WO1992004056A1 - UTILISATION DE COMPLEXES D'IONS METALLIQUES RADIOACTIFS AVEC all-cis-1,3,5-TRIAMINO-2,4,6-CYCLOHEXANTRIOL ET DE LEURS DERIVES A DES FINS DE DIAGNOSTIC RADIOGRAPHIQUE ET DE THERAPIE ANTI-TUMEURS, AINSI QUE POUR LA PRODUCTION D'AGENTS DE DIAGNOSTIC RADIOGRAPHIQUE ET D'AGENTS ANTI-TUMORAUX - Google Patents

UTILISATION DE COMPLEXES D'IONS METALLIQUES RADIOACTIFS AVEC all-cis-1,3,5-TRIAMINO-2,4,6-CYCLOHEXANTRIOL ET DE LEURS DERIVES A DES FINS DE DIAGNOSTIC RADIOGRAPHIQUE ET DE THERAPIE ANTI-TUMEURS, AINSI QUE POUR LA PRODUCTION D'AGENTS DE DIAGNOSTIC RADIOGRAPHIQUE ET D'AGENTS ANTI-TUMORAUX Download PDF

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Publication number
WO1992004056A1
WO1992004056A1 PCT/EP1991/001679 EP9101679W WO9204056A1 WO 1992004056 A1 WO1992004056 A1 WO 1992004056A1 EP 9101679 W EP9101679 W EP 9101679W WO 9204056 A1 WO9204056 A1 WO 9204056A1
Authority
WO
WIPO (PCT)
Prior art keywords
tumor therapy
alkyl groups
use according
ray diagnostic
cis
Prior art date
Application number
PCT/EP1991/001679
Other languages
German (de)
English (en)
Inventor
Isidor Erni
Walter Schneider
Hans Kaspar HEGGETSCHWEILER
Peter Geisser
Original Assignee
Laboratorien Hausmann Ag
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 Laboratorien Hausmann Ag filed Critical Laboratorien Hausmann Ag
Priority to KR1019920701057A priority Critical patent/KR920702235A/ko
Priority to AU84367/91A priority patent/AU658148B2/en
Publication of WO1992004056A1 publication Critical patent/WO1992004056A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • the invention relates to the use of complexes of all-cis-1,3,5-
  • Triamino-2,4,6-cyclohexanetriol and its derivatives with radioactive ions Triamino-2,4,6-cyclohexanetriol and its derivatives with radioactive ions
  • Metal isotopes for X-ray diagnostic purposes and in tumor therapy and for the production of agents for X-ray diagnostic purposes and for tumor therapy.
  • the object of the invention is to provide new possibilities for X-ray diagnostic imaging and for tumor treatment.
  • radioactive metals in particular radioactive metal cations with all-cis, 1,3,5-triamino-2,4,6-trihydroxycyclohexane and its derivatives, for X-ray diagnostic purposes and in tumor therapy or for the production of agents for X-ray diagnostic purposes and for tumor therapy.
  • the complexes used according to the invention are preferably radioactive
  • Underlying metal isotopes which are ⁇ , ß, or ⁇ emitters.
  • radioactive isotopes that can be used are those of
  • the ligands used for the complexes according to the invention are all-cis- 1,3,5-triamino-2,4,6-cyclohexanetriol and its derivatives, as they are
  • R 1 , R 2 , R 3 , R 4 , R 5 or R 6 are the same or different and stand for hydrogen atoms, alkyl groups or -CO- alkyl groups
  • the alkyl in the alkyl or -CO -Alkyl deficit has 1 to 18 carbon atoms
  • the alkyl and -CO- alkyl groups can each independently contain one or more, identical or different functional groups, and their salts with inorganic or organic pharmacologically common acids and their quaternary ammonium salts of the general formula (II), (IIa) or (Ilb)
  • R 9 independently of one another are the unsubstituted or substituted alkyl groups or -CO-alkyl groups defined above or all-cis- 1,3,5-tri-amino-2,4,6-trihydroxycyclohexane derivatives of the general formula
  • substituents on the nitrogen atoms are independently H or CH 3 and preferably all CH 3 .
  • radicals R 1 to R 6 in the ligands are alkyl or —CO— alkyl groups which are one or more, identical or different
  • R 1 to R 9 may contain functional groups. Of the symbols R 1 to R 9, there is preferably at most one symbol on each nitrogen atom
  • a preferred group of ligands are those in which all residues
  • R 1 to R 6 or R 1 to R 9 are methyl or -COCH 3 groups.
  • the alkyl groups or —CO-alkyl groups of the substituents R 1 to R 6 or R 1 to R 9 preferably have one or more functional groups which can coordinate with metal cations.
  • Examples of functional groups on the alkyl groups or -CO-alkyl groups are -OH, -COOH or salts thereof, -CONH 2 , -CON (OH) R, where R represents an alkyl group having 1 to 6, in particular 1 to 4, carbon atoms , -OPO 3 H 2 and their salts, -PO 3 H 2 or their salts, -SR (in which R has the above meaning), and the esters of the above acids, -CN,
  • Preferred examples are those of the ligands of the formulas (I), (II), (Ila) or (Ilb), in which one or more or all of the symbols R 1 to R 9 independently of one another have the following meaning:
  • n 1, 2 or 3, and their salts; as well as those in which one or more or all of the symbols R 1 to R 9 independently of one another have the following meaning:
  • n 1, 2 or 3, and their salts.
  • a particularly preferred group of ligands are those of the formula (I), (II), (Ila) and ((Ilb), in which at least one of the radicals R 1 to R 6 and in particular in each case the radicals R 1 , R 3 and R 5 represent the group - (CH 2 ) n -COOH, in which n has the meaning from 1 to 3 and particularly preferably from 2.
  • the remaining substituents R 2 , R 4 , R 6 and R 7 to R 9 are preferably Hydrogen or CH 3 , these remaining substituents preferably being the same
  • Such compounds of the formula (I) are particularly well suited for tumor therapy.
  • Complexes used are those that have positive charges, so that the complexes made from it are positively charged. Such complexes are particularly good, for example, for X-ray diagnostic purposes,
  • the positive charges can either be caused by the quaternary nitrogen atoms of the compounds of the formula (II), (Ila),
  • the positive charges can, for example, by
  • Functional groups are alkyl groups with quaternary ammonium groups, such as trimethylamino groups or triethylamino groups, for example those
  • the complexes used according to the invention are easily formed from aqueous solutions or suspensions of salts, hydroxides or oxides of the respective
  • radioactive metals of interest and aqueous solutions or suspensions of the ligands.
  • the aqueous solutions can be acidic, for example.
  • amounts are used for this purpose such that 2 mol of ligands of the formula (I), (II), (Ila), (Ilb) or 1 mol of the formula (III) or (IV) are present per 1 mol of metal ion. A slight excess of the ligand is preferably used.
  • Metals or metal cations can be replaced by corresponding non-radioactive isotopes.
  • the complexes can be in the form of mixtures of
  • Radioactive metals or metal cations and the radioactive metals or metal cations may be the same or different.
  • radioactive iron isotopes they can be present together with non-radioactive iron. In the manufacture of such preparations, for example
  • radioactive iron III ions occur.
  • the complexes used according to the invention can be obtained from the manufacturer or
  • positively charged complexes are preferably used.
  • ⁇ - or Are spotlights it is particularly favorable to choose such complexes that ⁇ - or Are spotlights; ⁇ -emitters are preferably used for combating tumors, for example combating cancer.
  • the complexes used according to the invention are used in the form of aqueous solutions; they can be used in various ways, particularly by intravenous administration.
  • the nitrile was hydrolyzed by refluxing in concentrated hydrochloric acid for 6 hours.
  • the all-cis-1,3,5-tris (2'ammoniopropionic acid) -2,4,6-cyclohexanetriol trichloride was obtained by concentrating on a rotary evaporator.
  • the precipitated 59 ferri-all-cis-1,3,5-tris (2'-aminopropionic acid) -2,4,6-cyclohexanetriol was suction filtered through a G4 filter and then purified by dissolving in 0.1 M HCl and precipitation at pH 4.5. The product was finally dried under high vacuum. Because of spectroscopic
  • the complex is soluble in or above a buffer with a physiological pH.
  • the structural identity with the non-radioactively labeled preparation was determined on the basis of spectroscopic properties.

