Title of Invention	"COMPOUND R-(-)-(E)-[4-(,4- DICHLOROPHENYL)-1,3- DITHIOLAN-2-YLIDENE]-1-IMIDAZOLYLACETONITRILE"
Abstract	R-(-)-(E)-[4-(2,4-Dichlorophenyl)-l,3-dithiolan-2-ylidene]-l-imidazolylacetonitrile or a salt thereof.

Full Text

ANT[FUNGAL AGENT, COMPOUND THEREFOR, PROCESS FOR PRODUCING THE SAME, AND METHOD FOR USING THE SAME FIELD OF THE INVENTION The present invention relates to an antifungal agent, a method for preventing or treating mycoses using the antifungal agent , a novel optically active derivative and a salt thereof, arid a process for producing the derivative. BACKGROUND OF THE INVENTION Various azcle compounds having antifungal activity have been known. For example, JP-A-60-218387 discloses imidazole compounds represented by the following formula (a) (the term "JP-A" as used herein means an "unexamined published Japanese patent app 1 i.cat i on ' ) : Moreover, JP-A-62-93227 discloses that these compounds are useful as an antifungal agent. Furthermore, JP-A-2-275877 discloses that the optically active compounds of specific compounds among the above imidazole compounds have antifungal activity against Trichophyton mentagrophytes about 1.4 times the activity of racemlc compounds thereof.SUMMARY OF THE INVENTION An object of the present invention is to provide antifungal agents comprising optically active compounds having more excellent antifungal activity than racemic compounds thereof, Another object of the present invention is to provide the optically active compounds, a process for producing them, and a method for using them. These and other objects of the present invention have been attained by a pharmaceutical composition comprising as an active ingredient H-( + )-(E)-[4-(2-chlorophenyl)-1,3-dithiolan-2-ylidene ]-l -imLdszolylacetonitrile (hereinafter referred to as "Compound (A)") or R-(-)-(E)-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile (hereinafter referred to as 'Compound (B)") represented by the following formula (I): (formula Removed)wherein R represents a hydrogen atom or a chlorine atom, or a pharmaceutically acceptable salt thereof; together with a pharmaceuticaLly acceptable carrier or diluent. Furthermore, these and other objects of the present invention have been attained by Compound (B) or a salt thereof. Morecvei, these and other objects of the present invention have been attained by a process for producing Compound (B) which comprises reacting an optically active glycol derivative represented by the following formula (II) or an equivalent i.hereof with a compound represented by the following formula (III): (formula Removed)wherein X.} and X, are the same or different and each represents a methanesuifonyloxy group, a benzenesulfonyloxy group, a p-toluenesu11onyloxy group, or a halogen atom:wherein M represents an alkali metal atom. Still furthermore, these and other objects of the present invention have been attained by a method for preventing or treating mycosis which comprises administering to human or animals in need of such prevention or treatment a pharmaceuticsLiy effective amount of Compound (A) or Compound(B), or a pharmaceutical acceptable salt thereof; optionally together with a pharmaceutical acceptable carrier or diluent. Still moreover, these and other objects of the present invention have been attained by use of Compound (A) or Compound (B), or a pharniaceutically acceptable salt thereof for preparing a pharmaceutical composition. DETAILED DESCRIPTION OF THE INVENTION Specifically, Compounds (A) and (B) are shown below. Compound (A) ; (formula Removed) Compound(B). (formula Removed) The (..'resent inventors have found that Compound (A) or Compound (B) represented by formula (I) and pharrnaceutically acceptable sal i.s thereof, namely, (R) -enantiomers, have antifungal activity several times that of racemic mixtures thereof against dermatophytes, especially highly sensitive strains, and that Compound (B) which has not been described inany literatures and is a novel compound has superior antifungal activity unexpectable from the racemic mixtures thereof. Thus, the present invention has been accomplished. Compounds (A) and (B) are highly sensitive to, especially, Tn chophyton rubrum. The antifungal