January 1966
127
4- (2-PIPERIDYL)-1,3-DIOXOLASES
4-(2-Piyericlyl)-l,3-clioxolanes w i t h Local Anesthetic, Spasmolytic, and Central Nervous System Activity' IT. R . HARDIE, J. HIDALGO, I. 17. HALVERSTADT, AXD R. E. ALLEN Oryumc Chemistry Department and Phaimacology Department, Cutter Laboratories, Berkeley, Calijomia Received J u n e
6,1965
A series of 2-(2-piperidyl)-1,4-dioxaspiro[4.5]decanes and 4-(2-piperidyl)-1,3-dioxolaneswith alkyl and aryl substituents was synthesized by the acid-catalyzed condensation of (2-piperidyl)-1,2-ethanediolwith ketones and acetals. The yields were best when using acetals. Local anesthetic propehes, generally with parallel papaverine-like activity, were widely distributed through the series and were most prominent when benzyl substituents were at the 2-position of the dioxolane ring. Several compounds had the unique property of shortening reaction time in the hot-plate test. The spectrum of activities of one structure, 2,2-dipheny1-4(2-piperidyl)-l,3dioxolarie, led to the separation of its racemates and the resolution of one of them.
Sub5tituted dioxolanes exhibit a variety of effects which include hypnotic and spinal depressantj2 para\ympath~mimetic,~ a n t i y a ~ n o d i c central .~ stiniulant,s and central depressant6 activities. We have prepared a group of 4-(2-piperidyl)-1,3-dioxolanes with substituents at position 2 (Y). One of the structures (V, R1, R2 = phenyl) proved to be particularly interesting and was additionally substituted on the piperidine nitrogen with various groups. The chemistry and those pharmacological properties most widely distributed in the series are described in this report. Additional pharmacological findings have been described e l s e ~ h e r or e ~are ~ ~ to be published. Chemistry.-The dioxolanes were prepared by the general method of condensing ketones or acetals with vicinal glycols in the presence of an acid catalyst. The acetals, some not previously reported, mere prepared by two methods. Method A, described by Lorette and Howard, n7as used successfully with several
be used successfully to prepare acetals of the substituted aromatic ketones, 4,4'-dimethoxybenzophenone and phenyl 2-thienyl ketone. Method Bl1 was used for substituted aromatic ketones and 9-fluorenone. These PClS
aliphatic aromatic was also sulfite.l0
+ 2ROH + CH3C(OCH3)z+ R1R2C(OR)2+ CHaCOCHa + 2CHaCH
and mixed ketones (Table I) and with one ketone, benzophenone, the methylal of which readily prepared by reaction with dimethyl I'eit'her method A nor dimethyl sulfite could
(1) Portions of this work were presented before t h e Division of SIedicinal Chemistry a t the 141st National Meeting of tlie American Chemical Society, Washington, D. C., March 1962. (2) (a) F. 11. Berger, J . Pharmacol. E x p t l . Therap., 96, 213 (1949); (bj V. Boekelheide, L. Liberman, J. Figueras, C. Krespan, F. C. Pennington, and D. S. Tarbell, J . A m . Chem. Soc., 71, 3303 (1949). (3) (a) E. Fourneau, D. B o r e t , F. Bovet, and G. SIontezin, Bull. soc. chim. bioi., 26, 516 (1944); (b) J. S . dmbache, J . Ph2/siol. (London), 110, 145 (1949); (e) R. Verbecke and G. R. Vlecschhouwer, Arch. Intern. Pharmacodun., 81, 1 (1960). (4) (a) F. F. Blicke and F. E. .knderson, J . A m . Chem. Soe., 74, 1 i 3 3 (1952); (b) F. F. Blicke and E. L. Schumann, ibid., 74, 2613 (1952); (c) F. F. 13licke and G. R. Toy, ibid., 77, 31 (1955); (d) F. F. I3licke and H. E. llillson, J r . , ibid.,7 7 , 32 (1955). ( 5 ) R. 32. Jacob and H . 31. Joseph, U. S. Patent 2,916,493 (1959). (6) (a) B. TVeiss and C. G. T. Ewing, .4m. J . Pharm., 131, 307 (1959); (b) F. Rlelson, Acta Bid. M e d . G e r . , 6, 395 (1961). (7) (a) J. Hidalgo, J. Gallin, A. Williams, and C. R. Thompson, Pharmacologist, 3, S o . 2 , 69 (1961); (b) C. R. Thompson, 5. Williams, L. G. Hershberger, and J. Hidalgo, ibid., 8, Xo. 2 (1961); (e) T. P. Pruss, J. Hidalgo, and C. R. Thompson, Proceedings of the Western Pharmacological Society, 1963, Vol. 6, p. 40; (d) T. P. Prnss and .J. Hidalgo, Federation Pror., as,
KO.2
(1964).
