METIRAMISOL ETHERS
Journal of Jfedicinal Chemistry, 1910, Vol. 1.3, .\-o. 6'
mole) in warm EtOH (250 ml) was run iiito a stirred solutioii of aminoguaiiidirie nitrate (134 g, 0.975 mole) iii 500 ml of H 2 0 arid 750 ml of EtOH. A ppt' was formed almost immediately. The suspension was warmed to about 70" to complete the reaction, then allowed to cool to room t,emp overnight. The ppt was filtered off, washed (HzO, a little EtOH, and EtZO), and suspended in 1.8 1. of HSO. This stirred susperision was warmed at 80" for 30 miii arid filtered hot to give t,he guanylhydrazoiie, nip 228-229" dec, yield 213 g (72y0). Anal. (C9Hl0C12S4.HiXO3) H, S , 0. C: calcd, 35.08; found, 35.53. The other guanylhydrazones in Table I1 were prepared similarly. A--Amino-S'-phenethylguanidine Hydrochloride.--S-Methylisothiosemicarbazide . H I (44.3 g, 0.19 mole) was suspended in a mixture of abs EtOH (100 ml) and phenethylamine (23.5 g, 0.193 mole) arid heated under gentle reflux until MeSH was no longer evolved. Removal of the EtOH i n C'UCILOgave an orangebrown oil which n-as taken up in n-PrOH and diluted wit,h Et2O. A small crimson ppt was rejected. The filtrate was treated
1057
with ethariolic HC1 to give a h i e white crystalliiie solid, mp 140-146", yield 38.7 g. (909;). Three recrystallixatioiis from EtOH gave fine pale-cream plates, mp 156-157" (10.1 g). Anal. (CgHlS4.2HCl) C , H, C1. S : calcd, 22.31; fouiid, 22.78. 2,6-DichlorophenethylguanidineSulfate.--A mixtiire of "6dichlorophenethylamine'2 (24 g, 0.125 mole), S-methyliaothiouronium sulfate (17.7 g, 0.063 mole), 93% EtOH (50 ml), aiid HzO (25 ml) was heated on a steam bath until the evolution of MeSH ceased. On cooling, a solid, mp 255-258', crystd; yield 12.7 g. Trituration, first with hot HzO, then with hot EtOH, gave a fine white powder, mp 258-260°, yield 10.4 g. And. (CgHiiClzS3.0.5HzSOd)C, H, C1, N, 0, S.
Acknowledgment.-The authors wish to thank Dr. H. Lehner and his staff for the microanalyses and ir spectra. (12) 8-(2,6-Dichlorophenyl)ethylamine~ HCl, m p 283-286') \\-as prepared by catalytic reduction of 2,6-dichlorophenylacetonitrile, h p 134' ( 4 mm).
Synthesis and Norepinephrine Depleting Activity of Some Metaraminol Ethers WALFRED S. SAARI,* ANDREW IT. RAAB,WILLIAM H. S T A A ~ , Jlerck Sharp and Dohme ResParch Laboratories, Davision of J l e r c k and Co., Ine., West Poznt, Pennsylvania 19486
11. L.
TORCHIANA,
c. c . P O R T E R , A N D c. h.STONE
Jlerck Institute for Therapeutic Research, Division of Merck and Co., Inc., West Point, Pennsylvania 19486
Received June 3, 1970
A series of ethers of (lR,2S)-o-(1-amiiioethy1)-m-hydroxybeiizyl alcohol (metaramiiiol) has beeii prepared. These compouiids deplete the mouse heart of iiorepinephrine. The more potent members, e.g.?the ethyl aiid cyclopropylmethyl ethers, exhibited acute predsor effects iii the dog while the ni- aiid p-chlorobeiizyl ethers of metaraminol were found t o produce norepinephrine depletion without sigiiificaiit acute pressor actioii. Evidence is presented t o show that the ethers are dealkylated in vivo t o metaramiiiol.
