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WO2000066127A1 - Nouveaux analogues de la camptothecine fortement liphophiles - Google Patents

Nouveaux analogues de la camptothecine fortement liphophiles Download PDF

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Publication number
WO2000066127A1
WO2000066127A1 PCT/US2000/012318 US0012318W WO0066127A1 WO 2000066127 A1 WO2000066127 A1 WO 2000066127A1 US 0012318 W US0012318 W US 0012318W WO 0066127 A1 WO0066127 A1 WO 0066127A1
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Prior art keywords
hydrogen
camptothecin
alkylene
lower alkyl
compound
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PCT/US2000/012318
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English (en)
Inventor
Harry Kochat
Xinghai Chen
Qiuli Huang
Seetharamulu Peddaiaghari
Frederick H. Hausheer
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Bionumerik Pharmaceuticals, Inc.
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Priority to AU48225/00A priority Critical patent/AU4822500A/en
Publication of WO2000066127A1 publication Critical patent/WO2000066127A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

Definitions

  • compositions of this invention include a seven-membered lactone ⁇ E' ring and/or ⁇ A' and ⁇ B' ring multiple substitutions.
  • the invention also includes pharmaceutical formulations of the new compositions, methods of treating various cancers and leukemias by administering an effective amount of the compositions to a patient, and processes for synthesizing the compositions from naturally occurring Camptothecin, as well as by total synthesis.
  • Camptothecin is a well-known naturally occurring compound that was discovered to possess anticancer properties by Wall and Wani in the early 1960s. Efforts have been made since then to improve upon the antineoplastic properties of Camptothecin and its analogs, to overcome certain clinical and pharmaceutical limitations, and to reduce the unwanted toxicities of this series of agents. Camptothecin and many of its analogs are very poorly soluble in water. Many such analogs exhibit water solubility of less than five micrograms per milliliter. This poor water solubility originally presented problems of administration of the intended drug, and efforts have continued towards making the drug practical for administration to human patients.
  • Poorly water-soluble Camptothecin analogs are formulated for administration with suitable solvents such as those disclosed in United States Patents 5,726,181; 5,447,936; 5,468,754; and others referred to in the Information Disclosure Sheet that accompanies this application.
  • suitable solvents for these poorly water-soluble Camptothecin analogs include dimethylacetamide (DMA), dimethylisosorbide (DMI) and N-methylpyrrolidinone (NMP) .
  • the poorly water-soluble Camptothecin analogs generally provide increased lactone stability and greater antitumor activity than the water-soluble analogs . Some analogs are also less susceptible to metabolism, particularly to the glucuronide form, which is frequently associated with the unwanted toxicities of Camptothecin analogs .
  • R and Ri are each individually hydrogen, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, halo, aryl, arylalkyl, arylalkenyl, arylalkynyl, -X ⁇ (C 0 -C 6 alkylene, C ⁇ -C 6 alkenylene or C2 ⁇ C 6 alkynylene) -SiRi2 ⁇ 3 i4, -X ⁇ ⁇ (C 0 -C 6 alkylene, Ci-C ⁇ alkenylene, C 2 -C 6 alkynylene, phenylene or benzylene) -NR 9 R 10 , or OR 6 ;
  • R 2 R 3 R , and R5 are each individually hydrogen, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, halo, aryl, arylalkyl, arylalkenyl, arylalkynyl, amino, nitro, protected amino, -X 2 -(C 0 -C 6 alkylene, Ci-C ⁇ alkenylene or C 2 -C6 alkynylene) -SiR ⁇ 2 R ⁇ 3 Ri4, -X 2 - (C 0 -C 6 alkylene, C ⁇ -C 6 alkenylene, C 2 -C6 alkynylene, phenylene or benzylene) -NR 9a R ⁇ o a , or ORa, wherein at least one of R 2 , R 3 and R 4 is other than hydrogen; and wherein when Ri is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, halo, aryl, ary
  • R is hydrogen, lower alkyl, aryl, -SiRi2R ⁇ 3 Ri4, or is absent when Rn is hydrogen;
  • Re is hydrogen, lower alkyl or -(C 0 -C 6 alkylene, Co-C 6 alkenylene or C 0 -C 6 alkynylene) -SiRi2R ⁇ 3 Ri4;
  • Rg, Rio, Rg a and R ⁇ o a are each individually hydrogen, lower alkyl or a nitrogen-protecting group
  • Rii is hydrogen, carbonyl, sulfonyl, thiocarbonyl, sulfoxo, C 1 -C 16 alkylene-, -0- or -S-;
  • R12, R1 3 , and R i4 are each individually hydrogen or C 1 -C 10 alkyl;
  • R15 is hydrogen, lower alkyl or a nitrogen-protecting group
  • X is -CH 2 - or absent; X x and X 2 are each individually sulfur, NR 15 or absent; or a pharmaceutically acceptable salt thereof.
