EP1385846A2 - Procede de synthese de promedicaments a base de pancratistatine - Google Patents

Procede de synthese de promedicaments a base de pancratistatine

Info

Publication number
EP1385846A2
EP1385846A2 EP02733993A EP02733993A EP1385846A2 EP 1385846 A2 EP1385846 A2 EP 1385846A2 EP 02733993 A EP02733993 A EP 02733993A EP 02733993 A EP02733993 A EP 02733993A EP 1385846 A2 EP1385846 A2 EP 1385846A2
Authority
EP
European Patent Office
Prior art keywords
pancratistatin
phosphate
sodium methoxide
dibenzyl
prodrug
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.)
Withdrawn
Application number
EP02733993A
Other languages
German (de)
English (en)
Other versions
EP1385846A4 (fr
Inventor
George R. Petit
Brian Orr
Sylvie Ducki
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.)
Arizona State University ASU
Original Assignee
Arizona State University ASU
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Arizona State University ASU filed Critical Arizona State University ASU
Publication of EP1385846A2 publication Critical patent/EP1385846A2/fr
Publication of EP1385846A4 publication Critical patent/EP1385846A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates generally to the discovery of a new and efficient synthesis of the (+)- ⁇ ancratistatin phosphate prodrug and fourteen (14) metal and ammonium cation derivatives thereof.
  • the pancratistatin phosphate prodrug denominated 2a in the enclosed Scheme was found to have exceptional solubility in water and therefore readily administerable in the treatment of human cancer.
  • the anti cancer phenanthridone (+)-pancratistatin (la) was isolated from the bulbs of the Hawaiian Hymenocallis (formally Pancratium) littoralis (Pettit et al., 1984a, Journal of the Chemical Society, Chemical Communications, 1693; Pettit et al, 1984b, Journal oj Natural Products, 41, 1018). The structure was determined by NMR spectroscopy and confirmed by x-ray crystallographic analysis of its 7-methoxy derivative (lb).
  • pancratistatin (la) was found to exhibit strong in vitro cancer cell growth inhibitory activities including against the U.S. National Cancer Institute (NCI) panel of cancer cell lines (Pettit et al, 1986, Journal of Natural Products, 49, 995; 1993 Journal of Natural Products, 56, 1682) and a series of in vivo experimental cancer systems.
  • NCI National Cancer Institute
  • a related area of promise involves its activity against a range of RNA viruses (Gabrielsen et al, 1992, Journal of Natural Products, 55, 1569). Due to the relatively low natural abundance ( ⁇ 0.039% of dry bulb) and its increasing potential as a clinically useful antitumor agent, pancratistatin has become an important target for total synthesis.
  • pancratistatin (la) pancratistatin (la) was earlier hampered due to its poor solubility in water ( ⁇ 53 ⁇ g/ml). This problem was addressed (Pettit et al, 1995a, Anti-Cancer Drug Design, 10, 243) by developing a synthesis of the phosphate prodrug (2a) which displayed greatly improved solubility characteristics in water and was found to exhibit equal activity against the murine P388 lymphocytic leukemia cell. Presumably, attachment of a phosphate is also beneficial for in vivo systems since human non-specific phosphatases will hydrolyze the phosphate prodrug following administration to release (+) -pancratistatin (l ).
  • Fig. 1 is a schematic showing of the step-by-step synthesis of the present invention. Detailed Description Of Preferred Embodiment
  • (+)-Pancratistatin (la) was isolated from Hymenocallis littoralis as previously described (Pettit et al, 1995b, Journal of Natural Products, 58, 37).
  • Acetic anhydride, pyridine, dibenzyl phosphite, N-ethyldiisopropylamine and 10% palladium over carbon catalyst were purchased from Lancaster Synthesis, Inc.
  • Carbon tetrachloride, 4-dimethylaminopyridine, anhydrous magnesium sulfate (MgSO 4 ), potassium dihydrogenphosphate, phosphomolybdic acid, and zinc acetate dihydrate were from Sigma- Aldrich Chemical Co.
  • Sodium methoxide, lithium hydroxide monohydrate, piperazine (anhydrous) and morpholine were from Acros Organics.
  • Calcium acetate and manganese acetate were purchased from Fisher Scientific Co. and magnesium acetate quinine, quinidine and imidazole from J. T. Baker Chem. Rubidium carbonate and cesium carbonate were supplied by Alfa Products, Inc. and potassium acetate from Mallinckrodt. All solvents were redistilled prior to use and dried when necessary. Solvent extracts of aqueous solutions were dried over magnesium sulfate.
  • the 1 ,0 M solutions of the metal bases were prepared in distilled water and the 1.0 M solutions of the amines in dry methanol.
  • sodium methoxide 87 mg, 1.61 mol
  • the mixture was stirred at room ' temperature for 2 hours and then water (50 ml) was added.
  • the aqueous mixture was extracted with dichloromethane (5 x 50 ml) and the combined organic extract was dried, filtered and evaporated in vacuo (NO HEAT) to give the crude deacetylated derivative as a white powder (1.8 g).
  • pancratistatin prodrugs (2b-o) Following General procedure for synthesis of the pancratistatin prodrugs (2b-o): To an aqueous methanol solution of the phosphoric acid derivative of pancratistatin (6, 50 mg in 1 ml water or methanol) was added a 1.0 M solution (250 ⁇ l) of the appropriate metal (carbonate or acetate) salt or amine free base. The solution became cloudy and the mixture was stirred for 6 hours. The mixture was freeze dried (or evaporated) to afford the desired prodrug salt (2b-o). The salts were further purified by trituration with wet methanol and/or diethyl- ether to remove un-reacted starting materials.
  • pancratistatin 7-O-phosphate (2e) Yellow oil (0.22 g); ⁇ /ppm (300 MHz, D 2 O) 6.63 (IH, bs, H-10), 6.01 (IH, s, OCH ⁇ H B O), 5.90 (IH, s, OCH A H 5 ⁇ ), 4.46 (1 ⁇ , bs, ⁇ -l), 4.17 (1 ⁇ , bs, ⁇ -2), 3.98 (1 ⁇ , bs, ⁇ -3), 3.85 (IH, m, H-4), 3.79 (IH, m, H-4a), 3.08 (IH, d, J 12 Hz, H-lOb); m/z (FAB) 669.9 [(M + H) + , 50%], 225.0 (100); HRFAB 669.8468 calculated for
  • OCH_H B O 5.96 (IH, s, OCH A H 5 O), 4.41 (1 ⁇ , bs, ⁇ -l), 4.14 (1 ⁇ , bs, ⁇ -2), 3.97 (l ⁇ , bs, H-3), 3.76 (2H, m, H-4, H-4a), 3.41 (IH, d, J l l Hz, H-lOb).
  • pancratistatin (la) was simply allowed to react with acetic anhydride and 4-dimethylaminopyridine in pyridine to give the 1,2,3,4,7-O-pentaacetoxy derivative (3) and then immediately converted to the desired 1,2,3,4-O-tetraacetate (4) by heating in refluxing water-pyridine (66% yield).
  • Reaction of the latter with dibenzyl phosphite in the presence of carbon tetrachloride, N-ethyldiisopropylamine and 4-dimethylaminopyridine afforded the heat sensitive pancratistatin 7-0- dibenzylphosphate (5) in 87%) yield.
  • prodrug derivatives exhibited activities analogous to that of (+)-pancratistatin (la) and the sodium prodrug (2a).
  • manganese (2i) and morpholine (2k) derivatives showed a 10- to 20-fold increase in activity, their poor water solubility made questionable their use for further preclinical development as potential prodrugs.
  • the sodium derivative (2a) continues to be the preferred choice owing to its high activity, adequate water solubility, and the efficient synthesis described herein.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Molecular Biology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de synthèse innovant et efficace d'un promédicament (2a) à base de (+)-pancratistatine phosphate. Dans ce procédé, la protection sélective (tetraacétate 4) de la (+)-pancratistatine (1a) est suivie par une phosphorylation (à 5) avec du chlorophosphite de dibenzyle (préparé in situ à partir de phosphite de dibenzyle). Le clivage des groupes de protection de l'acétate (avec du méthoxyde de sodium) et du benzyle (par hydrogénolyse) suivi par une réaction concomitante avec deux équivalents du méthoxyde de sodium permet d'obtenir un bon rendement de disodium (+)-pancratistatine phosphate (2a). Des augmentations supplémentaires dans le rendement du promédicament (2a) ont également été obtenues par élimination de la chaleur dans les étapes finales de purification. Ainsi, quatorze (2b-o) promédicaments supplémentaires à base de phosphate, dérivés de cations métalliques et de cations ammonium ont également été obtenus par synthèse.
EP02733993A 2001-04-18 2002-04-17 Procede de synthese de promedicaments a base de pancratistatine Withdrawn EP1385846A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US28471701P 2001-04-18 2001-04-18
US284717P 2001-04-18
PCT/US2002/011964 WO2002085848A2 (fr) 2001-04-18 2002-04-17 Procede de synthese de promedicaments a base de pancratistatine

