&\lay1969
HYPOGLYCEMIC ~ , ~ , , ~ - O X ~ U I A Z O L Y L PSALTS YI~IDI~IU~~
spectra6of all products (Tables I and 11),with absorptions a t 5.60-5.65 and 5.80-5.85 1 assigned to the carbonyl groups. T h e compounds in Table I1 mere screened for antibacterial activity by reported methods.' l l o s t of the hydantoins I showed slight i u vitro activity against gram-posit ive and gram-negative organisms. Tery limited activity was observed for these compounds (I) \Then tested against SalmoTiella typhosa and Staphylococcus aureus infections in mice. T h e 54trofurfurylidenehydrazides I1 showed slight to fair in vitro antibacterial activity, with limited activity against Salmonella typhosa and Staphylococcus aureus infections in mice. These compounds I1 exhibited parasiticidal activity8 in chicks against E i m e r i a teriella arid Histomorias meleagridis when mixed in feed at 0.001 arid 0.002% of thc ration, by the method of Johnson . g In conclusion, the antibacterial properties of both the 3- [ (5-nitrofurfurylidene)amino]hydantoins(I)and the 5nitrofurfurylidenehydrazides (11) were inferior to those of the 1-[ (5-nitrofurfurylidene) amino Ihydantoins. lo Experimental Section 3-Aminohydantoin (Method A).--A mixture of S-carboxyglycine dihydrazide (70 g, 0.48 mole) and D,MF (2290 ml) was (6) L. J. Bellamy, "The Infrared Spectra of Complex RIolecules," 2nd ed, John Wiley and Sons, Inc., New York, N. Y., 1958, p 221. (7) F. F. Ebetino, W.F. Care)., and B. F. Stevenson, J . M e d . Chem., 6 , 633 (1963). (8) G. C. JVright, U. S. Patent 3,096,347 (1063); Chem. Abstr., 6 0 , 66Oh (1964). (9) C. A. Johnson, Poullry Sei., 39, l O i 6 (1960).
38 1
heated to boiling in 0.5 hr, with mechanical st'irring. The react'ion solution was refluxed for 2.8 hr. The solution was evaporated under reduced pressure, and the solid residue was washed with EtOH (50 ml). Recrystallization from 25% EtOH (185 ml) gave white crystals. 3- [(5-Nitrof~rfurylidene)amino]hydantoin.-~4solution of 5nit,ro-2-furaldehyde (47.0 g, 0.33 mole) in Et,OH (350 ml) was added gradually to a solution of 3-aminohydantoin (38.4 g, 0.33 mole) in HzO (500 ml) at 25", with mechanical stirring. The mixture was stirred for 1.3 hr, then cooled in an ice bath. The resultant pale yellow, crystalline solid was collected and washed (HzO), mp 217-222", yield 33.8 g. A second crop (34.9 g, mp 223-225') was isolated. The combined product was recrystallized from 1\IeX02 (1800 ml). 5-Ethyl-5-methyl-3-aminohydantoin (Method C).--.1 solution of ethyl S-ethoxycarbonyl-Dcisovalinate (250 g, 1.15 moles), in hydrazine hydrate (570 ml, 11.4 moles) and EtOH (3300 ml), was refluxed for 82 hr. The solution was evaporated under reduced pressure, and the semicrystalline residue was triturated with Et20 (400 ml). The filtered product, mp 120-140") was washed with EtZO. Recrystallization from a mixture of Hz0 (4 ml) and EtOH (120 ml) gave a white, crystalline solid. 5-Ethyl-5-methyl-3-[( 5-nitrofurf'urylidene)amino]hydantoin was prepared by the same procedure as described for 3-[(5-nitrofurfury1idene)aminolhydantoin. N-Ethoxycarbonylglycine 5-Nitrofurfurylidenehydrazide.--To a solution of ,"-ethoxycarbonylglycine hydrazide (40.5 g, 0.25 mole) in 505, EtOH (100 ml) was gradually added a solution of 5-nitro-%furaldehyde (35.0 g, 0.25 mole) in EtOH (100 ml). The product was collected and washed with 70% EtOH; mp 174-176", yield 66.2 g (937,). Recrystallization from EtOH (3600 ml) gave yellow crystals.
Acknowledgments.-The authors wish to thank Mr. Grant Gustin and Mr. Marvin Tefft for the elemental analyses, and Mr. Raynrorid Freedman for the microbiologic testing data. (10) 6.bfintzer, E. R. Kadison, W.H. Shlaes, and 0. Felsenfeld, Antibiot. Chemotherapu, 3. 131 (1953).
1,2,4-Oxadiazolylpyridinium Salts. Oral Hypoglycemic Agents WILLIAMJ. FANSHAWE, VICTOR J. BAKER,S. R. SAFIR, Organtc Cheinzt a1 h'esearch Sect loti
D. A. BLICKENS, AKD S. J. Dcpco tvient of Ilctaholtc Cheviothe/ a p y , Ledeile I,ccborntorzes, Pearl IZmei, .\el*: 1 o,X
KIGGI
1 I l z ~ z s z o iof~ .lmc~iL L U I Z C'Uartatrizd Cot~ipanr/, 109G'i
Kecewed AVovember 19, 196s
-1series of 1,2,4-ouadiaLolylpyridinium quaternary salts has been synthebiLed. These compounds dibplay interesting hypoglycemic activity in mice.
44 3(5)-Pyrazol>l]pjridinium salts (1, for instance) have been found to displal interesting oral hypoglycemic activity in alloxan-diabetic mice.' As an initial development of this lead, the p j razole ring was replaced by aii isoxazole ring t c obtain some novel isoxazolylpyridiiiiuni salts2 which also exhibited interesting hypoglj cemic activity in laboratory a n i ~ n a l s . l-?vlethyl-4-(3-meth~ ~ 15-isoxazol>1)pyridinium chloride (2) has been chosen for extensive evaluation as a potential antidiabetic agent.4 As a further development of the lead, we now describe (1) V. J. Bauer, H. P. Dalalian, W. J. Fanshawe, S. R. Safir, E . C. Tocus, and C. R. Boshart, J. M e d . Chem., 11. 981 (1968). (2) V. J. Bauer, \T. J. Fanshawe. H. P. Dalalian, and S. R. Safir, ibid., 11,
984 (1968). 3) D. A . Blickens and S. J. Riggi, Tosicol. i l p p l . Pharmacol.. in press. (4) S. J. Riggi, D. A . Blicliens, and C. R. Boshart, Diabetes. 17, 646 (1968).
the s j nthesis and hypoglycemic activity of a number of new 1,2,4-oxadia~olj l p j ridiriium salts, 5 , for instance. CH, C1-
1
2
The slnthesis of uiisyminetrically substituted 1,2,4oxadiazoles by the condensation of an amidoxime with XczO has been d e ~ c r i b e d . ~Thus , ~ the reaction of X c 2 0 with isoiiicotiiiamidoxime (3)7 provided 4-(5-methj 1( 5 ) F. Tiemann, Ber., 17, 126 (1884). (6) K. Clarke, J . Chem. Soc., 4231 (1934). (7) E. Bernabeli, J . Org. Chem., 22, 1263 (1957).
1,2,4-oxadiazol-3-yl)pyridii1e (4). Quateriiization of tliv pyridiiic base 4 with methyl chloride afforded l-metliyl4-(5-inethy1-1,2,4-oxadiazol-3-y1)p?-ritiiniun1 c3h1oridc( 5 ) .
3
4
5
\J'lieii it \vas ol)s;erved that 5 tlisplxyctl iiiterestiiig liypoglyccmir activity iii mice (Table IT), the preparxtioii of a series of aiialogs was uiiclerttikcii. Thc choicc of substituents vas influeiiced the structure nctivit)' correlation alrcatly clevelopetl for tlic p\ razolylpyritliuium salts.' Reaction of the appropriate amidoxinit1 with various anhydrides gave the desired 1,2,4-oxadiazolylpj ridirie bases 6-14 (Table I). 4-(1,2,4-0xadiazol3-y1)pyridine (15) was prepared by the coiideiisatioii of 3 with triethyl orthoformate. Quaterriizatio~iof thesc Iiases with a vnriety of halides produced the 1,2,4oxadiazolylpyridiiiiurii salts 16-28 (Ta1)le 11).
27
25. R = CH 26. K = b
C'I 1 28
hctivitj is rc>t:uiiotl ulieii tlic 3 Iwsitioii oi tlic (1.2,4oxadiazo1-3-yl)pyricliiiiurii systeiii is substituted 11y ET (16), with ethyl (20), c j cloalkyl (21, 22), or phenyl (24). T h e isoinrriv (1.2,~-osadinzol-5-yl~~~yri~liriiurn system is also active with cit1ic.r :L inethjl (25) or cy~lopropjl group (26) in the 3 position. Eieplacemeiit of thv S-iiicthyl substitueiit of 5 n-it11 a11 cthyl (17), :illy1 (18), or 2-ethoxyethyl group 119) ttlso rcsults in conipouiicls 11 ith hypoglycemic acti\ it) . 1hc hypoglycemic act11 it). of c 4 i wnipouiicl w a s tested 111 C'arwortli F a r m iiiale m i c e (C'F-1or (IF-14). 25 30 g.8 The. coinpouiitls (1.3 or 3.0 iiinioles kg) ~ w w dissolved iii 0.gf snliiic or c.uspeiiih1 iii O.gG; aqucous ciirbosyiiieth) lcclluloic :riicl :ttliniiiistcrecl by g:t~ugcin :t volunic~ of 0.23 in1 23-g inouw. C'oiitrols rereiwtl : u i cqiial volunic of 1 chicale. 13loocl s:liIlplt~S (0.05 nil) ot~lalllt'cI froill rt~trol,ult,nl plcxust s :3 :tncl 5 hr a f t w (losilig I\ crt' a s ~ a y e dfoi ~ 1)lootl glucose (cstiniatecl a s I ctluciug sugar (witelit) usiiig til(. niethotl of Hoffniang :LS adapted for tlw 'Tc~hlicoii huto,liialyzcr. Result\ arc' inclutlcd iii Table>11. Farthr>rI\ orl; IS iii progress t o t1etcriiiiiic~)oteiitiul r1iiiir:tl utility o f t h c w ox:idiazolyl1)) ricliiiiuiii salt 5.
Con1pd 15
4
ti
7 7
7
8 9 10
Experimental Section'o 3-Methylisonieotinamidoxime (29 j.- To A stirt ed solutioii ot 5.0 g (0.042 molr) of 3-:~ietli\;lisoii:cotiiio1~itr1le~~ :tnd 2.h g - - __ a A = isoriicotinamido.\riine,iB = 5-meth?-lisonicotinamido?;ime, C = isonicotinic wid anhydride [.4.Jt-. Shrecker and P. R. lIaur>-, J . .-I m e / ' . C'hem. Soc., 76, 5803 (1054)], I1 = nicotin:imidoxime,".' 1.: = pic.olina~nidosime.~* Compounds have lwm aiialyzed for C, H, S. F. Fichter and H. Iteeh, Helv. Chitii. . I d a , 6, 457 (l92:3). Bp 105-108" (0.07 mm). e Characterixecl tis the rnethiodide 23 (TLtMe 11). nip 113".
'
(8) 'I'echnlLdl c ~ % i s t ~ ei i iof ( .\lisa I, \\ 111 and 311.5 A Gieeiilng 13 gredti\ appreriated (CI) U S Hoffman, J Hzol L i t e m 120, 31 ( 1 9 3 i ) (10) Nelting poliits a c r e dewrmiiied in a Hershherg nppnintus and art uncorrected. .\licroand\ v s u c r p performed I n 11r L .\I. Branrone and stafl , nheie analyses tire indicated onli b\ *J mbois of the elements, iinaljtiriil rewlts obtained for those eleinentc n e l e uithin 1 0 4% of the theoretic.il , d u e s Uv spectra nere dctermincd i n X r O H solution uith 'i C a r y 1I spectro pliotometer 1): 31r I\ I~ulniorand w t d f f ,11) H l d i i i . l u h u y u i u Zaudtz 81, 141 i l O G I ) .
