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WO1990010638A1 - Agents anti-tumoraux a affinite avec des recepteurs d'hormones steroides - Google Patents

Agents anti-tumoraux a affinite avec des recepteurs d'hormones steroides Download PDF

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Publication number
WO1990010638A1
WO1990010638A1 PCT/EP1990/000344 EP9000344W WO9010638A1 WO 1990010638 A1 WO1990010638 A1 WO 1990010638A1 EP 9000344 W EP9000344 W EP 9000344W WO 9010638 A1 WO9010638 A1 WO 9010638A1
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WO
WIPO (PCT)
Prior art keywords
amino
cytostatic
dichloromethane
mmol
conjugates
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/EP1990/000344
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German (de)
English (en)
Inventor
Gerhard Eisenbrand
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Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of WO1990010638A1 publication Critical patent/WO1990010638A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/66—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to halogen atoms or to nitro or nitroso groups
    • C07C275/68—N-nitroso ureas
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0038—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an androstane skeleton, including 18- or 19-substituted derivatives, 18-nor derivatives and also derivatives where position 17-beta is substituted by a carbon atom not directly bonded to a further carbon atom and not being part of an amide group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00

Definitions

  • Cytostatics that are used clinically to treat malignant tumors often have severe toxicity, particularly myelotoxicity, hepatoxicity, nephrotoxicity and lung toxicity, which are dose-limiting factors and limit clinical effectiveness
  • the object of the invention is accordingly compounds which achieve an accumulation in the tumor tissue through this linkage, which should result in an increase in the tumor-specific effect and a reduction in the systemic toxicities.
  • Zytostati kakonjugate with such carrier molecules that have a binding affinity for steroid hormone receptors.
  • the cytostatics and carriers are linked via
  • Suitable fasteners usually amide or ester bonds are made.
  • N-mustard derivatives and N- (2-chloroethyl) -N-nitrosoureas are alkylating agents. Some representatives are clinically established antineoplastics. Others show pronounced
  • -oligopeptides have a free acid group which is responsible for
  • Linkage can be exploited via a connecting element with carrier molecules.
  • N- (2-chloroethyl) -N '- (2-hydroxyethyl) -N-nitrosourea and N, N-bis- (2-chloroethyl) aminoethylamine can be
  • Link hydroxyl or amino group Linking antineoplastic antibiotics such as mitomycin, adriamycin, daunomycin, epirubicin, as well
  • Anthracenedione derivatives such as mitoxantrone and amethantrone is via an amino. or hydroxyl group.
  • Antineoplastic metal complexes such as
  • (1,2ridiominoethane) -cis-dichloroplatin (n) are connected via a suitable connecting element e.g. COOH or -OH bound to the carrier molecule.
  • a suitable connecting element e.g. COOH or -OH bound to the carrier molecule.
  • Steroids on the one hand and non-steroidal ones serve as receptor-affine carriers
  • steroid hormone repetitive affinity compounds on the other hand.
  • the term steroid includes compounds with the basic structure of the Estran-s, Androstan and Pregnan series.
  • Non-steroidal receptor-affine compounds are preferably those from the series of 2- [4- (1,2-diphenyl-1-butenyl) phenoxy] ethylamines. preferred starting materials, supports and connecting elements between supports and
  • Steroids preferably those with a basic structure from the Estrans, Androstani or Pregnan (Gonan) series.
