DE2362695A1 - NEW 2.7 TO BASIC VINYLENE DERIVATIVES OF XANTHENE AND THIOXANTHENE, THE PROCESS FOR THEIR PRODUCTION AND THE PHARMACEUTICAL COMPOSITIONS THESE CONTAINED - Google Patents

Description

Ec / tk

LAWYERS DR. JUR. DJPL-CHEM-WALTERBEIT

ALFRED HOSPPENSR

DR. JUR, DiPUCrScM. H.-J. WOLFF 14 Dec 1973

DR. JUR, HANS CHR. BEIL - -

* 23 FRAKI (FURT AM MAiN-HOCHS?

A0ELON5IRA5S £ 59

Our no.18 950

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

New 2.7 * -bis basic vinylene derivatives from Xahthene and thioxanthene, processes for their preparation and pharmaceutical compositions containing them.

The invention relates to new 2,7-bis-basic vinylene derivatives of xanthene and thioxanthene, processes for their preparation and pharmaceutical compositions containing them.

The compounds are useful as antiviral agents which inhibit or inactivate viruses when infected or to non-infected hosts.

There is a growing body of information that viruses have play a vital role in a large number of medical conditions, some of which are the most serious represent human suffering. With viruses as the causative principle, arthritis, juvenile arthritis, diabetes, Hodgkin's disease, as well as various immunological Diseases and degenerative diseases of the central nervous system connected.

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Currently, viral infection control is mainly achieved through immunization vaccines * For example were found in the well-known diseases of polio--. myelitis, smallpox, measles and influenza viral vaccines as effective. Usually, however, only had viral vaccines a moderate success in the prophylaxis of living things. Every vaccine works primarily against one specific virus and is not heterophile in the protection it provides. As a result, vaccines were not practical Solution to a larger number of transmittable viruses, even where these are limited, such as alone to Viruses of the respiratory tract.

A first step in the control of viral diseases and, in particular, the spread of such viral diseases was the search for medicinal or chemotherapeutic agents that are capable of preventing the growth of viruses to inhibit and thereby the spread of diseases and further damage to cells and tissues of the animal host, which have not yet been infected. So far, only a limited number of viral infections, such as smallpox, Asian influenza and herpes · keratitis prevented by chemical antiviral agents « Sulfonamides, and antibiotics, which revolutionized the treatment of bacterial infections, show im essentially no effect on viral infections. Certain infections caused by large viruses, such as e.g., Lymphogranuloma venereum, psittacosis and trachoma have been treated using antibiotics and sulfonamides successfully treated. The majority of virus infections however, was unresponsive to a chemotherapy drug attack. From this it follows that a need for new chemotherapeutic agents that are opposite to a

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wide range of viral diseases are effective, and which are at the same time non-toxic to the host.

It has now been the result of a long series of studies found that a new class of 2,7-bisbasic vinyl derivatives of xanthene and thioxanthene in particular are effective as antivirals. These compounds are opposed to a wide range of viral infections effective and they are effective in treating such Infections are useful both prophylactically and therapeutically.

BE-PS 776 535 and ZA-PA 71/5461 describe bisbasic Ketones of xanthene and thioxanthene, which have antiviral activity. The invention Compounds differ from the known compounds in that they are not bis-basic ketones, but rather represent bis-basic vinylene derivatives of xanthene and thioxanthene. Certain of the preferred ones described so far 2,7-ketones are suitable as starting materials for the production of the compounds according to the invention. The compounds described and claimed herein are new compounds not previously described or mentioned in the literature. In addition, there are none so far bis-basic vinylene derivatives of any kind are known which have been described as having antiviral activity. The invention Compounds exhibit a wide range of antiviral activities to varying degrees, that could not have been foreseen.

The compounds of the invention are 2,7-bis-basic Vinylene derivatives of xanthene and thioxanthene, which are effective as antiviral agents. The inventive

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bonds can be expressed by the following general formula being represented:

wherein Y represents an oxygen or sulfur atom, A represents a straight-chain or branched-chain alkylene group with 1 to H carbon atoms and R and FL each represent hydrogen, lower alkyl groups with 1 to 6 carbon atoms, cycloalkyl groups with 3 to 6 carbon atoms, alkenyl groups with 3 to 6 carbon atoms, in which the double bond is in a position other than the!

