US3301855A - Derivatives of 4-nu-(2-nu, nu-dimethylaminolower alkyl)-amino quinazoline - Google Patents
Derivatives of 4-nu-(2-nu, nu-dimethylaminolower alkyl)-amino quinazoline Download PDFInfo
- Publication number
- US3301855A US3301855A US348861A US34886164A US3301855A US 3301855 A US3301855 A US 3301855A US 348861 A US348861 A US 348861A US 34886164 A US34886164 A US 34886164A US 3301855 A US3301855 A US 3301855A
- Authority
- US
- United States
- Prior art keywords
- quinazoline
- group
- amino
- compound
- dimethylamino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 125000000217 alkyl group Chemical group 0.000 title description 29
- 238000000034 method Methods 0.000 description 65
- 150000001875 compounds Chemical class 0.000 description 57
- -1 1,2-phenylene (o-phenylene) radical Chemical class 0.000 description 51
- 150000003839 salts Chemical class 0.000 description 51
- 239000007858 starting material Substances 0.000 description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- 239000000203 mixture Substances 0.000 description 40
- 239000002253 acid Substances 0.000 description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- 239000000243 solution Substances 0.000 description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 19
- 230000000202 analgesic effect Effects 0.000 description 19
- 239000004615 ingredient Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- 208000002193 Pain Diseases 0.000 description 14
- 239000003153 chemical reaction reagent Substances 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 230000036407 pain Effects 0.000 description 13
- 239000003085 diluting agent Substances 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 239000001257 hydrogen Substances 0.000 description 11
- 229910052739 hydrogen Inorganic materials 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 239000000155 melt Substances 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 8
- 125000003396 thiol group Chemical group [H]S* 0.000 description 8
- 239000002775 capsule Substances 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 7
- CZAAKPFIWJXPQT-UHFFFAOYSA-N quinazolin-2-amine Chemical compound C1=CC=CC2=NC(N)=NC=C21 CZAAKPFIWJXPQT-UHFFFAOYSA-N 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 6
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 3H-quinazolinyl-4-one Natural products C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- 239000011261 inert gas Substances 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 150000007522 mineralic acids Chemical class 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 125000002030 1,2-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([*:2])C([H])=C1[H] 0.000 description 4
- TWWNPUZQYVWXJY-UHFFFAOYSA-N 1h-quinazoline-4-thione Chemical compound C1=CC=C2C(S)=NC=NC2=C1 TWWNPUZQYVWXJY-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 125000002947 alkylene group Chemical group 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 125000001246 bromo group Chemical group Br* 0.000 description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical compound C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000011343 solid material Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical compound C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 description 3
- 208000000094 Chronic Pain Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- UIQMVEYFGZJHCZ-SSTWWWIQSA-N Nalorphine Chemical compound C([C@@H](N(CC1)CC=C)[C@@H]2C=C[C@@H]3O)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 UIQMVEYFGZJHCZ-SSTWWWIQSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 125000004043 oxo group Chemical group O=* 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 3
- 229960003975 potassium Drugs 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 3
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- JUCDXPIFJIVICL-UHFFFAOYSA-N 6-methyl-1h-quinazolin-4-one Chemical compound N1C=NC(=O)C2=CC(C)=CC=C21 JUCDXPIFJIVICL-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- CFRJWLSNXCMWEE-UHFFFAOYSA-N C1=CC=CC2=[N+]([O-])C(N)=NC=C21 Chemical compound C1=CC=CC2=[N+]([O-])C(N)=NC=C21 CFRJWLSNXCMWEE-UHFFFAOYSA-N 0.000 description 2
- PHMQAUIPUIFUMQ-UHFFFAOYSA-N CNN(NC)C(C)C Chemical compound CNN(NC)C(C)C PHMQAUIPUIFUMQ-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 206010019233 Headaches Diseases 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 2
- 206010038678 Respiratory depression Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 229940025084 amphetamine Drugs 0.000 description 2
- 238000005349 anion exchange Methods 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 231100000869 headache Toxicity 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- ZQBAKBUEJOMQEX-UHFFFAOYSA-N phenyl salicylate Chemical compound OC1=CC=CC=C1C(=O)OC1=CC=CC=C1 ZQBAKBUEJOMQEX-UHFFFAOYSA-N 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011118 potassium hydroxide Nutrition 0.000 description 2
- 229940093932 potassium hydroxide Drugs 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 2
- VBCVBVXRDBPFIL-UHFFFAOYSA-N quinazoline-4-carbonitrile Chemical compound C1=CC=C2C(C#N)=NC=NC2=C1 VBCVBVXRDBPFIL-UHFFFAOYSA-N 0.000 description 2
- 230000011514 reflex Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- DYIOSHGVFJTOAR-JGWLITMVSA-N (2r,3r,4s,5r)-6-sulfanylhexane-1,2,3,4,5-pentol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CS DYIOSHGVFJTOAR-JGWLITMVSA-N 0.000 description 1
- AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical compound O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 description 1
- SLTGUVPFWOECBZ-UHFFFAOYSA-N 1,4-dihydroquinazoline-4-carbonitrile Chemical compound C1=CC=C2C(C#N)N=CNC2=C1 SLTGUVPFWOECBZ-UHFFFAOYSA-N 0.000 description 1
- YMDNODNLFSHHCV-UHFFFAOYSA-N 1-chloro-2-(diethylamino)ethane Natural products CCN(CC)CCCl YMDNODNLFSHHCV-UHFFFAOYSA-N 0.000 description 1
- TUQSVSYUEBNNKQ-UHFFFAOYSA-N 2,4-dichloroquinazoline Chemical compound C1=CC=CC2=NC(Cl)=NC(Cl)=C21 TUQSVSYUEBNNKQ-UHFFFAOYSA-N 0.000 description 1
- 125000005273 2-acetoxybenzoic acid group Chemical group 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- RMEPJMLKSVAPKT-UHFFFAOYSA-N 2-chloro-n,n-dimethylpropan-2-amine;hydrochloride Chemical compound Cl.CN(C)C(C)(C)Cl RMEPJMLKSVAPKT-UHFFFAOYSA-N 0.000 description 1
- YTRMTPPVNRALON-UHFFFAOYSA-N 2-phenyl-4-quinolinecarboxylic acid Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=CC=C1 YTRMTPPVNRALON-UHFFFAOYSA-N 0.000 description 1
- GVRRXASZZAKBMN-UHFFFAOYSA-N 4-chloroquinazoline Chemical compound C1=CC=C2C(Cl)=NC=NC2=C1 GVRRXASZZAKBMN-UHFFFAOYSA-N 0.000 description 1
- FXOQDTCSOJMDGD-UHFFFAOYSA-N 4-methoxy-1-oxidoquinazolin-1-ium Chemical compound C1=CC=C2C(OC)=NC=[N+]([O-])C2=C1 FXOQDTCSOJMDGD-UHFFFAOYSA-N 0.000 description 1
- QHHPPKHDJVVPQH-UHFFFAOYSA-N 4-methoxyquinazoline Chemical compound C1=CC=C2C(OC)=NC=NC2=C1 QHHPPKHDJVVPQH-UHFFFAOYSA-N 0.000 description 1
- QDKPQWRXXRKGAE-UHFFFAOYSA-N 6,7-dimethoxy-1h-quinazoline-4-thione Chemical compound C1=NC(S)=C2C=C(OC)C(OC)=CC2=N1 QDKPQWRXXRKGAE-UHFFFAOYSA-N 0.000 description 1
- GOBVWEUSCRFCPB-UHFFFAOYSA-N 6-chloro-1h-quinazolin-4-one Chemical compound N1C=NC(=O)C2=CC(Cl)=CC=C21 GOBVWEUSCRFCPB-UHFFFAOYSA-N 0.000 description 1
- ACIHIXHQFRGLRV-UHFFFAOYSA-N 6-methyl-1h-quinazoline-4-thione Chemical compound N1C=NC(=S)C2=CC(C)=CC=C21 ACIHIXHQFRGLRV-UHFFFAOYSA-N 0.000 description 1
- ZALFXJGMURTKRI-UHFFFAOYSA-N 6-methyl-2-[4-[2-[4-(6-methyl-7-sulfo-1,3-benzothiazol-2-yl)phenyl]iminohydrazinyl]phenyl]-1,3-benzothiazole-7-sulfonic acid Chemical compound C1=C(C)C(S(O)(=O)=O)=C2SC(C3=CC=C(C=C3)N=NNC3=CC=C(C=C3)C3=NC4=CC=C(C(=C4S3)S(O)(=O)=O)C)=NC2=C1 ZALFXJGMURTKRI-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- FDQGNLOWMMVRQL-UHFFFAOYSA-N Allobarbital Chemical compound C=CCC1(CC=C)C(=O)NC(=O)NC1=O FDQGNLOWMMVRQL-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- RMMXTBMQSGEXHJ-UHFFFAOYSA-N Aminophenazone Chemical compound O=C1C(N(C)C)=C(C)N(C)N1C1=CC=CC=C1 RMMXTBMQSGEXHJ-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- AAWZDTNXLSGCEK-UHFFFAOYSA-N Cordycepinsaeure Natural products OC1CC(O)(C(O)=O)CC(O)C1O AAWZDTNXLSGCEK-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- AAWZDTNXLSGCEK-ZHQZDSKASA-N Quinic acid Natural products O[C@H]1CC(O)(C(O)=O)C[C@H](O)C1O AAWZDTNXLSGCEK-ZHQZDSKASA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 240000006394 Sorghum bicolor Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- GANNOFFDYMSBSZ-UHFFFAOYSA-N [AlH3].[Mg] Chemical compound [AlH3].[Mg] GANNOFFDYMSBSZ-UHFFFAOYSA-N 0.000 description 1
- GXDVEXJTVGRLNW-UHFFFAOYSA-N [Cr].[Cu] Chemical compound [Cr].[Cu] GXDVEXJTVGRLNW-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- 229960000880 allobarbital Drugs 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 229940009868 aluminum magnesium silicate Drugs 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960000212 aminophenazone Drugs 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 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
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 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
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960002468 cinchophen Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- IQFVPQOLBLOTPF-HKXUKFGYSA-L congo red Chemical compound [Na+].[Na+].C1=CC=CC2=C(N)C(/N=N/C3=CC=C(C=C3)C3=CC=C(C=C3)/N=N/C3=C(C4=CC=CC=C4C(=C3)S([O-])(=O)=O)N)=CC(S([O-])(=O)=O)=C21 IQFVPQOLBLOTPF-HKXUKFGYSA-L 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000006477 desulfuration reaction Methods 0.000 description 1
- 230000023556 desulfurization Effects 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- GOMCKELMLXHYHH-UHFFFAOYSA-L dipotassium;phthalate Chemical compound [K+].[K+].[O-]C(=O)C1=CC=CC=C1C([O-])=O GOMCKELMLXHYHH-UHFFFAOYSA-L 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- FCQJEPASRCXVCB-UHFFFAOYSA-N flavianic acid Chemical compound C1=C(S(O)(=O)=O)C=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FCQJEPASRCXVCB-UHFFFAOYSA-N 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical group [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N hydroxymaleic acid group Chemical group O/C(/C(=O)O)=C/C(=O)O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- PANJMBIFGCKWBY-UHFFFAOYSA-N iron tricyanide Chemical compound N#C[Fe](C#N)C#N PANJMBIFGCKWBY-UHFFFAOYSA-N 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960000938 nalorphine Drugs 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 1
- 229960003893 phenacetin Drugs 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- 229960000969 phenyl salicylate Drugs 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000007686 potassium Nutrition 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- OGHBATFHNDZKSO-UHFFFAOYSA-N propan-2-olate Chemical compound CC(C)[O-] OGHBATFHNDZKSO-UHFFFAOYSA-N 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- 229940079101 sodium sulfide Drugs 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000001148 spastic effect Effects 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000563 toxic property Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
Definitions
- the present invention concerns Z-unsubstituted 4-N-(2- N,N-dimethylamin-o-lower alkyl)-almin-o-quinazoline compounds and salts thereof. More especially, it relates to compounds of the formula:
- Ph is a 1,2-phenylene (o-phenylene) radical
- group of the formula (C,,H is lower alkylene separting the two nitrogen atoms by two carbon atoms, and the salts thereof.
- o-phenylene 1,2-phenylene radical
- C,,H is lower alkylene separting the two nitrogen atoms by two carbon atoms, and the salts thereof.
- the 1,2-phenylene (o-phenylene) radical Ph representing the hexacyclic carbocyclic aryl portion of the quinazoline ring system, is preferably unsubstituted, but may be substituted by one or more than one of the same or of different substituents attached to any of the four positions available for substitution.
- Substituents are, for example, lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl and the like, etherified hydroxyl, particularly lower alkoxy, e.g.
- halogen-o (representing hydroxyl esterified by a hydrohalic acid), e.g. fluoro, chloro, bromo and the like, halogeno-lower alkyl, e.g. trifluoromethyl and the like, or any other suitable substituent.
- the 1,2-phenylene group Ph in the above formula is primarily 1,2-phenylene, but may also be (lower alkyl)-1,2-phenylene, (etherified hydroxy)-1,2-phenylene, such as (lower alkoxy)-1,2-lphenylene and the like, (esterified hydroxy)-1,2-phenylene, such as (halogeno)-1,2-phenylene and the like, (trifluoromethyl)-l,2-phenylene, or any other suitably substituted 1,2-phenylene group.
