Cryptophycin compounds

Details Cryptophycin compounds Cryptophycin compounds

1998-02-25

2004-01-20

Coleman, Brenda (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S340000, C514S365000, C514S397000, C514S414000, C514S422000, C514S443000, C514S444000, C514S471000, C540S454000, C540S455000, C540S460000

Reexamination Certificate

active

06680311

ABSTRACT:

This invention relates to the fields of pharmaceutical and organic chemistry and provides novel cryptophycin compounds useful as anti-microtubule agents.
Neoplastic diseases, characterized by the proliferation of cells not subject to the normal control of cell growth, are a major cause of death in humans and other mammals. Clinical experience in cancer chemotherapy has demonstrated that new and more effective drugs are desirable to treat these diseases.
The microtubule system of eucaryotic cells is a major component of the cytoskeleton and is a dynamic assembly and disassembly; this is heterodimers of tubulin are polymerized and form microtubule. Microtubules play a key role in the regulation of cell architecture, metabolism, and division. The dynamic state of microtubules is critical to their normal function. With respect to cell division, tubulin is polymerized into microtubules that form the mitotic spindle.
The microtubules are then depolymerized when the mitotic spindle's use has been fulfilled. Accordingly, agents which disrupt the polymerization or depolymerization of microtubules, and thereby inhibit mitosis, comprise some of the most effective cancer chemotherapeutic agents in clinical use.
Additionally, the compounds claimed herein possess fungicidal properties as well. Further, such agents having the ability to disrupt the microtubule system can be useful for research purposes.
Certain cryptophycin compounds are known in the literature; however, cryptophycin compounds having even greater solubility and stability are desired for most pharmaceutical uses. Further, a broader library of cryptophycin compounds could provide additional treatment options for the patient suffering from cancer. Applicants have now discovered novel compounds which can provide greater aqueous solubility as well as compounds having the ability to disrupt the microtubule system. Compounds of this invention can be useful for the treatment of neoplasms. Such compounds can be prepared using total synthetic methods and are therefore well suited for development as pharmaceutically useful agents.
The presently claimed invention provides novel cryptophycin compounds of Formula I
Ar is selected from the group consisting of phenyl, any simple unsubstituted aromatic, simple substituted aromatic, substituted heteroaromatic group, unsubstituted heteroaromatic group, heterocyclic, C
1
-C
12
alkyl, C
2
-C
12
alkenyl, C
2
-C
12
alkynyl, NR
51
R
52
, COR
52
, OR
53
, and Formula Ar′ —CH
2
—CH═CH-phenyl, —S-phenyl, 3-methoxyphenyl, 3,5-dimethoxyphenyl, 4-trifluoromethylphenyl, 4-TBDMSOH
2
C—Ph, 4-t-BocHNH
2
C—Ph, 3-t-BocHN—Ph,
4
—HOOCH
2
C—Ph, and 4-HOH
2
C—Ph.
R
51
is selected from the group consisting of hydrogen and C
1
-C
3
alkyl;
R
52
is selected from the group consisting of hydrogen and C
1
-C
3
alkyl;
R
53
is selected from the group consisting of C
1
-C
12
alkyl;
R
54
is selected from the group consisting of hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkyl(R
57′
R
57′
R
57′″
), simple unsubstituted aromatic, simple substituted aromatic, heterocyclic, phenyl, halogen, 4-(tert-butyldimethylsiloxy)-benzyltriphenylphosophonium, COOR
57
, PO
3
H, SO
3
H, SO
2
R
58
, N(R
59
)R
60
, NHOR
61
, NHCHR
61′
, CN, NO
2
, halogen, OR
62
, CH
2
(O)R
62′
, —CH
2
OC(O)R
95
, CH
2
N(R
96
)R
96′
, COR
100
, (C
1
-C
6
alkyl)OR
100
, SR
63
;
 and
R
95
is selected from the group consisting of —R
98
NH
2
;
R
96
and R
96′
are each independently selected from the group consisting of hydrogen and C
1
-C
6
alkyl, —R
97
NH
2
, and —R
99
NR
99′
R
99″
;
R
97
is selected from the group consisting of C
1
-C
6
alkyl;
R
98
is selected from the group consisting of C
1
-C
6
alkyl;
R
99
is C
1
-C
6
alkyl;
R
99′
and R
99″
are each independently selected from the group consisting of hydrogen and C
1
-C
6
alkyl;
R
100
is selected from the group consisting of hydrogen, and Si(R
101
R
102
R
103
);
R
101
is C
1
-C
6
alkyl;
R
102
is C
1
-C
6
alkyl;
R
103
is C
1
-C
6
alkyl;
R
104
is selected from the group consisting of C(O)C
1
-C
6
alkylN(R
106
) (R
59
)R
60
, C(O)C
1
-C
6
alkylN
+
, fused bicyclic, and NHR
105
N(R
106
) (R
59
)R
60
;
R
105
is selected from the group consisting of C(O)C
1
-C
6
alkyl, C
1
-C
6
alkyl;
R
106
is selected from the group consisting of hydrogen, C
1
-C
6
alkyl, C(O)OR
107
;
R
107
is selected from the group consisting of hydrogen, C
1
-C
6
alkyl, CR
108
R
109
R
110
;
R
108
is selected from the group consisting of hydrogen and C
1
-C
6
alkyl;
R
109
is selected from the group consisting of hydrogen and C
1
-C
6
alkyl;
R
110
is selected from the group consisting of hydrogen and C
1
-C
6
alkyl;
R
111
is selected from the group consisting of hydrogen, C
1
-C
6
alkyl, and C(O)OR
107
;
R
55
is selected from the group consisting of hydrogen, C
1
-C
6
alkyl, C(R
57′
R
57″
R
57′″
), simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR
57
, PO
3
H, SO
3
H, SO
2
R
58
, NR
59
R
60
, NHOR
61
, NHCHR
61′
, CN, NO
2
, halogen, OR
62
, and SR
63
;
R
56
is selected from the group consisting of hydrogen, C
1
-C
6
alkyl, C(R
57′
R
57″
R
57′″
), simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR
57
, PO
3
H, SO
3
H, SO
2
R
58
, NR
59
R
60
, NHOR
61
, NHCHR
61′
, (C
1
-C
6
)alkylNR
59
R
60
, CN, NO
2
, halogen, OR
104
, CR
104
, OR
62
, and SR
63
;
R
57
is selected from the group consisting of hydrogen and C
1
-C
12
alkyl;
R
57′
is selected from the group consisting of hydrogen, halogen, and C
1
-C
12
alkyl;
R
57″
is selected from the group consisting of hydrogen, halogen, and C
1
-C
12
alkyl;
R
57′″
is selected from the group consisting of hydrogen, halogen, and C
1
-C
12
alkyl;
R
58
is selected from the group consisting of hydrogen and C
1
-C
12
alkyl;
R
59
is selected from the group consisting of hydrogen, (C
1
-C
6
) alkyl, tert-butoxycarbonyl, carbo-tert-butoxy (t-BOC) and fluorenylmethoxycarbonyl (FMOC);
R
60
is selected from the group consisting of hydrogen and (C
1
-C
6
) alkyl;
R
61
is selected from the group consisting of hydrogen, OR
64
, CH
2
NHR
65
, NHR
65′
and fluorenylmethoxycarbonyl (FMOC);
R
61′
is selected from the group consisting of hydrogen, OR
64
, CH
2
NHR
65
, NHR
65′
and fluorenylmethoxycarbonyl (FMOC);
R
62
is selected from hydrogen, and C
1
-C
6
alkyl;
R
62′
is selected from hydrogen, OH, OR
62
, and C
1
-C
6
alkyl;
R
63
is selected from hydrogen and C
1
-C
6
alkyl;
R
64
is selected from the group consisting of hydrogen, (C
1
-C
6
) alkyl, CH
2
NR
66
R
67
;
R
65
is selected from the group consisting of hydrogen and C
1
-C
6
alkyl, NH
2
, and fluorenylmethoxycarbonyl (FMOC);
R
65′
is selected from the group consisting of hydrogen and C
1
-C
6
alkyl, NH
2
, and fluorenylmethoxycarbonyl (FMOC);
R
66
is selected from the group consisting of hydrogen and C
1
-C
6
alkyl and fluorenylmethoxycarbonyl (FMOC);
R
67
is selected from the group consisting of hydrogen and C
1
-C
6
alkyl;
R
1
and R
2
are each independently selected from the group consisting of halogen, monalkylamino, dialkylamino, trialkylammonium, alkylthio, dialkylsulfonium, sulfate, phosphate, OR
31
, SR
31
, NR
31
, OH, SH, NR
92
, R
93
, NR
94
, and NH
2
;
R
92
, R
93
, and R
94
are each independently selected from the group consisting of C
1
-C
6
alkyl;
provided that one selected from the group consisting of R
1
and R
2
is selected from the group consisting of OR
31
, SR
31
, R
31
, OH, and SH; or
R
1
and R
2
may be taken together with C-18 and C-19 to form an epoxide ring, an aziridine ring, an episulfide ring, a sulfate ring, a cyclopropyl ring or mono(C
1
-C
6
)alkylphosphate ring; or
R
1
and R
2
may be taken together to form a second bond between C-18 and C-19;
R
3
is a lower alkyl group;
R
4
is H or OH;
R
5
is H or OH;
R
4
and R
5
may be taken together to form a second bond between C
13
and C
14
;
R
6
is

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