IL43665A - 2,7-bis(dialkyl aminoalkenylene)xanthene and thioxanthene derivatives - Google Patents

Abstract

Novel, 2,7-bis basic vinylene derivatives of xanthene and thioxanthene, their preparation and use for the prevention and inhibition of viral infections are disclosed. [US3817992A]

Description

2 (7 -BIS- \_ DIALKYL (OR CYCLIC) AMINOALKYLENEJ XANTHENE AND THIOXANTHENE DERIVATIVES ljT?ij m3-ON ( - pD IK) 'P-' ^Ni-T^-J-'n^,? ΓΠΤ71Π XANTHENE AND THIOXANTHENE DERIVATIVES ABSTRACT OF THE DISCLOSURE Novel 2,7-bis basic vinyiene derivatives of xanthene and th i oxanthene, their preparation and use for the prevention and inhibition of viral infections are disclosed.

FIELD OF THE INVENTION This invention relates to new organic chemical compounds, to their preparation and to pharmaceutical compositions containing such compounds. The compounds described herein are antiviral agents which are useful in inactivating or inhibiting viruses by their administration to either an infected or to a non-infected host, respectively.

BACKGROUND OF THE INVENTION There is a growing body of information that viruses play a vital role in a broad range of diseases, some of which represent the most serious of man's il ls. Arthritis, juveni le arthritis, diabetes, Hodgkin's disease and various immunological diseases and degenerative diseases of the central nervous system have been l inked to viruses as the causative agents.

At present, the control of virus infections is primari ly achieved by means of . i mmun i zat i on vaccines.

For example, pol iomyel itis, smal lpox, measles and influenza are we 11 recognized diseases in which viral vaccines hs ^^ proven effective. In general, however, viral vaccines ■■ have had only a moderate success in animal prophylaxis. Each vaccine acts primarily against a specific virus and is not heterophil ic in the protection it offers. Hence, vaccines do not provide a practical solution against the wide array of infectious viruses, even where l imited as for example, solely to respiratory viruses.

One approach to the control of v i r us - re 1 a ted diseases and, particularly to the spread of such virus diseases, has been to search for medicinal agents or chemothera-peutic agents which are capable of inhibiting the growth of viruses, thereby preventing the spread of disease as well as preventing further damage to cel ls and tissues of the animal host which have not as yet been infected. Heretofore, only a l imited number of virus infections such as smallpox, Asian influenza and herpes keratitis have been susceptible to prevention by chemical antiviral agents. Sulfonamides and antibiotics which have revo-lutionized the treatment of bacterial infections1 have substantially no effect upon virus infections. Certain infections caused by large viruses, such as lymphogranuloma venereum, psittacosis and trachoma have been successful ly treated using antibiotics and sulfa drugs. However/ the majority of infections have not been responsive to attack by chemotherapeut ic agents. Thus, it can be seen that there is a need for new chemotherapeut ic agents which are effective against a broad range of virus diseases, and which at the same time, are non-toxic to the host.

As a result of a long series of investigations, appl i- cants have discovered a novel class of 2,7-bis bacis ene derivat ives of xanthene and thioxanthene which ar particularly useful as antiviral agents. These compounds are effective aga inst a wide spectrum of virus infect ions and are useful in treating such infections both prophy- lactical ly and therapeut ical ly.

U.S. Patent No. 3,859,.286 „ . , , OpeTra-rn^-app-l-i- at-i^fts---S^F-i-a-l--N€>-.--97-,-5-79-, f i 1 ed December 11, 1970, whose counterpart has been publ ished as Israel Patent No. 37755, and U.S. Patent Belgium Patent 776,535 and ST_rrrai--No"4- 7 f)¾7--f:-'rl-ed-- No. 3,856,789 ■A-pn*i-"-*3" — t^Yi-, whose counterpart has been publ ished as and Israel Patent No. 37544 South Africa Patent 1/5^61, represent the closest art known to appl icants and disclose bis basic ketones of xanthene and thioxanthene having antiviral activity. The compounds of the present invention differ from those of the prior art in that they are not bis basic ketones, but rather represent bis basic vinylene derivatives of xanthene and thioxanthene. Additional ly, certain of the preferred 2,7-ketones previously described are useful as starting materials in the preparation of the compounds of the present invention. To appl icants' knowledge the compounds described and claimed herein are novel compounds which have not previously been described nor reported in the l iterature. Furthermore, no bis basic vinylene derivatives of any type are known which have previously been reported to possess antiviral activity. The instant compounds demonstrate a wide spectrum of antivi ral activi ty in varying degrees which could not have been predicted from a knowledge of the present state of the art:.

