Macrocyclic analogs and methods of their use and preparation

Details Macrocyclic analogs and methods of their use and preparation Macrocyclic analogs and methods of their use and preparation

1999-06-16

2001-04-10

Owens, Amelia (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S337000, C514S338000, C514S410000, C514S432000, C514S443000, C548S417000, C549S024000, C549S041000, C549S348000, C546S281700, C546S282700

Reexamination Certificate

active

06214865

ABSTRACT:

BACKGROUND
The invention relates to pharmaceutically active macrolides. Halichondrin B is a potent anticancer agent originally isolated from the marine sponge
Halichondria okadai
, and subsequently found in Axinella sp.,
Phakellia carteri
, and Lissondendryx sp.
A total synthesis of Halichondrin B was published in 1992 (Aicher, T. D. et al.,
J. Am. Chem. Soc.
114:3162-3164). Halichondrin B has demonstrated in vitro inhibition of tubulin polymerization, microtubule assembly, beta
S
-tubulin crosslinking, GTP and vinblastine binding to tubulin, and tubulin-dependent GTP hydrolysis and has shown in vitro and in vivo anti-cancer properties.
SUMMARY OF THE INVENTION
The invention provides halichondrin analogs having pharmaceutical activity, such as anticancer or antimitotic (mitosis-blocking) activity. These compounds are substantially smaller than halichondrin B. The invention features a compound having the formula (I):
In formula (I), A is a C
1-6
saturated or C
2-6
unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having between 1 and 13 substituents, preferably between 1 and 10 substituents, e.g., at least one substituent selected from cyano, halo, azido, Q
1
, and oxo. Each Q
1
is independently selected from OR
1
, SR
1
, SO
2
R
1
, OSO
2
R
1
, NR
2
R
1
, NR
2
(CO)R
1
, NR
2
(CO)(CO)R
1
, NR
4
(CO)NR
2
R
1
, NR
2
(CO)OR
1
, (CO)OR
1
, O(CO)R
1
, (CO)NR
2
R
1
, and O(CO)NR
2
R
1
. The number of substituents can be, for example, between 1 and 6, 1 and 8, 2 and 5, or 1 and 4. Throughout the disclosure, numerical ranges are understood to be inclusive.
Each of R
1
, R
2
, R
4
, R
5
, and R
6
is independently selected from H, C
1-6
alkyl, C
1-6
haloalkyl, C
1-6
hydroxyalkyl, C
1-6
aminoalkyl, C
6-10
aryl, C
6-10
haloaryl (e.g., p-fluorophenyl or p-chlorophenyl), C
6-10
hydroxyaryl, C
1-4
alkoxy-C
6
aryl (e.g., p-methoxyphenyl, 3,4,5-trimethoxyphenyl, p-ethoxyphenyl, or 3,5-diethoxyphenyl), C
6-10
aryl-C
1-6
alkyl (e.g., benzyl or phenethyl), C
1-6
alkyl-C
6-10
aryl, C
6-10
haloaryl-C
1-6
alkyl, C
1-6
alkyl-C
6-10
haloaryl, (C
1-3
alkoxy-C
6
aryl)-C
1-3
alkyl, C
2-9
heterocyclic radical, C
2-9
heterocyclic radical-C
1-6
alkyl, C
2-9
heteroaryl, and C
2-9
heteroaryl-C
1-6
alkyl. There may be more than one R
1
, for example, if A is substituted with two different alkoxy (OR
1
) groups such as butoxy and 2-aminoethyoxy.
Examples of A include 2,3-dihydroxypropyl, 2-hydroxyethyl, 3-hydroxy-4-perfluorobutyl, 2,4,5-trihydroxypentyl, 3-amino-2-hydroxypropyl, 1,2-dihydroxyethyl, 2,3-dihyroxy-4-perflurobutyl, 3-cyano-2-hydroxypropyl, 2-amino-1-hydroxy ethyl, 3-azido-2-hydroxypropyl, 3,3-difluoro-2,4-dihydroxybutyl, 2,4-dihydroxybutyl, 2-hydroxy-2(p-fluorophenyl)-ethyl, —CH
2
(CO)(substituted or unsubstituted aryl), —CH
2
(CO)(alkyl or substituted alkyl, such as haloalkyl or hydroxyalkyl) and 3,3-difluoro-2-hydroxypent-4-enyl.
