NO162189B - Analogifremgangsm te for fremstilling av terapeutisk aktive imidazopyridiner. - Google Patents
Analogifremgangsm te for fremstilling av terapeutisk aktive imidazopyridiner. Download PDFInfo
- Publication number
- NO162189B NO162189B NO853100A NO853100A NO162189B NO 162189 B NO162189 B NO 162189B NO 853100 A NO853100 A NO 853100A NO 853100 A NO853100 A NO 853100A NO 162189 B NO162189 B NO 162189B
- Authority
- NO
- Norway
- Prior art keywords
- lower alkyl
- halogen
- indolyl
- acid
- alkyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 10
- 150000005232 imidazopyridines Chemical class 0.000 title 1
- 230000001225 therapeutic effect Effects 0.000 title 1
- -1 biphenylyl Chemical group 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims description 7
- 125000002905 alkanoylamido group Chemical group 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000001589 carboacyl group Chemical group 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 150000008064 anhydrides Chemical class 0.000 claims description 3
- 150000001540 azides Chemical class 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- TXWGINUZLBAKDF-UHFFFAOYSA-N N-Deschlorobenzoyl indomethacin Chemical compound COC1=CC=C2NC(C)=C(CC(O)=O)C2=C1 TXWGINUZLBAKDF-UHFFFAOYSA-N 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 2
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical class OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- AEJAPRPYYAHEJH-UHFFFAOYSA-N 2-[5-(dimethylamino)-2-methyl-1H-indol-3-yl]acetic acid Chemical compound CC=1NC2=CC=C(C=C2C1CC(=O)O)N(C)C AEJAPRPYYAHEJH-UHFFFAOYSA-N 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000008188 pellet Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010018691 Granuloma Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 125000003435 aroyl group Chemical group 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- NHVHYFAWHCJELN-UHFFFAOYSA-N benzene;n,n-dimethylformamide Chemical compound CN(C)C=O.C1=CC=CC=C1 NHVHYFAWHCJELN-UHFFFAOYSA-N 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Fremgangsmåte ved fremstilling av terapeutisk aktive substituerte 3-indolyllavere alifatiske syrer.
Foreliggende oppfinnelse angår en fremgangsmåte ved fremstilling av en ny gruppe terapeutisk aktive substituerte cc-(3-indolyl) - lavere alifatiske syrer med en eventuelt substituert benzoyl-, fenylbenzoyl-, eller nafthylgruppe bundet til nitro-genatomet i indol-ringen, samt salter av slike forbindelser.
De nye forbindelser som fremstilles ifblge oppfinnelsen har den generelle formel:
hvor It^ er 1'enyl, bifcnylyl eller nafthyl som han vrere substituert med hydroxyl, lavere alkyl, lavere alkoxy, carbo-lavere alkoxy, lavere alkanoyl, lavere alkanoyloxy, fcnyl, fonoxy, benzyl, benzyl-oxy, benzoyl, amino, mono- eller di-lavere alkylanino, lavere alkanoylamido, aminomethyl, N,H-di-(lavere alkyl)-carboxamido, nitro, cyano, halogen, halogen-lavere alkyl, halogen-lavere alkoxy, halogen-lavere alkanoyl, mercapto, lavere alkylthio, halogen-lavere
, alkylthio, fenylthio, benzylthio, benzoylthio, lavere alkyl-sulfonyl, lavere alkyl-sulfinyl eller di-(lavere alkyl) -sulfarnyl, lin er hydrogen eller lavere alkyl,
it^ or hydrogen, lavere alkyl eller lavere alkenyl,
lij er hydrogen, hydroxyl, lavere alkyl, lavere alkenyl, lavere alkoxy, dl-lavere alkylamino, lavere alkanoylamjdo, N-lavero alkyl-laverc alkanoylamido, dl-lavore alkyl-aminomethyl, halogen, poly-halogorunothyl, nitro, cyano, mercapto, benzylthio, di-lavero alkyl-sulf amyl, morfolinyl, J.:-inethyl-pipera:',inyl, N-pyrrolidyl oller N-aziicyclopropyl.
Et meget viktig trokk ved de nyo f rcmgangsm/jteforbindelser r.-r n::!rvisr av en av de angitte aroylgruppcr bundet til nitrogenatomot i-1-stillingen i indolet. Disse aroylgruppcr kan vmrc substituert i den aromat i uke ring med nubstituentcr som ovnjiror angitt.
