Journal of M(tlicina1 Chemistry, 1.970, Vol. 15, L\To. .$
I11 I1 5 isomer:para series 4 isomermeta series
673
R1
PhCH,SHI1,-EtCOhIc
VI
V
I\' H, I'd-C
H.,Pd-C
OH
1
H1. Pd-C
QH
CHCHNHR,
I
R, VI1
VI11
with metals arid of taking part in H bond formation although the pKa of the hydroxymethyl group will be much higher than those of the corresponding groups in Ia, IC, or Id. A similar approach was also envisaged for the less accecsible isomeric series in which the p-OH group of the catecholamine, Ia, is replaced by an acid or by a C H 2 0 Hgroup. Chemistry.-A general synthesis of the desired phenethariolamines from the methyl esters of 4- and k e y 1 ialicylic acids (11)is outlined in Scheme I. The 5-acyl salicylic esters were obtained by Fries rearrangement '0 of the corresponding phenolic esters of salicylic acid followed by esterification. Methyl 4-acetyl salicylate mas synthesized from methyl 4-amino salicylate by selective benzylation of the phenol, conversion of the amine into an acetyl group via diazotizatioii and reaction with acetaldoxime,ll and removal of the benzyl group by catalytic hydrogenation.12 The acyl esters I1 and the phenacyl bromides I11 derived from them by bromination a t room temperature in CHC1, are shown in Table I. Methyl 5-bromoacetyl salicylate condensed readily with secondary benzylamines on heating in E t C O l l e to give the amino ketones V. The use of primary amines was generally unsatisfactory as the product was often contaminated with a rionketonic base.13 However, the more hindered methyl 5-bromobutyryl salicylate failed to react with bulky secondary amines such as isopropylbenzylamine but gave a fair yield of the required product (24) 011 refluxing with i-PrNH2 in MeOH. Methyl 4-bromoacetyl salicylate reacted with il-'rSHCH2Phin EtCOAIe, EtOH, or THF a t room temperature but the resulting amino ketone was unstable (10) I\. \Y.Rosenmund and IV. Jcliniirr. Juslus L i e b i g s A n n . Chem., 460, 56 (1928). , (1954). (11) See IV. Beech, J . Chem. S O C .3297 (12) 4-Acetyl salicylic acid has been preriously prepared by a different route, see F. M a s e r , 0. Stark, and K. Scliiin, Ber.. 66B,1333 (lY32). (13) R . €lowe, A. F. Crowther, J . S . Stephenson, B. S. Rao, and L. H. Smith [ J . .Wed. Chem., 11, 1000 (1Y68)I have shown t h a t aminopsrroles are formed 11y self condensation of similar aminoketones.
IX
and was best processed Z H situ through the next stage of the synthesis to IV. The greater stability of a p hydrox yphenacylamine has been explained in terms of a resonance contribution which is not permitted for tlie m-OH isomer.14 The arylamino ketones prepared are listed in Table 11. Hydrolysis of the 5-glycyl esters V with HBr followed by catalytic reduction of the lietone and concomitant removal of the benzyl group gave the salicyclic acid derivatives IX. Catalytic hydrogenation of V gave the corresponding esters VIII. Where Rlis an alkyl group the products were predominantly the expected erythro isomers having nmr spin coupling constants of 4 H Z for the protons on adjacent asymmetric centers.'. Reduction of the amino ketones V with LAH in T H F followed by catalytic hydrogenolysis of the protective benzyl group over Pd-C gave the corresponding saligenin derivatives VII. I n this case, when R1 was an alkyl group, IV and VI1 showed coupling constants of S-9 Hz for protons on adjacent asymmetric C atoms in agreement with that expected for a tlweo configuration.15 The catalytic reduction of the saligenins occasionally resulted in some degree of hydrogenolysis of the primary alcohol group t o give an o-cresol, easily identified by the Me signal at ea. T 7.S in tlie nnir spectrum. This side reaction could be promoted by acid catalysis t o give the Ale compound (e.q., XIV) in high yield or could be suppressed by addition of a base such as EtSS. I n a modified procew to tlie p-saligenin derivative, XIII, the intermediate amiriolretone XI was first reduced with i\'aBHa prior to catalytic debenzylation, as shown in Scheme 11. The Ale ether XI1 wa5 also prepared from the amino ketone XI by refluxing with methanolic HCI arid subsequent catalytic debenzylation. The primary amine> of the para series (VI1 and VIII, R2 = H), obtained according to Scheme I from (14) .%. Gero. J . Org. Ciiem.. 16, 1222 (1951) (15) See ref 7 f u r analogous correlations.
s
OH I
Joiirtiul of Xcdicinal Clicmidrg, 1970, Vol. 13, 1Yo.