Publications (2)

Publication Number Publication Date
EP1385846A2 true EP1385846A2 (fr) 2004-02-04
EP1385846A4 EP1385846A4 (fr) 2005-11-30

Family

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Family Applications (1)

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EP02733993A Withdrawn EP1385846A4 (fr) 2001-04-18 2002-04-17 Procede de synthese de promedicaments a base de pancratistatine

Country Status (3)

Country Link
EP (1) EP1385846A4 (fr)
CA (1) CA2444471A1 (fr)
WO (1) WO2002085848A2 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180030095A1 (en) 2015-02-13 2018-02-01 George Robert Pettit Silstatin compounds

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5529989A (en) * 1995-01-09 1996-06-25 Arizona Board Of Regents Acting On Behalf Of Arizona State University Pancratistatin prodrug

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5529989A (en) * 1995-01-09 1996-06-25 Arizona Board Of Regents Acting On Behalf Of Arizona State University Pancratistatin prodrug

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PETTIT, GEORGE R. ET AL: "Antineoplastic agents 453. Synthesis of pancratistatin prodrugs" ANTI-CANCER DRUG DESIGN , VOLUME DATE 2000, 15(6), 389-395 CODEN: ACDDEA; ISSN: 0266-9536, 2001, XP008053529 *
See also references of WO02085848A2 *

Also Published As

Publication number Publication date
CA2444471A1 (fr) 2002-10-31
WO2002085848A2 (fr) 2002-10-31
WO2002085848A3 (fr) 2003-04-24
WO2002085848A8 (fr) 2003-05-30
EP1385846A4 (fr) 2005-11-30

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