Abstract:
A composition is reported that includes an elastase inhibitor in a pharmaceutically or cosmetically acceptable carrier, the inhibitor being at least one benzisothiazolinone-1-dioxide derivative having the formula: ##STR1## where R 1  is a hydrogen atom and R 2  is a monovalent C 12  -C 20  alkyl or alkenyl group.

Description:
This is a divisional application of Ser. No. 07/666,093 filed Mar. 7, 1991, now U.S. Pat. No. 5,338,747. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to benzisothiazolinone-1-dioxide derivatives that can be used as elastase inhibitors, and to compositions containing such inhibitors. 
     THE RELATED ART 
     It is well known that elastin is an elastic fibrous protein that occurs in the connective tissues of vertebrates. It is found in the walls of the blood vessels, the skin, lungs, cartilage, ligaments and other tissues. Elastin is the most durable protein in the body. Unfortunately but it suffers a particularly rapid degradation in all the elastin-rich tissues such as the vascular walls and the skin, in certain pathological conditions, as well as during the ageing process in general. 
     Elastin can be attacked only by certain proteases, called elastases or elastase-type proteases. These enzymes include pancreatic elastase and cell elastases, examples of the latter being leucocytic and platelet elastases, as well as the elastases found in macrophages, fibroblasts and the cells of the smooth muscles in the arteries. These enzymes can degrade the elastin in the tissues and organs mentioned above and so contribute to the development of disorders such as arteriosclerosis, emphysema, arthritis and diabetes, as well as to the ageing of the connective tissues in the body. 
     The activity of elastases is controlled and regulated by natural inhibitors present in the plasma (e.g. α-1-antitrypsin and α-2-macroglobulin) and in secretions from tissues (e.g. the bronchial secretion) [see e.g. W. Hornebeck et al., &#34;Control of elastic tissue destruction by elastase inhibitors&#34;, in Deyl and Adam (eds.), Connective Tissue Research: Chemistry, Biology and Physiology, pp. 233-246, A.R. Liss Inc., New York, 1981]. 
     Furthermore, numerous bacteria capable of entering the body secrete elastolytic proteases whose action greatly contributes to the pathogenic activity of these microorganisms. 
     It is also known that the growth of malignant rumours such as carcinomas and sarcomas, and the formation of metastases, which are often fatal to the patient, are also affected by the secretion of elastase-type proteases [see for example W. Hornebeck, D. Brechemier, G. Bellon, J. J. Adnet and L. Robert, &#34;Biological Significance of Elastase-like Enzymes in Arteriosclerosis and Human Breast Cancer&#34;, in P. Straulli, A. J. Barrett and A. Baici (eds.), Proteinases and Tumor Invasion, vol. 6, ORTC Monograph Series, pp. 117-141, Raven Press, New York, 1980]. These enzymes can destroy the surrounding tissues and thus enable the malignant cells to enter the blood circulation, as a result of which the rumour can invade the body. 
     For all these reasons, it is important to possess inhibitors that can control the activity of elastases. 
     However, some elastases are useful or even indispensable for the body, for example when they digest the bacteria that have been destroyed by the phagocytic action of macrophages. It is therefore important to possess elastase inhibitors that act selectively in the elastic fibres whose integrity is indispensable for the proper functioning of the body. 
     The fact is that the enzymatic hydrolysis of elastin by elastases can be seen as a decisive factor in numerous disorders of the elastic tissues, such as arteriosclerosis, emphysema and certain skin diseases. In the living body, this proteolysis occurs when the balance is upset between the level of proteases with an elastolytic action and the level of natural inhibitors originating in the plasma or the tissues. One method proposed for the treatment of a genetic or functional deficiency of these protease inhibitors is to introduce natural inhibitors such as α-1-antitrypsin as a replacement therapy. 
     However, the use of natural inhibitors has numerous disadvantages, including the cost of the treatment and the risk of adverse immunological reactions. Furthermore, the elastase inhibitors used in the experimental treatment of animals with emphysema are highly toxic. 
     Synthetic elastase-inhibitors have therefore been under investigation for some years now. Thus, U.S. No. 4,195,023 describes the use of 2-benzisothiazol-3-one derivatives and saccharin derivatives to inhibit elastases. The preferred compounds in that publication are derivatives substituted with a furoyl or a thenoyl group. The publication also gives some data for 2-(2-ethylbutyryl)-saccharin and 2-acryloylsaccharin. According to this document, the alkyl chain of the derivative contains at most 10 carbon atoms and is preferably branched, but the only example illustrated has a hydrocarbon chain with no more than five carbon atoms. 
     Although these inhibitors give satisfactory results, they are not sufficiently specific for the elastic fibres. 
     European Patent Specification EP-A 0 126009 describes some peptide derivatives that can be used as elastase inhibitors and are specific for elastic fibres. These derivatives are lipopeptides with a hydrophobic acyl group and a special peptide chain. However, these lipopeptides, which are consequently bifunctional, have the major disadvantage of containing a peptide moiety, which is susceptible to hydrolysis by other proteinases. 
     The aim of the present invention is therefore to incorporate into pharmaceutical or cosmetic compositions elastase inhibitors in the form of bifunctional benzisothiazolinone-1-dioxide derivatives with a) a hydrophobic chain that has an affinity for elastin and b) a moiety that is not a peptide group (so that it is more resistant to enzymatic hydrolysis) and which can also acrylate the active serine in the elastase. 
     SUMMARY OF THE INVENTION 
     The present invention therefore provides a composition comprising (i) an elastase inhibitor which is at least one benzisothioazolinone-1-dioxide derivative having the formula: ##STR2## where R 1  is a hydrogen atom or a C 1  -C 5  alkyl or alkoxy group, and 
     R 2  is a monovalent C 8  -C 20  alkyl or C 9  -C 20  alkenyl group, optionally substituted with OH or COOH group, 
     R 2  is a group with the formula: ##STR3## where R 3  is a divalent straight or branched C 2  -C 6  saturated or ethylenically unsaturated aliphatic group ##STR4## is an aromatic nucleus R 4  is OH, a C 1  -C 4  alkyl or a C 1  -C 4  alkoxy group 
     n is zero or an integer in the range of 1-5, and when n&gt;1, the R 4  groups can be different, or else 
     R 2  is a group with the formula: ##STR5## where R 1  is the same as above, and 
     R 5  is a divalent straight or branched C 8  -C 20  saturated or ethylenically unsaturated aliphatic group, 
     and (ii) a pharmaceutically or cosmetically acceptable carrier or vehicle. 
    