activity thereof is 2 to 4 times as high as that of the racemic mixtures thereof. Compound (A) can be produced, for example, by the process disclosed in JP-A-2-275877. Compound (B) can be produced by the? process illustrated below. (formula Removed)In formula, X, and X7 are the same or different and each represents a methanesulionyloxy group, a benzenesulfonyloxy group, a p-toluenesulnesu Ifonyloxy group or a halogen atom; and M represents an al.kali metal atom. Examples of the halogen atom represented by Xt or X-, include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Examples of the alkali ineLa.1 atom represented by M include Li, Na and K. That is, in the same manner as described in JP-A-2-275877, Compound { B) can be produced by reacting an optically active glycol derivative having a configuration of (S) represented by formula (II) or an equivalent thereof with a dithiolate salt represented by formula (III). The (; iti'.j olate salt represented by formula (III) can be produced by reacting 1-cyanomethylimidazole shown below with carbon disulfide in the presence of a base and an inert solvent. In formula, M is the same as defined above. Any i neit Holvents can be used in the above reaction as far as they do not inhibit the progress of the reaction. Examples thereof Include.' alcohols (e.g., methanol, ethanol, i sopropanol ) ,. poJar .solvents (e.g., dimethyl sulfoxide (DMSO), dimethyl f 01 formaide , acetonitrile ) , water, and mixed solvents thereof.Examples of the base include sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide. They can be used as they are in the form of solid or as a solution in an .inert solvent. Amount (mol) of the base can be selected from the range of 2 to 8 times, preferably 4 to 6 times, the amount (mol) of 1-cyanomethylimidazole. The compound represented by formula (II) can be used in an amount equimolar to or in excess of 1--cyanomethylimidazole. The reaction temperature can be selected from the range of 0 to 1000(', and is preferably about room temperature. The reaction time can be selected from the range of 0.5 to 24 hours. The resulting compound is a mixture of geometrical isomers E and 'L, and the desired E-isomer represented by formula (I) can bo isolated and purified by, e.g., silica gel column chroma tography, fractional crystallization. Examples of solvents for purification by fractional crystallization and recrysta. 1.1 j ,z« ti on .include ethanol, ethyl acetate, ether, hexane, acetone;, and mixed solvents thereof, but these are not 1Imi tat ive. The optically active starting compounds represented by formula (II) can be produced by known processes 1 to 3 i 1 lus tra ted be] c >w,Process 1: (formula Removed)In formula, X, and X2 are the same as defined above. That, is, they can be produced by reacting (S)-l-(2,4-dichlorophenyl)ethane-l,2-diol obtainable from 2,4-dichlorostyrene by a known process [J. Org. Chem. Soc., 57:2768 (1992)] with a suitable halogenating agent (e.g., thionyl chloride, puosphorus Lribromide, carbon tetrachloride/ LrLphenyl.phosph.ine) or an activating agent (e.g., methanesulfony] chloride, toluenesulfonyl chloride, benzenesu]fonyl chloride).Process 2: (formula Removed) In forimi.ia, X represents a chlorine atom or a bromine atom; and X, is th« same as defined above. As j Llustrated above, the compounds represented by formula (11) in which X[ is a chlorine atom or a bromine atom (i.e. the compounds represented by formula (Ila)) can be produced by reacting (R)-1-(2, 4-dichlorophenyl)styrene oxide obtainable from 2,4-dichJorostyrene by a known process [J. Am. Chem. Soc. , 113:7063 (1991)] with a hydrogen halide to prepare a haloalcohoi represented by formula (IV), and then reacting the haloalcohoi with a suitable halogenating agent (e.g., thionyl chloridt , phosphorus tribromide, carbon tetrachloride/ t riphenylphof.ph i ite ) or an activating agent (e.g., methanesul fony1 chloride, toluenesulfonyl chloride, benzenesu 1 f ony] cfiloride ) .Proces_s_J_: The compounds represented by formula (II) in which X2 is a chlorine or bromine atom (i.e., the compounds represented by formula (lib)) can be produced by process 3 shown below. (formula Removed)In formula, X represents a chlorine atom or