Antibacterial cephalosporins

Abstract: A compound of formula wherein Ac, R 1 and R 2 have various meanings, a process for a preparation thereof and its use as a pharmaceutical, i.e. as antibacterial agent

Description: The present invention relates to intermediate compounds useful in the production of antibacterial compounds which are 7-acylamino-3-(imino)methyl cephalosporins. FR 2248845 discloses intermediates in the production of cephalosporins wherein the intermediates have the formula wherein R 1 , R 2 , R 3 and R 4 denotes each hydrogen, (C 1-8 )-acyl, hydroxy, amino, nitro, carbamoyl, thiocarbamoyl, (C 1-8 )-acylamino, alkyl, alkoxy, alkenyl, alkinyl, aryl, aralkyl or (C 1-8 )-aralkenyl, whereby one or more of R 1 , R 2 , R 3 and R 4 might be combined. Particularly, the present invention provides a compound of formula wherein R x is a group of formula -NH-CH 2 CF 3 or -NH-(CH 2 ) 2 -N ⁺(CH 3 ) 3 or or or R y is NH and R z is hydrogen; or R x is a group of formula R y is NH and R z is CH 3 ; or R x is -SCH 3 R y is a group of formula and R z is hydrogen, or R x is the group R y is oxygen and R z is hydrogen. Compounds of formulae IVa are new and may be obtained analogously to conventional methods, or, as described in the examples. In another aspect the present invention provides a compound of formula wherein R 1 is hydrogen or an ester moiety, and R xx denotes the group wherein R x , R y and R z as defined above. In a preferred embodiment the present invention provides a trihydrochloride of 1-[hydrazino(methylimino)methyl]piperazine. If not otherwise stated therein any carbon containing group may contain up to 20 carbon atoms, e.g. alkyl includes (C 1-20 ), e.g. (C 1-8 ) alkyl. Lower alkyl includes e.g. (C 1-4 )alkyl, preferably (C 1-2 )alkyl. Alkenyl includes (C 2-20 ), e.g. (C 2-8 ) alkenyl. Lower alkenyl includes e.g. (C 3-5 )alkenyl, preferably C 3 alkyl. Cycloalkyl includes, for example, (C 3-6 )cycloalkyl, particularly C 3 , C 5 or C 6 cycloalkyl. Alkyl, alkenyl and cycloalkyl include unsubstituted alkyl, alkenyl and cycloalkyl; and, substituted alkyl, alkenyl and cycloalkyl, for example, by halogen, a sulphonic acid derivative, such as SO 3 H, CF 3 , hydroxy, alkoxy, acyl, alkylamino, pyridyl. Cycloalkyl is preferably unsubstituted. Acyl includes (C 1-12 ), e.g. (C 1-6 )acyl, particularly (C 1-4 )acyl. Acyl includes unsubstituted acyl and substituted acyl, for example, by hydroxy, alkoxy, amino. Aryl includes phenyl. Aryl may be unsubstituted aryl or substituted aryl, for example by alkyl, alkoxy, acyl, halogen, hydroxy, unprotected or protected amino. Alkoxy includes alkoxy wherein the alkyl part is as defined above. Heterocyclyl includes heterocyclyl having 5 or 6 ring members and 1 to 3 nitrogen, sulphur and/or oxygen hetero atoms including, for example, condensed heterocyclyl, such as for example benzthiazolyl. Heterocyclyl includes further unsubstituted hetercyclyl and substituted heterocyclyl, for example by oxo, alkoxy, hydroxy, thiono, mercapto, alkylthio, imino, alkylamino, alkylimino, amino, halogen, acyl, CF 3 , CHO, alkyl, cycloalkyl. Carbamoyl includes the carbamoyl group or carbamoyl having alkyl and aryl residues. The intermediate compounds of the present invention are particularly useful in the preparation of a compound of formula wherein W denotes CH or N V denotes CH or N-O R 1 denotes hydrogen or an ester moiety; An ester moiety includes alkyl, preferably (C 1-6 )alkyl; arylalkyl, for example benzyl, alkoxybenzyl, such as 4-methoxybenzyl; indanyl, phthalidyl, alkoxymethyl, e.g. methoxymethyl; (C 1-6 )alkanoyloxy(C 1-6 )alkyl, (C 1-6 )alkoxycarbonyl-oxy(C 1-6 )alkyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl and ester moieties which form with the COO- group a physiologically hydrolysable and acceptable ester, e.g. such known to be hydrolysable ester groups in the field of cephalosporins; A compound of formula I may thus be in the form of an physiologically-hydrolysable and -acceptable ester. By physiologically-hydrolysable and -acceptable esters as used herein is meant an ester in which the COO- group is esterified and which is hydrolysable under physiological conditions to yield an acid which is itself physilogically tolerable at dosages to be administered; The term is thus to be understood as defining regular pro-drug forms. An ester moiety may be preferably a group which is easily hydrolysable under physiological conditions; Such esters may be administered preferably orally. Parenteral administration may be indicated if the ester per se is an active compound or, if hydrolysis occurs in the blood; R 2 denotes a group of formula wherein R 4 denotes hydrogen, phenyl, cycloalkyl or lower alkyl R 5 denotes