    
     DETAILED DESCRIPTION 
     A benzisothiazolinone-1-dioxide derivative of formula (I) above, which is the active ingredient of a composition as above, has two functional groups, namely a &#34;lipid arm&#34; (R 2  or part of R 2 ), which has a high affinity for the elastic fibres in question, and the benzisothiazolinone-1-dioxide moiety, which can react with elastase in order to inhibit it. 
     Owing to the presence of this hydrophobic chain, the benzisothiazolinone-1-dioxide derivatives of the present invention can accumulate on the elastic fibres to be protected and therefore act exclusively or almost exclusively on the elastase located near these fibres. In view of this mode of action, it is possible to make the substance act specifically at the site of the target fibres to be protected, which ensures a more efficient inhibition of elastase. 
     The compounds according to the invention are therefore more efficient and more economical bifunctional inhibitors than the known synthetic inhibitors, which lack the functional group that has a special affinity for the elastic fibres present in the tissues to be protected. 
     The acylsaccharins described in U.S. Pat. No. 4,195,023, which have the formula: ##STR6## carry a hydrocarbon chain A with generally at most five carbon atoms, and this is not long enough to confer on the derivative either an affinity for elastin or an ability to occupy the hydrophobic site on elastase. As will be seen later, the affinity of the derivative for elastin and for the hydrophobic site on the elastase does not become detectable until the number of carbon atoms reaches nine, improving as the number reaches eleven and peaking when this number is 16. 
     As mentioned in the definition of the compounds according to the invention given above, a monovalent C 8  -C 20  straight-chain or branched alkyl group can carry at least one substituent in the form of an OH or COOH group. If the monovalent alkyl is not substituted with these groups, it preferably contains 11 carbon atoms. Such examples of such alkyl groups include the nonyl, undecyl, tridecyl, pentadecyl, heptadecyl and nonadecyl groups, while COOH--(CH 2 ) 8  -- is an example of the substituted alkyl groups. 
     A monovalent C 9  -C 20  alkenyl group is a monovalent alkylene group theoretically obtainable by removing a hydrogen atom from a carbon in an olefinic hydrocarbon. Such a group may contain a single ethylenic double bond or more than one ethylenic double bond. As before, these groups may be either unsubstituted or they may carry at least one OH or COOH group. Examples of such unsaturated groups are the dec-9-enyl, hepatadec-8-enyl, hepadeca-8,11-dienyl and the CH 3  --(CH 2 ) 5  --CHOH--CH 2  --CH═CH--(CH 2 ) 7  -- group. 
     A divalent group R 3  may in particular be a group theoretically obtainable by removing hydrogen from each of two terminal carbons in a straight-chain or branched alkane or alkene, examples being the --CH═CH-- group, the --CH 2  --CH 2  -- group and the --(CH 2 ) 3  group. 
     An aromatic nucleus, denoted ##STR7## may comprise one or more benzene rings, examples being the groups obtained from benzene, anthracene, naphthalene, biphenyl, terphenyl, triphenylbenzene, indene, diphenylene, fluorene and phenanthrene. 
     A divalent group R 5  may in particular be a group theoretically obtainable by removing a hydrogen atom from each of two terminal carbons in a straight-chain or branched C 8  -C 20  alkane, alkene or polyalkene, as exemplified by the --(CH 2 ) 8  -- group. 
     Furthermore, R 1  can be a hydrogen atom or a substituent chosen from amongst C 1  -C 5  alkyl or alkoxy groups. When R 1  is a substituent, it is desirably chosen such as to promote the hydrolytic opening of the heterocyclic ring. However, R 1  is generally a hydrogen atom. 
     As mentioned before, R 2  is the functional group that confers an affinity for the elastic fibres on the compound of the invention, owing to its lipophilic nature. 
     In the first embodiment of the invention, R 2  is a long-chain alkyl or alkenyl group whose long hydrocarbon chain confers a strongly lipophilic nature on the compound according to the invention. This facilitates its penetration into the skin and makes it suitable for cosmetic use. 
     In the second embodiment of the invention, R 2  is a group with the formula: ##STR8## where R 3  and R 4  are as defined before; 
     R 3  is preferably a divalent group obtained from an alkane ##STR9## is a benzene ring R 4  is a C 1  -C 4  alkoxy group or a hydroxyl group, and 
     n is 1 or 2. 
     These R 2  groups are exemplified by the 3,4-dimethoxycinnamoyl, cinnamoyl, dihydrocinnamoyl and pmethoxyphenylbutyryl radical. 
     In the second embodiment, the compound according to the invention is again lipophilic, this time because it comprises an aromatic nucleus. 
     In the third embodiment of the invention, R 2  has the following formula: ##STR10## where R 1  and R 5  are as defined before, but; 
     R  1  is preferably a hydrogen atom, and 
     R  5  is a divalent group obtained from an alkane. 
     In this case, this R 5  group confers on the compound both a lipophilic character and an affinity for the elastic fibres in question, while the presence of two benzisothiazolinone-1-dioxide rings increases the inhibitory activity. 
     The benzisothiazolinone-1-dioxide derivatives of this invention can be prepared by conventional methods in which the starting materials are an acid chloride and an alkali metal derivative of the corresponding benzisothiazolinone-1-dioxide. 
     Thus, it is possible to prepare the benzisothiazolinone-1-dioxide derivative of the invention, with the formula: ##STR11## where R 1  is a hydrogen atom or a C 1  -C 5  alkyl or alkoxy group, 
     R 2  is an optionally substituted monovalent C 9  -C 20  alkyl or alkenyl group, 
     R 2  is a group with the formula: ##STR12## all as defined before by reacting an alkali metal derivative of benzisothiazolinone-1-dioxide having the formula: ##STR13## where R 1  is as defined before, and M is an alkali metal with an acid chloride having the formula: 
     
