Multioligonanilinated fullerenes

Details Multioligonanilinated fullerenes Multioligonanilinated fullerenes

2001-04-23

2002-09-17

Geist, Gary (Department: 1623)

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

Organic compounds

Carboxylic acid esters

C564S123000

Reexamination Certificate

active

06452037

ABSTRACT:

BACKGROUND OF THE INVENTION
Free radicals have been shown to inhibit tumor growth by causing oxidative damage to lipids, proteins, and nucleic acids of the tumor cells. In clinical practice, a photo-sensitizer is first delivered to a tumor site and then activated by irradiation to generate free radicals, thus inhibiting tumor growth. Among known photo-sensitizers, Photofrin II has recently been approved by the U.S. Food and Drug Administration. Preparation of Photofrin II is tedious.
Fullerenes are conjugated olefins of a closed cage structure. When photo-excited, they are capable of transforming molecular oxygen into singlet oxygen and then the related free radicals, such as superoxide free radicals, i.e., O
2
−
. However, fullerenes have low bioavailability and must be chemically modified before they can be tested for their efficacy, if any, as photo-sensitizers in treating tumor.
SUMMARY OF THE INVENTION
One aspect of this invention relates to multioligoanilinated fullerenes (MOAFs) of the following formula:
In this formula, p and each q, independently, is an integer of 0-20; each a is an integer of 1-8; each b is 0 or 1; each c is an integer of 1-20, provided that when b is 0, c is 1; each n is 1 or 2; m is an integer of 1-20; F
1
and each F
2
, independently, is a C
60-66
or C
70-76
fullerene, preferably a C
60-66
or C
70
fullerene; each of S and T, independently, is —OH, —NH
2
, —NHR, or —SH, wherein R is C
1-20
alkyl; each A, independently, is an oligoaniline, the term “oligoaniline” referring to a linear chemical species, the backbone of which consists of 2-12 aniline units; each nitrogen atom of the oligoaniline is optionally substituted with —Z, —CH
2
—CO—OH, —CH
2
—CO—O—Z, —CH
2
—CO—S—Z, —CH
2
—CO—NH
2
, or —CH
2
—CO—NH—Z; and each benzene ring is optionally substituted with —O—Z, —S—Z, —NH—Z; Z being —E—D, wherein E is —R—, —R—Ar—, —Ar—R—, or —Ar—; and D is —OH, —SH, —NH
2
, —NHOH, —SO
3
H, —OSO
3
H, —CO
2
H, —CONH
2
, —CH—(NH
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
+
, -glycoside, —OCH
3
, —OCH
2
(CHOH)
4
—CH
2
OH, —OCH
2
(CHOH)
2
—CH
2
OH, —C
6
H
3
(OH)
2
, —NH
3
+
, —N
+
H
2
R
b
, —N
+
HR
b
R
c
, or —N
+
R
b
R
c
R
d
, each of R
b
, R
c
, and R
d
, independently, being C
1-20
alkyl; and Ar being aryl; each K, independently, is —H, —[N(X)—C
6
H
4
]
1-3
—NH
2
, —[N(X)—C
6
H
4
]
1-3
—NH—C(═S)—SH, —[N(X)—C
6
H
4
]
1-3
—N═CH—Ar—SH, —[N(X)—C
6
H
4
]
1-3
—NH—CO—Ar—SH, wherein X is —H, —Z, —CH
2
—CO—OH, —CH
2
—CO—O—Z, —CH
2
—CO—S—Z, —CH
2
—CO—NH
2
, —CH
2
—CO—NH—Z; and Ar is aryl; each G, independently, is —O—B—R—O—, —NH—B—R—NH—, —O—B—R—NH—, —NH—B—R—O—, —O—B—R—S—, —NH—B—R—S—, wherein R is C
1-30
alkyl; B, independently, is —R
1
—O—[Si(CH
3
)
2
—O—]
1-1000
, C
1-2000
alkyl, C
6-40
aryl, C
7-60
alkylaryl, C
7-60
arylalkyl, (C
1-30
alkyl ether)
1-100
, (C
6-40
aryl ether)
1-100
, (C
7-60
alkylaryl ether)
1-100
, (C
7-60
arylalkyl ether)
1-100
, (C
1-30
alkyl thioether)
1-100
, (C
6-40
aryl thioether)
1-100
, (C
7-60
alkylaryl thioether)
1-100
, (C
7-60
arylalkyl thioether)
1-100
, (C
2-50
alkyl ester)
1-100
, (C
7-60
aryl ester,
1-100
, (C
8-70
alkylaryl ester)
1-100
, (C
8-70
arylalkyl ester)
1-100
, —R
1
—CO—O—(C
1-30
alkyl ether)
1-100
, —R
1
—CO—O—(C
6-40
aryl ether)
1-100
, —R
1
—CO—O—(C
7-60
alkylaryl ether)
1-100
, —R
1
—CO—O—(C
7-60
arylalkyl ether)
1-100
, (C
4-50
alkyl urethane)
1-100
, (C
14-60
aryl urethane)
1-100
, (C
10-80
alkylaryl urethane
1-100
, (C
10-80
arylalkyl urethane)
1-100
, (C
5-50
alkyl urea)
1-100
, (C
14-60
aryl urea)
1-100
, (C
10-80
alkylaryl urea)
1-100
, (C
10-80
arylalkyl urea)
1-100
, (C
2-50
alkyl amide)
1-100
, (C
7-60
aryl amide)
1-100
, (C
8-70
alkylaryl amide)
1-100
, (C
8-70
arylalkyl amide)
1-100
, (C
3-30
alkyl anhydride)
1-100
, (C
8-50
aryl anhydride)
1-100
, (C
9-60
