FI58326B - FOERFARANDE FOER FRAMSTAELLNING AV SOM BETA-ADRENERGISKT STIMULERANDE MEDEL ANVAENDBARA ALFA-AMINOMETHYL-4-HYDROXI-3-METHYLSULFONYL-METHYL-BENZYL ALCOHOL - Google Patents
FOERFARANDE FOER FRAMSTAELLNING AV SOM BETA-ADRENERGISKT STIMULERANDE MEDEL ANVAENDBARA ALFA-AMINOMETHYL-4-HYDROXI-3-METHYLSULFONYL-METHYL-BENZYL ALCOHOL Download PDFInfo
- Publication number
- FI58326B FI58326B FI778/73A FI77873A FI58326B FI 58326 B FI58326 B FI 58326B FI 778/73 A FI778/73 A FI 778/73A FI 77873 A FI77873 A FI 77873A FI 58326 B FI58326 B FI 58326B
- Authority
- FI
- Finland
- Prior art keywords
- aminomethyl
- methylsulfonyl
- stimulerande
- adrenergiskt
- anvaendbara
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 16
- -1 methylsulfonylmethylbenzyl alcohols Chemical class 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000000021 stimulant Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 4
- 241000700199 Cavia porcellus Species 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 230000002269 spontaneous effect Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- LAMHAMBOLINJML-UHFFFAOYSA-N 1-[3-(chloromethyl)-4-hydroxyphenyl]ethanone Chemical compound CC(=O)C1=CC=C(O)C(CCl)=C1 LAMHAMBOLINJML-UHFFFAOYSA-N 0.000 description 2
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229960004050 aminobenzoic acid Drugs 0.000 description 2
- 230000001746 atrial effect Effects 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- JAHNSTQSQJOJLO-UHFFFAOYSA-N 2-(3-fluorophenyl)-1h-imidazole Chemical compound FC1=CC=CC(C=2NC=CN=2)=C1 JAHNSTQSQJOJLO-UHFFFAOYSA-N 0.000 description 1
- BSMGLVDZZMBWQB-UHFFFAOYSA-N 2-methyl-1-phenylpropan-1-one Chemical compound CC(C)C(=O)C1=CC=CC=C1 BSMGLVDZZMBWQB-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- XFWAPSSEBBURNO-UHFFFAOYSA-N CC(C)(C1=CC(=CC=C1)OCC2=CC=CC=C2)NCC3=CC=CC=C3 Chemical compound CC(C)(C1=CC(=CC=C1)OCC2=CC=CC=C2)NCC3=CC=CC=C3 XFWAPSSEBBURNO-UHFFFAOYSA-N 0.000 description 1
- RFRZNXUIYCHLIY-UHFFFAOYSA-N CC(C)(CC1=CC(=CC=C1)OC)NCC2=CC=CC=C2 Chemical compound CC(C)(CC1=CC(=CC=C1)OC)NCC2=CC=CC=C2 RFRZNXUIYCHLIY-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- JWZZKOKVBUJMES-NSHDSACASA-N L-isoprenaline Chemical compound CC(C)NC[C@H](O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-NSHDSACASA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 241001122767 Theaceae Species 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical class NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 210000005091 airway smooth muscle Anatomy 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000003182 bronchodilatating effect Effects 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229940039009 isoproterenol Drugs 0.000 description 1
- 229950008384 levisoprenaline Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- NSFUOQCLHUVYCH-UHFFFAOYSA-L magnesium;methanesulfinate Chemical compound [Mg+2].CS([O-])=O.CS([O-])=O NSFUOQCLHUVYCH-UHFFFAOYSA-L 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- XNEFVTBPCXGIRX-UHFFFAOYSA-N methanesulfinic acid Chemical compound CS(O)=O XNEFVTBPCXGIRX-UHFFFAOYSA-N 0.000 description 1
- LVHBHZANLOWSRM-UHFFFAOYSA-N methylenebutanedioic acid Natural products OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- MMNNFMKNCOKXLZ-UHFFFAOYSA-N n-benzyl-2-methylpropan-2-amine;hydrobromide Chemical compound Br.CC(C)(C)NCC1=CC=CC=C1 MMNNFMKNCOKXLZ-UHFFFAOYSA-N 0.000 description 1
