AU2004200949A1 - 16-halogen-epothilone derivatives, method for producing them and their pharmaceutical use - Google Patents

16-halogen-epothilone derivatives, method for producing them and their pharmaceutical use Download PDF

Info

Publication number
AU2004200949A1
AU2004200949A1 AU2004200949A AU2004200949A AU2004200949A1 AU 2004200949 A1 AU2004200949 A1 AU 2004200949A1 AU 2004200949 A AU2004200949 A AU 2004200949A AU 2004200949 A AU2004200949 A AU 2004200949A AU 2004200949 A1 AU2004200949 A1 AU 2004200949A1
Authority
AU
Australia
Prior art keywords
dihydroxy
methyl
hydrogen
dione
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
AU2004200949A
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU31567/00A external-priority patent/AU3156700A/en
Application filed by Schering AG filed Critical Schering AG
Priority to AU2004200949A priority Critical patent/AU2004200949A1/en
Publication of AU2004200949A1 publication Critical patent/AU2004200949A1/en
Abandoned legal-status Critical Current

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

I
Our Ref: 12228421 P/00/011 Regulation 3:2
AUSTRALIA
Patents Act 1990
ORIGINAL
COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): Schering Aktiengesellschaft Mullerstrasse 178, D-13353 Berlin Germany Address for Service: Invention Title: DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street Sydney, New South Wales, Australia, 2000 16-halogen-epothilone derivatives, method for producing them and their pharmaceutical use The following statement is a full description of this invention, including the best method of performing it known to me:- 5951
I
-1- 16-halogen-epothilone derivatives, method for producing them and their pharmaceutical use This application is a divisional of Australian Patent Application No. 31567/00, the entire disclosure of which is incorporated herein by reference.
H6fle et al. describe the cytotoxic action of the natural substances epothilone A (R hydrogen) and epothilone B (R methyl) 9,,R
S
2 O H ,O OH 0 Epothilone A (R Epothilone B (R CH 3 in, Angew. Chem. [Applied Chem.], 1996, 108, 1671-1673.
Because of their in-vitro selectivity for breast cell lines and intestinal cell lines and their significantly higher activity against P-glycoprotein-forming, multiresistant tumor lines in comparison to taxol as well as their physical properties that are superior to those of taxol, a water solubility that is higher by a factor of 30, this novel structural class is especially advantageous for the development of a pharmaceutical agent for treating malignant tumors.
The natural substances are not sufficiently stable either chemically or metabolically for the development of pharmaceutical agents. To eliminate these drawbacks, modifications to the natural substance are necessary. Such modifications are possible only with a total-synthesis approach and require synthesis strategies that make possible a broad modification of the natural substance. The purpose of the structural changes is also to increase the therapeutic range. This can be done by improving the selectivity of the action and/or increasing the active strength and/or reducing undesirable toxic side-effects, as they are described in Proc. Natl. Acad. Sci. USA 1998, 95, 9642-9647.
The total synthesis of epothilone A is described by Schinzer et al. in Chem. Eur. J. 1996, 2, No. 11, 1477-1482 and in Angew.
Chem. 1997, 109, No. 5, pp. 543-544). Epothilone derivatives were already described by H6fle et al. in WO 97/19086. These derivatives were produced starting from natural epothilone A or B. Also, epothilone C and D (double bond between carbon atoms 12 and 13: epothilone C deoxyepothilone A; epothilone D deoxyepothilone B) are described as possible starting products for this purpose.
Another synthesis of epothilone and epothilone derivatives was described by Nicolaou et al. in Angew. Chem. 1997, 109, No.
1/2, pp. 170-172. The synthesis of epothilone A and B and several epothilone analogs was described in Nature, Vol. 387, 1997, pp. 268-272; and the synthesis of epothilone A and its derivatives was described in J. Am. Chem. Soc., Vol. 119, No. 34, 1997, pp. 7960-7973 as well as the synthesis of epothilone A and B and several epothilone analogs in J. Am. Chem. Soc., Vol. 119, No. 34, 1997, pp. 7974-7991 also by Nicolaou et al.
Nicolaou et al. also describe in Angew. Chem. 1997, 109, No.
19, pp. 2181-2187 the production of epothilone A analogs using combinatory solid-phase synthesis. Several epothilone B analogs are also described there.
Epothilone derivatives, in some cases also epothilone C and D, are further described in Patent Applications WO 99/07692, WO 99/02514, WO 99/01124, WO 99/67252, WO 98/25929, WO 97/19086, WO 98/38192, WO 99/22461 and WO 99/58534.
In the epothilone derivatives that became known previously, no halogen atom can stand at carbon atom 16 of the epothilone skeleton.
The content of the priority documents DE 199 08 765.2 and DE 199 54 230.9 in this patent applicant as well as in WO 99/07692 of the applicant is incorporated by reference in these documents as part of the disclosure in this patent application.
The object of this invention consists in making available new epothilone derivatives, which are both chemically and metabolically stable enough for the development of pharmaceutical agents and which are superior to natural derivatives in terms of their therapeutic range, their selectivity of action and/or undesirable toxic side-effects and/or their active strength.
This invention describes.the new epothilone derivatives of general formula I, in which Rla, Rib are the same or different and mean hydrogen, C 1
-C
10 alkyl, aryl, C 7
-C
20 aralkyl, or -together a (CH 2 m group with m 2, 3, 4 or
R
2 a. R~b are the same or different and mean hydrogen, C 1
-C
10 alkyl, aryl, C 7
-C
20 aralkyl or together a (CH 2 groupwith n 4 or R3 means hydrogen, C 1
-C
1 O alkyl, aryl, C 7
-C
20 aralkyl, G means an oxygen atom or a group CH 2
R
4 RQb are the same or different and mean hydrogen, C -C 10 alkyl, aryl, C 7
-C
20 aralkyl or together a (CH2)p group with p 2, 3, 4 or D-E means a group
H
2
C-CH
2 HC=CH, HcjI 1 I{ H2G0 HC-CH I IIITOC H H H H H H
R
5 means hydrogen, C 1
-C
10 alkyl, aryl, C 7
-C
20 aralkyl, CO 2
H,
CO
2 -alkyl, CH20H, CH2O-alkyl, CH2O-acyl, CN, CH 2
NH
2
CH
2 N(alkyl, acyl) 1,2 CH 2 Hal R R 7 each mean a hydrogen atom, together an additional bond or an oxygen atom,
R
8 means a halogen atom, or a cyano group, X means an oxygen atom, two alkoxy groups OR 23 a C2-C1 alkylene-o,&-dioxy group, which can be straight-chain or branched, H/OR 9 or a grouping CR'R", whereby
R
23 stands for a C 1
-C
20 alkyl radical,
R
9 stands for hydrogen or a protective group PGX,
R
10
R
11 are the same or different and stand for hydrogen, a C 1
-C
20 alkyl, aryl, C 7
-C
20 aralkyl radical or R 10 and R 11 together with the methylene carbon atom together stand for a 5- to 7-membered carbocyclic ring, T-Y means a group O-CH 2 CHC NR 24
NR
24
SO
2
R
24 means hydrogen, C 1
-CI
0 alkyl, Z means an oxygen atom or H/OR 2 whereby
R
12 is hydrogen or a protective group PGZ.
Halogen atom R 8 can be a fluorine, chlorine, bromine or iodine atom. Fluorine, chlorine and bromine are preferred, and of the latter especially fluorine and chlorine.
R
2 a is preferably to mean a methyl, ethyl, propyl or butyl group.
A trimethylene group preferably commonly stands for substituents Ra and Rib, or R a and Rlb each mean a methyl group.
Rio/R 11 in group X preferably stand for a 2-pyridyl radical/hydrogen or a 2-methyl-4-thiazolyl radical/hydrogen or a 2-hydroxymethyl-4-thiazolyl radical/hydrogen or a 2-methyl-4oxazolyl radical/hydrogen or a 2-hydroxymethyl-4-oxazolyl radical/hydrogen.
T-Y is preferably a group or a group NR 24 Z primarily means an oxygen atom.
Between carbon atoms 10 and 11, there is a simple bond in the preferred compounds of general formula I, stands for an ethylene group.
In addition, R 3 usually stands for a hydrogen atom in the compounds according to the invention.
The combination H/CH 3 preferably stands for the two substituents R 4 a/R 4 b.
An embodiment of the invention calls for those compounds of general formula I in which R 8 stands for, a fluorine atom or chlorine atom and Ra Rib together mean a trimethylene group.
According to another embodiment, the invention relates to those compounds of general formula I in which R 8 stands for a fluorine atom or chlorine atom and R 1 1 stand for a 2-pyridyl radical/hydrogen.
Still another variant are those compounds of general formula I in which R 8 stands for a fluorine atom or chlorine atom, and
R
2 a/R 2 b stand for ethyl/hydrogen.
Still another embodiment of the invention are those compounds of general formula I, in which R 8 stands for a fluorine atom or chlorine atom, R la Rib together mean a trimethylene group and R2a/R 2 b stand for ethyl/hydrogen.
In addition, this variant for the compounds according to the invention can be mentioned in which R 8 stands for a fluorine atom or chlorine atom, R2a/R 2 b stand for ethyl/hydrogen and R' 1
/R
11 stand for a 2-pyridyl radical/hydrogen.
Further embodiments of this invention will emerge from the features of the subclaims.
The production of the new epothilone derivatives is based on the linkage of three partial fragments A, B and C. This process is described in DE 197 51 200.3, date of application 11/13/1997 as well as in the corresponding WO 99/07692 for the production of epothilone derivatives[ which as R 8 contain, for example, a methyl or longer alkyl group instead of the halogen atom according to the invention. The interfaces are as indicated in general formula I'.
A means a Cl-CE fragment (epothilone numbering system) of general formula R a, R IF e, R
R
R 140
A,
in which Ria', R 13 Rl1 3 a, Rib', R 2 a' and R 2 b' have the meanings already mentioned for Rla, Rib, R 2 a and R 2 b, and means CH 2 0Rl, CH 2 -Hal, CHO, C02R COHal, means hydrogen, OR 1 Ha, OS0 2 Rlb Rl 4 a mean hydrogen, S0 2 -alkyl, S0 2 -aryl, S0 2 -aralkyl or together a (CH 2 0 group or together a CRl 5 8R1Ib group,
R
13b
R
1 4 b mean hydrogen, C 1
-C
20 alkyl, aryl, C 7
-C
20 aralkyl,
R
1 5a, R15b are the same or different and mean hydrogen, C -C 0 l alkyl, aryl, C 7
-C
20 aralkyl or together a -(CH 2 )q group, Hal means halogen Cl, Br, I), o means 2 to 4, q means 3 to 6, including all stereoisomers as well as their mixtures, and free hydroxyl groups in R 13 and R 14 can be etherified or esterified, free carbonyl groups can be ketalized in A and R 3 converted into an enol ether or reduced, and free acid groups in A can be converted into their salts with bases.
B stands for a C7-C12 fragment (epothilone numbering system) of general formula
R
5 Ra' R4b' 1 2 EG7 R3' V DG
W
B
in which
R
3
R
4
R
4 b' and R 5 have the meanings already mentioned for
R
3
R
4a
R
4 b and R 5 and D, E and G have the meanings that are indicated in general formula I, and V means an oxygen atom, two alkoxy groups OR 17 a C2-C1 alkylene-a,)-dioxy group, which can be straight-chain or branched or H/OR 1 6 I I W means an oxygen atom, two alkoxy groups OR 19 a C 2
-C
10 alkylene-a,)-dioxy group, which can be straight-chain or branched or H/OR 1 8
R
16
R
18 independently of one another, mean hydrogen or a protective group PG 1
R
17
R
19 independently of one another, mean CI-C 20 alkyl.
C stands for a C13-C16 fragment (epothilone numbering system) of general formula
RV
3 Rr
R
U^^
C
in which
R
8 has the meaning already mentioned in general formula I for R 8 (halogen), and
R
7 means a hydrogen atom, T' means a group OR 20 whereby R 20 is a hydrogen atom or a protective group PG 2 a halogen atom, preferably a bromine or iodine atom, an azido group or a protected amino group,
R
21 means a hydroxy group, halogen, a protected hydroxy group OPG 3 a phosphonium halide radical PPh3+Hal" (Ph phenyl; Hal F, Cl, Br, a phosphonate radical P(O) (OQ) 2 (Q C1-Ci0 alkyl or phenyl) or a phosphine oxide radical P(O)Ph 2 (Ph phenyl), U means an oxygen atom, two alkoxy groups OR 23 a C 2 alkylene-a,B-dioxy group, which can be straight-chain or branched, H/OR 9 or a grouping CR 1
R
11 whereby
R
23 stands for a C 1
-C
20 alkyl radical,
R
9 stands for hydrogen or a protective group PG 3
R
10
R
1 are the same or different and stand for hydrogen, a C 1
-C
20 alkyl, aryl, C 7
-C
20 aralkyl radical or R 10 and R 11 together with the methylene carbon atom commonly stand for a 5- to 7-membered carbocyclic ring.
As alkyl groups R 1 a, Rb, R 2 a, R 2 b, R 3
R
4
R
5
R
9
R
10
R
11
R
12
R
13 b R 14 b, R 15 a, R 15 b, R 17 and R 23 straight-chain or branched-chain alkyl groups with 1-20 carbon atoms can be considered, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.
Alkyl groups Ra, Rib, R 2 a, R 2 b, R 3
R
4
R
5
R
9
R
10
R
11
R
12
R
13 b, R1 4 b, R 15 a, R 15 b, R 17 and R 23 can be perfluorinated or substituted by 1-5 halogen atoms, hydroxy groups, C,-C 4 alkoxy groups, C 6 -C 1 aryl groups (which can be substituted by 1-3 halogen atoms).
As aryl radicals R 1a RIb, R 2 a, R 2 b, R 3
R
4
R
5
R
9
R
10
R
1
R
12
R
13 b, R14b,, R 15 a and R 15 b, substituted and unsubstituted carbocyclic or heterocyclic radicals with one or more heteroatoms, such as, phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, which can be substituted in one or more places by halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, -NH 2
-NO
2
-N
3 -CN, C 1
-C
20 alkyl, C -C 20 acyl, CI-C 20 acyloxy groups, are suitable.
Heteroatoms in the heteroaryl radicals can be oxidized; thus, for example, the thiazole ring can be present in the form of N-oxide.
Unless otherwise indicated, the definition of "aryl" always also includes "heteroaryl." The aralkyl groups in Ria, Rb R 2 a, R 2 b, R 3
R
4
R
5
R
9
R
10
R
11
R
1 2
R
13 b, R 14 b, R 15 a and R 15 b can contain in the ring up to 14 C atoms, preferably 6 to 10, and in the alkyl chain 1 to 8, preferably 1 to 4 atoms. As aralkyl radicals, for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, and pyridylpropyl are suitable. The rings can be substituted in one or more places by halogen, OH, O-alkyl, CO 2
H,
CO
2 -alkyl, -NO 2
-N
3 -CN, C 1
-C
20 alkyl, C,-C 20 acyl, C2-C 20 acyloxy groups.
The alkoxy groups that are contained in X in general formula I are in each case to contain 1 to 20 carbon atoms, whereby methoxy, ethoxy, propoxy, isopropoxy and t-butyloxy groups are preferred.
As representatives of protective groups PG, alkyl- and/or aryl-substituted silyl, C 1
-C
2 o alkyl, C 4 cycloalkyl, which in addition in the ring can contain an oxygen atom, aryl, C 7
-C
20 aralkyl, CI-C 20 acyl and aroyl can be mentioned.
As alkyl, silyl and acyl radicals for protective groups PG, the radicals that are known to one skilled in the art are suitable. Preferred are alkyl or silyl radicals that can be easily cleaved from the corresponding alkyl and silyl ethers, such as, for example, the methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tertbutyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl, para-methoxybenzyl radical as well as alkylsulfonyl and arylsulfonyl radicals. As acyl radicals, e.g., formyl, acetyl, propionyl, isopropionyl, pivalyl, butyryl or benzoyl, which can be substituted with amino groups and/or hydroxy groups, are suitable.
Acyl groups PGX or PGz in R 9 and R 12 can contain 1 to carbon atoms, whereby formyl, acetyl, propionyl, isopropionyl and pivalyl groups are preferred.
As amino protective groups, the radicals that are known to one skilled in the art are suitable. For example, the Boc-, Z-, benzyl, f-Moc, Troc-, Stabase or Benzostabase groups can be mentioned.
Index m in the alkylene group that is formed from Ra and R1b preferably stands for 2, 3 or 4.
The C 2
-C
1 alkylene-a,&-dioxy group that is possible for X is preferably an ethyleneketal or neopentylketal group.
This invention relates in particular to the following compounds: (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-Dihydroxy-16-(l-fluoro- 2-(2-methyl-4-thiazolyl)ethenyl) -1-oxa-5,5,7,9,13-pentamethylcyclohexadec-13-ene-2,6-dione (1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(l-fluoro- 2-(2-methyl-4-thiazoly1)etheylY)8,8,10,12,16pentamethyl- 4 ,1 7 dioxabicyclo [14.1.0] heptadecane-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethlyl-16-(1fluoro-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5,9, 13tetramethyl-cyclohexadec-13-ele-2, 6-dione (1RS,3S(Z),7S,10R,11S,12S,1RS)7,11dihydroxy-10ethyl-3- (1-fluoro-2- (2-methyl-4-thiazolyl) ethenyl) -8,8,12, 16-tetramethyl- 4, 17-dioxabicyclo [14. 1.01 heptadecane-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-fluoro- 2- (2-methyloxazol-4-yl)ethelyl) -1-oxa-5,5,7,9,13-pefltamethylcyclohexadec-13-ele-2, 6-dione (1RS,3S(Z) ,7S,1OR,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluoro- 2- (2-methyloxazo1-4-yl)ethefyly)-8,8,10,12,16-pefltamethyl- 4 ,l 7 dioxabicyclo [14 .1.o0]heptadecane-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-1611l fluoro-2-(2-methyloxazol-4-y)ethefyl)loxa-5,5, 9 1 3 tetramethyl-cyc-ohexadec-13-ele-2, 6-dione C1(RS,3S(Z),7S,1OR,11S,12S,16RS)-7,11-dihydroxy-10-ethyl- 3 (i-fluoro-2- (2-methyloxazol-4-yl)etheli) -8,8,12,16-tetramethyl- 4, 17-dioxabicyclo [14.1.0] heptadecane-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(l-fluoro- 2- (2-pyridyl)ethenyl) -1-oxa-5,5,7,9, 13-pentamethyl-CyclohexadeC- 13 -ene-2, 6-dione (IRS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(l-fluoro- 2-(2-pyridyl)ethenyl)-8,8,10,-12,16-peftamethyl-4,17dioxabicyclo [14.1.0] heptadecane-5, 9-dione (4S,7R,8S,9S,13(Z or E),1GS(Z))-4,8-dihydroxy-7-ethyl-16- (1fluoro-2-(2-pyridyl)ethelyl) -1-oxa-5,5,9,13-tetramethylV cyclohexadec-13-efle-2 1 6-dione (lR.S, 3S(Z) ,7S,IOR,11S, 12S, 16RS) ii-dihydroxy-lO-ethyl-3- (1-fluor-o-2-(2-pyridy)etheylY18,8,12,16tetramethyl- 4 ,1 7 dioxabicyclo [14.1.0] heptadecane-5, 9-dione (4S,7R,.8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-fluoro- 2- (2-methyl-4-thiazolyl)ethelyl) -l-aza--5,5,7,9,13-pefltamethylcyclohexadec-l3-ele-2, 6-dione (lRS,3S(Z) ,7S,1OR,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluoro- 2- (2-methyl-4-thiazolyl)ethelyl) -8,8,1O,12,16-pentamlethyl-4-aza- 17-oxabicyclo [14.1.0] heptadecaie-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16-(l1 fluoro-2- (2-methyl-4-thiazolyl)ethelyl) -1-aza-5,5,9,13tetramethyl-cyclohexadec13-ele- 2 6-dione (lRS, 3 S(Z),7S,IOR,11S,12S,16RS)-7,11-dihydroxy-10-etbyl- 3 (1-fluor~o-2- (2-methyl-4-thiazolyl)ethelyl) -8,8,12,16-tetramethyl- 4-aza-17-oxabicyclo[14c1.0]heptadecafe-5,9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-fluoro- 2- (2-methyloxazol-4-y)ethelyl) -1-aza-5,'5,7,9,13-peltam~ethylcyclohexadec-13-ele-2, 6-dione (iRS, 3S(Z) ,75,10R,11S, 12S, 16RS) 11-dihydroxy-3- (l-fluoro- 2- (2-met.hyloxazoi-4-yl)ethelyl) -8,8,10,12,16-pentamethyl-4-aza 17-oxabicyclo [14.1. olheptadecane-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16- (1fluoro-2 -(2-methyloxazol-4-yl) ethenyl) -1-aza-5, 5,9,13tetramet.hyl-cyclohexadec-13-ele-2, 6-dione (1R;S,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-10-ethyl-3- (i-fluoro-2- (2-methyloxazol-4-yl)ethenyl) -8,8,12,16-tetramethyl- 4-aza-17j-oxabicyclo [14.1.0] heptadecane-5, 9-dione (4Sc,7R,8S,9S,13(Z or E),16S(Z))-4,.8-dihydroxy-167(1-fluoro- 2- (2-pyr-idyl) ethenyl) -1-aza-5, 5,7,9, 13-pentamethyl-cyclohexadec- 13-ene-2, 6-dione (1]RS,3S ,7S,1 OR, 11S,12S,16RS) -7,11-dihydroxy-3- (1-fluoro- 2-(2-pyr-idyl)ethel) 8, 10, 12, 16-pentamethyl-4-aza-17oxabicyclo [14.1.01 heptadecane-5, 9-diane (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16-(1fluoro-2- (2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethylcyclohexadec-13-ene-2, 6-dione (1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-1O-ethyl-3- (1-fluor-o-2- (2-pyridyl)ethenyl) -8,8,12,16-tetramethyl-4-aza-17oxabicyclo [14.1.01 heptadecane-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(l-chloro- 2- (2-methyl-4-thiazolyl)ethenyl) -l-oxa-5,5,7,9, 13-pentamethyl- cyclohexadec-13-ene-2., 6-dione (lRS,3S(Z),7S,1OR,11S,12S,16RS)-7,11-dihydroxy-3-(1-chloro- 2- (2-methyl-4-thiazolyl)ethenyl) -8,8,10,,12,16-pentamethyl-4,17dioxabicyclo [14.1,.0]heptadecane-S, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16- (1chloro-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,1 3 tetramethyl-cyclohexadec-13-ene-2, 6-dione (1RS,3S(Z) ,7S,10R,11S,12S,16RS)-7,11-dihydroxy-10-ethyl-3- (1-chloro-2- (2-methyJ-4-thiazolyl)ethenyl) -8,8,12,16-tetramethyl- 4, 17-dioxabicyclo [14.1.0] heptadecane-5, 9-dione (4ES,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(l-chloro- 2- (2-methyloxazol-4-yl)ethenyl) -1-oxa-5,5,7,9, 13-pentamethylcyclohex~adec-13-ene-2, 6-dione (1R-S,3S(Z) ,7S,1OR,11S,12S,16RS)-7,11-dihydroxy-3-(l-chloro- 2- (2-methyloxazol-4-yl)ethelyl) -8,8,10,12,16-pentamethyl-4,17dioxabicyclo [14 heptadecane-5, 9-dione (4Es,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16- (1chloro-2- (2-methyloxazol-4-yl)ethenyl) -1-oxa-5,5,9,13tetramethyl-cyclohexadec-13-ene-2, 6-dione (1]RS,3S(Z) ,7S,1OR,11S,12S,16RS)-7,11-dihydroxy-1O-ethy1-3- (1-chloro-2- (2-methyloxazol-4-yl)ethenyl) -8,8,12,16-tetramethyl- 4, 17-dicxabicyclo [14 heptadecane-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-chloro- 2- (2-pyr-idyl)ethenyl) -1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec- 13-ene-2, 6-dione (lRS,3S(Z) ,7S,1OR,11S,12S,16RS)-7,11-dihydroxy-3-(1-chloro- 2-(2-pyr-idyl)etheflyl)-8,8,10,12,16-pefltamethyl-4,17dioxabicyclo [14.1.0] heptadecane-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16- (1chloro-2- (2-pyridyl)ethenyl) -1-oxa-5,5,9.,13-tetramethylcyclohexadec-13 -ene-2, 6-dione .(1RS,3S(Z) ,7S,10R,11S,12S,16RS)-7,11-dihydroxy-1Q-ethyl-3- (1-chloro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17dioxabicyclo [14.1.0] heptadecane-5, 9-dione (4S,7R,8S,9S,13(Z or E),1GS(Z))-4,8-dihydroxy-16-(1-chloro- 2- (2-methyl-4-thiazolyl)ethenyl) -1-aza-5,5,7,9,13-pentamethylcyclohexadec-13 -ene-2, 6-dione (iR)S, 3S(Z) ,7S,10R, 115, 125,16RS) ii-dihydroxy-3- (1-chiara- 2- (2-met.hyil-4-thiazolyl) ethenyl) -8,8,10,12, 16-pentamethyl-4-aza- 17-oxabicyclo [14.1.0] heptadecane-5, 9-diane (4Es,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16- (1chloro-2-(2-methyl-4-thiazolyl)ethelyl)-1-aza-5,5,9,1 3 tetramethyi-cyclohexadec-13-ele-2, 6-diane (iR;S, 3S(Z) ,7S, OR, 115, 125, 1RS) 11-dihydroxy-10-ethyl-3- (1-chloara-2- (2-methyl-4-thiazolyl)ethelyl) -8,8,12,16-tetralnethyl- 4-aza-17'-oxabicycla [14.1.0] heptadecane-5, 9-diane (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-chloro- 2- (2-methyloxazol-4-yl)ethelyl) -1-aza-5,5,7,9,13-pefltamethylcyclohex~adec-13-ene-2, 6-diane (1]R5,3S(Z) ,7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-chloro- 2- (2-methyloxazol-4-yi)ethenyl) -8,8,10,12,16-pentamethyl-4-aza- 17-axabicycla [14 .1.01 heptadecane-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16- (1chioro-2- (2-methyloxazol-4-yl) ethenyl) -1-aza-5, 5,9,13tetramethyl-cyclohexadec-13-ele-2, 6.-diane (1RS,3S(Z),7S,1.OR,11S,12S,16RS)-7,11-dihydroxy-10-ethyl-3- (1-chlarao-2- (2-methyloxazol-4-y1)ethenyl,) -8,8,12,16-tetramethyl- 4 -aza-17-axabicycla [14.1.0] heptadecane-5, 9-diane (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-chloro- 2- (2-pyr-idyl)ethenyl) -1-aza-5,5,7,9,13-pentamethyl-cyclohexadec- 13-ene-2, 6-diane (iR.S, 3S(Z) ,7S,10R,11S, 125,16RS) i1-dihydraxy-3- (1-chiara- 2-(2-pyr-idyl)ethenyl)-8,8,10,12,16-pentamtethyl-4-aza-17axabicy clo [14 .1 0] heptadecane-5, 9-diane (4Sc,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16- (1chloro-!- (2-pyridyl) ethenyl) -l-aza-5, 5,9, 13-tetramethylcyclohexcadec-13-ene-2, 6-diane (1R)S,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-1-ethy.