CH551419A - 4-substd-6,7-methylenedioxy-(3,4-dihydro)-2(1-h)quinaloline - e(thi)ones - with antiinflammatory analgeis and antipyretic activity - Google Patents
4-substd-6,7-methylenedioxy-(3,4-dihydro)-2(1-h)quinaloline - e(thi)ones - with antiinflammatory analgeis and antipyretic activityInfo
- Publication number
- CH551419A CH551419A CH117774A CH117774A CH551419A CH 551419 A CH551419 A CH 551419A CH 117774 A CH117774 A CH 117774A CH 117774 A CH117774 A CH 117774A CH 551419 A CH551419 A CH 551419A
- Authority
- CH
- Switzerland
- Prior art keywords
- methylenedioxy
- carbon atoms
- formula
- alkyl
- isopropyl
- Prior art date
Links
- 230000003110 anti-inflammatory effect Effects 0.000 title description 3
- 230000001754 anti-pyretic effect Effects 0.000 title description 2
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 6
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 6
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 239000011593 sulfur Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical compound N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 claims description 3
- XLJMAIOERFSOGZ-UHFFFAOYSA-N anhydrous cyanic acid Natural products OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- HXHAAJFQYIBYKF-UHFFFAOYSA-N (6-amino-1,3-benzodioxol-5-yl)-phenylmethanone Chemical class NC1=CC=2OCOC=2C=C1C(=O)C1=CC=CC=C1 HXHAAJFQYIBYKF-UHFFFAOYSA-N 0.000 claims description 2
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical class C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 claims description 2
- MHBPJMUAIOKJNL-UHFFFAOYSA-N 1h-quinazoline-2-thione Chemical class C1=CC=CC2=NC(S)=NC=C21 MHBPJMUAIOKJNL-UHFFFAOYSA-N 0.000 claims description 2
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- -1 methylenedioxy Chemical group 0.000 abstract description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 16
- 229910052799 carbon Inorganic materials 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HJICZLOIHNWNNY-UHFFFAOYSA-N 8-(4-fluorophenyl)-5-propan-2-yl-[1,3]dioxolo[4,5-g]quinazolin-6-one Chemical compound N=1C(=O)N(C(C)C)C2=CC=3OCOC=3C=C2C=1C1=CC=C(F)C=C1 HJICZLOIHNWNNY-UHFFFAOYSA-N 0.000 description 2
- FITUMOSFDCKONA-UHFFFAOYSA-N 8-phenyl-5-propan-2-yl-[1,3]dioxolo[4,5-g]quinazolin-6-one Chemical compound N=1C(=O)N(C(C)C)C2=CC=3OCOC=3C=C2C=1C1=CC=CC=C1 FITUMOSFDCKONA-UHFFFAOYSA-N 0.000 description 2
- CJYKASQZGKZAKU-UHFFFAOYSA-N 8-phenyl-5-propan-2-yl-[1,3]dioxolo[4,5-g]quinazoline-6-thione Chemical compound N=1C(=S)N(C(C)C)C2=CC=3OCOC=3C=C2C=1C1=CC=CC=C1 CJYKASQZGKZAKU-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- YHVKPUHOOJSVGJ-UHFFFAOYSA-N 5-(cyclopropylmethyl)-8-phenyl-[1,3]dioxolo[4,5-g]quinazolin-6-one Chemical compound C12=CC=3OCOC=3C=C2N(CC2CC2)C(=O)N=C1C1=CC=CC=C1 YHVKPUHOOJSVGJ-UHFFFAOYSA-N 0.000 description 1
