NO811245L - Analogifremgangsmaate for fremstilling av fysiologisk aktive alfa-aminokarbonyl-1-benzyl-3,4-dihydro-isokinolin-derivater - Google Patents
Analogifremgangsmaate for fremstilling av fysiologisk aktive alfa-aminokarbonyl-1-benzyl-3,4-dihydro-isokinolin-derivaterInfo
- Publication number
- NO811245L NO811245L NO811245A NO811245A NO811245L NO 811245 L NO811245 L NO 811245L NO 811245 A NO811245 A NO 811245A NO 811245 A NO811245 A NO 811245A NO 811245 L NO811245 L NO 811245L
- Authority
- NO
- Norway
- Prior art keywords
- groups
- carbon atoms
- methoxy
- morpholino
- benzyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 4
- -1 hydroxy, methoxy Chemical group 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 239000007858 starting material Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 5
- 239000012458 free base Substances 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000004069 aziridinyl group Chemical group 0.000 claims description 3
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 3
- 125000005805 dimethoxy phenyl group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- WWYDYZMNFQIYPT-UHFFFAOYSA-N ru78191 Chemical compound OC(=O)C(C(O)=O)C1=CC=CC=C1 WWYDYZMNFQIYPT-UHFFFAOYSA-N 0.000 claims description 3
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical group C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 claims description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 125000002393 azetidinyl group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- BNFPXDXCATUYND-UHFFFAOYSA-N 1-benzyl-4-hydroxy-N-(1-hydroxyethyl)-6,7-dimethoxy-3-oxo-2H-isoquinoline-5-carboxamide hydrochloride Chemical compound Cl.N1C(=O)C(O)=C2C(C(=O)NC(C)O)=C(OC)C(OC)=CC2=C1CC1=CC=CC=C1 BNFPXDXCATUYND-UHFFFAOYSA-N 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims 1
- 230000003287 optical effect Effects 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- SARWVOSPNKRNQB-UHFFFAOYSA-N 3-ethoxy-3-oxo-2-phenylpropanoic acid hydrochloride Chemical compound Cl.CCOC(=O)C(C(O)=O)C1=CC=CC=C1 SARWVOSPNKRNQB-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JEDNYQRKVZBRQO-UHFFFAOYSA-N 2-(3,4-dihydroisoquinolin-1-yl)-2-phenylacetamide Chemical class N=1CCC2=CC=CC=C2C=1C(C(=O)N)C1=CC=CC=C1 JEDNYQRKVZBRQO-UHFFFAOYSA-N 0.000 description 1
- NKSZCPBUWGZONP-UHFFFAOYSA-N 3,4-dihydroisoquinoline Chemical compound C1=CC=C2C=NCCC2=C1 NKSZCPBUWGZONP-UHFFFAOYSA-N 0.000 description 1
- ANOUKFYBOAKOIR-UHFFFAOYSA-N 3,4-dimethoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1OC ANOUKFYBOAKOIR-UHFFFAOYSA-N 0.000 description 1
- INQWZSLKTMTMSK-UHFFFAOYSA-N 3-ethoxy-3-oxo-2-phenylpropanoic acid Chemical compound CCOC(=O)C(C(O)=O)C1=CC=CC=C1 INQWZSLKTMTMSK-UHFFFAOYSA-N 0.000 description 1
- GEPMAHVDJHFBJI-UHFFFAOYSA-N 7-[2-hydroxy-3-[2-hydroxyethyl(methyl)amino]propyl]-1,3-dimethylpurine-2,6-dione;pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1.CN1C(=O)N(C)C(=O)C2=C1N=CN2CC(O)CN(CCO)C GEPMAHVDJHFBJI-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- WMBSZJYXAMQSLH-UHFFFAOYSA-N CCOC(C(C(O)=O)C1=CC=CC=C1)=O.COC1=CC=C(CCN)C=C1OC Chemical compound CCOC(C(C(O)=O)C1=CC=CC=C1)=O.COC1=CC=C(CCN)C=C1OC WMBSZJYXAMQSLH-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- IUJDSEJGGMCXSG-UHFFFAOYSA-N Thiopental Chemical compound CCCC(C)C1(CC)C(=O)NC(=S)NC1=O IUJDSEJGGMCXSG-UHFFFAOYSA-N 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000004996 alkyl benzenes Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000013216 cat model Methods 