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Xerox University Microfilms 300 North Zeeb Road Ann Arbor, Michigan 48108 77-2428 KADOR, Peter Fritz, 1949- SYNTHESIS OF SELECTED TETRAHYDROISOQUINOLINE ANALOGS AND THEIR FRAGMENTED DERIVATIVES AS |3-ADRENERGIC AGONISTS. The Ohio State University, Ph.D., 1976 Chemistry, pharmaceutical Xerox University Microfiims, Ann Arbor, Michigan 4810e 0 1976 PETER FRITZ KADOR ALL RIGHTS RESERVED SYNTHESIS OF SELECTED TETRAHYDROISOQUINOLINE ANALOGS AND THEIR FRAGMENTED DERIVATIVES AS /3-ADRENERGIC AGONISTS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Peter Fritz Kador, B. A. **** The Ohio State University 1976 Reading Committee: Approved By Dr. Dennis R. Feller Dr. Neil J. Lewis Advisor Dr. Duane D. Miller College of Pharmacy ACKNOWLEDGMENTS I wish to express my sincere appreciation to Dr. Duane D. Miller, for his guidance and support as advisor throughout this study Dr. Dennis R. Feller, for his guidance in the biological aspects of this work Mrs. R. Venkatraman, for the biological evaluation of these compounds Dr. E. Fairchild and Mr. J. Fowble, for their technical assistance My wife, Suellen, for her love and confidence My Parents, to whom I dedicate this work, for their love, encouragement, understanding, confidence and many sacrifices that have made this possible. 11 VITA October 3, 1949................. Born - Regensburg, Germany 1972............................. B. A. Chemistry, Capital University, Columbus, Ohio 1972-1976........................NIH Pre-doctoral Trainee, College of Pharmacy, The Ohio State University, Columbus, Ohio PUBLICATIONS D. D. Miller, W. V. P. Merrit, P. F. Kador and D. R. Feller, Synthesis and Biological Actions of Fragmented Derivatives of Tetrahydroisoquinolines, J. Med. Chem., 18, 99 (1975). D. D. Miller, P. F. Kador, R. Venkatraman, and D. R. Feller, Synthesis and Biological Evaluation of Fragmented Deriva tives of Tetrahydroisoquinolines. 3. Trimetoquinol Studies, J. Med. Chem., 19, 763 (1976). FIELD OF STUDY Major Field: Medicinal Chemistry 111 TABLE OF CONTENTS Page ACKNOWLEDGMENTS....................................... ii VITA.................................................. iii LIST OF FIGURES...................................... vi LIST OF SCHEMES...................................... vii LIST OF TABLES .................................. viii INTRODUCTION.......................................... 1 OBJECTIVES....................................... 32 RESULTS AND DISCUSSION A. SYNTHETIC.................................... 36 I. Synthesis of 4-(3,4,5-Triraethoxybenzyl)- 6 .7-dihydroxy-l,2,3,4-tetrahydroisoquinoline hydrochloride (£4) and 2-(3,4- Dihydroxyphenyl)-3-(3,4,5-trimethoxyphenyl)propylamine hydrochloride (45).. 36 II. Synthesis of Fragmented Derivatives of Trimetoquinol (47-50; 51-54)........... 46 III. Synthesis of 3-(3,4-Dihydroxyphenyl)-6, 7.8-trimethoxy-l,2,3,4-tetrahydroisoquinoline hydrochloride (56) and the Attempted Synthesis of cis- and trans- 2-(3,4-Dihydroxyphenyl)-3-(3,4,5-trimethoxyphenyl)piperidine hydrochloride (57 and 58)............................. 62 B. BIOLOGICAL.................................. 68 I. Biological Activity of 4-(3,4,5-Tri- methoxybenzyl)-6,7-dihydroxy-l,2,3,4- tetrahydroisoquinoline hydrochloride (44) and 2-(3,4-Dihydroxyphenyl-3-(3,4, 5-trimethoxyphenyl)propylamine hydro chloride (45)...........■............... 69 iv II. Biological Activity of the Fragment ed of Trimetoquinol (47-50; 51-54),,. 71 III. Biological Activity of 3-(3,4-Di hydroxyphenyl) -6,7,8-trimethoxy-l,2, 3,4-tetrahydroisoquinoline hydro chloride (56) 75 EXPERIMENTAL...,........ .......................... 78 A. SYNTHETIC..................................... 79 B. BIOLOGICAL................................... 