Analgetics Based on the Pyrrolidine Ring. 9
Journal ofMedicinal Chemistry, 1973, Vol. 16, No. 10 1181
Analgetics Based on the Pyrrolidine Ring. 9 Ralph E. Bowman, Harry 0. J. Collier, Ian M. Lockhart,**?Cyril Schneider, Nigel E. Webb, and Michael Wright Chemical and Pharmacological Research Departments, Research and Development Division, Parke, Davis and Company, Hounslow, Middlesen, England. Received November 9, 1972 A series of m-(3-alkyl-l-allyl-3-pyrrolidinyl)phenols and related compounds has been synthesized for evaluation as potential nonaddicting analgesic drugs. The compounds have been tested in mice for their antinociceptive effect in an abdominal constriction (writhing) test and for their ability to antagonize morphine in the tail pressure test. The biological results are discussed in relation to chemical structure.
rn-[l-( 3-Methyl-2-butenyl)-3-propyl-3-pyrrolidinyl]phenol. Method D. 3-Propyl-3-(m-methoxypheny1)pyrrolidinewas acylated with 3-methylcrotonyl chloride and the resulting amide 0demethylated with boron tribromide. rn-[l-(3-Methyl-2-butenyl3-propyl-3-pyrrolidinyljphenol (compound 16) was obtained on LiAlH4 reduction of the crude amide. [3-Isobutyl-l-(2-methylallyl)-3-pyrrolidinyl]phenols. Method E. 3-Isobutyl-3-(m-methoxyphenyl)pyrrolidinewas N-acetylated with AcOH-AczO. 0-Demethylation with boron tribromide afforded m-(l-acetyl-3-isobutyl-3-pyrrolidinyl)phenol. A sample of the latter (20.5 g), 2H-3,4-dihydropyran (75 ml), and concentrated HC1 (0.5 ml) were stirred at 50" for 1 hr, cooled, and allowed to RO \ R' stand overnight. Excess dihydropyran was distilled off and the residue, in Et20 (200 ml), was washed with 2 N NaOH and H20, dried, and evaporated to give the crude N-acetyltetrahydropyranyl ether (28.5 g) which was refluxed with KOH (150 g) in EtOH (150 ml) and HzO (150 ml) for 24 hr. EtOH was removed by disI I tillation, H2O (300 ml) added, and the pyrrolidine extracted with R" Et2O. The Et20 extracts were washed with HzO, dried, and Ia, R = H; R' = Pr; R", = Me evaporated. 3-Isobutyl-3-[m-[(tetrahydro-2H-pyran-2-yl)oxy]phenyllpyrrolidine was obtained as a pale yellow liquid (13.7 g), b, R = H; R' = Pr; R" = CH2-c-C,H, bp 164-170" (0.2 mm). c, R = H; R' = alkyl; R" = CH,CH=CH, The above tetrahydropyranyl ether was converted to a 1 4 2 T h e present paper describes t h e synthesis and examinamethylallyl) derivative by alkylation with a 2-methylallyl halide tion of a number of such N-allylpyrrolidines. Like t h e N in the presence of KzC03 in DMF at room temperature (cf. method A). The tetrahydropyranyl protecting group was removed (cyclopropylmethyl)pyrrolidines, many of these comusing 2 N HzS04-EtOH (5:l) at 40" for 0.5 hr. The m-[3-isobutylpounds have proved t o be antinociceptive agents in an l-(2-methylallyl)-3-pyrrolidinyl]phenol was isolated by convenabdominal constriction (writhing) test in mice and simultional procedures. taneously have t h e ability to antagonize t h e analgesic efOptical Resolution of m-(Allyl-3-isobutyl-3-pyrrolidinyl)fects of morphine in a tail pressure test in t h e same phenol. Method F. m-(l-Allyl-3-isobutyl-3-pyrrolidinyl)phenol species. Pertinent structure-activity relationships are diswas resolved by fractional crystallization of its salt with (-)-dip-toluoyl-o-tartaric acid from EtOH. The salt of the (-) enancussed. tiomer crystallized first. Liberation of the base enriched in the Chemistry a n d E x p e r i m e n t a l Section (+) enantiomer from the salt in the mother liquors, followed by fractional crystallization of its salt with (+)-di-p-toluoyl-L-tartarThe synthetic procedures used were similar to those reported ic acid, led to the isolation of the (+) enantiomer. The resolved previously3-6 and are summarized below. The physicochemical bases after liberation from their. salts were each dissolved in properties of the compounds prepared for biological evaluation EtOH and EtOH-HC1 was added. The hydrochlorides, obtained are listed in Table I. on evaporation of the solution, were recrystallized from i-PrOH. 3-Alkyl-l-allyl-3-(m-methoxyphenyl)pyrrolidines. Method A. Pharmacological Methods. Antinociceptive