Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-07
2003-08-26
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S267000, C549S268000, C549S271000, C549S352000, C514S450000
Reexamination Certificate
active
06610736
ABSTRACT:
Höfle et al. describe the cytotoxic action of the natural substances epothilone A (R=hydrogen) and epothilone B (R=methyl)
Epothilone A (R=H), Epothilone B (R=CH
3
) in, e.g., 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, e.g., 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 Höfle 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
R
1a
, R
1b
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 5,
R
2a
, R
2b
are the same or different and mean hydrogen, C
1
-C
10
alkyl, aryl, C
7
-C
20
aralkyl or together a —(CH
2
)
n
group with n=2, 3, 4 or 5,
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
4a
, R
4b
are the same or different and mean hydrogen, C
1
-C
10
alkyl, aryl, C
7
-C
20
aralkyl or together a —(CH
2
)
p
group with p=2, 3, 4 or 5,
D—E means a group
R
5
means hydrogen, C
1
-C
10
alkyl, aryl, C
7
-C
20
aralkyl, CO
2
H, CO
2
-alkyl, CH
2
OH, CH
2
O-alkyl, CH
2
O-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 C
2
-C
10
alkylene-&agr;,&ohgr;-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 PG
X
,
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—C(═O), O—CH
2
, CH
2
C(═O), NR
24
—C(═O), NR
24
—SO
2
,
R
24
means hydrogen, C
1
-C
10
alkyl,
Z means an oxygen atom or H/OR
12
,
whereby
R
12
is hydrogen or a protective group PG
Z
.
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
2a
is preferably to mean a methyl, ethyl, propyl or butyl group.
A trimethylene group preferably commonly stands for substituents R
1a
and R
1b
, or R
1a
and R
1b
each mean a methyl group.
R
10
/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-4-oxazolyl radical/hydrogen or a 2-hydroxymethyl-4-oxazolyl radical/hydrogen.
T—Y is preferably a group O—C(═O) or a group NR
24
-C(═O).
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, i.e., —D—E— 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
4a
/R
4b
.
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 R
1a
+R
1b
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
10
/R
11
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
2a
/R
2b
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
1a
+R
1b
together mean a trimethylene group and R
2a
/R
2b
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, R
2a
/R
2b
stand for ethyl/hydrogen and R
10
/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 Nov. 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 C1-C6 fragment (epothilone numbering syste
Buchmann Bernd
Klar Ulrich
Schirner Michael
Schwede Wolfgang
Skuballa Werner
Coppins Janet L
Millen White Zelano & Branigan P.C.
Rotman Alan L.
Schering AG
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