E-isomeric fullerene derivatives

Details E-isomeric fullerene derivatives E-isomeric fullerene derivatives

2002-07-24

2004-09-14

Powers, Fiona T. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06790963

ABSTRACT:

BACKGROUND OF THE INVENTION
Cancer remains a formidable disease with a high mortality rate in today's society. Indeed, cancer is second only to cardiovascular disease as a cause of death, killing one out of four people in developed countries.
Cancerous tumors commonly originate from normal cells which transform into malignant cells or tumors. The initial tumor growth may be slow and thus may be difficult to detect. The growth often becomes more aggressive and invasive with time, eventually spreading throughout the whole body and resulting in death.
Photodynamic therapy (PDT) is one of the methods for treating tumors. For review, see Dougherty, T. J.
Photochem. Photobiol.
1993, 58, 895. At present, the most commonly used sensitizers for clinical PDT practices are Photofrin II, an enriched active fraction of hematoporphyrin derivatives, and disulfonated aluminum phthalocyanine. These compounds, once photoactivated, induce severe oxidative damage to the structure of lipids, proteins, and nucleic acids. Since many biologically active molecules, e.g., DNA, demonstrate higher affinity toward stereospecific ligands, it is therefore desirable to develop stereospecific PDT sensitizers to enhance cytotoxicity of such antitumor agents.
SUMMARY
An aspect of this invention relates to a compound of formula (I):
F
f
is F(—K)m(—Y—Z)
q
. F is a fullerene core. Each K, independently, is —OH, —SH, —NH
2
,
—NHOH, —SO
3
H, —OSO
3
H, —CO
2
H, —CONH
2
, —CONHNH
2
, —P(OH)
3
, —PO(OH)
2
, —O—PO(OH)
2
, —O—PO(OH)—O—PO(OH)
2
, —O—PO(O
−
)—O—CH
2
CH
2
—NH
3
+
, —O—PO(O
−
)—O—CH
2
CH
2
—N
+
(CH
3
)
3
, -glycoside, —OCH
3
, —OCH
2
(CHOH)
4
—CH
2
OH, —OCH
2
(CHOH)
2
—CH
2
OH, —NH—CH
2
—CO
2
H, —[CH(CO
2
H)—CH
2
]
1-100
—OH, —[CH(CO
2
R
a
)—CH
2
]
1-100
—OH, —[C(CH
3
)(CO
2
H)—CH
2
]
1-100
—OH, —[C(CH
3
)(CO
2
R
a
)—CH
2
]
1-100
—OH, —N(OH)
2
, —NH
3
+
, —N
+
H
2
R
a
, —N
+
HR
a
R
b
, or —N
+
R
a
R
b
R
c
. Each Y is —A—B—, in which A is —O—, —NH—, —S—, —CO—O—, —O—CO—, —O—CO—O—, —O—CO—NH—, —NH—CO—NH—, —CO—NH—, or —NH—CO—; and B is —R
a
—O—[Si(CH
3
)
2
—O—]
1-100
, C
1-2000
alkyl, C
6-40
aryl, C
7-2000
alkylaryl, C
7-2000
arylalkyl, (C
1-30
alkyl ether),
1-100
, (C
6-40
aryl ether)
1-100
, (C
7-2000
alkylaryl ether)
1-100
, (C
7-2000
arylalkyl ether)
1-100
, (C
1-30
alkyl thioether)
1-100
,(C
6-40
aryl thioether)
1-100
, (C
7-2000
alkylaryl thioether)
1-100
, (C
7-2000
arylalkyl thioether)
1-100
, (C
2-50
alkyl ester)
1-100
, (C
7-2000
aryl ester)
1-100
, (C
8-2000
alkylaryl ester)
1-100
, (C
8-2000
arylalkyl ester)
1-100
,—R
a
—CO—O—(C
1-30
alkyl ether)
1-100
, —R
a
—CO—O—(C
6-40
aryl ether)
1-100
, —R
a
—CO—O—(C
7-2000
alkylaryl ether)
1-100
, —R
a
—CO—O—(C
7-2000
arylalkyl ether)
1-100
, (C
4-50
alkyl urethane),
1-100
, (C
14-60
aryl urethane)-
1-100
, (C
10-2000
alkylaryl urethane)
1-100
, (C
10-2000
arylalkyl urethane)
1-100
, (C
5-50
alkyl urea)
1-100
, (C
14-60
aryl urea)
1-100
, (C
10-2000
alkylaryl urea)
1-100
, (C
10-2000
arylalkyl urea)
1-100
, (C
2-50
alkyl amide)
1-100
, (C
7-60
aryl amide)
1-100
, (C
8-2000
alkylaryl amide)
1-100
, C(
8-2000
arylalkyl amide)
1-100
, (C
3-30
alkyl anhydride)
1-100
, (C
8-50
aryl anhydride)
1-100
, (C
9-2000
alkylaryl anhydride)
1-100
, (C
9-2000
arylalkyl anhydride)
1-100
, (C
2-30
alkyl carbonate)
1-100
, (C
7-50
aryl carbonate)
1-100
, (C
8-2000
alkylaryl carbonate)
1-100
, (C
8-2000
arylalkyl carbonate)
1-100
, —R
a
—O—CO—NH—(R
b
or Ar—R
b
—Ar)—NH—CO—O—(C
1-30
alkyl ether, C
6-40
aryl ether, C
7-2000
alkylaryl ether, or C
7-2000
arylalkyl ether)
1-100
, —R
a
—O—CO—NH—(R
b
or Ar—R
b
—Ar)—NH—CO—O—(C
2-50
alkyl ester, C
7-60
aryl ester, C
8-2000
alkylaryl ester, or C
8-2000
arylalkyl ester)
1-100
, —R
a
—O—CO—NH—(R
b
or Ar—R
b
—Ar)—NH—CO—O—(C
1-30
alkyl ether, C
6-40
aryl ether, C
7-2000
alkylaryl ether, or C
7-2000
arylalkyl ether)
1-100
—CO—NH—(R
b
or Ar—R
b
—Ar)—NH—CO—O—, —R
a
—O—CO—NH—(R
b
or Ar—R
b
—Ar)—NH—CO—O—(C
2-50
alkyl ester, C
7-60
aryl ester, C
8-2000
alkylaryl ester, or C
8-2000
arylalkyl ester)
1-100
—R
c
—O—CO—NH—(R
b
or Ar—R
b
—Ar)—NH—CO—O—, —R
a
—NH—CO—NH—(R
b
or Ar—R
b
—Ar)—NH—CO—O—(C
1-30
alkyl ether, C
6-40
aryl ether, C
7-2000
alkylaryl ether, or C
7-2000
arylalkyl ether)
1-100
, —R
a
—NH—CO—NH—(R
b
or Ar—R
b
—Ar)—NH—CO—O—(C
2-50
alkyl ester, C
7-60
aryl ester, C
8-2000
alkylaryl ester, or C
8-2000
arylalkyl ester)
1-100
, —R
a
—NH—CO—NH—(R
b
or Ar—R
b
—Ar)—NH—CO—O—(C
1-30
alkyl ether, C
6-40
aryl ether, C
7-2000
alkylaryl ether, or C
7-2000
arylalkyl ether)
1-100
—CO—NH—(R
b
or Ar—R
b
—Ar)—NH—CO—O—, —R
a
—NH—CO—NH—(R
b
or Ar—R
b
—Ar)—NH—CO—O—(C
2-50
alkyl ester, C
7-60
aryl ester, C
8-2000
alkylaryl ester, or C
8-2000
arylalkyl ester)
1-100
—R
c
—O—CO—NH—(R
b
or Ar—R
b
—Ar)—NH—CO—O—, —R
a
—O—CO—NH—(R
b
or Ar—R
b
—Ar)—NH—CO—NH—(C
2-50
alkyl amide, C
7-60
aryl amide, C
8-2000
alkylaryl amide, or C
8-2000
arylalkyl amide)
1-100
, —R
a
—NH—CO—NH—(R
b
or Ar—R
b
—Ar)—NH—CO—NH—(
2-50
alkyl amide, C
7-60
aryl amide, C
8-2000
alkylaryl amide, or C
8-2000
arylalkyl amide)
1-100
, or a bond; each Z, independently, is —G—D, wherein G is —R
a
—, —R
a
—Ar—, —Ar—R
a
—, or —Ar—; and D is —H, —OH, —SH, —NH
2
, —NHOH, —SO
3
H, —OSO
3
H, —CO
2
H, —CONH
2
, —CONHNH
2
, —CH(NH
2
)—CO
2
H, —NH—CH
