WO1991004260A2 - Analogues de 10,11-methylenedioxy-20(rs)-camptothecine et de 10,11-methylenedioxy-20(s)-camptothecine - Google Patents

Analogues de 10,11-methylenedioxy-20(rs)-camptothecine et de 10,11-methylenedioxy-20(s)-camptothecine Download PDF

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WO1991004260A2
WO1991004260A2 PCT/US1990/005172 US9005172W WO9104260A2 WO 1991004260 A2 WO1991004260 A2 WO 1991004260A2 US 9005172 W US9005172 W US 9005172W WO 9104260 A2 WO9104260 A2 WO 9104260A2
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camptothecin
alkyl
salt
amino
methylenedioxy
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PCT/US1990/005172
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WO1991004260A3 (fr
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Monroe E. Wall
Mansukh C. Wani
Allan W. Nicholas
Govindarajan Manikumar
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Research Triangle Institute
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Priority to KR1019920700585A priority Critical patent/KR0180245B1/ko
Priority to CA002066780A priority patent/CA2066780C/fr
Publication of WO1991004260A2 publication Critical patent/WO1991004260A2/fr
Publication of WO1991004260A3 publication Critical patent/WO1991004260A3/fr

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    • 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

Definitions

  • the present invention relates to camptothecin analogs which are useful as antitumor agents. More specifically, the invention is directed to water-insoluble and
  • 10,11-methylenedioxy-20(S)-camptothecin These compounds are collectively referred to as 10,11-MDOCPT below.
  • Camptothecin is a pentacyclic alkaloid initially isolated from the wood and bark of Camptotheca acuminata by Wall et al (M.E. Wall, M.C. Wani, C.E. Cook, K.H. Palmer, A.T. McPhail, and G.A. Sim, J. Am. Chem. Soc.. 94:388
  • Camptothecin is highly biologically active and
  • camptothecin displays strong inhibitory activity toward the biosynthesis of nucleic acids. Additionally, camptothecin exhibits potent antitumor activity against experimentally
  • camptothecin and camptothecin analogs are known. These synthetic methods include (i) methods in which naturally occurring
  • camptothecin is synthetically modified to produce a number of analogs and (ii) totally synthetic methods.
  • Water-solubility is an important criterion in
  • camptothecin analogs known in the art have relatively poor water-solubility.
  • one object of the present invention is to provide camptothecin analogs containing the
  • the invention is directed to compounds which are derivatives of
  • 10,11-MDO-20(RS)-CPT and 10,11-methylenedioxy-20(S)-camptothecin (also called 10,11-MDO-20(S)-CPT) which are highly active camptothecin analogs.
  • Figure 1 shows the structure of CPT and derivatives thereof.
  • camptothecin analog is one of the most potent
  • 10,11-MDO-20(S)-CPT is also very potent in the L-1210 leukemia in vivo life prolongation assay.
  • the synthesis of 10,11-MDO-20(RS)-CPT is known and described in Wani et al, J. Med. Chem., 29 (11), 2358-2363 (1986) and in U.S. 4,894,456. Novel analogs of camptothecin have been prepared, all of which contain the 10, 11-methylenedioxy moiety. The structures of these compounds are shown below.
  • R is NO 2 , NH 2 , N 3 , hydrogen, halogen (F, Cl, Br, I), COOH, OH, O-C 1-3 alkyl, SH, S-C 1-3 alkyl, CN, CH 2 NH 2 , NH-C 1-3 alkyl, CH 2- NH-C 1-3 alkyl, N(C 1-3 alkyl) 2 , CH 2 N(C 1-3 alkyl) 2 , O-,NH- and
  • Z in the structure shown above is H or C 1-8 alkyl with the proviso that R and Z are not both hydrogen.
  • Z is H.
  • the structure shown above is understood to represent all isomers having the chemical structure indicated. The structure shown above, therefore, represents both
  • 9-substituted-10, 11-MDO-20(S) -CPT compounds of the present invention can be synthesized from the 10,11-MDOCPT starting materials described above by preparing a diazonium salt at the 9-position. To prepare the diazonium salts,
  • 10,11-MDO-20(S)-CPT or 10,11-MDO20(RS)-CPT is nitrated to form the corresponding 9-nitro compound. This nitro compound is then reduced to form the corresponding 9-amino compound which is used to prepare the diazonium salt.
