FIELD OF THE INVENTION
The present invention relates to the azole based anti-dandruff actives comprising 2-
mercaptoimidazole, 2-mercaptobenzimidazole and related derivatives. More particularly the
present invention relates to l-alkyl-1ll-imidazole-2-thiol, l-alkyl-Ill-benzimidazole-2-thiol
and related derivatives that display significant activity against Malassczia furfur, a dandruff
causing pathogen. Thus, the present anti-dandruff hair -care formulation comprising anti-
Malassczia actives helps in combating dandruff.
BACKGROUND AND PRIOR ART OF THE INVENTION
Anti-dandruff shampoos are well known in the art and are also commercially available. Antidandruff
shampoos typically incorporate anti-dandruff active and detersive surfactants.
Among the preferred type of anti-dandruff agents are particulate, crystalline anti-dandruff
agents, such as sulfur, selenium disulfide and heavy metal salts of pyridinethione.
Soluble anti-dandruff agents, such as ketoconazole are also known in the art to be highly
effective against dandruff causing pathogens. In spite of their effectiveness, they are also
associated with side effects such as skin irritation and toxicity. As a result they are restricted
to a maximum of 2% (by weight) in anti dandruff hair care formulations. Thus there is a
continuous search for new actives that are effective against dandruff and yet free of the above
side effects. One of the key causative factors for dandruff is Malasscazia spp. It is widely
believed that Malassczia yeasts, such as Malassczia fUrfur, are the main cause of dandruff.
Dandruff treatments mainly focus on actives that kill Malassazia and are incorporated in
various types of formulations. Candida albicans is also implicated with dandruff.
Benzimidazole is known in prior art to inhibit the growth of Malassczia species, and several
other antifungal agents containing imidazole and benzimidazole units are being continuously
developed for enhanced activity.
2
US 2003/0202952 relate to shampoo compositions comprising of a detersive surfactant, a
cationic polysaccharide polymer and anti-dandruff particles. It discloses various anti-dandruff
particles which could be used. It teaches azoles which include imidazoles such as
benzimidazole and others.
WO 2008/046795 teaches the use of benzimidazole as an antidandruff agent. Benzimidazole
inhibits growth of Malassczia.
EP 0788795 describes the use of various 2-mercaptobenzimidazole derivatives for the
treatment of neuropsychiatric disturbances and ischemic heart diseases.
GB 1234058 describes tuberculostatic, bactereostatic, insecticidal, fungicidal, antiviral,
anthelmintic and anti-inflammatory activities of pyridylalkyloxy and pyridylalkylthio azole
derivatives, which are complex derivatives with derivatization ofthe thiol group.
While the above article teaches the use of benzimidazole as antidandruff agent, it also
describes the increasing occurrence of potentially resistant (azole drug resistant) strains. Thus
there is a continuous search for new derivatives ofazoles with enhanced activity.
Several antifungal agents containing imidazole and benzimidazole units are being
continuously developed for enhanced activity. The inventors has developed several
derivatives of benzimidazole and explored their activity against fungi and yeast. The results
obtained suggest that, in spite of possessing imidazole unit, not all derivatives show activity
against Malassczia species. Thus it cannot be construed based on the information present in
prior art that all derivatives of iinidazole/benzimidazole would possess
antifungal/antidandruff activity. It is still a challenge to develop new actives as reasons for
anti-malassczia activity is not clearly known.
2-Mercaptobenzimidazole, and its derivatives have been used in prior art as intermediates for
the synthesis of various pharmaceutically active drugs such as Omeprazole.
OBJECTS OF THE INVENTION
The primary objective of the present invention is to provide novel azole based anti-dandruff
actives.
3
Another object of the present invention is to provide 2-mercaptoimidazole, 2-
mercaptobenzimidazole derivatives and/or combinations having significant anti-MaJassezia
activity.
BRIEF DESCRIPTION OF THE ACCOMPANYING FIGURES
Figure 1 shows synthesis of 2-mercaptobenzimidazole deriv~tives
Figure 2 shows the effect of different substituents on the anti-MaJassezia activity of
benzimidazole.
