DE2362577A1 - NEW BIS BASIC ETHERS OF 9-SUBSTITUTED PHENANTHRENE AND ITS OXA AND AZA DERIVATIVES AND THESE PHARMACEUTICAL COMPOSITIONS - Google Patents

Description

Richardson-Merrell Inc. New York, N.Y., V.St.A.

New bis-basic ethers of 9-substituted phenanthrene and its oxa and aza derivatives and those containing them pharmaceutical compositions.

The invention relates to new bis-basic ethers of 9-substituted phenanthrene and its oxa and aza derivatives and pharmaceutical compositions containing them.

The compounds are useful as antivi-rale agents _s which inhibit viruses or inactivate _s when infected or non-infected hosts are administered.

There are a growing number of information ^ that viruses play a crucial role in a large number of diseases ₅ some of which represent the ernsthaftesten human suffering. With viruses as

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The causative principle became arthritis, juvenile arthritis, diabetes, Hodgfcln's disease, as well as various Associated with immunological diseases and degenerative disorders of the central nervous system.

Currently, viral infection control is mainly achieved by immunization vaccines. For example, viral vaccines have been shown to be effective in the well-known diseases of poliomyelitis, smallpox, measles and influenza. As a rule, however, viral vaccines have had only moderate success in the prophylaxis of living things. Each Vaccln acts primarily to a particular virus and the protection it offers in _s, not heteroph.il. As a result, vaccines did not offer a practical solution to a larger view! of transmissible viruses, even where these are limited, such as only viruses of the respiratory tract.

A first step for "r control of viral diseases and in particular for the dissemination of such viral diseases v / ar searching for medical © chemotherapeutic agents that capable _s slnd the growth of Viren'und by the proliferation of" disease and further damage to cells and tissues of the animal host _s which have not yet been infected. Prevent see below »So far, only a limited number of viral infections, such as smallpox, Asian influenza and herpes keratitis, have been prevented by chemical antiviral agents. Sulfonamides and antibiotics, polygamy have revolutionized the treatment of bacterial infections, have substantially no effect on viral infections = Certain infections caused by large viruses such as _a Lymphogranuloiita venereura, psittacosis and trachoma were using antibiotics and Sulfonamlden

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successfully treated. However, the majority of viral infections indicated a chemotherapy attack not on. It follows that there is a need for new chemotherapeutic agents that are opposite to one wide range of viral diseases are effective, and which are at the same time non-toxic to the host.

It has now been found, as a result of a long series of studies, that a new class of fbis-basic Ethers of 9-substit.-phenanthrene and its oxa and aza derivatives of the formulas I and II below, in particular are effective as antivirals. These compounds are across a wide range of Viral infections are effective and they are both prophylactic and useful in treating such infections therapeutically useful.

US Pat. No. 3,592,819 discloses bis-basic ethers and thioethers of various substituted fluorene, 9-fluorenols and 9-fluorenones, which are used as antiviral Means are known to be useful. Some of the bis-basic ethers described there serve as starting materials for the preparation of some of the compounds of the invention. However, the compounds claimed herein are new. They have a wide range of antivirals Effectiveness in various degrees, which was not foreseeable on the basis of the prior art, since it is from a completely different and chemically unrelated 6,6,6-tricyclic aromatic ring system, which deviates significantly from the fluorine nucleus. Furthermore, it is not known that any previously known bis-basic derivatives of 9-phenanthrole,

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6 (5H) -phenanthridinone or 6H-dibenzofb, d 3pyran-6-one have antiviral activity.

The compounds according to the invention are 2,7-bis-base ethers of 9 "phenanthrol or 9-lower alkoxyphenanthrene ■ 3,8-bis-basic ethers of 6 (5H) -phenanthridinone and 3,8-bis-basic ethers of ÖH-dibenzo [b, d dpyran-6-one-, which have been found to be useful in preventing or inhibiting viral infections. The compounds according to the invention can be represented by the following general formulas:

ί) n- (ch ₂ ) -ο

and

\ / N- (CHz) -O
-R ^r

0- (CHa) _n -N

0- (CHz) -N ⁿ

wherein η is an integer from 2 to 6; R and FL each represent a hydrogen atom, a lower alkyl group of 1 to 6 Carbon atoms, a cycloalkyl group with 3 to 6 carbon atoms, an alkenyl group with 3 to 6 carbon atoms, where the double bond is in a different than

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the 1-position of the alkenyl group is ,, and R and R together with the nitrogen atom to which they are attached represent the pyrrolidinyl, piperidino or morpholino radical; and where Z is an oxygen atom, the group> NH or a ' Methylene group; Y is a nitrogen atom or a methylidene group; and R "is a hydrogen atom or a lower one Represent an alkyl group having 1 to 4 carbon atoms. Here, a methylene group means the radical -CHp-, while under a methylidene group the radical -CH = zu understand is.

The compounds of formulas I and .11 include both the free bases as well as their pharmaceutically acceptable addition salts. Generally the salts are these compounds crystalline substances that exist in water and various hydrophilic organic solvents are soluble, and which, compared to their free bases, generally have higher melting points and an increased Have stability.

It should be noted that the bis-basic ether side chains in the same relative configuration for the 9-substituted phenanthrenes, -6 (5H) -phenanthridinones and the 6H-dibenzofb, d3pyran-6-ones occur. However, due to the difference in the numbering systems shown below, those according to the invention Compounds referred to as 2,7-bis-basic ethers in the phenanthrene derivatives, while they both in the phenanthridine series as well as the 6H-dibenzo fb, d] -pyran series are referred to as 3,8-bis-basic ethers.

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8 9

Phenanthrene

Phenanthridine 6H-D ibenzofb ^ d] pyran

The 2,7-bis-basic ethers of 9-methoxyphenanthrene (V) are extended by a ring expansion of the related 2,7-bis-basic ethers of pluoren-9 ~ one (III), which in the
U.S. Patent 3,592,819. These reaction sequences can be based on the following reaction schemes,
where the symbols n, R, R. and R "have the aforementioned meaning, are best explained.

; N- (cH ₂ ) _n -o

ι> - (CH ₂ ) _n -0

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; ) N- (CH ₂ ) -O

^ ν) n- (CH ₂ ) -0 «-R

CH ₂ N ₂

0- (CH ₂ ) - ⁿ

0- (CH ₂ ) -N

The 3,8-bis-basic ethers of 6 (5H) -phenanthridinone (VI) are ring-expanded with hydrazoic acid using the 2 _a 7-bis-basic ethers of fluorene-9-one (III) in the presence of a strong Mineral acid produced. This reaction can be represented by the following general reaction scheme, in which the symbols n _s R and R _{1 have} the aforementioned meaning ₉ :

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/ N- (CH ₂ J _n -O ^v -R ■ ⁿ

(IN THE)

O- (CH ₂ ) -N / ^{n X} R- '

NaN ₃ H ⁺

The 3,8-bis-basic ethers of 6H-dibenzofb _s d 3pyran-6-one (X) can be obtained by a peracid or peroxide ring expansion of the related 2 j7 bis (u> -haloalkyl) ethers of fluorene-9- on (VII) in the presence of a strong mineral acid. The 3,8-bis- (w-haloalkyl) - ethers of 6H-dibenzofb, d3pyran-6-one (VIII), which were obtained in this way ₃ are subsequently condensed with an amine (IX), the desired 3 ₂ 8-bisbasic ethers of βΗ-dibenzofb, d} pyran-6-one (X) can be obtained. This reaction sequence can be illustrated by the following general reaction scheme _s where the symbols n ₃ R and R _{1 have} the meanings given above, and the symbol Hal represents a chlorine, bromine or iodine atom.