ANALOGS OF SYMPATHOMIMETIC CATECHOLAXINES
4
677
TABLE I1 ARYLAMINO KETONES
Crystnn solvent
Yield, Compd
P
AI
Ri
Rz
%
Ra
LIP. OC
Formula
Analysis
A1-E t bfe-Eab Me-Ea 8OC W 43 Me-Et 70 Et-Acd 98 E a 77 hfe-Ea 45 Et-A1 90' W 62f Me-Et 83 hfe-Ea 51 Me-Ea 87 Me-Ea
169-171 C19H21NO4. HC1 C, H, C1, N, 0 193-194 C2iHzjN04.HC1 C, H, C1, N 168-170 CzoH23NO4. HCI C, H, C1, N 188-189 ClgHslN04.HBr C, H, Br, N 250 ClSHziS04 *HCl Ci Hi N 160-162 C2iH2gT04.HCl c1, N 181-183 CnH27N04 *HCl C, H, C1, N C, H, C1, N, 0 182.5-183 CziHzsNOa .HC1 C, H, N 173-175 Cz4Hzg~OjHCl CsoHz6N03.HC1 C, H, C1, N 173 202-205 C~IHZ~~U'O~ .HCl c, H, N 184-186 C2iH2sN03*HC1 c, H, N 166-168 CzsHz5N04 * HCl C, H, C1, N 167-169 Cz4Hz3N04.HCl.O.5 C, H, C1, ?j HO Hz0 H 34 HO HOOC PhCH2 PhCHz 99" A1 163-164 C Z ~ H ~ ~ N O ~ . H BC,~ .H, H~ Br, ON 4-HOC6H4CH2CHhIe PhCHz 71 I p 35 HO MeOOC H H, N; Cg 177-181 CssHz7NOs* HC1 HZ 64 Ea-Et 161-163 CziH2gN05. HC1 H ; C, Nh 36 HO AIe00C Me ~ - & I ~ O C ~ H & H Z C PhCHz b Ea, EtOAc. c Prepared by hydrolysis of the preceding salicylic or anisic esters with refluxing aq 48% a See footnote a, Table I. HBr for 3 hr. d Ac, AcMe. e Prepared by hydrolysis of the preceding diacetate 28 with 5 N HC1 for 70 hr at room temperature. f See Experimental Section. C: calcd, 66.4; found, 66.9. C: calcd, 67.0; found, 67.5. N: calcd, 2.89; found, 3.39. 20 21 22 23 24 25 26 27 28 29 30 31 32 33
HO Me0 HO HO HO PhCH20 Me0 HO AcO HO HO H Me0
EtOOC RIeOOC RIeOOC HOOC MeOOC hIeOOC RleOOC MeOOC AcOCHz HOCHz RleOCHZ hIe00C RIeOOC RIeOOC
H H H H Et H H H H H H H H H
PhCHz PhCHz PhCHz PhCHz H PhCHz PhCHz PhCH2 PhCHz PhCHz PhCHz PhCHz PhCHz PhCHz
Me MezCH MezCH nle2CH Me2CH RlezCH Me& Me& Me3C Me& Me3C Me3C PhCHz PhCHz
52 45 34
TABLE I11
Yield, Compd
P
hI
RI
Ra
Method
A A Ab B
Yo 49 63 59 93
Crystn5 solvent
Et Et-Pe Et Ea
LIP, OC
Formula
Analysis
132-134 113-116 103-108 134-136
C17H21N03 C, H, N, 0 Cl9HZ5NO3 C, H, N, 0 CigHzjN03 C C27H31N04.HCl. C, H, N 0 . 5 H20 41 PhCH20 HOC(Me)l H RlezCII C 80 Ea-Tfd 174.5-175 C28H35?;03.HC1 H, N ; Ce 42 M e 0 HOCHz H Me& A 70 RIe-Ea 196-197 CZ1HZ9NO3.HC1 C, H, K, 0 43 HO HOCHz H Me& B 87 Et-Pe 109-111 Ct0Hz7NO3 c, H, N 44 H HOCHz H Me3C A 96' A1-Ea 173-174 CzoHz7N02.HC1 C, H, N 45 HO HOCHz H PhCHz A 80 Ea-C 110-111 C Z ~ H ~ S N O ~ C, H, N 46 HO HOCHz H 4-HOC6H4CHzCHMe AQ 50h Oil CzsHzs~Oa C Oil Cz6HaiNO4 C 47 HO HOCHz hfe ~ M ~ O C ~ H ~ ~ H ZAdC H63h Z b The intermediate arylamino ketone was formed in T H F and reduced in situ with L.4H. Not analyzed. a See footnote a, Table I. 0 p-[2-(Benzylamino)propyl]phenol prepared by red Tf, THF. e C: calcd, 71.5; found, 70.8; f Yield of free base isolated as an oil. ductive alkylation of p-hydroxyamphetamine with PhCHO (see Method F), 69%, mp 101-103'. Anal. (C&i&O)C, H, N. h Crude bp 142' (0.01 mm); K. Kindler, K. Schrader, yield; product is a mixture of diastereoisomers. i iV-Benzyl-p-methoxyphenethylamine, and B. Middelhoff [Arch.Pharm., 283,184 (1950)l reported bp 210' (13 mm). 37 38 39 40
HO HO HOCHz PhCHzO
HOCHz HOCHz HO MeOOC
H H H H
RIe Me2CH MezCH MeZCH
The p1ienethanolamines prepared by the above procedures are listed in Tables 111,IV, and V.
Experimental Section Melting points were determined in open capillary tubes on a Townson-Mercer apparatus and have not been corrected. Compounds gave satisfactory uv, ir, and nmr spectral data obtained, respectively, on a Perkin-Elmer Model 137 uv spectrophotometer, Unicam S P 100, and Varian Associates A-60A spectrometers. Microanalyses were determined on a F and M 185 C, H, and N analyser and by Dr. A. Bernhardt, 5251 Elbach uber Engelskirchen, West Germany. Where analyses are indicated only by the symbols of the elements, analytical values obtained were within ~k0.470of the calculated values.
Each general method discussed in the theoretical part of this paper is described here by only one representative example. Hydrogenations were carried out at room temperature and atmospheric pressure. Methyl 4-Amino-2-benzyloxybenzoate.-Methyl Caminosalicylate (20.88 g, 0.125 mol) in 5 7 , NaOH (100 ml) and DMSO (250 ml)16 was heated to 80" and PhCH2Br (21.38 g, 0.17 mol) slowly added with stirring. After a further 0.5 hr the mixture wm poured onto ice and the product isolated by extraction with CHC13. Two recrystallizations (PhH-cyclohexane) gave colorless needles 8.9 g (28%) mp 124-127'; Xmsx at 236 mp ( e 13,lO 0), 282 ( e 13,950), and 304 (15,000). Anal. (C15H15N03) C, H, N.
(16) DMSO added t o suppress P;-benaylation. Scliumaker, J . Org. Chem.,31, 1096 (1066).
S e e S. L. Solar and It. R.
31
IIOCtI? HOCH? HOCH?
I1I 11 €1
H
lIOCII2
11
I r oc 11I IIOCH? HOCH?
H H IT
HOCR?
H
HOCK2 HOCH? HOCH, HOCHI
H H AI e
HOCH? tIOCH2 HOCH,
H H Et
IIOC €I 2 IIOCHI IIOCH: .\leOCH?
