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WO2008034580A2 - Utilisations de cripowellines et de leurs dérivés pour le traitement de maladies tumorales - Google Patents

Utilisations de cripowellines et de leurs dérivés pour le traitement de maladies tumorales Download PDF

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Publication number
WO2008034580A2
WO2008034580A2 PCT/EP2007/008110 EP2007008110W WO2008034580A2 WO 2008034580 A2 WO2008034580 A2 WO 2008034580A2 EP 2007008110 W EP2007008110 W EP 2007008110W WO 2008034580 A2 WO2008034580 A2 WO 2008034580A2
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butyl
pentyl
group
unsubstituted
methyl
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WO2008034580A3 (fr
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Matthias Gehling
Olaf Weber
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Intermed Discovery GmbH
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Intermed Discovery GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • Cripowellins Uses of Cripowellins and their derivatives for the treatment of
  • the invention relates to the use of Cripowellinen and their derivatives for the preparation of medicaments for the treatment of tumor diseases.
  • Crypowellins have been described as insecticidal natural products first in 1997 (Nachr. Chem. Tech. Lab. 1997, 45, 778; Tetrahedron Letters 1998, 39 (13), 1737-1740). They are characterized by a unique basic body with an ethylene-bridged ten-ring system. The recovery, purification and characterization of Cripowelline from the plant Crinum powellii, the chemical production of derivatives of Cripowellinen and the use for controlling animal pests is described in detail in DE 196 10 279 and WO 97/34910. Synthetic access to Cripowelline's 1-epi aglycone was reported in 2005 by Enders et al. Ed., 2005, 44, 3766-3769), the term aglycone being understood to mean the glycoside-free parent compound. Another synthetic approach is described by Moon et al. in Organic Letters, 2005, 7 (6), 1031-1034.
  • these drugs have high potency and reduced side effects compared to conventional cytotoxic drugs.
  • the compounds of general formula I given below show highly potent, antiproliferative actions against tumor cell lines, such as H460 lung cancer cells and HCT116 colon carcinoma cells, and can therefore be used in particular for the production of a medicament for the treatment of tumor diseases.
  • R 1 is -H or -OR 6 ;
  • R 2 , R 3 , R 4 and R 5 independently of each other, each represents -H, -F, -Cl, -Br, -NO 2 , -CN, -OH, -SH or -OR 7 ;
  • R 3 and R 4 together are -O- (CH 2 ) n -O- with n being 1, 2 or 3; or R 2 and R 3 together are -O- (CH 2 ) n -O- with n being 1, 2 or 3; or R 4 and R 5 together are -O- (CH 2 ) n -O- with n being 1, 2 or 3;
  • D is -CH 2 -
  • R 11 9, R 12 "9, R 13" 9, R 14-9 and R 15'9 independently of one another each represent unsubstituted or at least monosubstituted alkyl, alkenyl or alkynyl; unsubstituted or at least monosubstituted cycloalkyl or cycloalkenyl; unsubstituted or at least monosubstituted heterocycloalkyl or heterocycloalkenyl; unsubstituted or at least monosubstituted mono- or disaccharide residues; or unsubstituted or at least monosubstituted - (alkylene) - aryl, - (alkenylene) -aryl or aryl;
  • alkyl embraces in the sense of the present invention acyclic saturated hydrocarbon residues which can be branched or straight chained and unsubstituted or at least may be monosubstituted with as in the case of Ci- 12 alkyl 1 to 12 (ie, 1, 2, 3, 4 , 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms or with as in the case of C 1-6 -alkyl 1 to 6 (ie 1, 2, 3, 4, 5 or 6) C-atoms.
  • Ci-1 2 alkyl radicals which may be unsubstituted or substituted one or more times, are for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl , 2-pentyl, 3-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, n-octyl, -C (H) (C 2 Hs) 2 , - C (H) (nC 3 H 7 ) 2 and -CH 2 - CH 2 -C (H) (CH 3 ) - (CH 2 ) 3 -CH 3 .
  • C 1-6 alkyl radicals may be For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2 Called hexyl and 3-hexyl.
  • multiply substituted alkyl radicals are meant those alkyl radicals which are monosubstituted, preferably triply or twice, at different or identical carbon atoms, for example, three times at the same carbon atom as in the case of -CF 3 or in different places as in the case of - (CHCI) - (CH 2 F). Multiple substitution can be with the same or different substituents.