- KCAPTTPXCZRLTD-UHFFFAOYSA-N n-benzylcyclobutanamine Chemical compound C=1C=CC=CC=1CNC1CCC1 KCAPTTPXCZRLTD-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 210000005062 tracheal ring Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
- C07C49/825—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups all hydroxy groups bound to the ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Pulmonology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
—I rRl .... KUULUTUSJULKAISU r Α7Λ / Μα (11) UTLÄGGN I NGSSKRIFT 5 8 3 2 6 v ^ (51) Kv.ik?/in».a.3 C 07 C 14-7/12 SUOMI —FINLAND (21) P«MnttIi»k.mu»-P»tt»K«öknln| 77Ö/73 (22) HakemttpUvi — AfMttknln|*d«| 1^.03.73 (23) AlkupCIvi—Gl(tl|h*t*dt* 1^.03.73 (41) Tullut lulklMlal — BIMt offmtllg 21.09.73 PUmtt j. r.kllttrll»Uttu· NBrtMkilpwonJ. lariJ.M», ...—I rRl .... ANNOUNCEMENT r Α7Λ / Μα (11) UTLÄGGN I NGSSKRIFT 5 8 3 2 6 v ^ (51) Kv.ik? / In ».a.3 C 07 C 14-7 / 12 FINLAND —FINLAND (21) P «MnttIi» k.mu »-P» tt »K« öknln | 77Ö / 73 (22) HakemttpUvi - AfMttknln | * d «| 1 ^ .03.73 (23) AlkupCIvi — Gl (tl | h * t * dt * 1 ^ .03.73 (41) Tullut lulklMlal - BIMt offmtllg 21.09.73 PUmtt j. R.kllttrll »Uttu · NBrtMkilpwonJ. LariJ.M», ...
Patent· och ragisteratyralaan ' Anaeiun utiagd och uti.»krtft*n pubiicmd 30.09.80 (32)(33)(31) löydetty utuolkuu*—B«gtrd priority 20.03.72 USA(us) 236177 (71) Smith Kline & French Laboratories, 1500 Spring Garden Street, Philadelphia, Pennsylvania 19101, USA(US) (72) Carl Kaiser, Haddon Heights, New Jersey, Stephen Torey Ross, Berwyn, Pennsylvania, USA(US) (7^) Berggren Oy Ab (5M Menetelmä 0-adrenergisesti kiihottavina aineina käyttökelpoistenPatent · och ragisteratyralaan 'Anaeiun utiagd och uti. »Krtft * n pubiicmd 30.09.80 (32) (33) (31) found utuolkuu * —B« gtrd priority 20.03.72 USA (us) 236177 (71) Smith Kline & French Laboratories, 1500 Spring Garden Street, Philadelphia, Pennsylvania 19101, USA (72) Carl Kaiser, Haddon Heights, New Jersey, Stephen Torey Ross, Berwyn, Pennsylvania, USA (7 ^) Berggren Oy Ab (5M Method Useful as 0-adrenergic stimulants
Or-aminometyyli-i+-hydroksi-3-metyylisulfonyyli-metyylibentsyyli alkoholien valmistamiseksi - Förfarande för framställning av som β-adrenergiskt stimulerande medel användbara <¥-aminometyl-U-hydroksi- 3-metylsulfonyl-metylbensylalkoholerOr-aminomethyl-1 + -hydroxy-3-methylsulfonyl-methylbenzyl for the preparation of alcohols - For the preparation of β-adrenergic stimuli with a further preparation of β-aminomethyl-U-hydroxy-3-methylsulfonyl-methylbenzyl alcohol
Esillä oleva keksintö koskee menetelmää uusien ot-aminome-tyyli-4-hydroksi-3-metyylisulfonyylimetyylibentsyylialkoholien valmistamiseksi, joilla on käyttökelpoinen farmakodynaaminen aktiivisuus. Tarkemmin sanoen voidaan keksinnön mukaisia yhdisteitä käyttää 3-adrenergisinä kiihotusaineina, joilla on suhteellisesti suurempi aktiivisuus hengityselinten sileisiin lihaksiin kuin sydänlihakseen. Tämän johdosta näillä yhdisteillä on suora keuhkoputkia laajentava vaikutus ja erittäin vähäinen sydäntä kiihottava vaikutus mikä on voitu todeta tavanomaisissa farmakologisissa kokeissa.The present invention relates to a process for the preparation of novel α-aminomethyl-4-hydroxy-3-methylsulfonylmethylbenzyl alcohols having useful pharmacodynamic activity. More specifically, the compounds of the invention can be used as 3-adrenergic stimulants with relatively higher activity in respiratory smooth muscle than in cardiac muscle. As a result, these compounds have a direct bronchodilator effect and a very low cardiovascular effect, which has been found in conventional pharmacological experiments.