  • the compounds of this invention are useful in treating various cancers and leukemias. They have demonstrated particularly potent activity, both in vi tro and in vivo, against several different solid tumors, including but not limited to cancers of the colon, breast, pancreas, stomach, kidneys, liver, prostate, testis, lung, brain, malignant melanoma, and others.
  • the compounds are preferably formulated for administration to a patient.
  • the formulations are designed for either oral, topical, or parenteral administration, and include one or more pharmaceutically acceptable solvents, excipients and/or diluents combined with the formula I compound (the "active compound”) .
  • Another object of this invention is to provide for Camptothecin compositions that possess enhanced antineoplastic properties.
  • Another object of this invention is to provide for novel formulations of Camptothecins .
  • Another object of this invention is to provide for novel methods of treating antineoplastic diseases, especially cancers and leukemias .
  • Fragments or “Moieties” are the variable parts of the molecule, designated in the formula by variable symbols, such as R x , X or other symbols. Fragments may consist of one or more of the following:
  • C x -C y alkyl means a straight or branched-chain aliphatic hydrocarbon containing as few as x and as many as y carbon atoms. Examples include “C ⁇ -C 6 alkyl” (also referred to as “lower alkyl”), which includes a straight or branched chain hydrocarbon with no more than 6 total carbon atoms, and C ⁇ -C ⁇ .6 alkyl, which includes a hydrocarbon with as few as one up to as many as sixteen total carbon atoms, and others;
  • C ⁇ -C y alkylene means a bridging moiety formed of as few as “x” and as many as “y” -CH 2 - groups;
  • C x -C y alkenyl or alkynyl means a straight or branched chain hydrocarbon with at least one double bond (alkenyl ) or triple bond (alkynyl) between two of the carbon atoms;
  • C x -C y alkoxy means a straight or branched hydrocarbon chain with as few as x and as many as y carbon atoms, with the chain bonded to the scaffold through an oxygen atom;
  • Alkoxycarbonyl (aryloxycarbonyl) means an alkoxy (aryloxy) moiety bonded to the scaffold through a carbonyl;
  • Halogen or “Halo” means chloro, fluoro, bromo or iodo
  • Acyl means -C(0)-R, where R is hydrogen, C x -C y alkyl, aryl, C x -C y alkenyl, C x -C y alkynyl, etc.;
  • Acyloxy means -0-C(0)-R, where R is hydrogen, C x -C y alkyl, aryl, etc.;
  • C x -C y Cycloalkyl means a hydrocarbon ring or ring system consisting of one or more rings, fused or unfused, wherein at least one of the ring bonds is completely saturated, with the ring(s) having from x to y total carbon atoms;
  • Aryl means an aromatic ring or ring system consisting of one or more rings, preferably one to three rings, fused or unfused, with the ring atoms consisting entirely of carbon atoms;
  • Arylalkyl means an aryl moiety as defined above, bonded to the scaffold through an alkyl moiety (the attachment chain) ;
  • Arylalkenyl and “Arylalkynyl” mean the same as “Arylalkyl", but including one or more double or triple bonds in the attachment chain;
  • Heterocycle means a cyclic moiety of one or more rings, preferably one to three rings, fused or unfused, wherein at least one atom of one of the rings is a non-carbon atom.