- the lower alkyl radical separating N,N dimethylamino from amino by two carbon atoms and represented in the above formula by the group of the formula -(C H stands for lower alkylene having from two to three carbon atoms (i.e. the letter It stands preferably for one of the integers 2 and 3) and separates N,N-dimethylamino from amino by two carbon atoms.
- Such alkylene group is preferably 1,2-ethylene, but may also be 1-rnethyl-1,2- ethylene or 2-mcthyl-1,2-ethylene.
- Salts of the compounds of this invention are acid addition salts, such as pharmaceutical acceptable acid addition salts with inorganic acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like, or organic acids, such as organic carboxylic acids, e.g. acetic, propionic, pivalic, glycolic, lactic, malonic, succinic, maleic, hydroxymaleic, malic, tartaric, citric, benz-oic,
- inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like
- organic acids such as organic carboxylic acids, e.g. acetic, propionic, pivalic, glycolic, lactic, malonic, succinic, maleic, hydroxymaleic, malic, tartaric, citric, benz-oic,
- salicylic 2-acetoxybenzoic, nicotinic, isonicotinic acid and ICE the like, or organic sulfonic acids, e.g. methane sulfonic, ethane sulfonic, ethane 1,2-disulfonic, 2-hydroxyethane sulfonic, p-toluene sulfonic, naphthalene 2-sulfonic acid and the like.
- Other acid addition salts may also be useful as intermediates, for example, in the preparation of pharmaceutically acceptable acid addition salts, or may serve in the purification of the free compounds, as well as for identification or characterization purposes. Salts for the latter are, for example, those with acidic organic nitro compounds, e.g.
- M-onoor poly-salts may be formed.
- the compounds of this invention exhibit strong analgesic eifects accompanied by a low degree of toxicity. They are, therefore, useful as annalgesic agents having an improved therapeutic ratio capable of raising the threshold of pain, and thus alleviate pain or the symptoms thereof, such as acute pain-s caused by surgery, accidents and the like, pain caused by spastic conditions, e.g. headaches and the like, or chronic pains connected with arthritic conditions and the like.
- the potent analgesic effects of known morphinetype compounds with addicting properties are potentiated by amphetamine, and are accompanied by respiratory depression and depression of the spinal reflexes; furthermore, these effects are antagonized by N-allyl-N-desmethyl-morphine (nalorphine). It has now been found that the analgesic effects of the compounds of this invention are not potentiated by amphetamine, and are not accompanied by respiratory depression or depression. of the spinal reflexes; furthermore, their effects are not antagonized by N-allyl-N-desmethyl-morphine. It appears, therefore, that the compounds of this invention are free from addicting properties at pha-rmacologically effective doses.
- the free compounds of this invention are to a surprisingly high degree, water-soluble. They can, therefore, be used directly in case the compounds of this invention are to be used in an aqueous solution and do not have to be converted into a watersoluble salt; furthermore, the pressure of a solubilizer in such solution would not be required.
- this compound has an improved degree of toxicity, and is, therefore, of improved therapeutic ratio.
- the compounds of this invention are prepared according to known methods, for example, by converting in a 2- unsubstituted 4-X-quinazoline compound, particularly in a compound of the. formula:
- Ph has the previously-given meaning
- X is a group capable of being converted into an N-(2-N,N-
- a preferred substituent X capable of beirig converted into the N-(2-N,N-dimethylamino-lower alkyl)-amiiio group, is a mercapto group, a thiono group or a substituted mercapto group.
- the preferred starting material is, therefore, a 2-unsubstituted 4-mrc'apto-quinazoline compound or a tautomer thereof, or a salt of such compound, particularly a compound having one of the tautorneric formulae:
- R is an organic radical, such as a lower aliphatic group, for example, lower alkyl, e.g. methyl, ethyl, isopropyl and the like, or any other suitable organic group, such as phenyl-lower alkyl, e.g. benzyl and the like, or a salt of such compound.
- R is an organic radical, such as a lower aliphatic group, for example, lower alkyl, e.g. methyl, ethyl, isopropyl and the like, or any other suitable organic group, such as phenyl-lower alkyl, e.g. benzyl and the like, or a salt of such compound.
- the conversion of the group X into the N-(2-N,N-dimethylamino-lower alkyl)-amino group is carried out by reacting the above 4-X-quinazoline starting material, in which X is a mercapto group, a thiono group, or a substituted mercapto group, with an N-(2-N,N-dimethylamino-lower alkyl)-amine or a salt thereof, particularly with a compound of the formula H N(C,,H )N(CH in which the group of the formula C,,H has the previously-given meaning, or a salt thereof.
- the reaction is preformed according to known methods, preferably at an elevated temperature; if desired, an excess of the N-(2-N,N-dimethylamino-lower alky1)-amine may be employed.
- the reaction may be carried out in the absence or in the presence of a diluent, e.g. ethanol and the like, or a mixture of solvents, if necessary, in a closed vessel, and/ or in the atmosphere of an inert gas.
- a diluent e.g. ethanol and the like, or a mixture of solvents, if necessary, in a closed vessel, and/ or in the atmosphere of an inert gas.
- the starting materials used in the above modification of the process of this invention are known or are prepared according to known methods; preferably, they are obtained, for example, by reacting a Z-unsubstituted quinazol-in-4-one compound or a tautomeric 4-hydroxy-quinazoline compound with a reagent capable of replacing 0x0 or hydroxyl by thiono or mercapto, such as phosphorus pentasulfide and the like, which is preferably used in the presence of a suitable diluent, e.g. xylene and the like, and at an elevated temperature.
- a suitable diluent e.g. xylene and the like
- An unsubstituted mercapto group may be converted into a substituted mercapto group according to known methods, for example, by forming an alkali metal derivative of the 4-mercapto-quinazoline compound and reacting it with a reactive ester compound, such as a lower alkyl halide, a di-lower alkyl sulfate, a phenyl-lower alkyl halide and the like.
- a reactive ester compound such as a lower alkyl halide, a di-lower alkyl sulfate, a phenyl-lower alkyl halide and the like.
- Another group representing X in the 4-X-quinazoline starting material is a reactive functionally converted hy- 4 dr'oxyl group, especially a reactive etherified hydroxyl group or a reactive esterified hydroxyl group.
- a suitable etherified hydroxyl group is especially lower alkoxy, e. g. methoxy, ethoxy and the like, whereas a reactive esterified hydroxyl group is especially halogeno (representing hydroxyl esterified with a hydrohalic acid) having preferably an atomic weight greater than 19, e.g.
- the conversion of a reactive functionally converted hydroxyl group, particularly of lower alkoxy or halogeno, into the desired N-(2-N,N-dimethylamino-lower alkyl)-- amino group is carried out according to the method described above, i.e. by treating the appropriate starting material with an N-(2-N,N-dimethylamino-lower alkyl)- amine, particularly with a compound of the formula H N(C,,H ,,)N(CH in which the group of the formula (C,,H has the previously-given meaning, or a salt thereof.
- the reaction is carried out in the absence or in the presence of a diluent or a mixture of diluents, preferably at an elevated temperature, and, if necessary, in a closed vessel, an-d/ or, in the atmosphere of an inert gas, e.g. nitrogen.
- a diluent or a mixture of diluents preferably at an elevated temperature, and, if necessary, in a closed vessel, an-d/ or, in the atmosphere of an inert gas, e.g. nitrogen.
- the above Z-unsubstituted 4-reactive functionally converted hydroxy-quinazoline starting materials are known or are prepared according to known methods.
- the 2-unsubstituted 4-halogeno-quinazoline starting materials are obtained from the corresponding quinazoline-4-0ne compounds or tautomeric 4-hydroxy-quinazoline compounds by treating such compounds with a suitable lralogenating reagent capable of replacing an oxo group or a hydroxyl group by halogeno, for example, with a phosphorus halide, e.g. phosphorus pentachloride, phosphorus tribromide and the like, or a thionyl halide, e.g.
- 4-reactive esterified hydroxy-quinazoline starting materials are prepared according to known esterification procedures.
- 2 unsubstituted 4-reactive etherified hydroxy-quinazoline starting materials, in which the reactive etherified hydroxyl group is especially lower alkoxy, are prepared, for example, by reacting a 2-unsubstituted 4-halogeno-quinazoline compound with a metal alcoholate, especially an alkali metal lower alkoxide, e.g.
- Another group X is a 4-X-quinazoline starting material, capable of being converted into the desired N-(2- N,N-dimethylamino-lower alkyl)-amino group, is the cyano group as represented by the formula I GEN Conversion of such group into N-(2-N,N-dimethylaminolower alkyl)-amino is carried out as described above, for example, by reacting a 2-unsubstituted 4-cyano-quinazoline compound with the appropriate N-(2-N,N-dimethylamino-lower alkyl)-amine, preferably in the presence of a diluent, such as a lower alkanol, e.g methanol and the like, if necessary, at an elevated temperature, and/ or in a closed vessel.
- a diluent such as a lower alkanol, e.g methanol and the like
- the starting materials used in the above modification of the procedure of this invention are known or may be prepared according to known methods, for example, by reacting a 2,4-unsubstituted quinazoline compound with a saturated solution of hydrogen cyanide in methanol in a sealed tube.
- Another group X in a 4-X-quinazoline starting material capable of being converted into the desired N-(2-N.
- a reactive ester of a 2-N,N-dirnethylamino-lower alkanol particularly with a compound of the formula in which the group of the formula (C,,H separating N,N-dimethylamino from X by two carbon atoms, has the previously-given meaning, and X is a reactive esterified hydroxyl group, or a salt of such compound.
- the reactive esterified hydroxyl group represented by X is particularly halogeno (i.e. hydroxyl esterified by a hydrohalic acid), having an atomic Weight greater than 19, e.g. chloro, bromo and the like, as well as an organic sulfonyloxy group, e.g.
- the above reaction is carried out according to known methods; preferably, it is performed at an elevated temperature, and, if necessary, in the presence of a diluent, and/or of a salt-forming reagent, such as an alkali metal hydride or an alkali metal amide, or any other corresponding reagent, and/or, of a base (which may'also be furnished by an excess of the basic 4-aminoquinazoline starting material) to neutralize any generated acid or to liberate the basic reagent from any acid addition salt, and/ or in a closed vessel, and/or in the atmosphere of an inert gas, e.g. nitrogen.
- a salt-forming reagent such as an alkali metal hydride or an alkali metal amide, or any other corresponding reagent
- a base which may'also be furnished by an excess of the basic 4-aminoquinazoline starting material
- the starting materials used in the above modification of the process of this invention are known or may be prepared according to known methods, for example, by converting in a Z-unsubstituted 4-X-quinazoline compound, in which X is mercapto or halogeno, the group X into the amino group, for example, by treatment with ammonia or an ammonia-furnishing reagent.
- the group X in the above 4-X-quinazoline starting material may also represent an N-(2-N,N-dimethylaminolower alkanoyl)-amino group or an N-(2-N,N-dimethyl amino-lower thioalkanoyl)-amino group, particularly the group of the formula Hl l( C YC n-iHzn-z) N (CH3) 2 in which Y stands for 0x0 of the formula :0 or thiono of the formula :8, and in which the portion of the forrnula CYC,, H separates N,N-dimethylamino from amino by two carbon atoms.
- Z-unsubstituted 4-N- (2 N,N dimethylamino lower alkanoyl) aminoquinazoline starting materials and 2-unsubstituted 4-N- (2 N,N dimethylamino lower thioalkanoyl) aminoquinazoline starting materials are converted into the desired compounds of this invention according to known methods capable of replacing oxo in a carbonyl group or thiono in a thiocarbonyl group by two hydrogen atoms.
- Replacement of 0x0 by two hydrogen atoms is carried out by reduction and is preferably achieved by treating the appropriate starting material with an aluminum hydride, particularly an alkali metal aluminum hydride, e.g. lithium aluminum hydride, sodium aluminum hydride and the like, or an alkaline earth metal aluminum hydride, e.g. magnesium aluminum hydride and the like, or aluminum hydride.
- an aluminum hydride particularly an alkali metal aluminum hydride, e.g. lithium aluminum hydride, sodium aluminum hydride and the like, or an alkaline earth metal aluminum hydride, e.g. magnesium aluminum hydride and the like, or aluminum hydride.
- activators such as, for example, aluminum chloride
- the reduction with these reagents is preferably performed in the presence of an inert solvent, particularly an ether, such as a di-lower alkyl ether, e.g.
- Conversion of the carbonyl por- 6 tion of an amide grouping may also be achieved by treating the appropriate starting material with hydrogen in the presence of certain catalysts, such as a copper-chro mium catalyst and the like, by electrolytic reduction or any other suitable method.
- Replacement of sulfur in a thiocarbonyl group by two hydrogens may be carried out by desulfurization according to known methods, for example, by treatment with a freshly prepared hydrogenation catalyst, such as Raney nickel, in an alcoholic solvent, e.g. methanol, ethanol and the like, if desired, in the presence of hydrogen, by electrolytic reduction and the like.
- a freshly prepared hydrogenation catalyst such as Raney nickel
- an alcoholic solvent e.g. methanol, ethanol and the like
- the starting materials used in the above modification of the procedure of this invention are prepared, for example, by reacting a 2-unsubstituted 4-amino-quinazoline compound with a 2-N,N-dimethylamino-lower alkanoic acid halide, e.g. chloride, bromide and the like; this reaction may be carried out in the presence of a liquid organic base, e.g. pyridine and the like, which may also serve as the diluent, and/or of an inert solvent, e.g. benzene, toluene and the like, if necessary, by using an excess of the basic starting material or an additional base, e.g. potassium carbonate and the like, to neutralize any generated acid.