De foretrukne iVcmgaiigsmutcprodukter1 or l-p-klorbcnzoyl-2-mothyl-5-inf:thoxy-3-indolyl-eddiksyro og l-p-klorbonxoyl-2-mcthyl-^-dimcthylamino^-indolyl-cddiksyré.
Do nt-( 3-lndolyl)-lavere ali fati.-.ko syror nom beskrives i dot foreliggende, or f.eks. «-(3-indolyl)-derjvater av eddiksyre, prop-ioucyrc, iimor^yro, valoriancyro og lignemlo syver. Galter av slike alifatiske syrer omfattes og sa av oppfinnelsen.
daltene av disne nye n<-( l-aroyl-3-indolyl) -lavere-alif atiske syrer kan erholdes ved at man behandler den frie r.yre med base under milde betingelser. På denne måte kan man fremstille alkali - metallsalter såsom natrium- og kalium-, aluminium eller magnesium-salter oller salter av .jordalkalimetaller, eksempelvis barium- og calciumsalter.
Framgangsmåter or bindclsene som er omtalt ovenfor, hor i hov grad anti-inflammatorisk aktivitet og kan brukes til å hindre og hemme dannelse av grarmloma-vev. Knkelte av dem har denne aktivitet i sterk grad og er av verdi ved behandling av arthritis og derma-tologiske sykdommer og lignende tilstander som reagerer på behandling med anti-inflammatoriske midler. Dertil har fromgnngsmåte-produktene i betydelig grad antipyretisk aktivitet. For disse for-mål blir de normalt anvendt oralt i form av tabletter eller kaps-ler, og den optimale dose avhenger selvsagt av don .spesielle forbindelse som brukes og av infeksjonens art og grad. Ckjont de optimale mengder av disse forbindelser vil avhenge av den forbindelse som anvendes, og av den spesielle sykdomstilstand som skal behand-les, kan de foretrukne forbindelser oralt brukes i mengder innen området 1,0 - 2000 mg pr. dag i tilfelle av arthritis, avhengig- av den spesielle forbindelses aktivitet og pasientens reaksjonsfulsom-het.
I henhold til oppfinnelsen fremstilles forbindelsene med formel I ved at en forbindelse med den generelle formel:
hvor K,-,, °£ er som overil"or angitt, og K cv et alkalimetall, aeyleres ved omsetning med et halogenid, anhydrid, azid eller en nitrofenylester av en syre av formelen U^COOII, hvor er som ovenfor angitt.
Acyleringsreaksjonen utfores fortrinnsvis ved at man behandler et oc-(3-indolyl)-syrematerlale med et alkalimetallhydrid, eksempel-• vis natriumhydrid, for å danne et alkalimetallsalt og derpå bringer saltet i intim kontakt med et halogenid av en syre av formelen. R^COOH i et vannfritt opplosningsmiddel. Det foretrekkes å bruke opplosningsmidler som dimethylformamid, dimethylformamid-benzen, benzen, toluen eller xylen. Det er å foretrekke å utfore acyleringen ved værelsetemperatur, skjont lavere temperaturer kan anvendes hvis det er fare for at de spesielle.reaktanter kan undergå spaltning.
En alternativ metode til acylering i 1-stillingen er å bruke en nitrofenylester av den acylerende syre, som f.eks. p-nitrofenylesteren. Sistnevnte fremstilles ved at man blander syren og p-nitrofenol i tetrahydrofuran og langsomt tilsetter dicyclohexyl-carbodiimid i tetrahydrofuran. Dicyclohexylurinstoffet som dannes, fjernes ved filtrering, og nitrofenylesteren utvinnes fra filtratet. Alternativt kan man bruke anhydridet eller azidet av den acylerende syre. I alle tilfelle utfores acyleringen av den som utgangs-<; >materiale anvendte a-(3-indolyl)-carboxylsyre ved at man går ut fra et alkalimetallsalt av syren, fremstilt ved omsetning av syren med et alkalimetallhydrid i et vannfritt opplosningsmiddel, og tilsetter nitrofenylesteren.
Fremstillingen av utgangsmaterialene som anvendes ved foreliggende fremgangsmåte, er beskrevet i belgisk patent nr. 615.395.
