WO1994000156A1 - Polymer-bound paclitaxel derivatives - Google Patents

Polymer-bound paclitaxel derivatives Download PDF

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Publication number
WO1994000156A1
WO1994000156A1 PCT/EP1993/001433 EP9301433W WO9400156A1 WO 1994000156 A1 WO1994000156 A1 WO 1994000156A1 EP 9301433 W EP9301433 W EP 9301433W WO 9400156 A1 WO9400156 A1 WO 9400156A1
Authority
WO
WIPO (PCT)
Prior art keywords
phe
gly
leu
βala
ala
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.)
Ceased
Application number
PCT/EP1993/001433
Other languages
English (en)
French (fr)
Inventor
Nicola Mongelli
Francesco Angelucci
Enrico Pesenti
Antonio Suarato
Giovanni Biasoli
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.)
Pfizer Italia SRL
Original Assignee
Farmitalia Carlo Erba SRL
Carlo Erba SpA
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
Priority to CZ94620A priority Critical patent/CZ62094A3/cs
Priority to EP93912905A priority patent/EP0600062B1/en
Priority to RU94016158A priority patent/RU2130462C1/ru
Priority to AU43233/93A priority patent/AU659750B2/en
Priority to KR1019940700488A priority patent/KR100281606B1/ko
Priority to DE69330776T priority patent/DE69330776T2/de
Priority to AT93912905T priority patent/ATE205725T1/de
Priority to PL93302437A priority patent/PL173898B1/pl
Application filed by Farmitalia Carlo Erba SRL, Carlo Erba SpA filed Critical Farmitalia Carlo Erba SRL
Priority to JP50198194A priority patent/JP3693340B2/ja
Priority to UA94005444A priority patent/UA39926C2/uk
Publication of WO1994000156A1 publication Critical patent/WO1994000156A1/en
Priority to FI940733A priority patent/FI940733A0/fi
Priority to NO940567A priority patent/NO940567L/no
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • POLYMER-BOUND PACLITAXEL DERIVATIVES The present invention is directed to polymer-bound paclitaxel and polymer-bound paclitaxel derivatives endowed with antitumor activity, to a method for their preparation and to pharmaceutical compositions containing them.
  • Paclitaxel (also named Taxol in several publications) is a member of the taxane family of diterpenes, isolated and characterized from an extract of bark of Taxus brevifolia L. ; other analogues of paclitaxel are also known and were prepared by semisynthesis starting from 10-deacetyl baccatin III, extracted from the needles of Taxus baccata L.. see Wain et al. in JACS, .93 . , 2325 (1971) and Lovelle et al., Proc. Am. Assoc. Cancer Res., 31. p. 417, (1990) .
  • the present invention provides a polymer conjugate of the formula I consisting essentially of: from 90 to 99.9 mol % of units of the formula:
  • R is a phenyl or t-butoxy group
  • R 3 is H or an acetyl group
  • a and A which may be the same or different, represent a chemical single bond, an amino acid residue or peptide spacer selected from ⁇ Ala, Gly, Phe-Gly, Phe-Phe-, Leu-Gly, Val-Ala, Phe-Ala, Leu- Phe, Leu-Ala, Phe-Leu-Gly, Phe-Phe-Leu, Leu-Leu-Gly, Phe- Tyr-Ala, Phe-Gly-Phe, Ph -Phe-Gly, Phe-Leu-Gly-Phe, Gly- Phe-Leu-Gly-Phe,Gly-3Ala, Phe-Gly- ⁇ Ala, Phe-Phe- ⁇ Ala, Leu-Gly- ⁇ Ala, Val-Ala- ⁇ Ala, Phe-Ala- ⁇ Ala, Leu-Phe- ⁇ A
  • the present invention provides polymer conjugates of paclitaxel and derivatives of paclitaxel with improved water solubility and decreased toxicity.
  • the mol % of units containing the paclitaxel and paclitaxel derivatives is from 0.5 to 2 , more preferably, the content of paclitaxel in the polymer was from 2 to 10 % (w/w) , most preferred compounds are those characterized by a content of from 4 to 7 % (w/w) .
