Alfred Oilman, Columbia I niversity* with /•'. /•'. lilicke, I nivvrsitr of Michigan, chairman of the Division of Medici­

nal Chemistry; M. J. Shear, ISational Cancer institute, and Leon Sweet, Parke, Davis and Co., secretary of the division

Chemists and Pharmacologists Collaborate in Symposium J7 ROMISI.M; progress and possibilities, now in experimental stages, lor the relief of pain and allergies and the combating of cancer and tuberculosis as well as other diseases and deficiencies, were reported at the first national medicinal chemistry symposium, held at the I'niversity ot Michigan, Aim Arbor, under the sponsor­ship of the Division of Medicinal Chem­istry of the AMKIUCAN CUKMKAI. S<>< N/I Y.

June 17, 18, and 1<>. The most striking over-all effect of the

meeting was the enthusiasm developed in both chemists and pharmacologists over the benefits of the unusual opportunity for discussion. The post meeting spirit \vn« one of exceptionally fruitful accomplish­ment in collaboration between researchers in chemistry and pharmacology, whose difficult task of understanding and corre­lating problems in the two fields has been approached, for the most part, through less thoroughly integrated discussions of small segments of various groups of agents ami maladies. Such discussions have been held by small groups horn individual laboratories or large general meetings. Strong interest was expressed in holding another similar meeting in 1950.

Antitubercular Drugs

In reviewing antitubercular drugs, Al­fred Burger, University of Virginia, pointed out that many of the old data in this field are valueless because the meth­ods were so subjective and because there are so many varieties of tubercule bacilli. A large number of drugs were discussed, and it was noted that only two, promizole [4-amino-phenyl-(2-amino-5-t hiazolyl)sul -feme] and streptomycin, are now in clinical use. Promin [sodium bis-(4-M-dcxtrose-sulfonatephenyl) sulfone], it was stated, has been found to cause anemia; it is now in use, through local application, for leprosy. Dr. Burger reported that an alkaloid, cepharanthine, has been indi­cated'to be quite active in this respect, but has not reached the stage where defi-

A S T A F P HKPOR'I

nite statements can be made as to its value.

The testing of antitubercular agents was discussed by ( luy P. Youmans, North­western I'niversity Medical School, who concluded that streptomycin is the most valuable drug aid to the treatment of tuberculosis now available.

Cancer

Optimism for the longtime view of progress in the chemotherapy of cancer ami a warning against hasty conclusions were* expressed by M. J. Shear, National Cancer Institute. Proof by thorough study and a five-year follow-up were urged as requirements for the acceptance of new cheinotherapeutic agents JUS "cures." As an illustration of a dis­appointment through premature optimism, Dr. Shear cited the much publicized Kit agent which came out of Russia a few-years ago. Careful study in several re­search centers in this country have shown entirely negative results to date, lie said. Other agents for which good results were claimed in the early stages of develop­ment, hut which Dr. Shear said have now been found ineffective, are H - l l , an ex­tract -of urine, and FA-2, a hog liver extract reported from Italy. "There are no agents which a physician can use with assurance of a complete cure," stated Dr. Shear, "hut there are some which are of aid in the treatment of cancer."

Nitrogen mustard, developed as a war poison, is now accepted in competent circles as an aid in the treatment of certain types of lymphatic tissues, he reported, while some bacterial polysaccharides, such as that produced from Serratia marceacens, have shown definite destructive action on sarcomas but are too toxic to use on patients. Urethane has been shown to be useful in the treatment of certain types of leukemia but has been found to cause pulmonary edema in mice.

None of the antibiotics has been found of value, Dr. Shear reported. Certain

plant extracts, particularly podophyllin, have been found beneficial in external local application but damage the host. There are some reports of benefits by folic acid to certain types of breast cancer, he said, while acute leukemia is accelerated by its use. Certain folic acid antagonists, including aminopterin, have been found effective, he stated, but are not to be used widely because of their highly toxic nature, although such materials do indi­cate a promising direction.

Folic acid antagonists were also dis­cussed by K. L. R. Stokstad, Lederle Division of American Cyanamid Co., in his paper "Pteroylglutamic Acid, Antag­onists and Antianemic Compounds."

Pain-Killer

The study of partial structures derived from morphine which led to the finding of highly active compounds was reported by J. IA?C, HorTmann-LaHoche, Inc. Dr. Lee

stated that the l,3-dialkyl-4-phenyi-4-propionoxypiperidines were particularly active. The 1,3-dimethyl homolog is of highest interest. It is now being clinically tested and has been found more active than isonipecaine (Demerol) or methodon.

Aralkylamincs as analgetics were the subject of a paper by K. J. Fellows and (1. E. L'llyot, Temple University and Smith, Kline, and French Laboratories, respect ively. p-Hydroxy-a-methylphen-ethylamine sulfate was found to be among the more active compounds in the series Ar(1nH.j„NMj, where 11= 1—5, which was the subject of their work. With this compound the dextro isomer was more active than the levo. However, its marked pressor activity precludes its usefulness as an analgetic agent. The p-methyl and p-methoxyl derivatives of amphetamine (Benzedrine) produced marked analgesia although the former gave central simula­tion in analgetic doses. Dr. Fellows pointed out that present methods of test­ing compounds for analgetic activity are useful only in detecting substances with a

1974 C H E M I C A L A N D E N G I N E E R I N G N E W S

potential in the range of morphine or codeine.

The analgetics of the amidone series were discussed by E. C. Kleiderer, Eli Lilly and Co., while G. M. Suter, Sterling-Win throp Research Institute talked on ''Arylpipcridines Derived from Aceto-nitrilcs." Methods of evaluation of anal­getics were described, by K. K. Chen and C. C. Scott, Kli Lilly and Co.

Anticonvulsants

Phenacetylurea is the most promising anticonvulsant found in the studies of scries of ureides, allophanates, and car­bamates carried out at Abbott Labora­tories, according to M. A. Spielman, of that organization. This drug is now in clinical trial, he stated, and was recently reported by Frederic Gibbs, Illinois Col­lege of Medicine, to have been found effective in preliminary work on cases of grand mal, petit mal, and psychomotor seizures.

Loren M. Long, Parke, Davis and Co., who also reported on anticonvulsants, stated that while phenobarbital and 5,5-diphenylhydantoin (Dilantin) are still the prominent leaders in the field, interesting results are being found with other com­pounds. 5-Methyl-5-phenylhydantoin is of some interest, particularly since i ts dextro isomer is less toxic than the levo. While it is less active as well, the activity is reduced less than the toxicity. In ex­perimental work, he stated, 5-phenyl-5-(2-thienyl)lrydantoin has given indication of being comparable to 5,5-diphenyl-hydantoin.

Antihistamine compounds were re­viewed by George Ilieveschl, Jr., Parke, Davis and Co. This presentation revealed that the number of drugs which have reached the market stage or which are very near it has increased greatly during the past year. Most of these are ethylene-diamine derivatives or alkamine ethers, with a few of miscellaneous classification.

The "vitamin P" effect and the action of certain flavonoid compounds in this respect were the subjects dealt with most extensively by T . A. Geissman, Univer­sity of California, in his paper, "Plant Pigments in Medicine.'' Reporting evi ­dence cited both for and against such compounds as rutin, hesperidin, epi-catechin, and related compounds in re­spect to their activity in this function,

Richard O. Roblin, Jr., of American Cyana mid Co., ami Etiwin Fellow, of Temple University

he indicated t'hat a clear and unequivocal effect of flavonoid compounds on capil­lary resistance has not been demonstrated al­

though it was stated that there appears to be some support for the belief that in capillary fragility of certain etiologies some clinical benefit may be produced. Xo convincing evidence was found which established ttavonoids in the role of accessory dietary factors.

The group of alkyl phosphates which cause an irreversible inactivation of cho-linesterase were the subject of a paper on ''Parasympathomimetic Drugs" by Alfred Oilman, Columbia University. Diiso-propyl rluorophosphate is thus far the only one of these to receive therapeutic trial, he stated, and has proved a highly effective agent in the symptomatic treat­ment of acute glaucoma. The results in the treatment of myasthenia gravis have proved disappointing, it was stated. Al­though a moderate, sustained increase in muscle strength can be observed, un­toward side actions on the bowel and cen­

tral nervous system prevent the adminis­tration of doses adequate to obtain maxi­mal effects. However, the actions of the b')wel provide the basis for the successful use of DFP in the management of post­operative ileus.

Richard (). Uoblin, Jr., American Cyanamid Co., in a lecture on •Chemo­therapy" expressed the idea that the finding ot chemotherapeutie agents which will control virus infections does not seem nearly so unlikely today as it did 10 years ago. Existing agents are inadequate for the treatment of numerous other infec­tions, he stated, and much remains to be done over the entire range of infectious diseases.

''The chemotherapy of noninfectious diseases presents, if anything, an even more fertile field for future exploration," said Dr. Uoblin. "It is here that we ex­pect to see the greatest progress in the next 10 years. Diseases such as hyper­tension, asthma, rheumatic fever, cancer, diabetes, and many others may eventually yield to the chemotherapeutie approach. Actually, in some instances, such as cancer and rheumatic fever, we are not certain which category, infectious or noninfectious, the disease should be cataloged. Con­sequently, I believe that more rapid progress can be made in the treatment of both infectious and noninfectious diseases if no arbitrary lines are drawn around chemotherapy, so that each field can take full advantage of the methods and prin­ciples of the other/'

C. M. Suter, Sterling-Win throp Research Institute, editor of Medicinal Chemistry Reviews; Glenn Ullyot, Smith, Kline, and French Laboratories, symposium program chairman; and Thomas Carney* Eli Lilly and Co.

M. L. Moore, Smith, Kline, and French Laboratories, a past president of the ilivisiim: Roland Feldkamp. Sterling-Winthrop Research Institute; and Leland Pence, Difco Laboratories, Inc.

V O L U M E 2 6, N O . 2 7 » » » » J U L Y 5, 1 9 4 8 1975