GB2068361A - Thiadiazolyl (Lower) Alkanoic Acid Derivatives and Processes for the Preparation Thereof - Google Patents

Abstract

The compounds have the formula:- <IMAGE> in which R<1> is amino or a protected amino group, R<2> is carboxy or a protected carboxy group, and A is lower alkylene, and salts thereof. The compounds have antimicrobial activity.

Description

SPECIFICATION Thiadiazolyl(lower)alkanoic Acid Derivatives and Processes for the Preparation Thereof The present invention relates to novel thiadiazolyl(lower)alkanoic acid derivatives and salts thereof. More particularly, it relates to novel thiadiazolyl(lower)alkanoic acid derivatives and salts thereof which have antimicrobial activities, to processes for the preparation thereof, to pharmaceutical composition comprising the same, and to a method of using the same therapeutically in the treatment of infectious diseases caused by pathogenic microorganisms in human being and animals.

Accordingly, one object of the present invention is to provide novel thiadiazolyl(lower)alkanoic acid derivatives and salts thereof, which are highly active against a number of pathogenic microorganisms and are useful as antimicrobial agents.

Another object of the present invention is to provide processes for the preparation of novel thiadiazolyl(lower)alkanoic acid derivatives and salts thereof.

A further object of the present invention is to provide a pharmaceutical composition comprising, as active ingredients, said thiadiazolyl(lower)alkanoic acid derivatives and salts thereof.

Still further object of the present invention is to provide a method of using said thiadiazolyl(lower)alkanoic acid derivatives and salts thereof in the treatment of infectious diseases by pathogenic microorganisms in human being and animals.

The object thiadiazolyl(lower)alkanoic acid derivatives are novel and can be represented by the following general formula:

wherein R1 is amino or a protected amino group, R2 is carboxy or a protected carboxy group, and A is lower alkylene.

Suitable salts of the object compounds (I) may include pharmaceutically acceptable salts such as salts with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylene diamine salt, etc.) etc.; an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic acid addition salt, for example, organic carboxylic or sulfonic acid addition salt (e.g. formate, trifluoroacetate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.); a salt with a basic amino acid (e.g.arginine, etc.); and the like.

According to the present invention, the object compounds (I) and salts thereof can be prepared by the processes as illustrated by the following reaction schemes.

(1) Process 1:

or salts thereof or salts thereof (2) Process 2:

or salts thereof or salts thereof (3) Process 3:

or salts thereof or salts thereof (4) Process 4:

or salts thereof or salts thereof wherein R1, R2 and A are each as defined above, R1 is a protected amino group, R2a is a protected carboxy group, R3 is lower alkyl and A1 is lower alkanetriyl.

Some of the starting compounds (II) used in Process 1 are new and can be prepared, for example, from the known compounds (III) by the method in the following reaction schemes, and others can be prepared in a similar manner thereto or in a conventional manner.

i) halogenation N H2N--C- ii) ii) M-SCN (m) NH a sun NH R2 (Process A) (m) (v) or salts thereof or salts thereof Introductiono; of (Process B) soR3 the amino t R1 Nn CocH the amino groop acocn protective groL?p \S/ Sss (Process C) S/ (w) (Z) Reduction | (Process D) I RalH \ B3 (Proces.s Ej dtAl TB CHCH S7 I ORE (x) Elimination Of the compound of.the (Process F) formula R4-OH Rt t < CH=C\ 7 9RB S' (II-a) wherein, R1, R2a and R3 are each defined above, R4 is acyl and M is an alkali metal.

Regarding the object compounds (I) and (I-a) to (I-d) and the starting compounds (II), (Il-a), (V), (VI), (Vlil), (IX) and (X), it is to be understood that said object and starting compounds may include tautomeric isomers relating to their thiadiazolyl group. That is, in case that the group represented by the formula:

(wherein R' is amino or a protected amino) in said object and starting compounds take a group of the formula:

(wherein R1 is as defined above), said group may also be alternatively represented by its tautomeric group of the formula:

(wherein R1' is imino or a protected imino).That is, both of the said groups may be in the state of equilibrium as so-called tautomeric forms which can be represented by the following equilibrium:

(wherein R' and R1' are each as defined above).

In the starting compounds (II), (Il-a) and (VIII) to (X), it is to be understood that there may be one or more stereoisomeric pair(s) such as optical and geometrical isomers due to asymmetric carbon atom and double bond in those molecules and such isomers are also included within the scope of said compounds.

