MXPA98002679A - Derivados de ditiolan, its preparation and its effect terapeut - Google Patents

Abstract

The present invention relates to compounds of the formula (I): wherein one of m and n is 0, and the other is 0, 1 or 2; k is 0 or an integer from 1 to 12; R1 is hydrogen, one of substituents A, which is defined below, or optionally a substituted alkyl group, A represents a single bond, an oxygen atom, a carbonyl group or a group of formula -N (R2) CO-, -N (R2) C, -N (R2) SO2-, -CON (R2) N (R3) CO-, -CON (R2) CO-, -CON (R2) CS, -CON (R2) SO2-, -O-CO-, -ON (R2) CO -, -ON (R2) CO-, -ON (RW) SO2-, -O-CON (R2) N (R3) CO-, -O-CON (R2) CO-, -O-CON (R2) SO2 -, -CO-O-, -CO-CO-, -CO-CON (R2) N (R3) CO-, -CO-CON (R2) CO-, -CO-CON (R2) SO2, -N ( R2) O-, -N (R2) COCO-, -N (R2) N (R3) CO-, -N (R2) N (R3) SO2 -N (R2) CON (R3) N (R4) CO- , -N (R2) CON (R3) CO-, -N (R2) CON (R3SO2, N (R2) CON (R3) SOWN (R4) CO-, wherein R2, R3 and R4 are the same or different and each is hydrogen, alkyl, aryl, aralkyl, acyl or one of the substituents A; B is a single bond, or a group of the formula -N (R5) - or N (R6) N (R5) - wherein R5 and R6 are the same or different is and each is hydrogen, alkyl, aryl, aralkyl, acyl or one of the substituents A, or R5 together with R1 and the nitrogen atom to which they are attached, can form a heterocyclic ring having from 5 to 7 atoms in the ring; or R1 may represent a group of the formula OR7, wherein R7 is alkyl, alkenyl, aralkyl or one of the substituents A, or R1 may represent a hydroxyl group or a group of the formula -OR7, and said substituents A are selected of aryl groups and heterocyclic groups and pharmaceutically acceptable salts thereof having an excellent ability to increase the activity of glutathione reductase and therefore can be used for the treatment or prevention of a variety of diseases, including cataracts

Description

DERIVATIVES OF DITIOIAN, ITS PREPARATION AND ITS THERAPEUTIC EFFECT BACKGROUND OF THE INVENTION The present invention relates to a series of novel dithiolan derivatives which have an excellent ability to increase the activity of glutathione reductase. The invention also provides a method for preparing these compounds and methods and compositions that use them. Glutathione is found in all tissues of the living body, is a reducing agent in cells and plays a very important role in the metabolic processes of oxidation-reduction. In particular, reduced glutathione (GSH), thanks to the presence of a thiol group, plays a key role in several cellular defense and repair mechanisms. Glutathione proxidase catalyses the reactions involved in these mechanisms, and is an important enzyme in the antioxidant system, where peroxidases (eg, hydrogen peroxide, lipid peroxides, etc.) are reduced by GSH. On the other hand, glutathione reductase is an enzyme that reduces oxidized glutathione (oxidized type glutathione: GSSG) in the presence of NADPH to regenerate GSH. The antioxidant system comprising these materials and enzymes protects the cells against the damaging effects of oxidizing materials (for example, the peroxides described above, free radicals, etc.). Oxidative adverse conditions occur when the balance between the oxidizing materials and the antioxidant mechanisms are changed in favor of the former [J. Appl. Physiol. 1996, Nov. 81 (5), 2199-2202]. It has been reported that adverse oxidative conditions are associated with several diseases, such as coronary heart disease, cataracts, lung diseases (for example, idiopathic pulmonary fibrosis, adult repiratory failure syndrome, emphysema, asthma, bronchopulmonary dysplasia and interstitial pulmonary fibrosis). , chronic kidney failure, nervous system disorders (eg, Parkinson's disease, schizophrenia, Alzheimer's disease, epilepsy, aminotrophic lateral sclerosis and cerebral ischemia), gastric ulcers, diabetes, hepatocyte necrosis and apoptosis including ethanol-induced liver disease, viral diseases (including influenza, hepatitis B and HIV), and colorectal cancer [J. Appl. Physiol. 1996, Nov. 81 (5), 2199-2202; Free Radical Biology & Medicine, Vol, 21 No. 6, 845-853 (1996); Free Radical Biology & Medicine, Vol. 20 No. 7, 925-931 (1996); Gastroenterology, 112, 855-863 (1997); Free Radical Biology & Medicine, Vol. 34, 161-165 (1996); Lancet, 338, 215-216 (1991); Diabetology, 39, 357-363 (1996); Eur. J. Cancer, 1996, Jan, 32A (1), 30-38; Am. J. Med., 1991, Sep. 30. 91 (3c), 95s-105s Alcohol. Clin. Exp. Res. 1996. Dec. 20 (9 Suppl.), 340A-346A Free Radical Biology & Medicine, Vol. 21 No. 5, 641-649 (1996) Pharmacol. Toxicol., 1997 Apr, 80 (4), 159-166; Cell. Mol. Biol. (Noisy-le-grand) 1996 Feb. 42 (1), 17-26; Prostaglandins. Leukot. Essent. Fatty Acids, 1996 Aug., 55 (1-2), 33-43; FASEB J., 1995 Sep., 9 (12), 1173-1182]. In addition to the above, it is thought that adverse oxidative conditions are a factor in Down's syndrome, nephritis, pancreatitis, dermatitis, fatigue, rheumatism, various malformations (for example, Duchenne muscular dystrophy, Becker's dystrophy, Dubin's syndrome). Johnson-Spring, favism, etc.), Fanconi anemia, cancers and metastases, septicemia, increased blood vessel permeability, leukocyte adherence, rhinopathy of prematurity, siderosis, toxic effects of drugs (eg, carcinostatic, including chelate, platinum, antibiotics, antiparasitics, paraquat, carbon tetrachloride and halothane) and rasiogenic damage [Yoshihiko Oyanagi, superoxide dismutase and agents that control active oxygen species]. In the W094 / 12527 patent it is described that the compounds that increase the synthesis of endogenous GSH are suitable for human therapy, in particular for the treatment of several diseases induced by glutathione deficiency, such as pathological states related to oxidative tissue damage, particularly when it occurs as a result of an excess of free radicals. Some examples of such diseases are: imbalance of intracellular oxidative state after excessive use of alcohol, exposure to xenobiotic agents, damage caused by radiation, liver diseases, intoxication by drugs and chemical agents, heavy metal poisoning, physiological brain aging (for example , Parkinson's disease), degeneration of the brain due to reduction in glutathione levels caused by altered antioxidant defense mechanisms, such as chronic neurodegenerative diseases (eg, acute pathologies, such as acute ischemic states, in particular cerebral stroke, hypoglycemia and epileptic attacks; chronic pathologies such as: amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's chorea), diseases related to immune system functionality, in particular that results from immunotherapy of tumors, and infertility, in particular, male infertility. It is also described that the examples are suitable for organ reperfusion followed by ischemic events mainly attributable to free radicals. Furthermore, in Japanese Patent Publication Kokai Showa 64-26516, it is disclosed that a compound that requires increased levels of glutathione is useful for the treatment and prevention of various diseases, including cataracts, liver disorders, nephritic diseases. At this time, lipoic acid (thioctic acid), which has a ring of dithiolan in its molecule, is known to influence the biosynthesis and regeneration of reduced glutathione [I. Maitra et al., Free Radical Biology & Medicine, Vol. 18, No. 4,823-829 (1995)]. In this literature, it is reported that the total level of glutathione (oxidized and reduced glutathione) is reduced by the administration of butionine sulfoxamide (BSO), which is an inhibitor of glutathione synthetase, to newborn rats, that the decrease is prevented by administering lipoic acid together with BSO, and that the formation of cataracts is suppressed. In addition, the literature describes a test about the effects on glutathione reductase achieved by administering only BSO or ad in both BSO and lipoic acid. Considering these results, it is understood that the activity of glutathione reductase does not change when only BSO is administered, and that the activity of glutathione reductase does not increase when lipoic acid is administered in addition to BSO. Therefore, from the literature it can be deduced that the total level of glutathione will increase and that the disorders can be treated when lipoic acid is administered to a patient suffering from a disease caused by deficiency of glutathione synthesis, but it is thought that that lipoic acid does not provide a sufficient effect against diseases that occur despite sufficient synthesis of glutathione since it is understood that it does not increase the activity of glutathione reductase. Conversely, if the activity of glutathione reductase can be increased, then whether or not the synthesis of glutathione is adequate, diseases will occur despite sufficient glutathione synthesis and what is caused by adverse oxidative conditions can be prevented or treated. since the supply of reduced glutathione is increased. In addition, in general, in the case of ophthalmological diseases, such as cataracts, topical application to the eyes is preferred to oral administration. However, since lipoic acid is a powerful stimulant, it is impossible to administer it to the eyes. A number of dithiolan derivatives have now been discovered, which have the ability to cause a significant increase in glutathione reductase activity and also eliminate peroxides. In addition, the compounds of the present invention are less stimulant for eyes than lipoic acid and similar known compounds are therefore especially suitable for topical application. For the avoidance of doubt, the compounds of the present invention are named following the IUPAC rules, using, as appropriate, lipoic acid (also known as thioctic acid) as the original compound. This compound has the formula: An object of the present invention is to provide a series of novel dithiolan derivatives. An additional and more specific object of the present invention is to provide compounds of this type that increase the activity of glutathione reductase.

BRIEF DESCRIPTION OF THE INVENTION The compounds of the present invention are those compounds of the formula (I): where one of m and n represents 0, and the other represents 0, 1 or 2. k represents 0 or an integer from 1 to 12; R 1 represents: a hydrogen atom, a selected group of substituents A, defined below, or an alkyl group having 1 to 12 carbon atoms which is unsubstituted or which is substituted by 1 to 3 substituents selected from the group which consists of substituents A and the substituents Ó or a substituted or unsubstituted alkyl group in which the carbon chain is interrupted by an oxygen atom and / or a sulfur atom; A represents a single bond, an oxygen atom, a carbonyl group or a group of formula -N (R2) C0-, -N (R2) C, -N (R2) S0 -, -CON (R2) N (R3) CO-, -CON (R2) CO-, -CON (R2) CS- , -CON (R2) S0 -, -O-CO-, -ON (R2) CO-, -ON (R2) CO-, -ON (R2) S0 -, -0-CON (R2) N (R3) CO-, -O-CON (R2) CO-, -O-CON (R2) S02-, -CO-O-, -CO-CO-, -CO-CON (R2) N (R3) CO-, - CO-CON (R2) CO-, -CO-CON (R2) S02-, -N (R2) 0-, -N (R2) COCO-, -N (R2) N (R3) CO-, -N ( R2) N (R3) S02 -N (R2) CON (R3) N (R4) CO-, -N (R2) CON (R3) CO-, -N (R2) CON (R3) S02, or -N ( R2) CON (R3) S02N (R) CO- wherein R2, R3 and R4 are the same or different and each represents a hydrogen atom, an alkyl group having from 1 to 12 carbon atoms, an aralkyl group, an aralkyl group whose aryl portion is substituted with 1 to 3 groups selected from the group consisting of the group of β substituents, an acyl group or a group selected from the group consisting of substituents A; B represents a single bond, or a group of the formula -N (R ^) - or N (R6) N (R5) - wherein R ^ and R ^ are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an aralkyl group, an aralkyl group whose aryl portion is substituted with 1 to 3 groups selected from the group consisting of the group of substituents β, an acyl group or a group selected from the group consisting of substituents Á or, wherein A represents a group of the formula -N (R2 ) CO-, - N (R2) CS-, -CON (R2) N (R3) CO-, -CON (R2) CO-, -CON (R2) CO-, - CON (R2) CS-, -O -CO-, -ON (R2) CO-, -O-CO (R2) N (R3) CO-, -0- CON (R2) CO-, -CO-CON (R2) N (R3) CO-, -C0-C0N (R2) CO-, N (R2) N (R3) CO-, -N (R2) CON (R3) N (R4) CO- or -N (R2) CON (R3) C0- [en where R2, R3 and R4 are as defined above] and B represents a single bond, R1 may represent a group of the formula -OR7 (wherein R7 represents a lower alkyl group, a lower alkenyl group, or aralkyl group, a group aralkyl whose aryl portion is substituted with 1 to 3 sele groups of the group consisting of the group of substituents β, an acyl group or a group. selected from the group consisting of substituents A); or, where A represents a group of the formula -CON (R2) S02-, - ON (R2) S02-, -O-CON (R2) S02-, -C0-C0-, -CO-CON (R2) S02-, N (R2) C0C0-, -N (R2) N (R3) S02 or -N (R2) CON (R3) S0 [where R2 and R3 are as defined above] and B represents a single bond, or, in where A does not represent an oxygen atom, a group of the formula -CO-O- or -N (R6) 0- and B represents -N (R5) - [where R5 is as defined above], R ^ can represent a hydroxyl group or a group of the formula -OR7 (wherein R7 is as defined above); Substituents A are selected from the group consisting of aryl groups, heterocyclic groups, aryl groups substituted with 1 to 3 of the β substituents, and substituted heterocyclic groups of 1 to 3 of the β substituents; The β substituents are selected from the group consisting of lower alkyl groups, halogenated lower alkyl groups, lower alkoxy groups, lower alkylthio groups, hydroxyl groups, carboxyl groups, carbamoyl groups whose nitrogen atom can be substituted, lower alkoxycarbonyl groups, halogen atoms , nitro groups, amine residues, sulfo groups, sulfamoyl groups, cyano groups, hydroxyl-substituted lower alkyl groups; The O substituents are selected from the group consisting of lower alkoxy groups, lower alkylthio groups, hydroxyl groups, nitroxy groups, carboxyl groups, lower alkoxycarbonyl groups, halogen atoms, sulfo groups, sulfamoyl groups, amine residues, carbamoyl groups whose nitrogen can be replaced; ALWAYS WHERE: where A represents an oxygen atom, B represents a single bond or a group of the formula -N (R ^) - [where R ^ is as defined above], where A represents a group of the formula -CO-O- or - N (R2) 0- [where R2 is as defined above], B represents a single bond, and where k represents 4, the group of the formula -ABR ^ does not represent a group carboxyl and pharmaceutically acceptable salts thereof. The present invention also provides a method for increasing the activity of glutathione reductase in a mammal, which can be a human, by administering to said mammal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.

The present invention also provides a method of treating or preventing cataracts in a mammal, which can be a human, by administering to said animal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION In the compounds of the present invention, one of myn reprsenta 0, and the other represents 0, 1 or 2. Preferably, any of m and n represents 0, or one of m and n represents 0 and the other represents 1. Very prudently, both m and n represents 0. The inventors of the present prefer those compounds of the formula (I) wherein k represents 0 or an integer from 1 to 6., most preferably, an integer from 2 to 6, and most preferably still an integer from 4 to 6. Where R ^ or substituent Á represents an aryl group, this is a carbocyclic aromatic hydrocarbon group having from 6 to 14 carbon atoms. ring carbon in one or more aromatic carbocyclic rings or is such a group that is fused to a cycloalkyl group having from 3 to 10 carbon atoms in the ring. Examples of carbocyclic aromatic hydrocarbon groups having from 6 to 14 ring carbon atoms in one or more aromatic carbocyclic rings include the fnyl, naphthyl (1- or 2-naphthyl), phenanthrenyl and anthracenyl groups. An example of a group in which an aromatic carbocyclic ring is fused to a cycloalkyl group is the 2-indanyl group. Where R1 or substituent A represents a heterocyclic group, it has from 5 to 7 ring atoms, of which 1 to 3 are heterogeneous atoms selected from the group consisting of heterogeneous atoms of sulfur, oxygen and nitrogen. The group can be saturated or can be unsaturated and preferably aromatic. Where the heterocyclic groups mentioned herein have 3 heterogeneous atoms, it is preferred that the three, two or one of these atoms are nitrogen and, correspondingly, none, one or two are sulfur and / or oxygen atoms. Examples of such saturated heterocyclic groups include, for example, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, dithiolanyl, thiadiazolidinyl, oxadiazolidinyl, dithiazolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl and homopiperazinyl groups. Of these groups, particularly preferred are saturated 5- to 7-membered heterocyclic groups having one or two nitrogen atoms or having a nitrogen atom and a sulfur atom or an oxygen atom, such as the pyrrolidinyl, thiazolidinyl, imidazolidinyl groups , piperidyl, morpholinyl, thiomorpholinyl and piperazinyl. If desired, the saturated heterocyclic groups described above may be substituted by one or two atoms selected from the group consisting of sulfur atoms and oxygen atoms to form an oxo group and / or a thioxo group. Examples of such groups include the piperidonyl, pyrrolidonyl, thiazolidonyl, dioxothiazolidinyl, thioxodithiazolidinyl, dioxoimidazolidinyl and dioxoxazolidinyl groups. Also, if desired, the saturated heterocyclic group described above may be fused with another cyclic group, preferably having 3, 4, 5 or 6 ring atoms, and which may be carbocyclic or heterocyclic, most preferably a benzene ring. Examples of such fused ring groups include the benzodioxanyl, indolinyl, isoindolinyl, benzooxazinium, benzothiazolidinyl, benzthiazinyl, chromanyl, 6-acetoxy-2,5,7,8-tetramethylchroman-2-yl and isoindol-1,3-dionium groups. 2-ilo. Examples of such aromatic heterocyclic groups include furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl groups. Of these, 5- to 7-membered aromatic heterocyclic groups having at least one nitrogen atom and may have an oxygen atom or a sulfur atom are preferred. Examples of such groups include pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl groups. The most preferred are the pyridyl, imidazolyl, oxazolyl, pyrazinyl and thiazolyl groups. Also, if desired, the aromatic heterocyclic group described above may be fused with another cyclic group, preferably having 3, 4, 5 or 6 ring atoms, and which may be carbocyclic or heterocyclic, most preferably a benzene ring. Examples of said fused ring groups include the indolyl groups, benzofuryl, benzothienyl, benzooxazolyl, benzoimidazolyl, quinolyl, isoquinolyl and quinoxalyl. Also, the aromatic heterocyclic groups described above may be substituted by one or more atoms selected from the group consisting of sulfur atoms and oxygen atoms to form an oxo group and / or a thioxo group, and examples of such groups include pyridonyl groups , oxazolonyl, pyrazolonyl, isoxazolonyl and thioxodithiazolyl.

If desired, the above aryl and heterocyclic groups can be substituted by one or more, preferably from 1 to 3, substituents selected from the group consisting of β substituents, defined above and illustrated below. Where R ^ represents an alkyl group having from 1 to 12 carbon atoms, this may be a straight or branched chain group which may be unsubstituted or may be substituted by 1 to 3 substituents selected from the group consisting of substituents O , defined above and illustrated below. Examples of such unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1, 1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylppopyl, hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylbutyl, 1,2-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-di-ethylbutyl, 1,1-trimethylpropyl, 1,2,2-trimethylpropyl, heptyl, 2-heptyl, 3-heptyl , 4-heptyl, 3, 3-dimethylpentyl, octyl, 2-methylheptyl, 2-ethylhexyl, 1, 1,3, 3-tetramethylbutyl, nonyl, 2-nonyl, 3-nonyl, 4-nonyl, 5-nonyl, 2 -methiloctyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 7-methyloctyl, 8-methyloctyl, 6,6-dimethylheptyl, decyl, 2-decyl, 3-decyl, 4-decyl, 5-decyl , 2-methylnonyl, 3-methylnonyl, 4-methylnonyl, 6,6-dimethyloctyl, undecyl, 2-undecyl, 3-undecyl, 4-undecyl, 5-undecyl, 6-undecyl, 2- methyldecyl, 3-methyldecyl, 4-methyldecyl, 5-methyldecyl, 6-methyldecyl, 7-methyldecyl, 8-methyldecyl, 9-methyldecyl, 7-ethylnonyl, dodecyl, 2-dodecyl, 3-dodecyl, 4-dodecyl, 5- dodecyl, 6-dodecyl, 2-methylundecyl, 3-methylundecyl, 4-methylundecyl, 5-methylundecyl, 6-methylundecyl, 7-methylundecyl, 8-methylundecyl, 9-methylundecyl and 10-methylundecyl. Of these, straight or branched chain alkyl groups having from 1 to 6 carbon atoms are preferred, straight or branched chain alkyl groups having from 1 to 4 carbon atoms are more preferred and the methyl, ethyl groups, propyl, isopropyl, butyl and t-butyl are most preferred. Alternatively, R - * - may represent an alkyl group in which the carbon chain is interrupted by one or more oxygen atoms and / or sulfur atoms. Examples of such groups include any of the above alkyl groups which are substituted by a single alkoxy or alkylthio group, which by itself can be substituted by a single alkoxy or alkylthio group, the alkoxy or alkylthio groups being as illustrated below in with the substituents β and Ó. Specific examples of such groups include alkoxyalkyl groups having from 2 to 10 carbon atoms, alkylthioalkyl groups having from 2 to 10 atoms, benzyloxyalkyl groups of which the alkyl part has from 1 to 5 carbon atoms and benzylthioalkyl groups of which the alkyl part has from 1 to 5 carbon atoms (the benzyl part of the benzyloxyalkyl and benzylthioalkyl groups can be unsubstituted or substituted with 1 to 3 substituents of the group consisting of substituents β). Of these, the methoxymethyl, methoxyethyl, ethoxymethyl, methylthiomethyl, methylthioethyl, ethylthiomethyl, benzyloxymethyl, benzyloxyethyl, benzylthiomethyl and 4-methoxybenzylthiomethyl groups are preferred. Where R2, R3, R4, R ^ or R6 represent an alkyl group having from 1 to 12 carbon atoms, this may be a straight or branched chain group, as defined and illustrated above in relation to R1. Where R2, R3, R4, R ^ or R ^ represent an aralkyl group, this is an alkyl group (preferably having 1 to 6 carbon atoms, most preferably 1 to 4 carbon atoms, most preferably still 1 to 3 carbon atoms, the most preferred being 1 or 2 carbon atoms) which is substituted by 1 to 3 aryl groups as defined and illustrated above in relation to R ^. Specific examples of said aralkyl groups include benzyl groups, 1-phenylethyl, 2-phenylethyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl and 9-anthrylmethyl. Of these, benzyl, 1-phenylethyl and 2-phenylethyl groups are preferred. Any of the above groups can be unsubstituted or can be substituted by 1 to 3 substituents selected from the group consisting of substituents Ó which are defined and illustrated below. Where R2, R3, R4, R5 or R6 represent an acyl group, this may be an aliphatic, aromatic or heterocyclic acyl group, for example: an alkylcarbonyl group having from 1 to 30, preferably from 1 to 21 and most preferably from 1 to 8 carbon atoms, such as the formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, isovaleryl, octanoyl, nonylcarbonyl, decylcarbonyl, 3-methylnonylcarbonyl, 8-methylnonylcarbonyl, 3-ethylhexylcarbonyl, 3,7-dimethyloctylcarbonyl, undecylcarbonyl group , didecylcarbonyl, tridecylcarbonyl, tetradecylcarbonyl, pentadecylcarbonyl, hexadecylcarbonyl, 1-methylpentadecylcarbonyl, 14-methylpentadecylcarbonyl, 13, 13-dimethyltetradecylcarbonyl, heptadecylcarbonyl, 15-methylhexadecylcarbonyl, octadecylcarbonyl, 1-methylheptadecylcarbonyl, nonadecylcarbonyl, eicosiscarbonyl and heneicosylcarbonyl; of these, groups having 1 to 5 carbon atoms are preferred; a halogenated alkylcarbonyl group having from 2 to 6 carbon atoms, preferably 2 or 3 carbon atoms, such as the chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl groups; a lower alkoxyalkylcarbonyl group in which the alkyl and alkoxy portions each preferably have 1 to 4 carbon atoms, such as the methoxyacetyl group; an unsaturated alkylcarbonyl group having from 3 to 6 carbon atoms, such as the acryloyl, propiolyl, methacryloyl, crotonoyl, allylcarbonyl, isocrotonoyl and (E) -2-methyl-2-butenoyl groups; an arylcarbonyl group, such as the benzoyl, α-naphthoyl and β-naphthoyl groups; a halogenated arylcarbonyl group, such as the 2-bromobenzoyl and 4-chlorobenzoyl groups; an arylcarbonyl lower-substituted alkyl group, such as 2, 6, trimethylbenzoyl and 4-toluoyl groups; a hydroxy-substituted arylcarbonyl group, such as the groups 3, 5-dimethyl-4-hydroxybenzoyl and 3,5-di-t-butyl-4-hydroxybenzoyl; an arylcarbonyl lower alkoxy substituted group, such as the 4-anisole group; a nitro-substituted arylcarbonyl group, such as the groups 4-nitrobenzoyl and 2-nitrobenzoyl; a lower substituted arylcarbonyl alkoxycarbonyl group, such as the 2- (methoxycarbonyl) benzoyl group; an aryl-substituted arylcarbonyl group, such as the 4-phenylbenzoyl group; a lower alkoxycarbonyl group preferably having from 2 to 7 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl and isobutoxycarbonyl groups; a lower alkoxycarbonyl group, preferably having 2 to 7 carbon atoms, which is substituted with a halogen atom or a lower trialkylsilyl group, such as the 2, 2, 2-trichloroethoxycarbonyl and 2-trimethylsilyl-ethoxycarbonyl groups; an aralkylcarbonyl group, which aryl ring may be unsubstituted or may be substituted with 1 or 2 lower alkoxy or nitro groups, such as the benzylcarbonyl, 4-methoxybenzylcarbonyl, 3,4-dimethoxybenzylcarbonyl, 2-nitrobenzylcarbonyl and 4-nitrobenzylcarbonyl groups; a lower alkanesulfonyl group, preferably having 1 to 6 carbon atoms, such as methanesulfonyl, ethanesulfonyl and propansulfonyl; a halogenated lower alkanesulfonyl group, preferably having 1 to 6 carbon atoms, such as chloromethanesulfonyl, trifluoromethanesulfonyl and pentafluoroethanesulfonyl; and an arylsulfonyl group, in which the aryl part is as defined and illustrated above in relation to R ^, such as the benzenesulfonyl and p-toluenesulfonyl group. Of the above groups, the aliphatic acyl groups, the aromatic acyl quotas, the alkoxycarbonyl groups and the lower alkanesulfonyl groups are preferred, most preferably the alkylcarbonyl groups and the lower alkoxycarbonyl groups. Where R ^, together with R ^ and the nitrogen atom to which they are attached forms a heterocyclic group, it has from 5 to 7, most preferably 5 or 6, atoms in the ring of which 1 to 3 are heterogeneous atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, at least one being a nitrogen atom. Preferably there are one or two nitrogen atoms and none or an oxygen or sulfur atom. Examples of such groups include pyrrolidino, 3-thiazolidinyl, piperidino, piperazino, morpholino, thiomorpholino, homopiperazino, imidazolidinyl and imidazolyl groups. Said groups can be substituted or unsubstituted, preferably with one or two oxygen atoms and / or with 1 to 3 substituents selected from the group consisting of β substituents, as defined above, and can be fused with cyclic gold group, preferably having 3, 4, 5 or 6 atoms in the ring, and which can be fused with another cyclic group, preferably a benzene ring. Examples of such groups are the N-methylpiperazino, N-t-butoxycarbonylpiprazino, 1-indolinyl, 2-carboxy-l-indolinyl groups, 2-methoxycarbonyl-1-indolinyl, 3,4-dimethyl-indolinyl-2, 5-dion-1-yl and isoindol-1, 3-dion-2-yl. Where R7 or a β substituent represents a lower alkyl group, this may be a straight or branched chain group having from 1 to 6, preferably from 1 to 4, carbon atoms, and examples thereof include the methyl, ethyl groups , propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl , 3, 3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl. Of these, alkyl groups having from 1 to 4 carbon atoms are preferred, particularly the methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl groups, particularly the methyl group. Where R7 represents a lower alkenyl group, this may be a branched or branched chain group having from 2 to 6, preferably 3 or 4, carbon atoms, and examples thereof include vinyl, allyl, methallyl, 1- groups propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl and 4-hexenyl, of which vinyl, allyl, methallyl, 1-propenyl, isopropenyl and butenyl groups are preferred, with allyl and 2-butenyl groups being most preferred. Where R7 represents an aralkyl group, this may be any of the aralkyl groups defined and illustrated above in relation to R. Where the β substituent represents a halogenated lower alkyl group, this may be any of the above alkyl groups which is substituted by at least one halogen atom. Although there is no critical limitation about the number of halogen substituents and, if desired, the group can be prehalogenated, in general, from 1 to 3 halogen atoms are preferred, selected from the group consisting of fluorine, chlorine, bromine and iodine. Examples of such groups include chloromethyl, fluoromethyl, trichloromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 3-chloropropyl groups. , 3-fluoropropyl, 2-bromopropyl, 3-iodopropyl, 3, 3, 3-trichloropropyl, 3, 3, 3-trifluoropropyl, 4-chlorobutyl, 4-fluorobutyl, 4-bromobutyl and 4-iodobutyl. Where the β substituent or a substituent O represents a lower alkoxy group, this may be a straight or branched chain group having 1 to 6, preferably 1 to 4, carbon atoms, and examples thereof include methoxy groups , ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, 2-methyl-pentyloxy, 1-ethylpentyloxy, 3, 3-dimethylbutoxy, 2,2-dimethylbutoxy, 1, 1 dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy and 2-ethylbutoxy. Of these, those alkoxy groups having 1 to 4 carbon atoms are preferred, particularly the methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy groups, and most preferably the methoxy group. Where the β substituent or a substituent O represents a lower alkylthio group, this may be a straight or branched chain group having 1 to 6, preferably 1 to 4, carbon atoms, and examples thereof include the methylthio groups , ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, t-butylthio, pentylthio, isopentylthio, neopentylthio, 2-methylbutylthio, 1-ethylpropylthio, hexylthio, isohexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1 -methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,3-dimethylbutylthio and 2-ethylbutylthio. Of these, alkylthio groups having from 1 to 4 carbon atoms are preferred, particularly the methylthio, ethylthio, propylthio, isopropylthio, butylthio and isobutylthio groups, and most preferably the methylthio group. Where the β substituent or a substituent O represents an amine residue, this is a group of the formula -NRaRb, where Ra and R ^ are the same or different and each represents a hydrogen atom, a lower alkyl group (as defined and illustrated above in relation to R7 or substituent ß), a cycloalkyl group having from 3 to 8, preferably 5 or 6 ring atoms, an aryl group (as defined and illustrated above in connection with R -'-), an aralkyl group (as defined and illustrated above in relation to R2), a heterocyclic group (as defined and illustrated above in relation to R ^), or Ra and Bz ° together with the nitrogen atom at which are attached represent a heterocyclic group containing nitrogen (as defined and illustrated above in relation to R ^ and R ^). Examples of such groups include: the amino group; alkylamino and dialkylamino groups, such as methylamino, ethylamino, isopropylamino, butylamino, dimethylamino, diethylamino, diisopropylamino and dibutylamino; cycloalkylamino and dicycloalkylamino groups, such as the cyclopentylamino, cyclohexylamino, dicyclopentylamino and dicyclohexylamino groups; saturated cyclic amino groups, that is, heterocyclic groups having a nitrogen atom in the ring, such as the pyrrolidino, piperidino, piperazino, N-methylpiperazino, morpholino and thiomorpholino groups; aryl- and alkylamino groups of which the nitrogen atom can be an atom substituted with a lower alkyl group, such as the anilino, benzylamino, N-methylanilino and N-methylbenzylamino groups; and a heterocyclic-substituted amino group, in which the nitrogen atom can be substituted with a lower alkyl group, such as the pyridylamino, N-methylpyridylamino and N-ethylpyridylamino groups. Of these, the amino group, mono- and dialkylamino groups, saturated cyclic amico groups (such as the pyrrolidino, piperidino, N-methylpiperazino, morpholino and thiomorpholino groups) and aryl- and aralkylamino groups from which the nitrogen atom can be used are preferred. to be substituted with a lower alkyl group (such as the anilino, benzylamino, N-methylanilino and N-methylbenzylamino groups). Where the β substituent or a substituent Ó represents a carbamoyl group whose nitrogen atom can be substituted, this is a group of the formula -C0NRa'Rk ', where Ra' and 'are the same or different and each represents any of the atoms or groups represented by Ra or Rb or one of Ra and represents a hydrogen atom and the other represents an acyl group (which may be any of the acyl groups defined and illustrated above in relation to R2) or an aminosulfonyl group. Examples of said carbamoyl groups include: the carbamoyl group; alkylcarbamoyl and dialkylcarbamoyl groups, such as the methylcarbamoyl, ethylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, diisopropylcarbamoyl and dibutylcarbamoyl groups; cycloalkylcarba oyl and dicycloalkylcarbamoyl groups, such as the cyclopentylcarbamoyl, cyclohexylcarbamoyl, dicyclopentylcarbamoyl and dicyclohexylcarbamoyl groups; unsaturated cyclic aminocarbonyl groups, i.e., carbonyl groups attached to a heterocyclic group having a ring nitrogen atom, such as the pyrrodinocarbonyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbonyl, morpholinocarbonyl and thiomorpholinocarbonyl groups; aryl- and aralkylcarbamoyl groups whose nitrogen atom can be substituted with a lower alkyl group, such as the phenylcarbamoyl, benzylcarbamoyl, N-methylphenylcarbamoyl and N-methylbenzylcarbamoyl groups; heterocyclic-substituted carbamoyl groups, in which the nitrogen atom can be substituted with a lower alkyl group, such as the pyridylcarbamoyl, N-methylpyridylcarbamoyl and N-ethylpyridylcarbamoyl groups; and acylcarbamoyl groups, especially alkanesulfonylaminocarbonyl, such as the methanesulfonylaminocarbonyl group and the aminosulfonylaminocarbonyl group. Of these, the carbamoyl group, mono- and dialkylcarbamoyl groups, saturated cyclic carbamoyl groups are preferred (such as the pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl, N-methylpiperazinocarbonyl, morpholinocarbonyl and thiomorpholinocarbonyl groups), aryl- and aralkylcarbamoyl groups of which the nitrogen atom can be substituted with a lower alkyl group (such as the phenylcarbamoyl, benzylcarbamoyl, N groups) -methylphenylcarbamoyl and N-methylbenzylcarbamoyl) or an alkanesulfonylaminocarbonyl group (such as the methanesulphonylaminocarbonyl group). Where the β substituent or a substituent O represents a lower alkylcarbonyl group, this may be a straight or branched chain group having from 1 to 6, preferably from 1 to 4, carbon atoms in the alkoxy part (ie, from 2 to 7 carbon atoms in the alkoxycarbonyl portion), and examples thereof include the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl groups, 2-methylbutoxycarbonyl, 1-ethylpropoxycarbonyl, hexyloxycarbonyl, isohexyloxycarbonyl, 4-methylpentyloxycarbonyl, 3,3-methylpentyloxycarbonyl, 2,2-methylpentyloxycarbonyl, 1-methylpentyloxycarbonyl, 3-methylpentyloxycarbonyl, 2-methylpentyloxycarbonyl, 1-methylpentyloxycarbonyl, 3,3- dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl, 2,3-dimethylbutoxycarbonyl and 2-ethylbutoxycarbonyl. Of these, alkoxycarbonyl groups having from 1 to 4 carbon atoms are preferred, particularly the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and t-butoxycarbonyl groups, and most preferably the methoxycarbonyl group. Where the substituent β or a substituent O represents a halogen atom, this may be a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom. Where the β-substituent represents a hydroxy-substituted lower alkyl group, this may be one of any of the alkyl groups defined and illustrated above in relation to R 2 which is substituted by one or more hydroxyl groups. Examples of such groups include the hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups. Of the compounds of the present invention, those compounds of the formula (I) in which the group of the formula - (CH2) ^ -ABRI is attached at the 3-position of the dithiolan ring are preferred. Said compounds can be represented by the formula (I '): (in which A, B, R1, k, m and n_ are as defined above). Where the compounds of the present invention possess a basic group, such as an amino or imino group, the compounds can form salts with acids. On the other hand, wherein the compounds of the present invention possess an acidic group, such as a carboxyl group or an imido group, can form salts with bases. There is no particular restriction on the nature of said salts, provided that, where they are intended for pharmaceutical use, they are pharmaceutically acceptable salts, that is, they are not less active (or unacceptably less active) than the compounds of the formula (I) , and are not more toxic (or unacceptably more toxic) than the compounds of the formula (I).

