EP0358684A1 - "Targeted"-Verbindungen zur Krebstherapie, deren Herstellung und Anwendung - Google Patents

"Targeted"-Verbindungen zur Krebstherapie, deren Herstellung und Anwendung

Info

Publication number
EP0358684A1
EP0358684A1 EP19880904232 EP88904232A EP0358684A1 EP 0358684 A1 EP0358684 A1 EP 0358684A1 EP 19880904232 EP19880904232 EP 19880904232 EP 88904232 A EP88904232 A EP 88904232A EP 0358684 A1 EP0358684 A1 EP 0358684A1
Authority
EP
European Patent Office
Prior art keywords
ppm
nitro
imidazole
compound
chloroethyl
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
EP19880904232
Other languages
English (en)
French (fr)
Inventor
Jean-Louis Imbach
Alain Jean Joseph Carminati
Jean Louis Paul Philippe Barascut
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.)
Centre National de la Recherche Scientifique CNRS
Original Assignee
Centre National de la Recherche Scientifique CNRS
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 Centre National de la Recherche Scientifique CNRS filed Critical Centre National de la Recherche Scientifique CNRS
Publication of EP0358684A1 publication Critical patent/EP0358684A1/de
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C07D233/92—Nitro radicals attached in position 4 or 5
    • C07D233/94—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C07D233/92—Nitro radicals attached in position 4 or 5
    • C07D233/95—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by nitrogen atoms, attached to other ring members

