Journal of Medicinal Chemistry, 1971, Vol. 14, No. 6 449
NOTES
TABLE I1 SUBSTITUTED 5,6--I)IHYDRO [C]BENZOCARBAZOLE
'
FUMAR.4TESn
I
CH,CH,R, %
NO.
R1
Ra
R2
M P , OC
yield
Formula
Minimal usefulb concentration, d m 1
60 CzzHziiNz C4HaOd 160 H N(Et)z 164-166 14 H 70 CZZHZSFNZ. CaH404 40 H N(Et)z 158-160 15 F 300 75 CzzHzbClNz.C4H404 H N(Et)z 170-172 16 c1 75 CzzHzsBrNzCaH404 C 156-158 H N(Et)z 17 Br 60 Cz&L:INz. C4HaOa C 160-162 H N(Et)z 18 T 65 Cz3HzaNz.CaHaOa 150 169-171 19 CH3 1% N(Et)z 30 60 Cz3HzsNzO. C4H404 H N(Et)z 148-1 50 20 OCH3 55 CzzHzsFNz CaHrOa 80 F N(Et)z 156-158 21 H 176-178 80 CzzHzjClNz. CaHaO4 40 22 H c1 N(Et)z 182-183 50 C22H25BrN2.CaH404 350 23 H Br N(Et)z I N(Et)z 158-160 60 CzzHz2V" CtHaOa C 24 H 180- 182 60 C~JHZSNZ. CiHaOa 80 CHa N(Et)z 28 H 70 Cz3HzaNzO. CiHaOa 160 N(Et)z 182-1 83 26 H OCH3 188-189 60 CzoHziFNz. C4H404 40 27 F N(Me)t H 50 Cz3HzbFNz. CaHa04 140 28 F NCsHiod 226-228 H 184-186 60 CzoHziClNz .C4HaOa 20 29 II N(Me)t c1 75 C23HzsClNz. C4HaOa 80 30 H NCbHiod 190-192 c1 50 CziHztNz0 * CaHaO4 80 31 ocfI3 N(Me)z 160- 162 H 32 OCH3 156-158 50 CzaHzsNzO C4HaO4 20 NCsHiod H All compds were analyzed for C, H, N, and the anal. results obtained for these elements were within 0.3% of theoretical values. All compds were recrystd from EtOH. The uv, ir, nmr, and mass spectra (of the bases) are in agreement with the proposed structures. Melting points were taken in capillaries and are uncorrected. b J. Gallo Pecca and S. M. Albonico, J . Med. Chem., 13, 327 (1970); Not resistant to sterilization; these tests were performed by Dr. hi. Alvarez, Instituto de Investigaciones de la Enfermedad de Chagas. see footnote b. d Piperidino. 1
a
several ~ v o r k e r s . Electronic ~ ~ ~ ~ ~ effects are not of major importance, since this difference is observed irrespective of the nature of the substituents. Hence the relatively low reactivity of the 2-substituted compounds has to be attributed to the position and not to the nature of the substituents.
were added. The mixt was refluxed for 1 hr under the same conditions and, after cooling, was poured into Hg0 (10 ml), and HOAc was added to pH 3. The aq phase was made alk (NazCOa) and extd (Et20, 200 ml). The combined exts were dried and evapd. The oily residue was dissolved in hot EtOH (1.5 ml), and 0.58 g of fumaric acid was added. After cooling, the crystalline fumarates were filtered and worked up as usual.
Experimental Section
J. A. Cerisola and M. J. Vernengo for helpful discus-
5,6-Dihydrobenzo[c]carbazole and 10-Substituted DHBC.A s o h of the 4-substituted phenylhydrazine (0.01 mole) and ptetralone (0.01 mole) in 15 ml of EtOH and 0.5 ml of HOAc was kept a t 20" for 1 hr. The cryst solid was filtered, dissolved in 10 ml of HOAc satd with HCl, and refluxed for 15 min. The pptd 10-substituted DHBC was filtered and worked up as usual. 8-Substituted 5,6-Dihydrobenzo[c]carbazoles.-A s o h of 2substituted phenylhydrazine (0.01 mole) and p-tetralone (0.01 mole) i n EtOII-HOAc (20 ml, 3 : l ) was heated to 60' for 15 min. On cooling, the phenylhydrazine crystd out. The solid was filtered and dissolved in 10 ml of HOAc with 10 mg of di-tertbutyl-p-cresol. The soln was satd with HCl and heated to 140' in a sealed ampoule under NZfor 1 hr, cooled, poured into 100 ml of 25% NHIOH, and extd (BzH, 200 ml). The combined exts were dried (MgSOd) and evapd under vacuum, leaving an oil; the oil was dissolved in CsHs-MeOH (19: 1)and filtered through a column with 50 g of silica gel. The eluent was worked up as usual. 8-Fluor-DHBC was purified through the picrate from which the base was removed as described by Bobbitt.8 Preparation of Compounds in Table 11.-A mixt of 0.005 mole of the respective DHBC and 0.25 g of NaXH2 in 10 ml of xylene x a s stirred at 140" (bath temp) for 2 hr. The 0.25 g of NaNHz and 0.01 mole of 2-diethylaminoethyl chloride .HCl (or the corresponding 2-substituted ethyl chloride. HCl for compounds 27-32) ( 6 ) 13. hl. Barclay and N. Campbell,
J. Chem.
Soc., 530 (1945).
(7) C.E. Dalgliesh and F. G. Mann, $bid., 653 (1947). ( 8 ) J. M. Iloblitt, J. OTU. Chem., 22, 1729 (1957).
Acknowledgment.-The
authors wish to thank Drs.
sions of this work.
Nitrofuryl Heterocyclics.
2
PJ~TE J.R ISLIP*A N D MICH.U:L I). CLOSII;R Research Laboratories, Parke Davis & Co., Hounslow, Middlesex, England Received November 6, 1970
In the previous paper of this series' it was shown that nitrofurans containing partial structure I a possessed marked antibacterial activity. This note is concerned with the synthesis and biological evaluation of some [5-(5-nitro-2-furyl) -1,3,4-thiadiazol-2-yl ]amides and -ureas (11) (ie., containing partial structure Ib). Chemistry.-The preparation of intermediate urea 1 and the alkylation of this compound and 2-acetamido-
*
To mhom t o address correspondence a t the Department of Chemistry, Wellcome Research Laboratorien, Langley Court, Beckenham, Kent. (1) For the previous paper in this series see M. D. Closier and P. J. Islip, J. M e d . Chem., 13, 638 (1970).
450 Journal of Medicinal Chemistry, 1971, Vol. 14, No. -5
NOTES
TABLE I [5-(5-??ITRO-2-FURYL)-1,3,4-THIADIAZOL-2-EL] AMIDES A N D -UREAS
NO,
J-&;--J ,co-z N, R ' I1
R
Compd no
Z
1 2 3 4
H H CH&( Me)=CC12 CHzCONHCOzEt 1 CHZC(Me)=CCh 6 CHzCONHZ 7 CHzCONEtz 8 CHzCONPrz 9 CHZCONBU~ 10 CHICONHCOZEt a Described in Experimental Section. calcd, 48.6; found, 48.1.
. NO,
*
.
x--N\
Yield,
LIethod
'z
NHCHzCH=CHz U 63 NHCH&H(Br)CHZBr a 22 NHCH&H=CHz Ab 40 NHCHzCH=CHz ,4c 35 Me Bh 28 Me Bc 63 Me Bc 33 Me Bc 47 Me BC 44 Me Bc,d 17 Alkylating agent HC1. c Alkylating agent ItBr.
,
e
I Iinimum ' ' inhibitory concentration, pg/mla---Streptococcus Staphylococcus Staphylococcus Shigella faecalis aureu,? aureus sonnei MGH-2 UC-76 S 18713c c-10
-----\
Compd
1
Experimental Section3
Formu18
CIOHSNBOIIS Cl0H9Br2NsO4S Ci,Hi3Clzr1'508 Ci5H16Xe.0,S C12Il1oC12N,O4S CioHoN50~S CiaHi~Ns0~S CisHziNa06S' Ci8Hn~Ns05S Ci3Hi3NaOiS From EtOAc. C:
TABLI:I1 I n Vitro Ah-TIn.4CrPER1.4LACTIVITYO F 1-10
c\
5-(5-nitro-2-fury1)-1,3,4-thiadiazole2 to give the amides or ureas I1 is described in the Experimental Section.
d
M p , OC
255-2d7 dec 210-213 dec 120-122 193-19.ie 180-181 267-268 198-200 1.50-153 115-1 16 200-201 2 hr at 80".
2 3 40
)
2 > 2,;
1, 5 1, 3
'2.5 2 , .i
2 1 . *j 2.5 2 , !5 2.5
5 1
>25 1 IO 6 2 ,3 2 5 10 20 ) ,5 20 a See W. Szybalski, Bacteria(. Proc., 36 (1932); W. Szybalski and V. Bryson, J . Bacteriol., 64,489 (1952); and V. Bryson and W. Szybalski, Science, 116,45 (1952). * N I C against Escherichia coli VOGEL and I'seudomonos acruginosa -28 was 10 rg/ml. Penicillin-resistant strain.
The physical propertlies of the iiitrofiiraiis prepared are collected iii Table I. l-Allyl-3-[5-(5-nitro-2-furyl)-l,3,4-thiadiazol-2-yl]urea (l).-A mixt' of allyl isocyanate (9.3 g) and 2-amino-5-(5-1iitro-2-furyl)1,3,4-thiadiazole2 (21.2 g) in T H F (120 ml) was stirred and refluxed 3 hr, then cooled. Solid was collected, washed with EtZO, 11) w:iz 6. Thi5 conipd ha5 EDs05.0 mg/kg (zc) and 11.4 mg/ and recrystd from AcOH. 1-(2,3-Dibromopropyl)-3- [5-(5-nitro-2-furyl)-l,3,4-thiadiazol-2- kg (PO) agaiiibt S. pyogenes, and El>5o155 mg/kg (sc) and 120 mg/kg (PO) again5t S. aureus UC-76 yllurea (2).--Br2 (1.04 ml) was added slowly t o a suspension of urea 1 (6.0 g ) in CHC13 (200 ml) a t O", and the mixt was theit Acknowledgments.-The authors \\ ish to thank stirred 4 hr at room temp. Itecrystn of the sepd solid from 96% R. E. Bowman for helpful discussions, Ah. F. H. Dr. EtOH afforded the product, after removal of some less sol material. Oliver for microanalyses, Mr. AI. C. h'eville for valuMethod A. 3-Allyl-l-(3,3-dichloro-2-methylallyl)-1-[5-(5- able technical assistance, Miss E. 11. Tanner for specnitro-%-furyl)-1,3,4-thiadiazol-2-yl]urea(3).--NaH (6170dispertral studies, and Dr. 81. W. Fisher and his associates sion i i i oil, 1.965 g, 0.05 mole) was added in port,ioris t o a stirred of the Department of fiIicroblology, Parke, Davis and suspension of urea 1 (14.75 g, 0.05 mole) iii IIMF (70 ml), folCo. Inc., Detroit, for the biological data. lowed by 1,1,3-trichloro-2-methylprop-l-ene(8.75 g, 0.055 mole). The mixt was stirred a t room temp until neutral ( 2 4 hr), theii poured into HzO. Solid was collected and recrystd from XeOH. Method B.-The procedure used was the same as for method .4 except that the nitrofuran alkylated was 2-acetamido-5-(5-nitroAntitumor Agents. Schiff Bases from 2-furyl)-1,3,4-thiadiazole.~The products were all recryst'd Benzaldehyde Nitrogen Mustards and from 96% EtOH. Screening Results.-The above compds mere tested in vitro 2-Phenyl-4-[(3-amino-4against a variety of bacteria according to procedures described methoxy)phenyl]thiazole p r e v i ~ u s l y ,and ~ the most active of the compds are listed i n Table II.5 When tested against Streptococcus pyogenes and Staphylococcus aureus infections in mice by oral and subcutaneous s. S.\HNIS, A N D c 1'. DLLI\\ I L k * ,J, 1). hIODI,'s administration,e the only nitrofuran to show appreciable activDcpai tnwnt of Chemotherapy, HafkinP Instztute, Bombay-18, Indaa (2) W.R . Sherman, J . Org. C h e m . , 26, 88 (1961). (3) Melting points are corrected, and were determined in a capillary tube. Analytical results were obtained for C, H, and N for all compounds, and unless otherwise stated were mithin &0,4% of the theoretical values. (4) W. Szybalski, B a c t e r i d . PTOC., 36 (1952); W.Szybalski and V. Bryson. J. Bacteriol., 64,489 (1952); and V. Bryson and W. Szybalski, Science, 116, 45 (1952). ( 5 ) Compds described in the note but not listed in Table I1 were less active than those given in the table. (6) For the general in v i v o test procedures see M . W.Fisher, M. C. Manning, L. A. Gagliardi, M. R. Gaetz, and A . R . Erlandson, Antibiot. Annu., 1969-1960, 293-303 (1960); and M .I+'. Fisher, Proc. Soc. E z p . B i d . M e d . , 86, 538 (1954).
12ectzved Dcceinbcr 2, 1970
We have already reported several Schiff bases from p-aminophenylt hiazoles and benzaldehyde nitrogen mustards as possessing good antitumor activity. 2,3 (1) Government of India Research Scholar. (2) S. S. Sabnis, I n d i a n J . C h e m . , 5, 619 (1967) (3) J. D. Modi, S. S. Sabnis, and C. V. Deliwala, J . .Wed. C h e m . , 13, 935 (1970).
