CA2386069A1 - Indolyl-3-glyoxylic acid derivatives as antitumor agents - Google Patents
Indolyl-3-glyoxylic acid derivatives as antitumor agents Download PDFInfo
- Publication number
- CA2386069A1 CA2386069A1 CA002386069A CA2386069A CA2386069A1 CA 2386069 A1 CA2386069 A1 CA 2386069A1 CA 002386069 A CA002386069 A CA 002386069A CA 2386069 A CA2386069 A CA 2386069A CA 2386069 A1 CA2386069 A1 CA 2386069A1
- Authority
- CA
- Canada
- Prior art keywords
- group
- groups
- indol
- glyoxylamide
- pyridin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 239000002246 antineoplastic agent Substances 0.000 title claims 13
- -1 N-substituted indol-3- glyoxylamides Chemical class 0.000 claims abstract 16
- 150000001875 compounds Chemical class 0.000 claims abstract 14
- 239000004037 angiogenesis inhibitor Substances 0.000 claims abstract 12
- 229940121369 angiogenesis inhibitor Drugs 0.000 claims abstract 12
- 206010029350 Neurotoxicity Diseases 0.000 claims abstract 11
- 206010044221 Toxic encephalopathy Diseases 0.000 claims abstract 11
- 230000000694 effects Effects 0.000 claims abstract 11
- 230000007135 neurotoxicity Effects 0.000 claims abstract 11
- 231100000228 neurotoxicity Toxicity 0.000 claims abstract 11
- 206010028980 Neoplasm Diseases 0.000 claims abstract 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 13
- 239000002253 acid Substances 0.000 claims 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 12
- 150000003839 salts Chemical class 0.000 claims 11
- 201000009030 Carcinoma Diseases 0.000 claims 10
- 229910052736 halogen Inorganic materials 0.000 claims 10
- 150000002367 halogens Chemical group 0.000 claims 10
- 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 9
- 229910052739 hydrogen Inorganic materials 0.000 claims 7
- 239000001257 hydrogen Substances 0.000 claims 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 7
- SOLIIYNRSAWTSQ-UHFFFAOYSA-N 2-[1-[(4-chlorophenyl)methyl]indol-3-yl]-2-oxo-n-pyridin-4-ylacetamide Chemical compound C1=CC(Cl)=CC=C1CN1C2=CC=CC=C2C(C(=O)C(=O)NC=2C=CN=CC=2)=C1 SOLIIYNRSAWTSQ-UHFFFAOYSA-N 0.000 claims 6
- 150000001204 N-oxides Chemical class 0.000 claims 6
- AMANDCZTVNQSNB-UHFFFAOYSA-N glyoxamide Chemical compound NC(=O)C=O AMANDCZTVNQSNB-UHFFFAOYSA-N 0.000 claims 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 5
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 5
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims 5
- KZLQSDSMMFVEEX-UHFFFAOYSA-N 2-(1-benzylindol-3-yl)-2-oxo-n-pyridin-4-ylacetamide Chemical compound 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 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 4
- 125000003277 amino group Chemical group 0.000 claims 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 4
- FUEPBJHYDRQTMG-UHFFFAOYSA-N n-(4-fluorophenyl)-2-oxo-2-[1-(pyridin-3-ylmethyl)indol-3-yl]acetamide Chemical compound C1=CC(F)=CC=C1NC(=O)C(=O)C(C1=CC=CC=C11)=CN1CC1=CC=CN=C1 FUEPBJHYDRQTMG-UHFFFAOYSA-N 0.000 claims 4
- 125000006624 (C1-C6) alkoxycarbonylamino group Chemical group 0.000 claims 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical class OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims 3
- 150000007513 acids Chemical class 0.000 claims 3
- 125000000217 alkyl group Chemical group 0.000 claims 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical class OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 2
- 150000001413 amino acids Chemical class 0.000 claims 2
- 230000015572 biosynthetic process Effects 0.000 claims 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims 2
- 229910052760 oxygen Inorganic materials 0.000 claims 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 2
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical class OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Chemical class OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 125000005862 (C1-C6)alkanoyl group Chemical group 0.000 claims 1
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical group C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 claims 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 claims 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims 1
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Chemical class OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Chemical class O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical class O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 claims 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 1
- 125000006294 amino alkylene group Chemical group 0.000 claims 1
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims 1
- 239000002775 capsule Substances 0.000 claims 1
