Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2000-12-22
2001-12-11
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C514S650000
Reexamination Certificate
active
06329552
ABSTRACT:
SUMMARY OF THE INVENTION
The invention relates to N-substituted 2-amino-1-[2,7-dichloro-9-(aryl)-9H-fluoren-4-yl]-ethanols, methods for the preparation of these compounds, new intermediate products, pharmaceutical preparations and fixed or variable combinations comprising these compounds, the use of these compounds (alone or in fixed or free combination) and/or combinations for the therapeutic or prophylactic treatment of diseases or for the preparation of pharmaceutical preparations and methods for the therapeutic or prophylactic treatment of warm-blooded animals comprising the administration of these compounds or combinations.
BACKGROUND TO THE INVENTION
Parasitic diseases, in particular those caused by protozoa (such as malaria, pathogens: plasmodia), or by trematodes (such as schistosomiasis, for example urinary schistosomiasis, caused by schistosomes, as Schistosoma haematobium), constitute a substantial proportion of the diseases, especially in developing countries. Malaria, transmitted by the Anopheles mosquito and caused by protozoa of the Plasmodium genus, is a disease which occurs in about 100 million people each year, of whom around one million die. A distinction is drawn between
Malaria tropica
(caused by
Plasmodium falciparum
),
Malaria tertiana
(caused by
Plasmodium vivax
or
Plasmodium ovale
) and
Malaria quartana
(caused by
Plasmodium malariae
).
Malaria tropica
is the most severe form of the disease.
Benflumetol (also lumefantrine), a compound of formula
is a compound which, in combination with artemether (see EP 0 500 823)—a sesquiterpene lactone derivative of the naturally occurring substance artemisinin with the name [3R-(3&agr;, 5&agr;&bgr;, 6&bgr;, 8&agr;&bgr;, 9&agr;, 10&agr;, 12&bgr;,-12aR)]-decahydro-10-methoxy-3,6,9-trimethyl-3,12epoxy-12H-pyrano[4,3j]-1,2-benzodioxepin, is in the review stage for approval worldwide as a treatment for malaria.
Because of phenomena such as the development of resistance, it remains an urgent necessity to find new compounds which show particularly good efficacy against malaria and minimal toxicity.
The different half-lives of the substances which are active against malaria also mean that further compounds should be made available which show a pharmacokinetic behaviour distinct from the antimalarial substances already established. Chloroquine, for example, has a very long half-life, artemether a relatively short half-life (2 hours in plasma), and benflumetol for example has a plasma half-life of 4-6 days in patients.
The solubility of benflumetol is also not very good, and when it is taken for example with foods having a high fat content the absorption can be up to 16 times higher than it is in the absence of such fatty foods, so that dosing cannot be optimally controlled.
Surprisingly, a new class of compounds has now been found which have a number of beneficial properties, meet one or more of the above requirements in particular, and facilitate for example the treatment of severe cases of malaria or a corresponding prophylaxis, or in the broader sense of schistosomiasis, the prevention or treatment of potentially multiresistant malaria, and new pharmaceutical formulations, and thus an improved pharmacokinetics, but in particular show especially good efficacy against plasmodia.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to a compound of formula I,
wherein R is an alkyl unsubstituted or substituted by one or more polar substituents or an alkenyl unsubstituted or substituted by one or more polar substituents, and X is aryl, or a salt thereof.
The general terms used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, unless otherwise indicated:
The prefix “lower” denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4 carbon atoms, the radicals in question being either linear or branched with single or multiple branching.
Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.
Any asymmetric carbon atoms may be present in the (R)—, (S)— or (R,S) configuration, preferably in the (R)— or (S) configuration. Substituents at a double bond or a ring may be present in cis- (═Z—) or trans (═E—) form. The compounds may thus be present as mixtures of isomers or as pure isomers, preferably as enantiomer-pure diastereomers. Especially preferred are in each case the E or Z form of a compound of formula 1, which with regard to the C—OH in formula I are present as an enantiomeric mixture (in particular a racemate). The enantiomer-pure E and Z forms are also important.
Alkyl may be a singly or multiply branched or straight-chain substituent; alkyl preferably has up to 10 carbon atoms and especially up to 8 carbon atoms, and is in particular C
1
-C
5
alkyl, for example n-pentyl, n-butyl, sec-butyl, tert-butyl, n-propyl, isopropyl, ethyl or methyl, or octyl, for example n-octyl. Methyl, n-pentyl, n-butyl and sec-butyl are especially preferred.
Alkyl with up to 8 carbon atoms which is substituted by a polar radical, preferably n-pentyl, n-butyl or sec-butyl, is especially substituted by one or more, especially up to three polar substituents selected from the group consisting of amino, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, hydroxy-lower alkoxy, such as 2-hydroxyethoxy, hydroxy-lower alkoxy-lower alkoxy, such as 2-(2-hydroxyethoxy)ethoxy, carboxy, amidino and guanidino, especially amino, hydroxy and guanidino. If otherwise unstable compounds are present, such substituents are preferably not bonded on the carbon-1 atom (which bonds R to the nitrogen in formula 1).
Alkenyl is preferably alkenyl with up to 8 carbon atoms and is in particular lower alkenyl with 3 to 7, especially 3 or 4 carbon atoms, wherein the carbon atom binding the nitrogen in formula I may not form a double bond (double bond only in the 2 position or higher, because otherwise the compound would be unstable).
Alkenyl which is substituted by a polar radical and has up to 8 carbon atoms, in particular C
3
-C
7
lower alkenyl, is substituted especially by one or more, in particular up to three polar substituents selected from the group consisting of amino, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, carboxy, amidino and guanidino, especially amino, hydroxy and guanidino. In the case of hydroxy, amino, lower alkylamino and guanidino, this substituent may not be bonded to a carbon atom which is linked to the radical of the molecule via a double bond. If otherwise unstable compounds are present, such substituents are moreover preferably not bonded on the carbon-1 atom (the atom which bonds R to the nitrogen in formula 1) (this is often the case especially with hydroxy, amino, and guanidino).
Halogen is above all fluorine, chlorine, bromine, or iodine, especially fluorine, chlorine, or bromine.
Aryl is in particular C
6
to C
14
aryl, especially fluorenyl, napthyl or in particular phenyl, the said radicals being unsubstituted or substituted by one or more substituents selected from the group comprising halogen, especially chlorine; hydroxy; substituted hydroxy, in particular lower alkanoyloxy, phenyl-lower alkoxy or lower alkoxy; amino; monosubstituted or disubstituted amino, in particular amino substituted by lower alkanoyl, phenyl-lower alkyl or lower alkyl monosubstituted or disubstituted amino; lower alkyl; substituted lower alkyl, such as phenyl-lower alkyl, halogen-lower alkyl, cyano-lower alkyl, carbamoyl-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl or phenyl-lower alkoxycarbonyl-lower alkyl substituted lower alkyl; phenyl; naphthyl; carboxy; esterified carboxy, for example lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl or phenoxycarbonyl, amidino, cyano, nitro and sulfo. Aryl is in particular 4-chlorophenyl.
Salts are primarily the pharmaceutically acceptable salts of compounds of formula I.
Such salts are formed, for example, as acid addition salts, preferably with organic or in
Allmendinger Thomas
Wernsdorfer Walther Helmut
Barts Samuel
Hess Susan
Novartis AG
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