Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-29
2001-07-31
Aulakh, Charandlt S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S041000, C435S184000, C435S233000
Reexamination Certificate
active
06268375
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to fluorinated camptothecin compounds which inhibit the enzyme topoisomerase I and have anticancer activity. This invention is also related to the treatment of tumors in animals with camptothecin compounds.
2. Background of the Invention
Camptothecin (CPT) is a naturally occurring cytotoxic alkaloid which is known to inhibit the enzyme topoisomerase I and is a potent anti-tumor agent. Camptothecin compounds have the general ring structure shown below.
Camptothecin was isolated from the wood and bark of
Camptotheca acuminata
by Wall et al. (Wall et al., 1966, J. Am. Chem. Soc., 88:3888).
Major synthetic efforts have been directed to derivatizing the A-ring and/or the B-ring to improve cytotoxic activity and to improve water-solubility.
The cytotoxic activity of camptothecin compounds is believed to arise from the ability of these compounds to inhibit both DNA and RNA synthesis and to cause reversible fragmentation of DNA in mammalian cells. Topoisomerase I relaxes both positively and negatively supercoiled DNA and has been implicated in various DNA transactions such as replication, transcription and recombination. The enzyme mechanism is believed to involve a transient breakage of one of the two DNA strands and the formation of a reversible covalent topoisomerase I enzyme-DNA complex. Camptothecin interferes with the DNA breakage-reunion reaction by reversibly trapping the enzyme-DNA intermediate termed the “cleavable complex”. The cleavable complex assay is a standard test for determining the cytotoxic activity of camptothecin compounds. The high levels of topoisomerase I in several types of human cancer and the low levels in correspondingly normal tissue provide the basis for tumor treatment with biologically active camptothecin analogs.
U.S. Pat. No. 4,894,456 describes methods of synthesizing camptothecin compounds which act as inhibitors of topoisomerase I and are effective in the treatment of leukemia (L-1210). U.S. Pat. No. 5,225,404 discloses methods of treating colon tumors with camptothecin compounds.
Numerous camptothecin compounds and their use as inhibitors of topoisomerase I are reported by U.S. Pat. No. 5,053,512; U.S. Pat. No. 4,981,968; U.S. Pat. No. 5,049,668; U.S. Pat. No. 5,106,742; U.S. Pat. No. 5,180,722; U.S. Pat. No. 5,244,903; U.S. Pat. No. 5,227,380; U.S. Pat. No. 5,122,606; U.S. Pat. No. 5,122,526; and U.S. Pat. No. 5,340,817.
U.S. Pat. No. 4,943,579 discloses the esterification of the hydroxyl group at the 20-position of camptothecin to form several prodrugs. This patent further discloses that the prodrugs are water soluble and are converted into the parent camptothecin compounds by hydrolysis.
Brangi et al.,
Cancer Research,
59, 5938-5946 Dec. 1, 1999, reports an investigation of Camptothecin resistance in cancer cells and reports the compound difluoro-10, 11-methylenedioxy-20(S)-camptothecin.
A need continues to exist, however, for camptothecin compounds having improved activity.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide camptothecin compounds having improved and novel biological activity and reduced toxicity.
Another object of the present invention is to provide a method of treating leukemia or solid tumors in a mammal in need thereof by administration of a camptothecin compound.
Another object of the present invention is to provide a method of inhibiting the enzyme topoisomerase I and/or alkylating DNA of associated DNA-topoisomerase I by contacting a DNA-topoisomerase I complex with a camptothecin compound.