2
—CO
2
H, —P(OH)
3
, —PO(OH)
2
, —O—PO(OH)
2
, —O—PO(OH)—O—PO(OH)
2
, —O—PO(O
−
)—O—CH
2
CH
2
NH
3
+
, —O—PO(O
−
)—O—CH
2
CH
2
—N
+
(CH
3
)
3
, -glycoside, -oligosaccharide, —CO-glycoside, —CO-oligosaccharide, —OCH
3
, —OCH
2
(CHOH)
4
—CH
2
OH, —OCH
2
(CHOH)
2
—CH
2
OH, —CO—OCH
2
(CHOH)
4
—CH
2
OH, —C
6
H
3
(OH)
2
, —N(CH
2
CO
2
H)
2
, —CO—N(CH
2
CO
2
H)
2
, —CO—NH—C(CH
2
CH
2
CO
2
H)
3
, —CO—NH—C(CH
2
CH
2
OH)
3
, —[CH
2
—CH(CO
2
R
a
)]
1-100
—H, —NH
3
+
, —N
+
H
2
R
a
, —N
+
HR
a
R
b
, or —N
+
R
a
R
b
R
c
. Each of R
a
, R
b
, and R
c
, independently, is C
1-20
alkyl and Ar is aryl, q is 0-30, and m is 0-30. Note that the sum of q and m is 0-30. Each of R
1
and R
4
, independently, is ═O or C
1-20
hydrocarbon. A hydrocarbon is a moiety containing carbon and hydrogen, e.g., alkyl, alkenyl, or alkynyl. Each of R
2
and R
5
, independently, is C
1-20
hydrocarbon; wherein R
1
and R
2
, or R
4
and R
5
can join together to form C
6-40
aryl which is optionally substituted with halide, —OH, —NHNH
2
, —NH
2
OH, —NH—CH
2
—CO
2
H, —CH
2
—CH
2
—D, —CH
2
—B—Z, —CO—CH
2
—D, —CO—B—Z, —O—B—Z, or —NH—B—Z. Each of R
3
and R
6
, independently, is —H, —CH
2
—D, —B—Z, —G—E, —G—CO—E, or a side chain of an amino acid. E is E
1
, E
2
, or E
3
, in which E
1
is Y
1
,Y
2
-amino, (Y
1
,Y
2
-alkyl)-amino, Y
1
,Y
2
-ethylenediamino, (dihydroxymethyl)alkylamino, (X
1
,X
3
-aryl)amino, or X
1
,X
3
-aryloxy; E
2
is Y
1
,Y
2
-alkoxy, (Y
1
,Y
2
-amino)alkoxy, (Y
1
,Y
2
, Y
3
-aryl)oxy, (dihydroxyalkyl)-aryloxy, (Y
1
,Y
2
,Y
3
-alkyl)amino, (Y
1
,Y
2
,Y
3
-aryl)amino, dihydroxyalkylamino, Y
1
,Y
2
,Y
3
-alkoxy, (trihydroxyalkyl)alkoxy, (trihydroxyalkyl)alkylamino, (dicarboxyalkyl)amino, (Y
1
,Y
2
,Y
3
-alkyl)thio, (X
1
,X
3
-aryl)thio, (Y
1
,Y
2
-alkyl)thio, (dihydroxyalkyl)thio, Y
1
, Y
2
-dioxoalkyl, or tri-(Y
1
,Y
2
,Y
3
-methylaminocarboxyethyl)methylamino; and E
3
is ((glycosidyl)oxoheteroaryl)amino, ((glycosidyl)oxoaryl)amino, (X
1
,X
2
,X
3
-heteroaryl)amino, (X
1
-diarylketone)amino, (X,X
1
-oxoaryl)amino, (X,X
1
-dioxoaryl)amino, (Y
1
-alkyl,Y
2
-alkyldioxoheteroaryl)amino, (Y
1
-alkyl,Y
2
-alkyldioxoaryl)amino, (di(Y
1
,Y
2
-methyl)dioxoheteroaryl)amino, (di(Y
1
,Y
2
-methyl)dioxoaryl)amino, ((glycosidyl)heteroaryl)amino, ((glycosidyl)aryl)amino, ((carboxylacetylalkyl)oxo-heteroaryl)amino, ((carboxylacetylalkyl)oxoaryl)amino, ((isopropylaminohydroxy-alkoxy)aryl)amino, (X
1
,X
2
,X
3
-alkylaryl)amino, (X
1
,X
2
,X
3
-heteroaryl)oxy, (isopropylaminohydroxyalkyl)aryloxy, (X
1
,X
2
,X
3
-oxoheteroaryl)oxy, (X
1
,X
2
,X
3
-oxoaryl)oxy, (X
1
,Y
1
-oxoheteroaryl)oxy, (X
1
-diarylketone)oxy, (X,X
1
-oxoaryl)oxy, (X
1
,X
2
-dioxoaryl)oxy, (

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