  • Preferred heteroatoms include oxygen, nitrogen and sulfur, or any combination of two or more of those atoms;
  • Substituted modifies the identified fragments (moieties) by replacing any, some or all of the hydrogen atoms with a moiety (moieties) as identified in the specification.
  • Protecting groups are those moieties which are attached to a particular atom, and which prevent reaction at that position of the scaffold under specified conditions. Examples of the above moieties are as follows :
  • Ci-C ⁇ alkyl includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, amyl and the like;
  • C 2 -C ⁇ alkenyl or alkynyl includes vinyl, propenyl, butenyl, acetylenyl, propynyl, and other like moieties with one or more double and/or triple bonds;
  • Alkoxy includes methoxy, ethoxy, propoxy, and the like
  • Alkoxycarbonyl and aryloxycarbonyl include methoxycarbonyl, ethoxycarbonyl, benzoxy and others; Acyl includes formyl, acetyl, propionyl, benzoyl and others;
  • Acyloxy includes formoxy, acetoxy, propionoxy, and the like;
  • Cycloalkyl includes cyclopropyl, cyclobutyl, cyclohexyl, indanyl, dihydronaphthalenyl, cyclohexenyl, and the like;
  • Aryl includes phenyl, naphthyl and anthracenyl, as well as substituted variants wherein one of the hydrogen atoms bonded to the ring atom is substituted by a halogen atom, an alkyl group, or another moiety;
  • Arylalkyl includes benzyl, phenethyl, and the like;
  • Arylalkenyl and arylalkynyl includes phenylvinyl, phenylpropenyl, phenylethylenyl, phenylpropynyl and the like; and Heterocycle includes furanyl, pyranyl, thionyl, pyrrolyl, pyrrolidinyl, prolinyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxathiazolyl, dithiolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, oxazinyl, thiazolyl, and the like.
  • Substitutions for hydrogen atoms to form substituted analogs include halo, alkyl, nitro, amino (also N-substituted, and N,N di-substituted amino), sulfonyl, hydroxy, alkoxy, phenyl, phenoxy, benzyl, benzoxy, benzoyl, and trifluoromethyl .
  • Protecting groups include specific moieties for protecting, in particular, nitrogen terminal moieties and oxygen terminal moieties .
  • Protecting groups are well known in the art and are described in detail in Kocienski , P. , Protecting Groups, Foundations of Organic Chemistry (Thieme, 1994); and Greene, Wuts , Protective Groups in Organic Synthesis (Wiley, 2d ed. 1990) .
  • the compounds of this invention are semisynthetic analogs of Camptothecin.
  • the compounds have either a seven-membered ⁇ E' ring and/or di- and tri-substituted analogs derived from the Camptothecin scaffold.
  • the analogs are of formula I, depicted below. It should be noted, that for purposes of this invention, the numbering scheme used to identify the CPT scaffold is as shown below. The rings are lettered from left to right across the scaffold.