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 150000008422 chlorobenzenes Chemical class 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- ZERULHNXBONJBS-UHFFFAOYSA-N n'-[2-(3-methoxyphenyl)ethyl]-n,n-dimethyl-2-phenylpropanediamide Chemical compound COC1=CC=CC(CCNC(=O)C(C(=O)N(C)C)C=2C=CC=CC=2)=C1 ZERULHNXBONJBS-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 229940072033 potash Drugs 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 229960003279 thiopental Drugs 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65C—LABELLING OR TAGGING MACHINES, APPARATUS, OR PROCESSES
- B65C2210/00—Details of manually controlled or manually operable label dispensers
- B65C2210/0037—Printing equipment
- B65C2210/004—Printing equipment using printing heads
- B65C2210/0045—Printing equipment using printing heads mechanically actuated, e.g. by a hand lever
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Denne oppfinnelse angår fremstilling av substituerte a-aminokarbonyl-l-benzyl-3,4-dihydro-isokinoliner med den generelle formel I
hvor
Rl'R2°g R3^etyr hydrogen, hydroksy-, metoksy- eller sammen metylendioksygrupper,
X betyr dialkylaminogrupper med 1-3 karbonatomer eller hetero-cykliske rester så som aziridinyl-, azetidinyl eller pyrrolidinylgrupper; morfolino- eller N'-metyl- resp.
N<1->benzylpiperazinorester; eller NHR hvor
R betyr lavere alkylgrupper med 1-4 karbonatomer, alkenyl-eller alkynylgrupper med 3 karbonatomer, cykloalkylgrupper med 3-6 karbonatomer, morfolino- eller pyridylgrupper eller di- resp. tri-metylenrester substituert med en hydroksy-, metoksy-, dimetylamino-, fenyl-, metoks<y>fenyl-, dimetoksy-fenyl-, metylendioksyfenyl-, morfolino- eller indolylgrupper, i racemisk eller optisk aktiv form, og deres syreaddisjonssalter med et fysiologisk godtagbart anion.
Som syreaddisjonssalter kan mån .fremstille alle fysiologisk godtagbare salter med uorganiske eller organiske syrer, f.eks. hydroklorider, hydrogensulf ater, (hydrogen-) fosfater,. tartrater, succinater, maleater, benzoater, acetater, propion-ater, laktater, askorbinater osv.
De nye forbindelser fremstilles ved at et (blandet) diamid av fenylmalonsyre med den generelle formel II hvor .substituentene R^, R^, R^og X har de ovenfor angitte betydninger, ringsluttes i nærvær av et egnet kondensasjonsmiddel til det tilsvarende 3,4-dihydroisokinolin, og eventuelt over-føres derefter et erholdt salt til den frie base og/eller den erholdte frie base overføres til et salt med en fysiologisk god-tagbar syre.
Som kondensasjonsmidler kan man anvende en rekke Lewis-syrer, f.eks. fosforoksyklorid, bortrifluorid, tinntetraklorid eller titantetraklorid, og også sterke mineralsyrer så som svovelsyre, fluorsulfonsyrer, fluorhydrogensyre eller poly-fosforsyre. De anvendes vanligvis i overskudd. Fosforoksyklorid foretrekkes.
Ringslutningsreaksjonen kan utføres i nærvær eller fravær av et oppløsningsmiddel. Alle inerte oppløsningsmidler er egnede forutsatt at de har en tilstrekkelig oppløselighetsevne for reaksjonskomponentene og et tilstrekkelig høyt kokepunkt. Eksempler er benzen, alkylbenzener, klorbenzener, dekalin, kloroform, metylenklorid, acetonitril o. 1. En variant av frem-gangsmåten består i at kondensasjonsmidlet, f.eks. fosforoksyklorid, selv anvendes som oppløsningsmiddel.
Når det gjelder reaksjonstemperaturen, eksisterer det ingen spesielle begrensninger. Omsetningen kan utføres innen-for et stort temperaturområde, fortrinnsvis under oppvarmning til omtrentlig oppløsningsmidlets kokepunkt.
