U.S. patent number 3,862,151 [Application Number 05/325,712] was granted by the patent office on 1975-01-21 for mercapto quinoline n-oxides and their use in combatting dandruff.
This patent grant is currently assigned to Ciba-Geigy Corporation. Invention is credited to Thomas E. Furia, David H. Steinberg.
United States Patent |
3,862,151 |
Furia , et al. |
January 21, 1975 |
MERCAPTO QUINOLINE N-OXIDES AND THEIR USE IN COMBATTING
DANDRUFF
Abstract
Novel compounds having the structural formula in tautomeric
form: ##SPC1## And metal salts and complexes thereof wherein
R.sub.1 and R.sub.2 are hydrogen, alkyl, cycloalkyl, aryl,
alkylthio, halogen, nitro, trifluoromethyl or alkoxy; x is an
integer from 1 to 4 and y is an integer from 1 to 2. The invention
also includes anti-dandruff shampoos containing the above metal
salts and complexes and to a method of combatting dandruff
comprising applying to the hair and scalp a detergent composition
containing the above metal complexes.
Inventors: |
Furia; Thomas E. (Hartsdale,
NY), Steinberg; David H. (Bronx, NY) |
Assignee: |
Ciba-Geigy Corporation
(Ardsley, NY)
|
Family
ID: |
26985055 |
Appl.
No.: |
05/325,712 |
Filed: |
January 22, 1973 |
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
842377 |
Jul 16, 1969 |
3723435 |
|
|
|
Current U.S.
Class: |
546/155;
106/18.32; 524/87; 546/7; 514/880; 524/89; 510/123; 510/319;
510/382; 510/492; 510/500; 510/390; 510/131; 510/119 |
Current CPC
Class: |
A61K
8/4933 (20130101); C07D 215/60 (20130101); A61Q
5/006 (20130101); Y10S 514/88 (20130101) |
Current International
Class: |
C07D
215/00 (20060101); C07D 215/60 (20060101); C07d
033/62 () |
Field of
Search: |
;260/283S
;424/245,258 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Daus; Donald G.
Assistant Examiner: Wheeler; D.
Parent Case Text
This is a divisional of application Ser. No. 842,377, filed on July
16, 1969, now U.S. Pat. No. 3,723,435.
Claims
What is claimed is:
1. A compound selected from the group consisting of compounds
having the following structural formula in tautomeric form:
##SPC5##
and metal salts and complexes thereof wherein R.sub.1 and R.sub.2
are each independently selected from the group consisting of
hydrogen, alkyl of one to 24 carbon atoms, phenyl, phenyl
substituted with chlorine or methyl, halogen, trifluoromethyl and
alkoxy of one to four carbon atoms; and wherein the metal is
selected from lithium, sodium, potassium, calcium.
2. A compound as claimed in claim 1 wherein R.sub.1 and R.sub.2 are
hydrogen.
3. Metal complexes of a compound having the following structural
formula in tautomeric form: ##SPC6##
wherein the metal is selected from lithium, sodium, potassium,
calcium.
4. A compound according to claim 3 wherein said metal is sodium.
Description
BACKGROUND OF THE INVENTION
The present invention relates to novel mercapto quinoline N-oxides,
metal complexes thereof and the utilization of the latter in
anti-dandruff shampoo compositions and in methods for combatting
dandruff.
The precise cause of dandruff in the scalp area is at present
unknown. It has been theorized that the skin particles normally
shed from the scalp surfaces during the process of aging accumulate
and combine with the oils exuded by the scalp to form a condition
which enhances the growth of those bacteria, fungi, or other
biological agents responsible for the propagation and accumulation
of dandruff.
It is emphasized, however, that the above mechanism is at best an
unproven theory. One of the major obstacles to a complete
acceptance of this theory is the fact that many extremely powerful
bactericides and fungicides have no effect whatsoever on the spread
of dandruff in the human scalp. Moreover, substances such as
elemental sulfur which are not recognized as having potent
bactericidal and fungicidal activity are extremely effective in the
control of dandruff. Obviously, then, factors other than bacteria
and fungi contribute to the growth and spread of dandruff.
