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WO2003031467A2 - Derives amino-substitues de polymere de camptothecine et utilisations de ces derives pour la fabrication d'un medicament - Google Patents

Derives amino-substitues de polymere de camptothecine et utilisations de ces derives pour la fabrication d'un medicament Download PDF

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Publication number
WO2003031467A2
WO2003031467A2 PCT/CH2002/000562 CH0200562W WO03031467A2 WO 2003031467 A2 WO2003031467 A2 WO 2003031467A2 CH 0200562 W CH0200562 W CH 0200562W WO 03031467 A2 WO03031467 A2 WO 03031467A2
Authority
WO
WIPO (PCT)
Prior art keywords
gly
amino
phe
leu
camptothecin
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/CH2002/000562
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English (en)
Other versions
WO2003031467A3 (fr
Inventor
Francesco Veronese
Andrea Guiotto
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.)
Debio Recherche Pharmaceutique SA
Yakult Honsha Co Ltd
Original Assignee
Debio Recherche Pharmaceutique SA
Yakult Honsha Co Ltd
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 Debio Recherche Pharmaceutique SA, Yakult Honsha Co Ltd filed Critical Debio Recherche Pharmaceutique SA
Publication of WO2003031467A2 publication Critical patent/WO2003031467A2/fr
Publication of WO2003031467A3 publication Critical patent/WO2003031467A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • 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
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1008—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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

