NO322614B1 - Indolyl-3-glycosyl acid derivatives having therapeutically valuable properties - Google Patents
Indolyl-3-glycosyl acid derivatives having therapeutically valuable properties Download PDFInfo
- Publication number
- NO322614B1 NO322614B1 NO20021367A NO20021367A NO322614B1 NO 322614 B1 NO322614 B1 NO 322614B1 NO 20021367 A NO20021367 A NO 20021367A NO 20021367 A NO20021367 A NO 20021367A NO 322614 B1 NO322614 B1 NO 322614B1
- Authority
- NO
- Norway
- Prior art keywords
- acid
- glyoxylamide
- indol
- pyridin
- fluorobenzyl
- Prior art date
Links
- 239000002253 acid Substances 0.000 title claims description 19
- 206010028980 Neoplasm Diseases 0.000 claims description 35
- -1 N-substituted indole-3-glyoxylamides Chemical class 0.000 claims description 30
- SOLIIYNRSAWTSQ-UHFFFAOYSA-N 2-[1-[(4-chlorophenyl)methyl]indol-3-yl]-2-oxo-n-pyridin-4-ylacetamide Chemical group C1=CC(Cl)=CC=C1CN1C2=CC=CC=C2C(C(=O)C(=O)NC=2C=CN=CC=2)=C1 SOLIIYNRSAWTSQ-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 206010027476 Metastases Diseases 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 239000004037 angiogenesis inhibitor Substances 0.000 claims description 12
- 229940121369 angiogenesis inhibitor Drugs 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 12
- 238000011161 development Methods 0.000 claims description 11
- 150000001204 N-oxides Chemical class 0.000 claims description 10
- 150000007524 organic acids Chemical class 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 9
- 239000002246 antineoplastic agent Substances 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 8
- 239000011707 mineral Substances 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 7
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims description 6
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- 235000005985 organic acids Nutrition 0.000 claims description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 238000001802 infusion Methods 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 201000009030 Carcinoma Diseases 0.000 claims description 3
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 239000006071 cream Substances 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
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- 239000004310 lactic acid Substances 0.000 claims description 3
- 235000014655 lactic acid Nutrition 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 239000011976 maleic acid Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 239000002674 ointment Substances 0.000 claims description 3
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 239000001384 succinic acid Substances 0.000 claims description 3
- 239000000829 suppository Substances 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 claims description 2
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 2
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 claims description 2
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 claims description 2
- 239000003708 ampul Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229940097043 glucuronic acid Drugs 0.000 claims description 2
- 231100000189 neurotoxic Toxicity 0.000 claims description 2
- 230000002887 neurotoxic effect Effects 0.000 claims description 2
- 238000011269 treatment regimen Methods 0.000 claims description 2
- PXZNKAFWRZAUAS-UHFFFAOYSA-N 2-[1-[(4-fluorophenyl)methyl]indol-3-yl]-2-oxo-n-pyridin-4-ylacetamide Chemical compound C1=CC(F)=CC=C1CN1C2=CC=CC=C2C(C(=O)C(=O)NC=2C=CN=CC=2)=C1 PXZNKAFWRZAUAS-UHFFFAOYSA-N 0.000 claims 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims 2
- KZLQSDSMMFVEEX-UHFFFAOYSA-N 2-(1-benzylindol-3-yl)-2-oxo-n-pyridin-4-ylacetamide Chemical group C=1N(CC=2C=CC=CC=2)C2=CC=CC=C2C=1C(=O)C(=O)NC1=CC=NC=C1 KZLQSDSMMFVEEX-UHFFFAOYSA-N 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- FUEPBJHYDRQTMG-UHFFFAOYSA-N n-(4-fluorophenyl)-2-oxo-2-[1-(pyridin-3-ylmethyl)indol-3-yl]acetamide Chemical group C1=CC(F)=CC=C1NC(=O)C(=O)C(C1=CC=CC=C11)=CN1CC1=CC=CN=C1 FUEPBJHYDRQTMG-UHFFFAOYSA-N 0.000 claims 1
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- 230000018109 developmental process Effects 0.000 description 9
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- 238000000338 in vitro Methods 0.000 description 4
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 4
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- AWMLDBKLOPNOAR-UHFFFAOYSA-N 2-(1h-indol-3-yl)-2-oxoacetamide Chemical compound C1=CC=C2C(C(=O)C(=O)N)=CNC2=C1 AWMLDBKLOPNOAR-UHFFFAOYSA-N 0.000 description 2
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- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
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- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
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- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Description
Oppfinnelsen vedrører den ytterligere fordelaktige utforming av den tyske indol-3-glyoksylamid patentsøknad 19814 838.0. The invention relates to the further advantageous design of the German indole-3-glyoxylamide patent application 19814 838.0.
