3-((y,a,a-TRIFLUORO-m-TOLYLOXY)-1,2-PROPANEDIOL 1-CARBAMATE
Journal of Medicinal Chemistry, 1971, Vol. 14, No. 10 969
Metabolism of 3-(cr,a,a-Trifluoro-rn-tolyloxy)-l,2-propanediol1-Carbamate in Man ARLINGTON A. FORIST,* DONALD R. BUHLER, HARRY HARPOOTLIAN, AND RAYW. JUDY Research Laboratories, The Upjohn Company, Kalamazoo, Michigan 49001 Received November 30, 1970 3-(a,a,a-Trifluoro-m-tolyloxy)-1,2-propanediol 1-carbamate was rapidly and efficiently absorbed in man. Peak serum levels were observed 1-4 hr after oral administration and detectable levels persisted for a t least 8 hr. Over 65% of the dose was excreted in the urine within 24 hr as the 0-glucuronide. Small amounts were excreted as: (a) intact drug, (b) a sulfate conjugate, (c) 3-(a,a,a-trifluoro-m-tolyloxy)lactic acid, (d) a,a,a-trifluoro-mtolyloxyacetic acid, and (e) a,a,a-trifluoro-m-cresol. A stereospecific metabolism was suggested.
3-( (Y, (Y, a-Trifluoro-m-tolyloxy)-l,2-propanediol 1carbamate (I) is a centrally acting muscle relaxant”* similar to chlorphenesin carbamate, [3-(p-chlorophenoxy)-1,2-propanediol 1- arba am ate].^ The metabolism of chlorphenesin carbamate in man and in animals The present study was underhas been taken to determine the magnitude and duration of circulating drug levels and to characterize the urinary metabolite pattern in man following oral administration of large single doses of I.
Ck3
I, I? = CHzCHOHCHzOCONHz 11, It = CHzCHOGCHzOCONHz; G = glucuronide 111, R = CH,CHOHCHzOH IV, R = CHeCHOHCOzH V, R = CH2COzH VI, R = H
TABLE 11 DISTRIBUTION O F MATERIAL EXTRACTED FROM URINE
Results and Discussion
Fraction
Serum Drug Levels.-Concns of I in the serum of the S subjects over the 10-hr sampling interval are shown in Table I. Peak levels were observed 1-4 hr after TABLE I SERUMLI;VP:LSOF In FOLLOWING ORALADMIXISTRATION Time, hr
1 2 3 4 5 6 8 10
Subject Fe
Sz
Ma
9 . 7 3 . 1 12.7 11.4 7 . 1 20.8 14.5 6.0 21.0 13.5 7 . 5 23.6 11.9 5 . 1 19.4 7 . 1 4 . 8 15.9 5 . 8 5 . 2 12.5 5.1 5.0 9.4 rg/ml after 2-g oral
Mi
____________
Mo
Pr
order. Deviations, suggestive of enterohepatic recirculation, occurred beyond 6 hr. Consequently, no attempt has been made to fit the data to a pharmacokinetic model. JIean serum levels of I are shown in Figure 1; mean serum chlorphenesin carbamate levels found in another study with the same subjects after a 2-g dose of that drug are presented for comparison. Similarities of the two curves indicate that the rate of absorption, the distribution, and the rate of elimination of I closely approximate those for chlorphenesin carbamate. Durations of action for I and chlorphenesin carbamate should be similar. Urinary Metabolite Pattern.-A pooled urine sample representing one-half of the 0- to 24-hr collection from each of two subjects was fractionated according to the procedure of Buhler. Distribution of materials among the 6 fractions is shown in Table I1 with similar data
Br
Jo
Mean
26.6 5 . 4 1 0 . 4 11.4 9 . 4 1 1 . 1 19.8 9 . 8 12.9 8 . 5 14.1 1 3 . 1 14.8 10.5 12.6 8 . 3 12.6 12.6 11.0 7 . 6 11.3 7.8 8 . 5 11.4 10.0 6 . 0 9 . 6 6 . 0 3 . 5 8 . 9 6 . 8 5 . 6 7 . 1 5 . 0 6..5 7 . 4 3 . 8 5 . 3 3 . 7 4 . 7 4 . 3 5.9 4.0 0 5.7 5 ~ 0 0 4.3 dose.