Definitions

  • the present invention relates to new amino-substituted camptothecin polymer derivatives useful as medicaments. It relates also to the use of said derivatives for the manufacture of a medicament.
  • Camptothecin an alkaloid which was first isolated from the Chinese tree Camptotheca acuminata, has attracted much attention because of its significant anti-tumour activity in animals and has initiated medicinal chemistry studies aiming to provide with analogues having improved pharmaceutical profile.
  • pre-clinical and clinical data on some Camptothecin analogues that are already being used in clinical practice or are currently in clinical development have been recently reviewed by Keher et al. in Anti-Cancer Drugs, 2001, 12, 89-105.
  • One of the aims of the present invention is to eliminate the above mentioned drawback by providing with new 9-, 10-, and 11-amino-A-ring- substituted 7-ethylcamptothecin derivatives, allowing the 9-, 10-, and 11-amino- A-ring-substituted 7-ethylcamptothecin pharmacophore to be administrated into the body with an effective plasma half-life and then targeted and accumulated to and into the tumour cells to be treated with a reduce efflux, in particular in multidrug-resistant cells.
  • the object of the present invention relates to amino- substituted camptothecin polymer derivatives, or their pharmaceutically acceptable salts, having the following general formula (I):
  • n is an integer between 10 and 1000;
  • -S- represents a cleavable spacer arm residue of a peptide selected among the following peptides: -Gly-Leu-Phe-Gly-, -Gly-Phe-Leu-Gly-,
  • -X 1 represents a linear or a branched CrC ⁇ -alkyl group and -X 2 is defined as above.
  • the polymeric part of the amino-substituted camptothecin polymer derivatives of the invention corresponds to a polyethylene fragment and it has been selected for its hydrophilic properties.
  • the size of this polyethylene fragment, represented by the integer n, or its molecular weight, is judiciously chosen in order to obtain an appropriate targeting and accumulation of the derivative of the invention to and into the tumour cells to be treated.
  • the preferred derivatives of the invention of general formula (I) are those in which n is an integer between 20 and 400. i.e. those in which the polyethylene fragment exhibits a molecular weight comprised between about 880 and about 17600. More preferably, the polyethylene fragment exhibits a molecular weight of about 10000, with n being equal about 250.
  • the camptothecin pharmacophore is attached to at least one of the two extremities of the polyethylene fragment through the cleavable peptidic spacer arm residue -S-.
  • the peptidic residues are selected for their sensitiveness to lysosomal enzymatic system or to other tumour-related enzymes, such as plasmine, and their capability to be cleaved by such enzymatic system.
  • the cleavable spacer arm residue -S- is selected among the following peptides:
  • the peptidic spacer arm residue is attached to the extremity of the polyethylene fragment through a carbamate group formed between the amino end group of the peptide and the end oxygen atom of the polyethylene fragment.
  • At least one of any of its alpha- and epsilon-amino groups can carry the polyethylene fragment through a carbamate bond.
  • both of the alpha- and epsilon-amino groups carry the polyethylene fragment through a carbamate bond in order to form a branched polymer derivative.
  • the amino group carried on the A-ring of the camptothecin framework of the camptothecin pharmacophore is on position 10. It forms an amide group with the carboxyl end group of the cleavable peptidic spacer arm residue.
  • methyl group preferably terminates the second extremity, through the oxygen atom.
  • the process for the preparation of the derivatives of the invention is based on the linkage of the peptidic spacer arm -S- to the hydroxyl function of mono- alkoxypolyethylene glycol through a carbamate linkage which involves the NH 2 group of the said peptidic arm. This reaction is followed by the activation of the COOH function of said peptidic arm to. an activated ester, which, thus, becomes reactive towards the amino group of the camptothecin pharmacophore.
  • the process consists of: a) reacting a mono-alkoxy-polyethylene glycol derivative of formula (III)
  • R is a linear or a branched CrC- 6 -alkyl group and n have the definition provided above, with benzotriazolchloroformate, 2,4,5-trichlorphenylchloroformate or 4-nitrophenylchloroformate to obtain the corresponding carbonate; b) reacting the carbonate thus obtained with an amino acid the peptide of formula (IV)
  • Steps a) through d) of the above-described process do not necessitate special reaction conditions and can be carried out according to the usual techniques. Furthermore, some of the activated carbonate polymers are commercially available. Details of each of the above reaction steps are provided in the Examples illustrating the invention.
  • Another of the objects of the present invention relates to the use of the amino-substituted camptothecin polymer derivatives of the invention for the manufacture of a medicament for the treatment of tumour cells.
  • the amino-substituted camptothecin polymer derivatives of the invention are water-soluble and show enhanced therapeutic index and/or anti-tumour activity and reduced toxicity in comparison with the corresponding amino- substituted camptothecin or its pharmaceutically acceptable salt. They are useful for treating neoplastic disease, reducing tumour burden, preventing metastasis of neoplasms and preventing recurrences of tumour/neoplastic growths in mammals in the treatment. More specifically, they are useful for treating leukaemia and solid tumours, such as colon, colo-rectal, ovarian, mammary, prostate, lung, kidney and also melanoma tumours. Applying a method comprising administering thereto a therapeutically effective amount of the amino-substituted camptothecin polymer derivatives of the invention can therefore treat a human patient.
  • the dosage range adopted will depend on the route of administration and on the age, weight and condition of the patient being treated.
  • the amino- substituted camptothecin polymer derivatives of the invention are typically administered by parenteral route, for example intramuscularly, intravenously or by bolus infusion.
  • a suitable dose range is from 10 to 500 mg/m2. This range is illustrative and the practitioner will determine the optimal dosing of the amino- substituted camptothecin polymer derivatives based on clinical experience and the treatment indication.
  • the amino-substituted camptothecin polymer derivatives of the invention may be formulated into a pharmaceutical composition well known by the person skilled in the art.
  • the composition may be in the form of solutions, suspensions, tablets, capsules and the like.
  • the compositions may be administrated by oral or parenteral routes.
  • the amino-substituted camptothecin polymer derivatives of the invention are formulated for parenteral administration, for example by dissolution in water for injection or physiological saline.
  • Other ways for administrating the compositions may be envisaged, for instance by inhalation or through intranasal routes.