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(VIi)

0- (CH ₂ ) _n -Ha1, ₊ H ₂ O ₂

Strong acid

h + Hal- (CH ₂ ) -0

(IX)

0- (CH ₂ ) _n -Hal

(V! Π)

'Ri (■) n- (ch ₂ ) "- o

-r '

0- (CH ₂ ) -ν '
η \ _R

To have an antiviral effect of the compound according to the invention To achieve this, they are administered to a suitable host using a variety of compositions. Such compositions can be used either prior to infection, for prophylactic use or Treatment, or after infection of the host, for curative use or for therapeutic treatment administered will.

Thus, the compounds according to the invention can be applied externally or topically directly to the site of infection

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or they can be administered internally or systemically, regardless of whether the treatment is prophylactic or curative in nature. In either case, the replication of the virus causing the infection inhibited or prevented, with the concomitant result that the different, for the pathogenic viral infection characteristic symptoms of the disease are either reduced become or no longer exist.

As can be seen from the general formulas I and II, the compounds according to the invention include bis-basic ones Ethers in which each side chain is bound to a benzene nucleus of the tricyclic fused core system. This means that these side chains are in the 2- and 7-position in the compounds of the phenanthrene series and in the corresponding 3 ~ and 8-cells are attached to the phenanthridine and oH-dibenzo [b, djbyran series. It is also to see the diaS. Side chains essentially from a basic ÄEsieogruppe at the end of the chain and an ether bridging group at the proximal end of the chain, with the basic amino group being different from the ether group by an alkylene chain of the previously defined Length is separated.

The basic amino represented by the symbol -Wf ι

group can be a primary, secondary or tertiary amino group be. Each amino group is preferably a tertiary amine. The symbols R and R. represent either Hydrogen atoms or lower alkyl groups. Under the term lower alkyl group in relation to the basic Amino group is to be understood as having 1 to 6 carbon atoms. Examples of such groups are straight

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chain or branched chain alkyl radicals, such as the Methyl, ethyl, n-propyl, isopropyl, η-butyl, sec-butyl, Isoamyl, n-pentyl or n-hexyl radical. A preferred one The class of compounds is that in which R and R .. each represent a lower alkyl group.

Each R and R ₁ can also represent a cycloalkyl group having 3 to 6 carbon atoms. Examples of such groups are the cyclopropyl, ₃ cyclobutyl ,, cyelopentyl and cyclohexy groups o

The symbols R and R ₁ can also have a Alkeny! Group having 3 to 6 carbon atoms "which inevitably present double bond must be present in other than the 1-position of the alkenyl group ₉ to prevent _s that hydrolysis occurs. Examples of such groups are the allyl, _S 3-butenyl and 4-hexenyl groups,

R and R may also together with the nitrogen atom to which they are bound _{s s} various saturated monocyclic - represent heterocyclic radicals ". Examples of such heterocyclic radicals are the 1-pyrrolidinyl or piperidino _S Morpholinoresto _s compounds which these radicals contain ₃ are easily accessible; they are typically saturated monocyclic heterocyclic radicals. _s which as a rule can be used instead of the di-lower-alkylamino groups in the compounds according to the invention «

The branched alkylene chain ₂ which the basic amino group of the tricyclic ring separates _s consists of 2 to 6 carbon atoms and may be either a straight or

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Be alkylene chain. The alkylene chain must separate the adjacent oxygen atom from the terminal nitrogen by at least 2 carbon atoms, ie the ether oxygen and the amino nitrogen cannot be connected to one and the same carbon atom of the alkylene group. Each of the alkylene groups may be the same or different, but preferably both alkylene groups are the same. Examples of groups of this type are ethylene, propylene, 1,3-propylene, butylene, 1,4-butylene, 2-methyl-1, ^1- butylene, pentamethylene, 3-methyl-1,5 pentylene and hexamethylene groups.

Examples of bases of the compounds according to the invention according to formula I are: 3,8-bis- (4-piperidinobutoxy) -6 (5H) -phenanthridinone, 2,7-bis-r [2- (diethylamino) ethoxy 3-9-phenanthrol , 3> 8-bis-r3 ~ (N-cyclohexyl-N-methylamino) -propoxy} -6H-dibenzo [b, d 3pyran-6-one, 3,8-bis-f2- (diisopropylamino) ethoxy 3- 6 (5H) -phenanthridinone, 3,8-bis- [2- (diisopentylamino) -ethoxy 3-6H-dibenzo [b , d 3py ** an-6-one and 2,7-bis-f2- (diallylamino) -ethoxy3-9-phenanthrole.

It must be taken into account that compounds of the formula I in which a hydrogen atom is adjacent to Keto function is present, are able to form the corresponding enol tautomers. The connections according to the Invention, which of the phenanthrene and the 6H-phenanthridinone series belong, can consequently also be represented by the general formula IA, which is preceded by the corresponding keto form, as shown below, is tautomeric.

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0 (I)

{ > - (CH ₂ ) _n -O-
^ OH

(IA)

Λ R- '

In the illustration above, that is of course Symbol Y restricted to a nitrogen atom and the methylidene group. When there is an oxygen atom, as is the case with the series of 6H-dibenzo fb, d !! pyrane is the case of course no enolizable oxygen atom available, and the compounds accordingly occur only in their keto form. Hence the connections of the phenanthrene and phenanthridine series, probably mixtures of tautomeric forms, their composition on such factors as the type of tricyclic core, the various side chains that are present, and the environment surrounding the molecule as a whole. In the case of the phenanthrene series, that predominates Enol or phenol form.

The enol form can be obtained by replacing the enol hydrogen in this position with a lower alkyl group, such as represented by the symbol R.

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- Ik -

As a result, the lower 6- and / or 9-alkyl ethers exist only in compounds of the phenanthrene and phenanthridine series, while the 6H-dibenzofb, d 3-pyran series of the compounds occurs only as 6-keto compounds and no corresponding lower 6-alkyl ethers forms. Examples of basic compounds according to the invention of general formula II are: 2,7-bis-Γ2- (diethylamino) -ethoxy3-9-methoxyphenanthrene, 2,7-bis-f3- (l-pyrrolidinyl) -propoxy 3-9- propoxyphenanthrene, 2,7-bis- [2- (cyclohexylamine) -ethoxy 3-9-methoxyphenanthrene, 2,7-bis- [H- (diallylamino) -butoxy3-9-methoxyphenanthrene, 3,8-bis-r2- ( diethylamino) ethoxy 3-6-methoxyphenanthridine and 3j8-bis-p * ~ (dimethylamine) -butoxy 3-6-ethoxyphenanthridine.

