DD287038A5 - benzodioxole - Google Patents

Abstract

The present invention relates to benzodioxole derivatives of the general formula which are suitable for the treatment of liver damage in humans and animals. Formula (I) {Benzodioxole derivatives; pharmacological; Salt; Activity; Drug; Treatment of liver damage; Human; Animal}

Description

(B)

and active compounds that are effective as a remedy in the treatment of liver damage, these compounds have been isolated from Petivella alllacea L and Clnnamonum porrectum (Rcxb.) Kotterm.

Thereafter, the authors of the present invention synthesized various compounds as the basic compounds using the above-mentioned compounds and examined the ρ · of their compounds for their pharmacological activity. As a result of the investigation, it has been found that benzodioxole derivatives represented by the general formula (I) or their pharmacologically acceptable salts are safer and more suitable as remedies for the control of liver damage. The present invention has been worked out on the basis of this finding.

The two subsequent patent publications disclose drugs against liver damage that differ in chemical structure from the benzodioxole derivatives of the present invention.

More specifically, the compounds described in Japanese Patent Laid-Open No. 29522/1987 each have a structure consisting of a benzodioxole ring and a saturated alkyl group bonded to the phenyl ring of the benzodioxole ring. and most of these compounds were already known.

Furthermore, Japanese Patent Laid-Open No. 3983/1987 (1,3-benzodioxol-5-yl) indicates methylthio derivatives. However, the group bonded to the S atom of these derivatives is a hsterocyclic group such as pyridine, pyrimidines or thiadiazole, so that the derivatives in the structure are clearly different from the compounds of the present invention.

As set forth above, the present invention has been accomplished on the basis of an indication taken from the compounds (A) and (B) developed by the authors of the present invention itself from plant components, and is thus different from the two Accordingly, the compounds of the present invention in the chemical structure are different from those of the above-mentioned two-part publications.

Object of the invention

The invention provides improved compounds for the treatment of liver damage in humans and animals.

Explanation of the essence of the invention

The invention relates to novel benzodioxole derivatives having the formula (I) and one of their pharmacologically acceptable salts

T .0

wherein T, U, V and W are each defined according to the corresponding six groups (a) to (f) below: (a) T is hydrogen, U is hydrogen, V is R ³ and W is the same

wherein R ¹ and R ^{2 may be the} same or different and each represents a hydrogen atom or an alkyl, arylalkyl or heteroarylalkyl group, R ^{3 represents} a hydrogen atom or a lower alkyl, arylalkyl or heteroarylalkyl group, R ^{4 represents} a hydrogen atom or a lower one R ² and R ^{3 may} together form an at least four-membered ring and X represents a group having the formula -S-,

-S- or -S-, O

with the proviso that R ^{1 is} an alkyl, arylalkyl or heteroarylalkyl group having at least 3 carbon atoms when X is an -S-group and R ³ and R ^{2 are} each a hydrogen atom; (b) T is hydrogen, U lsi is hydrogen, V is hydrogen and W ISt- (CHj) ₂ -XR wherein X represents a group having the formula:

g o

τ i

- S-, -S- or -S- and

R represents the following:

(1) a hydrogen atom or a lower alkyl group,

(2) a group having the formula - (CHj) _n -COOR ¹ , in which η is an integer between 1 and 5 and R ^{1 is} a hydrogen atom or a lower alkyl group,

(3) a group of the formula - (CH ₂ J _n -OR ² in which η is an integer between 1 and 5 and R ^{2 is} a hydrogen atom, a lower alkyl group or an acyl group,

R ³

(4) a group with the formula "fmr \ _COU / in which η represents a canze number between 1 and 5 and

R ³ and R ⁴ , which may be the same or different, each represents a hydrogen atom, a lower alkyl or carboxymethyl group,

(5) a group of the formula - (CHp) -N. »In which η represents an integer between 1 and 5 and

R ⁶ and R *, which may be the same or different, each represents a hydrogen atom or a lower alkyl group,

'7

(6) a group of the formula - (CH 3) -CH-COOR. in which η represents an integer between 1 and 5, and

R ^{7 represents} a hydrogen atom or a lower alkyl group,

(7) is a group of the formula shown above under item (2), but wherein one or more carbon atoms of the alkylene chain having η carbon atoms is bonded to a lower alkyl group or a group having the formula -COOR *, in which R ^{8 is} a hydrogen atom or a lower alkyl group instead of the hydrogen atom,

(8) a group having the formula as shown in item (3) above, but wherein one or more carbon atoms of the alkylene chain having η carbon atoms are bonded to a hydroxyl group in place of the hydrogen atom, or

(9) a group with the formula

in which η is an integer between 1 and 5 and rri is an integer 3 or 4, provided that a lower alkyl group can not be a methyl group when X represents a group of the formula -S- and R represents a lower alkyl group is; (c) T is hydrogen, U is hydrogen, V is R ¹ and W is

R ² s CH-CH-C00R ^r

wherein R 'represents a hydrogen atom or a lower alkyl or lower alkoxy-lower alkyl group, R ^{2 represents} a hydrogen atom or a lower alkyl or lower alkoxy group, R ^{3 represents} a hydrogen atom or a lower alkyl group and R * represents a hydrogen atom or a lower alkyl group R ¹ and R ¹ or R ¹ and R ³ together form a five- to seven-membered ring, provided that R ', R ² and R ³ can not simultaneously be all hydrogen atoms; (d) T is R ⁴ , U is R ⁵ , V is R ³ and W is the same

-6- 237

/ CH ₂ -CXA

V \ 2

R ^K R ^ ι

wherein R ¹ and R ^{2 may be the} same or different and each represents a hydrogen atom or a lower alkyl group, R ^{3 represents} a hydrogen atom, a lower alkyl group or a group having the formula - (CH ₂ ) (T-COOH in which η is an integer between 1 and 3, R ⁴ and R ^{E may be the} same or different and each represents a hydrogen atom or a lower alkyl group, X is a group with the formol -S-,

O P

-S- or -S-J

where A represents a lower alkyl group, a group having the formula - (CH ₇ ) n '- Het in which n' represents an integer between 1 and 3 and Het represents a substituted or unsubstituted heterocyclic ring, a group containing Formula -C-COOH, a group with the formula CN

-C-COOH, R ^{6 /} V

in which R * and R ^{7 may be the} same or different and each represents a hydrogen atom or a lower alkyl group, a group having the formula -CH ₂ -CN, a group having the formula

-CH ₂ -Cf-R ", in which R ^{8 represents} a lower alkyl group, or a group of the formula

R ⁹

in which ρ is an integer between 1 and 3 and R ⁹ and R ^{10 may be the} same or different and each represents a lower alkyl group; each) T is hydrogen, U is hydrogen, V is hydrogen and W is

X-S-S-CH-CHj-Y

R ¹ '

wherein X is a group of the formula -CHR-, -CHj-CHt-, -CH ₂ -CH ₂ -CH ₂ or -CH ₂ -CH-, R ^{1 is} a hydrogen atom or

CH ₃

a lower alkyl group is Y is a hydrogen atom or an alkyl, hydroxyl, carboxyl, aryl or heteroarylcarbonyloxy group - '(f) T is hydrogen, U is hydrogen is VR ³ and W is the same

R ¹ R ^{2 N} C ^/

^(CH 2 ⁾ n " ^S " ^CH 2 " ^Y

wherein R 'and R ^{1 may be the} same or different and each represents a hydrogen atom or a lower alkyl, aryl or arylalkyl group; η represents an integer of 0 or 1; Y is a group with the formula -COOH or

PfYN P ^ "(wherein R ⁴ and R ^{6 may be the} same or different and each represents a hydrogen atom

or a lower alkyl or carboxymethyl group) and R ^{3 represents} a hydrogen atom or a lower alkyl or arylalkyl group.

In addition, the invention provides a process for the preparation of the benzodioxole derivatives shown above and a pharmaceutical composition containing dioxin in association with a pharmacologically acceptable carrier. The compound of the invention (I) consists of six compounds (I-a), (I-b), (I-c), (I-d), (I-e) and (If). Each group is defined below and corresponds to the six group definitions (a), (b), (c), (d), (e) and (f) of T, U, V and W of formula (I).

Connection group (l-a) The linking group (I-a) has the formula (I-a):

wherein R ¹ and R ^{2 may be the} same or different and each represents a hydrogen atom or an alkyl, arylalkyl or heteroarylalkyl group. R ³ represents a hydrogen atom or a lower alkyl, arylalkyl or heteroarylalkyl group, R ^{4 represents} a hydrogen atom or a lower alkyl group or R ² and R ³ together form an at least four membered ring and X represents a group having the formula

-S, -S- or -ö-

with the proviso that R ^{1 is} an alkyl, arylalkyl or heteroarylalkyl group having at least 3 carbon atoms when X is an -S group and R ³ and R ^{2 are} each a hydrogen atom. In the formula (Ia), the alkyl for R ¹ and R ² includes a straight or branched alkyl, such as methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, 1-methylpropy I, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl, n -hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. Preference is given to methyl, ethyl, n-propyl, isopropyl and n-butyl. The lower alkyl group for R ³ and R ⁴ includes straight or branched alkyl of 1 to 6 carbon atoms, such as methyl, ethyl, n -propyl, η-butyl, isopropyl, isobutyl, 1-methylpropyl, terbutyl, n-pentyl, 1 Ethylprcoyl, isoamyl and n-hexyl. Preference is given to methyl, ethyl and n-propyl. The arylalkyl for R ¹ , R ² and R ³ includes benzyl and phonoethyl. The heteroarylalkyl for these symbols includes a heterocyclic ring linked to an alkyl such as methyl, ethyl and propyl. The heteroaryl includes a five- or six-membered ring with nitrogen, such as pyridine, pyrimidine, pyrrole, pyrazole and imidazole, thiazole, oxazole and furan. A preferred heteroarylalkyl is pyridylmethyl, pyrimidylmethyl or furylmethyl, wherein the alkyl is attached to the heterocyclic ring at any position. R ² and R ³ may together form a four or more membered cyclic ring. This is illustrated by Examples 15 and 17.

Connection group (l-b) The linking group (I-b) has the formula (I-b):

Ώ °

wherein X represents a group of the formula ¹ I or -S-!

and R represents:

(1) a hydrogen atom or a lower alkyl group,

(2) a group of the formula - (CH] I _n -COOR ^1, where η is an integer between 1 and 5 is and R ¹ represents a hydrogen atom or a lower alkyl group,

(3) a group having the formula - (CH ₂ J _n -OR ² in which η represents an integer between 1 and 5 and R ^{2 represents} a hydrogen atom, a lower alkyl group or an acyl group,

(4) a group with the formula _ / ιττ \η na in which η represents an integer between 1 and 5, and

- * H ₂ J-LlMK ₄ ,

R ¹ and R ⁴ , which may be the same or different, each represents a hydrogen atom, never represents an alkyl or carboxymethyl group,

a group having the formula - (CH ₀₎ -N ^'n where η is an integer between 1 ·: Η 5 illustrates and

^n. V

R ⁶ and R ^s , which may be the same or different, each represents a hydrogen atom or a lower alkyl group.

NH ₂ **

(6) a group having the formula - (CH _2n -CH-COOR ⁷ in which η is an integer between 1 and 5 and R ^{7 is} a hydrogen atom or a lower alkyl group,

(7) a group having the formula shown above under item (2), but wherein one or more carbon atoms of the alkylene chain having η carbon atoms are bonded to a lower alkyl group or a group in place of the hydrogen atom, which is the formula COOR ⁸ , wherein R ^{8 represents} a hydrogen atom or a lower alkyl group,

(8) a group having the formula shown above under item (3), but wherein one or more carbon atoms of the alkylene chain having η carbon atoms are bonded to a hydroxyl group of the hydrogen atom, or

(9) a group with the formula

0,

in which η is an integer between 1 and 5 and m is an integer of 3 or 4, provided that the lower alkyl group can not be a methyl group when X represents a group of the formula -S-- and R is a is lower alkyl group.

In formula (lb) close! the lower alkyl for R ¹ , R ² , R ³ , R ⁴ , R ^s , R ⁶ , R ⁷ and R ^{8 is} a straight or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, η- Butyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl and n-hexyl Preferred are methyl and ethyl. The azyl for R ² includes an organic acid residue such as an aliphatic saturated carboxylic acid, an aliphatic unsaturated carboxylic acid, a carbonaceous cyclic carboxylic acid and a heterocyclic carboxylic acid. It particularly includes a lower alkonoyl such as formyl, acetyl, propyonyl, butyryl, isobutyryl, valoryl, isovaleryl and pivalcyl, an aroyl such as benzoyl, toluoyl and naphthoyl and a heteroyroyl such as furoyl, nicotinoyl and isonicotinoyl.

Connection group (l-c) The linking group (Ic) has the formula (I-c):

CH-CH-COOR ⁴ .,.

wherein R ^{1 is} a lower atom or a lower alkyl or lower alkoxy lower alkyl group, R ^{2 is} a hydrogen atom or a lower alkyl or lower AIH. R ^{3 represents} a hydrogen atom or a lower alkyl group and R ⁴ represents a hydrogen atom or a lower alkyl group, or R ¹ and R ² or R ¹ and R ^{3 may} together form a 5- to 7-membered ring, with the proviso in that R ', R ² and R ³ can not all be simultaneously hydrogen atoms.

In the formula (Ic), the lower alkyl for R ¹ , R ² , R ³ and R ⁴ includes a straight or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl , Tert-butyl, pentyl (amyl), isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1,2-dimethylbutyl, 2-2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, and 1-ethyl-2-methylpropyl. Preference is given to methyl, ethyl, propyl and isopropyl. The lower alkoxy group for R ² includes a straight or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butyl Butoxy, pentyloxy, ss-pentyloxy, neopentyloxy, tert-pentyioxy, 1-methylbutoxy, 2-methylbutoxy, 1,2-D, methylpropoxy and hexyloxy. The methoxy and ethoxy groups are preferred. The lower alkoxy lower alkyl for R ¹ includes methoxy methyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl and propoxypropyl. Preference is given to methoxymethyl and ethoxymethyl. R ¹ and R ² may together form a five- to seven-membered ring. This is illustrated by Example 13. The five- to seven-membered ring may contain an oxygen atom adjacent to a ring made of carbon atoms. R ¹ and R ³ may also together form a five- to seven-membered ring, which is exemplified by Example 11.

Verblnung * group (Id) The linking group (I-d) has the formula (I-d):

(L-d)

wherein R ¹ and R ^{2 may be the} same or different and each represents a hydrogen atom or a lower alkyl group, R ^{3 represents} a hydrogen atom, a lower alkyl group or a group having the form! - (CHj) _n -COOH in which η is an integer between 1 and 3, R ⁴ and R ^{5 may be the} same or different and each represents a hydrogen atom or a lower alkyl group, X represents a group of the formula

A represents a lower alkyl group, a group of the formula - (CH ₂ ) "- Het in which n 'represents an integer between 1 and 3 and Het represents a substituted or unsubstituted heterocyclic ring, a group of the formula

0 -CH ₂ -C -COOH,

a group with the forms! -CH-COOH, a group with the formula

CN -C-COOH,

^{6 /}

wherein R ⁶ and R ^{7 may be the} same or different and each represents a hydrogen atom or a lower alkyl group, a group having the formula -CH ₂ -CN, a group having the formula

in which R ^{8 represents} a lower alkyl group, or a group having the formula

in which ρ is an integer between 1 and 3 and R ⁹ and R ^{10 may be the} same or different and each represents a lower alkyl group.

In formula (ld), the lower alkyl for R ¹ , R ² , R ³ , R ⁴ , R ^s , R *, R ⁷ , R ⁸ , R ⁹ and R ¹⁰ includes straight or branched alkyl of 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl (amyl), isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2- Dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylphenyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3 , 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-i-methylpropyl and 1-ethyl-2-methylpropyl. Preference is given to methyl, ethyl, propyl and isopropyl. By the heterocyclic ring designated A in Het is meant a nitrogen-containing heterocyclic ring such as pyridine, pyradine, pyrimidine, imidazole, pyrazole, oxazole, isooxazole, thiazole and isothiazole. The heterocyclic ring may have a substituent such as lower alkyl, for example methyl, and hydroxyl. Preference is given to pyridyl, imidazolyl and isooxyzolyl.

Compound Group (Ι · β) Compound Group (l-e) has the formula (I-e):

cxr

XSS-CH-CK ₂ -Y

(l-e) 1

wherein X is a group of the formula -CH _} , -CH ₂ -CH ₂ -, -CHj-CH ₂ -CH ₁ - or CHrCH-; R ¹ is a hydrogen atom or a

CH ₃

or an alkyl, hydroxyl, carboxyl, aryl or heteroarylcarbonyloxy group.

In the formula (Ie), the lower alkyl for R ¹ includes a straight-chain or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl, η pentyl, 1-ethylpropyl, isoamyl and n-hexyl. Preference is given to methyl, ethyl and n-propyl. The alkyl for Y includes straight chain or branched alkyl such as methyl, ethyl, n -propyl, η-butyl, isopropyl, isobutyl, 1-methylpropyl, tert -butyl, n -pentyl, 1-ethylpropyl, isoamyl, n -hexyl , n-heptyl, n-octyl, n-nonyl and n-decyl. The aryl for R ¹ includes phenyl, ToIyI, xylyl, biphenyl and naphthyl. Preference is given to phenyl. The hetnroarylcarboxyloxyl group includes a group derived from a nitrogen-containing, five- or six-membered cyclic ring, such as pyridine, pyrimidine, pyrrole, pyrazole and imidazole, thiazole, oxazole or furan. Preferred is nicotinoyloxy compound.

Connection group (l-f) The compound group (I-f) has the formula (I-f):

(L-f)

(CH ₂ ) _n -S-0H ₂ -Y

wherein R ¹ and R ^{2 may be the} same or different and each represents a hydrogen atom or a lower alkyl, aryl or arylalkyl group, η represents an integer of 0 or 1; Y represents a group represented by the formula -COOH or

-CON-R ⁴

V.

(wherein R ⁴ and R ^{5 may be the} same or different and each represents a hydrogen atom or a lower alkyl or carboxymethyl group), and R ³ represents a hydrogen atom or a lower alkyl or arylalkyl group.

The lower alkyl group in the above Difinition, based on the groups R ¹ , R ² , R ¹ , R ⁴ and R ^{s of} the compound (I) according to the

the present invention is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, n-3utyl, isopropyl, isobutyl, 1-MethylpropyI ₁ Teh-butyl, n-pentyl, 1- Ethylpropyl, isoamyl and n-hexyl groups.

The aryl group in the definition of the groups R 'and R ² includes phenyl, ToIyI and naphthyl groups, wherein the Penyl group is most preferred. Preferred examples of the arylalkyl group in the definition of the groups R ¹ , R ² and R ³ include groups derived from the

derived aryl groups, with benzyl and phenethyl groups being most preferred. Both

Compounds of the invention are those of formulas (1-1), (l-b) and (l-f), respectively. In formula (Ia) it is advantageous if X is -S-, R ^{3 is} a hydrogen atom or a lower alkyl group, and R ¹ and R ^{2 are} each hydrogen or a lower alkyl. The compound having the formula (ia) in which R ^{3 is} hydrogen, R ¹ Is hydrogen, R ^{2 is} n-propyl, X is -S- and R ^{4 is} hydrogen, and its sodium salt is most advantageous. In addition, the compound of formula (lf) wherein R ^{3 is} hydrogen, R 'and R ^{2 are} hydrogen, η is fines and Y is -COOH, and its sodium salt is very advantageous. In the formula (Ib), X is preferably -S-; if this is the case, eo is advantageous when R-CHr-COOH, - (CH ₂ ) "- CH (NH ^ -COOR ⁷ OdOr-CH ₂ -C (NH ₂ ) COCH. In addition, it is advantageous that X is -S-, R ^{3 is} hydrogen, R 'is hydrogen and R ^{2 is the} same C ₃ H ₈ is; X is -S-, R ^{3 is} hydrogen, R ¹ is -CH ₃ and R ² is -CH ₃ , or X is -S-, R ³ is -CH ₃ or-C ₂ H ₅ , R ^{1 is} hydrogen and R ² is -C ₂ H ₅ . All compounds used in the pharmacological experiments shown below are for the invention

particularly important. Particularly preferred are the compounds 1 to S shown in the table for

Compound Group (I-a) and the compounds 1,2,4,7,8,10,11,12,13 and 15 shown in Table 6 for the Connection group (l-f). The pharmacologically acceptable salts may be normal, non-toxic salts, and examples include salts

of alkali metals, such as sodium and potassium; Salts of alkaline earth metals, such as calcium and magnesium; Salts of organic

Amines such as trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine and N-N'-dibenzylethylenediamine and Ammonium salts, and also, depending on the substituent, inorganic acid salts such as hydrochloride, Hydrobromide, sulfate and phosphate; organic acid salts such as acetate, maleate, T: at, methanesulfonate, benzenesulfonate and Toluene sulfonate, and salts of amino acids such as arginine and Asprgin- and Glutaminsäuren. Besides, these salts can Form hydrates. Although the compounds of the present invention, depending on the substituents, an asymmetric Of course, in order to be present as optical isomers, it is a matter of course that these Isomers are included in the scope of the present invention. From the results of Experimental Examples 1 and 2, it should be apparent that the compounds of the present invention Remarkably prevent liver damage due to D-galactosamine or carbon tetrachloride. The Compounds of the present invention are therefore very useful as remedies for liver damage. Accordingly, the compounds of the present invention are useful as therapeutic and preventive drugs for

various liver damage from animals, including humans. Specifically, they can be used in the

Treatment and association of chronic or acute hepatitis, liver disorders by drugs, viral hepatitis,

alcohol-induced hepatitis, choloplanie and even cirrhosis as the end-symptom of these diseases.

In addition, it may be seen from the results of Experimental Example 3 that the precedents of

present invention have a remarkably low toxicity and are excellent in safety. The

Compounds of the present invention are therefore very valuable in this regard, as they are generally due to the nature of

the disease can be repeatedly administered over a longer period of time.

When the compounds of the present invention as a therapeutic and preventive drug for liver disorders

may be administered orally as a powder, granule, capsule, syrup or the like, or they may be administered parenterally as a suppository, injection, external preparation or as a drop. The dose for this varies greatly depending on the symptom, the age or the type of liver disorder, but is generally between about 0.1 and 1000 mg, preferably between 2 and 500 mg, and more preferably between 5 and 100 mg per adult and day, and may be given at once or in multiple doses per day.

The preparation of a medicament containing the compound of the present invention is carried out using

conventional carrier according to a normalon method.

More specifically, in the preparation of a solid preparation for oral administration, the actual active ingredient is included Filler and, if necessary, a binder, disintegrants, lubricants, colorants or corrosiveness

is added, and the resulting mixture is converted into a tablet, a dragee, granules, powder or a capsule according to a common Mothode.

Examples of fillers include lactose, corn starch. Sucrose, glucose, sorbitol, crystalline cellulose and silica. Examples of binders include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, calcium citrate, dextrin and pectin. Examples of the lubricant are u. a. Magr.esiumste irate, talc, polyethylene glycol, silica and hydrogenated vegetable oils, while as colorants those can be used which are suitable as additives for drugs. Corruptiveness includes powdered; Cocoa, mentholkrsut, aromatic powder, menthol oil, borneol and powdered cinnamon bark. Of course, these tablets and granules can be coated with sugar, gelatin or other material. In the preparation of an injection containing the compound of the present invention, is? Of course, the main active ingredient is necessary mixed with a pH regulating agent, a buffer, stabilizer, solubilizing agent or the like, which are then converted into a subcutaneous, intramuscular or intravenous injection according to conventional methods.

The above pharmacological activity of the compounds of the invention is underlined by the pharmacological experiments, the results of which are prescribed below for the compound groups (I-a) to (I-f).

Connection group (l-a)

Experimental Example 1 a

Effect on liver injury caused by D-G actosamines in rats Experimental method:

300mg / kg of D-galactosamine was administered to male FisclK. 'Ratton (F ₃₄₄ -RaItCn) π weighing about 180g by subcutaneous injection to cause liver injury. Every Vb. Bindunmg was dissolved in distilled water and given by oral administration at a dose of 50 mg / kg one hour after injection of D-galactosamine.

48 hours after the injection of D-galactosamine, blood was taken from the tail vein of the rats. The coagulation time of the blood was determined by the hepaplastin test (HPT) and the GPT activity by an enzymatic method.

The inhibition (%) of liver damage by the individual compounds is shown in Table 1a.

Experimental Example 2 a

Effect on liver damage caused by carbon tetrachloride (CCI ₄ ) Experimentella method:

Male Fischer rats (F ₃₄₄ rats) weighing about 180 g were administered intraperitoneal injection of 0.5 ml / kg of carbon tetrachloride to induce liver damage. In this experiment, carbon tetrachloride was diluted with olive oil avf to a final concentration of 0.25 ml / ml.

The individual compounds were dissolved in distilled water and given by oral administration at a dose of 100 mg / kg one hour before administration of the carbon tetrachloride.

24 hours after the injection of the carbon tetrachloride, blood was taken from the tail vein of the rats. The GPT activity in plasma as an index of liver damage was determined by an enzymatic method. Ligation (%) of liver damage by the individual compounds is given in Table 2a.

Connection group (l-b)

Experimental Example 1 b

The method was carried out in the same manner as in Experimental Example 1a, except that 400 mg / kg of D-galactoscmin was used in solution in physiological saline at a concentration of 200 mg / ml, which was diluted to pH 2 with 10N aqueous solution of potassium hydroxide. Value was adjusted to 7.0, and each test compound was administered in an amount of 100 mg / kg in a 0.5% Mylthylcellulose solution. The results are shown in Table 1b.

Experimental Example 2 b

The test was carried out in the same manner as in Experimental Example 1b, with ailerdeings administering the test compound of the rats orally in an amount of 100 mg / kg in 0.5% methyl cellulose monoside. The results are shown in Table 2b.

Connection group (l-c)

Experimental Examples 1c to 2c

The experiments were carried out in the same manner as in Experimental Examples 1a and 2a, respectively. The results are shown in Tables 1c and 2c, respectively.

Connection group (l-d)

Experimental Example 1 rl

The test was conducted in the same manner as in Experimental Example 1a, except that each test compound was used in solution in distilled water or as a dispersion in a 0.5% methyl cellulose solution. The results are shown in Table 1d.

Exporlmentalles Example 2d

The test was carried out in the same manner as in Experimental Example 2a, except that the individual test compounds were used in a solution in distilled Waiser. The results are shown in Table 1 2d.

Connection group (l-e) Experimental Example 1e

The test was carried out in the same manner as in Experimental Example 1a, except that 400 mg / kg D-galactosamine was administered and each test compound was used in an amount of 100 mg / kg in a dispersion of 0.5% aqueous methyl cellulose solution. The results are shown in Table 1 e.

Experimental Example 2e

The test was carried out in the same manner as in Experimental Example 2a except that the individual test compounds were used in a dispersion of 0.5% aqueous methylcellulose solution. The results are shown in Table 2 e.

Connection group (l-f) Experimental Example 1 f

The test was carried out in the same manner as in Experimental Example 1 a, except that 400 mg / kg D-galactosam was administered in the physiological saline solution at a concentration of 200 mg / ml, which was adjusted to pH with 10 N aqueous solution of potassium hydroxide of 7.0, and each test compound was used in an amount of 100 mg / kg in a 0.5% methyl cellulose liquid. The results are shown in Table 1 f.

Experimental Example 2f

The test was carried out in the same manner as in Experimental Example 1a, except that each test compound was used in an amount of 100 mg / kg in a dispersion in 0.5% methylelulose solution. The results are shown in Table 2 f.

Toxicological test of the linking groups (l-a) to (l-f)

We used male ddy mice with an age of 7 weeks and a weight of around 30g. Over 4 days, the mice were given 800 mg / kg of the corresponding compounds shown in Tables 1a, 1b, 1c, 1d and 1f and the corresponding compounds 1, 3, 6 and 7 of Table 1e orally administered. None of the mice died.

Table 1a Ζ ⁰ \ ³ R ¹ .R ² ₂ C0 ₂ Na Suppression ratio GPT S-CH (%) 90 \ ^R Getting Connected Kä R ³ HPT (Example 112) -CHpCHoCH. R ² 88 78 ^ C, J Connection 1 H 96 81 (Example 2) H Connection 2 -chō H 94 100 (Example 4) -CH ₃ Connection 3 -CHPCH ₁ -CH ₃ 100 82 (Example 6) - Connection 4 ^β \ J Xl λ \ J ΓΙ ο -CH ₃ 3 ⁹⁶ 45 (Example 8) D H Connection 5 H -CH ₂ CH- 51 (Compound 1 H Connection 6 -chō (Example Ί3) H

Table 1a. continuing R ^ R ^J -13- 287 038 GPT • Compound N2 R ¹ (Example N2) Interruption ratio (*) 56 92 - (CH ₂ ) ₂ - - (CH ₃ ) ₃ - HPT Compound 7H (Ex. 15) Compound 3H (Ex. 17) 86 100 Inhibition ratio (%) GPT Table 2a 96 88 98 80 Connection H2 Compound 1 Compound 2 Compound 3 Compound 4 Table 1b

- (V (CH ₂ J ₂ -XR

(I-b)

Connection N2 X (example KS)

Untied binding. (,%) HPT

GPT

Compound 1 -SH (Example 1)

91

Table 1b. continuing

Connection NS X (example N2)

Unterbindungsverh.

HPT

GPT

Compound 2 -S- (Example 10) Compound 3 -S- (Example 11) Compound 4 -S- (Example \ 2) Compound 5 -S- (Example 13) Compound 6 -S- (Example 14) Compound 7 -S - (Example 15) Compound 8 -SJ- (Example 3) Compound 9 -S- (Example 16) Example 10 -S- (Example 17) Compound 11 -S- (Example 18) Compound 12 -S- (Example 19) Compound 13 -S- (Example 20) Compound 14 -S- (Example 21) Compound 15 -S- (Example 22)

-CH ₂ CH ₂ CH,

-CH ₂ CH ₂ OH

- (CH ₂ )

94

94

98

.CH ₀ -CH-CH ₀ OH 65 2 ι 2

OH

-CH ₂ CH ₂ QCH ₃ 93

96

-CH ₂ COON ₂ 97

-CH ₂ CH ₂ COON ₂ 99

- (CH ₂ ) ₃ C 00 N _o 99

- (CH ₂ J ₄ COON ₂ 98

- (CH ₂ J ₃ COON ₂ 75 ^X

-CH-CH ₂ COON ₂ 99

CH ₃

-CH-CH ₂ COOH 50

COOH

-CH-COOH 90

CH ₃ 84 97 98 43 79 92 97 100

89 96 69

99 35 73

Table 1b, continued

X R 0 Binding relationship - (,%) 61 GPT Connection K2 ^{2 2} "Vn ^ 86 (Example NS) § /H HPT 100 -S -CH ₂ CONH ₂ -CH ₀ -CN ^ 94 97 Connection 16 ^ CH ₂ COOH 65 (Example 23) -S ? H 99 51 Connection 17 -CH ₂ CH ₂ -C -NH ₂ - (CH ₀ ) pCN ^ (Example 4) -S ⁰ CH 50 69 Connection 18 U • 9 H (Example 24) -S 0 90 Connection 19 -CH ₀ CH ₀ -C -Ni ³ 43 (Example 25) ₃ ^ά CH ₃ -S CH ₃ 71 93 ^X Connection 20 -CH ₀ CH ₀ -N ^ ^{J ά ά} CH, (Example 26) -S 3 -CH ₂ CH-COONa 93 ^X 67 Connection 21 NH ₂ (Example 2) -S 69 77 Connection 22 (Example 8) ..S- 92 Connection 23 86 (Example 9) -S 90 Connection 24 34 (Example 27) ^{d άCH} ₂ COOH -S -CHpCOOOpH - 100 Connection 25 C * Cm J (Example 5) 0 -CH ₃ 54 Connection 26 -S (Example 6) 0 *, -CH ₂ CH ₂ OH Connection 27 -S (Example 28)

Table 1b, continued

Connection MX (example Hi)

Unterbindungsverh. {%)

HPT

GPT

Compound 28 O (Example 7) -S-

Compound 29 (Example 29)

Compound 30 (Example 30)

Connection 31 (Example 3D

0 0

-S

0 0

-CH ₂ CH ₂ OH

-CH ₂ COOH

-CH ₂ CH ₂ COOH

95

Compound 32 0

- <CH ₂ ) ₃ C00H (Example 32) -S-

Table 2b

connection

Relationship (%) GPT

Compound 3 47

Compound 4 93

Compound 8 53

Compound 9 98

Connection 10 43

Connection 11 90

-17- 287 Table 2b. continuing

Compound H2 Inhibition ratio (%) GPT

Compound 13 86

Connection 16 61

Compound 17 98

Connection 21 34

Connection 25 21

Compound 26 97

Compound 28 97

Table 1c

2

R 'CH-CH-COONa

R ¹

Compound HJ R ¹ R ² R ³ Interlocking Comp. (%) (Example N2)

HPT GPT

Compound 1 -CH ₂ CH ₂ CH ₃ HH 78

(Example 2) Compound 2 -CH ₂ CH ₃ HH 75

(Example 4) Compound 3 -CH ₃ HH 89

(Affection 6) Compound 4 TCH ₂ OCH ₃ HH 67

(Example 8) Compound 5 -CH ₂ OCH ₂ CH ₃ HH 75

(Example 10)

-18- 287 Table 1c _t continued

1 2 3 Connection H2 R R R ^ Inhibition ratio.