Utgangsforbindelsene med formel II representerer delvis nye forbindelser og er fremstilt efter følgende skjema:
Innledningsvis behandles fenylmalonsyre med tionylklorid, og det derved oppnådde produkt omsettes videre med et amin HX. Utgangsforbindelsen med formel Ila får man Ved omsetning med 2-(3<1>,4<1->dimetoksyfenyl)-etylamin under nitrogenatmosfære.
De nye forbindelser forbedrer vevsgjennomblødningen og vevsoksygentilførsel, særlig i sentralnervesystemet. Dessuten har de kontraktilitetsøkende og blodtrykkspåvirkende virknings-komponenter.
Spesielt aktive er forbindelser hvor.X er et ringsluttet, heterocyklisk system eller et dialkylamin.
Forbindelsene med den generelle formel I i racemisk eller optisk aktiv form og deres syreaddisjonssalter kan også anvendes i kombinasjon med andre typer virkestoffer. Egnede galeniske tilberedelsesformer er for eksempel tabletter, kapsler, stikkpiller, oppløsninger eller pulvere, og for fremstilling av disse kan man anvende de vanlig anvendte galeniske hjelpe-, bære-, spreng- eller smøremidler resp. stoffer.som med-fører en depotvirkning.
De nye forbindelser har en signifikant lengre virknings-varighet enn handelsvanlige produkter. Sammenlignet med Xantinol-nikotinat, ligger overlegenheten ved 60%, basert på den økede hjernegjennomblødning på en kattemodell.
På grunnlag av hemningen av en tiopentalskade på rotte-poten finner man med den nevnte sammenligningsforbindelse for den gjennomblødnings-økende og kretsløp-toniserende virkning et doseforhold på 1 : 100. For resorpsjonskoeffisienten - altså forholdet mellom peroral og intravenøs dosering - har de nye forbindelser en overlegenhet på 2:1. Som dosering anbefales et område mellom 1 og 50 mg/kg, fortrinnsvis 10 - 40 mg/kg (peroral) eller 0,1 - 10 mg/kg, fortrinnsvis 2-7 mg/kg (intra-venøs) .
De følgende eksempler skal tjene til å illustrere opp-finnelsen ytterligere.
Utgangsmaterialer
Eksempel a
Fenylmalonsyremonoetylesterklorid
105 g (0,5 mol) fenylmalonsyremonoetylester (JACS 74,
5897 (1952) oppvarmes sammen med 119 g tibnylklorid i vannbad i 90 minutter under omrøring og tilbakeløpskjøling. Overskudd av tionylklorid avdrivés i vakuum, residuet destilleres under redusert trykk (130 - 135°/15 mm), hvorved man får 85,0 g (= 75% av det teoretiske) fenylmalonsyremonoetylesterklorid.
Eksempel b
Fenylmalonsyremonoetylester- 2-( 3', 4'- dimetoksyfenyl)- etylamid
295 g (1,3 mol) fenylmalonsyremonoetylesterklorid i 500 ml absolutt tetrahydrofuran settes dråpevis ved romtemperatur under omrøring og ^-beskyttelse, til en avkjølt blanding av 236 g
(1,3 mol) 2-(3', 4'-dimetoksyfenyl)-etylamin, 171 g trietylamin og 500 ml, absolutt tetrahydrof uran. Efter avsluttet omsetning avsuges utfelt trietylammoniumklorid, filtratet inndampes, og det faste residuurn fordeles mellom vann og metylenklorid. Den organiske fase tørres over Na2S0^. Efter avdampning av oppløs-ningsmidlet foretas omkrystallisering fra etylacetat.
Sm.p.: 103°, utbytte: 342 g (= 71% av det teoretiske).
Eksempel c
g- dietylaminokarbonyl- fenyleddiksyre- 2-( 3', 4'- dimetoksyfenyl)-etylamid
16,7 g fenylmalonsyremonoetylester-2-(3<1>,4'-dimetoksy-feny1)-etylamid og 120 ml dietylamin oppvarmes i autoklav i 48 timer til 120 - 130°. Til reaksjonsblandingen settes 500 ml etanol, og den behandles med aktivt kull ved koketemperatur. Efter avkjøling foretas avsugning og inndampning, og residuet krystalliseres fra etylacetat-petroleter 40 80°, idet det
når det er nødvendig, først renses over en silikagelkolonne (CH2Cl2:MeOH = 100:1 > 100:2).
