Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1994-06-24
1996-12-03
Gupta, Yogendra N.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514629, 564154, 564215, 564224, 568 22, A61K 3116, C07C23301
Patent
active
055809049
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a compound which can pass through the blood-brain barrier (BBB) carrying a drug and release the drug while being retained in brain, and to its use.
2. Background Art
Cerebral tissue or cells are separated from blood by very tightly combined cerebral capillary vessels (blood-brain barrier), that is, brain is protected by the strict limitation of the interchange of materials through the blood-brain barrier. Therefore, a drug administered systemically sometimes cannot successfully be delivered to brain being impeded by BBB.
In general, the permeability of materials through BBB is correlated with the lipophilicity of the materials. Thus, some lipophilic prodrugs have been synthesized for the purpose of facilitation of delivery to brain of a drug which is hard to permeate through BBB. On the other hand, brain also possesses a mechanism for active excretion of waste materials and drugs back to the periphery. Therefore, it is considered that the conventional prodrugs which only facilitate their distribution to brain by mainly an increase in the lipophilicity have limitations in maintaining the concentration and efficacy of the drug (Rahimy, M. H., et al., Pharm. Res., 10 (1990) 1061-1067). In other words, it is required to provide a means to enhance the transport of the drug across BBB and to prolong the residence in brain of the drug in order to maintain its efficacy following intravenous administration of a drug.
In order to solve the problem, Bodor (Florida University) has proposed a dihydropyridine prodrug which utilizes the NAD+-NADH redox system (Bodor, N., et. al., Science, 214 (1981) 1370-1372). The lipophilic derivative, when incorporated into cells, is oxidized mainly by the NAD.sup.+ oxidation system into a pyridinium cation and retained in brain due to the decrease of its permeability through biological membrane. This method is believed an excellent system for delivering drugs to brain, since the pyridinium cation carrying the drug releases it in a sustained manner. Bodor and his co-workers have already demonstrated the excellence of the method in more than twenty compounds (drugs). However, the dihydropyridine derivative is easily oxidized per se and thus is likely to lead to the deterioration of the quality for example by air oxidation after its synthesis.
The present inventors have examined further possibilities for obtaining the compounds which can pass through BBB and deliver a drug into brain. As a result, we have found that certain kinds of compounds have an excellent property as a carrier for delivering drugs into brain. Thus we have accomplished the present invention.
SUMMARY OF THE INVENTION
The object of the present invention is to provide novel compounds which can pass through the blood-brain barrier (BBB) with a drug carried thereon and release the drug while staying in brain as well as well-known compound groups which possess the above properties.
According to the present invention, there provides the compound represented by the formula (IA): ##STR3## and a salt thereof, wherein hydrogen atoms in the alkyl group or the alkenyl group may be substituted by a group selected from the group consisting of a hydroxyl group which may be esterified, etherified or carbamated, a carboxyl group which may be esterified or amidated, an amino group which may be acylated and a residue of cyclic compounds except 4-amino-2-methyl-5-pyridyl group, ##STR4## wherein, R.sup.2 and R.sup.3 represent independently a hydrogen atom, an alkyl group or an alkenyl group, in which one or more hydrogen atoms in the alkyl group or the alkenyl group may be substituted by a group selected from the group consisting of a hydroxyl group which may be esterified, etherified or carbamated, a carboxyl group which may be esterified or amidated, an amino group which may be acylated and a residue of cyclic compounds, represent 1, hydrogen atom, an alkyl group or an alkenyl group, in which one or more hydrogen atoms in the alkyl group or the a
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Horie Kazutoshi
Ishihara Hiroshi
Ishikura Toyoaki
Ito Teruomi
Kato Takashi
Drug Delivery System Institute, Ltd.
Gupta Yogendra N.
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