- 239000006071 cream Substances 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 239000001530 fumaric acid Chemical class 0.000 claims 1
- 239000000174 gluconic acid Chemical class 0.000 claims 1
- 235000012208 gluconic acid Nutrition 0.000 claims 1
- 229940097043 glucuronic acid Drugs 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 238000001802 infusion Methods 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- 239000004310 lactic acid Chemical class 0.000 claims 1
- 235000014655 lactic acid Nutrition 0.000 claims 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical class OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims 1
- 239000011976 maleic acid Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229940098779 methanesulfonic acid Drugs 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 239000002674 ointment Substances 0.000 claims 1
- 150000007524 organic acids Chemical class 0.000 claims 1
- 235000005985 organic acids Nutrition 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical class 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 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims 1
- 125000004193 piperazinyl group Chemical group 0.000 claims 1
- 239000000843 powder Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- 125000005493 quinolyl group Chemical group 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 239000001384 succinic acid Chemical class 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 239000000829 suppository Substances 0.000 claims 1
- 239000000725 suspension Substances 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 206010059866 Drug resistance Diseases 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 208000011645 metastatic carcinoma Diseases 0.000 abstract 1
- 206010061289 metastatic neoplasm Diseases 0.000 abstract 1
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
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Indole Compounds (AREA)
Abstract
The invention relates to the use of N-substituted indol-3- glyoxylamides of general formula (I) for treating tumors, in particular, in cases of drug resistance and metastatic carcinoma, and as angiogenesis inhibitors having distinctly fewer side effects, in particular, distinctly lower neurotoxicity . The invention also relates to medicaments containing the inventive compounds .
Claims (13)
1. Use of N-substituted indol-3-gloxylamides [sic]
of the general formula 1 as antitumor agents according to main patent application 19 814 838.0 for tumor treatment in particular in the case of pharmaceutical resistance and metastasizing carcinoma, and as angiogenesis inhibitors, with markedly lower side effects in particular markedly lower neurotoxicity where the radicals R, R1, R2, R3, R4 and Z have the following meaning:
R = hydrogen, (C1-C6)-alkyl, where the alkyl group can be mono- or polysubstituted by the phenyl ring and this phenyl ring, for its part, can be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with C1-C6-alkanols, trifluoro-methyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, and by a benzyl group which is mono- or polysubstituted in the phenyl moiety by (C1-C6) -alkyl groups, halogen atoms or trifluoromethyl groups, R is furthermore the benzyloxycarbonyl group (Z group) or the tertiary butoxycarbonyl radical (Boc radical), furthermore the acetyl group.
R1 can be the phenyl ring which is mono- or poly-substituted by (C1-C6) -alkyl, (C1-C6) -alkoxy, cyano, halogen, trifluoromethyl, hydroxyl, benzyloxy, nitro, amino, (C1-C6)-alkylamino, (C1-C6)-alkoxycarbonylamino and by the carboxyl group or by the carboxyl group esterified with C1-C6-alkanols, or is a pyridine structure of the formula 2 and its N-oxide [sic]
and its N-oxide, where the pyridine structure is alternatively bonded to the ring carbon atoms 2, 3 and 4 and can be substituted by the substituents R5 and R6. The radicals R5 and R6 can be identical or different and have the meaning (C1-C6)-alkyl, and the meaning (C3-C7) -cycloalkyl, (C1-C6) -alkoxy, nitro, amino, hydroxyl, halogen and trifluoro-methyl and are furthermore the ethoxycarbonylamino radical and the group carboxyalkyloxy in which the alkyl group can have 1-4 C atoms.
R1 can furthermore be a 2- or 4-pyrimidinyl heterocycle, where the 2-pyrimidinyl ring can be mono- or polysubstituted by the methyl group, furthermore the 2-, 3-, 4- and 8-quinolyl structure substituted by (C1-C6)-alkyl, halogen, the nitro group, the amino group and the (C1-C6) -alkyl amino radical, a 2-, 3- or 4-quinolylmethyl group, where the ring carbons of the pyridylmethyl radical of the quinolyl group and of the quinolylmethyl radical can be substituted by (C1-C6) -alkyl, (C1-C6) -alkoxy, nitro, amino and (C1-C6)-alkoxycarbonylamino.
R1 can furthermore be, in the case where R = hydrogen, the methyl or benzyl group and the benzyloxycarbonyl radical (Z radical), the tert-butoxycarbonyl radical (BOC radical) and the acetyl group, the following radicals:
-CH2COOH; -CH(CH3) -COOH ; - (CH3) 2-CH- (CH2)2-CH-COO;
H3C-H2C-CH (CH3) -CH (COOH)-; HO-H2C-CH (COOH) -;
phenyl-CH2-CH(COOH)-; (4-imidazolyl)-CH2-CH-COOH)-;
HN=C (NH2) -NH- (CH2)3 -CH(COOH)-; H2N- (CH2)4 -CH(COOH)-;
H2N-CO-CH2-CH- (COOH)-; HOOC(CH2)2-CH(COOH)-;
R1 can furthermore be, in the case where R is hydrogen, the Z group, the BOC radical, the acetyl or the benzyl group, the acid radical of a natural or unnatural amino acid, e.g. the .alpha.-glycyl, the .alpha.-sarcosyl, the .alpha.-alanyl, the .alpha.-leucyl, the .alpha.-isoleucyl, the .alpha.-seryl, the .alpha.-phenylalanyl, the .alpha.-histidyl, the .alpha.-prolyl, the .alpha.-arginyl, the .alpha.-lysyl, the .alpha.-asparagyl and the .alpha.-glutamyl radicals, where the amino groups of the respective amino acids can be present in unprotected or protected form. Possible protective groups for the amino function are the carbobenzoxy radical (Z radical) and the tert-butoxycarbonyl radical (BOC radical) as well as the acetyl group. In the case of the asparagyl and glutamyl radical claimed for R1, the second, unbonded carboxyl group is present as a free carboxyl group or in the form of an ester with C1-C6-alkanols, e.g. as a methyl, ethyl or as a tert-butyl ester.
R1 can furthermore be the allylaminocarbonyl-
of the general formula 1 as antitumor agents according to main patent application 19 814 838.0 for tumor treatment in particular in the case of pharmaceutical resistance and metastasizing carcinoma, and as angiogenesis inhibitors, with markedly lower side effects in particular markedly lower neurotoxicity where the radicals R, R1, R2, R3, R4 and Z have the following meaning:
R = hydrogen, (C1-C6)-alkyl, where the alkyl group can be mono- or polysubstituted by the phenyl ring and this phenyl ring, for its part, can be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with C1-C6-alkanols, trifluoro-methyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups, and by a benzyl group which is mono- or polysubstituted in the phenyl moiety by (C1-C6) -alkyl groups, halogen atoms or trifluoromethyl groups, R is furthermore the benzyloxycarbonyl group (Z group) or the tertiary butoxycarbonyl radical (Boc radical), furthermore the acetyl group.
R1 can be the phenyl ring which is mono- or poly-substituted by (C1-C6) -alkyl, (C1-C6) -alkoxy, cyano, halogen, trifluoromethyl, hydroxyl, benzyloxy, nitro, amino, (C1-C6)-alkylamino, (C1-C6)-alkoxycarbonylamino and by the carboxyl group or by the carboxyl group esterified with C1-C6-alkanols, or is a pyridine structure of the formula 2 and its N-oxide [sic]
and its N-oxide, where the pyridine structure is alternatively bonded to the ring carbon atoms 2, 3 and 4 and can be substituted by the substituents R5 and R6. The radicals R5 and R6 can be identical or different and have the meaning (C1-C6)-alkyl, and the meaning (C3-C7) -cycloalkyl, (C1-C6) -alkoxy, nitro, amino, hydroxyl, halogen and trifluoro-methyl and are furthermore the ethoxycarbonylamino radical and the group carboxyalkyloxy in which the alkyl group can have 1-4 C atoms.
R1 can furthermore be a 2- or 4-pyrimidinyl heterocycle, where the 2-pyrimidinyl ring can be mono- or polysubstituted by the methyl group, furthermore the 2-, 3-, 4- and 8-quinolyl structure substituted by (C1-C6)-alkyl, halogen, the nitro group, the amino group and the (C1-C6) -alkyl amino radical, a 2-, 3- or 4-quinolylmethyl group, where the ring carbons of the pyridylmethyl radical of the quinolyl group and of the quinolylmethyl radical can be substituted by (C1-C6) -alkyl, (C1-C6) -alkoxy, nitro, amino and (C1-C6)-alkoxycarbonylamino.
