May, 1963
S T R U C T U R E S RELATED T O J I O R P H I X E .
XXT'
323
TABLE I PHARYACOLOGY O F
( Z!Z )-&ALBYL AXD ( f)-~,9-DIALKYL-2-~\IETHYL-6,7-BEXZOMORPHANS
-5-Monoalkyl and a-5,Y-dialkyl compounds
R NO.
R
R1
EDso"
LD5un
VI1 1-111
RIe Et Pr RI e Me Ete Et Pr Pr
HI He H
10.4 2.3 2.1 3.0 1.5 4.9 4.2 2.9 71.2
li5 170 130 175 13-1 300 425 >300 >400
Va
IS XI S XI1 XI1 Vb I
Mec Ete Me"
Eth
lied Pr
Abstinence suppressant dose, mg./kg.7
2-60, 1-16, 3-30, 24 2-12, >40 2-60,
S o suppression S o suppression Yo suppression
Physical dependence capacity
S o suppression
Sone Low None Low Sone Low Sone
3-48, S o suppression
Iione
S o suppression
0.44 67 > 18 Low 0.47 100 Mee 0.2i 75 1. o b Intermediate XVI Eth 0.28 120 0.5-12, K O suppression Sone XVII Et Pr 0.87 55 .......... I Pr Morphine 2.1 550 3 High SYIII a Expressed in mg./kz. (mice, subcutaneous administration); c j . S. B. Eddy and D. Leinibach, J . Pharnmcd. EL^. Therap., 107,385 (1953). All ahstinence signs were not uniformly suppressed by any dose ( t o 12 mg./kg.'! which did not produce some side effects. See E. L. LIay and J. H. A4ger,J . Org. Chem., 24, 1432 (1959). J. H. Ager, personal communication. e See ref. 1. /See ref. 2 . ref. 3. See ref. 6. XIV
xv
>Ie
Me"
Me Et
Et"
v
The yields of Va and T'b4 (based on I a and Ib) mere ea. 30y0 and 20% respectively; IV was obtained in 3% over-all yield.4 Cyclizatioii of I11 (crude, or purified through the picrate) was effected with 48y0 hydrobromic acid (bath temperature 140-145') ; S5y0phosphoric acid gave low yields and principally decornpositioii products. Diastereoisomers IV and T'b were separated by fractional crystallizatioii from acetone iii which IV is much inore soluble. Infrared data were valuable in following these separatioiis ( c j . Experimental) as were rnethiodide rate ~ t u d i e s . ~
I
I1
Conversioii of T'a aiid Vb to the open iiitrogeii compounds YIa aiid TTb was accomplished as in aiialogous series6 by Hofmann degradation of the methyl ether and catalytic hydrogenation of tlie resultant methiiies. The product J-Ib was aromatized (570 palladium-charcoal)
to 7-methoxy-l,2-dipropyliiaphthaleiie, I n Table I are giveii the aiialgesic activity (mice), acute toxicity (mice) and physical dependeiice capacitf of 5-alkyl- and 5,9-dialkyl-2'-hydroxy-2-methyl6,7-benzoiiiorphaiis synthesized in our laboratory to date. Regarding activity, the 3-propyl derivative (compound TTa)aiid the 5-ethyl (VIII), although racemates,* are equivalent to morphine (XYIII), 5 times as potent as the 5-methyl homolog (VII). The racemic a-5,9-dialkyl coiiipoundsg except the dipropyl derivative (Yb) are of tlie same order of effectiveness as morphine, iiiaximum activity being shomii by the 5-methyl9-methyl analog (X). The first sigiiificant fall in activity is seen with the dipropyl derivative (1-b) which is (7) G A Deneau a n d bI 1% Seevers (Univ of Mich ) personal communications a n d Addenda t c the Minutes of the 193B 1960, 1961, and 1962 meetings of the Committee on Drug Addiction and Narcotics, Sational Research Council. Physical deoendence capacity is defined as the capacity of a conipound to suppress uithdrawal svmptoms in addicted monkeys (stabilizedon 3 mg./ky of morphine administered 4-6 times dails). hlorphine (XVIII) is g n e n as the reference compound (8) It is well k n o u n t h a t in this type cf structure (3-hvdroxy-T-methylmorphinan, 2'-hydroxy-2 5,9-trimeth~1-6,7-benzomorphan, etc ) almost all of the analgesic activity is due t o the ( - ) isomer; c f . E. L M a y a n d N. B. E d d y , J O w . Chem., 2 4 , 291 (195YJ. (9) The stereochemistry of the levo-isomers has been shown t o conform t o t h a t of leza-3-hydroxy-N-methylniorphinana n d morphine 4
