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WO1994005681A1 - Nouveaux acetals de phosphamide cetonique et d'alkylglycosides - Google Patents

Nouveaux acetals de phosphamide cetonique et d'alkylglycosides Download PDF

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Publication number
WO1994005681A1
WO1994005681A1 PCT/EP1993/002403 EP9302403W WO9405681A1 WO 1994005681 A1 WO1994005681 A1 WO 1994005681A1 EP 9302403 W EP9302403 W EP 9302403W WO 9405681 A1 WO9405681 A1 WO 9405681A1
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WO
WIPO (PCT)
Prior art keywords
chain
carbon atoms
branched alkyl
straight
compounds
Prior art date
Application number
PCT/EP1993/002403
Other languages
German (de)
English (en)
Inventor
Lutz F. Tietze
Michael Lögers
Original Assignee
Bayer Ag
Tietze Lutz F
Loegers Michael
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 Bayer Ag, Tietze Lutz F, Loegers Michael filed Critical Bayer Ag
Publication of WO1994005681A1 publication Critical patent/WO1994005681A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon or a metal, e.g. chelates or vitamin B12
    • 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
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical

Definitions

  • the present invention relates to new acetals of ketophosphamide and 10 alkyl glycosides, processes for their preparation and their use as highly selective cytostatics in cancer therapy.
  • comparison _ 5 compounds are non-toxic, as they can be converted by hydrolysis into compounds in which cytocidal karmie in the tumor tissue by Hypergly- reach pH. _? -
  • the present invention relates to new acetals of ketophosphamide and alkylglycosides of the general formula (I),
  • R 1 , R 2 , R 3 and R 4 are identical or different and represent hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or a hydroxyl protective group,
  • R 5 represents straight-chain or branched alkyl having up to 8 carbon atoms
  • R 6 for straight-chain or branched alkyl having up to 8 carbon atoms
  • R 7 and R 8 are the same or different and represent hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by chlorine,
  • sugar residue stands for aldohexoses and the corresponding pyranosides and can be present in the D or L form and with an ⁇ or ⁇ configuration at the anomalous center.
  • __ Hydroxy protective group in the context of the above definition generally stands for a protective group from the series: tert-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, terLButyldimethylsilyl, terL-butyldiphenylsilyl, 5 triphenylsilyl, trimethylsilylethoxycarbonyl, benzyl, benzyloxycarbonyl, 2-nitrobenzyl, 4-nitrobenzyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, tert.
  • Aldohexoses is, for example D - (+) - glucose, L - (-) - glucose, D - (+) - mannose 1 5 se, L - (-) - mannose, D - (+) - galactose and L (-) - Galactose.
  • D - (-) - glucose is preferred here.
  • R 1 , R 2 , R 3 and R 4 are the same or different and represent hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or acetyl, benzyl or benzoyl,
  • R 5 represents straight-chain or branched alkyl having up to 6 carbon atoms
  • R 6 for straight-chain or branched alkyl having up to 6 carbon atoms
  • R 7 and R 8 are the same or different and represent hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by chlorine and wherein the sugar residue stands for aldohexoses and the corresponding pyranosides and can be present in the D or L form and with an ⁇ or ⁇ configuration at the abnormal center.
  • R 1 , R 2 , R 3 and R 4 are the same or different and represent hydrogen, straight-chain or branched alkyl having up to 3 carbon atoms or acetyl, benzyl or benzoyl,
  • R 5 represents straight-chain or branched alkyl having up to 4 carbon atoms
  • R 6 represents straight-chain or branched alkyl having up to 4 carbon atoms
  • R 7 and R 8 are the same or different and represent hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by chlorine,
  • sugar residue stands for aldohexoses and the corresponding pyranosides and can be present in the D or L form and with an ⁇ or ⁇ configuration at the abnormal center.
  • R 1 , R 2 , R 3 and R 4 are identical or different and represent hydrogen, methyl, ethyl or acetyl, R 5 represents methyl or ethyl,
  • R 6 represents methyl
  • R 7 and R 8 represent hydrogen
  • sugar residue stands for D-glucose with an ⁇ or ⁇ configuration at an anomalous center.
  • R 1 ' , R 2 ⁇ R 3' and R 4 ' have the meaning given above for R 1 , R 2 , R 3 and R 4 , but do not represent hydrogen
  • R 5 and R 6 have the meaning given above
  • Suitable solvents are the customary organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloromethylene or chlorobenzene, tricholethylene Ethyl acetate, dimethyl sulfoxide, Dimeüyl formamide, acetonitrile, acetone or NiüOmethane. It is also possible to use mixtures of the solvents mentioned. Tetrahydrofuran, dichloromethane and toluene are preferred.
  • Suitable bases are 1, 8-diazabicyclo [5,4,0] undec-7-ene, imidazole, pyridine, tetrazole and the usual organic amines. These preferably include alkylamines such as triethylamine, diisopropylamine, dicyclohexylamine and ethyldiisopropylamine. Triethylamine, 1,8-diazabicyclo [5,4,0] undec-7-ene and pyridine are particularly preferred.
  • N-methylimidazole and dimethylaminopyridine are suitable as auxiliary substances.
  • N-methylimidazole is preferred.
  • the bases and auxiliaries are generally used in an amount of 1 to 5 mol, preferably 1 to 1.75 mol, in each case based on 1 mol of the compounds of the general formula (UI)
  • reaction is generally carried out under normal pressure, but it is also possible to carry out the process under positive or negative pressure (e.g. in a range from 0.5 to 5 bar).
  • the process according to the invention is generally carried out in a temperature range from 0 ° C. to + 60 ° C., preferably at room temperature
