Medicinal Agents

Since the discovery of the antibacterial activity of sulfonamides in 1935, some 15 000 derivatives of sulfanilamide (1 R = = H) have been synthezised (see 

R = COMe) with chlorosulfonic acid (five equivalents) at 60 °C (2 hours) to give A -acetylsulfanilyl ehloride (3 R = COMe). Treatment with ammonia and selective hydrolysis of the resultant acetylsulfanilamide afforded the product 4, (R = H). The chlorosulfonation of acetanilide is of eonsiderable industrial importance in the manufacture of sulfa drugs, consequently various modifications have been investigated to improve the yield of N -acetylsulfanilyl chloride (see Chapter 4, p 102). 

Sulfanilamide and other sulfa drugs owe their antibacterial properties to then-ability to mimic / -aminobenzoic acid (PABA) which is an essential metabolite for many baeteria (Chapter 6, ref. 33) since it is an intermediate in the biosynthesis of folic acid. Many strains of bacteria have now become resistant to the antibacterial action of sulfonamides and consequently their use has declined and they have been often superseded by antibioties in the treatment of many infectious diseases. However, sulfonamides are still important antimicrobial agents some of the most useful chemicals contain a heterocyclic nucleus, for instance sulfadiazine 5, sulfamethoxazole 6 and sulfaisoxazole 7.  

The antibacterial sulfone, dapson 8 is effective in the treatment of leprosy and malaria. It acts by a similar biochemical mechanism to the other sulfa drugs and 

A -chloro- and A/ iV-dichlorosulfonamides are widely used as antiseptics they are prepared by chlorination of the appropriate sulfonamide. For instance, 

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Marazano and co-workers have used the Zincke reaction extensively to prepare chiral templates for elaboration to substituted piperidine and tetrahydropyridine natural products and medicinal agents. For example, 3-picoline was converted to Zincke salt 40 by reaction with 2,4-dinitrochlorobenzene in refluxing acetone, and treatment with R- -)-phenylglycinol in refluxing n-butanol generated the chiral pyridinium 77. Reduction to... 

For the past few years, however, there has been a hiatus in the pace of discovery of novel medicinal agents. It has been postulated by some that the field has now slowed down due to the limitations of the almost strictly empirical approach that has been applied to date to drug development. It is possible, too, that the higher standards of efficacy and safety that a new drug must meet today, combined with the enormously increased costs of clinical trials, have acted to keep all but the most promising new drugs off the market. 

At the other end of the continuum there exist drugs that act by some as yet undefined general mechanisms. Much work is currently devoted to study of the fine physiochemical structure of medicinal agents in this class. Considerable progress has... 

As the preceding section correctly suggests, aromatic rings a-hound in compounds that show biologic activity. The reasons for this are many the role of the pi electrons in some form of charge transfer complex ranks among the more Important. There ire few monocyclic alicyclic compounds known that are used as medicinal agents. 

In the discussion of benzylamines, we have met medicinal agents that owe their activity to some particular functionality almost without reference to the structure of the rest of the molecule. The hydrazine group is one such function in that it frequently confers monamine oxidase-inhibiting activity to molecules containing that group. Such agents frequently find use as antidepressants. Thus, reduction of the hydrazone of phenyl-acetaldehyde (84) affords the antidepressant phenelzine (85). Similar treatment of the derivative of phenylacetone (86) gives pheniprazine (87). ... 

Although the morpholine ring is often used as a modified version of a tertiary nitrogen, the ring system finds only rare use as a nucleus for medicinal agents. Both compounds below, in fact, may be regarded as more properly related to cyclized forms of hydroxy-phenethylamines. 

Further chemical modification of the phenylpiperidine moiety has proven unusually fruitful in producing medicinal agents that affect the central nervous system. First, a series of compounds loosely related to the reversed meperidines produced several drugs with important antipsychotic activity. Further discussion of this pharmacologic activity, often referred to as major tranquilizer activity, will be found in the section on phenothiazines. The group led by Janssen took advantage of the chemistry of the... 

A miscellany of medicinal agents are based on heterocyclic systems that contain two hetero atoms. Unlike their counterparts unfused to an aromatic ring, these drugs do not show any unifying biologic activity. It is therefore likely that in most cases the... 

This class of medicinal agents was uncovered quite adventitiously in a chemical study, although due credit must be given for the acute pharmacologic studies that uncovered this novel type of activity. 

Fusion of an additional heterocyclic ring onto that already present in the benzodiazepines has led to some medicinal agents with considerable activity. Treatment of an intermediate like 15 with phosphorus pentasulfide affords the corresponding thio-amide (37). Condensation of this intermediate with acetyl hydra-zide affords triazolam )37). The same agent can be prepared by reaction of the amidine, 38, ° with acetylhydrazide. ... 

It would not be too far fetched to state that life on this planet is totally dependent on two compounds based on the purine nucleus. Two of the bases crucial to the function of DNA and flNA—guanine and adenine—are in fact substituted purines. It is thus paradoxical that the lead for the development of medicinal agents based on this nucleus actually came from observations of the biologic activity of plant alkaloids containing that heterocyclic system, rather than from basic biochemistry. 

Rational drug design is the ultimate goal of medicinal chemistry. By this is understood the design of medicinal agents on the basis of knowledge of the intimate biochemistry of the disease process. 

Trans-2-chloro-9-(aj-dimethylamino-propylidene)-thioxanthene [MP 98°C, MP of the hydrochloride 225°C (corr.)], is a valuable medicinal agent, being used as a tranquilizer and antiemetic agent, whereas the corresponding cis isomer (MP 44°C, MP of the hydrochloride 209°C) is not useful for these indications, as described in U.S. Patent 3,115,502, which describes procedures for conversion of the cis to the trans form. 

Each volume will be thematic, dealing with a specific and related subject that will cover fundamental, basic aspects including synthesis, isolation, purification, physical and chemical properties, stability and reactivity, reactions involving mechanisms, intra- and intermolecular transformations, intra- and intermolecular rearrangements, applications as medicinal agents, biological and biomedical studies, pharmacological aspects, applications in material science, and industrial and structural applications. 

The 1,2,4-triazole moiety was featured in the structures of several medicinal agents whose synthesis was reported during the year. Notable among these reports was the preparation of the... 

TALALAY p (2001) The importance of using scientific principles in the development of medicinal agents from plants , Acad Med, 76 238—47. 

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