Examples of such salts formed between a basic group in the compound of the present invention and an acid include: salts with mineral acids, especially halohydric acids (such as hydrofluoric acid, hydrobromic acid, iodhydric acid or hydrochloric acid), nitric acid, perchloric acid , carbonic acid, sulfuric acid or phosphoric acid; salts with lower alkylsulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonic acid, salts with arylsulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid; salts with organic carboxylic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid or citric acid; and salts with amino acids, such as glycine, lysine, arginine, ornithine, glutamic acid or aspartic acid. Examples of salts formed between an acid group in the compound of the present invention and a base include: salts with an alkali metal, such as sodium, potassium or lithium; salts with alkaline earth metal, such as barium or calcium salts; salts with another metal, such as magnesium, aluminum or iron; ammonium salts; organic base salts, such as a salt with t-octylamine, morpholine, glucosamine, an alkyl ester of phenylglycine, ethylenediamine, N-methylglucamine, guanidine, methylamine, dimethylamine, diethylamine, triethylamine, diisopropylamine, cyclohexylamine, dicyclohexylamine, N, N- dibenzylethylenediamine, chloroprocaine, procaine, diethanolamine, N-benzylphenethylamine, piperazine, tetramethylammonium and tris (hydroxymethyl) aminomethane; and salts with an amino acid, such as glycine, lysine, arginine, ornithine, glutamic acid or aspartic acid. Also, when a compound of the present invention is allowed to stand in air, it can absorb water to form a hydrate. Said hydrates also form part of the present invention. Where a compound of the present invention contains an asymmetric carbon atom in its molecule, it can form optical isomers which are in the R or S configuration. Although these are represented herein by a single molecular formula, the present invention includes the individual isomers isolated and mixtures, including racemates thereof. Where stereospecific synthesis techniques or optically active compounds are employed as starting materials, individual isomers can be prepared directly; on the other hand, if a mixture of isomers is prepared, the individual isomers can be obtained by conventional resolution techniques. Of the compounds of the present invention, those compounds of the formula (I) and salts thereof in which; (A) one of m and n is 0, and the other is 0 or 1; (B) k is 0 or an integer from 1 to 8; (C) R1 is a heterocyclic group, an alkyl group having 1 to 12 carbon atoms that is unsubstituted or is substituted by 1 to 3 substituents selected from the group consisting of substituents A and substituents O or said substituted alkyl group or unsubstituted in which the alkyl chain is interrupted by an oxygen atom and / or sulfur atom, or a hydroxyl group or an alkoxy group having from 1 to 5 carbon atoms; (D) A is a group of the formula -CO-, -C0N (R2) S0 -, -N (R2) C0-, -N (R2) CS-, -CON (R2) CO-, -N (R2 ) C0C0- or -N (R2) S02- [wherein R2 is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms or a benzyl group] (in particular, C0N (R2) S02-, - N (R2) CS-, -C0N (R2) C0-, -N (R2) C0C0- or -N (R2) S02-); (E) B is a single enlce, or a group of the formula -N (R ^) - or -N (R5) N (RÉ>) - [where R ^ and R ^ are the same or different and each one is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms or a benzyl group]; Of the above, those compounds of the formula (I) in which m and n are as defined in (A) above, are particularly preferred, k is as defined in (B) above, R ^ is as defined in (C) previously, A is as defined in (D) above, and B is as defined in (E) above. The most preferred compounds of the present invention are those compounds of the formula (I) and salts thereof in which: (F) m and n are 0; (G) k is an integer from 2 to 6; (H) R1 is an alkyl group having from 1 to 5 carbon atoms, an alkoxycarbonylalkyl group having from 3 to 8 carbon atoms, a carboxyalkyl group having from 2 to 7 carbon atoms, a hydroxyalkyl group having from 2 to 5 carbon atoms, a heterocyclic group, an alkoxy group having 1 to 5 carbon atoms or a hydroxyl group; (I) A is a group of the formula -CO-, -C0N (R2) S02-, -N (R2) C0-, -N (R2) CS-, -C0N (R2) C0-, -N (R2 ) C0C0- or -N (R2) S02- [wherein R2 is a hydrogen atom or an alkyl group having 1 to 12 carbon atoms] (in particular, -C0N (R2) S02-, -N (R2 ) CS-, -C0N (R2) C0-, -N (R2) C0C0- or -N (R2) S02-); (J) B is a single enlce, or a group of the formula -N (R5) - or -N (R5) N (R6) - [where R5 and R6 are the same or different and each is an hydrogen or an alkyl group having from 1 to 12 carbon atoms] Of the above, those compounds of the formula (I) in which m and n are as defined in (F) above, are particularly preferred, k is as defined in (G) above, R ^ - is as defined in (H) above, A is as defined in (I) above, and B is as defined in (J) above. The most preferred compounds of the present invention are those compounds of the formula (I) and salts thereof in which: (K) m and n are 0; (L) k is 4 or 5; (M) R1 is an alkyl group having from 1 to 5 carbon atoms, an alkoxycarbonylalkyl group having from 3 to 8 carbon atoms, a carboxyalkyl group having from 2 to 7 carbon atoms, a hydroxyalkyl group having from 2 to 5 carbon atoms, a heterocyclic group or an alkoxy group having from 1 to 5 carbon atoms; (N) A is a group of the formula -C0NHS02-, -C0NCH3S02-, -NHCO-, -NHCS-; -CONHCO-, -NHCOCO-, -NHS0-, O -CO-; (O) B is a single enlce, or a group of the formula -NH-, -NCH3- O -NHNCH3- (; (in particular, -CONHS0-, -CONCH3S02-, -NHCS-; -CONHCO-, -NHCOCO - O -NHS02-) Of the above, those compounds of the formula (I) in which m and n are as defined in (K) above, are particularly preferred, k is as defined in (L) above, R ^ is as defined in (M) above, A is as defined in (N) above, and B is as defined in (0) above. Specific examples of individual compounds of the present invention are shown in the following formulas (I-1), (1-2) and (1-3), in which the substituent groups are as shown in the corresponding table 1 a 3. In the tables, the following abbreviations are used: Ac acetyl; Bu butyl; iBu isobutyl; sBu sec-butyl; tBu t-butyl; Bz benzyl; 1,3-diox-IInd isoindol-1,3-dion-2-yl; 3, 4-diMe-2, 5-diox-l-Imdd 3, 4-dimethyl-imidazolidin-2,5-dion-l-yl; Ethyl hexyl hex; Indin indolinyl; I metyl; Mor morpholino; Ph phenyl; Pipra piperazino; Pipri piperidino; Pn pentyl; iPn isopentyl; Pr propyl; iPr isopropyl; Py pyridyl Pyr pyrrolidinyl; Thiad 3-thiazolidinyl; Thomor thomorpholino. Also, in the tables, the groups represented by Z-l to Z-12 have the following formulas: TABLE 1 TABLE 1 fcon TABLE 1 fcont) TABLE 1 fconti TABLE 1 (cont) TABLE 1 (cont) TABLE 1 (cont) TABLE 1 (cont) TABLE 1 (cont) 48 TABLE 1 (cont) TABLE 1 (cont) TABLE 1 (cont) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) 54 TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 (cont) TABLE 1 icon) 67 TABLE 1 icon) TABLE 1 icon) 69 TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 ícont) 76 TABLE 1 ícont) 77 TABLE 1 icon) 78 TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) 90 TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) 96 TABLE 1 ícont) 97 TABLE 1 icon) TABLE 1 ícont) 99 TABLE 1 ícont) 100 TABLE 1 icon) 101 TABLE 1 icon) 102 TABLE 1 ícont) 103 TABLE 1 icon) 104 TABLE 1 cont) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) 114 TABLE 1 icon) 115 TABLE 1 icon) 116 TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 (cont) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) 126 TABLE 1 (cont) 127 TABLE 1 icon) 128 TABLE 1 icon) TABLE 1 icon) 130 TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 1 icon) TABLE 2 TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) 150 TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) 169 TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 2 ícont) TABLE 3 TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) 253 TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 cont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 icon) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) TABLE 3 ícont) Of the above compounds, compounds No .: 1-1 are preferred, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 1-13, 1- 14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-21, 1-22, 1-23, 1-24, 1-25, 1-26, 1-27, 1-28, 1-29, 1-30, 1-31, 1-32, 1-33, 1-34, 1-35, 1-36, 1-37, 138, 1-39, 1-40, 1-41, 1-42, 1-43, 1-44, 1-45, 1-46, 1-47, 1-48, 1-49, 1-50, 1-51, 1- 52, 1-53, 1-54, 1-55, 1-56, 1-57, 1-58, 1-59, 1-60, 1-61, 1-62, 1-63, 1-64, 1-65, 1-66, 1-67, 1-68, 1-69, 1-70, 1-71, 1-72, 1-73, 1-74, 1-75, 1-76, 1- 77, 1-78, 1-79, 1-80, 1-81, 1-82, 1-83, 1-232, 1-233, 1-234, 1-235, 1-236, 1-237, 1-238, 1-239, 1-240, 1-241, 1-242, 1-243, 1-244, 1-245, 1-246, 1-247, 1-248, 1-249, 1- 250, 1-251, 1-252, 1-253, 1-254, 1-255, 1-256, 1-257, 1-258, 1-259, 1-260, 1-261, 1-262, 1-263, 1-264, 1-265, 1-266, 1-267, 1-268, 1-269, 1-270, 1-271, 1-272, 1-273, 1-274, 1-275, 1 -276, 1-277, 1-278, 1-279, 1-280, 1-281, 1-282, 1-283, 1-284, 1-285, 1-286, 1-287, 1-288 , 1-289, 1-290, 1-291, 1-292, 1-293, 1-294, 1-295, 1-296, 1-297, 1-298, 1-299, 1-300, 1 -301, 1-302, 1-303, 1-304, 1-305, 1-306, 1-307, 1-308, 1-309, 1-310, 1-311, 1-312, 1-313 1-314, 1-315, 1-316, 1-317, 1-318, 1-319, 1-320, 1-321, 1-322, 1-323, 1-324, 1-325, 1 -326, 1-327, 1-328, 1-329, 1-330, 1-331, 1-332, 1-333, 1-334, 1-335, 1-336, 1-337, 1-338 , 1-339, 1-340, 1-341, 1-342, 1-343, 1-344, 1-345, 1-346, 1-347, 1-348, 1-349, 1-350, 1 -351, 1-352, 1-353, 1-354, 1-355, 1-356, 1-357, 1-358, 1-359, 1-360, 1-361, 1-362, 1-363 , 1-364, 1-365, 1-366, 1-367, 1-368, 1-369, 1-370, 1-371, 1-372, 1-373, 1-374, 1-375, 1 -376, 1-377, 1-378, 1-379, 1-380, 1-381, 1-382, 1-383, 1-384, 1-385, 1-386, 1-387, 1-388 , 1-389, 1-390, 1-391, 1-392, 1-393, 1-394, 1-395, 1-396, 1-397, 1-398, 1-399, 1-400, 1 -401, 1-402, 1-403, 1-404, 1-405, 1-40 6, 1-407, 1-408, 1-409, 1410, 1-411, 1-412, 1-413, 1-414, 1-415, 1-416, 1-417, 1-418, 1- 419, 1- 420, 1-421, 1-422, 1-423, 1-424, 1-425, 1-426, 1-427, 1-428, 1-429, 1-430, 1-431, 1-432, 1-433, 1-434, 1-435, 1-436, 1-437, 1-438, 1-439, 1-440, 1-441, 1-442, 1-443, 1- 444, 1-445, 1-446, 1-447, 1-448, 1-449, 1-450, 1-451, 1-452, 1-453, 1-454, 1-455, 1-456, 1-457, 1-458, 1-459, 1-460, 1-461, 1462, 1-463, 1-464, 1-465, 1-466, 1-467, 1-468, 1-469, 1-470, 1-471, 1-472, 1-473, 1-474, 1-475, 1-476, 1-477, 1-478, 1-479, 1-480, 1-481, 1- 482, 1-483, 1-484, 1-485, 1-486, 1-487, 1-488, 1-489, 1-490, 1-491, 1-492, 1-493, 1-494, 1-495, 1-496, 1-497.1-498, 1-499, 1-500, 1-501, 1-502, 1-503, 1-504, 1-505, 1-506, 1-507, 1-508, 1-509, 1-510, 1-511, 1-512, 1-513, 1-514, 1-515, 1-516, 1-517, 1- 518, 1-519, 1-520, 1-521 1-522, 1-523, 1-524, 1-525, 1-526, 1-527, 1-528, 1-529, 1-530, 1 -531, 1-532, 1-533, 1-534, 1-535, 1-536, 1-537, 1-538, 1-539, 1-540, 1-541, 1-542, 1-543 , 1-544, 1-545, 1-546, 1-547, 1-548, 1-549, 1-550, 1-551, 1-552, 1-553, 1-554, 1-555, 1 -556, 1-557, 1-558, 1-559, 1-560, 1-561, 1-562, 1-563, 1-564, 1-565, 1-566, 1-567, 1-568 , 1-569, 1-570, 1-571, 1-572, 1-573, 1-574, 1-575, 1-576, 1-577, 1-578, 1-579, 1-580, 1 -581, 1-582, 1-583, 1-584, 1-585, 1-586, 1-587, 1-588, 1-589, 1-590, 1-591, 1-592, 1-593 , 1-594, 1-595, 1-596, 1-597, 1-598, 1-599, 1-600, 1-601, 1-602, 1-603, 1-604, 1-605, 1-606, 1-607, 1-608, 1- 609, 1-610, 1-611, 1-612, 1-613, 1-614, 1-615, 1-616, 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1-2613, 1-2614, 1-2657, 1-2665, 1 2667, 1-2669, 2-1, 2-2, 2-3, 2-4, 2-5. , 2-6, 2-7, 2-8, 2-9, 2-10, 2-11, 2-12, 2-13, 2-14, 2-15, 2-16, 2-17, 2-18, 2-19, 2-20, 2-21, 2-22, 2-23, 2-24, 2- 25, 2-26, 2-27, 2-28, 2-29, 2-30, 2-31, 2-32, 2-33, 2-34, 2-35, 2-36, 2-37, 2-38, 2-39, 2-40, 2-41, 2-42, 2-43, 2-44, 2-45, 2-46, 2-47, 2-48, 2-49, 2- 50, 2-51, 2-52, 2-53, 2-54, 2-55, 2-56, 2-57, 2-58, 2-59, 2-60, 2-61, 2-62, 2-63, 2-64, 2-65, 2-66, 2-67, 2-68, 2-69, 2-70, 2-71, 2-72, 2-73, 2-74, 2- 75, 2-76, 2-77, 2-78, 2-79, 2-80, 2-81, 2-82, 2-83, 2-232, 2-233, 2-234, 2-235, 2-236, 2-237, 2-238, 2-239, 2-240, 2-241, 2-242, 2-243, 2-244, 2-245, 2-246, 2-247, 2- 248, 2-249, 2-250, 2-251, 2-252, 2-253, 2-254, 2-255, 2-256, 2-257, 2-258, 2-259, 2-260, 2-261, 2-262, 2-263, 2-264, 2-265, 2-266, 2-267, 2-268, 2-269, 2-270, 2-271, 2-272, 2- 273, 2-274, 2-275, 2-276, 2-277, 2-278, 2-279, 2-280, 2-281, 2-282, 2-283, 2-284, 2-285, 2-286, 2-287, 2-288, 2-289, 2-290, 2-291, 2-292, 2-293, 2-294, 2-295, 2-296, 2-297, 2- 298, 2-299, 2-300, 2-301, 2-302, 2-303, 2-304, 2-305, 2-306, 2-307.2-308, 2-309, 2-310, 2-311, 2-312, 2-313, 2-314, 2-315, 2-316, 2-317, 2-318, 2-319, 2-320, 2-321, 2-322, 2-323, 2-324, 2-325, 2-326, 2-327, 2-3285 2-329 , 2-330, 2-331, 2-332, 2-333, 2-334, 2-335, 2-336, 2-337, 2-338, 2-339, 2-340, 2-341, 2 -342, 2-343, 2-344, 2-345, 2-346, 2-347.2-348, 2-349, 2-350, 2-351, 2-352, 2-353, 2-354 , 2-355, 2-356, 2-357, 2-358, 2-359, 2-360, 2-361, 2-362, 2-363, 2-364, 2-365, 2-366, 2- 367, 2-368, 2-369, 2-370, 2-371, 2-372, 2-373, 2-374, 2-375, 2-376, 2-377, 2-378, 2-379, 2-380, 2-381, 2-382, 2-383, 2-384, 2-385, 2-386, 2-387, 2-388, 2-389, 2-390, 2-391, 2- 392, 2-393, 2-394, 2-395, 2-396, 2-397, 2-398, 2-399, 2-400, 2-401, 2- 402, 2-403, 2-404, 2-405, 2-406, 2-407, 2-408, 2-409, 2-410, 2-411, 2-412, 2-413, 2-414, 2-415, 2-416, 2- 417, 2-418, 2-419, 2-420, 2-421, 2-422, 2-423, 2-424, 2-425, 2-426, 2-427, 2-428, 2-429, 2-430, 2-431, 2-432, 2-433, 2-434, 2-435, 2-436, 2-437, 2-438, 2-439, 2-440, 2-441, 2- 442, 2-443, 2-444, 2-445, 2-446, 2-447, 2-448, 2-449, 2-450, 2-451, 2-452, 2-453, 2-454, 2-455, 2-456, 2-457, 2-458, 2-459, 2-460, 2-461, 2- 462, 2-463, 2-464, 2-465, 2-466, 2-467, 2-468, 2-469, 2-470, 2-471, 2-472, 2-473, 2-474, 2-475, 2-476, 2-477, 2-478, 2-479, 2-480, 2-481, 2-482, 2-483, 2-484, 2-485, 2-486, 2- 487, 2-488, 2-489, 2-490, 2-491, 2-492, 2-493, 2-494, 2-495, 2-496, 2-497, 2-498, 2-499, 2-500, 2-501, 2-502, 2-503, 2-504, 2-505, 2-506, 2-507, 2-508, 2-509, 2-510, 2-511, 2- 512, 2-513, 2-514, 2-515, 2-516, 2-517, 2-518, 2-519, 2-520, 2-521, 2-522, 2-523, 2-524, 2-525, 2-526, 2-527, 2-528, 2-529, 2-530, 2-531, 2-532, 2-533, 2-534, 2-535, 2-536, 2- 537, 2-538, 2-539, 2-540, 2-541, 2-542, 2-543, 2-544, 2-545, 2-546, 2-547, 2-548, 2-549, 2-550, 2-551, 2-552, 2-553, 2-554, 2-555, 2-556, 2- 557, 2-558, 2-559, 2-560, 2-561, 2-562, 2-563.2-564, 2-565, 2-566, 2-567, 2-568, 2-569, 2-570, 2-571, 2-572, 2-573, 2-574, 2-575, 2-576, 2-577, 2-578 2-579, 2-580, 2-581, 2-582, 2-583, 2-584, 2-585 , 2-586, 2-587, 2-588, 2-589, 2-590, 2-591, 2-592, 2-593, 2-594, 2-595, 2-596, 2-597, 2 -598, 2-599, 2-600, 2-601, 2-602, 2-603, 2-604, 2-605, 2-606, 2-607, 2-608, 2-609, 2-610 , 2-611, 2-612, 2-613, 2-614, 2-615, 2-616, 2-617, 2-618, 2-619, 2-620, 2-621, 2-676, 2 -677, 2-678, 2-679, 2-680, 2-681, 2-682, 2-683, 2-684, 2-685, 2-686, 2-687, 2-688, 2-689 , 2-690, 2-691, 2-692, 2-693, 2-694, 2-695, 2-696, 2-697, 2-698, 2-699, 2-700, 2-701, 2 -702, 2-703, 2-704, 2-705, 2-706, 2-707, 2-708, 2-709, 2-710, 2-711, 2-712, 2-713, 2-714, 2-715, 2-716, 2-717, 2-718, 2-719, 2-720, 2-721, 2-722, 2-723, 2-724, 2- 725, 2-726, 2-727, 2-728, 2-729, 2-730, 2-731, 2-732, 2-733, 2-734, 2-735, 2-736, 2-737, 2-738, 2-739, 2-740, 2-741, 2-742, 2-743, 2-744, 2-745, 2-746, 2-747, 2-748, 2-749, 2- 750, 2-751, 2-752, 2-753, 2-754, 2-755, 2-756, 2-757, 2-758, 2-759, 2-760, 2-761, 2-762, 2-763, 2-764, 2-765, 2-766, 2-767, 2-768, 2-769, 2-770, 2-771, 2-772, 2-773, 2-774, 2- 775, 2-776, 2-777, 2-778, 2-779, 2-780, 2-781, 2-782, 2-783, 2-784, 2-785.2-786, 2-787, 2-788, 2-789, 2-790, 2-791, 2-792, 2-793, 2-794, 2-795, 2-796, 2-797, 2-798, 2-799, 2- 800, 2-801, 2-802, 2-803, 2-804, 2-805, 2-806, 2-807, 2-808, 2-809, 2-810, 2-811, 2-812, 2-813, 2-814, 2-815, 2-816, 2-817, 2-818, 2-819, 2- 820, 2-821, 2-822, 2-823, 2-824, 2-825, 2-826, 2-827, 2-828, 2-829, 2-830, 2-831, 2-832, 2-833, 2-834, 2-835, 2-836, 2-837, 2-838, 2-839, 2-840, 2-841, 2-842, 2-843, 2-844, 2- 845, 2-846, 2-847, 2-848, 2-849, 2-850, 2-851, 2-852, 2-853, 2-854, 2-855, 2-856, 2-857, 2-858, 2-859, 2-860, 2-861, 2-862, 2-863, 2-1112, 2-1113, 2-1114, 2-1115, 2-1116, 2-1117, 2- 1118, 2-1119, 2-1120, 21121, 2-1122, 2-1123, 2-1124, 2-1125, 2-1126, 2-1127, 2-1128, 2 1129, 2-1130, 2-1131, 2-1132, 2-1133, 2-1134, 2-1135, 2-1136, 2 1137, 2-1138, 2-1139, 2-1140, 2-1141, 2-1142, 2-1143, 2-1144, 2 1145, 2-1146, 2-1147, 2-1148, 2-1149, 2-1150, 2-1151, 2-1152, 2 1153, 2-1154, 2-1155, 2-1156, 2-1157, 2-1158, 2-1159, 2-1160, 2 1161 2-1162, 2-1163, 2-1164, 2-1165, 2-1166, 2-1167, 2-1168, 2 1169 2-1224, 2-1258, 2-1259, 2-1260, 2-1261, 2-1262, 2-1263, 2 1264 2-1265, 2-1266, 2-1267, 2-1268, 2-1269, 2-1270, 2-1271, 2 1272 2-1273, 2-1274, 2-1275, 2-1276, 2-1277, 2-1278, 2-1279 r 2 1280 2-1281, 2-1282, 2-1283, 2-1284, 2-1285, 2-1286, 2-1287, 2 1288 2-1289, 2-1290, 2-1291, 2-1292, 2-1293, 2-1294, 2-1295, 2 1296, 2-1297 2-1298, 2-1299, 2-1300, 2-1301, 2-1302, 2-1303, 2 1304, 2-1305, 2-1306, 2-1307, 2-1308, 2-1309, 2-1310, 2-1311, 2 1312, 2-1313 2-1314, 2-1315, 2-1316, 2-1317, 2-1318, 2-1319 2 1320, 2-1321, 2-1322, 2-1323, 2-1324, 2-1 325, 2-1326, 2-1327, 1328, 2-1329, 2-1330, 2-1331, 2-1332, 2-1333, 2-1334, 2-1335 2 1336, 2-1337 2-1338, 2-1339, 2-1340, 2-1341, 2-1342, 2-1343 2 1344, 2-1345, 2-1346, 2-1347, 2-1348, 2-1349, 2-1350, 2-1351 r 2 1352, 2-1353, 2-1354, 2-1355, 2-1356, 2-1357, 2-1358, 2-1359 r 2 1360, 2-1361, 2-1362, 2-1363, 2-1364, 2-1365, 2-1366, 2-1367 r 2 1368, 2-1369, 2-1370, 2-1371, 2-1372, 2-1373, 2-1374, 2-1375 r 1376, 2-1377, 2-1378, 2-1379, 2-1380, 2-1381, 2-1382, 2-1383 t 1532, 2-1533, 2-1534, 2-1535, 2-1536, 2-1537, 2-1538, 2-1539, 2 1540, 2-1541, 2-1542, 2-1543, 2-1544, 2-1545, 2-1546, 2-1547, 2 1548, 2-1549, 2-1550, 2-1551, 2-1552, 2-1553, 2-1554, 2-1555, 2 1556, 2-1557, 2-1558, 2-1559, 2-1560, 2-1561, 2-1562, 2-1563 r 1564 2-156 5, 2-1566, 2-1567, 2-1568, 2-1569, 2-1570, 2 1571.21572.2-1573, 2-1574, 2-1575, 2-1576, 2- 1577, 2-1578, 2-1579, 2-1580, 2-1581, 2-1582, 2-1583, 2-1584, 2-1585, 2-1586, 2-1587, 2-1588, 2-1589, 2-1590, 2-1591, 2- 1592, 2-1593, 2-1594, 2-1595, 2-1596, 2-1597, 2-1598, 2-1599, 2-1600, 2-1601, 2-1602, 2-1603, 2-1604, 2-1605, 2-1606, 2-1607, 2-1608, 2-1609, 2-1610, 2-1611, 2-1612, 2-1613, 2-1614, 2-1615, 2-1616, 2- 1617, 2-1618, 2-1619, 2-1620, 2-1621, 2-1622, 2-1623, 2-1624, 2-1625, 2-1626, 2-1627, 2-1628, 2-1629, 2-1630, 2-1631, 2-1632, 2-1633 2-1634, 2-1635, 2-1636, 2-1637, 2-1638, 2-1639, 2-1640, 2-1641, 2-1642 , 2-1643, 2-1644, 2-1645.2-1646, 2-1647.2-1648, 2-1649, 2-1650, 2-1651, 2-1652, 2-1653, 2-1654, 2 -1655, 2-1656, 2-1657, 2-1658, 2-1659, 2-1660, 2-1661, 2-1662, 2-1663, 2-1664, 2-1665, 2-1666, 2-1667 , 2-1668, 2-1669 2- 2-1671, 2-1672, 2-1673 2-1674 2-1675 2-1676, 2-1677 2- 2-1679, 2-1680, 2-1681 2-1682 2-1683 2-1684, 2-1685 2- 2-1687, 2-1688, 2-1689 2-1690 2-1691 2-1692, 2-1693 2- 2-1695, 2-1696, 2-1697 2 -1698 2-1699 2-1700, 2-1701 2- 2-1703, 2-1704, 2-1705 2-1706 2-1707 2-1708, 2-1709 2- 2-1711 , 2-1712, 2-1713 2-1714 2-1715 2-1716, 2-1717 2- 2-1919, 2-1720, 2-1721 2-1722 2-1723 2-1724, 2-1725 2- 2 -1727, 2-1728, 2-1729 2-1730 2-1731 2-1732, 2-1733 2- 2-1735, 2-1736, 2-1737 2-1738 2-1739 2-1740, 2-1741 2 - 2-1743, 2-1744, 2-1745 2-1746 2-1747 2-1748, 2-1749 2- 2-1751, 2-1752, 2-1753 2-1754 2-1755 2-1756, 2- 1757 2- 2-1759, 2-1760, 2-1761 2-1762 2-1763 2-1764, 2-1765 2- 2-1767, 2-1768, 2-1769 2-1770 2-1771 2-1772, 2-1773 2- 2-1775, 2-1776, 2-1777 2-1778 2-1779 2-1780, 2-1781 2-1782, 2-1783, 2-1784, 2-1785, 2-1786, 2 -1787, 2-1788, 2-1789, 21790.2-1791, 2-1792, 2-1793, 2-1794, 2-1795, 2-1796, 2-1797, 2-1798, 2-1799, 2 -1800, 2-1801, 2-1802, 2-1803, 2-1804, 2-1805, 2-1806, 2-1807, 2-1808, 2-1809, 2-1810, 2-1811, 2-1812 , 2-1813, 2-1814, 2-1815, 2-1816, 2-1817, 2-1818, 2-1819, 2-1820, 2-1821, 2-1822, 2-1823, 2-1824, 2 -1825, 2-1826, 2-1827, 2-1828, 2-1829, 2-1830, 2-1831, 2-1832, 2-1833, 2-1834, 2-1835, 2-1836, 2-1837. , 2-1838, 2-1839, 2-1840, 2-1841, 2-1842, 2-1843, 2-1844, 2-1845, 2- 1846, 2-1847, 2-1848, 2-1849, 2-1850, 2-1851, 2-1852, 2-1853, 2-1854, 2-1855, 2-1856, 2-1857, 2-1858, 2-1859, 2-1860, 2-1861, 2-1862, 2-1863, 2-1864, 2-1865, 2-1866, 2-1867, 2-1868, 2-1869, 2-1870, 2-1871, 2-1872, 2-1873, 2-1874, 2-1875, 2-1876, 2-1877, 2-1878, 2-1879, 2-1880, 2-1881, 2-1882, 2-18832-1884, 2-18852-1886, 2-1887, 2-1888, 2-1889, 2-1890, 2-1891, 2-1892, 2 -1893, 2-1894, 2-1895, 2-1896, 2-1897, 2-1898, 2-1899, 2-1900, 2-1901, 2-1902, 2-1903, 2-1904, 2-1905. , 2-1906, 2-1907, 2-1908, 2-1909, 2-1910, 2-1911, 2-1912, 2-1913, 2-1914, 2-1915, 2-1916, 2-1917, 2 -1918, 2-1919, 2-1920, 2-1921, 2-1962, 2-1963, 2-1964, 2-1965, 2-1966, 2-1967, 2-1968, 2-1969, 2-1970 , 2-1971, 2-1972, 2-1973, 2-1974, 2-1975, 2-1976, 2-1977, 2-1978, 2-1979, 2-1980, 2-1981, 2-1982, 2 -1983, 2-1984, 2-1985, 2-1986, 2-1987, 2-1988, 2-1989, 2-1990, 2-1991, 2-1992, 2-1993.2-1994, 2-1995, 2-1996, 2-1997, 2-1998, 2-1999, 2-2000, 2-2001, 2- 2002, 2-2003, 2-2004, 2-2005, 2-2006, 2-2007, 2-2008, 2-2009, 2-2010, 2-2011, 2-2012, 2-2013, 2-2014, 2-2015, 2-2016, 2-2017, 2-2018, 2-2019, 2-2020, 2-2021, 2-2022, 2-2023, 2-2024, 2-2025, 2-2026, 2- 2027, 2-2028, 2-2029, 2-2030, 2-2031, 2-2032, 2-2033, 2-2034, 2-2035, 2-2036, 2- 2037, 2-2038, 2-2039, 2-2040, 2-2041, 2-2042, 2-2043, 2-2044, 2-2045, 2-2046, 2-2047, 2-2048, 2-2049, 2-2050, 2-2051, 2- 2052, 2-2053 2-205 2-2055, 2-2056 2-2057 2-2058, 2-2059, 2-2060, 2-2061 2-2062 2-2063, 2-2064 2-2065 2-2066, 2- 2067, 2-2068, 2-2069 2-2070 2-2071, 2-2072 2-2073 2-2074, 2-2075, 2-2076, 2-2077 2-2078 2-2079, 2-2080 2-2081 2-2082, 2-2083, 2-2084, 2-2085 2-2086 2-2087, 2-2088 2-2089 2-2090, 2-2091, 2-2092, 2-2093 2-2094 2-2095, 2-2096 2-2097 2-2098, 2-2099, 2-2100, 2-2101 2-2102 2-2103, 2-2104 2-2105 2-2106, 2-2107, 2-2108, 2-2109 2 -2110 2-2111, 2-2112 2-2113 2-2114, 2-2115, 2-2116, 2-2117 2-2118 2-2119, 2-2120 2-2121 2-2122, 2-2123, 2- 2124, 2-2125 2-2126 2-2127, 2-2128 2-2129 2-2130, 2-2131, 2-2132, 2-2133 2-2134 2-2135, 2-2136 2-2137 2-2138, 2-2139, 2-2140, 2-2141 2-2142 2-2143, 2-2144 2-2145 2-2146, 2-2147, 2-2148, 2-2149 2-2150 2-2151, 2-2152 2 -2153 2-2154, 2-2155, 2-2156, 2-2157 2-2158 2-2159, 2-2160 2-2161 2-2162, 2-2163, 2-2429, 2-2430 2-2431 2- 2432, 2-2433 2-2434 2-2435, 2-2436, 2-2437, 2-2438 2-2439 2-2440, 2-2441 2-2442 2-2443, 2-2444, 2-2445, 2- 2446 2-2447 2-2448, 2-2449 2- 2450 2-2451, 2-2452, 2-2453, 2-2454 2-2455 2-2456, 2-2457 2-2458 2-2459, 2-2460, 2-2461, 2-2462 2-2463 2-2464 , 2-2465 2-2466 2-2467, 2-2468, 2-2469, 2-2470 2-2471 2-2472, 2-2473, 2-2474, 2-2475, 2-2476, 2-2477, 2 -2478 2-2479, 2-2480, 2-2481, 2-2482, 2-2483, 2-2484, 2-2485.2-2486, 2-2487, 2-2488, 2-2489, 2-2490, 2-2491, 2-2492, 2-2493, 2-2494, 2-2495, 2-2496, 2-2497, 2-2498, 2-2499, 2-2500, 2-2501, 2- 2502, 2-2503, 2-2504, 2-2505, 2- 2506, 2-2507, 2-2508, 2-2509, 2-2510, 2-2511, 2-2512, 2-2513, 2-2514, 2-2515, 2-2516, 2-2517, 2-2518, 2-2519, 2-2520, 2-2521, 2-2522, 2-2523, 2-2524, 2-2525, 2-2526, 2-2527, 2-2528, 2-2529, 2-2530, 2- 2531, 2-2532, 2-2533, 2-2534, 2-2535, 2-2536, 2-2537, 2-2538, 2-2539, 2-2540, 2-2541, 2-2542, 2-2543, 2-2544, 2-2545, 2-2546, 2-2547, 2-2548, 2-2549, 2-2550, 2-2551, 2-2552, 2-2553, 2-2554, 2-2555, 2- 2556, 2-2557, 2-2558, 2-2559, 2-2560, 2-2561, 2-2562, 2-2563, 2-2564, 2-2565, 2-2566, 2-2567, 2-2568, 2-2569, 2-2570, 2-2571, 2-2572, 2-2573, 2-2574, 2-2575, 2-2576, 2-2577, 2-2578, 2-2579, 2-2580, 2- 2581, 2-2582, 2-2583, 2-2584, 2-2585, 2-2586, 2-2587, 2-2588, 2-2589, 2-2590, 2-2591, 2-2592, 2-2593, 2-2594, 2-2595, 2-2596, 2-2597, 2-2598, 2-2599, 2-2600, 2-2601, 2-2602, 2-2603, 2-2604, 2-2605, 2- 2606, 2-2607, 2-2608, 2-2609, 2-2610, 2-2611, 2-2612, 2-2613, 2-2614, 2-2657, 2-2665, 2-2667 , 2-2669, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 3-11, 3 -12, 3-13, 3-14, 3-15, 3-16, 3-17, 3-18, 3-19, 3-20, 3-21, 3-22, 3-23, 3-24, 3-25, 3-26, 3-27, 3-28, 3-29, 3-30, 3- 31, 3-32, 3-33, 3-34, 3-35, 3-36, 3-37, 3-38, 3-39, 3-40, 3-41, 3-42, 3-43, 3-44, 3-45, 3-46, 3-47, 3-48, 3-49, 3-50, 3-51, 3-52, 3-53, 3-54, 3-55, 3- 56, 3-57, 3-58, 3-59, 3-60, 3-61, 3-62, 3-63, 3-64, 3-65, 3-66, 3-67, 3-68, 3-69, 3-70, 3-71, 3-72, 3-73, 3-74, 3-75, 3-76, 3-77, 3-78, 3-79, 3-80, 3- 81, 3-82, 3-83, 3-232, 3-233, 3-234, 3-235, 3-236, 3-237, 3-238, 3-239, 3-240, 3-241, 3-242, 3-243, 3-244, 3-245, 3-246, 3-247, 3-248, 3-249, 3-250, 3-251, 3-252, 3-253, 3-254, 3- 255, 3-256, 3-257, 3-258, 3-259, 3-260, 3-261.3-262, 3-263, 3-264, 3-265, 3-266, 3-267, 3-268, 3-269, 3-270, 3-271, 3-272, 3-273, 3-274, 3-275, 3-276, 3-277, 3-278, 3-279, 3-280, 3-281, 3-282, 3- 283, 3-284, 3-285, 3-286, 3-287, 3-288, 3-289, 3-290, 3-291, 3-292, 3-293, 3-294, 3-295, 3-296, 3-297, 3-298, 3-299, 3-300, 3-301, 3-302, 3-303, 3-304, 3-305, 3-306, 3-307, 3- 308, 3-309, 3-310, 3-311, 3-312, 3-313, 3-314, 3-315, 3-316, 3-317, 3-318, 3-319, 3-320, 3- 321, 3-322, 3-323, 3-324, 3-325, 3-326, 3-327, 3-328, 3-329, 3-330, 3-331, 3-332, 3-333, 3 -334, 3-335, 3-336, 3-337, 3-338, 3-339, 3-340, 3-341, 3-342, 3-343, 3-344, 3-345, 3-346 , 3-347, 3-348, 3-349, 3-350, 3-351, 3-352, 3-353, 3-354, 3-355, 3-356, 3-357, 3-358, 3 -359, 3-360, 3-361, 3-362, 3-363, 3-364, 3-365, 3-366, 3-367, 3-368, 3-369, 3-370, 3-371 , 3-372, 3-373, 3-374, 3-375, 3-376, 3-377, 3-378, 3-379, 3-380, 3-381, 3-382, 3-383, 3 -384, 3-385, 3-386, 3-387, 3-388, 3-389, 3-390, 3-391, 3-392, 3-393, 3-394, 3-395, 3-396 , 3-397, 3-398, 3-399, 3-400, 3-401, 3-402, 3-403, 3-404, 3-405, 3-406, 3-407, 3-408, 3-409, 3-410, 3-411, 3-412, 3-413, 3-414, 3- 415, 3-416, 3-417, 3-418, 3-419, 3-420, 3-421, 3-422, 3-423, 3-424, 3-425, 3-426, 3-427, 3-428, 3-429, 3-430, 3-431, 3-432, 3-433, 3-434, 3-435, 3-436, 3-437, 3-438, 3-439, 3- 440, 3-441, 3-442, 3-443, 3-444, 3-445, 3-446, 3-447, 3-448, 3-449, 3-450, 3-451, 3-452, 3-453, 3-454, 3-455, 3-456, 3-457, 3-458, 3-459, 3- 460, 3-461, 3-462, 3-463, 3-464, 3-465, 3-466, 3-467, 3-468, 3-469, 3-470, 3-471, 3-472, 3-473, 3-474, 3-475, 3-476, 3-477, 3-478, 3-479, 3-480, 3-481, 3-482, 3-483, 3-484, 3- 485, 3-486, 3-487, 3-488, 3-489, 3-490, 3-491, 3-492, 3-493, 3-494, 3-495, 3-496, 3-497, 3-498, 3-499, 3-500, 3- 3771, 3-772, 3-773, 3-774, 3- 775, 3-776, 3-777, 3-778, 3-779, 3-780, 3-781, 3-782, 3-783, 3-784, 3-785, 3-786, 3-787, 3-788, 3-789, 3-790, 3-791, 3- 792, 3-793, 3-794, 3-795, 3-796, 3-797, 3-798, 3-799, 3-800, 3-801, 3-802, 3-803, 3-804, 3-805, 3-806, 3-807, 3-808, 3-809, 3-810, 3-811, 3-812, 3-813, 3-814, 3-815, 3-816, 3-817, 3-818, 3-819, 3-820, 3-821, 3-822, 3-823, 3-824, 3-825, 3-826, 3-827, 3- 828, 3-829, 3-830, 3-831, 3-832, 3-833, 3-834, 3-835, 3-836, 3-837, 3-838, 3-839, 3-840, 3-841, 3-842, 3-843, 3-844.3-845, 3-846, 3-847, 3-848, 3-849, 3-850, 3-851, 3-852, 3- 853, 3-854, 3-855, 3-856, 3-857, 3-858, 3-859, 3-860, 3-861, 3-862, 3-863, 3-1112, 3-1113, 3-1114, 3-1115, 3-1116, 3-1117, 3-1118, 3-1119, • 33--11112200 ,, 3-1121, 3-1122, 3-1123, 3-1124, 3-1125 , 3-1126, 3-1127, 3-1128, 3-1129, 3-1130, 3-1131, 3-1132, 3-1133, 3-1134, 3-1135, 3-1136, 3-1137, 3 -1138, 3-1139, 3-1140, 3-1141, 3-1142, 3-1 1114433 ,, 3 3--11114444 ,, 3-1145, 3-1146, 3-1147, 3-1148, 3- 1149, 3-1150, 3-1151, 3-1152, 3-1153, 3-1154, 3-1155, 3-1156, 3-1157, 3-1158, 3-1159, 3-1160, 3-1161, 3-1162, 3-1163, 3-1164, 3-1165, 3-1166, 3-1167, 3-1168, 3-1169, 3-1224, 3-1258, 3-1259, 3-1260, 3- 1261, 3- 1262, 3-1263, 3-1264, 3-1265, 3-1266, 3-1267, 3-1268, 3-1269, 3-1 1227700, 3 3--11227711, 3-1272 , 3-1273, 3-1274, 3-1275, 3- 1276, 3-1277, 3-1278, 3-1279, 3-1280, 3-1281, 3-1282, 3-1283, 3-1284, 3-1285, 3-1286, 3-1287, 3-1288, 3-1289, 3-1290, 3-1291, 3-1292, 3-1293, 3-1294, 3-1295, 3-1296, 3-1297, 3-1298, 3-1299, 3-1300, 3- 1301, 3- 1302, 3-1303, 3-1304, 3-1305, 3-1306, 3-1307, 3-1308, 3-1309, 3-1 1331100, 3 3--11331111, 3-1312 , 3-1313, 3-1314, 3-1315, 3-1316, 3-1317, 3-1318, 3 3--11331199, 3-1320, 3-1321, 3-1322, 3-1323, 3-1324 , 3-1325, 31326.3-1327, 3-1328, 3-1329, 3-1330, 3-1331, 3-1332, 3-1333, 3-1334 3-1335, 3-1336 3-1337 3- 1338, 3-1339, 3-1340, 3-1341 3- 1342 3-1343 3-1344 3-1345, 3-1346, 3-1347, 3-1348, 3-1349 3- 1350 3-1351, 3- 1352, 3-1353, 3-1354, 3-1355, 3-1356, 3-1357 3- 1358 3-1359, 3-1360 3-1361, 3-1362, 3-1363, 3-1364, 3-1365 3-1366 3-1367 3-1368 3-1369 3-1370 3-1371, 3-1372, 3-1373 3- 1374 3-1375 3-1376 3-1377 3-1378, 3-1379, 3-1380, 3-1381 3- 1382 3-1383 3-1532 3-1533 3-1534, 3-1535, 3-1536, 3-1537 3- 1538 3-1539 3-1540 3-1541 3-1542, 3-1543, 3-1544, 3-1545 3- 1546 3-1547 3-154 8 3-1549 3-1550 3-1551, 3-1552, 3-1553 3- 1554 3-1555 3-1556 3-1557 3-1558 3-1559, 3-1560, 3-1561 3- 1562 3-1563 3-1564 3-1565 3-1566 3-1567, 3-1568, 3-1569 3-1570 3-1571 3-1572 3-1573 3-1574 3-1575, 3-1576, 3-1577 r 3- 1578 3-1579 3-1580 3-1581 3-1582 3-1583, 3-1584, 3-1585 r 3- 1586 3-1587 3-1588, 3-1589 3-1590 3-1591, 3-1592, 3- 1593 t 3- 1594 3-1595 3-1596 3-1597 3-1598 3-1599, 3-1600, 3-1601 r 3- 1602 3-1603 3-1604 3-1605 3-1606 3-1607, 3- 1608, 3-1609 r 3- 1610 r 3-1611, 3-1612, 3-1613 r 3-1614, 3-1615, 3-1616, 3-1617, 3-1618, 3-1619, 3-1620, 3-1621, 3-1622, 3-1623, 3-1624, 3-1625 r 3- 1626, 3-1627, 3-1628, 3-1629, 3-1630, 3-1631, 3-1632, 3- 1633 r 3- 1634 3-1635 3-1636, 3-1637 r 3-1638 3-1639, 3-1640, 3-1641, 3-1642, 3-1643, 3-1644, 3-1645, 3-1646 , 3-1647, 3-1648, 3-1649 r 3- 1650, 3-1651, 3-1652, 3-1653, 3-1654, 3-1655, 3-1656, 3-1657 r 3" 1658 3-1659 3-1660 3-1661 3-1662 3-1663, 3-1664, 3-1665 r 3- 1666 3-1667 3-1668, 3-1669 3-1670 3-1671, 3-1672, 3-1673 r 3- 1674 3-1675 3-1676 3-1677 3-1678 3-1679, 3-1680, 3-1681 r 3- 1682 3-1683, 3-168 '1, 3 -168 5, 3-16! 36, 3-1687, 3-1 688, 3-1 689, 31690.3-1691, 3-1692, 3-1693, 3-1694, 3-1695, 3-1696, 3-1697, 3-1698 3 -1699 3-1700 3-1701 3-1702 3-1703, 3-1704, 3-1705 3- 1706 3-1707 3-1708 3-1709, 3-1710 3-1711, 3-1712, 3-1713 3 - 1714 3-1715 3-1716, 3-1717 3-1718 3-1719, 3-1720, 3-1721 3-1722 3-1723 3-1724 3-1725 3-1726, 3-1727, 3-1728, 3-1729 3-1730 3-1731 3-1732 3-1733 3-1734 3-1735, 3-1736, 3-1737 3- 1738 3-1739 3-1740 3-1741 3-1742 3-1743, 3- 1744, 3-1745 3- 1746 3-1747 3-1748 3-1749 3-1750 3-1751, 3-1752, 3-1753 3- 1754 3-1755 3-1756 3-1757 3-1758 3-1759, 3-1760, 3-1761 3- 1762 3-1763 3-1764 3-1765 3-1766 3-1767, 3-1768, 3-1769 r 3" 1770 3-1771 3-1772 3-1773 3-1774 3-1775, 3-1776, 3-1777 r 3- 1778 3-1779 3-1780 3-1781 3-1782 3-1783, 3-1784, 3- 1785, 3- 1786 3-1787 3-1788 3-1789 3-1790 3-1791, 3-1792, 3-1793 r 3" 1794 3-1795 3-1796 3-1797 3-1798 3-1799, 3-1800, 3-1801 r 3- 1802 3-1803 3-1804 3-1805 3-1806 3-1807, 3-1808, 3- 1809 r 3" 1810 3-1811 3-1812 3-1813 3-1814, 3-1815, 3-1816, 3-1817 r 3" 1818 3-1819 3-1820 3-1821 3-1822 3-1823, 3-1824, 3-1825 r 3- 1826, 3-1827, 3-1828, 3-1829, 3-1830, 3-1831, 3 -1832, 3-1833 r 3- 1834, 3-1835 3-1836 3-1837, 3-1838, 3-1839, 3-1840, 3-1841 r 3- 1842 3-1843 3-1844 3-1845, 3-1846, 3-1847, 3-1848, 3-1849 r 3- 1850 3-1851 3-1852 3-1853 3-1854, 3-1855, 3-1856, 3-1857 r 3- 1858 3-1859 3-1860 3-1861, 3-1862, 3-1863, 3-1864, 3-1865 f 3- 1866 3-1867 3-1868 3-1869, 3-1870 3-1871, 3-1872, 3-1873 r 3- 1874 3-1875 3-1876 3-1877 3-1878 3-1879, 3-1880, 3-1881 r 3- 1882 3-1883 3-1884 3-1885 3-1886 3-1887, 3-1888 , 3-1889 r 3- 1890 3-1891 3-1892 3-1893 3-1894 3-1895, 3-1896, 3-1897 r 3" 1898 3-1899, 3-190C D, 3-190 1, 3-19 (32, 3-1903, 3-1904, 3-1 905, 31906,3-1907, 3-1908, 3-1909, 3- 1910, 3-1911, 3-1912, 3-1913, 3-1914, 3-1915, 3-1916, 3-1917, 3-1918, 3-1919, 3-1920.3-192151 3- 1962, 3 -1963, 3-1964, 3-1965, 3-1966, 3-1967, 3-1968, 3-1969, 3- 1970, 3-1971, 3-1972, 3-1973, 3-1974, 3-1975 , 3-1976, 3-1977, 3- 1978, 3-1979, 3-1980, 3-1981, 3-1982, 3-1983, 3-1984, 3-1985, 3-1986, 3-1987, 3 -1988, 3-1989, 3-1990, 3-1991, 3-1992, 3-1993, 3-1994, 3-1995, 3-1996, 3-1997, 3-1998, 3-1999, 3-2000 , 3-2001, 3-2002, 3-2003, 3-2004, 3-2005, 3-2006, 3-2007, 3-2008, 3-2009, 3-2010 3-2011 3-2012 3-2013 3-2014 3-2015 3-2016 3-2017, 3-2018 3-2019 3-2020 3-2021 3-2022 3-2023 3-2024 3-2025, 3-2026 3-2027 3-2028 3-2029 3-2030 3-2031 3-2032 3-2033, 3-2034 3-2035 3-2036 3-2037 3-2038 3-2039 3-2040 3-2040, 3-2042 3-2043 3-2044 3-2045 3-2046 3-2047 3-2048 3-2049, 3-2050 3-2051 3-2052 3- 2053 3- 2054 3- 2055 3-2056 3-2057, 3-2058 3-2059 3-2060 3- 2061 3- 2062 3- 2063 3-2064 3-2065, 3-2066 3-2067 3-2068 3- 2069 3- • 2070 3- 2071 3-2072 3-2073 , 3-2074 3-2075 3-2076 3- 2077 3- • 2078 3- 2079 3-2080 3-2081, 3-2082 3-2083 3-2084 3- 2085 3- • 2086 3- 2087 3-2088 3 -2089, 3-2090 3-2091 3-2092 3- 2093 3- • 2094 3- 2095 3-2096 3-2097, 3-2098 3-2099 3-2100 3- 2101 3- • 2102 3- 2103 3- 2104 3-2105, 3-2106 3-2107 3-2108 3- 2109 3- 2110 3- 2111 3-2112 3-2113, 3-2114 3-2115 3-2116 3- 2117 3- 2118 3- 2119 3- 2120 3-2121, 3-2122 3-2123 3-2124 3- 2125 3- 2126 3- 2127 3-2128 3-2129, 3-2130 3-2131 3-2132 3- 2133 3- 2134 3- 2135 3- 2136, 3-2137, 3-2138 3-2139, 3-2140, 3-2141, 3-2142, 3-2143, 3- 2144, 3-2145.3-2146, 3-2147, 3-2148, 3-2149, 3-2150, 3-2151, 3-2152, 3- 2153, 3-2154, 3- 2155, 3-2156, 3-2157, 3-2158, 3-2159, 3-2160, 3-2161, 3-2162, 3-2163, 3-2429, 3-2430, 3-2431, 3-2432, 3-2433, 3-2434 3-2435 3-2436 3-2437 3-2438 3-2439 3-2440, 3-2441, 3-2442 3-2443 3-2444 3-2445 3-2446 3-2447 3-2448, 3-2449, 3-2450 3-2451 3-2452 3-2453 3-2454 3-2455 3-2456, 3-2457, 3-2458 3-2459 3-2460 3-2461 3-2462 3-2463 3-2464, 3-2465, 3-2466 3-2467 3-2468 3-2469 3-2470 3-2471 3-2472, 3-2473, 3-2474 3-2475 3-2476 3-2477 3-2478 3-2479 3-2480, 3-2481, 3-2482 3-2483 3-2484 3-2485 3-2486 3-2487 3-2488, 3-2489, 3-2490 3-2491 3-2492 3-2493 3-2494 3-2495 3-2496, 3-2497, 3-2498 3-2499 3-2500 3-2501 3-2502 3-2503 3-2504, 3-2505, 3-2506 3-2507 3-2508 3-2509 3-2510 3-2511 3-2512, 3-2513, 3-2514 3-2515 3-2516 3-2517 3-2518 3-2519 3-2520, 3-2521, 3-2522 3-2523 3-2524 3-2525 3-2526 3-2527 3-2528, 3-2529, 3-2530 3-2531 3-2532 3-2533 3-2534 3-2535 3-2536, 3-2537, 3-2538 3-2539 3-2540 3-2541 3-2542 3-2543 3-2544, 3-2545, 3-2546 3-2547 3-2548 3-2549 3-2550 3-2551 3-2552, 3-2553, 3-2554 3-2555 3-2556 3-2557 3-2558 3-2559 3-2560, 3-2561, 3-2562 3-2563 3-2564 3-2565 3-2566 3-2567 3-2568, 3-2569, 3-2570 3-2571 3-2572 3-2573 3-2574 3-2575, 3-2576, 3-2577, 3-2578, 3-2579 3-2580, 3-2581, 3-2582, 3-2583, 3-2584, 3-2585, 3-2586, 3-2587, 3 -2588, 3 -2589, 3-2590 , 3-2591, 3-2592, 3-2593, 3-2594, 3-2595, 3 -2596, 3 -2597, 3-2598, 3-2599, 3-2600, 3-2601, 3-2602, 3 -2603, 3--2604, 3 -2605, 3-2606, 3-2607, 3-2608, 3-2609, 3-2610, 3-2611, 3-2612, 3-2613, 3-2614, 3- 2657, 3-2665, 3-2667 and 3- 2669, The following compounds are more preferred, ie the compounds No,: 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 1-13, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-21, 1-22, 1- 23, 1-24, 1-25, 1-26, 1-27, 1-28, 1-29, 1-30, 1-31, 1-32, 1-33, 1-34, 1-35, 1-36, 1-37, 1-38, 1-39, 1-40, 1-41, 1-42, 1-43, 1-44, 1-45, 1-46, 1-47, 1- 48, 1-49, 1-50, 1-51, 1-52, 1-53, 1-54, 1-55, 1-56, 1-57, 1-58, 1-59, 1-60, 1-61, 1-62, 1-63, 1-64, 1-65, 1-66, 1-67, 1-68, 1-69, 1-70, 1-71, 1-72, 1- 73, 1-74, 1-75, 1-76, 1-77, 1-78, 1-79, 1-80, 1-271, 1-272, 1-273, 1-274, 1-275, 1-276, 1-277, 1-278, 1-279, 1-280, 1-281, 1-282, 1-283, 1-284, 1-285, 1-286, 1-287, 1- 288, 1-289, 1-290, 1-291, 1-292, 1-293, 1-294, 1-295, 1-296, 1-297, 1-298, 1-299, 1-300, 1-301, 1-302, 1-303, 1-304, 1-305, 1-306, 1-307, 1-308, 1-309, 1-310, 1-311, 1-312, 1- 313, 1-314, 1-315, 1-316, 1-317, 1-318, 1-319, 1-320, 1-321, 1-322, 1-323, 1-324, 1-325, 1-326, 1-327, 1-328, 1-329, 1-330, 1-331, 1-332, 1-333, 1-334, 1-335, 1-3 36, 1-337, 1-338, 1-339, 1-340, 1-341, 1-342, 1-343, 1-344, 1-345, 1-346, 1-347, 1-348 , 1-349, 1-350, 1-351, 1-352, 1-353, 1-354, 1-355, 1-356, 1-357, 1-358, 1-359, 1-360, 1 -361, 1-362, 1-363, 1-364, 1-365, 1-366, 1-367, 1-368, 1-369, 1-370, 1-371, 1-372, 1-373 1-374, 1-375, 1-376, 1-377, 1-378, 1-379, 1-380, 1-381, 1-382, 1-383, 1-384, 1-385, 1 -386, 1-387, 1-388, 1-389, 1-390, 1-391, 1-392, 1-393, 1-394, 1-395, 1-396, 1-397, 1-398 , 1-399, 1-400, 1-401, 1-402, 1-403, 1-404, 1-405, 1-406, 1-407, '1-408, 1-409, 1-410, 1-411, 1-412, 1-413, 1-414, 1-415, 1-416, 1-417, 1-418, 1-419, 1-420, 1-421, 1-422, 1- 423, 1-424, 1-425, 1-426, 1-427, 1-428, 1-429, 1-430, 1-431, 1-432, 1-433, 1-434, 1-435, 1-436, 1-437, 1-438, 1- 439, 1-440, 1-441, 1- 442, 1-443, 1-444, 1-445, 1-446, 1-447 1-448, 1-449, 1-450, 1-451, 1-452, 1-453, 1-454, 1-455, 1-456, 1-457, 1-458, 1-459, 1-460, 1- 461, 1-462, 1-463, 1-464, 1-465, 1-466, 1-467, 1-468, 1-469, 1-470, 1-471, 1-472, 1-473, 1-474, 1-475, 1-476, 1- 477, 1-478, 1-479, 1- 480, 1-481, 1-482, 1-483, 1-484, 1-485, 1-486, 1-487, 1-488, 1-489, 1-490, 1-491, 1-492, 1-493, 1-494, 1-495, 1-496, 1-497, 1-498, 1- 499, 1-500, 1-501, 1-502, 1-503, 1-504, 1-505, 1-506, 1-507, 1-508, 1-509, 1-510, 1-511, 1-512, 1-513, 1-514, 1-515, 1-516, 1-517, 1-518, 1-519, 1-520, 1-521, 1-522, 1-523, 1- 524, 1-525, 1-526, 1-527, 1-528, 1-529, 1-530, 1-531, 1-532, 1-533, 1-534, 1-535, 1-536, 1-537, 1-538, 1-539, 1-676, 1-677, 1-678, 1-679, 1-680, 1-681, 1-82, 1-683, 1-684, 1- 685, 1-686, 1-687, 1-688, 1-689, 1-690, 1-691, 1-692, 1-693, 1-694, 1-695, 1-696, 1-697, 1-698, 1-699, 1-700, 1-701, 1-702, 1-703, 1-704, 1-705, 1-706, 1-707, 1-708, 1-709, 1- 710, 1-711, 1-712, 1-713, 1-714, 1-715, 1-716, 1-717, 1-718, 1-719, 1-720, 1-721, 1-722, 1-723, 1-724, 1-725, 1-726, 1-727, 1-728, 1-729, 1-730, 1-731, 1-732, 1-733, 1-734, 1- 735, 1-736, 1-737, 1-738, 1-739, 1-740, 1-741, 1-742, 1-743, 1-744, 1-745, 1-746, 1-747, 1-748, 1-749, 1-750, 1-751, 1-752, 1-753, 1-754, 1-755, 1-756, 1-757, 1-758, 1- 759, 1-760, 1-761, 1-762, 1-763, 1-764, 1-765, 1-766, 1-767, 1-768, 1-769, 1-770, 1-771, 1-772, 1-773, 1-774, 1-775, 1-776, 1-777, 1-778, 1-779, 1-780, 1-781, 1-782, 1-783, 1- 784, 1-785, 1-786, 1-787, 1-788, 1-789, 1-790, 1-791, 1-792, 1-793, 1-794, 1-795, 1-796, 1-797, 1-798, 1-799, 1-800, 1-801, 1-802, 1-803, 1-804, 1-805, 1-806, 1-807, 1-808, 1- 809, 1-810, 1-811, 1-812, 1-813, 1-814, 1-815, 1-816, 1-817, 1-818, 1-819, 1-820, 1-821, 1-822, 1-823, 1-824, 1-825, 1-826, 1-827, 1-828, 1-829, 1-830, 1-831, 1-832, 1-833, 1-834, 1- 835, 1-836, 1-837, 1-838, 1-839, 1-840, 1-841, 1-842, 1-843, 1-844, 1-845, 1-846, 1-847, 1-848, 1-849, 1-850, 1-851, 1-852, 1-853, 1-854, 1-855, 1-856, 1-857, 1-858, 1-859, 1- 860, 1-861, 1-862, 1-863, 1-1112, 1-1113, 1-1114, 1-1115, 1-1116, 1-1117, 1-1118, 1-1119, 1-1120, 1-1121, 1-1122, 1-1123, 1-1124, 1-1125, 1-1126, 1-1127, 1-1128, 1-1129, 1- 1130, 1-1131, 1-1132, 1-1133, 1134, 1-1135 1-1136, 1-1137, 1-1138, 1-1139, 1-1140, 1-1141, 11114422 ,, 11--11114433, 1-1144, 1-1145, 1-1146, 1-1147, 1-1148, 1-1224, 1258, 1-1259 1-1260, 1-1261, 1-1262, 1-1263, 1-1264, 1-1265, 1266, 1-1267 1-1268, 1-1269, 1-1270, 1-1271, 1-1272, 1-1273, 1274, 1-1275 1-1276, 1-1277, 1-1278, 1-1279, 1-1280, 1-1962, 1963, 1-1964 1-1965, 1-1966, 1-1967, 1-1968, 1-1969, 1-1970, 1971 1-1972 1-1973, 1-1974, 1-1975, 1-1976, 1-1977, 1-1978, 1979, 1-1980 1-1981, 1-1982, 1-1983, 1-1984, 1 -1985, 1-1986, 1987, 1-1988 1-1989, 1-1990, 1-1991, 1-1992, 1-1993, 1-2470, 2471, 1-2472 1-2473, 1-2474, 1 -2475, 1-2476, 1-2477, 1-2478, 2479, 1-2480 1-2481, 1-2482, 1-2483, 1-2484, 1-2485, 1-2486, 2487, 1-2488 1 -2489, 1-2490, 1-2491, 1-2492, 1-2493, 1-2494, 2495, 1-2496 1-2497, 1-2498, 1-2499, 1-2500, 1-2501, 1- 2502, 2503, 1-2504 1-2505, 1-2506, 1-2507, 1-2508, 1-2509, 1-2510, 2511, 1-2512 1-2513, 1-2514, 1-2515, 1- 2516, 1-2517, 1-2518, 2519, 1-2520 1-2521, 1-2522, 1-2523, 1-2524, 1-2525, 1-2526, 22552277, 11--22552288, 1-2529 , 1-2530, 1-2531, 1-2532, 1-2533, 1-2534 , 2535, 1-2536 1-2537, 1-2538, 1-2539, 1-2540, 1-2541, 1-2542, 2543, 1-2544 1-2545, 1-2546, 1-2547, 1-2548 , 1-2549, 1-2550, 2551, 1-2552, 1-2553, 1-2554, 1-2555, 1-2556, 1-2557, 1-2558, 1-2559, 1-2560, 1-2561 , 1-2562, 1-2563, 1-2564, 1-2565, 1-2566, 1-2567, 1-2568, 1-2569, 1-2570, 1-2571, 1-2572, 1-2573, 1 -2574, 1-2575, 1-2576, 1-2577, 1-2578, 1-2579, 1-2580, 1-2581, 1-2582, 1-2583, 1-2584, 1-2585, 1-2586 , 1-2587, 1-2588, 1-2589, 1-2590, 1-2591, 1-2592, 1-2593, 1-2594, 1-2595, 1-2596, 1-2597, 1-2598, 1 - 2599, 1-2600, 1-2601, 1-2602, 1-2603, 1-2604, 1-2605, 1-2606, 1- 2607, 1-2608, 1-2609, 1-2610, 1-2611 , 1-2612, 1-2613, 1-2614, 1-2657, 1-2665, 1-2667 and 1-2669, The following compounds are even more preferred, ie the compounds No,: 1-41, 1- 42, 1-43, 1-44, 1-45, 1-46, 1-47, 1-48, 1-49, 1-50, 1-51, 1-52, 1-53, 1-54, 1-55, 1-56, 1-57, 1-58, 1-59, 1-60, 1-61, 1-62, 1-63, 1-64, 1-65, 1-66, 1- 67, 1-68, 1-69, 1-70, 1-71, 1-72, 1-73, 1-74, 1-75, 1-76, 1-77, 1-78, 1-79, 1-80, 1-27 1-272, 1-273, 1-274, 1-275, 1-276, 1-277, 1-278, 1-279, 1-280, 1-281, 1-282, 1-283, 1 -284, 1-285, 1-286, 1-457, 1-458, 1-459, 1-460, 1-461, 1-462, 1-463, 1-464, 1-465, 1-466 , 1-467, 1-468, 1-469, 1-470, 1-471, 1-472, 1-473, 1-474, 1-475, 1-476, 1-477, 1-478, 1 -479, 1-480, 1-481, 1-482, 1-483, 1-484, 1-485, 1-486, 1-487, 1-488, 1-489, 1-490, 1-491 , 1-492, 1-493, 1-494, 1-495, 1-496, 1-497, 1-498, 1-499, 1-500, 1-501, 1-502, 1-503, 1 -504, 1-505, 1-506, 1-507, 1-508, 1-509, 1-510, 1-511, 1-512, 1-513, 1-514, 1-515, 1-516 , 1-517, 1-518, 1-519, 1-520, 1-521, 1-522, 1-523, 1-524, 1-525, 1-526, 1-527, 1-528, 1 -529, 1-530, 1-531, 1-532, 1-533, 1-534, 1-535, 1-536, 1-537, 1-538, 1-539, 1-733, 1-734 , 1-735, 1-736, 1-737, 1-738, 1-739, 1-740, 1-741, 1-742, 1-743, 1-744, 1-745, 1-746, 1 -747, 1-748, 1-749, 1-750, 1-815, 1-816, 1-817, 1-818, 1-819, 1-820, 1-821, 1-822, 1-823 , 1-824, 1-825, 1-826, 1-827, 1-828, 1-829, 1-830, 1-831, 1-832, 1-833, 1-834, 1-835, 1 -836, 1-837, 1-838, 1-839, 1-840, 1-8 41, 1-842, 1-843, 1-844, 1-845, 1-846, 1-847, 1-848, 1-849, 1-850, 1-851, 1-852, 1-853, 1-854, 1-855, 1-856, 1-857, 1-858, 1-859, 1-860, 1-861, 1-862, 1-863, 1-1129, 1-1130, 1- 1131, 1-1132, 1-1133, 1-1134, 1-1135, 1-1136, 1-1137, 1-1138, 1-1139 J ,, 1-1 J.1J.410SJ ,, 1 J-- 1 J.1J.4-11. ,, 1-1142, 1143, 1-1144, 1-1145, 1-1146, 1-1147,, 1-1148, 1-1224, 1-1258, 1-1259, 1-1260 1-1261, 1-1262 1-1263, 1-1264, 1-1265, 1-1266, 1-1267, 1-1268 1-1269, 1-1270 1-1271, 1-1272, 1- 1273, 1-1274, 1-1275, 1-1276 1-1277, 1-1278 1-1279, 1-1280, 1-1962, 1-1963, 1- 1964, 1-1965 1-1966, 1-1967 1-1968, 1-1969, 1-1970, 1-1971, 1-1972, 1-1973 1-1974, 1-1975 1-1976, 1-1977, 1-1978, 1-1979, 1-1980, 1-1981 1-1982, 1-1983 1-1984, 1-1985, 1-1986, 1-1987, 1-1988, 1-1989 1-1990, 1-1991 1-1992, 1-1993, 1- 2470, 1-2471, 1-2472, 1-2473 1-2474, 1-2475 1-2476, 1-2477, 1-2478, 1-2479, 1- 2480, 1-2481 1-2482, 1-2483 1-2484, 1-2485, 1-2486, 1-2487, 1- 2488, 1-2489 1-2490, 1-2491 1-2492, 1-2493, 1-2494, 1-2495, 1- 2 496, 1-2497 1-2498, 1-2499 1-2500, 1-2501, 1-2502, 1-2503, 1-2504, 1-2505 1-2506, 1-2507 1-2508, 1-2509, 1 -2510, 1-2511, 1-2512, 1-2513 1-2514, 1-2515 1-2516, 1-2517, 1-2518, 1-2519, 1-2520, 1-2521 1-2522, 1- 2523 1-2524, 1-2525, 1-2526, 1-2527, 1-2528, 1-2529 1-2530, 1-2531 1-2532, 1-2533, 1-2534, 1-2535, 1-2536 , 1-2537 1-2538, 1-2539 1-2540, 1-2541, 1-2542, 1-2543, 1-2544, 1-2545 1-2546, 1-2547 1-2548, 1-2549, 1 -2550, 1-2551, 1-2552, 1-2553 1-2554, 1-2555 1-2556, 1-2557, 1-2558, 1-2559, 1-2560, 1-2561 1-2562, 1- 2563 1-2564, 1-2565, 1-2566, 1-2567, 1-2568, 1-2569 1-2570, 1-2571 1-2572, 1-2573, 1-2574, 1-2575, 1-2576 , 1-2577, 1-2578, 1-2657, 1-2665, 1-2667 and 1-2669, The following compounds are still more preferred, ie the compounds No-: 1-46, 1-47, 1- 48, 1-49, 1-50, 1-51, 1-52, 1-53, 1-54, 1-55, 1-56, 1-57, 1-58, 1-59, 1-60, 1-61, 1-62, 1-63, 1-64, 1-65, 1-66, 1-67, 1-68, 1-69, 1-70, 1-71, 1-271, 1- 272, 1-273, 1-274, 1-275, 1-276, 1-277, 1-278, 1-279, 1-280, 1-281, 1-282, 1-283, 1-284, 1-285, 1-286, 1-457, 1-458, 1-459, 1-460, 1-461, 1-462, 1- 463, 1-464, 1-465, 1-466, 1-467, 1-468, 1-469, 1-470, 1-471, 1-472, 1-473, 1-474, 1-475, 1-476, 1-477, 1-478, 1-479, 1-480, 1-481, 1-482, 1-483, 1-484, 1-485, 1-486, 1-487, 1- 488, 1-489, 1-490, 1-491, 1-492, 1-493, 1-494, 1-495, 1-496, 1-497, 1-498, 1-499, 1-500, 1-501, 1-502, 1-503, 1-504, 1-505, 1-506, 1-507, 1-508, 1-509, 1-510, 1-511, 1-512, 1- 513, 1-514, 1-515, 1-516, 1-517, 1-518, 1-519, 1-520, 1-521, 1-522, 1-523, 1-524, 1-525, 1-526, 1-527, 1-528, 1-529, 1-530, 1-531, 1-532, 1-533, 1-534, 1-535, 1-536, 1-537, 1- 538, 1-539, 1-733, 1-734, 1-735, 1-736, 1-737, 1-738, 1-739, 1-740, 1-741, 1-742, 1-743, 1-744, 1-745, 1-746, 1-747, 1-748, 1-749, 1-750, 1-815, 1-820, 1-861, 1-1134, 1-1135, 1- 1136, 1-1137, 1-1138, 1-1139, 1-1140, 1-1141, 1-1142, 1-1143, 1-1144, 1-1145, 1-1146, 1-1147, 1-1148, 1-1224, 1-1258, 1-1259, 1-1260, 1-1261, 1-1262, 1-1263, 1-1264, 1-1265, 1-1266, 1-1267, 1-1268, 1- 1269, 1-127 0, 1-1271, 1-1272, 1-1273, 1-1274, 1-1275, 1-1276, 1-1277, 1-1278, 1-1279, 1-1280, 1-1963, 1-1993, 1-2470, 1-2520, 1-2566, 1-2567, 1-2568, 1-2569, 1-2570, 1-2571- 1-2572, 1-2573, 1-2574, 1-2575, 1- 2576, 1-2577, 1-2578, 1-2557, 1-2565, 1-2566 and 1-2569.

