US20010031761A1 - Derivatives of camptothecin and methods of treating cancer using these derivatives - Google Patents
Derivatives of camptothecin and methods of treating cancer using these derivatives Download PDFInfo
- Publication number
- US20010031761A1 US20010031761A1 US09/748,455 US74845500A US2001031761A1 US 20010031761 A1 US20010031761 A1 US 20010031761A1 US 74845500 A US74845500 A US 74845500A US 2001031761 A1 US2001031761 A1 US 2001031761A1
- Authority
- US
- United States
- Prior art keywords
- compound
- group
- cpt
- camptothecin
- mice
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- GKBHLSYNQPRWAE-UHFFFAOYSA-N C1CC1.C1CCCCC1.C1CO1.CC1CO1 Chemical compound C1CC1.C1CCCCC1.C1CO1.CC1CO1 GKBHLSYNQPRWAE-UHFFFAOYSA-N 0.000 description 6
- KSMZOYDIYLZOPM-JOCHJYFZSA-N CC(=O)O.CC[C@@]1(C)C(=O)OCC2=C1C=C1C3=NC4=C(C=C3CN1C2=O)C(C)=CC=C4 Chemical compound CC(=O)O.CC[C@@]1(C)C(=O)OCC2=C1C=C1C3=NC4=C(C=C3CN1C2=O)C(C)=CC=C4 KSMZOYDIYLZOPM-JOCHJYFZSA-N 0.000 description 4
- LBSFGIWWKVFROL-RHTCVXHSSA-N *.*.*.B.C.CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1.[2HH] Chemical compound *.*.*.B.C.CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1.[2HH] LBSFGIWWKVFROL-RHTCVXHSSA-N 0.000 description 1
- ZAJNGDIORYACQU-UHFFFAOYSA-N CCCCCCCCC(C)=O Chemical compound CCCCCCCCC(C)=O ZAJNGDIORYACQU-UHFFFAOYSA-N 0.000 description 1
Images
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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
wherein when R2 is H, R1 is a C2-C4 alkyl group, a C6-C15 alkyl group, a C3-C8 cycloalkyl group, a C2-C15 alkenyl group or a C2-C15 epoxy group; and when R2 is a nitro group, R1 is a C1-C15 alkyl group, a C2-C15 alkenyl group, a C3-C8 cycloalkyl group, or an epoxy group. Processes for making these derivatives and for using them in cancer treatment are also disclosed.
Description
- This application is a continuation-in-part of U.S. patent application Ser. No. 08/594,235 filed Jan. 30, 1996, and PCT Application No. PCT/US97/01728 filed Jan. 29, 1997, both of which are incorporated by reference herein.
- The present invention is directed to derivatives of camptothecin, preferably having low toxicity, and to the use of these derivatives for cancer treatment. The disclosures of all documents referred to in this application are incorporated herein in whole by reference.
-
- 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 α-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. Earlier data for the antitumor activity of camptothecin were obtained by employing experimentally transplanted malignancies such as leukemia L 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 (Gottlieb et al, Cancer Chemother. Rep. 54, 461, 1970, and 56, 103, 1972, Muggia et al, Cancer Chemother. Rep. 56, 515, 1972, Moertel et al, Cancer Chemother. Rep. 56, 95, 1972, and Schaeppi et al, Cancer Chemother. Rep. 5:25, 1974). These results caused the discontinuation of phase II trials. Continued evaluation of this agent showed that the sodium carboxylate salt is only 10% as potent as the native camptothecin with the closed lactone ring intact (Wall et al, In International Symposium on Biochemistry And Physiology of The Alkaloids, Mothes et al, eds, Academie—Verlag, Berlin, 77, 1969, Giovanella et al, Cancer res. 51, 3052, 1991). In addition, important parameters for antitumor activity in the camptothecin family have been established (Wall et al, Ann. Rev., Pharmacol. Toxicol. 17, 117, 1977). These results indicate that intact lactone ring E and α-hydroxyl group are essential for antitumor activity.
- In 1989, Giovanella et al. found that some of the non-water soluble derivatives of camptothecin have high antitumor activity against xenograft of human tumors (Giovanella et al.,Science, 246, 1046, 1989). It has also been shown that administration of camptothecin with closed lactone ring is superior to injections of water-soluble carboxylate salt (Giovanella et al, Cancer Res., 51, 3052, 1991). These findings further confirmed the importance of the intact lactone ring.
- Clearly, there is a need to modify 20(S)-camptothecin (“CPT”) to enable the lactone form to stay longer in the body while retaining the structural elements (i.e. 20-hydroxyl and lactone ring E) which are essential for its antitumor activity.
- Ring opening of CPT leads to much more potent anticancer activity in mice than in humans. In effect, CPT administered intramuscularly (“i.m.”), subcutaneously (“s.c.”), and intrastomach (“i.s.”) has proved to be a very potent anticancer agent against human tumors in mice, i.e., when growing as xenotransplants in nude mice (Giovanella et al, Cancer Res. 51:3052, 1991). However, when tumors were treated with CPT in humans, a lower degree of anticancer activity in humans, than in mice, was exhibited (Stehlin et al., In Camptothecins: New Anticancer Agents, 1995, CRC Press, pp. 59-65).
- The same phenomenon was observed with other CPT derivatives. In mice, 9-nitrocamptothecin (“9NC”) has proven to be 2-3 times more potent than CPT against human tumor xenografts causing the total eradication of all the human malignancies treated (Pantazis et al., Cancer Res. 53:1577, 1993; Pantazis et al., Int. J. Cancer 53:863, 1995).
- Pharmacological studies demonstrated that the majority (57%) of the 9NC drug present in the plasma after i.s. administration is in the closed lactone form (FIG. 3). Pharmacological studies on the plasma levels of 9NC after oral administration to Phase I clinical trial parents demonstrate that, on average, only˜3% of the drug present is in the closed lactone form (FIGS. 4 and 5).
- In perfect agreement with such findings, the clinical responses in this group of patients, although higher than those obtained with CPT are still a far cry below the results obtained in mice (32/32 complete tumor regressions in mice versus 2/32 in humans). Clearly, again there is a pressing need for a modification which will slow and delay the lactone ring opening upon its entrance into the blood circulation.
- A number of attempts have made to provide more active derivatives of camptothecin, but none of these compounds has been disclosed to be able to delay the opening of the lactone ring E.
- Accordingly, it is an object of the present invention to provide new CPT derivatives which are effective antitumor agents, preferably useful for the oral and intramuscular routes of drug administration.
- It is another object of the present invention to provide new active CPT derivatives which sustain the opening of the lactone ring E, which makes the antitumor activity last longer than its mother analog, CPT.
- It is still another object of the present invention to provide new CPT derivatives which retain significant antitumor activity as does the mother compound, CPT, and have much lower toxicity than its mother compound.
- It is still another object of the present invention to provide new CPT derivatives possessing good absorbability in the living body.
- It is a further object of the present invention to provide new CPT derivatives which retain the lactone ring E and the 20-hydroxyl group intact, which are important for antitumor activity.
- It is still a further object of the present invention to provide a method for preparing CPT derivatives.
- Additional objects and advantages of the present invention will be set forth in part in the description which follows, and in part will be apparent from the description, or may be learned by practice of the present invention. The objects and advantages of the present invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
-
- wherein R2 is H or NO2, and R1 is a C2-C4 alkyl group, a C6-C15 alkyl group, a C3-C8 cycloalkyl group, a C2-C15 alkenyl group, or an epoxy group when R2 is H; and R1 is a C1-C15 alkyl group, a C1-C15 alkenyl group, a C3-C8 cycloalkyl group, or an epoxy group when R2 is NO2.
- The invention also relates to a method for treating malignant tumors in a mammal and comprises administering an effective amount of one or more of the above compounds.
- FIG. 1 is a graph showing the presence of CPT in the closed lactone form in mice after intrastomach administration.
- FIG. 2 is a graph showing the amount of CPT and its closed lactone form in a human after oral administration.
- FIG. 3 is a graph of the amount of 9-nitrocamptothecin and its closed lactone ring form in a mouse after oral administration.
- FIGS. 4 and 5 show the amount of 9-nitrocamptothecin and its closed lactone ring in clinical trial patients who received the dosage by oral administration.
- FIG. 6 is a graph representing the antitumor activity of camptothecin 20(S) propionate in an implanted human breast carcinoma CLO in nude mice.
- FIG. 7 is a graph showing the presence of camptothecin 20(S) propionate and its closed lactone ring form in human plasma after oral administration.
- FIG. 8 is a graph showing the presence of 9-nitrocamptothecin-20-O-propionate in a patient who received the compound orally.
- FIG. 9 is a graph which shows the results obtained for SW48 colon carcinoma in nude mice treated 5 times a week with a CPT derivative of the present invention at the dosage of 20 mg/kg by intrastomach means.
- FIG. 10 is a graph which shows the results obtained for BRO melonoma in nude mice treated with a CPT derivative of the present invention at the dosage of 20 mg/kg by intrastomach means.
- FIG. 11 is a graph which shows the results obtained for BRE stomach carcinoma in nude mice treated with a CPT derivative of the present invention at a dosage of 10 and 20 mg/kg respectively by intrastomach means.
- FIG. 12 is a graph which shows the results obtained for DOY lung carcinoma in nude mice treated with CPT derivative of the present invention at a dosage of 10 and 20 mg/kg respectively by intrastomach means.
- FIG. 13 is a graph which shows the results obtained for 2774 ovarian carcinoma in nude mice treated with a CPT derivative of the present invention at a dosage of 10 and 20 mg/kg respectively by intrastomach means.
- FIG. 14 is a graph which shows the results obtained for McC colon carcinoma in nude mice treated with a CPT derivative of the present invention at a dosage of 20 mg/kg by intrastomach or intramuscular means.
- FIG. 15 is a graph which shows the results obtained for SQU colon carcinoma in nude mice treated with a CPT derivative of the present invention at a dosage of 10 mg/kg by intrastomach or intramuscular means.
- FIG. 16 is a graph which shows the results obtained for CLO breast carcinoma in nude mice treated with a CPT derivative of the present invention at a dosage of 8 mg/kg by intramuscular means.
- FIG. 17 sets forth the chemical structures of several CPT derivatives used in experiments.
- FIG. 18 shows the results of flow cytometry indicating treatment time, cell number, and DNA content for 20(S) CPT and CPT derivatives.
