July 5 , 1958
3471
THIAZOLINES WITH ANTITUBERCULOUS ACTIVITY
(I, Rz = aryl, RS = H) were the most toxic and most active hypothermic agents, although they were devoid of paralyzing and anticonvulsant properties. The most effective paralyzing and anticonvulsant compounds were those containing an alkyl group in the 3-position and a chloro- or dichloro-substituted phenyl group in the 2-position of the metathiazanone ring. A comparison of the 2-aryl-3-alkyl-4-metathiazanones with the corresponding 1-dioxides indicated that both types had similar pharmacological profiles but differed in oral absorption, toxicity and duration. The 1-dioxides showed the maximal activity but had a somewhat shorter duration than the parent compounds. I n general, the pharmacological profile found for those metathiazanone derivatives suggested a mephanesen-like type of action. One of the most active members of the present series, 2 - (4 - chlorophenyl) - 3 - methyl- 4 - metathiazanone-1-dioxide, in clinical testing, has been found to be an effective and promising skeletal muscle relaxant. Detailed pharmacology of most of the compounds reported in the present work will be published elsewhere. Acknowledgment.-\Ye are indebted to Mr. 11. E. Auerbach and Mr. K. D. Fleischer and staffs for the analytical data and corrected melting points, and to Dr. F. Coulston for preclinical studies in monkeys. Experimental6 2-Aryl-3-alkyl-4-metathiazanqnes.-The preparation of these compounds is illustrated below. 3-Methyl-2-(3-pyridyl)-4-metathiazanone.--,isolution of 43.2 g. of 3-pyridinecarboxaldehyde, 42.5 g. of P-mercaptopropionic acid and 14 g. of methylamine in 200 ml. of benzene was refluxed for 48 hours with a continuous separator connected to the reaction vessel for removal of water. After this time the theoretical amount of water was collected. The reaction mixture was cooled and washed with dilute ammonium hydroxide. T h e solid (53 g.) which separated (6) All melting points are corrected unless otherwise indicated
[CONTRIBUTION FROX
THE
from the benzene solution was collected, washed with water, dried and recrystallized from absolute ethyl alcohol to give 43.5 g. (527,) of product melting at 165.2-168.8'. Anal. Calcd. for CloH12N20S: N, 13.45; C, 57.65; H , 5.81. Found: N, 13.43; C, 57.43; H, 6.35. If no solid was obtained from the benzene solution after washing with ammonium hydroxide the solvent was removed in vacuo and the residue was vacuum distilled. I n several instances the viscous distillates solidified on standing. 3-Methyl-2-(2-pyridyI)-4-metathiazanone was prepared in 20y0 yield after refluxing for 72 hours. The product was recrystallized several times from a mixture of benzenehexane; m.p. 89.5592' (uticor.). Anal. Calcd. for CloH12N20S: C, 57.65; H , 5.81; N, 13.45. Found: C, 58.16; H , 6.46; N, 13.16. 3-Methyl-2-(2-thienyl)-4-metathiazanone was prepared in 59';i yield after refluxing for 72 hours. The product was recrystallized from Skellysolve C; m.p. 80.6-83.4'. A n a l . Calcd. for CgHllXOS2: C, 50.67; H , ,520. Found: C, 50.46; H , 5.50. 2-Aryl-4-metathiazanone-l-dioxides.-The following example illustrates the general procedure for the preparation of these compounds. 3-Methyl-2-(3-pyridyl)-4-metathiazanone 1-Dioxide.--A solution of 36.7 g. of potassium permanganate in 300 ml. of water was added dropwise to a well-stirred solution of 28.3 g. of 2-(3-pyridyl)-3-methyl-4-metathiazanone in 230 ml. of glacial acetic acid. T h e temperature was kept below 30" with external cooling. A concentrated aqueous sodium bisulfite solution then was added to remove the manganese dioxide. The reaction mixture was basified t o a p H of 6 and extracted several times with chloroform. The solvent from the combined extracts was distilled in z'acuo and the residue was triturated with hexane to give 12.5 g. of solid. After recrystallization from ethyl alcohol, 9 g. of product was obtained melting a t 193.2-171.8°. Anal. Calcd. for C1aH12S,03S: C, 49.98; H , 5.04; Ii, 11.03. Found: C , 50.30; H , 4.67; N, 11.46. In many instances a solid product was obtained after addition of the bisulfite solution and was filtered off and purified by recrystallization. Only in the case of the 2-(pyridyl) compounds was it necessary to adjust the pH. Most of the sulfones were recrystallized from either ethyl or isopropyl alcohol. 3-Methyl-2-(2-pyridyl)-4-metathiazanone 1-dioxide was prepared in 377; yield. After recrystallization from isopropyl alcohol the product melted a t 144.6-152.4'. Anal. Calcd. for CloH12S20JS: S, 13.34; N, 11.66. Found: S,13.11; N, 11.61. RENSSELAER, SEX YORK
RESEARCH DEPARTMENT, CIBA
P H A R M A C E U T I C A L PRODUCTS,
INC.]
Some Thiazolines and Thiazolidinones with Antituberculous Activity BY R. H. MIZZONIAND P. C. EISMAN RECEIVEDSOVEMBER 25, 1957 rl series of 3-aryl-2-arylimino-4-substituted-4-thiazolines and 3-aryl-2-arylimino-4-thiazolidinoneswere prepared and evaluated as antituberculous agents. Some of the substances are active in this regard.
Appropriately substituted 1,3-bis-thiocarbanilides display a high order of antituberculous activity in vitro and in experimental anima1s.l It seemed desirable, therefoie, to investigate this property among various cyclic modifications of the parent structure. Two such modifications may be found in the 3aryl-2-arylimino-4-thiazoline and 3-aryl-2-aryli(1) C. F. Huebner, J. L. Marsh, R. H. Mizzoni, R. P. Mull, D. C. Schroeder, H. A. Troxell and C. R. Scbolz, THISJOURNAL, 1 5 , 2275 (1953); R . L. Mayer, P . C. Eisman and E. A. Konopka. Proc. SOC. Erpll. B i d . M e d . , 89, 88 (1955).
mino-4thiazolidinone structures, I and I1 respectively R"CHXC0CHzR'
>
i HSCH~~'~ \NH.lr
1
RCHXCOzH
1
R. IS. ~ L ~ I Z Z O NAND I P.C. EISMAN
3472
TABLE I
Vol. 80
Rz()=N-
3-(R1-PHE~YL) -2-(R1-P~E~YLIM1~O) -4-(R3) -5-(Rz)-4-THIAZOLINES
. ,
R ~ - N - - ~ R ~ RI (Rz)
Ri
-OCHzCHzCH(CHa)z
Me
HX
HC1
Yield,
%
M.P., o c .
61.4'
180-181
52.0" 79.8"
234-234.5
-OCHzCHzCH( CH3)2
HBr HC1 (+1HzO) - C H ~ C H & C ~ H I O 2HBr
73.5b
184 dec.
OC3Hi(n)
-CH&H2NC6Hlo
2HBr
79.8h
175- 176
OCHzCH=CH2
-CH2CHzNCjHlo
2HBr
44.1'
210-212 d.
n-C4HB
-CH2CH2NC5HI~ 2HBr ( f l H z O ) 66,5'
213
Me
75.4"
173
67.Y
155
94. za
132
82.1"
140
77. 15
174,5176
-OCHzCHzCH( CHa) z -OCHzCH=CHz
4-BrCsHd Me
HC1
CsH5
HCl
76.7"
149.5-150.5
4-BrCsH4
HBr
68.4"
193.5-195
Me
HC1
72.4"
169-170
-CHzCHzNC6111a 2HBr
Ale
IICl
64. 7b 140 63.4'
182-182.5
53.0"
154-156.5
75.0"
179-180
70. 4c
181.5-182
58.4" 203.5-204.5 37.0
160.5
52.7" 81.1"
121-124 153-155
CII3
11c1
73.1"
160-161
CHI
..
29.7"
68-69
CHI
..
16.1"
63-64
C6Hj CH3
Me1 HC1
58.8' 61.7"
201-204 143
CHI
HCl ( +2Hz0)
33.7"
236 dec.
Empirical formula
Cz6H86ClNzOzS
%-.
-Analyses.
Found
S,
6.69 c1, 7.39 N, 4.19 S, 6.60 S, 7.29 S, 5 . 9 1 s, 4 . 7 8 N, 6 . 6 5 4.87 L-, 6 . 4 7 ,E, 4.87 Br, 24,81 C, 55.22 H, 6.91 S, 6 . 3 5 s, 7.08 S, 8 . 0 6 S, 6.00 C1, 7.63 S, 5 . 8 7 C1, 7 . 7 0 K, 5 . 9 7 C1, 7.58 N, 4 . 8 8 s, 5.34 S, 5 . 9 9 C1, 7.67 ii, 4.87 S, 5 . 3 8 S, 6.87 7.44 pu', 7.00 Br,26.91 K, 6 . 0 8 S, 7.07 C , 58.52 H , 5.46 x, 5.94 C, 69.48 H, 7.60 N, 7 . 0 5 N, 5.77 S, 6.44 Ii, 5 . 2 7 6.23 N, 5 . 2 4 S, 6.24 S, 6.37 K, 5.10 s, 5.49 S, 6 . 3 2 C1, 6.79 N, 6.32 S 6.96 N, 6.13 S, 6 . 8 8 K, 4 . 3 1 N, 5.79 C1, 7.80 N, 12.26 C1, 7.72
s,
s,
s,
Calculated
S,
6.74 7.46 N, 4 . 2 6 N, 6.47 S, 7.40 S, 6.02 4.59 S, 6 . 5 5 s, 4.99 iY, 6.59 S , 5.02 Br, 25.07 C, 54.95 H, 6 . 9 1 N, 6 . 4 1 s, 7.16 S, 8.20 E, 5.87 C1, 7.43 K, 6 . 1 8 C1, 7.82 hT, 5.87 C1, 7.43 iY, 4.66 5.33 N, 5.82 C1, 7.37 N, 4.66 S, 5 . 3 3 N, 6 . 6 8 s, 7 . 6 5 N, 6 . 8 5 Br, 26.05 s, 5.91 S, 6.77 C, 58.34 H , 5.32 s, 5.01 C, 69.45 H, 7.52 N, 6 . 7 5 N , 5.86 S, 6 . 7 1 S, 5 . 2 5 s, 0 . 00 L-, 5 . 3 7 S, 6.14 S, 6 . 4 0 ri, 5.00 5.73 S, 6.03 C1, 6 . 6 7 N, 6.38 S, 7.30 N, 6.00 S, 0 . 8 7 N, 4.36 K, 5.84 C1, 7.40 E, 11.95 C1, 7.56
c1,
s,
s,
s,
July 5 , 19.33
THIAZOLINES WITH ANTITUBERCULOUS ACTIT, ITY
3473
TABLE I (continued) Yield
R1
-COOH
HX
HC1
93
M.P., 'C
6 . 4 " ~282 ~ dec.
----Analyses, Found
% ' ,Calculated
N, C1, N, Br, N,
6.84 N, 7 . 1 7 9 . 1 3 C1, 9 . 0 7 5 . 0 3 N, 4 . 9 9 HBr 40.0" 165-167 -OCH2CHzCH( CH3)z 14.32 Br, 1 4 . 2 3 -OCH&H( C2Hs)z HCl 74.4" 153-155 5.40 S, 5 . 5 7 S, 6 . 2 6 S, 6 . 3 7 -OCH2CH2CH(Me) (Et) HCI 62.8" 174-176 K, 5 . 6 5 N, 5.57 s, 7 . 1 1 N, 7 . 2 5 .. 16.3" 246 dec. 3-OH-4-COOH S, 8 . 7 7 S, 8 . 3 0 S, 18.73 S, 18.96 -SCHzCHzCH(CH3) 2 HC1 40 ,O"sd 174 N, 4 . 9 5 IT, 4.85 HBr 28.2 166-169 -OCHzCHzCH(CHa)z Br, 14.03 Br, 13.84 AT, 6 . 2 8 N, 6 . 2 7 HC1 68.4" 173 -OCaHs(n) C1, 7.52 C1, 7 . 9 3 -OCHzCH(CH3)z N, 6 . 0 9 X, 6 . 2 7 HCl 72.0" 210 c1, 7 . 5 8 c1, 7 . 9 3 Adapted from procedure a, Experimental. * Adapted from procedure b, Experimental. Reference 3. The thiourea required for this synthesis, 1,3-bis-(p-isopentylthiophenyl) -2-thiourea, was prepared according to U.S. Patent 2,664,096. 63y0 of starting thiourea recovered; a trace of p-aminobenzoic acid was also isolated.
The preparation of 4-substituted-4-thiazolines Finzi and Angelini16 have reported the reaction of has been described by various workers from 1,3-bis- S-alkyl ethers of 1,3-bis-thiocarbanilideswith thiocarbanilides and phenacyl b r ~ m i d e . ~ -To ~ thioglycolic acid to give I11 (R = H). Certain thiazolines and thiazolidinones were our knowledge the analogous reaction with achloroaliphatic ketones has not been described. found to possess considerable antituberculous acBoth of these syntheses were found to proceed tivity. Microbiological findings, which have been equally well to furnish the desired 4-substituted-4- p ~ b l i s h e d , 'may ~ be summarized briefly as: (1) 3 - ( p - Alkoxyphenyl - 2 - ( p - alkoxyphenylimino) -4thiazolines and 4,5-disubstituted-4-thiazolines. The preparation of 3-aryl-2-arylimino-4-thiazoli-methyl-4-thiazolines, having ether groupings within dinones has been effected by reaction of symmetri- the range of CsH70 to CsH130 (including CH2= cal thiocarbanilides with a-haloacids.6-16 CHCH20) possess good in zivo activity against tuIn the presence of sodium acetate the reaction berculous infections of experimental animals. The leads to the formation of 3-aryl-2-arylimino-4- activity seems to reach a peak where the alkoxy subthiazolidinones(II1) ; in its absence 3-aryl-2,4- stituent is isopentyloxy. (2) Replacement of the thiazolidinediones (IV) arise by acid cleavage of ether groupings by an alkyl substituent (e.g., butyl) the imino function. results in maintenance of activity. ( 3 ) The 4-methyl group may be replaced by a dialkplaminoalkyl subClCHRC02H, stituent without detriment to antituberculous prop\-o CICHRCOzH /-kr Sa0.h --f 1 t------HSC\ erties. Replacement by an aryl substituent, how0=-N--Ar NHXr n ever, all but abolishes activity. (4) 3-Aryl-2-arylimino-4-thiazolidinones possess antituberculous acAr NH2.HC 1 tivity within the limits described under (1). 3-ArylIV 2,4-thiazolidinediones, however, are inactive. I11 The technical assistance of Mrs. Evelyn Wrobel (2) R. von Walther, J . p r a k l . Chem., 121 76, 187 (1907). and Miss Judith Ann Siragusa is gratefully acknowl65, 4998 (1933). (3) R . hi. Hann and E. E. Reid, THIS JOURNAL, edged.
R(s +
(4) Z. Horii, J . Pharm. Soc. J a p a n , 66, 21 (1935): C. A , , 29, 3338
(1935).
(5) N. P. Buu-HOT, N. D. X u o n g and N. H. Nam, J . Chem. Soc., 2160 (1936). (6) F. B. Dains, R. Irvin and C. G . Harrel, THISJOURNAL, 43, 613 (1921). (7) R. M. Hann and K. S. hIarkley, J. Wash. Acad. Sei., 16, 169 (1926); C. A., 2Q, 1980 (1926). (8) S. S. Kingsbury and K. S. Markley, J . Wash. Acad. Sci., 18, 558 (1928); C. A , , 23, 821 (1929). (9) R. S. Markley and E. E. Reid, THIS J O U R N A L , 62, 2137 (1930). (10) M. 0. Farooq and R. F. Hunter, J. Indian Chem. Soc., 9, 545 (1932); C. A., 27, 1870 (1933). (11) M. R. Chowdhury, R . D. Desai, R . F. Hunter and F. 11.K. Solangi, Rec. fraw. chim., 62, 853 (1953). (12) D. P. Ahuja and S. Dutt, J . Indian Chem. SOC.,28, 12 (1951). (13) P. N Bhargava, Bull. Chem. 5'06. Japan, 24, 51 (1951); C A , , 46, 11183 (1952). (14) P. N. Bhargava and C. L. Kaul, J . Indian Chem. Sac., 32, 49 1953); C. A , , 49, 13974 (1955). (13) P. N. Bhargava, THIS JOURNAL, 73, 2353 (1951). (16) C . Finzi and C. Angelini. A n n . chim. Roma, 43, 832 (1953); C. A.. 49, 6230 (1955).
