DE2123992C3 - 3,9-bis-ether of fluoranthene and its production - Google Patents

Description

in which A is an alkylene chain with 2 to 6 carbon atoms and R and R ¹ individually alkyl radicals with 1 to 6 carbon atoms or together with the adjacent nitrogen atom a pyrrolidino, piperidino, morpholino or N- (Ci -rAlkylJ-piperazino radical represent, and their pharmaceutically acceptable acid addition salts.

2. A method for producing a compound according to claim 1, characterized in that a fluoranthene diol of the formula is used in a manner known per se

HO

with a haloalkylamine of the general formula

Hal-A -N

R "

wherein A, R and R ^{1 have} the meaning given in claim 1 and Hal is chlorine, bromine or iodine, is reacted in the presence of a base

The present invention relates to 3,9-bis-ethers Fluoranthens, which are anti-virus agents. the Compounds according to the invention are both bases and pharmaceutically acceptable acid addition salts of corresponding bases. The bases are represented by general formula I above.

As can be seen from the above formula I, one of the side chains is in the naphthalene portion of the fluoranthene radical, while the other is in its benzene portion is bound.

With A in the above formula I becomes an alkylene group understood with 2 to 6 carbon atoms, which can be straight-chain or branched and the The ether oxygen from the nitrogen atom is separated by an alkylene chain of at least 2 carbon atoms Alkylene groups A can be identical or different; the groups are preferably identical. as Examples of alkylene groups A are: 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, 2-methyl-1,4-butylene, 2-ethyl-1,4-butylene or 3-methy! -1,5-pentylene residue

ίο R and R ¹ can be alkyl radicals with 1 to 6 carbon atoms. In the present description, this is understood to mean straight-chain or branched alkyl radicals. Examples of alkyl radicals R or R ¹ in the compounds of the formula I are, for. E. The methyl, ethyl, n-propyl, isopropyl, η-butyl, selc-butyl, tert-butyl, n-pentyl, isoamyl or n-hexyl radical understood.

Heterocyclic radicals -N (R ¹ JR in the formula I are

the pyrrolidino, piperidino, morpholino, N-alkyl piperazino radical, where the N-alkyl radical has 1 to 3 carbon atoms

has, e.g. B. the N-methyl or N-ethylpiperazino rest

The radicals R and R ¹ in each basic ether group can be identical or different. Preferably, however, both of the groups R and R ^{1 are the} same.

The following examples of compounds of the formula I according to the invention are listed: 3,9-bis [2- (diethylamino) ethoxy] -

fluoranthene, 3,9-bis [3- (diethylamino) propoxy] -

fluoranthene, 33-bis- [2- (diisopropylamino) ethoxy] -

fluoranthene,

33-bis [5- (dipropylamino) pentoxy] fluoranthene,

33- bis [2- (diethylamino) -1 -roethylethoxy] -

fluoranthene, 3,9-bis [3- (dimethylamino) -2-methylpropoxy] -

fluoranthene.

Pharmaceutically acceptable acid addition salts of the basic compounds according to the invention are those with suitable inorganic or organic ones Acids. Mono- or bis-acid addition salts can be formed, although in practice usually the Bis salts can be isolated. The salts can also be hydrated, for example as a monohydrate or are essentially anhydrous. Inorganic acids suitable for salt formation are, for example Mineral acids such as hydrochloric, hydrobromic, sulfuric or phosphoric acids. Suitable organic acids are e.g. lemon, apple, glycol, milk. Tartaric, malonic, succinic, maleic or fumaric acid.

The compounds according to the invention can be used for Prevention or inhibition of the following viruses

be administered: Picornavirus, for example against

Encephalomyocarditis; Myxoviruses, e.g. B. Influenza Aj

(Jap (305); arboviruses, e.g. Semliki Forest; viruses of the

Herpes group ι as herpes simplex and pox viruses,

z. B. Vaccinia IHD. With prophylactic administration this should be done within 0 to 96 hours prior to the

Infection of the animal with pathogenic viruses. at

therapeutic administration to inhibit a

Infection should be administered within 1 to 2 Days after infection by the pathogenic virus

occur.

The dose to be administered depends on the virus for which treatment or prophylaxis is sought. the type of animal to be treated, its age,

Health status, weight, extent of infection, the type and intensity of concurrent additional treatments and the degree to which they are to be achieved The following doses of active ingredient are examples called: for intravenous administration 0.1 to about 10 mg per kg; with intraperitoneal administration 0.1 up to about 50 rag per kg; when administered subcutaneously, 0.1 to about 250 mg per kg; when administered orally 0.1 up to about 500 mg per kg and preferably about 1 to 250 mg per kg; with intranasal administration 0.1 to about 10 mg per kg and as an aerosol 0.1 to about 10 mg per kg of body weight.