SUMMARY OF THE INVENTION This invention relates to new derivatives of xanthene and thioxanthene, to their preparation and to their use as pharmaceutical agents. More particularly, the compounds f the present invention are 2.7-bis basic vinylene derivatives of xanthene and thioxanthene which are useful as antiviral agents. Stil l more particularly, the compounds of the present invention may be represented by the fol lowing general formula: wherein Y is oxygen or sulfur; A is a straight or branched alkylene chain having from 1 to 4 carbon atoms; and R and ] are each s"e†etrtred--f-reprr-t ve--g - Hp--G-0R*-j-s-tiDjg._Qf_ Jiy_d r. £tg.e.n , lower alkyl having from 1 to 6 carbon atoms, rjrc"†TJa~rky1~~ h-ev-i-R g- -6-R-em- -5- - 1 «- -& - e-a-r-k© o- -a-t QROS-^ -a J iceji y J _ JoavjjTjg._fr.ora_2- Jto 6 — ee-rbf>i -at The 2,7-bis basic vinylene derivatives of xanthene and thioxanthene ( I) are prepared from the corresponding 2.7-bis basic ketones of xanthene and thioxanthene ( I I) in two stages. The f irst stage involves the reduction of the bis basic ketones to form the corresponding 2,7- bis bas i c α-a 1 kano 1 s ( I I I) . The second stage involves the dehydration of these alkanols to prepare the 2,7-; bis basic α,β -unsaturated vinylene derivatives of the present invention ( l) . These reactions can be il lustrated by the fol lowing reaction scheme: ( I) In the above reaction, the symbols A, R, Ri and Y have the i values previously assigned to them. To achieve an antiviral effect the compounds of this invention are administered to a suitable host using a variety of compositions. Such compositions may be administered either prior to infection, as with a prophylactic use or treatment, or they may be therapeutically administered subsequent to infection, as with a curative use or treatment. The compounds of this invention may also be appl ied external ly or topically directly at the situs of infection or they may be administered internal ly or systemical ly, irrespective of whether the treatment is prophylactic or curative in nature. In either event, replication of the virus is inhibited or prevented with the concomitant result that the various disease symptoms characteristic of the pathogenic virus infection are no longer present.

DETAILED DESCRIPTION OF THE INVENTION As can be seen from general formula ( I) above, there are two basic side chains, each of which is sepa-rately located on a benzenoid portion of the xanthene or thioxanthene nucleus. Additional ly, each side chain can be viewed as consisting essentially of a basic amino function located at the terminal end of the side chain, an α,β -unsaturated or vinyiene function located at the proximal end of the side chain, which also serves as a bridging function connecting the side chain to the armo-matic nucleus, and an aikylene chain of determinate length which separates the vinyiene function from the terminal basic amino function.

The aikylene chain which separates the vinyiene group from the basic amino group consists of from 1 to 4 carbon atoms and represents either a straight or branched aikylene chain. Additional ly, each of the aikylene groups may be the same or different; preferably, however, both aikylene groups are the same. I l lustrative of the various aikylene groups which can be represented by the symbol A are methylene, ethylene, tr imethy lene, 1-methyl-ethylene, tet ramethy 1 ene and 2-methy 1 tr imethy lene . 43665/2 The basic amino function represented by the symbol -N /Rl\ 1s a tertiary amino group. The symbols R and R. x R^' represent a lower alkyl group. The term lower alkyl as used herein with regard to the basic amino function relates to groups having from 1 to 6 carbon atoms. Illustrative of such groups can be mentioned both straight or branched chain alkyl radicals such as: methyl, ethyl, n_-propyl , 1sop opyl , n_-butyl , sec-butyl, Isoamyl, n_-pentyl and n_-hexyl. When R and R-j each represent lower alkyl, a preferred subgenus is formed.

R and R^ may also be joined with the nitrogen atom to which they are attached to represent the 1 -pyrrol i d1 nyl , piperidlno or morphoHno radicals. Compounds containing these groups are readily prepared and typify saturated monocyclic heterocyclic radicals which are generally useful 1n l ieu of the di lower alkylamino groups present in the ~ ' , compounds of this invention.

The vinylene portion of the molecule serves as a bridging function which anchors the basic alkylene side chain to the. aromatic nucleus. Thus, the compounds of the present invention are characterized by the fact that they are unsaturated and further, that th i s unsatu rat i on lies in an α,β-position with respect to the aromatic nucleus. The aromatic nucleus consists of either xanthene or th i oxanthene, depending upon whether the symbol Y is oxygen or sulfur. In either event substitution of the unsaturated bis basic side chains takes place only in the 2 and 7-positions of the aromatic nucleus.

I l lustrative of specific base compounds of the present invention represented by general formula ( I) above are: 2, 7- bis( -piperidino-l-butenyl) xanthene, 2,7-bis[3-(diethyl-am i no) - 1-propeny 1 ] xanthene, ■-?-,-7-feH-s-[- --(-N-'-ey-c-l-el:ie -yl--^ m t y-l-amiiw^^l^pf^^Ry-l^-xa^-^ePie, 2, 7-b i s[ 5-( d i methy 1 am i no) - 3 -methy 1 - 1-penteny 1 ] xanthene, 277—- -i-s-t-^—(-d^-a 4y-l-aw «o-)-»l* b-aieny\]χ-β-η-the-neT-2-,-7-b-i-s-f- -^-cycJ-ahexy-Vam-i-no)--1—ρ.μ©pe^y-I x-ant-he-ne, 2,7-bis[3-(l-pyrrol idinyl) -1-propeny 1 ] th ioxanthene, 2,7-bis[ -(dimethylamino)-l-butenyl]th ioxanthene, 2, 7-b i s [ -( d i i sopropy lami no) -1-propeny 1 ] th i oxanthene, 2-,-7— -i-s [~3= ^ra i fanriTro)^-l^ ro «ny -]-th <) n4:-hene and 2, 7-b is ( -mor phol ino-l-butenyl)thi oxanthene .