Accordingly, the selection of agents suitable for the control of
dandruff is necessarily a hit and miss proposition. It is only by
the process of trial and error that those skilled in the art have
been able to provide the art with effective anti-dandruff agents to
date.
One type of such anti-dandruff agent is described in U.S. Pat. No.
3,236,733. The compounds described therein as being useful for
combatting dandruff are certain metal salts or complexes of
1-hydroxy-2-pyridinothione. Although providing a high degree of
anti-dandruff activity, the metal salts of
1-hydroxy-2-pyridinethiones suffer from the disadvantage that they
are slightly toxic, particularly when applied to the scalps of
those individuals having unusually sensitive skin. Such individuals
experience irritation and reddening of the skin and in certain
cases, highly aggravated reactions in the form of open sores, etc.,
upon application of these thione salts to their scalps.
There exists in the prior art, therefore, the need for an
anit-dandruff agent which is highly effective in combatting
dandruff and, simultaneously, non-toxic to the scalp or skin.
Accordingly, it is an object of the present invention to provide
novel chemical compounds having a high degree of anti-dandruff
activity which are non-toxic to the skin or scalp.
It is further object of the present invention to provide an
anti-dandruff shampoo composition which is non-toxic to the scalp
or skin.
It is still a further object of the present invention to provide a
method for combatting dandruff with a composition which is
non-toxic to the scalp or skin.
SUMMARY OF THE INVENTION
The above and other objects of the present invention are achieved
by the provision of novel mercapto quinoline N-oxides having the
following structural formula in tautomeric form: ##SPC2##
and salts and complexes thereof with metals non-toxic to the scalp
or skin wherein R.sub.1 and R.sub.2 are independently selected from
the group consisting of hydrogen, alkyl of 1 to 24 carbon atoms,
cycloalkyl, aryl, alkylthio having 1 to 24 carbon atoms, halogen,
nitro, trifluoromethyl and alkoxy of 1 to 4 carbon atoms; x is an
integer from 1 to 4 and y is an integer from 1 to 2.
It has been found that metal complexes of the above mercapto
quinoline N-oxides possess a high degree of anit-dandruff activity
and are relatively non-toxic to the scalp and skin.
Shampoos containing the above-described mercapto quinoline N-oxide
metal complexes and methods involving the application thereof to
the scalp and hair have been found to be highly effective in
controlling the propagation and spread of dandruff. At the same
time, the application of these shampoo compositions to the scalp
produce no toxic effects thereon, even in individuals having
extremely sensitive skin.
DETAILED DESCRIPTION OF THE INVENTION
In the above tautomeric structural formula, R.sub.1 and R.sub.2
have been defined as hydrogen, alkyl, cycloalkyl, aryl, alkylthio,
halogen, nitro, trifluoromethyl and alkoxy.
The preferred mercapto quinoline N-oxides are those wherein R.sub.1
and R.sub.2 are each H.
Among the alkyl substituents, the most preferred are the lower
alkyl groups, i.e. having 1 to 4 carbon atoms, e.g. methyl, ethyl,
n-propyl, iso-propyl, butyl. Higher alkyl substituents include by
way of example dodecyl, tetradecyl, hexadecyl, octadecyl, eicosyl,
docosyl, tetracosyl.
Suitable cycloalkyl substituents include by way of example
cyclopentyl, methylcyclopentyl, ethylcyclopentyl, etc;
chlorocyclopentyl, dichlorocyclopentyl, cyclohexyl,
methylcyclohexyl, ethylcyclohexyl, etc., chlorocyclohexyl,
dichlorocyclohexyl.
Exemplary of the aryl substituents are phenyl, o-tolyl, m-tolyl,
p-tolyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl,
2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl,
3,5-dimethylphenyl, etc., 2-chlorophenyl, 3-chlorophenyl,
4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl,
2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl,
3,5-dichlorophenyl, etc.