         R.sup.2 --COCL                                             (V) 
    
     wherein R 2  is the same as before. 
     The benzisothiazolinone-1-dioxide derivative with formula I in which R 1  is as defined above and R 2  represents the group with formula (III) ##STR14## where R 1  and R 5  are as defined before can be prepared by reacting an alkali metal derivative of a benzisothiazolinone-1-dioxide having formula (IV) with an acid chloride represented by: 
     
         CLCO--R.sup.5 --COOH                                       (VI) 
    
     where R 5  is as defined before, the alkali metal being preferably sodium, but potassium can also be used. 
     The reaction between the alkali metal derivative and the 
     acid chloride can be carried out in both cases by refluxing 
     the alkali metal derivative of the benzisothiazolinone-1-dioxide (IV) with the acid chloride (V) or (VI) in a suitable solvent such as tetrahydrofuran, with stirring. The product formed can then be isolated by filtration and purified by recrystallization from a suitable solvent such as ethanol. 
     When an acid chloride with formula (VI) is used, the reaction leads to two different products (VII) and (VIII): ##STR15## which can be separated from each other by high-pressure liquid chromatography. 
     The present invention also relates to the new benzisothiazolinone-1-dioxide derivatives themselves with the formula: ##STR16## where R 1  is a hydrogen atom or a C 1  -C 5  alkyl or alkoxy group, and 
     R 2  is a monovalent C 8  -C 20  alkyl or C 9  -C 20  alkenyl group optionally substituted with at least one OH or COOH group, with the proviso that if R 2  is unsubstituted alkyl it is C 11  -C 20  alkyl, or 
     R 2  is a group with the formula: ##STR17## where R 3  is a divalent straight or branched C 2  -C 6  aliphatic group ##STR18## is an aromatic nucleus R 4  is OH, a C 1  -C 4  alkyl group or a C 1  -C 4  alkoxy group 
     n is zero or an integer in the range of 1-5, and when n&gt;1, the R 4  groups can be different, or else 
     R 2  is a group with the formula: ##STR19## where R 1  is as defined before and R 5  is a divalent straight or branched C 8  -C20 aliphatic group. 
     This invention also embraces methods of treatment comprising administration of compositions of this invention as specified above, especially cosmetic treatment by topical application. 
     The pharmaceutical compositions of this invention may be solutions, suspensions, emulsions, ointments, creams, powders, lotions or gels, with non-toxic carriers or vehicles and possibly also additives and excipients. 
     The compounds of the invention can thus be incorporated in conventional excipients such as polyethylene glycols, waxes, fats, stearic substances, talc, alcohols, vegetable oils (e.g. sweet or expressed almond oil), mineral oils, wetting agents, thickeners, preservatives, perfumes and colorants. 
     These pharmaceutical compositions are intended for oral, parenteral, and--most often--local or topical administration. 
     These compositions can be used to treat or prevent any undesirable biological or pathological change caused by elastase, such as: 
     the degradation of the cutaneous elastic fibres due to ageing or to exposure to the sun 
     lysis of the pulmonary elastic fibres due to smoking, ageing and various disorders 
     emphysema 
     the progressive lysis of the elastic layers in the arterial walls during the development of arteriosclerosis 
     arterial disorders due to ageing 
     inflammatory foci 
     destruction of tissues (e.g. ulcers and necrosis) 
     periodontal disorders (degeneration of the gum) 
     certain disorders of the bones and joints 
     the growth of tumours and the formation of metastases. 
     As mentioned before, the compounds of the invention can also be used as cosmetics intended to counteract the undesirable effects of elastase on the skin, such as ageing. These cosmetics are essentially intended for application to the skin and can be e.g. solutions, emulsions, creams, ointments, powders, lotions, gels, soaps, milks, face packs, aerosols or bath oils. In the case of emulsions, it is best to use the water-in-oil type, containing the compound of the invention solubilized in the oil phase. These compositions can be prepared by the conventional methods, using the carriers, excipients and additives normally incorporated in such compositions. 
     The concentration of the new derivative (I) in the composition is chosen according to its activity and the effect required. When intended for local administration once or twice a day, the composition can contain the compound of the invention in a concentration of 0.1 to 5 wt-%. 
