U.S. patent application number 11/013909 was filed with the patent office on 2005-05-05 for camptothecin analogs having an e-ring ketone.
This patent application is currently assigned to Research Triangle Institute. Invention is credited to Manikumar, Govindarajan, Wall, Michael A., Wall, Monroe E., Wani, Mansukh C..
Application Number | 20050096338 11/013909 |
Document ID | / |
Family ID | 33540511 |
Filed Date | 2005-05-05 |
United States Patent
Application |
20050096338 |
Kind Code |
A1 |
Wall, Monroe E. ; et
al. |
May 5, 2005 |
Camptothecin analogs having an E-ring ketone
Abstract
Camptothecin analogs having an E-ring ketone are effective anti
tumor compounds. These compounds inhibit the enzyme topoisomerase I
and may alkylate DNA of the associated topoisomerase I DNA
cleavable complex.
Inventors: |
Wall, Monroe E.; (Portland,
OR) ; Wani, Mansukh C.; (Durham, NC) ;
Manikumar, Govindarajan; (Raleigh, NC) ; Wall,
Michael A.; (Portland, OR) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
Research Triangle Institute
Research Triangle Park
NC
|
Family ID: |
33540511 |
Appl. No.: |
11/013909 |
Filed: |
December 17, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11013909 |
Dec 17, 2004 |
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10608207 |
Jun 30, 2003 |
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Current U.S.
Class: |
514/279 ;
514/283; 546/41; 546/51 |
Current CPC
Class: |
C07D 471/14
20130101 |
Class at
Publication: |
514/279 ;
514/283; 546/051; 546/041 |
International
Class: |
C07D 491/14; C07D
471/04; A61K 031/4745 |
Claims
1. A camptothecin analog having the structure: 6where X and Y are
each independently NO.sub.2, NH.sub.2, H. F. Cl, Br, I, COOH, OH,
O-C.sub.1-6 alkyl, SH, S--C.sub.1-6 alkyl, CN, NH--C.sub.1-6 alkyl,
N(C.sub.1-6 alkyl).sub.2, CHO, C.sub.1-8 alkyl, N.sub.3,
-Z-(CH.sub.2).sub.a-N-((CH.s- ub.2).sub.bOH).sub.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.sub.2).sub.a--N--(C.sub.1-6 alkyl).sub.2 wherein Z is
selected from the group consisting of O, NH and S, and a is an
integer of 2 or 3, or --CH.sub.2-L, where L is halogen (F, Cl, Br,
I), .sup.+N.sub.2, .sup.+(OR.sup.1).sub.2, .sup.+S(R.sup.1).sub.2,
.sup.+N(R.sup.1).sub.3, OC(O)R.sup.1, OSO.sub.2R.sup.1,
OSO.sub.2CF.sub.3, OSO.sub.2C.sub.4F.sub.9, C.sub.1-6
alkyl-C(.dbd.O)--, C.sub.4-18 aryl-C(.dbd.O)--, C.sub.1-6
alkyl-SO.sub.2--, perfluoro C.sub.1-6 alkyl-SO.sub.2-- or
C.sub.4-18 aryl-SO.sub.2--, (where each R.sup.1 independently is
C.sub.1-6 alkyl, C.sub.4-18 aryl or C.sub.4-18 ArC.sub.1-16 alkyl);
or --CH.sub.2NR.sup.2R.sup.3, where (a) R.sup.2 and R.sup.3 are,
independently, hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl,
C.sub.3-7 cycloalkyl C.sub.1-6 alkyl, C.sub.2-6 alkenyl, hydroxy
C.sub.1-6 alkyl, C.sub.1-6 alkoxy C.sub.1-6 COR.sup.4 where R.sup.4
is hydrogen, C.sub.1-6 alkyl, perhalo C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl-C.sub.1-6 alkyl, C.sub.2-6
alkenyl, hydroxyl-C.sub.1-6 alkyl, C.sub.1-6-alkoxy, or C.sub.1-6
alkoxy-C.sub.1-6 alkyl, or (b) R.sup.2 and R.sup.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.sup.5
group, where R.sup.5 is hydrogen, C.sub.1-6 alkyl,
perhalo-C.sub.1-6 alkyl, aryl, aryl substituted with one or more
groups selected from the group consisting of C.sub.1-6 alkyl,
halogen, nitro, amino, C.sub.1-6 alkylamino, perhalo-C.sub.1-6
alkyl, hydroxyl-C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6
alkoxy-C.sub.1-6 alkyl and --COR.sup.6 where R.sup.6 is hydrogen,
C.sub.1-6 alkyl perhalo-C.sub.1-6 alkyl, C.sub.1-6 alkoxy, aryl,
and aryl substituted with one or more C.sub.1-6 alkyl,
perhalo-C.sub.1-6 alkyl, hydroxyl-C.sub.1-6 alkyl, or C.sub.1-6
alkoxy-C.sub.1-6 alkyl groups; R.sup.7 is
C(O)--(CH.sub.2).sub.m--NR.sup.- 8R.sup.9, where m is an integer of
1-6 or --C(O)CHR.sup.10NR.sup.8R.sup.9, where R.sup.10 is the side
chain of one of the naturally occurring .alpha.-amino acids,
R.sup.8 and R.sup.9 are, independently, hydrogen, C.sub.1-8 alkyl
or --C(O)CHR.sup.11NR.sup.12R.sup.12' where R.sup.11 is the side
chain of one of the naturally occurring .alpha.-amino acids and
R.sup.12 and R.sup.12' are each independently hydrogen or C.sub.1-8
alkyl; W is independently H or F, R.sup.13 and R.sup.14 are each H
or combine to form a double bond; and n is an integer of 1 or 2,
and salts thereof.
2. The camptothecin analog of claim 1, wherein n is 1.
3. The camptothecin analog of claim 1, wherein Y is
--CH.sub.2-L.
4. The camptothecin analog of claim 1, wherein L is selected from
the group consisting of Cl, Br and I.
5. (canceled)
6. The camptothecin analog of claim 1, which is selected from the
group consisting of R isomers, S isomers and mixtures thereof.
7. The camptothecin analog of claim 6, wherein the analog is the S
isomer.
8. The camptothecin analog of claim 6, wherein tile analog is the R
isomer.
9. The camptothecin analog of claim 6, wherein the analog is an S
rich mixture of S and R isomers.
10. The camptothecin analog of claim 6, wherein the analog is a R
rich mixture of S and R isomers.
