GB2401865A - Antibacterial and antifungal glycerol monocarbonates - Google Patents

Abstract

Glycerol mono-carbonates having the formula <EMI ID=1.1 HE=36 WI=51 LX=467 LY=640 TI=CF> <PC>wherein R1 is hydrogen and R2 is hydroxymethyl; or R1 is hydroxymethyl and R2 is hydrogen, and wherein R is selected as follows: (a)R is selected from the group consisting of a branched or unbranched C8-20 alkyl; a branched or unbranched C8-20 alkenyl, preferably a terminally unsaturated alkenyl;a C8-20 alkylaryl; a C8-20 alkenylaryl; a C8-20 alkylarylalkyl; a C8-20 alkenylarylalkyl; a C8-20 alkylarylalkenyl; a C8-20 alkenylarylalkenyl; and (b) R together with the oxygen atom to which it is attached is a radical of a fragrant alcohol; are useful as anti-bacterial or anti-fungal compounds.

Description

30047/GB 1 2401 865 Anti-bacterial and Anti-fungal Compounds The present

invention relates to antibacterial or anti- fungal compounds, their use in consumer products and methods of making same.

As used herein, the term "anti-bacterial" or "anti-fungal" used in connection with a compound of the present invention is intended to refer to a compound of the present invention that displays bacteriostatic or bactericidal, or fungicidal or fungistatic properties, or both, depending on the condition to be prevented or treated and the concentration of compound or compounds employed.

Bacterial or fungal conditions are caused by microorganisms such as bacteria or fungi and may range from body malodour to manifestations of the skin or scalp such as acne, Athlete's foot or dandruff. Body malodour is formed by bacteria such as Staphylococci and Corynebacteria both of which genera belong to the class of gram-positive Eubacteriaceae. A major cause of foot malodour is Brevibacteria. Acne is attributed to Propionibacterium acnes. Dandruff is believed to be caused by the scalpinhabiting yeasts of the genus Malassezia furfur and Malassezia ovalis. Athlete's foot or Tinea pedis is a condition of the feet occuring especially under conditions of enhanced humidity when fungi of the genera Trichophyton and Epidermophytum floccosum colonise the skin between the toes.

Anti-bacterial or anti-fungal agents are used in consumer products to prevent or treat a variety of conditions mentioned above.

30047/GB 2 A principal method by which anti-bacterial or anti-fungal 3 compositions prevent or treat the aforementioned conditions employs active agents that reduce such bacterial or fungal flora on the skin or in the household. However, a problem with many known anti-bacterial agents or anti-fungal agents is that they may affect the entire microbial flora and not just the targeted micro-organism.

Many anti-bacterial or anti-fungal agents have been described as having use in treating one or more of the aforementioned conditions. Triclosan is an anti-bacterial agent that finds use in many products including household and personal care products. However, it being a chlorinated product, its use is questioned by consumer protection i organizations. Further, it has especially high activity; against low odour-forming Staphylococci bacteria, and as such may create favourable conditions in which the more problematic Corynebacteria may thrive.

There have been many disclosures in the art of perfume ingredients that have anti-bacterial or anti-fungal! properties. One such natural fragrance compound is Farnesol. However, the problem with using perfume ingredients as anti-bacterial agents is that to obtain anti-bacterial effects, they must generally be employed at higher levels than one would customarily wish to use in fragrance applications. Further, even if such materials could be used to achieve an anti-bacterial effect at low levels suitable for perfumers, their volatility is often so high that they will only be effective for a short period of time before they evaporate and leave the skin.

30047/GB 3 Non-perfume compounds have been employed as anti-bacterial and anti-fungal agents in household and consumer products 3 including personal care products and products applied to the skin. The use of monolaurin-glycerol and other glycerol esters or glycerol mono-ethers have been described in the art. These materials are non-chlorinated, are non-volatile and are non-perfumes and so are potentially very interesting anti-bacterial agents for the treatment of one or more of the conditions described above. However, because they are non-volatile, they must decompose to non-active and/or volatile materials to avoid a build up of excessive concentrations on the skin upon repeated application and to avoid the possibility of adversely affecting populations of skin microflora.

Applicant has now found a new class of compounds that are i odourless, and that have a reasonable residence time on the; skin of a user, thereby to exert a desirable anti-bacterial or anti-fungal effect, but which decompose within an acceptable time period in order that there is no significant build-up of the compounds over prolonged periods of time and as a result of repeated application. : Therefore the invention provides in one of its aspects a glycerol mono-carbonate according to the formula 0 R2 R. OH 30047/GB 4 wherein R1 is hydrogen and R2 is hydroxymethyl; or R1 is hydroxymethyl and R2 is hydrogen, and wherein R is selected as follows: (a)R is selected from the group consisting of a branched or unbranched C820 alkyl; a branched or unbranched C820 alkenyl, preferably a terminally unsaturated alkenyl; a C820 alkylaryl; a C820 alkenylaryl; a C820 alkylarylalkyl; a C8-20 alkenylarylalkyli a C8-2o alkylarylalkenyl; a C8-20 alkenylarylalkenyl; and (b) R together with the oxygen atom to which it is attached is a radical of a fragrant alcohol.

