CH520670A - 1-Acyl 3-indolyl acetates - Google Patents
1-Acyl 3-indolyl acetatesInfo
- Publication number
- CH520670A CH520670A CH1874271A CH1874271A CH520670A CH 520670 A CH520670 A CH 520670A CH 1874271 A CH1874271 A CH 1874271A CH 1874271 A CH1874271 A CH 1874271A CH 520670 A CH520670 A CH 520670A
- Authority
- CH
- Switzerland
- Prior art keywords
- acid
- group
- carbon atoms
- formula
- alkyl
- Prior art date
Links
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- -1 methylenedioxy Chemical group 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 125000004663 dialkyl amino group Chemical group 0.000 claims abstract description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 3
- 125000005504 styryl group Chemical group 0.000 claims abstract description 3
- 229910052736 halogen Inorganic materials 0.000 claims abstract 3
- 150000002367 halogens Chemical class 0.000 claims abstract 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- SEOVTRFCIGRIMH-UHFFFAOYSA-N indole-3-acetic acid Chemical class C1=CC=C2C(CC(=O)O)=CNC2=C1 SEOVTRFCIGRIMH-UHFFFAOYSA-N 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- JHAWWJQGHKGXHA-UHFFFAOYSA-N 6-tert-butylquinoline Chemical compound N1=CC=CC2=CC(C(C)(C)C)=CC=C21 JHAWWJQGHKGXHA-UHFFFAOYSA-N 0.000 claims description 2
- 229930194542 Keto Natural products 0.000 claims description 2
- SFYLHIMXJQGKGZ-RQOWECAXSA-N acetaldehyde (Z)-hydrazone Chemical compound C\C=N/N SFYLHIMXJQGKGZ-RQOWECAXSA-N 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- QYCSNMDOZNUZIT-UHFFFAOYSA-N benzhydrylidenehydrazine Chemical compound C=1C=CC=CC=1C(=NN)C1=CC=CC=C1 QYCSNMDOZNUZIT-UHFFFAOYSA-N 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 235000010755 mineral Nutrition 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 230000001419 dependent effect Effects 0.000 claims 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 230000036647 reaction Effects 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 16
- 206010030113 Oedema Diseases 0.000 abstract description 6
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 6
- 229940121363 anti-inflammatory agent Drugs 0.000 abstract description 4
- 239000002260 anti-inflammatory agent Substances 0.000 abstract description 4
- 239000008280 blood Substances 0.000 abstract description 4
- 210000004369 blood Anatomy 0.000 abstract description 4
- 231100000053 low toxicity Toxicity 0.000 abstract description 4
- 238000012360 testing method Methods 0.000 abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 3
- 241001465754 Metazoa Species 0.000 abstract description 3
- 230000000202 analgesic effect Effects 0.000 abstract description 2
- 230000001754 anti-pyretic effect Effects 0.000 abstract description 2
- 239000002221 antipyretic Substances 0.000 abstract description 2
- 229960002895 phenylbutazone Drugs 0.000 abstract description 2
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 abstract description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 abstract 4
- 229960000905 indomethacin Drugs 0.000 abstract 2
- 230000032050 esterification Effects 0.000 abstract 1
- 238000005886 esterification reaction Methods 0.000 abstract 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- 231100001274 therapeutic index Toxicity 0.000 abstract 1
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- 238000002844 melting Methods 0.000 description 15
- 230000008018 melting Effects 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 4