These and other objects of the present invention are made possible by camptothecin compounds having the structure:
where
X and Y are each independently NO
2
, NH
2
, H, F, Cl, Br, I, COOH, OH, O—C
1-6
alkyl, SH, S—C
1-6
alkyl, CN, NH—C
1-6
alkyl, N(C
1-6
alkyl)
2
, CHO, C
1-8
alkyl, N
3
,
—Z—(CH
2
)
a
—N—((CH
2
)
b
OH)
2
, wherein Z is selected from the group consisting of O, NH and S, and a and b are each independently an integer of 2 or 3,
—Z—(CH
2
)
a
—N—(C
1-6
alkyl)
2
wherein Z is selected from the group consisting of O, NH and S, and a is an integer of 2 or 3,
—CH
2
—L, where L is halogen (F, Cl, Br, I),
+
N
2
,
+
(OR
1
)
2
,
+
N(R
1
)
3
, OC(O)R
1
, OSO
2
R
1
, OSO
2
CF
3
, OSO
2
C
4
F
9
, C
1-6
alkyl-C—(═O)—, C
4-18
aryl-C(═O)—, C
1-6
alkyl-SO
2
—, perfluoro C
1-6
alkyl-SO
2
— and C
4-18
aryl-SO
2
—, (where each R
1
independently is C
1-6
alkyl, C
4-18
aryl or C
4-18
ArC
1-6
alkyl); or
—CH
2
NR
2
R
3
, where (a) R
2
and R
3
are, independently, hydrogen, C
1-6
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkyl-C
1-6
alkyl, C
2-6
alkenyl, hydroxy-C
1-6
alkyl, C
1-6
alkoxy-C
1-6
COR
4
where R
4
is hydrogen, C
1-6
alkyl, perhalo-C
1-6
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkyl-C
1-6
alkyl, C
2-6
alkenyl, hydroxy-C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkoxy-C
1-6
alkyl, or (b) R
2
and R
3
taken together with the nitrogen atom to which they are attached form a saturated 3-7 membered heterocyclic ring which may contain a O, S or NR
5
group, where R
5
is hydrogen, C
1-6
alkyl, perhalo-C
1-6
alkyl, aryl, aryl substituted with one or more groups selected from the group consisting of C
1-6
alkyl, halogen, nitro, amino, C
1-6
alkylamino, perhalo-C
1-6
alkyl, hydroxy-C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkoxy-C
1-6
alkyl and —COR
6
where R
6
is hydrogen, C
1-6
alkyl perhalo-C
1-6
alkyl, C
1-6
alkoxy, aryl, and aryl substituted with one or more C
1-6
alkyl, perhalo-C
1-6
alkyl, hydroxy-C
1-6
alkyl, or C
1-6
alkoxy-C
1-6
alkyl groups;
R
7
is H, or C(O)—(CH
2
)
m
—NR
8
R
9
, where m is an integer of 1-6 or —C(O)CHR
10
NR
8
R
9
, where R
10
is the side chain of one of the naturally occurring &agr;-amino acids, R
8
and R
9
are, independently, hydrogen, C
1-8
alkyl or —C(O)CHR
11
NR
12
R
13
, where R
11
is the side chain of one of the naturally occurring &agr;-amino acids and R
12
and R
13
are each independently hydrogen or C
1-8
alkyl; and
n is an integer of 1 or 2,
and salts thereof.
10,11-Difluoromethylenedioxycamptothecin is a potent inhibitor of topoisomerase I, being of the same order as 10,11-methylenedioxycamptothecin (i.e about 10 times camptothecin). Moreover, there has been concern that the 10,11-methylene dioxy ring may be metabolically cleaved to the corresponding catechol by cytochrome P450. However, it is well known that substitution of hydrogen by fluorine renders P450 metabolism relatively negligible. In a number of cases, 10,11-difluoromethylenedioxy compounds administered either iv or orally have shown less GI toxicity than other camptothecin analogs and have shown excellent activity against a number of mouse cancer cell lines, both in vitro and in vivo.
REFERENCES:
patent: 4894456 (1990-01-01), Wall et al.
patent: 4981968 (1991-01-01), Wall et al.
patent: 5049668 (1991-09-01), Wall et al.
patent: 5053512 (1991-10-01), Wani et al.
patent: 5106742 (1992-04-01), Wall et al.
patent: 5122526 (1992-06-01), Wall et al.
patent: 5122606 (1992-06-01), Wani et al.
patent: 5180722 (1993-01-01), Wall et al.
patent: 5224903 (1993-07-01), Langhof et al.
patent: 5227380 (1993-07-01), Wall et al.
patent: 5340817 (1994-08-01), Wall et al.
patent: 5364858 (1994-11-01), Wall et al.
patent: 5401747 (1995-03-01), Wall et al.
patent: 5496830 (1996-03-01), Shapiro et al.
patent: 5614529 (1997-03-01), Wall et al.
patent: 5646159 (1997-07-01), Wall et al.
patent: 5932588 (1999-08-01), Wall et al.
patent: 5985888 (1999-11-01), Wall et al.
Brangi, M. et al. : Camptothecin resistance : Role of the ATP-binding cassette, Mitoxantrone-resistance half-transporter, and potential for glucuronidation in MXR-expressing cells. Cancer Research, vol. 59, pp. 5938-5946, Dec. 1, 1999.
Balasubramanian Neelakantan
Manikumar Govindarajan
Vyas Dolatrai
Wall Monroe E.
Wani Mansukh C.
Aulakh Charandlt S.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Research Triangle Institute
LandOfFree
10, 11-difluoromethylenedioxycamptothecin compounds with... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 10, 11-difluoromethylenedioxycamptothecin compounds with..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 10, 11-difluoromethylenedioxycamptothecin compounds with... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2467407