SYNTHESIS OP GLUCOSE DERIVATIVES OF SOME BARBITURATES DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By GLENN ARTHUR PORTMANN, B.S., M.Sc ****** The Ohio State University 1957 Approved by; Adviser College of Pharmacy ACKNOWLEDGMENT The author acknowledges his adviser Professor Loyd E. Harris for suggesting this problem and for the assistance he has rendered during the course of my education at The Ohio State University. I would also like to acknowledge the help of my fellow graduate stu­ dents and the financial assistance of The American Founda­ tion for Pharmaceutical Education. ii TABLE OP CONTENTS Page STATEMENT OF P ROBLEM................................. 1 INTRODUCTION ...... ........... 2 HISTORICAL .............................................18 EXPERIMENTAL........................... 20 I Synthesis of Tetra-0~acetyl-OC.-D-glucopy- ranosylbroraide ................................. 20 II Nitrogen Glucosides .............................. 21 A. Synthesis of 5,5-DiethyI-l,3-di-^ -D- glucopyranosylbarbituric Acid ......... 22 B. Studies with Different Reaction Media . 29 C. Synthesis of 5-AlIyl-5-(l-methylbutyl)-, and 5-Ethyl“5-phenyl-1, 3-di- -D- glucopyranosylbarbituric Acid ......... 30 D. Synthesis of 9-Ethyl-5-isoamy1-1-jS -D- glucopyranosylbarbituric Acid ......... 32 E. Synthesis of 5-Ethyl-5-(l-methylbutyl)-I, 3-di-y0 -D-glucopyranosy 1-2-thiobarbi- turic A c i d .................... ... 33 III Oxygen Glucosides and Ethers ................... 35 A. Attempted Synthesis of Substituted Dialuric Acid Glucosides and Ethers ........ 35 B. Attempted Synthesis of Enolic Ethers and Glucosides of Substituted Barbituric A c i d s .................................. 38 C. Synthesis of 5,5-Diethyl-4-(tetra-0-acetyl-^ -D-glucopyranosyloxy)-2, 6-pyrimidinedione . 4l IV Pharmacological Testing ......................... 43 V Analysis of Infrared Spectra ................... 44 iii iv Page DISCUSSION.................................. » . 53 SUMMARY ................................ 57 AUTOBIOGRAPHY ....................................... 60 LIST OP FIGURES Figure Page 1. Infrared Spectrum of 5,5-Diethyl-4-(tetra~0~ acetyl-^ -D-glucopyranosyloxy)-2, 6- pyrimldinedione...................... , . 46 2. Infrared Spectrum of 5,5-Dlethylbarblturlc Acid . ....................................... 47 3. Infrared-Spectrum of 5,5-Diethyl-l, 3-di- (tetra-0-acetyl-/S -D-glucopyranosyl) barbituric A c i d ............................... 48 4. Infrared Spectrum of 5,5-Diethy1-1, 3-di-Æ -D- glucopyranosylbarbituric Acid ........ 49 5. Infrared Spectrum of 5-Ethyl-5-(l-methylbutyl) -2-thiobarbituric Acid ....................... 50 6. Infrared Spectrum of 5“Ethyl-5-(1-methylbutyl)- 1, 3“di-(tetra-0-acetyl-y$f-D-glucopyranosyl)- 2-thiobarbituric Acid ................. 51 7. Infrared Spectrum of 5-Ethyl-5-isoamy1-1- (tetra-0-acetyl-/Gp-D-glucopyranosyl) barbituric A c i d .......... 52 V STATEMENT OF PROBLEM Many glycosides have very pronounced and widely varied pharmacological effects. The type of pharmacological response depends on the specific structure of the aglycone but the sugar moiety contributes important absorption and distribution characteristics. Glucose and some of its metabolites will cause a prompt return to anesthesia if injected into various animals immediately after recovery from barbiturate anesthesia. Also glucose will significantly prolong the sleeping time if injected with the barbiturate. The question arises as to what effect glucose would have if chemically combined with barbiturates. Further, the only method which has been used, in the past, to prepare water-soluble barbiturates is salt forma­ tion, All of these salts have the undesirable property of forming alkaline aqueous solutions due to hydrolysis. Glucose derivatives of barbiturates should therefore be desirable because of their stability and water solubility. The purpose of this study was to prepare glucose derivatives of barbiturates with the expectation of form­ ing a more potent, stable, water-soluble barbiturate. INTRODUCTION Many investigators have studied the effect of glucose and its metabolic products on barbiturate anesthesia. Lamson and his co-workers (l) were the first to publish their observations made when glucose was injected into dogs which recovered from pentobarbital anesthesia. They found that the dogs returned to anesthesia and remained in this state for an average time of one hour. Upon subse­ quent injections of glucose, the duration of anesthesia decreased until eventually further anesthesia could not be produced by the injection of glucose solution. This pre­ liminary investigation was extended by Lamson and co­ workers (2,3). They observed that other substances such as products of glycolysis and the Krebs Cycle, vitamins, malonic acid, glycerine, and epinephrine would also potentiate barbiturate anesthesia as indicated by a return to sleep on intravenous injection. Sodium lactate, pyruvate, and glutamate definitely affected the rate at which (1) P. D. Lamson. M. E. Greig, and B. H. Robbins, Science, 110. 