I sammenheng med kjemoterapien ved tumorsykdommer resulterer de største problemer for det første ved opptreden av legemiddelresistens og for det andre ved de alvorlige bivirkninger av disse midler. In the context of chemotherapy for tumor diseases, the biggest problems result firstly from the appearance of drug resistance and secondly from the serious side effects of these agents.
Videre er det kjent at mange primærtumorer etter oppnåelse av en viss størrelse har tendens til for tidlig metastasedannelse over blod- og lymfebaner. Den fremskridende prosess med tumorinvasjon og dannelsen av metastaser er den hyppigste dødsårsak hos kreftpasienter. Furthermore, it is known that many primary tumors, after reaching a certain size, tend to metastasize prematurely via blood and lymphatic channels. The progressive process of tumor invasion and the formation of metastases is the most frequent cause of death in cancer patients.
For å forklare denne utbredelse, foreligger forskjellige utgangspunkter som blant annet forsterket angiogenese, forhøyet ekstracellulær matriksnedbygging, tumorcellemigrasjon og modulasjon av celleadhesjonen. Disse faktorer kan også sammenvirke, og er hittil bare delvis bare oppklart. To explain this prevalence, there are different starting points such as enhanced angiogenesis, elevated extracellular matrix degradation, tumor cell migration and modulation of cell adhesion. These factors can also interact, and have so far only been partially clarified.
Metastaseringen av en tumor er ofte fulgt av dårlige prognoser ved tumorbehandlingen. Forutsetningen for metastaseringen er løsningen av celler fra den primære tumor, vandringen av cellene til blodkarene, invasjonen i blodkarene og invasjonen av cellene fra blodkarene inn i andre vev. The metastasis of a tumor is often followed by poor prognoses in tumor treatment. The prerequisite for metastasis is the detachment of cells from the primary tumor, the migration of the cells to the blood vessels, the invasion of the blood vessels and the invasion of the cells from the blood vessels into other tissues.
Ved bestemte tumormidler som tamoksoifen er en hemmende virkning på migrasjonen og invasjonen av kreftceller kjent [J. Clin Endocrinol Metab 1995 jan; 80(1):308-13]. In the case of certain tumor agents such as tamoxifen, an inhibitory effect on the migration and invasion of cancer cells is known [J. Clin Endocrinol Metab 1995 Jan; 80(1):308-13].
Vedrørende hemming av tumorcelleinvasjonen ved verapamil, ble det rapportert Regarding the inhibition of tumor cell invasion by verapamil, it was reported
[Pigment Cell Res 1991 Dec; 4(5-6): 225-33.] [Pigment Cell Res 1991 Dec; 4(5-6): 225-33.]
Innvirkningen av melatonin på invasive og metastatiske egenskaper av MCF-7 humane brystkreftceller ble rapportert [Cancer res 1998 Oet 1; 58(19): 4383-90]. The impact of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells was reported [Cancer res 1998 Oet 1; 58(19): 4383-90].
I den offentliggjorte PCT-patentsøknad WO 96/2506 ble overvinnelse av legemiddelresistensen ved visse tumorfarmaka som følge av den ved slike tumormidler bevirkede genamplifikasjon av multilegemiddelresistensgenet ("Multi-Drug-Resistance Gens"(MDR-genet)) påvist. In the published PCT patent application WO 96/2506, overcoming the drug resistance of certain tumor drugs as a result of the gene amplification of the multi-drug resistance gene ("Multi-Drug-Resistance Genes" (MDR gene)) caused by such tumor agents was demonstrated.
Tumormidler som vinkristin og taksol fremviser videre en ikke uviktig nevrotoksisitet som ved kjemoterapien viser seg skadelig. Tumor agents such as vincristine and taxol also exhibit a not unimportant neurotoxicity, which proves harmful with chemotherapy.