- a liquid organic base e.g. pyridine and the like
- an inert solvent e.g. benzene, toluene and the like
- the carbonyl portion of the amide grouping can be replaced by thiocarbonyl, for example, by treatment with a reagent capable of replacing oxo by thiono, e.g. phosphorus pentasulfide and the like, as previously described.
- a reagent capable of replacing oxo by thiono e.g. phosphorus pentasulfide and the like, as previously described.
- the group X in a 4-X-quinazoline starting material may also represent an N-(2 N,N-dimethylamino-Z-oxolower alkyl)-amino group or an N-(2-N,N-dimethylamino-Z-thiono-lower alkyl)-amino group, particularly a group of the formula in which Y has the previously-given meaning, and the portion of the formula (C,, H CY) separates N,N-dimethylamino from amino by two carbon atoms.
- the starting materials used in the above modification of the process for the manufacture of the compounds of this invention are prepared according to known methods.
- a 2-unsubstituted 4-amino-quinazoline compound may be reacted with a Z-(reactive esterified hydroxy)-lower alkanoic N,N-dimethylamide, particularly a compound of the formula X (C H CO) N(CH in which X has the previously-given meaning (being particularly halogeno having an atomic weight greater than 19, e.g.
- the 0x0 group may be replaced by thiono, for example, by treating it with a suitable reagent, e.g. phosphorus pentasulfide and the like, as previously described.
- a suitable reagent e.g. phosphorus pentasulfide and the like, as previously described.
- the compounds of this invention are also prepared by reacting a 2-unsu-bstituted quinazoline compound, particularly a compound of the formula:
- Ph has the previously-given meaning, or a salt thereof with an N-(Z-N,N-dimethylamino-lower alkyl)- amine, especially a compound of the formula H N (C H N(CH in which the group of the formula (C H has the previously-given meaning, and, if necessary, converting any resulting Z-unsubstituted 4-N- (2-N,N-dimethylamino-lower alkyl)-amino-3,4-dihydroquinazoline compound into the desired Z-unsubstituted 4-N- 2-N,N-dimethylamino-lower alkyl -amino-quinazoline compound by oxidation, and, if desired, carrying out the optional steps.
- the above reaction is carried out according to known methods, preferably in the presence of a suitable saltforming reagent, such as an alkali metal hydride and the like, and in the presence of an appropriate diluent, e.g. N,N-dimethyl-aniline and the like. Usually it is performed at an elevated temperature, and if necessary, in a closed vessel, and/ or in the atmosphere of an inert gas.
- a suitable saltforming reagent such as an alkali metal hydride and the like
- an appropriate diluent e.g. N,N-dimethyl-aniline and the like.
- a resulting 4-N-(2-N,N-dimethylaminolower alkyl)-am.ino-3,4-dihydro-quinazoline compound is converted into the desired 4-N-(2-N,N-dimethylaminolower .alkyl)-amino-quinazoline by oxidation.
- oxidation is performed according to known methods, for example, by air oxidation, or by treatment with any other suitable oxidation reagent, such as potassium ferric cyanide, iodine and the like, preferably in the presence of a diluent.
- the compounds of this invention are also prepared by replacing in a 4-N-(2-N,N-dimethylamino-lower alkyl)- amino-2-R -quinazoline, particularly in a compound of the formula:
- a group R capable of being replaced by hydrogen is especially a reactive functionally converted hydroxyl group, such as a reactive esterified hydroxyl group, particularly halogeno, e.g. chloro, bromo and the like, or any other suitable group capable of being replaced by hydrogen.
- the group R is removed according to known methods, usually by reduction, e.g. treatment with hydrogen in the presence of a suitable catalyst, such as a palladium catalyst and the like, if necessary under increased pressure, and/ or at an elevated temperature, or any other equivalent reducing method.
- the starting material is prepared according to known procedures, usually by converting in a 2-R -4-X-quinazoline, in which R and'X have the previously-given meaning, the group X into the N-(2-N,N-dimethylaminolower alkyl)-amino group according to any of the previously-described procedures.
- the compounds of this invention are also prepared, for example, by eliminating in a Z-unsubstituted 4-N- (2- N,N-dimethylamino-lower alkyl)-amino-quinazoline N- oxide, particularly in a compound of the formula:
- a metal catalyst e.g. a nickel catalyst and the like, or any other procedure, such as reacting the starting material with a phosphorus halide, e.g. phosphorus trichloride and the like.
- a resulting acid addition salt of a compound prepared according to the process of this invention may be converted into the free compound, for example, by reacting it with an alkaline reagent, such as a metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydrox-ide, calcium hydroxide and the like, a metal carbonate, e.g. sodium, potassium or calcium carbonate or hydrogen carbonate and the like, ammonia and the like, or by treatment with a suitable hydroxyl ion exchange resin.
- an alkaline reagent such as a metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydrox-ide, calcium hydroxide and the like, a metal carbonate, e.g. sodium, potassium or calcium carbonate or hydrogen carbonate and the like, ammonia and the like, or by treatment with a suitable hydroxyl ion exchange resin.
- a resulting acid addition salt of a compound prepared according to the process of this invention may also be converted into another salt; for example, a salt with an inorganic acid may be reacted with a suitable metal, e.g. sodium, silver, barium and the like, salt of an acid, in the presence of a diluent, in which a resulting inorganic compound is insoluble and is thus removed from the reaction. Conversion of an acid addition salt into another acid addition salt may also be achieved by treatment with an anion exchange preparation.
- a suitable metal e.g. sodium, silver, barium and the like
- a free compound resulting from the process of this invention may be converted into an acid addition salt thereof by reacting it or a solution thereof in a suitable solvent or solvent mixture with an acid or a solution thereof, or with an anion exchange preparation, and
- a salt may be obtained in the form of a hydrate thereof or may include solvent of crystallization.
- a mixture of resulting isomeric compounds may be separated into the single isomers.
- racernates may be resolved into the optically active dand l-forms according to known resolution procedures, for example, by forming a salt of the free racemic compound with one of the optically active forms of an acid containing an asymmetric carbon atom.
- optically active forms of salt-forming acids having an asymmetric carbon atom are D-tartaric (l-tartaric) acid and L-tartaric (d-tartaric) acid, as well as the optically active forms of malic, mandelic, IO-camphor sulfonic, quinic acid and the like.
- a resulting mixture of salts is separated on the basis of physico-chemical differences, for example, by fractional crystallization; a separated salt may then be converted into the free and optically active compound as described above, and a free and optically active base may be converted into its acid addition salt according to the procedures described above.
- the invention also comprises any modification of the process, wherein a compound formed as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is(are) carried out, as well as any new intermediates.
- Example 1 To a solution of 0.95 g. of 4-mercapto-quinazoline (or its tautomer 3H-quinazolin-4-thione) in ml. of N,N- dimethylethylenediamine is added 10 ml. of ethanol. The solution is refluxed for four hours and is then evaporated to dryness under reduced pressure. The solid residue (yield: 0.70 g.) is crystallized from a mixture of acetone and hexane to yield the desired 4-N-(2-N,N-dimethylaminoethyl)-amino-quinazoline of the formula:
- the starting material used in the above procedure is prepared according to the method described by Leonard et al., J. Org. Chem., vol. 11, p. 349 (1946): A mixture of 7.3 g. of 4-hydroxy-quinazoline (or its tautomer 3H- quinazolin-4-one) and 11.1 g. of phosphorus pentasulfide in 500 ml. of xylene is refluxed for two hours while stirring. After cooling, the reaction mixture is extracted with 100 ml. of 2 N agueous sodium hydroxide; the aqueous phase is filtered and neutralized with glacial acetic acid.
- Example 2 To a diethyl ether solution of 4-N-(2-N,N-dimethylaminoethyl)-amino-quinazoline is added a solution of an equivalent amount of maleic acid in methanol; the resulting 4-N- 2-N,N-dimethylaminoethyl -amino-quinazoline maleate melts at 186188 (with decomposition) after.
- Example 3 solidifies and is recrystallized several times from pentane, M.P. 99l01.
- the N,N-dimethylamino-isopropylamine used as the reagent is prepared as follows: A mixture of 31.6 g. of N,N- dimethylaminoisopropyl chloride hydrochloride and 20.0 g. of potassium hydrogen carbonate in 200 ml. of toluene is heated until the evolution of carbon dioxide gas decreases. The solid material is filtered off; the filtrate is treated with 37.0 g. of potassium phthalimide, and the reaction mixture is refluxed for sixteen hours. After cooling and filtering, the filtrate is evaporated to dryness; the resulting oily residue solidifies upon adding pentane and cooling to yield 28.0 g. of N-(N,N-dimethylamino-isopropyl)-phthalimide, which melts at 57-59" after recrystallization from pentane.
- a mixture of 20.0 g. of N-(N,N-dimethylamino-isopropyl)-phthalimide in 100 ml. of 20 percent hydrochloric acid is refluxed for three hours and allowed to stand for several days.
- the solid material is filtered off and washed with water; the combined filtrates are concentrated to a small volume and made strongly 'basic with an aqueous solution of sodium hydroxide.
- the resulting oil is extracted with methylene chloride, the organic solution is dried over sodium sulfate and evaporated to dryness.
- the desired N,N-dimethylamino-isopropyl-amine is purified by distilling the residue and is collected at about 50/ 15 mm.
- Example 4 A solution of 2.3 g. of 4-N-(N,N-dimethyl-carbamylmethyl)-amino-qulnazoline in 30 ml. of tetrahydrofuran is added dropwise over a period of thirty minutes to a suspension of 0.38 g. of lithium aluminum hydride in 50 ml. of tetrahydrofuran while cooling in an ice-bath and maintaining vigorous stirring. The reaction mixture is then refluxed for sixhours; the resulting complex is destroyed by adding a small excess of water in tetrahydrofuran.
- the starting material used in the above procedure is prepared as follows: A mixture of 1.0 g. of 4-aminoquinazoline (prepared according to the method described by Morley et al., J. Chem. Soc., p. 1354 (1949)) and 0.16 g. of sodium hydride in 50 ml. of toluene is refluxed for two hours. A solution of 0.83 g. of u-chlOI'O-N,N- dimethylacetamide in 10 ml. of toluene is added dropwise over a period of fifteen minutes while stirring. The reaction mixture is refluxed for another hour and is then evaporated to dryness under reduced pressure. Water is added to the residue; the crude solid 4-N(N,N-dimethylcarbamyl-methyl)-amino-quinazoline is collected, dried on the filter and used without further purification.
- Example A mixture of 1.0 g. of 4-cyano-quinazoline and 1.0 g. of N,N-dimethyl-1,2-ethylenediamine is allowed to stand at room temperature for one hour, and is then warmed on the steam bath for fifteen minutes.
- the excess of N, N-dimethyI-LZethyIene diamine is evaporated under reduced pressure, and the residue is extracted with boiling cyclohexane.
- the organic extract is concentrated and allowed to stand while cooling to yield the desired 4-N- (2-N,N-dimethylarninoethyl)-amino-quinazoline, which is identical with the compound obtained according to the procedure described in Example 1.
- the starting material used in the previous procedure is prepared as follows: A solution of 1.0 g. of quinazoline in 30 ml. of methanol is cooled to 0 and is treated for 1%. hours with an excess of hydrogen cyanide. The solvent is then removed to yield the 4-cyano-3,4-dihydroquinazoline, M.P 128429". To a mixture of 0.5 g.
- Example 6 A mixture of 1.0 g. of 4-chloro-quinazoline and ml. of N,N-dimethyl-1,2-ethylenediamine is refluxed for three hours; the excess of N-N-dimethyl-1-2-ethylenediamine is removed under reduced pressure, and the residue is extracted with boiling cyclohexane. The organic extract yields 0.5 g. of the desired 4-N-(2-N,N-dimethyla minoeth yl)-amino-quinazoline which is identical with the compound formed according to the procedure described in Example 1.
- Example 7 A mixture of 1.0 g. of 4-amino-quinazoline and 0.2 g. of sodium hydride in 50 ml. of dry toluene is refluxed for two hours, and is then treated with a solution of 1.0 g. of 2-N,N-diethylamino-ethyl chloride (liberated from its hydrochloride with a cold, concentrated aqueous solution of sodium hydroxide in Water) in 50 ml. of toluene, which is added dropwise over a period of fifteen minutes while stirring and cooling in an ice bath. The reaction mixture is allowed to warm to room temperature and is then heated on the steam bath for thirty minutes. After evaporating the solvent under reduced pressure, the residue is extracted with boiling cyclohexane; the desired 4-N-(2-N,N-dimethylaminoethyl) amino quinazoline is obtained by concentrating and cooling the organic extract.
- 2-N,N-diethylamino-ethyl chloride liber
- the starting material used in the above procedure is prepared according to the method described by Morley et al., J. Chem. Soc., p. 1354 (1949).
- Example 8 A mixture of 4.0 g. of N,N-dimethyl-1,2-ethylenediamine, 1.0 g. of sodium hydride and ml. of N,N-dimethylaniline is heated at 145150 for two hours. Over aperiod of fifteen minutes and while maintaining that temperature, a total of 1.0 g. of quinazoline is added, and heating is continued for an additional two hours. After standing overnight, the reaction product is decomposed With a minimum amount of water; the aqueous phase is extracted with diethyl ether, and the organic extract is dried over anhydrous sodium sulfate and concentrated. The residue is taken up into boiling cycle-hexane; the solution is concentrated and chilled to yield the dried 4-N (2-N,N-dimethylaminoethyl) amino quinazoline, which is identical with the product obtained from the procedure described in Example 1.