The expression "pharmaceutical ly acceptable acid addition salts" is intended to apply to any non-toxic organic or inorganic acid addition salts of the base compounds represented by formula ( I) . I llustrative inorganic acids which form suitable salts include hydrochloric, hydrobrom i c, sulphuric and phosphoric acids^ -and acid metal salts such as sodium monohydrogen ortho-phosphate and potassium hydrogen sulfate. I l lustrative organic acids which form suitable salts include the mono, di and tricarboxyl ic acids. I llustrative of such acids are. for example, acetic, glycol ic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxyma 1 e i c, benzoic, p-hydroxy benzoic, pheny 1 acet i c, cinnamic, sal icylic, 2-phenoxy-benxoic and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid. Either the mono or the di-acid salts can be formed, and such salts can exist in either a hydrated or a substantially anhydrous form.

In general, the acid addition salts of these compounds are crystalline materials which are soluble in water and various hydrophilic organic solvents and which in comparison to their free base forms, generally demonstrate higher melting points and an increased chemical stabil ity.

The 2,7-bis basic ketones of xanthene and thioxanthene ( I I), w ch serve as starting materials for the compounds of the present invention are also prepared in a two-step process. The first step involves the Fr i ede 1 -C rafts acylation of xanthene or thioxanthene to form a 2,7-bis (uu-ha loa 1 kanoy 1 ) derivative. The second step involves amination of these derivatives to form the corresponding 2,7-bis basic ketones of xanthene and thioxanthene. The amination can take place under a variety of conditions.

For example, the uu -ha 1 oa 1 kanoy 1 derivatives can be heated with a large excess of an amine, the excess amine serving as both the reaction medium and hydrohal ide acceptor.

Alternatively, the compounds may be heated with an amine in a suitable solvent such as toluene, dioxane or dimethyl-formamide to effect condensation. Specific i llustrations for the preparation of these ketones are more ful ly U.S. Patent No. 3.859.286 disci osed i n ^^ a-l--Ne-.--977^7^T-4:-i-;ed-4)-eG-e^©c- -lT- - 0-,-whose counterpart has been publ ished as Belgium Patent Israel Patent 37544 776,535, and S¾-p†¾rl"No-.—t5T "055, filed April 23, 1971, whose counterpart has been published as South Africa Patent 71/5 61.

Treatment of the 2,7-bis basic ketones of xanthene and thioxanthene ( l l) with a reducing agent results in the reduction of the a-ketone to that of a secondary alkanol, i.e., the 2,7-bis basic alkanols of xanthene and thioxanthene ( I I I). In general, the reduction is accomplished in a suitable solvent using sodium borohydride as the reducing agent at temperatures which range from about -20° to about 100°C., for periods of time which range anywhere from about 30 minutes to about 2 hours. A variety of solvents can be suitably employed, including .etrahydrof uran, methanol, ethanol and water. When using aqueous or methanol ic solutions, a base such as sodium hydroxide is utilized in order to minimize the rate at which the sodium borohydride reagent decomposes. Preferably, the reduction of the 2,7-bis basic ketones of xanthene and thioxanthene is accomplished by dissolving the ketones in tetrahydrof uran and adding solid sodium borohydride in smal l increments with continued stirring. As a matter of convenience, ice bath temperatures are usual ly employed with stirring being continued for an additional period of from one to twelve hours.

The dehydration of the 2,7-bis basic alkanols of · ^ xanthene and thioxanthene ( I I I) to form the corresponding unsaturated vinylene derivatives of the present invention takes place under acidic conditions. Exposure to strong acids at high temperatures for extended periods of time should be avoided. Thus, t i me- temperature conditions are selected which provide maximum dehydration with the mildest expos.ure to the reaction conditions. Dehydration can be achieved by dissolving the 2,7-bis basic alkanol ( I I I) in a high boi ling solvent, as for example, ethylene glycol or ethylene glycol monoethyl ether, adding the dehydrating agent and heating the reaction mixture to about 100°C. on a steam bath for a period which ranges from about one to about thirty minutes. Preferably, concentrated hydrochloric acid or sulfuric acid is employed as the dehydrating agent. The minimum time required for dehydration can be ascertained by monitoring the reaction medium by means of conventional procedures, e.g., observing the disappearance of the OH-stretch ing frequency in the infrared spectrum. The isolation of the 2,7-bis basic vinylene derivatives of xanthene and thioxanthene ( I) so prepared is achieved using methods known to the art. Thus, for example, the reaction mixture can be made alkaline and the product extracted with ether; alternatively, any un-reacted starting material can be separated from the final product by passage through a chromatographic column.