- FIG. 19 also shows a flow cytometry analysis for 20(S) CPT and CPT derivatives reflecting treatment time, cell number, and DNA content.
- FIG. 20 is a set of graphs showing the results obtained for breast carcinoma in nude mice treated with CPT derivatives by intrastomach means.
- The metabolism studies of camptothecin in human plasma carried out in the laboratory showed that the only metabolite detected is the ring-opened sodium carboxylate salt which is toxic and inactive. The measurement of pharmacokinetics for CPT in human plasma indicates that the half-life time of the drug with lactone intact is 30 min. These results implies that the drug will lose 90% of its activity and produce a lot of toxicities in very short time after the patients take it.
- Comparative pharmacological studies in mice and humans have demonstrated that in mice the majority of the CPT present in the plasma after intrastomach administration is of the closed lactone form (FIG. 1), approximately 54% of the area under the curve. In humans, on the contrary, only about 0.4% of the area under the curve after oral administration of CPT is in the form of closed ring lactone (FIG. 2).
- This difference between a mouse and a human is caused by the fact that although the blood pH of the mouse and human are the same, i.e., 7.4, the human albumin, which catalyzes the conversion of CPT into its sodium salt is˜100 times more efficient in this process than mouse albumin (Mi and Burke, Biochem. 33:12540, 1994).
- According to the present invention, CPT is converted into more lipo-soluble molecules, hereinafter, also called prodrugs. When taken orally by patients, the prodrugs are rapidly introduced into the bloodstream of the patients and are readily converted to the parent compound in the body.
- Conversion of the 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 by which the mother camptothecin is released, which prevents CPT from precipitating in the bloodstream.
- In an attempt to synthesize new CPT derivatives with extrumely reduced toxicity, while maintaining the inherent antitumor activity, the present inventors have performed an acylation reaction of camptothecin with various organic acids, organic acid chlorides, and organic acid anhydrides. A number of new camptothecin derivatives have been obtained. They are characterized by the formula I as shown below:
-
-
- The analogues of 9-nitrocamptothecins are prepared by the acylation of 9-nitrocamptothecin with organic anhydrides. All epoxy derivatives can be prepared by the reactions of the corresponding alkenyl esters of the present invention with m-chloroperoxy benzoic acid in benzene at room temperature.
- The preferred derivatives display significant antitumor activity with much lower toxicity than their parent camptothecin, CPT. The animal experimental data for these new derivatives were collected. Camptothecin 20(S) propionate (where R1 is ethyl and R2 is H) is designated as
Prodrug 2 and taken as a example to disclose some in vivo experimental data. FIG. 6 represents the antitumor activity of this compound in different doses against the implanted human breast carcinoma (CLO) in nude mice. Table 1 represents the toxicity of this compound against nude mice with different doses. The change of body weight of mice is recorded with the time. There were no losses of mice body weights during the test time period.TABLE 1 The Changes of Body Weights of Mice during The Test Time Period Dose (mg/kg) Time (days)/Body weight (gms) Control 21/32.7 27/33.5 34/34.4 41/35.2 48/35.0 56/36.7 5 21/33 27/33.7 34/34.3 41/33.5 48/32.9 56/33.2 6 21/32.9 27/33.4 34/33.8 41/33.5 48/34.0 56/32.2 7 21/30.8 27/31.7 34/30.6 41/31.1 48/31.6 56/31.5 8 21/32.9 27/34.1 34/34.0 41/33.4 48/33.9 56/33.2 - The measurement of pharmacokinetics for
Prodrug 2, camptothecin 20(S) propionate, shows that the lactone ring remained intact in human plasma much longer than its mother camptothecin, CPT. Table 2 represents this result.TABLE 2 Comparison of Lactone % of 20(S) Propionate and Lactone % of Camptothecin in Human Plasma Time (Hr.) 0 1 2 4 6 Lactone % for prodrug 2100 86 77 68 56 Lactone % for camptothecin 100 12 0.5 0 0 - As reflected in the tables, augmenting the biological life of the closed lactone ring has been achieved. As shown in FIG. 2, the % of CPT present as closed lactone form in human blood after oral administration is 0.4%. Its analogue, 20-(S) propionate, under similar conditions reaches 2.8% (FIG. 7), an increase of sevenfold. This compound exhibits antitumor activity against human tumor xenografts and an exceptional lack of toxicity, even at enormous doses in mice. Even more striking are the results obtained with 9NC. As shown in FIGS. 4 and 5, after oral administration of this compound, only˜3% of it is present in the plasma as lactone. When its analogue,
Prodrug 11 of the present invention, (where R1 is ethyl and R2 is NO2) was prepared and administered orally to a patient, the lactone form constituted 68.7% of the total, an increase of more than twentyfold (FIG. 8). This compound also exhibited antitumor activity against xenografts of human tumors in nude mice, even higher than the camptothecin analogue,Prodrug 2, where R1 is ethyl and R2 is H and with very low toxicity. - The compounds of the present invention can be made in the following manner. 20(S)-camptothecin or 9-nitrocamptothecin can be reacted with organic anhydrides in pyridine for example. In particular, the anhydride is mixed with pyridine in about a 1:1 ratio to provide a homogeneous solution to which the 20(S)-camptothecin or 9-nitrocamptothecin is added all at once. The mixture is stirred under atmosphere for 24 to 48 hours. At the end of the reaction time, the mixture is poured onto a certain amount of petroleum ether while stirring. The product, precipitated from petroleum ether, is collected by filtration and washed with petroleum ether several times. The purity of the product by this procedure is usually 98% (analyzed by HPLC). This procedure is applicable to all of the compounds of the present invention except where R1 is C7-C15 alkyl or alkenyl, or an epoxy group in Formula (I). The derivative where R1 is a C7-C15 alkyl is obtained by the reaction of camptothecin with nonanoyl chloride in methylene chloride under reflux. The derivative where R1 contains an epoxy moiety is obtained by epoxidation of the compound of the present invention, where R1 is an alkenyl group in Formula (I).
- The compounds of the present invention are effective in treating malignant tumors in a mammal. The compounds of the present invention can be administered in any fashion known to those skilled in the art. Preferably, the compounds are administered intramuscularly, orally, or transdermally.
- As used herein, the term “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.
- In treating or retarding malignant tumors in mammals in accordance with the present invention, the aforedescribed CPT derivatives of the present invention are administered by means known to those skilled in the art, and are preferably administered intramuscularly, transdermally, or orally, using commonly known methods, for example, gelatin capsules for oral administration, as well as formulations such as microsuspensions 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. - As used herein, an “effective amount” of CPT derivatives of the present invention is intended to mean that amount of the 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.
- With mammals, including humans, the effective amounts can be administered on the basis of body surface area. The interrelationship of dosages varies for animals of various sizes and species, and for humans (based on mg/M2 of body surface) is described by E. J. Freireich et al., Cancer Chemother. Rep., 50(4):219 (1966). 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). An effective amount of the camptothecin compounds in the present invention can range from about 12.5 to about 31.3 mg/m2 of body surface per day.
- The preferred effective amounts or dosages of CPT derivatives or prodrugs of the present invention in mice are about 1 to about 4 mg Prodrug/kg of body weight twice a week for an intramuscular route and about 0.75 to about 1.5 mg Prodrug/kg/day for the oral route. Effective amounts or dosages of CPT derivatives or Prodrugs of the present invention in mice are, for instance, about 1.5 mg/kg/week to about 10 mg/kg/week of the Prodrug for the transdermal route. For all of the administering routes, the exact timing of administration of the dosages can be varied to achieve optimal results. Generally, when using
Intralipid 20 as the carrier for the CPT derivative, the actual dosage of CPT derivative reaching the patient will be less. This is due to some loss of the CPT derivative on the walls of the syringes, needles and preparation vessels, which is prevalent with theIntralipid 20 suspension. When a carrier, such as cottonseed oil is used, this above-described loss is not so prevalent because the CPT derivative does not adhere as much to the surfaces of syringes, etc . . . For instance and preferably, it has been found that generally about 2.5 mg Prodrug/kg of body weight twice per week using cottonseed oil, administered by an intramuscular route, will deliver the same amount to the patient as 4.0 mg Prodrug/kg of body weight twice perweek using Intralipid 20 as a carrier. Generally, about 1 mg to about 4 mg of CPT derivative is added to about 0.1 ml to about 1 ml of carrier. - Another important feature of the method provided by the present invention relates to the relatively low or no apparent overall toxicity of the CPT derivatives 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% of the initially recorded body weight (i.e., before treatment) can be considered as one sign of toxicity. In addition, loss of overall mobility and activity and signs of diarrhea or cystitis in a subject can also be interpreted as evidence of toxicity. In one of the examples which follow, the overall toxicity of the camptothecin compounds of the present invention was evaluated.
- The compounds of the present invention may be administered in combination with pharmaceutically acceptable carriers or diluents, such as
Intralipid - Another method of administering the compounds of the present invention is by a transdermal or transcutaneous route. One example of such an embodiment is the use of a patch. In particular, a patch can be prepared with a fine suspension of a compound disclosed in the present application in, for example, dimethylsulfoxide (DMSO), or a mixture of DMSO with cottonseed oil and brought into contact with the skin of the tumor carrying mammals away from the tumor location site inside a skin pouch. Other mediums or mixtures thereof with other solvents and solid supports would work equally as well. The patch can contain the CPT derivative of the present invention in the form of a solution or a suspension. The patch can then be applied to the skin of the patient, for example, by means of inserting it into a skin pouch of the 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 of the mammal. Besides using a skin pouch, any device can be used which ensures the firm placement of the patch in contact with the skin. For instance, an adhesive bandage could be used to hold the patch in place on the skin.
- The present invention will be further clarified by the following example, which is intended to be purely exemplary of the present invention.
-
- In a 100 ml round-bottomed flask were mixed 25 ml propionic acid anhydride and 20 ml pyridine. A homogeneous solution was obtained after shaking for 30 s. To this solution, 2.0 g of starting camptothecin was suspended. The mixture was stirred at 40±5° C. for 48 h. After cooling to room temperature, the reaction mixture was poured onto 400 ml petroleum ether while stirring. The product precipitated from petroleum ether was collected by filtration and washed with 150 ml petroleum ether (50 ml×3). After drying under air for 1 h, a white powder, 2.17 g, was obtained. The purity of the product which was measured by HPLC was 98%.