- Example 9 A mixture of 1.0 g. of 4-methoxy-quinazoline, 10 m1. of N,N-dimethyl-1,2-ethylenediamine and 10ml. of methanol is heated in a sealed tube at 150 for sixteen hours. The reaction product is then evaporated to dryness under reduced pressure and the residue is extracted with boiling cyclohexane. The organic extract is decolorized with a charcoal preparation, concentrated and chilled to yield the desired 4-N (2 N,N dimethylaminoethyl) aminoquinazoline.
- the starting material is prepared according to the procedure described b Breukink et al., Rec. Trav. Chim., vol. 76, p. 401 (1957).
- Example 10 A solution of 2.0 g. of 2-chloro-4-N-(2-N,N-dimethylaminoethyl)-amino-quinazoline in ml. of warm methanol is shaken with hydrogen in the presence of 6.0 g. of palladium-on-charcoal. The reduction is complete after two hours; the catalyst is filtered off, the filtrate is evaporated and the residue is treated with aqueous sodium hydroxide. The aqueous phase is extracted with diethyl ether; the organic extract is dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The desired 4-N-(2-N,Ndimethylaminoethyl)-amino-quinazoline is obtained by extracting the residue with cyclohexane, concentrating the solution and cooling it.
- the starting material used in the above procedure is prepared as follows: A mixture of 2.0 g. of 2,4-dichloroquinazoline (prepared according to the method described by Curd et al., J. Chem Soc., p. 775 (1947)), 20 ml. of water and 0.88 g. of N,N-dimethyl-1,2-ethylenediamine is stirred at room temperature. After one hour, the reaction mixture is made alkaline to Clayton yellow with 10 N aqueous sodium hydroxide solution. In order to maintain the alkalinity, the reaction mixture is treated at intervals with further amounts of sodium hydroxide until approximately the equivalent of 0.4 g. of sodium hydroxide has been added (about six hours).
- reaction mixture is then acidified to Congo red with hydrochloric acid and filtered; the filtrate is treated with an excess of aqueous sodium hydroxide to precipitate a gummy material.
- the liquid phase is decanted, and the residue is triturated with diethyl ether.
- the desired 2- chloro-4-N-(2-N,N-dimethylaminoethyl) -amino quinazoline is collected, washed with water, dried at room temperature and used without further purification.
- Example 1 I To a solution of 1.0 g. of 4-N-(2-N,N-dimethylaminoethyl)-amino-quinazoline-l-oxide in 20 ml. of methanol is added the Raney nickel catalyst, prepared from 1.5 g. of a 1: l-nickelzaluminum alloy and a 30 percent aqueous solution of sodium hydroxide, and the mixture is shaken under hydrogen at atmospheric pressure. After the absorption of the theoretical amount of hydrogen, the reaction is interrupted, the catalyst is filtered 01? and the filtrate is evaporated to dryness.
- the Raney nickel catalyst prepared from 1.5 g. of a 1: l-nickelzaluminum alloy and a 30 percent aqueous solution of sodium hydroxide
- the starting materials used in the above procedure is prepared as follows: A mixture of 1.0 g. of 4-methoxyquinazoline-l-oxide (prepared according to the method described by Yamanaka, Chem. Pharm. Bull. (Tokyo), vol. 7, p. 152 (1959)) and 10 ml. of N,N-dimethyl-1,2- ethylenediamine is placed in a sealed tube and heated at 100 for two hours. The reaction mixture is then evaporated to dryness under reduced pressure and the residue is crystallized from a mixture of diethyl ether and pentane to yield the 4-N-(2 N,N dimethylaminoethyl) aminoquinazoline-l-oxide.
- Example 12 A mixture of 2.5 g. of 6-chloro-4-mercapto-quinazoline (or its tautomer 6-chloro-3H-quinazolin-4-thione) and 15 ml. of N,N-dimethyl-1,2-ethylenediamine in 15 ml. of ethanol is refluxed for four hours. After evaporating the reaction mixture to dryness under reduced pressure, the solid residue is crystallized from diethyl ether to yield the 6-chloro-4-N (2-N,N dimethylamino) -amino-quinazoline of the formula:
- the starting material used in the above procedure is prepared as follows: To a suspension of 23.0 g. of 6- chloro-4-hydroxy-quinazoline (prepared according to the procedure described by Magidson et al., J. Gen. Chem, vol. 8, p. 1797 (1938); C.A., vol. 33, p. 4993 (1939)) in 250 ml. of pyridine is added 32.0 g. of phosphorus pentasulfide. The exothermic reaction is maintained by refluxing for three hours; after cooling to a lower temperature, the reaction mixture is poured into about 500 ml. of water. The yellow-brown solid is filtered off, dried and then dissolved in about 200 ml.
- Exaniple 13 melts at 162l64 after recrystallization from ethyl acetate.
- the starting material used in the above procedure is prepared as follows: A mixture of 5.0 g. of S-methylanthranilic acid and 4.5 g. of formamide is heated to 140- 150 for one hour. Upon cooling, the reaction product solidifies and is triturated three times with acetone to yield 4.6 g. of 6-methyl-quinazolin-4-one; the latter melts at 264266 after recrystallization from methanol.
- compositions for the relief of pain are those comprising essentially a pharmacologically efiective amount of 4-N-(2-N,N-dimethylaminoethyl)-amino-quinazoline or a pharmaceutically acceptable acid addition salt thereof, as the active analgesic ingredient, and a pharmaceutioally acceptable carrier.
- the analgesic compositions of this invention represent versatile tools in raising the threshold and suppressing the symptons of many types of pain. Thus, they can be used to counteract light pains (e.g. toothaches, headaches and the like), as well as severe pains (e.g. post-operative pains, pains in connection with fractures and the like), and chronic pains (e.g. pains caused by arthitic conditions and the like.) Light pains require correspondingly smaller doses of the active analgesic ingredient, whereas severe and chronic pains have to be treated with higher doses of theactive compound. Advantages of the pharmacologically active ingredient of the compositions of this invention are-the considerable lack of undesirable side-effects and, for all practical purposes, the absence of toxic properties.
- the analgesic compositions of this invention are prepared according to methods accepted in the art of manufacturing of pharmaceutical compositions, essentially by combining the active ingredient with a pharmaceutically acceptable, organic or inorganic carrier in specified proportions.
- the compositions usually contain at most equal amounts of the active analgesic ingredient and the inert carrier. Preferably, they are made up to contain from about 1 percent to at most 50 pen-cent, by weight, of the active analgesic ingredient in the composition.
- the percentage by weight is from about 5 percent to at most 50 percent of the active material.
- compositions for injection e.g. solutions and the like
- the percentage by weight is from about 1 percent to about 20 percent of the active ingredient.
- any one of a wide variety of preparations may be manufactured, such as tablets, capsules, pills, suppositories, solutions, suspensions and the like.
- additional substances commonly employed in the pharmaceutical art of manufacturing dosage unit compositions may include ex-cipients, binders, fillers, lubricants, stabilizers, wetting agents, emulsifiers, buffers, and/ or other ingredients.
- the tablet, capsule, dragee and the like provide for the preferred oral form of administration.
- These forms may be compounded to have from about 0.01 g. to about 0.1 g., such as from about 0.02 g. to about 0.05 g., of a 2-unsubstituted 4-N-(2-N,N-dimethylamino-lower alkyl)- amin-o-quinazoline com-pound, such as one of the above formula, particularly of 4-N-(2-N,N-dimethylaminoethyl)-amino-quinazoline, or a pharmaceutically acceptable acid addition salt thereof, such as those with one of the above-mentioned inorganic or organic acids, as the active analgesic ingredient, per single dosage unit.
- the inert fillers, binders, lubricants and other carrier materials normally used for the manufacture of the orally applicable tablets, capsules, dragees and the like, are employed in formulating the latter; examples of these materials are starches, e.g. corn starch, wheat starch, rice starch and the like, sugars, e.g. lactose, glucose, sucrose and the like, stearic acid, or salts thereof, e.g. magnesium stearate, calcium stearate and the like, aluminum magnesium silicate preparations, talc, tragacanth, acacia, polyethylene glycol and the like.
- the quantities of these ingredients may vary widely and depend, for example, upon the characteristics and size of the desired, orally applicable form, the method of its manufacture and the like. Encapsulation may also be effected, using, if necessary, the same excipients as those employed for the preparation of tablets. As has been indicated above, the compounding is generally etfected in the manner known in the art, usually by preparing a granulation suitable for compression. Any compatible colors, approved and certified under the provisions of the Federal Food, Drug and Cosmetic Law may be used for the purpose of identification and the like.
- Solutions for parenteral administration have from about .01 g./ml. to about 0.2 g./rnl., preferably from about 0.01 g./ml. to about 0.05 g./ml., of a 2-unsubstituted 4-N-(2-N,N,-dimethylamino-lower alkyl) -amino quinazoline compound, such as one of the above formula, particularly of 4-N-(2-N,N-dimethylaminoethy1)-aminoquinazoline, or a pharmaceutically acceptable acid addition salt thereof with one of the above-mentioned inorganic or organic acids, as the active analgesic ingredient.
- a 2-unsubstituted 4-N-(2-N,N,-dimethylamino-lower alkyl) -amino quinazoline compound such as one of the above formula, particularly of 4-N-(2-N,N-dimethylaminoethy1)-aminoquin
- Primary solvents for solutions of injection are water or Water-miscible organic solvents, such as lower alkanols, e.g. ethanol and the like.
- thiourea sodium sulfide, sodium metabisulfite, ascorbic acid, cysteine hydrochloride, sodium formaldehyde sulfoxylate and the like, mono-thioglycerol, thiosorbitol and the like, buffers or buffer combinations to maintain a pH of about 7, such as, for example, acetic acid, potassium phthalate and sodium hydroxide, potassium dihydrogen phosphate and di-sodium hydrogen phosphate, potassium dihydro- .gen phosphate and sodium hydroxide, acetic acid and sodium acetate and the like, salts for making isotonic solutions, e.g. sodium chloride and the like, are added to ensure stable solutions for injection.
- compositions of this invention may contain other pharmacologically active substances.
- Such combination preparations are prepared according to procedures analogous to those used for known combination preparations.
- Pharmacologically active compounds used in combination with the active analgesic ingredient of the compositions of this invention are, for example, other analgesic, such as those of the antipyretic type, e.g. Z-acetoxy-benzoic acid, phenyl salicylate, cinchophen, acetophenetidine, aminopyrin, 4-isopropyl-3-methyl 1,2 diphenyl-pyrazolone and the like.
- pharmacologically active compounds present in compositions containing the above described analgesic ingredient are, for example, narcotics, such as those of the barbiturate-type, e.g. phenobarbital, diallyl barbituric acid and the like, or any other pharmacologically active compound, which is known to be suitable in combination compositions having primarily analgesic effects.
- Example 14 Tablets each containing 0.025 g. of 4-N-(2-N,N-dimethylaminoethyl)-amino-quinazoline, are prepared as follows (for 10,000 tablets):
- the 4N- 2-N,N-dimethylaminoethyl) -amino-quinazoline, the lactose, the talc and the magnesium stearate are mixed in a suitable mixer, sieved through a No. 40 screen, again mixed and granulated with a solution of the polyethyleneglycol 6000 in the 3A alcohol.
- the wet granules are passed through a screen, dried, again screened through a No. 20 screen and compressed into tablets, weighing 0.2 g. each, using inch standard concave punches.
- Example 15 Tablets each containing 0.025 g. of 4-N-(2-N,N-dimethylaminoethyl)-amino-quinazoline maleate, are prepared as follows (for 20,000 tablets):
- the tablets are prepared as described in Example 14.
- Example 16 Capsules, each containing 0.025 g. of 4-N(2-N,N-dimethylaminoethyl)-amino-quinazoline are prepared as follows (for 10,000 capsules):
- the ingredients are mixed in a suitable mixer, sieved through a No. 40 screen, and again mixed; 0.25 g. portions of the resulting mixture are then filled into No. 3 capsules.
- a new method for the alleviation of pain which comprises administering to a host requiring relief from pain, a pharmaceutical composition consisting essentially of a pharmacologically effective amount of a 2-unsubstituted 4-N- (2-N,N-dimethylamino-lower alkyl) amino-quinazoline compound, such as a compound of the formula:
- compositions useful in the method of alleviating pain according to this invention are those described above.
- Ph 1,2-phenylene
- group of the formula --(C is lower alkylene separating the two nitrogen atoms by two carbon atoms, and an acid addition salt thereof.
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Description
United States Patent 3,301,855 DERIVATIVES 0F 4-N-(2-N,N-DIMETHYLAMING- LOWER ALKYL)-AMINO QUINAZOLINE Herbert Morton Blatter, Millburn, N.J., assignor to Ciba Corporation, New York, N.Y., a corporation of Dela-- ware No Drawing. Filed Mar. 2, 1964, Ser. No. 348,861 5 Claims. (Cl. 260-2564) This is a continuation-in-part application of my application Serial No. 292,136, filed July 1, 1963, which in turn is a continuation-in-part application of my application Serial No. 282,243, filed May 22, 1963, and now abandoned, which in turn is a continuation-in-part application of my application Serial No. 274,818, filed April 22, 1963, and now abandoned.
The present invention concerns Z-unsubstituted 4-N-(2- N,N-dimethylamin-o-lower alkyl)-almin-o-quinazoline compounds and salts thereof. More especially, it relates to compounds of the formula:
in which Ph is a 1,2-phenylene (o-phenylene) radical, and the group of the formula (C,,H is lower alkylene separting the two nitrogen atoms by two carbon atoms, and the salts thereof. Also included within the scope of this invention is a process for the preparation of these compounds.
