Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention is directed to cascade esters of camptothecin and is also directed to compositions including derivatives of cascade esters of camptothecin in delivery systems, preferably derivatives having low toxicity and side effects.
• the present invention also relates to the use of these derivatives for cancer or tumor treatment in mammals.
• the disclosures of all documents referred to in this application are incorporated herein in their entirety by reference. BACKGROUND OF THE INVENTION
• Camptothecin a cytotoxic alkaloid first isolated from the wood and bark of Camptotheca
• This compound has a pentacyclic ring system with only one asymmetrical center in ring E with a 20(S)-configuration.
• the pentacyclic ring system includes a pyrrolo [3, 4 - b] quinoline moiety (rings A, B and C), a conjugated pyridone (ring D), and a six-membered lactone (ring E) with an ⁇ - hydroxyl group. Camptothecin was of great interest from the time of its initial isolation due to its noteworthy activity in the mouse leukemia L 1210 system.
• camptothecin Previously data for the antitumor activity of camptothecin were obtained by employing experimentally transplanted malignancies such as leukemiaL 1210 in mice, or Walker 256 tumor in rats (Chem. Rev.23, 385, 1973, Cancer Treat. Rep. 60, 1007, 1967). Subsequent clinical studies showed that this compound was not usable as an anticancer agent in vivo due to its high toxicity. Camptothecin itself is insoluble in water. Therefore, camptothecin was evaluated clinically as a water-soluble sodium carboxylate salt in the early times. This form of camptothecin produced severe toxicity and seemed devoid of anticancer activity (Gott Kunststoff Kunststoffet al, Cancer Chemother. Rep.
• CPT administered intramuscularly i.m.
• s.c subcutaneously
• i.s. intrastomach
• i.s. intrastomach
• 9- nitrocamptothecin 9- nitrocamptothecin
• camptothecins exist in two distinct forms at physiological pH, i.e., 7 or above, as shown in the following equilibrium equation:
• the present invention describes new CPT-derivatives which delay the opening of the lactone ring E, enhancing and prolonging the antitumor activity as compared to the mother analog, CPT.
• the present invention overcomes one or more ofthe above-described disadvantages.
• the present invention relates to a compound ofthe general formula:
• the R group represents one or more substituents on one ofthe rings ofthe structure above.
• R represents H, NO 2 , NH 2 , N 3 , -OH, a halogen (e.g., F, Cl, Br, I), carboxyl (COOH), a C ⁇ - 16 alkyl group, C ⁇ -16 alkylenyl group, a C 3-8 cycloalkyl group, a C ⁇ .g alkoxyl group, an aroxyl group, CN, SO 3 H, a C ⁇ -8 halogenated alkyl group, (CH 2 ) n NR 2 7 (where R 7 is H, or a C ⁇ -8 alkyl group, n is an integer of from 1 to about 8), hydroxyl, SH, SR 8 (where R 8 is a C 1-8 alkyl group, or an unsubstituted or substituted phenyl group),.
• a halogen e.g., F, Cl, Br, I
• carboxyl
• a carbonyl group e.g., COR 9 , where R 9 can be a C ⁇ -8 alkyl group, an unsubstituted phenyl group, or a substituted phenyl group
• a SiR 3 10 where R 10 can be a Ci ⁇ alkyl group
• the R group is respectively positioned at the 9, 10, 11, or 12 position of ring A.
• R can also be a disubstituted 10, 1 l-O-(CH 2 ) y -O- group (where y can be an integer of from 1 to 3).
• R can also be C 2 alkenyl group(s), CF 3 (s), CC1 3 (s), CH 2 F(s), CH 2 Cl(s), CHF 2 (s), CHCl 2 (s), OR 12 (s) (where R 12 can be a C ⁇ -8 alkyl group, or a C ⁇ . 8 alkenyl group, or an aromatic group), NR 2 13 (s) (where R 13 can be H, or C ⁇ - alkyl group).