Den oppgave som ligger til grunn for oppfinnelsen er nå å utvide anvendelsesområdet av N-substituerte indol-3-glyoksylamider og dermed å berike den disponible legemiddelressurs. The task underlying the invention is now to expand the application area of N-substituted indole-3-glyoxylamides and thus to enrich the available pharmaceutical resource.
Dermed skal det åpnes for muligheten av en lavere, lenger vedvarende og bedre tålbar medikasjon for den i den tyske patentsøknad 19814 838.0 beskrevne stoffklasse med antitumorvirkning. Særlig skal den skadelige resistensutvikling som er kjent fra mange antitumormidler omgås. This should open up the possibility of a lower, longer lasting and better tolerable medication for the substance class with antitumor effect described in the German patent application 19814 838.0. In particular, the harmful development of resistance that is known from many antitumor agents must be avoided.
Videre skal en utvikling og utbedring av tumorer ved metastase motvirkes. Furthermore, the development and improvement of tumors in the case of metastasis must be prevented.
De etter nyere erkjennelser for tumorveksten og utviklingen av metastaser åpenbart også angiogenesen er ansvarlig utgjør egenskapene med angiogenesehemming av et ytterligere fordelaktig legemiddelpotensiale for eksempel innen kreftterapien. Following recent findings, angiogenesis is obviously also responsible for tumor growth and the development of metastases, making the properties of angiogenesis inhibition a further beneficial drug potential, for example in cancer therapy.
Virkningsforsterkningen oppnådd med de N-substituerte indol-3-glyoksylamider skal mer effektivt utgjøre legemiddelforbruket innenfor tumorterapien. Ut over dette skulle det være mulig å forkorte behandlingsvarigheten og forlenge terapiresistente tilfeller. Videre skal residiver og metastaser begrenses henholdsvis hindres og dermed overlevelsestiden for pasientene i tillegg forhøyes. Det er et formål å utvikle medikamenter som kan inngripe i metastaseringsprosessen. The enhancement of effect obtained with the N-substituted indole-3-glyoxylamides should more effectively account for the drug consumption within the tumor therapy. In addition to this, it should be possible to shorten the duration of treatment and prolong therapy-resistant cases. Furthermore, relapses and metastases must be limited or prevented, and thus the survival time for the patients will also be increased. It is an aim to develop drugs that can intervene in the metastasis process.
Det ble overraskende funnet at de i den tyske patentsøknad 19814 838.0 beskrevne N-substituerte indol-3-glyoksylamider med den i det følgende angitte generelle formel 1, som er egnet for behandling av tumorsykdommer, har ytterligere for tumorbehandlingen slike fordelaktige egenskaper som kan utvide deres anvendelsesområde. It was surprisingly found that the N-substituted indole-3-glyoxylamides described in the German patent application 19814 838.0 with the following general formula 1, which are suitable for the treatment of tumor diseases, have additional for tumor treatment such advantageous properties which can extend their area of application.
Anvendelse av N-substituerte indol-3-glyoksylamider med formel la Use of N-substituted indole-3-glyoxylamides of formula la
idet restene har følgende betydning as the remainders have the following meaning
R= hydrogen, R= hydrogen,
Ri = 4-pyridyl, 4-fluorfenyl R 1 = 4-pyridyl, 4-fluorophenyl
R2 = benzyl, 4-klorbenzyl, 4-fluorbenzyl, 3-pyridylmetyl, 4-brombenzyl R2 = benzyl, 4-chlorobenzyl, 4-fluorobenzyl, 3-pyridylmethyl, 4-bromobenzyl
R3 og R4 = hydrogen, og R3 and R4 = hydrogen, and
Z betyr O Z stands for O
for fremstilling av et farmasøytisk preparat for behandling av tumormiddelresistente tumorer, metasteserende karsinom inkludert utvikling og spredning av metastaser, tumorer sensitive overfor angiogeneseinhibitorer eller tumorer som er både antitumormiddelresistente og sensitive overfor angiogeneseinhibitorer, for the production of a pharmaceutical preparation for the treatment of tumors resistant to tumor drugs, metastasizing carcinoma including the development and spread of metastases, tumors sensitive to angiogenesis inhibitors or tumors that are both resistant to antitumor drugs and sensitive to angiogenesis inhibitors,
der det farmasøytiske preparat medfører færre neurotoksiske bivirkninger for pasienten enn tidligere kjente behandlingsregimer. where the pharmaceutical preparation causes fewer neurotoxic side effects for the patient than previously known treatment regimens.