11. The camptothecin analog of claim 6, wherein the analog is a
racemic mixture of R and S isomers.
12. A method of treating leukemia or solid tumors comprising
administering to a patient in need thereof, the camptothecin analog
of claim 1.
13. A pharmaceutical composition comprising the camptothecin analog
of claim 1.
14. A method for inhibiting the enzyme topoisomerase I, comprising
contacting a DNA-topoisomerase I complex with the camptothecin
analog of claim 1.
15. (canceled)
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to camptothecin analogs having an
E-ring ketone which inhibit the enzyme topoisomerase I and have
anticancer activity. This invention is also related to the
treatment of tumors in animals with camptothecin analogs.
[0003] 2. Background of the Invention
[0004] 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. 1
[0005] 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). It has been shown that if the E-ring
.alpha.-hydroxy lactone functions are altered or removed, that the
resulting compounds have no activity regarding topoisomerase I
inhibition or inhibition of cancer cells. (Wall, Plant Antitumor
Agents. V. Alkaloids with Antitumor Activity Symposiumsberichtes,
pp. 77 87, 4. Internationales Symposium, Biochemie und Physiologie
der Alkaloide, Halle (Saale) 25. Bis 28. Jun., 1969, edited by K.
Mothes, K. Schreiber, and H. R. Schutte, Akademie Verlag, Berlin,
1969; and Nicholas et al, J. Med. Chem., 33, 972 (1990).)
[0006] Another process that affects all camptothecin compounds is
that at an alkaline pH, as low as 7.5 or higher, the lacton E-ring
is readily hydrolyzed to give an E-ring opened carboxylate product.
This compound is much less active in the above mentioned
activities.
[0007] 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.
[0008] 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.
[0009] 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.
[0010] 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.
[0011] 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.
[0012] A need continues to exist, however, for camptothecin analogs
having improved stability under physiological conditions.
SUMMARY OF THE INVENTION
[0013] Accordingly, one object of the present invention is to
provide a camptothecin analog having improved stability under
physiological conditions.
[0014] 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 analogs.
[0015] 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 analog.
[0016] These and other objects of the present invention are made
possible by a camptothecin analog having the structure: 2
[0017] where
[0018] X and Y are each independently NO.sub.2, NH.sub.2, H, F, Cl,
Br, I, COOH, OH, O--C.sub.1-6 alkyl, SH, S--C.sub.1-6 alkyl, CN,
NH--C.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, CHO, C.sub.1-8
alkyl, N.sub.3,
[0019] -Z-(CH.sub.2).sub.a--N--((CH.sub.2).sub.bOH).sub.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,
[0020] -Z-(CH.sub.2).sub.2--N--(C.sub.1-6 alkyl).sub.2 wherein Z is
selected from the group consisting of O, NH and S, and a is an
integer of 2 or 3,
[0021] --CH.sub.2-L, where L is halogen (F, Cl, Br, I),
.sup.+N.sub.2, .sup.+(OR.sup.1).sub.2, .sup.+S(R.sup.1).sub.2,
.sup.+N(R.sup.1).sub.3, OC(O)R.sup.1, OSO.sub.2R.sup.1,
OSO.sub.2CF.sub.3, OSO.sub.2C.sub.4F.sub.9, C.sub.1-6
alkyl-C(.dbd.O)--, C.sub.4-18 aryl-C(.dbd.O)--, C-.sub.1-6 alkyl
SO-2-, perfluoro C.sub.1-6alkyl-SO.sub.2-- or C.sub.4-18
aryl-SO.sub.2--, (where each R.sup.1 independently is C.sub.1-6
alkyl, C.sub.4-18 aryl or C.sub.4-18ArC.sub.1-6 alkyl); or
--CH.sub.2NR.sup.2R.sup.3, where (a) R.sup.2 and R.sup.3 are,
independently, hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl,
C.sub.3-7 cycloalkyl-C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
hydroxyl-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 COR.sup.4
where R.sup.4 is hydrogen, C.sub.1-6 alkyl, perhalo-C.sub.1-6
alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl-C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, hydroxyl-C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or
C.sub.1-6 alkoxy-C.sub.1-6 alkyl, or (b) R.sup.2 and R.sup.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.sup.5 group, where R.sup.5 is hydrogen, C.sub.1-6 alkyl,
perhalo-C.sub.1-6 alkyl, aryl, aryl substituted with one or more
groups selected from the group consisting of C.sub.1-6 alkyl,
halogen, nitro, amino, C.sub.1-6 alkylamino, perhalo-C.sub.1-6
alkyl, hydroxyl-C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6
alkoxy-C.sub.1-6 alkyl and --COR.sup.6 where R.sup.6 is hydrogen,
C.sub.1-6 alkyl perhalo-C.sub.1-6 alkyl, C.sub.1-6 alkoxy, aryl,
and aryl substituted with one or more C.sub.1-6 alkyl,
perhalo-C.sub.1-6 alkyl, hydroxyl-C.sub.1-6 alkyl, or C.sub.1-6
alkoxy-C.sub.1-6 alkyl groups;
[0022] R.sup.7 is H, or C(O)--(CH.sub.2).sub.m--NR.sup.8R.sup.9,
where m is an integer of 1-6 or --C(O)CHR.sup.10NR.sup.8R.sup.9,
where R.sup.10 is the side chain of one of the naturally occurring
.alpha.-amino acids, R.sup.8 and R.sup.9 are, independently,
hydrogen, C.sub.1-8 alkyl or --C(O)CHR.sup.11NR.sup.12 R.sup.3,
where R.sup.11 is the side chain of one of the naturally occurring
.alpha.-amino acids and R.sup.12 and R.sup.13 are each
independently hydrogen or C.sub.1-8 alkyl;
[0023] W is independently H or F,
[0024] R.sup.13 and R.sup.14 are each H or combine to form a double
bond; and
[0025] n is an integer of 1 or 2,
[0026] and salts thereof.