• X represents H, a C 1-8 alkyl group, a C ⁇ -8 alkenyl group, a C ⁇ -8 alkoxyl group, an aroxyl group, a SiR 3 ⁇ group (where R ⁇ can be a C 1-4 alkyl group), or CH 2 NZY where Z and Y can be, independently, H, C 1-4 alkyl, or a C M halogenated alkyl group.
• R can be hydrogen, halogen, halogen containing group, alkyl group (e.g. C 1 -C 15 alkyl group), -NO 2 , - OH, alkoxy, or -NH 2 .
• Xi can be an alkyl chain ofthe type -CH 2 _ n where n can be 1 through 15 , or an aromatic radical, such as -Ar(Y ⁇ Y 2 Y 3 Y 4 ), where Ar can be an aromatic radical (e.g., acyl,benzyl), Y ls Y 2 , Y 3 , and Y 4 , which can be the same or different, can be hydrogen, alkyl groups, halogen groups, nitro groups, cyano groups, amino groups, hydroxyl groups, carbonyl groups, or carboxyl groups, and Ri can be an alkyl group, a halo alkyl group, or an aromatic group.
• the present invention also relates to a method for treating cancer and/or malignant tumors in a mammal and comprises administering an effective amount of one or more ofthe above CPT- derivatives, which may include any delivery system or other therapeutic means.
• the present invention relates to methods of making the compounds of the present invention to provide halo-alkyl esters of camptothecins which remain intact longer in a mammalian body, particularly in a human body.
• the present invention relates to cascade esters of camptothecins and their use for medicinal purposes.
• Camptothecins (“CPTs") have considerable anti-tumor and anticancer activity, but these compounds are susceptible to degradation under normal physiological conditions, and the metabolites produced often exhibit toxic properties. Therefore, the present invention provides CPT analogues which remain intact longer in a mammalian body, particularly in the human body, thus enhancing the anti-tumor and anti-cancer effects without producing undesirable side effects.
• the present invention provides new CPT-derivatives which retain the lactone ring E and the 20-hydroxyl group intact, as prior research has shown that these structural features are important for antitumor or anticancer activity.
• the compounds ofthe present invention are bio-active and/or are a pro-drug that generates a bio-active compound.
• the present invention provides C-20 hydroxyl of CPT to form new CPT analogs with desirable biological properties.
• the present invention relates to "cascade" esters, ofthe general structure given below.
• R group represents substituents on one ofthe rings ofthe structure above.
• R represents H, NO 2 , NH 2 , N 3 , -OH, a halogen (e.g., F, Cl, Br, I), carboxyl (COOH), a C ⁇ _
• the R group can be respectively positioned at the 9, or 10, or 11, or 12 position of ring A.
• R can also be a disubstituted 10, 1 l-O-(CH 2 ) y -O- group (where yean be an integer of from 1 to 3).
• R can also be C ⁇ - ⁇ 2 alkenyl group(s), CF 3 (s), CCl 3 (s), CH 2 F(s), CH 2 Cl(s), CHF 2 (s), CHCl 2 (s), OH(s), OR 12 (s) (where R 12 can be a - 8 alkyl group, or a C 1-s alkenyl group, or an aromatic group), NR 2 13 (s) (where R 13 can be H, or C ⁇ -4 alkyl group).
• X represents H, a C ⁇ -8 alkyl group, a C ⁇ -8 alkenyl group, a C ⁇ -8 alkoxyl group, an aroxyl group, a SiR 3 ⁇ group (where R 11 can be a C ⁇ -4 alkyl group), or CH 2 NZY where Z and Y can be, independently, H, C ⁇ -4 alkyl, or a
• R can be a hydrogen, halogen, halogen containing group, an alkyl group (e.g., C 1 -C 15 alkyl group), -NO 2 , -OH, alkoxy, or -NH 2 .
