Benzisoxazoles
A diuretic of the phenoxyacetic acid class is brocrinat 35 . Its synthesis begins with Friedel-Crafts acylation of resorcinol dimethyl ether 29 with 2-fluorobenzoyl chloride to give unsym-metrical benzophenone 30. The ortho-phenolic ether moiety is cleaved selectively in this acylation reaction. The product is converted predominantly to its E-oxime analogue 31 in the usual fashion and then acetylated Ac20 to its acetyl ester 32. This synthesis of the benzisoxazole ring concludes by NaH...
Cyclopentenopyrrolidine
Spirapril 37 is a clinically aclive antihypertensive agent closely related structurally and mechanistically to enalapril. Various syntheses are reported with the synthesis of the substituted proline portion being the key to the methods. This is prepared from l-carbobenzyloxy-4-oxopro-line methyl ester 33 by reaction with ethanedithiol and catalytic tosic acid. The product 34 is deprotected with 20 HBr to methyl 35 . Condensation of this with leads to the dipeptide ester which is deblocked to 36...
Pyrimidoindoles
The two carbonyl groups in isatin 153 show quite different reactivities since one is a ketone and the other an amide. Condensation of that compound with the Grignard reagent from o- chloro-bromobenzene thus gives 154. Conjugate addition of the anion from that product to acrylonitrile affords the proprionitrile 155. The cyano group is then reduced to the primary amine by means of LAH. Internal imine formation leads to cyclization. There is thus obtained the antidepressant agent ciclazindol 157...
CI Ogy
It has been shown that glycine amides of aminobenzophenones are readily converted to the corresponding benzodiazepines in vivo. Peptides which terminate in such a moiety should thus serve as a benzodiazepine prodrug after hydrolysis by peptidases. One of the glycine residues in lorzafone 194 is presumably removed metabolically in this manner to give a benzodiazepine precursor which spontaneously cyclizes. Acylation of benzophenone 190 with the trityl protected dipeptide 191, as its acid...
Phthalazines
Oxagrelate 104 is of interest as a platelet antiaggretory agent and is thus of potential value in preventing thrombus formation in blood vessels. It may also be of potential value in preventing arteriosclerotic lesions in coronary arteries - a substantial cause of morbidity and mortality in western countries. It is synthesized by reacting 4-ethoxycarbonyl-5-methylphthalic anhydride 101 itself derived from the Diels-Alder product of dimethylacetylenedicarboxylate and ethyl isodehydroacetate with...
Benzothiazole
Calcium channel antagonists have proven of great value as antianginal and antihypertensive agents. Most of these agents fall into one of three rather narrow structural classes. It is thus of interest to find that a structurally quite different benzothiazole shows the same type of activity. It is of note too that the agent in question, fostedil 63 , is one of the very few phosphorous containing agents to be developed for the clinic. Treatment of benzanilide 59 with phosphorous pentasul-fide or...
Mefexamide Organic Synthesis
Indomethacin, 1, 318 2, 345 3, 165 Isoproterenol, 1, 63 2, 37,107 3,20 Ketamine, 1, 57 2, 16 Ketanserin, 3, 193 Ketasone, 1, 237 Ketazocine, 2,238 Ketazolam, 1, 369 Ketobemidone, 1, 303 Ketoconazole, 3,132 Ketoprofen, 2, 64 Ketorolac, 4, 81 Ketorphanol, 4, 60 Ketotifen, 3, 239 Khellin, 1, 313, 335 Labetolol, 3, 24 4,20 Lamotrigine, 4, 120 Legotrile, 2,480 Leniquinsin, 2, 363 Lenperone, 2, 286 Letimide, 2, 393 Levalorphanol, 1,293 Levamisole, 4, 217 Levarterenol, 1, 63 Levocabastine, 4,110, 111...
Kcn
One of the more interesting syntheses for the anthelmintic agent praziquantel 123 involves an Oppolzer type electrocyclization reaction. Reduction of the nitrile in benzocyclobu- tane 117 by means of LAH gives the corresponding amine 118. This is alkylated with chloroacet- amide, and the product 119 is acylated with cyclohexylcarbonyl chloride. Reaction of the amide with formaldehyde in the presence of acetic anhydride leads to the carbinolamine acetate 121. Pyrolysis of this intermediate leads...