-3- (1-chlarao-2- (2-pyridyl)ethenyl) -8,8,12,16-tetramethyl-4-aza-17axabicyclo [14.1.0] heptadecane-5, 9-diane (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy--6-(1-fluorotrimethylene) cyclohexadec-13-ene-2, 6-diane (1R.s,3S(Z),7S,1OR,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluoro- 2-(2-methyl-4-thiazo1yl)ethenyly)-10,12,16trimethylV8,8i(1,3trimethylene) -4,17-dioxabicyclo[14.1.0]hepta-deca-5,9-difle (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-9,13-dimethyl- 7-ethyl-16- (l-fluoro-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-S, 3-trimethylene) cyclohexadec-13-ene-2,6-diane (1RS,3S(Z),7S,IOR,11S,12S,l6RS)-7,11-dihydroxy-12,16dimethyl-10-ethyl-3- (1-fluoro-2- (2-methyl-4-thiazolyl)ethenyl) 8,8- (1,3-trimethylene) .v4,17-dioxabicyco[14.1.0]hepta-decane-5,9diane (4S,7R,8S,9S,13(Z or E),165(Z))-4,8'-dihydroxy-16-(1-fluoro- 2- (2-methyl-4-thiazolyl) ethenyl) -1-aza-7, 9, 13-trimethyl-5, 5- (1,3trimethy-lene) cyclohexadec-13-ene-2, 6-diane (lRS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluora- 2-(2-methyl-4-thiazolyl)ethenyl)-10,12,16-trim~ethyl-8,8-(1,3triniethylene) -4-aza-17-oxabicyclo[14.1.0]hepta-deca-5,9-dione (4.S,7R,8S,9S,13(Z or E),1GS(Z))-4,8-dihydroxy-9,13-dimethyl- 7-ty-6(-loo2(-ehl--haoy~tey)laa55 3-trimethylele) cyclohexadec-13-ele-2, 6-dione (l1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-12,16dimethyi.-10-ethYl-3- (1-f luoro-2- (2-methyl-4-thiazolYl) ethenyl) 8,8- (1,3-trimethylene) -4-aza-17-oxabicyclo[14.1.O]hepta-decale- 9-dione (4S:,7R,8S,9S,13(Z or E),1GS(Z))-4,8-dihydroxy-16Ilchloro- 2-(2-methy-4thiazoly)ethefl)oxa7,9,13trimethyl-5,S-(1, 3 trimethylene) cyclohexadec-13-ene-2, 6-dione (1RS,3S(Z),7S,IOR,11S,12S,16RS)-7,11-dihydroxy-3-(1-chloro- 2- (2-methyl-4-thiazolyl)ethelyl) -10, 12, i6-trimethyl-8, 8- (1,3trimethylene) -4,17-dioxabicyclo[14.1.O]hepta-deca-5,9-diofle (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-9,13-dimethyl- 7-ethyl-16- (1-chloro-2- (2-methyl-4-thiazolyl) ethenyl) -l-oxa-5, 3-trimethylele) cyclohexadec-13-ene-2, 6-dione (l1RS,3S(Z) ,7S,10R,11S,12S,16RS)-7,11-dihydroxy-12,16dimethyl-10-ethyl-3- (1?.chloro-2- (2-methyl-4-thiazolyl)ethelyl) 8,8- (1,3-trimethylene) -4,17-dioxabicyclo[14.1.0]heptadecale-5,9dione 4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(l-ch10r- 2 (2-methy1-4-thiazoy)etheny)--aza-7,9,13trimethyl5,S-(1, 3 trimethy-lene) cyclohexadec-13-ene-2, 6-dione (1RS,3S(Z) ,7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-chloro- 2-(2-methyl-4-thiazolyl)etheflyl)-10,12,16-trimfethyl 8 8 il, 3 trimethy-lene) -4-aza-17-oxabicyclo[14.1.Olhepta-deca-5,9-diofle (4Sc,7R,8S,9S,13(Z or E) ,16S(Z))-4,8-dihydroxy-9,13-dimfethyl- 7-ethy1-16-(1-chloro-2-(2-mfethy-4-thiazolyl)ethefl1V-aza-5,5- 3-trimethylene) cyclohexadec-13-ene-2, 6-diane dimethyi.-10-ethYl-3- (1-chloro-2- (2-methyl-4-thiazolyl)ethelyl) 8,8- (1,3-trimethylele) -4-aza-17-oxabicyclo[14.1.0]heptadecale- 9-dian~e (4.c,7R,8S,9S,13(Z or E),1ES(Z))-4,8-dihydroxy-16-(1-fluoro-' trimethylene) cyclohexadec-13-ene-2, 6-diane (1]RS,3S(Z) ,7S,1OR,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluoro- 2- (2-pyr-idyl) ethenyl) -10, 12, 16-trimethyl-8, 8- 3-trimethylene) 4, 17-dicxabicycla [14 hepta-deca-5, 9-diane (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-,dihydroxy-9,13-dimfethyl- 7-ethyl-16- (1-fluoro-2- (2-pyridyl) ethenyl) -1-oxa-5, 5- (1,3trimethy-lene) cyclohexadec-13-ene-2, 6-diane (lRS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-12,16dimethyl-10-ethyl-3- (.1.fluoro-2- (2-pyridyl)etheny'l) (1,3trimethy-lene) 17-dioxabicyclo [14.1.01 hepta-decane-5, 9-diane 4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-fluoro-2- (2-pyridyl)ethenyl)-l-aza-7,9,13-trimfethyl-5,5- (1,3trimethylene) cyclohexadec-13-ene-2, 6-diane (lRS,3S(Z),7S,1OR,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluoro- 2- (2-pyr-idyl) ethenyl) -101 12, 16-trimethyl-8, 8- 3-trimethylene) 4-aza-17-oxabicyclo [14.1.0] hepta-deca-5, 9-diane (4S,7R,8S,9S,13(Z or E),1SS(Z))-4,8-dihydroxy-9,13-dimfethyl- 7-ethyl-16- (1-fluoro-2- (2-pyridyl)ethenyl) -1-aza-5,5- (1,3trimethy-lene) cyclohexadec-13-ene-2, 6-diane (lRS,3S(Z),7S,1OR,11S,12S,16RS)-7,11-dihydroxy-12,16dimethyl-10-ethyl-3-(1-f1uoro-2-(2-pyridyl)etheflyl)8, 8 il1, 3 trimethy'lene) -4-aza-17-oxabicyclo[14.1.0]hepta-decale-5,9-diofle (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-chloro- 2-(2-pyr-idyl)ethefl)--oxa-7,9,13-trimethy1-5,Silh, 3 trimethy'lene) cyclohexadec-13-ene-2, 6-diane (lRS,3S(Z),7S,1OR,11S,12S,16RS)-7,11-dihydroxy-3-(1-chloro- 2-(2-pyridyl)ethenyl)-10,12,16-trimethyl-8,8-(1,3-trimethylene)- 4, 17-diaxabicyClo [14 0] hepta-deca-5, 9-diane (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-9,13-dimethyl- 7-ethyl-16-(-choro-2-(2-pyridy)ethefyl)1oxa5,Sii 3 trimethy-lene) cyclohexadec-13-ene-2, 6-diane (lRS,3S(Z),7S,IOR,11S,12S,16RS)-7,11-dihydroxy-12,16dimethyl-1O-ethyl-3-(1-chloro-2-(2-pyridyl)etheflyl) 8 8 1 i 3 trirnethylene) 17-dioxabicycla [14.1.0] hepta-decane-5, 9-diane 4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-ch10r-2- (2-pyridyl)ethenyl)l-aza-7,9,13-trimethyl-S 1 5-( 1 3 trimethy-lene) cyclohexadec-13-ene-2, 6-diane (IR.S,3S ,7S,10R,11S, 12S, 16RS) ll-dihydraxy-3- (1-chloro- 2- (2-pyridyl) ethenyl) -10, 12, 16-trimethyl-8, 8- 3-trimethylene) 4-aza-17-oxabicyclo[14.1.0]hepta-deca-5,9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydrxy-9,13-dimethyl- 7-ethyl-16- (1-chloro-2- (2-pyridyl) ethenyl) -1-aza-5, 5- (1,3trimethylene) cyclahexadec-13-ene-2, 6-diane (1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-12,16dimethyl-i0-ethyl-3-(1-chloro-2-(2-pyridyl)ethenyl)- 8 8 trimethylene)-4-aza-17-oxabicyclo[14.1.0]hepta-decane-5,9-dione Representation of Partial Fragments A and B: The partial fragments (synthesis components) of general formulas A and B can be produced as described in DE 19751200.3 or the corresponding WO 99/07692.
Representation of Partial Fragments C: The representation of the partial fragments of formula C according to the invention, in which R 8 means a fluorine atom, can be performed as is indicated in the following formula schemes within the production of the compounds of Examples 1 to 4 according to the invention.
By variation of the (hetero)aryl radical in the starting product in reaction step a) (in this case, this is the 2-methyl= 4-thiazolyl radical), the correspondingly substituted components of formula C and ultimately compounds of formula I result.
The production of fragments of formula C, in which R 8 means a chlorine atom, is described within Example If R 8 represents a bromine atom, this is introduced analogously to a chlorine atom in fragments C.
Formula Schemes in Examples 1 to 4 Example 1 From phosphonium salt lj analogously to DE 19751200.3 Ia) "ZN3 CO Et I b) N CHO
S
/N'CHO
S
F
N 0 0 S F -A c 0 S
F
N OH S-
F
3":A OH N CHO S-
F
N CHO 0 0~N~,B 0 0
H
0kN O
N
~OOH
0' N'I-
FS
0~ OTBDMS
FI\
S
0 OTBDMS
I>N
F
S
0 OTBOMS
N
F
S
S
F
OH
OTBOMS
OTBOMS
HO N
F
NN
8TBDMS
OTBDMS
F
NTDM
-26- Exmple 2 From phosphonium salt lj analogously to DE 19751200.3 Example 3 0 S
F
N
OH
0 0 OH n C Title compound A Title compound B Example 4 Title compound A Title compound B In addition to the compounds of general formula I, this invention also relates to the new C13-C16 epothilone components of general formula C as intermediate products
RT
13 R1 /I p21
R
C
in which
R
8 has the meaning that is already mentioned in general formula I for R 8 and means a hydrogen atom, T' means a group OR 2 0 whereby R 2 0 is a hydrogen atom or a protective group PG 2 halogen or an azido group or a protected amino group,
R
21 means a hydroxy group, halogen, a protected hydroxy group OPG 3 a phosphonium halide radical PPh 3 Hal" (Ph phenyl; Hal F, Cl, Br, a phosphonate radical P(O) (OQ) 2 (Q C,-C, 0 alkyl or phenyl) or a phosphine oxide radical P(O)Ph 2 (Ph phenyl), U means an oxygen atom, two alkoxy groups ORZ 3 a C 2 -C0 alkylene-a,o-dioxy group, which can be straight-chain or branched, H/OR 9 or a grouping CRi 0
R
11 whereby
R
23 stands for a C 1
-C
20 alkyl radical,
R
9 stands for hydrogen or a protective group PG 3
R
10
R
11 are the same or different and stand for hydrogen, a C-C 20 alkyl, aryl, C 7
-C
20 aralkyl radical or
R
10 and R 11 together with the methylene carbon atom commonly stand for a 5- to 7-membered carbocyclic ring.
According to the invention, those compounds of general formula C are preferred, in which
R
8 stands for a fluorine, chlorine or bromine atom, and/or U stands for an oxygen atom, and/or the aryl radical that stands for R 10 and/or R 11 stands for a phenyl radical that is optionally substituted with 1 to 3 radicals, selected from the group of substituents halogen, free hydroxy group or protected hydroxy group
OPG
5 COH, C0 2 -alkyl, C 1
-C
4 alkyl, azido, nitro, nitrile, amino (NH 2 or for a 5- or 6-membered heteroaryl radical that is optionally substituted with 1 to 2 C 1
-C
4 alkyl radicals, especially for a substituent that is selected from the group of 3furanyl, 4-pyridinyl, 5-thiazolyl- and 4- and 5-imidazolyl radicals, which optionally is substituted by 1 or 2 C 1
-C
4 alkyl radicals, and/or
PG
2 and PG 3 are selected from the group of substituents methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tertbutyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, acetyl, propionyl, butyryl and benzoyl radicals, in particular PG 2 is a tert-butyldimethylsilyl, acetyl, benzoyl, benzyl or tetrahydropyranyl radical.
As protective groups PG 4 and PG 5 all protective groups that are indicated above for PG 2 and PG 3 are suitable.
In addition, this invention relates to partial fragments of general formula BC
R
R
4
R
S
R
OPG
1' OPG 1
BC
in which R 3
R
4a
R
4 b, R 5
R
8 D, E, G, T' and U have the already mentioned meanings, and PG 14 represents a hydrogen atom or a protective group PG.
In addition, this invention relates to partial fragments of general formula ABC
OPG'
4 R 1 ;W R ib
R
R 1 4
ABC
in which R 1 Rb', R 2 a' R, R R4a', R 4
R
5
R
6
R
7
R
8
R
13
R
14 D, E, G, U and Z have the already mentioned meanings.
Representation of partial fragments ABC and their cyclization to
I:
The representation and cyclization is also carried out analogously to what is described in DE 1,9751200.3 or the corresponding WO 99/07692, whereby now fragment C as substituent
R
8 exhibits in particular a fluorine, chlorine or bromine atom: Partial fragments of general formula AB
R
R
4 b| R 3 RIa R Rib' 7
OPG
14 6 R'
R
3
R'
4 Z R
AB,
in which Ria', Rib', R 2
R
2
R
3
R
4 4 b' 5
R
13
R
14 D, E, G, V and Z have the meanings already mentioned, and PG 14 represents a hydrogen atom or a protective group PG, are obtained from the previously described fragments A and B according to the process that is shown in Diagram 1.
Diagram 1 R'A Rb' R A R
A
RS' R4a R4b' J V a w
B
Step a (A B AB): Compound B, in which W has the meaning of an oxygen atom and optionally present additional carbonyl groups are protected, is alkylated with the enolate of a carbonyl compound of general formula A. The enolate is produced by action of strong bases, such as, lithium diisopropylamide, lithium hexamethyldisilazane at low temperatures.
Partial fragments of general formula ABC 7 R R R
R
R
a D ,G RV G R SR
OPG
R 14
F
ABC,
in which R la
R
1
R
2
R
2
R
3
R
4
R
4 R, R 6
R
7
R
8
R
13
R
14 D, E, G, U and Z have the already mentioned meanings, are obtained from previously described fragments AB and C according to the process that is shown in Diagram 2.
I
Diagram 2 7 R 6
R
R
5 R G\ 0 E, b 1 3E RGib 4a 4 R
R
R 1 R 2 R" R'
R
SABC
AB
C
Step b (AB C ABC): Compound C, in which R 21 has the meaning of a Wittig salt, and optionally present additional carbonyl groups are protected, is deprotonated by a suitable base, such as, nbutyllithium, lithium diisopropylamide, potassium tertbutanolate, sodium or lithium-hexamethyldisilazide and reacted with a compound AB, in which V has the meaning of an oxygen atom.
Step c (ABC 1): Compounds ABC, in which R 13 represents a carboxylic acid
CO
2 H, T' stands for OR 20 and R 20 represents a hydrogen atom, are reacted according to the methods that are known to one skilled in the art for the formation of large macrolides to compounds of formula I, in which T-Y has the meaning of Preferred is the method that is described in "Reagents for Organic Synthesis, Vol. 16, p. 353" with use of 2,4,6-trichlorobenzoic acid chloride and suitable bases, such as, triethylamine, 4dimethylaminopyridine, sodium hydride.
I
Step d (ABC 1): Compounds ABC, in which R 13 represents a group CHOH and R 20 represents a hydrogen atom, can be reacted preferably with use of triphenylphosphine and azodiesters, such as, for example, azodicarboxylic acid diethyl ester, to form compounds of formula I, in which T-Y has the meaning of O-CH 2 Compounds ABC, in which R 13 represents a group CH 2
OSO
2 alkyl or CH 2
OSO
2 aryl or CH 2
OSO
2 aralkyl and R 20 represents a hydrogen atom, can be cyclized to compounds of formula I, in which T-Y has the meaning of O-CH 2 after deprotonation with suitable bases, such as, for example, sodium hydride, n-butyllithium, 4dimethylaminopyridine, Hinig base, alkylhexamethyldisilazanes.
As an alternative to the route above, partial fragments of general formula BC
R
1 J "R'I R U R O-PG
BC
in which R 3
R
4a
R
4 b, R 5
R
8 D, E, T' and U have the already mentioned meanings, and PG 1 4 represents a hydrogen atom or a protective group PG, can be obtained from the above-described fragments B and C according to the process that is shown in diagram 3.
Diagram 3
R'
Ij
C
FF
R
4 3
OPG"
B
To introduce a nitrogen group at C-15, the oxygen group can be converted directly or with T' Nf azide or a protected amine) or via the intermediate step of a halogen atom into a nitrogen group as desired in step C' (fragment C with T'
OR
20 or BC' (fragment BC with T' OR 20 at position U J 15 13
R
2 1 C1 Hal R 2 U r7 W R 2 1
C,
C's U%
R
3
BC"
OR"
R
4 "PGRu D EG
R
3 b OR4 PG 14 R D E G R 4b R BC"' U R42 P 14 BC' Nf PG If R 20 represents a hydrogen, the hydroxyl group can be converted according to the processes that are known to one skilled in the art into a halogen atom, preferably a chlorine, bromine or iodine atom, which then is converted into a nitrogengroup Nf, whereby Nf preferably represents an azide or a protected amine. As an alternative, the hydroxyl group at
(R
20 in the meaning of hydrogen) can be qonverted into a leaving group, preferably into an alkyl- or aralkyl-sulfonate and the latter can be substituted by a nitrogen nucleophile Nf.
I
Partial fragments of general formula ABC
ABC
in which R 1 Rb', R 2a
R
2
R
3
R
4
R
4
R
5
R
6
R
7
R
8 R 1 3 R 14 D, E, G, U and Z have the already mentioned meanings, are obtained from the above-described fragments BC and A according to the process that is shown in Diagram 4.
Diagram 4
ABC
A
The introduction of the nitrogen group at C-15 can also take place in step ABC as already described for or The flexible functionalization of described components A, B, and C also ensures a linkage sequence that deviates from the abovedescribed process and that leads to components ABC. These processes are listed in the following table: Possible Linkages Linkage Methods a Prerequisites to e A A B a: Aldol (see Z =W oxygen Diagram 1) B C -C b: Wittig U oxygen and R 21 (analogously to Wittig salt or Diagram 2) phosphine oxide or e: McMurry phosphonate U =V =oxygen A C -C c: Esterification R 13 Co 2 R 1 3 b or 2,4,6- COHal and trichlorobenzoyl R 20 hydrogen chloride/4 dimethylamino pyridine) d: etherification- R 13 CH 2 OH and R 20 Mitsunobu) =hydrogen or SO 2 alkyl or SO0 2 aryl or S0 2 -aralkyl f: amide formation R 3 =CO 2R1 3 b or COHal- 24 ?(PhO )2P K) in the T NI- 1NHR 2 presence of a base (e.g NaHCO 3 in an inert solvent
DMF)
a According to these processes, components A, B and C, as indicated in Diagram 5, can be linked: Diagram b or e A-B-C c or d or f a A B A-B+C c or d or f
C-A-B
b or e c or d or f C-A-B bore A+ C C A B
B-C-A
b or e
C-B-A
b or e B C C B A c or d or f
I
a
A-C-B
c or d or f Free hydroxyl groups in I, A, B, C, AB, ABC can be further functionally modified by etherification or esterification, free carbonyl groups by ketalization, enol ether formation or reduction.
This invention relates to all stereoisomers of the described and claimed compounds and also their mixtures.
Biological Actions and Applications of the New Derivatives: The new compounds of formula I are valuable pharmaceutical agents. They interact with tubulin by stabilizing microtubuli that are formed and are thus able to influence the cell-splitting in a phase-specific manner. This relates mainly to quickgrowing, neoplastic cells, whose growth is largely unaffected by intercellular regulating mechanisms. Active ingredients of this type are in principle suitable for treating malignant tumors. As applications, there can be mentioned, for example, the therapy of ovarian, stomach, colon, adeno-, breast, lung, head and neck carcinomas, malignant melanoma, acute lymphocytic and myelocytic leukemia. The compounds according to the invention are suitable owing to their properties basically for anti-angiogenesis therapy as well as for treatment of chronic inflammatory diseases, such as, for example, psoriasis or arthritis. To avoid uncontrolled proliferation of cells and for better compatibility of medical implants, they can basically be applied or introduced into the polymer materials that-are used for this purpose. The compounds according to the invention can be used alone or to achieve additive or synergistic actions in combination with other principles and classes of substances that can be used in tumor therapy.
As examples, there can be mentioned the combination with o Platinum complexes, such as, cis-platinum, carboplatinum, o intercalating substances, from the class of anthracyclines, such as, doxorubicin or from the class of anthrapyrazoles, such as, Cl-941, o substances that interact with tubulin, from the class of vinca-alkaloids, such as, vincristine, vinblastine or from the class of taxanes, such as, taxol, taxotere or from the class of macrolides, such as, rhizoxin or other compounds, such as, colchicine, combretastatin A-4, o DNA topoisomerase inhibitors, such as, e.g., camptothecin, etoposide, topotecan, teniposide, o folate- or pyrimidine-antimetabolites, such as, e.g, lometrexol, gemcitubin, o DNA-alkylating compounds, such as, adozelesin, dystamycin A, o inhibitors of growth factors of PDGF, EGF, TGFb, EGF), such as, somatostatin, suramin, bombesin antagonists, o inhibitors of protein tyrosine kinases or protein kinases A or C, such as, erbstatin, genistein, staurosporine, ilmofosine, 8-Cl-cAMP, o antihormones from the class of antigestagens, such as, mifepristone, onapristone or from the class of antiestrogens, such as, tamoxifen or from the class of antiandrogens, such as, cyproterone .acetate, o metastases-inhibiting compounds, from the class of eicosanoids, such as, PGl 2 PGE,, 6-oxo-PGE 1 as well as their more stable derivatives iloprost, cicaprost, misoprostol), o inhibitors of oncogenic RAS proteins, which influence the mitotic signal transduction, such as, for example, inhibitors of the farnesyl-protein-transferase, o natural or synthetically produced antibodies, which are directed against factors or their receptors, which promote tumor growth, such as, for example, the erbB2 antibody.
In Vitro Activity of Epothilone Derivatives on Human Tumor Cell Lines a) IC) values [nM] for the growth inhibition of human MCF-7 breast- and multi-drug-resistant NCl/ADR carcinoma cell lines of the epothilone derivatives with 13Z-olefins in a crystal-violet assay in comparison to epothilone D.
Table 1: Compound MCF-7 NC1/ADR Selectivity* Epothilone D 23 50 2.2 Taxol 4.0 >>100 Example 1 4.3 12 2.8 Example 5 5.1 37 7.3 Example 9 5.0 .10 Example 13 5.8 28 4.8 Example 17 6.1 33 5.4 *:Selectivity IC 50 -(NCl/ADR): IC 50 (MCF-7) The compounds of Examples 1, 9, 13 and 17 have a significantly higher active strength in comparison to structurally similar reference compound epothilone D. Unlike in taxol, all compounds show an action on the multi-drug-resistant cell line NC1/ADR.
b) IC 50 values [nM] for the growth inhibition of human MCF-7 breast- and multi-drug-resistant NCl/ADR carcinoma cell lines of the epothilone derivatives with 13,14-a-'epoxide in a crystalviolet assay in comparison to epothilone B.
I
Table 2: Compound MCF-7 NC1/ADR Selectivity* Epothilone B 0.6 3.5 5.8 Taxol 4.0 >>100 Example 3B 0.3 1.4 4.7 Example 7A 0.8 6.0 Example 10A 2.1 3.9 1.9 Example 14A 0.5 3.5 Example 20A 0.6 4.6 7.6 :Selectivity IC 50 -(NCl/ADR): IC 0 (MCF-7) The compounds of Examples 3B, 14A, and 20A have a comparable or significantly higher active strength in comparison to structurally similar reference compound epothilone B. Unlike in taxol, all compounds show an action on the multi-drug-resistant cell line NC1/ADR. Compounds of Examples 3B and 10A show an improved selectivity in multi-drug-resistant cell line NCl/ADR in comparison to reference compound epothilone B.
The invention also relates to pharmaceutical agents that are based on pharmaceutically compatible compounds, compounds of general formula I that are nontoxic in the doses used, optionally together with commonly used adjuvants and vehicles.
According to methods of galenicals that are known in the art, the compounds according to the invention can be processed into pharmaceutical preparations for enteral, percutaneous, parenteral or local administration. They can be administered in the form of tablets, coated tablets, gel capsules, granulates, suppositories, implants, injectable, sterile, aqueous or oily solutions, suspensions or emulsions, ointments, creams and gels.
In this case, the active ingredient or ingredients can be mixed with the adjuvants that are commonly used in galenicals, such as, gum.arabic, talc, starch, mannitol, methyl cellulose, lactose, surfactants such as Tweens or Myrj, magnesium stearate, aqueous or non-aqueous vehicles, paraffin derivatives, cleaning agents, dispersing agents, emulsifiers, preservatives and flavoring substances for taste correction ethereal oils).
The compounds according to the invention can be present in the form of 9- or y-cyclodextrin clathrates or can be encapsulated in liposomes.
The invention thus also relates to pharmaceutical compositions that as active ingredients contain at least one compound according to the invention. A dosage unit contains about 0.1-100 mg of active ingredient(s). In humans, the dosage of the compounds according to the invention is approximately 0.1- 1000 mg per day.
The examples below are used for a more detailed explanation of the invention, without intending that it be limited to these examples.
I
Examples for the Production of the Compounds of General Formula I According to the Invention Example 1 (4S,7R,8S,9S,13(Z),16S(Z))-4,8-Dihydroxy-16-(1-fluoro-2-(2methyl-4-thiazolyl)ethenyl)-l-oxa-5,5,7,9,13-pentamethylcyclohexadec-13-ene-2,6-dione Analogously to the processes that are described in DE 19751200.3, 36.5 mg of the title compound is obtained from the phosphonium salt of Example Ij as a pale-yellow-colored oil.
IH-]NMR (DMSO-d6): 6 0.93 0.94 1.10 0.8- 1.4 1.21 1.62 1.66 1.87 2.24 (1H), 2.3-2.6 2.64 2.73 3.13 3.53 4.22 5.16 5.36 6.22 7.46 (1H) ppm.
