Aiialgetic Activity of Cyclized Basic =inilicles
In our search for new potent aiidgetics. we have synthesized a group of cyclized basic wnilides which arc ytructurally related t o the S-substituted propion:inilides.2 I t was our intentioil to compare the ~in:iIgetic activity of the cyclic basic anilides of varying ring sizes t o that of the propionanilides. The compounds reported here are listed in Tables 1-11- and may he represented by the general foriiiula I. 11) T o whom communications siiould Ibe directed. ( 2 ) (a) 1%'. B. Wright, Jr., H. J. Iirahander, and R. .\, Hardy. .Jr.. J . . t i n . Chem. Soc., 81, 1518 (1959); J . Org. C h e m . , 26, 476.485 11961): (b) 11.. 13. Wright, Jr., ibid.. 25, 1033 (1960); ( e ) S . Shigematsu, Yukugaku Z u , 423, 815 (1961); (d) X. Sugimoto, I
2
H
3
>i
I-ield. yo
Formula
Recrystn solvent
Mp, O C
Analyses
1
32. .i
200-201
PIIeOH-i-PrOH-Et20
C ~ I H Z ~ S Z O . C Z H H, ~ ON; ~ Ca
-S>C,H;
2
23
136-138
AIeOH-EtOAc-Et20
C Z ~ H ~ ~CzHzO4 X~O
N(total), K(basic)
H
-XV(CH.):
2
31
183-1 85
i-PrOH-Et OAc
C13Hi~N20HCl
s,c1
4
H
-S
2
27
148-130
i-PrOH-Et?O
C21H2jN30'C4H404
K(total), N(basic)
5
CHI
- y z
1
39.3
190-192
;\leOH-EtOhc
CI6H2zN2O. C2HaOi
H, S ; Cb
6
H
-.SZ'
53.5
234-236
i-PiOH
C?~HZ~T\T?O~. HCl
C, H, N
a
C,.H:
n SC,Hj u
1
C : c a l d , 67.20: foinidj 66.34.
C: calcd, 62.05; found, 61.54.
h L T B OF
TABLE I1 B.~SIC 3,4-DIHYDROC.\RBOSTYRILDERlT-.\TIVES (CHJnR'
I
Yield,
R"
so.
i
n
7c
~ T P ," C
Recrj s t n soh ent
H
2
10 237-238
i\leOH-H20-DlIF
H
3 40 210-211
i-PrOH-HnO-Et?O
9
H
3 50 137-139
i-PrOH-EtOAc-Et?O
10
H
3 50 178-179
MeOH-E t *O
11
6-OCH2CsHj 3 40
12
6-OH
3 40 245-246
AIeOH-L)AIF-H20
13
H
2
MeOH-L)AIF-H20
14
7-OCH2CsHj 3 18 163-164
l\IeOH-EtzO
15
i-OH
3 11 209-210
NeOH-Et2C
8
a
-1
$ 7 \C.H
C . calcd, 62,5\: foimd, 61.92.
15
185-186
164-165
RIeOH-Et,O
Reference 4.
3,4-Dihydrocarbostyril, 6-benzyloxy-3,4-dihydrocarbostyril, and T-benzyloxy-3,4-dihydrocarbostyril were prepared according t o the procedure of Shigem a t ~ u . The ~ desired derivatives of 3,4-dihydrocarbostyril (Table 11) were prepared by the same method as the other ring yystems. The hydroxyl derivatives were obtained by dehenzylation of the benzyloxy derivatives with loc; Pd-C and H,. The I-substituted derivatives of 2-indolinone (Table I) were prepared by treatment of the sodium salt of 2-indolinone with the appropriate aminoalkyl halide in an autoclave. Pharmacology.--;inalgetic activity of the cyclized basic anilides was determined by the subcutaneous or intraperitoneal routes by the method of Bianchi and (4) S . Shipematsu, C h r m . Phnrm. Bull. (Tokyo). 9, 970 (1961).
Franceschini.5 At 30 min following the subcutaneous administration or 5, 15, and 30 min following the intraperitoneal administration of the test compound, an artery clip (serrefine clamp) was placed at the base of the tail. Analgesia was considered present if the animal failed to bite the clip within 30 see. Twenty animals were used a t each dose level, and the median analgetic dose (ADj,) was determined by the Litchfield-Wilcoxon method6 using a minimum of three doses. Compounds 17 and 21 demonstrated analgetic activity which was comparable to meperidine (Table V). Carabateas, et al., report the analgetic potency of ( 5 ) C . Bianchi a n d J. Franceschini, Brit. J . Pharmacol., 9, 280 (1954). ( 6 ) J. T. Litchfield, Jr., a n d F. TVilcoxon, J . Pharmacol. Ezptl. Therap., 96, 99 (1949).
l-jl'-S-l~lien~-lpropionai~iidoethyl) - 4 - phenyl - 4-piperitlinol t o be 30 times that of meperidine.2f Thc nnalgetic activity of 21 decreased by one-half upon removing the +hydroxy group on the 4-phenylpiperidine moiety. Reduction of the size of the ring t o scven-, .is-, nrid five-membered structure> (16. 7, and 6, rc.pectively) iurther decreased the aiialgetic. properties. With respect to 17, analgesia W I S tlecretiseti upon increasing the ring size to eight member. (23) or decreasi n g it t o fivc members ( 2 ) .
