CA1069931A - Thiocarbamide derivatives and process for preparing thereof - Google Patents
Thiocarbamide derivatives and process for preparing thereofInfo
- Publication number
- CA1069931A CA1069931A CA247,778A CA247778A CA1069931A CA 1069931 A CA1069931 A CA 1069931A CA 247778 A CA247778 A CA 247778A CA 1069931 A CA1069931 A CA 1069931A
- Authority
- CA
- Canada
- Prior art keywords
- group
- hydroxyethyl
- denotes
- thiocarbamide
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical class NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 229940042794 thiocarbamide derivative for treatment of tuberculosis Drugs 0.000 title claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 title 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 45
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 37
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- -1 1,1-dimethyl-2-hydroxyethyl group Chemical group 0.000 claims abstract description 26
- 125000005843 halogen group Chemical group 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 12
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims abstract description 7
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 4
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims abstract description 4
- SXIFAEWFOJETOA-UHFFFAOYSA-N 4-hydroxy-butyl Chemical group [CH2]CCCO SXIFAEWFOJETOA-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims abstract description 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims abstract description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims abstract description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 4
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims abstract 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims abstract 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 24
- OPKOKAMJFNKNAS-UHFFFAOYSA-N N-methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 claims description 16
- 239000012442 inert solvent Substances 0.000 claims description 14
- 150000001412 amines Chemical class 0.000 claims description 13
- 239000000155 melt Substances 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 9
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 8
- 238000002844 melting Methods 0.000 claims description 7
- 230000008018 melting Effects 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- 150000002540 isothiocyanates Chemical class 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- LPVNPJMEWWUFHD-UHFFFAOYSA-N 1-fluoro-4-(isothiocyanatomethyl)benzene Chemical compound FC1=CC=C(CN=C=S)C=C1 LPVNPJMEWWUFHD-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- SUKSPZUQUKQLRX-UHFFFAOYSA-N methyl n-[(4-fluorophenyl)methyl]carbamodithioate Chemical compound CSC(=S)NCC1=CC=C(F)C=C1 SUKSPZUQUKQLRX-UHFFFAOYSA-N 0.000 claims description 2
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 12
- 239000001257 hydrogen Substances 0.000 claims 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 6
- 150000002431 hydrogen Chemical class 0.000 claims 6
- 150000003254 radicals Chemical class 0.000 claims 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- DEHXIHUIYSXZNH-UHFFFAOYSA-N 1-chloro-4-(isothiocyanatomethyl)benzene Chemical compound ClC1=CC=C(CN=C=S)C=C1 DEHXIHUIYSXZNH-UHFFFAOYSA-N 0.000 claims 2
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 claims 2
- LIMPKEZVOAQSOD-UHFFFAOYSA-N methyl n-[(4-chlorophenyl)methyl]carbamodithioate Chemical compound CSC(=S)NCC1=CC=C(Cl)C=C1 LIMPKEZVOAQSOD-UHFFFAOYSA-N 0.000 claims 2
- AHXHRYRWYFSRQJ-UHFFFAOYSA-N 1-(isothiocyanatomethyl)-4-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=C(CN=C=S)C=C1 AHXHRYRWYFSRQJ-UHFFFAOYSA-N 0.000 claims 1
- HHJNPMOABDDXEL-UHFFFAOYSA-N 1-fluoro-2-(isothiocyanatomethyl)benzene Chemical compound FC1=CC=CC=C1CN=C=S HHJNPMOABDDXEL-UHFFFAOYSA-N 0.000 claims 1
- KLNMIWGOGGBFNV-UHFFFAOYSA-N 1-isothiocyanatopropylbenzene Chemical compound S=C=NC(CC)C1=CC=CC=C1 KLNMIWGOGGBFNV-UHFFFAOYSA-N 0.000 claims 1
- 150000003560 thiocarbamic acids Chemical class 0.000 claims 1
- 230000000202 analgesic effect Effects 0.000 abstract description 4
- 230000001430 anti-depressive effect Effects 0.000 abstract description 3
- 239000002934 diuretic Substances 0.000 abstract description 3
- 230000001882 diuretic effect Effects 0.000 abstract description 3
- 230000002349 favourable effect Effects 0.000 abstract description 3
- 230000000894 saliuretic effect Effects 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 239000000935 antidepressant agent Substances 0.000 abstract 1
- 229940005513 antidepressants Drugs 0.000 abstract 1
- 230000036772 blood pressure Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 13
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 239000004202 carbamide Substances 0.000 description 4
- 235000013877 carbamide Nutrition 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000004531 blood pressure lowering effect Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- GNVMUORYQLCPJZ-UHFFFAOYSA-N carbamothioic s-acid Chemical compound NC(S)=O GNVMUORYQLCPJZ-UHFFFAOYSA-N 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 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
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 description 1
- 125000006325 2-propenyl amino group Chemical group [H]C([H])=C([H])C([H])([H])N([H])* 0.000 description 1
- 125000006494 2-trifluoromethyl benzyl group Chemical group [H]C1=C([H])C([H])=C(C(=C1[H])C([H])([H])*)C(F)(F)F 0.000 description 1
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 description 1
- ZQSCNOCLGUTXNV-UHFFFAOYSA-N 2h-thiazocine Chemical class C1=CC=CSNC=C1 ZQSCNOCLGUTXNV-UHFFFAOYSA-N 0.000 description 1
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 description 1
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000006180 3-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001318 4-trifluoromethylbenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C(F)(F)F 0.000 description 1
- RMMXTBMQSGEXHJ-UHFFFAOYSA-N Aminophenazone Chemical compound O=C1C(N(C)C)=C(C)N(C)N1C1=CC=CC=C1 RMMXTBMQSGEXHJ-UHFFFAOYSA-N 0.000 description 1
- RRXSYZFVDIRTFB-UHFFFAOYSA-N C[CH]C1=CC=C(OC)C=C1 Chemical group C[CH]C1=CC=C(OC)C=C1 RRXSYZFVDIRTFB-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229960000212 aminophenazone Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 description 1
- 229960004193 dextropropoxyphene Drugs 0.000 description 1
- 125000006286 dichlorobenzyl group Chemical group 0.000 description 1
- 239000012990 dithiocarbamate Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 125000006178 methyl benzyl group Chemical group 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 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
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- NYERMPLPURRVGM-UHFFFAOYSA-N thiazepine Chemical compound S1C=CC=CC=N1 NYERMPLPURRVGM-UHFFFAOYSA-N 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/06—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms
- C07C335/10—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C335/12—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- 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
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Psychiatry (AREA)
- Cardiology (AREA)
- Rheumatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
This invention relates novel thiocarbamide derivatives of the general formula I
(I) wherein R1, R2 and R3 may stand for identical or different groups, and they denote each a hydrogen atom, a C1-8 straight or branched-chain, saturated or unsaturated alkyl, or dialkylaminoalkyl groups, alkyl substituted with one or more halogen atoms, further hydroxy, dialkylamino, or nitro groups or halogen atoms; R4 denotes a hydrogen atom, a saturated or unsaturated straight or branched-chain C1-8 alkyl a C2-6 straight or branched-chain hydroxyalkyl a hydroxyl group; R5 denotes a C2-6 straight or branched-chain hydroxyalkyl group or a C3-6 straight or branched-chain unsaturated alkyl group; R6 denotes a hydrogen atom, a straight or branched-chain saturated or unsaturated C1-7 alkyl group which may be substituted with a hydroxy group or with one or more halogen atoms, or a C3-6 cycloalkyl group, with the proviso that R6 must have a meaning other than hydrogen atom when R1, R2, R3 and R4 each denote a hydrogen atom and R5 stands for a 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxy-butyl or 1,1-dimethyl-2-hydroxyethyl group; or when R2, R3, and R4 each denote a hydrogen atom, R5 denotes a 2-hydroxyethyl group and R1 denotes a 2-chloro, 4-chloro, 4-bromo or 2-methyl group; or when R1 denotes a 4-bromo group, R2, R3 and R4 each denote a hydrogen atom and R5 stands for a 4-hydroxybutyl group; or when R1 denotes a 2-methyl group, R2 a 4-methyl or 5-methyl group, R3 and R4 each stand for a hydrogen atom, and R5 is a 2-hydroxyethyl group;
or when R1 denotes a 2-methoxy group, R2 a 4-hydroxy group, R3 and R4 each a hydrogen atom and R5 a 2-hydroxyethyl group; or when R1, R2 and R3 each denote a hydrogen atom, R5 denotes a 2-hydroxyethyl group and R4 stands for a 2-hydroxyethyl or 2-methylpropyl group. It also relates to a process for the preparation of the new compounds of formula 1.
Certain of the compounds of this invention exhibit very favourable diuretic and saluretic effects even when administered in small doses. Other compounds of the invention exhibit blood-pressure lowering, analgesic or antidepressant affects combined with low toxicity. More details of this activity are dis-closed.
This invention relates novel thiocarbamide derivatives of the general formula I
(I) wherein R1, R2 and R3 may stand for identical or different groups, and they denote each a hydrogen atom, a C1-8 straight or branched-chain, saturated or unsaturated alkyl, or dialkylaminoalkyl groups, alkyl substituted with one or more halogen atoms, further hydroxy, dialkylamino, or nitro groups or halogen atoms; R4 denotes a hydrogen atom, a saturated or unsaturated straight or branched-chain C1-8 alkyl a C2-6 straight or branched-chain hydroxyalkyl a hydroxyl group; R5 denotes a C2-6 straight or branched-chain hydroxyalkyl group or a C3-6 straight or branched-chain unsaturated alkyl group; R6 denotes a hydrogen atom, a straight or branched-chain saturated or unsaturated C1-7 alkyl group which may be substituted with a hydroxy group or with one or more halogen atoms, or a C3-6 cycloalkyl group, with the proviso that R6 must have a meaning other than hydrogen atom when R1, R2, R3 and R4 each denote a hydrogen atom and R5 stands for a 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxy-butyl or 1,1-dimethyl-2-hydroxyethyl group; or when R2, R3, and R4 each denote a hydrogen atom, R5 denotes a 2-hydroxyethyl group and R1 denotes a 2-chloro, 4-chloro, 4-bromo or 2-methyl group; or when R1 denotes a 4-bromo group, R2, R3 and R4 each denote a hydrogen atom and R5 stands for a 4-hydroxybutyl group; or when R1 denotes a 2-methyl group, R2 a 4-methyl or 5-methyl group, R3 and R4 each stand for a hydrogen atom, and R5 is a 2-hydroxyethyl group;
or when R1 denotes a 2-methoxy group, R2 a 4-hydroxy group, R3 and R4 each a hydrogen atom and R5 a 2-hydroxyethyl group; or when R1, R2 and R3 each denote a hydrogen atom, R5 denotes a 2-hydroxyethyl group and R4 stands for a 2-hydroxyethyl or 2-methylpropyl group. It also relates to a process for the preparation of the new compounds of formula 1.
Certain of the compounds of this invention exhibit very favourable diuretic and saluretic effects even when administered in small doses. Other compounds of the invention exhibit blood-pressure lowering, analgesic or antidepressant affects combined with low toxicity. More details of this activity are dis-closed.
Description
93~
Thi.C invention relates to novel thiocarbamide derivatives of the general formula I ~ :
~ ~,
Thi.C invention relates to novel thiocarbamide derivatives of the general formula I ~ :
~ ~,
2 ~ - CH - NH - C - ~ ~ 4 wherein Rl, R2 and R3 may stand for identical or different groups, and they denote ;~
each a hydrogen atom, a Cl 8 straight or branched-chain, ;
saturated or unsaturated alkyl, or dialkylaminoalkyl groups, alkyl substituted with one or more halogen atoms, further hydroxy, dialkylamino, or nitro groups or halogen atoms, ~ ~ .
R~ denotes a hydrogen atom, a saturated or unsaturated straight or branched-chain Cl 8 alkyl or cycloalkyl group which may be substituted with a hydroxyl group, R5 denotes a C2 ~ straight or branched-chain hydroxyalkyl group or a C3 6 straight or branched-chain unsaturated alkyl group, .
R6 denote5 a hydrogen atom, a straight or branched-chain saturated or unsaturated Cl 7 alkyl group which may be substituted with a hydroxy group or with one or more halogen atoms, or a C3 6 cycloalkyl group, with the proviso that R6 must have a meaning other than hydrogen atom when Rl, R2, R3 :::
and R~ each denote a hydrogen atom and R5 stands for ~ .
a 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl or ; 1,1=dimethyls2-hydroxyethyl group; or when R2, R3 .and R4 each denote a hydrogen atom, R5 de- : ~
notes a 2~hydroxyethyl group and Rl denotes a 2-chloro, :;
4-chlor~j 4-bromo or~2-methyl group; or ~-~
when Rl denotes a 4-bromo group, R2, R3 and R4 each `~
denote a hydrogen atom and R5 s~ands for a 4-hydroxy-butyl group; or ".
when Rl denotes a 2-methyl group, R2 a 4-methyl or 5- : :
.. ..
methyl group, R3 and R4 each stand for a hydrogen atom, .
and R5 is a 2-hydroxyethyl group; or when Rl denotes a 2-methoxy group, R2 a 4-hydroxy group, R3 and R4 each a hydrogen atom and R5 a 2-hydroxyethyl group; or - :~
when Rl, R2 and R3 each denote a hydrogen atom, R5 ~;~
denotes a 2-hydroxyethyl group and R4 stands for a 2-hydroxyethyl or 2-methylpropyl group, and R6 must have ` ~
a meaning other than hydrogen atom when at least one of ~ .
