NOTES
January 1970 disubstituted hydrazones, only one derivative (24) mas active. Compound 9, was most active in vitro but inactive when tested topically in the guinea pig according to the method of Arnold, et aL3
159
S y n t h e s i s and Antimicrobial Activity of Some T h e n o y l Amides 11.L I K ~ R P., SCHWER, Institute of Mzcrobaology, I=/lzuersttyof Ljubljana, Ljubljana, I-icgoslat iu
h1. Experimental Section4 Preparation of para-Substituted Phenylglyoxal N,N-Disubstituted Hydrazones. Method A.-A mixture of 0.01 mole of a-ketoaldehyde, 0.011 mole of ?J,X-disubst>itutedhydrazine hydrochloride, and 0.011 mole of XaOAc in 10 ml of AcOH was Then a 2053 aqneous Na2C03was stirred for 2 hr at 20-25'. added to alkalinity. Some products precipitated as solids, other as thick oils which solidified on standing. The solids were collected and crystallized. Compounds 7, 9, arid 34 did not solidify and were extracted into EtzO. After drying, the solvent was evaporated and the residue way crystallized. Method B.-The N,S-disubstituted hydrazine hydrochloride (0.01 mole) and 0.01 mole of NaOAc were added a t 20" to a solritiori of 0.01 mole of a-ketoaldehyde in 20 ml of EtOH, and t,he mixt,ure was stirred for 24 hr at 20". When the products crystallized, they were collected, washed (HzO),and recrystallized. If 110 crystallization took place, H20 was added to cloudiness, and the solution was filtered with charcoal and cooled. The separate crystals were collected and recrj-btallized. Method C.-The S,N-disubstituted hydrazine hydrochloride (0.01 mole) aiid 0.01 mole of NaOAc were added at 20" to a solution of 0.01 mole of a-ketoaldehyde in 20 ml of EtOH, and the mixtiire was stirred for 24 hr a t 20". The mixture was filtered arid the solvent was evaporated to drynebs in vacuo at 20". Compounds 24, 27, arid 32 were crystallized, while 40 and 41 were dissolved in Et20 and the extracts were washed with aqueous SaOAc. After drying (Na2S04), the solvents were evaporated and the residues were crystallized. Method D.--,4 solution of 0.01 mole of a-ketoaldehyde arid 0.01 mole of S,N-disubstituted hydrazine in 20 ml of EtOH was stirred a t 25' for 4 hr. After cooling the crystals were collected aiid recrystallized. Pharmacological Methods.-For all tests XXIRI albino mice (18-20 g ) and Wistar albino rats (200-250 g) were used. For T . rnentayrophytes infection, Pirbright guinea pigs (250-300 g) were used. Acute Toxicity.-LDj, values were determined in mice intraperitoneally, and the mortality over 48 hr was recorded. The aiiimals were also observed for behavior arid objective symptoms according to the Irwin scheme.6 Other Tests.-All compoiiiids were screened albo for their antispasmodic activity in ritro following the methods described by Setriikar and Tirone6arid for their coronary vasodilator activity on the isolated rabbit heart following the method of Setnikar, E t al.' Antimicrobial and antifungal activity, antiviral activity, ariticorivulsarit activity, and antiinflammatory activity were determined according to the methods previously described?
