IL29033A - Morpholine derivatives - Google Patents
Morpholine derivativesInfo
- Publication number
- IL29033A IL29033A IL29033A IL2903367A IL29033A IL 29033 A IL29033 A IL 29033A IL 29033 A IL29033 A IL 29033A IL 2903367 A IL2903367 A IL 2903367A IL 29033 A IL29033 A IL 29033A
- Authority
- IL
- Israel
- Prior art keywords
- morpholine
- radical
- acid
- alkyl
- radicals
- Prior art date
Links
- 150000002780 morpholines Chemical class 0.000 title claims description 24
- -1 cycloalkyl radical Chemical class 0.000 claims description 109
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 71
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 52
- 239000000203 mixture Substances 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 30
- 230000008569 process Effects 0.000 claims description 29
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 150000003254 radicals Chemical class 0.000 claims description 10
- 230000003993 interaction Effects 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000000725 suspension Substances 0.000 claims description 8
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 230000009467 reduction Effects 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 5
- 239000000935 antidepressant agent Substances 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 125000001188 haloalkyl group Chemical group 0.000 claims description 5
- 150000002367 halogens Chemical group 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 229910052987 metal hydride Inorganic materials 0.000 claims description 5
- 150000004681 metal hydrides Chemical class 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 125000005248 alkyl aryloxy group Chemical group 0.000 claims description 4
- RMRFFCXPLWYOOY-UHFFFAOYSA-N allyl radical Chemical compound [CH2]C=C RMRFFCXPLWYOOY-UHFFFAOYSA-N 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 4
- 239000012458 free base Substances 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 3
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000005336 allyloxy group Chemical group 0.000 claims description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 3
- KBCDUOMJRACHMF-UHFFFAOYSA-N 2-(morpholin-2-ylmethoxy)phenol Chemical compound OC1=CC=CC=C1OCC1OCCNC1 KBCDUOMJRACHMF-UHFFFAOYSA-N 0.000 claims description 2
- QCZSSIYNGDQFGO-UHFFFAOYSA-N 2-[(2-ethoxyphenoxy)methyl]-3-methylmorpholine Chemical compound C(C)OC1=C(OCC2C(NCCO2)C)C=CC=C1 QCZSSIYNGDQFGO-UHFFFAOYSA-N 0.000 claims description 2
- VUMNCOIUUGRFQR-UHFFFAOYSA-N 2-[(2-methylphenoxy)methyl]morpholine Chemical compound CC1=CC=CC=C1OCC1OCCNC1 VUMNCOIUUGRFQR-UHFFFAOYSA-N 0.000 claims description 2
- UXANZBNZUHNWBR-UHFFFAOYSA-N 2-[(2-propoxyphenoxy)methyl]morpholine Chemical compound CCCOC1=CC=CC=C1OCC1OCCNC1 UXANZBNZUHNWBR-UHFFFAOYSA-N 0.000 claims description 2
- SVBAYZGWYSSQLN-UHFFFAOYSA-N 2-[(4-phenylphenoxy)methyl]-4-propan-2-ylmorpholine Chemical compound C1(=CC=C(C=C1)OCC1CN(CCO1)C(C)C)C1=CC=CC=C1 SVBAYZGWYSSQLN-UHFFFAOYSA-N 0.000 claims description 2
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims description 2
- OCUCCJIRFHNWBP-IYEMJOQQSA-L Copper gluconate Chemical class [Cu+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O OCUCCJIRFHNWBP-IYEMJOQQSA-L 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- 150000000994 L-ascorbates Chemical class 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 208000018737 Parkinson disease Diseases 0.000 claims description 2
- BQOWUDKEXDCGQS-UHFFFAOYSA-N [CH]1CCCC1 Chemical compound [CH]1CCCC1 BQOWUDKEXDCGQS-UHFFFAOYSA-N 0.000 claims description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical class OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000001961 anticonvulsive agent Substances 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 150000001558 benzoic acid derivatives Chemical class 0.000 claims description 2
- 239000002876 beta blocker Substances 0.000 claims description 2
- 229940030611 beta-adrenergic blocking agent Drugs 0.000 claims description 2
- UOCJDOLVGGIYIQ-PBFPGSCMSA-N cefatrizine Chemical group S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)[C@H](N)C=2C=CC(O)=CC=2)CC=1CSC=1C=NNN=1 UOCJDOLVGGIYIQ-PBFPGSCMSA-N 0.000 claims description 2
- 150000001860 citric acid derivatives Chemical class 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 150000003840 hydrochlorides Chemical class 0.000 claims description 2
- 150000003893 lactate salts Chemical class 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000003176 neuroleptic agent Substances 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims description 2
- KHUXNRRPPZOJPT-UHFFFAOYSA-N phenoxy radical Chemical compound O=C1C=C[CH]C=C1 KHUXNRRPPZOJPT-UHFFFAOYSA-N 0.000 claims description 2
- 235000021317 phosphate Nutrition 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 2
- 229920005990 polystyrene resin Polymers 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 150000003873 salicylate salts Chemical class 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000000932 sedative agent Substances 0.000 claims description 2
- 230000001624 sedative effect Effects 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims description 2
- 150000003892 tartrate salts Chemical class 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- MGIMCFRFUSJEMU-UHFFFAOYSA-N 2-(2,3-dihydro-1h-inden-4-yloxymethyl)-4-propan-2-ylmorpholine Chemical compound C1N(C(C)C)CCOC1COC1=CC=CC2=C1CCC2 MGIMCFRFUSJEMU-UHFFFAOYSA-N 0.000 claims 1
- PLGPGIGLYMFWJC-UHFFFAOYSA-N 2-[(2-chlorophenoxy)methyl]-4-propan-2-ylmorpholine Chemical compound C1N(C(C)C)CCOC1COC1=CC=CC=C1Cl PLGPGIGLYMFWJC-UHFFFAOYSA-N 0.000 claims 1
- HETODBVDFUTLCL-UHFFFAOYSA-N 2-[(2-methylphenyl)sulfanylmethyl]morpholine Chemical compound CC1=CC=CC=C1SCC1OCCNC1 HETODBVDFUTLCL-UHFFFAOYSA-N 0.000 claims 1
- CPAXVDGZFMOFIM-UHFFFAOYSA-N 2-[(2-phenoxyphenoxy)methyl]morpholine Chemical compound C1NCCOC1COC1=CC=CC=C1OC1=CC=CC=C1 CPAXVDGZFMOFIM-UHFFFAOYSA-N 0.000 claims 1
- LDTYVJVIAZQLRQ-UHFFFAOYSA-N 2-[(2-propan-2-yloxyphenoxy)methyl]morpholine Chemical compound C(C)(C)OC1=C(OCC2CNCCO2)C=CC=C1 LDTYVJVIAZQLRQ-UHFFFAOYSA-N 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims 1
- 150000003891 oxalate salts Chemical class 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
- 239000007858 starting material Substances 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000010992 reflux Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 229960004592 isopropanol Drugs 0.000 description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-M oxalate(1-) Chemical compound OC(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-M 0.000 description 8
- 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 7
- 239000000047 product Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 235000006408 oxalic acid Nutrition 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000012265 solid product Substances 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 150000005840 aryl radicals Chemical class 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 230000001519 thymoleptic effect Effects 0.000 description 3
- NIFKETYTGRVRLT-UHFFFAOYSA-N 1-(tert-butylamino)-3-naphthalen-1-yloxypropan-2-ol Chemical compound C1=CC=C2C(OCC(O)CNC(C)(C)C)=CC=CC2=C1 NIFKETYTGRVRLT-UHFFFAOYSA-N 0.000 description 2
- YVWNBNDYTKPZFP-UHFFFAOYSA-N 2-oxo-2-phenoxyacetic acid Chemical compound OC(=O)C(=O)OC1=CC=CC=C1 YVWNBNDYTKPZFP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- 101100277337 Arabidopsis thaliana DDM1 gene Proteins 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 208000020401 Depressive disease Diseases 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 101150052863 THY1 gene Proteins 0.000 description 2