  • R and Ri are each individually hydrogen, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, halo, aryl, arylalkyl, arylalkenyl, arylalkynyl, ⁇ X ⁇ - (C 0 -C 6 alkylene, C ⁇ -C 6 alkenylene or C 2 -C 6 alkynylene) -X ⁇ -(C 0 -C 6 alkylene, C ⁇ -C 6 alkenylene, C 2 -C 6 alkynylene, phenylene or benzylene) -NRgRio, or
  • OR 6 ; R 2? R 3A 4 ; and R 5 are each individually hydrogen, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, halo, aryl, arylalkyl, arylalkenyl, arylalkynyl, amino, nitro, protected amino, -X 2 - (Co-C 6 alkylene, Ci-C ⁇ alkenylene or C 2 -C e alkynylene) -SiR ⁇ 2 R ⁇ 3 Ri4, -X 2 - (C 0 -C 6 alkylene, C ⁇ -C 6 alkenylene, C 2 -C 6 alkynylene, phenylene or benzylene) -NR 9a R ⁇ 0a , or OR 8 , wherein at least one of R 2 , R 3 and R 4 is other than hydrogen; and wherein when Ri is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, halo,
  • R ⁇ is hydrogen, lower alkyl, or an oxygen-protecting group
  • R 7 is hydrogen, lower alkyl , aryl , -SiR ⁇ Ri3Ri4 r or is absent when R n is hydrogen;
  • R 8 is hydrogen , lower alkyl or - ( C 0 -C 6 alkylene , C 0 -C 6 alkenylene or C 0 -C6 alkynylene ) -SiRi2R ⁇ 3 Ri4 ;
  • R 9 , Rio , R 9a and R ⁇ 0a are each individually hydrogen, lower alkyl or a nitrogen-protecting group ;
  • Rii is hydrogen, carbonyl, sulfonyl, thiocarbonyl, sulfoxo, C1-C1 6 alkylene-, -0- or -S-;
  • i 2 , R I3 ⁇ and R ⁇ are each individually hydrogen or C1-C10 alkyl;
  • R 15 is hydrogen, lower alkyl or a nitrogen-protecting group;
  • X is -CH 2 - or absent
  • Xi and X 2 are each individually sulfur, NR 15 or absent; or a pharmaceutically acceptable salt thereof.
  • the formula I preferred compounds include those compounds wherein Ri is -X- (lower alkyl) -Si (alkyl ) 3 and one or more of the ⁇ A' ring moieties is other than hydrogen. This formula produces various di- and tri-substituted analogs of naturally occurring Camptothecin. The presence of one or more silane moieties on the scaffold enhances the high lipophilicity of the compound, and stabilizes the lactone ⁇ E' ring.
  • Rn moieties include hydrogen and lower alkylene, with preferred R 7 moieties including any silane moiety when R is lower alkylene.
  • Most preferred compounds include those compounds where Ri is a -lower alkyl-silane moiety, one or two of R 2 through R 4 is amino, substituted amino, hydroxy, alkoxy, -carbonyl-lower alkyl-heterocycle, -lower alkyl-trimethylsilyl, or aryloxy, R 5 is hydrogen, and Rn is hydrogen.
  • R 5 is hydrogen
  • Rn is hydrogen.
  • the principal solvent in the formulation is N- methylpyrrolidinone (NMP) or dimethylacetamide (DMA) or dimethylisosorbide (DMI).
  • NMP N- methylpyrrolidinone
  • DMA dimethylacetamide
  • DMI dimethylisosorbide
  • the preferred formulation also includes one or more pharmaceutically acceptable excipients, co-solvents, diluents or fillers as described in the prior patents. Formulations may be adapted for oral, topical, or parenteral administration as required.
  • the invention also includes methods of treating susceptible cancers by administering an effective amount of the formula I compound to a patient in need of treatment.
  • Effective amounts of the formula I compound depend upon the type and stage of the cancer being treated, ranging from 0.01 mg/m 2 to about 50 mg/m 2 . Most preferred doses range from 0.2 mg/m 2 up to about 10 mg/m 2 .
  • Administration may be through oral or parenteral routes, most preferably intravenous infusion or by oral administration.
  • Scheme 1 illustrates the preferred process for synthesizing the seven-membered ⁇ E' ring analogs from naturally occurring Camptothecin. Processes for synthesizing the A' and ⁇ B' ring substituted analogs are disclosed in United States Patent 5,910,491 and US Patent Application 09/178,780, both of which are incorporated herein by reference .
  • Camptothecin 1 is converted to the open ⁇ E' ring carboxylate salt by adding excess base to the solution. Treating Camptothecin 1 with acetic anhydride in the presence of excess base forms the desired acetate ester 2.
  • Acid chloride intermediate 3 is derived by reacting intermediate 2 with a corresponding acid chloride, and then to the diazoketone 4 by reacting 3 with diazomethane .
