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WO2000058269A1 - Esters dtpa avec groupes de protection amovibles orthogonaux - Google Patents

Esters dtpa avec groupes de protection amovibles orthogonaux Download PDF

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Publication number
WO2000058269A1
WO2000058269A1 PCT/US2000/007541 US0007541W WO0058269A1 WO 2000058269 A1 WO2000058269 A1 WO 2000058269A1 US 0007541 W US0007541 W US 0007541W WO 0058269 A1 WO0058269 A1 WO 0058269A1
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WO
WIPO (PCT)
Prior art keywords
benzyl
compound
butyl
carbon atoms
derivative
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/US2000/007541
Other languages
English (en)
Inventor
Samuel I. Achilefu
Ananthachari Srinivasan
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.)
Mallinckrodt Inc
Original Assignee
Mallinckrodt Inc
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 Mallinckrodt Inc filed Critical Mallinckrodt Inc
Priority to AU40191/00A priority Critical patent/AU4019100A/en
Publication of WO2000058269A1 publication Critical patent/WO2000058269A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
    • 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 to the synthesis of esters of diethylenetriaminepentaacetic acid (DTPA) and of intermediates useful in the synthesis of such esters.
  • DTPA diethylenetriaminepentaacetic acid
  • R ⁇ and R 2 are H, and R 3 , R 4 , and R 5 are t-butyl (compound (II)) or a similar protecting group.
  • Such compounds are useful in the preparation of nuclear pharmaceuticals where they serve as a metal chelate and a link between a peptide and a radionuclide.
  • Activation of the free dicarboxylic acid rapidly forms intramolecular acid anhydride which then reacts with the amino group on a peptide to form the DTPA-peptide conjugate.
  • Acid mediated cleavage of the esters gives free tetra-carboxylic acid which readily forms stable metal complexes with the radionuclide of choice.
  • Compound (IV) is commercially available.
  • Compound (III) was prepared by the method taught in Rapoport, J. Org. Chem. 1993, 58, 1151-1158 (incorporated herein by reference). This reaction yields two compounds in about a 1 :4 ratio.
  • the minor product is:
  • reaction product of (VI) and (VII) is:
  • This compound is subjected to catalytic hydrogenation at room temperature to yield
  • WO 98/05626 (Bracco: P. L. Anelli, et al.) teaches compounds that are similar to the compounds made by the instant invention.
  • the invention comprises a method of synthesis of compounds of the formula
  • the invention also comprises compound (XXXIII) per se. DETAILED DESCRIPTION OF THE INVENTION
  • the invention includes a method for synthesizing compounds of the formula:
  • each R ⁇ is a linking moiety having 1 to 10, desirably 1 to 6, preferably 1 to 4, and most preferably 2 carbon atoms; each R 4 is a removable protecting group, generally (a) an alkyl group having 1 to 15, desirably 2 to 10, more desirably 2 to 8, preferably 3 to 6, and more preferably 4 carbon atoms, and most preferably being t-butyl or (b) benzyl or a benzyl derivative such as methoxy benzyl or nitrobenzyl, preferably benzyl.
  • R 4 is t-butyl or a similar group
  • the compound (X) is more useful in fluorenylmethoxycarbonyl (Fmoc) peptide synthesis
  • R 4 is benzyl or a similar group
  • the compound (X) is more useful in acid labile t-butoxycarbonyl (Boc) peptide synthesis
  • R 9 is hydrogen or a C, to C 50 alkyl moiety such as that taught by US 5,514,810 (incorporated herein by reference), preferably hydrogen.
  • R 4 and Rg are as defined above; and R 5 is a removable protecting group different from and removable separately from R 4 , generally (a) t-butyl, allyl, or chlorotrityl, preferably t-butyl or (b) allyl, benzyl, or a benzyl derivative such as methoxy benzyl or nitrobenzyl, preferably benzyl or methoxy benzyl, and most preferably benzyl; and X is a group that will react with the amine of compound (XXXI), desirably a halide, a mesylate, or a triflate, more desirably a halide, preferably Cl or Br, and most preferably Br.
  • R 5 is preferably benzyl or a benzyl derivative, and if R 4 is benzyl or a similar group, R 5 is preferably t-butyl or allyl. This reaction produces:
  • Compound X can be reacted with a peptide to give a conjugate in high purity. These new compounds forms stable complexes with lanthanides and other metals, and have excellent in vivo stability. Since no free carboxylic acid is present after conjugation with the peptide (or other organic molecule), these compounds can be used for orthogonal synthesis, something not possible with prior art compounds (e.g., Compound (II)).
  • the ether solution was decanted and the oil was again triturated with a 500 ml portion of ether.
  • the ether was decanted and the combined ether solutions allowed to stand for about 2 hours to allow the triphenylphosphine oxide to crystallize.
  • the ether solution was decanted from the crystals and the solid washed with 500 ml of ether.
  • the volume of the combined ether abstracts was reduced with vacuum until a volume of about 80 ml was obtained. This was allowed to stand over night at 0°C.
  • Ether 100 ml was added to the cold mixture which was mixed to suspend the solid. The mixture was filtered and washed ten times with 4 ml of ether.
  • the two layers formed were separated and the organic phase was washed with water (100 ml) and brine (100 ml) in that order.
  • the dichloromethane layer was dried over magnesium sulfate and the solvent was removed en vacuo to give 2.5 g of the crude product.
  • the crude product was dissolved in hexane and purified by dry flash chromatography with 20% diethyl ether in hexane to give 1.8 g (86%) of the pure compound as a pale yellow liquid.
  • EXAMPLE 4 Synthesis of DTPA-Octreotate derivative.
  • the DTPA-Octreotate conjugate was prepared by solid phase synthesis using pre-loaded fluorenemethoxycarbonyl- threonine (Fmoc-Thr) Wang resin on 0.025 mmol scale.
  • Commercially available automated peptide synthesizer from Applied Biosystems (Model 432A SYNERGY Peptide Synthesizer) was used. Cartridges containing Fmoc-protected amino acids were used in the solid phase synthesis. Cysteines were protected with acetamidomethyl group.
  • Coupling reaction was carried out with 0.075 mmol of the protected amino acid and 2-(lH-benzotriazole-lyl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HBTU)/N-hydroxybenzotriazole (HOBT).
  • the amino acids and tetra-t-butyl DTPA (compound X) cartridges were placed on the peptide synthesizer and the product was synthesized from the C-terminal to the N-terminal position. After the synthesis was completed, the product was cleaved from the solid support with a cleavage mixture containing trifluoroacetic acid (85%):water (5%):phenol (5%):thioanisole (5%) for 6 hours.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention porte sur la synthèse des composés de la formule (XXXIII) dans laquelle chaque R4 est un groupe de protection amovible; R5 est un groupe de protection amovible différent de R4 et pouvant en être séparé; chaque R6 et R8 est une fraction de liaison possédant de 1 à 10 atomes de carbone; et R9 est un hydrogène ou une fraction alkyle C1 à C50. Ces composés sont utiles comme intermédiaires dans la synthèse des composés de la formule (X). Ces composés sont également utiles dans la préparation de produits pharmaceutiques nucléaires tels que ceux utilisés dans l'imagerie ou la thérapie des tumeurs.
PCT/US2000/007541 1999-03-26 2000-03-21 Esters dtpa avec groupes de protection amovibles orthogonaux Ceased WO2000058269A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU40191/00A AU4019100A (en) 1999-03-26 2000-03-21 Dtpa esters with orthogonal removable protecting groups