- 229910000091 aluminium hydride Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- VIROVYVQCGLCII-UHFFFAOYSA-N amobarbital Chemical compound CC(C)CCC1(CC)C(=O)NC(=O)NC1=O VIROVYVQCGLCII-UHFFFAOYSA-N 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 101150113676 chr1 gene Proteins 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- HBBXAHLNXBRICT-UHFFFAOYSA-N 2-(2,6-dimethoxyphenoxy)-2-oxoacetic acid Chemical compound C(C(=O)O)(=O)OC1=C(C=CC=C1OC)OC HBBXAHLNXBRICT-UHFFFAOYSA-N 0.000 description 1
- SXAAKGRBYUUBFV-UHFFFAOYSA-N 2-(2-methylphenoxy)-2-oxoacetic acid Chemical compound CC1=CC=CC=C1OC(=O)C(O)=O SXAAKGRBYUUBFV-UHFFFAOYSA-N 0.000 description 1
- MNBWXKNYELZSLS-UHFFFAOYSA-N 2-(naphthalen-1-yloxymethyl)-4-propan-2-ylmorpholine Chemical compound C1N(C(C)C)CCOC1COC1=CC=CC2=CC=CC=C12 MNBWXKNYELZSLS-UHFFFAOYSA-N 0.000 description 1
- AQCZCAJLZOBIBE-UHFFFAOYSA-N 2-(naphthalen-1-yloxymethyl)morpholine Chemical compound C=1C=CC2=CC=CC=C2C=1OCC1CNCCO1 AQCZCAJLZOBIBE-UHFFFAOYSA-N 0.000 description 1
- MGWHDGQSJMZLFU-UHFFFAOYSA-N 2-(naphthalen-1-yloxymethyl)morpholine;oxalic acid Chemical compound OC(=O)C(O)=O.C=1C=CC2=CC=CC=C2C=1OCC1CNCCO1 MGWHDGQSJMZLFU-UHFFFAOYSA-N 0.000 description 1
- OFBLNBCFCXAZGW-UHFFFAOYSA-N 2-(phenoxymethyl)morpholine Chemical compound C1NCCOC1COC1=CC=CC=C1 OFBLNBCFCXAZGW-UHFFFAOYSA-N 0.000 description 1
- LXUNZSDDXMPKLP-UHFFFAOYSA-N 2-Methylbenzenethiol Chemical compound CC1=CC=CC=C1S LXUNZSDDXMPKLP-UHFFFAOYSA-N 0.000 description 1
- VBBMCRRQNCBJQP-UHFFFAOYSA-N 2-[(2,6-dimethoxyphenoxy)methyl]morpholine Chemical compound COC1=CC=CC(OC)=C1OCC1OCCNC1 VBBMCRRQNCBJQP-UHFFFAOYSA-N 0.000 description 1
- RYWXNQIWNDSHQK-UHFFFAOYSA-N 2-[(2-chlorophenoxy)methyl]morpholine Chemical compound ClC1=CC=CC=C1OCC1OCCNC1 RYWXNQIWNDSHQK-UHFFFAOYSA-N 0.000 description 1
- KTPMMKCBDSREOW-UHFFFAOYSA-N 2-[(2-chlorophenoxy)methyl]morpholine;oxalic acid Chemical compound OC(=O)C(O)=O.ClC1=CC=CC=C1OCC1OCCNC1 KTPMMKCBDSREOW-UHFFFAOYSA-N 0.000 description 1
- YIUUQQVMBNHWQV-UHFFFAOYSA-N 2-[(2-ethoxyphenoxy)methyl]-4-propan-2-ylmorpholine Chemical compound CCOC1=CC=CC=C1OCC1OCCN(C(C)C)C1 YIUUQQVMBNHWQV-UHFFFAOYSA-N 0.000 description 1
- YWPHCCPCQOJSGZ-UHFFFAOYSA-N 2-[(2-ethoxyphenoxy)methyl]morpholine Chemical compound CCOC1=CC=CC=C1OCC1OCCNC1 YWPHCCPCQOJSGZ-UHFFFAOYSA-N 0.000 description 1
- CHUROPRTMCQLIS-UHFFFAOYSA-N 2-[(2-methoxyphenoxy)methyl]morpholine Chemical compound COC1=CC=CC=C1OCC1OCCNC1 CHUROPRTMCQLIS-UHFFFAOYSA-N 0.000 description 1
- CAIBSLGEKNOIJR-UHFFFAOYSA-N 2-[(3-methoxyphenoxy)methyl]morpholine Chemical compound COC1=CC=CC(OCC2OCCNC2)=C1 CAIBSLGEKNOIJR-UHFFFAOYSA-N 0.000 description 1
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- PAWZZPPFDBVHSV-UHFFFAOYSA-N 4-benzyl-2-[(2-chlorophenoxy)methyl]morpholine Chemical compound ClC1=CC=CC=C1OCC1OCCN(CC=2C=CC=CC=2)C1 PAWZZPPFDBVHSV-UHFFFAOYSA-N 0.000 description 1
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- 101100294106 Caenorhabditis elegans nhr-3 gene Proteins 0.000 description 1
- 241001630921 Chlorida Species 0.000 description 1
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- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
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- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- HWHLPVGTWGOCJO-UHFFFAOYSA-N Trihexyphenidyl Chemical compound C1CCCCC1C(C=1C=CC=CC=1)(O)CCN1CCCCC1 HWHLPVGTWGOCJO-UHFFFAOYSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- OCBFFGCSTGGPSQ-UHFFFAOYSA-N [CH2]CC Chemical compound [CH2]CC OCBFFGCSTGGPSQ-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229960000836 amitriptyline Drugs 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229960001301 amobarbital Drugs 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- ANTSCNMPPGJYLG-UHFFFAOYSA-N chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 description 1
- 229960004782 chlordiazepoxide Drugs 0.000 description 1
- VXIVSQZSERGHQP-UHFFFAOYSA-N chloroacetamide Chemical compound NC(=O)CCl VXIVSQZSERGHQP-UHFFFAOYSA-N 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 229960003914 desipramine Drugs 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000002631 hypothermal effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- HHRZAEJMHSGZNP-UHFFFAOYSA-N mebanazine Chemical compound NNC(C)C1=CC=CC=C1 HHRZAEJMHSGZNP-UHFFFAOYSA-N 0.000 description 1
- 229950006217 mebanazine Drugs 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical class O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 229960001158 nortriptyline Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000003901 oxalic acid esters Chemical class 0.000 description 1
- GEVPUGOOGXGPIO-UHFFFAOYSA-N oxalic acid;dihydrate Chemical compound O.O.OC(=O)C(O)=O GEVPUGOOGXGPIO-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- RLZZZVKAURTHCP-UHFFFAOYSA-N phenanthrene-3,4-diol Chemical compound C1=CC=C2C3=C(O)C(O)=CC=C3C=CC2=C1 RLZZZVKAURTHCP-UHFFFAOYSA-N 0.000 description 1
- 229960000964 phenelzine 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
- 229960002036 phenytoin Drugs 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229960002393 primidone Drugs 0.000 description 1
- DQMZLTXERSFNPB-UHFFFAOYSA-N primidone Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NCNC1=O DQMZLTXERSFNPB-UHFFFAOYSA-N 0.000 description 1
- WIKYUJGCLQQFNW-UHFFFAOYSA-N prochlorperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 WIKYUJGCLQQFNW-UHFFFAOYSA-N 0.000 description 1
- 229960003111 prochlorperazine Drugs 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 description 1
- 229960002324 trifluoperazine Drugs 0.000 description 1
- 229960001032 trihexyphenidyl Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
-
- D—TEXTILES; PAPER
- D04—BRAIDING; LACE-MAKING; KNITTING; TRIMMINGS; NON-WOVEN FABRICS
- D04B—KNITTING
- D04B1/00—Weft knitting processes for the production of fabrics or articles not dependent on the use of particular machines; Fabrics or articles defined by such processes
- D04B1/22—Weft knitting processes for the production of fabrics or articles not dependent on the use of particular machines; Fabrics or articles defined by such processes specially adapted for knitting goods of particular configuration
- D04B1/24—Weft knitting processes for the production of fabrics or articles not dependent on the use of particular machines; Fabrics or articles defined by such processes specially adapted for knitting goods of particular configuration wearing apparel
- D04B1/26—Weft knitting processes for the production of fabrics or articles not dependent on the use of particular machines; Fabrics or articles defined by such processes specially adapted for knitting goods of particular configuration wearing apparel stockings
-
- D—TEXTILES; PAPER
- D04—BRAIDING; LACE-MAKING; KNITTING; TRIMMINGS; NON-WOVEN FABRICS
- D04B—KNITTING
- D04B9/00—Circular knitting machines with independently-movable needles
- D04B9/42—Circular knitting machines with independently-movable needles specially adapted for producing goods of particular configuration
- D04B9/46—Circular knitting machines with independently-movable needles specially adapted for producing goods of particular configuration stockings, or portions thereof
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Textile Engineering (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Orthopedics, Nursing, And Contraception (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
PATENTS FORM NO. 3.