The compounds of the present invention are antiviral agents. Preferably, they are administered to an animal host to prevent or inhibit viral infections. The term host refers to any viable biological material or intact animal including humans which is capable of inducing the ^ formation of interferon and which serves as a support means for virus replication. The host can be of animal or mammalian origin. I llustratively such hosts include birds, mice, rats, guinea pigs, gerb i 1 s, ferrets, dogs, cats, cows, horses and humans. Other vialbe biological material such as used in the production of vaccines may also act as a host. Thus", tissue cultures prepared from organ tissues, such as mammal ian kidney or lung tissue, as wel l as tissue cultures prepared from embryo tissue, such as obtai ned from amn iotic cells or chick al lantoic fluid, have been found to be useful hosts. by means of compositions The treatment of virus infections f or--p-ar-po¾-es of the present invention encompasses both the prevention and the inhibition of characteristic disease symptoms in a mammal ian host susceptible to invasion by a pathogenic virus. M lustrat ive of mammal ian virus infections which can be prevented or inhibited by the administration of the compounds of the present invention are infections caused by p i cornav i ruses , such as encepha lomyocard i t i s virus; myxoviruses, such as influenza A2 ( Jap/305) virus; arboviruses; such as Seml iki forest virus; the herpes group of viruses, including herpes simplex; and the poxviruses, as for example vaccinia I HD . Thus, for example, the compounds of the present invention when administered oral ly or subcu taneous 1 y to mice in varying doses either shortly prior or subsequent to a fatal inoculation of a neurotropic virus such as encepha 1 omyoca rd i t i s virus, having a LD5o anywhere from 5 to 50, delay or prevent completely the onset of death. Salts of these compounds a 0.15/0 aqueous hydroxyethy 1 ce 11 u 1 ose vehicle, whereas the free base compounds are general ly administered in compositions containing a 10 aqueous surfactant vehicle in order to help solubil ize the compound. In general, ten mice are used for each treated group with an additional 20 mice serving as a control group. At the time of administration the test virus is titrated in order to determine the potency or LD5o f r the particular virus pool used as a challenge. The control animals are given a placebo containing the identical volume of vehicle without, of course, the active ingredient. Because of the lethal nature of the test system employed, the antiviral nature of the test compound is dramatically illustrated by a side by side comparison of the survival time of treated animals with the untreated control group of an ima 1 s .

Respiratory viruses, such as influenza A2 ( Jap/305) virus, which are also lethal to the test animals employed, are administered via intranasal instillation. Animals infected in this manner have the active ingredients, administered in the same manner as the test virus, and again a side by side comparison is made of the survivors of the animals treated with the untreated control animals.

Inexpl icably, a mouse treated with a normal ly fatal infection of encepha 1 omyoca rd i i s or influenza virus occasional ly survives without further treatment. This may be the result of a prior, i nterf eron- i nduced infection in the mouse, or perhaps due to some genetic factor or other natural defense mechanism not presently understood.

For this reason the control group selected is of suffici^t size as to statistical ly reduce to a negligible amount the influence of such a chance survivor upon the test resu Its.

The vaccinia test virus is typical of the dermato-trophic type viruses which respond to treatment with compositions containing the compounds of the instant invention. The vaccinia virus general ly produces a nonfatal infection in mice, producing characteristic tail lesions when the virus is subcutaneous 1 y administered to the tail of the mouse. The instant compounds are administered either oral ly or subcutaneous 1 y either prior to or subsequent to the vaccinia infection. Tail lesions are subjectively scored on the eighth day fol lowing infection against untreated animals which serve as a control group. The compounds of the present invention have been found to be effective in varying degrees against one or all of these test virus systems.

The mode of activity of the active ingredients of the present invention is not rigorously defined. Inter al ia, the compounds of the present invention may induce the formation of interferon in a viable host. Interferon is a biological substance of unknown chemical structure, presumably prote i naceous in nature, which is produced by host cells in response to a viral infection. The interferon so produced acts to induce a virus inhibiting substance, which inhibits in some yet unknown manner the intracel lular replication of the virus without appearing to have any inactivation effect per se upon the virus itself. A few of the viruses susceptible to interferon replication inhibition are described in Horsfall and Tanrn^ "Viral and Rickettsial Infections of Man" 4th Edition (1965),. J. B. Lippincott Company, pp. 328-9.

As previously indicated, the compounds of the present invention may be prophy 1 act i ca 11 y administered in order to prevent the spread of contagious viral diseases or they may be therapeutical ly administered to a host already infected intended for their curative effect. When administered prophy 1 act i ca 11 y, it is preferred that the administration be made within 0 to 96 hours prior to the infection of the host animal with a pathogenic virus.

When the compounds of the present invention are administered for their curative effect, it is preferred that they are administered within about 1 or 2 days fol lowing infection of the host in order to obtain the maximum therapeutic effect.