Suitable alkyl groups of the alkylthio and alkoxy substituents
include those mentioned above; the most preferred being the lower
alkyl groups.
Suitable halogen substituents include trifluoromethyl, fluoro,
chloro, bromo and iodo; the most preferred being chloro.
Salts or complexes of the above described mercapto quinoline
N-oxides with any metal which is non-toxic to the scalp or skin may
be employed in the present invention. Suitable metals include
lithium, sodium, potassium, zinc, calcium, tin, copper, antimony,
lead, manganese, and aluminum.
The preferred metals are sodium and zinc; zinc being the most
preferred. The most preferred anti-dandruff agent is the zinc
complex of 2-mercapto-quinoline-N-oxide.
The terms `salts or complexes` have been employed to define the
metal derivatives of the 2-mercapto-quinoline-N-oxides of the
present invention, the specific compound formed being determined by
the valence of the metal M. The structure may be depicted thusly:
##SPC3##
wherein R.sub.1, R.sub.2, x and y have the meanings given above; M
is a metal and n is the valence of said metal.
The compounds of the present invention may be prepared according to
methods well known in the prior art. Generally, the following
reaction scheme may be employed to prepare the compounds of the
invention: ##SPC4##
The starting materials (I) are well known in the prior art. They
are described, e.g. in: C. A., vol. 54, pp. 24741 and 24742; C. A.,
vol. 55, p. 18728; C. A., vol. 51, p 1959; C. A., vol. 44, p. 632;
C. A., vol. 41, p 2056; C. A., vol. 57, p 11832; C. A., vol. 58, p
13913; C. A., vol. 58, p 13744; C. A., vol. 59, pp. 8743 and 97432;
J. A. C. S., vol. 64, p 1357.
The starting materials (I) are converted to the N-oxides by methods
well known in the prior art, e.g. by contacting with a per-acid
such as per-maleic acid in a suitable solvent.
The intermediate 2-chloro-quinoline-N-oxide (II) may be converted
to the 2-mercapto-quinoline-N-oxide (III) or directly to the metal
salt or complex thereof (IV). The mercapto compound may be obtained
by reacting the chloro derivative with a mixture of NaSH and
Na.sub.2 S in the presence of an acid.
Optionally, the metal salt or complex may be prepared directly by
reacting the chloro derivative with MSH in the presence of a proton
acceptor solvent. It is to be understood that mixtures of complexes
of various metals with 2-mercapto-quinoline-N-oxide may be prepared
by reacting the chloro derivative with a mixture of metal salts.
Moreover, the metal complexes may be converted to complexes of
other metals by reaction with salts of metals which are lower on
the EMF scale.
Also, the mercapto-quinoline-N-oxides (III) may be converted to the
metal complex (IV) by reaction with the appropriate metal salt.
The anti-dandruff agents of the present invention may be
incorporated in any of the shampoo compositions well known in the
prior art. Generally, shampoo compositions comprise aqueous
detergent bases in liquid or paste form containing conventional
shampoo additives such as coloring agents, perfume, fillers,
thickeners, solvents, opacifiers, builders, conditioning agents
such as amine oxide surfactants, lanolin derivatives,
preservatives, buffers, anti-static agents, etc. The shampoos
generally contain from about 1 to about 30 percent by weight of a
detergent.
The detergents may be anionic, cationic, amphoteric or non-ionic.
Suitable anionic detergents include by way of example propylated
naphthalenesulfonic acid, sodium alkylnaphthalenesulfonate,
sulfonated monoglyceride of coconut fatty acids, sodium oleyl
sulfate.
Suitable examples of cationic detergents include
lauryltrimethylammonium chloride, cetyltrimethylammonium bromide,
cetyldimethylethylammonium bromide.
Suitable amphoteric detergents include N-alkyl taurines, such as
N-dodecyl taurine, alkyl .alpha.-alanines such as dodecyl
.beta.-alanine, long chain alkyl amino sulfonic acids, alkyl
sulfonamides and the like.
Among the non-ionic detergents which may be employed in the shampoo
compositions of the present invention may be mentioned by way of
example polyethylene glycol lauryl ether, polyethylene esters of
fatty acids or rosin acids, polyethylene glycol stearate, sorbitan
monopalmitate, sorbitan monooleate.
The anti-dandruff agents of the present invention may be
incorporated in the above shampoo compositions in amounts
sufficient to provide effective anti-dandruff control on the hair
and scalp. Generally, amounts ranging from about 0.1 to about 10
percent by weight are included.
It has been found that the anti-dandruff agents of the present
invention are highly substantive to the scalp and hair, ie., is
retained on the scalp and in the hair despite rinsing and builds up
a layer thereof on the scalp and in the hair upon repeated use. By
applying the above shampoos to the scalp and hair, the propagation
and spread of dandruff may be effectively controlled.
Because of their microbiological activity, the salts and complexes
of the present invention may be beneficially soaps; into other
products where antibacterial or fungicidal activity is desired such
as antibacterial and deodorant toilet soaps, including detergents
and combinations of detergents and soaaps; laundry detergents and
soaps; other laundry finishing compositions such as softeners, acid
sours, antichlors and both natural and synthetic starches; in hard
surface disinfecting compositions such as floor and wall cleaners;
various personal products such as creams, powders, talcs and
aerosol sprays; in water treatment, secondary oil recovery and heat
exchanges, polymers such as plasticized polyvinyl chloride and the
like for the prevention of microbiocidal deterioration; and in
paints and coatings in both oil base and latex types or in can
preservation and in improving weatherability.
The following non-limiting examples are illustrative of methods for
the preparation of the anti-dandruff agents of the invention.
EXAMPLE 1
a. 420 g of maleic anhydride was dissolved in 900 ml of chloroform
and cooled. 84 g of 30 percent hydrogen peroxide was added dropwise
thereto with stirring in an ice bath. The mixture was stirred at
0.degree.-5.degree.C for 1-2 hours. 49.2 g of 2-chloroquinoline in
90 ml of chloroform was added dropwise thereto with stirring in an
ice bath at 0.degree.-5.degree.C over 1.5 hours. The resulting
mixture was stirred overnight at 0.degree.-5.degree.C and stored at
5.degree.C. for 10 days. The mixture was then filtered, yielding
479.1 g of a precipitate having an melting point of
141.degree.-5.degree.. The filtrate was stripped to yield 99.7 g of
residue which was dissolved in chloroform and passed through a bed
of 2100 g of neutral alumina and eluted with chloroform. 12 .times.
200 ml fractions were obtained followed by 12 .times. 450 ml
fractions. The product fractions (8-14) were combined and stripped
to yield 28.0 g of residue. The residue was placed in a freezer and
previously prepared seeds were added which induced solidification
of the product. A sample of the purified product was dried to
constant weight at 55.degree./0.1 mm. It had a melting point of
84.degree.-8.degree. and gave satisfactory elemental analysis.
Analysis for C.sub.9 H.sub.6 ONCL:
Calc.: C, 60.18; H, 3.36; N, 7.80; Cl, 19.73.
Found: C, 60.40; H, 3.85; N, 7.88; Cl, 20.01
C, 60.14; H, 3.71; H, 7.86.
b. 840 g of maleic anhydride was dissolved in 1,800 ml of
chloroform at 40.degree.-50.degree.C and the mixture transferred to
a 3,000 ml, 3-neck flask equipped with a stirrer, condenser,
thermometer and dropper funnel. While cooling in an ice-bath, 168 g
of hydrogen peroxide (30%) was added to the mixture dropwise over
1.5 hours. While maintaining the temperature of the mixture at
5.degree.-10.degree.C, 88.4 g of 2-chloroquinoline (dissolved in
250 ml of chloroform) was added thereto dropwise with stirring over
1 hour. The reaction was continued with stirring for 3 hours at
5.degree.-10.degree.C. The reaction mixture was transferred to a
refrigerator and stored for 6 days.