The 2,7-bis-basic vinylene derivatives of xanthene and Thioxanthene (I) are in two stages from the corresponding 2,7-bis-basic ketones produced by xanthene and thioxanthene (II). In the first stage, the bisbasic Reduced ketones, the corresponding 2,7-bis-basic a-alkanols (III) being formed. In the second stage, these alkanols are formed with the formation of the 2,7-bis-basic α, ß-unsaturated vinylene derivatives present invention (I) dehydrated. These reactions can be illustrated by the following reaction scheme:

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-R

OH

Dehydration

-R

(IN THE)

I ")

Reduction

In the above reaction scheme, the symbols A, R ₃ R ₁ and Y have the meaning given above »

In order to exert an antiviral effect, the invention Compounds administered in the form of various preparations to a suitable host. Such preparations can be given before infection, such as prophylactic use or treatment, or they can be used therapeutically following infection administered as in a medicinal application or treatment. The compounds of the invention can also applied externally or topically directly to the site of the infection, or they. can be applied internally or on applied to the body, regardless of whether the treatment is prophylactic or curative. In

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the replication of the virus is inhibited or in each Pall -prevented so that the various disease symptoms characteristic of the pathogenic viral infection are no longer occurring.

As can be seen from the above general formula (I), the compounds according to the invention contain two basic side chains, each of which is attached separately to a benzenoid part of the xanthene or thioxanthene nucleus sits. Furthermore, each side chain can be understood to consist essentially of a basic amino function at the outer end of the side chain, a ct, ß-unsaturated or vinylene function on the one adjacent to the core End of the side chain ', which also serves as a bridging function between the side chain and the aromatic core, and a certain length alkylene chain which separates the vinylene function from the terminal basic amino function separates, exists.

The alkylene chain that separates the vinylene group from the basic Amino group separates, consists of 1 to 4 carbon atoms and represents either a straight-chain or a branched-chain Alkylene chain. The two alkylene groups can be the same or different, but they are preferably same. Examples of different alkylene groups that can be represented by the symbol A are the Methylene, ethylene, trimethylene, 1-methyl-ethylene, Tetramethylene and the 2-methyltrimethylene group.

/ l ^
The amino function represented by the symbol -N )

can be a primary, secondary or tertiary amino group. Preferably each amino group is tertiary Amino group .. The symbols R and R. represent either hydrogen represent atoms or lower alkyl groups. The term

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"Lower alkyl group" as used here for the basic amino function is used refers to alkyl groups having 1 to 6 carbon atoms. Examples of such groups are straight-chain or branched-chain alkyl groups, such as the methyl, ethyl, n-propyl, isopropyl, η-butyl, sec-butyl, Isoamyl, n-pentyl and n-hexyl groups. When R and R ^ each represent lower alkyl groups a preferred embodiment.

Each of the symbols R and R ^ can also be a cycloalkyl group represent having 3 to 6 carbon atoms. Examples of such groups are the cyclopropyl, cyelobutyl, Cyclopentyl and the cyclohexyl group.

The symbols R and R ^ can also be alkenyl groups with 3 to Represent 6 carbon atoms. Apart from the fact that the double bond must be present, this double bond must be present in a position other than the 1-position of the alkenyl group are present to prevent hydrolysis. Examples of such groups are the allyl, 3-butenyl and the 4-hexenyl group.

R and R ₁ , together with the nitrogen atom to which they are attached, can also represent various saturated monocyclic, heterocyclic radicals. Examples of such heterocyclic groups are the 1-pyrrolidinyl, piperidino or morpholino groups. Compounds containing these groups are easy to prepare and are typical examples of saturated monocyclic he-terocyclic radicals which can generally be used in place of the di-lower alkylamino groups of the compounds according to the invention. . ■.

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The vinyl part of the molecule serves as a bridging function, which the basic alkylene side chain with the aromatic Core connects. The compounds of the invention are therefore distinguished by the fact that they are unsaturated, and furthermore by the fact that this double bond is in the ot, ß-position to the aromatic core. The aromatic nucleus is either a xanthene nucleus or a thioxanthene nucleus, depending on whether the symbol Y is an oxygen or a sulfur atom. In each case there are the unsaturated ones bis-basic side chains in the 2- and 7-position of the aromatic nucleus.

Examples of novel compounds which are represented by the general formula (I) 'are könnenj: 2,7-bis (4-piperid3 _r no-l-butenyl) xanthene, 2,7-bis / ~ 3- ( diethylamino) -1-propenyl7-xanthene, 2,7-bis- / 3- (N-cyclohexyl-N-methylamino) -l-propenyl7-xanthene, 2,7 ^- Βί3- / 5- (dimethylamino) -3-methyl -l-pentenyl7-xanthene, 2,7-bis-A- (diallylamino) -l-butenyl7-xanthene, 2,7-bis- / 3- (cyclohexylamino) -1-propenyl7-xanthene, 2,7-bis- / 3- (l-pyrrolidinyl) -1-propenylj-thioxanthene, 2,7-bis - / ^ - (dimethylamino) -lbutenylj-thioxanthene, 2,7-bis- / 3- (diisopropylamino) -lpropenyl7-thioxanthene, 2 , 7-bis- / 3- (diallylamino) -1-propenyl-7-thioxanthene and 2,7-bis (4-morpholino-1-butenyl) thioxanthene.