The dosage to be administered will be dependent upon such parameters as the particular virus for which either treatment or prophylaxis is desired, the species of animal involved, its age, health, weight, the extent of infection, concurrent treatment, if any, frequency of treatment and the nature of the effect desired. A daily dose of the active ingredients will generally range from about 0.1 mg to about 500 mg per kg of body weight. I llustratively, dosage levels of the administered active ingredients for intravenous treatment range from about 0.1 mg to about 10 mg per kg of body weight; for intraperitoneal administration range from about 0.1 mg to about 50 mg per kg of body weight for subcutaneous administration range from about 0.1 mg to about 250 mg per kg of body weight; for oral administration may be from about 0.1 mg to about mg per kg of body weight; for intranasal instil lation from about 0.1 mg to about 10 mg per kg of body weight; and for aerosol inhalation therapy, the range is generally from about 0.1 mg to about 10 mg per kg of body weight.

The novel compounds described herein can also be administered in various different dosage unit forms, e.g., oral compositions such as tablets, capsules, dragees, lozenges, el ixirs, emulsions, clear liquid solutions and suspensions; parenteral compositions such as intramuscular, intravenous or intradermal preparations; and topical compositions, such as lotions, creams or ointments. The amount of active ingredient contained in each dosage unit form will, of course, vary widely according to the particular dosage unit employed, the animal host being treated, and the nature of the treatment, i.e., whether prophylactic or therapeutic in nature. Thus, a particular dosage unit may contain from about 2.0 mg to over .0 g of active ingredient in addition to the pharmaceutical excipients contained therein.

The novel compounds described herein can be employed in conjunction or admixture with additional organic or inorganic pharmaceutical excipients. Suitable sol id excipients include gelatin, lactose, starches, magnesium stearate and petrolatum. Suitable liquid excipients include water and alcohols such as ethanol, benzyl alcohol and the polyethylene alcohols either with or without the addition of a surfactant. In general, the preferred liquid excipients particularly for injectable prep-arations, include water, sal ine solution, dextrose and glycol solutions such as an aqueous propylene glycol or an aqueous solution of polyethylene glycol . Liquid preparations to be used as sterile injectable solutions will ordinari ly contain from about 0.5$ to about 25$ by weight, and preferably from about 1$ to about 10$ by weight, of the active ingredient in solution. In certain topical and parenteral preparat ions, , var ious oils are util ized as carriers or excipients. I l lustrative of such oils are mineral oils, glyceride oils such as lard oi l, cod liver oil, peanut oil, sesame oil, corn oil and soybean oil .

A suitable method of administration for the compounds of the present invention is orally either in a sol id dose form such as a tablet or capsule, or in a liquid dose form such as an elixir, suspension, emulsion or syrup. Ordinari ly the active ingredient comprises from about 0.5$ to about 10% by weight of an oral liquid composition.

In such compositions, the pharmaceutical carrier is general ly aqueous in nature, as for example, aromatic water, a sugar-based syrup or a pharmaceutical muci lage. For insoluble compounds suspending agents may be added as well as agents to control viscosity, as for example, magnesium aluminum silicate or carboxymet hy 1 ce 11 u 1 ose . Buffers, preservatives, emulsifying agents and other excipients can also be added.

For parenteral administration such as intramuscular, intravenous or subcutaneous administration, the proportion of active ingredient ranges from about 0.05% to about 20$ by weight, and preferably from about 0.1 to about 10$ by weight of the l iquid composition. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydroph i 1 e- 1 i poph i 1 e balance (HLB) of from about 12 to about 17· The quantity of surfactant in such formulations ranges from about 5$ to about 15$ by weight. The surfactant can be a single component having the above identified HLB, or a mixture of two or more components having the desired HLB. Illustrative of surfactants useful in parenteral formulations are the class of pol yoxyethy 1 ene sorbitan fatty acid esters as, for exampl sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The concentration of active ingredient contained in these various parenteral dosage unit forms varies over a broad range and comprises anywhere from about 0.05$ to about 20$ by weight of the total formulation, the remaining component or components comprising liquid pharmaceutical excipients previously mentioned.

The active ingredients of the present invention can also be admixed directly with animal feeds or incorporated into the drinking water of animals. For most purposes., an amount of active ingredient is used which provides from about 0.0001$ to about 0.1$ and preferably, from about 0.001$ to about 0.02$ by weight of the active ingredient based upon the total weight of feed intake. The active ingredients can be admixed in animal feed concentrates, suitable for use by farmers or l ivestock growers for incorporation in appropriate amounts with the final animal feeds. These concentrates ordinari ly comprise from about 0.5$ to about 95% by weight of the active ingredient compounded with a finely divided solid carrier or flour, such as wheat, corn, soybean or cottonseed flour. Depending upon the particular animal to be fed, nutrients and fillers may also be added such as ground cereal, charcoal, fuller's earth, oyster shel ls and finely divided attapulgite or bentonite.

