Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-01
2002-05-14
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S314000, C514S367000, C514S374000, C514S375000, C514S395000, C548S305100, C548S310100, C548S180000, C548S159000, C548S217000, C546S174000
Reexamination Certificate
active
06387927
ABSTRACT:
SUMMARY OF THE INVENTION
The invention relates to a new class of epothilone derivatives, the production of these compounds and new intermediates, pharmaceutical preparations containing these compounds, and the use of these compounds in the treatment of warm-blooded animals, such as humans, or their use in the production of pharmaceutical preparations for the treatment of warm-blooded animals, such as humans.
BACKGROUND TO THE INVENTION
Epothilones A and B represent a new class of microtubule-stabilising cytotoxic agents (see Gerth, K. et al., J. Antibiot. 49, 560-3 (1966)) of the formulae:
wherein R means hydrogen (epothilone A) or methyl (epothilone B).
These compounds have advantages over Taxol®, a branded product already introduced for the treatment of tumours, that has the same mechanism of action but has however a series of disadvantages, such as very poor water solubility, making the preparation of pharmaceutical formulations very difficult (at present, such formulations are normally characterised by the toxic side effects of the carrier materials), and inefficacy on a series of tumours. The advantages are as follows:
a) They have better water-solubility and are thus more readily accessible for formulations.
b) It has been reported that, in cell culture experiments, they are also active against the proliferation of cells, which, owing to the activity of the P-glycoprotein efflux pump making them “multidrug resistant”, show resistance to treatment with other chemotherapy agents including Taxol® (see Bolag, D. M., et al., “Epothilones, a new class of microtubule-stabilizing agents with a Taxol-like mechanism of action”, Cancer Research 55, 2325-33 (1995)). And
c) it could be shown that they are still very effective in vitro against a Taxol®-resistant ovarian carcinoma cell line with modified &bgr;-tubulin (see siehe Kowalski, R. J., et al., J. Biol. Chem. 272(4), 2534-2541 (1997)).
Pharmaceutical application of the epothilones, for example for tumour treatment, is possible in an analogous manner to that described for Taxol, see for example U.S. Pat. No. 5.641.803; U.S. Pat. No. 5.496.804; U.S. Pat. No. 5.565.478). One disadvantage of the epothilones is the relatively low therapeutic index, i.e. the dosage range between the necessary dose and the maximum tolerable dose is very small.
In the meantime, a series of epothilone derivatives have been published in the search for new, more effective and more versatile products.
Up until now, all epothilones described in the literature contain a methyl group shown in the above formula at C-16. This methyl group (C-17) was hypothesized to be necessary in order Ws to force the heterocycle (in the case of epothilones A and B a methylthiazolyl ring) out of the plane of the conjugated double bond between C-16 and C-18, and this was postulated to be necessary for efficacy.
It is an objective of the invention to provide a new class of epothilone derivatives, which have a new type of structure and which, through their advantageous biological and pharmacological properties, enable the armamentarium for the control of, in particular, proliferative diseases such as tumours to be expanded. Also, compounds must be found which have an improved therapeutic index compared with epothilones A and B.
DETAILED DESCRIPTION OF THE INVENTION
Surprisingly, a new class of epothilone derivatives has been found, which are pharmacologically highly effective, despite the absence of the methyl group on C-16 of the epothilones and even though the resulting heterocyclic ring lies on the plane of the C-16/C-18 double bond.
