CA2688206A1 - Novel indol-pyrrol derivatives for the treatment of proliferative and inflammatory diseases - Google Patents
Novel indol-pyrrol derivatives for the treatment of proliferative and inflammatory diseases Download PDFInfo
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Abstract
The invention relates to novel indol-pyrrol derivatives of formula I which are suitable for the production of pharmaceutical compositions for the prophylaxis and/or treatment of a proliferative or inflammatory disease.
Description
NOVEL INDOL-PYRROL DERIVATIVES FOR THE TREATMENT OF
PROLIFERATIVE AND INFLAMMATORY DISEASES
The invention relates to novel indole-pyrrole derivatives, to pharmaceutical compositions con-taining such compounds, to the uses of such com-pounds, and to methods for producing such com-pounds.
From the documents Sun, L. et al, J. Med.
Chem. 46:1116-1119 (2003), Manley, J. M. et al, J.
Org. Chem. 68:6447-6450 (2003) and Mendel, D.B. et al, Clin Cancer Res. 9 ( 1 ) : 3 2 7 - 3 3 7 (2003), various indole-pyrrole derivatives are known in the art.
These are suitable for the treatment of different types of cancer, mastocytosis, allergy-associated chronic rhinitis, diabetes, arthritis, angiogene-sis and various immunologic and cardiovascular diseases.
In principle, there is a strong demand of new and improved active substances, which are capable of inhibiting the proliferation of cancer cells and thus the growth of neoplastic tumors and of inhibiting excessive defense reactions of the body, such as e.g. septic shock, autoimmune dis-eases, transplant rejections and acute and chronic inflammation reactions, and that with simultane-ously only low to no cytotoxicity at all with re-spect to intact cells. Additionally, it is in-tended to inhibit the growth of unicellular organ-isms.
For this purpose, the invention teaches a com-pound according to Formula I
PROLIFERATIVE AND INFLAMMATORY DISEASES
The invention relates to novel indole-pyrrole derivatives, to pharmaceutical compositions con-taining such compounds, to the uses of such com-pounds, and to methods for producing such com-pounds.
From the documents Sun, L. et al, J. Med.
Chem. 46:1116-1119 (2003), Manley, J. M. et al, J.
Org. Chem. 68:6447-6450 (2003) and Mendel, D.B. et al, Clin Cancer Res. 9 ( 1 ) : 3 2 7 - 3 3 7 (2003), various indole-pyrrole derivatives are known in the art.
These are suitable for the treatment of different types of cancer, mastocytosis, allergy-associated chronic rhinitis, diabetes, arthritis, angiogene-sis and various immunologic and cardiovascular diseases.
In principle, there is a strong demand of new and improved active substances, which are capable of inhibiting the proliferation of cancer cells and thus the growth of neoplastic tumors and of inhibiting excessive defense reactions of the body, such as e.g. septic shock, autoimmune dis-eases, transplant rejections and acute and chronic inflammation reactions, and that with simultane-ously only low to no cytotoxicity at all with re-spect to intact cells. Additionally, it is in-tended to inhibit the growth of unicellular organ-isms.
For this purpose, the invention teaches a com-pound according to Formula I
L
( )CH2)n (.J .
NH
Y__..._Y =
~r/ t!
R
tq ,. Rs H
/"~.. / r~""R ~ /
4 Formula I
R
R
wherein R1 to R4 may be identical or different and may be -H, -F, -Cl, -Br, -I or (C1-C$) oxyalkyl, wherein R5 and R6 may be identical or different and may be -H or Cl-C4 alkyl, wherein X, Y and Z
may be identical or different and may be either a binding or -0- or -S-, at least one of the groups X, Y and Z being -0- or -S-, wherein n may be 0 to 8, and wherein R7 may be an arbitrary radical, or a metabolite of such a compound and physiologi-cally well tolerated salts of such compounds or metabolites.
Preferably, R1, R3 and R4 are -H, and R2 is -F, -Cl, -Br, -I or (C1-C$) oxyalkyl. R5 and R6 may be (C1-C3) alkyl, in particular methyl.
X preferably is a binding, wherein Y and/or Z
is -0-. n = 1 or 2 is preferred.
R7 preferably is an -NR8R9 group, in which R8 and R9 may be identical or different and may be -H, a(C1-Clo) alkyl group or (C1-C6) oxyalkyl, a (C1-Clo) alkyl group or, if applicable, a par-tially or completely halogenated, in particular fluorinated (C1-Clo) alkyl group, (C3-C-7 ) cycloal-kyl group, (C2-Clo) alkenyl group, (CZ-Clo) alkinyl group, (C1-CB) alkyl- (C3-C7) cycloalkyl group, (Cz-CB) alkenyl-(C3-C7) cycloalkyl group, heterocyclyl group, (C1-C$) alkylheterocyclyl group, (C2-C8) al-kenylheterocyclyl group, aryl group, (C1-C8) al-kylaryl group, (C2-Ca) alkenylaryl group, or (C2-C$) alkinylaryl group, or a, if applicable, mono-cyclic or bicyclic heteroaryl group substituted by 1-2 keto groups, 1-2 (C1-C5) alkyl groups, 1-2 (C1-C5) alkoxy groups, 1-3 halogen atoms, 1-2 exomethyl groups, and containing 1-3 nitrogen at-oms and/or 1-2 oxygen atoms and/or 1-2 sulfur at-oms, a (C1-C$) alkylheteroaryl group, or a.(C2-C8) alkenylheteroaryl group, a (C2-C8) alkinylhet-eroaryl group, wherein these groups may be linked at an arbitrary position with R2 and, if applica-ble, may be hydrated at one or several positions.
More specifically, R7 preferably is an -NR8R9 group, in which R8 and R9 may be identical or dif-ferent and may be -H, methyl, ethyl, methoxy or ethoxy, or wherein R7 is pyrrolidine-1-yl, mor-pholine-4-yl, pyrridine-4-yl, 1-methyl-4-pip-eridyl, or triazole-l-yl, optionally substituted singly or multiply with (C1-C6) alkyl, -F, -Cl, -Br, -I, or (C1-C6) oxyalkyl.
The alkyl groups for the described radicals, in particular R3, may be straight-chained or branched and may for instance be a methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-bu-tyl or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group, and the hexyl, heptyl, nonyl, decyl group and their arbitrarily branched derivatives. A methyl or ethyl group is preferred.
The mentioned alkyl groups may be, if applicable, substituted by 1-5 halogen atoms. A partially or completely halogenated, in particular fluorinated C1-C3 alkyl group may for instance be the follow-ing partially or completely fluorinated groups:
fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, tetrafluoroethyl, pentaflu-oroethyl. Among these are preferred the trifluoro-methyl or the pentafluoroethyl group, while the completely fluorinated group is also called per-fluoroalkyl group.
The alkoxy groups (= oxyalkyl) may be straight-chained or branched and may for instance be a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy or n-pentoxy, 2,2-.
dimethylpropoxy, 2-methylbutoxy or 3-methylbutoxy group. Cl-C5 alkoxy groups are preferred. A meth-oxy or ethoxy group is particularly preferred.
The cycloalkyl group is, if applicable, a saturated cyclic group with 3 to 7 ring carbon at-oms substituted by one or more halogen atoms, (C1-C5)alkyl groups, (C1-C5) alkoxy groups, NR10R11 groups, COOR12 groups, CHO, cyano, such as cyclo-propyl, methylcyclopropyl, cyclobutyl, methylcy-clobutyl, cyclopentyl, methylcyclopentyl, cyclo-hexyl, methylcyclohexyl, cycloheptyl, methylcyclo-heptyl.
A(C1-Cs.) alkyl-(C3-C7) cycloalkyl group is a cycloalkyl group, which is linked by a straight-chained or branched (C1-C8) alkyl unit with the ring system.
A (C2-C8) alkenyl- (C3-C7) cycloalkyl group is a cycloalkyl group, which is linked by a straight-chained or branched (C2-C8) alkenyl unit with the ring system.
The heterocyclyl group is not aromatic and may for instance be pyrrolidine, imidazolidine, pyra-zolidine, and piperidine. Perhydrochinoline and perhydroisochinoline also belong to the included heterocyclyl groups.
Aryl groups in the meaning of the invention are aromatic or partially aromatic carbocyclic groups with 6 to 14 carbon atoms, which comprise a ring, for instance phenyl or phenylene, or several condensed rings, such as naphthyl or anthranyl.
Examples are phenyl, naphthyl, tetralinyl, an-thranyl, indanyl, and indenyl.
The aryl groups may be substituted at any suitable position, which leads to a stable stereo-isomer, by one or more radicals from the group hy-droxy or halogen.
A(C1-C8) alkylaryl group is an aryl group, such as described above, which is linked by a straight-chained or branched (C1-C8) alkyl unit with the ring system.
A(C2-C8) alkenylaryl group is an aryl group, such as described above, which is linked by a straight-chained or branched (C2-C8) alkenyl unit with the ring system.
A (C2-C8) alkinylaryl group is an aryl group, such as described above, which is linked by a straight-chained or branched (C2-C8) alkinyl unit with the ring system.
Monocyclic heteroaryl groups may for instance be pyridine, pyrazine, pyrimidine, pyridazine, triazine, azaindolizine, 2H and 4H-pyran, 2H and 4H-thiopyran, furan, thiophene, 1H and 4H-pyrazole, 1H and 2H-pyrrole, oxazole, thiazole, furazan, 1H and 4H-imidazole, isoxazole, isothiazole, oxadiazole, triazole, tetrazole, thiadiazole.
Bicyclic heteroaryl groups may for instance be phthalidyl, thiophthalidyl, indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, benzothiazolyl, indolonyl, dihydroindolonyl, isoindolonyl, dihydroisoindolonyl, benzofuranyl, benzimidazolyl, dihydroisochinolinyl, dihy-drochinolinyl, benzoxazinonyl, phthalazinonyl, dihydrophthalazinonyl chinolinyl, isochinolinyl, chinolonyl, isochinolonl, chinazolinyl, chinoxalinyl, cinnolinyl, phthalazinyl, dihydrophthalazinyl, 1,7 or 1,8-naphthyridinylcumarinyl, cumarinyl, isocumarinyl, indolizinyl, isobenzofuranyl, azaindolyl, azaisoindolyl, furanopyridyl, furanopyrimidinyl, furanopyrazinyl, furanopyidazinyl, dihydrobenzofuranyl, dihydrofuranopyridyl, dihydrofuranopyrimidinyl, dihydrofuranopyrazinyl, dihydrofuranopyridazinyl, dihydrobenzofuranyl, chromenyl, isochromenyl, chromenonyl or the isochromenonyl group.
A(C1-Ca) alkylheteroaryl group is a heteroaryl group, such as described above, which is linked by a straight-chained or branched (C1-C$) alkyl unit with the ring system.
A(C2-C$) alkenylheteroaryl group is a hetero-aryl group, such as described above, which is linked by a straight-chained or branched (C2-C8) alkenyl unit with the ring system.