:: , Rl, R2 and R3 denotes a Cl 4 alkyl or a halo group, R4 .~ ~ denotes a hydrogen atom or a Cl 4 alkyl group and R5 ~ ~
deno~es an allyl group. : .
The invention also relates to a process for the preparation of ;: ::.
novel thiocarbamide derivatives of the general formula I
'.'' ~.
.:
R2 ~ C~ - NH - C - h \ (I)
each a hydrogen atom, a Cl 8 straight or branched-chain, ;
saturated or unsaturated alkyl, or dialkylaminoalkyl groups, alkyl substituted with one or more halogen atoms, further hydroxy, dialkylamino, or nitro groups or halogen atoms, ~ ~ .
R~ denotes a hydrogen atom, a saturated or unsaturated straight or branched-chain Cl 8 alkyl or cycloalkyl group which may be substituted with a hydroxyl group, R5 denotes a C2 ~ straight or branched-chain hydroxyalkyl group or a C3 6 straight or branched-chain unsaturated alkyl group, .
R6 denote5 a hydrogen atom, a straight or branched-chain saturated or unsaturated Cl 7 alkyl group which may be substituted with a hydroxy group or with one or more halogen atoms, or a C3 6 cycloalkyl group, with the proviso that R6 must have a meaning other than hydrogen atom when Rl, R2, R3 :::
and R~ each denote a hydrogen atom and R5 stands for ~ .
a 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl or ; 1,1=dimethyls2-hydroxyethyl group; or when R2, R3 .and R4 each denote a hydrogen atom, R5 de- : ~
notes a 2~hydroxyethyl group and Rl denotes a 2-chloro, :;
4-chlor~j 4-bromo or~2-methyl group; or ~-~
when Rl denotes a 4-bromo group, R2, R3 and R4 each `~
denote a hydrogen atom and R5 s~ands for a 4-hydroxy-butyl group; or ".
when Rl denotes a 2-methyl group, R2 a 4-methyl or 5- : :
.. ..
methyl group, R3 and R4 each stand for a hydrogen atom, .
and R5 is a 2-hydroxyethyl group; or when Rl denotes a 2-methoxy group, R2 a 4-hydroxy group, R3 and R4 each a hydrogen atom and R5 a 2-hydroxyethyl group; or - :~
when Rl, R2 and R3 each denote a hydrogen atom, R5 ~;~
denotes a 2-hydroxyethyl group and R4 stands for a 2-hydroxyethyl or 2-methylpropyl group, and R6 must have ` ~
a meaning other than hydrogen atom when at least one of ~ .
:: , Rl, R2 and R3 denotes a Cl 4 alkyl or a halo group, R4 .~ ~ denotes a hydrogen atom or a Cl 4 alkyl group and R5 ~ ~
deno~es an allyl group. : .
The invention also relates to a process for the preparation of ;: ::.
novel thiocarbamide derivatives of the general formula I
'.'' ~.
.:
R2 ~ C~ - NH - C - h \ (I)
3 ~ ~1 wherein Rl, R2 and R3 may stand for identical or different groups, and they :~
denote each a hydrogen atom, a Cl 8 straight or branched-chain, saturated or -~nsaturated alkyl, or dialkylaminoalkyl groups, alkyl substituted with one ~ 3 ~
. .
~69~3~ :
or more halogen atoms, further hydroxy, dialkylamino, or nitro groups, or halogen atoms; R4 denotes a hydrogen atom, a saturated or unsaturated straight ~;
or branched-chain Cl 8 alkyl or cycloalkyl group which may be substituted with ~-a hydroxyl group; R5 denotes a C2 6 straight or branched-chain hydroxyalkyl group or a C3 6 straight or branched-chain unsaturated alkyl group; R6 denotes a hydrogen atom, a straight or branched-chain saturated or unsaturated C
alkyl group which may be substituted with a hydroxyl group or with one or more halogen atoms, or a C3 6 cycloalkyl group, with the proviso that R6 must have .
a meaning o~her than hydrogen atom when Rl, R2, R3 and R4 each denote a hydro- ~ ,r gen atom and R5 stands for a 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl ~ -or l,l-dimethyl-2-hydroxyethyl group; or when R2, R3 and R4 each denote a , hydrogen atom, R5 denotes a 2-hydroxyethyl group, and Rl denotes a 2-chloro,
denote each a hydrogen atom, a Cl 8 straight or branched-chain, saturated or -~nsaturated alkyl, or dialkylaminoalkyl groups, alkyl substituted with one ~ 3 ~
. .
~69~3~ :
or more halogen atoms, further hydroxy, dialkylamino, or nitro groups, or halogen atoms; R4 denotes a hydrogen atom, a saturated or unsaturated straight ~;
or branched-chain Cl 8 alkyl or cycloalkyl group which may be substituted with ~-a hydroxyl group; R5 denotes a C2 6 straight or branched-chain hydroxyalkyl group or a C3 6 straight or branched-chain unsaturated alkyl group; R6 denotes a hydrogen atom, a straight or branched-chain saturated or unsaturated C
alkyl group which may be substituted with a hydroxyl group or with one or more halogen atoms, or a C3 6 cycloalkyl group, with the proviso that R6 must have .
a meaning o~her than hydrogen atom when Rl, R2, R3 and R4 each denote a hydro- ~ ,r gen atom and R5 stands for a 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl ~ -or l,l-dimethyl-2-hydroxyethyl group; or when R2, R3 and R4 each denote a , hydrogen atom, R5 denotes a 2-hydroxyethyl group, and Rl denotes a 2-chloro,
4-chloro, 4-bromo or 2-methyl group; or when Rl denotes a 4-bromo group, R2 R3 and R4 each denote a hydrogen atom, and R5 stands for a 4-hydroxybutyl group; or when Rl denotes a 2-methyl group, R2 a 4-methyl or 5-methyl group, R3 and R4 each stand for a hydrogen atom, and R5 is a 2-hydroxyethyl group;
or when Rl denotes a 2-methoxy group, R2 a 4-hydroxy group, R3 and R4 each a ::
hydrogen atom, and R5 a 2-hydroxyethyl group; or when Rl, R2 and R3 each ~:
denote a hydrogen atom, R5 denotes a 2-hydroxyethyl group, and R4 stands for a 2-hydroxyethyl or 2-methylpropyl group, ~dR6 must have a meaning other than `;
hydrogen atom when at ieast one o Rl, R2 and R3 denotes a Cl 4 alkyl or a halo group, R4 denotes a hydrogen atom or a Cl 4 alkyl group and R5 denotes an allyl group, characterized in that `
a) an isothiocyanate of the general formula II ~ `
2 ~ CH - N = C = S (II) 6 ; ;
3 :
wherein Rl, R2, R3 and R6 have the above-specified meanings, is reacted with an amine of the general formula III -.
~ :. ,; ~ - 3a - ::
" ., .~ .., .. " ., . . " ;"" . ....
~9~3~
\ (III) wherein R4 and R5 have the above-specified meanings, in a melt or in an inert -solvent, or bl) a compound of the general formula IV
' ~;
2~fH - NH - C \ (IV) wherein Rl, R2, R3 and R6 have the above-specified meanings, whereas Q de- ;~
notes an -SR7 group, wherein R7 denotes a short-chain alkyl, an aryl or an aralkyl group, is reacted with an amine of the general formula III, wherein R4 and R5 have the above-specified meanings, in a melt or in an inert solvent, or b2) a compound of the general formula IV, wherein Rl, R2, R3 and R6 have the above-specifiefd meanings, whereas Q denotes a halogen atom, is - ;
reacted with an amine of the general formula III, wherein R4 and R5 have the . .. .
above-specified meanings, in a melt or in an inert solvent, or b3) a compound of the general formula IV, wherein Rl, R2, R3 and R6 have the above-specified meanings, whereas Q denotes an SH group is re-acted with an amine of the general formula III, wherein R4 and R5 have the above-specified meanings, and then melting the obtained salt, optionally in the presence of an inert solvent.
According to the above statements the ;
~2 ~ CH -group may denote e.g. a benzyl, a 2-methylbenzyl, a 3-methylbenzyl, a 4-methylbenzyl, a 2,3-dimethylbenzyl, a 2,4-di-- 3b ~6~3~ `:
methylbenzyl, a 2~5-dimethylbenzyl, a 2,6-dimethylbenzyl, a 2-trifluoromethylbenzyl~ a 3-trifluoromethylbenzyl7 a `~
4-trifluoromethylbenzyl, a 4-methoxybenzyl, a 3J4-dimethoxy-benzyl9 a 2-fluorobenzyl, a 3-fluorobenzyl, a 4-fluorobenzyl~
S a 2-chlorobenzyl, a 3-chlorobenzyl, a 4-chlorobenæyl, a 3,4~dichlorobenzyl~ a l-phenylethyl, a 1~(4-octylphenyl)-ethyl, a 1-(4-methoxyphenyl)-ethyl, a 1-(2-fluorophenyl)-ethyl~ a 1-(3-fluorophenyl)-ethyl~ a 1-(4-fluorophenyl)-~: ,.,.:
ethyl, a l-phenylpropyl, a l~phenyl-2-methylpropyl, a l-phenylbutyl, a l-phenyloctyl~ a phenyl-cyclopropylmethyl, a phenyl-cyclohexylmethyl and similar groups, wher~s the group R
'`' : ~ ' R
may denote e.g. a 2-hydroxyethylamino, a 2-hydroxypropyl~
amino~ a 3-hydroxypropylamino9 a 2-methyl-3-hydroxypropyl-amino, a 4~hydroxybutylamino, ~n allylamino, a 2-methyl-allylamino~ a N-methyl-N~(2-hydroxyethyl)-amino~ a M-ethyl- ~
N-(2-hydroxyethyl)-amino, a N-butyl-N-~2-hydroxyethylamino, ~ -a N cyclohexyl~N-(2-hydroxyethyl)-amino, a N-methyl-N_ (3-hydroxypropyl)-amino and similar groups.
- According to the above~given definition the group of ~ -~
compounds of the general formula I embraces also the possible stereoisomers and their mixtures.
Only a few repr~sentatives of the compounds of the general formula I are known in literature, such as l-benzyl 3-(2-hydroxyethyl)-thiocarbamide (Bull. Soc. Chim.
France 5, 960 /1960); 1-(2-chlorobenzyl)~3-(2-hydroxyethyl)-thiocarbamide9 1~(4-chlorobenzyl)-3-(2-hydroxyethyl)-thio-., ~, , ~4~
~L~6~3193~L
carbamide, 1-(2~methylbenzyl)-3-(2-hydroxyethyl)-thio~
carbamide, 1-(2,4-dimethylbenzyl)-3-(2-hydroxy~thyl)-thio-carbamide~ l-)2~5-dimethylbenæyl) 3-(2-hydroxyethyl)-thio-carbamide (JO Indian Chem. Soc, 37~ 705 /1960); 1-~4-bromo- ~`
benzyl)-3.(2-hydroxyethyl)-thiocarbamide (Helv. Chim. Acta 48~ 1069 /1965); 1-(2-methoxy-4~hydroxybenzyl)-3-(2-hydroxyethyl)-thiocarbamide (Japanese Patent Appl. No.
7~0179524~ Dec. 24~ 1966); l~benzyl-3-(3-hydroxypropyl)-thiocarbamide (Acta Chem. Sc~nd. 12, 1746-58 l1958/); l-benzyl-3-(4~hydroxybutyl)~thiocarbamide, 1-(4-bromobenzyl)-3-(4~
hydroxybutyl)-thiocarbamide (Helv. Chim. Acta 49, 807 /1966);
l-benzyl-3-(2-methylpropyl)-3-(2-hydroxyethyl)~thiocarbamide, l-benzyl-3~bis-(2-hydroxyethyl)-thiocarbamide, and l-benzyl-3~ 1-dimethyl-2-hydroxyethyl)-thiocarbamide - ;
(Helv. Chim. Acta 48, 1069 /1965).
~": ' ' ' In the literature no reference to any favourable ~ ;
physiological effects of these known compounds can be found.
Now it has been found~ however, that certain representa- ~-~
tives of the compounds of the general for~ula I exhibit very favourable diuretic and saluretic effects appearing even when administered in small doses, whereas other rep~
resentatlves show blood-pressure lowering, analgesic or antidepressant effects at a low toxicity.