Abstract

Utilisation de complexes d'ions métalliques radioactifs avec all-cis-1,3,5-triamino-2,4,6-trihydroxy-cyclohexane, de leurs dérivés, sels ou sels quaternaires d'ammonium à des fins de diagnostic radiographique et de thérapie anti-tumeurs, ainsi que pour la production d'agents de diagnostic radiographique et d'agents anti-tumoraux.
PCT/EP1991/001679 1990-09-05 1991-09-05 UTILISATION DE COMPLEXES D'IONS METALLIQUES RADIOACTIFS AVEC all-cis-1,3,5-TRIAMINO-2,4,6-CYCLOHEXANTRIOL ET DE LEURS DERIVES A DES FINS DE DIAGNOSTIC RADIOGRAPHIQUE ET DE THERAPIE ANTI-TUMEURS, AINSI QUE POUR LA PRODUCTION D'AGENTS DE DIAGNOSTIC RADIOGRAPHIQUE ET D'AGENTS ANTI-TUMORAUX WO1992004056A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
KR1019920701057A KR920702235A (ko) 1990-09-05 1991-09-05 모든-시스-1,3,5-트리아미노-2,4,6-시클로헥산트리올 및 그 유도체와 방사능 금속이온의 착물에 대한 방사능 진단 목적과 종양치료를 위한 용도 및 방사능 진단 목적용과 종양치료용 시약의 제조를 위한 용도
AU84367/91A AU658148B2 (en) 1990-09-05 1991-09-05 Use of radioactive metal ion complexes with all-cis-1,3,5-triamino-2,4,6-cyclohexantriol and their derivates for x-ray diagnosis and in tumor therapy as well asfor producing x-ray diagnostic and tumor therapy agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4028139A DE4028139A1 (de) 1990-09-05 1990-09-05 Verwendung der komplexe radioaktiver metallionen mit all-cis-1,3,5-triamino-2,4,6-cyclohexantriol und seinen derivaten fuer roentgendiagnostische zwecke und in der tumortherapie sowie zur herstellung von mitteln fuer roentgendiagnostische zwecke und fuer die tumortherapie
DEP4028139.6 1990-09-05

