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Journal of Medicinal Chemistry, 1972, Vol. 15, No. 5
1,4-naphthoquinones were prepd by treating 2-methoxy-l,4-naphthoquinone in EtOH with the appropriate alkylamine at room temp in a manner similar to that previously describeds (Table I). After stirring at room temp, the reaction mixt was dild with Et,O or hexane or both and placed in the freezer. Generally, a dark red or orange ppt was collected and recrystd repeatedly from a suitable solvent(s), usually EtOH (charcoal) or EtOH-Et,O (charcoal).
Acknowledgments. We wish to thank Mrs. Alice Ma for excellent technical assistance with the in vitro studies. This work was supported by U. S. Army Medical Research and Development Command Contract No. DADA 17-69-C-9067. This is Contribution No. 992 from the Army Research Program on Malaria.
Biggs, Casy, and Jeffery
References (1) C. M. Bowman, F. S. Skelton, T. H. Porter, and K. Folker5. unpublished results. ( 2 ) T. H. Porter, F. S. Skelton, and K. Folkers. J. ,Wed. Chem , 14. 1029 (1971). (3) T. H. Porter. F. S. Skelton. and K. Folkers. ibid.. 15. 34 (19721. (4) L. F. Fieser,'J. Amer. Cherh. SOC.,48, 2922 (1926).' (5) L. F. Fieser,etal., and M. T. Leffler,etal., ibid., 70, 3212 (1948). (6) C. E. Dalgleish, ibid., 71, 1697 (1949). S. Osdene, P. B. Russell, and L. Rane, J. Med. Chem., 10, (7) 'I. 431 (1967). (8) A.-G. Farbenfabriken Bayer, Netherlands Patent Application 65-05,524; Chem. Abstr., 64,11215h (1965). (9) L. Szarkowska, Arch. Biochem. Biophys., 113,519 (1966).
Stereochemical Studies of Antimuscarinic Agents. Diastereoisomeric Esters of 3-Tropanol, 1,3-Dimethyl-4-piperidinol,and Related Compounds D. F. Biggs, A. F. Casy," and W. K. Jeffery Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada. Received November 16, 1971
The anticholinergic properties of a series of isomeric 3-tropanol and 1,3-dimethy1-4-piperidinol esters (diphenylacetates and/or benzilates) and related compounds have been determined by measuring their ability to antagonize ACh-induced contractions of guinea pig;eum (PA 2 values) and cause mydriasis in mice eyes. In the pA2 experiments, isomers with the smaller N...OCOR separation (acyloxy function axial in preferred piperidine chair conformation) were the more potent by factors of 2 to 3 in most cases, while differences in the mydriatic ED50values of isomeric pairs were insignificant. A Me substituent CY to the acyloxy group substantially reduced the cholinolytic potencies of 4-piperidyl esters but addition of a group was advantageous in this respect. Potency differences between hydrohalide-methiodide pairs were small except in the case of 1-methyl-3-piperidyl benzilate where N-methylation reduced potency by over a half in the ileum test. The relevance of the structure-activity variations observed to the characteristics of receptors for cholinergic agonists and antagonists in the guinea pig ileum and circular muscles of the mouse eye are discussed. This paper is concerned with the possible relationship between preferred geometry and antimuscarinic activity in atropine and related basic esters, attention being focussed upon the conformation of the amino alcohol moiety of cholinolytic esters. In atropine and other solanaceous alkaloids, the acyloxy function at C-3 is cis to the 2,6-bimethylene bridge of the tropane skeleton (lb). There have been
anticholinergic activities of pairs of isomers which differed in the orientation of the OCOR function. One tropinepseudotropine pair of esters has been examined but most esters tested are derivatives of 1-methyl-4-piperidinol. The piperidinol 3a is a simplified version of the 3-tropanols in that it lacks the 2,6-bimethylene bridge, and it forms esters with diphenylacetic and benzilic acids which have high antimuscarinic activities: corresponding esters of l-methyl-3piperidinol 6 have similar pharmacological proper tie^.^'^
L
1 a, R = H b, R = COR' 4 R = C(OH)Ph,
QoH Me 6
only a few studies of the pharmacology of analogs in which the acyloxy group is trans in the above sense, e.g., reports on benzoate and tropate esters of pseudotropine 2a9l7' and the chief object of the present work was to compare the
Introduction of a 3-Me substituent into 3 leads to cis and trans isomers which have the preferred conformation 4 and 5 , respectively.6 The esters 4 are therefore steric analogs of tropyl esters (axial ()COR function) while those of 5 are related to pseudotropyl derivatives (equatorial OCOR). Experimental Section
Me 3a, R = H, b, R = Me MeN -* OCOR OCOR cis 4
trans 5
When analyses are indicated, analytical results obtd for those elements were within +0.4% of the theoretical values. All benzilates were prepd by ester exchange between basic alcohols and methyl benzilate according to Cannon's procedure.' Salts were crystd from EtOH-Et,O unless otherwise stated. Pmr spectra were recorded on a Varian A-60 spectrometer with CDCI, or DMSO-d, as solvents and TMS as standard. Tropane Derivatives. Benzilate esters of tropine and pseudotropine.HC1 were obtd by a reported method;6 the former base gave a methiodide, mp 278" [Anal. (C,,H,,INO,) C, HI, and the latter a methiodide, mp 246-247"from acetone (Anal. C, H). Ester
Journal of Medicinal Chemistry, 1972, Vol. IS,No. 5
Diastereoisomeric Esters of Tropanol
501
Table I. Anticholinergic Activities of Some Diphenylacetates and Benzilates of 3-Tropanol, 3-, and 4-Piperidinols, and Related Compounds No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
18 19 20 21 22 23 24 25 26 21
Structure
Isomer
IC IC 2c 2c b 3a DPAC 3a DPA 3a ~d 3a B 3b DPA 3b DPA 3b DPA 3b DPA 3b B 3b B 3b B 3b B 6 DPA 6 DPA 6B 6B
3-0 3-0 3-P 3-6 2-0, 3-P
f
trans-ZMe/SMe, 5Me/OCORg
f
Atropine Hyoscine Ethopropazine Orphenadrine
Trans Trans Cis Cis Trans Trans Cis Cis
3-0 3-a
Form
PA, (ACh)
Relative' potency
HCl Me I HCI Me1 HC1 HBr Me1 HC1 Me1 HCI Me I HC1 Me I HCl Me1 HC1 Me1 HC1 Me1 HCI Me1 HC1
8.81 8.93 8.51 8.50 8.19 8.27 8.22 8.96 8.92 7.34 7.62 7.68 7.62 8.01 7.49 8.45 8.38 8.19 8.22 9.10e 8.71 8.62
794 1047 398 389 190 229 204 1122 1023 27 52 59 51 126 97 347 295 190 204 1549 630 512
Me1 HSO, HBr HC1 HCl
8.70 8.91h 8.753' 7.64 7.24
616 1000 69 1 54 21
PA 1 (histamine)
Relative' potency
Mydriatic activity, ED,,, mM/kg X104 5 4 5