PATENTS AND DESIGNS ORDINANCE SPECIFIC ION "MORPHOLINE DERIVATIVES" 1 * :vs-n» s? nn^in We, IMPERIAL CHEMICAL INDUSTRIES LIMITED, a British Company of Imperial Chemical House, Millbank, London, S. W.1. , England DO HEREBY DECLARE the nature of this invention and in what manner the same is to be performed, to be particularly ascertained in and by the following statement :- This invention relates to new morpholine derivatives which possess valuable therapeutic properties, for example they possess depressant action on the central nervous system of warm-blooded animals as demonstrated by the reduction of spontaneous motility of mice and the prevention of electroshock-induced convulsions in mice, and they are therefore useful in the treatment of anxiety, neurotic states and epilepsy in man. Furthermore, some of the compounds also possess thymoleptic (ariti-depressant) activity in warm-blooded animals as demonstrated by the reversal of reserpine-induced hypothermia in mice, and these compounds are therefore useful in the treatment or prophylaxis of depressive illness in man.
According to the invention we provide new morpholine derivatives of the formula: - wherein R and R , which may be the same or different, stand for hydrogen 3 or for alkyl radicals, wherein R stands for hydrogen or for an alkyl, alkenyl or cycloalkyl radical, and wherein X stands for a phenyl or naphthyl radical which may optionally be substituted by one or more substituents selected from halogen atoms; alkyl, alkoxy and alkylthio radicals; halogenoalkyl and halogenoalkoxy radicals; alkenyl, alkenyloxy, alkynyloxy and cycloalkoxy radicals; aryl, aryloxy, alkylaryloxy, aralkyl and ar alkoxy radicals; alkyl radicals substituted by alkoxy radicals; and hydroxy and m ethyl enedioxy radicals; or wherein S stands for an indanyl or tetrahydronaphthyl radical which may optionally bear one orj ore halogen substituents or alkyl or alkoxy substituents, and the acid-addition salts thereof.
It is to be understood that the above definition of morpholine derivatives encompasses all possible stereoisomers thereof, and mixtures thereof. 1 2 As a suitable value for R or R when it stands for an alkyl radical there may be mentioned, for example, an alkyl radical of not more than 3 aarbon atoms, for example the methyl radical.
As a suitable value for R when it stands for an alkyl radical there may be mentioned, for example, an alkyl radical of not more than 6 carbon atoms, for example the methyl, ethyl, isopropyl, n-propyl, s-butyl or t-butyl radical.
As a suitable value for R^ when it stands for an alkenyl radical there may be mentioned, for example, an alkenyl radical of not more than 6 carbon atoms* for example the allyl radical.
As a suitable value for R^ when it stands for a cyclo— alkyl radical there may be mentioned, for example, a cycloalkyl radical of not more than carbon atoms, for example the cyclo-propyl, cyclobutyl or cyclopentyl radical.
As a suitable value for X there may be mentioned, for example, a phenyl or naphthyl radical which may optionally be substituted by one or more substituents, and particularly one or two substituents, selected from halogen atoms, for example fluorine, chlorine and bromine atoms; alkyl, alkoxy and alkylthio radicals, for example alkyl, alkoxy and alkylthio radicals of not more than 10 carbon atoms, for example methyl, ethyl, isopropyl, n-butyl, t-butyl, t-amyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, n-heptyloxy and methylthio radicals; halogeno-alkyl and halogenoalkoxy radicals, for example halogenoalkyl and halogenoalkoxy radicals of not more than 5 carbon atoms, for example trifluoromethyl and 2, 2-dichloro-l,l-difluoroethoxy radicals; alkenyl, alkenyloxy, alkynyloxy and cycloalkoxy radicals, for example alkenyl, alkenyloxy, alkynyloxy and cycloalkoxy radicals of not more than 6 carbon atoms, for example allyl, allyloxy, propargyloxy and cyclopentyloxy radicals; aryl, aryloxy, alkylaryloxy, aralkyl and aralkoxy radicals, for example aryl, more than 10 carbon atoms, for example phenyl, phenoxy, 4-tolyloxy, benzyl and benzyloxy radicals? alkoxyalkyl radicals, for example alkyl radicals of not more than 5 carbon atoms substituted by alkoxy radicals of not more than 5 carbon atoms, for example methoxymethl, ethoxymethy] and n-pro oxymethyl radicals; and hydroxy and methylenedioxy radicals.
Alternatively, hid iid dabJ X may be an indanyl or tetrahydronaphthyl radical, for example the 4-indanyl, 5-indanyl, 5,6,7,8-tetrahydro-l-naphthyl or 5>6>7»8-tetrahydro-2-naphthyl radical, which radicals may optionally bear one or more, and particularly one or two halogen, alkyl or alkoxy substituents, for example chlorine or bromine atoms or alkyl or alkoxy radicals each of not more than 3 carbon atoms, for example methyl, ethyl, methoxy or ethoxy radicals.
A preferred group of compounds which possess thymoleptic (anti-depressant) activity comprises compounds of the formula given above wherein R 1 and R2 both stand for hydrogen, wherein R^ stands for hydrogen, or for an alkyl radical of not more than 3 carbon atoms, or for the allyl radical, and wherein X stands for a phenyl radical which bears a single substituent in the 2-position of the nucleus, and the acid-addition salts thereof. Suitable substituents in the 2-position are, for example, those substituents mentioned above as optional substituents in the phenyl or naphthyl radical X. Particularly preferred compounds of this group have the formula given above wherein R 1, R2 and R3 all stand for hydrogen and wherein X stands for a phenyl radical which bears as single substituent in the 2-position a halogen atom, for example the chlorine atom, or an alkyl, alkoxy or alkenyloxy radical each of ethoxy, n-propoxy or allyloxy radical, or the phenyl or phenoxy radical.
The particularly preferred compound which possesses thymoleptic activity is 2-(o,-ethoxyphenoxymethyl)morpholine.
Particular new morpholine derivatives of the invention are, for example, 4-isopropyl-2-(naphth-l-yloxymethyl)morpholine; 4-isopropyl-2-(m-toly1oxymethy1)morpholine; 2-( aphth-1-yloxymeth 1)-4~t-'butylmorpholine; 2-o-ethoxyphenoxymethyl-4-isopropylmorpholine; 2-(naphth-l-yloxymethyl)morpholine ; 4-allyl-2-(naphth-l-yloxy-methyl)morpholine; 4-met]^l-2-(naphth-l-yloxymethyl)morpholine; 2-(o-ethoxyphenoxymethyl)morpholine; 2-(o-methoxyphenoxymethyl)-morpholine; 2-(o-phenoxyphenoxymethyl)morpholinej 2-(o-tolyloxymethyl)morpholine; 2-(o-n-propoxyphenoxymethyl)morpholine; 2-phenoxymethylmorpholine; 2-(j3-methoxyphenoxymethyl)morpholine; 2-(m-methoxyphenoxymethyl)morpholine; 2-(2,6-dimethoxyphenoxy-methyl)morpholine; 2-(o-hydroxyphenoxymethyl)morpholine; 2-(o-n-heptyloxyphenoxymethyl)morpholine; 2-(o-i3opropoxyphenoxymethyl)-morpholine; 2-(o-allyloxyphenoxymethyl)-4-isopropylmorpholine; 2-(o-allyloxyphenoxymethyl)morpholine; 4-cyclopentyl-2-(naphth-l-yloxymethyl)morpholine; 4-isopropyl-2-(5»6»7»8-tetrahydronaphth- 1-yloxymethyl)morpholine; 4-isopropyl-2-(3»4-methylenedioxyphenoxy-methyl)morpholine; 2-(4-indany1oxymethyl)-4-isopropylmorpholne ; 4-isopropyl-2-(m-trifluoromethylphenoxymethyl)morpholne; 4-allyl- 2-(o-ethoxyphenoxymethyl)morpholine· 2-(4-biphenylyloxymethyl)-4-isopropylmorpholine; 2-Co-chlorophenoxymethyl)-4-isopropylmorpholine; 2-(o-ethoxyphenoxymethyl)-3-methylmorpholine; 4-isopropyl-6-methyl-2-(naphth-1- 1oxymethyl)morphoine; 2-(o-chlorophenoxymethyl)-morpholine; 2-(o-methylthiophenoxymethyl)morphoiine; and 2-(o- As suitable acid-addition salts of the morpholine derivatives of the invention there may be mentiohedi for examplej acid-addition salts derived from an inorganic or organic acid, for example hydrochlorides, hydrobromides, phosphates, sulphates, oxalates, lactates, tartrates, acetates, gluconates, salicylates, citrates, ascorbates, benzoates, β-naphthoates, adipates or 1,1-methylene-bis-(2-hydroxy-3-naphthoates) or acid-addition salts derived from acidic synthetic resins, for example sulphonated polystyrene resins, for example "Zeo-Karb" 225 ("Zeo-Karb'1 is a Trade Mark).