Kahta in vitro-koejärjestelmää käytettiin selektiivisen 3-kiihokeaktiivisuuden määräämiseksi: (1) vaikutus marsun henkitorvi-ketjun spontaaniseen tilaan 3-kiihokkeen (välitön rentoutusaine) vaikutuksen mittaamiseksi ilmatien sileisiin lihaksiin, ja (2) vaikutus marsun oikeanpuoleisen eteisen spontaaniseen lyöntinopeu-teen 3-kiihokkeen vaikutuksen mittaamiseksi sydänlihakseen. Keksinnön mukaisilla yhdisteillä on selektiivinen keuhkoputkia laajentava ominaisuus, koska ne ovat aktiivisia edellämainitussa kokeessa (1) alhaisempana annoksena kuin mitä vaaditaan edellä mainitussa kokeessa (2), jolloin aikaansaadaan positiivinen erotus-suhde .Two in vitro test systems were used to determine selective 3-stimulus activity: (1) effect on the spontaneous state of the guinea pig tracheal chain to measure the effect of 3-stimulus (immediate relaxant) on airway smooth muscle, and (2) effect on guinea pig right-sided 3-stage atrial spontaneous to measure the effect on the heart muscle. The compounds of the invention have a selective bronchodilator property because they are active in the above-mentioned Experiment (1) at a lower dose than that required in the above-mentioned Experiment (2), thus obtaining a positive separation ratio.
5832658326
Keksinnön mukaisia yhdisteitä voidaan esittää seuraavalla yleisellä rakennekaavallaThe compounds of the invention can be represented by the following general structural formula
HB
/X 0/ X 0
H^CS02CH2-Y J- CH-CH2~NHR^ kaava IH
H0—X''1 jossa kaavassa R^ on tert.butyyli, syklobutyyli, 2-(4-hydroksi-fenyyli)-l-metyylietyyli tai 2-(4-metoksifenyyli)-l,1-dimetyyli.H0-X''1 wherein R1 is tert-butyl, cyclobutyl, 2- (4-hydroxy-phenyl) -1-methylethyl or 2- (4-methoxyphenyl) -1,1-dimethyl.
Keksinnön mukaisia yhdisteitä voidaan käyttää sellaisen farmaseuttisesti sopivan happoadditiosuolan muodossa, jolla on sama käyttökelpoisuus kuin vapaalla emäksellä. Tällaisia suoloja, jotka valmistetaan alalta hyvin tunnetuilla menetelmillä, voidaan muodostaa sekä epäorgaanisten että orgaanisten happojen kanssa, joita ovat esim. seuraavat: maleiinihappo, fumaarihappo, bentsoe-happo, askorbiinihappo, pamoiinihappo, meripihkahappo, bismety-leenisalisyylihappo, metaanisulfonihappo, etaanidisulfonihappo, etikkahappo, oksaalihappo, propionihappo, viinihappo, salisyylihappo, sitruunahappo, glykonihappo, aspartiinihappo, steariini-happo, palmitiinihappo, itakonihappo, glykolihappo, p-aminobentsoe-happo, glutamiinihappo, bentseenisulfinihappo, kloorivetyhappo, bromivetyhappo, rikkihappo, sykloheksyylisulfamiinihappo, fosfori-happo ja typpihappo.The compounds of the invention may be used in the form of a pharmaceutically acceptable acid addition salt having the same utility as the free base. Such salts, which are prepared by methods well known in the art, can be formed with both inorganic and organic acids, e.g. ,, propionic acid, tartaric acid, salicylic acid, citric acid, glyconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, p-aminobenzoic acid, glutamic acid, benzoic acid, benzenesulfonic acid, benzene sulphonic acid,
Edelleen sisältävät keksinnön mukaiset yhdisteet ainakin yhden epäsymmetrisen hiiliatomin, joka voidaan liuottaa uudelleen d- ja 1-optisiksi isomeereiksi.The compounds of the invention further contain at least one asymmetric carbon atom which can be redissolved into the d- and 1-optical isomers.
