Patent GB-1295841-A (GB)
IPC: C07D501/36
Filed: 1969-10-27
Abstract: 1295841 Cephalosporins FUJISAWA PHARMACEUTICAL CO Ltd 27 Oct 1969 52616/69 Addition to 1206305 Headings C2A and C2C Novel 7 - acylamino - 3 - thiomethyl cephalosporin derivatives having the formula and their pharmaceutically acceptable salts and esters, wherein R<SP>1</SP> is R<SP>3</SP>-(Alk) m - or Alk being an alkylene group and m = 0 or 1 and R<SP>3</SP> and R<SP>2</SP> are the following optionally substituted heterocyclic groups: when R<SP>3</SP> is thiadiazolyl, R<SP>2</SP> is thiadiazolyl or 1H-tetrazolyl; when R<SP>3</SP> is thiazolyl, R<SP>2</SP> is thiadiazolyl, oxadiazolyl or 1H-tetrazolyl; when R<SP>3</SP> is oxadiazolyl, R<SP>2</SP> is thiadiazolyl or 1H-tetrazolyl; when R<SP>3</SP> is thienyl, R<SP>2</SP> is diazolyl, thiadiazolyl or diazinyl; when R<SP>3</SP> is 2H-tetrazolyl, R<SP>2</SP> is thiadiazolyl or 1H-tetrazolyl; and when R<SP>3</SP> is 1H-tetrazolyl, R<SP>2</SP> is thiadiazolyl, oxadiazolyl or 1H-tetrazolyl, are prepared by 7-acylating and 3-thiolating 7-aminocephalosporanic acid with respectively an appropriate acid or acylating derivative thereof, and a thiol or alkali metal salt thereof. R<SP>3</SP> and R<SP>2</SP> may be substituted, e.g. by C 1  to C 6  alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, alkylthio, alkylthioalkyl, dialkylaminoalkyl, carboxyl, alkoxycarbonyl, amino, carboxyalkyl, alkoxycarbonylalkyl, dialkylaminoalkylaminocarbonylalkyl, or alkoxyalkylaminocarbonylalkyl groups. The sodium salt of 7-(1H-tetrazol-l-ylacetamido) - 3 - (5 - methyl - 1,3,4 - thiadiazol - 2- ylthiomethyl) - 3 - cephem - 4 - carboxylic acid is prepared in three forms differentiated by their water content. There are two hydrated forms, the pentahydrate or α form containing 5 molecules of water and the trihemihydrate or # form containing 1¢ molecules of water. The α form is converted to the  # form by treatment with methanol or ethanol containing respectively less than 30%, and 20% of water (preferably less than 1 %). By treating the # form with more dilute aqueous methanol or ethanol it is converted to the α form; alternatively this may be effected by exposing the # form to a 100% humidity atmosphere. By drying either form (e.g. by heating, vacuum or freeze-drying) an anhydrous form having a water content below 2% is produced; on exposure to a moist atmosphere this form takes up moisture to yield solely the form (i.e. α or #) from which it originated. The claims also relate to the esters of the cephalosporin compounds of parent Specification. 5 - (3 - Methoxypropylaminocarbonylmethyl)- 1,3,4 - thiadiazole - 2 - thiol is prepared by refluxing an ethanolic solution of 3-methoxypropylamine with ethyl 2 - mercapto - 1,3,4- thiadiazole - 5 - acetate. The latter compound is prepared by reacting ethyl ethoxycarbonylmethyldithiocarboxylate with the triethylamine salt of dithiocarbazic acid in pyridine. The said acetate is also hydrolysed with alcoholic KOH to give 2-mercapto- 1, 3,4-thiadiazole-5- acetic acid. 5 - Dimethylaminomethyl - 1,3,4 - oxadiazole- 2-thiol is prepared by reacting dimethylamine with ethyl chloroacetate, treating the product with hydrazine hydrate and reacting the resulting compound in ethanol with potassium hydroxide and then refluxing with carbon disulphide. 1 - Methoxypropyl - 1H - tetrazole - 5 - thiol is prepared by ,reacting together methoxypropylamine, triethylamine and carbon disulphide and treating the product with methyl iodide; the resulting compound is then separated as an oil and treated with aqueous sodium azide. Pharmaceutical compositions having antibiotic activity comprise the inventive cephalosporin derivatives or their non-toxic salts and esters, or esters of the cephalosporin compounds of parent Specification, together with a pharmaceutically acceptable carrier.