The 1,2-phenylene (o-phenylene) radical Ph, representing the hexacyclic carbocyclic aryl portion of the quinazoline ring system, is preferably unsubstituted, but may be substituted by one or more than one of the same or of different substituents attached to any of the four positions available for substitution. Substituents are, for example, lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl and the like, etherified hydroxyl, particularly lower alkoxy, e.g. methoxy, ethoxy, n-propyloxy, iso-propyloxy, nbutyloxy and the like, esterified hydroxyl, especially halogen-o (representing hydroxyl esterified by a hydrohalic acid), e.g. fluoro, chloro, bromo and the like, halogeno-lower alkyl, e.g. trifluoromethyl and the like, or any other suitable substituent. The 1,2-phenylene group Ph in the above formula is primarily 1,2-phenylene, but may also be (lower alkyl)-1,2-phenylene, (etherified hydroxy)-1,2-phenylene, such as (lower alkoxy)-1,2-lphenylene and the like, (esterified hydroxy)-1,2-phenylene, such as (halogeno)-1,2-phenylene and the like, (trifluoromethyl)-l,2-phenylene, or any other suitably substituted 1,2-phenylene group.
The lower alkyl radical, separating N,N dimethylamino from amino by two carbon atoms and represented in the above formula by the group of the formula -(C H stands for lower alkylene having from two to three carbon atoms (i.e. the letter It stands preferably for one of the integers 2 and 3) and separates N,N-dimethylamino from amino by two carbon atoms. Such alkylene group is preferably 1,2-ethylene, but may also be 1-rnethyl-1,2- ethylene or 2-mcthyl-1,2-ethylene.
Salts of the compounds of this invention are acid addition salts, such as pharmaceutical acceptable acid addition salts with inorganic acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like, or organic acids, such as organic carboxylic acids, e.g. acetic, propionic, pivalic, glycolic, lactic, malonic, succinic, maleic, hydroxymaleic, malic, tartaric, citric, benz-oic,
salicylic, 2-acetoxybenzoic, nicotinic, isonicotinic acid and ICE the like, or organic sulfonic acids, e.g. methane sulfonic, ethane sulfonic, ethane 1,2-disulfonic, 2-hydroxyethane sulfonic, p-toluene sulfonic, naphthalene 2-sulfonic acid and the like. Other acid addition salts may also be useful as intermediates, for example, in the preparation of pharmaceutically acceptable acid addition salts, or may serve in the purification of the free compounds, as well as for identification or characterization purposes. Salts for the latter are, for example, those with acidic organic nitro compounds, e.g. picric, picrolonic, flavianic acid and the like, or with metal complex acid, e.g. phosphotungstic, phosphomolybdic, chloroplatinic, Reinecke acid and the like. M-onoor poly-salts may be formed.
The compounds of this invention exhibit strong analgesic eifects accompanied by a low degree of toxicity. They are, therefore, useful as annalgesic agents having an improved therapeutic ratio capable of raising the threshold of pain, and thus alleviate pain or the symptoms thereof, such as acute pain-s caused by surgery, accidents and the like, pain caused by spastic conditions, e.g. headaches and the like, or chronic pains connected with arthritic conditions and the like.
It is well-established that in pharmacological experiments, the potent analgesic effects of known morphinetype compounds with addicting properties are potentiated by amphetamine, and are accompanied by respiratory depression and depression of the spinal reflexes; furthermore, these effects are antagonized by N-allyl-N-desmethyl-morphine (nalorphine). It has now been found that the analgesic effects of the compounds of this invention are not potentiated by amphetamine, and are not accompanied by respiratory depression or depression. of the spinal reflexes; furthermore, their effects are not antagonized by N-allyl-N-desmethyl-morphine. It appears, therefore, that the compounds of this invention are free from addicting properties at pha-rmacologically effective doses.
It has also been found that the free compounds of this invention are to a surprisingly high degree, water-soluble. They can, therefore, be used directly in case the compounds of this invention are to be used in an aqueous solution and do not have to be converted into a watersoluble salt; furthermore, the pressure of a solubilizer in such solution would not be required.
Particularly useful is the 4-N-(2-N,N-dimethylaminoethyl)-amino-quinazoline, as well as the acid addition salts thereof, particularly its pharmaceutically acceptable acid addition salts; in addition to the above properties, this compound has an improved degree of toxicity, and is, therefore, of improved therapeutic ratio.
The compounds of this invention are prepared according to known methods, for example, by converting in a 2- unsubstituted 4-X-quinazoline compound, particularly in a compound of the. formula:
in which Ph has the previously-given meaning, and X is a group capable of being converted into an N-(2-N,N-
dimethylamino-lower a1kyl)--amino group, particularly into a group of the formula salt of such compound, the group X into the N-(2-N,N-
dimetliyla'mino-lower' alkyl)-amino group,- particularly into the group of the formula n-fr-rcuna-inzm):
in which the group of the formula (C,,H has the previously-given meaning, and, if desired, converting a resulting salt into the free compound or into another salt; and/ or, if desired, converting a resulting compound into a salt thereof, and/ or, if desi'red, separating a resulting mixture of isorriers into the single isomers.
In the starting material, a preferred substituent X, capable of beirig converted into the N-(2-N,N-dimethylamino-lower alkyl)-amiiio group, is a mercapto group, a thiono group or a substituted mercapto group. The preferred starting material is, therefore, a 2-unsubstituted 4-mrc'apto-quinazoline compound or a tautomer thereof, or a salt of such compound, particularly a compound having one of the tautorneric formulae:
in which formulae pH has the previously-given meaning, as well as a compound having the formula:
in which Ph has the previously-given meaning, and R is an organic radical, such as a lower aliphatic group, for example, lower alkyl, e.g. methyl, ethyl, isopropyl and the like, or any other suitable organic group, such as phenyl-lower alkyl, e.g. benzyl and the like, or a salt of such compound.
The conversion of the group X into the N-(2-N,N-dimethylamino-lower alkyl)-amino group is carried out by reacting the above 4-X-quinazoline starting material, in which X is a mercapto group, a thiono group, or a substituted mercapto group, with an N-(2-N,N-dimethylamino-lower alkyl)-amine or a salt thereof, particularly with a compound of the formula H N(C,,H )N(CH in which the group of the formula C,,H has the previously-given meaning, or a salt thereof. The reaction is preformed according to known methods, preferably at an elevated temperature; if desired, an excess of the N-(2-N,N-dimethylamino-lower alky1)-amine may be employed. The reaction may be carried out in the absence or in the presence of a diluent, e.g. ethanol and the like, or a mixture of solvents, if necessary, in a closed vessel, and/ or in the atmosphere of an inert gas.
The starting materials used in the above modification of the process of this invention are known or are prepared according to known methods; preferably, they are obtained, for example, by reacting a Z-unsubstituted quinazol-in-4-one compound or a tautomeric 4-hydroxy-quinazoline compound with a reagent capable of replacing 0x0 or hydroxyl by thiono or mercapto, such as phosphorus pentasulfide and the like, which is preferably used in the presence of a suitable diluent, e.g. xylene and the like, and at an elevated temperature. An unsubstituted mercapto group may be converted into a substituted mercapto group according to known methods, for example, by forming an alkali metal derivative of the 4-mercapto-quinazoline compound and reacting it witha reactive ester compound, such as a lower alkyl halide, a di-lower alkyl sulfate, a phenyl-lower alkyl halide and the like. v
Another group representing X in the 4-X-quinazoline starting material is a reactive functionally converted hy- 4 dr'oxyl group, especially a reactive etherified hydroxyl group or a reactive esterified hydroxyl group. A suitable etherified hydroxyl group is especially lower alkoxy, e. g. methoxy, ethoxy and the like, whereas a reactive esterified hydroxyl group is especially halogeno (representing hydroxyl esterified with a hydrohalic acid) having preferably an atomic weight greater than 19, e.g. chloro, brorno and the like, as well as any other hydroxyl group esterified with a strong inorganic or organic acid, such as a strong organic sulfonic acid, e.g. p-toluene sulfonic acid and the like.
The conversion of a reactive functionally converted hydroxyl group, particularly of lower alkoxy or halogeno, into the desired N-(2-N,N-dimethylamino-lower alkyl)-- amino group is carried out according to the method described above, i.e. by treating the appropriate starting material with an N-(2-N,N-dimethylamino-lower alkyl)- amine, particularly with a compound of the formula H N(C,,H ,,)N(CH in which the group of the formula (C,,H has the previously-given meaning, or a salt thereof. The reaction is carried out in the absence or in the presence of a diluent or a mixture of diluents, preferably at an elevated temperature, and, if necessary, in a closed vessel, an-d/ or, in the atmosphere of an inert gas, e.g. nitrogen.
The above Z-unsubstituted 4-reactive functionally converted hydroxy-quinazoline starting materials are known or are prepared according to known methods. For example, the 2-unsubstituted 4-halogeno-quinazoline starting materials are obtained from the corresponding quinazoline-4-0ne compounds or tautomeric 4-hydroxy-quinazoline compounds by treating such compounds with a suitable lralogenating reagent capable of replacing an oxo group or a hydroxyl group by halogeno, for example, with a phosphorus halide, e.g. phosphorus pentachloride, phosphorus tribromide and the like, or a thionyl halide, e.g. thionyl chloride and the like, preferably at an elevated temperature, and, if necessary, in the presence of a suitable diluent. Other 4-reactive esterified hydroxy-quinazoline starting materials are prepared according to known esterification procedures. 2 unsubstituted 4-reactive etherified hydroxy-quinazoline starting materials, in which the reactive etherified hydroxyl group is especially lower alkoxy, are prepared, for example, by reacting a 2-unsubstituted 4-halogeno-quinazoline compound with a metal alcoholate, especially an alkali metal lower alkoxide, e.g. sodium or potassium methoxide, ethoxide, isopropoxide or n-butoxide and the like, preferably in the presence of the corresponding alcohol, especially lower alkanol, and at an elevated temperature, if necessary, in a closed vessel, and/or in the atmosphere of an inert gas.
Another group X is a 4-X-quinazoline starting material, capable of being converted into the desired N-(2- N,N-dimethylamino-lower alkyl)-amino group, is the cyano group as represented by the formula I GEN Conversion of such group into N-(2-N,N-dimethylaminolower alkyl)-amino is carried out as described above, for example, by reacting a 2-unsubstituted 4-cyano-quinazoline compound with the appropriate N-(2-N,N-dimethylamino-lower alkyl)-amine, preferably in the presence of a diluent, such as a lower alkanol, e.g methanol and the like, if necessary, at an elevated temperature, and/ or in a closed vessel.
The starting materials used in the above modification of the procedure of this invention are known or may be prepared according to known methods, for example, by reacting a 2,4-unsubstituted quinazoline compound with a saturated solution of hydrogen cyanide in methanol in a sealed tube.
Another group X in a 4-X-quinazoline starting material, capable of being converted into the desired N-(2-N.
a reactive ester of a 2-N,N-dirnethylamino-lower alkanol, particularly with a compound of the formula in which the group of the formula (C,,H separating N,N-dimethylamino from X by two carbon atoms, has the previously-given meaning, and X is a reactive esterified hydroxyl group, or a salt of such compound. The reactive esterified hydroxyl group represented by X is particularly halogeno (i.e. hydroxyl esterified by a hydrohalic acid), having an atomic Weight greater than 19, e.g. chloro, bromo and the like, as well as an organic sulfonyloxy group, e.g. 4-methyl-phenyl-sulfonyloxy and the like, or any analogous reactive esterified hydroxyl group. The above reaction is carried out according to known methods; preferably, it is performed at an elevated temperature, and, if necessary, in the presence of a diluent, and/or of a salt-forming reagent, such as an alkali metal hydride or an alkali metal amide, or any other corresponding reagent, and/or, of a base (which may'also be furnished by an excess of the basic 4-aminoquinazoline starting material) to neutralize any generated acid or to liberate the basic reagent from any acid addition salt, and/ or in a closed vessel, and/or in the atmosphere of an inert gas, e.g. nitrogen.
The starting materials used in the above modification of the process of this invention are known or may be prepared according to known methods, for example, by converting in a Z-unsubstituted 4-X-quinazoline compound, in which X is mercapto or halogeno, the group X into the amino group, for example, by treatment with ammonia or an ammonia-furnishing reagent.
The group X in the above 4-X-quinazoline starting material may also represent an N-(2-N,N-dimethylaminolower alkanoyl)-amino group or an N-(2-N,N-dimethyl amino-lower thioalkanoyl)-amino group, particularly the group of the formula Hl l( C YC n-iHzn-z) N (CH3) 2 in which Y stands for 0x0 of the formula :0 or thiono of the formula :8, and in which the portion of the forrnula CYC,, H separates N,N-dimethylamino from amino by two carbon atoms. Z-unsubstituted 4-N- (2 N,N dimethylamino lower alkanoyl) aminoquinazoline starting materials and 2-unsubstituted 4-N- (2 N,N dimethylamino lower thioalkanoyl) aminoquinazoline starting materials are converted into the desired compounds of this invention according to known methods capable of replacing oxo in a carbonyl group or thiono in a thiocarbonyl group by two hydrogen atoms.
