CA1174978A - Xanthates - Google Patents
XanthatesInfo
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- CA1174978A CA1174978A CA000432785A CA432785A CA1174978A CA 1174978 A CA1174978 A CA 1174978A CA 000432785 A CA000432785 A CA 000432785A CA 432785 A CA432785 A CA 432785A CA 1174978 A CA1174978 A CA 1174978A
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Abstract
ABSTRACT
Xanthates of the formula
Xanthates of the formula
Description
XANTHATES
The invention relates to new xanthate compounds, a process for the manufacture thereof, compositions containing these compounds, and method of treating viruses therewith.
This application is a division of Canadian Application 390,861 filed November 25, 1981.
A few alkyl xanthates are already known. They have hitherto been used as flotation auxiliaries, pesticides, herbicides and vulcanization accelerators (cf. Ullmann's E~zyklopadie der technischen Chemie, 3rd Edition, Volume XVIII, pp. 718 - 728).
The aim of the present invention is to provide xanthates with acceptable pharmacological properties.
Unexpectedly, it was found that certain xanthates exhibit beneficial antimicrobial, antiviral effects as well as activites influencing ce~l growth.
Subject matter of the invention are therefore xanthates having the general formula I:
R - O - C (I) ~ S - R2 wherein Rl is adamantyl, norbornyl, tricyclodecyl, benzyl, straight or branched C3-C20-alkyl, C3-C20-cycloalkyl, furyl, pyridyl or quinuclidinyl, and wherein the aforementioned straight or branched C3-C20-alkyl group may be substituted by a hydroxy, Cl-C4-alkoxy group or a halogen atom, and wherein the aforementioned C3-C20-cyclo-alkyl group may likewise be substituted by a hydroxy, Cl-C4-alkoxy or Cl-C4- alkyl group or a halogen atom, and Merz 7 ~ l7~s7a wherein P~ is a mono- or polyvalent metal atom, a straight or branched C1-C6-alkyl group which may be substituted by a hydroxy, Cl-C4-alkoxy, amino, C1-C4-alkylamino, (Cl-C4-alkyl)2 amino or (Cl-C4-alkyl)3 ammonium group or a halogen atom, or represents a 2,3-dihydroxypropyl or ~-hydroxy-(Cl-C4-alkoxy) methyl group.
If Rl is a straight or branched C3- to C20 alkyl group, it may represent, for example, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl or pentadecyl groups~ in straight, mono- or multiple-branch form, preferably n-hexyll n-decyl, n-dodecyl and n-tetradecyl groups. The cycloalkyl groups preferably used are the cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclo-nonyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclo-tetradecyl and cyclopentadecyl groups. Utmost preference is given to the cyclohexyl and cyclododecyl groups. Bi- and tricyclic groups are also included.
The aforementioned halogen atoms comprise fluorine, chlorine, bromine and iodine. Chlorine or bromine are preferably used in halogen sub-stitution.
If R2 is a metal atom, it is preferably a monovalent metal, i.e., sodium or potassium.
The compounds according to the invention may be produced according to generally known methods by reacting an alcoholate of the formula Rl-O-Me, wherein Rl represents the aforementioned definitions and Me is an alkali metal atom, with carbon disulfide, or by reacting an alcohol of the formula R1-OH, wherein Rl represents the aforementioned definitions, with carbon disulfide in the presence of a strong alkali. This results in compounds of formula I, wherein R2 is an alkali rnetal atom. For preparing the compounds of formula I, wherein R2 represents one of the other aforementioned definitions, an alkali xanthate of formula I is reacted in an inert solvent with an alkylating agent appropriate to the R2 group.
Merz 7 The drugs according to the invention contain at least one of the aforementioned compounds having the general formula I, in a commonly used solid or liquid carrier. With drugs Rl may also be a methyl or ethyl group. The compounds according to the invention may also be com-bined with known actives. The compounds according to the invention are characterized by an antimicrobial, especially antiviral action.
The antiviral range of action comprises, for example, herpes, influenza and tumor viruses. In addition,it was found that the compounds according to the invention influence the growth of tumor cells.
In-vitro investigations by means of plaque reduction tests Gn various virus strains showed an inhibition of growth at substance concentrations ranging from 1 to loo yg/ml. The toxicity of the substances according to the invention is relatively low. The substances may, above all, be used as effective preventives of influenza and herpetic affections of the skin and mucous membranes. The daily dose to be administered to adults in the course of the disease is about 5-loo mg of the active per day.
If the compounds according to the invention are administered by the parenteral, subcutaneous, intravenous, intramuscular and intra-peritoneal route, the carrier is a sterile liquid such as water or oil, the oils being of vegetable, animal or synthetic origin.