A(C2-Ca) alkinylheteroaryl group is a hetero-aryl group, such as described above, which is linked by a straight-chained or branched (C2-Ca) alkinyl unit with the ring system.
( )CH2)n (.J .
NH
Y__..._Y =
~r/ t!
R
tq ,. Rs H
/"~.. / r~""R ~ /
4 Formula I
R
R
wherein R1 to R4 may be identical or different and may be -H, -F, -Cl, -Br, -I or (C1-C$) oxyalkyl, wherein R5 and R6 may be identical or different and may be -H or Cl-C4 alkyl, wherein X, Y and Z
may be identical or different and may be either a binding or -0- or -S-, at least one of the groups X, Y and Z being -0- or -S-, wherein n may be 0 to 8, and wherein R7 may be an arbitrary radical, or a metabolite of such a compound and physiologi-cally well tolerated salts of such compounds or metabolites.
Preferably, R1, R3 and R4 are -H, and R2 is -F, -Cl, -Br, -I or (C1-C$) oxyalkyl. R5 and R6 may be (C1-C3) alkyl, in particular methyl.
X preferably is a binding, wherein Y and/or Z
is -0-. n = 1 or 2 is preferred.
R7 preferably is an -NR8R9 group, in which R8 and R9 may be identical or different and may be -H, a(C1-Clo) alkyl group or (C1-C6) oxyalkyl, a (C1-Clo) alkyl group or, if applicable, a par-tially or completely halogenated, in particular fluorinated (C1-Clo) alkyl group, (C3-C-7 ) cycloal-kyl group, (C2-Clo) alkenyl group, (CZ-Clo) alkinyl group, (C1-CB) alkyl- (C3-C7) cycloalkyl group, (Cz-CB) alkenyl-(C3-C7) cycloalkyl group, heterocyclyl group, (C1-C$) alkylheterocyclyl group, (C2-C8) al-kenylheterocyclyl group, aryl group, (C1-C8) al-kylaryl group, (C2-Ca) alkenylaryl group, or (C2-C$) alkinylaryl group, or a, if applicable, mono-cyclic or bicyclic heteroaryl group substituted by 1-2 keto groups, 1-2 (C1-C5) alkyl groups, 1-2 (C1-C5) alkoxy groups, 1-3 halogen atoms, 1-2 exomethyl groups, and containing 1-3 nitrogen at-oms and/or 1-2 oxygen atoms and/or 1-2 sulfur at-oms, a (C1-C$) alkylheteroaryl group, or a.(C2-C8) alkenylheteroaryl group, a (C2-C8) alkinylhet-eroaryl group, wherein these groups may be linked at an arbitrary position with R2 and, if applica-ble, may be hydrated at one or several positions.
More specifically, R7 preferably is an -NR8R9 group, in which R8 and R9 may be identical or dif-ferent and may be -H, methyl, ethyl, methoxy or ethoxy, or wherein R7 is pyrrolidine-1-yl, mor-pholine-4-yl, pyrridine-4-yl, 1-methyl-4-pip-eridyl, or triazole-l-yl, optionally substituted singly or multiply with (C1-C6) alkyl, -F, -Cl, -Br, -I, or (C1-C6) oxyalkyl.
The alkyl groups for the described radicals, in particular R3, may be straight-chained or branched and may for instance be a methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-bu-tyl or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group, and the hexyl, heptyl, nonyl, decyl group and their arbitrarily branched derivatives. A methyl or ethyl group is preferred.
The mentioned alkyl groups may be, if applicable, substituted by 1-5 halogen atoms. A partially or completely halogenated, in particular fluorinated C1-C3 alkyl group may for instance be the follow-ing partially or completely fluorinated groups:
fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, tetrafluoroethyl, pentaflu-oroethyl. Among these are preferred the trifluoro-methyl or the pentafluoroethyl group, while the completely fluorinated group is also called per-fluoroalkyl group.
The alkoxy groups (= oxyalkyl) may be straight-chained or branched and may for instance be a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy or n-pentoxy, 2,2-.
dimethylpropoxy, 2-methylbutoxy or 3-methylbutoxy group. Cl-C5 alkoxy groups are preferred. A meth-oxy or ethoxy group is particularly preferred.
The cycloalkyl group is, if applicable, a saturated cyclic group with 3 to 7 ring carbon at-oms substituted by one or more halogen atoms, (C1-C5)alkyl groups, (C1-C5) alkoxy groups, NR10R11 groups, COOR12 groups, CHO, cyano, such as cyclo-propyl, methylcyclopropyl, cyclobutyl, methylcy-clobutyl, cyclopentyl, methylcyclopentyl, cyclo-hexyl, methylcyclohexyl, cycloheptyl, methylcyclo-heptyl.
A(C1-Cs.) alkyl-(C3-C7) cycloalkyl group is a cycloalkyl group, which is linked by a straight-chained or branched (C1-C8) alkyl unit with the ring system.
A (C2-C8) alkenyl- (C3-C7) cycloalkyl group is a cycloalkyl group, which is linked by a straight-chained or branched (C2-C8) alkenyl unit with the ring system.
The heterocyclyl group is not aromatic and may for instance be pyrrolidine, imidazolidine, pyra-zolidine, and piperidine. Perhydrochinoline and perhydroisochinoline also belong to the included heterocyclyl groups.
Aryl groups in the meaning of the invention are aromatic or partially aromatic carbocyclic groups with 6 to 14 carbon atoms, which comprise a ring, for instance phenyl or phenylene, or several condensed rings, such as naphthyl or anthranyl.
Examples are phenyl, naphthyl, tetralinyl, an-thranyl, indanyl, and indenyl.
The aryl groups may be substituted at any suitable position, which leads to a stable stereo-isomer, by one or more radicals from the group hy-droxy or halogen.
A(C1-C8) alkylaryl group is an aryl group, such as described above, which is linked by a straight-chained or branched (C1-C8) alkyl unit with the ring system.
A(C2-C8) alkenylaryl group is an aryl group, such as described above, which is linked by a straight-chained or branched (C2-C8) alkenyl unit with the ring system.
A (C2-C8) alkinylaryl group is an aryl group, such as described above, which is linked by a straight-chained or branched (C2-C8) alkinyl unit with the ring system.
Monocyclic heteroaryl groups may for instance be pyridine, pyrazine, pyrimidine, pyridazine, triazine, azaindolizine, 2H and 4H-pyran, 2H and 4H-thiopyran, furan, thiophene, 1H and 4H-pyrazole, 1H and 2H-pyrrole, oxazole, thiazole, furazan, 1H and 4H-imidazole, isoxazole, isothiazole, oxadiazole, triazole, tetrazole, thiadiazole.
Bicyclic heteroaryl groups may for instance be phthalidyl, thiophthalidyl, indolyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, benzothiazolyl, indolonyl, dihydroindolonyl, isoindolonyl, dihydroisoindolonyl, benzofuranyl, benzimidazolyl, dihydroisochinolinyl, dihy-drochinolinyl, benzoxazinonyl, phthalazinonyl, dihydrophthalazinonyl chinolinyl, isochinolinyl, chinolonyl, isochinolonl, chinazolinyl, chinoxalinyl, cinnolinyl, phthalazinyl, dihydrophthalazinyl, 1,7 or 1,8-naphthyridinylcumarinyl, cumarinyl, isocumarinyl, indolizinyl, isobenzofuranyl, azaindolyl, azaisoindolyl, furanopyridyl, furanopyrimidinyl, furanopyrazinyl, furanopyidazinyl, dihydrobenzofuranyl, dihydrofuranopyridyl, dihydrofuranopyrimidinyl, dihydrofuranopyrazinyl, dihydrofuranopyridazinyl, dihydrobenzofuranyl, chromenyl, isochromenyl, chromenonyl or the isochromenonyl group.
A(C1-Ca) alkylheteroaryl group is a heteroaryl group, such as described above, which is linked by a straight-chained or branched (C1-C$) alkyl unit with the ring system.
A(C2-C$) alkenylheteroaryl group is a hetero-aryl group, such as described above, which is linked by a straight-chained or branched (C2-C8) alkenyl unit with the ring system.
A(C2-Ca) alkinylheteroaryl group is a hetero-aryl group, such as described above, which is linked by a straight-chained or branched (C2-Ca) alkinyl unit with the ring system.
A(C1-C8) alkylheterocyclyl group is a hetero-cyclyl group, such as described above, which is linked by a straight-chained or branched (C1-Ca) alkyl unit with the ring system.
A(C2-C$) alkenylheterocyclyl group is a het-erocyclyl group, such as described above, which is linked by a straight-chained or branched (Cz-Ca) alkenyl unit with the ring system.
Examples for compounds according to the inven-tion are:
5-[5-fluoro-2-oxo-1,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[5-bromo-2-oxo-1,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[5-chloro-2-oxo-l,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[6-fluoro-2-oxo-1,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[6-chloro-2-oxo-1,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[6-bromo-2-oxo-1,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[5-methyl-2-oxo-1,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[5-methoxy-2-oxo-1,2-dihydro-indole-(3Z)-ylid-enemethyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[6-methyl-2-oxo-l,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[6-methoxy-2-oxo-l,2-dihydro-indole-(3Z)-ylid-enemethyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, or derivatives of the above compounds, wherein the 2-diethylamino-ethoxy group is replaced by one of the groups selected from "2-(triazole-l-yl) eth-oxy, 2-triazole-l-yl) methoxy, (pyridine-4-yl) methoxy, 2-(pyridiny-4-yl) ethoxy, 2-(morpholine-4-yl) ethoxy, (morpholine-4-yl) methoxy, (1-methyl-4-piperidyl) methoxy, 2-(1-methyl-4-piperidyl) ethoxy, 2-(pyrrolidine-l-yl) ethoxy, (pyrrolidine-l-yl) methoxy, 2-(dimethylamino) eth-oxy, (dimethylamino) methoxy and (dimethylamino) methoxy".
In all above specific compounds, X and Z are a binding, and Y is -0-. In all above specific com-pounds, Y may also be -S-. Further, in all above specific compounds, in addition to Y, X and/or Z
may also be -0-, instead of a binding. Further, in all above specific compounds, -Y- may be a bind-ing, if X and/or Z is -0- or -S-.
For obtaining pharmaceutical compositions, compounds according to the invention may be com-bined with other per se known active substances, for instance: aldesleukin, amifostine, atrasentan, bevacizumab, bexaroten, bortezomib, capecitabine, carboplatin, chlorambucil, cisplatin, cladribine, cyclophosphamid, cytamid, dacarbazin, docetaxel, droloxifene, edrecolomab, epothilone, erlotinib, etoposide, exemestane, flavopiridol, fludarabine, fuorouracil, formestane, fulvestrant, gefitinib, gemcitabine, idarubicin, irinotecan, ixabepilone, lonafarnib, miltefosine, mitomycin, neovastat, ox-aliplatin, pemetrexed, porfimer, rituximab, tega-fur, temozolomide, tipifarnib, topotecan, tri-metrexate, vorozole, vinblastine, and mixtures of two or more of such active substances. For the purpose of a single galenic preparation, the com-pound according to the invention may be mixed with the active substance. It is however also possible that the pharmaceutical composition consists of two (or more) different galenic preparations, wherein in a first preparation the compound ac-cording to the invention and in a second prepara-tion the active substance are contained. In the first preparation, an active substance being dif-ferent from the active substance of the second preparation may be provided.