- 210000003608 fece Anatomy 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 210000002683 foot Anatomy 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000248349 Citrus limon Species 0.000 description 1
- OEWDNWRLPFBZAR-UHFFFAOYSA-N Cl.C(C=CC1=CC=CC=C1)(=O)N(N)C1=CC=C(C=C1)OC Chemical compound Cl.C(C=CC1=CC=CC=C1)(=O)N(N)C1=CC=C(C=C1)OC OEWDNWRLPFBZAR-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229940058352 levulinate Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229940030966 pyrrole Drugs 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Low toxicity anti-inflammatory 1-acyl-3-indolylacetates. M3A. Are new compounds of formula:- and their acid addition salts. (R' = styryl, phenyl optionally subst. by halogen or methylenedioxy; R2, R3=H, alkyl (C1-C2); R4= H, halogen, alkyl (C1-C4), alkoxy (C1-C4); A=(CH2)2.0. (CH2)2-, -CnH2n where n= 1 to 6; B-NH2, alkylamino, dialkylamino or a heterocyclic ring (C5-C6) optionally substd. by aralkyl, phenyl, uralkenyl or alkyl, which contains 1 or 2 N atoms). - Used as highly active anti-inflammatory agents with low toxicity, also having antipyretic and analgesic activity. The therapeutic index is higher than that of indomethacin and phenylbutazone, doses of 400 mg/kg orally not giving rise to faecal occult blood in test animals. - Specifically beta-morphlinoethyl 1-cinnamoyl-2-methyl-5-methoxy-3-ind olylacetate hydrochloride is about as active in the rat food oedema test as indomethacin but the latter is more toxic at 10 mg/kg than (I) is at 200 mg/kg. Tests of 6 other compounds (I) are quoted. - Prepared by (a) esterification of corresponding acid and alcohol.
Description
Verfahren zur Herstellung von 3-Indolylessigsäurederivaten und deren Salzen Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von neuen 3-Indolylessigsäurederivaten und deren Salzen, die als entzündungshemmende Mittel von Wert sind.
Erfindungsgemäss werden 3-Indolylessigsäurederivate der Formel:
EMI0001.0001
hergestellt, worin R1 eine Styryl-, Phenyl-, halogensub stituierte Phenyl- oder Methylendioxyphenylgruppe, R2 und R3 je ein Wasserstoffatom oder eine Alkylgruppe mit 1 oder 2 Kohlenstoffatomen, R4 ein Wasserstoff atom, ein Halogenatom, eine Alkylgruppe mit 1 bis 4 Kohlenstoffatomen oder eine Alkoxygruppe mit 1 bis 4 Kohlenstoffatomen, A eine Gruppe der Formel:
-CH2-CH2-O-CH2 oder -CoH20 NI worin n eine ganze Zahl von 2 bis 6 darstellt, und B eine Aminogruppe, eine Alkylaminogruppe mit 1 bis 4 Kohlenstoffatomen, eine Dialkylaminogruppe mit je 1 bis 4 Kohlenstoffatomen in den Alkylgruppen oder einen gegebenenfalls durch Alkylgruppen mit 1 bis 4 Kohlen stoffatomen, Aralkyl-, Phenyl- oder Aralkenylgruppen substituierten 5- oder 6gliedrigen heterocyclischen Ring mit 1 oder 2 Stickstoffatomen bedeuten, sowie die Salze derselben hergestellt.
Es war bereits bekannt, dass gewisse Derivate von indolylsubstituierten aliphatischen Säuren als entzün dungshemmende Mittel brauchbar sind. Es wurde nun aufgrund umfangreicher Untersuchungen festgestellt, dass die neuen 3-Indolylessigsäurederivate der Formel I aus gezeichnete entzündungshemmende Mittel sind, da sie sehr geringe Toxizitäten, aber sehr starke entzündungs hemmende Wirkung besitzen.
Das Verfahren gemäss der Erfindung ist dadurch ge kennzeichnet, dass man ein -Acylphenylhydrazin der Formel:
EMI0001.0005
oder ein Salz oder Hydrazon desselben mit einem Keto- ester der Formel:
EMI0001.0008
oder einem Salz desselben in Berührung bringt, worauf man gewünschtenfalls das resultierende 3-Indolylessig- säurederivat mit einer Säure in Berührung bringt.