The term "pharmaceutically acceptable acid addition salts" should refer to all non-toxic organic or inorganic acid addition salts of the formula (I) ' refer to the connections shown. Examples of inorganic acids which form suitable salts are hydrogen chloride acid, hydrobromic acid, sulfuric acid and Phosphoric acid and acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Examples

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for organic acids that form suitable salts the mono-, di- and tricarboxylic acids. Examples of such acids are acetic 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 and sulfonic acids, such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. They can Mono- or the di-salts of the acids are formed, and these salts can hydrate in one or in one are practically anhydrous form. In general, the acid addition salts of these compounds are crystalline Substances which are soluble in water and various hydrophilic organic solvents and which .in comparison generally have higher melting points than their free bases and improved chemical resistance.

The 2,7-bis-basic ketones of xanthene and thioxanthene (II), which can serve as starting material for the preparation of the compounds according to the invention, are also described in produced in a two-step process. The first stage is a FriedelrCrafts acylation of xanthene or thioxanthene with formation of a 2,7-bis (<y-haloalkanoyl) derivative carried out. In the second stage, these derivatives are formed with the formation of the corresponding 2,7-bis-basic Ketones aminated by xanthene and thioxanthene. The amination can be carried out under various conditions. For example, the & / - haloalkanoyl derivatives with a large excess of an amine are heated, the excess amine both as a reaction medium and serves as a hydrogen halide acceptor. On the other hand you can

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the compounds but also with an amine in a suitable one Solvents such as toluene, dioxane or dimethylformamide can be heated to cause the condensation. The production of these ketones is described in BE-PS 776 535 and explained in more detail in ZA-PS 71/5461.

The treatment of the 2,7-bis-basic ketones of xanthene and thioxanthene (II) with a reducing agent leads to a reduction of the "ketones to secondary alcohols, ie to the 2,7-bis-basic alkanols of xanthene and thioxanthene (III ). In general, the reduction in a suitable solvent using sodium borohydride as reducing agent at temperatures of about -20 is carried out to about 100 ° C for a period of about 30 minutes to about 2 ¹ I hours. Various solvents are suitable as solvents, for example tetrahydrofuran, methanol, ethanol and water. When aqueous or methanolic solutions are used, a base such as sodium hydroxide is employed to minimize the degree to which the sodium borohydride reactant decomposes. The reduction of the 2,7-bis-basic ketones of xanthene and thioxanthene is preferably carried out by dissolving the ketones in tetrahydrofuran and adding small amounts of solid sodium borohydride with constant stirring. For convenience, ice bath temperatures are usually employed with stirring continued for 1 to 12 hours.

The dehydration of the 2,7-bis-basic alkanols of xanthene and thioxanthene (III) to form the corresponding unsaturated vinylene derivatives of the present invention takes place under acidic conditions. However, one should avoid using the alkanols of strong acids at high temperatures.

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Doors suspend for a long time. The time-temperature conditions are therefore chosen so that maximum dehydration occurs under the mildest reaction conditions. The dehydration can be carried out by dissolving the 2,7-bis-basic alkanol (III) in a high-boiling solvent such as ethylene glycol or ethylene glycol itfonoäthylather, adding the dehydrating agent and the reaction mixture for about 1 to about 30 minutes on a Steam bath heated to about 100 ^{° C.} Concentrated hydrochloric acid or sulfuric acid is preferably used as the dehydrating agent. The minimum time required for dehydration can be determined by monitoring the reaction medium using conventional methods, for example observing the disappearance of the OH stretching frequency in the infrared spectrum. The 2,7-bis-basic vinylene derivatives of xanthene and thioxanthene (I) thus prepared are isolated using customary methods. For example, the reaction mixture can be made alkaline and the product extracted with ether; However, any unreacted starting material can also be separated from the end product by means of column chromatography *

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12 -.