  • - Fig 1 represents a kinetic curve (circles) of the conversion of the amino- substituted camptothecin polymer derivative of Example 1 by in-vitro hydrolysis by Cathepsin B1 at pH 5.5 and a kinetic curve (crosses) of the release of 10-amino- 7-ethylcamptothecin
  • - Fig 2 represents a kinetic curve (circles) of the conversion of the amino- substituted camptothecin polymer derivative of Example 1 by in-vitro hydrolysis at pH 5.5 and a kinetic curve (crosses) of the release of 10-amino-7-ethyl- camptothecin
  • - Fig 3 represents a kinetic curve (circles) of the conversion of the amino- substituted camptothecin polymer derivative of Example 1 by in-vitro hydrolysis at pH 7.44 and a kinetic curve (crosses) of the release of 10-amino-7-ethyl- camptothecin;
  • - Fig 4 represents a kinetic curve (circles) of the conversion of the amino- substituted camptothecin polymer derivative of Example 1 by in-vitro hydrolysis in mice plasma and a kinetic curve (crosses) of the release of 10-amino-7-ethyl- camptothecin;
  • - Fig 5 represents a kinetic curve (circles) of the conversion of the amino- substituted camptothecin polymer derivative of Example 2 by in-vitro hydrolysis by Cathepsin B1 at pH 5.5 and a kinetic curve (crosses) of the release of 10-amino- 7-ethylcamptothecin;
  • - Fig 6 represents a kinetic curve (circles) of the conversion of the amino- substituted camptothecin polymer derivative of Example 2 by in-vitro hydrolysis at pH 5.5 and a kinetic curve (crosses) of the release of 10-amino-7-ethyl- camptothecin.
  • m-PEG-OH defines a monomethoxypoly- ethylene glycol residue having a molecular weight (mw) of about 10000 and the amino acids or peptides are described by means of the terms usual in the art.
  • m- PEG-benzo-triazolyl carbonate (m-PEG-BTC) and H-Gly-Leu-Phe-Gly-OH were commercially available.
  • reaction mixture was acidified with citric acid to pH 3, and extracted with chloroform (3 x 50 ml).
  • the combined organic solutions were dried over sodium sulphate and concentrated to a small volume at reduced pressure.
  • the resulting slurry was added drop-wise to 200 ml of vigorously stirred diethyl ether.
  • the white precipitate, which formed, was filtered and dried at reduced pressure, affording 0.96 g of crude product, which was applied to a QAE Sephadex A-50 ion exchange column. Elution with mQ grade H 2 0 afforded 0.125 g of starting material (m-PEG-OH); with increase of ionic strength (0.01 N NaCI) the desired compound eluted together with NaCI (0.896g combined).
  • the amount of 10-amino-7-ethylcamptothecin (2) determined in the obtained derivative was 16.7 mg, corresponding to a w/w % of 3.72 % (the theoretical 100% of loading is, for this conjugate, 3.72% according to UV absorption).
  • Buffer solution (A) at pH 5.5 was prepared using KH 2 P0 4 -2H 2 0 0.15 M, 10 "3 M EDTA.
  • Solution (B) was prepared from solution (A) by addition of 5 ⁇ M of GSH.
  • Solution (C) was prepared by addition of 850 ⁇ l of solution (B) to 50 ⁇ l of Cathepsin ⁇ solution, containing 0.285 mg/ml of enzyme (extracted from bovine spleen) in buffer solution (A) (1 mg of enzyme powder contains 11.36 units). The mixture (C) was incubated for 5 min at 37 °C.
  • a PBS buffer solution (D), pH 7.44, containing 0.156 g/ml NaH 2 P0 4 . H 2 0 and 0.88 g/ml of NaCI were prepared. 4.098 mg of derivative (2) was solubilised in 3 ml of PBS solution in volumetric flask.
  • the mixture (E) was incubated at 37°C. At fixed period of time a 50 ⁇ l sample of the mixture was injected in an HPLC system (RP-C18 column).
  • derivative (2) was progressively converted into 10-amino-7-ethylcamptothecin when placed in mouse plasma. After one day, about 18% of derivative (2) were converted.
  • Derivative (2) was tested against murine leukaemia P388 and P388 resistant to adriamycin (P388/ADM).
  • Female CDF1 mice were inoculated intra- peritoneally with P388 or P388/ADM at a dose of 1x10 6 cells/mouse on day 0, and injected intravenously with the derivative on days 1 , 5, and 9 at total doses of 5, 10, 20 or 25 mg/kg, then monitored survival times for 40 days. Due to poor water-solubility, the pharmacophore 10-amino-7-ethylcamptothecin was unable to be tested in comparison. However, one of its water-soluble analogues, namely CPT-11 was used.
  • Table 1 reports the anti-tumour activity of the derivative against P388, while Table 2 reports the same against P388/ADM.
  • Derivative (2) was tested against Meth A fibrosarcoma cells. 7 weeks old male BALB/c mice were inoculated subcutaneously with Meth A cells at a dose of 5x10 5 cells/mouse on day 0. Samples were injected intravenously with the derivative on day 5, and the tumours were weighed on day 21. Due to poor water-solubility, a first reference group was given 10-amino- 7-ethylcamptothecin as its open lactone sodium salt. A second reference group was given water-soluble analogue CPT-11. Control group was given with saline.
  • the reaction mixture was acidified with HC1 1 N to pH 3, and extracted with chloroform (5 x 50 ml). The organic phases were dried over Na 2 SO 4 , filtered and concentrated at reduced pressure. The remaining oil was dropped to 200 ml of diethyl ether. The mixture was maintained at 4°C for 1 hour, filtered and the resulting white powder was dried at reduced pressure. The crude yield was 96%.
  • the product was separated from the unreacted m-PEG-OH by Sephadex QAE A-50 ion exchange column. Elution with MQ grade H 2 O removed the undesired material (m-PEG-OH), while at increased ionic strength (0.01 N NaCI) the desired compound was recovered from the column. The solution was freeze- dried to obtain 603.7 mg, the product was treated with chloroform to remove the salts and filtered. After concentration of the chloroform solution the remaining oil was added drop-wise to diethyl ether. The final yield of (3) was 57% (w/w).
  • Derivative (4) was tested against P388 and P388/ADM in a similar method as described in Example 1 and demonstrated to have anti-cancer activities.
  • reaction mixture was then acidified with citric acid to pH 3, and extracted with chloroform (3 x 50 ml).
  • the combined organic solutions were dried over sodium sulphate and concentrated to a small volume at reduced pressure.
  • the resulting slurry was added drop-wise to 200 ml of vigorously stirred diethyl ether.
  • the white precipitate which formed was filtered and dried at reduced pressure, affording 0.96 g of crude product which was applied to a column packed with QAE Sephadex A-50 ion exchange resin. Elution with mQ grade H 2 0 afforded 0.095 g of starting material (PEG-OH).
  • the appropriate combined fractions were freeze-dried and the residue was suspended in chloroform to remove the salts. Recristallisation afforded 0.86 g (79%) of title compound.
  • Derivative (8) was tested against P388 and P388/ADM in a similar method as described in Example 1 and demonstrated to have anti-cancer activities.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un dérivé amino-substitué de polymère de 7-éthylcamptothécine, actif sur le plan pharmacologique, hydrosoluble et possédant une activité antitumorale.
PCT/CH2002/000562 2001-10-12 2002-10-14 Derives amino-substitues de polymere de camptothecine et utilisations de ces derives pour la fabrication d'un medicament Ceased WO2003031467A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/IB2001/001912 WO2003033525A1 (fr) 2001-10-12 2001-10-12 Derives polymeres de camptothecine amino-substitues et utilisation de ceux-ci pour la fabrication d'un medicament
IB01/01912 2001-10-12