Sm.p.: 81 85°. Utbytte: 14 g (= 78% av det teoretiske).
Eksempel 1.
g- dietylaminokarbonyl- l- benzyl- 6, 7- dimetoksy- 3, 4- dihydroisokinolin- hydroklorid
33 g a-dietylaminokarbonyl-fenyleddiksyré-2-(3<1>,4'-di-met6ks'yfenyl)-etylamid oppløses i 120 ml acetonitril og tilsettes 18 ml fosforoksyklorid. Reaksjonsblandingen oppvarmes i
ca. 2 timer til tilbakeløpstemperatur. Derefter foretas inndampning, residuet opptas i 200 ml metylenklorid og gjøres alkalisk ved innrøring av en isvann-pottaske-oppløsning. Efter den vanlige opparbeidelse - utristning med metylenklorid, tørring av den organiske fase over Na2S04, avdrivning av oppløsnings-midlet etc. - foretas rensning over en silikagelkolonne (CF^Cl,^/MeOH = 100/1 100/2).
Sm.p.: 170°. Utbytte: 26 g.
For fremstilling av hydrokloridet oppløses 26 g base i minst mulig etanol og tilsettes etanolisk saltsyre. Hydrokloridet bringes til utfelning ved dråpevis tilsetning av absolutt eter og petroleter 40 - 80° (1:1).
Sm.p.: 203 - 205°. Utbytte: 17 g (= 49,2% av det teoretiske).
Eksempel 2
1-( a- dimetylaminokarbonyl- benzy1)- 6- metoksy- 3, 4- dihydro-i sokinolin- hydroklorid
3,9 g (11,5 mmol) fenylmalonsyre-dimetylamid-[2-(3-metoksyfenyl)-etylamid] oppløste man i 60 ml kloroform, tilsatte 13,7 g (90 mmol) POCl^og kokte i 6 timer under tilbakeløpskjøling. Oppløsningsmidlet ble avdrevet på en rotasjonsinndamper, residuet ble oppløst i Ct^Cl-p og satt dråpevis til en kald, mettet I^CO^-oppløsning. Efter tre gangers ekstraksjon med CH2CI2ble de samlede organiske ekstrakter ekstrahert tre ganger med 2 n HCl. De samlede HCl-faser ble gjort alkaliske med l^CO^og igjen utristet med CP^Cl,,. Den organiske fase ble tørret, inndampet under redusert trykk, og residuet ble behandlet med eterisk HCl. Det utfelte hydroklorid ble oppløst i isopropanbl, behandlet med aktivt kull, og det ble tilsatt så meget dietyl-
eter at det akkurat oppsto uklarhet. Efter natten over i.kjøle-skap utkrystalliserte denønskede forbindelse som hydroklorid. Utbytte: 2,3 g (56% a<y>det teoretiske). Sm.p.: 124°C.
På analog måte ble de følgende forbindelser fremstilt:
Claims (4)
1. Analogifremgangsmåte for fremstilling av fysiologisk aktive forbindelser med den generelle formel
hvor
R^ , R^ og R^ betyr hydrogen, hydroksy-, metoksy- eller sammen
metylendioksygrupper,
X betyr dialkylaminogrupper med 1-3 karbonatomer eller hetero-
cykliske rester så som aziridinyl-, azetidinyl- eller pyrrolidinylgrupper; morfolino- eller N'-metyl- resp. N'-benzylpiperazinorester; eller
NHR hvor
R betyr lavere alkylgrupper med 1-4 karbonatomer, alkenyl-
eller alkynylgrupper med 3 karbonatomer, cykloalkylgrupper med 3-6 karbonatomer, morfolino- eller pyridylgrupper eller di- resp. tri-metylenrester substituert med en hydroksy-, metoksy-, dimetylamino-, feny1-, metoksyfenyl-, dimetoksy-fenyl-, metyléndioksyfenyl-, morfolino- eller indolylgruppe,
i racemisk eller optisk aktiv form, og deres syreaddisjonssalter med et fysiologisk egnet anion, karakterisert ved at et diamid av fenylmalonsyre med den generelle formel II
med de ovenfor angitte betydninger for R^ , R2 , R^ og X, ringsluttes, og eventuelt overføres et erholdt salt til den frie base og/eller den erholdte frie base overføres til sitt salt med en fysiologisk forlikelig syre, idet sluttproduktene med formel I eventuelt spaltes i sine optiske antipoder på kjent måte.