     The cosmetic and pharmaceutical compositions according to the invention that are intended for local application may also contain penetration enhancers or penetration potentiators, which can raise the beneficial effect of the elastase inhibitor by improving its diffusion through the epidermis until it reaches its site of action in the stratum corneum. 
     These penetration enhancers can act in different ways. For example, they can improve the distribution of the elastase inhibitor on the surface of the skin. Alternatively, they can improve its distribution in the skin after local application, thus promoting the migration of the elastase inhibitor within the stratum corneum. The penetration enhancers may also raise the efficiency of the elastase inhibitor by other mechanisms. 
     Consequently, the pharmaceutical and cosmetic compositions according to the invention can optionally comprise up to 30 wt-% and preferably 0.1-25 wt-% of a penetration enhancer, examples of which are listed below. 
     2-methylpropanol-2 
     2-propanol 
     ethyl 2-hydroxypropanoate 
     ethyl polyoxyethylene hexane-2,5-diol ether 
     di-(2-hydroxypropyl) ether 
     pentane-2,4-diol 
     acetone 
     methyl polyoxyethylene ether 
     2-hydroxypropionic acid 
     2-hydroxyoctanoic acid 
     1-propanol 
     1,4-dioxan 
     tetrahydrofuran 
     1,4-butanediol 
     propylene glycol dipelargonate 
     polyoxypropylene 15-stearyl ether 
     octanol 
     polyoxyethylene ester of oleyl alcohol 
     dioctyl adipate 
     dicapryl adipate 
     diisopropyl adipate 
     diisopropyl sebacate 
     dibutyl sebacate 
     diethyl sebacate 
     dimethyl sebacate 
     dioctyl sebacate 
     dibutyl suberate 
     dioctyl azeleate 
     dibenzyl sebacate 
     dibutyl phthalate 
     dibutyl azeleate 
     ethyl myristate 
     dimethyl azeleate 
     butyl myristate 
     urea 
     diethyl-m-toluamide 
     1-dodecylazacycloheptan-2-one 
     dibutyl succinate 
     dodecyl phthalate 
     decyl oleate 
     ethyl caproate 
     ethyl salicylate 
     isopropyl palmirate 
     ethyl laurate 
     2-ethylhexyl pelargonate 
     isopropyl isostearate 
     butyl laurate 
     benzyl benzoate 
     butyl benzoate 
     hexyl laurate 
     ethyl caprate 
     ethyl caprylate 
     butyl stearate 
     benzyl salicylate 
     2-hydroxypropanoic acid 
     2-hydroxyoctanoic acid. 
     Other substances that promote the penetration of the active ingredient into the skin include the esters of pyroglutamic acid having the formula: ##STR20## where R is either a C 1  -C 30  alkyl group or it is the group: ##STR21## where T&#39; and T&#34; (which may be identical or different) represent a hydrogen atom or the following group: 
     
         [(CH.sub.3).sub.u, (C.sub.2 OH).sub.v, (CH.sub.2).sub.w, (CH.sub.3 CH.sub.2).sub.x, (CHOH).sub.y, (CH═CH).sub.x ].sup.- 
    
     where 
     u is zero or 1 
     v is zero, 1 or 2 
     w is zero or an integer in the range of 1-21 
     x is zero or an integer in the range of 1-4 
     y is zero, 1 or 2 
     z is zero or an integer in the range of 1-22 
     and 
     u+v+w+x+y+z is an integer in the range of 1-22, but when the CH═CH group is present, the total number of carbon atoms in the above group is 10-22. 
     The following compounds are suitable examples of pyroglutamic acid esters in which the R group, featuring in formula (IX), is a C 1  -C 30  alkyl group: 
     methyl pyroglutamate 
     ethyl pyroglutamate 
     n-propyl pyroglutamate 
     n-butyl pyroglutamate 
     n-heptyl pyroglutamate 
     n-octyl pyroglutamate 
     n-nonyl pyroglutamate 
     n-decyl pyroglutamate 
     n-undecyl pyroglutamate 
     n-dodecyl pyroglutamate 
     n-tridecyl pyroglutamate 
     n-tetradecyl pyroglutamate 
     n-hexadecyl pyroglutamate 
     n-octadecyl pyroglutamate 
     n-eicosyl pyroglutamate 
     isopropyl pyroglutamate 
     2-methylhexyl pyroglutamate 
     2-ethylhexyl pyroglutamate 
     3,7-dimethyloctyl pyroglutamate 
     2-hexyldecyl pyroglutamate 
     2-octyldodecyl pyroglutamate 
     2,4,4-trimethyl-1-pentyl pyroglutamate and 
     methyloctyl pyroglutamate. 
     The preferred esters are those in which R is a straight-chain or branched alkyl group with 1-14 and preferably 1-6 carbon atoms. Other preferred examples of pyroglutamic acid esters are those in which R represents the group: ##STR22## where the symbols T&#39; and T&#34; stand for the group: 
     