According to a further feature of the invention we provide a process for the manufacture of the morpholine derivatives of the invention, and the acid-addition salts thereof, which comprises the reduction of a compound of the formula:- wherein R , R , R and X have the meanings stated above, with a complex metal hydride, whereafter if desired the product in free base form is reacted with an acid to form an acid-addition salt thereof.
The complex metal hydride may be, for example, an alkali metal aluminium hydride, for example lithium aluminium hydride.
The reduction may be carried out in an inert diluent or solvent, for example ether, tetrahydrofuran or 1,2-dimethoxyethane, and it may be accelerated or completed by the application of heat, for example by heating to the boiling point of the diluent or The starting material for the above process may be obtained by the interaction of a compound of the formulas X-O-CHg. CHOE. CHR1.NHR3 wherein and X have the meanings stated above, with a compound of the formula ZCHR 2 COZ 1 , wherein R 2 has the meaning stated above, and wherein Z and Z1, which may be the same or different, stand for halogen atoms, for example chlorine or bromine atoms, followed by the cyclisation of the compound of the formula X-0-CH2.CHOH.CHR1.NR3.COCHR2Z thus obtained. The compound of the formula: may itself be obtained by the interaction of a phenol of the formula X-OH, wherein X has the meaning stated above, with an epihalohydrin of the formulas CH2 - CH.CHRAZ wherein R^ and Z have the meanings stated above, followed by the inter action of the product thus obtained with an amine of the formula ½H,j, wherein R^ has the meaning stated above, as generally described in United Kingdom Patent Specifications Wos. 994» 18» 1, 023, 214 and 1, 069,345.
According to a further feature of the invention we provide a process for the manufacture of those of the morpholine derivatives of the invention, and the acid-addition salts thereof, wherein ^ stands for hydrogen which comprises the removal of the a-aryl-alkyl radical from an α-aryl-alkyl derivative of the formula J- X-0-CH2 ' wherein. Γ.'", R and X have the meanings stated above and wherein R^ stands for an α-aryl-alkyl radical, whereafter if desired the product in free base form is reacted with an acid to form an acid-addition salt thereof.
As a suitable value for R^ there may be mentioned, for example, the benzyl radical* The a-aryl-alkyl radical may be removed by catalytic hydrcgenolysis, for example by means of hydrogen in the presence of a palladium-on-charcoal catalyst, in a diluent or solvent.
The catalytic hydrogenolysis is conveniently carried out at ambient temperature and at atmospheric pressure, and is conveniently accelerated by the presence of an acidic catalyst, for example hydrochloric acid.
Alternatively, the a-aryl-alkyl radical may be removed by the interaction of the compound of the formula given above with an alkyl chloroformate, for example methyl or ethyl chloro-formate, during which interaction the α-aryl-alkyl radical is replaced by an alkoxycarbonyl radical, for example the methoxy-carbonyl or ethoxycarbonyl radical. The said alkoxycarbonyl radical may then be removed by hydrolysis of the alkoxycarbonyl derivative obtained as intermediate.
The interaction of the α-aryl-alkyl derivative with the alkyl chloroformate may be carried out in a diluent or solvent, for example benzene, and it may be accelerated or completed by the application of heat, for example by heating to the boiling point of the diluent or solvent.
The hydrolysis of the alkoxycarbonyl derivative may be carried out by means of an alkali, for example sodium or potassium solvent, for example water, aqueous methanol or aqueous ethanol. The hydrolysis may be accelerated or completed by the application of heat* for example by heating to the boiling point of the diluent or solvent.
It is to be understood that if the aryl radical X contains f a reactive substituent, for example an unsaturated substituent, for example an alkenyl, alkenyloxy or alkynyloxy radical, or a hydrogenolysable substituent, for example the benzyloxy radical, or a halogen substituent, for example the chlorine atom, and if the a-aryl-alkyl radical is removed by catalytic hydrogenol sis, then the reactive substituent may itself be modified. Thus, an alkenyl radical may be reduced to an alkyl radical; an alkenyloxy or alkynyloxy radical may be reduced to an alkoxy radical; the benzyloxy radical may be hydrogenolysed to the hydroxy radical; and the chlorine atom may be replaced by the hydrogen atom. Accordingly, if a reactive substituent as defined above is present in the aryl radical X, or if an alkylthio substituent which might poison a catalyst is present in the aryl radical X, the alternative procedure using an alkyl chloroformate is preferred for the removal of the a-aryl-alkyl radical.
The a-aryl-alkyl derivative used as starting material in the abovementioned process may be obtained by the reduction of the corresponding morpholin-5-one derivative with a complex metal hydride, for example lithium aluminium hydride, by a similar propess to that described above for the manufacture of the morpholine derivatives of the invention.
According to a further feature of the invention we provide pharmaceutical compositions which comprise as active ingredient acid-addition salt thereof, in association with a pharmkcev.tic3.lly-acceptable diluent or carrier therefore.
The pharmaceutical compositions may be, for example, in a form suitable for oral or parenteral administration, for which purposes they may be formulated by means known to the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions, or dispersible powders.
The pharmaceutical compositions of the invention may also contain, in addition to the morpholine derivative or salt thereof, one or more known drugs selected from neuroleptic agents, for example chlorpromazine, prochlorperazine, trifluoperazine and haloperidolj other sedative drugs and tranquillizers, for example chlordiazepoxide, phenobarbitone and amylobarbitone; anticonvulsant drugs, for example primidone and phenytoin; β-adrenergic blocking agents, for example propranolol; drugs used in the treatment of Parkinson's disease, for example benzhexol; and other antidepressant drugs, for example indpramine, desipramine, amitript-yline, nortriptyline, drugs of the aimphetamine type and monoamine-oxidase inhibitors, for example phenelzine and mebanazine.
Preferred pharmaceutical compositions of the invention are those suitable for oral administration in unit dosage form, for example tablets and capsules, which contain between 10 and 100 mg. of active ingredient.
The pharmaceutical compositions of the invention will normally be administered to man, both for the treatment of anxiety and neurotic states and for the treatment or prophylaxis of depressive illness, at such a dose that each patient receives a preferably, if a highly active compound is used, a total of between and 40 mg» VeT cLay* composition being administered 3 or 4 times per day.
The invention is illustrated but not limited by the following Examples in which the parts are by weight J -E ample 1 A mixture of 20 parts of 4-isopropyl-2-(naphth-l-yloxy-methyl) morpholin-5-one , 5 parts of lithium aluminium hydride and 1 ,000 parts of ether is heated under reflux for 6 hours. The ' mixture is cooled, 100 parts of ethyl acetate are added dropwise , and the mixture is then heated under reflux for 10 minutes. 1 ,000 Parts of water are added, and the organic phase is separated, washed with water and dried. A 1 ethereal solution of oxalic acid is added until precipitation of solid is complete , and the mixture is filtered. The solid residue is crystallised from butyl acetate and there is thus obtained 4-is°propyl-2-(naphth-l-yloxymethyl)morpholine hydrogen oxalate , m. p . 143-145°C.
The 4- -i s opropy 1 -2- (napht h-1 -y 1 oxyme thy 1 ) morphol in-5 -one used as starting material may be obtained as follows : - A solution of 75 parts of l-isopropylamino-3-(naphth-l-yloxy)-2-propanol in 1 , 500 parts of ethylene chloride is added to a solution of 12 parts of sodium hydroxide in 600 parts of water. The mixture is cooled to -5 °C. and is vigorously agitated to ensure thorough mixing of the two phases. 25 Parts of chloro-acetyl chloride are added dropwise during 30 minutes at such a rate that the temperature does not rise above 0°C. , and the mixture is then stirred at ambient temperature for 3 hours .
The organic phase is separated , washed with 10 aqueous hydro A solution of 86 parts of the N-( 2-hydroxy-3-naphth-l ! -yloxypropyl)- -isopropylchlo cacetamide thus obtained as residue in 1,000 parts of methanol is added to a solution of 6 parts of sodium in 1,000 parts of methanol and the mixture is heated under reflux for 6 hours. The mixture is evaporated to dryness and the residue is shaken with 2,000 parts of ether and 1,000 parts of 10$ aqueous hydrochloric acid. The ethereal layer is separated, dried and evaporated to dryness and the residue is crystallised from petroleum ether (b.p. 80-100°C) . There is thus obtained 4-isopropyl-2-(naphth-l-yloxymethyl)-morpholin-5-οηθ» ni.p. 110.5-111.5*0.
Example 2 A mixture of 0 parts of 2-o-e thoxy henoxyme thyl-4-isopropylmorpholin-5-one, 15 parts of lithium aluminium hydride and 2,000 parts of ether is heated under reflux for 6 hours. The mixture is cooled, 100 parts of ethyl acetate are added dropwise , and the mixture is then heated under reflux for 10 minutes. 1, 000 Parts of water are added, and the organic phase is separated, washed with water and dried. An ethereal solution of hydrogen chloride is added until precipitation of solid is complete, and the mixture is filtered. The solid residue is crystallised from butyl acetate and there is thus obtained 2- -ethoxyphenoxymethyl-4-isopropylmorpholine hydrochloride , m.p. 158-160°C.
The 2-o-ethoxyphenoxymethyl-4-isopropylmorpholiri-5-one used as starting material may be obtained as follows s- A solution of 44 parts of chloroacetyl chloride in 500 parts of ether is added gradually during 30 minutes to a stirred propanol and 44 parts of triethylamine in 4,000 parts of etbsr. The mixture is stirred at ambient temperature for 24 hours and then filtered, and the filtrate is evaporated to dryness.
A solution of 133 parts of the N-(2*hydroxy-3-£-«thoxy-phenoxypropyl)-N-isopropylohloroacetamide thus obtained in 500 parts of methanol is added gradually during 30 minutes to a solution of 9.3 parts of sodium in 2,000 parts of methanol.
The mixture is heated under reflux for 6 hours and then evaporated to dryness. The residue is shaken with 1,000 parts of ether and 500 parts of 10 aqueous hydrochloric acid, and the organic phase is separated, washed with water, dried and evaporated to dryness. There is thus obtained 2-^-ethoxy-phenoxymetliyl-4-isopropylmorpholin-5-one as an oil.
Example 3 The process described in Example 2 is repeated except that 2-(naphth-l-yloxymethyl)-4-t-butylmorpholin-5-one is used as starting material in place of 2-£-ethoxyphenoxymethyl-4-isopropyl-morpholin-5-one . The solid product is crystallised from ethanol and there is thus obtained 2-(naphth-l-yloxymethyl) -4-t-butyl-morpholine hydrochloride, m.p. 118-121*0. , The 2-(naphth-l-yloxymethyl) -4-t-butylmorpholin-5-one used as starting material may be obtained as follows :- 40 Parts of triethylamine are added to a stirred solution of 100 parts of 3-(naphth-l-yloxy)-l-t-butylamino-2-propanol in 4,000 parts of ether. A solution of 4I parts of chloroacetyl chloride in 5 0 parts of ether is then added gradually to the stirred mixture during 30 minutes, and the mixture is stirred at ambient temperature for 24 hours and is then filtered. The water, and is dried and evaporated to dryness, A solution of 122 parts of the N-( 2-hydroxy-3-naphth-l ' -yloxymethyl)^-t-lmtylchloroacetamide thus obtained in 500 parts of methanol is added to a solution of 8 parts of sodium in 2,000 parts of methanol. The mixture is heated under reflux for 6 hours and is then evaporated to dryness. The residue is shaken with 500 parts of 10 aqueous hydrochloric acid and 2,000 parts of ether and the ethereal solution is separated, washed with water, dried and evaporated to dryness. There is thus obtained 2-( naphth-1 -yl oxyme thyl ) -4- t-buty lmorpholin-5 -one as an oil.
Example 4 The process described in Example 2 is repeated except that 4-isopropyl-2-£-tolyloxymethylmorpholin-5-one is used as starting material in place of 2- -ethoxyphenoxymethyl-4-isopropyl-morpholiii-5-0-ie. The solid product is crystallised from ethyl acetate and there is thus obtained 4-isopropyl-2-m-tolyloxy-methylmorpholine hydrochloride, m.p. 174-175°c» The 4-isopropyl-2-m-tolyloxymetbylmorpholin-5-one used as starting material may be obtained as an oil by the procedure described in the second part of Example 3* except that 1-isopropyl-amino-3-m-tolyloxy-2-propanol is used as starting material in place of 3-(naphth-l-yloxy)-l-t-butylamino-2-propanol.
Example 5 A solution of 17. parts of 4-benzyl-2-(naphth-l-yl oxyme thyl) morpholine and 0.5 part of concentrated aqueous hydrochloric acid in 400 parts of ethanol is shaken with 7· parts of a 5$ palladium-on-charcoal catalyst in an atmosphere of hydrogen at ethyl aoeta e and a solution of parts of oxalic acid dihydr&te in 100 parts of ethyl acetate is added. The mixture is filtered and the solid residue is crystallised from a mixture of methanol and ethyl acetate. There is thus obtained 2-(naphth-l-yloxy-methyl) morpholine hydrogen oxalate, m.p. 160-162°C.
The 4-¾enz l-2-(naphth-l-yloxymethyl) morpholine used as starting material may be obtained as follows. - A solution of 37 parts of chloroacetyl chloride in 330 parts of methylene chloride and a solution of 33 parts of triethylamine in 330 parts of methylene chloride are separately and simultaneously added during 30 minutes to a solution of 100 parts of l-benzylamino-3-(naphth-l-yloxy)-2-propanol in 2,000 parts of methylene chloride which is stirred at a temperature of 0°C. The mixture is stirred at ambient temperature for 17 hours and is then washed successively with 2,500 parts of 10 aqueous hydrochloric acid and 2,500 parts of water, dried and evaporated to dryness.
A solution of 121 parts of the N-benzyl-N-(2-hydroxy-3-naphth-l' -yloxypropyl)chloroacetamide thus obtained as residue in 600 parts of methanol is added to a stirred solution of 7· parts of sodium in 600 parts of methanol, and the mixture is stirred and heated under reflux for 6 hours. The mixture is then 3tirred at ambient temperature for 16 hours and evaporated to dryness, and the residue is shaken with 2,500 parts of 10$ aqueous hydrochloric acid and 2,000 parts of ether. The organic phase is separated, washed with water, dried and evaporated to dryness. The residue is crystallised from petroleum ether (b.p. 100-120 °0.) and there is thus obtained 4-benzyl-2-(naphth-l- ° A suspension of 18 parts of lithi si aluminium hydride in 700 parts of ether is added gradually to a stirred suspension of 54 parts of 4-l3en2yl-2-(naphth-l-yloxynietliyl)morphoiin-5-one in IO7O parts of ether > and tin mixture is then stirred and heated under reflux for 3 hours. 2,000 Parts of water are gradually added, and the organic phase is separated and extracted with 2,000 parts of a 10$ aqueous hydrochloric acid. The extract is made alkaline with 20 aqueous sodium hydroxide solution and the mixture is extracted with ethyl acetate. The extract is washed with water and dried, and ethereal hydrogen chloride solution is added until precipitation of solid is complete. The mixture is filtered and the solid residue is crystallised from methanol. There is thus obtained 4-benzyl-2-(naphth-l-yloxy-methyl)morpholine hydrochloride , which melts between 170 and 230°C. Example 6 The process described in the last part of Example 5 is repeated except that 4-allyl-2-(naphth-l-yloxymethyl)morpholin-5 -one is used as starting material in place of 4-benzyl-2-(naphth-l-yloxymethyl)morpholin-5-one , and that ethereal oxalic acid solution is used in place of ethereal hydrogen ohloride solution during the isolation procedures The solid product is crystallised from methanol and there is thus obtained 4-allyl-2-(naphth-l-yloxymethyl)morpholine hydrogen oxalate, m. s 210-212°C.
The 4-allyl-2-(naphth-l-yloxymethyl)morpholin-5-one used as startin material may be obtained as a solid, m.p. 112.5-H4°C« after crystallisation from petroleum ether (b.p. 100-120°C ) , by the procedure described in the second and third parts of Example 5 except that l-allylaniino-3-(naphth-l-yloxy)-2-propanol is used as The process described in Example 6 is repeated except that 4-inethyl-2-(naph1^-l-ylosymethyl)morpholin-5-one is used as starting material in place of 4-allyl-2-(naphth-l-yloxymethyl)-morpholin-5-one . The solid product is crystallised from a mixture of methanol and ethyl acetate and there is thus obtained 4-methyl-2-(naphth-l-ylcxxymethyl)morpholine hydrogen oxalate, m.p. 180-182°C.
The 4-methyl-2-(naphth-l-yloxymethyl)morpholin-5-one used as starting material may be obtained as a solid, m.p. 105-107°C. after crystallisation from petroleum ether (b.p. 100-120°C.) , by the procedure described in the second and third parts of Example 5 except that l-methylamino-3-(naphth-l~yloxy)-2-propanol (m.p. 94-96°C. f prepared from l, 2-epoxy-3-(naphth-l-yloxy) propane and methylamine) is used as starting material in place of l-benzyl-amino-3-(naphth- 1-yloxy) -2-propanol .
Example 8 The process described in Example 5 is repeated except that the appropriate 4- e z 1 - 2-ar 1 oxynte t h lmor holine is used as starting material in place of 4-benzyl-2-(naphth-l-yloxymethyl) morpholine* There are thus obtained the compounds described in the following table: X Salt 2-ethoxyphenyl hydrogen oxalate 106-108 X Salt m. p, ( °C. ) 2-phenoxyphenyl hydrogen oxalate 158-160 2-tolyl hydrogen oxalate 117-120 2-n-propoxyphenyl hydrogen oxalate 133-135 * phenyl hydrogen oxalate 132-134 ** 4-methox phenyl hydrogen oxalate 146-149.5 3 -me t hox hen l hydrogen oxalate 159-161 2 , 6-dimethoxyphenyl hydrogen oxalate 153-156 2-hydroxyphenyl free base 157-158 *** 2-n-heptyloxyphenyl hydrogen oxalate 97-99 * 2-(o-allyloxyphenoxymethyl) -4-benzylmorpholine used as starting material, the allyl radical being reduced to the . n-propyl radical during hydrogenolysis. ** 4-benzyl-2-(o-chlorophenoxymethyl)morpholine used as starting material, the chlorine atom being replaced by hydrogen during hydrogenolysis. 'i<^4-benzyl-2-(o-ben-yloxypb5noxyinethyl)morpholine used as starting material, the benzyl oxy radical being reduced to the hydroxy radical during hydrogenolysis.
The 4-¾enzyl-2-aryloxymethylmorpholine derivatives used as starting materials in the above process may be obtained by similar processes to those described in the second, third and fourth parts of Example 5 » except that the appropriate 1 -benzyl -amino-3-aryloxy-2-propanol derivatives are used as starting materials.
The l-benzylamino-3-aryloxy-2-propanol derivatives themselves may be obtained by the condensation of the appropriate phenols with epichlorohydrin, followed by the interaction of the products thus obtained with benzylamine. Some of the said and some of them have not been characterised. i-Ben-ylamino-B--( o-ethoxyphenoxy) -2-propanol has m.p. 77-79°C. and l-benzylamno- 3- (o-allyloxyphenoxy) -2-propanol has m.p. 87-90-°C.
Example 9 A solution of 10.4 parts of 2-(o-allyloxyphenoxymethyl)- 4- isopropylraorpholin-5-one in 100 parts of dry ether is added gradually to a stirred suspension of 1.4 parts of lithium aluminium hydride in 150 parts of dry ether, and the mixture is stirred and heated under reflux for 3 hours, and then stirred for a further 14 hours at ambient temperature. 15 Parts of water are gradually added, and the organic phase is separated and extracted with 200 parts of 10 aqueous hydrochloric acid. The acidic extract is made alkaline with 45 aqueous sodium hydroxide solution and the mixture is extracted with ethyl acetate. The organic extract is washed with water, dried and evaporated to dryness. The residue is dissolved in 10 parts of ethyl acetate , and a solution of 2.5 parts of oxalic acid dihydrate in 10 parts of ethyl acetate is added. The mixture is filtered and the solid residue is crystallised from a mixture of methanol and ethyl acetate. There is thus obtained 2-(o-allyloxyphenoxymethyl)-4-isopropylmorpholine hydrogen oxalate, m.p. 132-134°C The 2-( o-allyloxyphenoxymethyl) -4-isopropylmorpholin-5-one used as a starting material may be obtained as follows »- A solution of 4.5 parts of chloroacetyl chloride in 25 parts of methylene chloride and a solution of 4.3 parts of triethylamine in 25 parts of methylene chloride are separately and simultaneously added during 30 minutes to a stirred solution with 200 parts of lO/c aqueous hydrochloric acid and 200 parts of water, dried, and evaporated to dryness.
A solution of 12.6 parts of the N-[2-hydroxy-3-(o-»aliylcxy-phenoxy)propyl]-N-is^ropylchloroaoetamide thus obtained as residue in 75 parts of dry methanol is added to a stirred solution of I.48 parts of sodium in 75 parts of dry methanol, and the mixture is stirred and heated under reflux for 6 hours. The mixture is then stirred at ambient temperature for 11 hours and evaporated to dryness, and the residue is shaken with 200 parts of 10$ aqueous hydrochloric acid and 200 parts of ethyl acetate. The organic phase is separated, washed with water, dried and evaporated to dryness. There is thus obtained 2-(o-allyloxyphenoxymethyl)-4-isopropylmorpholin-5-one as an oil.
Example 10 The process described in Example is repeated except that the appropriate 2-ary1oxymethylmor oiin-5-one is used as starting material in place of 2-(o-allyloxyphenoxymethyl)-4-isopropylmorpholin-5-one. There are thus obtained the compounds described in the following table1 X m.p. (°C.) of hydrogen oxalate salt. 2-allyloxyphenyl hydrogen 115-118 1-iiaphthyl cyclopentyl I63-I65 ,6,7,8-tetrahydro- isopropyl 166-168 1-iiaphthyl The 2-aryloxymethylmorpholin-5-one derivatives used as : starting materials in the above process may be obtained by similar processes to those described in the seoond and third parts of Example i except that the appropriate l-amino-3-aryloxy- 2- propanol derivatives are used as starting materials.
The l-amino-3-aryloxy-2--propanol derivatives themselves may be obtained by the condensation of the appropriate phenols ; with epichlorohydr n, followed by the interaction of the products thus obtained with ammonia or with the appropriate amines. 3- (£-- lyloxyphenoxy) -1-am 3 no-2-propanol has m.p. 57-60°C.
Example 11 The process described in Example 5 is repeated except that 4-¾en^l-2-(o-ethoxyphenoxymetl^l)-3-methylmorpholine is used as starting material in place of 4-benzQrl-2-(naphth-l-yloxymetbyl)- morpholine. There is thus obtained 2- (o-e thox phen oxyme thy 1 ) -3 - methylmorpholine as an oil, the structure of which is confirmed by infra-red spectroscopy.
The 4-benzyl-2-(o-ethoxyphenoxyit©thyl) -3-^thylmorpholine to those dosaribed in. the second, third end fourth parts of Example 5» ¾7 the reaction of o-ethoxyphenol successively with 3-chloro 1^ 2-epoxyiBHBi>ane , benzylajnine and chloroacetyl chloride, followed by cyclisation of the product obtained with sodium methoxide and reduction of the product then obtained with lithium aluminium hydride* Example 12 A Solution of parts of 4-isopropyl-6-methyl-2-(naphth-i^yloxymethyl)morphoiin-5^one in 100 parts of dry ether is added gradually to a stirred suspension of 1 part of lithium aluminium hydride in 100 parts of dry ether, and the mixture is stirred and heated under reflux for 3 hours, and then stirred for a further 14 hours at ambient temperature. 15 Parts of water are gradually added and the organic phase is separated and extracted with 200 parts of 10 aqueous hydrochloric acid. The acidic extract is made alkaline with 45$ aqueous sodium hydroxide solution and the mixture is extracted with ethyl acetate . The organic extract is washed with water, dried, and evaporated to dryness. The residue is dissolved in 10 parts of ethyl acetate and an ethereal solution of hydrogen chloride is added until preciptation of the solid is complete. The mixture is filtered and the solid residue is crystallised from a mixture of methanol and ethyl acetate. There is thus obtained 4-isopropyl-6-methyl-2-(naphth-l-yloxymethyl)morpholine hydrochloride, m.p. 199-205°C. The 4-isopropyl^-methyl-2-(naphth-l-yloxymethyl)-morpholine-5-one used as starting material may be obtained as follows 1- Δ solution of 3·6 parts of 2-bromopropian l chloride in triethylamine in 25 parts of methylene chloride are separately and simultaneously added during 30 minutes to a stirred solution, of 6 parts of l-isopropylami o~3-(naphth-l-yloxy)-2-propanol in 150 parts of methylene chlorida. The mixture is stirred at ambient temperature for 17 hours and is then washed successively with 200 parts of 10$ aqueous hydrochloric acid and 200 parts of watery dried, and evaporated to dryness.
A solution of 8.05 parts of the JT-( 2-by droxy-3-naphth-l 1 -yioxyp 0pyl)-N~isopropyl^2-hromopropio amide thus obtained as residue in 75 parts of dry methanol is added to a stirred solution of 0.5 part of sodium in 75 parts of dry methanol and the mixture is stirred and heated under reflux for 6 hours, and then stirred! for a further 11 hours at ambient temperature. The mixture is evaporated to dryness and the residue is shaken with 200 parts of 10 aqueous hydrochloric acid and 200 parts of ethyl acetate. The organic phase is separated, washed with water, dried and evaporated to dryness* There is thus obtained 4-isopropyl-6-methyl-2-(naphth-l-yloxymethyl)morpholin-5-one as an oil.
Example 13 0.33 Fart of ethyl chloroformate is added to a solution of 1 part of 4-ben.yl-2-(2^thoxyphenoxymethyl)morpholine in 20 parts of benzene, and the mixture is heated under reflux for 17 hours, and then evaporated to dryness. The residue is dissolved in 10 parts of methanol and the solution is added to a solution of 2 parts of potassium hydroxide in 30 parts of methanol. The mixture is heated under reflux for 24 hours, and then evaporated to dryness. The residue is shaken with 100 parts of 10$ aqueous hydrochloric acid and 100 parts of ether and the aqueous phase is and extracted with 100 parts of ether. The ethereal extract i.3 washed with water, dried, and evaporated to dryness. The residue is dissolved in 10 parts of ether and the solution is added to a solution of 0.3 par* of acetic acid in 10 parts of ether. The mixture is filtered and the solid residue is crystallised from a mixture of methanol and ether. There is thus obtained 2-(2-ethoxyphenoxymethyl)m rpholine acetate, m.p. 111-114°C.
The process described above is repeated except that 4-ben2yl-2-(o-chlorophenoxymethyj)morpholine is used as starting material in place of 4-¾enzyl-2-(o-ethoxyphenoxymethyl)morpholine, and that oxalic acid is used in place of acetic acid. There is : thus obtained 2-(o-chlorophenoxymethyl)morpholine hydrogen oxalate, m.p. 144-147°C.
The process described above is repeated except that 4-ben2yl-2-(^methylthiophenoxymethyl)morpholine (prepared by processes similar to those generally described in Examples 5 and 8 from o-methylthiophenol) is used as starting material in place of 4-benzyl-2-(o-ethoxvphenoxymethyl)morpholine, and that oxalic acid is used in place of acetic acid. There is thus obtained 2-(o-methylt ophenoxymethyl)morpholine hydrogen oxalate.
The process described above is repeated except that 4-ben.zyl-2-(o-allylphenoxymethyl)morpholine (prepared by processes similar to those generally described in Examples and 8 from o-allyl-phenol) is used as starting material in place of 4-benzyl-2- (o-ethoxyphenoxy ethyl)morpholine, and that oxalic acid is used in plaoe of acetic acid. There is thus obtained 2-(o-allylphenoxy-methyl)morpholine hydrogen oxalate, m.p. 87~94°C.
Claims (28)
1. Morpholine derivatives of the formula: wherein R arid R # which may be the same or different, stand for hydrogen 3 or for alkyl radicalp, wherein R stands for hydrogen or for an allcyl, alkenyl or cycloalkyl radical, and wherein X stands for a phenyl or naphthyl radical, which may l&e optionally be substituted by one or more substituents selected from halogen atoms; alkyl, alkoxy and alkylthio radicals; halogenoalkyl arid halogenoalkoxy radicals'; alkenyl, alkenyloxy, alkynyloxy and cycloalkoxy radicals; aryl, aryloxy, alkylaryloxy, aralkyl and aralkoxy radicals; alkyl radicals substituted by alkoxy radicals; and hydroxy and m ethyl enedioxy radicals; or wherein X stands for an indanyl or tetrahydronaphthyl radical which may optionally bear one or more halogen substituents or alkyl or alkoxy substituents, and the aeid -addition salts thereof.
2. Morpholine derivatives as claimed in claim 1 wherein R 2 and R , which may be the same or different, stand for hydrogen 3 or for alkyl radicals of not more than 3 carbon atoms, wherein R stands for hydrogen or for an alkyl or alkenyl radical each of not more than 6 carbon atoms or for a cycloalkyl radical of not more than 5 carbon atoms, and wherein X stands for a phenyl or naphthyl radical which may optionally be substituted by one or more substituents selected from halogen atoms; alkyl, alkoxy and alkylthio radicals each of not more than 10 carbon atoms; halogenoalkyl and halogenoalkoxy radicals each of not more than 5 carbon atoms; alkenyl, alkenyloxy, alkynyloxy and cycloalkoxy radicals each of not more than 6 carbon atoms; aryl, aryloxy, alkylaryloxy, aralkyl and aralkoxy radicals each of not more than 10 carbon atoms; alkyl radicals of not more than 5 carbon atoms substituted by alkoxy radicals of not more than 5 carbon atoms; and hydroxy and methyl enedioxy radicals; or wherein X stands for an indanyl or tetrahydronaphthyl radical which may optionally bear one or more halogen substituents or alkyl or alkoxy substituents each of not more than 3 carbon atoms, and the acid-addition salts thereof.
3. Morpholine derivatives as claimed in claim 2 wherein R1 R2 and , which may be the same or different^ stand for hydrogen or for methyl radioals, wherein R^ stands for hydrogen or for the methyl, ethyl, sopropyl, n-propyl, s-butyl, t-butyl, allyl, cylopropyl, cyclobutyl or cyclopentyl radical, and wherein X stands for a phenyl or naphthyl radical which may optionally be substituted by one or two substituents selected from fluorine, chlorine and bromine atoms and methyl, ethyl, isopropyl, n-butyl, t-butyl, t-amyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, n-heptyloxy, methylthio, trifluoromethyl, 2,2-dichloro-1,1-difluoroethoxy, allyl, allyloxy, propargyloxy, cyclopentyloxy, phenyl, phenoxy, 4-tolyloxy, benzyl, beneyloxy, methoxymethyl, ethoxymethyl, n-propoxymethyl, hydroxy and methylenedioxy radicals, or wherein X stands for the 4-indanyl, 5-indanyl, 5»6f7»8-tetra-hydro-1-naphthyl or 5»6,7»8-tetrahydro--2-naphthyl radical which may optionally bear one or two chlorine, bromine, methyl, ethyl, methoxy or ethoxy substituents, and the acid-addition salts thereof.
4. Morpholine derivatives as claimed in claim 1 wherein R^" 2 3 and R both stand for hydrogen, wherein R stands for hydrogen, or for an alkyl radical of not more than 3 carbon atoms, or for the allyl radical, and wherein X stands for a phenyl radical which bears a single substituent in the 2-position of the nucleus, and the acid-addition salts thereof.
5. Morpholine derivatives as claimed in claim 4 wherein the substituent in the 2-position of the phenyl nucleus is one of the phenyl or nephthyl radical X, and the acid-addition salts thereof.
6. · Morpholine derivatives as claimed in claim wherein the substituent in the 2-positxon of the phenyl nucleus is one of the eubstituents stated in claim 3 to be optional substituents in the phenyl or naphthyl radical X, and the acid-addition salts thereof.
7. » Morpholine derivatives as claimed in claim 4 wherein stands for hydrogen and wherein X stands for a phenyl radical which bears as single substituent in the 2-position a halogen atom or an alkyl, alkoxy or alkenoxy radical each of not more than 6 carbon atoms or the phenyl or phenoxy radical, and the acid-addition salts thereof. 7
8. Morpholine derivatives as claimed in claim & wherein the substituent in the 2-position of the phenyl nucleus is the chlorine atom or the methyl, ethyl, methoxy, ethoxy, n-propoxy, isopropoxy or allyloxy radioal, and the acid-addition salts thereof.
9. The compounds 4-isopropyl-2-(naphth-l-yloxymethyl)morpholine 4-isopropyl-2-m-tolyloxymethylmorpholine; 2-(naphth-l-yloxymethyl)-4-t-butylmorpholine; 2-o-ethoxyphenoxymethl-4-1soprop lmorpholine; 2-(naphth-l-yloxymethyl)morpholine} 4-allyl-2-(naphth-l-yloxymethyl) morpholine; and 4-metbyl-2-(naphth-l-yloxymethyl)morpholine and the acid-addition salts thereof.
10. » The compound 2-(o^thoxyphenoxymethyl)morpholine and the acid-addition salts thereof.
11. · The compounds 2-(o-methoxyphenoxymetbyl)morpholine; 2-(o-phenoxyphenoxymethyl)morpholine; 2-(o-tolyloxymethyl)morpholine; 2-(o-n-propoxyphenoxymethyl)morpholine; 2-(o-isopropoxyphenoxy-methyl)morpholine; 2-(o-allyloxyphenoxymethyl)morpholine; and
12. The compounds 2-phenoxymetbyimorph0line; 2-(jJ-methoxy-phenoxymethyl)morpholine5 2-(m-methoxyphenoxymethyl)morpholinej 2-( ,6-dimethoxyphenoxymethyl)morpholine; 2-(o-hydroxyphenoxy-methyl)morpholine; 2-(£-n-hepty-loxypheno3»ymethyl)morpholine; 2-(o-allyloxyphenoxymethyl)-4-isopropylmorpholine; 4-oyolopentyl-2-(naphth-l-yloxymethyl)morpholine; 4-isopropyl-2-(5>6,7>8-tetrahydronaphth-1-yloxymethy1)morpholine; 4-iaopropyl-2-(3$4-methylenediaxyphenoxyniethyl)morpholine; 2-(4-indanyloxymethyl)-4-isopropylmorpholine; 4-isopropyl-2-(m- rifluoromethylphenoxy- ethyl)morpholine,* 4-allyl-2-(o-ethoxyphe oxymethyl)morpholine; 2-(4-biphenylyloxymethyl)-4-isopropylmorpholine; 2-(o-chloro-phenoxymetyl)-4-isopropylmorpholine ; 2-(o-ethoxyphenoxymethyl)- 3-methylmorpholine; 4-isopropyl-6-methyl-2-(naphth-l-yloxymethyl)-morpholine* 2-(o-methylthiophenoxymethyl)morpholine; and 2-(o-allylphenoxymethyl)morpholine and the acid-addition salts thereof.
13. Acid-addition salts as claimed in any of claims 1 to 12 which are hydrochlorides, hydrobromides, phosphates, sulphates, oxalates, lactates, tartrates, acetates, gluconates, salicylates, citrates, ascorbates, benzoates, β-iiaphthoates, adipates or l,l-methylene-bis-(2-hydroxy-3-naphthoate8) or acid-addition salts derived from sulphonated polystyrene resins.
14. A process for the manufacture of the morpholine derivatives and the acid-addition salts thereof, claimed in any of claims 1 to 13» which comprises either the reduction of a compound of the formulai- wherein R , R , R and X have the meanings stated in olaim 1, with a complex metal hydride, or for the manufacture of those of the morpholine derivatives wherein ^ stands for hydrogen, which comprises the removal of the a-aryl-alkyl radical from a compound of the formula »- wherein R , R and X have the meanings stated above and wherein ^ stands for an a-aryl-alkyl radical, whereafter if desired the product in free base form is reacted with an acid to form an acid-addition salt thereof.
15. · A process as claimed in olaim 14 wherein the complex metal hydride is lithium aluminium hydride.
16. A process as claimed in claim 1 or 15 which is carried out in ether, tetrahydrofuran or 1,2-dimethox ethane as diluent or solvent.
17. A process as claimed in claim 14 wherein ^" stands for the benzyl radical.
18. A prooess as claimed in claim 14 or 17 wherein the removal of the α-aryl-alkyl radical R^ is carried out by means of catalytic hydrogenolysis in a diluent or solvent. 1 .
19. A process as claimed in claim 18 wherein a palladium-on-charcoal catalyst is used.
20. A process as claimed in claim 14 or 17 wherein the removal of the α-aryl-alkyl radical ^ is carried out by the interaction of the a-aryl-alkyl derivative with an alkyl ohloroformate thus obtained.
21. · A process as claimed in claim 20 wherein the alkyl chioroformate is methyl or ethyl chloroformate.
22. * A process as claimed in claim 20 or 21 wherein the hydrolysis of the alkoxycarbonyl derivative obtained as intermediate is carried out by means of an alkali in an aqueous diluent or solvent.
23. Pharmaceutical compositions which comprise as active ingredient at least one morpholine derivative or an acid-addition salt thereof, claimed in any of claims 1 to 13, in association with a pharmaoeutically-acceptable diluent or carrier therefor.
24. · Compositions as claimed in claim 23 which are suitable for oral or parenteral administration and which are in the form of tablets, capsules, aqueous or oily solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions, or dispersible powders.
25. · Compositions as claimed in claim 23 or 24 which additionally contain one or more known drugs selected from neuroleptic agents, sedative drugs, tranquillizers, anticonvulsant drugs, β-adrenergic blocking agents, drugs used in the treatment of Parkinson's disease, and antidepressant drugs.
26. Compositions as claimed in claim 23 or 24 which are in the form of tablets or capsules containing between 10 and 100 mg. of active ingredient.
27. » Morpholine derivatives, and acid-addition salts thereof, claimed in any of claims 1 to 3» 9 and 13» as hereinbefore particularly described in Examples 1 to 7·
28. Morpholine derivatives and acid-addition salts thereof, 29· Δ process for the manufacture of morpholine derivatives, claimed in any of claims 14 to 22» substantially as hereinbefore described in Examples 1 to 13» DATED the 28th November.1967 PH. 19864 t RPS/HMB I 2.II.67
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB57963/66A GB1138405A (en) | 1966-12-28 | 1966-12-28 | Morpholine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IL29033A true IL29033A (en) | 1972-01-27 |
Family
ID=10480469
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL29033A IL29033A (en) | 1966-12-28 | 1967-11-29 | Morpholine derivatives |
Country Status (11)
| Country | Link |
|---|---|
| AT (2) | AT274826B (en) |
| CH (1) | CH513904A (en) |
| DK (1) | DK120543B (en) |
| ES (1) | ES348087A1 (en) |
| FI (1) | FI47373C (en) |
| IL (1) | IL29033A (en) |
| MY (1) | MY7200092A (en) |
| NO (1) | NO126021B (en) |
| PL (1) | PL69864B1 (en) |
| SE (1) | SE334157B (en) |
| YU (3) | YU32606B (en) |
-
1967
- 1967-11-20 NO NO170607A patent/NO126021B/no unknown
- 1967-11-27 DK DK592367AA patent/DK120543B/en not_active IP Right Cessation
- 1967-11-28 AT AT1072967A patent/AT274826B/en active
- 1967-11-28 AT AT10148/68A patent/AT281853B/en not_active IP Right Cessation
- 1967-11-29 IL IL29033A patent/IL29033A/en unknown
- 1967-11-30 FI FI673216A patent/FI47373C/en active
- 1967-12-01 CH CH1760370A patent/CH513904A/en not_active IP Right Cessation
- 1967-12-09 ES ES348087A patent/ES348087A1/en not_active Expired
- 1967-12-13 SE SE17125/67A patent/SE334157B/xx unknown
- 1967-12-19 YU YU2475/67A patent/YU32606B/en unknown
- 1967-12-27 PL PL1967124356A patent/PL69864B1/en unknown
-
1972
- 1972-12-31 MY MY197292A patent/MY7200092A/en unknown
-
1973
- 1973-03-05 YU YU574/73A patent/YU34794B/en unknown
- 1973-03-05 YU YU575/73A patent/YU35130B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| YU247567A (en) | 1974-10-31 |
| DK120543B (en) | 1971-06-14 |
| YU35130B (en) | 1980-09-25 |
| CH513904A (en) | 1971-11-30 |
| YU57573A (en) | 1980-03-15 |
| YU34794B (en) | 1980-03-15 |
| AT274826B (en) | 1969-10-10 |
| SE334157B (en) | 1971-04-19 |
| MY7200092A (en) | 1972-12-31 |
| PL69864B1 (en) | 1973-10-31 |
| NO126021B (en) | 1972-12-11 |
| AT281853B (en) | 1970-06-10 |
| FI47373C (en) | 1973-11-12 |
| FI47373B (en) | 1973-07-31 |
| ES348087A1 (en) | 1969-03-01 |
| YU32606B (en) | 1975-04-30 |
| YU57473A (en) | 1979-09-10 |
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