hydrogen, lower alkyl, heterocyclyl or a group of formulae wherein R 7 denotes lower alkyl R 8 denotes hydrogen, cycloalkyl or lower alkyl R 9 denotes hydrogen or lower alkyl, R 10 denotes hydrogen, hydroxy; amino; phenyl; alkenyl; cycloalkyl; heterocyclyl; unsubstituted alkyl; substituted alkyl, by CF 3 , OH, alkoxy, carboxyl, halogen, amino, monoalkylamino, dialkylamino, trialkylamino, pyridyl or a a sulfonic acid residue; a group of formula wherein R 12 denotes hydrogen or lower alkyl, Z denotes oxygen, sulphur, or N-R 13 , wherein R 13 denotes hydrogen or lower alkyl, and R 11 denotes hydrogen; dihydroxyphenyl; cycloalkyl; heterocyclyl; unsubstituted lower alkyl; substituted lower alkyl by pyridyl or monoalkylamino, dialkylamino or trialkylamino; and, R 4 and R 5 and/or R 9 and R 10 independently of one another together with the nitrogen denote heterocyclyl, R 3 denotes hydrogen; acyl; carboxyl; unsubstituted alkyl; substituted alkyl by halogen or carboxyl. The configuration of R 3 in group of - C = V - R 3 may be syn [(Z)] and anti [(E)] and is preferably syn [(Z)]. A compound of formulae IA, IVa and VIa may exist in equilibrium with tautomeric forms. The present invention includes a compound of formulae IA, IVa and VIa in any tautomeric form in which it may exists. Compounds of the present invention may be used in a process for the production of a compound of formula IA by reaction of a compound of formula wherein W, V and R 3 have the same meaning as in formula IA, and a) either α) R b denotes hydroxy and R c and R d together form a bond, or β) R d denotes hydrogen, a cation, an ester forming group or a silyl group, and R b and R c together denote oxo, in free form or in form of an acid addition salt with a group of formula wherein R y , R x and R z are as defined above, or b) reacting a compound of formula wherein R 1 and R xx are as defined in formula IA above, with a compound of formula wherein V, W and R 3 are as defined in formula IA and X' denotes a leaving group. If desired reactive groups may be protected with protecting groups, which may be, or, which are split off under the reaction conditions, or after termination of the reaction described above. A compound of formula IA wherein R 1 denotes hydrogen may be converted into a compound of formula IA, wherein R 1 denotes an carboxylic acid ester group. A compound of formula IA may be isolated from the reaction mixture in conventional manner. Process a) may be carried out as follows: A compound of formula III in a solvent which is inert under the reaction conditions, such as water, a mixture of water and a lower alcohol and/or dioxane, or a dipolar aprotic solvent, for example dimethylformamide or dimethylsulfoxide, optionally mixed with an alcohol or water is reacted with a compound of formula IVa at a temperature of about -20 to 50° C. An optimal pH may be adjusted by addition of an inorganic or organic acid or base. A compound of formula IA thus obtained may be isolated in conventional manner, for example by addition of an anti-solvent or by chromatographic techniques. Process b) may be carried out as follows: The reaction may be carried out as conventional, e.g. a compound of formula VIa may be reacted with a compound of formula VII in a solvent, for example dissolved or suspended in a mixture of acetone/water, for example at room temperature. A reactive group may be protected, preferably by silyl protecting group technology. Suitable solvents include solvents which are inert under the reaction conditions, such as chlorinated hydrocarbons, nitriles, such as acetonitrile, ethers, such as tetrahydrofuran or a mixture of such solvents. Further suitable solvents include dipolar aprotic solvents, e.g. N,N-dimethylformamide. Protecting groups may be split off in conventional manner. A starting compound of formula II may, for example, be obtained by a) reaction of a compound of formula wherein either α) R a denotes a salt of -NH 2 with an inorganic or organic acid, R' b denotes hydroxy, and R' c and R' d denote together a bond, or β) R a denotes NH 2 , R' d denotes hydrogen and R' b and R' c together denote oxo, with a silylation agent and, a compound obtained in step a) of formula wherein Sil denotes a silyl group and either α) R'' b denotes -OSil and R'' c and R" d together denote a bond β) R'' d denotes Sil and R'' b and R'' c together denote oxo is acylated either directly in the reaction mixture or after isolation from the reaction mixture. Acylation may be carried out in conventional manner. A compound of formula IIIc may be obtained a) for the production of a compound of formula which is an the form of a salt of an inorganic or organic acid and wherein R''' b denotes hydroxy and R''' c