2. Fremgangsmåte som angitt i krav 1, karakterisert ved , at det anvendes utgangsmaterialer hvor Rl' R2 °^ betyr hydrogen, metoksy eller metylendioksy
grupper, og
X betyr dialkylaminogrupper med 1-3 karbonatomer eller hetero-
cykliske rester så som aziridinyl-, acetidinyl- eller pyridinylgrupper, en morfolino- eller N'-metyl resp. N <1-> benzylpiperazinorest.
3. Fremgangsmåte som angitt i krav 1 for fremstilling av a-dietylaminokarbony1-1-benzy1-6,7-dimetoksy-3,4-dihydroisokinolin, karakterisert ved at det anvendes et utgangsmateriale med formel II hvor
R^ og R,, betyr metoksy, R^ betyr hydrogen og X betyr dietylamino.
4. Fremgangsmåte som angitt i krav 1 for fremstilling av a-hydroksyetylaminokarbonyl-l-benzyl-6,7-dimetoksy-3,4-dihydroksyisokinolin-hydroklorid, karakterisert ved at det anvendes et utgangsmateriale med formel II hvor R^ og R2 betyr metoksy, R^ betyr hydrogen og X betyr hydroksy-.
etylamino.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19803013906 DE3013906A1 (de) | 1980-04-11 | 1980-04-11 | Substituierte (alpha) -aminocarbonyl-l-benzyl-3,4-dihydro-isochinoline, verfahren zu deren herstellung und deren verwendung |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO811245L true NO811245L (no) | 1981-10-12 |
Family
ID=6099734
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO811245A NO811245L (no) | 1980-04-11 | 1981-04-10 | Analogifremgangsmaate for fremstilling av fysiologisk aktive alfa-aminokarbonyl-1-benzyl-3,4-dihydro-isokinolin-derivater |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US4322418A (no) |
| EP (1) | EP0037934A3 (no) |
| JP (1) | JPS56158765A (no) |
| AU (1) | AU6938481A (no) |
| DE (1) | DE3013906A1 (no) |
| DK (1) | DK164281A (no) |
| ES (1) | ES8707502A1 (no) |
| FI (1) | FI811123L (no) |
| GB (1) | GB2074159A (no) |
| GR (1) | GR74904B (no) |
| HU (1) | HU183394B (no) |
| IL (1) | IL62621A0 (no) |
| NO (1) | NO811245L (no) |
| NZ (1) | NZ196788A (no) |
| PT (1) | PT72832B (no) |
| YU (1) | YU94181A (no) |
| ZA (1) | ZA812391B (no) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3143876A1 (de) * | 1981-11-05 | 1983-05-11 | Boehringer Ingelheim KG, 6507 Ingelheim | Neue1-furyl-3,4-dihydroisochinoline diese enthaltende arzneimittel sowie verfahren zu deren herstellung und deren verwendung |
| DE3621413A1 (de) * | 1986-06-26 | 1988-01-07 | Boehringer Ingelheim Kg | Verwendung carbocyclisch und heterocyclisch annelierter dihydropyridine als cardioprotektive mittel sowie neue heterocyclisch und carbocyclisch anellierte dihydropyridine, verfahren zu deren herstellung und zwischenstufen fuer deren herstellung |
| IL86131A0 (en) * | 1987-04-24 | 1988-11-15 | Boehringer Ingelheim Kg | Benzo-and thieno-3,4-dihydropyridine derivatives,their preparation and pharmaceutical compositions containing them |
| DE3827727A1 (de) * | 1988-08-16 | 1990-02-22 | Boehringer Ingelheim Kg | Anellierte tetrahydropyridinessigsaeurederivate, verfahren zu deren herstellung und verwendung solcher verbindungen zur kardioprotektion |
| DE9017900U1 (no) | 1990-12-22 | 1993-01-28 | Boehringer Ingelheim Kg, 6507 Ingelheim, De | |
| US5674878A (en) * | 1992-06-22 | 1997-10-07 | Boehringer Ingelheim Kg | Anellated dihydropyridines and the use thereof for the production of pharmaceutical preparations |
