C3-cyano epothilone derivatives

Details C3-cyano epothilone derivatives C3-cyano epothilone derivatives

2003-03-11

2004-04-13

Gerstl, Robert (Department: 1626)

Pumps

Motor driven

Axial thrust balancing means for rotary pump and motor

C548S204000

Reexamination Certificate

active

06719540

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to 3-cyano substituted macrolide compounds possessing anti-tumor activity, methods for the preparation of the compounds, pharmaceutical compositions containing the compounds and methods of using these compounds.
BACKGROUND OF THE INVENTION
Epothilones are macrolide compounds which find utility in the pharmaceutical field. For example, Epothilones A and B having the structures:
may be found to exert microtubule-stabilizing effects similar to paclitaxel (TAXOL®) and hence cytotoxic activity against rapidly proliferating cells, such as, tumor cells or other hyperproliferative cellular disease, see Hofle, G., et al.,
Angew. Chem. Int. Ed. Engl
., Vol. 35, No.13/14, 1567-1569 (1996); WO93/10121 published May 27, 1993; and WO97/19086 published May 29, 1997.
The widespread interest in epothilones that originated with the discovery of their mircotubulin-stabilization activity was furthered by the finding that epothilones were active in vitro against a number of paclitaxel-resistant human cancer cell lines (Bollag, D. M., et al.,
Cancer Res
., Vol. 55, 2325-2333 (1995); Kowalski, R. J., et al.,
J. Biol. Chem
., Vol. 272, 2534-2541 (1997)). Additionally, the relatively efficient total synthesis of epothilones, compared to that of paclitaxel, has lead to extensive efforts in the synthesis of epothilone analogs, as well as the characterization of their biological activity and strutcure/activity relationship (SAR) features. (Altmann, K.-H., et al.,
Curr. Opin. Chem. Biol
., Vol. 5, 424-431 (2001)).
Several groups have been active in this area including Danishefsky at the Memorial Sloan-Kettering Cancer Research Center, Nicolaou at the Scripps Research Institute, Altmann at Novartis Pharma AG and Klar at Shering AG. For example, the Danishefsky group has prepared and characterized the biological activity of 12,13-desoxyepothilone derivatives (Chou T.-C. et al.,
Proc. Natl. Acad. Sci
., Vol. 95, 9642 (1998)). The Nicolaou group at the Scripps Research Institute has synthesized 12,13-cyclopropyl, 12,13-cyclobutyl and related pyridine side-chain epothilone analogs. (Nicolaou, K. C.,
J. Amer. Chem. Soc
., Vol. 123, 9313-9323 (2001)). Epothilone derivatives containing 16-halo substitutions have been prepared by the group at Schering AG (WO 00/49021). Additionally, Altmann at Novartis Pharma AG has synthesized an epothilone analog in which the thiazole moitey is conformationally locked by a benzenoid functionality (Altmann, K.-H. et al.,
Chimica
, Vol. 54, No. 11,612-621 (2000)).
Examples of C-3 substituted Epothilone compounds are those possessing an ether, halo or sulfonyl group (see Schering AG, WO 00/66589); or where C-2 and C-3 together form a double bond (see Novartis, WO 00/25929 and WO 00/37473).
Derivatives and analogs of Epothilones A and B have been synthesized and tested against a variety of cancers and other abnormal proliferative diseases. Such analogs are disclosed in Hofle, G., et al.,
Angew. Chem. Int. Ed. Engl
., Vol. 35, No.13/14, 1567-1569 (1996); Nicolaou, K. C., et al.,
Angew. Chem. Int. Ed. Engl
., Vol. 36, No. 19, 2097-2103 (1997); Su, D.-S., et al.,
Angew. Chem. Int. Ed. Engl
., Vol. 36, No. 19, 2093-2097 (1997); Su, D.-S., et al.,
Angew. Chem. Int. Ed. Engl
., Vol. 36, 757-759 (1997); Meng, D., et al.,
J. Amer. Chem. Soc
., Vol. 119, 10073-10092 (1997); Yang, Z., et al.,
Angew. Chem. Int. Ed. Engl
., Vol. 36, 166-168 (1997); Nicolaou, K. C., et al.,
Angew. Chem. Int. Ed. Engl
., Vol. 36, 525-527 (1997); Nicolaou, K. C., et al.,
Nature
, Vol. 387, 268-272 (1997); Schinzer, D., et al.,
Angew. Chem. Int. Ed. Engl
., Vol. 36, 523-524 (1997); and Nicolaou, K. C., et al.,
Angew. Chem. Int. Ed. Engl
., Vol. 37, 2014-2045 (1998). Although natural product epothilones A and B have shown excellent in vitro cytotoxic activity against cancer cell lines, difficulties remain with respect to their in vivo use due to a lack of stability, including metabolic stability, and potential toxicity (Lee, F., et al.,