I en foretrukket utførelsesform angår oppfinnelsen anvendelse der de N-substituerte indol-3-glyoksylamider er i form av et syreaddisjonssalt av mineralsyrer og organiske syrer eller et N-oksid av disse, der mineralsyre eller den organiske syre er valgt fra gruppen bestående av saltsyre, svovelsyre, fosforsyre, salter av organiske syrer som for eksempel eddiksyre, melkesyre, malonsyre, maleinsyre, fumarsyre, glukonsyre, glukuronsyre, sitronsyre, embonsyre, metansulfonsyre, trifluoreddiksyre, ravsyre og 2-hydroksyetansulfonsyre. In a preferred embodiment, the invention concerns use where the N-substituted indole-3-glyoxylamides are in the form of an acid addition salt of mineral acids and organic acids or an N-oxide thereof, where the mineral acid or the organic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, salts of organic acids such as acetic acid, lactic acid, malonic acid, maleic acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, embonic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid and 2-hydroxyethanesulfonic acid.
I en annen foretrukken utførelsesform angår oppfinnelsen anvendelse der det N-substituerte indol-3-glyoksylamider er i form av et syreaddisjonssalt av mineralsyrer eller organiske syrer eller et N-oksid av disse, der mineralsyren eller den organiske syre er valgt fra gruppen bestående av saltsyre, svovelsyre, fosforsyre, eddiksyre, melkesyre, malonsyre, maleinsyre, fumarsyre, glukonsyre, glukoronsyre, sitronsyre, embonsyre, metansulfonsyre trifluoreddiksyre, ravsyre og 2-hydroksy etansulfonsyre sammen med et fysiologisk akseptabel eksipiens, fortynningsmiddel eller hjelpestoff, og preparatet er i form av en tablett, belagt tablett, kapsel, løsning for infusjon eller ampulle, stikkpille, plaster eller et pulverpreparat som kan administreres ved inhalasjon, suspensjon, krem eller salve. In another preferred embodiment, the invention concerns use where the N-substituted indole-3-glyoxylamides are in the form of an acid addition salt of mineral acids or organic acids or an N-oxide thereof, where the mineral acid or organic acid is selected from the group consisting of hydrochloric acid ) tablet, coated tablet, capsule, solution for infusion or ampoule, suppository, patch or a powder preparation that can be administered by inhalation, suspension, cream or ointment.
I en annen foretrukken utførelsesform angår oppfinnelsen behandling av metastaserende karsinom inkludert utvikling og spredning av metastaser, der N-substituerte indol-3-glykosylamidet er utvalgt fra gruppen bestående av; In another preferred embodiment, the invention relates to the treatment of metastatic carcinoma including the development and spread of metastases, where the N-substituted indole-3-glycosylamide is selected from the group consisting of;
N-(pyridin-4-yl)-[ 1 -(4-lfuorbenzyl)-indol-3-yl] glyoksylamid N-(pyridin-4-yl)-(l-benzylindol-3-yl)-glyoksylamid N-(pyridin-4-yl)-[ 1 -(4-fluorobenzyl)-indol-3-yl]glyoxylamide N-(pyridin-4-yl)-(1-benzylindol-3-yl)-glyoxylamide
N-(4-fluorfenyl)- [1 -(3-pyridylmetyl)-indol-3 -yl] -glyoksylamid N-(pyridin-4-yl)-[ 1 -(4-klorbenzyl)-indol-3 -yl] -glyoksylamid N-(pyridin-4-yl)-[l-(4-fluorbenzyl)-indol-3-yl] glyoksylamid HC1. N-(4-fluorophenyl)-[1-(3-pyridylmethyl)-indol-3-yl]-glyoxylamide N-(pyridin-4-yl)-[1-(4-chlorobenzyl)-indol-3-yl] -glyoxylamide N-(pyridin-4-yl)-[1-(4-fluorobenzyl)-indol-3-yl]glyoxylamide HCl.
eller et fysiologisk akseptabelt syreaddisjonssalt eller N-oksid av disse. or a physiologically acceptable acid addition salt or N-oxide thereof.