SUMMARY OF THE INVENTION
According to one aspect of present invention there is provided an anti-MaJassezia active
comprising the formula I;
I
wherein
R1 ishydrogen, halogen, tritluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl,
benzyl, alkoxy, acyl, nitro, amino, hydroxyl, formyl, carboxylic acid, ester;
R2 is hydrogen, halogen, tritluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl,
benzyl, alkoxy, acyl, nitro, amino, hydroxyl, formyl, carboxylic acid, ester;
Rs is alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl, benzyl, acyl, alkoxy carbonyl;
Rt; is H, a chemically labile group that is readily cleaved by enzymes, catalysts, changes
in pH, temperature etc
According to another aspect of present invention there is provided an anti-MaJassezia
active comprising the formula II;
4
II
wherein
R1 is hydrogen, halogen, trifluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl,
benzyl, alkoxy, acyl, nitro, amino, hydroxyl, formyl, carboxylic acid, ester;
R2 is hydrogen, halogen, trifluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl,
benzyl, alkoxy, acyl, nitro, amino, hydroxyl, formyl, carboxylic acid, ester;
R3 is hydrogen, halogen, trifluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl,
benzyl, alkoxy, acyl, nitro, amino, hydroxyl, formyl, carboxylic acid, ester;
14 is hydrogen, halogen, trifluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl,
benzyl, alkoxy, acyl, nitro, amino, hydroxyl, formyl, carboxylic acid, ester;
Rs is alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl, benzyl, acyl, alkoxy carbonyl;
Rti is H, a chemically labile group that is readily cleaved by enzymes, catalysts, changes
in pH, temperature etc formulated in anti-dandruff formulations.
Yet another aspect of present invention provides a formulation comprising anti-MaJassczia
active comprising the formula I as the active ingredient having 2-mercapto group
I
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to anti -MaJassczia compound comprising the formula I;
5
I
wherein
Rj ishydrogen, halogen, trifluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl,
benzyl, alkoxy, acyl, nitro, amino, hydroxyl, formyl, carboxylic acid ester;
R2 is hydrogen, halogen, trifluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl,
benzyl, alkoxy, acyl, nitro, amino, hydroxyl, formyl, carboxylic acid, ester;
Rs is alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl, benzyl, acyl, alkoxy carbonyl;
Rt; is H, a chemically labile group that is readily cleaved by enzymes, catalysts, changes
in pH, temperature etc formulated in anti-dandruff formulations.
The present invention further provides anti-MaJassezia active comprising the formula;
II
wherein
Rj is hydrogen, halogen, trifluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl,
benzyl, alkoxy, acyl, nitro, amino, hydroxyl, formyl, carboxylic acid, ester;
R2 is hydrogen, halogen, trifluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl,
benzyl, alkoxy, acyl, nitro, amino, hydroxyl, formyl, carboxylic acid, ester;
R3 is hydrogen, halogen, trifluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl,
benzyl, alkoxy, acyl, nitro, amino, hydroxyl, formyl, carboxylic acid, ester;
~ is hydrogen, halogen, trifluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl,
benzyl, alkoxy, acyl, nitro, amino, hydroxyl, formyl, carboxylic acid, ester;
Rs is alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl, benzyl, acyl, alkoxy carbonyl;
6
R<; is H, a chemically labile group that is readily cleaved by enzymes, catalysts, changes
in pH, temperature etc formulated in anti-dandruff formulations.
According to one embodiment of present invention, there is provided azole based antidandruff
actives comprising 2-mercaptoimidazole, 2-mercaptobenzimidazole related
derivatives that display significant anti-Malassczja activity.
More particularly, the present invention provides the azole based anti-dandruff actives
comprising I-alkyI-Il7-imidazole-2-thiol, I-alkyl-Il7-benzimidazole-2-thiol and related
derivatives which display significant anti-Malassczja activity.
The derivatives can be prepared by employing the following steps as described in Figure 1.
1. Protection of the -SH group using a suitable protecting group.
2. Reaction of the -NH group with various alkylating/arylating/acylating agents.
3. Removal ofthe protecting group.
The derivatives can also be prepared by functionalization of the -SH group with chemically
labile groups that are readily removed by enzymes, catalysts, changes in pH, temperature etc.
Representative examples of such groups include formates, carboxylates etc.
The present invention provides antidandruff compositions for treating the hair and the scalp,
based on an antidandruff agent! anti-Malassczja actives of the invention. The present
invention aims to provide a system for treating dandruff which has advantages over the prior
art methods and compositions.