Glucose solutions are usually used for injectable solutions. In general, the liquid carriers of the injectable solutions contain o.5 - 25 percent by weight of the active substance. The compounds according to the in-vention may also be successfully administered by the oral route, and are likewise suited for the treatment of pneumonias by applying them in vapor or spray form in the oronasal region. Best suited for oral administration are tablets, capsules, powders, solutions, suspensions or elixirs. With these administration forms the content of the active ingredient is at least 2 percent by weight, related to the total weight of the composition.
The invéntion will be further illustrated by the following examples:
tMelting points are in degrees Centigrade.) Merz 7 ~ 1749~8 Example 1: Sodium cyclododecyl xanthate loo g (o.54 mol) of cyclododecanol is heated to looC, 2.5 9 (o.11 mol) of sodium is added, the temperature of the mixture being maintained at 220C for 1 hour. The product is poured into a porcelain dish, pulver-ized after cooling, the powder being suspended in ether (400 ml), 9 9 (o.12 mol) of carbon disulfide being added drop by drop. After the addition of 200 ml of water, the aqueous phase is separated, and 20 9 of NaCl added. The precipitate is filtered and recrystallized twice from alcohol (120 ml).
Yield~ 17 9 (56% of the theoretical value) Mp: 218 - 219 . .
decomposltlon Elementary analysis calculatedfound C 55.32 54.42 H 8.16 8.o8 S 22.69 21.90 In the same manner, the correspondiny potassium salt is produced by employing potassium instead of sodium.
Example 2: Sodium benzyl xanthate 4.6 9 (o.2 mol) of sodium is added to 108 9 (1 mol) of benzyl alcohol under nitrogen . The mixture is heated to 160C for 2 hours, poured into a porcelain dish, and allowed to cool. The semi-solid product is suspended in ether (400 ml), 15.2 9 (o.2 mol) of carbon disulfide is added dropwise, and the mixture heated under reflux for 1 hour.The reaction solution is allowed to cool, the precipitate being filtered and washed with ether;
Yield: 16 9 (39% of the theoretical value) Mp: >l80decomposition Elementary analysis calculatedfound C 42.86 43.os (C8H7r~a 52 x H20) H 4.o2 4.31 S 28.57 26.78 Merz 7 ~ 1~4978 In the same manner, the corresponding potassium salt is produced by employing potassium instead of sodium.
Example 3: Sodium cyclohexyl xanthate 3.6 9 (o.16 mol) of sodium is added to loo ml (1 mol) of cyclohexanol under nitrogen, and heated under reflux until complete reaction of the sodium has taken place. The reaction solution is poured into a procelain dish and pulverized after cooling. The powder is suspended in ether (400 ml) and heated to reflux for 15 min. After cooling, 12.8 g (o.17 mol) of carbon disulfide is added dropwise. After the addition of 200 ml of water, the aqueous phase is separated, and 40 g of NaCl added.
The precipitate is filteredJ washed with ether and dried.
Yield: 25 9 (75% of the theoretical value) e Mp: >200decomposition Elementary analYsis calculatedfound C 42.42 42.21 H 5.55 5.52 S 32.32 31.87 ln the same manner, the corresponding potasslum salt is produced by employing potassium instead of sodium.
In the same manner, starting fxom n-hexanol, the corresponding sodium and potassium n-hexyl xanthates are prepared and found to be active virustatic agents.
Example 4: Cyclohexyl methyl xanthate 3 9 (o.ol5 mol) of sodium cyclohexyl xanthate is dissolved in 50 ml of dried methanol and heated to reflux with 10.7 9 (o.o75 mol) of methyl iodide for 1 hour ~fter coolir.,, the reaction solution is evaporated by using a rotary evaporator, dissolved in ether/water (50/50), the ether phase being separated and dried with sodium sulfate, purified with active carbon/bleaching earth, and evaporated with the aid of a rotary evaporator.
Yield: 2 9 (70~ of the theoretical value) Elementarv anal YSi S
calculated found C 50.52 50.47 H 7.36 7.28 Merz 7 ~ 17497~
Example S: Potassium adamantyl xanthate 15.2 9 (o.1 mol) of adamantanol is dissolved in dried tetrahydrofurane, nitrogen is introduced into the solution and 2 9 of potassium (o.oS mol) is added. The solution is heated under reflux for lo hours. After cooling, the product is suspended in 200 ml of ether and heated to reflux for 15 minutes. 3.8 9 (o.o5 mol) of carbon disulfide is added, and the solution is heated again for 45 minutes under reflux. After cooling, 200 ml of water is added. The aqueous phase is separated, 25 g of ~3aCl added, and the precipitate filtered.
Yield: 2 9 (8% of the theoretical value) Mp: ~3decOmposition Elementary analysis calculated found C 49.60 49.82 H 5.63 5.56 S 24.oS 23.50 In the same manner, the corresponding sodium salt is produced by employing sodium instead of potassium.
