Clinical materials, synthesis

Analytical methods continue to be improved while changes in the synthesis or quality of the drug substance are evaluated. The preferred methods of analysis are identified. The analytical methods are qualified using selected validation criteria and data are compiled for establishing IND specifications for clinical materials. 

J. Nieuwenhuis, Synthesis of Polylactides, Polyglycolides and Their Copolymers. Clinical Materials, Vol. 10, p. 59-67,1992. 

Process development history—K brief discussion of the development of the synthetic process may be expected in the marketing applications. This section allows the company to establish the bridge from the synthesis used to manufacture early development safety samples, clinical materials, pivotal clinical/stability batches, and API for commercial product. This bridge is particularly valuable for reviewers in the more sophisticated markets who may not have previously reviewed the processes contained in the investigational applications. Again, the level of detail provided for this section will vary considerably. 

Many notable examples of the synthesis of complex natural products from optically pure starting materials have been reported (70). One synthesis of considerable interest is that of taxol [33069-62-4] (74), a potent antitumor agent used clinically. The starting material (73) used ia the first total synthesis of taxol is produced ia enantiomericaHy pure form from inexpensive and readily available /-camphor [464-48-2] (72) (73). 

MK-677, an orally active spiroindoline-based growth hormone secretagogue (GHS) agonist, discovered by Merck and currently in Phase II clinical studies, was synthesized with a Fischer indolization as a key step. The synthesis of this agonist involved a Fischer indole/reduction process and was achieved in 48% overall yield from the relatively cheap starting material, isonipecotic acid 72. ... 

Although morphine has been prepared by total synthesis, the complexity of the molecule makes such an approach unattractive on a commercial scale. The drug in fact is obtained by fractionation of opium obtained from the poppy morphine in turn is used as starting material for various derivatives. If it were not for the importance of these drugs in the clinic, some progress might have been made in eradication of the plant. 

There are circumstances in which it is not possible to obtain the required enantiomer at manufacturing scale either by synthesis or isolation, e.g. because of difficulties with scale-up or failure to obtain material in a suitable physical form for pharmaceutical manufacture. In such cases, all the experimental results available should be described and the reason for the failure given. Likewise, if enantiomeric material could not be obtained for preclinical and clinical studies (see below), this should also be discussed. Advances in preparative techniques should eventually make this scenario less common. 

The synthesis of (+)-discodermolide shown in Scheme 13.74 was developed in the laboratories of the Novartis Pharmaceutical Company and was designed to provide sufficient material for initial clinical trials. The synthesis is largely based on the one... 

If an interesting activity is described, larger quantities (10-100 kg) of the plant material are collected, from which chemists purify and characterize the active principle. The active principle is known as a lead compound . Chemists will then usually attempt to modify the lead compound in order to render it more therapeutically useful (e.g. make it more potent, or perhaps increase its hydrophobicity so that it can pass through biological membranes). This is then subjected to further pre-clinical trials, and chemists determine whether an economically feasible method, allowing the drug s chemical synthesis, can be developed. 

To provide additional material for clinical trials, and to eliminate the use of hazardous reagents such as ICN, PhSeCl, and SeCh, an improved synthesis of 23 was devised [Fig. (9)]. 

Of these the last one has been most widely used, since heparin-modified polymeric materials exhibit the highest and by today unsurpassed effects of thromboresistance enhancement. Many of these materials have not only proved to be potent in trials on animals, but have already found clinical application. These achievements have stimulated continuous interest in heparin-containing polymers (HCP) which is best manifested by listing the investigations performed in the field in recent years and still under way. They involve the new procedures for the synthesis of HCP providing minimal loss of activity of bound heparin, the studies of interactions of HCP with blood and its individual components, as well as on the mechanism of enhanced thromboresistance of HCP, and the search for new tasks for HCP. 

Employing a stainless-steel continuous flow reactor, Zhang et al. (2004) described the synthesis of gram to kilogram quantities of material for use in early clinical studies. One reaction reported by the authors was the exothermic synthesis of N-methoxycarbonyl-L-ferf-leucine 210, as illustrated in Scheme 61. By continuously adding a solution of methyl chlor-oformate 211 to i-tod-leucine 212, in the presence of aq. NaOH 26, at a reactor temperature of —40°C afforded the target compound 210 in 91% yield with a throughput of 83.0 gh... 

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