I en annen foretrukken utførelsesform angår oppfinnelsen behandling av antitumormiddelresistente tumorer, tumorer sensitive overfor angiogeneseinhibitorer eller tumorer som er både antitumormiddelresistente og sensitive overfor angiogeneinhibitorer, der det N-substituerte indol-3-glyoksyamidet er utvalgt fra gruppen bestående av In another preferred embodiment, the invention relates to the treatment of antitumor drug-resistant tumors, tumors sensitive to angiogenesis inhibitors or tumors that are both antitumor drug resistant and sensitive to angiogenesis inhibitors, where the N-substituted indole-3-glyoxyamide is selected from the group consisting of
N-(pyridin-4-yl)-[ 1 -(4-fluorbenzyl)-indol-3-yl] glyoksylamid N-(pyridin-4-yl)-(l-benzylindol-3-yl)-glyoksylamid N-(pyridin-4-yl)-[ 1 -(4-fluorobenzyl)-indol-3-yl]glyoxylamide N-(pyridin-4-yl)-(1-benzylindol-3-yl)-glyoxylamide
N-(4-fluorfenyl)-[ 1 -(3-pyridylmetyl)-indol-3-yl]-glyoksylamid N-(pyridin-4-yl)- [ 1 -(4-klorbenzyl)-indol-3 -yl] -glyoksylamid N-(pyridin-4-yl)-[l-(4-fluorbenzyl)-indol-3-yl] glyoksylamid HC1, N-(4-fluorophenyl)-[ 1 -(3-pyridylmethyl)-indol-3-yl]-glyoxylamide N-(pyridin-4-yl)- [ 1 -(4-chlorobenzyl)-indol-3-yl] -glyoxylamide N-(pyridin-4-yl)-[1-(4-fluorobenzyl)-indol-3-yl]glyoxylamide HCl,
eller et fysiologisk akseptabelt salt eller N-oksid av disse. or a physiologically acceptable salt or N-oxide thereof.
I en annen foretrukken utførelsesform angår oppfinnelsen behandling av tumor som er sensitiv overfor angiogeneseinhibitorer, der det N-subsituterte indol-3-glyoksylamidforbindelsen er valgt fra gruppen bestående av In another preferred embodiment, the invention relates to the treatment of tumors that are sensitive to angiogenesis inhibitors, where the N-substituted indole-3-glyoxylamide compound is selected from the group consisting of
N-(pyridin-4-yl)-[l-(4-fluorbenzyl)-indol-3-yl] glyoksylamid N-(pyridin-4-yl)-( 1 -benzylindol-3-yl)-glyoksylamid N-(pyridin-4-yl)-[1-(4-fluorobenzyl)-indol-3-yl]glyoxylamide N-(pyridin-4-yl)-(1-benzylindol-3-yl)-glyoxylamide
N-(4-fluorfenyl)-[ 1 -(3-pyridylmetyl)-indol-3-yl]-glyoksylamid N-(pyridin-4-yl)-[ 1 -(4-klorbenzyl)-indol-3-yl]-glyoksylamid N-(pyridin-4-yl)-[l-(4-fluorbenzyl)-indol-3-yl] glyoksylamid HC1, N-(4-fluorophenyl)-[ 1 -(3-pyridylmethyl)-indol-3-yl]-glyoxylamide N-(pyridin-4-yl)-[ 1 -(4-chlorobenzyl)-indol-3-yl] -glyoxylamide N-(pyridin-4-yl)-[1-(4-fluorobenzyl)-indol-3-yl]glyoxylamide HCl,
eller et fysiologisk akseptabelt syreaddisjonssalt eller N-oksid av disse. or a physiologically acceptable acid addition salt or N-oxide thereof.
Både forbindelsene med formel la så vel som også deres salter er biologisk aktive. Forbindelsene med formel la kan tilføres i fri form eller som salter med fysiologisk tålbare syrer. Both the compounds of formula Ia as well as their salts are biologically active. The compounds of formula Ia can be supplied in free form or as salts with physiologically tolerable acids.
Tilførselen kan foretas peroralt, parenteralt, intravenøst, transdermalt eller inhalativt. It can be administered orally, parenterally, intravenously, transdermally or by inhalation.
Som tilførselsformer egner seg for eksempel tabletter, drageer, kapsler, løsninger for infusjon eller ampuller, stikkpiller, plastre, inhalativt anvendbare pulverpreparater, suspensjoner, kremer og salver. Suitable administration forms are, for example, tablets, dragees, capsules, solutions for infusion or ampoules, suppositories, plasters, inhalative powder preparations, suspensions, creams and ointments.