R1 can furthermore be, in the case where R = hydrogen, the methyl or benzyl group and the benzyloxycarbonyl radical (Z radical), the tert-butoxycarbonyl radical (BOC radical) and the acetyl group, the following radicals:
-CH2COOH; -CH(CH3) -COOH ; - (CH3) 2-CH- (CH2)2-CH-COO;
H3C-H2C-CH (CH3) -CH (COOH)-; HO-H2C-CH (COOH) -;
phenyl-CH2-CH(COOH)-; (4-imidazolyl)-CH2-CH-COOH)-;
HN=C (NH2) -NH- (CH2)3 -CH(COOH)-; H2N- (CH2)4 -CH(COOH)-;
H2N-CO-CH2-CH- (COOH)-; HOOC(CH2)2-CH(COOH)-;
R1 can furthermore be, in the case where R is hydrogen, the Z group, the BOC radical, the acetyl or the benzyl group, the acid radical of a natural or unnatural amino acid, e.g. the .alpha.-glycyl, the .alpha.-sarcosyl, the .alpha.-alanyl, the .alpha.-leucyl, the .alpha.-isoleucyl, the .alpha.-seryl, the .alpha.-phenylalanyl, the .alpha.-histidyl, the .alpha.-prolyl, the .alpha.-arginyl, the .alpha.-lysyl, the .alpha.-asparagyl and the .alpha.-glutamyl radicals, where the amino groups of the respective amino acids can be present in unprotected or protected form. Possible protective groups for the amino function are the carbobenzoxy radical (Z radical) and the tert-butoxycarbonyl radical (BOC radical) as well as the acetyl group. In the case of the asparagyl and glutamyl radical claimed for R1, the second, unbonded carboxyl group is present as a free carboxyl group or in the form of an ester with C1-C6-alkanols, e.g. as a methyl, ethyl or as a tert-butyl ester.
R1 can furthermore be the allylaminocarbonyl-
2-methylprop-1-yl group.
R and R1 can furthermore, together with the nitrogen atom to which they are bonded, form a piperazine ring of the formula 3 or a homopiperazine ring, if R1 is an aminoalkylene group in which R7 is an alkyl radical, a phenyl ring which can be mono- or polysubstituted by (C1-C6) -alkyl, (C1-C6) -alkoxy, halogen, the nitro group, the amino function and by the (C1-C6)-alkylamino group. R, is furthermore the benzhydryl group and the bis-p-fluorobenzylhydryl group.
R2 can be hydrogen or the (C1-C6) -alkyl group, where the alkyl group is mono- or polysubstituted by halogen and phenyl, which for its part can be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with C1-C6-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups. The (C1-C6)-alkyl group applying for R2 can furthermore be substituted by the 2-quinolyl group and the 2-,
R and R1 can furthermore, together with the nitrogen atom to which they are bonded, form a piperazine ring of the formula 3 or a homopiperazine ring, if R1 is an aminoalkylene group in which R7 is an alkyl radical, a phenyl ring which can be mono- or polysubstituted by (C1-C6) -alkyl, (C1-C6) -alkoxy, halogen, the nitro group, the amino function and by the (C1-C6)-alkylamino group. R, is furthermore the benzhydryl group and the bis-p-fluorobenzylhydryl group.
R2 can be hydrogen or the (C1-C6) -alkyl group, where the alkyl group is mono- or polysubstituted by halogen and phenyl, which for its part can be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with C1-C6-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups. The (C1-C6)-alkyl group applying for R2 can furthermore be substituted by the 2-quinolyl group and the 2-,
3- or 4-pyridyl structure, which can both each be mono- or polysubstituted by halogen, (C1-C4) -alkyl groups or (C1-C4) -alkoxy groups. R2 is furthermore the aroyl radical, where the aryl moiety on which this radical is based is the phenyl ring, which can be mono- or polysubstituted by halogen, (C1-C6) -alkyl, (C3-C7) -cycloalkyl, carboxyl groups, carboxyl groups esterified with C1-C6-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups.
R3 and R4 can be identical or different and are hydrogen (C1-C6) -alkyl, (C3-C7) -cycloalkyl, (C1-C6) -alkanoyl, (C1-C6) -alkoxy, halogen or benzyloxy. R3 and R4 can furthermore be the nitro group, the amino group, the (C1-C4)-mono- or dialkyl-substituted amino group, and the (C1-C6) -alkoxycarbonylamino function or (C1-C6) -alkoxycarbonylamino- (C1-C6) -alkyl function.
Z is O or S
2. Use of N-substituted indole-3-gloxylamides [sic] according to Claim 1 general formula la for tumor treatment in particular in the case of pharmaceutical resistance and metastasizing carcinoma, and as angiogenesis inhibitors with lower side effects, in particularly markedly lower neurotoxicity where the radicals R = hydrogen R1 = 4-pyridyl, 4-fluorophenyl R2 = benzyl, 4-chlorobenzyl, 4-fluorobenzyl, 3-pyridylmethyl, 4-bromobenzyl R3 and R4 = hydrogen and Z is oxygen.
