Epothilone derivatives, a process for their production thereof and their use

Abstract

The present invention relates to epothilon derivatives, processes for their production and their use in the manufacture of medicaments and plant protection agents.

Description

[0001] The present invention relates generally to epothilon derivatives, to processes for their production and to their use in the manufacture of medicaments and plant protection agents. The invention relates especially to epothilon derivatives of the general formulae 2 to 6 shown below and to their use as medicaments and plant protection agents. 1

[0002] In the above formulae:

[0003] R1=a H atom or a C1- to C8-alkyl group, preferably a C1- to C6-alkyl group, especially preferably a C1- to C4-alkyl group, especially a methyl, ethyl, propyl or butyl group,

[0004] R2=a monocyclic aromatic group, such as a 5- or 6-membered aromatic group (such as a phenyl ring) or a vinyl group, each of which may be substituted in the ortho- and/or meta- and/or para-position(s) by one, two, three, four or five, especially one or two, halogen atoms and/or OR4 and/or NR5R6 groups and/or alkyl and/or alkenyl and/or alkynyl groups, wherein R4, R5 and R6 each independently of the others have the same meanings as R1, but are independent of R1, or

[0005] R2=a monocyclic 5- or 6-membered heteroaromatic group which may have one or more, especially one or two, O and/or N and/or S atoms in the ring and/or may have OR4 and/or NR5R6 groups and/or alkyl and/or alkenyl and/or alkynyl groups as substituents, wherein R4, R5 and R6 are as defined above. In the definition of R2 there are especially preferred C1-C6-alkyl or C2-C6-alkenyl and -alkynyl groups, especially C1-C4-alkyl or C2-C4-alkenyl and -alkynyl groups. As alkyl groups there are especially preferred methyl, ethyl, propyl and butyl groups and as heteroaromatic groups 6-membered heteroaromatic groups,

[0006] Hal=a halogen atom, such as Br or I,

[0007] X-Y=a group of the formula —CH2CH—OP or —CH═CH—, and

[0008] P=a protecting group, such as TMS.

[0009] The compounds according to the invention may be produced as follows:

[0010] Compounds of the formula (2) may be produced by reacting compounds of the formula (1) 2

[0011] as described in DE 195 42 986, the radicals being as defined above. In that reaction, especially the following conditions (i), (iii) and optionally (after (i)) also (ii) may be used:

[0012] (i)

[0013] (a) O3 in a solvent, such as CH2Cl2, and

[0014] (b) reductive working-up, for example with Me2S;

[0015] (ii)

[0016] (a) (CH3CO)2O, HCO2H, NEt3, DMAP;

[0017] (b) DBU; and

[0018] (c) MeOH, NH3; and

[0019] (iii) Me3SiCl, NEt3.

[0020] Compounds of the formula (3) are obtainable by reacting a compound of the formula (2) with a compound of the formula HC[B(OR)2]3, such as tris(ethylenedioxyboryl)methane; R may be an alkyl or alkenyl group as defined above.

[0021] In the reaction there is optionally used a strong base, such as a C1-C4-alkyl-Li compound (such as butyllithium) or a di-C1-C4-alkylamine-Li compound (such as a dimethylamine-lithium compound). The reaction is generally carried out at low temperatures, such as, for example, at temperatures of less than −30° C., preferably at temperatures of less than −50° C., especially preferably at temperatures of at least −78° C. Further reaction conditions may be found in D. Schummer, G. Höfle in Tetrahedron 1995, 51, 11219.

[0022] For example, a compound of the formula (2) is reacted with tris(ethylenedioxyboryl)methane and butyllithium at −78° C. to form a compound of the formula (3).

[0023] A compound of the formula (4) may be produced from a compound of the formula (3) by reaction with N-iodo- or N-bromo-succinimide, optionally in a polar solvent, such as acetonitrile. Further reaction conditions may be found in the following literature reference: N. A. Petasis, I. A. Zavialor, Tetrahedron Lett. 1996, 37, 567.

[0024] For the production of a compound of the formula (5), a compound of the formula (3) may be reacted within the framework of a Suzuki coupling with a compound of the formula R2-Z, wherein R2 has the meanings given above and Z may be a halogen atom or a group of the formula —OSO2CF3, —CH═CHI, —CH═CHOSO2CF3. The group R2-Z may especially have the following structures: 3

[0025] wherein A1 represents O, S, N or C atoms and the substituents O—, N— and C— correspond to the above-described groups OR4, NR5R6 and alkyl, alkenyl and/or alkynyl groups.