Example la 2-Methylthiazole-4-carbaldehyde 476 ml of a 1.2 molar solution of DIBAH in toluene is slowly added in drops at -75 0 C under nitrogen to a solution of 60 g of 2-methylthiazole-4-carboxylic acid ethyl ester in 1070 ml of methylene chloride. It is stirred for 2 more hours. Then, 150 ml of isopropanol and then 230 ml of water are slowly added in drops to it, the cold bath is removed, and it is stirred vigorously at 25 0 C for 2 more hours. The precipitate that is produced is suctioned off and rewashed with ethyl acetate. The filtrate is concentrated by evaporation in a vacuum, and the residue that is thus obtained is purified by chromatography on silica gel. With hexane/ether 1:1, 35.6 g of the title compound is obtained as a colorless oil.
1 H-NMR (CDC1 3 6 2.8 8.05 10.0 (1H) ppm.
Example lb (2Z)-3-(2-Methylthiazol-4-yl)-2-fluoro-2-propenoic acid ethyl ester A solution of 58.7 g of phosphonofluoroacetic acid triethyl ester in 120 ml of dimethoxyethane is added at 0°C to a suspension of 9.64 g of sodium hydride (60% suspension in mineral oil) in 120 ml of dimethoxyethane. It is stirred for 40 minutes, and then a solution of 15.4 g of the aldehyde, produced under Example la, in 120 ml of dimethoxyethane is added in drops and then stirred for 2 hours at 24 0 C under argon. After the mixing with aqueous ammonium chloride solution, it is extracted three times with ethyl acetate, the organic phase is washed with dilute sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The mixture of the Zand E-configured olefins is separated by column chromatography on silica gel. With hexane/ethyl acetate 4.:6 to 3:7 and in addition to 3.9 g of a mixed fraction, 7.5 g of (2E)-3-(2-methylthiazol-4yl)-2-fluoro-2-propenoic acid ethyl ester and 7.3 g of the title compound are obtained as colorless oils.
'H-NMR (CDCl 3 6 1.36 2.73 4.33 7.20 7.67 (1H) ppm.
Example Ic (2Z)-3-(2-Methylthiazol-4-yl)-2-fluoro-2-propen-l-ol 136 ml of a 1.2 molar solution of DIBAH in toluene is added in drops at -70 0 C under nitrogen to a solution of 18.8 g of the above-produced ester in 260 ml of toluene. After one hour, 55 ml of isopropanol and then 68 ml of water are slowly added in drops to it, and it is stirred vigorously for 2 more hours. The precipitate that is produced is suctioned off and rewashed well with ethyl acetate. The filtrate is concentrated by evaporation in a vacuum, and the residue that is thus obtained is purified by chromatography on silica gel. With hexane/0-70% ethyl acetate, 13.4 g of the title compound is obtained as a colorless oil.
'H-NMR (CDC1 3 5 2.69 3.71 4.27 6.18 7.35 (1H) ppm.
Example Id (2Z)-3-(2-Methylthiazol-4-yl)-2-fluoro-2-propenal A total of 53.3 g;of manganese dioxide is added in portions to a solution of 13.28 g of the above-produced alcohol in 200 ml of toluene, and it is stirred vigorously under nitrogen for 4 more hours. Manganese dioxide is suctioned off on Celite, washed well with ethyl acetate, and the filtrate is concentrated by evaporation in a vacuum. The residue that is thus obtained by chromatography on silica gel is purified. With hexane/0-30% ethyl acetate, 9.93 g of the title compound is obtained as a colorless oil.
1 H-NMR (CDC1 3 6 2.77 6.95 7.88 9.36 (1H) ppm.
Example le (3S,4Z)-5-(2-Methylthiazol-4-yl) -1-[(4S,5R)-4-methyl-5-phenyl- 1,3-1,3-oxazolidin-2-on-3-yl]-3-hydroxy-4-fluoro-4-penten-1- one 17.6 g of anhydrous chromium(II) chloride in 210 ml of THF under argon is introduced and mixed with 766 mg of lithium iodide. A solution of 9.8 g of the above-produced aldehyde and 18.8 g of (4S,5R)-3-(bromoacetyl)-4-methyl-5-phenyloxazolidin-2one in 38 ml of THF is then added in drops to it. It is stirred for 3 more hours. 150 ml of saturated sodium chloride solution is added, to it, it is stirred for 30 minutes, and the phases are separated. The aqueous phase is extracted twice with ethyl acetate, the combined organic phases are extracted once with water and once with saturated sodium chloride solution. The organic phase is dried on sodium sulfate, filtered off, and thefiltrate is concentrated by evaporation in a vacuum. The residue that is thus obtained is purified by chromatography on silica gel. With hexane/0-60% ethyl acetate, 1-1.22 g of the title compound in addition to 9.53 g of a mixed fraction and 1.8 g of the corresponding diastereomeric title compound are obtained as light oils.
1 H-NMR (CDC1 3 6 0.93 2.71 3.36 3.52 4.82 5.72 6.29 7.2-7.5 (6H) ppm.
Example If (3S,4Z)-5-(2-Meththiazol-ylthl)-1- [(4S,5R)-4-methyl-5-phenyl- 1,3-1,3-oxazolidin-2n-3-yl]-3-(tert-butyl-dimethylsilyloxy)-4fluoro-4-penten-l-one 4.68 ml of lutidine is added in drops at -70 0 C under nitrogen to a solution of 11.2 g of the above-produced title compound in 86 ml of methylene chloride, and it is stirred for more minutes. Then, 8.56 ml of tert-butyldimethylsilyltrifluoromethane sulfonate is slowly added in drops. After one hour, it is mixed with saturated ammonium chloride solution, and the reaction mixture is allowed to heat to 25 0 C. It is diluted with ether, washed once with water and once with saturated sodium chloride solution. The organic phase is dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue that is thus obtained is purified by chromatography on silica gel. With hexane/ether 1:1, 9.3 g of the title compound is obtained as a colorless oil.
IH-]NMR (CDC 3 .6i= 0.15 0.90 0.93 2.70 3.27 3.57 4.77 4.90 5.66 6.15 7.26-7.50 (6H) ppm.
Example Ig (3S,4Z)-5-(2-Methylthiazol-4-yl)-3-(tert-butyl-dimethylsilyloxy)- 4-fluoro-4-pentenoic acid ethyl ester 2.8 ml of titanium(IV) ethylate is added to a solution of 15.5 g of the above-produced title compound in 70 ml of ethanol, and it is refluxed for 4 hours under nitrogen. The reaction solution is concentrated by evaporation in a vacuum, the residue is taken up in 70 ml of ethyl acetate, mixed with water and stirred for 20 minutes. Titanium oxide is suctioned off, washed well with ethyl acetate, and the filtrate is concentrated by evaporation in a vacuum. The residue is mixed with hexane, the crystals are suctioned off and washed twice with hexane. The filtrate is concentrated by evaporation in a vacuum. The residue that is thus obtained is purified by chromatography on silica gel. With hexane/0-50% ethyl acetate, 11.9 g of the title compound is obtained as a colorless oil.
1 H-NMR (CDC1 3 6 0.11 0.91 1.26 2.70 2.71 4.15 4.74 6.12 7.37 (1H) ppm.
Example lh (3S,4Z)-5-(2-Methylthiazol-4-yl)-3-(tert-butyl-dimethylsilyloxy)- 4-fluoro-4-penten-l-ol 58.6 ml of a 1.2 molar solution of DIBAH in toluene is slowly added in drops under nitrogen at -70 0 C to a solution of 10.5 g of the above-produced title compound in 250 ml of toluene, and it is stirred for one hour at -30 0 10 ml of isopropanol is slowly added in drops to it at -70 0 C, then 22 ml of water, and it is vigorously stirred at 25 0 C for 2 more hours. The precipitate is suctioned off, washed well with ethyl acetate, and the filtrate is concentrated by evaporation in a vacuum. The residue that is thus obtained is purified by chromatography on silica gel. With hexane/0-70% ethyl acetate, 7.73 g of the title compound is obtained as a yellow oil.
'H-NMR (CDC1 3 6 0.12 0.16 0.93 2.00 2.72 3.77 3.86 4.53 6.13 7.36 (1H) ppm.
Example li (3S,4Z)-5-(2-Methylthiazol-4-yl)-3-(tert-butyl-dimethylsilyloxy)- 1-iodo-4-fluoro-4-pentene 1.90 g of imidazole is added to a solution of 7.31 g of triphenylphosphine in 106 ml of methylene chloride. 7.07 g of iodine is added to this solution, allowed to stir for 10 minutes and then a solution of 7.7 g of the above-produced title compound in 28 ml of methylene chloride is added in drops and stirred for minutes. It is filtered off, washed well with ether, and the filtrate is concentrated by evaporation in a vacuum. The residue that is thus obtained is purified by chromatography on silica gel. With hexane/0-10% ethyl acetate, 8.2 g of the title compound is obtained as a colorless oil.
1 H-NMR (CDC1 3 5,6= 0.11 0.16 0.93 2.23 2.71 3.24 4.36 6.12 7.36 (1H) ppm.
Example lj (3S,4Z)-5-(2-Methylthiazol-4-yl)-3-(tert-butyl-dimethylsilyloxy)- 4 -fluoro-4-pentene-triphenylphosphonium iodide 8.16 g of the above-produced title compound is mixed with 5.33 g of triphenylphosphine and stirred under nitrogen at 100 0
C
for 2 hours. After cooling, the solid residue is pulverized twice with ether and a little ethyl acetate, whereby the supernatant solution is pipetted off. Then, the residue is dissolved in methanol and concentrated by evaporation in a vacuum. The solid foam is dissolved again in a little methanol, mixed with toluene and again concentrated by evaporation in a vacuum. This process is repeated twice, then the residue is dried under high vacuum. 12.4 g of the title compound is obtained as a solid substance.
Flash point: 70-72 0
C
Example 2 (4S,7R,8S,9S,13(E),16S(Z))-4,8-Dihydroxy-16-(l-fluoro-2-(2methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethylcyclohexadec-13-ene-2,6 dione Analogously to Example 1, 41.5 mg of the title compound is obtained as a light yellow-colored oil from the phosphonium salt of Example Ij.
IH-NMR (CDC1 3 6 0.99 1.05 0.8-1.4 (6H), 1.16 1.30 1.5-1.7 1.76 2.00 2.18 2.43 2.56 2.63 2.70 3.25 3.40 3.66 4.30 5.13 5..61 6.18 7.48 (1H) ppm.
U
Example .3 (iR, 3S ,7S,10OR,11S, 12S, 16S) 11-Dihydroxy-3 (1-fluoro-2 methyl--4-thiazolyl)etheiyl) -8,8,10,12, 16-pentamethyl-4, 17dioxabicyclo [14.1.0] heptadecane-5, 9-dione and (1S,3S(Zl),7S,10R,11S,12S,16R)-7,11-dihydroxy-3-(1-fluoro-2-(2methyl-41-thiaz olyl)ethelyl) -8,8,10,12, 16-pentaiiethyl-4, 17dioxabicyclo [14 heptadecane-5, 9-dione (B) 0.3-72 ml of EDTA and 0.288 ml of 1,1,1-trifluoroacetone, then a mixture of 35.0 mg of oxone and 20.2 mg of sodium bicarbonate are added at 0 0 C under argon to 15 mg of the title compound, produced in Example 1, in 0.3 ml of acetonitrile. It is stirred for 3.5 hours at 0 0 C. It is mixed with 2 ml of sodium thiosulfate solution, stirred for*5 minutes and diluted with ml of ethyl acetate. The organic phase is washed once with semisatUrated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue that is thus obtained is purified by 2x preparative thick-layer chromatography. With methylene chloride/ethyl acetate 2:8 (1.PDC) or methylene chloride/methanol 98:2 (2.PDC), 2.5 mg of title compound A as a nonpolar component'-and 6 mg of title compound B as a polar component are obtained as colorless oils.
1 NMR (MeOH-d4) of A: 6 0.99 O3H), 1.04 0.8-1.9 (11H), 1.30 1.41 2.17 2.47 2.58 (1H), 2.71 3.01 3.2-3.4 3.78 4.33 4.8-5.0 5.71 6.26 7.53 (1H1) ppm.
IH-NMR (MeOH-d4) of B: 6 =0.99 1.01 0.9-1.9 1.12 (3H1), 1.30 (3H1), 1.33 (3H1), 1.95-2.10 2.18 (211), 2.41 (111), 2.48 2.70 3.2-3.4 3.63 3.85 4.34 5.34 5.63 6.19 7.51 (1H) ppm.
Example 4 (1R,3S(Z),7S,1OR,11S,12S,16R)-7,11-Dihydroxy-3-(1-fluoro-2-(2methyl-4-thiazolyl)ethenyl)-8,8, 1,12,16-pentamethyl-4,17dioxabicyclo [14.1.0] heptadecane-5, 9-dione and (1S,3S(Z),7S,1OR,11S,12S,16S)-7,11-dihydroxy-3-(1-fluoro-2-(2methyl-4-thiazolyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17dioxabicyclo [14.1.0] heptadecane-5,9-dione (B) Analogously to Example 3, 8.8 mg of title compound A as a nonpolar component and 9.0 mg of title compound B as a polar component are obtained as colorless oils from 38 mg of the title compound that is produced in Example 2.
'H-NMR (MeOH-d4) of A: 6 0.95 1.00 0.8-1.65 1.14 1.28 1.33 1.91 (111), 2.18 2.54 2.68 3.05 3.43 3.63 4.26 5.66 6.24 7.52. (1H) ppm.
IH-NrMR (MeOH-d4) of B: 6 0.95 1.02 0.8-1.7 1.:L4 1.29 1.32 1-77 2.09 2.23 2.5-2.65 2.69 3.14 3.33 3.70 (1H), 4.38 5.66 6.21 7.51 (1H) ppm.
Example i (4S,7R,85,9S,13(Z), l6S(Z))-4,8-Dihydroxy-16-(1-chloro-2-(2methyl-4- thiazolyl)ethenyl) -1-oxa-5,5,7,9,13-pentamethylcyclohexadec-13-ene-2,6-dione Example 2-Methylthiazol-4-carbaldehyde g of ethyl-2-methylthiazole-4-carboxylate is dissolved in 700 ml of methylene chloride, cooled to -70 0 C and carefully mixed with 390 ml of diisobutylaluminium hydride (1.2 molar in toluene). After 1 hour, the reaction was still not complete, and ml of diisobutylaluminium hydride was added in drops once more. After another 40 minutes, the reaction mixture was carefully mixed with 100 ml of isopropanol and stirred for minutes. Then, 215 ml of water is added in drops, and the cooling bath is removed. After 2 hours, the crystalline precipitate was suctioned off via a frit, washed with ethyl acetate, and the filtrate was concentrated by evaporation in a vacuum. 36.1 g of the title compound is obtained.
1 H-MR (CDC1 3 6 2.8 8.05 10.00 (1H) ppm.
Example (2Z)-3-(2-Methylthiazol-4-yl)-2-chloro-2-propenoic acid ethyl ester A solution of 97 g of triethyl-2-chloro-2-phosphonoacetate in 165 ml of dimethoxyethane is added within 15 minutes at 0 C under nitrogen to a suspension of 9 g of sodium hydride suspension in mineral oil) in 165 ml of dimethoxyethane. It is stirred for 45 minutes at 24 0 C, and then a solution of 31.8 g of the title compound, produced under Example 5a, in 165 ml of dimethoxyethane is added in drops, and it is then stirred for 1 more hour. After mixing with aqueous ammonium chloride solution, it is extracted three times with ethyl acetate, the organic phase is washed-with dilute sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The mixture of Z- and E-configured olefins is separated by column chromatography on silica gel. After column chromatography with hexane/ethyl acetate 10-30% and subsequent crystallization from hexane, 32 g of the title compound is obtained. (FP. 61 0 C-62 0
C)
'H-NMR (CDCl) 6 1.37 2.76 4.33 8.13 8.18 (1H) ppm.
Example Sc (2Z) -3-(2-Methylthiazol-4-yl)-2-chloro-2-propen-1-ol Analogously to Example Ic, 22.8 g of the title compound is obtained from 32 g of the ester, produced in Example 5b, in toluene as a solvent.
Example (2Z)-3-(2-Methylthiazol-4-yl)-2-chloro-2-propenal 9.8 g of the alcohol that is produced in Example 5c is dissolved in 500 ml of methylene chloride and mixed with 26.14 ml of triethylamine. Then, 16.14 g of S0 3 -pyridine complex is added, and it is stirred for 1 hour at 24 0 C. Now, it is mixed with ammonium chloride solution, extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution and dried on sodium sulfate. After concentration by evaporation in a vacuum, 10.03 g of the title compound is obtained.
Example (3S,4Z) 5-(2-Methylthiazol-4-yl)-1- [(4S,5R)-4-methyl-5-phenyll,3-oxazolidin-2-on-3-yl] -3-hydroxy-4-chloro-4-penten-l-one Analogously to Example le, 1.4 g of the title compound is obtained. from 3.3 g of the aldehyde that is produced in Example 1 H-NMR (CDCl 3 0. 95 (3H) 2. 7 (3H) 3. 38 (1H) 3. 45 3.55 (1BH), 3.56 (1H) 4.8 (1H) 4.89 (1H) 5.7 (1H) 7.18 (iH) 7.28-7.48 7.83 (1H) ppm.
Example (3S,4Z) (2-Methylthiazol-4-yl) 5R) oxazolidin-2-on-3-yl] (tert-butyl-dimethylsilyloxy) -4-chloro-4penten- I-one Analogously to Example 1f, 580 mg of the title compound is obtained from 1.4 g of the alcohol that is produced in Example 1 H-IMR (CDCl 3 0.11 0.15 0.9 0.85- 0.95 2.7 3.26 3.58 (1H1), 4.77 (111), 4.99 (1H), 5.64 7.05 7.25-7.46 7..-83 (1H) ppm.
Example (3S,4Z) -5-(2-Methylthiazol-4-yl) (tert-butyl-dimethylsilyloxy) 4-chloro-4-pentenoic acid ethyl ester Analogously to Example 1g, 9.1 g of the title compound is obtained from 12.5 g of the silyl ether that is produced in Example 1 H-INMR (CDCl 3 6 0.09 O3H), 0.1 O3H), 0.9 (9H1), 1.26 O3H), 2.68-2.78 2.72 O3H), 4.15 (2H1), 4.82 7.04 (111), 7.8 (1H1) ppm.
Example (3S,4Z) (2-Methylthiazol-4-yl) (tert-butyl-dimethylsilyloxy) 4 -chloro-4 -penten- 1-cl Analogously to Example lh, 7.5 g-of the title compound is obtained from 9.1 g of the ethyl ester that is produced in Example 'H-NIMR (CDC1 3 6 0.09 0.14 (3H1), 0.94 (9H1), 1.92- 2.12 (3H1), 2.72 3.68-3.88 4.58 7.04 7.81 (111) ppm.
Example (3S,4Z) (2-Methylthiazol-4-yl) (tert-butyl-dimethylsilyloxy) 1-iodo-4 -chloro-4 -pentene Analogously to Example-li, 2.02 g of the title compound is obtained from 1.7 g of the alcohol that is produced in Example IH-1NMR (CDCl 3 6 =0.08 (3H1), 0.14 0.92 (911), 2.1- 2.33 2.72 (311), 3.2 (2H1), 4.45 7.03 (111), 7.82 (1H) ppm.
L
Example (3S,4Z)-5-(2-Methylthiazol-4-yl)-3-(tert-butyl-dimethylsilyloxy)- 4-chloro-4-pentene-triphenylphosphonium iodide Analogously to Example lj, 14.8 g of the title compound is obtained from 9.6 g of the iodide that is produced in Example Si.
'H-NMR (CDC1 3 6 0.1 0.18 0.9 2.07 2.69 3.47-3.63 3.68-3.85 4.99 7.21 7.67-7.87 (16H) ppm.
Example (2S,6E/Z,9S,10Z)-10-Chloro-9-[[dimethyl(1,1dimethylethyl)silyl]oxy]-11-(2-methyl-4-thiazolyl)-2,6-dimethylundeca-6,10-dienol-tetrahydropyran-2-yl-ether 6.94 ml of butyllithium (1.6 molar in hexane) is carefully added in drops at -0C under nitrogen to a solution of 8 g of phosphonium salt, produced in Example 5j, in 22 ml of tetrahydrofuran, and it is stirred for 20 minutes (dark red solution). 1.69 g of .6S)-6-methyl-7-(tetrahydro-2H-pyran-2yl(oxy)-heptan-2-one, dissolved in 11 ml of tetrahydrofuran, was now added in drops to the reaction mixture. The reaction mixture was stirred for 30 more minutes and was then mixed with 11 ml of saturated ammonium chloride solution. After another 5 minutes, the reaction mixture was diluted with ethyl acetate, washed once with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. After column chromatography with hexane/ether 0-50%, 4.8 g of the title compound is obtained.
1 H-NMR (CDC1 3 6 0.05-0.1 (611), 0.85-0.95 (12H), 2.52 (1411), 1.6 (3H1), 2.7 3.07-3.27 (111), 3.42-3.54 (311), 3.86 (111), 4.26 (1H1), 4.56 (111), 5.12 6.97 (111), 7.81 (1H) ppm.
Example 51 6E/2, 95, 1OZ) -1O-Chloro-9- [[dimethyl (1,1dimethylethyl) silyll oxy -11- (2-methyl-4-thiazolyl) -2,6-dimethylundeca-6, lO-dienol 134.38 mg of pyridinium-p-toluenesulfonate is added to a solution of 2.9 g of the olef in, produced in Example 5k, in 40 ml of ethanol, and it is stirred for 6 hours at 55 0 OC under nitrogen.
Then, it: is concentrated by evaporation in a vacuum. After column chromatography with hexane/ethyl Acetate 0-30%, 1.73 g of the title compound is obtained.
'H-N.MR (CDCl 3 6. 0. 05-0. 1 (611), 0. 92 (9H) 1. 02/1.09 (311), 1.59/1.61 1.15-1.8 (411), 1.93-2.08 2.23-2.52 (311), 2.72 5.15 (111), 6.95/6.98 (1H1), 7.81 (1H), 9.54/9.6 (1H) ppm.
Example Sm (2S,6E/Z',9S,lOZ) -1O-Chloro-9-[C[dimethyl(1,1dimethylethyl) silylloxy] -11-(2-methyl-4-thiazolyl) -2,6-dimethylundeca-6, lO-dienal 2.28 ml of triethylamine is added at room temperature under nitrogen to a solution of 1.5 g of the alcohol, produced in Example 51, in.32.7 ml of methylene chloride and 11 ml of dimethyl sulfoxide. Then, the reaction mixture is mixed with 1.042 g of SO 3 -pyridine complex and stirred for 35 minutes.
After saturated ammonium chloride solution is added, it is stirred for 5 more minutes, diluted with ether, washed with semisaturated sodium chloride solution, the organic phase is dried on sodium sulfate and concentrated by evaporation in a vacuum. 216 mg of the title compound is obtained.
Example (3S,6R,7S,8S,12E/Z,15S,Z16-16-Chloro-17-(2-methyl-4-thiazolyl)- 5-oxo-1,3,15-tris[[dimethyl(1,1-dimethylethyl)silyl]oxy]- 4,4,6,8,12-pentamethyl-heptadeca-12,16-dien-7-ol 3.3 ml of butyllithium (1.6 molar in hexane) is cooled to 0 C and mixed carefully with a solution of 535 mg of diisopropylamine in 12 ml of tetrahydrofuran. Then, the reaction mixture is cooled to -70 0 C and added in drops with a solution that consists of 1.78 g of (3S)-1,3-bis[[dimethyl(l,1dimethylethyl)silyl]oxy]-4,4-dimethyl-heptan-5-one in 12 ml of tetrahydrofuran. It is stirred for 1 hour at a constant temperature. A solution of 1.34 g of the aldehyde, produced in Example 5m, in 9.7 ml of tetrahydrofuran, is now added in drops to the reaction mixture and stirred again for 1.5 hours. Then, it is mixed with saturated ammonium chloride solution, diluted with ether, washed twice with semisaturated sodium chloride solution, the organic phase is dried with sodium sulfate and concentrated by evaporation in a vacuum. After column chromatography with hexane/ethyl acetate 25%, 2.52 g of the title compound is obtained.
1 H-NMR (CDCl 3 6 0.0-0.1 (18H), 0.77/0.81 0.7-1.8 0.85-0.9 (27H), 1.0 1.07 1.21 1.58 (3H), 1.9-2.04 2.34-2.47 2.71 3.28 3.53-3.7 3.88 4.18-4.28 5.11 6.92 7.79 (1H) ppm.
Example (3S,6R,7S,8S,12E/Z,15S,16Z)-16-Chloro-17-(2-methyl-4-thiazolyl)- 5-oxo-1,3,7,15-tetrakis[[dimethyl(1,1-dimethylethyl)silyl]oxy]- 4,4,6,8,12-pentamethyl-heptadeca-12,16-diene 722 Al of lutidine is added in drops at 0 C under nitrogen to a solution of 1.52 g of the alcohol, produced in Example dissolved in 21.3 ml of methylene chloride. After 5 minutes, 813 Ml of tert-butyldimethylsilyltriflate is added to the reaction mixture, and it is stirred for 1.5 more hours. Then, it is diluted with ether, washed once with 1N hydrochloric acid, twice with saturated sodium chloride solution, the organic phase is dried with sodium sulfate and concentrated by evaporation in a vacuum. After column chromatography with hexane/ether 0-20%, 221 mg of the title compound is obtained.
Example (3S,6R,7S,8S,12E/Z,15S,16Z)-16-Chloro-17-(2-methyl-4-thiazolyl)- 5-oxo-3,7,15-tris[[dimethyl(1,1-dimethylethyl)silyl]oxy]- 4,4,6,8,12-pentamethyl-heptadeca-12,16-dien-1-ol 453.45 mg of campher-10-sulfonic acid is added at 0°C under nitrogen to a solution that consists of 1.9 g of the silyl ether, produced in Example 50, in 15 ml of methylene chloride and 15 ml of methanol, and it is stirred for 2 more hours. Then, it is mixed with 13 ml of triethylamine, and after 5 minutes, the reaction mixture is added to saturated sodium bicarbonate solution, diluted with methylene chloride, the organic phase is washed once with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. 1.41 g of the title compound is obtained.
1 H-NMR (CDC1 3 6 0.02-0.13 (18H), 0.85-0.96 (30H), 1.08 1.23 1.6 1.0-2.1 (10H), 2.32-2.52 2.72 3.13 3.65 3.8 4.08 4.21-4.3 5.13 6.98 7.8 (1H) ppm.
Example (3S,6R,7S,8S,12E/Z,15S,16Z)-16-Chloro-17-(2-methyl-4-thiazolyl)- 5-oxo-3,7,15-tris[[dimethyl(1,1-dimethylethyl)silyl]oxy]- 4,4,6,8,12-pentamethyl-heptadeca-12,16-dienal 1.14 ml of triethylamine is added at room temperature under nitrogen to a solution that consists of 1.4 g of the alcohol, produced in Example 5p, in 19 ml of methylene chloride and 4.5 ml of dimethyl sulfoxide. Then, the reaction mixture is mixed with 520 mg of S0 3 -pyridine complex and stirred for 2 hours. After saturated ammonium chloride solution is added, it is stirred for minutes, diluted with ether, washed twice with semisaturated sodium chloride solution, the organic phase is dried on sodium sulfate and concentrated by evaporation in a vacuum. 1.44 g of the title compound is obtained.
Example (3S,6R,7S,8S,12E/Z,15S,16Z)-16-Chloro-17-(2-methyl-4-thiazolyl)- 5-oxo-3,7,15-tris[[dimethyl(1,1-dimethylethyl)silyloxy] 4,4,6,8,12-pentamethyl-heptadeca-12,16-dienoic acid 1.89 ml of Jones reagent is added at -30 0 C under nitrogen to a solution of 1.44 g of the aldehyde, produced in Example 5q, in ml of acetone. After 45 minutes, the reaction mixture is mixed with 1.3 ml of isopropanol, stirred for 10 minutes, diluted with ether, washed three times with semisaturated sodium chloride solution, the organic phase is dried on sodium sulfate and concentrated by evaporation in a vacuum. After the crude product is purified by preparative thin-layer chromatography with hexane/ether 50% (run three times), 202 mg of the title compound is obtained.
IH-NMR (CDC1 3 6 0.03-0.16 (18H), 0.88-0.94 (30H), 1.09 1.15 1.18 1.7 1.0-2.44 (12H), 2.7 (3H), 3.15 3.72 4.32 4.42 5.19 7.25 (1H), 7.87 (1H) ppm.
Example (3S,6R,7S,8S,12E/Z,15S,16z)-16-Chloro-17- (2-methyl-4-thiazolyl) 5-oxo-3,7-bis[CEdimethyl(1, 1-dimethiethyl) silyl] oxy] 4,4,6, 8,12-pentamnethyl-heptadeca-12,16-dieloic acid 433.7 mg of tetrabutylammonium fluoride is added at room temperature under nitrogen to a solution of 22 mg of the carboxylic acid, produced in Example 5r, in 4.3 ml of tetrahydrofuran, and it is stirred for 1.5 more hours. Then, it is diluted with ethyl acetate, washed once with 0.5 N hydrochloric acid, twice with semisaturat'ed sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. After column chromatography with hexane/ethyl acetate 50%, 43 mg of the title compound is obtained.