Of the compounds of the general formula I mainly the 1-(4-chlorobenzyl)-3-(3-hydroxypropyl)-thiorarbamide, 1-(4-fluorobenzyl)-3 methyl-3-(2-hydroxyethyl)-thiocarbamide~
4-chlorobenzyl)-3-methyl-3-(2-hydroxyethyl)-thioc2rbamide and 1-(4-trifluoromethylbenzyl)~3~methyl~3-(2-hydroxyethyl)-thiocarbamide showed durable blood-pressure lowering effects 3~ ~
,, ~;, of 20 to 40 % lasting for more than 90 minutes~ when ad-ministered either intravenouslg or intraduodenal in very low doses from 0.1 to 1 mg/kg.
The diuretic and saluretic effects of the compounds of Z 5 the general fonmula I are listed in Table II. The Lipschnitz method (J. Pharmacol. Ther~ 79, 97-110 /1943/) as modified by Kagawa, C~M. and Kalm~ J. (Arch. Int. Pharmacodyn. 137, 241-249 /1962/) was applied~
The analgesic effect of the compounds of the general~-~
formula I is presented in Table IIIJ The used methods were as follows: Z~
Writhing test(Witkin, L.B. et al.: J~ Pharm. exp. Ther. `
: . . .
133~ 400-408 /1961/)~ on mice;
hot-plate test (Porsza'sz~ J. et alD: Acta physiol.
:. :
Acad. Sci. ~ung~ 4~ 107-113 /1953~), on mice;
Randall-Sellito test (Randall~ LØ and Sellito~ J.:
Arch~ Int. Pharmacodyn. 111, 409-419 /1957/), on rats.
The antidepresssnt effect of the compounds of the general formula I is shown in Table IV. The applied method was that of Berly No Askew (Life Sci. 10, 725 /1963/).
In addition to the applications mentioned above, the compounds of the general fonmula I can be used also for the preparation of other therapeutically valuable thiazoline, thiazolidine, thiazine, thiazepine or thiazocine derivatives. ~
The compounds of the general formula I according to the -;
present in~ention can be prepared by the following methods: ~
a) reacting an isothiocyanate of the general fonmula II ~ -Z
R2 ~ ~ CH - N = C - S
', .,~" ' ' ~06~93~
wherein Rlg R29 R3 and R6 have the above meanings, with ;~ :
an amine of the general fonmula III ;~
/ R4 ;~
HN (III) ~
\ R :
wherein R4 and ~5 have the above meanings9 in a melt or in an inert solvent, or bl) reacting a compound of the general form~la IV
R~
R2 ~ CH - NH~C (IV) : R3 R6 Q
wherein Rl, R2, R3 and R6 have the above-specified meanings~
whereas Q denotes an -SR7 group, wherein R7 denotes a shor~-chain alkyl~ an aryl or an aralkyl group, with an amine of ; the general formula III, wherein R4 and R5 have the above meanings, in a melt or in an inert solvent, or `.
: b2) reacting a compound of the general formula IY, ~0 wherein Rl, R2, R3 and R6 have the abo~eOspecified meanings~ whereas Q denotes a halogen atom~ with an amine of the general formula III, wherein R4 and R5 have the -above meanings~ in a melt or in an inert solvent, or ) reacting a compound of the general formula IV~
wherein Rl, R2, R3 and R6 have the above-specified meanings, whereas Q denotes an SH group, with an amine of ~`:
' t~
the general formula III, wherein R4 and R5 have the above~ ~`
specified meanings, and then melting the obtained salt, ~ optionally in the presence of an inert solvent.
:` 30 Chlorofonm, dichloroethane 9 tetrachloromethane or ~ J
,. .
;' .
~6993~
benzene may be preerably applied as inert solvent.
Isothiocyanates of the general fonmula II are partly known from literature and partly they can be prepared by known methods (Org. SynthO Coll. Vol. 1~ 2nd edition~
p. 447, John Wiley and Sons Inc., New York, 1948; Chem.
Ber. 101, 1746 /1968/).
Secondary amines of the general fo~mula III are mostly known from literature or they can be prepared by known methods (Houben-Weyl: Methoden der organischen CheMie~
Vol. XI/l~ pp. 24~ 267 and 10057 Georg Thieme Verlag, Stuttgart~ 1957)~
Dithiocarbamic esters of the general fonmula IV
(Q ~ SR7) are partly know~ from literature or they can be : `
prepared by known methods (Canadian Patent specification No. 317,244; UOS~ patent specifications Nos. 2,997,382 and 3~2113711; Czecho-Slovak patent specification No. 133~718).
Thiocarbamic acid halogenides of the ~eneral-fonmula IV (Q = halogen3~are partly known from literature or they can be prepared by known methods (Chem. Rev. 55~ 193 ` 20 /1955/). -~
~- Dithiocarbamic acids of the general formula IV ~ -(Q = SH) are readily formed from the corresponding amine ~
and carbon disulphide in an inert solvent (Chem. Rev. 55~ ~;
189 /1955/), and their salts with inorganic or organic ~ ;
bases can be well identified.
The ne~ compounds according to the in~ention and their method of preparation are further illustrated by the following non~limiting Examples.
~0~93~
1~(4-Fluorobenzyl)-3-(2-hydroxyethyl)-thiocarbamide a) The solution oE 12.6 g. (0.0766 moles) of 4-fluoro- -benzyl isothiocyanate in 100 ml. of chloroform is dropwise ;~
added under stirring and ice-cooling to the soLution of 4.88 gO (0.08 mcles) of ethanolamine in S0 ml. of chloro- ;~
form. The reaction mixture is refluxed for an hour, then the solvent distilled off under vacuum~ affording 17.45 g.
~100 %) of yellow, honey-like 1-(4-fluorobenzyl)-3-(2-hydroxy-; 10 ethyl)-thiocarbamide which crystallizes on standing. After recrystallizing the product from a 1:1 mixture of ethyl acetate and cyclohexane~ its m.p. is 58-60 C.
b) The mixture of 21.;5 g. (0.1 moles) of methyl-N-(4-fluvrobenzyl)-dithiocarbamate and 12.2 g. (0.2 moles) of ethanolamine is melted for 3 hours at 80 C. During the ~; reaction, methyl mercaptan is liberated from the mixture~
Excess ethanolamine is removed from the reactlon mixture by distillation under vacuum, then the residual honey-like product (22.8 g.~ 100 %3 is recrystallized from a 1:1 mixture : .
of ethyl acetate and cyclohexane. The product melting at 58-60 C is identical with that obtained in Example la.
; c) The solution of 21.5 g. (0.1 moles) of methyl-N-(4-fluorobenzyl)-dithiocarbamate and 7032 g. (0.12 moles) of ethanolamine in 40 ml of isopropanol ls boiled for 3 hours. ~
Meanwhile methyl mercaptan is liberated from the reaction 3 mixture. Isopropanol together with ethanolamine applied in excess is removed from the reaction mixture by vacuum :: .
distillation, then the residual honey-like product (22.8 g 100 %) is recrystallized from a lol mixture of ethyl acetate and cyclohexane. The product (m.p. 58-60 C) is . . . .
~al6~3~
identical with that obtained in Example la~
d) One proceeds in the way specified in Example lc~
~ith the difference that boiling is carried out in chlorofcrm, instead of isopropanol. The obtained honey~
like product (22.8 g.~ 100 %) is re~rystalllzed from a 1:1 mixture of ethyl acetate and cyclohexane~ affording a --compound melting at 58~60 C. The produrt is iden~ical -~
with that prepared according to Example la.
e) One proceeds in the way as specified in Example lc~ `
with the difference that boiling is carried out in dloxane~
instead of isopropanolO The obtained honey-like product ~ -(22.ô g~, 100 %) when recrystalli~ed from a 1:1 mixture of e~hyl acetate ~nd cyclohexane, melts at 58~60 C. Ihe `
product is identical with that obtained in Example la.
f) To a solution of 3.13 g. (0.025 moles) of 4-fluoro-benzylamine in 25 ml. of anhydrous ethanol, 3~02 ml.
(0.05 moles) of carbon disulphide are dropwise added at O C under stirring and cooling with salted ice. The reaction mi*ture is stirred for half an hour below O C, then at the same temperature 2539 ml. (0.0~5 moles) of ethanolamine are dropwise added and the mixture is stirred for another half an hour a~ O CO The ethanol applied as ~ ~`
solvent is removed fxom the reaction mixture9 together with excess carbon disulphide, by distillation, then the residual `~
honey-like salt is heated for an hour on a 140 C oil bath.
Meanwhile hydrogen sulphide is beiag liberated from the reaction mixture~ On cooling, the obtained honey-like ; product is dissolved in 50 ml of benzeae~ shaken with 3 x 50 ml~ of water, dried, and evaporated to dry~ess under vacuum~ affording 4.85 g. (85 %) of honey-like 1-~4~fluoro-~L6169~31 benzyl)-3 (2-hydroxyethyl)-thiocarbamide. Recrystallization of ~he product from a 1:1 mixture of ethyl acetate and oyclohexane gives a product melting at 57-60 C~ me product is identical with that obtained in Example la.
~ Phenylbutyl)-3-methy1-3-(2-hydroxyethyl)-thio~
carbamide a) Th solution of 23.3 g. (0.15 moles) of l-phenyl-butyl isothiocyanate in 100 ml. of dirhloroethane is drop-wise added~ under stirring and ice-cooling~ to the solution o 12.0 g. (0.16 moles) of 2-methylaminoethanol in 50 ml.
of dlchloroethane. l~e reaction mixture is refluxed for an hour~ then the solvent is evaporated under vacuum~
affording 39.9 g~ (100 %) of honey-like l-(l-phenylbutyl)-~ 15 3-methyl~3-(2-hydroxyethyl)_thiocarbamide which crystallizes ; on standingO Recrystallization from ethyl acetate affords a product melting at 74-75 C. -~
b~ The solution of 14.9 gO (0.1 moles) of l-phenyl-butylamine and 17.2 g. (0.15 moles) of thiophosgene in 100 ml~ of anhydrous 1~2-dichloroethane is stirred for 4 hours at room temperature~ then the reaction mixture is ~; evaporated to dryness under ~acuum. The obtained N~
phenylbutyl)~thiocarbamic acid chloride is dissolved in 50 ml. of anhydrous benzene. The solution is filtered, then ~-` 25 the fil~rate is dropwise added slowly, under stirring, - ~
to a solution of 16.5 g. (0~22 moles) of 2-methylaminoethanol - -in 100 ml~ of benzene. me reaotion mixture is refluxed for 4 hours~ then allowed to cool~ and treated with 100 ml.
of water. The phases are separated. The benzene solution is shaken with 2 x 100 ml. of water~ dried~ and evaporated ~69~131 :: ~
`.'. ., to dryness under vacuum. In this way 25~5 g. t95.7 2) oE ;~
a crude honey-like product are obtained which crystallize on standing. When recrystalli~ed from ethyl acetate the product melts at 74-75 C, and is completely identical with the compound obtained in Example 2a.
When applying the methods specified in Example 1 and 2~ also other compounds of the general formula I listed in Table I can be prepared.
'.";
'"`''"' ... ' !
`' '' `~ '.
, '. '~
-12- ~ ~
6~ 9 3 Table I
Number M . p .
of C o m p o u n d C ~ x/
Example _ _ f ~; :
3 ~ 1 (1-Phenylethyl)-3~(2-hydroxyethyl)--thiocarbamide ~ 94-96 -4 ~ 1~ Phenylpropyl)-3-(2-hydroxyethyl)~ :
~thiocarbamide 97 98 ~ 1~ Phenyl-2-methylpropyl)-3--(2-hydroxyethyl)-thiocarbamide 73-75 :~
6 ~ 1-~1 Phenylbutyl)~3 (2-hydroxyethyl)--thiocarbamide 95-96 7 ~ 1-(1-Phenyloctyl)-3-(2-hydroxyethyl)- ~ -~thiocarbamide 82-85 8 ~ l-(l-Phenyl-l-cyclopropylmethyl)--3-(2-hydroxyethyl)-thiocarbamide 97-98.5 9 ~ 1~(1-Phenyl-l-cyclohexylmethyl)-3- honey-like -(2-hydroxyethyl)-thiocarbamide substance 0.45 .
1-(3,4-Dimethoxybenzyl)-3-(2-hydroxy ethyl)-thiocarbamide 115-117 11 + 1-Ll-(4-~Methoxyphenyl)-ethyl~-3-~(2-hydroxyethyl)-thiocarbamide 84-87 12 1-(2,6~Dimethylbenzyl)--3-(2-hydroxy-ethyl)-thiocarbamide 162-164 :~
13 ~ 1-Ll-(4-Octylphenyl)-ethyl~-3- .
-(2-hydroxyethyl)-thiocarbamide 41-43.5 14 1-(2-Fluorobenzyl)-3-(2-hydroxyethyl)- ` ;
-thlocarbamlde 109-110 :
1-(3-Fluorobenzyl)-3-(2-hydroxyethyl)-~thiocarbamide 92-94 16 1-(4-Fluorobenzyl)-3-(2-hydroxyethyl)--thiocarbamide 59-61 17 1--(3,4-Dichlorobenzyl)-3-(2-hydroxy-ethyl)-thlocarbamide 91.5-92.5 -.
18 1-(2-Trifluoromethylbenzyl)-3- :.
-(2-hydroxyethyl)-thiocarbamide 88~90 ,:, -13- `
, , ~L~6~93~
-14~
~ , . .
Table I (continued) Number C o m p o u n d M.p. -C ~f x/
Example :
19 1-(3-Trifluoromethylbenzyl)-3--(2-hydroxyethyl)-thiocarbamide 48-50 1-(4-Trifluoromethylbenzyl)-3~
-~(2-hydroxyethyl)~thiocarbamide 80-84 21 ~ 1-tl-Phenylethyl)~3-(3-hydroxypropyl)--thiocarbamide 129-131 22 1-~1-(2-Fluorophenyl)-ethy~ -3--(2-hydroxyethyl)-thioGarbamide 103-105.5 23 1-~ (3-Fluorophenyl)-ethy ~ -3- honey-like -(2-hydroxyethyl)-thiocarbamide substance 0.25 :
23a 1-Ll-(4-Fluorophenyl)-ethyl3-3--(2-hydroxyethyl)-thiocarbamide 91.5-92 24 1~ Phenyl-2,2,2-tri~luoroethyl)-~ -3-(2-hydroxyethyl)-thiocarbamide 115-116.5 1 25 ~ 1-(1-Phenylpropyl)-3-(3-hydroxypropyl)-~ -thiocarbamide 120.5-122 : ., 26 ~ 1-(1-Phenyl-2-methylpropyl)-3--(3-hydroxypropyl)-thiocarbamide 108-110 27 1-(3,4-Dimethoxybenzyl)-3-(3-hydroxy--; propyl)-thiocarbamide 70-73 28 ~rl-~1-(4-Methoxyphenyl)-ethy~ -3- ~-`
` -(2-hydroxyethyl)-thiocarbamide 117-118 ;~
29 1-(2-Fluorobenzyl)-3-(3-hydroxy-; propyl)-thiocarbamide 100-102 1-(3-Fluorobenzyl)-3-(3 hydroxy-propyl)-thiocarbamide 99-100.5 ;
31 1-(4-Fluorobenzyl)-3-(3-hydroxy-~
i propyl)-thiocarbamide 117-119 32 1-(4-Chlorobenzyl)-3-(3-hydroxy propyl)-thiocarbamlde 124-125.5 33 1-(3,4-Vichlorobenzyl)-3-(3-hydroxy-propyl)-thiocarbamide 128.5-130.5 ` :
~: , ,..-~.
~ : ' ~6g93~L
:
Table I (continued) Number No.p. R x/
of Compound C f Example 34 1-Benzyl~3_m~thyl-3-(2-hydroxy-ethyl)-thiocarbamide 54-56 ~ Phenylethyl)~3-methyl-3- honey-like ~(2-hydroxyethyl)-thiocarbamide substance 0.51 36+ 1-(1-Phenylpropyl)-3-methyl-3- ~;
_(2-hydroxyethyl)-thiocarbamide 80 82 37+ 1-(l~Phenyl-2-methylpropyl)-3-methyl- ;
-3_(2-hydroxyethyl)-thiocarbamide 71-76 ;~
38+ 1-(1-Phenylbutyl)-3~methyl-3--(2-hydroxyethyl)-thiocarbamide 74-75 391~ Phenyloctyl)-3-methyl-3--(2-hydroxyethyl)-thiocarbamide 72-73.5 40~ 1-(1-Phenyl-l-cyclopropylmethyl~-3- ` -_methyl-3-(2~hydroxyethyl)~
_thiocarbamide 114-116 41l-(394-Dimethoxybenzyl)-3-methyl~
-3-(2-hydroxyethyl)-thiocarbamide 89-91 42~ 1~ (4~Nethoxyphenyl)-ethyl7-3--methyl-3-(2-hydroxyethyl~
_thiocarbamide 62-65 431-(2-Nethylbenzyl~-3-methyl-3--(2-hydroxyethyl)-thiocarbamide 74-76 441-(2~6-Dimethylbenzyl)-3-methyl-3--(2-hydroxyethyl)-thiocarbamide 120-121.5 451-Ll-(4~0ctylphenyl)-ethyl/-3-methyl--3-(2-hydroxyethyl)-thiocarbamide 52-55 ., 461-(2-Fluorobenzyl)-3-methyl-3--(2-hydroxyethyl)-thiocarbamide 63-65 471~(3-Fluorobenzyl)-3-methyl-3 ~(2-hydroxyethyl)-thiocarbamide 61-63 481-(4-Fluorobenzyl)-3-methyl-3 -(2-hydroxyethyl)-thiocarbamide 103-105 . . ~
::
3L~6~931 ;. -Table I (continued Number M~po R x/
of Compound C f/
Example 491-(2-Chlorobenzyl~-3-methyl-3- honey-like -(2~hydroxyethyl~ thiocarbamide substance 0~40 : :.
501-(4-Chlorobenzyl~-3-methyl-3- ~
-(2-hydroxyethyl)-thiocarbamide 147-148 .
511-(3~4~Dichloxobenzyl)-3-methyl-3 -(2-hydroxyethyl)-thiocarbamide 104-106 ;
521-(2-Trifluoromethylben~.yl)-3-methyl- ;
-3-(2-hydroxyethyl)-thiocarbamide 93-94.5 531-(3-Trifluoromethylbenzyl)-3-methyl--3-(2-hydroxyethyl)-thiocarbamide 78-80 ;
541-(4-Dimethylaminobenzyl)-3-methyl-3_ ::
-(2-hydroxyethyl)-thiocarbamide 108-110 551-(4-Nitrobenzyl)-3-methyl~-3--(2-hydroxyethyl)~thiocarbamide 135-13~.5 56 1-(4-Fluorophenylethyl)-3-methyl-3- honey-like -(2-hydroxyethyl)-thiocarbamide substance 0.88 57l-(l-Phenyl-2j292-trifluoroethyl)-3-. ~
~methyl-3-(2-hydroxyethyl~-thio- ~:
carbamide 107-110 :~
S81-(4-Trifluoromekhylbenzyl)-3-methy~
-3-(2~hydroxyethyl)-thiocarbamide 91~92 S9~ 1-(l~Phenyl-2-methylpropyl)-3-ethyl~
-3-~2 hydroxyethyl)-thiocarbamide 82-84 + 1-(1-Phenyl-2-methylpropyl)-3-butyl- honey-like -3-(2~hydroxyethyl)-thiocarbamide substance 0.71 61+ 1-(1-Phenylethyl)-3~cyclohexyl-3- ~--2_hydroxyethyl)-thiocarbamide 89-90.5 62+ 1-(1-Phenylethyl)-3~3-bis- ~ .
-(2-hydroxyethyl~-thiscarbamide 67-69 :.
63+ 1-(1-Phenylethyl)-3-allyl-thlo-carbamLde 56-59 ;
;
_ 16 -~6993'~
-17- ~.
Table I (continued) Number C o m p o u n d M.p. x/ "~
Example C Rf s , ::
64 ~ 1-(1-Phenylpropyl)-3-allyl- honey-like -thiocarbamide substance 0.75 1-(2-Fluorobenzyl)-3-allyl- ~ i -thiocarbamide 50-53 ;
66 1-(4-Fluorobenzyl)-3-allyl- honey-like -thiocarbamide substance o.68 ~, :~
67 1-(3,4-Dimethoxybenzyl)-3-allyl- --thiocarbamide 117-119 ;i 68 t 1-(1-Phenylpropyl)-3-(2-methyl-allyl)-thiocarbamide 68-69 - -x/ R~ values are given in a 6:1 mi.xture of benzene and pyridine. The determination was carried out on a thin (0.1-0.2 mm~) layer o~ silica gel tMerck).
.:
'~: .' .
.,. ,~
;~ "` ~
-: :::
.: ::
, '.. ' :
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: :
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: , ' 11 ~69~33~
` ~
~ . .
-'~
.:
~ ,, o o ~ o I~ I~ oo ~ O a~ ~ ~ o o o o o ~ _~o o o o _~ u a : :
2; C~
I V
0 ~ ~,.
n1 a~ x ~ u~ ou~
~: ~ ~ ~ ~ ~
O ~1 I~C ~ C~ l V ~I N
~_~ ` ~ a~ ", ~a ~ _~ ~
_l I ~ x ~ ~ ~ ~ o o a~ o) O ,~, ' ''':
~ ~ ~ ~ _I ~ 00 r~ ~ ~ o ~ o o o ~ ~ ~ ~ v 8 ~ ;: ~
~ ~ ~ ~ ~ ~ O
a) + ~ ~ o u) u~ I
1~ u~ ~ ~ o o o _1 _1 ~ CU~ ~o ~0 _1 ~1 c~l CO ~ CO u~O C~
J ~ + 117 O` C~` O O u~I` O N1` .1 1~ ~
a~ ~oJ ~1 ~ ~ ~ ) o ~) ~ 1~ 0 0 C~ O~ O O 1` U~ O
u~ o X ~ O. `~
O ~ o o ~ O) -I '', ' 1~ ~ ~ ~ N ~ ~1 .X ~ ~ `
" ~ ~ a) L~. ,.
:a. o o o o o o o o o l~ ~0 0 El U~\ oD ~ O O O O Na~ a~ ~ `;t J :~ O ~ `~
o t: ~ ~ oN U'~ O~ 1 O ~ ~ C~ 1 3 .1 U
~ 00 W _1 ~ ~ ~ ~ ~O ~ ~ ~ ~ ~ ~ ~ , ..
~ O ~ ~ U~ ~ ~ i3 `: ~ '.
.t.~ U
U ~ U
1~ ~ O t~ O ` '~',:
~ I ~ ~ o u~ a) o . "'~
_l ~ -~ O~
U~ ~ ,~ U~ O
~ P~ u P~ J~ 8. ~ ~ JJ ~
~ ~ @ ~ ~ @ ~ ~ @ ~ ~ @ ~ ~ ~ o ~ ~ g ~ ~ ~
D ~ rq O
Q) ~ 1 O ~ h0 ~ ~~i I U ~E~
)~ ~ .~ t 0 ::~ ~ ~ ~ ~) ~ 3 ~ V ~ ~ ,~
3 ~ rl 3 ~ rl I '`J rl S4 N ~ E~ .C ~ :
O
~ ~ ~ u _ ~ u ~ ~ u ~ ~
Eol I t i ~ I ~ UI ~ I I I I D Q~ ~ CO :~ :
~ + + ~ ~ , .
~' :: ' ~ ..,, `
:~
- 1 8_ 3~
Table III
Analgesic effect ol some compounds o~ the general formula I, on mice and ra~s Compound Writhing test Hot plate Randall-Sellito test test ED50 mg/kg ED50 mg/kg s~imulation threshold + l-(Phenylethyl)-3- 3-10, oral 10-30, oral 200 mg/kg oral: 198 %
-~2-hydroxyethyl~- , lO0 mg/kg oral: 78 %
-thiocarbamide S0 mg/kg oral: 56 %
+ l-(Phenylpropyl)-3- 3-10, oral 10-30, oral 200 mg/kg oral: 593 % - ;;
-~2-hydroxyethyl)- 100 mg/kg oral: 199 %
-thiocarbamide 50 mg/kg oral: 103 %
+ l-~Phenyl, cyclopropyl)--methyl-3-~2-hydroxy-ethyl)-thiocarbamide 10-30, i.p. -- - - `
+ l-(l-Phenylethyl)-3- 10-30, oral 10-30, oral 200 mg/kg oral: 88 %
-methyl-3-(2-hydroxy- 100 mg/kg oral: 24 %
et~yl)-thiocarbamide 50 mg/kg oral: 5 %
Morphine 1.65 s.c. 2.50 s~c. 10 mg/kg s.c.: lO00 %
3 mg/kg s.c.: 90 %
1 mg/kg s.c.: 9 %
Propoxyphene 22.5 oral 70, oral100 mg/kg oral: 1000 %
( -(~)-1,2-dlphenyl- 30 mg/kg oral: 534 %
-3-methyl-2-propio- 10 mg/kg oral: 33 % ` ~;
n~loxy-4-dimethyl-aminobutane) Amidazophene 180 oral 60, oral200 mg/kg oral: 100 %
C l-Phenyl-2,3- 100 mg/kg oral: 69 %
-dimethyl-5- 50 mg/kg oral: 8 %
-~Yrazolone) :
; ':.