Den anti-inflammatoriske virkning av fremgangsmåteforbind-elsene fremgår av en granulomahemmende prove som er utfort som folger: Proven er en modifikasjon av den som er beskrevet av Meier og medarb. (Experientia 6, 1950, k6$). Den består hovedsakelig i implantering av steriliserte bomullspellets på rotter, fjernelse av pelletene etter 7 dager (systemprove) eller 5 dager (lokalprove), og bestemmelse av okningen i torrvekt av hver pellet. Den opprinne-lige vekt av pelletene varierte fra forsok til forsok, men innen ett og samme forsok var alle innen en toleranse på -f-1 mg. To pel-iets ble innfort i hvert dyr, en på hver side av bukhulen. Når lokalvirkningen av én forbindelse skulle studeres, ble forbindel-sen anbragt på en pellet i et medium inneholdende fuktemiddel, mene mediet alene ble brukt på den annen pellet, slik at hvert dyr var sin egen kontroll. Ved systemprover utgjorde den gjennomsnittlige granuloma-tbrrvekt av de to prover i hvert dyr det individuelle resultat. Proveforbindelsene ble gitt oralt en gang daglig ved inn-fbring i maven med sonde.
Ved alle forsok ble anvendt Holtzman-hanrotter over legems-vekt ca. 125 - 175 g. Aktiviteten ble uttrykt ved tallene 1 - h med folgende betydning:
De anvendte forbindelser og deres aktivitet fremgår av tabellen.
Eksempel 1
1-p-klor-bonzoy1-2-mcthy1-5-me thoxy-3- indolyl- eddikr. yre
Til en opplbsninc av 5,22 g 2-mcthyl-5-methoxy-3-indolyl-eddiksyre i 20 ml dimethyldiformamid setten en suspensjon av 1,2 r 51/i natrlumhydrld 1 mineralolje i 'i-O ml dimethylformamid. Ktter en times omrbrinc ved romtemperatur blir en opplbsning av 2, Kb ml p-klor-benzoylklorid i 10 ml dimethylformamid tilsatt for a initi-ere en moderat exotherm reaksjon med utfeining av natriumklorid. Ueaksjonsblandingen omrbres i 6 timor hvoretter den gies henstand, natten over. JJlandingen helles over i ca. 200 g is og ekstraheren tre ganger med ether. Ethcropplbsnlngen vaskes med vann, natrium-carbonat og tbrres over kaliumcarbonat. Etter filtrering inndampe-s: opplbsningen til en sirup og kroinatografnros i en kolonne inneholdende 100 g syrevåskeb nluminiumoxyd, idet der nom oluerings-middel anvendtes blandinger av benV.cn og petrolother i volumfor-hold 2:1 til 3:1. M*n fikk l-p-klorbonxoyl-2-m<p>Lhyl-5-methoxy-3-indolyl-eddiksyre mod sm.p. 151-153°(J. ;Eksempel 2 ;Til on suspensjon av 10,6 g 50/*i-ig nntriumhydridemulsjon
i 100 rnl xylen ved 120°C ble tilsatt nn opplesning av 21,9 g <"-methy.l-5-methoxy-3-iniJnlyl-oddiksyri: 1 100 ml dimethylfoi-m/iiiiii<1> :i lbpet av 3° minutter. Temperåturen ble holdt ved 120-122°C under tilsetningen og i yLherligore 1? minutter. iJlnhdingcn ble s?i av-kjolt til 10°C under nitrogen og L':,0 g p-klorbcn.".oylklorirl i 20 ml xylen ble tilratt ved ]0-l!?°(; i Ifipet av 30 mirmtter..-TLei-olding i en time ble 15 ml iseddik tilsatt dråpevis ved 15-20°U
i lbpet av 30 minutter. Suspensjonen ble eldet i en time or; ''crpf. filtrert. Kakon ble vasket !'ri i"or uorganiske salter mei vann o;: produktet turret i vakunn1. Omkrystalli sas jon fra t-butanol ga 1-p-klorbcn/".oyl-2-mothyl-5-met]ioxy-3-indolyl-cddiksyrn merl smeltepunkt 157-159°C
Eksempel 3
Nn r man ved freingangsmal.cn i eksempel 2 istedenfor 2-mothyl-5-methoxy-3-indolyl-eddiksyre anvender 23,2 g 2-mothyl-5-dimethyI-ami.no-3-indolyl-cddikr.yro Jacs l-p-klorbcn/.oyl-2-inclhyl-5-dimothyl-atnino-3-indolyl-eddiksyre med snmltnpunkt ]6^-171°(j.