         [(CH.sub.3).sub.u, (CH.sub.2 OH).sub.v, (CH.sub.2).sub.w, (CH.sub.3 CH.sub.2).sub.x, (CHOH).sub.y, (CH═CH).sub.x ].sup.- 
    
     and which comprise saturated or unsaturated straight-chain or branched C 1  -C 22  aliphatic groups such as the alkyl groups: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-valeryl, isovaleryl, n-caproyl, n-heptyl, n-caprylyl, n-capryl, lauryl, myristyl, palmityl, stearyl and arachidyl group, and the C 10  -C 22  alkenyl groups: linoleyl, linolenyl, y-linolenyl, arachidonyl and columbinyl group. 
     Other examples of these groups comprise hydroxyalkyl radicals with 1-22 carbon atoms, such as the hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl, 2-hydroxy-n-butyl, 3-hydroxy-n-butyl, 4-hydroxyl-n-butyl, 5-hydroxy-n-valeryl, 6-hydroxy-n-caproyl, 2,3-dihydroxy-n-propyl, 2,3-dihydroxy-n-butyl and 12-hydroxystearyl group. 
     This list is not exhaustive, and other alkyl or substituted alkyl groups can be added to it as further examples of T&#39; and T&#34;. 
     Other specific examples of pyroglutamic acid esters that are particularly suitable for use as penetration enhancers are as follows: 
     2-(pyroglutamoyloxy)-propionic acid 
     methyl 2-(pyroglutamoyloxy)-acetate 
     ethyl 2-(pyroglutamoyloxy)-n-propionate 
     ethyl 2-(pyroglutamoyloxy)-n-butyrate 
     ethyl 2-(pyroglutamoyloxy)-isobutyrate 
     ethyl 2-(pyroglutamoyloxy)-n-valerate 
     ethyl 2-(pyroglutamoyloxy)-n-caproate 
     ethyl 2-(pyroglutamoyloxy)-n-heptylate 
     ethyl 2-(pyroglutamoyloxy)-n-caprylate 
     ethyl 2-(pyroglutamoyloxy)-n-pelargonate 
     ethyl 2-(pyroglutamoyloxy)-3-hydroxybutyrate 
     isopropyl 2-(pyroglutamoyloxy)-n-propionate 
     isopropyl 2-(pyroglutamoyloxy)-n-caprylate 
     n-propyl 2-(pyroglutamoyloxy)-n-propionate 
     n-propyl 2-(pyroglutamoyloxy)-n-caprylate 
     stearyl 2-(pyroglutamoyloxy)-n-proplonate 
     12-hydroxystearyl 2-(pyroglutamoyloxy)-n-propionate 
     stearyl 2-(pyroglutamoyloxy)-n-stearate 
     palmityl 2-(pyroglutamoyloxy)-n-propionate 
     linoleyl 2-(pyroglutamoyloxy)-n-propionate 
     linoleyl 2-(pyroglutamoyloxy)-n-caprylate 
     lauryl 2-(pyroglutamoyloxy)-n-caprylate 
     stearyl 2-(pyroglutamoyloxy)-n-caprylate 
     glyceryl mono-2-(pyroglutamoyloxy)-n-propionate 
     glyceryl mono-2-(pyroglutarnoyloxy)-n-caprylate, and 
     glyceryl di-2-(pyroglutamoyloxy)-n-propionate. 
     These lists of specific examples of pyroglutamic acid esters are not exhaustive, and many other examples with the overall structure of these esters could be mentioned. 
     Other examples of penetration enhancers are as follows: 
     dimethylsulphoxide 
     N,N-dimethylacetamide 
     N,N-dimethylformamide 
     2-pyrrolidone 
     1-methyl-2-pyrrolidone 
     5-methyl-2-pyrrolidone 
     1,5-dimethyl-2-pyrrolidone 
     1-ethyl-2-pyrrolidone 
     phosphine oxides 
     sugar esters, and 
     tetrahydrofurfuryl alcohol. 
     Other features and advantages of the present invention will emerge from the following non-limitative examples, given here to illustrate the present invention. 
     EXAMPLE 1 
     Preparation of 2-lauroylbenzisothiazolinone-1-dioxide 
     21.8 g (0.1 mole) of lauroyl chloride and 22.66 g (0.11 mole) of dry sodium benzisothiazolinone-1-dioxide were refluxed for 4 h in 80 ml of tetrahydrofuran, with mechanical stirring. The reaction mixture was filtered, the filtrate was concentrated under vacuum, and the product was recrystallized from ethanol and dried in air. This gave 30 g of 2-lauroylbenzisothiazolinone-1-dioxide (m.p. 85° C.). 