• Xi can be an alkylene group,
• Ri can be an alkyl group, a halo alkyl group, an aromatic group, or a group including various different functional group as shown below in example 2 (i.e., ester of acetylsalicylic acid, or derivatives thereof) .
• alkyl groups, alkylene groups and/or aromatic groups can be substituted or unsubstituted, such as substituted with an alkyl group, halogen, or an aromatic group.
• the various substituents described herein can be linear, branched, cyclic, or combinations thereof.
• alkyl groups include C1-C15 alkyl groups.
• alkenyl groups include C 2 -C ⁇ 5 alkenyl groups.
• Examples of an epoxy group include C 2 -Ci 5 epoxidized alkenyl groups.
• cycloalkyl groups include C 3 -C 8 cycloalkyl groups.
• alkyl groups that can be used are -CH 3 , -CH 2 CH 3 , CH 3 CH 2 CH 2 -, CH 3 (CH 2 ) 3 -, CH 3 (CH 2 ) 4 -, CH 3 (CH 2 ) 5 -, and CH 3 (CH 2 ) 6-17 -, (CH 3 ) 2 CH- CH 3 -CH 3 - CH 2 CH-CH 3 , (CH 3 CH 2 ) 2 CH- (CH 3 CH 2 CH 2 ) 2 CH-, (CH 3 ) 3 C-, CH 3 (CH 3 CH 2 ) 2 C-.
• alkoxyl groups that can be used are MeO- EtO-, n-C 3 H 7 - i-C 3 H 7 -O-, n-C 4 H 9 -O-, i-C 4 H 9 -O-, t-C 4 H 4 -O-, n-C 5 -Hi 1 O-, (CH 3 ) 2 CHCH 2 CH 2 O-,
• aroxyl groups that can be used are p-CH 3 OC 6 H 4 -, m-CH 3 O- C ⁇ H t -, o-CH 3 OC 6 H - o,p-Dimethoxyl phenyl-, m,m-Dimethoxyl phenyl-, m,p-Dimethoxyl phenyl-, o-OTsCHjOCel , m-CH 3 CH 2 OC 6 H4- p-CH 3 CH 2 O-C 6 H4-.
• cycloalkyl groups that can be used are cyclo-C 3 , cyclo-C 4 , cyclo- C 5 , cyclo-C ⁇ , cyclo-C 7 , cyclo-C 8 , alkyl substituted cyclo-C 3 , alkyl substituted cyclo-C 4 , alkyl substituted cyclo-C 5 , alkyl substituted cyclo-C ⁇ , alkyl substituted cyclo-C 7 , and alkyl substituted cyclo-C 8 (where alkyl includes preferably those alkyl groups described above).
• X F, Cl, Br, 1
• the present invention provides new strategies of functionalizing the C-20 hydroxyl group with a protective group would be a productive way of enhancing the biological properties of the camptothecin series, as it appears that cleavage ofthe protective group precedes the opening ofthe lactone ring.
• the parent compound, CPT is the active agent from the biological standpoint.
• the compounds described above are preferably active in their form set forth above.
• the present invention provides CPT derivatives having a novel protective group that cleaves in two different positions in a cascade sequence before generating the parent compound. It is believed that the first cleavage occurs at the outside ester bond when the drug circulates in the blood, and the second cleavage occurs in the tumor tissues to liberate the active parent compound. Therefore, the sequential cleavage ofthe esters allows targeting ofthe tumor or cancer, in that generation ofthe parent compound occurs at the site ofthe tumor or cancer that is most susceptible to inhibition by the CPT.
• the compounds of the present invention may be produced by more than one synthetic pathway, and variations of the substituents on the protective groups are possible, as is clear to persons skilled in synthetic organic chemistry.
• a representative example of producing a cascade ester of camptothecins is set forth and discussed directly below.
• the general method involves reacting the CPT with an appropriately substituted organic acid in the presence of a suitable solvent, such as dimethyl formamide (DMF), and compounds known to facilitate esterifications.