Keksinnön mukainen eräs edullinen yhdiste on a-t-butyyli-aminometyyli- 4-hydroksi-3-(metyylisulfonyylimetyyli)bentsyylialko-holi, joka rauhoittaa marsun henkitorven rengaspreparaatin spon-taanisen tilan ED^-arvon ollessa 0,0051 mcg/ml, samalla kun se lisää marsun oikean eteisen lyöntinopeutta ED^-arvon ollessa 8,28 mcg/ml. Nämä aktiivisuudet aikaansaavat absoluuttiseksi ero-tussuhteeksi 1620, mikä on 33^0-kertainen parannus verrattuna d,l-isoproterenolin vastaavaan aktiivisuuteen (absoluuttinen erotus-suhde = 0,5) samanlaisissa in vitro-valmisteissa. Keksinnön mukai-r'f 1 la yhdi steel ]»j. a- /? - ( 4-hydroksifenyyli ) -1-metyy lietyy li -amino-muty.yli/-4-hydrok ui -3-metyylisulfonyylimetyylibentsyy 1 ialkoholilla edellä mainittu orotussuhde on 254, mikä on 508-kertainen parannus verrattuna d,1-isoproterenoliin.A preferred compound of the invention is tert-butylaminomethyl-4-hydroxy-3- (methylsulfonylmethyl) benzyl alcohol, which soothes the spontaneous state of the guinea pig tracheal ring preparation at an ED 2 of 0.0051 mcg / ml, while increasing guinea pig right atrial rate at an ED 2 of 8.28 mcg / ml. These activities give an absolute separation ratio of 1620, which is a 33- to 0-fold improvement over the corresponding activity of d, l-isoproterenol (absolute separation ratio = 0.5) in similar in vitro preparations. According to the invention, R'f 1 la combines steel] »j. a- /? With - (4-hydroxyphenyl) -1-methylaminaminomethyl) -4-hydroxy-3-methylsulfonylmethylbenzyl alcohol, the aforementioned ratio of the above is 254, which is a 508-fold improvement over d, 1-isoproterenol.
3 583263 58326
Keksinnön mukaisia yhdisteitä valmistetaan siten kuin seu-raavasta reaktiosarjasta ilmenee: 0 ϋΓ-ΓΗ /v \\ CH SO Na 3 C™fft -CH3 2 CH3S02Mg 0 0 BrThe compounds of the invention are prepared as shown in the following sequence of reactions: 0 ϋΓ-ΓΗ / v \\ CH SO Na 3 C ™ fft -CH 3 2 CH 3 SO 2 Mg 0 0 Br
/v II /v Il I/ v II / v Il I
h3cso2ch2-|^N- 6-ch3 c6h5ch2ci h3cso2ch2_|^N_ c-ch2 H0~^J PHT 06Η50Η2Ο-^/ o il H^CSO-CH^-^N— C-CH5-N-R, p, r _ 3 2 7- , 1 Jä-0 y ^ C6H5CH20-1^/J 2 6 5 3H2 onh3cso2ch2- | ^ N- 6-ch3 c6h5ch2ci h3cso2ch2_ | ^ N_ c-ch2 H0 ~ ^ J PHT 06Η50Η2Ο - ^ / o il H ^ CSO-CH2 - ^ N - C-CH5-NR, p, r _ 3 2 7-, 1 Ja-0 y ^ C6H5CH2O1 ^ / J 2 6 5 3H2 is
H3CS02CH2-ki^N|-CH-CH2-NHR1 Kaava IIH3CSO2CH2-ki2N1-CH-CH2-NHR1 Formula II