May, 1963
CHOLIXERGIC
1,3-DIOXoLASE ASALOGSO F hlUSCAROSE
mainder of the procedure was essentially the same as that used in the preparation of I I b ; yield of hygroscopic IIa, 28 g. (73%), m.p. 132-134". Rearrangement of 28 g. of I I a (dried a t 60' in vacuo) was effected as described for I I b and gave 23 g. of impure IIIa. This and 200 ml. of 48Yc hydrobromic were kept a t a bat.h temperature of 140-150' for 24 hr. and the resultant Va isolated of crude Va; 6.8 g. m.p. as described for Vb; yield 9.8 g. (,434;;;-) 214-217", after a recrystallization from acetone or methanol, Xl;:'6.14(w), 6.30(s) p . d n a l . Calcd. for C1sH&lSO: C, 68.19; H, 8.58. Found: C, 68.42; H, 8.60. cu-5,9-Dipropyl-2'-methoxy-2-methyl-6,7benzomorphan Methiodide.-RIethanol (45 ml.), 5 g. of Vh and 80 ml. of 39% ethereal diazoniethane were stirred to solution (4-6 hr.). .4n additional 80 nil. of diazomethane solution was added and the mixture kept a t 25' for 2-3 days. Solvents were distilled finally in. zucuo and the residue evaporatively distilled a t 0.2 mni. (bath temperature 145'). The 4.3 g. of distillate and methyl iodide in acetone gave the methiodide; prisms, n1.p. 245-247'. Anal. Calcd. for CnlHJSO: C, 56.88; H, 7.95. Found: C, 57.06; H, 7.85. 1,2-Dipropyl-7-methoxy-l(2-dimethylaminoethy1)-1,2,3,4tetrahydronaphthalene (VIb) Hydrochloride.-The above methiodide (4.3 g.), 4.3 g. of sodium hydroxide and 43 nil. of water were refluxed for 6 hr., cooled and extracted n-it,hether. Evaporation of the ether left 2.5 g. of oil which, with 0.2 g. of platinum oxide and 30 ml. of methanol, absorbed 1 molar equivalent of hydrogen in 30 min. The filtered solut'ion its evaporated to dryness and the residue converted to t'he hydrochloride (acetoneether-dry hydrogen chloride j. -4na2. Calcd. for C?lH3&1XO: C, 71.3; H, 10.3. Found: C, 71.5; H, 10.4.
823
1,2-Dipropyl-7-methoxynaphthalene Picrate.-One gram of VIb and 1.0 g. of 5 7 , palladium-charcoal were mixed intimately in a vented test tube which was then immersed in an oil bath, preheated to 250'. The temperature of the bath was raised to 315" during 10 min. and kept a t this temperature k 5 " for another 20 min. The cooled mixture was extracted 3 times with ether and these extracts were washed with dilute hydrochloric acid. Drying and evaporation of the ether and evaporative distillation at 100-110" (0.2 mm.) gave 0.6 g. of hydrocarbon which with 0.6 g. of picric acid and 3-5 ml. of ethanol (warming to solution) yielded, after cooling t o - 15", the crystalline picrate: orange needles from met,hanol, melting at 68-69" to a melt which did not flow freely until 100". Anal. Calcd. for C23HPhSaOR: C, 58.58; H, 5.35. Found: C, 58.45; H, 5.33. Cltraviolet maxima (in ethanol) of the crude distillate above or hydrocarbon prepared from the pure picrate were at, 234, 279, 288, 315 and 330 mH. These and extinction coefficients were consistent with the i-metlioxy-l,2-dialkylnaphthalenestructure.6 7-Methoxy-1- (2-dimethylaminoethyI)-l-propyl-1,2,3,4-tetrahydronaphthalene (VIa) Hydrochloride.-This compound was prepared essentially as described for VIb. The intermediate 2'-methoxy-2-methyl-5-propyl-6,7-benzomorphan methiodide crystallized from acetone-met'hanol; m.p. 199-204". I t was dried a t 100" for analysis. dnal. Calcd. for C I ~ H ~ ~ I SC,O53.89; : H, 7.03. Found: C, 54.06: H, 7 . 3 2 . The VIa hydrochloride prepared from this mrtliiodide crystallized from acetone in needles, m.p. 202-203": yield from Va 705;. I t was dried a t 100" for analysis. Anal. Calcd. for C18H~,CISO: C, 69.33; H, 9.70. Found: C, 69.36; H, 9.76.