JAPELJ,
31. GLOBOKAR, 21. OICLOBD~IJ i, A. Po\PE, T. SUNJIC~
i \ i ~
Research-Development Instztute, Ki k a , Pha, niaceirttcal and Chemical W o r k s , Soeo Jlesto, I'irgoslnn ia Received -4zrgust
4, 1969
Antitrichomonal activity of 2-(2-thenoylamino)-Znitrothiazole2 has often been ascribed to the nitrothiazole moiety3a in accord with the qanie activity of related heterocyclic c o r n p ~ u n d s ,eipecially ~~ 5-nitroimidazole^.^ A variety of derivative. of thiophene-2carboxylic acid have also been found to have some antimicrobial effects.; We have now synthe.ized a number of amides of thiophene-2-carboxylic acid with various aromatic arid heteroaromatic amines (Table I) in order to examine their biological properties. Results of Microbiological Assays.-Theno? 1 amides have been tested for their antimicrobial effectiveness according to -tandard techniques a- demibed else\\ here.6 A number of pathogenic and iaprophytic bacteria, fungi, and viruses uere used a- te-t organism and the requlth are presented in Table 11. Sone of the compounds were active againit Shigella jlexnerz, Haemophalus anjluenzae, Staphylococcus aureus, Streptococcus vii.iclans, Streptococcus pyoyenes, Lzsteixta nzonocytogenes, Pastewella pseudotuberculosis, Cot ynebacterium diphtheriae, Bacillus anthracis, Diplococcus pneumoniae, Salmonella typhi, JIzcimporurn canis. and Ttichoph yton inteidigztale. Some of the compounds (1, 4, 13) markedly reduced the titers of influenza A, virus grown in allantoic fluids of embryonated eggs. The most active substances were 1 and 13 which reduced the hemagglutinins of influenza A, virus in allantoic fluidf 20-fold. Comprotected all the mice infected pound 12 at 0.00406 with 1001,Djodose of pseudorabies vim-. number of compounds protected 30-609.', of mice infected with 100LDjodose of Semliki forest virus (arbovirus group A), i.e., 3 , 4 , 8, and 11.
(1) Correspondence should be addressed t o this author.
Acknowledgments.-We \\.ish to thank Miss B. Olgiati for microanalytical data and Miss 31. J. Magistretti for pharmacological screening of these compounds. 13) H. Arnold, L. Degen, J. Potel. and R . Rehling, Arz?ieimitteZ-Forach., 14, 68 (1964). (4) hlelting points are uncorrected and were determined on a Kofler micro
hot stage. Where analyses are indicated only b y symbols of elements analytical results obtained for those elements mere within ~ t 0 . 4 7of~ the theoretical values. (5) This scheme \vas discussed informally b y S. Irwin a t a Gordon Research Conference, S e w London, S . H.. 1959. (6) I. Setnikar and P. Tirone, Arrneimittel-Forsch., 16, 1146 (1966). (7) I . Setnikar, IT. Rlurmann, and AI. T. Ravasi, Arch. Intern. P k a r m a c o d y n . . 131, 187 (1961). (8) E. Massarani, D. Nardi, L. Degen, and M. J. Magistretti, J . M e d . Chem.. 9. 617 (1966).
( 2 ) (a) Innothera and K. D . Xuong, French Patent 1.306.603(Oct. 19, 1962); Chem. Abstr.. 68, 12569~(1963); (h) N.D. S u o n g and X. P. Buu Hoi. Compt. Rend., 263, 3115 (1961); (c) D . S u o n g and F. Lajdela, Bull. SOC. Chim. France, 1591 (1965). (3) (a) D. H.Henry, J . .Wed. Chem., 12, 303 (1969). (I,) G. G. Ehrhart and H. Rushig, "hreneimittel, Entwicklung, T\-irkung. Darstellung," Bd. 2,Verlag Chemie Gmbh. 1968,p p 1314-1319. (4) (a) C. Cosar, C . Crisan, R . Horclois, R . 11, Jacoh. J. Robert, S. Tche itcheff, and R. Vaupre, Arrneimittel-Foisch., 16, 23 (1966); [b) F. Kajfei, V. Sunjib, D. Kolhah, T. Fajdiga, and 11. Oklohdiija, J. M e d , Chem., 11, 167 (1968); (c) V. Sunjib. D . Kolhah, F. Iiajfei, and S . Blaievit, ibid., 11, 1264 (1968). ( 5 ) (a) K. Schmitt, E. Lindner,and W ,Heixner, German Patent 1,112,514 (July 29,1969); Chem. Abstr., 66, 1392d (1962); (b):O. Umezawa, T. Iiahayashi, and T. Kametani, Y a k u g a k u K e n k y u , 36, 256 (1963); Chem. Abatr., 64, 2451a (1966); (c) H.Raffa, AI. Di Bella, L. Di Bella, and G. h l . Lolli, Fnrmaco (Pavia), Ed. Sci., 20, 786 (1965). (6) (a) P. Schauer and AI. Likar, Pathol. Jficrobiol., 28, 3il (1965); (11) P. Schauer, >I. Likar, AI. TiBler. -1.KrbavEiE, and .i. Polak, ibid., 28, 382 (1965); ( c ) P. Schauer, A I . Likar, 11. TiBler, and -1.KrhavCii., ibid., 29, 506 (1966).
2
GH NH -
7
\
!I
IO
I1
SOTES
January 1970 T.IBLEI1 . ~ ? ; . ~ I H . \ C T I C K I . ~.\ND L .kiY:TlFUNGAL A c T i v i w OF T H E
CO?dPOUNDS TP:STEDa AIicroorganism
S e i s s e r i a catharrhalis Salmon~llaparat!jphi B Klebsiella sp. Pseudomonas aerirginosa C a n d i d a alhicans Crypt occociis neoformans -Yocardia asteroides -4 sperg illus fumigatus Trichoph yton rubriirii
1
3
4
5
6
8
9
1
1
1
1
3
+
+
+
+
+ + + + + + + + + +
+
OCH I
I
OCH,
+
1
+
+
required for the preparation of 11, was obtained employing the procediire described for analogous compound.12 1 Preparation of Compounds I-11.-Thenoyl chloride (3.66 g, 0.024 mole) was added dropwise during 0.5 hr to a aell-st,irred and ice-cooled solution of 0.02 mole of the particular amine in 20 ml of pyridine. To complete the reaction in the case of 1, 2,5, 6,and 10, the reaction mixture was stirred for 2 hr a t room t'emperature. T o prepare 3, 4,7-9, and I1 the mixture was refliixed for 6 hr. After cooling overnight, 9 and 10 separated. Crude products were collected on a filter, washed with dilute HC1 (ea. 3%),arid recrystallized. Other products crystallized on pouring t h e reaction mixture on ice aiid F-ere filtered off, washed with dilute HC1, and recrystallized. 2-( 2-Thenoylamino)-5-chlorobenzophenoneHydrazone (12).Compound 10 (6.7 g, 0.023 mole) and 0.81 g (0.025 mole) of hydrazine in 1.5 ml of EtOH were placed in a sealed titbe and heated for S hi- at 150". The reaction mixtru'e was cooled and poiired on ice. The crude product which separated was filtered off, dried (6.3 g, 70%), and recrystallized as indicated in Table
1. 2 4 2-Thenyl)-4-phenyl-6-chloroquinazoline ( 13).-Compound 10 ( 2 g, 0.0076 mole) in 13 ml of 6.5y0XH, solution in EtOH was sealed in a glass tube and heated for 5 hr at 140". On cooling the crude product which separated was collected on a filter, washed (EtOH), and recrystallized. 112) J. F. J. Dippy and V. Mass, J . Chem. Soc., 2205 (1952).
Synthesis of 5,s-Quinazolinedione
GIORGIO > ~ h L E S h N I ,FRAXCESCO hf ARCOLIN, AXD
studied in relation to their antibacterial and cytostatic activities.2 Recently also 5,8-isoquinolinedione3 and some 5,s-quinoxalinedione derivatives have been prepared and studied. We were therefore led to investigate the closely related 5,s-quinazolinedione. We recently prepared 5,8-dimethoxyquinazoline (1) and some derivatives,j for instance, 5-methoxy-Shydroxyquiriazoline. This compound was found to have antibacterial properties analogous to those of Shydroxyquinoline.
I
Trichophyton schoenleini TTichophyton mentayrophytes Histoplasma capszc latu m means a total inhibition of microbial growth.
+
2
161
GIOVANNI RODIGHIERO
Institute of Pharmaceutical Chemistry of the liniz'ersity of P a d u a , P a d u a , Italy Received July 28, 1969
Quinones containing heterocyclic rings appear to be interesting from various points of view. Of a large number of 4,7-indolequinone derivatives related to rnytomicin antibiotics,' several had interesting antibacterial activities. Various 5,8-quinolinediones were (1) 11. J . IVeiss, G . S. Redin, G. R . Allen, Jr., 4. C. Dornhush, H. L. Lindsay, J. F. Poletto, W. A. Remers, R. H . Roth, and A. E. Slohoda, .J. -Veri. Chem., 11, i 4 2 (1968).
OH I
0
II
OH
0 2
3
The complete demethylation of 1 was achieved by heat8ing t8he substance with hlCl3 at 1SO". 5,sQuinazolinedione (3) was prepared by I\'2Cr207oxidation. It mas stable under normal coriditioris of storage arid displayed typical quinoriic behavior to I