Fremstillingsmetoden for substansene kan tas ut fra eksemplene i det tyske patentskrift DE 196 36 150 Al. The production method for the substances can be taken from the examples in the German patent document DE 196 36 150 Al.
De fundne terapeutisk verdifulle egenskaper vedrører detaljert de følgende fordeler. The therapeutically valuable properties found relate in detail to the following benefits.
- Det ble ikke påvist noen resistensutvikling - No development of resistance was detected
- Det ble påvist parametere som er karakteristiske for hemming av metastasedannelse (migrasjon) - Det ble funnet parametere som bekrefter hemming av karnydannelse - Parameters characteristic of inhibition of metastasis formation (migration) were detected - Parameters were found that confirm inhibition of carny formation
(angiogenese) (angiogenesis)
- I forskjellige modeller kunne det med de N-substituerte indol-3-glyoksylamider ifølge krav 1 med den generelle formel lai motsetning til de fleste antitumorpreparater ikke finnes noen neurotoksisitet. - In different models, with the N-substituted indole-3-glyoxylamides according to claim 1 with the general formula la, in contrast to most antitumor preparations, no neurotoxicity could be found.
Den ikke forekommende resistensutvikling ble bevist ved hjelp av de etterfølgende farmakologiske modeller henholdsvis cellekulturer: 1. Den cytotoksiske aktivitet av forbindelse av N-(pyridin-4-yl)-[ 1 -(4-klorbenzyl)-indol-3-yl]-glyoksylamid, også betegnet D-24851 på den multilegemiddelresistente ("multidrug resistente" MDR) leukemicellelinje fra mus L 1210/VCR ble ikke påvirket in vivo og in vitro. Se figur 1,2 og 3. The non-occurring development of resistance was proven by means of the following pharmacological models and cell cultures respectively: 1. The cytotoxic activity of the compound of N-(pyridin-4-yl)-[1-(4-chlorobenzyl)-indol-3-yl]- glyoxylamide, also designated D-24851 on the multidrug resistant ("multidrug resistant" MDR) mouse leukemia cell line L 1210/VCR was unaffected in vivo and in vitro. See figures 1, 2 and 3.
Forbindelse N-(pyridin-4-yl)-[l-(4-klorbenzyl)-indol-3-yl]-glyoksylamid (D-24851) har en uendret cytotoksisk aktivitet mot den multilegemiddelresistente MDR museleukemicelle-sublinje L1210/VCR i motsetning til taksol, doksirubicin, vinkristin eller epotolon B. Compound N-(pyridin-4-yl)-[l-(4-chlorobenzyl)-indol-3-yl]-glyoxylamide (D-24851) has an unchanged cytotoxic activity against the multidrug-resistant MDR murine leukemia cell subline L1210/VCR in contrast to taxol, doxirubicin, vincristine or epotolone B.
Forsøksgj ermomføring: Experimental conversion:
Museleukemicellelinjen L 1210 ble adaptert på vinkristin. De ikke-adapterte (L1210) og de adapterte (L1210/VCR) celler ble utsatt for cytostatiske midler og celleveksten, bestemt ved den metaboliske aktivitet, ble bestemt (XTT testen). The mouse leukemia cell line L 1210 was adapted to vincristine. The non-adapted (L1210) and the adapted (L1210/VCR) cells were exposed to cytostatic agents and the cell growth, determined by the metabolic activity, was determined (XTT test).
Kurvene som forbinder XTT datapunktene ble beregnet under anvendelse av et ikke-lineært regresjonsprogram. The curves connecting the XTT data points were calculated using a non-linear regression program.
Disse forsøksresultater bekreftes in vitro også ved den humane resistente LT12/MDR cellelinje, se figur 4. 2. Påvisningen av en manglende metastasedannelse ble oppnådd ved migrasjonshemming av M04 celler. Se figur 5. D-24851 hemmer doseavhengig migrasjonen av M04 celler. Ut fra dette lar seg for D-24851 avlede en antiinvasiv og en antimetastatisk virkning. These experimental results are also confirmed in vitro with the human resistant LT12/MDR cell line, see figure 4. 2. The demonstration of a lack of metastasis formation was achieved by migration inhibition of M04 cells. See Figure 5. D-24851 dose-dependently inhibits the migration of M04 cells. Based on this, an anti-invasive and an anti-metastatic effect can be derived for D-24851.