The compounds can be used in conventional non-toxic pharmaceutical carriers for preparation orally, topically, buccally or parenterally Preparations of the usual type can be administered in dissolved or suspended form.

The compounds can be made in various ways, for example according to the following Reaction schemes:

Scheme

(1 equivalent)

Hal -A-HaI 3 (2 equivalents) Base (2 equivalents)

OH ₊ ^N _{NA Hal} Base (2 equivalents)

R ¹

(2 equivalents) R.

R ¹

Shark - A - O

Ν —Α —Ο

Formula I.

Scheme R

Ο - Α — Ν

4th \

R ¹

O-A-HaI

+ N-H

(1 equivalent)

(4 equivalents)

In the above reaction ^{schemes, R (R 1} JN- and have the meaning given above, while Hal denotes chlorine, bromine or iodine

Typical haloalkylamines 2 which can be used according to scheme 1 are N.N-diethyl-2-chloroethylamine or N- (2-chloroethyl) piperidine. Typical Dihalogenal Kane 3, which can be used in scheme 2, are, for example, l-bromo-2-chloroethane or 1,6-dibromohexane. To work according to scheme 2 are suitable as Amines 5 secondary amines such as diethylamine.

In the above reaction schemes, for example, sodium methylate, sodium hydride, sodium amide, sodium hydroxide or potassium hydroxide can be used as the base. turn around. Numerous solvents, including aromatic hydrocarbons such as benzene, toluene and halogenated xylene, are suitable as the reaction medium Aromatics such as chlorobenzene; aprotic solvents such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide, Dime thy sulfoxide; Alcohols such as ethanol, isopropanol; Ketones such as acetone, butanone; Ethers such as tetrahydrofuran, dioxane; Water or mixed solvents.

In a process in which, for example, sodium methylate, sodium amide or sodium hydride are used as the base, the reaction is carried out in an anhydrous medium, e.g. B. in anhydrous toluene or chlorobenzene. About 2 equivalents of the base are added to a suspension of, for example, 1 equivalent of compound 1 in the anhydrous solvent, then the mixture is heated to form the diphenylate. If sodium methylate is used, the methanol formed can expediently be removed by azeotropic distillation. About 2.5 equivalents of one of halides 2 or 3 are then added, after which the mixture is refluxed for about 4 to 24 hours. The products, ie the compounds of formula I and compound 4, are then isolated in a conventional manner are usually isolated as bis-acid addition salts.

If an alkali hydroxide, for example potassium hydroxide, is used as the base, two are available different procedures. According to one method, a 25 to 50% aqueous solution of the Alkali hydroxide (about 2.5 equivalents) to one

Suspension of, for example, 1 equivalent of compound 1 in an aromatic solvent such as for example xylene added. The mixture is then heated to the boil, with stirring if necessary can be, the water is distilled off azeotropically, conveniently using a Dean-Stark trap. The then essentially anhydrous reaction mixture is mixed with about 2.5 equivalents of the halide 2 or 3 as described ohsn implemented Gernäß one In further processes, the reaction takes place in a heterogeneous medium consisting of water and an aromatic medium Hydrocarbon, for example toluene or XyIoL, for example, 1 equivalent of Suspend compound 1 in the aromatic hydrocarbon. Then according to the scheme '. a solution is from about 2.5 equivalents of a hydrogen halide salt of the amino halide, i.e. H. of a hydrogen halide salt of 2, added in the minimum amount of water with vigorous stirring, and a 25-50% strength Alkali hydroxide solution (about 5 equivalents) is added. The mixture will be on for about 6 to 24 hours Boiled under reflux, then the product is isolated from the hydrocarbon layer according to scheme 2 is when using an aqueous aromatic medium for the preparation of compounds 4 that do not Have amine functions, an amount of alkali metal hydroxide in only a slight excess of 2.0 equivalents per liter Equivalent diphenol used, d. H. per connection 1. When using scheme 2, the reaction between the bis (w-haloalkyl) ether 4 and the Amine 5 can be carried out under various conditions. For example, you can use the connection 4 heat together with a large excess of the amine 5, with excess amine both as Reaction medium serves as a hydrogen halide acceptor. This method is particularly suitable for Working with readily available amines, the excess of which is easily removed from the reaction mixture can be, for example, by distillation at reduced pressure or by steam distillation. You can also use 1 equivalent of the bis (<u-haloalkyl) ether Heat 4 and 4 equivalents of amine 5 in one of the following solvents, for example in aromatic solvents such as benzene, toluene, xylene or chlorobenzene, in low molecular weight alcohols such as Methanol, ethanol, isopropyl alcohol, or in low molecular weight Ketones such as acetone or methyl ethyl ketone. 'The reaction between halogen compound and amine is usually accelerated by the addition of sodium or potassium iodide, the iodide being more catalytic or stoichiometric Men.iro can be used can. Occasionally it may be useful to only 2 To use equivalents of the amine 5 per equivalent of the ether 4, in which case an excess of pulverized In the case, sodium or potassium carbonate serves as an acceptor for the hydrogen halide formed Volatile amines, the reaction is best done under pressure in a bomb or in an autoclave carried out