  • the protective groups on the sugar residue are split off by a customary method in inert solvents in the presence of a base or by hydrogenolysis.
  • the usual inorganic bases are suitable as bases for the cleavage.
  • bases preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as, for example Sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate, or alkali alcohols such as sodium ethanolate, sodium methoxide, potassium ethanoate, potassium methoxide or potassium tert-butanol.
  • alkali metal hydroxides or alkaline earth metal hydroxides such as, for example Sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate, or alkali alcohols such as sodium ethanolate, sodium methoxide, potassium ethanoate, potassium methoxide or potassium tert-butanol.
  • Sodium carbonate or potassium carbonate are particularly preferably used.
  • Suitable solvents for cleavage are the organic solvents customary for saponification. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulfoxide. Alcohols such as methanol, ethanol, propanol or isopropanol are particularly preferably used. It is also possible to use mixtures of the solvents mentioned.
  • the cleavage is generally carried out in a temperature range from 0.degree. C. to + 60.degree. C., preferably from + 20.degree. C. to 40.degree. C. In general, the cleavage is carried out at normal pressure. It is also possible, however, under reduced pressure or under elevated pressure to work (e.g. from 0.5 to 5 bar).
  • Special hydroxy protective groups are cleaved off, for example, using tetrabutylammonium fluoride or by hydrogenolytic cleavage, in the case of the benzyl group in the presence of a catalyst, for example a mixture of palladium / C and palladium / CaCO 3 with hydrogen one of the solvents listed above, preferably methanol, in a temperature range from 0 ° C. to 40 ° C., preferably at room temperature.
  • a catalyst for example a mixture of palladium / C and palladium / CaCO 3 with hydrogen one of the solvents listed above, preferably methanol, in a temperature range from 0 ° C. to 40 ° C., preferably at room temperature.
  • N, N-bis (2-chloroethyl) phosphoric acid amide dichloride of the formula (III) is known [cf. J. Am. Chem. Soc. 76, 655 (1954)].
  • R 1 ', R 2' , R 3 ' and R 4 ' have the meaning given above,
  • R 5 has the meaning given above
  • R 7 represents one of the silylhydroxy protective groups listed above, preferably tert-butoxy-diphenylsilyl
  • R 1 ' , R 2' , R 3 ' , R 4' , R 5 , R 6 and R 7 have the meaning given above,
  • Suitable solvents are the halogenated hydrocarbons listed above, in particular methylene chloride.
  • the reaction with the enol ethers takes place in a protective gas atmosphere, in a temperature range from 0 ° C. to + 40 ° C., preferably at room temperature and normal pressure.
  • triethylamine is particularly suitable as the base.
  • Substituted arylsulfonic acids such as, for example, naphthylsulfonic acid, p-toluenesulfonic acid (PTS) or pyridinium-p-toluenesulfonate (PPTS) or C 1 -C 4 -alkylsulfonic acids, are generally used as catalysts.
  • PTS p-toluenesulfonic acid
  • PPTS pyridinium-p-toluenesulfonate
  • C 1 -C 4 -alkylsulfonic acids are generally used as catalysts.
  • Pyridinium-p-toluenesulfonate is preferred
  • the catalyst is used in an amount of 0.1 mol to 5 mol, preferably 0.1 mol to 0.5 mol, based on 1 mol of the compounds of the general formula (II).
  • desilylation is preferably carried out using tetra-n-butylammonium fluoride / H 2 O in the presence of tetrahydrofuran and at room temperature.
  • the compounds according to the invention show an unforeseeable, valuable spectrum of pharmacological activity.
  • the acid-labile derivatives of the inactivated keotphosphamide of the general formula (I) represent a cytostatic that is non-toxic in its transport form. At the pH value that can be achieved in tumor tissue by hyperglycaemia, they release a cytocidal compound, the Friedman acid, by hydrolysis.
  • a comparison of the IC 10 at pH 7.4 and at pH 6.2 showed a ratio of the required amounts of substance of 100: 1; ie to destroy 90% of the cell population at pH 7.4 (pH value of the normal cell) is 100 times the amount of the compound from Example VII as at pH 6.2 (pH value of a malignant tumor with hyperglycemia ) required.
  • the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds of the formula (I) or which consist of one or more active compounds of the formula (I), and processes for the preparation of these preparations.
  • the active compounds of the formula (I) should be present in the pharmaceutical preparations listed above, preferably in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95% by weight of the total mixture.
  • the pharmaceutical preparations listed above can also contain other active pharmaceutical ingredients.
  • the pharmaceutical preparations listed above are prepared in a customary manner by known methods, e.g. by dissolving the active ingredient (s) in a solvent, preferably a slightly basic aqueous buffer.
  • the active compound (s) according to the invention in total amounts of from about 0.5 to about 500, preferably from 1 to 150 mg / kg of body weight per 24 hours to be administered in the form of several individual doses to achieve the desired results.
  • a single dose contains the active ingredient (s) preferably in amounts of about 1 to about 100, in particular 1 to 80 mg / kg body weight.
  • PPTS pyridinium p-toluenesulfonate
  • PE petroleum ether
  • SiMe 2 tBu tert-butyl-dimethylsilyl
  • SiPh 2 OtBu tert-butoxy-diphenylsilyl
  • TBAF tributylammonium fluoride
  • siloxy compound (general formula VI), dissolved in 10 ml of THF! o 694 mg (2.20 mmol) of tetrabutylammonium fluoride x 3 H 2 O are added at 0 ° C, the mixture is stirred for 5 - 10 min at this temperature and, depending on the protective group, is left for 18 - 22 h (SiMe 2 tBu) or 30 - React 45 min (SiPh 2 OtBu) at room temperature.

