NO165146B - 1h-imidazo-(4,5-c)-kinolin-4-klorforbindelser. - Google Patents
1h-imidazo-(4,5-c)-kinolin-4-klorforbindelser. Download PDFInfo
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- NO165146B NO165146B NO890823A NO890823A NO165146B NO 165146 B NO165146 B NO 165146B NO 890823 A NO890823 A NO 890823A NO 890823 A NO890823 A NO 890823A NO 165146 B NO165146 B NO 165146B
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- Prior art keywords
- indolyl
- methyl
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- carbon atoms
- compounds
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- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 13
- -1 3-indolyl alcohols Chemical class 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 15
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 125000004432 carbon atom Chemical group C* 0.000 abstract 5
- ITIRVXDSMXFTPW-UHFFFAOYSA-N 1H-imidazo[4,5-c]quinoline Chemical class C1=CC=CC2=C(NC=N3)C3=CN=C21 ITIRVXDSMXFTPW-UHFFFAOYSA-N 0.000 abstract 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 229940093499 ethyl acetate Drugs 0.000 description 10
- 241000700159 Rattus Species 0.000 description 7
- 230000010933 acylation Effects 0.000 description 5
- 238000005917 acylation reaction Methods 0.000 description 5
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 5
- 229910052753 mercury Inorganic materials 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 210000002683 foot Anatomy 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002917 arthritic effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000008399 tap water Substances 0.000 description 2
- 235000020679 tap water Nutrition 0.000 description 2
- OZFPSOBLQZPIAV-UHFFFAOYSA-N 5-nitro-1h-indole Chemical compound [O-][N+](=O)C1=CC=C2NC=CC2=C1 OZFPSOBLQZPIAV-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010030124 Oedema peripheral Diseases 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 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
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical compound [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000009772 tissue formation Effects 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
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Physical Water Treatments (AREA)
- Macromonomer-Based Addition Polymer (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Quinoline Compounds (AREA)
- Alarm Systems (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Luminescent Compositions (AREA)
- Lubricants (AREA)
Description
Analogifremgangsmåte ved fremstilling av
terapeutisk aktive estere av 3-indolyl-alkoholer.
Foreliggende oppfinnelse angår en analogifremgangsmåte ved fremstilling av nye, terapeutisk aktive estere av f3-( 3-indolyl) -
lavere alifatiske alkoholer.
Fra belgisk patent 615-395 er det kjent å fremstille beslekt-
ede estere av substituerte 3-indolyl-lavere alifatiske syrer, men disse estere er ikke så aktive mot fot-oedema som fremgangsmåteforbindelsene.
Utgangsmaterialene som anvendes ved foreliggende fremgangsmåte,
er kjent fra nederlandsk patent ansøkning 6./f00.8l3 hvor de anvendes som utgangsmaterialer for fremstilling av de samme terapeutisk aktive estere av substituerte 3-indolyl-lavere alifatiske syrer som i det ovennevnte belgiske patent.
De nye 1-aroyl-3-indolyl-estere fremstilt ved foreliggende fremgangsmåte, har den generelle formel:
hvor
er fenyl som eventuelt er substituert med et halogenatom, R2 og R er hydrogen eller lavere alkyl,
R^ er lavere alkyl eller R^, og
R^ er lavere alkoxy eller di-lavere alkylamino,
karakterisert ved at en alkohol av formelen:
hvor R^ , R2 og R^ er som ovenfor angitt, og R^ er R^ eller nitro, omsettes med et acyleringsmiddel som inneholder gruppen R^-CO-, hvor R^ er som ovenfor angitt, og når R^ er nitro, overføres denne til di-lavere alkylamino på i og for seg kjent vis.
I de foretrukne fremgangsmåteforbindelser er R^ p-klorfenyl, R2 er hydrogen, methyl eller ethyl, R^ er hydrogen eller lavere alkyl, R^ er lavere alkyl, som methyl eller propyl, og R^ er lavere alkoxy, som methyloxy, ethoxy, isopropoxy og lignende, eller di-lavere alkylamino, som dimethylamino.
De p-(3-indolyl)-alifatiske alkoholestere som er beskrevet her, er avledet av lavere alifatiske alkoholer, som ethyl-, propyl-, butyl-. og pentylalkohol.