[0026] Especially preferred as substituents “C” are C1-C6-alkyl or C2-C6-alkenyl and/or -alkynyl groups, especially C1-C4-alkyl or C2-C4-alkenyl and/or -alkynyl groups. As alkyl groups there are especially preferred methyl, ethyl, propyl and butyl groups.

[0027] Alternatively, a compound of the formula (5) may be produced by reacting a compound of the formula (4) by means of a Stille coupling with R2—SnR33, wherein R2 is as defined above and R3 is a C1- to C6-alkyl group, preferably a C1- to C4-alkyl group and especially preferably a methyl, ethyl, propyl or butyl group. In addition, the compound R2—SnR33 may have one of the following structures: 4

[0028] wherein the radicals and substituents are as defined above.

[0029] Furthermore, according to the invention, a compound of the formula (6) may be produced by removing the protecting group from the compound of the formula (5), for example with a weak acid, such as citric acid, or compounds such as TBAF, pyridine×HF. Optionally an alcohol, such as methanol, may be used as solvent, the temperature preferably being adjusted to values of, for example, from 40 to 60° C., preferably about 50° C.

[0030] In summary, the compound of the formula (6) may be produced by the above-described steps (epothilon A or B→(2)→(3)→(4)→(5)→(6) or epothilon A or B→(2)→(3)→(5)→(6)).

[0031] According to the invention there are also disclosed medicaments that contain at least one of the compounds (2), (3), (4), (5) or (6) and optionally customary carriers, diluents and adjuvants.

[0032] Such compounds may especially be used also as cytostatic agents and for plant protection in agriculture and/or forestry and/or in horticulture, the compounds optionally being used together with one or more customary carriers, adjuvants and/or diluents.

EXAMPLES

[0033] Synthesis of the Ketone Derivatives 2

[0034] For a detailed description see DE 195 42 986 A1.

[0035] Synthesis of the Alkenylboronic Acid Derivatives 3

[0036] (see also D. Schummer, G. Höfle, Tetrahedron 1995, 51, 11219)

[0037] Typical Example (R1=H, X-Y=CH2CHOTMS):

[0038] A solution of tris(ethylenedioxyboryl)methane (0.30 g, 1.5 mmol) in CH2Cl2/THF (1:1; 4 ml) was prepared and cooled under inert gas to −78° C. At that temperature, butyllithium (1.6M solution in hexane; 0.73 ml, 1.2 mmol) was added drop-wise in the course of 10 minutes. After 2 hours, ketone 2 (81 mg, 0.15 mmol) in CH2Cl2/THF (1:1, 2 ml) was added, heated to room temperature and stirred for 17 hours. After the addition of MeOH (2 ml), the clear reaction solution was purified by means of preparative HPLC (Lichroprep RP-18, CH3CN/H2O 75:25). 57 mg (65%) of alkenylboronic acid 3 were obtained in the form of an E/Z-isomeric mixture (6:4).

[0039] Selected typical data: LC-MS (ESI-MS): 585 (M++H); 1H-NMR: (300 MHz, CD3OD): E-isomer: 1.91 (S, 3H), 5.16 (d, 1H, 10 Hz), 5.49 (s, 1H), Z-isomer; 1.85 (d, 3H, 1.1 Hz), 4.93 (s, 1H), 5.26 (d, 1H, 9.6 Hz).

[0040] Synthesis of the Iodovinyl Derivatives 4

[0041] (see also N. A. Petasis, I. A. Zavialor, Tetrahedron Lett. 1996, 37, 567)

[0042] Typical Example (R1=H, X-Y=CH2CHOTMS):

[0043] At room temperature, N-iodosuccinimide (6.0 mg, 27 &mgr;mol) was added under inert gas and with the exclusion of light to a solution of alkenylboronic acid 3 (12 mg, 21 &mgr;mol; E/Z 9:1) in CH3CN (150 &mgr;l) and stirred for 3 hours. After concentration, the residue was purified by means of preparative thin-layer chromatography (SiO2, CH2Cl2/MeOH 95:5). 9 mg (66%) of the iodovinyl derivative 4 were isolated in the form of an E/Z-isomeric mixture (9:1).

