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C & E N A N N U A L REVIEW > F Developments in the Chemical oui Process Industries
MEDICINAL CHEMISTS HAVE BUSY YEAR LEON A . SWEET, Director of Research, Parke, Davis & Co., Detroit, Mich.
The year 1949 has been marked by a further extension of the interest in " n a t u r a l " products . . . . . . Antibiotics and vitamins continued to make important news, and steroidal chemistry, which was about to be stored a w a y in mothballs, suddenly returned to the spotlight. Medicinal chemists were busy, not only with purely synthetic medicinals—creations of the test tube—but also in unravelling the mysteries of t h e natural products and in making them avail able more plentifully and economically by synthesis. Some of these new developments offered promise of broadening the base of thera peutics. Limited success of some of t h e newer antibiotics against virus infections offered hope that chemotherapy would yet succeed with such dread diseases as poliomyelitis. T h e success of several hor mones in arthritis opened a new door to the study of that disease. Cortisone and A C T H T h e pituitary and adrenal glands have long been known to be of extraordinary importance in mammalian physiology. T h e startling report in April from the Mayo Clinic of the successful control of rheuma toid arthritis with 17-hydroxy-ll-dehydrocorticosterone, a steroidal hormone from the adrenal cortex, as wel! as by the adrenocorticotrophic hormone ( ACTH ) from the anterior lobe of the pituitary» pointed to an even greater significance than had yet been appreciated. Further indications of their importance were given by subsequent reports of the usefulness of these hormones in rheumatic fever, gout, and the general phenomena of al lergy, along with suggestions of their possible value in som*» types of mental abnormalities and in suppressing lympho sarcoma. One of the brightest hopes from the discovery of these activities of cor tisone and A C T H is that a study of their mode of action will shed new light on the nature of the arthritic process, as well as some of the other chronic diseases, from which further therapeutic advances may stem. Both of these hormones are usually effective only in relatively large doses, 100 mg. per day, and must be used con tinuously, as w i t h insulin in diabetes. Fur thermore, at these dosages, which far ex c e e d normal physiological levels, u n pleasant and even dangerous hormonal
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side effects may be encountered. Exten sive clinical studies will be required to define the scope of their clinical usefulness as well as their toxicity potentialities. Unfortunately, these drugs are available only in very small amounts. The adrenal cortical hormone that has been known as Kendall's compound Ε and was recently renamed cortisone is available from animal glands only in small amounts and at prohibitive expense. The clinical studies have been made possible by an unusually complex synthesis, involving over 30 steps, from desoxycholic acid. Likewise, ACTH is a protein which is obtainable only in limited amounts from animal pituitaries. Hog glands, although small, are stated to contain 25C£ of the hormone by weight in the dried anterior lobe, yet it is estimated that the glands from 400,000 hogs are required to produce one pound of hormone. Digestion of ACTH with pepsin under controlled conditions is re ported to yield a peptide with an average of eight amino acid units which retains full activity. T h e tremendous potential importance of these drugs has proved a great stimulus to research and has furnished a challenge to the synthetic chemist either to make one or both of these hormones available economically and in quantity or to find, in cooperation with the physiologist and clinician, yet other substances which might prove effective and more practical to supply. T h e popular press has hailed sarmentogenin as a solution to the problem of cortisone supplies, without adequately
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stressing the considerable chemical proc essing which would b e required in the conversion. Even more of an obstacle is posed by the fact that there is no good known source of supply of the strophanthus plants and seeds from which it is derived. Their cultivation is expected to be a slow process since the plant requires five years to produce seed. Botogenin, derived from a Mexican plant, has also been publicized as a logical starting ma terial for cortisone synthesis, without suffi cient information on its availability. Antibiotics Penicillin and streptomycin continued to lead t h e parade of antibiotics, each being produced in the U. S. at the rate of about 14,000 pounds per month, according to figures released by the Department of Commerce for the first eight months of 1949. Meanwhile two comparative new comers, aureomycin and chloramphenicol (Chloromycetin), gained in importance as further clinical studies showed them to have broad, fields of therapeutic applica tion. Of particular interest was their effect on certain virus conditions, includ ing virus pneumonia, and on brucellosis, in cases where penicillin and the sulfon amide drugs had failed. Evidence also was accumulating that these drugs would be generally useful in Gram positive as well as Gram negative infections. When considered along with their effectiveness in rickettsial diseases and their reported promise in treating gonorrhea and possi bly also syphilis and amoebic dysentery, they rank with the most versatile chemo-
T EON A. SWEET is director of research and products development at Parke, Davis & Co., Detroit, where h e has climbed through successive positions since 1933, when h e joined the staff. H e is now serving as a member of the panel on chemical warfare and as chairman of the subpanel on the Committee on Chemical Warfare of the National Military Establishment. He also serves on the Committee on the Survey of Food and Nu trition Research of the Food and Nutrition Board, National Research Council. H e is a native of Illinois, graduated from Carthage College in 1930, and later did graduate work in organic chemistry at the University of Nebraska.