HO-%/ joissa kaavoissa R^ on määritelty kaavassa I. Täten, kuten edellä olevasta ilmenee, on 4-hydroksifenoli kloorimetyloitu formaldehydillä ja kloorivetyhapolla ja käsitelty metyylisulfiinihapon natrium- tai magnesiumsuolalla metyylisulfonyylimetyylijohdannaisen saamiseksi. Viimeksimainittu bromataan ja saatu a-bromifenoli saatetaan reagoimaan N-bentsyyliamiinin kanssa vastaavan a-bentsyyli-aminofenonin saamiseksi. Tämä johdannainen hydrataan katalyytti-sesti edullisesti hiilellä olevan palladiumin avulla, jolloin saadaan debentsyloitu alkyylisulfonyylimetyylibentsyyli-alkoholituote.HO -% / in which formulas R 1 is as defined in formula I. Thus, as shown above, 4-hydroxyphenol is chloromethylated with formaldehyde and hydrochloric acid and treated with the sodium or magnesium salt of methylsulphinic acid to give a methylsulphonylmethyl derivative. The latter is brominated and the resulting α-bromophenol is reacted with N-benzylamine to give the corresponding α-benzylaminophenone. This derivative is catalytically hydrogenated with palladium on carbon to give a debenzylated alkylsulfonylmethylbenzyl alcohol product.
On huomattu, että edellä mainitussa reaktiosarjassa kaavan II mukaiset aminoketoni-johdannaiset ovat käyttökelpoisia välituotteita.It has been found that the aminoketone derivatives of formula II in the above reaction series are useful intermediates.
Keksinnön mukaisia yhdisteitä voidaan annostella oraalisesti tai parenteraalisesti tavanomaisina annosyksikkömuotoina, kuten tabletteina, kapseleina, injektoituina aineina, aerosoleina jne., yhdistämällä sopiva annos kaavan I mukaista yhdistettä kantaja-aineen kanssa hyväksytyn farmaseuttisen käytännön mukaisesti.The compounds of the invention may be administered orally or parenterally in conventional unit dosage forms such as tablets, capsules, injectables, aerosols, etc., by combining an appropriate dose of a compound of formula I with a carrier in accordance with accepted pharmaceutical practice.
11 5832611 58326
Edellä esitetty on yleinen kuvaus siitä, miten keksinnön mukaisia yhdisteitä voidaan valmistaa. Seuraavissa esimerkeissä on esitetty sellaisten spesifisten yhdisteiden valmistus, joilla on β-adrenerginen stimulanttiaktiivisuus.The foregoing is a general description of how the compounds of the invention may be prepared. The following examples illustrate the preparation of specific compounds with β-adrenergic stimulant activity.
Esimerkki 1Example 1
Seokseen, jossa on 260 ml 37 $:sta formaldehydiä ja 1800 ml väkevää kloorivetyhappoa, lisätään 400 g p-hydroksiasetofenonia lämpötilassa noin 45°C. Seosta pidetään lämpötilassa 50°C kaksi tuntia, suodatetaan ja pestään vedellä, jolloin saadaan 3-kloori-metyyli-4-hydroksiasetofenonia, sp. 154°C, hajoaa.To a mixture of 260 ml of $ 37 formaldehyde and 1800 ml of concentrated hydrochloric acid is added 400 g of p-hydroxyacetophenone at a temperature of about 45 ° C. The mixture is kept at 50 ° C for two hours, filtered and washed with water to give 3-chloromethyl-4-hydroxyacetophenone, m.p. 154 ° C, decomp.