O 1
Enisoprost 70 is an antiulcerative cytoprotective prostaglandin. In addition to the well-known property of E series prostaglandins to inhibit gastric secretion of HC1 and pepsin, these agents enhance ulcer healing by stimulating formation of the mucin protective layer over the stomach lining. The well-known ulcer promoting action of nonsteroidal antiinflammatory agents such as aspirin can be rationalized by invoking the reversal of this effect. Thus, useful antiulcer properties can be...
Quinazolines And Quinazolinones
Doxazosin 84 is an adrenergic postsynaptic a-1 receptor antagonist with antihypertensive properties. The discerning eye will recognize a structural resemblance to the antihypertensive quinazoline prazosin, also an a-1 receptor antagonist. Doxazosin was produced in an attempt to develop agents which could be administered once daily to combat hypertension. It is synthesized by reacting 82 with 83 in an addition-elimination sequence leading to 84 23 . Trimetrexate 88 is an antineoplastic agent...
Benzoic Acid Derivatives
Pyrrolidone derivatives substituted on nitrogen with alkyl groups have shown some activity as cognition enhancing agents in the aged. It is thus of some interest that acylation on nitrogen also leads to active compounds. Thus, treatment of anisoyl chloride 128 with the anion from 2-pyrroli-dinone affords auiracetam 129 32 , Aniracetam is the product of an effort to discover agents to treat precocious senility Alzheimer's disease . Yet another nontricyclic antidepressant consists of a relatively...
Pyrazinopyridoindoles
Piperazine rings are a common structural feature in many compounds which act as antagonists at a-adrenergic receptors it is of interest that a compound which incorporates a fused piperazine acts as an antihypertensive agent by virtue of a-blocking activity. Reaction of the indole 95 with y-butyrolactone leads to acid 96. Friedel-Crafts type cyclization affords the tricyclic ketone 97. Treatment of that intermediate with bromine gives the product from a-bromination 98 . Reaction of the...
REFERENCES Sze
1. A. Stuetz and G. Petranyi, J. Med. Chem., 27, 1539 1984 . 2. K. Sestanj, F. Bellini, S. Fung, N. Abraham, A. Treasurywala, L. Humber, N. Simard-Duquesne, and D. Dvornik, J. Med. Chem., 27,255, 1984 . 3. D. L. Flynn and D. E. Nies, Tetrahedron Lett., 27, 5075 1986 . 4. G. H. Jones, M. C. Venuti, J. M. Young, D. V. Krishna Murthy, B. E. Loe, R. A. Simpson, A. H. Berks, D. A. Spires, P. J. Maloney, M. Kruseman, S. Rouhafza, K. C. Kappas, C. C. Beard, S. H. Unger, and P. S. Cheung, J. Med....
Piperazines
Yet another nonsedating zwitterionic H-1 antihistamine consists of the product from metabolism of the terminal hydroxyl of the potent antihistamine hydroxyzine terminating in hydroxymethyl instead of a carboxylic acid. This compound, cetirzine 123 , can be obtained in straightforward fashion by alkylation of the monosubstituted piperazine 120 with halide 121, via the amide 122 27 , A number of diarylmethyl alkylpiperazines, such as, for example lidoflazine, have found use as coronary...
H Eac
The discovery of the antiulcer activity of H2 antihistamine antagonists has revolutionized the treatment of that disease. A benzimidazole, Omeprazole 55 , inhibits gastric secretion and subsequent ulcer formation by a quite different mechanism. Studies at the molecular level suggest that this compound inhibits K H dependent ATPase and consequently shuts down the proton pumping action of this enzyme system. Treatment of pyridyl carbinol 51 with thionyl chloride leads to the corresponding...
Derivatives Of Aniline
The broad category of helminths includes a host of parasitic worms such as tapeworms and flukes infestations in domestic animals can have serious negative consequences on growth. Anthelmintic drugs as a result occupy an important place in the practice of veterinary medicine. Febantel 108 is representative of this class of agents. Acylation of nitroaniline 105 with methoxyacetyl chloride gives the corresponding amide 106. Reduction of the nitro group leads to the aniline 107. Reaction of that...