The invention relates to this new class of epothilone derivatives. The compounds in question are compounds of formula I,
wherein
T is O, NH or N(alkyl), wherein alkyl is alkyl, especially lower alkyl;
as A is a radical of formula Ia
which is bonded to the radical of the molecule according to formula I by one of the two carbon atoms marked with an arrow, especially by the lower carbon atom (the one nearer to the nitrogen in the fused heterocycylic ring or para to the atom X), and wherein
X is S; O; NH; N(alk); wherein alk is alkyl, hydroxy-lower alkyl, unsubstituted or substituted amino-lower alkyl or carbamoyl-lower alkyl; N(ar), wherein ar is aryl; C(Rk*)═N, N═C(Rk*) or C(Rk*)═C(Rk**), wherein Rk* and Rk**, independently of one another, are H, alkyl (especially lower alkyl), unsubstituted or substituted amino-lower alkyl, carbamoyl-lower alkyl, or in particular halogen-lower alkyl or hydroxy-lower alkyl, or further aminolower alkyl; and
Rk is H, alkyl (especially lower alkyl), unsubstituted or substituted amino-lower alkyl, carbamoyl-lower alkyl, or in particular halogen-lower alkyl or hydroxy-lower alkyl;
either Y is OH and Y* is hydrogen, or —Y and —Y* together form a bond (so that together with the adjoining bond connecting the two —Y and —Y* bearing carbon atoms they form a double bond);
R is hydrogen, lower alkyl or halogen-lower alkyl;
and Z is O, or —Z— is a bond between the two binding carbon atoms;
or salts thereof.
These compounds have advantageous pharmaceutical properties. For example, they are active against multidrug-resistant cell lines and tumours and/or they have an improved therapeutic index over natural epothilones.
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 unbranched 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 (“a” as an indefinite article or as a numeral meaning “one”).
Asymmetric carbon atoms that are optionally present in the substituents may exist in the (R), (S) or (R,S) configuration, preferably in the (R) or (S) configuration. Substituents on a double bond or on a ring, for example on the carbon atoms to which Z in formula I is bonded, may be present in cis- (=Z-) or trans- (=E-) form. The present compounds may thus exist as mixtures of isomers or as pure isomers, preferably as pure diastereoisomers.
T is either O, NH or N(alkyl), especially either O or NH, preferably O.
The radical A is bonded to the radical of the molecule of formula I by one of the two carbon atoms marked by an arrow in formula Ia. Bonding is preferably effected via the carbon atom of the benzene ring portion of A which is in para position to X.
Alkyl is preferably an alkyl radical with 1 to 10 carbon atoms, preferably lower alkyl, especially methyl.
Lower alkyl is unbranched or has mono- or multiple-branching and is in particular methyl or ethyl.
Aryl is preferably an aromatic radical with 6 to 14 carbon atoms, especially phenyl, naphthyl, fluorenyl or phenanthrenyl, whereby the said radical is unsubstituted or is substituted by one or more substituents, preferably up to three, primarily one or two substituents, especially those selected from amino; lower alkanoylamino, especially acetylamino; halogen, especially fluorine, chlorine or bromine; lower alkyl, especially methyl or also ethyl or propyl; halogen-lower alkyl, especially trifluoromethyl; hydroxy; lower alkoxy, especially methoxy or also ethoxy; phenyl-lower alkoxy, especially benzyloxy; nitro, cyano, C
8
-C
12
-alkoxy, especially n-decyloxy, carbamoyl, lower alkyl-carbamoyl, such as N-methyl- or N-tert-butylcarbamoyl, lower alkanoyl, such as acetyl, phenyloxy, halogen-lower alkyloxy, such as trifluoromethoxy or 1,1,2,2-tetrafluoroethyloxy, lower alkoxycarbonyl, such as ethoxycarbonyl, lower alkylmercapto, such as methylmercapto, halogen-lower alkyl-mercapto, such as trifluoromethylmercapto, hydroxy-lower alkyl, such as hydroxymethyl or 1-hydroxymethyl, lower alkanesulphonyl, such as methanesulphonyl, halogen-lower alkane-sulphonyl, such as trifluoromethanesulphonyl, phenylsulphonyl, dihydroxybora (-B(OH)
2
), 2-methyl-pyrimidin-4-yl
Altmann Karl-Heinz
Bold Guido
Caravatti Giorgio
Flörsheimer Andreas
D'Souza Andrew
Dohmann George R.
Novatis AG
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