In der Formel I kann die Gruppe der Formel: -CnH2n- verzweigt oder unverzweigt sein, während B die Grup pen: -NH2, -NH-CH3, -NH-C2H5-. -NH-C3H7, -NH-C4H9, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N(C4H9)2 sowie die oben genannten 5- oder 6gliedrigen hetero- cyclischen Ringe mit 1 oder 2 Stickstoffatomen, wie Pyridin, Piperidin, Piperazin, Pyrrolin, Pyrrolidin, Pyr rol, Pyrazol, Imidazol, Oxazol, Morpholin und derglei chen, darstellen kann.
Alle 3-Indolylessigsäurederivate der Formel I und ihre Salze sind neue Verbindungen und wurden noch nicht in der Literatur beschrieben. Diese Verbindungen haben ausgezeichnete antipyretische, analgetische und entzündungshemmende Eigenschaften.
Nach dem erfindungsgemässen Verfahren können, wie gesagt, die neuen 3-Indolylessigsäurederivate der Formel I und ihre Salze leicht in hoher Ausbeute erhal ten werden.
Als Salze der N1-Acylphenylhydrazine der Formel II kommen Säuresalze, wie Hydrochloride, Hydrobromide oder Phosphate, in Betracht.
Für die Umsetzung wird als Hydrazin der Verbin dung der Formel II vorzugsweise ein Acetaldehydhydra- zon, Benzaldehydhydrazon oder Diphenylketonhydrazon verwendet.
Die Umsetzung kann in Gegenwart oder Abwesen heit eines Lösungsmittels mit einem Kondensationsmittel ausgeführt werden. Als Lösungmittel eignen sich zum Beispiel Essigsäure, Propionsäure, Benzol, Toluol, Xylol, Cyclohexan, Dioxan, Isopropyläther, Butylalkohol, Äthylenglycol und dergleichen. Vorzugsweise werden als Kondensationsmittel Salzsäure, Schwefelsäure, Zinkchlo- rid, Polyphosphorsäure, Essigsäure, Propionsäure oder dergleichen verwendet. Die Reaktion wird vorzugsweise bei 60 bis 200 C ausgeführt.
Salze der Verbindungen der Formel I können herge stellt werden, indem man die Verbindungen mit einer Mineralsäure, wie Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Salpetersäure, Phosphorsäure oder der gleichen, oder mit einer organischen Säure, wie Malein säure, Weinsäure, Fumarsäure, Bernsteinsäure, Zitronen säure, Essigsäure oder dergleichen, behandelt.
Die vorliegenden Verbindungen besitzen eine hohe entzündungshemmende Wirkung und sind daher wert voll für die Linderung der Symptone, die bei rheumati schen und anderen entzündlichen Zuständen auftreten, sowie für die Vorbeugung gegen Entzündungen oder die Unterdrückung von Entzündungen. Die vorliegenden Verbindungen haben geringere Toxizitäten als die ent sprechenden Stammverbindungen und verursachen in Tierversuchen bei hohen Dosierungen, selbst bei 400 mg pro kg per os, selten okkulte Blutungen im Kot.
Trotz dieser bemerkenswert geringen Toxizität haben die vor liegenden Verbindungen eine ausgezeichnete hemmende Wirkung auf das durch Carraghenin hervorgerufene Pfo tenödem von Ratten, so dass die therapeutischen Indices (Dosis letalis / Dosis efficiens) dieser Verbindungen viel grösser sind als bei erstklassigen entzündungshemmenden Medikamenten, wie Indometasinum, Phenylbutazon usw.
(siehe Tabelle I). TABELLE I Entzündungshemmende Wirkung
EMI0002.0011
EMI0003.0000
(a) Die entzündungshemmende Wirkung wurde be wertet gemäss der hemmenden Wirkung auf das Ödem der Rattenhinterpfote, das durch Injektion von 0,05 cm3 einer 1%igen Lösung von Carraghenin in steriler 0,9%- iger Natriumchloridlösung hervorgerufen wurde.