The following compounds are also preferred, ie, compounds No .: 1-46, 1-47, 1-48, 1-49, 1-50, 1-71, 1-271, 1-496, 1-539, 1-733, 1-738, 1-739, 1-740, 1-741, 1-742, 1-815, 1-820, 1-861, 1-1135, 1-1145, 1-1224, 1-1258, 1-1260, 1-1275, 1-1276, 1-1280, 1-1963, 1- 1993, 1-2470, 1-2520, 1-2567, 1-2657, 1-2665, 1-2667 and 1-2669. The following compounds are particularly preferred, ie the compounds No .: 1-49, 1-271, 1-496, 1- 539, 1-733, 1-738, 1-739, 1-740, 1-741, 1-742, 1-820, 1-861, 1-1135, 1-1224, 1-1258, 1-1260, 1-1275, 1-1963, 1-2470, 1-2520, 1-2567, 1-2657, 1-2665, 1-2667 and 1-2669. The most preferred compounds are N- [5- (1,2-dithiolan-3-yl) pentanoyl] methanesulfonamide (Compounds No. 1-496); 3- [4- (1, 2-dithiolan-3-yl) butyl] ureidoacetate methyl (Compounds No. 1-739); Acid 2 (S) -. { 3- [4- (1, 2-dithiolan-3-yl) butyl] -ureido} propionic (Compound No. 1-740); 2 (S) -. { 3- [4- (1, 2-dithiolan-3-yl) butyl] -ureido} methyl propionate (Compound No. 1-742); 3- [4- (1, 2-dithiolan-3-yl) util] ethyl ethyl-1-methylureidoacetate (Compound No. 1-820 ethyl ester); and - [5- (1,2-dithiolan-3-yl) pentyl] -methanesulfonamide (Compound No. 1-2470); and pharmaceutically acceptable salts thereof. The compounds of the present invention can be prepared by a variety of well known methods for the preparation of compounds of this general type. For example, they can be prepared by the following methods A through G.

Method A In this method, a compound of the Formula (II) is reacted with a compound of the Formula (III), to give a compound of the Formula (Ia), which is a compound of the Formula (I) in which the meanings of A and B are somewhat restricted.