oral administration indicating rapid absorption. lleasurable levels were present i n all subjects for at least S hr. Holvever, for most of the subjects, the elimination of I could riot be considered ltineticnlly first (1) G . A. Youngdale, U. S. P a t e n t 3,103,533 (1963); Chem. A b s t r . , 69, 11361 (1963). (2) G. A. Youngdale, U. S. P a t e n t 3,169,908 (1965); Chem. Abrtr., 62, 14568 (1965). (3) R . J. h l a t t h e w s , J. P. Davanzo, R. J. Collins, and h f . J. VanderBrook, Arch. Inl. Z’hnrmncodyn., 143, 574 (1963). (4) D. R. Euhler, J . Z’hnrmacol. E z p . Ther., 146, 232 (1964). ( 5 ) L). R. Iubjeot. The meaii seriiiii blaiik for the 8 .\iibjecti wi:, ecjriiv to fraction \\as then methylated and acety1ated.j Tlc of 3.K ~g of I iiil. The methud i? sperific foi, I i i i the pre-:encr' of it-: the resulting product shon ed one p-dimethylaniinodetected metabolites. benzaldehyde positive zone with a color reaction and a Fractionation of Metabolites.-( hie-half of the 0- i ii 2+hr mobility very similar to authentic methyl [3-(p-chloroiiriiie ?ample from each of 2 siibjects ~ L cornbit1cd Y alid m i x t a h J lites n-ere frnctioii:ited hl- the method of Buhler.4 The 1 1 0 1 ) phenoxj.)-1,2-propanediol 1-carbamate %O-(tri-O-aceroiijiigated fraciiotr w:w e s t d froni a(-idified uritie with f?IlCl?. tyl-p-u-glucosid) ] ~ r o n a t e . ~Purification of this deThe relidlinl Iiririe \vas then h>-divlyxd with ~-gluciiroiiitl:1~(~ rivative by column chromatography gave a crystalline fKetodase, lVarrier-Chilcott Co., AIorris Plains, 1;.J.) :ind Ihc product characterized by elemental, functional group. gluc~riroiiidefiLicLi(Jtiwi. extd with CHC1,. The ie.-ullitrg iiiific and spectral analyses as methyl [3-(~~,a,a-trifluoro- residue wa. i n t u r t i hydrolyzed with .s.ulfatase [(~lmuItisejP;II&I Laboratoriea, Inc., liichmond Hill, ?;. Y . ) and the sulfate fra('ni-tolyloxy)-l,%-propanediol 1-carbamate 2-0-(tri-0tioti was extd with C"C1,. Knch CfICla est was further rcpd acetyl-p-n-glucosid) luronate. Excretion of I as the into neutral and :iridic frnciioiis. 0-glucuronide (11) \\-as confirmed. Characterization of I from the Glucuronide Neutral Fraction. Metabolism of I in man closely resembles that of --The glticyiroliide iiriitral fraci ioii 'iva~sre ,td from EtOII-IId) aiid then from CIT, olrtained on Cary 1Iodel 14 ( a s ) , Perkin-Elmer AIodeI 421 ( i r ) , and Varinn .\ssociates 1lodel .\GO (nmr) instruments. ($1) A. AI, I l o r g a n , E. T I . T r u i i t , and ,J. 11,I.ittle, J . .lmer. l ' l ( ~ i r f t i .. I . ? . \ . . Sci. E d . , 46, 374 (105ir.
ANALGETICSWITH EXOCYCLIC BASICCENTER
Journal of Medicinal Chemistry, 1971, Vol. 14, No. 10 971
109-111.5" (1it.l mp 108-109°); ID -6" ( c 0.64, CHCla); ir (mull) and nmr (DPrlSO-ds) spectra identical with those for C, H , F, N. authentic I. Anal. (C1,H1~F~N04) Characterization of the Glucuronide of 1.-A crude glucuronide fraction was isolated from the combined 0- to 48-hr urine of one subject using the basic lead acetate procedure.' The glucuronide gum was methylated with CHzNz in EtzO, and the resulting ester was acetylated with pyridine-A~~O.~ The crude product was purified by chromatog on a column (2.3 x 29 cm) contg 50 g of 100-200 mesh Florisil (Fisher Scientific Co., Fair Lawn, N. J.). Sample was introduced to the column in CH&L and elution accomplished with MezCO-isooctane mixtures of increasing polarity. A yield of 458 mg of crude crystals was obtained. This material was recrystd twice from C6H6-isooctane to give 285 mg ~ (e 0.78, CHC13); uv of crystals: mp 168.8-169'; [ a ]-17 and E); ir very similar to indistinguishable from that of I (A, the corresponding methyl tri-0-acetyl derivative of chlorphenesin carbamate 0-glucuronides and of the glucuronides of p-aminosalicylic acid,'Q p-hydroxybenzoic acid," and 3-hydroxycarbazole;12 nmr (CDC13) consistent with the structure methyl 13(a,a,a-trifluoro-m-tolyloxy)-1,2-propanediol1-carbamate 2-0(tri-0-acetyl-~-~-gluosid)] uronate based on sharply defined acetate peaks a t 6 1.83 and 2.03 (in the ratio of 1:2), a sharp peak at 3.7.5, broad multipleti attributed to carbinol and amide H between 3.a and 5.,5 and a typical meta-substituted aryl H pattern centered a t 7.21 (all values in ppm, 6, downfield from Me4Si); integration of the nmr spectrum accounted for 28 protons as 9 acetate, 3 Me, 4 Ar, and 12 carbinol and amide H. Anal. (CIZHW F3NO13) C, H, N, Ac; F : calcd, 9.57; found, 10.06. Chromatography.-Paper chromatog of the neutral fractions was carried out by the descending method on Whatman No. 2 (10) H. Tsukamoto, A. Yamamoto, and 0. Kamata, Chem. Pharm. Bull., 6, 565 (1957). (11) H. Tsukamoto and S. Terada, ibid., 10, 91 (1962). (12) S. R . Johns and S.E. Wright, J . M e d . Chem., 7 , 158 (1964).
paper (86 cm) in the Bush B-5 system (sheet equilibrated overnight a t 34' in t'he vapor from a mixed solvent composed of CsH6-MeOH-Hz0, 2: 1:1, and developed wit,h the C6H6 phase)la and in the Mattox I system (sheet satd with MeOH-formamide, 1: 1, dried 15 min at 37", and developed with n-BuOAc-formamide-HzO, 20: 1: l ) . l 4 Acidic metabolites were chromatographed on Whatman No. 1 paper with i-PrOH-NH40H-H20, 8: 1 : 1 (IAW)15 and with C&-AcOH-H20, 1 : 1 : 2 (BZAW). All chromat'ograms were viewed with a short-wavelength scanner16 to detect zones absorbing uv light. Carbamate-contg metabolites were detected by spraying with p-dimethylaminobenxaldehydeor with NaOCl and o-tolidine.' Acidic metabolites were sprayed with 0.1% bromphenol blue (BPB) to detect acids and with diazotized sulfanilic acid (DZSA) for visualization of phenols. Tlc of methyl tri-0-acetyl glucuronides was carried out on silica gel G F (Brinkmann Instrument Co., Great Neck, N. Y . ) using l.nYo (v/v) MeOH in CHCL or on alumina G F with 0.75% (v/v) MeOH in CHCI,. Glucuronide esters were located by spraying t'he dried plates with 1% p-dimethylaminobenzaldehyde in 4 N HC1 followed by 50% HzSO, and subsequent heating to yield reddish zones.
Acknowledgments.-The aut'hors thank Drs. S. S. Stubbs, E. W. Young, J. P. Webb, and H. L. Oster and nlr. 31. J. Whit'e for assistance with the clinical portion of the study, Dr. G. A. Youngdale for synthesis of authentic compound IV, and Dr. G. Slomp for the nmr analyses. (13) I . E . Bush, Biochem. J . , 60, 370 (1952). (14) V. R . Mattox and M. L. Lewbart, Arch. Biochem. Biophys., 7 6 , 362 (1958). (15) M. D. Armstrong, K . N. F. Shaw, and P. E. Wall, J. B i d . Chem., 818, 293 (1956). (16) N. A. Drake, W.J. Haines, R . E . Knauff, and E. D . Nielson. Anal. Chem., 88, 2036 (1956).
Synthesis and Analgetic Properties of Compounds Containing an Exocyclic Basic Center J. V. GREENHILL School of Pharmacy, University of Bradford, Bradford, England Received December 23. 1970
1-Dimethylamino-l-(2,2-diphenyl-2-hydroxyethyl)cyclohexane and 1-phenyl-3-piperidinocylohexan-1-01have been prepared and tested for analgetic activity. I n the latter case the two geometrical isomers were separated and esterified. Analgetic activity was present only in the trans (O/N) isomers. The conclusion is drawn that steric restrictions in the environment of the receptor site may be responsible for lack of activity in the cis isomers.
A very large number of pethidine reversed ester compounds have been prepared in the search for synthetic analgetics of high potency and low toxicity.' Potency equal to or greater than morphine has often been achieved, but toxic side effects have always accompanied an increase and no compd of real clinical importance has emerged since the original reversed esters of a- and ,&prodine were prepared by Ziering and Lee2in 1947. It is my belief that an improvement in therapeutic ratio is more likely to be achieved with compds which shoiv a more dramatic change in parent structure. The bulk of the evidence so far accumulated seems to indicate that an analegtic must possess a basic center and an aromatic ring which are separated by a suitable distance.
structures of type I1 had already been prepared and found to possess little or no a ~ t i v i t y . ~Therefore, the syntheses of I and I11 were undertaken. During the course of this work, IV has been reported4 with an
(1) For a review, see R . A . Hardy and AI. G. Howell, .$fed. Chem., Ser. Y o n o o r . , 6 , 179 (1965). (2) A. Ziering and J. Lee, J . Oro. Chem., 12, 911 (1947).
(3) St. Goldschmidt and W.L. C. Veer, Reel. Trau. Chim. Pays-Bas, 6 7 , 489 (1948). (4) M . P. Mertes, P. E. Hanna. and .\. .4. Ramsey, J. M e d . Chem., 18, 125 (1970).
With this in mind, 3 structures were first considered in which the piperidine nitrogen of the reversed ester compds was moved outside the ring. Of these, various Ph
HO -CI -CH5NMe2
P
h
e
I
Ph
I
I1
I11