(b) Die Testverbindungen wurden 1 Stunde vor der Injektion von Carraghenin per os verabreicht. Für jede Dosierung wurden 3 bis 6 Ratten verwendet.
(c) Das Volumen der Pfote wurde 3, 4 und 5 Stun den nach der Injektion des Carraghenins gemessen, und für jede Ratte wurde der Mittelwert dieser Messwerte berechnet. Die Hemmung des Ödems wird durch die Gleichung:
EMI0003.0003
<B>133</B> wobei T das durchschnittliche Volumen des Ödems bei der behandelten Gruppe und C das durch schnittliche Volumen des Ödems bei der Kontrollgruppe darstellt.
(d) Kein Blut im Kot, Zunahme des Körpergewichtes normal.
-I- Kein Blut im Kot, Abnahme des Körpergewichtes -I- -I- Blut im Kot, Abnahme des Körpergewichtes -I- -f- -I- Die gleichen Symptome wie bei -I- -I-, aber einige Tiere starben innerhalb von 4 Tagen nach der Verab reichung.
Die Verbindungen werden vorzugsweise per os ver abreicht. Die pharmazeutisch .unbedenklichen Säuread ditionssalze werden bevorzugt. Die vorliegenden Verbin dungen können entweder mit einem festen oder mit einem flüssigen Träger oder Verdünnungsmittel kombi niert und in verschiedenen Mengen in Form üblicher pharmazeutischer Präparate, wie Tabletten, Dragees, Kapseln, Pulver, Suspensionen und Lösungen, zur Ver fügung gestellt werden.
Die folgenden Beispiele erläutern die Erfindung. <I>Beispiel</I> Ein Gemisch aus 6,1 g N1-Cinnamoyl-p-methoxy- phenylhydrazin-hydrochlorid, 6 g b-N,N-Diäthylamino- äthyl-lävulinat und 50 g Isopropanol wird während 5 Stunden .unter Rückfluss gerührt. Das Lösungsmittel wird unter vermindertem Druck entfernt; der Rückstand wird mit Wasser versetzt und das Gemisch mit Benzol extrahiert. Die Benzolschicht wird mit Wasser gewaschen und über Natriumsulfat ge trocknet.
Das Lösungsmittel wird unter vermindertem Druck entfernt, wobei man ss-N,N-Diäthylaminoäthyl-l- -cinnamoyl-2-methyl-5-methoxy-3-indolylacetat erhält. In eine Lösung dieser Verbindung in Äther wird gasförmi ger Chlorwasserstoff eingeleitet. Die abgeschiedenen Kri stalle werden durch Filtration isoliert und aus Äthanol umkristallisiert, wobei man 3-N,N-Diäthylaminoäthyl-1- -cinnamoyl-2-methyl-5-methoxy- 3 -indolylacetat-hydro- chlorid vom Schmelzpunkt bis 134 C erhält.