~C16~D3~ -~
Table IV
Antidepressant effect of some compounds of the general formula I on mice Antagonization of the temperature~
lowering action of reserpine C o m p o u n d Dose Change in rectal ~
TempeOrature :,' mgtkg ' C : '' + 1-(2-Fluorobenzyl)-3--(2-hydroxyethyl)--thiocarbamide 30 + 3.4 :~
Phenylethyl)D3_ ~ ;
-methyl-3-(2-hydroxy-ethyl~-thiocarbamide 30 + 3.5 + l-(l-Phenylpropyl-3~
-methyl-3-~2-hydroxy-ethyl)-thiocarbamide 30 + 3.8 + 1-(4-Fluorobenzyl)-3-, -allyl-thiocarbamide 30 ~ 3.8 .
" :
,. :;
: : .~
..
;
:: ::;
~ .
:; :
~.
.` ' :
''~, -20- ~
or when Rl denotes a 2-methoxy group, R2 a 4-hydroxy group, R3 and R4 each a ::
hydrogen atom, and R5 a 2-hydroxyethyl group; or when Rl, R2 and R3 each ~:
denote a hydrogen atom, R5 denotes a 2-hydroxyethyl group, and R4 stands for a 2-hydroxyethyl or 2-methylpropyl group, ~dR6 must have a meaning other than `;
hydrogen atom when at ieast one o Rl, R2 and R3 denotes a Cl 4 alkyl or a halo group, R4 denotes a hydrogen atom or a Cl 4 alkyl group and R5 denotes an allyl group, characterized in that `
a) an isothiocyanate of the general formula II ~ `
2 ~ CH - N = C = S (II) 6 ; ;
3 :
wherein Rl, R2, R3 and R6 have the above-specified meanings, is reacted with an amine of the general formula III -.
~ :. ,; ~ - 3a - ::
" ., .~ .., .. " ., . . " ;"" . ....
~9~3~
\ (III) wherein R4 and R5 have the above-specified meanings, in a melt or in an inert -solvent, or bl) a compound of the general formula IV
' ~;
2~fH - NH - C \ (IV) wherein Rl, R2, R3 and R6 have the above-specified meanings, whereas Q de- ;~
notes an -SR7 group, wherein R7 denotes a short-chain alkyl, an aryl or an aralkyl group, is reacted with an amine of the general formula III, wherein R4 and R5 have the above-specified meanings, in a melt or in an inert solvent, or b2) a compound of the general formula IV, wherein Rl, R2, R3 and R6 have the above-specifiefd meanings, whereas Q denotes a halogen atom, is - ;
reacted with an amine of the general formula III, wherein R4 and R5 have the . .. .
above-specified meanings, in a melt or in an inert solvent, or b3) a compound of the general formula IV, wherein Rl, R2, R3 and R6 have the above-specified meanings, whereas Q denotes an SH group is re-acted with an amine of the general formula III, wherein R4 and R5 have the above-specified meanings, and then melting the obtained salt, optionally in the presence of an inert solvent.
According to the above statements the ;
~2 ~ CH -group may denote e.g. a benzyl, a 2-methylbenzyl, a 3-methylbenzyl, a 4-methylbenzyl, a 2,3-dimethylbenzyl, a 2,4-di-- 3b ~6~3~ `:
methylbenzyl, a 2~5-dimethylbenzyl, a 2,6-dimethylbenzyl, a 2-trifluoromethylbenzyl~ a 3-trifluoromethylbenzyl7 a `~
4-trifluoromethylbenzyl, a 4-methoxybenzyl, a 3J4-dimethoxy-benzyl9 a 2-fluorobenzyl, a 3-fluorobenzyl, a 4-fluorobenzyl~
S a 2-chlorobenzyl, a 3-chlorobenzyl, a 4-chlorobenæyl, a 3,4~dichlorobenzyl~ a l-phenylethyl, a 1~(4-octylphenyl)-ethyl, a 1-(4-methoxyphenyl)-ethyl, a 1-(2-fluorophenyl)-ethyl~ a 1-(3-fluorophenyl)-ethyl~ a 1-(4-fluorophenyl)-~: ,.,.:
ethyl, a l-phenylpropyl, a l~phenyl-2-methylpropyl, a l-phenylbutyl, a l-phenyloctyl~ a phenyl-cyclopropylmethyl, a phenyl-cyclohexylmethyl and similar groups, wher~s the group R
'`' : ~ ' R
may denote e.g. a 2-hydroxyethylamino, a 2-hydroxypropyl~
amino~ a 3-hydroxypropylamino9 a 2-methyl-3-hydroxypropyl-amino, a 4~hydroxybutylamino, ~n allylamino, a 2-methyl-allylamino~ a N-methyl-N~(2-hydroxyethyl)-amino~ a M-ethyl- ~
N-(2-hydroxyethyl)-amino, a N-butyl-N-~2-hydroxyethylamino, ~ -a N cyclohexyl~N-(2-hydroxyethyl)-amino, a N-methyl-N_ (3-hydroxypropyl)-amino and similar groups.
- According to the above~given definition the group of ~ -~
compounds of the general formula I embraces also the possible stereoisomers and their mixtures.
Only a few repr~sentatives of the compounds of the general formula I are known in literature, such as l-benzyl 3-(2-hydroxyethyl)-thiocarbamide (Bull. Soc. Chim.
France 5, 960 /1960); 1-(2-chlorobenzyl)~3-(2-hydroxyethyl)-thiocarbamide9 1~(4-chlorobenzyl)-3-(2-hydroxyethyl)-thio-., ~, , ~4~
~L~6~3193~L
carbamide, 1-(2~methylbenzyl)-3-(2-hydroxyethyl)-thio~
carbamide, 1-(2,4-dimethylbenzyl)-3-(2-hydroxy~thyl)-thio-carbamide~ l-)2~5-dimethylbenæyl) 3-(2-hydroxyethyl)-thio-carbamide (JO Indian Chem. Soc, 37~ 705 /1960); 1-~4-bromo- ~`
benzyl)-3.(2-hydroxyethyl)-thiocarbamide (Helv. Chim. Acta 48~ 1069 /1965); 1-(2-methoxy-4~hydroxybenzyl)-3-(2-hydroxyethyl)-thiocarbamide (Japanese Patent Appl. No.
7~0179524~ Dec. 24~ 1966); l~benzyl-3-(3-hydroxypropyl)-thiocarbamide (Acta Chem. Sc~nd. 12, 1746-58 l1958/); l-benzyl-3-(4~hydroxybutyl)~thiocarbamide, 1-(4-bromobenzyl)-3-(4~
hydroxybutyl)-thiocarbamide (Helv. Chim. Acta 49, 807 /1966);
l-benzyl-3-(2-methylpropyl)-3-(2-hydroxyethyl)~thiocarbamide, l-benzyl-3~bis-(2-hydroxyethyl)-thiocarbamide, and l-benzyl-3~ 1-dimethyl-2-hydroxyethyl)-thiocarbamide - ;
(Helv. Chim. Acta 48, 1069 /1965).
~": ' ' ' In the literature no reference to any favourable ~ ;
physiological effects of these known compounds can be found.
Now it has been found~ however, that certain representa- ~-~
tives of the compounds of the general for~ula I exhibit very favourable diuretic and saluretic effects appearing even when administered in small doses, whereas other rep~
resentatlves show blood-pressure lowering, analgesic or antidepressant effects at a low toxicity.
Of the compounds of the general formula I mainly the 1-(4-chlorobenzyl)-3-(3-hydroxypropyl)-thiorarbamide, 1-(4-fluorobenzyl)-3 methyl-3-(2-hydroxyethyl)-thiocarbamide~
4-chlorobenzyl)-3-methyl-3-(2-hydroxyethyl)-thioc2rbamide and 1-(4-trifluoromethylbenzyl)~3~methyl~3-(2-hydroxyethyl)-thiocarbamide showed durable blood-pressure lowering effects 3~ ~
,, ~;, of 20 to 40 % lasting for more than 90 minutes~ when ad-ministered either intravenouslg or intraduodenal in very low doses from 0.1 to 1 mg/kg.
The diuretic and saluretic effects of the compounds of Z 5 the general fonmula I are listed in Table II. The Lipschnitz method (J. Pharmacol. Ther~ 79, 97-110 /1943/) as modified by Kagawa, C~M. and Kalm~ J. (Arch. Int. Pharmacodyn. 137, 241-249 /1962/) was applied~
The analgesic effect of the compounds of the general~-~
formula I is presented in Table IIIJ The used methods were as follows: Z~
Writhing test(Witkin, L.B. et al.: J~ Pharm. exp. Ther. `
: . . .
133~ 400-408 /1961/)~ on mice;
hot-plate test (Porsza'sz~ J. et alD: Acta physiol.
:. :
Acad. Sci. ~ung~ 4~ 107-113 /1953~), on mice;
Randall-Sellito test (Randall~ LØ and Sellito~ J.:
Arch~ Int. Pharmacodyn. 111, 409-419 /1957/), on rats.
The antidepresssnt effect of the compounds of the general formula I is shown in Table IV. The applied method was that of Berly No Askew (Life Sci. 10, 725 /1963/).
In addition to the applications mentioned above, the compounds of the general fonmula I can be used also for the preparation of other therapeutically valuable thiazoline, thiazolidine, thiazine, thiazepine or thiazocine derivatives. ~
The compounds of the general formula I according to the -;
present in~ention can be prepared by the following methods: ~
a) reacting an isothiocyanate of the general fonmula II ~ -Z
R2 ~ ~ CH - N = C - S
', .,~" ' ' ~06~93~
wherein Rlg R29 R3 and R6 have the above meanings, with ;~ :
an amine of the general fonmula III ;~
/ R4 ;~
HN (III) ~
\ R :
wherein R4 and ~5 have the above meanings9 in a melt or in an inert solvent, or bl) reacting a compound of the general form~la IV
R~
R2 ~ CH - NH~C (IV) : R3 R6 Q
wherein Rl, R2, R3 and R6 have the above-specified meanings~
whereas Q denotes an -SR7 group, wherein R7 denotes a shor~-chain alkyl~ an aryl or an aralkyl group, with an amine of ; the general formula III, wherein R4 and R5 have the above meanings, in a melt or in an inert solvent, or `.
: b2) reacting a compound of the general formula IY, ~0 wherein Rl, R2, R3 and R6 have the abo~eOspecified meanings~ whereas Q denotes a halogen atom~ with an amine of the general formula III, wherein R4 and R5 have the -above meanings~ in a melt or in an inert solvent, or ) reacting a compound of the general formula IV~
wherein Rl, R2, R3 and R6 have the above-specified meanings, whereas Q denotes an SH group, with an amine of ~`:
' t~
the general formula III, wherein R4 and R5 have the above~ ~`
specified meanings, and then melting the obtained salt, ~ optionally in the presence of an inert solvent.
:` 30 Chlorofonm, dichloroethane 9 tetrachloromethane or ~ J
,. .
;' .
~6993~
benzene may be preerably applied as inert solvent.
Isothiocyanates of the general fonmula II are partly known from literature and partly they can be prepared by known methods (Org. SynthO Coll. Vol. 1~ 2nd edition~
p. 447, John Wiley and Sons Inc., New York, 1948; Chem.
Ber. 101, 1746 /1968/).
Secondary amines of the general fo~mula III are mostly known from literature or they can be prepared by known methods (Houben-Weyl: Methoden der organischen CheMie~
Vol. XI/l~ pp. 24~ 267 and 10057 Georg Thieme Verlag, Stuttgart~ 1957)~
Dithiocarbamic esters of the general fonmula IV
(Q ~ SR7) are partly know~ from literature or they can be : `
prepared by known methods (Canadian Patent specification No. 317,244; UOS~ patent specifications Nos. 2,997,382 and 3~2113711; Czecho-Slovak patent specification No. 133~718).
Thiocarbamic acid halogenides of the ~eneral-fonmula IV (Q = halogen3~are partly known from literature or they can be prepared by known methods (Chem. Rev. 55~ 193 ` 20 /1955/). -~
~- Dithiocarbamic acids of the general formula IV ~ -(Q = SH) are readily formed from the corresponding amine ~
and carbon disulphide in an inert solvent (Chem. Rev. 55~ ~;
189 /1955/), and their salts with inorganic or organic ~ ;
bases can be well identified.
The ne~ compounds according to the in~ention and their method of preparation are further illustrated by the following non~limiting Examples.
~0~93~
1~(4-Fluorobenzyl)-3-(2-hydroxyethyl)-thiocarbamide a) The solution oE 12.6 g. (0.0766 moles) of 4-fluoro- -benzyl isothiocyanate in 100 ml. of chloroform is dropwise ;~
added under stirring and ice-cooling to the soLution of 4.88 gO (0.08 mcles) of ethanolamine in S0 ml. of chloro- ;~
form. The reaction mixture is refluxed for an hour, then the solvent distilled off under vacuum~ affording 17.45 g.
