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WO1999011676A1 - Formulation - Google Patents

Formulation Download PDF

Info

Publication number
WO1999011676A1
WO1999011676A1 PCT/EP1998/005501 EP9805501W WO9911676A1 WO 1999011676 A1 WO1999011676 A1 WO 1999011676A1 EP 9805501 W EP9805501 W EP 9805501W WO 9911676 A1 WO9911676 A1 WO 9911676A1
Authority
WO
WIPO (PCT)
Prior art keywords
solid phase
matrix
formulation according
phase support
solid
Prior art date
Application number
PCT/EP1998/005501
Other languages
English (en)
Inventor
Nicholas William Hird
Ian Hughes
Vincenzo Re
Nigel Charles North
Original Assignee
Smithkline Beecham Plc
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 Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to JP2000508712A priority Critical patent/JP2001514266A/ja
Priority to EP98951330A priority patent/EP1015502A1/fr
Publication of WO1999011676A1 publication Critical patent/WO1999011676A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
    • C08L71/02—Polyalkylene oxides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/042—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers characterised by the nature of the carrier

Definitions

  • the present invention relates to novel formulations, processes for their preparation and their use in solid phase synthesis.
  • the combinatorial synthetic approach involves the creation of 'compound libraries' consisting of collections of chemical compounds based upon a common template/core structure.
  • the template/core structure will generally have a discrete number of independently variable substituents, each of which can have one of a defined range of values.
  • a library is designed so that, for the range of values selected for each of the independently variable substituents, compounds containing substantially all possible permutations of these substituents will be present in the library.
  • a typical library will contain 5 to 10,000, preferably 10 to 10,000, or more compounds.
  • Solid phase methods to facilitate the assembly of such libraries is well known in the art, particularly in the fields of peptide and oligonucleotide synthesis.
  • Solid phase methods are particularly suited to the preparation of libraries as a large excesses of reagents can be employed to drive reactions to completion and that excess can be readily removed. More recently, such methods have also been used for the synthesis of small molecule libraries wherein the template/core structure has a number of functional sites each of which can be reacted in a stepwise fashion with a number of different reagents.
  • a complementary approach to creating a library of compounds is to use the parallel synthesis method, whereby the compounds comprising the library are prepared separately and in parallel.
  • the use of solid phase supports is applicable to libraries prepared by the combinatorial 'split and mix' approach or by parallel synthesis.
  • the template/core structure may be linked to the solid phase support through a linker group.
  • Linker groups are chosen so that they are not only compatible with the conditions to be used for introducing the substituents on the template but will also allow release of the library from the solid phase support once synthesis is complete. Suitable linker groups include those present in Wang and Merrifield resins.
  • Solid phase supports such as resins are notoriously difficult to handle, e.g. to weigh out, primarily because of their electrostatic properties. Weighing aliquots of resin for solid phase synthesis is particularly time consuming and tedious when a large number of aliquots are involved.
  • One approach taken to overcome this problem is to dispense aliquots of resin from a suspension of the solid support in a solvent mixture having the same density as the solid support (a so-called “isopycnic" suspension or slurry) as described in Int. J. Peptide Protein Res., 1992, 40, 497. This method does, however, suffer from certain shortcomings that limit its use and applicability.
  • the present invention provides a solid formulation comprising a solid phase support dispersed within an inert matrix.
  • the solid formulations may be prepared by blending the matrix with a solid phase support and optionally forming the resulting mixture into discrete pieces having a defined shape.
  • the formulation will typically contain 5 to 75% w/w, or more typically 20 to 50% w/w of the solid phase support.
  • the formulation is preferably in the form of discrete pieces having a defined shape, for instance, tablets, discs or spheres.
  • Discrete pieces of the formulation may be prepared, for example, by compression in a suitable die, either manually or by an automated press; by solidification of a melt; or by extrusion.
  • a discrete piece of the formulation will contain a unit amount of solid phase support, typically up to 1 g, e.g. 5 to 100 mg of solid phase support.
  • Discrete pieces of the formulation containing different unit amounts may be differentiated by having different shapes and/or sizes. Different shapes may also be used to differentiate between formulations comprising different solid supports. Additionally, colour or impressed markings may be used to differentiate between materials.
  • the inert matrix which may comprise organic or inorganic materials, facilitates the delivery of the solid phase support to the reaction vessel and is dissolved and optionally removed prior to synthesis. Consequently the matrix should be soluble either in common organic solvents, such as dichloromethane, methanol, toluene or tetrahydrofuran; or in aqueous media. In addition, the matrix should be chemically inert, in the sense of not being capable of modifying the solid phase support in anyway. It will also be appreciated that the choice of matrix will be influenced by its physical properties, e.g. the ease of formulation and its ability to maintain its shape if it is formed into discrete pieces.