  • camptothecin itself, one obtains a mixture of the 12-nitro and 9-nitro-camptothecin analogs with the 12-nitro analog present in considerable excess.
  • the nitration reaction may be conducted using standard conditions for the nitration of aromatic compounds, and is generally conducted by dissolving/suspending the
  • 10,11-MDOCPT in concentrated sulfuric acid with cooling and stirring followed by the addition of a slight excess of concentrated nitric acid. After stirring for a period of time sufficient to substantially complete the reaction, the solution is poured into water, ice or a ice/water mixture to provide the desired 9-nitro-l0, 11-MDOCPT compound.
  • Purification can be effected by standard extraction and recrystallization processes.
  • the 9-nitro-10,11-MDOCPT may then be catalytically reduced using hydrogen and a hydrogenation catalyst such as platinum, palladium, etc., or other conventional
  • the hydrogenation catalyst is present on an inert support such as powdered carbon.
  • Reduction of the 9-nitro analog to the 9-amino analog is conducted using standard hydrogenation solvents and hydrogen pressure conditions.
  • the nitro compound is dissolved/suspended in ethanol and contacted with a hydrogen atmosphere.
  • the concentration of catalyst and of the nitro compound in the solvent is not critical. Concentrations of the nitro compound from about 1 mg/ml to 3 mg/ml may be used with catalyst concentrations ranging from about 20-100 wt.%.
  • the preferred solvent is absolute ethanol although other conventional inert solvents may be used.
  • the hydrogenation reaction is generally conducted at ambient temperature although temperatures above or below ambient temperature may be used so long as the camptothecin analog is not decomposed. Hydrogenation reaction times vary with the amount of nitro compound to be hydrogenated and can be easily determined by one skilled in the art.
  • reaction times ranging from 2-30 hours are sufficient to hydrogenate 9-nitro-10, 11-MDOCPT.
  • diazonium salts is a general reaction undergone by primary aromatic amines upon treatment with sodium nitrite in acidic solution. Accordingly, the
  • 9-amino-10, 11-MDOCPT can be treated with sodium nitrite in acid solution to form the corresponding diazonium salt. These diazonium salts are then reacted with nucleophiles or free radicals to generate nitrogen gas (N 2 ) and the desired 9-substituted-10,11-MDOCPT compound.
  • N 2 nitrogen gas
  • the overall reaction sequence is shown in scheme 1 below. In the scheme, the diazonium salt is shown as structure II where the counter anion X is derived from the acid HX.
  • MeCN, 25°C Additional 10,11-MDOCPT compounds can be prepared by further reactions on the compounds shown in Table A or by analogous reactions.
  • R is ethyl (C 2 H 5 ) or propyl (C 3 H 7 )
  • C 2 H 5 ethyl
  • C 3 H 7 propyl
  • Alkylation reactions of compounds in which R is OH, SH, NH 2 or CH 2 NH 2 yields compounds in which R is O-C 1-3 alkyl, S-C 1-3 alkyl, NH-C 1-3 alkyl or CH 2 NH-C 1-3 alkyl.
  • Dialkylation of the nitrogen-containing substituents is also possible to yield N(C 1-3 alkyl) 2 and CH 2 N(C 1-3 alkyl) 2 substituents as R.
  • Alkylation may be accomplished, for example, using C 1 -C 3 alkyl halides or tosylates (OTs).
  • Preferred alkyl halides are the C 1 -C 3 alkyl chlorides and bromides.
  • a base such as a tertiary amine may be added to facilitate the alkylation reaction.
  • alkyl 2 N-CH 2 CH 2 CH 2 -X, where X is halogen or OTs yields the correspondingly alkylated products containing the di-C 1-3 alkylaminoethyl or di-C 1-3 alkylaminopropyl group.
  • introduction of an oxygen atom is possible using alkylating agents having the formula
  • water-soluble analogs of 10,11-MDOCPT can be prepared by opening the lactone ring of 10,11-MDOCPT compounds to form water-soluble salts.
  • the open lactone compounds of the present invention have the structure shown below where R and Z have the same definition as given above for the closed lactone compounds and further Z and R may both be hydrogen.