  • substituted alkyl radicals for example -CF 3 , -CF 2 H, - CFH 2 , - (CH 2 K) H, - (CH 2 J-NH 2 , - (CH 2 J-CN, - (CH 2 HCF 3 ), - (CH 2 J- (CHF 2 ), - (CH 2 ) - (CH 2 F) 1 - (CH 2 HCHz) -OH, - (CH 2 ) - (CH 2 ) -NH 2 , - (CH 2 ) - (CH 2 ) -CN, - (CF 2 HCF 3 ), - (CH 2 ) - (CHzHCF 3 ) and - (CH 2 ) - (CH 2 ) - (CH 2 ) -OH ,
  • alkenyl in the context of the present invention comprises acyclic unsaturated hydrocarbon radicals which may be branched or straight-chain and unsubstituted or at least monosubstituted and have at least one double bond, preferably 1, 2 or 3 double bonds, as in the case of C 2 12 alkenyl 2 to 12 (ie 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms or with as in the case of C 2-6 alkenyl 2 to 6 ( ie 2, 3, 4, 5 or 6) carbon atoms.
  • the multiple substitution can be made with the same or different substituents
  • alkynyl includes within the meaning of the present invention, acyclic unsaturated hydrocarbon residues which can be branched or straight chained and unsubstituted or at least can be substituted one, and at least one triple bond, preferably 1 or 2 triple bonds, with, as in the case of C 2 i 2 Alkynyl 2 to 12 (ie 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) C atoms or with as in the case of C 2 - 6 alkynyl 2 to 6 (ie 2, 3, 4, 5 or 6) carbon atoms.
  • Suitable C 2 i 2 alkynyl radicals include for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl and called hexynyl.
  • multiply substituted alkynyl radicals are meant those alkynyl radicals which are either multiply substituted on different C atoms, for example twice on different C atoms as in the case of -CHCl-C ⁇ CCI.
  • suitable substituted alkynyl radicals are -C ⁇ C-F, -C ⁇ C-Cl and -C ⁇ C-I.
  • Ci -S-Al can be alkyl radicals are each linear or branched and the abovementioned phenyl radicals preferably having 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of - F 1 -Cl, -Br, -I, -CN, -CF 3 , -OH, - NH 2 , -O-CF 3 , -SH, -O-CH 3 , -O-C 2 H 5 , -O-C 3 H 7 , methyl, ethyl, n-propyl, isopropyl, n-butyl, 2- Butyl, isobutyl and tert-butyl may be substituted.
  • Particularly preferred substituents can be selected independently of one another from the group consisting of
  • cycloalkyl in the context of the present invention means a cyclic saturated hydrocarbon radical having preferably 3, 4, 5, 6, 7, 8 or 9 C atoms, particularly preferably 3, 4, 5, 6 or 7 C atoms. Atoms, most preferably having 5 or 6 carbon atoms, where the radical may be unsubstituted or monosubstituted or polysubstituted by identical or different substituents.
  • C 3-9 -cycloalkyl radicals which may be unsubstituted or monosubstituted or polysubstituted are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.
  • Suitable C 3-7 cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • cycloalkenyl in the context of the present invention means a cyclic unsaturated hydrocarbon radical having preferably 3, 4, 5, 6, 7, 8 or 9 C atoms, particularly preferably 3, 4, 5, 6 or 7 C atoms. Atoms, most preferably having 5 or 6 carbon atoms, which has at least one double bond, preferably a double bond, and unsubstituted or monosubstituted or polysubstituted by identical or different substituents.
  • C 3- g -cycloalkenyl radicals which may be unsubstituted or monosubstituted or polysubstituted, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclononenyl and cyclooctenyl may be mentioned.
  • Suitable C 5-6 -cycloalkenyl radicals are cyclopentenyl and cyclohexenyl.
  • heterocycloalkyl in the context of the present invention means a cyclic saturated hydrocarbon radical having preferably 3, 4, 5, 6, 7, 8 or 9 C atoms, particularly preferably 3, 4, 5, 6 or 7 C atoms. Atoms, very particularly preferably having 5 or 6 C atoms, in which one or more C atoms have in each case been replaced by a heteroatom independently of one another selected from the group consisting of oxygen, sulfur and nitrogen (NH) Heterocycloalkyl radicals may preferably 1, 2 or 3 heteroatom (s) independently selected from the group consisting of oxygen, sulfur and nitrogen (NH) as a ring member (s).