     EXAMPLE 2-6 
     The method described in Example 1 was used to prepare various compounds with formula I, in which the groups denoted by R 1  and R 2  are shown in Table 1. The acid chloride used here was myristoyl chloride in Example 2, palmitoyl chloride in Example 3, stearoyl chloride in Example 4, decanoyl chloride in Example 5 and undecenoyl chloride in Example 6. The melting points of the compounds obtained are given in Table 1. 
     EXAMPLE 7 
     Preparation Of 2-[(3,4)-dimethoxycinnamoyl]-benzisothiazolinone-1-dioxide 
     227 g (0.1 mole) of 1,4-dimethoxycinnamoyl chloride and 22.66 g (0.11 mole) of anhydrous sodium benzisothiazolinone-1-dioxide were refluxed for 5 h in 150 ml of dry tetrahydrofuran, with mechanical stirring. The reaction mixture was then filtered, the filtrate was concentrated under vacuum, and the product obtained was recrystallized from ethanol, giving 22 8 of 2-[(3,4)-dimethoxycinnamoyl]-benzisothiazolinone-1-dioxide (m.p. 171 ° C.) . 
     EXAMPLE 8-10 
     The method described in Example 7 was used to prepare various compounds with formula I, in which the groups denoted by R 1  and R 2  are shown in Table 1. The acid chloride used here was cinnamoyl chloride in Example 8, dihydrocinnamoyl chloride in Example 9, and p-methoxyphenylbutyryl chloride in Example 10. The melting points of the compounds obtained are given in Table 1. 
     EXAMPLE 11 
     Preparation of compounds (VIIa) and (VIIIA): 1,10-decanedioyl-bis-(2-benzisothiazolin-3-oxo-1,1-dioxide and 1-carboxynonanoyl-10-(2-benzisothiazolin-3oxo-1,1-dioxide) ##STR23## 
     A mixture of 9 g (0.05 mole) of sebacoyl chloride and 20.6 g (0.1 mole) of sodium benzisothiazolinone-1-dioxide was refluxed for 4 h. The reaction mixture was then filtered, and the filtrate was concentrated under vacuum. The resulting compounds VIIa and VIIIa were separated by preparative high-pressure liquid chromatography, using a reversed-phase C18 column and a water/acetonitrile gradient. The R f  value of compounds (VIIa) and (VIIIa) was respectively 0.8 and 0.2 when eluted on silica with a 99:1 chloroform-methanol mixture (by volume). 
     Both the mixture of compounds VIIa and VIIIa and each of them separately can be used as an elastase inhibitor. 
     EXAMPLE 12 
     Inhibition of human leucocytic elastase 
     The inhibition test was carried out by using succinyltrialanine p-nitroanilide as a synthetic substrate. Human leucocytic elastase, used at a concentration of 1 μg/ml, was first pre-incubated for 15 min with the compounds of the invention, used at a concentration of 0.5, 5, 10, 25 and 50 μg/ml. These compounds were added in the form of a solution in acetone, the final acetone concentration of the reaction mixture being 1%. 
     The degree of hydrolysis of the substrate was determined by measuring the amount of p-nitroaniline released, using a Philips PO 8700 spectraphotometer at 410 nm. The 50% inhibitory concentration (IC 50 ) in mole/liter was then determined by a graphical method, using the inhibition values obtained with the different concentrations of the substrate and the inhibitor. Table 1 shows the IC 50  values obtained for the compounds of the invention prepared in Examples 1-5. It can thus be seen that the inhibitory action of these compounds increases with the number of carbon atoms in the R 2  group on going from C 9  to C 17 . 
     