Another reaction sequence proceeds via the following scheme:

Scheme

R ² -A ¹ -O

O —A ¹ —R ² (excess)

7a: R ² = CN

O RR

Il / \

7b: R ² = —C —N Ν —Α —Ο

R ¹ R ¹

Ο —Α — Ν

= A ¹ + CH ₂ )

In the above reaction scheme 3, R, R ¹ and A have the meaning given above, while A ^{1 represents} an alkylene chain with one methylene group less than A, ie A = A ^! + CH ₂ .

The nitriles 7a and amides 7b can be prepared, for example, by the process of Scheme 1, by the ω-haloalkylamines 2 by the corresponding ω-HRlogenalkylnitrile and -amides replaced.

According to the process of scheme 3, compounds corresponding to the formula Γ, in which R and R ^{1 represent} hydrogen, either from the nitriles 7a or the unsubstituted amides 7b, in which R = R ¹ = H, are obtained. Secondary amines, that is compounds of formula Γ de ^r, in which R is H and R ^ ¹ H, may also be often obtained by this method from the corresponding secondary amides 7b in which R = H and R ¹ Φ Η.

The primary or secondary amines I 'obtained according to scheme 3 are then alkylated to give the tertiary amines I. The primary amines give rise to those with identical radicals R and R ¹ .

Reductive alkylation of primary amines with an excess of the corresponding ketone in the presence of molecular hydrogen and a catalyst such as platinum or Raney nickel leads to symmetrically substituted tertiary amines, ie compounds of the formula I in which R = R ¹ .

The alkylation of the primary amines with a large excess of the corresponding halide gives the symmetrically substituted tertiary amines, and the alkylation of the primary amines with formaldehyde and formic acid by the method of Eschweiler-Clarke leads to tertiary amines of the formula I in which R and R ¹ is a methyl group.

The alkylation of secondary amines, ie of compounds of the form! ! ', in which RH and R'# H can be used to prepare symmetrically substituted tertiary amines as well as asymmetrically substituted tertiary amines, ie of compounds of the formula I in which R and R ^{1 are} different.

One method of N-alkylation is to react the secondary amines with a corresponding halide. Another useful method is the reductive alkylation of the secondary amines with the corresponding aldehydes or ketones in the presence of molecular hydrogen and a catalyst such as platinum or Raney nickel. Another useful alkylation method is the two step

hi method in which secondary amines are acylated with the corresponding acyl halides or acyl anhydrides, whereupon the resulting N-acyl compounds are reduced with lithium aluminum hydride to the corresponding tertiary amines. the

ι ι alkylation of the secondary amines with formaldehyde and formic acid according to Eschweiler-Clarke leads to the formation of tertiary amines of the formula I, in which R is a Is methyl group.

Another useful one? Procedure mr florupllnnp

j "of the inventive ether of the formula I is im the following scheme is illustrated:

Scheme

CH ₁ -CO

O - C - CH, + N - A-Hal

base

(2 equiv.)

R ¹

(1 equivalent)

(2 equivalents)

N - Λ -

Rl '

yj— Ο— Λ - N

R ¹

Formula I.

According to the method in scheme 4, the basic ethers are obtained directly from the diacetates of fluoranthene diols i.e. compounds 8 are obtained. These compounds can sometimes be isolated more easily than that Diols, especially if they are difficult to purify.

In the above process it is often advisable to use the hydrochlorides of the haloalkylamines 2, in which case, however, the amount of base must be doubled. An alkali metal alkylate is expediently used as the base. z. B. sodium methylate or sodium ethy-IaL FQr this method suitable solvents are z. B. aromatic hydrocarbons such as benzene and toluene or halogenated aromas such as chlorobenzene. The reaction conditions can vary within a wide range with regard to reaction time and temperature. In general, however, the reaction is carried out at the reflux temperature of the solvent for 6 to 72 hours. The preferred method is to reflux a mixture of the compound 8, the hydrochloride of a compound 2 and 4 equivalents of sodium methylate in chlorobenzene for 24 hours.