  • the water-soluble analogs of the present invention are prepared by hydrolyzing the lactone ring of 10,11-MDOCPT or a 9-substituted-10, 11-MDOCPT by utilizing one equivalent of an aqueous alkali metal hydroxide. The hydrolysis is preferably carried out in an aqueous solution.
  • Preferred alkali metal hydroxides are potassium hydroxide and sodium hydroxide, with sodium hydroxide being
  • alkali metal hydroxide concentrations above or below one equivalent may be used in the present process. Concentrations below one equivalent result in incomplete formation of the metal salt.
  • camptothecin salt provides a convenient purification method. Unreacted camptothecin (closed lactone form) is only slightly soluble in water and can be filtered off from the aqueous solution containing the camptothecin sodium salt in solution. This provides a convenient method for separating and purifying camptothecin salts.
  • the hydrolysis reaction may be conducted at any temperature which allows adequate reaction of the 10,11-MDOCPT and alkali metal hydroxide so long as the temperature is sufficiently low to prevent decomposition of the starting materials. Suitable temperatures are from about 5-50°C with preferred temperatures being
  • the 10,11-MDOCPT is generally, but not necessarily suspended in a suitable solvent such as methanol or aqueous methanol and treated with aqueous alkali metal hydroxide.
  • a suitable solvent such as methanol or aqueous methanol
  • the reaction mixture may be gently heated.
  • the 10,11-MDOCPT metal salt may be isolated by standard recrystallization or chromatographic processes following removal of the methanol and water solvents. Any water miscible solvent conventionally used with
  • camptothecin analogs may be used instead of methanol.
  • Alkali metal salts (open lactone compounds) of other 10,11-MDOCPT analogs such as 9-substituted-10,11-MDOCPT compounds may also be prepared by analogous reactions.
  • 9-chloro-10,11-MDOCPT, 9-amido-10,11-MDOCPT or any other 9-substituted-10,11-MDOCPT derivative may also be used.
  • Water-soluble derivatives of 10,11-MDOCPT can also be prepared by reacting the amino group of
  • 9-amino-10,11-MDOCPT with appropriately protected amino acids and peptides, C 4-10 saturated or unsaturated carboxylic acid anhydrides, or the corresponding ester-acid halide derivatives.
  • 9-amino-10,11-MDOCPT may be reacted with the carboxylic acid group of an ⁇ -amino acid to give compounds having the structure shown below: in which Z is as defined above and R is the group
  • R 1 is the side-chain of an ⁇ -amino acid, preferably the side chain of a D or L-isomer of one of the naturally occurring amino acids, preferably one of the 20 commonly occurring amino acids
  • R 2 and R 3 are, independently, hydrogen or a lower alkyl group having 1-6 carbon atoms.
  • R 3 may be a peptide unit containing 1-3 amino acid units bonded to the nitrogen atom through a peptide bond.
  • amino acids which are not naturally occurring may also be used to prepare water-soluble salts.
  • 9-amido-10,11-MDOCPT derivatives so long as the amino acid has a carboxylic acid, acid halide or other reactive acyl functionality to form the required peptide bond with the 9-amino group of 9-amino-10,11-MDOCPT.
  • Other, preferred side chains R 1 are alkyl and aralkyl groups containing 2-20, preferably 2-10 carbon atoms.
  • these amino acid and peptide-containing derivatives are prepared using amino acids and peptides in which reactive functional groups such as amino groups and carboxylic acid groups are protected using standard amino acid and carboxylic protecting groups.
  • reactive functional groups such as amino groups and carboxylic acid groups
  • tBOC chloride to prepare the reactive tBOC-protected amino acid.
  • Appropriately protected amino acids are also available commercially.
  • the protected amino acid is reacted with 9-amino-10,11-MDOCPT and the tBOC group is then removed to give the water-soluble salt of the 9- glycinamido derivative, for example.
  • free amino groups on the amino acids or peptides may be derivatized by known nitrogen alkylation reactions, i.e., reaction with alkyl halides, to provide mono or dialkylamino acid amido derivatives as shown above
  • R 2 and/or R 3 alkyl
  • free amino groups are derivatized to form C 1-3 mono or dialkylamino groups.
  • Dibasic amino acids such as arginine, histidine, lysine, etc.