(Example H2)

"HPT GPT

Compound 6 H 67 60

(Example 12) ^CH 2

Compound 7 -CHgCHgO ^H 51 12

(Example 14)

Table 2c

Compound K2 lint connection « {%)

Compound 3 Compound 4 Compound 6 Compound 7 77 72 94 84 0 ^ 0-C ^ J Unterbind. -verh. Table 1d 0 ^^ s. / CH ₉ CH ₀ SCH ₀ CN HPT GPT Connection lis structural formula 100 89 Connection 1 100 88 Connection 2

Table Id. Continued

Compound K2 Structural formula Subbind «-verh.

HPT

GPT

Compound 4, 0

Connection 5

, 0

0 connection 6 .0

Connection 7

Connection 8 0 \

Connection 10

Connection 12

Connection Η

H ₃ C

Connection 16 0

Compound 18 _0/0

3 ^CH 3

CH ₂ CH ₂ SCH ₂ CCO ₂ H

H ₂ CH ₂ SCH ₂

N = I

CH ₀ CHOCH ₀ -AI

91 23

76 58 61 25

85

CH ₂ CH ₂ SCH ₂ CO ₂ Na

XJH ₂ CH ₂ SCH ₂ CO ₂ Na -CHo

H ₂ CH ₂ SCH ₂ CO ₂ Na

-CH ₂ CH ₃ 85

4I

62

84 23

64 37 28 35

85

09 25

60

Table 1d. continuing

Connection KS Structural formula Subbind.-verh

HPT

Compound 20 0 Compound 22 0 Compound 24 .0

Compound 26 0 Compound 28 Compound 29 0

ν 0

Connection 30

/ ^v

Connection 31

Compound 32 CHpCHpSCHpCOpNa 93

pCHpSCHpCOp

CH ₂ CH ₂ CO ₂ Na

CH

H ₂ C « ₂ SCHCO ₂ Na

" CN

SCHpCHpSOpN

SCHC

77

59

48

45

_CH CH ₃

22

0, SCH ₂ CH ₂

CH ₀ CH ₀ SCH

92

88

GPT

87 74 40

53

44

46

89

80

-21- 287 Table 1d. continuing

Compound M8 structural formula subbind.

Connection 33

^ O " ⁵ ^ 0

Connection 37

Table 2d

Compound KS inhibition ratio (%) GPT

Compound 1 90 Compound 2 99

HPT GPT

CH ₂ CH 78 82

Connection 34 0

0 ^^ N ^ · CH ₀ CH ₀ ScH ₀ CCHo 17

Compound 35 0

, 0 _{S /} / V ^CH o ^CH J ^c ¥ ^H i 8 °

/ Y ^ Ji <- c- jl & J

Compound 36 0

₀₀ o 68 59

ί ³

CH ₂ CH ₂ SCH ₂ CN 44 52 0

-22- 287 Table 2d. continuing

Link Ki Interference Ratio (%) GPT

Compound 16 73

Connection 18 82

Connection 86 55

Connection 28 75

Compound 33 99

Table 1e

Test Structural Formula, Underbonding NS

HPT GPT

Compound 1 (Fig. 1)

Connection 2 Ό (Fig. 2) *

Connection 3

(Inap. 3) ^ O ^ V "(CH ₂ ) ₂ SS (OH ₂ ) ₂ O-j ^ | \ 62

Compound 4 Q ^ _ ^ 59

(Beiap ,, 4) ^

Compound 5 0 ^^, (CH ₂ J ₃ SS (CH ₂ JgOH 51.

(Fig. 5)

Connection 6 ^. ^ / nu ^ qq / mr ^ «^ e c £ yO- ^ I ^ V ^ \ CH ₀ ; 0S-SCCH ₀ ; _n - ^ 7 53

-23- 287 Table Ie. continuing

Test- Structural formula Sub-binding

bond 0 (%)

G; ^λ

Compound 7 O 43 72

(Ex. 7) ^ C

Compound 8 O 55 87

(Ex. 8) sO ^^^ fACEr,) _O S

\ JT J " ^C Vs-H.HCl

Compound 9 49 53

(Ex. 9) ^ O ^ x V (CHp) pS-S (CHp) pCHp

Connection 10 0 ^^^ 43 72

(Example 10) 0 ^^. _% CH ₂ SS (CH _? ) PO

Connection 11 (Ex. 11) ^< Connection 12 (Ex. 12)> ^ O ^ nG ^ CHS »3 3 SCHH ₂ y> CH ₃ ¹ ^ O 88 45 76 63 Table 2e Inhibition ratio GPT (%) Connection K! 97 Connection 1

-24- 287 Table 2e. continuing

Connection H2 Inhibition ratio {%) GPT

Compound 3 97

Connection 4 94

Compound 5 91

Connection 6 66

Compound 7 91

Connection 8 82

Connection y 42

Connection 10 75

Table 1f

Test compound structural formula subbind.

egg (%)

HPT GPT 1 / CH ₂ 100

CH ₂ CH ₂ CH ₂ GH ₃ 83

CHOCH ₂ CO ₂ Na

OH., ^ CH ₀ CH- 100 1Φ0

\ V ² C-SCH ₂ CO ₂ Na

Table 1f "continued

Teetverbind. structural formula

Unterbind.-married.

HPT

GPT

CO:

CHSCH ₂ CO ₂ Na

CH ₂ CH ₂ CH ₃

Cl

CH.

CHSCH ₂ CO ₂ Na

H ₂ SCH ₂ CO ₂ Na

CH ₃ CH ₃

CH,

, CH \

CH,

CHSCH ₂ CO ₂ Na

FIN

<! I

100

67

100

67

O ^ * ^ "- CH,

* O 89

97

100

83

96 100 67 88

3H ₂ CH ₂ SCH ₂ CO ₂ Na 96 100

Table 1f. continuing

Test compound Structural formula K2 Sub-bond HPT

GPT

CH ₃

CHSCH ₂ CONH ₂

SCH ₂ CONH ₂

CH ₂ CH ₃

CHSCH ₂ CON (CH ₂ ) ₂ CH,

₂ H _{5) 2}

Ocho

68

76

17

32

50

76

70

97

75

50

33

42

96 91

Table 2f

Test compound-structural formula K2

Unterbind · -verb. "

HPT

GPT

<o

CH ₃

I ™ 3 HSCH _n COnNa

CHnCHpCH ^ CH CHschgCOgNa 100

100

94

95

CH ₂ CHSCH ₂ COgNa

CHgSCHnCOgNa ΐ7 ~ κ <

CH,

CH ₃

CH.

"TCHgCHgSCHgCOgNa

CHnCHnCH ₀

I 2 2

CH ₂ CHgCH ₃

Ή,! CH ₂ CONHCHgCOgNa 100

75

100

100

75

94

89

97

92

89

The symbol * in Table 1b indicates the administration of 50 mg / kg. The compounds of the invention can be prepared by various methods. Typical examples of these Methods are described below for the corresponding connection groups. Connection group (Ι · β) Production process A

(Preparation of compounds of the general formula (I) in which X represents a group of the formula -S-)

(II)

HS-CH _n- CO _n R

acid

(III) (IV)

wherein R ¹ , R ² and R ^{3 are} as defined above and R ^{4 is} H or a lower alkyl group.

In this process, an alcohol of the general formula (II) is reacted with a thiol of the general formula (III) to obtain a proposed compound (IV). This reaction is carried out by a usual method without the use of a solvent or in an organic solvent which is inert to the reaction and is selected from the group consisting of aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as ethyl ether, isopropyl ether , Tetrahydrofuran and dioxane, halogenated hydrocarbons such as Dichioromethyn, chloroform and carbon tetrachloride, esters such as ethyl acetate, ketones such as acetone and methyl ethyl ketone and acetonitrile, dimethylformamide and acetic acid, with cooling with ice, at room temperature or with heating for several hours. The reaction is easy when an acid such as sulfur, p-toluenesulfonic or D-10-camphorsulfonic acid is used as a catalyst.

Production process B

(Preparation of compounds of the general formula [I] in which X represents a group of the formula -S-)

shark

(V)

HS-CH ₂ -CO ₂ R

base

R ¹

(III)

S-CH ₉ CO ₀ R ^

ac.

(IV)

wherein Hal represents a halogen atom and R ', R ² , R ³ and R ^{4 are} as defined above.

In this method, a halogen compound represented by the general formula (V) is reacted with a thiol having the general formula (III) to obtain a proposed compound (IV).

This reaction is carried out by a usual method without the use of a solvent or in an organic solvent inert to the reaction and selected from the group consisting of aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran and dioxane, Ketones such as acetone and methyl ethyl ketone, alcohols such as methanol and ethanol, halogenated hydrocarbons such as chloroform and carbon tetrachloride and acetonitrile, dimethylformamide and dimethyl sulfoxide consists, with cooling with ice, at room temperature or with heating for several hours. The reaction is easy when an alkali metal carbonate or hydrogen carbonate such as sodium hydrogen carbonate, potassium carbonate or sodium carbonate, an alkali hydroxide such as sodium hydroxide or potassium hydroxide, an organic base such as triethylamine, pyridine or diethylaniline or sodium hydride is used as the dehydrohalogenating agent.

Production process C

(Preparation of compounds of the general formula (I) in which X represents a group of the formula -S-)

(Vl)

0, CU

HS-CH ₂ -CO ₂ R

(VII)

wherein R * and R ^{3 are} as defined above, R * represents a hydrogen atom or a lower alkyl group and R ⁵ and R ⁹ each represents a hydrogen atom or an alkyl, aryl, arylalkyl, heteroalkyl or heteroarylalkyl group. In this process, a compound having the general formula (VI) is reacted with a thiol having the general formula (III) to obtain the intended compound (VII). This reaction is carried out by a usual method without the use of a solvent or in an organic solvent selected from the group consisting of aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran and dioxane, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, ketones such as acetone and methyl ethyl ketone, esters such as ethyl acetate, and acetonitrile and dimethylformamide, under cooling with ice, at room temperature or by heating under reflux. When this reaction is slow, an acid such as sulfuric acid, p-toluenesulfonic acid or D-10-camphorsulfonic acid may be used as a catalyst. The compound (VII) thus obtained is an intended compound of the present invention represented by the above-mentioned general formula (I) in which X is -S- and R ^{2 is the} same

-CH

^is ·

Production process D

(Preparation of compounds of the general formula [I] in which X represents a group of the formula -S-)

(VIII)

Hal-CH ₂ -CO ₂ R ⁴ (ix)

(IV)

wherein Hal represents a halogen atom and R ¹ , R ² , R ³ and R ^{4 are} as defined above.

In this process, a thiol having the general formula (VIII) with a halogen compound having the general Formula (IX) under the same conditions as in Preparation B reacts to a proposed compound (IV) to

receive. Preferred results are achieved when using a base mentioned in connection with Preparation B.

The halogen atoms that can be used in Preparation B and D include bromine, chlorine and iodine. In

As a rule, bromine and chlorine are used.

Production process E

(Preparation of compounds of the general formula HI in which X represents a group of the formula -S- and R ⁴

Represent hydrogen atom)

ca ι

S-CH ₀ -COOR *

² (X)

hydrolysis

S-CH ₀ -COOH

U-υυυη (| _V) ·

wherein R ¹ , R ¹ and R ^{3 are} as defined above and R ⁴ 'is the same as R ⁴ except for the hydrogen atom, ie, R ⁴ ' represents a lower alkyl group.

An ester having the general formula (X) which is one of the intended compounds can be hydrolyzed by a usual method to obtain a proposed carboxylic acid having the general formula (IV). Specifically, the hydrolysis is carried out by a usual method in the presence of a base of an acid in a solvent suitably selected from the group consisting of 3'jS water, methanol, ethanol, aqueous methanol, aqueous ethanol, aqueous tetrahydrofuran, aqueous Acetonitrile and aqueous acetone. The bases include alkali metal carbonates such as sodium and potassium carbonates and alkali hydroxides such as sodium and potassium hydroxides. The acids include, for example, hydrochloric and sulfuric acid.

Production process F

(Preparation of compounds of general formula [I] in which X represents a group of the formula

S-CH ₂ -CO ₂ R

(IV)

Oxidation R ¹ R ²

(XI)

wherein R ¹ , R ² , R ³ and R ^{4 are} as defined above.

In this method, a proposed compound (XI) is prepared by oxidation of, for example, the intended compound (IV) prepared by the method described above. Specifically, the compound (IV) is dissolved in a solvent selected from the group consisting of aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, water, alcohols such as methanol and ethanol, ethyl acetate, Acetone and acetic acid, and an equimolar amount of an oxidizing agent such as hydrogen peroxide, peracetic acid, m-croroperbenzoic acid or sodium hypochlorite is added thereto under cooling with dry ice / alcohol or ice / water to carry out the reaction in a usual manner to prepare a proposed sulfoxide compound (XI) ,

Production process Q

(Preparation of compounds of the general formula [I] in which X represents a group of the formula - S ~

S-CH ₂ -CO ₂ R

(IV) (XIII)

wherein R ¹ , R ² , R ³ and R ^{4 are} as defined above.

In this process, a proposed compound (XII) is prepared by oxidizing a proposed compound (IV) prepared by, for example, the method described above. In particular, dip compound (IV) is dissolved in a solvent selected from the group consisting of aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, water, alcohols such as methanol and ethanol, ethyl acetate , Acetone and acetic acid, and thereto are added at least two equivalents of an oxidizing agent such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, sodium hypochlorite or sodium m-periodate under cooling with ice or at room temperature to carry out the reaction and thus the predetermined Snlfonverbindung ( XII).

In another production method, a sulfoxide compound (XI) is prepared, for example, according to Preparation Method F and dissolved in a solvent such as chloroform, and then an oxidizing agent such as m-chloroperbenzoic acid is added to carry out the reaction.

Pharmacologically acceptable salts of the contemplated compounds (I) also contemplated by the present invention may be prepared, for example, by reaction of a carboxylic acid compound of general formula (I) in which R ⁴ represents hydrogen with an alkali hydrogen carbonate such as NaHCO ₃ or KHCO ₃ , an alkali carbonate such as Na ₂ CO ₃ or K ₂ CO ₃ or an alkali hydroxide such as NaOH or KOH, to obtain a pharmacologically acceptable salt such as the sodium or potassium salt of the compound.

Connection group (l-b) Production process A

(Preparation of compounds of the general formula [I] in which X represents a group of the formula -S-)

HS-R

I

g) ₂ -HaI _(II)

dl »base

wherein Hal represents a halogen atom and R is as defined above.

In this method, 5- (2-haloethyl) -1,3-benzodioxole having the general formula (II) with a thiol with the Formula (III) reacts to obtain a proposed compound (IV). The reaction is carried out by a usual method, without the use of a solvent or in one

organic solvent that is inert to the reaction and is selected from the group consisting of benzene, ethanol,

Xylene, tetrahydrofuran, chloroform, carbon tetrachloride, Ν, Ν-dimethylformamide, etc., under cooling with ice, at Room temperature or under heating for several hours. The reaction is characterized by the use of an inorganic Base such as sodium hydrogen carbonate, potassium carbonate, sodium carbonate or sodium hydroxide, or an organic base

such as triethylamine, pyridine, pyrimidine or Ν, Ν-diethylaniline as a dehydrohalogenating agent.

Production process B

(Preparation of compounds n.'t of the general formula [I] in which X represents a group of the formula -S-)

(Vl)

- (CH ₉ ) pSR,

^ ^c '(IV)

wherein Hal represents a halogen atom and R is as defined above.

In this method, 2- (1,3-benzodioxol-5-yl) ethanethiol (V) is reacted with a halogenating agent represented by the general formula (VI) under the same conditions as in the preparation process A to obtain a intended compound (IV) , In this process too, advantageous results are achieved when a base as described above in connection with preparation process A is used. The halogen atoms used in preparation processes A and B include bromine, chlorine and iodine. As a rule, bromine or chlorine are used.

Production process C

(Preparation of compounds of the general formula [I] in which X represents a group with the formet -S-)

R ^ -CH = CH-R ¹ ° ^(V1I)

Ο- χ 7- (CH ₉ ) _o -S-CH-CH ₂ -R ¹⁰

τ = * p9; (Vim

wherein R ^{9 represents} a lower alkyl group and R ^{10 represents} a lower alkyloxy carbonyl, N, N 'bis (lower alkyd-aminocarbonyl or carbamoyl group.

In this process, a thiol (V) having an unsaturated precursor of the general formula (VII) becomes a

ordinary method reacts, without the use of a solvent or in a solvent selected from the group consisting of, for example, benzene, dichloromethane, tetrahydrofuran, N, N-dimethylk> rmamid and

Ethanol, with cooling with ice, at room temperature or by heating under reflux to give a proposed compound (VIII).

to obtain. When the reaction is slow, a catalyst such as piperidine, triethylamine, sodium ethylate, Triton B, may be used.

Sulfur or sulfuric acid can be used. The compound (VIII) thus obtained is a compound provided by the present invention, represented by the general Formula (I) in which X is -S- and R is -CH-CH ₂ -R ¹⁰ . Production process D

(Preparation of compounds of the general formula [I] in which X represents a group of the formula -S-)

^(IX>

(CH ₂ ) 2-SR

wherein R is as defined above.

In this method, 5-ethelyl-1,3-benzodioxole (IX) is reacted with a thiol having the general formula (III) by a usual method without the use of a solvent or in a solvent such as tetrahydrofuran under cooling with ice Room temperature or with heating under reflux to obtain a proposed compound (IV). When the reaction is slow, a peroxide such as benzoyl peroxide or azobisisobutyronitrile may be used as a catalyst.

Production process E

(Preparation of compounds of general formula [I] in which X represents a group of the formula

(IV)

(CH ₂ ) 2-SR

(X)

wherein R is as defined above.

In this method, a proposed compound (X) is prepared by oxidation of, for example, a proposed compound (IV) prepared by the method described above. Specifically, the compound (IV) is dissolved in a solvent selected from the group consisting of aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as oichloromethane, chloroform around carbon tetrachloride, water, alcohols such as methanol and ethanol, ethyl acetate, Acetone and acetic acid, and thereto is added an equimolar amount of an oxidizing agent such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid or sodium hypochlorite under cooling with dry ice / alcohol or ice / water to carry out the reaction in a usual manner, thereby preparing a proposed sulfoxide compound (X) manufacture.

Production process F

(Preparation of compounds of the general formula [I] in which X represents a group of the formula -S-

(IV)

oxidation

(XI)

wherein R is as defined above.

In this method, a proposed compound (XI) is prepared by oxidizing a proposed compound (IV) prepared by the method described above. Specifically, the compound (IV) is dissolved in a solution selected from the group consisting of aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, water, alcohols such as methanol and ethanol, ethyl azotate , Acetone and acetic acid, and two equivalents of an oxidizing agent such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, sodium hypochlorite or sodium m-periodate are added under cooling with ice or at room temperature to carry out the reaction to provide a proposed sulfone compound (Xl).

For example, according to another preparation method, the sulfoxide compound (X) prepared by Production Method E is dissolved in a solvent such as chloroform, and an oxidizing agent such as m-chloroperbenzoic acid is added to carry out the reaction.

-35- 297 038

Production process Q

(Preparation of compounds of the general formula [I] in which X is a group as ^r stsllt having the formula -S-)

Hal

¹¹

where η e is the integer between 1 and 5 and R "is a lower alkyl, aryl or heteroar group In this process, [2- (1,3-benzodioxol-5-yl) ethyl] thio-derivative having the general formula (XI) in its original state or in the form of a solution in, for example, benzene, dichloromethane, chloroform, tetrahydrofuran or N, N-dimethylformamide mixed with a base such as pyridine, triethylamine, Ν, Ν-dimethylaniline or sodium carbonate as the dehydrohalogenating agent. To the mixture, an acid halide of the general formula (XII) is added to carry out the reaction to thereby obtain an intended compound (XIII) .Pyridine can be used both as a solvent and as a dehydrohalogenating agent The reaction is carried out by cooling with water or water carried out by heating under reflux.

Production process H

(Preparation of compounds of the general formula [I] in which X is represented by a group with the Fo mel

K V- (CH ₂ ) ₂ -S- (CH ₂ ) _n -COOH

H ₀ N-CH ₀ -COOH 0 -f-7- (CH ₀ ) _o -S- (CH ₀ ) -C0NHCH _o C00H

< ^xvl >

where η is an integer between ^{1 and} B.

A 2- (1,3-bonzodioxol-5-yl) ethyl thio-derivative (XIV) prepared, for example, by the methods A, B or D described above is dissolved in a solvent such as benzene, chloroform or dimethylformamide. To the solution is added a chlorinating agent such as thionyl chloride, oxalyl chloride, phosphorus oxychloride or phosphorus pentachloride to conduct the reaction under cooling with ice, at room temperature or by heating under reflux to obtain an acid chloride derived from the compound (XIV). A solution of glycine (XV) in, for example, an aqueous sodium hydrogencarbonate solution, aqueous sodium carbonate solution or aqueous sodium hydroxide solution is stirred under cooling with ice / water to carry out the reaction to obtain the intended glycine amide (XVI). The compound (XVI) prepared by this process is an intended compound having the general formula (I) wherein X is -S- and R ^{2 is} - (CH ₁ I _n -CONHCH ₂ COOH.

Production process I

(Preparation of compounds of the general formula (I) in which X represents a group of the formula -S--)

0 -KL 7- (CH ₂ ) ₂ -Hal

(ID

shark

(XVIl)

(XVIII)

Alka-lihydrolyse

(CH ₂ ) ₂ -SH

(V)

wherein Hal represents a halogen atom.

A 5- (2-haloethyl) -1,3-benzodiaxole having the general formula (II) and the thiourea nV of the formula (XVII) are dissolved in a solvent such as methanol or ethanol to conduct the reaction at room temperature or by heating under reflux and to obtain a thiuronium salt (XVIII) which is hydrolyzed dsm - in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitably selected solvent such as water, methanol, ethanol, aqueous methanol or aqueous ethanol at room temperature or by refluxing 2- (1,3-benzodioxole-f-y-methanethiol (V) to be obtained.) The halogen atoms include bromine, chlorine and iodine, and bromine or chlorine are generally used.

Production process J

(Preparation of compounds of the general formula (I) in which X represents a group of the formula -S-)

(CH _{2) 2} -S- (CH _{2) n} -C00H

(XIV)

(XIX)

(XX)

wherein η is an integer between 1 and 5, and R ³ and R ^{4 may be the} same or different and each represents a hydrogen atom or a lower alkyl group.

The carboxylic acid prepared by the preparation process A, B or D, or their reactive derivative are used with

an amino compound of the general formula (XIX) to form an amide which is a proposed compound of the formula (XX).

The reactive derivatives of compound (XIV) include acid halides such as acid chlorides and acid bromides, acid azides, their

active esters with N-hydroxybenzotriazole and N-hydroxysuccinimides, symmetrical acid anhydrides and mixed

Acid anhydrides with alkylcarboxylic acid and p-toluenesulfonic acid. When a free carboxylic acid is used as the compound (XIV), the reaction is preferably in the presence of Condensing agent such as dicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole performed. The reaction is carried out using a compound (XIV) or its reactive derivative and a compound

vXIX) in equimolecular amounts or, alternatively, using one of the two compounds in a slightly excess amount, in an organic solvent inert to the reaction, such as pyridine, tetrahydrofuran,

Dioxati, ethers, benzene, toluene, xylene, methylene chloride, dichloroethane, chloroform, dimethylformamide, ethyl acetate or Acetonitrile. Depending on the nature of the reactive derivative, it is advantageous to use a base such as triethylamine, pyridine, picoline, lutidine, N ₁ N- Dimethylanilln, potassium carbonate or sodium hydroxide to be added in order to carry out the reaction quietly. The reaction temperature is not specifically restricted because it varies depending on the kind of the reactive derivative. Pharmacologically acceptable salts of the proposed compounds (I), products of the same intended use

The present invention can be prepared, for example, by reacting a carboxylic acid compound having the general formula (I) in which R is - (CH ₂ I _n -COOH, an amino acid compound having the general formula (I) wherein R is the same

-CH ₉ CH

* ^s COOH

or a glycine amide compound (XVI) in which R is - (CHj) _n -CONHCH! COOH, with a alkali metal percarbonate such as sodium bicarbonate or potassium hydrogen carbonate, with an alkali metal carbonate such as sodium carbonate or potassium carbonate or an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide to give a pharmacological to obtain acceptable salt such as the above-mentioned sodium or potassium salt.

Compound Group (Ic) Production Process A (Preparation of Compounds of General Formula (I) wherein R ^{4 represents} a hydrogen atom)

COOH

(H)

wherein R ¹ , R ² and R ³ are defined above wio.

In this method, a dicarboxylic acid having the general formula (II) is raised to a temperature of 15O < ⁰ > C or higher Lack of any solvent heated to obtain a proposed carboxylic acid (I) '. Production process B

(Preparation of compounds of the general formula (I) in which R ^{4 represents} a hydrogen atom)

-CH-CN

»3

R *

(III)

Hydrolysis R ² 0 ^^^^ CH-CH-COOH

(D '

wherein R ¹ , R ² and R ^{3 are} as defined above.

In this method, a nitrile of the general formula (III) is hydrolyzed in a usual manner to a designated Carboxylic acid (I) 'to get. More specifically, the hydride is prepared _by a usual method in the presence of a base in a solvent

suitably selected from the group consisting of water, alcohols such as methanol, ethanol and

Ethylene glycol, aqueous alcohols such as aqueous methanol, aqueous ethanol, aqueous ethylene glycol, aqueous Diethylene glycol and aqueous ethylene glycol, monoethyl ether, etc. consists. The bases used here include

for example, potassium hydroxide, sodium hydroxide and barium hydroxide.

Production process C When R ¹ in the general formula (I) is a lower alkoxy-lower alkyl group, the intended compound may be according to the

following methods are produced:

R CH-CH-COOR ^

Alkylene-X

MO. alkyl

I / ρ

CH-CH-COOR ⁴ '3

Alkylene-O-alkyl

(IV)

(V) (VI)

wherein R ^J , R ¹ and R ^{4 are} as defined above, X represents a halogen atom, M represents an alkali metal atom, "alkyl" represents a lower one

Alkyl group which is straight-chain or branched and has 1 to 6 carbon atoms, as described above, and

"Alkylene" means an alkylene group derived from the methyl group mentioned above.

In this method, a KaMd having the general formula (IV) with an alcoholate having the general formula (V) after

reacting in a common method in an organic solvent selected from the group consisting of

For example, from tetrahydrofuran, dimethylformamide, methanol, ethanol and 1-propanol, with cooling with ice, at

Room temperature or with heating to obtain a designated compound (VI). To the halogen atoms, which at

This method can include, for example, bromine, chlorine and iodine atoms. The alkali metal atomons include, for example, sodium and potassium.

The compound (VI) prepared by this process is a proposed compound of the present invention, which is characterized by

the general formula (I) is shown, in which R'-alkylene-O-alkyl daielih.

Production process D

A contemplated compound having the general formula (I) wherein R 'represents a lower alkyl lower alkoxy group of the formula -CHj-O-alkyl wherein "alkyl" is a lower alkyl group of 1 to 6 carbon atoms may also be prepared as follows Process are produced.

acid

CH-CH-COOR ^ ¹

CH ₂ OCOCH ₃

HO. alkyl

^ CH-pH-COOR ⁴ ^ H ₂ -OA Iky 1

(VIl) (VIII)

(IX)

wherein R ² , R ³ , R ⁴ and "alkyl" are as defined above.

In this process, an acetoxymethyl compound having the general formula (VII) is compounded with the compound

general formula (VIII) in the presence of an acid catalyst at room temperature or under heating, to

to obtain a proposed compound having the general formula (IX). This reaction is preferably carried out in the presence of a lower alcohol such as methanol, ethanol, 1-propanol or 2-propanol.

The acid catalysts include, for example, hydrochloric, sulfur ·, p-toluenesulfonic and D-10 Kamphcrsulfonsäure. The compound (IX) prepared by this process is a proposed compound of the present invention which is characterized by

the general formula (I) is shown, in which R 'represents -CHj-O-alkyl.

Production process E A compound of general formula (I) in which R 'and R ³ together form a ring may also be as follows Process to be produced:

COOR

(CH ₂ ) _n 0H

(X)

_f cyclization R ³

COOR

(XI)

wherein R ² , R ³ and R ^{4 are} as defined above and η represents an integer between 1 and 3.

An acrylic acid derivative of the general formula (X) is subjected to intramolecular cyclization to obtain a

to obtain the proposed compound (XI) according to the present invention. This reaction will after a usual

Method without the use of a solvent or in an organic solvent such as benzene, Eth & r.ol, Tetrahydrofuran or dimethylformamide with cooling with ice, at room temperature or with heating for several hours

carried out. The reaction readily occurs in the presence of a base such as sodium ethylate, potassium t-butoxide or

Sodium hydride. The compound (XI) prepared by the above-mentioned process is one of the intended compounds of the present invention

invention

Compound Group (l-d) Preparation Method A (Preparation of compounds of general formula (I) in which X represents a group of the formula -S-)

(II!)

(IV)

wherein Y represents a halogen atom or a methanesulfonyloxy or p-toluenesulfonyloxy group and A, R ¹ , R ', R ³ , R ⁴ and R ^{6 are} as defined above.

In this process, a thiol of the general formula (II) is reacted with a compound of the general formula (III) to produce a proposed compound (IV). This reaction is carried out by a usual method, without the use of a solvent or in a solvent which is organic, inert for the reaction, and selected from the group consisting of aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran and dioxane , Ketones such as acetone and methyl ethyl ketone, alcohols such as methanol and ethanol, halogenates hydrocarbons such as chloroform and carbon tetrachloride, acetonitrile, Ν, Ν-dimethylformamide and dimethyl sulfoxide, under cooling with ice, at room temperature or under heating for several hours. The reaction readily occurs when an alkali metal carbonate or hydrogen carbonate such as sodium hydrogen carbonate, potassium carbonate or sodium carbonate, an alkali hydroxide such as sodium hydroxide or potassium hydroxide or an organic base such as triethylamine, pyridine or diethylaniline are used as the dehydrohalogenating agent or a methanesulfonic or p-toluenesulfonic acid removing agent become.

Production process B

(Preparation of compounds of the general formula (I) in which X represents a group of the formula -S-)

R-

HS-A

(V) (VI)

(IV)

wherein Y is a halogen atom or a methanesulfonyloxy or p-toluenesulfonyloxy group and A, R ', R ² , R ³ , R ⁴ and R ^{5 are} as defined above.

In this process, a compound having the general formula (V) is reacted with a thiol having the general formula (VI)

under the same conditions as in the preparation process A to obtain a proposed compound (IV).

Also in this method, advantageous results are achieved when a base, as above in connection with Production method A is described is used. The halogen atoms used in preparation processes A and B include chlorine, bromine and iodine; in the As a rule, bromine and chlorine are used. Production process C

(Preparation of compounds of the general formula (I) in which X represents a group of the formula -S-)

^ CH = C

HS-A

(VII)

(Vl)

O -

R-

(IV)

wherein A, R ¹ , R ² , R ^J , R ⁴ and R ^{6 are} as defined above.

A compound of the general formula (VII) is reacted with a thiol of the general formula (VI) to form a

to obtain the proposed compound (IV). This reaction is carried out by a usual method without the

Use of a solvent or in a solvent selected from the group consisting of aromatic Hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran and dioxane, halogenated Hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, ketones such as acetone and methyl ethyl ketone, Esters such as ethyl acetate, acetonitrile and N, N-D! Methylformamide, under cooling with ice, at room temperature or below Heating under reflux. When the reaction is slow, a peroxide such as benzoyl peroixd or a catalyst such as azobisisobutyronitrile

be added.

Production process D

(Preparation of compounds of the general formula (I) in which X represents a group of the formula -S-)

CH ₀ -CS-CH ₀ CN

vs

R ¹ R ^d

CH ₀ -CS-CH-COOH

₂

R IT CN

(VIII)

(IX)

wherein R ¹ , R ² , R ¹ , R ⁴ and R ^{5 are} as defined above.

A cyano compound having the general formula (VIII) which is also a designated compound is reacted with carbon dioxide in the presence of a base to obtain a proposed carboxylic acid having the general formula (IX). In this process, a compound (VIII) in its original form or in the form of a solution in an anhydrous ether solvent such as anhydrous ethyl ether, anhydrous tetrahydrofuran or ethylene glycol anhydride is reacted with a strong base such as n-butyllithium, phenyl lithium, lithium diisopropylamide or sodium amide under cooling with dry ice / Alcohol or with ice, and the reaction product is further reacted under cooling with dry ice / alcohol or with ice with carbon dioxide to obtain the compound (IX).

The compound (IX) is a proposed compound of the present invention represented by the general formula (I) in which X is -S- and A represents -CH-COOH.

CN

Production process E

(Preparation of compounds of the general formula (I) in which X represents a group of the formula -S-)

, CH ₉ -CS- (CH ₀₎ SO.Na

R ¹ 'R ² · (X)

ch ₂ -cs- (ch ₂ ) _p so ₂ n < _r1o

R ¹ R ²

wherein R ¹ , R ² , R ³ , R ⁴ , R ^s , R ⁹ , R ¹⁰ and ρ as defined above t \ nd.

A sodium sulfonate represented by the general formula (X) is added to the suspension in, for example, benzene or chloroform. Then, thionyl chloride or the like is added, and the reaction is carried out by heating under reflux to obtain an acid chloride of the compound (X). This product is reacted with an amine (XI) in the presence of a base and in the absence of a solvent or in a solvent such as water, methanol, ethanol, benzene, dichloromethane, tetrahydrofuran or Ν, Ν-dimethylformamide to obtain a proposed compound (XII) receive. Examples of suitable bases include the amine (XI) as such, pyridine, Ν, Ν-dimethylaniline or triethylamine. The compound (XII) is a proposed compound of the present invention represented by the general formula (I) wherein X is -S- and A \

R ⁹

- (CH ₂ IpSO ₂ N represents

_R io

Production process F

(Preparation of compounds of general formula (I),

1,

where X represents a group with the formula

, 4

(IV)

wherein A, R ¹ , R ', R', R ⁴ and R ^{s are} as defined above.