Yield 94%, mp 250-252° C. (dec.). 1HNMR in CDCl3: 0.98 (3H, t, J=7.5 Hz, 19-methyl protons), 1.17 (3H, t, J 7.51 Hz, 24-methyl protons), 2.12-2.34 (2H, m, 18-methylene protons), 2.48-2.58 (2H, m, 23-methylene protons), 5.29 (2H, s, 5-methylene protons), 5.39-5.72 (2H, dd, J=17.12, 17.12 Hz, 17-methylene protons), 7.23 (1H, s, 14-H), 7.68 (1H, t, J=6.96 Hz, 10-H), 7.84 (1H, t, J=6.96 Hz, 11-H), 7.95 (1H, d, J=8.43 Hz, 9-H), 8.23 (1H, d, J=8.06 Hz, 12-H), 8.40 (1H, s, 7-H); 1H NMR in TFA: 1.18 (3H, t, J=7.5 Hz, 19-methyl protons), 1.32 (3H, t, J=7.30 Hz, 24-methyl protons), 2.30-2.80 (4H, m, 18-and 23-methylene groups), 5.60-6.10 (4H, s+dd, s at 5.86 for 5-methylene protons, dd with J=18.96, 18.32 Hz for 17-methylene protons), 7.99 (1H, s, 14-H), 8.19 (1H, t, J=8.06 Hz, 10-H), 8.20-8.46 (2H, m, 9-Hand 11-H), 8.54 (1H, d, J=8.79 Hz, 12-H), 9.43 (IH, s, 7-H); 13C NMR (TFA): 7.42 (C19), 8.55 (C24), 28.61 (C18), 33.07 (C23), 53.14 (C5), 68.77 (C17), 78.31 (C20), 105.68, 113.19, 117.35, 125.87, 131.23, 131.36, 132.59, 133.40, 139.30, 139.89, 140.78, 144.62, 147.00, 149.43 (C2, C3, C6-C16, C16a), 172.50, 179.76 (C21, C22); mass m/e (relative intensity): 405 [(M+H)+, 100%], 404 (M+, 15%), 331 [(M-CH3CH2COO), 17%], 317 [(M-C2H5COO—CH3+H), 10%], 303 [(M-C2H5COO—CO), 15%], 287 [(M-C2H5COO—CO2), 9%], 261 (9%). - Using 20 ml butyric anhydride, 18 ml pyridine, and 1.61 g camptothecin, the reaction is carried out in the same manner as in Example 1 whereby 1.77 g of the title compound was obtained as a brownish powder, yield 92%, mp 225-227° C. (dec.).1H NMR in CDCl3: 0.98 (6H, t, J=7.51 Hz, 19-and 25-methyl groups), 1.65-1.74 (2H, m, 24-methylene protons), 2.14-2.30 (2H, m, 18-methylene protons), 2.44-2.51 (2H, m, 23-methylene protons), 5.29 (2H, s, 5-methylene protons), 5.38-5.71 (2H, dd, J=17.59, 17.59 Hz, 17-methylene protons), 7.23 (1H, s, 14-H), 7.68 (1H, t, J=8.06 Hz, 10-H), 7.84 (1H, t, J=7.96 Hz, 11-H), 7.95 (1H, d, J=6.96 Hz, 9-H), 8.23 (1H, d, J=8.06 Hz, 12-H), 8.40 (1H, s, 7-H); 1H NMR in TFA: 0.75-1.15 (6H, m, 19-and 25-methyl groups), 1.70-1.80 (2H, m, 24-methylene protons), 2.10-2.80 (4H, m, 18-and 23-methylene groups), 5.50-6.00 (4H, s +dd, s at 5.73 for 5-methylene protons, dd for 17-methylene protons), 7.86 (1H, s, 14-H), 8.05 (1H, s, 10-H), 8.30 (2H, brs, 9-H and 11-H), 8.40 (1H, s, 12-H), 9.30 (1H, s, 7-H); 13C NMR (TFA): 7.23 (C19), 13.20 (C25), 19.20 (C24), 32.91 (C18), 36.91 (C23), 52.96 (C5), 68.58 (C17), 78.00 (C20), 105.56, 113.40, 113.50, 117.00, 117.10, 131.00, 132.40, 133.16, 139.06, 139.15, 140.00, 144.36, 146.90, 149.40 (C2, C3, C6-C16, C16a), 172.50, 178.00 (C12, C22); mass m/e (relative intensity): 419 [(M+H)+, 100%], 331 [(M-C3H7COO), 17%], 303 [(M-C3H7COO—CO), 13%], 287 [(M-C3H7COO—CO2), 8%], 273 (2%), 261 (3%).
- Using 15 ml valeric anhydride, 14 ml pyridine, and 1.51 g starting camptothecin, the reaction was carried out in the same manner as in Example 1 whereby 1.68 g of the title compound was obtained as a gray-white powder, yield 90%, mp 265° C. (dec.).1H NMR in CDCl3: 0.92 (3H, t, J=7.33 Hz, 26-methyl protons), 0.98 (3H, t, J=7.51, 19-methyl protons), 1.37-2.00 (4H, m, 24-and 25-methylene protons), 2.10-2.28 (2H, m, 18-methylene protons), 2.46-2.53 (2H, m, 23-methylene protons), 5.30 (2H, s, 5-methylene protons), 5.38-5.71 (2H, dd, J=17.22, 17.21 Hz, 17-methylene protons), 7.23 (1H, s, 14-H), 7.70 (1H, t, J=6.96 Hz, 10-H), 7.82 (1H, t, J=6.96 Hz, 11-H), 7.95 (1H, d, J=7.32 Hz, 9-H), 8.22 (1H, d, J=8.42 Hz, 12-H), 8.40 (1H, s, 7-H); 1H NMR In TFA: 0.83 (3H, brs, 26-methyl protons), 0.99 (3H, brs, 19-methyl protons), 1.32 (2H, m, 25-methylene protons), 1.60 (2H, m, 24-methylene protons), 2.19-2.58 (4H, m, 18-and 23-methylene protons), 5.49-5.82 (4H, s+dd, s at 5.67 for 5-methylene protons, dd with J=17.58, 18.68 Hz for 17-methylene protons), 7.80 (1H, s, 14-H), 7.99 (1H, s, 10-H), 8.23 (2H, brs, 9-H and 11-H), 8.33 (1H, s, 12-H), 9.24 (1H, s, 7-H); 13C NMR (TFA): 4.48 (C26), 10.37 (C19), 20.23 (C24), 24.98 (C25), 30.15 (C18), 32.03 (C23), 50.20 (C5), 65.82 (C17), 75.36 (C20), 102.84, 109.89, 110.24, 114.06, 114.39, 128.25, 128.39, 129.65, 130.41, 136.30, 137.00, 141.62, 148.57, 149.28 (C2, C3, C6-C16, C16a), 169.00, 176.80 (C21, C22); mass m/e (relative intensity): 433 [(M+H)+, 100%], 331, [(M-C4H9,COO), 17%], 303 [(M-C4H9COO—CO), 13%], 287 [(M-C4H9COO—CO2), 7%], 273 (2%), 261 (4%).
- Using 15 ml heptanoic anhydrides, 13 ml pyridine, and 1.55 g starting camptothecin, the reaction was carried out in the same manner as in Example 1 whereby 2.0 g of the title compound was obtained as a gray-white powder, yield 98%, mp 270° C. (deformed at 210° C.).1H NMR in CDCl3: 0.82 (3H, t, J=7.51 Hz, 28-methyl protons), 0.98 (3H, t, J=7.01 Hz, 19-methyl protons), 1.20-1.80 ( 8H, m, 24-, 25-, 26-, and 27-methylene protons), 2.10-2.30 (2H, m, 18-methylene protons), 2.40-2.60 (2H, m, 23-methylene protons), 5.29 (2H, s, 5-methylene protons), 5.38-5.72 (2H, dd, J=17.69, 17.22 Hz, 17-methylene protons), 7.23 (1H, s, 14-H), 7.68 (1H, t, J=7.30 Hz, 10-H), 7.84 (1H, t, J=7.42 Hz, 11-H), 7.95 (1H, d, J=8.06 Hz, 9-H), 8.22 (1H, d, J=8.32 Hz, 12-H), 8.40 (1H, s, 7-H); 1H NMR in TFA: 0.74 (3H, s, 28 -methyl protons), 0.99 (3H, s, 19-methyl protons), 1.21 (6H, brs, 25-, 26-, and 27-methylene protons), 1.62 (2H, s, 24-methylene protons), 2.10-2.30 (4H, m, 18-and 23-methylene groups), 5.50-6.00 (4H, s+dd, s at 5.67 for 5-methylene protons, dd for 17-methylene protons), 7.80 (1H, s, 14-H), 7.99 (1H, s, 10-H), 8.23 (2H, s, 9-H and 11-H), 9.24 (1H, s, 7-H); 13C NMR (TFA): 8.63 (C19), 14.99 (C28), 24.66 (C27), 27.14 (C26), 31.07 (C24), 33.68 (C25), 34.29 (C18), 36.45 (C23), 54.34 (C5), 69.98 (C17), 79.50 (C20), 106.97, 114.39, 118.55, 127.11, 132.41, 133.79, 134.55, 140.46, 141.11, 142.00, 145.79, 148.14, 150.62, 153.00 (C2, C3, C6-C16, C16a), 180.57, 193.10 (C21, C22); mass m/e (relative intensity): 461 [(M+H)+, 100%], 331 [(M-C6H13COO), 20%], 317 [(M-C6H13COO—CH3+H), 10%], 303 [(M-C6H13COO—CO), 15%], 287 [(M-C6H13COO—CO2), 8%], 273 (2%), 261 (2%).