The active ingredients of the present invention can be packaged in a suitable pressurized container together with an aqueous or volatile propellant for use as an aerosol. A suitable discharge valve is fitted to an opening in the container from which the active ingredients may be conveniently dispensed in the form of a spray, liquid, ointment or foam. Additional adjuvants such as co-solvents, wetting agents and bactericides may be employed as necessary. Normal ly, the propellant used is a l iquified gaseous compound, preferably a mixture of low molecular weight fluorinated hydrocarbons. These halo-alkanes are preferred because of their compatibility with the active ingredients of the present invention, and because they are non- i r r i tat i ng when applied to skin surfaces. Other useful propel lants include ethylene oxide, carbon dioxide, propane and nitrogen gas.

The invention described herein is more particularly i llustrated by means of the fol lowing specific examples.- EXAMPLE i 2,7-B i s( -ch lorobuty ry 1 )xanthene To a mixture of 91-1 9 (0.5 mole) of xanthene, 176 .3 g (I.25 moles) of 4-chlorobutyryl chloride and liters of dry methylene chloride, chi lled to -20°C., is slowly added over a 30 minute period 146.7 g (l.l moles of aluminum chloride, during which the temperature is maintained below -10°C. Fol lowing the addition, the reaction temperature is slowly permitted to rise to room temperature and then refluxed for an additional 4 hours. Upon cool ing, the mixture is decomposed by cautiously pouring into 2 l iters of an ice-water mixture. The l iquid layers are separated and the aqueous layer extracted with methylene chloride. The combined organic layers are evaporated to a small volume and cooled. The resulting 2, 7-b i s( 4-ch lorobutyry 1 )xanthene so obtained is recrystal-1 ized f rom acetone to yield the desired product having a m.p. 131-2°C.

EXAMPLE I I 2, 7-Bis(3-chloropropionyl)th ioxanthene To a mixture of 99 - 2 g (0. 5 mole) of th ioxanthene, 158 .5 g (I.2 moles) of -ch 1 oroprop i ony 1 chloride, and l iters of previously dried methylene chloride, chil led to -20°C, is slowly added 146. 7 g (1.1 moles) of aluminum chloride over a 30 minute period while maintaining the temperature at below -10°C. Following the addition of aluminum chloride the reaction mixture is slowly permitted to rise to room temperature a nd then refluxed for an additional 4 hours. The reaction mixture is cooled to room temperature and decomposed by cautiously poured into 2 l iters of an ice-water mixture. The l iquid layers are separated and the aqueous layer re-extracted with methylene chloride. The combined organic layers are evaporated to a smal l volume and cooled. The desired 2, 7-b i s( 3-ch 1 oroprop i ony 1 ) th i oxanthene which separates on standing is recrys ta 11 i zed from acetone to yield the desired product having a m.p. of 175-7°C.

EXAMPLE I I I 2,7-Bis(4-p?peridi nobutyr y 1 )xanthene A mixture of 19.6 (0.05 mole) of 2, 7-b i s( 4-ch 1 oro-butyry 1 )xanthene, 34.0 g (0.4 mole) of piperidine, 16.6 g (O.l mole) of potassium iodide and 200 ml of butanone is ref luxed with st irring for a period of 60 hours. The reaction mixture is cooled and poured into 1 l iter of water. The sol id which precipitates is f i ltered, crystal l ized from a methyl chloride-acetone solution and again recr ysta 11 i zed from acetone to yield the desired , 7-b i s( 4-p i per i d i nobuty ry 1 ) xanthene having a m.p. of 115-7°C EXAMPLE IV 2,7-Bis[3-(diethylamino)propionyl]th i oxanthene d i hydrochl or ide dihydrate A mixture of 13.0 g (0.034 mole) of 2J7-bis(3-ch loro-p rop i ony 1 ) th i oxanthene, 1 g of potassium iodide, 75 ml of diethylamine and 75 ml of tet rahydrof uran is permitted to stand at room temperature for a period of 72 hours and f i ltered. The residue is thoroughly washed with tetra- hydrofuran and the combined fi ltrate is evaporated to dryness. The residue so obtained is dissolved in a minimum of ethanol, treated with ethanol ic HC 1 to form the d i hydroch 1 or i de salt and diluted with diethyl ether. The product which forms is filtered, crystal lized from a methanol -d ieth 1 ether solution and hydrated in a constant humidity chamber to give the desired ,7-b i s[3- ( i ethy 1 -am i no) prop i ony 1 ] th i oxanthene as the d i hydroch 1 or ide dihydrate having a m.p. of 137_^0°C.

EXAMPLE V α,α' -Bis(3-piper id i nopropy! )xanthene -2,7-d imethanol To a cooled, stirred solution of 25-6 g (0.053 mole) of 2 ,7-b i s( 4- p i per ί d i nobutyr y 1 ) xant hene dissolved in 200 ml of tet rahyd rofu ran is added a solution of 4.2 g (0.11 mole) of sodium borohydr!de contained in a solution of 50 ml of methanol and 5 ml of a 10 sodium hydroxide solution. The resulting mixture is al lowed to warm gradually to room temperature and stirring continued overnight. The reaction mixture is diluted with water and the sol id which forms is filtered, washed with water and air dried. The solid product is dissolved in a 10 hydrochloric acid solution, filtered and the filtrate made alkaline with a 10 sodium hydroxide solution.

The alkaline fi ltrate is extracted with methylene chloride The organic extract is then washed with water, fol lowed by a wash of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness _ni a uo . The residue containing the ^ desired a,a' -bis(3-piperidi nop ropy 1) xanthene -2, 7-dimethanol is recrysta 11 i zed twice from benzene to yield a product having a m.p. of 145-6°C.

Fol lowing essential ly the same procedure, but substituting: 2, 7-b i s[ 4-( d iethy 1 ami no] butyry 1 ) anthene, ^,-7- hS-^ -{-d -l-Vy emi-ne^4wty^V†xaTr he ne, 2, 7-b i s [3 -(diethyl am i no) pr op i ony 1 ] xanthene, 2,7-bis[4-(diethylamino) butyryl]thi oxanthene, 2 , -b i s( 4-p i per i d i nobu ty r y 1 ) th i o-xanthene or 2 , 7-b i s[ >- ( d imethy 1 ami no) prop i ony 1 ] th i o-xanthene for the 2, 7_b i s( 4-p i per i d i nobutyry 1 ) xanthene above, results in the formation of EXAMPLE VI 2,7-Bis( -piperidino-l-butenyl)xanthene A solution of 17.4 g (0.035 mole) of cc,a' -bis( -p i per id i nopropy 1 )xanthene- , 7-d i methano 1 is dissolved in a mixture of 25 nil of ethylene glycol monoethyl ether and 25 ml of concentrated hydrochloric acid and heated on the steam bath for 5 minutes. The solution is di luted with an equal volume of water and made alkal ine with a 20% sodium hydroxide solution. The resulting solut ion is extracted twice with ether, and the extracts are combined, washed with water, washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness _i_n vacuo . The residue is re-crystallized twice from ethanol and twice from isopropanol to give 2, 7-b i s( -p i per i di no- 1-bu teny 1 )xanthene having a m.p. 158.5-160.5°C .

Following essentially the same procedure, however, substituting: a, a' -bis[3-(diethylamino)propyl]xanthene-2,7-d imethanol , a-j-et-'-^W-s-C-Jr^-duaJJ-y_Laoiijo).pxj pyJ_]ji Q±-he.De_-__ 2-r —d-i-ffle-t-hano-1-, a, α' -b i s[ 2-( d iethy 1 ami no) ethy 1 Jxanthene-2, 7- di methanol, aia'-bis[3-(diethylamino) propy 1 ] th io-xanthene-2, 7~d i methanol , α,α' -bis(^-piper id inopropyl ) th i oxanthene-2 , 7-d Imethano 1 and α^α ' - i s[ 2- ( d imethy lam i no) ethy 1 ] th ?oxanthene-2, 7- imethanol for the α,α' -b i s(j5-p i per i d i nopropy 1 ) xanthene-2, 7-d i methanol above, results in the formation of 2, 7~bi s[ -( d i ethy 1 ami no) -1-buteny 1 ] xanthene, 277— -i-s{-lJ~(-d-i-a-Vly-l-amai-p ^^l-J- i- ecw- j-xa^ -heAe.^ 2,7-bis[ -(diethylamino) -1-propeny 1 ] xanthene, 2,7_b i s [ 4-(diethylamino)-l-butenyl]thioxanthene, 2,7-bis( -p i per id i no- 1-bu teny 1 ) th i oxanthene and 2, 7-b i s[j5-( d imethy 1 -amino) -1-propenyl ] th i oxanthene, respect ive 1 y .

EXAMPLE VI I The following Example is illustrative of the antiviral activity for the compounds of the present invention.

Thirty mice each weighing approximately 12-15 gms are divided into two groups, a control group containing 20 animals and a test group of 10 animals. All of the animals are chal lenged with a fatal dose (8LD50) of | encepha 1 omyocard i t i s .virus. The test group of animals are treated both prophy lact ica 1 ly and therapeutical ly using a parenteral composition containing 2,7_bis(4-p i per id i no- 1-buteny 1 )xanthene as the active ingredient dissolved in a 10% solution of sorbitan monooleate. The composition contains the active ingredient in an amount such that each dosage contains 0.25 ml which is equivalent to a dose level of 50 mg per kg. The control group receives a subcutaneous placebo containing the same volume of vehicle without, of course, the active ingredient.

Observations over a ten day period show a termination of all the control animals within a period of from to 5 days, with the treated group of animals surviving for a statistically longer period of time.

EXAMPLE VI I I Preparation of a capsule formulation An i llustrative composition for hard gelatin capsules is as fol lows : Per Capsule (a) 2,7-b i s[ 4-( d imethy lami no) -1-buteny 1 ] xanthene d i hydroch lor ide 200 mg (b) Talc 35 mg The formulation is prepared by passing the dry powders of both (a) and ( b) through a fine mesh screen and mixing them well . The powder is then filled into No. 0 hard gelatin capsules at a net fill of 235 mg per capsule In a similar fashion, a soft gelatin capsule is prepared in which the talc is omitted. The dry 2,7-bis [ 4- ( d i methy 1 ami no) -1-buteny 1 ]xanthene d i hydroch 1 or i de powder can be illed as a granulation, slug or compressed tablet directly into the rotary dye or plate mold in which the soft gelatin capsule is formed.