Experimental Pertinent analytical data have been included in the tables. Procedure a. 3-(p-Isopentyloxyphenyl)-Z-(p-isopentyloxyphenylimino)-4-methyl-4-thiazoline Hydrochloride.-A solution of 144 g. (0.34 mole) of 1,3-bis-(isopentyloxyphenyl)2-thiourea and 33.6 g. (0.36 mole) of chloroacetone in 1200 ml. of anhydrous alcohol was refluxed for 10 hours. The solution was concentrated to about 500 ml. and diluted with 6 volumes of ether. The substance obtained on chilling (152 g., m.p. 174-177') was recrystallized twice from isopropyl alcohol-ether, giving 105 g. of the desired product. Procedure b. 3-(p-Isopentyloxyphenyl)-2-(p-isopentyl-
oxyphenylimino)-4-(2-piperidinoethyl)-4-thiazoline Dihydrobromide.-A solution of 20 g. (0.048 mole) of 1,3-bis(p-isopentyloxyphenyl)-2-thioureaand 15.8 g. (0.05 mole) of l-bromo-4-piperidino-2-butanone hydrobromide in 200 ml. of anhydrous ethanol was refluxed for 3 hours. The solution was filtered hot. Addition of ether and chilling caused the separation of a light yellow crystalline substance; (17) P. C. Eisman, E. A. Konopka, T. Gisi, R. H. Mizzoni and R. L. Mayer, A m . Rev. Tuberc., 77, 703 (1958).
R. H. MIZZONI AND P. C. EISMAN
3474
Vol. 80
TABLE I1 R / S \=K-=Rl 3-(R 1 - P ~ -2~ (~1 ~ 1~ 7 1~ ) YFjd,
I?i
'1
~ -5-(R2) ~ -~-THIAZOLIDISONES" ~ ~ ~ ~ ~ ~ ~ ~ ~ ) O=---S--aR, \ / AI p , o c
/c
-OCH?CH( CHa) 2
38 6
142-145
0C4H y-n
41.7
106
-0CiHij-12
20.1
-0CflH13-?I
62.0
104-106 5
-OCH2CH2CH(Me) (Et)
73 . 0
109-1 11
-OCH2CH(C2Hj)?
63.2
82-83
OCHnCH2CH(CH3)ph (MCl)
17.7
164-166 d .
-OC*H,j
66.5
111-113
S(CHa)n
72 9
215-216
OCH2CHzCH(CHI)?
55.6
130-132
-0CaH7
40.7
97-98
-0CHzCH-CH2
27.6
76-77
OCH*CH2CH(CH3)2C
64.5
172-1 74
HX as noted; Rr = H except
ab
noted.
97 5-98 5
,----Analyses, Found
Y?---
C, 66 94 H , 6 95 N, 6 83 s, 8 02 S, 6 05 6 90 s, 6 23 s, 7 42 s,6 30 S, 6 86 s, 6 29 s, 7 24 S, 6 74 C1, 6 86 s, 7 94 s, 8 93 K, 15 68 S, 9 13 s, 6 48 6 94 x, 7 25 S, 8 34 h-, 7 48 8 85 s, 7 98 S, 6 21
C, 66 95 H, 6 84 N, 6 79 s, 7 77 h-, 5 64 6 45 s, 6.39 7 31 N, 6 39 S, 7 31 s, D 39 S, 7 91 S, 6 53 c1, 7 22 s, 7 80 s, 8 99 h-, 15 81 s, 9 01 S, 6 36 s, 7 28 s, 7 29 8 34 N, 7 34 s, 8 40 N, 7 93 6 05
Calculated
s,
s, s,
s,
s,
s,
s,
R2 = 3-pyridylmetli?.n)l-.
R 2 = CH,.
TABLE I11 .S,
R/ 3-(P-I