• a suitable solvent such as dimethyl formamide (DMF)
• DMF dimethyl formamide
• An example of a compound known to facilitate esterification is a coupling agent like an dialkylcarbodiimide, an example of which is dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP), an example of which is 4- dimethylaminopyridine (or other suitable catalyst).
• DCC dicyclohexylcarbodiimide
• DMAP dimethylaminopyridine
• the reaction takes place at room temperature (w25° C) and under nitrogen atmosphere, wherein the reaction time is from about 1 day to about 1 week.
• the purity and the concentration of the CPT are not important.
• the solvent can be any solvent that does not include a hydroxy group, which can react with acylating and/or esterification agents.
• any solvent can be used that is capable of dissolving the CPT, but does not react with the acylating/esterification agent.
• An example of suitable solvent is chloroform, and more preferably, DMF.
• the solvents used in this reaction are commonly available and do not need to be pure (e.g. it can be industrial-grade solvent); however, for organic reactants, it is preferable to use highly purified solvents. Additionally, the solvents can have any pH that does not cause the CPT to decompose. Preferably, the solvents are not basic, and more preferably, the solvents are neutral.
• the pH ofthe organic acid in the present invention is not important.
• the organic acid acts as the acylating agent. More preferably, the organic acid is acetylsalicylic acid.
• the organic acid can have a general formula Ri COOXi COOH, wherein Xi can be an alkylene group, such as an alkyl chain ofthe type -CH 2 _ n where n can be 1 through 15, or an aromatic radical, for example, ofthe type -Ar(Y ⁇ Y 2 Y 3 Y 4 ), where Yi, Y 2 , Y 3 , and Y 4 , which can be the same or different, can be hydrogen, alkyl groups, halogen groups, nitro groups, cyano groups, amino groups, hydroxyl groups, carbonyl groups, or carboxyl groups, Ar can be an aromatic radical, such as aryl and benzyl.
• Ri can be an alkyl group, a halo alkyl group, an aromatic group, or a group consisting of various different functional groups as shown below in example 2 (i.e., ester of acetylsalicylic acid, or derivatives thereof).
• the organic acids ofthe present invention are commercially from places such as Aldrich Chemical Co., Milwaukee, WI.
• One example of an organic acid that can be used is acetylsalicylic acid, which is commercially available.
• the organic acids ofthe present invention can also be synthesized to have the desired chemistry.
• any catalyst can be used that facilitates esterifiication.
• a commonly used catalyst in this type of reaction is DMAP; however, other catalysts can also be used that have the same characteristics as the DMAP. The purity ofthe catalyst is not important, so long as the impurities do not react with the reactants.
• a coupling agent can also be used.
• One example of a commonly used coupling agent is DCC. If DCC is used in the present invention, then it is preferable to use a catalyst, such as DMAP or other catalysts having the same characteristics as DMAP.
• the CPT can be added to a solvent, which preferably is DMF.
• the ratio ofthe solvent to the CPT can be from about 10 ml or less of solvent to about 1 gram ofthe CPT to about 1000 ml ofthe solvent to about 1 gram of CPT. However, at a ratio 1000 ml ofthe solvent to 1 gram of CPT more reaction time may be required.
• the coupling agent such as DCC
• DMF solvent
• the molar ratio ofthe DCC to the CPT is about 1 to about 2.2.
• the catalyst can also be added to the solvent (DMF) before, during, or after adding the CPT or the DCC to the solvent.
• the amount ofthe catalyst added to the solvent for the reaction to properly take place can be half or less than half of the molar amount ofthe DCC added to the solvent.
• an organic acid which can act as the acylating agent having a general formula
• R ! COpXiCOOH can also be added to the above mixture.
• the organic acid which is preferably acetylsalicylic acid or the acid employed in example 2, shown below, can be added to the solvent before, during, or after adding the CPT, the DCC, and the catalyst to the solvent.