  • Diazoketone 4 is converted to the corresponding ester 5 via a Wolff-Hoffman rearrangement.
  • the ester 5 is then hydrolyzed to its free acid.
  • the ⁇ E' ring is then closed by acidification to form the 7-membered ⁇ E' ring compound 6, which is a formula I compound.
  • Scheme la depicts an alternative and known process for synthesizing the 7-membered E' ring compound of formula I.
  • This known process is described in detail in Lavergne , et . al . , Homocamptothecins : Synthesis and Antitumor Activity of Novel E-Ring-Modified Camptothecin Analogues, J. Med. Chem. 1998, 41, 5410-5419. Specific examples of the process are described in the publication, which is attached to the Information Disclosure Sheet accompanying this application, and is incorporated herein by reference.
  • Scheme 6 depicts the conversion of underivatized CPT to 9-Bromo CPT by selective nitration, amination and protection, and finally bromination and deamination. Nitration of underivatized Camptothecin yields a mixture of 9-nitro and 12- nitro CPT.
  • the 9-nitro CPT can be derivatized to 9-Bromo CPT by direct amination and then bromination by known methods .
  • 12-Nitro CPT is separated from the 9-Nitro CPT by flash column chromatography using ethyl acetate as an eluent.
  • Amination of the 12-Nitro CPT is effected by hydrogenation using platinum oxide as catalyst. Protection of the 12-Amino CPT is achieved by reacting with a suitable acid chloride. Bromination is then accomplished with the sole substitution at the para-position by adding elemental bromine to the protected 12-Amino CPT. Deprotection and deamination is accomplished by adding a strong acid followed by sodium nitrite to remove the 12-Amino group and yield pure 9-Bromo CPT.
  • Scheme 7 illustrates the conversion of 9-Hydroxy CPT to 9-Bromo CPT. This conversion is through a known process, in which the 9-Hydroxy CPT is first aminated, then brominated. The process is disclosed in several publications of record, and involves aminating the 9-Hydroxy CPT by adding concentrated nitric acid, then hydrogenating, and finally adding elemental bromine to displace the 9-Amino group.
  • Scheme 8 illustrates the conversion of the 9-Bromo CPT intermediate (10) to the 9-Silyl analogues (13) of this invention.
  • the transformation is preferably achieved by reacting intermediate (10) with hexamethyldisilane and methyl lithium, converted to an organic soluble homogenous cuprate reagent according to the principles of Nyori .
  • the transformation is preferably accomplished by reacting intermediate (10) with a tributyltin analogue of the respective trimethylsilyl hydrocarbon using palladium chemistry techniques. This process is similar to the process for adding C7 substitutions, as disclosed in U. S. Patent 5,910,491, incorporated herein by reference .
  • 10-substituted analogues (as well as the 10,7- disubstituted analogues) are formed by first triflylating a 10-hydroxy Camptothecin analogue, then performing the silylation through a modified Stille coupling. This process is also disclosed in the prior art.
  • Camptothecin (3 gm, 8.6 mmols) is recrystallized from hot dimethyl formamide suspended in methanol (10 ml) and sodium borohydride (1 gram, 26.3 mmols) is added. The reaction mixture is stirred at room temperature overnight. The reaction mixture is concentrated to one-third volume and crushed ice added to precipitate the product. The product is then filtered and washed with ether, dried under vacuum and analyzed. Since the product is found substantially pure, it is taken over to the subsequent step without further purification. 23
  • chlorotrimethyl silane are then introduced to activate the
  • Homocamptothecin was prepared according to the process disclosed in Lavergne , et al , Homocamptothecins : Synthesis and Antitumor Activity of Novel E-Ring-Modified Camptothecin Analogues, J. Med. Chem., 1998, vol. 41, p. 5414.
  • reaction mixture is diluted with chloroform (5 mL) and water (5 mL) .
  • the aqueous phase is extracted with chloroform (3 X 5 mL) .
  • the combined organic extracts are then washed with brine, dried over anhydrous sodium sulfate, filtrated through silica gel, and concentrated by rotary evaporator.