activity was meaRedistilled allyl bromide (0.1 mol) was added to the appropriate sured using the mouse abdominal constriction test,g in which ace3-alkyl-3-(rn-methoxyphenyl)pyrrolidine (0.073 mol) and tylcholine (3.2 mg/kg) was the intraperitoneal challenge subNaHC03 (10 g) in DMF (100 ml). The mixture was maintained stance. Antimorphine activity was measured in a mouse tail presat 50" overnight. The cooled mixture was evaporated to half-volsure test based on the method of Bianchi and Franceschini,lo ume and filtered, H20 (250 ml) was added, and the basic product using a special apparatus described by Collier.11 The test drug was extracted into CHC13. The base was purified by distillation was administered subcutaneously in solution together with a dose in uacuo. Alternatively, has been used instead of of morphine (22.2 mg/kg) having an antinociceptive effect in 95% NaHC03. of animals treated. A median effective antimorphine dose ( E D ~ o ) m-(3-Alkyl-l-allyl-3-pyrrolidinyl)phenol Hydrochlorides. of the test drug was that increasing to 50% the proportion of aniwere Method B. 3-Alkyl-l-allyl-3-(m-methoxyphenyl)pyrrolidines mals showing a nociceptive response after morphine with the test prepared as described in method A and 0-demethylated with drug. boron tribromide as reported earlier.',a Where a 3-(m-isopropoxyThe ED60 values for antinociceptive activity and antimorphine pheny1)pyrrolidine was used, it was converted t o the 3-pyrroliactivity for the various compounds are listed in the Table I. Not dinylphenol (compound 18) with refluxing 6 N HC1 for 4 hr. less than ten mice were used at each dose level. Where the pyrro3-(rn-Methoxyphenyl)-1-(3-methyl-2-butenyI)-3-propy1pyrrol- lidines were only available in the free-base form, aqueous soluidine. Method C. 3-(m-Methoxyphenyl)-3-propylpyrrolidine was tions were prepared in the presence of 1 mol of o-tartaric acid. acylated with 3-methylcrotonyl chloride in the presence of NEt3. Similar experiments have used CHZC12 as solvent, and in others, Discussion the acylation was carried out in the presence of anhydrous KzCO3 Examination of t h e biological results in Table I shows in DMF. The resulting amide was reduced to 3-(rn-methoxyphenyl)-l-(3-methyl-2-butenyl)-3-propylpyrrolidine (compound 15) t h a t many of these N-allylpyrrolidines show both antinousing LiA1H4. ciceptive and antimorphine activity in mice. This is in contrast to many piperidine analgesics where N-allyl substitution frequently fails to confer the dual activity on the t Address correspondence to this author at Prochem, The British Oxygen Company, Ltd., London, SW19 3CF, England. compound.12 However, t h e activity is often not so marked T h e interesting activity of a series of 1-(cyclopropylmethy1)pyrrolidines has been discussed in a previous paper of this series.' Replacement of t h e N-methyl group of profadol (Ia), a clinically effective analgetic2 with an N-(cyclopropylmethyl) group, afforded an antinociceptive agent Ib t h a t antagonized t h e analgesic effect of morphine in mice. As an extension of our work in this field we have prepared and examined t h e pharmacological properties of some N-allylpyrrolidines of type IC.
Lockhart, et ai
1973, Vol. 16, NO.10
h
9 N
t-
c:0
v
m rn
Y
h
'9 01
c-
'9 0
v
N
orn 01
i
N 0 1 0 0 0 0 9 O f f i 9 r i ~ r ( m m i o m ~ a
* I
A
Journal ofMedicinal Chemistry, 1973, Vol. IS,No. 10 1183
Analgetics Based on the P>rrolidine Ring 9
Table 11. Comparison of Antinociceptive a n d Antimorphine Activities of N-Allyl- a n d N-Cyclopropylmethylpyrrolidines of General Formula I
R’ (formula I)
__ a
Me Et Pr CHMez CH2CHMep CH2CHMe2* CH2CMe3
Antinociceptive activity, E D j o ,m g / k g sc R”= R”=CH?CH2CH=CH2 c-C~H: 5.3 1.2 2.9 2.5 0.35 0.12 0.47
Antimorphine activity, EDeo, m g / k sc R“= R ” CHQCH&H=CHz C-C~HS-
20 0.58 0.3 0.76 0.11 0.06 0.19
1.7 1.3 3.7 2.5 1.5 0.57 1.6
Antimorphine EDto/ antinociceptive ED54 R”= R”=CH?CH&H=CH* C-C3H3 -
0.9 1.4 4.3 3.O 1.7 1.1 3.3
0.32 1.1 1.3 1.o 4.3 4.75 3.4
0.045 2.4 14.4 4 .O 15.4 18.2 17.2
Racemate as succinate salt. * ( - ) enantiomer as succinate salt. Other details as in Table I.
