Halogenophenyl glyceride esters for use in the prophylaxis and/or therapy of acne vulgaris

The invention concerns novel glyceride esters of anti-bacterial halogenated phenols having the formula I in which Ra and Rb are independently (3-20C)alkyl or (3-20C)alkenyl; Rc and Rd are independently chloro or bromo; Re is hydrogen, chloro or bromo; and A is (1-6C)alkylene optionally bearing one or two (1-4C)alkyl substituents. The esters are of use in the prophylaxis and/or therapy of acne vulgaris. Pharmaceutical compositions for topical administration and processes for the manufacture of the esters are also provided.

This invention concerns novel halogenophenyl glyceride esters and, more 
particularly, novel glyceride esters of anti-bacterial halogenophenols, 
which esters are useful in the topical therapy and/or prophylaxis of acne 
vulgaris and related infected skin conditions. 
Acne vulgaris is a multi-factorial disease which appears during puberty and 
affects a high proportion of mankind between the ages of 12 and 25. A 
major contributory factor is the presence of bacteria within the 
pilosebaceous follicle coupled with hormone induced hyperactivity of the 
sebaceous glands. The principal bacterium involved is Propionibacterium 
acnes, which bacterium is to be found towards the base of pilosebaceous 
follicles and contributes to the inflammatory component of acne, for 
example by the lipase catalysed production of free fatty acids from 
sebaceous secretions. It is possible to treat acne vulgaris by systemic 
administration of potent antibiotics such as tetracycline. However, the 
use of potent antibiotics for non life-threatening conditions such as acne 
vulgaris is in general undesirable because of induction of unnecessary 
bacterial resistance. There is thus a continuing need for a simple 
alternative form of therapy. 
It is known that various halogenophenols are valuable anti-bacterial and 
disinfectant agents (UK patent specification Ser. No. 1038185). Several of 
these agents have been used as antibacterials in a variety of skin 
cleansing and disinfecting preparations. At least one such agent, 
2,4,4'-trichloro-2'-hydroxydiphenyl ether (triclosan), has been clinically 
evaluated in the topical treatment of acne vulgaris (J. Int. Med. Res., 
1978, 6, 72-77). However, a major problem in any topical anti-bacterial 
treatment of acne is to ensure that the anti-bacterial agent penetrates 
into, and persists, in the pilosebaceous follicles containing the P.acnes. 
In addition, it is generally desirable to minimise the exposure of other 
parts of the skin to the anti-bacterial agent. In this way systemic 
absorption may be reduced. The sebaceous secretion contains various lipid 
components and improved penetration by an anti-acne agent might be 
expected to result from an increase in its lipophilicity. Improved 
persistence might be expected through progressive release of an 
anti-bacterial agent specifically within the pilosebaceous follicles. We 
have now discovered various novel, lipophilic glyceride esters of 
anti-bacterial halogenophenols, which are, unexpectedly, relatively stable 
towards hydrolysis by esterases, but labile towards hydrolysis by lipases. 
These esters are expected to be of value in the treatment and/or 
prophylaxis of acne vulgaris by virtue of progressive, lipase catalysed 
release of the anti-bacterial halogenophenol within the pilosebaceous 
follicle in the presence of P.acnes. 
According to the invention there is provided an ester of the formula I 
wherein Ra and Rb are independently (3-20C)alkyl or (3-20C)alkenyl; Rc and 
Rd are independently chloro or bromo; Re is hydrogen, chloro or bromo; and 
A is (1-6C)alkylene optionally bearing one or two (1-4C)alkyl 
substituents. 
In this specification the terms Ra, Rb, et cetera, are used to depict 
generic radicals and have no other significance. Formula drawings 
corresponding to the Roman numerals are attached hereafter. 
A particular value for Ra or Rb when it is (3-20C)alkyl is, for example, 
propyl, butyl, pentyl, hexyl, heptyl, undecyl, pentadecyl or heptadecyl; 
and when it is (3-20C)alkenyl is, for example 8-heptadecenyl or 
8,11-heptadecadienyl. 
