Organic compounds -- part of the class 532-570 series – Organic compounds – Halocarbonate esters
Patent
1992-02-26
1995-03-28
Higel, Floyd D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Halocarbonate esters
544335, 546318, 546326, 548201, 548236, 5483345, 548531, 548535, 549 71, 549484, 549486, 538282, 538248, C07C 6963, C07C 6962, C07C 6996, A61K 3160
Patent
active
054018684
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to hitherto unknown intermediates of the below formula I for use in the synthesis of prodrugs.
In recent years, chemical modification of drugs into labile derivatives (prodrugs) with improved physicochemical properties that enable better transport through biological barriers has become a useful approach for improving-drug delivery. Such transformation is often practised on ionizable molecules containing e.g. a carboxylic acid, an amino, or a hydroxy group that can be utilized for derivatization, in order to modify their ionization at physiological pH and to render desirable partition and solubility properties.
A necessary requirement of this approach is that the said prodrug is non-toxic and, when administered to a warm-blooded animal including a human being, is enzymatically and/or chemically cleaved in such a manner as to release the drug at its target or site of activity, quantitatively and at a desirable rate, while the remaining cleaved moiety remains non-toxic and is metabolized in such a manner that non-toxic metabolic products are produced.
It is, of course, also desirable that the prodrug can be provided without excessive costs in connection with its production, in particular without an appreciable loss of drug itself during its production and recovery, since the drug is usually the more expensive part of the prodrug.
The intermediate used to react with the drug in providing the prodrug should advantageously be stable and still be reasonably reactive.
In recent years, acyloxyalkoxycarbonyl derivatives have become interesting bioreversible prodrug moieties of drugs and medicaments which are more readily bioavailable than the drug itself, and further are less irritating to topical and gastric mucosal membranes and are more permeable through such membranes. An example of such prodrug is shown in the formula II ##STR1## where D-H=the drug (D-H containing an OH, SH, NH.sub.2 or a monosubstituted N function), and R.sup.1 COOH=non-toxic carboxylic acid, R.sup.1 for instance meaning hydrogen or a straight or branched aliphatic C.sub.1 -C.sub.20 carbon chain or an aryl or aralkyl group, aryl and `ar` meaning an aromatic or heterocyclic, 5- or 6-membered ring substituent containing 1 or 2 hetero atoms selected among O, S and N. As examples of such aromatic or heterocyclic substituents, mention may be made of phenyl, furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, and pyrimidinyl. R.sup.1 may be further substituted, and its chain be interrupted by hetero atoms like oxygen, or by carbonyl group(s). R.sup.3 means hydrogen or C.sub.1 -C.sub.3 alkyl. Esters of this type have for instance been used as prodrugs of R.sup.1 COOH and have been shown to be enzymatically hydrolyzed in man. Obviously such esters will also liberate D-H.
Some esters of the formula II have been produced in a multi-step procedure, confer J. Med. Chem. 1988, 31, p. 318ff, where the drug (containing a primary or secondary amine group being the point of reaction) is reacted with a compound of formula III ##STR2## in which formula, R.sup.1' and R.sup.3' are hydrogen or lower alkyl.
The intermediates of formula III have the disadvantage of reacting rather slowly, if at all, when used in the production of prodrugs of formula II (Chemistry and Industry, 1967, p. 1960). Also, they seem to-be non crystalline and not very stable and are therefore difficult and costly to use technically (purification by chromatography).
It has now surprisingly turned out that intermediates of the formula I ##STR3## in which formula R.sup.1 and R.sup.3 have the above meanings can be provided which are both stable and of high purity following simple distillation or recrystallization, and which are still very reactive so that they can be used in a one step method for producing the desired prodrugs of the formula II in a high purity and without appreciable loss of the drug itself which is normally the most expensive part of the prodrug.
The intermediates of formula I, in which R.sup.3 stands for hydrogen have been shown to
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Jose Alexander et al, "(Acyloxy) alkyl Carbamates as Novel Bioreversible Prodrugs for Amines; Increased Permeation through Biological Membranes", J. med Chem, vol. 31, 1988, pp. 318, 322 the whole article.
F. H. C. Stewart, "Formation of Depsipeptide Ester Bonds by Accelerated . . . ", Chemistry and Industry, 1967, pp. 1960-1961 the whole article.
Higel Floyd D.
Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske / Fabrik
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