| CN1056832C (zh) * | 1992-06-22 | 2000-09-27 | 贝林格尔·英格海姆公司 | 稠合二氢吡啶衍生物及其制法和含有其的药物组合物 |
| WO1994000435A1 (de) * | 1992-06-22 | 1994-01-06 | Boehringer Ingelheim Kg | Anellierte dihydropyridine und deren verwendung für die herstellung von pharmazeutischen zubereitungen |
| ATE198328T1 (de) * | 1992-09-28 | 2001-01-15 | Hoechst Ag | Antiarrhythmische und cardioprotektive substituierte 1(2h)-isochinoline, verfahren zu deren herstellung, diese enthaltende arzneimittel und ihre anwendung für die herstellung eines arzneimittels zur behandlung von herzinsuffizienzen |
| CN1138324A (zh) * | 1993-12-21 | 1996-12-18 | 贝林格尔·英格海姆公司 | 增环的二氢吡啶及其在制备药物制剂中的应用 |
| DE4343683A1 (de) * | 1993-12-21 | 1995-06-22 | Boehringer Ingelheim Kg | Anellierte Dihydropyridine und deren Verwendung für die Herstellung von pharmazeutischen Zubereitungen |
| CA2679985A1 (en) * | 2007-03-15 | 2008-09-18 | F. Hoffmann-La Roche Ag | Malonamides as orexin antagonists |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2769810A (en) * | 1955-08-15 | 1956-11-06 | Shionogi & Co | Process for preparing hydroxy-n-methylmorphinan |
| US3207759A (en) * | 1962-08-01 | 1965-09-21 | Hoffmann La Roche | Isoquinoline acetamides and acetonitriles |
| JPS5242886A (en) * | 1975-10-02 | 1977-04-04 | Takeda Chem Ind Ltd | Preparation of esoquinoline compounds |
-
1980
- 1980-04-11 DE DE19803013906 patent/DE3013906A1/de not_active Withdrawn
-
1981
- 1981-03-25 EP EP81102233A patent/EP0037934A3/de not_active Withdrawn
- 1981-04-03 US US06/250,667 patent/US4322418A/en not_active Expired - Fee Related
- 1981-04-09 PT PT72832A patent/PT72832B/pt unknown
- 1981-04-09 GB GB8111211A patent/GB2074159A/en not_active Withdrawn
- 1981-04-09 IL IL62621A patent/IL62621A0/xx unknown
- 1981-04-10 NO NO811245A patent/NO811245L/no unknown
- 1981-04-10 HU HU81942A patent/HU183394B/hu unknown
- 1981-04-10 DK DK164281A patent/DK164281A/da not_active IP Right Cessation
- 1981-04-10 AU AU69384/81A patent/AU6938481A/en not_active Abandoned
- 1981-04-10 ZA ZA00812391A patent/ZA812391B/xx unknown
- 1981-04-10 NZ NZ196788A patent/NZ196788A/xx unknown
- 1981-04-10 JP JP5425181A patent/JPS56158765A/ja active Pending
- 1981-04-10 FI FI811123A patent/FI811123L/fi not_active Application Discontinuation
- 1981-04-10 ES ES501245A patent/ES8707502A1/es not_active Expired
- 1981-04-10 YU YU00941/81A patent/YU94181A/xx unknown
- 1981-05-14 GR GR64639A patent/GR74904B/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI811123L (fi) | 1981-10-12 |
| IL62621A0 (en) | 1981-06-29 |
| YU94181A (en) | 1983-04-30 |
| DE3013906A1 (de) | 1981-10-15 |
| EP0037934A3 (de) | 1982-05-12 |
| GR74904B (no) | 1984-07-12 |
| PT72832A (de) | 1981-05-01 |
| ZA812391B (en) | 1982-12-29 |
| GB2074159A (en) | 1981-10-28 |
| NZ196788A (en) | 1983-05-10 |
| EP0037934A2 (de) | 1981-10-21 |
| PT72832B (de) | 1983-01-10 |
| ES8707502A1 (es) | 1986-04-16 |
| HU183394B (en) | 1984-04-28 |
| ES501245A0 (es) | 1986-04-16 |
| DK164281A (da) | 1981-10-12 |
| US4322418A (en) | 1982-03-30 |
| AU6938481A (en) | 1981-10-29 |
| JPS56158765A (en) | 1981-12-07 |
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