Preferred are compounds wherein R is an unbranched C1014 alkyl or unbranched C10l4 alkenyl, preferably a terminally unsaturated alkenyl or compounds wherein R is branched C 16 alkyl or branched C10l6 alkenyl, preferably a terminally unsaturated alkenyl.

A preferred compound according to the present invention is selected from the group consisting of Carbonic acid 2,3- dihydroxypropyl ester undec-10-enyl ester, Carbonic acid 2- hydroxy-1-hydroxymethyl-ethyl ester undec-10-enyl ester, Carbonic acid dec-9-enyl ester 2,3-dihydroxypropyl ester, Carbonic acid decyl ester 2,3- dihydroxypropyl ester, Carbonic acid 2,3-dihydroxypropyl ester 3,7-dimethyl-oct-6- enyl ester, Carbonic acid 2,3-dihydroxypropyl ester 3- methyl-5-phenylpentyl ester, Carbonic acid 2-butyl-octyl ester 2,3-dihydroxypropyl ester, Carbonic acid 2,3dihydroxypropyl ester 2-ethyl-hexyl ester, and Carbonic acid 2,3dihydroxypropyl ester octa-2,7-dienyl ester.

30047/GB 5 In another embodiment of the present invention, the residue R together with the carbonate oxygen atom to which it is attached may be the residue of a fragrant alcohol. In such an embodiment, there is the secondary benefit that as the anti-bacterial agent decomposes, one of its degradation products will contribute to an overall pleasant odour impression of a product in which it is employed. Still further, if some of these materials themselves have anti- bacterial or anti-fungal properties, they may contribute to the overall anti-bacterial or anti-fungal effect of the compounds.

Fragrant alcohols may preferably comprise 5 to 30, more preferably 8-20, most preferably 10-16, even more preferably 10-14 carbon atoms.

As fragrant alcohols there may be mentioned amyl alcohol; hexyl alcohol; 2-hexyl alcohol; heptyl alcohol; octyl alcohol; nonyl alcohol; decyl alcohol; undecyl alcohol; lauryl alcohol; myristic alcohol; 3-methyl-but2-en-1-ol; 3-methyl-1-pentanol; cis-3-hexenol; cis-4-hexenol; 3,5,5trimethylhexanol; 3,4,5,6,6-pentamethylheptan-2-ol; citronellol; geraniol; oct-1-en-3-ol; 2,5,7-trimethyl octan-3-ol; 2-cis-3,7-dimethyl-2,6-octadien-1-ol; 6-ethyl- 3-methyl-5-octen-1-ol; 3,7-dimethyl-octa-3,6-dienol; 3,7- dimethyloctanol; 7-methoxy-3,7-dimethyl-octan-2-ol; cis-6- nonenol; 5-ethyl-2-nonanol; 6,8-dimethyl-2-nonanol; 2,2,8- trimethyl-7(8)-nonen-3-ol; nona-2,6-dien-1-ol; 4-methyl-3- decen-5-ol; dec-9-en-1-ol; benzylalcohol; 2-methyl- undecanol; 10-undecen-1-ol; 1-phenyl ethanol; 2-phenyl- ethanol; 2-methyl-3-phenyl-3-propenol; 2-phenyl propanol; 3-phenyl propanol; 4-phenyl-2-butanol; 2-methyl-5-phenyl 30047/GB 6 pentanol; 2-methyl-4-phenyl-pentanol; 3-methyl-5-phenyl pentanol; 2-(2-methylphenyl)ethanol; 4-(1- - methylethyl)benzene methanol; 4-(4-hydroxyphenyl)butan-2 ol; 2-phenoxy ethanol; 4-(1-methylethyl)-2-hydroxy-1-methyl benzene; 2-methoxy-4-methyl- phenol; 4-methyl-phenol; anisic alcohol; p-tolyl alcohol; cinnamic alcohol; vanillin; ethyl vanillin; eugenol; isoeugenol; thymol; anethol; decahydro 2-naphthalenol; borneol; cedrenol; farnesol; fenchyl alcohol; menthol; 3, 7,11-trimethyl-2,6,10-dodecatrien-1-ol; alpha-ionol; tetrahydro-ionol; 2(1,1-dimethylethyl) cyclohexanol; 3-(1,1-dimethylethyl)-cyclohexanol; 4(1,1 dimethylethyl)cyclohexanol; 4-isopropylcyclohexanol; 6,6 dimethylbicyclo[3.3.1]hept-2-ene-2-ethanol; 6,6-dimethyl bicyclo[3.1.1]hept-2-enemethanol; p-menth-8-en-3-ol; 3,3,5-trimethyl-cyclohexanol; 2,4,6-trimethyl-3- - cyclohexenyl-methanol; 4-(1-methylethyl)-cyclohexyl methanol; 4-(1,1- dimethylethyl)cyclohexanol; 2-(1,1 dimethylethyl)cyclohexanol; 2,2,6- trimethyl-alpha propylcyclohexane-propanol; 5-(2,2,3-trimethyl-3-cyclo- pentenyl)-3-methylpentan-2-ol; 3-methyl-5-(2,2,3 trimethylcyclopent-3-en1-yl)pent-4-en-2-ol; 2-ethyl-4 (2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol; 4(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexanol; 2-(2- methylpropyl)-4-hydroxy-4-methyl-tetrahydropyran; 2 cyclohexylpropanol; 2(1,1-dimethylethyl)-4-methyl cyclohexanol; 1-(2-tert-butyl-cyclohexyloxy)2-butanol; 1 (4-isoporpyl-cyclohexyl)ethanol; 1-(4-hydroxyphenyl)butan 3-one; 2,6-dimethyl-oct-7-en-2-ol; 2,6-dimethyl-heptan-2 ol; and 3,7dimethyl-octa-1,6-dien-3-ol.

If R is a C820 alkylaryl, or a C820 alkenylaryl, the aryl group may be, for example, a phenyl.

30047/GB 7 If R is a C820 alkylarylalkyl, or a C820 alkenylarylalkyl, the arylalkyl group may be, for example, a C1-C4 If R is a C820 alkylarylalkenyl or a C820 alkenylarylalkenyl the arylalkenyl group may be, for example, a C2-C4 alkenyl-substituted phenyl.

A compound according to the present invention exerts good anti-microbial or anti-fungal activity when used in consumer products and applied in the household or on the human body.

Compounds of the present invention exert an improved or - comparable anti-bacterial or anti-fungal effect compared with known glycerol esters, such as monolaurin-glycerol, known glycerol ethers, or known fragrance oils. In tests, - the anti-bacterial Minimum Inhibitory Concentration (MIC) - of the compounds may range from 0.008 to greater than 0.5% (weight/volume) depending on the micro-organism treated.

These values, including the values for many of the common bacteria, and in particular the Corynebacteria, compare - favourably with known glycerol mono-esters or mono-ethers, and a known antibacterial fragrance compound, Farnesol.

Further details as to how the MIC test data are generated are provided in Example 11 below.

Compounds of the present invention perform favourably in comparative anti-fungal testing with known glycerol mono- esters or mono-ethers and other commercially available anti-fungal agents. The MIC of the compound typically 30047/GB 8 varies from 0.002 to greater than 0.25% (weight/volume) depending on the type of skin fungi tested against.

As stated hereinabove, the suitability of compounds of the present invention as anti-bacterial agents or anti-fungal agents is not simply a matter of their efficacy, they must also be capable of establishing a sufficient residency time on human skin or scalp to exert their effect, and thereafter degrade to inactive and/or volatile components.

Applicant has found that the compounds of the present invention degrade in aqueous media at a desirable rate. For example, 4 hours after application, typically about 50% of the applied compound decomposes, whereas at 24 hours typically up to 99% of the compound decomposes. Thus, degradation is sufficiently slow to exert a long-lasting anti-bacterial or anti-fungal effect. Furthermore, upon degradation, the compounds of the present invention degrade to produce inert degradation products, that is glycerol, an alcohol and carbon dioxide. This is in contrast to the glycerol esters which degrade to fatty acids (lauric acid in the case of monolaurin-glycerol), which are often skin irritants.

Compounds of the present invention may be formed starting from an alcohol R-OH, wherein R is as defined above. Such alcohols are either commonly available or they may be formed from easily-accessible starting materials. The alcohol may be converted to its corresponding chloroformate using phosgene (commercially available as a 20%w/w solution in toluene) in a manner known per se, and the resultant chloroformate may be reacted with DL-(+)-1,2- isopropylideneglycerol or cis-1,3-benzylidene-glycerol to 30047/GB 9 give the 1-, or 2-carbonate respectively. The compounds may then be de- protected by trans-acetalisation with methoxyethanol/boric acid to give the glycerol mono- carbonates of the present invention. Further details of the preparative methods are disclosed in the Examples hereinbelow.

The present invention provides in another of its aspects the use of at least one compound as hereinabove described as an active agent in compositions for the prevention or treatment of bacterial or fungal conditions. The amount of a compound employed in such compositions will depend upon the nature of the product and the condition to be treated.

However, in the case of products that are applied to and left on the skin, it is preferred that a compound or mixtures of compounds be present in said compositions in an amount of about 0.1 to about 1.0% by weight, preferably about 0.1 to 0.5% by weight. If a compound or a mixture of compounds is to be used in a composition intended to be applied to, and subsequently rinsed off, the skin or scalp, e.g. a shampoo composition for the treatment of dandruff, then it is preferred to use the compound or mixture of compounds in higher amount, e.g. from about 1.0 to 3.0% by weight.

In all the above compositions, the compound or mixtures thereof may be used as the sole active agent, or it may be used in conjunction with other active agents such as Triclosan (CAS 3380-34-5) or other commercially available anti-bacterial or anti-fungal agents, or with known fragrance oils having anti-bacterial or anti-fungal properties.