  • the crude product is purified by preparative TLC using 3% MeOH/CHCl 3 as eluents to yield the title compound (19 mg) as a yellow solid: mp, 250 °C dec;
  • the combined organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered through silica gel, and concentrated using a rotary evaporator.
  • the crude product was purified by column chromatography (silica gel, 2% methanol/chloroform) to furnish 30 mg of the title compound.
  • the combined organic extract is washed with brine, dried over anhydrous sodium sulfate, filtered through silica gel, and concentrated by a rotary evaporator.
  • the crude product is purified by radial PLC using 2% methanol/ethyl acetate as eluents to yield 8.8 mg of the title compound as a yellow solid.
  • N-oxide 50 mg is taken along with peroxide free dioxane (50 mL) and purged with nitrogen for a period of 60 minutes in a photo-irradiation assembly equipped with High Pressure Mercury Lamp and double-jacketed chilled water circulation. To it is then added 0.5-1 mL of 5% sulfuric acid. The contents were then irradiated for a period of approximately 40 minutes.
  • the crude product was obtained by concentrating the reaction mixture over a rotary evaporator at room temperature and by ishing the residue using cold water to remove the last traces of sulfuric acid.
  • the crude product was then chromatographed over silica gel using 20% chloroform- methanol mixture to obtain 20 mg of the desired product along with 25 mg of 7- (2-trimethylsilyl) ethyl camptothecin as the deoxygenated N-oxide bye-product.
  • the by-product, 7- (2- trimethylsilyl) ethyl camptothecin is usually recycled for the subsequent batch to make the title compound.
  • Camptothecin (5.82g) from recrystallization was dissolved in 25 mL 98% concentrated sulfuric acid. The solution was stirred at room temperature overnight. Potassium carbonate (1.5 g) was added and the reddish reaction solution was stirred for 48 hours. An additional 1.5 g of K 2 C0 3 is added and the solution was stirred for one more day. Cold water (100 mL) was added dropwise to the reaction solution in an ice bath. The resulting mixture was extracted with chloroform, 300 mL x 5. Chloroform solution was concentrated to c.a. 200 mL, heated to 60 °C for 30 minutes, and cooled to room temperature. The precipitate, 12-nitro camptothecin, was isolated, 3.28g, 50% yield. The mother liquor was concentrated, purified by column, and eluted with ethyl acetate. 1.72g of 9-nitro camptothecin was isolated (29% yield) .
  • 9-Nitro camptothecin (0.95g, 2.42 mmol) was dissolved in a mixed solvent of ethanol (75 mL) and dioxane (75 mL) . Platinum oxide (89 mg) was added as a catalyst. The reaction mixture was vigorously stirred and bubbled with hydrogen. The hydrogenation was monitored by NMR, and the reaction was completed in two hours. The mixed solvent was removed in vacuo . Without further purification, the crude product of 9- amino camptothecin was used in the following reaction. The crude 9-amino camptothecin was dissolved in 16% hydrobromic acid (60 mL) in an ice bath.
  • Acetyl chloride is removed in vacuo . Residue is dissolved in chloroform, washed with brine, dried with sodium sulfate. The solvent is removed to give 1.648 g crude product. 12- Acetamido-camptothecin is purified from crude product by recrystallization in methanol, l.Olg brown solid, 67% yield.
  • 12- acetamido-camptothecin-20-acetate is the major product, along with 5-acetyl-12-acetamido-camptothecin-20-acetate .

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Abstract

L'invention concerne de nouveaux analogues de la camptothécine. Ces analogues comprennent diverses substitutions de noyaux A' et B' et/ou un noyau E' à 7 éléments, et comprennent des analogues mono- et multi-substitués de camptothécine. De préférence, une ou plusieurs de ces substitutions comprend un atome de silicium dans la fraction du fragment et ces composés sont fortement lipophiles et présentent une forte stabilité du noyau E'.