- To 40 ml methylene chloride in a 100 ml round-bottomed flask were added 5 ml nonanoyl chloride and 2 g starting camptothecin. The mixture was stirred under reflux for 48 h. After the solvent was evaporated by a rotary evaporator, the residue was chromatographically separated with methylene chloride—THF as eluent. The title compound, 169 mg, was obtained as a pale yellow powder, yield 6%, mp 180° C.1H NMR in CDCl3: 0.84 (3H, t, J=6.60 Hz, 30-methyl proyons), 1.02 (3H, t, J=7.69 Hz, 19-methyl protons), 1.20-1.80 (12H, m, 24-29 methylene protons), 2.10-2.38 (2H, m, 18-methylene protons), 2.40-2.60 (2H, m, 23-methylene protons), 5.33 (2H, s, 5-methylene protons), 5.40-5.80 (2H, dd, J=17.22, 17.22 Hz, 17-methylene protons), 7.26 (1H, s, 14-H), 7.71 (1H, t, J=8.06 Hz, 10-H), 7.88 (1H, t, J=8.43 Hz, 11-H), 7.99 (1H, d, J=7.33 Hz, 9-H), 8.26 (1H, d, J=8.79 Hz, 12-H), 8.44 (1H, s, 7-H); 1HNMR in TFA: 0.96 (3H, s, 30-methyl protons), 1.24 (3H, s, 19-methyl protons), 1.38 (10H, brs, 25-29-methylene protons), 1.87 (2H, m, 24-methylene protons), 2.40-2.90 (4H, m, 18-and 23-methylene protons), 5.74-6.07 (4H, s+dd, s at 5.91 for 5-methylene protons, dd with J=17.90, 18.21 Hz for 17-methylene protons), 8.05 (IH, s, 14-11), 8.24 (1H, t, 10-H), 8.48 (2H, m, 9-H and 11-11), 8.57 (1H, d, 12-H), 9.48 (1H, s, 7-11); 13C NMR (TFA): 4.99 (C30), 11.45 (C19), 21.17 (C29), 23.53 (C28), 27.82 (C24, C26-27), 30.52 (C25), 30.63 (C18), 32.80 (C23), 103.28, 110.73, 114.91, 123.47, 128.79, 128.90, 130.14, 130.93, 136.84, 137.46, 138.33, 142.17, 144.47, 146.94 (C2, C3, C6-C16, C16a), 169.98, 176.92 (C21, C22); mass m/e (relative intensity): 489 [(M+H)+, 100%], 33 1[(M-C8H17COO, 23%], 317 [(MC8H17COO—CH3+11), 13%], 303 [(M-C8H17COO—CO), 17%], 287 [(M-C2H17COO—CO2), 8%], 273 (3%), 216 (2%).
- Crotonic anhydride (40 ml) and pyridine (30 ml) were mixed in a 100 ml round-bottomed flask. To this solution, the starting camptothecin (8 g) was added. The mixture was stirred at 90±10° C. for 15 h. After cooling to room temperature, the crude product was precipitated in 1000 ml petroleum ether and collected by filtration. After column chromatography, the compound (3 g) was obtained, yield 31%, mp 218-220° C. (deformed at 155° C.).1H NMR (CDCl3): 1.00 (3H, t, J=7.51 Hz, 19-methyl protons), 1.94 ( 3H, dd, JH25 H24=6.96 HZ, JH25-H23=1.89 Hz, 25-methyl protons), 2.15-2.35 (2H, m, 18-methylene protons), 5.28 (2H, s, 5-methylene protons), 5.38-5.74 (2H, dd, J=17.22, 17.22 Hz, 17-methylene protons), 5.99 (1H, d, J=13.92 Hz, 23-H), 7.05-7.14 (1H, dq, JH24- H23=15.38 Hz, JH24-H25=6.96 Hz, 24-H), 7.24 (1H, s, 14-H), 7.67 (1H, t, J=6.96 Hz, 10-H), 7.83 (1H, t, J=6.96 Hz, 11-H), 7.94 (1H, d, J=7.70 Hz, 9-H), 8.21 (IH, d, J=8.43 Hz, 12-H), 8.39 (1H, s, 7-H); mass m/e (relative intensity): 416 (M+, 20%), 330 [(M-CH3CH═CHCOOH), 100%], 315 [(M-CH3CH═CHCOOH—CH3), 40%], 302 [(M-CH3CH═CHCOOH—CO), 73%], 287 [(M-CH3CH═CHCOOH—CO2+11), 30%], 274 (10%), 259 (9%), 246 (9%), 234 (3%), 218 (5%), 205 (4%), 191 (3%); precise mass: found 416.137, C24H20N2O5 requires 416.137.
- To 50 ml benzene in a 100 ml round-bottomed flask were added 160 mg of the starting compound of Example 6 and 150 mg m-chloroperoxybenzoic acid (57-86%, Aldrich Chemical Co., Milwaukee, Wis.). The mixture was stirred at room temperature for a week. The solvent was removed by a rotary evaporator. The residue was chromatographically separated. The compound (120 mg) was obtained as white powder, yield 72%, mp: the compound deformed at 175° C. and decomposed at 210-213° C.1H NMR (CDCl3): 0.99 (3H, t, J=7.51 Hz, 19-methyl protons), 0.90-1.94 (3H, dd, JH25-H24=6.96 Hz, JH25-H23=1.84 Hz, 25-methyl protons), 2.07-2.33 (2H, m, 18-methylene protons), 5.30 (2H, s, 5-methylene protons), 5.38-5.72 (2H, dd, J=17.59, 17.95 Hz, 17-methylene protons), 5.95-6.02 (IH, dd, JH23-H24=15.75 Hz, JH23-H25=1.83 Hz, 23-H), 7.04-7.12 (1H, dq, JH24-H25=6.59 Hz, JH24-H23=15.38 Hz, 24-H), 7.22 (1H, s, 14-H), 7.75-8.01 (4H, m, 9-12 aromatic protons), 8.78 (1H, d, J=8.06 Hz, 7-H); mass m/e (relative intensity): 432 (M+, 28%), 416 [(M-O), 12%,], 346 [(M-C4H6O2), 100%], 331 [(M-C4H5O3), 53%], 318 [M-C4H6O2—CO), 75%], 303 [(M-C4H5O3—CO), 54%], 287 [(M-C4H5O3—CO2), 27%], 275 (15%), 259 (7%), 246 (8%), 231 (5%), 218 (8%), 205 (10%), 191 (5%); precise mass: found 432.132, C24H20N2O6 requires 432.132.
- Acetic anhydride (3 ml) and pyridine (2 ml) were mixed in a 50 ml round-bottomed flask in which 140 mg 9-nitrocamptothecin was placed. The mixture was stirred at room temperature for 24 h. The mixture was then separated by chromatotron. The title compound, 70 mg, was obtained as a yellow powder, yield 45%, mp 195° C. (deformed at 165° C.).1H NMR (CDCl3): 1.02 (3H, t, J=7.51 Hz, 19-methyl protons), 2.10-2.40 (5H, s+m, s at 2.26 for 23-methyl protons, m for 18-methylene protons), 5.40 (2H, s, 5-methylene protons), 5.41-5.75 (2H, dd, J=17.59, 17.95 Hz, 17-methylene protons), 7.23 (1H, s, 14-H), 7.96 (1H, t, J=6.96 Hz, 11-H), 8.53 (1H, d, J 10.99 Hz, 10-H), 8.58 (1H, d, J=9.98 Hz, 12-H), 9.31 (1H, s, 7-H); mass m/e (relative intensity): 435 (M+, 25%), 375 [(M-CH3COOH), 100%], 360 [(MCH3COOH—CH3), 40%], 347 [(M-CH3COOH—CO), 87%], 332 [(M-CH3COOH—CO—CH3), 37%], 319 (13%), 302 (11%), 291 (10%), 286 (11%), 274 (10%), 258 (4%), 246 (5%), 216 (8%); precise mass: found 435.107, C22H17N3O7 requires 435.107.
- Using 6 ml propionic anhydride, 5 ml pyridine, and 600 mg starting 9-nitrocamptothecin, the reaction was carried out in the same manner as in Example 8. After the reaction, the crude product was allowed to precipitate from 200 ml petroleum ether, collected by filtration, separated by column chromatography, and purified by reprecipitation from 200 ml petroleum ether. The pure compound (500 mg) was obtained as a yellow powder, yield 73%, mp 163° C. (deformed at 155° C.).1H NMR (CDCl3): 0.99.(3H, t, J 7.51 Hz, 19-methyl protons), 1.18 (3H, t, J=7.46 Hz, 24-methyl protons), 2.10-2.30 (2H, m, 18-methylene protons), 2.52-2.70 (2H, m, 23-methylene protons), 5.37 (2h, s, 5-methylene protons), 5.39-5.73 (2H, dd, J=17.58, 17.58 Hz, 17-methylene protons), 7.22 (1H, s, 14-H), 7.93 (1H, t, J=8.06 Hz, 11-H), 8.50 (1H, d, J=10.60 Hz, 10-H), 8.54 (1H, d, J=8.43 Hz, 12-H, 9.28 (1H, s, 7-H); mass m/e (relative intensity): 449 (M+, 28%), 375 [(M-C2H5COOH), 100%], 360 [(M-C2H5COOH—CH3), 35%], 347 [(M-C2H5COOH—CO), 82%], 332 [(M-C2H5COOH—CO—CH3), 26%], 319 (9%), 302 (8%), 291 (7%), 274 (7%), 258 (2%), 245 (2%), 216 (2%); precise mass: found 449.122, C23H19N3O7 requires 449.122. butyrate.
- Using 2 ml butyric anhydride, 2 ml pyridine, and 60 mg starting 9-nitrocamptothecin, the procedure for preparation of the compound was the same as Example 8. The title compound (40 mg) was obtained as a yellow powder, yield 56%, mp 182° C.1H NMR (CDCl3): 0.98 (6H, m, 19-and 25-methyl groups), 1.65-1.70 (2H, m, 24-methylene protons), 2.10-2.40 (2H, m, 18-methylene protons), 2.41-2.60 (2H, m, 23-methylene protons), 5.36 (2H, s, 5-methylene protons), 5.38-5.72 (2H, dd, J=17.59, 17.96 Hz, 17-methylene protons), 7.22 (1H, s, 14-H), 7.92 (1H, t, J=7.52 Hz, 11-H), 8.49 (1H, d, J=10.80 Hz, 10-H), 8.53 (1H, d, J=9.53 Hz, 12-H), 9.27 (1H, s, 7-H); mass m/e (relative intensity): 463 (M+, 14%), 375 [(MC3H7COOH), 100%], 360 [(M-C3H7COOH—CH3), 32%], 347 [(M-C3H7COOH—CO), 78%], 332 [(M-C3H7COOH—CO—CH3), 25%], 319 (9%), 302 (8%), 291 (7%), 274 (7%), 258 (2%), 245 (3%), 216 (5%); precise mass: found 463.137, C24H21LN3O7.