Reaction Scheme A: In the above formulas: R1, k, m and n are as defined above; A1 represents any of the groups defined above for A, other than the groups of -CO-O- and -N (R2) 0- [where R ^ is as defined above]; B1 represents a group of the formula -N (R ^) - or -N (R5) N (R6) - [wherein R ^ and R ^ are as defined above]; and Y represents a group that has to be eliminated. There is no particular restriction on the group to be eliminated, as long as it can be eliminated as a nucleophilic residue, and examples of such groups are well known to those skilled in the art. Specific examples of such groups include: halogen atoms such as chlorine, bromine and iodine atoms; trihalogenomethyl groups, such as the trichloromethyl group; lower alkanesulfonyloxy groups, such as the methanesulfonyloxy and ethanesulfonyloxy groups; halogenoalkanesulfonyloxy groups, such as trifluoromethanesulfonyloxy groups and pentachloroethanesulfonyloxy groups; and arylsulphonyloxy groups, such as benzenesulphonyloxy, p-toluenesulphonyloxy and p-nitrobenzenesulphonyloxy groups.

Of these, a halogen atom or an alkanesulfonyl group is preferred.

Step Al In this step, a derivative of dithiolan of the formula (la) is prepared by reacting a compound of the formula (II) with a compound of the formula (III) in a solvent in the presence of a base. The reaction is normally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that there is no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some degree. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, doxyne, dimethoxyethane and diethylene glycol dimethyl ether; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitriles, such as acetonitrile, propionitrile and isobutyronitrile; amides, such as formamide, dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide; sulfoxides, such as dimethyl sulfoxide and sulfones, such as sulfolane. Of these, ketones, ethers and amides are preferred, most preferably acetone, tetrahydrofuran, dimethylformamide and N, N-dimethylacetamide. Also, there is no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type can also be used. Examples of such bases include: inorganic bases, such as alkali metal carbonates, (e.g. sodium, potassium carbonate, lithium carbonate or cesium carbonate), alkali metal bicarbonates (eg, sodium bicarbonate, potassium bicarbonate or lithium bicarbonate), alkali metal hydrides (eg, lithium hydride, hydride sodium or potassium hydride), alkali metal or alkaline earth metal hydroxides (eg, sodium hydroxide, potassium hydroxide, barium hydroxide or lithium hydroxide) and alkali metal fluorides (eg, sodium fluoride or sodium fluoride) potassium); and alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide or lithium methoxide. Of these, alkali metal carbonates, alkali metal hydrides and alkali metal alkoxides are preferred, and potassium carbonate, sodium hydride and potassium t-butoxide are most preferred. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent, and the starting material or reagent used. However, in general, it is convenient to carry out the reaction at a temperature of -20 ° C to 100 ° C, most preferably 0 ° C to 50 ° C. The time required for the reaction can also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvents employed. However, as long as the reaction is carried out under the preferred conditions outlined above, a period of 10 minutes to 24 hours, most preferably from 30 minutes to 12 hours, will usually suffice.

Method B This demonstrates the preparation of a compound of the formula (Ib), ie a compound of the formula (I) in which A represents an oxygen atom, or a group of the formula -N (R2) CO-, N (R2) S02-, -ON (R2) CO-, -ON (R2) S02-, -N (R2) N (R3) CO-, -N (R2) N (R3) S02-, -N ( R2) CON (R3) N (R4) CO-, -N (R2) CON (R3) CO-, or -N (R) CON (R3) S02- [wherein R2, R3 and R4 are as defined above ] Reaction scheme B: In the above formulas: B, Rl, Y, J and n are as defined above; and A2 represents an oxygen atom, or a group of the formula -N (R2) C0-, N (R2) S0-, -ON (R2) CO-, -ON (R2) S0 -, -N (R2) N (R3) CO-, -N (R2) N (R3) S02-, -N (R2) CON (R3) N (R4) CO-, -N (R2) CON (R3) CO-, or -N (R2) CON (R3) S02- [where R2, R3 and R4 are as defined above].

Step Bl In this step, a dithiolan derivative of the formula (lb) is prepared by reacting a compound of the formula (IV) with a compound of the formula (V) in a solvent in the presence of a base. The reaction is essentially the same as described above in step Al, and can be carried out using the same solvents, bases and reaction conditions.

Method C This demonstrates the preparation of a compound of the formula (le), ie a compound of the formula (I) in which A represents a groups of the formula N (R2) CO-, N (R2) S0 -, -C0N (R2) N (R3) C0-, -CON (R2) CO- CON (R2) CO-, -CON (R2) S02-, -O-CO-, -ON (R2) CO-, -ON (R2 ) S02-, -O-CO (R2) N (R3) CO-, -O-CON (R2) CO-, -0-CON (R2) S0 -, -CO-CON (R2) N (R3) CO -, -C0-C0N (R2) CO-, -COCONA2) S02", -N (R2) C0-C0-, -N (R2) N (R3) CO-, -N (R2) N (R3) S02", -N (R2) CON (R3) N (R4) CO-, -N (R2) CON (R3) N (R4) CO-, - (R2) CON (R3) CO- or -N (R2) CON (R3) S02- [where R2, R3 and R4 are as defined above], and B represents a single bond Reaction Scheme C: In the above formulas: RL, nyn are as defined above, D- represents an oxygen atom, or a group of the formula -N (R2) -, -C0N (R2) -, -0N (R2) -, - O-CON (R2) -, -N (R2) N (R3) - or -N (R2) CON (R3) - [where R2 and R3 are as defined above], E ^ - represents a carbonyl group, a sulfonyl group or a group of the formula -COCO-, and Y1 represents a group to be eliminated, as in the definition of Y; however, the imidazolyl group, or an active ester residue, including acyloxy group, such as the acetoxy group, or alkoxyacyloxy groups, such as the methoxyacetoxy group, are preferred.

Step Cl In this step, the diitolan derivative of the formula (le) is prepared by acylating or sulfonylating a compound of the formula (VI) with a compound of the formula (VII) in a solvent in the presence of a base. The reaction is normally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that there is no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some degree. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, doxyne, dimethoxyethane and diethylene glycol dimethyl ether; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitriles, such as acetonitrile, propionitrile and isobutyronitrile; and amides, such as formamide, dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide. Of these, aromatic hydrocarbons, halogenated hydrocarbons, ethers and amides are preferred, and halogenated hydrocarbons, ethers and amides are more preferred. Likewise there is no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type can be used equally, Examples of such bases include: organic bases, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methyldicyclohexylamine, N-ethylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t -butyl) -methylpyridine, quinoline, N, Nf -dimethylaniline, N, N'-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo- [2.2.2 ] octane (DABCO) and 1,8-diazabicyclo [5. .0] undec-7-ene (DBU), of these, triethylamine and diisopropylethylamine are preferred. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent, and the starting material or reagent used. However, in general, it is convenient to carry out the reaction at a temperature of -20 ° C to 100 ° C, most preferably 0 ° C to 80 ° C. The time required for the reaction can also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvents employed. However, as long as the reaction is carried out under the preferred conditions outlined above, a period of from 5 minutes to 2 days, most preferably from 20 minutes to 1 day, will usually suffice. As an alternative, wherein the compound of the formula (VI) is reacted with a compound of the formula (VII) wherein E1 represents a carbonyl group, the reaction can also be achieved by using a compound of the formula HOOC-R1 (wherein R ^ is as defined above) making reacting the compound of the formula (VI) with the compound of the formula (VII) using a condensing agent in a solvent in the presence or absence of a base. There is no particular restriction on the nature of the condensing agents used, and any condensing agent commonly used in reactions of this type can also be used here. Examples of such condensation agents include: (1) a combination of phosphoric acid ester, such as diethyl phosphonophosphate or diphenylphosphoryl azide, and the base described below; (2) a carbodiimide, such as 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide; a combination of one or more of the foregoing carbodiimides and the base described below; a combination of one or more of the foregoing carbodiimides and an N-hydroxy compound, such as N-hydroxysuccinimide, 1-hydroxybenzotriazole or N-hydroxy-5-norbormen-2,3-dicarboxyimide; (3) a combination of a disulfide, such as 2,2'-dipyridyl disulfide or a 2,2'-dibenzothiazolyl disulfide, and a phosphine, such as triphenylphosphine or tributylphosphine; (4) a carbonate, such as N, N'-disuccinimidyl carbonate, di-2-pyridyl carbonate or S, S'-bis (1-phenyl) -lH-tetrazol-5-yl dithiocarbonate); (5) a phosphinic chloride, such as N, N'-bis (2-oxo-3-oxazolidinyl) phosphinic chloride; (6) an oxalate, such as N, N'-disuccinimidyl oxalate, N, N '-diftalamide oxalate, N, N'-bis (5-norbornene-2,3-dicarboxyimidyl) oxalate, oxalate of 1, 1'-bis (benzotriazolyl), 1,1'-bis (6-chlorobenzotriazolyl) oxalate or 1,1'-bis (6-trifluoromethylbenzotriazolyl) oxalate; (7) a combination of one or more of the above phosphines and an azodicarboxylic acid ester, such as diethyl azodicarboxylate, or an azodicarboxylic amide, such as 1,1 '- (azodicarbonyl) dipyridine; a combination of one or more of the above phosphines and the base described below; (8) a 3'-N-lower alkyl-5-arylisoxazolium sulfonate, such as a 3'-N-ethyl-5-phenylisoxazolium sulfonate; (9) a diheteroaryldiselenide, such as di-2-pyridyl diselenide; (10) an arylsulfonyltriazolide, such as p-nitrobenzensulfonyltriazolide; (11) a lower 2-halogeno-l-alkylpyridino halide, such as 2-chloro-1-methylpyridinium iodide; (12) an imidazole, such as 1,1 '-oxalyldiimidazole or N, N' -carbonyldiimidazole; (13) a 3-lower alkyl-2-halogenobenzotriazolium fluoroborate such as 3-ethyl-2-chloro-benzothiazolium fluoroborate; (14) a 3-lower alkyl-benzothiazole-2-serone, such as 3-methyl-benzothiazole-2-serone; (15) a phosphate, such as phenyldichlorophosphate or polyphosphate ester; (16) a halogensulfonyl isocyanate, such as chlorosulfonyl isocyanate; (17) a halogensilane, such as trimethylsilyl chloride or triethylsilyl chloride; (18) a combination of a lower alkanesulfonyl halide, such as methanesulfonyl chloride and the base described below; (19) a N, N, N ', N'-lower tetraalkyl chloride-halogenoformamide, such as N, N, N', N'-tetramethylchloroformamide chloride; and (20) a combination of lower alkyloxycarbonyl halide, such as ethyl chlorocarbonate and the base described below; preferably (1), (2), (7), (12) and (20) above. The reaction is normally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that there is no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some degree. Examples of suitable solvents include: aliphatic hydridocarbons, such as hexane and heptane; aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters, such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, doxyne, dimethoxyethane and diethylene glycol dimethyl ether; nitriles, such as acetonitrile and isobutyronitrile; and amides, such as formamide, dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide. Also, there is no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type can also be used. Examples of such bases include: organic bases, such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine , N-methylpiperidine, pyridine, 4-pyrrolidinopiperidine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline and N, N -diethylaniline. If desired, 4- (N, N-dimethylamino) pyridine and 4-pyrrolidinopyridine can be combined with other bases and used in a catalytic amount. Also, to carry out the most effective manner reaction, a dehydrating agent such as a molecular sieve, a quaternary ammonium salt (for example, benzyltriethylammonium chloride or tetrabutylammonium chloride), a crown ether, such as dibenzo-18 -Cone-6, or an acid trap agent, such as 3,4-dihydro-2H-pyrido [1,2-a] pyrimidin-2-one, can be added to the reaction mixture. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent, and the starting material or reagent used. However, in general, it is convenient to carry out the reaction at a temperature of -20 ° C to 80 ° C, most preferably 0 ° C to room temperature. The time required for the reaction can also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvents employed. However, as long as the reaction is carried out under the preferred conditions outlined above, a period of 10 minutes to 3 days, most preferably 30 minutes to 1 day, will usually suffice.

Method D This demonstrates the preparation of a compound of the formula (Id), ie a compound of the formula (I) in which A represents a carbonyl group, or a group of the formula -CON (R2) N (R3) CO-, -CON (R2) CO- -C0N (R2) S02-, -CO-O-, -CO-CON (R2) N (R3) CO-, -CO-CON (R2) CO- or -CO -CON (R2) S02 [where R2 and R3 are as defined above].

Reaction scheme D: In the previous formulas: B, Rl, Y ', k, _p? and n are as defined above, D2 represents a carbonyl group or a group of the formula -C0-C0-, and E2 represents an oxygen atom or a group of the formula -N (R2) N (R3) CO-, - N (R2) C0- or -N (R2) S02 [wherein R2 and R3 are as defined above].

Step DI In this step, a dithiolan derivative of the formula (Id) is prepared by acylating a compound of the formula (IX) with a compound of the formula (VIII) in a solvent in the presence of a base. The reaction is essentially the same as described above in step Cl, and can be carried out using the same solvents, bases and reaction conditions. Alternatively, the dithiolan derivative of the formula (Id) can be prepared by reacting a compound of the formula (VIII ') with the compound of the formula (IX) using a condensing agent in a solvent in the presence or absence of a base . (where D2 k¿_ m and n are as defined above). The reaction is normally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that there is no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some degree. Examples of suitable solvents include: aliphatic hydridocarbons, such as hexane and heptane; aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters, such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate, ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, doxyne, dimethoxyethane and diethylene glycol dimethyl ether; nitriles, such as acetonitrile and isobutyronitrile; and amides, such as formamide, dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide. Also, there is no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type can also be used. Examples of such bases include: organic bases, such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, cyclohexylamine , N-methylpiperidine, pyridine, 4-pyrrolidinopiperidine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline and N, N -diethylaniline. If desired, 4- (N, N-dimethylamino) pyridine and 4-pyrrolidinopyridine can be combined with other bases and used in a catalytic amount. Also, to carry out the most effective manner reaction, a dehydrating agent such as a molecular sieve, a quaternary ammonium salt (for example, benzyltriethylammonium chloride or tetrabutylammonium chloride), a crown ether, such as dibenzo-18 -Cone-6, or an acid trap agent, such as 3,4-dihydro-2H-pyrido [1,2-a] pyrimidin-2-one, can be added to the reaction mixture. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent, and the starting material or reagent used. However, in general, it is convenient to carry out the reaction at a temperature of -20 ° C to 80 ° C, most preferably 0 ° C to room temperature. The time required for the reaction can also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvents employed. However, as long as the reaction is carried out under the preferred conditions outlined above, a period of 10 minutes to 3 days, most preferably 30 minutes to 1 day, will usually suffice.

Method E This demonstrates the preparation of a compound of the formula (le), ie a compound of the formula (I) in which: A represents a group of the formula -N (R2) CO- [wherein R 2 represents a hydrogen], and B represents a group of the formula -N (R ^) N (R ^) - [wherein R ^ and R6 are as defined above].

Reaction Scheme E In the above formulas: B ^, R !, k, _m and n are as defined above.

Step El In this step, an isocyanic acid ester of the formula (XI) is prepared by acidifying the carboxyl group of a compound of the formula (X) in a solvent in the presence or absence of a catalyst to obtain an acid azide compound and after heating it. The azidation reaction is normally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some degree. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, such as methylene chloride and chloroform; ethers, such as diethyl ether, tetrahydrofuran, doxyne, dimethoxyethane; nitriles, such as acetonitrile; and amides, such as formamide, dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide. Of these, aromatic hydrocarbons, halogenated hydrocarbons and ethers are preferred. There is also no particular restriction on the nature of the azidation agents used, and any azidation agent used in reactions of this type can also be used here. Examples of such azidation agents include: diarylphosphoryl azide derivatives, such as diphenylphosphoryl azide, tialkylsilyl azide, such as trimethylsilyl azide or triethylsilyl azide, and alkali metal salt azides, such as sodium azide, potassium azide or lithium azide. . Of these, the diarylphosphoryl azide derivatives are preferred. There is also no particular restriction on the nature of the catalysts used, and any any catalyst commonly used in reactions of this type can also be used here. Examples of such catalysts include: Lewis acids, such as trialkylsilyl triflates (for example, trimethylsilyl triflate and triethylsilyl triflate), trifluoroborane etherate, aluminum chloride and zinc chloride; and organic bases, such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di-t-butyl -4-methylpyridine, quinoline, N, N-dimethylaniline and N, N-diethylaniline. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent, and the starting material or reagent used. However, in general, it is convenient to carry out the reaction at a temperature of 20 ° C to 180 ° C, most preferably 50 ° C to 150 ° C. The time required for the reaction can also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvents employed. However, as long as the reaction is carried out under the preferred conditions outlined above, a period of 10 minutes to 24 hours, most preferably from 30 minutes to 8 hours, will usually suffice.

Step E2 In this step, a dithiolan derivative of the formula (le) is prepared by reacting an isocyanic acid ester (XI) with a compound of the formula (XII) in a solvent. The reaction is normally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that there is no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some degree. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, doxyne, dimethoxyethane and diethylene glycol dimethyl ether; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitriles, such as acetonitrile, propionitrile and isobutyronitrile; and amides, such as formamide, dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide; sulfoxides, such as dimethyl sulfoxide; and sulfones, such as sulfonalo. Of these, aromatic hydrocarbons, halogenated hydrocarbons, ethers, nitriles and amides are preferred, most preferably aromatic hydrocarbons, halogenated hydrocarbons, ethers, nitriles and amides. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent, and the starting material or reagent used. However, in general, it is convenient to carry out the reaction at a temperature of -20 ° C to 100 ° C, most preferably 0 ° C to 80 ° C. The time required for the reaction can also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvents employed. However, as long as the reaction is carried out under the preferred conditions outlined above, a period of from 5 minutes to 2 days, most preferably from 20 minutes to 1 day, will usually suffice. Alternatively, the compound of the formula (I) in where A represents a group of the formula -N (R2) CON (R3) N (R4) CO-, -N (R2) CON (R3) CO- or -N (R2) CON (R3) S02-, [en where R 2 represents a hydrogen atom, R 3 and R 4 are as defined above] can be prepared by reacting the above isocyanic acid ester of the formula (XI) with a compound of the formula: H-D 3 -B-R 1. { wherein B and R ^ are as defined above, and D3 represents a group of the formula -N (R3) N (R4) CO-, -N (R3) CO- or -N (R3) S0 - [where R3 and R4 are as defined above]} , following the same procedure as described above. A compound of the formula (I) wherein A represents a group of the formula -N (R2) CO- (wherein R2 represents a hydrogen atom), B represents a single bond, and R1 represents an OR7 group (wherein R7 is as defined above) can be prepared by reacting the above isocyanic acid ester of the formula (XI) with a compound of the formula: HOR7 (wherein R7 is as defined above), following the same procedure as defined before. A hydrogen atom of an amino, amide or imide group can be replaced by another group by reacting a compound of the formula (I) in which R 2, R 3, R 4, R 5 and / or R 6 represent a hydrogen atom with a compound of the formula Y-R8 (in Y is as defined above and R8 represents a group other than the hydrogen atom in the definition of R2, R3, R4 and R6) according to Method A above, or by alkylation using a combination of an alcohol and a carbodiimide, such as dicyclohexylcarbodiimide. For example, after the dithiolan derivative of the present invention is synthesized according to Method E above, a hydrogen atom of an amide group in the compound can be replaced by another group by these methods.

Method F This demonstrates the preparation of a compound of the formula (If), that is to say a compound of the formula (I) in which: A represents a group of the formula -O-CO-, -N (R2) C0-, - N (R2) CS-, -CON (R2) CO-, -C0N (R2) CS-, -ON (R2) CO-, -0-C0N (R2) C0-, -N (R2) N (R3) C0-, or -N (R2) CON (R3) CO-, [where R2 and R3 are as defined above], B represents a single link or a group of the formula -N (R5) - [wherein R5 represents the groups other than hydrogen in the definition of R ^], and R1 represents a group as defined above other than the hydrug.

Reaction Scheme F: In the previous formulas: D! k, _m and n are as defined above, E3 represents a single link or a group of the formula -N (R5) - [where R ^ is as defined above], G represents an oxygen atom or a sulfur atom, and R1 'represents a group as defined above for R1 other than hydrogen Step Fl In this step , a derivative of dithiolan of the formula (If) is prepared by reacting an isocyanic acid ester or an isothiocyanic acid ester of the formula (XIII) with a compound of the formula (VI). The reaction is essentially the same as described above in step E2, and can be carried out using the same solvents, bases and reaction conditions. The compound of the formula (If) where E3 represents a single bond and R1 'represents a hydrogen atom can also be prepared by carrying out the reaction using a compound of the formula G = CN-R9 [wherein G is as defined above and R ^ represents a silyl group, such as a lower trialkylsilyl group, for example, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyl-di-t-butylsilyl or triisopropylsilyl, or a lower trialkylsilyl group substituted by one or two allyl groups, such as a diphenylmethylsilyl group, defenylbutylsilyl, diphenylisopropylsilyl or phenyldiisopropylsilyl] in place of the isocyanic acid ester or the isothiocyanic acid ester of the formula (XIII). Where the dithiolan ring is subjected to ring opening in the course of carrying out the reactions described in Methods A to F to produce a dithiol compound, a dithiolan derivative can be obtained by oxidizing the compound opened in the ring to form a disulfide bond. The oxidation reaction is generally carried out using an oxidation agent in the presence of a solvent. The reaction is normally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that there is no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some degree. Preferred solvents include organic solvents containing water. Said organic solvent includes: ketones, such as acetone; halogenated hydrocarbons, such as methylene chloride, chloroform or carbon tetrachloride; nitriles, such as acetonitrile; ethers, such as diethyl ether, tetrahydrofuran and dioxane; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; sulfoxides, such as dimethyl sulfoxide; and alcohols, such as methanol and ethanol. There is also no particular restriction on the nature of the oxidizing agents used, and any oxidizing agent commonly used in reactions of this type can also be used here as long as it can form a disulfide bond. Examples of said oxidizing agents include: ferric chloride. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent, and the starting material or reagent used. However, in general, it is convenient to carry out the reaction at a temperature of 0 ° C to 150 ° C. The time required for the reaction can also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvents employed. However, as long as the reaction is carried out under the preferred conditions outlined above, a period of 10 minutes to 24 hours will usually suffice.

Method G This illustrates the preparation of a compound of the formula (I) in which at least one of yn is 1 or 2, ie a compound of the formula (Ig) of a compound of the formula in which m and n are zero, that is, a compound of the formula (Ig ').

Reaction Scheme G: In the above formulas: A, B, R1 and k are as defined above; and m / _ and n_ are as defined above for m and n provided that at least one is not zero.

Step Gl In this step, a dithiolan derivative of the formula (Ig) is prepared by oxidizing a compound of the formula (Ig ') [a compound of the formula (I) wherein n and m are 0]. There is no particular restriction on the nature of the oxidizing agents used, and any oxidizing agent commonly used in reactions of this type can also be used here, provided that it is capable of oxidizing a sulfide to a sulfoxide or a sulfone. Examples of said oxidizing agents include: hydroperoxides, such as hydrogen peroxide, t-butyl hydroperoxide or pentyl hydroperoxide; dialkyl peroxides, such as di-t-butyl peroxide, peracids, such as perbenzoic acid, m-chloroperbenzoic acid or peracetic acid; peracid esters, such as methyl perbenzoate; and diacyl peroxides, such as benzoyl peroxide. Of these, hydrogen peroxide, m-chloroperbenzoic acid and t-butyl hydroperoxide are particularly preferred. In this step, a dithiolan derivative of the formula (la) is prepared by reacting a compound of the formula (II) with a compound of the formula (III) in a solvent in the presence of a base. The reaction is normally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that there is no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some degree. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, doxyne, dimethoxyethane and diethylene glycol dimethyl ether; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitriles, such as acetonitrile, propionitrile and isobutyronitrile; amides, such as formamide, dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphoric triamide; sulfoxides, such as dimethyl sulfoxide; sulfones, such as sulfonal; alcohols, such as methanol and ethanol; esters, such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; and water. Of these, aromatic hydrocarbons, halogenated hydrocarbons, ketones, amides, alcohols and water are preferred, most preferably halogenated hydrocarbons, ketones, amides, alcohols and water. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent, and the starting material or reagent used. However, in general, it is convenient to carry out the reaction at a temperature of -50 ° C to 100 ° C, most preferably -20 ° C to 50 ° C. The time required for the reaction can also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvents employed. However, as long as the reaction is carried out under the preferred conditions outlined above, a period of 10 minutes to 2 days, most preferably 30 minutes to 12 hours, will suffice. After completing each of the above reactions, the desired compounds can be recovered from the reaction mixture by conventional methods. For example, the desired compound can be obtained by: adequately neutralizing the reaction mixture; removing insoluble compounds by filtration if insoluble compounds exist; adding an organic solvent immiscible with water, such as ethyl acetate to the reaction mixture; washing with water or another suitable solvent; separating the organic layer containing the desired compound; drying it over a drying agent, such as anhydrous sodium sulfate or anhydrous magnesium sulfate; and removing the solvent, for example, by evaporation. The compound thus obtained can be separated and purified, if necessary, by appropriately combining conventional methods, for example, recrystallization, reprecipitation or other methods commonly used in the separation and purification of organic compounds, for example, adsorption column chromatography using such a vehicle. as silica gel, alumina or magnesium-silica gel of Florisil type; a method using a synthesized adsorbent such as split column chromatography using a vehicle such as Ephadex LH-20 (trade name, manufactured by Pharmacia Co, Ltd.) Amberlite XAD-11 (trade name, manufactured by Rohm and Haas Co. Ltd.) and Diaion HP-20 (trade name, manufactured by Mitsubishi Kasei Corporation), a method that uses an ion exchange chromatogram, or a column chromatography Reverse phase or normal phase using silica gel or alkylated silica gel (preferably high performance liquid chromatography), and eluting with a suitable eluent. The starting materials in Methods A to G are known compounds or are compounds synthesized from a compound known by conventional methods, for example, the amino derivative of the formula (Ih), which is a starting material in Method A , Method C and Method F can be prepared by the following Method H.

Method H Reaction Scheme H: In the formulas above, k, m and n are as defined above.

Step Hl In this step, a phthalimide derivative of the formula (XVI) is prepared by carrying out a Mitsunobu reaction between a compound of the formula (XIV) and phthalimide of the formula (XV). There is no particular restriction on the nature of the reagents used in the Mitsunobu reaction, and any reagent commonly used in reactions of this type can likewise be used here. Examples of such reagents include: a combination of an azo compound, such as dialkyl lower azodicarboxylate (eg, dimethyl azodicarboxylate, diethyl azodicarboxylate or diisopropyl azodicarboxylate) or an azodicarboxamide [such as 1,1'- (azodicarbonyl) dipiperidine] and a phosphine, such as a triarylphosphine (for example, triphenylphosphine) or a lower trialkyl phosphine (for example tributylphosphine), very particularly a combination of a lower dialkyl azodicarboxylate and a triarylphosphine, most preferably a combination of dimethyl azodicarboxylate and triphenylphosphine. In this step, a dithiolan derivative of the formula (la) is prepared by reacting a compound of the formula (II) with a compound of the formula (III) in a solvent in the presence of a base. The reaction is normally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that there is no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some degree. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene and xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters, such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, doxyne, dimethoxyethane and diethylene glycol dimethyl ether; nitriles, such as acetonitrile and isobutyronitrile; amides, such as formamide, dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and tria-idahexamethylphosphoric; and sulfoxides such as dimethyl sulfoxide and sulfonyl. Of these, aromatic hydrocarbons and ethers are preferred. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent, and the starting material or reagent used. However, in general, it is convenient to carry out the reaction at a temperature of -20 ° C to 100 ° C, most preferably 0 ° C to 50 ° C. The time required for the reaction can also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvents employed. However, as long as the reaction is carried out under the preferred conditions outlined above, a period of 10 minutes to 3 days, most preferably from 30 minutes to 12 hours, will usually suffice.

Step H2 In this step, an amino derivative of the formula (Ih) is prepared by reacting the phthalimide derivative of the formula (XVI) with butylamine or hydrazine in a solvent. For example, it can be achieved by reacting the phthalimide derivative of the formula (XVI) with butylamine in methanol at room temperature for 6 hours. Since the dithiolan derivatives have the effect of increasing the activity of glutathione rductase, a composition which increases the activity of glutathione reductase, which contains these compounds or pharmaceutically acceptable salts thereof, can be used for the prevention or treatment of diseases which result from adverse oxidative conditions. Examples of diseases that result from adverse oxidative conditions are diseases or disease states that include damage caused by alcohol abuse, exposure to xenobiotic agents or radiation; intracellular oxidative states caused by liver diseases; intoxication by drugs and chemical agents (eg, carcinoatics including a platinum chelator, antibiotics, antiparasitics, paraquat, carbon tetrachloride and halothane); heavy metal poisoning; nervous system disorders including brain and degenerative disorders of neurons (e.g., cerebral ischemia, cerebral stroke, hypoglycemia, epileptic seizure, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's chorea); diseases related to impaired functionality of the immune system, in particular immunotherapy of tumors; infertility, in particular male infertility; coronary heart disease; ophthalmological disorders such as cataracts, retinopathy of prematurity and siderosis; pulmonary diseases such as ideopathic pulmonary fibrosis, respiratory distress syndrome in adults, emphysema, asthma, bronchopulmonary dysplasia and interstitial pulmonary fibrosis, chronic renal failure; gastric ulcer; cancer cancers and metastases including colorectal cancer; diabetes; hepatocyte necrosis and apoptosis including ethanol-induced liver disease; viral diseases including influenza, hepatitis B and HIV; blood vessel and blood abnormalities such as Fanconi anemia, septicemia, increased permeability through blood vessels and leukocyte adhesion; various malformations such as Down syndrome, Duchenne muscular dystrophy, Becker's dystrophy, Dubin-Johnson-Spring syndrome and favism; and inflammatory diseases such as nephritis, pancreatitis, dermatitis, fatigue and rheumatism. In particular, the dithiolan derivatives and pharmaceutically acceptable salts thereof of the present invention are useful for the prevention or treatment of diseases or pathological conditions such as damage caused by radiation, intracellular oxidative states caused by liver diseases, intoxication (i.e. collateral effects) by carcinostats including platinum chelator, nervous system disorders, cataracts, diabetes, hepatocyte necrosis and apoptosis, viral diseases and inflammatory diseases. Among the diseases described above that result from an oxidative adverse condition, there are some diseases where the effects are irreversible, once they occur. A therapeutic agent for said disease means a medicament that prevents or retards the progress of the disease.

The dithiolan derivatives of the formula (I) or pharmaceutically acceptable salts thereof of the present invention can be used together with a medicament which is known as a preventive agent or therapeutic agent for a disease listed above as the diseases resulting from the adverse condition. oxidative and may show a cinergistic effect. The cyanamide, disulfiram, adenine and cysteine are known as drugs to treat the damage caused by alcohol abuse, exposure to xenobiotic agents or radiation; Aminoethylsulfonic acid, protoporphyrin-disodium and diisopropylamine dichloro acetate are known as drugs for treating intracellular oxidative states caused by liver diseases; glutathione, dimercaprol, and disodium-calcium edetate are known as drugs to treat intoxication by drugs and chemical agents (eg, carcinostatics including platinum chelator, antibiotics, antiparasitics, paraquat, carbon tetrachloride and halothane) or to treat metal poisoning heavy phenobarbital, phenytoin, bromocriptine mesylate, sulpiride, sodium valproate, haloperidol, levodopa-carbidopa, idebenone and aniracetam are known as drugs for treating nervous system disorders including degenerative disorders of the brain and neurons (eg cerebral ischemia, cerebral stroke, hypoglycemia, epileptic seizures, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's chorea); cyclophosphamide, interferon-A and interferon-ß with known drugs for treating diseases related to altered functionality of the immune system, in particular tumor immunotherapy; Sildenafil is known as a medication to treat infertility, particularly infertility in men; Digitoxin and digoxin are known as medications to treat coronary heart disease; Pyrenoxin is known as a medication to treat ophthalmological disorders such as cataracts, retinopathy or prematurity and siderosis; theophylline, cetotifen fumarate, epinastine hydrochloride, pranlukast tosylate and suplatast are known as drugs for treating lung diseases such as ideopathic pulmonary fibrosis, respiratory distress syndrome in adults, emphysema, asthma, bronchopulmonary dysplasia and interstitial pulmonary fibrosis; furosemide, ethacrynic acid and bumetanide are known as drugs to treat chronic renal failure; Teprenone, rebamipide, ecabet-sodium, plaunotol, famotidine, ranitidine hydrochloride and lansoprazole are known as drugs to treat gastric ulcer; BB-2516 and AG3340 are known as useful compounds against cancer cancers and metastasis including colorectal cancer; epalrestat, voglibose, acarbose, insulin, glibenclamide and troglitazone are known as medications to treat diabetes; aminoethylsulfonic acid, protoporphyrin-disodium and disopropylamine dichloro acetate are known as medicaments for treating hepatocyte necrosis and apoptosis including ethanol-induced liver disease; Acyclovir, zidovudine, interferon-A, interferon-ß and interferon- are known as drugs to treat viral diseases including influenza, hepatitis B and HIV; erythropoietin derivatives are known as drugs to treat abnormalities of blood and blood vessels such as Fanconi anemia, septicemia, increased permeability through blood vessels and leukocyte adhesion; Phenipentol, camostat mesylate, indomethacin, loxoprofen-sodium and diclofenac-sodium are known as medications to treat various inflammatory diseases such as nephritis, pancreatitis, dermatitis, fatigue and rheumatism. The compounds of the present invention can be administered in any conventional pharmaceutical formulation, the nature of which will depend on the patient and the intended route of administration. For example, for oral administration, suitable formulations include tablets, capsules, granules, powders or syrups. For parenteral administration, suitable formulations include injections or suppositories. those formulations can be prepared by well known methods using additives such as excipients, lubricants, binders, disintegrating agents, stabilizers, corrigents and diluents. Examples of suitable excipients include organic excipients, for example: sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin or carboxymethyl starch; cellulose derivatives such as crystalline cellulose, low substituted hydroxy-phenyl cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose-calcium or carboxymethylcellulose-sodium bridging internally; gum arabic; dextran; and Swarm; inorganic excipients including silicate derivatives such as light silicic acid anhydride, synthetic aluminum silicate or magnesium metasilic acid aluminate; phosphates such as calcium phosphate, carbonates such as calcium carbonate; and sulfates such as calcium sulfate. Examples of suitable lubricants include stearic acid, metal stearates such as calcium stearate or magnesium stearate; talc, colloidal silica, waxes such as beeswax or spermatine, boric acid, adipic acid, sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; sodium salts of fatty acids; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicates such as silicic acid anhydride or silicic acid hydrate; and the above starch derivatives. Examples of suitable binders include polyvinyl pyrrolidones, Macrogol and compounds similar to the excipients described above. Examples of stable disintegrating agents include compounds similar to the excipients described above, and chemically modified starches, celluloses such as sodium croscarmellose, sodium carboxymethylstarch or bridged polyvinylpyrrolidone. Examples of suitable stabilizers include paraoxybenzoates such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; and sorbic acid. Examples of suitable corrigents include sweeteners, vinegar or perfumes such as those conventionally used. In addition, since the dithiolan derivative or the pharmaceutically acceptable salt thereof of the present invention is less stimulating to the eyes, it can be administered topically to the eyes. Formulations suitable for topical administration to the eyes include solutions, suspensions, gels, ointments and solid insertion agents. The formulation of these formulations for topical administration may contain the dithiolan derivative or the pharmaceutically acceptable salt thereof at a level of 0. 001% (preferably 0.01%) as a limit of less than 10% (preferably 5%) as an upper limit. The pharmaceutical formulation containing an active compound, if desired, may be mixed with an inorganic or organic carrier non-toxic to pharmaceuticals. Typical pharmaceutically acceptable carriers include water, a mixture of water and a water-miscible solvent such as lower alkanol or lower aralkanol, a vegetable oil, polyalkylene glycol, a jelly using petroleum as a base material, ethylcellulose, ethyl oleate, carboxymethylcellulose , polyvinyl pyrrolidone, isopropyl myristate and other acceptable vehicles that can be used preferably. The formulation may contain non-toxic auxiliary substances such as an emulsifier, a preservative, a wetting agent and an excipient, for example, polyethylene glycol 200, 300, 400 and 600, carbowax 1000, 1500, 4000, 6000 and 10000, acid esters -hydroxybenzoic acid such as methyl p-hydroxybenzoate or propyl g-hydroxybenzoate, a quaternary ammonium compound (e.g., benzethonium chloride or benzalkonium chloride) which are known as compounds having antifungal properties at low temperatures and which are non-toxic when used, an antifungal agent such as a methylmercury salt, a pH regulating component such as thimerosal, methyl -and propylparaben, benzyl alcohol, phenylethanol, sodium chloride, sodium borate and sodium acetate, a pH regulator of gluconic acid and sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitate, sodium dioctyl sulfosuccinate, monothioglycerol, thiosorbitol and acid ethylenediaminetetraacetic Ophthalmological excipients can be used as a desired support medium for the compounds of the present invention and examples of these include the usual phosphoric acid pH regulating excipients (e.g., phosphate pH regulator of sodium phosphate or phosphate pH regulator). potassium), excipients of boric and isotonic acid, excipients of isotonic sodium chloride and excipients of isotonic sodium borate. As a further alternative, the pharmaceutical formulations can be in the form of a solid insert which remains thus intact after the formulation has been administered, or which can be formulated as a disintegrating insert that dissolves in the tear fluid or is disintegrated by others. methods The dose of the dithiolan derivative of the formula (I) or the pharmaceutically acceptable salt thereof of the present invention will vary depending on the conditions and age of the patient and the manner and route of administration. However, for example, in the case of oral administration, for an adult human patient it is desirable to administer 0.1 mg (preferably 1 mg) as a lower limit to 10000 mg (preferably 5000 mg) as an upper limit per day. In the case of intravenous administration, it is desirable to administer 0.01 mg (preferably 0.1 mg) as a lower limit to 5000 mg (preferably 2000 mg) as an upper limit per day. In the case of topical administration to the eyes it is desirable to administer from 0.001 mg (preferably 0.01 mg) as a lower limit to 500 mg (preferably 200 mg) as an upper limit per day. All of the above can be administered as a single dose or in divided doses. The dose and dosage regimen will depend on the patient's condition. The pharmaceutical preparations of the present invention are illustrated by the following non-limiting formulation examples.EXAMPLE OF FORMULATION 1 Powder 5 g of N- [5- (1, 2-dithiolan-3-yl) pentanoyl] methanesulfonamide (the compound of Example 2 given below), 895 g of lactose and 100 g of corn starch are mixed by half of a blender to obtain a powder.