30047/GB 10 Having regard to the nature of the anti-bacterial or antifungal product, compounds of the present invention may also be combined with other excipients commonly employed in consumer products such as household products and products for use on the human body. The exact nature of the excipients will depend on the nature of the product; useful selections may be found in << CTFA Cosmetic Ingredient Handbook >>, J.M. Nikitakis (ad.), 1st ea., The Cosmetic, Toiletry and Fragrance Association, Inc., Washington, 1988, which is hereby incorporated by reference. In general excipients may include, e.g. solvents, surfactants, colorants, opacifiers, buffers, antioxidants, vitamins, emulsifiers, W absorbers and silicones. All products can also be buffered to the desired pH using commonly available excipients in a known manner.

There now follows a series of non-limiting examples that serve to illustrate the invention.

Example 1: General procedure for the synthesis of glycerol monocarbonates.

1st step: To a mechanically stirred mixture of phoagene (500 ml of a solution in toluene, 20% w/w, 0.9 mol), cooled to 5 C in an ice-water bath, is added dropwise an alcohol R-OH (0.45 mol) within 1 h. The temperature is kept between and 15 C with cooling. The mixture is allowed to warm to room temperature and stirring is continued for 3 h. Nitrogen is bubbled through the mixture for 16 h in order to remove the excess phosgene. The solid is filtered off 30047/GB 11 and washed with a little toluene. The filtrate is concentrated to a volume of approx. 200 ml.

2nd step: A mixture of either DL-(+)-1,2-isopropylidene- glycerol or cis-1,3-benzylidene-glycerol (0.4 mol)with 4- (dimethylamino)pyridine (DMAP, 4.9 g, 0.04 mol. 0.1 egiv.) and pyridine (80 g, 1 mol. 2.5 equiv.) in toluene (800 ml) is cooled to 5 C with an ice-water bath and the previously-prepared filtrate containing the crude chloroformate (<0.45 mol) is added within 1 h, keeping the temperature of the reaction mixture between 5 and 8 C. The resulting off-white suspension is stirred continuously at 5 C for a further 2 h, allowed to warm to room temperature and stirring continued for a further 3 h, after which the reaction is usually complete. The course of the reaction is monitored by TLC, which shows the completion of the reaction. The mixture is poured into aqueous hydrochloric acid (5%, 1.5 l). This is extracted with tert.-butyl methyl ether (3 x 400 ml) and the organic phases are washed with aqueous sodium hydrogencarbonate (sat., 400 ml), water (400 ml) and brine (400 ml). The combined organic layers are dried over sodium sulfate and concentrated in vacuo to give the crude ace/al-protected glycerol mono-carbonate.

If the alcohol R-OH is an allylic alcohol, the 1st and 2nd step as described above is modified as follows: the chloroformate of DL-(-1,2-isopropylidene-glycerol or cis- 1,3-benzylidene-glycerol is prepared, and the chloroformate is then reacted with the allylic alcohol R-OH.

3rd step: A mixture of the crude ace/al-protected glycerol mono-carbonate and boric acid (248 g, 4 mol. 10 equiv.) in 2-methoxyethanol (750 ml) is heated at 100 C (oil bath) 30047/GB 12 until the reaction is complete, which usually occurs after about 2.5 h and is tested by TLC. The mixture is poured into water (1 l) and extracted with tert.-butyl methyl ether (3 x 400 ml). The organic phases are washed with aqueous sodium hydrogencarbonate (sat., 400 ml), water (400 ml) and brine (400 ml). The combined organic layers are dried over sodium sulfate and concentrated in vacuo (O. 05 mbar, to constant weight) to afford the desired glycerol mono-carbonate as a colourless oil in an overall yield of 80-90%. Schematically, this synthesis is shown below: Scheme 1 Lo

POOH

DL-1,2-isopropylidene-glycerol If H3BO3 OH pyrdine, DMAP cat. Outdo 0MeOCH2CH2OH HOOP. O::OR 1, o 1 0 COCK, K2CO3 Cl: On toluene ó R (2nd step) (3rd step) ( 1 st step) O o} o cis-1,3-benzylidene-glycerol OJ4O, H3BO3,R pyridne, DMAP cat. l MeOCH2CH2OH O O 1 ' HOOH Ph

Examples 2-10

The compounds of Examples 2 through 8 are formed according to the general synthesis described in Example 1 2.

30047/GB 13 OH; HOOrO o Carbonic acid 2,3-dihydroxy-propyl ester undec-10enyl ester H-NMR (400 MHz, CDCl3, coupling constants in Hz): 1.22 1.41 (12H, m, 6 x CH2); 1.67 (2H, aft, J 7, 7, CH2); 2.03 (2H, q, J 7, CH2CH=); 2.6 (2H, br m, 2 x OH); 3.63 (1H, dd, J 12, 6, OCHH) ; 3.72 (2H, dd, J 12, 4, OCHH); 3.93-4.00 (1H, m, CH); 4.09-4.25 (4H, m, 2 x OCH2); 4.89-5.03 (2H, m, =CH2); 5.75-5.88 (1H, m, =CH).

IR (vmax, cm1, ATR): 3387brw, 2925m, 2855w, 1745s, 1259s.