  • dicarboxylic amino acids such as aspartic acid, glutamic acid, etc.
  • standard addition salts may be prepared by reacting the free amino groups of any amino acid with a mineral acid such as HCl, HBr, H 3 PO 4 or organic acids such as malic, maleic or tartaric acids.
  • free carboxylic acid groups on any amino acid may be derivatized by the formation of monovalent metal cation salts, ammonium salts or quaternary ammonium salts by the addition of monovalent metal hydroxides, ammonia or amines.
  • Quaternary ammonium salts may be formed with primary, secondary or tertiary amines in which the nitrogen atom of the amine contains 1, 2 or 3 lower alkyl or substituted lower alkyl groups. Substituted lower alkyl groups
  • Sodium salts, triethylammonium and triethanol ammonium salts are particularly preferred.
  • Other water-soluble derivatives can also be prepared by reacting 9-amino-10,11-MDOCPT with a C 4-10 saturated or unsaturated acid anhydride, the corresponding ester-acid halide or other reactive acyl derivatives to provide analogs having structure I in which R is
  • reaction is optionally carried out in a suitable solvent and produces the corresponding half acid.
  • reaction of 9-amino-10,11-MDOCPT with glutaric anhydride gives the 9-glutaramide half acid.
  • reaction of 9-amino-10,11-MDOCPT with the C 1-6 ester-acid halide corresponding to glutaric anhydride results in the 9-glutaramide half acid ester.
  • Conventional hydrolysis of the ester produces the half acid. Water solubility may be imparted in each case by reaction with one equivalent of any of the bases noted above.
  • anhydride or other reactive acyl compound is preferably carried out in the presence of a weak base such as a tertiary amine to facilitate the formation of the product amide.
  • a weak base such as a tertiary amine to facilitate the formation of the product amide.
  • Suitable amines include cyclic amines such as pyridine as well as lower alkyl tertiary amines.
  • a suitable alkylene diamine NHR 2 - (CH 2 ) n -NR 2 R 3
  • 9-glutaramido-10,11-MDOCPT with a suitable diamine such as 3-(dimethylamino)-1-propylamine gives the corresponding amino acid amide as shown below.
  • Acid and base addition salts of these derivatives may also be prepared in a manner analogous to that described above.
  • water-soluble urea and urethane analogs can be prepared by reacting 9-amino-10,11-MDOCPT with phosgene followed by reaction with an appropriate diamine or tertiary-amino alcohol to give compounds having the formula I in which R is -NHCO-B-(CH 2 ) n -NR 2 R 3 , where B is oxygen or NH, and compounds in which R is
  • Suitable diamines are primary and secondary straightchain, branched or cyclic diamines containing 3-15 carbon atoms.
  • straight-chained and branched diamines include diaminoethane, 1,2- and 1,3-diaminopropane, 1,4-diaminobutane, etc.
  • cyclic diamines included pyrazolidine, imidazolidine, piperazine, etc.
  • Preferred diamines are diamines in which one of the amino groups is derivatized to form a di-lower-alkyl-amino group such as, for example, NH 2 CH 2 CH 2 CH 2 N(CH 2 CH 32 ) 2 .
  • the reaction of 9-amino-10,11-MDOCPT with phosgene followed by a diamine is represented below.
  • urethane analogs include N,N-di-C 1-6 -alkylamino alkanols prepared from straight chain or branched amino alkanols having 2-10 carbon atoms, for example,
  • Water soluble standard acid and base addition salts can be prepared from the urea and urethane analogs in a manner similar to that described above for other, amino and carboxylic acid group-containing analogs.
  • Preferred derivatives within the scope of the present invention are 10,11-MDOCPT analogs having glycinamido, succinamido, glutaramido, (4-methylpiperazino)
  • the salts of the present invention exhibit substantially improved water-solubility relative to conventional camptothecin analogs and may be formulated into solid and aqueous pharmaceutical compositions by conventional methods.
  • the compounds of the present invention exhibit substantially improved water-solubility relative to conventional camptothecin analogs and may be formulated into solid and aqueous pharmaceutical compositions by conventional methods.
  • 10,11-MDO-20(RS)-CPT has three to five times the potency of camptothecin in the inhibition of topoisomerase I.
