244
J o u m l of Medicinal Chemistry, 1971, Vol. 14, No. 3
ml of CFaCOOH and stirred a t 0" for 3 hr. The CFaCOOH was removed zn Vacuo to yield a yellow oil which was then dissolved in slightly basic aq soln. The aq phase was extd several times with CHC13 to remove any urireacted starting material. The aq solti was made slightly acidic arid the org acid which pptd wab removed by filtration arid dried to give 0.90 g (81% yield) of white solid. Recrystn from PhH-Me2C0 gave 0.86 g of product; mp 180.0-180.5". Anal. (CI&N80,) HI N , Calcd C, 67.45, found, 68.08.
Acknowledgment.-The authors wish to thank Dr. H . S. Ragheb of the Department of Biochemistry, Purdue University for performing biological testing of la,b,c,d.
Synthetic Biologically Active Polymers. 7. Antibacterial Activity of Some SulfonamideFormaldehyde Copolymers L.
GUY
1)ONARUM.I'
.&NU
JOHN1tAZZLNO'
Department of Cheruislry, Institute of Colloid and Surface Scaence, Clarkson College of Technology, Potsdani, New York
1,;678
Zieceived September 10, 1870.
Chemistry.-In previous publications2 \I e have described the preparation and certain biological net ivities of a number of synthetic biologically active polymers. Activities dealing with antimalarial properties of some sulfonamide-formaldehyde copolymers 11ere among these reports.2c-e Since these latter reports, we havc beguri to screen the same or analogous copolymers more broadly. This report concerns the antibacterial activity of three sulfonamide-formaldehyde copolymers (see Table I) and a sulfone-formaldehyde copoIymer. The copolymers \\ere prepared by methods reported earlier. 2c-e Biological Activity.- As can be seen from Table I , iir most teste, the monomer and the polymer had approximately equivalent antibacterial activity under the test conditions employed ivith a general tendency for the monomer activity t o be higher. Thus, it continues t u appear that polymerization of drugs may be useful as a method to prepare novel drug systems. Employing three samples of the 4,4'-diarnixiodiphenylsulfone-formddehyde copolymer of differing molecular weightszein the antibacterial testing gave results (see Table I) which indicated that in this copolymer system, only a very minor indication of variation of activity with molecular weight was observed. Experimental Section
All formaldehyde copolymera were prepared and characterized as reported earlier.2c-e Antibacterial screening was carried out by seeding hluellerHinton agar with the test organisms and adding antibiotic assay cylinders to each petri dish. Each compound tested was added t o the cylinders as a 1% solution in DMF. Each monomeric sulfonamide drug and the corresponding formaldehyde copolymer (1) Taken in part from the thesis to be submitted by Mr. John Razzano in partial fulfillment of the requirements for the Pt1.1). degree. (2) (a) R . J. Cornell and L. G . Donaruma, J. Folym. S e i . , SA,827 (1965). (1)) K . J. Cornell and L. G . Donaruma, J . M e d . Chem., 8, 388 (1065). (c) L. G . Donaruma and J. Raaaano, ibid., 9, 25831966). (d) J. R . Dombroski, L. G. Donaruma, and J. Raazano, ibid., 10, 963 (1967). (e) J. R . Uombroski, L. G . Donaruma, and J . Razzann, ibid., 10,964 (1967).
NOTES
Sulf apy ndiiie
Sulfabenzamide
Staphylococcus pyogenes Eschcrzchza colz Aerobacter aerogenes Pseudonionah aeruginosa Staph pyogents E coli A . aerogenrs Staph. pyogencs E COlL A . aerogenrs E's. aeruginosa Staph. pyogencs
1.1
1 0
1.7 1.0 1.1 1.0
1.1 1.0
1 5 1 0 1 0 1 0 14 1 0 Sulf anilamide 1 % 1 0 1 2 1 0 1 1 1 0 1 5 1 0 4,4'-L)ianiinodi1 4 1 0 (61, = 4700p pherigl~ulfoiie 1 7 1 0 ( f i , = 7600) 1 3 1 0 ( f i , = 10,000) * fir, = weight average molecular weight f 10(,$.2e weie te5ted at the same time After overnight iiicubatioti at 3 7 O , the zone:, of inhibition were meaaured. They were getierally of the order of maguitude of 20-30 mm, even though the total loweat value observed wa5 10 mm and the highest 35 mm.
Acknowledgments.-We are indebted to the Public Health Service for support of this \I ork under Research Grant 5ROl-AIOGGG2, and to hyerst Laboratories for carrying out the antibacterial testing.
New Thiocarboxamides Derivatives with Specific Gastric Antisecretory Properties CHARLLS E. MALI-~N, BERNARD 13. DANIWL, Chemical Research Divisaon, L N D S.IVIF.R13.
L. P.ISCAULI*
Pharniacological Kesearch Dzvzsion, Science Union el ilssoci&s Groupe de Recherches des Laboraloires Servier- 92-Suresnes, France Krccived July 11, 1970
Atropine-like drugs with their troublesome systemic side effects were, for a long time, the only products available for gastric antisecretory properties in ulcer therapy. During the past few years attempts have been made to find specific gastric antisecretory products acting by a nonanticholinergic pathway. A well-documented review has just been published 011 this subject. Among newrly described chemicals, the most studied, 2-phenyl-2-(2-pyridyl)thioacetamide (PPT), although not possessing really specific antigastrin proper tie^,^ seems to be the most available. Surprisingly, very few derivatives of this structure have been described. I n the course of a research program on antiulcer compounds, we therefore synthesized some thiocarboxamides. Although completely devoid of anticholinergic activity, most of these compounds pos(1) D. E. Butler. R . A . Purdon, and P. Bass, Amer. J . D i w s t . Diseases, 16 157 (1970). (2) D. L. Cook and K. G . Uianchi, Lzfe S c i . , 6, 1381 (1967). (3) G . Gillespie, V. I. MeCusker, B. S. Bedi, H. T. Debas, and I . E. Gillespie, Gastroenterology, 56, 81 (1968).
Journal of Medicinal Chemistry, 1971, Vol. 14, No. 3 245
NOTES
TABLE I RiRzCHCSNHz No.
RE
MP, OC
Crystallization Solvent
-Corresponding BP, OC (mm) or mp, OC
Formula
nitrile----7LD'O
65-70 (0.05)' 1.5262 (23) CTHSNZS. HC1 2-Py 190-192" MeOH 2-Yy 90-92" C7H 8N zS HzO 50-54 (0.05)' 1.5072 (26) CsHioNzS .HC1 2-Py 163-164 ACOEt 2-Py 112-1 13 C&,-CyClOheXane CsH ioN zS 60-65 (0.1)g 1.5058 (22) C 9HitNzS. HCl 2-Py ACOEt-EtOH 180-1 81 2-Py 108-109 C9HizNzS CeHs CioHirNzS .HC1 68-70 (0.l)g 1.5037 (23) 2-Py 160-162 EtOH 2-Py CloHi4NzS 93-94 Cyclohexane 48-52 (0.01) 1.5028 (22) 2-Py EtOH-cy clohexane CioHirNzS. HC1 198-200 2-Py 163-164 ACOEt CioHirNzS 76-80 (0.04)Q 1.5008 (20) 2-Py C~iHisNzs*HC1 EtOH 159-160 2-Py 104-105 Cyclohexane CiiHisNzS 76-80 (0.1)g 1.4982 (22) 2-Py 138-140 C~,H6-cyclohexane CiiHi8NzS 97-100 (0.04)o 1.4971 (19) 2-Py Cyclohexane CiaHzoNzS 75-76 8 72-74 (0.3)' 1.5175 (24) 2-Py CioHizNzS .HC1 140-141 9 ACOEt-EtOH 2-Py 9a 74-75 Cyclohexane CioHizNzS 139-140h 2-Py 10 MeOH CizHiiNaS *2HC1 195 2-Py EtOH loa 161-162 CizHiiNaS 193-194 2-Py 214-215 11 Sublimation CiiHioNiS 80-87 (0.1);' mp 33-34" 2-Pyrazinyl ceH,h'as 12 113-114 CsHs 72-74 (0.06)' 1.5142 (24) 2-Pyrazinyl 88-90 13 CsHiiNaS CsHs 133-134' 2-Pyrazinyl 142-143 14 MeCN CizHiiNaS 132-140 (0.03);' mp 64-65' 2-Pyrimidyl 185-186 MeCN 15 CizHiiNaS 2-Pyrimidyl 155-158 150-160 (0.2); mp 71-73' 16 E tOH-H*0 ClzHioCINaS 2-(4,6-Mez)- 149-150 80-81 17 EtOH CsHiiNaS p yrimidyl 138-139' 4(5)-Imida18 183-184 EtOH C6H7NaS zolyl 19 115-125 (0.01);' mp 42-44' 2-Thiazolyl 125-126 EtOH CiiHioNtS 20 152-153* CSHS MeOH CirHiaNS 21 H 80-85 (0.1)'" 1.5211 (23) 196-198 EtOH CaHioNZS. HCl 21a H 139-140 EtOH CsHioNzS 22 H 140-141' CsH6 CIHSNZS Acetamide 23 123-124d C7HsNzS E. Maruszewska-Wieczoekowtika and J. Michalsky, Rocz. Chem., 31, 543 (1957). E. E. Van Tamelen and J. S. Baran, J . Amer. Chem. Soc., 80,4659 (1958). T. S. Gardner, E. Wenis, and J. Lee, J. Org. Chem., 19,753 (19.54). * J. Klosa, Pharmazie, 9,754 (1954). A. Adams and 13. Salck, J . Chem. SOC.,3061 (1959). d F. Zymalkowski and W. Schauer, Arch. Pharm., 290,218 (1957). e K. Winterfield and K. Fuck, ibid., 26,448 (1956). f Adapted procedure from M. Protiva, J. 0. Jilek, and J. Plinel, Collect. Czech. Chem. Commun., 16,640 (1951). 0 C. 1).Gutsche and H. W. Voges, J. Org. Chem., 32,2685 (1967). h N. Sperber, 1).Papa, E. Schwenk, and M. Sherlock, J.Amer. Chem. Soc., 73,3856 (1951). French Patent 1,404,514, July 2, 1965. i Japanese Patent 630 (,54), Feb 4, 1954. k Bioc h a . Prep., 5, 97 (1957). I German Patent 896,809, Nov 16, 1953. V. Roekelheide, W . S. Linn, P. O'Grady, and M. Laniborg, J. Amer. Chem. SOC.,75, 3243 (1953). 1 la 2 2a 3 3a 4 4a 5 5a 6 6a 7
sess specific and powerful gastric antisecretory properties. I n this note, we report the synthesis, preliminary pharmacological results, and a first approach to structure-activity relationships of 22 thiocarboxamides. A few of these were selected for a more complete pharmacological study which will be published in detail later. Chemistry.-All thiocarboxamides synthesized are listed in Table I. The derivatives with sufficiently basic properties to give nonhydrolyzable salts in aq s o h were studied as hydrochlorides. The thiocarboxamides were synthesized from the corresponding nitriles by reaction with H2Sin pyridineEt3N at ordinary temp or in sealed tubes at The nitriles were synthesized by known procedures (cf. Table I). Purity was determined by potentiometric titration in AcOH and, if possible, by glc (SElo 5% on Aeropak or CAR 20 M 5% on Chromosorb). Structure-Activity Relationship.-Compounds 1, 2, 4, 5, 6, 8, 9, 13, 14, and 16 are more active than PPT, an agent fully described.2 Based on their therapeutic (4) A. E. S. Fairfull, J. 1,. Lowe, and D. A. Peak, J . Chem. Soc., 742 (1952).
index* the activity of 1,5, and 16 is about the same as that of atropine ip. In a first approach to a structure-activity relationship, it seems that the antisecretory activity is related to the grouping S / NCyCaCa
N'
The following substitutions have been made, and either lower the activity very much, or completely suppress it: (a) the substitution of S by 0 (23); (b) two instead of one NC chain in the y position to the thiocarboxamide group (10,ll); (c) no N in the side chain (20 and thioacetamide); (d) lengthening of the distance between the nonamide N and the thiocarboxamide group (21). N in the y position to the thiocarboxamide group seems to be necessary for the activity, and it may or may not be implicated in a ring (22). However, two compounds with a pentacyclic ring, though having N in
* Therapeutic 448; 1 = 404; 6
Index
> 526;
=
16
EDM /LDN (Shcty rat). Atropine sulfate2 667; PPT,HC1 = 222.
246 Journal of Medicinal Chemistry, 1971, Vol. 1.4,N o . 3
TABLE I1 Gastric an tisecretory activity EDw, m g / k Shay ratb
Toxicity
LD50,mg/kg No.
1
2 3 4 5
6 7 8 9 10 11 12 13
14 15 16 17 18 19 20 21 22 23
per os (mice)
570d (545-595) 618 (573-668) 673 (576-787) 628 (576-686) >1.000 470 (398-554) >1.000 >1.000 575 (532-623) 70 (58.6-83.6) >1.000 >1 .ooo 830 (686-1004) 924 (775-1101)
1.42 2.30
>10- 4
3.5.10-5
5.10
>io-'
4.05
>io-'
1.90 2.64
>io-'
11.50 3.70 3.25
1.25.10-4
>io-' >io-'
>10-4
NA (20)
>1.000
NA (100) 16.2 4.28
>10-4 >10-4
4.32
>10-4
7.90 1.50 7.82 NA (100) 50 82 NA (50)
>1.000 >1.000 >1.000
>1.000 >1.000 653 (568-751) >1.000
4.60 NA (100)
>1.000
Reference products
Anticholinergic activity pAiC
LDwa
NOTES
vacuum. The solid residue was recrystd from CeHe to give 6 g (60%)) mp 108-109°. Anal. (CsH12NS)N, S. The hydrochloride was prepared by adding etheral 4 N HC1 (6 ml) to 3a (4 g) in EtOH (150 ml). The solvents werc removed under vacuum and the residue was recrpstdfrom 90 ml of EtOAcEtOH (50:40); yield 3.9 g (8070), mp 180-181' dec. A n d . (CsHizNS.HC1) N, S. Gastric Antisecretory Activity in the Rat.-Gastric antisecretory activity was evaluated in the 4 hr polyrus-ligated rat, using the technique of Shay? The compds were suspended in 20'/;, gum syrup, and were administered intraduodenally immediately after pyloric ligation to groups of 6 male Sprague Dawley/CD rat.s weighing 221 f 1.77 g . t Free acid output was calcd for each rat and expressed as pequiv/4 hr per 100 g of body weight. Data of the whole test series have been pooled for the control group (183 rats),$ and the mean value of each group receiving drugs was compared to the mean value of this control group using t.he Student's "t" test. Per cent inhibition whs calcd in comparison with the control values representing loo%, and plotted on semilogarithmic paper vs. mg/kg of dose. EDbowas read from the graph. Three to five doses were used for each compound. After completion of this manuscript, some pharmacological results on 2-pyridyl thioacetamide were described by J. Borsy, el al., a t the 4th World Congress of Gast,roenterology i n Copenhagen. These results are in full agreement with ours. ~
>10- 4
>io-' >10-4
(5) H.G.Shay, S. A. Komarow, S. 9.Felds. I). Meranse, h l . Gruenstein, and H. Siplet, Gastroenterology, 5 , 43 (1945). t m zk standard error of the mean. Control values for these experiments with 185 rats were: vol: 3.09 i 0.06 m1/4 hr per 100 g . Free acid concn: 85.8 f 1.2 mequiv/l. Free acid output: 271.8 zk 7.9 pequiv/4 hr per 100 g. Total acid concn: 111.0 zk 1.0 mequiv/l. Total acid output: 348 ct 8.6 pequiv/4 hr per 100 E .