• the organic acid such as acetylsalicylic acid, can be added in any amount; however, it is preferable to not add the organic acid (acetylsalicylic acid) in large excess. More preferably, the molar ratio ofthe organic acid to the DCC is about 1:1.
• all ofthe above compositions are added to a reactor and are agitated under an inert atmosphere, such as N 2 , at room temperature, and at ambient pressure. It is preferable to agitate the solution at a sufficient agitation speed to form the desired product.
• the agitation speed is moderate, which is about 100 rpm to about 250 rpm.
• the reaction time depends on several variables, such as the ratio ofthe solvent to the CPT.
• the reaction is preferably continued until the reaction is completed, which can be determined for instance, by a color change in the solution. Additionally, when the solution turns from a homogeneous solution into a suspension solution, the reaction is completed. The reaction may take from about 1 day to about 1 week to complete.
• the solvent can be removed by any commonly known separation methods, such as an evaporation method or a vacuum system method.
• the residue that remains after removing the solvent can be filtered by a column chromatography.
• the residue can be chromatographically separated on silica, using THF-methylene chloride as the eluting solvent.
• the final product, identified as CZ183, was obtained as a yellow powder in a 38% yield after the solvents were removed by a rotary evaporator.
• the yields ofthe final products in the synthetic pathways set forth above typically are 10- 90%, depending on the exact reaction conditions, the purity ofthe starting materials, the nature ofthe acylating agent, the choice of solvent, and other factors or parameters common to synthetic organic chemistry.
• the methods of producing the compounds ofthe present invention, as set forth above, are not meant to be exclusive or limiting, but rather are exemplary only, and other means for generating these compounds or optimizing the reaction conditions are possible for persons skilled in the art.
• the compounds ofthe present invention are effective in treating malignant tumors or cancers in mammals.
• malignant tumor is intended to encompass all forms of human carcinomas, sarcomas and melanomas which occur in the poorly differentiated, moderately differentiated, and well differentiated forms.
• the compounds ofthe present invention and formulations ofthe present invention can be used in the treatment of a number of tumors and/or cancers including, but not limited to, human cancers ofthe lung, breast, colon, prostate, melanoma, pancreas, stomach, liver, brain, kidney, uterus, cervix, ovaries, urinary track, gastrointestinal, and other solid tumors which grow in an anatomical site other than the blood stream, as well as blood borne tumors such as leukemia.
• Other solid tumors include, but are not limited to, colon and rectal cancer.
• the compounds ofthe present invention are also useful as inhibitors ofthe enzyme topoisomerase I.
• the compounds of the present invention can be administered by any acceptable route including, but not limited to, orally, intramuscularly, transdermally, intravenously, through an inhaler or other air borne delivery systems, and the like.
• the compounds and the formulations of the present invention are administered orally, intramuscularly, or transdermally and most preferably delivered orally. Examples of transdermally delivery systems can be found, for instance in U.S. Patent No. 5,552,154 and 5,652,244 incorporated in their entirety by reference herein.
• the compounds or formulations ofthe present invention can also be administered to a patient through a liposome system such as ones described in U.S. Patent Nos.
• the compounds ofthe present invention may be incorporated or encapsulated in, surrounded or entrapped by, or otherwise restrained by a liposomal delivery system to form "liposomal prodrugs" using the compounds ofthe present invention.
• compositions such as microsuspensions ofthe liposomal prodrugs in lipid and in lipid-like emulsions (e.g. - Intralipid 20, cottonseed oil and peanut oil) for intramuscular administration and inclusion in cholesterol pellets for subcutaneous long-term administration.
• the prodrugs When taken orally by patients, the prodrugs are rapidly introduced into the bloodstream of a patient and readily converted to the parent compound in the body. Conversion ofthe prodrugs to the mother compound, CPT, is mediated by a group of enzymes called esterases present in the blood of many animals, including humans. Since the prodrugs are rapidly distributed throughout the body in a short period of time after delivery, these compounds exist at a very low concentration at the time they undergo enzymatic hydrolysis to the parent compound, and this prevents the CPT from precipitating in the bloodstream.