                       TABLE I______________________________________ExampleNo.    R.sup.1        R.sup.2          M.p. °C.                                IC.sub.50 mole/l______________________________________1      H     C.sub.11 H.sub.23                         85     1.1 × 10.sup.-52      H     C.sub.13 H.sub.27                         89     9.2 × 10.sup.-63      H     C.sub.15 H.sub.31                         94     2.1 × 10.sup.-64      H     C.sub.17 H.sub.35                         90     4.7 × 10.sup.-65      H      C.sub.9 H.sub.19                         84     8.6 × 10.sup.-56      H     C.sub.10 H.sub.19                         75     7.5 × 10.sup.-57      H         ##STR24##       171      5 × 10.sup.-68      H         ##STR25##       222      9 × 10.sup.-59      H         ##STR26##       142    4.8 × 10.sup.-510     H         ##STR27##       142    3.6 × 10.sup.-5______________________________________ 
    
     EXAMPLE 13 
     Protective action of 2-lauroylbenzisothiazolinone-1-dioxide on elastin and its inhibition of human leucocytic elastase 
     Three series of tests were carried out here to illustrate the manner by which the compound prepared in Example 1 inhibits the elastase. 
     1) Inhibitory action. The elastase, used in a concentration of 1 μg/ml, was incubated for 10 min with different amounts of 2-lauroylbenzisothiazolinone-1-dioxide in a 100-mM tris-HCl buffer (pH 8.4) containing 0.01% of BriJ 35 and 0.01% of NaN 3 . Tritiated insoluble elastin extracted from the nuchal ligament was then added in a concentration of 75 μg/ml, corresponding to a radioactivity level of 2.2×10 6  counts per minute (cpm) per ml. 
     2) Protective action. The substances and concentrations were the same as above, but the insoluble elastin was incubated with 2-lauroylbenzisothiazolinone-1-dioxide for 30 min before the introduction of human leucocytic elastase. 
     3) Third series. Again the same substances and concentrations were used as before, but the insoluble elastin was first incubated with 2-lauroylbenzisothiazolinone-1-dioxide for 10 min. The mixture was then centrifuged, the supernatant was discarded, and the residue was suspended in the buffer that contained human leucocytic elastase. 
     The degree of the hydrolysis of elastin was calculated in all three cases after incubation with elastase for 7 h at 37° C. by determining the radioactivity in the solubilized peptides derived from the elastin. 
     The aim of the first series was to determine the direct ability of 2-lauroylbenzisothiazolinone-1-dioxide to inhibit the activity of human leucocytic elastase. The results show that, when used in a concentration of 45 μg/ml, 2-lauroylbenzisothiazolinone-1-dioxide inhibits the elastin-cleaving activity of human leucocytic elastase by 80%, the value of IC 50  being 7.5×10 -5  M. 
     The second and third series of investigations showed that the compound of the invention also protects the insoluble elastic fibres from the action of human leucocytic elastase with a maximum inhibition of 50% when used in a concentration of 50-100 μg/ml, the IC 50  value being 1.3-2.9×10 -4  M. 
     EXAMPLE 14 
     Protective action of 2-lauroylbenzoisothiazolinone-1-dioxide on the elastin in rabbit skin 
     Frozen biopsy specimens of rabbit skin having a thickness of 6μ were treated either with human leucocytic elastase in a concentration of 15 μg/ml or with a mixture of this and 2-lauroylbenzisothiazolinone-1-dioxide, prepared in Example 1 and used in a concentration of 350 μg/ml. 
     The segments of rabbit skin were incubated for 1.5 h at 37° C. In the control experiment, they were incubated only with the buffer (100-mM tris-HCl, 0.1% of Brim 35, pH 8) under the same conditions. 
     Thin sections of the skin specimens were then fixed for 2 min in 95% ethanol and stained for 3 h by a modified Verhoeff method, described by Godeau et al. [cf. Pathol. Biol., 32 (1984) pp. 215-6]. After a suitable contrast treatment, the surface density of the elastic fibres was determined by automatic image analysis, carried out directly on the microscope slides. 
     In the absence of elastase, the volume fraction V occupied by the cutaneous elastic fibres was 6.25±0.5%. After treatment with human leucocytic elastase, this value was only 4.1±0.8%. When the elastase was first incubated with 2-lauroylbenzisothiazolinone-1-dioxide, however, the value of V was 6.00±1%, which indicates a virtually complete (96%) protection from the action of elastase. 
     EXAMPLE 15 
     Determination of the inhibition of other serine-containing proteases 
     The inhibition exerted by the following two compounds on serine-containing proteases other that, human leucocytic elastase was determined in this Example: 
     2-butyryl-benzisothiazolinone-1-dioxide (B) and 
     2-palmitoyl-2-benzisothiazolinone-1-dioxide (P). 
     More specifically, the activity of a) pig pancreatic elastase, b) trypsin, c) thrombin and d) plasmin was determined in the presence of these inhibitors and of the synthetic substrates: a) succlnyltrialanine p-nitroanilide, b) N-benzoyl-DL-arginine p-nitroanilide, c) N-p-tosyl-gly-pro-arg p-nitroanilide and d) N-p-tosyl-gly-pro-lys p-nitroanilide, respectively. 
     Each enzyme was first incubated for 15 min with 0-50 μg/ml of compound B or P mentioned above, which had been dissolved in acetone as in the test with burned leucocytic elastase, the final concentration of this solvent in the reaction mixture being 1%. 
     The appropriate substrate was then added to each enzyme, and its hydrolysis was monitored with a Philips 8700 spectraphotometer at 410 nm by measuring the amount of p-nitroaniline appearing in the medium. 
     The results were used to plot the inhibition of the enzymatic activity against the amount of inhibitor present in tile medium. These curves were then used to find the median inhibitory concentration (IC 50 ) in mole/l, which inhibits 50% of the enzymatic activity. 
     Inhibition of human leucocytic elastase was also determined, as in Example 12. 
     To be able to compare the inhibitory power of the compounds tested on the various enzymes used, the E/IC 50  value was calculated, where E is the concentration of the enzyme in the reaction mixture (also expressed in mole/l). The higher the value of this quotient, the stronger the inhibitory activity, and therefore the lower the number of moles of the inhibitor that are needed to obtain a 50% inhibition for the same number of moles of the enzyme. 
     The results listed in Table 2 show that palmitoylbenzisothiazolinone-1-dioxide is a better inhibitor than butyrylbenzisothiazolinone-1-dioxide, irrespective of the enzyme used. Furthermore, these inhibitors show different specificities for the different serine proteases employed. Thus, 2-butyrylbenzisothiazolinone-1-dioxide inhibits human leucocytic elastase and pi E  pancreatic elastase more strongly than it inhibits thrombin; it has no effect on plasmin and in fact activates trypsin. 2-Palmitoyl-2-benzisothiazolinone-1-dioxide inhibits human leucocytic elastase, pig pancreatic alasrase and trypsin 20-40 times as strongly as it inhibits thrombin. This indicates that the compound according to the invention, i.e. 2-palmitoyl-benzisothiazolinone-1-dioxide, is much more efficient than 2-butyrylbenzisothiazolinone-1-dioxide, in which the hydrocarbon chain contains fewer than nine carbon atoms. 
     