The present invention also provides a formulation comprising imidazole derivatives
comprising the compound of the formula I as the active ingredient having 2-mercapto group
in an amount of 0.75-10 % by weight. Further these derivatives have been used as anti-
Malassczja actives in various anti dandruff hair care formulations including shampoos,
conditioners, creams and serums.
The surfactant in the present formulation is selected from anionic, cationic, nonionic,
amphoteric and zwitter ionic surfactants.
The term 'surfactant' means an ingredient that is used in a cosmetic formulation and exhibits
the ability to reduce the interfacial tension between two immiscible substances, wets skin and
7
hair surfaces, emulsifies or solubilizes oil. The term is synonymous with wetting agents,
surface cleansing agents, surface-active agents and the like.
Suitable anionic surfactants of the present invention include, but are not limited to, the alkyl
sulphates, alkyl ether sulphates, alkaryl sulphonates, alkanoyl isethionates, alkyl succinates,
alkyl sulphosuccinates, N-alkoyl sarcosinates, alkyl phosphates, alkyl ether phosphates, alkyl
ether carboxylates, and alpha-olefin sulphonates, especially their sodium, magnesium,
ammonium and mono-, di- and triethanolamine salts. The alkyl and acyl groups generally
contain from 8 to 18 carbon atoms and may be unsaturated. The alkyl ether sulphates, alkyl
ether phosphates and alkyl ether carboxylates may contain from 1 to 10 ethylene oxide or
propylene oxide units per molecule, and preferably contain 2 to 3 ethyene oxide units per
molecule. Examples of suitable anionic surfactants of the present invention include, but are
not limited to, sodium oleyl succinate, ammonium lauryl sulphosuccinate, ammonium lauryl
sulphate, sodium dodecylbenzene sulphonate, triethanolamine dodecylbenzene sulphonate,
sodium cocoyl isethionate, sodium lauroyl isethionate and sodium N-Iauryl sarcosinate. The
most preferred anionic surfactants are sodium lauryl sulphate, triethanolamine lauryl
sulphate, triethanolamine monolauryl phosphate, sodium lauryl ether sulphate lEO, 2EO, and
3 EO, ammonium lauryl sulphate and ammonium lauryl ether sulphate lEO, 2EO and 3 EO.
Suitable cationic surfactants of the present invention include, but are not limited to,
quaternary ammonium and esterquats, more particularly quaternized fatty acid
trialkanolamine ester salts, aliphatic mono, di and polyamines derived from fatty and rosin
acids, amine oxides, ethoxylated alkyl amines and imidazolines.
The nonionic surfactants of the present invention suitable for use in formulations of the
invention may include condensation products of aliphatic (Cs-C1S) primary or secondary
linear or branched chain alcohols or phenols with alkylene oxides, usually ethylene oxide and
generally having from 6 to 30 ethylene oxide groups. Other suitable nonionics include monoor
di-alkyl alkanolamides. Example includes coco mono- or di-ethanolamide and coco monoisopropanolamide.
The amphoteric and zwitterionic surfactants suitable for use in formulations of the invention
may include alkyl amine oxides, alkyl betaines, alkyl amidopropyl betaines, alkyl
sulphobetaines (sultaines), alkyl glycinates, alkyl glycinates, alkyl carboxyglycinates, alkyl
amphopropionates, alkylamphoglycinates alkyl amidopropyl hydroxysultaines, acyl taurates
and acyl glutamates, wherein the alkyl and acyl groups have from 8 to 19 carbon atoms.
8
Examples include lauryl amine oxide, cocodimethyl sulphopropyl betaine and preferably
lauryl betaine, cocamidopropyl betaine and sodium cocamphopropionate.
Generally, the surfactants are present in formulations of the invention in an amount of from
15 to 50%, preferably from 10 to 30%, more preferably from 5 to 25% by weight.
The other ingredients in the present formulation are selected from conditioning systems,
moisturizing systems, additives, and anti-inflammatory agents.
As used herein the term 'conditioning system' refers to individual or combination of hair care
products that help in improving at least one of the sensorial of touch, feel, softness, volume,
manageability and appearance of hair or fibres. The term is synonymous with a hair care
product capable of providing a soft feel to the coat and provides hairs that lay flat and are
easily combable.
The conditioning system for use in the present invention further comprises suitable
dimethiconol microemulsion, which is commercially available in a pre-emulsified form. Such
pre-formed emulsions can be incorporated into the formulation by simple mixing, which is
particularly advantageous for ease of processing. Pre-formed emulsions are available from
suppliers of silicone oils such as Dow Coming, General electric, Union Carbide, Wacker
Chernie, Shin Etsu, Toshiba, Toyo Beauty Co, and Toray Silicone Co.
The conditioning system for use in the present invention may also contain high molecular
weight cationic polymers. Preferred cationic polymers used in the formulation are
acrylamidopropyltrimonium chloride/acrylamide copolymer and polymeric quaternary
ammonium salt of hydroxyethyl-cellulose.
The conditioning system for use in the present invention may also contain quaternary
conditioning agents such as Polyquaternium 7, Polyquaternium 10, GHTC etc and silicon
based conditioning agents. Cationic surfactants such as mono-, di- and tri-alkyl quaternary
ammonium salts may also be used as the cationic conditioning agent. Suitable examples are
cetyl trimethylammonium chloride, cetyl trimethylammonium bromide and
stearyltrimethylammonium chloride.
The quaternary conditioning systems are used in an amount of 0.01 - 2% by weight and
Silicon based conditioning agents are sued in an amount of 0.1 - 10% by weight.
The term 'moisturizing system' as used herein refers to chemical compositions and
combinations thereof which when applied provide a moisturizing effect to hair follicles.
9
The term 'moisturizing effect' as used herein refers to effects shown by moisturizers such as
retention/increase in water content, holding and redistribution of water and maintenance of
the integrity and appearance of hair.
'Moisturizer' refers to the action of a material, which after one or more applications,
minimized to a desired extent whatever drying effect a shampoo might have on the hair of an
animal. The preferred moisturizing system for use in the present invention comprises of zinc
salt of L-pyrrolidone carboxylic acid (L-PCA) acid, glycerine, polyethylene glycol, Na PCA,
Zn PCA and hydroxyethyl urea, etc. Moisturizing agent are used in an amount of 0.01 - 10%
by weight.
Anti-inflammatory agents which may optionally be added to the formulations of the present
invention may be chosen from allantoin, phytic acid, lutein, azulene, forskolin, adandrine etc.
Thickening agents which may optionally be added to the formulations of the present
invention may be chosen from acrylic acid derivatives, natural thickeners such as xanthan
gum etc. Thickeners in the present invention are used in an amount of 0.01- 5% by weight.
Pearlizing agents which may optionally be added to the formulations of the present invention
may be chosen from ethylene glycol distearate etc. Pearlizing agents used in the formulation
is in an amount of 0-5% by weight. Foam boosters are additionally used in present
formulation in an amount of 0-5% by weight.
The formulation of the present invention may further comprise one or more of the
conventional optional components known for use in hair care formulations, provided that the
components used are compatible with the essential components of the formulation both
physically and chemically. These optional components should generally not impair the
stability, aesthetics or performance of the product.
Such conventional optional ingredients are well known to those skilled in the art and may be
selected from the group comprising but not restricted to preservatives such as benzyl alcohol,
methyl paraben, propyl praben, imidazolidinyl urea, methylchloroisothiazolinone; thickeners
and viscosity modifiers such as coconut ethanolamide, sodium chloride, ammonium chloride,
sodium sulfate, carboxymethyl cellulose, methyl cellulose, polyvinyl alcohol, and ethyl
10
alcohol; perfumes; dyes; sequestring agents such as disodium ethylenediamine tetraacetate;
pH adjusting agents such as citric acid, phosphoric acid, sodium hydroxide, sodium
carbonate, etc. The concentrations of such optional components typically range from about
0.00 I% to about 10% by weight of the formulation.
DETAILED DESCRIPTION OF THE ACCOMPANYING FIGURES
Figure 1 provides synthesis of 2-mercaptobenzimidazole derivatives used as anti Malassczja
actives, wherein Rj is hydrogen, halogen, trifluoromethyl, alkyl, cycloalkyl, alkenyl, allyl,
aryl, heteroaryl, benzyl, alkoxy, acyl, nitro, amino, hydroxyl, formyl, carboxylic acid, ester;
R2 ishydrogen, halogen, trifluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl,
benzyl, alkoxy, acyl, nitro, amino, hydroxyl, formyl, carboxylic acid, ester; R3 is hydrogen,
halogen, trifluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl, benzyl, alkoxy,
acyl, nitro, amino, hydroxyl, formyl, carboxylic acid, ester; ~ is hydrogen, halogen,
trifluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl, benzyl, alkoxy, acyl, nitro,
amino, hydroxyl, formyl, carboxylic acid, ester; Rs is alkyl, cycloalkyl, alkenyl, allyl, aryl,
heteroaryl, benzyl, acyl, alkoxy carbonyl ~ is H, a chemically labile groups that is readily
cleaved by enzymes, catalysts, changes in pH, temperature etc
Figure 2 shows the structures of various anti-Malassczja actives investigated.
The present invention is now demonstrated by way of illustrative non - limiting examples.
Other variations as may be obvious to one skilled in the art may be made in compounds,
formulations, and methods described herein without departing from the essential features of
the invention. These and such others may be considered illustrative and non restrictive to the
scope of the present invention.
Example 1
Representative procedure for the synthesis of N-alkyl derivatives of 2-
mercaptobenzimidazole as described in figure 1.
Synthesis of S-trityl derivative of 5-nitro-2-mercapto-1If-benzimidazole:
a. Protection of the thiol group: 5-Nitro-2-mercapto bezimidazole (1.05 g, 5.38 mmol, I eq.)
was weighed into a 50 mL round bottom flask and dissolved in 20 mL of anhydrous THF.
Triethyl amine (1.09 g, 10.77 mmol, 2 eq.) and a solution oftriphenylmethyl chloride (1.50 g,
5.38 mmol, I eq.) in dry THF (10 mL) were simultaneously added to the above yellow
coloured solution. The colour of solution turned orange brown and the mixture was stirred for
11
8 h under an atmosphere of N2 gas. Progress of reaction was followed by TLC using
hexane:ethylacetate mixture (6:4) as eluent. After completion of reaction, the precipitated
solid was removed by filtration and the residue was washed with THF. The combined organic
layer was concentrated to obtain a yellow solid. The crude product was further purified by
recrystallization from toluene and dried under vacuum to finally obtain the desired
compound. Yield: 2.22 g (94.7%).
IH NMR (Acetone-~): 87.20-7.37 (m, Ar-H, 15H), 7.49-8.21 (m, Ar-H, 3H), 12.81 (s, br, -
NH, IH); IR (cm-l): 3059, 2970 (N-H), 1621, 1600 (C=N), 728, 698 (C-S).
b. Alkylation with methyl iodide: The S-tritylated derivative (1.44 g, 3.29 mmol, 1 eq)
obtained above was taken in a 50 mL round bottom flask and dissolved in anhydrous THF
with continuous stirring under N2 atmosphere. Powdered KOH (0.37 g, 6.60 mmol, 2 eq) was
added to the above yellow solution and kept under vigorous stirring for an hour. In another 50
mL round bottom flask, CH3I (0.94 g, 6.62 mmol, 2 eq) was dissolved in 15 mL of dry THF
and added slowly to the above solution and stirred for 8 h. Progress of reaction was analyzed
with TLC studies using hexane: ethyl acetate (7:3) as eluant. After completion of reaction, the
reaction mixture was filtered and the filtrate was concentrated to obtain an orange solid which
was suspended in water. The product was extracted with dichloromethane (4xI5mL) and
concentrated to a yellow solid. The product was purified by column chromatography (silica
gel 100:200 mesh) using hexane: ethyl acetate (9: 1) as eluant. Yield: 1.17 g (78.7%).
IH NMR (Acetone-~): 83.82 (s, N-CH3, 3H), 7.30-7.66 (m, Ar-H, 3H), 8.08 - 8.38 (m, Ar-
H, 15H). IR (cm-I
): 1616 (C=N), 1367 (C-N), 1507, 1337 (N·O), 747, 667 (C-S).
c. Removal of the trityl group: The compound, Nmethyl-S-tritylated NMBI (0.50 g, 1.11
mmol, 1 eq) derivative was taken into a round bo~om flask and refluxed with acetic
acid/methanol (0.5:10 mL) for 4 h. To this reaction mixture, water was added and excess of
acid was neutralized with anhydrous potassium carbonate. From the aqueous phase, desired
compound was extracted with dichloromethane (6xl0 mL) and then solvent was dried with
anhydrous sodium sulphate. Evaporation of the solvent yielded compound 15 as a yellow
solid. Yield: 0.20 g (87.2 %).
IH NMR (Acetone-~): 83.79 (s, N-CH3, 3H), 7.24-8.22 (m, Ar-H, 3H), 11.94 (s, SH, IH);
IR (cm-I):3084 (N-H), 1618 (C=N), 1367 (C-N), 1490, 1338 (N-O), 730 (C-S).
12
Additional examples of derivatives prepared by the procedure described above.
I-Benzyl-l..fl:.benzimidazole-2-thiol (using benzylbromide in step b): IH NMR (CD30D):
£55.51(s, C6HSCH2, 2H), 7.19-7.62 (m, ArB, 9H); IR (em-I): 3151, 3058 (NH), 1618 (C=N),
1359, 1220 (C-N), 725 (C-S).
1-(4-Fluorobenzyl)-I..fl:.benzimidazole-2-thiol (4-fluorobenzylbromide in step b): IH
NMR (CD30D): £55.52 (s, C6HsCH2, 2H), 7.16-7.65 (m, ArB, 8H); m(em-I): 3148, 3058
(NH), 1612 (C=N), 1356, 1230(C-N), 1161 (C-F), 738 (C-S).
I-Methyl-l..fl:.benzimidazole-2-thiol (6) (using methyliodide in step b): IH NMR (CDCh):
£53.83(s, CHJ, 3H), 7.20-7.36 (m, ArB, 4H), 11.67 (s, SH, IH); IR (em-I): 3140,3104 (NH),
1661 (C=N), 1348, 1235(C-N), 736 (C-S).
Example 2:
Synthesis of S-1..fl:.benzimidazol-2-yl butanethioate (13):
MBI (0.84 g, 5.59 mmol, 1 eq.) was weighed into a 50 mL round bottom flask and dissolved
in 20 mL of anhydrous THF. Triethyl amine (1.15 g, 11.36 mmol, 2 eq.) and a solution of
butyryl chloride (0.60 g, 5.63 mmol, 1 eq.) in dry THF (10 mL) were added to the above
solution. Reaction mixture was stirred for 8 h under inert atmosphere of N2 gas. Progress of
reaction was followed by TLC studies. After completion of reaction, the reaction mixture was
filtered and the residue was washed several times with THF. The combined THF layer was
concentrated to a white solid. The crude product (1.28 g) was further purified by column
chromatography using silica gel (100:200 mesh) and dried under vacuum to obtain compound
13 as a white solid. Yield: 0.74 g (87.67 %).
IH NMR (CD30D): £51.06 (t, -CH2CHJ, 3H), 1.84 (m, - CH2CH~H3, 2H), 3.62 (t, -
COCH~H2, 2H), 7.16-8.07 (m, ArB, 4H); IR (em-I): 3149,3107 (NH), 1717 (SC=O), 1623
(C=N), 738, 633 (C-S).
Example 3:
Synthesis of S-(I-methyl-1H-benzimidazol-2-yl)ethanethioate (14).
13
To a solution of6 (.25 g, 1.53 mmol, 1 eq) in anhydrous THF (25 mL) acetic anhydride (0.16
g, 1.54 mmol, 1 eq) was slowly added and the contents were refluxed for 6 h under an
atmosphere of nitrogen. Progress of reaction was monitored by TLC using hexane-ethyl
acetate (7:3). After completion of the reaction the solvent was removed and the resulting
solid was washed with water (l0 mL). The compound was extracted with ethyl acetate (25
mL) and concentrated to get 14 as a white solid. It was further purified by column
chromatography using silica gel (100:200 mesh). Yield: 0.30 g (94.16%).
IH NMR (CDCh): 3.07 (s, -COCH;, 3H), 3.70 (s, -NCH;, 3H), 7.06-8.17 (m, ArH, 4H); IR
(em-I): 3140, 3104 (NH), 1755 (SC=O), 1615 (C=N), 1385 (C-N), 736, 613 (C-S).
Example 4
Test solutions were prepared by dissolving the actives in DMSO in amounts as provided in
Table 1. The in vitro anti-malassczia activities of the solutions were then assessed through
zone of inhibition method as per BIS 1811479 (Part 2): 2001, i.c., measuring the clear zone of
inhibition of growth around the disc containing the active ingredient.