I 2-stilling på indolringen (R2) kan der være hydrogen, skjønt det foretrekkes at der i denne stilling er en lavere alkylgruppe, som methyl, ethyl, propyl og butyl.
Representative for de forbindelser som fremstilles ifølge oppfinnelsen, er p-[ 1 -(p-klorbenzoyl) -2-methy 1-5-methoxy -3-indolylQ —
ethylacetat.
Fremstillingen av de p-(1-aroyl-3-indolyl)-lavere alifatiske alkoholer og derivater derav som ifølge oppfinnelsen anvendes for å fremstille de verdifulle estere, er nærmere beskrevet i nederlandsk ansøkning nr. 6.6l4«354.
De p-(1-acylert-3-indolyl)-lavere alifatiske estere og derivater derav som fremstilles ifølge oppfinnelsen, har en høy grad av anti-inflammatorisk aktivitet og er effektive til å forhindre og inhibere granulomavevdannelse. Visse av dem har denne aktivitet i høy grad og er verdifulle ved behandling av arthritiske og dermato-logiske lidelser, og ved lignende tilstander som lar seg behandle med ant i-inflammatoriske midler. Dessuten har fremgangsmåteforbindelsene en nyttig grad av antipyretisk aktivitet. For disse formål administreres de vanligvis oralt i tabletter eller kapsler, idet den optimale dose avhenger selvsagt av den spesielle forbindelse som anvendes og typen og graden av infeksjon som behandles. Skjønt de optimale mengder av fremgangsmåteforbindelsene som skal anvendes på denne måte, vil avhenge av den anvendte forbindelse og den spesielle type av lidelse som behandles, er orale doser av foretrukne forbindelser i området IO - 4000 mg pr. dag nyttige ved bekjempelse av arthritiske tilstander, avhengig av aktiviteten av den spesielle forbindelse og pasientens reaksjonsfølsomhet.
Den terapeutiske aktivitet ble bestemt som følger:
Inhibering av oedema ble bestemt ved å administrere ved sonde-innføring i maven på rotter en vandig suspensjon av forsøksforbind-elsen i et volum på 1 ml pr. lOO g legemsvekt, øyeblikkelig fulgt av springvann til et totalvolum på 3 - 5 ml (avhengig av den anvendte sats) pr. rotte. Kontrolldyr fikk bare springvann. 1 time senere ble 0,05 til 0,1 ml (avhengig av den anvendte sats) av en 1%-ig suspensjon av Carrageenin i steril 0,9%-ig koksaltoppløsning innført i fotsålevevet på den høyre baklabb på hver rotte. Straks derefter ble volumet av den injiserte fot målt. Økningen i fotvolum ble målt 3 timer senere. Fremgangsmåten ved måling av fotvolumet i rottene var som følger: Rottens labb ble neddykket i kvikksølv nøyaktig til et blekkmerke på skinnet over den laterale malleolus. Kvikksølvet var anbrakt i en glassylinder av 25 mm diameter og éOrnn dybde. Kvikk-sølvsøylen var forbundet med en "Statham pressure transducer model P23BB range 0.5 cm Hg". Signalet fra "transduceren" ble ført over en "Statham Control unit" drevet av en 12 V transformator til en Fisher laboratorieskriver. Neddykning i kvikksølvet av en gjen-stand frembrakte et utslag av pennen på skriveren som var kalibrert i ml volum av fortrengt kvikksølv. Alle forsøk ble utført på voksne Holtzman hanrotter av 125 - 165 g legemsvekt. De angitte inhiber-inger var gjennomsnittsresultatet fra 6 rotter i hvert enkelt for-
Av disse forsøk fremgår at fremgangsmåteforbindelsene er mere aktive enn sammenligningsforbindelsen som er kjent fra belgisk patent nr. 615.395.
Ved foreliggende fremgangsmåte foretrekkes det å anvende acylhalogenider da reaksjonen kan tvinges nærmere fullstendighet ved nærvær av et reagens som vil reagere med saltsyren eftersom denne; dannes. Syreanhydrider er meget egnet for acyleringen når en tobasisk gruppe ønskes, da produktet er en énbasisk ester.
Om ønskes, kan alkoholene acyleres med syrer. En mere full-stendig acylering vil lettere oppnåes med et overskudd av syren til-stede og ved å fjerne vannet som dannes som biprodukt ved reaksjonen .
