Syntheses of some N-substituted thiocarbamylpiperidines (I-VIII) and thiocarbamylμiorpholines (IX-XVIII) from piperidine or morpholine and the corresponding isothiocyanaites are described. The substances were tested for their tuberculostatic activity

M. Tišler

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CR 0 AT I CA CHEM IC A ACT A 29 (1957) 409 CCA-97 547.822.3.07 + 547.867.4 01 Syntheses of Some N~Substituted Thiocarbamylpiperidines and Thiocarbamylmorpholines M. Tisler Institute of Organic Chemistry, University of Ljubljana, Slovenia, Yugoslavia Received May 16, 1957 Syntheses of some N-substituted thiocarbamylpiperidines (!-VIII) and thiocarbamylµiorpholines (IX-XVIII) from piperidine or morpholine and the corresponding isothiocyanaites are de-scribed. The substances were tested for their tuberculostatic activity. · ' Pursuing our work on synthetic tuberculostatics and related com-pounds19· 20• 21 we have synthesized some N-substituted thiocarbamylpiperidines and thiocarbamylmorpholines, which were tested for their tuberculostatic activity. It is known that thiourea exhibits a week tuberculostatic activity and there are known many substituted thioreas with tuberculostatic activity of different degree. Some of them were also active when tested against .human leptosy2 and influenza-virus infections in mice3• Thiourea is incorporated also' in thiosemicarbazones and this fact prompted extensive research of rriany related compounds. Investigations of Mantegazza and coworkers15 who synthesized and tested many N-arylthioureas, and of other authors disclosed· that N,N'-disubstituted thioureas do not give satisfactory results in the treatment of experimental tuberculosis4, 6, 7, 12, 14, 16. Subsequently some thiourea derivatives of sulphanil-amides and aromatic amino acids were synthesized and tested11• . · · On the other side, Barry and Twomey1 have established that some pi-peridine derivatives of long chain fatty acids exhibited good tuberculostatic activity in vitro. These findings incited the preparation of new piperidine and morpholine derivatives with incorporation of thiourea group. Some of the above mentioned compounds are already known in the literatui;e and we have prepared some new compounds from piperidine and morpholine and the corresponding isothiocyanates in ethereal solution. The advantage of this method is that the formed derivatives are of low solubility in ether .. Substances, which are presented in Tables I and II exhibit no appreciable tuberculostatic activity, which was measured in vitro on 'the liquid culture medium Sula18 with the strain of Mycobacterium tuberculosis H 37Rv. Only N-(4'-dimethylaminophenyl)-thiocarbamylpiperidine (VII) showed complete in-hibition at the concentration of 5 y/ml. Using the above described procedure, some N-substituted thio.carbamyl-piperidines, which are already described in the literature were synthesized. 410 M. TISLER These substances are presented in Table III and none of them showed an inhibition effect at the concentration of 1 and 5 y/ml. TABLE I. N-Substituted Thiocarbamylpiperidines Compound No. I II III IV v VI VII VIII / CH2-CH2 "'-CH2 N-CS-NH-R "'-._ CH2-CH2 / R 2',3' -dimethylphenyl-2',4' -dimethyl phenyl-2',5' -dimethylphenyl-2' -methoxyphenyl; 4' -methoxyphenyl-3' -chlorophenyl-4' -dimethy larhinopheny 1-Cyclohexyl-M.p. oc 138 119 118 61 146 135 129 133 Formula C14H20N2S C14H20N2S C14H20N2S C13H1sON2S C1sH1sON2S C12H1sN2SCl C14H21NaS C12H22N2S TABLE II. Analyses, O/oN