31e H
H O CI T ?
tr
AI e HOC(Ph)? HOC(hle):
H
H
tl 11
H
H €1 H H
llelative p(i~riicyiisoproterenol = 100) from Koiizett li(~+lrr See footnote a, Table I, footnote b, Table 11, footiiote d, Table 111. preparation. r Relative potency (i.mprotereno1 = 100) from iwlat ed guiiiea pig titria preparation. d Product is a mixture of disstereo11. ,J. Roth : i d H. lIoehrle [.4rch. Z'horni., 297, isomers. e Hydrated p-anisate salt. J l-~Iorpholirio-2-pt.opaiiorletip T2-76" (0.5i n 58 (1964)] reported bp 98' (14 mmj. 0 C : calcd, 71.73: found, T2.4h. 0: calcd, I foiind, 1.i.i.i. 1-(3,4,.i-Trimethos~pheri~-I )2-propanone, mp 6%-6.5'. J. AI. Pepper :tiid 31.Saha [Can. J . Chcvi., 42,113 (I964)l reported nip 66-67". ' Not phenoxy)-2-propanone prepared by refluxing p-ethoxyphenol with C1CH2COCH3-K2C:Osi n EtCOlIe for 24 h r , 4 C,H. h We thank 1 1 r . S. Biichanan fc inm), mp 37-39' [from petroleum ether (bp 40-60°)]. d n a l . ICIIII,403) pound. crythro. fhreo. li Xcetate salt. 0 C: calcd, 64.43: foiiiid, 63,s. 7' \Teak $-adrenergic antagonist. See Experimeiitd Section. C: ralcd, 63.58; f o u n d 64.9: C: calcd, 69.9; f o i i r i . 1 . 70.6. o-Berisc I b e l l Z ~ J f t t e. d t . Debenaylation of 45 t'ook 6 hi.. 1. C : calcd, 59.0: found, ; a-.1drenoreceptor stimulant, 0. I lime- the aotivit o f i i ~ i i ~ ~ p i ~ i r ~ ~ iMaleste i ~ i i i e . salt. !' C: c x l ( d . , ~~-.4dreriorec,eptor stimiilarit 0.1 time. the :ic.livity of epinephriiit.. .-1:3,67; found, 53.1. 8
ll.
f
1(
AKALOGSOF SYMPATHOMIMETIC CATECHOLAMINES solved in MeOH (285 ml) and heated to reflux with Girard "P" reagent (10 g) in HOAc (15 ml) for 1 hr. The solution was cooled, added to NaOH (9.5 g) in H20 (1 l.), and extracted with Et2O. The aq phase was then acidified with concentrated HC1 (50 ml), left at room temperature for 1 hr, and again extracted with EtrO. The extracts were washed with NaHC03solution, dried (hfgso,), and evaporated to give a colorless solid 1.05 g (lo%), mp 68-70'. Recrystallization from cyclohexane gave pure product. Methyl 4-Acetylsalicylate (9).-The preceding ester (2.6 g, 0.009 mol) in 90% EtOH (250 ml) was hydrogenated over 10% Pd-C (0.3 g). The rate of hydrogenation markedly decreased when 270 ml of H2 had been absorbed. The catalyst was removed, the filtrate evaporated to dryness, and the residue crystallized from cyclohexane to give9 as needles 1.2 g (767,), mp 120-121.5'. 4'-Hydroxy-3'-hydroxymethylacetophenone Diacetate (lo).3'-Chloromethyl-4'-hydroxyacetophenone17(110 g, 0.6 mol), NaOAc (49 g, 0.6 mol), ACZO(110 ml), and HOAc (200 ml) were heated at 100" for 2 hr and then evaporated to dryness under reduced pressure. The residue was dissolved in PhH, washed with 10% Na?C03solution and H20, and dried (Na&04). The PhH was evaporated and the residue distilled in uacuo to give 10 as a colorless liquid which solidified on cooling. Preparation of Phenacyl Bromides. Methyl 5-Bromoacetylsalicylate (12).