A compound (IV), which is also an intended compound prepared by, for example, the method described above, is oxidized to obtain a desired or intended compound (XIII). In this process, the compound (IV) is dissolved in a solvent selected from the group consisting of aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, water, alcohols such as methanol and ethanol, ethyl acetate , Acetone and acetic acid, and then reacted with an equimolar amount of an oxidizing agent such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid or sodium hypochlorite by a usual method under cooling with dry ice / alcohol or with ice / water to obtain an intended sulfoxide compound (XIII) ,

Production process G

(Preparation of compounds of general formula (I) in which X represents a group of the formula

(XIV)

wherein A, R ¹ , R ² , R ³ , R ⁴ and R ^{s are} as defined above.

In this method, a proposed compound (IV), for example, according to the method described above

was prepared, oxidized to obtain a proposed compound (XIV). In detail, the compound (IV) in a

Dissolved solvent selected from the group consisting of aromatic hydrocarbons such as benzene, toluene

and xylene, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, water, alcohols such as methanol and ethanol, ethyl acetate, acetone and acetic acid. For this purpose, at least two equivalents one ";

Oxidizing agent such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, sodium hypochlorite or Natriu n-m

periodate under cooling with ice or at room temperature to carry out the reaction while keeping a voi seen

To obtain sulfone compound (XIV). In another method, a sulfoxide compound (XIII) prepared by, for example, Preparation Method F

is dissolved in a solvent such as chloroform, and then the solution is an oxidizing agent such as m-

Added chloroperbenzoic acid to carry out the reaction. Pharmacologically acceptable salts of the proposed compounds (I), which are also intended products according to the

can be prepared, for example, by the reaction of a compound with the

/ ^r6

general formula (I) wherein A is -C-y-COOH, R ^{3 is} - (CH ₂ J _n COOH or A is - (CH ₂ ) ₂ OH

CH ₃

with sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide to obtain a pharmacologically acceptable salt, such as its sodium or potassium salt.

Compound Group (l-e) Preparation Method A

HS-CH-CH ₀ -Y p ²

oxidation

^ X-S-S-CH-CHo-Y

wherein X, R ¹ and Y are defined above.

That is, a thiol represented by the general formula (II) is reacted with a thiol represented by the general formula Formula (III) is prepared to obtain a compound (I) which is one of the target compounds of the present invention More specifically, the reaction of a compound (II) with a compound (III) in the absence of any solvent or in

a solvent that is inert to the reaction and has been selected from alcohols such as methanol, ethanol and

Propanol, acetic acid and an aqueous solution of potassium iodide or the like, either under cooling with ice or below Heat at room temperature using a. Oxidizing agents such as iodine, hydrogen peroxide, lead dioxide, Oxygen, copper sulfate, iron chloride, potassium permanganate, potassium ferricyanide, sulfuryl chloride, dimethylsulfide id. Sulfur dioxide or phosphorus pentachloride by a usual method to obtain a compound (I) which is one of Target connections is. Production process B XSS-OH ₉ CH ₉ OlI

(IV)

S ₅

OK-C-R

(V)

wherein X is as defined above, R ^{1 represents} a lower alkyl, aryl or heteroaryl group and Hal represents a halogen atom. More specifically, the reaction of an alcohol represented by the general formula (IV) with an acid halide represented by the general formula V is carried out in the absence of a solvent or in the presence of a solvent such as dichloromethane, chloroform, tetrahydrofuran or Ν, Ν-dimethylformamide using a base such as pyridine, triethylamine, Ν, Ν-dimethylaniline, sodium carbonate or sodium hydrogencarbonate as a dehydrohalogenating agent to obtain a compound (Vl) which is one of the target compounds. In the reaction, pyridine may serve as a solvent and also as a dehydrohalogenating agent. The reaction can be carried out either under cooling with ice or under reflux by heating.

The preparation of pharmacologically acceptable salts of the compounds (I) belonging to the target compounds of the present invention can be carried out, for example, by reacting a compound represented by the general formula (I) in which Y represents door

-ο-3 / Λ,

with hydrochloric, sulfuric or hydrobromic acid. That's how you get that

Hydrochloride, sulfate or hydrobromide of compound (I). Compound group (M) Production method A

(II)

HS-CII ₂ -GO ₂ Il

(! II)

(IV)

wherein the formula (II) to (IV), R ¹ , R ² and R ^{3 are} as defined above.

That is, an alcohol represented by the general formula (II) is reacted with a mercaptoacetic acid represented by the general formula (III) to obtain a compound represented by the general formula (IV), which is one of the target compounds of the present invention. This reaction is carried out without any solvent or in the presence of an organic solvent which is inert to the reaction and has been selected from aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as ethers, isopropyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as dichloromethane, chloroform and Carbon tetrachloride, esters such as ethyl acetate, ketones such as acetone and methyl ethyl ketone, acetonitrile, dimethylformamide and acetic acid, either under cooling with ice or under heating or at room temperature for several hours, according to a conventional method. The progress of the reaction is facilitated by the use of an acid such as sulfonic, p-toluenesulfonic or D-10-camphorsulfonic acid as a catalyst.

Production process B

(V)

(Ml) (VI)

wherein the formula (V) and (Vl) are as defined above. Hal represents a halogen atom or a methanesulfonyloxy or p-toluenesulfonyloxy group, and R ¹ , R ² , R ³ and η are as defined above.

That is, a precursor represented by the general formula (V) is reacted with a mercaptoacetic acid represented by the formula (III) to obtain a compound represented by the general formula (VI) which is one of the objective compounds of the present invention Inventions is.

Specifically, the above reaction is carried out without any solvent or in the presence of an organic solvent which is inert to the reaction and selected from aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, alcohols such as methanol and ethanol, halogenates hydrocarbons such as chloroform and carbon tetrachloride, azo nitrile, N, N-dimethylformamide and dimothylsulfoxide, either under cooling with ice or under heating or at room temperature for several hours, according to a conventional method. The progress of the reaction can be facilitated by the use of an alkali metal carbonate or hydrogen carbonate such as sodium hydrogencarbonate or potassium or sodium carbonate; an alkali hydroxide such as sodium or potassium hydroxide; an organic base such as triethylamine, pyridine or diethylaniline or sodium chloride as dehydrohalogenating, demethanesulfonating or de-ptoluensulfonatierendem agent.

In preparation processes A and B, the halogen atom may be chlorine, bromine and iodine, in which case bromine and iodine are generally used.

Production process C

(CH _p ) -S-CH 2 CO 2 _p H

^{2 n 2} (IV)

_f (VIII)

wherein R ⁴ and R ^{6 may be the} same or different and each is a hydrogen atom or a lower one

Represent alkyl group and R ¹ , R ² , R ¹ and η are as defined above. That is, a carboxylic acid represented by the general formula (VI) or its reactive derivative, e.g.

can be prepared by the production process A or B described above, is reacted with an amine represented by the general formula (VII) to obtain a compound represented by the general formula (VIii) which is one of the objective compounds of the present invention Invention is.

The reactive derivatives of compound (VI) include acid halides such as acid chloride and acid bromide, acid azide, their

reactive esters with N-hydroxybenzotriazole, N-hydroxysuccinimide or the like, symmetrical acid anhydride and their mixed acid anhydride with alkylcarboxylic acid and p-toluenesulfonic acid.

When a compound (VI) having a free carboxyl group is used, the reaction is preferably in the presence

a condensing agent such as dicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole.

The reaction is carried out using a compound (VI) or its reactive derivative and a compound (VII)

in equimolar amounts or in such amounts that one of the two compounds is present in slight excess over the other, in an organic solvent inert to the reaction and selected from pyridine, tetrahydrofuran, dioxane, ether, benzene, toluene , Xylene, methylene chloride, dichloroethane,

Chloroform, dimethylformamide, ethylacetate, acetonitrile and the like. When some types of reactive derivatives are used, the addition of a base such as triethylamine, pyridine, picoline, Lutidine, Ν, Ν-dimethylaniline, potassium carbonate or sodium hydroxide advantageous to accelerate the course of the reaction. The reaction temperature is not specifically limited and depends on the type of reactive derivative used.

-27- 287 Manufacturing Process D

₅ ) -S-CH ₅ CO ₅ H 2 η 2 · 2

(IX) (X)

wherein R ¹ , R ² , R ⁵ and η are defined as cb & r €.

Specifically, a compound (VI) which can be prepared by the preparation process A or B is dissolved in a solvent such as benzene, chloroform or dimethylformamide, followed by the addition of thionyl chloride, oxalyl chloride, phosphorus oxychloride or phosphorus pentachloride. The resulting mixture is reacted either under cooling with ice or under reflux by heating or at room temperature to prepare an acid chloride of the compound (VI). A solution of glycine (IX) in an aqueous solution of sodium hydrogen carbonate, sodium carbonate or sodium hydroxide ( ¹ ) or the like is poured into the recovered reaction mixture with stirring and cooling with ice to carry out the reaction. Consequently, a glycine amide (X), which is one of the target compounds, is obtained.

The glycine amide (X) obtained above corresponds to a compound represented by the general formula (I) in which R ⁴ or R * is a carboxymethyl group, and thus is one of the Ziilveibindungen according to the present invention. The preparation of a pharmacologically acceptable salt of compound (I). which is also one of the target compounds of the present invention can be carried out, for example, by the reaction of a carboxylic acid (VI) corresponding to a compound represented by the general formula (I) in which Y is a -COjH, or a glycine amine (X) corresponding to a compound represented by the general formula (I) wherein R ⁴ or R ^{5 is} a carboxymethyl group, with an alkali hydrogen carbonate such as sodium or potassium dibium carbonate, an alkali carbonate such as sodium or Potassium carbonate or an alkali metal hydroxide such as sodium or potassium hydroxide.

Embodiments of the invention

The invention will be described below by way of examples and the preparation of the starting materials for the compounds of the invention according to the invention groups (I-a) to (I-f) of compounds.

Connection group (l-a)

HerstQllungsbelsplel 1 2 · (1,3 · ζβηζοαΙοχοΙ · 5 · νΙ) · 2 · ρκ> ρ8ηοΙ

About 600 ml of 1.5 M methyl lithium (solution in ether) was added 50 ml of tetrahydrofuran. These were added under cooling

-2O ⁰ C 93.45g siner suspension of 5-acetyl-1,3-benzodioxole in 900ml tetrahydrofuran. The mixture was stirred under these conditions for 1 h. Water was added to the reaction mixture. The product was extracted with ethyl acetate, washed with a saturated, aqueous, ordinary saline solution and dried over anhydrous magnesium sulfate. After filtering, the filtrate was concentrated to give 97 g of the intended compound as a

¹ H-MKROOMHz ₁ CDCI)) S;

1.54 (s, 6H), 1.72 (bs, 1H), 5.88 (s, 2H), β, β ~ 7.0 (m, 3H).

Preparation Bels 2 2- (1,3-benzodioxol-5-yl) propene

14.52 g of 2- (1,3-benziodioxol-5-yl) -2-propanol were dissolved in 20 ml of Berite. To the solution was added a catalytic amount of p-toluenesulfonic acid monohydrate, and the mixture was refluxed in a Kjeldahl short-necked flask equipped with a Dean-Stark reflux condenser. Treatment time 2.5 hours. The reaction mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then with a saturated aqueous ordinary saline solution, and dried over anhydrous sodium magnesium sulfate. After filtering, the filtrate was concentrated to give 14.33 g of the intended compound as an oil. ¹ H-MKR (90MHz, CDCl ₃ ) δ; 2.08 (bs, 3H), 4.8 ~ 5.0 (m, 1H), 5.19 (bs, 1H) 5.89 (s, 2H), 6.5 ~ 7.0 (m, 3H).

Preparation sheet 3 1- (6-methyl-1,3-benzodloxy-5-yl) ethanol

32 ml of a 1.4M solution of methyl lithium in diethyl ether were dissolved in 50 ml of anhydrous tetrahydrofuran, and the

Solution was cooled at -40 ° C in a nitrogen atmosphere. To the solution was added 5.0 g of solid (6-methyl-1,3-benzodioxol-5

yD Carboxaldehyde was added and the temperature was gradually raised to room temperature over one hour. the

Reaction mixture was added to water. After extraction with ether, the organic layer was washed with an aqueous layer

washed ordinary saline solution. After drying over magnesium sulfate, the solvent was distilled off to give a white solid which was obtained from diisopropalyl ether / n-hexane. was recrystallized and 2.8g of the intended

Compound in the form of white crystals resulted. Melting point: 61 ° C-62 ° C.

¹ H-MKROOMHz ₁ CDCl ₃ ) O;

1.39 (d, J = 7Hz, 3H), 1.72 (bs, 1H), 2.22 (s, 3H), 4.99 (m, 1H), 5.83 (s, 2H ), 6.53 (s, 1H), 6.94 (s, 1H).

Prepared Example 4 1- (6-Methyl-1,3-benzodioxol-5-yl) -1-propanol

θ-

OH Ο-

A solution of 2.0 g (6-methyl-1,3-benzodioxol-5-yl) carboxaldehyde in 15 ml of anhydrous tetrahydrofuran was added dropwise at room temperature to a Grignard reagent consisting of 0.32 g of magnesium tape, 20 ml of anhydrous tetrahydrofuran and 1.4 g Bromoethane had been prepared. The mixture was stirred for 2 hours. To the reaction mixture was added a saturated ammonium chloride solution. The solvent was distilled off. After extraction with ethyl acetate followed by drying over magnesium sulfate and concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 2: 8) to give 2.27 g of the intended compound as white crystals

Melting point: 71 ^e C-72 ° C

'H-KMR (90 MHz, CDCl ₁ ) δ; 0.92 (t, J - 7Hz, 3H), 1.68-1.92 (m, 2H), 1.8 (bs, 1H), 2.20 (s, 3H), 4.72 (t , J = 7Hz, 1H), 5.82 (s, 2H), 6.52 (s, 1H), 6.88 (s, 1H).

Production Example 5

1- (6-ethyl-1,3-benzodioxol-5-yl) -1-propanol

A solution of 3.2 g of (6-ethyl-1,3-benzodioxol-5-yl) carboxaldehyde in 10 mL of anhydrous tetrahydrofuran was added dropwise at room temperature to a Grignard reagent consisting of 0.54 g of magnesium tape, 10 mL of anhydrous tetrahydrofuran, and 2, 4 g of bromoethane had been produced. The reaction was carried out at this temperature for 2 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution. The solvent was distilled off. After extraction with ethyl acetate, followed by drying over magnesium sulfate and concentration under reduced pressure, 3.9 g of the crude alcohol were obtained in the form of a yellow oil which was used without purification in the subsequent reaction

¹ H-MKR (90MHz, CDCl,) δ:

0.96 (t, J = 7Hz, 3H), 1.18 (t, J = 7Hz, 3H), 1.72 (m, 3H), 2.32-2.80Jm, 2 H), 4.76 (t, J = 7Hz, 1H), 5.84 (s, 2H), 6.58 (s, 1H), 6.88 (s, 1H).

Preparation Example 5,6-Met'-> ylendioxylndan-1-ol

A solution of 30 g of 5,6-methylenedioxyindan-1-one in 120 ml of tetrahydrofuran was added dropwise to a suspension of 2.4 g Lithium aluminum hydride in 160ml of anhydrous tetrahydrofuran while cooling with ice. The mixture was over Stirred at room temperature overnight. To this was added 2.4 ml of water, then 2.4 ml of 15% aqueous Sodium hydroxide solution and finally 7.2 ml of water, and the insoluble substances were filtered out. The Filtrate was distilled and the residue was washed with diisopropyl ether to give 24.3g of the intended Compound in the form of pale brown crystals. Melting point: 92 ^° C-94 "C.

¹ H-MKROOMHz ₁ CDCI]) O;

1.76 (d, J = 7Hz, 1H), 1.93 (m, 1H), 2.28-3.08 (m, 3H), 5.10 (m, 1H), 5.92 (s, 2H), 6.65 (s, 1H), 6.83 (s, 1H).

Example 1 [{1- (1,3-Benzodloxot-5-yl) -1-butyl} thio] acetate

A mixture of 103 g of 1- (1,3-benzodioxol-5-yl) -1-butanol, 73.3 g of mercaptoacetic acid, 0.1 g of D-10 camphorsulfonic acid and 500 ml of benzene was heated under reflux for 2 hours. To the reaction mixture was added 2000 ml of ether. After washing with water, the product was redissolved in 750 ml of 1 N NaOH and then in 100 ml of it. The solution thus obtained was washed with ether and then with chloroform, made acidic with concentrated hydrochloric acid and extracted with 800 ml and then with 400 ml of ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 132 g of the crude product. It was purified by silica gel column chromatography (ethyl acetate / hexane / formic acid = 100: 900: 1) to give 127 g of the intended compound as a colorless oil

¹ H-MKR (90MHz, CDCl ₃ ) δ;

0.88 (m, 3H), 1.12-1.52 (m, 2H), 1.78-1.94 (m, 2H), 2.92 and 3.03 (ABq, J = 15Hz, 2H), 3.92 (t, J = 7Hz, 1H), 5.92 (s, 2H), 6.68-6.80 (m, 3H).

Example 2 Notrium [t1- (1,3-benzodloxol-5-yl) -1-butyl] thiol] acetate

100 g of [{1- (1,3-benzodioxol-5-yl) -1-butyl} thio] acetic acid were dissolved in 500 ml of ethanol. To this was added 372 ml of 1 N aqueous sodium hydroxide solution. Ethanol and water were removed by azeotropic distillation from the

Reaction mitch was removed, and the residue was added to the residue to solidify it. The thus formed Precipitate was collected by filtration and dried to give 102g of the intended compound

white powder.

Melting point: 193 ° C-207'C (decomposition).

¹ H-MKH (400MHz, DMSO-d,) δ;

0.82 (t, J - 7.3Hz, 3H), 1.11-1.2e (m, 2H), 1.59-1.77 (m, 2H), 2, e4 and 2.73 (ABqJ = 13.9Hz , 2H), 3.87 (dd, J = 9.2Hz, 6.2Hz, 1H), 5.97 (a, 2H), 6.71 (dd, J - 8.1Hz, 1H), 6 , 79 (d, J ° 8.1 Hz, 1H), 6.84 (d, J = 1.8Hz, 1H). MS (FAB) m / z: 291 (MH ').

Example 3 [(2- (1,3-Benzodloxol-5-yl) -2-propyl] thio] -salicylic acid

'S

600ml of benzene, 69.5g of mercaptoacetic acid and a catalytic amount of D-10 camphorsulfonic acid were added to 97g of 2- (1.3-

Benzodioxol-5-yl) -2-propanol and the mixture was heated at reflux for 4 hours. The solvent

was triturated and the pH of the residue was adjusted to 10 with 1 N aqueous sodium hydroxide solution. After washing with ethyl acetate, 4N hydrochloric acid was added under cooling with ice to acidify the aqueous layer. After extraction with chloroform, the extract was washed with water and dried over anhydrous magnesium sulfate. It was filtered and the filtrate was concentrated. The crystals thus formed were recrystallized from diisopropyl ether to give 62.70 g of the intended compound as colorless crystals.

Of 38.73 g of 2- (1,3-benzodioxol-5-yl) propene were also prepared in the same manner as described above, 37.32 g Won the connection. Melting point: 78.5 ° C-80 ^e C.

¹ H-MKR (90MHz, CDClI) δ;

1.68 (s, 6H), 2.99 (s, 2H), 5.88 (s, 2H), 6.64 (d, J = 8.3Hz, 1H), 6.86 (dd, J = 8.3Hz, 2.5Hz, 1H), 6.99 (d, J = 2.5Hz, 1H), 8.0-9.0 (br,

Example 4 Sodium um - [{2- (1,3-benzodioxol-5-yl) -2-propyl) thio] acetate

Goona

107.62 g of the intended compound in the form of colorless crystals were recovered from 99.88 g of [{2- (1,3-benzodiuxol-5-yl) -2-propyl} thio) acid in the same manner as in Example 2.

Melting point: 229.5 ° C-230.5 ^c C.

¹ H-KMR (400MHz, DMSOd ₆ ) δ;

1.54 (s, 6H), 2.69 (s, 2H), 5.98 (s, 2H), 6.80 (d, J = 8.1Hz, 1H), 6.88 (dd , J = 8.1 Hz, 1.8Hz, 1H), 7.06 (d, J = 1.8Hz, 1H).

MS (FAB) m / e: 277 (MH ')

Example 5 [{1- (6-Methyl-1,3-benzodioxol-5-yl) ethyl} thio] essential acid

3.7g of mercaptoacetic acid and a catalytic amount of D-10 camphorsulfonic acid were added to 3.2g of 1- (6-methyl-1,3-benzodioxol-5-yl) ethanol and the mixture was refluxed in 100ml benzene over Heated hour. The reaction mixture was washed with water and then extracted with an 11N sodium hydroxide solution. The aqueous layer was washed with ethyl acetate, acidified with 1 N hydrochloric acid and extracted with chloroform. The organic layer was dried over magnesium sulfate and the solvent was distilled off to obtain a crystalline residue. After recrystallization from diisopropyl ether, 4.2 g of the intended compound were obtained in the form of white crystals

Melting point: 93.5 ° C-94.5 ^C C

¹ H-MKR (90MHz, CDCl ₅ ) δ;

1.51 (d, J = 7Hz, 3H), 2.26 (s, 3H), 2.92 and 3.12 (ABq, J = 16Hz, 2H), 4.39 (q, J = 7Hz, 1 H), 5.85 (s, 2H), 6.54 (s, 1H), 6.94 (s, 1H), 10.12 (m, 1H).

Example 6 Sodium [(1- (6-Mothyl-1,3-benzodioxol-5-yl) ethyl) thio] a2etate

CO ₂ Na

4.0 g of the intended compound in the form of white crystals were recovered from 3.85 g of [{1- (6-methyl-1,3-benzodioxol-5-yl) ethyl} thio) acetic acid in the same manner as in Example 2.

Melting point: 189 ° C-192 ° C (decomposition).

¹ H-MKR (400MHz, DMSO-d,) δ;

1.39 (d ₍ J = 7.0Hz, 3H _< 2.24 (s, 3H), 2.78 (s, 2H), 4.28 (q, J = 7 ₍ 0Hz, 1H), 5.92 (m , 2H), s, 68 (s, 1H), 6.92 (s, 1H); MS (FAB) m / z: 227

Example 7 [{1- (6-Methyl-1,3-benzodioxol-5-yl) -1-propyl) thiol] acid

2.27 g of 1- (6-methyl-1,3-benzodioxol-S -yl) -1-propanol, 0.1 g of p-toluenesulfonic acid and 1.52 g of mercaptoacetic acid were dissolved in 80 ml of benzene. The solution was refluxed for 12 hours, removing water. The reaction mixture was poured into water. The aqueous layer was made alkaline and washed with ether. Then, the aqueous layer was made acidic and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give a pale yellow solid. This was purified by silica gel column chromatography (ethyl acetate / hexane = 2: 8) to give 2.83 g of the intended compound as white crystals

 Melting point: 98 ° C-99 ° C

¹ H-MKR (90MHz, CDCl ₃ ) δ;

0.88 (t, J = 7Hz, 3H), 1.60-2.12 (m, 2H), 2.24 (s, 3H), 2.96 and 3.08 (ABq, J = 14Hz, 2H), 4.26 (dd, J = 7Hz, 1H), 5.92 (s, 2H), 6.62 (s, 1H), 6.98 (s ₍ 1 H).

Example 8 Natrlum [{1- (5-methyl-1,3-benzodioxol-5-yl) 1-propyl} thio] acetate

CO ₂ Na

2.9 g of the intended compound in the form of white crystals were prepared from 2.83 g of [(1- (6-methyl-1,3-benzodioxol-5-yl) -1-propyl) thiol] (glycerol in the same manner as prepared in Example 2.

Melting point: 215 ° C-216 * C (decomposition).

¹ H-MKR (400MHz, DMSO-d,) δ;

0.78 (t, J = 7Hz, 3H), 1.62-1.69 (m, 1H), 1.78-1.86 (m, 1H), 2.21 (s, 3 H), 2.71 and 2.73 (ABq, J = 13.0Hz, 2H), 4.07 (dd, J = 9.2Hz, 5.9Hz, 1H), 5.93 ( m, 2H), 6.69 (s, 1H), 6.86 (s, 1H).

MS (FAB) m / z: 292 (MH ").

Example 9 Ethyl ki-te-ethyl-La-benzodloxol-S-yD-i-propyl-thiol acetate

3.9 g of 1- (6-ethyl-1,3-benzodioxol-5-yl) -1-propanol, 0.1 g of p-toluenesulfonic acid and 3.35 g of ethyl mercaptoacetate were dissolved in 80 ml of benzene. The solution was heated at reflux for 12 hours, removing water. Subsequently, water was added. Extraction with benzene was followed by drying over magnesium sulfate and concentration under reduced pressure. Then, the product was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 9) to obtain 4.0 g of the intended compound as a colorless, transparent oil. 'H-MKR (90MHz, CDCI ₁ ) δ;

0.92 (t, J = 7Hz, 3H), 1.16 (t, J = 7Hz, 3H), 1.26 (t, J = 7Hz, 3H), 1.50-2.21 (m, 2H ), 2.44-2.80 (m, 2H), 2.96 and 3.08 (ABq, J - 14Hz, 2H), 4.16 (q, J = 7Hz, 2H), 4.24 (dd, J = 9Hz, 7Hz, 1H), 5.92 (s, 2H). 6.64 (s, 1H), 7.00 (s, 1H).

Example 10 [{1- (6-Ethyl-1,3-benzodloxol-5-yl) -1-propyl} thiol] oleic acid

4.0 g of ethyl - [{1- (3-ethyl-1,3-benzodioxol-5-yl) -1-propyl} -thio] a! And 2.6 g of sodium hydroxide were dissolved in a mixture of 20 ml of water and 20 ml of ethanol dissolved. The solution was heated at reflux for 2 hours. The ethanol was distilled off and the residue was washed with ether. The aqueous layer was acidified and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 2: H) to give 2.8 g of the intended compound as white crystals

Melting point: 88 ° C ^O C-89

¹ H-MKR (90MHz, CDCI ₃ )?.;

0.92 (t J = 7Hz, 3H), 1.1β (t, J = 7Hz, 3H), 1.56 to 2.12 (m, 2H), 2.24-2 , 76 (m, 2H), 2.95 and 3.08 (ABq, J = 16 Hz, 2H), 4.20 (t, J = 7Hz, 1H), 5.88 (see 2H) , 6.58 (s, 1H), 6.90 (s, 1H), 9.72 (bs, ΊH).

Example 11 Natrlum [{1- (6-ethyl-1,3 - ':> enzodloxol-5-yl) -1-propyl} thlo] -a ;: etat

CO ₂ Na

3.0 g of the intended compound in the form of woke crystals were prepared from 2.83 g of {1- (6-ethyl-1,3-benzodioxol-5-yl) -1-propyl) thio] -acetyl in the same manner as in Example 2 won.

Melting point: 221 ° C-223 ° C (decomposition).

¹ H-MKR (400MHz, DMSO-d,) δ;

0.79 (t, J · »7Hz, 3H), 1.0a (t, J = 7Hz, 3H), 1.63-1.70 (m, 1H), 1.80-1.88 (m, 1H), 2.47-2 _l 66 (m, 1H), 2.60 to 2.67 (m, 1H), 2.73 and 2.77 (ABq, J - 13.9 Hz, J: H), 4, 06 (dd, J «8.4 Hz, 6.2 Hz, 1H), 5.93 (m, 2H), 6.69 (s, 1H), 6.87 (s, 1H).

MS (FAB) m / z: 305 (MH ").

Example 12 ({(6-Methyl-1,3-benz, idloxol-5-yl) methyl} thio] -acetic acid

CQP

S CO ₂ H

CH.

A suspension of 6.0 g of 5-chloromethyl-6-methyl-1,3-benzodioxole, 6.0 g of mercaptoacetic acid and 6.5 g of sodium hydroxide in 130 ml of aqueous 50% ethanol was heated under reflux for one hour. The reaction mixture was concentrated. Water was added thereto and the mixture was washed with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid. After extraction with chloroform, the extract was dried over magnesium sulfate. The solvent was distilled off and the product was isolated by silica gel column chromatography (chloroform). The crystals thus obtained were recrystallized from diisopropyl ether to obtain 1.6 g of the intended compound as white crystals

 Melting point: 90 ° C-92 ° C

¹ H-MKR (90MHz, CDCl ₃ ) δ; 2.30 (s, 3H), 3.14 (s, 2H), 3.76 (s, 2H), 5.86 (s, 2H), 6.60 (s, 1H), 6.70 (s, 1H) I

Example 13 Natrlum [((6-methyl-1,3-benzodloxol-5-yl) methyl) thiol] acetate

CO ₂ Na

1.7 g of the intended compound in the form of white crystals were recovered from 1.6 g of {(6-methyl-1,3-benzodioxol-5-yl-methyl) thio] acetic acid in the same manner as in Example 2.

Melting point: 214 ° C-215 ° C (decomposition).

¹ H-MKR (400MHz, DMSO-d ") δ;

2.23 (s, 3H), 2.85 (s, 2H), 3.63 (s, 2H), 5.93 (s, 2H), 6.73 (s, 1H), 6.81 (s, 1H)

MS (FAB; Neg) m / z: 239 (M "Na").

Example 14 {(5,6-methylene-1-oxy! Ndan-1-yl) thio} oleic acid

COQ

0.94 g of 5,6-methylenedioxyindan-1-yl, 0.98 g of mercaptoacetic acid and a catalytic amount of D-10 camphorsulfonic acid were refluxed in 30 ml of benzene for 30 min. The reaction mixture was washed with water and extracted with an aqueous 1N sodium hydroxide solution. The aqueous layer was acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was dried over magnesium sulfate. The solvent was distilled off, and the product was purified by silica gel chromatography (chloroform) and isolated, to give 1.14 g of the intended compound as a pale brown oil

¹ H-MKROOMHz ₁ CDCl ₃ ) O; 2.07-3.09 (m, 4H), 3.22 (s, 2H), 4.37 (m, 1H), 5.88 (s, 2H), 6.61 (s, 1H), 6.77 (s, 1H), 9.72 (m, 1H).

Example 15 Sodium {(5,6-methylendloxy-1-yl) thiol} acetate

, 0

CO ₂ Na

2.3 g of the intended compound in the form of white crystals were recovered from 2.4 g of {(5,6-methylenedioxyindan-1-yl) thio) acetic acid in the same manner as in Example 2.

Melting point: 210 ° C-224 ° C (decomposition).

¹ H-MKR (40OMHz, DMSO-d,) 6;

2.01 (m, 1H), 2.39 (m, 1H), 2.67 (ddd, J = 15.4Hz, 8.4Hz, 4.4Hz, 1H), 2.84 (m , 1 H). 2.89, 2.89 and 294 (ABq, J = 13..6 Hz, 2 H), 4.28 (dd, J => 7.3 Hz, 4.0 Hz, 1 H), 5.96 (m, 2H), 6.76 (s, 1H), 6.84 (s, 1H)

MS (FAB, Neg) m / z: 251 (m-Na ").

Example 16 {(6,7-Methylendloxytetraln-1-yl) thiol) eselic Acid

1.2 g of 6,7-methylenedioxy-1-tetralone was added to a suspension of 0.2 g of lithium aluminum hydride in 20 ml of tetrahydrofuran while cooling with ice. The mixture was stirred at room temperature overnight and cooled with ice / water. To this was added 0.2 ml of water, then 0.2 ml of an aqueous 15% sodium hydroxide solution and finally 0.6 ml of water. Insoluble substances were removed by filtering. The fitrate was concentrated to give a crystalline residue. To the residue was added 1.1 g of mercaptoacetic acid and a catalytic amount of D-10-camphor-sulfonic acid, and the mixture was refluxed in 30 ml of benzene for one hour. The reaction mixture was washed with water. After extraction with a 1N sodium hydroxide aqueous solution, the aqueous layer was acidified with 1N hydrochloric acid. After extraction with chloroform, the extract was dried over magnesium sulfate, and the solvent was distilled off. The crystalline residue thus obtained was treated by silica gel column chromatography (chloroform) to give 1.4 g of the intended compound as white crystals

Melting point: 138'C-139 ^e C

¹ H-MKROOMHz ^ DCIj) O; 1.6-2.2 fm, 4H), 2.65 (m, 2H), 32.0 and 3.34 (ABq, J = 16Hz, 2H), 4.18 (m, 1H), 5 , 83 (s, 2H), 6.45 (s, ίH), 6.79 (s, 1H).

Example 17 Sodium - {(6,7-methylenedioxytetraolln-1-yl) thio} acetate

.CO ₂ Na

1.3 g of the intended compound in the form of white crystals were prepared from 1.3 g of {(6,7-methylenedioxytetralin-1-yl) thio} acetic acid in the same manner as in Example 2.

Melting point: 180 ° C-184 ° C (decomposition).

