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WO2012007619A1 - Procédé d'obtention de dérivés solubles dans l'eau de 20(s) camptothécine en tant qu'agents antitumoraux - Google Patents

Procédé d'obtention de dérivés solubles dans l'eau de 20(s) camptothécine en tant qu'agents antitumoraux Download PDF

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Publication number
WO2012007619A1
WO2012007619A1 PCT/ES2011/070450 ES2011070450W WO2012007619A1 WO 2012007619 A1 WO2012007619 A1 WO 2012007619A1 ES 2011070450 W ES2011070450 W ES 2011070450W WO 2012007619 A1 WO2012007619 A1 WO 2012007619A1
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WIPO (PCT)
Prior art keywords
process according
general formula
compound
alkyl
group
Prior art date
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Ceased
Application number
PCT/ES2011/070450
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English (en)
Spanish (es)
Inventor
Guillermo RODRÍGUEZ BERNA
María José DÍAZ CABAÑAS
Avelino CORMA CANÓS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Consejo Superior de Investigaciones Cientificas CSIC
Universidad Politecnica de Valencia
Original Assignee
Consejo Superior de Investigaciones Cientificas CSIC
Universidad Politecnica de Valencia
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Publication date
Application filed by Consejo Superior de Investigaciones Cientificas CSIC, Universidad Politecnica de Valencia filed Critical Consejo Superior de Investigaciones Cientificas CSIC
Publication of WO2012007619A1 publication Critical patent/WO2012007619A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