3. Pharmaceutical composition for tumor treatment in particular in the case of pharmaceutical resistance and metastasizing carcinoma, and as angiogenesis inhibitors with lower side effects in particular markedly lower neurotoxicity characterized in that they contain at least one of the compounds of the general formula 1 or 1a if appropriate also they [sic] as acid addition salts, for example as salts of mineral acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, salts of organic acids, such as, for example, 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-hydrop0xyethanesulfonic [sic] acid and possible [sic], their N-oxides.
R3 and R4 can be identical or different and are hydrogen (C1-C6) -alkyl, (C3-C7) -cycloalkyl, (C1-C6) -alkanoyl, (C1-C6) -alkoxy, halogen or benzyloxy. R3 and R4 can furthermore be the nitro group, the amino group, the (C1-C4)-mono- or dialkyl-substituted amino group, and the (C1-C6) -alkoxycarbonylamino function or (C1-C6) -alkoxycarbonylamino- (C1-C6) -alkyl function.
Z is O or S
2. Use of N-substituted indole-3-gloxylamides [sic] according to Claim 1 general formula la for tumor treatment in particular in the case of pharmaceutical resistance and metastasizing carcinoma, and as angiogenesis inhibitors with lower side effects, in particularly markedly lower neurotoxicity where the radicals R = hydrogen R1 = 4-pyridyl, 4-fluorophenyl R2 = benzyl, 4-chlorobenzyl, 4-fluorobenzyl, 3-pyridylmethyl, 4-bromobenzyl R3 and R4 = hydrogen and Z is oxygen.
3. Pharmaceutical composition for tumor treatment in particular in the case of pharmaceutical resistance and metastasizing carcinoma, and as angiogenesis inhibitors with lower side effects in particular markedly lower neurotoxicity characterized in that they contain at least one of the compounds of the general formula 1 or 1a if appropriate also they [sic] as acid addition salts, for example as salts of mineral acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, salts of organic acids, such as, for example, 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-hydrop0xyethanesulfonic [sic] acid and possible [sic], their N-oxides.
4. Use of N-substituted indole-3-glyoxylamides of the general formula 1 or 1a and their physiologically tolerable acid addition salts for the production of antitumor agents for use in particular in the case of pharmaceutical resistance and metastasizing carcinoma, and as angiogenesis inhibitors with markedly lower side effects in particular markedly lower neurotoxicity, to be specific in particular of the following compounds or their salts with physiologically tolerable acids or if possible their N-oxides:
D 24241 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]
glyoxylamide D 24843 N-(pyridin-4-yl)-(1-benzylindol-3-yl) glyoxylamide D 24850 N-(4-fluorophenyl)-[1-(3-pyridylmethyl)indol-3-yl] glyoxylamide D 24851 N-(pyridin-4-yl)-[1-(4-chlorobenzyl)indol-3-yl]
glyoxylamide D 25505 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]
glyoxylamide HCL [sic]
D 24241 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]
glyoxylamide D 24843 N-(pyridin-4-yl)-(1-benzylindol-3-yl) glyoxylamide D 24850 N-(4-fluorophenyl)-[1-(3-pyridylmethyl)indol-3-yl] glyoxylamide D 24851 N-(pyridin-4-yl)-[1-(4-chlorobenzyl)indol-3-yl]
glyoxylamide D 25505 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]
glyoxylamide HCL [sic]
5. Antitumor agent comprising as active compound one or more N-substituted indole-3-gloxylamides [sic]
according to the general formula 1 or 1a and, if appropriate, their physiologically tolerable acid addition salts of antitumor agents for use in particular in the case of pharmaceutical resistance and metastasizing carcinoma, and as angiogenesis inhibitors with markedly lower side effects in particular markedly lower neurotoxicity but in particular one or more compounds according to Claim 4.
according to the general formula 1 or 1a and, if appropriate, their physiologically tolerable acid addition salts of antitumor agents for use in particular in the case of pharmaceutical resistance and metastasizing carcinoma, and as angiogenesis inhibitors with markedly lower side effects in particular markedly lower neurotoxicity but in particular one or more compounds according to Claim 4.