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US12638399P 1999-03-26 1999-03-26
US60/126,383 1999-03-26

Publications (1)

Publication Number Publication Date
WO2000058269A1 true WO2000058269A1 (fr) 2000-10-05

Family

ID=22424532

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/007541 Ceased WO2000058269A1 (fr) 1999-03-26 2000-03-21 Esters dtpa avec groupes de protection amovibles orthogonaux

Country Status (2)

Country Link
AU (1) AU4019100A (fr)
WO (1) WO2000058269A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001052898A1 (fr) * 2000-01-21 2001-07-26 Mallinckrodt Inc. Procedes permettant d'incorporer des chelateurs de metaux a des sites de peptides a terminaison carboxyle
WO2001052900A3 (fr) * 2000-01-21 2002-01-10 Mallinckrodt Inc Nouveaux chelateurs d'acides amines a protection orthogonale pour des applications biomedicales

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5514810A (en) * 1995-02-21 1996-05-07 Schering Aktiengesellschaft Process for the production of DTPA-tetraesters of terminal carboxylic acids
DE19601060A1 (de) * 1996-01-04 1997-07-10 Schering Ag Neue monofunktionalisierte EDTA-, DTPA- und TTHA-Derivate und deren Verwendung in der medizinischen Diagnostik und Therapie
US5676923A (en) * 1995-02-21 1997-10-14 Schering Aktiengesellschaft Substituted DTPA monoamides of the central carboxylic acid group and their metal complexes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5514810A (en) * 1995-02-21 1996-05-07 Schering Aktiengesellschaft Process for the production of DTPA-tetraesters of terminal carboxylic acids
US5676923A (en) * 1995-02-21 1997-10-14 Schering Aktiengesellschaft Substituted DTPA monoamides of the central carboxylic acid group and their metal complexes
DE19601060A1 (de) * 1996-01-04 1997-07-10 Schering Ag Neue monofunktionalisierte EDTA-, DTPA- und TTHA-Derivate und deren Verwendung in der medizinischen Diagnostik und Therapie

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WILLIAMS M A ET AL: "SYNTHESIS OF ENANTIOMERICALLY PURE DIETHYLENETRIAMINEPENTAACETIC ACID ANALOGUES L-PHENYLALANINE AS THE EDUCT FOR SUBSTITUTION AT THE CENTRAL ACETIC ACID", JOURNAL OF ORGANIC CHEMISTRY,US,AMERICAN CHEMICAL SOCIETY. EASTON, vol. 58, no. 5, 26 February 1993 (1993-02-26), pages 1151 - 1158, XP000569373, ISSN: 0022-3263 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001052898A1 (fr) * 2000-01-21 2001-07-26 Mallinckrodt Inc. Procedes permettant d'incorporer des chelateurs de metaux a des sites de peptides a terminaison carboxyle
WO2001052900A3 (fr) * 2000-01-21 2002-01-10 Mallinckrodt Inc Nouveaux chelateurs d'acides amines a protection orthogonale pour des applications biomedicales

Also Published As

Publication number Publication date
AU4019100A (en) 2000-10-16

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