Seosta, jossa on 40 g 3-kloorimetyyli-4-hydroksiasetofenonia ja 26 g magnesiummetyylisulfinaattia 500 ml:ssa etanolia, kuumennetaan palautusjäähdyttäen ja sekoittaen 3 tuntia. Reaktioseos vä-kevöidään sitten tyhjössä. Saatu öljy liuotetaan uudelleen kloroformiin ja pestään vedellä. Kloroformi kuivataan ja haihdutetaan, jolloin saadaan 4-hydroksi-3_metyylisulfonyylimetyyliasetofenonia, sp. 206,5-208,5°C.A mixture of 40 g of 3-chloromethyl-4-hydroxyacetophenone and 26 g of magnesium methylsulphinate in 500 ml of ethanol is heated under reflux with stirring for 3 hours. The reaction mixture is then concentrated in vacuo. The resulting oil is redissolved in chloroform and washed with water. The chloroform is dried and evaporated to give 4-hydroxy-3-methylsulfonylmethylacetophenone, m.p. 206.5 to 208.5 ° C.
Seosta, jossa on 14,0 g 4-hydroksi-3-metyylisulfonyylime-tyyliasetofenonia, 9,3 g kaliumkarbonaattia, 7,8 ml bentsyyliklo-pidia ja katalyyttinen määrä natriumjodidia 250 ml:ssa asetonia ja 250 ml:ssa vettä, kuumennetaan palautusjäähdyttäen ja sekoittaen 16 tuntia. Asetoni poistetaan ja vesifaasi uutetaan kloroformilla, pestään vedellä, kuivataan ja haihdutetaan, jolloin saadaan öljy, joka kiteytetään uudelleen isopropyylialkoholista, jolloin saadaan kiteistä 4-bentsyylioksi-3~metyylisulfonyylimetyyli-asetofenonia, sp. 94-97°C.A mixture of 14.0 g of 4-hydroxy-3-methylsulfonylmethylacetophenone, 9.3 g of potassium carbonate, 7.8 ml of benzyl chloride and a catalytic amount of sodium iodide in 250 ml of acetone and 250 ml of water is heated to reflux and stirring for 16 hours. The acetone is removed and the aqueous phase is extracted with chloroform, washed with water, dried and evaporated to give an oil which is recrystallized from isopropyl alcohol to give crystalline 4-benzyloxy-3-methylsulphonylmethylacetophenone, m.p. 94-97 ° C.
Sekoitettuun liuokseen, jossa on 7,7 g 4-bentsyylioksi~3-metyylisulfonyylimetyyliasetofenonia ja 2,15 g 2-pyrrolidonia 300 ml:ssa tetrahydrofuraania, lisätään 12,5 g pyrrolidonihydrotribro-midia (PHT) ja sekoittamista jatketaan 56 tuntia huoneen lämpötilassa. Seos suodateaan ja suodos väkevöidään tyhjössä, jolloin saadaan öljy, joka kiteytyy seistessään. Kiteet liuotetaan uudelleen kloroformiin. Kloroformiliuos pestään vedellä, kuivataan ja väkevöidään, jolloin saadaan kiinteä aine, joka kitetytetään uudelleen asetonitriilistä, jolloin saadaan 4-bentsyylioksi-a-bromi-3-metyylisulfony,ylimetyyliasetofenonia, sp. l43-l44°C. Viimemainittu (100 g) liuotetaan 1 litraan asetonitriiliä ja tähän lisätään 82 g M-bentsyyli-N-t-butyyliamiinia. Seosta sekoitetaan ja kuumennetaan palautusjäähdyttäen 4 tuntia, jäähdytetään ja laimennetaan eetterillä. Kiteinen N-bentsyyli-N-t-butyyliamiini-hydro- 5 58326 bromidi suodatetaan. Suodos hapotetaan eetteripitoisella kloori-vetyhapolla ja eetteriä lisätään tämän jälkeen, jolloin saadaan 4-bentsyylioksi-a(N-bentsyyli-N-t-butyyliamino)-3-metyyli-sulfo-nyylimetyyliasetofenoni-hydrokloridia, sp. 152-15^0.To a stirred solution of 7.7 g of 4-benzyloxy-3-methylsulfonylmethylacetophenone and 2.15 g of 2-pyrrolidone in 300 ml of tetrahydrofuran is added 12.5 g of pyrrolidone hydrotribromide (PHT) and stirring is continued for 56 hours at room temperature. The mixture is filtered into tea and the filtrate is concentrated in vacuo to give an oil which crystallizes on standing. The crystals are redissolved in chloroform. The chloroform solution is washed with water, dried and concentrated to give a solid which is recrystallized from acetonitrile to give 4-benzyloxy-α-bromo-3-methylsulfone, dimethylacetophenone, m.p. L43-L44 ° C. The latter (100 g) is dissolved in 1 liter of acetonitrile and 82 g of M-benzyl-N-t-butylamine are added. The mixture is stirred and refluxed for 4 hours, cooled and diluted with ether. Crystalline N-benzyl-N-t-butylamine hydrobromide is filtered off. The filtrate is acidified with ethereal hydrochloric acid and ether is then added to give 4-benzyloxy-α (N-benzyl-N-t-butylamino) -3-methylsulfonylmethylacetophenone hydrochloride, m.p. 152-15 ^ 0.