6. Antitumor agents for tumor treatment in particular in the case of pharmaceutical resistance and metastasizing carcinoma, and as angiogenesis inhibitors with lower side effects in particular markedly lower neurotoxicity, to be specific in particular comprising as active compound D 24241 N-(pyridin-4-yl)-(1-(4-fluorobenzyl)indol-3-yl]
glyoxylamide or its hydrochloride
glyoxylamide or its hydrochloride
7. Antitumor agents for tumor treatment in particular in the case of pharmaceutical resistance and metastasizing carcinoma, and as angiogenesis inhibitors with markedly lower side effects in particular markedly lower neurotoxicity, to be specific in particular comprising as active compound D 24843 N-(pyridin-4-yl)-(1-benzylindol-3-yl)glyoxyl-amide
8. Antitumor agents for tumor treatment in particular in the case of pharmaceutical resistance and metastasizing carcinoma, and as angiogenesis inhibitors with markedly lower side effects in particular markedly lower neurotoxicity, to be specific in particular comprising as active compound D 24850 N-(4-fluorophenyl)-[1-(3-pyridylmethyl)indol-3-yl]glyoxylamide
9. Antitumor agents for tumor treatment in particular in the case of pharmaceutical resistance and metastasizing carcinoma, and as angiogenesis inhibitors with markedly lower side effects in particular markedly lower neurotoxicity, to be specific in particular comprising as active compound D 24851 N-(pyridin-4-yl)-[1-(4-chlorobenzyl)indol-3-yl]
glyoxylamide
glyoxylamide
10. Antitumor agents for tumor treatment in particular in the case of pharmaceutical resistance and metastasizing carcinoma and as angiogenesis inhibitors with markedly lower side effects in particular markedly lower neurotoxicity comprising as active compound one or more N-substituted indole-3-gloxylamides [sic]
according to the general formula 1 or 1a and, if appropriate, their physiologically tolerable acid addition salts and, if possible, N-oxides, but in particular one or more compounds according to Claims 4 and 6 to 8 and a pharmaceutically utilizable vehicle and/or diluent or excipient in the form of tablets, coated tablets, capsules, solutions for infusion or ampoules, suppositories, patches, powder preparations which can be employed by inhalation, suspensions, creams and ointments.
according to the general formula 1 or 1a and, if appropriate, their physiologically tolerable acid addition salts and, if possible, N-oxides, but in particular one or more compounds according to Claims 4 and 6 to 8 and a pharmaceutically utilizable vehicle and/or diluent or excipient in the form of tablets, coated tablets, capsules, solutions for infusion or ampoules, suppositories, patches, powder preparations which can be employed by inhalation, suspensions, creams and ointments.
11. Use of N-substituted indole-3-glyoxylamides of the general formula 1 or 1a and their physiologically tolerable acid addition salts as angiogenesis inhibitors, to be specific in particular of the following compounds or their salts with physiologically tolerable acids or if possible their N-oxides:
D 24241 N- (pyridin-4-yl) - [1-(4-fluorobenzyl) indol-3-yl]
glyoxylamide D 24843 N-(pyridin-4-yl)-(1-benzylindol-3-yl)glyoxyl-amide D 24850 N-(4-fluorophenyl)-[1-(3-pyridylmethyl)indol-3-yl]glyoxylamide D 24851 N-(pyridin-4-yl)-[1-(4-chlorobenzyl)indol-3-yl]
glyoxylamide D 25505 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]
glyoxylamide HCL [sic]
D 24241 N- (pyridin-4-yl) - [1-(4-fluorobenzyl) indol-3-yl]
glyoxylamide D 24843 N-(pyridin-4-yl)-(1-benzylindol-3-yl)glyoxyl-amide D 24850 N-(4-fluorophenyl)-[1-(3-pyridylmethyl)indol-3-yl]glyoxylamide D 24851 N-(pyridin-4-yl)-[1-(4-chlorobenzyl)indol-3-yl]
glyoxylamide D 25505 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]
glyoxylamide HCL [sic]
12. Use of N-substituted indole-3-glyoxylamides of the general formula 1 or 1a and their physiologically tolerable acid addition salts for use in particular in the case of pharmaceutical resistance and as a replacement for antitumor agents which are no longer active on account of resistance formation in particular of the compounds D 24241 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]
