dihydroxyfluoranthene and 3-chloroethyl-1-methy1- piperidine, the desired product is obtained.

What is claimed is: 1. A compound seelcted from a base of the formula wherein each Y is a member selected from the group consisting of oxygen or divalent sulfur; and each X is a member selected from the group consisting of (A) the group wherein each A is an alkylene chain having from 2 to 8 carbon atoms and which separates the amino nitrogen and Y by at least 2 carbon atoms; R and R are individually selected from the group consisting of hydrogen, (lower)alky1 having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, alkenyl of from 3 to 6 carbon atoms and having the unsaturation in other than the l-position of the alkenyl group; or each set of R and R taken together with the nitrogen atom to which they are attached is a saturated monocyclic heterocyclic group such as pyrrolidino, piperidino, mor-pholino or N-(lower)alkylpiperazino; or

(B) the group wherein n is a whole integer of from 0 to 2, m is 1 or 2, and R is a member selected from the group consisting of hydrogen, (lower)alkyl having from 1 to 6 carbon atoms, or alkenyl of 3 to 6 carbon atoms and having the vinyl unsaturation in other than the 1-position of the alkenyl group;

or a pharmaceutically acceptable acid addition salt of said base.

2. A 'COl'llP0llIld of claim 1 wherein each Y is oxygen and each X is the group and one of said -YX groups is in the 3-position of the fluoranthene ring system and the remaining -Y-X group is in the 8- or 9-position.

3. A compound of claim 2 wherein R is (lower)alkyl having from 1 to 6 carbon atoms.

4. A compound of claim 1 where Y is oxygen and X is the group R AN wherein each R and R is (lower)alkyl having from 1 to 6 carbon atoms, or each set of R and R taken together with the nitrogen atom to which they are attached is a saturated monocyclic heterocyclic group such as pyrroli- 15 dino, piperidino, morpholino or N-(lower)alkylpiperazino; and wherein one of the groups is in the 3-position of the fluoranthene ring system and the other such group is in the 8- or 9-position of the fluoranthene ring system.

5. A compound of the formula.

wherein each A is an alkylene chain of 2 to 6 carbon atoms and which separates the ether oxygen from the amino nitrogen by an alkylene chain of at least 2 carbon atoms; each R and R is (lower)alkyl, or each set of R and R taken together with the nitrogen atom to which they are attached is a saturated monocyclic heterocyclic group such as pyrrolidino, piperidino, morpholino or N- (lower) alkylpiperazino; or a pharmaceutically acceptable acid addition salt thereof.

6. A compound of claim 5 which is 3,9-bis(3-piperidinopropoxy)fiuoranthene or a pharmaceutically acceptable acid addition salt thereof.

7. A compound of claim 5 which is 3,9-bis(2-piperidinoethoxy)fluoranthene or a pharmaceutically acceptable acid addition salt thereof.

8. A compound of claim 5 which is 3,9-bis[3-(dibutylamino)propoxy]fluoranthene or a pharmaceutically acceptable acid addition salt thereof.

9. A compound of claim 5 which is 3,9-bis[2-(diethylamino)-1-methylethoxy]fluoranthene or a pharmaceutically acceptable acid addition salt thereof.

10. A compound of claim 5 which is 3,9-bis[3-(diethylamino)propoxy]fluoranthene or a pharmaceutically acceptable acid addition salt thereof.

References Cited UNITED STATES PATENTS 2,075,359 3/1937 Salzberg et a1. 424-250 2,652,417 9/1953 Steinberg 260-469 JOHN D. RANDOLPH, Primary Examiner S. D. WINTERS, Assistant Examiner US. Cl. X.R.

424-248, 250, 267, 274, 330; 260-246B, 268Pc, 326.3, 326.5G, 326.83, 326.84, 455R, 465F, 559R, 570.55, 570.7, 609R