Patent GB-1410505-A (GB)
Title: Pleuromutilins
IPC: C07C323/58
Filed: 1972-10-02
Abstract: 1410505 Pleuromutilins SANDOZ Ltd 2 Oct 1972 [5 Oct 1971 (2) 25 May 1972 (3) 45259/72 Heading C2C The invention comprises pleuromutilins, other than 14 - desoxy - 14 - [(2 - diethylaminoethyl) mercaptoacetoxy]mutilin, which have Formula I wherein either (a) R 1  is ethyl or vinyl; n is 2-5, X is sulphur, a group of Formula A or a group = N-R<SP>1</SP> 4 , wherein Y = Z = sulphur or one of Y and Z is sulphur and the other is oxygen, and R<SP>1</SP> 4  is hydrogen or a group of Formula II wherein R 1  is as defined above R 2  and R 3  are C 1-10  alkyl or R 2  and R 3  together with the nitrogen atom form a 5-7 membered heterocycle which may contain a further member selected from S, O and N-R<SP>I</SP> 5  wherein N-R<SP>I</SP> 5  is C 1-5  alkyl or C 1-4  hydroxyalkyl, or R 2  and R 3  together with the nitrogen atom form a piperazinyl radical, the second nitrogen of which is substituted by a radical R<SP>II</SP> 5  which is (C 2-4  acyl)oxy(C 1-4 )alkyl or benzoyloxy (C 1-4 ) alkyl; or (b) R 1  is as defined above, n=2, R 3 = C 1-10  alkyl, C 1-4  hydroxyalkyl, C 2-4  acyloxy (C 1-4 ) alkyl or benzoyloxy (C 1-4 )-alkyl; X is =N-R<SP>II</SP> 4  and R 2  together with R<SP>II</SP> 4  forms an ethylene bondage between both nitrogen atoms. The compounds of Formula I as defined, and 14 - desoxy - 14 - [(2 - di - ethylaminoethyl)-mercaptoacetoxy]mutilin are prepared by (i) reacting a compound of Formula III in which R 6  is alkyl or aryl, with a compound of Formula IV wherein n is as defined above; X<SP>1</SP> is S or a group of Formula B wherein Y<SP>1</SP> and Z<SP>1</SP> are as defined above for Y and Z provided that Z is sulphur, R<SP>I</SP> 2  and R<SP>1</SP> 3  are C 1-10  alkyl or together with the nitrogen atom from a 5-7 membered heterocycle which may also contain S, O or NR<SP>I</SP> 5  as defined above, to obtain a product of Formula Ia or (ii) reacting a compound of Formula III (above) with a compound of Formula V or Va to produce products of Formula Ib or Ib<SP>1</SP> or (iii) reacting a compound of Formula IIIa with a compound of Formula VI wherein A is the acid radical of a reactive ester to produce a product of Formula Ic or (iv) reacting a compound of Formulae Ie or Ie<SP>1</SP> wherein R<SP>IV</SP> 2  and R<SP>IV</SP> 3  together with the nitrogen atom form a piperazinyl radical, the second nitrogen of which is substituted by a C 1-4  hydroxyalkyl group, with a compound of formula in which B is alkoxy carbonyl, chloro or bromoformyl or a group and R 7  is C 1-3  alkyl or phenyl, to produce products of Formula Id and Id<SP>1</SP> 14 - Desoxy - 14 - tosyloxyacetoxy - dihydromutilin is prepared by reaction of p-toluenesulphonylchloride with dihydropleuromutilin and by hydrogenation of 14-desoxy- 14-tosyloxyacetoxymutilin. 3 - (2 - Diethylaminoethylmercapto)thiophenol is prepared by reacting 2- diethylaminoethylchloride hydrochloride with benzene - 1,3 - thiol in the presence of sodium methoxide. 14 - Desoxy - 14 - (4 - hydroxyphenylmercapto) acetoxydihydromutilin is prepared by reaction of 14 - desoxy - 14 - tosyloxyacetoxydihydromutilin with thiohydroquinone. 14 - Desoxy - 14 - (2 - hydroxyphenylmercapto) acetoxymutilin is prepared by reacting 14- desoxy - 14 - tosyloxyacetoxymutilin with 2-mercaptophenol in the presence of sodium ethoxide. 2-Pyrrolidinoethanol is prepared by reacting pyrrolidine with ethyl-2-mercaptoethylcarbonate. 2 - [N,N - bis - (2 - ethylhexyl)amino]ethanethiol, 2 - [4 - (2 - hydroxy ethyl) - 1 - piperazinyl]ethane thiol, (2 - morpholino)ethanethiol and (hexahydro - 1H - azepinyl)ethanethiol are prepared by reaction of ethylene sulphide with the appropriate secondary amine. Pharmaceutical compositions having antibiotic properties for injection or instillation comprise a compound of Formula I in free base or pharmaceutically acceptable acid addition or quaternary ammonia salt form together with a pharmaceutically acceptable diluent or carrier.