Group medicinal chemistry

In the area of medicinal chemistry, Haemers and coworkers synthesized a series of 4 -hydroxy-3-methoxyflavones that exhibited antiviral activity against poliomyelitis and rhinoviruses. A representative number of compounds is shown below. First, O-hydroxyacetophenones 61 were converted to the corresponding flavones 64 using standard conditions in yields of 74-92%. Cleavage of the benzyloxy groups of 64 was then achieved under acidic conditions to deliver the requisite flavones 65. 

The aromatic portion of the molecules discussed in this chapter is frequently, if not always, an essential contributor to the intensity of their pharmacological action. It is, however, usually the aliphatic portion that determines the nature of that action. Thus it is a common observation in the practice Ilf medicinal chemistry that optimization of potency in these drug classes requires careful attention to the correct spatial orientation of the functional groups, their overall electronic densities, and the contribution that they make to the molecule s solubility in biological fluids. These factors are most conveniently adjusted by altering the substituents on the aromatic ring. 

The concept of isosterism 481 has been used in medicinal chemistry. Molecules or groups which possess physicochemical similarity (e.g., similarity in size or the number of valence electrons) are called isosteres. The classical isosteres include, for instance, the following two pairs of groups ... 

Aminoalcohols are an important class of compounds in medicinal chemistry because many drugs contain this structure. For their resolution, there are two possibilities acylation of amino function or an enzymatic transesterification with vinyl esters through the hydroxyl group. However, the amino or hydroxyl group must be protected, because if the starting material is the free aminoalcohol, the O- and N-acylation can take place, and in addition, there are migrations obtaining... 

Preparation of optically active P-aminoesters, P-aminonitriles, and P-aminocarbox-amides are of special relevance for the synthesis of enantiomerically pure P-aminoacids compounds of special relevance in several areas of medicinal chemistry. The resolution of P-aminoesters can be carried out by acylation of the amino groups or by other biocatalytic reactions of the ester groups, such as hydrolysis, transesterification, or aminolysis. The resolution of ethyl ( )-3-aminobutyrate... 

Searching journal information continues to be the primary use of SciFinder for the medicinal chemist. One finds it especially useful for searching various topics, for instance, anti-inflammatory treatments. When performing structure/reaction-based searches, many chemists also use Beilstein CrossFire in conjunction with SciFinder. The reaction information from these systems is often complementary, and it is quite useful to have both SciFinder and CrossFire in a medicinal chemistry group. However, companies with restricted budget may have to choose one or the other. 

Lipophilicity is the measure of the partitioning of a compound between a lipidic and an aqueous phase [1]. The terms lipophilicity and hydrophobicity are often used inconsistently in the literature. Lipophilicity encodes most of the intramolecular forces that can take place between a solute and a solvent. Hydrophobicity is a consequence of attractive forces between nonpolar groups and thereby is a component of lipophilicity [2]. Lipophilicity is one of the most informative physicochemical properties in medicinal chemistry and since long successfully used in quantitative structure-activity relationship (QSAR) studies. Its... 

My first personal contact to Henk Timmerman happened on the wonderful island of Capri during a symposium on pharmaceutical sciences. Henk Timmerman headed one of the largest and most important departments of Medicinal Chemistry in European academia. It was very impressive to face his views on our research field, and his integrated and straightforward way to guide research projects. For several years I collaborated with his group and, as an added bonus, became a great fan of Amsterdam. 

The group at Johnson and Johnson has published several reports on their efforts to find potent H3 antagonists. High-throughput screening using the recombinant human receptor identified the imidazopyridine RWJ-20085 (30) as a weak H3 receptor ligand K — 4 pM). Medicinal chemistry efforts then led to the discovery of the piperidine propyloxy compound (31) [100]. This imidazopyridine has a A) at the human H3 receptor of 2nM and... 

At the beginning of the project, we had studied the introduction of the pMB group to 4 as a nitrogen protecting group, as used in the Medicinal Chemistry route. There was a classical regioselectivity problem, O- versus N-alkylation. Under the Medicinal Chemistry conditions, the desired N-alkylated product 5 was mainly formed, but around 10-12% of the corresponding O-alkylated product 16 was also... 

Obviously, there are two ways to prepare Efavirenz from the pMB protected chiral amino alcohol 50 (i) creation of the benzoxazinone first then removal of the pMB group or (ii) removal of the pMB first then formation of benzoxazinone. Preparation of the benzoxazinone was demonstrated by Medicinal Chemistry from the amino-alcohol with CDI. 

Perhaps the advantage of the medicinal chemistry route lies in the flexibility of introducing different alkyl groups on the primary amine through reductive amination on 2-aminoethyl indole 10 and hence allows access to various N, N-dialkyl tryptamine derivatives for structure-activity relationship (SAR) studies. 

In our retro-synthetic analysis, we envisioned the pyrrolidinylethanol side chain could be installed via the Ullmann ether formation or the analogous reachons from the aryl-iodide functional group. The key intermediate 9 (cis) in the Medicinal Chemistry route was not stable under strongly acidic or basic conditions since it was easily isomerized to the thermodynamically more stable trans-isomer 9a via... 

As seen in the retro-synthetic Scheme 5.3, intermediate 15 is useful for both routes. The choice of benzyl protection group was made based on the robust stability of benzyl phenol ethers toward most reactions and several possible avenues to remove it, although it was reported from Medicinal Chemistry that benzyl group removal via hydrogenolysis posed challenges in this compound. The choice of iodide substitution was born out of the known high reactivity of iodides in the Ullmann-type coupling reaction with alcohols and the robust stability of aryl iodides in many other common reactions. 

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