EXAMPLE OF FORMULATION 2 Granules 5 g of N- [5- (1, 2-dithiolan-3-yl) pentanoyl] sulfonamide (the compound of Example 7 given below), 865 g of lactose and 100 g of low substituted hydroxypropyl cellulose are mixed. 300 g of a 10% w / v aqueous solution of hydroxypropyl cellulose are then added to the mixture, and then the reaction mixture is kneaded. The mixture is then granulated using an extruder granulator, after which it is dried to obtain a granule formulation.

EXAMPLE OF FORMULATION 3 Capsules 5 g of N- [4- (1, 2-dithiolan-3-yl) butyl-N '-methylurea (the compound of Example 8 given below), 115 g of lactose, 58 g of corn starch and 2 g of magnesium stearate are mixed using a V-type blender. 180 mg of the mixture is then encapsulated in a No. 3 capsule to obtain a capsule formulation.

EXAMPLE OF FORMULATION 4 Tablets 5 g of (R) -N- [5- (1, 2-dithiolan-3-yl) pentanoyl] methansulfonamide (the compound of Example 40 given below), 90 g of lactose 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate are mixed by means of a blender. The mixture is then pelletized by a tabletting machine to obtain tablets.

EXAMPLE OF FORMULATION 5 Drops for the eyes The following components are mixed: (R) -N- [5- (1,2-dithiolan-3-yl) pentanoyl] -0.2 g methan-sulfonamide (the compound of Example 40) Disodium phosphate 0.716 g Sodium phosphate 0.728 g Sodium Chloride 0.400 g methyl p-Hydroxybenzoate 0.026 g propyl p-Hydroxybenzoate 0.014 g Sterilized purified water c.b.

Sodium hydroxide c.b. DDDDDDDDDDDDDDDODDDDDDDGDDDDDDDDDDDDDDDaDDDDDDDDDDDDDDDDDDDDGD Total 100 ml The pH of the mixture is adjusted to 7.0 and eye drops are prepared by a conventional method.

EXAMPLE OF FORMULATION 6 Eye drops The following components are mixed: (R) -N- [5- (1, 2-dithiolan-3-yl) pentanoyl] -0.2 g methan-sulfonamide (the compound of Example 40) Disodium Phosphate 0.716 g Sodium Phosphate 0.728 g Sodium Chloride 0.400 g methyl p-Hydroxybenzoate 0.026 g Propyl P-Hydroxybenzoate 0.014 g Sterilized purified water c.b. Ascorbic acid c.b. Sodium hydroxide c.b. aaaasaaaaaaaaaaaaaaassaaasDDDaasaassaaDaaaDDDDDaaaaaaaaaaaDaaa Total 100 ml The pH of the mixture is adjusted to 7.0 and eye drops are prepared by a conventional method.

BIOLOGICAL ACTIVITY The biological activity of the compounds of the present invention is illustrated by means of the following test examples.

EXAMPLE OF TEST 1 Measurement of glutathione reductase activity (a) Crystalline tissue culture The test animals were male SD rats 6 to 8 weeks of age (supplier: Nippon SLC). The animals were sacrificed by suffocation by inhaling carbon dioxide. Both eyeballs of each test animal were excised. An incision was made in the sclera on the back of the eyeballs and then the vitreous body and iris-ciliary body were removed, and then the lens was removed. Each crystalline obtained in this way was cultured by immersion in 3 ml of the culture solution described below in a 6-cavity tissue culture box (FALCON). The culture was performed for 72 hours in a CO2 incubator at 37 ° C and 100% humidity in the presence of 5% CO (in air). Medi 199 (Gibco) containing penicillin (20 units / ml) and streptomycin (20 μg / ml) was used as the control culture solution. The test culture solution contained the test compound added to the aforementioned culture solution. The cultured lenses were placed in storage under freezing until the time of the test. (b) Measurement of glutathione reductase activity After homogenizing each frozen rat crystalline in 2 ml of distilled water, the resulting homogenate was separated by centrifugation (10,000 g, 20 minutes) after which the resulting supernatant was used as the enzyme sample. 400 μl of enzyme sample was added to 0.6 ml of phosphate pH buffer containing 1 mM oxidized glutathione (GSSG) and 100 μM NADPH. After the mixture had reacted at 25 ° C for 6 minutes, the absorbance of the reaction mixture was measured (at 340 mm, ie OD340nm) • The difference (DELTA-D? 34onm) between the OD340nm value before of the reaction and the value of D? 340nm after completion of the ration was used as an indicator of the activity of glutathione reductase. The results for the compound of Example 2 are shown in the following Table 4.

TABLE 4 Concentration of the compound of Example 2 (uM) DO340nm'p ?: /? Í protein 0 3.10 ± .ll 10 3.24 ± 0.10 30 3.20 ± 0.09 100 3.59 ± 0.05 (p < 0.05) 300 3.70 ± 0.08 (p < 0.05 ) 1000 4.16 ± 0.18 (p < 0.05) The dithiolan derivative of the present invention EXAMPLE OF TRIAL 2 Anti-cataracts test The test animals were 6-week-old male SD rats (provider: Nippon SLC). The animals were sacrificed by suffocation by inhaling carbon dioxide. Both eyeballs of each test animal were excised. The excised lenses were cultured at 37 ° C for 24 hours in medium 199 (Gibco) containing 0.05 mg / ml of the test compound and 5 mM of hydrogen peroxide. For the control test, the excised lenses were cultured at 37 ° C. ° C for 24 hours in normal culture liquid (medium 199, Gibco) or medium 199 (Gibco) containing 5 mM hydrogen peroxide. After being cultured for 24 hours, the crystals were washed with physiological saline. Surface moisture was removed by placing the crystals on a piece of filtrom paper, and then the crystals were placed on a glass slide whose crystalline turbidity was graded under the stereoscopic microscope from "-" (degree of turbidity of the lens grown in normal culture medium) up to "++++" (degree of turbidity of the crystalline lens cultured in a medium containing hydrogen peroxide). The results are shown in table 5.

TABLE 5 Crystalline Turbidity Compound Example of a rat in 5 mM H 0 for 24 hours 1 ++ 2 ++ 7 ++ 21 ++ 43 ++ 45 ++ 46 + 50 + 52 + 55 + 56 ++ 57 59 TABLE 5 (CONTINUED) Crystalline Turbidity Compound Example of a rat in 5 mM H20 for 24 hours 70 ++ 74 ++ 79 ++ 80 ++ 86 ++ 103 ++ 106 ++ 109 + 118 ++ 123 ++ Lipoic acid +++ normal crystals without drug ++++ 63 ++ 63 ++ As can be seen from the above results, the compounds of the present invention substantially improve the opacity of the lens.

EXAMPLES The present invention is further illustrated by reference to the following non-limiting examples.

EXAMPLE 1 N-Acetyl-α-thioctamide (Compound No. 1-271) A mixture of 0.76 g of D, L-α-thioctamide, 1.5 g of acetic anhydride and 10 ml of pyridine was heated under reflux for 20 hours. The pyridine was then removed from the reaction mixture by distillation under reduced pressure and water was added to the residue, which was then extracted with ethyl acetate. The extraction solution was washed twice with water and dried over anhydrous magnesium sulfate. 0.76 g of the crude product obtained by evaporation of the solvent under reduced pressure was purified by silica gel column chromatography, using a 2: 1 volume mixture of hexane and ethyl acetate as eluent, to obtain 0.45 g of 3- ( 4-cyanobutyl) -1,2-dithiolan having [an Rf value of 0.84 (thin-layer chromatography of silica gel, using a 1: 1 volume mixture of hexane and ethyl acetate as the developing solvent)] as a first component and 0.17 g of the title compound, melting at 67 ° C to 69 ° C as a second component.

EXAMPLE 2 N- [5- (1,2-Dithiolan-3-yl) pentanoyl] methanesulfonamide (Compound No. 1-496) (a) 0.88 g of sodium hydride (as a 55% by weight dispersion in mineral oil) was washed with hexane, and 20 ml of dimethylformamide and 1.96 g of methanesulfonamide were added to the dispersion at room temperature. The resulting mixture was subjected to ultrasonic treatment for 3 hours and allowed to stand at room temperature overnight, to give a reaction mixture (A). Separately, 2.06 g of D, L-Á-lipoic acid were dissolved in 20 ml of dimethylformamide, and 1.63 g of N, N'-carbonyldiimidazole were added to the solution, while cooling with ice. The resulting mixture was then allowed to stand at room temperature overnight. At the end of this time the reaction mixture was added dropwise to the above reaction mixture (A) at room temperature, and the mixture was stirred for 7 hours. The reaction mixture was then stirred at 130 ° C for 3 hours, after which it was allowed to cool, and then emptied into ice water. Aqueous hydrochloric acid was added to the mixture to adjust the pH to 5, and the mixture was extracted with ethyl acetate. The extraction solution was washed three times with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a mixture of 4: 1 by volume of ethyl acetate and hexane and then ethyl acetate alone as eluent, to obtain 0.12 g of the title compound, melting at 87 ° C to 88 ° C. (b) 25.0 g of D, L-α-lipoic acid were dissolved in 500 ml of anhydrous dimethylformamide, and 21.57 g of N, N'-carbonyldiimidazole were added to the solution, while cooling with ice, after which the The resulting mixture was stirred at room temperature for 2 hours and 30 minutes. Then 12.65 g of methanesulfonamide and 5.80 g of sodium hydride (as a dispersion of 55% w / w in mineral oil) were added, while cooling with ice, to the reaction mixture, and the mixture was stirred at room temperature during 4 hours and then allowed to stand at room temperature overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography using mixtures of 1: 1, 2: 1 and 3: 1 by volume of ethyl acetate and hexane as eluent to obtain 19.85 g of the title compound, melting at 85 ° C. ° C to 88 ° C.

EXAMPLE 3 N- [5- (l-Oxo-l, 2-dithiolan-3-yl) pentanoyl] methanesulfonamide Compound No. 2-496 500 mg of N- [5- (1, 2-dithiolan-3-yl) pentanoyl] methanesulfonamide (prepared as described in Example 2) were dissolved in 10 ml of acetone, and 0.44 ml of a 31% aqueous solution p / v hydrogen peroxide was added to the solution, while cooling with ice. The mixture was stirred and then allowed to stand at room temperature overnight. At the end of this time, 0.2 ml of a 31% w / v aqueous solution of hydrogen peroxide was added to the reaction mixture, and after the mixture was stirred at room temperature for 30 minutes, and then stirred in a bath of oil at 50 ° C for 1 hour. The mixture was then allowed to stand at room temperature for 3 days, after which it was stirred on an oil bath at 50 ° C for 10 hours; then it was allowed to stand at room temperature overnight. The solvent was removed after the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate., and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by reverse phase preparative silica gel column chromatography, using 1: 3 and 2: 3 by volume mixtures of acetonitrile and water as the eluent. The solvent was evaporated from the eluted reaction thus obtained under reduced pressure, and the fraction was lyophilized, to obtain 0.15 g of the title compound (mixture of diastereomers) as a colorless oil having an Rf value of 0.43 (thin layer chromatography). of silica gel, using a mixture of 10: 1 by volume of ethyl acetate and methanol as the developing solvent).

EXAMPLE 4 Sodium salt of N [5- (1, 2-dithiolan-3-yl) pentanoyl] methanesulfonamide (Compound No. 1-496, sodium salt) 750 mg of N- [5- (1, 2-dithiolan-3-yl) pentanoyl] methanesulfonamide (prepared as described in Example 2) was dissolved in 15 ml of ethyl acetate, and 482 mg of 2- Sodium ethylexate to the mixture at room temperature. The mixture was stirred for 2 hours after which it was allowed to stand for 2 days at room temperature. The crystals that were precipitated from the reaction mixture were collected by filtration to obtain 550 mg of the title compound, melting at 202 ° C to 204 ° C.

EXAMPLE 5 5- (Ethyl l-oxo-l, 2-dithiolan-3-yl) pentanoate and ethyl 5- (2-oxo-l, 2-dithiolan-3-yl) pentanoate (Compound No. 2-208 and Compound No. 3-208) 1.00 g of D, L-Á-lipoic acid was dissolved in 20 ml of acetone, and 0.58 g of a 31% w / v aqueous solution of hydrogen peroxide was added to the solution in a dry ice-acetone bath. The mixture was stirred for 2 hours and then allowed to stand at room temperature overnight. At the end of this time, the solvent was removed from the reaction mixture by evolution under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. 16 ml of anhydrous ethanol and 4 ml of a 4 N solution of hydrochloric acid in ethyl acetate were added to the residue thus obtained, and the mixture was stirred for 2 hours. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and the residue thus obtained was purified by silica gel column chromatography, using mixtures of 1: 1, 2: 1 and 3: 1 by volume of acetate of ethyl and hexane as eluent, to obtain 0.26 g of ethyl 5- (2-oxo-l, 2-dithiolan-3-yl) pentanoate having an Rf value of 0.41 (silica gel thin layer chromatography; using a mixture of 2: 1 by volume of ethyl acetate and hexane as the developing solvent) and 0.67 g of ethyl 5- (1-oxo-l, 2-dithiolan-3-yl) pentanoate having an Rf value 0.29 (silica gel thin layer chromatography; using a mixture of 2: 1 by volume of ethyl acetate and hexane as the developing solvent) EXAMPLE 6 N- [4- (1, 2-Dithiolan-3-yl) butyl] -N ', N' -dimethylurea (Compound No. 1-815) 1.00 g of D, L-Á-lipoic acid was dissolved in 20 ml of toluene, and 2.00 ml of triethylamine and 1.25 ml of diphenylphosphoryl azide were added to the resulting solution at room temperature, and then the mixture was stirred in a water bath. oil at 80 ° C for 2 hours. Then 0.47 g of dimethylamine hydrochloride was added to the reaction mixture, and the mixture was stirred at room temperature for 4 hours. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and 20 ml of anhydrous tetrahydrofuran and 0.52 ml of a 50% v / v aqueous solution of diethylamine were added to the residue thus obtained; the mixture was then allowed to stand overnight at room temperature. The solvent was removed from the reaction mixture by evaporation under reduced pressure and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using ethyl acetate and then a 9: 1 by volume mixture of ethyl acetate and methanol as eluent. The solvent was evaporated from the fraction including the title compound under reduced pressure, and the residue thus obtained was dissolved in dioxane. The solution was lyophilized to obtain 832 mg of the title compound, melting at 52 ° C at 53 ° C.

EXAMPLE 7 [5- (1, 2, -dithiolan-3-yl) pentanoyl] sulfamide (Compound No. 1-539) To the solution was added 50 mg of D, L-α-lipoic acid in 10 ml of anhydrous dimethylformamide, and 421 mg of N, N'-carbonyldiimidazole, while cooling with ice, and the mixture was then stirred at room temperature during 3 hours. Then 461 mg of sulfamide and 113 mg of sodium hydride (as a 55% w / w dispersion in mineral oil) were added to the reaction mixture, while cooling with ice, and the mixture was stirred for 4 hours and then it was allowed to stand at room temperature overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water and 2N aqueous hydrochloric acid was added to the residue thus obtained to adjust the pH to 5 to 6, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography, using a mixture of 3: 2 and then a 2: 1 by volume ethyl acetate and hexane as the eluent, and the resulting fraction was then recrystallized from a mixture of 1: 2: 1 by volume of ethanol, diisopropyl ether and hexane, for 119 mg of the title compound, melting at 141 ° C to 142 ° C.

EXAMPLE 8 N- [4- (1, 2-dithiolan-3-yl) butyl-N'-methylurea (Compound No. 1-733) 1.00 g of D, L-α-lipoic acid was dissolved in 20 ml of toluene, and 2.00 ml of triethylamine and 1.25 ml of diphenylphosphoryl azide were added to the resulting solution at room temperature, after which the reaction mixture was added. stirred in an oil bath at 80 ° C for 3 hours. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and 20 ml of tetrahydrofuran and 0.45 ml of a 40% v / v aqueous solution of methylamine were added to the residue thus obtained, while cooling with ice, and The mixture was stirred at room temperature for 3 hours and allowed to stand at room temperature overnight. The solvent was removed from the reaction mixture by evaporation under reduced pressure and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography using ethyl acetate and then mixtures of 20: 1 and 10: 1 by volume of ethyl acetate and methanol as the eluent, to obtain 425 mg of the title compound, melting at 89 ° C to 90 ° C.

EXAMPLE 9 N- [4- (l-2-dithiolan-3-yl) butyl] urea (Compound No. 1-693) 1.00 g of D, L-α-lipoic acid were dissolved in 20 ml of toluene, and 0.70 ml of triethylamine and 1.25 ml of diphenylphosphoryl azide were added to the solution at room temperature, after which the resulting mixture was stirred in an oil bath at 80 ° C for 4 hours. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and 20 ml of tetrahydrofuran and 0.49 ml of 28% w / v aqueous ammonium were added to the residue thus obtained. The mixture was then stirred at room temperature for 4 hours, after which time it was allowed to stand overnight. The solvent was removed from the reaction mixture by evaporation under reduced pressure and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography using mixtures of 10: 1, 4: 1 and 3: 1 volume of ethyl acetate and methanol as eluent, to obtain 340 mg of the title compound, melting at room temperature. 110 ° C to 113 ° C.

EXAMPLE 10 N- [5- (1, 2-dithiolan-3-yl) pentanoyl-3-benzensulfonamide (Compound No. 1-457) 1.00 g of D, L-α-lipoic acid was dissolved in 20 ml of anhydrous dimethylformamide, and 0.86 g of N, N'-carbonyldiimidazole was added to the solution while cooling with ice. The mixture was then stirred at room temperature for 2 hours and 30 minutes. 0.83 g of benzensulfonamide and 0.23 g of sodium hydride (as a dispersion in 55% w / w mineral oil) were added to the reaction mixture, while cooling with ice, and the mixture was stirred for 2 hours. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water and 2N aqueous hydrochloric acid was added to the residue thus obtained to adjust the pH to 2, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography using mixtures of 1: 2, 1: 1 and 2: 1 by volume of ethyl acetate and hexane as eluent, and then by preparative silica gel column chromatography. of reverse phase using mixtures of 3: 7, 1: 1 and 7: 3 by volume of acetonitrile and water as eluent. The solvent was evaporated under reduced pressure from the fraction containing the title compound, and the residue thus obtained was dissolved in dioxane. The resulting solution was lyophilized to obtain o.61 g of the title compound having an Rf value of 0.51 (silica gel thin layer chromatography, using a mixture of 2: 1 by volume of ethyl acetate and hexane as the revealing solvent).

EXAMPLE 11 N- [5- (1, 2-dithiolan-3-yl) pentanoyl] benzensulphonamide sodium salt (Compound No. 1-457.Sodium salt) 492 mg of N- [5- (1, 2-dithiolan-3-yl) pentanoyl] benzensulfonamide (prepared as described in Example 10) was dissolved in a mixture of 8 ml of ethyl acetate and 1 ml of tetrahydrofuran, and 283 mg of sodium 2-ethylhexoate was added to the mixture at room temperature. The resulting mixture was stirred for 1 hour and 30 minutes, after which it was allowed to stand for 2 days. The crystals that were precipitated from the reaction mixture were collected by filtration to obtain 349 mg of the title compound, melting at 213 ° C at 215 ° C.

EXAMPLE 12 - [5- (1,2-Dithiolan-3-yl) pentanoyl] -Nim-t-butoxycarbonylhistidine methyl ester (Compound No. 1-70) (Boc is t-butoxycarbonyl) 500 mg of D, L-Á-lipoic acid was dissolved in 10 ml of anhydrous dimethylformamide, and 422 mg of N, N'-carbonyldiimidazole was added to the solution, while cooling with ice. The mixture was then stirred at room temperature for 2 hours. At the end of this time, 629 mg of L-histidine methyl ester hydrochloride salt and 0.70 ml of triethylamine were added to the reaction mixture, while cooling with ice, and the mixture was stirred for 1 hour while cooling with ice, and then stirred at room temperature for an additional 1 hour. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using ethyl acetate and then mixtures of 20: 1, 10: 1 and 5: 1 by volume of ethyl acetate and methanol as eluent. The solvent was evaporated from the fraction containing the product under reduced pressure, and then 5 ml of ethyl acetate was added to the residue thus obtained. 0.55 ml of di-t-butyl dicarbonate, 0.33 ml of triethylamine and a catalytic amount of N were added., N-dimethylaminopyridine to the resulting solution, and the mixture was stirred for 1 hour. The reaction mixture was then purified by silica gel column chromatography, using a mixture of 2: 1 by volume of ethyl acetate and hexane and then ethyl acetate alone as eluent. The solvent was evaporated from the fraction containing the title compound under reduced pressure and the residue thus obtained was dissolved in dioxane. The solution was lyophilized, to obtain 844 mg of the title compound having an Rf value of 0.41 (silica gel thin layer chromatography); using ethyl acetate as the developing solvent).

EXAMPLE 13 N ^ - [5- (1, 2-dithiolan-3-yl) pentanoyl] histidine (Compound No. 1-71) 764 mg of NA- [5- (1,2-dithiolan-3-yl) pentanoyl] -NÍm-t-butoxycarbonylhistidine methyl ester (prepared as described in Example 12) was dissolved in 5 ml of methanol, and they added 5.1 ml of a 1 N aqueous solution of sodium hydroxide to the solution at room temperature, after which the resulting mixture was stirred for 2 hours and 30 minutes. Then 2.60 ml of 2N aqueous hydrochloric acid was added to the mixture and the resulting mixture was stirred and then allowed to stand overnight. The solvent was removed from the reaction mixture by evaporation under reduced pressure and the residue thus obtained was purified by preparative reversed-phase silica gel column chromatography using a mixture of 3: 7 by volume of acetonitrile and water as eluent, obtain 0.51 g of a mixture of the title compound (77%), melting at 122 ° C to 126 ° C, and sodium chloride (23%).

EXAMPLE 14 5- [5- (1, 2-Dithiolan-3-yl) pentanoylamino] -1,4-dithiazole-3-thione (Compound No. 1-72) 500 mg of D, L-α-lipoic acid in 10 ml of anhydrous dimethylformamide was added, and 428 mg of N, N'-carbonyldiimidazole was added to the solution while cooling with ice. The mixture was then stirred at room temperature for 3 hours, after which 391 mg of 3-amino-1,2,4-dithiazole-5-thione was added to the reaction mixture, while cooling with ice, and the The mixture was stirred for 1 hour and 30 minutes. Then it was allowed to stand at room temperature overnight. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 1: 2, 1: 1 and 2: 1 by volume mixtures of ethyl acetate and hexane as eluent, and then recrystallized from an acetate mixture. of ethyl and hexane, to obtain 372 mg of the title compound, melting at 158 ° C to 161 ° C.

EXAMPLE 15 4- (1, 2-Dithiolan-3-yl) butylamine diphenyl phosphate (Compound No. 1-1123 diphenyl phosphate) diphenyl phosphate 1.00 g of D, L-α-lipoic acid was dissolved in 20 ml of toluene, and 2.00 ml of triethylamine and 1.25 ml of diphenylphosphoryl azide were added to the solution at room temperature, after which the resulting mixture was stirred on an oil bath at 80 ° C for 2 hours and 30 minutes. The solvent was removed after the reaction mixture by evaporation under reduced pressure and 20 ml of tetrahydrofuran and 1. 21 ml of an aqueous solution at 40% w / v of 0-methylhydroxylamine hydrochloride to the residue thus obtained, while cooling with ice. Then 2 ml of methanol was added to the mixture, after which the mixture was stirred at room temperature for 6 hours and then allowed to stand overnight. The solvent was removed after the reaction mixture by evaporation under reduced pressure, and water and 2N aqueous hydrochloric acid were added to the residue thus obtained to adjust the pH to 2, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using ethyl acetate and then a 3: 1 by volume mixture of ethyl acetate and methanol as eluent, followed by preparative phase silica gel column chromatography. Inverse (using mixtures of 1: 4 and 1: 1 by volume of acetonitrile and water as the eluent). The solvent was then removed from the fraction containing the title compound by evaporation under reduced pressure and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation under reduced pressure. Ethyl acetate was added to the residue thus obtained to recrystallize it, giving 116 mg of the title compound melting at 100 ° C to 103 ° C.

EXAMPLE 16 N, N'-Bis [4- (1, 2-dithiolan-3-yl) butyl] urea (Compound No. 1-765) 3.0 g of D, L-Á-lipoic acid was dissolved in 60 ml of toluene, and 2.40 ml of triethylamine and 3.70 ml of diphenylphosphoryl azide were added to the resulting solution at room temperature, after which the resulting mixture was stirred in an oil bath at 80 ° C for 2 hours. The solvent was then removed from the reaction mixture by evaporation under reduced pressure and 60 ml of t-butanol was added at room temperature to the residue thus obtained. The mixture was then stirred and allowed to stand for 5 days. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure and the residue thus obtained was purified by silica gel column chromatography, using mixtures of 1: 5 and 1: 3 by volume of acetate of ethyl and hexane as eluent. The solvent was then removed by evaporation under reduced pressure, and 5 ml of dioxane was added to the resulting residue. The solvent was then removed by evaporation under reduced pressure. 5 ml of 2N aqueous hydrochloric acid and 10 ml of methanol were added to the residue thus obtained, and the mixture was stirred in an oil bath at 60 ° C for 2 hours. The solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue and the mixture was neutralized with triethylamine, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure and the residue was recrystallized from ethyl acetate to obtain 260 mg of a crude product. 160 mg of this crude product was purified by reverse phase preparative silica gel column chromatography using mixtures of 2: 3, 1: 1, 3: 2 and 7: 3 by volume acetonitrile and water as the eluent. The solvent was then evaporated from the fraction containing the title compound under reduced pressure to obtain 87 mg of the title compound, melting at 115 ° C to 116 ° C.

EXAMPLE 17 5- (1,2-dithiolan-3-yl) pentanohydroxamic acid (Compound No. 1-58) 500 mg of D, L-Á-lipoic acid was dissolved in 10 ml of anhydrous dimethylformamide and 428 mg of N, N'-carbonyldiimidazole was added to the solution, while cooling with ice, and then the mixture was stirred at room temperature. environment for 2 hours and 30 minutes. Then 0.67 ml of triethylamine and 334 mg of hydroxylamine hydrochloride were added to the reaction mixture, while cooling with ice, and the mixture was stirred at room temperature for 2 hours and then allowed to stand overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water and 2N aqueous hydrochloric acid was added to the residue thus obtained to adjust the pH to 6 to 7, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using a mixture of 4: 1 by volume of ethyl acetate and hexane, followed by a mixture of 20: 1 by volume of ethyl acetate and methanol, as eluent , and then by preparative reverse phase silica gel column chromatography, using mixtures of 3: 7 and 1: 1 by volume of acetonitrile and water as eluent. The product thus obtained was lyophilized, to obtain 0.38 g of the title compound, melting at 63 ° C to 64 ° C.

EXAMPLE 18 N- [4- (1, 2-dithiolan-3-yl) butyl-N '- [1-methoxycarbonyl-2- (4-methoxybenzylthio) ethyl] urea (Compound No. 1-766) 300 mg of D, L-Á-lipoic acid was dissolved in 6 ml of toluene, and 0.24 ml of triethylamine and 0.37 ml of diphenylphosphoryl azide were added to the solution at room temperature.

The mixture was then stirred in an oil bath at 80 ° C for 2 hours. At the end of this time, a solution of 434 mg of S- (4-methoxybenzyl) -L-cysteine methyl ester in 3 ml of anhydrous tetrahydrofuran was added to the reaction mixture, while cooling with ice, and the mixture was stirred at room temperature for 3 hours, and then allowed to stand overnight. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and the mixture was recrystallized from ethyl acetate, to obtain 434 mg of the title compound, melting at 105 ° C to 107 ° C.

EXAMPLE 19 Hydrazino-N, N'-dicarboxylic acid bis [4- (1, 2-dithiolan-3-yl) butylamide] (compound No. 1-936) 1.00 g of D, L-α-lipoic acid was dissolved in 20 ml of toluene and 2.00 ml of triethylamine and 1.25 ml of diphenylphosphoryl azide were added to the resulting solution. The mixture was then stirred in an oil bath at 70 ° C for 2 hours.

Then 0.19 ml of anhydrous hydrazine was added to the reaction mixture, while cooling with ice, and the mixture was stirred at room temperature for 2 hours. The solvent was removed after the reaction mixture by evaporation under reduced pressure, and the residue thus obtained was washed with water and with ethyl acetate. The insoluble components were then collected by filtration. The insoluble components thus obtained were washed with a mixture of 5: 2: 1 by volume of methanol, tetrahydrofuran and dimethylformamide, to obtain 401 mg of the title compound, melting at 205 ° C at 207 ° C.

EXAMPLE 20 N- [5- (1, 2-dithiolan-3-yl) pentanoyl] ethanesulfonamide (Compound No. 1-497) 500 mg of D, L-Á-lipoic acid was dissolved in 10 ml of anhydrous dimethylformamide and 428 mg of N, N'-carbonyldiimidazole was added to the solution while cooling with ice. The mixture was then stirred at room temperature for 1 hour. At the end of this time, a solution of 284 mg of ethanesulfonamide in 3 ml of dimethylformamide and 113 mg of sodium hydride ((as a 55% w / w dispersion in mineral oil) was added to the reaction mixture, while cooled with ice, and the mixture was stirred at room temperature for 1 hour and then allowed to stand for 3 days.The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water and 2N aqueous hydrochloric acid were added. to the residue thus obtained to adjust the pH to 2, after which it was extracted with ethyl acetate.The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent The residue thus obtained was purified by silica gel column chromatography, using mixtures of 1: 1 and 2: 1 by volume of ethyl acetate and hexane as eluent, followed by chromatography. Reverse phase preparative silica gel column raffia, using mixtures of 3: 7, 2: 3 and 1: 1 by volume of acetonitrile and water as eluent. The solvent was then removed from the eluted fraction thus obtained by evaporation under reduced pressure, and the residue thus obtained was dissolved in dioxane. The solution was lyophilized to obtain 30 mg of the title compound, melting at 98 ° C to 100 ° C.

EXAMPLE 21 l, l-dimethyl-4- [4- (1, 2-dithiolan-3-yl) butyl] semicarbazide (Compound No. 1-861) 1.00 g of D, L-Á-lipoic acid was dissolved in 10 ml of toluene and 0.80 ml of triethylamine and 1.25 ml of diphenylphosphoryl azide were added to the resulting solution, after which the resulting mixture was stirred in a water bath. oil at 80 ° C for 1 hour. Then 0.55 ml of 1,1-dimethylhydrazine was added to the mixture, while cooling with ice, and the mixture was stirred at room temperature for 1 hour and then allowed to stand overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using a mixture of 3: 1 by volume of ethyl acetate and hexane and then a mixture of 10: 1 by volume of ethyl acetate and methanol as eluent, followed by reverse phase preparative silica gel column chromatography, using 7:13 mixtures. and 2: 3 by volume of acetonitrile and water as eluent. The eluted fraction thus obtained was lyophilized, to obtain 0.99 g of the title compound, melting at 60 ° C to 61 ° C.

EXAMPLE 22 4- (1, 2-dithiolan-3-yl) butylamine of morpholino-carboxylic acid (Compound No. 1-1142) 500 mg of D, L-Á-lipoic acid were dissolved in 10 ml of toluene and 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide was added to the resulting solution, after which the resulting mixture was stirred in a water bath. oil at 80 ° C for 1 hour and 30 minutes. Then 0.23 ml of morpholine was added to the mixture, while cooling with ice, and the mixture was stirred at room temperature for 2 hours and then allowed to stand overnight. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using ethyl acetate and then a mixture of 10: 1 by volume of ethyl acetate and methanol as eluent, followed by preparative phase silica gel column chromatography. Inverse, using 2: 3 by volume mixtures of acetonitrile and water as eluent. The solvent was evaporated from the eluted fraction thus obtained under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was dissolved in dioxane and the solution was lyophilized to obtain 0.51 g of the title compound, melting at 74 ° C at 11 ° C.

EXAMPLE 23 N-Hydroxy-N '- [4- (1, 2-dithiolan-3-yl) butyl] urea (Compound No. 1-750) 500 mg of D, L-α-lipoic acid was dissolved in 10 ml of toluene and 0.69 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide was added to the resulting solution, after which the resulting mixture was stirred in a water bath. oil at 80 ° C for 2 hours. The solvent was removed after the reaction mixture by evaporation under reduced pressure and 10 ml of anhydrous tetrahydrofuran and 181 mg of hydroxylamine hydrochloride were added to the residue thus obtained in a bath containing ice and an aqueous solution of sodium chloride. The mixture was stirred for 2 hours at the bath temperature, and then stirred at room temperature for 3 hours, after which it was allowed to stand for 3 days. The solvent was removed after the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained to adjust the pH to 5 to 6, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography, which was eluted first with a mixture of 2: 1 by volume of ethyl acetate and hexane, and then with ethyl acetate alone, and finally with a mixture of 10. : 1 volume of ethyl acetate and methanol. The solvent was removed from the eluted fraction thus obtained by evaporation under reduced pressure, and the precipitated powder was washed with a mixture of dimethylformamide, tetrahydrofuran, methanol and ethyl acetate and subjected to reverse phase preparative silica gel column chromatography. , using mixtures of 3: 7 and 1: 1 by volume of acetonitrile and water as eluent. The eluted fraction thus obtained was concentrated by evaporation under reduced pressure, and the crystals which were precipitated were collected by filtration to obtain 85 mg of the title compound, melting at 100 ° C to 101 ° C.

EXAMPLE 24 2- [5- (1, 2-Dithiolan-3-yl) pentanolimino] ethanesulfonic acid imidazole salt (Compound No. 1-57 Imidazole salt) 500 mg of D, L-Á-lipoic acid was dissolved in 10 ml of anhydrous dimethylformamide, and 428 mg of N, N'-carbonyldiimidazole was added to the resulting solution, while cooling with ice and then the mixture was stirred to dryness. room temperature after 4 hours. At the end of this time, 0.50 ml of tritylamine and 450 mg of 2-aminoethanesulfonic acid were added to the reaction mixture, while cooling with ice and the mixture was stirred at room temperature for 4 hours and 30 minutes and then allowed to stand for 2 days. After this time, the reaction mixture was stirred in an oil bath at 50 ° C for 6 hours and then stirred in an oil bath at 70 ° C for 1 hour. Then it was allowed to stand at room temperature overnight. The reaction mixture was then stirred in an oil bath at 70 ° C for 2 hours and the solvent was removed from the reaction mixture by evaporation under reduced pressure. The residue thus obtained was washed with ethyl acetate and preparative reversed-phase silica gel column chromatography was subjected using a mixture of 1: 9 by volume of acetonitrile and water as eluent. The eluted fraction thus obtained was lyophilized, to obtain 268 mg of the title compound, melting at 96 ° C to 99 ° C.