Replacement of 0x0 by two hydrogen atoms is carried out by reduction and is preferably achieved by treating the appropriate starting material with an aluminum hydride, particularly an alkali metal aluminum hydride, e.g. lithium aluminum hydride, sodium aluminum hydride and the like, or an alkaline earth metal aluminum hydride, e.g. magnesium aluminum hydride and the like, or aluminum hydride. If necessary, activators, such as, for example, aluminum chloride, may be used together with the hydride reducing reagent. The reduction with these reagents is preferably performed in the presence of an inert solvent, particularly an ether, such as a di-lower alkyl ether, e.g. diethyl ether, dipropyl ether and the like, a cyclic ether, e.g. tetrahydrofuran, p-dioxane and the like, or any other suitable solvent, and preferably at an elevated temperature. Conversion of the carbonyl por- 6 tion of an amide grouping may also be achieved by treating the appropriate starting material with hydrogen in the presence of certain catalysts, such as a copper-chro mium catalyst and the like, by electrolytic reduction or any other suitable method.
Replacement of sulfur in a thiocarbonyl group by two hydrogens may be carried out by desulfurization according to known methods, for example, by treatment with a freshly prepared hydrogenation catalyst, such as Raney nickel, in an alcoholic solvent, e.g. methanol, ethanol and the like, if desired, in the presence of hydrogen, by electrolytic reduction and the like.
The starting materials used in the above modification of the procedure of this invention are prepared, for example, by reacting a 2-unsubstituted 4-amino-quinazoline compound with a 2-N,N-dimethylamino-lower alkanoic acid halide, e.g. chloride, bromide and the like; this reaction may be carried out in the presence of a liquid organic base, e.g. pyridine and the like, which may also serve as the diluent, and/or of an inert solvent, e.g. benzene, toluene and the like, if necessary, by using an excess of the basic starting material or an additional base, e.g. potassium carbonate and the like, to neutralize any generated acid.
In a resulting 4-N-(2-N,N-dimethylamino-lower :alkanoyl)-amino-quinazoline starting material, the carbonyl portion of the amide grouping can be replaced by thiocarbonyl, for example, by treatment with a reagent capable of replacing oxo by thiono, e.g. phosphorus pentasulfide and the like, as previously described.
The group X in a 4-X-quinazoline starting material may also represent an N-(2 N,N-dimethylamino-Z-oxolower alkyl)-amino group or an N-(2-N,N-dimethylamino-Z-thiono-lower alkyl)-amino group, particularly a group of the formula in which Y has the previously-given meaning, and the portion of the formula (C,, H CY) separates N,N-dimethylamino from amino by two carbon atoms. In the 2-unsubstituted 4-N-(2-N,N-dimethylamino-Z-oxolower alkyl)-amino-quinazoline starting materials and 2- unsubstituted 4-N.-(2-N,N-dimethylamino-2-thiono-lower alkyl)-amino-quinazoline starting materials, the 0x0 group or the thiono group are replaced by two hydrogens according to known methods, such :as those previously described.
The starting materials used in the above modification of the process for the manufacture of the compounds of this invention are prepared according to known methods. For example, a 2-unsubstituted 4-amino-quinazoline compound may be reacted With a Z-(reactive esterified hydroxy)-lower alkanoic N,N-dimethylamide, particularly a compound of the formula X (C H CO) N(CH in which X has the previously-given meaning (being particularly halogeno having an atomic weight greater than 19, e.g. chloro, bromo and the like) and substitutes the u-carbon atom, and the portion of the formula (C H CO) separates N,N-dimethylamino from the reactive esterified hydroxyl group X by two carbon atoms. The reaction of the 2-unsu-bstituted 4-amino-quinazoline intermediate with the Z-(reactive esterified hydroxy)-lower alkanoic N,N-dimethylamide is carried out in the presence of an appropriate diluent, for example, a liquid organic base, e.g. pyridine and the like, to neutralize any generated acid, and, if necessary, at an elevated temperature.
In a resulting 4-N-(2-N,N-dimethylamino-2-oxo-lower alkyl)-amino-quinazoline starting material, the 0x0 group may be replaced by thiono, for example, by treating it with a suitable reagent, e.g. phosphorus pentasulfide and the like, as previously described.
The compounds of this invention are also prepared by reacting a 2-unsu-bstituted quinazoline compound, particularly a compound of the formula:
in which Ph has the previously-given meaning, or a salt thereof with an N-(Z-N,N-dimethylamino-lower alkyl)- amine, especially a compound of the formula H N (C H N(CH in which the group of the formula (C H has the previously-given meaning, and, if necessary, converting any resulting Z-unsubstituted 4-N- (2-N,N-dimethylamino-lower alkyl)-amino-3,4-dihydroquinazoline compound into the desired Z-unsubstituted 4-N- 2-N,N-dimethylamino-lower alkyl -amino-quinazoline compound by oxidation, and, if desired, carrying out the optional steps.
The above reaction is carried out according to known methods, preferably in the presence of a suitable saltforming reagent, such as an alkali metal hydride and the like, and in the presence of an appropriate diluent, e.g. N,N-dimethyl-aniline and the like. Usually it is performed at an elevated temperature, and if necessary, in a closed vessel, and/ or in the atmosphere of an inert gas.
If necessary a resulting 4-N-(2-N,N-dimethylaminolower alkyl)-am.ino-3,4-dihydro-quinazoline compound is converted into the desired 4-N-(2-N,N-dimethylaminolower .alkyl)-amino-quinazoline by oxidation. The latter is performed according to known methods, for example, by air oxidation, or by treatment with any other suitable oxidation reagent, such as potassium ferric cyanide, iodine and the like, preferably in the presence of a diluent.
The compounds of this invention are also prepared by replacing in a 4-N-(2-N,N-dimethylamino-lower alkyl)- amino-2-R -quinazoline, particularly in a compound of the formula:
in which Ph and the group of the formula-(C H )-have the previously-given meaning, and R, is a substituent capable of being replaced by hydrogen, or a salt thereof, the group R by hydrogen, and, if desired, carrying out the optional steps.
A group R capable of being replaced by hydrogen is especially a reactive functionally converted hydroxyl group, such as a reactive esterified hydroxyl group, particularly halogeno, e.g. chloro, bromo and the like, or any other suitable group capable of being replaced by hydrogen. The group R is removed according to known methods, usually by reduction, e.g. treatment with hydrogen in the presence of a suitable catalyst, such as a palladium catalyst and the like, if necessary under increased pressure, and/ or at an elevated temperature, or any other equivalent reducing method.
The starting material is prepared according to known procedures, usually by converting in a 2-R -4-X-quinazoline, in which R and'X have the previously-given meaning, the group X into the N-(2-N,N-dimethylaminolower alkyl)-amino group according to any of the previously-described procedures.
The compounds of this invention are also prepared, for example, by eliminating in a Z-unsubstituted 4-N- (2- N,N-dimethylamino-lower alkyl)-amino-quinazoline N- oxide, particularly in a compound of the formula:
in which Ph and the group of the formula -(C H .have the previously-given meaning, or a salt thereof, the N- hydrogen activated by a metal catalyst, e.g. a nickel catalyst and the like, or any other procedure, such as reacting the starting material with a phosphorus halide, e.g. phosphorus trichloride and the like.
The starting materials used in the above procedure,
' especially those having the above formula, and particularly the 4-N-(2-N,N-dimethylaminoethyl)-am-ino-quinazoline-l-oxide, as well as the acid addition salts thereof, are new. Apart from serving as starting materials, they also show analgesic effects and are intended to be included within the scope of this invention. They are prepared according to known methods, preferably by converting in a 2-unsubstituted 4-X-quinazoline N-oxide, especially a compound of the formula:
in which Ph and X have the previously-given meaning or a salt thereof, the group X into the N-(2-N,N-dimethylamino-lower alkyl)-amino group, especially into the group of the formula H-N(C ,H211)N(-CH in which the group of the formula (C H has the previouslygiven meaning, and, if desired, carrying out the optional steps. The conversion of the group X, which is above all a reactive functionally converted hydroxyl grou especially a reactive etherified hydroxyl group, such as lower alkoxy, into desired N-(2-N,N-dimethylamino-lower alkyl)-amino group is carried out as previously described.
A resulting acid addition salt of a compound prepared according to the process of this invention may be converted into the free compound, for example, by reacting it with an alkaline reagent, such as a metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydrox-ide, calcium hydroxide and the like, a metal carbonate, e.g. sodium, potassium or calcium carbonate or hydrogen carbonate and the like, ammonia and the like, or by treatment with a suitable hydroxyl ion exchange resin.
A resulting acid addition salt of a compound prepared according to the process of this invention may also be converted into another salt; for example, a salt with an inorganic acid may be reacted with a suitable metal, e.g. sodium, silver, barium and the like, salt of an acid, in the presence of a diluent, in which a resulting inorganic compound is insoluble and is thus removed from the reaction. Conversion of an acid addition salt into another acid addition salt may also be achieved by treatment with an anion exchange preparation.
A free compound resulting from the process of this invention may be converted into an acid addition salt thereof by reacting it or a solution thereof in a suitable solvent or solvent mixture with an acid or a solution thereof, or with an anion exchange preparation, and
isolating the desired salt. A salt may be obtained in the form of a hydrate thereof or may include solvent of crystallization.
A mixture of resulting isomeric compounds may be separated into the single isomers. For example, racernates may be resolved into the optically active dand l-forms according to known resolution procedures, for example, by forming a salt of the free racemic compound with one of the optically active forms of an acid containing an asymmetric carbon atom. Especially useful as optically active forms of salt-forming acids having an asymmetric carbon atom are D-tartaric (l-tartaric) acid and L-tartaric (d-tartaric) acid, as well as the optically active forms of malic, mandelic, IO-camphor sulfonic, quinic acid and the like. A resulting mixture of salts is separated on the basis of physico-chemical differences, for example, by fractional crystallization; a separated salt may then be converted into the free and optically active compound as described above, and a free and optically active base may be converted into its acid addition salt according to the procedures described above.
The invention also comprises any modification of the process, wherein a compound formed as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is(are) carried out, as well as any new intermediates.
In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.
The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperature are given in degrees centigrade.
Example 1 To a solution of 0.95 g. of 4-mercapto-quinazoline (or its tautomer 3H-quinazolin-4-thione) in ml. of N,N- dimethylethylenediamine is added 10 ml. of ethanol. The solution is refluxed for four hours and is then evaporated to dryness under reduced pressure. The solid residue (yield: 0.70 g.) is crystallized from a mixture of acetone and hexane to yield the desired 4-N-(2-N,N-dimethylaminoethyl)-amino-quinazoline of the formula:
which upon further recrystallizations from cyclohexane melts at l46148.
The starting material used in the above procedure is prepared according to the method described by Leonard et al., J. Org. Chem., vol. 11, p. 349 (1946): A mixture of 7.3 g. of 4-hydroxy-quinazoline (or its tautomer 3H- quinazolin-4-one) and 11.1 g. of phosphorus pentasulfide in 500 ml. of xylene is refluxed for two hours while stirring. After cooling, the reaction mixture is extracted with 100 ml. of 2 N agueous sodium hydroxide; the aqueous phase is filtered and neutralized with glacial acetic acid. The resulting precipitate is filtered off and washed with water; the desired 4-mercapto-quinazoline is purified by recrystallization from N,N-dimethylformamide and melts above 300 after washing it with diethyl ether; yield: 4.2 g.
Example 2 To a diethyl ether solution of 4-N-(2-N,N-dimethylaminoethyl)-amino-quinazoline is added a solution of an equivalent amount of maleic acid in methanol; the resulting 4-N- 2-N,N-dimethylaminoethyl -amino-quinazoline maleate melts at 186188 (with decomposition) after.
several recrystallization from a mixture of methanol and diethyl ether.
Upon treating a solution of 4-N-(2-N,N-dimethyli0 aminoethyl)-amino-quinazoline in ethanol with picric acid, the 4-N-(2-N,N-diethylamino-ethyl)-amino-quinazoline picrate is formed.
Example 3 solidifies and is recrystallized several times from pentane, M.P. 99l01.
The N,N-dimethylamino-isopropylamine used as the reagent is prepared as follows: A mixture of 31.6 g. of N,N- dimethylaminoisopropyl chloride hydrochloride and 20.0 g. of potassium hydrogen carbonate in 200 ml. of toluene is heated until the evolution of carbon dioxide gas decreases. The solid material is filtered off; the filtrate is treated with 37.0 g. of potassium phthalimide, and the reaction mixture is refluxed for sixteen hours. After cooling and filtering, the filtrate is evaporated to dryness; the resulting oily residue solidifies upon adding pentane and cooling to yield 28.0 g. of N-(N,N-dimethylamino-isopropyl)-phthalimide, which melts at 57-59" after recrystallization from pentane.
A mixture of 20.0 g. of N-(N,N-dimethylamino-isopropyl)-phthalimide in 100 ml. of 20 percent hydrochloric acid is refluxed for three hours and allowed to stand for several days. The solid material is filtered off and washed with water; the combined filtrates are concentrated to a small volume and made strongly 'basic with an aqueous solution of sodium hydroxide. The resulting oil is extracted with methylene chloride, the organic solution is dried over sodium sulfate and evaporated to dryness. The desired N,N-dimethylamino-isopropyl-amine is purified by distilling the residue and is collected at about 50/ 15 mm.
Example 4 A solution of 2.3 g. of 4-N-(N,N-dimethyl-carbamylmethyl)-amino-qulnazoline in 30 ml. of tetrahydrofuran is added dropwise over a period of thirty minutes to a suspension of 0.38 g. of lithium aluminum hydride in 50 ml. of tetrahydrofuran while cooling in an ice-bath and maintaining vigorous stirring. The reaction mixture is then refluxed for sixhours; the resulting complex is destroyed by adding a small excess of water in tetrahydrofuran. The mixture is filtered, the filtrate is evaporated to dryness, and the resulting oil crystallizes on adding cyclohexane to yield the crude 4-N-(2-N,N-dimethylamino-ethyl)-amino-quinazoline, which, upon further recrystallization from cyclohexane, melts at 146-148".
