Derivatives of aromatic benzoates as inhibitors of esterase-producing micro-organisms

Inhibitors of esterase-producing micro-organisms comprise, as active ingredient, a benzyl or phenyl benzoyloxybenzoate (I) which is hydrolysed by esterases to produce three mononucler benzene compounds which between them bear at least two hydroxyl and two carboxyl substances, and which which an anti-microbial action. The inhibitors may be formulated as personal deodorants or dermatological agents.

BACKGROUND OF THE INVENTION 
This invention relates to derivatives of aromatic benzoates as inhibitors 
of esterase-producing micro-organisms, for use primarily in deodorant 
compositions. 
The human skin has a large natural population of micro-organisms. These 
organisms are nourished by various skin-secreted substances, skin cell 
debris, breakdown products of the skin and the organisms themselves. The 
skin secretions are conveniently divided into two groups, those containing 
water-soluble materials and constituted by eccrine and apocrine sweat, and 
sebum which contains lipid-soluble materials. These secretions will be 
referred to as `liquid body-secretions` and they will now be described, as 
will their functions as they are generally understood. 
Eccrine sweat consists mainly of a watery solution of dissolved salts and 
is produced by glands distributed over the whole skin surface. In 
conditions of occlusion, e.g. feet enclosed in socks and shoes, the 
eccrine sweat accumulates, and in these warm damp conditions, the skin 
debris, together with nutrients from the sweat, provide a medium for 
micro-organism growth with the possibility of massive overgrowth of one 
type. This can result, in the first instance, in odorous metabolic 
products, and in the second, in clinical infection with maceration of the 
skin and irritation. 
Apocrine sweat is produced by the apocrine glands at specific sites on the 
body, notably the axillae, the anogenital area and around the nipples. 
Although present at birth, the apocrine glands are not functional until 
puberty when they are influenced by circulating androgens. Apocrine 
secretion differs from eccrine sweat in containing lipids (fatty 
materials) and proteins. In the warm, damp occlusion met in the axillae, 
certain skin micro-organisms metabolise this secretion, forming free fatty 
acids and other breakdown products. These materials are odorous and 
responsible for `body odour`. 
The sebaceous glands are distributed over the skin surface except the palms 
and dorsae. They are most numerous on the scalp, forehead, face, back and 
chest. The secretion, sebum, consists mainly of fatty materials, wax 
esters, cholesterol and its esters and squalene. Normally, sebum flows 
freely from the glands, spreading over the skin surface. In acneic and 
certain other skin conditions, the sebaceous duct through which the sebum 
is normally secreted becomes hyperkeratinised and the opening of the duct 
becomes blocked. The gland continues to produce sebum and the blocked duct 
distends to form a comedone. Also blocked in the duct, the (normally) 
commensal micro-organisms produce esterases which hydrolyse the sebum 
lipids, liberating free fatty acids. These fatty acids are irritant and 
can result in an inflammatory reaction along the wall of the duct. 
Leucocytes invade the inflamed area and the comedone develops into a 
papule and then a pustule. This is a typical acne `spot`. 
The scalp is well supplied with sebaceous glands, and the scalp, like all 
skin, undergoes desquamation. Due to the presence of hair, the squames 
tend to be retained at the scalp surface. Sebum accumulates beneath these 
squames and in dandruff conditions is hydrolysed by micro-organism 
produced esterases to form irritant fatty acids. The irritation causes 
proliferation of the epidermis and increased formation of the stratum 
corneum which again desquamates unevenly in large clumps--the dandruff 
scale or flake. 
In our International Application No. PCT/GB87/00323 (Publication No. 
W087/06827) we disclosed an inhibitor of esterase-producing microorganisms 
in which the active ingredient comprised an aromatic acid ester of a 
phenol or of an aromatic alcohol, the phenol or aromatic alcohol being 
sufficiently water-soluble to impart an anti-microbial action and the 
aromatic acid being sufficiently water-soluble to impart an anti-microbial 
action and/or to lower the pH of liquid body-secretion to a level which at 
least inhibits the growth of micro-organisms in the liquid 
body-secretions; for use in deodorants the active ingredient may be 
incorporated in a perfume composition which is then incorporated in a 
vehicle such as ethanol; for use in a dermatological composition, the 
active ingredient may be incorporated in an acceptable vehicle containing 
for example, a polyol or dimethyl suphoxide which may also act as a skin 
penetrant. 
The effect of the active ingredient is produced by the aforementioned 
microbial enzymes acting to split the constituents of the ester and so 
hydrolyse the ester back into the aromatic acid and the phenol or aromatic 
alcohol. On a skin surface, such as in deodorant applications, this action 
occurs almost immediately but, where skin penetration is involved, as in 
most dermatological applications, the action is progressive. 
The above term `anti-microbial action` means an action which inhibits 
microbial growth, rather than one which eliminates microbial growth 
completely as can be achieved by a microbicide. In such skin-surface and 
skin-penetrating applications, the esterases produced by the 
micro-organism hydrolyse a portion of the active ingredient and, in so 
doing, inhibit the action of the esterase and further growth of the 
micro-organism. After a period of time, the micro-organism may resume its 
metabolic activity and the above-mentioned process is repeated, and 
repetition will occur until the active ingredient is used up.