The compounds according to the invention are antiviral active ingredients; preferably they are administered to an animal or human host to prevent viral infections prevent or inhibit. Be under the term "host" any viable biological material, intact animal or human understood, capable of forming of interferon and which act as carriers for virus replication. The host can of animal or of mammalian origin. Examples of such Hosts are: birds, mice, rats, guinea pigs, ferrets, Gerbils, dogs, cats, cows, horses and humans. Other viable biological materials, such as those used in the manufacture of vaecins, can also be used serve as host. These have been shown to be made from organic tissues such as mammalian kidney or lung tissue Tissue cultures as well as cultures made from embryonic tissues as well as from amniotic tissues Cells or from the allantoic fluid of chicks are useful hosts.

Treatment of viral infections involves both preventing and inhibiting characteristic disease symptoms in a host mammal susceptible to attack by a pathogenic virus. Examples of viral infections in mammals which can be prevented or inhibited by administration of the compounds according to the invention are infections caused by picornaviruses, such as the encephalomyocarditis virus, myxoviruses such as influenza A ₂ (Jap / 3O5) ~ Virus, arboviruses such as; the ". Semliki Forest virus, the group of herpes viruses, including herpes simplex, and by .pox viruses ^.

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e.g. Vaccinia IHD, causes v / ground. For example, the compounds according to the invention delay or completely prevent the onset of death when they are administered orally or subcutaneously to mice in various doses, either shortly before or after a fatal inoculation of a rieurotropic virus such as, for example, encephalomyocarditis virus, with an LDcq of; 5 to 50 will. The salts of the compounds according to the invention are generally administered in compositions which contain a 0.15% aqueous solution of hydroxyethyl cellulose as a diluent, while the free bases are generally administered in compositions, many an aqueous solution Surfactant solution • Included as an extender to aid in solubilizing the compound. Typically 10 mice are used in each treated group and 20 mice are used as a control group. At "the time of administration, the test virus is titrated to determine the potency or LD ^ value for the particular virus used to cause infection." The control animals are given a placebo containing an identical volume of the vehicle without the active ingredient. Due to the lethal nature of the test system used, the antiviral effectiveness of the test compound is clearly expressed by a side-by-side comparison of the treated surviving animals with the untreated control group of animals. . ■

Viruses of the respiratory tract, such as the influenza Ap (Jap / 3O5) virus, which are also fatal to the test animals, are administered by intranasal instillation. Animals infected in this way are administered the active substances in the same way as the test virus, and it. will again-a side-by-side comparison of the survivors treated animals with the untreated control animals.

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In "- as yet unexplained ways, someone with encephalomyocarditis viruses or influenza viruses survives fatally infected mouse without further treatment. That may be the result of a previous interferon formation causative infection in the mouse, perhaps the result of certain genetic factors or of others, hitherto unexplained natural defense mechanisms. -. For this reason the selected control group is from of sufficient size to over- ~ statistically, to reduce the chance of life of the test results to a negligible value. · "-. · -

The Vaeeinia test virus is typical of dermatotrophic type viruses that respond to treatment with compositions containing the compounds of the invention. The vaccinia virus generally causes a non-fatal infection in the mouse and leads to pathological changes in the tail when the virus is administered subcutaneously to the mouse tail. The Vierden compounds are administered either orally or subcutaneously, either before or after vaccinia infection _} . The flawed 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 with one another. 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 the formation of Evoke interferon in a viable host. Interferon is a biological substance of unknown -. chemical structure * presumably of proteinaceous nature, killed by host cells on viral infection will. The interferon formed in this way works by causing the formation of a substance that inhibits the virus, which in a manner not yet known, the 4 0 9 8 2 6/1165

inhibits intracellular replication of the virus> without appearing to have an inactivating effect ^; Per se on the virus. Some viruses susceptible to the inhibition of replication by interferon are in the monograph Ho rs fall and Tamm, "Viral and Rickettsial • Infections of Man", H. ed. (1965) , JB, Lippincott. Company, pp. 328-32.9.

As mentioned above, the compounds according to the invention can administered prophylactically to prevent the spread of contagious viral diseases, or they can be administered therapeutically to an already infected host for healing purposes. With the prophylactic Administration, it is preferred that this occur within 0 to 96 hours prior to infection of the host is made with a pathogenic virus. If the compounds according to the invention for the purpose of a healing effect administered, it is preferred that the administration within one to 2 days after infection, des 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 animal, its age, health status, Weight, . the extent of the infection, possibly 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. For example .be doses of the active ingredient to be administered for intravenous treatment about 0.1 mg to about 10 mg / kg Body weight; for intraperitoneal administration, for example

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0.1 mg to about 50 mg / kg body weight; to subcutaneous Administration from about 0.1 rag to about 250 mg / kg body weight; for oral administration from about 0.1 mg / kg to about 500 mg / kg Body weight;' for internal instillation about 0.1 mg up to about 10 mg / kg body weight and for aerosol inhalation therapy usually about 0.1 mg to about 10 mg / kg • body weight. . · - - '- ".-- ....