• a transdermal or transcutaneous route is by a transdermal or transcutaneous route.
• a patch can be prepared with a fine suspension of a prodrug ofthe present application in, for example, dimethylsulfoxide (DMSO), or a mixture of DMSO with cottonseed oil and brought into contact with the skin ofthe tumor carrying mammals away from the tumor location site inside a skin pouch.
• DMSO dimethylsulfoxide
• Other mediums or mixtures thereof with other solvents and solid supports would work equally as well for delivering the prodrugs.
• the patch can contain the CPT-derivative-containing prodrug ofthe present invention in the form of a solution or a suspension.
• the patch can then be applied to the skin ofthe patient, for example, by means of inserting it into a skin pouch ofthe patient formed by folding and holding the skin together by means of stitches, clips or other holding devices.
• This pouch should be employed in such a manner so that continuous contact with the skin is assured without the interference ofthe mammal.
• any device can be used which ensures the firm placement ofthe patch in contact with the skin.
• an adhesive bandage could be used to hold the patch in place on the skin.
• an "effective amount" ofthe compounds and formulations of the present invention is intended to mean that amount ofthe compound which will inhibit the growth of, or retard cancer, or kill malignant cells, and cause the regression and palliation of malignant tumors, i.e., reduce the volume or size of such tumors or eliminate the tumor entirely.
• the effective amounts can be administered on the basis of body surface area.
• Body surface area may be approximately determined from the height and weight of an individual (see, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y. pp. 537-538 (1970).
• a preferred effective amount ofthe camptothecin compounds in the present invention can range from about 12.5 to about 31.3 mg/m 2 of body surface per day, and for the prodrugs an effective amount can range from about 12.5 to about 3000 mg/m 2 of body surface area per day based on the weight ofthe prodrug and the delivery system.
• the preferred effective amounts or dosages ofthe prodrugs ofthe present invention in mice are from about 1 to about 400 mg prodrug per kg of body weight twice a week for an intramuscular route and from about 0.75 to about 150 mg prodrug/kg/day for the oral route.
• Effective amounts or dosages ofthe prodrugs ofthe present invention in mice are, for instance, from about 1.5 mgkg/week to about 1000 mg/kg/week of the prodrug for the transdermal route.
• the exact timing of administration ofthe dosages can be varied to achieve optimal results.
• Intralipid 20 as the liposomal carrier for the CPT-derivative, the actual dosage of CPT-derivative reaching the patient will be less.
• the compounds used in the present invention may first be combined with pharmaceutically acceptable carriers or diluents, such as Intralipid 10 or 20 or natural oils, or other suitable emulsifiers for lipophilic compounds, prior to being incorporated, encapsulated, surrounded, entrapped, or otherwise restrained in, on, or by the lipsomal delivery system.
• pharmaceutically acceptable carriers or diluents such as Intralipid 10 or 20 or natural oils, or other suitable emulsifiers for lipophilic compounds
• Liposomes have been used successfully to administer medications to cancer patients, and have been shown to be useful clinically in the delivery of anticancer drugs such as doxorubicin, daunorubicin, and cisplatinum complexes.
• anticancer drugs such as doxorubicin, daunorubicin, and cisplatinum complexes.
• Administration involving liposomes may include, for example, lipids such as cholesterol, phospholipids, or micelles comprised of surfactant such as, for example, sodium dodecylsulfate, octylphenolpolyoxyethylene glycol, or sorbitan mono-oleate.
• the prodrugs bind to the lipid bilayer membrane ofthe liposome with high affinity.
• the liposome bound prodrug can preferably intercalate between the acyl chains of the lipid.
• the lactone ring of the camptothecin-derivative, membrane-bound prodrug is thereby removed from the aqueous environment inside and outside of the liposome and thus protected from hydrolysis.
• the liposome-bound drug is protected from hydrolysis, the antitumor activity ofthe drug is preserved.