690 (1949). (2 ) P. D. Lamson. et al,, J. Pharmacol. Exptl. Therap., 101, 460 (1951). (3) P. D. Lamson, et aL, Ibid., I0 6 . 219 (1952). 2 3 barbiturates entered the brain but glucose had little or no influence on the rate of entry. Acetylcholine completely blocked the action of sodium lactate. Adams and Larson (4) also investigated the effect of sodium succinate, malonate, acetate and citrate on the duration of pentobarbital anesthesia and found all of the ions to be potentiating agents. However, Westfall (5) stated that pyruvates are antagonistic to pentobarbital anesthesia and believed that the antagonism was due to polymers of the acid which form very readily, Bester and Nelson (6) found that sodium citrate, lactate, acetate, succinate, and pyruvate produced the symptoms of alkalosis but did not induce sleep in rabbits that had been anesthe­ tized with pentobarbital as determined by response to stimuli. The discrepancy between their results and those of Lamson, et al was explained as probably being due to the use of different criteria in deciding whether the animals were anesthetized. (4) J, P* Adams and E, Larson, Fed. Froc, 253 (1950), (5) B, A, Westfall, Anesthesia and Analgesia, 28, l6l (1949). (6) J, F, Bester and J, W. Nelson, J, Am, Pharm, A, (Scientific Edition), 42, 421 (1953). 4 Previously, Bester (7) substantiated the potentia­ tion of pentobarbital anesthesia by glucose. He also found a significant increase in sleeping time when glucose was injected with pentobarbital, and that normal blood glucose levels did not have an apparent affect on the duration of anesthesia following pentobarbital administration. A com­ petitive inhibition mechanism was proposed by Bester and Nelson to explain this potentiation phenomenon. Since glucose metabolism and barbiturate detoxification probably involve the same oxidative enzyme system, an increase in concentration of glucose could delay oxidation of the barbiturate causing increased blood and brain levels. The depressant action of barbiturates upon the central nervous system is brought about by inhibition of glucose utiliza­ tion. By injecting glucose, nerve tissue metabolism would be increased requiring the presence of greater amounts of barbiturate to inhibit this increased metabolism and cause anesthesia. However, if the increase in barbiturate blood level is great enough, the over-all effect would be a prolongation of barbiturate anesthesia. Recent work (8) indicates that barbiturates may block the Cytochrome Oxidase-Cytochrome-C system. It was observed that rabbits given lethal doses of pentothal would (T) J. P, Bester, M, S, Thesis, The Ohio State Univer­ sity (1950), also J. W. Nelson, and J, P, Bester, Can, Pharm. J, 8^, 22 (1952), (8) B. Giovanni, Giorn. ital, chir, IJ^, 15OO (1955), through Chem, Abs, ^0^ 9622 (1956). 5 survive if Cytochrome-C was injected intravenously either mixed with or given immediately after the drug. Pretreat­ ment with Cytochrome-C had no effect. Ratcliff, et al (9) found that, in insulin treated animals, there was a need for more frequent administration and greater quantities of pentothal to produce deep surgical anesthesia than was required in animals not given insulin. Whether the fall in blood glucose level caused by insulin is directly related to potentiation by injection of glucose is not known. Many other compounds will prolong the hypnotic effect of barbiturates. Some of them are iodides, bromides (10), antihistamines (11,12), cholesterol (13,14), (9) C. M. Ratcliff, et al. Fed, Froc. 8, 326 (1949). (10) J, C, Krantz, Jr, and M, J, Fassel, J. Am. Pharm. A. (Scientific Edition), 511 (1951). (11) H. Lightstone and J, W. Nelson, Ibid.. 43. 263 (1954), (12) C. A, Winter, J, Pharmacol. Explt. Therap., 24, 7 (1948). (13) E, Starkenstein and H. Weden, Arch. Explt, Pathol, Pharmakol,, 182. 700 (1936). (14) C. B. deFarson, C, J, Carr, and J. C. Krantz, Jr., J. Pharmacol, Exptl, Therap,, 82.» 222 (1947). 6 thiamine (15), nitrites (16), and uracil (17). Their mechanism of potentiation is not known. One of the purposes of the present investigation was to observe what effect glucose would have on the hypnotic properties of barbiturates when chemically combined with them. A survey of the literature was made to determine how the glucose moiety affected the pharmacological properties of other drugs and to determine if any generalizations could be made. The pharmacological