The invention further relates to a method for producing compounds according to the invention, wherein a substance of Formula II
H n R. }~2:z__O
N~~'R5 f Formula II
is reacted with a substance of Formula III
Z_R7 ~
Y (CH2)n f.,i 2N F o r m u l a I I I
A(C2-C$) alkenylheterocyclyl group is a het-erocyclyl group, such as described above, which is linked by a straight-chained or branched (Cz-Ca) alkenyl unit with the ring system.
Examples for compounds according to the inven-tion are:
5-[5-fluoro-2-oxo-1,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[5-bromo-2-oxo-1,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[5-chloro-2-oxo-l,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[6-fluoro-2-oxo-1,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[6-chloro-2-oxo-1,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[6-bromo-2-oxo-1,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[5-methyl-2-oxo-1,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[5-methoxy-2-oxo-1,2-dihydro-indole-(3Z)-ylid-enemethyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[6-methyl-2-oxo-l,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[6-methoxy-2-oxo-l,2-dihydro-indole-(3Z)-ylid-enemethyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, or derivatives of the above compounds, wherein the 2-diethylamino-ethoxy group is replaced by one of the groups selected from "2-(triazole-l-yl) eth-oxy, 2-triazole-l-yl) methoxy, (pyridine-4-yl) methoxy, 2-(pyridiny-4-yl) ethoxy, 2-(morpholine-4-yl) ethoxy, (morpholine-4-yl) methoxy, (1-methyl-4-piperidyl) methoxy, 2-(1-methyl-4-piperidyl) ethoxy, 2-(pyrrolidine-l-yl) ethoxy, (pyrrolidine-l-yl) methoxy, 2-(dimethylamino) eth-oxy, (dimethylamino) methoxy and (dimethylamino) methoxy".
In all above specific compounds, X and Z are a binding, and Y is -0-. In all above specific com-pounds, Y may also be -S-. Further, in all above specific compounds, in addition to Y, X and/or Z
may also be -0-, instead of a binding. Further, in all above specific compounds, -Y- may be a bind-ing, if X and/or Z is -0- or -S-.
For obtaining pharmaceutical compositions, compounds according to the invention may be com-bined with other per se known active substances, for instance: aldesleukin, amifostine, atrasentan, bevacizumab, bexaroten, bortezomib, capecitabine, carboplatin, chlorambucil, cisplatin, cladribine, cyclophosphamid, cytamid, dacarbazin, docetaxel, droloxifene, edrecolomab, epothilone, erlotinib, etoposide, exemestane, flavopiridol, fludarabine, fuorouracil, formestane, fulvestrant, gefitinib, gemcitabine, idarubicin, irinotecan, ixabepilone, lonafarnib, miltefosine, mitomycin, neovastat, ox-aliplatin, pemetrexed, porfimer, rituximab, tega-fur, temozolomide, tipifarnib, topotecan, tri-metrexate, vorozole, vinblastine, and mixtures of two or more of such active substances. For the purpose of a single galenic preparation, the com-pound according to the invention may be mixed with the active substance. It is however also possible that the pharmaceutical composition consists of two (or more) different galenic preparations, wherein in a first preparation the compound ac-cording to the invention and in a second prepara-tion the active substance are contained. In the first preparation, an active substance being dif-ferent from the active substance of the second preparation may be provided.
The invention further relates to a method for producing compounds according to the invention, wherein a substance of Formula II
H n R. }~2:z__O
N~~'R5 f Formula II
is reacted with a substance of Formula III
Z_R7 ~
Y (CH2)n f.,i 2N F o r m u l a I I I
to a substance of Formula IV
1%
z (CH 2)~
y HN
N
Q~ H Formula IV
wherein then the substance of Formula IV is react-ed with a substance of Formula V
2~ 0 N
R
Formula V
to a compound of Formula VI
/ Z,R r 0 P-1 2) n Rb A `f NI-I
~
, t, c 5 N
1%
z (CH 2)~
y HN
N
Q~ H Formula IV
wherein then the substance of Formula IV is react-ed with a substance of Formula V
2~ 0 N
R
Formula V
to a compound of Formula VI
/ Z,R r 0 P-1 2) n Rb A `f NI-I
~
, t, c 5 N
Formula VI
wherein the radicals Rl to R7 and the groups Y and Z have the above meanings, and wherein preferably at least Y is -0- or -S-.
Substances of Formula II may for instance be synthesized by a reaction of compounds of Formulas VII and VIII or Formulas IX and X with each other and by a subsequent reaction to the substance of Formula II, wherein at least the respective reac-tive group Y or Z is -0- or -S-.
~- rv ~
H3C Formula VII
(CH2)n p7 Formula VIII
r ti..
J
H3C Y --(CH2)n J
Formula IX
H Rr'' Formula X
Exemplary suitable reaction conditions for the above reactions can be taken from the examples of execution.
wherein the radicals Rl to R7 and the groups Y and Z have the above meanings, and wherein preferably at least Y is -0- or -S-.
Substances of Formula II may for instance be synthesized by a reaction of compounds of Formulas VII and VIII or Formulas IX and X with each other and by a subsequent reaction to the substance of Formula II, wherein at least the respective reac-tive group Y or Z is -0- or -S-.
~- rv ~
H3C Formula VII
(CH2)n p7 Formula VIII
r ti..
J
H3C Y --(CH2)n J
Formula IX
H Rr'' Formula X
Exemplary suitable reaction conditions for the above reactions can be taken from the examples of execution.
Compounds according to the invention may be produced for instance according to the following synthesis scheme:
OH
+'1 FhN O/~ N~~; tiN,i tJ' --_- r ~ ; H
N~\.~
C H CG1376.4 N CC.1376.7 H C.4}}MN303 C.yHyP4C13 Mol. J4t:; 281,35 Mot ft.: 167.16 u msix~ i:illy atiii>3ahle ! F
,F }W H
C_ !dbi. M. 73:019 cornnxxciatl} available etxrn;;iMcli4iy [ivi:iitible % CqHr6FPdp N aid. lht: 151,14 0 H.
N
YOI 0 j't-,;
N
H
Ni' ... N CG1376.3 F
~0 t~H~xFN4f1 p{r:; PM. VLi: 414,47 {::,il c{;c;`d C)}{2D},}20 {;C-13'76.0 Mkl. I.W. 172.10 Atlp;. UVt.: 172.27 corrnr i.ire31 avaiiniiie Other compounds of the invention may be pro-duced in an analogous manner by using educts, in which the radicals Ri to R7 are modified according to the definition.
The invention further teaches a pharmaceutical composition containing a compound according to the invention. Optionally, one or more physiologically well tolerated auxiliary substances and/or carrier substances can be mixed with the compound, and the mixture is galenically prepared for the local or systemic administration, in particular oral, par-enteral, for the infusion or infundation in a tar-get organ, for the injection (e.g. i.v., i.m., in-tracapsulary or intralumbal), for the application in tooth pockets (space between root of the tooth and the gum) and/or for inhalation. The selection of the additional and/or auxiliary substances will depend on the selected type of administration. The galenic preparation of the pharmaceutical composition according to the invention may be performed in a conventional manner. As counter ions for ionic compounds may for instance be used Ca++, CaCl+, Na+, K+, Li+ or cyclohexylammonium or C1-, Br-, acetate, trifluoroacetate, propionate, lactate, oxalate, malate, maleate, malonate, maleinate, citrate, benzoate, salicylate etc.
Suitable solid or liquid galenic forms of preparation are instance granulates, powders, dra-gees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions (i.v., i.p., i.m., s.c.) or fine dispersions (aerosols), forms of preparation for dry powder inhalation, transdermal systems, and preparations with protracted release of active substance, for the production of which usual means are used, such as carrier substances, explosives, binding, coating, swelling, sliding or lubricating agents, tasting agents, sweeteners and solution mediators. It is also possible to encapsulate the active substance in preferably biologically decom-posable nanocapsules, for instance for making a preparation for the inhalation. As auxiliary sub-stances are named here magnesium carbonate, tita-nium dioxide, lactose, mannite and other sugars, talcum, milk protein, gelatin, starch, cellulose and derivatives, animal and vegetable oils such as cod-liver oil, sunflower, peanut or sesame oil, polyethylene glycols and solvents, such as sterile water and mono or multi-valent alcohols, for in-stance glycerin. A pharmaceutical composition ac-cording to the invention can be produced by that at least one combination of substances used ac-cording to the invention is mixed in a defined dose with a pharmaceutically suitable and physio-logically well tolerated carrier and possibly fur-ther suitable active, additional or auxiliary sub-stances in a defined dose, and is prepared in the desired form of administration.
As dilution agents, polyglycols, ethanol, wa-ter and buffer solutions can be used. Suitable buffer solutions are for instance N,N'-diben-zylethylenediamine, diethanolamine, ethylenedia-mine, N-methylglucamine, N-benzylphenethylamine, diethylamine, phosphate, sodium bicarbonate, or sodium carbonate. It is however also possible not to use any dilution agent at all.
Physiologically tolerated salts are salts with inorganic or organic acids, such as hydrochloric acid, sulfuric acid, acetic acid, citric acid, p-toluolsulfonic acid, and in particular malic acid, or with inorganic or organic bases, such as NaOH, KOH, Mg(OH)2, diethanolamine, ethylenediamine, or with amino acids, such as arginine, lysine, glutamine acid etc., or with inorganic salts, such as CaC12, NaCl or the free ions thereof, such as Ca2+, Na+, Cl , S042 or combinations thereof. They are also produced by using standard methods. In addition, reference is made to suitable counter ions, as mentioned in the context with the galenic preparation.
The invention is based on the finding that by the introduction of at least one -0- for one of the groups X, Y, or Z, an improved efficiency is obtained, since compounds with -N-O- groups on one hand competitively bind natural ligands, and on the other hand cannot be metabolized. The inhibi-tory effect is thus substantially increased.
OH
+'1 FhN O/~ N~~; tiN,i tJ' --_- r ~ ; H
N~\.~
C H CG1376.4 N CC.1376.7 H C.4}}MN303 C.yHyP4C13 Mol. J4t:; 281,35 Mot ft.: 167.16 u msix~ i:illy atiii>3ahle ! F
,F }W H
C_ !dbi. M. 73:019 cornnxxciatl} available etxrn;;iMcli4iy [ivi:iitible % CqHr6FPdp N aid. lht: 151,14 0 H.
N
YOI 0 j't-,;
N
H
Ni' ... N CG1376.3 F
~0 t~H~xFN4f1 p{r:; PM. VLi: 414,47 {::,il c{;c;`d C)}{2D},}20 {;C-13'76.0 Mkl. I.W. 172.10 Atlp;. UVt.: 172.27 corrnr i.ire31 avaiiniiie Other compounds of the invention may be pro-duced in an analogous manner by using educts, in which the radicals Ri to R7 are modified according to the definition.