  • Hydroxy-bearing steroids are preferably used from the group consisting of Estra 1,3,5 (10) triene, Androstane, Androst-4-ene, Androst-5-ene, Estr-4-ene, Estr-5 (10) ene, Estra- 4,9,11-triene, Pregn-4-ene,
  • hydroxyl group (s) are preferably esterified in position 11, 17 or 21.
  • non-steroidal steroid receptor-affine compounds preferably from the
  • Antitumor agents are preferably used: - carboxalkyl groups
  • the conjugates are produced by linking the connecting element on the one hand to the antitumor agent, and on the other hand to the steroid receptor-affine carrier via an ester or an amide bond.
  • the esterification is preferably carried out with carbonyldiimidazole or dicyclohexylcarbodiimide (DCC) with or without the addition of p3dimethylaminopyridine (DMAP).
  • DCC dicyclohexylcarbodiimide
  • DMAP p3dimethylaminopyridine
  • the amidation takes place by means of dicyclohexylcarbodiimide or carbonyldiimidazole with or without the addition of p-dimethylaminopyridine or via an active N-hydroxysuccinimide ester or via an azide of the acid.
  • the esterification or amidation is carried out at room temperature.
  • the reaction time is between 1 - 24 h, at room temperature or a little less at a slightly elevated temperature, e.g. 1 - 12 h.
  • the conjugates are presented in pure form either by column chromatography on suitable adsorbents, preferably on silica gel, eluted with a suitable solvent or solvent mixture, or by recrystallization.
  • Example 1 17ß-O- (CNC-1-alanylaminohexylamino-1,4-dioxo-butyl) estradiol 1.4 g (3 mmol)
  • Tetrahydrofuran (THF) dissolved and slowly a solution of 1.05 g (3.6 mmol) of N- (CNC-L-alanyloxy) tetrahydropyrrole in 10 ml of THF is added dropwise. After 4 hours you do that
  • estradiol-17-succinato-HECNU-ester-3-tetrahydropyranol ether is prepared and the protective group is split off with p-toluenesulfonic acid
  • Example 4 is presented analogously to example 3, with the difference that the steroid hormone is none
  • Example 5 is presented analogously to example 4,
  • Example 6 17ß-O- (CNC-aminoethoxy-1,4-dioxo-butyl) -19-nortestosterone
  • Adriamycin hydrochloride (0.055 mmol) suspended in 12 ml of absolute dimethylformamide. To release the
  • Dichloromethane / triethylamine are 2 ml at 0 ° C.
  • Acetylmelphalan are dissolved in dichloromethane and at 0 ° C with 660 mg (3.5 mmol) DCC and 370 mg (3.5 mmol)
  • UV septa 3300, 2940, 1760, 1650, 1610, 1510, 1465, 1440, 1370, 1290, 1240, 1218, 1198, 1180, 1035, 840 UV septa:
  • the mixture is acidified with ice-cold NaHSO 4 solution and extracted twice with dichloromethane.
  • the organic phase is washed with saturated NaCl solution, dried over sodium sulfate, evaporated, the residue taken up in acetonitrile, the suspension is filtered and evaporated.
  • UV-Spectrum 1370, 1290, 1240, 1220, 1200, 1175, ' 1110, 1030, 1020, 840 UV-Spectrum:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des conjugués cytostatiques, par exemple des alkylants, des antibiotiques, des anthracènediones, des composés métalliques et des substances d'origine végétale ou des dérivés semi-synthétiques à effet antinéoplastique, sont liés par des éléments de liaison appropriés, notamment une liaison amide et/ou ester, à des molécules porteuses ayant une affinité de liaison avec des récepteurs d'hormones stéroïdes. Selon leur procédé de préparation, on relie l'élément de liaison de manière connue en soi d'une part à l'agent anti-tumoral et d'autre part au porteur ayant une affinité avec les récepteurs de stéroïdes, notamment au moyen d'une liaison amide et/ou ester.
PCT/EP1990/000344 1989-03-07 1990-03-02 Agents anti-tumoraux a affinite avec des recepteurs d'hormones steroides Ceased WO1990010638A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP3907290.8 1989-03-07
DE19893907290 DE3907290A1 (de) 1989-03-07 1989-03-07 Steroidhormonrezeptoraffine antitumorwirkstoffe

