September 1969
933
SOTES
Me1 according to the procedure of Gaj and Moorez3and had rnp Aminoisoyuiriuclidiric ( M a ) J V ~ Sprepared by LAH 195-198' (EtOH); mass spectrum (70 eV) m/e 285 (?VI), 284 reduction of the 2-nitroso compound. Complete con(hT - 1, CsHlJNOz), 228 (31 - 57, C~HIIINO), 224 (R.1 - 61, version of the latter and maximum yield of I I I a was CeHliIN), 183 (AI - 102, CzHJO), 158 (31 - 127, CEHI~NOZ), obtained if the reduction was carried out for prolonged 155 ( h l - 100, C3H410),142 (M - 143, C&I), 141 (hl - 144, periods of time in the presence of a large excess of CHJ), 85 (31 - 200, C4H602). Anal. (CsHloINO*)C, H, I, N. l-Chloro-2,3-dihydroxy-2-methylpropane.-Performic acid LAH. Catalytic hydrogenation of the 2-nitroso comoxidation*',*2 of 3-chlom-2-methylpropene afforded 35y0 of pound using PtOz, 5% Pd-C, or Raney S i catalysts in product with bp 53-55' (0.75 mm). Anal. (CIHOCIOZ) C, H, C1. a variety of solvents invariably gave excellent yields of ~s,trans-2,4-Dimethyl-4-chloromethyl-l,3-dioxolane was prepared in 44%1, yield from l-chloro-2,3-dihydroxy-2-methyl- isoquinuclidine. propane and paraldehyde in refluxing CsH6 with azeotropic Condensation of I I I a with benzaldehyde or premoval of H 2 0and had bp 29-32' (0.5 mm), lit.24148-151" (760 chlorobenzaldehyde gave the benzylidene derivatives mm). Glpc (loyoCarbowax column, 110" isothermal, He 30 which mere reduced (LAH in THE')3to the substituted ml/min) revealed two major peaks wlth retention times of 9 and benzyl compounds I I I b and IIIc, respectively. The 10 min; nmr (neat, Jle4Si as internal reference), 2-H T 4.88 and "methylamino derivative IIId was prepared from the 4.93 (two overlapping quartets), 2-CH3 and 4-CH3 8.65-8.70 (overlapping), remaining- multiplet a t 3.82-6.60. And. (C6H11%formyl compound by reduction (LAH).3a ClOr) d,-HYCI. I n addition, the sulfonylurea derivatives IV, precis.~rans-2.4-Dimethvl-4-dimethvIaminometh~l-l,3-dioxolane Methiodide (V) was obtained in $795 yield frhm cis,trans-2,4dimethyl-4-chloromethyl-l,3-dioxolaneand hIez9H in CeH6 followed by quaternization with MeI1 and had mp 185-187" (EtOH), lit.24 139-140"; nmr (CD3CK, ;\le4Si as internal reference), N+(CH3)3 T 6.74 (singlet), 4-CH3 8.47, 2-CH3 8.67 (doublet). IVa, X = CH, Biological Section.-Muscarinic activities were determined b,X=Cl using the rat ileum preparation as described previously.1p20 (23) B. J. G a j and D. R. Moore, Tetrahedron Lett., 2155 (1967). (24) E. Gryszkiewica-Trochimowski. 0. Gryszkiewica-Trochino~ski,-and R. Levy. Bull. Soc. C h z m . France, 610 (19581, have reported this melting point for material derived from t h e dioxolane obtained through the SnC14catalyzed reaction of MeCHO a n d 2-chloromethyl-Z-methylethylene oxide.
Derivatives of 2-Azabicyclo[2.2.2]octane. 111. Substituted Phenylsulfonylcarbamoyl Derivatives
V pared from 8-aniinoquiriuclidine, the sulfonyl carbamates derived from 3-quinuclidinol (V), 3-tropinol (VI) , and 3-tropinone oxime (VII) were prepared.
FILAXK J. 1 7 ~ r 2 ~ELIZ . ~ ~\BETH ~ , A. W E F ~ I L , THOMAS 8.I ~ I A x x A, N D CLAIREA. ELLIS
u
VI
Jf edicinal Chemical Research Department, Schering Corporalion, Bloomjield, S e w Jersey 07003 Receiued April 7 , 1969
VI1
Continuing our studies' on the replacement of simple amine functions in clinically effective drugs by the bicyclic 2-azabicyclo [2.2.2]octane moiety we have prepared the title compounds as potential hypoglycemic :Igents. Compounds of formulas I and I1 (Table I)
I
I1
CJ NA'HR
IIIa. R = H t i , R = C,,H,CH, C, R p-CIC,HjCH2 d. R=Me
were prepared by the condensation of isoquinuclidine or a 2-aminoisoquinuclidine with a substitut'ed phenylsulfonyl isocyanate or a substituted phenylsulfonyl carbamate ester according to known procedures. 2(1) For preceding papers in this series see F. J. Villani, and C. .4.Ellis, J . , U e d Chem.. 9, 185, 264 (1966). ( 2 ) Tliroughout this work t h e common name, isoquinuclidine, is used.
These compounds, list'ed in Table 11, were inactive in the hypoglycemic screen. The hypoglycemic potency4 of t'hexe compounds was det'ermined in normal mice and in diazoxide-induced hyperglycemic mice.5 The act'ivities of compounds of formulas I arid I1 were compared with Imown hypoglycemic agents. At the screening dose of 160 mg/kg orally in normal mice, 2 (Table I ) arid 1-(p-chlorophenylsulfonyl)-3-propylurea were equally potent for periods of 1-3 hr after treatment. Compound 1 and l-(p-tolylsulfonyl)-3-butylureawere equally effective a t the 1-hr bleeding period but 1 mas of lower potency a t the 3-hr period. Compound 4 (Table I) was the most potent' compound in t'his series. On :i milligram basis, 4 wts (3) Contrary t o t h e results frurn other laboratories on t h e reduction of aimilar types of compounds, t h e benzylidene derivatives of this ring system resisted catalytic hydrogenation or NaBHi reduction: LAH in Et20 gave variable results. See, for example, (a) M. J . Kalm. J . .Wed. Chem., 7, 427 (1964); (b) J. H. Riel. A. E. Drukker, T. F. Mitcliell, E. P. Sprrugeler, P. A. Nuhfer, A. C. Conway. an,I .A. 1Iorita. J . A m e r . Chem. SOC.,81, 2805 (1959). (4) T h e biological d a t a herein reported were obtained by Miss A. G1111>e11kian and Dr. I. Tabachnick of t h e Biological Research Division of the Schering Corporation. ( 5 ) I. Tabachnick, A. Gulbenkian, and F. Seidman, Diabetes, 13, 408
(1964).
\'Ill. I2 I .
I.\lJl,l:
yampie -was recrystallized from hexane. mp 140-142 '.
(CiHi~Na0)C. H, N. 2-Aminoisoquinuclidine [IIIa).
[ii
:L
.d nd.
typical expelirnetit, 42
g
I
