Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1995-06-07
2001-11-20
Berch, Mark L (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S557000, C540S581000
Reexamination Certificate
active
06319919
ABSTRACT:
The present invention is directed to galanthamine-analogues having cholinesterase inhibiting properties and their preparation and use for treatment of Alzheimer's disease and related dementias, some of the analogues are novel.
U.S. Pat. No. 4,663,318 issued on May 5, 1987 describes the use of galanthamine for the treatment of Alzheimer's disease and related dementias.
Published European Patent Application 236684 describes the use of galanthamine and certain analogues for the treatment of Alzheimer's disease and related dementias, such analogues are those wherein the hydroxy group of naturally occurring galanthamine may be replaced by methoxy, ethoxy or lower alkanoyloxy, the methoxy group of galanthamine may be replaced by hydrogen, methoxy, ethoxy or lower alkanoyloxy and the N-bonded methyl group may be replaced by other straight or branched chain alkyl groups, cyclopropylmethyl, cyclobutylmethyl or allyl groups or substituted lower alkyl phenyl groups or wherein other hydrogen atoms are substituted by chloro or fluoro atoms.
The literature shows the epigalanthamine wherein the hydroxy group is in the equatorial position so that hydrogen bond stabilization of structure is not possible has an anti-cholinesterase activity of only 10% of galanthamine. (Chem. Abstr., 77, 109461s)
A number of galanthamine analogs occur naturally or have been obtained from natural products including the following compounds described in the text book The Alkaloids (edited by R. H. F. Manske published by Academic Press, N.Y., 15th Edition):
Narwedine has been reported to have weak anticurare activity at 3 mg/kg (Chem. Abstr., 78, 131941r) and to have cholinergic effects on respiration and heart activity, 50-80% lower than galanthamine (Chem. Abstr., 80, 103864r), Schmidt et al in Acta. Biol. Ned. Ger. 7: 402-410 (1961) report that the anticholinesterase activity of Narwedine is less than 1% of that of galanthamine.
It has been reported that the concentration of lycoramine required to stimulate EEG—recorded activity is about five times that required for galanthamine (Chem. Abstr., 62, 15306e). deoxylycoramine
and N-mesityl and N-benzyl derivatives of galanthamine. Reference is also made to compounds of the formulae:
The latter compound has been reported to have activity similar to that of galanthamine (J. Chem. Soc., (C) 1043 (1971).
An earlier edition The Alkaloids (R. H. F. Manske editor, Academic Press) of this book had also referred to (+) N-demethyldihydrogalanthamine of the formula:
N-Desmethyldihydrogalanthamine is described by Kametani et al in J. Heterocyclic Chem., 10, 35-37 (1973). The same paper also refers to galanthamine O, N-diacetate leucotamine
and its O-methyl and O-methyl acetic acid ester are described by Kobayashi et al in Chem. Pharm. Bull., 33:, 5258-5263 (1985).
O-Desmethyldihydrogalanthamine (also known as O-demethyllycoramine) and O-demethylgalanthamine (sanguinine) are also described by Kobayashi et al in Chem. Pharm. Bull., 28:, 3433-3436 (1980).
Subsequently, Kobayashi disclosed the extraction of O-demethyl lycoramine (also known as dihydrosanguinine) from bulbs of
Lycoris radiata Herb.
(Chem. Pharm. Bull., 28: 3433-6 (1980), Chem. Abstr. 95,25351.
A bromo-narwedine of the formula:
is described as an intermediate in the synthesis of galanthamine by Kametani et al in Chem. Comm., 425 (1969) and J. Chem. Soc. (C), 2602 (1969).
Chem. Abstr. 61,14727g Chem. Pharm. Bull., 12:1012-20 (1964) describes the production of compounds of the formula:
wherein R may be hydrogen, methyl or ethyl.
A dihydro derivative of childanthine obtained by hydrogenation of the parent compound is described by Boit in
Chem. Ber,
90: 57-9 (1957): Chem. Abstr., 51,8120f.
Chemical Abstracts 81 638193 describes n.m.r. studies on dihydrogalanthamine and its acetic acid esters.
Fales, Giuffrida and Wildman in Journal of American Chemical Society, 78:4145 (1956) report that the bulbs of King Alfred daffodils contain the known alkaloids galanthamine, galanthamine, lycoramine, haemolycoramine, haemanthamine and narcissamine and a new alkaloid pseudo lycorine. They also reported that narcissamine has been shown to be N-demethyl galanthamine.
Latho and Fales in J. Am. Chem. Soc., 4434-4438 (1964). report that contrary to what had previously been believed, narcissamine was in fact a mixture of N-demethylgalanthamine and N-demethyllycoramine.
Tetsuji Kametani et al. in Yakuyaku Zasshi 12: 1353-1358 (1977) describe a synthetic route to convert 2-benzazepin-3-ones to galanthamine analogues in anticipation of them having analgesic activity. Among the analogues including those where the phenol ring is substituted by bromine or hydroxy methyl on the carbon atom adjacent to the phenolic hydroxy group.
In German OS 2945161 there is described the production of certain narwedine type enones and their derivatives, including those where the benzene ring is bromo-substituted and the nitrogen containing ring contains a keto group adjacent to the nitrogen.
Shimizu et al in Heterocycles, 8: 277-282 (1977) (abstracted in Chemical Abstracts, 88, 136821t) describe certain narwedine derivatives used as intermediates having the following formulae:
Irwin and Smith in Arch. Int. Pharmacodyn., 127:314-330 described the cholinesterase activity of galanthamine and some of its analogues including lycoramine acetate methiodide, neopin methiodide (both of which were ineffective) and deoxydemethyl lycoramine methiodide (which demonstrated good activity) and deoxylycoramine (which exhibited some activity). It was hypothesized that the presence of a free hydroxy group in the cyclohexane ring conferred activity on the molecule since the acetylation of this group led to a drop in activity.
In J. Pharm. Exp. Ther., 134:53 (1961), Irwin, Smith and Hein expanded on the work just described and reported that replacement of the hydroxyl group of deoxydemethyl lycoramine methiodide by a carbamate group resulted in useful pharmacological activity.
Subsequently, Irwin and Hine, J. Pharm. Exp. Ther., 136:20 (1962) described the activity of a number of carbamates including deoxydemethyl lycoramine carbamate on cholinesterase activity in rat brain.
Subsequently, Somers et al. in Neurology, 13:543 (1663) reported that some of Irwin's compounds were useful in treating myasthenia gravis.
One of the characteristics of Alzheimer's disease and certain other considerations is a reduction in the amount of acetyl choline in the brain (see for example, Perry et al British Medical Journal 2:1457-1459 (1978). Acetylcholine is a compound that is involved in the transmission of electrical impulses between nerve endings. Excessive amounts of acetyl choline cause undesirable side effects so that the brain also contains a cholinesterase enzyme to prevent build up of acetyl choline. Thus, if the production of acetyl choline cannot be increased, one way to approach the problem of low acetylcholine levels is to reduce the amount or activity of the cholinesterase so that such acetyl choline is present may be used. Unfortunately, finding a useful treatment for Alzheimer's disease is not simply a matter of feeding a patient with a cholinesterase inhibitor. To be effective, a compound must pass the blood brain barrier easily and distribute itself between the central and peripheral nervous systems in such a way that its effect is mainly central, and it must not have significant side effects. It must have a reasonably long half life in the brain. It must be reversible to at least some extent (otherwise nerve gasses would be effective treatment—which they are not) and it must be able to be formulated in a way that makes it suitable for use by those suffering from the disease. Loss of acetyl choline in the brain can exist alongside other conditions where Alzheimer's disease is not the primary indication where the same neurochemistry exists. References herein to “related dementias” are intended to include to such situations. Similar problems of cholinergic deficiency and dementia accompanied by plaques and tangles in the brain also a
Davis Bonnie
Joullie Madeleine M.
Berch Mark L
Davis Bonnie
Ladas & Parry
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