compounds used in the method of this invention are available from commercial sources , including symrise gmbh and takasago international usa , among others . the menthol carbonate derivatives may , if desired , be prepared from readily available starting materials , in the manner described in u . s . pat . no . 5 , 703 , 123 to pelzer , et al . and u . s . pat . no . 3 , 419 , 543 to mold , et al . the following definitions apply with reference to compounds encompassed by formula i , above : the term “ alkyl ” refers to straight - or branched - chain unsubstituted alaphatic hydrocarbon groups of 1 - 12 carbon atoms . similarly , the term “ alkyl ”, when used in combination form to name a substituent such as “ hydroxyalkyloxy ”, “ hydroxyalkyl ”, “ alkylamine ” or the like , refers to a straight - or branched - chain alaphatic hydrocarbon group of 1 - 12 carbon atoms . the expression “ lower alkyl ” refers to unsubstituted , straight - or branched - chain alkyl groups of 1 - 6 carbon atoms . the term “ substituted alkyl ” refers to an alkyl group substituted by , for example , 1 - 25 substituents , and most preferably 1 - 4 substituents . substituents may include , without limitation , hydroxy , alkoxy , halo , cycloalkoxy , oxo , amino , monoalkylamino , dialkylamino , aryl and substituted aryl . among the alkyl substituents noted above , particularly preferred are hydroxy substituents . the term “ lower alkenyl ” refers to straight - or branched - chain , unsubstituted , unsaturated hydrocarbon groups of 1 - 6 carbon atoms . examples of lower alkenyl groups include ethenyl , propenyl , butenyl , pentenyl and the like . the term “ substituted alkenyl ” refers to an alkenyl group substituted by , for example , 1 - 12 substituents , and most preferably , 1 - 4 substituents . the substituents are the same as those described above with reference to the alkyl groups . the term “ aryl ” refers to monocyclic or polycyclic aromatic hydrocarbon groups having 6 - 15 carbon atoms in the ring portion , such as phenyl , naphthyl , biphenyl , indenyl , fluorenyl or the like , each of which may be substituted . the term “ substituted aryl ” refers to an aryl group , as defined above , substituted by , for example , 1 - 7 substituents , and preferably , 1 - 4 substituents , such as those described above with reference to the substituted alkyl and alkenyl groups . when a moiety is described herein as substituted with more than one substituent , it is intended that each of the multiple substituents be chosen independently from among the substituents mentioned above . compounds encompassed by formula i , above , have asymmetric carbon atoms , and therefore , can exist as paired enantiomers , differing in their optical activity . the compounds may be used in enantiomerically pure form , in racemic form or in other mixed forms . preferred compounds for use in the methods of this invention include : menthol propyleneglycol - carbonate , isopulegol propyleneglycol - carbonate , menthyl - 9 - hydroxynonyl - carbonate , menthoxy - propane - 1 , 2 - diol , and n - ethyl - p - menthane - 3 - carboxamide . in carrying out the methods of the invention , compounds of formula i may be used neat , or as a component of a composition or preparation obtained by admixture with a suitable carrier or vehicle . the nature of the carrier or vehicle will depend on the end use of the composition , i . e . the effect sought to be produced , and the mode of administration . compounds of formula i are preferably formulated with a pharmaceutically acceptable carrier material for administration as an anti - inflammatory agent . a safe and effective amount of the active component for this application is from about 1 wt % to about 30 wt % based on the total weight of the formulation . satisfactory anti - inflammatory effects have been obtained using menthoxy - propane - 1 , 2 - diol , racemic menthol propyleneglycol - carbonate , isopulegol propyleneglycol - carbonate and menthyl - 9 - hydroxynonyl carbonate . when used in an anti - angiogenic formulation , a safe and effective amount of the compound of formula i is in the range from about 1 wt % to about 80 wt % based on the total weight of the composition . satisfactory anti - angiogenic effect has been obtained using racemic menthol propyleneglycol - carbonate . the specific amount of compound of formula i to be used as an anti - inflammatory agent or anti - angiogenic agent may vary depending on differences in potency among the compounds encompassed by formula i . in formulations for therapeutic applications , as described above , the formulation may contain one or more compounds of formula i , above , as the active agent , and , optionally , at least one supplemental active agent . the supplemental active agents may include other anti - inflammatory agents , other anti - angiogenic agents , analgesic agents , antibacterial agents , antiviral agents , antifungal agents , antiparasitic agents , tumoricidal or anti - cancer agents , toxins , enzymes , hormones , neurotransmitters , immunoglobulins , immunomodulators , local anesthetics or the like . various auxiliary ingredients may be added to the above - described compositions to impart desired properties or characteristics thereto or to facilitate administration in a particular way . these auxiliary ingredients may include , without limitation , fragrances , surfactants , propellants , emulsifiers , dispersants , buffers , preservatives , antioxidants , diluents , solvents , fixatives , pharmaceutical excipients and adjuvants , as is common practice in the art . the deleterious activity of microorganisms may be inhibited by the inclusion of various antibacterial and antifungal agents , e . g ., paraben , chlorobutanol , phenol , sorbic acid and the like . the compositions described above may be prepared in various forms depending on the mode of administration . thus , compositions may be in the form of a lotion , cream , ointment , gel or powder for topical application or a solution or suspension for administration as an atomized or aerosol spray . alternatively , the composition may , if desired , be in the form of tablets , capsules or microparticulates filled into gelatin capsules , or the like , for oral administration . the composition may also be formed as a suppository for rectal or vaginal administration . the compounds and compositions described herein may be formulated with sustained release components or carriers of various types , e . g . in alcohol or in water - based formulations for topical use , as is well known in the art . compositions used in practicing the invention can be prepared by various methods well known in the art . typically , such compositions are prepared by intimately mixing a compound of formula i with a suitable carrier material and optionally one or more supplemental active agents of auxiliary ingredients , as desired , and putting the resulting mixture into a suitable container or dispenser . the compounds and compositions described herein may be administered systemically or locally , e . g . by application to inflamed areas of skin or by rectal or vaginal delivery . the expression “ systemic administration ” refers to delivery of an active agent such that it enters the recipient &# 39 ; s system and thus , is subject to metabolic processes . systemic administration encompasses both enteral and parenteral administration , the latter including , without limitation , intravenous , intramuscular , intramedullary , intraperitonal and subcutaneous administration , as well as administration by inhalation . the compounds and compositions described herein are beneficially administered to mammals , particularly to humans , to produce the desired anti - inflammatory or anti - angiogenic effect . the following examples set forth further details regarding the invention . these examples are provided for illustrative purposes only , and are not intended to limit the invention in any way . these examples show the results of tests conducted to determine the efficacy of certain compounds of formula i , above , as anti - inflammatory agents and anti - angiogenic agents . example 1 shows the anti - inflammatory effect of compounds of formula i , above . edema was induced in mice by topical application of 10 μl of tpa ( tetradecnoylphorbol acetate ) in acetone ( 2 . 5 μg / ear ) to both the inner and outer surface of one ear of each mouse used in the experiment . each test compound , diluted with acetone to a concentration of 10 % was applied topically to the inflamed mouse ear immediately after tpa application , so as to deliver 2 . 5 mg / ear . the reference drug , indomethacin ( 0 . 5 mg / ear ), was administered as a positive control . the thickness of each ear was measured before treatment and 4 hours after induction of inflammation , using a micrometer ( mitutoyo co .). anti - inflammatory effect was expressed as the reduction in ear thickness with respect to the control group . the results obtained are presented in table i . table i anti - inflammatory effect chemical name (% of control ) ( l )- menthol 0 menthoxy - propane - 1 , 2 - diol 27 n - ethyl - p - menthane - 3 - carboxyamide 11 menthol propyleneglycol - carbonate 27 racemic menthol propyleneglycol - carbonate 23 isopulegol propyleneglycol - carbonate 33 menthyl - 9 - hydroxynonyl - carbonate 45 indomethacin 96 the data show that all of the compounds of the invention that were tested exhibited substantial inhibition of tpa - induced inflammatory response , in comparison to menthol , which showed no appreciable anti - inflammatory effect under the test conditions employed . the effect of racemic menthol propyleneglycol - carbonate on angiogenesis was studied by culturing aortic explants in three - dimensional matrix gels according to the procedure of kruger and figg ( kruger e . a . and figg , w . d . protein binding alters the activity of suramin , carboxyamidotriazole , and ucn - 01 in an ex vivo rat aortic ring angiogenesis assay clinical