in t h e N-allyl pyrrolidines as in t h e N-cyclopropylmethyl analogs. A possible reference point for compounds of this type is pentazocine. T h e arbitary levels of activity proposed in t h e previous paper,l namely, a n EDSO of less t h a n 10 mg/kg subcutaneously in each test, were therefore taken t o delineate the compounds of interest. T h i s criterion gave ten compounds t o be discussed (namely, 3, 5, 7-11, 14, 19, and 21). T h e first thing t h a t was immediately apparent was that all of t h e compounds except two (namely, 19 a n d 21) h a d unsubstituted allyl groups suggesting t h a t substitution of t h e allyl generally had a n unfavorable effect on activity, particularly on t h e antimorphine activity. Within the rather narrow range of comparison t h a t is possible, these findings tend t o bear out t h e trends found by Archer, et a1.,13 in their examination of pentazocine analogs for meperidine antagonist activity. N-(2-Propynyl) h a d a similar deleterious effect on activity and, a s has been found in previous series of pyrrolidines, etherification of t h e phenol reduced the potency in both tests. I n T a b l e 11, t h e activities of a series of m-(3-alkyl-1allyl-3-pyrrolidiny1)phenols are compared with those reported earlier1 for t h e corresponding N-cyclopropylmethyl analogs. I t is apparent in t h a t with t h e exception of t h e 3-methylpyrrolidines, N-cyclopropylmethyl substitution gave rise t o greater antinociceptive a n d slightly less antimorphine activity t h a n did N-allyl substitution. It may be argued t h a t the differences in t h e antimorphine activity in t h e two series were not really significant, b u t it is instructive t o examine t h e last two columns of figures in Table I1 giving t h e ratios antimorphine EDso/antinociceptive EDbo. T h i s ratio was almost always lower in the N-allyl t h a n in t h e N-cyclopropylmethyl series. S u c h a difference could well be of profound importance in t h e clinical use-
fulness of such a n agent, particularly with respect t o abuse liability. However, only clinical evaluation c a n provide a n answer t o such a question.
Acknowledgments. T h e authors wish t o t h a n k Mr. F. H. Oliver for microanalyses, Miss E. M. T a n n e r for physical chemistry measurements, a n d Mrs. c. A. Dinneen for technical assistance with t h e pharmacological studies. Messrs. P. J. Hattersley a n d D. J. Peters helped with some of t h e early synthetic work.
References (1) R. E. Bowman, H. 0. J. Collier, P. J. Hattersley, I. M. Lock-
hart, D. J. Peters, C. Schneider, N. E. Webb, and M. Wright, J . Med. Chern., 16, 1177 (1973). (2) W. T. Beaver, S. L. Wallenstein, R. W. Moude, and A. Rogers, Clin. Pharrnacol. Ther., 10,314 (1969). (3) J. F. Cavalla, D. C. Bishop, R. A. Selway, N. E. Webb, C. V. Winder, and M. Welford, J. Med. Chern., 8, 316 (1965). (4) I. M. Lockhart, British Patent 1,186,481 (1970). (5) I. M. Lockhart, British Patent 1,198,973 (1970). (6) I. M. Lockhart, N. E. Webb, M. Wright, C. V. Winder, and P. Varner, J. Med. Chern., 15,930 (1972). (7) D. C. Bishop, J . F. Cavalla, I. M. Lockhart, M. Wright, C. V. Winder, A. Wong, and M. Stephens, ibid.,11,466 (1968). (8) J . F. Cavalla, I. M. Lockhart, N. E. Webb, C. V. Winder, M. Welford, and A. Wong, ibid.,13,794 (1970). (9) H. 0. J. Collier, L. C. Dinneen, C. A. Johnson, and C. Schneider, Brit.J. Pharrnacol. Chernother., 32,295 (1968). (10) C. Bianchi and J . Franceschini, ibid.,9,280 (1954). (11) H. 0. J. Collier in “Evaluation of Drug Activities: Pharmacometrics,” D. R. Laurence and A. L. Bacharach, Ed., Academic Press, London, 1964, p 185. (12) H. Kugita, T. Oine, H. Inove, and G. Hayashi, J. Med. Chem.,-8,313 (1965). (13) R. E. Bowman. H. 0. J. Collier. I. M. Lockhart. and C. Schneider, Brit. i.Pharrnacol., submitted for publication.