Under the term "pharmaceutically acceptable acid addition salts" become all non-toxic organic or inorganic acid addition salts of the basic compounds understood according to the general formulas I and II. Examples of inorganic acids, polyhydric salts are: hydrochloric acid, hydrobromic acid, Sulfuric and phosphoric acids and acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Examples of organic acids that form suitable salts are mono-, di- and tricarboxylic acids, such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, Glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, Benzoic acid, p-hydroxybenzoic acid, phenylacetic acid, Cinnamic acid, salicylic acid, 2-phenoxybenzoic acid as well

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Sulphonic acids such as methanesulphonic acid and 2-hydroxyethanesulphonic acid. Either the mono- or di-acid salts can be formed, and such salts can either in a hydrate or in a substantial way in anhydrous form.

In general, the compounds of the invention are prepared from various 2,7-disubstituted-9-fluorenones as precursors, which are described in detail in US Pat. No. 3,592,819. The preparation of the compounds involves various ring expansions of the 9 ^ fluorenone nucleus, the corresponding 9 ~ substituted phenanthrene, 6 (5H) -phenanthridines and 6H-dibenzo fb _s d3pyran-6-one rings being formed. In particular, the reaction with diazomethane leads to the formation of the 2 _s 7-bis-basic ethers of 9-methoxyphenanthrene; the reaction with hydrazoic acid leads to the formation of 3,8-bis-basic ethers of 6 (5H) -phenanthridinone, while the reaction with peracids or with hydrogen peroxide leads to the formation of the 3,8-bis-basic ethers of 6H-dibenzofb _s d] pyran-6- ■ on leads.

It is known that cyclic aliphatic ketones received with diazomethane ring expansion _s wherein cyclic aliphatic ketones are formed with a larger ring. In some cases, this reaction can also be carried out with aromatic ketones, a wide variety of homologous ring-expanded ketones being formed, and the formation of enols, enol ethers and ethylene oxides also occurring. For example, in J.Am. Chem. Soc, Vol. 62, pp. 2902-2904 (1940) describes the reaction of diazomethane with fluorenone,

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with a yield of 5 % 9-phenanthral, 30 % 9-methoxyphenanthrene, 1.5 % di-9-phenanthryl ether and an unknown substance, and 30 % of the pluorenone was not converted. It is also known that certain substituents on the aromatic ring change the ratio of the various products obtained and cause the formation of additional isomeric, homologous ketones and by-products. As a result, the application of the diazoraethane reaction to 2,7-bis-basic ethers of 9-fluorenone was not obvious and its result could not be foreseen.

The reaction is most often carried out by treating a methanolic solution containing a carbonyl group-

the connection with an essential solution of diazomethane carried out, in the presence or in the absence a catalyst. But you can also use a solution of the carbonyl compound in methanol with nitrosomethyl urethane treat in the presence of a base. The diazomethane can be produced either ex situ or in situ will. As a rule it is preferable to generate the diazomethane ex situ and to use it together with ether in to distill a methanolic solution of the carbonyl group-containing compound. Suitable inert solvents, which can also be used are e.g. dioxane, benzene, toluene, chloroform and methylene chloride, a mixture of ether and methanol is the solvent combination of choice. It also turned out that methanol has a high catalytic effectiveness for ring expansion with diazomethane. Useful Catalysts for this conversion include trace amounts of metal salts, such as zinc chloride or lithium

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O * 3 f * ^ er π? ""? L * J U & o Ό II

chloride. Typically, at least 2 equivalents of diazomethane _s are used wherein an equivalent is provided for the ring expansion _s while the other equivalent to the starting material to form the corresponding 9-Methoxyphenanthrenäthers (V) "reacts addition to the variety byproducts j that form ^ remain some 2j.7 ⁼ bis-basic ether of 9 ⁼ phenanthrol (IY) as intermediates. The intermediates can easily be separated from the reaction mixture in the form of their sodium salts. The other 9-lower alkoxyphenanthrene derivatives of the formula H _9, which differ from the 9 °° methoxyphenanthrene derivatives, are produced by reacting the 9-phenanthrols (IV) with other lower diazoalkanes.

Due to the complicated and large variety of possible side reactions, no more than 8 equivalents of diazomethane are required in the production of the 2 _? 7 "to-basic ethers useful 9-Methoxyphenanthren. The reaction is exothermic and is carried out at room temperature or below. The reaction takes place at a temperature von'etwa -5o ° C to room temperature instead of, a temperature is conveniently carried out preferably from 0 ⁰ C The reaction can be carried out for a period of from 1 hour to about 7 days.

The 9-phenanthrol derivatives, which are also formed in the ring expansion, with diazomethane, are by their ^f non-acidic materials by extraction with chloroform from a sij / trk alkaline reaction mixture freed = 9-phenanthrol derivatives _s which aqueous in the Remaining medium can then be neutralized by the

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aqueous medium to a »? pH around 9 to 10 and subsequent extraction of the neutralized medium with chloroform removes four den. The 9 ~ Phenanthrols can then be etherified by reaction with a lower diazoalkane, the corresponding 9-lower alkoxyphenanthrene ethers are formed.

The production of the 3,8-bis-basic ethers of 6 (5H) -phenanthridinone (VI) is carried out via a modification of the so-called Schmidt reaction. Essentially, this method results, as it is applied here to introduce a hetero nitrogen atom via a ring expansion in the 5-membered fluoren-9-on ring _s wherein hydrazoic acid used in the presence of a strong mineral acid such as sulfuric acid and the 6-membered heterocyclic 6 (5H) -phenanthridinone ring is formed. It is known that hydrazoic acid reacts with simple cyclic ketones to form ring-expanded cyclic amides or lactams. For example, cyclohexanone reacts with hydrazoic acid to form caprolactam. However, the use of hydrazoic acid to react with the 5-membered cyclopentanone ring of the tricyclic 9- pluorenone nucleus has not yet been reported. Since an excess of hydrazoic acid favors tetrazole formation, approximately equimolecular amounts of hydrazoic acid are used. The reaction can be carried out by adding a solution of hydrazoic acid in a suitable organic solvent to a solution of the fluorene-9-one. Hydrazoic acid

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however, it can also be prepared in situ by adding sodium azide to the reaction mixture. Because of the extremely hazardous handling of hydrazoic acid, the use of sodium azide is preferred, eliminating the need to isolate the toxic hydrazoic acid. This reaction is exothermic and is therefore best carried out with stirring and cooling. The reaction can be carried out at temperatures from about -20 to about 50 ^° C. for about 30 minutes to about 1 week. For reasons of expediency, a temperature of 0 ^° C. with a reaction time of about 1 hour is generally preferred. If the reaction appears to be sluggish, higher temperatures can advantageously be used. Due to the rapidity of the reaction with hydrazoic acid, the reaction is conveniently regulated by the rate at which the hydrazoic acid or sodium azide is added to the stirred solution of the 9-fluorenone derivative dissolved or suspended in a suitable solvent. Examples of suitable solvents. are sulfuric acid, chloroform, benzene, dioxane and diethyl ether, but especially trifluoroacetic acid, which was found to be particularly useful. In general, the sodium azide will be made into a solution of the in small proportions. 9-pluorenone ether derivative in trifluoroacetic acid was added until no further evolution of nitrogen can be observed. For all practical purposes, it can be assumed that at this point the implementation is complete. An acid catalyst is also used. Any strong acid can be used, but concentrated sulfuric acid is most advantageous. The isolation of the 3,8-bis-basic