The new compounds can also be administered in various dosage unit forms / z, B *. oral compositions in the form of tablets, capsules, dragees, lozenges, 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, of course, varies within wide ranges, 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 dosage unit can contain from about 2.0 mg to over 3> 0 g "of active ingredient, in addition to the pharmaceutical excipients contained therein. ■

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 '

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with or without the addition of a surface-active agent »As a rule, the preferred liquid excipients, especially for injectable preparations, include water, saline, dextrose and glycol solutions. such as an aqueous propylene glycol solution or an aqueous solution of polyethylene glycol. Liquid preparations, ·; which as sterile injectable solutions used werdeny usually contain from about 0.5 to about 25 wt .- ^, preferably about 1 to about 10 wt -.% active ingredient in _a solution. Various oils are used as carriers or excipients in certain topical and parenteral preparations. Examples of such oils are mineral oils, glyceride oils, such as, for example, bacon oil, cod liver oil, peanut oil, sesame oil, corn oil and soybean oil.

A preferred method of administration for the compounds according to the invention 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, "typically the active ingredient component is .about 0.5 to about 10 wt." The pharmaceutical carrier in such compositions is typically aqueous, such as, for example, flavored water, a sugar-based syrup or a pharmaceutical mucilage. For insoluble compounds, suspension agents and viscosity regulators, such as magnesium aluminum silicate or carboxymethyl cellulose _y can be added. It can also contain buffers, preservatives, emulsifiers and others. Excipients are added.

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For parenteral administration, such as intramuscular, intravenous or subcutaneous administration, the proportion of active ingredient is about 0.05 to about 20 percent by weight, preferably about 0.1 to about 10 percent by weight, of the liquid Composition. (In order to reduce or eliminate irritation at the injection site, "such compositions may contain non-ionic surface-active agents with a hydrophilic-lipophilic balance (HLB) of about 12 to about 17." the amount of surfactant in such formulations is from about 5 to about 15 wt -.% the surface active agent may be a single HLB with the aforementioned, or a mixture of two or more components having the desired HLB be "Examples of surface active agents. which are useful in parenteral formulations, are the class of Polyoxyäthy lens orbit fatty acid esters, "such as sorbitan monooteate 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. The concentration of drug in these various parenteral dosage forms schänkt within a range of about 0.05 to about 20 wt -.% Of the total formulation, with the remaining component or other components are made from the liquid pharmaceutical excipients previously mentioned.

The new active ingredients can also be mixed directly with animal feed or incorporated into the drinking water of animals. For most purposes, an amount of active ingredient is used, an amount of active ingredient from about 0.0001 to about 0.1 wt -.%, Preferably about 0.001 to about 0.02 wt -.% ₃ ■. * ' based on

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the total weight of the feed intake, perm * provides. The active ingredients can be mixed into animal feed concentrates which are suitable for use by the farmer or cattle breeder for incorporation in suitable amounts into the final animal feed. These concentrates usually comprise from about 0.5 to about 95% by weight of active ingredient, which has a finely divided solid carrier; or. Flour, such as cereal, corn, soybean or cottonseed flour, is mixed. Depending on the. special animals to be fed, nutrients and fillers can also be added, such as ^{ground grain, charcoal, fuller f} s soil, oyster shells and finely divided attapulgite or bentonite. -. "

For use as an aerosol, the active ingredients can be packed into a , suitable pressure vessel together with an aqueous or volatile propellant. 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. Other auxiliaries, such as co-solvents, wetting agents and - Bactericides can be used if necessary. Usually the propellant used is a liquefied petroleum gas, preferably a mixture of low molecular weight fluorocarbons. These are haloalkanes preferred because they are compatible with the new active ingredients, and because they are applied to the Do not irritate 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 (4-chlorobutyryl) -xanthene

A chilled to -20 ⁰ C mixture of 91.1 g (0.5 mol) of xanthene, 176.3 g (1.25 mol) of 4-chlorobutyryl chloride and 3 liters of dry methylene chloride was added slowly over 30 minutes with 146.7 g (1.1 mol) of aluminum chloride were added while the temperature was kept below -10 ° C. After completion of the addition the reaction was allowed temperature rise slowly to room temperature and then the mixture was heated at reflux for H h. After cooling, the mixture was decomposed by carefully pouring it into 2 liters of a mixture of ice and water. The liquid layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were concentrated to a small volume and cooled. The 2,7-bis ( ⁱ f-chlorobutyryl) -xanthene obtained in this way was recrystallized from acetone, the desired product having a melting point of 131 to 132 ° C. being obtained.