Clin. Can. Res
., Vol. 7, 1429-1437 (2001)). Thus, there remains a need in the art for biologically active epothilone compounds with improved stability and improved safety profiles.
SUMMARY OF THE INVENTION
The present invention is directed to novel epothilone compounds possessing anti-proliferative and anti-neoplastic activity, and to methods for preparation of these compounds. Further, the invention encompasses pharmaceutical containing compounds of the invention. The invention further comprises treating or preventing proliferative diseases or disorders and primary or metastatic cancer using the compounds of the present invention. The compounds of the present invention are particularly useful for treating or preventing cancers that are responsive to microtubule-stabilization agents.
In one embodiment, the invention relates to compounds which may generally be classified as “3-cyano epothilone compounds”; having the following formula:
wherein
Q is selected from the group consisting of
M is O, NR
9
, CR
10
R
11
;
X is O or NH;
R
1
, R
2
, R
3
, R
4
and R
5
are independently selected from the group consisting of hydrogen or lower alkyl;
R
6
is selected from the group consisting of aryl, substituted aryl, and heterocyclo;
R
7
and R
8
are selected from the group consisting of hydrogen, alkyl, substituted alkyl, and cyano;
R
9
is selected from the group consisting of hydrogen, hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, substituted aryl, cycloalkyl, heterocyclo, —C(═O) R
12
, —C(═O)OR
13
, —S(O
2
)R
14
, —C(═O)NR
15
R
16
, —S(O
2
)N R
17
R
18
, and —NR
19
R
20
;
R
10
and R
11
are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, cycloalkyl, heterocyclo, —C(═O)R
21
, —C(═O)OR
22
, —C(═O)NHR
23
, and —NR
24
R
25
; and
R
12
, R
13
, R
14
, R
15
, R
16
, R
17
, R
18
, R
19
, R
20
, R
21
, R
22
, R
23
, R
24
, and R
25
are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and heterocyclo with the proviso that
R
13
and R
14
cannot be hydrogen;
R
15
and R
16
, R
17
and R
18
, R
19
and R
20
, R
24
and R
25
can each independently be taken together to form a heterocyclic ring; and
isomers, clathrates, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof.
In another embodiment, the present invention relates to methods for treating a variety of conditions by administering a therapeutically or prophylactically effective amount of a compound of formula (I) to an animal, preferably a mammal, especially a human subject in need thereof (referred to herein as a “patient”). Prior to administration, one or more compounds of this invention are typically formulated as a pharmaceutical composition which contains an effective dosage amount of one or more of such compounds in combination with one (or more) pharmaceutically acceptable carrier(s) or vehicle(s).
In another embodiment, the present invention is directed to methods of inducing microtubule-stabilization in mammalian cells by contacting the cells with a compound of the present invention.
Conditions that may be treated or prevented by the compounds of this invention, or a pharmaceutical composition thereof, include but are not limited to primary cancers, metastatic cancers, solid tumors, and blood-borne tumors. In one embodiment, the present invention is directed to methods of treating and/or preventing cancers of the brain, breast, central nervous system, stomach, bladder, prostate, colon, rectum, liver, lung (both small cell and non-small cell), pancreas, esophagus, mouth, pharynx, kidney, bone, pituitary, ovary, uterine, skin, head and neck, cervix and larynx.
In another embodiment, the present invention further provides pharmaceutical compositions comprising a therapeutically effective or a prophylactically effective amount of one or more compounds of the invention and a pharmaceutically acceptable carrier or vehicle. A pharma

Affiliated with

Also associated with

Rating

C3-cyano epothilone derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with C3-cyano epothilone derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and C3-cyano epothilone derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3197959