~100 %) of yellow, honey-like 1-(4-fluorobenzyl)-3-(2-hydroxy-; 10 ethyl)-thiocarbamide which crystallizes on standing. After recrystallizing the product from a 1:1 mixture of ethyl acetate and cyclohexane~ its m.p. is 58-60 C.
b) The mixture of 21.;5 g. (0.1 moles) of methyl-N-(4-fluvrobenzyl)-dithiocarbamate and 12.2 g. (0.2 moles) of ethanolamine is melted for 3 hours at 80 C. During the ~; reaction, methyl mercaptan is liberated from the mixture~
Excess ethanolamine is removed from the reactlon mixture by distillation under vacuum, then the residual honey-like product (22.8 g.~ 100 %3 is recrystallized from a 1:1 mixture : .
of ethyl acetate and cyclohexane. The product melting at 58-60 C is identical with that obtained in Example la.
; c) The solution of 21.5 g. (0.1 moles) of methyl-N-(4-fluorobenzyl)-dithiocarbamate and 7032 g. (0.12 moles) of ethanolamine in 40 ml of isopropanol ls boiled for 3 hours. ~
Meanwhile methyl mercaptan is liberated from the reaction 3 mixture. Isopropanol together with ethanolamine applied in excess is removed from the reaction mixture by vacuum :: .
distillation, then the residual honey-like product (22.8 g 100 %) is recrystallized from a lol mixture of ethyl acetate and cyclohexane. The product (m.p. 58-60 C) is . . . .
~al6~3~
identical with that obtained in Example la~
d) One proceeds in the way specified in Example lc~
~ith the difference that boiling is carried out in chlorofcrm, instead of isopropanol. The obtained honey~
like product (22.8 g.~ 100 %) is re~rystalllzed from a 1:1 mixture of ethyl acetate and cyclohexane~ affording a --compound melting at 58~60 C. The produrt is iden~ical -~
with that prepared according to Example la.
e) One proceeds in the way as specified in Example lc~ `
with the difference that boiling is carried out in dloxane~
instead of isopropanolO The obtained honey-like product ~ -(22.ô g~, 100 %) when recrystalli~ed from a 1:1 mixture of e~hyl acetate ~nd cyclohexane, melts at 58~60 C. Ihe `
product is identical with that obtained in Example la.
f) To a solution of 3.13 g. (0.025 moles) of 4-fluoro-benzylamine in 25 ml. of anhydrous ethanol, 3~02 ml.
(0.05 moles) of carbon disulphide are dropwise added at O C under stirring and cooling with salted ice. The reaction mi*ture is stirred for half an hour below O C, then at the same temperature 2539 ml. (0.0~5 moles) of ethanolamine are dropwise added and the mixture is stirred for another half an hour a~ O CO The ethanol applied as ~ ~`
solvent is removed fxom the reaction mixture9 together with excess carbon disulphide, by distillation, then the residual `~
honey-like salt is heated for an hour on a 140 C oil bath.
Meanwhile hydrogen sulphide is beiag liberated from the reaction mixture~ On cooling, the obtained honey-like ; product is dissolved in 50 ml of benzeae~ shaken with 3 x 50 ml~ of water, dried, and evaporated to dry~ess under vacuum~ affording 4.85 g. (85 %) of honey-like 1-~4~fluoro-~L6169~31 benzyl)-3 (2-hydroxyethyl)-thiocarbamide. Recrystallization of ~he product from a 1:1 mixture of ethyl acetate and oyclohexane gives a product melting at 57-60 C~ me product is identical with that obtained in Example la.
~ Phenylbutyl)-3-methy1-3-(2-hydroxyethyl)-thio~
carbamide a) Th solution of 23.3 g. (0.15 moles) of l-phenyl-butyl isothiocyanate in 100 ml. of dirhloroethane is drop-wise added~ under stirring and ice-cooling~ to the solution o 12.0 g. (0.16 moles) of 2-methylaminoethanol in 50 ml.
of dlchloroethane. l~e reaction mixture is refluxed for an hour~ then the solvent is evaporated under vacuum~
affording 39.9 g~ (100 %) of honey-like l-(l-phenylbutyl)-~ 15 3-methyl~3-(2-hydroxyethyl)_thiocarbamide which crystallizes ; on standingO Recrystallization from ethyl acetate affords a product melting at 74-75 C. -~
b~ The solution of 14.9 gO (0.1 moles) of l-phenyl-butylamine and 17.2 g. (0.15 moles) of thiophosgene in 100 ml~ of anhydrous 1~2-dichloroethane is stirred for 4 hours at room temperature~ then the reaction mixture is ~; evaporated to dryness under ~acuum. The obtained N~
phenylbutyl)~thiocarbamic acid chloride is dissolved in 50 ml. of anhydrous benzene. The solution is filtered, then ~-` 25 the fil~rate is dropwise added slowly, under stirring, - ~
to a solution of 16.5 g. (0~22 moles) of 2-methylaminoethanol - -in 100 ml~ of benzene. me reaotion mixture is refluxed for 4 hours~ then allowed to cool~ and treated with 100 ml.
of water. The phases are separated. The benzene solution is shaken with 2 x 100 ml. of water~ dried~ and evaporated ~69~131 :: ~
`.'. ., to dryness under vacuum. In this way 25~5 g. t95.7 2) oE ;~
a crude honey-like product are obtained which crystallize on standing. When recrystalli~ed from ethyl acetate the product melts at 74-75 C, and is completely identical with the compound obtained in Example 2a.
When applying the methods specified in Example 1 and 2~ also other compounds of the general formula I listed in Table I can be prepared.
'.";
'"`''"' ... ' !
`' '' `~ '.
, '. '~
-12- ~ ~
6~ 9 3 Table I
Number M . p .
of C o m p o u n d C ~ x/
Example _ _ f ~; :
3 ~ 1 (1-Phenylethyl)-3~(2-hydroxyethyl)--thiocarbamide ~ 94-96 -4 ~ 1~ Phenylpropyl)-3-(2-hydroxyethyl)~ :
~thiocarbamide 97 98 ~ 1~ Phenyl-2-methylpropyl)-3--(2-hydroxyethyl)-thiocarbamide 73-75 :~
6 ~ 1-~1 Phenylbutyl)~3 (2-hydroxyethyl)--thiocarbamide 95-96 7 ~ 1-(1-Phenyloctyl)-3-(2-hydroxyethyl)- ~ -~thiocarbamide 82-85 8 ~ l-(l-Phenyl-l-cyclopropylmethyl)--3-(2-hydroxyethyl)-thiocarbamide 97-98.5 9 ~ 1~(1-Phenyl-l-cyclohexylmethyl)-3- honey-like -(2-hydroxyethyl)-thiocarbamide substance 0.45 .
1-(3,4-Dimethoxybenzyl)-3-(2-hydroxy ethyl)-thiocarbamide 115-117 11 + 1-Ll-(4-~Methoxyphenyl)-ethyl~-3-~(2-hydroxyethyl)-thiocarbamide 84-87 12 1-(2,6~Dimethylbenzyl)--3-(2-hydroxy-ethyl)-thiocarbamide 162-164 :~
13 ~ 1-Ll-(4-Octylphenyl)-ethyl~-3- .
-(2-hydroxyethyl)-thiocarbamide 41-43.5 14 1-(2-Fluorobenzyl)-3-(2-hydroxyethyl)- ` ;
-thlocarbamlde 109-110 :
1-(3-Fluorobenzyl)-3-(2-hydroxyethyl)-~thiocarbamide 92-94 16 1-(4-Fluorobenzyl)-3-(2-hydroxyethyl)--thiocarbamide 59-61 17 1--(3,4-Dichlorobenzyl)-3-(2-hydroxy-ethyl)-thlocarbamide 91.5-92.5 -.
18 1-(2-Trifluoromethylbenzyl)-3- :.
-(2-hydroxyethyl)-thiocarbamide 88~90 ,:, -13- `
, , ~L~6~93~
-14~
~ , . .
Table I (continued) Number C o m p o u n d M.p. -C ~f x/
Example :
19 1-(3-Trifluoromethylbenzyl)-3--(2-hydroxyethyl)-thiocarbamide 48-50 1-(4-Trifluoromethylbenzyl)-3~
-~(2-hydroxyethyl)~thiocarbamide 80-84 21 ~ 1-tl-Phenylethyl)~3-(3-hydroxypropyl)--thiocarbamide 129-131 22 1-~1-(2-Fluorophenyl)-ethy~ -3--(2-hydroxyethyl)-thioGarbamide 103-105.5 23 1-~ (3-Fluorophenyl)-ethy ~ -3- honey-like -(2-hydroxyethyl)-thiocarbamide substance 0.25 :
23a 1-Ll-(4-Fluorophenyl)-ethyl3-3--(2-hydroxyethyl)-thiocarbamide 91.5-92 24 1~ Phenyl-2,2,2-tri~luoroethyl)-~ -3-(2-hydroxyethyl)-thiocarbamide 115-116.5 1 25 ~ 1-(1-Phenylpropyl)-3-(3-hydroxypropyl)-~ -thiocarbamide 120.5-122 : ., 26 ~ 1-(1-Phenyl-2-methylpropyl)-3--(3-hydroxypropyl)-thiocarbamide 108-110 27 1-(3,4-Dimethoxybenzyl)-3-(3-hydroxy--; propyl)-thiocarbamide 70-73 28 ~rl-~1-(4-Methoxyphenyl)-ethy~ -3- ~-`
` -(2-hydroxyethyl)-thiocarbamide 117-118 ;~
29 1-(2-Fluorobenzyl)-3-(3-hydroxy-; propyl)-thiocarbamide 100-102 1-(3-Fluorobenzyl)-3-(3 hydroxy-propyl)-thiocarbamide 99-100.5 ;
31 1-(4-Fluorobenzyl)-3-(3-hydroxy-~
i propyl)-thiocarbamide 117-119 32 1-(4-Chlorobenzyl)-3-(3-hydroxy propyl)-thiocarbamlde 124-125.5 33 1-(3,4-Vichlorobenzyl)-3-(3-hydroxy-propyl)-thiocarbamide 128.5-130.5 ` :
~: , ,..-~.
~ : ' ~6g93~L
:
Table I (continued) Number No.p. R x/
of Compound C f Example 34 1-Benzyl~3_m~thyl-3-(2-hydroxy-ethyl)-thiocarbamide 54-56 ~ Phenylethyl)~3-methyl-3- honey-like ~(2-hydroxyethyl)-thiocarbamide substance 0.51 36+ 1-(1-Phenylpropyl)-3-methyl-3- ~;
_(2-hydroxyethyl)-thiocarbamide 80 82 37+ 1-(l~Phenyl-2-methylpropyl)-3-methyl- ;
-3_(2-hydroxyethyl)-thiocarbamide 71-76 ;~
38+ 1-(1-Phenylbutyl)-3~methyl-3--(2-hydroxyethyl)-thiocarbamide 74-75 391~ Phenyloctyl)-3-methyl-3--(2-hydroxyethyl)-thiocarbamide 72-73.5 40~ 1-(1-Phenyl-l-cyclopropylmethyl~-3- ` -_methyl-3-(2~hydroxyethyl)~
_thiocarbamide 114-116 41l-(394-Dimethoxybenzyl)-3-methyl~
-3-(2-hydroxyethyl)-thiocarbamide 89-91 42~ 1~ (4~Nethoxyphenyl)-ethyl7-3--methyl-3-(2-hydroxyethyl~
_thiocarbamide 62-65 431-(2-Nethylbenzyl~-3-methyl-3--(2-hydroxyethyl)-thiocarbamide 74-76 441-(2~6-Dimethylbenzyl)-3-methyl-3--(2-hydroxyethyl)-thiocarbamide 120-121.5 451-Ll-(4~0ctylphenyl)-ethyl/-3-methyl--3-(2-hydroxyethyl)-thiocarbamide 52-55 ., 461-(2-Fluorobenzyl)-3-methyl-3--(2-hydroxyethyl)-thiocarbamide 63-65 471~(3-Fluorobenzyl)-3-methyl-3 ~(2-hydroxyethyl)-thiocarbamide 61-63 481-(4-Fluorobenzyl)-3-methyl-3 -(2-hydroxyethyl)-thiocarbamide 103-105 . . ~
::
3L~6~931 ;. -Table I (continued Number M~po R x/
of Compound C f/
Example 491-(2-Chlorobenzyl~-3-methyl-3- honey-like -(2~hydroxyethyl~ thiocarbamide substance 0~40 : :.
501-(4-Chlorobenzyl~-3-methyl-3- ~
-(2-hydroxyethyl)-thiocarbamide 147-148 .
511-(3~4~Dichloxobenzyl)-3-methyl-3 -(2-hydroxyethyl)-thiocarbamide 104-106 ;
521-(2-Trifluoromethylben~.yl)-3-methyl- ;
-3-(2-hydroxyethyl)-thiocarbamide 93-94.5 531-(3-Trifluoromethylbenzyl)-3-methyl--3-(2-hydroxyethyl)-thiocarbamide 78-80 ;
541-(4-Dimethylaminobenzyl)-3-methyl-3_ ::
-(2-hydroxyethyl)-thiocarbamide 108-110 551-(4-Nitrobenzyl)-3-methyl~-3--(2-hydroxyethyl)~thiocarbamide 135-13~.5 56 1-(4-Fluorophenylethyl)-3-methyl-3- honey-like -(2-hydroxyethyl)-thiocarbamide substance 0.88 57l-(l-Phenyl-2j292-trifluoroethyl)-3-. ~
~methyl-3-(2-hydroxyethyl~-thio- ~:
carbamide 107-110 :~
S81-(4-Trifluoromekhylbenzyl)-3-methy~
-3-(2~hydroxyethyl)-thiocarbamide 91~92 S9~ 1-(l~Phenyl-2-methylpropyl)-3-ethyl~
-3-~2 hydroxyethyl)-thiocarbamide 82-84 + 1-(1-Phenyl-2-methylpropyl)-3-butyl- honey-like -3-(2~hydroxyethyl)-thiocarbamide substance 0.71 61+ 1-(1-Phenylethyl)-3~cyclohexyl-3- ~--2_hydroxyethyl)-thiocarbamide 89-90.5 62+ 1-(1-Phenylethyl)-3~3-bis- ~ .
-(2-hydroxyethyl~-thiscarbamide 67-69 :.
63+ 1-(1-Phenylethyl)-3-allyl-thlo-carbamLde 56-59 ;
;
_ 16 -~6993'~
-17- ~.
Table I (continued) Number C o m p o u n d M.p. x/ "~
Example C Rf s , ::
64 ~ 1-(1-Phenylpropyl)-3-allyl- honey-like -thiocarbamide substance 0.75 1-(2-Fluorobenzyl)-3-allyl- ~ i -thiocarbamide 50-53 ;
66 1-(4-Fluorobenzyl)-3-allyl- honey-like -thiocarbamide substance o.68 ~, :~
67 1-(3,4-Dimethoxybenzyl)-3-allyl- --thiocarbamide 117-119 ;i 68 t 1-(1-Phenylpropyl)-3-(2-methyl-allyl)-thiocarbamide 68-69 - -x/ R~ values are given in a 6:1 mi.xture of benzene and pyridine. The determination was carried out on a thin (0.1-0.2 mm~) layer o~ silica gel tMerck).
.:
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~ ~ ~ ~ ~ ~ O
a) + ~ ~ o u) u~ I
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a~ ~oJ ~1 ~ ~ ~ ) o ~) ~ 1~ 0 0 C~ O~ O O 1` U~ O
u~ o X ~ O. `~
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:a. o o o o o o o o o l~ ~0 0 El U~\ oD ~ O O O O Na~ a~ ~ `;t J :~ O ~ `~
o t: ~ ~ oN U'~ O~ 1 O ~ ~ C~ 1 3 .1 U
~ 00 W _1 ~ ~ ~ ~ ~O ~ ~ ~ ~ ~ ~ ~ , ..
~ O ~ ~ U~ ~ ~ i3 `: ~ '.
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1~ ~ O t~ O ` '~',:
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~ P~ u P~ J~ 8. ~ ~ JJ ~
~ ~ @ ~ ~ @ ~ ~ @ ~ ~ @ ~ ~ ~ o ~ ~ g ~ ~ ~
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Eol I t i ~ I ~ UI ~ I I I I D Q~ ~ CO :~ :
~ + + ~ ~ , .
~' :: ' ~ ..,, `
:~
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Table III
Analgesic effect ol some compounds o~ the general formula I, on mice and ra~s Compound Writhing test Hot plate Randall-Sellito test test ED50 mg/kg ED50 mg/kg s~imulation threshold + l-(Phenylethyl)-3- 3-10, oral 10-30, oral 200 mg/kg oral: 198 %
-~2-hydroxyethyl~- , lO0 mg/kg oral: 78 %
-thiocarbamide S0 mg/kg oral: 56 %
+ l-(Phenylpropyl)-3- 3-10, oral 10-30, oral 200 mg/kg oral: 593 % - ;;
-~2-hydroxyethyl)- 100 mg/kg oral: 199 %
-thiocarbamide 50 mg/kg oral: 103 %
+ l-~Phenyl, cyclopropyl)--methyl-3-~2-hydroxy-ethyl)-thiocarbamide 10-30, i.p. -- - - `
+ l-(l-Phenylethyl)-3- 10-30, oral 10-30, oral 200 mg/kg oral: 88 %
-methyl-3-(2-hydroxy- 100 mg/kg oral: 24 %
et~yl)-thiocarbamide 50 mg/kg oral: 5 %
Morphine 1.65 s.c. 2.50 s~c. 10 mg/kg s.c.: lO00 %
3 mg/kg s.c.: 90 %
1 mg/kg s.c.: 9 %
Propoxyphene 22.5 oral 70, oral100 mg/kg oral: 1000 %
( -(~)-1,2-dlphenyl- 30 mg/kg oral: 534 %
-3-methyl-2-propio- 10 mg/kg oral: 33 % ` ~;
n~loxy-4-dimethyl-aminobutane) Amidazophene 180 oral 60, oral200 mg/kg oral: 100 %
C l-Phenyl-2,3- 100 mg/kg oral: 69 %
-dimethyl-5- 50 mg/kg oral: 8 %
-~Yrazolone) :
; ':.
~C16~D3~ -~
Table IV
Antidepressant effect of some compounds of the general formula I on mice Antagonization of the temperature~
lowering action of reserpine C o m p o u n d Dose Change in rectal ~
TempeOrature :,' mgtkg ' C : '' + 1-(2-Fluorobenzyl)-3--(2-hydroxyethyl)--thiocarbamide 30 + 3.4 :~
Phenylethyl)D3_ ~ ;
-methyl-3-(2-hydroxy-ethyl~-thiocarbamide 30 + 3.5 + l-(l-Phenylpropyl-3~
-methyl-3-~2-hydroxy-ethyl)-thiocarbamide 30 + 3.8 + 1-(4-Fluorobenzyl)-3-, -allyl-thiocarbamide 30 ~ 3.8 .
" :
,. :;
: : .~
..
;
:: ::;
~ .
:; :
~.
.` ' :
''~, -20- ~
Claims (25)
PROPERY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of novel thiocarbamide derivatives of the general formula I
(I) wherein R1, R2 and R3 may stand for identical or different groups, and they denote each a hydrogen atom, a C1-8 straight or branched-chain, saturated or unsaturated alkyl, or dialkylaminoalkyl groups, alkyl substituted with one or more halogen atoms, further hydroxy, dialkylamino, or nitro groups, or halogen atoms; R4 denotes a hydrogen atom, a saturated or unsaturated straight or branched-chain C1-8 alkyl or cycloalkyl group which may be substituted with a hydroxyl group; R5 denotes a C2-6 straight or branched-chain hydroxyalkyl group or a C3-6 straight or branched-chain unsaturated alkyl group; R6 denotes a hydrogen atom, a straight or branched-chain saturated or unsaturated C1-7 alkyl group which may be substituted with a hydroxyl group or with one or more halogen atoms, or a C3-6 cycloalkyl group, with the proviso that R6 must have a meaning other than hydrogen atom when R1, R2, R3 and R4 each denote a hydrogen atom, and R5 stands for a 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl or 1,1-dimethyl-2-hydroxyethyl group; or when R2, R3 and R4 each denote a hydrogen atom, R5 denotes a 2-hydroxyethyl group, and R1 denotes a 2-chloro, 4-chloro, 4-bromo or 2-methyl group; or when R1 denotes a 4-bromo group, R2, R3 and R4 each denote a hydrogen atom, and R5 stands for a 4-hydroxybutyl group; or when R1 denotes a 2-methyl group, R2 a 4-methyl or 5-methyl group, R3 and R4 each stand for a hydrogen atom, and R5 is a 2-hydroxyethyl group; or when R1 denotes a 2-methoxy group, R2 a 4-hydroxy group, R3 and R4 each a hydrogen atom, and R5 a 2-hydroxyethyl group; or when R1, R2 and R3 each denote a hydrogen atom, R5 denotes a 2-hydroxyethyl group, and R4 stands for a 2-hydroxyethyl or 2-methylpropyl group, R6 must have a meaning other than hydrogen atom when at least one or R1, R2 and R3 denotes a C1-4 alkyl or a halo group, R4 denotes a hydrogen atom or a C1-4 alkyl group and R5 denotes an allyl group, character-ized in that a) an isothiocyanate of the general formula (II) wherein R1, R2, R3 and R6 have the above-specified meanings, is reacted with an amine of the general formula III
(III) wherein R4 and R5 have the above-specified meanings, in a melt or in an inert solvent, or b1) a compound of the general formula IV
(IV) wherein R1, R2, R3 and R6 have the above-specified meanings, whereas Q denotes an -SR7 group, wherein R7 denotes a short-chain alkyl, an aryl or an aralkyl group, is reacted with an amine of the general formula III, wherein R4 and R5 have the above-specified meanings, in a melt or in an inert solvent, or b2) a compound of the general formula IV, wherein R1, R2, R3 and R6 have the above-specified meanings, whereas Q denotes a halogen atom, is reacted with an amine of the general formula III, wherein R4 and R5 have the above-specified meanings, in a melt or in an inert solvent, or b3) a compound of the general formula IV, wherein R1, R2, R3 and R6 have the above-specified meanings, whereas Q denotes an SH group, is reacted with an amine of the general formula III, wherein R4 and R5 have the above-specified meanings, and then melting the obtained salt, optionally in the presence of an inert solvent.
(I) wherein R1, R2 and R3 may stand for identical or different groups, and they denote each a hydrogen atom, a C1-8 straight or branched-chain, saturated or unsaturated alkyl, or dialkylaminoalkyl groups, alkyl substituted with one or more halogen atoms, further hydroxy, dialkylamino, or nitro groups, or halogen atoms; R4 denotes a hydrogen atom, a saturated or unsaturated straight or branched-chain C1-8 alkyl or cycloalkyl group which may be substituted with a hydroxyl group; R5 denotes a C2-6 straight or branched-chain hydroxyalkyl group or a C3-6 straight or branched-chain unsaturated alkyl group; R6 denotes a hydrogen atom, a straight or branched-chain saturated or unsaturated C1-7 alkyl group which may be substituted with a hydroxyl group or with one or more halogen atoms, or a C3-6 cycloalkyl group, with the proviso that R6 must have a meaning other than hydrogen atom when R1, R2, R3 and R4 each denote a hydrogen atom, and R5 stands for a 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl or 1,1-dimethyl-2-hydroxyethyl group; or when R2, R3 and R4 each denote a hydrogen atom, R5 denotes a 2-hydroxyethyl group, and R1 denotes a 2-chloro, 4-chloro, 4-bromo or 2-methyl group; or when R1 denotes a 4-bromo group, R2, R3 and R4 each denote a hydrogen atom, and R5 stands for a 4-hydroxybutyl group; or when R1 denotes a 2-methyl group, R2 a 4-methyl or 5-methyl group, R3 and R4 each stand for a hydrogen atom, and R5 is a 2-hydroxyethyl group; or when R1 denotes a 2-methoxy group, R2 a 4-hydroxy group, R3 and R4 each a hydrogen atom, and R5 a 2-hydroxyethyl group; or when R1, R2 and R3 each denote a hydrogen atom, R5 denotes a 2-hydroxyethyl group, and R4 stands for a 2-hydroxyethyl or 2-methylpropyl group, R6 must have a meaning other than hydrogen atom when at least one or R1, R2 and R3 denotes a C1-4 alkyl or a halo group, R4 denotes a hydrogen atom or a C1-4 alkyl group and R5 denotes an allyl group, character-ized in that a) an isothiocyanate of the general formula (II) wherein R1, R2, R3 and R6 have the above-specified meanings, is reacted with an amine of the general formula III
(III) wherein R4 and R5 have the above-specified meanings, in a melt or in an inert solvent, or b1) a compound of the general formula IV
(IV) wherein R1, R2, R3 and R6 have the above-specified meanings, whereas Q denotes an -SR7 group, wherein R7 denotes a short-chain alkyl, an aryl or an aralkyl group, is reacted with an amine of the general formula III, wherein R4 and R5 have the above-specified meanings, in a melt or in an inert solvent, or b2) a compound of the general formula IV, wherein R1, R2, R3 and R6 have the above-specified meanings, whereas Q denotes a halogen atom, is reacted with an amine of the general formula III, wherein R4 and R5 have the above-specified meanings, in a melt or in an inert solvent, or b3) a compound of the general formula IV, wherein R1, R2, R3 and R6 have the above-specified meanings, whereas Q denotes an SH group, is reacted with an amine of the general formula III, wherein R4 and R5 have the above-specified meanings, and then melting the obtained salt, optionally in the presence of an inert solvent.