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WO2003031467A2 true WO2003031467A2 (fr) 2003-04-17
WO2003031467A3 WO2003031467A3 (fr) 2003-08-28

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PCT/IB2001/001912 Ceased WO2003033525A1 (fr) 2001-10-12 2001-10-12 Derives polymeres de camptothecine amino-substitues et utilisation de ceux-ci pour la fabrication d'un medicament
PCT/CH2002/000562 Ceased WO2003031467A2 (fr) 2001-10-12 2002-10-14 Derives amino-substitues de polymere de camptothecine et utilisations de ces derives pour la fabrication d'un medicament

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7462627B2 (en) 2006-02-09 2008-12-09 Enzon Pharmaceuticals, Inc. Multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin for treatment of breast, colorectal, pancreatic, ovarian and lung cancers
US7671067B2 (en) 2006-02-09 2010-03-02 Enzon Pharmaceuticals, Inc. Treatment of non-hodgkin's lymphomas with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamtothecin
US7744861B2 (en) 2003-09-17 2010-06-29 Nektar Therapeutics Multi-arm polymer prodrugs
US7928095B2 (en) 2007-02-09 2011-04-19 Enzon Pharmaceuticals, Inc. Treatment of resistant or refractory cancers with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin
US8354549B2 (en) 2006-11-30 2013-01-15 Nektar Therapeutics Method for preparing a polymer conjugate
US8394365B2 (en) 2003-09-17 2013-03-12 Nektar Therapeutics Multi-arm polymer prodrugs
US8410045B2 (en) 2006-03-30 2013-04-02 Drais Pharmaceuticals, Inc. Camptothecin-peptide conjugates and pharmaceutical compositions containing the same
US8637466B2 (en) 2008-08-11 2014-01-28 Nektar Therapeutics Multi-arm polymeric alkanoate conjugates
US10098865B2 (en) 2010-12-22 2018-10-16 Nektar Therapeutics Multi-arm polymeric prodrug conjugates of taxane-based compounds
US10894087B2 (en) 2010-12-22 2021-01-19 Nektar Therapeutics Multi-arm polymeric prodrug conjugates of cabazitaxel-based compounds

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9320781D0 (en) * 1993-10-08 1993-12-01 Erba Carlo Spa Polymer-bound camptothecin derivatives
JPH08333370A (ja) * 1995-06-08 1996-12-17 Kyorin Pharmaceut Co Ltd 水に可溶な新規フルオロエチルカンプトテシン誘導体、及びその製造方法
SG50747A1 (en) * 1995-08-02 1998-07-20 Tanabe Seiyaku Co Comptothecin derivatives
JP4094710B2 (ja) * 1997-11-06 2008-06-04 株式会社ヤクルト本社 新規なカンプトテシン誘導体
ES2175919T3 (es) * 1999-03-09 2002-11-16 Sigma Tau Ind Farmaceuti Derivados del camptothecin con actividad antitumoral.