The precipitate was filtered from the reaction mixture and washed
with chloroform to yield 910 g of insoluble material. The filtrate
was placed in a 4-liter separatory funnel and washed with 1,000 ml
of a 10 percent solution of potassium carbonate. The wash solution
was separated therefrom and the filtrate again washed with 500 ml
of a 10 percent potassium carbonate solution. The product contained
in the chloroform layer was separated and placed in a refrigerator
over solid potassium carbonate to dry overnight.
The chloroform solution was then passed through a layer of neutral
alumina on a sintered glass funnel under light suction to remove
potassium carbonate and water. A clear chloroform solution was
obtained. The alumina was washed with 200 cc of chloroform and
combined with the original filtrate. The combined solutions were
stripped on a rotary evaporator keeping the temperature below
40.degree.C. to yield a dark colored syrupy residue. The residue
was treated with 250 ml of anhydrous ethyl ether. The resulting
mixture was shaken with 100 ml of water for 5 minutes to yield a
copious light colored precipitate. The mixture was cooled to
5.degree.-10.degree.C and filtered. The precipitate was washed with
200 ml of water followed by washing with 200 ml of ethyl ether. The
precipitate was then dried over phosphorous pentoxide in a
dessicator, under vacuum for 5 days to yield 48.7 g (51.4 percent
yield) of product having a melting point of 77.degree.-84.degree.C.
Comparison by thin layer chromatography using silica gel
(absorbent), 4:1 benzene-methanol (developer) and iodine (detector)
indicated identity with the previously prepared product.
EXAMPLE 2
Preparation of 2-Mercapto-Quinoline-N-Oxide
30.5 g of 2-chloro-quinoline-N-oxide and 850 ml of water were added
to a 2-liter flask equipped with a stirrer, condenser, thermometer
and dropping funnel. The mixture was heated with stirring to
45.degree.C. 5.8 g of sodium hydrosulfide (50 percent assay) and
41.7 g of sodium sulfide (32.5 percent assay) in 155 ml of water
were added to the dropping funnel and added dropwise over 2 hours,
to the contents of the flask while heating at 65.degree.C for 45
minutes. The reaction mixture which was completely in solution was
cooled to room temperature. A solution of 70 g of concentrated
hydrochloric acid in 70 ml of water was placed in a dropping funnel
and added dropwise to the reaction mixture with stirring. Hydrogen
sulfide evolved from the reaction mixture was collected in a 20%
NaOH trap. After 1 hour sufficient hydrochloric acid solution was
added to bring the pH of the reaction mixture to 1.0. The copious
precipitate deposited from the reaction mixture was filtered on a
sintered glass funnel, washed with 700 ml of water and dried
overnight under vacuum. The product weighed 19.0 g (63.2% yield),
had a melting point of 65.degree.-67.degree.C. and was identified
by infrared spectroscopy to be 2-mercapto-quinoline-N-oxide.
Using procedures analogous to those of this example employing
equivalent amounts of the appropriate starting materials, other
compounds falling within the scope of the present invention are
readily prepared.
EXAMPLE 3
Preparation of the Sodium Complex of
2-Mercapto-Quinoline-N-Oxide
a. A mixture of 1.8 g of 2-chloro-quinoline-N-oxide, 1.1 g of
sodium hydrosulfide and 10 ml of dimethylformamide was heated on a
steam bath for 1 hour and allowed to stand overnight. The reaction
mixture was stripped to dryness to remove dimethylformamide.
Approximately 25 ml of ethyl alcohol was added and the mixture
filtered to remove a small amount of a white precipitate of NaCl.
The filtrate was stripped and gave 2.3 g residue. This residue (R1)
was triturated with benzene which left a new residue (R2) of 1.0 g
having a melting point of 235.degree.-250.degree.. This was
recrystallized from a mixture of acetone (60 ml) and heptane (60
ml) and afforded 0.8 g of product. After drying overnight at
65.degree./0.2 mm, it had a melting point of
255.degree.-260.degree. (dec.). A neutral equivalent established
that the product was the sodium salt of
2-mercapto-quinoline-N-oxide.