Seos, jossa on 20 g 4-bentsyylioksi-a(N-bentsyyli-N-t-butyyliamino)-3-metyylisulfonyylimetyyliasetofenoni-hydrokloridia, 10 g 5 %:sta hiilellä olevaa palladiumia ja 125 ml etanolia,hyd- 2 rataan Parr-laitteessa huoneen lämpötilassa käyttäen H,2 kp/cm suuruista alustavaa vedyn painetta. Reaktioseos suodatetaan ja suodos väkevöidään tyhjössä. Jäännös kiteytetään eetteri-etanolista, jolloin saadaan a-(t-butyyliamincmetyyli )-4-hydroksi-Ji-metyylisulfonyylimetyylibentsyylialkoholi-hydrokloridia, sp. 219-220°C.A mixture of 20 g of 4-benzyloxy-α (N-benzyl-Nt-butylamino) -3-methylsulfonylmethylacetophenone hydrochloride, 10 g of 5% palladium on carbon and 125 ml of ethanol is hydrogenated in a Parr apparatus at room temperature. using an initial hydrogen pressure of H, 2 kp / cm. The reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is crystallized from ether-ethanol to give α- (t-butylaminomethyl) -4-hydroxy-1'-methylsulfonylmethylbenzyl alcohol hydrochloride, m.p. 219-220 ° C.
Esimerkki 2 Käytettäessä esimerkin 1 mukaista käsittelytapaa saatetaan 4-bentsyylioksi-a-bromi-3-metyylisulfonyylimetyyliasetofenoni reagoimaan N-bentsyyli-/5-bentsyylioksifenyyli-isopropyyli7amiinin kanssa, josta hydrauksen jälkeen saadaan a-/2-(4-hydroksifenyyli)- l-metyyli-etyyliaminometyyli7-i4-hydroksi-3-metyylisulfonyylime-tyylibentsyylialkoholi. Yhdiste on amorfinen aine ilman selvää sulamispistettä.Example 2 Using the procedure of Example 1, 4-benzyloxy-α-bromo-3-methylsulfonylmethylacetophenone is reacted with N-benzyl- [5-benzyloxyphenyl-isopropyl] -amine to give α- [2- (4-hydroxy-phenyl) -1-methyl] after hydrogenation. -etyyliaminometyyli7-i4-hydroxy-3-metyylisulfonyylime-tyylibentsyylialkoholi. The compound is an amorphous substance without a clear melting point.
Esimerkki 3Example 3
Seurattaessa esimerkin 1 mukaista käsittelytapaa saatetaan 4-bentsyylioksi-a-bromi-3-metyylisulfonyylimetyyliasetofenoni reagoimaan N-bentsyyli-/5-metoksifenyyli-t-butyyli7amiinin kanssa ja hydrattaessa tämän jälkeen saadaan a-/2-(4-metoksifenyyli)-l,l-dimetyy li etyyliamincmetyy li 7-i4-hydroksi-3-metyy li sulfonyylimetyy li-bentsyylialkoholi.Following the procedure of Example 1, 4-benzyloxy-α-bromo-3-methylsulfonylmethylacetophenone is reacted with N-benzyl- [5-methoxyphenyl-t-butyl] -amine, followed by hydrogenation to give α- [2- (4-methoxyphenyl) -1,11]. -dimethylethylaminomethyl-14-hydroxy-3-methylsulfonylmethylbenzyl alcohol.
Alkoholi käsitellään kloorivedyllä metanoli-eetterissä, jolloin saadaan a-Zl-C^-metoksifenyylii-ljl-dimetyylietyyliaminometyy-li7-4-hydroksi-3-metyylisulfonyylimetyylibentsyylialkoholi-hydro-kloridia värittöminä kiteinä, sp. l80-l82°C.The alcohol is treated with hydrogen chloride in methanol-ether to give α-Z1-C4-methoxyphenyl-1H-dimethylethylaminomethyl-4- (4-hydroxy-3-methylsulfonylmethylbenzyl alcohol hydrochloride) as colorless crystals, m.p. L80-L82 ° C.
Samalla tavoin käytettäessä N-bentsyylisyklobutyyliamiinia edellä mainitussa reaktiossa, jota seuraa hydraus ja saadun alkoholin käsittely kloorivedyllä metanoli-eetterissä, saadaan a-(syk-lobutyyliaminometyy li)-4-hydroksi-3-metyylisulfonyylimetyyli bentsyy-lialkoholihydrokloridi,sp. 193~19i*0C.Similarly, the use of N-benzylcyclobutylamine in the above reaction followed by hydrogenation and treatment of the resulting alcohol with hydrogen chloride in methanol-ether gives α- (cyclobutylaminomethyl) -4-hydroxy-3-methylsulfonylmethyl benzyl alcohol hydrochloride, m.p. 193 ~ 19i * 0C.
Claims (4)
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US23617772A | 1972-03-20 | 1972-03-20 | |
US23617772 | 1972-03-20 |
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BR (1) | BR7301986D0 (en) |
CA (1) | CA1007662A (en) |
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DE (1) | DE2313625C2 (en) |
DK (1) | DK145082C (en) |
ES (1) | ES412799A1 (en) |
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GB (2) | GB1386029A (en) |
HU (1) | HU166931B (en) |
IE (1) | IE38206B1 (en) |
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IT (1) | IT1061426B (en) |
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US3966770A (en) * | 1975-03-25 | 1976-06-29 | Smithkline Corporation | 4-Hydroxy-α-[(3,4-methylenedioxyphenyl)isopropylaminoethyl]-3-(methylsulfonylmethyl)benzyl alcohol |
DE3880868D1 (en) * | 1987-03-26 | 1993-06-17 | Ciba Geigy Ag | Neue alpha-aminoacetophenone als photoinitiatoren. |
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ZA723611B (en) * | 1971-06-01 | 1973-03-28 | Smith Kline French Lab | N,n'-bis(2-(3-substituted-4-hydroxyphenyl)-ethyl or-2-hydroxyethyl)-polymethylene-diamines |
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1973
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SE403773B (en) | 1978-09-04 |
ES412799A1 (en) | 1976-06-01 |
DK145082B (en) | 1982-08-23 |
FR2183681B1 (en) | 1976-10-22 |
GB1386028A (en) | 1975-03-05 |
ZA731903B (en) | 1974-01-30 |
BR7301986D0 (en) | 1974-07-25 |
FI58326C (en) | 1981-01-12 |
BE796894A (en) | 1973-09-17 |
JPS5636188B2 (en) | 1981-08-22 |
CH576435A5 (en) | 1976-06-15 |
AR196924A1 (en) | 1974-02-28 |
AU469666B2 (en) | 1976-02-19 |
CA1007662A (en) | 1977-03-29 |
PH9436A (en) | 1975-11-26 |
HU166931B (en) | 1975-06-28 |
IL41758A0 (en) | 1973-05-31 |
DE2313625A1 (en) | 1973-10-25 |
IE38206L (en) | 1973-09-20 |
NL7303715A (en) | 1973-09-24 |
IL41758A (en) | 1976-03-31 |
DK145082C (en) | 1983-03-21 |
AU5341073A (en) | 1974-09-19 |
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