¹ H-MKR (400MHz, DMSO-d _f) δ;

1.63 (m, 1H) .1.85 (m, 1H), 1, '95 (m, 2H), 2.59 (m, 2H), 2.89 and 3.04 (ABq, J = 13.9Hz , 2H), 4.18 | m, 1H), 5.91 (m, 2H), 6.55 (s, 1H),

MS (FAB) m / e: 289 (ΜΗ ')

Example 18 [{! (E-Methyl-La-benzodioxol-S-ylethyl} -butyl-lactic acid

1.7 g of 80% m-Chloroperbenzosaure wl \ 1s a solution of 2.0 g of [(1 - (6-MethyM, 3-benzodioxol-5-yl) ethyl} -thiolessigsSure in 40ml of chloroform under cooling \ i with ice was added. the mixture was stirred at room temperature overnight, and was by filtering an insoluble ^«1, obtained crystalline substance and washed with ether to give 0.24 g of the intended compound (as a single diastereomer) in the form of white crystals.

Melting point: 129 ° C-130 ° C (decomposition).

¹ H-MKR (90MHz, DMSO-d,) δ; 1.53 (d, J = 7Hz, 3H), 2.23 (s, 3H), 3.13 and 3.54 (ABq, J = -14Hz, 2H), 4.26 (q, J = 7Hz, 1H), 5.92 (s, 2H), 6.72 (s, 1H), 6.86 (s, 1H).

The filtrate recovered by the above-described treatment was concentrated to give a crystalline residue, which

was washed with benzene. The wash was concentrated to give a crystalline residue, which was washed with ether to give 1.4 g of the intended compound (as the other diastereomer) as white crystals.

Melting point: 111 ⁰ C-112 ⁰ C (decomposition).

¹ H-MKR (90MHz, DMSO-d,) δ; 1.52 (d, J = 7Hz, 3H), 2.26 (s, 3H), 3.51 and 3.60 (ABq, J = 14Hz, 2H), 4.27 (q, J = 7Hz, 1H), 5.92 (s, 2H), 6.73 (s, 3H)

Example 19 [{1- (1,3-Benzodloxol-5-yl) -1-butyl} sulfinyl] diacetic acid

2.0 g of the intended compound (as a diastereomer Gernisch of 3: 1, determined by nuclear magnetic resonance) in the form

of a colorless oil were recovered from 2.9 g of [(1- (1,3-benzodioxol-5-yl) -1-butyl) thiojacetic acid in the same manner as in Example.

¹ H-MKR (400MHz, DMSO-d,) δ; 0.86 (t, J = 7.3Hz, 3HχVt ). 0.88 (t, J = 7.6Hz, 3H x V <<), 1.14-1.33 (m, 2H), 1.80-2.07 Im, 2H), 2.89 and 3.55 (ABq , J = 14.4Hz, 2Hx Ά), 3.40 and 3.43 (ABq, J = 14.3Hz, 2H x Va). 3.85 (dd, J = 9.2Hz, 7.0Hz, 1H x V "), 4.04 (dd, J = 11.9Hz, 3.9Hz, 1H XV <), 6.02 (s, 2H ), 6.74-6.95 (m, 3H).

Example 20 [(1- (6-Methyl-1,3-benzodloxol-5-yl) -ethyl] sulfonyl) -salicylate

3.4 g of 80% m-chloroperbenzoic acid was added to a solution of 2.0 g of {1- (6-methyl-1,3-benzodioxol-y-yl) ethyl} -thio] acetic acid under cooling with ice Stirring was carried out at room temperature overnight, benzene was added, and the crystals thus formed were collected by filtration, the crystals were dissolved in ethyl acetate, and an insoluble matter was filtered, the filtrate was concentrated, and the resulting crystalline residue became washed with ether to give 0.9 g of the intended compound in the form of white crystals. melting point: 143 ⁰ C-144 ^o C (decomposed)

¹ H-MKR (90MHz, DMSOd ₆ ) δ; 1.62 (d, J = 7Hz, 3H), 2.27 (s, 3H), 3.96 and 4.36 (ABq, J = 15Hz, 2H), 4.92 (q, J = 7Hz, 1H), 5.94 (s, 2H), 6.74 (s, 1H), 6.87 (s, 1H).

Compound Group * (l-b) Example 1 (Compound 1) 2- (1,3-Benzodloxol-5-yl) ethanthlol

750 g of 5- (2-bromoethyl) -1,3-benzodioxole were dissolved in 11% ethanol. To the solution was added 312g of thiourea and the mixture was heated under reflux on a boiling water bath for 2 hours. The reaction mixture was cooled. To this was added a solution of 300 g of sodium hydroxide in 11 g of water, and the mixture was heated under reflux on a boiling water bath for 45 min. After cooling, 31% water was added thereto and the product was extracted with 51% ethyl acetate. The extract was washed with dilute hydrochloric acid. It was then washed with water until substantially neutral, and dried over anhydrous sodium sulfate. The solvent was distilled off at 40 ° C to yield about 570 g of a pale yellow oil. It was purified by column chromatography with about 3 kg of silica gel (hexane: benzene = 2: 1) to give 310 g of the intended compound as a colorless oil

 MKR (90MHz, CDCI,) δ; 1.36 (m, 1H), 2.6-2.9 (m, 4H), 5.87 (s, 2H), 6.50-6.74 (m, 3H).

Example 2 (Compound 21) Natrlum-2-amlno> 3> ({2- (1,3-benzodioxol-6-yl) ethyl} thio] propyl

COONa

406 g of L-cysteine.HCl.HjO were added to the suspension in a mixture of 11% water and 500 ml of ethanol. To the suspension was added a solution of 370 g of sodium hydroxide in 1.5 l of water. To this was added 527 g of 5-ethenyl-1,3-benzodioxole and then 600 ml of ethanol, and the mixture was heated to reflux for 2.5 hours to carry out the reaction. Ethanol was distilled off under reduced pressure and the residue was filtered. The filtrate was acidified with acetic acid to form colorless crystals, which were collected by filtration and then recrystallized from 3 l of water to give 250 g of 2-ΑΓηίηο-3 × (2 × (1.3 × θηζοαίοχοΙ × 5-γΙ). θΐΓ> νΙ) ΐΓ> 1ο | ρωρΙοη53ικθ in the form of colorless needles. The crystals were dissolved in a solution of 37 g of sodium hydroxide in 11 water. The solution was filtered and the filtrate was concentrated to about half the volume. To this was added 1.5 L of ethanol to recrystallize the product. 100 g of the intended product were obtained in the form of colorless crystals. Melting point: 170 * C-172 ^e C

 MKR (400MHz, DMSO-d ") δ;

2.64-2.74 (m, 5H), 2.91 (dd, J = "12.8Hz, 3.7Hz, 1H), 3.01 (m, 1H), 3.3 (m, 2H), 5.95, (s, 2H), 6.68 (dd, J - 8.1Hz, 1.8Hz, 1H) 6.79 (d, J = 8.1 Hz, 1H), 6.83 (d, J = 1.8Hz, 1H)

MS (FAB) m / z: 314 (M + + Na), 292 (M ⁺ + 1) elemental analysis for CuHuNO ₄ SNa:

CHN Calculated (%) 49.48 4.84 4.81 Determined (%) 49.58 4.91 4.91

Example 3 (compound 8) [ril] {2- (1,3-benzenoxal-5-yl) ethyl} thiol] acetate

S .. COONa

100 g of 2- (1,3-benzodioxol-5-yl) ethanethiol and 75.1 g of bromoacetic acid were dissolved in 11% ethanol (to which was added a solution of 44 g of sodium hydroxide in 12SmL of water followed by 2L of ethanol The reaction mixture was concentrated under reduced pressure to which 2.5 L of water was added, the mixture basified with 1N sodium hydroxide, washed with 35% hydrochloric acid, extracted with ethyl acetate, and washed four times with water The solvent was distilled off under reduced pressure to obtain 121 g of {2- (1,3-benzodioxol-5-yl) ethyl} thioacetic acid in the form of a pale yellow oil.

MKR (9OMHz, CDCIj) O;

2.80 (β, 4H), 3.20 (s, 2H), 5.85 (s, 2H), 6.44-6.74 {m, 3H), 10.24 (bs, 1H)

MS (E) m / z: 240 (M ⁺ ), 135 (Baals) To the oily product was added a solution of 20.27 g of sodium hydroxide to obtain a solution. After Recrystallization from dilute ethanol gave 102.5 g of the intended compound as colorless crystals. Melting point: 224 ° C-226 ° C. MKR (400 MHz, DMSO-de) S;

2.69 (m, 4H), 2.95 (s, 2H), 5.95 (s, 2H), 6.66 (dd, J = 7.7Hz, 1.5Hz, 1H), 6.79 (d, J = 7.7Hz, 1H), 6.81 (d, J = 1.5Hz, 1H).

MS (FAB) m / z: 285 (M ⁺ + Na), 263 (M ⁺ + 1) Elemental analysis for C _n H _n O ₄ SNa:

C H

Calculated (%) 50.38 4.23 Determines (%) 50.27 4.31

Example 4 (compound 17)

ο--

5 g of 2- (1,3-benzodioxol-6-yl) ethanethiol and 4 g of acrylamide were dissolved in 100 ml of ethanol and the solution was taken under

Reflux is heated to carry out the reaction. Duration 20 hours. The reaction mixture was cooled with ice. To this was added 100 ml of ethanol and the resulting crystal parts were collected by filtration to give 4.2 g of the

provided compound in the form of colorless needles.

Melting point: 103 ° C-104'C. MKR (90MHz, CDCI ₃ ) δ;

2.50 (m, 2H), 2.89 (s, 4H), 2.73-2.93 (m, 2H), 5.6 (br, s, 2H), 5.91 ( s, 2H), 6.68 (m, 3H).

MS (El) m / z: 253 (M *), 149.136 (basis)

Example 5 (Compound 25) Ethyl [(- (1,3-benzodloxol-5-yl) ethyl} thiol] acetate

3.24g of ethyl thioglycolate was added to 6g of 5-ethenyl-1,3-benzodioxole, and the mixture was stirred at room temperature for 14 hours. The reaction product was purified by silica gel column chromatography (benzene ethyl acetate = 40: 1) to give 5 g of the intended compound as a colorless oil.

MKR (90MHz, CDCI ₁ ) O;

1.27 (t, J = 7Hz, 3H), 2.80 (2.4H), 3.18 (s, 2H), 4.15 (q, J = 7Hz, 2H). 5.86 (s, 2H), 6.62 (m, 3h ')

MS (El) m / z: 268 (M ⁺ ), 149 (basis)

Example 6 (Compound 26) 5- [2- (Methylsulfinyl) ethyl] 1,3-benzodloxole

3 g of 5- {2- (methylthio) ethyl) 1,3-benzodioxole were dissolved in 100 ml of chloroform. The solution was added with stirring and under

Recycle with dry ice / alcohol to a fiqulmolare amount of m chloroperbenzoic acid added to the reaction over one hour

perform. To this was added 300 ml of chloroform and 300 ml of water, followed by addition to the mixture

Sodium carbonate added until the aqueous layer became alkaline; after the separation of the layers was the Chloroform layer washed twice with water and dried over sodium sulfate. The solvent was added

distilled off under reduced pressure. The oily product was purified by silica gel column chromatography

(Chlorine form: methanol »20: 1) to give 1.6 g of the intended compound as a colorless oil.

MKR (90MHz, CDCI)) O;

2.55 (s, 3H), 2.74-3.12 (m, 4H), 5.87 (s, 2H), 6.64 (m, 3H)

MS (El) m / z: 212 (M '). 196.148 (basis)

Example 7 (Compound 28) 5- {2- (Methylsulfonyl) ethyl) -1,3-benzodioxole

3.5 g of 5- {2- (methylthio) ethyl} -1,3-benzodioxole were dissolved in 10 μl of Ch'.oro orm. To the solution was added 8.8 g of m-chloroperbenzoic acid while cooling with ice / water to carry out the reaction for 2 hours. To this was added 300 ml of chloroform and 300 ml of water, then sodium carbonate was added to the mixture until the aqueous layer became alkaline. After separation of the layers, the cliloroform layer was washed twice with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure. After recrystallization from ethyl acetate / isopropyl ether, 3 g of the intended compound were obtained in the form of colorless needles. MKR (90MHz, CDCI ₁ ) δ;

2.80 (s, 3H), 2.93-3.36 (m, 4H), 5.88 (s, 2H), 6.65 (m, 3H!

MS (El) m / z: 228 (M ⁺ ), 148 (basis)

Example 8 (Compound 22) [{2- (1,3-Benzodloxol-5-yl) ethyl} thio] ethylnickelate

4 g of I {2- (1,3-benzodioxol-5-yl) ethyl) thio] ethanol, prepared as in Example 2, were dissolved in 20 ml of pyridine. To the solution was added 50 ml of benzene. To this was added 4.7 g of nicotine chloride hydrochloride with stirring, and the mixture was heated for 2 hours on a boiling water bath. The reaction mixture was poured into ice / water. To this was added 100 ml of water and sodium hydrogen carbonate to make it slightly alkaline. After extraction with ethyl acetate, the ethyl acetate layer was washed four times with water and dried over sodium sulfate.

The solvent was distilled off and the residue was purified by silica gel column chromatography

(Benzone: ethyl acetate "= 3: 1) to give 2g of the intended compound in the form of a colorless oil.

MKR (90MHz, CDCI ₃ ) δ;

2.80 (s, 4H), 2.85 (t, J = 7Hz, 2H), 4.44 (t, J = 7Hz, 2H), 5.86 (s, 2H), 6.61 (m, 3H), 7.31 (m, 1H), 8.20 (m 1 H), 8.69 (m, 1H), 9.13 (m,

MS (El) m / z: 331 (M ⁺ , base), 148 Example 9 (compound 23)

COOH

5.3 g of the (2- (1,3-benzodioxol-5-yl) ethyl) thio) acetic acid prepared in Example 2 were dissolved in 20 ml of benzene. The

To the solution was added 6.43 ml of thionyl chloride and the mixture was heated at reflux for 2 hours to complete the reaction

perform. The solvent was distilled off under reduced pressure. To a solution of 1.6 g of sodium hydroxide in 10 ml of water was added 3 g of glycine. To this was added the above-obtained reaction product with stirring and with cooling with ice / water. The mixture was stirred at 10 ° C for 15 minutes, followed by 2 hours

Room temperature, the reaction was carried out. The reaction mixture acidified with concentrated hydrochloric acid

Wassor was added. The precipitates formed were collected by filtration, washed with water and repeatedly recrystallised from dilute ethanol to give 3 g of the intended compound as colorless

Needles received. Melting point: 121.5 ^{c C} to 122.5'C. MKR (90MHz, COCI _1- CDjOD) ö;

2.84 (s, 4H), 3.26 (s, 2H), 3.99 (s, 2H), 5.92 (<2H), 6.71 (m, 3H), 7.54 (s, 1H).

MS (El) m / z: 297 (M ⁺ ), 149 (base), 148. In the following Examples 10 to 27, compounds having the following general formula (Γ) were prepared

where R is a group shown below.

The preparation processes A, B, C, D and E were the same ν., Ο those of Examples 2,3,4,5 and 9, respectively.

- (CH ₂ ) ₂ -SR ^In

Example 10 (compound 2) R = -CHjCH ₂ CH) (Production method B) MKR (9OMHz, CDCl,) δ;

0.98 (t, J = 7Hz, 3H), 1.4-1.8 (m, 2H), 2.51 (t, J = 7Hz, 2H), 2.75 (s, 4H), 5.91 (s, 2H), 6.7 (m, 3H)

MS (El) m / z: 224 (M ⁺ ), 148,135.77 (base) Example 11 (compound 3) R = -CH] CH ₃ OH (Preparation method B) MKR (90MHz, CDCI,) δ;

2.72 (t, J = βHz, 2H), 2.78 (s, 4H), 3.72 (q, J = 6Hz, 2H), 5.92 (s, 2H), 6.6-6.8 (m, 3H) MS (FD! M / z: 226 (M ⁺ )

Elemental analysis for C ₁₁ Ht ₄ O ₃ S:

CHS Calculated (%) 58.39 6.24 14,17

Determined (%) 58.61 6.22 13.83

Example 12 (compound 4) R = - (CH ₂ I) OH (Preparation Method B) MKR (90MHz, CDCI ₃ );

1.59 (m, 1H), 1.85 (m, 2H), 2.66 (t, J = 7Hz, 2H), 2.78 (s, 4H), 3.76 (m , 2H), 5.93 (s, 3H), 6.70 (m, 3H).,

MS (El) m / z: 240 (M ⁺ ), 148 (basis), Example 13 (compound 5) R = -CH ₂ -CH-CH] OH (Preparation method A) MKR (90MHz, CDCI ₃ ) δ;

2.02 (t, J = 6Hz, 1H), 2.6-2.9 (m, 3H), 2.80 (s, 4H), 3.4-3.9 (m, 3H), 5 , 94 (s, 2H), 6.70 (m, 3H) MS (El) m / z; 256 (M ⁺ ), 149,135.91, 77.65 (base)

Example 14 (compound 6) R = -CH ₂ CH! OCH ₁ (Production method B) MKR (90MHz, CDCI ₁ ) δ;

2.68 (t, J = 7Hz, 2H), 2.76 (s, 4H), 3.33 (s, 3H), 3.52 (t, J = 7Hz, 2H), 5.87 (s, 2H), 6.62 (m, 3H)

MS (El) m / z; 740 (M ⁺ ), 148,135.77 (base) Example 15 (compound 7)

R = -CH ₂ J 1 J (Production method B)

MKR (90MHz, CDCI ₁ ) δ;

1.5-2.2 (m, 4H), 2.46 (m, 2H), 2.79 (s, 4H> 2.6-3.1 (m, 3H), 5.91 (s, 2H ), 6.68 (m, 3H)

MS (El) m / z; 266 (M ⁺ ), 149 (base) Example 16 (compound 9) R = -CH ₂ CH ₂ COOH (free form) (preparation process A, B or D) Melting point: 63, O ⁰ C- ^ O ⁰ C MKR (90MHz, CDCI,) δ;

2.77 (m, 4H), 2.50-290 (m, 4H), 5.91 (s, 2H), 6.67 (m, 3H), 8.0 (br, s, 1 H)

MS (El) m / z; 254 (M, base), 148.135 R = -CH ₂ CH ₂ COONa (Preparation method A, B or D Melting point: 187'C-189 ° C MKR (400MHz, d ₆ -DMSO) ö;

2.11 (m, 2H), 2.62-2.74 (m, 6H), 5.95 (s, 2H), 6.68 (dd, J = 7.7Hz, 1.5 Hz, 1H), 6.79 (d, J = 7.7Hz, 1H), 6.82 (d, J = 1.5Hz, 1H)

MS (FAB) m / z; 299 (M ⁺ + Na), 277 (M * + 1) Elemental analysis for C ₁₁ H ₁ ] O ₄ SNa:

C H

Calculated (%) 52.17 4.74 Determined (%) 52.15 4.80

Example 17 (compound 10) R = - (CH ₂ I) COONa (Preparation Method B)

MKR (90MHz, D ₂ O) δ; 1.90 (m, 2H), 2.30 (t, .1-7 Hz, 2H), 2.59 (t, J = 7Hz, 2H), 2.85 (s, 4H), 5, 94 (s, 2H), 6.80 (m, 3H)

MS (FAB) m / s; 313 (M ⁺ + Na), 291 (M ⁺ + 1) BeltpUM 8 (connection 1) R - - (CH ₁ I ₄ COONa (Preparation Method B) MKR (90MHz, CDCI,) δ;

1.69 (m, 4H), 2.48 (m, 4H), 2.74 (s, 4H), 6.87 (s, 3H), 6.61 (m, 3H), 7.20 (br, 1H)

MS (Ne-SaIz) (FAB) m / z; 327 (M ⁺ + Na), 305 (M ⁺ + 1) Example 19 (compound 12) R = - (CH ₂ ) SCOONa (Preparation method B) Melting point: 248 ° C-251 ⁰ C.

MKR (90MHz, D ₂ O) S; 1.16-1.70 (m, 6H), 2.17 (m, 2H), 2.45 (m, 2H), 2.66 (s, 4H), 5.82 (s, 2H), 6.66 (m, 3H)

MS (FmB) m / z; 341 (M ⁺ + Νεί. 319 (M ⁺ + 1) Pr'spiel 20 (compound 13) H = -CH-CH ₂ COOH (free form) (Production method B) MKR 49OMHz, CDCi ₃ ) δ;

1.35 (d, J = 7Hz, 3H), 2.57 (m, 2H). 2.76 (s, 4H), 3.18 (m, 1H), 5.86 (s, 2H), 6.62 (m, 3H), 7.2 (br, 1H) R = -CH-CH ₂ OONa (Preparation ancestor B)

Melting point: 126 ° C-128.5 ° C MKR (400MHz, DMSO-d ") δ; 1.18 (d, J = 6.6Hz, 3H), 1.88 (dd, J = 14.7Hz, 9.9Hz, 1H), 2.20 (dd, J = 14.7Hz, 4.4Hz, 1 H), 2.69 {m, 4H), 3.14 (m, 1H), 5.95 (s, 2H), 6.68 (dd, J = 8.0Hz, 1.8Hz, 1H ), 6.79 (d, J = 8.0Hz, 1H), 6.82 (d, J = 1.8Hz, 1H) MS (FAB) m / z: 313 (M ⁺ + Na), 291 (M ⁺ + 1) Elemental analysis for O ₁₃ H ₁₆ O ₄ SNa 3 / 4H ₂ O

C H

Calculated (%) 51.39 5.47 Retrieved (%) 61.22 5.52

Example 21 (compound 14) R = -CH-CH ₂ COOH (Preparation method D)

Melting point: 139 "C-140 ° C MKR (90MHz, DMSO-d,) δ;

2.77 (br, s, 4H), 3.28 (br, s, 2H), 3.50 (m, 1H), 5.88 (s, 2H), 6.69 (m, 3H ) MS (El) m / z; 298 (M ⁺ ), 280.148 (basis)

Example 22 (compound 15) R = -CH-COOH (Preparation ancestor D)

MKR (90MHz, D ₂ O) δ; 1.40 (d, J = <7Hz, 3H), 2.86 (s, 4H), 3.43 (q, J = 7Hz, 1H), 5.93 (s, 2H) , 6.80 (m, 3H) MS (FAB) rr./z; 299 (M ⁺ + Na), 277 (M ⁺ + 1)

Example 23 (compound 16)

R = -CH ₂ CONH ₂ (Preparation Method B) Melting point: 93.5 "0-94.5" C MKR (90MHz, CDCl ₃ ) δ;

2.78 (s, 4H), 3.18 (s, 2H), 5.6-6.9 (br, s, 2H), 5.86 (s, 2H), 6.61 (m, 3 H) MS (El) m / z; 229 (M *), 148 (base)

Elemental analysis for C ₁ ) Hi ₃ O ₃ MS:

CCNS Calculated (%) 55.21 5.48 5.85 13.40

Determined!%) 55,38 5,42 5,82 13,34

Example 24 (Compound 1B)

R = -CH ₀ -CNC * ° (Preparation Method B)

^{2 C} 2 ^H 5

MKR (90MHz, CDCI ₃ ) δ;

1.7 (q, J = 7Hz, 6H), 2.86 (s, 2H), 3.28 (s, 2H), 3.37 (q, -1 = 7Hz, 2H) , 3.39 (q, J = 7Hz, 2H), 5.92 (s, 2H), 6.72 (m, 3H)

MS (Ei) m / z; 295 (M ⁺ ), 148 (base) Example 25 (compound 19)

R = -CH ₀ CH ₀ -CN '-> (Preparation C) ^{dd N} CH

MKR (90MHz, CDCI ₃ ) δ;

2.44-2.85 (m, 4H), 2.75 (s, 4H), 2.92 (s, 3H), 2.96 (s, 3H), 5.84 (s, 2H), 6.61 (m, 3H)

MS (El) m / z; 281 (M ⁺ ), 149 (base)

-80- 287 Example 26 (compound 20)

CH. R = -GH ₀ CH ₀ -Nv (Preparation method A)

^{ά ά} CH

Melting point: 146 "C-148 ^e C MKR (90MHz, CDCl ₃ ) δ; 2.79 (s, 6H), 2.84 (s, 4H), 3.06 (m, 4H), 5, 94 (s, 2H), 6.72 (m, 3H) MS (El) m / z, 253 (M ⁺ ), 149.135.105.91 (basis)

Example 27 (compound 24)

R = - (CH ₀ ) oQW (Production method E)

^{d ά N} CH ₂ C00H

Melting point: 152'C-153'C

MKR (90MHz, CDCl ₃ -CD ₃ OD) δ; 2.53 (m, 2H), 2.73-2.92 (m, 6H), 3.94 (s, 2H), 5.90 (s, 2H), 6.69 (m, 3 H), 7.58, s, 1 H) MS (El) m / z; 311 (M ⁺ ), 149 (base). In Example 28 below, compounds having the general formula (Γ) given below were prepared in which R is the indicated group.

These compounds were prepared in the same manner as those in Example 6.

(CH ₂ ) ₂ -SR

Example 28 (compound 27)

R = -CH ₂ CHjOH

Melting point: 107 ⁰ C-IOO ⁰ C MKR (90MHz, CDCI ₃₎ δ; 2.8-3.3 (m, 7H). 4.18 (m, 2H), 5.94 (s, 2H), 6.72 (m, 3H) MS (FAB) m / z, 243 (M ⁺ + 1) In the following Examples 29 to 32, compounds having the general formula (ΓΊ below) in which R is the specified group.

These compounds were prepared in the same manner as that of Example 7.

d ")

Example 29 (compound 29) R = CH ₂ CH ₁ OH

Melting point: 78 ° C-80 ° C MKR (90MHz, CDCl ₃ ) δ; 2.37 (t, J = 6Hz, 1H), 2.9-3.5 (m, 6H). 4.12 (rn, 2H), 5.95 (s, 2H), 6.72 (m, 3H) MS (El) m / z; 258 (M ⁺ ), 149,119 (basis)

Example 30 (Compound 30) R = -CH ₂ COOH

Melting point: 144.5 ^o C-145 ° C MKR (90MHz, DMSO-de-CDCb) δ; 3.04 (m, 2H), 3.52 (m, 2H), 4.07 (s, 2H), 5.3 (br, 1H), 5.95 (s, 2H), 6.86 (m, 3H) MS (El) m / z; 272 (M ⁺ ), 148 (base)

Example 31 (compound 31)

R = -CH ₂ CHjCOOH Melting point: 176.5 ° C-177.5 ° C MKR (90MHz ₁ DMSOd.) Δ;

2.60-3.10 (m, 4H), 3.24-3.50 (τ », 4H), 5.93 (s, 2H), 6.81 (m, 2H), 6.92 ( m, 1H), 12.3 (br, 1H) MS (El) m / z; 286 (M ⁺ , base)

Example 32 (compound 32)

R = HCH ₂ ) JCOOH

Melting point 153.5 ⁰ C-155.5 ⁰ C MKR (90MHz, DMSO-d _e ) 6;

1.95 (m, 2H), 2.40 (t, J = 7Hz, 2H), 2.80-3.46 (m, 6H), 5.96 (s, 2H), 6 , 80 (m, 1H), 6.91 (m, 1H), 12.5 (br, 1H)

MS (El) m / z; 300 (M ⁺ ), 149 (base), 148 Connection group (l-c) example 1

3- (6-propyl-1,3-benzodioxol-5-yl) proplons8ure

COOH

(1) Synthesis of 5-chloromethyl-6-propyl-1,3-benzod! Oxole

⁰ t

22g of an aqueous, 37% formaldehyde solution and 20 ml of ethyl acetate were added to 10 ml of concentrated hydrochloric acid. The mixture was heated to 55 ^° C. To the mixture was added dropwise a solution of 10.9 g of 5-propyl-1,3-benzodioxole in 100 ml of ethyl acetate while simultaneously introducing hydrogen chloride gas. The mixture was stirred for 2 hours and 45 minutes. To this was added 300 ml of ethyl acetate and 300 ml of water. The formed layers were separated. The ethyl acetate layer was washed three times with water and dried over anhydrous sodium sulfate. The solvent was distilled off to give 16.1 g of the intended crude compound as a colorless oil

¹ H-MKROOMHz ₁ CDCl ₃ ) O; 0.99 (t, J = 7.2Hz, 3H), 1.36-1.06 (m, 2H), 2.64 (t, J = 7.2Hz, 2H), 4, B7 (s, 2H), 5.95 (s, 2H), 6.70 (s, 1H), 6.83 (s, 1H)

(2) Synthesis of diethyl (6-propyl-1,3-benzodloxol-5-yl) methyl malonate

, COOEt 'COOEt

24.3 g of diethyl malonate, 42 g of potassium carbonate, 300 ml of acetone and a catalytic amount of tetrabutylammonium bromide were added to 16.1 g of the crude S-chloromethyl-e-propyl-i, 3, benzodioxols, and the mixture was refluxed for Heated for 25 hours. The reaction mixture was filtered and the residue was washed with acetone. The wash was combined with the filtrate. The solvent was distilled off. To this was added 500 ml of ethyl acetate and 500 ml of water, and the layers thus formed were separated. The ethyl acetate layer was washed three times with water and dried over hydrated sodium sulfate. The solvent was distilled off to give 16.5 g of crude compound as a colorless oil

¹ H-MKROOMHz ₁ CDCl ₃ ) O;

0.96 (t, J = 7.2Hz, 3H), 1.22 (t, J = 7.2Hz, 6H), 1.30-1.80 (m, 2H), 2.32 -2.60 (m, 2H), 3.10 (d, J = 7.2Hz, 2H), 3.50 (t, J = 7.2Hz, 1H), 4.14 (q , J = 7.2Hz, 4H), 5.83 (s, 2H) 6.58 (s, 2H)

(3) Synthesis of (6-propyl-1,3-benzodloxol-5-yl) methyl malonate

"C00H COOH

16.5 g of diethyl (6-propyl-1,3-benzodioxol-5-yl) methylmononate were dissolved in 150 ml of ethanol. To the solution was added 20 g of sodium hydroxide and 50 ml of water, and the mixture was heated on a boiling water bath for 30 minutes. The reaction mixture was concentrated. To this was added 300 ml of ethyl acetate and 300 ml of water, and the layers thus formed were separated. The aqueous layer was acidified with concentrated hydrochloric acid. After extraction with ethyl acetate, the ethyl acetate layer was washed three times with water and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 15.2 g of the intended compound as a white powder

¹ H-MKR (90MHz, DMSO-d _e ) δ;

0.91 (t, J = 7.2Hz, 3H), 1.31-1.66 (m, 2H), 2.50 (t, J = 7.2Hz, 2H), 2.98 (d, J = 7.2Hz, 2H), 3.47 (t, J = 7.2Hz, 1H), 5.94 (s, 2H), 6.74 is, 2H), 12.7 (br, 2H)

(4) Synthesis of 3- (6-propyl-1,3-benzodioxol-5-yl) -proplonic acid

0OH

10 g of (6-propyl-1,3-benzodioxol-5-yl) methylmalonic acid were heated for 1 hour on an oil bath at 15O ⁰ C to 16O ⁰ C.

This was followed by purification by silica gel column chromatography, (chloroform / methanol - 20.1) Recrystallization from isopropyl ether gave 6.9 g of the intended compound as colorless crystals.

¹ H-MKR (90MHz, CDCI ₃ ) 6; 0.95 ^ t, J = 7.0 Hz, 3H), 1.28-1.80 (m, 2H), 2.08-3.00 (m, 6H), 5.85 (s , 2H), 6.58 (s, 2H).

Example 2 Natrlum-3- (6-propyl-1,3-benzodloxol-5-yl) propyl lactate

COONa

29.2 ml of a 1N aqueous sodium hydroxide solution and 100 ml of ethanol were added to 6.9 g of 3- (6-propyl-1,3-benzodioxol-5-yl) -proplonic acid to give a solution. The solvent was distilled off and ether was added to the residue. The resulting precipitate was collected by filtration and dried to give 7.5 g of the intended

Compound in the form of a colorless powder. Melting point: 213 ° C-216 ° C

¹ H-MKR (90MHz, DMSO-d,) δ; 0.90 (t, J = 7.4Hz, 3H), 1.20-2.71 (m, 2H), 1.92-2.22 (m, 2H), 2.26-2.80 (m , 4H), 5.82 (s, 2H), 6.57 (s, 1H), 6.64 (s, 1H)

MS (FAB) m / z; 281 (MNa "), 259 (MH")

Example 3 3- (6-Ethyl-1,3-benzodioxol-5-yl) propanoic acid

COOH

1.42g of the intended compound in the form of colorless crystals were made from 5.4g of 5-ethyl-1,3-benzodioxole to the same

Wise in Example 1 won.

¹ H-MKROOMHz ₁ CDCl ₃ ) O; 1.20 (t, J = 7Hz, 3H), 2.32-3.08 (m, 6H), 5.84 (s, 2H), 6.60 (s, 1H), 6.64 (s, 1 H)

Example 4 Natrlum-3- (6-ethyl-1,3-benzodloxol-5-yl) propyl

1.53 g of the intended compound in the form of colorless crystals were recovered from 1.42 g of 3- (6-ethyl-1,3-b3nzodioxole-5-y-propionic acid in the same manner as in Example 2.

Melting point: 202 ° C-204 ° C (decomposition)

¹ H-MKR (400MHz, DMSO-d,) δ; i, 10 (t, J = 7Hz, 3H), 2.06 (t, J = 8Hz, 2H), 2.51 (q, J = 7Hz, 2H), 2.66 (t, J = 8Hz, 2H ), 5.88, (s, 2H), 6.68 (s, 1H), 6.71 (s, 1H) MS (FB) m / z; 245 (MH ")

Example 5 3- (6-Methyl-1,3-benzodloxol-5-yl) propoxylic acid

80g of the intended compound in the form of colorless crystals were prepared from 150g of 5-methyl-1,3-benzodioxole in the same

Won as in Example 1. Melting point: 129 ^β ΰ-132Χ

¹ H-MKR (90MHz, CDCl ₃ ) δ; 2.20 (s, 3H), 2.36-2.98 (m, 4H), 5.81 (s, 2H), 6.56 (s, 2H), 11.24 (bs, 1H)

Examples Natrlum-3- (ethyl-1,3-benzodloxol-5-yl) propylate

COONa

0.59 g of the intended compound in the form of a white powder was recovered from 0.54 g of 3- (6-methyl-1,3-benzodioxol-5-yl) propionic acid in the same manner as in Example 2.