Denne siste rekke av reaksjoner kan illustreres ved ligningen som viser fremstillingen av (3-( l-benzoyl-2 -methyl-5-methoxy -3-indolyl)-ethylacetat, ved å gå ut fra (3-(2-methyl-5-methoxy-3-indolyl)-ethyl-benzylether.
Syntesen av de forskjellige fremgangsmåteforbindelser som har en 5-di-lavere alkylamino-substituent, er i alminnelighet basert på 5-nitroforbindelsen. Denne overfores til den onskede 5-di-lavere alkylamino-substituent. Slik overforing kan skje for eller efter acylering av hydroxylgruppen, avhengig av graden i hvilken den onskede 5~substituent kan gripe forstyrrende inn i acyleringen.
Hvis en slik forstyrrelse er mulig, bor acyleringen utfores på 5-nitroindolen og nitrogruppen senere overfores til den onskede 5-di-lavere alkylaminosubstituent. Slik overforing kan skje på i og for seg kjent vis, f.eks. ved å redusere nitrogruppen og omsette den dannede aminogruppe med et alkylhalogenid.
Oppfinnelsen skal så illustreres ved folgende eksempler: Eksempel 1
( 3- f l-( p- klorbenzoyl) - 2- methyl- 5- methoxy- 3- indolyll - ethylacetat
Tilsammen 0,1 mol p-[l-(p-klorbenzoyl)-2-methyl-5-methoxy-3-indolyl]-ethanol blandes med 0,12 mol acetylklorid og 20 ml av en 20^-ig natriumhydroxydopplosning og oppvarmes ved 50°C i 1 time. Produktet som felles, frafUtreres, vaskes med vann og torres, hvorved man får (3-[l-(p-klorbenzoyl)-2-methyl-5-methoxy-3-indolyl]-ethylacetat, sm.p. llh - 115°C.
Eksempel 2
( 3- f l-( p- klorbenzoyiy2- methyl- 5- dimethylamino- 3- indolyl" l- ethylacetat
Tilsammen 0,025 mol p-[l-(p-klorbenzoyl)-2-methyl-5-nitro-3-indolyl]-ethylacetat i 100 ml ethanol hydrogeneres i nærvær av 120 mg av en 10$-ig palladium-på-trekullkatalysator ved værelsetemperatur og et trykk på 2,8 kg/cm 2. Efter at den teoretiske mengde hydrogen var forbrukt, ble hydrogeneringen stanset og oppløsningen filtrert for å fjerne katalysatoren. Filtratet ble konsentrert til torrhet i vakuum, hvorved man fikk B-[l-(p-klorbenzoyl)-2-methyl-5-amino-3-indolyl]-ethylacetat.
Det erholdte B-[l-(p-klorbenzoyl)-2-methyl-5-amino-3-indolyl]-ethylacetat ble så på kjent vis behandlet med methylklorid hvorved man fikk B-[l-(p-klorbenzoyl)-2-methyl-5-dimethylamino-3-indolyl]-ethylacetat.
Eksempel 3
( 3-[ 1 - ( p- klorbenzoyl) - 2- methyl- 5- dimethylamino- 3- indolylJ - ethylacetat
Til en oppløsning av 0,001 mol (3-[ 1 -(p-klorbenzoyl) -2-methyl-5-nitro-3-indolyT/^ethylacetati20 ml destillert dimethoxyethan til-settes 1,5 ml iseddik og 0,5 ml av en 37%-ig vandig formaldehydopp-løsning. Denne blanding reduseres med Raney-nikkel ved 2,8 kg/cm<2 >og værelsetemperatur. Efter at den teoretiske mengde hydrogen har reagert, filtreres reaksjonsblandingen, konsentreres i vakuum til lite volum og fortynnes med ether. Etheroppløsningen vaskes med natriumbicarbonat, derpå med vann, tørres med vannfritt natrium-sulfat og konsentreres i vakuum, hvorved man får R-[l-(p-klorbenzoyl) -2 -methyl -5 -dimethylamino.-3-indolyl/-ethylacetat ,
Claims (1)