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

Abstract

L'invention concerne de nouveaux acétals de phosphamide cétonique et d'alkylglycosides de la formule générale (I), dans laquelle R1, R2, R3, R4, R5, R6, R7 et R8 ont la notation mentionnée dans le descriptif. L'invention concerne leur procédé de préparation et leur utilisation comme agents cytostatiques hautement sélectifs dans la thérapie du cancer.
PCT/EP1993/002403 1992-09-08 1993-09-06 Nouveaux acetals de phosphamide cetonique et d'alkylglycosides WO1994005681A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4229903.9 1992-09-08
DE19924229903 DE4229903A1 (de) 1992-09-08 1992-09-08 Neue Acetale von Ketophosphamid und Alkylglycosiden

Publications (1)

Publication Number Publication Date
WO1994005681A1 true WO1994005681A1 (fr) 1994-03-17

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PCT/EP1993/002403 WO1994005681A1 (fr) 1992-09-08 1993-09-06 Nouveaux acetals de phosphamide cetonique et d'alkylglycosides

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DE (1) DE4229903A1 (fr)
WO (1) WO1994005681A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19524515A1 (de) * 1995-07-05 1997-01-09 Deutsches Krebsforsch Saccharid-Konjugate
US7220824B1 (en) 2000-08-28 2007-05-22 Bayer Aktiengesellschaft Integrin-mediated drug targeting

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1238678A1 (fr) 2001-03-08 2002-09-11 Bayer Aktiengesellschaft Conjugués d'agents cytostatiques et de ligands d'intégrine activés par des enzymes
IL282748B1 (en) 2018-11-05 2025-03-01 Bayer Pharma AG Cytostatic conjugates with integrin ligands
US20250032477A1 (en) 2021-10-04 2025-01-30 Vincerx Pharma Gmbh Compounds, pharmaceutical compositions, and methods for the treatment, prevention, or management of hyperproliferative disorders
KR20240105377A (ko) 2021-10-04 2024-07-05 빈서스 파마 게엠베하 과증식성 질환의 치료, 예방 또는 관리를 위한 화합물, 약학 조성물 및 방법
US20240408222A1 (en) 2021-10-04 2024-12-12 Vincerx Pharma Gmbh Compounds, pharmaceutical compositions, and methods for the treatment, prevention, or management of hyperproliferative disorder

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0415198A2 (fr) * 1989-08-30 1991-03-06 Tietze, Lutz F., Prof. Dr. Glycosides ketophosphamidyls, procédé pour leur préparation et leur utilisation comme agents pharmaceutiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0415198A2 (fr) * 1989-08-30 1991-03-06 Tietze, Lutz F., Prof. Dr. Glycosides ketophosphamidyls, procédé pour leur préparation et leur utilisation comme agents pharmaceutiques

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19524515A1 (de) * 1995-07-05 1997-01-09 Deutsches Krebsforsch Saccharid-Konjugate
US7220824B1 (en) 2000-08-28 2007-05-22 Bayer Aktiengesellschaft Integrin-mediated drug targeting

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