A particular value for A is, for example, methylene, ethylene, trimethylene 
or tetramethylene, optionally bearing one or two methyl or ethyl 
substituents. 
A preferred group of esters comprises those compounds of formula I wherein 
Rc, Rd and Re are all chloro; Ra and Rb are both (3-15C)alkyl; and A has 
the meanings defined above. 
A further preferred group of esters comprises those compounds of formula I 
wherein Rc, Rd and Re are all chloro, Ra and Rb are both pentadecyl and A 
is trimethylene optionally bearing 1 or 2 methyl substituents. 
Specific esters according to the invention are described in the 
accompanying Examples. However, of these, the following are of special 
interest:-2-butyryloxy-1-(butyryloxymethyl)ethyl 
5-chloro-2-(2,4-dichlorophenoxy)phenyl glutarate, 
5-chloro-2-(2,4-dichlorophenoxy)phenyl 
2-octanoyloxy-1(octanoyloxymethyl)ethyl glutarate and 
5-chloro-2-(2,4-dichlorophenoxy)phenyl 
2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethyl glutarate. 
The esters of formula I may be obtained by conventional procedure of 
organic chemistry well known in the art. The invention further provides a 
process for the manufacture of an ester of formula I by such a 
conventional procedure, for example as follows, wherein Ra, Rb, Rc, Rd, Re 
and A have the meanings defined above:- 
(a), reacting an acid of the formula II, or a reactive derivative thereof, 
with a glyceride of the formula III; 
(b), reacting an acid of the formula IV or a reactive derivative thereof, 
with a phenol of the formula V; or 
(c), reacting an acid of the formula VI, wherein Rf has the same meaning as 
Ra or Rb, or a reactive derivative therof, with an alcohol of the formula 
VII, wherein Rg is hydrogen or a group of the formula Ra.CO-- or Rb.CO--. 
It will be appreciated that procedures (a)-(c) are all general 
esterification processes well known in the art, which may be performed 
under generally similar reaction conditions. 
Particularly suitable reactive derivatives for acids of formula II or IV 
are, for example, acid halides (especially acid chlorides or bromides), 
acid azides, acid anhydrides or mixed anhydrides especially with formic 
acid or trifluoroacetic acid. Similarly, particularly suitable reactive 
derivatives for acids of formula VI are, for example, acid halides such as 
acid chlorides or bromides, and acid anhydrides. 
The esterification is generally carried out at a temperature in the range, 
for example, 0.degree.-100.degree. C.; and conveniently at or near ambient 
temperature. A suitable solvent or diluent such as chloroform, 
dichloromethane, 1,2-dimethoxyethane, tetrahydrofuran or diethyl ether is 
preferably employed. 
A suitable base such as pyridine, 2,6-lutidine or triethylamine may also be 
present and is preferred when an acid halide is used as a reactant. 
Alternatively, when a reactive derivative of an acid of formula II, IV or 
VI is employed, the alcoholic or phenolic component of formula III, V or 
VII may be conveniently used in the form of its salt, such as its sodium, 
potasium, thallium or lithium salt, which may be preformed in situ by 
conventional procedures prior to addition of the remaining reagents. 
When the free acids of formula II, IV or VI are employed, a condensing 
agent, for example dicyclohexylcarbodiimide or a mixture of 
triphenylphosphine and a lower alkyl ester of azodicarboxylic acid, is 
used in a suitable solvent or diluent. 
The starting materials of the formula II may be obtained by acylation of a 
phenol of formula V with a diacid of the formula: HO.sub.2 C.A.CO.sub.2 H, 
or an anhydride or acid chloride thereof, using conventional procedures. 