  • the matrix material may comprise a single material, or of a mixture of materials, to confer suitable blending and/or compression characteristics.
  • the matrix comprises materials commonly employed as binders or diluents in the field of pharmaceutical formulations.
  • Suitable matrix materials include alginic acid, polyethylene glycols such as polyethylene glycol 6000, hydrogenated vegetable oil, glycerylpalmitostearate, ethyl cellulose, hydroxypropyl cellulose, polymethacrylates and povidone.
  • Preferred matrix materials include polyethylene glycols such as polyethylene glycol 6000. It will also be appreciated that the choice of matrix is not limited to substances that are suitable for human dosing.
  • the matrix could be selected from inorganic compounds such as potassium bromide and sodium chloride, or organic compounds such as anthracene and naphthalene.
  • Suitable solid phase supports are well known in the art and include resin beads, pellets, disks, capillaries, hollow fibers, needles, solid fibers, cellulose beads, pore-glass beads, silica gels, glass particles coated with a hydrophobic polymer such as POLY- HIPETM, TENTAGELTM, etc.
  • Suitable resin beads include polystyrene beads optionally cross-linked with divinylbenzene, cross-linked polystyrene and polyethylene glycol beads, grafted co-poly beads, poly-acrylamide beads, latex beads, and dimethylacrylamide beads optionally cross-linked with N,N-bis-acryloyl ethylene diamine.
  • the solid phase support may be derivitised e.g. with linker groups and/or template/core structures prior to or after formulation with the inert matrix.
  • the solid phase support may also comprise a scavenger resin, e.g. N-(2-aminoethyl)aminomethyl polystyrene or N-(2-mercaptoethyl)aminomethyl polystyrene which are used for scavenging electrophilic reagents; or an immobilised reagent, e.g. bis-(6-carboxy-HOBt)-N-(2- aminoethyl)aminomethyl polystyrene which is a solid phase catalyst for acylation reactions.
  • the formulations of the invention are particularly useful for dispensing solid phase supports into vessels, particularly reaction vessels for use in chemical synthesis.
  • the invention provides a method for dispensing a solid phase support into a vessel, comprising dispensing a solid formulation comprising a solid phase support dispersed within an inert matrix into the vessel.
  • the method according to this aspect of the invention is preferably used to dispense a known quantity of solid phase support into a vessel.
  • the method finds particular application in automated techniques for dispensing solid phase supports into multiple vessels.
  • the solid formulations of the invention have numerous advantages, in particular the handling and dispensing of solid phase supports into reaction vessels is greatly simplified.
  • the solid formulations have flexibility in terms of their shape and size and hence formulations can easily be adjusted to suit the particular reaction vessel in which they are to be used; a specific example is the dispensing of resin into mesh cans used in library synthesis, e.g. IRORI MICROKANSTM, which are low volume and have a limited aperture for the introduction of the solid phase support
  • the solid formulations may be produced and dispensed volumetric ally rather than by weighing, the mixing of the solid phase support with an inert matrix prior to dispensing improves the flow of the solid phase support into a volumetric measure since it reduces or eliminates static build up on the solid phase support.
  • FMOC phenylalanine on Wang resin 75 to 150 ⁇ m bead size, 0.76 mmol/g loading) (500 mg) was mixed thoroughly with finely milled polyethylene glycol 6000 (1.0 g). Aliquots (0.25 ml) were compressed at 2 tonnes for 15 sec to give opaque white discs. The compression was carried out in a conventional press which is typically used for the formation of KBr discs utilised in infra-red spectroscopy.
  • Example 2 Use of discs in automated synthesis of 4-tert-butylbenzoylphenylalanine using ACT 396 Multiple Peptide Synthesiser (MPS)
  • Example 1 Eight discs from Example 1 were individually placed into the ACT 396 reaction block. The wells were then washed according to ACT programme 1 as shown below. The beads all appeared free from polyethylene glycol excipient. The automated synthesis procedure was then carried out using ACT programme 2 as shown below. To each well, trifluoroacetic acid in dichloromethane (1 ml, 1:1 v/v) was added and the reaction block was allowed to stand for 90 minutes. The contents of the wells were drained under vacuum to separate vials, and the residue was washed with dichloromethane (1 ml). The combined filtrate was evaporated using a ZYMARK TURBO VAPTM to give the following product yields and purities.
  • Example 5 Use of discs in automated synthesis of 4-tert-butyIbenzoylphenylalanine using ACT 396 MPS.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Polymers & Plastics (AREA)
  • Analytical Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention porte sur de nouvelles formulations, leurs procédés de préparation et leur utilisation dans la synthèse en phase solide.
PCT/EP1998/005501 1997-08-29 1998-08-26 Formulation WO1999011676A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2000508712A JP2001514266A (ja) 1997-08-29 1998-08-26 処 方
EP98951330A EP1015502A1 (fr) 1997-08-29 1998-08-26 Formulation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9718415A GB9718415D0 (en) 1997-08-29 1997-08-29 Formulation
GB9718415.4 1997-08-29

