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WO2003033525A1 - Derives polymeres de camptothecine amino-substitues et utilisation de ceux-ci pour la fabrication d'un medicament - Google Patents

Derives polymeres de camptothecine amino-substitues et utilisation de ceux-ci pour la fabrication d'un medicament Download PDF

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Publication number
WO2003033525A1
WO2003033525A1 PCT/IB2001/001912 IB0101912W WO03033525A1 WO 2003033525 A1 WO2003033525 A1 WO 2003033525A1 IB 0101912 W IB0101912 W IB 0101912W WO 03033525 A1 WO03033525 A1 WO 03033525A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
general formula
polymer derivative
substituted camptothecin
substituted
Prior art date
Application number
PCT/IB2001/001912
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English (en)
Original Assignee
Debio Recherche Pharmacuetique S.A.
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 Pharmacuetique S.A. filed Critical Debio Recherche Pharmacuetique S.A.
Priority to PCT/IB2001/001912 priority Critical patent/WO2003033525A1/fr
Priority to PCT/CH2002/000562 priority patent/WO2003031467A2/fr
Publication of WO2003033525A1 publication Critical patent/WO2003033525A1/fr

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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.
  • One oM ie 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 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: GlyLeuPheGly, GlyPheLeuGly, GiyPhePheAla, GlyPhePheLeu, GlyPheTyrAla, AlaGlyValPhe, GlyPheTyrAla, GlyLeuAla, GlyLeuGly, GlyPheGIy, GlyPheAla, DAIaPheLys, DValLeuLys, and LysGlyLeuPheGly with at least one of any of the alpha- and epsilon-amino groups of lysine being linked to the corresponding remaining part of formula (I); or -X 1 represents -a linear or a branched CrC 6 -alkyl group.
  • the polymeric part of the amino-substituted camptothecin polymer derivatives of the invention correspond 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 f such enzymatic system.
  • the cleavable spacer arm residue 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 f such enzymatic system.
  • the cleavable spacer arm residue is selected for their sensitiveness to lysosomal enzymatic system or to other tumour- related enzymes, such as plasmine, and their capability to be cleaved by f such enzymatic system.
  • the cleavable spacer arm residue are selected for their sensitive
  • -S- is selected among the following peptides: GlyLeuPheGly,
  • 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.
  • 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 carbamaie 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.
  • the second extremity is preferably terminated, through the oxygen atom, by methyl group.
  • 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 monoalkoxypolyethylene 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 d-C ⁇ -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 method 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.
  • m-PEG-OH defines the monomethoxypolyethylene glycol 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-benzotriazolyl carbonate (m-PEG-BTC) and H-GlyLeuPheGly-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 dropwise 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 NaCl) the desired compound eluted together with NaCl (0.896g combined).
  • the derivative (2) was tested against murine leukemias P388 and P388 resistant to adriamycipf (P388/ADM).
  • Female CDF1 mice were inoculated intraperitoneally 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.
  • the survival rate (T/C%) is calculated using the following formula:
  • T/C (%) (Mean survival days of treated group / mean survival days of control group) x 100.
  • Table 1 reports the anti-tumour activity of the derivative against P388, while Table 2 reports the same against P388/ADM.
  • Derivative (4) was tested against P388 and P388/ADM in a similar method as described m Example 1 and demonstrated to have anti-cancer activities.
  • Derivative (6) was tested against P388 and P388/ADM in a similar method as described in Example 1 a ⁇ d 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)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un dérivé polymère de 7-éthylcamptothécine amino-substitué actif au niveau pharmacologique, qui présente une activité anti-tumorale et qui est hydrosoluble.
PCT/IB2001/001912 2001-10-12 2001-10-12 Derives polymeres de camptothecine amino-substitues et utilisation de ceux-ci pour la fabrication d'un medicament WO2003033525A1 (fr)

Priority Applications (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
PCT/CH2002/000562 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

Applications Claiming Priority (1)

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

Publications (1)

Publication Number Publication Date
WO2003033525A1 true WO2003033525A1 (fr) 2003-04-24

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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
PCT/CH2002/000562 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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Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUE036290T2 (hu) 2003-09-17 2018-06-28 Nektar Therapeutics Többkarú polimer vegyületek
US8394365B2 (en) 2003-09-17 2013-03-12 Nektar Therapeutics Multi-arm polymer prodrugs
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
WO2007113687A2 (fr) 2006-03-30 2007-10-11 Diatos S.A. Conjugués de camptothécine et de peptide et compositions pharmaceutiques les contenant
CN101583380B (zh) 2006-11-30 2013-07-10 尼克塔治疗公司 用于制备聚合物轭合物的方法
BRPI0807232A2 (pt) 2007-02-09 2014-04-29 Enzon Pharmaceuticals Inc Tratamento de cânceres resistentes ou refratários com conjugados poliméricos multi-braços de 7-etil-10-hidroxicamptotecina
CN102159250B (zh) 2008-08-11 2014-08-06 尼克塔治疗公司 多臂的聚合烷酸酯偶联物
WO2012088445A1 (fr) 2010-12-22 2012-06-28 Nektar Therapeutics Conjugués promédicaments polymères à plusieurs bras de composés à base de cabazitaxel
WO2012088422A1 (fr) 2010-12-22 2012-06-28 Nektar Therapeutics Conjugués promédicaments polymères à plusieurs bras de composés à base de taxane

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0757049A1 (fr) * 1995-08-02 1997-02-05 Tanabe Seiyaku Co., Ltd. Dérivés de campthothécin
EP0861842A1 (fr) * 1995-06-08 1998-09-02 Kyorin Pharmaceutical Co., Ltd. Nouveau derive hydrosoluble de la fluoroethylcamptothecine et son procede de production
EP1029863A1 (fr) * 1997-11-06 2000-08-23 Kabushiki Kaisha Yakult Honsha Nouveaux derives de la camptothecine
EP1044977A1 (fr) * 1999-03-09 2000-10-18 Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Dérivés de camptothécine à activité anti-tumorale

Family Cites Families (1)

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Publication number Priority date Publication date Assignee Title
GB9320781D0 (en) * 1993-10-08 1993-12-01 Erba Carlo Spa Polymer-bound camptothecin derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0861842A1 (fr) * 1995-06-08 1998-09-02 Kyorin Pharmaceutical Co., Ltd. Nouveau derive hydrosoluble de la fluoroethylcamptothecine et son procede de production
EP0757049A1 (fr) * 1995-08-02 1997-02-05 Tanabe Seiyaku Co., Ltd. Dérivés de campthothécin
EP1029863A1 (fr) * 1997-11-06 2000-08-23 Kabushiki Kaisha Yakult Honsha Nouveaux derives de la camptothecine
EP1044977A1 (fr) * 1999-03-09 2000-10-18 Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Dérivés de camptothécine à activité anti-tumorale

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KEHRER DFS ET AL.: "Modulation of camptothecin analogs in the treatment of cancer: a review", ANTI-CANCER DRUGS, vol. 12, February 2001 (2001-02-01), pages 89 - 105, XP008002866 *
SINGER JW ET AL.: "Conjugation of Camptothecins to Poly-(L-Glutamic Acid)", ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, vol. 922, 2000, pages 136 - 150, XP001023451 *

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

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