(8) (a) J. Hidalgo and C. R. Thompson, Pmc. S o r . Bzptl. B i d . M e d . , 114, 92 (1963); (b) J. Hidalgo and c'. K. Thompson, Arch. Intern. Pharmacodun., 153, 105 (1Y65). (9) S. B. Lorette and W. L. Howard, J . O r g . Chem., 2 5 , 521 (1960). (10) IT. Voss, A n n . Chem., 485, 283 (1931).
R1R2C(OCHa)2
H
H+
IL1R2C0
NaOCHs
acetals (Table I) were found to be free of ketones, as shoxm by the absence of infrared absorption in the carbonyl band, except for 5 and 8 which nonetheless gave satisfactory yields of dioxolanes. The vicinal glycol was obtained by hydrogenating (2-pyridyl)-1,2-ethanediolhydrochloride12 (I) in water, acetic acid, or methanol using platinum oxide catalyst to give (2-piperidyl)-1,2-ethanediolhydrochloride (11). Rhodium on carbon was also a suitable catalyst.
HC1 Rlethod A:
-
Method B: R1R2C0+R1RzCC12
I
HC1
11
This glycol (11) has two asymmetric centers (*) resulting in a mixture of two racemates. A portion of the higher melting (p) racemate hydrochloride could be separated from the crude hydrogenation product by fractional crystallization from 2-propanol, but a more practical separation, which gave pure samples of each racemate, was to condense the mixture of glycols with the methylal of benzophenone (method D). The resulting dioxolane racemates were then separated (see Experimental Section) and hydrolyzed to give high recoveries of the glycols. The compounds in Table I1 were prepared either by condensation of (2-piperidyl)-1,2-ethanediol hydrochloride (11) with ketones (111) (method C) or by COIIdensation of the glycol xith acetalb (IV) (method D). ?\lethod C n a s reasonably satisfactory for the 2-(2piperidyl)-1 ,A-dioxaspiro[4,5]decanes but was conipletely inadequate for the 2-substituted 4-(2-piperidyl)1,3-dioxolanes since aromatic and mixed ketones were quite unreactive with the (2-piperidyl)-l,2-ethanediol hydrochloride. However, their acetals (IV) reacted smoothly by iiiethod D to give good yields. 2-Propanol was a good solvelit for tlie coiideiisatioii aiid encouraged the separation of crystalline crude product\. A very (11) Jl Wilenk and E Bergmann, %bid 463, 1Y9 (1928) (12) I E Cislak, U b Patent 2,743,277 (1956).
128
l'ol. 9
Conigd. 110.
1 1
3 4 > ti
h 9 IO 11
H\ ,c=u n2 Ill method C (-H20)
method D (-ZROH)
H', /OR
$/c" O H IV
slight excess of hydrogen chloride in the reaction imxture would initiate the reaction, ehpecially when iiiethod D was employed. The (2-piperidyl)-1,2-ethaiiediol hydrochloride condensed satisfactorily, either as the L Y , ~racemate mixture or as one of the pure racemate.. When a pure raceinate of the glycol was used, its racemate assignment was also given to the dioxolaiie produrt. Because of important p1ianii:LcologicaI properties of -01110 of the iiiixed r:tceniateu, iiuiiiei-ou~1m-e raceriiatcs were prepared. ~~-dl-2,2-Dip2ienyl-4-(%-piperidyl)-l,3clioxolarie hydr~chloride'~ (20) was of particular interest. This was first separated from the p-racemate by fractional crystallization but TW:, later purified on a sub5t:~ntialrcale by the preparation of the uL-tartrate salt. The (Y,P mixture (method D) wac fractionally crystallizetl from ethanol-methanol which precipitated a portion of the 6 form. This left a mixture enriched to an m a t e d 85% of the LY form : \ i d prevented the coprec*il)it:ttion of the /3 racemate in the subsequent prcri1tit:ttion step. The 83: 15 niixture of hydrochlor W:LS treated with aqueou5 caustic and the free b \\-ere treated with DL-tartaric acid in methanol to give it precipitate of the DL-tartrate salt of the pure cy racemate. The free base of the CY racemate was also reqolvecl through D- mid L-tartrate salts. The tartrates of the d uiid 2 enantiomers were then converted to thc hytlroc.hlorides. Larger rprntitics of the a-d14 (24) ant1 I 1s) Dioxadrul [ 1 1) Dexoxadrol.
conipound and papaverine ivere determined and the activit,y was expressed as their ratio. Analgesic properties were detected by the hot-plate methodlg after an oral dose of one-fourth of the LDjo. At the time of peak action (determined in the ALES test') groups of ten mice were tested and activity was expressed as the percentage change from mean pretreatment reaction times. Results.-Many compounds in this series protected the mice against' electroshock seizures and several were effective at doses less than one-fourth of the LDjo. The most active compound (18) had a phenyl substituent at position 2 on the dioxolane and the next most active conipounds n-ere both racemates (28, 29) of a struct,urecontaining the fluoren-9-ylidene group. There was 110 correlation between the LIES and local anesthetic activity. Sone of the compounds protected the inice against strychnine- or pentylenetetrazoleinduced seizures, but two (18, 24) showed partial protection us. strychnine lethalit'y and heterogeneous protection against peritylenetetrazole-induced seizures. X a n y compounds in the series were local anesthetics. Least potent were the spirodecanes (Table 11) in which local anest'hetic potency was diminished by a chloro substituent' and augmented by multiple methyl or phenyl substituents. The 2-substituted dioxolanes (Table 11) mere also relatively low in potency when a single benzene group was present (13, 16, 17, 18, 19), but the 2,2-diaryldioxolanes were consist'ently pot'ent'. The highest potency was associated mit'h aralkyl subst,ituents (15, 31, 32). These compounds were 50-80 times as potent as procaine in terms of minimal effective concent'rations. The local anesthetic potency associated wit'h the 2,2-diphenyl-4-(2-piperidyl)-1,3-dioxolane (21) was not diminished by hydrogenation of the phenyl groups. Activity remained with the introduction of a new basic nitrogen in the side chain attached to the piperidine nitrogen (51, 52, 53). Converting the piperidine nitrogen to a tertiary amine by methylation (34, 37) had little effect', but propylation (43, 44), benzylation (47, 50), S-oxide forination (54, 5 5 ) , and quateriiizat'ion (38, 39) of the basic nitrogen caused a sharp drop in potency. The spasmolytic activity of these compounds was papaverine-like. The in vitro activity against BaCI2 was considerable and was generally parallel to local anesthetic potency. Interestingly, the activity against' BaClz reached its peak in the LY racemate (14) of one structure, but the local anesthetic activity was at its inaximum in the racemate (15) of the same structure. Although the data are not included in Table 11, the in vitro anticholinergic activity of t'hese compounds was less than lY0 of that' of atropine with the not'able exception of 2,2-diphenyl-4-(2-piperidyl)-l,3-dioxolane which, when 5-methylated (34) and yuaternized (39), was about 25% as active as at>ropine. The reaction times on the hot' plate were unexpected. A few compounds (12, 13,29,31) showed a conventional increase in reaction time. On the other hand, the LY racemate (20) of 2,2-diphenyl-4-(2-piperidyl)-l,3-dioxolane hydrochloride caused an unusual decrease in the reaction t'ime, a property also possessed by certain other a racemates (18, 20, 40, 43, 47). I n those race(19) K.B.Eddy and D. Leimbach, J . Pharmacol. Esptl. Therap., 107, 383 (1953).
mates where the separate enaritioniers were tested, this property was confined to the a-d isomer, such as 24, which is under clinical investigation. This decrease in reaction time was shown by other a-d isomers (35, 48, 57), but not by their corresponding a-1 enantiomers (36, 49). The racemates which either decreased or increased reaction time also were highly effective i n the inaxiinal electroshock seizure pattern test, although the latter property was riot confined to these racemates alone. Experimental Section 2o Anhydrous 1- and 2-propanol, 1-butanol, 2,2-dimethoxyhydratropaldehyde, and propane, l,l-dimethoxy-2-phenylethane, the tartaric acids vere obtained froni commercial sources. Conimercial grade ketones were used except for the substituted hexanones supplied by the Dow Cheniical Co. 3,5-1hi alytic hydrogenation of lohexanone was prepared by commercially available 3,s-dimethyl loheseiioiie. Uiinet hosyphenylmethaiie was prepared from benzaldehyde in acidified methanol.21 We are grateful to Dr. F. E. Cislak of lteilly Tar and Chemical Co. for supplies of (2-pyridyl)-1,2-ethanediolhydrochloride.22 Catalytic hydrogenations were done at 4.2 kg./cni.z (60 p.s.i.) of hydrogen in a Parr low-pressure apparatus at room temperature. In the descriptions of product isolations, solvents were evaporated a t 15-20-mm. pressure on the steam bath. (2-Piperidyl)-1,2-ethanediol Hydrochloride (II).-A solution of 116 g. (0.66 mole) of (2-pyridy1)-1,2-ethanediol hydrochloridezz in 60 ml. of water, in which was suspended 2 g. of Pt&, was hydrogenated for a period of 30 hr. or until approximately the theoretical amount of hydrogen was absorbed. The filtered solution was evaporat,ed t o a syrup which was dilut'ed with an equal volume of 2-propanol and re-evaporakd. This dilution and evaporation was repeated twice, leaving a viscous hygroscopic syrup weighing 120 g. Anal. Calcd. for C7HI5SO2.HC1:C, 46.28; H, 8.88; C1, 19.52; X, 7.71. Found: C, 46.4; H, 8.8; C1, 19.4; K,7.9. A 1% water solut,ion of this mat,erial had a lo%--intensitybroadband ultraviolet absorption spectrum, while a 0.001% water ~ 0 1 ~ tion of the aromatic starting material had a strong peak at 260 mp indicating that the hydrogenation was more than 997, coniplete. A portion of the syrup, dissolved in saturated aqueous potassium carbonate solution containing a small amount of potassium hydroxide, was ext,racted with chloroform. The solvent was evaporated and the residue was distilled to give the free base of (2-piperidyl)-1,2-ethanediol(59% recovery), b.p. 120-123" ( 2 mm.), n 2 5 1.5070. ~ ilnal. Calcd. for C7&?;02: C, 57.90; H, 10.41; s,9.65. Found: C, 58.2; H, 10.1; X, 9.3. A. CY Racemate.-A solutioii of 305 g. (0.68 niole) of C Y - ~ / - Z , ~ dipheiiyl-4-(2-piperidyl)-l,3-dioxolanehydrochloride (20),5 ml. of coucentrated HC1, and 25 nil. of n-ater in 2 1. of methanol was warmed on a steam bath overnight aud evaporated at reduced pressure, and the residue was washed with ether. The ether phase was discarded and the residue was dissolved in 150 nil. of butanol and evaporated, crystals formiiig in the process. Xft'er recrystallization from a mixture of 250 ml. of ethanol, 50 ml. of 2-propanol, and 50 ml. of ether, 122 g. ( 7 6 5 ) of ~dl-(2-piperidyl)1,2-ethanediol hydrochloride was obtained, melting at 101". B. /3 Racemate.-By the same process, 450 g. of p-dl-2,2diphenyl-4-( 2-piperidyl)-l,3-diosolanehydrochloride (21)gave a 9070 yield of p-dl-( 2-piperidyl)-1,2-ethanediolhydrochloride, m.p. 138", after recrystallization from a mixed solvent of 2 1. of 2propanol and 300 ml. of methanol. (20) hlelting points were determined on a Fisher-Johns block and are corrected. Elemental analyses were done b y Berkeley hnal>-tical Lahoratory. Berkeley, Calif., and West Coast Analytical Laboratories, E1 Cerrito, Calif. Infrared spectra mere recorded on a Baird Model 4-55 spectrophotometer using K B r disks for solids and thin layers between disks for hqnids. Ultraviolet spectra were recorded on a Car. Model 14 ultraviolet spectrophotometer. Optical rotations were observed using a Gaertner Model L-320 polarimeter. (21) R. D. Haworth and A. Lapworth, J . Chem. Soc., 121, 79 (1922). (22) h1.p. 12C"22°. Anal. Calcd. for C;HsNO?. HC1: C , 4 i . 8 i ; H, 5.74; C1, 20.19; S , 7.98. Found: C, 47.83; H, 5.67; C1, 19.96; S , 7.99.
130
d:q
. HC1
IO II I'
S-C( CH,,):j
S-CHo, 8-CeH;
H CH, C'iH,
c',H ('oH C,H
131
January 1966
-Hydrogen, 70Calcd. Found
--Chlorine, Calcd.
c/cFound
--Nitrogen, c/cCalcd. Found
13.25
13.53
12.86
12.82
12.23
12.13
23.94 23.94
23.76 23.78
8.09
23.94
24.15
10.15 8.59
9.44 8.71
11.15 10.08
11.25 10.32
4.41
7.x2 7.55
7.67 7.58
12.49
12.29
4.94 3.75
5.12 3.73
7.55
7.70
3.75
3.71
7.47 7.81 8.12
7.77 7.98 8.22
5.19 4.94 4.70
5.40 4.97 4.76
8.12 6.99 6.99 6.10 5.35 6.99
8.16 7.08 6.85 6.50 5.13 6.89
4.70 4.05 4.05 3.68 3.38
6.99 6.30
6.84 6.22
6.30 6.45 6.45 10.14 7.55 7.28 6.95
6.14 6.69 6.31 9.52 7.60 7.22 7.09
9.24 9.50 9.50 9.50 9.50 9.74 9.74 7.83 7.83
9.05 9.38 9.31 9.76 9.25 9.77 9.56 7.76 7.67
7.83
10.25
10.06
18.65
18.33
10.25
10.15
10.25
10.41
10.31 10.31 9.91 9.48
10.08 10.25 9.51 9.55
8.73
8.65
5.35 5.08 5.08 5.08 5.08 4.83 4.83
5.58 5.29 5.01 5.01 5.04 4.95 5.01
4.87
LD50. mdkg. orally in mice
7 9 600 600 600 600 500 800 800 600 750 800 1500 600 400
300 200 250 200 37.50
--
Comparatire pharmacology-----------Local Bariolytic Hotactivity, plate' anesthesia, LIES' min. eff. tn nitro, reaction EDso, % concn.d rabbit ileum time, % of mg./kg. (proc. = 2) (papav. = 1) control
>7jh 150 150 >l50 >l50 >125 >200 200 >150 200 150 l50 50
1 0.1 0.1 0.1 0.25 0.1
1 2 1.5 3 0.5 1
4.05 9.12q
4.22 9.54q
230 400
r -
0 .1 0.5
1 3
100 100 69" 82" 126" 63" 100 100 100 52p 70" 100 100
9.129
9.34*
0.1 0.4 0 . 4 neg. 0.1 0.025
3.89
4.01
600 300 300 600 400 600 800
3 1 1 3 1.5 1.5 0.7
100 100 184 100 131 125 95
iD
ia
>50 (100 >lo0 150 50 mI J
>200
75
0.1
1
100
>75
0.25
4
100
>150
0.25 neg.k
1
100
>l50 >75 200
0.25 neg.k 0.25