- Analogifremgangsmåte ved fremstilling av terapeutisk aktive estere av 3-indolyl-alkoholer av den generelle formel:hvor R^ er fenyl som eventuelt er substituert med et halogenatom, R2 og R^ er hydrogen eller lavere alkyl, R^ er lavere alkyl eller R^, og Rc- er lavere alkoxy eller di-lavere alkylamino,karakterisert ved at en alkohol av formelen: hvor R^ , R^ og R^ er som ovenfor angitt, og R^ er R,- eller nitro, omsettes med et acyleringsmiddel som inneholder gruppen R^-CO-, hvor R^ er som ovenfor angitt, og når R^ er nitro, overføres denne til di-lavere alkylamino på i og for seg kjent vis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO890823A NO165146C (no) | 1983-11-18 | 1989-02-27 | 1h-imidazo-(4,5-c)-kinolin-4-klorforbindelser. |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US55315783A | 1983-11-18 | 1983-11-18 | |
| US55315883A | 1983-11-18 | 1983-11-18 | |
| NO844565A NO163819C (no) | 1983-11-18 | 1984-11-15 | Analogifremgangsmaate for fremstilling av terapeutisk aktive 1h-imidazo(4,5-c)kinolin og derivater derav. |
| NO890823A NO165146C (no) | 1983-11-18 | 1989-02-27 | 1h-imidazo-(4,5-c)-kinolin-4-klorforbindelser. |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO890823L NO890823L (no) | 1985-05-20 |
| NO890823D0 NO890823D0 (no) | 1989-02-27 |
| NO165146B true NO165146B (no) | 1990-09-24 |
| NO165146C NO165146C (no) | 1991-01-02 |
Family
ID=27070262
Family Applications (7)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO844565A NO163819C (no) | 1983-11-18 | 1984-11-15 | Analogifremgangsmaate for fremstilling av terapeutisk aktive 1h-imidazo(4,5-c)kinolin og derivater derav. |
| NO890826A NO168705C (no) | 1983-11-18 | 1989-02-27 | 3-nitro-kinoliner. |
| NO890824A NO165147C (no) | 1983-11-18 | 1989-02-27 | 1h-imidazo(4,5-c)-kinolin-5-oxydforbindelser. |
| NO890822A NO165145C (no) | 1983-11-18 | 1989-02-27 | Analogifremgangsmaate for fremstilling av terapeutisk aktive 1h-imidazo-(4,5-c)-kinolin-4-aminderivater. |
| NO890823A NO165146C (no) | 1983-11-18 | 1989-02-27 | 1h-imidazo-(4,5-c)-kinolin-4-klorforbindelser. |
| NO890825A NO169437C (no) | 1983-11-18 | 1989-02-27 | 3-amino-kinoliner. |
| NO1999015C NO1999015I1 (no) | 1983-11-18 | 1999-07-08 | Imiquimod |
Family Applications Before (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO844565A NO163819C (no) | 1983-11-18 | 1984-11-15 | Analogifremgangsmaate for fremstilling av terapeutisk aktive 1h-imidazo(4,5-c)kinolin og derivater derav. |
| NO890826A NO168705C (no) | 1983-11-18 | 1989-02-27 | 3-nitro-kinoliner. |
| NO890824A NO165147C (no) | 1983-11-18 | 1989-02-27 | 1h-imidazo(4,5-c)-kinolin-5-oxydforbindelser. |
| NO890822A NO165145C (no) | 1983-11-18 | 1989-02-27 | Analogifremgangsmaate for fremstilling av terapeutisk aktive 1h-imidazo-(4,5-c)-kinolin-4-aminderivater. |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO890825A NO169437C (no) | 1983-11-18 | 1989-02-27 | 3-amino-kinoliner. |
| NO1999015C NO1999015I1 (no) | 1983-11-18 | 1999-07-08 | Imiquimod |
Country Status (15)
| Country | Link |
|---|---|
| EP (2) | EP0145340B1 (no) |
| JP (1) | JPS60123488A (no) |
| KR (1) | KR900005657B1 (no) |
| AT (2) | ATE84525T1 (no) |
| AU (2) | AU581190B2 (no) |
| CA (1) | CA1271477A (no) |
| DE (3) | DE19975027I2 (no) |
| DK (6) | DK164280C (no) |
| ES (1) | ES537677A0 (no) |
| IE (1) | IE57874B1 (no) |
| IL (2) | IL84537A (no) |
| NL (2) | NL980043I1 (no) |
| NO (7) | NO163819C (no) |
| NZ (1) | NZ210228A (no) |
| PH (1) | PH22338A (no) |
Families Citing this family (72)