Publications (1)

Publication Number Publication Date
WO1999011676A1 true WO1999011676A1 (fr) 1999-03-11

Family

ID=10818278

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/005501 WO1999011676A1 (fr) 1997-08-29 1998-08-26 Formulation

Country Status (4)

Country Link
EP (1) EP1015502A1 (fr)
JP (1) JP2001514266A (fr)
GB (1) GB9718415D0 (fr)
WO (1) WO1999011676A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6822088B2 (en) * 2001-07-17 2004-11-23 Isis Pharmaceuticals, Inc. Synthesis of oligonucleotides on solid support

Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB781177A (en) * 1954-04-06 1957-08-14 Styrene Products Ltd Improvements in and relating to vinyl aromatic polymers
GB1181003A (en) * 1967-03-20 1970-02-11 Mead Johnson & Co Therapeutic Compositions
DE2206636A1 (de) * 1971-02-11 1972-08-24 National Research Development Corp., London Trennung von Enzymen
US4193910A (en) * 1978-10-16 1980-03-18 Uop Inc. Preparation of support matrices for immobilized enzymes
WO1987002704A1 (fr) * 1985-10-22 1987-05-07 Eric Robinson Procede pour immobiliser des cellules
JPS62127350A (ja) * 1985-11-28 1987-06-09 Ibiden Co Ltd 熱硬化性樹脂をマトリツクスとする複合材料及びその製造方法
GB2193503A (en) * 1986-08-04 1988-02-10 Bohuslav Vaclav Kokta Bonded composites of cellulose based fibers in polystyrene polymers characterized by a bonding agent
WO1990000609A1 (fr) * 1988-07-08 1990-01-25 The University Of British Columbia Proteines de fusion se liant a la cellulose
JPH0394679A (ja) * 1989-09-08 1991-04-19 Nippon Mining Co Ltd 固定化菌体及びその製造方法
WO1992004384A1 (fr) * 1990-08-31 1992-03-19 Regents Of The University Of Minnesota Derives de polyethylene-glycol destines a des applications en phase solide
DE4239612A1 (de) * 1992-11-25 1994-05-26 Cultor Oy Bioreaktor mit immobilisierten, Milchsäure-produzierenden Bakterien und dessen Verwendung in Fermentationsverfahren
GB2297551A (en) * 1995-02-04 1996-08-07 Zeneca Ltd Labelled chemical library
JPH0948917A (ja) * 1995-08-07 1997-02-18 Dainichiseika Color & Chem Mfg Co Ltd 連結されたミクロゲルの製造方法及びそれで処理された物品
WO1997015195A1 (fr) * 1995-10-25 1997-05-01 Transkaryotic Therapies, Inc. Implants et explants de matrices hybrides
US5653922A (en) * 1994-06-06 1997-08-05 Biopore Corporation Polymeric microbeads and method of preparation