Definitions

  • the present invention relates to a new method of synthesis of a series of water soluble derivatives of camptothecin, which act as antitumor agents, with application within the scope of the pharmaceutical industry as drugs for curing, stopping or alleviating tumors or cancer, such Like uterine cancer
  • the CPT is a pentacyclic alkaloid isolated for the first time by Wall et al. (J. Am. Chem. Soc, vol. 88 (16), pp. 3888-90, 1966) from a tree of Chinese origin (Campoteca acuminatá) in 1966. Due to the presence of a hydroxylated lactone ring in the alkaloid structure, under physiological pH conditions, a balance is established between the form of "lactone-closed” and "carboxylate-open" in the CPT.
  • Topotecan (Hycamtin ® ), [20- (S) -9-dimethylaminomethyl-10-hydroxycamptothecin] is a semi-synthetic derivative that incorporates a basic chain at position 9 of the quinolinic ring of 10-Hydroxycamptothecin which allows the drug to be solubilized in hydrochloride form.
  • the obtaining of Topotecan is widely studied and has different variants, although all of them imply a Mann ⁇ ch reaction between 10-hydroxycoatotecine, dimethylamine and formalin in an acidic medium, obtaining the final product in a clearly viable yield.
  • neutropenia, thrombocytopenia and hemorrhagic cystitis are some of the side effects of the compound.
  • the Mannich reaction has allowed to obtain numerous soluble analogs of CPT based on the reactivity of primary or secondary amines of different size, nature and polarity.
  • synthetic routes alternative to the Mannich reaction simple and with acceptable yields, when obtaining water-soluble aminomethyl Camptothecin derivatives substituted at position 9.
  • the present invention relates to a new and surprising method of synthesis of 9-aminomethyl camptotecine derivatives that act as antitumor agents, with application within the scope of the pharmaceutical industry, as drugs to cure, stop or alleviate tumors or cancer, such as cancer of the epithelial type, for example and without limitation, uterine cancer.
  • the present invention relates to a method of synthesis of 9-aminomethyl camptothecin of general formula (I)
  • R 1 and R 4 are the same or different and are independently selected from hydrogen or a C C alkyl group
  • R 2 is selected from the list comprising hydrogen, a Crdo alkyl, C 2 -Ci 0 alkenyl, C 2 -C 10 alkynyl, -COR 11 , -COOR 12 , aryl or heterocyclic group,
  • R3 is selected from the list comprising an alkyl group C1-C10 alkyl , C 2 -C 10 alkynyl, C 2 -C 10, -NR 9 R 10, -COR 11, -COOR 12, aryl, heterocycloalkyl or joined R 2 formed a heterocycloalkyl,
  • R 5 , R 6 , R 7 and R 8 are the same or different, and are independently selected from hydrogen or a C 1 -C 10 alkyl group
  • R 9 , R 10 and R 12 are the same or different, and are independently selected from hydrogen or a C 1 -C- 10 alkyl group, and R 1 1 is selected from the list comprising hydrogen, C1-C10 alkyl or aryl.
  • alkyl refers, in the present invention, to radicals of hydrocarbon chains, linear or branched, having 1 to 10 carbon atoms, preferably 1 to 4, and which are attached to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, / -propyl, n-butyl, tere-butyl, sec-butyl, n-pentyl, n-hexyl, etc.
  • the alkyl groups may be optionally substituted by one or more substituents such as halogen, hydroxyl, alkoxy, carboxyl, carbonyl, cyano, acyl, alkoxycarbonyl, amino, nitro, mercapto and alkylthio.
  • alkenyl refers to radicals of hydrocarbon chains, linear or branched, having 2 to 10 carbon atoms, preferably 2 to 4, and containing one or more double carbon-carbon bonds, for example, vinyl, 1-Propenyl, allyl, isoprenyl, 2-butenyl, 1, 3- butadiene, etc.
  • Alkenyl radicals may be optionally substituted by one or more substituents such as halo, hydroxy, alkoxy, carboxyl, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto and alkylthio.
  • alkynyl refers to radicals of hydrocarbon chains, linear or branched, having 2 to 10 carbon atoms, preferably 2 to 4, and containing one or more triple carbon-carbon bonds, for example 1 - propynyl, 2-butynyl, 1,3-butadiinyl, etc.
  • aryl refers in the present invention to an aromatic carbocyclic chain, having from 6 to 12 carbon atoms, which may be single or multiple ring, for example a phenyl, naphthyl, indenyl, phenanthryl or anthracil radical.
  • the aryl radical may be optionally substituted by one or more substituents such as alkyl, haloalkyl, aminomethyl, dialkylamino, hydroxyl, alkoxy, phenyl, mercapto, halogen, nitro, cyano and alkoxycarbonyl.
  • heterocycloalkyl refers, in the present invention, to a stable monocyclic or bicyclic radical of 3 to 15 members, which is unsaturated, saturated or partially saturated, and consisting of carbon atoms and at least one heteroatom selected from the group consisting of nitrogen, oxygen or sulfur. Preferably it has 4 to 8 members with one or more heteroatoms and more preferably 5 to 6 members with one or more heteroatoms.
  • the heterocycle may be a monocyclic, bicyclic or tricyclic system, which may include fused rings.
  • the nitrogen, carbon and sulfur atoms of the heterocyclic radical may optionally be oxidized;
  • the nitrogen atoms may optionally be quaternized and the heterocyclic radical may be partially or fully saturated or aromatic.
  • heterocycles may be, but are not limited to: azepines, indols, imidazoles, isothiazoles, thiaadiazoles, furan, tetrahydrofuran, benzimidazole, benzothiazole, piperidine, piperazine, purine, quinoline.
  • R 1 and R 4 are independently selected from H or C1-C2 alkyl.
  • R 1 is hydrogen.
  • R 4 is hydrogen.
  • R 4 is an ethyl group.
  • R 4 is a methyl group.
  • R 2 is hydrogen.
  • R 3 is a C1-C10 alkyl chain. According to a preferred embodiment R 3 is a methyl group.
  • R 3 is attached to R 2 forming a heterocycloalkyl group of general formula (VI):
  • heterocycloalkyl group of the general formula (VI) is selected from the list comprising pyrrolidinone, maleimide, succinimide, hydantoin, glutaridime, urazole and N- (hydroxymethyl) phthalimide, preferably pyrrolidinone, maleimide, or phthalimide and more preferably N - (hydroxymethyl) phthalimide.
  • R 5 , R 6 , R 7 and R 8 are hydrogen.
  • the compound of general formula (I) is selected from:
  • the compound of general formula (I) is selected from: -20 ⁇ S) -10-Hydroxy-9-aminomethylcamptothecin
  • the compound of general formula (II) is selected from:
  • the compound of general formula (II) is selected from:
  • the compound of general formula (IV) is selected from:
  • the compound of general formula (V) is hydrazine.
  • step (a) is carried out under standard conditions of the Tscherniac-Einhorn reaction.
  • alcohol in the second stage, in which the compound of general formula (IV) reacts with the compound of general formula (V), is understood as any hydroxyalkyl chain of 1 to 6 carbon atoms, as per example and without limitation methanol or ethanol.
  • the second stage can be carried out in acidic medium without the compound of general formula (V), by standard conditions, for example of HCI or dilutions thereof with alcohols or water.
  • the compounds of the present invention represented by formula (I) may include isomers, depending on the presence of multiple bonds (eg, Z, E), including optical isomers or enantiomers, depending on the presence of chiral centers.
  • the individual isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention, that is, the term isomer also refers to any mixture of isomers, such as diastereomers, racemic, etc., even their optically isomers. assets or mixtures in different proportions thereof.
  • the individual enantiomers or diastereoisomers, as well as mixtures thereof, can be separated by conventional techniques.
  • the compounds of the invention may be in crystalline form as free compounds or as solvates.
  • solvate includes both pharmaceutically acceptable solvates, that is, solvates of the compound of formula (I) that can be used in the manufacture of a medicament, as pharmaceutically acceptable solvates, which may be useful in the preparation of pharmaceutically acceptable solvates or salts.
  • the nature of the pharmaceutically acceptable solvate is not critical as long as it is pharmaceutically acceptable.
  • the solvate is a hydrate.
  • Solvates can be obtained by conventional solvation methods known to those skilled in the art.
  • the compound of general formula (I) is in the form of a pharmaceutically acceptable salt selected from the group consisting of acetates, methane sulphonates, mono or dihydrochlorides, or alkali metal salts such as sodium, potassium.
  • a pharmaceutically acceptable or substantially pure form that is, having a pharmaceutically acceptable level of purity excluding pharmaceutical additives. normal such as diluents and carriers, and not including material considered toxic at normal dosage levels.
  • the purity levels for the active ingredient are preferably greater than 50%, more preferably greater than 70%, and still more preferably greater than 90%. In a preferred embodiment, they are greater than 95% of the compound of formula (I), or of its salts, isomers or solvates.
  • the synthesis process presented in the present invention shows optimal yields for industrial development and possible scaling processes.
  • N- (Hydroxymethyl) phthalamide (00mgrs, 0.56mmol) was gradually added to a continuously stirred solution of 10-Hydroxycamptothecin (204mgrs, 1 eq) in concentrated sufuric acid at 0 ° C, the reaction was followed by TLC and added water and ice when considered finished. The precipitated reaction crude was kept in a refrigerator for 12 hours, then filtered and dried in vacuo.
  • the solid obtained can be considered pure enough to be used later, obtaining 261 mgrs (0.498 mmol)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne un nouveau procédé de synthèse d'une série de dérivés de camptothécine solubles dans l'eau, qui servent d'agents antitumoraux, pouvant être utilisés dans le domaine de l'industrie pharmaceutique en tant que médicaments pour soigner, stopper ou réduire des tumeurs ou un cancer, tels que le cancer de l'utérus.
PCT/ES2011/070450 2010-07-16 2011-06-21 Procédé d'obtention de dérivés solubles dans l'eau de 20(s) camptothécine en tant qu'agents antitumoraux Ceased WO2012007619A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ESP201031098 2010-07-16
ES201031098A ES2373172B1 (es) 2010-07-16 2010-07-16 Proceso de obtención de derivados solubles en agua de 20 (s) camptotecina como agentes antitumorales.