Example 2

2 ₅ 7 bis (3 chloropropionyl) thioxanthene

A chilled to -20 ⁰ C mixture of 99.2 g (0.5 mol thioxanthene, 158.5 g (1.25 mol) of 3-chloropropionyl chloride and 3 liters of previously dried methylene chloride was added slowly over 30 minutes with 146.7 g (1.1 mole) of aluminum chloride are added, while the temperature was kept below -10 ⁰ C. After the aluminum chloride was added, the reaction mixture was slowly

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Warmed to room temperature and then refluxed for a further 4 hours. The reaction mixture was on Cooled room temperature and decomposed by carefully pouring it into 2 liters of a mixture of ice and water. the liquid layers were separated and the aqueous layer was extracted several times with methylene chloride. The combined organic layers were concentrated to a small volume and cooled. That is when standing separating, desired 2,7-bis- (3-chloropropionyl) -thioxanthene was recrystallized from acetone, the desired product having a melting point of 175 to 177 ° C was obtained.

Example. 3 . .

2,7-bis- (4-piperidinobutyry1) -xanthene -

A mixture of 19.6 g (0.05 mol) of 2,7-bis- (4-chlorobutyryl) -xanthene, 34.0 g (0.4 mol) piperidine, 16.6 g (0.1 mol) Potassium iodide and 200 ml of butanone were refluxed with stirring for 60 hours. The reaction mixture was cooled and poured into 1 l of water. The precipitated pesticide was filtered from a solution of methyl chloride and acetone recrystallized and recrystallized again from acetone, the desired 2,7-bis ~ (4-piperidinobutyryl) -xanthene with a melting point of 115 to 117 ° C. was obtained.

Example 4 -

2 _? 7-bis - ^ - (diethylamino) -propiony! _7-thioxanthendihydr ο eh lorid dihydrate

A mixture of 13.0 g (0.034 mol) 2.7 ~ bis- (3-chlorpro-

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pionyl) thioxanthene, 1 g of potassium iodide, 75 ml of diethylamine and 75 ml of tetrahydrofuran were allowed to stand at room temperature for 72 hours and then filtered. The residue was washed carefully with tetrahydrofuran and the combined filtrates were evaporated to dryness. The residue obtained in this way was dissolved in a small amount of ethanol, treated with ethanolic HCl to form the dihydrochloride salt and diluted with diethyl ether. The resulting product was filtered, recrystallized from a solution of methanol and diethyl ether, and hydrated in a constant humidity room, the desired 2,7-bis- / 3- (diethylamino) -propionyl7-thioxanthene as the dihydrochloride dihydrate with a Melting point of 137 to 1 ^ 0 ⁰ C was obtained.

Example 5

q, q'-bis (3 ~ piperidinopropyl) -xanthene-2,7 ~ dimethanol

A cooled, stirred solution of 25.6 g (0.053 mol) of 2,7-bis ( ⁱ J-piperidinobutyryl) -xanthene in 200 ml of tetrahydrofuran was with a solution of 4.2 g (0.11 mol) of sodium borohydride in a Solution of 50 ml of methanol and 5 ml of a 10% sodium hydroxide solution are added. The resulting mixture was slowly warmed to room temperature and further stirred overnight. The reaction mixture was diluted with water and the solid which formed was filtered, washed with water / water and air dried. The solid product was dissolved in a 10% hydrogen chloride solution, filtered, and the filtrate was made alkaline with a 10% sodium hydroxide solution. The alkaline filtrate was extracted with methylene chloride. The organic extract was then mixed with water

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washed, then again with a saturated one
Washed sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness in vacuo. The residue containing the desired &, cx '-Bis- (3-piperidinopropyl) -xanthene-2,7-dimethanol was recrystallized twice from benzene, a product having a melting point of 145 to 146 ^° C. being obtained.

After practically the same procedure, but using: 2,7-bis- / 4- (diethylamino) -butyryl7-xanthene, 2,7-bis-A- (diallylamino) -butyryl7-xanthene, 2,7-bis- / 3- (diethylamino) propionyl ^ -xanthene, 2,7-bis- Lk- (diethylamino) -butyry17-thioxanthene, 2,7-bis- (4-piperidinobutyryl) -thioxanthene or 2,7-bis- / 3 - (dimethylamino) propiony] _w 7-thioxanthene "instead of 2,7-bis- (4-piperidinobutyryl) -xanthene the following products were obtained: -α, α'-bis- / 3- (diethylamino) -propyl. 7-xanthene-2, -7-dimethanol, α, α'-bis-i ^ - (diallylamino) -propyl7-xanthene-2,7-dimethanol, α, α'-bis- / 2- (diethylamino) -ethylJ -xanthene-2,7-dimethanol, α, α ¹ -Bis-Z3- (diethylamino) -propyl _> 7-thioxanthene-2., 7-dimethanol, α, α'-bis- (3-piperidinopropyl) -thioxanthene- 2,7-dimethanol and α, α'-bis- £ 2- (dimethylamino) -äthy Ij- thioxanthene-2,7-dimethanol. '-