alkylaryl anhydride)
1-100
, (C
9-60
arylalkyl anhydride)
1-100
, (C
2-30
alkyl carbonate)
1-100
, (C
7-50
aryl carbonate)
1-100
, (C
8-60
alkylaryl carbonate)
1-100
, (C
8-60
arylalkyl carbonate)
1-100
, —R
1
—O—CO—NH—(R
2
or Ar—R
2
—Ar)—NH—CO—O—(C
1-30
alkyl ether, C
6-40
aryl ether, C
7-60
alkylaryl ether, or C
7-60
arylalkyl ether)
1-100
, —R
1
—O—CO—NH—(R
2
or Ar—R
2
—Ar)—NH—CO—O—(C
2-50
alkyl ester, C
7-60
aryl ester, C
8-70
alkylaryl ester, or C
8
70
arylalkyl ester)
1-100
, —R
1
—O—CO—NH—(R
2
or Ar—R
2
—Ar)—NH—CO—O—(C
1-30
alkyl ether, C
6-40
aryl ether, C
7-60
alkylaryl ether, or C
7-60
arylalkyl ether)
1-100
—CO-NH-(R
2
or Ar—R
2
—Ar)—NH—CO—O—, —R
1
—O—CO—NH—(R
2
or Ar—R
2
—Ar)—NH—CO—O—(C
2-50
alkyl ester, C
7-60
arylaryl ester, C
8-70
alkylaryl ester, or C
8-70
arylalkyl ester)
1-100
—R
3
—O—CO—NH—(R
2
or Ar—R
2
—Ar)—NH—CO—O—, —R
1
—NH—CO—NH—(R
2
or Ar—R
2
—Ar)—NH—CO—O—(C
1-30
alkyl ether, C
6-40
aryl ether, C
7-60
alkylaryl ether, or C
7-60
arylalkyl ether)
1-100
, —R
1
—NH—CO—NH—(R
2
or Ar—R
2
—Ar)—NH—CO—(C
2-50
alkyl ester, C
7-60
aryl ester, C
8-70
alkylaryl ester, or C
8-70
arylalkyl ester)
1-100
, —R
1
—NH—CO—NH—(R
2
or Ar—R
2
—Ar)—NH—CO—O—(C
1-30
alkyl ether, C
6-40
aryl ether, C
7-60
alkylaryl ether, or C
7-60
arylalkyl ether)
1-100
—CO—NH—(R
2
or Ar—R
2
—Ar)—NH—CO—O—, —R
1
—NH—CO—NH—(R
2
or Ar—R
2
—Ar)—NH—CO—O—(C
2-50
alkyl ester, C
7-60
aryl ester, C
8-70
alkylaryl ester, or C
8-70
arylalkyl ester)
1-100
—R
3
O—CO—NH—(R
2
or Ar—R
2
—Ar)—NH—CO—O—, —R
1
—O—CO—NH—(R
2
or Ar—R
2
—Ar)—NH—CO—NH—(C
2-50
alkyl amide, C
7-60
aryl amide, C
8-70
alkylaryl amide, or C
8-70
arylalkyl amide)
1-100
, or —R
1
—NH—CO—NH—(R
2
or Ar—R
2
—Ar)—NH—CO—NH—(C
2-50
alkyl amide, C
7-60
aryl amide, C
8-70
alkylaryl amide, or C
8-70
arylalkyl amide)
1-100
; wherein each of R
1
, R
2
, and R
3
, independently, is C
1-30
alkyl; and Ar is aryl.
Also within the scope of this invention are pharmaceutically acceptable salts of the MOAFs described above. Such a salt can be formed between a negatively charged ionic group (e.g., sulfonate or carbonate) in an MOAF and a positively charged counterion (e.g., a sodium ion). Likewise, a positively charged ionic group (e.g., ammonium) in an MOAF can also form a salt with a negatively charged counterion (e.g., chloride).
One subset of the MOAFs of this invention are featured by that a is an integer of 3-6. Another subset of the MOAFs are featured by that b is 1, or b is 0 and c is 1. Still another subset of the MOAFs are featured by that n is 2. Yet stilled another subset of the MOAFs are featured by that A is tetraaniline, optionally substituted at nitrogen atoms with Z; E is —R— or —R—Ar—; and D is —OH, —SH, —NH
2
, —NHOH, —SO
3
H, —OSO
3
H, —CO
2
H, —CONH
2
, —P(OH)
3
, —PO(OH)
2
, —O—PO(OH)
2
, —O—PO(OH)—O—PO(OH)
2
, or —NH
3
+
.
Another aspect of this invention relates to a pharmaceutical composition which includes a pharmaceutically effective amount of an MOAF described above and a pharmaceutically acceptable carrier. Examples of such a carrier include water, colloidal silica oxide, magnesium sterate, and cellulose.
An MOAF of this invention can be used as a photodynamic therapeutic agent to inhibit growth, including causing death, of tumor cells in a tumor site. Accordingly, this invention also relates to use of an MOAF for the manufacture of a medicament for this application.
Details of several embodiments of this invention are set forth in the accompanying description below. Other features, objects, and advantages of this invention will be apparent from the description and from the claims.
DETAILED DESCRIPTION OF THE INVENTION
An MOAF of this invention can be synthesized by methods well known in the art. For instance, a fullerene can be first converted to a fullerene carboxylate by reacting it with a carboxylating agent such as diethyl bromomalonate. The fullerene carboxylate derivative is then oligoanilinated and, optionally, modified at the introduced oligoaniline moieties to generate ionic groups, e.g., alkylsulfonyl. Another suitable moiety, such as fullerene, can b

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