Publications (1)

Publication Number Publication Date
WO1992004056A1 true WO1992004056A1 (fr) 1992-03-19

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1991/001679 WO1992004056A1 (fr) 1990-09-05 1991-09-05 UTILISATION DE COMPLEXES D'IONS METALLIQUES RADIOACTIFS AVEC all-cis-1,3,5-TRIAMINO-2,4,6-CYCLOHEXANTRIOL ET DE LEURS DERIVES A DES FINS DE DIAGNOSTIC RADIOGRAPHIQUE ET DE THERAPIE ANTI-TUMEURS, AINSI QUE POUR LA PRODUCTION D'AGENTS DE DIAGNOSTIC RADIOGRAPHIQUE ET D'AGENTS ANTI-TUMORAUX

Country Status (10)

Country Link
EP (1) EP0504339A1 (fr)
JP (1) JPH05502456A (fr)
KR (1) KR920702235A (fr)
AU (1) AU658148B2 (fr)
CA (1) CA2073050A1 (fr)
DE (1) DE4028139A1 (fr)
MX (1) MX9100967A (fr)
PT (1) PT98869A (fr)
TW (1) TW197951B (fr)
WO (1) WO1992004056A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013171048A1 (fr) 2012-05-18 2013-11-21 Bayer Pharma Aktiengesellschaft Complexes de métaux lourds à base de bis-aza-inositol pour imagerie par rayons x
EP2796152A1 (fr) 2013-04-25 2014-10-29 Bayer Pharma Aktiengesellschaft Complexes au Bis Azainositol Hafnium asymétriques pour imagerie par rayons X
EP2873670A1 (fr) 2013-11-14 2015-05-20 Bayer Pharma Aktiengesellschaft Complexes de zirconium bis azainositol pour imagerie par rayons X

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5830430A (en) 1995-02-21 1998-11-03 Imarx Pharmaceutical Corp. Cationic lipids and the use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0190676A1 (fr) * 1985-02-02 1986-08-13 Laboratorien Hausmann AG Dérivés de cis-1,3,5-triamino 2,4,6-cyclohexanetriol, leur utilisation, leur procédé de préparation et préparations pharmaceutiques les contenant
WO1990008138A1 (fr) * 1989-01-13 1990-07-26 Nycomed As Agents heterocycliques de chelation
WO1991010454A1 (fr) * 1990-01-09 1991-07-25 Byk Gulden Lomberg Chemische Fabrik Gmbh Complexes d'elements de transition pour diagnostic par resonance magnetique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0190676A1 (fr) * 1985-02-02 1986-08-13 Laboratorien Hausmann AG Dérivés de cis-1,3,5-triamino 2,4,6-cyclohexanetriol, leur utilisation, leur procédé de préparation et préparations pharmaceutiques les contenant
WO1990008138A1 (fr) * 1989-01-13 1990-07-26 Nycomed As Agents heterocycliques de chelation
WO1991010454A1 (fr) * 1990-01-09 1991-07-25 Byk Gulden Lomberg Chemische Fabrik Gmbh Complexes d'elements de transition pour diagnostic par resonance magnetique

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013171048A1 (fr) 2012-05-18 2013-11-21 Bayer Pharma Aktiengesellschaft Complexes de métaux lourds à base de bis-aza-inositol pour imagerie par rayons x
EP2796152A1 (fr) 2013-04-25 2014-10-29 Bayer Pharma Aktiengesellschaft Complexes au Bis Azainositol Hafnium asymétriques pour imagerie par rayons X
WO2014173857A1 (fr) 2013-04-25 2014-10-30 Bayer Pharma Aktiengesellschaft Complexes de hafnium à base de bis-aza-inositol pour imagerie par rayons x
CN105142679A (zh) * 2013-04-25 2015-12-09 拜耳医药股份公司 用于x射线成像的双(氮杂肌醇)铪络合物
EP2873670A1 (fr) 2013-11-14 2015-05-20 Bayer Pharma Aktiengesellschaft Complexes de zirconium bis azainositol pour imagerie par rayons X
WO2015071201A1 (fr) 2013-11-14 2015-05-21 Bayer Pharma Aktiengesellschaft Complexes de bis azainositol-zirconium pour l'imagerie radiographique

Also Published As

Publication number Publication date
DE4028139A1 (de) 1992-03-12
KR920702235A (ko) 1992-09-03
TW197951B (fr) 1993-01-11
PT98869A (pt) 1992-07-31
AU8436791A (en) 1992-03-30
AU658148B2 (en) 1995-04-06
CA2073050A1 (fr) 1992-03-06
MX9100967A (es) 1992-05-04
EP0504339A1 (fr) 1992-09-23
JPH05502456A (ja) 1993-04-28

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