MS [m/z (EI)]: 289 (M+H+, 3%), 152 (35), 137 (34), 119 (36), 110 (50), 97 (76), 82 (87), 68 (67), 55 (100). 3. )040

Carbonic acid 2-hydroxy-1-hydroxymethyl-ethyl ester undec 10-enyl ester H-NMR (400 MHz, CDCl3, coupling constants in Hz): 1.24 1.41 (12H, m, 6 x CH2); 1.66 (2H, aft, J 7, 7, CH2); 2.03 (2H, q, J 7, CH2CH=); 2.55 (2H, br m, 2 x OH); 3.82-3.92 (4H, m, 2 x OCH2); 4.14 (2H, t, 3 7, OCH2); 4.78 (1H, aft, J 4.5, 4.5, CH); 4.91-5.03 (2H, m, =CH2); 5.75-5.88 (1H, m, =CH).

IR (vmax' cm1, ATR): 3372brw, 2925m, 2854w, 1744s, 1259s.

30047/GB 14 MS [m/z (E1)]: 289 (M+H+, 2%), 152 (20), 137 (18), llD (21), 110 (34), 96 (58), 82 (73), 69 (63), 55 (100). 4.

OH

HO l:,O:rO, Carbonic acid dec-9-enyl ester 2,3-dihydroxy-propyl ester H-NMR (400 MHz, CDCl3, coupling constants in Hz): 1.23- 1.42 (1OH, m, 5 x CH2); 1.67 (2H, aft, J 7, 7, CH2); 2.03 (2H, q, J 7, CH2CH=); 2.2 (1H, br m, OH); 2.7 (1H, br m, OH); 3.64 (1H, dd, J 12, 6, OCHH); 3.73 (1H, dd, J 12, 4, OCHH); 3.94-4.01 (1H, m, CH); 4.10-4.27 (4H, m, 2 x OCH2); 4.90-5.02 (2H, m, =CH2); 5.74-5.87 (1H, m, =CH).

IR (vmax, cm1, ATR): 3400brw, 2926m, 2855w, 1746s, 1253s.

MS [m/z (El)]: 275 (M+H+, 3%), 138 (39), 119 (34), 109 (40), 96 (79), 83 (98), 68 (62), 55 (100). 5.

OH

HO'OrO, Carbonic acid decyl ester 2,3-dihydroxy-propyl ester H-NMR (400 MHz, CDCl3, coupling constants in Hz): 0.88 (3H, t, J 6.5, CH3); 1.22-1.41 (14H, m, 7 x CH2); 1.67 (2H, aft, J 7, 6.5, CH2); 2.5 (1H, br m, OH); 3.0 (1H, br m, OH); 3.62 (1H, dd, J 11.5, 5.5, OCHH); 3.73 (2H, dd, J 11.5, 4, OCHH); 3.94-4. 01 (1H, m, CH); 4.10-4.27 (4H, m, 2 x OCH2).

30047/GB 15 IR (vmax' cm1, ATR): 3388brw, 2924m, 2854w, 1747s, 1259s.

MS [m/z (APCI)]: 294 (M+NH4+, 88%), 277 (M+H+, 100).

OH

HOJ - 'O:rO ' Carbonic acid 2,3-dihydroxy-propyl ester 3,7-dimethyl-oct6-enyl ester H-NMR (400 MHz, CDCl3, coupling constants in Hz): 0.92 (3H, d, J 6.5, CH3); 1.12-1.24 (1H, m, CHH); 1.28-1.40 (1H, m, CHH); 1.42- 1.56 (H. m, CHCH3); 1.50-1.64 (H. m, CHH); 1.60 (3H, s, =CCH3); 1.66-1.78 (H. m, CHH); 1.68 (3H, s, =CCH3); 1.90-2.08 (2H, m, CH2CH=); 2.6 (2H, br m, 2 x OH); 3.63 (1H, dd, 11, 5.5, OCH); 3.73 (2H, dd, J 11, 4, OCHH); 3.94-4.01 (1H, m, CH); 4.14-4.25 (4H, m, 2 x OCH2); 5.00 (1H, t, J 7, =CH).

IR (vmax, cm1, ATR): 3381brw, 2914m, 1746s, 1260s.

NS [m/z (APCI)]: 292 (M+NH4+, 100%), 275 (M+H+, 60).

HO:,Oj:O,, (3 Carbonic acid 2,3-dihydroxy-propyl ester 3-methyl-5-phenylpentyl ester H-NMR (400 MHz, CDCl3, coupling constants in Hz): 0.97 (3H, d, J 6.5, CH3); 1.43-1.59 (2H, m, CH2); 1.55-1.70 (2H, m, CH2); 1.72- 1.81 (H. m, CHCH3); 2.52-2.71 (2H, m, PhCH2); 30047/GB 16 2.9 (1H, m, OH); 3.3 (H. m, OH); 3.59 (1H, dd, J 11.5, 5.5, OCHH); 3.73 (2H, dd, J 11.5, 4, OCHH); 3.90-4.00 (1H, m, CH); 7.15-7.20 (3H, m, Ph); 7.24-7.29 (2H, m, Ph).

IR (vmax, cm1, ATR): 3375brw, 2926m, 1744s, 1260s.