-Br2 (6.3 g, 0.039 mol) in CHC13 (75 ml) was added dropwise with stirring to methyl 5-acetylsalicylate (7.5 g, 0.039 mol) in CHC13 (25 ml) at room temperature. Evaporation to dryness and crystallization from petroleum ether (bp SO-SO0) gave 12. Preparation of Arylamino Ketones. Methyl 5-(N-Benzyl-Nt-butylglycy1)salicylate.HCI (%?).-The preceding phenacyl bromide (10 g, 0.0366 mol) in EtCOMe (250 ml) was added to 121t-butylbenzylamine (10.75 g, 0.066 mol) and gently heated at reflux for 3 hr. The mixture was cooled and filtered and the filtrate was evaporated under reduced pressure. The hydrochloride of the residue was formed in EtsO and recrystallized 230 mp (E 21,300) and 280 (13,160). from MeOH-EtOAc; A,, 2- (Benzyl-t-butylamino)-4'-hydroxy-3'-methoxymethylacetophenone .HCI (30).-2-(Benzyl-t-butylamino)-4'-hydroxy-3'-hydroxymethylacetophenone.HCl(29) (50 g, 0.138 mol) in MeOH (500 ml) containing 1%HCl was refluxed for 48 hr and then evaporated. The residue was crystallized from MeOH-Et20 to give 30. Methyl 5-Dihydroxyacetylsalicylate (XV).-Methyl 5-bromoacetylsalicylate (12) (44.7 g, 0.164 mol) in DMSO (150 ml) was left at room temperature for 1 week and then poured into HzO (2 1). The precipitate was extracted continuously (Soxhlet) with HzO (3 1). The glyoxal hydrate XV, separated on cooling as white crystals: 23.6 g; 64%; mp 110-113"; Amax 273 mp (E 13,570) and 306 (sh) (3,680). Anal. (CloHloOe) C, H. Preparation of Phenethanolamines (See Tables 111, IV, and V). Method A. a1-Benzylisopropylaminomethyl-4-hydroxy-m-xylene-a1,a3-diol (38).-Methyl 5-(N-benzyl-N-isopropylglycyl)salicylate.HC1 (22) (11 g, 0.029 mol) was converted into the free base, dissolved in dry T H F (150 ml), and added with stirring to LAH (3.8 g, 0.1 mol) in dry T H F (300 ml). After heating under reflux for 2 hr the excess hydride was decomposed by the cautious addition of HzO and the solvent removed under reduced pressure. The residue was dissolved in dilute HCl, basified with NaHC03solution, and extracted continuously (EtQO). Evaporation of the ether and crystallization of the residue from EtPOpetroleum ether (bp 60-80") gave 38. Method B. a1-(Benzyl-t-butylaminomethyl)-4-hydroxy-mxylene-a1,a3-diol (43).-NaBH4 (1.51 g, 0.04 mol) in 1 N NaOH (20 ml) was added slowly to a solution of 29.HC1 (7.27 g, 0.02 mol) in EtOH (40 ml) below 15'. After 48 hr at room temperature the mixture was acidified with 5 N and the EtOH removed under reduced pressure. The aq phase was adjusted to pH 8 with 10% NazC03 solution and extracted with EtOAc. The extracts were concentrated to 20 ml and petroleum ether (SO-SO") (30 ml) was added to give white crystals of 43. Method C. a1-Benzylisopropylaminomethyl-4-benzyloxya1,a3-dimethyl-m-xylene-~~,a~-diol .HCl (41).-A solution of 40 (1.5 g, 0.0035 mol) in T H F (50 ml) was treated with MeMgBr (0.05 mol) in Et20 (50 ml) and stirred a t room temperature overnight. The mixture was decomposed with saturated NH4Cland the organic layer. separated, dried (MgS04), and evaporated. Trituration of the crude product with dilute HC1 gave 41 as an insoluble hydrochloride which was recrystallized from THF-EtOAc. (17) R . Travo, Gazz. C h z m . l t a Z , 81, 773 (1951).
Journal of Medicinal Chemistry, 1970, Vol. 13, 1210.