Definitions

  • Anti-tumor targeting agents their preparation and applications
  • the present invention relates to new compounds which result from the coupling of a molecule having a chemosensitizing structure and a molecule having a cytotoxic structure, their preparation process, as well as their application as medicaments.
  • a molecule having a chemosensitizing structure and a molecule having a cytotoxic structure
  • their preparation process as well as their application as medicaments.
  • Another problem is that caused by solid tumors; the hypoxic cells present in these tumors show therapeutic resistance to most anti-cancer agents.
  • the resistance mechanism of these cells is quite complex and involves kinetic, metabolic and physical factors.
  • these cells are known to be placed at a distance from blood vessels, which prevents certain drugs from diffusing to the desired location.
  • Radiosensitizers have already been proposed having an affinity for hypoxic cells, teksquele Misonidazole.
  • the present invention aims to overcome the drawbacks listed above by providing new compounds which result from the coupling of a molecule having a chemosensitizing structure and a molecule having a cytotoxic structure. These compounds will make it possible to chemosensitize hypoxic tumor cells and to specifically deliver to them a cytotoxic entity interacting on their DNA.
  • the molecule having a cytotoxic structure is, more preferably, derived from an alkylating cytotoxic molecule. It can be a molecule derived from a nitrosourea or a nitrogen mustard.
  • the molecule having a chemosensitizing structure will, preferably, be derived from a molecule with an aromatic cycle, or pseudo-aromatio
  • the compounds of the present invention correspond to farmule I in which X is a residue of a benzene ring or of a heterocycle comprising nitrogen as the heteroatom of formula XH in which H represents hydrogen, X being substituted by at least one group -NO 2 , R 1 is H, or SH and R 2 is a group derived from nitrosourea or nitrogen mustard.
  • X is chosen from the following radicals: benzyl, triazolyl, benzymidazolyl, imidazolyl, tetrazolyl.
  • R 2 is -NH-CO-N (NO) -CH 2 -CH 2 -Cl provided that R 1 is a hydrogen atom, or R 2 is CH 2 -NH- CO-N (NO) -CH 2 -CH 2 Cl, provided that R 1 is OH or SH.
  • Particularly preferred compounds are the following: [[(2-chloro-ethyl) -3 3-nitroso-ureido] -3-2-hydroxypropyl] -1 4-nitro imidazole, [[(2-chloro-ethyl) -3 nitroso-3 ureido] -3 hydroxy-2 propyl] -1 nitro-5 imidazole,
  • R 2 is NH-CH 2 -CH 2 - Cl or N (CH 2 -CH 2 -Cl) 2 or NH-C 6 H 4 -N (CH 2 CH 2 Cl) 2 provided that R 1 is a hydrogen atom or R 2 is CH 2 -NH- CH 2 -CH 2 -Cl or CH 2 -N (CH 2 CH 2 Cl) 2 or CH 2 -NH-C 6 H 4 -N (CH 2 CH 2 Cl) 2 provided that R 1 is OH or SH.
  • Particularly preferred compounds are the following:
  • the present invention also relates to a process for the preparation of compounds of formula I.
  • R 2 is a nitrosourea
  • R 2 -NH-CO-N (CO) -N (NO) -CH 2 -CH 2 -Cl or
  • R NO 2
  • R 3 CH 2 CH 2 Cl
  • XH H is linked to the heteroatom when X represents a heterocycle comprising nitrogen as the heteroatom.
  • -R 6 , -R 7 chosen from in particular H, CH 2 -CH 2 OH and
  • the invention therefore provides molecules aiming to chemosensitize hypoxic tumor cells and to specifically deliver to them a cytotoxic entity which inter-reacts with their DNA.
  • the compounds of the present invention are useful as medicaments.
  • the present invention therefore therefore also relates to the application of the compounds as medicaments as well as pharmaceutical compositions comprising, in addition to a pharmaceutically acceptable carrier, an active principle comprising at least one compound as described above.
  • an active principle comprising at least one compound as described above.
  • - Figure 1 represents, for certain compounds of the present invention, the evolution of the number of surviving cells of a Mer- line as a function of the quantity administered ( ⁇ moles)
  • - Figure 2 represents, for certain compounds of the present invention, the evolution of the number of surviving cells of a Mer + line as a function of the quantity administered (in ⁇ moles).
  • nitrosoureas of the A and B series were synthesized by coupling between the amine and an active ester comprising the N- (2-chloroethyl) N-nitrosocarbamate unit according to the " active esters "used in peptide synthesis (Diagram 1)).
  • the alkanolamines were synthesized by treatment of (epoxyalkyl) -1 nitro-2 imidazoles with a number of secondary and primary amines. By this method of synthesis secondary and tertiary amines are obtained.
  • the primary alkanolamines are prepared by the reaction of ammonia with the epoxides.
  • 1 '(2-aminoethyl) -1 2-nitro imidazole can be obtained by the action of aziridine on 2-nitro imidazole.
  • Nitroimidazoles (hydroxyaminoalkyl) -1 are obtained via nitro-imidazole intermediates N- (hydroxyalkyl) phthalimides.
  • R H 19 28 (71%)
  • R nltro-4 20 29 (89%)
  • R nitro-3 21 30 (67%)
  • R nitro-2 23 37 (81%)
  • the oil bath is brought to 100 ° C for 10 minutes.
  • the solution is then brought to room temperature; 12 ml (155 mmol) of 1,2-dichloroethane are then added.
  • the duration of the addition is 1 hour.
  • reaction mixture is then evaporated under vacuum; the oily residue is thrown into a mixture of 200 ml of ice water. Neutralized with ammonia and extracted 5 times with 50 ml of toluene then 3 times with 30 ml of dichloromethane.
  • This compound was prepared in a manner analogous to Example 3 of compound 14 with a yield of 60%.
  • This compound was prepared in a manner analogous to Example 12 from compound No. 7 with a yield of 69%.
  • This compound was prepared in a manner analogous to Example 12 from the non-MS compound with a yield of 70%.
  • This compound was prepared in a manner analogous to Example 20 from compound No. 16 with a yield of 72%.
  • This compound was prepared in a manner analogous to Example 20 from compound No. 17 with a yield of 56%.
  • This compound was prepared in a manner analogous to Example 20 from compound 20 with a yield of 69%.
  • This compound was prepared in a manner analogous to Example 20 from compound No. 21 with a yield of 67%.
  • This compound was prepared in a manner analogous to Example 28 from commercial nitro-4 (5) imidazole. The yield obtained is 71%.
  • R H, Nitro-4, Nitro-5, Nitro-2.
  • the difference between these two types of cells is the presence or absence of a separating enzyme, 0-6 methyltransferase.
  • BME Eagle base medium
  • the cells used in an aerobic environment are suspended in 10 ml of Eagle base medium (BME) at a concentration of 1 to 2.10 per milliliter, and placed in a type I treatment flask as described by Whilliams and Rauth.
  • BME Eagle base medium
  • the cells are added to the vials containing the BME only after the medium has remained in a gaseous mixture 97% N 2 /3% CO 2 for 3 hours.
  • the cells are incubated for 10 minutes at a concentration of 2 ⁇ 10 7 cells / ml in a Hamilton syringe
  • the relative aerobic and hypoxic toxicity of the various compounds was calculated using the DEF factor defined as the ratio of the amounts required to reduce the surviving cells to 0.01, respectively, under aerobic and hypoxic conditions.
  • Figures 1 and 2 illustrate the results obtained and give the percentage of surviving cells as a function of the dose of compound administered (in ⁇ mol).
  • N2 represents the hypoxic medium while O2 represents the aerobic medium.
  • Figure 1 expresses more precisely the results obtained with Mer- cells while Figure 2 expresses the results obtained with Mer + cells.
  • the compounds tested are cytotoxic with respect to Mer- cells (Hela-MR), both under aerobic and hypoxic conditions, except for the non-nitrated imidazole derivatives I-273 (no24) and 1-283 (no. 28).
  • the Mer + cells (Hela - 53) are, as should be expected, more resistant to the products tested. All the compounds of the A series are less toxic than those of the B series.
  • the compounds I-278 and I-282 (31 and 27) once again exhibit increased cytotoxicity under conditions hypoxic (DEF close to 1.3).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP19880904232 1987-05-04 1988-05-03 "Targeted"-Verbindungen zur Krebstherapie, deren Herstellung und Anwendung Ceased EP0358684A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8706241A FR2614890B1 (fr) 1987-05-04 1987-05-04 Compose resultant du couplage d'une molecule a structure chimiosensibilisante et d'une molecule a structure cytotoxique, procede de preparation, application a titre de medicament et compositions pharmaceutiques le contenant
FR8706241 1987-05-04