MS [m/z (APCI)]: 314 (M+NH4+, 221), 297 (M+H+, 100). 8. OH /

HO,O:rO o Carbonic acid 2-butyl-octyl ester 2,3-dihydroxy-propyl ester HNMR (400 MHz, CDCl3, coupling constants in Hz): 0.87 (3H, t, J 6.5, CH3); 0.89 (3H, t, J 6.5, CH3); 1.22-1.38 (16H, m, 8 x CH2); 1.62-1.69 (1H, m, CH); 2.11 (1H, br t, OH); 2.60 (1H, br d, OH); 3.63 (lH, dd, J 11.5, 5.5, OCHH); 3.72 (2H, dd, J 11.5, 4, OCHH); 3.93-4.00 (1H, m, CH); 4.10-4.27 (4H, m, 2 x OCHz).

IR (vmax' cml, ATR): 3392brw, 2956m, 2927m, 2858m, 1746s, 1459w, 1400w, 1252s.

MS [m/z (APCI)]: 322 (M+NH4+, 16%), 305 (M+H+, 100). 9.

HO Oj:O o Carbonic acid 2,3-dihydroxy-propyl ester 2-ethyl-hexyl ester 30047/GB 17 H-NMR (400 MHz, CDCl3, coupling constants in Hz): 0.90 (6H, t, J 6.5, 2 x CH3); 1.24-1.43 (8H, m, 4 x CH2); 1.56- 1.64 (1H, m, CH); 2.5 (2H, br m, 2 x OH); 3.61 (1H, dd, J 11.5, 5.5, OCHH); 3.71 (2H, dd, J 11.5, 4, OCHH); 3.94-4.00 (1H, m, CH); 4.02-4.10 (2H, m, OCH2); 4.14-4.22 (2H, m, OCH2).

IR (vmax, cm1, ATR): 3381brw, 2959m, 2930m, 2874w, 1745s, 1460w, 1400m, 1249s.

MS [m/z (APCI)]: 266 (M+NH4+, 23%), 249 (M+H+, 100). 10.

OH E/Z HO,OtO o Carbonic acid 2,3-dihydroxy-propyl ester octa-2(E/Z),7dienyl ester H-NMR (400 MHz, CDCl3, coupling constants in Hz): 1.45- 1.53 (2H, m, CH2); 2.02-2.17 (4H, m, 2 x =CHCH2); 2.5 (2H, br m, 2 x OH); 3.62 (1H, dd, J 12, 6, OCHH); 3.72 (1H, dd, J 12, 4, OCHH); 3.92-3.98 (1H, m, CH); 4.18-4.27 (2H, m, OCH2); 4.59 (2H, d, J 7, OCH2CH=); 4.94-5.04 (2H, d, =CH2); 5.55-5.87 (2H, m, CH=CH).

IR (vmax' cm1, ATR): 3377brw, 2930m, 2862w, 1745s, 1641w, 1455m, 1395m, 1248s.

MS [m/z (EI)]: 213 (M±CH2OH, <11), 170 (3), 137 (5), 119 (10), 109 (72), 93 (70), 79 (62), 67 (100), 54 (78).

30047/GB 18

Example 11

The anti-bacterial effects of the compounds of the present invention are compared with known anti-bacterial agents against human skin bacteria. The results are shown below in

Table 1.

The different axilla bacteria are isolated from the human axilla according to techniques known in the art and according to standard microbiological practice. They are taxonomically identified by cell morphology, gram-reaction and biochemical tests included in the Api coryne test kit (BioMerieux, France). Strain Staphylococcus epidermidis Ax25 is identified by fatty acid methyl ester analysis (FAME; German type strain collection DSMZ, Germany).

Brevibacterium epidermidis DSM 9586; Propionibacterium acne DSM 1897, Escherichia cold DSM 682, Staphylococcus aureus DSM 799, Pseudomonas aeruginosa DSM 939 and Corynebacterium xerosis DSM 20170 are obtained from the German type strain collection.

The strains are maintained on Tryptic soy broth plates, this standard medium being modified with 5 g per Litre of Tween 80. Plates are incubated at 36 C for a period 48 hours. The bacteria are then swabbed from the plates and suspended in 4 ml of Muller-Hinton broth modified with 100 mg of Tweed 80 per Litre (MH-Tween) and incubated again at 36 C for 16 hours. Following incubation the bacterial suspensions are diluted in MH-Tween to obtain a final cell density of 107 colony-forming units per ml. To different columns of a microtiter plate these diluted suspensions of the different test organisms are distributed, 100 pl per well. The test compounds are dissolved in dimethylsulfoxide 30047/GB 19 (DMSO) at various test concentrations and five Al of these different DMSO solutions are added to the different wells of the test plates. The plates are covered with plastic films and incubated for 24 h at 36 C with shaking at 250 rpm. The turbidity developing in the microtiter plates is then examined after 24 h to determine microbial growth. The minimal concentration of test compounds inhibiting the growth of an organism by at least 80% is determined as the minimal inhibitory concentration (MIC). The tests with Propionibacterium acne are conducted under anaerobic conditions and evaluation is done after 72 hours.