Melting point: 209 ° C-212 ^e C '-Mite (90MHa DMSO-dj) δ; 2.54 (s, 3H), 186-2.84 (m, 4H), 5.80 (s, 2H) 6.56 (s, 1H), 6.63 (s, 1H) MS (FAB) m / z; 253 (MNa "), 231 (MH")

Example 7 3- (6-Methoxymethyl-1,3-benzodioxol-5-yl) propionic acid

COOH

"0

1.6 g of 3- (6-acetoxymethyl-1,3-benzodioxol-5-yl) -propionic acid were dissolved in 100 ml of methanol. To the solution was added a catalytic amount of p-toluenesulfonic acid, and the mixture was refluxed for 4 hours and 15 minutes. The solvent was distilled off from the reaction mixture. To the residue was added a solution of 1 g of sodium hydroxide in a mixture of SmI water and 45 ml of ethanol, and the mixture was refluxed for 20 minutes. The reaction mixture was concentrated. 200 ml of ethyl acetate and 200 ml of water were added to the concentrate. The mixture was acidified with concentrated hydrochloric acid ^r. The layers thus formed were separated. The product was washed three times with Wa and then dried over anhydrous sodium sulfate. The

Solvent was distilled off, and α 1.25 g of the above compound in the form of a white powder. ¹ H-MKROOMHz ₁ CDCi ₃ ) O; 2.24-3.10 (m, 4H), 3.34 (s, 3H), 4.33 (s, 2H), 5.86 (s, 2H), 6.64 (s, 1H), 0.74 (s, 1H)

Example 8 Sodium 3- (e-methoxymethyl-1,3-benzodioxol-5-yl) propylate

COONa

on

1.3 g of the intended compound in the form of a white powder were recovered from 1.25 g of 3- (6-methoxymethyl-1,3-benzodioxol-5-y) propionic acid in the same manner as in Example 2.

Melting point: 155 "0-159 ⁰ C ¹ H-MKR (90MHz, DMSO-d") δ; 1.88-2.90 (m, 4H), 3.23 (s, 3H), 4.28 (s , 2H), 5.87 (s, 2H), 6.71 (s, 1H), 6.74 (s, 1H) MS (FAB) m / z, 283 (MNa "), 261 (MH) )

Example 9 3- (6-Ethoxymethyl-1,3-bonzodloxol-5-yl) propionic acid

COOH

0.6 g of metallic sodium was dissolved in 100 ml of ethanol. To the solution was added in small portions 2.0 g of 3- (6-chloromethyl-1,3-benzodioxol-5-yl) propionic acid. The mixture was heated at 5O ⁰ C for 2 hours. The solvent was distilled off and the residue was made acidic with 1N hydrochloric acid. After extraction with chloroform, the organic layers were dried over magnesium sulfate. The solvent was distilled off. After separation by silica gel column chromatography (chloroform), 0.73 g of the intended compound was obtained as colorless crystals.

Melting point: 97 ° C-98 ^C C 'H-MKR (90MHz, CDCl _3. ) Δ; 1.23 (t, J = 7Hz, 3H), 2.61 (m, 2H), 2.91 (m, 2H), 2.91 (m, 2H), 3.51 (q, H = 7Hz, 2H7,4,38 (s, 2H), 5,87 (s, 2H), 6,64 (s, 1H), 6,76 (s,

Example 10 Sodium 3- (6-ethoxymethyl-1,3-benzodioxol-5-yl) propionate

COONa

0.7 g of the intended compound in the form of colorless crystals were recovered from 0.71 g of 3- (6-ethoxymethyl-1,3-benzodioxol-5-yhopropionic acid in the same manner as in Example 2.

Melting point: 165 ^C C-182 ° C (decomposition)

¹ H-MKR (400MHz DMSO-d,) δ;

1.13 (t, J = 7.0Hz, 3H), 2.07 (m, 2H), 2.68 (m, 2H), 3.45 (q, J = 7.0Hj, 2H), 4, 36 (s, 2H), 5.92 (s, 2H), 6.78 (s, 1H), 6.81 (s, 1H)

MS (FAB) m / z: 297 (MNa "), 275 (MH")

B "ltpttl11 (5,6-methylenedioylndsn-2-yl) carboxylic acid

(1) Synthesis of 6,6-Methyiendloxylnden

Bleaching of 10.8 g of 1-hydroxy-6,6-methylenedloxylandane and 16 ml of acetic acid in 100 ml of toluene was refluxed for

Heated for 4 hours. Water and a small amount of potassium carbonate were added to the reaction mixture. After extraction with ethyl acetate, the organic layer was washed with water and an aqueous ordinary saline solution

washed and dried over magnesium sulfate.

The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform / Hexane = 1: 3) to give 9.0 g of the intended compound as colorless crystals. Melting point: 85 ° C-86 ^C C

¹ H-MKROOMHz ₁ CDCl ₃ ) O;

3.29 (m, 2H), 5.92 (s, 2H), 6.43 (dt, J = 2Hz and 6Hz, 1H), 6.74 (m, 1H), 6.86 (2.1 H), 6.95 (s, 1H).

(2) Synthesis of 5,6-methylenedioxylindnan-2-ol

COO

A solution of 9.0 g of 5,6-methyldioxyindene in 23 ml of tetrahydrofuran was cooled to ⁰ ° C. in a nitrogen atmosphere. To this was added dropwise a solution of 2.2 ml of 10, OM borane-methylsulfide complex in 5 ml of tetrahydrofuran. The temperature of the mixture was heated from ⁰ ° C. to room temperature over a period of 4 hours, and then 1.8 ml of water was added dropwise thereto. To this was added, under cooling with ice, 7.4 ml of a 3M aqueous sodium hydroxide solution and ansc. .5.5 ml of an aqueous, 35% hydrogen peroxide solution was added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with an aqueous common salt solution and dried over magnesium sulfate. The solvent was distilled off and the residue was crystallized from ethyl acetate to give 6.4 g of the intended compound as white crystals. Melting point: 99 ⁰ C-IOO ⁰ C ¹ H-MKR (90MHz, CDCI ₃ J 6; 1.73 (m, 1 H), 2.79 (dd, J = 4Hz and 16Hz, 2H) 3.14 (dd , J = 6Hz and 16Hz, 2H), 4.68 (m, 1H), 5.91 (s, 2H), 6.71 (s, 2H)

(3) Synthesis of 2-cyano-5,6-methylenedloxylndane

7.45 g of methanesulfonyl chloride was added dropwise to a solution of 5.8 g of 5,6-methylenedioxyindan-2-ol and 9.1 ml of triethylamine in 150 ml of dichloromethane while cooling with ice. The mixture was stirred at ⁰ C for one hour. To the reaction mixture was added a mixture of ice and water, and the resulting mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and dried over magnesium sulfate. The solvent was distilled off to give 8.0 g of methanesulfonate, which was used without purification for the subsequent reaction.

A mixture of 2.6 g of methanesulfonate, 1.0 g of sodium cyanide and a solution of a catalytic amount of Ni triumjodid in 20 ml of dimethylformamide was heated at 8O ⁰ C h. Water was added to the reaction mixture. After extraction with ether, the aqueous layer was washed with water and an aqueous ordinary brine and transferred

Dried magnesium sulfate. The solvent was distilled off and the residue was passed through Silica gel column chromatography to give 0.4 g of the intended compound in the form of colorless Crystals. Melting point: 124 ^o C-125 ° C

¹ H-MKROOMHz ₁ CDCl ₃ ); 3.19 (m, 5Hi, 5.87 (s, 2H), 6.60 (s, 2H)

(4) Synthesis of (5, S-methylenedioxyindan-2-yl) carboxylsure • • 0

0 0.

3.9 ml of an aqueous, 35% hydrogen peroxide solution was added dropwise to a mixture of 1.4 g of 2-cyano-5,6-methylenedioxyindane, 50 ml of an aqueous 30% potassium hydroxide solution and 50 ml of ethanol. Then, the mixture was heated at 60 ° C for 2 hours, and the solvent was distilled off. To the residue was added dilute hydrochloric acid. After extraction with chloroform, the organic layer was dried over magnesium sulfate. The solvent was distilled off and the residue was recrystallized from diisopropyl ether to give 1.4 g of the intended compound as colorless crystals. Melting point: 168 ° C-169 ° C ¹

3.00-3.44 (m, 5H), 5.85 (s, 2H), 6.60 (s, 2H), 10.0 (bs, 1H)

Example 12 Sodium (5,6-methylerdloxylndan-2-yl) carboxylate

COONa

1, F.g of the intended compound in the form of colorless crystals were prepared from 1,4g (5,6-methylenedioxyindan-2-y-carboxylic acid in the same manner as in Example 2.

Melting point:> 270 ° C

¹ H-MKR (400MHz, DMSO-d ") S; 2.77-3.04 (m, 5H), 5.89 (m, 2H), 6.68 (s, 2H)

MS (FAB) m / z: 251 (MNa ^- ), 2.29! ΜΗΊ

Example 13 (7,8-Dlhydro-5H-1,3-dloxolo [4,5-g] [2] benzopyran-5-yl) -salicylic acid

.COOEt

1) Synthesis of ethyl (7,8-dlhydro-5 H-1,3-dioxolo- [4,5-gM2] -benzopyrene-5-yl) -acetate 1.3 g of ethyl 3- {6- (2-hydroxyethyl) ) -1,3-benzodioxol-5-yl} acrylate were dissolved in 30 ml of ethanol. To the solution was added a catalytic amount of sodium ethylate, and the mixture was heated under reflux for 2 hours. The solvent was distilled off, and to the residue were added 1N hydrochloric acid and water. After extraction with ethyl acetate followed by washing with saturated aqueous common salt solution and drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / ethyl azatate = 85:15) to give 0.78 g of the intended compound as a colorless oil.

¹ H-MKROOMHz ₁ CDCj ₁ O; 1.27 (t, = 7.2Hz, 3H), 2.35-3.1 (m, 4H), 3.5 ^, 37 (m, 2H), 4.17 (q, J = 7.2 HZ, 2H), 5.09 (dd, J = 7.2 Hz and J = 5.6Hz, 1H) 5.85 (s, 2H), 6.46 (s, 1H ), 6.51 (s, 1H)

(2) Synthesis of (7,8-Dihydro-5H-1,3-dioxolo [4,5-g] [2] benzopyran-5-yl) essential acid 0.

0.78 g of ethyl (7,8-dihydro-5H-1,3-dioxolo [4,5-g] | 2] benzopyran-5-yl) -8 acetate was dissolved in 20 ml of ethanol. To this was added a solution of 0.35 g of sodium hydroxide in 4 ml of water, and the mixture was stirred with heating at 60 ° C. The solvent was washed with ethyl acetate and acidified with 1 N hydrochloric acid. After extraction with chloroform, the extract was washed with a saturated aqueous common salt solution and dried over anhydrous magnesium sulfate. After filtering, the solvent was distilled off and the residue was subjected to silica gel column chromatography (chloroform) to give 0.67 g of the intended compound as colorless crystals

¹ HMKROOMHz, CDCI ₃ ) δ; 2.35-3.20 (m, 4H), 3.5-3.95 (m, 1H), 3.92-4.28 (m, 1H), 4.95-5.25 ( m, 1H), 5.87 (s, 2H), 6.46 (s, 1H), 6.52 (s, 1H), 7.2-8.6 (br, 1H) Example 14% sodium (7,8-diazinyl-5H-1,3-dioxolo [4,5-g] [2] benzopyran-5-yl) acetate

COONa

0.69 g of the intended compound in the form of colorless crystals were prepared from 0.66 g of (7,7-dihydro-5H-1,3-dioxolo- | 4,5-g] | 2 | benzopyran-5-yl) acetic acid on same way as in Example 2 won.

Melting point: 257.5 ° C-258 ° C (decomposition)

¹ HMKR (90MHz, DMSOd ₆ ) δ;

2.26 (d, J = 6.5Hz, 2H), 2.3-2.55 (m, 2H), 3.35-4.05 (m, 2H), 4.89 (t, J = 6 , 5Hz, 1H), 5.83 (s, 1H), 6.52 (s, 1H), 6.75 (s, 1H)

MS (FAB) m / z: 281 (MNa ^- ), 259 (MH ") Connection group (l-d) Production Example 1

2- (1,3-Benzodloxol-5-yl) ethanthlol

<: Xr

CH ₂ CH ₂ SH

750 g of 5- (2-bromoethyl) -1,3-benzodioxole were dissolved in 11% ethanol. To the solution was added 312 g of thiourea and the mixture was heated under reflux on a boiling water bath for Dauei η for 2 hours. The reaction mixture was cooled and a solution of 300 g of sodium hydroxide in 11 water was added. The resulting mixture was heated to reflux on a boiling water bath for 45 minutes. After cooling, 3 liters of water were added. After extraction with 5% ethyl acetate, the extract was washed with dilute hydrochloric acid and then with water until the wash became approximately neutral. After drying over anhydrous sodium sulfate, followed by distillation of the solvent at 4O ⁰ C, to obtain about 570g of a pale yellow oil. This product was purified by silica gel column chromatography (hexane / benzene = 2: 1) using about 3 kg of silica gel to give 31 g of the intended compound as a colorless oil. ¹ H-MKROOHMCDCI ₃ ) O; 1.36 (m, 1H), 2.0-2.9 (m, 4H), 5.87 (s, 2H), 6.50-6.74 (m, 3H)

Production Example 2 3-Acetoxy-4- (2-hydroxyethyl) -5-methyllsoxazole

HIGH ₂ CH ₂ ^ OCOCH ₃

CH

xf

7.8 g of 4- (2-hydroxyethyl) -5-methylisoxazol-3-ol were dissolved in 11 g of tetrahydrofuran. To the solution was added 1.7Og sodium hydride while cooling with ice. The mixture was stirred at room temperature for 30 minutes and then cooled again with ice. To this was added 4.7 g of acetyl chloride, and the mixture was stirred at room temperature. The solvent was distilled off, and water was added to the residue. After extraction with chloroform, the extract was washed with saturated, aqueous common salt solution and dried over anhydrous magnesium sulfate. After filtering, the solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform) to give 2.96 g of the intended compound as colorless prismatic crystals. ¹ H-MKROOMHz, CDCl ₃ ) δ; 2.30 s, 3H), 2.49 (t, J = 6.1 Hz, 2H), 2.56 (s, 3H), 3.76 (t, J = 6.1 Hz, 2H)

Hertzellunsbelsplel 3 5- (2-Hydroxyethyl) -2-methyl-1, J-benzod! Oxole

, 0

« ₃ c - < _o

A suspension of 1, 0g 3,4-dihydroxyphenylacetic acid, 1.4 g vinyl acetate, G mg mercury oxide (yellow) and 0.03 ml borofluoride / ethyl etherate in 9 ml toluene was stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate and washed with water and an aqueous common salt solution. The organic layer was dried over magnesium sulfate and the solvent was distilled off. The oil thus obtained was dissolved in 10 ml of tetrahydrofuran, and the solution was added dropwise to a suspension of 0.5 g of lithium aluminum anhydride in tetrahydrofuran while cooling with ice. The mixture was stirred for one hour at room temperature. To this was added 0.5 ml of water, then 0.5 ml of an aqueous 15% sodium hydroxide solution and finally 1.5 ml of water, and an insoluble matter was filtered out. The filtrate was concentrated and treated by silica column chromatography (ethyl acetate / hexane 1: 1) to give 0.8 g of the intended compound as a colorless oil. ¹ H-MKROOMHz) O;

= 5Hz, 3H), 1.74 (m, 1H), 2.73 {t, J = 6Hz, 2H), 3.72 (m, 2H), 6.14 (q, J = 5Hz, 1H), 6.59 | s, 3H)

Example 4 2,2-Dimethyl-5- (2-hydroxy-thyl) -1,3-benzodloxol

CH ₂ CH ₂ OH

1.7 g of 3,4-dihydroxyphenylacetic acid, one catalytic amount of p-toluenesulfonic acid, 10 ml of acetone and 10 ml of benzene were heated at reflux for 18 hours. The reflux solution was adehydated with the molecular sieve 4. The reaction mixture was concentrated and the recovered dark brown? Oil was dissolved in 20 ml of tetrahydrofuran. The solution was added to a suspension of 0.8 g of lithium aluminum hydride in 30 ml of tetrahydrofuran while cooling with ice. The mixture was stirred at room temperature for one hour and then cooled with ice / water. To this was added 0.8 ml of water, then 0.8 ml of an aqueous 15% sodium hydroxide solution and finally 2.4 ml of water, and an insoluble matter was filtered out. The filtrate was concentrated and treated with silica gel column chromatography (ethyl acetate / n-hexane = 1: 1) to give 1.1 g of the intended compound as a colorless oil. ¹ H-MKR (90MHz, CDCl ₃ ) δ; 1.67 (s, 6H), 1.7 (m, 1H), 2.73 (t, J = 6Hz, 2H), 3.75 (bt, J = 6Hz, 2H), 6.56 (m , 3H)

Preparation Example S 2- (6-Methyl-1,3-benzodloxol-5-yl) ethanol

(a) 5- (2'-Benzyloxyethyl) -6-bromo-1,3-benzodloxole

H ₂ CH ₂ OCH ₂

15.0 g of 5- (2-acetoxyethyl) -1,3-benzodioxole were dissolved in 10 ml of carbon tetrachloride. To the solution was added 4.6 g of bromine while cooling with ice. The temperature was raised to room temperature and the reaction was continued for 2 hours. To this was added an aqueous sodium hydrogen carbonate solution. After extraction with chloroform, the extract was washed with a solution of sodium bisulfate and dried over magnesium sulfate. After

Concentration under reduced pressure gave a Bromrohverbindung in the form of brown needles. This product (unpurified) was added to a solution of 8.6 g of sodium hydroxide in methanol and the reaction was followed

60 ⁰ C over 1.5 hours. Methanol was removed and water added to the backsheet. After extraction with

Ethyl acetate, the extract was washed with water, dried over magnesium sulfate and under reduced pressure

concentrated to give a yellow, oily residue.

This residue (unpurified) was added to a solution of 3.8 g of sodium hydride in 150 ml of dimethylformamide Mixture was stirred at 60 ^° C for 30 minutes and the reaction was cooled to room temperature. In addition were

13.7 g of benzyl chloride were added dropwise and the reaction was again carried out at 60 ^° C. for one hour. The

Reaction mixture was poured into Lis / water. After the extractive. With ethyl acetate, the extract was over magnesium sulfate

dried and concentrated under reduced pressure, giving a: · rtohbenzylether. After cleaning with

Silica gel column chromatography (ethyl acetate / hexane = 3:97) gave 12.0 g of the intended compound in the form

a pale yellow oil.

¹ H-MKROOMHz ₁ CDCl ₃ ) O;

2.98 (t, J - 7Hz, 2), 3.66 (t, J = 7Hz, 2H), 4.54 (s, 2H), 5.95 (s, 2H), 6 , 82 (s, 1H), 7.02 (s, 1H), 7.34 (s, 5H)

(b) 5- (2-Benzyloxyethyl) -e-methyl, 3-benzodloxol

0 ^ P \ ^ CH ₂ CH ₂ OCH ₂ 0

3.0 g of 5- {2-benzyloxyethyl) -6-bromo-1,3-benzodioxole were dissolved in 100 ml of anhydrous ether. The solution was added

-78 ° C δ, 5ml of a 1.6M solution of n-butyllithium in hexane was added, and the reaction became at -50 ° C over 2 hours

guided. The reaction mixture was cooled again to -78 ° C. To this was added 6.4 g of methyl iodide and the temperature was gradually raised to room temperature.

To the reaction mixture was added methanol and water. After extraction with ethyl acetate, the extract was over Dried magnesium sulfate and concentrated under reduced pressure, giving a Methylrohverbindung. After this Purification by silica gel column chromatography (ethyl acetate / hexane = 2:98) gave 1.9 g of the intended Compound in the form of a pale yellow oil.

¹ H-MKR (90MHz) δ;

2.20 (s, 3H), 2.82 (t, J = 7Hz, 2H), 3.58 (tJ = 7Hz, 2H), 4.48 (s, 2H), 5, 82 (s, 2H), 6.56 (s, 1H), 6.60 <s, 1H), 7.44 (s, 5H).

(c) 2- (6-methyl, 3-benzodioxo-5-yl) ethanol

0 - ^ j ^ V ^ CH ₂ CH ₂ OH 0

1.9 g of 5- (2-benzyloxyethyl) -6-methyl-1,3-benzodioxoi were dissolved in 80 ml of ethanol. To this was added 0.2 g of 10% palladium /

Carbon (with a water content of 50%) and 4 ml of acetic acid were added, and the catalytic reduction was over Stur.de under 3at / cm ² performed. After removal of palladium / carbon, the ethanol was distilled off, and the Product was purified by silica gel column chromatography (ethyl acetate / hexane = 2: 3) to give 1.0 g of the product

provided compound in the form of a pale yellow oil.

'H-MKROOMHcCDCIi) O;

1.88 (bs, 1H), 2.32 (β, 3H), 2.88 (t, J = 7Hz, 2H), 3.88 (t, J = 7Hz, 2H), 5.96 (s, 2H), 0.76 (bs, 2H).

Heritella ligation β 2- (6-ethyl-1,3-benzodloxol-5-yl) ethanol

CH ₂ CH ₂ OH

(a) (6-EthyM, 3-benzodloxol-5-yl) egg lgilure

CH ₂ CH ₃

Gaseous hydrogen chloride was added to a mixture of 500 ml of concentrated hydrochloric acid, 11% ethyl acetate and

Introduced 900ml of an aqueous formaldehyde solution. A solution of 600 g of 5-Ethyl-1-1,3-benzodioxole in 300 ml of ethyl acetate was added at 55 ⁰ C was added dropwise, and the reaction was performed for one hour. To this was added benzene and the product was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give a crude chloro compound in the form of a pale yellow oil.

The chloro crude compound was dissolved in 41 dimethyl sulfoxide. The solution was thoroughly distilled at room temperature 400g

added triturated sodium cyanide, and the mixture was 12 hours. nj stirred. For this purpose, water was added. After

Extraction with ethyl acetate, the extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure Concentrated pressure, which gave a Zyanorohverbindung in the form of a brown oil. A solution of the cyanohanol compound prepared above in 21% ethanol was added to a solution of 800 g of sodium hydroxide

was added and the mixture was refluxed for 16 hours. The reaction mixture became ethanol

distilled off and water was added to the residue. After washing with ether, the aqueous layer was acidified. After extraction with chloroform, the extrak; washed with water, dried over magnesium sulfate and concentrated under reduced pressure.

The solid residue was recrystallized from ethyl acetate to give 400 g of the intended compound as colorless Crystals. Melting point: 114 ^o C-116 ° C

'H-MKR (SOMHz ₁ CDCl) Ie;

= 7Hz, 3H), 2.52 (q, J = 7Hz, 2H), 3.54 (s, 2H), 5.84 (s, 2H), 6.62 (s, 2H).

(b) 2- (6-ethyl-1,3-benzodloxol-5-yl) ethanol

CH ₂ CH ₂ OH

62 g of lithium aluminum hydride were brought to suspension in 1.51 anhydrous tetrahydrofuran. To the suspension was added dropwise a solution of 200 g of (6-ethyl-1,3-benzodir Ol-5-yl) acetic acid in 200 ml of tetrahydrofuran, and the reaction was stirred at room temperature for 12 hours. After completion of the reaction, water was added thereto, and the precipitate was filtered out. The filtrate was concentrated under reduced pressure and the residue became

Waters added. After extraction with ethyl acetate, the extract was washed with water over magnesium sulfate

dried, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / hsxan = 1: 4) to give 169 g of the intended compound as a pale yellow oil.

¹ H-MKR (90MHz, CDCl ₃ ) δ

1.16 (t, J = 7Hz, 3H), 2.80 (bs, 1H), 2.54 (q, J = 7Hz, 2H), 2.78 (t, J = 7Hz , 2 H), 3.74 (t, '= 7 Hz, 2), 5.84 {s, 2 H), 6.60 (s, 1 H), 6.62 (s,

Herculatory Bullet 7

2- (6-propyl-benzodioxol-5-yl) ethanol

Y ^ * CH ₀ CH ₀ OH

(a) (6-Propyl-1,3-benzodioxol-5-yl) acetonitrile

CH ₂ CN CH ₂ CH ₂ CH,

15 g of piperonyl butoxide and 300 ml of concentrated hydrochloric acid were dissolved in 100 ml of benzene and the solution was heated under reflux for 3 hours. The crude lactone mixture was cooled to room temperature and it became

Added water. After extraction with ethyl acetate, the extract was washed with water over magnesium sulfate

and concentrated under reduced pressure, giving 12g of e-propyl-5-chloromethyl-1,3-benzodioxole in the form of a

pale brown oil.

2.0 g of the product was dissolved in 30 ml of dimethylsulfoxide. To the solution was added 1.5 g of thoroughly triturated sodium cyanide, and the reaction was conducted at room temperature for 2 hours. The reaction mixture was poured into water. After extraction with ethyl acetate, the extract was washed with water, dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / hexane = 7:93) to give 1.7 g of the above compound as colorless noodles.

Melting point: 66 ° C-67 ° C

¹ H-MKROOMHz ₁ CDCl ₃ ) O;

0.98 it, J = 7Hz, 3H), 1.60 (sec, J = 7Hz, 2H), 2.52 (t, J = 7Hz, 2H), 3.64 (s, 2H), 5.96 (s, 2H), 6.72 Is ₁ .1H), 6.84 {s, 1H)

(b) 2- (6-Propyl-1,3-benzodioxol-5-yl) ethanol

I ₂ CH ₂ OH

1.7 g of (6-propyl-1,3-benzodioxo! -5-yl) acetonitrile were added to a solution of 1.7 g of potassium hydroxide in 40 ml of 50% hydr

Ethanol added. The mixture was heated under reflux for 14 hours, long. Ethanol became under reduced pressure

The reaction mixture distilled out, and the residue wu.de added water. After washing with ether, the aqueous layer was acidified. After extraction with chloroform, the extract was washed with water, over

Dried magnesium sulfate and concentrated under reduced pressure, giving 2- (6-propyl-1,3-b9nzodioxol-5-yl) acetic acid

revealed.

This product was added to a solution of 0.64 g of lithium ammine hydride in 20 ml of tetrahydrofuran at 0 ° C, and αιβ Reaction was conducted for one hour. Water was added to the reaction mixture and the precipitate so formed

was filtered out. The filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate / ethyl acetate).

Hexane = 3: 7) to yield 1.4 g of the intended compound as a colorless oil.

¹ HMKR (90MHz, CDCI ₁ Jd;

0.96 (t, J = 7Hz, 3H), 1, S6 (sec, J = 7Hz, 2H), 2.52 (t, J = 7Hz, 2H), 2.80 (t, J = 7Hz , 2H), 3.78 (t, J = 7 Hz, 2H), 5.89 (s, 2H), 6.68 (ä,

Synthesis bead 8 1- (1-3-benzodloxol-5-yl) -2-methyl-proppropene

CH

° ^{CH = (} C

62.5 ml of a 1.6M solution of butyl lithium in hexane was added to 500 ml of anhydrous ether. To this was added 38.5 g of isopropyltriphenylphosphonium bromide in a nitrogen atmosphere (nitrogen gas stream) and the mixture was stirred for 4 hours. To the reaction mixture was added 18 g of pipercnal, and the result was that the mixture was stirred for 5.5 hours and then fumed. The filtrate was washed with 11% ether, concentrated under reduced pressure

and purified by silica gel chromatography (hexane / ethyl acetate = 10: 1), which provided 13.1 g of the envisaged

Compound in the form of a colorless Ölf resulted.

¹ H-MKR (90MHz, CDCl ₃ ) δ;

1.83 (d, J-1Hz, 3H), 1.86 (d, J = 1Hz, 3H), 5.92 (β, 2H), 6.15 (m, 1H), 6.56 -6.82 (m, 3H)

Preparative Example 9 2 - [{2- (1,3-Benzodloxo-5-yl) ethyl) thio] ethanesulfonyl chloride

(a) Sodium 2 - [{2- (1,3-benzodioxol-5-yl) ethyl} thio] ethanesulfonate

15 g of 2- (1,3-benzodioxol-5-yl) ethanethiol and 17.4 g of sodium 2-bromocethanesulfonate were dissolved in a mixture of 280 ml of ethanol and 120 ml of water. To the solution was added 3.3 g of sodium hydroxide, and the mixture was heated under reflux for one hour. The RoAktionsrjemis'-S was concentrated by adding 500 ml of ethyl acetate and 500 ml of water. After separation of the layers, the aqueous layer was made acidic with hydrochloric acid. After extraction with n-butanol, the extract was washed with saturated aqueous common salt solution. The solvent was distilled off to give 19 g of a pale yellow residue. This product was dissolved in a solution of 2.94 g of sodium hydroxide in dilute methanol and recrystallized therefrom to give 14.7 g of the intended compound as colorless crystals

¹ H-MKR (90MHz, DMSO-J ₆₎ δ; 2.72 (s, 8H), 5.94 (s, 2H), 6.56-6.88 (m, 3H)

(b) 2 - [{2- (1,3-benzodioxol-5-yl) ethyl} thio] ethanesulfonyl chloride / 0-

1.9 g of sodium 2 - [{2- (1,3-benzodioxol-5-yl) -2-ethyl} thio] ethanesulfonate were brought to suspension in 4 ml of Ν, Ν-dimethylformamide. To the suspension were added dropwise while cooling with ice / water 0.89 g of thionyl chloride. The mixture was stirred with cooling with water for 20 minutes. After the addition of ice / water followed by a mixture of 200 ml of chloroform and 200 ml of water to the reaction mixture, the layers thus formed were separated. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to give 2.1 g of the intended compound as a colorless oil. ¹ H-MKR (90MHz, CDCl ₃ ) δ; 2.83 (s, 4H), 2.92-3.15 (m, 2H), 3.65-3.94 (m, .. '\ 5.94 (s, 2H), 6.56-6 , 85 (m, 3H).

Example 1 [{2- (1,3-Benzodioxol-5-yl) ethyl} thio] propan-2-one

10 g of 2- (1,3-benzodioxol-5-yl) ethanethiol and 5.1 g of 1-chloro-2-propanone were dissolved in 200 ml of 90% ethanol. To the solution was added 2.2 g of sodium hydroxide, and the mixture was refluxed for 10 minutes to conduct the reaction. The reaction mixture was concentrated under reduced pressure. To this was added 200 ml of ethyl acetate to make a solution which was washed three times with water. After drying over anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by silica gel column chromatography (benzene / ethyl acetate = 30: 1) to give 11.1 g of the intended compound as a colorless oil. 'H-MKR (90MHz, CDCl ₃ ) δ;

2.25 (s, 3H), 2.50-2.90 (m, 4H), 3.17 (s, 2H), 5.85 (s, 2H), 6.40-6.75 (m, 3H), MS m / z; 238 (M "), 149

Example 2 [(2- (1,3-Benzodioxol-5-yl) ethyl} thio] acetone tril

CH ₂ CH ₂ SCH ₂ CN

8.5 g of the intended compound in the form of a colorless oil were prepared from 4.2 g of 2- (1,3-benzodioxol-5-yl) ethanethiol and 4.2 g

Chloroacetone nitrile prepared in the same manner as in Example 1.

¹ H-MKR (90MHz, CDCl ₃ ) δ;

2.76-3.03 (m, 4H), 3.22 (s, 2H), 5.91 (s, 2H), 6.56-6.82 (m, 3H)

MS m / z; 221 (M "), 135

Example 3 2-Methyl-2 - [{2- (1,3-benzodloxol-5-yl) ethyl} thio] propoxylic acid

, 0 »n ^> ^ y CH ₂ CH ₀ SCCO ₀ H

6 g of the intended compound in the form of a colored oil were recovered from 6 g of (2- (1,3-benzodioxol-5-yl) ethanethiol and 4,6 g of 2-bromo-2-methylpropionic acid in the same manner as in Example 1.

¹ H-MKROOrV ₁ Hz ₁ CDCl ₃ ) O;

1.53 (s, 6H), 2.70-2.90 (m, 4H), 5.90 (s, 2H), 652-6.80 (m, 3H)

Example 4 Natrium-2-methyl-2 - [{2- (1,3-benzodloxol-5-yl) ethyl} thio] propyl

CH ₂ CH ₂ SCCO ₂ Na

(TU / TtT j

O J j

A solution of 0.90 g of sodium hydroxide in 9.0 ml of water was added to 6 g of 2-methyl-2 - [{2- (1,3-benzodioxole-5-

yl) ethyl} thio) propionic acid to prepare a solution. To the solution was added 100 ml of ethanol, and the

Solvent was distilled off. After filtering, the product was dried under reduced pressure to give βg of

provided compound in the form of a white powder.