Claims (3)
1. Fremgangsmåte ved fremstilling av terapeutisk aktive, substituerte 3-indolyl-lavere alifatiske syrer med den generelle formel:
hvor R^ er fenyl, bifenylyl eller nafthyl som kan være substituert med hydroxyl, lavere alkyl, lavere alkoxy, carbo-lavere alkoxy,
lavere alkanoyl, lavere alkanoyloxy, fenyl, fenoxy, benzyl, benzyl-oxy, benzoyl, amino, mono- eller di-lavere alkylamino, lavere alkanoylamido, aminomethyl, N,N-di-(lavere alkyl)-carboxamido, nitro, cyano, halogen, halogen-lavere alkyl, halogen-lavere alkoxy, halogen-lavere alkanoyl, mercapto, lavere alkylthio, halogen-lavere alkylthio, fenylthio, benzylthio, benzoylthio, lavere alkyl-sulfonyl, lavere alkyl-sulfinyl eller di-(lavere alkyl)-sulfamyl,
R2 er hydrogen eller lavere alkyl, R^ er hydrogen, lavere alkyl eller lavere alkenyl, og . Rj er hydrogen, hydroxyl, lavere alkyl, lavere alkenyl, lavere •alkoxy, di-lavere alkylamino, lavere alkanoylamido, N-lavere alkyl-lavere alkanoylamido, di-lavere alkylaminomethyl, halogen, ipolyhalogenmethyl, nitro, cyano, mercapto, benzylthio-, di-lavere ;alkylsulfamyl, morfolinyl, N-methyl-piperazinyl, N-pyrrolidyl .eller N-azacyclopropyl, samt salter derav,
karakterisert ved at en forbindelse med den generelle formel:
hvor R,,, R^°S ^5 er som ovenfor angitt, og M er et alkalimetall, acyleres på i og for seg kjent vis med et halogenid, anhydrid, azid, eller en nitrofenylester av en syre rncd den generelle formel: R-^COOII, hvor R^ er som ovenfor angitt, og, om bnskes, overfores den erholdte syre til et salt på i og for seg kjent vis.
2. Fremgangsmåte ifolge krav 1, karakterisert ved at et N^-alkalimetallsalt av 2-methyl-5-methoxy-3-indolyl-eddiksyre omsettes med et derivat av p-klorbenzoecyre.
3. Fremgangsmåte ifolge krav 1, karakterisert ved at et H^-alkalimetallsalt av 2-methyl-5-dimethylamino-3-indolyl-eddiksyrc omsettes med et derivat av p-klorbenzoesyre.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8412447A FR2568880B1 (fr) | 1984-08-07 | 1984-08-07 | Derives d'acylaminomethyl-3 imidazo(1,2-a)pyridines, leur preparation et leur application en therapeutique |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO853100L NO853100L (no) | 1986-02-10 |
| NO162189B true NO162189B (no) | 1989-08-14 |
| NO162189C NO162189C (no) | 1989-11-29 |
Family
ID=9306856
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO853100A NO162189C (no) | 1984-08-07 | 1985-08-06 | Analogifremgangsmaate for fremstilling av terapeutisk aktive imidazopyridiner. |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US4650796A (no) |
| EP (1) | EP0172096B1 (no) |
| JP (1) | JPS6147485A (no) |
| KR (1) | KR910004450B1 (no) |
| AR (1) | AR241185A1 (no) |
| AT (1) | ATE40365T1 (no) |
| AU (1) | AU575190B2 (no) |
| CA (1) | CA1261830A (no) |
| CZ (1) | CZ357691A3 (no) |
| DE (1) | DE3567867D1 (no) |
| DK (1) | DK163923C (no) |
| ES (1) | ES8604592A1 (no) |
| FI (1) | FI80696C (no) |
| FR (1) | FR2568880B1 (no) |
| GR (1) | GR851928B (no) |
| HU (1) | HU193799B (no) |
| IE (1) | IE58347B1 (no) |
| IL (1) | IL76020A (no) |
| MX (1) | MX160845A (no) |
| NO (1) | NO162189C (no) |
| NZ (1) | NZ213013A (no) |
| PT (1) | PT80921B (no) |
| ZA (1) | ZA855939B (no) |
Families Citing this family (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2593180B1 (fr) * | 1986-01-22 | 1990-10-26 | Synthelabo | Derives d'acylaminomethyl-1 imidazo (1,2-a)quinoleines, leur preparation et leur application en therapeutique |