129 SUM14ARY......................................... 132 BIBLIOGRAPHY........................................... 135 V LIST OF FIGURES Figure Page 1 Factors Affecting the Physiological Tone of Bronchial Smooth Muscles....,............. ■ 6 2 90 MHz NMR Temperature Study of 4-(3,4,5- Trimethoxybenzyl)-2,6,7-triacetyl-l,2,3,4- tetrahydroisoquinoline. ..................... 45 3 Possible General Fragmentation Pattern for Compounds 47-50............................... 60 4 90 MHz Temperature Study of N-Methyl-N- . acetyl-1-(3,4-diacetoxyphenyl)-2-(3,4,5- trimethoxyphenyl ) ethylamine.................. 61 5 Comparison of Trimetoquinol and 4-Substi- tuted Analogs in Guinea Pig Trachea and Atria.......................................... 70 6 Comparison of Trimetoquinol and Fragment ed Analogs in Guinea Pig Atria and Trachea... 72 7 Dose-Response Curves For Trimetoquinol and Fragmented Analogs on the Release of Glycerol From Epididymal Fat Cells........... 73 8 Comparison of l-Benzyl-6,7-dihydroxy-l,2, 3,4-tetrahydroisoquinoline and Fragmented Analogs in Guinea Pig Atria and Trachea..... 76 9 Dose-Response Curves For N-Methyl~l-(3,4- dihydroxypheny1)-2-(3,4,5-trimethoxyphenyl)- ethylamine and 3-(3,4-Dihydroxyphenyl)- 6,7,8-trimethoxy-l,2,3,4-tetrahydroiso quinoline in Guinea Pig Trachea.............. 77 VI LIST OF SCHEMES Scheme Page 1 Synthesis of 4-(3,4,5-Trimethoxybenzyl)- 6,7-dihydroxy-l,2,3,4-tetrahydroiso quinoline hydrochloride ( ^ ) ............... 37 2 Synthesis of 2-(3,4-Dibenzyloxyphenyl)-2- (3,4,5-trimethoxyphenyl)propylamine hydro chloride (66)............................... 40 3 Synthesis of 1-(3,4-Dibenzyloxyphenyl)- 2-(3,4,5-trimethoxyphenyl)ethanone (76a) and 1-(3,4-Dibenzyloxyphenyl)-2-phenyl- ethanone ( 76b).............................. 48 4 Synthesis of 1-(3,4-Dihydroxyphenyl)-2- (3,4,5-trimethoxyphenyl)ethylamine hydro chloride (48) and 1-(3,4-Dihydroxyphenyl)- 2-phenylethylamine hydrochloride ( ^ 1 ) ...... 51 5 Synthesis of the Fragmented Derivatives £7, 4£_and M ............................... 52 6 Synthesis of the Fragmented Derivatives £ 2 ^ - ^ ........................................ 55 7 Attempted Synthesis of 5-(3,4,5-Trimethoxy- phenyl)-6-(3,4-dibenzyloxyphenyl)piperidine- 2-one (109)................................. 65 V I 1 LIST OF TABLES Table Page I Reaction Yields Obtained via Scheme 5 55 II Reaction Yields Obtained via Scheme 6 56 Vlll INTRODUCTION Adrenergic drugs are those chemical compounds that produce an effect on the adrenergic nervous system or that part of the peripheral nervous system mediated by the neurotransmitter norepinephrine (1). H o k ^ NHR 2 R = CH3 Originally epinephrine (2), isolated in the late 1890's from the nerve endings of the adrenal gland^, was assumed to be the neurotransmitter. Named sympathin and later called adrenaline, the nervous system utilizing epinephrine became known as the sympathetic or adrenergic nervous system. Finally von Euler^ demonstrated in the late 1950's that norepinephrine (1^) is the principal neurotransmitter. Most of the actions of the adrenergic drugs, which generally resemble responses to the stimulation of adrener gic nerves, may be classified into five broad types; (1) a peripheral excitatory action on certain types of smooth muscle, such as those in blood vessels supplying the skin and mucous membranes, and also on salivary and certain sweat glands; (2) a peripheral inhibitory action on certain other types of smooth muscle, such as those in the wall of 1 the gut, in the bronchial tree, and in the blood vessels sup plying skeletal muscles; (3) a cardiac excitatory action, responsible for an increase in heart rate and force of con traction; (4) metabolic actions, such as an increase in the rate of glycogenolysis in liver and muscles, and liberation of free fatty acids from adipose

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