EXAMPLE 25-β- [5- (1, 2-dithiolan-3-yl) pentanoyl] histamine (Compound No. 1-75) 500 mg of D, L-Á-lipoic acid was dissolved in 10 ml of anhydrous dimethylformamide and 422 mg of N, N'-carbonyldiimidazole was added to the resulting solution while cooling with ice. The mixture was then stirred at room temperature for 2 hours and 30 minutes. Then 0.73 ml of triethylamine and 479 mg of histamine hydrochloride were added to the reaction mixture at room temperature, and the mixture was stirred for 4 hours and 30 minutes. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using mixtures of 1: 0, 5: 1 and 3: 1 by volume of ethyl acetate and ethanol as eluent. It was then recrystallized from a 1: 2 by volume mixture of ethyl acetate and diisopropyl ether, to obtain 270 mg of the title compound, melting at 108 ° C to 110 ° C.

EXAMPLE 26 N, N'-bis [4- (1, 2-dithiolan-3-yl) butylcarbamoyl] sulfamide (Compound No. 1-2614) 500 mg of D, L-Á-lipoic acid was dissolved in 10 ml of toluene and then 0.36 ml of triethylamine was added and 0. 56 ml of diphenylphosphoryl azide was added to the mixture, after which the resulting mixture was stirred in an oil bath at 80 ° C for 2 hours. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and 6 ml of anhydrous dimethylformamide was added to the residue thus obtained, to give a solution of dimethylformamide. Separately, 113 mg of sodium hydride (as a 55% w / w dispersion in mineral oil) was dispersed in 4 ml of dimethylformamide, and 252 mg of sulfonamide was added to the suspension, while cooling with ice, after which the resulting mixture was stirred at room temperature for 2 hours. The above dimethylformamide solution was then added to the reaction mixture in a bath containing ice and an aqueous solution of sodium chloride, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. The reaction mixture was then stirred at room temperature for 4 hours, after which it was allowed to stand at room temperature overnight. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was neutralized by the addition of 2N aqueous hydrochloric acid. The crystals that were precipitated were washed with ethyl acetate, with water and with ethanol, to obtain 223 mg of the title compound, melting at 154 ° C to 156 ° C.

EXAMPLE 27 N ^, Nim-bis [4- (l, 2-dithiolan-3-yl) butylcarbamoyl] histamine 500 mg of D, L-α-lipoic acid was dissolved in 10 ml of toluene and then 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to the solution, after which the resulting mixture was stirred in a water bath. oil at 80 ° C for 1 hour and 30 minutes. The solvent was then removed from the reaction mixture by evaporation under reduced pressure and 5 ml of tetrahydrofuran was added to the residue thus obtained, to give a tetrahydrofuran solution. Separately, 479 mg of histamine dihydrochloride was dissolved in 2 ml of anhydrous dimethylformamide and then 0.72 ml of triethylamine was added to the solution, after which the resulting mixture was stirred at room temperature for 1 hour and 30 minutes. Then 30 ml of anhydrous tetrahydrofuran was added to the reaction mixture and then the anhydrous tetrahydrofuran solution was added thereto while cooling with ice. The mixture was stirred at room temperature for 3 hours and then allowed to stand overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography, using mixtures of 1: 0, 5: 1 and 3: 1 by volume of ethyl acetate and methanol as the eluent, after which it was subjected to preparative reverse phase silica gel column, using mixtures of 1: 4, 3: 7, 2: 3 and 1: 1 by volume of acetonitrile and water as eluent. The solvent was evaporated under reduced pressure from the fraction containing the title compound, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed from the extraction solution by evaporation under reduced pressure and the residue thus obtained was dissolved in dioxane and lyophilized, to obtain 52 mg of the title compound, melting at 115 ° C to 117 ° C.

EXAMPLE 28 N- [4- (1, 2-dithiolan-3-yl) butyl] - '-methanesulfonylurea (Compound No. 1-1069) 0 500 mg of D, L-α-lipoic acid were dissolved in 10 ml of toluene and then 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to the solution, after which the resulting mixture was stirred in a The solvent was removed from the reaction mixture by evaporation under reduced pressure, and 5 ml of anhydrous dimethylformamide was added to the residue thus obtained, for a solution of dimethylformamide. 247 mg of methanesulfonamide were dissolved in 5 ml of anhydrous dimethylformamide and then 113 mg of sodium hydride (as a 55% w / w dispersion in mineral oil) was added to the solution, after which the resulting mixture was stirred at room temperature for 2 hours The above anhydrous dimethylformamide solution was then added to the reaction mixture, while cooling with ice, and the mixture was stirred at room temperature for 3 hours and then allowed to stand room temperature for 3 days. The solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue thus obtained, and the mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using ethyl acetate as eluent, and the active fraction was then recrystallized from ethyl acetate, to obtain 302 mg of the title compound, melting at 125 ° C. at 127 ° C.

EXAMPLE 29 4- [4- (1, 2-Dithiolan-3-yl) butyl] semicarbazide diphenyl phosphate (Compound No. 1-858 diphenyl phosphate) diphenyl phosphate 500 mg of D, L-Á-lipoic acid was dissolved in 10 ml of toluene and 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to the solution, after which the resulting mixture was stirred in a water bath. oil at 80 ° C for 1 hour and 30 minutes. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and 3.5 ml of anhydrous tetrahydrofuran was added to the residue thus obtained. The solution was added to 0.75 mg of hydrazine and then 2 ml of anhydrous dimethylformamide was added thereto. The mixture was stirred at room temperature for 5 hours and then allowed to stand overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and a saturated aqueous solution of sodium chloride was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using mixtures of 1: 0, 10: 1 and 5: 1 by volume of ethyl acetate and methanol as eluent, after which it was recrystallized from a 1: 1 mixture of ethyl acetate and diisopropyl ether to obtain 125 mg of the title compound, melting at 134 ° C to 139 ° C.

EXAMPLE 30 N- [4- (1, 2-dithiolan-3-yl) butyl] -N '-aminosulfonylurea (Compound No. 1-1112) 500 mg of D, L-Á-lipoic acid was dissolved in 10 ml of toluene and then 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to the solution, after which the resulting mixture was stirred in a water bath. oil at 70 ° C for 2 hours. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and 5 ml of anhydrous dimethylformamide was added to the residue thus obtained, to give a solution of dimethylformamide. Separately, 1.15 g of sulfamide was dissolved in 10 ml of anhydrous dimethylformamide, and then 524 mg of sodium hydride (as a 55% w / w dispersion in mineral oil) was added to the solution, while cooling with ice, after which the resulting mixture was stirred at room temperature for 1 hour and 30 minutes. The above dimethylformamide solution was then added to the reaction mixture, while cooling with ice, and the mixture was stirred at room temperature for 4 hours and then allowed to stand for 2 days. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained. The mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using mixtures of 1: 1, 2: 1 and 4: 1 by volume of ethyl acetate and hexane as eluent. It was then recrystallized from ethanol, to obtain 126 mg of the title compound, melting at 123 ° C at 125 ° C.

EXAMPLE 31 Methyl N- [4- (1, 2-dithiolan-3-yl) butyl] carbamate (Compound No. 1-676) 500 mg of D, LA-lipoic acid was dissolved in 10 ml of toluene and then 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to the solution, after which the resulting mixture was stirred in an oil bath to a 80 ° C for 1 hour. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and 10 ml of anhydrous methanol was added to the residue thus obtained. The mixture was stirred at room temperature for 6 hours and then allowed to stand overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained to adjust the pH to 5 to 6, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 1: 4 and 1: 2 by volume mixtures of ethyl acetate and hexane as eluent, after which it was subjected to silica gel column chromatography. preparatory phase reverse, using me <1: 4, 3: 7, 2: 3 and 1: 1 by volume of acetonitrile and water as eluent. The solvent was evaporated under reduced pressure from the fraction containing the title compound and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and lyophilized, to obtain 324 mg of the title compound, melting at 31 ° C to 32 ° C.

EXAMPLE 32 N- [1- (5-methoxy-lH-indol-3-yl) ethyl] lipoamide (Compound No. 1-80) 500 mg of D, L-Á-lipoic acid was dissolved in 10 ml of anhydrous dimethylformamide, and 422 mg of N, N'-carbonyldiimidazole was added to the solution, while cooling with ice. The mixture was then stirred at room temperature for 3 hours and 30 minutes. At the end of this time, 495 mg of 5-methoxytryptamine was added to the reaction mixture, while cooling with ice, and the mixture was stirred at room temperature for 3 hours and then allowed to stand at room temperature overnight. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained. The residue was extracted with ethyl acetate and then dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using mixtures of 2: 1, 4: 1 and 1: 0 by volume of ethyl acetate and hexane as eluent, to obtain 515 mg of the title compound as a yellow oil that had an Rf value of 0.26 (silica gel thin layer chromatography, using a 2: 1 by volume mixture of ethyl acetate and hexane as the developing solvent).

EXAMPLE 33 N- [4- (1, 2-Dithiolan-3-yl) butyl] -N '- [2- (5-methoxy-lH-indol-3-yl) ethyl] urea (Compound No. 1-772 ) 500 mg of D, L-α-lipoic acid was dissolved in 10 ml of toluene and then 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to the solution, after which the resulting mixture was stirred in a water bath. oil at 80 ° C for 1 hour. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and 5 ml of anhydrous tetrahydrofuran was added to the residue thus obtained, to give a tetrahydrofuran solution. Separately, 1.37 mg of 5-methoxytryptamine was dissolved in admixture with 10 ml of anhydrous tetrahydrofuran and 4 ml of anhydrous dimethylformamide, and the resulting solution was added to the above anhydrous tetrahydrofuran solution while cooling with ice. The mixture was stirred, while cooling with ice, for 1 hour and then at room temperature for 4 hours, after which it was allowed to stand at room temperature overnight. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and a saturated aqueous solution of sodium chloride was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using mixtures of 3: 1 and 1: 0 by volume of ethyl acetate and hexane and then a mixture of 10: 1 by volume of ethyl acetate and methanol as eluent, after which it was recrystallized from ethyl acetate, to obtain 674 mg of the title compound, melting at 100 ° C to 101 ° C.

EXAMPLE 34 N- [4- (1,2-Dithiolan-3-yl) butyl] -pyrrolidine-1-carboxamide (Compound No. 1-1139) 500 mg of D, L-Á-lipoic acid was dissolved in 10 ml of anhydrous toluene and 0.56 ml of diphenylphosphoryl azide was added to the solution, after which the resulting mixture was stirred in an oil bath at 80 ° C. for 1 hour and 30 minutes. Then 0.22 ml of pyrrolidine was added to the reaction mixture, while cooling with ice, and the mixture was stirred at room temperature for 1 hour and then allowed to stand at room temperature overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using mixtures of 1: 0 and 10: 1 by volume of ethyl acetate and methanol as eluent, after which it was recrystallized from a mixture of 1: 1: 1 by volume of ethyl acetate, methanol and acetonitrile, to obtain 231 mg of the title compound, melting at 91 ° C to 93 ° C.

EXAMPLE 35 l- [5- (1, 2-dithiolan-3-yl) pentanoyl] pyrrolidine (Compound No. 1-1129) 500 mg of D, L-Á-lipoic acid was dissolved in 10 ml of anhydrous dimethylformamide and then 422 mg of N, N'-carbonyldiimidazole was added to the solution. The resulting mixture was stirred at room temperature for 1 hour and 30 minutes. 0.22 ml of pyrrolidine was added to the reaction mixture, while cooling with ice, and the mixture was stirred at room temperature for 2 hours. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using mixtures of 2: 1, 3: 1 and 1: 0 by volume of ethyl acetate and hexane as eluent, after which it was dissolved in dioxane and lyophilized to obtain 364 mg of the title compound as a yellow oil having an Rf valor of 0.15 (silica gel thin layer chromatography, using ethyl acetate as the developing solvent).

EXAMPLE 36 N- [4- (1, 2-dithiolan-3-yl) butyl] piperidine-l-carboxamide (Compound No. 1-1140) 500 mg of D, L-Á-lipoic acid was dissolved in 10 ml of anhydrous toluene, and then 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to the solution, after which the resulting mixture was stirred in a Oil bath at 80 ° C for 1 hour. 0.26 ml of piperidine was added to the reaction mixture, while cooling with ice, and the mixture was allowed to stand at room temperature overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using mixtures of 2: 1, 4: 1 and 1: 0 by volume of ethyl acetate and hexane as eluent. It was then recrystallized from a mixture of 1: 1 by volume of ethyl acetate and methanol, to obtain 252 mg of the title compound, melting at 90 ° C to 91 ° C.

EXAMPLE 37 1- [5- (1, 2-dithiolan-3-yl) pentanoyl] piperidine (Compound No. 1-1130) 500 mg of D, L-Á-lipoic acid was dissolved in 10 ml of anhydrous dimethylformamide and then 422 mg of N, N'-carbonyldiimidazole was added to the solution. The mixture was then stirred at room temperature for 3 hours. At the end of that time, 0.26 ml of piperidine was added to the reaction mixture and the mixture was stirred at room temperature for 4 hours and then allowed to stand overnight. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 3: 2 and 3: 1 by volume mixtures of ethyl acetate and hexane as eluent. It was then dissolved in dioxane and lyophilized, to obtain 381 mg of the title compound as a yellow oil having an Rf value of 0.30 (silica gel thin layer chromatography, using a 3: 2 volume mixture of acetate of ethyl and hexane as the developing solvent).

EXAMPLE 38 N- [4- (1, 2-dithiolan-3-yl) butyl] -thiomorpholino-4-carboxamide (Compound No. 1-1143) 500 mg of D, L-Á-lipoic acid was dissolved in 10 ml of anhydrous toluene, and then 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to the solution, after which the resulting mixture was stirred in a Oil bath at 80 ° C for 1 hour. Then 0.25 ml of thiomorpholine was added to the reaction mixture at room temperature and the mixture was stirred for 5 hours and then allowed to stand for 2 days. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using mixtures of 3: 2, 3: 1 and 1: 0 by volume of ethyl acetate and hexane as eluent. It was then dissolved in dioxane and lyophilized to obtain 583 mg of the title compound, melting at 80 ° C to 81 ° C.

EXAMPLE 39 (S) -N- [5- (1, 2-dithiolan-3-yl) pentanoyl] methanesulfonamide not (S) -N- [5- (1, 2-dithiolan-3-yl) pentanoyl] methanesulfonamide ( Compound No. 1-496) 300 mg of (S) -Á-lipoic acid was dissolved in 6 ml of anhydrous dimethylformamide and 276 mg of N, N'-carbonyldiimidazole and 1 ml of anhydrous dimethylformamide were added to the solution while cooling with ice. The mixture was then stirred at room temperature for 1 hour and 30 minutes. At the end of that time, 162 mg of methanesulfonamide and 74 mg of sodium hydride (as a 55% w / w dispersion in mineral oil) were added to the reaction mixture, while cooling with ice and the mixture was stirred at room temperature for 1 hour and then allowed to stand for 2 days. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using 1: 1 and 3: 1 by volume mixtures of ethyl acetate and hexane as eluent. It was then recrystallized from a 1: 2 by volume mixture of ethyl acetate and hexane to obtain 154 mg of the title compound, melting at 91 ° C to 92 ° C.

EXAMPLE 40 (R) -N- [5- (1, 2-dithiolan-3-yl) pentanoyl] methanesulfonamide (Compound No. 1-496) 100 mg of (R) -Á-lipoic acid was dissolved in 2 ml of anhydrous dimethylformamide, and 97 mg of N, N'-carbonyldiimidazole was added to the solution while cooling with ice. The mixture was then stirred at room temperature for 4 hours. At this time, 57 mg of methanesulfonamide and 26 mg of sodium hydride (as a 55% w / w dispersion in mineral oil) were added to the reaction mixture, while cooling with ice, and the mixture was stirred at room temperature. environment for 5 hours and then left to rest overnight. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained. The resulting mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using mixtures of 1: 1 and 3: 1 in volumn of ethyl acetate and hexane as eluent, after which it was dissolved in dioxane and lyophilized, to obtain 68 mg of the title compound, melting at 71 ° C to 73 ° C.

EXAMPLE 41 4- [5- (1, 2-dithiolan-3-yl) pentanoyl] thiomorpholine (Compound No. 1-1133) 500 mg of D, L-Á-lipoic acid was dissolved in 10 ml of anhydrous dimethylformamide and then 422 mg of N, N'-carbonyldiimidazole was added to the solution. The mixture was stirred after room temperature for 1 hour and 30 minutes, after which it was allowed to stand overnight. At the end of this time, 0.25 ml of thiomorpholine was added to the reaction mixture and the mixture was stirred at room temperature for 5 hours and then allowed to stand overnight. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed from the extraction solution by evaporation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using mixtures of 1: 1 and 2: 1 by volume of ethyl acetate and hexane as eluent. It was then dissolved in dioxane and lyophilized to obtain 385 mg of the title compound as a yellow amorphous substance, melting at 31 ° C to 32 ° C.

EXAMPLE 42 N- [4- (1, 2-dithiolan-3-yl) butyl] -1-piperazinylcarboxamide (Compound No. 1-1141) 500 mg of D, L-α-lipoic acid was dissolved in 10 ml of toluene and then 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to the solution, after which the resulting mixture was stirred in a water bath. oil at 80 ° C for 2 hours. A solution of 1.03 g of piperazine in 10 ml of anhydrous dimethylformamide was added and then added to the reaction mixture, while cooling with ice, and the mixture was stirred at room temperature for 3 hours and 30 minutes and then allowed to stand overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was neutralized by the addition of 2N aqueous hydrochloric acid. precipitated were collected by filtration and washed with water and ethyl acetate, to obtain 107 mg of the title compound, melting at 175 ° C at 177 ° C.

EXAMPLE 43 3- [5- (1, 2-dithiolan-3-yl) pentanoyl] thiazolidine (Compound No. 1-1258) 422 mg of N, N'-carbonyldiimidazole acid was added to a solution of 500 mg of D, L-Á-lipoic acid in 10 ml of anhydrous dimethylformamide. The reaction mixture was stirred at room temperature for 1 hour and 30 minutes. Then 0.20 ml of thiazolidine was added dropwise to the reaction mixture and then the mixture was stirred at room temperature for 4 hours. The reaction mixture was allowed to stand overnight at room temperature and then the solvent was removed by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using mixtures of 1: 1, 3: 1 and 1: 0 by volume of ethyl acetate and hexane as eluent, followed by preparative phase silica gel column chromatography. Inverse, using a mixture of 2: 3 by volume of acetonitrile and water as eluent. Acetonitrile was removed from the eluate thus obtained by distillation under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure, and the resulting residue was dissolved in dioxane. The resulting solution was lyophilized to give 317 mg of the title compound as a pale yellow amorphous substance, melting at 40 ° C to 41 ° C.

EXAMPLE 44 N- [4- (1, 2-dithiolan-3-yl) butyl] -N '- (1-piperidyl) urea (Compound No. 1-1145) 0.36 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to a solution of 500 mg of D, L-α-lipoic acid in 10 ml of anhydrous toluene. The resulting mixture was stirred in an oil bath at 80 ° C for 1 hour and 30 minutes. Then 0.28 ml of 1-aminopiperidine was added dropwise to the reaction mixture, while cooling with ice, and then the mixture was stirred at room temperature for 5 hours. The reaction mixture was allowed to stand overnight at room temperature. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate was removed from the distillation extract under reduced pressure and the residue was subjected to silica gel column chromatography using 1: 1 and 5: 1 by volume mixtures of ethyl acetate and ethanol as eluent. The solvent was removed from the product eluted by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilized, to give 593 mg of the title compound as a yellow amorphous substance, melting at 67 ° C to 69 ° C.

EXAMPLE 45 N- [1-piperidyl) -5- (1, 2-dithiolan-3-yl) pentanamide (Compound No. 1-1135) The reaction was carried out as described in example 43, but using 500 mg of D, L-α-lipoic acid, 10 ml of anhydrous dimethylformamide, 422 mg of N, N'-carbonyldiimidazole and 0.28 ml of 1-aminopiperidine. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate was removed from the distillation extract under reduced pressure. The residue was subjected to silica gel column chromatography, using mixtures of 2: 1 and 1: 0 by volume of ethyl acetate and hexane as eluent, after which it was recrystallized from ethyl acetate, to give 298 mg of the title compound as yellow crystals in needle form, melting at 108 ° C to 109 ° C.

EXAMPLE 46 3- [4- (1, 2-Dithiolan-3-yl) butyl] ureidoacetate methyl (Compound No. 1-739) 0.73 ml of triethylamine and 0.56 ml of diphenylphosphoryl azide were added to a solution of 500 mg of D, L-α-lipoic acid in 10 ml of anhydrous toluene. The resulting mixture was stirred in an oil bath at 80 ° C for 1 hour and 30 minutes. The solvent was removed after the reaction mixture by distillation under reduced pressure. Then 10 ml of anhydrous dimethyldormamide was added to the residue, after which 301 mg of L-glycine methyl ester hydrochloride was added, while cooling with ice. The resulting mixture was then stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was allowed to stand overnight at room temperature, after which the solvent was removed by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, using mixtures of 2: 1 and 1: 0 by volume of ethyl acetate and hexane as eluent, followed by preparative reverse phase silica gel column chromatography, using mixtures of 3:17, 3: 7 and 3: 2 by volume of acetonitrile and water as eluent. Acetonitrile was removed from the eluate thus obtained by distillation under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilized, to give 336 mg of the title compound as a pale yellow amorphous substance, melting at 62 ° C to 64 ° C.

EXAMPLE 47 [5- (1, 2-Dithiolan-3-yl) pentanoylamino] methyl acetate (Compound No. 1-47) 422 mg of N, N'-carbonyldiimidazole was added to a solution of 500 mg of D, L-α-lipoic acid in 10 ml of anhydrous dimethylformamide. The resulting mixture was stirred at room temperature for 2 hours, after which 0.36 ml of triethylamine was added dropwise to the reon mixture. Then 301 mg of glycine methyl ester hydrochloride was added to the reon mixture and then the mixture was stirred at room temperature for 1 hour. The reon mixture was allowed to stand at room temperature for 2 days, and then the solvent was removed by distillation under reduced pressure. Water was added to the residue, after which it was extrd with ethyl acetate. The extrwas washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extrby distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using mixtures of 3: 1 and 1: 0 by volume of ethyl acetate and hexane as eluent, followed by preparative reverse phase silica gel column chromatography, using mixtures of 1: 4, 3: 7 and 1: 1 by volume of acetonitrile and water as eluent. Acetonitrile was removed from the eluate thus obtained by distillation under reduced pressure, and the residue was extrd with ethyl acetate. The extrwas washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extrby distillation under reduced pressure and the residue was dissolved in dioxane, after which it was lyophilized, to give 320 mg of the title compound as a yellow oil having an Rf value of 0.26 ( thin layer of silica gel, using a 3: 1 by volume mixture of ethyl acetate and hexane as the developing solvent).

EXAMPLE 48 Acid. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido} acetic (Compound No. 1-738) 2.1 ml of a 1 N aqueous solution of sodium hydroxide were added dropwise to a solution of 218 mg of . { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido} methyl acetate (prepared as described in example 46) in 4 ml of methanol, and then the mixture was stirred at room temperature for 5 hours. The reon mixture was allowed to stand at room temperature overnight, after which the solvent was removed from the reon mixture by distillation under reduced pressure. Water was added to the residue. The resulting mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extrd with ethyl acetate. The extrwas washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extrby distillation under reduced pressure. The residue was recrystallized from a 3: 1 by volume mixture of ethyl acetate and hexane to give 64 mg of the title compound as a pale yellow powder, melting at 95 ° C to 96 ° C. EXAMPLE 49 Acid [5- (1, 2-dithiolan-3-yl) pentanoylamino (Compound No. 1-46) 0.28 g of methyl 5- (1,2-dithiolan-3-yl) pentanoylamino acetate (prepared as described in Example 47) were dissolved in a mixture of 2 ml of methanol and 2 ml of tetrahydrofuran. 2.0 ml of a 1 N aqueous solution of sodium hydroxide was added dropwise to the resulting solution, and then the mixture was stirred at room temperature for 2 hours. The reon mixture was allowed to stand at room temperature overnight, after which the solvent was removed from the reon mixture by distillation under reduced pressure. Water was added to the residue. The resulting mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extrd with ethyl acetate. The extrwas washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extrby distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilized, to give 156 mg of the title compound as a yellow oil having an Rf value of 0.12 (silica gel thin layer chromatography; using a mixture of 5: 1 volume of ethyl acetate and methanol as the developing solvent).

EXAMPLE 50 2 (S) -. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido} Methyl Propionate (Compound No. 1-742) The reaction was carried out as described in example 46, but using 500 mg of D, L-α-lipoic acid in 10 ml of anhydrous toluene, 0.73 ml of triethylamine, 0.56 ml of diphenylphosphoryl azide, 10 ml of anhydrous dimethylformamide and 335 mg of L-alanine methyl ester hydrochloride. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was subjected to silica gel column chromatography, using mixtures of 2: 1 and 1: 0 by volume of ethyl acetate and hexane as eluent. Ethyl acetate was removed from the eluted product by distillation under reduced pressure, and the residue was recrystallized from a mixture of 1: 1: 1 by volume ethyl acetate, diisopropyl ether and hexane, to give 142 mg of the title compound as yellow crystals, melting at 90 ° C to 92 ° C.

EXAMPLE 51 2 (S) - [5- (1, 2-Dithiolan-3-ylpentanoylamino] methyl propionate (Compound No. 1-50) The reaction was carried out as described in example 47, but using 500 mg of D, L-α-lipoic acid, 10 ml of anhydrous dimethylformamide, 422 mg of N, N'-carbonyldiimidazole, 0.36 ml of triethylamine and 335 mg of L-alanine methyl ester hydrochloride. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using a mixture of 2: 1 by volume of ethyl acetate and hexane as eluent, followed by preparative reverse phase silica gel column chromatography, using mixtures of 3: 7 and 1: 1 of acetonitrile and water as eluent. Acetonitrile was removed from the eluate thus obtained under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilized, to give 271 mg of the title compound as a pale yellow amorphous substance, melting at 48 ° C to 49 ° C.

EXAMPLE 52 Acid 2 (S) -. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido} Propionic (Compound No. 1-740) The reaction was carried out as described in the example 46, but using 1.00 g of D, L-α-lipoic acid, 20 ml of anhydrous toluene, 1.47 ml of triethylamine, 1.14 ml of dimethyl phosphoryl azide, 740 mg of L-alanine methyl ester hydrochloride and 20 ml of anhydrous dimethylformamide. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using mixtures of 2: 1 and 1: 0 by volume of ethyl acetate and hexane as eluent, after which it was recrystallized from ethyl acetate, to give 0.80. g of yellow crystals.

The resulting crystals were dissolved in a mixture of 10 ml of methanol and 3 ml of tetrahydrofuran, and then 16.8 ml of a 1 N aqueous solution of sodium hydroxide were added dropwise thereto. The resulting mixture was stirred at room temperature for 6 hours and 30 minutes. The solvent was removed after the reaction mixture by distillation under reduced pressure. Water was added to the residue. The resulting mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was recrystallized from ethyl acetate, to give 141 mg of the title compound as pale yellow crystals, melting at 128 ° C to 130 ° C.

EXAMPLE 53 2 (S) - [5- (1, 2-dithiolan-3-yl) pentanoylamino] propionic acid (Compound No. 1-48) The reaction was carried out as described in the example 49, but using 153 mg of ethyl 2 (S) - [5- (1, 2-dithiolan-3-yl) pentanoylamino] propionate (prepared as described in example 51), 3 ml of methanol and 1.3 ml of an aqueous solution of 1 N of sodium hydroxide. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. The resulting mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in hexane, after which it was lyophilized, to give 90 mg of the title compound as a yellow oil having an Rf value of 0.18 (silica gel thin layer chromatography; revealing solvent).

EXAMPLE 54 3-. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido) methyl propionate (Compound No. 1-741 methyl ester) The reaction was carried out as described in example 46, but using 500 mg of D, L-α-lipoic acid, 10 ml of anhydrous toluene, 0.74 ml of triethylamine, 0.56 ml of diphenylphosphoryl azide, 335 mg of ester hydrochloride. ß-alanine methyl ester and 10 ml of anhydrous dimethylformamide. The solvent was removed from the reaction mixture by distillation under reduced pressure, water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was subjected to silica gel column chromatography, using mixtures of 3: 1 and 1: 0 by volume of ethyl acetate and hexane as eluyenye, after which was recrystallized from a 1: 2 by volume mixture of ethyl acetate and hexane, to give 213 mg of the title compound as yellow crystals, melting at 67 ° C to 69 ° C.

EXAMPLE 55 3- [5- (1, 2-dithiolan-3-yl) pentanoylamino] propionate methyl (Compound No. 1-49 methyl ester) The reaction was carried out as described in example 47, but using 500 mg of D, L-α-lipoic acid, 10 ml of anhydrous dimethylformamide, 422 mg of N, N'-carbonyldiimidazole, 0.36 ml of triethylamine and 335 mg of ß-alanine methyl ester hydrochloride. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using mixtures of 2: 1 and 1: 0 by volume of ethyl acetate and hexane as eluent, after which it was recrystallized from a mixture of 1: 2 and volume of ethyl acetate and hexane, to give 333 mg of the title compound as yellow crystals in the form of a plate, melting at 54 ° C to 55 ° C.

EXAMPLE 56 Acid 3-. { 3- (4- (1, 2-dithiolan-3-yl) butyl] ureido} propionic (Compound No. 1-741) The reaction was carried out as described in example 48, but using 115 mg of 3-. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido} propionate (prepared as described in example 54), 3 ml of methanol, 2 ml of tetrahydrofuran and 1.40 ml of a 1 N aqueous solution of sodium hydroxide. The solvent was removed after the reaction mixture by distillation under reduced pressure. Water was added to the residue.

The resulting mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the crystals thus precipitated were collected by filtration, to give 70 mg of the title compound as a yellow powder, melting at 109 ° C at 110 ° C. EXAMPLE 57 3- [5- (1, 2-Dithiolan-3-yl) pentanoylamino] propionic acid (Compound No. 1-49) The reaction was carried out as described in Example 49, but using 213 mg of methyl 3- [5- (1, 2-dithiolan-3-yl) pentanoylamino] propionate (prepared as described in Example 55), ml of methanol and 1.80 ml of a 1 N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. The resulting mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilized, to give 0.11 g of the title compound as a pale yellow amorphous substance, melting at 74 ° C to 76 ° C. EXAMPLE 58 2- [5- (1, 2-dithiolan-3-yl) pentyl] isoindol-1,3-dione (Compound No. 1-2606) 6.5 ml of dimethyl azodicarboxylate was added dropwise to a solution of 5.77 g of triphenylphosphine in 20 ml of tetrahydrofuran, while cooling with ice, and then the mixture was stirred at room temperature for 30 minutes. Then 3.24 g of phthalimide was added to the reaction mixture, after which a mixture of 20 mmoles of 5- (1, 2-dithiolan-3-yl) pentanol (prepared as described in the preparation) was added dropwise. 1) in 30 ml of toluene and 10 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was allowed to stand overnight at room temperature, after which 1.57 g of triphenylphosphine and 0.89 ml of dimethyl azodicarboxylate were added. The reaction mixture was stirred at room temperature for 7 hours and 30 minutes. Then 0.88 g of phthalimide, 1.57 g of triphenylphosphine and 0.89 ml of dimethyl azodicarboxylate were added to the reaction mixture. The reaction mixture was allowed to stand at room temperature for 4 days. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, using mixtures of 1: 6 and 1: 4 by volume of ethyl acetate. ethyl and hexane as eluent. The solvent was removed from the product eluted by distillation under reduced pressure, and 30 ml of toluene was added to the residue. 1 ml of the resulting mixture was weighed and the solvent was removed therefrom by distillation under reduced pressure, to give 165 mg of the title compound as an orange oil having an Rf value of 0.35 (gel thin layer chromatography). silica, using a 1: 4 mixture by volume of ethyl acetate and hexane as the developing solvent).

EXAMPLE 59 N- [5- (1, 2-dithiolan-3-yl) pentyl] methanesulfonamide (Compound No. 1-2470) 1 ml of butylamine was added to a solution of 0.24 g of 2- [5- (1, 2-dithiolan-3-yl) pentyl] isoindol-1,3-dione in 1 ml of methanol. The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was allowed to stand at room temperature overnight. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. 2 ml of tetrahydrofuran was added to the residue and then 0.22 ml of triethylamine and 0.12 ml of methanesulfonyl chloride were added dropwise thereto, while cooling with ice, the mixture was then stirred at room temperature for 3 hours. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was then added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was subjected to silica gel column chromatography, using 1: 1 and 2: 1 by volume mixtures of ethyl acetate and hexane as eluent, followed by preparative reverse phase silica gel column chromatography, using a 1: 1 mixture of acetonitrile and water as eluent. Acetonitrile was removed from the eluate thus obtained by distillation under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was dissolved in dioxane, after which it was lyophilized, to give 100 mg of the title compound as a pale yellow amorphous substance, melting at 43 ° C to 46 ° C. C.

EXAMPLE 60 N- [5- (1,2-dithiolan-3-yl) pentyl] acetamide (Compound No. 1-1962) 1 ml of a mixture of 1.3 mmoles of 2- [5- 1, 2-dithiolan-3-yl) pentyl] isoindol-1,3-dione, 9 ml of toluene and 2 ml of methanol was added. The resulting mixture was stirred at room temperature for 3 hours, after which the reaction mixture was allowed to stand at room temperature for 2 days. Then 1 ml of butylamine was added to the reaction mixture. The resulting mixture was stirred at room temperature for 3 hours. The solvent was then removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. Then 5 ml of anhydrous tetrahydrofuran was added to the residue. Then 0.28 ml of triethylamine and 0.14 ml of acetyl chloride were added dropwise to the resulting mixture while cooling with ice and then the mixture was allowed to stand at room temperature for 1 hour and 30 minutes. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using 1: 0 and 10: 1 by volume mixtures of ethyl acetate and methanol as eluent. The solvent was removed from the product eluted by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilized, to give 161 mg of the title compound as yellow crystals, melting at 28 ° C to 33 ° C. EXAMPLE 61 N- [5- (1, 2-dithiolan-3-yl) pentyl] propionamide (Compound No. 1-1963) 2 ml of methanol and 2 ml of butylamine were added to a solution of 1.6 mmoles of 2- [5- (1,2-dithiolan-3-yl) pentyl] isoindol-1,3-dione in 3 ml of toluene. The resulting mixture was stirred at room temperature for 6 hours. Then the reaction mixture was allowed to stand overnight at room temperature. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. Then 5 ml of pyridine was added to the residue. 0.31 ml of propionic anhydride was added dropwise to the resulting mixture, and then the mixture was stirred at room temperature for 2 hours and 30 minutes. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was then subjected to silica gel column chromatography, using mixtures of 2: 1, 3: 1 and 1: 0 by volume of ethyl acetate and hexane as eluent, followed by preparative silica gel column chromatography. reverse phase, using mixtures of 1: 4, 3: 7, 2: 3 and 1: 1 by volume of acetonitrile and water as eluent. Acetonitrile was removed from the eluate thus obtained by distillation under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilized, to give 125 mg of the title compound as a yellow oil having an Rf value of 0.45 (silica gel thin layer chromatography; revealing solvent).

EXAMPLE 62 [5- (1, 2-dithiolan-3-yl) pentyl] urea (Compound No. 1-1993) 2 ml of methanol and 2 ml of butylamine were added to a solution of 1.6 mmoles of 2- [5- (1,2-dithiolan-3-yl) pentyl] isoindol-1,3-dione in 3 ml of toluene. The resulting mixture was stirred at room temperature for 5 hours and 30 minutes. Then the reaction mixture was allowed to stand overnight at room temperature. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the resulting residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. Then 5 ml of tetrahydrofuran was added to the residue. Then 0.32 ml of trimethylsilyl isocyanate was added dropwise to the resulting mixture, while cooling with ice, and then the mixture was stirred at room temperature for 3 hours and 30 minutes. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the resulting residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, using mixtures of 1: 0, 5: 1 and 1: 0 by volume of ethyl acetate and methanol as eluent The solvent was removed from the product eluted by distillation under reduced pressure. The residue was recrystallized from ethyl acetate, to give 80 mg of the title compound as yellow crystals, melting at 74 ° C to 78 ° C.

EXAMPLE 63 l- [5- (1, 2-dithiolan-3-yl) pentyl] -3-methylthiourea (Compound No. 1-2567) The reaction was carried out as described in the example 62, but using a solution of 1.5 mmole of 2- [5- (1,2-dithiolan-3-yl) pentyl] -? Soindol-1,3-dione in 3 ml of toluene, 2 ml of methanol, 2 ml of butylamine, 5 ml of anhydrous tetrahydrofuran and 0.12 ml of methyl isocyanate. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using 1: 0 and 20: 1 by volume mixtures of ethyl acetate and methanol as eluent, followed by preparative reverse phase silica gel column chromatography, using mixtures of 3: 7 and 1: 1 in volume of acetonitrile and water as eluent. The residue was subsequently extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was recrystallized from a 1: 1 by volume mixture of ethyl acetate and hexane to give 183 mg of the title compound as yellow crystals, melting at 64 ° C. at 65 ° C.