cancer research 7 : 1867 - 1872 , 2001 ). thoracic aortas were excised from 8 - week - old mail sprague dawley rats and the fibroadipose tissue was removed . the aortas were sectioned into 1 - mm - long cross - sections , rinsed with human endothelial - sfm ( gibco ), placed on the matrigel - coated wells , covered with additional 50 μl matrigel , and allowed to gel for more than 30 min at 37 ° c ., 5 % co 2 . all the rings were cultured in human endothelial - sfm ( gibco ) supplemented with 200 μl / ml of ecgs ( endothelial cell growth supplement , sigma ) as an angiogenesis inducer . racemic menthol propylene - carbonate diluted with enthanol was added to the culture medium at final concentrations of 1 , 10 , and 100 μm . ethanol alone ( 1 %) was added to the culture medium as a vehicle control . all assays were performed by using 5 aortic rings per sample . aortic rings were photographed on day 10 . these photographs are shown in fig2 . the area of angiogenic sprouting was calculated using image - pro plus software ( media cybernetics ). the image analysis quantitation of the dose - response activity of racemic menthol propyleneglycol - carbonate is shown in table ii . microvessel densities are reported in square pixels . table ii microvessel density concentration ( um ) ( pixel 2 ) % inhibition 0 15 . 8 ± 4 . 0 0 1 13 . 4 ± 4 . 1 15 10 12 . 2 ± 2 . 5 22 100 10 . 6 ± 3 . 8 33 the data indicate that racemic menthol propylene - carbonate inhibited microvessel formation in rat aortic ring assay in a dose dependent manner . example 3 describes the results of a cell cytotoxicty assay performed to evaluate the ctytoxic effect of racemic menthol propyleneglycol - carbonate on normal cells . 5 × 10 3 ha - cat cells were plated in each well of 96 well plates and racemic menthol propyleneglycol - carbonate was added at various concentrations . the plates were incubated for another 48 hours and the viable cells were measured by xtt cell proliferation kit ( roche ). more than 70 % of ha - cat cells were viable even at high concentration of 100 μm . the results of this experiment are shown in table iii . table iii concentration ( um ) cell viability (%) 0 . 1 100 1 . 0 100 5 . 0 96 . 5 10 . 0 96 . 3 50 . 0 81 . 8 100 70 . 4 these data show that racemic menthol propyleneglycol - carbonate is non - toxic against normal cells . example 4 shows the results of an experiment conducted to determine the effect of racemic menthol propyleneglycol carbonate on huve cell proliferation . huve ( human umbilical vein endothelial ) cells were isolated from human umbilical cord veins by a method of jaffe et al . ( jaffe , e . a ., nachman , r . l ., becker , c . g ., and minick , c . r . culture of human endothelial cells derived from umbilical veins . j . clin . invest . 52 : 2745 - 2756 , 1973 ). huve cells were confirmed by immunostaining with antibody against factor viii . the cells were grown in m199 medium ( gibco brl , grand island , n . y .) supplemented with 10 % fetal bovine serum , 100 units / ml penicillin , 100 μg / ml streptomycin , 50 μg / ml endothelial cell growth supplement , and 5 units / ml heparin at 37 ° c . in an atmosphere of 5 % co 2 - 95 % air . 1 × 10 4 huve cells were plated in each well of 96 well plates and five different concentrations ranging from 1 to 100 of racemic menthol propyleneglycol - carbonate were tested in the presence of bfgf used as maximum proliferation control . cells were cultured for an additional 48 hours , and relative cell numbers in each well were determined by xtt cell proliferation kit ( roche ). no bfgf mpc - r * mpc - r mpc - r mpc - r mpc - r bfgf only 100 μm 50 μm 10 μm 5 μm 1 μm average 0 . 2283 1 . 0830 0 . 9121 1 . 0621 1 . 0425 1 . 0305 1 . 0623 proliferation 0 . 0 100 . 0 80 . 0 97 . 6 95 . 3 93 . 9 97 . 6 (%) * mpc - r = racemic menthol propyleneglycol - carbonate as can be seen from the data in table iv , 100 um of menthol propyleneglycol - carbonate weakly inhibited huve cell proliferation by 20 %. the results show that this compound does not have detrimental effects on the normal proliferation of endothelial cells . the data set forth in the foregoing examples indicate that compounds of formula i , above , are : ( 1 ) effective as insect repellents ; ( 2 ) effective as anti - inflammatory agents when applied topically ; and ( 3 ) effective as anti - angiogenesis agents . while certain embodiments of the present invention have been described and / or exemplified above , various other embodiments will be apparent to those skilled in the art from the foregoing disclosure . the present invention is , therefore , not limited to the particular embodiments described and / or exemplified , but is capable of considerable variation and modification without departure from the scope of the appended claims .
menthol propyleneglycal - carbonate , analogs thereof and compositions containing such compounds are administered to mammals , preferably humans , to produce anti - inflammatory or anti - angiogenic effects .