The invention further teaches a pharmaceutical composition containing a compound according to the invention. Optionally, one or more physiologically well tolerated auxiliary substances and/or carrier substances can be mixed with the compound, and the mixture is galenically prepared for the local or systemic administration, in particular oral, par-enteral, for the infusion or infundation in a tar-get organ, for the injection (e.g. i.v., i.m., in-tracapsulary or intralumbal), for the application in tooth pockets (space between root of the tooth and the gum) and/or for inhalation. The selection of the additional and/or auxiliary substances will depend on the selected type of administration. The galenic preparation of the pharmaceutical composition according to the invention may be performed in a conventional manner. As counter ions for ionic compounds may for instance be used Ca++, CaCl+, Na+, K+, Li+ or cyclohexylammonium or C1-, Br-, acetate, trifluoroacetate, propionate, lactate, oxalate, malate, maleate, malonate, maleinate, citrate, benzoate, salicylate etc.
Suitable solid or liquid galenic forms of preparation are instance granulates, powders, dra-gees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions (i.v., i.p., i.m., s.c.) or fine dispersions (aerosols), forms of preparation for dry powder inhalation, transdermal systems, and preparations with protracted release of active substance, for the production of which usual means are used, such as carrier substances, explosives, binding, coating, swelling, sliding or lubricating agents, tasting agents, sweeteners and solution mediators. It is also possible to encapsulate the active substance in preferably biologically decom-posable nanocapsules, for instance for making a preparation for the inhalation. As auxiliary sub-stances are named here magnesium carbonate, tita-nium dioxide, lactose, mannite and other sugars, talcum, milk protein, gelatin, starch, cellulose and derivatives, animal and vegetable oils such as cod-liver oil, sunflower, peanut or sesame oil, polyethylene glycols and solvents, such as sterile water and mono or multi-valent alcohols, for in-stance glycerin. A pharmaceutical composition ac-cording to the invention can be produced by that at least one combination of substances used ac-cording to the invention is mixed in a defined dose with a pharmaceutically suitable and physio-logically well tolerated carrier and possibly fur-ther suitable active, additional or auxiliary sub-stances in a defined dose, and is prepared in the desired form of administration.
As dilution agents, polyglycols, ethanol, wa-ter and buffer solutions can be used. Suitable buffer solutions are for instance N,N'-diben-zylethylenediamine, diethanolamine, ethylenedia-mine, N-methylglucamine, N-benzylphenethylamine, diethylamine, phosphate, sodium bicarbonate, or sodium carbonate. It is however also possible not to use any dilution agent at all.
Physiologically tolerated salts are salts with inorganic or organic acids, such as hydrochloric acid, sulfuric acid, acetic acid, citric acid, p-toluolsulfonic acid, and in particular malic acid, or with inorganic or organic bases, such as NaOH, KOH, Mg(OH)2, diethanolamine, ethylenediamine, or with amino acids, such as arginine, lysine, glutamine acid etc., or with inorganic salts, such as CaC12, NaCl or the free ions thereof, such as Ca2+, Na+, Cl , S042 or combinations thereof. They are also produced by using standard methods. In addition, reference is made to suitable counter ions, as mentioned in the context with the galenic preparation.
The invention is based on the finding that by the introduction of at least one -0- for one of the groups X, Y, or Z, an improved efficiency is obtained, since compounds with -N-O- groups on one hand competitively bind natural ligands, and on the other hand cannot be metabolized. The inhibi-tory effect is thus substantially increased.
The invention therefore further teaches the use of a compound according to the invention for producing a pharmaceutical composition for treat-ing one or several diseases from the group con-sisting of "cancer, such as lung cancer, leukemia, ovary cancer, sarcoma, meningioma, intestine can-cer, lymph node cancer, brain tumors, breast can-cer, pancreas cancer, prostate cancer, skin can-cer, chronic inflammations, asthma, allergy, rhi-nitis, uveitis, urticaria, arthritis, osteoarthri-tis, chronic polyarthritis, rheumatoid arthritis, inflammatory bowl disease, degenerative joint dis-eases, diseases of the rheumatic form circle with cartilage breakdown, sepsis, autoimmune diseases, type I diabetes, Hashimoto thyreoiditis, autoim-munethrombozytopenia, multiple sclerosis, myasthe-nia gravis, chronic inflammatory intestinal dis-eases, morbus Crohn, oveitis, psoriasis, atypical dermatitis, collagenoses, Goodpasture syndroma, diseases with disturbed leukocyte adhesion, cachexia, diseases by increased TNF-alpha concen-tration, diabetes, adipositas, bacterial infec-tions, in particular with resistant bacteria, heart insufficiency and the chronic cardiac fail-ure (CCF)". The term treatment also comprises the prophylaxis.
For the purpose of the invention, various fur-ther embodiments are possible. For instance, a pharmaceutical composition according to the inven-tion may comprise several different compounds fal-ling under the above Formula I. Further, a pharma-ceutical composition according to the invention may in addition comprise an active substance dif-ferent from the compound of Formula I. Then it is a combination preparation. The different used ac-tive substances may be prepared in a single unit of administration, i.e. the active substances are mixed in the unit of administration. It is however also possible to prepare the different active sub-stances in separate units of preparation of the same or different kind.
The invention also relates to a method for producing a pharmaceutical composition, wherein at least one compound according to the invention is mixed with a pharmaceutically suitable and physio-logi.cally well-tolerated carrier substance and, if applicable, further suitable active, additional or auxiliary substances, and brought into a suitable form of administration.
Preferably, the pharmaceutical composition is produced and administered in dosage units, wherein every unit contains as an active component a de-fined dose of the compound according to the inven-tion according to Formula I. For solid dosage units such as tablets, capsules, dragees or sup-positories, this dose may be 0.1 to 1,000 mg, preferably 1 to 300 mg, and for injection solu-tions in vial form 0.01 to 1,000 mg, preferably 1 to 100 mg.
For treating an adult of 50 to 100 kg, for in-stance 70 kg, patients are injected for instance daily doses of 0.1 to 1,000 mg active substance, preferably 1 to 500 mg. Under certain circum-stances, however, higher or lower daily doses may also be suitable. The administration of the daily dose may be performed once a day in the form of a single dosage unit or in several smaller dosage units as well as by multiple administration of dosage portions in certain intervals.
However, a combination of one or more of the active substances according to the invention with aminooxyacetate (AOA, NH2 O-CH2-COOH or salts or esters thereof, for instance C1-C10 alkyl or hy-droxyalkylester) is also possible. AOA is particu-larly effective against small tumors (< 0.1 to 1 cm3) or inhibit the generation thereof, in par-ticular the spreading of metastases, whereas com-pounds according to the invention are particularly effective against the large tumors. The reason for this is the different metabolism in small and large tumors. The above explanations for combina-tions apply in an analogous manner.
In the following, synthesis examples for com-pounds according to the invention are described.
1.1: Synthesis of acetone (3-diethylaminoethyl oxime (CC-1376.3).
Reaction:
;............__...__.__. _._.___.._ _._.__..,_._._ \-N
I-1C:1 \1 \
OH
(.61115C'12N GafiNO C4W420 L 172,10 Md. Vlk.: 73,09 CC-1376.4:
Mol. Vtit.: 172,27 Batch CC-1376.3-1:
Sodium (EH-122.5-5, 18.4 g, 0.8 mole) is dis-solved in 600 ml dry ethanol under an argon atmos-phere. After addition of acetoxime (29.2 g, 0.4 mole) and diethylaminoethylchloride hydrochloride (EH-873.3-2, 68.8 g, 0.4 mole) it is heated to re-flux. After 2 h stirring the heating bath is re-moved and stirring is performed over night at am-bient temperature. After filtration, acidification with 2N aqueous HCl (pH 5), and condensation in vacuum is performed. The residue is received in 10% NaOH, extracted twice with 250 ml diethyl ether each, and the organic phases are condensed in vacuum. After vacuum distillation (56 - 68 C, approx. 6 mbar), CC 1376.3-1 (43.94 g, 64 %) is obtained.
1.2: Synthesis of (3-diethylaminoethoxyamine (CC-1376.4) Reaction:
... ........
N N
~ - - ->
C~0F-12CN7O Cr;III [;N<<) F<,4o1. ti1R.: 172,27 1\1ol. Wt.: 132,20 Batch CC-1376.4-1:
Acetone B-diethylaminoethyl oxime (CC-1376.3-1, 43.94 g, 255 mmole) is reacted in 3N aqueous HC1 (450 ml) and brought to reflux. After 3h stir-ring at this temperature, it is cooled down and condensed in vacuum. The residue is alkalized with a 10 % and 50% sodium hydroxide solution. The aqueous phase is extracted twice with 250 ml di-ethyl ether each, dried over sodium sulfate and condensed in vacuum. After vacuum distillation (62 - 66 C, approx. 6 mbar) CC-1376.4-1 (27.2g, 81 slightly contaminated, is obtained, which is used without further purification in the next step.
For the purpose of the invention, various fur-ther embodiments are possible. For instance, a pharmaceutical composition according to the inven-tion may comprise several different compounds fal-ling under the above Formula I. Further, a pharma-ceutical composition according to the invention may in addition comprise an active substance dif-ferent from the compound of Formula I. Then it is a combination preparation. The different used ac-tive substances may be prepared in a single unit of administration, i.e. the active substances are mixed in the unit of administration. It is however also possible to prepare the different active sub-stances in separate units of preparation of the same or different kind.
The invention also relates to a method for producing a pharmaceutical composition, wherein at least one compound according to the invention is mixed with a pharmaceutically suitable and physio-logi.cally well-tolerated carrier substance and, if applicable, further suitable active, additional or auxiliary substances, and brought into a suitable form of administration.
Preferably, the pharmaceutical composition is produced and administered in dosage units, wherein every unit contains as an active component a de-fined dose of the compound according to the inven-tion according to Formula I. For solid dosage units such as tablets, capsules, dragees or sup-positories, this dose may be 0.1 to 1,000 mg, preferably 1 to 300 mg, and for injection solu-tions in vial form 0.01 to 1,000 mg, preferably 1 to 100 mg.
For treating an adult of 50 to 100 kg, for in-stance 70 kg, patients are injected for instance daily doses of 0.1 to 1,000 mg active substance, preferably 1 to 500 mg. Under certain circum-stances, however, higher or lower daily doses may also be suitable. The administration of the daily dose may be performed once a day in the form of a single dosage unit or in several smaller dosage units as well as by multiple administration of dosage portions in certain intervals.
However, a combination of one or more of the active substances according to the invention with aminooxyacetate (AOA, NH2 O-CH2-COOH or salts or esters thereof, for instance C1-C10 alkyl or hy-droxyalkylester) is also possible. AOA is particu-larly effective against small tumors (< 0.1 to 1 cm3) or inhibit the generation thereof, in par-ticular the spreading of metastases, whereas com-pounds according to the invention are particularly effective against the large tumors. The reason for this is the different metabolism in small and large tumors. The above explanations for combina-tions apply in an analogous manner.