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| CA1306260C (en) * | 1985-10-18 | 1992-08-11 | Shionogi & Co., Ltd. | Condensed imidazopyridine derivatives |
| US4942168A (en) * | 1987-07-13 | 1990-07-17 | Hoechst-Roussel Pharmaceuticals Inc. | Hydroxyquinoline amines, and method of enhancing memory in mammals |
| CA1335996C (en) * | 1988-02-16 | 1995-06-20 | Susumu Takada | 2-substituted carbonylimidazo¬4,5-c|quinolines |
| EP0361489A3 (en) * | 1988-09-30 | 1991-06-12 | Chugai Seiyaku Kabushiki Kaisha | Novel 3,4-diaminoquinoline and pyridine compounds |
| ES2094141T3 (es) * | 1989-02-27 | 1997-01-16 | Riker Laboratories Inc | 1h-imidazo(4,5-c)quinolin-4-aminas como antivirales. |
| US4994468A (en) * | 1989-03-07 | 1991-02-19 | Kyowa Hakko Kogyo Co., Ltd. | Imidazoquinolone derivatives |
| US4929624A (en) * | 1989-03-23 | 1990-05-29 | Minnesota Mining And Manufacturing Company | Olefinic 1H-imidazo(4,5-c)quinolin-4-amines |
| CA2021338C (en) * | 1989-07-18 | 1996-07-16 | Fumio Suzuki | Imidazoquinolone derivatives |
| US4988815A (en) * | 1989-10-26 | 1991-01-29 | Riker Laboratories, Inc. | 3-Amino or 3-nitro quinoline compounds which are intermediates in preparing 1H-imidazo[4,5-c]quinolines |
| FR2654021B1 (fr) * | 1989-11-07 | 1992-02-28 | Simond Jacques | Procede de vitrification de cendres volantes et dispositif pour sa mise en óoeuvre. |
| GB8928281D0 (en) * | 1989-12-14 | 1990-02-21 | Smith Kline French Lab | Compounds |
| CA2043715C (en) * | 1990-06-01 | 1997-01-07 | Fumio Suzuki | Imidazonaphthyridine derivatives |
| CZ285050B6 (cs) * | 1991-03-01 | 1999-05-12 | Minnesota Mining And Manufacturing Company | 1-Substituované, 2-substituované-1H-imidazo/4,5-c /chinolin-4-aminy |
| US5266575A (en) * | 1991-11-06 | 1993-11-30 | Minnesota Mining And Manufacturing Company | 2-ethyl 1H-imidazo[4,5-ciquinolin-4-amines |
| IL105325A (en) * | 1992-04-16 | 1996-11-14 | Minnesota Mining & Mfg | Immunogen/vaccine adjuvant composition |
| US5395937A (en) * | 1993-01-29 | 1995-03-07 | Minnesota Mining And Manufacturing Company | Process for preparing quinoline amines |
| US5693811A (en) * | 1996-06-21 | 1997-12-02 | Minnesota Mining And Manufacturing Company | Process for preparing tetrahdroimidazoquinolinamines |
| JP4101302B2 (ja) * | 1997-01-09 | 2008-06-18 | テルモ株式会社 | 新規アミド誘導体および合成中間体 |
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| JP2000119271A (ja) | 1998-08-12 | 2000-04-25 | Hokuriku Seiyaku Co Ltd | １ｈ―イミダゾピリジン誘導体 |
| US7253199B2 (en) * | 2001-10-23 | 2007-08-07 | Applied Research Systems Ars Holding N.V. | Azole derivatives and pharmaceutical compositions containing them |
| GB0211649D0 (en) | 2002-05-21 | 2002-07-03 | Novartis Ag | Organic compounds |
| ATE338044T1 (de) | 2002-07-23 | 2006-09-15 | Teva Gyogyszergyar Zartkoeruen | Herstellung von 1h-imidazoc4,5-c)chinolin-4- aminen ber 1h-imidazoc4,5-c)chinolin-4- phthalimidzwischenprodukte |
| AU2003254221A1 (en) | 2002-07-26 | 2004-02-16 | Biogal Gyogyszergyar Rt. | Preparation of 1h-imidazo (4,5-c) quinolin-4-amines via novel 1h-imidazo (4,5-c) quinolin-4-cyano and 1h-imidazo (4,5-c) quinolin-4-carboxamide intermediates |
| JP2007502293A (ja) | 2003-08-12 | 2007-02-08 | スリーエム イノベイティブ プロパティズ カンパニー | ヒドロキシルアミン置換イミダゾ含有化合物 |