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therapeutic agents yet discovered. Both drugs are effective by mouth and are relatively nontoxic, although gastrointes tinal distress is sometimes encountered with aureomycin. Chloramphenicol has been shown to by n( — ) -//irt?(?-2-diehloroaectamido-l -wnitrophenyl-l,3-propanediol, which is un usual in containing the dichloroacctyl and nitro groups. The structure was con firmed by synthesis, first from benzaldehyde and subsequently from acctophenone and p-nitroacctophcnoiie. It is the first antibiotic to be made synthetically on a commercial scale. Aureomycin is a weak base with a molecular weight of about 508. Like chloramphenicol, it contains nitrogen and chlorine, but the two drugs do not appear to be closely related chemically. Aureomycin and bacitracin have shown some valut· in the treatment of amoebic dysentery, because of their antibacterial action as well as some inhibiting action on the multiplication of amoebae. Due to its toxicity, the use of bacitracin has been otherwise limited to topical application. Neomycin was found by Waksman, dis coverer of streptomycin, to be formed by an organism related to Streptomyces fracliae. It has been reported to show some promise as an agent for the treatment of tuberculosis as well as for urinary infec tions. However, the impure concentrates with which much of the work has been done have also proved toxic, a short coming which may be minimized when the pure antibiotic is available for study. One fraction has been isolated in crystal line form and designated Neomycin A. Mycomycin has also been reported to be effective in experimental tuberculosis, but instability of the drug has handi capped further study. Nisin was stated by workers in England to be effective in experimental tuberculosis, and its com bination with streptomycin produces more than additive activity. Polymyxin and aerosporin have been shown to be basic polypeptides. Their
Steps in produc tion of cortisone
toxic effects on the kidney preclude their general use. Tuberculosis Salts of streptomycin and dihydrostreptomycin c ο ηtinued to head the list of agents for treating tubercu;^? losis. Dihydrostreptomycin "'HI has not proved as advanta- . tg gcous as anticipated, and a -;'V definite trend back to wider \f< use or streptomycin is in ^ progress. p-Aminosalicylic fj acid ( PAS ) and its sodium salt have gained increased acceptance for the treatment of tubercu losis, but attempts to find more active drugs by varying the molecule have proved disappointing. Both PAS and the sulfones have been found in experimental tuberculosis in animals to show an addi tive effect in combinations with strepto mycin, and in clinical use also have delayed significantly the emergence of strains of tubercle bacilli resistant to streptomycin. One of the sulfone drugs, Promizole, ( 4,2'-diaminophenyl-5-thiazolyl sulfone), was reported particularly effec tive in the treatment of meningeal and miliary tuberculosis in children. Another drug, known as TB-1, or Tibione (thiosemicarbazone of p-formylacetanilide), has been developed in Ger many and studied there on 7,000 cases of tuberculosis. A recent survey of re sults showed it to be of no value in meningeal and miliary tuberculosis but apparently quite effective in pulmonary tuberculosis. It was concluded that the drug, while toxic, is feasible for clinical use and that the results, while less striking than with streptomycin, appear sufficiently pronounced to warrant a thorough clinical evaluation in this country. An excel lent study of related com pounds published by British workers confirms the activity of this type of compound and lists the thiosemicarba/.one of p-ethylsulfonylbenzuldehyde as showing great est activity in experimentally infected mice. Radioactive
Materials
The availability of lowpriced radioactive isotopes of the common elements has
Still and recovery system used for the final step in the synthesis of Chlo romycetin.