In vitro kan migrasjonsevnen av M04 celler måles ved at cellene inokkuleres i midten av en cellekulturskål og vandringen bestemmes ved hjelp av radius henholdsvis den avdekkede flate av cellene etter forskjellige dager med og uten D-24851. Figur 4 viser at migrasjonen av cellene avtar med stigende D-24851 konsentrasjon. In vitro, the migration ability of M04 cells can be measured by inoculating the cells in the middle of a cell culture dish and the migration is determined using the radius or the uncovered surface of the cells after different days with and without D-24851. Figure 4 shows that the migration of the cells decreases with increasing D-24851 concentration.
For å teste om også D-24851 virker antiinvasivt, ble invasjonen av M04 fibrosarkomceller i hønsehjerte undersøkt. Også her viste det seg at ved konsentrasjon på 260 og 1000 nM hemmes invasjonen fullstendig, mens ved mindre konsentrasjoner tiltar invasjonsevnen av M04 celler. På grunn av disse funn viste det seg at D-24851 både hemmer migrasjonen så vel som også invasjonen av tumorceller og derved har et sterkt antimetastatisk potensiale. 3. Fra sammenligningsforsøk med forbindelsen ifølge oppfinnelsen D-24851 med vinkristin og taksol med rotter hvorved ataksi, traksjon og reaksjon ble bedømt (figur 6) fremgår at denne forbindelse i motsetning til taksol og vinkristin ikke har noen nevrotoksisk virkning. D-24851 har videre i sammenligning med toksol og vinkristin ingen negativ innvirkning på nerveledningshastigheten (se figur 7). To test whether D-24851 also acts anti-invasively, the invasion of M04 fibrosarcoma cells in chicken hearts was investigated. Here, too, it turned out that at concentrations of 260 and 1000 nM the invasion is completely inhibited, while at lower concentrations the invasion ability of M04 cells increases. Due to these findings, it turned out that D-24851 both inhibits the migration as well as the invasion of tumor cells and thereby has a strong antimetastatic potential. 3. From comparison experiments with the compound according to the invention D-24851 with vincristine and taxol with rats in which ataxia, traction and reaction were assessed (figure 6) it appears that this compound, in contrast to taxol and vincristine, has no neurotoxic effect. D-24851 also has no negative effect on nerve conduction velocity in comparison with toxol and vincristine (see Figure 7).
Dette bekrefter at D-24851 på grunn av den manglende nevrotoksisitet forføyer over tydelig mindre bivirkninger enn andre kjemoterapeutika. 4. Fra ytterligere undersøkelser ifølge figurene 8 og 9 sees det at forbindelsen D-24851 har et potensiale som angiogenesehemmer. This confirms that D-24851, due to its lack of neurotoxicity, has significantly fewer side effects than other chemotherapeutics. 4. From further investigations according to figures 8 and 9, it can be seen that the compound D-24851 has a potential as an angiogenesis inhibitor.
Angiogenesehemmere er som følge av den fysiologiske sammenheng til tumorvekst samtidig også midler til hemming av tumorveksten, idet dannelsen av nye blodkar som skal ernære tumoren, hemmes. D-24851 fremkaller in vitro i en antiangiogenesemodell på endoteliumceller en fullstendig hemming av kardannelsen som ikke beror på en cytotoksisk effekt. As a result of the physiological connection to tumor growth, angiogenesis inhibitors are also agents for inhibiting tumor growth, as the formation of new blood vessels that will nourish the tumor is inhibited. D-24851 induces in vitro in an antiangiogenesis model on endothelial cells a complete inhibition of vessel formation which is not due to a cytotoxic effect.
I figur 8 sees det at D-24851 nærmest fullstendig oppløser bestående celle-cellekontakter med 0,1 uMol/L D24851 (se vitalfarging). Normalt holder cellene i det minste delvis kontakt. Cellemigrasjonen er tydelig redusert idet mange celler er avrundet. In Figure 8, it can be seen that D-24851 almost completely dissolves existing cell-cell contacts with 0.1 uMol/L D24851 (see vital staining). Normally, the cells maintain at least partial contact. Cell migration is clearly reduced as many cells are rounded.