- Identical cultures of HL-60 cells received 0.2 μM of 20(S) CPT or 0.2 μM of a CPT ester (identified in FIG. 17) and cell cycle perturbations and apoptosis were detected by flow cytometry analysis of the relative DNA count using an Epics-Elite laser flow cytometry (Coulter) and analyzed with the Multicycle program (Phoenix Flow Systems). Histograms A,H,Q: untreated cells; B,I,P:+CPT; C,J,Q:+CPT-acetate; D,K,R:+SF6A; E,L,S:+SF6B; F,M,T:+SF6C; G,N,U:+SF6D. The cells were treated for 24 hr (A,B,C,D,E,F,G), 72 hr (H,I,J,K,L,M,N) and 120 hr (O,P,Q,R,S,T,U). See FIG. 17 for meaning of SF6 numbers. G1=G0+G1 cells; G2=G2+M cells; AP=apoptotic cells. The number in parenthesises indicates percent of apoptotic cells in the cell culture. The results are shown in FIG. 18.
- U-937 cells were treated with 0.2 μM of each compound identified in FIG. 17 (including 20(S) CPT), then analyzed by flow cytometry as reflected in FIG. 18. U-937 cells were untreated (AA,FF,KK) or treated with 0.2 μM of CPT-acetate (BB,GG,LL), SF6C (CC,HH,MM) SF6A (DD,II,NN) and SF6B (EE,JJ,OO) for 6 days (BB,CC,DD,EE), 8 days (FF,GG,HH,II,JJ) and 10 days (KK,LL,MM,NN,OO), then subjected to flow cytometry analysis. The results are set forth in FIG. 19.
- Human breast tumors were grown as xenografts in nude mice and were allowed to reach measurable size before treatment with SF6A was initiated. Tumor bearing but untreated mice served as a control (A,F). SF6A was administered intragastrically using doses of 5 mg/kg (B,G), 6 mg/kg (C,H), 7 mg/kg (D,I) and 8 mg/kg (E,J). Maintenance, xenografting, drug treatment and tumor measurements were performed according to procedures described above. Tumor size (in cm3) and body weight (in g) were measured as functions of the treatment period (in days). Tumor size: panels A,B,C,D,E,; and Body weight: panels F,G,H,I,J are shown in FIG. 20.
- Growth inhibition of U-937 cells treated with various CPT esters
- Each identified compound was added to reach a culture of U-937 cell having a final concentration of 0.2 μM. The treatment time was for 120 hr. Growth inhibition in each of the treated cultures was then estimated as a percent of the exponential growth of the cells that was considered 100%. Each estimate was the mean value of four estimates. The results are set forth on the Table below.
Treatment Growth % Untreated cells + 100 ± 2 CPT + 0.0 CPT-acetate + 92 ± 4 SF6A + 31 ± 2 SF6B + 44 ± 2 SF6C + 96 ± 5 SF6D + 92 ± 5 SF6E 94 ± 4 - Determination of SF6A (Prodrug 2) and CPT in liver homogenate
- Mouse liver was homogenized in 4 volumes of ice-cold 0.15 M KCl with the aid of a Dounce homogenizer, then centrifuged at 15000 G for 10 min to remove particulate material. The supernatant, designated as liver homogenate, was transferred into a capped polypropylene tube, mixed with 2 μg SF6A/ml and incubated in a 37° C. water-bath. At the desired times, samples were removed and mixed with 4 volumes of ice-cold ethanol to precipitate proteins. The samples were stored at −20° C. until all were collected. Following centrifugation at 15000 G for 10 min, the clarified supernatants were subjected to analysis for determination of SF6A and CPT lactones by high pressure liquid chromatography (HPLC). The compounds were detected by fluorescence spectroscopy setting the excitation and emission wavelengths at 347 nm and 418 nm, respectively. CPT and SF6A have characteristic retention times of 3.5 min and 13.5 min, respectively. The results are shown in the Table below.
Incubation Amount determined (μg/ml) time SF6A CPT 0 min 1.95 0.00 10 min 2.06 0.00 60 min 2.05 0.00 6 hr 2.05 0.00 24 hr 0.96 0.47 48 hr 0.90 0.30 - Stability of lactone forms of CPT and SF6A in the human plasma
- CPT or SF6A lactone was added to human plasma (1 μg/ml) and an incubation and lactone determination were made as described in Example 15. The lactone amount at each time-point was detected after removing the carboxylate form, and subsequently was calculated as percent of the initial lactone amount added. The results shown in this Table below were derived from one of the three independent experiments performed using different incubation times. The pattern of quantitation of the lactones was similar in all three experiments.
Incubation Percent in plasma time (hr) CPT lactone SE6A lactone 0.0 100.0 100.0 0.5 40.0 NT 1.0 12.0 86.0 2.0 0.5 77.0 4.0 0.0 68.0 6.0 0.0 56.0 27.0 0.0 9.0 - Swiss nude mice of the NIH high fertility strain were bred and maintained pathogen-free in a laboratory. (Giovanella, B. C. and Stehlin, J. S. “Heterotransplantation of human malignant tumors in ‘nude’ thymusless mice. I. Breeding and maintenance of ‘nude’ mice.”J. Natl. Cancer Inst. 51:615-619; 1973.)
- Human malignant carcinomas of the colon, breast, lung, ovary, stomach, pancreas, bladder, prostate, osteosarcoma and malignant melanomas were heterotransplanted directly from a patient into the nude mice and passaged serially. In particular, the tumors CLO, MUR, CAS, SW 48, SQU and BRO as described in Giovanella, B. C., Stehlin, J. S., Shepard, R. C. and Williams, L. J. “Correlation between response to chemotherapy of human tumors in patients and in nude mice. ”Cancer 52:1146-1152; 1983, tumor SCH as described in Heim, S., Mandahl, N., Arheden, K., Giovanella, B. C., Yim, S. O., Stehlin, J. S., Jr. and Mitehman, F. “Multiple karyotypic abnormailites including structural rearrangements of 11P in cell lines from malignant melanomas. ” Cancer Genet. Cytogent, 35:5-20; 1988, and Verschraegen, C., Giovanella, B. C., Mendoza, J. T., Kozielski, A. J. and Stehlin, J. S., Jr. “Specific organ metastases of human melanoma cells injected into the arterial circulation of nude mice. ” Anticancer Res., In Press, and tumor PC-3 as described in Invest. Urol. 17, 16-23, 1979, were used. Tumors DOY and HAR (undifferentiated non-oat cell carcinomas of the lung), DIL (a poorly differentiated squamous cell carcinoma of the lung), SPA (a moderately differentiated adenocarcinoma of the lung), LAN (an undifferentiated carcinoma of the ovary), and BRE (a moderately differentiated adenocarcinoma of the stomach) where heterotransplanted. For the experiments, the tumor tissue was finely minced in complete MEM medium and 0.5 ml of a 10% v/v suspension was inoculated subcutaneously on the upper back of groups of 10-30 mice. When the tumors became palpable and measurable in all the animals, they were divided into groups of 4-8 and treated with the desired dose of the drug in experiment or with the vehicle only for the controls.
- A typical sample preparation for IM-injection or oral
administration using Intralipid 20 or cottonseed oil for example includes the dispersion of the test compound by sonication (3 pulses for 30 seconds each) inIntralipid 20 or cottonseed oil at the standard concentration of 1 mg/ml injections were performed through a 27-gauge needle into the deep muscles of the prosterior legs of the mice twice a week. The animals received up to 70 such injections consecutively without suffering ill effects except for some local fibrosis. Intravenous injections, usingintralipid 20 as the suspending agent, were performed through a 30-gauge needle in one of the trial veins. No pulmonary embolism was observed after over 200 injections. - Oral administration was achieved by mixing the required amounts of
drugs Intralipid 20 or cottonseed oil with a previously autoclaved dietary supplement composed of whole wheat bread saturated with whole milk. The supplement containing the drug was then thoroughly mixed to form a paste. Mice were fed 1 g of dietary supplement containing the required dose of the drugs once a day and then 5 g of autoclaved mouse feed. (At this regime, the animals initially lose about 4 g out of 30 g of body weight, regain 2 g within a few days, and stabilize at this level). This regime can be carried on indefinitely. Actually, the mice fed in this manner (a slightly lower maximum caloric intake) were healthier and longer-lived then mice fed ad lib (Giovanella, B. C., Shepard, R. C., Stehlin, J. S., Venditti, J. M. and Abbott, B. J. “Calorie restriction: Effect on growth of human tumors heterotransplanted in nude mice. ” J. Natl. Cancer Inst. 68:249-257; 1982). Oral administration was accomplished by injecting the mixture of compound with cottonseed oil directly into the stomach (IS). Table 3 below provides some of the results obtained by the treatment with CPT and derivatives thereof, and the description and Figures thereafter provide additional results.TABLE 3 Treat- ment Of # of Prodrug # of Treat- Tumor 2 Animals Results ments Observations Breast Ca IM, 5 3/5 CR 13 Day CLO 2 ×/ wk 2/5 PR 4/5 Controls Alive 4 mg/kg Breast Ca IM, 5 3/5 PR 9 Day 56, 4/5 Alive,CLO 2 ×/ wk 2/5 PR 1 inj. Death, 5 mg/ kg 5/5 Controls Alive IM, 5 2/5 PR 9 4/5 Alive, 1 inj. Death 2 ×/ wk 3/5 PR 6 mg/kg IM, 5 4/5 CR 9 5/5 Alive 2 ×/ wk 1/5 PR 7 mg/kg IM, 5 5/5 CR 9 5/5 Alive 2 ×/ wk 8 mg/kg CLO IM, 3 3/3 CR 26 Day 110, 3/3 Alive,2 ×/ wk 0/4 Controls Alive 12 mg/ kg IM, 4 4/4 CR 26 3/4 Alive 2 ×/ wk 16 mg/ kg IM, 2 2/2 CR 26 2/2 Alive 2 ×/ wk 20 mg/ kg Colon IS. 5+/ 6 6/6 PR 28 Day 62, 6/6 Alive,Ca 2-20 2/6 Controls Alive SW48 mg/kg SQU IS. 5+/ 6 3/6 CR 68 Day 2-30 2/6 PR 1/6 Controls Alive mg/ kg 1/6 NR IS. 5+/ 6 5/6 CR 68 4/6 Alive 2-50/ 1 PR mg/kg IS. 5+/ 6 4/6 CR 68 5/6 Alive 2-70 2/6 PR mg/kg Lung CA IS. 5+/ 4 3/4 CR 65 Day 41, 4/4 Alive,SPA 2-100 1/4 PR 1/4 Controls Alive, mg/kg Day 90 4/4 Alive, 1/4 Controls Alive, Day 107, 1/4 Alive,1/4 Controls Alive Colon CA IS. 5+/ 5 1/5 CR 48 Day HT29 2-100 1/5 PR (injec- 1/5 Controls Alive, mg/ kg 3/5 NR tion Day 116 1/5 Alive, stopped, 0/5 Controls day 82) IS. 5+/ 5 3/5 CR 48 Day 2-200 1/5 PR (injec- Day 116 2/5 Alive mg/ kg 1/5 NR tion stopped day 82) IS. 5+/ 5 4/5 CR 51 Day 2-300 1/5 PR (injec- Day 116 4/5 Alive mg/kg tion stopped, day 87) - FIG. 9 shows the effectiveness of a compound of formula (I) wherein R2 is NO2 and R1 is a ethyl group (hereinafter “Compound IA”), against colon cancer when administered by interstomach means. One group of six nude mice where treated interstomach with 10 or 20 mg/kg body weight Compound IA in cottonseed oil per day for five consecutive days with two day intervals of no treatment (i.e., five days of treatment then two days no treatment, and five day treatment and so on). Another group of six nude mice were treated with 10 or 20 mg/kg body weight Compound IA in the same manner. There were also two control groups of six nude mice each. The designation of “fast” means no food was fed to the mice for at least 12 hours before treatment and the designation of “non-fast” means fed normally. Thus, in this experiment, there were 4 groups of mice with 6 mice in each group. The treatment was ended after 34 days and FIG. 9 shows the results from day 13-34 wherein those mice receiving Compound IA saw a decline in the tumor size while the tumor size in the two control groups continued to increase in size.