Cited By (26)

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US9333200B2 (en) 2003-09-17 2016-05-10 Nektar Therapeutics Multi-arm polymer prodrugs
US9808533B2 (en) 2003-09-17 2017-11-07 Nektar Therapeutics Multi-arm polymer prodrugs
US8771662B2 (en) 2003-09-17 2014-07-08 Nektar Therapeutics Multi-arm polymer prodrugs
US7744861B2 (en) 2003-09-17 2010-06-29 Nektar Therapeutics Multi-arm polymer prodrugs
US10463659B2 (en) 2003-09-17 2019-11-05 Nektar Therapeutics Multi-arm polymer prodrugs
US8394365B2 (en) 2003-09-17 2013-03-12 Nektar Therapeutics Multi-arm polymer prodrugs
US8263062B2 (en) 2003-09-17 2012-09-11 Nektar Therapeutics Multi-arm polymer prodrugs
US8318145B2 (en) 2003-09-17 2012-11-27 Nektar Therapeutics Multi-arm polymer prodrugs
US7723351B2 (en) 2006-02-09 2010-05-25 Enzon Pharmaceuticals, Inc. Multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin for treatment of breast, colorectal, pancreatic, ovarian and lung cancers
US7671067B2 (en) 2006-02-09 2010-03-02 Enzon Pharmaceuticals, Inc. Treatment of non-hodgkin's lymphomas with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamtothecin
US7462627B2 (en) 2006-02-09 2008-12-09 Enzon Pharmaceuticals, Inc. Multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin for treatment of breast, colorectal, pancreatic, ovarian and lung cancers
US8299089B2 (en) 2006-02-09 2012-10-30 Enzon Pharmaceuticals, Inc. Multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin for treatment of breast, colorectal, pancreatic, ovarian and lung cancers
US8048891B2 (en) 2006-02-09 2011-11-01 Enzon Pharmaceuticals, Inc. Treatment of non-hodgkin's lymphomas with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin
US8410045B2 (en) 2006-03-30 2013-04-02 Drais Pharmaceuticals, Inc. Camptothecin-peptide conjugates and pharmaceutical compositions containing the same
US8354549B2 (en) 2006-11-30 2013-01-15 Nektar Therapeutics Method for preparing a polymer conjugate
US8541608B2 (en) 2006-11-30 2013-09-24 Nektar Therapeutics Method for preparing a polymer conjugate
US8937180B2 (en) 2006-11-30 2015-01-20 Nektar Therapeutics Method for preparing a polymer conjugate
US7928095B2 (en) 2007-02-09 2011-04-19 Enzon Pharmaceuticals, Inc. Treatment of resistant or refractory cancers with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin
US9220790B2 (en) 2008-08-11 2015-12-29 Naktar Therapeutics Multi-arm polymeric alkanoate conjugates
US8962566B2 (en) 2008-08-11 2015-02-24 Nektar Therapeutics Multi-arm polymeric alkanoate conjugates
US10039737B2 (en) 2008-08-11 2018-08-07 Nektar Therapeutics Multi-arm polymeric alkanoate conjugates
US8637466B2 (en) 2008-08-11 2014-01-28 Nektar Therapeutics Multi-arm polymeric alkanoate conjugates
US11672776B2 (en) 2008-08-11 2023-06-13 Nektar Therapeutics Multi-arm polymeric alkanoate conjugates
US10098865B2 (en) 2010-12-22 2018-10-16 Nektar Therapeutics Multi-arm polymeric prodrug conjugates of taxane-based compounds
US10894087B2 (en) 2010-12-22 2021-01-19 Nektar Therapeutics Multi-arm polymeric prodrug conjugates of cabazitaxel-based compounds
US11813241B2 (en) 2010-12-22 2023-11-14 Nektar Therapeutics Multi-arm polymeric prodrug conjugates of taxane-based compounds

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Publication number Publication date
WO2003033525A1 (fr) 2003-04-24
WO2003031467A3 (fr) 2003-08-28

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