Publications (1)

Publication Number Publication Date
EP0358684A1 true EP0358684A1 (de) 1990-03-21

Family

ID=9350728

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19880904232 Ceased EP0358684A1 (de) 1987-05-04 1988-05-03 "Targeted"-Verbindungen zur Krebstherapie, deren Herstellung und Anwendung

Country Status (3)

Country Link
EP (1) EP0358684A1 (de)
FR (1) FR2614890B1 (de)
WO (1) WO1988008840A1 (de)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5691371A (en) * 1993-05-25 1997-11-25 Auckland Uniservices Limited Nitrobenzyl mustard quaternary salts and their use as hypoxia-selective cytotoxic agents
CN1270062A (zh) * 1999-04-08 2000-10-18 广州山河药业股份有限公司 一种放射、化学治疗增效剂—甘氨双唑金属盐及其制法和用途
US9056136B2 (en) * 2006-10-06 2015-06-16 Natural Pharmacia International, Inc. Weakly basic 2-nitroimidazoles for the non-invasive detection of tissue hypoxia
WO2022210190A1 (ja) * 2021-03-30 2022-10-06 ナミックス株式会社 アミン誘導体
CN116745281A (zh) * 2021-03-30 2023-09-12 纳美仕有限公司 固化催化剂、树脂组合物、密封材料、粘接剂和固化物

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58188892A (ja) * 1982-04-26 1983-11-04 Tetsuo Suami 新規なニトロソウレア化合物
FR2540491A1 (fr) * 1983-02-08 1984-08-10 Centre Nat Rech Scient Nouvelles nitrosourees, leur procede de preparation et leur application therapeutique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8808840A1 *

Also Published As

Publication number Publication date
FR2614890A1 (fr) 1988-11-10
WO1988008840A1 (fr) 1988-11-17
FR2614890B1 (fr) 1989-08-11

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