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[(Arylcarbonyl)Oxy]Propanolamines. 1. Novel Beta

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[(Arylcarbonyl)Oxy]Propanolamines. 1. Novel Beta J. Med. Chem. 1984,27,1007-1016 1007 All substances to be tested were dissolved in saline immediately Motor activity was then followed and recorded for the subsequent before use. Reserpine was dissolved in a few drops of glacial acetic 60 min. Each box was equipped with a semitransparent mirror acid and made up to volume with 5.5% glucose. Injection volumes that allowed gross behavior observations of the animals during were 5 or 10 mL/kg, and injection solutions had approximately the experiments. The motor activity results are shown in Table neutral pH. I. The biochemical experiments and the spectrophotometric Acknowledgment. The authors thank Ingrid Bergh determinations of Dopa were performed as previously described.l’ Separate dose-response curves based on four to six dose levels and Lucia Gaete-Valderrama for their assistance in the for each substance (subcutaneous administration) and brain area pharmacological testing and Goran Everitt for the 100- were constructed (cf. ref 11). From these curves, the dose of the MHz lH NMR spectra. The finacial support from AB drug yielding a half-maximal decrease of the Dopa level, the EDw Hiissle, Molndal, Sweden, Astra Lakemedel AB, Sodertrilje, value (presented in Table I), was graphically estimated. In each Sweden, The Swedish Board for Technical Development, point of the curves, the SEM was less than 15% of the mean value. The Swedish Academy of Pharmaceutical Sciences, Motor Activity. The motor activity was measured by means “Stiftelsen Clas Groschinskys Minnesfond”, “Magnus of photocell recordings (“M/P 40 Fc Electronic Motility Meter”, Bergvalls Stiftelse”, and the Medical Faculty, University Motron Products, Stockholm) as previously described.l’ of Gothenburg, is gratefully acknowledged. The rats were treated with reserpine (10 mg/kg ip) and DL- a-methyl-p-tyrosine methyl ester hydrochloride (tyrosine hy- Registry No. 3,90295-42-4; 3.HBr, 90295-43-5; 4,90295-44-6; droxylase inhibitor; 250 mg/kg ip) 6 and 1h, respectively, prior 4.HBr, 90295-45-7; 5.HBr, 90295-46-8; 7,33892-75-0; 8,90295-47-9; to the motility testing (carried out between 1 and 6 p.m.). The 9,90295-48-0; 9*HC1,90295-49-1;9 N-propionyl deriv., 90295-50-4; different compounds under investigation were then administered 10,42263-75-2;11,90295-51-5; ll*HC1,90295-52-6; 12,90365-41-6; subcutaneously in the neck region (n= 4), in a dose of 1mg/kg 12.HC1, 90365-42-7; 13, 90295-53-7; 13.HC1, 90295-54-8; 14, (3000 nmol/kg: compounds 3 and 6) or 10 mg/kg (30000 nmol/kg; 90365-43-8; 14qHC1, 90365-44-9; 15, 4003-87-6; 16, 90295-55-9; compound 4). Controls received isotonic saline. 16-HC1,90295-56-0;17,78950-90-0; 17.HC1,90295-57-1;5-meth- Immediately after drug administration, the rats were placed oxy-1-methyl-2-tetralone oxime, 90295-58-2;propionyl chloride, in the test cages (one rat per cage) and put into the motility meters. 79-03-8; n-propylamine, 107-10-8. [ (Arylcarbonyl)oxy]propanolamines. 1. Novel P-Blockers with Ultrashort Duration of Action Sheung-Tsam Kam,*l William L. Matier, Khuong X. Mai, Cynthia Barcelon-Yang, Robert J. Borgman,2 John P. O’D~nnell,~Herman F. Stampfli, Check Y. Sum, William G. Anderson: Richard J. Gorczynski, and Robert J. Lee Department of Pharmaceutical Research, American Critical Care, American Hospital Supply Corporation, McGaw Park, Illinois 60085. Received September 30, 1983 Novel [(arylcarbonyl)oxy]propanolamines were synthesized and investigated as potential ultrashort-acting /3-adrenergic receptor blockers. Many of these analogues exhibited good potency and short duration. The N-ureidoalkyl analogue 85 (ACC-9089) has a potency equal to propranolol and a duration of action of about 21 min in the dog. It has been selected as a candidate for further clinical study. Structureactivity relationships and structure-duration relationships for these new /3-blockers are also discussed. In certain clinical situations, drugs with very short bi- ultrashort-acting @-blockerhas recently been published.s ological half-lives may be preferred over their longer acting We felt that an ideal ultrashort-acting @-blockershould counterparts. Intravenous infusion of an ultrashort-acting have the following profile: (1) Duration. The duration of drug into a patient will allow rapid achievement of a @-blockingactivity in patients should last from 10 to 30 steady-state therapeutic effect: a rapid alteration of the min after termination of the infusion of the drug. A du- desired effect in a dose-titration manner, and a rapid ration of action of about 15 min seems to be most desirable. termination of undesirable responses should they occur. A duration longer than 30 min or shorter than 10 min is An ultrashort-acting