In the above and subsequent description of the present specification, suitable examples and illustration of the various definitions to be included within the scope thereof are explained in detail as follows.

The term "lower" in the present specification is intended to mean a group having 1 to 6 carbon atoms, unless otherwise indicated.

"Protected amino group" means an amino group substituted by a conventional aminoprotective group, and suitable amino-protective group may include, for example, acyl as mentioned below, mono(or di or tri)-phenyl(lower)alkyl (e.g. benzyl, benzhydryl, trityl, etc.), lower alkoxycarbonyl(lower)alkylidene or its enamine tautomer (e.g. 1 -methoxycarbonyl-1 -propen-2-yl, etc.), and the like.

Suitable "acyi" may include an aliphatic acyl, an aromatic acyl, a heterocyclic acyl and an aliphatic acyl substituted with aromatic or heterocyclic group(s).

The aliphatic acyl may include saturated or unsaturated, acyclic or cyclic ones, such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, veleryl, isovaleryl, pivaloyl, hexanoyl, etc.), lower alkanesulfonyl, (e.g. mesyl, ethanesulfonyl, propanesulfonyl, etc.), lower alkoxycarbonyl (e.g.

methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, etc.), lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.),(C3-C7)-cycloalkanecarbonyl (e.g.

cyclohexanecarbonyl, etc.), and the like.

The aromatic acyl may include aroyl (e.g. benzoyl, toluoyl, xyloyl, etc.), arenesulfonyl (e.g.

benzenesulfonyl, tosyl, etc.), and the like.

The heterocyclic acyl may include heterocyclecarbonyl (e.g. furoyl, thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, etc.), and the like.

The aliphatic acyl substituted with aromatic group(s) may include phenyl(lower)alkanoyl (e.g.

phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.), phenyl(lower)alkoxycarbonyl (e.g.

benzyloxycarbonyl, phenethyloxycarbonyl, etc.), phenoxy(lower)alkanoyl (e.g. phenoxyacetyl, phenoxypropionyl, etc.), and the like.

The aliphatic acyl substituted with heterocyclic group(s) may include thienylacetyl, imidozolylacetyl, furylacetyl, tetrazolylacetyl, thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl, thiadiazolylpropionyl and the like.

These acyl groups may be further substituted with one or more suitable substituents such as lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc.), halogen (e.g. chloie, bromine, iodine, fluorine), lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc.), lower alkylthio (e.g. methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc.), nitro and the like, and preferable acyl having such substituent(s) may be mono (or di or tri)halo(lower)alkanoyl (e.g. chloroacetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl, etc.), mono (or di or tri)halo(lower)alkoxycarbonyl (e.g. chloromethoxycarbonyl, dichloromethoxycarbonyl, 2,2,2-tri-chloroethoxycarbonyl, etc.), nitro-(or halo or lower alkoxy)phenyl(lower)alkoxycarbonyl (e.g. nitrobenzyloxycarbonyl, chlorobenzyloxycarbonyl, methoxybenzyloxy carbonyl, etc.), and the like, in which the preferred one is lower alkanoyl and mono(or di ortri)phenyl(lower)alkyl.

Suitable "protected carboxy" group may be an esterified carboxy group, and suitable "ester moiety" in said "esterified carboxy group" may include lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, tert-pentyl ester, hexyl ester, etc.), lower alkenyl ester (e.g. vinyl ester, allyl ester, etc.), lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.), lower alkoxy(lower)alkyl ester (e.g. methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.), lower alkylthio(lower)alkyl ester (e.g. methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester, etc.), mono(or di or tri)halo(lower)alkyl ester (e.g. 2-iodoethyl ester, 2,2,2trichloroethyl ester, etc.), lower alkanoyloxy(lower)alkyl ester (e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, etc.), lower alkanesulfonyl(lower)alkyl ester (e.g. mesylmethyl ester, 2-mesylethyl ester, etc.), mono(or di or tri)phenyl(lower)alkyl ester which may have one or more suitable substituent(s) (e.g. benzyl ester, 4methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, benzhydryl ester, trityl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.), aryl ester which may have one or more suitable substituents (e.g. phenyl ester, tolyl ester, tbutylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, salicyl ester, etc.), and the like, in which the preferred one is lower alkyl ester.

Suitable "lower alkyl" group may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl and the like, in which the preferred one is C1-C4a Ikyl.