The fluoranthene diols can be prepared as follows : The general methods for the preparation of 3,9-dihydroxy fluoranthene [N. Campbell and NH Kier, J. Chem. Soc. 1233 (1955)] consist in the alkali melt of fluoranthene-3,9-disulfonic acid (obtained by disulfonation of fluoranthene) and the Baeyer-Villiger oxidation of 33-diacetyl-nioranthene

eo with subsequent hydrolysis. The diacetates 8 can be formed by acetylation of the above diols.

example 35-bis (3-piperidinopropoxy) fluoranthene

200 ml of water, which contained 16.0 g (0.4 mol) of sodium hydroxide and 15 J g (0.067 mol) of 3,9-dihydroxyfluoranthene, were added 20O ml of toluene and 29.8 g

(0.15MoI) S-piperidinopropyl chloride hydrochloride added, then the heterogeneous reaction mixture was refluxed with stirring for 24 hours. To after cooling, the organic layer was washed with water, dried over magnesium sulfate and im Reduced vacuum. The residue was crystallized from ether, the title compound was obtained from Melting point 92 to 93 ° C, λ J,!, ',' "242. Egg '; 910.

Example 2

3,9-bis [3- (diethylamino) propoxy] fluoranthene dihydrochloride

The procedure of Example 1 is repeated, but using 3- (diethylamino) propyl chloride instead of the S-piperidinopropyl chloride hydrochloride, see above the title compound is obtained as a free base, which is then converted into the

L / IC3C3 »Ti

L / inyuruviiKJ! iu uuci'iui'ii'i Vv

Recrystallized methanol-butanone. Melting point 235> o up to 2363 ° C, A! £, ',' 241. E Γ; 786.

Example 3

3,9-bis [3- (dibutylamino) propoxy] fluoranthene dihydrochloride

If you work according to the method of Example 2, but using 3- (dibutylamino) propyl chloride instead of the diethylamino compound, the title compound is obtained with a melting point of 170 w t.sl72 ° CA ^, V298, El. 623.

Example 4

3,9-bis [2- (diethylamino) ethoxy] fluoranthene dihydrochloride

If the procedure of Example 2 is followed, but using 2- (diethylamino) ethyl chloride hydrochloride instead of 3- (diethylamino) propyl chloride, the title compound is obtained κ> with a melting point of 220 to 222 ° C, A * '.', '"242nd egg;
906

Example 5

3,9-bis (2-morpholinoethoxy) fluoranthene dihydrochloride

To 450 ml of chlorobenzene were 10.6 g (0.033 mol) of fluoranthene ^ -diol diacetate, 12.4 g (0.066 mol) of N- (2-ChloräthylJ-morpholin-hydrcchlorid and 7.2 g ■ <(0,132MoI) of sodium methylate was added, then The mixture was refluxed for 24 hours with stirring, cooled and filtered. The filtrate was washed several times with water and dried over anhydrous magnesium sulfate. The chlorobenzene solution was then evaporated in vacuo, the oily residue was dissolved in ether and treated with ethereal hydrogen chloride, whereby the desired product was obtained. This was recrystallized from methanol-acetone, mp 284-286 ° C. (decomp.), λ £ "241. El
783

Example 6

3,9-bis [2- (dimethylamino) -l-methylethoxy] fluoranthene

If the procedure of Example 5 is followed, but using 2- (dimethylamino) -lmethylethyl chloride instead of N- (2-chloroethyl) morpholine, this is obtained after subsequent chromatography the free base on alumina using chloroform as the eluate to give the title compound in the form of a yellow viscous oil, λ £ "" 243, E! ..., 1060.

Example 7
3,9-bis (2-piperidinoethoxy) fluorine then

If the procedure of Example 6 is repeated, but using 2-piperidinoethyl chloride, the title compound is obtained, which is recrystallized from chloroform-pentane; F. 122-123.S = C. A ^ ¹ , ', " ¹ 302. E | 961.

Example 8

3,9-bis [2 (diethylamino) -1-methylathoxy]
-fluoranthene

Repeating the procedure of example b. but using 2 (diethylamino) -l-methylethyl chloride. this gives the title compound in the form of a viscous oil, A ^ ₁ ',' ¹ '243. E | 940

Example 9
3,9-bis [3- (dimethytamino) propoxy] fluoranthine M

If the procedure of Example 6 is followed, but using 3- (dimethylamino) propyl chloride, the title compound is obtained after crystallization from methylene chloride-pentane with a melting point of 80 to 82 ° C./. J ¹ , ', ¹ "243.F .: lObO.

Example 10
3,9-bis [2- (dihxylamino) ethoxy] fluoranthene

Prepare by the method of Example I. However, using 2 - (dihexylamino) -äthylchlorid hydrochloride instead of the 3-Pipcridinopropylchlorid hydrochloride, one obtains the title compound.

Claims (1)

Patent claims: 1.3,9-bis-uter of fluoranthene of the general formula N-A-O R ¹ O-A-N