DESCRIPTION OF THE INVENTION 
According to the present invention we have now found that phenyl or benzyl 
benzoates of the following general formula (I) 
##STR1## 
wherein R represents a hydrogen or halogen atom or a C.sub.1-4 alkyl, 
methoxy, ethoxy or acyloxy group, p is 0 or 1, and x, y and z are each 0 
or an integer of from 1 to 5, are particularly effective as inhibitors of 
esterase-producing micro-organisms. 
Benzoates of the formula (I) are hydrolysed by esterases to produce three 
mononuclear benzene compounds which between them bear at least two 
hydroxyl substituents and two carboxyl substituents. (The hydrolysis of 
benzyl 4-benzoyloxybenzoate and phenyl 2-benzoyloxybenzoate are shown in 
FIGS. 1 and 2, respectively, of the accompanying drawings.) The hydrolysis 
products are thus highly active in performing the previously-mentioned 
anti-microbial and pH-lowering functions, but not to the extent of being 
bacteriocidal as are most conventional deodorants: not only is the 
elimination of cutaneous flora medically undesirable, but the use of some 
conventional deodorants has caused adverse reactions. Moreover, the 
benzoates (I) afford the further advantages of being completely odourless 
and non-irritant. 
Preferred benzoates (I) are those in which p equals 0 or 1; and x, y and z 
are each zero. Such compounds have the advantage of being easy to 
manufacture from cheap starting materials, although the 
4-benzoyloxybenzoates are preferred from the point of view of easy 
purification, being solids and therefore easy to crystallize. Such 
unsubstituted benzoates (I) have the further advantage of being generally 
more soluble than compounds having substituted nuclei. 
Although the presence of hydroxyl substituents on the nuclei of the parent 
molecule increases its solubility in water, such hydroxyl substitution can 
lead to increased toxic effects, and is therefore generally less 
preferred: and although the presence of halogen substituents increases the 
activity of the hydrolysis products, such halogen substitution can again 
lead to increased toxic effects and is also less preferred. As the 
2-benzoyloxybenzoates of the general formula (I) yield a salicylic acid 
among their hydrolysis products, which can have an irritant effect, and 
the presence of a group at the 2-position can give rise to instability 
because of steric hindrance, and as the 3-benzoyloxybenzoates are more 
expensive to produce, the 4-benzoyloxybenzoates are generally preferred. 
The primary use of benzoates (I) is as the active ingredient in a personal 
deodorant composition. For such an application the benzoate is first 
dissolved in, preferably, a perfume to form a perfume concentrate 
containing 5% to 50%, preferably say 10% benzoate, which is then added in 
an amount of about 1% to 2% to a suitable vehicle, for example ethyl 
alcohol, to form a deodorant composition in which the active ingredient is 
present in an amount of 0.1% to 0.2% and which is suitable for application 
by aerosol or mechanical spray. 
A further use of the benzoates (1) is in the treatment of dandruff and acne 
where decomposition of the skin fats causes irritation. To prepare a skin 
lotion, for the treatment of acne, between 0.5% and 20%, and preferably 
about 5%, of active ingredient is incorporated in a vehicle which may be 
composed of dimethyl sulphoxide, polyol, ethanol and water in suitable 
proportions. Anti-inflammatory substances such as hydrocortisone or 
glycyrrhetic acid and healing agents such as allantoin, may also be 
incorporated in the end product. 
As a scalp lotion for the treatment of dandruff, active ingredient within 
the above percentages is incorporated in a hydro-alcoholic vehicle, using 
solubilising agents as necessary. 
As a powder for the treatment of tinea pedis and foot odour, active 
ingredient (if liquid), within the above percentages, is adsorbed onto 
amorphous silica powder or light magnesium carbonate which is then mixed 
with say 50% talcum, starch or other suitable powder. If the active 
ingredient is solid, usually crystalline, the crystals are finely ground, 
for example in a microniser, and then mixed with say 50% talcum, starch or 
other suitable powder. 
Suitable perfume compositions may also be incorporated in the scalp/skin 
lotions and foot powders. 
The skin and scalp lotions may be supplied in sprinkler bottles for 
application to the scalp or the affected skin area in the form of liquid 
droplets which are massaged into the scalp/skin. Alternatively, the lotion 
may be applied by means of a pad or compress which is pre-impregnated and 
supplied in a sealed package; the pad is partially exposed and then 
applied to an affected skin area, at least once per day. In further 
alternative forms, the inhibitors for use in treating the scalp or skin 
may comprise ointments, gels, creams, lotions, sprays or powders. 
The inhibitors for foot treatment are preferably in powder form, as 
indicated above, but might also be supplied as liquids or in sprays etc. 
An example of the preparation of what is believed to be the most soluble 
and active ingredient for use in the above compositions will now be 
described. 
EXAMPLE 
Preparation of Benzyl-4-benzoyloxybenzoate 
0.5 mol (114 g) of benzyl 4-hydroxybenzoate was dissolved in 500 mol of 5% 
sodium hydroxide solution. 0.51 mol (72 g) of benzoyl-chloride was then 
added with rapid stirring. The reaction began almost immediately 
accompanied by a rise in temperature. 
The reaction was completed in about 30 minutes when the odour of benzoyl 
chloride had disappeared and benzyl 4-benzoyloxybenzoate had precipitated 
as a fine powder or dense oil. The reaction mixture was then cooled and 
the aqueous liquid decanted. The reaction product was washed with water 
until the washings were neutral, and then filtered. Finally the crude 
product was recrystallized from hot 80% ethanol. 
The reaction scheme may be represented as follows: 
##STR2## 
It will be appreciated that all the substituted products may be prepared 
by this general method.