  • Table B shown below shows the potent topoisomerase I inhibitory activity of the compounds of the present
  • the cleavable complex assay was performed according to the method described in Hsiang, Y-H. et al., J. Biol. Chem., 260:14873-14878 (1985).
  • the cleavable complex assay correlates well with in vivo anti-tumor activity in animal models for camptothecin analogs. See Hsiang et al., Cancer Research, 49:4385-4389 (1989) and Jaxel et al., Cancer Research, 49:1465-1469 (1989).
  • ** EC 50 is the concentration of a compound which gives 50% topoisomerase I inhibition as revealed by cleavable complex formation. All EC 50 values represent the mean of several independent assays; all values are normalized with respect to #9, 20(S)-CPT, which was always assayed as a control.
  • the present compounds are active against murine tumors, such as lymphocytic leukemia L-1210, RAW117-H10 lymphosarcoma and K1735-M2 melanoma. Activity in one or more of these tumor tests has been reported to be
  • the compounds of the present invention demonstrate significant activity, measured as inhibition of tumor cell proliferation during treatment with the compounds of the present invention.
  • cancer is synonymous with the terms "malignant tumor” and more generally "tumor”.
  • the data shown in Table C demonstrate the activity of the present compounds against human colon cancer, which is well known to be a very resistant cancer to chemotherapy. See H.L. Davis, Chemotherapy of Large Bowel Cancer, Cancer (Phila.) 50: 2638-2646 (1982); J.R. Neefe and P.S. Schein, Chapter 43: The Management of Disseminated Large-Bowel Cancer in
  • the compounds of the present invention exhibit antitumor activity against human colon cancer, which is known to exhibit de novo drug resistance, and thus be difficult to treat chemotherapeutically. Therefore, it is believed that the present compounds will be active against a wide spectrum of mammalian (including human) cancers such as cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx), esophagus, stomach, small intestine, large intestine, rectum, liver and biliary passages, pancreas, larynx, lung, bone, connective tissue, skin, breast, cervix uteri, corpus endometrium, ovary, prostate, testis,
  • mammalian (including human) cancers such as cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx), esophagus, stomach, small intestine, large intestine, rectum, liver and biliary passages, pancreas, larynx,
  • the present compounds may be used to treat other cancers not specifically named so long as antitumor
  • the present invention also includes pharmaceutical compositions containing the camptothecin derivatives of the present invention.
  • pharmaceutically acceptable binding agents, carriers and/or adjuvant materials may be included as part of the composition pharmaceutically acceptable binding agents, carriers and/or adjuvant materials.
  • the active materials can also be mixed with other active materials which do not impair the desired action and/or supplement the desired action.
  • the active materials according to the present invention can be administered by any route, for example, orally, parenterally, intravenously, intradermally,
  • the active ingredient may be incorporated into a solution or suspension.
  • the solutions or suspensions may be incorporated into a solution or suspension.
  • suspensions may also include the following components: a sterile diluent such as water for injection, saline
  • antioxidants such as ascorbic acid or sodium bisulfite
  • chelating agents such as ethylenediaminetetraacetic acid
  • buffers such as acetates, citrates or phosphates
  • agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • the aforesaid compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
  • the tablets, pills, capsules, troches and the like may contain the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, corn starch and the like; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin or flavoring agent such as peppermint, methyl salicylate, or orange flavoring may be added.
  • a liquid carrier such as a fatty oil.
  • dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings.
  • tablets or pills may be coated with sugar, shellac, or other enteric coating agents.
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various sweetening agents, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various
  • compositions should be pharmaceutically pure and non-toxic in the mounts used.
  • dosage values will vary with the specific cancer to be treated, the stage of tumor
  • an effective oral, parenteral or intravenous dose of from about 0.1 to about 100 mg per day per patient. It is to be understood, however, that for any particular subject, specific dosage regimens should be adjusted to the
  • 10,11-MDO-20(RS)-CPT and 10,11-MDO-20(S)-CPT were prepared according to Wani et al., J. Med. Chem.. 29. 2358 (1986) and the process disclosed in U.S. application serial no. 07/511,953.
  • Example 7 - 9-Cyano-10,11-MDO-20(S)-CPT fIII, R CN).
  • Example 14 - 9-Methyl-10,11-MDO-20(S)-CPT (III, R Me).