| ES2032455T3 (es) * | 1986-01-22 | 1993-02-16 | Synthelabo | Procedimiento para preparar derivados de 3-acilaminometil-imidazo (-1,2-a)piridinas. |
| FR2593818B1 (fr) * | 1986-02-05 | 1988-04-29 | Synthelabo | Derives d'acylaminomethyl-3 imidazo(1,2-a)pyridine, leur preparation et leur application en therapeutique |
| US4990506A (en) * | 1986-02-05 | 1991-02-05 | Synthelabo | 3-(acylaminomethyl)imidazo[1,2-a]pyridine derivatives and their application in therapy |
| FR2606409B1 (fr) * | 1986-11-07 | 1989-05-05 | Synthelabo | Derives d'imidazopyridine, leur preparation et leur application en therapeutique |
| EP0289371B1 (fr) * | 1987-03-27 | 1991-09-25 | Synthelabo | Dérivés d'imidazopyridines, leur préparation et leur application en thérapeutique |
| FR2615513B1 (fr) * | 1987-05-21 | 1989-07-13 | Synthelabo | Derives d'acylaminomethyl-3 tetrahydro-5,6,7,8 imidazo(1,2-a)pyridines, leur preparation et leur application en therapeutique |
| FR2654933B1 (fr) * | 1989-11-30 | 1994-06-10 | Synthelabo | Utilisation d'une imidazopyridine pour la fabrication de medicaments anesthesiques. |
| KR910011852A (ko) * | 1989-12-04 | 1991-08-07 | 폴 디. 매튜카이티스 | 신경독 장해 치료용 이미다조[1,2-a]피리디닐알킬 화합물 |
| US5716964A (en) * | 1989-12-04 | 1998-02-10 | G.D. Searle & Co. | Tetrazolyl substituted imidazo 1,2-a!pyridinylalkyl compounds for treatment of neurotoxic injury |
| IE904346A1 (en) * | 1989-12-04 | 1991-06-05 | Searle & Co | IMIDAZO[1,2-a]PYRIDINYLALKYL COMPOUNDS FOR TREATMENT OF¹NEUROTOXIC INJURY |
| US5464843A (en) * | 1992-06-23 | 1995-11-07 | G.D. Searle & Co. | Imidazo[1,2-a]pyridinyldiacid compounds for cognitive enhancement and for treatment of cognitive disorders and neutrotoxic injury |
| AUPP278498A0 (en) * | 1998-04-03 | 1998-04-30 | Australian Nuclear Science & Technology Organisation | Peripheral benzodiazepine receptor binding agents |
| DE10019714A1 (de) * | 2000-04-20 | 2002-01-10 | Gruenenthal Gmbh | Salze von bicyclischen, N-acylierten Imidazo-3-aminen und Imidazo-5-aminen |
| AU2001270297A1 (en) * | 2000-06-30 | 2002-01-14 | Neurogen Corporation | 2-phenylimidazo(1,2-a)pyridine derivatives: a new class of gaba brain receptor ligands |
| US6596731B2 (en) | 2001-03-27 | 2003-07-22 | Hoffmann-La Roche Inc. | Substituted imidazo[1,2-A] pyridine derivatives |
| DE10247269A1 (de) | 2002-10-10 | 2004-04-22 | Grünenthal GmbH | Substituierte C-Imidazo[1,2-a]pyridin-3-yl-methylamine |
| WO2005044818A2 (en) * | 2003-10-28 | 2005-05-19 | Sepracor, Inc. | Imidazo[1,2-a]pyridine anxiolytics |
| WO2005081749A2 (en) * | 2004-01-23 | 2005-09-09 | Avanir Pharmaceuticals, Inc. | Neutralizing human antibodies to anthraxtoxin |
| FR2874611B1 (fr) * | 2004-08-31 | 2006-11-17 | Servier Lab | Nouveaux derives d'imidazopyridine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| ES2321858T3 (es) * | 2004-11-11 | 2009-06-12 | Ferrer Internacional, S.A. | Compuestos de imidazo(1,2-a)piridina, composiciones, usos y metodos relacionados. |
| EP2308870A3 (en) | 2005-06-01 | 2011-10-19 | UCB Pharma S.A. | 2-oxo-1-pyrrolidine deriatives, processes for preparing them and their uses |
| WO2008132142A2 (en) * | 2007-04-27 | 2008-11-06 | Ucb Pharma S.A. | New heterocyclic derivatives useful for the treatment of cns disorders |
| CA2724842A1 (en) * | 2008-05-19 | 2009-11-26 | Sunovion Pharmaceuticals Inc. | Imidazo[1,2-a]pyridine compounds |