Metaraminol (I), (-)-erythro, appears to possess t,he attributes of a nearly ideal substitute adrenergic transmitter.1,2 Thus metaraminol has a high intrinsic ability to ent'er and displace the normal transmitter norepinephrine from storage sit'es within t'he adrenergic neuron; it is released during stimulation of the sympathetic nervous system; it is not a substrate for monoamine oxidase; arid it possesses considerably less transmitter pot,ential than norepinephrine. Crout2 has report,ed that metaraminol has a significant ant'ihypertensive effect in a few subjects given the drug orally in small dosages over several days. However, administration of metaraminol under certain conditions can produce acut'e pressor effects which makes testing of the compound for therapeutic ut,ility precarious. The amino acid a-methyl-m-tyrosine, which is met,abolized to metaraminol in a n i r n a l ~ ,has ~ also been reported t'o be eff ect'ive in lowering t8heblood pressure of hypertensive patients when administered intrav e n o ~ n l y . ~However, the amino acid was not effective * T o whom correspondence should be addressed. (1) For leading references t o t h e substitute transmitter hypothesis, see: I. J. Kopin, Annu. Rev. Pharmacol.. 8, 377 (1968); C. A. Stone a n d C. C. Porter, Advan. Drug Res., 4, 71 (1967). (2) J. R. Crout, Circ. Res., 18, 19, S u p p l . , I, 120 (1966). (3) A. Carlsson a n d .X. Lindquist, Acta Phi.riol. Scand., 64, 87 (1962); P. A . Shore, D. Bushfield, a n d H. 9. Alpers, J . Pharmacol. E z p . Ther. 146, 194 (1964). (4) D. Horwita and .\. Sjoerdsma, Life Sci.. S, 41 (1964); H,J. Holtmeier, A . vonKlein-\~~isenberg, and F. Marongiu, Deut. M e d . Vochensehr., 91, 198 (1 966).
after oral administration. In addition central nervous system effects have been observed with a-methyl-nztyrosine which have discouraged further clinical trials. It seemed desirable, therefore, to develop other derivatives of metaraminol which would be susceptible to metabolic conversion into the phenolic amine without causing acute cardiovascular effects. Chemistry.-The ethers reported ill Table I were prepared from metaramiiiol (I), (-)-erythro, by the route outlined in Scheme I. The acetyl intermediates SCHEME I
OH
OH
I
I
CHCHCH, NH,
I
NHCOCH;
\
I1
1
Iv I11 IT ere usually not isolated, but n-ere hydrolyzed directly to the optically active ethers I V with KaOH.
1058
XU.
1
-> I
.I 1
ti
I
S !I
I I1
II I:!
I :: 14 I .i 1 ti
17 IS 1 !I 2 1 31
--
2:j "4 2.i :!li
37
Journul of Jlllcrlicznal Chcniistrg, 1970, Vol. 13, LYo. 6 1059
led to isolation of only the 0,N-dialkylated metaraminol derivative. Reaction of cyclopropylmethyl tosylate'O with I1 and anhydrous K&03 in acetone followed by NaOH hydrolysis gave the cyclopropylmethyl ether IV in low yield. The appearance of the ether CH2 as a doublet centered a t 3.S7 ppm ( 2 H, J = 7 Hz) in the nmr spectrum and the presence of a complex cyclopropyl H multiplet a t 0.5 ppm indicated that the cyclopropylmethyl group had remained intact during this sequence of reactions. Solvolysis of cyclopropylmethyl tosylate in a number of solvents has been reported to give mainly unrearranged cyclopropylmethyl products. However under the same conditions, 1-phenylcyclopropylmethyl tosylate undergoes a rearrangement which leads to l-phenylcyclobutyl products. lo Reaction of l-phenylcyclopropylmethyl tosylate with I1 was investigated with the aim of preparing the phenylcyclobutyl ether
(IV,R = @C,H,!.
Unfortunately no pure products
could be isolated. The phenyl ether (IV, 1%= CeHJ was prepared by alkylation of the Ka salt of 11 with diphenyliodonium chloride. l 1 Testing Methods Norepinephrine and Metaraminol Determinations.Female mice (Carworth CF 1) were given metaraminol or the ethers listed in Table I orally, except as noted, in aq solutions. Doses were calculated as base weight, mg/kg of body weight. After 16 hr the animals were sacrificed by decapitation, the hearts i t ere excised immediately and chilled a t 0" until assayed, not more than 1 hr later. The hearts, in pools of 5 , were homogenized in HClOJ. The extracts, after purification by h120d chromatography,12were assayed for norepinephrine13 arid for metaramin01.~~Results are reported as concentration of amine, either norepinephrine or metaraminol, in the hearts divided by the concn of norepinephrine in the hearts of untreated mice. The metaraminol ethers were assayed by the o-phthalaldehyde method14 before use, and were found to contain insignificant quantities of metaraminol. Sympathomimetic Actions.-The sympathomimetic actions of the compounds were assessed in anesthetized dogs. The initial study was made to determine whether pressor effects resulted early after iv administration. Mongrel dogs of either sex were anesthetized with viribarbital (50 mg/kg, iv) and artificially respired. A Waltoii-Brodie strain gauge was sutured to the right ventricle to measure myocardial contractility. Fenioral arterial pressure and heat rate were monitored continuously during the experiment. The metaraminol ethers were given in doses of 0.05, 0.25, and 1.26 mg/kg iv in the order stated every 15 min, and metaraminol was tested a t 0.1 of the above doses. Epinephrine (10) D. D . Roberts, J . O r g . Chem,. 30, 23 (1965); J. TV. Wilt and D . D. Roberts, ibid., 27, 3430 (1962). (11) F. M. Beringer, A . Brierly, M. Drexler, E. M. Gindler, a n d C . C. Lumpkin, J . Amer. Chem. Soc.. 7 6 , 2708 (1953). (12) A. H . Anton and D. F. Sayre, J . Pharmacal. E z p . Ther., 138, 360 (1962). (13) C. C. Porter, J. A . Totaru, a n d A. Liuroin, ibzd., 160, 17 (IUti5). (14) P. A. Shore and H. 9.Alpers, L i f e Sci., 3, 551 (1964).