• camptothecin prodrugs which have a lower affinity for the liposome membrane and thus disassociate from the liposome membrane to reside in the interior of liposome, the pH ofthe interior ofthe liposomes may be reduced thereby preventing hydrolysis of such camptothecin-derivative prodrugs.
• micelles have also been used to deliver medications to patients, (Brodin et al., Acta Pharm. Suec. 19267-284 (1982)) and micelles have been used as drug carriers and for targeted drug delivery, (D. D. Lasic, Nature 335: 279-280 (1992); and, Supersaxo et al., Pharm. Res.8: 1286-1291 (1991)), including cancer medications, (Fung et al., Biomater. Artif. Cells. Artif. Organs 16: 439 et. seq. (1988); and Yokoyamaet al., Cancer Res. 51: 3229-3236 (1991)), all of which are incorporated herein in their entireties by reference.
• the liposomes and/or micelles of the present invention containing the camptothecin- derivative prodrugs can be administered to a cancer patient.
• the liposomes and/or micelles are carried by the circulatory system to the cancer cells where the membrane ofthe vesicle fuses to the membrane ofthe cancer cell thereby releasing the camptothecin-derivative prodrug to the cancer cell, or where the liposomes and/or micelles remain adjacent to the cancer cells, the camptothecin- derivative prodrug diffuses from the liposomes and/or micelles to be taken up by the cancer cells.
• lipid or mixture of lipids which forms liposomes and/or micelles is suitable for use in the present invention.
• the liposomes and/or micelles may be coated with polyethyleneglycol or GM j
• micelles may be composed of lipid, such as phospholipid, and mixtures of lipids. Also, micelles may be composed of both lipid and a suitable surfactant.
• liposomes and micelles are described in U.S. Patent Nos. 5,552, 156, and 5,736, 156, which are herein incorporated in their entireties by reference.
• a preferred group of liposomal delivery systems which may be used in accordance with the present invention include those described in U.S. Patent Nos.5,552,156 and 5,736,156, which are herein incorporated in their entireties by reference.
• Other liposomal delivery systems which may be employed in accordance with the present invention include liposomes containing active agents aggregated with lipids or surfactants as described in U.S.
• Patent Nos.5,827,533 and 5,882,679 lipid vesicles formed with alkyl ammonium fatty acid salts as described in U.S. Patent No. 5,874,105; liposomes for encapsulating active agent dry powder compositions as described in U.S. Patent No. 5,783,211; liposomal drug delivery systems for topical patches as described in U.S. Patent No. 5,718,914; the liposomes described in U.S. Patent No. 5,631,237; the liposome and lipid complex compositions described in U.S. Patent Nos. 5,549,910 and 5,077,057; the liposomes used for sustained release of steriodial drugs as described in U.S. Patent No.
• the present invention also inhibits topoisomerase I in mammals be administering an effective amount of one ofthe above-identified compounds using, for instance, the amounts described above.
• one of the most important advantages provided by the present invention relates to the relatively low or no apparent overall toxicity ofthe compounds administered in accordance with the teachings herein. Overall toxicity can be judged using various criteria. For example, loss of body weight in a subject over 10%> ofthe initially recorded body weight (i.e., before treatment) can be considered as one sign of toxicity.
• 13 C 7.9(C19, 13.2(C40-methyl carbon), 25.5, 29.5, 3.15(C18, C23, C25), 49.2(C29-methoxy carbon), 50.6(C5), 61.4(C17), 67.2(C20), 97.0(C14), 100.8, 112.0, 112.1, 114.5, 121.0, 125.8, 127.0, 128.2, 129.1, 130.5, 131.0, 131.5, 133.6, 135.8, 136.5, 139.5, 145.0, 145.5, 145.6, 148.5, 154.5, 155.8, 156.9, 157.0(C2, C3, C6-C16a,C26-C40), 166.5, 167.5, 170.5(C21, C22, C24).

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