The glycerides of formula III may be obtained by standard procedures, for 
example as described by Bentley and McCrae (J. Org. Chem., 1970, 35, 
2082). The acids of formula IV may be made by acylation of a glyceride of 
formula III with a diacid of the formula: HO.sub.2 C.A.CO.sub.2 H, or an 
anhydride or acid chloride thereof, using conventional procedures. The 
alcohols of formula VII may be made, for example, using an analogous 
procedure to (a) above but using a glycerol derivative of the formula VIII 
in place of the glyceride III and then removing the protecting benzylidene 
group by a conventional procedure to give the alcohol VII in which Rg is 
hydrogen. The alcohol VII in which Rg is Ra.CO-- or Rb.CO-- may then be 
obtained by careful reaction with one molecular equivalent of the acid VI, 
or a reactive derivative thereof. 
A further convenient procedure (d) for the production of compounds of 
formula I involves the reaction of a phenol V with a reactive derivative 
of an acid of the formula: HO.sub.2 C.A.CO.sub.2 H, and a glyceride III. 
This procedure is a combination of procedures (a) and (b). The reactive 
derivative is, for example, conveniently the acid chloride or bromide, and 
the procedure is carried out under generally similar conditions to those 
for (a) and (b) described above. 
It will be appreciated that certain esters of formula I possess one or more 
asymmetrically substituted carbon atoms, for example when A is 
(1-6C)alkylene bearing a single (1-4C)alkyl substituent. Such esters may 
be obtained in racemic and optically active forms. The present invention 
includes esters of formula I in racemic or optically active form 
possessing the above mentioned useful properties, which may be 
demonstrated using the tests described hereinbelow. The preparation of 
optically active forms may be accomplished by standard means, for example 
by synthesis from optically active starting materials. 
As stated above, the compounds of formula I are unexpectedly more readily 
hydrolysed by lipases than by esterases. This difference in hydrolytic 
stability may be demonstrated by a conventional study of the 
anti-bacterial effects [as measured by minimum inhibitory concentration 
(M.i.c.)] of the compounds alone and in the presence of added esterase and 
lipase against the organism Streptococcus faecalis (A02). The results 
obtained for various representative esters of formula I, exemplified 
hereinafter, in comparison with the relevant phenol V, in which 
Rc.dbd.Rd.dbd.Re.dbd.chloro (triclosan), are shown in the Table I below:- 
TABLE I 
______________________________________ 
M.i.c. (.mu.g/ml) against 
Streptococcus faecalis (A02) 
Organism + 1 mg/ml + 1 mg/ml 
+ 1 mg/ml 
Compound* only Esterase A 
Esterase B 
Lipase C 
______________________________________ 
Ester 1 NA NA** NA 6 
Ester 2 NA NA NA 8 
Ester 3 NA NA NA 10 
Ester 4 NA NA NA 13 
Ester 5 NA NA NA 16 
Ester 6 NA NA NA 10 
Ester 7 NA NA NA 15 
Ester 8 NA NA NA 13 
Triclosan 4 8 8 8 
______________________________________ 
*Numbers refer to Examples hereafter. 
**Not Active, M.i.c. &gt;256 .mu.g./ml. 
Esterase A: ex-porcine liver, pH8 optimum. 
Esterase B: ex porcine liver, pH6 optimum. 
Lipase C: ex Candida cylindracae. 
Enzyme preparations available from Sigma London Chemical Co. Ltd., Poole, 
UK 
These results demonstrate the absence of anti-bacterial effects for the 
esters of formula I except in the presence of added lipase which makes 
them specially suitable for use in the therapy and/or prophylaxis of acne 
vulgaris as aforesaid. 
The penetration and improved persistence of esters of formula I in 
pilosebaceous follicles in relation to that of the parent phenol V may be 
demonstrated under laboratory conditions as follows. The inner surface of 
rabbit ears is pretreated with coal tar to produce a precomedo type lesion 
analogous with comedo formation in human acne vulgaris. .sup.14 
C-Radio-labelled samples of the test substances are then applied to three 
areas on the inner surface of the rabbit ear 1,6 and 24 hours prior to 
killing. In general, samples of esters in a suitable formulation (for 
example a hydroalcoholic formulation such as a lotion containing 1% w/w 
ester in a mixture of ethanol, benzyl alcohol and water, 28:30:42 w/w or 
in a cream formulation such as described in Example 17) are applied to one 
ear and samples of the parent phenol V in the same vehicle to the 
contralateral ear. After the animal is killed, each area of application is 
excised, frozen flat and then biopsied. By gently scraping the surface, 
residual vehicle and stratum corneum is removed and then digested for 
estimation of residual radio-activity on the skin surface. Serial frozen 
sections (20 .mu.m) are then cut from the biopsy, mounted on adhesive 
tape, freeze dried and autoradiographs produced. From these 
autoradiographs the relative radioactivity at any depth can be assessed. 