Letalfargingen i monolag foran angiogeneseinduksjon viste med D-24851 ingen forhøyet cellemortalitet. Også i de første 22 timer etter induksjon var i sammenligning til kontroller ennå ingen forhøyet cellemortalitet påvisbar (se letalfarging i figur 9, hvite punkter). The lethal staining in monolayers before angiogenesis induction showed no increased cell mortality with D-24851. Also in the first 22 hours after induction, in comparison to controls, no elevated cell mortality was yet detectable (see lethal staining in figure 9, white points).
Cellene stammet fra human navlsnorvene (arteriell funksjon). De ble anvendt i tredje og fjerde passasje for undersøkelse. Angiogenesen ble utløst ved en naturlig stimulus. Primære utløsere av den endoteliale migrasjon er et protein som forsterket uttrykkes i vaskulariserende vev. Substansene ble tilsatt til dyrkingsmediet kort før angiogeneseinduksjon. The cells were derived from human umbilical nerves (arterial function). They were used in the third and fourth passages for examination. The angiogenesis was triggered by a natural stimulus. Primary triggers of the endothelial migration is a protein that is strongly expressed in vascularizing tissue. The substances were added to the culture medium shortly before angiogenesis induction.
Konsentrasjonen for den antiangiogenetiske virkning av D-24851 ligger tydelig under konsentrasjonen for den cytotoksiske aktivitet. Det er derved mulig å skille de to virkningskvaliteter (cytotoksisk aktivitet og antiangiogenetisk virkning) fra hverandre. The concentration for the antiangiogenic effect of D-24851 is clearly below the concentration for the cytotoxic activity. It is thereby possible to separate the two qualities of action (cytotoxic activity and antiangiogenic action).
Uten å ville begrense omfanget av oppfinnelsen ved den følgende angivelse er å si at orale daglige doseringer fra omtrent 20 mg til 500 mg er mulig. Without wanting to limit the scope of the invention by the following statement it is to say that oral daily dosages from about 20 mg to 500 mg are possible.
Ved intravenøs tilførsel som injeksjon eller som infusjon, kan alt etter kroppsvekt av pasienten og individuell tålbarhet tilføres opp til 250 mg/dag eller mer. For intravenous administration as an injection or as an infusion, depending on the patient's body weight and individual tolerance, up to 250 mg/day or more can be administered.
Som følge av manglende resistensutvikling og undertrykkelse av metastasering, er en høy effektivitet og en bred anvendelse av midlene også ved tumorrefraktære pasienter å vente. As a result of the lack of development of resistance and the suppression of metastasis, a high efficiency and a wide application of the agents also in tumor-refractory patients is to be expected.
Angiogenesevirkningen er i tillegg egnet for å undertrykke utbredningen av tumoren. The angiogenesis effect is also suitable for suppressing the spread of the tumor.
En ytterligere gjenstand for oppfinnelsen er også den bundne eller fri i kombinasjon av de N-substituerte indol-3-glyoksylamider ifølge krav 1 med den generelle formel la med i og for seg kjente antitumormidler, så vel som erstatningen av antitumormidler som er blitt uvirksomme som følge av resistensutvikling med N-substituerte indol-3-glyoksylamider ifølge krav 1 med den generelle formel la. A further object of the invention is also the bound or free in combination of the N-substituted indole-3-glyoxylamides according to claim 1 with the general formula la with per se known antitumor agents, as well as the replacement of antitumor agents that have become ineffective as result of resistance development with N-substituted indole-3-glyoxylamides according to claim 1 with the general formula la.
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| DE19946301A DE19946301A1 (en) | 1998-04-02 | 1999-09-28 | Antitumor agents and angiogenesis inhibitors having low neurotoxicity, comprise indole-3-glyoxylamide derivatives, are effective against resistant and metastasis-forming carcinomas |
| PCT/EP2000/009390 WO2001022954A2 (en) | 1999-09-28 | 2000-09-26 | Indolyl-3-glyoxylic acid derivatives serving as antitumor agents |
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| EP1289952A1 (en) | 2000-05-31 | 2003-03-12 | AstraZeneca AB | Indole derivatives with vascular damaging activity |
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| US20050124623A1 (en) | 2003-11-26 | 2005-06-09 | Bender John A. | Diazaindole-dicarbonyl-piperazinyl antiviral agents |
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