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB781177A (en) * 1954-04-06 1957-08-14 Styrene Products Ltd Improvements in and relating to vinyl aromatic polymers
GB1181003A (en) * 1967-03-20 1970-02-11 Mead Johnson & Co Therapeutic Compositions
DE2206636A1 (de) * 1971-02-11 1972-08-24 National Research Development Corp., London Trennung von Enzymen
US4193910A (en) * 1978-10-16 1980-03-18 Uop Inc. Preparation of support matrices for immobilized enzymes
WO1987002704A1 (fr) * 1985-10-22 1987-05-07 Eric Robinson Procede pour immobiliser des cellules
JPS62127350A (ja) * 1985-11-28 1987-06-09 Ibiden Co Ltd 熱硬化性樹脂をマトリツクスとする複合材料及びその製造方法
GB2193503A (en) * 1986-08-04 1988-02-10 Bohuslav Vaclav Kokta Bonded composites of cellulose based fibers in polystyrene polymers characterized by a bonding agent
WO1990000609A1 (fr) * 1988-07-08 1990-01-25 The University Of British Columbia Proteines de fusion se liant a la cellulose
JPH0394679A (ja) * 1989-09-08 1991-04-19 Nippon Mining Co Ltd 固定化菌体及びその製造方法
WO1992004384A1 (fr) * 1990-08-31 1992-03-19 Regents Of The University Of Minnesota Derives de polyethylene-glycol destines a des applications en phase solide
DE4239612A1 (de) * 1992-11-25 1994-05-26 Cultor Oy Bioreaktor mit immobilisierten, Milchsäure-produzierenden Bakterien und dessen Verwendung in Fermentationsverfahren
US5653922A (en) * 1994-06-06 1997-08-05 Biopore Corporation Polymeric microbeads and method of preparation
GB2297551A (en) * 1995-02-04 1996-08-07 Zeneca Ltd Labelled chemical library
JPH0948917A (ja) * 1995-08-07 1997-02-18 Dainichiseika Color & Chem Mfg Co Ltd 連結されたミクロゲルの製造方法及びそれで処理された物品
WO1997015195A1 (fr) * 1995-10-25 1997-05-01 Transkaryotic Therapies, Inc. Implants et explants de matrices hybrides

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 8728, Derwent World Patents Index; Class A26, AN 87-196477, XP002092691 *
PATENT ABSTRACTS OF JAPAN vol. 015, no. 275 (C - 0849) 12 July 1991 (1991-07-12) *
PATENT ABSTRACTS OF JAPAN vol. 097, no. 006 30 June 1997 (1997-06-30) *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6822088B2 (en) * 2001-07-17 2004-11-23 Isis Pharmaceuticals, Inc. Synthesis of oligonucleotides on solid support

Also Published As

Publication number Publication date
JP2001514266A (ja) 2001-09-11
EP1015502A1 (fr) 2000-07-05
GB9718415D0 (en) 1997-11-05

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