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resulted in their widespread use in the study of living processes and in the be havior of drugs. They have found limited use as therapeutic agents under special circumstances. Radioiodine is re ported to be of some use in hyperthy roidism, and in the treatment of cancer of the thyroid, since t h e thyroid gland selectively absorbs ingested iodine. Radiophosphorus has been used by surgeons to locate brain tumors, for which tissue it has a selective avidity. It is also used therapeutically in polycythemia vera and in leukemia. Vitamins Further clinical study of vitamin fiu has shown it to be the long-sought antipernicious anemia factor of liver. Its control of this disease in a daily paren teral dose of 1 Mg. marks it as the most active known therapeutic substance. It is relatively inactive b y mouth in per nicious anemia patients but active at 5 jig. when administered with normal gastric juice. Crystalline vitamin B12 has been shown to yield 5.6-dimethylbenzimidazole on acid hydrolysis. T h e molecular for mula is suggested to be Ceji-oaH^-roNuOi.— PCo. Catalytic hydrogénation of B12 yielded a crystalline compound, biologically active, which has been designated Bu»a. A second biologically active pigment derived from liver shows about one third the activity of B12 and has been designated B1211. While it is evidently closely related to B12 it was separable by chromatography and showed different absorption spectra maxima. This is but one example of the increasing use of chromatographic methods and particularly the new techniques of paper chromatography. The demonstration that vitamin B12 is an important component of the animal protein factor complex has added an important stimulus to its commercial production. It is available as concentrates and in crystalline form from fermentation processes, and particularly from the mold which produces streptomycin. Experimental details were published for
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one of the previously announced syn theses of vitamin A. While t h e synthetic vitamin is still available in only limited amounts, manufacturers continue to pre dict that it will soon displace natural vita min A to an important extent. Other Products A number of other developments in the field of medicinal agents also deserve brief mention. T h e antihistamine drugs continued as the subject of much attention. Several new additions were made to t h e already large group of marketed drugs, and re search attention centered more on the development of active drugs which would be free of sedative action and other un desirable side effects. Further reports on t h e allergic factor in the common cold increased interest in the use of anti histamine drugs for its prevention and control. T h e climax w a s reached late in the year when some of these agents were offered for sale without prescription and, as aptly termed by one newspaper, rival makers girded for the "cold war." There was also interest in the use of some of them for t h e prevention of motion sickness. Sufferers with parkinsonism were offered several additional agents, each of which had shown some clinical usefulness. T h e list of drugs, perhaps headed by Artane, 3 - (N - piperidyl ) - 1 - phenyl - 1 - cyclohexyl-1-propanol hydrochloride, also in-
eluded Parpanit, diethylaminoethyl - 1 pheny ley clopentane- 1-carboxy late hydro chloride; Diparcol. N-/9-diethylaminoethylphenothiazine, and Benadryl, /3-dimethylaminoethylbenzhydryl ether hydrochloride. N e w curarizing agents included Syncurine, decam ethylene-1,10-bis-trimethylammonium dibromide, and Flaxedil, 1,2,3tris ( diethylaminoethoxy ) benzene triethiodide. An analgesic, l,3-dimethyl-4-phenyl-4propionoxy-piperidine (Nisentil) w a s re ported useful in relieving acute pain, such as is encountered in obstetrics. A new type of local anesthetic, Xylocaine, a-diethylamino-2,6-acetoxy)idide, was found superior to procaine in dental surgery. Norepinephrine was found to occur with epinephrine in the adrenal medulla and to b e converted to the latter in the per fused gland. The presence of ATP (adenosine triphosphate) was shown to be essential for the methylation. Nor epinephrine was also found in some lots of commercial epinephrine of glandular origin to the extent of 10 to 20 r /c. Orthoxine, o-methoxy-/3-phenylisopropylmethy lamine hydrochloride, is effective orally as a bronchodilator without raising the blood pressure or stimulating the cen tral nervous system. A novel approach to the difficult prob lem of chronic alcoholism was introduced from Denmark. Persons w h o have re ceived tetraethylthiuram disulfide, recently