30047/GB 20 Table 1. Shows results for Minimal inhibitory concentration (MIC) for human skin bacteria and standard bacterial reference strains of compounds of the invention and some comparative anti-bacterial agents. Data are expressed in % (weight/ volume). :d

2. 0.016 0.008 0.016 0.016 0.012 0.016 0.045 0.063 0.024 3. 0.016 0.016 0.016 0.016 0.016 0.016 0.063 0.063 0.016 4. 0.032 0.032 0.032 0.063 0.016 0.032 0.063 0.032 0.125

_

5. 0.016 0.016 0.016 0.024 0.008 0.016 0.063 0.063 0.032 6. 0.032 0.063 0.063 0.016 0.032 0.032 0.125 0.125 0.125

_

7. 0.063 0.063 0.063 0.045 0.032 0.032 0.063 0.125 0.125

_

8. 0.004 0.004 0.008 0.006 n.d. n.d. 0.25 >0.5 0.004 9. 0.25 0.125 0.088 0.25 n.d. n.d. >0.5 0.18 0.25 10. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d.

_

C1 < 0.008 0.032 0.016 0.125 0.008 0.008 0.063 >0.5 0.008 C2 0.125 0.063 0.125 0.125 0.063 0.063 0.063 0.063 0.063

_

C3 0.016 0.008 0.014 0.016 n.d. n.d. >1 >1 0.016 C4 0.00001 0.001 0.003 0. 003 n.d. n.d. >1 0.0005 0.0005 2 = Carbonic acid 2,3-dihydroxy-propyl ester undec-10-enyl ester, 3 = Carbonic acid 2-hydroxy-1-hydroxymethyl-ethyl ester undec-10-enyl ester, 30047/GB 21 4 = Carbonic acid dec-9-enyl ester 2,3-dihydroxy-propyl ester, = Carbonic acid decyl ester 2,3-dihydroxy-propyl ester, 6 = Carbonic acid 2,3-dihydroxy-propyl ester 3,7-dimethyl oct-6-enyl ester, 7 = Carbonic acid 2,3-dihydroxy-propyl ester 3-methyl-5 phenyl-pentyl ester, 8 = Carbonic acid 2-butyl-octyl ester 2,3-dihydroxy-propyl ester 9 = Carbonic acid 2,3-dihydroxy-propyl ester 2-ethyl-hexyl ester = Carbonic acid 2,3-dihydroxy-propyl ester octa 2(E/Z),7-dienyl ester C1 = Dodecanoic acid 2,3-dihydroxy-propyl ester: (1-mon- lauroyl-glycerol), C2 = a commercial glycerol mono-ether: 3-(2-Ethyl- hexyloxy)-propane-1,2-diol, C3= Farnesol, C4= Triclosan Ax 25 is identified as Staphylococcus epidermidis by FAME analysis. Ax 7 is identified as Corynebacterium group G and Ax 15 as Corynebacterium jeikeJum with the Api Coryne test kit. The latter two strains are isolated from the axilla of human volunteers and are able to generate axilla malodor when incubated in vitro with human axilla secretions.

It can be seen from Table 1 that, for all strains studied, compounds of the present invention are better performing than the mono-ether (C2) and are comparable or better than the mono-ester (C1) and Farnesol (C3), which commonly are 30047/GB 22 used in perfumes, personal care products and perfumed consumer goods, such as eaux de Cologne, eaux de toilette, extracts, lotions, creams, ointments, shampoos, soaps, bath salts, salves, sprays, powders, deodorants, detergents; and in solid fragranced products such as powders, soaps, detergent powders, tissues, fabrics, room deodorizers, room deodorising gels, and candles.

Example 12:

The anti-fungal efficacy of the compounds of the present invention and comparative compounds is shown in table 2. Trichophyton mentagrophytes DSM 4 8 7 0, Candida albicans DSM 1665 and

Malassezia furfur DSM 6170 are obtained from the German type strain collection. The fungi are cultivated and MIC values are determined as described in the previous Example, with the following exceptions: The growth medium for C. albicans is Sabouraud liquid medium and for M. furfur this same medium is modified with 0.1% Tween 80.

T. mentagrophytes growth medium is the medium M90 as described by the German Type strain collection (DSMZ). The MIC tests are incubated for 48 hours until evaluation.

30047/GB 23 Table 2. Minimal inhibitory concentration (MIC) for human skin fungi of relevant materials described in this invention disclosure. Data are expressed in % (weight/ volume). h s t)

Àa qua Carbonic acid 2,3-dihydroxy-propyl 0.002 0.016 0.006 ester undec10-enyl ester Carbonic acid 2-hydroxy-1- 0.002 0.032 0.008 hydroxymethylethyl ester undec-10 enyl ester Carbonic acid dec-9-enyl ester 2,3- 0. 004 0.016 0.016 dihydroxy-propyl ester Carbonic acid decyl ester 2,3- 0. 002 0.016 0.016 dihydroxy-propyl ester Carbonic acid 2,3-dihydroxy- propyl 0.016 0.063 0.024 ester 3,7-dimethyl-oct-6-enyl ester Carbonic acid 2,3-dihydroxy-propyl 0.016 0.063 0.016 ester 3-methyl-5-phenyl- pentyl ester Dodecanoic acid 2,3-dihydroxy-propyl 0.002 0.063 0.063 ester 3-(2-Ethyl-hexyloxy)-propane-1,2- 0.032 0.09 0.024 dial Undecylenic acid 0.0032 0.0125 0.0016 The results clearly show that the compounds of the present invention are usually better than or as good as compounds including the known anti-fungal agent undecylenic acid, 30047/GB 24 which is employed in perfumes, personal care products and perfumed consumer goods.