Recryst. calc'd found EtOH:H20 11,28 11,28 11,28 11,19 11,19 11,00 15,95 12,38 11,02 11,24 11,33 11,38 11,16 11,03 15,83 12,30 3:1 1:1 2:1 2:1 3:1 1:0 1:1 3:1 N-substituted Thiocarbamyimorphoiines / CH2-CH2 '\,._ 0 , N-CS-NH-R "' . CH2-CH2 / Compound R M.p. Formula Analyses, 0/oN Recryst. No. oc calc'd found EtOH:H20 IX Phenyl- 134 C11H140N2S 12,60 12,68 1:0 x 2' -methylphenyl- 144 C12H150N2S 11,85 12,02 1:0 XI 2' -methoxyphenyl- 91 C12H1602N2S 11,10 11,16 1:1 XII 2',3' -dime thy lpheny 1- 147 C1sH1sON2S 11,19 11,07 1:0 XIII 2' ,4' -dime thy lpheny 1- 148 C1aH1sON2S 11,19 11,30 1:0 XIV 2' ,5' -dimethy !phenyl- 156 C13H1sON2S 11,19 11,33 1:0 xv 3' -chlorophenyl- 162 C11H1aON2SCl 10,91 11,08 . 1:0 XVI 4' -dime thy laminopheny 1 170 C1aH190NaS 15,84 15,98 1:0 XVI! Benzyl- 100 C12H160N2S 11,85 12,00 3:1 XVIII Cyclohexyl- 136 C11H200N2S 12,27 12,33 2:1 TABLE III. N-substituted Thiocarbamylpiperidines R Phenyl-2' -methylphenyl-3' -methylphenyl-4' :-methylphenyl-4' -chlorophenyl-4' -bromophenyl-Benzyl-l' -naphtyl-Methyl-M. p. observed oc 99 98 102 134 153 166 88 125 131 M ; p. reported in literature, oc 969, 9310, 9913, 103'..417 9810 955 13210 1475 1595 87-88 1205 12510, 12913 THIOCARBAMYLPIPERIDINES AND THIOCARBAMYLMORPHOLINES 411 EXPERIME NTAL All melting-points were determined with Kofler's heating microscope. General procedure for the preparation of N-substituted thiocarbamylpiperi-dines and thiocarbamylmorpholines. 0.02 mole of piperidine or morpholine was dissolved in ether (10 ml.) and the solution was cooled with ice. Separately, 0.02 mole of the corresponding isothiocyanate was dissolved in ether (10 ml.; in the case of some sparingly soluble isothiocyanates some more ether was required) and added, in one portion, to the cooled ethereal solution of piperidine or morpholine. The formed derivative soon precipitates and after standing on ice for further 15 min. it was filtered and recrystallised from alcohol or alcohol-water mixture, as indicated in Table I and II. Yields were 82-900/o. Acknowledgements. Grateful acknowledgement is m ade to Professor M. Perpar for her interest and to Dr. S . Banic of the Microbiological Institute of the F aculty of Medicine in Ljubljana for testing the compounds. REFERENCES 1. V. C. Barry and D. Twomey, Proc. Roy. Irish Acad. 55 B (1952) No. 1.; cit. from Chem. Abstr. 48 (1954) 7183. 2. N . P. B u u - Ho i, Internat. J . Leprosy, 22 (1954) 16. 3. N. P . . Buu-Hoi, P. Gley, N. D. Xuong and A . Bouff a n a is, Compt. Tend. 238 (1954) 2582. 4. N. P . B u u - Ho i and N. D. Xu on g, Compt. rend. 237 (1953) 498. 5. N. P. Buu-Hoi, N. D. Xuong, J.M. Gazave, C. T. Long and N. H . Nam, Bull. soc. chim. FTance, 1956, 307. \ 6. N. P . B u u - Ho i, N. D. Xu on g and N. H . Nam, J. Chem. Soc., 1955, 1573. 7. N. P . Buu-Hoi, N. D. 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Acta 28 (1956) 147. 21. M. Ti s 1 er, V estnik Slov. k em . druStva, in press. IZVOD Sinteze nekih N-supstituiranih tiokarbamilpiperidina i tiokarbamilmorfolina M . Tisler Pripravljeni su N-supstituirani tiokarbamilpiperidini (I-VIII) i tiokarbamil-morfolini (IX-XVIII) iz piperidina ili morfolina i odgovarajucih izotiocianata. Kod sintetiziranih spojeva ispitivana je njihova tuberkulostatiena aktivnost . INSTITUT ZA ORGA NSKU KEM IJU UNIVERZE U LJUBLJ ANI SLOVENIJA P rlmljen o 16. svibnja 1957. 

Syntheses of Some N-Substituted Thiocarbamylpiperidines and Thiocarbamylmorpholines

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