  • Example 16 Conversion of 9-Amino-10,11-MDOCPT to 9-Glycinamido-10,11-MDOCPT Hydrochloride.
  • hydrochloride salt as a yellow microcrystalline solid (57 mg, 73%), mp darkening above 230°C with no apparent melting below 340°C.
  • the 9-glutaramido derivative was synthesized from 9-amino-10,11-MDOCPT by the following method:
  • the 9-glutaramido derivative can be prepared by hydrolysis of its ethyl ester which is prepared by the following general method: 9-Amino-10,11-MDOCPT in dry N,N-dimethylformamide containing pyridine is reacted at 0-10°C with a slight excess of ethylglutaryl chloride in N,N-dimethylformamide solution. After work-up and
  • 9-amino-10,11-MDOCPT in the following manner: 9-(4-Methylpiperazino)carbonylamino-10,11-MDOCPT.
  • 9-Amino-10,11-MDOCPT was added to chloroform (treated with alumina to remove hydroxylic components) containing triethylamine. The resulting solution was treated with phosgene gas and filtered to remove solids. The filtrate containing the intermediate carbamoyl chloride was treated with N-methylpiperazine under nitrogen and left overnight. The turbid mixture was washed several times with aqueous sodium bicarbonate solution, dried and evaporated to affordthe crude title compound. Chromatography on silica gel provided 9-(4-methylpiperazino)carbonylamino-10,11-MDOCPT.
  • the free base urea obtained above was suspended in methanol and treated with one equivalent of dilute aqueous hydrochloric acid. The methanol was evaporated and the aqueous residue filtered through a membrane filter. The sample was lyophilized to provide the title compound.
  • Example 5 The free base from Example 5 was suspended in methanol and treated with one equivalent of dilute aqueous
  • 10,11-MDO-20(RS)-camptothecin (Wani et al., J. Med. Chem. 29 , 2358 (1986)) by hydrolytic action of sodium hydroxide.
  • 10,11-MDO-20(RS)-CPT (77 mg, 0.194 mmol) was
  • Example 22 9-Amino-10,11-MDO-20(RS)-Camptothecin Sodium Salt.
  • the title compound was prepared by an analogous alkaline hydrolysis of 9-amino-10,11-MDO-20 (RS) CPT which was prepared as described above.
  • RS 9-amino-10,11-MDO-20
  • a suspension of 9-amino-10,11-MDO-20(RS)CPT in aqueous methanol was warmed with one equivalent of aqueous sodium hydroxide to provide a clear solution. Isolation as above provided the water soluble title compound as an orange-yellow solid.

Abstract

Analogues de camptothécine ayant la structure illustrée par les formules (I) ou (II), dans lesquelles Z représente H ou alkyle contenant 1 à 8 atomes de carbone, et R représente NO2NH2N3 hydrogène, halogène, COOH, OH, alkyle O-C1-3, SH, alkyle S-C1-3, CN, CH2NH2, alkyle NH-C1-3, alkyle CH2-NH-C1-3, N(alkyle C1-3)2, CH2N(alkyle C1-3)2, O-, NH- ou S-CH2CH2N(CH2CH2CH2OH)2, O-, NH- ou S-CH2CH2CH2N(CH2CH2OH)2, O-, NH- ou S-CH2CH2N(CH2CH2CH2OH)2, O-, NH- ou S-CH2CH2CH2N(CH2CH2CH2OH)2, O-, NH- ou S-CH2CH2N(alkyle C1-3)2, O-, NH- ou S-CH2CH2CH2N(alkyle C1-3)2, CHO, alkyle contenant 1 à 3 atomes de carbone ou NHCOCHR?1NR2R3, où R1¿ représente la chaîne latérale d'un acide aminé α et R2 et R3 représentent indépendamment hydrogène ou un groupe alkyle inférieur, où R3 représente une unité pepditique contenant 1 à 3 unités d'acides aminés liées à l'azote par une liaison peptidique; NHCO-C¿2-8?-alkylène-X, ou NHCO-C1-8-alcénylène-X où X représente COOH; CONR?2-(CH¿2)n-NR2R3, où n = 1-10, et R2 ainsi que R3 sont définis comme précédemment; NHCO-B-(CH¿2?)n-NR?2R3¿, où B = oxygène ou NH, ou la formule (III) dans laquelle m + y = 3-6, ainsi que leurs sels.