Publications (1)

Publication Number Publication Date
WO1990010638A1 true WO1990010638A1 (fr) 1990-09-20

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1990/000344 Ceased WO1990010638A1 (fr) 1989-03-07 1990-03-02 Agents anti-tumoraux a affinite avec des recepteurs d'hormones steroides

Country Status (2)

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DE (1) DE3907290A1 (fr)
WO (1) WO1990010638A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994029327A1 (fr) * 1993-06-07 1994-12-22 British Technology Group Limited Composes anti-cancer
EP0646592A1 (fr) * 1993-10-05 1995-04-05 Kureha Kagaku Kogyo Kabushiki Kaisha Conjugué d'agent d'alcoylation de dérivé d'estradiol
EP1023315A4 (fr) * 1997-05-14 2004-12-29 Sloan Kettering Institutefor C Methodes et compositions de destruction de proteines selectionnees
US8063249B1 (en) 2008-04-25 2011-11-22 Olema Pharmaceuticals, Inc. Substituted triphenyl butenes
US9796683B2 (en) 2015-05-29 2017-10-24 Eisai R&D Management Co., Ltd. Tetrasubstituted alkene compounds and their use
US10640483B2 (en) 2016-11-28 2020-05-05 Eisai R&D Management Co., Ltd. Salts of indazole derivative and crystals thereof
US11826430B2 (en) 2019-05-14 2023-11-28 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US11834458B2 (en) 2021-03-23 2023-12-05 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US11952349B2 (en) 2019-11-13 2024-04-09 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US12006314B2 (en) 2021-05-03 2024-06-11 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US12398121B2 (en) 2018-05-14 2025-08-26 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0489220A1 (fr) * 1990-12-02 1992-06-10 American Cyanamid Company Dérivés N,N-bis(succinyl-peptidiques) cytotoxiques d'1,4-bis(aminoalkyl)-5,8-dihydroxyanthraquinones et leurs conjuqués d'anticorps
WO1995018141A1 (fr) * 1993-12-29 1995-07-06 Iskra Industry Co., Ltd. Composition medicinale inhibitrice de la resorption osseuse et favorisant l'osteogenese
DE19831648B4 (de) * 1998-07-15 2004-12-23 Stiebel Eltron Gmbh & Co. Kg Verfahren zur funktionalen Adaption einer Regelelektronik an ein Gasheizgerät
DE10012120A1 (de) * 2000-03-13 2001-09-27 Ktb Tumorforschungs Gmbh Therapeutische und diagnostische Ligandensysteme mit Transportmolekülbindenden Eigenschaften und diese enthaltende Arzneimittel

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2201419A (en) * 1987-02-24 1988-09-01 Erba Farmitalia Anthracycline-oestrone derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2201419A (en) * 1987-02-24 1988-09-01 Erba Farmitalia Anthracycline-oestrone derivatives

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994029327A1 (fr) * 1993-06-07 1994-12-22 British Technology Group Limited Composes anti-cancer
EP0646592A1 (fr) * 1993-10-05 1995-04-05 Kureha Kagaku Kogyo Kabushiki Kaisha Conjugué d'agent d'alcoylation de dérivé d'estradiol
US5478818A (en) * 1993-10-05 1995-12-26 Kureha Kagaku Kogyo Kabushiki Kaisha Estradiol derivative-alkylating agent conjugate with reduced hormonal activity, process for preparing the same, compounds useful for the preparation thereof, and growth inhibiting composition containing the conjugate or estradiol derivative
US5480878A (en) * 1993-10-05 1996-01-02 Kureha Kagaku Kogyo Kabushiki Kaisha Method for treating prostatic hypertrophy with estradiol derivatives
US5491138A (en) * 1993-10-05 1996-02-13 Kureha Kagaku Kogyo Kabushiki Kaisha Estradiol derivative alkylating agent conjugate with reduced hormonal activity, process for preparing the same, compounds useful for the preparation thereof, and growth inhibiting composition containing the conjugate or estradiol derivative
US5561125A (en) * 1993-10-05 1996-10-01 Kureha Kagaku Kogyo Kabushiki Kaisha Estradiol derivative and growth inhibiting composition thereof
US5633393A (en) * 1993-10-05 1997-05-27 Kureha Kagaku Kogyo Kabushiki Kaisha Estradiol derivative-alkylating agent conjugate with reduced hormonal activity, process for preparing the same, compounds useful for the preparation thereof, and growth inhibiting compositon containing the conjugate or estradiol derivative.
JP2009256388A (ja) * 1997-05-14 2009-11-05 Sloan-Kettering Inst For Cancer Research 選択された蛋白質を分解する方法および複合化合物
EP1023315A4 (fr) * 1997-05-14 2004-12-29 Sloan Kettering Institutefor C Methodes et compositions de destruction de proteines selectionnees
US8063249B1 (en) 2008-04-25 2011-11-22 Olema Pharmaceuticals, Inc. Substituted triphenyl butenes
US9796683B2 (en) 2015-05-29 2017-10-24 Eisai R&D Management Co., Ltd. Tetrasubstituted alkene compounds and their use
US10851065B2 (en) 2015-05-29 2020-12-01 Eisai R&D Management Co., Ltd. Tetrasubstituted alkene compounds and their use
US10640483B2 (en) 2016-11-28 2020-05-05 Eisai R&D Management Co., Ltd. Salts of indazole derivative and crystals thereof
US12398121B2 (en) 2018-05-14 2025-08-26 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US11826430B2 (en) 2019-05-14 2023-11-28 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US12208141B2 (en) 2019-05-14 2025-01-28 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US11952349B2 (en) 2019-11-13 2024-04-09 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US11834458B2 (en) 2021-03-23 2023-12-05 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US12006314B2 (en) 2021-05-03 2024-06-11 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds

Also Published As

Publication number Publication date
DE3907290A1 (de) 1990-09-13

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