Gemäss der oben beschriebenen Verfahrensweise können die folgenden Verbindungen erhalten werden: <B>137</B> P ,( P P 164 ,p P b-N,N-Dimethylaminoäthyl-l-(3',4'-methylendioxyben- zoyl)-2-methyl-5-methoxy-3-indolylacetat-hydrochlorid vom Schmelzpunkt bis 138 C, b-Dimethylaminopropyl-1-cinnamoyl-2-methyl-5-meth- oxy-3-indolylacetat-hydrochlorid vom Schmelzpunkt 170 bis 172 C, b-N,N-Dimethylaminoäthyl-1-cinnamoyl-2-methyl-5- -methoxy-3-indolylacetat-hydrochlorid vom Schmelzpunkt 194 bis 194,5 C, γ
-N,N-Dimethylaminopropyl-1-cinnamoyl-2-methyl-5- -methoxy-3-indolylacetat-hydrochlorid vom Schmelzpunkt 156 bis 157 C, γ-Morpholinopropyl-l-cinnamoyl-2-methyl-5-methoxy- -3-indolylacetat-hydrochlorid vom Schmelzpunkt 166 bis 167 C, b-Morpholinoäthyl-l-cinnamoyl-2-methyl-5-methoxy-3- -indolylacetat-hydrochlorid vom Schmelzpunkt 187 bis 188 C, b-(N4-Benzylpiperazino)-äthyl-1-cinnamoyl-2-methyl-5- -methoxy-3-indolylacetat-dihydrochlorid vom Schmelzpunkt 188 bis 189 C,
b-Piperidinoäthyl-1-cinnamoyl-2-methyl-5-methoxy-3- -indolylacetat-hydrochlorid vom Schmelzpunkt bis 165 C, -Piperidinoäthyl-1-(p-chlorbenzoyl)-2-methyl-5-meth- oxy-3-indolylacetat-hydrochlorid vom Schmelzpunkt 210 bis 211 C, -Morpholinoäthyl-1-(3',4'-methylendioxybenzoyl)-2- -methyl-5-methoxy-3-indolylacetat-hydrochlorid vom Schmelzpunkt 120 C (Zersetzung), ss-Morpholinoäthyl-1-(p-chlorbenzoyl)-2-methyl-5-meth- oxy-3-indolylacetat-hydrochlorid vom Schmelzpunkt 201 bis 202 C, ss-[2'-(N-Methylpiperidyl)
]-äthyl-l-cinnamoyl-2-methyl- -5-methoxy-3-indolylacetat-hydrochlorid vom Schmelzpunkt 128 bis 129 C, g-Piperidinopropyl-l-cinnamoyl-2-methyl-5-methoxy-3- -indolylacetat-hydrochlorid vom Schmelzpunkt 144 bis 145 C, Diäthylaminoäthoxyäthyl-l-cinnamoyl-2-methyl-5-meth- oxy-3-indolylacetat-citrat vom Schmelzpunkt 72,5 bis 73,5 C.
Process for the preparation of 3-indolylacetic acid derivatives and their salts The present invention relates to a process for the preparation of new 3-indolylacetic acid derivatives and their salts which are of value as anti-inflammatory agents.
According to the invention, 3-indolylacetic acid derivatives of the formula:
EMI0001.0001
produced, wherein R1 is a styryl, phenyl, halogen-substituted phenyl or methylenedioxyphenyl group, R2 and R3 each have a hydrogen atom or an alkyl group with 1 or 2 carbon atoms, R4 a hydrogen atom, a halogen atom, an alkyl group with 1 to 4 carbon atoms or a Alkoxy group with 1 to 4 carbon atoms, A is a group of the formula:
-CH2-CH2-O-CH2 or -CoH20 NI where n is an integer from 2 to 6, and B is an amino group, an alkylamino group with 1 to 4 carbon atoms, a dialkylamino group with 1 to 4 carbon atoms in each of the alkyl groups or optionally one 5- or 6-membered heterocyclic ring with 1 or 2 nitrogen atoms substituted by alkyl groups with 1 to 4 carbon atoms, aralkyl, phenyl or aralkenyl groups, and the salts thereof are prepared.
It was previously known that certain derivatives of indolyl-substituted aliphatic acids are useful as anti-inflammatory agents. It has now been found on the basis of extensive investigations that the new 3-indolylacetic acid derivatives of the formula I are excellent anti-inflammatory agents, since they have very low toxicities but very strong anti-inflammatory effects.
The process according to the invention is characterized in that an acylphenylhydrazine of the formula:
EMI0001.0005
or a salt or hydrazone of the same with a keto ester of the formula:
EMI0001.0008
or a salt thereof, whereupon, if desired, the resulting 3-indolyl acetic acid derivative is brought into contact with an acid.