383
I R2
Retrxstn Conipd
It 1
16
H CHs CHa CHa
€I H H H
CHa C2H. c-CaHs C-CIHI CHs C6Ha
H H H H CHa H See 2.5 in
J
17 18 1'3 20
21 22 23 24 25 26 27 28
R1
R2 CHI
CHI CiHs CHzCH=CII2 CHCHIOCIH~ CHJ CHs CHI CHz CHI text
See 26 in t e x t See 27 in text See 28 in text
s Cl CI
1 C1
Cl CIOJ C1 C1
1111,"C dec 206 103-165 140-142 188-100 18i-188
C1
128-1213 211-212 20(t203 108-110 26n-262
Cl
Ii3-1i5
CI
226-227 203-205 156
I
I I
solvent
i-Pro11 CHCN i-I'rOH i-I'rOHhexane i- 1'1 0H- E t 10 EtOH CHCN CHCN i-I'rOH CIISCN i-I'rOHhexane CHCN MrOH i-I'rOH
1.3 illmoles, k g
3.0 mmolrs,hg
Control
35 i5 d 34 i d 34 i 2 13 :
30 i 4 e 68 1 7 e 48 5 41 11
7 1 6 3'3 zt 6 -8 1 4 6 1 4
14
27 = 4 !I3 If 1 S i i3
-:
*
*
2
3
j i i8
(i2 + 13 I!) i (i ,X + 10 3:
5
22 i 4 33 = 2 2 i zk i
0 i3
*5
33 =k 5
6 1 4 s i 4 4 i . 5 31 -C i 15 i 4
29 i 4 38 & 6 50 i 12
6 1 3 18 i 8 13 1 6
*
ti0 11 82 i 3
I3
:?I
32
+ +
a Compounds have been analyzed for C, H, S , halogen. * \.dues are means =tstandard errorb of fodr t o a i s mice. .\lasinid reductions in blood glucose concentrations 3 or 5 hr after dosing are expressed as per cent decrease from predoae values. Control animals were dosed orally with vehicle. An increase in I)lood glucose is indicated !iy a flegative sign (----). ;\\rerage predose liloo3 glucose concentration for 88 control mice was 128 & 2 mg (;. e i O . 5 of the theoretical value. 1.6 mnioles/kg. e 3 . 2 iiiniolesikg. I' The crude S-methyl chloride was converted t o the perchlorate salt for characterization. 1k0.G of the theoretical value.
(0.042 mole) of HONHS'Cl- in 25 ml of EtOH and 10 nil of H20 was slowly added 2.2 g (0.021 mole) of SazCOa. The solution mas heated under reflux for 3 hr and then concentrated under reduced pressure to give a white solid residue. The solid was taken up in hot EtOH, filtered, and concentrated under reduced pressure to give a tacky, white solid. The solid was recrystallized (i-PrOHhexane) to yield 1.32 g (18%) of colorless crystals, mp 102-log", and an additional recrystallization aflorded colorless crystals, mp 135-139". Anal. (C7HsS30.0.5HzO) C, H, S. Cyclopropanecarboxamidoxime Hydrochloride (30).--A MeOH solution (200 ml) of 20 g (0.37 mole) of SaOAIe was slowly added t o a MeOH solution (200 ml) of 25 g (0.37 mole) of cyclopropyl cyanide and 25.7 g (0.37 mole) of HO?;H3+C1-. The mixture was filtered and concentrated under reduced pressure to a viscous liquid which was taken up in EtOH. The mixture was filtered and the filtrate was concentrated under reduced pressure t o 33 g (89:;) of a clear, viscous liquid. ,A 3-g sample of the cyclopropanecarboxaniidoxime was treated with an excess of ethanolic HC1. The addition of Et20 precipitated a solid which was twice recrystallized (i-PrOH-hexane) to provide of'-white crystals, mp 178-181 '. Anal. (C4HsC1S20) C, H, C1, X.
4-(5-Methyl-1,2,4-oxadiazoI-3-yl)pyridine (4).---4 mixture of 27 g (0.2 mole) of isonicotinamidoxime~(3) and 50 ml of AclO was heated under reflux for 3 hr. The solvent was distilled and the residual brown liquid was treated with 100 ml of aqueous Na2COa. The solid which separated was twice recrystallized (EtOH) to yield 10 g (31:;;) of off-white crystals: mp Y.2-93'; uv, 226 m,u ( e 10,200) and 273 mp ( e 2500). =Id. (Table I). l-Methyl-4-(5-metliyl-l,2,4-oxadiazol-3-yl)pyridinium Chloride (5).--A mixture of 4.5 g (0.028 mole) of 4 and 10 in1 of MeCl was heated for 18 hr at 120' in a glass-lined steel bomb. The excess lIeC1 was allowed to evaporate and the residual solid was recrystallized ( X e C S ) to yield 4.1 g (69%) of colorless crystals: mp 150-152"; uv, 253 mp ( t 10,600). Anal. (Table 11). 1,2,4-Oxadiazolylpyridines(Table I).-Compounds 6-15 were prepared by the condensation of an amidoxime with the appropriate anhydride or with triethyl orthoformate using the procedure described for 4. 1,2,4-OxadiazolyIpyridinium Salts (Table II).-Compounds 16-28 xvere prepared hy the reaction of the 1,2,4-oxadiazolylpyridines 6-15 with :in alkyl halide in a bonih (as for 5, above) or in an alcoholic solvent under reflux.
