Adamantane derivatives

Alcaraz etal, US Patent 6,492,355 (December 10, 2002) Assignee AstraZeneca AB Utility Treatment of Cardiovascular Disorders 

To 3-chloro-2-nitrobenzoic acid (2.68 g) suspended in 10 ml CH2CI2 was added 3 ml oxalyl chloride and 1 drop DMF. The mixture was stirred 1 hour at 0°C, concentrated, the 

3-(4- l,l-Dimethylethyl oxocarbonyl)-piperazin-l-yl-2-nitro-N-(tricycle[3.3.1.1 ] dec-1 -ylmethyl-benzamide 

The product from Step 1 (2.80 g) and piperazine-1-carboxylic acid, t-butyl ester were added to 10 ml DMSO, heated to 120 °C 2 hours, cooled, diluted with water, and extracted with EtOAc. The material was purified using chromatography on silica gel with iso-hexane/EtOAc, 2 1, and the product isolated. H-NMR data supplied. 

2-Nitro-piperazin-1 -yl-N- (tricycle [3.3.1. ] dec-1 -ylmetbyl-benzamide bydrogen chloride 

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Unusual Si/P compounds are also beginning to appear, for example, the tetrasilahexaphospha-adamantane derivative [(Pr Si)4(PH)6] (1), which is made by reacting Pc SiCl3 with Li[Al(PH2)4]- Again, reaction of white phosphorus, P4, with tetramesityldisilene, Mes2Si=SiMes2, in toluene... 

The preparation of adamantane from readily available starting materials (Chapter 13, Section I) has opened the door to a study of its many substitution products, both from a chemical and a biological point of view (/). Adamantylamine hydrochloride for example, has been found to exhibit antiviral activity. Presented below are several procedures for the preparation of adamantane derivatives. 

In pharmacology, two adamantane derivatives. Amantadine (1-adamanta-neamine hydrochloride) and Rimantadine (a-methyl-1-adamantane methyla-mine hydrochloride) (see Fig. 24), have been well known because of their antiviral activity [129]. The main application of these drugs is prophylaxis (treatment to prevent the onset of a particular disease) and treatment of influenza-A viral infections. They are also used in the treatment of parkinsonism and inhibition of hepatitis-C virus. Memantine (1-amino-3,5-dimethyladaman-tane) (see Fig. 24) has been reported effective in slowing the progression of Alzheimer s disease [130]. 

Rimantadine in young adults), utilization of adamantane derivative carriers can probably prolong drug presence time in blood circulation. 

Extensive investigations have been performed related to the synthesis of new adamantane derivatives with better therapeutic actions and less adverse effects. For example, it has been proved that adamantylamino-pyrimidines and -pyridines are strong stimulants of mmor necrosis factor-a (TNF-a) [132]. TNF is a substance that can improve the body s namral response to cancer by killing cancer cells. Another example is 1,6-diaminodiamantane [87], which possesses an antitumor and antibacterial activity. Also, many derivatives of aminoadamantanes have antiviral activity like 3-(2-adamantyl) pyrolidines with two pharmacophoric amine groups, which have antiviral activity against influenza-A virus [133]. 

Some derivatives of adamantane with antagonist or agonist effects have also been synthesized. For instance, monocationic and dicationic adamantane derivatives block the a-amino-3-hydroxy-5-methylisoxazole -propionic acid (AMPA) receptors, A-methyl-o-aspartate (NMDA) receptors [134—136] and 5-hydroxytryptamine (5-HT3) receptors [137]. 

The monocationic and dicationic adamantane derivatives have been used to investigate the topography of the channel binding sites of AMPA and NMDA receptors [135]. 

Adamantane derivatives can be employed as carriers for drug delivery and targeting systems. Due to their high lipophUicity, attachment of such groups to drugs with low hydrophobicity could lead to a substantial increase of drug solubihty in lipidic membranes and thus increases of its uptake. 

Some other types of macrocycle compounds have been synthesized using adamantane and its derivatives. Recently, a new class of cyclobisamides has been synthesized using adamantane derivatives, which shows the general profiles of amino acid (serine or cystine)-ether composites. They were shown to be efficient ion transporters (especially for Na+ ions) in the model membranes [159]. Another interesting family of compounds to which adamantane derivatives have been introduced in order to obtain cyclic frameworks is crown ethers [160]. The outstanding feature of these adamantane-bearing crown ethers (which are also called diamond crowns ) is that ot-amino acids can be incorporated into the adamantano-crown backbone [160]. This family of... 

Figure 30 Lateral stereo views of adamantane derivative thiacalix[4]arene top) presented in Fig. 29. A CHCI3 molecule has been entrapped inside the inclusion compound. The bottom view left bottom) and top view right bottom) are also shown. H atoms have been removed from the inclusion compound for more clarity [128].

Furthermore, some adamantane derivatives possess special affinity to bind to DNA, thereby stabilizing it. This is an essential feature for a gene vector. Some polymers have been synthesized using adamantane derivatives, the application of which is under investigation for dmg delivery. 

Of course carbene C-H insertion reactions are well known absolute kinetics have been reported for the insertions of ArCCl into isooctane, cyclohexane, and n-hexane,67 and of PhCCl into Si-H, Sn-H, and C-H bonds.68 More recently, detailed studies have appeared of PhCCl insertions into a variety of substrates bearing tertiary C-H bonds, especially adamantane derivatives.69 Nevertheless, because QMT is considered important in the low temperature solution reactions of MeCCl,60,63 and is almost certainly involved in the cryogenic matrix reactions of benzylchlorocarbene,59 its possible intervention in the low temperature solution reactions of the latter is a real possibility. We are therefore faced with two alternative explanations for the Arrhenius curvature exhibited by benzylchlorocarbene in solution at temperatures < 0°C either other classical reactions (besides 1,2-H shift) become competitive (e.g., solvent insertion, azine formation), or QMT becomes significant.7,59,66... 

It is interesting to mention the cyclizations of allene systems which are accompanied by rearrangements. Protonation of the bis-cumulene 74 by 5% H2SO4 in aqueous acetone produces the adamantane derivative 75 in 95% yield (equation 28)43. 

Cleavage of carbon-carbon bonds is illustrated by the electrochemical oxidation of some adamantane derivatives. In this series of substrates 6, there is competition... 

Chemical Class Adamantane derivative tricyclic amine... 

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