- FIG. 10 shows the effectiveness of Compound IA on melanoma where the treatment regimen and number of mice weere the same as in FIG. 9 except there was only one control group and one Compound IA tested group. The treatment was ended after 20 days and as can be seen in FIG. 10, the tumor size in the mice receiving Compound IA decreased in size while the tumor size in the control group increase dramatically.
- FIG. 11 shows the effectiveness of Compound IA on stomach cancer. The dosage regimen and manner of administration are the same as in FIG. 9 except there were 5 mice per group and only one control group. Again, the Compound IA showed a prevention of the growth in the tumor size over a number of days until the experiment was terminated on
day 34. The control group showed a dramatic increase in tumor size and only 2 of the 5 mice survived the 84 day test. - FIG. 12 shows the effectiveness of Compound IA on lung cancer where the same dosage and administration regimen were used as in FIG. 9 except there were 5 mice per group and only one control group. As can be seen from FIG. 12, the tumor size showed a dramatic reduction over the length of the experiment which ended on
day 34. None of the mice in the control group survived the experiment and in fact all mice were dead byday 27. - FIG. 13 shows the effectiveness of Compound IA at high dosages against ovarian cancer. Unlike some other cancers, ovarian cancer was more resistant and thus high concentrations of Compound IA were more effective. The route of administration and the dosage regimen were the same as in FIG. 9 except there were only 5 mice in each group and only one control group was used. The experiment ended after day 41 and all mice survived the experiment in each group. The Compound IA administered in higher dosage amounts was quite effective in reducing the tumor size while the control group and the group receiving the lesser dosage amount of Compound IA showed a steady increase in tumor size throughout the experiment.
- FIG. 14 shows the effectiveness of Compound IA against human colon cancer. One group of 5 mice received Compound IA by intrastomach means as in FIG. 9. The other group of 5 mice received the Compound IA in the same dosage amount by intramuscular means twice a week in the manner described above. As shown in FIG. 14, the tumor size in the groups of mice receiving the Compound IA increased slightly but then stabilized where there was no increase in the tumor size from
day 11 to the end of the experiment which was onday 25. The control, on the other hand, showed a steady increase in tumor size throughout the experiment fromday 6 today 25. - FIG. 15 shows the effectiveness of Compound IA against another form of human colon cancer where there was one control group and one group of 6 mice that received Compound IA intramuscularly and one group of 6 mice that received the Compound IA by intrastomach means in the same manner as in FIG. 14. As shown in FIG. 15, the tumor size of the mice in the groups receiving Compound IA was essentially stabilized throughout the experiment which ended on
day 111 while the tumor size for the control group showed a large increase in size until the mice in the control group all died which was on day 53. - FIG. 16 shows the effectiveness of Compound IB, which is a compound of formula (I) where R2 is hydrogen and R1 is a C3 alkenyl group. FIG. 16 also shows the effectiveness of Compound IB which is a group of formula (I) where R2 is hydrogen R1 is a C3 epoxy ring. In this experiment, a group of six mice received Compound IB in an amount of 8 mg/kg body weight twice a week and another group of six mice received Compound IC, which is a compound of formula (I), where R2 is hydrogen and R1 is a C3 epoxy ring, in the same amount twice a week. In each case, the mice received the drug by intramuscular means in the manner described above. The experiment was ended after day 55. FIG. 16 shows the effectiveness of Compound IB in actually reducing the tumor size of the breast cancer, while Compound IC showed the ability to stabilize the tumor size after a certain amount of time and showed a lower tumor size than the control.
- It is clear from these studies, that CPT derivatives have been demostrated to possess an astonishing level of anitcancer activity. This applies both to the spectrum of tumors covered and to the quality of the responses. The method of the present invention has been able to block growth completely and to totally regress human xenografts of carcinomas (e.g., lung, breast, colon, stomach, pancreas, bladder, prostate, osteosarcoma and ovaries) and malignant melanomas. This has been accomplished without any observable toxicity. Many of the mammals which have been treated continuously for six months have shown no ill effects nor regrowth of the tumor they once carried.
- Other embodiments of the present invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
Claims (38)
2. The compound of , wherein R1 is a linear C2-C4 alkyl group or C6-C15 alkyl group when R2 is H and R1 is a linear C1-C15 alkyl group when R2 is NO2.
claim 1
3. The compound of , wherein R1 is a linear C2-C15 alkenyl group.
claim 1
4. The compound of , wherein R1 is a C2-C15 epoxy group.
claim 1
5. A compound of , wherein R2 is H.
claim 2
6. The compound of , wherein R2 is NO2.
claim 2
7. The compound of , wherein R2 is H.
claim 3
8. The compound of , wherein R2 is NO2.
claim 3
9. The compound of , wherein R2 is H.
claim 4
10. The compound of , wherein R2 is NO2.
claim 4
11. The compound of , wherein R1 is a linear ethyl, propyl, butyl, hexyl or octyl group, and R2 is H.
claim 2
12. The compound of , wherein R1 is ethyl.
claim 11
13. The compound of , wherein R1 is a linear methyl, ethyl or propyl group and R2 is NO2.
claim 2
14. The compound of , wherein R1 is ethyl.
claim 13
15. The compound of , wherein R1 is a C3-C8 cycloalkyl group.
claim 1
16. The compound of , wherein R2 is H.
claim 15
17. The compound of , wherein R2 is NO2.
claim 15
20. A method for treating a malignant tumor in a patient comprising administering a composition comprising an effective amount of the compound of , wherein said malignant tumor is responsive to said composition.
claim 1
21. The method of , wherein R1 is a linear C2-C4 alkyl group or a C6-C15 alkyl group where R2 is H and R1 is a linear C1-C15 alkyl group when R2 is NO2.