EXAMPLE 64 [ethyl 5- (1,2-dithiolan-3-yl) pentyl] carbamate (Compound No. 1-1977) 2 ml of methanol and 2 ml of butylamine were added to a solution of 1.6 mmole of 2- [5- (1,2-dithiolan-3-yl) pentyl] -isoindole-1,3-dione in 3 ml of toluene. The resulting mixture was stirred at room temperature for 7 hours. At the end of this time, the reaction mixture was allowed to stand overnight at room temperature. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the resulting residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. 2 ml of anhydrous tetrahydrofuran was added to the residue, and then 0.33 ml of triethylamine and 0.23 m of ethyl chloroformate were added dropwise while cooling with ice. The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was subjected to silica gel column chromatography, using mixtures of 1: 3 and 1: 2 by volume of ethyl acetate and hexane as eluent, followed by chromatography. of reverse phase preparative silica gel column, using a mixture of 1: 1 by volume of acetonitrile and water as eluent. The acetonitrile was removed from the eluate thus obtained by distillation under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilized, to give 75 mg of the title compound as a red oil having an Rf value of 0.46 (silica gel thin layer chromatography).; using a 1: 2 volume mixture of ethyl acetate and hexane as the developing solvent).

EXAMPLE 65 N- [5- (1, 2-Dithiolan-3-yl) pentyl] oxalamidate (Compound No. 1-2590) 2 ml of methanol and 2 ml of butylamine were added to a solution of 1.5 mmoles of 2- [5- (1,2-dithiolan-3-yl) pentyl] -isoindole-1,3-dione in 3 ml of toluene. The resulting mixture was stirred at room temperature for 1 hour. Then the reaction mixture was allowed to stand overnight at room temperature. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. 4 ml of anhydrous tetrahydrofuran was added to the residue and then 0.32 ml of triethylamine and 0.21 ml of methoxyloxalyl chloride were added dropwise while cooling with ice. The resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was subjected to reverse phase preparative silica gel column chromatography, using a mixture of 2: 3 by volume of acetonitrile and water as eluent. Acetonitrile was removed from the eluate thus obtained by distillation under reduced pressure. The residue was then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilized, to give 154 mg of the title compound as a pale yellow amorphous substance, melting at 42 ° C to 43 ° C.

EXAMPLE 66 N- [5- (1, 2-Dithiolan-3-yl) pentyl] succinamic acid (Compound No. 1-1970) The reaction was carried out as described in Example 61, but using a solution of 1.5 mmoles of 2- [5- (1,2-dithiolan-3-yl) pentyl] -isoindole-1,3-dione in 3 ml of toluene, 2 ml of methanol, 2 ml of butylamine, 4 ml of pyridine and 230 mg of succinic anhydride. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was subjected to preparative reverse phase silica gel column chromatography, using mixtures of 2: 3, 1: 1 and 3: 2 by volume acetonitrile and water as eluent. Acetonitrile was removed from the eluate thus obtained by distillation under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilized, to give 166 mg of the title compound as a pale yellow amorphous substance, melting at 74 ° C.

EXAMPLE 67 4- [5- (1, 2-Dithiolan-3-yl) pentylcarbamoyl] butanoic acid (Compound No. 1-2577) The reaction was carried out as described in Example 61, but using a solution of 1.5 mmoles of 2- [5- (1,2-dithiolan-3-yl) pentyl] -isoindole-1,3-dione in 3 ml of toluene, 2 ml of methanol, 2 ml of butylamine, 4 ml of pyridine and 262 mg of glutaryl anhydride. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate.

The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was subjected to reverse phase preparative silica gel column chromatography, using a mixture of 2: 3 by volume of acetonitrile and water as eluent. Acetonitrile was removed from the eluate thus obtained by distillation under reduced pressure. The residue was then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilized, to give 132 mg of the title compound as a pale yellow amorphous substance, melting at 60 ° C to 62 ° C.

EXAMPLE 68 [5- (1, 2-Dithiolan-3-yl) pentylamino] methyl acetate (Compound No. 1-2584) 2 ml of methanol and 2 ml of butylamine were added to a solution of 1.6 mmole of 2- [5- (1,2-dithiolan-3-yl) pentyl] -isoindole-1,3-dione in 3 ml of toluene. The resulting mixture was allowed to stand overnight at room temperature. Then the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the resulting residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. 4 ml of anhydrous tetrahydrofuran was added to the residue and then 0.33 ml of triethylamine and 0.17 ml of methyl bromoacetate were added dropwise while cooling with ice. The resulting mixture was stirred for 1 hour, while cooling with ice and then for 5 hours at room temperature. Then, the reaction mixture was allowed to stand overnight at room temperature for 2 days.

At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was subjected to silica gel column chromatography, using mixtures of 1: 0 and 20: 1 by volume of ethyl acetate and methanol as eluent. The solvent was removed from the product thus obtained by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilized, to give 195 mg of the title compound as a yellow oil having an Rf value of 0.55 (silica gel thin layer chromatography, using a mixture of 4: 1 volume of ethyl acetate and methanol as the developing solvent).

EXAMPLE 69 3- [5- (1, 2-Dithiolan-3-yl) pentylamino] propionate methyl (Compound No. 1-2586 methyl ester) The reaction was carried out as described in the example 68, but using a solution of 1.5 mmoles of 2- [5- (1,2-dithiolan-3-yl) pentyl] -isoindole-1,3-dione, 2 ml of methanol, 2 ml of butylamine, 4 ml of anhydrous tetrahydrofuran, 0.24 ml of triethylamine and 0.19 ml of methyl bromopropionate. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using a mixture of 1: 0, 20: 1 and 4: 1 by volume of ethyl acetate and methanol as eluent. The solvent was removed from the eluate thus obtained by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilized, to give 161 mg of the title compound as a yellow oil having an Rf value of 0.21 (silica gel thin layer chromatography, using a 4: 1 mixture). in volume of ethyl acetate and methanol as the developing solvent).

EXAMPLE 70 2 (R) -. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido} Methyl Propionate (Compound No. 1-742) The reaction was carried out as described in example 46, but using 0.56 g of D, L-α-lipoic acid, 10 ml of anhydrous toluene, 0.75 ml of triethylamine, 0.59 ml of diphenylphosphoryl azide, 10 ml of anhydrous dimethylformamide and 0.34 g of alanine methyl ester hydrochloride. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using mixtures of 1: 1 and 1: 0 by volume of ethyl acetate and hexane as eluent. The solvent was removed from the eluate thus obtained by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilized, to give 0.27 g of the title compound as a yellow powder, melting at 72 ° C to 82 ° C.

EXAMPLE 71 2 (R) -. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido} Propionic (Compound No. 1-740) The reaction was carried out as described in the example 48, but using 1.74 2 (R) -. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido} methyl propionate (prepared as describes in Example 70), 30 ml of methanol, 22 ml of »Tetrahydrofuran and 17.0 ml of a 1 N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. After neutralization with 2N aqueous hydrochloric acid, the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was recrystallized from ethyl acetate, to give 0.56 g of the title compound as yellow crystals, melting at 131 ° C to 134 ° C.

EXAMPLE 72 N- (2- { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido.] Propionyl) methanesulfonamide (Compound No. 1-1280) (a) 127 mg of N, N'-carbonyldiimidazole was added to a solution of 208 mg of 2 (R) - acid. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido} propionic (prepared as described in example 71) in 2 ml of anhydrous dimethylformamide, and then the mixture was stirred at room temperature for 3 hours and 10 minutes. (b) Meanwhile, 34 mg of sodium hydride (as a 55% w / w dispersion in mineral oil) were washed with hexane and then 3 ml of anhydrous dimethylformamide was added. 74 mg of methanesulfonamide was added to the resulting mixture, while cooling with ice, and then the mixture was stirred at room temperature for 3 hours and 45 minutes. At the end of this time, the solution prepared as described in step (a) above was added dropwise to the reaction mixture and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was allowed to stand overnight at room temperature. The solvent was removed after the reaction mixture by distillation under reduced pressure. Water was added to the residue. After neutralization with 2N aqueous hydrochloric acid, the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was recrystallized from methanol to give 77 mg of the title compound as a pale yellow powder, melting at 140 ° C to 150 ° C.

EXAMPLE 73 4- [5- (1, 2-dithiolan-3-yl) pentanoylamino] butanoate methyl (Compound No. 1-1275 methyl ester) (a) 0.86 g of N, N'-carbonyldiimidazole was added to a solution of 1.00 g of D-acid., L-α-lipoic acid in 20 ml of anhydrous dimethylformamide, while cooling with ice. The resulting mixture was stirred at room temperature for 1 hour and 25 minutes. (b) Meanwhile, 0.23 g of sodium hydride (as a 55% w / w dispersion in mineral oil) were washed with hexane, after which 20 ml of anhydrous dimethylformamide was added. 0.82 g of methyl 4-aminobutanoate hydrochloride was added, while cooling with ice, and then the mixture was stirred at room temperature for 1 hour and 45 minutes. The solution prepared as described in step (a) above was then added dropwise to the reaction mixture, while cooling with ice, and then the mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was allowed to stand overnight at room temperature, after which the solvent was removed after the reaction mixture by distillation under reduced pressure. Water was added to the residue. After neutralization with 2N aqueous hydrochloric acid, the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was subjected to silica gel column chromatography, using mixtures of 1: 1 and 1: 0 by volume of ethyl acetate and hexane as eluent. The ethyl acetate was removed from the eluate thus obtained by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilized, to give 0.83 g of the title compound as a yellow powder, melting at 30 ° C to 32 ° C.

EXAMPLE 74 4- [5- (1, 2-Dithiolan-3-yl) pentanoylamino] butanoic acid (Compound No. 1-1275) The reaction was carried out as described in the example 49, but using 0.65 g of methyl 4- [5- (1, 2-dithiolan-3-yl) pentanoylamino] butanoate (prepared as described in example 73), 13 ml of methanol and an aqueous solution to IN of sodium hydroxide. The solvent was removed after the reaction mixture by distillation under reduced pressure. Water was added to the residue. After neutralization with 2N hydrochloric acid, the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was recrystallized from ethyl acetate, to give 0. 28 g of the title compound as yellow crystals, melting at 56 ° C to 58 ° C.

EXAMPLE 75 4-. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido} methyl butanoate (Compound No. 1-1276 methyl ester) The reaction was carried out as described in the example 46, but using 1.00 g of D, L-α-lipoic acid, 20 ml of anhydrous toluene, 1.48 ml of triethylamine, 1.15 ml of diphenylphosphoryl azide and 0.74 g of methyl 4-aminobutanoate hydrochloride. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, using ethyl acetate as eluent. The ethyl acetate was removed from the eluate thus obtained by distillation under reduced pressure, to give 1.18 g of the title compound as yellow crystals, melting at 63 ° C to 70 ° C.

EXAMPLE 76 N- [5- (1, 2-Dithiolan-3-yl) pentyl] oxalamic acid (Compound No. 1-2589) The reaction was carried out as described in example 49, but using 92 mg of methyl N- [5- (l, 2-dithiolan-3-yl-pentyl] oxalamidate (prepared as described in example 65), ml of methanol, 1 ml of tetrahydrofuran and 0.6 ml of an aqueous IN-sodium hydroxide solution The solvent was removed after the reaction mixture by distillation under reduced pressure, water was added to the residue, the resulting mixture was neutralized by The addition of aqueous hydrochloric acid at 2 N, after which it was extracted with ethyl acetate, The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Extraction by distillation under reduced pressure The residue was dissolved in dioxane, after which it was lyophilized, to give 64 mg of the title compound as a pale yellow amorphous substance, melting at 75 ° C to 79 ° C.

EXAMPLE 77 N- [5- (1, 2-dithiolan-3-yl) pentyl] succinamidate methyl (Compound No. 1-1970 methyl ester) 0.25 ml of a solution of hexane containing 2.0 M (trimethylsilyl) diazomethane was added dropwise to a mixture of 89 mg of N- [5-1,2-dithiolan-3-yl) pentyl] -succinnamic acid, 1 ml of methanol and 1.5 ml of toluene, and the mixture was stirred at room temperature for 30 minutes. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure. The resulting residue was subjected to silica gel column chromatography, using mixtures of 1: 1 and 1: 0 by volume of ethyl acetate and hexane as eluent. Ethyl acetate and hexane were removed from the eluate thus obtained by distillation under reduced pressure. The resulting residue was dissolved in dioxane, after which it was lyophilized, to give 77 mg of the title compound as a pale yellow amorphous substance, melting at 46 ° C to 48 ° C.

EXAMPLE 78 4- [5- (1, 2-dithiolan-3-yl) pentylcarbamoyl] butanoate methyl (Compound No. 1-2577 methyl ester) The reaction was carried out as described in example 77, but using 68 mg of 4- [5- (1, 2-dithiolan-3-yl-pentylcarbamoyl] butanoic acid (prepared as described in example 67), 1 ml of methanol, 1 ml of toluene and 0.40 ml of a hexane solution containing 2.0 M of (trimethylsilyl) diazomethane The solvent was removed after the reaction mixture by distillation under reduced pressure. silica gel, using mixtures of 3: 1 and 1: 0 by volume of ethyl acetate and hexane as eluent.The solvent was removed from the eluate thus obtained by distillation under reduced pressure.The residue was dissolved in dioxane, after which was lyophilized, to give 62 mg of the title compound as a pale yellow amorphous substance, melting at 69 ° C to 71 ° C.

EXAMPLE 79. { N- [5- (1, 2-dithiolan-3-yl) pentanoyl] -N-methylamino) ethyl acetate (Compound No. 1-2520 ethyl ester) The reaction was carried out as described in the example 47, but using 500 mg of D, L-α-lipoic acid, 10 ml of anhydrous dimethylformamide, 422 mg of N, N'-carbonyldiimidazole, 0.36 ml of triethylamine and 399 mg of sarcosine ethyl ester hydrochloride. The solvent was removed after the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was subjected to silica gel column chromatography, using a mixture of 2: 1 by volume of ethyl acetate and hexane as eluent. The solvent was removed from the product eluted by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilized, to give 558 mg of the title compound as a yellow oil having an Rf value of 0.39. (silica gel thin layer chromatography, using a 2: 1 by volume mixture of ethyl acetate and hexane as the developing solvent).

EXAMPLE 80 4-. { N- [5- (1, 2-dithiolan-3-yl) pentanoyl] -N-methylamino] butanoate of methyl (Compound No. 1-2669 methyl ester) The reaction was carried out as described in example 47, but using 500 mg of D, L-α-lipoic acid, 10 ml of anhydrous dimethylformamide, 422 mg of N, N'-carbonyldiimidazole, 0. 36 ml of triethylamine and 486 mg of methyl 4-methylaminobutanoate hydrochloride. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure and the residue was subjected to silica gel column chromatography, using mixtures of 2: 1 and 4: 0 by volume of ethyl acetate and hexane as eluent, followed by chromatography. of reverse phase preparative silica gel column, using mixtures of 2: 3 and 9:11 by volume of acetonitrile and water as eluent. The acetonitrile was removed from the eluate thus obtained by distillation under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilized, to give 229 mg of the title compound as a yellow oil having an Rf value of 0.37 (silica gel thin layer chromatography; using a 4: 1 mixture of ethyl acetate and hexane as the developing solvent).

EXAMPLE 81 2- [4- (2, -dioxothiazolidin-5-ylmethyl) phenoxymethyl] -2,5,7,8,8- (l, 2-dithiolan-3-yl) pentanoate of tetramethylchroman-6-yl 0.36 ml of triethylamine and then 0.25 ml of ethyl chloroformate were added dropwise to 10 ml of a solution of 500 mg of D, L-α-lipoic acid in anhydrous dimethylformamide, while cooling with ice, and the mixture was stirred. stirred at room temperature for 2 hours. At the end of this time, 1.06 g of 5- [4- (2, 5, 7, 8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione was added to the reaction solution, while cooling with ice, and the mixture was stirred at room temperature for 5 hours, after which it was allowed to stand at room temperature overnight. The mixture was then stirred in an oil bath at 50 ° C for 1 hota and then the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure and the residue was subjected to silica gel column chromatography, using a 3: 2 by volume mixture of ethyl acetate and hexane as the eluent. The residue was then subjected to preparative reverse phase silica gel column chromatography, using 3: 1 and 4: 1 by volume mixtures of ethyl acetate and water as eluent. The acetonitrile was removed from the solution by evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilized, to obtain 0.57 g of the title compound as a yellow oil having an Rf value of 0.42 ( silica gel layer chromatography, using a 1: 2 by volume mixture of ethyl acetate and hexane as developer solvent).

EXAMPLE 82 5- (1, 2-dithiolan, 3-yl) 2- (3-4-dibenzyloxy-5-oxo-2, 5-dihydrofuran-2-yl) -2-hydroxyethyl) swazoate 276 mg of N, N'-carbonyldiimidazole was added, while cooling with ice, to 6 ml of a solution of 300 mg of D, L-α-lipoic acid in anhydrous dimethylformamide and the mixture was stirred at room temperature for 1 hour. hour and 30 minutes. At the end of this time, 0.24 ml of triethylamine and 536 mg of 2,3-O-dibenzylasecorbic acid were added, while cooling with ice, to the reaction mixture and the mixture was stirred at room temperature for 1 hour, after which the reaction mixture was allowed to stand at room temperature for 2 days. The solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using values of 1: 3 and 1: 1 by volume of ethyl acetate and hexane as the eluent The residue was subjected to reverse phase preparative silica gel column chromatography, using mixtures of 11: 9, 3: 2 and 13: 7 by volume of acetonitrile and water as eluent, and the acetonitrile was removed from the solution by evaporation. under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane then lyophilized, to obtain 321 mg of the title compound as a yellow oil having an Rf value of 0.34 ( thin layer of silica, using a mixture of 1: 2 by volume of ethyl acetate and hexane as the developing solvent).

EXAMPLE 83 5- (1, 2-dithiolan-3-yl) -1- (imidazol-1-yl) pentan-1-one 0.86 g of N, N'-carbonyldiimidazole was added, while cooling with ice, to 20 ml of a solution of 1.00 g of D, L-α-lipoic acid in anhydrous dimethylformamide, and the mixture was stirred at room temperature during 1 hour. At the end of this time, 311 mg of chloromethanesulfonamide and 104 mg of sodium hydride (as a 55% w / w dispersion in mineral oil) were added, while cooling with ice, to the reaction solution, and the mixture was added to the reaction solution. stirred at room temperature for 1 hour. The reaction mixture was allowed to stand at room temperature overnight, after which the solvent was removed after the reaction mixture by evaporation under reduced pressure. Water was added to the residue and the mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was chromatographed on silica gel, using mixtures of 2: 1 4: 1 and 1: 0 by volume of ethyl acetate and hexane as eluent. The residue was then subjected to reverse phase preparative silica gel column chromatography, using mixtures of 2: 3 and 1: 1 by volume of acetonitrile and water as eluent, and the acetonitrile was removed from the solution by evaporation under reduced pressure. , after which the residue was then extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilized, to obtain 245 mg of the title compound as a pale yellow amorphous substance, melting at 37 ° C to 39 ° C. ° C.

EXAMPLE 84 4- [5- (1, 2-dithiolan-3-yl) pentanoyl] piperazine-1-t-butyl carboxylate (Compound No. 1-1131 derived from t-butoxycarbonyl) ("Boc" is t-butoxycarbonyl) The reaction was carried out as described in example 43, but using 500 mg of D, L-Á-lipoic acid, 10 ml of anhydrous dimethylformamide, 422 mg of N, N'-carbonyldiimidazole and 484 mg of Nt- butoxycarbonylpiperazine. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using mixtures of 2: 1 and 1: 0 by volume of ethyl acetate and hexane as the eluent . The residue was dissolved in dioxane and then lyophilized to obtain 520 mg of the title compound as a pale yellow amorphous substance, melting at 70 ° C to 71 ° C.

EXAMPLE 85 5- (1,2-dithiolan-3-yl) -1- (piperazin-1-pentan-1-yl hydrochloride (Compound No. 1-1131 hydrochloride) 3 ml of a 4 N solution of hydrochloric acid in ethyl were added dropwise to 5 ml of a solution of 260 mg of 4- [5- (1,2-dithiolan-3-yl) pentanoyl] -piperazine-1 t-butylcarboxylate (prepared as described in Example 84) in ethyl acetate, and the mixture was stirred at room temperature for 3 hours. The crystals that were precipitated were then collected by filtration, to obtain 217 mg of the title compound as a pale yellow powder, melting at 84 ° C to 86 ° C.

EXAMPLE 86 [4- (l, 2-dithiolan-3-yl) butyl] thiazolidine-3-carboxylic acid amide (Compound No. 1-1260) The reaction was carried out as described in Example 44, but using 500 mg of D, L-Á-lipoic acid, 10 ml anhydrous toluene, 0.36 ml triethylamine, 0.56 ml diphenylphosphoryl azide and 0.20 ml thiazolidine. The solvent was removed from the reaction mixture by evaporation under reduced pressure and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using mixtures of 2: 1 and 1: 0 by volume of ethyl acetate and hexane as the eluent The solvent was removed after the product eluted by evaporation under reduced pressure, and the residue was recrystallized from a mixture of 1: 1 by volume of ethyl acetate and hexane, to obtain 386 mg of the title compound as yellow crystals, melting at room temperature. 76 ° C to 77 ° C.

EXAMPLE 87 5- (1, 2-dithiolan-3-i1) pentanoic acid (l-methyl-2-nitroxyethyl) amide (Compound No. 1-2665 nitrate) The reaction was carried out as described in example 47, but using 300 mg of D, L-α-lipoic acid, 9 ml of anhydrous dimethylformamide, 259 mg of N, N'-carbonyldiimidazole, 0.22 ml of triethylamine and 251 mg of l-methyl-2-nitroxyethylamine hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using mixtures of 3: 2 and 2: 1 by volume of ethyl acetate and hexane as the eluent. The residue was then subjected to reverse phase preparative silica gel column chromatography, using mixtures of 3: 7, 2: 3 and 7: 3 by volume acetonitrile and water as eluent, and the acetonitrile was removed from the solution by evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane, and then lyophilized, to obtain 119 mg of the title compound as a yellow oil having an Rf value of 0.39 (chromatography of delegated layer of silica gel, using a mixture of 2: 1 by volume of ethyl acetate and hexane as the developing solvent).

EXAMPLE 88 1- [4- (1, 2-dithiolan-3-yl) butyl] -3- (2-nitroxyethyl) urea (Compound No. 1-2661 nitrate) The reaction was carried out as described in Example 46, but using 500 mg of D, L-Á-lipoic acid, 10 ml of anhydrous toluene, 0.72 ml of triethylamine, 0.56 ml of diphenylphosphoryl azide, 10 ml of anhydrous dimethylformamide. and 342 mg of 2-nitroxyethylamine hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using using mixtures of 2: 1 and 1: 0 by volume of ethyl acetate and hexane as the eluent. The solvent was removed from the product eluted by evaporation under reduced pressure, and the residue was recrystallized from a mixture of 1: 2 by volume of ethyl acetate and hexane, to obtain 58 mg of the title compound as a pale yellow powder, having an Rf value of 0.31 (silica gel thin layer chromatography, using a 2: 1 volume mixture of ethyl acetate and hexane as the developing solvent).

EXAMPLE 89 3- (1,2-dithiolan-3-yl) propionic acid 1.3 ml of 2 N aqueous hydrochloric acid was added to a solution of 500 mg of 4,6-dithioxyhexanoic acid in 5 ml of a 1 N aqueous solution of sodium hydroxide. Then 5 drops of a 1% w / v aqueous solution were added dropwise to the reaction solution, and the resulting mixture was stirred at room temperature for 1 hour while blowing air through the mixture. After it was added to the reaction solution, which was then washed with ethyl acetate, the aqueous layer was neutralized by the addition of 2N aqueous hydrochloric acid and then extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilized, to obtain 388 mg of the title compound as a yellow oil having an Rf value of 0.59 (chromatography thin-layer silica gel; using a 2: 1 volume mixture of ethyl acetate and hexane as the developing solvent).

EXAMPLE 90 2- [5- (1, 2-dithiolan-3-yl) pentanoylamino] acetamide (Compound No. 1-46 amide) The reaction was carried out as described in example 47, but using 500 mg of D, L-α-lipoic acid, 10 ml of anhydrous dimethylformamide, 422 mg of N, N'-carbonyldiimidazole, 0.36 ml of triethylamine and 265 mg of glycinamide hydrochloride.

The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and crystals which were precipitated were collected by filtration to obtain 330 mg of the title compound as yellow crystals, melting at 105 ° C to 108 ° C.

EXAMPLE 91 2-. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido} Acetamide (Compound No. 1-738 amide) The reaction was carried out as described in example 46, but using 500 mg of D, L-Á-lipoic acid, 10 ml of anhydrous toluene, 0.56 ml of triethylamine, 0.72 ml of diphenylphosphoryl azide, 10 ml of anhydrous dimethylformamide. and 265 mg of glycinamide hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from ethyl acetate, to obtain 149 mg of the title compound as a yellow powder, melting at 141 ° C to 143 ° C. .

EXAMPLE 92 1- (indolin-1-yl) -5- (1, 2-dithiolan-3-yl) pentan-1-one (Compound No. 1-2674) The reaction was carried out as described in example 43, but using 1.00 g of D, L-α-lipoic acid, 30 ml of anhydrous dimethylformamide, 0.86 g of N, N'-carbonyldiimidazole, 0.73 ml of triethylamine and 1.13 of methyl indolin-2-carboxylate hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1: 4 and 1: 2 by volume mixtures of ethyl acetate and hexane as eluent . The residue was then subjected to preparative reverse phase silica gel column chromatography using a 3: 2 by volume mixture of acetonitrile and water as eluent, and the acetonitrile was removed from the solution by evaporation under reduced pressure, after which extracted the residue with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilized, to obtain 0.84 g of the title compound as a pale yellow powder, melting at 65 ° C to 66 ° C. C.

EXAMPLE 93 1- [4- (1, 2-dithiolan-3-yl) butylcarbamoyl] -indoline-2-carboxylic acid methyl ester (Compound No. 1-2676 methyl ester) The reaction was carried out as described in example 44, but using 1.00 g of D, L-α-lipoic acid, 25 ml of anhydrous toluene, 0.73 ml of triethylamine, 1.14 ml of diphenylphosphoryl azide and 0.94 g of indolinium. 2-methyl carboxylate. The reaction solution was washed with water, and the toluene layer was separated and washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Toluene was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using mixtures of 1: 2, 1: 1 and 2: 1 by volume of ethyl acetate and hexane as the eluent. The solvent was removed from the product eluted by evaporation under reduced pressure, and the residue was recrystallized from ethyl acetate, to obtain 485 mg of the title compound as yellow crystals, melting at 86 ° C to 89 ° C.

EXAMPLE 94 1- [4- (1, 2-Dithiolan-3-yl) butylcarbamoyl] indoline-2-carboxylic acid (Compound No. 1-2676) The reaction was carried out as described in Example 48, but using 200 mg of methyl 1- [4- (1, 2-dithiolan-3-yl) butylcarbamoyl] indoline-2-carboxylate (prepared as described in Example 1). Example 93), 4 ml of methanol, 2 ml of tetrahydrofuran and 1.0 ml of a 1 N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2N aqueous hydrochloric acid and extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilized, to obtain 98 mg of the title compound as a pale yellow amorphous substance having an Rf value of 0.12. (silica gel thin layer chromatography, using a 2: 1 by volume mixture of ethyl acetate and hexane as developer solvent).

EXAMPLE 95 3- [3- (1, 2-dithiolan-3-yl) propionylamino] methyl propionate ml of anhydrous tetrahydrofuran was added to 6 ml of a mixture of 2.5 mmole of 3- (1, 2-dithiolan-3-yl) propionic acid in a mixture of ethyl acetate and dimethylformamide. 0.6 ml of triethylamine, 349 mg of β-alanine methyl ester hydrochloride and 0.38 ml of diethyl cyanophosphate were added to the reaction solution, while cooling with ice, and the resulting mixture was stirred, while cooling with ice, for 1 hour. At the end of this time, the reaction mixture was stirred at room temperature for 30 minutes, and then the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using mixtures of 2: 1, 3: 1 and 1: 0 by volume of ethyl acetate. and hexane as the eluent. The residue was then subjected to reverse phase preparative silica gel column chromatography, using a mixture of 2: 3 by volume of acetonitrile and water as eluent, and the acetonitrile was removed from the solution by evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilized, to obtain 229 mg of the title compound as a yellow oil having an Rf value of 0.24 (chromatography thin-layer silica gel; using a 3: 1 by volume mixture of ethyl acetate and hexane as developer solvent).

EXAMPLE 96 l, 2-dithiolan-4-carboxylic acid 40 ml of 5 N aqueous hydrochloric acid was added to 20 ml of a solution of 3.60 g of methyl (1,2-diacetylthio) propyl-2-carboxylate in methanol, and the mixture was heated under reflux for 5 hours and 30 minutes. minutes At the end of this time, the reaction mixture was allowed to stand at room temperature overnight, and then the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extraction solution was washed with dilute aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution, after which it was dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure., and 150 ml of saturated aqueous sodium bicarbonate solution and a catalytic amount of ferric chloride 6 hydrate were added to the residue, and then the mixture was stirred at room temperature for 8 hours. The reaction mixture was then allowed to stand at room temperature overnight, after which the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the resulting mixture was washed with ethyl acetate. The pH of the aqueous layer was adjusted to a value of 2 by the addition of aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate, the extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried on anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilized, to obtain 0.25 g of the title compound as yellow crystals having an Rf value of 0.56 ( thin layer of silica gel; using a mixture of 5: 1 by volume of ethyl acetate and methanol as the developing solvent).

EXAMPLE 97 l, methyl 2-dithiolan-4-ylcarbonylaminoacetate ml of anhydrous tetrahydrofuran, 1.01 ml of triethylamine and 398 mg of glycine methyl ester hydrochloride were added to 5 ml of a solution of 3.3 mmoles of 1,2-dithiolan-4-carboxylic acid (prepared as described in the example 96) in anhydrous dimethylformamide, and then added 0. 55 ml of diethyl cyanophosphate to the resulting mixture, while cooling with ice, after which the mixture was stirred at room temperature for 5 hours. At the end of this time, the reaction mixture was allowed to stand at room temperature overnight, after which the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a mixture of 2: 1 by volume of ethyl acetate and hexane as the eluent. The solvent was then removed from the eluted solution by evaporation under reduced pressure, and the residue was recrystallized from a mixture of 1: 2 by volume of ethyl acetate and hexane, to obtain 54 mg of the title compound as pale yellow crystals. , melting at 73 ° C to 75 ° C.

EXAMPLE 98 3- (1, 2-dithiolan-4-ylcarbonyl) aminopropionate methyl The reaction was carried out as described in example 97, but using 5 ml of a solution of 3.3 mmol of 1,2-dithiolan-4-carboxylic acid (prepared as described in example 96) in anhydrous dimethylformamide, ml of anhydrous tetrahydrofuran, 1.01 ml of triethylamine, 502 mg of ß-alanine methyl ester hydrochloride and 0.55 ml of diethyl cyanophosphate. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a mixture of 2: 1 by volume of ethyl acetate and hexane as the eluent. The solvent was removed from the eluted solution by evaporation under reduced pressure, and the residue was recrystallized from a mixture of 2: 1 by volume of ethyl acetate and hexane, to obtain 73 mg of the title compound as pale yellow crystals which had a Rf value of 0.41 (silica gel thin layer chromatography, using a 2: 1 volume mixture of ethyl acetate and hexane as a developing solvent).

EXAMPLE 99 C-Chloro-N- [5- (1, 2-dithiolan-3-yl) pentyl] methanesulfonamide (Compound No. 1-2473) The reaction was carried out as described in example 60, but using 3 ml of a solution of 1.6 mmoles of 2- [5- (1,2-dithiolan-3-yl) pentyl] isoindoline-1,3-dione (prepared as described in example 58) in toluene, 2 ml of methanol, 2 ml of butylamine, 5 ml of anhydrous tetrahydrofuran, 0.33 ml of triethylamine and 0.21 ml of chloromethanesulfonyl chloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using mixtures of 2: 5 and 2: 3 by volume of ethyl acetate and hexane as the eluent. The ethyl acetate was removed from the eluted solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilized, to obtain 42 mg of the title compound as a brown oil having an Rf value of 0.29 (chromatography thin layer silica gel; using a 2: 5 volume mixture of ethyl acetate and hexane as developer solvent).

EXAMPLE 100 N- [5- (1, 2-dithiolan-3-yl) pentyl] benzamide (Compound No. 1-1923) 2 ml of methanol and 2 ml of butylamine were added to 3 ml of a 1.6-mmol solution of 2- [5- (1,2-dithiolan-3-yl) pentyl] -isoindolin-1,3-dione (prepared as described in Example 58) in toluene, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then allowed to stand at room temperature for 2 days, after which the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and 5 ml of anhydrous tetrahydrofuran, 0.33 ml of triethylamine and 0.28 ml of benzoyl chloride were added to the residue. The mixture was then stirred at room temperature for 6 hours. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography; using mixtures of 1: 8 and 1: 4 and 1: 2 by volume of ethyl acetate and hexane as the eluent. The residue was then subjected to reverse phase preparative silica gel column chromatography, using mixtures of 2: 3 and 1: 1 by volume of acetonitrile and water as eluent, and the acetonitrile was removed from the solution by evaporation under reduced pressure. , after which the residue was then extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilized, to obtain 56 mg of the title compound as a yellow amorphous substance, melting at 58 ° C to 59 °. C.

EXAMPLE 101 N- [5- (1, 2-dithiolan-3-yl) pentyl] nicotidamine (Compound No. 1-1991) The reaction was carried out as described in example 100, but using 3 ml of a 1.6 mmol solution of 2- [5- (1,2-dithiolan-3-yl) pentyl] isoindoline-1,3-dione (prepared as described in example 58) in toluene, 2 ml of methanol, 2 ml of butylamine, 5 ml of anhydrous tetrahydrofuran, 0.33 ml of triethylamine and 427 mg of nicotinoyl chloride hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using mixtures of 3: 1 and 1: 0 by volume of ethyl acetate and hexane and a 20: 1 by volume mixture of ethyl acetate and methanol as the eluent. The solvent was removed from the product eluted by evaporation under reduced pressure and the residue was dissolved in dioxane and then lyophilized, to obtain 156 mg of the title compound as a yellow amorphous substance, melting at 41 ° C to 44 ° C.

EXAMPLE 102 N-Butyl-N '- [5- (1, 2-dithiolan-3-yl) pentyl] phthalamide (Compound No. 1-1936 N-butylamide (a) 4 ml of methanol and 4 ml of butylamine were added to 6 ml of a 3.0 mmole solution of 2- [5- (1,2-dithiolan-3-yl) pentyl] isoindoline-1,3-dione ( prepared as described in example 58) in toluene, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was allowed to stand at room temperature overnight, after which the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, to give a residue. (b) 584 mg of N, N'-carbonyldiimidazole was added to 5 ml of a solution of 770 mg of N-t-butoxycarbonyl thiazolidine in anhydrous dimethylformamide, and the mixture was stirred at room temperature for 3 hours. Then a solution of the residue prepared as described in step (a) above in 3 ml of anhydrous dimethylformamide was added to the reaction mixture, while cooling with ice, and the resulting mixture was stirred at room temperature for 5 hours and 30 minutes. minutes The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to reverse phase preparative silica gel column chromatography, using a mixture of 1: 1 by volume of acetonitrile and water as eluent. The acetonitrile was removed from the solution by evaporation under reduced pressure, and the precipitated insoluble components were collected by filtration to obtain 118 mg of the title compound as a white powder having an Rf value of 0.44 (gel thin layer chromatography). silica; using a 1: 1 mixture by volume of ethyl acetate and hexane as developer solvent).

EXAMPLE 103 N- [4- (1, 2-Dithiolan-3-yl) butyl] -N '- (2-hydroxy-1-methylethyl) urea (Compound No. 1-2667) The reaction was carried out as described in example 46, but using 1.00 mg of D, L-α-lipoic acid, 25 ml of anhydrous toluene, 0.74 ml of triethylamine, 1.15 ml of diphenylphosphoryl azide and 0.39 ml of D, L-alaninol. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by distillation evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using mixtures of 40: 1 and 20: 1 by volume of ethyl acetate and ethanol as the eluent. The solvent was removed from the product eluted by evaporation under reduced pressure, and the residue was recrystallized from methanol to obtain 0.63 g of the title compound as yellow crystals, melting at 87 ° C to 89 ° C.