Organoplatinum Complexes
Whereas the medical practice of the Middle Ages contained many inorganic medicaments, modern medicine is dominated by organic drugs. There are, however, notable exceptions. Among these, a number of organoplatinum complexes have shown high potency against a variety of tumors and much work has been carried out in order to reduce their toxicity, enhance their water solubility, and sharpen their anticancer potency. The work has demonstrated that the activity resides in the cis complexes and that...
Benzofurans
Thromboxane A-2 has been implicated in a number of disorders of the circulatory system including coronary artery spasms, unstable angina pectoris, traumatic and endotoxic shock, and heart attacks. It is formed normally very near its receptors and is rapidly deactivated by metabolizing enzymes so circulating levels are quite low. Furthermore, it is opposed in its actions by the prostacyclins. When these controls are defective, pathology results and drugs can be the resort in attempts to restore...
REFERENCES Nyk
7. S. Yoshizaki, K. Tanimura, S. Tamada, Y. Yabuuchi, and K. Nakagawa, J. Med. Chem., 19,1138 1976 . 8. H. Koga, A. Itoh, S. Murayama, S. Suzue, and T. Irikura, J. Med. Chem., 23,1358 1980 . 9. H. Egawa, T. Miyamoto, and J.-I. Matsumoto, Chem. Pharm. Bull., 34,4098 1986 . 10. I. Hayakowa, T. Hiramitsu, and Y. Tanaka, Chem. Pharm. Bull., 32,4907 1984 . 11. L. A. Mitscher, P. N. Sharma, L. L. Shen, and D. T. W. Chu, J. Med. Chem., 31,2283 1988 . 12. D. T. W. Chu, P. B. Fernandes, A. K. Claiborne,...
Alicyclic Compounds
An interesting appetite suppressant very distantly related to hexahydroamphetamines is somanta-dine 24 . The reported synthesis starts with conversion of 1-adamantanecarboxylic acid 20 via the usual steps to the ester, reduction to the alcohol, transformation to the bromide 21 , conversion of the latter to a Grignard reagent with magnesium metal, and transformation to tertiary alcohol 22 by reaction with acetone. Displacement to the forniamide 23 and hydrolysis to the tertiary amine 24...
Ii I I Ii
The classical antipsychotic agents, such as the phenothiazines and butyrophenones, owe much of their efficacy to their dopamine antagonist activity. A number of these agents find some utility as antiemetic compounds since emesis is also at least partly mediated by dopaminergic nerves. A dopamine antagonist from a quite different structural class seems to show some selectivity for those GI functions which involve dopamine receptors. The prototype, metoclopramide 140 , has been found useful as an...
CN Rcb
Treatment of the piperidine 74, obtainable from an aminonitrile such as 73, under N-methylation conditions leads to the dimethylamino derivative 75. The carbobenzoxy protecting group is then removed by catalytic hydrog nation. Reaction of the resulting secondary amine 76 with cyclohexene oxide leads to the alkylated trans aminoalcohol. There is thus obtained the antiarrhythmic agent transcainide 77 18 .
O Bbb
Sertraline 17 is a tetralin analogue possessing nonsedative antidepressant activity. At subtherapeutic doses it potentiates the action of a subthreshhold dose of morphine in the classic tail flick model for analgesia. This effect is apparently mediated through serotonin and adrenergic neurones and apparently therefore satisfies the stated goals of the program by possessing antidepressant activity by a different pharmacological mechanism than the classical agents which appear to inhibit...
Condensation Of Ethyl Acetoacetate With Cho
Random incorporation of two different acetoacetates can also be avoided by converting one of the acetoacetates to a derivative which carries the future pyridine nitrogen. For example, treatment of ethyl acetoacetate with ammonia gives the corresponding p-aminocrotonate 32. The aldehyde 34 required for preparation of such an unsymmetrical compound is prepared by reaction of the product from direct metallation of 33 with dimethylformamide. Condensation of that aldehyde with methyl acetoacetate...