Experimental Section' I1 12 1:; 14 I .i 1 (i 17 1s 1 !J 20 21 22 2;::
Meperidine HCL
>.io IC' ,>27.2 ,>c >7.5 .c 100 >e > 1.00 > c
-
.?(id
1 2 . 0 t Y 8-16.5) sc >.is . x so >16 ip
>30 ip 1 2 . 7 ('3.3-17.4) ip 2 3 . 8 120.6-34,8) ip >.io ip l t i . 2 112.2-21 6 ) a c Y.6 t6 0-12.:3) ip
JIedian analgetic dose (Y5!c confidence limits). Base. At 100 mg,kg, 1005; death. dHigher doses produce toxi? eftects.
The followiiig detailed procedure,. :ire wprewit:itivt, of the preparation of compoinids with varied iiiig size.>. 1 [2-(4-Hydroxy-4-pheny l-l -piperidyl)ethyl]-2-indolinone Hydrochloride (6).--4 mixt.ure of 2-indidinwie i 7.4 g, 0.056 mole), l-(~-chlciroethyl)-4-hydros~--~-pheri~lI~ipe~idine hydrohromide (1s g, 0.056 mole), and 6.1 g !0.11:3 mole) of S a 0 3 I e \Tab siispended ill 50 ml of C,H, arid t,he mistrue was heated in a steel autoclave at 110-120° for 3 hr. The mixture was filtered and the red filtrate was concentrated. The residual red oil was treated with HC1. The nonbasic material was extracted with CHCI,. The hydrochloride, which was i n d u b l e in both Hi0 and CHC13, %-asrecrystallized from i-PrOH: yield 10 g. For further plirification, the mat,erial was sublimed (160", 0.5 mm) and again recrystallized from i-PvOH; yield 2.5 g, nip 234-236".
-
( i ) All melting points are uncorrected a n d nere determined n.it11 a Baohi capillary melting point apparatus (W. Biichi, Glasapparatefabrik, Flawil, Switzerland). I r spectra were determined with a Perkin-Elmer Model 237 grating spectrophotometer. Titrations were carried out with a Sargent Model D recording titrator. Where anal>-ses are indicated h y symbols, the elements or functions were within i O . . l o , of t h e calculated valiies.
July 1969
,hALGETIC
3-PYRROL1DINYLA4NILIDESA S D DIHYDROBEKZOXSZINONES
3,4,5,6-Tetrahydro-1- [2-(4-hydroxy-4-phenyl-l-piperidyl)ethyl] -l-benzazocin-2( 1H)-one Hydrochloride (21).-To 10.0 g (0.057 mole) of 3,4,5,6-tetrahydrobenzazocin-2( lH)-one in 100 ml of xylene was carefully added 3.0 g of NaH with stirring. The reaction mixture was then refluxed with stirring for 2 hr. To the mixture was added 3.0 g of NaH and 19.2 g (0.06 mole) of 1-(2-chlorethyl)-4-hydroxy-4-phenylpiperidine hydrobromide. The reaction mixture was stirred under reflux for 8 hr, then treated with HzO and CHC13. The organic solvents xere concentrated in vacuo leaving an oily residue. The starting amide was removed by vacuum distillation; the remaining residue weighed 17.0 g. The hydrochloride was prepared by adding exce.r HC1 in 2-PrOH t o a solution of the base in 3IeOH. Upon addition of EtlO, a solid formed which was recrystallized three timei from 3IeOH-EtzO; yield 3.5 g, mp 237-238". 1 [ 34 4-p-Fluorophenyl-1-piperazyl)propyl] -3,4-dihydro-7-
-
553
hydroxycarbostyril Hemioxalate (15).-To 15.0 g (0.032 mole) of 7-benzyloxy-1- [ 3-(4-p-fluorophenyl-l-piperazyl)propyl] -3,4dihydrocarbostyril in 200 ml of absolute EtOH was added 2.5 g of 10% Pd-C and the mixture was hydrogenated at 3.5 kg/cmZfor 2 hr. The solution was filtered t o remove the catalyst and the filtrate was concentrated in vacuo leaving an oil. The oxalate was prepared by adding 3.0 g (0.034 mole) of oxalic acid in Et20 to 13.0 g (0.034mole) of the free base. A solid material was obtained which was recrystallized from NeOH-Et20; yield 5.0 g, mp 209-210".
