EP0594595A1 - Novel 4-methyl thiazole derivatives, preparation methods therefor and pharmaceutical compositions containing said derivatives - Google Patents
Novel 4-methyl thiazole derivatives, preparation methods therefor and pharmaceutical compositions containing said derivativesInfo
- Publication number
- EP0594595A1 EP0594595A1 EP91904815A EP91904815A EP0594595A1 EP 0594595 A1 EP0594595 A1 EP 0594595A1 EP 91904815 A EP91904815 A EP 91904815A EP 91904815 A EP91904815 A EP 91904815A EP 0594595 A1 EP0594595 A1 EP 0594595A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- methyl
- piperazinyl
- thiazole
- thiazolyloxy
- propanol
- 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.)
- Withdrawn
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
- QMHIMXFNBOYPND-UHFFFAOYSA-N 4-methylthiazole Chemical class CC1=CSC=N1 QMHIMXFNBOYPND-UHFFFAOYSA-N 0.000 title claims description 5
- 238000000034 method Methods 0.000 claims abstract description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 7
- 208000013403 hyperactivity Diseases 0.000 claims abstract description 7
- 210000002820 sympathetic nervous system Anatomy 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 3
- 229910052736 halogen Inorganic materials 0.000 claims abstract 2
- 150000002367 halogens Chemical class 0.000 claims abstract 2
- -1 4-phenyl-1-piperazinyl Chemical group 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 32
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 28
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 26
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 21
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 12
- IIMLZWMRQNCPTM-UHFFFAOYSA-N 5-bromo-4-methyl-1,3-thiazole Chemical compound CC=1N=CSC=1Br IIMLZWMRQNCPTM-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 6
- 239000001294 propane Substances 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- 231100000252 nontoxic Toxicity 0.000 claims description 4
- 230000003000 nontoxic effect Effects 0.000 claims description 4
- 159000000000 sodium salts Chemical class 0.000 claims description 4
- RNVYQYLELCKWAN-UHFFFAOYSA-N solketal Chemical compound CC1(C)OCC(CO)O1 RNVYQYLELCKWAN-UHFFFAOYSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
- 230000031709 bromination Effects 0.000 claims description 2
- 238000005893 bromination reaction Methods 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 230000009615 deamination Effects 0.000 claims description 2
- 238000006481 deamination reaction Methods 0.000 claims description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims 2
- 239000004480 active ingredient Substances 0.000 claims 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000003981 vehicle Substances 0.000 claims 1
- 208000024172 Cardiovascular disease Diseases 0.000 abstract 1
- 239000000047 product Substances 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000012429 reaction media Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 229960002748 norepinephrine Drugs 0.000 description 6
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 6
- UPUWMQZUXFAUCJ-UHFFFAOYSA-N 2,5-dihydro-1,2-thiazole Chemical compound C1SNC=C1 UPUWMQZUXFAUCJ-UHFFFAOYSA-N 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- XZYIDZIGJVUTKE-UHFFFAOYSA-N 5-bromo-4-methyl-1,3-thiazol-2-amine Chemical compound CC=1N=C(N)SC=1Br XZYIDZIGJVUTKE-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 230000036772 blood pressure Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 231100000111 LD50 Toxicity 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 230000001077 hypotensive effect Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 208000001953 Hypotension Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 102000004305 alpha Adrenergic Receptors Human genes 0.000 description 2
- 108090000861 alpha Adrenergic Receptors Proteins 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Substances OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000004508 fractional distillation Methods 0.000 description 2
- 230000008570 general process Effects 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 208000021822 hypotensive Diseases 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229960001783 nicardipine Drugs 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 210000001177 vas deferen Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AKPNZOHONDXXES-UHFFFAOYSA-N 1-phenyl-2-propoxypiperazine Chemical compound CCCOC1CNCCN1C1=CC=CC=C1 AKPNZOHONDXXES-UHFFFAOYSA-N 0.000 description 1
- OUQMXTJYCAJLGO-UHFFFAOYSA-N 4-methyl-1,3-thiazol-2-amine Chemical compound CC1=CSC(N)=N1 OUQMXTJYCAJLGO-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 1
- IFJOCHBDHXGFAA-UHFFFAOYSA-N CC([CH2-])=O.OCC(O)CO Chemical compound CC([CH2-])=O.OCC(O)CO IFJOCHBDHXGFAA-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000002908 adrenolytic effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N anhydrous n-heptane Natural products CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 208000037849 arterial hypertension Diseases 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000005792 cardiovascular activity Effects 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- BGGXRVPCJUKHTQ-AHCAJXDVSA-L carumonam sodium Chemical compound [Na+].[Na+].O=C1N(S([O-])(=O)=O)[C@H](COC(=O)N)[C@@H]1NC(=O)C(=N/OCC([O-])=O)\C1=CSC(N)=N1 BGGXRVPCJUKHTQ-AHCAJXDVSA-L 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 125000005484 neopentoxy group Chemical group 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000926 not very toxic Toxicity 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- ZRHANBBTXQZFSP-UHFFFAOYSA-M potassium;4-amino-3,5,6-trichloropyridine-2-carboxylate Chemical compound [K+].NC1=C(Cl)C(Cl)=NC(C([O-])=O)=C1Cl ZRHANBBTXQZFSP-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/34—Oxygen atoms
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
Definitions
- New derivatives of 4-methyl-thiazole processes for their preparation and pharmaceutical compositions containing them.
- the subject of the present invention is new derivatives of 4-methyl-thiazole, more specifically amino derivatives of 4-methyl-5-thiazole, their methods of preparation and pharmaceutical compositions containing them.
- the compounds according to the invention are derivatives of 4-methyl thiazole corresponding to the general formula:
- R 1 and R 2 are chosen from a hydrogen atom, a halogen atom, a hydroxy group, a trifluoromethyl group, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 5 carbon atoms.
- the invention also includes within its scope all the possible optical isomers of the compounds of formula (I) as well as their mixtures.
- the invention also includes within its scope the salts of the above-mentioned compounds of formula (I).
- a halogen atom is preferably a chlorine or fluorine atom.
- the alkyl and alkoxy groups can be straight or branched chain groups.
- An alkyl group having from 1 to 4 carbon atoms is for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl group, preferably methyl or ethyl.
- alkoxy group having from 1 to 5 carbon atoms is for example a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiobutoxy, n-pentoxy, isopentoxy or neopentoxy group, preferably methoxy, ethoxy, propoxy or isopropoxy.
- the general process for the preparation of the compounds according to the invention, of formula (I), as defined above, in laguelle n is equal to 0 comprises the condensation reaction of 5-bromo-4-methyl-thiazole on the sodium salt d 'a (4-aryl piperazinyl-1) -2-ethanol of formula:
- R 1 and R 2 have the same meaning as indicated above.
- 5-bromo-4-methyl-thiazole is obtained by bromination of 2-amino-4-methyl-thiazole under conditions allowing the obtaining of 2-amino-5-bromo-4-methyl-thiazole;
- Amino-2-methyl-4 thiazole is a known product, the preparation process of which is described in the literature (Merck Index, 10th edition, n ° 454).
- R 1 and R 2 have the same meaning as indicated above.
- (4-methyl-5 thiazolyloxy) -3-1,2-epoxy propane is obtained by:
- Glycerol acetonide (or 2,2-dimethyl-1,3-dioxolane-4 methanol), sold by the company ALDRICH, is a known product whose preparation process is for example described in Beilstein 19, 65, Merck Index 10, 3236.
- the compounds of formula (I) according to the invention and their pharmaceutically acceptable salts have advantageous pharmacological properties which suggest a therapeutic application of these compounds in particular in the treatment of cardiovascular manifestations linked to hyperactivity of the sympathetic nervous system of type ⁇ -adrenergic.
- the invention also aims to cover new pharmaceutical compositions, characterized in that they contain, in combination with a pharmaceutically acceptable excipient, at least one compound of formula (I) or its non-toxic addition salt, as a principle active.
- the pharmaceutically acceptable salts of the compounds of formula (I) are obtained in a manner known per se, by bringing the products of formula (I) into contact with a suitable quantity of pharmaceutically acceptable acid such as for example a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as citric, tartaric or fumaric acid.
- a suitable quantity of pharmaceutically acceptable acid such as for example a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as citric, tartaric or fumaric acid.
- compositions according to the invention can generally be prepared by conventional methods and administered in an appropriate pharmaceutical form.
- the compounds can be administered, for example, orally in 1 to 3 doses per day, at a rate of 2 to 2 mg per dose depending on the compound, for example in the treatment of cardiovascular manifestations linked to hyperactivity of the sympathetic nervous system of ⁇ -adrenergic type.
- the invention aims to cover a process for the preparation of a pharmaceutical composition, characterized in that a pharmaceutically effective amount of at least one compound of formula (I) as defined above is incorporated, or a non-toxic addition salt of this compound, in a pharmaceutically acceptable excipient.
- the invention aims to cover a method for the treatment of cardiovascular manifestations linked to hyperactivity of the sympathetic nervous system of the oc-adrenergic type, characterized in that it comprises administration to a mammal comprising man and l animal, of a therapeutically effective amount of at least minus a compound of formula (I) as defined above, or of a pharmaceutically acceptable addition salt of this compound.
- Step 1 Synthesis of 2-amino-5-bromo-4-methyl-thiazole.
- reaction medium is then filtered and the hydrobromide is washed with dichloromethane, then with pentane.
- the hydrobromide is dissolved in 2000 ml of water, then basified by the addition of 850 ml of 10% aqueous sodium bicarbonate solution.
- Step 2 Synthesis of 4-methyl-5-bromo thiazole.
- the reaction medium is left under stirring at this temperature for 30 min.
- the hypophosphorous acid (50%, 197 ml) is then added slowly to the reaction medium at -10 ° C.
- the reaction medium supplemented with dichloromethane is centrifuged at 3000 rpm for 15 min. After decantation and evaporation under vacuum of the solvent, the (4-o-ethoxyphenyl-piperazinyl-1) -2 ethanol is removed by fractional distillation under reduced pressure. The distillation residue is purified by chromatography on a column of silica gel (AcOEt).
- the hydrochloride is prepared in anhydrous ethyl ether by addition of dry HCl gas, then recrystallized from a mixture of isopropanol and pentane.
- Step 1 Synthesis of (4-methyl-5 thiazolyloxy) -3-1,2-propanediol acetonide.
- 5-bromo-4-methyl thiazole can be obtained by following the experimental process described in steps 1 and 2 of Example 1.
- the reaction medium is stirred for 15 h.
- the hydrochloride is crystallized from a mixture of isopropanol and ethyl ether.
- the base is released by adding a 10% sodium bicarbonate solution, then purified by recrystallization from a mixture of ethyl acetate and pentane (80/20). 19.1 g of white crystals are obtained.
- the reaction medium is heated for 10 h at 70 C.
- the filtrate is concentrated to dryness under reduced pressure and the (methyl -4 thiazolyloxy-5) -3 epoxy-1,2 propane is purified by chromatography on a column of silica gel (AcOEt). 6.75 g of epoxide are obtained, in the form of a pale yellow oil.
- Step 4 Synthesis of (4-o-propoxyphenyl-1 piperazinyl-1) -3 (4-methylthiazolyloxy-5) -1-propanol-2 monohydrochloride (B 1395).
- the reaction medium is heated at 40 ° C for 21 h.
- the solvent is removed by distillation under reduced pressure.
- the monohydrochloride is obtained by adding a stoichiometric amount of an ethanolic solution of hydrochloric acid previously dosed, in an ethanolic solution of the base cooled by an ice bath. After 1 h of stirring and elimination of the ethanol by distillation under reduced pressure, the product is crystallized from a mixture of ethyl ether and acetone and then recrystallized from acetone.
- mice I. Acute toxicity in mice.
- the products were administered orally at a single dose in male mice weighing 22 g. Mortality was recorded after a 14-day observation period.
- LD 50 lethal dose 50
- the concentration of product is determined in the presence of which the concentration of noradrenaline must be multiplied by two to obtain the same effect as in the absence of said product.
- the logarithm changed sign of this concentration constitutes the pA 2 of the products.
- noradrenaline 0.4 mg.kg -1
- the prior administration of a substance with an alpha-blocking property makes it possible to reduce this toxicity.
- B 1431, B 1510, B 1525, B 1548 and B 1552 prove to be particularly active in the whole animal, thus confirming their action demonstrated in vitro.
- Blood pressure is measured by catheterization of the left carotid artery in the anesthetized male rabbit.
- the increase in blood pressure is induced by an intravenous injection of norepinephrine. This hypertension can be inhibited by the prior administration of molecules with alpha-blocking potential.
- ID 50 50% inhibitory dose
- ID 50 the dose of product which, administered by IV, inhibits by 50% the arterial hyperpressure.
- Compound B 1395 is particularly effective with an active dose of less than 1 mg.kg V. Determination of cardiovascular activity
- the products are administered intravenously in increasing doses. Three animals are tested per product. The dose causing a 25% drop in average blood pressure
- the products have dose-dependent hypotensive effects but have little or no effect on the heart rate (Table 7).
- the most hypotensive in terms of effective dose is B 1395 (DE 25 at 0.004 mg.kg -1 ).
- the ED 25 evaluated 5 min after injection make it possible to locate the hypotensive potential of the products B 1395, B 1396, B 1431 and B1552 at the level of Nicardipine.
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Abstract
La présente invention a pour objet de nouveaux dérivés du méthyl-4 thiazole, leurs procédés de préparation et les compositions pharmaceutiques en contenant. Selon l'invention, ces dérivés répondent à la formule générale (I) dans laquelle n est égal à 0 ou 1 et R1 et R2, identiques ou différents, sont choisis parmi un atome d'hydrogène, un halogène, un groupe hydroxy, un groupe trifluorométhyle, un groupe alkyle ayant de 1 à 4 atomes de carbone, un groupe alcoxy ayant de 1 à 5 atomes de carbone. Application dans le traitement des maladies cardiovasculaires liées à une hyperactivité du système nerveux sympathique.The subject of the present invention is new derivatives of methyl-4 thiazole, their methods of preparation and the pharmaceutical compositions containing them. According to the invention, these derivatives correspond to the general formula (I) in which n is equal to 0 or 1 and R1 and R2, identical or different, are chosen from a hydrogen atom, a halogen, a hydroxy group, a trifluoromethyl group, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 5 carbon atoms. Application in the treatment of cardiovascular diseases linked to hyperactivity of the sympathetic nervous system.
Description
Nouveaux dérivés du méthyl-4 thiazole, leurs procédés de préparation et les compositions pharmaceutiques en contenant. New derivatives of 4-methyl-thiazole, processes for their preparation and pharmaceutical compositions containing them.
La présente invention a pour objet de nouveaux dérivés du méthyl-4 thiazole, plus précisément des dérivés aminés du méthyl-4 oxy-5 thiazole, leurs procédés de préparation et des compositions pharmaceutiques en contenant. The subject of the present invention is new derivatives of 4-methyl-thiazole, more specifically amino derivatives of 4-methyl-5-thiazole, their methods of preparation and pharmaceutical compositions containing them.
Les composés selon l'invention sont des dérivés du méthyl-4 thiazole répondant à la formule générale : The compounds according to the invention are derivatives of 4-methyl thiazole corresponding to the general formula:
dans laquelle n est égal à 0 ou 1, R1 et R2, identiques ou différents sont choisis parmi un atome d'hydrogène, un atome d'halogène, un groupe hydroxy, un groupe trifluorométhyle, un groupe alkyle ayant de 1 à 4 atomes de carbone, un groupe alcoxy ayant de 1 à 5 atomes de carbone. in which n is equal to 0 or 1, R 1 and R 2 , identical or different, are chosen from a hydrogen atom, a halogen atom, a hydroxy group, a trifluoromethyl group, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 5 carbon atoms.
L'invention comprend également dans son cadre tous les isomères optiques possibles des composés de formule (I) ainsi que leurs mélanges. The invention also includes within its scope all the possible optical isomers of the compounds of formula (I) as well as their mixtures.
L'invention comprend en outre dans son cadre les sels des composés de formule (I) précités. The invention also includes within its scope the salts of the above-mentioned compounds of formula (I).
Dans cette formule, un atome d'halogène est de préférence un atome de chlore ou de fluor. In this formula, a halogen atom is preferably a chlorine or fluorine atom.
Les groupes alkyle et alcoxy peuvent être des groupes à chaîne droite ou ramifiée. The alkyl and alkoxy groups can be straight or branched chain groups.
Un groupe alkyle ayant de 1 à 4 atomes de carbone est par exemple un groupe méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, ou tertiobutyle, de préférence méthyle ou éthyle. An alkyl group having from 1 to 4 carbon atoms is for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl group, preferably methyl or ethyl.
Un groupe alcoxy ayant de 1 à 5 atomes de carbone est par exemple un groupe méthoxy, éthoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiobutoxy, n-pentoxy, isopentoxy ou néopentoxy, de préférence méthoxy, éthoxy, propoxy ou isopropoxy.
Le procédé général pour la préparation des composés selon l'invention, de formule (I), telle que définie précédemment, dans laguelle n est égal à 0 comporte la réaction de condensation du bromo-5 méthyl-4 thiazole sur le sel de sodium d'un (aryl-4 pipérazinyl-1)-2-éthanol de formule : An alkoxy group having from 1 to 5 carbon atoms is for example a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiobutoxy, n-pentoxy, isopentoxy or neopentoxy group, preferably methoxy, ethoxy, propoxy or isopropoxy. The general process for the preparation of the compounds according to the invention, of formula (I), as defined above, in laguelle n is equal to 0 comprises the condensation reaction of 5-bromo-4-methyl-thiazole on the sodium salt d 'a (4-aryl piperazinyl-1) -2-ethanol of formula:
- CH2 - CH2- ONa
dans laquelle R1 et R2 ont la même signification qu'indiqué précédemment. - CH 2 - CH 2 - ONa in which R 1 and R 2 have the same meaning as indicated above.
Selon une caractéristique particulière, le bromo-5 méthyl-4 thiazole est obtenu par bromation de l'amino-2 méthyl-4 thiazole dans des conditions permettant l'obtention de l'amino-2 bromo-5 méthyl-4 thiazole ; et According to a particular characteristic, 5-bromo-4-methyl-thiazole is obtained by bromination of 2-amino-4-methyl-thiazole under conditions allowing the obtaining of 2-amino-5-bromo-4-methyl-thiazole; and
la déamination de l'amino-2 bromo-5 méthyl-4 thiazole ainsi obtenu. deamination of 2-amino-5-bromo-4-methyl thiazole thus obtained.
L'amino-2 méthyl-4 thiazole est un produit connu dont le procédé de préparation est décrit dans la littérature (Merck Index, 10ème édition, n° 454). Amino-2-methyl-4 thiazole is a known product, the preparation process of which is described in the literature (Merck Index, 10th edition, n ° 454).
Le procédé de préparation des composés conformes à l'invention, de formule (I) dans laquelle n est égal à 0 est donc réalisé de préférence en trois étapes suivant le processus réactionnel décrit ci-après : The process for preparing the compounds in accordance with the invention, of formula (I) in which n is equal to 0 is therefore preferably carried out in three stages according to the reaction process described below:
ETAPE 1 STEP 1
ETAPE 2 2ND STEP
Etape 3 Stage 3
Le procédé général pour la préparation des composés selon l'invention, de formule (I), telle que définie précédemment, dans laquelle n est égal à 1 comporte la réaction du (méthyl-4- thiazolyloxy-5)-3 époxy-1,2 propane sur une aryl-4 pipérazine de formule :
The general process for the preparation of the compounds according to the invention, of formula (I), as defined above, in which n is equal to 1 comprises the reaction of (methyl-4-thiazolyloxy-5) -3 epoxy-1, 2 propane on a 4-aryl piperazine of formula:
dans laquelle R1 et R2 ont la même signification qu'indiquée précédemment. in which R 1 and R 2 have the same meaning as indicated above.
Selon une caractéristique particulière, le (méthyl-4 thiazolyloxy-5)-3 époxy-1,2 propane est obtenu par : According to a particular characteristic, (4-methyl-5 thiazolyloxy) -3-1,2-epoxy propane is obtained by:
a - réaction du sel de sodium du glycérol acétonide sur le bromo-5 méthyl-4 thiazole ; a - reaction of the sodium salt of glycerol acetonide with 5-bromo-4-methyl-thiazole;
b - hydrolyse acide du composé ainsi obtenu dans des conditions permettant l'obtention du (méthyl-4 thiazolyloxy-5)-3 propanediol 1,2 ; et b - acid hydrolysis of the compound thus obtained under conditions allowing the obtaining of (methyl-4 thiazolyloxy-5) -3 propanediol 1,2; and
c - réaction du composé obtenu à l'étape b, avec l'azodicarboxylate d'éthyle et la triphényle phosphine. c - reaction of the compound obtained in step b, with ethyl azodicarboxylate and triphenyl phosphine.
Le glycérol acétonide (ou 2,2-diméthyl-1,3-dioxolane-4 methanol), vendu par la société ALDRICH, est un produit connu dont le procédé de préparation est par exemple décrit dans Beilstein 19, 65, Merck Index 10, 3236. Glycerol acetonide (or 2,2-dimethyl-1,3-dioxolane-4 methanol), sold by the company ALDRICH, is a known product whose preparation process is for example described in Beilstein 19, 65, Merck Index 10, 3236.
Ainsi, le procédé de préparation des composés conformes à l'invention de formule (I) dans laquelle n est égal à 1, est donc réalisé de préférence en quatre étapes suivant le processus réactionnel décrit ci-après : Thus, the process for preparing the compounds according to the invention of formula (I) in which n is equal to 1, is therefore preferably carried out in four stages according to the reaction process described below:
Etape 1 Step 1
Les composés de formule (I) selon l'invention et leurs sels pharmaceutiquement acceptables présentent des propriétés pharmacologiques intéressantes qui laissent présager une application thérapeutique de ces composés notamment dans le traitement des manifestations cardio-vasculaires liées à une hyperactivité du système nerveux sympathique de type α-adrénergique. The compounds of formula (I) according to the invention and their pharmaceutically acceptable salts have advantageous pharmacological properties which suggest a therapeutic application of these compounds in particular in the treatment of cardiovascular manifestations linked to hyperactivity of the sympathetic nervous system of type α -adrenergic.
Ainsi, selon un autre aspect. l'invention vise également à couvrir de nouvelles compositions pharmaceutiques, caractérisées en ce qu'elles contiennent, en association avec un excipient pharmaceutiquement acceptable, au moins un composé de formule (I) ou son sel d'addition non toxique, en tant que principe actif. So according to another aspect. the invention also aims to cover new pharmaceutical compositions, characterized in that they contain, in combination with a pharmaceutically acceptable excipient, at least one compound of formula (I) or its non-toxic addition salt, as a principle active.
Les sels acceptables en pharmacie des composés de formule (I) sont obtenus de façon connue en soi, en mettant en contact les produits de formule (I) avec une quantité convenable d'acide pharmaceutiquement acceptable comme par exemple un acide minéral tel que l'acide chlorhydrique ou l'acide sulfurique, ou un acide organique tel que l'acide citrique, tartrique ou fumarique. The pharmaceutically acceptable salts of the compounds of formula (I) are obtained in a manner known per se, by bringing the products of formula (I) into contact with a suitable quantity of pharmaceutically acceptable acid such as for example a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as citric, tartaric or fumaric acid.
Les compositions pharmaceutiques selon l'invention peuvent être généralement préparées par des procédés classiques et administrées sous une forme pharmaceutique appropriée. The pharmaceutical compositions according to the invention can generally be prepared by conventional methods and administered in an appropriate pharmaceutical form.
Les composés peuvent être administrés par exemple par voie orale en 1 à 3 prises par jour, à raison de 2 à 2CO mg par prise suivant le composé, par exemple dans le traitement des manifestations cardio- vasculaires liées à une hyperactivité du système nerveux sympathique de type α-adrénergique. The compounds can be administered, for example, orally in 1 to 3 doses per day, at a rate of 2 to 2 mg per dose depending on the compound, for example in the treatment of cardiovascular manifestations linked to hyperactivity of the sympathetic nervous system of α-adrenergic type.
Selon encore un autre aspect, l'invention vise à couvrir un procédé de préparation d'une composition pharmaceutique, caractérisé en ce qu'on incorpore une quantité pharmaceutiquement efficace d'au moins un composé de formule (I) tel que défini précédemment, ou un sel d'addition non toxique de ce composé, dans un excipient pharmaceutiquement acceptable. According to yet another aspect, the invention aims to cover a process for the preparation of a pharmaceutical composition, characterized in that a pharmaceutically effective amount of at least one compound of formula (I) as defined above is incorporated, or a non-toxic addition salt of this compound, in a pharmaceutically acceptable excipient.
L'invention vise enfin à couvrir un procédé de traitement des manifestations cardio-vasculai res liées à une hyperactivité du système nerveux sympathique de type oc-adrénergique, caractérisé en ce qu'il comprend l'administration à un mammifère comprenant l'homme et l'animal, d'une quantité thérapeutiquement efficace d'au
moins un composé de formule (I) tel que défini précédemment, ou d'un sel d'addition pharmaceutiquement acceptable de ce composé. Finally, the invention aims to cover a method for the treatment of cardiovascular manifestations linked to hyperactivity of the sympathetic nervous system of the oc-adrenergic type, characterized in that it comprises administration to a mammal comprising man and l animal, of a therapeutically effective amount of at least minus a compound of formula (I) as defined above, or of a pharmaceutically acceptable addition salt of this compound.
L'invention sera illustrée à l'aide des exemples non limitatifs suivants : The invention will be illustrated with the aid of the following nonlimiting examples:
EXEMPLE 1 EXAMPLE 1
Synthèse c'u méthyl-4 [(o-éthoxyphényl-4 pipérazinyl-1)-2 éthoxy]-5 thiazole (B 1258). Synthesis ce'u methyl-4 [(o-ethoxyphenyl-4 piperazinyl-1) -2 ethoxy] -5 thiazole (B 1258).
Etape 1 : Synthèse de l'amino-2 bromo-5 méthyl-4 thiazole. Step 1: Synthesis of 2-amino-5-bromo-4-methyl-thiazole.
Une solution chloroformique de brome, 66,7 ml (1,30 mol) de Br2 dans 1 000 ml de CHCl3, est additionnée goutte à goutte et sous agitation à une solution de 120 g (1,05 mol) d'amino-2 méthyl- 4 thiazole dans 2 300 ml de CHCl3. A chloroformic solution of bromine, 66.7 ml (1.30 mol) of Br 2 in 1000 ml of CHCl 3 , is added dropwise and with stirring to a solution of 120 g (1.05 mol) of amino -2 methyl- 4 thiazole in 2300 ml of CHCl 3 .
Un précipité apparaît au cours de l'addition. L'agitation est maintenue durant 48 h. A precipitate appears during the addition. Stirring is continued for 48 h.
Le mi lieu réactionnel est ensuite filtré et le bromhydrate est lavé au dichlorométhane, puis au pentane. The reaction medium is then filtered and the hydrobromide is washed with dichloromethane, then with pentane.
Le bromhydrate est dissous dans 2 000 ml d'eau, puis basifié par addition de 850 ml de solution aqueuse à 10 % de bicarbonate de sodium. The hydrobromide is dissolved in 2000 ml of water, then basified by the addition of 850 ml of 10% aqueous sodium bicarbonate solution.
Cette solution est ensuite extraite par du dichlorométhane. La phase organique est séchée sur sulfate de sodium. Après élimination du solvant sous vide, un résidu cristallisé est obtenu. This solution is then extracted with dichloromethane. The organic phase is dried over sodium sulfate. After removing the solvent under vacuum, a crystallized residue is obtained.
Cristaux bruns : m = 155 g (rendement brut : 76 %) Brown crystals: m = 155 g (gross yield: 76%)
FDK = 112-113°C F DK = 112-113 ° C
RMN1H (δ ppm, DMSO) 2,05 (s, 3H, CH3) 1 H NMR (δ ppm, DMSO) 2.05 (s, 3H, CH 3 )
7,15 (s, 2H, NH2). 7.15 (s, 2H, NH 2 ).
Etape 2 : Synthèse du méthyl-4 bromo-5 thiazole. Step 2: Synthesis of 4-methyl-5-bromo thiazole.
70,7 g (0,366 mol) d'amino-2 bromo-5 méthyl-4 thiazole obtenu à l'étape 1 sont dissous dans un mélange d'acide nitrique (65 %, 102 ml) et d'acide phosphorique (85 %, 480 ml) et diazotés entre -10°C et -5 C avec une solution de nitrite de sodium : 39,4 g 70.7 g (0.366 mol) of 2-amino-5-bromo-4-methyl-thiazole obtained in step 1 are dissolved in a mixture of nitric acid (65%, 102 ml) and phosphoric acid (85% , 480 ml) and diazotized between -10 ° C and -5 C with a sodium nitrite solution: 39.4 g
(0,571 mol) dans 130 ml d'eau. (0.571 mol) in 130 ml of water.
Le milieu réactionnel est laissé sous agitation à cette température durant 30 min. L'acide hypophosphoreux (50 %, 197 ml) est ensuite additionné lentement au milieu réactionnel à -10°C. The reaction medium is left under stirring at this temperature for 30 min. The hypophosphorous acid (50%, 197 ml) is then added slowly to the reaction medium at -10 ° C.
Après addition, celui-ci est maintenu sous agitation à cette tempe
rature pendant 3 h, puis l'ensemble est laissé toute la nuit à température ambiante. After addition, it is stirred at this temperature cross off for 3 h, then the whole is left overnight at room temperature.
On neutralise par une solution aqueuse de soude à 30 % (1,670 mol) puis on extrait par du dichlorométhane. La phase organique est séchée sur sulfate de sodium, le solvant est éliminé par évaporation sous vide, l'huile ainsi recueillie est purifiée par passage au chlorhydrate, et relibération de la base. Neutralized with a 30% aqueous sodium hydroxide solution (1.670 mol) and then extracted with dichloromethane. The organic phase is dried over sodium sulfate, the solvent is removed by evaporation under vacuum, the oil thus collected is purified by passage through the hydrochloride, and reliberation of the base.
Huile jaune : m = 31,28 g (rendement : 48 %) Yellow oil: m = 31.28 g (yield: 48%)
1,5735 1.5735
C4H4BrNS : C 4 H 4 BrNS:
% Cale. C 26,98 H 2,26 Br 44,88 N 7,87 % Trouv. C 26,80 H 2,29 Br 44,80 N 7,78 % Wedge. C 26.98 H 2.26 Br 44.88 N 7.87% Found C 26.80 H 2.29 Br 44.80 N 7.78
RMN1H (δ ppm, DMSO) 2,35 (s, 3H, CH3) 1 H NMR (δ ppm, DMSO) 2.35 (s, 3H, CH 3 )
9,05 (s, H, Ar.) 9.05 (s, H, Ar.)
Etape 3 : Step 3:
1,4 g (0,061 mol) de sodium sont additionnés à 83,5 g (0,33 mol) d'(o-éthoxyphényl-4 pipérazinyl-1)-2 éthanol à 40°C. La formation du sel de sodium nécessite un chauffage de 5 h à 120°C. 1.4 g (0.061 mol) of sodium are added to 83.5 g (0.33 mol) of (o-ethoxyphenyl-4 piperazinyl-1) -2 ethanol at 40 ° C. The formation of the sodium salt requires heating for 5 h at 120 ° C.
9,43 g (0,053 mol) de méthyl-4 bromo-5 thiazole obtenu à l'étape 2 sont alors introduits sous agitation dans le milieu réactionnel à 60-65°C. Cette température est maintenue pendant 5 h, puis élevée à 80°C durant 1 h. 9.43 g (0.053 mol) of 4-methyl-5-bromo thiazole obtained in step 2 are then introduced with stirring into the reaction medium at 60-65 ° C. This temperature is maintained for 5 h, then raised to 80 ° C for 1 h.
Le milieu réactionnel additionné de dichlorométhane est centrifugé à 3 000 tr/min pendant 15 min. Après décantation et évaporation sous vide du solvant, l'(o-éthoxyphényl-4 pipérazinyl- 1)-2 éthanol est éliminé par distillation fractionnée sous pression réduite. Le résidu de distillation est purifié par chromategraphie sur colonne de gel de silice (AcOEt). The reaction medium supplemented with dichloromethane is centrifuged at 3000 rpm for 15 min. After decantation and evaporation under vacuum of the solvent, the (4-o-ethoxyphenyl-piperazinyl-1) -2 ethanol is removed by fractional distillation under reduced pressure. The distillation residue is purified by chromatography on a column of silica gel (AcOEt).
Le trichlorhydrate est préparé dans l'éther éthylique anhydre par addition d'HCl gazeux sec, puis recristallisé dans un mélange d'isopropanol et de pentane. The hydrochloride is prepared in anhydrous ethyl ether by addition of dry HCl gas, then recrystallized from a mixture of isopropanol and pentane.
FBK = 170°C (sublimation). C18 H28 Cl3 O2 S : 456,85
C.H.N % Cale. 47,32 6,18 9,20 F BK = 170 ° C (sublimation). C 18 H 28 Cl 3 O 2 S: 456.85 CHN% Wedge. 47.32 6.18 9.20
% Trouv. 47,34 6,23 9,05 % Find. 47.34 6.23 9.05
RMN 1H (δ ppm) DMSO d6 δ H Thiazole H Phényle O-CH2 CH2 aliph. O-CH2-CH2 1 H NMR (δ ppm) DMSO d 6 δ H Thiazole H Phenyl O-CH 2 CH 2 aliph. O-CH 2 -CH 2
8,85 7 ,00 4,60 4 ,05 3,10 8.85 7.00 4.60 4.05 3.10
(s, 1H) (s, 4H) (t, 2H) (q, 2H) (t, 2H) (s, 1H) (s, 4H) (t, 2H) (q, 2H) (t, 2H)
CH2 pi|oérazine CH3 thiazole CH3 aliph. CH 2 pi | oérazine CH 3 thiazole CH 3 aliph.
2 ,80 2,30 1,35 2.80 2.30 1.35
(m, 8H) (s, 3H) (t, 3H) (m, 8H) (s, 3H) (t, 3H)
EXEMPLES 2 à 12 EXAMPLES 2 to 12
En utilisant des processus expérimentaux analogues à ceux décrits à l'exemple 1, et que l'homme de métier retrouvera facilement, on a préparé les composés suivants : Using experimental procedures analogous to those described in Example 1, and which the skilled person will easily find, the following compounds were prepared:
- méthyl-4[(m-trifluorométhylphényl-4 pipérazinyl-1)-2 éthoxy]-5 thiazole (B 1194), - methyl-4 [(m-trifluoromethylphenyl-4 piperazinyl-1) -2 ethoxy] -5 thiazole (B 1194),
- méthyl-4[(phényl-4 pipérazinyl-1)-2 éthoxy]-5 thiazole (B 1216),- 4-methyl [(4-phenyl-1-piperazinyl) -2 ethoxy] -5 thiazole (B 1216),
- méthyl-4[(o-méthoxyphényl-4 pipérazinyl-1)-2 éthoxy]-5 thiazole (B 1223), - methyl-4 [(o-methoxyphenyl-4 piperazinyl-1) -2 ethoxy] -5 thiazole (B 1223),
- méthyl-4[(p-fluorophényl-4 pipérazinyl-1)-2 éthoxy]-5 thiazole (B 1227), - methyl-4 [(p-fluorophenyl-4 piperazinyl-1) -2 ethoxy] -5 thiazole (B 1227),
- méthyl-4[[(chloro-4 méthyl-2 phényl)-4 pipérazinyl-1]-2 éthoxy]- 5 thiazole (B 1259), - 4-methyl [[(4-chloro-2-methyl-phenyl) -4 piperazinyl-1] -2 ethoxy] - 5 thiazole (B 1259),
- méthyl-4[(o-fluorophényl-4 pipérazinyl-1)-2 éthoxy]-5 thiazole (B 1305), - methyl-4 [(o-fluorophenyl-4 piperazinyl-1) -2 ethoxy] -5 thiazole (B 1305),
- méthyl-4[[(chloro-5 méthyl-2 phényl)-4 pipérazinyl-1]-2 éthoxyj- 5 thiazole (B 1313), - 4-methyl [[(5-chloro-2-methylphenyl) -4 piperazinyl-1] -2 ethoxyj-5 thiazole (B 1313),
- méthy 1-4[(m-éthoxyphényl-4 pipérazinyl-1)-2 éthoxyj-5 thiazole (B 1325), - methyl 1-4 [(m-ethoxyphenyl-4 piperazinyl-1) -2 ethoxyj-5 thiazole (B 1325),
- méthyl-4[(o-propoxyphényl-4 pipérazinyl-1)-2 éthoxy]-5 thiazole (B 1342), - methyl-4 [(o-propoxyphenyl-4 piperazinyl-1) -2 ethoxy] -5 thiazole (B 1342),
- méthyl-4[[(chloro-6 méthyl-2 phényl)-4 pipérazinyl-1]-2 éthoxy]- 5 thiazole (B31366),
- méthyl-4[(o-hydroxyphény 1-4 pipérazinyl-1)-2 éthoxy]-5 thiazole (B 1430). - 4-methyl [[(6-chloro-2-methylphenyl) -4 piperazinyl-1] -2 ethoxy] - 5 thiazole (B31366), - methyl-4 [(o-hydroxypheny 1-4 piperazinyl-1) -2 ethoxy] -5 thiazole (B 1430).
On a regroupé au tableau 1 les principales données concernant les produits synthétisés aux exemples 1 à 12.
The main data concerning the products synthesized in Examples 1 to 12 have been grouped in Table 1.
EXEMPLE 13 EXAMPLE 13
Etape 1 : Synthèse du (méthyl-4 thiazolyloxy-5)-3 propanediol-1,2 acétonide. Step 1: Synthesis of (4-methyl-5 thiazolyloxy) -3-1,2-propanediol acetonide.
6,17 g (0,268 mol) de sodium sont additionnés à 430 ml de glycérol acétonide. Après 3 h 30 à température ambiante et 1 h 30 à 50 C, 36,8 g (0,207 mol) de bromo-5 méthyl-4 thiazole sont introduits et le milieu réactionnel chauffé 7 h à 110°C. 6.17 g (0.268 mol) of sodium are added to 430 ml of acetonide glycerol. After 3 h 30 min at room temperature and 1 h 30 min at 50 ° C., 36.8 g (0.207 mol) of 5-bromo-4-methyl thiazole are introduced and the reaction medium heated for 7 h at 110 ° C.
Le bromo-5 méthyl-4 thiazole peut être obtenu en suivant le processus expérimental décrit aux étapes 1 et 2 de l'exemple 1. 5-bromo-4-methyl thiazole can be obtained by following the experimental process described in steps 1 and 2 of Example 1.
Après filtration du milieu, reprise par du dichlorométhane, puis concentration sous pression réduite. le composé est purifié par distillation fractionnée sous vide. After filtration of the medium, taken up in dichloromethane, then concentration under reduced pressure. the compound is purified by fractional distillation under vacuum.
Eb/0,4 mbar = 95-100°C Eb / 0.4 mbar = 95-100 ° C
27,5 27.5
nD : 1,5010 n D : 1.5010
nD 1 n D 1
RMN 1H(CCl4)(δ ppm) 1 H NMR (CCl 4 ) (δ ppm)
δ H Thiazole 2 CH2-CH CH3 Thiazole 2 CH3 acétonideδ H Thiazole 2 CH 2 -CH CH 3 Thiazole 2 CH 3 acetonide
8,20 3,45-4,50 2,30 1,358.20 3.45-4.50 2.30 1.35
(s, 1H) (m, 5H) (s, 3H) (s, 6H) Etape 2 : Synthèse du (méthyl-4 thiazolyloxy-5)-3 propanediol 1,2. (s, 1H) (m, 5H) (s, 3H) (s, 6H) Step 2: Synthesis of (methyl-4 thiazolyloxy-5) -3 propanediol 1,2.
400 ml d'acide chlorhydrique aqueux 1 N sont additionnés à une solution contenant 30 g (0,31 mol) de (méthyl-4 thiazolyloxy-5)-3 propanediol-1,2 acétonide obtenu à l'étape 1 dans 1 600 ml de methanol à température ambiante. 400 ml of 1N aqueous hydrochloric acid are added to a solution containing 30 g (0.31 mol) of (4-methyl-5 thiazolyloxy) -3-1,2-propanediol acetonide obtained in step 1 in 1,600 ml methanol at room temperature.
Le milieu réactionnel est agité durant 15 h. The reaction medium is stirred for 15 h.
Après concentration à sec sous pression réduite du milieu, le chlorhydrate est cristallisé dans un mélange d'isopropanol et d'éther éthylique. La base est libérée par addition d'une solution de bicarbonate de sodium à 10 %, puis purifiée par recristallisation dans un mélange d'acétate d'éthyle et de pentane (80/20). On obtient 19,1 g de cristaux blancs. After concentrating to dryness under reduced pressure of the medium, the hydrochloride is crystallized from a mixture of isopropanol and ethyl ether. The base is released by adding a 10% sodium bicarbonate solution, then purified by recrystallization from a mixture of ethyl acetate and pentane (80/20). 19.1 g of white crystals are obtained.
FBK = 72-73°C
CRMN 1H(DMSO)(δ ppm)] F BK = 72-73 ° C CRMN 1 H (DMSO) (δ ppm)]
δ H Thiazole CH-OH -CH2-OH CH2/CH CH3 Thiazole
δ H Thiazole CH-OH -CH 2 -OH CH 2 / CH CH 3 Thiazole
8,45 5 4,65 3,25-4,20 2,25 (s, 1H) (d, 1H) (t, 1H) (m, 5H) (s, 3H) Etape 3 : Synthèse du (méthyl-4 thiazolyloxy-5)-3 époxy-1,2 propane. 8.45 5 4.65 3.25-4.20 2.25 (s, 1H) (d, 1H) (t, 1H) (m, 5H) (s, 3H) Step 3: Synthesis of (methyl- 4 thiazolyloxy-5) -3 epoxy-1,2 propane.
12,2 g (0,07 mol) d'azodicarboxylate d'éthyle sont additionnés goutte à goutte à une solution contenant 10 g (0,053 mol) de (méthyl-4 thiazolyloxy-5)-3 propanediol-1,2 obtenu à l'étape 2, et 14 g (0,053 mol) de triphényle phosphine dans 200 ml de toluène à température ambiante. 12.2 g (0.07 mol) of ethyl azodicarboxylate are added dropwise to a solution containing 10 g (0.053 mol) of (methyl-4 thiazolyloxy-5) -3-1,2-propanediol 'step 2, and 14 g (0.053 mol) of triphenyl phosphine in 200 ml of toluene at room temperature.
Le milieu réactionnel est chauffé 10 h à 70 C. Après cristallisation sélective de la dicarbéthoxy- hydrazine et de l'oxyde de triphényle phosphine, par addition de pentane dans le milieu réactionnel, le filtrat est concentré à sec sous pression réduite et le (méthyl-4 thiazolyloxy-5)-3 époxy-1,2 propane est purifié par chromatographie sur colonne de gel de silice (AcOEt). On obtient 6,75 g d'époxyde, sous forme d'une huile jaune pâle. The reaction medium is heated for 10 h at 70 C. After selective crystallization of the dicarbethoxyhydrazine and of the triphenylphosphine oxide, by addition of pentane in the reaction medium, the filtrate is concentrated to dryness under reduced pressure and the (methyl -4 thiazolyloxy-5) -3 epoxy-1,2 propane is purified by chromatography on a column of silica gel (AcOEt). 6.75 g of epoxide are obtained, in the form of a pale yellow oil.
I.R. : 3 080 cm-1, 1 560 C = C, 1 260 C-O, 840 C-O IR: 3,080 cm -1 , 1,560 C = C, 1,260 CO, 840 CO
C = N C = N
Thiazole Thiazole Thiazole Epoxyde Thiazole Thiazole Thiazole Epoxide
RMN 1Η,(DMSO) (δ ppm) 1 N NMR, (DMSO) (δ ppm)
δ H Thiazole CH2/CH CH3 Thiazole δ H Thiazole CH 2 / CH CH 3 Thiazole
8,4 2,6-4,5 2,2 8.4 2.6-4.5 2.2
(s, 1H) (m, 5H) (s, 3H) (s, 1H) (m, 5H) (s, 3H)
Etape 4 : Synthèse du monochlorhydrate de l'(o-propoxyphényl-4 pipérazinyl-1)-3 (méthyl-4 thiazolyloxy-5)-1 propanol-2 (B 1395). Step 4: Synthesis of (4-o-propoxyphenyl-1 piperazinyl-1) -3 (4-methylthiazolyloxy-5) -1-propanol-2 monohydrochloride (B 1395).
2,5 g (0,0113 mol) d'o-propoxyphényl pipérazine sont additionnés goutte à goutte à une solution contenant 1,94 g (0,0113 mol) de (méthyl-4 thiazolyloxy-5)-3 époxy-1,2 propane obtenu à l'étape 3 dans 90 ml d'éthanol à température ambiante. 2.5 g (0.0113 mol) of o-propoxyphenyl piperazine are added dropwise to a solution containing 1.94 g (0.0113 mol) of (4-methyl-5 thiazolyloxy) -3-epoxy-1, 2 propane obtained in step 3 in 90 ml of ethanol at room temperature.
Le milieu réactionnel est chauffé à 40°C pendant 21 h. Le solvant est éliminé par distillation sous pression réduite. On obtinnt une huile.
Le monochlorhydrate est obtenu par addition d'une quantité stoechiométrique d'une solution éthanolique d'acide chlorhydrique préalablement dosée, dans une solution éthanolique de la base refroidie par un bain de glace. Après 1 h d'agitation et élimination de l'éthanol par distillation sous pression réduite, le produit est cristallisé dans un mélange d'éther éthylique et d'acétone puis recristal lise dans l'acétone. The reaction medium is heated at 40 ° C for 21 h. The solvent is removed by distillation under reduced pressure. We get an oil. The monohydrochloride is obtained by adding a stoichiometric amount of an ethanolic solution of hydrochloric acid previously dosed, in an ethanolic solution of the base cooled by an ice bath. After 1 h of stirring and elimination of the ethanol by distillation under reduced pressure, the product is crystallized from a mixture of ethyl ether and acetone and then recrystallized from acetone.
On obtient des cristaux blancs : 3,21 g. White crystals are obtained: 3.21 g.
FBK = 144-145°C F BK = 144-145 ° C
C20 H30 Cl N3 O3 S : C 20 H 30 Cl N 3 O 3 S:
Cale. % C 56,13 H 7,07 N 9 ,82 Hold. % C 56.13 H 7.07 N 9.82
Trouv. % C 56,50 H 7,01 N 9,80Find. % C 56.50 H 7.01 N 9.80
RMN 1H (DMSO) ( ppm) 1 H NMR (DMSO) (ppm)
OH H Thiazole H Phényle CH2-0OH H Thiazole H Phenyl CH 2 -0
11,0 8,35 6,85 4,4511.0 8.35 6.85 4.45
(m, 1H) (s, 1H) ("s", 4H) (m, 2H)(m, 1H) (s, 1H) ("s", 4H) (m, 2H)
CH2 N CH3 Thiazole CH2 propoxy CH3 propoxyCH 2 N CH 3 Thiazole CH 2 propoxy CH 3 propoxy
CH2 pipérazine CH 2 piperazine
CH CH
CH CH
3,4 2,2 1,7 1 3.4 2.2 1.7 1
(m, 13H) (s, 3H) (m, 2H) (t, 3H) (m, 13H) (s, 3H) (m, 2H) (t, 3H)
EXEMPLES 14 à 24 EXAMPLES 14 to 24
En utilisant les processus expérimentaux analogues à ceux décrits à l'exemple 13, et que l'homme de métier retrouvera facilement, on a préparé les composés suivants : Using the experimental procedures analogous to those described in Example 13, and which the skilled person will easily find, the following compounds were prepared:
- (o-éthoxyphényl-4 pipérazinyl-1)-3 (méthyl-4 thiazoly loxy-5)-1 propanol-2 (B 1392), - (4-ethoxyphenyl-1 piperazinyl) -3 (4-methyl-thiazoly loxy-5) -1 propanol-2 (B 1392),
- (o-hydroxyphényl-4 pipérazinyl-1)-3 (méthyl-4 thiazolyloxy-5)-1 propanol-2 (B 1396), - (4-hydroxyphenyl-piperazinyl-1) -3 (4-methyl-thiazolyloxy-5) -1 propanol-2 (B 1396),
- C(chloro-4 méthyl-2 phényl)-4 pipérazinyl-1] -3 (méthyl-4 thiazolyloxy-5)-1 propanol-2 (B 1406), - C (4-chloro-2-methylphenyl) -4 piperazinyl-1] -3 (4-methyl-thiazolyloxy-5) -1 propanol-2 (B 1406),
- (o-isopropoxyphényl-4 pipérazinyl-1)-3 (méthyl-4 thiazolyloxy-5)-1 propanol-2 (B 1429),
- (o-isobutoxyphényl-4 pipérazinyl-1)-3 (méthyl-4 thiazolyloxy-5)- 1 propanol-2 (B 1431), - (4-isopropoxyphenyl-1 piperazinyl) -3 (4-methyl-5 thiazolyloxy) -1 propanol-2 (B 1429), - (o-isobutoxyphenyl-4 piperazinyl-1) -3 (4-methyl-thiazolyloxy-5) - 1 propanol-2 (B 1431),
- (m-trifluorouéthylphényl-4-pipérazinyl-1)-3 (méthyl-4 - (m-trifluorouethylphenyl-4-piperazinyl-1) -3 (methyl-4
thiazolyloxy-5)-1 propanol-2 (B 1489), thiazolyloxy-5) -1 propanol-2 (B 1489),
- (o-méthoxyphényl-4 pipérazinyl-1)-3 (méthyl-4 thiazolyloxy-5)-1 propanol-2 (B 1510), - (4-o-methoxyphenyl-1-piperazinyl) -3 (4-methyl-5 thiazolyloxy) -1 propanol-2 (B 1510),
- (o-pentoxyphényl-4 pipérazinyl-1)-3 (méthyl-4 thiazolyloxy-5)-1 propanol-2 (B 1525), - (o-pentoxyphenyl-4 piperazinyl-1) -3 (4-methyl-thiazolyloxy-5) -1 propanol-2 (B 1525),
- (m-chlorophényl-4 pipérazinyl-1)-3 (méthyl-4 thiazolyloxy-5)-1 propanol-2 (B 1548), - (4-m-chlorophenyl-piperazinyl-1) -3 (4-methyl-thiazolyloxy-5) -1 propanol-2 (B 1548),
- (o-isopentoxyphényl-4 pipérazinyl-1)-3 (méthyl-4 - (o-isopentoxyphenyl-4 piperazinyl-1) -3 (methyl-4
thiazolyloxy-5)-1 propanol-2 (B 1552), thiazolyloxy-5) -1 propanol-2 (B 1552),
- (o-néopentoxyphényl-4 pipérazinyl-1)-3 (méthyl-4 - (4-o-neopentoxyphenyl-1 piperazinyl) -3 (4-methyl
thiazolyloxy-5)-1 propanol-2 (B 1562). thiazolyloxy-5) -1 propanol-2 (B 1562).
On a regroupé au tableau 2 les formules et les principales propriétés physiques concernant les produits synthétisés aux exemples 13 à 24.
The formulas and the main physical properties relating to the products synthesized in Examples 13 to 24 are grouped in Table 2.
La toxicité et les propriétés pharmacologiques des produits de formule (I) ont été testés et les résultats obtenus sont décrits ci-après : The toxicity and pharmacological properties of the products of formula (I) were tested and the results obtained are described below:
I. Toxicité aiguë chez la souris. I. Acute toxicity in mice.
Principe de la mesure. Principle of measurement.
Les produits ont été adm és par voie orale à dose unique chez la souris mâle d'un poid n de 22 g. La mortalité a été enregistrée après une période d'observation de 14 jours. The products were administered orally at a single dose in male mice weighing 22 g. Mortality was recorded after a 14-day observation period.
Les résultats sont, exprimés sous forme de dose létale 50 (DL 50) : dose théorique en mg.kg- 1, par voie orale, provoquant la mort de 50 % des animaux. The results are, expressed in the form of a lethal dose 50 (LD 50): theoretical dose in mg.kg - 1 , orally, causing the death of 50% of the animals.
Résultats Results
Ils sont rapportés dans le tableau 3. La plupart des molécules ont une DL 50 supérieure à 1 g. kg-1. Ce sont donc des produits peu toxiques après une seule administration. II. Détermination de l'activité alpha-bloquante sur canal déférent isolé de rat. They are reported in Table 3. Most of the molecules have an LD 50 greater than 1 g. kg -1 . They are therefore not very toxic products after a single administration. II. Determination of alpha-blocking activity on isolated rat vas deferens.
Principe Principle
La stimulation des récepteurs alpha-adrénergiques post- synaptiques par la noradrénaline provoque la contraction du canal déférent isolé. The stimulation of post-synaptic alpha-adrenergic receptors by norepinephrine causes the isolated vas deferens to contract.
On détermine la concentration de produit en présence de laquelle il faut multiplier par deux la concentration de noradrénaline pour obtenir le même effet qu'en l'absence dudit produit. Le logarithme changé de signe de cette concentration constitue la pA2 des produits. The concentration of product is determined in the presence of which the concentration of noradrenaline must be multiplied by two to obtain the same effect as in the absence of said product. The logarithm changed sign of this concentration constitutes the pA 2 of the products.
Résultats Results
Les valeurs des pA2 rapportées dans le tableau 4 montrent que les produits se comportent comme des antagonistes compétitifs de la noradrénaline au niveau des récepteurs alpha-adrénergiques.
Leur activité alpha-bloquante est importante puisqu'elle apparaît pour des concentrations faibles entre 10-6 M et 10-8 H. The pA 2 values reported in Table 4 show that the products behave as competitive norepinephrine antagonists at the alpha-adrenergic receptors. Their alpha-blocking activity is important since it appears for low concentrations between 10 -6 M and 10 -8 H.
III. Détermination de l'activité adrénoLytique "in vivo" chez le rat. III. Determination of adrenoLytic activity "in vivo" in rats.
Principe de la mesure. Principle of measurement.
L'injection intra-veineuse de noradrénaline (0,4 mg.kg-1) chez le rat mâle vigile provoque la mort de 100 % des animaux. L'administration préalable d'une substance à propriété alphabloquante permet de réduire cette toxicité. The intravenous injection of noradrenaline (0.4 mg.kg -1 ) in the vigilant male rat causes the death of 100% of the animals. The prior administration of a substance with an alpha-blocking property makes it possible to reduce this toxicity.
Résultats Results
Les résultats sont exprimés sous forme de dose efficace 50 (DE 50), dose en mg.kg-1, protégeant 50 % des animaux (tableauThe results are expressed in the form of an effective dose 50 (ED 50), dose in mg.kg -1 , protecting 50% of the animals (table
5). Les produits B 1258, B 1242, B 1392, B 1395, B 1396, B 1429 et5). Products B 1258, B 1242, B 1392, B 1395, B 1396, B 1429 and
B 1431, B 1510, B 1525, B 1548 et B 1552 se révèlent particulièrement très actifs chez l'animal entier, confirmant ainsi leur action mise en évidence in vitro. B 1431, B 1510, B 1525, B 1548 and B 1552 prove to be particularly active in the whole animal, thus confirming their action demonstrated in vitro.
IV. Détermination de l'activité inhibitrice de l'hypertension artérielle chez le lapin. IV. Determination of the inhibitory activity of arterial hypertension in rabbits.
Principe de la mesure. Principle of measurement.
La pression artérielle est mesurée par cathétérisme de la carotide gauche, chez le lapin mâle anesthésié. L'augmentation de la pression artérielle est induite par une injection intra-veineuse de noradrénaline. Cette hypertension peut être inhibée par l'administration préalable de molécules à potentiel alpha-bloquant. Blood pressure is measured by catheterization of the left carotid artery in the anesthetized male rabbit. The increase in blood pressure is induced by an intravenous injection of norepinephrine. This hypertension can be inhibited by the prior administration of molecules with alpha-blocking potential.
Seuls les composés B 1216, B 1258, B 1305, B 1342, Only compounds B 1216, B 1258, B 1305, B 1342,
B 1392, B 1395 et B 1431 ont été essayés sur ce modèle. B 1392, B 1395 and B 1431 have been tested on this model.
Résultats Results
Ils sont présentés dans le tableau 6 sous forme de dose inhibitrice 50 % (DI 50) définie comme étant la dose de produit qui, administrée en I.V., inhibe de 50 % l 'hyperpression artérielle
induite par la noradrénaline. Le composé B 1395 est particulièrement efficace avec une dose active inférieure à 1 mg.kg V. Détermination de l'activité cardiovasculaire They are presented in table 6 in the form of a 50% inhibitory dose (ID 50) defined as being the dose of product which, administered by IV, inhibits by 50% the arterial hyperpressure. noradrenaline-induced. Compound B 1395 is particularly effective with an active dose of less than 1 mg.kg V. Determination of cardiovascular activity
Principe de la mesure. Principle of measurement.
Les effets cardiovasculaires de trois produits ont été recherchés chez le rat anesthésié au pentobarbital et placé sous respiration artificielle. La pression artérielle fémorale et la fréquence cardiaque sont enregistrées à l'aide du matériel GOULD- The cardiovascular effects of three products were investigated in rats anesthetized with pentobarbital and placed under artificial respiration. Femoral blood pressure and heart rate are recorded using GOULD-
BRUSH. BRUSH.
Les produits sont administrés par voie intra-veineuse à doses croissantes. Trois animaux sont testés par produit. La dose provoquant une baisse de pression artérielle moyenne de 25 % The products are administered intravenously in increasing doses. Three animals are tested per product. The dose causing a 25% drop in average blood pressure
(DE 25) a été évaluée pour chaque produit et comparée à la(DE 25) was assessed for each product and compared to the
Nicardipine 1 à 5 min après administration. Nicardipine 1 to 5 min after administration.
Résultats Results
Les produits ont des effets hypotenseurs dose- dépendants mais n'affectent pas ou peu la fréquence cardiaque (tableau 7). Le plus hypotenseur en terme de dose efficace est le B 1395 (DE 25 à 0,004 mg.kg-1). Les DE 25 évaluées 5 min après injection permettent de situer le potentiel hypotenseur des produits B 1395, B 1396, B 1431 etB1552 au niveau de la Nicardipine.
The products have dose-dependent hypotensive effects but have little or no effect on the heart rate (Table 7). The most hypotensive in terms of effective dose is B 1395 (DE 25 at 0.004 mg.kg -1 ). The ED 25 evaluated 5 min after injection make it possible to locate the hypotensive potential of the products B 1395, B 1396, B 1431 and B1552 at the level of Nicardipine.
Tableau n° 7 : Table n ° 7:
Ces données laissent présager une bonne activité thérapeutique des composés de formule (I) dans les manifestations cardiovasculaires liées à une hyperactivité du système nerveux sympathique de type alpha-adrénergique.
These data suggest good therapeutic activity of the compounds of formula (I) in cardiovascular manifestations linked to hyperactivity of the sympathetic nervous system of the alpha-adrenergic type.
Claims
1. Dérivés du méthyl-4 thiazole répondant à la formule générale : 1. 4-Methyl thiazole derivatives corresponding to the general formula:
dans laquelle n est égal à 0 ou 1, et R1 et R2, identiques ou différents sont choisis parmi un atome d'hydrogène, un halogène, un groupe hydroxy, un groupe trif luorométhyle, un groupe alkyle ayant de 1 à 4 atomes de carbone, un groupe alcoxy ayant de 1 à 5 atomes de carbone ; et leurs sels pharmaceutiquement acceptables. in which n is equal to 0 or 1, and R 1 and R 2 , which are identical or different, are chosen from a hydrogen atom, a halogen, a hydroxy group, a trifluoromethyl group, an alkyl group having from 1 to 4 atoms carbon, an alkoxy group having 1 to 5 carbon atoms; and their pharmaceutically acceptable salts.
2. Dérivés de formule (I) selon la revendication 1, dans laquelle n est égal à 0, caractérisés en ce qu'il s'agit des composés suivants : 2. Derivatives of formula (I) according to claim 1, in which n is equal to 0, characterized in that they are the following compounds:
- méthyl-4[(m-trifluorométhylphényl-4 pipérazinyl-1)-2 éthoxy]-5 thiazole (B 1194), - methyl-4 [(m-trifluoromethylphenyl-4 piperazinyl-1) -2 ethoxy] -5 thiazole (B 1194),
- méthyl-4[(phényl-4 pipérazinyl-1)-2 éthoxy]-5 thiazole (B 1216), - 4-methyl [(4-phenyl-1-piperazinyl) -2 ethoxy] -5 thiazole (B 1216),
- méthyl-4[(o-méthoxyphényl-4 pipérazinyl-1)-2 éthoxy]-5 thiazole (B 1223), - methyl-4 [(o-methoxyphenyl-4 piperazinyl-1) -2 ethoxy] -5 thiazole (B 1223),
- méthyl-4[(p-fluorophényl-4 pipérazinyl-1)-2 éthoxy]-5 thiazole (B 1227), - methyl-4 [(p-fluorophenyl-4 piperazinyl-1) -2 ethoxy] -5 thiazole (B 1227),
- méthyl-4[[(chloro-4 méthyl-2 phényl)-4 pipérazinyl-1]-2 éthoxy]- 5 thiazole (B 1259), - 4-methyl [[(4-chloro-2-methyl-phenyl) -4 piperazinyl-1] -2 ethoxy] - 5 thiazole (B 1259),
- méthyl-4[(o-fluorophényl-4 pipéraziny1-1)-2 éthoxy]-5 thiazole (B 1305), - 4-methyl [(4-o-fluorophenyl piperaziny1-1) -2 ethoxy] -5 thiazole (B 1305),
- méthyl-4[[(chloro-5 méthyl-2 phényl)-4 pipérazinyl-1]-2 éthoxy}- 5 thiazole (B 1313), - 4-methyl [[(5-chloro-2-methylphenyl) -4 piperazinyl-1] -2 ethoxy} - 5 thiazole (B 1313),
- méthyl-4[(m-éthoxyphényl-4 pipérazinyl-1)-2 éthoxy]-5 thiazole (B 1325), - methyl-4 [(m-ethoxyphenyl-4 piperazinyl-1) -2 ethoxy] -5 thiazole (B 1325),
- méthyl-4[(o-propcxyphényl-4 pipérazinyl-1)-2 éthoxy]-5 thiazole (B 3342), - méthyl-4[[(chloro-6 méthyl-2 phényl)-4 pipérazinyl-1]-2 éthoxy]- 5 thiazole (B 1366), - methyl-4 [(o-propcxyphenyl-4 piperazinyl-1) -2 ethoxy] -5 thiazole (B 3342), - 4-methyl [[(6-chloro-2-methylphenyl) -4 piperazinyl-1] -2 ethoxy] - 5 thiazole (B 1366),
- méthyl-4[(o-hydroxyphényl-4 pipérazinyl-1)-2 éthoxy]-5 thiazole (B 1430). - methyl-4 [(o-hydroxyphenyl-4 piperazinyl-1) -2 ethoxy] -5 thiazole (B 1430).
3. Dérivés de formule (I) selon la revendication 1, où n est égal à 1, caractérisés en ce qu'il s'agit des composés suivants :3. Derivatives of formula (I) according to claim 1, where n is equal to 1, characterized in that they are the following compounds:
- (o-éthoxyphényl-4 pipérazinyl-1)-3 (méthyl-4 thiazolyloxy-5)-1 propanol-2 (B 1392), - (4-o-ethoxyphenyl-1-piperazinyl) -3 (4-methyl-5-thiazolyloxy) -1 propanol-2 (B 1392),
- (o-hydroxyphényl-4 pipérazinyl-1)-3 (méthyl-4 thiazolyloxy-5)-1 propanol-2 (B 1396), - (4-hydroxyphenyl-piperazinyl-1) -3 (4-methyl-thiazolyloxy-5) -1 propanol-2 (B 1396),
- [(chloro-4 méthyl-2 phényl-4)pipérazinyl-1]-3 (méthyl-4 thiazolyloxy-5)-1 propanol-2 (B 1406), - [(4-chloro-2-methyl-4-phenyl) piperazinyl-1] -3 (4-methyl-5-thiazolyloxy) -1 propanol-2 (B 1406),
- (o-isopropoxyphényl-4 pipérazinyl-1)-3 (méthyl-4 thiazolyloxy-5)- 1 propanol-2 (B 1429), - (4-isopropoxyphenyl-1 piperazinyl) -3 (4-methyl-5 thiazolyloxy) - 1 propanol-2 (B 1429),
- (o-isobutoxyphényl-4 pipérazinyl-1)-3 (méthyl-4 thiazolyloxy-5)- 1 propanol-2 (B 1431). - (o-isobutoxyphenyl-4 piperazinyl-1) -3 (4-methyl-thiazolyloxy-5) - 1 propanol-2 (B 1431).
- (m-trifluorométhylphényl-4-pipérazinyl-1)-3 (méthyl-4 - (m-trifluoromethylphenyl-4-piperazinyl-1) -3 (methyl-4
thiazolyloxy-5)-1 propanol-2 (B 1489), thiazolyloxy-5) -1 propanol-2 (B 1489),
- (o-méthoxyphényl-4 pipérazinyl-1)-3 (méthyl-4 thiazolyloxy-5)-1 propanol-2 (B 1510), - (4-o-methoxyphenyl-1-piperazinyl) -3 (4-methyl-5 thiazolyloxy) -1 propanol-2 (B 1510),
- (o-pentoxyphényl-4 pipérazinyl-1)-3 (méthyl-4 thiazolyloxy-5)-1 propanol-2 (B 1525), - (o-pentoxyphenyl-4 piperazinyl-1) -3 (4-methyl-thiazolyloxy-5) -1 propanol-2 (B 1525),
- (m-chlorophényl-4 pipérazinyl-1)-3 (méthyl-4 thiazolyloxy-5)-1 propanol-2 (B 1548), - (4-m-chlorophenyl-piperazinyl-1) -3 (4-methyl-thiazolyloxy-5) -1 propanol-2 (B 1548),
- (o-isopentoxyphényl-4 pipérazinyl-1)-3 (méthyl-4 - (o-isopentoxyphenyl-4 piperazinyl-1) -3 (methyl-4
thiazolyloxy-5)-1 propanol-2 (B 1552), thiazolyloxy-5) -1 propanol-2 (B 1552),
- (o-néopentoxyphényl-4 pipérazinyl-1)-3 (méthyl-4 - (4-o-neopentoxyphenyl-1 piperazinyl) -3 (4-methyl
thiazolyloxy-5)-1 propanol-2 (B 1562). thiazolyloxy-5) -1 propanol-2 (B 1562).
4. Procédé pour la préparation des dérivés répondant à la formule générale (I) selon la revendication 1, dans laquelle n égal 0, caractérisé en ce qu'il comprend la réaction de condensation du bromo-5 méthyl-4 thiazole sur le sel de sodium d'un amino-2 éthanol de formule : dans laquelle R1 et R2 ont la même signification qu'indiqué précédemment. 4. Process for the preparation of the derivatives corresponding to the general formula (I) according to claim 1, in which n equals 0, characterized in that it comprises the condensation reaction of 5-bromo-4-methyl-thiazole on the salt of sodium of a 2-amino ethanol of formula: in which R 1 and R 2 have the same meaning as indicated above.
5. Procédé selon la revendication 4, caractérisé en ce que le bromo-5 méthyl-4 thiazole est obtenu par : 5. Method according to claim 4, characterized in that the 5-bromo-4-methyl thiazole is obtained by:
bromation de l'amino-2 méthyl-4 thiazole dans des conditions permettant l'obtention de l'amino-2 brorr.o-5 méthyl-4 thiazole, et déamination de l'amino-2 bromo-5 méthyl-4 thiazole. bromination of the amino-2 methyl-4 thiazole under conditions allowing the obtaining of the amino-2 brorr.o-5 methyl-4 thiazole, and deamination of amino-2 bromo-5 methyl-4 thiazole.
6. Procédé pour la préparation des dérivés répondant à la formule générale (I) selon la revendication 1, dans laquelle n égal 1, caractérisé en ce qu'il comprend la réaction du (méthyl-4 thiazolyloxy-5)-3 époxy-1,2 propane sur une aryl-4 pipérazine de formule : 6. Process for the preparation of the derivatives corresponding to the general formula (I) according to claim 1, in which n equals 1, characterized in that it comprises the reaction of (4-methyl-thiazolyloxy-5) -3 epoxy-1 , 2 propane on a 4-aryl piperazine of formula:
dans laquelle R1 et R2 ont la même signification qu'indiquée précédemment. in which R 1 and R 2 have the same meaning as indicated above.
7. Procédé selon la revendication 6, caractérisé en ce que le (méthyl-4 thiazolyloxy-5)-3 époxy-1,2 propane est obtenu par : a - réaction du sel de sodium du glycérol acétonide sur le bromo-5 méthyl-4 thiazole ; 7. Method according to claim 6, characterized in that the (methyl-4 thiazolyloxy-5) -3 epoxy-1,2 propane is obtained by: a - reaction of the sodium salt of glycerol acetonide on bromo-5 methyl- 4 thiazole;
b - hydrolyse acide du composé ainsi obtenu dans des conditions permettant l'obtention du (méthyl-4 thiazolyloxy-5)-3 propanediol- 1,2 ; et b - acid hydrolysis of the compound thus obtained under conditions allowing the obtaining of (methyl-4 thiazolyloxy-5) -3 propanediol-1,2; and
c - réaction du composé obtenu à l'étape b, avec l 'azodicarboxylate d'éthyle et la triphényle phosphine. c - reaction of the compound obtained in step b, with ethyl azodicarboxylate and triphenyl phosphine.
8. Compositions pharmaceutiques, caractérisées en ce qu'elles contiennent à titre d'ingrédient actif, au moins un composé selon l'une quelconque des revendications 1 à 3, en association avec un véhicule ou support non toxique, pharmaceuti quement acceptable. 8. Pharmaceutical compositions, characterized in that they contain, as active ingredient, at least one compound according to any one of claims 1 to 3, in combination with a non-toxic, pharmaceutical carrier or support. only acceptable.
9. Compositions pharmaceutiques utiles dans le traitement des mεnifestations cardiovasculaires liées à une hyperactivité du système nerveux sympathique de type alpha-adrénergique, caractérisées en ce qu'elles contiennent, à titre d'ingrédient actif, au moins un composé selon l'une quelconque des revendications 1 à 3, en association avec un véhicule ou support non toxique, pharmaceutiquement acceptable. 9. Pharmaceutical compositions useful in the treatment of cardiovascular manifestations linked to hyperactivity of the sympathetic nervous system of alpha-adrenergic type, characterized in that they contain, as active ingredient, at least one compound according to any one of Claims 1 to 3, in association with a non-toxic, pharmaceutically acceptable vehicle or support.
10. Procédé de préparation d'une composition pharmaceutique notamment utile dans le traitement des manifestations cardiovasculaires liées à une hyperactivité du système nerveux sympathique de type α-adrénergique, caractérisé en ce qu'on incorpore une quantité pharmaceutiquement efficace d'au moins un corrposé de formule (I) selon l'une des revendications 1 à 3, dans un excipient pharmaceutiquement acceptable. 10. A process for the preparation of a pharmaceutical composition especially useful in the treatment of cardiovascular manifestations linked to hyperactivity of the sympathetic nervous system of the α-adrenergic type, characterized in that a pharmaceutically effective amount of at least one compound of formula (I) according to one of claims 1 to 3, in a pharmaceutically acceptable excipient.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9001979 | 1990-02-19 | ||
| FR9001979A FR2658514B1 (en) | 1990-02-19 | 1990-02-19 | NOVEL 4-METHYL THIAZOLE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME. |
| PCT/FR1991/000118 WO1991012246A1 (en) | 1990-02-19 | 1991-02-14 | Novel 4-methyl thiazole derivatives, preparation methods therefor and pharmaceutical compositions containing said derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0594595A1 true EP0594595A1 (en) | 1994-05-04 |
Family
ID=9393877
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP91904815A Withdrawn EP0594595A1 (en) | 1990-02-19 | 1991-02-14 | Novel 4-methyl thiazole derivatives, preparation methods therefor and pharmaceutical compositions containing said derivatives |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US5322846A (en) |
| EP (1) | EP0594595A1 (en) |
| JP (1) | JPH05503537A (en) |
| CA (1) | CA2075998A1 (en) |
| FR (1) | FR2658514B1 (en) |
| IE (1) | IE910540A1 (en) |
| PT (1) | PT96808A (en) |
| WO (1) | WO1991012246A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2186499A1 (en) * | 1994-03-30 | 1995-10-12 | Kiyoshi Yoshida | Indole derivative and medicine containing the same |
| DE19728996A1 (en) | 1997-07-07 | 1999-01-14 | Basf Ag | Triazole compounds and their use |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE756127A (en) * | 1969-09-12 | 1971-03-15 | Hoechst Ag | HETEROCYCLIC ETHERS AND THEIR PREPARATION |
| US3850946A (en) * | 1972-07-10 | 1974-11-26 | Syntex Inc | 3-thiazol-5'-oxy-aminopropanol cardiovascular agents |
| FR2209557A1 (en) * | 1972-12-12 | 1974-07-05 | Roussel Uclaf | Piperazo alkyl thiazolyl ketones/ethers - adrenolytics and antihypertensives prepd. from a piperazine and a halo alkyl thiazole |
| FR2637596B1 (en) * | 1988-10-11 | 1992-09-04 | Irceba | METHYL-4 ((ARYL-4 PIPERAZINYL-1) -2 ETHYL) -5 THIAZOLE AND ITS DERIVATIVES, THEIR PREPARATION METHOD AND THE MEDICINAL PRODUCTS CONTAINING THEM |
-
1990
- 1990-02-19 FR FR9001979A patent/FR2658514B1/en not_active Expired - Lifetime
-
1991
- 1991-02-14 EP EP91904815A patent/EP0594595A1/en not_active Withdrawn
- 1991-02-14 WO PCT/FR1991/000118 patent/WO1991012246A1/en not_active Application Discontinuation
- 1991-02-14 JP JP3505502A patent/JPH05503537A/en active Pending
- 1991-02-14 CA CA002075998A patent/CA2075998A1/en not_active Abandoned
- 1991-02-14 US US07/916,846 patent/US5322846A/en not_active Expired - Fee Related
- 1991-02-15 IE IE054091A patent/IE910540A1/en unknown
- 1991-02-19 PT PT96808A patent/PT96808A/en not_active Application Discontinuation
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9112246A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2075998A1 (en) | 1991-08-20 |
| FR2658514B1 (en) | 1992-06-19 |
| FR2658514A1 (en) | 1991-08-23 |
| US5322846A (en) | 1994-06-21 |
| JPH05503537A (en) | 1993-06-10 |
| IE910540A1 (en) | 1991-08-28 |
| PT96808A (en) | 1991-10-31 |
| WO1991012246A1 (en) | 1991-08-22 |
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