In the formula I, the group of the formula: -CnH2n- can be branched or unbranched, while B represents the groups: -NH2, -NH-CH3, -NH-C2H5-. -NH-C3H7, -NH-C4H9, -N (CH3) 2, -N (C2H5) 2, -N (C3H7) 2, -N (C4H9) 2 and the above-mentioned 5- or 6-membered heterocyclic rings with 1 or 2 nitrogen atoms, such as pyridine, piperidine, piperazine, pyrroline, pyrrolidine, pyr role, pyrazole, imidazole, oxazole, morpholine and the like, may represent.
All 3-indolylacetic acid derivatives of the formula I and their salts are new compounds and have not yet been described in the literature. These compounds have excellent antipyretic, analgesic and anti-inflammatory properties.
According to the process according to the invention, as said, the new 3-indolylacetic acid derivatives of the formula I and their salts can easily be obtained in high yield.
Suitable salts of the N1-acylphenylhydrazines of the formula II are acid salts, such as hydrochlorides, hydrobromides or phosphates.
An acetaldehyde hydrazone, benzaldehyde hydrazone or diphenyl ketone hydrazone is preferably used as the hydrazine of the compound of the formula II.
The reaction can be carried out in the presence or absence of a solvent with a condensing agent. Suitable solvents are, for example, acetic acid, propionic acid, benzene, toluene, xylene, cyclohexane, dioxane, isopropyl ether, butyl alcohol, ethylene glycol and the like. Hydrochloric acid, sulfuric acid, zinc chloride, polyphosphoric acid, acetic acid, propionic acid or the like are preferably used as the condensing agent. The reaction is preferably carried out at 60 to 200.degree.
Salts of the compounds of the formula I can be prepared by treating the compounds with a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like, or with an organic acid such as maleic acid, tartaric acid, fumaric acid, succinic acid, lemon acid, acetic acid or the like.
The present compounds have a high anti-inflammatory activity and are therefore valuable for relieving the symptoms associated with rheumatic and other inflammatory conditions, as well as for preventing or suppressing inflammation. The present compounds have lower toxicities than the corresponding parent compounds and, in animal experiments at high doses, even at 400 mg per kg per os, rarely cause occult bleeding in the faeces.
Despite this remarkably low toxicity, the present compounds have an excellent inhibitory effect on carraghenin-induced paw edema in rats, so that the therapeutic indices (dose letalis / dose efficiens) of these compounds are much greater than with first-class anti-inflammatory drugs such as indometasinum Phenylbutazone, etc.
(see Table I). TABLE I Anti-inflammatory Effect
EMI0002.0011
EMI0003.0000
(a) The anti-inflammatory effect was evaluated according to the inhibitory effect on the edema of the rat hind paw, which was caused by injection of 0.05 cm 3 of a 1% solution of carraghenin in sterile 0.9% sodium chloride solution.
(b) The test compounds were administered orally 1 hour before the injection of carraghenin. 3 to 6 rats were used for each dose.
(c) The volume of the paw was measured 3, 4 and 5 hours after the injection of the carraghenin, and the mean of these measurements was calculated for each rat. The inhibition of edema is given by the equation:
EMI0003.0003
133 where T is the average volume of edema in the treated group and C is the average volume of edema in the control group.
(d) No blood in the feces, increase in body weight normal.
-I- No blood in the faeces, decrease in body weight -I- -I- Blood in the faeces, decrease in body weight -I- -f- -I- The same symptoms as with -I- -I-, but some animals died within 4 days after administration.
The compounds are preferably administered orally. The pharmaceutically acceptable acid addition salts are preferred. The present connec tions can either be combined with a solid or with a liquid carrier or diluent and are made available in various amounts in the form of conventional pharmaceutical preparations, such as tablets, coated tablets, capsules, powders, suspensions and solutions.
The following examples illustrate the invention. <I> Example </I> A mixture of 6.1 g of N1-cinnamoyl-p-methoxyphenylhydrazine hydrochloride, 6 g of bN, N-diethylaminoethyl levulinate and 50 g of isopropanol is stirred under reflux for 5 hours . The solvent is removed under reduced pressure; the residue is mixed with water and the mixture is extracted with benzene. The benzene layer is washed with water and dried over sodium sulfate.