In the following, synthesis examples for com-pounds according to the invention are described.
1.1: Synthesis of acetone (3-diethylaminoethyl oxime (CC-1376.3).
Reaction:
;............__...__.__. _._.___.._ _._.__..,_._._ \-N
I-1C:1 \1 \
OH
(.61115C'12N GafiNO C4W420 L 172,10 Md. Vlk.: 73,09 CC-1376.4:
Mol. Vtit.: 172,27 Batch CC-1376.3-1:
Sodium (EH-122.5-5, 18.4 g, 0.8 mole) is dis-solved in 600 ml dry ethanol under an argon atmos-phere. After addition of acetoxime (29.2 g, 0.4 mole) and diethylaminoethylchloride hydrochloride (EH-873.3-2, 68.8 g, 0.4 mole) it is heated to re-flux. After 2 h stirring the heating bath is re-moved and stirring is performed over night at am-bient temperature. After filtration, acidification with 2N aqueous HCl (pH 5), and condensation in vacuum is performed. The residue is received in 10% NaOH, extracted twice with 250 ml diethyl ether each, and the organic phases are condensed in vacuum. After vacuum distillation (56 - 68 C, approx. 6 mbar), CC 1376.3-1 (43.94 g, 64 %) is obtained.
1.2: Synthesis of (3-diethylaminoethoxyamine (CC-1376.4) Reaction:
... ........
N N
~ - - ->
C~0F-12CN7O Cr;III [;N<<) F<,4o1. ti1R.: 172,27 1\1ol. Wt.: 132,20 Batch CC-1376.4-1:
Acetone B-diethylaminoethyl oxime (CC-1376.3-1, 43.94 g, 255 mmole) is reacted in 3N aqueous HC1 (450 ml) and brought to reflux. After 3h stir-ring at this temperature, it is cooled down and condensed in vacuum. The residue is alkalized with a 10 % and 50% sodium hydroxide solution. The aqueous phase is extracted twice with 250 ml di-ethyl ether each, dried over sodium sulfate and condensed in vacuum. After vacuum distillation (62 - 66 C, approx. 6 mbar) CC-1376.4-1 (27.2g, 81 slightly contaminated, is obtained, which is used without further purification in the next step.
1.3: Synthesis of 5-formyl-2,4-dimethyl-lH-pyr-role-3-carboxylic acid (2-diethylaminoeth-oxy) amide (CC-1376.7).
Reaction:
~-~ 0 ;j- N _ N O ~
- H
C H { CC=1376.4 AJ N(C-13763 H C; 1~r.atdDa Mos. Wt.: 281.35 tOoi O,t.: 16'1.16 Batch CC-1376.7-1:
Hydroxybenzotriazole (EH-I100.2-2, 300 mg, 2.22 mmole), EDCI (430 mg, 2.24 mmole) and 3,5-di-methyl-2-formylpyrrole-4 carbonic acid (EH-1195.10-1, 250 mg, 1.5 mmole) are provided under argon atmosphere at ambient temperature in 10 ml dry DMF and reacted with triethylamine (EH-18.3-13, 0.42 ml, 3 mmole). Then CC-1376.4-1 (400 mg, 3 mmole) is quickly added in drops and stirred over night at ambient temperature. The reaction solu-tion is diluted with 5 ml water, 3 ml NaCl and 5 ml NaHCO3 solution, extracted twice with 10 ml DCM/MeOH 9:1 each, dried over sodium sulfate and condensed in vacuum. The residue is co-evaporated with toluene, reacted with 10 ml hexane/diethyl ether 3:1, and the supernatant solution is de-canted off. The residue is again co-evaporated with toluene, and after cleaning over flash silica gel (DCM/MeOH 1:1) and drying in high vacuum, CC-1376.7-1 as a brown solid material (114 mg, 28 %) is obtained.
Reaction:
~-~ 0 ;j- N _ N O ~
- H
C H { CC=1376.4 AJ N(C-13763 H C; 1~r.atdDa Mos. Wt.: 281.35 tOoi O,t.: 16'1.16 Batch CC-1376.7-1:
Hydroxybenzotriazole (EH-I100.2-2, 300 mg, 2.22 mmole), EDCI (430 mg, 2.24 mmole) and 3,5-di-methyl-2-formylpyrrole-4 carbonic acid (EH-1195.10-1, 250 mg, 1.5 mmole) are provided under argon atmosphere at ambient temperature in 10 ml dry DMF and reacted with triethylamine (EH-18.3-13, 0.42 ml, 3 mmole). Then CC-1376.4-1 (400 mg, 3 mmole) is quickly added in drops and stirred over night at ambient temperature. The reaction solu-tion is diluted with 5 ml water, 3 ml NaCl and 5 ml NaHCO3 solution, extracted twice with 10 ml DCM/MeOH 9:1 each, dried over sodium sulfate and condensed in vacuum. The residue is co-evaporated with toluene, reacted with 10 ml hexane/diethyl ether 3:1, and the supernatant solution is de-canted off. The residue is again co-evaporated with toluene, and after cleaning over flash silica gel (DCM/MeOH 1:1) and drying in high vacuum, CC-1376.7-1 as a brown solid material (114 mg, 28 %) is obtained.
1.4: Synthesis of 5-[5-fluoro-2-oxo-l,2-dihydro-indole-(3Z)-ylidenemethyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide (CC-1376.0).
Reaction:
-..-_ ' tx 1376.7 O 7 ~'.N' b H
N' N 0 H C-, 41 H
b1rr. W.: 281,35 --=--r~_...~ _~ ~~~`,-'`\
n Gy ti = FN iC3 F ~~ ~N Moi. ~fld.: 414.4?
r~ H
=C CC-1378.0 H
C9Ft~f NCt tr'Icl.1M,.: 151.14 Batch CC-1376.0-3:
5-fluoroxindole (0.33 g, 2.18 mmole) is dis-solved in 12 ml EtOH. Then, 5-formyl-2,4-dimethyl-1H-pyrrole-3-carbonic-acid-(2-diethylaminoethoxy)-amide (CC-1376.7-2, 620 mg, 2.20 mmole) and pyr-rolidine (18 p1, 0.22 mmole) are added. After ad-dition, heating for 3 h to 78 C is performed, and an orange solid material is deposited. The reac-tion mixture is cooled down, and the precipitate is sucked of through a frit, re-washed with etha-nol and again stirred with ethanol at 78 C. An-other filtration of the precipitate and drying in high-vacuum results in CC-1376.0-3 as a yellow solid material (0.21 g, 23 %).
Reaction:
-..-_ ' tx 1376.7 O 7 ~'.N' b H
N' N 0 H C-, 41 H
b1rr. W.: 281,35 --=--r~_...~ _~ ~~~`,-'`\
n Gy ti = FN iC3 F ~~ ~N Moi. ~fld.: 414.4?
r~ H
=C CC-1378.0 H
C9Ft~f NCt tr'Icl.1M,.: 151.14 Batch CC-1376.0-3:
5-fluoroxindole (0.33 g, 2.18 mmole) is dis-solved in 12 ml EtOH. Then, 5-formyl-2,4-dimethyl-1H-pyrrole-3-carbonic-acid-(2-diethylaminoethoxy)-amide (CC-1376.7-2, 620 mg, 2.20 mmole) and pyr-rolidine (18 p1, 0.22 mmole) are added. After ad-dition, heating for 3 h to 78 C is performed, and an orange solid material is deposited. The reac-tion mixture is cooled down, and the precipitate is sucked of through a frit, re-washed with etha-nol and again stirred with ethanol at 78 C. An-other filtration of the precipitate and drying in high-vacuum results in CC-1376.0-3 as a yellow solid material (0.21 g, 23 %).
2: Structures and analytical data.
2.1: 5-[5-fluoro-2-oxo-l,2-dihydro-indole-(3Z)-ylidenemethyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide.
/-"CHs N
0 \---CH3 H3C\ hiH
N' 'C H3 F H
T>o Nf H
Mol.Wt.: 414.47 g/mol.
Melting point: 216.0 C (Electrothermal IA
9200, heating rate 1 C/min).
1H-NMR (measured with Bruker Avance 400 (400 MHz, dmso-d6, TMS as internal standard): S(ppm) =
0.96 (t, 6H, J = 7.1 Hz, Me), 2.43 (s, 3H, Me), 2.50 (m, 4H, NCH2CH3), 2.68 (t, 2H, J = 6.1 Hz, NCH2CH2), 3.92 (t, 2H, J = 6.1 Hz, NCH2CH2), 6.83 - 6. 86 (m, 1H, Hindole) r 6.91 - 6.96 (m, 1H, Hin-dole) r 7.71 (s, 1H, C=CH), 7.75 - 7.79 (m, 1H, Hin-dole)r 10.92 (bs, 1H, NH), 13,71 (bs, 1H, NH).
13C-NMR (measured with Bruker Avance 400 (100, 6 MHz, dmso-d6, TMS as internal standard) :
b(ppm) = 10.43 (s, 2C, NCH2CH3), 13.21 (s, 1C, Me), 46.75 (s, 2C, NCH2CH3), 50.4-3 (s, iC, NCH2CH3) , 73. 69 (s, 1C, NCH2CH3) , 105. 97 (d, 1C, J
2.1: 5-[5-fluoro-2-oxo-l,2-dihydro-indole-(3Z)-ylidenemethyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide.
/-"CHs N
0 \---CH3 H3C\ hiH
N' 'C H3 F H
T>o Nf H
Mol.Wt.: 414.47 g/mol.
Melting point: 216.0 C (Electrothermal IA
9200, heating rate 1 C/min).
1H-NMR (measured with Bruker Avance 400 (400 MHz, dmso-d6, TMS as internal standard): S(ppm) =
0.96 (t, 6H, J = 7.1 Hz, Me), 2.43 (s, 3H, Me), 2.50 (m, 4H, NCH2CH3), 2.68 (t, 2H, J = 6.1 Hz, NCH2CH2), 3.92 (t, 2H, J = 6.1 Hz, NCH2CH2), 6.83 - 6. 86 (m, 1H, Hindole) r 6.91 - 6.96 (m, 1H, Hin-dole) r 7.71 (s, 1H, C=CH), 7.75 - 7.79 (m, 1H, Hin-dole)r 10.92 (bs, 1H, NH), 13,71 (bs, 1H, NH).
13C-NMR (measured with Bruker Avance 400 (100, 6 MHz, dmso-d6, TMS as internal standard) :
b(ppm) = 10.43 (s, 2C, NCH2CH3), 13.21 (s, 1C, Me), 46.75 (s, 2C, NCH2CH3), 50.4-3 (s, iC, NCH2CH3) , 73. 69 (s, 1C, NCH2CH3) , 105. 97 (d, 1C, J
= 25.5 Hz, CH-indole) i 109. 96 (d, 1C, J= 8. 6 Hz, CH-indole) , 112.45 (d, 1C, J= 24.1 Hz, CH-indole) i 114.94 (d, 1C, J = 3.8 Hz), 117.51 (s, 1C), 124.72 (s, 1C), 125.85 (s, 1C, C=CH), 126.96 (d, 1C), 130.42 (s, 10), 134.50 (d, 10, J = 1.3 Hz), 136.52 (s, 1C), 156.97 (s, 1C), 159.30 (s, 1C), 169.47 (d, 1C, J = 0.86 Hz).