Example 13: Degradation of the Compounds of the present invention in the presence of water and bacteria In order to evaluate whether the compounds of the present invention will degrade in an acceptable period of time, the compounds are added to a phosphate buffer at a pH of 7. In a further treatment, a culture of the typical skin bacterium Corynebacterium so. is added at a concentration of 109 cfu/ ml to the buffer, in order to evaluate whether the lipases produced by the skin bacteria accelerate the degradation of the compounds. As a comparision, the degradation of 1-monolauroyl-glycerol is investigated.

These results are summarized in Table 3. As a further comparision, the molecules are added to 100% ethanol.

The results show clearly, that the Compounds are subject to a slow hydrolysis in water. This hydrolysis is slow enough, that the Compounds can provide a sufficiently long lasting action after application, but at the same time hydrolysis will lead to a slow release of the alcohol, and the compounds will not accumulate on the skin and in the body if used on a regular basis. As is the case with monolaurin- glycerol, the compounds are also cleaved by bacterial lipases and this mechanism will accelerate the degradation depending on the size of the bacterial population that is present. On the skin this population is normally lower than it is under these experimental conditions.

30047/GB 25 Table 3. Hydrolysis and bacterial degradation Compound incubation condition % of added compound left after 4 h 7 h 24 h Carbonic acid 2,3- 100% ethanol 100.0 100.0 100.0 dihydroxy- propyl ester undec-10-enyl ester Carbonic acid 2,3- Phosphate buffer 102. 7 89.6 62.7 dihydroxy-propyl ester undec-10-enyl Carbonic acid 2,3- Corynebacteria in 54.8 32.5 1.1 dihydroxy-propyl phosphate buffer ester undec-10-enyl ester Dodecanoic acid Phosphate buffer 100.0 100.0 100.0 2,3-dihydroxy propyl ester Dodecanoic acid Corynebacteria in 65.2 78.2 52. 3 2,3-dihydroxyphosphate buffer propyl ester These results show that in the phosphate buffer (used to mimic the conditions in sweat), the compounds degrade in a desirable manner over time.

Claims (7)

1. 30047/GB 26 Claims: 1. A glycerol monocarbonate of the formula 0 R2

   RO R1 OH

   wherein R1 is hydrogen and R2 is hydroxymethyl; or R1 is hydroxymethyl and R2 is hydrogen; and wherein R is selected as follows: (a)R is selected from the group consisting of a branched or unbranched C820 alkyl; a branched or unbranched C820 alkenyl, preferably a terminally unsaturated alkenyl; a C820 alkylaryl; a C820 alkenylaryl; a C820 alkylarylalkyl; a C820 alkenylarylalkyl; a C820 alkylarylalkenyl; a C820 alkenylarylalkenyl; and (b) R together with the oxygen atom to which it is attached is a radical of a fragrant alcohol.
2. 2. A compound according to claim 1 selected from the group consisting of Carbonic acid 2,3-dihydroxypropyl ester undec-10-enyl ester, Carbonic acid 2-hydroxy-1- hydroxymethyl-ethyl ester undec-10-enyl ester, Carbonic acid dec-9-enyl ester 2,3-dihydroxypropyl ester, Carbonic acid decyl ester 2,3dihydroxypropyl ester, Carbonic acid 2,3-dihydroxypropyl ester 3,7-dimethyl-oct-6-enyl ester, Carbonic acid 2,3-dihydroxypropyl ester 3-methyl-5-phenyl- pentyl ester, Carbonic acid 2-butyl-octyl ester 2,3dihydroxypropyl ester, Carbonic acid 2,3-dihydroxypropyl 30047/GB 27 ester 2-ethyl-hexyl ester, and Carbonic acid 2,3-dihydroxy- propyl ester octa-2,7-dienyl ester.
3. 3. An anti-bacterial or anti-fungal composition comprising a compound or mixture of compounds as defined in claim 1 or claim 2.
4. 4. A composition according to claim 3 wherein the compound or mixture of compounds is present in an amount of from o.1 to 3.0% by weight.
5. 5. A composition according to claim 4 wherein the compound or mixture of compounds is present in an amount of from o.1 to 0.5% by weight.
6. 6. A composition according to any of the claims 3 to 5 selected from a composition for a household product, a composition for a consumer product for application to the human skin or hair, a composition for the treatment of acne, a composition for the treatment of fungal infections of the skin, more particularly athlete's foot infections, and an anti- dandruff composition.
7. 7. Use of a compound as defined in claim 1 or claim 2 as an antibacterial or anti-fungal agent.