During the present study it has been observed that imidazole and several derivatives of
benzimidazole as described in figure-l and table 1 provided as below do not possess any
activity against Malassczia species. While 2-mercaptobenzimidazole showed no activity,
introduction of functional groups on the aromatic ring provided derivatives that are effective
against Malassczia species. The activity can further be enhanced through Nalkylation.
It has been surprisingly found that only derivatives having a mercapto group at the 2nd
position of the imidazole ring show considerable activity. This observation is further
strengthened by the fact that the activity is lost when the mercapto group is protected with
alkyl, aryl and benzyl groups or when a hydroxy group is present at that position. It has also
been surprisingly found that introduction of certain groups on the mercapto group enhances
the activities of the inactive molecules. For e.g., 3 and 11 do not show any activity against M
furfur. However 13 and 12 obtained upon introduction of carboxylate unit on the mercapto
unit and the second N-atom respectively are effective against M furfur.
Table1. Anti Malassazia activity of2-mercaptobenzimidazole derivatives
14
S.No 2-Mercapto benzimidazole derivative8 Zone of Inhibition
(mm)b
M.furfur
I Imidazole (1) No activity
2 5-Nitrobenzimidazole (2) No activity
3 2-Mercapto Ill-benzimidazole (3) No activity
4 5-Nitro-2-benzimidazolinone (4) No activity
5 2-(Methylthio )-Ill-benzimidazole (5) No activity
6 I-Methyl-lll-benzimidazole-2-thiol (6) 22
7 5-Nitro-1 ll-benzimidazole-2-thiol (7) 10
8 5-(Difluoromethoxy)-2-mercapto-1 ll- 10
benzimidazole (8)
9 2-«2,4-Dichlorobenzyl)thio )-5-nitro- No activity
Ill-benzimidazole (9)
10 1-(2,4-Dichlorobenzyl)-2-«2,4- No activity
dichlorobenzyl)thio )-5-nitro-lllbenzimidazole
(10)
11 I-Methyl-lll-imidazole-2-thiol (11) No activity
12 Ethyl 3-methyl-2-thioxo-imidazole-l- II
carboxylate (12)
13 S-1ll-benzimidazol-2-yl butanethioate 7
(13)
14 S-acetyl-I-Methyl-I ll-benzimidazole-2- 11
thiol (14)
15 Zinc Pyrithione 23
MSO.~ disc diffusion method. a2% in D y
The benzimidazole derivatives (6-8, 12-14) display significant activity against Ma/assezia
furfurat concentrations above 0.75% (wt% in DMSO).
The present invention is to develop an effective anti-dandruff active other than those known
in the art e.g. ZPTO. Hence the actives and their activity against Ma/assezia in the present
invention is consistent with HIS recommendations).
15
Example 5
A shampoo formulation according to the present invention comprising an active 2-
mercaptobenzimidazole derivative as mentioned in Table 1 is prepared and the composition
of the same is provided in Table 2.
Table 2: Shampoo Formulation according to Example 2
Ingredient Concentration (%)
Sodium laureth sulphate 12.5
Sodium lauryl sulphate 1.5
2-mercapto benzimidazole derivative 2
Quatemary conditioning agents 0.4
Silicon based conditioning agents 1.5
Moisturizing agents 1
Thickeners 0.5
Neutralizing agent QS to desired pH
Preservative QS
Perfume QS
DM Water 'QS to 100
Colour QS
Pearlizing agent 1.5
Foam boosters 3.5
Example 6
Procedure for the preparation of a formulation containing 2-mercaptobenzimidazole
derivative
Method for the preparation of the shampoo:
16
Phase A: In a 1000 mL thick walled beaker, weighed amount of sodium laureth sulphate,
sodium lauryl sulphate, and Lamesoft P065 (cocoglucoside and glyceryl oleate) were taken
and heated till 55°C. To this hot mixture, weighed amount of 2-mercaptobenzimidazole
derivative (0.75-10%) was added and heated to 75°C.
Phase B: In a separate beaker, polyquaternium 10 was dispersed in weighed amount of water
and acrylamidopropyltrimonium chloride/acrylamide copolymer was slowly added to it. This
dispersed mixture was then added to phase A at 55-60°C.