referred to as Antabuse, experience s series of disagreeable symptoms which are the result of increased concentrations of acetaldehyde. T h e added drug stops the normal oxidative metabolism of alco hol at t h e aldehyde stage. T h e treat ment is combined with psychotherapy and is dangerous in cases with cardio vascular disease. Research on the cardiovascular-renal disease group, which accounted for 4 8 % of all deaths in the U. S. in 1945 and 1946, was conducted at a greatly acceler ated pace, because of t h e increased avail ability of reseaivh funds from both public and private sources. T h e veratrine alka loids received considerable attention for the relief of hypertension. Khellin, a drug derived from the seeds of an Egyptian plant, is being studied in angina pectoris. Dicumarol showed favorable results in the management of coronary thrombosis but continued administration with careful control of blood prothrombin levels is required. Adrenergic blocking agents continued to be a popular research subject, with 2 [ ( m - hydroxyphenyl ) ( ρ - tolyl ) aminomethyl] imidazoline showing especial promise as an orally effective, nontoxic agent. T h e principal clinical application of these drugs appears t o be in the group of peripheral vascular diseases. Tetraethylammonium chloride was reported to b e of some benefit in multiple sclerosis.
C & E N A N N U A L R E V I E W OF Developments in the Chemical and Process Industries
PLASTICS CATCH UP P. O. POWERS, Battelle Memorial Institute, Columbus, Ohio
The y e a r 1949 w i l l perhaps b e best remembered in the plastics industry a s the y e a r w h e n t h e supply caught up w i t h the d e m a n d . . . . . . Quite suddenly early i n the year, materials which had been in short supply for a long time became readily available, and practically all plastic materials were obtainable for the first time. The steel strike resulted in some reduction in the supply of coal-tar resins. However, the full effect of this m a y not have yet been seen. There is, however, an indi cation that inventories of plastic materials have been used up, and an increase in demand may b e expected. In spite of reduced demand for some types of plastic materials, t h e total pro duction in 1 9 4 9 will probably b e as great as in 1948. T h e loss in volume of some of the thermosetting resins has b e e n counter balanced b y t h e increasing demand for some of the thermoplastic resins. T h e supply of coal-tar resins will be limited by t h e amount of raw materais available. Chemical uses absorb nearly all of these at the present time. T h e supply of raw
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materials from natural gas and petroleum, however, is much greater, and these plas tics are, in general, the type whose pro duction is being expanded. Formalde hyde from natural gas is now a significant factor as a plastics raw material, and re newed interest has been noticed in several resins from formaldehyde. Chemicals
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from the Fischer-Tropsch process, while their immediate outlet will b e in solvents and plasticizers, will also offer raw ma terials for plastics. T h e rapid growth of plastics manufacturing plants in the Ohio Valley and Texas Gulf Coast is noticeable. During the year, several n e w plants for the manufacture of plastic materials were
" D A U L O. POWERS has b e e n a technical advisor in
the field of plastics at Battelle Memorial Insti tute, Columbus, Ohio, since 1946. l i e began his career at Mellon Institute in 1924 after receiving a P h . D . from the University of Pittsburgh, and later worked for Calco Chemical, then for Newport In dustries in Pensacola, and Armstrong Cork C o . , where he was chief chemist for 10 years. H e has to his credit about 2 5 published works, including a book, on the subject of plastics, synthetic rubber, and terpenes, and 15 patents.
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