| RU2006105101A (ru) * | 2003-08-27 | 2007-10-10 | 3М Инновейтив Пропертиз Компани (US) | Арилокси и арилалкиленокси замещенные имидазохинолины |
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| US7544697B2 (en) | 2003-10-03 | 2009-06-09 | Coley Pharmaceutical Group, Inc. | Pyrazolopyridines and analogs thereof |
| AU2004278014B2 (en) | 2003-10-03 | 2011-04-28 | 3M Innovative Properties Company | Alkoxy substituted imidazoquinolines |
| ITMI20032121A1 (it) * | 2003-11-04 | 2005-05-05 | Dinamite Dipharma Spa In Forma Abbr Eviata Dipharm | Procedimento per la preparazione di imiquimod e suoi intermedi |
| JP2007511527A (ja) | 2003-11-14 | 2007-05-10 | スリーエム イノベイティブ プロパティズ カンパニー | オキシム置換イミダゾ環化合物 |
| US8598192B2 (en) | 2003-11-14 | 2013-12-03 | 3M Innovative Properties Company | Hydroxylamine substituted imidazoquinolines |
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| WO2005066170A1 (en) | 2003-12-29 | 2005-07-21 | 3M Innovative Properties Company | Arylalkenyl and arylalkynyl substituted imidazoquinolines |
| CA2551399A1 (en) | 2003-12-30 | 2005-07-21 | 3M Innovative Properties Company | Imidazoquinolinyl, imidazopyridinyl, and imidazonaphthyridinyl sulfonamides |
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| US7915281B2 (en) | 2004-06-18 | 2011-03-29 | 3M Innovative Properties Company | Isoxazole, dihydroisoxazole, and oxadiazole substituted imidazo ring compounds and method |
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| JP5313502B2 (ja) | 2004-12-30 | 2013-10-09 | スリーエム イノベイティブ プロパティズ カンパニー | 置換キラル縮合［１，２］イミダゾ［４，５−ｃ］環状化合物 |
| JP5543068B2 (ja) | 2004-12-30 | 2014-07-09 | スリーエム イノベイティブ プロパティズ カンパニー | キラル縮合［１，２］イミダゾ［４，５−ｃ］環状化合物 |
| JP2008530022A (ja) | 2005-02-04 | 2008-08-07 | コーリー ファーマシューティカル グループ，インコーポレイテッド | 免疫反応調節物質を含む水性ゲル処方物 |
| AU2006213746A1 (en) | 2005-02-11 | 2006-08-17 | Coley Pharmaceutical Group, Inc. | Oxime and hydroxylamine substituted imidazo(4,5-c) ring compounds and methods |
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| ES2577514T3 (es) | 2005-08-22 | 2016-07-15 | The Regents Of The University Of California | Antagonistas de TLR |
| EP2029597A4 (en) | 2006-05-31 | 2011-11-23 | Univ California | purine analogs |
| WO2008008432A2 (en) | 2006-07-12 | 2008-01-17 | Coley Pharmaceutical Group, Inc. | Substituted chiral fused( 1,2) imidazo (4,5-c) ring compounds and methods |
| PL2510946T3 (pl) | 2007-02-07 | 2015-12-31 | Univ California | Koniugaty syntetycznych agonistów tlr i ich zastosowania |
| EP2009002A1 (en) * | 2007-06-21 | 2008-12-31 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | New process for the manufacture of 1H-imidazo [4,5-c]-quinoline ring systems |
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| US8729088B2 (en) | 2009-02-11 | 2014-05-20 | The Regents Of The University Of California | Toll-like receptor modulators and treatment of diseases |
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| US8728486B2 (en) | 2011-05-18 | 2014-05-20 | University Of Kansas | Toll-like receptor-7 and -8 modulatory 1H imidazoquinoline derived compounds |
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| CN115252792A (zh) | 2016-01-07 | 2022-11-01 | 博笛生物科技有限公司 | 用于治疗肿瘤的抗-egfr组合 |
| CN115554406A (zh) | 2016-01-07 | 2023-01-03 | 博笛生物科技有限公司 | 用于治疗肿瘤的抗-cd20组合 |