Example 6: Potass;um 2 endo-bicyclo L2.2.11'4~ -heptyl xanthate 340 g (about 3 mol) of endo-norborneol is melted (160C) under nitrogen atmosphere and reacted in portions with a total of 19.55 9 (o.5 mol) of crust-free potassium. The temperature is maintained at lSo until complete dissolution of the metal has taken place. Subsequently, excess nor-borneol is distilled off, the colorless residue dried under high vacuum for a short time, and dissolved in 500 ml of absolute tetra-hydrofurane. With cooling, 31 ml (o.5 mol) of carbon disulfide -dissolved in 150 ml of absolute ether - is added to this alcoholate dro~ by drop. The reaction mixture is stirred for 1 hour at 40C.
The xanthate separating already in the course of the reaction as a pale yellow precipitate is precipitated to a large extent by the addition of 1 1 of dry ether. The precipitate is suction filtered and thoroughly rinsed with ether on the suction filter apparatus.
Mer~ 7 ~ 17~978 The xanthate crystallizes from concentrated alcoholic solution by forming fine, pale yellow needles.
Yield: 95 9 (83,' of the theoretical value) ~lp: 256 - 258deComposition Elementary analysis calculated found C 42.44 42.40 H 4.go 4.92 S 28.32 27.90 In the same manner, the corresponding sodium salt is produced by employing sodium instead of p~tassium.
Example 7: Potassi~n 8(9)-tricyclo ~5.2.1 o2'6] decyl xanthate 457 9 (about 3 mol) of tricyclo~5.2.1.02'6] decanol-8(9) (TCD alcohol A, isomer mixture distributed by Hoechst AG) is reacted under protective gas atmosphere (nitrogen) in portions with a total of 19.55 g (o.5 mol) of crust free potassium with stirring at 150-160C. The temperature of the mixture is kept at this level until complete reaction of the metal has taken place. Subsequently, excess alcohol is distilled off under vacuum, the alcoholate being dried under high vacuum and dissolved in 500 ml of absolute tetrahydrofurane. With cooling, 31 ml (o.5 mol) of carbon disulfide in 150 ml of absolute ether is gradually added to the reaction solution. The mixture is stirred for 1 hour at 40C, the xanthate is precipitated by adding 1 1 of dry ether, suction filtered and thoroughly rinsed with ether on the suction filter apparatus. After recrystallization from ethanol, fine pale yellow crystals are obtained.
Yield: 104 9 (78q, of the theoretical value) Mp: 26odecomposition ElementarY analYsis calculated found C 49.58 49.60 H 5.67 5.62 S 24.o7 24.19 Merz 7 In the same manner, the corresponding sodium salt is produced by employing sodium instead of potassium.
The compounds according to the invention are characterized by valuable pharmacodynamic properties and may, therefore, be successfully applied in human and veterinary medicine.
The virustatic properties have been demonstrated by the in-vitro testing of virus inhibition in an inhibition areola ~plaque inhibition test) and by the plaque reduction method. The following virus strains were used:
Influenza A2 Vaccine virus Herpes virus Tumor viruses of the SV 40 type In this plaque inhibition test tissue cultures of influenza and vaccine viruses (chick fibroblasts), parainfluenza (monkey renal epithelial cells) and herpes viruses (human amnion cells) are infected in such a manner that closely packed but individual plaques form. The test substance is then applied as a 1% solution, and the diameter of the inhibition areola is determined. The results are represented in the following table.
Merz 7 ~ 17497~
Table .
Virustatic properties of the compounds according to the invention demonstrated in the plaque inhibition test Substa~ce concen- 200~/o,o2 ml o = no inhibition areola tration: ~ S ~ = moderate (IA 10-20 mm) Rl - O - C +~ = good (IA 20-30 mm) \ SR2 ++~ = very good ( IA ~ 30 mm) Virustatic properties Rl R2 Influenza Vaccine Herpes Cyclododecyl Na +++ ++t +++
n-Dodecyl Na +++ +++ +
Cy clohexyl Na ++ ++~ +++
Benzyl Na + + +
1-Norbornyl Na ++ +~ +
1-Adamantyl K +
Standard 1-Aminoadamantane hydrochloride +++ o o IA = inhibition areola The action of the test substances on various virus strains has also been determined by in-vitro plaque reduction tests. After the appli-cation of the test substance, followed by infecticn with the respective viruses and incubation, the number of plaques produced by the viruses is determined. The smaller the nurnber of plaques is in comparison with the control, the more effective is the substance under testing. The test results are summarized in the following table:
Merz 7 ~ 1~4978 Table 2 Virustatic action of the compounds according to the invention demonstrated in the plaque reduction test Substance Concentration Plaque reduction in X
Sodiu~ cyclododecyl xanthate 20 ~/ml loo Sodium dodecyl xanthate 20 ~/ml loo Sodium cyclohexyl xanthate 20 ~ /ml loo Standard aminoadamantane hydrochloride 20 ~/ml lo Tables 1 and 2 shoh the superior virust~tic action of the compounds according to the invention.
Method of Treating, i.e., Controlling Viruses The antiviral treatment of a host suffering from such insufficiency, comprising the step of ad~inistering to the patient, host, or situs suffering from such viral contamination or infection the selected xanthate of the foregoing formLla I in an anti-viral amDunt effective for such purpose by the oral, topical, or parenteral route, the said amount administered preferably being 10 to 100 mg per dosage unit by the oral route or 0.05 to 5 mg per dosage unit by parenteral route, constitutes the method-of-treating embodiment of the present invention, in its broadest concepts. Representative dosage forms follow.
~he dosages of xanthates in general will approximate the dosages of the standard aminoadamantane hydrochloride anti-viral agent and, in many cases, because of the enhanced antiviral activity of the xanthate compounds, will be considerably less.
Merz 7 l 174978 Dosage Forms Unit dosage forms for antiviral or other use according to the present invention may be of any suitable and/or conventional type. For oral administration, the unit dosage form generally contains about 10 to 100 mg of selected active ingredient, whether xanthate ester or salt, preferably about 50 mg thereof. For parenteral administration in sterile solution, the unit dose usually contains 0.05 to 5 mg of the active ingredient selected, preferably about 2.5 mg thereof.
As already stated, the selected compound is preferably ad-ministered together or in conjunction with a pharmaceutically-acceptable carrier, and preferably in the form of a tablet.
According to the usual practice of the art, the active xanthate compound is therefore generally associated with a non-toxic pharmaceutical diluent or carrier which may be either a solid material or a liquid. Bland carriers are preferred for some applications. The composition can take the form of tablets, powders, capsules, liquid solutions, emulsions or suspensions, or other dosage forms which are particularly useful for oral administration. Liquid or semi-liquid diluents may be em-ployed for oral use. Such a medium can be or contain a solvent such as water. The only basic limitations of the liquid diluent used are compatibility and palatability. The compositions can take the form of the selected xanthate admixed with solid diluents and/or tableting adjuvants such as rice starch, corn starch, potato starch, lactose, sacharose, gelatin, talc, stearic acid, magnesium stearate, carboxy-methylcellulose, gums such as gu~ acacia or tragacanth, chicle, agar agar, or the like. When in liquid form, the composition may be a sterile or non-sterile solution, suspension, dis-persion, elixir, or the like, all as is well known in the art.
For topical application, the composition may, e.g., be in solution, lotion, ointment, salve, tincture, or like form.
It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds, com-positions, methods, or procedures shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art.
The invention relates to new xanthate compounds, a process for the manufacture thereof, compositions containing these compounds, and method of treating viruses therewith.
This application is a division of Canadian Application 390,861 filed November 25, 1981.
A few alkyl xanthates are already known. They have hitherto been used as flotation auxiliaries, pesticides, herbicides and vulcanization accelerators (cf. Ullmann's E~zyklopadie der technischen Chemie, 3rd Edition, Volume XVIII, pp. 718 - 728).
The aim of the present invention is to provide xanthates with acceptable pharmacological properties.
Unexpectedly, it was found that certain xanthates exhibit beneficial antimicrobial, antiviral effects as well as activites influencing ce~l growth.
Subject matter of the invention are therefore xanthates having the general formula I:
R - O - C (I) ~ S - R2 wherein Rl is adamantyl, norbornyl, tricyclodecyl, benzyl, straight or branched C3-C20-alkyl, C3-C20-cycloalkyl, furyl, pyridyl or quinuclidinyl, and wherein the aforementioned straight or branched C3-C20-alkyl group may be substituted by a hydroxy, Cl-C4-alkoxy group or a halogen atom, and wherein the aforementioned C3-C20-cyclo-alkyl group may likewise be substituted by a hydroxy, Cl-C4-alkoxy or Cl-C4- alkyl group or a halogen atom, and Merz 7 ~ l7~s7a wherein P~ is a mono- or polyvalent metal atom, a straight or branched C1-C6-alkyl group which may be substituted by a hydroxy, Cl-C4-alkoxy, amino, C1-C4-alkylamino, (Cl-C4-alkyl)2 amino or (Cl-C4-alkyl)3 ammonium group or a halogen atom, or represents a 2,3-dihydroxypropyl or ~-hydroxy-(Cl-C4-alkoxy) methyl group.
If Rl is a straight or branched C3- to C20 alkyl group, it may represent, for example, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl or pentadecyl groups~ in straight, mono- or multiple-branch form, preferably n-hexyll n-decyl, n-dodecyl and n-tetradecyl groups. The cycloalkyl groups preferably used are the cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclo-nonyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclo-tetradecyl and cyclopentadecyl groups. Utmost preference is given to the cyclohexyl and cyclododecyl groups. Bi- and tricyclic groups are also included.
The aforementioned halogen atoms comprise fluorine, chlorine, bromine and iodine. Chlorine or bromine are preferably used in halogen sub-stitution.
If R2 is a metal atom, it is preferably a monovalent metal, i.e., sodium or potassium.
The compounds according to the invention may be produced according to generally known methods by reacting an alcoholate of the formula Rl-O-Me, wherein Rl represents the aforementioned definitions and Me is an alkali metal atom, with carbon disulfide, or by reacting an alcohol of the formula R1-OH, wherein Rl represents the aforementioned definitions, with carbon disulfide in the presence of a strong alkali. This results in compounds of formula I, wherein R2 is an alkali rnetal atom. For preparing the compounds of formula I, wherein R2 represents one of the other aforementioned definitions, an alkali xanthate of formula I is reacted in an inert solvent with an alkylating agent appropriate to the R2 group.
Merz 7 The drugs according to the invention contain at least one of the aforementioned compounds having the general formula I, in a commonly used solid or liquid carrier. With drugs Rl may also be a methyl or ethyl group. The compounds according to the invention may also be com-bined with known actives. The compounds according to the invention are characterized by an antimicrobial, especially antiviral action.
The antiviral range of action comprises, for example, herpes, influenza and tumor viruses. In addition,it was found that the compounds according to the invention influence the growth of tumor cells.
In-vitro investigations by means of plaque reduction tests Gn various virus strains showed an inhibition of growth at substance concentrations ranging from 1 to loo yg/ml. The toxicity of the substances according to the invention is relatively low. The substances may, above all, be used as effective preventives of influenza and herpetic affections of the skin and mucous membranes. The daily dose to be administered to adults in the course of the disease is about 5-loo mg of the active per day.
If the compounds according to the invention are administered by the parenteral, subcutaneous, intravenous, intramuscular and intra-peritoneal route, the carrier is a sterile liquid such as water or oil, the oils being of vegetable, animal or synthetic origin.
Glucose solutions are usually used for injectable solutions. In general, the liquid carriers of the injectable solutions contain o.5 - 25 percent by weight of the active substance. The compounds according to the in-vention may also be successfully administered by the oral route, and are likewise suited for the treatment of pneumonias by applying them in vapor or spray form in the oronasal region. Best suited for oral administration are tablets, capsules, powders, solutions, suspensions or elixirs. With these administration forms the content of the active ingredient is at least 2 percent by weight, related to the total weight of the composition.
The invéntion will be further illustrated by the following examples:
tMelting points are in degrees Centigrade.) Merz 7 ~ 1749~8 Example 1: Sodium cyclododecyl xanthate loo g (o.54 mol) of cyclododecanol is heated to looC, 2.5 9 (o.11 mol) of sodium is added, the temperature of the mixture being maintained at 220C for 1 hour. The product is poured into a porcelain dish, pulver-ized after cooling, the powder being suspended in ether (400 ml), 9 9 (o.12 mol) of carbon disulfide being added drop by drop. After the addition of 200 ml of water, the aqueous phase is separated, and 20 9 of NaCl added. The precipitate is filtered and recrystallized twice from alcohol (120 ml).
Yield~ 17 9 (56% of the theoretical value) Mp: 218 - 219 . .
decomposltlon Elementary analysis calculatedfound C 55.32 54.42 H 8.16 8.o8 S 22.69 21.90 In the same manner, the correspondiny potassium salt is produced by employing potassium instead of sodium.
Example 2: Sodium benzyl xanthate 4.6 9 (o.2 mol) of sodium is added to 108 9 (1 mol) of benzyl alcohol under nitrogen . The mixture is heated to 160C for 2 hours, poured into a porcelain dish, and allowed to cool. The semi-solid product is suspended in ether (400 ml), 15.2 9 (o.2 mol) of carbon disulfide is added dropwise, and the mixture heated under reflux for 1 hour.The reaction solution is allowed to cool, the precipitate being filtered and washed with ether;
Yield: 16 9 (39% of the theoretical value) Mp: >l80decomposition Elementary analysis calculatedfound C 42.86 43.os (C8H7r~a 52 x H20) H 4.o2 4.31 S 28.57 26.78 Merz 7 ~ 1~4978 In the same manner, the corresponding potassium salt is produced by employing potassium instead of sodium.
Example 3: Sodium cyclohexyl xanthate 3.6 9 (o.16 mol) of sodium is added to loo ml (1 mol) of cyclohexanol under nitrogen, and heated under reflux until complete reaction of the sodium has taken place. The reaction solution is poured into a procelain dish and pulverized after cooling. The powder is suspended in ether (400 ml) and heated to reflux for 15 min. After cooling, 12.8 g (o.17 mol) of carbon disulfide is added dropwise. After the addition of 200 ml of water, the aqueous phase is separated, and 40 g of NaCl added.
The precipitate is filteredJ washed with ether and dried.
Yield: 25 9 (75% of the theoretical value) e Mp: >200decomposition Elementary analYsis calculatedfound C 42.42 42.21 H 5.55 5.52 S 32.32 31.87 ln the same manner, the corresponding potasslum salt is produced by employing potassium instead of sodium.
In the same manner, starting fxom n-hexanol, the corresponding sodium and potassium n-hexyl xanthates are prepared and found to be active virustatic agents.
Example 4: Cyclohexyl methyl xanthate 3 9 (o.ol5 mol) of sodium cyclohexyl xanthate is dissolved in 50 ml of dried methanol and heated to reflux with 10.7 9 (o.o75 mol) of methyl iodide for 1 hour ~fter coolir.,, the reaction solution is evaporated by using a rotary evaporator, dissolved in ether/water (50/50), the ether phase being separated and dried with sodium sulfate, purified with active carbon/bleaching earth, and evaporated with the aid of a rotary evaporator.
Yield: 2 9 (70~ of the theoretical value) Elementarv anal YSi S
calculated found C 50.52 50.47 H 7.36 7.28 Merz 7 ~ 17497~
Example S: Potassium adamantyl xanthate 15.2 9 (o.1 mol) of adamantanol is dissolved in dried tetrahydrofurane, nitrogen is introduced into the solution and 2 9 of potassium (o.oS mol) is added. The solution is heated under reflux for lo hours. After cooling, the product is suspended in 200 ml of ether and heated to reflux for 15 minutes. 3.8 9 (o.o5 mol) of carbon disulfide is added, and the solution is heated again for 45 minutes under reflux. After cooling, 200 ml of water is added. The aqueous phase is separated, 25 g of ~3aCl added, and the precipitate filtered.
Yield: 2 9 (8% of the theoretical value) Mp: ~3decOmposition Elementary analysis calculated found C 49.60 49.82 H 5.63 5.56 S 24.oS 23.50 In the same manner, the corresponding sodium salt is produced by employing sodium instead of potassium.
Example 6: Potass;um 2 endo-bicyclo L2.2.11'4~ -heptyl xanthate 340 g (about 3 mol) of endo-norborneol is melted (160C) under nitrogen atmosphere and reacted in portions with a total of 19.55 9 (o.5 mol) of crust-free potassium. The temperature is maintained at lSo until complete dissolution of the metal has taken place. Subsequently, excess nor-borneol is distilled off, the colorless residue dried under high vacuum for a short time, and dissolved in 500 ml of absolute tetra-hydrofurane. With cooling, 31 ml (o.5 mol) of carbon disulfide -dissolved in 150 ml of absolute ether - is added to this alcoholate dro~ by drop. The reaction mixture is stirred for 1 hour at 40C.
The xanthate separating already in the course of the reaction as a pale yellow precipitate is precipitated to a large extent by the addition of 1 1 of dry ether. The precipitate is suction filtered and thoroughly rinsed with ether on the suction filter apparatus.
Mer~ 7 ~ 17~978 The xanthate crystallizes from concentrated alcoholic solution by forming fine, pale yellow needles.
Yield: 95 9 (83,' of the theoretical value) ~lp: 256 - 258deComposition Elementary analysis calculated found C 42.44 42.40 H 4.go 4.92 S 28.32 27.90 In the same manner, the corresponding sodium salt is produced by employing sodium instead of p~tassium.
Example 7: Potassi~n 8(9)-tricyclo ~5.2.1 o2'6] decyl xanthate 457 9 (about 3 mol) of tricyclo~5.2.1.02'6] decanol-8(9) (TCD alcohol A, isomer mixture distributed by Hoechst AG) is reacted under protective gas atmosphere (nitrogen) in portions with a total of 19.55 g (o.5 mol) of crust free potassium with stirring at 150-160C. The temperature of the mixture is kept at this level until complete reaction of the metal has taken place. Subsequently, excess alcohol is distilled off under vacuum, the alcoholate being dried under high vacuum and dissolved in 500 ml of absolute tetrahydrofurane. With cooling, 31 ml (o.5 mol) of carbon disulfide in 150 ml of absolute ether is gradually added to the reaction solution. The mixture is stirred for 1 hour at 40C, the xanthate is precipitated by adding 1 1 of dry ether, suction filtered and thoroughly rinsed with ether on the suction filter apparatus. After recrystallization from ethanol, fine pale yellow crystals are obtained.
Yield: 104 9 (78q, of the theoretical value) Mp: 26odecomposition ElementarY analYsis calculated found C 49.58 49.60 H 5.67 5.62 S 24.o7 24.19 Merz 7 In the same manner, the corresponding sodium salt is produced by employing sodium instead of potassium.
The compounds according to the invention are characterized by valuable pharmacodynamic properties and may, therefore, be successfully applied in human and veterinary medicine.