(1.0 ,ug/kg) was given alternately with the above to assure that the preparation responded to sympathomimetic stimulation. A minimum of 2 animals were studied with each compound. In order to determine whether sympathomimetic actions could be obtained after a longer interval than observed in the above experiments, additional studies were made after intraduodenal administration of some of these compounds. I n these studies, the animals were anesthetized with pentothal (10 mg/kg) and barbital (250 mg/kg) ; bretylium (2.5 mg/kg, iv) was given 30 min before the test compounds to prevent inordinate increases in heart rate during the 6-hr period of continuously recordirig heart rate and blood pressure. Results and Discussion All of the metaraminol ethers of Table I having the lR,2S configuration (( -)-erythro) were found to deplete the mouse heart of norepinephrine to some extent. The two ethers prepared in the 1S,2R series ((+)erythro), 26, and 27, were essentially inactive in this respect.15 The cyclopropylmethyl ether 2 was the most active compound of the series being almost as potent as metaraminol (1). The methyl (8) and m-chlorobenzyl (9) ethers are compared with metaraminol in Table I1 for their ability TABLK I1 IRTH~BITION OF ;\IETAE.~MINOL ETHI:IEH Y SKF-ZLdA
Compound
NO.
Methyl ether
8
rra-Chlorobeiizyl ether
9
SKF525.i," Dose. 35 mg/kg, mg/kg ip PO
0 0 0..5 0 ,3
0 0 1.3
1.5
0
+ 0 + 0
+ 0 +
Heart norepi iract of normal'
Heart metaramino1 iract of normal norepib
1.000 1.063 0.321 0.94.5 0.092r 1.000 1.052 0.296
0.864
0.813d
0.136 0.0.m 0 , OSlC Metaramiiiol 1 0 0 1.000 0 1.0s2 0.4 0 0.23.5 0.386 0.4 0.230e 0.40.5 0 ,0.i2c 0 .03lC (1 Giveii 45 mitt before inetaramiiiol or the ether. Sixteeii hours after admittistratiori of metaraminol or the ether; t'hree groups of 5 mice/t,reatment,. c Standard deviation. d p 0.25.
+ +
to deplete norepinephrine from the hearts of mice. I n addition, the concentration of metaraminol, as determined by the relatively specific method of Shore and A l p e r ~ , 'is~ also tabulated. These data show that as the concentration of norepinephrine in the heart decreases, the amount of metaraminol increases, strongly suggesting that norepinephrine depletion produced by (15) For a discussion of norepinephrine depletion by t h e threo isomers of a-(1-aminoethy1)-m-hydruxybenzylalcohol, see ref 7, 16, and 17. (16) M. L. Torohiana, C. C . Porter, and C. A . Stone, Arch. Int. Pirurmucodyn. Ther., 174, 118 (1968). (17) N. F. Albertsun, F. C . hIoKay, H. E. Lape, J. 0. Hoppe, W. H. Selberis, and A , Arnold, J . M e d . Chem., 13, 132 (1970).