  • the wavy line denotes that the oxygen linked at position 7 of the paclitaxel structure may be in both configurations, i.e. ⁇ (natural) or ⁇ .
  • R represents a phenyl group
  • R 3 is an acetyl group
  • A is a Phe-Leu-Gly or Phe-Leu-Gly- ⁇ Ala residue. All the amino acid residues have the natural L- configuration.
  • the polymer conjugate is a copolymer of 1-methacryloylamino- 2-hydroxypropane, (methacryloylglycyl-phenylalanyl- leucylglycyl) 3-amino-2 hydroxypropane and 2'- (methacryloylglycylphenylalanylleucylglycyl-/3alanyl) paclitaxel.
  • Samples were extracted by adding 75 ⁇ l of Tetra Butyl Ammonium Phosphate (TBAP) 0.5 M, 1250 ⁇ l CH 3 CN and 150 ⁇ l of NaCl 5M and vigorously shacked for 20' at 4°C. After that time samples were spun at 15000 x g for 10' and the supernatants were collected and evaporated using a high vacuum centrifuge . Samples were recovered by adding 500 ⁇ l of MeOH:H 2 0 (75:25 V/V) and injected into HPLC for determining the total paclitaxel percentage content.
  • TBAP Tetra Butyl Ammonium Phosphate
  • the present invention also provides a process for preparing a polymer conjugate which process comprises reacting a compound of the formula II
  • a 2 and A 3 are a chemical bond and the other one is A, and A, R and R 3 are as defined above, with an activated polymer consisting essentially of from 90 to 99.9 mol % of units represented by formula
  • reaction between the compounds of the formula II and the activated polymer is carried out in an anhydrous polar organic solvent such as dimethylsulfoxide or dimethylformamide optionally in presence of an organic or inorganic base such as an alkaline carbonate, dimethyla inopyridine or triethylamine.
  • an organic or inorganic base such as an alkaline carbonate, dimethyla inopyridine or triethylamine.
  • the reaction is typically carried out at a temperature of from 15 to 40°C, preferably at room temperature.
  • the alkaline carbonate is, for example, an alkali metal carbonate or an alkaline earth metal carbonate.
  • 7-epi derivatives may be prepared by refluxing in toluene paclitaxel or its analogs in the presence of a base (Na 2 C0 3 or diazabicycloundecene)
  • a base Na 2 C0 3 or diazabicycloundecene
  • Other compounds of the formula II are new, in particular those in which A 3 is ⁇ hla residue and those in which either A 2 or A 3 represents di, tri, or tetra peptide spacer as defined above for A and are within the scope of the invention.
  • the compounds of formula II wherein A 2 is not a chemical single bond may be prepared by reacting a paclitaxel or a paclitaxel analog with protected amino acid or peptide in the presence of a condensating reagent, and with or without the additional presence of a catalyst, preferably at room temperature, followed by the removal of the protecting group with known methods.
  • the condensation may be also carried out using activated esters such as paranitrophenyl ester of peptide or amino acid.
  • Suitable condensing reagents include carbodiimides such as dicyclohexyl carbodii ide (DCC) .
  • Suitable catalysts include 4-dimethylamino-pyridine (DMAP) , pyridine or triethylamine.
  • Various known amino protecting groups can be utilized and commercially available protected amino acid or peptide ⁇ can be utilized as the starting materials.
  • Amino acids or peptides protected with t-BOC, trityl, FMOC or carbobenzyloxy (CBZ) can be utilized.
  • Amino Acid or peptides procted with t-BOC, trityl or FMOC groups are preferred.
  • the compounds of the formula II wherein A 3 is not a chemical single bond may be prepared by protecting or blocking the 2'-hydroxy group and then esterifying the 7- position hydroxyl and then removing the 2'-protecting or blocking group.
  • the compounds of the formula II wherein A 3 is Gly or Ala residue are prepared by reacting paclitaxel with 2-3 equivalents of N-protected amino acid to produce 2' ,7-disubstituted paclitaxel, the 2'-position amino acid is cleaved and then the 7-position amino acid is deprotected.