2.2: N-[2-(diethylamino) ethoxy]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indole-3-ylidene) methyl]-2,4-dimethyl-lH-pyrrole-3-carboxamide, (2S)-hydroxybutanedionate (1:
0.5) .
>-C H3 /-N
1y "`
~ C H 3 N H
1~ t IN C Fi:3 F
H
0.5 malate N
H
Mol.Wt.: 481,52 g/mol.
Melting point: 203 C, decomposition (Electro-thermal IA 9200, heating rate 1 C/min).
1H-NMR (measured with Bruker Avance 400 (400 MHz, dmso-d6, TMS as internal standard): b(ppm) =
1.08 (t, 6H, J = 7.0 Hz, Me), 2.33 (dd, 0.5H, J=
4.0 Hz, J = 15. 6 Hz, CH2malic) , 2.41 (B, 3H, Me), 2. 44 (s, 3H, Me), 2.50 (m, 0. 5H, CH2malic) ~ 2- 84 (bs, 4H, NCH2CH3), 2.97 (bs, 2H, NCH2CH2), 3.90 (dd, 0.5H, J= 3. 9 Hz, J 10.0 Hz CHmalic) , 4.05 (m, 2H, J = 6.1 Hz, NC2CHZ) , 6.85 (dd, 1H, J = 4. 6 Hz, J = 8.4 Hz, Hindole) i 6.89 - 6. 98 (m, 1H, Hindole) 7= 73 (s, 1H, C=CH) , 7.78 (dd, 1H, J = 2. 4 Hz, J = 9. 4 Hz, Hindole) , 10. 94 (bs, 1H, NH), 13. 76 (bs, 1H, NH).
2.3: N-[2-(diethylamino) ethoxy]-5-[(Z)-(5-flu-oro-1,2- dihydro-2-oxo-3H-indole-3-ylidene) methyl]-2,4-dimethyl-lH-pyrrole-3-carbox-amide, (2S)-hydroxybutanedionate (1:1).
f""`C I-13 Q 0 ~-`"CH3 ~ /
H3Cr. 1JH
{y CH3 F =~~~ ~y H
Ci N
H 1.0 malate Mol.Wt.: 548.56 g/mol.
1H-NMR (measured with Bruker Avance 400 (400 MHz, dmso-d6r TMS as internal standard): b(ppm) =
1.12 (t, 6H, J = 7.1 Hz, Me), 2.34 (dd, 1H, J =
4. 0 Hz, J= 15. 6 Hz, CH2malic) r 2. 42 (S, 3H, M e ) , 2. 45 (s, 3H, M e ) , 2. 50 (m, 1H, CH2malic) i 2. 95 (bs, 4H, NCH2CH3), 3.08 (bs, 2H, NCH2CH2)1 3.95 (dd, 1H, J = 4. 6 Hz, J = 9.1 Hz CHmalic) r 4.09 (m, 2H, NCH2CH2), 6.85 (dd, 1H, J = 4.6 Hz, J = 8.5 Hz, Hindole) , 6.89 - 6. 98 (m, 1H, Hindole) r 7.73 (s, 1H, C=CH) , 7. 78 (dd, 1H, J = 2. 5 Hz, J 9.4 Hz, Hin-dole) i 10. 94 (bs, 1H, NH), 13.76 (bs, 1H, NH) .
2.2: N-[2-(diethylamino) ethoxy]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indole-3-ylidene) methyl]-2,4-dimethyl-lH-pyrrole-3-carboxamide, (2S)-hydroxybutanedionate (1:
0.5) .
>-C H3 /-N
1y "`
~ C H 3 N H
1~ t IN C Fi:3 F
H
0.5 malate N
H
Mol.Wt.: 481,52 g/mol.
Melting point: 203 C, decomposition (Electro-thermal IA 9200, heating rate 1 C/min).
1H-NMR (measured with Bruker Avance 400 (400 MHz, dmso-d6, TMS as internal standard): b(ppm) =
1.08 (t, 6H, J = 7.0 Hz, Me), 2.33 (dd, 0.5H, J=
4.0 Hz, J = 15. 6 Hz, CH2malic) , 2.41 (B, 3H, Me), 2. 44 (s, 3H, Me), 2.50 (m, 0. 5H, CH2malic) ~ 2- 84 (bs, 4H, NCH2CH3), 2.97 (bs, 2H, NCH2CH2), 3.90 (dd, 0.5H, J= 3. 9 Hz, J 10.0 Hz CHmalic) , 4.05 (m, 2H, J = 6.1 Hz, NC2CHZ) , 6.85 (dd, 1H, J = 4. 6 Hz, J = 8.4 Hz, Hindole) i 6.89 - 6. 98 (m, 1H, Hindole) 7= 73 (s, 1H, C=CH) , 7.78 (dd, 1H, J = 2. 4 Hz, J = 9. 4 Hz, Hindole) , 10. 94 (bs, 1H, NH), 13. 76 (bs, 1H, NH).
2.3: N-[2-(diethylamino) ethoxy]-5-[(Z)-(5-flu-oro-1,2- dihydro-2-oxo-3H-indole-3-ylidene) methyl]-2,4-dimethyl-lH-pyrrole-3-carbox-amide, (2S)-hydroxybutanedionate (1:1).
f""`C I-13 Q 0 ~-`"CH3 ~ /
H3Cr. 1JH
{y CH3 F =~~~ ~y H
Ci N
H 1.0 malate Mol.Wt.: 548.56 g/mol.
1H-NMR (measured with Bruker Avance 400 (400 MHz, dmso-d6r TMS as internal standard): b(ppm) =
1.12 (t, 6H, J = 7.1 Hz, Me), 2.34 (dd, 1H, J =
4. 0 Hz, J= 15. 6 Hz, CH2malic) r 2. 42 (S, 3H, M e ) , 2. 45 (s, 3H, M e ) , 2. 50 (m, 1H, CH2malic) i 2. 95 (bs, 4H, NCH2CH3), 3.08 (bs, 2H, NCH2CH2)1 3.95 (dd, 1H, J = 4. 6 Hz, J = 9.1 Hz CHmalic) r 4.09 (m, 2H, NCH2CH2), 6.85 (dd, 1H, J = 4.6 Hz, J = 8.5 Hz, Hindole) , 6.89 - 6. 98 (m, 1H, Hindole) r 7.73 (s, 1H, C=CH) , 7. 78 (dd, 1H, J = 2. 5 Hz, J 9.4 Hz, Hin-dole) i 10. 94 (bs, 1H, NH), 13.76 (bs, 1H, NH) .
13C-NMR (measured with Bruker Avance 400 (100.6 MHz, dmso-d6, TMS as internal standard):
b(ppm) = 9.92 (s, 2C, NCH2CH3), 10.47 (s, 1C, Me), 13.29 (s, 1C, Me), 35.40 (s, 1C, NCH2CH2), 41.05 (s, 1C), 46.62 (s, 2C, NCH2CH3), 49.87 (s, 1C, NCHZCH2) , 65. 94 (s, 1C, CHmalic) , 71.58 (d, 1C, NCH2CH2), 106.06 (d, 1C, J = 26.0 Hz, CH-indole) i 110.03 (d, 1C, J = 8.7 Hz, CH-indole) r 112.60 (d, 1C, J = 23. 9 Hz, CH-indole) - 115.30 (d, 1C, J= 3.1 Hz) , 112. 60 .(d, 1C, J = 23. 9 Hz, CH-indole) , 115.30 (d, 1C, J 3.1 Hz), 116.71 (s, 1C), 124.67 (s, 1C, C=CH), 125.94 (s, 1C), 126.90 (d, 1C, J = 9.5 Hz), 130.34 (s, 1C), 134.57 (d, 1C, J = 1.4 Hz), 136.76 (s, 1C), 158.15 (d, 1C, J = 234.3 Hz), 163.75 (s, 1C), 169.47 (d, 1C, J= 0.9 Hz), 171.82 (s, 1C, C0), 175.97 (s, 1C, C0).
3: Biological data.
3.1: Cell culture results.
The substances of Examples 2.1 to 2.3 were tested for different cell lines in presence and absence of pyruvate in the nutrient medium for their proliferation inhibiting effect. The sub-stances were each dissolved in DMSO. Then, the ac-tive substance was tested in eight concentration intervals. The calculation of the IC50 values was based in each concentration on eight individual values. The IC50 value is the substance concentra-tion, at which compared to the control group, which has been treated exclusively with the sol-vent DMSO, there was a 50 % inhibition of the cell proliferation.
The IC50 values for SO 272 were between 1 and 11 pM. The obtained values are shown in Table 1.
b(ppm) = 9.92 (s, 2C, NCH2CH3), 10.47 (s, 1C, Me), 13.29 (s, 1C, Me), 35.40 (s, 1C, NCH2CH2), 41.05 (s, 1C), 46.62 (s, 2C, NCH2CH3), 49.87 (s, 1C, NCHZCH2) , 65. 94 (s, 1C, CHmalic) , 71.58 (d, 1C, NCH2CH2), 106.06 (d, 1C, J = 26.0 Hz, CH-indole) i 110.03 (d, 1C, J = 8.7 Hz, CH-indole) r 112.60 (d, 1C, J = 23. 9 Hz, CH-indole) - 115.30 (d, 1C, J= 3.1 Hz) , 112. 60 .(d, 1C, J = 23. 9 Hz, CH-indole) , 115.30 (d, 1C, J 3.1 Hz), 116.71 (s, 1C), 124.67 (s, 1C, C=CH), 125.94 (s, 1C), 126.90 (d, 1C, J = 9.5 Hz), 130.34 (s, 1C), 134.57 (d, 1C, J = 1.4 Hz), 136.76 (s, 1C), 158.15 (d, 1C, J = 234.3 Hz), 163.75 (s, 1C), 169.47 (d, 1C, J= 0.9 Hz), 171.82 (s, 1C, C0), 175.97 (s, 1C, C0).
3: Biological data.
3.1: Cell culture results.
The substances of Examples 2.1 to 2.3 were tested for different cell lines in presence and absence of pyruvate in the nutrient medium for their proliferation inhibiting effect. The sub-stances were each dissolved in DMSO. Then, the ac-tive substance was tested in eight concentration intervals. The calculation of the IC50 values was based in each concentration on eight individual values. The IC50 value is the substance concentra-tion, at which compared to the control group, which has been treated exclusively with the sol-vent DMSO, there was a 50 % inhibition of the cell proliferation.
The IC50 values for SO 272 were between 1 and 11 pM. The obtained values are shown in Table 1.