claim 20
22. The method of , wherein R1 is a linear C2-C15 alkenyl group.
claim 20
23. The method of , wherein R1 is a C2-C15 epoxy group.
claim 20
24. The method of , wherein R2 is H.
claim 21
25. The method of , wherein R2 is NO2.
claim 21
26. The method of , wherein R2 is H.
claim 22
27. The method of , wherein R2 is NO2.
claim 22
28. The method of , wherein R2 is H.
claim 23
29. The method of , wherien R2 is NO2.
claim 23
30. The method of , wherein R1 is a linear ethyl, propyl, butyl, hexyl or octyl group, and R2 is H.
claim 21
31. The method of , wherein R1 is ethyl.
claim 30
32. The method of , wherein R1 is a linear methyl, ethyl or propyl group and R2 is NO2.
claim 21
33. The method of , wherein R1 is ethyl.
claim 32
34. The method of , wherein R1 is a C3-C8 cycloalkyl group.
claim 20
35. The method of , wherein R2 is H.
claim 34
36. The method of , wherein R2 is NO2.
claim 34
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/748,455 US20010031761A1 (en) | 1996-01-30 | 2000-12-26 | Derivatives of camptothecin and methods of treating cancer using these derivatives |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/594,235 US5731316A (en) | 1996-01-30 | 1996-01-30 | Derivatives of camptothecin and methods of treating cancer using these derivatives |
PCT/US1997/001728 WO1997028165A1 (en) | 1996-01-30 | 1997-01-29 | Derivatives of camptothecin for use in treating cancer |
US09/030,357 US5968943A (en) | 1996-01-30 | 1998-02-25 | Derivatives of camptothecin and methods of treating cancer using these derivatives |
US09/345,062 US6120793A (en) | 1996-01-30 | 1999-06-30 | Methods of treating cancer using these derivatives |
US09/591,232 US6218399B1 (en) | 1996-01-30 | 2000-06-09 | Derivatives of camptothecin and methods of treating cancer using these derivatives |
US09/748,455 US20010031761A1 (en) | 1996-01-30 | 2000-12-26 | Derivatives of camptothecin and methods of treating cancer using these derivatives |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/591,232 Continuation US6218399B1 (en) | 1996-01-30 | 2000-06-09 | Derivatives of camptothecin and methods of treating cancer using these derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
US20010031761A1 true US20010031761A1 (en) | 2001-10-18 |
Family
ID=24378090
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/594,235 Expired - Lifetime US5731316A (en) | 1996-01-30 | 1996-01-30 | Derivatives of camptothecin and methods of treating cancer using these derivatives |
US09/030,357 Expired - Lifetime US5968943A (en) | 1996-01-30 | 1998-02-25 | Derivatives of camptothecin and methods of treating cancer using these derivatives |
US09/345,062 Expired - Lifetime US6120793A (en) | 1996-01-30 | 1999-06-30 | Methods of treating cancer using these derivatives |
US09/591,232 Expired - Lifetime US6218399B1 (en) | 1996-01-30 | 2000-06-09 | Derivatives of camptothecin and methods of treating cancer using these derivatives |
US09/748,455 Abandoned US20010031761A1 (en) | 1996-01-30 | 2000-12-26 | Derivatives of camptothecin and methods of treating cancer using these derivatives |
Family Applications Before (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/594,235 Expired - Lifetime US5731316A (en) | 1996-01-30 | 1996-01-30 | Derivatives of camptothecin and methods of treating cancer using these derivatives |
US09/030,357 Expired - Lifetime US5968943A (en) | 1996-01-30 | 1998-02-25 | Derivatives of camptothecin and methods of treating cancer using these derivatives |
US09/345,062 Expired - Lifetime US6120793A (en) | 1996-01-30 | 1999-06-30 | Methods of treating cancer using these derivatives |
US09/591,232 Expired - Lifetime US6218399B1 (en) | 1996-01-30 | 2000-06-09 | Derivatives of camptothecin and methods of treating cancer using these derivatives |
Country Status (13)
Country | Link |
---|---|
US (5) | US5731316A (en) |
EP (2) | EP1829880A3 (en) |
JP (1) | JP3297877B2 (en) |
CN (1) | CN1107069C (en) |
AT (1) | ATE447576T1 (en) |
AU (1) | AU2005997A (en) |
CA (1) | CA2244698C (en) |
DE (1) | DE69739644D1 (en) |
DK (1) | DK0879236T3 (en) |
ES (1) | ES2332160T3 (en) |
HK (1) | HK1018449A1 (en) |
NO (1) | NO322511B1 (en) |
WO (1) | WO1997028165A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003095461A1 (en) * | 2002-05-06 | 2003-11-20 | The Stehlin Foundation For Cancer Research | Halo-alkyl esters of camptothecins and methods of treating cancer using these compounds |
WO2003095460A1 (en) * | 2002-05-06 | 2003-11-20 | The Stehlin Foundation For Cancer Research | Cascade esters of camptothecins and methods of treating cancer using these compounds |
WO2009055633A1 (en) * | 2007-10-25 | 2009-04-30 | The Christus Stehlin Foundation For Cancer Research | Hydrated crystalline esters of camptothecin for the treatment of cancer |
Families Citing this family (40)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5731316A (en) * | 1996-01-30 | 1998-03-24 | The Stehlin Foundation For Cancer Research | Derivatives of camptothecin and methods of treating cancer using these derivatives |
US6096336A (en) * | 1996-01-30 | 2000-08-01 | The Stehlin Foundation For Cancer Research | Liposomal prodrugs comprising derivatives of camptothecin and methods of treating cancer using these prodrugs |
US6407118B1 (en) | 1996-01-30 | 2002-06-18 | The Stehlin Foundation For Cancer Research | Derivatives of camptothecin and methods of treating cancer using these derivatives |
SG88737A1 (en) | 1996-10-30 | 2002-05-21 | Tanabe Seiyaku Co | S type 2-substituted hydroxy-2-indolidinylbutyric ester compounds and process for preparation thereof |
US5922877A (en) * | 1997-08-05 | 1999-07-13 | The Stehlin Foundation For Cancer Research | Methods of preparing and purifying 9-nitro-20-camptothecin |
USRE38408E1 (en) | 1997-08-05 | 2004-01-27 | The Stehlin Foundation For Cancer Research | Methods of preparing and purifying 9-nitro-20-camptothecin |
US6111107A (en) * | 1997-11-20 | 2000-08-29 | Enzon, Inc. | High yield method for stereoselective acylation of tertiary alcohols |
US6485514B1 (en) | 1997-12-12 | 2002-11-26 | Supergen, Inc. | Local delivery of therapeutic agents |
US6057303A (en) * | 1998-10-20 | 2000-05-02 | Bionumerik Pharmaceuticals, Inc. | Highly lipophilic Camptothecin derivatives |
US6228855B1 (en) * | 1999-08-03 | 2001-05-08 | The Stehlin Foundation For Cancer Research | Aromatic esters of camptothecins and methods to treat cancers |
US6352996B1 (en) * | 1999-08-03 | 2002-03-05 | The Stehlin Foundation For Cancer Research | Liposomal prodrugs comprising derivatives of camptothecin and methods of treating cancer using these prodrugs |
CA2385528C (en) | 1999-10-01 | 2013-12-10 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
US6191119B1 (en) * | 1999-10-15 | 2001-02-20 | Supergen, Inc. | Combination therapy including 9-nitro-20(S)-camptothecin |
US6420378B1 (en) | 1999-10-15 | 2002-07-16 | Supergen, Inc. | Inhibition of abnormal cell proliferation with camptothecin and combinations including the same |
US6777387B2 (en) | 2000-03-31 | 2004-08-17 | Enzon Pharmaceuticals, Inc. | Terminally-branched polymeric linkers containing extension moieties and polymeric conjugates containing the same |
US6756037B2 (en) | 2000-03-31 | 2004-06-29 | Enzon, Inc. | Polymer conjugates of biologically active agents and extension moieties for facilitating conjugation of biologically active agents to polymeric terminal groups |
US6350756B1 (en) | 2001-01-18 | 2002-02-26 | California Pacific Medical Center | Camptothecin derivatives |
US6403604B1 (en) | 2001-03-01 | 2002-06-11 | California Pacific Medical Center | Nitrogen-based camptothecin derivatives |
US6855720B2 (en) | 2001-03-01 | 2005-02-15 | California Pacific Medical Center | Nitrogen-based camptothecin derivatives |
US20040029906A1 (en) * | 2001-07-31 | 2004-02-12 | Michael Christman | Inhibitors of dna polymerase sigma |
US7049322B2 (en) * | 2002-02-21 | 2006-05-23 | Supergen, Inc. | Compositions and formulations of 9-nitrocamptothecin polymorphs and methods of use therefor |
AU2003243380A1 (en) | 2002-06-03 | 2003-12-19 | California Pacific Medical Center | Nitrogen-based homo-camptothecin derivatives |
US20040034050A1 (en) * | 2002-06-03 | 2004-02-19 | Yang Li-Xi | Homo-camptothecin derivatives |
CN100363366C (en) * | 2002-06-27 | 2008-01-23 | 中国科学院上海药物研究所 | Camptothecin derviative and preparation process thereof |
CN100393724C (en) * | 2002-07-12 | 2008-06-11 | 中国医学科学院药物研究所 | 20-esterifiable camptothecine derivative and method for making same and pharmaceutical combination and uses |
US20040047835A1 (en) * | 2002-09-06 | 2004-03-11 | Cell Therapeutics, Inc. | Combinatorial drug therapy using polymer drug conjugates |
US20040204435A1 (en) * | 2003-04-09 | 2004-10-14 | Joachim Liehr | Alternating treatment with topoisomerase I and topoisomerase II inhibitors |
WO2005062985A2 (en) * | 2003-12-23 | 2005-07-14 | American Bioscience, Inc. | Di-ester prodrugs of camptothecin, process for their preparation and their therapeutical applications |
WO2005070936A1 (en) * | 2004-01-09 | 2005-08-04 | Institute Of Mataria Medica, Chinese Academy Of Medical Sciences | 20-esterized camptothecin derivatives, their preparation and the pharmaceutical compositions and the use |
US20060135546A1 (en) * | 2004-12-16 | 2006-06-22 | Jagadevappa Basavaraja | Methods for the purification of 20(S)- camptothecin |
US7875602B2 (en) | 2005-10-21 | 2011-01-25 | Sutter West Bay Hospitals | Camptothecin derivatives as chemoradiosensitizing agents |
US20070167349A1 (en) * | 2005-12-06 | 2007-07-19 | Cell Therapeutics, Inc. | Estrogen cancer therapy |
WO2008021015A2 (en) * | 2006-08-11 | 2008-02-21 | The Christus Stehlin Foundation For Cancer Research | Methods of making esters of camptothecins |
EP2269072B1 (en) | 2008-03-31 | 2017-08-23 | Boston Medical Center Corporation | Predictive marker for topoisomerase i inhibitors |
JP6205095B2 (en) | 2011-11-03 | 2017-09-27 | タイワン リポサム カンパニー、エルティーディー. | Pharmaceutical composition of hydrophobic camptothecin derivative |
US10980798B2 (en) | 2011-11-03 | 2021-04-20 | Taiwan Liposome Company, Ltd. | Pharmaceutical compositions of hydrophobic camptothecin derivatives |
US11467158B2 (en) | 2012-10-29 | 2022-10-11 | Boston Medical Center Corporation | BRCA1 mutations as predictive markers for topoisomerase inhibitions |