  • Reaction of paclitaxel and the protected amino acid is conducted in the presence of a condensing reagent and a catalyst, like those above defined.
  • Cleavage of the 2'-amino acid is conducted by adjusting the pH of the 2'-7-(amino acid) paclitaxel solution to pH 7-7.4 for example by mixture of the 2' ,7-di(amino acid) paclitaxel in a phosphate buffer at pH 7-7.4 or with a slight excess of NaHC0 3 .
  • Deprotection of the amino acid is conducted under a known amino acid deprotection method, such as mild acid treatment with, for example, acetic acid, or by reduction.
  • paclitaxel is allowed to react with 2- 3 mol. equivalent of N-protected amino acid (t.boc, CBZ or FMOC protected) in methylene chloride in the presence of DCC and a catalytic amount of 4-dimethylaminopyridine.
  • the protected amino acid is introduced at 2' and 7-position.
  • the 2',7-bis amino acid derivative of paclitaxel is allowed to stand in presence of NaHC0 3 in H 2 0/MeOH for 2-5 hours, whereby selective deprotection at the 2'-position occurs to yield the 7-substituted derivative of paclitaxel.
  • the protecting groups are removed by appropriate deprotecting agent (e.g., acid, mild base or hydrogenolysis) .
  • the activated polymer is a synthetic, water soluble polymer prepared by the copolymerization of N'-(2- hydroxypropyl) methacrylamide with p-nitrophenylesters of N-methacryloyl oligopeptides, as described in US-A- 4062831 and US-A-4097470.
  • the polymer conjugates of the formula I and the new paclitaxel derivatives of the formula II exhibit good water solubility, biocompatibility and release the paclitaxel or paclitaxel derivative in the plasma or after internalization into cells by cleaving of the oligopeptide spacers.
  • Biological activity Microtubule assembly and disassembly assay
  • Calf brain tubulin was prepared by two cycles of assembly-disassembly (Shelanski M.L. Gaskin F. and Cantor C.R., Proc. Natl. Acad.Sci. U.S.A. 70, 765-768, 1973) and stored in liquid nitrogen in MAB (0.1 M MES, 2.5 mM EGTA, 0.5 mM MgS0 4 , 0.1 mM EDTA, 0.1 mM DTT pH 6.4) . All the experiments were carried out on protein stored for less than 4 weeks. Before each experiment, the tubulin was kept 30 min at 4°C.
  • copolymer-paclitaxel prepared in Example 6 was tested in vivo against B16 F10 murine melanoma in comparison with paclitaxel.
  • mice C57B16 female mice were obtained from Charles River Italy.
  • paclitaxel was dissolved in a vehicle consisting of polyoxyethylated castor oil (Cremophor EL) 50% and ethanol 50% and then diluted with glucose 5% solution at the desidered concentrations. The solution was slightly hazy and precipitates formation was observed after short time.
  • Cremophor EL polyoxyethylated castor oil
  • the compound of example 6 was easily dissolved in glucose 5% and the resulting solution was clear for long time (more than 2 hours) . Final concentrations were referred to the paclitaxel content of the compound (4% of total) .
  • the murine melanoma B16F10 was used. A suspension of 10 5 tumor cells in 0.2 ml was injected ⁇ ubcutaneously in the flank of mice. Tumor size was measured with caliper and tumor weight was calculated with the formula:
  • Paclitaxel was given intraperitoneally because of its poor solubility and vehicle toxicity.
  • the compound of example 6 was injected intravenously. Both compounds were administered at day 1, 5, 9 after tumor implantation.
  • TOX number of mice which died for toxicity. TOX determination was made when mice died before the control or when significant body weight loss and/or spleen and or/or liver size reduction were observed. From the above data, it can be seen that the polymer conjugates of the present invention exhibit excellent antitumor activity. These compounds, therefore, are useful antitumor agents due to the lower toxicity and increased water solubility as compared to paclitaxel or its derivative. Examples of tumors that can be treated are for istance, sarcomas, carcinoma, lymphomas, neuroblastoma, melanoma, myeloma, Wilms tumor, leukemias and adenocarcinoma.
  • the improved solubility ad decreased toxicity of the polymer-conjugates of the present invention means that they are suitable for intravenous injection or infusion.
  • the dosage depends upon the age, weight and condition of the patient.
  • the dosage may be from 1 mg/kg body weight to 1 g/kg body weight, preferably from 4 to 800 mg/kg body weight.
  • Typical formulations contain a quantity of polymer-bound paclitaxel/poly erbound paclitaxel derivative equivalent to 0.5, 1.5, 10, 20, 25, or 50 mg of the active paclitaxel/paclitaxel derivative.
  • the polymer conjugates may be formulated as pharmaceutical compositions with a pharmaceutically acceptable carrier or diluent. Any appropriate carrier or diluent may be used.
  • the solutions for intravenous injection or infusion may contain as carrier or diluent, for example, sterile water or preferably they may be in the form of sterile, aqueous or isotonic saline solutions.
  • carrier or diluent for example, sterile water or preferably they may be in the form of sterile, aqueous or isotonic saline solutions.
  • reaction solution was quenched with 0.3 ml glacial acetic acid, concentrated under vacuum to a small volume, and then poured into 200 ml of acetone. Ater 30' mixing, the precipitate was filtered and washed with acetone to yield 1.25 g of the title compound.
  • the paclitaxel content was 4.5% (evaluated by enzymatic hydrolysis and HPLC analysis) .
  • the compound 2' (N-Trit-Phe-Leu-Gly)paclitaxel (250 mg) was dissolved into a mixture of glacial acetic (22 ml) and water (6 ml) and the whole was stirred for 1 hour at room temperature. The solvents were evaporated in vacuum to the dryness, the residue stirred with diethylether-hexane 1:1 for 30 minutes and filtered to obtain 160 mg of the title compound.
  • Copolymer of l-methacryloylamino-2-hydroxy -propane, 1(methacryloyl-glycyl)amino-2-hydroxypropane and 2' (methacryloyl-glycyl)paclitaxel To a solution of 1.6 g of copolymer of 1-methacryloyl - amino-2-hydroxypropane and N-(methylen-carbonyl-4-nitro- phenoxy)methacrylamide in 16 ml of anhydrous dimethyl ⁇ formamide were added 100 mg of paclitaxel and 20 mg of dimethylamino-pyridine.
  • the reaction solution was quenched with 0.3 ml of glacial acetic acid, concentrated under vacuum to a small volume and poured in 250 ml of acetone. The mixture was stirred for 1 hour, the precipitate was filtered and washed with acetone to yield 1520 mg of the title compound.
  • the paclitaxel content was 7.8% w/w%.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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  • Peptides Or Proteins (AREA)
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PCT/EP1993/001433 1992-06-19 1993-06-07 Polymer-bound paclitaxel derivatives Ceased WO1994000156A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
AT93912905T ATE205725T1 (de) 1992-06-19 1993-06-07 Polymergebundene paclitaxel-derivate
RU94016158A RU2130462C1 (ru) 1992-06-19 1993-06-07 Полимерный конъюгат, способ его получения и фармацевтическая композиция
AU43233/93A AU659750B2 (en) 1992-06-19 1993-06-07 Polymer-bound paclitaxel derivatives
KR1019940700488A KR100281606B1 (ko) 1992-06-19 1993-06-07 중합체-결합 된파클리탁셀 유도체, 이의 제조방법 및 이를 포함하는 약제학적 조성물
DE69330776T DE69330776T2 (de) 1992-06-19 1993-06-07 Polymergebundene Paclitaxel-derivate
PL93302437A PL173898B1 (pl) 1992-06-19 1993-06-07 Koniugat polimeru zawierający pochodne paklitakselu i sposób jego wytwarzania
JP50198194A JP3693340B2 (ja) 1992-06-19 1993-06-07 ポリマー結合型パクリタキセル誘導体
CZ94620A CZ62094A3 (en) 1992-06-19 1993-06-07 Paclitaxel derivatives bound onto a polymer
EP93912905A EP0600062B1 (en) 1992-06-19 1993-06-07 Polymer-bound paclitaxel derivatives
UA94005444A UA39926C2 (uk) 1992-06-19 1993-07-06 Полімерний кон'югат, фармацевтична композиція з протипухлинною активністю
FI940733A FI940733A0 (fi) 1992-06-19 1994-02-16 Polymeerisitoutuneet paklitakselijohdannaiset
NO940567A NO940567L (no) 1992-06-19 1994-02-18 Polymerbundne paclitaxelderivater

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9213077.2 1992-06-19
GB929213077A GB9213077D0 (en) 1992-06-19 1992-06-19 Polymerbound taxol derivatives

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WO1994000156A1 true WO1994000156A1 (en) 1994-01-06

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PCT/EP1993/001433 Ceased WO1994000156A1 (en) 1992-06-19 1993-06-07 Polymer-bound paclitaxel derivatives

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US (4) US5362831A (https=)
EP (1) EP0600062B1 (https=)
JP (1) JP3693340B2 (https=)
KR (1) KR100281606B1 (https=)
CN (1) CN1041281C (https=)
AT (1) ATE205725T1 (https=)
AU (2) AU659750B2 (https=)
CA (1) CA2112482A1 (https=)
CZ (1) CZ62094A3 (https=)
DE (1) DE69330776T2 (https=)
ES (1) ES2164663T3 (https=)
FI (1) FI940733A0 (https=)
GB (1) GB9213077D0 (https=)
HU (2) HUT67914A (https=)
IL (1) IL106023A (https=)
MX (1) MX9303598A (https=)
MY (1) MY109213A (https=)
NZ (1) NZ253116A (https=)
PL (1) PL173898B1 (https=)
RU (1) RU2130462C1 (https=)
SG (1) SG49248A1 (https=)
TW (1) TW266201B (https=)
UA (1) UA39926C2 (https=)
WO (1) WO1994000156A1 (https=)
ZA (1) ZA934388B (https=)

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EP0693485A3 (en) * 1994-06-28 1996-05-08 Tanabe Seiyaku Co Baccatin derivatives and process for their preparation
US5608073A (en) * 1994-11-17 1997-03-04 Tanabe Seiyaku Co., Ltd. Baccatin derivatives and processes for preparing the same
WO1998034968A1 (en) * 1997-02-11 1998-08-13 The Council Of The Queensland Institute Of Medical Research Polymers incorporating peptides
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EP2380606A1 (en) 2006-06-30 2011-10-26 Cook Incorporated Methods of manufacturing and modifying taxane coatings for implantable medical devices
US8313521B2 (en) 1995-06-07 2012-11-20 Cook Medical Technologies Llc Method of delivering an implantable medical device with a bioabsorbable coating
WO2012162010A1 (en) 2011-05-25 2012-11-29 Cordis Corporation Expandable devices coated with a paclitaxel composition
WO2012162007A1 (en) 2011-05-25 2012-11-29 Cordis Corporation Expandable devices coated with a rapamycin composition
US8409601B2 (en) 2008-03-31 2013-04-02 Cordis Corporation Rapamycin coated expandable devices
US8420110B2 (en) 2008-03-31 2013-04-16 Cordis Corporation Drug coated expandable devices
WO2014004760A1 (en) 2012-06-28 2014-01-03 Covidien Lp Post-processing of a medical device to control morphology and mechanical properties
US8642063B2 (en) 2008-08-22 2014-02-04 Cook Medical Technologies Llc Implantable medical device coatings with biodegradable elastomer and releasable taxane agent
US9085605B2 (en) 2010-05-27 2015-07-21 Shenzhen Salubris Pharmaceuticals Co., Ltd. Chemical synthesis and anti-tumor and anti-metastatic effects of dual functional conjugate
WO2017053920A1 (en) 2015-09-25 2017-03-30 Zy Therapeutics Inc. Drug formulation based on particulates comprising polysaccharide-vitamin conjugate

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