- MPWKIPSTLQUONU-UHFFFAOYSA-N 5-methyl-8-phenyl-[1,3]dioxolo[4,5-g]quinazolin-6-one Chemical compound N=1C(=O)N(C)C2=CC=3OCOC=3C=C2C=1C1=CC=CC=C1 MPWKIPSTLQUONU-UHFFFAOYSA-N 0.000 description 1
- UHPOQYHLZCBLAS-UHFFFAOYSA-N 5-propan-2-yl-8-(4-propan-2-ylphenyl)-[1,3]dioxolo[4,5-g]quinazoline-6-thione Chemical compound C1=CC(C(C)C)=CC=C1C(C1=C2)=NC(=S)N(C(C)C)C1=CC1=C2OCO1 UHPOQYHLZCBLAS-UHFFFAOYSA-N 0.000 description 1
- SXQHCQAZAACMHI-UHFFFAOYSA-N 8-(1,3-benzodioxol-5-yl)-5-propan-2-yl-[1,3]dioxolo[4,5-g]quinazolin-6-one Chemical compound C1=C2OCOC2=CC(C=2C3=CC=4OCOC=4C=C3N(C(N=2)=O)C(C)C)=C1 SXQHCQAZAACMHI-UHFFFAOYSA-N 0.000 description 1
- GROXQEHQMMQDDR-UHFFFAOYSA-N 8-(2-methylphenyl)-5-propan-2-yl-[1,3]dioxolo[4,5-g]quinazolin-6-one Chemical compound N=1C(=O)N(C(C)C)C2=CC=3OCOC=3C=C2C=1C1=CC=CC=C1C GROXQEHQMMQDDR-UHFFFAOYSA-N 0.000 description 1
- OVTFLEXPCHUYRC-UHFFFAOYSA-N 8-(2-nitrophenyl)-5-propan-2-yl-[1,3]dioxolo[4,5-g]quinazolin-6-one Chemical compound N=1C(=O)N(C(C)C)C2=CC=3OCOC=3C=C2C=1C1=CC=CC=C1[N+]([O-])=O OVTFLEXPCHUYRC-UHFFFAOYSA-N 0.000 description 1
- ZHWQKGZCQHQEGO-UHFFFAOYSA-N 8-(3,4-dichlorophenyl)-5-propan-2-yl-[1,3]dioxolo[4,5-g]quinazolin-6-one Chemical compound N=1C(=O)N(C(C)C)C2=CC=3OCOC=3C=C2C=1C1=CC=C(Cl)C(Cl)=C1 ZHWQKGZCQHQEGO-UHFFFAOYSA-N 0.000 description 1
- XNNKONGIXZLMJM-UHFFFAOYSA-N 8-(3-fluorophenyl)-5-propan-2-yl-[1,3]dioxolo[4,5-g]quinazolin-6-one Chemical compound N=1C(=O)N(C(C)C)C2=CC=3OCOC=3C=C2C=1C1=CC=CC(F)=C1 XNNKONGIXZLMJM-UHFFFAOYSA-N 0.000 description 1
- XHVYMYCBNAHLGY-UHFFFAOYSA-N 8-(3-fluorophenyl)-5-propan-2-yl-[1,3]dioxolo[4,5-g]quinazoline-6-thione Chemical compound N=1C(=S)N(C(C)C)C2=CC=3OCOC=3C=C2C=1C1=CC=CC(F)=C1 XHVYMYCBNAHLGY-UHFFFAOYSA-N 0.000 description 1
- MQVHTSFXNCAGHZ-UHFFFAOYSA-N 8-(3-methoxyphenyl)-5-propan-2-yl-[1,3]dioxolo[4,5-g]quinazolin-6-one Chemical compound COC1=CC=CC(C=2C3=CC=4OCOC=4C=C3N(C(C)C)C(=O)N=2)=C1 MQVHTSFXNCAGHZ-UHFFFAOYSA-N 0.000 description 1
- JOWHKIRRPMHEKH-UHFFFAOYSA-N 8-(3-nitrophenyl)-5-propan-2-yl-[1,3]dioxolo[4,5-g]quinazolin-6-one Chemical compound N=1C(=O)N(C(C)C)C2=CC=3OCOC=3C=C2C=1C1=CC=CC([N+]([O-])=O)=C1 JOWHKIRRPMHEKH-UHFFFAOYSA-N 0.000 description 1
- WQWGBYMRVRHSPV-UHFFFAOYSA-N 8-(3-nitrophenyl)-5-propan-2-yl-[1,3]dioxolo[4,5-g]quinazoline-6-thione Chemical compound N=1C(=S)N(C(C)C)C2=CC=3OCOC=3C=C2C=1C1=CC=CC([N+]([O-])=O)=C1 WQWGBYMRVRHSPV-UHFFFAOYSA-N 0.000 description 1
- OQDUDVHEXRQMRX-UHFFFAOYSA-N 8-(4-fluorophenyl)-5-propan-2-yl-[1,3]dioxolo[4,5-g]quinazoline-6-thione Chemical compound N=1C(=S)N(C(C)C)C2=CC=3OCOC=3C=C2C=1C1=CC=C(F)C=C1 OQDUDVHEXRQMRX-UHFFFAOYSA-N 0.000 description 1
- VETUCQMBNGYRNM-UHFFFAOYSA-N 8-(4-methylphenyl)-5-propan-2-yl-[1,3]dioxolo[4,5-g]quinazolin-6-one Chemical compound N=1C(=O)N(C(C)C)C2=CC=3OCOC=3C=C2C=1C1=CC=C(C)C=C1 VETUCQMBNGYRNM-UHFFFAOYSA-N 0.000 description 1
- DZRVUYWTROBVBX-UHFFFAOYSA-N 8-(5-chlorothiophen-2-yl)-5-propan-2-yl-[1,3]dioxolo[4,5-g]quinazolin-6-one Chemical compound N=1C(=O)N(C(C)C)C2=CC=3OCOC=3C=C2C=1C1=CC=C(Cl)S1 DZRVUYWTROBVBX-UHFFFAOYSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- SOIFLUNRINLCBN-UHFFFAOYSA-N ammonium thiocyanate Chemical compound [NH4+].[S-]C#N SOIFLUNRINLCBN-UHFFFAOYSA-N 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 229940125716 antipyretic agent Drugs 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 238000010952 in-situ formation Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- GRHBQAYDJPGGLF-UHFFFAOYSA-N isothiocyanic acid Chemical compound N=C=S GRHBQAYDJPGGLF-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- MLCSTNUFLFUNRL-UHFFFAOYSA-N phenyl-[6-(propan-2-ylamino)-1,3-benzodioxol-5-yl]methanone Chemical compound CC(C)NC1=CC=2OCOC=2C=C1C(=O)C1=CC=CC=C1 MLCSTNUFLFUNRL-UHFFFAOYSA-N 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Cpds. of formula (I): (where X is O or S, R is 1-5C alkyl, 3-6C cycloalkyl or 4-7C cycloalkylalkyl (in which the cycloalkyl is 3-6C and the alkyl is a 1-3C straight chain), AB is -CR1:N- or -CH1NH-, R1 is phenyl opt. substd. by 1 or 2 F, Cl, 1-3C alkyl and/or alkoxy gps. and/or 1 NO2, CF3 or methylenedioxy gp. or R1 is 2-thienyl opt. substd. by F, Cl or 1-3C alkyl) are prepd in a manner known for similar cpds e.g. by reacting a cpd. (II): with CXCl2 to give (I, AB = CR1:N).
Description
Die Erfindung betrifft ein Verfahren zur Herstellung von 4Phenyl- bzw. 4(2'-Thienyl)-6,7-methylendioxy-2(1H)- -chinazolinonen bzw. -2(1H)-chinazolinthionen der Formel 1,
EMI1.1
worin X Sauerstoff oder Schwefel bedeutet, R für Alkyl mit 1-5 Kohlenstoffatomen, Cycloalkyl mit 3-6 Kohlenstoffatomen oder Cvcloalkylalkyl mit insgesamt 4-7 Kohlenstoffatomen steht, wobei das Cycloalkyl 3-6 Kohlenstoffatome aufweist und das Alkyl geradkettig ist und 1-3 Kohlenstoffatome enthält, und entweder Rt einen Phenylrest der Formel II
EMI1.2
bedeutet, worin Z und Z1 gleich oder verschieden sind und für Wasserstoff, Fluor, Chlor, Alkyl oder Alkoxy mit je 1-3 Kohlenstoffatomen, Nitro oder Trifluormethyl stehen,
jedoch höchstens einer der Substituenten Z und Z, Trifluormethyl oder Nitro bedeutet, oder worin Z und Zt an benach barten Kohlenstoffatomen liegen und zusammen für Methylendioxy stehen, oder R1 einen Thienylrest der Formel III
EMI1.3
bedeutet, worin Z2 für Wasserstoff, Fluor, Chlor oder Alkyl mit 1-3 Kohlenstoffatomen steht.
Von den Verbindungen der oben genannten Formel I sind diejenigen der Formel In
EMI1.4
neu, in welcher Rt obige Bedeutung hat und R' sowie X' die gleiche Bedeutung besitzen wie R sowie X, mit der Aus- nahme, dass X' Schwefel bedeutet, falls R' für Alkyl mit 1-5 Kohlenstoffatomen steht.
Das erfindungsgemässe Verfahren zur Herstellung von Verbindungen der Formel I ist dadurch gekennzeichnet, dass man 2-Amino-4,5-methylendioxy-benzophenone bzw. 2-Ami no-4,5-methylendioxy-1-(2'-thenoyl)-benzole der Formel IV,
EMI1.5
worin R und RX obige Bedeutung haben, mit Isocyansäure oder Isothiocyansäure der Formel V,
H-N=C=X Y worin X obige Bedeutung besitzt, cyclisiert.
Bei dem erfmdungsgemässen Verfahren arbeitet man zweckmässigerweise bei Temperaturen zwischen 50 und 150 C, vorzugsweise 100 und 140"C. Da die Verbindungen der Formel V bekanntermassen instabil sind, werden sie am besten in situ hergestellt. Zu diesem Zweck kann man das Verfahren in einem sauren Medium unter Verwendung eines Salzes der Formel VI,
M-N=C=X VI worin M für Alkali, Erdalkali oder Ammonium steht und X obige Bedeutung besitzt, durchführen. Die Verbindung der Formel VI ist vorzugsweise ein Alkalisalz, wie Natriumoder Kaliumsalz, oder insbesondere das Ammoniumsalz.
Als Säure zur in situ Bildung der gewünschten Isocyansäure aus der Verbindung der Formel VI verwendet man vorzugsweise eine niedere Carbonsäure, zweckmässigerweise Essigsäure, die sich gleichzeitig als Lösungsmittel für die Reaktion verwenden lässt.
Die Verbindungen der Formel I können in an sich bekannter Weise isoliert und gereinigt werden.
Die als Ausgangsprodukte verwendeten Verbindungen der Formel IV sind bekannt oder in an sich bekannter Weise herstellbar.
Die Verbindungen der Formel I sind pharmakologisch wirksam und können daher als Heilmittel verwendet werden.
Sie wirken insbesondere entzündungshemmend, so dass sie sich als entzündungshemmende Mittel einsetzen lassen.
Die täglich zu verabreichende Menge liegt beispielsweise zwischen etwa 60 und 2000 mg für Verbindungen der Formel I, worin X für Sauerstoff steht, zwischen etwa 90 und 2000 mg für Verbindungen der Formel I, worin X für Schwefel steht.
Die oben angegebenen Dosen werden vorzugsweise verabreicht in mehreren Teilmengen zwischen etwa 15 und 1000 mg, sowie etwa 25 und 1000 mg, und zwar zwei- bis viermal täglich oder in Retardform.
Die Verbindungen der Formel I wirken ferner analgetisch, so dass sie sich als Analgetika sowie Antipyretika einsetzen lassen. Die hierbei täglich zu verabreichenden Mengen entsprechen denjenigen für die entzündungshemmende Wir- kung.
Die Verbindungen der Formel I können oral oder par- enteral verabreicht werden und lassen sich zur Herstellung geeigneter Arzneiformen mit üblichen Hilfs- und Zusatzstoffen verarbeiten. Eine geeignete Kapsel besteht beispielsweise aus 50 Gew.-Teilen einer Verbindung der Formel I, z.B. 1 -Isopropyl-4-phenyl-6,7-methylendioxy-2(1H)-chinazolinon und 200 Gew.-Teilen eines inerten, festen Verdünnungsmittels, beispielsweise Kaolin.
Von den Verbindungen der Formel I werden wegen ihrer pharmakologischen Wirkung diejenigen der Formel I bevor zugt, worin R für Isopropyl steht, beispielsweise l-Isopropyl-4-phenyl-6,7-methylendioxy-2(1H)-chinazolinon, 1-Isopropyl-4-(p-fluorphenyl)-6,7-methylendioxy-2(1H)-chinazolinon und 1-Isopropyl-4-phenyl-6,7-methylendioxy-2(1H)-chinazolinthion.
Beispiel 1 1-Isopropyl-4-phenyl-6,7-methylendioxy-2(1H)-chinazolinthion
Eine Lösung von 5,6 g 2-Isopropylamino-4,5-methylen- -dioxybenzophenon in 50 ml Essigsäure wird mit 1,5 g Ammoniumthiocyanat versetzt. Das Gemisch wird 3 Stunden zum Rückfluss erhitzt und dann zur Trockne eingeengt. Eine Probe des Rückstandes wird dünnschichtchromatographisch untersucht (Absorptionsmittel: Siliciumoxid, 20% Athylace- tat/Chloroform). Die Substanz mit einem Rf-Wert von 0,5 wird in an sich bekannter Weise abgetrennt, wobei man zur Titelverbindung vom Smp. 202-204 C gelangt.
Beispiel 2
Analog Beispiel 1 und unter Verwendung geeigneter Aus- gangsprodukte in entsprechenden Mengen gelangt man zu folgenden Verbindungen der Formel I: a) 1-Isopropyl-4-phenyl-6,7-methylendioxy-2(1H)-chinazolinon, Smp. 202-205 C, b) 1-Isopropyl-4-(m-fluorphenyl)-6,7-methylendioxy -2(1H)-chinazolinon, Smp. 169-170 C, c) 1-Isopropyl-4-(m-methoxyphenyl)-6,7-methylendioxy -2(1H)-chinazolinon, Smp. 189-191 C, d) 1-Isopropyl-4-(p-methylphenyl)-6,7-methylendioxy -2(1H)-chinazolinon,
Smp. 188-190 C, e) 1-Isopropyl-4-(o-nitrophenyl)-6,7-methylendioxy -2(1H)-chinazolinon, Smp. 148-150 C, f) 1-Isopropyl-4-(5'-chlor-2-thienyl)-6,7-methylendioxy -2(1H)-chinazolinon, Smp. 192-201 C, g) 1-Isopropyl-4-(3,4-methylendioxyphenyl)-6,7-methylendioxy-2(1H)-chinazolinon, Smp.
234-235 C, h) 1-Isopropyl-4-(m-nitrophenyl)-6,7-methylendioxy -2(1H)-chinazolinon, Smp. 230-232 C, i) 1-Isopropyl-4-(o-methylphenyl)-6,7-methylendioxy -2(1H)-chinazolinon, Smp. 155-157 C, j) 1-Isopropyl-4-(p-fluorphenyl)-6,7-methylendioxy -2(1H)-chinazolinon, Smp. 238-240 C, k) 1-Isopropyl-4-(3,4-dichlorphenyl)-6,7-methylendioxy -2(1H)-chinazolinon, Smp.
239-242 C, l) 1-Methyl-4-phenyl-6,7-methylendioxy-2(1H)-chinazolinon, Smp.¯257-260 C, m) 1-Cyclopropylmethyl-4-phenyl-6,7-methylendioxy -2(1H)-chinazolinon, n) 1-Isopropyl-4-(m-fluorphenyl)-6,7-methylendioxy -2(1H)-chinazolinthion, Smp. 210-214 C, o) 1-Isopropyl-4-(p-isopropylphenyl)-6,7-methylendioxy -2(1H)-chinazolinthion, Smp. 167-170 C, p) 1-Isopropyl-4-(p-fluorphenyl)-6,7-methylendioxy -2(1H)-chinazolinthion, Smp. 220-223 C, q) 1-Isopropyl-4-(m-nitrophenyl)-6,7-methylendioxy -2(1H)-chinazolinthion, Smp. 199-202 C.
The invention relates to a process for the preparation of 4-phenyl- or 4 (2'-thienyl) -6,7-methylenedioxy-2 (1H) - -quinazolinones or -2 (1H) -quinazolinethiones of the formula 1,
EMI1.1
wherein X is oxygen or sulfur, R is alkyl with 1-5 carbon atoms, cycloalkyl with 3-6 carbon atoms or cycloalkylalkyl with a total of 4-7 carbon atoms, the cycloalkyl having 3-6 carbon atoms and the alkyl being straight-chain and 1-3 carbon atoms contains, and either Rt is a phenyl radical of the formula II
EMI1.2
means in which Z and Z1 are identical or different and represent hydrogen, fluorine, chlorine, alkyl or alkoxy with 1-3 carbon atoms each, nitro or trifluoromethyl,
but at most one of the substituents Z and Z is trifluoromethyl or nitro, or in which Z and Zt are on adjacent carbon atoms and together represent methylenedioxy, or R1 is a thienyl radical of the formula III
EMI1.3
denotes in which Z2 represents hydrogen, fluorine, chlorine or alkyl having 1-3 carbon atoms.
Of the compounds of the above formula I are those of the formula In
EMI1.4
new, in which Rt has the above meaning and R 'and X' have the same meaning as R and X, with the exception that X 'denotes sulfur if R' stands for alkyl with 1-5 carbon atoms.
The inventive method for the preparation of compounds of the formula I is characterized in that 2-amino-4,5-methylenedioxy-benzophenones or 2-amino-4,5-methylenedioxy-1- (2'-thenoyl) benzenes of formula IV,
EMI1.5
wherein R and RX have the above meaning, with isocyanic acid or isothiocyanic acid of the formula V,
H-N = C = X Y where X has the above meaning, cyclized.
The process according to the invention is expediently carried out at temperatures between 50 and 150 ° C., preferably 100 and 140 ° C. Since the compounds of the formula V are known to be unstable, they are best prepared in situ. For this purpose, the process can be carried out in an acidic Medium using a salt of the formula VI,
M-N = C = X VI where M stands for alkali, alkaline earth or ammonium and X has the above meaning. The compound of the formula VI is preferably an alkali salt, such as sodium or potassium salt, or in particular the ammonium salt.
The acid used for the in situ formation of the desired isocyanic acid from the compound of the formula VI is preferably a lower carboxylic acid, conveniently acetic acid, which can also be used as a solvent for the reaction.
The compounds of the formula I can be isolated and purified in a manner known per se.
The compounds of the formula IV used as starting materials are known or can be prepared in a manner known per se.
The compounds of formula I are pharmacologically active and can therefore be used as medicaments.
In particular, they have anti-inflammatory effects, so that they can be used as anti-inflammatory agents.
The amount to be administered daily is, for example, between about 60 and 2000 mg for compounds of the formula I in which X stands for oxygen, between about 90 and 2000 mg for compounds of the formula I in which X stands for sulfur.
The doses given above are preferably administered in several partial amounts between about 15 and 1000 mg, and about 25 and 1000 mg, two to four times a day or in sustained release form.
The compounds of the formula I also have an analgesic effect, so that they can be used as analgesics and antipyretics. The amounts to be administered here daily correspond to those for the anti-inflammatory effect.
The compounds of the formula I can be administered orally or parenterally and can be processed with customary auxiliaries and additives to produce suitable pharmaceutical forms. A suitable capsule consists, for example, of 50 parts by weight of a compound of formula I, e.g. 1-Isopropyl-4-phenyl-6,7-methylenedioxy-2 (1H) -quinazolinone and 200 parts by weight of an inert, solid diluent, for example kaolin.
Of the compounds of the formula I, those of the formula I are given because of their pharmacological action, in which R is isopropyl, for example l-isopropyl-4-phenyl-6,7-methylenedioxy-2 (1H) -quinazolinone, 1-isopropyl 4- (p-fluorophenyl) -6,7-methylenedioxy-2 (1H) -quinazolinone and 1-isopropyl-4-phenyl-6,7-methylenedioxy-2 (1H) -quinazolinethione.
Example 1 1-Isopropyl-4-phenyl-6,7-methylenedioxy-2 (1H) -quinazolinethione
A solution of 5.6 g of 2-isopropylamino-4,5-methylene-dioxybenzophenone in 50 ml of acetic acid is mixed with 1.5 g of ammonium thiocyanate. The mixture is refluxed for 3 hours and then concentrated to dryness. A sample of the residue is examined by thin layer chromatography (absorbent: silicon oxide, 20% ethyl acetate / chloroform). The substance with an Rf value of 0.5 is separated off in a manner known per se, giving the title compound with a melting point of 202-204 ° C.
Example 2
Analogously to Example 1 and using suitable starting materials in appropriate amounts, the following compounds of the formula I are obtained: a) 1-isopropyl-4-phenyl-6,7-methylenedioxy-2 (1H) -quinazolinone, melting point 202-205 C, b) 1-isopropyl-4- (m-fluorophenyl) -6,7-methylenedioxy -2 (1H) -quinazolinone, m.p. 169-170 C, c) 1-isopropyl-4- (m-methoxyphenyl) - 6,7-methylenedioxy -2 (1H) -quinazolinone, m.p. 189-191 C, d) 1-isopropyl-4- (p-methylphenyl) -6,7-methylenedioxy -2 (1H) -quinazolinone,
M.p. 188-190 C, e) 1-isopropyl-4- (o-nitrophenyl) -6,7-methylenedioxy -2 (1H) -quinazolinone, M.p. 148-150 C, f) 1-isopropyl-4- ( 5'-chloro-2-thienyl) -6,7-methylenedioxy -2 (1H) -quinazolinone, m.p. 192-201 C, g) 1-isopropyl-4- (3,4-methylenedioxyphenyl) -6,7- methylenedioxy-2 (1H) -quinazolinone, m.p.