Publications (1)

Publication Number Publication Date
WO2012007619A1 true WO2012007619A1 (fr) 2012-01-19

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PCT/ES2011/070450 Ceased WO2012007619A1 (fr) 2010-07-16 2011-06-21 Procédé d'obtention de dérivés solubles dans l'eau de 20(s) camptothécine en tant qu'agents antitumoraux

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ES (1) ES2373172B1 (fr)
WO (1) WO2012007619A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103145720A (zh) * 2013-02-20 2013-06-12 上海北卡医药技术有限公司 一种10-羟基喜树碱的一水合物的制备方法
US10711235B2 (en) 2014-12-22 2020-07-14 Saint-Gobain Performance Plastics Corporation Gas permeable material
US11050098B2 (en) 2016-05-20 2021-06-29 HYDRO-QUéBEC Process for the recycling of lithium battery electrode materials
US12029736B2 (en) 2020-02-25 2024-07-09 Mediboston Limited Camptothecin derivatives and conjugates thereof
US12521444B2 (en) 2021-02-25 2026-01-13 Fortvita Biologics Limited Anti-HER2 antibody-drug conjugates and uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0540099A1 (fr) * 1991-10-29 1993-05-05 Glaxo Wellcome Inc. Dérivés de camptothécine solubles dans l'eau
WO2004087715A1 (fr) * 2003-03-31 2004-10-14 Council Of Scientific And Industrial Research Procede pour preparer du topotecan a partir de 10-hydroxy-4-(s)-camptothecine
WO2008127606A1 (fr) * 2007-04-11 2008-10-23 Scinopharm Taiwan, Ldt. Procédé de fabrication du topotécan

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0540099A1 (fr) * 1991-10-29 1993-05-05 Glaxo Wellcome Inc. Dérivés de camptothécine solubles dans l'eau
WO2004087715A1 (fr) * 2003-03-31 2004-10-14 Council Of Scientific And Industrial Research Procede pour preparer du topotecan a partir de 10-hydroxy-4-(s)-camptothecine
WO2008127606A1 (fr) * 2007-04-11 2008-10-23 Scinopharm Taiwan, Ldt. Procédé de fabrication du topotécan

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103145720A (zh) * 2013-02-20 2013-06-12 上海北卡医药技术有限公司 一种10-羟基喜树碱的一水合物的制备方法
US10711235B2 (en) 2014-12-22 2020-07-14 Saint-Gobain Performance Plastics Corporation Gas permeable material
US11142736B2 (en) 2014-12-22 2021-10-12 Saint-Gobain Performance Plastics Corporation Gas permeable material
US11050098B2 (en) 2016-05-20 2021-06-29 HYDRO-QUéBEC Process for the recycling of lithium battery electrode materials
US12029736B2 (en) 2020-02-25 2024-07-09 Mediboston Limited Camptothecin derivatives and conjugates thereof
US12521444B2 (en) 2021-02-25 2026-01-13 Fortvita Biologics Limited Anti-HER2 antibody-drug conjugates and uses thereof

Also Published As

Publication number Publication date
ES2373172B1 (es) 2012-12-10
ES2373172A1 (es) 2012-02-01

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