4
679
Method D. 5-(1-Hydroxy-2-isopropylaminoe.thyl)salicylic Acid.HBr (51)-A solution of 23.HBr (2.9 g, 0.0071 mol) in EtOH (50 ml) was hydrogenated in the presence of 107, Pd-C (0.5 g) until uptake of HPceased (23 hr). Removal of the catalyst and solvent left an amber syrup which gave the crystalline hydrobromide 51 on trituration with EtOAc. Method E. Methyl 5 - ( [2-(l-Methyl-2-phenoxyethyl)amino1-hydroxylethyl ]salicylate (54).-The amine eHC1 48 (6.6 g, 0.0267 mol) in MeOH (250 ml) was neutralized with NaOMe [from Na (0.614 g) in MeOH (50 ml)], phenoxyacetone (4 g, 0.0267 mol) was added and the mixture was gently refluxed for 2 hr. The cooled solution was then hydrogenated in the presence of 10% Pd-C (1 g) until uptake of HPceased (18 hr). The catalyst and solvent were removed and the oil partitioned between Et20 and dilute HC1. The aq extracts were neutralized with NaHC03 solution and extracted exhaustively (EtnO). The ether extracts were dried (hIgSO4) and evaporated, and the yellow oil crystallized after trituration with petroleum ether (40-60"). Recrystallization from cyclohexane gave 54. Method F. Methyl 5 - ( [2-(l-Adamantylamino)-l-hydroxy] ethyl }salicylate.HCI (57).-l-Adamantylamino (3.3 g, 0.022 mol) and the glyoxal (XV) (5.65 g, 1.25 mol) were gently refluxed in MeOH (200 ml) for 1 hr. The cooled solution was then hydrogenated in the presence of 10% Pd-C (1 g) until the theoretical uptake of Hz was achieved (30 hr). Because of catalyst poisoning by traces of S compounds in X V it was sometimes necessary to add further Pd-C. Catalyst and solvent were removed and the residue was crystallized by trituration with 2 N HC1 and EtzO. Recq stallization from hleOH-EtOAc gave the hydrochloride 57. Method G . a1-(t-Butylaminomethyl)-4-hydroxy-m-xylenea1,a3-diol(61).-The phenethanolamine 43 (0.8 g, 0.0024 mol) in EtOH (20 ml) was hydrogenated in the presence of 107, Pd-C (0.5 g) until uptake of HPceased (within 10 min). The product crystallized after removal of the catalyst and solvent and trituration of the residue with Et2O-cyclohexane. Recrystallization from EtOAc-cyclohexane gave 61. a-(t-Butylaminomethyl)-4-hydroxy-3-methylbenzyl Alcohol (79).-The phenethanolamine 43 (16.5 g, 0.05 mol) in 1 X (45 ml) was hydrogenated in the presence of 10% Pd-C (2 g) until 0.1 mol of HPhad been absorbed. The catalyst was removed, the solution basified to pH 8 and the product extracted with EtOAc. Crystallization from EtOAc gave 79. Biological Test Procedures.18-All the phenethanolamines were tested by iv administration for their effect against temporarily increased airway resistance caused by iv injections of acetylcholine, histamine, 5-hydroxytryptamine, and bradykinin in anesthetized guinea pigs. An effective P-adrenoreceptor stimulant antagonized the responses of all the spasmogens whereas a 0-adrenoreceptor antagonist potentiated them. The action on cardiac muscle was ascertained zn vztro by measuring the increase in isometric tension in the electrically driven left atrium of the guinea pig. The a-stimulant activity was estimated in the pithed rat preparation from the vasopressor responses to graded iv doses of the compound. Structure-Activity Relationships.-Although the salicylic acid 51, our primary objective, was inactive as a 0-adrenoreceptor stimulant, the saligenin 64 was about 0.4 times as potent as isoproterenol and our interest in structure-activity relationships centered, therefore, around this compound (Table V). An understanding of the molecular nature of processes occurring at p-adrenoreceptors has received great impetus from the speculation of Bloom and Goldman19 and BelleauPO which rationalize earlier observations on structure-activity relationships of the catecholamines. Both hypotheses invoke interactions of the phenethanolamine side chain with adenylcyclase-bound ATP which result in pyrophosphate fission and activation of 0adrenergic pathways via cyclic AMP. The analogous structural requirements of the ethanolamine side chain of our saligenins allow a similar interpretation. Thus the enhancement of psympathomimetic action by specific branched alkyl and arylalkyl substituents, e.g., 59, 60, 61, and 63, is in good agreement
-
-~
(18) See 1 '. A. Cullum. J. B. Farmer, D. Jack, and G . P. Levy, [Brit.J . Pharmacol., 36, 141 (1969)l for detailed procedures. (19) l3. R I . Bloom and I. M. Goldman, Aduan. Drug Res.. 3, 121-169 (1966). (20) r(. Helleau. Ann. S . Y . Bcad. Sci., 139, 580 (196i).