The virustatic properties have been demonstrated by the in-vitro testing of virus inhibition in an inhibition areola ~plaque inhibition test) and by the plaque reduction method. The following virus strains were used:
Influenza A2 Vaccine virus Herpes virus Tumor viruses of the SV 40 type In this plaque inhibition test tissue cultures of influenza and vaccine viruses (chick fibroblasts), parainfluenza (monkey renal epithelial cells) and herpes viruses (human amnion cells) are infected in such a manner that closely packed but individual plaques form. The test substance is then applied as a 1% solution, and the diameter of the inhibition areola is determined. The results are represented in the following table.
Merz 7 ~ 17497~
Table .
Virustatic properties of the compounds according to the invention demonstrated in the plaque inhibition test Substa~ce concen- 200~/o,o2 ml o = no inhibition areola tration: ~ S ~ = moderate (IA 10-20 mm) Rl - O - C +~ = good (IA 20-30 mm) \ SR2 ++~ = very good ( IA ~ 30 mm) Virustatic properties Rl R2 Influenza Vaccine Herpes Cyclododecyl Na +++ ++t +++
n-Dodecyl Na +++ +++ +
Cy clohexyl Na ++ ++~ +++
Benzyl Na + + +
1-Norbornyl Na ++ +~ +
1-Adamantyl K +
Standard 1-Aminoadamantane hydrochloride +++ o o IA = inhibition areola The action of the test substances on various virus strains has also been determined by in-vitro plaque reduction tests. After the appli-cation of the test substance, followed by infecticn with the respective viruses and incubation, the number of plaques produced by the viruses is determined. The smaller the nurnber of plaques is in comparison with the control, the more effective is the substance under testing. The test results are summarized in the following table:
Merz 7 ~ 1~4978 Table 2 Virustatic action of the compounds according to the invention demonstrated in the plaque reduction test Substance Concentration Plaque reduction in X
Sodiu~ cyclododecyl xanthate 20 ~/ml loo Sodium dodecyl xanthate 20 ~/ml loo Sodium cyclohexyl xanthate 20 ~ /ml loo Standard aminoadamantane hydrochloride 20 ~/ml lo Tables 1 and 2 shoh the superior virust~tic action of the compounds according to the invention.
Method of Treating, i.e., Controlling Viruses The antiviral treatment of a host suffering from such insufficiency, comprising the step of ad~inistering to the patient, host, or situs suffering from such viral contamination or infection the selected xanthate of the foregoing formLla I in an anti-viral amDunt effective for such purpose by the oral, topical, or parenteral route, the said amount administered preferably being 10 to 100 mg per dosage unit by the oral route or 0.05 to 5 mg per dosage unit by parenteral route, constitutes the method-of-treating embodiment of the present invention, in its broadest concepts. Representative dosage forms follow.
~he dosages of xanthates in general will approximate the dosages of the standard aminoadamantane hydrochloride anti-viral agent and, in many cases, because of the enhanced antiviral activity of the xanthate compounds, will be considerably less.
Merz 7 l 174978 Dosage Forms Unit dosage forms for antiviral or other use according to the present invention may be of any suitable and/or conventional type. For oral administration, the unit dosage form generally contains about 10 to 100 mg of selected active ingredient, whether xanthate ester or salt, preferably about 50 mg thereof. For parenteral administration in sterile solution, the unit dose usually contains 0.05 to 5 mg of the active ingredient selected, preferably about 2.5 mg thereof.
As already stated, the selected compound is preferably ad-ministered together or in conjunction with a pharmaceutically-acceptable carrier, and preferably in the form of a tablet.
According to the usual practice of the art, the active xanthate compound is therefore generally associated with a non-toxic pharmaceutical diluent or carrier which may be either a solid material or a liquid. Bland carriers are preferred for some applications. The composition can take the form of tablets, powders, capsules, liquid solutions, emulsions or suspensions, or other dosage forms which are particularly useful for oral administration. Liquid or semi-liquid diluents may be em-ployed for oral use. Such a medium can be or contain a solvent such as water. The only basic limitations of the liquid diluent used are compatibility and palatability. The compositions can take the form of the selected xanthate admixed with solid diluents and/or tableting adjuvants such as rice starch, corn starch, potato starch, lactose, sacharose, gelatin, talc, stearic acid, magnesium stearate, carboxy-methylcellulose, gums such as gu~ acacia or tragacanth, chicle, agar agar, or the like. When in liquid form, the composition may be a sterile or non-sterile solution, suspension, dis-persion, elixir, or the like, all as is well known in the art.
For topical application, the composition may, e.g., be in solution, lotion, ointment, salve, tincture, or like form.
It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds, com-positions, methods, or procedures shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art.