J o ~ ~ r n of a l Medzcinal Chenasfry, 1570, T'o[. 13, S o . 6 in a minimum quantity of warm EtOH and converted into the hydrogen maleate ~ a l t , ~[a]% 7 - 15' (c 2, HgO), as described fur the Me ether. B.--A solution of 2.1 g (0.012 mole) of PhCH2Br in 10 ml of 1)NSO was added slowly to a stirred mixt,iu'eof 2.0 g (0.012 mole) of (1R,2S)-a-( l-aminoet~hyl)-rn-hydroxybenzylalcohol (metarainiiiol) i l l 100 ml of DMSO and 6.0 ml of 2 ,V NaOII at' Xh'. Aft,er addition was complet,e, t,he reaction mixtiire 11-as stirred a t S.5" for an additional 2 hr and then poured into 500 ml of ice H20. Bfter saturating with NaC1, and extracting with four 200ml portions EtOAc, the organic extracts were combined, dried (Na2S04), filtered, and concentrated. The crude product was converted into the hydrogen maleate salt and recrystallized (EtOH-Et20) to give 3.2 g (72Yl) of product, mp 150.0-154.0'. Repeated recrystallization did not improve the melting point. Anal. (C,,H,,,ru0,.C4H4O4~H; C : calcd, 64.32, found 65.16, 65.1.5. ( 1 K,2S)-a-(1-AminoethyI)-m-(4-cyanobenzyloxy)benzylAlcohol Methanesulfonate (IV, R = CH2C6H4CN).-The inter( 1R,2S)-a-( l-acetamidoethyl)-m-(4-cpanobenzyloxy)mediate beiizyl alcohol w a ~prepared by the general method using 9.2 g (0.0405 mole) of ( 1R,L)S)-a-(1-acet,amidoethyl)-m-hydroxybenzyl alcohol h ~ d r a t e ,7.6 ~ g (0.050 mole) of p-cyaiioberizyl chloride, aiid 80.4 g of K&OI in ll.le2C0(500 ml). -4solution of 6 g (0.0185 mole) ( i f t.he amide in EtOH (50 ml) was converted into t,he correspoiidiiig amitie by heating 4 hr at reflux with 1 S HCI (100 nil). After removing moyt of the EtOH under reduced pressure, the residue was neutralized with excess satd NaHC03 solution. The product was extracted into EtOAc, dried (Xa2S04),filtered, arid coilcentrated t o 4 g of a yellow oil. The crude product was coiiverted into the methanesulfonate salt in the usual manner. Whet1 purificat,iori proved difficult, the salt was reconverted into the free base with dil S a O H and EtOSc extraction. The 1.7 g of recovered oil was chromatographed on 85 g of silica gel. Elution with CHCl3 then 10-50yc MeOH-CHC13 removed 0.7 g of
1061
side products. The desired ether (0.7 g) was eluted from the column with X\leOH (YO0 ml). The methanesulfonate salt was prepared in the usual manner and recrystallized from i-PrOHEt20 t o give an analytical sample.27 ( 1 R,ZS)-a- [1-(4-CyanobenzyIamino)ethyll -m-(4-cyanobenzyloxy)benzyl Alcohol Methanesu1fonate.-A solution of 3.0 g (0.020 mole) of p-cyanobenzyl chloride in 20 ml of DMSO was added slowly to a stirred solution of 3.4 g (0.020 mole) of ( l R , Z S ) - a (1-aminoethy1)-m-hydroxybenzylalcohol (metaraminol) in 200 ml of DMSO and 8.0 ml of 2 S XaOH a t 85'. Aft8erstirring 2.5 hr at, %I", the reaction mixture was poured int,o1 1. of ice H20 aud extracted with EtOAc (4 x 200 ml). The combined extracts were dried (Xa2SOa), filtered, and concentrated. The crude product was converted into the methanesulfonate and recrystallized from i-PrOH-Eta0 to give 0.8 g (16.2%) of product, mp 194.5-196.5'. Anal. (CijHa3Xj302.CHI03S)C, H, S. Hydrogenolysis of (1R,2S)-~-(l-Aminoethyl)-m-benzyloxybenzyl Alcohol.-The free base (1.3 g, 5.06 mmoles), liberat'ed from 2 g of the hydrogen maleat,e salt of t,he benzyl ether, was hydrogenated in 23 ml of EtOH with a 5yo Pd-C catalyst at at,mospheric pressure until 1 equiv of H2 was taken up. After filteriiig and conceiitrat,ing under reduced pressure, the crude product was converted into a fumarate salt (0.86 g), mp 192-195' dec. Further recrystallization (AIeOH-Et,OAc) gave 0.70 g (6l.5yo)of the pure fumarate salt of metaraminol, mp 199-200' dec, [a]% - 22.3" (c 2, H20). This product was identical by mmp and nmr with an authentic sample of metaraminol fumarate, mp 200-201" dec, prepared from metaraminol.
Acknowledgment.-We wish to thank K. B. Streeter, Y. C. Lee, and their staff for elemental analyses, W. R. 3TcGaughran and Donna Kessler for the ir and nmr spectra, and Dr. I