EXAMPLE 4
Preparation of Zinc Complex of 2-Mercapto-Quinoline-N-Oxide
a. 1.5 g of 2-mercapto-quinoline-N-oxide, 0.68 g of 50% NaOH
solution and 20 ml of water were mixed and vigorously stirred. The
insoluble matter was filtered off. The filtrate was back-titrated
with dilute hydrochloric acid to a pH of 9.0. With continuous
vigorous stirring a solution of 1.26 g of zinc chloride in 20 ml of
water was added dropwise to the filtrate to give a copious light
green-yellow precipitate. The precipitate was collected by
filtration, washed twice with 30 ml portions of water, once with 20
ml of ethanol and once with 20 ml of anhydrous ethyl ether. The
precipitate of the zinc complex of 2-mercapto-quinoline-N-oxide was
then dried under vacuum at 56.degree.C at 2 mm for 2 hours to give
1.7 g (96.2 percent yield) having a melting point of
243.degree.-46.degree. (dec.).
b. 17.7 g of 2-mercapto-quinoline-N-oxide was added portion wise
over 1/2 hour to 8.8 g of sodium hydroxide in 250 ml of water with
stirring to yield a mixture having a pH of 12. The insoluble matter
was filtered off and the filtrate back-titrated with dilute HCl to
a pH of 9.0-9.5. A solution of 13.63 g of zinc chloride in 200 ml
of water was added portionwise to the filtrate with vigorous
stirring to give a copious precipitate of the zinc complex of
2-mercapto-quinoline-N-oxide. The product was filtered and washed
twice with 200 ml of water, once with 200 ml of ethanol and once
with 200 ml of anhydrous ethyl ether. The product was dried under
vacuum (2mm) over phosphorous pentoxide for 17 hours to give 19.6 g
(94 percent yield); melting point 244.degree.-46.degree..
Analysis for:
Calc.: C, 51.74; H, 2.90; S, 15.35; N, 6.71; Zn, 15.65.
Found: C, 51.26; H, 3.00; S, 14.46; N, 6.56; Zn, 15.76
C, 51.28; H, 2.93; S, --; N, 6.67; Zn, 15.80.
c. A clear solution of 68.1 mg zinc chloride in 10 ml of water was
added to a clear solution of 199 mg of the sodium complex of
2-mercapto-quinoline-N-oxide in 5 ml of water with swirling. The
resulting tan precipitate was filtered, washed successively with 3
.times. 15 ml portions of water, 2 .times. 15 ml portions of
ethanol and 2 .times. 15 ml portions of anhydrous ethyl ether. The
zinc complex product was air dried, then dried to constant weight
at 110.degree. at 0.1 mm. This afforded 170 mg of product having a
melting point of 250.degree.(dec.).
d. A clear solution of 1.02 g of zinc chloride in 125 ml of water
was added to a clear solution of 3.32 g of the sodium complex of
2-mercapto-quinoline-N-oxide in 100 ml of water with stirring.
After 15 minutes of stirring, the resulting precipitate of the zinc
complex of 2-mercapto-quinoline-N-oxide was filtered, washed
successively with 3 .times. 50 ml portions of water, 4 .times. 25
ml portions of ethanol and 6 .times. 25 ml portions of anhydrous
ethyl ether, and air dried. The product (2.8 g - 90 percent yield)
had a melting point of 250.degree.-260.degree. (dec.). Following
drying in a vacuum oven at 90.degree.-100.degree.10.3 mm for 2
hours, the product had a melting point of
240.degree.-250.degree.(dec.).
Analysis for:
Calc.: N, 6.70; S, 15.34; Zn, 15.64.
Found: N, 6.58; S, 14.61.+-.0.03; Zn, 15.53.+-.0.23.
The foregoing procedures are employed to prepare salts or complexes
of the other metals (M) listed above.