drug is also useful for testing the less desirable since the former would prevent strict control patient response and tolerance to the therapy before using of activity over an ever-changing situation and the latter a long-acting compound. would make precise minute to minute control too difficult The wide clinical indications of @-adrenergicblocking to achieve. Our approach to try to achieve short duration agents and the dangerous side effect of inducing cardiac of action was to incorporate into the skeleton of the @- failure during surgery6 or after myocardial infarction7 blocker a “metabolically unstable” ester function that on suggest a need for an ultrashort-acting @-blocker.A more breakdown in vivo by esterases would lead to products that detailed discussion of the pharmacological rationale for an are devoid of @-blockingactivity. Esterases are widely distributed in body fluids and tissue^.^ (2) Toxicity. Due (1) Send correspondence and reprint requests to: Class of 1986, to the fast breakdown of the drug, the compound has to College of Medicine, University of Illinois at Chicago, Chicago, be replenished continuously to maintain a constant drug IL 60612. level in the blood. It is thus obvious that the cumulative (2) Present address: G.D. Searle and Co., P.O. Box 5110, Chicago, IL 60680. (3) School of Pharmacy, West Virginia University Medical Center, (8) Zarowlinski, J.; Borgman, R. J.; ODonnell, J. P.; Anderson, W. Morgantown, WV 26506. G.; Erhardt, P. W.; Kam, S-T.;Reynolds, R. D.; Lee, R. J.; (4) Present address: Department of Pharmacology, William H. Gorczynski, R. J. Life Sci. 1982, 31, 899. Rorer Inc., Fort Washington, PA 19034. (9) Levine, R. M.; Clark, B. B. J. Pharmacol. Exptl. Ther. 1956, (5) Cocchetto, D. M. J. Pharm. Sci. 1981, 70, 578. 113,272. Wynne, D.; Ginsburg, S.; Shalitin, Y. Arch. Biochem. (6) Chung, D. C. Cand. Anesth. SOC.J. 1981, 28, 105. Biophys. 1973,154, 204. O’Brien, J. E.; Abbey, V.; Hinsvark, (7) Lee, R. J. Life Sci. 1978, 23, 2539. 0.; Perel, J.; Finster, M. J. Pharm. Sci. 1979, 68, 75. 0022-2623/84/1827-1007$01.50/00 1984 American Chemical Society 1008 Journal of Medicinal Chemistry, 1984, Vol. 27, No. 8 Kam et al. Scheme I Scheme I1 ArCOCI 9 HOCHzCH-CHz t HzNR - HOCHpCHCHzNHR I O/ I HOOCCHCHpCI f HzNCHzCHz OH 7 1 8 2 ArCOOCHZCHCHzNHR OH 1 P-CH~OC~H~CH~OCONS I OH I 2 OHP, HI HOOCC HC HpNHCHpC Hp 4-H. 3 H* Scheme I11 3 OTHP I JOCH3 I I CDI 9 HOOCCHCHeNCHzCHz I ArCOOCHzCHCH2NHR COOC H2C6 H40CH3 I OH 4 OCH3 Scheme IV 0 OTHP OR ArOC-CHCH2NCH2CH2II I aOCH3H* i PH II I I ArCOCH2CHCH2NHR - ArC-NCH2CH(OH)CH&H COOCH2C6H40CH3 10 5 phenethylamine (2) to produce the amino acid 3. The 0 amino group of 3 was then protected by p-methoxy- benzyloxycarbonyl azide. Treatment of the intermediate ArOCCHCH,NHCHZCHZII &iC H3 with excess dihydropyran (DHP) followed by selective I hydrolysis of the tetrahydropyranyl ester gave the acid 4. OH Coupling of 4 with phenol or a substituted phenol was 6a-d facilitated by carbonyldiimidazole (CDI) to give 5. De- dose of a short-acting drug over a period of time will be protection of 5 with acid in nonaqueous medium gave the much greater than that of a long-acting drug. Since the final products 6a-c (Table I). Compound 6d was obtained short-acting drug will exist in the body mainly in the by direct esterification of 3 with 2-methoxybenzyl alcohol. metabolized form, it is extremely important that those The @-blockerswith benzoate esters 11-13 (Table I and metabolites should be inactive and innocuous, even at a Table 11) have been reported by Tatsuno et al." They high concentration. (3) Potency. A potent compound will synthesized these compounds through the reaction of help to reduce the amount of drug required and therefore 3,4-(methy1enedioxy)benzoic acid salts with epichloro- the amount of metabolites produced. An ultrashort-acting hydrin in the presence of a phase-transfer catalyst to ob- @-blockerwith an in vivo potency comparable to propra- tain the intermediate glycidyl ester 9 (Scheme 111),which nolol would be desirable. (4) Cardioselectivity. This is a was then treated with amines to obtain the blockers. We desirable feature for patients with bronchial disease. attempted to repeat these syntheses but failed to isolate However, @-blockersthat are cardioselective (e.g., atenolol, any desired product 12 from the reaction of the glycidyl metoprolol) usually are considerably less potent than the ester and isopropylamine. Two alternate routes were nonselective blockers (e.g., propranolol, nadolol, timolol). therefore developed. In the first synthesis (Scheme 11), Since the amount of metabolites generated increases with glycidol7 was allowed to react with an amine to form the a less potent compound, a potent nonselective short-acting amino diol 8 which was then mixed with an acid chloride @-blockerwould also be acceptable.
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