and R''' d together denote a bond, reacting a salt of an inorganic or organic acid of a compound of formula wherein R 14 and R 15 are the same or different and each denote hydrogen or an organic residue in an organic solvent optionally in the presence of water with ozone b) for the production of a compound of formula treating a compound of formula IIIe wherein R''' b , R''' c and R''' d ar as defined above, with a base. Compounds of formulae IVa are new and may be obtained analogously to conventional methods, or, as described in the examples. In this specification unless otherwise indicated terms such as "compound of formula IA, IVa and VIa" embrace the compound in any form, for example in salt form and free base form. The present invention thus includes a compound in free or base form or, where such forms exist, in salt form, for example in form of an acid addition salt, inner salt, quaternary salt and/or in solvate, for example hydrate form thereof. A salt may be a pharmaceutically acceptable salt of a compound of formulae IA such as a metal salt or an amine salt. Metal salts include for example sodium, potassium, calcium, barium, zinc, aluminum salts, preferably sodium or potassium salts. Amine salts include for example trialkylamine, procaine, dibenzylamine and benzylamine salts. A free form of a compound of formulae IA, IVa and VIa may be converted into a salt form and vice versa. In a further aspect the present invention provides a compound of formulae IA, IVa and VIa in free form; or in salt form, for example in acid addition salt form or in metal salt form; and a compound of formulae IA, IVa and VIa in solvate form. The compounds of formula IA, hereinafter designated as "active compound(s)" exhibits pharmacological activity and are therefore useful as pharmaceuticals. In particular, the active compounds show antimicrobial, e.g. antibacterial, activity against gram negative and gram positive bacteria such as Pseudomonas, e.g. Pseudomonas aeruginosa, Pseudomonas fluorescens; Enterobacter, e.g. Enterobacter cloacae; Enterococcus, e.g. Enterococcus faecalis; Moraxella, e.g. Moraxella catarrhalis; Haemophilus, e.g. Haemophilus influenza; Klebsiella, e.g. Klebsiella edwardsii, Klebsiella pneumoniae; Streptococcus, e.g. Streptococcus pneumoniae, Streptococcus durans, Streptococcus faecium, Streptococcus pyogenes; Staphylococcus, e.g. Staphylococcus aureus, Staphylococcus pyogenes; Escherichia, e.g. Escherichia coli; and Proteus, e.g. Proteus mirabilis in vitro in the Agar Dilution Test according to National Commitee for Clinical Laboratory Standards (NCCLS) 1993, Document M7-A3Vol.13, No. 25: "Methods for dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically - Third Edition, Approved Standard" and in vivo in the septikaemic mouse model. The active compounds show activity in the mouse when administerd at dosages from about 0.05 to 50 mg/kg body weight (ED 50 values).The active compounds show an MHK(µg/ml) in the Agar Dilution Test from about 0.005 to ca. 50. The active compounds show an surprising overall activity spectrum. The active compounds of formula IA are therefore useful for the treatment of microbial, e.g. bacterial diseases. The compounds of formula IA may be administered in pharmaceutically acceptable salt form, e.g. acid addition salt form or base addition salt form or in the corresponding free forms, optionally in solvate form. Such salts exhibit the same order of activity as the free forms. In the following Examples the temperatures indicated are in degree Celsius. Example 1 Dihydrochloride of 7-[(2-Amino-4-thiazolyl)-(Z)-(methoxyimino)acetyl]amino-3-[[(aminoimino-methyl)hydrazono]methyl]-3-cephem-4-carboxylic acid (Process a) 1.24 g of the hydrogen carbonate of aminoguanidine are dissolved in 9.15 ml of 2 N HCl and added under stirring to a solution of 3.2 g of the trifluoroacetate of N-(1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]-thiazin-6-yl)-2-(2-aminothiazol-4yl)-(Z)-2-methoxyimino acetic acid amide in 125 ml of 4% aqueous acetonitrile. After ca. 90 minutes the precipitated dihydrochloride of 7-[(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino-3-[[(aminoimino-methyl)-hydrazono]methyl]-3-cephem-4-carboxylic acid is filtered off, washed with acetonitrile and dried. Example 2 Dihydrochloride of 7-[[(2-Amino-4-thiazolyl)-(Z)-(hydroxyimino)acetyl]amino]-3-[[(amino-iminomethyl)hydrazono]methyl]-3-cephem-4-carboxylic acid (Process a) a) 10 g of the hydrochloride of N-(1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]-thiazin-6-yl)-2-(2-aminothiazol-4-yl)-(Z)-2-(acetoxyimino)-acetic acid amide are suspended in 160 ml of acetonitrile and treated with 53 ml of water and 11 ml of 8 N HCl. The reaction mixture