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See the ether of 6 (5H) -phenanthridinone is achieved using well-known standard procedures. An alternative way of preparing the 6 (5H) -phenanthridinone ethers is the Beckmann rearrangement of the corresponding pluorenone oximes. From J. Am »Chem. Soc. BQ. 49 _S p. 2618 • (1927) - the preparation of 7-nitro-6 (5H) -phenanthridinone by treating 2-nitrofluoren-9-one-oxime with phosphorus pentachloride dissolved in phosphorus oxychloride _{9 is} known. In a similar way, the 3s8-bis-basic ethers of 6 (5H) -phenanthridinone can be prepared from 2 ₃ 7-bis-basic ethers of fluorene-9-one-oxini _{5 as} shown in the following reaction scheme ₃ :

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0- (CH ₂ ) -ν; ι

- ^ N- (CHa) _n -O

■ R

\) n- (ch ₂ )

^ R ⁿ

0- (CHa) -I

0- (CHa) _n -N

ι) n- (ch ₂ ) -o

^ R ⁿ

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The first stage in the preparation of 3s "8-up ~ basic ether of 6 H-dibenzo fb ₃ d Dpyi-on on-6 is the oxidation of a 2,7 'bis - («) - haloalkyl) of -äthers. Fluoren-9-one (VII) "with a peracid or a peroxide under Baeyer- 'Villiger conditions. Essentially, this reaction leads to a ring expansion of the 5-membered fluorene-9-one ring and the introduction of an oxygen atom, a 6-membered, ring-enlarged lactone or the 6H-bibenzo [b, d-pyran-6-membered nucleus being formed . Thus, the oxidation of a 2,7-bis (α> -haloalkyl) ether of fluoren-9-one (VII) (see US Pat. No. 3,592-819) with a peracid or hydrogen peroxide in the presence of a strong acid, such as, for example, sulfuric acid, for the formation of a 5,8-bis («> - haloalkyl) ether of 6H-dibenzo- [b, d] 3pyran-6-one (VIII). The 6H-Dibeng; o- = fb, d J> yran (ö> -haloalkyl) ethers prepared in this way can with an amine

(IX) are condensed, whereby the desired 3,8-bis-basic ethers of 6H-dibenzo [b, d3pyran ~ 6-cm

(X) which are compounds according to the invention. The oxidation is exothermic, and the temperature of the The reaction mixture can expediently be controlled by the rate of addition of the oxidizing agent. The reaction temperatures can vary from about -20 to about 40 ° C, with a temperature of about 25 ° C being preferred. At the lower temperatures fluctuate the reaction times from about 30 minutes to about 1 week. Large excesses of peroxide are to be avoided, as there is always the risk that the peroxide oxidations are under Explosion proceed. If larger amounts of peroxide remain after the reaction is complete, they can under Use of reducing agents such as sodium bisulfite

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or ferrous sulfate are decomposed. When performing the ring expansion are typically 2- or 3-fold excess amounts of hydrogen peroxide The reaction is favored by sufficient polar solvents and s are as z.Bο sulfuric extends in a variety of solvents _s acetic acid or acetic, säureanhydridο In the second stage, the 3 <, 8-bis- (ü> -haloalkyl) ethers of 6H-dibenzo- [b _s d] pyran-6-one (VIII) then for the production of the 3 _S 8-bis-basic ethers of 6H-dibenzo fb _s d jiyran-6-one (X) condensed.

The condensation of the bis (ü> -haloalkyl) ethers (VIII) with an amine (IX) can be carried out using various conditions »For example, can the ethers together with a large excess of amine

are heated ₅ the excess amine serving both as a reaction medium and as a hydrogen halide acceptor. This method is particularly useful in those amines which are easily accessible _s can be easily removed than any excess amine from the reaction mixture by distillation at reduced pressure or steam distillation so far. The u> -haloalkyl ethers (VIII) can, however, also be heated with an excess of amine in a suitable organic solvent. Examples of suitable organic solvents are benzene, toluene, xylene and chlorobenzene, alcohols of low molecular weight such as "methanol, ethanol and isopropyl alcohol _s and ketones of low molecular weight such as acetone and Methyläthy! Ketone" The implementation of this ether with an amine is in the Usually promoted by adding sodium or potassium iodide, _s

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the iodide being in either catalytic or stoichiometric Quantities is applied. In some cases, e.g. when the amine is difficult to access, it can be beneficial be to use only 2 equivalents of the amine for each equivalent of the «ί-Halagenalkyläthers used, being in the presence of an excess of powdered sodium or potassium carbonate as hydrogen halide acceptor is being worked on. In the case of volatile amines, the condensation can best be carried out under pressure in a suitable bomb or an autoclave.

The inventive compounds are antiviral agents, preferably they xverden an animal or human host to _a given vlrale infections to prevent or inhibit. The term "host" were each viable biological material is _a intact animals or humans understood ^ polygamy are capable of the formation of interferon to cause ₉ and which serve as carriers for viral replication. The host can be of animal or mammalian origin. Examples of such hosts include: birds, _"Mouse's rats Meersctmeinchen, ferrets, gerbils, dogs, cats, cows, horses and humans Other viable biological materials as in the production of..

. Vaecins used can also serve as a host. Tissue cultures made from organic tissues, such as kidney or lung tissue from mammals, as well as those made from embryonic tissues have been shown to be Cultures such as those obtained from or from amniotic cells allantoic fluid obtained from chicks x ^ ground, as useful hosts.

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ORIGINAL! NSPECTiD

The treatment of viral infections includes both the prevention * as the inhibition also typically * KrankheitsSymptome'bei a mammal as a host _s which is susceptible to the attack of a pathogenic virus. Examples of virus infections in mammals ₃ which can be prevented or inhibited by administration of the compounds according to the invention are infections j, vrelche by picornaviruses, such as the Enee_j? Halomyo cardl t is virus, myxoviruses, such as ζ-Β. the influenza A ₃ (Jap / 3O5) ~ _s virus arboviruses _s such as the Semlikl-Porest-Virus's the group of herpes viruses ^. including herpes siniplex _s and by smallpox viruses such as Vaccinia IHD. For example, delay or completely prevent the inventive compounds death inlet ₃ when "they _n orally or · subcutaneously in different doses, either just before or after a fatal inoculation of a iieurotropen virus, such as Enceohalomyocarditis-Vlrusj with an LD. ^ 5 to 50, The salts of the compounds according to the invention are generally administered in compositions which contain a 0.15 # aqueous hydroxyethyl cellulose solution as a diluent, while the free bases are generally administered in compositions · Which contain a 10 # aqueous solution of a surface-active agent as an extender to aid in the solubilization of the compound. Typically 10 mice are used in each treated group, ₃ and 20 mice are used as a control group. At the time of administration , the · _: test virus is titrated to determine efficacy or LB ^

YOU

for the particular virus that kills as a cause of infection j The control animals receive a placebo j which contains an identical volume of stretching

.; ..-. . :. ■ 4-09826 / 1162

medium, but of course does not contain any active substance, Due to the lethal nature of the test system employed, the antiviral effectiveness of the test compound is reduced by a side-by-side comparison of the treated surviving animals with the untreated Control animal group clearly expressed «,

Viruses of the respiratory tract, such as s "B. the influenza A _? "(Jap / 3O5) ~ Virus _a which are also fatal for the test animals." are administered by intranasal instillation. Animals infected in this way receive the active ingredients in the same way as the test virus, and the surviving treated animals are again compared with the untreated control animals in parallel.