The solvent is removed under reduced pressure to give β-N, N-diethylaminoethyl-1-cinnamoyl-2-methyl-5-methoxy-3-indolyl acetate. Gaseous hydrogen chloride is introduced into a solution of this compound in ether. The crystals deposited are isolated by filtration and recrystallized from ethanol, 3-N, N-diethylaminoethyl-1-cinnamoyl-2-methyl-5-methoxy-3-indolylacetate hydrochloride with a melting point of up to 134 ° C. being obtained.
The following compounds can be obtained according to the procedure described above: <B> 137 </B> P, (PP 164, p P bN, N-dimethylaminoethyl-1- (3 ', 4'-methylenedioxybenzoyl) -2- methyl 5-methoxy-3-indolylacetate hydrochloride with a melting point of up to 138 C, b-dimethylaminopropyl-1-cinnamoyl-2-methyl-5-methoxy-3-indolylacetate hydrochloride with a melting point of 170 to 172 C, bN, N -Dimethylaminoethyl-1-cinnamoyl-2-methyl-5-methoxy-3-indolylacetate hydrochloride, melting point 194 to 194.5 C,?
-N, N-Dimethylaminopropyl-1-cinnamoyl-2-methyl-5-methoxy-3-indolylacetate-hydrochloride of melting point 156 to 157 C, γ-morpholinopropyl-1-cinnamoyl-2-methyl-5-methoxy- - 3-indolylacetate hydrochloride with a melting point of 166 to 167 ° C, b-morpholinoethyl-1-cinnamoyl-2-methyl-5-methoxy-3-indolylacetate hydrochloride with a melting point of 187 to 188 ° C, b- (N4-benzylpiperazino) ethyl -1-cinnamoyl-2-methyl-5-methoxy-3-indolylacetate dihydrochloride with a melting point of 188 to 189 C,
b-Piperidinoethyl-1-cinnamoyl-2-methyl-5-methoxy-3-indolylacetate hydrochloride with a melting point of up to 165 ° C. -piperidinoethyl-1- (p-chlorobenzoyl) -2-methyl-5-methoxy-3 -indolylacetate hydrochloride with a melting point of 210 to 211 ° C, -Morpholinoethyl-1- (3 ', 4'-methylenedioxybenzoyl) -2- -methyl-5-methoxy-3-indolylacetate hydrochloride with a melting point of 120 ° C (decomposition), ss- Morpholinoethyl 1- (p-chlorobenzoyl) -2-methyl-5-methoxy-3-indolylacetate hydrochloride with a melting point of 201 to 202 C, ss- [2 '- (N-methylpiperidyl)
] Ethyl-l-cinnamoyl-2-methyl-5-methoxy-3-indolylacetate hydrochloride with a melting point of 128 to 129 C, g-piperidinopropyl-l-cinnamoyl-2-methyl-5-methoxy-3-indolylacetate hydrochloride with a melting point of 144 to 145 C, diethylaminoethoxyethyl-1-cinnamoyl-2-methyl-5-methoxy-3-indolylacetate citrate with a melting point of 72.5 to 73.5 C.
