Note: Descriptions are shown in the official language in which they were submitted.
1174978
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.
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1 1 74978
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.)
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~ 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
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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
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~ 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.
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~ 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
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1 174978
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.
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~ 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:
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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.
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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.
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