IH-NMR (CDCl 3 5 0.03-0.17 0.83-0.98 (21H), 1.08 1.18 1.1-2.6 (12H), 1.73 1.95 (2H1), 2.22 (2H1), 2.71 3.16 (1H1), 3.77 4.33 (111), 4.42 (1H1), 5.2 (W1), 7.29 (1H1), 7:85 (111) ppm.
Example St (4S,,7R,8S,9S,13(E),16S(Z))-4,8-Bis[[dimethyl(1,1dimethy]Lethyl) silylloxy] -16- (1-chloro-2- (2-methyl-4thiazolyrl) ethenyl) -1-oxa-5, 5,7,9, 13-pentamethyl-cyclohexadec-13ene-2, 6-diane (4S,7R,8S,9S,13(Z),16S(Z))-4,8-bis[[dimethyl(1,1dimethyl-ethyl) silylloxy] -16- (1-chloro-2- (2-methyl-4thiazolyrl) ethenyl) -1-oxa-5, 5,7,9, 13-pentamethyl-cyclohexadec-13ene 6 -diane 72.7 J#l of triethylamine is added at 0 0 C under nitrogen to a solution Of 180 mg of the alcohol, produced in Example 5s, in 3.4 ml of tetrahydrofuran. Then, 48.2 fgl of 2,4,6-trichlorobenzoyl chloride is added, and it is stirred for one hour. This suspension is now added in drops over 3 hours with a metering pump to a solution that consists of 289.91 mg of 4-N,Ndimethylaminopyridine in 25.4 ml of toluene, and it is stirred for 1 hour. Then, the reaction mixture is concentrated by evaporation in a vacuum. After column chromatography with hexane/ethyl acetate 20% and subsequent purification using preparative thin-layer chromatography with methylene chloride/methanol 32 mg (E-compound) of title compound A and 81 mg (Z-compound) of title compound B are obtained.
(B)l1.-NR (CDCl 3 0.02-10.15 (12H), 0.85 0.97 (9H), 0.9-2.95 (11H), 1.0 1.1 (3H1), 1.15 (3H1), 1.27 (311), 1.57 (3H1), 2.71 3.04 3.9 4.0 3 (1H1), 5.13 (1H1), 5.19 7.06 7.83 (1H1) ppm.
Example (4S,7R,8S,9S,13Z),16S(Z))-4,8-Dihydroxy-16-(1-chloro-2-(2-methyl- 4-thiazolyl)ethenyl)-l-oxa-5,5,7,9,13-pentamethyl-cyclohexadec- 13-ene-2,6-dione 702 il of a 20% solution of trifluoroacetic acid in methylene chloride is added at -20 0 C under nitrogen to a solution of 80 mg of title compound B, produced in Example 5t, in 314 Al of methylene chloride, and it is stirred for 5.5 more hours at 0C. Then, the reaction mixture is concentrated by evaporation in a vacuum. After column chromatography with hexane/ethyl acetate 50%, 43.8 mg of the title compound is obtained.
'H-NMR (DMSO-d 6 100 0 6 0.94 0.82-3.3 (14H), 1.11 1.23 1.67 2.64 3.58 4.27 5.16 5.39 7.06 7.77 (1H) ppm.
Example 6 (4S,7R,8S,9S,13(E),16S(Z))-4,8-Dihydroxy-16-(1-chloro-2-(2methyl-4-thiazolyl)ethenyl)-l-oxa-5,5,7,9,13-pentamethylcyclohexadec-13-ene-2,6-dione 395 /l of a 20% solution of trifluoroacetic acid in methylene chloride is added at -20 0 C under nitrogen to a solution that consists of 45 mg of title compound A, produced in Example in 177 l1 of methylene chloride, and it is stirred for more hours at 0 C. Then, the reaction mixture is concentrated by evaporation in a vacuum. After column chromatography with hexane/ethyl acetate 50%, 27 mg of the title compound is obtained.
1 H-:NMR (DMSO-d 6 1 100 0 C) :0.8-2.7 (13H) 0.91 O3H) 1.11 1.12 1.6 2.65 3.25 3.54 4.46 5.18 (1H1), 5.44 7.05 7.83 (1H) ppm.
Example-7 (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-chloro- 2 (2-methyl1-4-thiazolyl)ethelyl) -8,8,10,12,16-pentamethyl-4,17dioxabicyclo [14.1.0] heptadecane-5, 9-dione (1R,3S(Z),7S,10R,IIS,12S,16S)-7,11-dihydroxy-3-(1-chloro-2- (2-methyl-4-thiazolyl) ethenyl) 10,12,16-pentamethyl-4, 17dioxabicyclo [14.1.0] heptadecane-5, 9-dione 154.8 yig of ethylenediamine tetraacetic acid-di-sodium salt and 324.73 p~g of 1,1,1-trifluoroacetone are added at 0 0 C under nitrogen. to a solution of 14 mg of the epothilone-D derivative, produced. in Example S, in 0.3 ml of acetonitrile. Then, 34.65 Aig of oxone and 17.74 y.g of sodium bicarbonate are added to the reaction-mixture and stirred for 4 hours. Now, it is mixed with 2 ml of sodium thiosulfate solution, diluted with 100 ml of ethyl acetate, washed with semisaturated sodium chloride solution, dried on. sodium sulfate and concentrated, by evaporation in a vacuum. After the crude product is purified using preparative thin-layer chromatography with methylene chloride/methanol 3.8 mg (polar) of A and 2.5 mg (nonpolar) of B of the title compound. are obtained.
'H -NMR (MeOH -d 4 5 0 .8 6 (9H) 1. 03 (3 H) 1. 2 1.29 1.33 2.7 2.93 3.67 4.23 (1H1), 5.63 (1Hi), 7.12 7.44 (lH) ppm.
Example 8 (1S,3S(Z),7S,1OR,11S,12S,16S)-7,11-Dihydroxy-3-(1-chloro-2- (2-methyl-4-thiazolyl)etheflyl) -8,8,10,12,16-pentamethyl-4,17dioxabicyclo [14.1.01 heptadecane- 519-dione (1R,3S(Z),7S,1OR,11S,12S,16R)-7,11-dihydroxy-3-(1-chloro-2- (2-methyl-4-thiazolyl) ethenyl) -8,8,10,12, 16-pentamethyl-4, 17dioxabicyclo [14.1.0] heptadecane-5, 9-dione 154.8 jig of ethylenediaminetetraace-tic acid-di-sodium salt and 324.73 jig of 1,1,1-trifluoroacetone are added at 0 0 C under nitrogen to a solution that consists of 14'mg of the epothilone-D derivative, produced in Example 6, in 0.3 ml of acetonitrile.
Then, 34.65 jig of oxone and 17.74 jig of sodium bicarbonate are added to the reaction mixture and stirred for 4 hours. Now, it is mixed with 2 ml of sodium thiosulfate solution, diluted with 100 ml of ethyl acetate, washed with semisaturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. After the crude product is purifiedusing preparative thin-layer chromatography with methylene chloride/methanol 20%, 6.8 mg (polar) of A and 3.4 mg (nonpolar) of B of the title compound are obtained.,.
Example 9 (4S,7R,8S,9S,13 ,16S(Z)) -4,8-Dihydroxy-16- (1-fluoro-2- (2methyl-4-thiazolyl)ethelyl) -1-oxa-7,9,13-trimethyl-5,5- (1,3trimethy-lene) cyclohexadec- 13 -ene- 2, 6-dione Analogously to Example 5, 235 mg of the title compound is obtained. from 431 mg (0.585 mmol) of compound A that is described under 9j.
1 H-]IMvR (CDC1 3 1.00 O3H), 1.27 1.66 2.70 2.75-3.04 3.43 3.68 4.42 (111), 5.13 (1H), 5.37-5.46 6.15-6.29 7.36 (1H) ppm.
Example 9a (2S,6E/Z,9S,1OZ) [[Dimethyl(l,1-dimethylethyl)silyl]oxy] fluoro-il- (2-methyl-4-thiazolyl) 6-dimethylundeca-6, lO-dienoltetrahydropyran- 2-yl- ether Analogously to Example 5k, 3.52 g of the title compound is obtained from 2.47 g (10.8 mmol) of 6(S)-6-methyl-7-(tetrahydro- 2H-pyran-2-yl(oxy))heptan-2-one (for production see: DE 19751200.3) and 11.4 g (16.2 mmol) of the compound that is described under Example ij.
IH-N4MR (CDCl 3 6 0.08 0.85-0.95 (12H), 0.60 0.69 2.37-2.50 2.70 3.10-3.30 (111), 3.45-3.65 (2H), 3.82-3.9 2 4.13-4.26 4.57 5.14 5.98-6.12 7.33 (1H) ppm.
Example 9b (2S, 6E/Z, 9S, 1OZ) [[Dimethyl 1-dimethylethyl) silyll oxy] fluoro-il- (2-methyl-4-thiazolyl) 6-dimethylundeca-6, lO-dienol Analogously to Example 51, 2.81 g of the title compound is obtained from 3.52 g (6.70 mmol) of the compound that is described under 9a.
1 H-NIVIR (CDCl 3 0.09 0.87 0.91 (911), 1.58 1.69 1.95-2.05 2.35-2.52 (211), 2.70 3.38-3.55 (211),,4.32 (1H1), 5.14 (1H1), 5.95-6.12'(1H1), 7.34 (1H) ppm.
Example 9c (2S, 6E/Z, 9S, 1OZ) [[Dimethyl 1-dimethylethyl) silyl] oxy] fluoro-li- (2-methyl-4-thiazolyl) 6-dimethylundeca-6, lO-dienal Analogously to Example 5m, 2.80 g of- the title compound is obtained from 2.81 g (6.37 mmol) of the compound that is described under 9b.
IH-NqMR (CDC1 3 6 0.08 (6H) 0.90 1.03-1.10 (3H1), 1.58 1.67 1.95-2.11 2.24-2.51 2.70 (3H1), 3.75 (111), 4.15-4.27-(lH), 5.118 5.97-6.14 7.34 9.55 9.591111) ppm.
Example 9d (3S,6R,7S,8S,12E/Z,15S,16Z)-16-Fluoro-17-(2-lethyl-4-thiazolyl)trisC[dimethyl 1-dimethylethyl) silyl] oxy] heptadeca-12, 16-dien- 7-ol Analogously to Example Sn, 2.18 g of the title compound is obtained from 2.77 g (6.68 mmol) of (S)-l-(1,3-bis[[dimethyl(1,1dimethylethyl) silyl] oxypropyl] cyclobutyl) -propan-1-one (for production see: DE 19751200.3) and 1'.65 g (3.75 mmol) of the compound that is described under 9c.
'H-NMR (CDC1 3 0.04 (6H1), 0.08 (6H1), 0.15 0.17 0.79 0.86-0.97 (27H1), 1.03 1.25-1.41 (2H1), 1.59 1.68 1.69-1.87 1.90-2.09 (2H1), 2.23-2.50 2.70 3.20-3.36 3.58 4.08-4.25 5.14.(1H), 5.98- 6.13 7.33 (1H1) ppm.
Example 9e (3S,67S,8S12E/ ,5,16Z) -16-Fluoro-17- (2-methyl-4-thiazolyl) 5-oxo-1, 3,7,15-tetrakis[[ dimethyl(l, 1-dimethylethyl) silyl] oxy] 6,8,12-trimethyl-4,4- (1,3-trimethylene)heptadeca-12,16-diele Analogously to Example 5o, 2.47 g of the title compound is obtained from 2.18 g (2.55 mmol) of the compound that is described under 9d.
IH-NTMR (CDC1 3 6 =0.00-0.20 (24H1), 0.85-1.00 (39H), 1.06 1.48 1.67 (3H1), 2.20-2.47 2.72 3.08 (1H1), 3.59 3.78 (111), 4.10 4.14-4.25 (1H1), 5.15 (1H1), G.00- 6.13 (111), 7.35 (111) ppm.
Example 9f (3S,6R,7S,18S,12E/Z,15S,16Z)-16-Fluoro-17-(2-methyl-4-thiazolyl)tris dimethyl(1, 1-dimethylethyl) silyl] oxy] heptadeca-12, 16-dien- Analogously to Example 5p, 1.626 g of the title compound is obtained from 2.47 g (2.55 mmol) of the compound that is described under 9e.
IH-N4MR (CDC1 3 6 0.03-0.13 (12H), 0.04-0.20 0.86- 1.03 (30H), 1.08 1.59+1.68 1.70-2.50 (10H), 2.72 3.12 3.64 3.81 4.08 4.13-4.27 (1H), 5.15 (1H),I 6.00-6.17 7.35 (1H) ppm.
Example 9g (3S,6R,7S,8S,12E/Z,15S,16Z)-16-Fluoro-17- (2-methyl-4-thiazolyl) tris [[dimethyl -dimethylethyl) silyl] oxy] heptadeca-12, 16-dienal Analogously to Example Sq, 1.628 g of the title compound is obtained from 1.626 g (1.91 mmol) of the compound that is described under 9f.
1 H-NSMR (CDC1 3 6 =0.02-0.12 (1511), 0.18 0.85-1.00 1.05-1.10 (3H1), 1.59 1.68 1.70-2.55 (10H), 2.71 3.75 (1H1), 4.12-4.25 4.53 5.17 6.00-6.15 (1H1), 7.33 (1H1), 9.75 (1H) ppm.
Example 9h (3S,6R,7S,8SS,12E/Z,15S,16Z)-16-Fluoro-17-(2-methyl-4-thiazolyl)tris [[dimethiyl 1-dimethylethyl) silyll oxy] heptadeca-12, 16dienoic acid Analogously to Example 5r, 1.161 g of the title compound is obtained from 1.628 g (1.91 mmol) of the compound that is described under 9g.
IH-N4MR (CDCl 3 6 0.02-0.15 (15H), 0.19 0.84-1.00 1.10-1.07 1.56 1.69 2.10-2.55 (10H1), 2.70 2.97-3.14 (111), 3.78 (1H1), 3.84 (111), 4.09-4.27 4.41 4.48 (1H1), 5.10-5.23 6.10 6.31 (1H1), 7.37 (1H1) ppm.
Example 9i (3S,6R,7S,8S,12E/Z,15S,16Z)-3,7-Bis[[dimethyl(1,1dimethylethyl) silyl] oxy] -16-f luoro-15-hydroxy-17- (2-methyl-4thiazolyl)-5-oxo-6,8,12-trimethyl-4,4-(1,3trimethylene) heptadeca.,2, 16-dienoic acid Analogously to Example 5s, 1.01 g of the title compound is obtained from 1.161 g (1.34 mmol) of the,compound that is described under 9h.
IH-NTMR (CDCJ.
3 6 0.01-0.15 0.17 0.83-1.01 (21H1), 1.07-1.15 1.61 1.73 2.07-2.60 (10H1), 2.71, 2.92-3.11 2.85 (1H1), 3.80 4.18-4.30 (1H1), 4.40 4.48 (1H1), 5.11-5.22 6.19 6.37 (1H1), 7.37 (1H) ppm.
Example 9j 4S,7R,SS, 9S, 13(Z) ,16S -4,8-Bis [[dimethyl(1, 1dimethylethyl)silyJ.Ioxy]-16- (1-f luoro-2- (2-methyl-4thiazolyl)ethefyl-1-oxa-7,9,13-trimethyl- (1,3trimethylene) cyclohexa-dec-13 -ene-2, 6-dione and 4S, 7R, BS, 9S, 13 ,16S 8-Bis [[dimethyl (1,1dimethyleathyl) silylloxyi -16- (1-f luoro-2- (2-methyl-4thiazolyl)ethenyl-1-oxa-7,9,13-trimethyl-5,5- (1,3trimethylene) cyclohexa-dec -13 -ene-2, 6-dione (B) Analogously to Example St, 434 mg of title compound A and 395 mg of title compound B are obtained from 1.01 g (1.34 mmol) of the compound that is described under 9i.
1 H-INMR (CDCl 3 of A: 6 -0.07 0.07-0.20 (9H1), 0.80 0.93 (911), 0.98 1.22 (311), 1.68 1.80-1.90 (1H), 2.00-2.10 (1H1), 2.20-2.50 (4H1), 2.60-2.68 (4H1), 2.72 2.76- 3.00 3.92 4.41 5.08-5.12 6.08-6.22 (1H1), 7.38 (1H) ppm.
'H-NMR .(CDCl 3 of, B: 6 0. 02 (3H) 0. 07 (3H) 0. 11 (3H), 0.14 (311), 0.90 (911), 0.93 (911), 1.02 1.25 1.51 (3H), 1.70-2.15 2.30-2.60 2.72 2.77-2.93 4.19 (1H1), 4.59 (1H1), 5.10 (111), 5.42 (1H1), 6.09-6.23 7.36 (1H1) ppm.
I
Example (1S,3S(Z,) ,7S,1OR,11S,12S,16R)-7,11-Dihydroxy-3- ((1-fluoro)-2-(2methyl-4-thiazolyl)etheyl)-10,12,16-trimethyl-B,8-(1,3trimethy-lene) -4,17-dioxabicyclo[14.l.0]hepta-deca-5,9-dione
(A)
and (1R,3S(Z),7S,1OR,11S,12S,16S)-7,11-dihydroxy-3-((1-fluoro)-2- (2-methy-l-4-thiazolyl)ethenyl) -10,12,16-trimethyl-8,8-(1,3trimethy-lene) -4,17-dioxabicyclo[14.l.0]hepta-deca-5,9-dione
(B)
Analogously to Example 7, 31 mg of title compound A and 7 mg of title compound B are obtained from'50 mg (0.098 mmol) of the compound that is described under Example 9.
1 H-IvIMR (CDCl 3 of A: 6 0.99 1.25 1.28 (31), 2.71 2.81 3.02-3.12 3.62-3.77 4.40 (1H), 5.56-5.68 6.17-6.81 7.37 (1H) ppm.
'H-NMR (CDC1 3 of B: 6 0.92 1.20 1.38 (31), 2.75 3.00 3.11 3.86 4.42 5.29 (1H), 6.26-6.39 7.41 (1H) ppm.
Example 11 (4S,7R, 85,9S,13(Z) ,16S(Z))-4,8-Dihydroxy-16-((1-fluoro-2-(2methyl-4-thiazolyl)ethenyl) -1-oxa-7,9,13.,-trimethyl-5,5- (1,3trimethylene)cyclohexadec-13-ene-2,6-diane Analogously to Example St, 200 mg of the title compound is obtained from 395 mg (0.54 mmol) of compound B that is described under 9j.
IH-ITM (CDCl 3 6 =1.00 1.25 1.54 2.69 2.97-3.08 3.63 4.44 5.09 5.54-5.63 6.11-6.25 7.38 (1H) ppm.
Example 12 (1S,3S(Z),7S,1OR,11S,12S,16S)-7,11-Dihydroxy-3-((1-fluoro)-2-(2methyl-4-thiazolyl)etheyl)-1O,12,16-trimethyl-8,8-(1,3trimethylene)-4,17-dioxabicyclo[14..0]heptadeca-5,9-diane
(A)
and (1R,3S(Z) ,7S,1OR,11S,123,16R)-7,11-dihydroxy-3- (1-fluoro) -2- (2-methyl-4-thiazolyl)ethenyl) -1,12,16-trimethyl-8,8-(1,3trimethylene)-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione
(B)
Analogously to Example 7, 41 mg of title compound A and 36 mg of title compound B are obtained from 100 mg (0.197 mmol) of the compound that is described under Example 11.
'H-NTMR (CDC1 3 of A: 6 0.93 1.19 (31H), 1.22 (3H), 2.70 2.88 3.11 3.19 3.65 3.72 (1H), 4.45 5.61-5.72 6.12-6.26 7.37 (1H) ppm.
1 H-NTMR (CDCl 3 of B: 6 0.98 1.22-1.27 2.72 2.93 3.07-3.17 3.30 3.67 3.85 (11), 4.40 5.68-5.77 6.22-6.36 7.41 (1H) ppm.
Example 13 7R, 8, 9S, 13(Z) 165 8-Dihydroxy-9, 13-dimethyl-7-ethyl- 16- (1-f luoro-2- (2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5- (1,3trimethylene)cyclohexadec-13-ene-2,6-diane Analogously to Example 5, 181 mg of the title compound is obtained from 400 mg (0.534 mmol) of the compound that is described under 13g.
1 H-NMR (CDCl 3 6 0.94 1.01 1.69 2.68- 2.82 (1H1), 2.71 2.96 3.38 3.68 4.42 (1H), 5.10 5.42 6.13-6.27 7.37 (11) ppm.
I
Example .13a 3 S,6R,7;B,8S,12E/Z,15S,16Z)-8,12 Dimethyl 6-ethyl-16 fluoro 17 (2-methy.l-4-thiazolyl)-5-oxo- 4 4 (1,3-trimethylene) -1,3,15tris[[dirnethyl(1,1-dimethylethyl)silyl]oxy]heptadeca-12,16-dien- 7-ol Analogously to Example Sn, 2.042 g of the title compound is obtained from 2.975 g (6.937 mmol) of bis [dimethyl 1-dimethylethyl) silyl] oxypropyl -cyclobutyl) butan-1-one (For production see: DE 19751200.3) and 1.695 g (3.854 mmol) of the compound that is described under 9c.
1 H-NMR (CDCl 3 6 0.01-0.20 (18H), 0.84-1.00 (33H), 1.60 1.69 2.69 3.11 3.22 3.40 3.62 4.06-4.25 5.97-6.12 7.34 (IH) ppm.
Example 13b 3 S,6R,7,9,8S,12E/Z,15S,16Z)-8,12-Dimethyl 6-ethyl-16-fluoro-l 7 (2-methyl-4-thiazoJlyl) -oxo-1,3,7,15-tetrakis[dimethyl(1,1dimethylethyl)silylloxy]-4,4-(1,3-trimethylene)heptadeca-12,16diene Analogously to Example 5o, 2.311 g of the title compound is obtained from 2.042 g (2.351 mmol) of the compound that is described under 13a.
1 1-NMR (CDCl 3 6 0.00-0.20 (24H), 0.80-0.99 (421), 1.60 1.68 2.70 3.02 3.60 3.86 4.04- 4.25 5.97-6.13 7.32 ppm.
Example 13c 6R,7S5,8S,12E/Z,15S,16Z) -8,12-Dimethyl-6-ethyl-16-fluoro-17- (2-methyl1-4-thiazolyl)-5-oxo-4,4- (1,3-trimethylene) -3,7,15tris [[dimethyl -dimethylethyl) silyl] oxy] heptadeca-12, 16-dien- 1-ol Analogously to Example 5p, 1.593 g of the title compound is obtained. from 2.311 g (2.351 mmol) of the compound that is described under 13b.
1 H-NMR (CDCl 3 8 0.02-0.19 (18H), 0.80-0.99 (33H),.1.57 (3H) 1.67 O3H), 2.70 O3H), 3.04 3.60-3.71 3.87 4.04-4.25 (2H1), 5.13 5.95-6.11 (1H1), 7.33 (1H1) ppm.
Example 13d (3S,6R,75,8S,12E/Z,15S,16Z)-8,12-Dimethyl -6-ethyl-16-fluoro-17- (2-methyl1-4-thiazolyl)-5-oxo-4,4-(1,3-trimethylele)-3, 7 ,lStris [[dimethyl -dimethylethyl) silyl] oxy] heptadeca-12, 16-dienal Analogously to Example 5q, 1.589 g of the title compound is obtained from 1.593 g, (1.834 mmol) of the compound that is described under 13c.
IH-NMR (CDCl 3 5 0.04-0.20 (18HY,, 0.82-1.00 (33H1), 1.58 (3H) 1.68 2.71 3.04 (1H1), 3.86 4.19 (111), 4.55 5.17 (1H1), 5.98-6.12 7.33 9.79 (1H) ppm.
Example 13e (3S,GR,7S,8S,12Z,lSS,16Z)-8,12-Dimethyl-6-ethyl-16-fluoro-17- (2tris dimethyl(1, 1-dimethylethyl) silyl] oxylhepta-deca-12,16dienoic acid and (3S,6R,7S,8S,12E,15S,16Z)-8,12-dimethyl-6ethyl-16-fluoro-17- (2-methyl-4-thiazolyl)-5-oxo-4,4-(1,3.trimethylene) -3,7,15-tris[[dimethyl(1,1dimethylethyl) silyl] oxy] hepta-deca-12, 16-dienoic acid (B) Analogously to Example 5r, 664 mg of title compound A and 566 mg of title compound Bare obtained from 1.589 g (1.834 mrnol) of the compound that is described under 13d.
1 H-NIMR (CDCl 3 of A: 6 0.00 (3H),0.07-0.09 0.12 0.19 0.86-1.03 (3311), 1.70 (311), 2.70 2.90 3.73 4.21 (111), 4.48 (111), 5.21 (111),-6.38-6.52 (1H), 7.38 (1H) ppm.
.H-NIMR (CDCl 3 of B: 65 0.00 0.05 0.07 (3H), 0.09 0.15 0.20 0.84-0.99 (33H), 1.56 2.69 (31) 2.98 (1H) 3.87, 4.40 (111), 5.12 6.07-6.22 (111), 7.38 (111) ppm.
Examiple 13f (3S, 6R, 7S, SS, 12Z, iSS, 16Z) 7-Bis[C[diznethyl (1,1dimethylethyl) silyll oxyl -8,12-dimethyl-6-ethyl-16-fJluoro-15hydroxy-17-(2-methyl-4-thiazoly1)-5-oxo-4,4-(1, 3 trimethylene) heptadeca-12, 16-dienoic acid Analogously to Example 5s, 578 mg of the title compound is obtained from 663 mg (0.752 mmol) of compound A that is described under 13e.
IH-N4MR (CDCl 3 6 0.03 0'.06 0.09 0.17 0.85-1.00 (24H), 1.75 2.17.(3H), 2.89 3.78 4.25 4.49 5.21 6.43-6.57 7.39 (1H) ppm.
Example 13g 4S,7R,SS,9S,13(Z),16S(Z)-4,8-Bis[[dimethyl(1,ldimethylethyl) silyll oxy] 13-dimethyl-7-ethyl-16- (1-f luoro-2- (2methyl-4-thiazolyl)ethenyl) -1-oxa-5,5-(1,3trimethylene) cyclohexadec-13 -ene-2, 6-dione Analogously to Example 5t, 400 mg of the title compound is obtained from 578 mg (0.752 mmol) of the compound that is described under 13f.
IH-NMR (CDCl 3 6 -0.09 0.09 0.15 0.17 0.80-0.97 (21H), 1.00 1.68 2.70 2.75-2.88 2.98 4.04 4.42 5.17 6.07-6.20 (1H), 7.37 (1H) ppm.
Example 14 (1S,3S(Z) ,7S,1OR,11S,12S,1SR)-7,11-Dihydroxy-12,16-dimethyl-10ethyl-3- (1-fluoro-2- (2-methyl-4-thiazolyl)ethelyl) (1,3trimethylene) -4,17-dioxabicyclo [14 hepta-decane-5, 9-diane (A) and (1R,3S(Z) ,7S,10R,11S,12S,1GS) -7,11-dihydroxy-12,16-dimethyl- 10-ethyl-3- (1-fluara-2-(2-methyl-4-thiazolyl)ethelyl) (1,3trimethylene) 17-dioxabicyclo [14 .1.01 hepta-decane-5, 9-diane (B) Analogously to Example 7, 26 mg of title compound A and 6 mg of title compound B are obtained from 40 mg (0.0767 mmol) of the compound that is described under Example 13.
IH-NNMR (CDCl 3 of A: 6 0.95 0.98 (3H1), 1.29 (3H), 2.71 2.78 (1H1), 3.03 3.67 4.40 (1H1), 5.66 (1H), 6.16-6.79 7.38 (1H1) ppm.
'H-NTMR (CDCl 3 of B: 6 0.95-1.00 1.26 2.70.
2.91 2.95-3.05 3.34 (1H1), 3.73-(1H), 4.48 (1H), 5.73 6.22-6.35 (1H1), 7.40 (1H) ppm.
Example (45,7R,8S,9S,13(E) ,16S(Z))-4,8-Dihydraxy-9,13-dimethyl-7-ethyl- 16- (1-fluoro-2- (2-methyl-4-thiazolyl)ethenyl) -1-oxa-5,S- (1,3trimethylene) cyclohexadec- 13 -ene-2, 6-diane Analogously to Example 5, 214 mg of the title compound is obtained from 433 mg (0.5778 mmol) of the compound that is described under IH-IM (CDCl 3 0. 94 1. 02 (3H1), 1. 54 2.61- 2.74 (1H1), 2.68 (3H1), 3.08 3.73 (111), 3.98 (2H1), 4.52 (1H1), 5.09 (1H1), 5.54 (111), 6.06-6.20 (111), 7.37 (111) ppm.
Example (3S,6R,7S,8S,12E,15S,16Z)-3,7-Bis[[dimethyl(1,1dimethylethyl)silyl]oxy]-8,12-dimethyl-6-ethyl-16-fluoro-15hydroxy-17- (2-methyl-4-thiazolyl)-5-oxo-4,4-(1,3trimethylene)heptadeca-12,16-dienoic acid Analogously to Example 5s, 493 mg of the title compound is obtained from 566 mg (0.642 mmol) of compound B that is described under 13e.
1 H--NMR (CDCl 3 6 0.01 0.04 0.09 0.17 0.82-0.95 (24H), 1.62 2.68 2.95 3.82 4.17-4.30 4.40 5.15 6.15-6.28 7.37 (1H) ppm.
Example 4S,7R,8S,9S,13(E),16S(Z)-4,8-Bis[[dimethyl(1,1dimethylethyl) silyl oxy] -9,13-dimethyl-7-ethyl-16- (1-f luoro-2- (2methyl-4-thiazolyl)ethenyl)-l-oxa-5,5-(1,3trimethylene)cyclohexadec-13-ene-2,6-diane Analogously to Example St, 433 mg of the title compound is obtained from 493 mg (0.642 mmol) of the, compound that is described under 1 H-NMR (CDCl 3 6 0.07 0.10 0.12 0.15 0.85-1.04 (24H), 2.71 2.92 4.06 5.15 5.36-5.47 6.10-6.23 7.37 (1H) ppm.
Example 16 (1S,3S(Zl),7S,1OR,11S,12S,16S) -7,11-Dihydroxy-12,16-dimethyl-10ethyl-3- (1-fluoro-2- (2-methyl-4-thiazolyl)ethelyl) (1,3trimethrlene) 17-dioxabicyclo [14.1.0] heptadecane-5, 9-dione (A) and (IR,.3S(Z) ,7S,1OR,11S,12S,16R) -7,11-dihydroxy-12,16-dimethyl- 10-ethy]L-3- (l-fluoro-2-(2-methyl-4-thiazolyl)ethelyl) trimethyrlee) 17-dioxabicyclo [14 .1.0]heptadecane-5, 9-dione (B) Analogously to Example 7, 40 mg of title compound A and 39 mg of title compound B are obtained from 100 mg (0.1917 mmol) of the compound that is described'under Example 1 H-NMR (CDCl 3 of A: 6 0.94 0.96 1.27 (3H), 2.68 (311), 2.90 3.08 3.59 3.77 (1H1), 5.67 (1H), 6.11-6.24 7.37 (1H) ppm.
IH-NMR (CDCl 3 of B: 6 0.89-1.00 1.24 2.67 2.89 3.11 3.47 3.68-3.81 4.46 (1H1), 5.68 (1i1), 6.19-6.32 7.38 (1H) ppm.
Example 17 (4S, 7R, 8S, 9S, 13Z, 16S 8-Dihydroxy-16- (1-fluoro-2- (2pyridyl) ethenyl) -7-ethyl-l-oxa-5, 5,9, 13-,Jetramethyl-cyclohexadec- 13-ene-2, 6-dione Example 17a 2- Pyridyl carbaldehyde The solution of 50 ml (370 mmol) of 2-picolinic acid ethyl ester in 1 1 of anhydrous dichloromethane is cooled under an atmosphere of dry argon to -78 0 C, mixed with 500 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene and stirred for one more hour. It is mixed with 152 ml of isopropanol, 253 ml of water, allowed to heat to 23 0 C and stirred until a fine-grained precipitate has formed. After filtration and removal of the solvent, 32.6 g (304 mmol, 82%) of the title compound is isolated as a pale yellow oil.
'H-NMR (CDC1 3 5 7.52 7.89 7.99 8.80 10.10 (1H) ppm.
Example 17b (2E/Z)-3-(2-Pyridyl)-2-fluoro-2-propenoic acid ethyl ester The solution of 115 g of 2-fluoro-2-phosphonoacetic acid triethyl ester in 230 ml of ethylene glycol dimethyl ether is added in drops under an atmosphere of dry argon at 0°C to 20.7 g of a 55% sodium hydride dispersion in 230 ml of anhydrous ethylene glycol dimethyl ether, and it is stirred for one more hour. Then, it is mixed with the solution of 27.6 g (258 mmol)of the title compound, ;presented according to Example 17a, in 230 ml of ethylene glycol dimethyl ether, and it is allowed to heat within one hour to 23 0 C. It is poured onto a saturated ammonium chloride solution, extracted several times with ethyl acetate, the combined organic extracts are washed with saturated sodium chloride solution and dried on sodium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by vacuum distillation. 33.7 g (173 mmol, 67%) of the title compounds is isolated as a colorless oil.
'H-NMR (CDC1) 6 1.22+1.39 4.25+4.37 6.90- 7.13 7.23+7.26 756+7.90 7.67+7.76 (1H), 8.59+8.67 (1H) ppm.
Example 17c (2Z)-3-(2-Pyridyl)-2-fluoro-2-propenoic acid ethyl ester The solution of 29.2 g (149 mmol) of the E/Z mixture, presented according to Example 17b, in 280 ml of anhydrous toluene is mixed under an atmosphere of dry argon with 2.0 g of iodine, and it is heated for seven days to 100 0 C. The cooled solution is washed with saturated sodium thiosulfate solution and dried on sodium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by chromatography on about 1 1 of fine silica gel with a gradient system that consists of n-hexane and ethyl acetate. 26.3 g (135 mmol, 90%) of the title compound is isolated as a colorless oil.
'H-NMR (CDC1 3 1.39 4.37 7.13 7.26 7.76 7.90 8.67 (1H) ppm.
Example 17d (2Z)-3-(2-Pyridyl)-2-fluoro-2-propen-l-ol The solution of 26.3 g (135 mmol) of the compound, presented according to Example 17c, in 800 ml of anhydrous tetrahydrofuran is cooled under an atmosphere of dry argon to -78 0 C, mixed with g of lithium-tri-tert-butoxyaluminium hydride, allowed to heat to 23 0 C and stirred for 16 hours. It is mixed with water, extracted several times with ethyl acetate, the combined organic