Table 1 Cell line Substance IC50 (XTT) IC50 (XTT) (XXT) (from example) with pyruvate without pyruvate MCF-7 2.1 11 8 2.2 8 11 2.3 9 10 HT-29 2.1 3.5 2.2 3 2.3 3 BxPC-3 2.1 1.3 2 2.2 2 2 2.3 2 2 MDA-MB-453 2.1 11 7 2.2 8 7 2.2 8 7 NK1 2.1 2 2.2 4 2.3 4 Wi-38 2.1 11 KBV-600 2.1 5 MCF-7: human breast cancer cell line; MDA-MB-453: human breast cancer cell line; HT29: human colon carcinoma cell line; BxPC-3: human pancreas tumor cell line; KBV600: multidrug-resistant de-scendant of HeLa cells (KB-V1), cultivated with 600 ng/ml Vinblastine; Wi-38: human, fetal cell line similar to fibroblasts of the lung; NK: No-vikoff rat hepatoma cell line.
The substances inhibit several receptors of thyrosinkinases, which are important for the growth and angiogenesis of the tumors. The multi-thyrosinkinase inhibitor is preferably also suit-able e.g. for the second therapy of metastasized renal cell carcinomas (RCC) or metastasized gas-trointestinal stroma tumors (GIST). In all, the results show that by means of the substances ac-cording to the invention not only specific tumor types can be treated, but that very different tu-mor types can be subjected to a therapy.
3.2: Colony assays.
In a colony assay, tumor stem cells of differ-ent human tumor entities were cultivated in soft agar, and the generation of tumor colonies in presence and in absence of the substance according to the invention (Example 2.1, if applicable as a malate of Example 2.2 or 2.3) was counted. Alto-gether 25 different tumor models were tested.
Thereto belong colon, pancreas and stomach carci-nomas, small-cell and non-small-cell lung tumors, breast, ovary, and kidney carcinomas and melano-mas. The wide range of different tumor entities and the large number of models permit after the cell culture another test for the efficiency of the substance and give first hints, whether the substance has a selective effect on certain tumor entities.
The results are shown in Figure 1 (graphic analysis of the mean values for the substance based on the IC70 values). The bars represent the IC70 concentrations referred to the mean values of all IC70 data. For bars towards left, the IC70 value is lower than the mean value of all IC70 models, i.e. these models are more sensitive com-pared to the average of all models. Bars towards right mean higher IC70 values than the average of the models and thus a lower sensitivity.
Tumor models: CXF = colon carcinomas, GXF =
stomach carcinomas, LXFA = non-small-cell adeno-carcinomas of the lung, LXFE = squamous cell car-cinomas of the lung, FXFL = large-cell lung carci-nomas, LXFS = small-cell lung carcinomas, MAXF =
breast tumors, MEXF = melanomas, OVXF = ovary car-cinomas, PAXF = pancreas carc.inomas, and RXF =
kidney carcinomas.
It can be seen that the substance in the col-ony assay was tested with very good results. The substance led for all 25 models to a dose-depend-ent inhibition of the colony formation. The mean IC50 value was 15 M. The mean IC70 value was 20 M. The highest sensitivity had a non-small-cell lung tumor model with an IC50 value of 4 M and an IC70 value of 6 M. The highest IC50 value (30 M) or IC70 value (40 M), respectively, was detected for a breast tumor model.
These results, too, confirm again that the substance has a very good spectrum of effects.
There was not a single model, which was not inhib-ited. The cell culture results of Example 3.1 showed for the six tested tumor models a mean IC50 value of 6 M and comprised values between 1 and 11 M, so that the results in the colony assay were in the range of results of the cell culture tests of Example 3.1 and therefore confirmed these results.
In general, all colony assays showed that the substance is advantageous over the prior art, since it has a broad therapeutic potential. The broad spectrum of effects reflects that the sub-stance influences metabolic processes, which are common to all tumors, irrespective of the entity.
3.3: Comparison tests.
In a colony assay according to Example 3.2, for an ovary carcinoma (OVXF 550) the following values were measured for SU11248, 5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-di-methyl-lH-pyrrole-3-carboxylic acid (2-diethylami-noethyl) amide, known from literature (PCT WO 01/
60814 A2 and J. Med. Chem. 2003, 46, 1116-1119):
OVXF 550: IC50 = 18.0 M, IC70 = 26.7 M
In the same colony assay and under identical experimental conditions, the following values were found for the substance according to the invention (5-[5-fluoro-2-oxo-l,2-dihydro-indol-(3Z)-ylidene-methyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide (preferable the salt of the malic acid, malate):
OVXF 550: IC50 = 16.7 M, IC70 = 21.6 M
It can be seen that the values for the sub-stance according to the invention are better than those for the prior art substance.
It has an essential importance that these ad-vantages are caused by the (single) structural difference, which is the -NH-O- partial structure according to the invention. In addition, for sub-stances according to the invention less side ef-fects can be expected due to this partial struc-ture.
The substances inhibit several receptors of thyrosinkinases, which are important for the growth and angiogenesis of the tumors. The multi-thyrosinkinase inhibitor is preferably also suit-able e.g. for the second therapy of metastasized renal cell carcinomas (RCC) or metastasized gas-trointestinal stroma tumors (GIST). In all, the results show that by means of the substances ac-cording to the invention not only specific tumor types can be treated, but that very different tu-mor types can be subjected to a therapy.
3.2: Colony assays.
In a colony assay, tumor stem cells of differ-ent human tumor entities were cultivated in soft agar, and the generation of tumor colonies in presence and in absence of the substance according to the invention (Example 2.1, if applicable as a malate of Example 2.2 or 2.3) was counted. Alto-gether 25 different tumor models were tested.
Thereto belong colon, pancreas and stomach carci-nomas, small-cell and non-small-cell lung tumors, breast, ovary, and kidney carcinomas and melano-mas. The wide range of different tumor entities and the large number of models permit after the cell culture another test for the efficiency of the substance and give first hints, whether the substance has a selective effect on certain tumor entities.
The results are shown in Figure 1 (graphic analysis of the mean values for the substance based on the IC70 values). The bars represent the IC70 concentrations referred to the mean values of all IC70 data. For bars towards left, the IC70 value is lower than the mean value of all IC70 models, i.e. these models are more sensitive com-pared to the average of all models. Bars towards right mean higher IC70 values than the average of the models and thus a lower sensitivity.
Tumor models: CXF = colon carcinomas, GXF =
stomach carcinomas, LXFA = non-small-cell adeno-carcinomas of the lung, LXFE = squamous cell car-cinomas of the lung, FXFL = large-cell lung carci-nomas, LXFS = small-cell lung carcinomas, MAXF =
breast tumors, MEXF = melanomas, OVXF = ovary car-cinomas, PAXF = pancreas carc.inomas, and RXF =
kidney carcinomas.
It can be seen that the substance in the col-ony assay was tested with very good results. The substance led for all 25 models to a dose-depend-ent inhibition of the colony formation. The mean IC50 value was 15 M. The mean IC70 value was 20 M. The highest sensitivity had a non-small-cell lung tumor model with an IC50 value of 4 M and an IC70 value of 6 M. The highest IC50 value (30 M) or IC70 value (40 M), respectively, was detected for a breast tumor model.
These results, too, confirm again that the substance has a very good spectrum of effects.
There was not a single model, which was not inhib-ited. The cell culture results of Example 3.1 showed for the six tested tumor models a mean IC50 value of 6 M and comprised values between 1 and 11 M, so that the results in the colony assay were in the range of results of the cell culture tests of Example 3.1 and therefore confirmed these results.
In general, all colony assays showed that the substance is advantageous over the prior art, since it has a broad therapeutic potential. The broad spectrum of effects reflects that the sub-stance influences metabolic processes, which are common to all tumors, irrespective of the entity.
3.3: Comparison tests.
In a colony assay according to Example 3.2, for an ovary carcinoma (OVXF 550) the following values were measured for SU11248, 5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-di-methyl-lH-pyrrole-3-carboxylic acid (2-diethylami-noethyl) amide, known from literature (PCT WO 01/
60814 A2 and J. Med. Chem. 2003, 46, 1116-1119):
OVXF 550: IC50 = 18.0 M, IC70 = 26.7 M
In the same colony assay and under identical experimental conditions, the following values were found for the substance according to the invention (5-[5-fluoro-2-oxo-l,2-dihydro-indol-(3Z)-ylidene-methyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide (preferable the salt of the malic acid, malate):
OVXF 550: IC50 = 16.7 M, IC70 = 21.6 M
It can be seen that the values for the sub-stance according to the invention are better than those for the prior art substance.
It has an essential importance that these ad-vantages are caused by the (single) structural difference, which is the -NH-O- partial structure according to the invention. In addition, for sub-stances according to the invention less side ef-fects can be expected due to this partial struc-ture.
Claims (15)
1) A compound according to Formula I
wherein R1 to R4 may be identical or different and may be -H, -F, -Cl, -Br, -I or (C1-C8)oxyalkyl, wherein R5 and R6 may be identical or different and may be -H or C1-C4 alkyl, wherein X, Y and Z may be identical or different and denote either a binding or -O- or -S-, at least one of the groups X, Y and Z being -O- or -S-, wherein n may be 0 to 8, and wherein R7 may be an arbitrary radical, or a metabolite of such a compound and stereoisomers and physiologically well-toler-ated salts of such compounds or metabolites.
wherein R1 to R4 may be identical or different and may be -H, -F, -Cl, -Br, -I or (C1-C8)oxyalkyl, wherein R5 and R6 may be identical or different and may be -H or C1-C4 alkyl, wherein X, Y and Z may be identical or different and denote either a binding or -O- or -S-, at least one of the groups X, Y and Z being -O- or -S-, wherein n may be 0 to 8, and wherein R7 may be an arbitrary radical, or a metabolite of such a compound and stereoisomers and physiologically well-toler-ated salts of such compounds or metabolites.
2) The compound according to claim 1, wherein R1, R3 and R4 are -H, and wherein R2 is -F, -Cl, -Br, -I or (C1-C8)oxyalkyl.
3) The compound according to claim 1 or 2, wherein R5 and R6 are (C1-C3)alkyl, in particular methyl.
4) The compound according to one of claims 1 to 3, wherein X is a binding, and wherein Y and/or Z
is -O-.
is -O-.
5) The compound according to one of claims 1 to 4, wherein n is 1 or 2.
6) The compound according to one of claims 1 to 5, wherein R7 is an -NR8R9 group, in which R8 and R9 may be identical or different and may be -H, a (C1-C10) alkyl group or (C1-C6) oxyalkyl, a (C1-C10) alkyl group or, if applicable, a partially or com-pletely halogenated, in particular fluorinated (C1-C10) alkyl group, (C3-C7) cycloalkyl group, (C2-C10) alkenyl group, (C2-C10) alkinyl group, (C1-C8) alkyl-(C3-C7) cycloalkyl group, (C2-C8) al-kenyl-(C3-C7) cycloalkyl group, heterocyclyl group, (C1-C8) alkylheterocyclyl group, (C2-C8) al-kenylheterocyclyl group, aryl group, (C1-C8) al-kylaryl group, (C2-C8) alkenylaryl group, or (C2-C8) alkinylaryl group, or a, if applicable, mono-cyclic or bicyclic heteroaryl group substituted by 1-2 keto groups, 1-2 (C1-C5) alkyl groups, 1-2 (C1-C5) alkoxy groups, 1-3 halogen atoms, 1-2 exomethyl groups, and containing 1-3 nitrogen at-oms and/or 1-2 oxygen atoms and/or 1-2 sulfur at-oms, a (C1-C8) alkylheteroaryl group, or a (C2-C8) alkenylheteroaryl group, a (C2-C8) alkinylhet-eroaryl group, wherein these groups may be linked at an arbitrary position with R2 and, if applica-ble, may be hydrated at one or several positions.