In a way that has not yet been clarified, a mouse fatally infected with encephalomyocarditis virus or influenza virus survives without further treatment For this reason the selected control group is of sufficient size to statistically reduce the influence of such a chance of survival on the test results to a negligible fourth.

The vaccinia test virus is typical of viruses of the dermatotrophic type which are responsive to treatment with compositions containing the compounds of the invention. The vaccinia virus generally causes and results in non-fatal infection in mice

409826/1162 '

to: -krankhaften changes of the tail ₃ i \ racing the virus subcutaneously administered at the mouse's tail is The compounds are administered either orally or subcutaneously, and administered either before or after the vaccinia infection "?. The strong tail changes are assessed subjectively on the 8th day after infection against untreated animals, which serve as control group. The compounds according to the invention were found to differing degrees compared to one - or; all of these test viruses are effective. ". '

The nature of the effectiveness of the active ingredients according to the invention cannot be strictly defined. Among other things, the compounds of the invention can induce the formation of interferon in a viable host. Interferon is a biological substance of unknown chemical structure _, presumably of protein-like nature _3, which is killed by host cells following a viral infection. The interferon formed in this way acted in that it caused the formation of a substance that _{inhibits the virus 3} which, in a manner not yet known, inhibits the intracellular replication of the virus without apparently having an inactivating effect per se on the virus. Some viruses., Polygamy are susceptible to the inhibition of replication by interferon ₅ are described in the monograph Horsfall and Tamrn, "Viral and Riekettsial -Infections of Man", 4th ed. (1965) _s JB, Lippincott Company ₃ pp. 328-329. ·

As previously mentioned _three compounds of the invention can be administered prophylactically to prevent _s the dissemination of infectious viral diseases, or they may be used therapeutically for healing one ^already.:

409826/1162

infected host. In prophylactic administration, it is preferred that this be within from 0 to 96 hours prior to infection of the host. is made with a pathogenic virus. When the compounds of the invention for the purpose of a medicinal effect are administered, it is preferred that the administration within one to 2 days after infection of the Host is made to achieve the maximum therapeutic effect. .

The dosage to be administered depends on such parameters as the particular virus for which either one Treatment or prophylaxis is desired, the type of infected living being, its age, state of health, Weight, the extent of the infection, any simultaneous treatment, the frequency of treatment and the type of effect you want. A daily dose of the active ingredients is usually around 0.1 mg to about 500 mg / kg body weight. Example catfish Dosages of the active ingredient to be administered for intravenous treatment are about 0.1 mg to about 10 mg / kg Body weight ; for intraperitoneal administration from about 0.1 mg to about 50 mg / kg body weight; to subcutaneous Administration et v / a 0.1 mg to about 250 mg / kg body weight; for oral administration about 0.1 mg to about 500 mg / kg Body weight; for internal instillation about 0.1 mg to about 10 mg / kg body weight and for aerosol inhalation -.tion therapy usually about 0.1 mg to about 10 rag / kg body weight.

The new compounds can also be administered in various dosage forms, e.g. oral Compositions in the form of tablets, capsules, dragees,

A09 82 6 / .1162

Pastilles, elixirs, emulsions, clear liquid solutions and suspensions; parenteral compositions in the form of intramuscular, intravenous or intradermal preparations and topical compositions in the form of lotions, creams or ointments. The amount of active ingredient which is present in each dosage unit form varies, of course, within a wide range, depending on the dosage unit used, the treated animal or human as host and the type of treatment, ie, depending on whether it is prophylactic or therapeutic . Thus, a particular unit dosage of about 2.0 mg 'to 3 ₅ O g of active ingredient, in addition to the information contained herein pharmaceutical excipients ;, included. .

The new compounds can be used together or in a mixture with additional organic or inorganic pharmaceutical excipients. Suitable solid excipients include gelatin, lactose, starches, magnesium stearate and petroleum jelly. Suitable liquid excipients include water and alcohols such as ethanol, benzyl alcohol and polyethylene alcohols, either with or without the addition of a surfactant. As a rule, the preferred liquid excipients, especially for injectable preparations, include water, saline, dextrose and glycol solutions, such as, for example, an aqueous propylene glycol solution or an aqueous solution of polyethylene glycol. Liquid preparations, which are used as sterile injectable solutions, usually contain about O ₃ 5 to about 25 wt -.% ₉ preferably about 1 to about 10 wt .- ^, active ingredient in solution. In certain topical and parenteral preparations, various oils are used as carriers or excipients. Examples of such oils are mineral -'_

4 0 9 8 2 6/1162 '

oils, glyceride oils such as bacon oil, cod liver oil, peanut oil, sesame oil, corn oil and soybean oil.

A preferred method of administration for the inventive Compounds is oral, either in a solid dosage form, such as a tablet or capsule, or in a liquid dosage form such as an oral elixir, syrup, or an oral suspension. or emulsion. In an oral liquid composition, the active ingredient component is usually about 0.5 to about 0.5 10 wt. "- JJ. The pharmaceutical carrier is in such Compositions usually aqueous, such as flavored Water, a syrup. Sugar-based or a pharmaceutical one. Mucus. For insoluble connections suspending agents and viscosity regulating agents, such as magnesium aluminum silicate or Carboxymethyl cellulose added to the earth. It can also Buffers, preservatives, emulsifiers and other excipients are added.

For parenteral administration, such as intramuscular, intravenous or subcutaneous administration, the proportion of active ingredient is about 0.05 to about 20 Wt. G, preferably about 0.1 to about 10 wt. #, Of the liquid composition. To reduce or eliminate irritation at the injection site, Such compositions can be nonionic surface active Compounds with a hydrophilic lipophilic balance (HLB) of about 12 to about. 17 included. The amount of surfactants in such formulations is from about 5 to about 15 percent by weight. That Surfactants can be a single one with the aforementioned HLB, or a mixture of 2 or more Components with the desired HLB. Examples of surfactants used in parenteral formulas

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The class of polyoxyethylene sorbitol fatty acid esters, such as, for example, sorbitol monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, which is formed by the condensation of propylene oxide with propylene glycol about 0.05 to about 20 wt -.% of the total formulation, with the remaining component bzw-, remaining components from any of the liquid pharmaceutical excipients previously mentioned exist.