is stirred for ca. 14 hours at room temperature. A clear solution is obtained in which the acetoxyimino group being hydrolyzed to give the hydroxyimino group. b) 3 g of the hydrogen carbonate of aminoguanidine are dissolved in 11 ml of 1 N HCl and added dropwise to the solution obtained in step a) which is cooled to 0°. After ca. 30 minutes the reaction mixture is warmed to room temperature and stirred for ca. another 2.5 hours. The dihydrochloride of 7-[[(2-Amino-4-thiazolyl)-(Z)-(hydroxyimino)acetyl]amino]-3-[[(amino-iminomethyl)hydrazono]methyl]-3-cephem-4-carboxylic acid precipitate, is filtered off, washed with a mixture of acetonitrile and water, acetonitrile and with ether and dried. Example 3 Sodium salt of 7-[(2-Amino-4-thiazolyl)(methoxyimino)acetyl)amino-3-[(methoxyimino)methyl]-3-cephem-4-carboxylic acid (Process b) 0.5 g of 7-amino-3-[(methoxyimino)methyl]-3-cephem-4-carboxylic acid and 0.75 g of (2-amino-4-thiazolyl)(methoxyimino)acetic acid mercaptobenzthiazolyl ester are suspended in a mixture of 2.4 ml of water and 4.8 ml of acetone. Ca. 1.8 ml of 2N sodium hydroxide solution are added dropwise in such a way that a pH of 8.0 is kept. The reaction mixture is stirred at 20° for ca. I hour. 2.4 ml of acetone are added dropwise. A clear solution is obtained within 3 hours. 120 ml of acetone are slowly added. A suspension is obtained which is cooled to 0°. After ca. 5 hours the precipitate formed is filtered off and redissolved in 4 ml of water. The clear solution is treated with 0.2 g of active charcoal and stirred for ca. 15 minutes. Active charcoal is filtered off and 100 ml of acetone are added within ca. 1 hour at 0°. The sodium salt of 7-[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino-3-[(methoxy-imino)methyl]-3-cephem-4-carboxylic acid is obtained in form of colourless crystals, which are filtered off, washed with ca. 5 ml of acetone and dried. The compounds of the following TABLE 1 of formula IA (V is =N-O- in all of the Examples; and W is CH in Examples 4 to 68 and 70 to 138; and W is N in Examples 69 and 139 of TABLE 1) may be obtained in analogous manner to that described in Examples 1 to 3. Salt forms are exemplified. The configuration of R 3 in group - C = N - R 3 is syn [(Z)]. Example 148 Dihydrocbloride of 7-[[(2-amino-4 thiazolyl)-(Z)-[(carboxymethoxy)imino]actyl]-amino]-3-[[(aminoiminomethyl)hydrazono]methyl]-3-cephem-4-carboxylic acid (Compound of Example 5) a) Dihydrochloride of 7-Amino-3-[[(aminoiminomethyl)hydrazono]methyl]-3-cephem-4-carboxylic acid To 1.0 g of 7-amino-3-formyl-3-cephem-4-carboxylic acid in a mixture of 50 ml of acetonitrile and 5 ml of 2N HCl are added dropwise 0.6 g of the hydrogen carbonate of aminoguanidine, dissolved in 2.2 ml of 2N HCl. The dihydrochloride of 7-amino-3-[[(aminoiminomethyl)hydrazono]methyl]-3-cephem-4-carboxylic acid precipitates, is filtered off, washed with acetonitrile and dried. b) Hydrochloride of 7-[[(2-amino-4-thiazolyl)-(Z)-[[2-(1,1-dimethylethoxy)-2-oxoetoxy]imino]acetyl]amino]-3-[[(aminoiminomethyl)hydrazono]methyl]-3-cephem-4-carboxylic acid 4 g of the dihydrochloride of 7-amino-3-[[(aminoiminomethyl)hydrazono)methyl]-3-cephem-4-carboxylic acid are dissolved in 80 ml of methanol. The solution is cooled to 0° and treated with a solution of 7 g of (2-amino-4-thiazolyl)-(Z)-[2-(1,1-dimethylethoxy)-2-oxoethoxy]imino]thioacetic acid S-benzothiazol ester in 50 ml of methylene chloride. The reaction mixture is stirred for about 2.5 hours at 20°. About a third of the solvent is evaporated off and 120 ml of ether are added to the residue. The hydrochloride of 7-[[(2-amino-4-thiazolyl)-(Z)-[[2-(1,1-dimethylethoxy)-2-oxoetoxy]imino]-acetyl]amino]-3-[[(aminoiminomethyl)hydrazano]methyl]-3-cephem-4-carboxylic acid precipitates, is filtered off, washed with ether and dried. c) Dihydrochloride of 7-[[(2-amino-4 thiazolyl)-(Z)-[(carboxymethoxy)imino]actyl]-amino]-3-[[(aminoiminomethyl)hydrazono]methyl]-3-cephem-4-carboxylic acid 3.5 g of the hydrochloride of 7-[[(2-amino-4-thiazolyl)-(Z)-[[2-(1,1-dimethylethoxy)-2-oxoetoxy]imino]acetyl]amino]-3-[[(aminoiminomethyl)hydrazono]methyl]-3-cephem-4-carboxylic acid are dissolved in 20 ml of trifluoroacetic acid at 0°. The solution is stirred for ca. 15 minutes at 0° and for ca. 1 hour at 20°. The reaction mixture is treated with 40 ml of ether. A precipitate forms, is filtered off, washed with ether, dried, dissolved in 15 ml of 2N HCl and stirred for ca. 1 hour at 20°. A light brownish precipitate of the dihydrochloride of 7-[[(2-amino-4 thiazolyl)-(Z)-[(carboxy-methoxy)imino]actyl]-amino]-3-[[(aminoiminomethyl)hydrazono]methyl]-3-cephem-4-carboxylic acid is obtained, filtered off and dried. The compounds of Examples 1 to 146 