a bromine atom; and Xs is the same as defined above. That is, ehe desired compounds can be obtained by reacting a haloaLcohol represented by formula (V) which can be synthesized f:rom a 2,4-dichlorophenacyl halide by a known process [Moderri Synthetic Methods, 5:115 (1989)] with a suitable ha 1 oqeruit i rig agent (e.g., thionyl chloride, phosphorus tribroinide, carbon tetrachloride/triphenylphosphine) or an activating agent (e.g., methanesulfonyl chloride, toluenesulfonyl chloride, benzenesulfonyl chloride). The compositions of the present invention are antifungal aqerits useful for curing mycotic infection of human or animals. Foi example, these can be used for curing local mycotic infection, niucosa mycotic infection, generalized mycotic; infection caused by, e.g., fungi of the genera 1'richophyton, Candida, and Aspergillus. Compound (A), Compound (B) and a pharmaceutically acceptable salt thereof are each used alone or in the form of a composition comprising the compound and a pharmaceutically acceptable carrier or diluent. They are formed into preparations suitable for oral or non-oral administration, such as liquid formulation, tablet, emulsion, ointment, cream, lotion, and poultice. The amount administered can be any convenient amount according to age, body weight, and administration form, but is normally at least 0,05 mg, preferably from 0.5 to 50 mg, per 1 kg of body weight and per one day for general treatment of adults and the agent, can be administered at one time or several times in par;.s ;.n one day. In tne case of Local treatment, for example, in the form of topical application, the concentration of the active ingredient i; preferably at least 0.001%, more preferably from 0.1 to 2%. The amount of treatment is preferably from 30 to 100 mg per cm2. The anti. fungal agent of the present invention may be used in admixture with other antifungal agents or antibacterial agents such as amphoterLcin B, trichomycin, varitotin, and clotrimazoJe The present invention will now be illustrated in greater detail with reference to the following Examples, Reference Examples!, Formulation Examples, and Test Examples, but it should be understood that the invention is not construedas being limited thereto. Unless otherwise indicated, all the per cents are by weight. EXAMPLE 1. Preparation of Compound (B) by Process 3: ]-(a). Preparation of (S)-1-(2,4-dichlorophenyl)-2-bromoethanol: (formula Removed) To 5 ml oJ dry tetrahydrofuran (THF) was added 300 mg of ( S ) - 3 , ,3 -ci i pheny 1 - 1-me thyl tetrahydro- III, 3H-pyrrolo-[ 1, 2-c I | 1, 3 , '.-' Joxazaborole , and then thereto was added dropwise 8 ml of 1.0 M borane-TMF solution at -20°C. At the same temperature, thereto was further added dropwise a solution of 2.7 g of 2.4 -d i eh Lorophenacyl bromide in 8 ml of THF. The resultant mixture was heated to room temperature, and then stirred for I hours. Next, 10 ml of methanol was added to decompose excess borane, and then the reaction mixture was poured into water and extracted with ether. The organic layer was washed «,;iUi water and dried over anhydrous magnesium suJlate. The solvent was distilled off under reduced pressure and the r (formula Removed)In 30 nil of methylerie chloride was dissolved 1.6 g of ( S ) - 1 - ( 2 , 4-d :.ch i 01 opheny i ) -2-bromoethanol, and then 660 mg of triethylaniJ no was added to the solution. Next, 750 mg of methanesulfony] chloride was further added dropwise thereto under ice oooling. One hour after stirring at room temperature, tho reaction mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.9 g of a crude product of the desired compound. The resulting crude product was used .for tho next reaction without purification. l-(c). Preparation of (R)-(-)-(E)-[4-(2,4-dichlorophenyl)-1,3-d Ltdj oLan-2-ylidene]-1-imidazolylacetonitrile (Compound (B)): (formula Removed) To .! J 1=1 L of DMSO was added 440 mg of potassium hydroxide, and, under cooling in a water bath, thereto was added dropwi.se t EXAMPLE 2 Preparation of Compound (B) by Process 1: 2-(a). Preparation of (S)- 1-( 2,4-dichlorophenyl)-ethane-1,2- bi smethanesu ifonate: (formula Removed) (S) - i -( '; , 4 -Dj.chlorophenyl )-l, 2-ethanediol (1.5 g; optical purity