Example 6

2,7-bis - (^ - piperidino-1-buteny1) -xanthene

17.4 g (0.035 mol) of a, a ^f -Bis- (3-piperidinopropyl) -xanthene-2,7-dimethanol were dissolved in a mixture of 25 ml of ethylene glycol monoethyl ether and 25 ml of concentrated hydrochloric acid and placed on the steam bath for 5 minutes heated. The solution was diluted with an equal volume of water and made alkaline with a 20% sodium hydroxide solution. The resulting solution was extracted twice with ether, and

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2H -

236269S

the extracts were combined, washed with water, washed with a saturated sodium chloride solution, over dried anhydrous magnesium sulfate, filtered and evaporated to dryness in vacuo. The residue was Recrystallized 2 times from ethanol and 2 times from isopropanol, with 2,7-bis- (4-piperidino-l-butenyl) -xanthene with a melting point of 158.5-160.5 ° C was obtained.

After practically the same procedure, but using: a, cc ^l -Bis- / 3- (diethylamino) -propyl / -xanthene-2,7-dimethane-pl, α, α ¹ -Bis- C $ ~ (diallylamino) - propy17-xanthene-2,7-dimethanol, a, a'-bis- / 2- (diethylamino) -ethyl.7-xanthene-2,7-dimethanol, α ^ α'-bis- ^ J- (diethylamino) - propy17-thioxanthene-2,7-dimethanol, a, a ^l -bis- (3-piperidinopropyl) -thioxanthene-2,7-dimethanol and α, α'-bis-Z ^ -Cdimethylamino) -ethyl7-thioxanthene-2, 7-dimethanol instead of α, α'-bis- (3-piperidinopropyl) -xanthene-2,7-dimethanol, the following products were obtained: 2,7-bis- / 4- (diethylamino) -lbutenyl7-xanthene, 2, 7-BiS-Z "^ - (diallylamino) -l-butenyl7-xanthene, 2,7-bis- / 3- (diethy! Amino) -1-propeny 1,7-xanthene, 2,7-bis- / V (diethylamino) -l-butenyl7-thioxanthene ₉ 2,7-bis- (4-piperidino-l-butenyl) -thioxanthene and 2,7-bis-Z ~ 3- (dimethylamino) -l-propenyl7-thioxanthene.

Example 7

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

Thirty 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 given a lethal dose (8 LD ₁ .-) of

5ü

Encephalomyocarditis virus infected. The test group of the.

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Animals were treated both prophylactically and therapeutically using a parenteral composition containing 2,7-bis- ( ⁱ -piperidino-1-butenyl) -xanthene as an active ingredient, which was dissolved in a 10% aqueous solution of sorbitan monooleate was. The composition contained the active ingredient in such an amount that each dosage contained 0.25 ml, which corresponds to a dosage level of 50 mg / kg. The control group received a subcutaneous placebo containing the same volume of the extender but no active ingredient, observations carried out over a period of 10 days showed that all control animals died within 4 to 5 days, while the treated group of animals survived for a statistically longer period . .

Example 8. '■ · ".:, .- ■'

Manufacture of a formulation for capsules

A typical composition for hard gelatin capsules was made as follows:

per capsule

(a) 2,7-Bis-ZV (dimethylamino) -l-. butenylj-xanthene dihydrochloride 200 mg

(b) Talc 35 mg

The formulation was prepared by passing the dry powders (a) and (b) through a fine-mesh sieve and then mixed well. The powders were then placed in hard gelatin capsules with a net fill weight of 235 mg per capsule No. 0 filled. Soft gelatin capsules can be filled in a similar manner, but with the talc is omitted. The 2,7-bis- / 4- (dimethylamino) -l-

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butenylj-xanthene dihydrochloride, which is available as a dry powder -Available, can as granules, slurry or as ge. Compressed tablet can be filled directly into the circulating mold or platen mold in which the soft gelatin capsules are placed are formed.