may be obtained as described in Example 148 using the appropriate starting material. Compounds used as starting material may be prepared as follows: Example H) Dihydrochloride of 1-(hydrazinoiminomethyl)piperazine a) Hydroiodide of 4-formyl-1-[imino(methylthio)methyl]piperazine 25.5 g of 4-formyl-1-piperazinecarbothioamide are suspended in 80 ml of methanol, treated with 22 g of methyliodide and refluxed. Within ca.10 minutes a clear solution is obtained. The mixture is cooled to room temperature. The solvent is evaporated. Crystalline hydroiodide of 4-formyl-1-[imino(methylthio)methyl]piperazine is obtained. b) Hydrochloride of 4-formyl-1-(hydrazinoiminomethyl)piperazine 48.1 g of the hydroiodide of 4-formyl-1-[imino(methylthio)methyl]piperazine are dissolved in 100 ml of water, run through a column filled with 800 ml of a strong basic ion exchanger in chloride form and eluated with 850 ml of water. The solvent is evaporated to obtain a volume of ca. 100 ml which is treated with 7.35 g of hydrazinehydrate. The reaction mixture is stirred for ca. 1 hour at room temperature and the solvent is evaporated off. The oily hydrochloride of 4-formyl-1-(hydrazinoiminomethyl)piperazine crystallizes on drying. c) Dihydrochloride of 1-(hydrazinoiminomethyl)piperazine 11 g of the hydrochloride of 4-formyl-1-(hydrazinoiminomethyl)piperazine are dissolved in 400 ml of methanol and treated with 50 of HCl conc. . The reaction mixture is stirred for ca. 14 hours at room temperature. A white precipitate forms, is filtered off, washed with methanol and ether, dried and recrystallized with water/ethanol. The dihydrochloride of 1-(hydrazinoiminomethyl)-piperazine is obtained in crystalline, colourless form. Analogous in the manner as described in Example H) compounds of formula IV of TABLE 2 may be obtained: Example Q) Hydrochloride of 1,1-dimethyl-4-(hydrazinoiminomethyl)piperaziniumchloride a) Hydroiodide of 1,1-dimethyl-4-[imino(methylthio)methyl]piperaziniumiodide 3.2 g of 4-methyl-1-piperazinecarbothioamide are suspended in 100 ml of methanol. 6.2 g of methyliodide are added and the mixture is refluxed for ca. 2 hours and cooled to 20° ab. The hydroiodide of 1,1-dimethyl-4-[imino(methylthio)methyl]piperaziniumiodide precipitates, is filtered off and dried. b) Hydrochloride of 1,1-dimethyl-4-(hydrazinoiminomethyl)piperaziniumchloride 6.57 g of the hydroiodide of 1,1-dimethyl-4-[imino(methylthio)methyl]piperaziniumiodide are dissolved in 70 ml of water, run through a column filled with 150 ml of a strong basic ion exchanger in chloride form and eluated with 250 ml of water. Water is evaporated off the eluate to obtain to a volume of ca. 50 ml, which is treated with 0.9 ml of hydrazinehydrate and stirred overnight. The solvent is evaporated off and the residue obtained is treated with n-hexane. The hydrochloride of 1,1-dimethyl-4-(hydrazinoiminomethyl)piperaziniumchloride is obtained. Example R) Trihydrochloride of 1-[hydrazino(methylimino)methyl]piperazine a) Hydrochloride of S-methyl-2-methylisothiosemicarbazide A solution of 239.8 g of the hydroiodide of S-Methyl-2-methylisothiosemicarbazide in 100 ml of water is run through a column filled with 1500 ml of a strong basic ion exchanger in chloride form and eluated with water. The eluate is lyophilized and the lyophilization residue is treated with ether. The precipitate is filtered off and dried. The hydrochloride of S-methyl-2-methylisothiosemicarbazide is obtained as a white solid. Melting point: 116° b) Hydrochloride of 4-formyl-1-[hydrazino(methylimino)methyl]piperazine A mixture of 20 g of freshly distilled formylpiperazine and 27.3 g of the hydrochloride of S-methyl-2-methylisothiosemicarbazide in 250 ml of ethanol is refluxed overnight and the solvent is evaporated. The oily residue is dissolved in 70 ml of hot isopropanol and the solution is slowly cooled to 20°. A precipitate forms and the mixture is allowed to stand for ca. 2 hours at 4°. The hydrochloride of 4-formyl-1-[hydrazino(methylimino)methyl]piperazine is filtered off and recrystallized from isopropanol. c) Trihydrochloride of 1-[hydrazino(methylimino)methyl]piperazine 10 g of the hydrochloride of 1-formyl-4-[hydrazino(methylimino)methyl]piperazine are dissolved in 250 ml of methanol. 