Acknowledgment.-The authors u-ish to thank Dr. Dale Stauffer and associates for the analytical services. We are indebted to Nessrs. Ted Leipzig. Richard Kulp, and Fred Ward for the preparation of intermediates.
Spnthesis and Analgetic Activity of Some 1- Substituted 3-Pyrrolidinylanilides and Dihydrobenzoxazinones GROVER C. HELSLET, CARLD. LUNSFORD, WILLIAIIJ. WELSTEAD, JR., ROBERTF. BOSWELL, JR.,WILLIAMH. FUNDERBURK, - 4 S D DAVID S.JOHXSON Research Laboratories, A . H . Robins Company, Inc., Richmond, Virginia Received December 9, 1968 Some 1-substituted 3-pvrrolidinvlanilides and 1-substituted 3-pvrrolidinvl-2H-l,4-benzoxazin-3(4H)-one~ have been prepared and &ted for- analgetic activity. Several of t h e compounds show moderate to potent activity.
Anilides of the structural type I have been shown to be strong analgetics.' I n this paper the preparation and analgetic properties of a series of 1-substituted 3pyrrolidinylanilides (11) and dihydrobenzoxazinones (111) are described. These structures can be viewed as cyclized versions of I.
? I
I
R
R I
I1
111
Chemistry.-The synthetic routes used to obtain these compounds are shown in Chart I. The anilinopyrrolidines (V) were prepared by the nucleophilic displacement of the toluenesulfonate ester of a 3-pyrrolidinol or a 3-bromopyrrolidine (IV) by an aniline derivative. This tosylate displacement reaction has been previously reported.2 The properties of new compounds are given in Table I. The N-substituent was varied by starting with the appropriate l-substituted pyrrolidine (IV) or by catalytically hydrogenating the 1-benzylpyrrolidine (V, R = benzyl) to the corresponding secondary amine and alkylating with the appropriate alkyl halide. Treatment of the anilinopyrrolidines with an acid chloride or anhydride gave the anilides (VI) in good yield. The hydroxyanilides (VI, X = OH) were prepared by the reaction of the hydroxyanilinopyrrolidines and 2 equiv of propionic (1) R. A. Hardy, Jr., and M. G . Howell in "Analgetics," G . destevens, Ed., Scademic Press Inc., New York, N. Y., 1965, Chapter V. (2) 17.J. Welstead, Jr., J. P. DaVanao, G. C . Helsley, C. D. Lunsford, and C. R. Taylor, Jr., J . -\!fed. Chem., 10, 1015 (1967).
anhydride or propionyl chloride and subsequent hydrolysis of the ester with dilute S a O H . The first equivalent of anhydride or acid chloride gave a mixture of ester and amide as shown by ir and nmr spectra. The dihydrobenzoxazinones (IX) were prepared by the reaction of the 2-hydroxyanilinopyrrolidines (VII) with chloroacetyl chloride and treatment of the resulting amide (VIII) with base. The experimental details are given in Tables 1-111 and in the Experimental Section. The ir and nmr spectra of the compounds described are consistent with the proposed structureq. I t is interesting to note, however, that the aroniatic hydrogen a t position 8 (ortho to N) in 21, 22, 24, and 25 are at unusually low-field positions (7 2.3-1.9) for compounds of this type. Molecular models suggest that the ohydrogen of these compounds is crowded into close proximity with the nitrogen of the pyrrolidine ring, thereby experiencing a deshielding influence from the unshared electrons on the S. Related proximity effects have been d e ~ c r i b e d . ~ Pharmacology.-Compounds n ere tested for analgetic activity in female mice (ICR strain) using a modification of the method of Nilsen4 aq previously de~cribed.~ Toxicity was estimated in female mice of the same strain, using two animals per dose level. The results of these tests are summarized in Table IV. Some of the compounds were also investigated for analgetic activity using the method of Randall and Selitto.6 In BI. J. T. Robinson, Tetrahedron Letters. 1153 (1968). (4) P. Nilsen, Acta Pharmacal. Tozzcol., 18, 10 (1961). (5) G. C. Helsley, J. -4.Richman, C. D. Lunsford. H. Jenkins, R. P. (3)
Mays, W. H . Funderburk, and D. N. Johnson, J . M e d . C h e m . , 11, 472 (1968). (6) L. 0. Randall and J. J. Selitto, Arch. I n t e r n . Phnrmacodyn., 111, 409 (1957).