The new active compounds can also be mixed directly with animal feeds or incorporated into the drinking water von.Tieren be "an amount of active ingredient is used, the j an amount of active ingredient from about 0.0001 to about 0.1 percent for most purposes -. _3%, preferably about OjOOl to about 0.02% by weight > based on

the total weight of the feed intake. The active ingredients can be incorporated into animal feed concentrates for use by the farmer or cattle breeder in suitable amounts in the final animal feed are suitable. These concentrates include usually about 0.5 to about 95 wt .-% active ingredient, which with a finely divided solid carrier, or Flour such as grain, corn, soybean or cottonseed flour is mixed. Depending on the special animal to be fed, nutrients and fillers can also be added, such as ground Cereals, charcoal, fuller's earth, oyster shells as well finely divided attapulgite or bentonite. ","

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For use as an aerosol, the active ingredients can be packed into a suitable pressure vessel together with a liquid or volatile propellants. An opening in the container, of which the active ingredients are expediently in the form of a spray, a liquid, a Ointment or foam is provided with a suitable discharge valve. V / other aids, such as cosolvents, wetting agents and bactericides can be used if necessary. Usually the propellant used is a liquefied petroleum gas, preferably a mixture of fluorocarbons low molecular weight. These haloalkanes are preferred because they work with the new active ingredients are compatible, and especially they do not irritate when applied to the skin surface. Other propellants that can be used are e.g. the gases ethylene oxide, carbon dioxide, propane and nitrogen.

The invention is explained in more detail with the aid of the following examples explained »

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example 1

2,7-bis [2- (diethylamino) ethoxy D-fluorene-g-one dihydrochloride

A mixture of 6.4 g (0 ₅ 03 mol) 2 _s 7-dihydroxy-fluorene-9-one and 3> 3 g (0 _s 06 mol) sodium methylate in 200 ml toluene (dried over molecular sieves) was with a solution of [2- (diethylamino) ethy3i] chloride was added, which was obtained from 15.5 g (0 _s 09 mol) [2- (diethylamino) ethyi] chloride hydrochloride in 100 ml of toluene (dried over molecular sieves) . The resulting mixture was heated to its reflux temperature with stirring for 3 hours. After cooling, the mixture was filtered to remove the precipitated sodium chloride. The toluene solution was washed 3 times with water, 1 time with saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The mixture was filtered and the piltrate was acidified to the Congo red point of change with an ethereal hydrogen chloride solution. The precipitated Peststoff was filtered off from butanone _s which a sufficient amount to cause a solution, methanol was added to _9, umkristallisi ^ ert, and the product was dried for 2k hours under vacuum at 100 ° C: Melting point: 235-237 ° C, λ «2θ = ₂ 69 and EJ * = 1,600.

Example 2

2,7-bis [2 ° (diethylamino) ethoxy 3 "9-methoxyphenanthrene

A solution of H ₃ 7 g (0.028 mol) 2 _S 7-bis [2- (diethylamino) ethoxy 3 ™ fluoren ~ 9 ~ one in 20 ml ether and 50 ml ■ methanol was stirred and mixed with about 0.085 mole diazomethane ,

409826/1162

which was distilled into the reaction mixture at 10-28 ° C together with diethyl ether, treated. The reaction mixture was stirred for 24 hours at room temperature and most of the volatiles were removed in vacuo. The residue was treated with a dilute sodium hydroxide solution and extracted several times with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate, treated with activated charcoal, filtered, and the product was converted into its hydrochloride by treatment with ethereal hydrogen chloride solution. This salt was then dissolved in 200 ml of ethanol and treated with 3.8 g of Girard's reagent T to allow subsequent removal of any unreacted starting materials. The resulting solution was refluxed for 3 hours, treated with 200 ml of a 5% sodium hydroxide solution and extracted with ether. The combined ether extracts were washed with water, dried, and most of the volatiles were removed. The residue obtained was dissolved in petroleum ether at 40-60.degree. C., filtered, applied to an aluminum oxide chromatography column and eluted with petroleum ether at HO-60.degree. The initial eluate was collected, the volatile constituents were removed, and the 2,7-bis-f2- (diethylamino) -ethoxyf> 9-methoxyphenanthrene thus obtained was recrystallized from petroleum ether at 40-60 ° C. and then from a pentane solution: melting point 63 - 65 ⁰ C, ^

This procedure was essentially repeated, except that the 2,7-bis-f2- (diethylamino) -ethox3i] -fluoren-9-one was used by the corresponding molar equivalent amounts of 2,7-bis [2- (dibutylamino) ethox5] -fluoren-9 ~ one;

409826/1162

2,7-bis [2- (diisopropylamino) ethoxy. 3-fluorene-9-one, 2,7-bis-f3- (dimethylamino) -propoxy-3-fluorene-9-one and 2,7-bis-f3- (dibutylamino) -propoxy] -fluoren-9-one was replaced , and the following compounds were obtained: 2,7-bis- [2- (dibutylamino) ethoxy 3-9-methoxyphenanthrene, 2,7-bis-f2-diisopropylamino) ethoxy; ] -9-methoxyphenanthrene, 2,7-bis-r [3- (dimethylamino) -propoxy 3-9 -niethoxyphenanthrene or 2,7-bis- [3- (dibutylamino) -propoxy] 3-9-methoxyphenanthrene.

Example 3

2,7-bis (3-piperidinopropoxy) fluorene-9 ~ one dihydrochloride

A mixture of 63.6 g (0.30 mol) 2,7-dihydroxy-fluorene-9-one, 188 g (0.95 mol) 1- (3-chloropropyl) piperidine hydrochloride, 132 g (2.0 mol ) an 85 # strength potassium hydroxide solution in 900 ml of toluene and 300 ml of water was refluxed with vigorous stirring for 20 hours. After cooling, the layers were separated and the organic layer was washed 3 times with water, 1 time with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The mixture was filtered and the solvent was removed in vacuo. The residue was taken up in isopropyl alcohol and acidified with an ethereal hydrogen chloride solution to the Congo red transition point. The precipitated solid was filtered off, from a mixture of 3 parts of isopropyl alcohol and one part methanol recrystallized _s and 2,7 ~ bis (3-piperidinopropoxy) fluorene-9 ~ one dihydrochloride Under vacuum for 2k hours at 100 ° C dried:

409 8 26/1162

3b

Melting point: 279.5 - 28O.5 ° C, λ ^ 2 ° = 270 and E J *

iuäx 'x a

1-370.

example

9-methoxy-2,7-bis (3-piperidinopropoxy) phenanthrene

A solution of ¹ IJ g (0.01 mol) of 2,7-bis- (3-piperidinopropoxy) -fluoren-9-one in methanol was stirred and
with about 0.085 mole of diazomethane, which together with
Ether was distilled into the reaction mixture at a temperature of -15 ° - -31 ° C, treated. The reaction mixture was allowed to slowly warm to room temperature overnight. The volatiles were removed on the steam bath in vacuo and the residue triturated with pentane to induce crystallization. The obtained pesticide was in a mixture of
Pentane and ether dissolved, washed several times with a dilute solution of sodium hydroxide then with water, dried over anhydrous sodium sulfate, treated with charcoal and filtered. Most of the volatile solvents were removed from the Pilfcrat. The residue was recrystallized from pentane and then again from a methanol-water mixture, the desired 9-methoxy-2,7-bis- (3-piperidinopropoxy) -phenanthrene being obtained: melting point 118.5-119.5 ° C .; λ ^Μ ® ^0Η = 259 ι ζ max