Claims (1)
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6545868A JPS4843739B1 (en) | 1968-09-10 | 1968-09-10 | |
| JP6545768A JPS4843738B1 (en) | 1968-09-10 | 1968-09-10 | |
| JP6545668 | 1968-09-10 | ||
| JP6545968 | 1968-09-10 | ||
| JP8336868 | 1968-11-14 | ||
| JP8336768A JPS4927190B1 (en) | 1968-11-14 | 1968-11-14 | |
| JP985769 | 1969-02-10 | ||
| CH1355969A CH522639A (en) | 1968-09-10 | 1969-09-08 | Process for the preparation of 3-indolylacetic acid derivatives and their salts |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH520670A true CH520670A (en) | 1972-03-31 |
Family
ID=27570385
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1874271A CH520670A (en) | 1968-09-10 | 1969-09-08 | 1-Acyl 3-indolyl acetates |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH520670A (en) |
-
1969
- 1969-09-08 CH CH1874271A patent/CH520670A/en not_active IP Right Cessation
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DD207714A5 (en) | PROCESS FOR THE PREPARATION OF BENZIMIDAZOLENE | |
| DD159071A5 (en) | METHOD FOR THE PREPARATION OF PYRIDOXIN DERIVATIVES AND THEIR USE IN THERAPEUTICA | |
| EP0174464B1 (en) | Substituted benzyl phthalazinone derivatives | |
| DE2128375C3 (en) | Basic substituted alkylideneamino-oxyalkyl-carboxylic acid esters, their acid addition salts, processes for their production and pharmaceutical preparations containing them | |
| DE1695111B1 (en) | Indole derivatives | |
| DE1967080C3 (en) | t- (3,4-Methylenedioxybeiizoyl) -2methyl-5-methoxy-3-indolylacetic acid ester, process for their preparation and medicinal preparations | |
| CH645368A5 (en) | 2-HYDROXY-5- (1-HYDROXY-2-PIPERAZINYLETHYL) BENZOESIC ACID DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF. | |
| DD202563A5 (en) | PROCESS FOR PREPARING 1,5-DIPHENYLPYRAZOLIN-3-ON COMPOUNDS | |
| DE2404050A1 (en) | NEW HETEROCYCLIC BINDINGS AND METHODS FOR THEIR PRODUCTION | |
| CH520670A (en) | 1-Acyl 3-indolyl acetates | |
| DE2609397A1 (en) | 8-AMINOTHEOPHYLLINE DERIVATIVES, METHOD FOR THEIR MANUFACTURING AND MEDICINAL PREPARATIONS CONTAINING THEM | |
| DE1934392C3 (en) | New 2-pyridylthioamides and process for their preparation | |
| CH493467A (en) | Dibenzosuberene derivs | |
| DE2624918A1 (en) | MEDICINAL PRODUCTS WITH ANTIARRHYTHMIC EFFECT | |
| DE2331721A1 (en) | PROCESS FOR PRODUCING NEW HETEROCYCLIC COMPOUNDS | |
| AT383806B (en) | Process for the preparation of novel compounds of furo[3,4-c]pyridine derivatives and of the salts thereof | |
| CH644125A5 (en) | BENZO-AS-TRIAZINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF. | |
| DE2516317A1 (en) | O-DIAKYLAMINOALKYL-5-NITRO-2-FURANAL DOXIMES AND THE METHOD FOR THEIR PRODUCTION | |
| AT362358B (en) | METHOD FOR PRODUCING NEW 6-ARYL-2,3, 6,7-TETRAHYDRO-5H-PYRROLO (1,2-A) IMIDAZOLES AND THEIR ACID ADDITION SALTS | |
| AT336017B (en) | PROCESS FOR THE PRODUCTION OF NEW 2-AMINOINDANE DERIVATIVES AND THEIR ACID ADDITIONAL SALTS | |
| DE1470319C3 (en) | Benzimidazole derivatives, processes for their preparation and pharmaceuticals containing them | |
| DE2429755A1 (en) | NITROIMIDAZOLE DERIVATIVES, THEIR SALT, PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS | |
| AT331216B (en) | PROCESS FOR THE PRODUCTION OF NEW AMINOBENZYLAMINES AND THEIR ACID ADDITION SALTS | |
| DE2753391A1 (en) | BENZISOTHIAZOLONE, METHOD FOR THE PRODUCTION THEREOF AND MEDICAL PREPARATIONS CONTAINING THESE COMPOUNDS | |
| AT212827B (en) | Process for the production of new 3-aralkyl-2-tert. aminoalkyl indenes, their acid addition salts, quaternary ammonium compounds and N-oxides |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |