Chemical and Biological Properties of Some Derivatives of cisand trans-1-Hy droxyquinolizidine' JAMES D O N ENGLASD,~ DAVIS TEMPLE, A S D JOSEPH SAM Deparfnient of Pharn7ac~7ificalChemistry, University of Jlzssissippi, rniziersity, Jlisszssippl Received J u l y ZQ,lQ67 The syntheseq of esters of cis- aiid tians-1-hydioxyq~linoliaidlrleare described. Data pertaining to the stereochemistrv of the corresponding methyl halides are reported. Some preliminary phaimacological ohservat 1011' in expercmental animal; are recorded.
A
Chemical structures with fixed conformations have provided useful information regarding structure-activity relationship^.^ Qui~iolizidine~ (I), which is present in many alkaloids, including veratrum5 and rauwolfia,fi served as a nucleus for our studies of the effect of .;triictures on biological activity.
I
The trans-fused E-F ring system of protoveratrine7 A (11) arid B (111)is ideritical with that of cis-l-hydroxyquinolizidine (IV). Both the C1 hydroxyl of the latter and the Csl hydroxyl of the protoveratrines are axial. Furthermore, trans-1-hydroxyquinolizidinecontains 5 molecular fragment which has interatomic dimensions identical with the transoid conformation of the choline molecule, whereas the cis isomer is a 60" skew conformation of choline. The stereochemistry of the quaternary salts (V and VI) of trans-quinolizidin-1-yl acetate and the transoid conformation of acetylcholine, respectively, are likewise similar. This was of particular nterest in view of the observations of Belleau,sa+bsc Cavallito,8d Archer,8e Smissmansf and co-workers regarding the conformation of receptor-bound acetylcholine in biological systems. The relationship of V to VI and the fact that aromatic esters of 1-, 2-, and 3hydroxyquinolizidines possess some antispasmodic and local anesthetic properties and also affect spontaneous motor activity9 prompted further investigations in this area. Our studies involved the preparation of esters of cisand trans-1-hydroxyquinolizidine. The acids (as acid chlorides and anhydrides) employed in the esterification of the respective alcohols were mainly those that also (1) Taken from the dissertation presented hy J. D. England, J a n 1966, to the Graduate School of t h e Unirersity of Mississippi, in partial fulfillment of the requirements for the Ph.D. degree. (2) National Institutes of Health Predoctoral Fellow, 1963-1966. (3) R . B. Barlow, "Introduction t o Chemical Pharmacology," 2nd ed, John \ \ l e y and Sons, Inc., New York, N. Y., 1964. (4) 13. 9. Thyagarajan, Chem. Rei.., 54, 1019 (1954). (5) R . H. bfanske and H. L. Holmes, "The Alkaloids, Chemistry and Physiology," Vol. 111, Academic Press Inc.. New York, N. Y., 1953. ( 6 ) R. B. Woodward, F. E. Bader, H. Biokel, A. J. Frey, and R. W. Kierstead, J. A m . Chem. Soc., 78, 2023 (1956). (7) (a) S. M. Kupchan and C. I. Ayers, i b i d . , 81, 1009 (1959); (b) S. 11. Kupchan and C. I. Ayers, ibid., 83, 2252 (1960). (8) (a) D. J. Triggle and B. Belleau, Can. J. Chem., 40, 1201 (1962): (b) B. Belleau and J. Puranen, J . M e d . Chem., 6 , 325 (1963); ( c ) 8. Belleau and G . Lacasse, ibid., 7, 768 (1964); (d) C. J. Cavallito a n d A. P. Gray, Progr. Drug Rea., 3, 135 (1960); (e) 9. Archer, A. &I. Lands, and T. R. Lewis, J . M e d . Pharm. Chem., 5 , 423 (1962); (f) E. E. Smissman, JT-. L. Nelson, J. B. LaPidus. and J. I,. Day, ibid.. 9, 458 (1966). (9) R. E . Counsel1 a n d T. 0. Soine, J . A n . Pharm. Assoc., 49, 289 (1960).