2. Thiocarbamide derivatives of the general formula I as defined in claim 1 whenever prepared by the process of claim 1 or an obvious chemical equivalent.
3. A process according to claim 1(b3) in which the dithiocarbamic acids of formula IV are prepared by reacting compounds of the formula with carbon disulphide.
4. A process according to claim 1(b2) in which the thiocarbamic acids of formula IV are prepared by reacting compounds of the formula with thiophosgene.
5. A process according to claim 1 in which two of R1, R2 and R3 are hydrogen and the remaining radical 4-chloro, R4 and R6 are hydrogen, and R5 is 2-hydroxypropyl.
6. A process according to claim 1 which comprises reacting 4-chloro-benzyl isothiocyanate with propanolamine to yield 1-(4-chlorobenzyl)-3-(3-hydroxypropyl)-thiocarbamide.
7. A process according to claim 1 which comprises reacting methyl-N-(4-chlorobenzyl)-dithiocarbamate with propanolamine to yield 1-(4-chloro-benzyl)-3-(3-hydroxypropyl)-thiocarbamide.
8. A process according to claim 1 in which two of R1, R2 and R3 are hydrogen and the remaining radical is 4-fluoro, R6 is hydrogen, R4 is methyl and R5 is 2-hydroxyethyl.
9. A process according to claim 1 which comprises reacting 4-fluoro-benzyl isothiocyanate with 2-methylaminoethanol to yield 1-(4-fluorobenzyl)-3-methyl-3-(2-hydroxyethyl)-thiocarbamide.
10. A process according to claim 1 which comprises reacting methyl-N-(4-fluorobenzyl)-dithiocarbamate with 2-methylaminoethanol to yield 1-(4-fluorobenzyl)-3-methyl-3-(2-hydroxyethyl)-thiocarbamide.
11. A process according to claim 1 in which two of R1, R2 and R3 are hydrogen and the remaining radical 4-chloro, R6 is hydrogen, R4 is methyl and R5 is 2-hydroxyethyl.
12. A process according to claim 1 which comprises reacting 4-chlorobenzyl isothiocyanate with 2-methylaminoethanol to yield 1-(4-chloro-benzyl)-3-methyl-3-(2-hydroxyethyl)-thiocarbamide.
13. A process according to claim 1 which comprises reacting methyl-N-(4-chlorobenzyl)-dithiocarbamate with 2-methylaminoethanol to yield 1-(4-chlorobenzyl)-3-methyl-3-(2-hydroxyethyl)-thiocarbamide.
14. A process according to claim 1 in which two of R1, R2 and R3 are hydrogen and the remaining radical is 4-trifluoromethyl, R6 is hydrogen, R4 is methyl and R5 is 2-hydroxyethyl.
15. A process according to claim 1 which comprises reacting 4-tri-fluoromethylbenzyl isothiocyanate with 2-methylaminoethanol to yield 1-(4-trifluoromethylbenzyl)-3-methyl-3-(2-hydroxyethyl)-thiocarbamide.
16. A process according to claim 1 which comprises reacting methyl-N-(4-trifluoromethylbenzyl-dithiocarbamate with 2-methylaminoethanol to yield 1-(4-trifluoromethylbenzyl)-3-methyl-3-(2-hydroxyethyl)-thiocarbamide.
17. A process according to claim 1 in which each of R1, R2, R3 and R4 are hydrogen, R6 is ethyl, and R5 is 2-hydroxyethyl.
18. A process according to claim 1 which comprises reacting 1-phenyl-propyl isothiocyanate with ethanolamine to yield ? 1-(1-phenylpropyl)-3-(2-hydroxyethyl)-thiocarbamide.
19. A process according to claim 1 which comprises reacting N-(1-phenylpropyl)-thiocarbamic acid chloride with ethanolamine to yield ? 1-(1-phenylpropyl)-3-(2-hydroxyethyl)-thiocarbamide.
20. A process according to claim 1 in which two of R1, R2 and R3 are hydrogen and the remaining radical is 2-fluoro, R4 and R6 are hydrogen and R5 is 2-hydroxyethyl.
21. A process according to claim 1 which comprises reacting 2-fluoro-benzyl isothiocyanate with ethanolamine to yield 1-(2-fluorobenzyl)-3-(2-hydroxyethyl)-thiocarbamide.
22. A process according to claim 1 which comprises reacting methyl-N-(2-fluorobenzyl)-dithiocarbamate with ethanolamine to yield 1-(2-fluoro-benzyl)-3-(2-hydroxyethyl)-thiocarbamide.
23. A process according to claim 1 in which each of R1, R2, R3 and R4 are hydrogen, R6 is methyl and R5 is 2-hydroxyethyl.
24. A process according to claim 1 which comprises reacting l-phenyl-ethyl isothiocyanate with ethanolamine to yield ? 1-(1-phenylethyl)-3-(2-hydroxyethyl)-thiocarbamide.
25. A process according to claim 1 which comprises reacting-N-(1-phenylethyl)-thiocarbamic acid chloride with ethanolamine to yield ? 1-(1-phenylethyl)-3-(2-hydroxyethyl)-thiocarbamide.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU75GO1303A HU173459B (en) | 1975-03-14 | 1975-03-14 | Process for preparing new thiourea derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1069931A true CA1069931A (en) | 1980-01-15 |
Family
ID=10996785
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA247,778A Expired CA1069931A (en) | 1975-03-14 | 1976-03-12 | Thiocarbamide derivatives and process for preparing thereof |
Country Status (18)
| Country | Link |
|---|---|
| AT (1) | AT347476B (en) |
| BE (1) | BE839502A (en) |
| CA (1) | CA1069931A (en) |
| CH (1) | CH619210A5 (en) |
| CS (1) | CS188132B2 (en) |
| DD (1) | DD125615A5 (en) |
| DE (1) | DE2610865A1 (en) |
| DK (1) | DK107876A (en) |
| EG (1) | EG12505A (en) |
| FR (1) | FR2303532A1 (en) |
| GB (1) | GB1499485A (en) |
| HU (1) | HU173459B (en) |
| IL (1) | IL49194A (en) |
| IN (1) | IN143559B (en) |
| NL (1) | NL7602670A (en) |
| PL (1) | PL101310B1 (en) |
| SE (1) | SE7603242L (en) |
| SU (1) | SU795462A3 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU206082B (en) * | 1988-12-23 | 1992-08-28 | Sandoz Ag | Process for producing capsaicin derivatives and pharmaceutical compositions comprising such compounds |
| US6545182B2 (en) * | 2000-04-13 | 2003-04-08 | Allergan Sales, Inc. | Methods and compositions for modulating alpha adrenergic receptor activity |
| US7335803B2 (en) | 2001-10-19 | 2008-02-26 | Allergan, Inc. | Methods and compositions for modulating alpha adrenergic receptor activity |
| US6313172B1 (en) * | 2000-04-13 | 2001-11-06 | Allergan Sales, Inc. | Methods and compositions for modulating alpha adrenergic receptor activity |
| US6534542B2 (en) | 2001-02-27 | 2003-03-18 | Allergen Sales, Inc. | (2-hydroxy)ethyl-thioureas useful as modulators of α2B adrenergic receptors |
| US7276522B2 (en) | 2002-05-21 | 2007-10-02 | Allergan, Inc. | 4-(substituted cycloalkylmethyl) imidazole-2-thiones, 4-(substituted cycloalkenylmethyl) imidazole-2-thiones, 4-(substituted cycloalkylmethyl) imidazol-2-ones, 4-(substituted cycloalkenylmethyl) imidazol-2-ones and related compounds |
| US7358269B2 (en) | 2002-05-21 | 2008-04-15 | Allergan, Inc. | 2-((2-Thioxo-2,3-dihydro-1H-imidazol-4-yl)methyl)-3,4-dihydronapthalen-1(2H)-one |
| US7091232B2 (en) | 2002-05-21 | 2006-08-15 | Allergan, Inc. | 4-(substituted cycloalkylmethyl) imidazole-2-thiones, 4-(substituted cycloalkenylmethyl) imidazole-2-thiones, 4-(substituted cycloalkylmethyl) imidazol-2-ones and 4-(substituted cycloalkenylmethyl) imidazol-2-ones and related compounds |
| US7323485B2 (en) | 2002-05-21 | 2008-01-29 | Allergan, Inc. | 4-(substituted cycloalkylmethyl) imidazole-2-thiones, 4-(substituted cycloalkenylmethyl) imidazole-2-thiones, 4-(substituted cycloalkylmethyl) imidazol-2-ones and 4-(substituted cycloalkenylmethyl) imidazol-2-ones and related compounds |
| BRPI0516025A (en) | 2004-09-24 | 2008-08-19 | Allergan Sales Inc | 4- (heteroaryl-methyl and substituted heteroaryl-methyl) -imidazol-2-thione acting as alpha2-adrenergic agonists |
| JP2008514601A (en) | 2004-09-24 | 2008-05-08 | アラーガン、インコーポレイテッド | 4- (Phenylmethyl and substituted phenylmethyl) -imidazole-2-thiones as specific α2 adrenergic agonists |
| MX2007003094A (en) | 2004-09-24 | 2007-06-07 | Allergan Inc | 4-(condensed cyclicmethyl)-imidazole-2-thiones acting as alpha2 adrenergic agonists. |
| KR101202066B1 (en) | 2004-09-28 | 2012-11-15 | 알러간, 인코포레이티드 | Unsubstituted and substituted 4-benzyl-1,3-dihydro-imidazole-2-thiones acting as specific or selective alpha2 adrenergic agonists and methods for using the same |
| US7390829B2 (en) | 2005-06-29 | 2008-06-24 | Allergan, Inc. | Alpha-2 adrenergic agonists |
| US7902247B2 (en) | 2008-01-09 | 2011-03-08 | Allergan, Inc. | Substituted-aryl-2-phenylethyl-1H-imidazole compounds as subtype selective modulators of alpha 2B and/or alpha 2C adrenergic receptors |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB974545A (en) * | 1963-03-14 | 1964-11-04 | Baxter Laboratories Inc | Thioureas |
-
1975
- 1975-03-12 SU SU752333906A patent/SU795462A3/en active
- 1975-03-14 HU HU75GO1303A patent/HU173459B/en unknown
-
1976
- 1976-03-10 IL IL49194A patent/IL49194A/en unknown
- 1976-03-11 CS CS761604A patent/CS188132B2/en unknown
- 1976-03-12 CH CH307076A patent/CH619210A5/en not_active IP Right Cessation
- 1976-03-12 DK DK107876A patent/DK107876A/en not_active Application Discontinuation
- 1976-03-12 FR FR7607110A patent/FR2303532A1/en active Granted
- 1976-03-12 CA CA247,778A patent/CA1069931A/en not_active Expired
- 1976-03-12 AT AT185776A patent/AT347476B/en not_active IP Right Cessation
- 1976-03-12 SE SE7603242A patent/SE7603242L/en not_active Application Discontinuation
- 1976-03-12 DD DD191816A patent/DD125615A5/xx unknown
- 1976-03-12 BE BE165107A patent/BE839502A/en unknown
- 1976-03-13 PL PL1976187917A patent/PL101310B1/en unknown
- 1976-03-14 EG EG152/76A patent/EG12505A/en active
- 1976-03-15 DE DE19762610865 patent/DE2610865A1/en not_active Withdrawn
- 1976-03-15 GB GB10200/76A patent/GB1499485A/en not_active Expired
- 1976-03-15 NL NL7602670A patent/NL7602670A/en not_active Application Discontinuation
- 1976-03-15 IN IN456/CAL/1976A patent/IN143559B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK107876A (en) | 1976-09-15 |
| IL49194A (en) | 1980-09-16 |
| IN143559B (en) | 1977-12-24 |
| DE2610865A1 (en) | 1976-09-30 |
| ATA185776A (en) | 1978-05-15 |
| CS188132B2 (en) | 1979-02-28 |
| HU173459B (en) | 1979-05-28 |
| SE7603242L (en) | 1976-10-15 |
| NL7602670A (en) | 1976-09-16 |
| PL101310B1 (en) | 1978-12-30 |
| FR2303532B1 (en) | 1978-12-15 |
| FR2303532A1 (en) | 1976-10-08 |
| IL49194A0 (en) | 1976-05-31 |
| CH619210A5 (en) | 1980-09-15 |
| SU795462A3 (en) | 1981-01-07 |
| GB1499485A (en) | 1978-02-01 |
| BE839502A (en) | 1976-07-01 |
| EG12505A (en) | 1980-07-31 |
| DD125615A5 (en) | 1977-05-04 |
| AT347476B (en) | 1978-12-27 |
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