Active pharmaceutical related compounds

Memfield s concept of a solid phase method for peptide synthesis and his devel opment of methods for carrying it out set the stage for an entirely new way to do chem ical reactions Solid phase synthesis has been extended to include numerous other classes of compounds and has helped spawn a whole new field called combinatorial chemistry Combinatorial synthesis allows a chemist using solid phase techniques to prepare hun dreds of related compounds (called libraries) at a time It is one of the most active areas of organic synthesis especially m the pharmaceutical industry... 

Structure-activity relationships are generally applied in the pharmaceutical sciences to drug molecules. The value of any structure-activity correlation is determined by the precision of the biological data. So it is with studies of the interaction of nonionic surfactants and biomembranes. Analysis of results is complicated by the difficulty in obtaining data in which one can discern small differences in the activity of closely related compounds, due to i) biological variability in tissues and animals, ii) potential differential metabolism of the surfactants in a homologous series (2), iii) kinetic and dynamic factors such as different rates of absorption of members of the surfactant homologous series (2) and iv) the typically biphasic concentration dependency of nonionic surfactant action (3 ). 

Ho, P.C., Saville, D.J. Inhibition of human CYP3A4 activity by grapefruit flavenoids, furanocoumarins and related compounds. J. Pharm. Pharmaceut. Sci. 4, 217-227, 2001. 

Penicillin is but one of a series of closely related compounds isolated from fermentation broths of Penicillium notatum. This compound, also known as penicillin G (1-1) or benzyl penicillin, is quite unstable and quickly eliminated from the body. Initial approaches to solving these problems, as noted above, consisted of preparing salts of the compound with amines that would form tight ion pairs that in effect provided a controlled release of the active dmg. Research on fermentation conditions aimed at optimizing fermentation yields succeeded to the point where penicillin G or penicillin V (26-1), in which the phenylacetyl group is replaced by phenoxyacetyl, is now considered a commodity chemical. Another result of this research was the identification of fermentation conditions that favored the formation of the deacylated primary amine, 6-aminopenicillanic acid (2-4) or 6-APA, a compound that provided the key to semisynthetic compounds with superior pharmaceutical properties than the natural material. An elegant procedure for the removal of the amide side chain proved competitive with 6-APA from fermentation. This method, which is equally applicable to penicillin V, starts by conversion of the acid to the corresponding silyl ester (2-1). Treatment of that compound with phosphoms pentachloride in the... 

In the present context, the term safe drug on the one hand includes the properties of a pharmaceutical related to its effectiveness, efficacy, and absence of unwanted side effects. On the other hand, the desired effects for its use, such as stability and biological activity, will be likely to have undesired consequences if the molecule enters the environment. This conflict can only be resolved if either the API compounds are not allowed to enter the environment, or they can quickly disintegrate... 

More than 220 producers of CRMs throughout the world produce today 12,000 20,000 materials with dif ferent matrixes, analytes and properties [4]. However, many testing (analytical) laboratories cannot find suitable CRMs in the market and develop in-house reference materials (IHRMs) themselves. Often IHRMs are developed in a laboratory to conserve the corresponding expensive CRMs. For example, a pharmaceutical company Chemagis Ltd. produces 30 active pharmaceutical ingredients steroids, benzodiazepines, antihistamines, hipolipidaemics, blood flow reactants, etc. Only for a few of them Mo-metasone Furoate, Fluticasone Propionate and Dobutamine Hydrochloride are of fi-cial reference standards for assay supplied by US, British and European Pharmacopoeias with prices of about 180 per unit (50 200 mg). Thus, to support its customers Chemagis is forced to develop IHRMs for assay as well as for impurities and related substances of each produced compound. Therefore, certification of such IHRMs that leads to traceable values is very important. 

A more detailed discussion of the stationary phase types and mechanism of interaction and separation theory in relation to chiral compounds is given in Chapter 22. A large number of chiral stationary phases are currently available to meet the needs of the pharmaceutical industry for determination of the enantiomeric purity of active pharmaceutical ingredients, raw materials, and metabolites. As a consequence, there are a multitude of options in terms of columns, separation mode, and separation conditions to explore in achieving an enantioseparation. 

Recently, a group at Teijin Pharmaceuticals reported on two closely related compounds (14-11) (TEI-5624) and (14-12) (TEI-6344) [203]. Although these two compounds are significantly less active in vitro than the best compounds reported by the Syntex group, in vivo they showed promising activity. Measurement of their in vivo efficacy was limited to i.t., studies since after an i.v. dose both compounds were rapidly removed from the circulation (t,/2 = 5 min.) while after i.t. administration they had t 2 values of 85 and 240 min., respectively. In the hamster ALI model, both of... 

These problems are based on some of the highest volume and highest value pharmaceutical compounds at the time of writing. In most cases, the desired product is an active pharmaceutical ingredient (API), although a few of the problems relate to other compounds used in drug formulation. 

Another advantage of SS-NMR is that the observed chemical shift differences between polymorphs can be related to particular molecular sites based on known assignments (see Figure 6). Site-specific mobility can also be determined by probing the relaxation properties of the compound. This is an important application, since mobility is usually related to polymorphic interconversions and solid-state reactions.94 Solid-state reactions between active pharmaceutical ingredients and excipients can also be followed by SS-NMR. The study of polymorphic transitions can be performed by variable temperature experiments. 

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