The starting material used in the above procedure is prepared as follows: A mixture of 1.0 g. of 4-aminoquinazoline (prepared according to the method described by Morley et al., J. Chem. Soc., p. 1354 (1949)) and 0.16 g. of sodium hydride in 50 ml. of toluene is refluxed for two hours. A solution of 0.83 g. of u-chlOI'O-N,N- dimethylacetamide in 10 ml. of toluene is added dropwise over a period of fifteen minutes while stirring. The reaction mixture is refluxed for another hour and is then evaporated to dryness under reduced pressure. Water is added to the residue; the crude solid 4-N(N,N-dimethylcarbamyl-methyl)-amino-quinazoline is collected, dried on the filter and used without further purification.
Example A mixture of 1.0 g. of 4-cyano-quinazoline and 1.0 g. of N,N-dimethyl-1,2-ethylenediamine is allowed to stand at room temperature for one hour, and is then warmed on the steam bath for fifteen minutes. The excess of N, N-dimethyI-LZethyIene diamine is evaporated under reduced pressure, and the residue is extracted with boiling cyclohexane. The organic extract is concentrated and allowed to stand while cooling to yield the desired 4-N- (2-N,N-dimethylarninoethyl)-amino-quinazoline, which is identical with the compound obtained according to the procedure described in Example 1.
The starting material used in the previous procedure is prepared as follows: A solution of 1.0 g. of quinazoline in 30 ml. of methanol is cooled to 0 and is treated for 1%. hours with an excess of hydrogen cyanide. The solvent is then removed to yield the 4-cyano-3,4-dihydroquinazoline, M.P 128429". To a mixture of 0.5 g.
' of the latter in a solution of 0.66 g. of potassium hydroxide in 2 ml. of water and ml. of benzene is added 2.65 g. of potassium ferricyanide in 13 ml. of water over a period of one hour. The organic layer is separated to yield 0.2 g. of 4-cyano-quinazoline, whereas the aqueous phase yields another 0.18 g. of the same compound.
Example 6 A mixture of 1.0 g. of 4-chloro-quinazoline and ml. of N,N-dimethyl-1,2-ethylenediamine is refluxed for three hours; the excess of N-N-dimethyl-1-2-ethylenediamine is removed under reduced pressure, and the residue is extracted with boiling cyclohexane. The organic extract yields 0.5 g. of the desired 4-N-(2-N,N-dimethyla minoeth yl)-amino-quinazoline which is identical with the compound formed according to the procedure described in Example 1.
The starting material used in the above procedure is described by Gabriel et al., Chem. Ber., vol. 29, p. 1300 (1896).
Example 7 A mixture of 1.0 g. of 4-amino-quinazoline and 0.2 g. of sodium hydride in 50 ml. of dry toluene is refluxed for two hours, and is then treated with a solution of 1.0 g. of 2-N,N-diethylamino-ethyl chloride (liberated from its hydrochloride with a cold, concentrated aqueous solution of sodium hydroxide in Water) in 50 ml. of toluene, which is added dropwise over a period of fifteen minutes while stirring and cooling in an ice bath. The reaction mixture is allowed to warm to room temperature and is then heated on the steam bath for thirty minutes. After evaporating the solvent under reduced pressure, the residue is extracted with boiling cyclohexane; the desired 4-N-(2-N,N-dimethylaminoethyl) amino quinazoline is obtained by concentrating and cooling the organic extract.
The starting material used in the above procedure is prepared according to the method described by Morley et al., J. Chem. Soc., p. 1354 (1949).
Example 8 A mixture of 4.0 g. of N,N-dimethyl-1,2-ethylenediamine, 1.0 g. of sodium hydride and ml. of N,N-dimethylaniline is heated at 145150 for two hours. Over aperiod of fifteen minutes and while maintaining that temperature, a total of 1.0 g. of quinazoline is added, and heating is continued for an additional two hours. After standing overnight, the reaction product is decomposed With a minimum amount of water; the aqueous phase is extracted with diethyl ether, and the organic extract is dried over anhydrous sodium sulfate and concentrated. The residue is taken up into boiling cycle-hexane; the solution is concentrated and chilled to yield the dried 4-N (2-N,N-dimethylaminoethyl) amino quinazoline, which is identical with the product obtained from the procedure described in Example 1.
12 Example 9 A mixture of 1.0 g. of 4-methoxy-quinazoline, 10 m1. of N,N-dimethyl-1,2-ethylenediamine and 10ml. of methanol is heated in a sealed tube at 150 for sixteen hours. The reaction product is then evaporated to dryness under reduced pressure and the residue is extracted with boiling cyclohexane. The organic extract is decolorized with a charcoal preparation, concentrated and chilled to yield the desired 4-N (2 N,N dimethylaminoethyl) aminoquinazoline.
The starting material is prepared according to the procedure described b Breukink et al., Rec. Trav. Chim., vol. 76, p. 401 (1957).
Example 10 A solution of 2.0 g. of 2-chloro-4-N-(2-N,N-dimethylaminoethyl)-amino-quinazoline in ml. of warm methanol is shaken with hydrogen in the presence of 6.0 g. of palladium-on-charcoal. The reduction is complete after two hours; the catalyst is filtered off, the filtrate is evaporated and the residue is treated with aqueous sodium hydroxide. The aqueous phase is extracted with diethyl ether; the organic extract is dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The desired 4-N-(2-N,Ndimethylaminoethyl)-amino-quinazoline is obtained by extracting the residue with cyclohexane, concentrating the solution and cooling it.
The starting material used in the above procedure is prepared as follows: A mixture of 2.0 g. of 2,4-dichloroquinazoline (prepared according to the method described by Curd et al., J. Chem Soc., p. 775 (1947)), 20 ml. of water and 0.88 g. of N,N-dimethyl-1,2-ethylenediamine is stirred at room temperature. After one hour, the reaction mixture is made alkaline to Clayton yellow with 10 N aqueous sodium hydroxide solution. In order to maintain the alkalinity, the reaction mixture is treated at intervals with further amounts of sodium hydroxide until approximately the equivalent of 0.4 g. of sodium hydroxide has been added (about six hours). The reaction mixture is then acidified to Congo red with hydrochloric acid and filtered; the filtrate is treated with an excess of aqueous sodium hydroxide to precipitate a gummy material. The liquid phase is decanted, and the residue is triturated with diethyl ether. The desired 2- chloro-4-N-(2-N,N-dimethylaminoethyl) -amino quinazoline is collected, washed with water, dried at room temperature and used without further purification.
Example 1 I To a solution of 1.0 g. of 4-N-(2-N,N-dimethylaminoethyl)-amino-quinazoline-l-oxide in 20 ml. of methanol is added the Raney nickel catalyst, prepared from 1.5 g. of a 1: l-nickelzaluminum alloy and a 30 percent aqueous solution of sodium hydroxide, and the mixture is shaken under hydrogen at atmospheric pressure. After the absorption of the theoretical amount of hydrogen, the reaction is interrupted, the catalyst is filtered 01? and the filtrate is evaporated to dryness. The residue is crystallized from cyclohexane and yields the desired 4-N-(2-N, N-dimethylaminoethyl)-amino-quinazoline, which is identical with the compound prepared according to the procedure described in Example 1.
The starting materials used in the above procedure is prepared as follows: A mixture of 1.0 g. of 4-methoxyquinazoline-l-oxide (prepared according to the method described by Yamanaka, Chem. Pharm. Bull. (Tokyo), vol. 7, p. 152 (1959)) and 10 ml. of N,N-dimethyl-1,2- ethylenediamine is placed in a sealed tube and heated at 100 for two hours. The reaction mixture is then evaporated to dryness under reduced pressure and the residue is crystallized from a mixture of diethyl ether and pentane to yield the 4-N-(2 N,N dimethylaminoethyl) aminoquinazoline-l-oxide.
13 Example 12 A mixture of 2.5 g. of 6-chloro-4-mercapto-quinazoline (or its tautomer 6-chloro-3H-quinazolin-4-thione) and 15 ml. of N,N-dimethyl-1,2-ethylenediamine in 15 ml. of ethanol is refluxed for four hours. After evaporating the reaction mixture to dryness under reduced pressure, the solid residue is crystallized from diethyl ether to yield the 6-chloro-4-N (2-N,N dimethylamino) -amino-quinazoline of the formula:
l n-rv-orn-om-Monm which melts at 169-171".
The starting material used in the above procedure is prepared as follows: To a suspension of 23.0 g. of 6- chloro-4-hydroxy-quinazoline (prepared according to the procedure described by Magidson et al., J. Gen. Chem, vol. 8, p. 1797 (1938); C.A., vol. 33, p. 4993 (1939)) in 250 ml. of pyridine is added 32.0 g. of phosphorus pentasulfide. The exothermic reaction is maintained by refluxing for three hours; after cooling to a lower temperature, the reaction mixture is poured into about 500 ml. of water. The yellow-brown solid is filtered off, dried and then dissolved in about 200 ml. of a ten percent solution of sodium hydroxide in water. The solution is filtered, the filtrate is neutralized with hydrochloric acid (a 1:10-mixture of concentrated hydrochloric acid and water), and the yellow solid material is filtered off and dried at room temperature. The desired 6-chl-oro-4-mercaptoquinazoline melts over 300; yield: 22.5 g.
Exaniple 13 melts at 162l64 after recrystallization from ethyl acetate.
The starting material used in the above procedure is prepared as follows: A mixture of 5.0 g. of S-methylanthranilic acid and 4.5 g. of formamide is heated to 140- 150 for one hour. Upon cooling, the reaction product solidifies and is triturated three times with acetone to yield 4.6 g. of 6-methyl-quinazolin-4-one; the latter melts at 264266 after recrystallization from methanol.
To a solution of 1.0 g. of 6-methyl-quinazolin-4-one in 25 ml. of pyridine is added 1.25 i g. of phosphorus pentasulfide; the mixture is refluxed for three hours and, after cooling, is poured into water. The solid material is fi ltered off and dissolved in a ten percent aqueous solution of sodium hydroxide. Upon neutralizing with dilute hydrochloric acid, the yellow 4-merc-apto-6-methyl-quinazoline precipitates and is filtered off; it melts above 310".
By substituting the 4mercapto-7-methoxy-quinazoline, the 6,7-dimethoxy-4-mercapto-quinazoline, the 4-rnercapto-7-trifluorornethyl-quinazoline or analogous 4-mercaptoquinazoline compounds for the 4-mercapto-6-methylquinazoline in the above procedure, and reacting them t in w ieh Ph and the group of the formula (C,,H
have the previously-given meaning, or a pharmaceutically acceptable acid addition salt thereof, as the active analgesic ingredient, and a pharmaceutically acceptable carr1er.
Preferred compositions for the relief of pain are those comprising essentially a pharmacologically efiective amount of 4-N-(2-N,N-dimethylaminoethyl)-amino-quinazoline or a pharmaceutically acceptable acid addition salt thereof, as the active analgesic ingredient, and a pharmaceutioally acceptable carrier.
The analgesic compositions of this invention represent versatile tools in raising the threshold and suppressing the symptons of many types of pain. Thus, they can be used to counteract light pains (e.g. toothaches, headaches and the like), as well as severe pains (e.g. post-operative pains, pains in connection with fractures and the like), and chronic pains (e.g. pains caused by arthitic conditions and the like.) Light pains require correspondingly smaller doses of the active analgesic ingredient, whereas severe and chronic pains have to be treated with higher doses of theactive compound. Advantages of the pharmacologically active ingredient of the compositions of this invention are-the considerable lack of undesirable side-effects and, for all practical purposes, the absence of toxic properties.
The analgesic compositions of this invention are prepared according to methods accepted in the art of manufacturing of pharmaceutical compositions, essentially by combining the active ingredient with a pharmaceutically acceptable, organic or inorganic carrier in specified proportions. The compositions usually contain at most equal amounts of the active analgesic ingredient and the inert carrier. Preferably, they are made up to contain from about 1 percent to at most 50 pen-cent, by weight, of the active analgesic ingredient in the composition. In compositions for oral use (e.g. tablets, capsules and the like), the percentage by weight is from about 5 percent to at most 50 percent of the active material. In compositions for injection (e.g. solutions and the like), the percentage by weight is from about 1 percent to about 20 percent of the active ingredient.
In preparing pharmaceutically acceptable dosage unit forms, any one of a wide variety of preparations may be manufactured, such as tablets, capsules, pills, suppositories, solutions, suspensions and the like. In addition to the pharmacologically active component, there may be present additional substances commonly employed in the pharmaceutical art of manufacturing dosage unit compositions. These may include ex-cipients, binders, fillers, lubricants, stabilizers, wetting agents, emulsifiers, buffers, and/ or other ingredients.
The tablet, capsule, dragee and the like, provide for the preferred oral form of administration. These forms may be compounded to have from about 0.01 g. to about 0.1 g., such as from about 0.02 g. to about 0.05 g., of a 2-unsubstituted 4-N-(2-N,N-dimethylamino-lower alkyl)- amin-o-quinazoline com-pound, such as one of the above formula, particularly of 4-N-(2-N,N-dimethylaminoethyl)-amino-quinazoline, or a pharmaceutically acceptable acid addition salt thereof, such as those with one of the above-mentioned inorganic or organic acids, as the active analgesic ingredient, per single dosage unit.