234-235 C, h) 1-isopropyl-4- (m-nitrophenyl) -6,7-methylenedioxy -2 (1H) -quinazolinone, m.p. 230-232 C, i) 1-isopropyl-4- (o- methylphenyl) -6,7-methylenedioxy -2 (1H) -quinazolinone, m.p. 155-157 C, j) 1-isopropyl-4- (p-fluorophenyl) -6,7-methylenedioxy -2 (1H) -quinazolinone, M.p. 238-240 C, k) 1-isopropyl-4- (3,4-dichlorophenyl) -6,7-methylenedioxy -2 (1H) -quinazolinone, m.p.
239-242 C, l) 1-methyl-4-phenyl-6,7-methylenedioxy-2 (1H) -quinazolinone, m.p. ¯257-260 C, m) 1-cyclopropylmethyl-4-phenyl-6,7- methylenedioxy -2 (1H) -quinazolinone, n) 1-isopropyl-4- (m-fluorophenyl) -6,7-methylenedioxy -2 (1H) -quinazolinethione, m.p. 210-214 C, o) 1-isopropyl-4 - (p-Isopropylphenyl) -6,7-methylenedioxy -2 (1H) -quinazolinethione, m.p. 167-170 C, p) 1-isopropyl-4- (p-fluorophenyl) -6,7-methylenedioxy -2 (1H ) -quinazolinethione, m.p. 220-223 C, q) 1-isopropyl-4- (m-nitrophenyl) -6,7-methylenedioxy -2 (1H) -quinazolinethione, m.p. 199-202 C.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US14099071A | 1971-05-06 | 1971-05-06 | |
| US14101171A | 1971-05-06 | 1971-05-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH551419A true CH551419A (en) | 1974-07-15 |
Family
ID=26838683
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH117774A CH551419A (en) | 1971-05-06 | 1972-04-26 | 4-substd-6,7-methylenedioxy-(3,4-dihydro)-2(1-h)quinaloline - e(thi)ones - with antiinflammatory analgeis and antipyretic activity |
| CH118374A CH551423A (en) | 1971-05-06 | 1972-04-26 | PROCESS FOR THE PREPARATION OF 6,7-METHYLENIOXY-2 (1H) QUINAZOLINONES OR -2 (1H) -CHINAZOLINTHIONS. |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH118374A CH551423A (en) | 1971-05-06 | 1972-04-26 | PROCESS FOR THE PREPARATION OF 6,7-METHYLENIOXY-2 (1H) QUINAZOLINONES OR -2 (1H) -CHINAZOLINTHIONS. |
Country Status (5)
| Country | Link |
|---|---|
| AT (2) | ATA393472A (en) |
| CA (1) | CA983930A (en) |
| CH (2) | CH551419A (en) |
| ES (1) | ES429706A1 (en) |
| HU (1) | HU164668B (en) |
-
1972
- 1972-04-26 CH CH117774A patent/CH551419A/en not_active IP Right Cessation
- 1972-04-26 CH CH118374A patent/CH551423A/en not_active IP Right Cessation
- 1972-05-03 CA CA141,170A patent/CA983930A/en not_active Expired
- 1972-05-04 HU HUSA002351 patent/HU164668B/hu unknown
- 1972-05-05 AT AT393472A patent/ATA393472A/en not_active IP Right Cessation
-
1974
- 1974-04-19 AT AT324474A patent/AT328442B/en not_active IP Right Cessation
- 1974-08-31 ES ES429706A patent/ES429706A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ATA324474A (en) | 1975-06-15 |
| AT328442B (en) | 1976-03-25 |
| CA983930A (en) | 1976-02-17 |
| HU164668B (en) | 1974-03-28 |
| ATA393472A (en) | 1975-05-15 |
| ES429706A1 (en) | 1977-03-16 |
| CH551423A (en) | 1974-07-15 |
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