As stated above, the 2-mercapto-quinoline-N-oxide metal complexes
of the present invention have an effectiveness against dandruff
comparable to that of the metal complexes of the
hydroxy-pyridinethiones of U.S. Pat. No. 3,236,733 but are
comparatively less toxic to the scalp and skin.
The following examples illustrate the effectiveness of the
compositions of the invention in controlling dandruff.
EXAMPLE 6
The microbiological activities of the zinc and sodium complexes of
2-mercapto-quinoline-N-oxide (MQNO) against P. Ovale were compared
with the sodium and zinc salts of pyridinethione-N-oxide (PTO) and
other conventional soapbacteriostats. P. Ovale is a microorganism
associated with dandruff conditions.
Equal amounts of the respective compounds were dissolved in methyl
cellosolve, dimethylformamide, or water, serially diluted in ten
fold sequence and incorporated into plates of molten Agar. The
plates were allowed to solidify, were then inoculated with P. Ovale
(ATCC 14521), incubated at 27.degree.C. for 4 days and inspected
for growth. The results are set forth in Table I.
TABLE 1 ______________________________________ Activity of Various
Antimicrobial Agents Against P. Ovale Compounds MIC* in PPM
______________________________________ Zn MQNO 50-60 Na MQNO 50-60
Zn PTO 7-10 Na PTO 7-10 2-mercaptoquinoline >1000
2-mercaptopyridine >1000 Tetrachloro salicyanilide 1000
Trichloro salicyanilide >1000 Tribromo salicyanilide 1000
Hexachlorophene >1000 Trichlorocarbanilide >1000
2.2'-dihydroxy-5.5'-dichlorodiphenyl >1000 monosulfide Thio
bis(dichlorophenol) >1000 P-chloro-m-xylenol 1000
5-chloro-6-bromobenzoxazo-linone 1000 50% m-alkyldimethyl
ethyl-benzyl ammonium chloride-50% m-alkyl dimethyl-benzyl ammonium
chloride >1000 m-alkyl-dimethyl-ethyl-benzyl ammonium >1000
chloride Benzethonium chloride >1000 N-alkyl-dimethyl-benzyl
ammonium chloride >1000 N-alkyl-dimethyl-ethyl-benzyl ammonium
cyclohexyl sulfamate >1000 Undecylenyl polypeptide >1000
Sodium salt of sulphosuccinate of undecylenic-monoalkylolamide
>1000 Diiodohydroxyquinoline 1000 8-Hydroxyquinoline 100
Undecylenic acid 1000 Undecen-1-ol >1000
______________________________________ *Minimum Inhibitory
Concentration
It is apparent from the results of Table 1 that the activity of the
compositions of the present invention are comparable to that of the
pyridinethione-N-oxides of U.S. Pat. No. 3,236,733. It is also
apparent that the other conventional bacteriostats, fungistats and
quaternary ammonium compounds are totally void of activity or are
vastly inferior to the compositions of the invention.
EXAMPLE 7
The substantivity/activity of the zinc complex of
2-mercapto-quinoline-N-oxide of the invention in calf-skin were
compared with the zinc salt of pyridinethione-N-oxide in the
following manner. ZnMQNO and ZnPTO were incorporated by blending on
a 3-roll mill in amounts of 1% and 2% by weight into a
non-bacteriostatic paste shampoo of the following composition.
______________________________________ Long chain modified
alkanolamide, anionic 25.4% Lauric acid 11.9% Coconut alkanolamide,
non-ionic 1.9% Triethanolamine salt of lauroyl sulfate 1.9%
Trisodium hydroxyethyl ethylenediamine triacetate (41% solution)
1.1% Water 57.8% 100.0% ______________________________________
Calf skin specially prepared by the method of Vinson IN VITRO TESTS
FOR MEASURING ANTIBACTERIAL ACTIVITY OF TOILET SOAP AND DETERGENT
BARS by L. J. Vinson, E. L. Ambye, A. G. Bennet, Journal of
Pharmaceutical Sciences, Vol. 50, P. 10, October, 1961. 0.3 g of
shampoo was applied in each instance to 12.5 sq. in. of calf skin
(equivalent to 3.5 g of shampoo per 90.2 sq. in. of human scalp)
and a rich lather worked up for 2 minutes. The calf skin was then
rinsed in running tap water for 30 seconds with vigorous massage to
remove all lather. The moist skin was then given a second lather
identical to the first and again rinsed as before. After air
drying, the calf skins were cut into 2.1 cm discs and placed on
agar inoculated with P. Ovale. After 4 days incubation at
27.degree.C, the zones of inhibition size were recorded. The
results are set forth in Table 2.