7) The compound according to one of claims 1 to 6, wherein R7 is an -NR8R9 group, in which R8 and R9 may be identical or different and may be -H, methyl, ethyl, methoxy or ethoxy, or wherein R7 is pyrrolidine-1-yl, morpholine-4-yl, pyrridine-4-yl, 1-methyl-4-piperidyl, or triazole-1-yl, optionally substituted singly or multiply with (C1-C6) alkyl, -F, -Cl, -Br, -I, or (C1-C6) oxyalkyl.
8) The compound according to one of claims 1 to 7, namely 5-[2-oxo-1,2-dihydro-indole-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-di-ethylaminoethoxy)-amide, 5-[5-fluoro-2-oxo-1,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[5-bromo-2-oxo-1,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[5-chloro-2-oxo-1,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[6-fluoro-2-oxo-1,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[6-chloro-2-oxo-1,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[6-bromo-2-oxo-1,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[5-methyl-2-oxo-1,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[5-methoxy-2-oxo-1,2-dihydro-indole-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbox-ylic acid (2-diethylamino-ethoxy)-amide, 5-[6-methyl-2-oxo-1,2-dihydro-indole-(3Z)-ylidene-methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethoxy)-amide, 5-[6-methoxy-2-oxo-1,2-dihydro-indole-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbox-ylic acid (2-diethylamino-ethoxy)-amide, or derivatives of the above compounds, wherein the 2-diethylamino-ethoxy group is replaced by one of the groups selected from one of the groups "2-(triazole-1-yl) ethoxy, 2-triazole-1-yl) methoxy, (pyridine-4-yl) methoxy, 2-(pyridiny-4-yl) ethoxy, 2-(morpholine-4-yl) ethoxy, (morpholine-4-yl) methoxy, (1-methyl-4-piperidyl) methoxy, 2-(1-methyl-4-piperidyl) ethoxy, 2-(pyrrolidine-1-yl) ethoxy, (pyrrolidine-1-yl) methoxy, 2-(dimethyl-amino) ethoxy, (dimethylamino) methoxy and (di-methylamino) methoxy".
9) A pharmaceutical composition containing a physiologically effective dose of a compound ac-cording to one of claims 1 to 8 and optionally physiologically well tolerated auxiliary and/or carrier substances.
10) A pharmaceutical composition according to claim 9, additionally containing an active sub-stance being different from the compound, in par-ticular selected from the group consisting of "aldesleukin, amifostine, atrasentan, bevacizumab, bexaroten, bortezomib, capecitabine, carboplatin, chlorambucil, cisplatin, cladribine, cyclophos-phamid, cytamid, dacarbazin, docetaxel, drol-oxifene, edrecolomab, epothilone, erlotinib, etoposide, exemestane, flavopiridol, fludarabine, fuorouracil, formestane, fulvestrant, gefitinib, gemcitabine, idarubicin, irinotecan, ixabepilone, lonafarnib, miltefosine, mitomycin, neovastat, ox-aliplatin, pemetrexed, porfimer, rituximab, tega-fur, temozolomide, tipifarnib, topotecan, tri-metrexate, vorozole, vinblastine, and mixtures of two or more of such active substances".
11) The use of a compound according to one of claims 1 to 8, optionally in a mixture with an ac-tive substance or several active substances ac-cording to claim 10, for producing a pharmaceuti-cal composition for the prophylaxis or treatment of a proliferative or inflammatory disease.
12) The use according to claim 11, wherein the disease is selected from the group consisting of "cancer, such as lung cancer, leukemia, ovary can-cer, sarcoma, meningioma, intestine cancer, lymph node cancer, brain tumors, breast cancer, pancreas cancer, prostate cancer, skin cancer, chronic in-flammations, asthma, allergy, rhinitis, uveitis, urticaria, arthritis, osteoarthritis, chronic pol-yarthritis, rheumatoid arthritis, inflammatory bowl disease, degenerative joint diseases, dis-eases of the rheumatic form circle with cartilage breakdown, sepsis, autoimmune diseases, type I
diabetes, Hashimoto thyreoiditis, autoimmunethrom-bozytopenia, multiple sclerosis, myasthenia gra-vis, chronic inflammatory intestinal diseases, morbus Crohn, oveitis, psoriasis, atypical derma-titis, collagenoses, Goodpasture syndroma, dis-eases with disturbed leukocyte adhesion, cachexia, diseases by increased TNF-alpha concentration, diabetes, adipositas, bacterial infections, in particular with resistant bacteria, heart insuffi-ciency and the chronic cardiac failure (CCF)".
diabetes, Hashimoto thyreoiditis, autoimmunethrom-bozytopenia, multiple sclerosis, myasthenia gra-vis, chronic inflammatory intestinal diseases, morbus Crohn, oveitis, psoriasis, atypical derma-titis, collagenoses, Goodpasture syndroma, dis-eases with disturbed leukocyte adhesion, cachexia, diseases by increased TNF-alpha concentration, diabetes, adipositas, bacterial infections, in particular with resistant bacteria, heart insuffi-ciency and the chronic cardiac failure (CCF)".
13) The use according to one of claims 11 or 12, wherein a compound according to one of claims 1 to 8 is mixed in a physiologically effective dose with at least one carrier and/or auxiliary sub-stance and brought into a galenic form of admini-stration.
14) A method for the prophylaxis or treatment of a disease, which is accompanied by a proliferative or inflammatory disease, in particular from the group consisting of "cancer, such as lung cancer, leukemia, ovary cancer, sarcoma, meningioma, in-testine cancer, lymph node cancer, brain tumors, breast cancer, pancreas cancer, prostate cancer, skin cancer, chronic inflammations, asthma, al-lergy, rhinitis, uveitis, urticaria, arthritis, osteoarthritis, chronic polyarthritis, rheumatoid arthritis, inflammatory bowl disease, degenerative joint diseases, diseases of the rheumatic form circle with cartilage breakdown, sepsis, autoim-mune diseases, type I diabetes, Hashimoto thy-reoiditis, autoimmunethrombozytopenia, multiple sclerosis, myasthenia gravis, chronic inflammatory intestinal diseases, morbus Crohn, oveitis, pso-riasis, atypical dermatitis, collagenoses, Good-pasture syndroma, diseases with disturbed leuko-cyte adhesion, cachexia, diseases by increased TNF-alpha concentration, diabetes, adipositas, bacterial infections, in particular with resistant bacteria, heart insufficiency and the chronic car-diac failure (CCF)", wherein a person needing the prophylaxis or treatment is administered a physio-logically effective dose of a compound according to one of claims 1 to 8 or a pharmaceutical compo-sition according to claim 9 or 10.
15) The method for producing a compound according to one of claims 1 to 8, wherein a substance of Formula II
is reacted with a substance of Formula III
to a substance of Formula IV
wherein then the substance of Formula IV is re-acted with a substance of Formula V
to a compound of Formula VI
wherein the radicals R1 to R7 and the groups Y and Z have the meanings of claims 1 to 8.
is reacted with a substance of Formula III
to a substance of Formula IV
wherein then the substance of Formula IV is re-acted with a substance of Formula V
to a compound of Formula VI
wherein the radicals R1 to R7 and the groups Y and Z have the meanings of claims 1 to 8.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102006024834.1 | 2006-05-24 | ||
| DE102006024834A DE102006024834B4 (en) | 2006-05-24 | 2006-05-24 | New indole pyrrole derivatives and their uses |
| PCT/DE2007/000888 WO2007134578A1 (en) | 2006-05-24 | 2007-05-14 | Novel indol-pyrrol derivatives for the treatment of proliferative and inflammatory diseases |
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| CA2688206A1 true CA2688206A1 (en) | 2007-11-29 |
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| CA002688206A Abandoned CA2688206A1 (en) | 2006-05-24 | 2007-05-14 | Novel indol-pyrrol derivatives for the treatment of proliferative and inflammatory diseases |
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| Country | Link |
|---|---|
| EP (1) | EP2029580B1 (en) |
| JP (1) | JP2009537574A (en) |
| CN (1) | CN101495471A (en) |
| AT (1) | ATE471318T1 (en) |
| CA (1) | CA2688206A1 (en) |
| DE (2) | DE102006024834B4 (en) |
| WO (1) | WO2007134578A1 (en) |
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|---|---|---|---|---|
| WO2008033743A1 (en) | 2006-09-11 | 2008-03-20 | Curis, Inc. | Substituted 2-indolinone as ptk inhibitors containing a zinc binding moiety |
| DE102008021699A1 (en) | 2008-04-25 | 2009-10-29 | Schebo Biotech Ag | New pyrrolopyrimidine compounds are epidermal growth factor receptor tyrosine kinase inhibitors useful for preventing or treating proliferative or inflammatory disease, where the disease is e.g. cancer, asthma, allergy and psoriasis |
| DE102009019852A1 (en) | 2009-05-06 | 2010-11-11 | Schebo Biotech Ag | New polymer compound comprising amine structural elements, useful as synthetic resins, coatings, foams, liquid crystals, adhesives, paints, varnishes, composite materials, in cosmetics, and in polymer electronics |
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| EP1255752B1 (en) * | 2000-02-15 | 2007-08-08 | Sugen, Inc. | Pyrrole substituted 2-indolinone protein kinase inhibitors |
| AR042042A1 (en) * | 2002-11-15 | 2005-06-08 | Sugen Inc | COMBINED ADMINISTRATION OF AN INDOLINONE WITH A CHEMOTHERAPEUTIC AGENT FOR CELL PROLIFERATION DISORDERS |
| GT200500321A (en) * | 2004-11-09 | 2006-09-04 | COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF PROTEIN KINASE. |
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2006
- 2006-05-24 DE DE102006024834A patent/DE102006024834B4/en not_active Expired - Fee Related
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- 2007-05-14 AT AT07722436T patent/ATE471318T1/en active
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- 2007-05-14 CN CNA2007800279840A patent/CN101495471A/en active Pending
- 2007-05-14 WO PCT/DE2007/000888 patent/WO2007134578A1/en active Application Filing
- 2007-05-14 CA CA002688206A patent/CA2688206A1/en not_active Abandoned
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| EP2029580B1 (en) | 2010-06-16 |
| JP2009537574A (en) | 2009-10-29 |
| DE502007004142D1 (en) | 2010-07-29 |
| CN101495471A (en) | 2009-07-29 |
| WO2007134578A1 (en) | 2007-11-29 |
| DE102006024834B4 (en) | 2010-07-01 |
| DE102006024834A1 (en) | 2007-11-29 |
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