PCT/US1990/005172 1989-09-15 1990-09-17 Analogues de 10,11-methylenedioxy-20(rs)-camptothecine et de 10,11-methylenedioxy-20(s)-camptothecine WO1991004260A2 (fr)

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KR1019920700585A KR0180245B1 (ko) 1989-09-15 1990-09-17 10,11-메틸렌디옥시-20(rs)-캠프토테신 및 10,11-메틸렌디옥시-20(s)-캠프토테신 동족체
CA002066780A CA2066780C (fr) 1989-09-15 1990-09-17 Analogues de la 10,11-methylenedioxy-20(rs)-camptothecine et de la 10,11-methylenedioxy-20(s)-camptothecine

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995022549A1 (fr) * 1994-02-16 1995-08-24 Pharmacia S.P.A. Derives de la camptothecine et leur procede de preparation
US5525527A (en) * 1992-02-20 1996-06-11 Minnesota Mining And Manufacturing Company Process for producing a solid state radiation detector
WO1996037496A1 (fr) * 1995-05-26 1996-11-28 Pharmacia & Upjohn S.P.A. Derives de camptothecine substitues et leur procede de preparation
US5837673A (en) * 1995-08-02 1998-11-17 Tanabe Seiyaku Co., Ltd. Camptothecin derivatives
US5843954A (en) * 1994-09-06 1998-12-01 Kabushiki Kaisha Yakult Honsha Camptothecin derivatives, preparations thereof and antitumor agents
US6310210B1 (en) 1997-11-06 2001-10-30 Kabushiki Kaisha Yakult Honsha Camptothecin derivatives
US7067666B2 (en) * 2003-06-27 2006-06-27 Research Triangle Institute 7-substituted camptothecin and camptothecin analogs and methods for producing the same
US20180170944A1 (en) * 2014-03-26 2018-06-21 Canget Biotekpharma, Llc Use of the fl-one hundred eighteen core chemical structure platform to generate fl-one hundred eighteen derivatives for treatment of human disease

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US5525527A (en) * 1992-02-20 1996-06-11 Minnesota Mining And Manufacturing Company Process for producing a solid state radiation detector
WO1995022549A1 (fr) * 1994-02-16 1995-08-24 Pharmacia S.P.A. Derives de la camptothecine et leur procede de preparation
US5602141A (en) * 1994-02-16 1997-02-11 Pharmacia & Upjohn S.P.A. Camptothecin derivatives and process for their preparation
US5843954A (en) * 1994-09-06 1998-12-01 Kabushiki Kaisha Yakult Honsha Camptothecin derivatives, preparations thereof and antitumor agents
WO1996037496A1 (fr) * 1995-05-26 1996-11-28 Pharmacia & Upjohn S.P.A. Derives de camptothecine substitues et leur procede de preparation
US5856333A (en) * 1995-05-26 1999-01-05 Pharmacia & Upjohn S.P.A. Substituted camptothecin derivatives and process for their preparation
US5837673A (en) * 1995-08-02 1998-11-17 Tanabe Seiyaku Co., Ltd. Camptothecin derivatives
US6310210B1 (en) 1997-11-06 2001-10-30 Kabushiki Kaisha Yakult Honsha Camptothecin derivatives
US7067666B2 (en) * 2003-06-27 2006-06-27 Research Triangle Institute 7-substituted camptothecin and camptothecin analogs and methods for producing the same
US20180170944A1 (en) * 2014-03-26 2018-06-21 Canget Biotekpharma, Llc Use of the fl-one hundred eighteen core chemical structure platform to generate fl-one hundred eighteen derivatives for treatment of human disease
US10344037B2 (en) * 2014-03-26 2019-07-09 Canget BioTek Pharma LLC Use of the FL-one hundred eighteen core chemical structure platform to generate FL-one hundred eighteen derivatives for treatment of human disease
US20190367529A1 (en) * 2014-03-26 2019-12-05 Canget Biotekpharma, Llc Use of the fl-one hundred eighteen core chemical structure platform to generate fl-one hundred eighteen derivatives for treatment of human disease

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