Epothilone derivatives and their synthesis and use

Details Epothilone derivatives and their synthesis and use Epothilone derivatives and their synthesis and use

2001-04-19

2003-03-11

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S390000, C548S182000, C548S186000, C548S184000, C548S193000

Reexamination Certificate

active

06531497

ABSTRACT:

CROSS-REFERENCE
This application is a 371 of PCT/EP 99/04287 filed Jun. 21, 1999.
SUMMARY OF THE INVENTION
The present invention relates to epothilone analogs having side chain modifications and to methods for producing such compounds, their use in the therapy of diseases or for the manufacture of pharmaceutical preparations for the treatment of diseases, as well as to novel intermediates used in the synthesis of such analogs and new methods of synthesis.
BACKGROUND OF THE INVENTION
The epothilones (1-5) are natural substances which exhibit cytotoxicity even against paclitaxel-resistant tumor cells by promoting the polymerization of &agr;- and &bgr;-tubulin subunits and stabilizing the resulting microtubule assemblies. Epothilones displace paclitaxel (the active principle of TAXOL™) from its microtubuli binding site and are reported to be more potent than paclitaxel with respect to the stabilization of microtubules.
What is needed are analogs of epothilone A and B that exhibit superior pharmacological properties, especially one or more of the following properties: an enhanced therapeutic index (e.g. a larger range of cytotoxic doses against e.g. proliferative diseases without toxicity to normal cells), better pharmakokinetic properties, better pharmacodynamic properties, better solubility in water, better efficiency against tumor types that are or become resistant to treatment with one or more other chemotherapeutics, better properties to facilitate manufacture of formulations, e.g. better solubility in polar solvents, especially those comprising water, enhanced stability, convenient manufacture of the compounds as such, improved inhibition of proliferation at the cellular level, high levels of microtubule stabilizing effects, and/or specific pharmacologic profiles.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to new compounds that surprisingly have one or more of the above-mentioned advantages.
One major aspect of the invention relates to an epothilone analog compound represented by the formula I
wherein
the waved bond indicates that bond “a” is present either in the cis or in the trans form;
(i) R
2
is absent or oxygen; “a” can be either a single or double bond; “b” can be either absent or a single bond; and “c” can be either absent or a single bond, with the proviso that if R
2
is oxygen then “b” and “c” are both a single bond and “a” is a single bond; if R
2
is absent then “b” and “c” are absent and “a” is a double bond; and if “a” is a double bond, then R
2
, “b” and “c” are absent;
R
3
is a radical selected from the group consisting of hydrogen; lower alkyl, especially methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl; —CH═CH
2
; —C≡CH; —CH
2
F; —CH
2
Cl; —CH
2
—OH; —CH
2
—O—(C
1
-C
6
-alkyl), especially —CH
2
—O—CH
3
; and —CH
2
—S—(C
1
-C
6
-alkyl), especially —CH
2
—S—CH
3
;
R
4
and R
5
are independently selected from hydrogen, methyl or a protecting group, preferably hydrogen; and
R
1
is a radical selected from the following structures:
 aspect of the invention, of the formula
wherein R and R′ are lower alkyl, especially methyl, or, in a broader aspect of the invention, furthermore R′ is hydroxymethyl or fluoromethyl and R is hydrogen or methyl;
(ii) and, if R
3
is lower alkyl, especially methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl; —CH═CH
2
; —C≡CH; —CH
2
F; —CH
2
Cl; —CH
2
—OH; —CH
2
—O—(C
1
-C
6
-alkyl), especially —CH
2
—O—CH
3
; or —CH
2
—S—(C
1
-C
6
-alkyl), especially —CH
2
—S—CH
3
, and the other symbols except R
1
have the meanings given above, R
1
can also be a radical selected from the following structures:
 or, if R
3
has one of the meanings given in the definition of R
3
above under (ii) other than methyl, R
1
can also be a radical of the formula
(iii) and, if R
3
is hydrogen, lower alkyl, especially methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl; —CH═CH
2
; —C≡CH; —CH
2
F; —CH
2
Cl; —CH
2
—OH; —CH
2
—O—(C
1
-C
6
-alkyl), especially —CH
2
—O—CH
3
; or —CH
2
—S—(C
1
-C
6
-alkyl), especially —CH
2
—S—CH
3
, and
R
2
is oxygen, “b” and “c” are each a single bond and “a” is a single bond, then R
1
can also be a radical of the partial formula:
(iv) and, if R
3
is lower alkyl other than methyl, especially ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl; or preferably is —CH═CH
2
; —C≡CH; —CH
2
F; —CH
2
Cl; —CH
2
—OH; —CH
2
—O—(C
1
-C
6
-alkyl), especially —CH
2
—O—CH
3
; or —CH
2
—S—(C
1
-C
6
-alkyl), especially —CH
2
—S—CH
3
; and the other symbols except for R
1
have the meanings given above under (i), R
1
can also be a moiety of the formula
or a salt of a compound of the formula I where a salt-forming group is present.
A further aspect of the invention relates to a method of synthesis of a compound of the formula
(wherein Q is hydrogen or preferably methyl) and/or a method of synthesis of a compound of the formula
The general terms used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, unless otherwise indicated:
The term “lower” means that the respective radical preferably has up to and including 7, more preferably up to and including 4 carbon atoms.
Lower alkyl can be linear or branched one or more times and has preferably up to and including 7, more preferably up to and including 4 carbon atoms. Preferably, lower alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl or further n-pentyl or n-hexyl.
A protecting group is preferably a standard protecting group. If one or more other functional groups, for example carboxy, hydroxy, amino, or mercapto, are or need to be protected in a compound of formulae I, because they should not take part in the reaction, these are such groups as are usually used in the synthesis of peptide compounds, and also of cephalo-sporins and penicillins, as well as nucleic acid derivatives and sugars.
The protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products. The specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned hereinabove and hereinafter.
The protection of such functional groups by such protecting groups, the protecting groups themselves, and their removal reactions are described for example in standard reference works, such as J. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973, in T. W. Greene, “Protective Groups in Organic Synthesis”, Wiley, New York 1981, in “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in “Methoden der organischen Chemie” (
Methods of organic chemistry
), Houben Weyl, 4th edition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, “Aminosäuren, Peptide, Proteine” (
Amino acids, peptides, proteins
), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharide und Derivate” (
Chemistry of carbohydrates: monosaccharides and derivatives
), Georg Thieme Verlag, Stuttgart 1974. Especially preferred protecting groups are hydroxy protecting groups, such as tert-butyldimethylsilyl or trityl.
R
4
and R
5
are preferably hydrogen.
The waved bond starting from the carbon atom bearing R
3
means that bond “a” is present in the trans- or preferably the cis-form.
Salts are especially the pharmaceutically acceptable s

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