Claims (9)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A composition having virustatic and tumor cell growth influencing properties which comprises an effective amount of a known xanthate of the formula:
wherein R1 is benzyl, straight or branched C3-C20-alkyl, or C3-C20-cycloalkyl, wherein the aforementioned straight or branched C3-C20-alkyl group may be substituted by a hydroxy, C1-C4-alkoxy group, or a halogen atom, and wherein the aforementioned C3-C20-cycloalkyl group may be likewise substituted by a hydroxy, C1-C4-alkoxy, or C1-C4-alkyl group, or a halogen atom, and wherein R2 is a mono- or polyvalent metal atom, a straight or branched C1-C6-alkyl group which may be substituted by a hydroxy, C1-C4-alkoxy, amino, C1-C4-alkylamino, or (C1-C4-alkyl)2 amino group, or (C1-C4-alkyl)3 ammonium group, or a halogen atom, or represents a 2,3-dihydroxypropyl group or .omega.-hydroxy-(C1-C4-alkoxy) methyl group, in admixture with a carrier which does not interfere with the antiviral effect of the active compound, with the proviso that R1 does not include norbornyl, tricyclodecyl, cyclododecyl, or isobornylcyclohexyl.
wherein R1 is benzyl, straight or branched C3-C20-alkyl, or C3-C20-cycloalkyl, wherein the aforementioned straight or branched C3-C20-alkyl group may be substituted by a hydroxy, C1-C4-alkoxy group, or a halogen atom, and wherein the aforementioned C3-C20-cycloalkyl group may be likewise substituted by a hydroxy, C1-C4-alkoxy, or C1-C4-alkyl group, or a halogen atom, and wherein R2 is a mono- or polyvalent metal atom, a straight or branched C1-C6-alkyl group which may be substituted by a hydroxy, C1-C4-alkoxy, amino, C1-C4-alkylamino, or (C1-C4-alkyl)2 amino group, or (C1-C4-alkyl)3 ammonium group, or a halogen atom, or represents a 2,3-dihydroxypropyl group or .omega.-hydroxy-(C1-C4-alkoxy) methyl group, in admixture with a carrier which does not interfere with the antiviral effect of the active compound, with the proviso that R1 does not include norbornyl, tricyclodecyl, cyclododecyl, or isobornylcyclohexyl.
2. A composition of Claim 1, wherein the xanthate compound is an alkali metal xanthate.
3. A composition of Claim 1 or Claim 2 wherein the carrier is a pharmaceutically-acceptable carrier.
MERZ-7-CAN: 390,861 DIV
MERZ-7-CAN: 390,861 DIV
4. A composition of Claim 1, wherein the xanthate compound is an alkali metal benzyl xanthate.
5. A composition of Claim 1, wherein the xanthate compound is an alkali metal dodecyl or cyclohexyl xanthate.
6. A composition of Claim 1 , wherein the xanthate compound is sodium benzyl xanthate.
7. A composition of Claim 1, wherein the xanthate compound is sodium cyclohexyl or dodecyl xanthate.
8. A composition of Claim 1, wherein the xanthate compound is cyclohexyl methyl xanthate.
9. A composition of Claim 1, wherein the xanthate compound is a cyclohexyl lower-alkyl xanthate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000432785A CA1174978A (en) | 1980-11-26 | 1983-07-19 | Xanthates |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3044525 | 1980-11-26 | ||
| DEP3044525.1 | 1980-11-26 | ||
| CA000390861A CA1175047A (en) | 1980-11-26 | 1981-11-25 | Xanthates |
| CA000432785A CA1174978A (en) | 1980-11-26 | 1983-07-19 | Xanthates |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000390861A Division CA1175047A (en) | 1980-11-26 | 1981-11-25 | Xanthates |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1174978A true CA1174978A (en) | 1984-09-25 |
Family
ID=27167174
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000432785A Expired CA1174978A (en) | 1980-11-26 | 1983-07-19 | Xanthates |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1174978A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT388499B (en) * | 1985-08-02 | 1989-06-26 | Merz & Co Gmbh & Co | METHOD FOR PRODUCING AN ANTIVIRAL AND ANTITUMOR COMPOSITION, AND THE USE THEREOF |
| US4851435A (en) * | 1985-08-02 | 1989-07-25 | Merz +Co. Gmbh & Co. | Antiviral and antitumor xanthate pharmaceutical compositions |
| CN114478339A (en) * | 2022-02-14 | 2022-05-13 | 中南大学 | Preparation method of xanthate collecting agent |
-
1983
- 1983-07-19 CA CA000432785A patent/CA1174978A/en not_active Expired
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT388499B (en) * | 1985-08-02 | 1989-06-26 | Merz & Co Gmbh & Co | METHOD FOR PRODUCING AN ANTIVIRAL AND ANTITUMOR COMPOSITION, AND THE USE THEREOF |
| US4851435A (en) * | 1985-08-02 | 1989-07-25 | Merz +Co. Gmbh & Co. | Antiviral and antitumor xanthate pharmaceutical compositions |
| CN114478339A (en) * | 2022-02-14 | 2022-05-13 | 中南大学 | Preparation method of xanthate collecting agent |
| CN114478339B (en) * | 2022-02-14 | 2023-12-08 | 中南大学 | Preparation method of xanthate collector |
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