Suitable "lower alkylene" group may include methylene, ethylene, trimethylene and the like, in which the preferred one is C1-C4alkylene and the most preferred one is methylene.

Suitable "lower alkanetriyl" group may include methylidyne, ethanetriyl, propanetriyl and the like, in which the preferred one is C1-C4alkanetriyl and the most preferred one is methylidyne.

Suitable "acyl" may include those as exemplified for the acyl group in the amino-protective group mentioned above, in which the preferred one is lower alkanoyl.

Suitable "alkali metal" may include sodium, potassium, lithium, and the like.

The processes 1 to 4 for the preparation of the object compounds (I) of the present invention are explained in detail in the following.

(1) Process The compounds (I) or salts thereof can be prepared by reacting the compound (II) or salts thereof with an alcohol or water in the presence of an acid.

Suitable salts of the compounds (II) may include the same acid addition salt for the compounds (I).

Suitable "alcohol" used in this reaction may be a hydroxy compound having a group as exemplified for the "ester moiety" in the protected carboxy.

In this reaction, in case that the alcohol is used as a reagent, the object compounds (I), wherein R2 is a protected carboxy, are always obtained, while in case that water is used as a reagent, the compounds (I), wherein R2 is carboxy, are always obtained.

Suitable acid may be an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), an organic acid (e.g. formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc, and in case that the alcohol is used in this reaction, the reaction can preferably be carried out by using hydrogen chloride, hydrogen bromide, etc., as an acid.

The reaction temperature is not critical and the reaction is usually carried out from under cooling to warming.

(2) Process 2: The compounds (I-b) or salts thereof can be prepared by removing the amino-protective group from the compounds (I-a) or salts thereof.

Suitable method for this removal reaction may include conventional one such as hydrolysis, reduction and the like.

(i) For Hydrolysis: Hydrolysis is preferably carried out in the presence of an acid, or a base.

Suitable acid may be an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), an organic acid (e.g. formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), an acidic ion-exchange resin and the like. In case that trifluoroacetic acid is used in this reaction, the reaction is preferably carried out in the presence of cation trapping agents (e.g. anisole, etc.).

Suitable base may be an inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.); an organic base (e.g.

hydrazine, N,N-dimethyl-1 ,3-propanediamine, etc.), and the like.

The acid or base suitable for this hydrolysis can be selected according to the kinds of the protective group to be removed, for example, this hydrolysis can preferably be applied to the aminoprotective group for R such as substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted lower alkanoyl.

The hydrolysis is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, tetrahydrofuran, N,~-diniethylformamide, dioxane, and the like or a mixture thereof, and further the above-mentioned acid or base can also be used as a solvent when they are in liquid.

The reaction temperature of this hydrolysis is not critical, and the reaction is usually carried out from under cooling to heating.

(II) For Reduction: Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are a combination of a metal (e.g. tin, zinc, iron, etc.) or metallic compounds (e.g. chromium chloride, chromium acetate, etc.) and an organic or inorganic acid as mentioned above.

Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g. platinum plane, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g. reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g. reduced iron, Raney iron, etc.), copper catalysts (e.g.

reduced copper, Raney copper, Ullman copper, etc.) and the like.

The reduction manner can be selected according to the kinds of the protective group to be removed, for example, the chemical reduction can preferably be applied to the amino-protective group for R' such as halo(lower)alkoxycarbonyl and the like, the catalytic reduction can preferably be applied to that such as substituted or unsubstituted ar(lower)alkoxycarbonyl, and the like.

The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide, and the like or a mixture thereof. Additionally, in case that the above-mentioned acid to be used in chemical reduction is in liquid, it can also be used as a solvent. Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent, such as diethyl ether, dioxane, tetrahydrofuran, and the like, or a mixture thereof.

The reaction temperature of this reduction is not critical and the reaction is usually carried out from under cooling to warming.

The present invention includes, within the scope of the invention, a case that the protected carboxy group for R2 is transformed into free carboxy group during the reaction.

(3) Process 3: The compounds (I-d) or salts thereof can be prepared by removing the carboxy-protective group from the compounds (I-c) or salts thereof.

The reaction is carried out by a conventional method such as hydrolysis, reduction, and the like.

The method of hydrolysis and reduction, and the reaction conditions (e.g. reaction temperature, solvent, etc.) are substantially the same as those illustrated for the removal reaction of the aminoprotective group of the compound (I-a) in Process 2, and therefore can be referred to said explanation.

The present invention includes, within the scope of the invention, a case that the protected amino group in R is transformed into free amino group during the reaction.

(4) Process 4: The compounds (I-a) or salts thereof can be prepared by introducing the amino-protective group into the compounds (I-b) or salts thereof.

The introducing agent of the amino-protective group to be used in this reaction may include a conventional acylating agent such as the corresponding acid to the acyl group in the explanation of the protected amino group as aformentioned, or its reactive derivative (e.g. acid halide, acid anhydride, activated ester, activated amide, etc.), 2-lower alkoxycarbonyloxyimino-2'-phenylacetonitrile (e.g. 2tert-butoxycarbonyloxyimino-2-phenylacetonitrile, etc.), alkyl ketone substituted by lower alkoxycarbonyl (e.g. lower alkyl acetoacetate, for example, methyl acetoacetate, etc.), mono(or di or tri)phenyl(lower)alkanol or its reactive derivative [e.g. mono(or di or tri)phenyl(lower)alkyl halide, etc.], and the like.

The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, tetrahydrofuran, dioxane, methylene chloride, chloroform, and the like, or a mixture thereof.

The reaction is preferably carried out in the presence of a base, and suitable examples thereof may include the same base as those in Process 2, and in addition, alkali metal (e.g. lithium, sodium, potassium, etc.), alkaline earth metal (e.g. calcium, etc.), alkali metal hydride (e.g. sodium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), trialkylamine (e.g. triethylamine, etc.), pyridine compound (e.g. pyridine, lutidine, picoline, etc.), quinoline, diaza compound (e.g. 1,5 diazabicyclo[5,4,01undecene-5,1,4-diazabicyclo[2,2,2]octane, 1 ,5-diazobicyclo[4,3,O] nonene-5, etc.); and the like.

The reaction temperature is not critical and the reaction is usually carried out from under cooling to warming.

Processes A to F for the preparation of the starting compounds (Il-a) are explained in detail in the following.

(A) Process A: The compound (V) or salts thereof can be prepared by reacting the compound (III) or salts thereof with a halogenating agent and the compound (IV).

Suitable salts of the compounds (III) and (V) may include the same acid addition salt for the compounds (I).

Suitable halogenating agent to be used in this reaction may include bromine, chlorine and the like.

The reaction is preferably carried out in the presence of a base, and suitable examples thereof may include the same base as those in Processes 2 and 4.

The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as methanol, ethanol and the like.

The reaction temperature is not critical and the reaction is usually carried out from under cooling to at ambient temperature.

(B) Process B: The compounds (VI) can be prepared by introducing the amino-protective group into the compounds (V) or salts thereof.

This reaction can be carried out by substantially the same method as Process 4, and therefore, the reaction conditions (e.g. reaction temperature, solvent, etc.), etc. can be referred to said explanation.

(C) Process C: The compounds (VIII) can be prepared by reacting the compounds (VI) with the compounds (VII).

This process is usually carried out in the presence of a base such as an alkali metal hydride (e.g.

sodium hydride, potassium hydride, etc.), an alkaline earth metal hydride (e.g. calcium hydride, etc.) and the like, and usually carried out in a solvent which does not adversely influence the reaction such as dimethylformamide and the like.

The reaction temperature is not critical and the reaction is usually carried out from under cooling to warming.

(D) ProcessD: The compounds (IX) can be prepared by reducing the compounds (VIII).

The reduction can be carried out by a conventional method such as reduction using a reducing agent, catalytic reduction, and the like.

Suitable reducing agent may include a conventional one used for conversion of a carbonyl group to a hydroxymethyl group such as metal hydride, for example, alkali borohydride (e.g. sodium borohydride, potassium borohydride, sodium cyanoborohydride, etc.), lithium alminumhydride, etc.; diborane; and the like.

The catalyst to be used in the catalytic reduction may include the same ones as exemplified for the reduction in Process 2.

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, tetrahydrofuran, dioxane, and the like, or a mixture thereof.

The reaction temperature is not critical and the reaction is usually carried out from under cooling to warming.

(E) Process: The compounds (X) can be prepared by acylating the compounds (IX).

The acylating agent to be used in this reaction may be the same ones as explained in Process 4.

The reaction can be carried out by substantially the same method as Process 4, and therefore, the reaction conditions (e.g. reaction temperature, solvent, etc.), etc. can be referred to said explanation.

In this reaction according to the kinds of the amino-protective group for R' of the compounds (IX) and the acylating agent to be used, the amino-protective group for R' is occasionally transformed into the acyl group from the acylating agent, and such a case is included within the scope of the present process.

(F) Process F: The compounds (Il-a) can be prepared by eliminating the compounds of the formula: R4OH (wherein R4 is as defined above) from the compounds (X).

The reaction can be carried out in the presence of a base, and suitable examples thereof are the same as those as exemplified in Process 2.

The reaction can also be carried out in a solvent which does not adversely influence the reaction such as methylene chloride, chloroform, and the like, or a mixture thereof.

The reaction temperature is not critical and the reaction can usually carried out from under cooling to warming.

In case that the object compounds (I) have a free amino or free carboxy group, it may be transformed into their salts by a conventional method.

The object compound (I)- and salts thereof are novel and exhibit high antimicrobial activity, inhibiting the growth of a wide variety of pathogenic microorganisms including bacteria and fungi and are useful as antimicrobial agents. For example, 2-(5-amino-1 ,2,4-thiadiazol-3-yl)acetic acid hydrochloride exhibits antimicrobial activities against Escherichia coli NIHJ JC-2, Candida albicans Yu1200 and Trichophyton asteroides.

In addition to the above utility, the object compounds (I) and salts thereof are also useful as key intermediate for preparing antimicrobial compounds, for example, 7-acylaminocephalosporin compounds which can be prepared by reacting the corresponding 7-aminocephalosporin compounds with the object compounds (I) as acylating agents, and accordingly are also useful as intermediates for preparing other antimicrobial agents.

For therapeutic administration, the object compounds (I) and salts thereof of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound, as active ingredients, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration. The pharmaceutical preparations may be in solid form such as tablet, granule, powder, capsule, or solution form such as syrup, emulsion, lemonade, and the like. If needed, there may be included in the above preparations auxiliary substances, stabilizing agents, wetting agents and other commonly used additives such as lactose, magnesium stearate, terra alba, sucrose, corn starch, talc, stearic acid, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethyleneglycol and the like.

While the dosage of the compounds (i) may vary from and also depend upon the age, conditions of the patient, a kind of disease, a kind of the compounds (I)-to be applied, etc. In general, amounts between 1 mg and about 4,000 mg or even more per day may be administered to a patient. An average single dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, 2000 mg of the object compounds (I) of the present invention may be used in treating diseases infected by pathogenic microorganisms.

The following examples are given for the purpose of illustrating the present invention.

Preparation of the Starting Compounds Preparation 1 To a solution of 1-ethoxycarbonylformamidine hydrobromide (16.6 g) in absolute methanol (84 ml) was added a solution of sodium (1.93 g) in absolute methanol (42 ml) at OOC. To the mixture were added alternately bromine (12.8 g) and a solution of sodium (1.S3 g) in absolute methanol (42 ml) at 0 C and then to the suspension was added potassium thiocyanate (8.1 g) in absolute methanol (100 ml). The reaction mixture was stirred for an hour at 0 C and for an additional 6 hours at ambient temperature. The mixture was filtered through cellulose powder and the filtrate was evaporated to dryness.The residue was dissolved in a mixture of ethyl acetate and water, and then the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was triturated with diethyl ether to give methyl 5-amino-I ,2,4-thiadiazole-3-carboxylate (9.0 g), mp. 202 to 2050C.

l.R. (Nujol): 3400,3250,3100, 1710, 1610, 1540 cam~' N.M.R. a ppm (d,-DMSO): 3.85 (3H, s), 8.25 (2H, s).

Preparation 2 To a mixture of formic acid (33 g) and acetic anhydride (22 g) was added methyl 5-amino-1 ,2,4- thiadiazole-3-carboxylate (6.2 g), and then the mixture was stirred for 2 days at ambient temperature.

The reaction mixture was concentrated under reduced pressure and the residue was triturated in a mixture of diethyl ether and n-hexane to give methyl 5-formamido-1 ,2,4-thiadiazole-3-carboxylate (7.2 g), mp. 210 to 2150C.

i.R. (Nujol): 3100, 1720, 1680 cm~1 N.M.R. â ppm (d0-DMSO): 3.90 (3H, s), 8.85 (1 H, s).