^{and E} l cm = ¹ ^ ³⁰ -

According to this, essentially the same procedure, except that the 2,7-bis- (3-piperidinopropoxy) -fluoren-9-one
by corresponding molar equivalent amounts of
2,7-bis- [2- (1-pyrrolidinyl) -ethoxy,] -fluoren-9-one or
2,7-bis- ( ⁱ -morpholinobutoxy) -fluoren-9-one was replaced,

409826/1 162

the compounds 9 ~ methoxy-2,7-bis- [2- (l-pyrrolidinyl) ethoxy] phenanthrene and 9-methoxy-2,7-bis (4-morpholinobutoxy) phenanthrene, respectively obtain"

Example 5

2,7-bis- [2- (dimethylamine) ethoxy Ί-9-phenanthrole

A solution of 8.1 g (0.023 mol) of 2,7-bis [2- (dimethylamino) ethoxy.3-fluorene-9-one in 50 ml of methanol and 25 ml of ether was stirred and finely mixed with 0.5 g -powdered sodium carbonate treated. To this mixture was added 75 g (0.06 mol) of ethyl N-methyl-N-nitrosocarbamate in 20 ml of methanol over a period of 2 hours. The temperature of this reaction mixture was kept below 30 ⁰ G for 2Ά hours. The reaction mixture was then freed from most of the volatile material in vacuo, dissolved in an aqueous hydrochloric acid solution and extracted several times with diethyl ether. The obtained aqueous solution was made strongly alkaline with an aqueous sodium hydroxide solution and extracted with ether. The remaining aqueous solution was neutralized with a 10% hydrochloric acid solution to a pH of about 10 and extracted with ether. Evaporation of the combined ether extracts in vacuo and recrystallization from a mixture of methanol and water led to the desired 2 _S 7- Bis-r2- (dimethylamino) -ethoxy3-9-phenanthrole.

The preparation of the lower 9 ~ Alkoxyäther is further sales of a methanolic solution of 2,7-bis [2- (dimethylamino) -ethoxy; 3-9-phenanthrol with a lower diazoalkane, for example _s or diazoethane

• 409826/116

Diazopropane. The one made in this way. 2,7-Bisf2- ( ^/ methylamino) -ethoxs * 3-9-ethoxyphenanthrene or 2,7 ~ Bisf2- (d.imethylamino) -ethoxj? 3-9-propoxyphenantbrene can be separated off by removing the volatile materials in vacuo and recrystallizing the residue from aqueous methanol.

Example 6

3,8-bis- [2- (diethylamino) -ät hoxj *] -6 (5H) -phenanthridinone dihydrochloride

Using the product prepared according to Example 1, 10 g (0.027 mol) of 2,7-bis [2- (diethylamino) ethoxylt 3-fluorene-9-one dihydrochloride were dissolved in 75 ml of trifluoroacetic acid and brought to a temperature of about 0.5 ⁰ C cooled. 3> 5 g of sodium azide was added in portions with stirring, followed by 10 ml of sulfuric acid, which was added dropwise. Stirring and cooling was continued for an additional hour - and the solution was made alkaline with an excess of 20 # potassium hydroxide solution. The basic reaction mixture was extracted several times with methylene chloride, the extracts were combined, washed with water, dried over anhydrous sodium sulfate and filtered. The PiI step was evaporated in vacuo. The residue was dissolved in ether and acidified with an ethereal hydrogen chloride solution. Recrystallization of the residue from a mixture of methanol and butanone led to the dihydrochloride salt of the 3 _s 8-bis [2-diethylamino) ethoxy. 3-6 (5H) -phenanthridinon5i melting point 250 - 252 ⁰ C,

409826/1162

According to this, essentially the same procedure, but the 2,7-bis-f2- (diethylamino) -äthpxj> ] -fluoren-9 ~ one dihydrochloride by the appropriate molar ■ equivalent amounts of 2,7-bis- (2-piperidinoethoxy) -fluoren-9-one dihydrochloride, 2,7-bis ^ [3 ~ (dimethylamine?) -Propoxyi } -fluoren-9 ~ one dihydrochloride and 2,7 ~ bis [2- (diallylamino ) -ethoxj »3-fluorene-9 ~ one dihydrochloride was replaced, the following compounds were obtained: 3,8-bis- (2-piperidinoethoxy) -6 (5H) -phenanthridinone dihydrochloride, 3,8-bis- [3-dimethylamino) -propoxj? 3-6 (5H) -phenanthridinone dihydrochloride or, 3 »8-bis- £ 2- (diallylamino) -ethox ^ ] -6 (5H) -phenanthridinone dihydrochloride.

Example 7

3,8-bis [2- (dimethylamino) ethoxy. 3 ~ 6H-dibenzo [b, d 3 pyran-6-one dihydrochloride

A solution of 13.5 g (0.04 mol) of 2,7-bis (2-chloroeth- " oxyH "luoren-9-one in 100 ml of concentrated sulfuric acid. was slowly mixed with 12 ml of a 30 # solution of hydrogen peroxide reacted at room temperature. The reaction, which is highly exothermic, was stirred by cooling the The reaction mixture is controlled in an ice-water bath. The cooled reaction mixture was made up to 500 ml Poured mixture of ice and water, and the resulting 3,8-bis (2-chloroethoxy) -6H-dibenzo fb, d jpyran-6-one, the dropped out, was isolated.

A mixture of 4.6 g (0.013 mol) of 3,8-bis (2-chloroethoxy) -6H-dibenzo ["b, d] jpyran-6-one, which was obtained in the aforementioned manner, 2 g of potassium iodide and 100% ml of a HO $ aqueous dimethylamine solution, contained in 50 ml of tetrahydrofuran, was in a Parr pressure reactor

409826/116 2

heated with stirring at 120 ^° C. for 16 hours. The reaction vessel was cooled and most of the volatiles were removed in vacuo. The residue was treated with an aqueous sodium hydroxide solution and extracted with ether. The ethereal solution was washed twice with water, once with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and treated with an ethereal hydrogen chloride solution. The product which separated out was then recrystallized from a mixture of methanol and anhydrous ether, the desired 3 * 8-bis-Γ2- (dimethylamine) -ethoxj! ] -6H-dibenzo fb, d tpyran-6-one dihydrochloride was obtained.

Example 8

This example illustrates the antiviral effectiveness of the compounds according to the invention.