| ES2403633T3 (es) * | 2008-12-04 | 2013-05-20 | Proximagen Limited | Compuestos de imidazopiridina |
| WO2014187922A1 (en) | 2013-05-24 | 2014-11-27 | Iomet Pharma Ltd. | Slc2a transporter inhibitors |
| WO2017087885A1 (en) | 2015-11-19 | 2017-05-26 | Dana-Farber Cancer Institute, Inc. | Methods of identifying compounds that interfere with erg-driven misguidance of baf complexes in tmprss2-erg driven prostate cancers |
| CN112153984A (zh) | 2018-01-30 | 2020-12-29 | 福宏治疗公司 | 化合物及其用途 |
| WO2020081588A1 (en) | 2018-10-17 | 2020-04-23 | Dana-Farber Cancer Institute, Inc. | Swi/snf family chromatin remodeling complexes and uses thereof |
| AU2019416589B2 (en) * | 2018-12-29 | 2023-04-06 | Wuhan Ll Science And Technology Development Co., Ltd. | Heterocyclic compound intermediate, preparation method therefor and application thereof |
| US12384776B2 (en) | 2019-01-29 | 2025-08-12 | Foghorn Therapeutics Inc. | Compounds and uses thereof |
| WO2020160100A1 (en) | 2019-01-29 | 2020-08-06 | Foghorn Therapeutics Inc. | Compounds and uses thereof |
| US20230121497A1 (en) * | 2020-01-29 | 2023-04-20 | Foghorn Therapeutics Inc. | Compounds and uses thereof |
| JP7561195B2 (ja) | 2020-01-29 | 2024-10-03 | フォグホーン セラピューティクス インコーポレイテッド | 化合物及びその使用 |
| US12383555B2 (en) | 2020-05-20 | 2025-08-12 | Foghorn Therapeutics Inc. | Methods of treating cancers |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB991589A (en) * | 1963-04-30 | 1965-05-12 | Selvi & C Lab Bioterapico | Novel [1,2-ª‡]imidazopyridines and a process for the manufacture thereof |
| GB1076089A (en) * | 1965-11-09 | 1967-07-19 | Selvi & C Lab Bioterapico | New derivatives of imidazo [1,2-a]-pyridine and a process for the manufacture thereof |
-
1984
- 1984-08-07 FR FR8412447A patent/FR2568880B1/fr not_active Expired
-
1985
- 1985-07-30 DE DE8585401554T patent/DE3567867D1/de not_active Expired
- 1985-07-30 AT AT85401554T patent/ATE40365T1/de not_active IP Right Cessation
- 1985-07-30 EP EP85401554A patent/EP0172096B1/fr not_active Expired
- 1985-08-06 CA CA000488165A patent/CA1261830A/en not_active Expired
- 1985-08-06 PT PT80921A patent/PT80921B/pt not_active IP Right Cessation
- 1985-08-06 MX MX206217A patent/MX160845A/es unknown
- 1985-08-06 IL IL76020A patent/IL76020A/xx not_active IP Right Cessation
- 1985-08-06 JP JP60173977A patent/JPS6147485A/ja active Granted
- 1985-08-06 AU AU45809/85A patent/AU575190B2/en not_active Ceased
- 1985-08-06 ZA ZA855939A patent/ZA855939B/xx unknown
- 1985-08-06 NO NO853100A patent/NO162189C/no unknown
- 1985-08-06 HU HU852991A patent/HU193799B/hu not_active IP Right Cessation
- 1985-08-06 NZ NZ213013A patent/NZ213013A/en unknown
- 1985-08-06 AR AR85301203A patent/AR241185A1/es active
- 1985-08-06 KR KR1019850005660A patent/KR910004450B1/ko not_active Expired
- 1985-08-06 DK DK356885A patent/DK163923C/da not_active IP Right Cessation
- 1985-08-06 GR GR851928A patent/GR851928B/el unknown
- 1985-08-06 IE IE193785A patent/IE58347B1/en not_active IP Right Cessation
- 1985-08-06 ES ES545928A patent/ES8604592A1/es not_active Expired
- 1985-08-06 FI FI853026A patent/FI80696C/fi not_active IP Right Cessation
-
1986
- 1986-02-07 US US06/826,966 patent/US4650796A/en not_active Expired - Lifetime
-
1991
- 1991-11-25 CZ CS913576A patent/CZ357691A3/cs unknown
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