Ind. Eng. Chern. Prod. Res. Dev. 1980, 19, 172-174
172
AIME Fall Meeting, Chicago, IL, Oct 20, 1977. (To be published in an AIME Proceedings volume). Mayer, J. W., Rimini. E., Ed., "Ion Beam Handbook for Materials Analysis", Academic Press, New York, NY, 1977. Mitchell, C., Hurley, G. F., Materials and Approaches for Improved Stress Corrosion Inhibitive Coatings", AFML-TR-72-192, Air Force Materials Laboratory, Wright-Patterson AFB, OH, Oct 1974. Pourbaix, M., "Theory of Stress Corrosion Cracking of Alloys". pp 17, J. C. Scully, Ed., NATO, Brussels, 1971. Promisel, N. E., Schultze, W. A., Staehie, R. W., Hammersley, E. J., Sippel, A. O., Serlour, G., Brunin, M., Bezaud, C., AGARD-LS-84, "The Theory, Significance, and Prevention of Corrosion in Aircraft" (Available from NASA, Langley Field, VA 23365 1976). Richard, 0. E., Snelling, H. J., "Weather Data and Its Use in Corrosion Studies", in "Proceedings of the 1974 Tri Service Corrosion Conference", AFMLTR-75-42, Vol. 11, pp 325-327, Air Force Materials Laboratory, WrightPatterson AFB, OH, Sept 1975. Ruggeri, R. T., Beck, T. R., "A Model for Mass Transport in Paint Films", The Electrochemical Society, Seattle, WA, May 22, 1978. Sandoz, G . , Fujii, C. T., Brown, R. F., Corrosion, 10, 839 (1970). Singhal, S.,Herman, H.. Hirvonen, J. K., Appl. Phys. Left., 32, 25 (1978). Smith, J. A., Peterson, M. H., Brown, B. F., Corrosion, 26, 539 (1970). Sprowls, D. O., Ed., "A Proposed Standard SCC Test for High Strength 7000 Series Aluminum Alloy Products", ASTM Symposium on New Approaches
to Stress Corrosion, Montreal, Canada, June 23-25, 1975. Staehle, R. W., Ed., "Metallic Corrosion in the USSR", Fontana Corrosion Center, Ohio State University, Columbus, OH, 1976. Summitt, R., "Corrosion Tracking and Prediction for C-141A Aircraft Maintenance Scheduling", AFML-TR-78-29, Air Force Materials Laboratory, Wright-Patterson AFB, OH, Apr 1978. Vahldiek, F. W., Lynch, C. T., Thornton, F.. "Effects of Temperature and Humidity on Corrosion Fatigue Behavior of 4340 Steel", Symposium on Corrosion Prevention and Control in Military Appilcations, AIME, Denver, CO, Mar 2, 1978. Verink, E. D., Jr., Ed., "AFOSR/AFML Workshop on Corrosion of Aircraft", University of Florida Report, Gainesville, FL, Sept 1978. Verink, E. D., Jr., Das, K. B., "Research on Inhibition for Corrosion Fatigue of High Strength Alloys", AFML-TR-78-178, Air Force Materials Laboratory, Wright-Patterson AFB, OH, Dec 1978.
Receiued f o r reuiew December 26, 1979 Accepted January 10, 1980
Paper presented on June 4,1979 at National Symposium on Wear and Corrosion, Carnegie Institution, Washington, D.C. Republished by Permission of Symposium Chairman, R. Shane.
REVIEW SECTION Benzomorphans-Clinically Used Synthetic Analogues of Morphine. A Short Review for Nonpharmacologists David C. Palmer' Department of Chemistry, Princeton University, Princeton, New Jersey 08544
Michael J. Strauss Department of Chemistry, University of Vermont, Burlington, Vermont 05405
The search for the ideal nonaddicting analgesic continues, for such a substance still does not exist. The syntheses and mechanism of action of some classical analgesics will be discussed.
The universal problems of physical pain and mental anguish, the effectiveness of morphine and its synthetic analogues in relieving these experiences, and the resulting difficulties of opiate dependence and addiction have been the subject of extensive study by chemists and pharmacologists for decades. Recent studies on the opiate receptor in the brain and other nervous tissue, as well as the discovery and synthesis of the naturally occurring opiate peptides, endorphins and enkephalins, have served to intensify these efforts. The search for the ideal nonaddicting analgesic continues, for such a substance still does not exist. None of the active peptide opiates, synthetic or natural, have been reported to be nonaddicting. Mechanisms of action of both the endogenous opiates and the classical analgesics (i.e., morphine and its synthetic analogues) are becoming clarified, however. 0196-4321/80/ 12 19-01 72$01 .OO/O
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HO
morphine For hundreds of years opium was the most effective remedy for pain. As long ago as 1680 Sydenham wrote "Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium." Morphine is responsible for the analgesic actions of opium and it is still the narcotic analgesic of primary clinical importance a t the present time. Almost of equal importance are the simpler synthetic morphine analogues, however. Of the latter, perhaps the most prominent are the benzomorphans. Of primary importance in the development of benzomorphans (2,6methano-3-benzazocines) and other simpler synthetic analgesics was the observation that only a portion of the morphine structure is necessary for very potent analgesic activity. This fact may now seem obvious when the 0 1980
American Chemical Society
eo &bo mcH
Ind. Eng. Chem. Prod. Res. Dev., Vol. 19, No. 2, 1980
173
Scheme I
I. C I / V N ( C H 3 1 2
UoNHZ 2 ,,rHOAc
2. HBr/HOAc 3 :?40H NH40H 3.
ad
morphine
benzomorphans ( 2,6-methano-3-benzazocines)
structures of the endogenous opiates are considered since these peptides appear superficially not at all like morphine. A careful analysis does show certain peptide conformations which place specific peptide functionality in the same spatial configuration as similar functionality in morphine, however, and it is now quite clear that both occupy the same receptor site in effecting their physiological actions. It is thus not surprising that compounds like the benzomorphans are also quite active. The sequence of events in development of the synthetic narcotic analgesics started with morphine as the prototype. As noted previously, morphine is still a preferred drug for pain relief, primarily because of confidence gained from many years of use. Of the synthetic narcotic analgesics patterned after morphine, 6,7-benzomorphans are one of the most extensively investigated analogues. These were first prepared and studied in detail by May and Eddy a t the National Institutes of Health. A number of novel synthetic routes to benzomorphans have been developed, and chemical modifications have provided valuable new narcotic analgesics and narcotic antagonists of practical and theoretical importance. The eventual development of effective, strong analgesics which antagonize the dependence producing effects of morphine may be a reasonable goal. Some useful analgesics which approach this ideal may well be benzomorphan derivatives. Pentazocine and phenazocine are two effective analgesic benzomorphans which have had extensive clinical use. One other, cyclazocine, is a strong analgesic-antagonist with
CH3
3 I. dry distill 2 . HCI 3. 9 5 % NH2NH2/KOH
-
2
3
Scheme I1
CH,
6 r
-
-
N
7
/""
@:'-"
jH
- @ - $ 3.H30+
CH3
Ho
CH3 HO
8
9
Scheme I11 R
/
cyclazocine
pentazocine 2 LiLIH4
R = CH,CH,Ph
9
hd phenazocine
investigational statue. The pharmacological properties of the morphine-like opiates can vary from pure agonist to mixed agonist-antagonist to pure antagonist, depending on the nature of the nitrogen substituent. Phenazocine (Prinadolj is a classical narcotic analgesic although it is not commonly used anymore because it appears to be no more effective than morphine. Like the latter, it is highly addicting, produces a physical dependence, and thus has a high abuse liability. Pentazocine, a weak narcotic antagonist, is a more promising alternative to morphine. It has similar analgesic properties and does produce respir-
atory depression but may have a lower abuse potential. The first synthesis of the benzomorphan ring system was reported by Barltrop (19471, but it was nearly 10 years before May and his associates adapted this work to prepare 3,6-dimethylbenzomorphan(3) as shown in Scheme I (May and Murphy, 1955). Alkylation of 1-methyl-2-tetralone with 0-dimethylaminoethyl chloride followed by formation of the amine hydrobromide, bromination, and subsequent base catalyzed cyclization produced the methobromide 2
174
Ind. Eng. Chem. Prod. Res. Dev., Vol. 19, No. 2, 1980
Scheme IV
"'
I. PhCHO
/
Hd
CH30
10 C4wH3
I.
K$o,
CICO(CH2)3CO$H3
CH30
I
..
Fll
11
CPh COzCH3
12
f
f
ph 48% HBr
CHjO
14
rPh
I. Na(CH30CH2CH20)2AIH2
@P
2. H,/Pd
--CH3
Hc
0
- 9
C"3
15
which was pyrolytically demethylated, converted to the amine hydrochloride, and subjected to Wolff-Kishner reduction (Huang-Minlon modification) to afford 3. Unfortunately, all attempts to extend this route to prepare the 3,6,lla-trimethyl analogues 4 and 5 were unsuccessful
4, X = H 5, X = O H
(May, 1957). As a result of these failures a new approach was devised which has since proven to be the most general and widely applicable method for the synthesis of benzomorphans. Analogous to Grewe's morphinan synthesis (Grewe and Mondon, 1948; Grewe et al., 19491, this method involved acid-catalyzed cyclization of an appropriately substituted tetrahydropyridine. The preparation of 9 (Fry and May, 1959), a key intermediate in the synthesis of phenazocine, cyclazocine, and pentazocine, is described in Scheme 11. Reaction of lutidine methiodide with p methoxybenzylmagnesium chloride followed by catalytic reduction gave the 1,2,5,6-tetrahydropyridine7 which, upon treatment with 48% HBr underwent ring closure with concomitant 0-demethylation to yield 8 (May and Fry, 1957). Acetylation, von Braun demethylation, and hydrolysis then yielded 6,lla-dimethyl-8-hydroxynorbenzomorphan, 9. As shown, acylation of 9 with phenylacetyl chloride followed by LAH reduction afforded phenazocine (May and Eddy, 19591, whereas the analogous sequence using cyclopropanecarbonyl chloride produced cyclazocine (Archer et al. 1964). Archer's group prepared pentazocine by alkylation of 9 with 3-methyl-2-butenyl bromide (Archer et al., 1964). (See Scheme 111.) Recently, Kametani's group has reported a synthesis of pentazocine from tyrosine via a Grewe cyclization (Kametani et al., 1974,1975). Thus, in Scheme IV, L-tyrosine was converted to methyl-p-methoxy-L-phenylalanate(10) which was reductively alkylated to the N-benzyl ester (11). Acylation of 11 with methyl-3-chloroformyl propionate/ K2C03followed by Dieckmann cyclization produced the lactam (12). This was methylated and subjected to acid catalyzed hydrolysis/decarboxylation to yield the ketolactam (13). Treatment of 13 with methylmagnesium iodide affored the piperidinol (14) which, upon treatment with 48% HBr, suffered dehydration and ring closure with concomitant 0-demethylation to give 15. Amide reduction with sodium bis(2-methoxyethoxy)aluminum hydride followed by hydrogenolysis then gave 9. Conversion of 9 to pentazocine was accomplished as described (vide supra). Although much effort has been expended to devise other routes to benzomorphans, none of these approaches can compare favorably with the Grewe cyclization for overall simplicity and versatility (Palmer and Strauss, 1977).
Literature Cited Archer, S., Albertson, N. F., Harris, L. S., Pierson, A. K., Bird, J. G., J . Med. Chem., 7, 123 (1964). Barltrop, J. A,, J . Chem. Soc.. 399 (1947). Fry, E. M.. May, E. L.. J . Org. Chem., 24. 116 (1959). Grewe, R., Mondon, A,, Chem. Ber.. 81, 279 (1948). Grewe, R., Mondon, A,, None, E., Justus Liebgs, Ann. Chem., 564, 161 (1949). Kametani, T., Huang, S.-P., Ihara, M., Fukumoto, K., Chem. Pharm. Bull., 23, 2010 (1975). Kametani, T., Kigasawa, K., Hiiragi. M., Wagatsuma, N., Heterocycles, 2, 79 (1974) (for a review of the synthetic approaches to pentazocine). May, E. L., Murphy, J. G., J . Org. Chem., 20, 257 (1955). May, E. L., J . Org, Chem. 22, 593 (1957). May, E. L., Fry, E. M., J , Org. Chem., 22, 1366 (1957). May, E. L., Eddy, N. B., J , Org. Chem., 24, 294 (1959). Palmer, D. C., Strauss, M. J., Chem. Rev., 77, 1 (1977) (for a review of all methods used to prepare benzomorphans).
Received f o r review October 21, 1979 Accepted December 31, 1979