30 mice, each weighing about 12 to 15 g, were divided into 2 groups, a control group consisting of 20 animals and a test group consisting of 10 animals. All animals were infected with a lethal dose (28 LD ₅₀ ) of encephalomyocarditis virus. The test group of animals was treated both prophylactically and therapeutically using a parenteral composition containing 3,8-bis-f2- (diethylamino) -ethoxy "} - 6 <5H) -phenanthridinone dihydrochloride as an active ingredient, which in one 0.15 # aqueous solution of hydroxyethyl cellulose was dissolved. The composition contained the active ingredient in such an amount that each dose contained 0.25 ml, which corresponds to a dose level of 50 mg / kg. The control group received one

409826/116 2

subcutaneous placebo containing the same volume of the extender but no active ingredient over a period of time Observations carried out over 10 days indicated that all control animals died within 4 to 5 days, while the treated group of animals survived for a statistically longer period of time /

Example 9

Preparation of a tablet formulation

A batch for 10,000 tablets, each 100 mg 3,8-bis- [2- (diethylamino) ethoxys 3 ~ 6 (5H) -phenanthridinone contains was manufactured as follows

(a) 3,8-bis- [2- (diethylamino) -ethox3O-

6 (5H) -phenanthridineη 1,000

(b) lactose ■. 1,000

(c) starch paste (10 wt. Jf / vol. starch

in water) 100

(d) magnitude 32.5

(e) calcium stearate 6.5

The active ingredient is mixed uniformly with the lactose and granulated by adding the starch paste. The granules formed were dried for 20 hours at a temperature of 49 ° C. and _{pressed through a No. 16 sieve (mesh size: O 5} , 991 mm) = After the starch and calcium stearate had been added as lubricants, the granules were compressed into tablets. Each tablet produced in this way contained. 100 mg active ingredient «,

409826/1162

Example 10

Manufacture of a formulation for capsules

A typical composition used to make 1,000 two-part hard gelatin capsules, each capsule mg 2,7-bis- f2- (diethylamino) -ethoxj * 3-9-methoxyphenanthrene was made as follows:

(a) 2,7-bis-f2- (diethylamino) ethoxy, 3-9-methoxyphenanthrene 100

(b) corn starch 150

(c) Magnesium stearate 25

(d) 1,000 hard gelatin capsules

The finely powdered ingredients were mixed until until they were evenly distributed, and then filled into hard gelatin capsules of suitable size.

In a similar manner, soft gelatin capsules can be prepared using the aforementioned composition granulated or as a compact in the circulating mold or platen mold in which the soft gelatin capsule is produced can be filled in or pressed in directly. However, the above-mentioned excipients can also can be omitted, and the active ingredient can be poured directly into the soft gelatin capsule as a powder.

Example 11

Manufacture of a formulation for an oral syrup

A syrup having a content of 2 wt -.% 3,8-bis (JL-

409826/1162

piperidinobutoxy) -6 (5H) -phenanthridinone dihydrochloride per volume was prepared according to standard pharmaceutical procedures. The wording was as follows:

(a) 3,8-bis- (^ - idinobutoxy) -6 (5H) -phenanthridinone dihydrochloride distributed in P .2.0

(b) sucrose 33.3

(c) chloroform 0.25

(d) sodium benzoate x 0.4

(e) methyl p-hydroxybenzoate 0.02

(f) vanillin "0.04

(g) Glycerin 1.5 (h) purified water ad 100.0 ml

Example 12 ■ · -..-

Preparation of a formulation for an ointment

1,000 g of an ointment for topical use were produced from the following ingredients, which contained 1 % 3,8-bis- [2- (diethy lamino) -ethoxji] -6 (5H) -phenanthridinone dihydrochloride:

(a) 3,8-bis [2- (diethylamino) ethoxy. ] -

6 (5H) -phenanthridinone dihydrochloride 10

(b) light paraffin oil 250

(c) wool fat. 200

(d) white vaseline ad 1,000

409826/1 162

The wool grease, the white petroleum jelly and 200 g of the light one Paraffin oils were made liquid and kept at a temperature of 43 ° C. The active ingredient was with the remaining paraffin oil mixed and passed through a colloid mill. After that, the mixture went into the melt stirred in, and the mixture was continued with continued Stir left to cool until solidified.

Example 13

Preparation of a formulation for a parenteral emulsion

A typical composition for an emulsion that is parenterally injectable is as follows:

Each ml -.

contains ingredients quantity

50 mg of 3,8-bis- [2- (diethylamino) -ethoxjO-

6 (5H) -phenanthridinone ipOO g

100 mg polyoxyethylene sorbitol monooleate 2 pOO g Q.0064 sodium chloride 0.128 g

Injection water ad 20p00 ml

The parenteral composition is prepared by dissolving 0.64 sodium chloride in 100 ml of water suitable for injection. The polyoxyethylene sorbent monooleate is mixed with the active ingredient, and an amount of the previously prepared aqueous sodium chloride solution sufficient to make a total volume of 20 ml is added. The solution obtained is shaken and ^{kept in the autoclave for 20 minutes at 110 °} C. and at a vapor pressure of 2.08 kg / cm.

409826/116 2

The composition can be packed in a single ampoule for multiple dose use or in 10 or 20 ampoules single ampoules for use as single dose 3 units be bottled.

409826/1162

Claims (1)

- ¹ UJr - Patent claims: 1. Bis-basic ethers of the general formulas and \, N- (CHa) -O-
* OR ₂ O- (CH «) _n -N- _N J in which η 2 to 6, R and R ₁ each represent a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, a cycloalkyl group with 3 to 6 carbon atoms, an alkenyl group with 3 to 6 carbon atoms in which the double bond is in a different than in the 1 Position of the alkenyl group, and R and R ^ together with the nitrogen atom to which they are bonded represent a pyrrolidinyl, piperidino or morpholino radical, and in which Z is an oxygen atom, the group> NH or a methylene radical, Y is a nitrogen atom or is a methylidene group and Rp is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, 408826/1 162 2352577 and their pharmaceutically useful ones. Acid addition salts. 2. 3 _s 8-bis-r2- (diethylamino) -ethox5i> 6 (5H) -phenanthridinone and its pharmaceutically acceptable. Acid addition salts » 3. 2,7rBis-f2- (diethylamino) -ethox ^ 3-9-methoxyphenanthrene and its pharmaceutically acceptable. Acid addition salts. k. Process for the preparation of compounds according to Claim 1 of the general formula R ₁ wherein n, R and R. have the meaning given in claim 1 have, and R, a hydrogen atom or a methyl group represents, characterized in that a 2,7-bis-basic ether of fluoren-9-one of the general formula 409826/1162 MS? reacts with diazomethane, 5, a process for the preparation of compounds according to claim 1 of the general formula in which n, R and R have the meaning given in claim 1, characterized in that a 2,7 ~ bi? ^T basic ether of fluorene-9-Όη of the general formula with nitrogen nitrogen in the presence of a strong Mineral acid converts. 6, a process for the preparation of a compound according to claim 1 of the general formula 0- (CH ₂ )
■ U 09826/116 2 in which η, R · and PL have the meaning given in claim 1 own, characterized in that one is a 2,7-bis ~ (ü> haloalkoxy) -fluoren-9-one the general formula O- (CH _? ) _N -Ha in which Hai denotes a chlorine, bromine or iodine atom, with a peracid or with hydrogen peroxide in the presence of a strongly acidic catalyst to form 3,8-bis- (ci ⁱ -haloalkoxy) -6H-dibenzofb, d] pyran -6-one and this compound with an amine of the general formula wherein R and R _{1 have} the aforementioned meaning, condensed. 7. Antiviral agent, consisting of one of the compounds according to claim 1 to 6 as an active ingredient and customary pharmaceutical Carriers. 8. Antiviral agent according to claim 7 in dosage unit form, characterized by a content of 2 mg to 3 g of the active ingredient. For Richardson-Mafrrell Inc. 4 (Dr. H ^ J. Wolff) Attorney 4098 2 6/1162