Antimicrobial Compounds. 1. Synthesis and Antimicrobial Activity of Some Alkylidene, Cycloalkylidene, and Arylidene Derivatives of 3-Hydrazinopyridazine
>io-'
ED% Shay-rat
Atropine sulfatee
207 ip 0.462 ip (182-227) PPT * HClf 592 PO 5.406 >10 - 4 (526-667) Thioacetamideo ~ 2 2 ip 0 35.0 ip a Acute toxicity was determined orally in male albino mice CJI strain. LDm calcd by C. S. Weil's method [Biometrics, 8, 249 (1962)l. Numbers in parentheses are fiduciary limits of LDw. Compounds are given by intraduodenal route. NA = inactive compound. Numbers in parentheses are the maximum dose assayed. Anticholinergic activity was established on perfused guinea pig ileum by pA2 technique [E. Bulbring, A. Grema, and 0. It. Saxby, Brit. J . Pharmacol., 13, 440 (1958)l. Drugs were dissolved in 0.97, saline. Van Tamelen and Baran (footnote a, Table I ) have LDu mice as 750 mg/kg sc. Atropine sulfate from FLUKA AG, Buchs (Switzerland). f 2-Phenyl-2-(2-pyridy1)thioacetamide .HCl synthesized in our laboratories. 0 Thioacetamide from Schuchardt, Munchen (Germany).
this position, were inactive (18) or showed only mild activity (19). Experimental Section
2 4 2-Pyridy1)butanothioamide (5a).--2( 2-Pyridy1)butanonitrile (8.2 g, 0.056 mole) was dissolved into a mixture of EtaN (5.6 g, 0.056 mole) and pyridine (8 9). The soln was satd with dry HzS a t room temp and treated in a sealed tube to 100' and maintained for 15 hr. After cooling, the mixture was poured into H20 (100 ml). The suspension was extracted with CHCla, the extracts were washed (HzO), dried (NazSOd), and concd under
31. LIKAR,B. DRINOVEC,
Institute of Microbiology, University of Ljubljana, Ljubljana, Yugoslavia
M.
JAPELJ,
* A, POLLAX,A.
POVSE, AND
P. JERMAN
Research and Development Institute, Krka, Pharmaceutical and Chemical Works, Novo Mesto, Yugoslavia Received June 1 1970 I
Various sulfonamidopyridazines1v2have been reported to have antibacterial activity with a low toxicity. In our experiments we have found that 3-thenoylamino6-chl~ropyridazine~ exhibits good antimicrobial activand a few ity. A number of hydrazin~pyridazines~ alkylidenehydrazinopyridazines5 have been reported to (1) (a) G.W. Anderson, H. E. Faith, H. W. Marson, P. 9. Winnek, and R. 0. Roblin, J . Amer. Chem. Soc.. 64, 2902 (1942); (b) G. Grundmann, Chem. Be?., 81, 1 (1948); (e) W. G , Overend and L. F. Wiggins, J. Chem. Soc., 239 (1947); C. Pedrali and A. Mantegani, J . O w . Chem., 28, 778 (1958); (d) T. Horie, K. Kinjo, and T.Ueda, Chem. Pharm. Butt,, 10,580 (1962); (e) I. Satoda, F. Kuaada, and K. Mori, Yakugaku Zasshi, 8% 233 (1962); (f) 8. Kukolja, Z. CeniC, and D. Kolbah, Tetrahedron, 19, 1153 (1963). (2) M. Kumagai and M. Bando, Nippon Kagaku Zasshi, 84,995 (1963). (3) M . Likar. P. Schauer, M. Japelj, M. Globokar, M. Oklobdtija, A. Povbe, and V. Sunjib, J . Med. Chem., 18, 159 (1970). (4) (a) E. Schlitter, J. Druey and A , Marxner, Foriechr. Arsneim.-Forsd. 4, 295 (1962); (b) J. Druey and A . Marxner, J . Med. Pharm. Chem., 1, 1 (1959); (c) D.Bargeton and J. Roquet, Arch. Ent. Pharmacodyn., 187,428 (1962). (5) (a) D. Libermann, BdZ. Soc. Chim. F r . , 1430 (1954); (b) Britislr Patent 856,409; Chem. Abstr., 65, 13459 (1961); (c) British Patent 788,502; Chem. Abstr., 66, 11967 (1961); (d) E.Bellasio, F,Parravioini, and E. Testa, Formoco Ed. Sci., 84, 919 (1869).