I
extracts are washed with saturated sodium chloride solution and dried on sodium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by chromatography on about 1.5 1 of fine silica gel with a gradient system that consists of n-hexane and ethyl acetate. 17.3 g (113 mmol, 84%) of the title compound is isolated as a colorless oil.
'H-NMR (CDC1 3 6 1.93 4.32 6.19 7.16 7.69 7.77 8.52 (1H) ppm.
Example 17e (2Z)-3-(2-Pyridyl)-2-fluoro-2-propenal The solution of 17.3 g (113 mmol) of the compound, presented according to Example 17d, in 2.5 1 of anhydrous toluene is mixed with 100 g of manganese dioxide, and it is stirred for 16 hours at 23 0 C. It is filtered on Celite, and 13.8 g (91 mmol, 81%) of the title compound is isolated as a pale yellow oil.
1 H-NMR (CDC1 3 6 6.87 7.32 7.81 7.99- 8.72 9.43 (1H) ppm.
Example 17f (3S,4Z)-5-(2-Pyridyl)-1-[(4S,5R)-4-methyl-5-phenyl-1,3oxazolidin-2-on-3-yl]-3-hydroxy-4-fluoro-4-penten-l-one and (3R,4Z)-5-(2-pyridyl)-1-[(4S,5R)-4-methyl-5-phenyl-l,3oxazolidin-2-on-3-yl]-3-hydroxy-4-fluoro-4-penten-i-one
(B)
ml of a 2.4 molar solution of n-butyllithium in n-hexane is added. in drops at -30 0 C under an atmosphere of dry argon to the solution of 16.8 ml of diisopropylamine in 800 ml of anhydrous tetrahydrofuran, stirred for 20 minutes, cooled to 0 C and mixed within 4 hours with the solution of 23.6 g of (4S,5R)-3-acetyl-4-methyl-5-phenyloxazolidin-2-one in 800 ml of tetrahydrofuran. After 1 hour, the solution of 10.3 g (68 mmol) of the title compound, presented according to Example 17e, in 390 ml of tetrahydrofuran is added in drops within 2 hours, and it is stirred for 16 hours at -70 0 C. It is poured onto a saturated ammonium chloride solution, extracted several times with ethyl acetate, the combined organic extracts are washed with saturated sodium chloride solution and dried on sodium sulfate. The residue that is obtained after filtration and removal of the solvent is separated by repeated chromatography on fine silica gel with a gradient system that consists of n-hexane, ethyl acetate and ethanol. 8.60 g (23.2 mmol, 34%) of title compound A is isolated as a crystalline solid, and 5.04 g (13.6 mmol, of title compound B is isolated as a colorless foam.
'H-NMR (CDCl 3 of A: 5 0.94 3.38 3.56 (1H), 4.83 4.89 5.70 6.33 7.14 7.23-7.48 7.68 7.76 8.58 (1H) ppm.
IH-NMR (CDC13) of B: 6 0.94 3.47 4.19 (1H), 4.81 4.89 5.72 6.29 7.16 7.22-7.49 7.69 7.76 8.59 (1H) ppm.
Example 17g (4Z)-5-('2-Pyridyl)-l- [(4S,5R) -4-methyl-5-phenyl-1,3-oxazolidil-2on-3-yl] -4-fluoro-4-penten-1, 3-diane Analogously to Example 17e, 3.54 g (9.56 mmol) of compound B that is presented according to Example 17f is reacted, and after working-.up, 3.01 g (8.17 mmol, 85%) of the title compound is isolated as a crystalline solid.
IH-NMR (CDCl 3 as a ketone/enol mixture; 6 =0.97 (3H), 4.39+7.17+13.19 (2H) 4.88 (1H1), 5. 72+5.76 6.99+7.07 7.20-7.50 7.57+7.78 (1H1), 7.91 8.65+8.70 (lH) ppm.
Example 17h (3S,4Z)-5S-(2-Pyridyl)-l- [(4S,SR) -4-methyl-5-phenyl-l,3oxazolicLin-2-on-3-yll -3-hydroxy-4-fluoro-4-peltenl-ofle and.
(3R,4Z) (2-pyridyl) -4-meth yl-5-pheflyl-1,3oxazolicLin-2-on-3-yl] -3-hydroxy-4-fluoro-4-peltel-ofle
(B)
The solution of 12.2 g (33.1 mmol) of the compound, presented according tor'Example 17g, in a mixture of 610 ml of anhydrous dichloromethane and 65 ml of anhydrous methanol is mixed under an atmosphere of dry argon at -40 0 C with 732 mg of sodium borohydride, and it is stirred for 1 hour. It is poured into a saturated sodium bicarbonate solution, extracted several times with dichloromethane, and the combined organic extracts are dried on sodium sulfate. The residue that is obtained after filtration and removal of the solvent is separated by chromatography on fine silica gel with a gradient system that consists of dichloromethane and ethanol. In addition to starting material, 3.46 g (9.3 mmol, 28%) of title compound A and 3.38 g (9.1 mmol, 28%) of title compound B, which in each case are identical to the compounds that are described under Example 17f, are isolated.
Example 17i (3S,4Z)-5-(2-Pyridyl)-1-[(4S,5R)-4-methyl-5-phenyl-1, 3 oxazolidin-2-on-3-yl] [[dimethyl(1,1-dimethylethyl) silyl]oxy] 4-fluoro-4-penten-l-one The solution of 9.96 g (26.89 mmol) of compound A, presented according to Example 17f and/or 1h, in 85 ml of anhydrous dichloromethane, is cooled under an atmosphere of dry argon to 0 C, mixed with 7 ml of 2,6-lutidine, 12.4 ml of trifluoromethanesulfonic acid-tert-butyldimethylsilylester, and it is stirred for 2 hours. It is poured onto a saturated sodium bicarbonate solution, extracted several times with dichloromethane, the combined organic extracts are washed with saturated sodium chloride solution and dried on sodium sulfate.
The residue that is obtained after filtration and removal of the solvent is separated by chromatography on fine silica gel with a gradient system that consists of n-hexane, ethyl acetate and ethanol. 12.9 g (26.6 mmol, 99%) of the title compound is isolated as a colorless oil.
IH-NMR (CDC1 3 6 0.16 0.90 (12H), 3.29 3.59 4.78 4.92 5.67 6.12 7.13 (1H), 7.24-7.47 7.68 7.76 8.58 (1H) ppm.
Example 17j (3S,4Z)-.5-(2-Pyridyl)-3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]- 4-fluoro-4-pentenoic acid ethyl ester The solution of 12.8 g (26.5 mmol) of the compound, presented according to Example 17i, in 130 ml of anhydrous ethanol is mixed at 23 0 C under an atmosphere of dry argon with 6.7 ml of titanium tetraethylate, and it is heated for 2 hours to 0 C. It is concentrated by evaporation, and the residue is purified by chromatography on fine silica gel with a gradient system that consists of n-hexane and ethyl acetate. 9.3 g (26.3 mmol, 99%) of the title compound is isolated as a colorless oil.
'H-NMR (CDC1 3 6 0.12 0.91 1.28 2.72 4.17 4.77 6.09 7.15 7.68 7.73 8.59 (1H) ppm.
Example 17k (3S,4Z) -5-(2-Pyridyl)-3- [dimethyl(1,1-dimethylethyl)silyl]oxy]- 4-fluoro-4-penten-1-ol Analogously to Example 17a, 9.7 g (27.4 mmol) of the title compound that is presented according to .Example 17j is reacted, and after working-up and purification, 6.8 g (21.8 mmol, 80%) of the title compound is isolated as a colorless oil.
1 H-NMR (CDC1 3 6 0.12 0.14 0.93 1.83 2.00 3.78 3.85 4.53 6.09 7.12 7.65 7.72 8.57 (1H) ppm.
Example 171 (3S,4Z)-5-(2-Pyridyl)-3-[[dimethyl(1,1-dimethylethyl)silylloxy]l-iodo-4-fluoro-4-pentene The solution of 6.75 g of triphenylphosphine in 120 ml of anhydrous dichloromethane is mixed at 23 0 C under an atmosphere of dry argon with 1.78 g of imidazole, 6.47 g of iodine, and the solution of 6.8 g (21.8 mmol) of the compound, presented according to Example 17k, in 40 ml of dichloromethane is added in drops while being cooled. It is stirred for 1 hour and purified .directly by chromatography on fine silica gel with a gradient system that consists of n-hexane and ethyl acetate. 6.7 g (15.9 mmol, 73%) of the title compound is isolated as a colorless oil.
'H-NMR (CDC1 3 6 0.13 0.19 0.93 2.25 3.28 4.38 6.09 7.17 7.69 7.75 8.58 (1H) ppm.
Example 17m (3S,4Z)-5-(2-Pyridyl)-3-[[dimethyl(I,1-dimethylethyl)silyl]oxy]- 4-fluoro-4-penten-l-triphenylphosphonium iodide 6.7 g (15.9 mmol) of the compound that is presented according to Example 171 is mixed with 8..4 ml of ethyldiisopropylamine, 50.3 g of triphenylphosphine, and it is heated for 4 hours to 85 0 C. The oily residue is purified by chromatography on fine silica gel with a gradient system that consists of n-hexane and ethyl acetate. 8.9 g (13.0 mmol, 82%) of the title compound is isolated as a crystalline solid.
'H-IMR (CDC1 3 6 0.16 0.22 0.90 2.01 2.18 3.50 4.07 4.90 6.19 7.12 7.59-7.88 (17H), 8.54 (1H) ppm.
Example 17n (2S,6E/Z,9S,10Z)-9-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-10fluoro-1- (2-pyridyl) (tetrahydropyran-2-yloxy) -2,6-dimethylundeca-6,10-diene The suspension of 3.32 g (4.86 mmol) of the compound, presented according to Example 17m, in 22 ml of anhydrous tetrahydrofuran is mixed at 0 C under an atmosphere of dry argon with 4.86 ml of a 1 M solution of sodium-bis-(trimethylsilyl)amide in tetrahydrofuran. The solution of 753 mg (3.30 mmol) of (2S)-2-methyl-6-oxo-heptane-1-(tetrahydropyran-2-yloxy), which was produced analogously to the processes described in DE 197 51 200.3, in 22 ml of tetrahydrofuran, is slowly added in drops to the red solution, allowed to stir for 3 hours, poured onto saturated ammonium chloride solution and extracted several times with ethyl acetate. The combined organic extracts are dried on sodium sulfate and concentrated by evaporation in a vacuum.
After column chromatography on silica gel with a gradient system that consists of n-hexane and ethyl acetate, in addition 1.30 g (2.57 mmol, 78%) of the title compound is obtained as a colorless foam.
1 H-NMR (CDC1 3 6 0.10 0.83-0.96 (12H), 1.10 (1H), 1.20-2.07 (12H), 1.60+1.68 2.43 3.04-3.27 3.42- 3. 63 3.85 (1H) 4.22 (1H1), 4. 57 (1H) 5. 19 (1H) 6. 04 (lH), 7. 13 (1H1) 7. 68 (1H1), 7. 76 (1H) 8. 57 (1H1) ppm.
Examnple 17o (2S, 6EZ, 9S, 1OZ) [[Dimethyl(1, 1-dimethylethyl) silyl] oxy] fluoro-il- (2-pyridyl) -1-hydroxy-2,6-dimethyl-ufldeca-6, lO-diene 700 mg of pyridinium-p-toluenesulfoflate is added to a solution of.1.30 g (2.57 mmol) of the compound, produced according to Example 17n, in 50 ml of ethanol, and it is stirred for 3 hours at 23 0 C. Then, it is concentrated by evaporation in a vacuum, and the residue that is thus obtained is purified by chromatography on silica gel with a gradient system that consists of n-hexane and ethyl acetate. 832 mg (1.97 mmol, 7716) of the title compound is isolated as a colorless oil.
1 1-NMR (CDC1 3 6 0.11 0.88+0.91 0.95 (9H), 1.07 (1H1), 1.24-1.71 (511), 1.60+1.69 1.92-2.11 2.34- 2.58 (211), 3.34-3.54 4.24 5.19 6.00+6.02 (111)7 7.12 (1H1), 7.66 (1H1), 8.56 (1H1) ppm.
Example 17p (2S,6E/Z,9S,10Z) [[Dimethyl(1,1-dimethylethyl)silylloxy] fluoro-il- (2-pyridyl) 6-dimethyl-undeca-6,10-dielal .971 pgl of dimethyl sulfoxide is carefully added in drops under nitrogen at -70 0 C to 598 A~l of oxalyl chloride, dissolved in 25 ml of dichloromethane, and it is stirred for 10 minutes at this temperature. Then, a solution of 1.45 g (3.44 mmol) of the alcohol, produced according to Example 17o, in 25 ml of
I
dichloromethane is added, and it is stirred for 0.5 hour between 0 C and -70 0 C. Then, 2.84 ml of triethylamine is added, and after 1 hour of stirring at -60 0 C, the reaction mixture is added to 30 ml of water. After phase separation, the aqueous phase is extracted several times with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution. After drying on sodium sulfate and filtration, it is concentrated by evaporation in a vacuum. The residue is purified by chromatography on fine silica gel with a gradient system that consists of n-hexane and ethyl acetate. 1.31 g (3.12 mmol, 91%) of the title compound is obtained as a colorless oil.
Example 17q (4S (4R,5S, 6S, 10E/Z, 13S, 14Z)) (13- Dimethylethyl)dimethylsilyl]oxy] -4-ethyl-14-fluoro-15- (2pyridyl)-3-oxo-5-hydroxy-2,6,10-trimethyl-pentadeca-l0,14-dien-2yl)-2,2- dimethyl-[1,3]dioxane and (4S (4S, R,6S,10E/Z, 13S, 14Z)) (13- dimethyethyl)dimethylsilyl]oxy]-4-ethyl-14-fluoro-15-(2-pyridyl)- 3-oxo-5-hydroxy-2,6,10-trimethyl-pentadeca-10,14-dien-2-yl)-2,2dimethyl-[1,3]dioxane (B) The solution of 1.57 ml of diisopropylamine in 40 ml of anhydrous tetrahydrofuran is cooled under an atmosphere of dry argon to -30 0 C, mixed with 4.72 ml of a 2.4 molar solution of nbutyllithium in n-hexane, and it is stirred for 30 more minutes.
At -78 0 C, the solution of 1.31 g (3.12 mmol) of the compound, presented according to Example 17p, in 40 ml of tetrahydrofuran is added in drops and allowed to react for 1 hour. Then, it is mixed with the solution of 2.36 g (10.3 mmol) of methyl-3-oxo-hex-2-yl)-2,2-dimethyl-[1,3]dioxane, which was produced according to the process described in DE 19751200.3, in ml of tetrahydrofuran, and after 60 minutes, it is poured into a saturated ammonium chloride solution. It is diluted with water, extracted several times with ethyl acetate, the combined organic extracts are washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. After column chromatography on silica gel with a gradient system that consists of n-hexane and ethyl acetate, in addition to starting material, 1.56 g (2.41 mmol, 77%) of title compound A and 287 mg (0.44 mmol, 14%) of title compound B are obtained.
1 H-NMR (CDC13) of A: 6 0.09 0.81 0.85 (3H), 0.92 1.00 1.08 1.18-1.83 1.26 1.32 1.39 1.60+1.68 1.88-2.08 2.32-2.52 (2H); 2.87+2.91 3.19 3.44 3.87 3.98 4.16 4.22 5.18 6.00 7.11 7.65 7.73 8.56 (1H) ppm.
Example 17r (3S,6R, -fS,8SS,12E/Z,1SS,16Z) -IS- (1,1- Dimaethyi~ethyl)dimethylsilyll oxy] -6-ethyl-16-fluoro-1,3, 7trihydro~xy-4,4, 8,12-tetramethyl-17- (2-pyridyl) -heptadeca-12, 16dien- The solution of 1.45 g (2.24 mmol) of the compound, presented according to Example 17q, in 36 ml of anhydrous ethanol is mixed under an atmosphere of dry argon with 1.06 g of pyridinium-p-toluenesulfonate, and it'is stirred for 4 hours at 23 0 C. After removal of the solvent, the residue is chromatographed on fine silica gel with a mixture that consists of n-hexane and ethyl acetate. 1.36 g (2.24 mmcl, 93%) of the title compound is isolated as a colorless oil.
1 H-'NMR (CDCl 3 6 0.10 0.78-0.90 0.92 (9H), 0.99-2.1.2 (11H), 1.08 1.26 1.58+1.68 2.32-2.53 2.79-3.03 3.19 3.41 3.73-3.93 4.06- 4.25 5.13+5.21 5.93 7.13 7.67 7.77 (1H1), 8. 58 (1H) ppm.
Example 17s (3S,6R,7S,SS,12E/Z,15S,16Z)-6-Ethyl-1,3,7,15-tetrakis-[E(1,1dimethyl.ethyl) dimethylsilyl] oxy] -16-f luoro-4, 4,8, 12-tetramethyl- 17- (2-pyridyl) -heptadeca-12, 16-dien-5-one The solution of 1.36 g (2.24 mmcl) of the compound, presented according to Example 17r, in ml of anhydrous dichloromethane is cooled under an atmosphere of dry argon to 100 -78 0 C, mixed with 3.45 ml of 2,6-lutidine, 3.36 ml of trifluoromethanesulfonic acid-tert-butyl dimethyl silyl ester, allowed to heat within 2 hours to 0°C and stirred for 2 more hours. It is poured into saturated sodium bicarbonate solution and extracted several times with dichloromethane. The combined organic extracts are dried on sodium sulfate and concentrated by evaporation in a vacuum. After column chromatography on silica gel with a gradient system that consists of n-hexane and ethyl acetate, 1.83 g (1.92 mmol, 86%) of the title compound is isolated as a colorless oil.
'H-NMR (CDCl 3 6 0.00-0.12 (24H), 0.83 0.85-0.98 (39H), 1.00-1.82 1.03 1.21 1.61+1.68 1.98 2.42 3.01 3.47-3.73 3.82 3.91 (1H), 4.21 5.19 6.01 7.12 7.65 7.73 (1H), 8.58 (1H) ppm.
Example 17t (3S,6R, 7S,8S,12E/Z,15S 16Z) -6-Ethyl-3,7,15-tris- dimethylethyl)dimethylsilyl]oxy]-1-hydroxy-16-fluor-4,4,8,12tetramethyl-17-(2-pyridyl)-heptadeca-12,-16-dien-5-one The solution of 1.83 g (1.92 mmol) of the compound, presented according to Example 17s, in a mixture of 20 ml of dichloromethane and 20 ml of methanol is mixed at 23 0 C under an atmosphere of dry argon with 446 mg of campher-10-sulfonic acid, and it is stirred for 2 hours. It is poured into a saturated sodium bicarbonate solution and extracted several times with dichloromethane. The combined organic extracts are dried on 101 sodium sulfate and concentrated by evaporation in a vacuum.
After column chromatography on fine silica gel with a gradient system that consists of n-hexane and ethyl acetate, 1.40 g (1.67 mmol, 87%) of the title compound is isolated as a colorless oil.
'H-NMR (CDC1 3 6 0.02-0.14 (18H), 0.85 0.88-0.97 1.03-1.80 1.08 1.20 1.60+1.68 (3H), 1.90-2.06 2.42 3.01 3.68 3.83 4.08 4.21 5.18 6.01 7.12 7.63 7.72 8.56 (1H) ppm.
Example 17u (3S,6R,7S,8S,12E/Z,15S,16Z)-6-Ethyl-3,7,15-tris-[[(1,1dimethylethyl)dimethylsilyl]oxy]-16-fluoro-5-oxo-4,4,8,12tetramethyl-17- (2-pyridyl)-heptadeca-12,16-dienal The solution of 400 il of oxalyl chloride in 16 ml of anhydrous dichloromethane is cooled under an atmosphere of dry argon to -70 0 C, mixed with 650 il of dimethyl sulfoxide, the solution of 1.51 g mmol) of the compound, presented according to Example 17t, in 16 ml of anhydrous dichloromethane, and it is stirred for 0.5 hour. Then, it is mixed with 2 ml of triethylamine, allowed to react for 1 hour at -30 0 C and mixed with n-hexane and saturated sodium bicarbonate solution. The organic phase is separated, the aqueous phase is extracted several more times with n-hexane, the combined organic extracts are washed with water and dried on magnesium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel with a 102 gradient system that consists of n-hexane and ethyl acetate.
1.48 g (1-77 mmol, 98%) of the title compound is isolated as a pale yellow oil.
'H-NMR (CDC13) of a purified sample: 6 0.02-0.13 (18H), 0.82 0.85-0.97 (30H), 1.10-1.80 1.10 1.22 (3H), 1.60+1.68 1.89-2.07 2.32-2.48 2.57 3.00 3.81 4.21 4.48 5.18 6.01 7.12 7.66 7.73 8.57 9.78 (1H) ppm.
Example 17v (3S,6R,7S,8S,12Z,15S,16Z)-6-Ethyl-3,7,15-tris-[[(1,1dimethylethyl)dimethylsilyl]oxy] -16-f luoro-5-oxo-4,4,8,12tetramet:hyl-17-(2-pyridyl)-heptadeca-12,16-dienoic acid and (3S,6R,7;S,8S,12E,15S,16Z) -6-ethyl-3,7,15-tris- dimethylethyl)dimethylsilyl]oxy] -16-fluoro-5-oxo-4, 4 ,8,12tetramethyl-17-(2-pyridyl)-heptadeca-12,16-dienoic acid (B) The solution of 1.48 g (1.77 mmol) of the compound, presented according to -Example 17u, in 54 ml of tert-butanol is mixed with 50 ml of a 2 molar solution of 2-methyl-2-butene in tetrahydrofuran, cooled to 2 0 C, mixed with 14 ml of water, 731 mg of sodium dihydrogen phosphate, 1.24 g of sodium chloride, allowed to heat to 15 0 C and stirred for 2 hours. It is poured into saturated sodium thiosulfate solution, diluted with water and extracted several times with ethyl acetate. The combined organic extracts are dried on sodium sulfate, and the residue that is obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel with a gradient 103 system that consists of n-hexane and ethyl acetate. 487 mg (573 /Lmol, 32%) of title compound A as well as 506 mg (595 jLmol, 34%) of title compound B are isolated in each case as a colorless oil.
1 H-NMR (CDC13) of A: 6 0.00 0.03-0.11 (12H), 0.13 0.79-0.98 (33H), 1.03-1.80 1.12 1.20 1.71 1.89 2.18 2.30-2.48 2.52 3.03 (1H), 3.75 4.22 4.41 5.20 6.38 7.20 (1H), 7.72 (1H),7.82 8.51 (1H) ppm.
1 H-NMR (CDCl 3 of B: 6 0.00 0.04 0.07 (3H), 0.09 0.11 0.15 0.74-0.95 (33H), 0.99-1.72 (8H), 1.10 1.22 1.53 1.86 1.98 2.27-2.66 3.08 3.82 4.16 4.33 5.13 6.04 7.18 7.71 7.82 8.52 (1H) ppm.
Example 17w (3S,6R,7S,8S,12Z,15S,16Z)-6-Ethyl-3,7-bis-[[(1,1dimethylethyl)dimethylsilyl]oxy] -16- fluoro-15-hydroxy- 5 -oxo- 4,4,8,12 tetramethyl-17- (2-pyridyl)-heptadeca-12,16-dienoic acid The solution of 487 mg (573 tmol) of compound A, presented according to Example 17v, in 23 ml of anhydrous tetrahydrofuran is mixed under an atmosphere that consists of dry argon with 8.55 ml of a 1 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, and it is stirred for 1.5 hours at 23 0 C. It is mixed with saturated sodium bicarbonate solution, extracted several times with ethyl acetate, washed with saturated sodium chloride solution and dried on sodium sulfate. The residue that 104 is obtained after filtration and removal of the solvent is further reacted without purification.
Example 17x (4S,7R,8S, 9S,13Z,16S (Z)-4,8-Bis- [[dimethyl(1,1dimethylethyl) silyl]oxy]-16-(1-fluoro-2-(2-pyridyl) ethenyl)-7ethyl-1-oxa-55,59,13-tetramethyl-cyclohexadec-13-ene-2,6-dione The solution of 486 mg (max. 570 Amol) of the compound, presented according to Example 17w, in a mixture of 5 ml of anhydrous tetrahydrofuran and 50 ml of toluene is mixed under an atmosphere of dry argon with 474 gl of triethylamine, 454 Al of 2,4,6-trichlorobenzoyl chloride, and it is stirred for minutes. This solution is added in drops within 4.5 hours to the solution of 727 mg of 4-dimethylaminopyridine in 215 ml of toluene, and it is stirred for another 0.5 hour at 23 0 C. It is concentrated by evaporation, taken up in a little dichloromethane and purified by chromatography on fine silica gel with a gradient system that consists of n-hexane and ethyl acetate. 310 mg (432 /mol, 76%) of the title compound is isolated as a colorless oil.
Example 17 (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-(1-fluoro-2-(2pyridyl)ethenyl)-7-ethyl-1-oxa-5,5,9,13-tetramethyl-cyclohexadec- 13-ene-2,6-dione The solution of 308 mg (429 Amol) of the compound, presented according to Example 17x, in 27 ml of anhydrous tetrahydrofuran is mixed under an atmosphere of dry argon in portions with a 105 total of 4.6 ml of HF-pyridine complex, and it is stirred at 23 0
C
for 24 hours. It is poured into saturated sodium bicarbonate solution, extracted several times with dichloromethane, and the combined organic extracts are dried on sodium sulfate. After filtration and removal of the solvent, the residue that is obtained is purified by chromatography on fine silica gel with a mixture that consists of n-hexane and ethyl acetate. 135 mg (276 Aimol, 64%) of the title compound is isolated as a colorless oil.
1HkM (CDCl 3 6 0. 88 (3H1), 1. 03 (3R1), 1. 10 (3H1), 1. 13 1.95 1.32 1.71.(3H), 2.28 (111), 2.34-2.49 2.56 2.80 3.21 3.56 3.70 (1H1), 4.22 5.13 5.41 6.12 7.16 7.63-7.75 8.53 (1H) ppm.
Example 18 (4S,7R,8S9,9S,13E,16S(Z))-4,8-Dihydroxy-16- (1-fluoro-2- (2pyridyl) ethenyl) -7-ethyl-1-oxa-5,5, 9,13-tetraniethyl-cyclohexadee- 13-ene-2,6-dione Example 18a (3S,6R,7S9,SS,12E,I5S,16Z)-6-Ethyl-3,7-bis-EU1,1ldimethyleathyl) dimethylsilyl] oxyl -16-f luoro-15-hydroxy-5-oxo- 4,4,8, 12-tetramethyl-17- (2-pyridyl) -heptadeca-12, 16-dienoic acid Analogously to Example 17w, 506 mg (595 A~mol) of compound B that is presented according to Example 17v is reacted, and the crude product that is obtained after working-up is further reacted.
I
106 Example 18b (4S,7R,8S,9S,13E,16S(Z))-4,8-Bis-[[dimethyl(1,1dimethylethyl)silyl] oxy]-16-(1-fluoro-2-(2-pyridyl)ethenyl)-7ethyl-1-oxa-5,5,9,13-ttret hyl-cyclohexadec-13-ene-2, 6 -dione Analogously to Example 17x, 577 mg (max. 595 pmol) of the compound that is presented according to Example 18a is reacted, and after working-up and purification, 273 mg (380 Amol, 64%) of the title compound is isolated as a colorless oil.
1 H-NIMR (CDC 3 6 0.01-0.13 (12H), 0.78-0.96 (24H), 1.09 1.20 1.26-1.90 1.59 2.16 2.39 (1H), 2.59 2.68 2.91 3.91 4.35 5.22 (1H), 5.45 6.08 7.12 7.65 7.71 8.56 (1H) ppm.
Example 18 (4S,7R, 85,9S,13E,16S(Z))-4,8-Dihydroxy-16-(1-fluoro-2-(2pyridyl)ethenyl)-7-ethyl-1-oxa-5,5,9,13-tetramethyl-cyclohexadec- 13-ene-2,6-dione Analogously to Example 18, 273 mg (380 Amol) of the compound that is presented according to Example 1:8b is reacted, and after working-up and purification, 115 mg (235 pmol, 62%) of the title compound is isolated as a colorless oil.
1 H-MR (CDC1 3 6 0.72 0.84 1.00 1.22- 2.02 1.30 1.60 2.21 2.33-2.57 2.62 3.40 3.78 4.51 5.09 5.22 5.53 6.11 7.16 7.70 7.80 8.43 (1H) ppm.
107 Example 19 (1SR,3S(Z),7S,1R,I1S,12S,16RS)-7,11-Dihydroxy-1O-ethyl-3-(1fluoro-!- (N-oxido-2-pyridyl)ethenyl) -8,8,12, 16-tetramethyl-4,17dioxabicyclo [14 heptadecane-5,9-dione The solution of 50 mg (102 Amol) of the compound, presented according to Example 17, in 3 ml of acetonitrile is mixed at 0 0
C
with 958I Al of a 0.1 M aqueous solution of ethylene diamine tetraacetate, 1.45 ml of trifluoroacetone, 373 mg of sodium bicarbonate, 448 mg of oxone, and it is stirred for 1.5 hours at 23 0 C. It is mixed with sodium thiosulfate solution, extracted several times with ethyl acetate, the combined organic extracts are washed with saturated sodium chloride solution and dried on sodium sulfate. 61 mg (max. 102 Amol) of the title compounds, which are further reacted without purification, is isolated.