glyoxylamide D 24843 N-(pyridin-4-yl)-(1-benzylindol-3-yl)glyoxyl-amide D 24850 N-(4-fluorophenyl)-[1-(3-pyridylmethyl)indol-3-yl]glyoxylamide D 24851 N-(pyridin-4-yl)-[1-(4-chlorobenzyl)indol-3-yl]
glyoxylamide D 25505 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]
glyoxylamide HCL
glyoxylamide D 24843 N-(pyridin-4-yl)-(1-benzylindol-3-yl)glyoxyl-amide D 24850 N-(4-fluorophenyl)-[1-(3-pyridylmethyl)indol-3-yl]glyoxylamide D 24851 N-(pyridin-4-yl)-[1-(4-chlorobenzyl)indol-3-yl]
glyoxylamide D 25505 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]
glyoxylamide HCL
13. Use of N-substituted indole-3-glyoxylamides of the general formula 1 or 1a and their physiologically tolerable acid addition salts for use in particular in the case of pharmaceutical resistance in fixed or free combination with known antitumor agents and as a replacement for antitumor agents which are no longer active on account of resistance formation in particular of the compounds D 24241 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]
glyoxylamide D 24843 N-(pyridin-4-yl)-(1-benzylindol-3-yl)glyoxyl-amide D 24850 N-(4-fluorophenyl)-[1-(3-pyridylmethyl)indol-3-yl]glyoxylamide D 24851 N-(pyridin-4-yl)-[1-(4-chlorobenzyl)indol-3-yl]glyoxylamide D 25505 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]glyoxylamide HCL
glyoxylamide D 24843 N-(pyridin-4-yl)-(1-benzylindol-3-yl)glyoxyl-amide D 24850 N-(4-fluorophenyl)-[1-(3-pyridylmethyl)indol-3-yl]glyoxylamide D 24851 N-(pyridin-4-yl)-[1-(4-chlorobenzyl)indol-3-yl]glyoxylamide D 25505 N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]glyoxylamide HCL
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
| DE19946301.8 | 1999-09-28 | ||
| PCT/EP2000/009390 WO2001022954A2 (en) | 1999-09-28 | 2000-09-26 | Indolyl-3-glyoxylic acid derivatives serving as antitumor agents |
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| Publication Number | Publication Date |
|---|---|
| CA2386069A1 true CA2386069A1 (en) | 2001-04-05 |
| CA2386069C CA2386069C (en) | 2012-08-14 |
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| CA2386069A Expired - Fee Related CA2386069C (en) | 1999-09-28 | 2000-09-26 | Indolyl-3-glyoxylic acid derivatives as antitumor agents |
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| EP (1) | EP1218006B1 (en) |
| JP (1) | JP2003510274A (en) |
| KR (1) | KR100759242B1 (en) |
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| DE19962300A1 (en) * | 1999-12-23 | 2001-06-28 | Asta Medica Ag | New N-benzylindolyl glyoxylic acid derivatives are useful as antitumor agents |
| AU2001258628A1 (en) | 2000-05-31 | 2001-12-11 | Astrazeneca Ab | Indole derivatives with vascular damaging activity |
| DE10037310A1 (en) | 2000-07-28 | 2002-02-07 | Asta Medica Ag | New indole derivatives and their use as medicines |
| JP4878285B2 (en) * | 2003-06-05 | 2012-02-15 | エテルナ ツェンタリス ゲゼルシャフト ミット ベシュレンクテル ハフツング | Indole derivatives with apoptosis-inducing action |
| EP1595878A1 (en) * | 2004-05-15 | 2005-11-16 | Zentaris GmbH | Indole derivatives with apoptosis inducing activity |
| EP1484329A1 (en) * | 2003-06-06 | 2004-12-08 | Zentaris GmbH | Indole derivatives with apoptosis inducing activity |
| US20050124623A1 (en) | 2003-11-26 | 2005-06-09 | Bender John A. | Diazaindole-dicarbonyl-piperazinyl antiviral agents |
| ES2777924T3 (en) * | 2004-05-23 | 2020-08-06 | Hmi Medical Innovations Llc | Teramutein modulators |
| WO2006052712A1 (en) * | 2004-11-08 | 2006-05-18 | Baxter International Inc. | Nanoparticulate compositions of tubulin inhibitor |
| US20060100432A1 (en) | 2004-11-09 | 2006-05-11 | Matiskella John D | Crystalline materials of 1-(4-benzoyl-piperazin-1-yl)-2-[4-methoxy-7-(3-methyl-[1,2,4]triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-ethane-1,2-dione |
| US8604055B2 (en) | 2004-12-31 | 2013-12-10 | Dr. Reddy's Laboratories Ltd. | Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors |
| US9040558B2 (en) | 2004-12-31 | 2015-05-26 | Dr. Reddy's Laboratories Ltd. | Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors |
| US7851476B2 (en) | 2005-12-14 | 2010-12-14 | Bristol-Myers Squibb Company | Crystalline forms of 1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-YL)-1-[(phosphonooxy)methyl]-1H-pyrrolo[2,3-C]pyridin-3-YL]-1,2-dioxoethyl]-piperazine |
| US7807671B2 (en) | 2006-04-25 | 2010-10-05 | Bristol-Myers Squibb Company | Diketo-piperazine and piperidine derivatives as antiviral agents |
| CA2670778A1 (en) * | 2006-11-28 | 2008-06-05 | Ziopharm Oncology, Inc. | Use of indolyl-3-glyoxylic acid derivatives including indibulin, alone or in combination with further agents for treating cancer |
| US9199967B2 (en) | 2011-08-18 | 2015-12-01 | Dr. Reddy's Laboratories Ltd. | Substituted heterocyclic amine compounds as cholestryl ester-transfer protein (CETP) inhibitors |
| IN2014CN02290A (en) | 2011-09-27 | 2015-06-19 | Reddys Lab Ltd Dr | |
| US9353150B2 (en) | 2012-12-04 | 2016-05-31 | Massachusetts Institute Of Technology | Substituted pyrazino[1′,2′:1 ,5]pyrrolo[2,3-b]-indole-1,4-diones for cancer treatment |
| CA2905509A1 (en) | 2013-03-15 | 2014-09-18 | Memorial Sloan-Kettering Cancer Center | Hsp90-targeted cardiac imaging and therapy |
| WO2017197045A1 (en) | 2016-05-11 | 2017-11-16 | Movassaghi Mohammad | Convergent and enantioselective total synthesis of communesin analogs |
| WO2018209239A1 (en) | 2017-05-11 | 2018-11-15 | Massachusetts Institute Of Technology | Potent agelastatin derivatives as modulators for cancer invasion and metastasis |
| CN109111501B (en) * | 2017-06-23 | 2022-04-22 | 首都医科大学 | Fatty amino acid-modified indoleethanol derivatives, their synthesis, activities and applications |
| US10640508B2 (en) | 2017-10-13 | 2020-05-05 | Massachusetts Institute Of Technology | Diazene directed modular synthesis of compounds with quaternary carbon centers |
| US11535634B2 (en) | 2019-06-05 | 2022-12-27 | Massachusetts Institute Of Technology | Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof |
| WO2022182415A1 (en) | 2021-02-24 | 2022-09-01 | Massachusetts Institute Of Technology | Himastatin derivatives, and processes of preparation thereof, and uses thereof |
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| AU4128089A (en) | 1988-09-15 | 1990-03-22 | Rorer International (Overseas) Inc. | Monoclonal antibodies specific to human epidermal growth factor receptor and therapeutic methods employing same |
| RU2047603C1 (en) * | 1991-12-09 | 1995-11-10 | Матвей Абрамович Рехтер | 1-alkyl-2-acylindoles and methods of their synthesis |
| NZ314207A (en) * | 1992-09-28 | 2000-12-22 | Vertex Pharma | 1-(2-Oxoacetyl)-piperidine-2-carboxylic acid derivatives as multi drug resistant cancer cell sensitizers |
| EP0617961A4 (en) * | 1992-10-20 | 1995-03-29 | Toray Industries | Eosinophil infiltration inhibitor. |
| DE19636150A1 (en) * | 1996-09-06 | 1998-03-12 | Asta Medica Ag | N-substituted indole-3-glyoxylamides with antiasthmatic, antiallergic and immunosuppressive / immunomodulating effects |
| CA2286038A1 (en) | 1997-04-08 | 1998-10-15 | Banyu Pharmaceutical Co., Ltd. | Cancerous metastasis-associated gene |
| CA2322162A1 (en) * | 1998-02-25 | 1999-09-02 | Genetics Institute, Llc | Inhibitors of phospholipase enzymes |
| JP2004500308A (en) * | 1998-03-12 | 2004-01-08 | ノボ ノルディスク アクティーゼルスカブ | Modulator of protein tyrosine phosphatase |
| DE19814838C2 (en) * | 1998-04-02 | 2001-01-18 | Asta Medica Ag | Indolyl-3-glyoxylic acid derivatives with anti-tumor effects |
| TR200003130T2 (en) * | 1998-04-28 | 2001-01-22 | Arzneimittelwerk Dresden Gmbh | Novel hydroxyindoles, processes for their use and preparation as phosphodiesterase 4 inhibitors |
| JP2000239252A (en) * | 1999-02-16 | 2000-09-05 | Mitsubishi Chemicals Corp | Indole derivatives |
| AU4834200A (en) * | 1999-05-10 | 2000-11-21 | Protarga, Inc. | Fatty acid-n-substituted indol-3-glyoxyl-amide compositions and uses thereof |
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