wit,h the corresponding catecholamines.*l The most potent coinpound was the p-hydroxyphenylisopropyl derivative 59, the catecholamine arialog of which is about 8 times as act,ive as isoproterenol. This increase in efficacy has been attributed to high binding efficiency of the phenyl group to a flat portion of the receptor surface.21a I n our compounds introduction of a phenyl group does not consistently enhance (3-stimulant action, e.g., 65, 66, 67,68,70, and 71 are less active than 64, while the morpholino derivative, 62, although nonplanar, is a potent (3-stimulant,. The poor activity of the cyclopetityl compound 72 hits no precedent in the catechol series where the analogoti> cornpoiind is t.wice as active as ihoproterenol on giiine:~pig bronchial tissue.22 The adamantyl derivative, 75, is inact,ive, hiit the corresponding c.:iiechol has not heen described. As i i i the catecholamines, introduction of an alkyl group R t the e-(:!e.g., 69, 73, and 74, rnarkedly reduces p-stimulant potency :it id increases aelectivit y for bronchial over heart niiiscle. hlodification of the saligenin moiety is limited by the synthetic routes used. Ilowever, it, is clear t h a t the labile protons on the phenol and hydroxj-methyl groups are key factors sinre etherification, as iu 76 and 77, or replacement of either OH function by T I , as it1 78 and 79 abolishes stimulant artioii o i l hrrinc.hial mrisc~lt~. The cresol, 79, shows a slight but seleibtive cardiac stimrilatit atcltivity whereas 76, 77, :irid 78 :ire weak 3-adrenrirereptiir bliickws. l i t the tertiary alcohols, 80 and 81, it appe:irs th:il :in rinfavcirable steric factor abolishes stirnulatit :rct,ivity anti the ['iiriipoiinds are (3-adrenoreceptor blorkrrs. The ability of the saligenin moiety to siihserve also its it cale~~li~il fiinc~tioiii t i wadrenoreceptor stinidaiits is shown in 83 arid 84 althoiigh the pot,ency ratios relative io thoye of norepinephrine arid epinepririe are lesv than that olwerved for the p-miniet,ic proress when 64 is compared with is)priiterericil. Compound 84 differs from epinephrine but resembles the correspunding methanes\ilfotiamide analog*in having no 8-atlretioreceptijr stimiilant act.ioti. .4 remarkable feature of the saligetiiris i.; the loss of activity wheii the position of the phew1 and hydroxymethyl groiips are reversed as in 82. -4 similar observatioii was reported by Larseti, el in the "pPe~iduc:ttechol" series where only the compoant-1 with [,he ,m-niethai!esiilforiariiide sitbstitiitent (sot erenol) is avt ive. They suggested that the active c:onforni:ttion of sotereno1 and isoproterenol a t the receptor site is determined by primary binding of the most acidic group, whicah is the m t a substituent, in each case. When the para isomer is more acidic as in the reversed isomer of sotereiiiil an unfavorable fit on the receptor is induced. I n the same ~ a y it1 , the moiiopheiiolic analogs of isoproterenol the ci~mpoiiridhaving the acidic group in the meta position is some 10 times niow active than t~hepara isomer :il met,abolir Ilowever, oitr resrtlts clearly cannot IJV interpreted in these t r r m i . Instead they emphasize the critical iiatiire of the p n r u phenolic. group. Iii view of the relatively pimr chelating properties of the saligenin groiip compared wit8h ihose of catechol and salicylic wid, :ridaIw taking into accoiurt ihe inactivity of the reversed isomer 82, i t seems iinlikely that, met,al chelation as proposed by Bellenug and adopted by Bloom and Goldmanlg is a ma,ior factor i i t the potency enhailcement of 6'responses. On the uiher hand, the piistiilate t,hat t,he saligenin group mity initiate formation of an ordered water rrust that, interacts with adenylcgclase to indiire n highly favorable and sperific conformat,ional pertnrbation, is in accord with Belleau'q l a t ~ r hypothesis.20 Some refinemelit of this model, however, will tie necessary i,o explain citir observed striictiire -activity relatiouships which emphasize eqiially rhe importance [if the ptrru phenolir groirp mid of a mcln qiibstitiieiit rcintaiiiitig a labile pro1011. A recent, hypoLhesisZ3has sought t o explain both these i,2l) ( a ) 11. 1 1 . I l o e d . .I, r a n [ J i j k , ani1 l f . Siewin