Melting point: 261-265 ° C

¹ H-MKR (90MHz ₁ DMSOd ₆ ) δ;

1.32 (s, 6H), 2.52-2.82 (m, 4H), 5.90 (s, 2H), 6.48-6.80 (m, 3H)

MS (FAB m / z; 313 (MNa '), 291 (MH))

Example 5 2-Oxo-3 - [{2- (1,3-benzodioxol-5-yl) ethyl} thio] propionic acid

VO

0.21 g of the intended compound was added as a tautomeric keto-enol mixture of 2: 1 in the form of pale yellow crystals of 0.50 g of 2- (1,3-benzodioxol-5-yl) ethanethiol and 0.43 g of 3-bromopyrivinic acid Won as in Example 1. Melting point: 131 "-132'C ¹ H-MKR (90MHz, CDCl 3 -DMSO-de) δ;

2.40-3.08 (m, 2H-1H x Vs), 5.87 (s, 2H), 6.20 (s, 1H x Va), 6.40-6.84 (m, 3H), 8.10 (bs, 1H) MS m / z; 268 (M ")

Example 6

^Ο ^ έ? * Γ ' CH ₀ CH ₀ SCH

3.30 g of 2- (1,3-benzodioxol-5-yl) ethanethiol were dissolved in 30 ml of ethanol. To the solution was added 1.65 g of sodium hydroxide and then 2.70 g of 4-pikclyl chloride hydrochloride, and the mixture was heated under reflux for 30 minutes. The solvent was distilled off, and water was added to the residue. After extraction with ethyl acetate, 1N hydrochloric acid was added to the extract. The aqueous layer was acidified, taken up and washed with ethyl acetate. The pH of the aqueous layer was adjusted to 8 with potassium carbonate. After extraction with ethyl acetate, the extract was washed with saturated aqueous common salt solution and dried over anhydrous Mg sulfate. After filtering, the solvent was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 4) to give 2.69 g of the intended compound as a colorless oil

¹ H-MKR (90MHz, CDCl ₃ ) δ;

2.4-2.87 (m, 4H), 3.60 (s, 2H), 5.86 (β, 2H), 6.35-6.75 (m, 3H), 7.05-7, 25 (m, 2H), 8.25-8.57 (m, 2H) MS (FD) m / z; 273 (M ")

-72- 237 038

Example 7 2- (1,3-Benzodioxol-J-Yl) ethyl (pyrldin-2-yl) methylsulfide

2.3 g of the intended compound in the form of a colorless oil were recovered from 3.0 g of 2- (1,3-benzodioxol-5-yl) ethynediol and 2.7 g of 2-picolyl chloride hydrochloride in the same manner as in Example 6.

¹ H-MKROOMHz ₁ CDCl ₃ ) O;

2.55-2.9 (m, 4H), 3.86 (s, 2H), 5.91 (s, 2H), 6.45-6.8 (m, 3H), 7.0-7, 3 (m, 1H), 7.33 (bd, J = 7.9Hz, 1H), 7.61 (td, J = 7.9 and 2.2Hz, 1H), 8.51 {bp , J = 5.8Hz, 1H)

MS (FD) m / z; 723 (M ")

Example 8 2- {1,3-Benzodloxol-5-yl) ethyl- (imidazol-4-yl) methyl sulfide

40ml of thionyl chloride was added to 2.50g of 4-hydroxyethylimidazole hydrochloride. The mixture was stirred under heating at 7O ⁰ C for one hour. Thionyl chloride was distilled off. The residue were added 3,39g of 2- (1,3-benzodioxol-5-yDethanthiol, 40ml of ethanol and 1.50 g sodium hydroxide was added, and the mixture was stirred under heating at 70 ° to 8O ⁰ C for one hour. The solvent was distilled Water was added to the residue, and after extraction with chloroform containing 5% of methanol, the extract was dried over anhydrous magnesium sulfate and filtered, the solvent was distilled off, and the residue was purified by silica gel column chromatography (methanol / chloroform = 1:49). . to afford 1.94 g of the intended compound in the form of colorless prismatic crystals melting point: 81 ^O-C 83 ° C ¹ H-MKR (90MHz, CDCI ₃₎ δ;

2.4E-2.9 (m, 4H), 3.68 (s, 2H), 5.34 (s, 2H), 5.8-6.9 (broad, 1H), 6.4-6 , 75 (m, 3H), 6.86 (bs, 1H), 7.53 (bs, 1H) MS m / z; 262 (M ")

Example 9 4- [2- (2- (1,3-Benzodioxol-5-yl) ethyl} thio] ethyl 5-methyl-1-oxazol-3-ol

CH ₂ CH ₂ SCH ₂ CH ₂

100 ml of tetrahydrofuran and 4.66 g of triethylamine were added to 2.84 g of 3-acetoxy-4- (2-hydroxyethyl) -5-methylisoxazole. 4,39g by methanesulfonyl chloride were added at -15 ⁰ C was added dropwise, and the mixture was stirred at 0 ° C or below for

Stirred for one hour. The solvent was distilled off. After the addition of ice / water, followed by extraction with chloroform, the Extract with 1 N hydrochloric acid, water, a saturated aqueous sodium hydrogen carbonate solution and a

saturated, aqueous ordinary saline solution in this order and then washed over anhydrous

Dried magnesium sulfate. The solvent was removed by distillation and the resulting methanesulfonate became a Solution formed from 4.19 g of 2- (1,3-benzodioxol-5-yl) ethanethiol, 30 ml of ethanol and 1.53 g of sodium hydroxide,

and the mixture was stirred under heating at 70 ⁰ C. The solvent was distilled off and the residue became

Added water. After extraction with chloroform containing 5% methanol, the extract was treated with a saturated,

washed aqueous ordinary saline solution and dried over anhydrous magnesium sulfate. After filtering, the filtrate was concentrated, purified by silica gel column chromatography and recrystallized from ethyl acetate / hexane to give 0.96 g of the intended compound as colorless needles.

Melting point: 81 ^"C-O C 81.5

'H-MKROOMHz ₁ CDH ₃ ) O;

2.25 \\ 3H), 2.35 to 2.85 (m, 8H), 5.87 (s, 2H), 5.4 to 6.5 (br, qH), 6.45 to 6.75 (m, 3H) MS m /. ·; 307 (M ")

BelipleHC

NaO '° ^ tf ^ N ^ CH ₂ CH ₂ SCH ₂ CH ₂

\O

H ₃ C

1.01 g of the intended compound in the form of a white powder were prepared from 0.95 g of 4- [2- {2- {1,3-benzodioxol-5-yl) ethylthio] ethyl 5-methylisoxazole-3. ol in the same manner as prepared in Example 4.

Melting point: 144'0-152 "C (decomposition)

¹ H-MKR (90 MHz), DMSO-d ") δ; 1.98 (s, 3H), 2.1-2.8 (m, 4H), 2.68 (bs, 4H), 5.88 (s, 2H), 6.48-6.9 (m, 3H)

MS (FAB) m / z; 352 (MNa "), 330 (MH")

Example 11 [{2- (2-Methyl-1,3-benzodloxol-5-yl) ethyl} thiol] acid

0.97 g of methanesulfonyl chloride was added dropwise to a solution of 0.76 g of (5- (2-hydroxyethyl) -2-methyl-1,3-benzodioxole and 1.2 ml of triethylamine in 10 ml of methylene chloride, and the mixture was stirred at room temperature for 30 minutes The reaction mixture was diluted with chloroform, washed with cold water, then with a saturated sodium hydrogen carbonate solution and finally with an aqueous common salt solution and dried over magnesium sulfate, the solvent was distilled off, and the resulting oil (mesylate) was added with 0.9 g of mercaptoacetic acid. 10 ml of a 10% sodium hydroxide solution and 1 mM of ethanol, and the mixture was stirred at f) ° C for 30 minutes. The reaction mixture was concentrated and the aqueous layer was washed with ethyl ether and then acidified with dilute hydrochloric acid. The aqueous layer was extracted with chloroform, then dried over magnesium sulfate. The solvent was distilled off and the product was purified by silica gel column chromatography (methanol / chloroform = 1:99) to give 1.0 g of the intended compound as a biaxial oil. ¹ H-MKROOMHz ₁ CDCl ₃ ) O; 1.66 (d, J = 5Hz, 3H), 2.84 (s, 4H), 3.24 (s, 2H), 6.20 (q, J = 5Hz, 1H), 6.63 (m, 3H), 9.95 (m, 1H)

Example 12 Sodium - [{2- (2-methyl-1,3-benzodioxol-5-yl) ethyl} thioacetate

CH ₀ CH ₀ SCH ₀ CO ₀ Na

IpUUp Ul / ilpl / VpI

0.7 g of the intended compound in the form of a white powder was prepared from 1.0 g of [{2- (2-methyl-1,3-benzodioxol-5-yl) ethyl} thio] acetic acid in the same manner as in Example 4.

Melting point: 200 ^e C-205 ° C (decomposition)

¹ H-MKR (400MHz, DMSO-d _e ) δ; 1.58 (d, J = 4.8Hz, 3H), 2.68 (m, 4H), 2.96 (s, 2H), 6.28 (q, J = 4.8Hz, 1H) , 6.62-6.75 (m, 3H)

MS (FAB) m / z: 299 (MNa "), 276 (MH")

Example 13 [{2- (2,2-Dimethylmethyl-1,3-benzodioxol-5-yl) ethyl) thio] oleic acid

^H 1 ^G V ^ Ov ^^ K ^ CH ₀ CH ₀ SCH ₀ CO ₀ H

J \ / ^ ^ {r Ύ \ dddd

X.

H ₃ C 0

3.4 g of the intended compound in the form of a colorless oil were prepared from 4.3 g of 2,2-dimethyl-5- (2-hydroxyethyl) -1,3-benzodioxole in the same manner as in Example 11.

¹ H-MKROOHMCDCI ₃ ) O; 1.65 (s, 6H), 2.84 (s, 4H), 3.25 (s, 2H), 6.61 (m, 3H), 9.84 (m, 1H)

Example 14 Sodium - [(2- (2,2-dilmethyl-1,3-benzodixol-5-yl) ethyl} thiol] acetate

3.3 g of the intended compound in the form of a white Powders were do 3,3g I {2- (2,2-dimethyl-1 _l 3-benzodioxol-5-yl) ethyl) thio | acetic acid in the same manner as in Example 4 manufactured.

Melting point: 199 ^e C-202 ° C (decomposition)

¹ H-MKR (400MHz, DMSO-d ") δ; 1.60 (s, 6H), 2.68 (s, 4H), 2.95 (s, 2H), 6.60-6.71 (m, 3H)

MS (FAB m / z), 313 (MNa "), 291 (MH")

Example 15 [{2- (6-Methyl-1,3-benzodloxol-5-yl) ethyl} thiol] oleic acid

CH ₀ CII ₀ SCH ₀ Co ₀ II cd dc

CH ₃

1.5 g of the intended compound in the form of a white powder were prepared from 1.5 g of 2- (6-methyl-1,3-benzodioxol-5-yl) ethanol in the same manner as in Example 11.

¹ H-MKROOMHz ₁ CDCl ₃ ) O;

2.22 (s', 3H), 2.82 (s, 4H) ₁ 3.26 (s, 2H), 5.88 (s, 2H), 6.66 (s, 2H), 10.56 ( bs, 1 H)

Example 16 Natrium - [{2- (6-methyl-1,3-benzodioxol-5-yl) ethyl} thiol] acetate

1.6 g of the intended compound in the form of a white powder were prepared from 1.5 g of [{2- (6-methyl-1,3-benzodioxol-5-yl) ethyl} thio] acetic acid in the same manner as in Example 4.

Melting point: 194 ° C-195 ^O C

¹ H-MKR (400MHz, DMSO-d ") δ;

2.17 (s, 3H), 2.59-2.63 (m, 2H), 2.67-2.72 (m, 2H), 2.96 (s, 2H), 5.90 (s, 2H), 6.70 (s, 1H), 6.75 (s, 1H)

MS (FAB) m / z; 277 (MH ") _Λ Example 17

t {2- (C-ethyl, 1,3-benzodioxol-5-yl) ethyl) thio) acetic acid

H ₂ CH ₂ SCH ₂ CO ₂ H

CH ₂ CH ₃

85 g of the intended compound in the form of a white powder were prepared from 169 g of 2- (6-ethyl-1,3-benzodioxol-5-yl) ethanol in the same manner as in Example 11.

Melting point: 63 ° C-64 ° C

¹ H-MKROOHMCDCI ₃ ) O;

1.16 (t, J = 7Hz, 3H), 2.52 (q, J = 7Hz, 2H), 2.82 (s, 4H), 3.24 (s, 2H), 5.84 ( s, 2H), 6.58 (s, 1H), 6.60 (s, 1H), 9.80 (bs, 1H)

Example 18 Nutrium-iil-ie-ethyl-1S-benzodloxol-B-y-di-ethyll-lolate

H ₂ CH ₂ SCH ₂ CO ₂ Nq

CH ₂ CH ₃

91 g of the intended compound in the form of a white powder were prepared from 85 g of ((2- (6-ethyl-1,3-benzodioxol-5-yl) -ethyl} -hio] acetic acid in the same manner as in Example 4.

Melting point: 193 ^ο ΰ-196 "ΰ (decomposition)

¹ H-MKR (400MHz, DMSO-d ₆ ) δ;

1.10 (t, J = 7Hz, 3H), 2.51 (q, J = 7Hz, 2H), 2.60 to 2.65 (m, 2H), 2.69-2.74 (m, 2H ), 2.79 (s, 2H), 5.91 (s, 2H), 6.71 (s, 1H), 6.75 (s,

MS (FAB) m / z; 291 (MH ")

Example 19 [(2- (6-Propyl-1,3-benzodloxol-5-yl) ethyl} thio) -salicylate

CH ₂ CH ₂ SCH ₂ CO ₂ HH ₂ CH ₂ CH ₃

1.4 g of the intended compound in the form of colorless crystals were prepared from 1.4 g of 2- (6-propyl-1,3-benzodioxol-5-yl) ethanol in the same manner as in Example 11.

Melting point: 72.5 ° C-73.5 ° C

¹ H-MKROOMH ^ CDClI) O;

0.96 (t, J = 7Hz, 3H), 1.56 (sec, J = 7Hz, 2H), 2.52 (t, J = 7Hz, 2H), 2.84 (s, 4H), 3 , 48 (s, 2H), 5.90 (s, 2H), 6.64 (s, 2H)

Example 20 Natrium - [{2- (6-propyl, 3-benzodloxol-5-yl) ethyl} thiol] acetate

CH ₂ CH ₂ SCH ₂ CO ₂ Na CH ₂ CH ₂ CH ₃

1.5 g of the intended compound were in the form of a white powder of 1.4 g of [{2- (6-propyl-1,3-benzodioxol-5-yl) ethyl} thio] acetic acid in the same manner as ir.ι Example 4 prepared.

Melting point: 189-190 ⁰ C

¹ H-MKR (400MHz, DMSO-d,) δ;

0.96 (t, J = 7Hz, 3H), 1.49 (sec, J = 7Hz, 2H). 2.46 (t, J = 8Hz, 2H), 2.62-2.64 (m, 2H), 2.69-2.72 (m, 2H), 3.00 (s, 2 H), 5.90 (s, 2H), 6.69 (s, 1H), 6.75 (s, IH).

MS (FAB) m / z; 305 (MH ")

Example 21 3- {6- (2-Ethylthio) ethyl-1,3-benzodigoxol-5-yl} propylonic acid

>'0 \ ^ _> ^ CH ₂ CH ₂ SCH ₂ CH ₃

0- ^ ^ V ^ CH ₂ CH ₂ CO ₂ H

2.2 g of the intended compound in the form of a white powder were prepared from 3.5 g of ethyl 3-6- (2-methanesulfonyloxy) ethyl-1,3-benzodioxol-5-yl propionate and 1 g of ethyl mercaptan in the same manner as in Example 11 produced.

¹ H-MKR (SOMHz ₁ CDCl ₃ ) S;

1.28 (t, J = 7.2Hz, 3H), 2.50-3.10 (m, 10H), 5.99 (s, 2H), 6.75 (s, 2H)

Example 22 Natrum-3- {6- (2-ethylthio) ethyl-1,3-benzodloxol-5-yl} propontate

1 0 - ^^^^ »« yjCHpCHpSCHpCH-5

\ 0 - "^ ^ ¹ N) K ₂ CH ₂ CO ₂ Na

1.9 g of the intended compound in the form of a white powder were prepared from 2.2 g of 3-6- (2-ethylthio) ethyl-1,3-benzodioxol-5-yl-propionic acid in the same manner as in Example 4.

Melting point: 218-222 ° C

¹ H-MKR (90MHz, DMSO-d,) δ;

1.20 (t, J = 7.2Hz, 3H), 1.94-2.26 (m, 2H), 2.28-2.88 (m, 8H), 5.84 (s , 2H), 6.67 (s, 2H)

MS (FAB) m / z; 327 (MNa "), 305 (MH")

Example 23 [[{2- (1,3-Benzodioxol-5-yl) -1,1-dl-methyl} ethyl] thio] -acetic acid

CH ₃ CH ₃

30ml benzene was added to a mixture of 5g 1- (1,3-benzodioxol-5-yl) -2-methyl-1-propene, 2,6g mercaptoacetic acid and a catalytic! Quantity u, «- azobisisobutyronitrile. The mixture was refluxed for two days. To this was added 2.6 g of mercaptoacetic acid and the mixture was refluxed for one week. the

To the reaction mixture was added 200 ml of ethyl acetate and 200 ml of water, and the layers thus formed were separated. To the ethyl acetate layer was added an aqueous sodium carbonate solution to extract the intended compound. The aqueous layer was made acidic with dilute hydrochloric acid. After extraction with ethyl acetate, the extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane / Ethyl acetate / acetic acid = 20: 80: 1). The product was dissolved in ethyl acetate, washed with water to remove the acetic acid and anhydrous Dried sodium sulfate. The solvent was distilled off to give 3.33 g of the intended compound in the form

a colorless oil.

¹ H-MKROOMHz ₁ CDCl ₃ ) O;

1.29 (s, 6H), 2.78 (s, 2H), 3.29 (s, 2H), 5.92 (s, 2H), 6.52-6.80 (m, 3H)

Example 24 Sodium um - ([{2- (1,3-benzodloxol-5-yl) -1,1-dimethyl} ethyl] -thio] acetate

CH ₀ CSGH ₀ GO ₀ Na W ²

CH ₃ CH ₃

2.1 g of the intended compound in the form of colorless crystals were prepared from 3.33 g of [I {2- (1,3-benzodioxol-5-yl) -1,1-dimethyl} ethyl] acetic acid in the same manner as in Example 4 produced.

Melting point: 206-210 ⁰ C

¹ H-MKROOMHz ₁ DMSCkI ₁₁ ) O;

1.14 (s, 6H), 2.68 (s, 2H), 3.02 (s, 2H), 5.94 (s, 2H), 6.52-6.88 (m, 3H)

MS (FD) m / z; 313 (MNa "), 291 (MH")

Example 25 i [1 - {(1,3-benzodloxol-5-yl) -othyl) -propyl-thiosulfonic acid

₂ C0 ₂ H CH ₂ CH ₃

2.2 g of 5- {1-butenyl) -1,3-benzodioxole and 5.4 g of mercaptoacetic were heated for a period of 3 hours at 6O ⁰ C. The reaction mixture was diluted with ethyl acetate, washed with water and an aqueous ordinary brine, and dried over magnesium sulfate. The solvent was distilled off and the product was separated by silica gel column chromatography (chloroform) to give 1.8 g of the intended compound as a colorless oil.

1.00 (t, J = 7Hz, 3H), 1.54 (m, 2H), 2.69-3.00 (m, 3H), 3.14 (s, 2H), 5.87 (s, 2H), 6.62 (m, 3H), 8.7 (m, 1H)

Example 26 Sodium - [[1 - {(1,3-benzodioxol-5-yl) methyl} propyl] thiol] acetate CH ₂ CHSCH ₂ CO ₂ Na

CH ₂ CH ₃

1.7 g of the intended compound in the form of a white powder were prepared from 1.7 g of [1 - {(1,3-benzodioxol-5-yl) methyl} propyl) thio] acetic acid in the same manner as in Example 4.

Melting point: 184-188 ° C (decomposition)

¹ H-MKR (400MHz, DMSO-d,) δ;

0.85 »; J = 7.3 Hz, 3H), 1.31 (m, 1H), 1.48 (m, 1H), 2.43 to 2.59 (m, 1H) , 2.80 to 2.90 (m, 2H), 2.90 and 2.96 (ABq, J = 13.2Hz, 2H), 5.96 (m, 2H), 6.65 ( m, 1H), 6, / 7 to 6.82 (m, 2H) MS (FAB) m / z; 291 (MH ")

Example 27 ((2- (1,3-benzodio) ol-5-yl) ethyl) thiol] cyanoacetic acid

CH ₂ CH ₂ SCHCO ₂ H

CN

5.0 g of 2- (1,3-benzodioxol-5-yl) ethyl} thio) acetonitrile were dissolved in 50 ml of anhydrous ether. To the solution was added at -78 ⁰ C 22ml of a 1.6M solution of n-butyllithium in hexane. The mixture was stirred at -50 ° C for two hours. It was again cooled to -78 ° C and 10 g of dry ice was added. The temperature of Gemisct as was on

Room temperature increased. Water was added to the reaction mixture. After extraction with chloroform, the Extract dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography

(Chloroform) and recrystallized from ethyl acetate / hexane to give 0.70 g of the intended compound as colorless needles.

Melting point: 106-107 ° C

¹ H-MKR (90MHz, DMSOd ₆ ) δ;

2.62-3.10 (m, 4H), 5.12 (s, 1H), 5.90 (s, 2H), 6.50-6.86 (m, 3H) MS (FAD) m / z; 265 (MH ")

Example 28 Sodium - [{2- (1,3-benzodioxol-5-yl) ethyl} thio] cyanoacetate

CH ₉ CH ₉ SCHCO ₉ Na

CN

0.59 g of the intended compound in the form of a white powder was prepared from 0.70 g of [{2- (1,3-benzodioxol-3-yl) ethyl} thio] cyanoacetic acid in the same manner as in Example 4.

Melting point: 202-208 ° C (decomposition)

¹ H-MKR (400MHz, DMSO-d ") δ; 2.80-2.84 (m, 2H), 2.88-2.92 (m, 2H), 4.25-4.50 (bs, 1H), 5.97 (s, 2H ), 6.70-6.86 (m, 3H)

MS (FAB) m / z; 310 (MNa ")

Example 29 N, N-Dimethyl-2 - [{2- (1,3-benzodloxol-5-yl) -2-ethyl} thio] ethanesulfonamide

4g 2 - [{2- (1,3-benzodioxol-5-yl) ethyl} thio] ethansuitonyichit> i id wuiciön dissolved in chicreform. While stirring, gaseous dimethylamine was introduced. The chloroform solution was washed with water and anhydrous

Dried sodium sulfate. The solvent was distilled off and the residue was passed through Silica gel column chromatography (chloroform). The product was recrystallized from isopropyl ether / ethanol

to give 3.0 g of the intended compound as colorless crystals.

Melting point: 93 to 94.5 ⁰ C

¹ H-MKR (90MHz, CDCl ₃ ) δ; 2.75 (8.4 H), 2.83 (s, 6H), 2.68-3.19 (m, 4H), 5.86 (s, 2H), 6.48-6, 76 (m, 3 H) rViS m / z; 317 (M "), 149.135

Example 30 [{2- (1,3-Benzodloxo-5-yl) ethyl} sulfinyl] propan-2-one

r

.CH ₂ CH ₂ SCH ₂ CCII ₃

4 g of I {2- (1,3-bonzodioxol-5-yl) ethyl} thiolpropan-2-one were dissolved in 70 ml of chloroform. 3.2 g of 90% m-chloroperbenzoic acid was added to the solution while cooling with ice / water. The mixture was stirred for 40 minutes. the

Reaction mixture was added to 150 ml of chloroform and an aqueous sodium carbonate solution. After the separation of the so

The chloroform layer was washed three times with water and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was recrystallized from isopropyl ether to give 3.5 g of the intended! Compound in the form of colorless crystals.

Melting point: 82 to 84.5 ⁰ C

¹ H-MKR (90MHz, CDCl ₃ ) O; 2.32 (s, 3H), 2.99 (s, 4H), 3.65 and 3.77 (ABq, J = 13.5Hz, 2H), 5.89 (s, 2H) , 6.50-6.77 (m, 3 Hi MS (FAB) m / z; 255 (MH "),

Example 31 5- {2- (Ethylsulfine) ethyl} -1,3-benzodioxole

-O-jjis. CH ₂ CH ₂ SCH ₂ CH ₃

3.0 g of the intended compound in the form of colorless crystals were prepared from 4 g of 5- (2- (ethylthio) ethyl) -1,3-benzodioxole in the same manner as in Example 30.

Melting point: 60.5 to 61.5 ⁰ C

^ -MKRßOMHz.CDCIslö; 1.33 (t, J = 7.2Hz, 3H), 2.71 (q, J = 7.2Hz, 2H), 2.72 to 3.18 (m, 4H), 5.92 (s, 2H ), 6.54-6.83 (m, 3H) MS (FAB) m / z; 227 (MH)

Example 32 5- {2- (1-Methylethylsulfinyl) ethyl} -1,3-inuodioxole

, CH ₂ CH ₂ SCHH ₃

3.7 g of the intended compound in the form of a colorless oil were prepared from 4 g of 5- {2- (1-methylethyl) thio} ethyl-1,3-benzodioxole

prepared in the same manner as in Example 30.

¹ H-MKR (90MHz, CDCl ₃ ) δ;

1.24 (d, J = 5.4 Hz, 3 H), 1.31 (d, J = 5.4 Hz, 3 H), 2.45 to 3.27 (m, 5 H), 5, 88 (s, 2H), 6.53-6.78 (m, 3H) MS (FAB) m / z; 241 (MH "), 149

Example 33 [{2- {1,3-Benzodioxol-5-yl) ethyl} sulfinyl] acetonitrile

CH ₂ CH ₂ SCH ₂ CN

3.0 g of the intended compound in the form of colorless crystals were prepared from 3 g of [{2- {1,3-benzodioxol-5-yl) ethyl} thio] acetonitrile in the same manner as in Example 30.

Melting point: 57-59.5'C

¹ H-MKR (90MHz, CDCl ₃ ) δ;

2.76-3.34 (m, 4H), 3.53 and 3.69 (ABq, J = 16.4Hz, 2H), 5.90 (s, 2H), 6.52-6.79 (m , 3H) MS (FAB) m / z; 238 (MH "), 149

Example 34 [{2- (1,3-Benzodioxol-5-yl) ethyl} sulfinyl] propan-2-one

ο o

ti N CH ₂ CH ₂ SCH ₂ CCH ₃

4 g of [{2- (1,3-benzodioxol-5-yl) ethyl} thio] propan-2-one were dissolved in 70 ml of chloroform. To the solution was added 8.1 g of 90% m-chloroperbenzoic acid under cooling with ice / water, and the mixture was stirred for two hours.

To the reaction mixture was added 150 ml of chloroform and an aqueous sodium carbonate solution. After the separation of

Thus, the chloroform layer was washed with water three times and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was recrystallized from ethyl acetate / isopropyl ether to give 4.1 g of the intended compound as colorless crystals.

Melting point: 97-99 "C

¹ H-MKROOMH ^ cDCI ₃ ) O;

2.39 (s, 3H), 2.88-3.47 (m, 4H), 3.92 (s, 2H), 5.89 (s, 2H), 6.50-6, 77 (m, 3H) MS (FAB) m / z; 270 (M '), 149

Example 35 5- (2- (Ethylsulfonyl) ethyl) -1,3-benzodioxole

/ O

3.5 g of the intended compound in the form of colorless crystals were prepared from 4g of 5- (2- (E (hylthio) ethyl-1,3-benzodioxole in the same manner as in Example 34.

Melting point: 90-91 ° C

¹ H-MKROOMH ^ cDCI ₃ ) O;

1.38 (t, J = 7.4Hz, 3H), 2.92 (q, J = 7.4Hz, 2H), 3.00 to 3.22 (m, 4H), 5, 93 (s, 2H), 6.57-6.81 (m, 3H) MS (FAB) m / z; 243 (MH "), 149

Example 36 5- (2- (1-Methylethylsulfonyl) ethyl) -1,3-benzodioxole

4.0 g of the intended compound in the form of colorless crystals were prepared from 4 g of 5- ({2- {1-methylethyl) thio} ethyl-1,3-benzodioxole in the same manner as in Example 34.

Melting point: 83-85 ⁰ C

¹ H-MKR (90MHz, CDCl ₃ ) δ;

1.39 (d, J = 6.8Hz, 6H), 2.82-3.27 (m, 5H), 5.90 (s, 2H), 6.44-6.78 (m , 3H)

MS m / z; 256 (MH "), 149

Example 37 [{2- (1,3-Benzodioxol-5-yl) ethyl} sulfonyl] acetonitrile

.CH ₂ CH ₂ SCH ₂ CN

2.95 g of the intended compound in the form of colorless crystals were prepared from 3 g of {(2- {1,3-benzodioxol-5-yl) ethyl) thio] acetonitrile in the same manner as in Example 34.

Melting point: 93-95 ⁰ C

¹ H-MKB (90MHz, CDCl ₃ ) δ;

2.95-3.30 (m, 2H), 3.33-3.67 (m, 2H), Λ75 (s, 2H), 5.91 (s, 2H), 6.56-6.88 ( m, 3H) MS m / z; 253 (M "), 149

Compound Group (I-O) Preparation Example 1 2- (1,3-benzodlexo-5-yl) ethanethiol

CH ₂ CH ₂ SH

750 g of 5- (2-bromoethyl) -1,3-benzodioxole were dissolved in 11% ethanol, followed by the addition of 312 g of thiourea. The

Mixture was heated under reflux on a boiling bath (water) for 2 hours and cooled, followed by the addition of a Solution of 300g sodium hydroxide in 11 water. The recovered mixture was refluxed to a boiling point Water bath heated for 45 minutes and cooled, followed by the addition of 3I water. The recovered mixture

was extracted with 5 I ethyl acetate. The extract was washed with dilute hydrochloric acid and then with water until the washings were neutral, dried over anhydrous sodium sulfate and tilliert at 40 ⁰ C rie ^ to the

Remove solvent. This gave about 570 g of a yellow oil. This oil was through Silica gel column chromatography (hexane / benzene = 2: 1) to give 310g of the title compound as a

colorless oil.

¹ H-MKR (90MHz, CDCI ₃ ) 6;

1.36 (m, 1H), 2.6-2.9 (m, 4H), 5.87 (s, 2H), 6.50 to 6.74 (m, 3H). "

Preparation 2 3- (1,3-benzodioxol-5-yl) propanthlol

CH ₂ CH ₂ CH ₂ SH

25g of thioacetic acid was added to 53.5g of safrol in portions, with the mixture stirred at room temperature or with ice / water cooling. The reaction was conducted over 30 minutes. To the reaction mixture was added a solution of 20 g of sodium hydroxide in a mixture containing 100 ml of water and 200 ml of ethanol. The resulting mixture was heated at reflux for a period of 20 minutes, cooled, neutralized with dilute sulfuric acid and extracted with 11 benzen. The extract was washed with water and the benzene layer was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (hexanes) to give 42.8 g of the title compound as a colorless oil

¹ H-MKROOMH ^ CDClI) O; 1.20-1.46 (m, 1H), 1.68-2.10 (m, 2H), 2.34-2.78 (m, 4H), 5.84 (s, 2H), 6 , 44-6.75 (m, 3H).

Manufacture Example 3 2- (1,3-Benzodloxol-5-yl) -1-methylethanethiol

co ·

.CH ₂ CHSH

5g of anhydrous stannous chloride was added to 100g of safrol. Hydrogen chloride gas was passed through the mixture while cooling with ice for 1.5 hours. To the mixture was added 21% ethyl acetate followed by dissolution. The recovered mixture was washed twice with water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography (hexane / benzene = 10: 1) to give 41.7 g of 5- (2-chloropropyl) -1,3-benzodioxole as a colorless oil. This oil was dissolved in 150 ml of ethanol, then 48 g of thiourea was added. The mixture thus prepared was refluxed for 7 days, cooled and filtered. To the filtrate was added a solution of 12.8 g of sodium hydroxide in 100 ml of water. The recovered mixture was heated under reflux for 2 hours, cooled and acidified with dilute sulfuric acid. To the mixture was added 11 benzen and 11 Wt-sser to carry out the phase separation. The benzene layer was washed twice with water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography (hexane / benzene = 10: 1) to give 8.5 g of the title compound as a colorless oil

¹ H-MKR (90MHz, CDCl ₃ ) δ; 1.32 (d, J = 6Hz, 3H), 1.54 (d, J = 6Hz, 1H), 2.61-2.84 (m, 2H), 2.90-3.35 ( m, 1H) ₁ 5.86 (s, 2H), 6.46-6.76 (m, 3H)

Example 1 (Compound 1) 2 - [{2- (1,3-Benzodioxol-5-yl) ethyl} d] thio] ethanol

(CH ₂ ) ₂ S-3 (CH ₂ ) ₂ OH

35 g of 2- (1,3-benzodioxol-5-yl) ethanethiol and 75 g of 2-mercaptoethanol were dissolved in 150 ml of ethanol, then 43 g of iodine were added. The resulting mixture was stirred at room temperature for 30 minutes, after which 21 ethyl acetate and 21% water were added. The mixture was separated into two phases. The Ethylazetatschicht was twice with water, then twice with 11 of an aqueous 1% solution of sodium hydrogen sulfite and finally with three times

Washed water, dried over anhydrous sodium sulfate and filtered. The filtrate was distilled to the Remove solvent. The residue was purified by silica gel column chromatography (benzene / ethyl acetate = 10: 1).

to give 11.5 g of the title compound as a colorless oil.

¹ H-MKROOMHz ₁ CDCl ₃ ) O;

1.98 (t, J = 7Hz, 1H), 2.85 (t, J = 7Hz, 2H), 2.91 (s, 4H), 3.89 (q, J = 7Hz , 2H), 5.92 (s, 2H), 6.55-6.84 (πι, 3H).