[0044] Selected typical data: LC-MS (ESI-MS): 667 (M++H); 1H-NMR: (300 MHz, CDCl3); E-isomer: 1.82 (d, 3H, 1.1 Hz), 5.36 (d, 1H, 11 Hz), 6.43 (s, 1H), Z-isomer: 1.84 (d, 3H, 1.1 Hz), 5.54 (d, 1H, 10.5 Hz), 6.09 (s, 1H).

[0045] Suzuki Coupling of the Alkenylboronic Acid 3

[0046] (see also A. Suzuki, Acc. Chem. Res. 1982, 15, 178; A. Torrado, S. Lopez, R. Alvarez, A. R. De Lera Synthesis, 1995, 285)

[0047] Typical Example (R1=H, X-Y=CH2CHOTMS, R2=Ph):

[0048] A solution of alkenylboronic acid 3 (12 mg, 21 &mgr;mol; E/Z 2:8) and thallium ethanolate (2M solution in EtOH; 12 &mgr;l, 24 &mgr;mol) in THF (150 &mgr;l) was stirred at room temperature for 15 minutes, then a solution of phenyl iodide (4.0 &mgr;l, 6.0 mg, 29 &mgr;mol) and tetrakis(triphenylphosphino)-palladium (7.1 mg, 6.2 &mgr;mol) in THF (150 &mgr;l) was added drop-wise in 30 minutes and again stirred for 30 minutes. After purification by means of preparative thin-layer chromatography (SiO2, CH2Cl2/Et2O 95:5) the phenyl-analogous epothilon 5 (10 mg, 79%, E/Z 2:8) was obtained in the form of a colourless solid.

[0049] Selected typical data: LC-MS (ESI-MS): 617 (M++H); 1H-NMR: (300 MHz, CDCl3): E-isomer: 1.87 (d, 3H, 1.4 Hz), 5.35 (d, 1H, 10.7 Hz), 6.54 (s, 1H), Z-isomer: 1.80 (d, 3H, 1.5 Hz), 5.61 (d, 1H, 10.2 Hz), 6.41 (s, 1H).

[0050] Stille Coupling of the Iodovinyl Derivatives 4

[0051] (see also K. C. Nicolaou, Y. He, F. Roschangar, N. P. King, D. Vourloumis, T. Li Angew. Chem. 1998, 110, (1/2), 89)

Claims

1-17. (cancelled)

18. A compound of formula:

5

wherein

R1 is a H atom or a C1- to C8-alkyl group,

X-Y is a group of the formula —CH2CH(OP)— or —CH═CH—,

P is a protecting group, and

each R is independently a C1- to C8-alkyl group or a C2- to C6-alkenyl group.

19. The compound of claim 18 wherein at least one R is a C1- to C6-alkyl group.

20. The compound of claim 18 wherein at least one R is a C1- to C4-alkyl group.

21. The compound of claim 18 wherein at least one R is a C2- to C6-alkenyl group.

22. The compound of claim 18 wherein at least one R is a C2- to C4-alkenyl group.

23. The compound of claim 18 wherein R1 is a H atom or a C1- to C6-alkyl group.

24. The compound of claim 18 wherein R1 is a H atom or a methyl group.

25. A process for preparing a compound of the formula

6

wherein

R1 is a H atom or a C1- to C8-alkyl group,

X-Y is a group of the formula —CH2CH(OP)— or —CH═CH—,

P is a protecting group, and

each R is independently a C1- to C8-alkyl group or a C2- to C6-alkenyl group;

comprising: reacting a compound of the formula 2:

7

with a compound of the formula HC[B(OR)2]3.

26. The process according to claim 25 wherein the compound of the formula HC[B(OR)2]3 is tris(ethylenedioxyboryl)methane.

27. The process according to claim 25 wherein the compound of the formula 2 and the compound of the formula HC[B(OR)2]3 are reacted in the presence of a strong base.

28. The process according to claim 27 wherein the strong base is a C1-C4-alkyl lithium compound or a di-C1-C4-alkylamine lithium compound.

29. The process according to claim 28 wherein the strong base is butyllithium or dimethylamine lithium compound.

30. The process according to claim 25 wherein the compound of the formula II and the compound of the formula HC[B(OR)2]3 are reacted at a temperature of less than about −30° C.