It is apparent from these results that the substantivity and
activity of the compositions of the invention are comparable to
those of the agents described in U.S. Pat. No. 3,236,733. It should
be noted that the smaller zone size produced by ZnMQNO does not
indicate a lesser activity than ZnPTO since zone size is largely
dependent upon diffusion characteristics in agar. Since ZnMQNO is
less soluble than ZnPTO it would be expected to exhibit a smaller
zone size.
The following example illustrates the antimicrobial spectrum of the
compositions of the invention as compared with those of U.S. Pat.
No. 3,236,733.
EXAMPLE 8
Equivalent amounts of ZnMQNO, NaMQNO, ZnPTO and NaPTO were
solubilized in methyl cellosolve (PTO) and dimethyl formamide
(MQNO). Ten fold serial dilutions were prepared employing
additional solvent and equal aliquots pipetted into molten
(50.degree.C) agar support media. Nutrient Agar was employed for
all bacteria and Mycological Agar was employed for the fungi and
dermatophyte. After preparing pour plates for the bacteria and
streaks for the fungi and dermatophyte, the plates were incubated
(37.degree.C and 27.degree.C, respectively) and observed for
growth. The results are set forth in Table 3.
As is apparent from these results, zinc and sodium PTO may be
classed as broad-spectrum antimicrobial agents showing good
activity at low concentrations against Gram-positive and negative
bacteria, fungi and dermatophytes.
Table 2
__________________________________________________________________________
Replicate Zone of Inhibition Against P. Ovale - Calf Skin Plates 2%
Zinc PTO.sup.(1) 2% MQNO.sup.(2) 1 Application 2 Applications 1
Application 2 Applications
__________________________________________________________________________
1 4.5 10.0 0.5 2.0 2 4.0 7.0 1.5 4.5 3 5.0 10.0 1.5 2.0 4 4.0 5.0
1.0 2.5
__________________________________________________________________________
.sup.(1) Zinc pyridienthione-N-oxide from commercial `Head and
Shoulders` shampoo .sup.(2) Zinc 2-mercaptoquinoline-N-oxide from
formulated paste shampoo a described in Example 6.
Table 3
__________________________________________________________________________
Organisms ATCC No. Minimum Inhibitory Concentration in PPM NaPTO
ZnPTO NaMQNO ZnMQNO
__________________________________________________________________________
Staph. aureus.sup.(1) 6538 0.1 1.0 0.1 1.0 0.1 1.0 0.1 1.0 E.
Coli.sup.(1) 4352 1.0 10 1.0 10 1.0 10 1.0 10 Proteus
vulgaris.sup.(2) 9920 1.0 10 1.0 10 0.1 1.0 1.0 10 Aspergillus
oryzae.sup.(3) 10196 10 100 10 100 10 100 10 100 T.
interdigitale.sup.(4) 9533 1.0 10 1.0 10 1.0 10 10 100
__________________________________________________________________________
.sup.(1) The strains of Staph. aureus and E. Coli employed are the
official test organisms used in AATCC Test Method 90-1965T.
.sup.(2) Proteus vulgaris 9920 is a strong ammonia producer and
employed by many organizations to test treated diapers. .sup.(3)
Aspergillus oryzae 10196 is employed by industry and the U.S. Army
to test the degradation of paint films in tropical chambers.
.sup.(4) Trichophyton interdigitale 9533 is used for germicide
testing in the U.S. and included by the USDA for testing the
fungicidal activity of aerosol hard-surface cleaners.
* * * * *