                       TABLE 2______________________________________        E/IC.sub.60        Butyrylbenziso-                  Palmitoylbenziso-        thiazolinone-                  thiazolinone-        1-dioxide 1-dioxide______________________________________Human leucocytic elastase            7 × 10.sup.-4                      8.1 × 10.sup.-3Pig pancreatic elastase          3.7 × 10.sup.-6                      3.2 × 10.sup.-3Trypsin        activator   4.2 × 10.sup.-3Thrombin       2.3 × 10.sup.-6                      1.8 × 10.sup.-4Plasmin        inactive______________________________________ 
    
     Examples 16-21 illustrate some cosmetic compositions containing elastase inhibitors according to the present invention. 
     EXAMPLE 16 
     This Example illustrates a gel for the treatment of hair, this product containing the compound mentioned in Example 2, i.e. 2-myristoylbenzisothiazolinone-1-dioxide, and having the following composition. 
     
         ______________________________________           Amount, wt-%______________________________________Emulsifier        20.00Silicone oil      20.00Inhibitor from Example 2             2.00Sodium hydroxide  4.551,3-Butanediol    11.00Lactic acid       5.00Water             37.45             100.00______________________________________ 
    
     EXAMPLE 17 
     This Example illustrates a face pack containing the inhibitor used in Example 4, i.e. 2-stearoylbenzisothiazolinone-1-dioxide, and having the following composition, the product being prepared by mixing the ingredients together. 
     
         ______________________________________             Amount, %______________________________________Kaolin              35.00Bentonite           5.00Cetyl alcohol       2.00Potassium dodecyl sulphate               1.00Glycerol            10.00Nipagin M           0.10Inhibitor from Example 4               5.00Perfume             5.00Water               36.90               100.00______________________________________ 
    
     EXAMPLE 18 
     This Example illustrates a lotion suitable for the treatment of nails, containing the inhibitor used in Example 6, i.e. 2-undecenoylbenzisothiazolinone-1-dioxide, and having the following composition, the lotion (which had a pH of 4.4) being prepared by homogenizing the mixture of its ingredients. 
     
         ______________________________________            Amount, %______________________________________Inhibitor from Example 6              6.00Sodium hydroxide   1.50Ethanol            10.001,2-Propanediol    55.00Water              27.50              100.00______________________________________ 
    
     EXAMPLE 19 
     This Example illustrates a skin cream formed by a water-in-oil emulsion and containing the inhibitor from Example 1, i.e. 2-lauroylbenzisothiazolinone-1-dioxide in its continuous oil phase, the composition of the cream being as follows. 
     
         ______________________________________            Amount, wt-%______________________________________Silicones          24.00Sodium chloride    2.00Inhibitor from Example 1              3.00Lactic acid        5.00Humectants         5.00Bleaching agent    0.15Preservatives      0.05Oil of evening primrose              3.00Sunscreens         4.00Bactericides       0.30Water              53.50              100.00______________________________________ 
    
     This skin cream, which had a pH of 4, was prepared by mixing the silicones, the bleaching agent and the preservatives together, adding a mixture of the other ingredients in small portions, and homogenizing the product. 
     EXAMPLE 20 
     This Example illustrates a water-in-oil type cream, which contained sunscreens in its continuous oil phase, together with the inhibitor from Example 7, i.e. 2- (3,4-dimethyoxycinnamoyl)-benzisothiazolinone-1-dioxide. This cream had the following composition. 
     
         ______________________________________            Amount, %______________________________________Silicones          24.00Humectants         10.00Bleaching agent    0.15Preservatives      0.05Oil of evening primrose              3.00Sunscreens         4.00Bactericides       0.30Inhibitor from Example 7              1.00Ammonium hydroxide 2.00Ammonium chloride  2.00Lactic acid        5.00Water              48.50              100.00______________________________________ 
    
     EXAMPLE 21 
     This Example illustrates a water-in-oil type cream that contained sunscreens in its continuous oil phase, together with the inhibitor with formula (VIIa) from Example 11, i.e. 1,10-decanedioyl-bis-(benzisothiazolin-3-oxo-1,1-dioxide), the cream having the following composition. 
     
         ______________________________________            Amount, %______________________________________Silicones          24.00Humectants         10.00Bleaching agent    0.15Preservatives      0.05Oil of evening primrose              3.00Sunscreens         4.00Bactericides       0.30Inhibitor from Example              1.0011 (with formula VIIa)Ammonium hydroxide 2.00Ammonium chloride  2.00Lactic acid        5.00Water              48.50              100.00______________________________________