EXAMPLE IX Preparation of a tablet formulation An i llustrative composition for tablets is as follows Per Tablet (a) 2 , 7-b i s( 4-p i per id i no- 1-buteny 1 ) xanthene d i hydroch 1 or ide ICO mg (b) Wheat starch 15 mg (c) Lactose 33.5 mg (d) Magnesium stearate 1.5 mg The granulation obtained upon mixing lactose starch and granulated starch paste is dried, screened and mixed with the active ingredient and magnesium stearate. The mixture is compressed into tablets weighing 150 mill igrams each.

EXAMPLE X Preparation of an oral syrup formulation A 2% weight per volume syrup of 2 , 7-b i s[ 4- ( d i ethy 1 -ami no) -1-buteny 1 Jxanthene d i hydroch lor ide is prepared by the usual pharmaceutical techniques in accordance with the fol lowing formula: Grams (a) 2,7-bis[ -(diethylamino)-l-butenyl] xanthene d i hydroch 1 or i de 2.0 Grams ( b) Sucrose 33 -3 (c) Chloroform 0.25 (d) Sodium benzoate 0.4 (e) Methyl p-hydroxybenzoate 0.02 ( f ) Vani 11 in 0.04 (g) Glycerol 1.5 (h) Purified water to 100.0 ml EXAMPLE XI Preparation of parenteral formulation An illustrative composition for a parenteral injection is the fol lowing emulsion: Each ml Conta i ns I nqred ients Amount 50 mg 2, 7-b i s[ 4- ( d i et y lami no) - 1-buteny 1 ]xanthene 1.000 g 100 mg Pol yoxyethy lene sorbitan monooleate 2.000 g 0.0064 Sodium chloride 0.128 g Water for injection, q.s. 20.000 ml The parenteral composition is prepared by dissolving 0.64 g of sodium chloride in 100 ml of water for injection, mixing the po 1 yoxyethy 1 ene sorbitan monooleate with the 2, 7-b i s[ 4- ( d iethy lam ino) -1-buteny 1 Jxanthene, adding a sufficient solution of the sodium chloride in water to the active ingredient and pol yoxyethy 1 ene sorbitan monooleate to make 20 ml, shaking the mixture and then autoclaving the mixture for 20 minutes at 110°C. at 15 p.s.i.g. steam pressure. The composition can be dispensed in a single amuple for multiple dosage or in 10 or 20 ampules for single dosages.

EXAMPLE X I I Preparation of dusting powder formulation The fol lowing formulation il lustrates a dusting powder for topical use: Per K Ϊ 1 oram (a) 2,7-bis[3-(diethylamino) - 1-propeny 1 ] thioxanthene d i hydroch lor i de 20 gm (b) Sil ica aerogel 980 gm The dusting powder is prepared by intimately blending the ingredients. The resulting mixture is then packaged in suitable dispensing containers.

Claims (7)

43665/2 WHAT IS CLAIMED IS: al kenylene

1. A 2,7-b1s basic xinyi¾rne derivative of xanthene and thioxanthene having the general formula: wherein Y is oxygen or sul fur; A is a straight or branched alkylene chain having from 1 to 4 carbon atoms; R and R^ are each lower alkyl having from 1 to 6 carbon atoms, and when R and R-j are taken together with the nitrogen atom to which they are attached represent the morphoHno or piperldino radical ; and the pharmaceutically acceptable add addition salts thereof.

2. A compound of claim 1 wherein each R and R-j 1 s a lower alkyl group haying from 1 to 6 carbon atoms.

3. The compound 2,7-bis(4-p1per1dino-l -butenyl ) xanthene and the pharmaceutical ly acceptable add addition salts thereof.

4. The compound 2,7-b1s[4-d1ethylam1no)-l-butenyl ] thioxanthene and the pharmaceutical ly acceptable a d addition salts thereof.

5. A process of preparing a compound of claim 1 which comprises reacting a 2,7-b1s basic alkanol of xanthene and thioxanthene having the general formula: wherein Y is oxygen or sulfur; A 1s a straight or branched alkylene chain having from 1 to 4 carbon atoms; R and R are each lower al kyl 43665/2 with the nitrogen atom to which they are attached represent the pyrrolldinyl, nrarpholino or piperidino radical; reacting said aikanol 1n solution with a dehydrating agent; and isolating the resulting 2,7-b1s basic vinyiene derivative of xanthene and thioxanthene therefrom.

6. An antiviral composition 1n dosage unit form comprising from 2 milligrams to 3 grams of a compound of claim 1 and a pharmaceutical carrier.

7. An oral dosage unit of an antiviral composition comprising from 2 milligrams to 3 grams of a compound of claim 1 and a pharmaceutical carrier.