MS m / z; 258 (M "), 149

Example 2 (Compound 2) Bls (2- (1,3-benzo-oxo-5-yl) ethyl} dlsulfld

(CH ₂ J ₂ SS (CH ₂ )

2 g of the title compound were prepared from 3g of 2- (1,3-benzodioxol-5-yl) ethanethiol in the form of a colorless oil after the same

Process v> ie prepared in Example 1. Melting point: 76-78 ⁰ C

¹ H-MKR (90MHz, CDCl ₃ ) δ;

2.87 (s, 8H), 5.90 (s, 4H), 6.51-6.81 (m, 6H),

MS m / z; 362 (M "). 149

Example 3 (Compound 3) 2 - [{2- (1,3-Benzodloxol-5-yl) ethyl} dithlo] ethylnickelate

4 g of the 2 - ({2- (1,3-benzodioxol-5-yl) ethyl} dithioi) ethanol prepared in Example 1 were dissolved in a mixture consisting of 20 ml of pyridine and 50 ml of benzene to prepare a solution. To the solution was added 4 g of nicotinyl chloride hydrochloride. The recovered mixture was heated under reflux for 2 hours and poured into ice / water. The resulting mixture was made weakly basic with sodium hydrogen carbonate. To the mixture was added ethyl acetate to obtain the

Phase separation. Wash the ethyl acetate layer with water five times, dry over anhydrous sodium sulfate, and distill to remove the solvent. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3: 1) to give 5.4 g of the riveting compound as a colorless oil.

¹ H-MKROOMHz ₁ CDCl ₃ ) O; 2.92 (s, 4H), 3.06 (t, J = 7Hz, 2H), 4.62It, J = 7Hz, 2H), 5.92 (s, 2H), 6 , 40-6.86 (m, 311), 7.30--7.5O in, 1H), 8.20-6.41 (m, 1H), 8.08-8.85 (m, 1H), 9.14-9.34 (m, 1H) MS m / z; (363 [M "D, 149

Example 4 (Compound 4) 2 - [{2- (1,3-Benzodioxol-5-yl) ethyl} dithlo] ethyl picotassium hydrochloride

.HCl

2.5 g of 2 - ({2- (1,3-benzodioxol-5-yl) ethyl} dithio) ethyl nicotinate, which in Beispie! 3 was dissolved in 20 ml of ethyl acetate, followed by the addition of a solution of hydrochloric acid in ethyl acetate. The mixture was distilled to remove the solvent. The residue was dissolved in a methanol-ethanol mixture, followed by filtering. The fittrate was concentrated and recrystallized from ethanol-isopropyl ether-mixed to give 2.5 g of the title compound as colorless crystals.

Melting point: 113-122 ° C ¹ H-MKR (90MHz, DMSO-d ") δ; 2.66-3.00 (m, 4H), 3.11 (t, J = 7Hz, 2H), 4.53 (t, J = 7Hz, 2H), 5.90 (s, 2 H), 6.48 to 6.92 (m, 3 H), 7.62 to 7.91 (m, ¹ H), 8.36 to 8.60 (m, 1 H), 8,78- 9.02 (m, 1H), 9.02 to 9.24 (m, 1H); MS m / z; 363.149 Elemental analysis for C ₁₇ H ₁ CNS ₂ HCl

C H N Cl

Calculated (%) 51.06 4.54 3.50 8.87

Calculated (%) 51.05 4.51 3.59 8.84

Example 5 (Compound 5) 2 - [{3- (1,3-BenzodloKol-5-yl) propyl} dithio] et alienol

/ 0

8.4 g of the title compound were prepared from 27.8 g of 3- (1,3-benzodioxol-5-yl) propanethiol and 5.5 g of 2-mercaptoethanol by the same procedure as in Example 1 in the form of a colorless oil.

1.72-2.14 (m, 3H), 2.48-2.72 (m, 4H), 2.80 (t, J = 7Hz, 2H), 3.84 (q, J = 7Hz, 2H), 5.85 (s, 2H), 6.44-6.74 (m, 3H) MS m / z; 272 (M "), 135

Example 6 (Compound 6) 3- (1,3-Benzodloxol-5-yl) propylphenethyl disulfide

1.5 g of the title compound were prepared from 5 g of 3- (1,3-benzenodioxol-5-yl) propanethiol and 5 g of phenethylmercaptan after the same

Process as prepared in Example 1 in the form of a colorless oil.

¹ H-MKR (90MHz, CDCl ₃ ) δ; 1.70-2.20 (m, 2H), 2.50-2.80 (m, 4H), 2.92 (s, 4H), b, 85 (s, 2H), 6, 44-6.78 in, 3H), 7.00-7.52 (m, 5H) MS m / z; 332 (M ")

Bebplel? (Compound 7) 2 - [(3- (1,3-Benzodioxol-5-yl) propal) dithlo] hexyl nicotine

(CH ₂ ) 3 S-S (CH ₂ )

56.1 g of the title compound was prepared from 50 g of 2 - [{3- (1,3-benzodioxol-5-yl) propyl} dithio] ethanol and 50 g

Nicotinyl chloride hydrochloride was prepared by the same method as Example 3 in the form of a colorless oil.

'H-MKR (90MHz, CDCl ₃ ) δ; 1.72-2.12 fm, 2H), 2.65 (q, J = 7Hz, 4H), 3.00 (t, J = 7Hz, 2H), 5.85 (s, 2H) , 4.56 (t, J = 7Hz, 2H), 6.42 to 6.70 (m, 3H), 7.20 to 7.40 (m, 1H), 8.10 to 8.30 ( m, 1H), 8.58 to 8.78 (m, 1H), 9.06 to 9.22 (m, 1H) MS m / z; 377 (M ")

Example 8 (Compound 8) 2-t {3- (1,3-benzodioxol-5-yl) -propyl} -dlthlo] ethyl nicotinic hydrochloride

N.HCl

48.5 g of the title compound were prepared from 46.1 g of 2 - [{3- (1,3-benzodioxol-5-yl) -propyl} dithio] ethyl-1-n-cinate

Process as in Example 4 prepared in the form of colorless crystals. Melting point: 105-110 ° C

¹ H-MKR (90MHz, DMSO-d ₆ ) δ; 1.68-2.08 (m,:? H), 2.71 (q, J = 7Hz, 4H), 3.13 (t, J = 7Hz, 2H), 4.58 (t , J = 7Hz, 2H), 5.96 (s, 2H), 6.54-6.87 (m, 3H), 7.69-7.90 (m, 1H), 8, 44-8.64 (m, Ί H), 8.87-9.02 (m, 1H), 9.12-9.24 (m, 1H) MS m / z; 377

Elomentaranalyse for C ₁₈ H) ₉ O ₄ NS ₂ · HCl

C H H Cl

Calculated (%) 52.23 4.87 3.38 8.56

Find (%! 52.32 4.80 3.47 8.58

Example 9 (Compound 9) 3- (1,3-Benzodioxol-5-yl) propylnonyldilsulfide

6.2 g of the title compound was prepared from 10 g of 3- (1,3-benzodioxol-5-yl) propanethiol and 5 g of nonylmarkaptan after the same

Process as prepared in Example 1 in the form of a colorless oil.

'H-MKR (90MHz, CDCl ₃ ) δ; 0.74-1.02 (m 3H), 1.08-1.48 (bs, 14H), 1.80-2.12 (in, 2H), 2.50-2.76 (m 6H) , 5.83 (s, 2H), 6.46-6.75 (m, 3H) MS m / z; 354 (M ')

Example 10 (Compound 10) 2 - [{(1,3-Benzodioxol-5-yl) -methyl} -dlthlo] ethylnickel

0-

2.8 g of the title compound were prepared by the same method as in Example 3 from 2g 2 - [((1,3-benzodioxol-5-yl) -]

methyl} dithio] ethanol and 2.2g NiKotinylchloridhydrochlcrid prepared in the form of a colorless oil.

'H-MKR (90 MHz, CDCl ₃ ) δ; 2.76 (t, J = 7Hz, 2H), 3.82 (s, 2H), 4.45 (t, J = 7Hz, 2H), 5.89 (s, 2H), 6.52-6.91 (m, 3H), 7.12-7.42 (m, 1), 8.10-8.34 (m, 1H), 8.64-8.87 (m , 1H), 9.07 to 9.28 (m, 1H) MS m / z; 349 (M ")

Example 11 (Compound 11) Bis (2- (1,3-benzodioxol-5-yl) 1-methylethyl) disulfide

_CH ₉ CHSvSCHCH

² I ι CH-

3.5 g of the T'telverbindung were prepared by the same method as in Example 1 in the form of a colorless oil of 4g 2- (1,3-

Benzodioxol-5-yl) -1-methylethanethiol.

'H-MKR (90 MHz, CDCl ₁ ) δ; 1.24 (d, J = 7Hz, 6H), 2.32-2.71 (m, 2H), 2.72-3.16 (m, 4H), 5.91 (s, 4H ), 6.48-6.82 (m, 6H) MS m / z; 390 (M).

Example 12 (Compound 12) α-t ^ -IU-benzodioxole-B-y-O-i-methyl-butyl-thiolethanol

JCH ₂ CHS-S (CH ₂ ) ₂ OH

CH ₃

5.0 g of the title compound were prepared by the same method as in Example 1 in the form of a colorless oil of 8.4 g of 2- (1,3-benzodioxol-5-yl) -1-methylethane! Hiol and 2.24 g of 2- Merkaptoethanol produced.

¹ H-MK :. (90 MHz, CDCl ₃ ) δ;

1.27 (d, J = 7Hz, 3H), 1.80-2.20 (br, 1H), 2.40-2.80 (m, 1H), 2.68-3.25 (m, 4H), 3.60-4.10 (br, 2H), 5.90 (s, 2H), 6.50-6.88 (m, 3H) MS m / z; 272 (M ")

Compound Group (M) Prepar. 1 2- (1,3-benzodloxol-5-yl) -2-propanol

About 600 ml of a 1.5M solution of methyl lithium in ether was added to 500 ml of tetrahydrofuran to prepare a mixture. To the mixture was added a suspension of 93,45g 5-acetyl-1,3-benzodixol added in 900ml of tetrahydrofuran, and this case 'Ihlen by "at -2O ⁰ C held as mixture thus obtained was stirred as such one hour. The Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous common salt solution and dried over anhydrous magnesium sulfate, the resulting mixture was filtered, and the filtrate was concentrated to give 97 g of the titled compound in the form an oil

¹ H-MKROOMHz ₁ CDCl ₃ ) S; 1.54 (s, 6H), 1.72 (bs, 1H), 5.88 (s, 2H), 6.6-7.0 (m, 3H)

Preparation sheet 2 2- (1,3-benzodloxol-5yl) propene

? ^H 3

C = CHR

14.52 g of 2- (1,3-benzodioxol-5-yl) -2-propanol were dissolved in 20 mM benzene, after which a catalytic amount of p-toluenesulfonic acid monohydrate was added. The recovered mixture was refluxed in a short-necked Kieldahl flask equipped with a Dean-Stark reflux condenser for 2.5 hours. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated aqueous ordinary saline solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to give 14.33g of the title compound as an oil

'H-MKR (90MHz, CDCl ₃ ) δ; 2.08 (bs, 3H), 4.8-5.0 (m, 1H), 5.19 (bs, 1H), 5.89 (s, 2H), 6.5-7.0 ( m, 3H).

Preparation Example 3 1-l6-MethyM, 3-benzodioxol-5-yl) ethanol

5 ml of a 1.4M solution of methyl lithium in diethyl ether was dissolved in 50 ml of anhydrous tetrahydrofuran. The thus-obtained solution was cooled to -40 ° C in a nitrogen atmosphere, after which 5.0 g of a solid (6-methyl-1,3-l) enzodioxol-5-yl) carboxaldehyde was added. The mixture was heated to room temperature over a period of one hour, after which water was added. The mixture thus obtained was extracted with ether, and the recovered organic layer was washed with an aqueous solution of ordinary salt, dried over magnesium sulfate and distilled to remove the solvent. The white solid thus obtained was recrystallized from diisopropyl ether / n-hexane to give 2.8 g of the title compound as colorless crystals.

Melting point: 61-62 ° C

¹ H-MKROOMHz ₁ CDCl ₃ ) O;

1.39 (d, J = 7Hz, 3H), 1.72 (bs, 1H), 2.22 (s, 3H), 4.99 (m, 1H), 5.83 (s , 2H), 6.53 (s, 1H), 6.94 (s, 1H)

Production Example 4

1- (6-methyl-1,3-benzodioxol-5-yl) -1-propanol

H ₂ CH ₃ HOH

A solution of 2.0 g (6-methyl-1,3-benzodioxol-5-yl) carboxaldehyde in 15 ml of anhydrous tetrahydrofuran was added dropwise at room temperature to a Grignard reagent consisting of 0.32 g of magnesium, 20 ml of anhydrous tetrahydrofuran and 1, 4g bromoethane, then stirred for 2 hours. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, and the recovered mixture was distilled to remove the solvent. The residue was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 2: 8) to give 2.27 g of the title compound as a colorless crystal.

Schmelzpunktk: 71-72 ⁰ C.

¹ H-MKROOrVIHz ₁ CDCl ₃ ) O;

0.92 (t, J = 7Hz, 3H), 1.68-1.92 (m, 2H), 1.80 (bs, 1H), 2.20 (s, 3H), 4 , 72 (t, J = 7Hz, 1H), 5.82 (s, 2H), 6.52 (s, 1H), 6.88 (s, 1H)

Production Example 5 1- (6-Ethyl-1,3-benzodioxol-5-yl) -1-propanol

CH ₂ CH ₃

A solution of 3.2 g (6-ethyl-1,3-benzodioxol-5-yl) carboxaldehyde in 10 mL of anhydrous tetrahydrofuran was added dropwise at room temperature to a Grignard reagent consisting of 0.54 g of magnesium tape, 10 mL of anhydrous tetrahydrofuran and 2.4 g Bromoethane was prepared to carry out the reaction for 2 hours at this temperature. To the reaction mixture was added a saturated aqueous solution of ammonium chloride. The resulting mixture was distilled to remove the solvent and the residue was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give 3.9 g of a crude alcohol in the form of a yellow oil. This oil was used as such in the subsequent reactions. ¹ HMKR (90 MHz, CDCl ₃ );

0.96 (t, J = 7Hz, 3H), 1.18 (t, J = 7Hz, 3H), 1.72 (m, 3H), 2.32-2.80 (m, 2H), 4 , 76 (t, J = 7Hz, 1H), 5.84 (s, 2H), 6.58 (s, 1H), 6.88 (s, 1H)

Preparation 6 2- (1,3-benzodioxol-5-yl) -2-butanol

H ₂ CH ₃

15ml of tetrahydrofuran and a catalytic amount of iodine were added to 340mg of magnesium tape to make a mixture. To the mixture was gradually added 1.59 g of bromoethane in a nitrogen stream so that the reaction system had a weak reflux. The resulting mixture was heated at reflux for 30 minutes and then cooled, then a solution of 2 g of 5-acetylM, 3-benzodioxole in tetrahydrofuran was added. The mixture thus obtained was stirred at room temperature for 20 minutes, followed by addition of a saturated aqueous solution of ammonium chloride and water. The mixture thus obtained was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ordinary salt, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. This gave 2.27 g of the title compound as a crude oil.

Preparation Sheet 7 5-Chloromethyl-6-isopropyl-1,3-benzodioxole

A mixture consisting of 30 g of 37% formalin, 13 ml of concentrated hydrochloric acid and 100 ml of ethyl acetate was heated to 55 ° C with hydrochloric acid gas passed through the mixture. To the resulting mixture was added dropwise a solution of 7.5 g of 5-isopropyl-1,3-benzodioxole in 20 ml of ethyl acetate, and the mixture thus obtained was stirred and cooled as such for 2.5 hours, after which benzene was added. The resulting mixture was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to give 10.22 g of the title compound as a crude oil

¹ H-MKROOMHz ₁ CDCl ₃ ) O; 1.18 (d, J = 7.2Hz, 6H), 3.31 (sept.J = 7.2Hz, 1H), 5.88 (s, 2H), 6.70 (s, 1H), 6.91 (s, 1H).

Preparation 8 5-BK> mo-6-isopropyl-1,3-benzodioxole

2.94 g of '5-isopropyl, 1-1,3-benzodioxole was dissolved in 30 ml of carbon tetrachloride to give a solution. The solution was at a temperature of --5 ⁰ C to 5 ° C was added dropwise a solution of 3,15g of bromine in 5 ml of carbon tetrachloride. The resulting mixture was stirred at 10 ° C for 8.5 hours. Nitrogen gas was passed through the resultant mixture, followed by the addition of a saturated aqueous solution of sodium hydrogen carbonate and an aqueous solution of sodium thiosulfate. The mixture thus obtained was extracted with chloroform, and the organic layer was washed with a saturated aqueous ordinary saline solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give 4.38 g of the title compound as a crude oil. ¹ H-MKROOMHz ₁ CDCl ₃ ) O; 1.18 (d, J = 7.2Hz, 6H), 3.31 (sept, J = 7.2Hz 1H), 5.38 (s, 2H), 6.70 (s, 1 H), 6.91 (s, 1H).

Preparation Sheet 9 5- (6-Isopropyl-1,3-benzodioxole) carboxaldehyde

CHO

7.8 ml of a 1.6M solution of n-dutyllithium in hexane was added to a solution of 2.34 g of 5-bromo-6-isopropyl-1,3-benzodioxole (crude oil) in 50 ml of anhydrous ether at -40 ° C. The mixture thus obtained was heated to -10 ° C and cooled again to -5O ⁰ C, then 4.48 ml of Ν, Ν-dimethylformamide were added. The resulting mixture was heated with stirring to raise the temperature slowly to ⁰ ° C. Then, the resulting mixture was acidified with 1N hydrochloric acid, stirred for 30 minutes and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous common salt solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by silica gel column chromatography (hexane) to give 1.40 g of the title compound as a colorless oil. ¹ H-MKROOMHz ₁ CDCIj) O; 1.28 (d, J = 6.5Hz, 6H), 3.84 (sept, J = 6.5Hz, 1H), 5.96 (s, 2H), 6.81 (s, 1H), 7.23 {s, 1 H).

Prepared 10a- (6-isopropyl-1,3-benzodloxol-5-yl) benzyl alcohol

8.1 ml of a 2.0M solution of phenyl lithium in cyclohexane / diethyl ether (7: 3) was added to a solution of 2.08 g of 5- (6-isopropyl-1,3-benzodioxol-5-yl) carboxaldehyde in anhydrous form. - Added ether at -6O ⁰ C. The resulting mixture was stirred overnight so that the temperature slowly rose to room temperature. Ice / water was added to the resulting mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ordinary salt, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 2:98) to give 2.49 g of the title compound as a colorless prismatic crystal. ¹ H-MKROOMHz ₁ CDCIj) O;

1.03 (d, J 6.8Hz, 3H), 1.18 (d, J = 6.8Hz, 3H), 2.03 (d, J = 1.8Hz, 1H), 3.18 ( m, 1H), 5.86 (s, 2H), 6.05 (d, J = 1.8Hz, 1H), 6.72 (s, 1H), 6.84 (s, 1H) , 7.05-7.4 (m, 5H)

-86- 267 038

Herstellungsbelsple! 11 5-cyanomethyl-6-isopropyl-1,3-benzodloxol

CH ₂ CN

6.9 g of 5-chloromethyl-6-fsopropyl-1,3-benzodioxole were dissolved in 10 mM of dimethylsulfoxide, followed by 3.12 g

Added sodium cyanide. The resulting mixture was stirred at room temperature for 3 hours and distilled to give

to remove the solvent. Ethyl acetate was added to the residue and the resulting mixture was washed with

Water and then washed with a saturated aqueous solution of ordinary salt, over anhydrous Dried magnesium sulfate and filtered, the filtrate was concentrated to give 6.26g of the title compound as a

Crude oil.

'H-MKROOMHz ₁ CDCI]) S;

1.21 (d, J = 7.2Hz, 6H), 2.96 (sept, J = 7.2Hz, 1H), 3.60 (s, 2H), 5.88 (s, 2H), 6.73 (bs, 2H).

Treatment bulst 12 (6-isopropyl-1,3-benzodloxol-5-yl) acetate

6.22 g of 5-cyanomethyl-6-isopropyl-1,3-benzodioxole (crude oil) were dissolved in 120 ml of ethanol, then 40 ml of water and 12.24 g of sodium hydroxide were added. The mixture thus obtained was stirred for 20 hours, whereby the temperature of an oil bath was kept at 100 ⁰ C. The reaction mixture was concentrated, then water was added. The resulting mixture was washed with ethyl acetate. The aqueous layer was made acidic with concentrated hydrochloric acid and extracted with chloroform. The organic layer was washed with a saturated aqueous solution of ordinary salt, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to give 6.31 g of the title compound as a crude crystal

¹ H-MKR (90MHz, CDCl ₃ ) δ; 1.17 (d, J = 6.5Hz, 6H), 2.99 (sept, J = 6.5Hz, 1H), 3.58 (s, 2H), 5.85 (s, 2H), 6 , 60 (s, 1H), 6.72 (s, 1H)

Preparation Bolene 13 2- (6-Isopropyl-1,3-benzodloxol-5-yl) ethanol

CH ₂ CH ₂ OH

A solution of 6.25 g (6-isopropyl-1,3-benzod) oxol-5-yl) acetic acid (crude crystal) in 30 ml of tetrahydrofuran was added dropwise to a suspension of 1.6 g of lithium aluminum hydride in 40 ml of tetrahydrofuran while cooling with ice. The resulting mixture was stirred overnight. The resulting mixture was added successively, while cooling with ice, to 1.6 ml of water, 1.6 ml of a 15% aqueous solution of sodium hydroxide and 4.8 ml of water. The resulting mixture was filtered and the filtrate was concentrated. The residue was goronated by silica gel column chromatography to give 4.51 g of the title compound as a colorless oil

'H-MKROOMHz ₁ CDCI ₃ ) O;

1.19 (d, J = 6.8Hz, 6H), 1.3-1.6 (br, 1H), 2.82 (t, J = 6.8Hz, 2H), 3.10 (sept, J = 6.8Hz, iH), 3.5-3.9 (br, 2H), 5.84 (s, 2H), 6.59 (s, 1H), 6.72 (s, 1H)

Preparatory Bule 14 (6-Benzyl-1,3-benzodloxol-5-yl) -salicylate

6.0 g of 5-benzyl-1,3-benzodioxole were dissolved in 100 ml of ethyl acetate and a solution prepared. This solution was added dropwise at 55'C to a mixture consisting of 10 ml of concentrated hydrochloric acid, 20 ml of ethyl acetate and 22 g of 37% formalin and into which hydrogen chloride was blown. The reaction was carried out at this temperature for 1.5 hours. The reaction mixture was washed four times with water, dried over εε-magnesium sulfate and concentrated in vacuo to give 10.6 g of a chloroarohyde derivative as a pale yellow oil.

7.1 g of the chlorooroh derivative (unpurified) was dissolved in 50 ml of dimethylsulfoxide, followed by the addition of 2.0 g of well-milled sodium cyanide. The reaction was carried out for 2 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed twice with water, dried over magnesium sulfate and concentrated in vacuo to give 4.4 g of a cyanohir derivative as a yellow oil. This cyanogen derivative and 7 g of sodium hydroxide were dissolved in a mixture consisting of 20 ml of ethanol and 20 ml of water. The recovered solution was heated under reflux for 20 hours. After the completion of the reaction, the reaction mixture was distilled in vacuo to remove the ethanol, followed by the addition of 200 .mu.l of water. The resulting mixture was washed with ether. The aqueous layer was acidified with 6N hydrochloric acid and extracted with chloroform. The organic layer was washed with a saturated aqueous common salt solution, dried over magnesium sulfate and concentrated in vacuo to give a brown solid. This solid was recrystallized from ethyl acetate to give 1.83 g of the title compound as pale yellow needles. Melting point: 116-117 ⁰ C. ¹ H-MKR (90MHz, CDCI ₃₎ δ; 3.48 (s, 2H), 3.88 (s, 2H), 5.86 (s, 2H), 6.56 (s, 1H), 6.64 (s, 1H), 6.80 -7.40 (m, 5H), 8.40-10.0 (bs, 1H)

Preparatory Specification 15 2- (6-Benzyl-1,3-benzodloxol-5-yl) ethanol

CH ₂ CH ₂ OH

A solution of 1.82 g of (6-benzyl-1,3-benzodioxol-5-yl) acetic acid in 22 ml of anhydrous tetrahydrofuran was added dropwise at ⁰ ° C. to a suspension of 0.38 g of lithium aluminum hydride in anhydrous tetrahydrofuran. The thus-obtained mixture was warmed to room temperature to conduct the reaction for 4 hours, followed by the addition of water. The mixture was filtered to remove the precipitate. The filtrate was concentrated in vacuo to give a yellow residue of oil. This residue was purified by silica gel column chromatography (ethyl acetate / hexane = 2: 8) to give 1.42 g of the title compound as colorless crystals. Melting point: 64-65 ° C ¹ H-MKR (90MHz, CDCl ₃ ) δ; 2.76 (t, J = 7Hz, 2H), 3.64 (m, 2H), 3.90 (s, 2H), 5.86 (s, 2H), 6.56 (s, 1 H), 6.66 (s, 1H), 6.80-7.34 (m, 5H)

Example 1 [{1- (1,3-Benzodioxol-5-yl) -butyl} thio] -sulfure

CH ₀ CH ₀ CH

 223

CHSCH ₀ CO ₀ H

The mixture consisting of 103 g of 1- (1,3-benzodioxol-5-yl) 1-butanol, 73.3 g of mercaptoacetic acid, 0.1 g of D-10 camphorsulfonic acid and 500 ml of benzene was refluxed for 2 hours heated, then 2000 ml of ether were added. The resulting mixture was washed with water and extracted with 750 ml and then with 100 ml of 1N sodium hydroxide. The extracts were combined, washed sequentially with ether and chloroform, acidified with concentrated hydrochloric acid and extracted with ethyl acetate (800 ml and 400 ml). The extracts were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo to give 132 g of a crude product. This crude product was purified by silica gel chromatography (ethyl acetate / hexane / formic acid = 100: 900: 1) to give 127 g of a colorless oil. This oil was recrystallized from η-hexane to give the title compound as a white, crystalline powder.

Melting point: 59-61 ° C 'H-MKR (90MHz, CDCl ₃ ) δ;

0.88 (m, 3H), 1.12-1.52 (m, 2H), 1.78-1.94 (m, 2H), 2.92 and 3.03 (ABq, J = 15Hz, 2H), 3.92 (t, J = 7H '1H), 5.92 (s, 2H), 6.68-6.80 (m, 3H).

Example 2 [{1- (1,3-Benzodloxot-5-yl) -1-methylethyl) thio] acetic acid

600ml of benzene, 59.5g of mercaptoacetic acid and a catalytic amount of D-10 camphorsulfonic acid were added to 97g of 2- (1,3-benzodioxol-5-yl) -2-propanol. The mixture thus obtained was refluxed for 4 hours and distilled to remove the solvent. The pH of the residue was adjusted to 10 with 1 N aqueous solution of sodium hydroxide. The resulting mixture was washed with ethyl acetate. To the mixture was added 4N hydrochloric acid

while cooling with ice to acidify the aqueous layer. The resulting mixture was chloroform

extrahisrt. The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered.

The filtrate was concentrated and a crude crystal was obtained. This crude crystal was recrystallized from diisopropyl ether and

gave 62.70 g of the title compound as colorless Ki.

The procedure described above was repeated, but using 38.72 g of 2- (1,3-benzodioxol-5-yl) propene in place of the

corresponding propanol were used to give 37.32g of the title compound.

Melting point: 78.5 to 80 ⁰ C.

¹ H-MKROOMHz ₁ CDCI]) O;

1.68 (s, 6H), 2.99 (s, 2H), 5.88 (s, 2H), 6.64 (d, J = 8.3Hz, 1H), 6.86 (dd, J = 8.3 Hz, 2.5 Hz, 1 H), 6.99 (d, J = 2.5 Hz, 1 H), 8.0-9.0 (br,

Example 3 [{i-ie-Methyl-i ^ -benzodloxol-S-yl-ethyll-3-yl-acid

- CH ₂ OH ₂ CO ₂ H \ JL IL-CH.

3.7 g of mercaptoacetic acid and a catalytic amount of D-10 camphorsulfonic acid were added to 3.2 g of 1- (6-methyl-1,3-benzodioxol-5-yl) ethanol, then 100 ml of benzene was added. The resulting mixture was heated at reflux for one hour, washed with water and extracted with a 1 N aqueous solution of sodium hydroxide. The aqueous layer was washed with ethyl acetate, acidified with 1 N hydrochloric acid and extracted with chloroform. The organic layer was dried over magnesium sulfate and distilled to remove the solvent. The crystalline residue thus obtained was recrystallized from diisopropyl ether to give 4.2 g of the title compound as colorless crystals

Melting point: 93.5-94.5 ⁰ C ¹

1.51 (d, J = 7Hz, 3H), 2.26 (s, 3H), 2.92 and 3.12 (ABq, J = 16Hz, 2H), 4.39 (q, J = 7Hz, 1H), 5.85 (s, 2H), 6.54 (s, 1H), 6.94 (s, 1H), 10.12 (m, 1H)

Example 4 [(V (6-Methyl-1,3-benzodloxol-5-yl) propyl} thiol] acetic acid

OH ₂ CH ₃

CHSCH ₂ CO ₂ H

2.27 g of 1- (6-methyl-1,3-benzodioxol-5-yl) -1-propanol, 0.1 g of p-toluenesulfonic acid and 1.52 g of mercaptoacetic acid were dissolved in 80 ml of benzene to give a solution. This solution was heated at reflux for 12 hours with the generated water removed. The reaction mixture was poured into water. The aqueous layer was basified and washed with ether. The aqueous layer was acidified and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate and concentrated in vacuo to give a pale yellow solid

 This solid was purified by silica gel column chromatography (ethyl acetate / hexane 2: 8) to give 2.83 g of the title compound as white crystals

Melting point: 98-99 ⁰ C

0.88 (t, J = 7Hz, 3H), 1.60-2.12 (m, 2H), 2.24 (s, 3H), 2.96 and 3.08 (ABq, J = 14Hz, 2H), 4.26 (dd, J = 9Hz, 7Hz, 1H), 5.92 (s, 2H), 6.62 (s, 1H), 6.98 ( s, 1H)

Example 5 [{1- (8-Ethyl-1,3-bonzodioxol-5-yl) -propyl} thio] esstgsa'ure

OH ₂ CH ₃

.CH ₂ CO ₂ HH ₂ CH ₃

4.0 g of ethyl | {1- (e-ethyl-1,3-benzodioxol-5-yl) propyl} thiol acetate and 2.6 g of sodium hydroxide were dissolved in a mixture consisting of 20 ml of water and 20 ml of ethanol. The resulting solution was heated under reflux for 2 hours and distilled to remove the ethanol. The residue was washed with ether. The aqueous layer was acidified and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 2: 8) to give 2.8 g of the title compound as colorless crystals.

Melting point: 88-89T

¹ H-MKR (90MHz, CDCl ₃ ) δ;

0.92 (t, J = 7Hz, 3H), 1.16 (t, J = 7Hz, 3H), 1.56-2.12 (m, 2H), 2.24-2.76 (m, 2H ), 2.95 and 3.08 (ABq.J = 16Hz, 2H), 4.20 (t,

J = 7Hz, 1H), 5.88 (s, 2H), 6.58 (s, 1H), 6.90 (s, 1H), 9.72 (bs, 1H)

Example β [{(6-methyl, 3-benzodioxol-G-yl) methyl} thio] acetic acid

.CH ₂ SCH ₂ OO ₂ H

A suspension of 6.0 g of S-chloromethyl-e-methyl-i ^ -benzodioxole, 6.0 g of mercaptoacetic acid and 6.5 g of sodium hydroxide in

130 ml of aqueous 50% ethanol was heated at reflux for one hour and concentrated, then water was added. The mixture was washed with ethyl acetate. The aqueous layer was acidified with 1 N hydrochloric acid and extracted with chloroform. The organic layer was dried over magnesium sulfate and distilled to give the

Remove solvent. The residue was chromatographed on silica gel column and with chloroform

eluted to give a crude crystal. This crude crystal mass was recrystallized from diisopropyl ether to give 1.6 g of the

Title compound in the form of colorless crystals. Melting point: 90-92 ° C

¹ H-MKROOMHz ₁ CDCIj) S;

2.30 (s, 3H), 3.14 (s, 2H), 3.76 (s, 2H), 5.86 (s, 2H), 6.60 (s, 1H), 6.70 (s, 1H).