Examples of Q
1
include —NH(CO)(CO)-(heterocyclic radical or heteroaryl), —OSO
2
-(aryl or substituted aryl), —O(CO)NH-(aryl or substituted aryl), aminoalkyl, hydroxyalkyl, —NH(CO)(CO)-(aryl or substituted aryl), —NH(CO)(alkyl)(heteroaryl or heterocyclic radical), O(substituted or unsubstituted alkyl)(substituted or unsubstituted aryl), and —NH(CO)(alkyl)(aryl or substituted aryl).
Each of D and D′ is independently selected from R
3
and OR
3
, wherein R
3
is H, C
1-3
alkyl, or C
1-3
haloalkyl. Examples of D and D′ are methoxy, methyl, ethoxy, and ethyl. In some embodiments, one of D and D′ is H.
The value for n is 1 or preferably 0, thereby forming either a six-membered or five-membered ring. This ring can be unsubstituted or substituted, e.g., where E is R
5
or OR
5
, and can be a heterocyclic radical or a cycloalkyl, e.g. where G is S, CH
2
, NR
6
, or preferably O.
Each of J and J′ is independently H, C
1-6
alkoxy, or C
1-6
alkyl; or J and J′ taken together are ═CH
2
or —O-(straight or branched C
1-5
alkylene or alkylidene)-O—, such as exocyclic methylidene, isopropylidene, methylene, or ethylene. Q is C
1-3
alkyl, and is preferably methyl. T is ethylene or ethenylene, optionally substituted with (CO)OR
7
, where R
7
is H or C
1-6
alkyl. Each of U and U′ is independently H, C
1-6
alkoxy, or C
1-6
alkyl; or U and U′ taken together are ═CH
2
or —O-(straight or branched C
1-5
alkylene or alkylidene)-O—. X is H or C
1-6
alkoxy. Each of Y and Y′ is independently H or C
1-6
alkoxy; or Y and Y′ taken together are ═O, ═CH
2
, or —O-(straight or branched C
1-5
alkylene or alkylidene)-O—. Each of Z and Z′ is independently H or C
1-6
alkoxy; or Z and Z′ taken together are ═O, ═CH
2
, or —O-(straight or branched C
1-5
alkylene or alkylidene)-O—.
The invention features compounds of sufficient stability to be suitable for pharmaceutical development. The invention also features pharmaceutically acceptable salts of disclosed compounds, disclosed novel synthetic intermediates, pharmaceutical compositions containing one or more disclosed compounds, methods of making the disclosed compounds or intermediates, and methods of using the disclosed compounds or compositions. Methods of use include methods for reversibly or irreversibly inhibiting mitosis in a cell, and for inhibiting cancer or tumor growth in vitro, in vivo, or in a patient. The invention also features methods for identifying an anti-mitotic or anti-cancer agent, such as a reversible or, preferably, an irreversible agent.


REFERENCES:
patent: 5338865 (1994-08-01), Kishi et al.
patent: 5436238 (1995-07-01), Kishi et al.
patent: 0 572 109 A1 (1993-12-01), None
patent: WO 93/17690 (1993-09-01), None
Aicher et al., “Total Synthesis of Halichondrin B and Norhalichondrin B,” J. Am. Chem. Soc. 114:3162-3164 (1992).
Horita et al., “Synthetic Studies of Halichondrin B, an Antitumor Polyether Macrolide Isolated from a Marine Sponge. 8. Synthesis of the Lactone Part (C1-C36) via Horner-Emmons Coupling Between C1-C15 and C16-C36 Fragments and Yamaguchi Lactonization,” Tetrahedron Letters 38:8965-8968 (1997).
Stamos et al., “New Synthetic Route to the C.14-C.38 Segment of Halichondrins,” J. Org. Chem. 62:7552-7553 (1997).

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