• Example 9 Preparation of a formulation for tablets

A typical composition for tablets was made as follows:

per tablet

(a) 2,7-bis (4-piperidino-1-butenyl) -xanthene dihydrochloride 100 mg

(b) Wheat starch and granulated starch - 15 mg,. _T paste (10 % w / v) ,,, _

(c) lactose 33.5 mg

(d) Magnesium stearate 1.5 mg

The granules obtained by mixing lactose, starch and granulated starch paste were dried, sieved and mixed with the active ingredient and the magnesium stearate. That. Mixture was compressed into tablets each weighing 150 mg.

Example 10 Manufacture of a formulation for an oral syrup

A 25% (weight / volume) syrup of 2,7-bis- / "4- (diethylamino) -l-bute'nyl7-xanthene dihydrochloride was prepared using standard pharmaceutical techniques from the following ingredients:

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2,7-Bis-ZV (fliethylamino) -i- 2.0 butenyl7-xanthene dihydrochloride 33.3 Sucrose 0.25 chloroform 0.4 Sodium benzoate 0.02 Methyl p-hydroxybenzoate ' 0.04 Vanillin 1.5 Glycerin purified water to 100.0 ml

G_

Example 11 Preparation of a parenteral formulation

The following emulsion is a typical composition for parenteral injection: . - ''

Each ml

contains ingredients quantity

50 mg 2,7 ~ bis-A- (diethylamino) -l-

butenyl7-xanthene 1,000 g .100 mg polyoxyethylene sorbitan

monooleate 2,000 g

0.0064 mg sodium chloride 0.128 g

Injection water to 20,000 ml

The parenteral composition was prepared by adding 0.64 g of sodium chloride in 100 ml of water which is used for Injection is suitable, dissolved. The polyoxyethylene sorbitan monooleate was mixed with the active ingredient, and a quantity of the previously prepared aqueous sodium chloride solution, sufficient to make a total volume of 20 ml was added. The solution obtained was

40 9 8 26 / TI 6 b

shaken and for 20 minutes at 110 ⁰ C and at

a vapor pressure of 2.08 kg / cm in the autoclave. The composition can be used in a single ampoule for multiple doses or in 10 or 20 individual ampoules for use as single dose units be bottled.

Example 12

Production of a powder formulation (dusting powder formulation)

The following formulation illustrates a sprinkling powder for local use:

per kilogram

(a) 2 _s 7-bis- / 3- (diethylamino) -lpropenylj-thioxanthene dihydrochloride 20 g

(b) silica airgel 98O g

The sprinkling powder was prepared by intimately mixing the ingredients. The resulting mixture was then packed in suitable distribution vessels.

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Claims (7)

~ 29 - claims 1. 2,7-bis-basic vinylene derivatives of xanthene and thioxanthene with the general formula: ί ^ NA-CH -CH-f ^ V ^ N ^ r- CH = CH-AN ⁷ sR ⁷ . J Il Il I wherein Y represents an oxygen or sulfur atom, A represents a straight-chain or branched-chain alkylene group having 1 to 4 carbon atoms and R and R each. Hydrogen atoms, lower alkyl groups with 1 to 6 carbon atoms, cycloalkyl groups with 3 to 6 carbon atoms, alkenyl groups with 3 to 6 carbon atoms in which the double bond is in a position other than the 1-position of the alkenyl group, or R. and R ₁ together with the nitrogen atom to which they are bonded represent the pyrrolidinyl, morpholine or piperidino radical, as well as their pharmaceutically acceptable acid addition salts. 2. Compounds according to claim 1, characterized in that that R and R. lower alkyl groups having 1 to 6 carbon atoms represent. 3. 2,7-bis-, (4-piperidino ~ l-butenyl) -xanthene and its pharmaceutically acceptable acid addition salts. 409826 / 116S - ίο - 4. 2,7-Bis-A- (diethylamino) -l-butenyl-7-thioxanthene and its pharmaceutically acceptable acid addition salts. 5. Process for the preparation of the compounds according to Claim 1 ", characterized in that a 2,7-bisbasic Alkanol of xanthene and thioxanthene with the general formula: ^ R ₁ ^v -r ' wherein the symbols Y, A, R and R are those given in claim 1 Have meaning, reacts in solution with a dehydrating agent and the resulting 2,7-bis-basic Vinylene derivative of xanthene and thioxanthene isolated therefrom. 6. Medicines for combating viruses, characterized in that it is a compound according to claim 1 together with a pharmaceutical carrier. 7. Medicament according to claim 6, characterized in that it is 2 mg to 3 g of the unit dosage form Compound of claim 1 together with the pharmaceutical carrier. For: Richardsön-Merrell Inc. Lawyer 409826/1 1 6 p