[0027] These compounds have the necessary .alpha.-hydroxy-ethyl
substitutents at C.sub.20 and a ketone in place of the lactone
structure. Such a compound has a spatial orientation virtually
identical with that of camptothecin, however it is much more stable
than CPT under alkaline conditions.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] A more complete appreciation of the invention and many of
the attendant advantages thereof will be readily obtained as the
same become better understood by reference to the following
detailed description when considered in connection with the
accompanying drawings, wherein:
[0029] FIG. 1 illustrates the synthesis of a tricyclic ketone used
to form the compound of the present invention;
[0030] FIG. 2 illustrates a synthetic reaction scheme for preparing
compounds according to the present invention; and
[0031] FIG. 3 illustrates a synthetic reaction scheme for preparing
compounds according to the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0032] Unless indicated to the contrary, the term "alkyl" as used
herein means a straight chain or branched chain alkyl group with
1-30, preferably 1-18 carbon atoms, more preferably 1-8 carbon
atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl,
n-heptyl, n-octyl, 2-ethylhexyl, n-nonyl, n-decyl, undecyl,
dodecyl, myristyl, heptadecyl and octadecyl groups. The term
"alkyl" also includes C.sub.3-30 cycloalkyl groups such as
cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl
groups.
[0033] Unless indicated to the contrary, the term "aryl" as used
herein means a carbocyclic aromatic ring having 6-18 carbon atoms,
preferably 6 10 carbon atoms in the aromatic ring structure. The
aromatic rings may be substituted by one or more alkyl group,
preferably alkyl groups having 1-10 carbon atoms. A particularly
preferred aryl group is phenyl.
[0034] Unless indicated to the contrary, the term "aralkyl" as used
herein means a straight chain or branched chain alkyl group as
defined above for the term "alkyl" bonded to an aryl group as
defined above for the term "aryl". Preferred aralkyl groups are
benzyl, phenethyl, etc.
[0035] As used herein, the term "acyl" means formyloxy and acyl
moieties derived from aromatic carboxylic acids, heterocyclic
carboxylic acids, aralkyl carboxylic acids, as well as alkyl and
aromatic sulfonic acids. The alkyl groups of these acyloxy moieties
may be a straight chain or branched chain alkyl group with 1-7
carbon atoms. Additionally, the acyl moiety may contain one or more
unsaturated carbon carbon bonds and may also carry one or more
substituents such as halogen, amino and hydroxyl groups.
[0036] The camptothecin analogs of the present invention may bear a
leaving group at one or more of the positions C.sub.7 or Cg of the
camptothecin ring structure. More specifically, the leaving group
is a group of the formula --CH.sub.2-L, where L is a functional
group which can be easily displaced, i.e. L is a good leaving group
in nucleophilic substitution reactions. Suitable groups L include
halogen (F, Cl, Br, I), .sup.+N.sub.2, .sup.+O(R.sup.1).sub.2,
.sup.+S(R.sup.1).sub.2, .sup.+N(R.sup.1).sub.3, OC(O)R.sup.1,
OSO.sub.2R.sup.1, OSO.sub.2CF.sub.3, and OSO.sub.2C.sub.4F.sub.9,
C.sub.1-6alkyl-C(.dbd.O)-- -, C.sub.4-18aryl-C(.dbd.O)--, C.sub.1-6
alkyl-SO.sub.2--, perfluoroC.sub.1-6 alkyl-SO.sub.2-- and
C.sub.4-18 aryl-SO.sub.2--, (where each R.sup.1 independently is
C.sub.1-6 alkyl, C.sub.4-18 aryl or C.sub.4-18 ArC.sub.1-6
alkyl).
[0037] While not being bound by any particular theory, it is
believed that nucleophilic groups on DNA displace leaving group L
from the camptothecin analogs of the present invention resulting in
alkylation of the DNA by the alkylating group of the camptothecin
ring structure. Suitable nucleophilic groups present in DNA include
the nucleophilic groups found in DNA bases adenine, guanine,
thymine, and cytosine, such as NH.sub.2, --NH-- and .dbd.N--
groups. When a camptothecin analog of the invention having a
--CH.sub.2-L group is contacted with DNA, nucleophilic displacement
of leaving group L results in alkylation of the nucleic acid. The
compounds of the present invention exhibit a novel anti tumor
activity by alkylating DNA.
[0038] Camptothecin analogs have an asymmetric carbon atom at the
20-position making two enantiomeric forms, i.e., the (R) and the
(S) configurations, possible. This invention includes each
enantiomeric form individually, as well as combinations or mixtures
of these forms. The invention also includes other forms of the
camptothecin analogs including solvates, hydrates, polymorphs,
salts, etc. Particularly preferred compounds are camptothecin
derivatives having the (S) configuration at the 20-position.
[0039] In a preferred embodiment, X is NO.sub.2, NH.sub.2, H, F,
Cl, Br, I, COOH, OH, O--C.sub.1-6 alkyl, SH, S--C.sub.1-6 alkyl,
CN, CH.sub.2NH.sub.2, NH--C.sub.1-6 alkyl, CH.sub.2NH--C.sub.1-6
alkyl, N(C.sub.1-6 alkyl).sub.2, CH.sub.2N(C.sub.1-6 alkyl).sub.2,
O--CH.sub.2CH.sub.2N(CH.sub.2CH.sub.2OH).sub.2,
NH--CH.sub.2CH.sub.2N(CH.- sub.2CH.sub.2OH).sub.2,
S--CH.sub.2CH.sub.2N(CH.sub.2CH.sub.2OH).sub.2,
O--CH.sub.2CH.sub.2CH.sub.2N(CH.sub.2CH.sub.2OH).sub.2,
NH--CH.sub.2CH.sub.2CH.sub.2N(CH.sub.2CH.sub.2OH).sub.2,
S--CH.sub.2CH.sub.2CH.sub.2N(CH.sub.2CH.sub.2OH).sub.2,
O--CH.sub.2CH.sub.2N(CH.sub.2CH.sub.2CH.sub.2OH).sub.2,
NH--CH.sub.2CH.sub.2N(CH.sub.2CH.sub.2CH.sub.2OH).sub.2,
S--CH.sub.2CH.sub.2N(CH.sub.2CH.sub.2CH.sub.2OH).sub.2,
O--CH.sub.2CH.sub.2CH.sub.2N(CH.sub.2CH.sub.2CH.sub.2OH.sub.2).sub.2,
NH--CH.sub.2CH.sub.2CH.sub.2N(CH.sub.2CH.sub.2CH.sub.2OH.sub.2).sub.2,
S--CH.sub.2CH.sub.2CH.sub.2N(CH.sub.2CH.sub.2CH.sub.2OH.sub.2).sub.2,
O--CH.sub.2CH.sub.2N(C.sub.1-6 alkyl).sub.2,
NH--CH.sub.2CH.sub.2N(C.sub.- 1-6 alkyl).sub.2,
S--CH.sub.2CH.sub.2N(C.sub.1-6 alkyl).sub.2,
O--CH.sub.2CH.sub.2CH.sub.2N(C.sub.1-6 alkyl).sub.2,
NH--CH.sub.2CH.sub.2CH.sub.2N(C.sub.1-6 alkyl).sub.2,
S--CH.sub.2CH.sub.2CH.sub.2N(C.sub.1-6 alkyl).sub.2, CHO, N.sub.2,
C.sub.1-8 alkyl, CH.sub.2-L where L is halogen (F, Cl, Br, I),
.sup.+N.sub.2, .sup.+O(R.sup.1).sub.2 (where each R.sup.1
independently is alkyl, aryl or aralkyl as defined above),
.sup.+S(R.sup.1).sub.2, .sup.+N(R.sup.1).sub.3, OC(O)R.sup.1,
OSO.sub.2R.sup.1, OSO.sub.2CF.sub.3, OSO.sub.2C.sub.4F.sub.9,
C.sub.1-6alkyl-C(.dbd.O)--, C.sub.4-8aryl-C(.dbd.O)--,
C.sub.1-6alkyl-SO.sub.2--, perfluoro C.sub.1-6alkyl-SO.sub.2-- and
C.sub.4-18aryl-SO.sub.2--.
[0040] In a preferred embodiment Y is H, C.sub.1-8 alkyl, or
CH.sub.2NR.sup.2R.sup.3 where (a) R.sup.2 and R.sup.3 are,
independently, hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl,
C.sub.3-7 cycloalkyl-C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
hydroxyl-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 COR.sup.4
where R.sup.4 is hydrogen, C.sub.1-6 alkyl, perhalo C.sub.1-alkyl,
C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl-C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, hydroxyl-C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
C.sub.1-6 alkoxy-C.sub.1-6 alkyl, or (b) R.sup.2 and R.sup.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.sup.5 group, where R.sup.5 is hydrogen, C.sub.1-6 alkyl,
perhalo C.sub.1-6 alkyl, aryl, aryl substituted with one or more
groups selected from the group consisting of C.sub.1-6 alkyl,
halogen, nitro, amino, C-6 alkylamino, perhalo-C.sub.1-6 alkyl,
hydroxyl-C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
C.sub.1-6-alkoxy-C.sub.1-6 alkyl and --COR.sup.6 where R.sup.6 is
hydrogen, C.sub.1-6 alkyl perhalo-C.sub.1-6 alkyl, C.sub.1-6
alkoxy, aryl, and aryl substituted with one or more C.sub.1-6
alkyl, perhalo-C.sub.1-6 alkyl, hydroxyl-C.sub.1-6 alkyl, or
C.sub.1-6 alkoxy-C.sub.1-6 alkyl groups.
[0041] The group R.sup.7 may be an ester of a naturally occurring
or non naturally occurring amino acid such as an ester of glycine
or .beta.-alanine. In particular, the present invention is directed
to camptothecin analogs where the group R.sup.7 is
C(O)--(CH.sub.2).sub.m--N- R.sup.8R.sup.9, where m is the integer
1, 2, 3, 4, 5 and 6 and R.sup.8 and R.sup.9 are each H.
[0042] Suitable side chains R.sup.10 and R.sup.1 appearing on the
group R.sup.7 are the side chains of the amino acids glycine,
.alpha.-alanine, .beta.-alanine, valine, leucine, isoleucine,
phenylalanine, tyrosine, tryptophan, lysine, arginine, histidine,
aspartate, glutamate, asparagine, glutamine, cysteine and
methionine. Moreover, the group R.sup.7, may comprise two amino
acid units linked by a peptide linkage. In particular the group
R.sup.7 may comprise a .beta.-alanine group linked to a lysine of
the structure 3
[0043] Moreover, the group R.sup.7 may provide basis for the
formation of a mono or di salts, via the free amine groups, such as
a hydrochloride or dihydrochloride.
[0044] A synthon for attaching such a group to a terminal hydroxyl
group is described by Hudkins et al. Bioorg. Med. Chem. Lett, 8
(1998) 1873 1876).
[0045] Particularly preferred esters are glycinate esters and the
peptide ester based on .beta.-alanine lysine. These esters are pro
drugs which are converted to the camptothecin analog compound by
hydrolysis of the ester bond. The esters may be prepared by the
method described in U.S. Pat. No. 4,943,579 which is incorporated
herein by reference for a more complete description of the process
of preparing the esters and for a description of suitable esters
formed by the process. The esterification synthon may need to
introduced in a protected form, such that the reaction of amine
groups is inhibited, followed by removal of the protecting group.
Such protecting groups are well known to those of ordinary skill in
the art and are described by Hudkins et al. Bioorg. Med. Chem.
Lett, 8 (1998) 1873 1876).
[0046] Specific examples of non limiting compounds include
10,11-difluoromethylenedioxy-20-(S)-camptothecin E-ring ketone;
7-ethyl 10,11-difluoromethylenedioxy-20-(S)-camptothecin E-ring
ketone; 7-chloromethyl
10,11-difluoromethylenedioxy-20-(S)-camptothecin E-ring ketone;
7-bromomethyl 10,11-difluoromethylenedioxy-20-(S)-camptothecin
E-ring ketone; 7-hydroxymethyl
10,11-difluromethylenedioxy-20-(S)-camptot- hecin E-ring ketone,
9-nitro 10,11-difluoromethylenedioxy-20-(S)-camptothe- cin E-ring
ketone, 9-amino 10,11-difluoromethylenedioxy-20-(S)-camptotheci- n
E-ring ketone, 7-ethyl-9-nitro
10,11-difluoromethylenedioxy-20-(S)-campt- othecin E-ring ketone
and 7-ethyl-9-amino 10,11-difluoromethylenedioxy-20--
(S)-camptothecin E-ring ketone.
[0047] Specific non limiting examples further include the C.sub.20
amino acid ester of the above identified compounds
10,11-difluoromethylenedioxy- -20-O-glycinyl-20-(S)-camptothecin
E-ring ketone; 7-ethyl
10,11-difluoromethylenedioxy-20-O-glycinyl-20-(S)-camptothecin
E-ring ketone; 7-chloromethyl
10,11-difluoromethylenedioxy-20-O-glycinyl-20-(S)-- camptothecin
E-ring ketone; 7-bromomethyl 10,11-difluoromethylenedioxy-20--
O-glycinyl-20-(S)-camptothecin E-ring ketone; 7-hydroxymethyl
10,11-difluromethylenedioxy-20-O-glycinyl-20-(S)-camptothecin
E-ring ketone, 9-nitro
10,11-difluoromethylenedioxy-20-O-glycinyl-20-(S)-camptot- hecin
E-ring ketone, 9-amino
10,11-difluoromethylenedioxy-20-O-glycinyl-20- -(S)-camptothecin
E-ring ketone, 7-ethyl-9-nitro 10,11-difluoromethylenedi-
oxy-20-O-glycinyl-20-(S)-camptothecin E-ring ketone,
7-ethyl-9-amino
10,11-difluoromethylenedioxy-20-O-glycinyl-20-(S)-camptothecin
E-ring ketone,
10,11-difluoromethylenedioxy-20-O--N-methylglycinyl-20-(S)-campto-
thecin E-ring ketone; 7-ethyl 10,11-difluoromethylenedioxy 20-O--N
methylglycinyl-20-(S)-camptothecin E-ring ketone; 7-chloromethyl
10,11-difluoromethylenedioxy 20-O--N
methylglycinyl-20-(S)-camptothecin E-ring ketone; 7-bromomethyl
10,11-difluoromethylenedioxy 20-O--N
methylglycinyl-20-(S)-camptothecin E-ring ketone; 7-hydroxymethyl
10, 11 difluromethylenedioxy 20-O--N
methylglycinyl-20-(S)-camptothecin E-ring ketone, 9-nitro
10,11-difluoromethylenedioxy 20-O--N
methylglycinyl-20-(S)-camptothecin E-ring ketone, 9-amino
10,11-difluoromethylenedioxy 20-O--N
methylglycinyl-20-(S)-camptothecin E-ring ketone, 7-ethyl-9-nitro
10,11-difluoromethylenedioxy 20-O--N
methylglycinyl-20-(S)-camptothecin E-ring ketone, 7-ethyl-9-amino
10,11-difluoromethylenedioxy 20-O--N
methylglycinyl-20-(S)-camptothecin E-ring ketone,
10,11-difluoromethylenedioxy 20-O--N,N
dimethylglycinyl-20-(S)-camptothecin E-ring ketone; 7-ethyl
10,11-difluoromethylenedioxy 20-O--N,N
dimethylglycinyl-20-(S)-camptothec- in E-ring ketone;
7-chloromethyl 10,11-difluoromethylenedioxy 20-O--N,N
dimethylglycinyl-20-(S)-camptothecin E-ring ketone; 7-bromomethyl
10,11-difluoromethylenedioxy 20-O--N,N
dimethylglycinyl-20-(S)-camptothec- in E-ring ketone;
7-hydroxymethyl 10,11-difluromethylenedioxy 20-O--N,N
dimethylglycinyl-20-(S)-camptothecin E-ring ketone, 9-nitro
10,11-difluoromethylenedioxy 20-O--N,N
dimethylglycinyl-20-(S)-camptothec- in E-ring ketone, 9-amino
10,11-difluoromethylenedioxy 20-O--N,N
dimethylglycinyl-20-(S)-camptothecin E-ring ketone, 7-ethyl-9-nitro
10,11-difluoromethylenedioxy 20-O--N,N
dimethylglycinyl-20-(S)-camptothec- in E-ring ketone and
7-ethyl-9-amino 10,11-difluoromethylenedioxy 20-O--N,N
dimethylglycinyl-20-(S)-camptothecin E-ring ketone.
[0048] Additional specific non limiting examples further include
10,11-difluoromethylenedioxy-20-O--O-ala-lys-20-(S)-camptothecin
E-ring ketone; 7-ethyl
10,11-difluoromethylenedioxy-20-O--O-ala-lys-20-(S)-campt- othecin
E-ring ketone; 7-chloromethyl 10,11-difluoromethylenedioxy-20-O-.b-
eta.-ala-lys-20-(S)-camptothecin E-ring ketone; 7-bromomethyl
10,11-difluoromethylenedioxy-20-O-.beta.-ala-lys-20-(S)-camptothecin
E-ring ketone; 7-hydroxymethyl
10,11-difluromethylenedioxy-20-O-.beta.-al-
a-lys-20-(S)-camptothecin E-ring ketone, 9-nitro
10,11-difluoromethylenedi-
oxy-20-O-.beta.-ala-lys-20-(S)-camptothecin E-ring ketone, 9-amino
10,11-difluoromethylenedioxy-20-O-.beta.-ala-lys-20-(S)-camptothecin
E-ring ketone, 7-ethyl-9-nitro
10,11-difluoromethylenedioxy-20-O-.beta.-a-
la-lys-20-(S)-camptothecin E-ring ketone and 7-ethyl-9-amino
10,11-difluoromethylenedioxy-20-O-.beta.-ala-lys-20-(S)-camptothecin
E-ring ketone.
[0049] Additional specific non limiting examples further include
10,11-difluoromethylenedioxy-20-O-.beta.-ala-20-(S)-camptothecin
E-ring ketone; 7-ethyl
10,11-difluoromethylenedioxy-20-O-B-ala-20-(S)-camptothec- in
E-ring ketone; 7-chloromethyl
10,11-difluoromethylenedioxy-20-O-.beta.-- ala-20-(S)-camptothecin
E-ring ketone; 7-bromomethyl
10,11-difluoromethylenedioxy-20-O-.beta.-ala-20-(S)-camptothecin
E-ring ketone; 7-hydroxymethyl
10,11-difluromethylenedioxy-20-O-.beta.-ala-20-(S- )-camptothecin
E-ring ketone, 9-nitro 10,11-difluoromethylenedioxy-20-O-.b-
eta.-ala-20-(S)-camptothecin E-ring ketone, 9-amino
10,11-difluoromethylenedioxy-20-O-.beta.-ala-20-(S)-camptothecin
E-ring ketone, 7-ethyl-9-nitro
10,11-difluoromethylenedioxy-20-O-.beta.-ala-20-(- S)-camptothecin
E-ring ketone and 7-ethyl-9-amino 10,11-difluoromethylened-
ioxy-20-O-.beta.-ala-20-(S)-camptothecin E-ring ketone.
[0050] The compounds of the present invention may be prepared by
conventional methods known to those of ordinary skill in the art,
without undue experimentation.
[0051] For example, the claimed compounds may be prepared by
condensation of a aminophenylcarbonyl of formula IV or V 4
[0052] where X, Y, W and n are as defined for formula I
[0053] with a tricyclic ketone of formula III 5
[0054] where R.sup.13 and R.sup.14 are defined as for formula
I.
[0055] The condensation reaction is analogous to the condensation
reaction described by Wall et al. U.S. Pat. No. 5,122,526, the
relevant portions of which are hereby incorporated by
reference.
[0056] The synthetic sequence is described with reference to FIG.
1. The 20-desoxy tricyclic analog (1) is treated with an
appropriate amine as shown in the example. It is a cyclopentyl
amine and the corresponding amide (2) is obtained. On acetylation,
2 is converted to the acetate 3. The next step is a homologolation
reaction. Other homologolation reactions may be carried out by
converting 2 to a bromide, etc. The compound 4 is converted to a
hydroxy derivative containing one more carbon atom, compound 5.
Compound 5 may be brominated to the bromo analog 6. Compound 6 in
turn is converted as shown to the tricyclic 20-desoxy ketone 7.
Compound 7 may be hydroxylated to the (RS)-20-hydroxy compound 8.
Finally, acidic cleavage of the ketal yields the 20(RS)-hydroxy
ketone 9 which is the reactant that can be converted now to many
camptothecin analogs (as shown in the attached example).
[0057] Additional, non limiting examples of condensation reactions
are illustrated in FIG. 2.
[0058] Alternatively, suitable E-ring ketone compounds may also be
prepared from the corresponding compothecin compound bearing an
E-ring lactone, illustrated in FIG. 3, by the following reaction
sequence:
[0059] i) reaction of the E-ring lactone with a primary alkylamine
to form an .alpha.-hydroxy alkylamide;
[0060] ii) activation of a pendant D ring hydroxymethylene group to
form a leaving group, such as by formation of an acetate, followed
by a displacement reaction with a dialkyl malonate, such as
diethylmalonate;
[0061] iii) esterification of the alkylamide to an alkyl ester;
[0062] iv) cyclization of a D-ring methylene malonate onto the
alkyl ester to form the E-ring ketone followed by decarboxylation
of an ester group; and
[0063] v) decarboxylation of the remaining ester group.
[0064] In a further embodiment, an .alpha.-.beta. E-ring
unsaturation may be introduced by conventional methods known to
those of ordinary skill in the art, such as by reacion with
DDQ.
[0065] An alternative procedure for preparing the E-ring ketone
from camptothecin is attached and involves a procedure as shown. If
the E-ring ketone can be prepared at the very end, a conjugated B
ring can be prepared as shown in the very last step. Such a
compound might have very interesting properties. It might possibly
intercalate with DNA whereas camptothecin does not.
[0066] Substitution at the C.sub.7 position may be conducted by
condensation with the corresponding aldehyde of the C.sub.7
substituent. Esterification with an amino acid at C.sub.20 is
possible by conventional methods known to those of ordinary skill
in the art. Substitution at C.sub.9 with groups such a nitro and
amino is also possible in a manner analogous to that described in
the literature.
[0067] The compounds of the invention having the group --CH.sub.2-L
at C.sub.9 are prepared from known 20(S)--CPT compounds bearing a
halogen, for example, a bromine atom, at the C.sub.9 position. The
halogen atom can be readily converted into the corresponding cyano
analog by reaction with CuCN, followed by hydrolysis to form the
corresponding carboxy analog. The carboxy analog is reduced to the
corresponding hydroxy methyl analog which can be reacted with
Ph.sub.3P--CCl.sub.4 to provide the corresponding chloromethyl
analog. The chloromethyl analog can be readily converted to the
bromomethyl and iodomethyl analogs using LiBr or LiI. The remaining
compounds of the invention are prepared from these compounds by
reaction with the corresponding acid chloride, sulfonyl chloride,
etc. These reactions are well known to one having ordinary skill in
this art.
[0068] Compounds in which L is Br or I are readily prepared from
the compound in which L is Cl by simple halide exchange employing
LiBr or LiI in dimethylformamide (DMF) solution (Larock, R. C.,
Comprehensive Organic Transformations, VCH Publishers, Inc., p.
337, N.Y. 1989).
[0069] Alternatively, the 7-methyl compounds (L is H) can be
prepared either by a Friedlander reaction employing the
corresponding acetophenone, or by a free radical alkylation
reaction (Sawada et al., 1991, Chem. Pharm. Bull., 39: 2574). Free
radical bromination of 7-methyl substrates can be accomplished by
employing N-bromosuccinimide (NBS) in acetic acid (HOAc) under
catalysis by benzoyl peroxide to give compounds in which L is
Br.
[0070] 9-Nitro-difluoro-10,11-methylenedioxy-20-(S)-camptothecin
may be prepared from
difluoro-10,11-methylenedioxy-20-(S)-camptothecin by treatment with
HNO.sub.3. 9-Amino difluoro-10,11-methylenedioxy-20-(S)-ca-
mptothecin may be prepared from 9-nitro
difluoro-10,11-methylenedioxy-20-(- S)-camptothecin via reduction
with SnCl.sub.2.
[0071] Other compounds which possess oxygen derived leaving groups,
such as triflate or tosylate, are prepared from the 7-hydroxymethyl
and/or 7-halomethyl compounds. The 7-hydroxymethyl compounds are
prepared from the corresponding parent compounds by the
hydroxymethylation reaction. (e.g. Sawada et al., 1991, Chem.
Pharm. Bull., 39: 2574) Treatment of these compounds with readily
available sulfonic acid chlorides or anhydrides using known
procedures (Stang et al., 1982, Synthesis, 85) provides the highly
electrophilic substrates noted above. Alternatively, the compounds
described above can be generated from any of the substrates where L
is Cl, Br or I by reaction with the silver salt of the
corresponding acid (e.g., silver trifluoromethanesulfonate, silver
tosylate, etc.) as described generally by Stang et al. and more
specifically by Gramstad and Haszeldine (T. Gramstad and R. N.
Haszeldine, 1956, J. Chem. Soc., 173).
[0072] C.sub.20 esters may be prepared by esterifying the
20-position hydroxyl group of a camptothecin analog to form an
ester containing a water soluble moiety. Generally, the
camptothecin analog is initially suspended in methylene chloride or
other inert solvent, stirred and cooled. To the cooled mixture is
added one equivalent of an acid having the formula
HOOC--CHR.sup.10--NR.sup.8R.sup.9 or HOOC--(CH.sub.2).sub.m---
NR.sup.8R.sup.9, where m is an integer from 1-6, preferably 2-6,
and R.sup.10 is the side chain of one of the naturally occurring
.alpha.-amino acids. R.sup.8 and R.sup.9 are, independently,
hydrogen or C.sub.1-8 alkyl. Suitable side chains R.sup.10 are the
side chains of the amino acids glycine, .alpha.-alanine,
.beta.-alanine, valine, leucine, isoleucine, phenylalanine,
tyrosine, tryptophan, leucine, arginine, histidine, aspartate,
glutamate, asparagine, glutamine, cysteine and methionine.
Particularly preferred esters are glycinate esters. One equivalent
of dicyclohexylcarbodiimide (DCC) and a catalytic amount of an
amine base, preferably a secondary or tertiary amine, are also
added to the mixture, which is then stirred to complete the
reaction. Any precipitate which forms is removed by filtration and
the product is isolated after removal of the solvent.
[0073] The free amine(s) may be converted to an acid addition salt
by the addition of a pharmaceutically acceptable acid. Suitable
acids include both inorganic and organic acids. Suitable addition
salts include, but are not limited to hydrochloride, sulfate,
phosphate, diphosphate, hydrobromide, nitrate, acetate, malate,
maleate, fumarate, tartrate, succinate, citrate, lactate,
methanesulfonate, p-toluenesulfonate, palmoate, salicylate and
stearate salts. The salts may be purified by crystallization from a
suitable solvent.
[0074] The water soluble 20-hydroxyl esters of the present
invention are substantially less toxic than the parent compounds
from which the esters are prepared.
[0075] The camptothecin analogs are administered in a dose which is
effective to inhibit the growth of tumors. As used herein, an
effective amount of the camptothecin analog is intended to mean an
amount of the compound that will inhibit the growth of tumors, that
is, reduce the site of growing tumors relative to a control in
which the tumor is not treated with the camptothecin analog. These
effective amounts are generally from about 1-60 mg/kg of body
weight per week, preferably about 2-20 mg/kg per week.
[0076] The compounds of the present invention may be administered
as a pharmaceutical composition containing the camptothecin analog
and a pharmaceutically acceptable carrier or diluent. The active
materials can also be mixed with other active materials which do
not impair the desired action and/or supplement the desired action.
The active materials according to the present invention can be
administered by any route, for example, orally, parenterally,
intravenously, intradermally, subcutaneously, or topically, in
liquid or solid form.
[0077] For the purposes of parenteral therapeutic administration,
the active ingredient may be incorporated into a solution or
suspension. The solutions or suspensions may also include the
following components: a sterile diluent such as water for
injection, saline solution, fixed oils, polyethylene glycols,
glycerine, propylene glycol or other synthetic solvents;
antibacterial agents such as benzyl alcohol or methyl parabens;
antioxidants such as ascorbic acid or sodium bisulfite; chelating
agents such as ethylenediaminetetraacetic acid; buffers such as
acetates, citrates or phosphates and agents for the adjustment of
tonicity such as sodium chloride or dextrose. The parenteral
preparation can be enclosed in ampoules, disposable syringes or
multiple dose vials made of glass or plastic.
[0078] Another mode of administration of the compounds of this
invention is oral. Oral compositions will generally include an
inert diluent or an edible carrier. For the purpose of oral
therapeutic administration, the aforesaid compounds may be
incorporated with excipients and used in the form of tablets,
gelatine capsules, troches, capsules, elixirs, suspensions, syrups,
wafers, chewing gums and the like. Compositions may be prepared
according to any method known to the art for the manufacture of
pharmaceutical compositions and such compositions may contain one
or more agents selected from the group consisting of sweetening
agents, flavoring agents, coloring agents and preserving agents.
Tablets containing the active ingredient in admixture with nontoxic
pharmaceutically acceptable excipients which are suitable for
manufacture of tablets are acceptable. These excipients may be, for
example, inert diluents, such as calcium carbonate, sodium
carbonate, lactose, calcium phosphate or sodium phosphate
granulating and disintegrating agents, such as maize starch, or
alginic acid; binding agents, such as starch, gelatin or acacia;
and lubricating agents, such as magnesium stearate, stearic acid or
talc. Tablets may be uncoated or may be coated by known techniques
to delay disintegration and adsorption in the gastrointestinal
tract and thereby provide a sustained action over a longer period.
For example, a time delay material such as glyceryl monostearate or
glyceryl distearate alone or with a wax may be employed.
Formulations for oral use may also be presented as hard gelatin
capsules wherein the active ingredient is mixed with an inert solid
diluent, for example calcium carbonate, calcium phosphate or
kaolin, or as soft gelatin capsules wherein the active ingredient
is mixed with water or an oil medium, such as peanut oil, liquid
paraffin or olive oil.
[0079] The tablets, pills, capsules, troches and the like may
contain the following ingredients: a binder such as
microcrystalline cellulose, gum tragacanth or gelatin; an excipient
such as starch or lactose, a disintegrating agent such as alginic
acid, Primogel, corn starch and the like; a lubricant such as
magnesium stearate or Sterotes; a glidant such as colloidal silicon
dioxide; and a sweetening agent such as sucrose or saccharin or
flavoring agent such as peppermint, methyl salicylate, or orange
flavoring may be added. When the dosage unit form is a capsule, it
may contain, in addition to material of the above type, a liquid
carrier such as a fatty oil. Other dosage unit forms may contain
other various materials which modify the physical form of the
dosage unit, for example, as coatings. Thus tablets or pills may be
coated with sugar, shellac, or other enteric coating agents. A
syrup may contain, in addition to the active compounds, sucrose as
a sweetening agent and certain preservatives, dyes and colorings
and flavors. Materials used in preparing these various compositions
should be pharmaceutically or veterinarially pure and non-toxic in
the amounts used.
[0080] Aqueous suspensions of the invention contain the active
materials in admixture with excipients suitable for the manufacture
of aqueous suspensions. Such excipients include a suspending agent,
such as sodium carboxymethylcellulose, methylcellulose,
hydroxypropylethyl cellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing
or wetting agents such as a naturally occurring phosphatide (e.g.,
lecithin), a condensation product of an alkylene oxide with a fatty
acid (e.g., polyoxyethylene stearate), a condensation product of
ethylene oxide with a long chain aliphatic alcohol (e.g.,
heptadecaethylene oxycetanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
(e.g., polyoxyethylene sorbitol mono-oleate), or a condensation
product of ethylene oxide with a partial ester derived from fatty
acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono
oleate). The aqueous suspension may also contain one or more
preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or
more coloring agents, one or more flavoring agents and one or more
sweetening agents, such as sucrose, aspartame, saccharin, or
sucralose.
[0081] Oil suspensions may be formulated by suspending the active
ingredient in a vegetable oil, such as arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oil suspensions may contain a thickening agent, such
as beeswax, hard paraffin or cetyl alcohol. Sweetening agents may
be added to provide a palatable oral preparation. These
compositions may be preserved by the addition of an antioxidant
such as ascorbic acid.
[0082] Dispersible powders and granules of the invention suitable
for preparation of an aqueous suspension by the addition of water
may be formulated from the active ingredients in admixture with a
dispersing, suspending and/or wetting agent, and one or more
preservatives. Suitable dispersing or wetting agents and suspending
agents are exemplified by those disclosed above. Additional
excipients, for example sweetening, flavoring and coloring agents,
may also be present.
[0083] The pharmaceutical composition of the invention may also be
in the form of oil in water emulsions. The oily phase may be a
vegetable oil, such as olive oil or arachis oil, a mineral oil,
such as liquid paraffin, or a mixture of these. Suitable
emulsifying agents include naturally occurring gums, such as gum
acacia and gum tragacanth, naturally occurring phosphatides, such
as soybean lecithin, esters or partial esters derived from fatty
acids and hexitol anhydrides, such as sorbitan mono-oleate, and
condensation products of these partial esters with ethylene oxide,
such as polyoxyethylene sorbitan mono oleate. The emulsion may also
contain sweetening and flavoring agents.
[0084] Syrups and elixirs may be formulated with sweetening agents,
such as glycerol, sorbitol or sucrose. Such formulations may also
contain a demulcent, a preservative, a flavoring or a coloring
agent.
[0085] The pharmaceutical compositions of the invention may be in
the form of a sterile injectable preparation, such as a sterile
injectable aqueous or oleaginous suspension. This suspension may be
formulated according to the known art using those suitable
dispersing or wetting agents and suspending agents which have been
mentioned above. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a nontoxic
parenterally acceptable diluent or solvent, such as a solution of
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water and Ringer's solution, an isotonic sodium
chloride. In addition, sterile fixed oils may conventionally be
employed as a solvent or suspending medium. For this purpose any
bland fixed oil may be employed including synthetic mono or
diglycerides. In addition, fatty acids such as oleic acid may
likewise be used in the preparation of injectables. Sterilization
may be performed by conventional methods known to those of ordinary
skill in the art such as by aseptic filtration, irradiation or
terminal sterilization (e.g. autoclaving).
[0086] Aqueous formulations (i.e oil in water emulsions, syrups,
elixers and injectable preparations) may be formulated to achieve
the pH of optimum stability. The determination of the optimum pH
may be performed by conventional methods known to those of ordinary
skill in the art. Suitable buffers may also be used to maintain the
pH of the formulation.
[0087] The compounds of this invention may also be administered in
the form of suppositories for rectal administration of the drug.
These compositions can be prepared by mixing the drug with a
suitable nonirritating excipient which is solid at ordinary
temperatures but liquid at the rectal temperatures and will
therefore melt in the rectum to release the drug. Non limiting
examples of such materials are cocoa butter and polyethylene
glycols.
[0088] They may also be administered by intranasal, intraocular,
intravaginal, and intrarectal routes including suppositories,
insufflation, powders and aerosol formulations.
[0089] The compounds of the present invention may also be
administered in the form of liposome or microvesicle preparations.
Liposomes are microvesicles which encapsulate a liquid within lipid
or polymeric membranes. Liposomes and methods of preparing
liposomes are known and are described, for example, in U.S. Pat.
No. 4,452,747, U.S. Pat. No. 4,448,765, U.S. Pat. No. 4,837,028,
U.S. Pat. No. 4,721,612, U.S. Pat. No. 4,594,241, U.S. Pat. No.
4,302,459 and U.S. Pat. No. 4,186,183. The disclosures of these
U.S. patents are incorporated herein by reference. Suitable
liposome preparations for use in the present invention are also
described in WO-9318749-A1, J-02056431-A and EP-276783-A.
[0090] The camptothecin analogs may be used individually to inhibit
the growth of tumors. Alternatively, combinations of two or more
camptothecin analogs may be used or combinations of one or more
camptothecin analogs with one or more known anti tumor compounds.
When a camptothecin analog is combined with a conventional anti
tumor compound, the camptothecin analog will generally be present
in an amount ranging from about 1-99 wt. %, preferably, 5-95 wt. %
of the combined amount of camptothecin and conventional anti tumor
compound. The pharmaceutical compositions noted above may contain
these combinations of compounds together with an acceptable carrier
or diluent.
[0091] The ester compounds of the invention may be administered to
treat leukemia and solid tumors in mammals, including humans. The
esters of the present invention are prodrugs which are hydrolyzed
to camptothecin analogs demonstrating inhibitory activity on
topoisomerase I. The camptothecin analogs formed by hydrolysis of
the esters of the invention are also effective in treating leukemia
and solid tumors in mammals. Numerous camptothecin analogs have
been shown to be effective against leukemia using the standard
L1210 leukemia assay (Wall et al. (1993), Journal of Medicinal
Chemistry, 36: 2689-2700). High activity of camptothecin and
camptothecin analogs has also been shown in the P388 leukemia assay
(Wall (1983), Medical and Pediatric Oncology, 11: 480A-489A). The
later reference also provides a correlation between anti leukemia
activity as determined by the L1210 and the P388 leukemia assays
with efficacy of camptothecin analogs against solid tumors.
Compounds reported as active in the leukemia assays also have
demonstrated activity in a number of solid tumors including a colon
xenograft, a lung xenograft, a Walker sarcoma and a breast
xenograft (Wall (1983), Table IV, page 484 A). Recent studies have
confirmed the correlation between topoisomerase I inhibitory
activity and anti leukemia/anti tumor activity of camptothecin
analogs (Giovanella et al. (1989), Science, 246: 1046-1048). The
compounds of the present invention are particularly effective in
the treatment of colon, lung, breast and ovary solid tumors, brain
glioma and leukemia. These compounds may also be used to treat
malaria.
[0092] Obviously, numerous modifications and variations of the
present invention are possible in light of the above teachings. It
is therefore to be understood that within the scope of the appended
claims, the invention may be practiced otherwise than as
specifically described herein.
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