Examp~le (1S,3S(Z),7S,IOR,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-3-(1fluoro-2- (2-pyridyl)ethenyl) -8,8,12,16-tetramethyl-4,17dioxabicyclo [14.1.0]heptadecane-5, 9-dione and fluoro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17dioxabicyclo-[14.1.0] heptadecane-5, 9-dione (B) The solution of 60 mg (max. 102 gmol) of the compounds, presented according to Example 19, in 12 ml of trichloromethane is mixed under an atmosphere of dry argon with a molecular sieve, 2.2 ml of isopropanol, 39 mg of tetrapropylammonium perruthenate, and it is stirred for 2 days at 60 0 C. It is concentrated by 108 evaporation, and the residue is purified by chromatography on analytic: thin-layer plates. A mixture of dichioromethane and isopropanol is used as a mobile solvent, and a mixture of dichloromethane and methanol is used as an eluant. 17 mg (34 jmol, 28%) of title compound A and 4.3 mg (9 jimol, 81) of title compound B are isolated.
1H-NMR (CDC1 3 of A: 8 0 .87 1. 00 (3H) 1. 04 (3H) 1.25-1.918 1.29 1.37 2.10-2.21 2.42 (1H), 2.51 2.62 2.89 3.33'(1H), 3.69 4.21 (1H), 4.44 5.69 6.17 (1H1), 7.18 (1Hi), 7.70 8.54 (1H) ppm.
"NMR (CDCl 3 of.B: 6 0.83 0.94 1.07 (3H), 1.16-2.0'3 (10H), 1.30 1.38 2.27 (1H1), 2.49-2.52 (2H), 2.90-3.0'4 3.21 3.72 3.89 4.32 5.78 (1H),.6.19 7.18 7.61-7.79 8.52 (iH) ppm.
Example 21 (1SR,3S(Z) ,7S,IOR,11.S,12S,16SR)-7,11-Dihydroxy-1O-ethyl-3-(lfluoro- 2- (N-oxido-2 -pyridyl) ethenyl) -8,8,12,16 -tetramethyl-4, 17dioxabicyclo (14 heptadecane-5, 9-dione Analogously to Example 19, 112 mg (229 Azmol) of the compound that is presented according to Example 18 is reacted, and after working-up, 150 mg (max. 229 ,Lmol) of the title compounds is isolated. as a colorless oil.
Example 22 109 (4S,7R,SS,9S,13(Z)),16S(Z)-4,8-Dihydroxy-7-ethy1-16-(1-f1uoro-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5,91 13-tetraziethylcyclohexadec-13 -ene-2, 6-dione Analogously to Examples 1 and 5 with use of (3S)-l,3bis [dimethyl 1-dimethyl) silyl] oxy] -4 ,4 -dimethyl-octal-5 -one as an aldol component (see Example 5n), 86 mg of the title compound is obtained as a pale yellow-colored oil.
IH-24MR (CDCl 3 6 0.87 (31H), 1.04 1.15-1.75 (8H1), 1.10 1.33 (311), 1.72 1.86 2.20-2.40 (211), 2.42 (111), 2.56 2.73 2.82 (1Hi), 3.23 3.71 4.18 5.12 5.42 6.23 (1H1), 7.38 (111) ppm.
Example 23 (4S, 7R, 8S, 9S, 13 ,16S 8 -Dihydroxy--7-ethyl- 16 fluoro-2 (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5, 9,13-tetramethylcyc lohexadec -13 -ene 6-diane Analogously to Examples 2 and 6 with use of bis [dimethyl 1-dimfethyl) silyl] oxyI -4,4 -dimethyl-octan-5 -one as an aldol component (see Example 5n), 96 mg of the title compound is obtained as a pale yellow-colored oil..
1 H-NMR (CDCl 3 6 0. ,85 0.7-1.6 1.00 (311), 1.02 (311), 1.31 (311), 1.62 1.78 (1H1), 1.82-2.01 (211), 2.20 (1H1), 2.40-2.67 (3H) 2.68 (3H) 3.37 (1H1), 3.73 (1H) 4.40 (11) 4.48 (1H1), 5.10 (1H1), 5.53 6.15 (1H1), 7.35 (111) ppm.
110 Example 24 fluoro-2- (2-methyl-4-thiazolyl) ethenyl) -8,8,12, 16-tetramethyl- 4,17-dioxabicycla [14 .1.O]heptadecane-5, 9-diane and (1S,3S(Z),7S,1OR,11S,12S,16R)-7,11-dihydroxy-1O-ethyl- 3 fluoro-2- (2-methyl-4-thiazolyl)ethelyl) -8,8,12, 16-tetramethyl- 4 ,17-dio:bicyclo[14.1.]heptadecale-5,9-diofle
(B)
Analogously to Example 3, 8 mg of title compounds A and B at a 1:4 ratio is obtained as a pale yellow-colored oil from the title compound that is produced in Example 22.
'H-NMR (characteristic signals of mixture A and B, CDCl 3 &=0.86 0.94 (3H, 1.00 (3H, 1.05 1.26 (3H), 1.29 1.36 1.69 (1H, 1.75-1.95 2.34 (1H, B), 2.22 (1H, 2.44 2.60 (1H1), 2.75 2.86 (1H, 2.97 (1H1, 3.22 (1H, 3.35 (1H, 3.70 (1H, B) 3..88 (1H, A), 4.21 (1H, 4.31 (1H, 5.68 (1H, 5.76 (1H, 6.29 7.41 (21H) ppm.
The pure title compounds A and B are separated by HPLC on a Chiralpak AD 10 h-column with hexane/ethanol 20-50%.
ill Example (1R,3S(Z),7S,10R,IIS,12S,16R)-7,11-Dihydroxy-1O-ethyl-3-(1fluoro-2- (2-methyl-4-thiazolyl) ethenyl) 8,12,16-tetra-methyl- 4,17-dio~xabicyclo [14 .1.O]heptadecane-5, 9-dione and fluoro-2- (2-methyl-4-thiazolyl) ethenyl) 8,12, 16-tetramethyl- 4,17-dioxabi cyclo[14.1.O]heptadecane-5,9-diofle
(B)
Analogously to Example 3, 4.9 mg of title compound A as a nonpolar component and 3.4 mg of title compound B as a polar component are obtained as colorless oils from the title compound that is produced in Example 23.
IH-]SIMR (CDC1) of A, 6 0.86 0.95 1.0-1.7 (6H1), 1.04 1.30 1.38 (311), 1.76 (1H1), 1.85 (211), 1.90-2.30 2-.55 2.70 2.89 (111), 3.32 3.79 4.13 (111), 4.30 5.66 (111), 6.25 7.39 (1H) ppm.
'H-NMR (CDCl 3 of B, 6 0. 86 (3H1), 0. 96 (311), 1. 10 (3H) 1.15-1.93 (7H1), 1.23 1.35 (3H1), 1.95-2.38 (4H1), 2.58 (2H1)7 2.70 2.99 (1H),.3.1O 3.27 3.65-3.75 4.24 (1H1), 5.62 (1H1), 6.21 7.35 (1H1) ppm.
Example 26 (4S,7R, aS, 9S, 13(Z) ,165(Z)) 8-Dihydroxy-7-ethyl-16- (1-chloro-2- (2-methyl1-4-thiazolyl)ethenyl) -1-oxa-5,5,9,13-tetramethylcyclohexadec-13-ene-2, 6-diane The title compound is obtained analogously to Example 5 with use of (3S)-1,3-bis[[dimethyl(1,1-dimethyl)silyl]oxyI-4,4as an aldol component (see Example 112 Example 27 4 S,7R,S,9S,13(E),16S(Z))-4,8-Dihydroxy-7-ethyl-16-(l-chloro- 2 (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5, 9,13-tetra-methylcyclohexadec-13-Qfle- 2 ,6-dione The title compound is obtained analogously to Example 6 with use of (3S)-l,3-bis[[dimethyl(1,1-dimethyl)silylIoxyI- 4
I
4 as an aldol component (see Example Examtple 28 (1S,3S(Z) ,7S,1OR,11S,12S,16SR) -7,11-Dihydroxy-1O-ethyl-3- (1chloro-2- (2-methyl-4-thiazolyl) ethenyl) 8,12, 16-tetramethyl- 4,17-dioXabiCyclo [14 .1.O]heptadecane-5, 9-dione and chloro-2- (2-methyl-4-thiazolyl) ethenyl) 8,12, 16-tetra-methyl- 4,17-dioxabicyc1o[14.1.O]heptadecafle5,9-dione
(B)
Analogously to Example 3, the title compound is obtained from the title compound that is produced in Example 26.
Example 29 chloro-2- (2-methyl-4-thiazolyl) ethenyl) 8,12, 16-tetraznethyl- 4, 17-dioxabicyclo[14.1.O]heptadecale-5, 9-dione and chloro-2- (2-methyl-4-thiazolyl) ethenyl) -8,8,12, 16-tetraniethyl- 4,17-dioxabicyclo[14.1.olheptadecale-5,9-diofle
(B)
Analogously to Example 3, the title compound is obtained from the title compound that is produced in Example 27.
113 Example (1S,3S(Z),7S,1OR,11S,12S,1S)-7,11-Dihydroxy-10-ethyl-3-(1fluoro-2- (2-pyridyl)ethenyl) -8,8,12,16-tetramethyl-4,17dioxabiclyclo[14 .1.Olheptadecane-5, 9-diane and (1R,3S(Z) ,7S,1OR,11S,12S,16R)-7,11-dihydroxy-10-ethyl-3-(1fluoro-2- (2-pyridyl)ethenyl) -8,8,12,16-tetramethyl-4,17dioxabic-yclo [14 .1.0 1 heptadecane-5, 9-dione (B) Analogously to Example 20, 150 mg (max. 229 jimol) of the compounds that are presented according to Example 21 is reacted, and after working-up and purification, 19 mg (38 ,mol, 16%) of title compound A as well as 35 mg (69 1imol, 30%) of title compound B are isolated in each case as colorless oils.
1 H-NrMR (CDCl 3 of A: 6 0.83 0.93. 1.08 (31), 1.18-1.97(9H), 1.21 1.36 (3H),.2.09 2.31 .2.59 2.99 3.30 3.44 3.70 4.33 4.40 5.67 6.19 7.18 7.70 8.51 (1H) ppm.
1 H-NMR (CDCl 3 of B: 6 0.85 0.94 1.00-1.97 (9H),.1.02 1.29, 1.38 2.06 2.28 2.54 2.90 3.35 3.61 3.79 4.39 5.67 6.22 7.18 7.69 7,78 8.51 (1H) ppm.
Example 31 (4S,7R, BS, 9S, 13Z,16S 8-Dihydroxy-16- (1-chloro-2- (2pyridyl)thenyl)-7-ethyl-1-oxa-5,5,9,13-tetramethyl-cyclohexadec- 13-ene-2,6-dione 114 Example 31a 3-(2-Pyridyl)-2-propin-l-ol The mixture that consists of 16.6 ml (173 mmol) of 2bromopyridine, 21.6 ml of propargyl alcohol, 2.5 g of palladiumbis-triphenylphosphine-dichloride and 173 mg of copper(I) iodide is mixed with 510 ml of diethylamine and heated for 1.5 hours to 0 C. After filtration and removal of the solvent, the residue is purified by chromatography on fine silica gel with a gradient system that consists of n-hexane and ethyl acetate. 17.8 g (134 mmol, 77%) of the title compound is isolated as a colorless oil.
'H-NMR (CDC1 3 6 3.70 4.54 7.24 7.42 7.67 8.53 (1H) ppm.
Example 31b (2Z)-3-(:2-Pyridyl)-2-chloro-2-propen-l-ol 12.3 g (92.6 mmol) of the compound that is presented according to Example 31a is mixed with 238 ml of concentrated solution and heated for 2.5 hours to 80 0 C. After cooling, it is carefully poured into saturated potassium carbonate solution, extracted several times with dichloromethane, the combined organic extracts are washed with saturated sodium chloride solution and dried on sodium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel with a gradient system that consists of n-hexane and ethyl acetate. 14.8 g (87.3 mmol, 94%) of the title compound is isolated as a crystalline solid.
115 1 H-NTMR (CDCl 3 4.36 (2H1), 5.47 (1H1), 7.18 (1H1), 7.21 7.72 7.99 8.56 (1H) ppm.
Example 31c (2Z) (2-Pyridyl) -2-chloro-2-propenal Analogously to Example 17e, 14.8 g (87.5 mmol) of the compound that is presented according to Example 31b is reacted, and after working-up, 14.6 g (87.1 mmol, 9 9k) of the title compound is isolated as a pale yellow oil.
IH-NTMR (CDCl 3 7.36 7.74 (111), 7.83 8.34 8.77 (111), 9.57 (1H) ppm.
Example 31d (3S,4Z) (2-Pyridyl) -4-methyl-5-phenyl-1,3oxazolidin-2-on-3-yl] -3-hydroxy-4-chloro-4-penten-1-ofle and (3R,4Z) (2-py-ridyl) -4-methyl-5-phenyl-1,3oxazolidin-2-on-3-yll -3-hydroxy-4-chloro-4-p enten-1-ofle (B) Analogously to Example 17f, 14.6 g (87.1 mmol) of the compound that is presented according to Example 31c is reacted, and afte~r working-up and separation, 12.3 g (31.8 mmol, 37%) of crystalline title compound A as well as 9.6 g (24.8 mmol, 28k) of title compound B are isolated as colorless oils.
IH-DNMR (CDCl 3 of A: 6 0.94 3.42 3.58 (111), 4.50 (111), 4.81 (1H1), 4.91 (1H1), 5.70 7.14-7.48 (711), 7.72 (111), 7.;96 8.62 (1H1) ppm.
116 1 H-NqMR (CDCl 3 of B: 6 0.96 3.50 4.82 (1H), 4.96 (111); 5.72 7.13-7.50 7.73 7.97 8.65 (1H) ppm.
Example 31e (4Z) -5-(2-Pyridyl) [(4S,SR) -4-methyl-5-phenyl-1,3-oxazolidin-2on-3-yl] -4-chloro-4-pentene-1,3-diole Analogously to Example 17g, 11.3 g (29.2 mmol) of compound B that is presented according to Example 31d is reacted, and after working-up, 9.8 g (25.5 mmol, 87%) of the title compound is isolated as a crystalline solid.
'H-TIMR (CDC 3 as a ketone/enol mixture: 6 0.99 (3H), 4.49 (0.6H1), 4.60 (0.6H1), 4.87 5.71+5.76 (1H1), 7.21-7.52 (6.4H1), 7.79 7.92 (1H1), 8.10+8.20 8.72 13.66 4H) ppm.
Example 31f (3S, 4Z) -5-(2-Pyridyl) 71-[(4S, 5R) -4-methyl-5-phenyl-1, 3oxazolidin-2-on-3-ylJ [[dimethyl(1, 1-dimethylethyl) silylloxy] 4 -chloro-4 -penten- 1-one Analogously to Example 17i, 12.3 g (31.7 mmol) of compound A that is 'resented according to Example 31d and/or Example 31f is reacted, and after working-up and purification, 12.2 g (24.3 mmol, 77%) of the title compound is isolated as a colorless oil.
1 H-NNR (CDCl 3 6 0.13 0.90 (1211), 3.30 3.59 4.78 (1H1), 5.01 5.66 (111), 7.02 (1H1), 7.19 (1H1), 7.23-7.48 (511), 7.71 7.97 8.62 (1H) ppm.
117 Example 31g (3S,4Z) (2-Pyridyl) [[dimethyl(1,1-dimethylethyl)silyl]oxy] 4-chloro-4-penteioic acid ethyl ester Analogously to Example 17j, 12.1 g (24.1 mmol) of the compound that is presented according to Example 31f is reacted, and after working-up and purification, 8.3 g (22.4 mmcl, 93%) of the title compound is isolated as a colorless oil.
IH-INMR (CDCl 3 6 0.11 (6H1), 0.90 (911), 1.26 2.75 4.14 (211), 4.83 7.00 7.18 7.69 (1H1), 7.92.
(1H1), 8.61 (111) ppm.
Example 31h (3S,4Z) (2-Pyridyl) [[dimethyl(1,1-dimethylethyl)si1y1]oxy] 4 -chloro-4 -penten-1-ol Analogously to Example 17k, 8.1 g (21.9 mmol) of the compound that is presented according to Example 31g is reacted, and afte~r working-up and purification, 6.3 g (19.2 mmol, 88%) of the title compound is isolated as a colorless oil.
1 H-NTMR (CDCl 3 5 0.13 (3H1), 0.18 (311), 0.96 (9H1), 1.98- 2.10 3.70-3.91 (2H1), 4.60 (1H1), 7.00O (1H1), 7.19 7.70 (111), 7.93 (1H1), 8.62 (111) ppm.
Example 31i (3S,4Z) (2-Py-ridyl) -3-C [dimethyl(1,1-dimethylethyl)silyl]oxy] 1-iodo-4 -chloro-4 -pentene Analogously to Example 171, 6.3 g (19.2 mmcl) of the compound that is presented according to Example 31h is reacted, 118 and after working-up and purification, 7.8 g (17.8 mmol, 93%) of the title-compound is isolated as a colorless oil.
'H-,NMR (CDC1 3 6 0.12 0.19 0.93 2.25 3.24 4.48 7.00 7.20 7.71 7.97 8.63 (1H) ppm.
Example 31k (3S,4Z) -5-(2-Pyridyl)-3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]- 4-chloro-4-penten-1-triphenylphosphonium iodide Analogously to Example 17m, 7.8 g (17.8 mmol) of the compound that is presented according to Example 31i is reacted, and after working-up and purification, 11.4 g (16.3 mmol, 91%) of the title compound is isolated as a crystalline solid.
'H-NMR (CDC1 3 6 0.15 0.21 0.90 (911), 1.96- 2.20 (211), 3.52-3.91 5.02 7.18 7.25 7.63- 7.88 (17H), 8.61 (1H) ppm.
Example 311 (2S,6E/Z,9S,10Z)-9-[[Dimethyl(1,1-dimethylethyl)silyl] chloro-LI-(2-pyridyl)-1-(tetrahydropyra,-2-yloxy)-2,6-dimethylundeca-6,10-diene Analogously to Example 17n, 3.00 g of the compound, presented according to Example 31k, is reacted with 653 mg (2.86 mmol) of (2S)-2-methyl-6-oxo-heptane-l-(tetrahydropyran-2-yloxy), which was produced analogously to the process described in DE 197 51 200.3 or WO 99/07692, and after working-up and purification, 119 in addition to starting material, 202 mg (0.39 rnmol, 14%) of the title compound is isolated as a colorless oil.
1 H-.NMR (CDCl 3 6 0.08 0.80-0.96 (12H), 1.08 1.22-2.05 (12H), 1.61+1.67 2.31-2.55 3.03-3.25 (1H), 3.40-3.62 3.84 4.28 4.53 5.15 (1H1), 6.91 7.16 7.68 7.95 8.60 (1H) ppm.
Example 31m chioro-1- (2-pyridyl) -l-hydroxy-2, 6-dimethyl-undeca-6, lO-diene Analogously to Example 17o, 472 mg (904 pimol) of the compound. that is presented according to Example 311 is reacted, and after working-up and purification, 278 mg (635 gmol, 70%) of the title compound is isolated as a color-less oil.
IH-]qIMR (CDCl 3 6 0.09 (6H1), 0.82-0.97 (12H), 0,.98-2.12 1.60+1.68 2.32-2.58 3.63-3.54 4.30 (1H1), 5.11+5.19 6.89+6.92 (1H1), 7.19 (1H1), 7.70 7.98+8.04- 8. 59 (111) ppm.
Example 31n (2S,6E/Z,9S,1OZ) [[Dimethyl(1,1-dimethylethyl)silylloxy] chioro-li- (2-pyridyl) 6-dimethyl-undeca-6, lO-dienal Analogously to Example 17p, 278 mg (635 jAmol) of the compound that is presented according to Example 31m is reacted, and after working-up, 273 mg (626 junol, 99%) of the title compound is isolated as a pale yellow oil.
120 Example 31o (4R, 5 65, 1OE/Z, 13, S14Z)) (13- Dimethy]Lethyl)dimethylsilyll oxy] -4-ethyl-14-chloro-15- (2pyridyl)-3-oxo-5-hydroxy-2,6,10-trimethyl-pentadeca-lO,14-dien-2yl) -2,2-dimethyl- 1,3]dioxane and (4S (4S, 6S, 1OE/Z, 135, 14Z)) (13- 1-dimethylethyl) dimethyLsilyl]oxy-4-ethyl-14-chloro-15-(2-pyridyl)-3-oxo-5hydroxy-2, 6,10-trimethyl-pentadeca-10, 14-dien-2-yl) -2,2-dimethyl- 31dioxane (B) Analogously to Example 17q, 273 mg (626 jtmol) of the compound, presented according to Example 31n, is reacted with (4S) -4-1 2-methyl-3-oxo-hex-2-yl)-2,2-dimethyl-[1,3]dioxane, which was produced according to the process that is described in DE 19751200.3 or WO 99/07692, and after working-up and purification, 275 mg (414 Almol, 66%) of title compound A, and after purification, 58 mg (87 Amol, 14%) of title compound B are isolated in each case as colorless oils.
1 H-NMR (CDC1) of A: 6 0.07 0.82 0.91 (9H), 0.99 (3H1), 1.08 1.17-2.08 1.23 1.31 1.39 1.60+1.68 2.31-2.56 2.,89 3.19 3.43 3.88 3.98 4.18 4.29 5.16 6.91 7.18 7.69 7.97 8.60 (1H) ppm.
121 Example 31p (3S,6R,75,-8S,12E/Z,15S,16Z) -15- Dimethylethyl) dimethylsilylloxyl -6-ethyJ.-16-chloro-1,3,7trihydro~xy-4,4,8, 12-tetramethyl-17- (2-pyridyl) -heptadeca-12, 16dien- Analogously to Example 17r, 275 mg (414 mmol) of compound A that is presented according to Example 31o is reacted, and after working-up and purification, 234 mg (375 Amol, 91U) of the title compound, is isolated as a colorless oil.
IH-NIIR (CDC1 3 6 0.03-0.12 0.78-0.95 (1511), 0.98- 2.18 (10H1), 1.09 1.26 1.60+1.68 (311), 2.32-2.58 (211), 2.72-2.98 3.19 3.41 (1H1), 3.71-4.00 4.12 (1H1), 4.28 5.11+ 5.21 (1H1), 6.82+6.83 7.20 7.71 (1H1), 8.03 8.63 (1H1) ppm.
Example 31q (3S,6R,7S,SS,12E/Z,I5S,16Z)-6-Ethyl-1,3,7,1S-tetrakis-E(1,1- dimethylethyl) dimethy lsilyl] oxyl -16-chloro-4,4, 8, 12-tetramethyl- 17- (2-pytridyl) -heptadeca-12,16-dien-5-one Analogously to Example 17s, 234 mg JX375 jimol) of the compound that is presented according to Example 31p is reacted, and after working-up and purification, 325 mg (336 !Lmol, 90U) of the title compound is isolated as a colorless oil.
'H-1,T4R (CDCl 3 6 -0.04-0.10 (2411), 0.7G-1.78 (51H1), 1.01 1.23 (311), 1.59+1.63 (311), 1.89-2.03 (211), 2.29-2.54 (211),.
3.00 (1H1), 3.50-3.71 3.80 (111), 3. (111), 4.26 (111), 5.13 (1H1), 6.91 (111), 7.15 (1H1), 7.68 (111), 7.94 (1H1), 8.60 (1H1) ppm.
122 Example 31r (3S,6R,7'S,8S,12E/Z,15S,16z)-6-Ethyl-3,7,15-tris-[[(1,ldimethylethyl) dimethylsilyl] oxy] -1-hydroxy-16-chloro-4, 4,8,12tetranlethyl-17- (2-pyridyl) -heptadeca-12,16-dien-5-ofle Analogously to Example 17t, 325 mg (336 Amol) of the compound[ that is presented according to Example 31q is reacted, and after working-up and purification, 264 mg (310 iAmol, 92%) of the title compound is isolated as a colorless oil.
IH-:NMR (CDCJ.
3 6 0.01-0.12 (1811), 0.79-0.97 (3311), 1.01- 2.08 (12H), 1.08 (311), 1.19 1.60+1.68 2.31-2.56 (2H), 3.01 3.68 3.84 4.08 (1H1), 4.29 (1H1), 5.18 (111), 6.93 7.19 7.69 7.97 (1H1), 8.61 (1H) ppm.
Example 31s (3S,6R,7S,8S,12E/Z,15S,16Z)-6-Ethyl-3,7,15-tris-[[Ul,ldimethylethyl)dimfethylsilylJoxy] -16-chloro-5-oxo-4,4, 8,12tetramethyl-17- (2-pyridyl) -heptadeca-12, 16-dienal Analogously to Example 17u, 264 mg (310 JAmol) of the compound. that is presented according to Example 31r is reacted, and after working-up, 238 mg (280 JAmol, 90!k) of the title compound. is isolated as a pale yellow oil, which is further reacted without purification.
123 Example 31t (3S,6R, 73,S S,12Z,15S,16Z)-6-Ethyl-3,7,15-tris-U(1, 1dimethy]Lethyl)dimethylsilylloxyl -16-chloro-5-oxo-4,4, 8,12tetrametihyl-17-(2-pyridyl)-heptadeca-12,16-dienoic acid and (3S,6R, 7S,8S,12E,15S,16Z) -6-ethyl-3,7,15-tris- [C (1,1dimethyJLethyl)dimethylsilyl oxy] -16-chloro-5-oxo-4,4, 8,12tetramet:hyl-17- (2-pyridyl) -heptadeca-12, 16-dienoic acid (B) Analogously to Example 17v, 238 mg (280 jimol) of the compound that is presented according to Example 31s is reacted, and after working-up and purification, 111 mg (128 Amol, 46%) of title compound A as well as 102 mg (118 Amol, 42%) of title compound B are isolated in each case as colorless oils.
H-NMR (CDCl 3 of A: 6 -0.01-0.15 (18H), 0.79-0.97 (33H), 1.02-2.4:3 1.12 1.21 1.71 2.56 3.01 3.77 4.31 4.39 5.19 7.16 7.24 7.76 8.09 8.59 (1H) ppm.
1 H-.NMR (CDC1 3 of B: 6 0.00-0.19 (18H), 0.78-0.97 (33H),- 1.00-1.73 1.11 1.21 1.58 1.87 2.00 2.29-2.43 2.53 2.63 3.09 3.87 (1H), 4.32 5.13 6.93 7.26 7.78 8.12 (1H), 8.61 (lH) ppm.
124 Example 3lu (3S,6R,7FSSS,12Z,15S,16Z)-6-Ethyl-3,7-bis-[[(1,1dimethylethyl) dimethylsilyl] oxy] -16-chloro-15-hydroxy-5-oxo- 4,4,8, 12'.-tetramethyl-17- (2-pyridyl) -heptadeca-12, 16-dienoic acid Analogously to Example 17w, 111 mg (128 11mol) of compound A that is presented according to Example 31t is reacted, and after working-.up, 105 mg (max. 128 /Lmol) of the title compound is isolated as a crude product, which is further reacted without purif icat ion.
Example 31v (4S,7R,8;S,9S,13Z,16S(Z))-4,8-Eis-[Edimethyl(1,1dimethylethyl) silyl] oxy] -16- (1-chloro-2- (2-pyridyl) ethenyl) -7- 9, 13-tetramethyl-cyclohexadec-13-ele-2, 6-dione Analogously to Example 17x, 105 mg (max. 128 jmol).of the compound that is presented according to Example 31u is reacted, and after working-up and purification, 61 mg (83 pmol, 65%) ofthe title compound isi solated as a colorless oil.
IH-'NMR (CDC1 3 6 -0.11 O3H), 0.08 0.11 0.69- 1.98 (19H), 0.73 0.84 (9H1), 0.94 1.22 (3H1), 1.68 2.29 (1H1), 2.45 (111), 2.65 (1H1), 2.84 (1H1), 3.02 3.99 5.14 6.98 7.19 (1H1), 7.69 (1H1), 7.98 (1H1), 8.61 (1H1) ppmr.
125 Example 31 (4S,7R,8S,-9S,13Z,16S(Z))-4,8-Dihydroxy-16-(1-chloro-2- (2pyridyl) ethenyl) -7-ethyl-l-oxa-5, 519, 13-tetramethyl-cyclohexadec- 13-ene-2, 6-dione Analogously to Example 17, 61 mg (83 JAmol) of the compound that is -resented according to Example 31v is reacted, and after working-up and purification, 24 mg (47 jimol, 57t) of the title compound is isolated as a colorless oil.
1 H-NMR (CDC1 3 6 0.88 1.03 1-09 1.20- 1.92 1.36 1.86 (3H1), 2.24-2.62 2.82 3.22 3.49 3.70 4.06" (1H1), 4.32 5.12 (1H1), 5.41 (1H1), 7.00 7.22 7.72 7.91 8.57 (1H1) ppm.
Example 32 7R, 85, 95,13E, 165(Z)) 8-Dihydroxy-16- (1-chloro-2- (2pyridyl) ethenyl) -7-ethyl-1-oxa-5, 5,9, 13-tetrainethyl-cyclohexadec- 13-ene-2, 6-dione Example .32a (3S,6R,7;S,8S,12E,15S,16Z)-6-Ethyl-3,7-bi3s-[[(1,1dimethyleathyl) dimethylsilyl] oxy] -16-chloro-15-hydroxy-5-oxo- 4,4,8, 12-tetramethyl-17- (2-pyridyl) -heptadeca-12, 16-dienoic acid Analogously to Example 17w, 102 mg (118 Amol) of compound B that is presented according to Example 31t is reacted, and after working-up, 92 mg (max. 118 Asmol) of the title compound is isolated as a crude product, which is further reacted without purification.
126 Example 32b (4S,7R,8s;,-9S,13E,16S(Z))-4,8-Eis-[[dimethyl(1idimethylethyl) silyijoxy] -16- (1-chloro-2- (2-pyridyl) ethenyl) -7- 5,9, 13-tetramethyl-cyclohexadec-13-ele-2, 6-diane Analogously to Example 17x, 92 mg (max. 118 JAmol) of the compound that is presented according to Example 32a is reacted, and after working-up and purification, 62 mg (84 !Lmol, 72%) of the title compound is isolated as a colorless oil.
1 H-NIvR (CDCl 3 6 0.04-0.19 (12H), 0.78-2.00 (14H), 0.58 0.90 1.11 1.22 1.62 2.16 2.41 2.52-2.81 2.91 3.91 4.36 5.23 (1H), 5.47 (1H1), 6.98 7.18 (1H1), 7.69 7.89- 8.61 (1H) ppm.
Example 32 (4S,7R, 85-, 9S, 13E, 165(Z)) 8-Dihydroxy- 16- (1-chloro-2- (2pyridyl) ethenyl) -7-ethyl-1-oxa-5, 5,9, 13-tetramethyl-cyClohexadee- 13-ene-2,6-dione Analogously to Example 17, 62 mg (84 Amol) of the compound that is presented according to Example 3,2b is reacted, and after working-up and purification, 17 mg (34 jrnol, 40%) of the title compound is isolated as a colorless oil.
IH-NMR (CDCl 3 6 0.76 0.83 0.99 1.02 1.28 1.37-2.00 1.61 2.21 2.42 (1H1), 2.51 2.61 (2H1), 3.40 (1H1), 3.76 4.55 5.04 (1R1), 5.10 5.51 6.96 7.21 (1H1), 7.73 8.17 (1H), 8.49 (111) ppm.
127 Example 33 (1RS,3S(Z),7S,1R,11S,12S,16RS)-7,11-Dihydroxy-10-ethyl-3-(1fluoro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17dioxabic-yclo [14 heptadecane-5, 9-dione Analogously to Example 19, 17 mg (34 pmol) of the compound that is presented according to Example 32 is reacted, and after working-up, 23 mg (max. 34 ymol) of the title compounds is isolated as a colorless oil.
Example :34 (1S,3S(Z) ,7S,1OR,11S,12S,16S) -7,11-Dihydroxy-10-ethyl-3-(1fluoro-2 -(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17dioxabiciyclo [14.1.01heptadecane-5, 9-dione and (1R,3S(Z) ,7S,1OR,11S,12S,16R)-7,11-dihydroxy-1O-ethyl-3-(1fluoro-2- (2-pyridyl)ethenyl) -8,8,12,16- tetramethyl-4,17dioxabicyclo[14 .1.0]heptadecane-5, 9-dione (B) Analogously to Example 17, 23 mg (max. 34 itmol) of the compounds that are presented according to Example 32 is reacted, and after working-up and purification, 3.6 mg (6.9 Atmol, 20.3%) of title compound A as well as 4.9 mg jimol, 27.7%) of title compound B are isolated in each case as colorless oils.
'H-NMR (CDCl 3 of A: 5 0.85 0.95 1.08 1.24 1.37 1.72-1.95 2.24 2.50-2.64 (2H), 2.98 3.23 3.30 3.69 4.07 4.34 (1H), 5.64 7.07 7.23 7.73 7.97 8.58 (1H) ppm.
I
128 'H-NMR (CDC1 3 of B: 6 0.87 0.97 1.04 (3H), 1.29 1.37 1.75-2.09 2.40 2.54 2.87 3.38 3.80 4.20 4.47 5.61 7.11 7.23 7.76 8.10 8.57 (1H) ppm.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

