Epothilones with modified side chain

Details Epothilones with modified side chain Epothilones with modified side chain

1999-08-17

2002-03-19

Gerstl, Robert (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06359140

ABSTRACT:

Epothilones A and B have been disclosed; cf. for example, DE 4 138 042, WO 93 10 121 and WO 97 19 086.
The mentioned art suggests said epothilones as therapeutic agents. In PNAS USA, 95 (1998) 1369-1374 epothilones are described as useful therapeutic agents. According to Angew. Chem., Int. Ed., 36 (1997) 2097-2103 an extensive library of such compounds is provided based on their therapeutic effects.
The invention now relates to a process for the preparation of epothilones which are modified in the 16,17-position, in which process the starting materials are 3,7-protected or unprotected epothilones A or B and
a) these are hydrogenated on the 16,17-double bond or
b) subjected to an addition reaction with halogen on the 16,17-double bond or
c) epoxidized on the 16,17-double bond and, if appropriate, the resulting epoxide is reduced to give the 16-alcohol.
The process according to the invention may be characterized in that,
in method (a), hydrogenation is affected with diimine or hydrogen and a heterogeneous or homogenous metal catalyst or
in method (c), epoxidation is affected with a peracid or a dioxirane.
Furthermore, the invention concerns a process for the preparation of 2,3-unsaturated epothilbne N-oxides in which either (i) 3,7-protected epothilones A or B are converted into an N-oxide in a manner known per se and, the 3-substituent is eliminated by a base to give the 2,3-double bond, or (ii) 7-protected or 7-unprotected epothilones A or B which have a double bond in the 2,3-position are converted into an N-oxide in a manner known per se and, if appropriate, the resulting N-oxide is subjected to O-alkylation and an O-alkylation product is obtained.
Furthermore, the invention relates to a process for the preparation of epothilone N-oxides in which 3,7-protected or unprotected epothilones A or B are converted into an N-oxide in a manner known per se and, if appropriate, the resulting N-oxide is subjected to O-alkylation and an O-alkylation product is obtained.
This process according to the invention may be characterized in that N-oxidation is performed with peracid or a dioxirane and electrophilic alkyl, aryl or heteroaryl reagents, in particular methyl iodide or trimethyloxonium tetrafluoroborate, are used for the optional O-alkylation.
Furthermore, this process according to the invention may be characterized in that a resulting N-oxide is subjected to a Katada reaction, in particular as described in Houben-Weyl, Volume E7b, page 646.
Furthermore, this process according to the invention may be characterized in that the Katada reaction is performed with an activated carboxylic acid derivative, in particular carboxylic anhydride or carboxylic acid chloride.
Furthermore, this process according to the invention may be characterized in that the Katada reaction is carried out with acetic anhydride and, if appropriate, the 21-acetoxyepothilones obtained are cleaved in a manner known per se to give 21-hydroxyepothilones A or B (epothilones E and F, respectively).
Furthermore, this process according to the invention may be characterized in that the optional cleavage process is performed hydrolytically or enzymatically.
Furthermore, the invention relates to a process for the preparation of epothilones which are modified in the C19-position, in which process 3,7-protected or unprotected epothilones A or B are metalated in the C19-position and captured with electrophilic reagents in a manner known per se as alkyl-, aryl-, heteroaryl-, halogen-, oxygen- or sulphur-substituted epothilones which are modified in the C19-position.
This process according to the invention may be characterized in that metalation is performed using butyllithium.
Furthermore, the invention relates to a process for the preparation of epothilones which are modified in the C27-position, in which process the allyl group (C17, C16 and C27) is substituted in a manner known per se on the C27-methyl group by a hetero atom.
This process according to the invention may be characterized in that the C27-methyl group is substituted by a bromine atom, in particular with the aid of N-bromo-succinimide, and, if appropriate, the resulting bromide is converted into a C27-hydroxy compound.
Finally, the invention relates to compounds prepared by the process according to the invention.
Experiment 1
Diepoxyepothilone A. 1a)
A solution of epothilone A (5 mg, 10 &mgr;mol) in acetone (1 ml) was treated at 0° C. with dimethyldioxirane (0.4 ml, 28 &mgr;mol, 0.07 M in acetone). The solution was brought to room temperature in the course of a few hours and was stirred for 20 hours at this temperature. Since TLC confirmed that starting material was still present, more dimethyldioxirane (0.25 ml, 17 &mgr;mol) was added, and the reaction mixture was again stirred for 20 hours at room temperature. The solvent was removed and the residue was purified by means of PLC (0.25×200×200 mm, 10% MeOH:CH
2
Cl
2
). The following were isolated:
1. 1.4 mg (27%) of diepoxyepothilone A (3:2 epimer mixture on C16-C17). R
f
0.63 (10% MeOH:CH
2
Cl
2
); R
t:
6.79 (isomer 1) and 7.39 (isomer 2) min (RP 18, 250×4 mm, MeOH:H
2
O 65:35, 1 ml/min) ; MS: (m/z)=510 (M
+
);
1
H NMR (400 MHz, CDCl
3
, selected signals, isomer 1): &dgr;=6.96 (s, 1H, H-19), 5.48 (dd, J=12.2 and 2.5 Hz, 1H, H-15), 4.37 (dbr, J=10.7 Hz, 1H, H-3), 4.10 (s, 1H, H-17), 3.67 (dd, J=5.6 and 2.5 Hz, 1H, H-7), 3.14 (qd, J=6.6 and 2.5 Hz, 1H, H-6), 3.00 (ddd, J=9.7, 3.6 and 2.5 Hz, 1H, H-13), 2.88 (dt, J=8.6 and 3.6 Hz, 1H, H-12), 2.71 (s, 3H, H-21), 2.53 (dd, J=13.7 and 11.7 Hz, 1H, H-2a), 1.41 (s, 3H, H-22), 1.27 (s, 3H, H-26), 1.17 (d, J=6.6 Hz, 3H, H-24), 1.08 (s, 3H, H-23), 0.97 (d, J=7.1 Hz, 3H, H-25); (isomer 2) &dgr;=6.98 (s, 1H, H-19), 5.11 (dd, J=11.7 and 2.5 Hz, 1H, H-15), 4.27 (dbr, J=10.7 Hz, 1H, H-3), 4.14 (s, 1H, H-17), 3.06 (qd, J=6.6 and 2.9 Hz, 1H, H-6), 2.96 (ddd, J=9.7, 3.6 and 2.5 Hz, 1H, H-13), 2.31 (dt, J=14.7 and 2.0 Hz, 1H, H-14a), 1.36 (s, 3H, H-22), 1.15 (d, J=6.6 Hz, 3H, H-24), 1.14 (s, 3H, H-26), 1.07 (s, 3H, H-23).
2. 0.8 mg (16%) of epothilone A N-oxide. R
f
0.44 (10% MeOH:CH
2
Cl
2
); R
t:
4.25 min (RP 18, 250×4 mm, MeOH:H
2
O 65:35, 1 ml/min); MS: (m/z)=510 (M
+
);
1
H NMR: see method 1
Experiment 2
Dihydroepothilone A. (1c)
Palladium on charcoal (5 mg, 10%) was added to a solution of epothilone A (11 mg, 22 &mgr;mol) in ethanol (2 ml) and the black suspension was exposed to an H
2
atmosphere for 24 hours at room temperature. Since TLC indicated that the reaction was not yet complete, a further portion of Pd/C was added and the reaction mixture was stirred for a further 20 hours under an H
2
atmosphere. The products were separated by means of PLC (1×200×200 mm, 10% MeOH:CH
2
Cl
2
). The following were isolated:
1. 0.5 mg (5%) of dihydroepothilone A. R
f
0.60 (10% MeOH:CH
2
Cl
2
); R
t:
10.80 min (RP 18, 250×4 mm, MeOH:H
2
O 65:35, 1 ml/min); MS: (m/z)=496 (M
+
), 478, 407, 308;
1
H NMR (400 MHz, CDCl
3
, selected signals): &dgr;=7.05 (d, J=6.6 Hz, 1H, OH), 6.77 (s, 1H, H-19), 5.23 (dd, J=12.4 and 2.3 Hz, 1H, H-15), 4.42 (ddd, J=11.7, 6.6 and 3.0 Hz, 1H, H-3), 3.70 (ddd, J=5, 3 and 2 Hz, 1H, H-7), 3.12 (qd, J=6.6 and 3.0 Hz, 1H, H-6), 3.07 (d, J=12.7 Hz, 1H, H-17a), 2.96 (ddd, J=9.7, 3.6 and 2.0 Hz, 1H, H-13), 2.91 (ddd, J=9.7, 3.6 and 2.6 Hz, 1H, H-12), 2.68 (s, 3H, H-21), 2.51 (dd, J=13.7 and 11.7 Hz, 1H, H-2a), 2.24 (d, J=12.7 Hz, 1H, H-17b), 2.19 (m, 1H, H-16), 2.13 (dd, J=13.7 and 3.0 Hz, 1H, H-2b); 1.35 (s, 3H, H-22), 1.15 (d, J=6.6 Hz, 3H, H-24), 1.09 (s, 3H, H-23), 0.99 (d, J=7.1 Hz, 3H, H-25), 0.93 (d, J=6.6 Hz, 3H, H-26).
2. 8 mg (72%) of 15-deoxydihydroepothilonic acid. R
f
0.10 (10% MeOH:CH
2
Cl
2
).
Experiment 3
16-Hydroxyepothilone A. (1b)
Palladium on charcoal (10 mg, 10%) was added to a solution of diepoxyepothilone A (7 mg, 14 &mgr;mol), 1:1 epime

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