  • a heterocycloalkyl radical can be unsubstituted or monosubstituted or polysubstituted by identical or different substituents.
  • Heterocycloalkyl radicals may preferably be 3- to 9-membered, particularly preferably 3- to 7-membered, very particularly preferably 5- to 7-membered.
  • heterocycloalkenyl in the context of the present invention means a cyclic unsaturated hydrocarbon radical having preferably 4, 5, 6, 7, 8 or 9 C atoms, more preferably having 4, 5, 6 or 7 C atoms, very particularly preferably having 5 or 6 C atoms, which has at least one double bond, preferably a double bond, and in which one or more C atoms have each been replaced by a heteroatom independently selected from the group consisting of oxygen, sulfur and nitrogen (NH) Heterocycloalkenyl radicals may preferably have 1, 2 or 3 heteroatom (s) independently of one another selected from the group consisting of oxygen, sulfur and nitrogen (NH) as ring member (s) A heterocycloalkenyl radical may be unsubstituted or monosubstituted or polysubstituted or heterocycloalkenyl radicals may preferably have 4- to 9-membered, more preferably 4-7-membered, very particularly preferably It may be 5- to 7-membered.
  • heterocycloalkyl radicals or suitable 3- to 9-membered heterocycloalkyl radicals which may be unsubstituted or monosubstituted or polysubstituted are imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, oxetanyl , Azepanyl, azocanyl, diazepanyl, dithiolanyl, (1, 3) -dioxolan-2-yl, isoxazolidinyl, isothioazolidinyl, pyrazolidinyl and oxazolidinyl.
  • heterocycloalkenyl radicals or of suitable 5- to 7-membered heterocycloalkenyl radicals which may be unsubstituted or monosubstituted or polysubstituted are (2,3) -dihydrofuranyl, (2,5) -dihydrofuranyl, (2, 3) - dihydrothienyl, (2,5) -dihydrothienyl, (2,3) -dihydropyrrolyl, (2,5) -dihydropyrrolyl, (2,3) -dihydroisoxazolyl, (4,5) -dihydroisoxazolyl, (2,5) Dihydroisothiazolyl, (2,3) -dihydro- pyrazolyl, (4,5) -dihydropyrazolyl, (2,5) -dihydropyrazolyl, (2,3) -dihydrooxazolyl, (4,5) -dihydrooxazolyl, (
  • Cycloalkyl radical, heterocycloalkyl radical, cycloalkenyl radical or heterocyclalkenyl radical may be condensed (annelated) within the meaning of the present invention with an unsubstituted or at least monosubstituted monocyclic or bicyclic ring system.
  • a monocyclic or bicyclic ring system is understood as meaning monocyclic or bicyclic hydrocarbon radicals which may be saturated, unsaturated or aromatic and may optionally have one or more heteroatoms as ring members.
  • the rings of the abovementioned monocyclic or bicyclic ring systems are each 4-, 5- or 6-membered and may each preferably preferably be 0, 1, 2, 3, 4 or 5 heteroatom (s), particularly preferably 0, Have 1 or 2 heteroatom (s) as a ring member (s) independently selected from the group consisting of oxygen, nitrogen and sulfur. If a bicyclic ring system is present, the different rings, each independently, may have a different degree of saturation, i. saturated, unsaturated or aromatic.
  • C 1-5 alkyl radicals may each be linear or branched and the cyclic Substituents or the cyclic radicals of these substituents themselves each with optionally 1, 2, 3, 4 or 5, preferably with optionally 1, 2, 3 or 4, substituents independently selected from the group consisting of -F, -Cl,
  • cycloalkyl radical As suitable cycloalkyl radical, heterocycloalkyl radical, cycloalkenyl radical or heterocyclalkenyl radical, which may be unsubstituted or monosubstituted or polysubstituted, and which are condensed with a monocyclic or bicyclic ring system, are exemplary (1, 2,3,4 ) -Tetrahydroquinolinyl, (1, 2,3,4) -tetrahydroisoquinolinyl, (2,3) -dihydro-1H-isoindolyl, (1,2,3,4) -tetrahydronaphthyl, (2,3) -dihydro-benzo [1.4] - dioxinyl, benzo [1.3] dioxolyl, (3,4) -dihydro-2H-benzo [1,4] oxazinyl and octahydro-pyrrolo [3,4-c] pyrrolyl.
  • aryl means a monocyclic or polycyclic, preferably a monocyclic or bicyclic, aromatic hydrocarbon radical having preferably 6, 10 or 14 carbon atoms
  • An aryl radical may be unsubstituted or monosubstituted or polysubstituted Examples of suitable aryl radicals which may be mentioned are phenyl, 1-naphthyl, 2-naphthyl and anthracenyl, and particularly preferably an aryl radical is a phenyl radical.
  • aryl radicals may be condensed (fused) with a monocyclic or bicyclic ring system.
  • aryl radicals which are condensed with a monocyclic or bicyclic ring system are C 2 3) -dihydrobenzo [b] thiophenyi, (2,3) -dihydro-1H-indenyi, indolinyl, (2,3) Dihydrobenzofuranyl, (2,3) -dihydrobenzo [d] oxazolyl, benzo [d] - [1,3] dioxolyl, benzo [d] [1,3] oxathiolyl, isoindolinyl, (1,3-dihydroisobenzofuranyl, (1 , 3) -dihydrobenzo [c] thiophenyl, (1, 2,3,4) -tetrahydronaphthyl, (1, 2,3,4) -tetrahydroquinolinyl, chromanyl, thiochromanyl, (1,2,3,4) -tetrahydroisoquinoliny
  • the substituents each independently selected from the group consisting of -F, -Cl, -Br, -I, -CN, -NO 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , 2-butyl, tert-butyl, n-pentyl, neo-pentyl, ethenyl, allyl, ethynyl, propynyl, -OH, -SH, -NH 2 , -C (O) -OH, -S-CH 3 , - O-CH 3 , -O-C 2 H 5 , -O-C 3 H 7 , -OC (CH 3 ) 3 , -CF 3 , -CHF 2 , -CH 2 F, -O-CF 3 , -O -CHF 2 , -O-CH 2 F,
  • alkylene in the context of the present invention comprises acyclic saturated hydrocarbon chains which connect an aryl, cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical with the compounds of the general formula I or with another substituent may be branched or straight chained and unsubstituted or at least monosubstituted with as in the case of Ci -12 alkylene 1 to 12 (ie, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) C-atoms, with as in the case of Ci -6 alkylene 1 to 6 (that is, 1, 2, 3, 4, 5 or 6) carbon atoms, or (as in the case of using Ci -3 alkylene 1 to 3 ie, 1, 2 or 3) carbon atoms Examples include Ci -6 alkylene groups such as -.
  • substituents are an alkylene or alkenylene radical or have such a group which is monosubstituted or polysubstituted, this may preferably have, if appropriate, 1, 2, 3, 4 or 5, more preferably optionally 1 , 2 or 3, substituents independently selected from the group consisting of phenyl, -F, -Cl 1 -Br, -I, -NO 2 , -CN, -OH, -SH, -NH 2 , -OC 1-5 alkyl , -S-Ci- 5 -alkyl, -NH-C 1-5 -alkyl, -N (C 1-5 -alkyl) 2 , -NH-phenyl, -Ntd-s-alkylXPhenyl), -N (Ci -) 5 -alkyl) (CH 2 -phenyl), -N (C 1-5 -alkyl) (CH 2 -CH 2 -phenyl), -N (
  • alkylene or alkenylene groups having 1, 2 or 3 substituents can be selected independently of one another from the group consisting of phenyl, -O-CH 3 , -O-C 2 H 5 , -O-C 3 H 7 , - S-CH 3 , -SC 2 H 5 , -SC 3 H 7 , -NH-CH 3 , -NH-C 2 H 5 , -NH-C 3 H 7 , -F, -Cl, -Br, -I , -NO 2 , -CN, -OH, -SH, -NH 2 , -N (CH 3 J 2 , -N (C 2 H 5 ) 2 and -N (CH 3 ) (C 2 H 5 ) ,
  • monosaccharide residues are 1-, 2- or 6-fructosyl, 6- or 4-allosyl, 6- or 4-altrosyl, 6- or 4-glucosyl, 6- or 4-mannosyl, 6- or 4-gulosyl , 6- or 4-ldosyl, 6- or 4-galactosyl, 6- or 4-talosyl, 4-arabinosyl, 4-xylosyl, 4-lysosyl, rhamnosyl, 4-ribosyl, dexofuranosyl, dexopyranosyl, deoxyribosyl and amino sugar residues ,
  • Particularly preferred monosaccharide residues are pyranosyl residues such as glucopyranosyl, galactopyranosyl and mannopyranosyl; Furanosyl residues such as glucofuranosyl, ribofuranosyl and arabinofuranosyl and amino sugar residues such as D-glucosamine,
  • the mono- and disaccharide moieties may be attached via an exocyclic or a ring carbon atom to the backbone of the compounds of general formula I, thereby forming a series of positional isomers for each individual mono- and disaccharide moiety.
  • the same or different monosaccharides can each be linked to one another via a glycosylic oxygen bridge, the bridging oxygen atom being bonded to an endocyclic and / or exocyclic carbon atom of the individual monosaccharide radicals, so that in turn all positional isomers are possible.
  • radicals A, B, D, E, G and R 1 have the abovementioned meaning.
  • R 1 is -H or -OR 6 ;
  • D is -CH 2 -
  • R 6 is -H; for a group selected from the group consisting of
  • R 8 is -H; a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, iso-pentyl, neo Pentyl and n-hexyl; for a tetrahydropyranyl radical; a radical selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, 2-amino-2-deoxy-.beta.-D-glucopyranosyl and 2-acetyl-amino-2-deoxy-.beta.-D-glucopyranosyl, each of which is unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -CH 2 I,
  • R 9 is -H; for a group selected from the group consisting of
  • Phenyl radicals which are unsubstituted or having 1, 2, 3, 4 or 5 substituents selected from the group consisting of -F, -Cl, -Br, -NO 2 , methyl, ethyl, n-propyl, -O-CH 3 and
  • -0-C 2 H 5 may be substituted
  • R 1 is -H or -OR 6 ;
  • D is -CH 2 -
  • R 6 is -H; a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, iso-pentyl, neo Pentyl and n-hexyl; for a tetrahydropyranyl radical; a radical selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, 2-amino-2-deoxy-.beta.-D-glucopyranosyl and 2-acetylamino-2-deoxy-.beta.-D-glucopyranosyl, each of which is unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -CH 2 I, -CH
  • R 7 is methyl, ethyl, n -propyl, isopropyl, n -butyl, tert -butyl or -CF 3 or -C (O) -R 11 "7 ;
  • R 8 is -H; a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, iso-pentyl, neo Pentyl and n-hexyl; for a tetrahydropyranyl radical; a radical selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, 2-amino-2-deoxy-.beta.-D-glucopyranosyl and 2-acetylamino-2-deoxy-.beta.-D-glucopyranosyl, each of which is unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -CH 2 I, -CH
  • R 9 is -H; a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, iso-pentyl, neo Pentyl and n-hexyl; for a tetrahydropyranyl radical; a radical selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, 2-amino-2-deoxy-.beta.-D-glucopyranosyl and 2-acetylamino-2-deoxy-.beta.-D-glucopyranosyl, each of which is unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -CH 2 I, -CH
  • R 11 "7 , R 10" 8 , R 11 "6 , R 13'6 , R 11" 8 , R 13 “8 , R 10" 9 , R 11 "9, and R 13" 9 independently of one another, respectively for a group selected from the group consisting of
  • Phenyl radicals which are unsubstituted or having 1, 2, 3, 4 or 5 substituents selected from the group consisting of -F, -Cl, -Br, -NO 2 , methyl, ethyl, n-propyl, -O-CH 3 and
  • -0-C 2 H 5 may be substituted
  • R 1 is -H or -OR 6 ;
  • R 6 is -H; a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, iso-pentyl, neo Pentyl and n-hexyl; for a tetrahydropyranyl radical; a radical selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, 2-amino-2-deoxy-.beta.-D-glucopyranosyl and 2-acetylamino-2-deoxy-.beta.-D-glucopyranosyl, each of which is unsubstituted or optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -CH 2 I, -CH
  • R 9 is -H; a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, iso-pentyl, neo Pentyl and n-hexyl; for a tetrahydropyranyl radical; a radical selected from the group consisting of glucopyranosyl, galactopyranosyl, mannopyranosyl, 2-amino-2-deoxy-.beta.-D-glucopyranosyl and 2-acetyl amino-2-deoxy-.beta.-D-glucopyranosyl, each unsubstituted or optionally having 1, 2, 3 or 4 substituents selected from the group consisting of -CH 2 I 1 -CH 2 F, -CH
  • R 10 "8 , R 11 6 , R 13" 6 , R 10 9 , R 11 9 and R 13 9 independently of one another, each represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n - Butyl, -CF 3 , -CF 2 H and -CFH 2 or for a phenyl radical which is unsubstituted or with 1, 2, 3, 4 or 5 substituents selected from the group consisting of -F, -Cl, -Br , -NO 2 , methyl, ethyl, n-propyl, -O-CH 3 and -O-C 2 H 5 may be substituted;
  • substituted compounds according to the invention of the abovementioned general formula I, IA, IB, IC, ID, II, MA, MB, HC, HD and IM-A are obtained by customary methods known to those skilled in the art in the form of corresponding salts, in particular in the form of corresponding physiologically acceptable salts, wherein the medicament according to the invention may comprise one or more salts of one or more of these compounds.
  • the respective salts of the compounds of general formula I according to the invention and corresponding stereoisomers can be obtained, for example, by reaction with one or more inorganic acids and / or one or more organic acids.
  • Suitable acids may preferably be selected from the group consisting of perchloric, hydrochloric, hydrobromic, sulfuric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, formic, acetic, oxalic, succinic, tartaric, succinic, fumaric, lactic, citric, glutamic , Sacharic acid, acetic acid, propionic acid, cyclohexanesulfamic acid, aspartame, monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, benzoic acid, 2-aminobenzoic acid, 3-a
  • Suitable acids may preferably be selected from the group consisting of alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts and ammonium salts such as salts of ammonia or organic amines such as diethylamine, triethylamine, Ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, 1-ephenamine and methylpiperidine.
  • alkali metal salts such as sodium and potassium salts
  • alkaline earth metal salts such as calcium and magnesium salts
  • ammonium salts such as salts of ammonia or organic amines such as diethylamine, triethylamine, Ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, 1-ephenamine and methylpiperidine.
  • Solvates in the context of the invention are those forms of the compounds of general formula I which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water.
  • the compounds of the general formula I according to the invention are obtained after their preparation and / or isolation in the form of a mixture of their stereoisomers, preferably in the form of their racemates or other mixtures of their various enantiomers and / or diastereomers, these can be separated by customary methods known to the person skilled in the art and possibly isolated. Examples which may be mentioned are chromatographic separation processes, in particular liquid chromatography processes under atmospheric pressure or under elevated pressure, preferably MPLC and HPLC processes, and also fractional crystallization processes.
  • the compounds of the general formula I according to the invention have an antiproliferative action against tumor cell lines and can therefore be used in particular for the production of a medicament for the treatment of tumor diseases.
  • the compounds of the general formula I according to the invention and, if appropriate, corresponding stereoisomers and in each case the corresponding salts and solvates appear toxicologically harmless and can therefore be employed for the preparation of a medicament for the treatment of tumor diseases.
  • the use of at least one compounds of the general formula I in H460 lung cancer cells an IC 5 o value ⁇ 20 E-08 uM, preferably ⁇ 10 E-08 uM, particularly preferably ⁇ 5 E-08 .mu.m, very particularly preferably ⁇ 2 E-08 ⁇ M, which is determined by means of a non-radioactive proliferation assay.
  • the exact determination of the IC 50 value is given in the section Pharmacological Methods and Data.
  • tumor diseases selected from the group consisting of fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, enotheliosarcoma, lymphangiosarcoma, Lymphangioendotheiiosarkom, synovioma , Mesothelioma, Ewing's tumor, leiosarcoma, rhabdomyosarcoma, colon carcinoma,
  • tumor diseases selected from the group consisting of fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, enotheliosarcoma, lymphangiosarcoma, Lymphangioendotheiiosarkom, synovioma , Mesothelioma, Ewing's tumor, leiosarcoma,
  • tumor diseases selected from the group consisting of lung carcinoma, non-small cell lung cancer, small cell lung carcinoma, melanoma, pancreatic cancer, hepatocellular carcinoma, lymphoid tumors and colon carcinoma.
  • the compounds of general formula I can be used with other active substances which are suitable for the treatment of tumor diseases.
  • active substances which are suitable for the treatment of tumor diseases include asparaginase, bleomycin, carboplatin, carmustine, chlorobucuril, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide , 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methothrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen, thioganin, topotecan, Vinblastine, vincristine,
  • the compounds of the general formula I according to the invention can be administered in the form of pharmaceutical preparations which contain inert, non-toxic, pharmaceutically suitable excipients and carriers.
  • the compounds of the general formula I are present in these preparations in a concentration of from 0.1 to 99.5% by weight, preferably from 0.5 to 95% by weight, of the total mixture.
  • the pharmaceutical preparations may also contain other active pharmaceutical ingredients.
  • the pharmaceutical preparations according to the invention may be in the form of liquid, semisolid or solid dosage form, for example in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, patches, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, optionally compressed into tablets, filled into capsules or suspended in a liquid, are present and administered as such.
  • the pharmaceutical preparation according to the invention usually contains further physiologically acceptable pharmaceutical excipients, which can preferably be selected from the group consisting of excipients, fillers, solvents, diluents, surfactants, dyes, preservatives, disintegrants, lubricants, lubricants, flavors and binders.
  • physiologically acceptable excipients and the amounts to be used depend on whether the pharmaceutical preparation is administered orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example for infections on the skin which Mucous membranes and on the eyes, should be applied.
  • Preparations in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups are preferred for oral administration, solutions, suspensions, readily reconstitutable dry preparations and sprays for parenteral, topical and inhalative administration.
  • substituted compounds of the general formula I used in the pharmaceutical preparation according to the invention in a depot in dissolved form or in a plaster, optionally with the addition of skin penetration-promoting agents, are suitable percutaneous administration preparations.
  • compositions of the present invention are prepared by conventional means, devices, methods and methods well known in the art, as described, for example, in "Remington's Pharmaceutical Sciences", Ed. AR Gennaro, 17th Edition, Mack Publishing Company, Easton, Pa , 1985, especially in part 8, chapters 76 to 93. The corresponding description is hereby incorporated by reference and is considered part of the disclosure.
  • the amount of the general formula I to be administered to the patient may vary and depends, for example, on the weight or age of the patient as well as on the mode of administration, the indication and the severity of the disease.
  • H460 lung cancer cells ATCC no. HTB-177) and HCT116 colon carcinoma cells (ATCC no. CCL247) of the American type culture collection (ATCC) were cultured under standard conditions (Dulbecco's Modified Eagle Medium (DMEM), 10% fetal bovine serum (FBS), 10 mM (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES), 2 mM glutamine, 100 U / mL penicillin, 100 ⁇ g / mL streptomycin at 37 ° C in 5% CO 2 in a humid incubator) Dissolved by trypsin from the culture bottles and seeded in a density of about 3000 cells / well in a total of 100 .mu.l medium / well in a 96-well plate ..
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS fetal bovine serum
  • HPES 4- (2-hydroxyethyl) -1-piperazine
  • test substance 24 hours after sowing, the test substance was added in various concentrations Cell number was determined 72 hours later using a commercially available MTS assay (Promgega CellTiter 96 Aqueous One Solution Cell Proliferation Assay, # G3581) according to the manufacturer's instructions provided.
  • the test compounds were dissolved in 100% dimethyl sulfoxide [DMSO] to make a 10 mM stock. These stocks were further cultured 1: 250 in standard medium to obtain a 40 ⁇ M working solution.
  • the test substance was diluted in standard medium to a concentration of 3.3x10 -8 M maintaining a constant concentration of 0.4% DMSO.
  • the IC 5 o values were determined with the "least square” analysis, wherein the substance concentration was plotted against the percentage inhibition of cell growth.
  • T 72 hT est LDH activity 72 hours in the course of the test substance

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Abstract

L'invention concerne l'utilisation de cripowellines et de leurs dérivés en vue de la production de médicaments pour le traitement de maladies tumorales.
PCT/EP2007/008110 2006-09-21 2007-09-17 Utilisations de cripowellines et de leurs dérivés pour le traitement de maladies tumorales Ceased WO2008034580A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006045097A DE102006045097A1 (de) 2006-09-21 2006-09-21 Verwendungen von Cripowellinen und deren Derivate zur Behandlung von Tumorerkrankungen
DE102006045097.3 2006-09-21

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WO2008034580A2 true WO2008034580A2 (fr) 2008-03-27
WO2008034580A3 WO2008034580A3 (fr) 2008-08-07

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DE19610279A1 (de) * 1996-03-15 1997-09-18 Bayer Ag Cripowelline und synthetische Derivate
DE102005029126A1 (de) * 2005-06-23 2006-12-28 Bayer Cropscience Ag Cripowelline und synthetische Derivate davon als Arzneimittel

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