CN104163823B (en) * | 2014-04-30 | 2016-03-09 | 浙江工业大学 | A kind of camptothecine and Artesunate conjugate and preparation method thereof and application |
US9675609B2 (en) | 2015-11-11 | 2017-06-13 | Cao Pharmaceuticals Inc. | Nano- and micro-sized particles of 20-camptothecin or derivative thereof and pharmaceutical compositions containing same, and treatment of cancers therewith |
CN105646546B (en) * | 2015-12-29 | 2018-03-02 | 遵义医学院 | The position 20 of camptothecins ester derivant and its antitumor application thereof of acid-sensitive type |
Family Cites Families (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US32518A (en) * | 1861-06-11 | Improvement in city railroads | ||
US3894029A (en) * | 1971-08-26 | 1975-07-08 | Basf Ag | Production of camptothecin and camptothecin-like compounds |
US4399282A (en) * | 1979-07-10 | 1983-08-16 | Kabushiki Kaisha Yakult Honsha | Camptothecin derivatives |
JPS56108787A (en) * | 1980-01-31 | 1981-08-28 | Sato Yakugaku Kenkyusho:Kk | Camptothecin coline salt and its preparation |
US4473692A (en) * | 1981-09-04 | 1984-09-25 | Kabushiki Kaisha Yakult Honsha | Camptothecin derivatives and process for preparing same |
US4399828A (en) * | 1981-10-29 | 1983-08-23 | Kontos Nicholas G | Methods and apparatus for treating work pieces |
US4894456A (en) * | 1987-03-31 | 1990-01-16 | Research Triangle Institute | Synthesis of camptothecin and analogs thereof |
US5106742A (en) * | 1987-03-31 | 1992-04-21 | Wall Monroe E | Camptothecin analogs as potent inhibitors of topoisomerase I |
US5053512A (en) * | 1987-04-14 | 1991-10-01 | Research Triangle Institute | Total synthesis of 20(S) and 20(R)-camptothecin and compthothecin derivatives |
US5180722A (en) * | 1987-04-14 | 1993-01-19 | Research Triangle Institute | 10,11-methylenedioxy-20(RS)-camptothecin and 10,11-methylenedioxy-20(S)-camptothecin analogs |
CA1332413C (en) * | 1987-06-25 | 1994-10-11 | Kabushiki Kaisha Yakult Honsha | Camptothecin derivatives and process for preparing same |
JPS6461482A (en) | 1987-08-31 | 1989-03-08 | Yakult Honsha Kk | Dehydrocamptothecin and production thereof |
US4943579A (en) * | 1987-10-06 | 1990-07-24 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Water soluble prodrugs of camptothecin |
JP2524803B2 (en) * | 1988-03-29 | 1996-08-14 | 株式会社ヤクルト本社 | Novel camptothecin derivative and method for producing the same |
JP2524804B2 (en) * | 1988-03-29 | 1996-08-14 | 株式会社ヤクルト本社 | Novel camptothecin derivative and method for producing the same |
US5225404A (en) * | 1989-11-06 | 1993-07-06 | New York University | Methods of treating colon tumors with tumor-inhibiting camptothecin compounds |
US5552154A (en) * | 1989-11-06 | 1996-09-03 | The Stehlin Foundation For Cancer Research | Method for treating cancer with water-insoluble s-camptothecin of the closed lactone ring form and derivatives thereof |
WO1992005785A1 (en) * | 1990-09-28 | 1992-04-16 | Smithkline Beecham Corporation | Water soluble camptothecin analogues, processes and methods |
US5122383A (en) * | 1991-05-17 | 1992-06-16 | Theratech, Inc. | Sorbitan esters as skin permeation enhancers |
US5126351A (en) * | 1991-01-24 | 1992-06-30 | Glaxo Inc. | Antitumor compounds |
JP3126799B2 (en) * | 1992-03-31 | 2001-01-22 | 第一製薬株式会社 | Optically active camptothecin derivative and method for producing the same |
US5391745A (en) * | 1992-07-23 | 1995-02-21 | Sloan-Kettering Institute For Cancer Research | Methods of preparation of camptothecin analogs |
EP0602361B1 (en) * | 1992-11-17 | 1997-01-22 | C. Rob. Hammerstein GmbH | Backrest articulation for vehicle seat |
US5527913A (en) * | 1993-02-25 | 1996-06-18 | The Stehlin Foundation For Cancer Research | Methods for purifying camptothecin compounds |
US5352789A (en) * | 1993-02-25 | 1994-10-04 | The Stehlin Foundation For Cancer Research | Methods for purifying camptothecin compounds |
US5613958A (en) * | 1993-05-12 | 1997-03-25 | Pp Holdings Inc. | Transdermal delivery systems for the modulated administration of drugs |
GB9319944D0 (en) * | 1993-09-28 | 1993-11-17 | Erba Carlo Spa | Process for the preparation of 9-amino camptothecin |
US5646159A (en) * | 1994-07-20 | 1997-07-08 | Research Triangle Institute | Water-soluble esters of camptothecin compounds |
US5505958A (en) * | 1994-10-31 | 1996-04-09 | Algos Pharmaceutical Corporation | Transdermal drug delivery device and method for its manufacture |
US5785991A (en) * | 1995-06-07 | 1998-07-28 | Alza Corporation | Skin permeation enhancer compositions comprising glycerol monolaurate and lauryl acetate |
US6096336A (en) | 1996-01-30 | 2000-08-01 | The Stehlin Foundation For Cancer Research | Liposomal prodrugs comprising derivatives of camptothecin and methods of treating cancer using these prodrugs |
US5731316A (en) * | 1996-01-30 | 1998-03-24 | The Stehlin Foundation For Cancer Research | Derivatives of camptothecin and methods of treating cancer using these derivatives |
US5922877A (en) | 1997-08-05 | 1999-07-13 | The Stehlin Foundation For Cancer Research | Methods of preparing and purifying 9-nitro-20-camptothecin |
-
1996
- 1996-01-30 US US08/594,235 patent/US5731316A/en not_active Expired - Lifetime
-
1997
- 1997-01-29 CA CA002244698A patent/CA2244698C/en not_active Expired - Fee Related
- 1997-01-29 AT AT97904193T patent/ATE447576T1/en active
- 1997-01-29 EP EP07007232A patent/EP1829880A3/en not_active Withdrawn
- 1997-01-29 EP EP97904193A patent/EP0879236B1/en not_active Expired - Lifetime
- 1997-01-29 JP JP52391297A patent/JP3297877B2/en not_active Expired - Fee Related
- 1997-01-29 AU AU20059/97A patent/AU2005997A/en not_active Abandoned
- 1997-01-29 ES ES97904193T patent/ES2332160T3/en not_active Expired - Lifetime
- 1997-01-29 DE DE69739644T patent/DE69739644D1/en not_active Expired - Lifetime
- 1997-01-29 DK DK97904193.6T patent/DK0879236T3/en active
- 1997-01-29 CN CN97193264A patent/CN1107069C/en not_active Expired - Fee Related
- 1997-01-29 WO PCT/US1997/001728 patent/WO1997028165A1/en active Application Filing
-
1998
- 1998-02-25 US US09/030,357 patent/US5968943A/en not_active Expired - Lifetime
- 1998-07-29 NO NO19983487A patent/NO322511B1/en not_active IP Right Cessation
-
1999
- 1999-06-30 US US09/345,062 patent/US6120793A/en not_active Expired - Lifetime
- 1999-08-10 HK HK99103455A patent/HK1018449A1/en not_active IP Right Cessation
-
2000
- 2000-06-09 US US09/591,232 patent/US6218399B1/en not_active Expired - Lifetime
- 2000-12-26 US US09/748,455 patent/US20010031761A1/en not_active Abandoned
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003095461A1 (en) * | 2002-05-06 | 2003-11-20 | The Stehlin Foundation For Cancer Research | Halo-alkyl esters of camptothecins and methods of treating cancer using these compounds |
WO2003095460A1 (en) * | 2002-05-06 | 2003-11-20 | The Stehlin Foundation For Cancer Research | Cascade esters of camptothecins and methods of treating cancer using these compounds |
US6699875B2 (en) | 2002-05-06 | 2004-03-02 | The Stehlin Foundation For Cancer Research | Cascade esters of camptothecins and methods of treating cancer using these compounds |
US6703399B2 (en) | 2002-05-06 | 2004-03-09 | The Stehlin Foundation For Cancer Research | Halo-alkyl esters of camptothecins and methods of treating cancer using these compounds |
WO2009055633A1 (en) * | 2007-10-25 | 2009-04-30 | The Christus Stehlin Foundation For Cancer Research | Hydrated crystalline esters of camptothecin for the treatment of cancer |
US7572803B2 (en) | 2007-10-25 | 2009-08-11 | The Christus Stehlin Foundation For Cancer Research | Hydrated crystalline esters of camptothecin |
RU2483071C2 (en) * | 2007-10-25 | 2013-05-27 | Дзе Кристус Стелин Фаундейшн Фор Кэнсер Рисерч | Hydrated crystalline camptothecin esters for treating cancer |
CN101730701B (en) * | 2007-10-25 | 2013-05-29 | 克里斯特斯斯特林癌症研究基金会 | Hydrated crystalline esters of camptothecin for the treatment of cancer |
Also Published As
Publication number | Publication date |
---|---|
HK1018449A1 (en) | 1999-12-24 |
ATE447576T1 (en) | 2009-11-15 |
CN1107069C (en) | 2003-04-30 |
NO983487L (en) | 1998-07-29 |
EP0879236A1 (en) | 1998-11-25 |
CA2244698C (en) | 2004-10-05 |
NO983487D0 (en) | 1998-07-29 |
US5968943A (en) | 1999-10-19 |
JP2000516909A (en) | 2000-12-19 |
ES2332160T3 (en) | 2010-01-27 |
AU2005997A (en) | 1997-08-22 |
DK0879236T3 (en) | 2010-01-18 |
CN1214686A (en) | 1999-04-21 |
WO1997028165A1 (en) | 1997-08-07 |
EP1829880A3 (en) | 2008-03-26 |
JP3297877B2 (en) | 2002-07-02 |
EP1829880A2 (en) | 2007-09-05 |
CA2244698A1 (en) | 1997-08-07 |
US6120793A (en) | 2000-09-19 |
DE69739644D1 (en) | 2009-12-17 |
EP0879236B1 (en) | 2009-11-04 |
US6218399B1 (en) | 2001-04-17 |
NO322511B1 (en) | 2006-10-16 |
US5731316A (en) | 1998-03-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6218399B1 (en) | Derivatives of camptothecin and methods of treating cancer using these derivatives | |
US6352996B1 (en) | Liposomal prodrugs comprising derivatives of camptothecin and methods of treating cancer using these prodrugs | |
US6096336A (en) | Liposomal prodrugs comprising derivatives of camptothecin and methods of treating cancer using these prodrugs | |
US6228855B1 (en) | Aromatic esters of camptothecins and methods to treat cancers | |
JP4584538B2 (en) | Nitrogen-based camptothecin derivatives | |
US6407118B1 (en) | Derivatives of camptothecin and methods of treating cancer using these derivatives | |
US6699875B2 (en) | Cascade esters of camptothecins and methods of treating cancer using these compounds | |
Yang et al. | Novel camptothecin derivatives. Part 1: oxyalkanoic acid esters of camptothecin and their in vitro and in vivo antitumor activity | |
US6703399B2 (en) | Halo-alkyl esters of camptothecins and methods of treating cancer using these compounds | |
JP4990620B2 (en) | 7-substituted camptothecins and camptothecin analogs and methods for their preparation | |
Cao et al. | Structure-activity relationship of alkyl 9-nitrocamptothecin esters | |
US7071204B2 (en) | Camptothecin analogs having an E-ring ketone | |
EP0778024B1 (en) | Oral or intramuscular treatment of pancreatic cancer with water-insoluble S-Camptothecin of the closed lactone ring form |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |