Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-02
2001-09-18
Kifle, Bruck (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06291676
ABSTRACT:
TECHNICAL FIELD
The present invention relates to water-soluble camptothecin and homocamptothecin compounds. More particularly, the invention relates to C-7 substituted camptothecin derivatives prepared by C-7 haloalkylation, Hydroalkylation and aminoalkylation of camptothecin or its C-12 substituted 7-membered E-ring analog 5-ethyl-5-hydroxy -1,4,5,13-tetrahydro-3H,15H-oxepino[3′,4′:6,7]indolizino-[1,2-b]quinoline-3,15-dione (homocamptothecin) derivatives prepared by C-12 haloalkylation, hydroalkylation and aminoalkylation of homocamptothecin to form water-soluble camptothecin/homocamptothecin compounds.
BACKGROUND OF THE INVENTION
Camptothecin, a plant alkaloid isolated from trees indigenous to China, and analogs thereof such as 9-aminocamptothecin, 9-nitrocamptothecin, 10-hydroxycamptothecin, 10,11-methylenedioxycamptothecin, 9-nitro-10,11-methylenedioxycamptothecin, 9-chloro-10,11-methylenedioxycamptothecin, 9-amino-10,11-methylenedioxycamptothecin, 7-ethyl-10-hydroxycamptothecin (SN-38), topotecan, DX-8951, Lurtotecan (GI147221C), and other analogs (collectively referred to herein as camptothecin drugs) are presently under study worldwide in research laboratories and cancer clinics. In lab tests and in clinical trials, these camptothecin drugs have aroused considerable interest as a result of their ability to halt the growth of a wide range of human tumors. For example, these drugs exhibit unprecedented high levels of antitumor activities against human colon cancer [Giovanella, et al.
Science
246: 1046-1048 (Washington, D.C.) (1989)]. Camptothecin drugs have also been shown to be effective against other experimental cancer types such as lung, breast, and malignant melanoma.
Camptothecin drugs are thought to inhibit the proliferation of cancer cells by interfering with the breakage/reunion reaction of the enzyme topoisomerase I, a nuclear enzyme implicated in DNA replication and RNA transcription. A camptothecin drug stabilizes and forms a reversible enzyme-camptothecin-DNA ternary complex, designated the cleavage complex. The formation of the cleavable complex specifically prevents the reunion step of the breakage/union cycle of the topoisomerase reaction. Topoisomerase I inhibitors are also known to be useful in the treatment of HIV.
Camptothecin and homocamptothecin both contain five-membered ring systems as shown below.
For both camptothecin (top structure) and homocamptothecin (bottom structure), Z=hydrogen. Unfortunately, camptothecin/homocamptothecin and many structurally-related camptothecin analogs/derivatives are water-insoluble. This water insolubility makes administration of camptothecin drugs difficult. In an effort to address this problem a number of synthetic efforts have been directed to derivatizing the A-ring and/or B-ring to improve water-solubility while maintaining cytotoxic activity.
To date, some water-soluble camptothecin derivatives have been prepared by derivatizing the A and B rings and by opening the lactone E-ring. See, for example, U.S. Pat. Nos. 5,646,159, 5,559,235, 5,670,500, 5,663,177, 5,677,286, and 5,734,056. U.S. Pat. No. 5,646,159 discloses water-soluble pro-drug type camptothecin compounds, in which the 20-position hydroxyl group is esterified. Enzymes present within the body can break the ester bond after injection to form the parent camptothecin compound.
U.S. Pat. No. 5,559,235 discloses water-soluble camptothecin compounds, in which the A ring has 10,11-ethylene or methylenedioxy rings and substituents at C-7. U.S. Pat. No. 5,670,500 discloses water-soluble camptothecin drugs, in which the A ring is connected to the substituted furan-ring. U.S. Pat. No. 5,663,177 discloses water-soluble camptothecin analogs, in which the A- and B rings are connected with a heterocyclic ring containing nitrogen. U.S. Pat. No. 5,677,286 discloses water-soluble camptothecin analogs in which the A ring has non-ionic sugar moieties, which increase the water solubility. U.S. Pat. No. 5,734,056 discloses the process for the preparation of 10-hydroxy-9-alkyl analogs of camptothecin.
A need continues to exist for the development of new and better camptothecin and homocamptothecin compounds having still higher antitumor activity and still more improved water-solubility while exhibiting low levels of toxicity.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of the present invention to provide new camptothecin and homocamptothecin compounds including analogs and derivatives displaying cytotoxic activity and improved water-solubility for ease and efficiency of administration/delivery.
Still another object of the present invention is to provide new camptothecin and homocamptothecin drugs including analogs and derivatives, processes for preparing said analogs and derivatives and formulations containing such analogs and derivatives.
Yet another object of this invention is the provision of new camptothecin and homocamptothecin drugs including derivatives possessing high anti-tumor activity and water solubility and minimal toxicity.
Other objects and advantages of the present invention will become apparent as the description thereof proceeds. In satisfaction of the foregoing objects and advantages, there is provided by this invention camptothecin and homocamptothecin drugs having the structures shown below.
The compounds of the present invention are prepared by substitution of the 7-position of camptothecins or 12-position of homocamptothecins to form water-soluble compounds containing an aminoalkyl moiety. The aminoalkyl moiety may incorporate either an unbranched or branched alkyl chain. The homocamptothecin structure can be readily prepared starting from camptothecin according to a published method (Bigg et al., Biorganic and Medicinal Chemistry Letters (1997) 17 2235-2238) or can be prepared following derivitazation at position 7. Generally, the camptothecins serving as starting materials are suspended in organic solvents or water, stirred and cooled. To the mixture is added the following compounds which give equivalent structure to Z: halo alcohols, amino alcohols, amino aldehydes, halo aldehydes, halo ketones, azido alcohols, azido aldehydes, sulfuric acid, iron sulfate and oxidizing reagents such as peracids and hydrogen peroxide. The mixture 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.
Z in the structure shown above is:
A) C
1-20
NR
1
R
2
where
(1) R
1
is hydrogen, C
1-18
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkyl-C
1-18
alkyl, C
2-18
alkenyl, hydroxy-C
1-18
alkyl, C
1-18
alkoxy-C
1-18
alkyl and R
2
is C
1-20
NR
3
R
4
where: (a) R
3
and R
4
are independently, hydrogen, C
1-18
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkyl-C
1-18
alkyl, C
2-18
alkenyl, hydroxy-C
1-18
alkyl, C
1-18
alkoxy-C
1-18
alkyl, 3-7 membered heterocyclic ring which may contain a O, S or N group; (b) R
3
is hydrogen and R
4
is C
1-18
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkyl-C, alkyl, C
2-18
alkenyl, hydroxy-C
1-18
alkyl or C
1-18
alkoxy-C
1-18
alkyl, perhalo-C
1-18
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkyl-C
1-18
alkyl, C
2-18
alkenyl, hydroxy-C
1-18
alkyl, C
1-18
alkoxy, C
1-18
alkoxy-C
1-18
alkyl; (c) R
3
and R
4
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
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,
(2) R
1
is hydrogen, C
1-18
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkyl-C
1-18
alkyl, C
2-18
alkenyl, hydroxy-C
1-18
alkyl, C
1-18
alkoxy-C
1-18
alkyl,
Burke Thomas G.
Chavan Ashok J.
Demir Ayhan S.
Pommier Yves
Tanyeli Cihangir
Kifle Bruck
King and Schikli, PLLC
University of Kentucky Research Foundation
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