PCT/US2000/012318 1999-05-04 2000-05-04 Nouveaux analogues de la camptothecine fortement liphophiles WO2000066127A1 (fr)

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Cited By (9)

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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
US6933302B2 (en) 2002-06-03 2005-08-23 California Pacific Medical Center Nitrogen-based homo-camptothecin derivatives
WO2008011992A1 (fr) * 2006-07-26 2008-01-31 Indena S.P.A. Dérivés de camptothécine à activité antitumorale
JP2011500674A (ja) * 2007-10-16 2011-01-06 バイオニューメリック・ファーマスーティカルズ・インコーポレイテッド Ｃ１０−置換カンプトテシン類似体
JP2011500675A (ja) * 2007-10-16 2011-01-06 バイオニューメリック・ファーマスーティカルズ・インコーポレイテッド Ｃ７−置換カンプトテシン類似体
US7875602B2 (en) 2005-10-21 2011-01-25 Sutter West Bay Hospitals Camptothecin derivatives as chemoradiosensitizing agents
WO2024212922A1 (fr) * 2023-04-11 2024-10-17 映恩生物制药（苏州）有限公司 Composé de camptothécine et conjugués de celui-ci, procédé de préparation correspondant et utilisation associée

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WO1998007727A1 (fr) * 1996-08-19 1998-02-26 Bionumerik Pharmaceuticals, Inc. Derives de camptothecine hautement lipophiles
WO1998035940A1 (fr) * 1997-02-14 1998-08-20 Bionumerik Pharmaceuticals, Inc. Derives de camptothecine hautement lipophile
US6057303A (en) * 1998-10-20 2000-05-02 Bionumerik Pharmaceuticals, Inc. Highly lipophilic Camptothecin derivatives

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WO1998007727A1 (fr) * 1996-08-19 1998-02-26 Bionumerik Pharmaceuticals, Inc. Derives de camptothecine hautement lipophiles
US5910491A (en) * 1996-08-19 1999-06-08 Bionumerik Pharmaceuticals, Inc. Highly lipophilic camptothecin derivatives
WO1998035940A1 (fr) * 1997-02-14 1998-08-20 Bionumerik Pharmaceuticals, Inc. Derives de camptothecine hautement lipophile
US6057303A (en) * 1998-10-20 2000-05-02 Bionumerik Pharmaceuticals, Inc. Highly lipophilic Camptothecin derivatives

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USRE39707E1 (en) 2001-01-18 2007-06-26 Catholic Healthcare West Camptothecin derivatives
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
US6933302B2 (en) 2002-06-03 2005-08-23 California Pacific Medical Center Nitrogen-based homo-camptothecin derivatives
US7875602B2 (en) 2005-10-21 2011-01-25 Sutter West Bay Hospitals Camptothecin derivatives as chemoradiosensitizing agents
US8779138B2 (en) 2005-10-21 2014-07-15 Sutter West Bay Hospital Camptothecin derivatives as chemoradiosensitizing agents
US8563537B2 (en) 2005-10-21 2013-10-22 Sutter West Bay Hospital Camptothecin derivatives as chemoradiosensitizing agents
US8076351B2 (en) 2006-07-26 2011-12-13 Indena S.P.A. Camptothecin derivatives with antitumor activity
WO2008011992A1 (fr) * 2006-07-26 2008-01-31 Indena S.P.A. Dérivés de camptothécine à activité antitumorale
JP2011500675A (ja) * 2007-10-16 2011-01-06 バイオニューメリック・ファーマスーティカルズ・インコーポレイテッド Ｃ７−置換カンプトテシン類似体
JP2011500674A (ja) * 2007-10-16 2011-01-06 バイオニューメリック・ファーマスーティカルズ・インコーポレイテッド Ｃ１０−置換カンプトテシン類似体
WO2024212922A1 (fr) * 2023-04-11 2024-10-17 映恩生物制药（苏州）有限公司 Composé de camptothécine et conjugués de celui-ci, procédé de préparation correspondant et utilisation associée

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