Stereochemistry of the Interaction of Enantiometic 1,3-Dioxolane Analogs of Muscarone with Cholinergic Receptors' B. BELLEAU AXD J. PURAKEN Department of Chemistry, L'niversity of Ottawa, Ottawa, Ontario Received A\-oveinber1.9, 1962
+
Starting from D-isopropyhdene glycerol, the synthesis of L( )-czs-2-methyl-4-trimethylammoniumniethyl-1,3dioxolane iodide (XVI) and its enantiomer (VIII) is described as outlined in Charts 1 and 2. The relative configurations were established by direct comparison of the key intermediates VI and XIV with corresponding racemates of previously established configurations. Comparison of the cholinomimetic activity of VI11 with that of XVI revealed the latter to be approximately 100 times more active than the former and 6 times more potent than acetylcholine. I t is pointed out that these observations are not consistent with Waser's interpretation of the active conformation of o-muscarone. The inversion of the optical specificity of the receptors toward the enantiomers of muscarone but not toward the dioxolane analogs VI11 and XVI is accounted for if the presence of an accessory nucleophilic site on the receptor is postulated. 111 the first paper of this series,' the synthesis, stereochemistry and cholinomimetic activity of quaternary salts of the 1,3-dioxolane series (the Fouriieau series?) was reported. The effect of optical isomerism on act#ivit>y in this group was also studied in a preliminary fashion' and the results suggested that the enantiomers of cis-%met hyl-4-t rimet h ylammoniumme t h yl- 1,X-dioxolane iodide (cis-F2268) (I, R = CH,) should be of special interest because optimum activity is associated with the c i s configuration. Resolution experiments having produced negative results, the synthesis of the desired enantiomers (VIII) and (XVI) was approached using a starting material of known absolute configuration. We have shown' that the 1,3-dioxolane I (R (1) Published as part I1 of tlie series entitled "Studies on the Chpmical Basis for Cholinominietic and Cholinolytic Activity." lLur p a r t I , see L). Triggle and B. Belleau, Can. J. Chem., 40, 1201 (1902). (2) .J. P. Fourneau, D. Bovet, F. Bovet, and G . Montkzin. Bull. SOC. Ch7m. Bid.. 26, 134. $516 ( 1 9 4 4 ) .
= CH,) referred to as F2268 in the literature? consists of a 60:40 mixture of cis- and trans-isomers. The synthesis of pure dl-cis- and dl-trans-F2268 was successfully accomplished and the configurations rigorously established.' We nom wish to report the synthesis and cholinoniinietic activity of the enantiomers of dl-cis F2268. Starting from D-isopropylidene glycerol, the sequence described in Chart I was applied to the synthesis of optically pure D(-) (T'III) (~-ce's-F2268). Intermediates (111) and (IV) were described in part 1.' We had observed' previously that the separation of cis, trans isomers in the 1,3-dioxolane series could be accomplished best when a trichloromethyl substituent rathpr than a methyl group was present a t position 2 . As expected, the reaction of chloral with IT' led to a 60-40 mixture of D-trans-(T') and ~-cis-(VI)from which pure T'I could be separated by crystallization albeit