50 ml of HCl conc. are added, the mixture obtained is stirred overnight and the solvent is evaporated. A solid residue is obtained which is dried over solid KOH. The trihydrochloride of 1-[hydrazino(methylimino)methyl]piperazine is obtained in form of a white product. In analogous manner as described in Example R) but reacting the hydrochloride of S-methyl-isothiosemicarbazide or the hydrochloride of S-methyl-2-methylisothiosemicarbazide or the hydrochloride of S-methyl-4-methylisothiosemicarbazide with a corresponding amine compounds of formula IV of TABLE 3 may be obtained. Example W) Hydrochloride of 1-Amino-3-(3,4-dibydroxybenzylidenamino)guanidine 1 g of the hydrochloride of diaminoguanidine are dissolved in 10 ml of 4 N HCl and diluted with 20 ml of methanol. This solution is treated quickly with a solution of 1 g of 3,4-dihydroxybenzaldehyde in 40 ml of methanol. The reaction mixture is stirred for some minutes at room temperature and the solvent is evaporated off. The residue is suspended in 50 ml of acetonitrile. The precipitate formed is filtered off and dried. The hydrochloride of 1-amino-3-(3,4-dihydroxybenzylidenamino)-guanidine is obtained. Example X) Hydroiodide of S-Methyl-4-cyclopropylthiosemicarbazide 295 mg of 4-cyclopropylthiosemicarbazide are dissolved in 5 ml of dry methanol and treated with 154 ml of methyliodide. The mixture is stirred at 40° under nitrogen for ca. 5 hours, cooled and treated with diethylether. A colourless precipitate of the hydroiodide of S-Methyl-4-cyclopropylthiosemicarbazide is formed, filtered off, washed with diethylether and dried. Example Y) Hydroiodide of S-methyl-4-n-butylthiosemicarbazide 147 mg of 4-n-butylthiosemicarbazide in 2,5 ml of dry methanol are treated with 149 mg of methyliodide. The mixture is stirred under nitrogen for ca. 5 hours, cooled and treated with diethylether. A colourless precipitate of the hydroiodide of S-methyl-4-n-butylthiosemicarbazide is formed, filtered off, washed with diethylether and dried. Example Z) 1-Methyl-5-mercapto-1,2,4-triazol-3-carboxylic acid hydrazide 0.48 g of 1-methyl-5-mercapto-1,2,4-triazol-3-carboxylic acid methyl ester are dissolved in 10 ml of methanol, treated with 450 µl of hydrazinehydrate and stirred for ca. 2 hours at 20°. A precipitate of 1-methyl-5-mercapto-1,2,4-triazol-3-carboxylic acid hydrazide is formed, filtered off, washed with methanol and dried. IR (KBr): 1669 cm -1 , 1608 cm -1 , 1517 cm -1 13 C-NMR (300 MHz, DMSO-d 6 ): 35.4 (NCH 3 ); 143.3, 154.3 and 166.7 Example AA) Hydroiodide of 1,5-dimethyl-2-(hydrazinoiminomethyl)pyrrol a) 1,5-Dimethylpyrrol-2-carbothioamide 5 g of 2-cyano-1,5-dimethylpyrrol are dissolved in 40 ml of ethanol and treated with 10 ml of triethylamine. 50 ml of an ethanolic H 2 S solution (3.8 g/100 ml) are added and the mixture is heated for ca. 15 hours in an autoclave at 70°. The reaction mixture is cooled and the solvent is evaporated off to obtain ca. a quarter of its volume. 1,5-dimethylpyrrol-2-carbothioamide crystallizes upon cooling at 0° in the form of a light yellow precipitate. b) Hydroiodide of 1,5-dimethyl-2-[imino(methylthio)methyl]pyrrol 1 g of 1,5-dimethylpyrrol-2-carbothioamide are dissolved in 20 ml of methanol and treated with 1.7 g of methyliodide. The reaction mixture is stirred for about 5 hours at room temperature. The solvent is evaporated until crystallization starts. The residue is cooled to ca. 0°. The crystalline hydroiodide of 1,5-dimethyl-2-[imino(methylthio)methyl]pyrrol is filtered off, washed with methanol and dried. c) Hydroiodide of 1,5-dimethyl-2-(hydrazinoiminomethyl)pyrrol 1.3 g of the hydroiodide of 1,5-dimethyl-2-[imino(methylthio)methyl]pyrrol are dissolved in 20 ml of methanol. 0.28 g of hydrazinehydrate are added. The reaction mixture is stirred for ca. 3 hours, the solvent is evaporated off and the residue is recrystallized from acetonitrile/ether. The hydroiodide of 1,5-dimethyl-2-(hydrazinoiminomethyl)pyrrol is obtained. Example AB) Hydroiodide of 3,4-dihydroxy-2-(hydrazinoiminomethyl)benzene is obtained in analogous manner as described in Example AA), but using 3,4-dihydroxy-thiobenzamide instead of 1,5-dimethylpyrrol-2-carbothioamide. 1 H-NMR-Spectra of the compounds obtained according to the Examples (Ex.) Ex. Spectrum 1 (300 MHz, CD 3 OD): 8.43 (s, 1H, CH=N); 6.96 (s, 1H, CH); 5.99 (d, J=4.9 Hz, 1H, CH); 5.22 (d, J=4.9 Hz, 1H, CH); 4.04 (s, 3H, OCH 3 ); 3.99 and 3.56 (AB quartet, J=17.8 Hz, 2H, SCH 2 ). 2 (90 MHz, DMSO-d 6 + D 2 O): 3.6 and 4.3 (AB quartet, J=18 Hz, 2H, SCH 2 ); 5.3 (d, J=5.1 Hz, 1H, β-lactam-H); 5.95 (d, J=5.1 Hz, 1H, β-lactam-H); 6,95 (s, 1H, thiazolyl-H); 8.35 (s, 1H, CH=N). 3 (300 MHz, CD 3 OD): 7.97 (s, 1H, CH=N); 6.84 (s, 1H, CH); 5.69 (d, J=4.9 Hz, 1H, CH); 5.13 (d, J=4.9 Hz, 1H, CH); 4.13 and 3.93 (AB quartet, J=16.8 Hz, 2H, SCH 2 ), 3.81 (s, 3H, OCH 3 ); 3.67 (s, 3H, OCH 3 ). 32 (90 MHz, DMSO-d 6 ) : 2.85 (s, 2 H); 3.55 and 4.6 (AB quartet, J = 18 Hz, 2H, SCH 2 ); 3.95 (s, 3 H, O-CH 3 ); 5.3 (d, J = 5 Hz, 1 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 6.95 (s, 1 H, thiazolyl-H); 8.65 (s, 1 H, CH=N); 9.9 (d, J = 8 Hz, NH). 