Claims (48)

1. Epothilone derivatives of general formula I, in which Rla, Rib are the same or different and mean hydrogen, C 1 -C 1 0 alkyl, aryl, C 7 -C 20 aralkyl, or together a -(CH 2 )m group with m 2, 3, 4 or R 2a R 2b are the same or different and mean hydrogen, C 1 -C alkyl, aryl, JC 7 -C 20 aralkyl or together a (CH 2 n group with n 2, 3, 4 or R 3 means hydrogen, C 1 -C 10 alkyl, aryl, C 7 -C 20 aralkyl, G means an oxygen atom or a group -CH 2 R 4 a, R 4b are the same or different and mean hydrogen, C 1 -C 1 l alkyl, aryl, C,-C 20 aralkyl or together a -(CH 2 group with p 2, 3, 4 or D-E means a group O H? H HT H H H HC-CH, HC=CH. C-C HZC-0o-CH HH HHCH H H H H H H H H 130 R 5 means hydrogen, C 1 -C 10 alkyl, aryl, C 7 -C 20 aralkyl, CO2H, CO 2 -alkyl, CH 2 OH, CHO-alkyl, CH20-acyl, CN, CH 2 NH 2 CH 2 N(alkyl, acyl) 1 2 CH 2 Hal R 6 R 7 each mean a hydrogen atom, together an additional bond or an oxygen atom, R 8 means a halogen atom, or a cyano group, X means an oxygen atom, two alkoxy groups OR 23 a C2-C10 alkylene-a,&-dioxy group, which can be straight-chain or branched, H/OR 9 or a grouping CR 10 R 11 whereby R 23 stands for a C 1 -C 20 alkyl radical, R 9 stands for hydrogen or a protective group PGX, R 10 R 11 are the same or different and stand for hydrogen, a C,-C 2 0 alkyl, aryl, C 7 -C 20 aralkyl radical or R 10 and R 11 together with the methylene carbon atom together stand for a 5- to 7-membered carbocyclic ring, T-Y means a group O-CH 2 CH 2 NR 24 NR 24 SO 2 R 24 means hydrogen, CI-C 0 alkyl, Z means an oxygen atom or H/OR 12 whereby R 12 is hydrogen or a protective group PGz.
2. Compounds according to claim 1, in which R 8 is a fluorine atom.
3. Compounds according to claim 1, in which R 8 is a chlorine atom. 131
4. Compounds according to claim 1, in which R 2 a means a methyl, ethyl or propyl group. Compounds according to claim 2, in which R 2 a means a methyl, ethyl or propyl group.
6. Compounds according to claim 3, in which R 2a means a methyl, ethyl or propyl group.
7. Compounds according to claim 1, in which Ria and RIb together mean a trimethylene group.
8. Compounds according to claim 2, in which Ria and Rlb together mean a trimethylene group.
9. Compounds according to claim 3, in which R l a and Rib together mean a trimethylene group. Compounds according to claim 1, in which R l a and Rib each mean a methyl group.
11. Compounds according to claim 2, in which Ria and Rib each mean a methyl group.
12. Compounds according to claim 3, in which R l a and Rlb each mean a methyl group.
13. Compounds according to claim 1, in which R 1 I/R 11 stand for a 2-pyridyl radical/hydrogen.
14. Compounds according to claim 2, in which R'O/R 11 stand for a 2-pyridyl radical/hydrogen. Compounds according to claim 3, in which R 1 °/R 1 1 stand for a 2-pyridyl radical/hydrogen.
16. Compounds according to claim 1, in which R 10 /R 11 stand for a 2-methyl-4-thiazolyl radical/hydrogen. 132
17. Compounds according to claim 2, in which RI°/R 1 stand for a 2-methyl-4-thiazolyl radical/hydrogen.
18. Compounds according to claim 3, in which RO/R 11 stand for a 2-methyl-4-thiazolyl radical/hydrogen.
19. Compounds according to claim 1, in which R 10 /R 11 stand for a 2-hydroxymethyl-4-thiazolyl radical/hydrogen or a 2-methyl- 4-oxazolyl radical/hydrogen or a 2-hydroxymethyl-4-oxazolyl radical/hydrogen. Compounds according to claim 2, in which R 1 °/R 11 stand for a 2-hydroxymethyl-4-thiazolyl radical/hydrogen or a 2-methyl- 4-oxazolyl radical/hydrogen or a 2-hydroxymethyl-4-oxazolyl radical/hydrogen.
21. Compounds according to claim 3, in which RI°/R 11 stand for a 2-hydroxymethyl-4-thiazolyl radical/hydrogen or a 2-methyl- 4-oxazolyl radical/hydrogen or a 2-hydroxymethyl-4-oxazolyl radical/hydrogen.
22. Compounds according to claim 1, in which T-Y is a group
23. Compounds according to claim 2, in which T-Y is a group
24. Compounds according to claim 3, in which T-Y is a group Compounds according to claim 1, in which T-Y is a group NR 24 with R 24 in the already indicated meaning.
26. Compounds according to claim 2, in which T-Y is a group NR 24 with R 24 in the already indicated meaning. 133
27. NR 4 -C
28. methyl ene
29. methylene methylene
31. Compounds according to claim 3, in which T-Y is a group with R 24 in the already indicated meaning. Compounds according group. Compounds according group. Compounds according group. Compounds according to claim 1, in which G is a to claim 2, in which G is a to claim 3, in which G is a to claim 1, atom. atom.
32. Compounds according to claim 2,
33. Compounds according to claim 3, in which Z is an oxygen in which Z is an oxygen in which Z is an oxygen atom.
34. Compounds according for an ethylene group. Compounds according for an ethylene group,
36. Compounds according for an ethylene group.
37. Compounds according a hydrogen atom.
38. Compound according t hydrogen atom. to claim 1, to claim 2, to claim 3, to claim 1, in which -D-E stands in which -D-E stands in which -D-E stands in which R 3 stands for :o claim 2, in which R 3 stands for a
39. Compounds according to claim 3, in which R 3 stands for a hydrogen atom. 134 Compounds according to for H/CH3.
41. Compounds according to for H/CH 3
42. Compounds according to for H/CH 3
43. Compounds according to for methyl or ethyl/hydrogen.
44. Compounds according to for methyl or ethyl/hydrogen. Compounds according to for methyl or ethyl/hydrogen.
46. Compounds according to for methyl or ethyl/hydrogen.
47. Compounds according to for a 2-pyridyl radical/hydrogen in which R 4 a/R 4 b stand claim 2, in which R 4 a/R 4 b stand claim 3, claim 2, claim 3, claim 8, claim 9, claim 8, in which R 4 a/R 4 b stand in which R 2 a/R 2 b stand in which R 2 a/R 2 b stand in which R 2 a/R 2 b stand in which R 2 a/R 2 b stand in which R 1 /R 1 stand or a 2-methyl-4-thiazolyl radical/hydrogen or a 2-hydroxymethyl-4-thiazolyl radical/hydrogen or a. 2-methyl-4-oxazolyl radical/hydrogen or a 2-hydroxymethyl-4-oxazolyl radical/hydrogen.
48. Compounds according to claim in which R'I/R" stand for a 2-pyridyl radical/hydrogen or a 2-methyl-4-thiazolyl radical/hydrogen or a 2-hydroxymethyl-4-thiazolyl radical/hydrogen or a 2-methyl-4-oxazolyl radical/hydrogen or a 2-hydroxymethyl-4-oxazolyl radical/hydrogen.
49. Compounds according to claim 11, in which RI 0 /R 11 stand for a 2-pyridyl radical/hydrogen or a 2-methyl-4-thiazolyl radical/hydrogen or a 2-hydroxymethyl-4-thiazolyl 135 radical/hydrogen or a 2-methyl-4-oxazolyl radical/hydrogen or a 2-hydroxymethyl-4-oxazolyl radical/hydrogen. Compounds according to claim 12, in which R 10 /R 11 stand for a 2-pyridyl radical/hydrogen or a 2-methyl-4-thiazolyl radical/hydrogen or a 2-hydroxymethyl-4-thiazolyl radical/hydrogen or a 2-methyl-4-oxazolyl radical/hydrogen or a 2 -hydroxymethyl-4 -oxazolyl radical/hydrogen.
51. Compounds according to claim 47, in which R 2 2 b stand for methyl or ethyl/hydrogen.
52. Compounds according to claim 48, in which R 2a/R 2b stand for methyl or ethyl/hydrogen.
53. Compounds according to claim 49, in which R 2 a/R 2 b stand for methyl or ethyl/hydrogen.
54. Compounds according to claim 50, in which R 2 a/R 2 b stand for methyl or ethyl/hydrogen. Compounds of general formula I, namely (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-Dihydroxy-16-(1-fluoro- 2- (2-methyl-4-thiazolyl)ethenyl) -1-oxa-S,5,7,9,13-pentamfethyl- cyclohexadec-13-ene-2, 6-dione (IR.S,3S ,75,IOR,11S, 12S, 16RS) -71 1.1-dihydroxy-3- (1-fluoro- 2- (2-methyl-4-thiazolyl)ethenyl) -8,8,1O,12,i6-pentamethyl-4,17- dioxabicyclo [14 0] heptadecane-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16Gi1 fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-l-oxa-5,5, 9 ul 3 tetramethyl-cyclohexadec-13-ene-2, 6-dione 136 (iRS, 3S ,7S,10R, bS, 12S, b6RS) bi-dihydroxy-10-ethyl-3- (1-fluoro-2- (2-methyl-4-thiazolyl)ethelyl) -8,8,12,16-tetramethyb- 4, 17-dia~xabicyCba [14. 1.0] heptadecane-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-fluora- 2- (2-met.hyloxazob-4-yl) ethenyb) -1-oxa-5, 5,7,9, 13-pentamethyb- cyclohexadec-13-ele-2, S-diane (lRS,3S(Z) ,7S,1OR,11S,12S,16RS)-7,11-dihydraxy-3-(1-fluoro- 2-(2-metilyoaazol-4-y1)ethelb) -8,8,1O,12,16-pentamethyl-4,17- dioxabic-ycla [14.1. 01heptadecane-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethYb-16- (1- fluoro-2- (2-methyloxazol-4-y1) ethenyl) -1-oxa-5, 5,9,13- tetramethlyl-cyclohexadec-13-ele- 2 6-diane (1RS,3S(Z) ,7S,10R,11S,12S,16RS)-7,11-dihydroxy-10-ethyl-3- (1-fluoro-2- (2-methyloxazol-4-y)ethelyl) -8,8,12,16-tetramethyl- 4, 17-diaxabicyclo [14 01heptadecane- 5, 9-diane (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16- (1-fluora- 2- (2-pyridyl)ethenyb) -1-axa-5,5,7,9,13-pentamethy1-cyclahexadec- 13-ene-2,6-dione (lRS,3S(Z),7S,1OR,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluoro- 2-(2-pyridy1)ethefl)-8,8,10,12,16-pentamIethylb 4 ,l 7 diaxabicycla [14.1.0] heptadecane-5, 9-diane (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydrxy-7-ethYlbG6 (1 fluaro-2- (2-pyridyl)ethenyl) -1-oxa-5,5,9,13-tetramfethyl- cyclahexadec-13-ene-2, S-diane (iRS, 3S(Z) ,7S,1bR, bS, 12S, 16RS) i1-dihydraxy-1O-ethyl-3- (1-fluaro-2- (2-pyridyl)ethenyl) -8,8,12,16-tetramethyl-4,17- diaxabicycia [14.1.0] heptadecane-5, 9-diane 137 (4.S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-fluoro- 2- (2-methyl-4-thiazolyl)ethelyl) -1-aza-5,5,7,9,13-pefltamethyl- cyclohexadec-13-ene-2, 6-dione (lR1S,3S(Z),7S,1OR,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluoro- 2- (2-ret:hyl-4-thiazolyl)ethelyl) -8,8,10,2.2,16-pentamethyl-4-aza- 17-oxabicyclo [14.1.01 heptadecane-5, 9-dione (4Sc),7R,8S,9 S,13(Z or E),1ES(Z))-4,8-dihydroxy-7-ethyllG(1(l fluoro-2!-(2-methyl-4-thiazolyl) ethenyl) -1-aza-5, 5,9,13- tetramethyl-cyclohexadec-13-efe-2, 6-dione (1R)S,3S(Z),7S,1OR,11S,12S,16RS)-7,11-dihydroxy-10-ethyl-3- (1-fluort.o-2-(2-methy14-thiazoly)ethel) -8,8,12..16-tetramethyl- 4-aza-17,--oxabicyclo [14.1. O]lheptadecane-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-flupro- 2- (2-methyloxazol-4-y)ethelyl) -l-aza-5,5,7,9,13-pentamethYl- cyclohexadec-13-ele-2, 6-dione (1RtS,3S(Z),7S,1OR,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluoro- 2- (2-methyloxazol-4-y)ethelyl) -8,8,10,12, 16-pentamethyl-4-aza-- 17-oxabicyclo [14.1.0] heptadecane-5, 9-diane (4.S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16-(1- fluoro-2'- (2-methyloxazol-4-yl)ethelyl) -l,-aza-5,5,9,13- tetramethyl-cyclohexadec-13-ele-2, 6-dione (1RZS,3S(Z),7S,1OR,11S,12S,16RS)-7,11-dihydroxy-10-ethy.-3- (1-flUo3ro-2- (2-methyloxazol-4-yl)ethenyl) -8,8,12,16-tetramethyl- 4-aza-l17-oxabicyclo [14.1.01 heptadecane-5, 9-dione (4.S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(l-fluoro- 2- (2-pyr.idyl)ethenyl) -1-aza-5,5,7,9,13-pentalnethyl-cyclohexadec- 13-ene-2, 6-dione 0 138 (iR S, 35 Z) ,7S,10R,11S, 125, 1GRS) ii-dihydroxy-3- (1-fluoro- 2- (2-pyr.idyi)ethelyl) -8,8,10,12,16-pentamethyl-4-aza-17- oxabicycba [14.1.0] heptadecane-5, 9-diane (4_S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7--ethyl-16- (1- fluoro-2,-(2-pyridyl)ethel) -1-aza-5,5,9,13-tetramethyl- cyclohexadec-13-ele-2, 6-dione (1R'S,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-10-ethyl-3- (1-fluor-o-2- (2-pyridyl) ethenyl) -8,8,12, 16-tetramethyi-4-aza-17- oxabicyclo [14 0] heptadecane 9-diane (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-chloro- 2- (2-methyl-4-thiazolyl)ethelyl) -1-oxa-5,5,7,9,13-peltamfethyl- cyclohexadec-13-ele-21 6-diane (i]RS, 3S(Z) ,75,10R,1S, 125, 16RS) ii-dihydroxy-3- (1-chlora- 2- (2-methyl-4-thiazolyl)ethelyl) -8,8,10,12,16-pentaiuethyl-4,17- dioxabicyclo [14.1.0] heptadecane-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16- (1- chloro-2- (2-methyl-4-thiazalyl)ethelyl) -1-oxa-5,5,9,13- tetramethy1-cyclohexad, c-13-ene-2, 6-dione (iR.S,3S ,75,IOR,11S, 125, 1RS) 11-dihydroxy-10-ethyl-3- (1-chloara-2- (2-methyl-4-thiazoy)ethelyL) -8,8,12,16-tetramethyl- 4, 17-dicxabicycio [14.1.0] heptadecane-5, 9-diane (4S,7R,8S,9S,13(Z or E) ,16S(Z))-4,8-dihydroxy-1.6-(1-chioro- 2- (2-methyloxazol-4-yl)ethel) -1-oxa-5,5,7,9, 13-pentamethyl- cyclahex~adec-13-ene-2,6-diane (iR.S,3S ,7S,IOR,11S, 12S, 16RS) 11-dihydroxy-3- (1-chlara- 2- (2-methyloxazol-4-yl)ethenyl) -8,8,10,12,16-pentamethyl-4,17- diaxabicycia [14.1.0] heptadecane-5, 9-diane 139 (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethy).-16-(l- chloro-2-12-methyloxazol14-y)ethefylY)1oxa-, 9 ,1 3 tetramethyl-cyclohexadec13 -ene-2, 6-dione (1RS,3S(Z),7S,1OR,11S,12S,16RS)-7,1l-dihydroxy-10-ethyl-3- (1-chlor-o-2- (2-methyloxazol-4-yl)ethelyl) -8,8,12,16-tetramethyl- 4,17-dic~xabicyclo[14.1.0]heptadecale-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-chloro- 2- (2-pyriidyl)ethenyl) -1-oxa-5,5,7,9,13-peftamethYl-cyclohexadec- 13-ene-2, 6-dione (IR.S, 3S(Z) 7S,10R,1S, 12S, 16RS) 11-dihydroxy-3- (1-chloro- 2- (2-pyr-idyl)ethenyl) -8,8,10,12,16-pen tamethyl-4,17- dioxabicyclo [14 heptadecane-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16- (1- chloro-2- (2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl- cyclohexadec-13-ele-2, 6-dione (iR.S,3S ,7S,10R, 115,12S, 16RS) il-dihydroxy-10-ethyl-3- (i-chlor-o-2- (2-pyridyl)ethenyl) -8,8,12,16-tetramethyl-4,17- dioxabicyclo [14. 1.0] heptadecane-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(l-chloro- 2- (2-methyl-4-thiazolyl)ethelyl) -1-aza-5.,5,7,9,13-pefltamethy1- cyclohexadec-13-ene-2, 6-dione (iR.S,3S ,7S, baR, 11S, 125, 6RS) -7,11-dihydroxy-3- (l-chloro- 2- (2-methy1-4-thiazolyl)ethefyly)-8,8,10,12,16-peftamethyb 4 -aza- 17-oxabicyclo [14 .1.01 heptadecane-5, 9-diane (4S,7R,8S,9S,13(Z or E),1ES(Z))-4,8-dihydroxy-7-ethyl-16-(1- chloro-2- (2-methyl-4-thiaz olyl )ethenyb) -1-aza-5, 5,9,13- tetramethyl-cyclohexadec-13-ene-2, 6-diane 140 (1R'S,3S(Z) ,7S,1OR,11S,1L2S,16RS)-7,11-dihydroxy-1O-ethyl-3- (1-chlor~o-2- (2-methyl-4-thiazolyl)ethefyl)-8,8,12,l6-tetramethyl- 4-aza-17 -oxabicyclo [14.1.0] heptadecane-5, 9-diane (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-chloro- 2- (2-methyloxazol-4-y)ethelyl) -1-aza-5,S,7,9,13-pefltamethyl- cyclohexadec-13-ele-2, 6-diane (1]RS,3S(Z) ,7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-chloro- 2- (2-methyloxazol-4-y)ethelyl) -8,8,10,12,16-peftamethyl4-aza 17-oxabicyclo [14.1.0] heptadecane-5, 9- diane (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-16- (1- chloro-2-(2-methyloxazol-4-y)etheflyl)1aza-5,5, 9 1 3 tetramethyl-cyclohexadeC-13-ele-2, 6-diane (lRS,3S(Z) ,7S,1OR,11S,12S,16RS)-7,11-dihydroxyl10ethYl-3 (1-chlar-o-2- (2-methyloxazol-4-yl)ethenyl) -8,8,12,16-tetramethyl- 4-aza-17-oxabicyclo [14.1.0] heptadecane-5, 9-diane (4S,7R,8S,9S,13(Z or E),1ES(Z))-4,8-dihydroxy-16-(1-chloro- 2- (2-pyr:idyl)ethenyl) -1-aza.-5, 5,7,9, 13-pentamethyl-CyClohexadec- 13-ene-2,6-diole (1RS,3S(Z) ,7S,1OR,11S,12S,16RS)-7,11-dihydroxy-3-(1-chloro- 2- (2-pyridyl)ethenyl) -8,8,1O,12,16-pentamethyl-4-aza-17- oxabicyclo [14.1.0] heptadecane-5, 9-diane (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-7-ethyl-1611l chlora-2- (2-pyridyl) ethenyl) -1-aza-5, 5,9, 13-tetramethyl- cyclahex~adec-13 -ene-2, 6-diane (1R.RS,3S(Z),7S,1R,11S,12S,16RS)-7,11-dihydroxy-10-ethyl-3- (1-chlo-o--2- (2-pyridyl)ethenyl) -8,8,12,16-tetramethyl-4-aza-17- oxabicyclo [14.1.0] heptadecane-5, 9-diane 141 (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-fluoro- 2- (2-methyl-4-thiazolyl) ethenyl) -l-oxa-7, 9, 13-trimethyl-5, 5- (1,3- trimeth-ylene) cyclohexadec-13-ene-2, 6-dione 3S(Z) ,7S,10R, 115, 12S, 1ERS) ii-dihydroxy-3- (1-fluoro- trimethy'lene) 17-dioxabicyclo [14.1.0] hepta-deca-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-9,13-dimethyl- 7-ty-6(-loo2(-ehl--haoy~tey)ioa55 3-trimethylele) cyclohexadec-13-ene*-2, 6-dione (1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-12,16- dimethyl-10-ethyl-3- (1-f luoro-2- (2-methyi-4-thiazolyl) ethenyl) 8,-13tiehln)41-ixbcco1..]et-eae59 dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8--dihydroxy-16-(1-fluoro- 2-2mty--haoy~tey)laa791-rmty-,-13 trimethy-lene) cyclohexadec-13 -ene-2, 6-dione (iR.S,3S ,7S,IOR, 11S,125, 16RS) ii-dihydroxy-3- (1-fluoro- trimethy-lene) -4-aza-17-oxabicyclo [14.1.0] hepta-deca-5, 9-dione (4S,7R,8S,9S,13(Z or E) ,16S(Z))-4,8.,-dihydroxy-9,13-dimfethyl- 7-ethyl-16- (1-fluoro-2- (2-methyl-4-thiazolyl) ethenyl) -l-aza-5, 3-trimethylene) cyclohexadec-13-ene-2, 6-dione (lRS,3S(Z),7S,1OR,11S,12S,16RS)-7,11-dihydroxy-12,16- dimethyl-10-ethyl-3- (1-f luoro-2- (2-methyl-4-thiazolyl) ethenyl) 8,8- (1,3-trimethylene) -4-aza-17-oxabicyclo[14.1.0]hepta-decale 9-dion~e 142 (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-chloro- 2-(2-methyl-4-thiazolyl)etheflyl)-l-oxa-7,9,13-trimethyl-5,5-i1,3- trimethy-lene) cyclohexadec-13-ene-2, 6-dione (iR.S,3S ,7S,10R,11S, 12S, 16RS) 11-dihydroxy-3- (1-chloro- 2-(2-methyl-4-thiazolyl)ethelyl)-1O,12,16-trimfethyl-8,8-i1,3- trimethy-lene) 17-dioxabicyclo (14 .1.o0]hepta-deca-S, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-9,13-dimethyl- 7-ethyl-16- (1-chloro-2- (2-methyl-4-thiazolyl)ethenyl) -1-oxa-5,5- 3-trimethylene) cyclohexadec-13-ene,-2, 6-dione (1RS,3S(Z),7S,1OR,11S,12S,16RS)-7,11-dihydroxy-12,16- dimethyl--10-ethyl-3- (1-chloro-2- (2-methyl-4-thiazolyl) ethenyl) 8,8-(1,3-trimethylene)-4,17-dioxabicyclo[14.1.O]heptadecale-5,9- dione 4S,7R,8S,9S,2.3(Z or E),16S(Z))-4,.8-dihydroxy-16-(1-chloro-2- (2-methyl-4-thiazolyl)ethenyl)-l-aza-7,9,13-trimethyl-5,5-(1,3- trimethylene) cyclohexadec-13-ene-2, 6-dione (iRS, 3S ,7S,10R,11S, 12S, 16RS) 11-dihydroxy-3- (1-chioro- 2-(2-methyl-4-thiazoli)etheflyl)-1O,12,16-trimethyl-8,8-(1,3- trimethylene) -4-aza-17-oxabicyclo [14.1. 0] hepta-deca-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8. 7 dihydroxy-9,13-dimethyl- 7-ethyl-26-(l-chloro-2-(2-methyi-4-thiazoiyl)etheflyl)-1-aza-5,5- 3-trimethylene) cyclohexadec-13-ene-2, 6-dione (1RS,3S(Z),7S,1OR,11S,12S,16RS)-7,11-dihydroxy-12,16- dimethyl-1O-ethyl-3- (1-chloro-2- (2-methyl-4-thiazolyl) ethenyl) 8,8- (1,3-trimethylene) -4-aza-17-oxabicyclo[14.1.O]heptadecane- 9-dione 143 (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(2.-fluoro- 2 -(2-pyridy)etheyl)1oxa7,9,13-trimethyl-5,5(1, 3 trimethyleie) cyclohexadec -13-ene-2, 6-dione (lRS,3S(Z),7S,1OR,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluoro- 2 2 -pyridy)etheylY)1,12,16trimethyl-8,8-(1,3-trimethylene)- 4, 17-dioxabiCyclo [14.1.0] hepta-deca-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-9,13-dimethyl- 7-ethyl-16- (1-fluoro-2- (2-pyridyl)ethelyl) -1-oxa-5,5- (1,3- trimethylene) cyclohexadec-13 -ene-2, 6-dione (IRS,3S(Z),7S,1OR,11S,12S,16RS)-7,11-dihydroxy-l 2 ,lE- dimethyl-10-ethyl-3 (1-fluoro-2- (2-pyridyl) ethenyl) (1,3- trimethylene) 17-dioxabicyclo [14 hepta-decane-5, 9-diane 4S,7R,8S,9S,13-(Z or E),16S(Z))-4,8-dihydroxy-16-(1-fluoro-2- trimethylene) cyclohexadec-13-ene-2, 6-diane (1RS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-3-(1-fluoro- 4-aza-17-oxabicyClo [14 0] ohepta-deca-5, 9-diane (4S,7R,8S,9S,13 (Z or E) ,16S(Z))-4,8-dihydroxy-9,13-dimethyl- 7-ethyl-16-(1-f1uoro-2-(2-pyridy1)ethefy )lY-aza-5, 5 3 trimethylene) cyclohexadec-13-ene-2, 6-diane. (lRS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-12,lE- dimethy1l-10-ethy-3-(-fuoro-2(2-pyridyl)etheflyl)S:, 8 il, 3 trimethylene) -4-aza-17-oxabicyclO [14. 1.0] hepta-decane-5, 9-diane (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-chloro- trimethylene) cyclohexadec-13 -ene-2, 6-diane 144 (]RS,3S(Z),7S,1OR,11S,12S,16RS)-7,l1-dihydroxy-3-(l-chloro- 2 -(2-pyr-idyl)ethenyl)-10,12,16-trimfethyl-8,8-(1,3-trimethylele)- 4, 17-dicxabicyclo [14.1.0] hepta-deca-5, 9-dione (4S,7R,8S,9S,13(Z or E) ,16S(Z))-4,8-dihydroxy-9,13-dimethYl- trimethy-lene) cyclohexadec-13 -ene-2, 6-dione (lRS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-12,16- dimethyl-10-ethyl-3- (1-chloro-2- (2-pyridyJ.)ethenyl) (1,3- trimethylene) 17-dioxabicyclo [14.1.0] hepta-decane-5, 9-dione 4S,7R,8S,9S,13(Z or E),16S(Z))-4,8-dihydroxy-16-(1-chloro-2- (2-pyridyl) ethenyl) -l-aza-7, 9, l3-trimethyl-5, 5- (1,3- trimethy-lene) cyclohexadec-13-ene-2, 6-dione (1RS,3S(Z) ,7S,1OR 11S,12S,16RS)-7,11-dihydroxy-3-(l-chloro- 2- (2-pyridyl) ethenyl) -10, 12, 16-trimethyl-8, 8- 3-trimethylene) 4-aza-17-oxabicyclo [14 hepta-deca-5, 9-dione (4S,7R,8S,9S,13(Z or E),16S(Z))-4,8--dihydroxy-9,13-dimethyl- 7-ethyl-16-(1-chloro-2-(2-pyridy)etheny)-l-aza5,Sil, 3 trimethy-lene) cyclohexadec-13 -ene-2, 6-dione (lRS,3S(Z),7S,10R,11S,12S,16RS)-7,11-dihydroxy-12,16- dimethyl1-10-ethyl-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8-(li 3 -trimethy'lene) -4-aza-17-oxabicyclo[14.1.0]hepta-decale-5,9-diofle
56. Pharmaceutical preparations that contain at least one compound[ of general formula I according to one of preceding claims 1. to 55 as well as a pharmaceutically compatible vehicle.
57. Use of the compounds of general formula I according to preceding claims 1 to 55 for the production of pharmaceutical agents. 145
58. Intermediate products of general formula C R' U R C in which R 8 has the meaning that is mentioned in general formula I for R 8 and R 7 means a hydrogen atom, T' means a group OR 20 whereby R 20 is a hydrogen atom or a protective group PG 2 a halogen atom, preferably a bromine or iodine atom, an azido group or a protected amino group, R 21 means a hydroxy group, halogen, a protected hydroxy group OPG 3 a phosphonium halide radical PPh 3 Hal" (Ph phenyl; Hal F, Cl, Br, a phosphonate radical P(O) (OQ) 2 (Q L C 1 -C 10 alkyl or phenyl) or a phosphine oxide radical P(O)Ph 2 (Ph phenyl), U means an oxygen atom, two alkoxy groups OR 23 a C2-C10 alkylene-a,w-dioxy group, which can be straight-chain or branched, H/OR 9 or a grouping CRIoR 11 whereby R 2 3 stands for a C 1 -C 20 alkyl radical, R 9 stands for hydrogen or a protective group PG 3 146 R 10 R 1 are the same or different and stand for hydrogen, a C,-C 20 alkyl, aryl, C,-C 20 aralkyl radical or R 10 and R 11 together with the methylene carbon atom commonly stand for a 5- to 7-membered carbocyclic ring.
59. Intermediate products of general formula BC R R 8 G U R3 -OOPG14 BC in which R 3 R 4 a, R 4 b, R 5 R 8 D, E, G, T' and U have the already mentioned meanings, and PG 14 represents a hydrogen atom or a protective group PG. Intermediate products of general formula ABC R 7 R R' R R D E'G UR^R 4b' S R 4a" rOPG 14 ABC, 147 in which Ri' Rb, Ra' Rb' R Rb' R, R, R, R 8 R 13 R 14 D, E, G, U and Z have the already mentioned meanings. DATED this 5th day of March 2004 SCHERING AKTIENGESELLSCHAFT By its Patent Attorneys DAVIES COLLISON CAVE
AU2004200949A 1999-02-18 2004-03-05 16-halogen-epothilone derivatives, method for producing them and their pharmaceutical use Abandoned AU2004200949A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2004200949A AU2004200949A1 (en) 1999-02-18 2004-03-05 16-halogen-epothilone derivatives, method for producing them and their pharmaceutical use