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| US11697851B2 (en) | 2016-05-24 | 2023-07-11 | The Regents Of The University Of California | Early ovarian cancer detection diagnostic test based on mRNA isoforms |
| TWI674261B (zh) | 2017-02-17 | 2019-10-11 | 美商英能腫瘤免疫股份有限公司 | Nlrp3 調節劑 |
| CN108794467A (zh) | 2017-04-27 | 2018-11-13 | 博笛生物科技有限公司 | 2-氨基-喹啉衍生物 |
| WO2018232725A1 (en) | 2017-06-23 | 2018-12-27 | Birdie Biopharmaceuticals, Inc. | PHARMACEUTICAL COMPOSITIONS |
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Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3700674A (en) * | 1969-04-30 | 1972-10-24 | American Cyanamid Co | 4-alkylamino-3-nitroquinolines |
| RO86850B (ro) * | 1982-05-03 | 1985-05-31 | Eli Lilly And Company | Procedeu pentru prepararea unor 2-fenilimidazo [4,5 c] piridine |
-
1984
- 1984-11-13 CA CA000467706A patent/CA1271477A/en not_active Expired - Lifetime
- 1984-11-14 AU AU35402/84A patent/AU581190B2/en not_active Expired
- 1984-11-15 ES ES537677A patent/ES537677A0/es active Granted
- 1984-11-15 DK DK542684A patent/DK164280C/da not_active IP Right Cessation
- 1984-11-15 NO NO844565A patent/NO163819C/no not_active IP Right Cessation
- 1984-11-16 IE IE2952/84A patent/IE57874B1/en not_active IP Right Cessation
- 1984-11-16 DE DE1999175027 patent/DE19975027I2/de active Active
- 1984-11-16 EP EP84307974A patent/EP0145340B1/en not_active Expired - Lifetime
- 1984-11-16 NZ NZ210228A patent/NZ210228A/xx unknown
- 1984-11-16 DE DE8484307974T patent/DE3481124D1/de not_active Expired - Lifetime
- 1984-11-16 AT AT88116137T patent/ATE84525T1/de not_active IP Right Cessation
- 1984-11-16 AT AT84307974T patent/ATE49763T1/de active
- 1984-11-16 IL IL84537A patent/IL84537A/xx not_active IP Right Cessation
- 1984-11-16 DE DE8888116137T patent/DE3486043T2/de not_active Expired - Lifetime
- 1984-11-16 PH PH31451A patent/PH22338A/en unknown
- 1984-11-16 EP EP88116137A patent/EP0310950B1/en not_active Expired - Lifetime
- 1984-11-17 KR KR1019840007224A patent/KR900005657B1/ko not_active IP Right Cessation
- 1984-11-17 JP JP59243142A patent/JPS60123488A/ja active Granted
-
1987
- 1987-11-19 IL IL84537A patent/IL84537A0/xx unknown
-
1989
- 1989-02-14 AU AU29911/89A patent/AU611997B2/en not_active Expired
- 1989-02-27 NO NO890826A patent/NO168705C/no not_active IP Right Cessation
- 1989-02-27 NO NO890824A patent/NO165147C/no not_active IP Right Cessation
- 1989-02-27 NO NO890822A patent/NO165145C/no not_active IP Right Cessation
- 1989-02-27 NO NO890823A patent/NO165146C/no not_active IP Right Cessation
- 1989-02-27 NO NO890825A patent/NO169437C/no not_active IP Right Cessation
-
1991
- 1991-07-16 DK DK136191A patent/DK164452C/da not_active IP Right Cessation
- 1991-07-16 DK DK136091A patent/DK164451C/da not_active IP Right Cessation
- 1991-07-16 DK DK135791A patent/DK169179B1/da not_active IP Right Cessation
- 1991-07-16 DK DK135991A patent/DK165921C/da not_active IP Right Cessation
- 1991-07-16 DK DK135891A patent/DK164455C/da not_active IP Right Cessation
-
1998
- 1998-12-14 NL NL980043C patent/NL980043I1/nl unknown
- 1998-12-14 NL NL980041C patent/NL980041I2/nl unknown
-
1999
- 1999-07-08 NO NO1999015C patent/NO1999015I1/no unknown
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| MM1K | Lapsed by not paying the annual fees |