35 (90 MHz, DMSO-d 6 ): 0.4 to 1 (m, 4 H, -CH 2 -CH 2 -); 2.5 to 2.8 (m, 1 H), 3.55 and 4.6 (AB quartet, J = 18 Hz, 2H, SCH 2 ); 3.95 (s, 3 H, O-CH 3 ); 5.3 (d, J = 5 Hz, I H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8=Hz, β-lactam-H); 6.9 (s, 1 H, thiazolyl-H); 8.35 (s, 1 H, CH=N); 9.85 (d, J = 8 Hz, NH). 52 (90 MHz, DMSO-d 6 ): 3.7 (s, 3 H, N-CH 3 ); 3.65 and 4.1 (AB quartet, J = 18 Hz, 2H, SCH 2 ); 3.95 (s, 3 H, O-CH 3 ); 5.35 (d, J = 5 Hz, 1 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 7.0 (s, 1 H, thiazolyl-H); 8.75 (s, 1 H, CH=N); 9.9 (d, J = 8 Hz, NH). 62 (300 MHz, DMSO-d 6 ): 3.13 (broad duplet, 3 H, N-CH 3 ); 3.29 (broad s, 6 H, N + (CH 3 ) 2 ); 3.4 to 3.75 (m, 5 H, -CH 2 -N + -CH 2 - and 1H of SCH 2 ); 3.85 (s, 3 H, O-CH 3 ); 4 to 4.3 (m, 4 H, -CH 2 -N-CH 2 -); 4.65 (part of the AB quartet, J = 18 Hz, 1H of SCH 2 ); 5.27 (d, J = 5 Hz, 1 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 7.6 Hz, β-lactam-H); 6.78 (s, 1H, thiazolyl-H); 8.75 (s, 1H, CH=N); 9.75 (d, J = 7.6 Hz, NH). 66 (90 MHz, DMSO-d 6 ): 3.2 (broad singulet, 3 H, N-CH 3 ); 3.0 to 3.4 (m, 4 H, -CH 2 -N-CH 2 ); 3.4 to 3.8 (m, 5 H, -CH 2 -NH + -CH 2 - and 1H of SCH 2 ); 3.95 (s, 3 H, O-CH 3 ); 4.3 (part of the AB quartet, J = 18 Hz, 1H of SCH 2 ); 5.35 (d, J = 5 Hz, 1 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 7.0 (s, 1 H, thiazolyl-H); 8.15 (s, 1 H, CH=N); 9.9 (d, J = 8 Hz, NH). 67 (90 MHz, DMSO-d 6 ): 3.3 (s, 3 H, N-CH 3 ); 3.3 (broad s, 6 H, N+(CH 3 ) 2 ); 3.3 to 3.7 (m, 9H, piperazinyl-H's and 1H of SCH 2 ); 3.85 (s, 3 H, OCH 3 ); 4.25 (part of the AB quartet, J = 18 Hz, 1H of SCH 2 ); 5.25 (d, J = 5 Hz, 1 H, β-lactam-H); 5.8 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 6.8 (s, 1 H, thiazolyl-H); 8.1 (s, 1 H, formyl-H); 8.15 (s, 1 H, CH=N); 9.75 (d, J = 8 Hz, NH). 68 (90 MHz, DMSO-d 6 ): 2.25 (s, 3 H); 3.65 (s, 3 H, N-CH 3 ); 3.7 and 4.6 (AB quartet, J = 18 Hz, 2H, SCH 2 ); 3.9 (s, 3 H, O-CH 3 ); 5.3 (d, J = 5 Hz, 1 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 6.05 (d, J = 4 Hz, pyrrol-H); 6.85 (d, J = 4 Hz, pyrrol-H); 6.9 (s, 1 H, thiazolyl-H); 8.75 (s, 1 H, CH=N); 9.9 (d, J = 8 Hz, NH). 80 (300 MHz, DMSO-d 6 ): 2.75 (s, 2H, N-CH 2 ); 3.55 and 4.54 (AB quartet, J=18.1 Hz, 2H, S-CH 2 ); 5.32 (d, J=5.1 Hz, 1H, β-lactam-H); 5.93 (dd, J=5.1 and 7.9 Hz, 1H, β-lactam-H); 6.79 (s, 1H, CH thiazol); 8.59 (s, 1H, CH=N); 9.73 (d, J=8.0 Hz, 1H, NH); 12.13 (s, 1H, OH). 82 (300 MHz, DMSO-d 6 ): 0.64 (m, 2H, cyclopr. CH 2 ); 0.83 (m, 2H, cyclopr. CH 2 ); 2.62 (m, 1H, cyclopr. CH); 3.53 and 4.49 (AB quartet, J=18.1 Hz, 2H, S-CH 2 ); 5.29 (d, J=5.0 Hz, 1H, β-lactam-H); 5.89 (dd, J=5.0 and 8.0 Hz, 1H, β-lactam-H); 6.79 (s, 1H, CH thiazol); 8.09 (s, 2H, NH); 8.35 (s, 1H, CH=N); 8.59 (s, 1H, NH); 9.70 (d, J=8.0 Hz, 1H, NH); 12.08 (s, 1H, OH); 12.13 (s, 1H, OH). 105 (300 MHz, DMSO-d 6 ): 0.64 (m broad 2H, CH 2 ); 0.84 (m broad 2H, CH 2 ); 1.50 (s, 3H, C-CH 3 ); 1.52 (s, 3H, C-CH 3 ); 2.61 (m broad 1H, N-CH); 3.53 and 4.53 (AB quartet, J=18.2 Hz, 2H, S-CH 2 ); 5.31 (d, J=5.0 Hz, 1H, β-lactam-H); 5.96 (dd, J=5.0 and 8.2 Hz, 1H, β-lactam-H); 6.90 (s, 1 H, CH thiazol); 8.10 (s broad 2H, NH); 8.34 (s, 1H, CH=N); 8.60 (s broad 1H, NH); 9.70 (d, J=8.2 Hz, 1H, NH); 12.08 (s, 1H, OH). 109 (300 MHz, DMSO-d 6 ): 0.64 (m broad 2H, CH 2 cyclopr); 0.84 (m broad 2H, CH 2 cyclopr); 2.62 (m broad 1H, N-CH cyclopr); 3.54 and 4.51 (AB quartet, J=18.1 Hz, 2H; S-CH 2 ); 4:66 (s, 2H, O-CH 2 ); 5.30 (d, J=5.0 Hz, 1H, β-lactam-H); 5.93 (dd, J=5.0 and 8.1 Hz, 1H, β-lactam-H); 6.93 (s, 1H, CH thiazol); 8.09 (broad 2H, NH); 8.35 (s, 1H, CH=N); 8.58 (broad, 1H, NH); 9.77 (d, J=8.0 Hz, 1H, NH); 12.04 (s, 1H, OH). 121 (300 MHz, DMSO-d 6 ): 3.22 (s, 6H, N-CH 3 ); 3.54 and 4.55 (AB quartet, J=18.5 Hz, 2H, S-CH 2 ); 3.6 (broad, 4H, N-CH 2 ); 4.0 (broad, 4H, N-CH 2 ); 5.30 (d, J=5.0 Hz, 1H, β-lactam-H); 5.91 (dd, J=5.0 and 7.9 Hz, 1H, β-lactam-H); 6.82 (s, 1H, CH thiazol); 8.73 (s, 1H, CH=N); 9.75 (d, J=7.6 Hz, 1H, NH); 12.30 (s, 1H, OH); 12.76 (s, 1H, OH). 122 (300 MHz, DMSO-d 6 ): 2.76 (s, 3H, N-CH 3 ); 3.1-3.3 (broad, 2H, N-CH 2 ); 3.4-3.6 (broad, 2H, N-CH 2 ); 3.5-3.7 (broad, 2H, N-CH 2 ); 3.55 and 4.53 (AB quartet, J=18.1 Hz, 2H, S-CH 2 ); 4.2-4.4 (broad, 2H, N-CH 2 ); 5.31 (d, J=5.0 Hz, 1H, β-lactam-H); 5.90 (dd, J=5.0 and 7.8 Hz, 1H, β-lactam-H); 6.82 (s, 1H, CH thiazol); 8.66 (s, 1H, CH=N); 9.77 (d, J=7.8 Hz, 1H, NH); 11.74 (s, 1H, NH); 12.36 (s, 1H, OH); 12.56 (s, 1H, OH). 123 (300 MHz, DMSO-d 6 ): 2.90 (d, J=4.7 Hz 3H, N-CH 3 ); 3.34 (s, 3H, N-CH 3 ); 3.55 and 4.59 (AB quartet, J=18.1 Hz, 2H, S-CH 2 ); 5.30 (d, J=5.0 Hz, 1H, β-lactam-H); 5.91 (dd, J=5.0 and 7.9 Hz, 1H, β-lactam-H); 6.81 (s, 1H, CH thiazol); 8.09 (s, 1H, CH=N); 8.25 (s, 2H, NH); 8.37 (s, 1 H, NH); 9.72 (d, J=7.9 Hz, 1H, NH); 12.14 (s, 1H, OH). 126 (300 MHz, DMSO-d 6 ): 3.60 and 4.56 (AB quartet, J=18.1 Hz, 2H, S-CH 2 ); 5.32 (d, J=5.0 Hz, 1H, β-lactam-H); 5.92 (dd, J=5.0 and 7.9 Hz, 1H, β-lactam-H); 6.83 (s, 1H, CH thiazol); 6.8-6.9 (m, 1H, CH aromatic); 7.1-7.2 (m, 1H, CH aromatic); 7.3-7.4 (m, 1H, CH aromatic); 8.23 (s, 1H, CH=N); 8.37 ( 2H, NH/OH); 8.51 (s, 1H, CH=N); 9.78 (d, J=7.9 Hz, 1H, NH); 12.27 (s, 1H, OH). 128 (300 MHz, DMSO-d 6 ): 3.25 (broad, 4H, N-CH 2 ); 3.31 (s, 3H, N-CH 2 ); 3.62 and 4.27 (AB quartet, J=18.0 Hz, 2H, S-CH 2 ); 3.74 (broad, 4H, N-CH 2 ); 5.30 (d, J=5.0 Hz, 1H, β-lactam-H); 5.89 (dd, J=4.9 and 7.9 Hz, 1H, β-lactam-H); 6.79 (s, 1H, CH thiazol); 8.11 (s, 1H, CH=N); 9.03 (broad, 1H, NH); 9.31 (broad, 1H, NH); 9.67 (d, J=7.9 Hz, 1H, NH); 9.87 (s, 2H, NH); 12.07 (s, 1H, OH). 131 (300 MHz, D 2 O): 0,74 (m, 2H); 0,88 (m, 2H); 2,58 and 2,38 (two singulets, 3H, SCH 3 ); 2,68 (m, 1H); 3,45 and 3,94 (AB-system, broad, 2H, SCH 2 ); 3,95 (s, 3H, O-CH 3 ); 5,23 (d, J=4,7 Hz, 1H, β-lactam-H); 5,75 (d, J=4,7 Hz, 1H, β-lactam-H); 7,03 (s, 1H, thiazolyl-H); 8,36 (s, broad, 1H, CH=N). H) a) (300 MHz, DMSO-d 6 ): 2.7 (s, 3H, S-CH 3 ); 3.5-3.6 (m, 4H, N-CH 2 ); 3.7-3.8 (m, 2H, N-CH 2 ); 3.8-3.9 (m, 2H, N-CH 2 ); 8.1 (s, 1H, CH=O); 9.6 (broad, 2H, NH). H) b) (300 MHz, DMSO-d 6 ): 3.42 (s, 4H, N-CH 2 ); 3.4-3.6 (m, 4H, N-CH 2 ); 4.8 (broad, 2H, NH); 7.9 (broad, 2H, NH); 8.1 (s, 1H, CH=O); 9.5 (broad, 1H, NH). H) c) (300 MHz, DMSO-d 6 ): 3.1-3.2 (s, 4H, N-CH 2 ); 3.7-3.8 (m, 4H, N-CH 2 ); 4.8 (broad, 2H, NH); 8.0 (broad, 2H, NH); 9.6 (broad, 1H, NH); 10.0 (broad, 2H, NH). L) (90 MHz, DMSO-d 6 + D 2 O): 2,8 ppm (s, 3H, NCH 3 ); 3,4 - 3,65 ppm (m, 4H); 4,0 - 4,4 ppm (m, 4H). Q) a) (90 MHz, DMSO-d 6 ): 2,65 ppm (s, 3H, S-CH 3 ); 3,35 ppm (s, 6H, NCH 3 ) 2 ); 3,65 - 4,0 ppm (m, 4H); 4,0 - 4,3 ppm (m, 4H), 9,45 ppm (broad singulet, 1H, NH). Q) b) (90 MHz, DMSO-d 6 ): 3,3 ppm (s, 6H, NCH 3 ) 2 ); 3,5 - 3,8 ppm (m, 4H); 3,8 - 4,2 ppm (m, 4H). R) a) (90 MHz, DMSO-d 6 ): 2,55 ppm (s, 3H, SCH 3 ); 3,45 ppm (s, 3H, NCH 3 ). R) b) (90 MHz, DMSO-d 6 ): 3,15 ppm (s, 3H, NCH 3 ); 3,2 - 3,28 ppm (m, 2H); 3,28 - 3,35 ppm (m, 2H); 3,4 - 3,55 ppm (m, 4H); 5,18 ppm (broad singulet, 2H); 8,05 (s, 1H, -CH=O); 8,1 - 8,3 (broad singulet, 2H). R) c) (300 MHz, DMSO-d 6 ): 3,16 ppm (m, 3 + 4 H); 3,63 ppm (m, 4H); 6,7 ppm (broad singulet, 5H); 8,5 (broad singulet, 1H); 10,0 ppm (broad singulet, 2H). S) (300 MHz, DMSO d 6 ): 2.55 (s, 2H, N-CH 2 ); 5.92 (s, 2H, NH). T) (300 MHz, DMSO d 6 ): 0.5 (m, 2H, CH 2 ); 0.7-0.8 (m, 2H, CH 2 ); 2.4-2.5 (m, 1H, N-CH); 4.7 (broad, 2H, NH); 7.5 (broad, 2H, NH); 8.2 (broad, 1H, NH); 8.9 (broad, 1H, NH). V) (300 MHz, DMSO d 6 ): 2.79 (d, J=4.8Hz 6H, N(CH 3 ) 2 ); 3.20 (s, 3H, N-CH 3 ); 3.2 (m, 2H, N-CH 2 ); 3.6 (m, 2H, N-CH 2 ); 4.7 (very broad, 2H, NH); 7.7 (broad, 2H, NH); 10.4 (broad, 1H, NH). W) (300 MHz, D 2 O): 6.75-6.85 (m, 1H, CH aromatic); 6.9-7.0 (m, 1H, CH aromatic); 7.1-7.15 (m, 1H, CH aromatic); 7.7 (s, 1H, CH=N). X) (300 MHz, D 2 O): 2,0 (m, 1H); 2,47, 2,35 (s, s, together 3H, -SCH 3 ); 0,84 (m, 2H); 0,69 (m, 2H). Y) (300 MHz, D 2 O): 3,36 (t, J=7 Hz, 2H); 2,51, 2,43 (s, s, together 3H, -SCH 3 ); 1,55 (quintet, J=7 Hz, 2H); 1,29 (sextet, J=7 Hz, 2H); 0,85 (t, J=7 Hz, 3H). Z) (90 MHz, DMSO-d 6 ): 3,65 ppm (s, 3H, NCH 3 ). AA) a) (300 MHz, DMSO d 6 ): 2.19 (s, 3H, C-CH 3 ); 3.84 (s, 3H, N-CH 3 ); 5.84 (d, J=3.8Hz 1H, C=CH); 6.58 (d, J=3.8Hz 1Hz, C=CH); 8.76 (s, 1H, NH); 8.93 (s, 1H, NH). AA) b) (300 MHz, DMSO d 6 ): 2.3 (s, 3H, C-CH 3 ); 2.75 (s, 3H, S-CH 3 ); 3.65 (s, 3H, N-CH 3 ); 6.2 (d, J=4Hz 1H, C=CH); 7.1 (d, J=4Hz 1Hz, C=CH); 10.6 (s, broad 5H, NH). AA) c) (300 MHz, DMSO d 6 ): 2.2 (s, 3H, C-CH 3 ); 3.1 (s, 3H, N-CH 3 ); 5.95 (d, J=4Hz 1H, C=CH); 6.5 (d, J=4Hz 1Hz, C=CH); 7.2 (very broad 5H, NH). AB) (300 MHz, DMSO d 6 /D 2 O): 6.75-6.85 (m, 1H, CH aromatic); 7.00-7.05 (m, 1H, CH aromatic); 7.05-7.10 (m, 1H, CH aromatic).

Claims: A compound of formula wherein R x is a group of formula -NH-CH 2 CF 3 or -NH-(CH 2 ) 2 -N ⁺(CH 3 ) 3 or or or R y is NH and R z is hydrogen; or R x is a group of formula R y is NH and R z is CH 3 ; or R x is - SCH 3 R y is a group of formula and R z is hydrogen; or R x is the group R y is oxygen and R z is hydrogen. A compound of formula wherein R 1 is hydrogen or an ester moiety, and R xx denotes a group wherein R x , R y and R z as defined in claim 1. A compound according to claim 1 or claim 2 in salt form. A compound according to claim 3 in acid addition salt form. A compound according to claim 1 which is a trihydrochloride of 1-[hydrazino(methylimino)methyl]piperazine.

Inventors: ASCHER GERD, LUDESCHER JOHANNES, ASCHER, GERD, LUDESCHER, JOHANNES
Applicants: SANDOZ AG
Application year: 1996
Main classification: C07D501
IPC codes: C07D501, A61K31, A61P31