yO%ee) synthesized by a known process [J". Org. Chem,, 57:2/68 (1992)] and 3.1 g of triethylamine were dissolved in SO ml of methylene chloride and 3.3 g of methanesulfony1 chloride was added dropwise to the solution under ice coo Ling. Two hours after stirring at room temperature, the reaction mixture was washed with water and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2.6 g of a crude product of the desired compound. The resulting crude? product was used for the next reaction without purificat i on. 2-(b). Preparation of (R)-(-)-(E)-[4-(2,4-dichlorophenyl)-1,3~dithiolan-2-ylidene]-1-imidazolylacetonitrile (Compound (B)): (formula Removed)To 20 ml of DMSO was added 1.09 g of potassium hydroxide, and, under cooling in a water bath, thereto was added dropwise 2G ml of DMSO. Two hours after stirring at room temperature, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was disUlled off under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/n-hexane =; 2/1 i. The resulting crystal was recrystallized from a mixed solvent, ol: ethyl acetate-n-hexane to obtain 1.2 g of the desired product at an optical purity of 99%ee. In the above examples, the optical purity was calculated from area percentage >n HPLC using an optical active HPLC column (Chiralcel 01) ( i.Trademark, Dai eel Chemical Industry Ltd.)). REFERENCE EXAMPLE 1 Preparation of > '.}-( E )-[ 4-( 2-chlorophenyl)-1, 3-dithiolan-2-ylidene]-1-ImidazuJylacetonitrile: Synthesis was carried out by the process described in Example 1 of JP-A-62-93227 to obtain a racemic compound having a melting po.nl ol 1.4 3.4 "C and a purity of 99.4%. REFERENCE EXAMPLE 2 Preparation of U- (-*•)-( E ) ~ [ 4- ( 2-chlorophenyl) -1 , 3-dithiolan-2~ ylidene]-1 -imidazolylacetonitrile (Compound (A)): The racemic compound (100 g) obtained in Reference Example 1 wr=s dissolved in 700 to 800 ml of acetone with heating to prepare a supersaturated solution. To this solution was added about 10 mg of a seed crystal of the optically active substance obtained by the process disclosed in JP-A-2-275877, followed by :oo I i rig to 25 °C and leaving for 4 to 15 hours,during which composition of the crystallized solution was analyzed by HPLC using an optical active column and the filtration point was determined. The precipitating crystals were collected by filtration and repeatedly subjected to the same procedure l.o obtain 25 g of R-enantiomer having an optical purity of 99,0%ee. In the above examples, the optical purity was calculated from area percentage in HPLC using an optical active HPLC column (Chiralcel ODR (trademark, Daicel Chemical Industry Ltd,)). FORMULATION EXAMPLE 1 Compound (A) or (B) 10 parts Magnesium stearate 10 parts Lactose 80 parts The above ingredients were uniformly mixed and the mixture was made into powders or fine particles to obtain a p o wd e r p r e p a ;; a t i. o i 'i. FORMULATION EXAMPLE 2 Compound (A) or (B) 50 parts Starch 10 parts Lactose 15 parts Ethy.i ce i lulose 20 parts Pol yv-iny.l. alcohol 5 parts Watei 30 parts The above ingredients were uniformly mixed and kneaded, and then the mixture was ground. The resulting particles were sifted to obtain a granular preparation.FORMULATION EXAMPLE 3 Compound (A) or (B) 0.5 part Nonj.mic surface active agent 2.5 parts Physiological saline solution 97 parts The above ingredients were heated and mixed, and then sterilized to obtain an injection. FORMULATION EXAMPLE 4 Compound (A) or (B) 0.01 part 0,5?, Carboxymethylcellulose 99.99 parts The former was suspended in the latter to obtain a suspens ion, FORMULATION EXAMPLE 5 Compound (A) or (B) 1 part Polyethylene glycoi 400 99 parts The abovei ingredients were mixed to dissolve the compound (A; or (B) to obtain a liquid preparation for pa inting. FORMULATION EXAMPLE 6 Compound ?A) or (B) 2 parts Polyethylene glycoi 400 49 parts Polyethylene glycoi 4000 49 parts The above .ingredients were mixed by heating to dissolve Compound (Ai or (B), and the obtained mixture was cooled to obtai.n an ointment. FORMULATION EXAMPLE 7 Compound (A) or (B) 3 parts 1 , 2-Propanediol 5 parts Glycoroi stearate 5 parts Spermaceti 5 parts Isopropy.l myristate 10 parts PoJys;orbate 4 parts A nij xture of the above ingredients was heated and cooled, and >>8 parts of water was added thereto with stirring to obtain a <:ream> FORMULATION EXAMPLE 8 One pan. of Compound (A) or (B), 5 parts of benzyl alcohol, 30 parts of ethanol and 47 parts of propylene glycol were mixed to dissolve Compound (A) or (B). Then, an aqueous solution compr.i s ing 1 part of Hiviswako 104 (trademark, Wako Junyaku Co., Ltd.) and 1 r> parts of purified water to obtain a uniform solution was added to this solution. Next, 1 part of diisopropanoiami.no was added thereto with stirring to obtain a ge .1. prepa ra t. .• on , FORMULATION EXAMPLE 9 One part, :>f Compound (A) or (B) was dissolved in 5 parts of benzyl alcohol and 5 parts of diethyl sebacate, and thereto were added 5 parts of cetyl alcohol, 6 parts of stearyl alcohol, 1 ;>ari; of soibitan monostearate and 8 parts of po.lyoxyethyl.ene monostearate, followed by heating to 70°C to dissolve them. To the resulting uniform solution kept at 70°C was added a purified water heated to 70°C, followed by cooling with stirrinq to obtain a cream composition. TEST EXAMPLE 1 In vitro Activity against: trichophyton spp.: Minimum inhibitory concentrations (MICs) were determined by the twofold macro-broth dilution method with Sabouraud's glucose broth which constituted with 1% bacto-peptone and 4% qjucose. To each tube containing 9.8 ml of the broth, 0.1 in i of: each testing compound dissolved in DMSO and 0.1 ml of a ; on .i dial suspension (IxlO6 conidia/ml) were added. The fungal growth was observed after incubation for 7 days at 27°C. The MIC was determined as the lowest drug concentration which prevented a visible fungal growth. The results are shown in Table 1, TABLE 1(formula Removed) (Motes) A: Ti i chophyton mentagrophytes B: Trichophyton rubrum TBF : (K)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl- 1-naphthalenemethanearaine hydrochloride (general name: terbinafine) Racemic Compounds (A) and (B) are racemic mixtures of Compounds (A) and (B), respectively. TEST EXAMPLE 2 Therapeutic Hfficacy on Experimental Tinea Pedis in Guinea Pigs with Compound (A): Male Hartley guinea pigs (Japan SLC Inc.) weighing 400 to 620 g wer ; used for the infection study. One side of a paper disc (i .5 mm thick x 8 mm diameter) was covered with a piece of aluminum !:oi 1 while the other side was free to carry the inoculum suspension. The disc was immersed with 50 ul of the inoculum suspension (trichophyton mentagrophytes TIMM 2789, lx.1.08 con id i a-'m.1 ), and was then fixed on the planta pedis of animal feet with an adhesive elastic tape. The disc was removed on the seventh day postinfection. Each agent dissolved in PEG 400 (0 . ] mJ/Locus) was topically applied to the whole soles of guinea pigs once a day for 3 consecutive days, starting on the 10th day postinfection. Five days after the last treatment;, the skin tissue from each planta pedis and the corresponding tarsus of all animals was cut into small blocks (about 2 > 2 ;nm) . Ten skin bJocks obtained from each part ofthe foot, were implanted on a Sabouraud' s glucose agar plate containing antibiotics, and were cultured at 27°C for 14 days. The skin blocks yielding fungal growth were regarded as culture-positive, and the foot, (planta pedis plus tarsus) with more than one culture-positive skin block was considered f ungus-pos.) t : ve In addition, the intensity of infection was assessed by !he scores' based on the number of culture-positive skin blocks. Namely, -MO, + 9, +8, + 7, +6, +5, +4, +3, +2, +1 or 0 was given as the score according to the corresponding number of culture-positive skin blocks out of ten skin blocks studied. Statistical analyses for the rate of fungus-positive feet and th«> average intensity of infection were assessed by Fisher's exact probably test and Mann-Whitney's U-test, respectively ' results are shown in Table 2.TABLE 2 (formula Removed) (Notes) A: p-.O.Ol vs untreated control group B: p C: p'O.OS vs 1% Racemic Compound (A) treated group The ; unquii-positlve rate of the untreated group was 100% and f'unqi. were detected from all of the infected feet. In terms of the average intensity of infection, a high value of t7.7 was obtained in the planta pedis, but it was +5.4 in the tarsus. Thus, this shows a tendency that the degree of infection in the tarsus was lower than in the planta pedis. Nearly the same results were obtained in the PEG 400 treated group and the curative effect by the solvent was not recognjzed. The 1% Racemic Compound (A) treated group showed a significant curative effect as compared with the untreated group and ! he LM-iG 400 treated group, but the fungus-positive ra*te was 40% and the average intensity of infection of the planta pedis and the tarsus was +0.6 and +0.2, respectively, and fungi were detected from four feet among the inoculated ten feet. In the 0,5% Compound (A) treated group, the fungus-positive rate was 20%, which shows that the effect of Compound (A) was twice that, of 1% Racemic Compound (A) , and in the 1% Compound (A) treated group, the remarkable effect that all of the infected feet were cure fungus-negative was obtained, namely, rnyco.iog.icaL.ly complete healing was attained. As a result: of the comparison between Compound (A) and Racemi.c Compound (i\), it became clear that Compound (A) showed a curative effect, markedly higher than Racemic Compound (A) at the same concentration and that when 0.5% Compound (A) and 1% Racemic Compound (A) which were the same in concentration in terms of active ingredient (A.I.) which was Compound (A) were compared, Compound (A) showed the higher effect more than twice that of 1% Raconuc Compound (A) . Considering MIC for T. mentagrophytes TIMM 2789 used for the test, it is clear that Compound (A) had in vitro antifungal activity of 4 times that of Racemic Compound (A) , and this difference in antifungal action was reflected a.) so in the curative test for the .infection model in vivo. TEST EXAMPLE 3 In vitro ant:; fungal activity against Candida albicans: MICs were determined by the twofold micro-broth dilution method with RPMI L640 buffered with morphorino-propanesulf onic acid to a final molarity of 0.165 M (pH 7.0). One hundred µl of a yeast cell suspension (1 to 5xl03 cells/ml) and 100 ul of the compound-containing medium were pipetted into each well flat-bottomed microtiter plates. After incubation for 48 hours at Hf.°C, the turbidity of each well was measured at 630 nm. The MIC was determined as the lowest drug concentraLion which showed 80% inhibition of a control fungal growth (as measured i.n turbidity-increase). The results are shown i.n Tab: e .-. ,TABLE 3 MIC (µa/ml) (formula Removed) (Note ) FCZ: 2- ( 2 ( 4-Difluorophenyl)-1 , 3-bis(1H-1,2,4-triazol-1 yl)-2-propanol (general name: fluconazole) TEST EXAMPLE 4 In vitro anlifungal activity of Compound (B) against Aspergi11 us fumigatus: MICs were determined by the twofold agar dilution method with ras.i tone agar which constituted with 0.9% bacto-casitone, 1% oaoto -yeas t extract, 2% glucose, 0.1% KH7PO/,, 0.1% Na2HPO,,, 1. % Na3C6.H6O1 and 1.6% agar. A loopful of each inoculum (1xlO6 conidj a/ml. ) was streaked onto the agar plate containing a compound, and a fungal growth was observed after incubation for 48 hours at 35°C. The MIC was determined as the lowest drug concentration which prevented a visible fungal growth. The results are shown in Table 4. TABLE 4 MIC (µq/ml) (formula Removed) (Note) ITZ: ( 1 )-l-sec-Butyl-4-[p-[4-[p-[[2R 4S* ] -2-(2 , 4-dichlorophenyl)-2-(1H-1,2,4-triazol-l-y.l methyl )-' , 3-dioxoIan-4-yl jmethoxy ] phenyl ] -1-p.i perazinyl ]phenyl-A2-l,2,4-triazolin-5-one (qeneral name: itraconazol) While the .invent Lon has been described in detail and with reference to specific embodiments thereof, it will be apparent, to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. WE CLAIM: 1. R-(-)-(E)-[4-(2,4-Dichlorophenyl)-l,3-dithiolan-2-ylidene]-l- imidazolylacetonitrile or a salt thereof. 2. A compound as defined in claim 1 substantially as herein described with reference to the foregoing examples.

Documents:

1414-DEL-1999-Abstract.pdf

1414-DEL-1999-Claims.pdf

1414-del-1999-correpondence-others.pdf

1414-del-1999-correpondence-po.pdf

1414-del-1999-description (complete).pdf

1414-DEL-1999-Form-1.pdf

1414-del-1999-form-13.pdf

1414-del-1999-form-19.pdf

1414-DEL-1999-Form-2.pdf

1414-del-1999-form-3.pdf

1414-DEL-1999-Form-5.pdf

1414-del-1999-gpa.pdf

1414-del-1999-petition-137.pdf

abstract.jpg