Heating was stopped at this point and the above mixture was cooled. Cocamidopropyl betaine
was added at 50°C, followed by addition of polydimethylsiloxane and PEG-15
cocopolyamine below 45°C with continuous stirring. After this step, acrylate copolymer
(Carbopol Aqua SF-I) was added. The pH of the system was adjusted with NaOH solution.
After neutralizing the system, ginseng extract, yogurtene, allantoin, papain and Zinc PCA
were added, followed by hydroxyethyl urea and preservative (Methylchloroisothiazolinone
and methylisothiazolinone). Required amount of water was added and the mixture was stirred
further for 10-15 min and then 0.1% sodium chloride solution in water was added. Viscosity
of the system was adjusted to -4000-5000 cps (preferably by adding more amount of 0.1%
sodium chloride). Finally the pH of the shampoo was adjusted between 6-6.5 (by adding
NaOH).

We claim:
I. An anti-Malassczia active comprising the formula I;
I
wherein
R) is hydrogen, halogen, trifluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl,
benzyl, alkoxy, acyl, nitro, amino, hydroxyl, formyl, carboxylic acid, ester;
R2 is hydrogen, halogen, trifluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl,
benzyl, alkoxy, acyl, nitro, amino, hydroxyl, formyl, carboxylic acid, ester;
Rs is alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl, benzyl, acyl, alkoxy carbonyl;
~ is H, a chemically labile group that is readily cleaved by enzymes, catalysts, changes
in pH or temperature.
2. An anti-Malassczia active comprising the formula II; R1 R1 Re R2*N R2*N I ~SRe < b I )=s
R .oN R .oN
3 I 3 I
R.. Rs R4 Rs II
wherein
R) is hydrogen, halogen, trifluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl,
benzyl, alkoxy, acyl, nitro, amino, hydroxyl, formyl, carboxylic acid, ester;
R2 is hydrogen, halogen, trifluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl,
benzyl, alkoxy, acyl, nitro, amino, hydroxyl, formyl, carboxylic acid, ester;
R3 is hydrogen, halogen, trifluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl,
benzyl, alkoxy, acyl, nitro; amino, hydroxyl, formyl, carboxylic acid, ester;
~ is hydrogen, halogen, trifluoromethyl, alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl,
benzyl, alkoxy, acyl, nitro, amino, hydroxyl, formyl, carboxylic acid, ester;
Rs is alkyl, cycloalkyl, alkenyl, allyl, aryl, heteroaryl, benzyl, acyl, alkoxy carbonyl;
Rt; is H or a chemically labile group that is readily cleaved by enzymes, catalysts, changes
in pH, temperature etc.
3. A formulation comprising imidazole derivatives comprising the compound of the
formula I as the active ingredient having 2-mercapto group
I
4. A formulation as claimed in claim 3 wherein, the active ingredient is selected
from I-alkyl-I H-benzimidazole-2-thiol, S-I H-benzimidazole-2-ylbutanethioate,
S-(I-methyl-I H-benzimidazole-2-yl)ethanethioate, Ethyl-3-methyl-2-thioxoimidazole-
I-carboxylate derivatives and combinations thereof.
5. The formulation as claimed in claim 3, wherein said formulation is selected from
hair care, skin care and personal care.
6. The formulation as claimed in claim 5 further comprising atleast one of
surfactants selected from anionic, cationic, nonionic, amphoteric and zwitterionic
surfactants.
7. The formulation as claimed in claim 6 comprises surfactants from 15 to 50%,
preferably from 10 to 30%, more preferably from 8 to 25% by weight.
8. The formulation as claimed in claim 5 further comprises conventional agents
selected from conditioning systems, moisturizing systems, additives, and antiinflammatory
agents.
9. The formulation as claimed in claim 8, wherein said conditioning system
comprises quaternary conditioning agents, silicone based conditioning agents and
combinations thereof.
10. The formulation as claimed in claim 9, comprising quaternary conditioning agents
from 0.01% to 2.% by weight
11. The formulation as claimed in claim 9, comprising silicone based conditioning
agents from 0.1% to 10% by weight.
12. The formulation as claimed in claim 8, wherein said moisturizing system
comprises from 0.01% to 10% by weight.
13. The formulation as claimed in claim 5, wherein said formulation is selected from
shampoos, conditioners, serums, sprays, gels, lotions, styling agents, soaps,
deodorants, and creams.