Example 7 [{1- (1,3-Benzodioxol-5-yl) -2-methylpropyl} thio] acetic acid

A mixture consisting of 2 g of 1- (1,3-benzodioxol-5-yl) -2-methyl-1-propanol, 1.3 g of mercaptoacetic acid, a catalytic amount of p-toluenesulfonic acid and 50 ml of benzene was refluxed 5.5 Heated for hours, then ethyl acetate was added. The mixture was washed with water and extracted with a 2N aqueous solution of sodium hydroxide. The aqueous layer was washed with chloroform, made acidic with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. This residue was purified by silica gel column chromatography (chloroform / methanol = 20: 1) to give 2.14 g of the title compound as a colorless oil. ¹ H-MKROOMHz ₁ CDCl ₃ ) O;

0.81 (d, J = 7.0Hz, 3H), 1.09 (d, J = 7.0Hz, 3H), 1.80 to 2.23 (m, 1H), 2.88 and 3.01 (ABq, J = 15.1Hz, 2H), 3.73 (d, J 5.89 (s, 2H), 6.61-6.89 (m, 3H), 8.18-8.69 (bs, 1H) )

Example 8 Natrium - [{1- (1,3-benzodloxol-5-yl) -2-methylpropyl} thiol] acetate

CH,

CHSCH ₂ CO ₂ Na

3.99 ml of a 2 N aqueous solution of sodium hydroxide was added to 2.14 g of {1- (1,3-benzoxodol-5-yl) -2-methyl-1-propyl} thio) acetic acid to prepare a solution which was added to ethanol. The mixture was distilled to remove the solvent. Ether was added to the residue so as to produce a precipitate. This precipitate was separated by filtration and dried to give 2.2 g of the title compound as a white powder. Melting point: 243 ° C-250 ° C (decomposition) ¹ H-MKR (90MHz, DMSO-d,) 6;

0.75 (d, J = 7.0 Hz, 3 H), 1.01 (d, J = 7.0 Hz, 3 H), 1.61 to 2.22 (m, 1 H), 2, 62 and 2.70 (ABq, J = 13.5Hz, 2H), 3.63 (d, J = 8.3Hz, 1H), 5.97 (s, 2H), 6.50-7 , 02 (m, 3H) MS (FAB) m / z; 313 (MNa ")

Examples [{1- (1,3-benzodloxol-5-yl) pentyl} thio] acetic acid

CH ₂ CH ₂ CH ₂ CH ₃ y O ^ yC

2.0 g of the title compound were obtained in the form of a colorless oil according to the same procedure as in Example 7 from 2 g of 1- (1.3-

Benzodioxol-5-yl) -1-pentanol.

¹ H-MKR (90MHz, CDCl ₃ ) O;

0.70-0.98 (m, 3H), 1.04-1.54 (m, 4H), 1.60-2.02 (m, 2H), 2.90 and 3.02 (ABv ;, J = 14.4Hz, 2H), 3.88 (t, J = 7Hz, 1H), 5.90 (s, 2H), 6.62-6.90 (m, 3H), 6.62-7 , 34 (bs, 1H)

Example 10 Sodium·! (1 - (1,3-benzodioxol-5-yl) pentyl) thiol] acetate

CH ₂ CH ₂ CH ₂ CH ₃

θ ^ v> ^ CHSCH ₂ CO ₂ Ne

X) -

1.9 g of the title compound in the form of a white powder was prepared by the same method as in Example 8 from 2.0 g l {1- (1,3-)

Benzodioxol-5-yl) pentyl} thiolacetic acid. Melting point: 232 ° C-242 ° C (decomposition)

¹ H-MKR (90MHz, DMSOd ₈ ) ö;

0.62-0.80 (m, 3H), 0.94-1.38 (m, 4H), 1.54-1.88 (m, 2H), 2.67 and 2.75 ( ABq, J = 13.3Hz, 2H), 3.83 (t, J = 7.0Hz, 1H), 5.97 (s, 2H), 6.60-6.90 (m, 3H) MS (FAB) m / z, 327 (MNa ")

Example 11 [{1- (1,3-Benzodloxol-5-yl) -1-methylpropyl} thio] acylgure

CH, CH ₉ CH, .C-SOH ₂ CO ₂ H

50 ml of benzene, 1.29 g of mercaptoacetic acid and a catalytic amount of p-toluenesulfonic acid monohydrate were added to 2.27 g of 2- (1,3-benzodioxol-5-yl) -2-butanol (crude oil). The resulting mixture was heated at reflux for 11 hours and cooled, then benzene was added. The resulting mixture was washed with water, then an aqueous 1N solution of sodium hydroxide was added. The alkaline layer was separated, washed with ethyl acetate, acidified with concentrated hydrochloric acid and extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by silica gel chromatography (chloroform) to give 1.11 g of the title compound as a colorless oil

¹ H-MKR (90MHz, CDCl ₃ ) O;

0.82 (d, J = 7.2Hz, 3H), 1.66 (s, 3H), 1.7-2.1 (m, 2H), 5.90 (s, 2H), 6.65 ( d, J = 7.9Hz, 1H), 6.82 (dd, J = 7.9Hz and 1.8Hz, 1H), 6.96 (d, J = 1.8Hz, 1H), 7 , 4-6,8 (br, 1H)

Example 12 Natrum - ((1- (1,3-benzodloxol-5-yl) -1-methylpropyl) thiol] acetate

CH, CH ₀ CH, S ^{3/2 3}

Ογχ ^ C-SCH ₂ CO ₂ Na

1.0Og of the title compound in the form of a white powder was prepared by the same method as in Example 8 from 1.04 g of [{1- (1,3-benzodioxol-5-yl) -1-methylpropyl} thio] acetic acid.

Melting point:> 280 ^cC

¹ H-MKR (90MHz, DMSOd,) 6;

0.72 (bt, J «7.2Hz, 3H), 1.52 (s, 3H), 1.6-2.1 (m, 2H), 2.70 (ABq, J = 13 , 3 Hz, Av - 20.5), 5.97 (s, 2 H), 6.5 to 7.1 (m, 3 H)

MS (FAB) m / z; 313 (MNa "), 291 (MH ')

Example 13 [[1- [1- (1,3-Benzodioxol-5-yl) -2-phenyl} ethyl] thio] essential acid

5.5 g * of the title compound in the form of colorless needles were η: h from the same procedure as in Example 7 from 5.0 g of {1- (1,3-)

Benzo-.xol-5-yl) -2-phenyl} ethan-1-ol. Melting point: 99 "C-IOO ⁰ C

¹ H-MKR (90MHz, CDCl ₃ ) δ;

2.92 and 3.04 (ABq, J = 14.4Hz, 2H), 2.88-3.36 (m, 2H), 4.20 (t, J = 7.2Hz, 1H), B, 90 (s, 2H), 6.48-6.70 (m, 2H), 6.43 (s, 1H), 6.88-7.36 (m, 5H), 9.50-10.00 (br, 1H)

Example 14 Natrlum - [[1- {1- (1,3-benzodloxol-5-yl) -2-phenyl} ethyl] thiol] acetate

OHSCH ₂ CO ₂ Na

1.7 g of the title compound in the form of a white powder were prepared by the same method as in Example 8 from 2.0 g of [1- {1- (1,3-benzodioxol-5-yl) -2-phenyl} ethyl] thio]. produced acetic acid.

Melting point: 20rC-215 ⁰ C (decomposition)

¹ H-MKR (400MHz, DMSO-d ») δ;

2.71 and 2.79 (ABq, J = 13.9 Hz, 2 H), 3.00 (dd, J = 9.2 Hz and 13.7 Hz, 1H), 3.12 (dd, J = 6.2Hz and 13.9Hz, 1H), 4.19 (dd, J = 6.2Hz and 9.5Hz, 1H), 5.95 (m, 2H), 6.64 (dd, J = 1.5Hz and 8.1 Hz, 1H), 6.72 (d, J = 7.7Hz, 1H), 6.865 (d, J = 1.8Hz, 1H), 7.08-7.19 (m,

MS (FAB) m / z; 339 (MH ")

Example 15 [{1- (6-Methyl-1,3-benzodioxol-5-yl) -butyl} thio] -sulic acid

A solution of 5.0 g (6-methyl-1,3-benzodioxol-5-yl) -carboxaldehyde in 20 ml of tetrahydrofuran was added at room temperature

A Grignard reagent is added tropically, which consists of 0.86 g of magnesium tape, 10 ml of tetrahydrofuran and 4.4 g 1-

Bromopropane had been prepared. The resulting mixture was stirred at room temperature for one hour,

Subsequently, a saturated aqueous ammonium chloride solution was added. The mixture thus obtained was extracted with ether. The organic layer was washed with an aqueous solution of ordinary salt, dried over magnesium sulfate and distilled to remove the solvent. This gave 5.6 g (6-methyl-1,3-benzodioxol-5-yl) -butan-1-ol.

Melting point: 65.5 ° C-66.5 ° C (isopropyl ether / petroleum ether)

¹ H-MKROOMHz ₁ CDCl ₃ ) O;

0.92 (m, 3H), 1.16-1.80 (m, 5H), 2.21 (s, 3H), 4.83 (m, 1H), 5.85 (s, 2H), 6.55 (s, 1H), 6.92 (s, 1H).

This product was used without purification in the following reaction. A solution of 5.6 g of (6-methyl-1,3-benzodioxol-5-yl) butan-1-ol, 4.8 g of mercaptoacetic acid and a catalytic amount of D-10-camphorsulfonic acid in 60ml benzene was heated at reflux for 3 hours, then ethyl acetate

added. The mixture thus obtained was washed with water and extracted with an aqueous 1N solution of sodium hydroxide. The aqueous layer was washed with ethyl acetate, adjusted with 1 N hydrochloric acid and washed with

Extracted chloroform. The organic layer was dried over magnesium sulfate and distilled to the solvent

remove. The residue thus obtained was chromatographed over a silica gel column and eluted with chloroform to give colorless crystals. These crystals were recrystallized from isopropyl ether / hexane to give 4.1 g of the

Title compound in the form of colorless, prismatic crystals. Melting point: 77.5 * C-78'C

¹ H-MKR (90MHz, CDClI) δ;

0.88 (m, 3H), 1.10-1.50 (m, 2H), 1.60-1.90 (m, 2H), 2.22 (s, 3H), 2.89 and 3.05 (ABq, J = 16Hz, 2H), 4.26 (t, J = 7Hz, 1H), 5.86 (s, 2H), 6.52 (s, 1H), 6.89 (s, 1H )

Example 16 Sodium - [{1- (6-methyl-1,3-benzodloxol-5-yl) butyl} thiol] acetate

CHnCHnCHn

223

3.2 g of the title compound in the form of a dried powder were prepared from 3.0 g [((1 (6) by the same method as in Example 8].

Methyl, 3-benzodioxol-5-yl) butyl} thiolacetic acid. Melting point: 233 ° C-236 ° C (decomposition).

¹ H-MKR (400MHz, DMSO-d,) δ;

0.82 (t, J = 7.3Hz, 3H), 1.12-1.27 (m, 2H), 1.58-1.68 (m, 1H), 1.70-1.79 ( m, 1 H), 2.21 (s, 3H), 2.67 and 2.71 (ABq, J = 13.9Hz, 2H), 4.15 (dd, J = 6.2Hz and 8.8Hz, 1H), 5.93 (m, 2H), 6.67 (s, 1H), 6.87 's, 1H).

MS (FAB) m / z; (MNa "), 305 (MH").

Example 17 [{(6-isopropyl-1,3-benzodioxol-5-yl) methyl} thiol] oleic acid

CH ₂ SCH ₂ CO ₂ H

A suspension of 3.3 g of 5-chloromethyl-6-isopropyl-1,3-benzodioxole (crude oil) in 10 ml of ethanol became a liquid mixture

which consisted of 2, i1 g of mercaptoacetic acid, 3 g of sodium hydroxide, 25 ml of ethanol and 25rr, ^{1 of} water, and the reaction was carried out at 80 ° C for 40 minutes. The reaction mixture was concentrated, then water was added.

The resulting mixture was washed with ethyl acetate.). The mixture was concentrated hydrochloric acid

was added to acidify the v / sweet layer followed by extraction with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by column chromatography to give 2.45 g of the title compound as colorless prismatic crystals.

Melting point: 83 ° C-84 ° C

¹ H-MKROOMHz ₁ CDCl ₃ ) O;

1.21 (d, J = 7.2Hz, 6H), 3.16 (s, 2H), 3.18 (sept, J = 7.2Hz, 1H), 3.82 (s, 2H), 5.90 (s, 2H), 6.68 (s, 1H), 6.72 (s, 1H), 6.6-8.0 (br, 1H).

Example 18 Natrium - [{(6-propyl-1,3-benzodioxol-5-yl) methyl} thiol] acetate

CH ₃ CH ₃

H ₂ SCH ₂ CO ₂ I Yes

2.01 g of the title compound in the form of a white powder were prepared by the same method as in Example 8 from 2.03 g of [{(6-isopropyl-1,3-benzodioxol-5-yl) methyl} thio] acetic acid.

Melting point: 213 ° C-215 ⁰ C (decomposition)

¹ H-MKR (90MHz, DMSO-d ,,) δ;

1.13 (d, J = 6.8Hz, βH), 2.87 (s, 2H), 3.20 (sept, J = 6.8Hz, 1H), 3.66U '2 H), 5.87 (s, 2H), 6.74 (s, 1H), 6.76 (s, 1H)

MS (FAB) m / z; 313 (MNa "), 291 (MH").

Example 19 [{α- (6-Liopropyl-1,3-berodloxol-5-yl) benzyl} thiol] essential acid

HSCH ₂ CO ₂ H

1.2 g of α- (e-isopropyl, 3-benzodioxol-5-yl) benzyl alcohol were dissolved in 10 ml of benzene followed by the addition of 490 mg of mercaptoacetic acid and a catalytic amount of p-toluenesulfonic acid monohydrate. The mixture thus obtained

was heated under reflux for one hour and cooled, then benzene was added. The mixture was washed with water, then an aqueous 1N sodium hydroxide solution was added. The alkaline layer was separated, acidified with concentrated hydrochloric acid and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by silica gel column chromatography (hexane / chloroform - 3: 7) to give 1.42 g of the title compound as colorless prismatic crystals. Melting point: 113.5 ⁰ C 114.5 ⁰ C 'H-MKR (90MHz, CDCI ₃₎ δ; 1.05 (d, J = 6.8Hz, 3H), 1.22 (d, J = 7.2Hz, 3H), 3.10 (s, 2H), 3.28 (m, 1H), 5.73 (s, 1H), 5.7-6.0 (m, 2H), 6.68 (s, 1H), 6.98 (s, IH), 7.05 -7.60 (m, 5H).

Example 20 Natrium - [{a- (6-isopropyl-1,3-benzodloxol-5-yl) -bonzyl} thioacetate

^CH ₂ OHOHSOH ₂ OQ ₂ Na

1.21 g of the title compound In the form of a white powder were prepared by the same method as in Example 8 from 1.28 g of {a- (e-isopropyl-1,3-benzodioxol-5-yl) benzyl} thio] acetic acid manufactured.

Melting point: 199-203 ⁰ C (decomposition)

¹ H-MKR (90MHz, DMSO-d.) Δ; 0.93 (d, J = 6.8Hz, 3H), 1.14 (d, J = 6.8Hz, 3H), 2.78 (s, 2H), 3.0-3, 7 (m 1 H), 5.68 (s, 2H), 5.8-6.05 (m, 2H), 6.76 (s, 1H), 6.94 (s, 1H) , 7.05-7.45 (m 5H). MS (FAB) m / z; 389 (MNa ").

Example 21 [{(6-Benzyl-1,3-benzodloxol-5-yl) -methyl} -thiol] -acetic acid

OH ₂ SCH ₂ CO ₂ H

0.93 g of the title compound was prepared from 3.5 g of 6-benzyl-5-chloromethyl-1,3-benzodioxole in the form of colorless crystals> by the same method as in Example 17.

Melting point: 99.5-100.5 ° C

'H-MKR (90MHz, CDCl ₃ ) δ; 3.10 (s, 2H), 3.72 (s, 2H), 3.98 (s, 2H), 5.86 (s, 2H), 6.54 (s, 1H), 6.76 ( s, 1H), 6.92-7.35 (m, 5H), 8.0 " ¹ Js 8.80 (br, IH).

Example 22

.0H ₂ SOH ₂ OO ₂ Na

0.95 g of the titre compound in the form of a white powder was prepared by the same method as in Example 8 from 0.93 g of [{(6-benzyl-1,3-benzodioxol-5-yl) methyl) thio] acetic acid.

Melting point: 195-205 ⁰ C (decomposition)

¹ H-MKR (4COMHz, DMSO-d,) 6; 2.86 (s, 2H), 3.65 is, 2H), 4.00 (s, 2H), 5.94 (s, 2H), 6.64 (s: 1H), 6.87 (s , 1H), 7.16-7.18 (m, 3H), 7.25 to 7.29 (m, 2H).

Example 23 [{2- (6-Isopropyl-1,3-benzodloxol-5-yl) ethyl} thiol] oleic acid

2.41 g of 2- (6-isopropyl-1,3-benzodioxol-5-yl) ethanol were dissolved in 50 ml of methylene chloride, then 3.51 g of triethylamine were added. The mixture thus obtained were added dropwise 3.31 g of C methanesulfonyl chloride at -1O ^0th The mixture thus obtained was for 40 minutes at - 1O ⁰ C stirred, then ice was / water was added. The resulting mixture was acidified with 1N hydrochloric acid and extracted with methylene chloride. The extract was washed successively with water and a saturated aqueous common salt solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to give a methanesulfonate derivative as a crude oil. A solution of this derivative in 15 ml of ethanol was added dropwise to a mixture consisting of 1.60 g of mercaptoacetic acid, 2.3 g of sodium hydroxide, 15 ml of ethanol and 15 ml of water. The mixture thus obtained was stirred at ⁰ C for 2 hours at 8O ⁰ C to 9O and concentrated, then water was added. The mixture was washed with ethyl acetate, acidified with concentrated hydrochloric acid and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by silica gel column chromatography (chloroform) to give 2.72 g of the title compound as colorless prismatic crystals

Melting point: 75.5 to 76 ⁰ C 'H-MKR (SOMHz, CDCI ₃₎ δ;' 1.18 (d _/ J = 7.2Hz, 6H), 2.81 (bs, 4H), 3.04 (sept, J = 7.2Hz, 1H), 3.24 (s, 2H), 5, 83 (s, 2H), 6.56 (s, 1H), 6.69 (s, 1H), 8.1 to 9.0 (br, 1H).

Example 24 Natrium - [{2- (6-isopropyl-1,3-benzodioxol-5-yl) ethyl} thio] acetate

2.45 g of the title compound in the form of a white powder were prepared by the same method as in Example 8 from 2.36 g

I {2- (6-Isopropyl-1,3-benzodioxol-5-yl) ethyl} thio) acetic acid. Melting point: 213-21S ⁰ C (decomposition)

'H-MKR (90MHz, DMSO-d,) δ;

1.12 (d, J = 6.8Hz ₁ 6H), 2.45-2.85 (m, 4H), 2.96 (s, 2H), 3.04 (sept, J = 6.8Hz, 1 H), 5.86 (s, 2H), 6.66 (s, 1H), 6.74 (s, 1H).

MS (FAB) m / z; 327 (MNa ", 305 (MH").

Example 25 [^ • (B-benzyl-LS-benzodloxolinyl-y-ethyl-thio-silicic acid

COC

.0H ₂ CB ₂ SCH ₂ CO ₂ H

CH ₂ -

0.93 g of the title compound in the form of a colorless, transparent oil were prepared by the same method as in Example 23 from 1.4 g of 2- (6-benzyl-1,3-benzodioxol-5-yl) ethanol.

¹ H-MKR (90MHz, CDCI ₃ ) 5;

2.44-2.96 (m, 4H), 3.14 (s, 2H), 3.90 (s, 2H), 5.88 (s, 2H), 6.56 (s, 1H), 6.64 (s, 1H), 6.76-7.36 (m, 5H).

Example 26 Natrium - [{2- (6-benzyl, 3-benzenodioxol-5-yl) ethyl} thiol] acetate

-OH ₂

1.0 g of the title compound in the form of a white powder was prepared by the same method as in Example 8 from 0.93 g of {2- (6-benzyl-1,3-benzodioxol-5-yl) ethyl} thiolossigure.

Melting point: 185-205 ⁰ C (decomposition)

¹ H-MKR (400MHz, DMSO-d.) Δ;

2.50-2.54 (m, 2H), 2.68-2.70 (m, 2H), 2.89 (s, 1 ri), 3.90 (s, 1H), 5.93 ( s, 1H), 6.69 (s, 1H), 6.80 (s, 1H), 7.12-7.18 (m, 3H), 7.25-7.28

MS (FAB) m / z; 353 (MH ")

Example 27 [{i-d.S-Benzodioxot-S-yl-methyl-thio-o-thiolacetame

OH-CH ₃

500 mg of [{(1- (1,3-benzodioxol-5-yl) -1-methylethyl} -thio] acetic acid were dissolved in 10 ml of benzene, then 0.79 ml of thionyl chloride was added and the resulting mixture was stirred at room temperature for 15 hours and distilled to remove the solvent To the residue was added 3.5 ml of tetrahydrofuran, and the resulting mixture was added dropwise to 30 ml of aqueous ammonia The mixture was stirred at room temperature for 30 minutes and extracted with chloroform, the extract was then washed The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 4: 6) to give 240 mg of the title compound as colorless needles.

Melting point: 70-71.5 "C ¹ H-MKROOMH ^ cDCI ₃ ) S; 1.67Js, 6H), 2.95 (s, 2H), 5.2-57 (bs, 1H), 5.90 ( s, 2H), 6.2-6.7 (bs, 1H), 6.68 (d, J = 7.9Hz, 1H), 6.87 (dd, J = 7.9Hz and 1.8 Hz, 1H), 6.99 (d, J = 1.8Hz, 1H).

MS (FAB) m / z; 507 (2MH "), 254 (MH").

Example 28 M-Methyl! - [{1- (1,3-benzodloxol-5-yl) -butyl} thio] -acetamld

OH ₂ OH ₂ CH ₃

OHSCH ₂ OOIiCH ₃

2.5 g of the title compound in the form of a colorless oil were prepared by the same method as in Example 27 from 2.7 g of ({1 -0,3-benzodioxol-5-yl) butyl} thio] acetic acid using an aqueous, 40% methylamiril solution prepared.

¹ H-MKR (90MHz, CDCI ₃ ) S; 0.87 (m, 3H), 1.10-1.50 (m, 2H), 1.67-1.93 (m, 2H), 2.72 (d, J = 5Hz, 3H), 3, 00 (s, 2H), 3.62 (t, J = 7Hz, 1H), 5.88 (s, 2H), 6.50-6.73 (m, 3H), 6.58 (m, 1H ).

MS m / z; 281 (M ").

Example 29 1 {1- (1,3-Benzodloxot-5-yl) butyl} thiol] azetamide

CH ₂ CH ₂ CH ₃ HSCH ₂ CONH ₂

1.8 g of the title compound in the form of a white powder were prepared by the same method as in Example 27 from 2.7 g of [{1- (1,3-benzodioxol-5-yl) butyl} thio] acetic acid.

Melting point: 91-92 ⁰ C (ethyl acetate / isopropyl ether) ¹ H-MKROOMH ^ CDCI ₃₎ S; 0.88 (m, 3H), 1.11-1.50 (m, 2H), 1.68-1.94 (m, 2H), 2.93 and 3.02 (ABq ₁ J = 17 Hz, 2H ), 3.68 (t, J = 7Hz, 1H), 5.46 (brs, 1H), 5.89 (s, 2H), 6.45 (brs, 1H), 6.52 to 6 , 75 (m, 3H).

Ms m / z; 267 (M ").

Example 30 [(1- (6-Methyl-1,3-benzodloxol-5-yl) ethyl} thiol] acetamide

OH ₃ CHSCH ₀ CONH,

X ^ s ₁ / CHSCH ₂ CONH ₂

CXC,

^l 3

1.5 g of the title compound was prepared from 2.6 g of [{1- (6-methyl-1,3-benzodioxol-5-yl) ethyl} thioacetic acid in the form of a white powder by the same method as in Example 27.

Melting point: 121-122 ⁰ C. ¹ _H-1 MKROOMHz CDCI ₃₎ O; 1.53 (d, J = 7Hz, 3H), 2.22 (s, H), 2.93 and 3.05 (ABq, J = 16Hz, 2H), 4.21 (q, J = 7Hz, 1 H), 5.68 (brs, 1H), 5.8C (s, 2H), 6.50 (brs, 1H), 6.53 (s, 1H), 6.87 (s, iH).

MS m / z; 253 (M ").

Example 31 [{2- (6-Ethym, 3-benzodioxol-5-yl) ethyl) thio] acetaldehyde

1.1 g of the title compound in the form of colorless crystals were prepared by the same method as in Example 27 from 2.0 g

I {2- (6-ethyl-1,3-benzodioxol-5-yl) ethyl} thio] acetic acid. Melting point: 98-99 ⁰ C.

¹ H-MKR (400MHz, DMSO-d ») δ;

1.10 (t, J = 7.5Hz, 3H), 2.49-2.54 (m, 2H), 2.68-2.77 (m, 4H), 3.11 (s, 2 H), 5.92 (s, 2H), 6.73 (s, 1H), 6.76 (s, 1H), 7.01 (s, 1H), 7.43 (s,

MS (FD) m / z; 267 (MH ").

Example 32 N, N-Dimethyl [{1- (6-methyl-1,3-benzodioxol-5-yl) ethyl} thio] azetamide

CH ₃

2.6 g of t {1- (6-methyl-1,3-benzodioxol-5-yl) ethyl} thio] acetic acid were dissolved in 20 ml of benzene, followed by 1.4 ml

Thionyl chloride added. The mixture thus obtained was refluxed for one hour and heated in the Concentrated vacuum to give a SSurechloridderivat in the form of a brown oil. Separately, 2.0 g of sodium hydroxide was dissolved in 10 ml of water and a solution prepared. The solution was under Cool with ice dimethylamine hydrochloride added. The mixture thus obtained was added dropwise the above Derivative added. The resulting mixture was stirred at room temperature overnight, then water

added. The mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and distilled to remove the solvent, then the residue was passed through

Silica gel column chromatography (ethyl acetate / Hoxan = 5:95) to give 2.1 g of the title compound in the form

a colorless oil.

¹ H-MKROOMHz ₁ CDCl ₃ ) O;

1.53 (d, J = 7Hz, 3H), 2.27 (s, 3H), 2.90 (s, 3H), 2.95 (s, 3H), 3.08, and 3.19 (ABq, J = 14Hz, 2H), 4.34 (q, J = 7Hz, 1H), 5.85 (s, 2H), 6.55 (S, 1H), 6.94 (8.1H).

MS m / z; 281 (M ").

Example 33 N, N-Dimethyl - [{2- (6-ethyl-1,3-benzodloxol-5-yl) ethyl} thio] acetamide

CH ₂ CH ₂ SGH ₂ CON (C ₂ H ₅ ),

2.1 g of the title compound in the form of a pale yellow oil were synthesized by the same method as in Example 32 from 2.0 g of {2- (8-ethyl-1,3-benzodioxol-5-yl) ethyl} thio) acetic acid made of 2.7g diethylamine.

¹ H-MKR (400MHz, DMSO-d ") δ;

1.01 (t, J = 7.1Hz, 3H), 1.0 (t, J = 7.5Hz, 3H), 1.12 (t, J = 7.1Hz, 3H), 2.52 ( q, J = 7.3 Hz, 2H), 2.68 to 2.78 (m, 4H), 3.25 (q,

J = 7,0Hz, 2H), 3,33 (q, J = 7,0Hz, 2H), 3,39 (s, 2H), 5,92 (s, 2H), 6,72 (s, 1H ), 6.76 (s, 1H).

MS (FD) m / z; 323 (M ").

Example 34 N- [2 - [((1,3-Benzodloxol-5-yl) -butyl) thlo] -1-oxoethyl] arnhioacetic acid

1, '1g ({(1,3-benzodioxol-5-yl) butyl) thiolacetic acid was dissolved in 10 ml of benzene, then 0.8 ml of thionyl chloride was added. The resulting mixture was heated at reflux for 1.5 hours and concentrated in vacuo to give a residue. Separately, 0.43 g of sodium hydroxide was dissolved in 4 ml of water and 0.8 g of glycine was added thereto to prepare a mixture. The above residue was dissolved in a small amount of tetrahydrofuran

dissolved to make a solution. This solution was added dropwise to the above while cooling with ice / water

Mixture added. The resulting mixture was stirred for 30 minutes, then water was added. The Mixture was acidified with concentrated hydrochloric acid and extracted with chloroform. The organic layer

was dried over magnesium sulfate and distilled to remove the solvent. That's how you got one

brown oil. This oil was crystallized from isopropyl ether to give 1 g of the title precursor in the form of light brown

Crystals. Melting point: 95-96 ° C.

¹ H-MKROOMHz ₁ CDCl ₃ ) O;

0.87 (m, 3H), 1.20-1.50 (m, 2H), 1.68-1.93 (m, 2H), 3.02 and 3.07 (ABq, J = 17Hz, 2H ), 3.76 (t, J = 7Hz, 1H), 3.99 (t, J = 5Hz, 2H), 5.88Js, 2H), 6.63-6.75 (m, 3H), 7 , 16 (m, 1H), 7.49 (brs, 1H).

Example 35 Natrum N- [2 - [{(1,3'-benzodloxol-5-yl) butyl} thlo] -1-oxoethyl] aminoacetate

CH ₂ CH ₂ CH ₃

SCH ₂ CONHCH ₂ CO ₂ Na

0-

0.5 g of the titanium powder in the form of a white powder was prepared by the same method as in Example 8 from 0.5 g of N- (2 - [{(1,3-benzodioxol-5-yl) butyl} thio] -1-oxoethyl] aminoacetic acid produced.

Melting point: 264-27O ⁰ C (decomposition)

¹ H-MKR (400MHz, DMSO-d _e ) δ;

0.82 (t, J = 7.3Hz, 3H), 1.11-1.28 (m, 2H), 1.67-1.80 (m, 2H), 2.80 and 3.03 (ABq, J = 15.0Hz, 2H), 3.25 (d, J = 4.0Hz, 2H), 3.91 (dd,

J = 6.6Hz and 8.8Hz, 1H), 5.99 (s, 2H), 6.73 (dd, J = 1.5Hz and 7.7Hz, 1H), 6.80 ( d, J = 7.7 Hz, 1H), 6.87 (d, J = 1.5 Hz, 1H), 7.44 MS (FAB) m / z; 370 (MNa "), 348 (MH").

Claims (1)

Process for the preparation of a benzodioxole derivative having the formula (I) and its pharmacologically acceptable salt: in which are defined: T is hydrogen, U is hydrogen, V is R ³ and W is wherein R ¹ and R ^{2 may be the} same or different and each represents a hydrogen atom or a lower alkyl, aryl or arylalkyl group, η represents an integer of 0 or 1, Y represents a group represented by the formula -COOH or -CON-R ⁴ V, (wherein R ⁴ and R ^{5 may be the} same or different and each represents a hydrogen atom or a lower alkyl or carboxymethyl group) and R ^{3 represents} a hydrogen atom or a lower alkyl or arylalkyl group, characterized by a) an alcohol of Formula Il with a mercaptoacetic acid of formula III HS-CH ₂ -CO ₂ H (III) to the general form! IV wherein the reaction is carried out without any solvent or in the presence of an organic solvent inert to the reaction, either under cooling, with heating or at room temperature, according to a conventional method, wherein the forms (II) to (IV) R ¹ , R ² and R ^{3 are} as defined above,
or
b) a general formula V O ^ .C (V) with a mercaptoacetic acid of formula III HSCH ₂ CO ₂ to the general & my formula Vl (III) (CH ₂ J _n -S-CH ₂ CO ₂ H (Vl) implements, wherein the formula (V) and (VI) are as defined above, Hal represents a halogen atom or a methanesulfonyloxy or p-toluenesulfonyloxy group, and R ¹ , R ² , R ³ and η are as defined above, wherein the reaction without any solvent or in the presence of an organic solvent which is inert to the reaction, either under cooling or under heating or at room temperature, according to a conventional method,
or
c) a carboxylic acid of the general formula Vl "1 _n 2 (CH ₂ J _n -S-CH ₂ CO ₂ H or their reactive derivative with an amine of general formula VII "4 (IV) HN (VII) to the general formula VIII (CH ₂ J _n -S-CH ₂ CON ^ (VIII) ^RJ implements, wherein R ⁴ and R ^{5 may be the} same or different and each represents a hydrogen atom or a lower alkyl group and R ¹ , R ² , R ³ and η are as defined above, wherein the reaction is in an organic solvent inert to the reaction is carried out d) a compound of general formula VI (CH ₂ J _n -S-CH ₂ CO ₂ H (Vl) O ^ ^> ^ ^ _R 3 with a formula H ₂ KCH ₂ CO ₂ H to the general formula X. (IX) (CH ₂ ) _n -S-CH ₂ CONHCH ₂ CO ₂ H (X) implements, wherein R ¹ , R ² , R ³ and η are as defined above, wherein the reaction is carried out either under cooling or under Heating or at room temperature. Field of application of the invention The invention relates to benzodioxole derivatives or their pharmacologically acceptable salts which have excellent activity as medicaments. Characteristic of the known state of the art The development of a cure for liver damage is very difficult because of cause, appearance and pathophysiology Of liver damage very different, mostly ambiguous. Among the representative drugs used and widely used in the treatment and prevention of liver damage considered to be clinically effective include glycyrrhizinicsparate. It is generally accepted that the Glycyrrhizin preparations are effective in the treatment of liver disease, cirrhosis and hepatitis and in the protection of the liver After surgery, however, none of these preparations have sufficient effect, and they are also problematic in that they produce a steroidal adverse effect. Besides, it is a disadvantage of Glycyrrhizin preparations that their oral administration is ineffective, so that they are administered as intravenous injections need to have an effect. Under these circumstances, it is highly desirable to develop an excellent drug that is excellent in Safety is and can be administered orally and thereby brings an excellent effect. Based on this, the authors have conducted intensive research to find a new cure for the treatment of To develop liver damage. The authors have long dealt with plants that :. Is used and have folk medicine use 2- | (phenylmethyl) trithio] ethanol (A) and Kubebin (B!), Represented by the following general formulas become: CH ₂ -SSS-CH ₂ CH ₉ OH (A)