July 196s
TABLE I:
NO.
793
CEKTRAL STIMULANT 3-PIPERIDINOLS
Y
3-PTPERIDIKOLS A N D
DERIVATIVES
Salt"
MP, ' C b
Crystn solventC
218-2 19 I 160- 162 EA H 96-98 298-300 A HC1 199-201 A AS A 171-174 1-PS E 94-96 H 4 214-215 &AT. HZO A-W 211-212 A AS* 170-1 90 d-AT.H,O A-W H 5 210-212 A AS 190-192 A OII 6 281-286 HC1 A 171-174 IA H 7 224-226 A-E HCl 270-274 I-E IICl H 8 104-106 H €1 9 305-307 €IC1 263-265 IJCl AC H 10 312-314 HC1 W II 11 131-133 €1 II 12 194-195 I Ah1 148-1 50 ?\I H 13 253-254 A HC1 127-129 I II 14 269-270 A HC1 218-220 2-APS A-W 270-273 A HC1 H 15 237-238 Ah1 I H 16 139-142 E OH 17 286-288 HCI A-E 142-143 H H 18 287-289 A HC1 307-310 HC1 W H 19 I 159-161 H 20 268-269 HCl A-E 184-186 B H 21 231-233 A H 22 H 315-318 HCl A 23 H 318-322 HC1 A 24 90-92 H II 25 All 159-160 A-E H 114-116 H 26 I-E 248-252 HC1 H H 98-99 27 227-228 A-E HC1 H 93-94 H 28 253-255 HC1. A-E 242-243 H HC1 A-E 29 2 12-21 4 H AM A-E A 30 I-4 168-170 H 31 192-195 €1 HC1 B 32 249-250 HC1 H A 33 197-199 111 H 34 0 AAI, acid maleate; AS, acid succinate; APS, acid phenylsuccinate; AT, acid tartrate; PS, phenylsuccinate. b Melting points were taken in capillary tubes in a Hershberg apparatus and are uncorrected. A, EtOH; AC, Me2CO; B, benzene; EA, EtOAc; E, EtpO; H, hexane; I, i-PrOH; IA, i-PrOAc; A I , MeOH; W, H,O. d From the pyridine analog with H2 and Pt in AcOH. e Base bp 218-220" (1 mm). By the procedure of H. H. Hatt in "Organic Syntheses," Coll. Vol. IT, A. H. Blatt, Ed., John Wiley and Sons, From 2 with Inc., S e w York, S. Y., 1943, p 211. 0 C: calcd, 71.75; found, 70.80. * I isomer. ' [a]"D +26.6". 2 D isomer. LAII in ether (Soxhlet addition procedure). 2 For this compound replace phenyl in the formula by cyclohexyl. Cyclohexyl. Cyclopentyl. By X-methylation with HCHO-HC02H. p I isomer, [a]z s -4.6", ~ obtained by acetylating the d-piperidine derivative. * By rearrangement of 22, [ a ] Z j -48". ~ From 3 with Et1 and KsC03 in Me2C0. From 3 with allyl bromide and K2C03in acetone. d isomer, [ a I z 5+133.4, ~ from acetylation of 14. Sesquihydrate, [ a I Z ' " D +60.2. * c : calcd, 69.50; found, 69.07. w C; calcd, 70.45; found, 71.00. H : calcd, 7.49; found, 8.08. Analyses for the elements indicated were C: calcd, 76.24; found, 75.82. within 0.42-;,of the theoretical values. 1
6 3
I1 H H
ITCl
w
70.1
S
11 11
II I1 CR3
CH3 Hydrochloride
CH3 CHj IIydrochloiide CII, ir CH3 CH, Acid malea t e CII I Acid m:ilrnt c Ilp 11
11 TI
0-ClCJT p-CIC'ell CrlT.,
Metliosiilfatt.
I1 11 ('113 C'IT,
CII, 11%
CTI, 11 CI I, IT c A, CH3CO Methoidfate CIl, CZH6 (CI33),NCC) llethosulfate
:tiid piperidine groups. The hydrogenation of the pyridinols as their ether or acyl derivatives gave cleaner Ijroducts. although some hydrogenolysis of the ether and ester functions did occur. The catalytic reduction of the S-methylpyridinium derivatives, either as the phcriols or its their ethers or esters likewise did not give single products. 111large-scale runs hydrogenation of :'-dil,hei~yln?ethq.l-3-pSridinol with Raney nickel mas more successful. Only one conformational isomer of 2di~)heriylmethyl-3-~~iperidinol was isolated from all the procedureb, probably the cis form with an axial hydroxjrl siiicc its S-acetyl derivative rearranged to the ester in :wid solution.
The lactoiic (\-) of ol-(Y-2iydrox?--"-i~i~eri~~l~~)lic.ti~ Iitcctic acid also was prepared since it possesses the m:tiii structural features of methylphenidate (IT). Tlim 2-benzyl-3-methoxypyridine was carbethoxylnted n i t h ethyl carbonate and the product was hydrogeriatcd : i d cyclized to the lactone. In addition to the compounds prepared as stiinulaiits. 2-benzyl-3-methoxypyridine and its p-chloro anitlog were alkylated with dimethylaminoethyl chloride to give the 3-methoxypyridyl analogs of the antihist:iniines pheniraniine and chlorphenirainirie. Pharmacology. -Thc htimulant effects of the piperidinoly on mice wcrc deterniiiied iri tlic Phnrimcolog~
July 196s
CEXTRAL STIhIULANT
79;
3-PIPERIDINOLS
TABLEI11 ~ - F U R KETONES YL
BP (my)' or mp, C
R
Crystnb solvent
Yield,
%
Formula
hnalysesd
87-88 nI 5 -5 Ci?HsClOj c, H p-Chlorobenzyl 138-139 A 78 C18Hi2Oa H , ce 9-FlLiorenyl 112-1 14 11 SO CisHu03 c, I1 9-Xanthyl 206-212 (1) 35 CisHuC102 H a-(p-Chloropheny1)benzyl 210-216 (4), S2-84 H 66 C1eT-T,,ClO* c, II a-(0-Chloropheny1)benzyl 101-103 Diphenylmethyl €1 70 CldTllO2 c, I1 163-164 B 63 C,sH,EO? c, H Diphenylmethylc 11 01-( p-Methoxypheny1)benzyl 115-118 CI~~II,GOI c, H * See footnote c, Table I. For this compound replace fury1 by 5-methylfuryl i n the formula. d See foot4 See footnote b, Table I. note z, Table I. e C: calcd, 83.06; found, 83.75.
c,
TABLE IV EFFECTSO F 3-PIPERIDINOLS A N D NO.
Stimulant dose,a.b m d k e ip
nERIVATIVES IN RlICE
Lethal dose,"c mg/kg ip
300 l00J 100 3 100 100 100 0.3 30 10 100 3 100 3 100 3 30 100 3 100 10 100 1 30 1 100 300 300 10 100 17 30 100 18 100 100 19 30 100 20 10 100 23 10 100 24 0.3 30 25 3 30 26 10 100 27 3 30 28 30~ 1008 29 10 100 30 30 300 33 1 100 Amphetamine 1 60 a Lowest dose producing moderate increases in motor activity or reactivity (visual observation). * Compounds were administered i n water as soluble salts: the dose is calculated as the free base. Lowest dose administered a t which deaths occurred; initial screen a t doses of 3, 30, and 100 mg/kg. The deaths were invariably convulsive. d S o stimulation ; depression and muscle relaxation only. e Per oral administration. 1 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Department of these laboratories. Dr. Samuel Irwin supervised this study and the procedure has been published.3 The results are given in Table IV. Briefly summarized, the 3-piperidinols I, where R is hydrogen or alkyl, I-is hydrogen, and R ' is phenyl, were potent stimulants. The ether and ester derivatives, excepting 24, were less active as were the diphenylcarbinols and most compounds with substituents in the phenyl ring. (3) S. Irwin, N. Slabok, P. DeBiasse, and W.Govier, Arch. I n t . P h a r m a codyn. Ther., 118, 358 (1959).
Compounds 5 and 14, the d isomers of 3 and 13, respectively, accounted for the activity of the latter since the 1 isomers were almost inactive. Compound 14 had minimal cardiac arid respiratory effects at stimulant doses and was tried ~linically.~It was a potent stimulant, but the dose-response effect mas too marked. At a given dose, due to the variation in the individual patient response, the level of stimulation attained frequently was above or below that desired. The lactone V had 0.01 times the activity of amphetamine. Subsequent studies5correlating the activity and configuration of the methylphenidate isomers have shown that the threo form (amino and ester groups adjacent) is responsible for the activity and that the erythro form is almost inactive. Molecular models indicate that in both the cis and trans forms of the lactone V, the amino and ester groups are more widely separated than they are in the threo form of methylphenidate, and this may account for its lack of activity. Compounds 49 and 48, the 3-methoxy analogs of pheniramine and chlorpheniramine, respectively, had 0.1 times the antihistaminic activity of the parent compound when tested in vitro on guinea pig ileum.
Experimental Section a-2-Furoyl-p-chlorophenylacetonitrile.-A solution of 75,s g of p-chlorophenylacetonitrile in 100 ml of CsHs was added dropwise to a stirred refluxing mixture of 70 g of ethyl furoate and 30 g of PiaOCHI in 300 ml of CsHe. During the reaction the benzene-alcohol azeotrope was removed through a helice-filled column topped by a total-reflux partial-takeoff condenser. After 4 hr the mixture was cooled and filtered, and the orange salt was washed (CGH,). I t was stirred with 20% AcOH and Et,O until it dissolved and the ether extract was washed neutral with NaHC03, dried (NanSOa), filtered, and dist>illed. The yield of yellow viscous oil, bp 183-186" (1 mm), was 106 g ( S 4 5 ) . Anal. (CiaHSClNO) N. p-Chlorobenzyl 2-Fury1 Ketone.-The above nitrile (94 g), in 500 ml of MeOH, was saturated with dry HC1 below 5' and kept at room temperature for 3 days. 4 crystalline imino ester salt separated. HZO (1 1.) was added, the mixture refluxed vigorously for 3 hr, and the MeOH distilled. The product solidified when cooled. Diphenylmethyl 2-Fury1 Ketones.-The diphenylmethane ( 1 mole) was added with stirring to KYH2 (1 mole) in 1200 nil of liquid NH, contained in an insulated (vermiculite) flask. Ten minutes after this addition, 0.5 mole of finely powdered ethyl furoate was added during 13 min and several hours later 500 (4) J. Nodine, T. Rode. J. Slap. H. Lery, a n d P. Siegler, Antzbiol. M e d . Clzn. T h e r a p y , 7 , 771 (1960). (5) I. Weise and A . Dudas, Monatsh. Chem., 91, 840 (1960).