As an illustration, using such a procedure, the ester of formula I 
described in Example 1 hereafter has been found to penetrate to similar 
depths as its parent phenol (triclosan) but to persist at that depth for 
longer than the parent phenol. For example, after both 6 and 24 hours the 
ester described in Example 1 is present deep in the follicles in amounts 
significantly greater than those of triclosan. 
The esters of formula I will be used in the form of various conventional 
formulations suitable for topical administration. According to a further 
feature of the invention there is provided a pharmaceutical composition 
which comprises an ester of formula I as defined hereinbefore together 
with a pharmaceutically acceptable diluent or carrier in a form suitable 
for topical administration, for example in the form of an ointment, gel, 
aqueous or oily solution or suspension, emulsion or aerosol formulation. 
Normally, compositions which are non-greasy are preferred, and 
compositions according to this aspect of the invention will generally 
contain in the range, for example, 0.1-6% w/w and preferably in the range 
1-4% w,/w of an ester of formula I. 
The pharmaceutical compositions may be made by methods well known in the 
art for the production of topical formulations, using conventional, 
pharmaceutically acceptable excipients. 
A particular gel formulation may be prepared by adding a gelling agent, for 
example carboxy-poly-methylene, to a solution of an active ingredient as 
defined above in a suitable organic solvent, for example isopropyl 
alcohol. 
A particular emulsion formulation, for example a cream or a lotion, may be 
prepared by mixing an active ingredient as defined above with a suitable 
conventional emulsifying system and water. 
The pharmaceutical compositions may also conveniently contain one or more 
other conventional excipients, for example a solubilising agent such as 
polyethylene glycol, propylene glycol, diethylene glycol monomethyl or 
monoethyl ether, or benzyl alcohol, and/or a penetration enhancer such as 
dimethyl sulphoxide, 1-dodecyl-hexahydro-2H-azepin-2-one, 
N-methyl-2H-pyrrolidin-2-one or 2H-pyrrolidin-2-one, and/or conventional 
stabilising agents and antioxidants, in order to produce a stable topical 
formulation which results in significant absorption of the active 
ingredient into the pilosebaceous follicles. 
The compositions may also contain one or more other active ingredients 
already known to be of value in the therapy or prophylaxis of acne 
vulgaris. 
When used in the treatment of acne vulgaris it is envisaged that an ester 
of formula I will be administered so that a daily dose in the range 10-100 
.mu.g/cm.sup.2 is applied to the affected area of the skin, given if 
necessary in divided doses. However, it will be appreciated that the total 
daily amount of ester of formula I administered necessarily depends on the 
extent and severity of the condition under treatment. 
The invention will now be illustrated by the following non-limiting 
Examples each of which constitutes a specific embodiment of the invention 
and in which, unless otherwise stated:- 
(i) petroleum ether (b.p. 60.degree.-80.degree. C.) is referred to as 
"petrol 60-80"; 
(ii) evaporations were performed by rotary evaporation in vacuo until all 
volatile solvents were removed; 
(iii) all operations were carried out at ambient temperature, that is in 
the range 18.degree.-27.degree. C.; 
(iv) NMR data relates to protons determined at 60 or 90 MHz and is 
presented in terms of chemical shift (delta values) relative to an 
internal standard of tetramethylsilane using conventional abbreviations 
for description of the absorption signals: s, singlet; d, doublet; t, 
triplet; m, multiplet; br, broad; 
(v) all the esters of formula I had satisfactory elemental microanalyses; 
and 
(vi) yields (where given) are for illustration and are not necessarily the 
maximum attainable:-