Journal of Medicinal Chemistry, 1971, Vol. 14, N o . 2 175
NEWCOMPOUNDS
TABLE I
Experimental Section2 (1).-A soln of KCNO (3.57 g, 0.044 mole) in HzO (55 ml) was added to a soln of 5,6-dihydro-7H,12H-dibenz [c,f]azocine .HC13 (10.8 g, 0.044 mole) in H 2 0 (6500 ml). After 15 days stirring a t room temp, the reaction mixture afforded, when concd, a solid which was recrystd from EtOH to give 1 (6.6 g, 59.47,) as colorless crysAnal. (C16H16N20)C, H, N. tals, mp 237-239'. 5,7,12,13-Tetrahydro-6-carbamyldibenz[c,g]azonine(2).Compound 2 %-asobtained similarly in 73.2% yield from 5,7,12,13-tetrahydro-6H-dibenz [c,g]azonine .HC14 (12 g, 0.046 mole) and KCNO (3.75 g, 0.046 mole) in HzO (2000 ml). Colorless crystals from 967, EtOH, mp 194-196'. Anal. (C17H18N20) C, H, N. l-Cyano-2,3-diphenylaziridine(3).-A soln of BrCS (20.36 g, 0.19 mole) in Et20 (80 ml) was dropped a t 0-5' for 20 min into a soln of cis-2,3-diphenyla~iridine~(31.2 g, 0.16 mole) and EtsN (19.4 g, 0.19 mole) in Et20 (400 ml). The mixture was stirred for 4 hr at room temp and then filtered, the cake was repeatedly washed with EtzO, and the combined filtrates were evapd to dryness. The residue was taken up with hexane and filtered to give 3 (33 g, 94%) as a colorless solid, mp 116-117'. Anal. cC15Hi2NQ) .~ ~,C. H , N . l-Carbaniyl-2,3-diphenylaziridine(4).-A mixture of 3 (41.3 g, 0.187 mole), NaOH (75 g), HzO (130 ml), and dioxane (950 ml) was stirred for 7 days a t room temp and then for 24 hr at 50". The resulting cloudy soln was evapd to dryness under reduced pressure, and the residue was taken up with HsO and little Et20 and then recrystd from CsH6 to give 4 (11.2 g, 25%) as colorless crystals, mp 158-160'. Anal. (CljHlaN20) C, H, N.
ApproxC
5,6-Dihydro-7H,12H-6-carbamyldibenz [c,f] azocine
(2) Melting points are corrected a n d mere taken on a Buchi capillary melting point apparatus. A11 compounds vere analyzed for C, H, and anal. results were x i t h i n zk0.47, of t h e theoretical values. ( 3 ) G. Pala, A. Mantegani, and E. Zugna, Tetrahedron, Z6, 1275 (1970). (4) G . Pala, E. Crescenzi, and G . Bietti, ibid., in press. ( 5 ) A . Weissberger and H. Bach, C h e m . Ber., 64B,1095 (1931).
Some Derivatives of i'-Oxabicyclo[2.2.l]heptaneexo-cis-2,3-dicarboxylicAcid SAMUEL J. DOMINIANXI* A N D RONALD L. YOUNG The Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46206 Received August 15, 1970
N-Ar
a
H CO,H
$OH I
H O 1
H
C02CH2CH20Ar
2
R or h r
Formulao
LD,
'C
mg/kg
l a o-FCsH4 Ci4Hi2FNOa 135-137 1000 l b m-FCsH4 Ci4HizFNOa 136-138 300 I C p-FC6H4 CirHizFNOa 168-169 300 3a (CH3)zCH CiiHi605 127-129 300 3b o - C H ~ O C ~ H ~ C H Z C16H1806 98-100 30 3~ VZ-CH~OCBHICHZ C16H1806 127-128 30 3d ~ - C H Z O C ~ H I C H ~ Ci6H1806 110-112 10 C ~ S H ~ ~ O J 122-124 30 3e C ~ H & H Z 3f V L - C ~ C ~ H ~ C H Z CiaH15ClOa 143-145 30 3g p-CIC6H4CHz CisHisCl0,j 158-160 30 3h P-FC~HICHZ CisHlsFOs 135-136 10 3i 3,4-(0cH~O)C&cH2 Cdf1607 146-147 10 a All new compounds described gave elemental analyses for C and H within =t0.470 of the calculated values. Ir and nmr spectra were also in agreement with the assigned structures; in particular, the nmr spectra confirmed the assignment of exo-cis stereochemistry.' b Uncorr; recorded on a Mel-Temp apparatus. c Dose a t which fatalities occurred; compds were administered ip to mice. 150" for 1-2 hr. The cooled residue was then recrystd from EtOH. Monoesters. 3.-A mixture of anhydride and the appropriate alcohol was heated a t 125' for 1-2 hr. The cooled residue was extd with aq Na2CO3 and the aq extracts were acidified with HC1. The ppt was collected, washed with H20, dried, and recrystd from an appropriate solvent, usually C6H6-Skelly B. The i-Pr deriv 3a was prepared by refluxing the anhydride in i-PrOH containing pyridine.