IV
x-
V 1 .
x-
CHjCO,
vI occur in the veratrum ester alkaloids.'O The alcohols were obtained from the cyclization of ethyl a-?-carbethoxypiperidinobutyrate" to 1-ketoquinolizidine9 followed by reduction. The reduction procedures of Rader and co-workers12were employed t o obtain a 9 3 / i trans/cis epimeric ratio and a 71/29 cisltrans ratio, respectively. The cis- and trans-l-hydroxyquinolizidines were obtained by preparative gas chromatography and elution chromatography. l 3 The melting points of the geometrical isomers agreed with values reported hy previous l4 Of particular interest in this investigation was the ring-fusion stereochemistry of the compounds reported in Table I. Aaron and associate^^^^'^^^^^ have shown that the ring fusion in both cis- and trans-1- mid -3(10) 0. Wintersteiner, Record Chem. P r o g r . (Kresge-Hooker Sci. Lih.), 1 4 , 19 (1953). (11) G . R. Clemo and G. R. Ramage, J . Chem. SOC.,437 (1931). (12) C. P. Rader, G . E. Wicks. Jr., R . L. Toting, Jr., and H. S. Aaron, J . Org. Chem., 29, 2252 (1964). (13) H. S. Aaron, G. E. Wicks, J r . , and G . P. Rader, ibid.. 29, 2246 (1964). (14) (a) N. J. Leonard, A. S. Hay, R. W. Fulmer, and V. \V. Gash, J . A m . Chem. SOC.,77, 439 (1955); (b) G . A. Swan, J . Chem. SOC., 2051 (19,jS); (0) H. S. Aaron a n d C. P. Rader, J . A m . Chem. Soc.. 85, 3016 (1963).
Xtic:uih~~lricle and the resultiiig esters were c.cnivctrtetl t o the methyl yuateriiai-J- salts. The methyl (~u:iterii:it*J. salt of the cis :icetatc and propiorlate wew ~ ~ r q ) a i w lT. h e r i m spectr:i of the acetat (, >iilt.s are rcm)rded in Figure> 1 and '2' resl)ectivel>.. Thc tloithlct centered at 6 2.21 of the acetate salt is due t o thc t eimiiial methyl group of the ester moietJ- and was fererice signal. The peaks at 6 3.10 igried t o the N-methyl groups of the aternrtry nitrogen of both the cis and ft,u.ris isomers. T h e signal at 6 3.10 integrates t o 1.5 l i i * o t ( i i i .:uid ~ thc +rial at 6 3.35 integrates t o 1.5protons. 'l'ho siiiii I I these ~ two irit~egrntedvalues (3 protons) is vty!. clos;c3 t o t h c i ilitclriial reference methyl group. siioii
(
'I I \
.M -
lilicl\viscy
I h ( w otwr'vatior
provided rviderice that the mateigure 1 is :q)proximately :i 50:50 n i i x t i i i ~ (o~f the methohalide of cia-fused (VII) and transt'iisc~l( V I I I ) ti.a7is-ciuiriolizidiIi-1-yl:icetttt,e. Structure IX, althoiigh Imsihle, was riot seriously considered t witis is(^ of t h e stereor1iemic:d i t i t eract ions inherent in I ,
1 Ilk
(xi
)iifoi.in:it
ion. Ib
OCOC l i 1X
The methobromide of I,.a,~s-C~uiriolizidi~l-l-~ 1 acetutc did not form rendil\ ; it M hygroscopic and difficult t o Iiandle. Thc inethobro des of the other e\ter+ of the t i a n s alcohol behaved iii a himilar manner. llor(Lover, the heptatioate derivative w:ib easier to work w t l i t h a n the alkyl ester> ot less bulk. The methiodides of trans-yuinolizidirir-1-J 1 acetate and propionate on the other hand were cr\ -t;illiiie, iionhygroscopic, and readih, oh t airied. The methohalide of c.u-yuinolizidin-l-yl acetat e 1 ~ ~ 5ented a somewhat difl'erent picture as been in Figure '2. Only one quaternary methyl signal at 6 3.28 c v a ~ l)rewit, indicating t h c 1)reience of one 1s0mer.l~ In coiitr:tst to the prepitnit 1011 of' the t ~ a n methobromide.;, s thc niethobromitlc i i f Iiiiric ihzidiii-1-yl wet ate formed rendil? and ci llinc : ~ n dqhowed no hJ (19) K. L \\iIliamwn, 1'. H , t \ $ e l l d u d T. A. Spencer, J
88, 3 ? i (IBfifi)
1m. Ci e m
,
-
]\larch 10GS
I
XI1
IT-r.4.0
__.
~
_ I
3 .O
2.0
l.@
Figlire l.-Kmr spectnim ( 7 ) of the methohalide of Iransqiiirioliziditi-1-yl acetate i i t D,O (105;) (mixtiire of c i s and trans Tirig-fused salts).
?;-niethylquinolizidiries t o 9-methyldecalir1, structure XI tentatively has been assigned t o the qunternary ammonium salts of the cis (axial) esters (X).
Pharmacological Results2? Toxicity and General Observations in Mice.--A number of similarities among the observable effevts of this series of compounds were seen. 1,ocomotor activity was reduced within several minutes after riontoxic doses of the hydrochlorides of 1-3, 5, 8, 16, 17 and the methobromides of 9-11, 13, 16, 18. Sedation with ptosis was noted with the hydrochlorides of 2, 8, 16. Brief tremors or twitches appeared with the hydrochlorides of 1, 3, 6, 14, 17 and the methobromides of 9-13, 15, 16 with muscle fasciculations being prevalent in animals receiving the methobromides except for 18. Clonic and/or tonic corivulsions were associated n-ith lethal dosage levels (Table 11) of nearly all of the cwnpounds. Deaths commonly occurred within G mi11arid seldom were delayed later than 15 min after injection. The hydrochlorides of 1 , 2 , 6, 16 caused cutaneous vnsodilation which was, however, not of great iiiteiisitv or
I
TABLE I1 I N MICE ACVTETOXICITY QUIXOLIZIDINE DERIVATIVES.
.
4 0 Figure 2.--Nmr
3.0
2.0
1.0
Ni0.O
spectnim ( 7 ) of the methohalide of cis-quinolizidin-I-yl acetate in DlO (10%).
scopic tendency. This was t,rue also of the methiodide. The methohalides of cis- and [inns-quinolizidin-1-yl propionate provided spectral data similar t o the corresponding acetates. The observed data indicated that the original trans-fused ester (X) was converted entirely either t o the cis-fused conformation (XI) or t o the trans-fused salt (XII). frans-Quinolizidine is analogous t o tmns-decalin with one tert,iary hydrogen removed. l6 Turnerz0has shown that tvans-decalin is more stable than cis-decalin by 2.7 kea1 /mole. However, in 9-methyldecalin t’he introduction of additional skew interactions in the trans form lowers the energy diff ereuce between the trans and t,he cis isomers.” Because of the close similarity of the (20) R. B. Turner, J . Am. Chem. Soc.. 74, 2118 (1952). (21) M. 9.Kewman, “Steric Effects in Organic Chemistry,” John \\iley and Sons, Inc.. New Tork, N. T.,1956, p p 3C-31.
LDso. mg/kg ip (95% confidence limits) Hydrochlorides Xlethohromides
1 2 3 5 6
709 (587-855) 892 (769-1040) 562 353 328 (272-396)
8
... ...
9 10 11 12 13 14 15 16 17 18
... ...
... ... 446 (370-339 ...
242 (208-382) 3x:3
. . .h ... ... ... ... 93 (64-13.5)
8:1 261 83 178 (143-221) 121 (9-150) . . .d 77 (60-98) 7 2 (55-02) ...
...
l.i4 ( 1 19-199) The niimbers refer t o the parent striictiire of the cornpoiin+ of Table I. * See S. See 11. cl See IS. ‘[
( 2 2 ) The aothors are grateful to T)r. Marvin Davis, Del,artment of Pharmacology, School of Pharmacy. T h e Cnirersity of Missisnippi. for the pharmacological results. T h e niimliers in the pharmsrology s ~ c t i o n srefer t o the compounds in t h e t,ables.
ester in anhydrous Et2O. tlnhydrous MeOH (1 ml) was added and the soliition was perniitted to st’arid at room teniperatiirc. The precipitated salt’ was collected by filtration over a period of several weeks. This was the method utilized for the preparation of all of the methobromides reported in Table I. Quantitative yields were obtained but the salts were very hygroscopic (except the cis acetate) and generally resisted purification by recrystallization (see Table I). Method E.-The methiodides were prepared in quantitative yield by refluxing for 12 hr a soltition of the ester in Ka-dried CeH, with a n excess of bIeI. Pharmacological Procedure. Toxicity in Mice.-All compornids were injected intraperitoneally in aqueous solution (made wit,h aid of diliite HCI in the case of 6) over a range of a t least foiir dosages. Five albino mice were used at each dosage level and the proportion of animals dying was used to determine approximate LII~o’s, and confidence limits when the data permitted, by the method of Horn.24 Cardiovascular Effects in Rats.-Recordings of arterial blood presaiire, respiration, and the electrocardiogram were made by means of an E R- 11 Physiograph and appropriate transdncers. Blood pressure was recorded via the cannulated carotid artery. Injections were made via a needle-cannula in the femoral vein. All materials administered were flushed in with a small voliime of 0.!,C, saline solution. (2-1) H. J. Horn, Biometric., 12, 311 (1956).
AIale albino rats of the Holtzmann strain weighing 275-375 g were aiiesthetixed with iii,ethaii (1.26 g/kg ip). The test, compounds and a standard consisting of protoveratrines A and B were administered at dosages coiistit,uting 3, 10, and 30% of the approximate LDao for mice. Observations for changes in the physiological parameters were made after each of these dosages. Then, upon eqiiilibration from any changes evoked, standard doses of histamine, epinephrine, and methacholine were admiiiixtered siircessively. Responses to these agents after the test, compoinid were compared to response6 to like qiiantities that had been ohserved prior to any administration of the test, siihstance. I n several cases the 30”; dosage was lethal. I n some others it was repeated or even a 60Yc dosage was admiiiirtered if the preparation was still fiinctioning. Smooth Muscle Effects.-The compoiinds were tested on sections of rabbit ileum which were suspended in an oxygenated Ringer’s solution in a 30-ml muscle bath maintained a t 37”. The muscle strip was attached to a myograph transdiicer to record miisciilar activity on an E R- 1\2 physiograph. Response to sohitions of the test compound were observed in comparison to responses to O.5-ml qiiantities of standard solutions of acetylcholine chloride (1: 100,000) and epinephrine (1: l0,000), or in conjiinction with the cholinergic receptor blocking action of alropine siilfate (1 : 400). The two solutions (1 : 100 and 1 : 1000) of each compound which were tested yielded iipon addition t o the bath in 0.5-ml quantities final diiig concentrations of aboiit 13 and 150 pg/ml, respect’ively.
Synthesis and Pharmacological Evaluation of Some Tetrahydrooxadiazinones and Some Dihyciroaminooxadiazines D. L. TREPANIER, J. IY.EBLE,ASD G. H. HARRIS Chemistry Research and Pharmacology Departments, Human Health Research and Development Center, The Dow Chemical Company, Zionsville, Indtana 46077 Received August 31, 1967 The synthesis of cis-(+)- and cis-( - )-tet’rahydrooxadiazinone derivatives of (+)- and ( - )-ephedrines and t,wo relat,ed tetrahydrooxadiazinones is reported. The resnlts of a n attempted synthesis of a dihydroaminooxadiazine derivative of ephedrine and the successful synthesis of three related dihpdroaminooxadiaeines is also reported. The cis-( - )-tetrahydrooxadiazinone derived from ( - )-ephedrine wns found to be a monoamine oxidase inhibitor in pharmacological testing.
One widely used approach for the synthesis of new compounds that possess some type of central nervous system stimulant activity is the cyclization of substituted phenethanolamines into heterocycles, such as morpholine, piperidine, and 2-oxazoline in such a manner that more or less of the phenethanolamine skeleton becomes part of the heterocyclic ring. Well-known drugs of this type are phenmetrazine. piprado1,Z and nminorex.3
CaH5xcH3 0-NH
NH? phenmetrazine
pipradol
aminorex
The ephedrines and norephedrines are useful starting materials for a study of this type because they possess some central activity and because all eight of the isomers are readily available. Morpholine, 2-oxazo(1) L. S. Goodman and A . Gilman. “ T h e Pharmacological Basis of Therapeutics,” 3rd ed. T h e Rlacmillan Co.. New York. N. Y.. 1965, p 516. (2) R . F. Gould. “hlolecular Modification in Drug Design.” Advances in Chemistry Series, N o 45, American Chem~calSociety, Washington, D. C., 1964, p 116. ( 3 ) C. K. Cain, “Annual Reports in Medicinal Chemistry, 1965,” ilcademic Press Inc., New York. N. Y., 1966, p 54.
line,4 oxazolidine,5 di- and tetrahydro-1,3,4-oxadia~ i n e s , ~2-thiazoline,* ,’ thia~olidine,~ dihydro-1,3,4-thiadiazine,’O tetrahydro-as-triazine,lland imidazolidine’z heterocyclic derivatives of the ephedrines and norephedrines have been reported. Certain of these heterocycles exhibit central-stimulating appetite-depressingl1S4 monoamine oxidase inhibiting antidepressant,flgslObcentral nervous system d e p r e ~ s a n t , ~ ~ ,analgetic,” ~,’,~~ hypoch~lesterolemic,~antiinflammatorj~,~antimicro(4) G. I. Pons, J. R . Carson, J. D. Rosenau. -4.P. Rosakowski, N . 11. Kelly, and J. IIcGowin, J . .\fed. Chem., 6, 266 (1963). ( 5 ) H. Pfanz and G. Kirchner, Ann., 614, 149 (1958). (6) (a) D. L. Trepanier, V. Sprancmanis, and K. G. Wiggs, J . Ory. Chem., 29, 668 (1964); (b) D. L . Trepanier and 1‘. Sprancmanis, ibid., 29, 673 (1964); ( c ) ibid., 29, 2151 (1964); (d) D . L. Trepanier, V. Sprancmanis, D. S.Tharpe. and P . E. Krieger, J. Heterocyclic Chem., 2 , 403 (1965); (e) D. L. Trepanier, P . E. Krieger, and J. K . Eble. J. M e d . Chem., 8, 802 (1965); (f) D . L. Trepanier, V. Sprancmanis, and J. ?i. Eble. i b i d . . 9 , 753 (1966); ( g ) D. L. Trepanier. U.S. P a t e n t 3,122,537 (1964). (T) XI. J. Kalm. U. S. Patent 3,251,838 (1966). (8) RI. Kojima, Y a k u g a k u Zasshi, 79, 1 (1959). (9) A . P. Rosakowski and G. €3. Koelle, J. Pharmacol. E z p . Ther., 128, 227 (1960). (10) (a) D. L. Trepanier, W. Reifschneider, IT. Shumaker, and D. S. Tharpe, J . Ow. Chem., SO, 2228 (1965); (b) D. L. Trepanier, U. S. Paten 3,290,303 (1966). (11) D. L. Trepanier, E. R. Wagner, G. Harris, and A . D. Rudaik, J . M e d . Chem., 9, 881 (1966). (12) 11. Murakami and T. Fukumoto, 5 i p p o n Kagaku Zasshi, 76, 270
(1955).