Preparation 3 To a mixture of methyl 5-formamido-l ,2,4-thiadiazole-3-carboxylate (9.2 g) and methyl methylthiomethyl sulfoxide (6.1 g) in N,N-dimethylformamide (100 ml) was added 50% sodium hydride (7.1 g) with cooling in an ice-bath. The mixture was stirred for an hour at ambient temperature and for an additional one hour at 400 C. After cooling to ambient temperature, methylene chloride (300 ml) was added to the reaction mixture, and the resulting precipitates were collected by filtration and washed with methylene chloride. The precipitates were added to a stirred mixture of hydrochloric acid (14.7 ml), ice-watsr (200 ml) and methylene chloride (200 ml). An insoluble material was filtered off and the methylene chloride layer was separated from the filtrate.The solution was dried over anhydrous magnesium sulfate, evaporated and the residue was triturated in diethyl ether to give 5 formamido-3-(2-methanesulfinyl-2-methylthioacetyl)-1 ,2,4-thiadiazole (4.5 9), mp. 130 to 1320 C.

I.R. (Nujol): 3100, 1680, 1670 cam~' N.M.R. a ppm (dl-DMSO): 2,22, 2.28 (3H, 2s), 2.68,2.85 (2H 2s), 5.70, 5.80 (1H, 26), 8.86(1H, s).

Preparation 4 To a stirred solution of 5-formamido-3-(2-methanesulfinyl-2-methylthioacetyl)-1,2,4-thiadiazole (14.0 g) in methanol 250 ml) was added portionwise sodium borohydride (1.90g) under cooling in an ice bath, and the stirring was continued at ambient temperature for 30 minutes. To a reaction mixture was added acetone (20 ml) and the mixture was evaporated to dryness. The residue was dissolved in a mixture of acetic acid (5 ml), water (140 ml), chlorofdrm (150 ml) and ethanol (100 ml), and the organic layer was separated out. The remained aqueous layer was salted out and extracted with a mixture of chloroform and ethanol.This extract and the organic layer separated before were combined, dried over anhydrous magnesium sulfate and evaporated to dryness. the residue was triturated in diisopropyl ether to give 5-formamido-3-(1 -hydroxy-2-methanesulfinyl-2-methylthioethyl)- 1,2,4 thiadiazole (10.5 g), mp. 15015700.

I.R. (Nujol): 340O31 00, 1680, 1530, 1320, 1260, 1100, 1020, 870 cam~' N.M.R. a ppm (DMSO-d0): 2.12 (3 x 1/3H, s),2.17 (3 x2/3H, s), 2.70 (3 x2/3H, s), 2.76 (3 x 1/3H, 5), 4.25 (1 H, m), 5.47 (1 H, m), 8.80 (1 H, s).

Preparation 5 To a solution of 5-formamido-3-( 1 -hydroxy-2-methanesulfinyl-2-methylthioethyl)-1 2,4- thiadiazole (8.9 g) in pyridine (50 ml) was dropped acetic anhydride (50 ml) below 1 00C under cooling in an ice-salt bath and stirring. The stirring was continued at ambient temperature for 1.5 hours and the mixture was concentrated at 700C under reduced pressure (4 mmHg). The residual oil was subjected to column chromatography on silica gel (85 g) using ethyl acetate as an eluent. Fractions containing a desired constituent were collected and evaporated to give 5-acetamido-3-(1-acetoxy-2 methanesulfinyl-2-methylthioethyi)-l ,2,4-thiadiazbe (6.9 g) as an oil.

I.R. (Film): 3603300, 1750-1710, 1680, 1540, 1260, 1220, 1140, 1030, 850, 700 cam~' N.M.R. a ppm (CDC13): 2.3 (9H, m), 2.87 (3x2/3H, s), 3.03 (3x 1/3H, s), 4.9 (1 H, m), 6.9 (1 H, m), 12.1 (1H,broads).

Preparation 6 To a solution of 5.-acetamido-3-(1-acetoxy-2-methanesulfinyl-2-methylthioethyí)-1,2,4-thiadiazole (6.7 g) in methylene chloride (67 ml) was added 1,5-diazabicyclo[5,4,0]undecane-5 (6.0 g) below 300C under stirring, and the stirring was continued at ambient temperature for 3 hours. The reaction mixture was evaporated and the residue was dissolved in cold water (60 ml). The aqueous solution was adjusted to pH 5 to 6 with 1 N hydrochloric acid and a resulting precipitate was collected by filtration, washed with water and diisopropyl ether and dried to give 5-acetamido-3-(2-methanesulfinyl-2 methylthiovinyl)-l ,2,4-thiadiazole (4.7 g), mp. 234-237 0C (dec.).