EXAMPLE 104 6- (1, 2-Dithiolan-3-yl) hexanoic acid (Compound No. 1-1467) ml of water and 60 ml of aqueous hydrochloric acid were added to 7.16 g of 6- (2-oxo-l, 3-dithian-4-yl) hexanenitrile, and the mixture was heated under reflux for 5 hours. The reaction mixture was then allowed to stand at room temperature overnight, after which it was heated under reflux for 2 hours and 30 minutes. The solvent was removed after the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and 150 ml of a 1 N aqueous solution of sodium hydroxide, 40 ml of 2 N aqueous hydrochloric acid and 10 drops of an aqueous solution were added. 1% w / v ferric chloride to the residue. The mixture was then stirred at room temperature for 2 hours and 30 minutes while air was blown through it. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was washed with ethyl acetate. The aqueous layer was neutralized by the addition of 2N aqueous hydrochloric acid, and ethyl acetate was added to the solution. The aqueous layer (a) and the ethyl acetate layer were separated after mixing. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and dried and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a mixture of 1: 1 by volume of ethyl acetate and hexane as the eluent. The solvent was removed from the product eluted by evaporation under reduced pressure, and the residue was dissolved in 40 ml of toluene. The ethyl acetate was evaporated from the ethyl acetate layer released from the above aqueous layer (a), and 90 ml of a 1N aqueous solution of sodium hydroxide, 17 ml of 2 N aqueous hydrochloric acid and 5 drops of a 1% w / v aqueous solution of ferric chloride were added to the residue, and then the mixture was stirred at room temperature for 1 hour while blowing air through the mixture. The reaction mixture was allowed to stand at room temperature overnight, and the solvent was removed from the reaction mixture by evaporation under reduced pressure, water was added to the residue and the mixture was washed with ethyl acetate. The aqueous layer was neutralized by the addition of 2N aqueous hydrochloric acid and extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The extraction solution was combined with the aforementioned toluene solution, and the solvent was removed from the solution by evaporation under reduced pressure. The residue was subjected to reverse phase preparative silica gel column chromatography, using mixtures of 2: 3 and 1: 1 by volume of acetonitrile and water as eluent, and acetonitrile was removed from the solution by evaporation under reduced pressure, then of which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in 50 ml of toluene. The toluene was evaporated from 2 ml of the resulting toluene solution, and the residue was dissolved in dioxane and then lyophilized, to obtain 69 mg of the title compound as a yellow oil having an Rf value of 0.39 (layer chromatography). thin silica gel; using a 1: 1 mixture by volume of ethyl acetate and hexane as developer solvent).

EXAMPLE 105 Methyl 6- (1, 2-dithiolan-3-yl) hexanoylaminoacetate (Compound No. 1-1347) The reaction was carried out as described in example 47, but using 5 ml of a solution of 1.6 mmole of 6-6- (1,2-dithiolan-3-yl) hexanoic acid (prepared as described in example 104 ) in toluene, 7 ml of anhydrous dimethylformamide, 373 mg of N, N'-carbonyldiimidazole, 0.25 ml of triethylamine and 199 mg of glycine methyl ester hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using mixtures of 2: 1 and 3: 1 by volume of ethyl acetate and hexane as the eluent The residue was subjected to reverse phase preparative silica gel column chromatography, using mixtures of 2: 3 and 1: 1 by volume of acetonitrile and water as eluent, and the acetonitrile was removed from the solution by evaporation under reduced pressure, then of which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilized, to give 61 mg of the title compound as a pale yellow amorphous substance, having a Rf value of 0.28 (silica gel thin layer chromatography, using a 2: 1 by volume mixture of ethyl acetate and hexane as developer solvent).

EXAMPLE 106 2 (S) -. { N- [5- (1,2-dithiolan-3-yl) pentanoyl] -N-methylamino} Methyl Propionate (Compound No. 1-1224) The reaction was carried out as described in example 47, but using 500 mg of D, L-Á-lipoic acid, 13 ml of anhydrous dimethylformamide, 422 mg of N, N'-carbonyldiimidazole, 0.36 ml of triethylamine and 399 mg of N-methyl-L-alanine methyl ester hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography; using mixtures of 3: 1 and 1: 0 by volume of ethyl acetate and hexane as the eluent. The solvent was evaporated from the eluted product and the residue was dissolved in dioxane and then lyophilized, to obtain 374 mg of the title compound as a yellow oil having an Rf value of 0.29 (silica gel thin layer chromatography; ethyl acetate as a revealing solvent).

EXAMPLE 107 N- [6- (1, 2-dithiolan-3-yl) hexanoyl] methanesulfonamide (Compound No. 1-1796) 6 ml of anhydrous dimethylformamide and 276 mg of N, N'-carbonyldiimidazole were added to 10 ml of a solution of 1.5 mmoles of 6- (1,2-dithiolan-3-yl) hexanoic acid (prepared as described in the example 104) in toluene and the mixture was stirred at room temperature for 4 hours and 30 minutes. Then 162 mg of methanesulfonamide and 74 mg of sodium hydride (as a 55% w / w dispersion in mineral oil) were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then allowed to stand at room temperature overnight and the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue and the mixture was washed with ethyl acetate and neutralized by the addition of 2 N aqueous hydrochloric acid., after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a mixture of 2: 1 by volume of ethyl acetate and hexane as the eluent. The solvent was evaporated from the eluted product, and the residue was subjected freshly to silica gel column chromatography, using 2: 3 and 3: 2 by volume mixtures of ethyl acetate and hexane as the eluent. The solvent was removed from the product eluted by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilized, to obtain 98 mg of the title compound as a yellow oil having an Rf value of 0.37 (thin layer chromatography). silica gel; using a 3: 2 volume mixture of ethyl acetate and hexane as developer solvent).

EXAMPLE 108 3- [5- (1, 2-dithiolan-3-yl) pentyl] ureidoacetate methyl (Compound No. 1-2039) The reaction was carried out as described in example 46, but using 10 ml of a solution of 1.5 mmol of 6- (1,2-dithiolan-3-yl) hexanoic acid (prepared as described in example 104) in toluene, 6 ml of anhydrous toluene, 0.42 ml of triethylamine, 0.39 ml of diphenylphosphoryl azide, 6 ml of anhydrous dimethylformamide and 254 mg of glycine methyl ester hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using pisces of 1: 4 and 3: 2 by volume of ethyl acetate and hexane as the eluent The solvent was removed from the product eluted by evaporation under reduced pressure, and the residue was dissolved in hexane and then lyophilized, to obtain 16 mg of the title compound as yellow crystals having an Rf value of 0.62 (thin layer chromatography of silica gel, using a 2: 3 volume mixture of ethyl acetate and hexane as developer solvent).

EXAMPLE 109 Ethyl 3- [4- (1, 2-dithiolan-3-yl) butyl] -l-methylureidoacetate (Compound No. 1-820 ethyl ester) The reaction was carried out as described in example 46, but using 500 mg of D, L-Á-lipoic acid, 10 ml of anhydrous toluene, 0.73 ml of triethylamine, 0.56 ml of diphenylphosphoryl azide, 10 ml of anhydrous tetrahydrofuran and 399 mg of ethyl ester hydrochloride d sarcosine. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using mixtures of 2: 1 and 1: 0 by volume of ethyl acetate and hexane as the eluent The residue was then subjected to reverse phase preparative silica gel column chromatography, using mixtures of 7:13 and 2: 3 by volume of acetonitrile and water as eluent, and the acetonitrile was removed from the solution by evaporation under reduced pressure. , after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilized, to obtain 194 mg of the title compound as a pale yellow amorphous substance having an Rf value of 0.43. (thin layer chromatography of silica gel, using ethyl acetate as the developing solvent).

EXAMPLE 110 3- [4- (1, 2-Dithiolan-3-yl) butyl] -1,5 (S) dimethylimidazolidino-2,4-dione (Compound No. 1-2682) The reaction was carried out as described in Example 46, but using 500 mg of D, L-Á-lipoic acid, 10 ml of anhydrous toluene, 0.73 ml of triethylamine, 0.56 ml of diphenylphosphoryl azide, 5 ml of anhydrous tetrahydrofuran. , 5 ml of anhydrous dimethylformamide and 399 mg of N-methyl-L-alanine methyl ester hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using mixtures of 3: 2 and 1: 1 by volume of ethyl acetate and hexane as the eluent. The residue was then subjected to silica gel column chromatography, using mixtures of 2: 3 and 1: 1 by volume of acetonitrile and water as eluent, and acetonitrile was removed from the solution by evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilized, to obtain 283 mg of the title compound as a yellow oil having an Rf value of 0.29 (chromatography thin-film silica gel; using a 3: 2 volume mixture of ethyl acetate and hexane as developer solvent).

EXAMPLE 111 4-. { 3- [4- (1, 2-dithiolan-3-yl) butyl] -1-methylureido} methyl butanoate (Compound No. 1-2670 methyl ester) The reaction was carried out as described in example 46, but using 500 mg of D, L-α-lipoic acid, 10 ml of anhydrous toluene, 0.73 ml of triethylamine, 0.56 ml of diphenylphosphoryl azide, 5 ml of anhydrous dimethylformamide and 477 mg of methyl 4- (methylamino) butanoate hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using mixtures of 1: 0 and 20: vol volume of ethyl acetate and methanol as the eluent . The solvent was removed from the product eluted by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilized, to obtain 589 mg of the title compound as a pale yellow amorphous substance having an Rf value of 0.47. thin layer of silica gel, using a mixture of 20: 1 by volume of ethyl acetate and methanol as developer solvent).

EXAMPLE 112 N- [6- (1, 2-dithiolan-3-yl) hexanoyl] sulfamide (Compound No. 1-1839) The reaction was carried out as described in example 107, but using 5 ml of a solution of 1.6 mmol of 6- (1,2-dithiolan-yl) hexanoic acid (prepared as described in example 104) in toluene , 7 ml of dimethylformamide, 308 mg of N, N'-carbonyldiimidazole, 365 mg of sulfamide and 83 mg of sodium hydride (as a 55% w / w dispersion in mineral oil)). The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using mixtures of 3: 2 and 2: 1 by volume of ethyl acetate and hexane as the eluent The solvent was removed from the product eluted by evaporation under reduced pressure, and the residue was recrystallized from a mixture of 1: 2 by volume of ethyl acetate and hexane, to obtain 92 mg of the title compound as pale yellow crystals, melting at 130 ° C to 132 ° C.

EXAMPLE 113 N-. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureidoacetyl} methanesulfonamide (Compound No. 1-2643) The reaction was carried out as described in example 73, but using 201 mg of methyl 3- [4- (1, 2-dithiolan-3-yl) butyl] ureidoacetate (prepared as described in example 46) , 4 ml of anhydrous dimethylformamide, 129 mg of N, N'-carbonyldiimidazole, 76 mg of methanesulfonamide and 35 mg of sodium hydride (as a 55% w / w dispersion in mineral oil). The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from methanol, to obtain 150 mg of the title compound as white crystals, melting at 157 ° C at 158 ° C.

EXAMPLE 114 N-. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureidoacetyl} Sulfonamide (Compound No. 1-2647) The reaction was carried out as described in example 73, but using 0.20 g of 3- [4- (1, 2-dithiolan-3-yl) butyl] ureidoacetic acid (prepared as described in Example 48), 4 ml of anhydrous dimethylformamide, 0.13 g of N, N'-carbonyldiimidazole, 0.15 g of sulfonamide and 0.04 g of sodium hydride (as a 55% w / w dispersion in mineral oil). The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of aqueous hydrochloric acid to 2 N, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from a mixture of methanol and ethyl acetate, to obtain 76 mg of the title compound as yellow crystals, melting at 143 ° C. at 145 ° C.

EXAMPLE 115 N- (2 (R) -. {3- [4- (1, 2-dithiolan-3-yl) butyl] ureido}. Propionylsulfonamide (Compound No. 1-2655) The reaction was carried out as described in Example 73, but using 0.21 g of 2 (R) - acid. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido} propionic (prepared as described in example 71), 5 ml of anhydrous dimethylformamide, 0.13 g of N, N'-carbonyldiimidazole, 0.15 g of sulafide and 0.04 g of sodium hydride (as a 55% dispersion w / w in mineral oil) . The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from ethyl acetate, to obtain 114 mg of the title compound as a pale yellow powder, melting at 156 ° C to 157 °. C.

EXAMPLE 116 N- (2 (S) - { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureidopropyl) methanesulfonamide (Compound No. 1-2655) The reaction was carried out as described in Example 73, but using 0.13 g of 2 (S) - acid. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido} propionic (prepared as described in example 52), 4 ml of anhydrous dimethylformamide, 0.08 g of N, N'-carbonyldiimidazole, 0.05 g of methanesulfonamide and 0.02 g of sodium hydride (as a 55% dispersion w / w in mineral oil) . The solvent was removed after the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from ethyl acetate, to obtain 80 mg of the title compound as a white powder, melting at 142 ° C at 147 ° C. .

EXAMPLE 117 Acid 4-. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido} butanoic (Compound No. 1-1276) The reaction was carried out as described in Example 48, but using 0.65 g of 4-. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido} methyl butanoate (prepared as described in example 75), 13 ml of methanol and 7.10 ml of a 1 N aqueous sodium hydroxide solution. The solvent was removed after the reaction mixture by evaporation under reduced pressure, and Water was added to the residue. The mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from ethyl acetate, to obtain 0.46 g of the title compound as a pale yellow powder, melting at 94 ° C to 99 ° C. C.

EXAMPLE 118 5- [5- (1, 2-dithiolan-3-yl) pentanoylamino] methyl pentanoate (Compound No. 1-2657 methyl ester) The reaction was carried out as described in example 47, but using 1.00 g of D acid, L-α-lipoic acid, 40 ml of anhydrous dimethylformamide, 0.86 g of N, N'-carbonyldiimidazole, 0.74 of triethylamine and 0.89 g of methyl 5-aminopentanoate hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using mixtures of 2: 1 and 1: 0 by volume of ethyl acetate and hexane as the eluent It was then recrystallized from ethyl acetate, to obtain 1.10 g of the title compound as pale yellow crystals, melting at 60 ° C. 62 ° C.

EXAMPLE 119 5-. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido} methyl pentanoate (Compound No. 1-2659 methyl ester example 46 anhydrous toluene, 1.48 ml of triethylamine, 1.15 ml of diphenylphosphoryl azide and 0.81 g of methyl 5-aminopentanoate hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a mixture of 2: 1 by volume of ethyl acetate and hexane, followed by mixing of 9: 1 by volume of ethyl acetate and ethanol, as the eluent, to obtain 1.27 g of the title compound as a pale yellow powder, melting at 90 ° C to 92 ° C.

EXAMPLE 120 5- [5- (1, 2-Dithiolan-3-yl) pentanoylamino] pentanoic acid (Compound No. 1-2657) Example 4 il) pentane? iammojpentanoate methyl (prepared as described in example 118), 13 ml methanol and 5.09 ml of an aqueous solution of sodium hydroxide. The solvent was removed after the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from ethyl acetate, to obtain 0.33 g of the title compound as pale yellowish green crystals, melting at 98 ° C to 100 ° C. C.

EXAMPLE 121 Acid 5 { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido} pentanoic (Compound No. 1-2659) The reaction was carried out as described in example 48, but using 0.30 g 5-. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido methylpentanoate (prepared as described in example 119), 10 ml of methanol and 3.14 ml of a 1 N aqueous solution of sodium hydroxide. sodium. The solvent was removed from the reaction mixture by evaporation under reduced pressure and water was added to the residue. The resulting mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from ethyl acetate, to obtain 0.23 g of the title compound as pale yellow crystals, melting at 125 ° C to 132 ° C. .

EXAMPLE 122 5- (1, 2-dithiolan-3-yl) -N- (2-hydroxyethyl) pentanamide (Compound No. 1-2661) 0. 86 g of N, N'-carbonyldiimidazole were added to 20 ml of a solution of 1.00 g of D, L-α-lipoic acid in anhydrous dimethylformamide, and the mixture was stirred at room temperature for 1 hour and 20 minutes. Then 0.32 ml of 2-aminoethanol was added to the reaction solution, and the resizing mixture was stirred at room temperature for 4 hours and 10 minutes. The solvent was removed from the reaction mixture by evaporation under reduced pressure and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a mixture of 19: 1 by volume of ethyl acetate and ethanol as the eluent. The solvent was removed from the product eluted by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilized, to obtain 0.71 g of the title compound as a yellow amorphous substance having an Rf value of 0.38 (layer chromatography). thin silica gel; using a 19: 1 by volume mixture of ethyl acetate and ethanol as a developing solvent).

EXAMPLE 123 5- (1,2-dithiolan-3-yl) -N- (2-hydroxy-1-methylethyl) pentanamide (Compound No. 1-2665) The reaction was carried out as described in example 122, but using 1.00 g of D, L-α-lipoic acid, 20 ml of anhydrous dimethylformamide, 0.86 g of N, N'-carbonyldiimidazole and 0.42 ml of anhydrous acid. D, L-alaninol. The solvent was removed from the reaction mixture by evaporation under reduced pressure and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using ethyl acetate as the eluent. The solvent was removed from the product eluted by evaporation under reduced pressure, and the residue was dissolved in dioxane and lyophilized, to obtain 0.39 g of the title compound as a yellow amorphous substance, melting at 52 ° C to 56 ° C.

EXAMPLE 124 N- [4- (1,2-Dithiolan-3-yl) butyl] -N'- (2-hydroxyethyl) urea (Compound No. 1-2663) The reaction was carried out as described in example 46, but using 1.00 g of D, L-Á-lipoic acid, 20 ml of anhydrous toluene, 0.74 ml of triethylamine, 1.15 ml of diphenylphosphoryl azide and 0.29 ml of 2- hydroxy-l-ethylamine. The solvent was removed from the reaction mixture by evaporation under reduced pressure and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using mixtures of 39: 1 and 19: 1 by volume of ethyl acetate and ethanol as the eluent The solvent was removed from the product eluted by evaporation under reduced pressure, and the residue was recrystallized from methanol to obtain 352 mg of the title compound as yellow crystals, melting at 50 ° C to 65 ° C.

EXAMPLE 125 N- [5- (1, 2-dithiolan-3-yl) pentanoyl] -N-methylmethanesulfonamide (Compound No. 1-2672) 40 mg of copper chloride was added to 20 ml of a solution of 1.36 g of dicyclohexylcarbodiimide in anhydrous methanol, and the mixture was allowed to stand at room temperature for 1.5 hours. The solvent was then removed from the mixture by distillation under reduced pressure. Then 20 ml of anhydrous dimethylformamide and 1.00 g of N- [5- (1, 2-dithiolan-3-yl) pentanoyl were added} methanesulfonamide (prepared as described in example 2) to the residue, and the mixture was stirred at 70 ° C in an oil bath for 1 hour. The mixture was then allowed to stand at room temperature overnight, after which it was stirred at 70 ° C in an oil bath for 1 hour, and the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The insoluble material of the extract was removed by filtration, and the filtrate was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate was removed from the solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using mixtures of 2: 3 and 1: 1 by volume of ethyl acetate and hexane as the eluent. The solvent was removed from the product eluted by evaporation under reduced pressure, and the residue was subjected to reverse phase preparative silica gel column chromatography, using 1: 1 and 3: 2 by volume mixtures of acetonitrile and water as eluent, and the acetonitrile was removed from the solution by evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilized, to obtain 660 mg of the title compound as a pale yellow amorphous substance having an Rf value of 0.27. (silica gel thin layer chromatography, using a 2: 3 volume mixture of ethyl acetate and hexane as developer solvent).

EXAMPLE 126 Allyl N- [4- (l, 2-dithiolan-3-yl) butyl] carbamate The reaction was carried out as described in Example 31, but using 1.00 g of D, L-Á-lipoic acid, 10 ml of anhydrous toluene, 0.73 ml of triethylamine, 1.14 ml of diphenylphosphoryl azide and 2 ml of allyl alcohol . The reaction mixture was washed with water, the water layer was washed with ethyl acetate, and the ethyl acetate baths were combined with the aforementioned toluene solution.The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed from the extract by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1: 4 and 1: 2 by volume mixtures of ethyl acetate and hexane as the eluent. The solvent was removed from the product eluted by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilized, to obtain 944 mg of the title compound as an oily yellow substance having an Rf value of 0.49 (layer chromatography). thin silica gel; using a 1: 2 by volume mixture of ethyl acetate and hexane as developer solvent). PREPARATION 1 5- (1,2-dithiolan-3-yl) pentanol 44 ml of a solution containing (trimethylsilyl) -diazomethane at 2.0 M was added dropwise, while cooling with ice, to a mixture of 15.00 g of D, L-α-lipoic acid in 15 ml of methanol and 150 ml of methanol. ml of toluene, and then the mixture was stirred at room temperature for 1 hour. Then 11 ml of a hexane solution containing (trimethylsilyl) diazomethane was added dropwise to the reaction mixture. The resulting mixture was stirred at room temperature for 2 hours. Then the reaction mixture was allowed to stand at room temperature for 2 days. The solvent was then removed from the reaction mixture by distillation under reduced pressure, to give ethyl 5- (1, 2-dithiolan-3-yl) pentanoate as a yellow oil. A solution of ethyl 5- (1, 2-dithiolan-3-yl) pentanoate in 40 ml of anhydrous tetrahydrofuran was added dropwise, while cooling with ice and sodium chloride, to a suspension of 3.34 g of sodium hydride. lithium-aluminum in 150 ml of anhydrous tetrahydrofuran. The resizing mixture was stirred at room temperature for 3 hours and 30 minutes. Then sodium sulfate decahydrate was added to the reaction mixture, while cooling with ice and sodium chloride, and then the mixture was stirred at room temperature for 3 hours. The reaction mixture was allowed to stand overnight at room temperature, and the insoluble material was filtered using a Celite filter aid (trade name). The solvent was removed from the filtrate by distillation under reduced pressure. 50 ml of methanol, 25 ml of a 1N aqueous solution of sodium hydroxide and 10 ml of 2N aqueous hydrochloric acid were added to the residue. Then air was blown into the resulting mixture. Five drops of a 1% aqueous solution of ferric chloride were added dropwise to the reaction mixture, and then it was stirred at room temperature for one hour. The reaction mixture was allowed to stand overnight at room temperature, and the solvent was removed by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, using mixtures of 1: 2 and 1: 1 by volume of ethyl acetate and hexane as eluent. The solvent was removed from the resulting eluate by distillation under reduced pressure, and 30 ml of toluene was added to the residue. 1 ml of the resulting solution was taken, and the solvent was removed by distillation under reduced pressure, to give 0.13 g of the title compound as a yellow oil having an Rf value of 0.39 (thin-layer gel chromatography). silica, using a 1: 1 mixture by volume of ethyl acetate and hexane as the eluent).

Claims (28)

NOVELTY OF THE INVENTION CLAIMS

1. - Compounds of the formula (I | where one of m and n represents 0, and the other represents 0, l or 2; k represents 0 or an integer from 1 to 12; R 1 represents: a hydrogen atom, a selected group of substituents A, defined below, or an alkyl group having 1 to 12 carbon atoms which is unsubstituted or which is substituted by 1 to 3 substituents selected from the group which consists of substituents A and the substituents Ó or a substituted or unsubstituted alkyl group in which the carbon chain is interrupted by an oxygen atom and / or a sulfur atom; A represents a single bond, an oxygen atom, a carbonyl group or a group of formula -N (R2) CO-, -N (R2) C, -N (R2) S02-, -CON (R2) N (R3 ) CO-, -CON (R2) CO-, -CON (R2) CS-, CON (R2) S02-, -O-CO-, -ON (R2) CO-, -ON (R2) CO-, - ON (R2) S02-, -0-CON (R2) N (R3) CO-, -O-CON (R2) C0-, -O-CON (R2) S02-, -CO-O-, -CO- CO- -CO-CON (R2) N (R3) CO-, -CO-CON (R2) CO-, -CO-CON (R2) S02-, N (R2) 0-, -N (R2) COCO-, -N (R2) N (R3) CO-, -N (R2) N (R3) S02 N (R2) CON (R3) N (R4) CO -, -N (R2) CON (R3) CO-, -N (R2) CON (R3) S02, OR -N (R2) CON (R3) S02N (R4) CO- wherein R2, R3 and R4 are the same or different and each represents a hydrogen atom, an alkyl group having from 1 to 12 carbon atoms, an aralkyl group, an aralkyl group whose aryl portion is substituted with 1 to 3 groups selected from the group consisting of the group of β-substituents, an acyl group or a group selected from the group consisting of substituents A; B represents a single bond, or a group of the formula -N (R ^) - or N (R ^) N (R ^) -, where R ^ and R ^ are the same or different and each represents an atom of hydrogen, an alkyl group having from 1 to 12 carbon atoms, an aralkyl group, an aralkyl group whose aryl portion is substituted with 1 to 3 groups selected from the group consisting of the group of substituents β, an acyl group or a group selected from the group consisting of substituents Á or, wherein A represents a group of the formula -N (R2) C0-, -N (R2) CS-, -CON (R2) (R3) CO-, -CON (R2 ) CO-, -CON (R2) CO-, -C0N (R2) CS-, -O-CO-, -ON (R2) CO-, -O-CON (R2) N (R3) C0- -0- CON (R2) CO-, -CO-CON (R2) N (R3) CO-, -CO-CON (R2) CO-, N (R2) N (R3) CO-, -N (R2) CON (R3) N (R4) CO- or -N (R2) CON (R3) CO- [where R2, R3 and R4 are as defined before] and B represents a single bond, R- ^ can represent a group of the formula -OR ^ (wherein R7 represents a lower alkyl group, a lower alkenyl group, or aralkyl group, an aralkyl group whose aryl portion is substituted with 1 to 3 groups selected from the group consisting of the group of substituents β, an acyl group or a group selected from the group consisting of substituents A); or, where A represents a group of the formula -CON (R2) S02-, -ON (R2) S02-, -O-CON (R2) S02-, -CO-CO-, -CO-CON (R2) S0 -, N (R2) COCO-, -N (R2) N (R3) S02 or -N (R2) CON (R3) S0 [where R2 and R3 are as defined above] and B represents a single bond, or, where A does not represent an oxygen atom, a group of the formula -CO-O- or -N (R6) 0- and B represents -N (R5) - [where R ^ is as defined above] , R1 may represent a hydroxyl group or a group of the formula -OR7 (wherein R7 is as defined above); Substituents A are selected from the group consisting of aryl groups, heterocyclic groups, aryl groups substituted with 1 to 3 of the β substituents, and substituted heterocyclic groups of 1 to 3 of the β substituents; The β substituents are selected from the group consisting of lower alkyl groups, halogenated lower alkyl groups, lower alkoxy groups, lower alkylthio groups, hydroxyl groups, carboxyl groups, carbamoyl groups whose nitrogen atom can be substituted, lower alkoxycarbonyl groups, halogen atoms , nitro groups, amine residues, sulfo groups, sulfamoyl groups, cyano groups, hydroxyl-substituted lower alkyl groups; The substituents O are selected from the group consisting of lower alkoxy groups, lower alkylthio groups, hydroxyl groups, carboxyl groups, lower alkoxycarbonyl groups, halogen atoms, sulfo groups, sulfamoyl groups, amine residues, carbamoyl groups whose nitrogen atom can be replaced; ALWAYS WHERE: where A represents an oxygen atom, B represents a single bond or a group of the formula -N (R5) - [where R ^ is as defined above], where A represents a group of the formula -CO-O- or -N (R2) 0- [wherein R2 is as defined above], B represents a single bond, and where k represents 4, the group of the formula -ABR ^ does not represent a carboxyl group and pharmaceutically acceptable salts thereof.

2. A compound in accordance with the claim 1, represented by the formula (I '): (in which A, B, R1, k, m and n_ are as defined in claim 1) and sais thereof.

3. A compound according to claim 1 or claim 2, wherein one of m and n is 0, and the other is 0 or 1.

4. A compound according to any of claims 1 to 3, in which k is 0 or an integer from 1 to 8.

5. A compound according to any of claims 1 to 4, wherein R ^ represents a heterocyclic group, an alkyl group having from 1 to 12 carbon atoms. carbon that is unsubstituted or is substituted by 1 to 3 substituents A and substituents Ó or said substituted or unsubstituted alkyl group in which the alkyl chain is interrupted by an oxygen atom and / or sulfur atom.

6. A compound according to any of claims 1 to 4, wherein R ^ - represents a hydroxyl group or an alkoxy group having from 1 to 5 carbon atoms.

7. A compound according to any of claims 1 to 6, wherein A represents a group of the formula -CO-, -C0N (R2) S02-, -N (R2) CO-, -N (R2 ) CS-, -CON (R2) CO-, -N (R2) COCO- or -N (R2) S02- wherein R2 represents a hydrogen atom, an alkyl group having from 1 to 12 carbon atoms or a benzyl group.

8. - A compound according to any of claims 1 to 7, wherein B represents a single bond or a group of the formula -N (R ^) - or -N (R5) N (R6) -, wherein R5 and R > they are the same or different and each is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms or a benzyl group.

9. A compound according to claim 1 or claim 2, wherein: one of m and n is 0, and the other is 0 or 1; k is 0 or an integer from 1 to 8; R ^ represents a heterocyclic group, an alkoxy group having from 1 to 5 carbon atoms, an alkyl group having from 1 to 12 carbon atoms which is unsubstituted or is substituted by 1 to 3 substituents O and / or substituents E or said substituted or unsubstituted alkyl group in which the alkyl chain is interrupted by an oxygen atom and / or sulfur atom; A represents a group of the formula -CO-, -C0N (R2) S0-, -N (R2) CO-, -N (R2) CS-, -CON (R2) CO-, -N (R2) C0C0- or -N (R2) S02- wherein R2 is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms or a benzyl group; B represents a single enlce, or a group of the formula -N (R ^) - or -N (R ^) N (R ^) - where R5 and R ^ are the same or different and each is an atom of hydrogen, an alkyl group having 1 to 12 carbon atoms or a benzyl group.

10. A compound according to claim 1 or claim 2, wherein m and n are 0.

11. A compound according to any of claims 1, 2 and 10, wherein k is an integer of 2. to 6.

12. A compound according to any of claims 1, 2, 10 and 11, in which R1 represents an alkyl group having from 1 to 5 carbon atoms, an alkoxycarbonylalkyl group having from 3 to 8 carbon atoms, a carboxyalkyl group having from 2 to 7 carbon atoms, a hydroxyalkyl group having from 2 to 5 carbon atoms, a heterocyclic group, an alkoxy group having from 1 to 5 carbon atoms or a hydroxyl group .

13. A compound according to any of claims 1, 2 and 10 to 12, wherein A represents a group of the formula -CO-, -C0N (R2) S02-, -N (R2) C0-, -N (R2) CS-, -CON (R2) CO-, -N (R2) C0C0- or -N (R2) S02- wherein R2 is a hydrogen atom or an alkyl group having 1 to 12 atoms of carbon.

14. A compound according to any of claims 1, 2 and 10 to 13, in which B represents a single enlce, or a group of the formula -N (R ^) - or -N (R ^) N (R ^) - wherein R ^ and R ^ are the same or different and each is a hydrogen atom or an alkyl group having 1 to 12 carbon atoms.

15. A compound according to claim 1 or claim 2, wherein m and n are 0; k is an integer from 2 to 6; R ^ represents an alkyl group having from 1 to 5 carbon atoms, an alkoxycarbonylalkyl group having from 3 to 8 carbon atoms, a carboxyalkyl group having from 2 to 7 carbon atoms, a hydroxyalkyl group having from 2 to 5 carbon atoms, a heterocyclic group, an alkoxy group having 1 to 5 carbon atoms or a hydroxyl group; A represents a group of the formula -CO-, -CON (R2) S02-, -N (R2) CO-, -N (R2) CS-, -CON (R2) CO-, -N (R2) COCO- or -N (R2) S0 - wherein R2 is a hydrogen atom or an alkyl group having 1 to 12 carbon atoms; B represents a single enlce, or a group of the formula -N (R5) -O-N (R5) (R) - wherein R ^ and R ^ are the same or different and each is a hydrogen atom or a alkyl group having from 1 to 12 carbon atoms.

16. A compound according to claim 1 or claim 2, wherein k is 4 or 5.

17. A compound according to any of claims 1, 2 and 16, wherein R- ^ represents an alkyl group having from 1 to 5 carbon atoms, an alkoxycarbonylalkyl group having from 3 to 8 carbon atoms, a carboxyalkyl group having from 2 to 7 carbon atoms, a hydroxyalkyl group having from 2 to 5 carbon atoms; carbon, a heterocyclic group or an alkoxy group having from 1 to 5 carbon atoms.

18. A compound according to any of claims 1, 2 and 16 to 17, wherein A represents a group of the formula C0NHS02-, -CONCH3S02-, -NHCO-, -NHCS-; -CONHCO-, -NHCO-, -NHCOCO-, -NHS0-, or -CO-.

19. A compound according to any of claims 1, 2 and 16 to 18, in which B represents a single enlce, or a group of the formula -NH-, -NCH3-0 -NHNCH3-.

20. A compound according to claim 1 or claim 2, wherein m and n are 0; k is 4 or 5; R ^ represents an alkyl group having from 1 to 5 carbon atoms, an alkoxycarbonylalkyl group having 3 to 8 carbon atoms, a carboxyalkyl group having from 2 to 7 carbon atoms, a hydroxyalkyl group having from 2 to 5 carbon atoms, a heterocyclic group or an alkoxy group having from 1 to 5 carbon atoms; A represents a group of the formula CONHS02-, -CONCH3S02-, -NHCO-, -NHCS-; -CONHCO-, - NHCO-, -NHCOCO-, -NHS0-, or -C0-; and B represents a single enlce, or a group of the formula -NH-, -NCH3- O -NHNCH3-.

21. N- [5- (1, 2-dithiolan-3-yl) pentanoyl] methanesulfonamide and pharmaceutically acceptable salts thereof.

22. Methyl 3- [4- (1, 2-dithiolan-3-yl) butyl] ureidoacetate and pharmaceutically acceptable salts thereof.

23.- Acid. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido} -acetic and pharmaceutically acceptable salts thereof.

24.- 2 (S) -. { 3- [4- (1, 2-dithiolan-3-yl) butyl] ureido} methylpropionate and pharmaceutically acceptable salts thereof.

25. 3- [4- (1, 2-dithiolan-3-yl) butyl] -l-methylureido-ethyl acetate and pharmaceutically acceptable salts thereof.

26.- N- [5- (1, 2-dithiolan-3-yl) pentyl] methanesulfonamide and pharmaceutically acceptable salts thereof.

27. The use of a compound according to any of claims 1 to 26, for the manufacture of a medicament for increasing the activity of glutathione reductase in a mammal.

28. The use of a compound according to any of claims 1 to 26, for the manufacture of a medicament for the treatment or prevention of cataracts in a mammal. SUMMARY OF THE INVENTION Compounds of the formula (I i where one of m and n is 0, and the other is 0, l or 2; __ k is 0 or an integer from 1 to 12; R1 is hydrogen, one of the substituents A, which is defined below, or optionally a substituted alkyl group; A represents a single bond, an oxygen atom, a carbonyl group or a group of formula -N (R) C0-, -N (R) C, -N (R2) S02-, -C0N (R2) N (R3 ) C0-, -CON (R2) CO-, -CON (R2) CS-, CON (R2) S02-, -O-CO-, -ON (R2) CO-, -ON (R2) CO-, - ON (R2) S02-, -0-CON (R2) N (R3) CO-, -O-CON (R2) C0-, -O-CON (R2) S02-, -CO-O-, -C0- C0- -CO-CON (R2) N (R3) CO-, -CO-CON (R2) CO-, -CO-CON (R2) S02-, N (R2) 0-, -N (R2) COCO- , -N (R2) N (R3) CO-, -N (R2) N (R3) S02 N (R2) CON (R3) N (R4) CO-, -N (R2) CON (R3) CO-, -N (R2) CON (R3) S02, or -N (R2) C0N (R3) S02N (R) C0-, wherein R2, R3 and R4 are the same or different and each is hydrogen, alkyl, aryl, aralkyl, acyl or one of substituents A; B is a single bond, or a group of the formula -N (R5) - or N (R6) N (R5) - wherein R5 and R6 are the same or different and each is hydrogen, alkyl, aryl, aralkyl, acyl or one of the substituents A, or R5 together with R ^ - and the nitrogen atom to which they are attached, can form a heterocyclic ring having from 5 to 7 ring atoms; or R ^ - may represent a group of the formula -OR7, wherein R7 is alkyl, alkenyl, aralkyl or one of substituents A; or R1 may represent a hydroxyl group or a group of the formula -OR7; and said substituents are selected from aryl groups and heterocyclic groups] and pharmaceutically acceptable salts thereof which have an excellent ability to increase the activity of glutathione reductase and therefore can be used for the treatment or prevention of a variety of diseases, including cataracts. JJ P98 / 323