The inert fillers, binders, lubricants and other carrier materials normally used for the manufacture of the orally applicable tablets, capsules, dragees and the like, are employed in formulating the latter; examples of these materials are starches, e.g. corn starch, wheat starch, rice starch and the like, sugars, e.g. lactose, glucose, sucrose and the like, stearic acid, or salts thereof, e.g. magnesium stearate, calcium stearate and the like, aluminum magnesium silicate preparations, talc, tragacanth, acacia, polyethylene glycol and the like. The quantities of these ingredients may vary widely and depend, for example, upon the characteristics and size of the desired, orally applicable form, the method of its manufacture and the like. Encapsulation may also be effected, using, if necessary, the same excipients as those employed for the preparation of tablets. As has been indicated above, the compounding is generally etfected in the manner known in the art, usually by preparing a granulation suitable for compression. Any compatible colors, approved and certified under the provisions of the Federal Food, Drug and Cosmetic Law may be used for the purpose of identification and the like.
Solutions for parenteral administration have from about .01 g./ml. to about 0.2 g./rnl., preferably from about 0.01 g./ml. to about 0.05 g./ml., of a 2-unsubstituted 4-N-(2-N,N,-dimethylamino-lower alkyl) -amino quinazoline compound, such as one of the above formula, particularly of 4-N-(2-N,N-dimethylaminoethy1)-aminoquinazoline, or a pharmaceutically acceptable acid addition salt thereof with one of the above-mentioned inorganic or organic acids, as the active analgesic ingredient.
Primary solvents for solutions of injection are water or Water-miscible organic solvents, such as lower alkanols, e.g. ethanol and the like. Other ingredients, particularly stabilizers, such as, for example, anti-oxidants, e.g. thiourea, sodium sulfide, sodium metabisulfite, ascorbic acid, cysteine hydrochloride, sodium formaldehyde sulfoxylate and the like, mono-thioglycerol, thiosorbitol and the like, buffers or buffer combinations to maintain a pH of about 7, such as, for example, acetic acid, potassium phthalate and sodium hydroxide, potassium dihydrogen phosphate and di-sodium hydrogen phosphate, potassium dihydro- .gen phosphate and sodium hydroxide, acetic acid and sodium acetate and the like, salts for making isotonic solutions, e.g. sodium chloride and the like, are added to ensure stable solutions for injection.
In addition to the active analgesic compound and the pharmaceutically acceptable carrier, pharmaceutical compositions of this invention may contain other pharmacologically active substances. Such combination preparations are prepared according to procedures analogous to those used for known combination preparations. Pharmacologically active compounds used in combination with the active analgesic ingredient of the compositions of this invention are, for example, other analgesic, such as those of the antipyretic type, e.g. Z-acetoxy-benzoic acid, phenyl salicylate, cinchophen, acetophenetidine, aminopyrin, 4-isopropyl-3-methyl 1,2 diphenyl-pyrazolone and the like. Other pharmacologically active compounds present in compositions containing the above described analgesic ingredient, are, for example, narcotics, such as those of the barbiturate-type, e.g. phenobarbital, diallyl barbituric acid and the like, or any other pharmacologically active compound, which is known to be suitable in combination compositions having primarily analgesic effects.
1 6 Example 14 Tablets, each containing 0.025 g. of 4-N-(2-N,N-dimethylaminoethyl)-amino-quinazoline, are prepared as follows (for 10,000 tablets):
Ingredients Grams 4-N-(2 N,N dimethylaminoethyl) aminoquinazoline 250.0 Lactose U.S.P 1600.0 Polyethyleneglycol 6000 80.0 Talc 60.0 Magnesium stearate 10.0
Alcohol 3A, q.s.
The 4N- 2-N,N-dimethylaminoethyl) -amino-quinazoline, the lactose, the talc and the magnesium stearate are mixed in a suitable mixer, sieved through a No. 40 screen, again mixed and granulated with a solution of the polyethyleneglycol 6000 in the 3A alcohol. The wet granules are passed through a screen, dried, again screened through a No. 20 screen and compressed into tablets, weighing 0.2 g. each, using inch standard concave punches.
Example 15 Tablets, each containing 0.025 g. of 4-N-(2-N,N-dimethylaminoethyl)-amino-quinazoline maleate, are prepared as follows (for 20,000 tablets):
Ingredients: Grams 4-N-(2 N,N dimethylaminoethyl) aminoquinazoline maleate 500.0 Lactose U.S.P. 3200.0 Polyethyleneglycol 6000 160.0 Talc 120.0 Magnesium stearate 20.0
Alcohol 3A, q.s.
The tablets are prepared as described in Example 14.
Example 16 Capsules, each containing 0.025 g. of 4-N(2-N,N-dimethylaminoethyl)-amino-quinazoline are prepared as follows (for 10,000 capsules):
Ingredients: Grams 4-N-(2 N,N dimethylaminoethyl) aminoquinazoline 250.0 Lactose U.S.P s 2210.0 Magnesium stearate 40.0
The ingredients are mixed in a suitable mixer, sieved through a No. 40 screen, and again mixed; 0.25 g. portions of the resulting mixture are then filled into No. 3 capsules.
Also included within the scope of this invention is a new method for the alleviation of pain, which comprises administering to a host requiring relief from pain, a pharmaceutical composition consisting essentially of a pharmacologically effective amount of a 2-unsubstituted 4-N- (2-N,N-dimethylamino-lower alkyl) amino-quinazoline compound, such as a compound of the formula:
1 7 methylaminoethyl)-amino-quinazoline or a pharmaceutically acceptable acid addition salt of such compound, as the active analgesic ingredient, and a pharmaceutically acceptable carrier; compositions useful in the method of alleviating pain according to this invention are those described above.
What is claimed is:
1. 4-N-(2-N,N-dimethylaminoethyl)-amino quinazoline.
2. An acid addition salt of 4-N-(2-N,N-dimethylaminoethyl) -amino-quinaz0line.
3. 4-N-(2-N,N-dimethylaminoethyl)-amino quinazoline maleate.
4. A member selected from the group consisting of a compound of the formula:
18 in which Ph is 1,2-phenylene, and the group of the formula --(C is lower alkylene separating the two nitrogen atoms by two carbon atoms, and an acid addition salt thereof.
5. 4-N-(2-N,N-dimethylamino-lower alkyl) aminoquinazoline-l-oxide.
References Cited by the Examiner UNITED STATES PATENTS 2,497,347 2/1950 Curd et a1. 260256.4 2,742,397 4/1956 Ott 16765 2,770,569 11/ 19 56 Fromherz et a1. 16765 2,945,859 7/1960 Hitchings et a1. 260256.4 3,131,187 5/1962 Marxer 260256.4 3,184,462 5/1965 Scarborough et a1. 260256.4
UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 301, 855 January 31, 1967 Herbert Morton Blatter r appears in the above numbered pat- It is hereby certified that erro e said Letters Patent should read as ent requiring correction and that th corrected below.
Column 13, line 9, for "dimethy1amino)" read dimethylaminoethyl) a Signed and sealed this 28th day of November 19670 (SEAL) Attest:
EDWARD J BRENNER Edward M. Fletcher, Jr.
Commissioner of Patents Attesting Officer
Claims (1)
1. 4-N-(2-N,N-DIMETHYLAMINOETHYL)-AMINO - QUINAZOLINE.
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US348861A US3301855A (en) | 1963-04-22 | 1964-03-02 | Derivatives of 4-nu-(2-nu, nu-dimethylaminolower alkyl)-amino quinazoline |
GB16296/64A GB1019124A (en) | 1963-04-22 | 1964-04-20 | Quinazolines and process for their manufacture |
FR971618A FR1404488A (en) | 1963-04-22 | 1964-04-21 | Process for the preparation of new quinazolines, including 4- (beta-dimethylamino-ethylamino) -quinazoline |
BE646856A BE646856A (en) | 1963-04-22 | 1964-04-21 | |
FR980783A FR3439M (en) | 1963-04-22 | 1964-07-06 | New quinazoline which can be used in therapy, in particular as an analgesic. |
FR980784A FR3644M (en) | 1963-04-22 | 1964-07-06 | New quinazolines which can be used in therapy, in particular as analgesics. |
Applications Claiming Priority (4)
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US27481863A | 1963-04-22 | 1963-04-22 | |
US28224363A | 1963-05-22 | 1963-05-22 | |
US29213663A | 1963-07-01 | 1963-07-01 | |
US348861A US3301855A (en) | 1963-04-22 | 1964-03-02 | Derivatives of 4-nu-(2-nu, nu-dimethylaminolower alkyl)-amino quinazoline |
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ID=27501117
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US348861A Expired - Lifetime US3301855A (en) | 1963-04-22 | 1964-03-02 | Derivatives of 4-nu-(2-nu, nu-dimethylaminolower alkyl)-amino quinazoline |
Country Status (4)
Country | Link |
---|---|
US (1) | US3301855A (en) |
BE (1) | BE646856A (en) |
FR (3) | FR1404488A (en) |
GB (1) | GB1019124A (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3449498A (en) * | 1965-11-18 | 1969-06-10 | Ciba Geigy Corp | Analgesic compositions of a 4-aminoal-kylamino-quinazoline and 1-amino-alkoxybenzimidazole |
US3470182A (en) * | 1967-02-09 | 1969-09-30 | Sandoz Ag | 4-amino-substituted quinazolines |
US3483205A (en) * | 1967-12-22 | 1969-12-09 | Ciba Geigy Corp | Bicyclic tetrahydropyrimidines |
US3609152A (en) * | 1965-03-23 | 1971-09-28 | Pfizer | Certain 2-amino-3,4-dihydrogen-inazolin-4-ones and 4-thiones |
US3753981A (en) * | 1970-07-15 | 1973-08-21 | Squibb & Sons Inc | 4-amino-2-styrylquinazoline compounds |
US9840498B2 (en) | 2013-07-24 | 2017-12-12 | Novartis Ag | Substituted quinazolin-4-one derivatives |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5658902A (en) * | 1994-12-22 | 1997-08-19 | Warner-Lambert Company | Quinazolines as inhibitors of endothelin converting enzyme |
CN111233926B (en) * | 2018-11-28 | 2021-04-16 | 上海日馨生物科技有限公司 | Thiamine compound, preparation method and pharmaceutical composition thereof |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2497347A (en) * | 1944-09-05 | 1950-02-14 | Ici Ltd | Quinoline derivatives |
US2742397A (en) * | 1953-06-09 | 1956-04-17 | Commercial Solvents Corp | Analgetic compositions of n-(1-methyl propyl) cyclohexylamine |
US2770569A (en) * | 1952-08-01 | 1956-11-13 | Hoffmann La Roche | Analgesic compositions |
US2945859A (en) * | 1960-07-19 | Diaminoquinazolines and method of | ||
US3131187A (en) * | 1964-04-28 | Certain z-guantoino-x-aryl-quinazolines | ||
US3184462A (en) * | 1960-06-09 | 1965-05-18 | Mead Johnson & Co | Certain 4-substituted quinazolines |
-
1964
- 1964-03-02 US US348861A patent/US3301855A/en not_active Expired - Lifetime
- 1964-04-20 GB GB16296/64A patent/GB1019124A/en not_active Expired
- 1964-04-21 FR FR971618A patent/FR1404488A/en not_active Expired
- 1964-04-21 BE BE646856A patent/BE646856A/xx unknown
- 1964-07-06 FR FR980783A patent/FR3439M/en not_active Expired
- 1964-07-06 FR FR980784A patent/FR3644M/en not_active Expired
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2945859A (en) * | 1960-07-19 | Diaminoquinazolines and method of | ||
US3131187A (en) * | 1964-04-28 | Certain z-guantoino-x-aryl-quinazolines | ||
US2497347A (en) * | 1944-09-05 | 1950-02-14 | Ici Ltd | Quinoline derivatives |
US2770569A (en) * | 1952-08-01 | 1956-11-13 | Hoffmann La Roche | Analgesic compositions |
US2742397A (en) * | 1953-06-09 | 1956-04-17 | Commercial Solvents Corp | Analgetic compositions of n-(1-methyl propyl) cyclohexylamine |
US3184462A (en) * | 1960-06-09 | 1965-05-18 | Mead Johnson & Co | Certain 4-substituted quinazolines |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3609152A (en) * | 1965-03-23 | 1971-09-28 | Pfizer | Certain 2-amino-3,4-dihydrogen-inazolin-4-ones and 4-thiones |
US3449498A (en) * | 1965-11-18 | 1969-06-10 | Ciba Geigy Corp | Analgesic compositions of a 4-aminoal-kylamino-quinazoline and 1-amino-alkoxybenzimidazole |
US3470182A (en) * | 1967-02-09 | 1969-09-30 | Sandoz Ag | 4-amino-substituted quinazolines |
US3483205A (en) * | 1967-12-22 | 1969-12-09 | Ciba Geigy Corp | Bicyclic tetrahydropyrimidines |
US3753981A (en) * | 1970-07-15 | 1973-08-21 | Squibb & Sons Inc | 4-amino-2-styrylquinazoline compounds |
US9840498B2 (en) | 2013-07-24 | 2017-12-12 | Novartis Ag | Substituted quinazolin-4-one derivatives |
Also Published As
Publication number | Publication date |
---|---|
FR3644M (en) | 1965-10-25 |
FR1404488A (en) | 1965-07-02 |
BE646856A (en) | 1964-10-21 |
FR3439M (en) | 1965-07-19 |
GB1019124A (en) | 1966-02-02 |
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