I.R. (Nujol): 1680, 1 530, 1330, 1280, 1020, 955, 720 cm-l N.M.R. a ppm DMSO-d6): 2.30 (3H, s), 2.50 (3H, s), 2.83 (3H, s), 7.27 (1 H, s).

Preparation of the Object Compounds Example 1 A mixture of 5-aceta mido-3-(2-methanesu lfinyi-2-methylthiovinyi)- 1 ,2,4-thiadiazole (4.5 g) and 30% ethanolic hydrogen chloride (90 ml) was stirred at ambient temperature for 16 hours and then evaporated to dryness. The residue was dissolved in ethyl acetate and an insoluble substance was filtered off. To the filtrate was added an aqueous solution of sodium bicarbonate to adjust the aqueous layer to pH 7. The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated to give ethyl 2-(5-acetamido-1 ,2,4-thiadiazol-3-yl)acetate (2.2 g) as an oil.

IR. (Film):3150, 1735,1690,1645,1540, 1190,1030, 1020,810,730cm1 N.M.R. a ppm (CDCl3+D20): 1.27 (3H, t, J=7Hz), 2.27 (3H, s), 3.93 (2H,s), 4.21 (2H, q, J=7Hz).

Example 2 2-(5-Acetamido- 1 ,2,4-thiadiazol-3-yl)acetic acid was obtained by reacting 5-acetamido-3-(2 methanesulfinyl-2-methylthiovinyl)-l ,2,4-thiadiazole with hydrochloric acid according to a similar manner to that of Example 1.

I.R. (Nujol):3150, 1710--1670, 1540, 1340, 1225, 1210, 825, 720 cm-l.

Example 3 Ethyl 2-(5-amino-1 ,2,4-thiadiazoi-3-yi)acetate hydrochloride was obtained by reacting 5-amino 3-(2-methanesulfinyl-2-methylthiovlnyl)- ,2,4-thiadiazole with ethanolic hydrogen chloride according to a similar manner to that of Example 1.

I.R. (Nujol):3160,2700, 1730,1640,1610,1400, 1200, 1025,785,710cm1.

Example 4 A mixture of ethyl 2-(5-acetamido-1 ,2,4-thiadiazol-3-yl)acetate (1.2 g) and 10% ethanolic hydrogen choride (15 ml) was refluxed for 1.5 hours. The reaction mixture was cooled in an ice bath and a resulting precipitate was filtered, and washed with cold ethanol and diethyl ether to give ethyl 2 (5-amino-1 ,2,4-thiadiazoi-3-yl)acetate hydrochloride (0.71 g), mp. 1 79-1 830C (dec.). The filtrate and the washings were combined and evaporated to dryness. The residue was triturated in diethyl ether to recover the additional same compound (0.35 g). Total yield: 1.06 g.

i.R. (Nujol): 3160,2700, 1730, 1640, 1610, 1400,) 200, 1025, 785, 710 cm-' N.M.R. a ppm (DMSO-d6): 1.17 (3H, t, J=7Hz), 3.68 (2H, s), 4.07 (2H, q, J=7Hz), 9.43 (3H, broad s).

Example 5 2-(5-Amino-1 ,2,4-thiadiazol-3-yl)acetic acid hydrochloride was obtained by reacting 2-(5 acetamido-1 ,2,4-thiadiazol-3-yl)acetic acid with ethanolic hydrogen chloride according to a similar manner to that of Example 4.

I.R. (Nujol): 3180, 1715, 1625, 1585, 1410, 1210, 1180, 1060,935,850, 770 cm-'.

Example 6 A mixture of ethyl 2-(5-amino-1,2,4-thiadiazol-3-yl)acetate hydrochloride (300 mg) and concentrated hydrochloric acid (3 mi) was stirred at 1 00oC for 30 minutes. The mixture was evaporated to dryness and the residue was triturated in acetone to give 2-(5-amino-1 ,2,4-thiadiazol-3- yi)acetic acid hydrochloride (190 mg), mp. 170--1740C (dec.).

I.R. (Nujoi):3180, 1715,1625,1585,1410, 1210,1180, 1060,935,850,770cm-1 N.M.R. a ppm (DMSO-dó+D20): 3.66 (2H, s).

Example 7 A solution of ethyl 2-(5-acetamido-1 ,2,4-thiadiazol-3-yl)acetate (68 mg) in a mixture of ethanol (0.5 ml) and 1 N aqueous solution of sodium hydroxide (1 ml) was stirred at ambient temperature for 20 minutes. The reaction mixture was washed with diethyl ether, and then ethyl acetate was added to the resulting aqueous solution. The mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated in diisopropyl ether to give 2-(5-acetamido-1 ,2,4-thiadiazol-3-yl)acetic acid (15 mg), mp. 161-1640C (dec.).

I.R. (Nujol): 3150, 1710--1670, 1540, 1340, 1225, 1210, 825, 720 cam~' N. M. R. S ppm (DMSO-d): 2.24 (3H, 5)3.76 (2H, s), 12.8 (1 H, broad s).

Example 8 (1) To a suspension of ethyl 2-(5-amino-1 ,2,4-thiadiazol-3-yl)acetate hydrochloride (4.47 g) in chloroform (100 ml) was added triethylamine (5.1 g) under stirring and cooling in an ice bath, followed by an addition of trityl chloride (7.25 g). The reaction mixture was stirred at ambient temperature for 4 hours and then washed with water, dried over anhydrous magnesium sulfate and evaporated to give a crude oil (11 g) of ethyl 2-(5-tritylamino-1 ,2,4-thiadiazol-3-yl)acetate.

(2) This crude product was dissolved in ethanol (100 ml) and cooled in an ice bath. To the cold solution was added 2N aqueous solution of sodium hydroxide (20 ml) and the mixture was stirred at ambient temperature for 2 hours. The mixture was concentrated to a third volume and neutralized with 6N hydrochloric acid. The aqueous solution was washed with ethyl acetate and the washings were reextracted with an aqueous solution of sodium bicarbonate. The aqueous solution and the aqueous extract were combined and adjusted to pH 2 with 6N hydrochloric acid and extracted with ethylacetate. The extract was washed with an aqueous solution of sodium chloride, dried over an hydros magnesium sulfate, treated with activated charcoal and evaporated to dryness.The residue was triturated in n-hexane to give 2-(5-tritylamino-1 ,2,4thiadiazol-3-yl)acetic acid (4.6 g), mp. 174- 1 770C (dec.).

I.R. (Nujol): 3400,3200, 1720, 1690, 1520, 1500, 1250, 1220, 820, 730, 690 cm-l N.M.R. 6 ppm (DMSO-dtl): 3.51 (2H, s), 7.30 (1 5H, broad s), 9.58 (1H, broad s).

Example 9 2-(5-Acetamido-1 ,2,4-thiadiazol-3-yl)acetic acid was obtained by reacting 2-(5-amino-1 2,4- thiadiazol-3-yl)acetic acid with acetyl chloride according to a similar manner to that of Example 8-( 1).

I.R. (Nujol): 3150, 1710-1670, 1540,1340, 1225, 1210,825,720 cm~'.

Claims (3)

Claims

1. A compound of the formula:

wherein R' is amino or a protected amino group, R2 is carboxy or a protected carboxy group, and A is lower alkylene, or salts thereof.

2. A process for preparing a compound of the formula:

wherein R' is amino or a protected amino group, R2 is carboxy or a protected carboxy group, and A is lower alkylene, or salts thereof, which comprises (1) reacting a compound of the formula:

wherein R' is lower alkanetriyl, R3 is lower alkyl, and R' is as defined above, or salts thereof with an alcohol or water in the presence of an acid to give a compound of the formula:

wherein R1, R2 and A are each as defined above, or salts thereof; or (2) removing an amino-protective group from the compound of the formula:

wherein R' is a protected amino group, and R2 and A are each as defined above, or salts thereof to give a compound of the formula:

wherein R2 and A are each as defined above, or salts thereof; or (3) removing a carboxy-protective group from a compound of the formula:

wherein R2a is a protected carboxy group, and R1 and A are each defined above, or salts thereof to give a compound of the formula:

wherein R1 and A are each as defined above, or salts thereof; or (4) introducing an amino-protective group into a compound of the formula:

wherein R2 and A are each as defined above, or salts thereof to give a compound of the formula:

wherein R81, R2 and A are each as defined above, or salts thereof.

3. A pharmaceutical composition comprising, as an active ingredient, a compound of the claim 1 in admixture with a pharmaceutically acceptable carrier.