3- tert - Butylamino-2- (substituted phenyl) - 1-propanols
Journal of Medicinal Chemistry, 1977, Vol. 20, No.10 1263
Adrenergic Agents. 8.' Synthesis and P-Adrenergic Agonist Activity of Some 3- tert-Butylamino-2-(substitutedphenyl)-1-propanols Timothy Jen, James S. Frazee, Mark S. Schwartz, Karl F. Erhard, Carl Kaiser,* Department of Chemistry
Donald F. Colella, and Joe R. Wardell, Jr. Department of Biological Sciences, Research and Development Division, Smith Kline & French Laboratories, Philadelphia, Pennsylvania 19101. Received October 28, 1976 Replacement of the benzylic hydroxyl group of N-tert-butylnorepinephrinewith a hydroxymethyl substituent affords a propanolamine homologue which retains a high degree of @-adrenergicagonist activity. As modification of the meta substituent of catecholic ethanolamines, such as N-tert-butylnorepinephrine,often provides compounds that exert a more pronounced effect in relaxing tracheobronchial smooth muscle (&adrenergic agonist) than in stimulating 4-hydroxyphenyl)-l-propanols cardiac muscle (&-adrenergic response), a series of 3-tert-butylamino-2-(3-substituted was prepared. The 3-meta substituents included HOCHz (lb), H2NCONH (IC), MeSOzNH (la),H (le),and NH2 (If). These phenylpropanolamine derivatives were compared with their phenylethanolamine counterparts in in vitro tests that measure the ability of these compounds to relax spontaneously contracted guinea pig tracheal smooth muscle (a measure of potential bronchodilating activity) and to increase the rate of contraction of a spontaneously beating guinea pig right atrial preparation (an indicator of potential cardiac stimulating activity). In these tests all of the propanolamine derivatives included in the study were less potent than their ethanolamine relatives. In both series replacement of the catecholic m-hydroxyl group with the indicated substituents usually resulted in compounds with increased selectivity for tracheobronchial vs. cardiac muscle.
The influence of structure upon the biological activity of adrenergic catecholamines has been extensively inve~tigated.'-~The nature of the amino substituent influences selectivity for a-and (3-adrenoreceptors: whereas modification of the meta catecholic hydroxyl often has a pronounced effect on selectivity of the compound for &and /3z-adrenoreceptors.4~5,7 The benzylic hydroxyl group has been implicated in the reaction of molecules of this kind with postulated adrenoreceptors involving adenylate ~ y c l a s e ~ ~as" 'well ~ as in other models"J2 which rationalize the @-adrenergic actions of phenylethanolamines. Its presence in the proper configuration seems essential for potent P-adrenergic agonist activity.13-'* Removal of isoproterenol's benzylic hydroxyl markedly reduces 0adrenergic agonist a c t i ~ i t y , ' ~whereas ~ ' ~ replacement with a carbonyl group2' results in a compound with little, or no, apparent activity of this kind in various tests for adrenergic agonist a ~ t i v i t y . ~ ,Replacement ~~-~* of this hydroxyl group with a methyl ether25also results in a significant reduction in P-adrenoreceptor agonist activity.26 Even addition of a methyl group to the benzylic position of N-tert-butylnorepinephrine, i.e., to form a tertiary carbinol,27results in a pronounced decrease in @-adrenergicagonist potency.% Conversely, in some instances alteration of the benzylic hydroxyl group results in compounds that retain a high order of @-adrenergicagonist activity. For example, replacement of the benzylic hydroxyl group of epinephrine by an amino group provides a pressor agent29having a positive inotropic effect on isolated frog heart.30 Also, the hydroxymethyl homologue la of N-tert-butylnorepinephrine (2a) retains a marked @-adrenergicagonist potencya31 Our laboratory testing results showed that this phenylpropanolamine la was about 0.2 times as potent as isoproterenol (2f) in an in vitro test23,32 for relaxation of guinea pig tracheal smooth muscle. In a similar test that measures changes in the rate of contraction of spontaneously beating guinea pig right atria,23la also displayed a high order of potency (Table I). Although la was more selective for P2-adrenoreceptors than for @'-adrenoreceptors, it was significantly less selective than salbutamol (2b),33carbuterol (2121,~~ soterenol (2d)," and sulfonterol (2g).34 In our continuing search' for new selective bronchodilators it was of interest to determine if modi-
l a , R = HO b, R = HOCH, c, R = H,NCONH d, R = MeS0,NH e,R=H f, R = H,N
2a, R = HO; R' = t-Bu b, R = HOCH, ; R' = t-BU C, R = H,NCONH; R' = t-Bu d, R = MeS0,NH; R' = i-Pr e, R = H; R' = i-Pr f, R = HO; R' = i-Pr g, R = MeSO,CH,; R' = t-Bu
fication of the meta catecholic hydroxyl group would have a pronounced effect on selectivity in the phenylpropanolamine series 1, as it does in the phenylethanolamine series 2. For this reason, the m-hydroxyl group of the catecholic phenylpropanolamine la was replaced by various functionalities that increase P2- vs. P1-adrenoreceptor agonist selectivity in the phenylethanolamine series 2. The synthesis and results of in vitro testing in the Scheme I
3a, R = OCH b, R = HOCH, I M e O , Ht
2 NaOH, H20
3. ?-Su-NHCH$h, DCC
4a, R = OMe b,R=OH C, R = N( t-Bu)CH,Ph -OH I Pd/C. H2
2 HCI, H 2 6
2 HzCO 3 LiAIH4
CHpPh
5a, R = 0 b, R = H,
lb
Kaiser et al.
1264 Journal of Medicinal Chemistry, 1977, Vol. 20, No. 10
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Journal of Medicinal Chemistry, 1977, Vol. 20, No. 10 1265
3-tert-Butylamino-2-(substitutedphenyl)-1 -propanols Scheme 11
02Nm
Scheme I11
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DCC
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