Potential Antidiabetics. 7. N1-(p-Hydroxybenzylmethyl)-3-methyl-4arylhydrazono-2-pyrazolin-5-ones and N1-(P-Hydroxybenzylmethyl)-3-methyl4-arylazo-5-methyl- or -phenylpyrazoles H. G. GARG.4ND CHANDRA PRAKASH Department of Chemistry, University of Roorkee, Roorkee, India
Recently some 7-oxabicyclo [2.2.1]heptane-2,3-dicarboximides (1) with anticonvulsant activity were described.' Some aryloxyethyl esters 2 were also reported2 as plant growth regulators. We record herein the preparation of additional examples of 1 and of some mono esters 3, all of which proved t o be highly toxic C S S depressants (Table I).
$
Compd
MP!
: CO,R
H
3
Experimental Section S-Fluoroarylimides. 1.-A mixture of equimolar amts of 7-oxabicycloL2.2.11heptane- ezo - cis- 2,3- dicarboxylic anhydride and the appropriate fluoroaniline was heated without solvent a t
* T o whom correspondence should be addressed. (1) E. R. Bockstahler, L. C. Weaver, and D. L. Wright, J. M e d . Chem.. 11, 603 (1968). ( 2 ) V. A. K r a f t and N . N . hlel'nikov, B i d . Aktiun. Soedin., 255 (1965); C h e n . Abstr., 64, 673g (1966).
Received August 4, 1970
A few pyrazoles and related compounds appear t o give promising results in antidiabetic tests', and, therefore, further combinations seem worthwhile studying. This paper describes the synthesis of N'-(P-hydroxybenzylmethyl)-3-methyl-4-arylhydrazono - 2-pyrazolin5-ones and N1-(~-hydroxybenzylmethyl)-3-methyl-4arylazo-bmethyl- or -phenylpyrazoles and also includes the hypoglycemic activity of 3-methyl-4-arylazo-5-phenylisoxazoles. Biological Results.-On oral administration at various doses (25-100 mg/kg) in fasted guinea pigs for 18hr prior to and during testing, 4-phenylazo-, 4-(2-nitrophenylazo)-, 4-(3-nitrophenylazo)-, 4-(2-methylphenylazo)-, 4-(2-methoxyphenylazo)-, 4-(3-methoxyphenylazo)-, 4-(4-ethoxyphenylazo)-, 4-(2,5-dichlorophenylazo)-, and 4-(2,6-dichlorophenylazo)-3-methyl-5-phenylisoxazoles essentially displayed no hypoglycemic activity as compared with chloropropamide. After a predetermined time of peak effect the blood was ana(1) H. G. Garg, D.Sc. Thesis, Agra University, India (1969). (2) H. G. Garg and P. P. Singh, J . M e d . Chem., 13, 1250 (1970), a n d ref
cited therein.
176 Journal of Medicinal Chemistry, 1971, Vol. 14, iYo. 2 TABLE I Ni-(~-HYDROXY BENZYLMETHYL)-3-METHYL-&ARYLHYDRAZONO,!I-PYRAZOLIN-~-ONES
CHzCHOHC6H5 No.
x
Yield,
Rlp,
%
OC:
Color'"
55 133 1 H 50 89 2 3-C1 3 4-C1 52 139 4 2-iUe0 55 157 5 2-NO2 53 178 6 4-bfe 50 98 7 4-SOzNHz 65 227 8 2,4-Br~ Fj8 143 B, Brown; D, dark; X, Pe, pale; R, red; P,yellow. Q
Formula
Anal.
YN C18H18N40z C, H, N Ci8Hi~ClNa02 N, C1 OP CisH1,ClNaOz N, C1 OK OP CigHz0N403 C, H, N 12P C ~ S H ~ ~ N S C, O ~H, N DON CigHz0N40z C, H, N ON CisHIgSN504 N, S DYP C18H16Br~N.LhBr, ?J Needles; 0, orange: P, plates;
a-(Hydrazinomethy1)benzyi alcoh01,~ethyl 2,3-dioxobutyra 2-arylhydrazones,S 2,3,4-pentanetrione 3-arylhydrazones,6 an l-phenyl-2-arylhydrazono-lJ2,3-butanetriones~ were prepared previously described. AVl-(p-HydroxybenzylmethyI)-3-methyl-4-arylhydrazonopyrazolin-5-one.-A hot solution of a-(hydrazinomethy1)benz alcohol (2 mmoles) in EtOH (10 ml) was added to ethyl 2,3-diox butyrate-2-arylhydrazone(2 mmoles) in EtOH (1.5 ml). TI mixture was refluxed on a steam bath for 3 hr, followed by tl addition of glacial AcOH (4 ml). It was refluxed for another hr and allowed to stand overnight at 5-10', when a cryst su' stance sepd. This was recrystd from EtOH (see Table I ) . XI-(@-HydroxybenzylmethyI)-3,5-dimethyl-4-arylazopyrazol~ were obtained by using the same procedure as for I (see Tab 11).
.V1-(~-HydroxybenzylmethyI)-3-methyl-4-arylazo-5-pheny pyrazoles were also prepared by the same method (see Tab 111) TABLE I11 S'-(p-HY DROXYBENZYLMETHYL)-3-METHYL-4-ARYLAZO-5PHENYLPYRAZOLES
TABLEI1
'vi-(@-HYDROXYBENZYLMETHYL)-3, j-DIMETHYL-4ARYLAZOPYRAZOLES
CHzCHOHCGHs Yield, SO.
CH~CHOHC~H~ NO.
s
Yield,
Mp,
Vo
O C
50 129 1 H 32 131 2 2-Me 36 139 3 4-Me 60 170 4 3-C1 62 164 5 4-C1 65 161 6 2-Br 30 147 7 3-NOz - - 103 *J*) 8 4-Et0 9 2,3-C1z 32 118 56 126 10 2,3-Rfe~ 56 114 11 2,4-ivIe~ 12 2,4-(MeO)~ 55 159 97 13 2-Cl-6-Me 60 14 2-Cl-4-NOz 62 181 See footnote a, Table I.
Colora
DYN PeYN DYN YP YN 0P ON YN PeYN YS PN
Y1; YN ORP
Formula
Anal.
C, H, IS CisHzoN4O C, H, X C20H22N40 C, H, N CzoH22~4O CigHigClX'aO C1, N CigHigClN40 C1, N Cl9H19BrN4O Br, N C, H, I?; ClgHlsNaOs C, H, N CzIHz4NaOz C I V H I ~ C ~ Z Nc1, ~ Opi C, H, N C21H24x40 C, H, N CZ~HZ~N~O C Z ~ H Z ~ N ~C, O H, ~ N C20H21C1N40 C1, N CigH18ClNsOs C1, N
lyzed for glucose with the aid of a Technician AutoAnalyzer using the modified method of H ~ f f m a n . ~
1 2 3 4 5 6 7
s
%
H 34 50 2-NO2 37 2-Br 5,: 2-Me0 -2,3-C1z ai) 2,4-C1z ,J+I 2,4-(&1e0)z 30 8 2,3-hfe~ 58 a See footnote a, Table
--
Mp, OC
140 123 101 157 141 160 167 178 I.
Colora
Anal.
DYP DYP OP DYN YP YP BP YP
C, H, K
c,
HJ
Br, N C, H, N Cl, x c1, ?i C, H, K C, H, N
3-Methyl-4-arylazo-5-phenylisoxazoleshad been synthesize in our laboratories earlier.2
Acknowledgments.-We thank Professor W. T. Nalik, Head of this Department, for the facilities fc the work, and the State C.S.I.R., Lucltnow, for a Junic Research Assistantship (to C.P.). &4 15-g sample ( a-(hydrazinomethy1)benzyl alcohol was kindly supplie by Dr. D. T. ;\fanning of the Research and Develor ment Department, Union Carbide Corporation, Sout Charleston, W. Va. 2,5303.
Experimental Section Melting points were taken with a Kofler hot-stage apparatus and are uncorrected. (3) W. S. Hoffman, J . B i d . Chem.. 120, 51 (1937).
(4) D. T . Manning and H. A . Coleman, J . Org. Chem., 34, 2746 (1969) (5) H. G . Garg a n d P. P. Singh, J. M e d . Chem., I t , 1104 (1968). (6) H. G. Garg a n d P. P. Singh, i b i d . , 11, 1103 (1968). (7) H. G. Garg and P. P. Singh, J. Chsm. SOC.C, 1111 (1969).