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE19908765 1999-02-18
DE19954230 1999-11-04
AU31567/00A AU3156700A (en) 1999-02-18 2000-02-18 16-halogen-epothilone derivatives, method for producing them and their pharmaceutical use
AU2004200949A AU2004200949A1 (en) 1999-02-18 2004-03-05 16-halogen-epothilone derivatives, method for producing them and their pharmaceutical use

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
AU31567/00A Division AU3156700A (en) 1999-02-18 2000-02-18 16-halogen-epothilone derivatives, method for producing them and their pharmaceutical use

Publications (1)

Publication Number Publication Date
AU2004200949A1 true AU2004200949A1 (en) 2004-04-01

Family

ID=34229764

Family Applications (1)

Application Number Title Priority Date Filing Date
AU2004200949A Abandoned AU2004200949A1 (en) 1999-02-18 2004-03-05 16-halogen-epothilone derivatives, method for producing them and their pharmaceutical use

Country Status (1)

Country Link
AU (1) AU2004200949A1 (en)

Similar Documents

Publication Publication Date Title
KR100718616B1 (en) 16-Halogen-Epothilone Derivatives, Method for producing them, and their Pharmaceutical Use
CA2651653C (en) 6-alkenyl-, 6-alkinyl- and 6-epoxy-epothilone derivatives, process for their production, and their use in pharmaceutical preparations
US20030144523A1 (en) Epothilone derivatives, method for producing same and their pharmaceutical use
US20100168179A1 (en) 6-alkenyl-, 6-alkinyl- and 6-epoxy-epothilone derivatives, process for their production, and their use in pharmaceutical preparations
KR20010094763A (en) Epothilon Derivatives, Method For The Production And The Use Thereof As Pharmaceuticals
AU2004200949A1 (en) 16-halogen-epothilone derivatives, method for producing them and their pharmaceutical use
DE10020899A1 (en) New 9-oxa-epothilone derivatives, are phase-specific cell division regulators useful for treating malignant tumors, angiogenesis or inflammatory disease
ZA200107648B (en) 16-Halogen-epothilone derivatives, method for producing them and their pharmaceutical use.
DE10041470A1 (en) New 6-substituted 12,13-(cyclopropyl or azacyclopropyl)-epothilone derivatives, useful as cell division regulators for treating e.g. malignant tumors, psoriasis or arthritis
UA74542C2 (en) Epothilone 16-halogen derivatives, a pharmaceutical agent based thereon, intermediary compounds (variants)
JP2009513498A (en) Method for producing epothilone C1-C15-fragment and derivatives thereof
AU2004200948A1 (en) Epothilon derivatives, method for the production and the use thereof as pharmaceuticals
AU4438602A (en) New epothilone derivatives, process for their production, and their pharmaceutical use

Legal Events

Date Code Title Description
MK4 Application lapsed section 142(2)(d) - no continuation fee paid for the application